HK1183871B - Process for the synthesis of cyclic carbamates - Google Patents

Description

Method for synthesizing cyclic carbamate

Technical Field

The present invention relates to a process for the preparation of a compound of the formula and suitable salts thereof,

wherein R is¹、R²、R⁸、R⁹And R¹⁰As defined below.

Another aspect of the present invention relates to a process for the synthesis of chiral propargyl alcohols as starting compounds for the preparation of the cyclic carbamates described above. Some cyclic carbamates of formula I are key intermediates for the preparation of pharmaceuticals and agrochemicals and as precursors for compounds in material science.

Background

WO-A-98/27073 provides anthranilic acid esters of the formulA (SD573)

Cyclization with phosgene in an organic solvent system comprising heptane and tetrahydrofuran to yield DMP-266 of formula I, wherein R¹Is trifluoromethyl, R²Is cyclopropyl, R⁸Is 6-chloro, R⁹Is hydrogen and R¹⁰Is hydrogen. WO-A-98/51676 and WO-A-99/61026 provide related cyclization processes of such ortho-aminobenzyl alcohols with phosgene in the presence of potassium bicarbonate in A two-phase solvent system comprising methyl tert-butyl ether/water or toluene/water.

There are various published methods in the prior art for preparing compounds of the formula,

the compound is a precursor compound before cyclization. The prior art processes require more than one protic reagent and sometimes require high levels of zinc catalyst. Since the cyclized product is an API (active pharmaceutical ingredient), it is important to reduce the heavy metal catalyst as much as possible.

Jiang et al, tetrahedron Lett.2002, 43, 8323-. Chiral compounds are not mentioned at all.

WO-A-95/20389, WO-A-96/37457, WO98/30543 and WO98/30540 disclose various methods for the preparation of chiral propargyl alcohols useful for the synthesis of pharmaceuticals. WO-A-98/51676 discloses A process wherein A chiral product is obtained in high correspondent excess by adding A first chiral agent and optionally A second additive in A zinc (II) -mediated reaction. The disadvantage of the process is the use of large amounts of expensive zinc catalyst and chiral compounds.

It was therefore a further object of the present invention to provide an alternative process for preparing chiral propargyl alcohols in high molar excess of the corresponding compound. Another problem is to reduce the amount of catalyst and other components to be added during the reaction to facilitate the handling procedure of the product and to facilitate industrial production.

The problem to be solved is to provide an alternative process for the preparation of compounds of formula I in high yield and quality.

Disclosure of Invention

The problem is solved by the invention.

There is provided a process for the preparation of a compound of the formula and/or a suitable salt thereof,

wherein

R¹Selected from hydrogen, straight-chain or branched C_1-6-alkyl or (C)_1-6-alkoxy) carbonyl, and any alkyl or alkoxy group optionally substituted with one or more halogen atoms,

R²selected from straight-chain or branched C_1-6Alkyl radicals, (C)_1-6-alkoxy) carbonyl, C_3-6-alkenyl, C_3-6-alkynyl and C_3-6Cycloalkyl, wherein each alkyl, alkoxy, alkenyl, alkynyl and cycloalkyl group may carry an aryl, aralkyl, C_1-6Alkyl and (1' -R)³)-C_3-6-another substituent of cycloalkyl, wherein R³Is hydrogen, methyl or ethyl, and wherein any alkyl, cycloalkyl, aryl and aralkyl group is optionally substituted with one or more halogen atoms, cyano, C_1-6Alkyl radical, C_3-6-cycloalkyl, -NR⁴R⁵、-SR⁶、S(O)R⁶Or S (O)₂)R⁶and/OR-OR⁷Is substituted, and R⁶Is C_1-6-an alkyl group, optionally substituted with one or more halogen atoms,

R⁷is hydrogen or C_1-6-an alkyl group, optionally substituted with one or more halogen atoms,

wherein

(a)R⁴And R⁵Independently selected from hydrogen or C_1-6-alkyl, or

(b)R⁴Is hydrogen and R⁵Is C_2-7-acyl or (C)_1-6-alkoxy) carbonyl, wherein R⁵Each of the acyl and alkoxy groups in turn being optionally substituted with one or more halogen atoms, or

(c)R⁴And R⁵Together with the nitrogen atom form a 5-to 7-membered heterocyclic ring, or

(d)R⁴And R⁵Together being ═ CH-aryl, the aryl moiety optionally being selected from one or more halogen atoms, -NH₂、-NH(C_1-6-alkyl), -N (C)_1-6-alkyl groups)₂Or C_1-6-substituent substitution of alkyl, or

(e)R⁴And R⁵Together being CH-N (C)_1-6-alkyl groups)₂，

R⁶Is C_1-6-alkyl, optionally substituted with one or more halogen atoms, and

R⁷is hydrogen or C_1-6-an alkyl group, optionally substituted with one or more halogen atoms,

R⁸and R⁹Independently selected from hydrogen, halogen atoms and C optionally substituted with one or more halogen atoms_1-6-an alkyl group,

R¹⁰is hydrogen or is selected from aryl, aralkyl, C_1-6-alkyl and (C)_1-6-alkoxy) carbonyl group, in any ofThe aryl group and the aryl moiety in the aralkyl group are optionally selected from one or more of C_1-6Alkyl radical, C_{1- 6}-alkoxy or C_3-8Substituents in cycloalkyl, each alkyl, alkoxy or cycloalkyl substituent being optionally substituted with one or more halogen atoms,

said process comprising reacting a compound of the formula and/or a suitable salt thereof with a cyclisation agent selected from phosgene, diphosgene, triphosgene and mixtures thereof,

wherein R is¹、R²、R⁸、R⁹And R¹⁰As defined above, the above-mentioned,

characterized in that the reaction is carried out in the presence of an aqueous base and a water-immiscible organic solvent, wherein at least 90% (w/w) of the organic solvent is selected from the group consisting of at least one C_2-5-carboxylic acid C_{2- 5}Alkyl esters with at least one C_5-8-mixture of alkanes and C_2-5-carboxylic acid C_2-5-at least one member of the group consisting of alkyl esters.

In a preferred embodiment, the process is applied to the optically active compound of formula II. Substituent R attached to the carbinol carbon atom of the compound of formula I after cyclisation¹and-C ≡ C-R²Then have the same structure in the respective compounds of formula II.

Here and hereinafter, the term "alkyl" denotes a straight-chain or branched alkyl group. Just use the form "C_1-n-alkyl "means having from 1 to n carbon atoms. C_1-6Alkyl represents, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl or hexyl.

Here and hereinafter, the term "alkenyl" denotes a straight-chain or branched radical carrying at least one carbon-carbon double bond. Just use the form "C_3-n-alkenyl "means that the backbone of the alkenyl has 3 to n carbon atoms. C_3-6Alkenyl represents, for example, propen-2-yl, propen-3-yl (allyl), buten-1-yl or hexen-1-yl.

Here and hereinafter, the term "alkynyl" denotes a straight-chain or branched radical carrying at least one carbon-carbon triple bond. Just use the form "C_3-n-alkynyl "means that the backbone of the alkynyl group has 3 to n carbon atoms. C_3-6Alkynyl represents, for example, 1-propynyl, 3-propynyl or 1-hexynyl.

Here and in the following, the term "alkoxy" denotes straight-chain or branched alkoxy. Just use the form "C_1-n-alkoxy "said alkyl group means having from 1 to n carbon atoms. C_1-6Alkoxy represents, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy or hexyloxy.

Here and hereinafter, the term "C_3-n-cycloalkyl "denotes a cycloaliphatic radical having from 3 to n ring carbon atoms. C_3-8-cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

Here and hereinafter, the term "aryl" denotes an aromatic or heteroaromatic radical selected from the group consisting of phenyl, naphthalen-1-yl, naphthalen-2-yl, furan-3-yl, thiophen-2-yl, thiophen-3-yl, benzo [ b ] furan-2-yl, and benzo [ b ] thiophen-2-yl.

Here and hereinafter, the term "aralkyl" denotes a group consisting of an alkyl and an aryl moiety, wherein the alkyl moiety of the aralkyl residue is C_1-8Alkyl and the aryl moiety is selected from phenyl, 1-naphthyl, 2-naphthyl, furan-2-yl, furan-3-yl, thiophen-2-yl, thiophen-3-yl, benzo [ b]Furan-2-yl and benzo [ b]Thiophen-2-yl.

Here and hereinafter, the term "C_2-5-carboxylic acid C_2-5-alkyl ester "means a mixture ofAn acyl and alkoxy moiety wherein said acyl moiety is selected from the group consisting of acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, sec-valeryl and pivaloyl.

Here and hereinafter, the term "C_5-8Alkane "means a linear or branched aliphatic or cycloaliphatic hydrocarbon having from 5 to 8 carbon atoms. In industrial chemistry, medium chain aliphatic hydrocarbons such as hexane, heptane and octane are often used as mixtures of the respective linear hydrocarbons together with their branched (i.e. isomeric) forms. However, n-hexane, n-heptane and n-octane can also be used in pure form.

Here and hereinafter, the term "dialkyl" independently means an alkyl group attached to a linking atom. For example, in dialkylzinc (II) compounds, two alkyl groups are attached to zinc, whereas in dialkylamines, two alkyl groups are attached to nitrogen.

Contrary to previous attempts, it was surprising that the pH of the reaction mixture did not need to be controlled within a certain range, but the formation of side products was limited when the pH of the aqueous phase was maintained at a pH between about pH6 to 11. Also, at a pH of the tai acid, the compound of formula I or II may be extracted from the water-immiscible solvent into the aqueous phase. The adjustment of the pH can be carried out, for example, by pre-charging a suitable base in the reaction vessel and/or by controlling the addition of a suitable base, preferably a water-miscible and/or water-soluble base, more preferably an organic or inorganic base selected from alkali or alkaline earth metal carbonates, bicarbonates and hydroxides, piperidines, C_1-4Alkyl piperidines, pyridines C_1-4-alkylpyridines, morpholines and tri-C_1-4-an alkylamine. Weak bases such as alkali or alkaline earth metal carbonates, bicarbonates are preferred.

