RU2392277C2 - Method of nebivolol racemate obtainment - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention refers to novel method of obtaining [2S*[R*[R*[R*]]]] and [2R*[S*[S*[S*]]]]-(±)α,α'-[iminobis(methylene)]bis[6-fluoro-3,4-dihydro-2H-1-benzopyrane-2-methanol] racemate of the formula (I) (nebivolol) and its pharmaceutically acceptable salts

, involving stages indicated in the claim, and to intermediate compounds and methods of obtainment thereof.

EFFECT: improved method.

106 cl, 12 tbl, 20 ex

Description

BACKGROUND

1. TECHNICAL FIELD

The present invention relates to a new method for producing racemic nebivolol, its enantiomeric forms and to new compounds obtained by this method

2. DESCRIPTION OF THE PRIOR ART

Nebivolol (see Figure 1A for d-Nebivolol, chemical name [2R * [R * [R * (S *)]]] - α, α '- [iminobis (methylene)] bis [6-fluoro- 3,4-dihydro-2H-1-benzopyran-2-methanol] or alternatively [2R * [R * [R * (S *)]]] α, α '- [iminobis (methylene)] bis [6- fluorochroman-2-methanol], and Figure 1B, which shows racemic nebivolol, which is a mixture of l- and d-nebivolol) is known as an adrenergic beta antagonist, antihypertensive agent, platelet aggregation inhibitor and vasodilator.

Nebivolol is administered in tablet form (for example, a dose of nebivolol hydrochloride of 5.45 mg is equivalent to 5 mg of nebivolol) which contains nebivolol in the form of a racemic mixture of enantiomers: SRRR-nebivolol (dextrorotatory d-nebivolol) and RSSS-nebivolol (levorotatory l-nebivolol).

Nebivolol contains four asymmetric centers, and therefore 16 stereoisomers are theoretically possible. However, due to structural features and configuration of stereoisomers (for example, axial symmetry), only 10 stereoisomers (6 diastereomers: 4 dl-forms and 2 meso-forms) can be formed (table 1).

The non-stereo-selective preparation of these stereoisomers is generally described in US Pat. No. 4,654,362 to Van Lommen et al. (Janssen Pharmaceutica N. V.) (and its analogue EP 0145067). The stereoselective synthesis of the [2R, αS, 2'S, α'S] -isomer of α, α '- [iminobis (methylene)] bis [6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol] is described in US patent No. 6545040 (Janssen Pharmaceutica NV) (and its analogue EP 0334429).

The separation technique of the diastereomeric mixture consisting of (±) - [2R * [1S *, 5S * (S *)]] + [2R * [1S * [5R * (S *)]]] - α, α '- [ iminobis (methylene)] bis [6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanols] by fractional crystallization of the corresponding hydrochloride salts is described in US patent No. 5759580 (Janssen Pharmaceutica NV) (and its analogue EP 0744946) . Nebivolol hydrochloride can only be obtained in a very low yield of 6.6%.

PCT Patent Application Publication WO 2004/041805 (Egis Gyogyszergyar RT.) Describes a new method for preparing racemic [2S [2R * [R [R *]]]] and [2R [2S * [S [S *]]]] - (±) α, α '- [iminobis (methylene)] bis [6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol] and its pure [2S [2R * [R [R *] ]]] and [2R [2S * [S [S *]]]] enantiomers.

Alternative and enantioselective syntheses of d-nebivolol are described in articles (J. Am. Chem. Soc. 1998, 120, 8340-8347 and Tetrahedron 56, 2000, 6339-6344).

Table 1.
Stereoisomers of Nebivolol

общая формула изомеров небиволола

general formula for nebivolol isomers

SRRS
Stereoisomer 1 Srrr
Stereoisomer 2 d-nebivolol SRSR
Stereoisomer 3
meso form 1 Sss
Stereoisomer 4

Rrrs
Stereoisomer 2 d-nebivolol Rrrr
Stereoisomer 5 RRSR
Stereoisomer 6 RRSS
Stereoisomer 7
meso form 2

RSRS
Stereoisomer 3
meso form 1 RSRR
Stereoisomer 6 RSSR
Stereoisomer 8 RSSS
Stereoisomer 9 l-nebivolol

SSRS
Stereoisomer 4 SSRR
Stereoisomer 7
meso form 2 Sssr
Stereoisomer 9 l-nebivolol Ssss
Stereoisomer 10

The methods for producing nebivolol described in the above references are summarized below.

but. U.S. Patent No. 4,654,362 (and its analogue EP 0145067 U.S.) (Janssen Pharmaceutica N. V.)

The synthetic route for the non-stereoselective preparation of nebivolol is described starting from 6-fluoro-4-oxo-4H-1-benzopyran-2-carboxylic acid a1 (Scheme 1a).

To obtain nebivolol according to Scheme 1a in US patent No. 4654362 and its analogue EP 0145067 contains detailed examples of the synthesis of only components a1, a2, a3, a4 and a8. All other examples are analogues of methods that describe the preparation of related derivatives (for example, derivatives without a fluorine substituent in the aromatic ring). The general strategy for the preparation of nebivolol or its corresponding derivatives is based on the synthesis of 2-oxiranylchromanes (a6 and a7) as key intermediates for the final stages of the combination. Due to the presence of two asymmetric carbon atoms, these compounds can be formed from racemic aldehydes a5 in the form of two diastereomeric racemates ("A forms" a7 = RS / SR and "B forms" a6 = SS / RR), which can be separated by chromatography. In the considered link for the desired intermediates, descriptions of processing techniques, crystallization and purification or separation of stereoisomers, outputs, etc. are not provided.

Racemates a6 or a7 can be converted to the corresponding benzylated amino alcohols a8 and a9 by reaction with benzylamine. The benzyl protected AB mixture of a10 nebivolols can be prepared by reacting a8 racemate (RS / SR) with a6 epoxide racemate (RR / SS) or by reacting a9 racemate (RR / SS) with a7 epoxide racemate (RS / SR). The protecting group can be removed in the last step by catalytic hydrogenation, which leads to the formation of an AB mixture of nebivolols a11.

Scheme 1b shows additional methods for the synthesis of similar 2-chromanyl aldehydes (a14) and 2-oxiranylchromanes (a16) as key intermediates for the synthesis of nebivolol derivatives containing various substituents in the aromatic group.

Aldehyde a14 can be obtained by low-temperature reduction of imidazolid a12 or the same reduction of ester a13. A14 aldehyde is then converted to a16 2-oxiranylchromanes by reaction with sodium hydride and trimethyl sulfoxonium iodide in dimethyl sulfoxide according to a reaction similar to that described above. Another possibility for the synthesis of a16 2-oxiranylchromanes is the oxidation of 2-vinylchroman a15 with 3-chloroperoxybenzoic acid (the source of 2-vinylchroman a15 is not indicated in these patents, but according to EP 0334429 (see also below), compound a14 can be converted to compound a15 by the Wittig reaction) .

Scheme 1c shows that diastereomeric mixtures consisting of desired and undesired diastereomers (i.e. RSSS / SRRR and RSRR / SRSS) can be obtained by the method shown in scheme 1a.

The synthesis strategy described in US patent No. 4654362 and its analogue EP 0145067, has the following disadvantages:

1. The synthesis of aldehydes a6 and a14 requires very low temperatures and therefore requires special equipment, which complicates and increases the cost of the method.

2. Aldehyde a5 is a very unstable compound, as described in PCT publication WO 2004/041805.

3. The synthesis of a6 / a7 from a5 can be dangerous, as it is known that the use of sodium hydride in solvents like DMSO, dimethylformamide (DMF), dimethylacetamide (DMA) and DMI can cause an exothermic reaction and, therefore, can cause an uncontrolled reaction (see UK Chemical Reaction Hazards Forum: "Sodium Hydride / DMF process stopped").

4. Compounds a6 and a7 were characterized as oily substances (see PCT application publication WO 2004/041805). Since preparation according to the described procedure leads to the formation of a diastereomeric mixture of a6 and a7, chromatographic purification, which is commercially unprofitable, may be required.

5. Compounds a10 and a11 can be prepared by reacting racemic intermediate a8 ("isomer A") with racemate a6 ("isomer B") or alternatively by reacting racemic intermediate a8 ("isomer B") with racemate a7 ("isomer A") with subsequent removal of protection. US Pat. No. 4,654,362 and its analogue EP 0145067 do not provide a clear description of whether individual compounds isomers or a mixture of isomers of compounds a10 and a11 (described only as the "AB" isomeric form). No consideration was given to the separation of such mixtures. Obviously, such techniques can lead to the formation of diastereomeric mixtures consisting of the desired RSSS / SRRR diastereomer and the undesired RSRR / SRSS diastereomer (Scheme 1c; see also table 1, showing a combination of different fragments that gives all possible diastereomers). In addition, it is known from the prior art (see WO 2004/041805) that racemic nebivolol obtained by the method described in US patent No. 4654362 (and its analogue EP 0145067) (schemes 1a and 1c) in the form of a diastereomeric racemate with SRSS / The RSRR configuration could not be successfully separated by fractional crystallization; and

6. Losses of expensive substances due to the formation of undesirable isomers of nebivolol, especially during the last stages of the process.

b. European Patent Publication EP 0334429 and US Patent No. 6545040 (Xhonneux et al., Janssen Pharmaceutica N.V.)

A similar strategy for the synthesis of nebivolol is described in EP 0334429 and US patent No. 6545040, but the difference is that l-nebivolol is obtained by enantioselective synthesis, in which enantiopure fragments b6 and b11 are used as key intermediates (Scheme 2).

For this technique, it is necessary to separate the racemic 6-fluorochroman-2-yl-carboxylic acid b2 by forming the diastereomeric amide b3 with (+) - dehydroabietylamine followed by fractional crystallization of the diastereomers and hydrolysis of the amides. The following stages of the synthesis of fragments b6 and b11 are carried out by convergent pathways using the (S) -form and (R) -form of 6-fluorochroman-2-yl-carboxylic acids b4 and b8. First, (S) -6-fluorochroman-2-yl-carboxylic acid b4 is converted to aldehyde b5 according to the procedure already mentioned in Scheme 1b. Then, b6 epoxide can be prepared by reacting b5 with sodium hydride and trimethyl sulfoxonium iodide in dimethyl sulfoxide. In the case of the second pathway, (R) -6-fluorochroman-2-yl-carboxylic acid b8 is first esterified to form b9. Epoxide b10 is synthesized by the method of “no isolation” by reduction of b9 to the corresponding aldehyde, followed by reaction with sodium hydride and trimethyl sulfoxonium iodide in dimethyl sulfoxide. The b10 epoxide ring is opened with a benzylamine substitution reaction that yields a second key fragment of b11, the latter is then reacted with b6 epoxide to give benzyl protected l-nebivolol b12. The last step of deprotecting by catalytic hydrogenation of b12 gives l-nebivolol.

The strategy described in EP 0334429 and US patent No. 6545040, has the following disadvantages:

1. The steps for preparing compounds b5 from b4 and b10 from b9 require very low temperatures for reduction with diisobutylaluminium hydride (DIBAH), which complicates and increases the cost of the process due to the need for special refrigeration equipment.

2. The steps for the preparation of compounds b6 from b5 and b10 from b9 can be a safety hazard, since it is known that the use of sodium hydride in solvents such as DMSO, DMF, DMA and DMI can lead to an exothermic reaction and, therefore, can cause an uncontrolled reaction (see UK Chemical Reaction Hazards Forum: "Sodium Hydride / DMF process stopped").

3. Compounds b5, b6, b9 and b10 are oily substances and therefore difficult to clean; in the event that compounds b6 and b10 are contaminated with undesired diastereomers, separation by column chromatography, which is not a commercially viable method, may be required.

4. Low yields, especially yields at the stages of preparation of compounds b2-b3-b4, b2-b7-b8 and b5-b6, b9-b10, result in a very low overall yield (less than 0.5%) for the synthesis of l- nebivolol, which makes the method under consideration unprofitable.

5. Since only l-nebivolol is obtained, and a racemic mixture is required to obtain nebivolol, additional steps are necessary for the synthesis of the corresponding d-form (ie, d-nebivolol); and

6. In the interaction of intermediate b2, diastereomers b3 and b7 are formed, which then have to be separated and processed separately to obtain b6 and b11, then combined to obtain b12, therefore, the process requires many additional steps.

from. PCT Patent Publication WO 2004/041805 (Trinka et al., EGIS GYOGYSZERGYAR RT)

WO 2004/041805 describes the enantioselective synthesis of d- and l-nebivolol (see Schemes 3a-c).

The strategy of this pathway is based on the synthesis and separation of isomers protected by an isopropylidene group of (1`, 2`-dihydroxyethyl) -6-fluorochroman-4-one isomers c11, c12, c13, c14 (Scheme 3a). These compounds are synthesized starting from the acylation of 4-fluoroanisole with C1 chloroacetyl chloride according to Friedel-Crafts with the formation of a chloroacetyl derivative c2, which is then transformed under the action of triphenylphosphine followed by treatment with a weak base to the stable phosphanilidene derivative c4. Compound c4 is then reacted with either protected glycerol aldehydes c6 (derived from vitamin C) to give c11 and c12; or with c8 (derived from D-mannitol) to give c13 and c14 after cyclization.

Each of these isomers was further transformed in four ways and in a similar way (Schemes 3b and 3c), whereby l-nebivolol was obtained by ways 1 and 2, using c11 and c12 as the starting compounds (Scheme 3b).

The enantiomeric d-nebivolol is prepared in a similar manner, with the starting materials being the S, R isomer c13 and R, the R isomer c14 (1`, 2`-dihydroxyethyl) -6-fluorochroman-4-one protected by an isopropylidene group (paths 3 and 4, Scheme 3c).

A typical reaction sequence for each path begins with the deprotection of c11 (path 1, Scheme 3b), c12 (path 2, Scheme 3b), c13 (path 3, Scheme 3c), c14 (path 4, Scheme 3c) and obtaining the corresponding diols c15 , c19, c25, s29. Selective tosylation of the primary alcohol group gives compounds c16, c20, c26, c30, which can then be converted to epoxides c17, c21, c27, c31 by treatment with a base. After the conversion of these epoxides by the action of benzylamine into c18, c22, c28, c32 and substitution with the desired epoxides (c18 + c21, c22 + c17, c28 + c31, c32 + c27), diketro derivatives c23 and c33 protected by a benzyl group are formed. Deprotection and reduction of carbonyl groups can be carried out in a single reactor by catalytic hydrogenation and either l-nebivolol or d-nebivolol can be obtained.

Racemic nebivolol is prepared by preparing a mixture (1: 1) of intermediates c23 and c33 before carrying out the last hydrogenation step (52% yield).

The strategy described in WO 2004/041805 has the following disadvantages:

1. Although the strategy is based on the use of all stereoisomers for the synthesis of either l-nebivolol or d-nebivolol, the main disadvantage is that to obtain a racemic mixture, it is necessary to carry out 30 steps using all the intermediates, which makes such synthesis long and unprofitable; and

2. The steps for preparing compounds c23 from cl8, c23 from c22, c33 from c28 and c33 from c32 are carried out without the use of a solvent at 145 ° C (mainly after reagent melting). This technique is not suitable for use on a large scale.

d. Johannes et al., J. Am. Chem. Soc. (1998), 120, 8340-8347

Johannes et al. Described enantioselective preparation of d-nebivolol (Scheme 4).

The strategy is based on the synthesis of chiral chromane fragments d12 (R, R configurations) and d21 (S, S configurations) as key intermediates in convergent pathways that, as a result, combine and give d-nebivolol after deprotection. An essentially important stage in the synthesis of the aforementioned chiral chromanes is the Zr-catalyzed kinetic separation of racemic intermediates d7 and d16.

According to the first route, the starting material for the preparation of the d12 chromane fragment is salicylic aldehyde d3, which is synthesized either by formylation of compound d1, or by reaction of lithiated compound d2 with DMF at -60 ° C. Then, allylic cycloheptene epoxide, which can be obtained by epoxidation of cycloheptadiene, is reacted with d4 aldehyde to obtain racemic compound d7 by regioselective and stereoselective nucleophilic opening of the d8 epoxide cycle. Protection of the d7 hydroxyl group using TBSOT followed by 5 equiv. EtMgCl and 10 mol% (R) - (EBTHI) of Zr-biphenol gave d8 with a yield of 44% and> 98% ee. The Mo-catalyzed metathesis reaction in an ethylene atmosphere followed by oxidation of the Wacker terminal double bond and subsequent catalytic hydrogenation gives d10 with a total yield of 83%. To synthesize d11 from d10, a Norrish type II photochemical cleavage is necessary. The following sequence of three stages: ozonolytic cleavage, the Mitsunobu reaction, which uses tributylphosphine and phthalide, and subsequent hydrazinolysis, to remove the phthalimidyl group gives intermediate d12. The second way begins with the synthesis of the d16 racemate with a cis configuration, which is then separated in the presence of the zirconium catalyst (S) - (EBTHI) Zr-biphenol. Compound d17 is converted to compound d18 by a Mo-catalyzed metathesis reaction. The Wacker oxidation of the terminal double bond and subsequent catalytic hydrogenation give intermediate d19, which is then converted by Norrish type II photochemical cleavage and ozonolysis to d21 aldehyde. D-Nebivolol is then prepared by reductive amination of compounds d12 and d21, followed by removal of the silyl ester protecting groups.

The strategy described by Johannes et al. Has the following disadvantages:

1. The production of d3 aldehyde occurs either in a low yield by the d1 formylation reaction using chloroform in the presence of a base, or requires a low temperature for lithiation and formylation of the d2 derivative. In addition, working with n-BuLi on an industrial scale requires special precautions.

2. The steps for preparing derivatives of d8 from d7 and d16 and d17 from d13 / d14 also require a low temperature (-78 ° C) for silylation. In addition, a difficult separation step is required that utilizes a particular commercially available Zr catalyst.

3. The steps for the preparation of compounds d10-d11 and d19-d20 require special equipment for the photochemical reaction (Norrish cleavage, type 2).

4. The step for preparing compound d12 from d11 requires a low temperature (-78 ° C) and special equipment for ozonolysis.

5. For the synthesis of one enantiomer of nebivolol (d-form), 16-20 stages are necessary, but a racemic mixture is required; therefore, additional steps are needed to synthesize the corresponding l-form (i.e., l-nebivolol).

e. Chandrasekhar et al., Tetrahedron (2000), 56, 6339-6344

An article by Chandrasekhar et al. Describes yet another technique for the enantioselective synthesis of d-nebivolol (see Scheme 5).

The basis for the enantioselective strategy mentioned is the asymmetric one-reactor epoxidation of Sharpless e7 allyl alcohol, which uses (-) - DET and (+) - DET to obtain both enantiomeric diols e8 and e12 after the cyclization step.

The starting compound is 4-fluorophenol e1, which is first converted to the allyl ether e2. Kleisen rearrangement at 210 ° C followed by protection of the phenolic group (e3) of TBDMS-Cl leads to the formation of e4 intermediate. Primary alcohol e5 is obtained by hydroboration and subsequent oxidative treatment with H ₂ O ₂ . Product e5 is converted to the α, β-unsaturated ester es6 by one-step oxidation with Dess-Martin periodan and Wittig olefination. Compound e6 is then reduced with DIBAL-H to allyl alcohol e7. At this stage, the path is divided into two paths, each of which begins with asymmetric Sharpless epoxidation and cyclization in one reactor. According to the first route, diol e8 can be obtained in 65% yield by the action of (-) - DET. Selective tosylation of the primary alcohol e8 and substitution of e9 with azide followed by catalytic reduction of e10 gives the amino alcohol e11. In a second way, the diol e12 is synthesized, almost analogously to the diol e8, except that they use (+) - DET for Sharpless epoxidation to obtain the corresponding enantiomeric compound. Inversion on the C ₂ carbon atom under the Mitsunobu reaction by the action of p-nitrobenzoic acid leads to the formation of compound e13, protected by two PNB groups. After deprotection, the diastereomeric diol e14 can be obtained. Selective tosylation of e14 and treatment of the resulting e15 with base gives the epoxide e16. The synthesis of d-nebivolol hydrochloride can be completed by the reaction of combining the amino alcohol E11 with epoxy E16, followed by transformation into the hydrochloride salt.

The strategy described in an article by Chandrasekhar et al. Has the following disadvantages:

1. The step of preparing compound e3 from e2 requires a high temperature to reorganize Kleisen, which is practically unattainable on an industrial scale.

2. For the synthesis of only one enantiomer of nebivolol, up to 16 stages are required, but a racemic mixture is required.

3. The last stage of the combination gives d-nebivolol with a low yield (20%).

4. Asymmetric Sharpless epoxidation, as is known, does not lead to enantiopure products. Therefore, contamination with other stereoisomers is likely. To determine such possible contaminants, the method of measuring optical purity described above is not sufficiently described, as already mentioned in WO 2004/041805.

5. Almost all intermediates are purified by column chromatography, since most of the intermediates are oily compounds.

Thus, numerous stages (over 13), low yield, the use of unusual catalysts, reaction conditions, special equipment and column chromatography for the purification of predominantly oily intermediates make the available strategies and most stages too labor-consuming and economically unacceptable for the industrial process.

Despite the above work, there is a need for a new, effective and practically feasible on an industrial scale method for producing racemic nebivolol with an increased overall yield.

All references cited herein are incorporated by reference in their entireties.

SUMMARY OF THE INVENTION

The present invention relates to new compounds and intermediates, as well as to methods that can be used directly for the selective synthesis of nebivolol or racemic ([2S * [R * [R [R *]]] - and ([2R * [S * [ S [S *]]]] - (±) -α, α`- [iminobis (methylene)] bis [6-fluorochroman-2-methanol] of the formula (I)

and its pure ([2S [2R * [R [R *]]]] - and ([2R * [S * [S [S *]]]] - enantiomeric forms and pharmaceutically acceptable salts.