When used as a compound of formula II, chiral anthranilic acid is used as a starting compound in the process, the conformation of the starting compound being maintained in the compound of formula I. In a preferred embodiment, the compound of formula (I) is selected from the group consisting of¹And R²Different compounds were subjected to the reaction.

In a further preferred embodiment, in the compounds of the formula II, the substituent R¹Is C_1-4-perfluoroalkyl radical, R²Is cyclopropyl or 1-methyl-cyclopropyl, R⁸Is a halogen atom para to the amino group, preferably chlorine, R⁹Is hydrogen and R¹⁰Is hydrogen.

The reaction is preferably carried out using the free base of the formula II as starting compound, but it is also possible to use salts of the base with inorganic or organic acids. Suitable salts are for example the hydrochloride, sulfate, methanesulfonate, oxalate or tartrate salts. Since the free base of formula II is an amine, typically such salts contain an excess of acid. Thus, both stoichiometric and non-stoichiometric mixtures and/or salts of the compound of formula II with at least one acid are useful. A preferred salt is the methane sulfonate, which contains methane sulfonic acid in molar equivalents of about 1:1 to 1.5:1 with the free amino base of formula II. Where appropriate, additional amounts of base must be taken into account to neutralize the hydrolysis effect of the acid salt to avoid side reactions, since the cyclization of the process is preferably carried out at a pH of the aqueous phase of between about pH6 to 11. In the case of strongly acidic salts (such as methane sulfonate), an additional step for releasing the free base may be useful. In a preferred embodiment, the release of the free base from the acidic salt may be carried out in a mixture of a water-immiscible organic solvent and an aqueous solution of a weak base, preferably a water-miscible base and/or a water-soluble base, more preferably an inorganic or organic base selected from alkali or alkaline earth metal carbonates, bicarbonates, phosphates and hydroxides; ammonium carbonate, ammonium bicarbonate, ammonium phosphate, and ammonia; piperidine, C_1-4Alkyl piperidines, pyridines C_1-4-alkylpyridines, morpholines and tri-C_1-4-an alkylamine.

If the salt of the compound of formula II is released in an additional step prior to cyclisation, in a preferred embodiment the release is carried out in the same solvent as the cyclisation which is then carried out, to ease handling. Since the solvent of the present invention is considered to be water-immiscible, the base release can be easily performed by extracting the organic solvent with an aqueous base solution.

As outlined above, in a preferred embodiment, the organic solvent of the extraction consists essentially of at least one C selected from_2-5-carboxylic acid C_2-5Alkyl esters with at least one C_5-8-mixture of alkanes and C_2-5-carboxylic acid C_2-5-at least one member of the group consisting of alkyl esters. Most preferred solvents are selected from the group consisting of acetate, hexane, heptane and mixtures thereof.

Phosgene or two equivalents thereof diphosgene and triphosgene can be equivalently used as cyclizing agents in the present process, either in pure form or as a mixture. For the use of phosgene, diphosgene and triphosgene as cyclisation agents in the above process, it will be appreciated that 1 molar equivalent of diphosgene replaces 2 molar equivalents of phosgene, while 1 molar equivalent of triphosgene replaces 3 molar equivalents of phosgene. The reactivity of all three compounds is essentially the same.

Under standard conditions (20 ℃,1 bar), phosgene is a gas, diphosgene is a liquid and triphosgene is a solid, respectively. Thus, which cyclizing agent is used depends mainly on the desired reaction conditions and local availability.

In a preferred embodiment, in the process as described above, the cyclisation agent is provided in gaseous form.

In another preferred embodiment, in the process as described above, the cyclizing agent is provided in pure form, as a solution or as a liquid in suspension. Phosgene, diphosgene and triphosgene can be dissolved in an aprotic solvent to be provided in liquid form.

In another preferred embodiment, in the process as described above, the cyclisation agent is provided in solid form.

To improve the processing procedure, it may be useful to provide a slight excess of cyclizing agent. In the process described above, the molar ratio of cyclizing agent to compound of formula II, calculated as molar equivalents of phosgene, should be in the range of 1:4, preferably in the range of 1:1 to 2.5:1, more preferably in the range of 1.1:1 to 1.5: 1. Generally, the most preferred molar ratio is about 1.2: 1. It should be noted that, surprisingly, even a large excess of 10:1 molar ratio of phosgene equivalent to compound of formula II has little negative effect in view of product formation.

The requirement of the present invention is that the base is a water miscible base and/or a water soluble base to allow extraction of the base into the aqueous phase after cyclization is complete.

The base used in the reaction may be an inorganic base or an organic base.

Examples of inorganic bases are carbonates, bicarbonates and hydroxides of alkali metals or alkaline earth metals.

Examples of suitable organic bases are piperidine, C_1-4Alkyl piperidines, pyridines C_1-4-alkylpyridines, morpholines or tri-C_1-4-alkylamines, wherein any alkyl moiety is independently selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl. Using weak bases, e.g. carbonates, bicarbonates of alkali metals or alkaline earth metals, or having different pK' s_bThe combination of different bases of (a) creates a buffer system. In the case of a strong base, such as an alkali or alkaline earth metal hydroxide, similar amounts of phosgene and base may be advantageous.

The process as described above, wherein the weight ratio of water to organic solvent is in the range of 1:1 to 5:1, preferably in the range of 2:1 to 3.5: 1.

In a preferred embodiment, at least 90% (w/w) of said organic solvent is selected from the group consisting of at least one C_2-5-carboxylic acid C_2-5Alkyl esters with at least one C_5-8-mixture of alkanes and C_2-5-carboxylic acid C_2-5-at least one member of the group consisting of alkyl esters.

In another preferred embodiment, at least 95% (w/w), even more preferably at least 98% (w/w) of said organic solvent is selected from the group consisting of at least one C_2-5-carboxylic acid C_2-5-alkyl estersAnd at least one C_5-8-mixture of alkanes and C_2-5-carboxylic acid C_2-5-at least one member of the group consisting of alkyl esters. In another preferred embodiment, the water-immiscible organic solvent is selected from the group consisting of at least one C_2-5-carboxylic acid C_2-5Alkyl esters with at least one C_5-8-mixture of alkanes and C_2-5-carboxylic acid C_2-5-at least one member of the group consisting of alkyl esters.

Will be different from that of at least one C_2-5-carboxylic acid C_2-5Alkyl esters with at least one C_5-8-mixture of alkanes and C_2-5-carboxylic acid C_2-5A fraction of compounds of the group consisting of alkyl esters forming up to 10% (w/w), in a preferred embodiment up to 5% (w/w), and in an even more preferred embodiment up to 2% (w/w) of the solvent is defined as additional organic co-solvent. The term "additional organic co-solvent" also encompasses mixtures of more than one organic compound.

The additional organic co-solvent also needs to be immiscible with water and should not act as a solubilizer or emulsifier between the aqueous and organic phases in the reaction mixture. In the presence of water, the additional cosolvent must be miscible with at least one C_2-5-carboxylic acid C_2-5Alkyl esters with at least one C_5-8-mixture of alkanes and C_2-5-carboxylic acid C_2-5-at least one miscible of the group consisting of alkyl esters. At least after dissolution in the water-immiscible solvent, the additional co-solvent is required to have a lower density than water to avoid separation of the solvent into the three phases.

The additional organic solvent may comprise a compound selected from the group consisting of: aromatic compounds such as benzene, toluene, substituted naphthalenes; or a fully or partially hydrogenated compound such as decalin or tetralin.

Preferably, said C_2-5-carboxylic acid C_2-5-alkyl ester is selected from acetic acid C_2-5Alkyl esters, propionic acid C_2-5-alkyl esters and butyric acidC_2-5-an alkyl ester.

In another preferred embodiment, said C_2-5-carboxylic acid C_2-5-alkyl ester is selected from acetic acid C_2-5Alkyl esters and propionic acid C_2-5-an alkyl ester.

Suitably, said C_5-8-the alkane is selected from pentane, cyclopentane, hexane, cyclohexane, heptane, cycloheptane and octane.

Even more suitably, said C_5-8-the alkane is selected from hexane, cyclohexane, heptane and cycloheptane, preferably from heptane.

Preferably, the cyclisation is carried out at a temperature of-30 to +40 ℃, even more preferably 0 to +20 ℃.

The work-up procedure for removing excess phosgene, diphosgene or triphosgene and organic solvent to facilitate crystallization of the compound of formula I is preferably carried out in a manner known in the art.

According to the invention, the product can be obtained with normal liquid-liquid extraction. Dissolving the product as a free base in said organic solvent comprising at least one C selected from_2-5-carboxylic acid C_2-5Alkyl esters with at least one C_5-8Mixture of alkanes and C_2-5-carboxylic acid C_2-5-at least one of alkyl esters.

After extraction, the product can be crystallized directly in an organic solvent. Thus, the cyclization, optional liquid-liquid extraction and crystallization can be carried out without any solvent change with respect to the organic solvent. Advantageously, the crystallization is carried out by seeding the organic solvent containing the product with seed crystals of the product.

The present process also comprises a novel process for the preparation of the compound of formula II, therefore, we also claim a process for the preparation as described above, wherein the compound is obtained by the following process. Only the main methods as mentioned above are stated. For the avoidance of doubt, all of the above mentioned preferred embodiments also apply to the following process.

There is provided a process for the preparation of a compound of the formula and/or a suitable salt thereof,

said process comprising reacting a compound of the formula and/or a suitable salt thereof with a cyclisation agent selected from phosgene, diphosgene, triphosgene and mixtures thereof,

wherein R is¹、R²、R⁸、R⁹And R¹⁰As defined above, the above-mentioned,

wherein the reaction is carried out in the presence of an aqueous base and a water-immiscible organic solvent, wherein at least 90% (w/w) of the organic solvent is selected from the group consisting of at least one C_2-5-carboxylic acid C_2-5Alkyl esters with at least one C_5-8-mixture of alkanes and C_2-5-carboxylic acid C_2-5-at least one member of the group consisting of alkyl esters, and wherein the compound of formula II is obtained by a process comprising the steps of:

(i) reacting a protic chiral auxiliary with a diorganozinc (II) compound in the presence of an aprotic solvent at a temperature in the range of from 0 to 40 ℃, and

(ii) (ii) the mixture of step (i) is kept at the first maturation period until the reaction is complete, preferably under stirring, but for at least 20 minutes, preferably between about 20 and 120 minutes, and

(iii) (iii) reacting the mixture obtained after step (ii) with a compound of formula,

wherein R is²As defined above, the above-mentioned,

(iv) (iv) maintaining the mixture of step (iii) in a second maturation period until the reaction is complete, preferably under stirring, but for at least 10 minutes, preferably between about 10 and 120 minutes, and

(v) (iii) reacting the mixture obtained after step (iv) with a compound of formula and an organolithium base and/or other organoalkali metal at a temperature in the range of from 0 to 40 ℃,

wherein R is¹、R⁸、R⁹And R¹⁰As defined above, and

(vi) (vi) maintaining the mixture obtained in step (v) at 0 to 50 ℃ until the reaction is complete to obtain the compound of formula II.

The main advantage of the process is the reduction of the zinc (II) catalyst in respect of the compound of formula IV, only requiring a protic compound to react first with the zinc (II) catalyst, in particular avoiding the possibility of adding fluorinated alcohols.

In contrast to known methods, which require the addition of two different proton sources, the additional proton source can be methanol, ethanol, propanol, isopropanol, butanol, isobutanol, sec-butanol, tert-butanol, pentanol, (CH)₃)₃CCH₂OH、(CH₃)₃CCH(CH₃)OH、Cl₃CCH₂OH、CF₃CH₂OH、CH₂＝CHCH₂OH、(CH₃)₂NCH₂CH₂OH or even other chiral compounds. The process of the invention can be carried out with only one proton source which simultaneously acts as a chiral auxiliary. In this sense, the preferred proton source is a ephedrine derivative, more preferably a phenylnorephedrine derivative (PNE derivative).

The present invention relies on the specific order of addition of the diorganozinc (II) compound, compounds of formulae III and IV, which includes the two maturation stages of steps (II) and (IV), respectively. The term "until the reaction is complete" in steps (ii), (iv) and (vi) means that at least 90% conversion, preferably at least 95%, more preferably at least 98%, is achieved in the respective step. The course of the conversion can be tracked, for example, by thermal measurement, "ReactIR" or FT-IR. Off-line methods such as gas chromatography or HPLC may also be used. Correlations between the transformation and the output of the analytical method can be easily constructed with computer-aided systems. It is suspected that a first catalytic species may be formed during the first maturation stage and a second catalytic species may be formed during the second maturation stage. The first catalytic species may comprise a compound of formula (alkyl) Zn (chiral auxiliary), which may be dissolved in the mixture or aggregated. The second catalytic species may comprise the formula (C ≡ C-R)²) Zn (chiral auxiliary) compound, wherein R²As defined above. By using diethyl zinc, an ethane release of about 1 equivalent relative to diethyl zinc can be observed in steps (ii) and (iv), respectively. Ethane formation can be detected during the addition of diethyl zinc. A delay in ethane evolution relative to the diethylzinc addition was observed. It is assumed that ethane is first dissolved in the reaction solution and then released into the gas phase.¹H-NMR analysis showed that some ethane was still dissolved in the reaction mixture. Only the structure of the catalytic species can be proposed, since it is difficult to separate the catalytic species from the respective precursor. In particular, because the catalytic material may be highly sensitive to air and humidity.

In step (v), the compound of formula IV and the organolithium base and/or other alkali metal organyl group may be fed simultaneously to add, separately or as a mixture. Advantageously, the feeding of the organolithium base and/or other organoalkali metal is started before the feeding of the compound of formula IV, preferably up to 20 minutes, more preferably up to about 10 minutes, in advance.

The process is designed to obtain a compound of formula I having an enantiomeric purity (ep) of at least 90%, preferably having an ep of at least 95%, more preferably at least 96%, and even more preferably at least 97%.

The protic chiral auxiliary initiates the desired enantiomer formation during the reaction of the compounds of the formulae III and IV. The expression "protic chiral auxiliary" means that the chiral auxiliary comprises at least one proton, which is easily removable, most preferably in the hydroxyl group.

In a preferred embodiment, the chiral auxiliary is selected from protic N, N-disubstituted ephedrine derivatives.

Suitable protic N, N-disubstituted ephedrine derivatives are, for example, the diastereomers of: 2- (di-C)_1-4-alkylamino) -1-phenyl-propan-1-ol, such as 2- (dimethylamino) -1-phenyl-propan-1-ol, 2- (diethylamino) -1-phenyl-propan-1-ol, 2- (diisopropylamino) -1-phenyl-propan-1-ol, and 2- (dibutylamino) -1-phenyl-propan-1-ol; 2- (N, N-C)_4-6-alkylene) -1-phenyl-propan-1-ol such as 1-phenyl-2- (piperidinyl) propan-1-ol and 1-phenyl-2- (pyrrolidinyl) propan-1-ol; and 2- (1-heteroaryl) -1-phenyl-propan-1-ol, such as 1-phenyl-2- (1-pyridyl) propan-1-ol, and. A more specific example is (1R,2S) -2- (dimethylamino) -1-phenyl-propan-1-ol (CAS [552-79-4 ]](1S,2R) -2- (dimethylamino) -1-phenyl-propan-1-ol (CAS [42151-56-4 ]]) (1R,2R) -2- (dimethylamino) -1-phenyl-propan-1-ol (CAS [14222-20-9 ]]) And (1S,2S) -2- (dimethylamino) -1-phenyl-propan-1-ol (CAS [51018-28-1 ]]) (1R,2S) -1-phenyl-2- (pyrrolidinyl) propan-1-ol (CAS [127641-25-2 ]]) (1S,2R) -1-phenyl-2- (pyrrolidinyl) propan-1-ol (CAS [123620-80-4 ]](1S,2R) -PNE), (1R,2R) -1-phenyl-2- (pyrrolidinyl) propan-1-ol, and (1S,2S) -1-phenyl-2- (pyrrolidinyl) propan-1-ol.

In a preferred embodiment, the protic chiral auxiliary is (1R,2S) -phenylnorephedrine ((1R,2S) -PNE), (1R,2S) -1-phenyl-2- (pyrrolidinyl) propan-1-ol) to obtain ((S) -2- (2-amino-5-chlorophenyl) -4-cyclopropyl-1, 1, 1-trifluorobut-3-yn-2-ol (SD573) or one of its salts from 1- (2-amino-5-chlorophenyl) -2,2, 2-trifluoroacetone and cyclopropylacetylene.

The amount of zinc (II) catalyst required in the reaction can be significantly reduced compared to methods known in the art. It must be noted that the amount of zinc (II) catalyst can be surprisingly much lower than the amount of chiral auxiliary.

In a preferred embodiment, the molar ratio of protic chiral auxiliary agent to diorganozinc (II) compound is in the range of 1.5:1 to 1:1, preferably in the range of 1.3:1 to 1.2:1, most preferably about 1.24: 1.

The chiral auxiliary mediates the catalytic process. Although the zinc (II) catalyst and the protic chiral auxiliary agent are contemplated to form a zinc (II) complex with specific stoichiometric properties, it is not necessary to add the chiral auxiliary agent and the zinc (II) catalyst in equimolar amounts. Preferably, the amount of the chiral auxiliary is slightly higher than the amount of the diorganozinc (II) catalyst.

Suitable diorganozinc (II) compounds are selected, for example, from di (C)_1-8-alkyl) and di (C)_3-6-cycloalkyl), wherein the alkyl moiety is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl, pentyl, hexyl, heptyl and octyl, and wherein the cycloalkyl moiety is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

In another embodiment, the diorganozinc (II) compound is diphenylzinc or Zn (OTf)₂Wherein OTf represents a "triflate" (trifluoromethanesulfonate) group.

In a preferred embodiment, in step (i), the molar ratio of protic chiral auxiliary agent to compound of formula III is in the range of 1:1 to 1:10, preferably in the range of 1:2 to 1:6, more preferably in the range of 1:3 to 1: 6.

The addition of the compound of formula III may be carried out at a temperature of from 0 to +40 c, preferably from +10 to about +30 c.

In a preferred embodiment, the compound of formula III is selected from terminal C_3-8Alkyl alkynes, cyclopropyl acetylenes, (1' -methyl) -cyclopropyl acetylenes and phenyl acetylenes.

It is recommended that in step (III) the compound of formula III is used in a molar ratio to the compound of formula IV of from 1:0.6 to 1: 1.3.

In another preferred embodiment, an organolithium base is added in a molar ratio to the compound of formula III in the range of 1:0.8 to 1:1.5, preferably 1:0.8 to 1: 1.2.

Suitable organolithium bases in the present process are selected from (C)_1-6-alkyl) lithium, Lithium Diisopropylamide (LDA), lithium hexamethyldisilazide (LiHMDS), phenyllithium and lithium napthyl.