Accordingly, the method of obtaining racemic [2S * [R * [R * [R *]]]] and [2R * [S * [S * [S *]]]] - (±) α, α`- [iminobis (methylene )] bis [6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol] and its pharmaceutically acceptable salts includes

(a) providing a compound of formula (VIII)

as a diastereomerically pure compound containing at least 95% RS / SR configuration or RR / SS configuration, where PG is hydrogen or an amino protecting group, wherein the amino protecting group is at least one of an allyl group or an aryl-C ₁ alkyl group ;

(b) providing a racemic compound of formula (V)

where LG is selected from the group consisting of chlorine, bromine, iodine, alkylsulfonyloxy and arylsulfonyloxy;

(c) N-alkylating a compound of formula (VIII) with a compound of formula (V), wherein said N-alkylation is carried out in an inert organic solvent in the presence of a base and optionally in the presence of a catalyst, to obtain a compound of formula (IX),

the compounds of formula (IX '), which is a cyclic semi-ketal form of the compounds of formula (IX),

or mixtures thereof, wherein the compound of formula (IX) and the compound of formula (IX ') are mixtures of diastereomers;

(d) separating the diastereomers of a compound of formula (IX) or a compound of formula (IX ') by at least one of (d1) or (d2) methods, wherein

(d1) separating the diastereomers of a compound of formula (IX) or a compound of formula (IX ') by fractional crystallization after salt formation or after modification to obtain substantially pure diastereomers of formula (IX) or formula (IX') containing at least 50% RSS / SRR or RRS / SSR configuration;

(d2) separating the diastereomers of the compound of formula (IX) or the compound of formula (IX ') to obtain substantially pure diastereomers of the formula (IX) or formula (IX') containing at least 50% of the RSS / SRR or RRS / SSR configuration, stage simultaneous epimerization-crystallization, where the stage of epimerization-crystallization includes:

(1) epimerizing a compound of formula (IX) or formula (IX ') RSR / SRS configuration to obtain a mixture of diastereomers of formula (IX) or formula (IX') RSS / SRR configuration and RSR / SRS configuration or

epimerizing a compound of formula (IX) or (IX ') RRR / SSS configuration to obtain a mixture of diastereomers of formula (IX) or formula (IX') RRS / SSR configuration and RRR / SSS configuration, provided that the epimerization is carried out in the presence of a base and an organic solvent where the mixture is optionally cooled using a temperature gradient and where diastereomers of the RSS / SRR configuration or RRS / SSR configuration in the mixture are obtained at least twice as much as the diastereomers of the RSR / SRS configuration and RRR / SSS configuration; and

(2) crystallization of the substantially pure diastereomers of formula (IX) or formula (IX ') with the RSS / SRR configuration or RRS / SSR configuration at least in excess of the diastereomers of the RSR / SRS configuration and the RRR / SSS configuration;

separation of the mixture by fractional crystallization, optionally after salt formation or after modification, to produce substantially pure diastereomers of formula (IX) or formula (IX ') with RSS / SRR or RRS / SSR configuration;

(e) recovering substantially pure diastereomers of formula (IX) or formula (IX ') with an RSS / SRR or RRS / SSR configuration to give a compound of formula (X)

as an RSSS / SRRR diastereomeric mixture in which the ratio of RSSS / SRRR of the diastereomeric configuration to the SRSR or RRSS of the diastereomeric configuration is at least 1;

(f) deprotecting a compound of formula (X), provided that PG is not H (and if RG is H, then deprotecting is canceled) to obtain a compound of formula (I) or a pharmaceutically acceptable salt thereof; and

(g) removing the compound of formula (I) or its pharmaceutically acceptable salts RSRS or RRSS diastereomeric configuration, if any, by recrystallization or suspension to obtain racemic [2S * [R * [R * [R *]]]] and [2R * [S * [S * [S *]]]] - (±) [α, α '- [iminobis (methylene)] bis [6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol ] or its pharmaceutically acceptable salts.

Additionally, racemic ([2S * [R * [R * [R *]]]] - and ([2R * [S * [S * [S *]]]] - (±) -α, α`- [ imino bis (methylene)] bis [6-fluorochroman-2-methanol] compounds of formula (I) obtained by the method described above.

A preferred embodiment of the method is shown in scheme 6a.

The starting compound is 6-fluorochroman-2-carboxylic acid II, which is converted by appropriate transformations (steps 1, 2 and 3) into compound V containing a suitable leaving group (LG). Selective reduction of compound V followed by the formation of an epoxide and substitution with a protected amine gives compound VIIIa after fractional crystallization. In this case, the order of transformations can be changed without the need for epoxide formation. The reaction of combining compound VIIIa with compound V gives a diastereomeric mixture of compounds IXa and Xb, after which compound IXa is selectively isolated and almost selectively reduced to a mixture of compounds Xa (main product) and Xb (minor product). The resulting mixture was then deprotected and, after formation of the salt with HCl, the racemic nebivolol I hydrochloride selectively crystallized. The total yield is 8%, however, the additional amounts of compound V used in step 7 are not taken into account.

In a preferred embodiment, the protecting group is a benzyl group. In some embodiments, the leaving group is chloro or bromo.

In some embodiments of the method of step (b), a compound of formula (V) is prepared in an amount of about 1.0 to about 1.5 equivalent.

In some embodiments of the method of step (c), the organic solvent is a polar aprotic solvent selected from the group consisting of DMF, DMA and NMP.

In some embodiments of the method of step (c), the base is at least one of tertiary amines, alkali metal carbonates or alkali metal hydrogen carbonates. A preferred base is sodium bicarbonate. Preferably, about 1.5 to about 2.5 equivalents of base are used.

In some embodiments of the method in step (c), the catalyst is at least one of alkali metal bromides, alkali metal iodides, tetraalkylammonium bromides or tetraalkylammonium iodides. A preferred catalyst is sodium bromide. Preferably, about 0.1 to about 0.25 equivalents of the catalyst are used, and most preferably 0.15 equivalents of the catalysts are used.

In some embodiments of the invention, in step (c), said N-alkylation is carried out at a temperature of from about room temperature to about 80 ° C.

In some embodiments, the implementation of stage (d) fractional crystallization is carried out in a solvent. A preferred solvent is acetonitrile. It is preferable to use a free amine for fractional crystallization. In some embodiments, from about 0.4 / n to about 0.6 / n equivalent of a silylating reagent is used, and n is the number of transferred silyl groups per silylating reagent. Preferably, the silylating reagent is at least one of trimethylsilyl chloride, HMDS or BSU.

In some embodiments of the invention, in step (d1), a silylating reagent is used for modification prior to fractional crystallization from the solvent. The modification is preferably carried out in the presence of from about 1.0 to about 2.0 equivalents of base. A preferred base is imidazole.

In some embodiments, in step (d1), said separation of the diastereomers of a compound of formula (IX) or a compound of formula (IX ′) is carried out in acetonitrile, methyl tert-butyl ether (MTBE), cyclohexane, or mixtures thereof.

In some embodiments of the method, step (d2) is carried out for a compound of formula (IX) or (IX`) RSR / SRS configuration. The RSS / SRR configuration in the mixture is preferably obtained with an approximately nine-fold excess of RSR / SRS.

In some embodiments of the method in step (d2), the mixture is cooled at a temperature gradient of from about 70 ° C to about 20 ° C. In a preferred embodiment, the temperature gradient is from 70 ° to 40 ° C.

In some embodiments of the method in step (d2), said epimerization is carried out in the presence of at least 0.1 equivalent of base. In some embodiments, said epimerization is carried out in the presence of at least 0.25 equivalents of base.

In some embodiments, in step (d2), the base is a compound selected from the group consisting of alkoxide, amidine, guanidine, and phosphazene. A preferred base is amidine. In a preferred embodiment, the base is diazabicycloundecene.

In some embodiments, in step (d2), the water content, if present, cannot exceed 1.0%. In some embodiments, in step (d2), the water content, if present, cannot exceed 0.1%.

In some embodiments, in step (e), said reduction is carried out for a compound of formula (IX) or a compound of formula (IX ') RSS / SRR configuration in a solvent by the action of an alkali metal borohydride, tetrabutylammonium borohydride, alkali metal selectride (SELECTRIDE) or zinc borohydride optionally in the presence of Lewis acid. In some embodiments, the Lewis acid is at least one substance of Ti (OAlkyl) ₄ , ZnCl ₂ , an alkali metal halide or an alkaline earth metal halide. Preferably, the solvent is at least one of ether, alcohol or a halogenated hydrocarbon. In some embodiments, said reduction is carried out at temperatures from about −20 ° C. to about room temperature.

In some embodiments, in step (f), said deprotection is carried out by catalytic hydrogenation.

In some embodiments, in step (g), said purification of the compound of formula (I) is carried out by suspending its hydrochloride salt in a solvent. Suspension is preferably carried out in methanol as a solvent.

In some embodiments of the invention, said provision of a compound of formula (VIII) includes:

(i) reducing the racemic compound of formula (V) in a solvent and optionally in the presence of a Lewis acid, where LG is bromine or chlorine, to form a diastereomeric mixture of compounds of formula (VI)

(ii) the formation of a mixture of diastereomers of the compounds of formula (VII)

;

;

(iii) reacting diastereomers of a compound of formula (VII) with NH ₂ PG to form a mixture of diastereomers of a compound of formula (VIII)

and

(iv) separating the diastereomers of the compound of formula (VIII) by fractional crystallization of the mixture of diastereomers optionally after salt formation. In a preferred embodiment, PG is a benzyl group.

In some embodiments, at least one of the diastereomers of a compound of formula VIII having an RR / SS or RS / SR configuration is isolated.

Another aspect of the present invention relates to a method for recycling undesired diastereomers obtained during the process, which reduces costs and makes the process for producing nebivolol more efficient. Specifically, during the selective preparation of compounds VIIIa and Xa, undesired diastereomers are formed as minor products. Therefore, waste recycling is an economic and environmental advantage over previous methods for producing nebivolol.

Alkylation of compound VIIIa with compound V also forms a diastereomeric mixture (mixture IXa and IXb, 1: 1), where the recirculation step makes it possible to transform the undesired form IXb either by selective cleavage to form compound VIIIa, or by carrying out a suitable epimerization step into a mixture of compounds IXa and IXb with subsequent selective isolation of the desired diastereomer IXa.

In some embodiments of the method, a compound of formula (VIII) RR / SS is recycled to a configuration that includes:

providing a compound of formula (VIII) with a protective group RR / SS configuration; and

inverting the alcohol configuration to form a compound of formula VIII SR / RS configuration.

In some embodiments, in step i), the reducing agent is selected from an alkali metal borohydride, tetraalkylammonium borohydride, zinc borohydride, alkali metal triacetoxyborohydride, SUPERHYDRIDE, RED-AL, alkali metal selectride (SELECTRIDE) or coordination borohydrides. In some embodiments, in step i), said reduction is carried out under the conditions of the Meerwein-Ponndorf-Verley reaction. In some embodiments, in step i), said reduction is carried out by catalytic hydrogenation. In some embodiments, in step i), the Lewis acid is an acid selected from the group consisting of alkali or alkaline earth metal chlorides, zinc chloride, titanium (IV) alkoxide, and aluminum trialkoxide. In some embodiments, in step i), said reduction is carried out under conditions that result in the formation of an excess of the compound of formula (VI) of the RR / SS isomer. In some embodiments, in step i), said reduction is carried out at a temperature of from about −78 ° C. to about room temperature. It is preferable to carry out the mentioned reduction at a temperature of from -20 ° C and to room temperature. In some embodiments, in step i), the solvent is a solvent selected from the group consisting of alcohols, ethers, halogenated hydrocarbons, and aromatic solvents.

In some embodiments, in step ii), said formation of a mixture of diastereomers of the compound of formula (VII) is carried out in a solvent and in the presence of a base. The solvent is preferably an alcohol and the base is an alkali metal alcoholate. Preferably 1.0-2.0 equivalents of base are used.

In some embodiments, in step ii), said formation of a mixture of diastereomers of the compound of formula (VII) is carried out at temperatures from 0 ° C to 40 ° C.

In some embodiments, in step iv), fractional crystallization is carried out in toluene, acetonitrile, C ₁ -C ₃ alcohol, ether, or mixtures thereof. A preferred C ₁ -C ₃ alcohol is 2-propanol, and the ether is at least one diisopropyl ether or MTBE.

In some embodiments of the invention, said provision of a racemic compound of formula (V) includes:

(1) the conversion of the compounds of formula (II)

an activated acid derivative;

(2) the interaction of the activated acid derivative with Meldrum acid in the presence of a base to form a compound of formula (III)

;

;

(3) the conversion of a compound of formula (III) into a compound of formula (IV)

where R is hydrogen or COOR` and where R` is C ₁ -C ₆ alkyl or aryl-C ₁ alkyl; and

(4) halogenating a compound of formula (IV) and optionally hydrolyzing and decarboxylating to form a compound of formula (V).

In some embodiments of the invention, in step (1), the carboxylic acid is converted to the corresponding acid chloride.

In some embodiments of the invention, in step (2), the base is a tertiary amine. In some embodiments, 1-3 equivalents of Meldrum acids are used. In some embodiments, in the step (2), the reaction temperature is from about −10 ° C. to about + 30 ° C.

In some embodiments, in step (3), the compound of formula (III) is hydrolyzed in a mixture of organic acid and water to give a compound of formula (IV), where R is H. In a preferred embodiment, the organic acid is acetic acid and the hydrolysis is carried out at boiling point. In some embodiments, in step (3), a compound of formula (IV) containing R in the form of COOR ′ and R ′ in the form of C ₁ -C ₆ alkyl or aryl-C ₁ alkyl is prepared by alcoholysis of a compound of formula (III). Alcoholysis is preferably carried out with ethanol and tert-butanol. Alcoholysis is preferably carried out at temperatures from about 70 ° C to about 80 ° C.

In some embodiments of the invention, in step (3), the solvent is at least one of alcohol or toluene.

In some embodiments, in step (4), prior to halogenation, the compound of formula (IV) in which R is H is converted by silylation to the corresponding silylenol ether containing a terminal double bond. In some embodiments, silylation is carried out by kinetically controlled deprotonation of lithium diisopropylamide (LDA), followed by silylation at a temperature of from about −78 ° C. to about −40 ° C. Silylation is preferably carried out at a temperature of from -78 ° C to -70 ° C. In a preferred embodiment, the silylating agent is TMSCl.

In some embodiments, in step (4), after conversion to a silylenol ether, halogenation is carried out using a brominating reagent. A preferred brominating reagent is N-bromosuccinimide.

In some embodiments of the invention, in step (4), the compound of formula (IV), where R is COOR`, is first halogenated and then converted to the compound of formula (V) by hydrolysis of the ether followed by decarboxylation. It is preferable to carry out halogenation in the presence of a catalyst. In some embodiments, from about 1.0 to about 1.5 equivalents of N-bromosuccinimide, N-chlorosuccinimide, or SO ₂ Cl ₂ are used as halogenating reagents. In some embodiments, about 0.2-0.4 equivalents of Mg (ClO ₄ ) ₂ are used as a catalyst.

In some embodiments of the invention, in step (4), said halogenation is carried out at temperatures from 0 ° C. to about room temperature.

In some embodiments, in step (4) after said halogenation, the ester is hydrolyzed, followed by decarboxylation in an aqueous solution of an organic acid. The organic acid is preferably at least one of trifluoroacetic acid, formic acid and acetic acid. It is preferable to carry out hydrolysis and decarboxylation at temperatures from about 75 ° C to about 90 ° C.

In some embodiments, the method further comprises recycling a compound of formula (IX) or (IX ′) RSR / SRS or RRR / SSS configuration, wherein said recycling comprises:

epimerizing a compound of formula (IX) or (IX ') RSR / SRS or RRR / SSS configuration, to obtain a mixture of diastereomers of formula (IX) or formula (IX') RSS / SRR configuration containing diastereomers of RSR / SRS configuration, or a mixture of diastereomers of formula (IX) or formula (IX ') RRS / SSR configuration containing diastereomers of the RRR / SSS configuration, and

separation of the mixture by fractional crystallization after salt formation or after modification, resulting in substantially pure diastereomers of formula (IX) or formula (IX ') having an RSS / SRR or RRS / SSR configuration.

In some embodiments, the method further comprises recycling a compound of formula (IX) or (IX ') RSR / SRS or RRR / SSS configuration, wherein said recycling comprises:

cleavage of a compound of formula (IX) or (IX ') RSR / SRS or RRR / SSS configuration, which gives a mixture containing diastereomers of formula (VIII) RS / SR or RR / SS configuration; and

separation of the RS / SR or RR / SS configuration of the diastereomers of the formula (VIII).

An additional aspect is the compound of formula (III)

An additional aspect is the compound of formula (IV)

where R represents hydrogen or COOR 'and R` represents C ₁ -C ₆ alkyl or aryl-C ₁ alkyl.

An additional aspect is a compound of formula (V)

where LG is bromine or chlorine.

An additional aspect is the compound of formula (VI)

where LG is bromine or chlorine.

An additional aspect is the compound of formula (IX)

or its cyclic semi-ketal form of the formula (IX '),

where PG is a protecting group selected from hydrogen, allyl and aryl-C ₁ alkyl.

An additional aspect is the compound of formula (IX) with RSS / SRR configuration

or its cyclic semi-ketal form of the formula (IX ')

where PG is a benzyl group.

An aspect of the invention is also a method for preparing racemic [2S * [R * [R * [R *]]]] and [2R * [S * [S * [S *]]]] - (±) α, α`- [ iminobis (methylene)] bis [6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol] and its pharmaceutically acceptable salts, including: providing a compound of formula (IX); and reducing a compound of formula (IX) to obtain a compound of formula (X) containing not more than 50% stereoisomer having an RSRS configuration. The specified method further includes obtaining a compound (VIII) and a compound of formula (V).

Enantiomerically pure nebivolol (l-nebivolol or d-nebivolol) can also be prepared according to the present invention, for example, after the separation of compound II (see Schemes 6b and 6c). Each of the enantiomers (S-II and R-II) can be transformed by the same methods as described for the corresponding racemic compound II (cf. Scheme 6a) to give the first key intermediates S-V and R-V. The l-nebivolol hydrochloride (Scheme 6b) can then be prepared by synthesizing R-VIIIa starting from R-V, followed by coupling reaction with S-V (step 11), selective reduction (step 12), deprotection and salt formation (step 13). The d-nebivolol hydrochloride can be obtained in the same way, except that, unlike the synthesis of l-nebivolol, the enantiomeric intermediate S-VIIIa is obtained from S-V and then coupled with R-V (Scheme 6c, step 11). Selective reduction (step 12) followed by deprotection and salt formation gives d-nebivolol hydrochloride.

For a person skilled in the art it is obvious that various changes and modifications of the considered paths can be used for enantioselective syntheses of l- or d-nebivolol. Therefore, the use of intermediates for the enantioselective synthesis of l- or d-nebivolol obtained according to schemes 6b and 6c is not limited to the described routes. For example, epoxides R-VIIa, R-VIIb, S-VIIa and S-VIIb (obtained from key intermediates RV or SV) can also be used directly for the synthesis of each enantiomer of nebivolol, for example, along the route described in Scheme 2. It depends on the reducing agent whether epoxides R-VIIa, R-VIIb, S-VIIa and S-VIIb are obtained as the main or minor compound.

A method of obtaining a compound of formula (I) in the form of a racemic mixture or in an enantiomerically pure form and its pharmaceutically acceptable salts includes:

(a) the separation of the compounds of formula (II)

to obtain a compound of formula (II) S configuration and R configuration;

(b) converting a compound of formula (II) S configuration into a compound of formula (V) S configuration,

where LG is a substituent selected from the group consisting of chloro, bromo, iodo, alkylsulfonyloxy and arylsulfonyloxy through the formation of a compound of formula (III) S configuration and a compound of formula (IV) S configuration;

(c) converting a compound of formula (II) R configuration into a compound of formula (V) R configuration through the formation of a compound of formula (III) R configuration and a compound of formula (IV) R configuration;

(d) providing a compound of formula (VIII)

where PG is hydrogen or an amino protecting group, where the amino protecting group is at least one of an allyl group or an aryl-C ₁ alkyl group and where the compound of formula (VIII) is an enantiomeric compound with an RS or SR configuration;

(e) N-alkylating (i) a compound of formula (VIII) RS configuration with a compound of formula (V) S configuration; or (ii) compound (VIII) SR configuration with a compound of formula (V) R configuration, provided that said N-alkylation carried out in an inert organic solvent in the presence of a base and optionally in the presence of a catalyst to obtain an RSS or SRR enantiomeric form of a compound of formula (IX)

or RSS or SRR of the enantiomeric form of compound (IX`), which is a cyclic semi-ketal form of a compound of formula (IX)

(f) recovering at least one of the RSS or SRR enantiomeric forms of the compound of formula (IX) or formula (IX ') to obtain at least one RSSS or SRRR of the enantiomeric form of the compound of formula (X)

(g) deprotecting at least one of the RSSS or SRRR enantiomeric forms of the compound of formula (X), provided that PG is not H (and if PG is H, then said deprotection step is deselected) to obtain a compound of formula (I) or its pharmaceutically acceptable salts; and

(h) removing the compound of formula (I) or its pharmaceutically acceptable salts of the RSRS diastereomeric configuration, if any, as a by-product, by recrystallization or suspension to give at least one of ([2S * [R * [R * [R * ]]]] - and ([2R * [S * [S * [S *]]]] - enantiomers of the compound of formula (I) and its pharmaceutically acceptable salts; and

(i) optionally combining ([2S * [R * [R * [R *]]]] and ([2R * [S * [S * [S *]]]] - enantiomers of the compound of formula (I) and its pharmaceutically acceptable salts for the formation of racemic ([2S * [R * [R * [R *]]]] - and ([2R * [S * [S * [S *]]]] - (±) α, α` - [imino-bis (methylene)] bis [6-fluorochroman-2-methanol] of the formula (I) and its pharmaceutically acceptable salts.

Another aspect of the invention is a method for producing racemic [2S * [R * [R * [R *]]] - and [2R * [S * [S * [S *]]]] - (±) α, α` - [iminobis (methylene)] bis [6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol] and its pharmaceutically acceptable salts, including:

(a) providing a compound of formula (VIII) as a diastereomer with an RR / SS configuration wherein PG is hydrogen or an amino protecting group, wherein the amino protecting group is at least one of an allyl group or an aryl-C ₁ alkyl group;

b) providing a racemic compound of formula (V) wherein LG is a substituent selected from the group consisting of chloro, bromo, iodo, alkylsulfonyloxy and arylsulfonyloxy;

(c) N-alkylating a compound of formula (VIII) with a compound of formula (V), wherein said N-alkylation is carried out in an inert organic solvent in the presence of a base and optionally in the presence of a catalyst, and a compound of formula (IX) is obtained, a compound of formula (IX '), which is the cyclic semi-ketal form of the compound of formula (IX), or a mixture thereof, wherein the compound of formula (IX) and the compound of formula (IX ') are mixtures of diastereomers having the RRR / SSS and RRS / SSR configuration;

(d) separating the diastereomers of the compound of formula (IX) or the compound of formula (IX ′) by fractional crystallization after salt formation or after modification to obtain substantially pure diastereomers of the formula (IX) or formula (IX ′) having at least 50% RRR / SSS or RRS / SSR configuration;

(e) recovering substantially pure diastereomers of formula (IX) or formula (IX ') of the RRS / SSR configuration, which gives a compound of formula (X) as an RSSS / SRRR diastereomeric mixture in which the ratio of RSSS / SRRR of the diastereomeric configuration to SRSR or RRSS diastereomeric configuration is at least 1;

(f) deprotecting a compound of formula (X), provided that PG is not H to give a compound of formula (I) or pharmaceutically acceptable salts thereof; and

(g) removing the compound of formula (I) or its pharmaceutically acceptable salts of the RSRS diastereomeric configuration, if any, by recrystallization or suspension, resulting in the formation of racemic [2S [2R * [R [R *]]]] and [2R [2S * [ S [S *]]]] - (±) α, α`- [iminobis (methylene)] bis [6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol] or its pharmaceutically acceptable salts .

In some embodiments of the invention, the method further comprises cleaving a compound of formula (IX) or a compound of formula (IX ') of the RRR / SSS configuration to form a compound of formula (VIII) as a diastereomer of the RR / SS configuration.

In one embodiment, the method further comprises epimerizing a compound of formula (IX) or a compound of formula (IX ′) of an RRR / SSS configuration to form said mixtures of diastereomers of a compound of formula (IX) or a compound of formula (IX ′) of RRR / SSS and RRS / SSR of configuration. In yet another embodiment of the aforementioned embodiment, the method further comprises splitting a compound of formula (IX) or a compound of formula (IX ′) of the RRR / SSS configuration to form a compound of formula (VIII) as a diastereomer of the RR / SS configuration.