Preferably, the organolithium base is an organolithium compound or a lithium organic salt.

In a preferred embodiment, such organometallic lithium compounds are selected from phenyllithium and (C)_1-6-alkyl) lithium.

Preferably said (C)_1-6-alkyl) lithium is selected from methyllithium, n-butyllithium, sec-butyllithium, tert-butyllithium and hexyllithium.

In another preferred embodiment, the lithium organic salt is C_1-6-a lithium alkoxide.

Preferably the other organic base alkali metal is selected from C_1-6Sodium alkoxide or C_1-6-potassium alcoholate, sodium or potassium diisopropylamine, and sodium or potassium hexamethyldisilazide.

The organolithium base and/or other organoalkali metals can be used independently or as a mixture of at least two different species.

The reaction mixture is preferably maintained at a temperature of about +10 to +30 ℃ during the addition of the organolithium base and/or other organoalkali metal.

In the present process, the aprotic solvent is preferably selected from the group consisting of aprotic non-polar solvents, aprotic polar solvents and mixtures thereof.

The solvents of the reagents added to the solution can be chosen independently of each other. Particularly preferred solvents are selected from the group consisting of tetrahydrofuran, benzene, chlorobenzene, o-dichlorobenzene, m-dichlorobenzene, p-dichlorobenzene, dichloromethane, toluene, o-xylene, m-xylene, p-xylene, hexane, heptane, cyclohexane, pentane, 1, 4-dioxane, cyclohexane, diethyl ether, tert-butyl methyl ether, diisopropyl ether, N-methylpyrrolidine, and mixtures thereof.

Detailed Description

Example (b):

two chiral alkynylation reactions were performed with the respective starting compounds (examples 1, 2 and 4). (1R,2S) -1-phenyl-2- (pyrrolidinyl) propan-1-ol ((1R,2S) -PNE) was used once as a ligand, and (1S,2R) -1-phenyl-2- (pyrrolidinyl) propan-1-ol ((1S,2R) -PNE) was used once as a ligand. This allowed a clear determination of both enantiomers of the product by HPLC. In the following experimental details, only the experiment using (1S,2R) -PNE is described in detail, since there is no major difference between (1R,2S) -PNE and (1S,2R) -PNE. For all examples using cyclopropylacetylene added to the diethylzinc catalyst, ethane evolution can be observed as described in example 1. The product configurations of examples 2 to 4 can be determined initially based on the following assumptions: the reaction in the presence of the ligand (1S,2R) -PNE preferably gives a product with the (R) -configuration analogous to example 1(SD573 method), both enantiomers being well known. In the SD573 method, (1R,2S) -PNE preferably gives rise to a product having the (S) -configuration. The procedure for analytical methods a to D is attached to the examples.

In all cyclization examples, ee is not measured, except where not explicitly mentioned, since in all cyclization examples with final ee-measurement the product (e.g. DMP-266) always corresponds to the ee of the respective starting compound, for example in the case of cyclization to DMP-266 of the SD573-MSA or SD573 free base (CAS [209412-27-7], 99.6% ee).

ee-enantiomeric excess ((S) - (R))/((S) + (R))

enantiomeric purity (S)/((S) + (R))

Example 1: (S) -2- (2-amino-5-chlorophenyl) -4-cyclopropyl-1, 1, 1-trifluorobut-3-yn-2-ol methanesulfonate (2:3mol/mol) (SD573-MSA)

A solution of (1R,2S) -PNE in a THF/toluene mixture (9: 1-w/w) (18.1% (w/w), 171.6g, 151mmol) was charged to a vessel and cooled to 17 ℃. A solution of diethylzinc (29% (w/w), 52.0g, 122mmol) in toluene was added at 15 to 20 ℃ and the mixture was aged at that temperature for 30 minutes. Ethane (about 1 equivalent relative to diethylzinc) is formed during the divinyl zinc addition and is partially released from the reaction mixture. The ethane release was observed to have a delay relative to the diethylzinc addition, as ethane first dissolved in the reaction solution and then released to the gas phase. According to¹H-NMR analysis, some ethane was still dissolved in the reaction mixture. Cyclopropyl acetylene (compound of formula III, wherein R is in toluene) is added at 15 to 20 deg.C²Is cyclopropyl) solution (70% (w/w), 57.0g, 600mmol) and the resulting mixture is aged at 20 ℃ for 1 hour. During the addition of cyclopropylacetylene, additional ethane (about 1 equivalent relative to diethylzinc) was formed and released into the gas phase. To the reaction mixture were added in parallel a solution of butyllithium (BuLi) in toluene (157.6g, 2.92mol/kg, 460mmol) and 1- (2-amino-5-chlorophenyl) -2,2, 2-trifluoroacetone (SD570, compound of formula IV, where R is R570) in THF/toluene (1: 1-w/w) at 20 ℃ over 180 min¹Is trifluoromethyl, R⁸Is 5-chloro, R⁹Is hydrogen and R¹⁰Hydrogen) solution (40.1% (w/w), 278.0g, 500 mmol). BuLi addition was started 10 minutes before SD570 addition. Butane was formed during the BuLi addition. However, most of the butane still dissolved in the reaction mixture and only weak gas formation was observed. The course of the reaction can be tracked on-line, for example, by thermal measurement or by "ReactIR", also known as "in situ FTIR". After complete addition of SD570, at 20 ℃ willThe reaction mixture was stirred for 30 minutes, then heated to 30 ℃ over a period of 60 minutes and aged at 30 ℃ for 6 hours. The reaction mixture was stirred at 0 ℃ overnight, diluted with toluene (218g) at 20 ℃ and quenched by addition of aqueous citric acid (1M, 375 g). After stirring for 15 minutes, the phases were separated and the aqueous phase was discarded. With water (76g), NaHCO in sequence₃The aqueous solution (5% (w/w), 200g) and the organic phase washed again with water (100 g). The organic phase is partially concentrated and then diluted with toluene (250g), again partially concentrated and diluted with toluene (976g residue). According to method B, (S) -2- (2-amino-5-chlorophenyl) -4-cyclopropyl-1, 1, 1-trifluorobut-3-yn-2-ol (SD573) in the crude product has an enantiomeric purity (ep) of about 96 to 97%. Although not a preparative method, a method of converting the product in a more stable form as a methane sulfonate is also described. The residue was diluted with isopropanol (126.6 g). Methane sulfonic acid (43.3g) was then added over a period of 30 minutes at 30 ℃. Seeds (between 1 and 10 mg) were added and the mixture was aged at 30 ℃ for 30 minutes. A second portion of methanesulfonic acid (26.5g) was added over a period of 60 minutes at 30 ℃. The resulting solution was aged at 30 ℃ for 30 minutes and then cooled to 5 ℃ over a period of 60 minutes. After an additional 30 minutes of aging at 5 ℃, the product was filtered and washed with cold toluene/isopropanol (10: 1-w/w, 262g) at 5 ℃. The wet methanesulfonate salt of SD573 ((S) -2- (2-amino-5-chlorophenyl) -4-cyclopropyl-1, 1, 1-trifluorobut-3-yn-2-ol methanesulfonate (2:3mol/mol, SD573-MSA, compound of formula II, where R is R, was dried at 40 ℃ in vacuo¹Is trifluoromethyl, R²Is cyclopropyl, R⁸Is 5-chloro, R⁹Is hydrogen and R¹⁰Hydrogen)) to obtain 188.3g (432mmol, 86.5% yield). According to method A, SD573-MSA is obtained with a purity of 99.9% and an ep of 99.7%.

Example 2: (R) -2- (2-aminobiphenyl-3-yl) -4-cyclopropyl-1, 1, 1-trifluorobut-3-yn-2-ol methanesulfonate (1:1mol/mol)

THF/toluene (9: 1-w/w, 18.2% (w/w) was added under a nitrogen atmosphere) Was charged into a dry 150mL jacketed reactor with a stirrer (1S,2R) -PNE (20.3g, 18.0 mmol). Diethyl zinc in toluene (29.9% (w/w), 6.48g, 15.7mmol) was added via syringe, maintaining the temperature at 17 to 22 ℃, and the mixture was aged for 30 minutes at 17 ℃. Cyclopropylacetylene (69.6% (w/w), 6.84g, 72.0mmol) in toluene was added at 17 deg.C and the resulting mixture was aged at 20 deg.C for about 60 minutes. BuLi (3.06mol/kg, 19.9g, 60.9mmol) in toluene and 1- (4-aminobiphenyl-3-yl) -2,2, 2-trifluoroacetone (CN46225, compound of formula IV where R is R46225) in THF/toluene (1:1 w/w) are added to the reaction mixture in parallel over a period of 3 hours at 20 deg.C¹Is trifluoromethyl, R⁸Is 5-phenyl, R⁹Is hydrogen and R¹⁰Hydrogen) (43.0% (w/w), 37.0g, 60 mmol). The BuLi addition was started about 10 minutes before the CN46225 addition. After complete addition of BuLi and CN46225, the reaction mixture was stirred at 20 ℃ for 30 minutes, then heated to 30 ℃ over a period of 1 hour and aged at 30 ℃ for 6 hours. The reaction mixture was stirred at 0 ℃ overnight. According to method B, HPLC indicated 94.3% conversion and 95.6% ep. The reaction mixture was diluted with toluene (27.6g) at room temperature and quenched by the addition of aqueous citric acid (1M, 45.3 g). The phases were separated and the aqueous phase was discarded. With water (9.1g), NaHCO in sequence₃The organic phase was washed with an aqueous solution (5% (w/w), 24.2g) and water (12.0 g). The organic phase was heated under reduced pressure to partially remove THF while adding toluene to finally obtain (R) -2- (4-aminobiphenyl-3-yl) -4-cyclopropyl-1, 1, 1-trifluorobut-3-yn-2-ol (CN46630, compound of formula II, wherein R is¹Is trifluoromethyl, R²Is cyclopropyl, R⁸Is 5-phenyl, R⁹Is hydrogen and R¹⁰Hydrogen) was added to the residue (54.5 g). The residue was diluted with isopropanol (16.7g) and toluene (60.0 g). A first portion of methanesulfonic acid (5.48g, 57.0mmol) was added via a syringe pump over a period of 30 minutes at 30 ℃. Seeds (between 1 and 10mg in small portions) were added and the mixture was aged at 30 ℃ for 30 minutes. A second portion of methanesulfonic acid (2.88g, 30.0mmol) was added via syringe pump over a period of 45 minutes at 30 ℃. The mixture was gradually aged and cooled during 1 hour 45 minutesTo finally reach 5 ℃. The product was filtered and the filter cake was washed with toluene/isopropanol (10: 1-w/w, 27.0g) and dried in vacuo at 40 ℃. The dried product (R) -2- (4-aminobiphenyl-3-yl) -4-cyclopropyl-1, 1, 1-trifluorobut-3-yn-2-ol methanesulfonate (1:1mol/mol, CN46630-MSA) (15.2g, 35.6mmol, 59% yield) was obtained as an off-white solid (purity 99.4% and ep 99.7% according to method B). The combined mother liquor and washings were concentrated (46.7g residue). During storage at 3 ℃ overnight, a white solid crystallized from the residue. The product was filtered, washed with toluene, and then toluene/isopropanol (10: 1-w/w, 10g) was added. After stirring the slurry at 30 ℃ for 60 minutes, the mixture was cooled to 3 ℃ and filtered. The product was washed with toluene/isopropanol (10: 1-w/w) and dried in vacuo at 40 ℃. CN46630-MSA (second crop, 3.8g, 8.0mmol, 13% yield) was obtained as an off-white solid (purity 89.7% and ep 99.7% according to method B).

Example 3: (R) -4- (cyclopropylethynyl) -6-phenyl-4- (trifluoromethyl) -1, 4-dihydro-2H-3, 1-benzoxazin-2-one.

(R) -2- (4-aminobiphenyl-3-yl) -4-cyclopropyl-1, 1, 1-trifluorobut-3-yn-2-ol methanesulfonate (CN46630-MSA) from example 2(14.7g, 34.4mmol) in ethyl acetate/heptane (1:1v/v, 27.9g) was charged with caustic in a 150mL jacketed reactor with a stirrer and a vent gas scrubber. After adding Na₂CO₃After an aqueous solution (12% (w/w), 32.3g, 36.4mmol, gas formation during addition!) the mixture was stirred for 15 minutes at 15 ℃. The aqueous phase was separated and discarded. Mixing Na₂CO₃The organic phase was charged with an aqueous solution (12% (w/w), 41g, 46mol) and ethyl acetate (20 g). Triphosgene (4.41g, 14.9mmol) was added portionwise over a period of 25 minutes at 10 ℃. The reaction mixture was stirred at 8 ℃ for 2 hours. The mixture was diluted with ethyl acetate (45g) and the phases were separated. The aqueous phase was discarded. The organic phase was washed with water (12mL) and over MgSO₄Drying, filtering and concentrating, and heating at 50 deg.CDrying under reduced pressure to obtain (R) -4- (cyclopropylethynyl) -6-phenyl-4- (trifluoromethyl) -1, 4-dihydro-2H-3, 1-benzoxazin-2-one (CN46685, Compound of formula I, wherein R is¹Is trifluoromethyl, R²Is cyclopropyl, R⁸Is 6-phenyl, R⁹Is hydrogen and R¹⁰Hydrogen) (12.1g, 33.9mmol, 98%) (99.5% purity according to method C).

Example 4: (R) -2- (2-amino-5-fluorophenyl) -4-cyclopropyl-1, 1, 1-trifluorobut-3-yn-2-ol methanesulfonate (2:3mol/mol)

A dry 150mL jacketed reactor with a stirrer was charged with (1S,2R) -PNE (18.2% (w/w), 20.3g, 18.0mmol) in THF/toluene (9: 1-w/w) under nitrogen. Diethylzinc (29.9% (w/w), 6.20g, 15.0mmol) in toluene was added via syringe while maintaining the temperature at 17 to 22 ℃. The mixture was then aged at 17 ℃ for 30 minutes. Cyclopropylacetylene (69.6% (w/w), 6.82g, 71.8mmol) in toluene was added at 17 deg.C and the reaction mixture was aged for 60 minutes at 20 deg.C. BuLi (19.3g, 3.06mol/kg, 59.1mmol) in toluene and 1- (2-amino-5-fluorophenyl) -2,2, 2-trifluoroacetone (CAS [ 214288-07-0) in THF/toluene (1:1 w/w) were added to the reaction mixture in parallel over a period of 3 hours at 20 deg.C]CN46221, a compound of formula IV, wherein R is¹Is trifluoromethyl, R⁸Is 5-fluoro, R⁹Is hydrogen and R¹⁰Hydrogen) (36.9% (w/w), 33.7g, 60 mmol). The addition of BuLi was allowed to proceed 10 minutes before the addition of CN 46221. After the addition was complete, the reaction mixture was stirred at 20 ℃ for 30 minutes, then heated to 30 ℃ over a period of 60 minutes and aged at 30 ℃ for 6 hours. The reaction mixture was stirred at 0 ℃ overnight. According to method B, HPLC indicated 82.4% conversion and 96.0% ep of (R) -2- (2-amino-5-fluorophenyl) -4-cyclopropyl-1, 1, 1-trifluorobut-3-yn-2-ol (CN 46619). The reaction mixture was diluted with toluene (27.6g) and quenched by the addition of aqueous citric acid (1M, 45.3 g). The phases were separated and the aqueous phase was discarded. With water (9.1g), NaHCO in sequence₃The organic phase was washed with an aqueous solution (5% (w/w), 24.2g), and water (12.0 g). The organic phase was reconcentrated and diluted with toluene to remove THF. The resulting residue (51.0g) was diluted with isopropanol (16.7g) and toluene (60.0 g). Methanesulfonic acid (8.36g, 87.0mmol) was added via a syringe pump over a period of 75 minutes at 30 ℃. Before the mixture was filtered, the mixture was aged and gradually cooled to reach 5 ℃ during 2 hours and 10 minutes. The filter cake was washed with toluene/isopropanol (10: 1-w/w, 27.0g) and dried at 40 ℃ under reduced pressure. The dry product (R) -2- (2-amino-5-fluorophenyl) -4-cyclopropyl-1, 1, 1-trifluorobut-3-yn-2-ol methanesulfonate (2:3mol/mol, CN46619-MSA, compound of formula II, where R is R) was obtained as a yellowish solid¹Is trifluoromethyl, R²Is cyclopropyl, R⁸Is 5-fluoro, R⁹Is hydrogen and R¹⁰As hydrogen) (19.46g, 46.6mol, 78% yield) (according to method B, by¹H-NMR, 99.8% (w/w), and 99.8% ep).

Example 5: (R) -4- (cyclopropylethynyl) -6-fluoro-4- (trifluoromethyl) -1, 4-dihydro-2H-3, 1-benzoxazin-2-one

(R) -2- (2-amino-5-fluorophenyl) -4-cyclopropyl-1, 1, 1-trifluorobut-3-yn-2-ol methanesulfonate (CN46619-MSA) from example 4(14.0g, 33.5mmol) in ethyl acetate/heptane (40g, 6/4v/v) was charged with caustic into a 150mL jacketed reactor with a stirrer and a vent gas scrubber. After adding Na₂CO₃After an aqueous solution (12% (w/w), 26.9g, 30.3mmol), the mixture was stirred at 15 ℃ for 5 minutes. The aqueous phase was separated and discarded. Mixing Na₂CO₃The organic phase was charged with an aqueous solution (12% (w/w), 34.1g, 38.4mmol) and triphosgene (3.73g, 12.6mmol) was added portionwise over a period of 25 minutes at 10 ℃. The reaction mixture was stirred at 8 ℃ for 2 hours. The mixture was charged with heptane (15.9g), the phases separated and the aqueous phase discarded. The organic phase was washed with water (12mL) and over MgSO₄Dried, filtered and concentrated to dryness. After drying at 50 ℃ under vacuum, obtained as yellowishThe solid product (R) -4- (cyclopropylethynyl) -6-fluoro-4- (trifluoromethyl) -1, 4-dihydro-2H-3, 1-benzoxazin-2-one (CN46686, compound of formula I, wherein R is¹Is trifluoromethyl, R²Is cyclopropyl, R⁸Is 6-fluoro, R⁹Is hydrogen and R¹⁰Hydrogen, 9.78g, 32.7mmol, 97%) (99.4% purity according to method C).