A method for preparing a compound of formula (VIII) is also provided.

the method includes

(i) providing a racemic compound of formula (V)

;

;

(i) reducing the racemic compound of formula (V) in a solvent and optionally in the presence of a Lewis acid, where LG is bromine or chlorine, to obtain a diastereomeric mixture of a compound of formula (VI)

;

;

(ii) the formation of a mixture of diastereomers of the compounds of formula (VII)

;

;

(iii) reacting diastereomers of a compound of formula (VII) with NH ₂ PG, where PG is a hydrogen or amino protecting group and where the amino protecting group is at least one of an allyl group or an aryl-C ₁ alkyl group that gives a compound of formula (VIII ) as a mixture of diastereomers; and

(iv) optionally separating the diastereomers of the compound of formula (VIII) from a mixture of diastereomers by fractional crystallization.

A method for producing racemic [2S * [R * [R * [R *]]]] and [2R * [S * [S * [S *]]]] - (±) α, α`- [iminobis ( methylene)] bis [6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol] and its pharmaceutically acceptable salts, including:

(a) providing a compound of formula (IX), a compound of formula (IX ′), which is a cyclic semi-ketal form of a compound of formula (IX), or mixtures thereof, wherein the compound of formula (IX) and the compound of formula (IX ′) are mixtures of diastereomers;

(b) separating the diastereomers of a compound of formula (IX) or a compound of formula (IX ') by at least one of (b1) or (b2) methods, wherein

(b1) separating the diastereomers of a compound of formula (IX) or a compound of formula (IX ') by fractional crystallization after salt formation or after modification to obtain substantially pure diastereomers of formula (IX) or formula (IX') containing at least 50% RSS / SRR or RRS / SSR configuration; (b2) separating the diastereomers of the compound of formula (IX) or the compound of formula (IX ′) to obtain substantially pure diastereomers of the formula (IX) or formula (IX ′) containing at least 50% of the RSS / SRR or RRS / SSR configuration on stage simultaneous epimerization-crystallization, where the stage of epimerization-crystallization includes:

(1) epimerizing a compound of formula (IX) or (IX ') RSR / SRS configuration to obtain a mixture of diastereomers of formula (IX) or formula (IX') RSS / SRR configuration and RSR / SRS configuration or

epimerizing a compound of formula (IX) or (IX ') of an RRR / SSS configuration to obtain a mixture of diastereomers of formula (IX) or formula (IX') of an RRS / SSR configuration and an RRR / SSS configuration, provided that said epimerization is carried out in the presence of a base and an organic solvent, where the mixture is optionally cooled using a temperature gradient, and where the RSS / SRR configuration or RRS / SSR configuration in the mixture is obtained at least twice in excess with respect to the RSR / SRS configuration and the RRR / SSS configuration; and

(2) crystallization of substantially pure diastereomers of formula (IX) or formula (IX ') having an RSS / SRR configuration or an RRS / SSR configuration in at least a twofold excess with respect to the RSR / SRS configuration and the RRR / SSS configuration;

separation of the mixture by fractional crystallization, optionally after salt formation or after modification, to produce substantially pure diastereomers of formula (IX) or formula (IX ') RSS / SRR or RRS / SSR configuration;

(c) recovering substantially pure diastereomers of formula (IX) or formula (IX ') of an RSS / SRR or RRS / SSR configuration to obtain a compound of formula (X) as an RSSS / SRRR diastereomeric mixture with a ratio of RSSS / SRRR of diastereomeric configuration to SRSR or RRSS diastereomeric configuration, which is at least 1;

(d) deprotecting a compound of formula (X) provided that PG is not H (and if PG is H then deprotecting step is canceled) to obtain a compound of formula (I)

or pharmaceutically acceptable salts; and

(e) removing the compound of formula (I) RSRS or RRSS of the diastereomeric configuration or its pharmaceutically acceptable salts, if any, by recrystallization or suspension to give racemic [2S * [R * [R * [R *]]]] and [2R * [S * [S * [S *]]]] - (±) α, α`- [iminobis (methylene)] bis [6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol] or its pharmaceutically acceptable salts.

New compounds obtained by the authors of the present invention include the following

и

and

BRIEF DESCRIPTION OF SEVERAL VIEWS OF THE DRAWINGS

The invention will be described together with the following drawings, in which like reference numbers indicate like elements and where:

Figure 1A shows the structural formula of d-nebivolol, figure 1B shows the structural formula of racemic nebivolol.

Figure 2 is a schematic representation of a molecule of compound VIIIa with numbered atoms (50% probability of ellipsoids; arbitrary parameters of the displacement of H atoms are given for clarification).

Figure 3 is a ¹³ C-NMR image of the spectrum of compound IXa in cyclic semi-ketal form.

Figure 4 is a ¹³ C-NMR image of the spectrum of compound IXb in cyclic semi-ketal form.

Figure 5 is a schematic representation of a molecule of compound IXb in cyclic semi-ketal form.

Figure 6 is a diagram showing a method for producing racemic nebivolol and its pharmaceutically acceptable salts.

Figure 7 is a diagram showing the method of simultaneous epimerization-crystallization according to the invention.

Figure 8 is a diagram showing a preferred example of the simultaneous epimerization-crystallization technique of the invention, wherein the protecting group is a benzyl group.

Figure 9 is a diagram illustrating a method for producing racemic nebivolol and its pharmaceutically acceptable salts, in which stage 7b represents the simultaneous epimerization-crystallization according to the invention.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to new compounds and methods for the synthesis of racemic nebivolol and its pharmaceutically acceptable salts, as well as enantiomerically pure nebivolol and its pharmaceutically acceptable salts. The present invention is stimulated by the desire to create a more efficient method containing fewer reaction steps in order to avoid the steps of separating the enantiomers to obtain a racemic mixture. One example of the separation of enantiomers is described in WO 2004/041805 (Scheme 3b). Since all enantiomers are separated during the earlier steps of the process, up to 30 steps are required in four convergent pathways to obtain racemic nebivolol. Therefore, a method for producing racemic nebivolol based on such a strategy is complex and ineffective. The present invention provides a solution that enables the selective preparation of intermediates, as shown in Scheme 6a, where each of the intermediates is obtained as a racemic mixture without prior separation of the enantiomers that are formed during the process.

In addition, the present invention makes it possible to obtain enantiomerically pure nebivolol, for example, after separation of the selected racemic compounds, for example compound II (Schemes 6b and 6c).

The invention also relates to a method for the preparation of racemic nebivolol in which the formation of undesired diastereomers (e.g. SRSS / RSRR) in the final stages is minimized by facilitating purification and increasing efficiency. The authors of the present invention were surprised to find that for the efficient production of nebivolol, it is possible to take advantage of the differences in solubility of other diastereomeric derivatives of nebivolol in the form of their salts with HCl. Specifically, the inventors observed that the mesoform of the racemic nebivolol (as the HCl salt) of the RSRS configuration has increased solubility compared to the nebivolol hydrochloride, while the second mesoform of the RRSS configuration has a solubility comparable to the solubility of nebivolol hydrochloride. The solubility of HCl salts in MeOH is 1.5% for nebivolol, 1.0% for the RRSS meso form, and more than 15% for the RSRS meso form. In a preferred embodiment of the present invention, selective preparation of racemic nebivolol is provided, which may contain only the selected diastereomer (e.g., RSRS-meso-form) as a possible impurity that can be easily removed by simple recrystallization due to its higher solubility. Therefore, using this synthesis strategy, it is possible to avoid difficult and inefficient (low yield) purification of the final product, since the formation of poorly soluble nebivolol diastereomers (SRRS / RSSR, RRSS, SRSS / RSRR and RRRR / SSSS) is prevented.

Another aspect of the present invention relates to diastereoselective synthesis of intermediate VIIIa containing the preferred syn configuration. The specified compound is a useful intermediate in the above synthetic strategy for the selective preparation of racemic nebivolol, since it can form only the RSRS diastereomer configuration as a contaminant, which can be easily removed at the final stages (Scheme 6a, stages 8 and 9).

Another aspect of the present invention relates to an effective method for the selective reduction of compound IXa, in which the formation of the undesired RSRS isomer is minimized.

The inventors of the present invention have found that the efficiency of the method is further enhanced by recycling methods for reusing undesired diastereomers that may be obtained during the synthesis of intermediates.

A method for producing racemic nebivolol (as shown in Scheme 6a) will now be described in detail.

The starting material for the present method is compound II, racemic acid, which can be obtained in various ways according to the methods described in US patent No. 5171865 (see also patent analogue EP 0331078) and US patent No. 4985574 (see also patent analogue EP 0264586 )

Step 1 involves the preparation of (±) -5- [6-fluorochroman-2-carbonyl] -2,2-dimethyl [1,3] dioxane-4,6-dione (compound III) from compound II, as shown in Scheme 7 .

First, racemic acid II is converted into an activated acid derivative, which is then reacted with Meldrum acid in an organic solvent and gives the corresponding acylated meldrumate III, which is a new compound and a useful intermediate for the synthesis of nebivolol.

Acylation with Meldrum acid can be carried out by a method similar to the traditional one, for example, the method described in (J. Org. Chem. 43 (10), 1978, 2087).

The carboxyl group can be activated by a conventional method, for example, conversion to an acid halide using PHaI ₅ , PHaI ₃ , SOHaI ₂ , (COHaI) ₂ , in the form of a carboxylic acid anhydride, an activated ester, and the like. Activation to produce the acid halide is preferred, and the acid chloride is the most preferred acid halide, which is prepared using 1-5 equivalents of SOCl ₂ , preferably 1-3 equivalents in the presence of catalytic amounts of DMF. Said reaction can be carried out without the use of any solvent or in a solvent such as, for example, benzene, alkyl or halogen substituted benzene, halogenated hydrocarbons and the like. Alkyl substituted or halogen substituted benzenes are preferred solvents, and toluene is the most preferred solvent.

The reaction temperature may vary from room temperature to the boiling point of the solvent. In a preferred embodiment, the temperature range is from 60 ° C to 90 ° C in toluene as a solvent. Acyl chloride can be obtained in almost quantitative yield by evaporation of the solvent along with an excess of the chlorinating reagent.

The acylation of Meldrum acid can be carried out in the same solvent used to activate the carboxylic acid. Halogenated hydrocarbons are preferred solvents, and methylene chloride is most preferred. Typically, Meldrum acid is used in a molar ratio of 1-3 moles per mole of compound II, preferably 1-1.5 moles per mole of compound II. The reaction is carried out in the presence of an organic or inorganic base, preferably in the presence of an organic base, such as, for example, a tertiary amine, and most preferably in the presence of pyridine. In some embodiments, 1-5 equivalents, preferably 1.5-3 equivalents of pyridine, are used as the base. The reaction temperature may vary from -10 ° C (but not lower than the melting point of a pure solvent, for example benzene) to about + 30 ° C, preferably in the range from 0 ° C to room temperature. The reaction, which is carried out in the indicated temperature range (0 ° C-room temperature), usually ends in 2 hours.

At the end of the reaction, the mixture is hydrolysed and extracted with water or a dilute aqueous solution of an inorganic acid, preferably a 5% -10% aqueous solution of hydrochloric acid.

After separation of the layers, the organic solvent is evaporated and the residue can be used directly in the next step or can be purified by recrystallization or suspension in an organic solvent. It is preferable to purify the residue by suspension in ether, and most preferably in methyl tert-butyl ether (MTBE) or diisopropyl ether.

If you want to obtain enantiomerically pure nebivolol, it can be obtained by separation of compound II, using, for example (+) - dehydroabietylamine, as described in US patent No. 6545040.

Step 2 involves the preparation of compound IV, scheme 6a, where R is H, then (±) -1- (6-fluorochroman-2-yl) -ethanone is obtained (compound IVa, scheme 8, path A), or COOR ', where R 'is alkyl or substituted alkyl, then (±) -3- (6-fluoro-chroman-2-yl) -3-oxopropionic acid alkyl ester is obtained (compound IVb, Scheme 9, route B).

Meldrum acylated acids are suitable intermediates for the preparation of the corresponding methyl ketone after hydrolysis and decarboxylation, or for the preparation of the corresponding beta keto acids after alcoholysis and decarboxylation. The reactions can be carried out in a manner analogous to the generally accepted methodology, for example, described in (J. Org. Chem. 43 (10), 1978, 2087 and Synth. Commun., 10, 1980, 221).

Way a

The hydrolysis and decarboxylation of compound III to form compound IVa (Scheme 8) as a new compound and a useful intermediate for the synthesis of nebivolol can be carried out in an aqueous acid solution at boiling point. Inorganic or organic acid may be used; acetic acid is preferred. Water can be used in excess; equal volumes of water and acetic acid are preferred. The compound can be used directly as a crude product or it can be further purified by column chromatography.

Path B

The reaction of compound III with alcohols gives the corresponding beta keto ester IVb as a new compound and a useful intermediate for the synthesis of nebivolol, in which R 'is alkyl or substituted alkyl. This alcoholysis can be carried out by primary, secondary or tertiary alcohols, preferably primary and tertiary alcohols, and most preferably ethanol or tert-butanol. As a solvent, you can use the alcohol itself or an inert aromatic solvent. Ethanol is the preferred solvent for the synthesis of the corresponding ethyl ester, and toluene is the preferred solvent for the synthesis of tert-butyl ether. The reaction temperature may vary from the boiling point of low boiling alcohols to the boiling point of toluene or the boiling point of the corresponding toluene / alcohol azeotrope. Preferred temperatures for producing beta-ketoethyl ether as well as for beta-keto-tert-butyl ether are in the range of from about 70 ° C to about 80 ° C. After completion of the reaction, the reaction mixture can be processed in the usual manner, for example, by extraction, and the crude product can either be used directly in the next step or purified by column chromatography.

Stage 3 involves the preparation of compound V from compound IV, for example (±) -2-bromo-1- (6-fluorochroman-2-yl) ethanone (compound Va) and (±) -2-chloro-1- (6-fluorochroman -2-yl) ethanone (compounds Vb) (Schemes 10 and 11 ac).

Compound IV obtained in step 2 can be used to synthesize compound V containing a suitable leaving group (LG). Non-limiting examples of suitable leaving groups include substituted and unsubstituted alkyl and aryl sulfonic acid derivatives and halogen atoms. In a preferred embodiment, the leaving groups are halogen atoms, and the most preferred leaving groups are bromine (compound Va) and chlorine (compound Vb).

Compounds Va and Vb can be obtained by way A of scheme 10 or by way B of schemes 11a-c, as described below.

Way A:

The synthesis of bromketone (compound Va) by direct bromination of methyl ketone (compound IVa) with bromine or NBS in most cases leads to competitive bromination of the aromatic ring. However, after the preliminary conversion of methylketone IVa to the corresponding silylenol ether containing a terminal double bond, the selective preparation of compound Va is possible (see Scheme 10).

By the general procedure, silylenol ether can be obtained by kinetically controlled deprotonation by the action of a strong base followed by silylation. Examples of the solvent include ethers or mixtures of ethers with such solvents in which strong base solutions are usually available. In a preferred embodiment of the preparation of silylenol ether, lithium diisopropylamide (LDA) is used as the base, trimethylsilyl chloride (TMSCl) is used as the silylating agent, and tetrahydrofuran (THF) is used as the ether. The reaction begins at -78 ° C by adding compound IVa to a mixture of 1-1.5 equivalents of LDA and 1-2 equivalents of TMSCl. Preferred are 1.2 equivalents of LDA and 1.6 equivalents of TMSCl. Then the reaction mixture was allowed to warm to room temperature, the mixture was first extracted and then concentrated. Bromination can be carried out in a suitable solvent with N-bromosuccinimide (NBS), 1,3-dibromo-5,5-dimethylhydantoin or pyridine hydrobromide perbromide at a temperature of from 0 ° C to room temperature. Suitable solvents include, for example, halogenated hydrocarbons, preferably methylene chloride. After completion of the reaction, the mixture is extracted, and the product can be purified by column chromatography or recrystallization. Since non-selective bromination results in the formation of by-products, which complicates the purification, a more selective and efficient method for preparing compound V has been developed (see path B, Scheme 11a).

Way B:

Route B is an alternative route to the preparation of halogenated compounds Va and Vb, which is more selective than route A (see Scheme 11a).

An advantage of pathway B is the possibility of carrying out the reaction at higher, more convenient temperatures by sequentially halogenating the beta-ketoester IVb, followed by hydrolysis and decarboxylation. Halogenation can be carried out with a suitable halogenating reagent with or without a catalyst. Typical halogenating reagents to produce the corresponding bromides or chlorides include, for example, NBS, NCS, and SO ₂ Cl ₂ . A non-limiting example of a catalyst includes Mg (ClO ₄ ) ₂ . Suitable solvents for the reaction in question include acetonitrile, esters or halogenated hydrocarbons; acetonitrile, ethyl acetate and methylene chloride are preferred. In some embodiments, 1.0-1.5 equivalents of a halogenating reagent and 0.3 equivalents of a catalyst can be used. The reaction occurs at a temperature of from 0 ° C to room temperature until complete conversion within 3-4 hours. Higher temperatures for halogenation should be avoided due to possible adverse reactions, and the reaction time may increase at lower temperatures. Subsequent hydrolysis of the ester and decarboxylation to form compound V can be carried out in aqueous or non-aqueous solutions of acids at higher temperatures. Organic and inorganic acids may be used.

Compound IVb in the form of ethyl or tert-butyl ether can be used as starting material, with tert-butyl ether being preferred. In the case of ethyl ester, the hydrolysis and decarboxylation of the corresponding halogenated beta-ketoester can preferably be carried out with an aqueous solution of trifluoroacetic acid. When the tert-butyl ether form is used, the hydrolysis and decarboxylation of the corresponding halogenated beta-keto ester is preferably carried out in a mixture of formic acid and acetic acid, preferably in the presence of water. The temperature for the ether hydrolysis and decarboxylation reaction is in the range of from about 60 ° C to about 100 ° C, preferably 75-90 ° C. The purification of compound V can be carried out as described above for compound Va. Since compound Vb has greater storage stability than compound Va, compound Vb is preferred.

Compound V containing substituted and unsubstituted derivatives of alkyl and arylsulfonic acids as leaving groups can be obtained, for example, by the transformation of compound IVb` or Ivb '' (LG = halogen) with carboxylic acid salts to compound Ivb '' 'followed by hydrolysis of the complex ether, then decarboxylation and sulfonylation under the action of the corresponding acid chlorides of alkyl or arylsulfonic acids (see Scheme 11b). Alternatively, the compound Vc can be obtained by a similar transformation, starting directly with the halogen ketones Va or Vb (see Scheme 11c)

Stage 4 involves the preparation of compound VI as shown in Scheme 12 below. Non-limiting examples of compound VI include (±) -2-chloro-1- [6-fluoro- (2R *) -chroman-2-yl] - (1R *) - ethan-1-ol (intermediate VIa), (±) -2-chloro-1- [6-fluoro- (2R *) - chroman-2-yl] - (1S *) - ethan-1-ol (intermediate VIb) ), (±) -2-bromo-1- [6-fluoro- (2R *) - chroman-2-yl] - (1R *) - ethan-1-ol (intermediate VIc) and (±) -2- bromo-1- [6-fluoro- (2R *) - chroman-2-yl] - (1S *) - ethan-1-ol (intermediate VId).

A number of reducing agents can be used to produce halogenated methyl alcohols (compound VI) from racemic halogenated methyl ketones (compound V) (see Scheme 12). In general, two racemic diastereomers having syn (RR / SS) or anti (RS / SR) configurations can form. Regarding the nebivolol synthesis strategy, as shown in Scheme 6 (a), reduction methods are preferred that lead to the formation of an excess of halogenated methyl alcohol having a syn (RR / SS) configuration. Surprisingly, there are very few studies on the selective reduction of halogen methyl ketones containing an alkoxy-substituted chiral center at the alpha position (e.g., Tetrahedron Letters, 40 (1999), 2863-2864). Prior to the present invention, the effect of the alkoxy substituted chiral center in the alpha position of the halogen methyl ketones on the formation of a new chiral center in the alpha position was not understood, and diastereoselectivity for such reactions has not been precisely established.

Usually, there are no restrictions on the use of reducing agents, for example, borohydride and aluminum hydride reducing agents, as well as reagents that are applicable for the Meervein-Pondorf-Verley reduction. Non-limiting examples of reducing agents include LiBH ₄ , NaBH ₄ , KBH ₄ N (nBu) ₄ BH ₄ , Zn (BH ₄ ) ₂ , NaH (Oac) ₃ , Superhydride®, Red-Al, Li-Selectride (Li-Selectride), BH ₃ x SME ₂ or the like. In the case of catalytic hydrogenation, suitable catalysts are those that do not give adverse reactions with halogenated compounds (for example, the catalysts described and cited in WO 03/064357). The reduction can be carried out in the absence or presence of a Lewis acid, such as, for example, MgCl ₂ , CaCl ₂ , BaCl ₂ , ZnCl ₂ Al (Oalkyl) ₃ , Ti (Oalkyl) ₄ BF ₃ xOEt ₂ , etc. Suitable solvents include ethers, alcohols, halogenated hydrocarbons, halogenated or alkylated aromatic solvents and the like, except that halogenated solvents are not suitable for catalytic reduction reactions. Preferred halogen methyl ketones of compound V contain chlorine or bromine as the substituent “LG”. Recovery is conveniently carried out at temperatures from about -78 ° C to about room temperature, preferably at a temperature of from -20 ° C to room temperature. Table 2 shows representative results of the reduction of chloromethyl ketone Vb (LG = Cl).

Table 2 Reagent (equiv.) Catalyst (eq.) Solvent Temperature [° C] Time [h] Attitude
RR / SS // RS / SR LiBH ₄ (1) absent THF -20 to -15 one 58.3 // 41.7 LiBH ₄ (1) absent Meoh -20 to -15 one 60.2 // 39.8 LiBH ₄ (1) absent iPrOH -20 to -15 one 51.0 // 49.0 LiBH ₄ (1) absent CH ₂ Cl ₂ -20 to -15 3 42.8 // 57.2 LiBH ₄ (1) absent toluene -20 to room Temper. During the night 41.5 // 58.5 LiBH ₄ (1) absent Dme -20 to -15 one 53.8 // 46.2 LiBH ₄ (1) ZnCl ₂ (2) THF -20 to -15 one 56.9 // 43.1 LiBH ₄ (1) ZnCl ₂ (2) Meoh -20 to -15 one 63.7 // 36.3 LiBH ₄ (1) ZnCl ₂ (2) iPrOH -20 to -15 one 60.3 // 39.7 LiBH ₄ (1) ZnCl ₂ (2) CH ₂ Cl ₂ -20 to the rooms. Temperature During the night 59.3 // 40.7 LiBH ₄ (1) ZnCl ₂ (2) toluene -20 to room Temper. During the night 53.0 // 47.0 LiBH ₄ (1) ZnCl ₂ (2) Dme -20 to -15 2 46.7 // 53.3 LiBH ₄ (1) Ti (OiPr) ₄ (2) THF -20 to -15 one 48.8 // 51.2 LiBH ₄ (1) Ti (OiPr) ₄ (2) Meoh -20 to -15 one 59.3 // 40.7 LiBH ₄ (1) Ti (OiPr) ₄ (2) iPrOH -20 to -15 one 47.3 // 52.7 LiBH ₄ (1) Ti (OiPr) ₄ (2) CH ₂ Cl ₂ -20 to -15 one 35.6 // 64.4 LiBH ₄ (1) Ti (OiPr) ₄ (2) toluene -20 to -15 one 38.1 // 61.9 LiBH ₄ (1) Ti (OiPr) ₄ (2) Dme -20 to -15 one 43.4 // 56.6 LiBH ₄ (1) MgCl ₂ (2) THF -20 to -15 3 57.8 // 42.2 LiBH ₄ (1) MgCl ₂ (2) Meoh -20 to -15 1,5 59.5 // 40.5 LiBH ₄ (1) MgCl ₂ (2) iPrOH -20 to -15 1,5 41.1 // 58.9 LiBH ₄ (1) MgCl ₂ (2) CH ₂ Cl ₂ -20 to -15 2.5 44.3 // 55.7 LiBH ₄ (1) MgCl ₂ (2) toluene -20 to -15 2.5 42.9 // 57.1 LiBH ₄ (1) MgCl ₂ (2) Dme -20 to -15 one 52.4 // 47.6 LiBH ₄ (1) Al (OiPr) ₃ (2) THF -20 to -15 one 54.7 // 45.3 LiBH ₄ (1) Al (OiPr) ₃ (2) Meoh -20 to -15 one 59.7 // 40.3 LiBH ₄ (1) Al (OiPr) ₃ (2) iPrOH -20 to -15 one 50.5 // 49.5 LiBH ₄ (1) Al (OiPr) ₃ (2) CH ₂ Cl ₂ -20 to -15 one 41.9 // 58.1 LiBH ₄ (1) Al (OiPr) ₃ (2) toluene -20 to -15 one 39.6 // 60.4 LiBH ₄ (1) Al (OiPr) ₃ (2) Dme -20 to -15 one 51.1 // 48.9 LiBH ₄ (1) BF ₃ xOEt ₂ (2) THF -20 to room Temper. During the night 61.5 // 38.5 * LiBH ₄ (1) BF ₃ xOEt ₂ (2) Meoh -20 to room Temper. During the night 56.3 // 43.7 * LiBH ₄ (1) BF ₃ xOEt ₂ (2) iPrOH -20 to room Temper. During the night 55.4 // 44.6 * LiBH ₄ (1) BF ₃ xOEt ₂ (2) CH ₂ Cl ₂ -20 to -15 3 44.9 // 55.1 LiBH ₄ (1) BF ₃ xOEt ₂ (2) toluene -20 to room Temper. During the night 45.6 // 54.6 * LiBH ₄ (1) BF ₃ xOEt ₂ (2) Dme -20 to -15 one 46.0 // 54.0 NaBH ₄ (1) absent THF -20 to -15 one 51.8 // 48.2 NaBH ₄ (1) absent Meoh -20 to -15 one 60.2 // 39.8 NaBH ₄ (1) absent iPrOH -20 to room Pace. 22.25 59.1 // 40.9 NaBH ₄ (1) absent CH ₂ Cl ₂ -20 to room Pace. 21 50.9 // 49.1 * NaBH ₄ (1) absent toluene -20 to room Temper. 21 51.7 // 48.3 * NaBH ₄ (1) absent Dme -20 to -15 one 54.7 // 45.3 NaBH ₄ (1) absent EtOH -78 ° C to room temperature 3 56.8 // 43.2 NaBH ₄ (0.5) absent iPrOH room Pace. 0.5 50.4 // 49.6 NaBH ₄ (1) ZnCl ₂ (2) THF -20 to -15 one 58.3 // 41.7 NaBH ₄ (1) ZnCl ₂ (2) Meoh -20 to -15 one 63.4 // 36.6 NaBH ₄ (1) ZnCl ₂ (2) iPrOH -20 to room Pace. eighteen 59.7 // 40.3 NaBH ₄ (1) ZnCl ₂ (2) CH ₂ Cl ₂ -20 to room Pace. 21 63.8 // 36.2 * NaBH ₄ (1) ZnCl ₂ (2) toluene -20 to room Temper. 21 61.5 // 38.5 *

NaBH ₄ (1) ZnCl ₂ (2) Dme -20 to -15 2 49.3 // 50.7 NaBH ₄ (1) Ti (OiPr) ₄ (2) THF -20 to -15 one 42.8 // 57.2 NaBH ₄ (1) Ti (OiPr) ₄ (2) Meoh -20 to -15 one 58.8 // 41.2 NaBH ₄ (1) Ti (OiPr) ₄ (2) iPrOH -20 to -15 3 46.4 // 63.6 NaBH ₄ (1) Ti (OiPr) ₄ (2) CH ₂ Cl ₂ -20 to room Pace. eighteen 38.4 // 61.6 NaBH ₄ (1) Ti (OiPr) ₄ (2) toluene -20 to room Temper. eighteen 41.4 // 58.6 NaBH ₄ (1) Ti (OiPr) ₄ (2) Dme -20 to -15 2 44.9 // 55.7 NaBH ₄ (1) MgCl ₂ (2) THF -20 to room temperature eighteen 44.4 // 55.6 * NaBH ₄ (1) MgCl ₂ (2) Meoh -20 to -15 2 58.1 // 41.99 NaBH ₄ (1) MgCl ₂ (2) iPrOH -20 to -15 2 53.4 // 46.6 NaBH ₄ (1) MgCl ₂ (2) CH ₂ Cl ₂ -20 to room Pace. eighteen 58.2 // 41.8 * NaBH ₄ (1) MgCl ₂ (2) toluene -20 to room Temper. eighteen 47.9 // 52.1 NaBH ₄ (1) MgCl ₂ (2) Dme -20 to -15 one 47.8 // 52.2 NaBH ₄ (1) Al (OiPr) ₃ (2) THF -20 to room temperature 46.5 // 53.5 NaBH ₄ (1) Al (OiPr) ₃ (2) Meoh -20 to -15 one 59.6 // 40.4 NaBH ₄ (1) Al (OiPr) ₃ (2) iPrOH -20 to -15 3 48.6 // 51.4 NaBH ₄ (1) Al (OiPr) ₃ (2) CH ₂ Cl ₂ -20 to -15 3 55.0 // 45.0 * NaBH ₄ (1) Al (OiPr) ₃ (2) toluene -20 to -15 3 52.0 // 48.0 * NaBH ₄ (1) Al (OiPr) ₃ (2) Dme -20 to -15 one 50.4 // 49.6 NaBH ₄ (1) BF ₃ xOEt ₂ (2) THF -20 to room temperature twenty 52.3 // 47.7 * NaBH ₄ (1) BF ₃ xOEt ₂ (2) Meoh -20 to room temperature twenty 57.0 // 43.0 * NaBH ₄ (1) BF ₃ xOEt ₂ (2) iPrOH -20 to room temperature twenty 53.4 // 46.6 * NaBH ₄ (1) BF ₃ xOEt ₂ (2) CH ₂ Cl ₂ -20 to room temperature twenty 60.0 // 40.0 * NaBH ₄ (1) BF ₃ xOEt ₂ (2) toluene -20 to room temperature twenty 61.5 // 38.5 * NaBH ₄ (1) BF ₃ xOEt ₂ (2) Dme -20 to -15 one 41.47 // 58.3 NaBH ₄ (1) MgCl ₂ (2) Meon 0 to 5 0.5 54.0 // 46.0 NaBH ₄ (1) MgCl ₂ (2) Meon -78 to room temperature 0.5 65.9 // 34.1 NaBH ₄ (1) MgCl ₂ (2) THF 0 to room temp. 22 41.0 // 59.0 NaBH ₄ (1) CaCl ₂ (2) Meon 0 to 5 0.5 47.0 // 53.0

NaBH ₄ (1) BaCl ₂ (2) Meon 0 to 5 0.5 50.0 // 50.0 NaBH ₄
(11.1) CeCl ₃ (2) Meon 0 to 5 2 36.9 // 63.1 NaBH ₄ (1) ZnCl ₂ (2) Meon 0 to 5 0.5 61.0 // 39.0 NaBH ₄ (1) ZnCl ₂ (2) Meon -78 to room temperature 2 64.7 // 35.5 NaBH ₄ (1) ZnCl ₂ (2) THF -10 0.25 57.0 // 43.0 NaBH ₄ (1) ZnCl ₂ (2) Et ₂ O -10 0.25 56.0 // 44.0 NaBH ₄ (1) ZnCl ₂ (2) Dme -10 0.25 50.0 // 50.0 NaBH ₄ (1) ZnCl ₂ (2) EtOH -20 to -15 one 64.0 // 36.0 NaBH ₄ (1) ZnCl ₂ (1.5) EtOH -20 to -15 1,5 64.2 // 35.8 NaBH ₄ (1) ZnCl ₂ (1.0) EtOH -20 to -15 1,5 64.7 // 35.3 NaBH ₄ (1) ZnCl ₂ (0.5) EtOH -20 to -15 1,5 64.9 // 35.1 NaBH ₄ (1) ZnCl ₂ (0.3) EtOH -20 to -15 1,5 63.8 // 36.2 NaBH ₄ (1) ZnCl ₂ (0.2) EtOH -20 to -15 1,5 63.2 // 36.8 NaBH ₄ (1) ZnCl ₂ (0.1) EtOH -20 to -15 1,5 63.0 // 37.0 NaBH ₄ (1) absent EtOH -20 to -15 1,0 54.7 // 45.3 Bu ₄ NH ₄ (1) ZnCl ₂ (0.3) Meoh -20 to -15 one 63.9 // 36.1 Bu ₄ NH ₄ (1) Al (OiPr) ₃ (2) Meoh -20 to -15 one 60.5 // 39.5 Bu ₄ NH ₄ (1) ZnCl ₂ (2) EtOH -20 to -15 one 62.7 // 37.3 Zn (BH ₄ ) ₂
(1,0) absent Et ₂ O -78 to room 3 64.9 // 34.1 Zn (BH ₄ ) ₂
(1.4) absent Et ₂ O -78 0.5 59.1 // 40.9 Zn (BH ₄ ) ₂
(1.4) absent THF / Et ₂ O
(1/1) -78 0.5 59.4 // 40.6 Zn (BH ₄ ) ₂
(1.4) absent THF / Et ₂ O
(1/2) -78 0.5 58.4 // 41.6 Zn (BH ₄ ) ₂
(1.4) absent THF / Et ₂ O
(2/1) -78 0.5 62.2 // 37.8 Bu ₄ NVH ₄
(1.1) absent THF -78 2 59.8 // 40.2 Bu ₄ NVH ₄
(1.3) absent CH ₂ Cl ₂ -78 2 39.2 // 60.8 Bu ₄ NVH ₄
(1,1) absent THF / CH ₂ Cl ₂
(1/1) -78 2 66.7 // 33.3 Bu ₄ NVH ₄
(1,1) absent THF / CH ₂ Cl ₂
(1/1) 0 2 52.2 // 47.8 Bu ₄ NVH ₄
(1,1) ZnCl ₂ (2) THF / CH ₂ Cl ₂
(1/1) -78 2 60.7 // 39.3

NaBH (Oac) ₃
(2) ZnCl ₂ (2) THF / Et ₂ O
(2/1) 0 to room 22 52.2 // 47.8 * BH ₃ xSMe ₂
(1,1) absent THF / CH ₂ Cl ₂
(1/1) -78 2 57.7 // 42.3 BH ₃ xSMe ₂
(1,1) ZnCl ₂ (2) THF / CH ₂ Cl ₂
(1/1) -78 2 61.8 // 38.2 Red-Al (1.3) absent CH ₂ Cl ₂ / toluene (1/1) -78 3 52.9 // 48.0 Red-Al (1.3) ZnCl ₂ (2) CH ₂ Cl ₂ / toluene (1/1) -78 3 54.1 // 45.9 * Superhydride®
(1,1) absent THF / CH ₂ Cl ₂ (1/1) -78 2 35.5 // 64.4 Superhydride®
(1,1) ZnCl ₂ (2) THF / CH ₂ Cl ₂ (1/1) -78 2 37.4 // 62.6 Dibah
(1,1) absent THF / CH ₂ Cl ₂ (1/1) -78 2 60.1 // 39.9 * Li (tBuO) ₃ AlH absent THF / CH ₂ Cl ₂ (1/1) -78 2 44.4 // 55.6 Li (tBuO) ₃ AlH ZnCl ₂ (2) THF / CH ₂ Cl ₂ (1/1) -78 2 56.6 // 43.4 Al (OiPr) ₃ (0.5)
iPrOH (7.0) CH ₃ SO ₃ H (0.5) toluene 35-45 1,5 27.9 // 72.1 Al (OiPr) ₃ (0.5)
Binapthol
iPrOH (5.0) absent toluene 20-25 16 25.6 // 74.4 DIBAH (2.0)
Acetone (2.0) absent THF 20-25 16 27.6 // 72.4 DIBAH (2.0)
Acetone (2.0) absent THF / Toluene
(1/1) 20-25 16 27.6 // 72.4 Al (OtBu) ₃ (0.5)
D / L-phenethyl alcohol (2.0) absent toluene 20-25 2 28.0 // 72.0 Al (OtBu) ₃ (0,1)
D / L-phenethyl alcohol (2.0) absent toluene 20-25 6 28.0 // 72.0 Al (OsBu) ₃ (0.5)
sBuOH (7.0) CH ₃ SO ₃ H
(0.5) toluene 20-25 one 25.7 // 74.3 Al (OiPr) ₃ (0.5)
Cyclohexanol
(7.0) CH ₃ SO ₃ H (0.5) toluene 20-25 5 19.6 // 80.4 Al (OtBu) ₃ (0.5)
Cyclohexanol
(7.0) CH ₃ SO ₃ H (0.5) toluene 20-25 3 18.4 // 81.6 Al (OtBu) ₃ (0.5)
Cyclohexanol
(7.0) CH ₃ SO ₃ H (0.5) toluene 0-5 6 14.5 // 85.5 Al (OtBu) ₃ (0.5)
3-pentanol
(7.0) CH ₃ SO ₃ H (0.5) toluene 0-5 3 18.0 // 82.0 Al (OtBu) ₃ (0.5)
9-hydroxyfluorene
(3.4) CH ₃ SO ₃ H (0.5) toluene 0-5 4,5 27.1 // 72.9 Al (OtBu) ₃ (0.5)
9-diphenylcarbinol CH ₃ SO ₃ H (0.5) toluene 0-room temp. 31 11.7 // 88.3

In Table 2, incomplete conversion is indicated by the symbol “*”.

The ratio of the diastereomeric configurations of RR / SS to RS / SR is from about 0.3 to about 2, preferably 1.1 to 2, most preferably 1.2 to 2.

It was found that the best diastereomer ratio (compound VIa, cin RR / SS configuration) diastereoselective reduction reactions give at temperatures above -20 ° C, when the reduction is carried out, for example, NaBH ₄ in MeOH or EtOH in the presence of a catalyst, for example ZnCl ₂ (0, 1-2.0 equivalent). The formation of a diastereomer having an anticonfiguration (compound VIb, RS / SR) is promoted by the Mevervein-Pondorf-Verley reduction. In this case, the ratio of RS / SR to RR / SS is 9.

After almost complete conversion, the reaction can be subjected to a procedure similar to that described in the prior art, by concentrating the reaction mixture and dissolving the residue in a solvent which is not miscible with water, preferably in toluene or MTBE, then washing it successively with an aqueous acid solution, preferably with 2N HCl solution, followed by washing with water and / or an alkaline solution, preferably a solution of NaHCO ₃ . The mixture of diastereomeric products can be purified by column chromatography or used directly for the next step.

It was found that, in contrast to the reduction of compound Vb, the reduction of compound Va occurs with partial cyclization to the corresponding epoxides (compounds VIIa and VIIb, see below).

Step 5 includes the preparation of compound VII from compound VI, as shown in Scheme 13. Non-limiting examples of compound VII include (±) -6-fluoro - [(2R *) - oxiran-2-yl] - (2S *) - chroman (compound VIIa) and (±) -6-fluoro - [(2R *) - oxiran-2-yl] - (2R *) chroman (compound VIIb).

The formation of epoxides of compound VII from halogenomethyl alcohols of compound VI is conveniently carried out in solvents, such as for example ethers and alcohols, with a base such as, for example, hydroxides of alkali and alkaline earth metals, alkoxides of alkali and alkaline earth metals, carbonates of alkali and alkaline earth metals, tertiary amines or alkali metal hydrides. The use of alkali metal alkoxides in alcohols used as a solvent is preferred, and the use of sodium methoxide in methanol as a solvent is most preferred. The temperature for this reaction can vary from about 0 ° C to about 40 ° C, preferably from 15 ° C to 25 ° C. About 1.0-2.0 equivalents of the base can be used, preferably 1.1 equivalents. After completion of the reaction, the excess base is usually neutralized by the addition of acid, preferably acetic acid. The mixture is then concentrated and the residue is dissolved in a suitable solvent, for example, ether or a halogenated hydrocarbon. Washing the resulting solution with a semi-saturated aqueous solution of sodium chloride and concentrating the organic layer afforded the epoxides of compound VII. If the reaction is carried out using a mixture of diastereomeric halogenomethyl alcohols of the formula VI, then a mixture of the corresponding diastereomeric epoxides VII is formed. The diastereomeric mixture of epoxides can be used directly in the next step or separated by column chromatography. In a preferred embodiment of the present method, the mixture is used in the next step without separation of the diastereoisomers.

Step 6 includes the preparation of compound VIII from compound VII, as shown in Scheme 14, and the separation of diastereomers. Non-limiting examples of compound VIII include (±) -2-benzylamino-1- [6-fluoro- (2R *) - chroman-2-yl] - (1S *) - ethan-1-ol (compound VIIIa) and (±) -2-benzylamino-1- [6-fluoro- (2R *) - chroman-2-yl] - (1R *) - ethan-1-ol (compound VIIIb).

Examples of suitable protecting groups (PGs) include hydrogen or a suitable amino protecting group. Preferred are protecting groups that allow the subsequent alkylation step (step 7) to be carried out and can be easily removed at the final stage by a simple deprotection method. Therefore, a preferred PG is an allyl group, a substituted or unsubstituted arylmethyl group. If PG is a benzyl group, the preparation of compound VIII can be carried out in the same manner as described in EP 0145067, but without prior separation of the diastereomeric mixture of compounds VIIa and VIIb. The inventors of the present invention have found that chromatographic separation of oily compounds VIIa and VIIb is not necessary in the present method and that the diastereomeric mixture can be separated by fractional crystallization after conversion to VIIIa and VIIIb. Therefore, in a preferred embodiment, the mixture of VIIa and VIIb is reacted with benzylamine to form the corresponding diastereomeric mixture of compounds VIIIa and VIIIb, which is further separated by fractional crystallization. Since compounds VIIIa and VIIIb possess basic properties, fractional crystallization can be carried out not only with the free amine, but also with the corresponding salt. Compound VIIIa, as well as compound VIIIb are intermediates useful in the preparation of nebivolol and, therefore, the method can be used to selectively produce these two isomers on an industrial scale.

With respect to this strategy for producing nebivolol, the most preferred is the selective preparation and isolation of compound VIIIa.

Typically, an equimolar or enriched diastereomeric mixture of compounds VIIa (syn) and VIIb (anti) with a syn / anti ratio of 1 or more obtained in steps 4 and 5 is treated with an excess of benzylamine (≥ 3 equivalents) in C ₁ -C ₃ alcohol as a solvent at temperatures from about room temperature to about 50 ° C. In a preferred embodiment, the reaction is carried out at 40 ° C. with 3 equivalents of benzylamine in 2-propanol.

After complete conversion, the reaction mixture is cooled to cause crystallization. It has been shown that a solvent preferred for the reaction is also suitable for fractional crystallization. Additional portions can be obtained by additional crystallization of the concentrated mother liquors from the same alcohol or from a mixture of this alcohol with ethers, preferably with diisopropyl ether. An additional increase in the diastereomeric ratio with respect to compound VIIIa can be obtained by recrystallization or suspension in C ₁ -C ₃ alcohols, ethers, toluene, acetonitrile or mixtures thereof.

Starting from a diastereomeric mixture of compounds VIIa and VIIb with a diastereomer ratio of about 57/43, by the above method, it is possible to obtain compound VIIIa containing 5% or less of compound VIIIb.

The relative configuration of the preferred compound VIIIa (see figure 2) is confirmed by the data of x-ray diffraction analysis on a single crystal, as shown below in table 3.

Table 3.
Crystallographic data for compound VIIIa Crystallization from diisopropyl ether / CH ₂ Cl ₂ Empirical formula
Molecular Weight [g ^-1 · mol]
Crystal color, appearance
Crystal Size [mm]
Temperature [K]
Crystal system
space group
Z
Cell Reflections
2θ cell detection interval [°] C ₁₈ H ₂₀ FNO ₂
301.6
colorless prisms
0.15 × 0.20 × 0.25
160 (1)
monoclinic
P2 ₁ / s (# 14)
four
4489
4-60 Cell options a [Å] 4,5882 (1) b [Å] 26,3162 (5) c [Å] 12,4357 (3) α [°] 90 β [°] 92,288 (1) γ [°] 90 V [Å ³ ] 1,500.34 (6) F (000) 640 D _x [g · cm ^-3 ] 1,334 µ (Mo Kα) [mm ^-1 ] 0.0947 Scan type ϕ and ω

2θ (max) [°] 60 The total number of measured reflections 35736 Symmetrically Independent Reflections 4388 R _int 0,061 Reflections with I> 2σ (I) 3005 Reflections Used In Refinement 4386 Refined Parameters 208 Finite R (F) [I> 2σ (I) reflections] 0.0480 wR (F ² ) (all data) 0.1162 Masses: w = [σ ² (F _o ² ) + (0,0419P) ² + 0,2604P] ^-1 , where P = (F _o ² + 2F _c ² ) / 3 Compliance criterion 1,036 Secondary extinction coefficient 0.012 (2) The final Δ _max / σ 0.001 Δρ (max; min) [e Å ^-3 ] 0.24; -0.19 σ (d _(CC) ) [Å] 0.002

Step 7 includes the preparation of compound IX from compounds VIII and V and the separation of the diastereomers of compound IX. Non-limiting examples of compound IX include (±) -2- {benzyl- [2- (6-fluoro- (2R *) - chroman-2-yl) - (2S *) - hydroxyethyl] amino} -1- (6-fluoro - (2S *) - chroman-2-yl) ethanone (compound IXa) (Scheme 15) and (±) -2- {benzyl- [2- (6-fluoro- (2R *) - chroman-2-yl) - (2S *) - hydroxyethyl] amino} -1- (6-fluoro- (2R *) - chroman-2-yl) ethanone (compound IXb) (see Scheme 17).

The reaction of the preferred racemic diastereomer of compound VIIIa with racemic compound V containing the corresponding reactive leaving group (LG) gives a diastereomeric mixture of the new compounds IXa and IXb. The resulting mixture can be separated by column chromatography or fractional crystallization to obtain the desired compound IXa as a suitable intermediate for the synthesis of racemic nebivolol. Since compounds IXa and IXb have basic properties, fractional crystallization can be carried out using a free amine or an appropriate salt.

As described above in step 3, suitable leaving groups (LG) of compound V include halogen, alkylsulfonyloxy groups, substituted or unsubstituted arylsulfonyloxy groups or the like. The preferred leaving groups are halogens and the most preferred leaving groups are bromine (compound Va) and chlorine (compound Vb). Protecting groups (PGs) are described in step 6; the most preferred protecting group is a benzyl group.