Example 6: cyclization of SD573 with diphosgene

Mixing Na₂CO₃Aqueous solution (12% (w/w), 183g, 0.206mol) SD573-MSA ((S) -2- (2-amino-5-chlorophenyl) -4-cyclopropyl-1, 1, 1-trifluorobut-3-yn-2-ol methanesulfonate (2:3mol/mol) ═ the S-enantiomer of the compound of formula II, wherein R is methanesulfonate, charged into ethyl acetate/heptane (203g, 1.5:1v/v)¹Is trifluoromethyl, R²Is cyclopropyl, R⁸Is 5-chloro, R⁹Is hydrogen and R¹⁰Is hydrogen; 100g, 0.23mol, corresponding to 66.8gSD573 free base, 99.6% ee, prepared according to example 1). The mixture was stirred at 15 ℃ for 5 minutes. The hydrolysis of the methanesulfonate salt ended at a pH of the aqueous phase of about 9.0. The phases were then separated and the aqueous phase was removed. Mixing Na₂CO₃The organic phase was charged with an aqueous solution (12% (w/w), 232g, 0.262 mol). To the biphasic mixture was added liquid diphosgene (24g, 120mmol) over 90 min at 12 ℃. According to method C, after a conversion of 99.7% or more was reached, heptane (204g) was charged. The reaction mixture was then heated to 20 ℃, the aqueous phase was separated and discarded, while the organic phase was washed with water (about 80 g). The organic layer was heated under reduced pressure, ethyl acetate was distilled off and heptane was charged into the reaction mixture to reach a residual ethyl acetate content of 5.5% (weight/weight) and the ratio of heptane and organic substance was 10L/kg in consideration of the initially added SD 573-MSA. The mixture was then heated to dissolve all organic material. 0.8g of DMP-266(DMP-266 ═ S-enantiomer of the compound of formula I, where R is present, is used at 55 deg.C¹Is trifluoromethyl, R²Is cyclopropyl, R⁸Is 6-chloro, R⁹Is hydrogen and R¹⁰Is hydrogen) to be dissolvedThe solution was seeded and stirred at 55 ℃ for about 15 minutes then the mixture was cooled to 50 ℃ and held for 120 minutes then the mixture was further cooled from 50 ℃ to 25 ℃ over 2 hours and ramped to about-10 ℃ over another 2 hours finally the mixture was stirred for about 1 hour at up to-10 ℃ and then filtered the filter cake (wet product) was washed with pre-cooled heptane (2 × 50mL) at up to 0 ℃ the solids were dried under vacuum to give 94.2% yield of DMP-266(68.4g, 216mmol) according to method D with a purity of 99.9% (w/w) the sample contained 99.8% (w/w) of the S-enantiomer, i.e. 99.6% enantiomeric excess (ee).

Example 7: cyclization of SD573 with diphosgene

Mixing Na₂CO₃The aqueous solution (12% (w/w), 91.5g, 0.103mol) was charged to SD573-MSA (50g, 0.115mol, corresponding to 33.4gSD573 free base, 99.6% ee, prepared according to example 1) in ethyl acetate/heptane (101.5g, 1.5:1 v/v). The mixture was stirred at 15 ℃ for 5 minutes. The hydrolysis of the methanesulfonate salts ended at a pH of 6.4 in the aqueous phase. The phases were separated and the aqueous phase was removed. The remaining organic phase was cooled to 12 ℃ and charged with Na₂CO₃Aqueous solution (12% (w/w), 106g, 0.12 mol). To the biphasic mixture was added liquid diphosgene (11.4g, 57mmol) over 90 min at 12 ℃. According to method C, heptane (68.8g) was charged after complete conversion was achieved. The reaction mixture was then heated to 20 ℃, stirred for 30 minutes, and the aqueous phase was removed. The organic phase was heated under reduced pressure, ethyl acetate was distilled off and heptane was charged into the reaction mixture to obtain a residual ethyl acetate content of 4.4% by weight, and the ratio of heptane and organic matter was 6.5L/kg in view of the initially added SD 573-MSA. The resulting mixture is then heated to dissolve all organic material. The solution was seeded with DMP-266(0.4g) at 55 deg.C and stirred at 55 deg.C for about 15 minutes. The mixture was then cooled to 50 ℃ and held for 120 minutes. The mixture was then cooled further from 50 ℃ to 25 ℃ over a period of 2 hours and cooled to maximum within a further 2 hoursFinally, the mixture was stirred at-13 ℃ for about 1 hour and then filtered at-0 ℃, the filter cake (wet product) was washed with pre-cooled heptane (2 × 50mL) at maximum 0 ℃, the solids were dried under vacuum to give DMP-266(33.45g, 105mmol) in 92.1% yield, according to method D, with a purity of 99.9% (w/w). the sample contained 99.8% (w/w) of the S-enantiomer, i.e. 99.6% ee.

Example 8: cyclization of SD573 with triphosgene

SD573-MSA (50g, 0.114mol, corresponding to 33.4gSD573 free base, 99.6% ee, prepared according to example 1) is dissolved in an ethyl acetate/heptane mixture (164g, 1:1v/v) and charged with Na₂CO₃Aqueous solution (12% (w/w), 91.5g, 0.104 mol). After hydrolysis of the methanesulfonate, the pH in the aqueous phase was measured to be about 7.0. The mixture was stirred at 15 ℃ for at least 5 minutes. The phases were then separated and the aqueous phase was removed. Cooling the mixture to below 12 deg.C and charging with Na₂CO₃Aqueous solution (12% (w/w), 116g, 0.131 mol.) triphosgene (12.5g, 42mmol) was added to the biphasic mixture in five portions at up to 10 ℃ in90 minutes and the mixture was stirred for a further 15 minutes at below 15 ℃ according to method C, after complete conversion was reached heptane (54g) was charged then the reaction mixture was heated to 20 ℃ and the aqueous phase was removed the organic phase was washed with water (40g) and then heated under reduced pressure, ethyl acetate was distilled off and heptane was charged to the reaction mixture to obtain a residual ethyl acetate content of 4.6% (w/w) and, taking into account the initially added SD573-MSA, the ratio of heptane and organic substance was 6.5L/kg. at 57 ℃ seeding the solution with DMP-266(0.4g) and gradually cooled under stirring to-10 ℃ in 2 hours within 15 minutes, the mixture was stirred and then filtered at up to 0 ℃ and then washed with pre-cooled heptane (2.38) with 90% by weight of DMP (2 × 50mL) to obtain an enantiomeric yield of 99.6% p, 10% solids, 100% by vacuum purity, i.e. 90% DMP-28% p-95/10% solids.

Example 9: cyclization of SD573 with triphosgene

SD573-MSA (100g, 0.23mol, corresponding to 66.8gSD573 free base, 99.6% ee, prepared according to example 1) is dissolved in ethyl acetate/heptane (203g, 1.5:1v/v) and charged with Na at about 15 ℃₂CO₃Aqueous solution (12% (w/w), 183g, 0.207 mol). A pH of 7 to 9 is reached in the aqueous phase. The mixture was stirred at 15 ℃ for at least 5 minutes. The phases were then separated and the aqueous phase was removed. Cooling the mixture to below 12 deg.C and charging with Na₂CO₃Aqueous solution (12% (w/w), 232g, 0.263mol) triphosgene (24.08g, 81mmol) is added to the biphasic mixture in 10 parts over 120 minutes at less than 12 ℃ and the mixture is stirred for a further 10 minutes at about 12 ℃ according to method C, after complete conversion is reached heptane (204g) is charged and the reaction mixture is then heated to 20 ℃ and the aqueous phase is removed, the organic phase is washed with water (80g) and then heated under reduced pressure to partially remove ethyl acetate, while heptane is charged to the reaction mixture to achieve a residual ethyl acetate content of 5.8% (w/w) and, taking into account the initially added SD573-MSA, the ratio of heptane and organic substance is 7.0L/kg. at 55 ℃ with DMP-266(0.8g) seeding the solution and stirring for 15 minutes, the mixture is then cooled to 50 ℃ within 20 minutes, kept for 2 hours, cooled to 25 ℃ within 2 hours, cooled to about-10 ℃ after 2 hours and filtered to obtain a product which is separated under vacuum of 2% enantiomeric purity, 358% by filtration, 2.8% p-84, 2.8% is separated by vacuum, 2% p-3585, after which the product is dried under vacuum, 1.8% p, 1.8% separation, 1.8% p, which is obtained.

Example 10: cyclization of SD573 with triphosgene

Adding Na at 15 deg.C₂CO₃Aqueous solution (14% (w/w), 135g, 0.178mol) of SD573 free base (33.4g, 0.115mol) in ethyl acetate/heptane (70.4g, 45:55v/v), cooling the mixture to 8 ℃ and adding triphosgene (26.8% (w/w), 112g, 101mmol) in heptane over 60 minutes while keeping the temperature at 5 ℃ to 12 ℃ according to method C to achieve complete conversion after 60 minutes, heating the reaction mixture to 25 ℃ then carrying out phase separation and removing the aqueous phase, heating the organic phase under reduced pressure, partially distilling off the ethyl acetate and charging heptane to the reaction mixture to obtain a residual ethyl acetate content of about 2.5% (w/w), and taking into account the initially added SD573 free base, the ratio of heptane to organic substance is about 15L/kg. then heating the mixture to dissolve all organic substances and thereafter at 55 ℃ under reduced pressure adding DMP-266 (1.4 g in total) to seed the product without crystallization and thus heating the organic phase to remove the ethyl acetate while charging the mixture with DMP-266 (1.4 g) to obtain a residual ethyl acetate content of 1.4% by weight under stirring and after that the reaction mixture is heated to obtain a slurry containing the highest DMP concentration of 5.7.8% DMP under vacuum, 7% DMP under stirring and after that the reaction mixture is heated to 10% DMP under stirring to obtain a residual ethyl acetate concentration of 1.7% DMP under vacuum of 5% DMP, and after that the reaction mixture is added.

Example 11: cyclization of SD573 with triphosgene

Mixing Na₂CO₃The aqueous solution (12% (w/w), 91.5g, 0.103mol) was charged with SD573-MSA (50g, 0.115mol, corresponding to 33.4gSD573 free base, prepared according to example 1) in ethyl acetate/heptane (90.8g, 55:45 v/v). The mixture was stirred at 15 ℃ for 5 minutes to give an aqueous phase with a pH of 6.8. Then carrying out phase separationThe aqueous phase was separated and removed. The organic phase was heated under reduced pressure and the solvent was partially removed (32.3g, 41mL) to obtain an SD573 free base to solvent ratio of about 1:1.75 (weight/weight). The distillate contained about 53.2 wt% ethyl acetate. The mixture containing the SD573 free base was cooled to 12 ℃ and charged with Na₂CO₃Aqueous solution (12% (w/w), 96g, 0.109 mol.) triphosgene in ethyl acetate (31% (w/w), 32.7g, 34mmol) was added to the biphasic mixture over 66 minutes at 7 to 12 ℃ the mixture was stirred for 15 minutes at maximum 12 ℃ according to method C, after 90.2% conversion was reached, additional heptane (86g) was charged and the reaction mixture was heated to 20 ℃ and then phase separation and removal of the aqueous phase was carried out, the organic phase was heated under reduced pressure to partially remove ethyl acetate while heptane was charged to the organic phase to obtain a residual ethyl acetate content of 6.8% (w/w) (target 3 to 7% (w/w)), and considering the initial addition of SD573-MSA, the ratio of heptane to organic substance was 6.8L/kg., the solution was seeded with DMP-266(0.4g) and stirred for 150 minutes at 47 to 55 ℃ under 47 ℃ and then the mixture was slowly cooled to-10 ℃ and filtered off under pre-10 ℃ and washed with 2 × 25% weight of DMP-266 (97% solids under vacuum to obtain a yield of filter cake, 1.2% p-091 mL) after pre-drying at maximum 10 ℃ to obtain a purity of 3.2.2% by vacuum.

Example 12: cyclization of SD573 with triphosgene

Mixing Na₂CO₃The aqueous solution (12% (w/w), 275.1g, 0.311mol) was charged to SD573-MSA (150g, 0.345mol, corresponding to 100.2gSD573 free base, prepared according to example 1) in ethyl acetate/heptane (272.1g, 55:45 v/v). After stirring the mixture at 15 ℃ for 5 minutes, the pH was measured to be 7.7. The phases were then separated and the aqueous phase discarded. The organic phase (ethyl acetate/heptane ratio 61.5/38.5 w/w) was divided into 3 portions, each portion containing about 33g of SD573 free base. To test the stability of the SD573 free base in an ethyl acetate/heptane mixture, part 1 was taken at 4 ℃ before example 12.1 was carried outStorage was 4 days, part 2 was stored at 4 ℃ for 7 days before example 12.2 was performed, and part 3 was stored at 4 ℃ for 10 days before example 12.3 was performed.

Example 12.1:

portion 1 of the organic phase from example 12 (123.5g) was heated under reduced pressure to partially remove the solvent until the distillate contained 60 wt% ethyl acetate (ca. 33 g). The remaining mixture was cooled to 12 ℃ and charged with Na₂CO₃Aqueous solution (12% (w/w), 117g, 0.132 mol.) the biphasic mixture is charged with triphosgene in ethyl acetate (36% (w/w), 35g, 42 mmol.) over 60 minutes at less than 12 ℃, the mixture is stirred for 15 minutes at less than 12 ℃ according to method C, after complete conversion, heptane (86g) is charged and the reaction mixture is heated to 20 ℃ and then phase separation and removal of the aqueous phase is carried out, the organic phase is washed with water (40g), the organic phase is heated under reduced pressure to partially remove ethyl acetate, while heptane is charged to the reaction mixture to obtain a residual ethyl acetate content of 5.5% (w/w) (target 3 to 7% (w/w)). for crystallization, a ratio of 6.3L/kg of heptane to organic matter is obtained, taking into account the initially added SD573-MSA, a seeding of the solution is obtained with DMP-266(0.4g) and the solution is seeded at 57 ℃ with stirring for 15 minutes, the mixture is gradually cooled over 6 hours to 20 minutes under stirring and the filtration with 10g of DMP-266 at a filtration yield of filter cake of up to 10% (w/w) and a filtration yield of 10.4 g of 10% of filter cake under vacuum, 10g, 10.4 g under stirring, 10g of DMP, 10mg, 10% of filtered cake, 10% p, with stirring, 10% of filtered, with stirring, and with stirring.

Example 12.2:

portion 2 (122.0g) of the organic phase from example 12 was heated under reduced pressure to partially remove the solvent until the distillate contained 53 wt% ethyl acetate (about 31 g). The mixture was cooled to 12 ℃ and charged with Na₂CO₃Aqueous solution (12% by weight)117g, 0.132 mol.) triphosgene in ethyl acetate (36% (w/w), 35g, 42mmol) was added to the biphasic mixture over 60 minutes at maximum 12 ℃ complete conversion was obtained according to method C heptane (86g) was charged and the reaction mixture was heated to 20 ℃ then phase separation and removal of the aqueous phase was carried out the organic phase was washed with water (40g) and then heated under reduced pressure to partially remove ethyl acetate while heptane was charged to the reaction mixture to obtain 5.7% (w/w) residual ethyl acetate content (target 3 to 7% (w/w)). for crystallization, a ratio of 6.4L/kg of heptane and organic material was obtained taking into account the initial addition of SD573-MSA, the mixture was seeded with DMP-266(0.4g) at 57 ℃ and gradually cooled under stirring to reach-15 ℃ over 6 hours, then the mixture was stirred under-10 ℃ and filtered overnight under pre-10 ℃ with filtered 852% heptane (84 g) to obtain a yield of dry cake with 100% p 102-102 (14 mL) under vacuum).

Example 12.3:

portion 3 (122.5g) of the organic phase from example 12 was heated under reduced pressure to partially remove the solvent until the distillate contained 53.6 wt% ethyl acetate (about 32.3 g). The mixture was cooled to 9 ℃ and then charged with Na₂CO₃Aqueous solution (12% (w/w), 117g, 0.132 mol). The biphasic mixture was charged with triphosgene (36% (w/w), 35g, 42mmol) in ethyl acetate over 60 minutes at a temperature of up to 12 ℃ and the mixture was stirred for 1 hour at a temperature of up to 12 ℃. According to method C, complete conversion was obtained. Heptane (86g) was charged and the reaction mixture was heated to 20 ℃. The phases were separated and the aqueous phase was removed. The organic phase was washed with water (40g) and then heated under reduced pressure to partially remove ethyl acetate while the reaction mixture was charged with heptane to obtain a residual ethyl acetate content of 5.8% (w/w). For the crystallization, 6.2L/kg of heptane and organic material are obtained, taking into account the initial addition of SD573-MSARatio the mixture was seeded with DMP-266(0.4g) at 57 ℃ and gradually cooled to-15 ℃ over 6 hours with stirring the mixture was stirred overnight at-10 ℃ and then filtered the filter cake was washed with pre-cooled heptane (2 × 25mL) at up to-10 ℃ the solid was dried under vacuum to give DMP-266(32.4g, 103mmol) in 90% yield according to method D with 100% (w/w) purity.

Example 13: cyclization of SD573 with triphosgene

Mixing Na₂CO₃The aqueous solution (14% (w/w), 160g, 0.211mol) was charged with SD573-MSA (100g, 0.229mol, corresponding to 66.8gSD573 free base, prepared according to example 1) in ethyl acetate/heptane (158.8g, 1:1 v/v). The mixture was stirred at about 15 ℃ to produce an aqueous phase with a pH of 6.8. The phases were then separated and the aqueous phase was removed. The organic phase was cooled to 12 ℃ and charged with Na₂CO₃Aqueous solution (14% (w/w), 214g, 0.283 mol). The biphasic mixture was charged with triphosgene (35.7% (w/w), 67.2g, 81mmol) in ethyl acetate over 60 minutes at a temperature of up to 12 ℃. The mixture was stirred for 30 minutes at maximum 12 ℃. Heptane (96g) was charged and complete conversion was obtained according to method C. The reaction mixture was heated to 20 ℃. The phases were then separated and the aqueous phase was removed. Adding Na to the organic phase₂CO₃Aqueous solution (14% (w/w), 92g, 0.121mol) and stirred at 20 ℃ for 25 minutes. The phases were then separated and the aqueous phase was removed. The organic phase (360g) was divided into two portions.

Example 13.1:

part 1 (180g) of the organic phase from example 8 was washed with water (80g), the phases were separated and the aqueous phase was removed. The organic phase was then heated under reduced pressure, ethyl acetate was partially distilled off and the reaction mixture was charged with heptane to obtain a residual ethyl acetate content of 3% (w/w) (target 3 to 7% (w/w)). For crystallization, a final total of 10L/kg of SD573-MSA heptane was obtained. The solution was seeded with DMP-266(0.2g) at 55 ℃ and cooled gradually to-15 ℃ over 7 hours with stirring, the mixture was stirred overnight at-15 ℃ and then filtered. The filter cake was washed with pre-cooled heptane (2X 50mL) at up to-10 ℃. The solid was dried under vacuum to give DMP-266 in 93% yield (33.47g, 105mmol) with a purity of 98.8% (w/w) according to method D.

Example 13.2:

part 2 (180g) of the organic phase from example 8 was heated under reduced pressure to partially remove ethyl acetate while the reaction mixture was charged with heptane to obtain a residual ethyl acetate content of 3.4% (w/w) (target 3 to 7% (w/w)). For the crystallization, 10L/kg of heptane to organic material ratio was obtained, taking into account the initial addition of SD 573-MSA. The mixture was seeded with 0.2g of DMP-266 at 55 ℃ and gradually cooled to-15 ℃ over 6 hours and 40 minutes with stirring. The mixture was stirred at-10 ℃ overnight and then filtered. The filter cake was washed with pre-cooled heptane (2X 50mL) at up to-10 ℃. The solid was dried under vacuum to give DMP-266 in 96% yield (34.87g, 110mmol) with a purity of 97.7% (w/w) according to method D.