The alkylation reactions are conveniently carried out in a suitable inert organic solvent or in a mixture of such solvents and in the presence of a base and an appropriate amount of catalyst. Typical solvents include substituted or halogenated hydrocarbons such as methylene chloride, dichloroethane and the like; ethers, for example THF, dioxane, dimethoxyethane, and polar aprotic solvents, for example DMF, DMA, N-methylpyrrolidone (NMP), dimethyl sulfoxide (DMSO) and the like. Preferred solvents are polar aprotic solvents. 1.0-1.5 equivalents of compound V can be used, preferably 1.1 equivalents. Typical bases include tertiary amines, for example triethylamine, pyridine, alkali metal carbonates, alkali metal hydrogen carbonates or sodium hydride. Preferred bases are alkali metal bicarbonates, and sodium bicarbonate is the most preferred base. 1.5-2.5 equivalents of base can be used, preferably 2.0 equivalents. Typical catalysts for accelerating the reaction include alkali metal halides or tetraalkylammonium halides. If the leaving group is chloride, then the preferred catalysts are bromides and iodides, and the most preferred are sodium bromide and sodium iodide. At least 0.1 equivalents of catalyst can be used, preferably 0.15 equivalents. In a preferred embodiment, the reaction can be carried out at temperatures from about room temperature to about 80 ° C. Lower temperatures can increase reaction time, and higher temperatures can cause adverse reactions. After completion of the reaction, the mixture can be treated with an extraction method known in the art. Evaporation of the solvent after extraction and crystallization of the diastereomeric mixture with a suitable anti-solvent gives the diastereomeric compounds IXa and IXb, which can be isolated by column chromatography or fractional crystallization from a suitable solvent. Since compounds IXa and IXb have basic properties, fractional crystallization can be carried out with a mixture of free amines or the corresponding salts. The separation of the mixture of compounds IXa and IXb can be effectively carried out by fractional crystallization of free amines from acetonitrile as a solvent.

A suitable modification of compounds IXa and IXb may also be applicable for the separation of the diastereomeric mixture. The inventors of the present invention have been surprised to find that diastereomer IXb can be selectively silylated in the presence of diastereomer IXa. Due to the higher solubility of the silylated compound IXb compared to non-silylated compounds, the efficiency of fractional crystallization can be significantly increased. Typically, silylation can be carried out in organic solvents or a mixture of solvents such as ethers, esters, halogenated hydrocarbons, aromatic solvents (e.g. toluene, chlorobenzene, etc.), polar aprotic solvents (e.g. DMF, DMSO), silylating reagent if necessary, in the presence of a base. Preferred organic solvents include acetonitrile, THF, MTBE, and mixtures thereof. If bases are necessary, then amines, for example triethylamine, pyridine, imidazole and the like, alkali metal carbonates or alkali metal hydrogen carbonates can be used. Amines are preferred organic solvents, and imidazole is most preferred. 1.0-2.0 equivalents of base can be used, preferably 1.5 equivalents. As the silylating reagent, TMSCl, HMDS, BSU and the like can be used, but TMSCl is preferred. For successful separation of diastereomers, it is important to use a silylating reagent with a molar ratio of 0.40 / n to 0.60 / n relative to the total number of both diastereomers, where n is the total number of transferred silyl groups per silylating reagent. Fewer equivalents may result in insufficient separation, and more equivalents may result in lower yields. The reaction is usually carried out in a temperature range from about 0 ° C to about room temperature. Lower temperatures can increase reaction time, and higher temperatures can lead to insufficient selectivity.

As regards this strategy for producing nebivolol, it is preferable to isolate compound IXa from a mixture consisting of IXa and IXb, fractional crystallization or selective modification of IXb followed by crystallization of IXa. The term “substantially pure diastereomers,” as used herein, means diastereomers of at least 50% purity, preferably 80% purity, and more preferably 95% purity.

The NMR data recorded for the isolated diastereomers indicate that both isomers cyclize to a semi-ketal form. ¹³ C NMR spectra show that instead of the peaks of the carbonyl group, the spectra have new peaks at 94,616 and 94,707, respectively, which indicate a carbon atom of cyclic semi-ketal form (see Schemes 16 and 17 and Figures 3 and 4).

The relative configuration of the preferred compound IXb` is confirmed by X-ray diffraction analysis on a single crystal, as shown in table 4 below.

Table 4.
Crystallographic data of compound IXb` Crystallization from Mecn Empirical formula C ₂₉ H ₂₉ F ₂ NO ₄ Molecular Weight [g · mol ^-1 ] 493.55 Crystal color, appearance colorless prisms Crystal Size [mm] 0.25 × 0.25 × 0.28 Temperature [K] 160 (1) Crystal system monoclinic space group P 2 ₁ / n (# 14)

Z four Cell Reflections 5882 2θ cell detection interval [°] 4-55 Cell options a [Å] 14,0502 (3) b [Å] 11.3937 (3) c [Å] 15,5302 (3) α [°] 90 β [°] 100,145 (1) γ [°] 90 V [Å ³ ] 2447.3 (1) F (000) 1040 D _x [g · cm ^-3 ] 1,339 µ (Mo Kα) [mm ^-1 ] 0.0986 Scan type ϕ and ω 2θ (max) [°] 55 The total number of measured reflections 54789 Symmetrically Independent Reflections 5601 R _int 0,057 Reflections with I> 2σ (I) 4092 Reflections Used In Refinement 5598 Refined Parameters 330 Finite R (F) [I> 2σ (I) reflections] 0.0468 wR (F ² ) (all data) 0.1252

Masses: W = [σ ² (F _o ² ) + (0,0616P) ² + 0,3697P] ^-1 , where P = (F _o ² + 2F _c ² ) / 3 Compliance criterion 1,052 Secondary extinction coefficient 0.012 (2) The final Δ _max / σ 0.001 Δρ (max; min) [e Å ^-3 ] 0.27; -0.21 σ (d _(CC) ) [Å] 0.002

Step 8 involves the preparation of compound X, as shown in Scheme 18. Non-limiting examples of compound X include (±) - [2R * [R * [R * (S *)]]] - α, α` - [[(phenylmethyl) imino ] bis (methylene)] - bis [6-fluorochroman-2-methanol] (intermediate Xa) and (±) - [2R * [S * [R * (S *)]]] - α, α` - [[ (phenylmethyl) imino] bis (methylene)] bis [6-fluorochroman-2-methanol] (compound Xb). A variety of reducing agents can be used to reduce compound IXa, wherein two racemic diastereomers can form RSSS / SRRR configurations (compound Xa) or RSRS configurations (compound Xb). Regarding the synthesis strategy of nebivolol, as shown in Schemes 6 (a) and 18, reduction methods are preferred that lead to the formation of an excess of compound Xa. There are very few studies on the selective reduction of chiral 1-hydroxy-5-keto compounds regulated by stereogenic centers at remote positions of the chain (distance of 4 or more atomic centers; Tetrahedron Letters, 35 (1994), 4891-4894), Tetrahedron Letters 40 (1999) 593-596, J. Org. Chem. 63 (1998) 7964-7981). In contrast to the compounds described in the above studies, compound IXa contains three asymmetric centers, especially at positions 1-2, as well as at positions 1-5 and 1-6, which can regulate diastereoselectivity when restoring the keto group.

PG may be hydrogen or an amino protecting group as defined above. Preferred are the same protecting groups that have already been described for steps 6a-c and 7.

In principle, there are no restrictions on the use of borohydride or aluminum hydride reducing agents, which can be selected, for example, from LiBH ₄ , NaBH ₄ , KBH ₄ N (nBu) ₄ BH ₄ , Zn (BH ₄ ) ₂ , NaH (Oac) ₃ , Superhydride® ( sodium triethyl borohydride), Red-Al® (sodium bis (2-methoxyethoxy) aluminum hydride), Li-Selectride® (tri-sec-butyl borohydride, Li, K), BH ₃ x SME ₂ or the like, or such reagents that are applicable for restoration according to Meerwein-Pondorf-Verley. However, it should be borne in mind that the reaction of reduction according to Meerwein-Pondorf-Verley is reversible (Oxidation according to Oppenauer). Since compound Xa contains two secondary alcohol groups which may be in equilibrium oxidation / reduction with a reducing agent, a mixture of three diastereomers (benzylated nebivolol (RSSS / SRRR) and two of their mesoforms (RSRS and RRSS) can be formed.

In order to prevent such adverse reactions, the hydroxyl group of compound IXa can be protected before reduction according to Meerwein-Pondorf-Verley. Another possibility is the continuous distillation of the ketone (for example, acetone, if isopropanol is used as a hydride donor).

The catalytic hydrogenation of compound IXa may be an additional option, but if PG is a protecting group that is unstable upon reduction (e.g. benzyl), then deprotection should be taken into account.

Reduction reactions can be carried out in the absence or in the presence of Lewis acids selected from MgCl ₂ , CaCl ₂ , BaCl ₂ , ZnCl ₂ Al (Oalkyl) ₃ , Ti (Oalkyl) ₄ BF ₃ xOEt ₂ , etc. Suitable solvents are ethers, alcohols, halogenated hydrocarbons or the like, except that halogenated solvents are not suitable for catalytic reduction reactions. Recovery is conveniently carried out at temperatures from -20 ° C to room temperature. Although selectivity can increase at lower temperatures, the reaction time will increase, and higher temperatures can lead to a decrease in selectivity. Table 5 presents typical results of the selective reduction of compound IXa.

Table 5 Reagent (equiv.) Catalyst (eq.) Solvent Temperature [° C] Time [h] Attitude
RSSS / SRRR
// RSRS NaBH ₄ (1) absent THF / EtOH / H ₂ O Room temp. 3 50 // 50 LiBH ₄ (1) absent THF 0-5 5 70 // 30 LiBH ₄ (1) Ti (OiPr) ₄ (2) THF -20 to room temp. 3 78 // 22 LiBH ₄ (1) Ti (OiPr) ₄ (2) THF 0-5 2 82 // 18 Zn (BH ₄ ) ₂ (1) absent Et ₂ O / THF room temper 3 77 // 23 * KBH ₄ (1) ZnCl ₂ (2) MeOH / THF 0-5 2 83 // 17 * K-selectride (2) absent THF 0-5 3 84 // 16 K-selectride (4) Ti (OiPr) ₄ (2) DCM / THF 0-5 3 83 // 17 * KBH ₄ (1) LiCl THF 0-5 eighteen 70 // 30 Bu ₄ BH ₄ (1) absent THF 0-room temp. 24 94.4 // 5.6 KBH ₄ (1) Ti (OiPr) ₄ (2)
Diglyme (3) THF 0-room temp. 26 94.5 // 4.5 KBH ₄ (1) Ti (OiPr) ₄ (2) Dme 0-room temp. 26 94.5 // 4.5

In Table 2, incomplete conversion is indicated by the symbol “*”.

The ratio of diastereomeric RSSS / SRRR configurations to RSRS is from about 1 to about 20, preferably 2-20, most preferably 4-20.

After complete conversion, the reaction mixture can be processed in a standard manner. The diastereomeric mixture of products can be separated by column chromatography or fractional crystallization. Since compounds Xa and Xb have basic properties, salt formation before fractional crystallization is an additional possibility. A mixture of diastereomeric products can also be used in the next step as a crude product without further purification.

Step 9 includes the preparation of the hydrochloride (±) - [2R * [R * [R * (S *)]]] - α, α`- [iminobis (methylene)] bis [6-fluorochroman-2-methanol] (compound I ) and separation from the by-product of the hydrochloride (±) - [2R * [S * [R * (S *)]]] - α, α`- [iminobis- (methylene)] bis [6-fluorochroman-2-methanol] as shown in diagram 19.

The final steps for the preparation of nebivolol racemic hydrochloride include deprotection, salt formation and fractional crystallization purification to remove by-products, mainly of the undesired diastereomer, having an RSRS configuration.

PG can be the same groups as already described above, and if PG is a group other than hydrogen, deprotection can be carried out by known methods. Since benzyl groups are most preferred, deprotection can be carried out by catalytic hydrogenation. If compound Xa contains compound Xb as a by-product, then purification can be carried out by fractional crystallization. Since compounds Xa and Xb, after deprotection, possess basic properties, fractional crystallization can be carried out after the formation of the corresponding salt. It was found that a mixture consisting of nebivolol and its RSRS diastereomer can be easily separated by fractional crystallization after formation of a salt with HCl or any other pharmaceutically acceptable salt.

Compound I can be converted into its pharmaceutically acceptable non-toxic acid addition salt, which is formed by treatment with appropriate acids, such as, for example, inorganic acids, such as hydrohalic acid, for example, hydrochloric, hydrobromic and the like, sulfuric acid, nitric acid, phosphoric acid and the like; or organic acids, such as, for example, acetic, propanoic, hydroxyacetic, 2-hydroxypropanoic, 2-oxo-propanoic, ethanedioic, propanedioic, butanedioic, (Z) -2-butanedioic, (E) -2-butanedioic, 2-hydroxybutanedioic, 2 , 3-dihydroxybutanedioic, 2-hydroxy-1,2,3-propanetricarboxylic, methanesulfonic, ethanesulfonic, benzenesulfonic, 4-methylbenzenesulfonic, cyclohexanesulfamic, 2-hydroxybenzoic, 4-amino-2-hydroxybenzoic and the like acids.

Salt formation with HCl is preferred for fractional crystallization, providing a pharmaceutically acceptable nebivolol hydrochloride salt. Fractional crystallization can usually be carried out in suitable solvents in which nebivolol is less soluble than its RSRS diastereomer. Alcohols are preferred as solvents for fractional crystallization, and methanol is the most preferred solvent.

STAGES OF RECYCLING DIASTEROMERS

The present invention also includes the steps of recycling diastereomers formed during the process.

I. Possibilities for recycling intermediates formed in stage 5 and stage 6

A non-limiting example of recirculation is illustrated in Scheme 20, where Cl is used as a leaving group.

The recycle step can be carried out using, for example, the Mitsunobu reaction to invert the secondary alcohol group to recycle the undesired diastereomer VIIIb formed in step 6. However, a suitable protecting group (PG`) for the nitrogen-containing group may be required. One skilled in the art will appreciate that examples of the introduction of suitable PG` protecting groups include the formation of the corresponding carbamates, for example, by the action of alkyl chloroformates, or the formation of the corresponding amides by the action of acid chlorides or carboxylic anhydrides. The protective group can be introduced after separation of the diastereomeric mixture by fractional crystallization, followed by isolation of the undesired diastereomer from the mother liquors.

II. The possibility of recycling the compounds formed in stage 7

In step 7, a mixture of two diastereomers (compounds IXa and IXb) is formed, which are separated by fractional crystallization. There are two possibilities for recycling the undesired diastereomer IXb (Scheme 21, Tables 6, 7, 8). The first possibility is the epimerization of the undesired diastereomer IXb again with the formation of a mixture consisting of IXa and IXb, which can be separated as described above.

Table 6.
Studies of epimerization in various solvents containing 10% 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), starting from an IXa / IXb ratio of about 23/77. Solvent Temperature [° C] compound ratio
IXa / IXb compound ratio
IXa + IXb / VIIIa Meoh Room temp. 69/31 20/80 DMF Room temp. 53/47 85/15 Acn Room temp. 53/47 71/29 THF 40 53/47 61/39 AcOEt 40 54/46 74/26 Toluene 40 55/45 81/19

The mixtures were analyzed by HPLC after 40 hours. The results presented in table 6 show that the cleavage of compounds IXa / IXb in methanol with the formation of compound VIIIa occurs faster than epimerization. In all other solvents, after 40 hours, epimerization gave a mixture of diastereomers IXa and IXb (almost 1/1), while the tendency to cleavage to form compound VIIIa was clearly suppressed especially in solvents such as DMF and toluene. The results of additional studies of epimerization in DMF and toluene are shown in tables 7 and 8.

Table 7.
Epimerization studies in DMF containing 5% 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) at 30 ° C, starting from an IXa / IXb ratio of about 23/77. Mixtures were analyzed by HPLC. Time [h] compound ratio
IXa / IXb compound ratio
IXa + IXb / VIIIa one 28/72 98.3 / 1.7 2.5 31/69 97.4 / 2.6 5.5 37/63 95.6 / 4.4 22.5 50/50 91.3 / 8.7 45.5 54/46 87.8 / 12.2

Table 8.
Epimerization in toluene containing 5% 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) at 30 ° C, starting from the IXa / IXb ratio of about 23/77. Mixtures were analyzed by HPLC. Time [h] compound ratio
IXa / IXb compound ratio
IXa + IXb / VIIIa one 24/76 99.7 / 0.3 5.5 27/73 99.4 / 0.6 22.5 33/67 98.3 / 1.7 45.5 43/58 96.0 / 4.0

A second recycle possibility involves splitting the undesired diastereomer IXb to form a mixture of compound VIIIa and certain by-products. The cleavage can be carried out by tautomeric conversion of aminoketone into enamine form, followed by hydrolysis by known methods. Compound VIIIa can then be isolated and reintroduced into the process, as shown in Scheme 21.

III. Alternative synthesis of nebivolol using diastereomer VIIIb

Although in accordance with the above synthesis strategy, it is preferable to obtain diastereomer VIIIa as an intermediate, the undesired diastereomer VIIIb can also be used as an intermediate for the preparation of racemic nebivolol, as shown in Scheme 22.

Other similar recycling methods are possible. For example, unlike the way in which the preferred compound VIIIa is used, the use of compound VIIIb gives, after the alkylation step, a diastereomeric mixture of compounds IXc and IXd. The reduction of compound IXd after deprotection gives nebivolol and a second meso form having the RRSS configuration (as opposed to the preferred pathway that leads to the formation of the meso form having the RSRS configuration). As indicated above, the mesoform having the RSRS configuration has a higher solubility than the second mesoform having the RRSS configuration, and therefore, nebivolol contaminated with RSRS diastereomer (in the preferred way) can be easily purified by recrystallization. In the case of contamination of nebivolol with the meso-form of the RRSS configuration, purification can also be carried out by recrystallization, but since the solubilities of the RRSS of the diastereomer and nebivolol are close, purification is much more difficult and lower yield must be taken into account.

IV. Recirculation of Meso-Forms of Nebivolol (RSRS and RRSS)

Both meso forms of nebivolol obtained by the above methods can be converted directly to nebivolol after suitable protection (e.g., cyclic carbamate, cyclic silyl group, etc.), subsequent inversion of the secondary alcohol group (e.g., Mitsunobu reaction) and deprotection as shown in diagram 23.

Reactions for protection, deprotection and inversion can be carried out by methods known in the art.

Although the described methods reduce costs and increase efficiency by recycling the undesired diastereomer, they still require additional steps to recycle and isolate the desired compounds. To reduce costs and environmental impacts, further refinements have been made to the process for preparing compounds IXa / IXa`, as described below.

In addition, it was found that under certain conditions additional enrichment promoting the formation of IXa can be achieved by epimerization of an equimolar mixture of IXa and IXb, which leads to a more efficient method than the recycling methods described above. Such an increase in the ratio of the desired diastereomer to the undesired diastereomer in the mixture leads to an increase in yield and volumetric yield and promotes the isolation of IXa by fractional crystallization. And finally, this method also reduces waste and shortens the production time.

Thus, the invention relates to new methods and conditions for increasing the ratio of diastereomers IXa and IXb in stage 7 (Figure 6) from about 1: 1 to 9: 1 before performing isolation of IXa (see figures 7-9).

An increase in the diastereomeric ratio can be obtained using a simultaneous epimerization-crystallization technique, including the epimerization of a mixture of compounds IXa and IXb in a ratio of about 1: 1, in the presence of a suitable base and in an organic solvent in which the solubility of compound IXa is slightly worse than the solubility of IXb. Figure 7 shows the simultaneous epimerization-crystallization, which is a dynamic process of increasing the diastereomeric ratio and obtaining the desired diastereomer (compounds IX are shown in acyclic forms).

The protecting group (PG) may be any suitable amino protecting group. PG is preferably selected from an allyl group or a substituted or unsubstituted arylmethyl group; most preferred (PG) is the benzyl group (Bn). Suitable bases for epimerization may be selected from alkoxides, amidines, guanidines or phosphazenes, the preferred bases are amidines, such as, for example, diazabicycloundecene (DBU), diazabicyclononene (DBN), and the most preferred base is DBU. The base can be used in an amount of at least 0.05 equivalent and 0.25 equivalent preferably. Epimerization is preferably carried out in the temperature range from 20 ° C to 70 ° C and most preferably in the range from 40 ° C to 70 ° C. Lower temperatures can also be used, but they increase the reaction time, and higher temperatures can lead to a high rate of degradation. Epimerization can also be carried out under isothermal conditions, but it is preferable to slowly cool the mixture in the indicated temperature range. The organic solvent can be selected from solvents in which a suspension can be formed in the indicated temperature range for simultaneous crystallization-epimerization according to the invention. Suitable solvents are usually selected from aprotic solvents, for example aromatic solvents, ethers, esters, amides or nitriles or protic solvents, such as, for example, alcohols. Acidic solvents that inactivate the base by salt formation are preferably excluded. Aprotic solvents are preferred and acetonitrile is the most preferred solvent. Since the presence of water can cause degradation of compounds IXa and IXb, it is also preferable to use solvents in which the water content is less than 1.0% and most preferably less than 0.1%.

The reaction is conveniently carried out by slowly cooling a suspension containing equimolar amounts of compounds IXa and IXb in the presence of a base. Compound IXa, in which the amount of undesired diastereomer is less than 1%, can be isolated in up to 74% yield and in only one step without the need for several crystallizations, selective modifications or additional recycling steps, as described above.

Thus, simultaneous epimerization-crystallization involves the simultaneous (a) epimerization of a mixture consisting of compounds IXa and IXb in the presence of a suitable base and in an organic solvent, and (b) promotes crystallization of IXa from the mixture. It is necessary that, during epimerization, compound IXa is removed from the equilibrium system by simultaneous crystallization. Epimerization studies were carried out in solution and not in suspension.

The simultaneous epimerization-crystallization procedure for the synthesis of compound IXa is superior to the crystallization and recycling methods described above, since IXa is obtained by the selective modification method with a yield of only 41% compared with a yield of 74% by the simultaneous epimerization-crystallization method. To obtain the same yield by other methods, it is necessary to carry out several stages of recycling, which requires more time, reagents and gives more waste. In addition, small amounts of IXa / IXb compounds that are lost in the new process during IXa isolation can be easily removed from the mother liquor and reused for the next epimerization experiment. The recovery of the lost substance and its use in the next experiment further increases the efficiency of the method of simultaneous epimerization-crystallization.

The method of simultaneous epimerization-crystallization will now be described using figure 8 as an example. Figure 8 shows the epimerization of a mixture of compounds IXa and IXb, where PG is a benzyl group (Bn). Compounds IXa and IXb are shown in an open chain form (acyclic form). In the solution, the acyclic forms IXa and IXb are in equilibrium with the corresponding cyclic forms IXa 'and IXb'. Epimerization requires an acyclic form that contains an acidic proton at the chiral center in the alpha position to the carbonyl group.

A suspension of the mixture consisting of compounds IXa and IXb in an almost equimolar ratio is heated in acetonitrile to an internal temperature of 70 ° C. After cooling to 60 ° C., DBU (0.25 equiv.) Was added and epimerization was carried out, cooling the mixture to 40 ° C. using the temperature gradient described in Table 9.

Table 9 Time [h] internal temperature [° C] 0 60 0.5 55 1,5 fifty 5.5 fifty 5.75 45 8.5 45 8.75 40 13.5 40

The reaction was stopped by the addition of acetic acid (0.25 equiv.) And the mixture was cooled to 25 ° C. The crude product is isolated by filtration and further purified by suspension in acetonitrile. Filtration is carried out after simultaneous epimerization-crystallization is completed to isolate IXa. The formation of a suspension in acetonitrile is only an additional purification step to remove any remaining impurities and small amounts of undesired diastereomer. Table 10 shows the successful epimerization controlled by continuous process control (IPC) (HPLC).

Table 10 IPC Time [h] Temperature [° C] the attitude
IXa / IXb one 0 - 50.8 / 49.2 (starting material) 2 0.5 55.5 56.1 / 43.9 3 1,5 fifty 62.9 / 37.1 four 2.5 fifty 66.3 / 33.7 5 3,5 fifty 71.0 / 29.0 6 4,5 fifty 75.1 / 24.9 7 5.5 fifty 78.7 / 21.3 8 7.5 45 85.0 / 15.0 9 8.5 45 87.3 / 12.7 10 9.5 40 82.0 / 18.0 eleven 10.5 40 85.2 / 14.8 12 11.5 40 89.7 / 10.3 13 13.5 40 89.2 / 10.8

Since the decomposition of IXa / IXb during epimerization is promoted by H ₂ O, it is preferable that the starting material as well as acetonitrile be almost anhydrous (Table 11). The IXa / IXb mixture was incubated at 50 ° C. in the presence of 0.25 equiv. DBU and various amounts of H ₂ O. The amount of remaining IXa / IXb is determined periodically by HPLC. The results are shown in table 11.

Table 11 % H ₂ O in ACN (V / V) 2 h 7 h 22 h 0.01 91% 86% 73% 0.2 91% 86% 75% 1,0 89% 81% 66%

Temperatures above 70 ° C should be avoided for more than 30 minutes, since IXa / IXb is not completely stable at temperatures above 70 ° C. Decomposition and epimerization is monitored when IXa suspension in ACN is mixed for 21 hours at the appropriate temperature, as shown in Table 12.

Table 12 Temperature [° C] Decomposition [%] Epimerization [%] ¹⁾
(IXa-> IXb) 75-78 6.8 5,6 65 0.8 0.2 fifty Undefined Undefined

¹⁾ Since the decomposition rate of IXa and IXb may be different, it is not known whether the change in the ratio is caused by a faster decomposition of IXa, rather than epimerization.

Figure 9 shows a method for producing racemic nebivolol and its pharmaceutically acceptable salts, where step 7b depicts the simultaneous epimerization-crystallization step of the invention.

The parameters of the simultaneous epimerization-crystallization step of the invention are selected based on the understanding that the solubility of compound IXa is lower than the solubility of compound IXb. Thus, it was found that IXa can crystallize and therefore be removed from equilibrium, although in solution the equilibrium of both diastereomers can be regenerated by epimerization of the undesired IXb diastereomer in the presence of a base. The equilibrium was studied at various temperatures in the presence of some base in a certain solvent at certain cooling rates. Cooling is necessary to complete crystallization and optimize yield. Since cooling reduces the solubility of both diastereomers, conditions are created for additional crystallization conducive to the desired diastereomer. Since epimerization is slower at lower temperatures, equilibrium is also regulated more slowly. A balanced relationship is obtained between the rate of epimerization to adjust the equilibrium in solution and the cooling of the mixture, which promotes the crystallization of IXa. Therefore, the temperature gradient (as shown in table 9 and below in examples 19 and 20), it is necessary to maintain a balanced relationship between the rate of epimerization and crystallization stages. Since higher temperatures can also cause degradation of compounds IXa and IXb, which is facilitated by the presence of water, the conditions for epimerization of crystallization have to be sought when degradation is minimized in order to prevent a decrease in yield.

The invention will be illustrated in more detail with reference to the following examples, but it should be understood that the present invention is not considered limited by them.

EXAMPLES

Example 1

Step 1. Preparation of ( + ) -5- [6-fluorochroman-2-carbonyl] -2,2-dimethyl [1,3] dioxane-4,6-dione (compound III).

In a nitrogen atmosphere, thionyl chloride (109.21 g, 918 mmol) is added at 20-25 ° C to a suspension of 6-fluorochroman-2-carboxylic acid (90.00 g, 459 mmol) and DMF (1.68 g, 23 mmol) in toluene (635 ml). Then the suspension is heated to an internal temperature of 60-70 ° C and get a clear yellow solution with simultaneous evolution of gas. At this temperature, the reaction is completed in 70 minutes, after which the mixture is concentrated in vacuo (bath temperature 45-50 ° C, pressure ≤35 mbar) and chroman-2-carboxylic acid chloride is obtained as a yellow oil (112.65 g). The crude product is dissolved in methylene chloride (65 ml) and slowly added in a nitrogen atmosphere to a solution of Meldrum acid (70.90 g, 482 mmol) and pyridine (72.62 g, 918 mmol) in methylene chloride (261 ml) at an internal temperature of 0- 10 ° C. The reaction mixture was allowed to warm to 20-25 ° C for 50 minutes and stirred at this temperature for an additional 30 minutes. Then, methylene chloride (325 ml) and water (325 ml) are added to the resulting brown suspension. The biphasic mixture was stirred for 5 min, separated and the organic layer was then extracted with water twice (200 ml each time), then with 2N aqueous HCl (250 ml) and finally with water (250 ml). After drying over Na ₂ SO _{4, the} organic layer was filtered and concentrated in vacuo (≤50 mbar) to give a brown viscous oil (170.76 g), which crystallized after 10 minutes at room temperature. The solid is suspended in diisopropyl ether (500 ml) at 20-25 ° C. for 2 hours. After filtering the suspension, the wet product is washed with diisopropyl ether (70 ml) and dried in vacuo (13 hours at 40 ° C.) to obtain a color solid yellow ocher (yield: 114.71 g; HPLC purity: 96.98%).

Example 2

Step 2, path A. Preparation of (±) -1- (6-fluorochroman-2-yl) ethanone (compound IVa).

Example 1 is reproduced with 16 g of 6-fluorochroman-2-carboxylic acid and the residue obtained after processing and evaporation of methylene chloride is used directly for step 2, path A. A mixture of the crude product (compound III) thus obtained with water (40 ml) and acetic acid (40 ml) is heated for 70 minutes at the boil under reflux and then cooled to room temperature. The reaction mixture was extracted with methylene chloride (40 ml) and the organic layer was washed twice with 1 N aqueous NaOH solution (20 ml each time). After drying over MgSO _{4, the} organic layer was filtered and evaporated. The residue was purified by silica gel column chromatography using ethyl acetate / cyclohexane (1/3 by volume) as an eluent. A second fraction was collected, the solvent was evaporated, and the product was obtained as a yellow oil (yield: 11.89 g, HPLC purity: 98.76%).

Example 3

Step 2, Route B. Preparation of (±) -3- (6-fluoro-chroman-2-yl) -3-oxopropionic Acid Ethyl (Compound IVb as Ethyl Ester)

Example 1 is reproduced with 16 g of 6-fluorochroman-2-carboxylic acid and the residue obtained after treatment and evaporation of methylene chloride is used directly for step 2, path B. A suspension of this crude product (compound III) in ethanol (150 ml) is heated under reflux under reflux for 75 minutes, the result is a clear solution. After cooling the solution to room temperature and evaporation, the residue was partitioned between methylene chloride (80 ml) and water (80 ml). The phases were separated and the organic layer was extracted with 1 N aqueous NaOH solution (40 ml). The methylene chloride solution was dried over MgSO ₄ , filtered and evaporated. The residue was purified by silica gel column chromatography using ethyl acetate / cyclohexane (1/4 by volume) as an eluent. The first fraction was collected, the solvent was evaporated, and the product was obtained as a tan oil (yield: 11.89 g, HPLC purity: 92.45%).

Example 4

Step 2, Path B. Preparation of (±) -3- (6-fluoro-chroman-2-yl) -3-oxopropionic acid tert-butyl ester (compound IVb as tert-butyl ether)

tert-Butanol (83.90 g) was added at room temperature to a suspension of compound III (94.00 g) (obtained by the method described in example 1) in toluene (280 ml). The suspension is heated to an internal temperature of 70-80 ° C, the result is a clear solution with simultaneous evolution of gas. The reaction is completed in 80 minutes. The mixture was cooled to room temperature and extracted sequentially with a solution of NaHCO ₃ (235 ml) and a saturated solution of NaCl. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give the product as an orange-brown oil (yield: 95.79 g, HPLC purity: 97.20%; the crude product contained small amounts of toluene). The crude product is used in the next step without further purification.

Example 5

Step 3, Route A. Preparation of (±) -2-bromo-1- (6-fluorochroman-2-yl) -ethanone (Compound Va).

TMSCl (3.2 ml) was added to a solution of 2 M LDA (9.0 ml) in 20 ml of THF at -78 ° C for 10 minutes. Then a solution of compound IVa (3.0 g) (obtained by the method described above in Example 2) in THF (3 ml) is added, after 10 minutes the reaction mixture is allowed to warm to room temperature over 40 minutes. The precipitated white solid and the precipitate were partitioned between cyclohexane (100 ml) and cold 10% NaHCO ₃ solution (60 ml). The aqueous layer was diluted with water (20 ml) and separated. The organic layer was extracted twice with 10% NaHCO ₃ solution (30 ml each time), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was dissolved in methylene chloride (15 ml) and cooled to an internal temperature of 0-5 ° C. To the resulting mixture was added a suspension of NBS (2.94 g) in methylene chloride (10 ml). After stirring for 1.5-2 hours at the indicated temperature, the reaction mixture was poured into a 10% solution of NaHCO ₃ (15 ml), the organic layer was separated and concentrated. The residue was purified by silica gel column chromatography using ethyl acetate / cyclohexane (1/5 by volume) as eluent. The first fraction was collected, the solvent was evaporated, and a product mixture was obtained consisting of compound Va (78.1% by HPLC) and the corresponding by-product (VaBP1),

which is formed by non-selective bromination followed by elimination in the form of a tan oil (yield: 2.17 g, since compound Va is apparently less stable than compound Vb, it should preferably be stored in the dark at -20 ° C) .

Example 6

Step 3, path B: Preparation of (±) -2-bromo-1- (6-fluorochroman-2-yl) ethanone (compound Va).

N-Bromosuccinimide (NBS) (5.04 g) was added in portions at 5-10 ° C to a solution of tert-butyl ether of compound IVb (10.0 g) (obtained by the method described in example 4) and Mg (ClO ₄ ) ₂ (2.32 g) in ethyl acetate (100 ml). Subsequently, the reaction is monitored by HPLC. After addition, the mixture was stirred at 5-10 ° C for 45 minutes. After 16% of the adduct remained, an additional amount of NBS (1.0 g) was added. The mixture is stirred for 20 minutes at 5-10 ° C, then allowed to warm to room temperature and stirred for 20 minutes at this temperature. The precipitate was filtered off and the mother liquor was concentrated in vacuo to give 2-bromo-3- (6-fluorochroman-2-yl) -3-oxopropionic acid tert-butyl ester as a red oil (15.3 g). To carry out hydrolysis and decarboxylation, red oil is dissolved in acetic acid (42 ml) and formic acid (49 ml) and the mixture is heated to an internal temperature of 80-85 ° C, while gas evolution is observed. After 60 minutes, the reaction was completed and the mixture was concentrated in vacuo to give a brown oil. The oil was then dissolved in ethyl acetate (50 ml) and n-hexane (50 ml), and the solution was extracted successively with twice a half-saturated NaCl solution (20 ml each time) and a saturated solution of NaHCO ₃ (20 ml). The organic layer was dried over MgSO ₄ , filtered and concentrated in vacuo to give an amber-colored oil, which was dissolved in cyclohexane. Crystallization is caused by seeding at room temperature. After 45 minutes, the suspension was filtered to give compound Va (2.98 g, beige solid) after drying. Additional amounts of compound Va (1.9 g) were obtained from the mother liquor after stirring at 6-7 ° C for 1.5 hours, filtering and drying (total yield: 4.88 g, HPLC purity: 98.5%; since compound Va is apparently less stable than compound Vb, it should preferably be stored in the dark at a temperature of -20 ° C).

Example 7

Stage 3, path B: Preparation of (±) -2-chloro-1- (6-fluorochroman-2-yl) ethanone (compound Vb)

At room temperature, Mg (ClO ₄ ) ₂ (21.40 g) was slowly added to a solution of tert-butyl ether compound IVb (105.59 g) (obtained by the method described in example 4) in ethyl acetate (800 ml). Then, NCS (41.80 g) was added in portions at 20-25 ° C over 3.5-4 hours, and the reaction was subsequently monitored by HPLC. After completion of the addition, the yellow suspension is stirred for 30 minutes at 20-25 ° C. and then filtered. The filter layer was washed with ethyl acetate (100 ml) and the combined filtrates were extracted sequentially with saturated NaCl (150 ml) and water (150 ml), then concentrated in vacuo (60 mbar) to give a brown oil (116.82 g). For hydrolysis and decarboxylation, brown oil is dissolved in a mixture of acetic acid (420 ml), formic acid (390 ml) and water (80 ml). The solution is heated to an internal temperature of 80-90 ° C, while gas evolution is observed. After completion of the reaction (within 2 hours), the solution was concentrated in vacuo ( < 30 mbar) to obtain a dark orange oil (83.25 g), which was dissolved in ethyl acetate (400 ml). The resulting solution was sequentially extracted with a half-saturated NaCl solution (300 ml), saturated NaHCO ₃ solution (300 ml) and water (100 ml). After drying over Na ₂ SO _{4, the} suspension is filtered and concentrated, first obtaining a red oil (80.00 g), which slowly crystallizes at room temperature. For further purification, the crude product (77.0 g) is dissolved in isopropanol (240 ml) at an internal temperature of 45-50 ° C. The solution is seeded to cause crystallization, and cooled to 0-5 ° C. After 75 minutes of stirring at 0-5 ° C, the suspension is filtered and the filter layer washed with cold isopropanol (40 ml). The wet product was dried in vacuo at 35-40 ° C to give a yellowish solid (57.13 g, HPLC purity: 99.00%).

Example 8

Stage 1-3. Preparation of (±) -2-chloro-1- (6-fluorochroman-2-yl) ethanone (compound Vb) from 6-fluorochroman-2-carboxylic acid (II)

A mixture of 6-fluorochroman-2-carboxylic acid (114.4 g, assay = 99%, 577 mmol), thionyl chloride (83.15 g, 692 mmol) and DMF (2.18 g, 30 mmol) in toluene (471 g ) slowly heated in an atmosphere of nitrogen to an internal temperature of 70-80 ° C (at an internal temperature of 57 ° C gas evolution begins). When the reaction is complete (within 40 minutes at 78 ° C, HPLC analysis shows 98.6% of the corresponding acid chloride), 208 g of solvent are distilled off in vacuo (pressure: 220 (initial) - 155 (final) mbar, internal temperature: 73 ( initial) - 69 (final) ° С, vapor temperature: 39 (initial) - 63 (final) ° С). Meldrum acid (89.1 g, 606 mmol), pyridine (89 ml, 1.11 mol) and methylene chloride (375 ml) were charged into a second flask. Then the mixture is cooled to an internal temperature of 0-5 ° C, the previously prepared solution of 6-fluorochroman-2-carboxylic acid chloride in toluene at an internal temperature of 0-5 ° C is slowly added. The reaction mixture was allowed to warm to 20 ° C for 80 minutes (during the reaction, HPLC showed 92.6% of the product). Tert-butanol (81.0 g, 1.08 mol) is slowly added to the mixture, and the mixture is slowly (over 4 hours) heated to an internal temperature of 70-80 ° C. while the solvent is distilled off and gas is isolated. During heating (after 75 minutes and at an internal temperature of 56 ° C) an additional amount of tert-butanol (75 g, 1.00 mol) is added. Distillation and gas evolution cease when the internal temperature reaches 70-80 ° C (by this time 370 g of solvent is distilled off). When the HPLC analysis of the process indicates completion of the reaction, the mixture is cooled to 20 ° C and a solution of sulfuric acid (41.8 g) in water (200 ml) is added. The organic layer was separated, extracted twice with saturated NaHCO ₃ solution (200 ml each time), then concentrated in vacuo to approximately 60% volume (pressure: 370-150 mbar; it is noted that water should be completely removed during distillation) and diluted at room temperature temperature with ethyl acetate (450 ml). After the addition of Na ₃ PO ₄ (91.5 g), sulfuryl chloride (53 ml) was added slowly (over 3 hours) at an internal temperature of 10-20 ° C and stirring was continued until the HPLC analysis of the process showed the completion of the reaction ( approximately 1 h). The mixture was extracted twice with water (150 ml each time) and distilled in vacuo (pressure: 150-170 mbar) until 305 g of distillate was obtained. Then acetic acid (400 ml) was added and the mixture was again distilled in vacuo (pressure: 30-40 mbar) until an additional 292 g of distillate was obtained. Concentrated hydrochloric acid (84 ml) was added and the mixture was stirred at an internal temperature of 40-50 ° C until completion of the reactions (hydrolysis and decarboxylation) (4 hours, HPLC control). After distillation of another 100 g of the solvent in vacuo (pressure: 200-40 mbar; removal of the remaining toluene and tert-butanol), the emulsion was diluted with acetic acid (70 ml) at an internal temperature of 20 ° C and a solution was obtained. Then water (20 ml) and crystals (seeder) are added to cause crystallization. When crystallization begins, additional water (230 ml) is slowly added. The suspension is stirred at room temperature (15 h), then filtered and the filter layer washed with a mixture of acetic acid and water (v / v = 1/1, 100 ml). The wet product was dried in vacuo at 40 ° C. to give an ocher solid (total yield 101.84 g, purity (HPLC): 98.9%).

Example 9

Step 4. Preparation of (±) -2-chloro-1- (6-fluoro- (2R *) - chroman-2-yl) - (1R *) - ethan-1-ol (compounds VIa) and (±) - 2-chloro-1- (6-fluoro- (2S *) - chroman-2-yl) - (1R *) - ethan-1-ol (compounds VIb)

Compound Vb (33.74 g) was added at 0-5 ° C to a solution of ZnCl ₂ (40.3 g) in methanol (470 ml) and the mixture was stirred until all solids were completely dissolved (1 h). The solution was cooled to -10 ° C and NaBH _{4 was} added in portions over 35 minutes. After completion of the reaction monitored by HPLC, the mixture was concentrated to a volume of about 150 ml and then diluted with toluene (400 ml). The organic layer was extracted twice successively with 1.0 N HCl solution (200 ml each time) and saturated NaHCO ₃ solution (100 ml). After drying over MgSO _{4, the} suspension is filtered and the solvent evaporated in vacuo to give a brownish oil (35.28 g, VIa / VIb ratio = 61/39; the crude product mixture contains small amounts of toluene). The crude product is used in the next step without further purification.

Example 10

Step 5. Preparation of (±) -6-fluoro - [(2R *) - oxiran-2-yl] - (2S *) - chroman (compound VIIa) and ( + ) -6-fluoro - [(2R *) - oxiran-2-yl] - (2R *) - chroman (compound VIIb)

A methanol solution of NaOMe (30%, 30.9 g) was added at 20-25 ° C to a solution of a mixture of compounds VIa and VIb (37.9 g, ratio VIa / VIb = 61/39) in methanol (380 ml). The reaction was monitored by HPLC and, after stirring for 3.5 hours at 20-25 ° C., an additional amount of methanolic NaOMe solution (30%, 1.4 g) was added. After completion of the reaction (within 3.5 hours), the mixture was neutralized by the addition of acetic acid and then concentrated in vacuo. The residue was partitioned between methylene chloride (300 ml) and a half-saturated NaCl solution (200 ml). The phases were separated and the organic layer was dried over MgSO ₄ . After filtration, the filtrate was concentrated to give a brownish oil (32.1 g, ratio VIIa / VIIb = 61/39). The crude product is used directly in the next step.

Example 11

Step 6. Preparation of (±) -2-benzylamino-1- (6-fluoro- (2R *) - chroman-2-yl) - (1S *) - ethan-1-ol (compounds VIIIa) and (±) - 2-benzylamino-1- (6-fluoro- (2R *) - chroman-2-yl) - (1R *) - ethan-1-ol (compounds VIIIb) and the separation of compounds VIIIa and VIIIb

A mixture of compounds VIIa and VIIb (ratio: 57/43) was slowly added (over 1.5 h) at an internal temperature of 40 ° C to a solution of benzylamine (5.4 g) in 2-propanol (30 ml). After completion of the reaction monitored by HPLC, the solution was cooled to room temperature and a seed substance was added. Then diastereomers VIIIa and VIIIb are separated by fractional crystallization. The suspension was stirred at room temperature for 1 h and filtered, obtaining a colorless solid (1.01 g) after drying in vacuo. The mother liquor is concentrated until 25 g of residue is left. Then the concentrated mixture is heated to 60 ° C and cooled for 3 hours to 0-5 ° C. An additional portion of the product is obtained after filtering and drying the wet product in vacuo (0.3 g). The mother liquor is concentrated until 15 g of residue is left and diisopropyl ether (15 g) is added. A third portion is obtained after filtering and drying the wet product in vacuo (0.33 g). The second and third portions are recrystallized from 2-propanol (3.7 g) and after filtration, the wet product (0.6 g) is dissolved with the first portion in 2-propanol (10 g) under reflux. The mixture is cooled to 0-5 ° C and then filtered. The wet product was dried in vacuo to give a colorless solid (yield: 1.1 g, VIIIa / VIIIb ratio = 96/4).

Diastereomer VIIIb can be obtained, for example, from the mother liquor after concentration to dryness, followed by extractive processing and crystallization.

Example 12

Stage 4-6. Preparation of (±) -2-benzylamino-1- [6-fluoro- (2R *) - chroman-2-yl] - (1S *) - ethan-1-ol (compounds VIIIa) and (±) -2-benzylamino -1- [6-fluoro- (2R *) - chroman-2-yl] - (1R *) - ethan-1-ol (compounds VIIIb) from (±) -2-chloro-1- (6-fluorochroman- 2-yl) ethanone (compounds Vb) and the separation of compounds VIIIa and VIIIb

Compound Vb (76.31 g, 324 mmol) and ZnCl ₂ (22.53 g, 162 mmol) were dissolved in ethanol (648 ml) at an internal temperature of 20-30 ° C. The resulting solution was then cooled to an internal temperature of -15 ° C - (-20) ° C and a solution of NaBH ₄ (12.77 g, 324 mmol) and NaOMe (4 ml of a 30% solution of MeOH) in MeOH (136 ml) was slowly added. During the addition, an internal temperature of -20 to -10 ° C was maintained and the reaction was monitored by HPLC. After completion of the reaction, the mixture was allowed to warm to 0-5 ° C and hydrochloric acid (160 ml of a 2N HCl solution) was added. The mixture gives the opportunity to warm to 20-25 ° C and mix at this temperature for 30 minutes. The solvent was almost completely removed in vacuo to give a brown suspension (191.3 g). This residue was partitioned between hydrochloric acid (160 ml of a 2N HCl solution) and MTBE (450 ml). The organic layer was separated, extracted with hydrochloric acid (30 ml of a 2N aqueous HCl solution), then twice with water (each time 250 ml) and concentrated in vacuo to give a brown oil (79.77 g, ratio VIa / VIb = 63.5 / 36 ,5). After dissolving the oil in 2-propanol, a solution of NaOMe in MeOH (64.18 g, concentration: 30%) is added at an internal temperature of 20-25 ° C. The reaction is monitored by HPLC. After completion of the reaction, the mixture was cooled to 0-5 ° C and neutralized by the addition of acetic acid (1.9 ml). The suspension is filtered through celite and the layer on the filter is washed with 2-propanol (25 ml). The filtrate was concentrated in vacuo to give a semi-concentrated cloudy, brownish solution (115.97 g). The resulting mixture was again filtered and the filter layer was washed with 2-propanol (25 ml) to obtain a clear brown solution, which was then slowly added (over 3 hours) to a solution of benzylamine (105.2 g, 972 mmol) in 2-propanol (352 ml) at an internal temperature of 33-38 ° C. The reaction was monitored by HPLC and seed was added to cause crystallization of the product during the reaction. After completion of the addition, the mixture is stirred for 3.5 hours at 25-30 ° C, then cooled to 0-5 ° C and stirred at the indicated temperature for 1.5 hours. The suspension is filtered and the layer on the filter washed with pre-cooled (0- 5 ° C) 2-propanol (46 ml). The wet product is dried in vacuo at 50-55 ° C to obtain a light beige solid (42.23 g, ratio VIIIa / VIIIb = 92/8). The crude product was dissolved in acetonitrile (294 ml) by heating under reflux. The solution was slowly cooled to 0-5 ° C (6-7 h), filtered and the filter layer washed with acetonitrile (38 ml). The wet product is dried in vacuo at 50-55 ° C to give a white solid (total yield: 38.2 g, ratio VIIIa / VIIIb = 98.8 / 1.2, purity (HPLC) of product VIIIa: 98.62%) .

Example 13

Step 7. Preparation of (±) -2- {benzyl [2- (6-fluoro- (2R *) - chroman-2-yl) - (2S *) hydroxyethyl] amino} -1- (6-fluoro- (2S *) - chroman-2-yl) ethanone (compounds IXa), (±) -4-benzyl-2- [6-fluoro- (2R *) - chroman-2-yl] - (6S *) - [6- fluoro- (2S *) - chroman-2-yl] morpholin-2-ol (compounds IXa`), (±) -2- {benzyl [2- (6-fluoro- (2R *) - chroman-2-yl ) - (2S *) - hydroxyethyl] amino} -1- (6-fluoro- (2R *) - chroman-2-yl) ethanone (compounds IXb) and (±) -4-benzyl- (6S *) - 2 , 6-bis- [6-fluoro- (2R *) - chroman-2-yl] -morpholine- (2S *) - ol (compounds IXb`) and the separation of diastereomers

Compound V (14.62 g) was added at an internal temperature of 40 ° C. to a suspension of compound VIIIa (17.5 g), NaHCO ₃ (9.6 g) and NaBr (0.9 g) in DMF (70 ml). When the reaction is complete (in 3-3.5 hours, control by HPLC), the suspension is cooled to room temperature and diluted with MTBE (400 ml) and water (200 ml). Then the phases are separated, the organic layer is extracted with water (100 ml) and the combined aqueous layers are re-extracted with MTBE (100 ml). After evaporation of the combined organic layers, the remaining amber-colored oil (35.0 g) was dissolved in diisopropyl ether (400 ml) and seeded. The suspension was first stirred at room temperature for 1.5 hours and then at 0-5 ° C. for 0.5 hours. After filtration, the wet product was dried in vacuo to give a light yellow solid (yield: 23.95 g, HPLC - purity 97.5%, ratio IXa / IXa` to IXb / IXb` = 52/48).

The mother liquor is concentrated to 56 g, then cooled to 0-5 ° C and seeded. The second portion is obtained after filtration and drying (yield: 2.62 g, HPLC purity 92.6%, ratio IXa / IXa` to IXb / IXb` = 43/57).

The separation of diastereomers is carried out by fractional crystallization from acetonitrile.

The diastereomeric mixture of compounds IXa / IXa` and IXb / IXb` (ratio: 55/45, 2.31 g) is dissolved in acetonitrile at an internal temperature of 70 ° C. The light yellow solution is seeded, cooled to room temperature (within 2-3 hours) and stirred at the indicated temperature for 1.5-2 hours. By filtration of the suspension and drying of the wet product, the first portion is obtained (yield: 0.26 g , ratio IXa / IXa` to IXb / IXb` = 95/5).

The mother liquor is concentrated to 30 g and stirred at room temperature after seeding. Filtration of the suspension gave a wet product (1.12 g), which was recrystallized from acetonitrile (11.2 g). After drying the wet product in vacuo, a second portion is obtained (0.50 g, ratio IXa / IXa` to IXb / IXb` = 62/38). This portion was recrystallized from acetonitrile (10 ml) to give a wet product (0.57 g), which was again dissolved in acetonitrile (8 ml) with heating. The solution was cooled to room temperature and seeded. After filtering the suspension and drying the wet product, a third portion is obtained (yield: 0.16 g, ratio IXa / IXa` to IXb / IXb` = 98/2).

The separation of diastereomers is also carried out by selective silylation and fractional crystallization.

Method A.

Imidazole (0.417 g) is added at 0-5 ° C to a suspension of compounds IX (2.0 g obtained by the above procedure, the ratio of IXa / IXa` to IXb / IXb` = 52/48) in a mixture of acetonitrile (13.5 ml ) and THF (1.5 ml). Then TMSCl (0.228 mg) was slowly added at the indicated temperature for 3.5-4 hours and under the control of HPLC. After completion of the addition, the mixture was concentrated in vacuo to 8-10 ml and then acetonitrile (5 ml) was added. Stirring the suspension at 0-5 ° C for 1-1.5 hours, followed by filtration gives a white wet product (1.31 g), which is dried in vacuum (yield: 0.82 g, ratio IXa / IXa` to IXb / IXb` => 98/2).

Method B.

Imidazole (0.21 g) is added at 0-5 ° C to a suspension of compounds IX (1.0 g obtained by the above procedure, the ratio of IXa / IXa` to IXb / IXb` = 52/48) in MTBE (10 ml) . Then, TMSCl (0.115 mg) was slowly added at the indicated temperature for 3.5-4 hours and under the control of HPLC. The reaction was completed by adding 4 drops of TMSCl. Then the suspension is filtered and the wet product (0.87 g) is dried in vacuum, obtaining a white crude product (0.51 g, the ratio of IXa / IXa` to IXb / IXb` = 98/2, the product contains imidazole hydrochloride). To remove imidazole hydrochloride, the crude product is suspended at room temperature in a mixture of acetonitrile and water (3.0 ml, 4/1 by volume) for 2.5-3 hours. Filter the suspension and dry the wet product (0.65 g) in vacuo give a white solid (yield: 0.31 g, ratio IXa / IXa` to IXb / IXb` = 98/2).

Example 14

Step 7. Preparation of (±) -2- {benzyl [2- (6-fluoro- (2R *) - chroman-2-yl) - (2S *) - hydroxyethyl] amino} -1- (6-fluoro- ( 2S *) - chroman-2-yl) ethanone (compounds IXa), (±) -4-benzyl-2- [6-fluoro- (2R *) - chroman-2-yl] - (6S *) - [6 -fluoro- (2S *) - chroman-2-yl] morpholin-2-ol (compounds IXa`), (±) -2- {benzyl [2- (6-fluoro- (2R *) - chroman-2- il) - (2S *) - hydroxyethyl] amino} -1- (6-fluoro- (2R *) - chroman-2-yl) ethanone (compound IXb) and (±) -4-benzyl- (6S *) - 2,6-bis- [6-fluoro- (2R *) - chroman-2-yl] -morpholine- (2S *) - ol (compounds IXb`) and the separation of diastereomers

A mixture of compound VIIIa (49.0 g, 162.6 mmol obtained by the method of example 12), compound Vb (42.5 g, 178.9 mmol obtained by the method of example 8), NaBr (1.68 g, 16, 3 mmol) and NaHCO ₃ (20.5 g, 243.9 mmol) in DMF (200 ml) are heated to an internal temperature of 60-65 ° C until HPLC analysis of the process shows an almost complete conversion (approximately 1 h) . Then the suspension is filtered and the layer on the filter washed with DMF (70 ml). Water was added to the filtrate at 50 ° C (15 ml) and seed crystals were added to cause crystallization. Then the product is carefully precipitated by the slow addition of water (for 4 hours) at 50 ° C. Ultimately, the precipitation is completed by adding water (25 ml) at 50 ° C. The suspension is cooled to 20-25 ° C and filtered. The wet product was washed with 2-propanol (100 ml), dried in vacuo at 50 ° C and a white solid was obtained (yield: 70.15 g, purity (HPLC): 99.1%, ratio IXa / IXa` to IXb / IXb `= 52/48). To a suspension of the obtained solid (70.0 g) and imidazole (14.6 g, 214 mmol) in acetonitrile (385 ml), TMSCl (7.56 g, 68.2 mmol) was slowly added (1.75 ml / h) at an internal temperature of -10 - (- 15) ° C. Then the suspension is stirred for 2 hours at -5-0 ° C, monitoring by HPLC. The reaction was completed by the addition of TMSCl (1.34 g, 12.3 mmol). The suspension is filtered and the wet product is dried in vacuo at 40 ° C to give a white solid (66.45 g, ratio IXa / IXa` to IXb / IXb` = 92/8). The resulting product was suspended in a mixture of cyclohexane (285 ml) and MTBE (95 ml) at an internal temperature of 60 ° C for 10 minutes. Then the suspension is cooled to 25 ° C and filtered, the wet product is washed with cyclohexane (50 ml) and again suspended in cyclohexane (350 ml). The suspension is stirred at 60-65 ° C for 20 minutes, then cooled to 25 ° C and filtered. The wet product was washed with cyclohexane (50 ml) and dried in vacuo at 40 ° C to give a white solid (total yield: 28.83 g, ratio IXa / IXa` to IXb / IXb` = 98.6 / 1.4).

Example 15

Step 8. Preparation of (±) - [2R * [R * [R * (S *)]]] - α, α` - [[(phenylmethyl) imino] bis (methylene)] bis [6-fluorochroman-2- methanol] (compounds Xa) and (±) - [2R * [S * [R * (S *)]]] - α, α` - [[(phenylmethyl) imino] bis (methylene)] bis [6-fluorochroman -2-methanol] (compounds Xb)

A solution of compound IXa / IXa` (0.40 g, containing 2% IXb) in THF (8.0 ml) was cooled to an internal temperature of -10 - (-15) ° C. Ti (OiPr) ₄ (0.485 mg) was added to the cooled solution, followed by LiBH ₄ (18 mg). After stirring at -10 - (- 15) ° C for 1 hour and at 0-5 ° C for 1.5-2 hours, the reaction mixture was poured into a mixture of methylene chloride (10 mL) and saturated NaHCO ₃ solution (10 ml) . The suspension is filtered through celite and the phases are separated. After drying over MgSO _{4, the} organic layer was concentrated to give a colorless foam (418 mg Xa / Xb ratio = 78/22). The crude product is used in the next step without further purification.

Example 16

Step 8. Preparation of (±) - [2R * [R * [R * (S *)]]] - α, α` - [[(phenylmethyl) imino] bis- (methylene)] bis [6-fluorochroman-2 methanol] (compounds Xa)

To a solution of compound IXa / IXa` (28.0 g, obtained as in Example 14) and Ti (OiPr) ₄ (32.9 g, 113.5 mmol) in DME (280 ml) was added KBH ₄ (3.15 g , 56.73 mmol) at an internal temperature of 0 ° C. After stirring at the indicated temperature for 21 hours (HPLC control), the mixture was allowed to warm to room temperature and hydrochloric acid (280 ml, 10% aqueous solution) was slowly added. The suspension is stirred for 2.5 hours. The suspension is filtered and the wet product is washed first with a mixture of DME (25 ml) and hydrochloric acid (25 ml, 2N aqueous solution), then hydrochloric acid (50 ml, 2N aqueous solution) and twice with water ( each time 50 ml). The wet product is suspended in ethanol (120 ml) and heated to 50 ° C. An aqueous NaOH solution (8.3 g, 30%) was then added, initially obtaining a clear solution, and the mixture was heated to 60 ° C. After crystallization began, water (33 ml) was added and the suspension was cooled to room temperature. The suspension is filtered and the wet product is washed with a mixture of EtOH / water (20 ml, v / v = 3/1). Next, the wet product is dissolved in EtOH (160 ml) by heating to 70-75 ° C and then cooled to 65 ° C. Water (40 ml) and seed crystals were added, the mixture was cooled to room temperature and stirred at that temperature overnight. After filtration, the wet product is washed with a mixture of EtOH / water (30 ml, v / v = 3/1), dried in vacuo at 50 ° C and a white solid is obtained (yield: 21.66 g, HPLC purity: 99.85% )

Example 17

Stage 9. Obtaining hydrochloride (±) - [2R * [R * [R * (S *)]]] - α, α`- [iminobis (methylene)] bis [6-fluorochroman-2-methanol] (compound I ) and separation from the by-product of the hydrochloride (±) - [2R * [S * [R * (S *)]]] - α, α`- [iminobis (methylene)] bis [6-fluorochroman-2-methanol]

Compounds Xa and Xb (418 mg, Xa / Xb ratio = 78/22, prepared according to the procedure for Example 11) were dissolved in a mixture of EtOH containing 14% HCl (0.665 g) and MeOH (10 ml). The resulting mixture was hydrogenated at normal pressure and at room temperature with a catalyst of 5% palladium-carbon (100 mg). After completion of the reaction (within 3 hours), the mixture was diluted with MeOH (25 ml), heated to 40 ° C and then filtered through celite. The filter layer was washed with hot MeOH (40 ° C, 30 ml), the combined filtrates were concentrated in vacuo to an amount of 7-8 g. The resulting suspension was filtered to obtain a colorless solid after drying the wet product (yield: 0.17 g, compound I ratio / by-product = 95.5 / 4.5). The mother liquor is concentrated and the residue is dissolved in 2.0 ml of MeOH. The suspension was stirred at room temperature for 0.5 h, then filtered to give an additional portion (yield: 28 mg) after drying the wet product in vacuo. Both portions were recrystallized from MeOH (2.0 ml) and, after drying, a colorless solid was obtained (yield: 0.161 g, compound I / by-product ratio = 98/2).

Example 18

Step 9. Preparation of (±) - [2R * [R * [R * (S *)]]] hydrochloride - α, α`- [iminobis- (methylene)] bis [6-fluorochroman-2-methanol] (compounds I)

A mixture of compound Xa (21.0 g, 42.3 mmol obtained by the method of example 16) and a catalyst of 5% palladium on carbon (1.35 g) in acetic acid (150 ml) is hydrogenated at normal pressure and at an internal temperature of 40 ° FROM. After HPLC analysis shows complete deprotection, the suspension is filtered through celite. The filtrate was cooled to 20 ° C. and concentrated aqueous hydrochloric acid (4.59 g, 46.5 mmol) was added. After filtration, the wet product was washed first with acetic acid (10 ml), then with ethanol (20 ml) and dried in vacuo to give a white solid (yield: 18.05 g, HPLC purity: 99.7%).

Example 19

Preparation of (±) -2- {benzyl [2- (6-fluoro- (2R *) - chroman-2-yl) - (2S *) hydroxyethyl] amino} -1- (6-fluoro- (2S *) - chroman-2-yl) ethanone (compounds IXa) ⇔ (±) -4-benzyl-2- [6-fluoro- (2R *) - chroman-2-yl] - (6S *) - [6-fluoro- ( 2S *) - chroman-2-yl] morpholin-2-ol (compounds IXa`)

A mixture of compounds IXa / IXb (100 g, 202.6 mmol, ratio IXa / IXb = 50.8 / 49.2) and acetonitrile (311 g, water 0.01% KF) are charged into a 1-liter double-jacketed glass reactor. . The colorless suspension is heated to an internal temperature (IT) = 70 ° C and stirred at this temperature for 13 minutes. After slowly cooling the mixture to 60 ° C (30 minutes), DBU (7.79 g, 50.7 mmol) was added and the reaction mixture was cooled with the following gradient:

Time [h] IT [° C] 0 60 0.5 55 1,5 fifty

Then the suspension was stirred for 1 h at 50 ° C and the ratio IXa / IXb was monitored by HPLC (result: IXa / IXb = 66.3 / 33.7). Stirring is continued at 50 ° C. until the ratio IXa / IXb is greater than 75/25 (HPLC control). In this case, the suspension is stirred for 4 hours at 50 ° C (IXa / IXb ratio = 75.1 / 24.9). The mixture was then cooled to 45 ° C. and stirred at this temperature until the IXa / IXb ratio was greater than 84/16 (HPLC control). The suspension is stirred for 2 hours at 45 ° C (IXa / IXb ratio = 85/15). The mixture is then cooled to 40 ° C and stirred at this temperature until the ratio IXa / IXb becomes greater than 89/11 (HPLC control), but no longer than 8 hours (in this case, the reaction mixture should be treated in the same way as described below). In this case, the suspension is stirred for 5 hours at 40 ° C (IXa / IXb ratio = 89.2 / 10.8). The reaction mixture was neutralized with acetic acid (3.051 g, 50.7 mmol) and then cooled to 25 ° C. After stirring for 2 hours at 25 ° C, the suspension was filtered off and the filter layer was washed four times with acetonitrile (31 g each time) (IXa / IXb ratio in the filter layer after washing = 99.06 / 0.94). The amber-colored mother liquor is further treated (see below, recovery, ML1). The wet product is suspended in acetonitrile (249 g) and the suspension is heated to 70 ° C. After suspension at this temperature for 1-10 minutes, the mixture is cooled to 20 ° C (within 2 hours 45 minutes) and stirred for 1.5 hours at 20 ° C. After filtration, the wet product was washed twice with acetonitrile (31 g each time) and dried in vacuo at 50 ° C to obtain a colorless solid (yield: 74.09 g, 73.4%, HPLC purity: 99.33%, IXa ratio / IXb = 99.37 / 0.63, analysis = 99.1%). Suspension stock solution (ML2) is used for the extraction step (see below).

Example 20

Extraction of the starting material from the mother liquor obtained in Example 19.

Water (117 g) was added to the mother liquor (ML1, 350.02 g) at IT = 24 ° C, and IXa / IXb (0.05 g) was introduced into the resulting mixture. Crystallization begins in a few minutes. After stirring for 1.5 hours at 20 ° C - 25 ° C, the beige suspension is cooled to 0 ° C-5 ° C and stirred at the indicated temperature for 3.5 hours. The suspension is filtered off and the wet product is washed with acetonitrile mixture ( 31 g) and water (10 g). The amber-colored mother liquor is removed and the wet product is suspended at 20 ° C-25 ° C in a second mother liquor (ML2, 279 g, see above). Then water (93 g) was added and the mixture was stirred at 0 ° C - (- 5 ° C) for 1.5 hours. After filtering the suspension, the wet product was washed with a mixture of acetonitrile (31 g) and water (10 g) and dried in vacuum at 50 ° C, obtaining an off-white solid (yield: 7.74 g, 7.6%, HPLC purity: 99.49%, the sum of both diastereomers), ratio IXa / IXb = 39.1 / 60.9 analysis = 98.2% (sum of both diastereomers)).

Although the invention has been described in detail and with reference to specific examples thereof, it will be apparent to those skilled in the art that various changes and modifications can be made without departing from the spirit and scope of the invention.

Claims (106)

1. The method of obtaining racemic [2S * [R * [R * [R *]]]] and [2R * [S * [S * [S *]]]] - (±) α, α '- [iminobis ( methylene)] bis [6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol] and its pharmaceutically acceptable salts, comprising (a) providing a compound of formula (VIII)

as a diastereomerically pure compound containing at least 95% of the diastereomer of the RS / SR configuration or RR / SS configuration, where PG is a hydrogen or amino protecting group, wherein the amino protecting group is at least one allyl group or an aryl-C ₁ alkyl group ;
(b) providing a racemic compound of formula (V)

where LG is selected from the group consisting of chlorine, bromine, iodine, alkylsulfonyloxy and arylsulfonyloxy;
(c) N-alkylating a compound of formula (VIII) with a compound of formula (V), wherein said N-alkylation is carried out in an inert organic solvent in the presence of a base and optionally in the presence of a catalyst, to obtain a compound of formula (IX)

,
the compounds of formula (IX '), which is a cyclic semi-ketal form of the compounds of formula (IX)

or mixtures thereof, wherein the compound of formula (IX) and the compound of formula (IX ') are mixtures of diastereomers;
(d) separating the diastereomers of a compound of formula (IX) or a compound of formula (IX ') by at least one of the methods (dl) or (d2), where (d1) separating the diastereomers of a compound of formula (IX) or a compound of formula (IX') fractionally crystallization after salt formation or after modification to produce substantially pure diastereomers of formula (IX) or formula (IX) containing at least 50% RSS / SRR or RRS / SSR configuration;
(d2) separating the diastereomers of the compound of formula (IX) or the compound of formula (IX ') to obtain substantially pure diastereomers of the formula (IX) or formula (IX') containing at least 50% RSS / SRR or RRS / SSR configuration , at the stage of simultaneous epimerization-crystallization, where the stage of epimerization-crystallization includes:
(1) epimerizing a compound of formula (IX) or (IX ') RSR / SRS configuration to obtain a mixture of diastereomers of formula (IX) or formula (IX') RSS / SRR configuration and RSR / SRS configuration or
epimerizing a compound of formula (IX) or (IX ') RRR / SSS configuration to obtain a mixture of diastereomers of formula (IX) or formula (IX') RRS / SSR configuration and RRR / SSS configuration, provided that the epimerization is carried out in the presence of a base and an organic solvent where the mixture is optionally cooled using a temperature gradient, and diastereomers of the RSS / SRR configuration or RRS / SSR configuration in the mixture are obtained at least twice as much as the diastereomers of the RSR / SRS configuration and RRR / SSS configuration; and
(2) crystallization of the substantially pure diastereomers of formula (IX) or formula (IX ') of the RSS / SRR configuration or RRS / SSR configuration at least in excess of the diastereomers of the RSR / SRS configuration and the RRR / SSS configuration;
separation of the mixture by fractional crystallization, optionally after salt formation or after modification, to produce substantially pure diastereomers of formula (IX) or formula (IX ') with RSS / SRR or RRS / SSR configuration;
(e) recovering substantially pure diastereomers of formula (IX) or formula (IX ') with an RSS / SRR or RRS / SSR configuration to give a compound of formula (X)

as an RSSS / SRRR diastereomeric mixture in which the ratio of the RSSS / SRRR of the diastereomeric configuration to the SRSR or RRSS of the diastereomeric configuration is at least 1;
(f) deprotecting a compound of formula (X), provided that PG is not H (and if PG is H, then the deprotection step is omitted) to obtain a compound of formula (I)

or its pharmaceutically acceptable salts; and
(g) removing the compound of formula (I) or its pharmaceutically acceptable salts RSRS or RRSS diastereomeric configuration (if any) by recrystallization or suspension, to obtain racemic [2S * [R * [R * [R *]]]] and [2R * [S * [S * [S *]]]] - (±) [α, α '- [iminobis (methylene)] bis [6-fluoro-3,4-dihydro-2H-1-benzopyran-2- methanol] or its pharmaceutically acceptable salts. 2. The method according to claim 1, where the protective group is a benzyl group. 3. The method according to claim 1, where the leaving group is chlorine or bromine. 4. The method according to claim 1, where in step (c) the organic solvent is a polar aprotic solvent selected from the group consisting of dimethylformamide, dimethylacetamide and N-methylpyrrolidone. 5. The method according to claim 1, wherein in step (c), the base is at least one of the tertiary amines, alkali metal carbonates or alkali metal hydrogen carbonates. 6. The method according to claim 5, where the base is sodium bicarbonate. 7. The method according to claim 6, where from about 1.5 to about 2.5 equivalent bases are used. 8. The method according to claim 1, where in step (c) the catalyst is at least one of alkali metal bromides, alkali metal iodides, tetraalkylammonium bromides or tetraalkylammonium iodides. 9. The method of claim 8, where the catalyst is sodium bromide. 10. The method according to claim 9, where from about 0.1 to about 0.25 equivalent of catalyst is used. 11. The method of claim 10, wherein 0.15 equivalent of catalyst is used. 12. The method according to claim 1, where in stage (C) the specified N-alkylation is carried out at a temperature of from about room temperature to about 80 ° C. 13. The method according to claim 1, where in stage (b) the compound of formula (V) is used in an amount of from about 1.0 to about 1.5 equivalent. 14. The method according to claim 1, where in stage (d1) fractional crystallization is carried out in a solvent. 15. The method according to 14, where in stage (d1) use a free amine for fractional crystallization. 16. The method according to 14, where the solvent is acetonitrile. 17. The method according to claim 1, where in step (d1) a silylating reagent is used for modification before fractional crystallization from a solvent. 18. The method according to 17, where the silylating reagent is at least one of trimethylsilyl chloride, hexamethyldisilazane or bis-trimethylsilylurea. 19. The method according to 17, where from about 0.4 / n to about 0.6 / n equivalents of a silylating reagent is used, and where n is the number of transferred silyl groups per silylating reagent. 20. The method according to 17, where the modification is carried out in the presence of from about 1.0 to about 2.0 equivalent base. 21. The method according to claim 20, where the base is imidazole. 22. The method according to 17, where the specified separation of the diastereomers of the compounds of formula (IX) or compounds of the formula (IX ') is carried out in acetonitrile, methyl tert-butyl ether, cyclohexane or mixtures thereof. 23. The method according to claim 1, where in step (e), said reduction is carried out for a compound of formula (IX) or a compound of formula (IX ') RSS / SRR configuration in a solvent using alkali metal borohydride, tetrabutylammonium borohydride, tri-sec- alkali metal butyl borohydride or zinc borohydride optionally in the presence of a Lewis acid. 24. The method according to item 23, where the Lewis acid is one of the compounds: Ti (Oalkyl) ₄ , ZnCl ₂ , an alkali metal halide or an alkaline earth metal halide. 25. The method according to item 23, where the solvent is at least one of ether, alcohol or a halogenated hydrocarbon. 26. The method according to item 23, where the specified recovery is carried out in the temperature range from about -20 ° C to about room temperature. 27. The method according to claim 1, where in step (f), said deprotection is carried out by catalytic hydrogenation. 28. The method according to claim 1, where in stage (g) the specified purification of the compounds of formula (I) is carried out by suspending its hydrochloride in a solvent. 29. The method according to p, where the suspension is carried out in methanol as a solvent. 30. The method according to claim 1, where the specified provision of the compounds of formula (VIII) includes:
(i) reducing the racemic compound of formula (V) in a solvent and optionally in the presence of a Lewis acid, where LG is bromine or chlorine, to obtain a mixture of diastereomers of the compound of formula (VI)

(ii) the formation of a mixture of diastereomers of the compounds of formula (VII)

(iii) reacting diastereomers of a compound of formula (VII) with NH ₂ PG to obtain a mixture of diastereomers of a compound of formula (VIII)

and
(iv) isolating the individual diastereomers of a compound of formula (VIII) from a mixture of diastereomers of a compound of formula (VIII) by fractional crystallization, optionally after salt formation. 31. The method of claim 30, wherein at least one of the diastereomers of the compound of formula VIII with the RR / SS or RS / SR configuration is isolated. 32. The method according to p, further comprising recycling a compound of formula (VIII) RR / SS configuration, wherein said recycling comprises:
providing a compound of formula (VIII) an RR / SS configuration with a protecting group; and
inverting the alcohol configuration to obtain a compound of formula (VIII) SR / RS configuration. 33. The method according to claim 30, wherein in step i) the reducing agent is selected from alkali metal borohydride, tetraalkylammonium borohydride, zinc borohydride, alkali metal triacetoxyborohydride, sodium triethyl borohydride, sodium bis (2-methoxyethoxy) aluminum hydride, tri-sec-butyl alkali metal hydride or coordination borohydrides. 34. The method according to clause 30, where in stage i) carry out the restoration in the conditions of Meerwein-Pondorf-Verley. 35. The method according to clause 30, where in stage i) the specified recovery is carried out by catalytic hydrogenation. 36. The method according to clause 30, where in stage i) the Lewis acid is selected from the group consisting of alkali metal or alkaline earth metal chlorides, zinc chloride, titanium (IV) alkoxide and aluminum trialkoxide. 37. The method of claim 30, wherein in step i), said reduction is carried out under conditions that result in an excess of the RR / SS isomer of the compound of formula (VI). 38. The method according to clause 30, where in stage i) the specified recovery is carried out in the temperature range from about -78 ° C to about room temperature. 39. The method according to § 38, where the specified recovery is carried out at a temperature of from -20 ° C to room temperature. 40. The method according to clause 30, where in stage i) the solvent is selected from the group consisting of alcohols, ethers, halogenated hydrocarbons and aromatic solvents. 41. The method according to clause 30, where PG is a benzyl group. 42. The method according to clause 30, where in stage ii) the specified formation of a mixture of diastereomers of the compounds of formula (VII) is carried out in a solvent and in the presence of a base. 43. The method according to § 42, where the solvent is an alcohol, and the base is an alkali metal alcoholate. 44. The method according to item 43, where they use 1.0 to 2.0 equivalents of base. 45. The method according to clause 30, where in stage ii) the specified formation of a mixture of diastereomers of the compounds of formula (VII) is carried out at temperatures from 0 to 40 ° C. 46. The method according to clause 30, where in stage iv) fractional crystallization is carried out in toluene, acetonitrile, C ₁ -C ₃ alcohol, ether, or mixtures thereof. 47. The method of claim 46, wherein C ₁ -C ₃ -alcohol is 2-propanol, and ether is at least one of diisopropyl ether or methyl tert-butyl ether. 48. The method according to claim 1, where the specified provision of a racemic compound of formula (V) includes:
(1) the transformation of the compounds of formula (II)

an activated acid derivative;
(2) reacting the activated acid derivative with Meldrum acid in the presence of a base to give a compound of formula (III)

(3) the conversion of a compound of formula (III) into a compound of formula (IV)

where R is hydrogen or COOR 'and where R' is C ₁ -C ₆ alkyl or aryl-C ₁ alkyl; and
(4) halogenating a compound of formula (IV) and optionally hydrolyzing and decarboxylating to obtain a compound of formula (V). 49. The method according to p, where in stage (1) the carboxylic acid is converted into the corresponding acid chloride. 50. The method according to p, where in stage (2) the base is a tertiary amine. 51. The method according to p, where in stage (2) use 1-3 equivalents of Meldrum acid. 52. The method according to p, where in stage (2) the reaction temperature is from about -10 ° C to about + 30 ° C. 53. The method according to p, where in stage (3) the compound of the formula
(III) hydrolyzed in a mixture of organic acid and water, obtaining the compound of formula (IV), where R represents N. 54. The method according to item 53, where the organic acid is acetic acid and the hydrolysis is carried out at boiling point. 55. The method according to p, where in stage (3) the compound of the formula
(IV) in which R is COOR 'and R' is C ₁ -C ₆ alkyl or aryl-C ₁ alkyl, are obtained by alcoholysis of a compound of formula (III). 56. The method of claim 55, wherein the alcoholysis is carried out with ethanol and tert-butanol. 57. The method according to p, where in stage (3) the solvent is at least one of alcohol or toluene. 58. The method according to p, where in stage (3) alcoholysis is carried out at temperatures from about 70 ° C to about 80 ° C. 59. The method of claim 48, wherein, in step (4), prior to the halogenation, the compound of formula (IV), where R is H, is converted by silylation to the corresponding silylenol ether containing a terminal double bond. 60. The method according to § 59, where the silylation is carried out through kinetically controlled deprotonation using lithium diisopropylamide, followed by silylation at a temperature of from about -78 ° C to about -40 ° C. 61. The method according to p, where silylation is carried out at a temperature of from -78 ° C to -70 ° C. 62. The method of claim 60, wherein trimethylsilyl chloride is used as the silylating reagent. 63. The method according to p, where in stage (4) after conversion to silylenol ether, halogenation is carried out using a brominating reagent. 64. The method of claim 63, wherein the brominating reagent is N-bromosuccinimide. 65. The method of claim 48, wherein in step (4), the compound of formula (IV) in which R is COOR ′ is first halogenated and then converted to the compound of formula (V) by hydrolysis of the ester followed by decarboxylation. 66. The method of claim 65, wherein the halogenation is carried out in the presence of a catalyst. 67. The method according to p, where from about 1.0 to about 1.5 equivalents of N-bromosuccinimide, N-chlorosuccinimide or SO ₂ Cl ₂ used as halogenating reagents. 68. The method of claim 67, wherein from about 0.2 to about 0.4 equivalents of Mg (ClO ₄ ) _{2 is} used as a catalyst. 69. The method of claim 48, wherein in step (4), said halogenation is carried out at temperatures from 0 ° C to about room temperature. 70. The method according to p, where in stage (4) after said halogenation, the ester is hydrolyzed, followed by decarboxylation in an aqueous solution of an organic acid. 71. The method of claim 70, wherein the organic acid is at least one of trifluoroacetic acid, formic acid, and acetic acid. 72. The method according to p, where the hydrolysis and decarboxylation is carried out at temperatures from about 75 ° to about 90 ° C. 73. The method according to claim 1, further comprising recycling a compound of formula (IX) or (IX ') RSR / SRS or RRR / SSS configuration, wherein said recycling comprises:
epimerizing a compound of formula (IX) or (IX ') RSR / SRS or RRR / SSS configuration to obtain a mixture of diastereomers of formula (IX) or formula (IX') RSS / SRR configuration containing diastereomers of RSR / SRS configuration, or a mixture of diastereomers of formula ( IX) or formula (IX ') RRS / SSR configuration containing diastereoisomers of the RRR / SSS configuration, and
separating the mixture by fractional crystallization after salt formation or after modification to obtain substantially pure diastereomers of formula (IX) or formula (IX ') having an RSS / SRR or RRS / SSR configuration. 74. The method according to claim 1, further comprising recycling a compound of formula (IX) or (IX ') RSR / SRS or RRR / SSS configuration, wherein said recycling comprises:
cleavage of the compounds of formula (IX) or (IX ') RSR / SRS or RRR / SSS configuration, with the formation of a mixture of diastereomers of the formula (VIII) RS / SR or RR / SS configuration; and
separation of the diastereomers of the formula (VIII) RS / SR or RR / SS configuration. 75. A compound selected from the following group:
(a) a compound of formula (III)

(b) a compound of formula (IV)

where R represents COOR 'and where R' represents C ₁ -C ₆ alkyl or aryl-C ₁ alkyl,
(c) a compound of formula (V)

where LG is bromine or chlorine,
d) a compound of formula (IX)

or its cyclic semi-ketal form of the formula (IX ')

where PG is a protective group selected from hydrogen, allyl and aryl-C ₁ alkyl,
(e) a compound of formula (IX) having an RSS / SRR configuration,

or its corresponding cyclic semi-ketal form of the formula (IX ')

where PG is a benzyl group, or
f) a compound having the formula depicted below

. 76. The compound according to item 75, having the formula (IV)

where R is COOR 'and where R' is C ₁ -C ₆ alkyl or aryl-C ₁ alkyl. 77. The compound according to item 75, having the formula (V)

where LG is bromine or chlorine. 78. The compound according to item 75, having the formula (IX)

or its cyclic semi-ketal form of the formula (IX ')

where PG is a protecting group selected from hydrogen, allyl and aryl-C ₁ alkyl. 79. The compound according to item 75, having the formula (IX) having the RSS / SRR configuration,

or its corresponding cyclic semi-ketal form of the formula (IX ')

where PG is a benzyl group. 80. The compound according to item 75, having the formula depicted below

81. The compound according to item 75, having the formula (III)

82. The method of obtaining racemic [2S * [R * [R * [R *]]] and [2R * [S * [S * [S *]]]] - (±) α, α '- [iminobis ( methylene)] bis [6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol] and its pharmaceutically acceptable salts, including:
providing a compound of formula (IX)

its salt or its derivative;
separating the stereoisomers of the compound, salt or derivative of formula (IX) by fractional crystallization to obtain substantially pure diastereomers thereof which contain at least 50% RSS / SRR or RRS / SSR configurations; and
recovering substantially pure diastereomers to give a compound of formula (X),

containing at most 50% stereoisomer with RSRS configuration. 83. The method of claim 82, wherein the compound of formula (IX) is prepared by N-alkylating a compound of formula (VIII) with a compound of formula (V) as defined in claim 1. 84. A method of obtaining a compound of formula (I) and its pharmaceutically acceptable salts,

including:
(a) the separation of the compounds of formula (II)

to obtain a compound of formula (II) with an S configuration and an R configuration;
(b) converting a compound of formula (II) with an S configuration into a compound of formula (V) with an S configuration,

wherein LG is a substituent selected from the group consisting of chloro, bromo, iodo, alkylsulfonyloxy and arylsulfonyloxy through the formation of a compound of formula (III) with an S configuration and a compound of formula (IV) with an S configuration;
(c) converting a compound of formula (II) with an R configuration into a compound of formula (V) with an R configuration through the formation of a compound of formula (III) with an R configuration and a compound of formula (IV) with an R configuration;
(d) providing a compound of formula (VIII),

where PG is hydrogen or an amino protecting group, where the amino protecting group is at least one of an allyl group or an aryl-C ₁ alkyl group and where the compound of formula (VIII) is an enantiomeric compound with an RS or SR configuration;
(e) N-alkylating (i) a compound of formula (VIII) with an RS configuration by a compound of formula (V) with an S-configuration or (ii) a compound of formula (VIII) with an SR configuration by a compound of formula (V) with an R configuration, provided that said N-alkylation is carried out in an inert organic solvent in the presence of a base and optionally in the presence of a catalyst, to obtain an RSS or SRR enantiomeric form of the compound of formula (IX)

or RSS or SRR of an enantiomeric form of a compound of formula (IX '), which is a cyclic semi-ketal form of a compound of formula (IX)

(f) recovering at least one of the RSS or SRR enantiomeric forms of the compound of formula (IX) or formula (IX ') to obtain at least one RSSS or SRRR of the enantiomeric form of the compound of formula (X);

(g) deprotecting at least one of the RSSS or SRRR enantiomeric forms of the compound of formula (X), provided that PG is not H (and if PG is H, then the deprotection step is canceled) to obtain a compound of formula
(I) or its pharmaceutically acceptable salts; and
(h) removing the compound of formula (I) or its pharmaceutically acceptable salts of the RSRS diastereomeric configuration, if present as a by-product, by crystallization or suspension to obtain at least one of ([2S * [R * [R * [R *] ]]] - and ([2R * [S * [S * [S *]]]] - enantiomers of the compounds of formula (I) and their pharmaceutically acceptable salts; and
(i) optionally combining ([2S * [R * [R * [R *]]]] - and ([2R * [S * [S * [S *]]]] - enantiomers of the compounds of formula (I) and their pharmaceutically acceptable salts to form the racemic ([2S * [R * [R * [R *]]]] and ([2R * [S * [S * [S *]]]] - (±) α, α ' - [imino-bis (methylene)] bis [6-fluorochroman-2-methanol] of the formula (I) and its pharmaceutically acceptable salts. 85. The method of obtaining racemic [2S * [R * [R * [R *]]] - and [2R * [S * [S * [S *]]]] - (±) -α, α '- [ iminobis (methylene)] bis [6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol] and its pharmaceutically acceptable salts, including:
(a) providing a compound of formula (VIII)

as a diastereomer having an RR / SS configuration wherein PG is hydrogen or an amino protecting group, wherein the amino protecting group is at least one of an allyl group or an aryl-C ₁ alkyl group;
(b) providing a racemic compound of formula (V),

where LG is a Deputy selected from the group consisting of chlorine, bromine, iodine, alkylsulfonyloxy and arylsulfonyloxy;
(c) N-alkylating a compound of formula (VIII) with a compound of formula (V), wherein said N-alkylation is carried out in an inert organic solvent in the presence of a base and optionally in the presence of a catalyst, to obtain a compound of formula (IX)

the compounds of formula (IX '), which is a cyclic semi-ketal form of the compounds of formula (IX),

or mixtures thereof, wherein the compound of formula (IX) and the compound of formula (IX ') are mixtures of diastereomers having the RRR / SSS and RRS / SSR configuration;
(a) separating the diastereomers of a compound of formula (IX) or a compound of formula (IX ') by fractional crystallization after salt formation or after modification to obtain substantially pure diastereomers of formula (IX) or formula (IX') containing at least 50% stereoisomers of RRR / SSS or RRS / SSR configuration;
(e) recovering substantially pure diastereomers of formula (IX) or formula (IX ') having an RRS / SSR configuration to give a compound of formula (X)

as an RSSS / SRRR diastereomeric mixture in which the ratio of RSSS / SRRR of the diastereomeric configuration to the SRSR or RRSS of the diastereomeric configuration is at least 1;
(f) deprotecting a compound of formula (X), provided that PG is not H, to give a compound of formula (I)

or its pharmaceutically acceptable salts; and
(g) removing the compound of formula (I) or its pharmaceutically acceptable salts, if any, of the RSRS diastereomeric configuration by recrystallization or suspension, to obtain racemic [2S [2R * [R [R *]]]] and [2R [2S * [ S [S *]]]] - (±) α, α '- [iminobis (methylene)] bis [6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol] or its pharmaceutically acceptable salts . 86. The method of claim 85, further comprising:
epimerizing a compound of formula (IX) or a compound of formula (IX ') of an RRR / SSS configuration to obtain a mixture of diastereomers of a compound of formula (IX) or a compound of formula (IX') having an RRR / SSS and RRS / SSR configuration. 87. The method of claim 85, further comprising splitting a compound of formula (IX) or a compound of formula (IX ') in an RRR / SSS configuration to form a compound of formula (VIII) as a diastereomer having an RR / SS configuration. 88. The method according to p, further comprising splitting a compound of formula (IX) or a compound of formula (IX ') in an RRR / SSS configuration to form a compound of formula (VIII) as a diastereomer having an RR / SS configuration. 89. A method of producing RS / SR or RR / SS diastereomers of compound (VIII),

including:
(i) providing a racemic compound of formula (V)

(ii) reducing the racemic compound of formula (V) in a solvent and optionally in the presence of a Lewis acid, where LG is bromine or chlorine, to obtain a diastereomeric mixture of a compound of formula (VI)

(iii) the formation of a mixture of diastereomers of the compounds of formula (VII)

(iv) reacting diastereomers of a compound of formula (VII) with NH ₂ PG, wherein PG is hydrogen or an amino protecting group, wherein the amino protecting group is at least one of an allyl group or an aryl-C ₁ alkyl group to produce a compound of formula (VIII) as a mixture of diastereomers; and (v) isolating the RS / SR or RR / SS diastereomers of the compound of formula (VIII) from the mixture of diastereomers by fractional crystallization. 90. The method according to claim 1, where stage (d2) is carried out for the compounds of formula (IX) or (IX ¹ ) with RSR / SRS configuration. 91. The method of claim 90, wherein the RSS / SRR diastereomer configuration in the mixture is obtained in approximately nine-fold excess relative to the RSR / SRS diastereomer configuration. 92. The method according to claim 1, where in stage (d2) the mixture is cooled using a temperature gradient from about 70 ° C to about 20 ° C. 93. The method according to paragraph 92, where the temperature gradient is from about 70 ° to about 40 ° C. 94. The method according to claim 1, where in stage (d2) the organic solvent is acetonitrile. 95. The method according to claim 1, where in stage (d2) the specified epimerization is carried out in the presence of at least 0.1 equivalent of base. 96. The method according to claim 1, where the specified epimerization is carried out in the presence of at least 0.25 equivalent of base. 97. The method according to claim 1, where in stage (d2), the base is a compound selected from the group consisting of alkoxide, amidine, guanidine and phosphazene. 98. The method of claim 97, wherein the base is amidine. 99. The method according to p, where the base is a diazabicycloundecene. 100. The method according to claim 1, where in stage (d2) the water content, if present, cannot exceed 1.0%. 101. The method according to claim 1, where in stage (d2) the water content, if present, cannot exceed 0.1%. 102. A method of obtaining racemic [2S * [R * [R * [R *]]] and [2R * [S * [S * [S *]]]] - (±) α, α '- [iminobis ( methylene)] bis [6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol] and its pharmaceutically acceptable salts, including:
(a) providing a compound of formula (IX),

the compounds of formula (IX '), which is a cyclic semi-ketal form of the compounds of formula (IX),

or mixtures thereof, wherein the compound of formula (IX) and the compound of formula (IX ') are mixtures of diastereomers;
(b) separating the diastereomers of a compound of formula (IX) or a compound of formula (IX ') in at least one of (b1) or (b2), where
(b1) separating the diastereomers of the compound of formula (IX) or the compound of formula (IX ′) by fractional crystallization after salt formation or after modification to obtain substantially pure diastereomers of the formula (IX) or formula (IX ′) containing at least 50% RSS / SRR or RRS / SSR configuration;
(b2) separating the diastereomers of the compound of formula (IX) or the compound of formula (IX ') to obtain substantially pure diastereomers of the formula (IX) or formula (IX') containing at least 50% RSS / SRR or RRS / SSR configuration at the stage of simultaneous epimerization-crystallization, where the stage of epimerization-crystallization includes:
(1) epimerizing a compound of formula (IX) or (IX ') RSR / SRS configuration to obtain a mixture of diastereomers of formula (IX) or formula (IX') RSS / SRR configuration and RSR / SRS configuration, or
epimerizing a compound of formula (IX) or (IX ') RRR / SSS configuration to obtain a mixture of diastereomers of formula (IX) or formula (IX') RRS / SSR configuration and RRR / SSS configuration, provided that the epimerization is carried out in the presence of a base and an organic a solvent where the mixture is optionally cooled with a temperature gradient and where diastereomers of the RSS / SRR configuration or RRS / SSR configuration in the mixture are obtained in at least two-fold excess relative to the diastereomers of the RSR / SRS configuration and RRR / SSS configuration; and
(2) crystallization of the substantially pure diastereomers of formula (IX) or formula (IX ') of the RSS / SRR configuration or RRS / SSR configuration at least in excess of the diastereomers of the RSR / SRS configuration and the RRR / SSS configuration;
separation of the mixture by fractional crystallization, optionally after salt formation or after modification, to produce substantially pure diastereomers of formula (IX) or formula (IX ') having an RSS / SRR or RRS / SSR configuration;
(c) recovering substantially pure diastereomers of formula (IX) or formula (IX ') having an RSS / SRR or RRS / SSR configuration to give a compound of formula (X)

as an RSSS / SRRR diastereomeric mixture in which the ratio of RSSS / SRRR of the diastereomeric configuration to the SRSR or RRSS of the diastereomeric configuration is at least 1;
(d) deprotecting a compound of formula (X), provided that PG is not H (and if PG is H, then the deprotection step is canceled) to obtain a compound of formula (I)

or its pharmaceutically acceptable salts; and (e) removing the compound of formula (I) or its pharmaceutically acceptable salts RSRS or RRSS diastereomeric configuration, if any, by recrystallization or suspension, to obtain racemic [2S * [R * [R * [R *]]]] and [ 2R * [S * [S * [S *]]]] - (±) α, α '- [iminobis (methylene)] bis [6-fluoro-3,4-dihydro-2H-1-benzopyran-2- methanol] or its pharmaceutically acceptable salts. 103. The method according to paragraph 102, where stage (b) is carried out for the compounds of formula (IX) or (IX ') RSR / SRS configuration. 104. The method of claim 103, wherein the RSS / SRR diastereomer configuration in the mixture is obtained in approximately nine-fold excess relative to the RSR / SRS diastereomer configuration. 105. The method according to p. 102, where in stage (b) the mixture is cooled at a temperature gradient from about 70 ° C to about 20 ° C. 106. The method according to p, where the temperature gradient is from 70 to 40 ° C.

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