Example 14: cyclization of SD573 with triphosgene

Mixing Na₂CO₃The aqueous solution (14% (w/w), 80g, 0.106mol) was charged with SD573-MSA (50g, 0.115mol, corresponding to 33.4gSD573 free base, prepared according to example 1) in ethyl acetate/heptane (79.4g, 1:1 v/v). After stirring for 15 minutes, the pH in the aqueous phase was measured to be 6.4. The mixture was stirred at 15 ℃ for 5 minutes. The phases were then separated and the aqueous phase was removed. The mixture was cooled to 12 ℃ and charged with Na₂CO₃Aqueous solution (14% (w/w), 107g, 0.141 mol). Triphosgene (35.7% (w/w), 33.6 g) in ethyl acetate was added to the biphasic mixture over 60 minutes at a temperature of up to 12 deg.C40.5 mmol). The mixture was stirred for 30 minutes at maximum 12 ℃. Heptane (48g) was charged and complete conversion was obtained according to method C. The reaction mixture was heated to 20 ℃. The phases were then separated and the aqueous phase was removed. The organic phase was washed with water (80g) and then heated under reduced pressure to partially remove ethyl acetate while the reaction mixture was charged with heptane to obtain a residual ethyl acetate content of 3.2% (w/w). For the crystallization, a heptane to organic material ratio of 9.6L/kg was obtained, taking into account the initial addition of SD 573-MSA. The mixture was seeded with 0.2g of DMP-266 at 55 ℃ and gradually cooled to-15 ℃ over 7 hours with stirring. The mixture was stirred at-15 ℃ overnight and then filtered. The filter cake was washed with pre-cooled heptane (50mL) at up to-10 ℃. The solid was dried under vacuum to give DMP-266(34.49g, 110mmol) in 97% yield with a purity of 96.5% (w/w) according to method D.

Example 15: cyclization of SD573 with triphosgene

Mixing Na₂CO₃The aqueous solution (14% (w/w), 80g, 0.106mol) was charged with SD573-MSA (50g, 0.114mol, corresponding to 33.4gSD573 free base, prepared according to example 1) in ethyl acetate/heptane (79.4g, 1:1 v/v). After stirring for 15 minutes, the pH in the aqueous phase was measured to be 6.1. The mixture was stirred at 15 ℃ for 5 minutes. The phases were then separated and the aqueous phase was removed. The mixture was cooled to 12 ℃ and charged with Na₂CO₃Aqueous solution (14% (w/w), 135g, 0.178 mol). Triphosgene (35.7% (w/w), 33.6g, 40.5mmol) in ethyl acetate was added to the biphasic mixture over 60 min at a temperature of up to 12 ℃. The mixture was stirred for 30 minutes at maximum 12 ℃. Heptane (48g) was charged and according to method C, complete conversion was obtained. The reaction mixture was heated to 20 ℃. The phases were then separated and the aqueous phase was removed. The organic phase was washed with water (80g) and then heated under reduced pressure to partially remove the ethyl acetate, while the reaction mixture was charged with heptane to reach a residual ethyl acetate content of 2.8% (w/w). For crystallization, initial addition is consideredSD573-MSA was added to obtain a ratio of 9.5L/kg heptane to organic material, the solution was seeded with DMP-266(0.2g) at 55 ℃ and gradually cooled over 4 hours 35 minutes with stirring to reach-15 ℃, the mixture was stirred overnight at-15 ℃ and then filtered, the filter cake was washed with pre-cooled heptane (2 × 50mL) at up to-10 ℃, the solid was dried under vacuum to give DMP-266(35.12g, 111mmol) in 97.6% yield, 95.1% (w/w) purity according to method D.

Example 16: cyclization of SD573 with phosgene

Mixing Na₂CO₃The aqueous solution (12% (w/w), 183g, 0.207mol) was charged to SD573-MSA (100g, 0.228mol, corresponding to 66.8gSD573 free base, prepared according to example 1) in ethyl acetate/heptane (203g, 1.5:1 v/v). After stirring for 15 minutes, the pH in the aqueous phase was measured to be 7.2. The mixture was stirred at 15 ℃ for 5 minutes. The phases were then separated and the aqueous phase was removed. The mixture was cooled to 12 ℃ and charged with Na₂CO₃Aqueous solution (12% (w/w), 232g, 0.263mol) phosgene (24.8g, 251mmol) was added to the biphasic mixture over 90 minutes at maximum 12 ℃, complete conversion was obtained charging heptane (136g) to the mixture and according to method C, the reaction mixture was heated to 20 ℃ then phase separation and removal of the aqueous phase, the organic phase was washed with water (80g) and then heated under reduced pressure to partially remove ethyl acetate while charging the reaction mixture with heptane to obtain a residual ethyl acetate content of less than 7% (w/w), for crystallization a ratio of 9.7L/kg of heptane to organic material was obtained taking into account the initial addition of SD573-MSA, the solution was seeded with DMP-266(0.8g) at 55 ℃ and gradually cooled over 6 hours and 15 minutes under stirring to reach-15 ℃ and then filtered, washed with cooled heptane ((2 × 50mL) at maximum 0 ℃ to obtain a yield of 95.7% solids in vacuum 68.91% by weight, dry cake purity (DMP) 35218 g) at maximum 0 ℃.

Example 17: cyclization of SD573 with phosgene

SD573-MSA (50g, 0.114mol, corresponding to 33.4gSD573 free base, prepared according to example 1) is dissolved in ethyl acetate/heptane (102g, 55:45v/v) and charged with Na₂CO₃Aqueous solution (12% (w/w), 91g, 0.103 mol). After stirring for 15 minutes, the pH of the aqueous phase was measured to be about 7. The mixture was stirred at 15 ℃ for 5 minutes. The phases were then separated and the aqueous phase was separated and discarded. The organic phase was cooled to 12 ℃ and charged with Na₂CO₃Aqueous solution (12% (w/w), 157g, 0.178mol) phosgene (16.9g, 171mmol) was added to the biphasic mixture at maximum 12 ℃ over 130 minutes, heptane (43g) was charged and complete conversion was obtained according to method C. the reaction mixture was heated to 20 ℃ before phase separation and removal of the aqueous phase the organic phase was washed with water (80g) and then heated under reduced pressure to partially remove ethyl acetate while heptane was charged to the reaction mixture to reach a residual ethyl acetate content of 3.5% (w/w). for crystallization, about 10L/kg of heptane to organic material ratio was obtained taking into account the initial addition of SD 573-MSA. the solution was seeded with DMP-266(0.4g) at 62 ℃ and gradually cooled to-5 ℃ overnight under stirring and then filtered. the filter cake was washed with pre-cooled heptane ((2 × 50mL) at maximum 0 ℃ the solid was dried under vacuum to give a DMP-266(33.86g, 107mmol) of 93% yield according to method D98.5% (w/w).

Example 18: (S) -2- (2-amino-5-methylphenyl) -4-cyclopropyl-1, 1, 1-trifluorobut-3-yn-2-ol

A solution of (1R,2S) -PNE (17.6% (w/w), 21.0g, 18.0mmol) in a THF/toluene mixture (9: 1-w/w) was charged to a vessel at room temperature. A solution of diethylzinc (29.9% (w/w), 6.10g, 14.8mmol) in toluene was added at 17 to 25 ℃ and the mixture was aged for 30 minutes at the temperature range indicated. Cyclopropylacetylene (compound of formula III) in toluene was added at 18 deg.CWherein R is²Is cyclopropyl) solution (69.6% (w/w), 8.55g, 90.0mmol) and the resulting mixture is aged at 20 ℃ for 60 minutes. To the reaction mixture was added in parallel a solution of butyllithium (BuLi) in toluene (3.09mol/kg, 17.6g, 54.4mmol) and 1- (2-amino-5-methylphenyl) -2,2, 2-trifluoroacetone (CN46217, compound of formula IV, where R is R46217) in THF/toluene (1: 1-w/w) at 20 ℃ over 3 hours¹Is trifluoromethyl, R⁸Is 5-methyl, R⁹Is hydrogen and R¹⁰Hydrogen) solution (36.5% (w/w), 33.4g, 60.0 mmol). BuLi addition was started 10 minutes before CN46217 addition. After complete addition of CN46217, the reaction mixture was stirred at 20 ℃ for 30 minutes, then heated to 30 ℃ during 60 minutes and aged at 30 ℃ for 6 hours. The reaction mixture was stirred at 0 ℃ overnight. HPLC (method B) indicated 72.3% conversion and 96.7% enantiomeric purity. The reaction mixture was diluted with toluene (25.8g) and quenched by the addition of aqueous citric acid (1M, 73.9 g). After stirring for 15 minutes, the phases were separated and the aqueous phase was discarded. With water (9.1g), NaHCO in sequence₃The organic phase was washed with an aqueous solution (5% (w/w), 24.0g), and water (12.0 g). The organic phase is partially concentrated (60g of residual solution), then diluted with toluene (30g) and partially concentrated again (52g of residue). The residue was diluted with toluene (65g), cooled to 5 ℃ and aged overnight. The crystals were filtered, washed with cold (about 5 ℃) toluene (10g) and dried under vacuum at 40 ℃. The wet product (10.8g) was obtained as an off-white solid with a purity of 99.2% and an ep of 100% according to method B. The crude product was purified by slurrying it in a mixture of toluene (10mL) and heptane (40mL) for 1 hour at room temperature, filtered and dried under vacuum at 40 ℃. The product (compound of formula II, wherein R is¹Is trifluoromethyl, R²Is cyclopropyl, R⁸Is 5-methyl, R⁹Is hydrogen and R¹⁰Hydrogen) (10.6g, 38mmol, 64% yield), purity 99.4% and ep 100% according to method B. According to¹H-NMR showed 97.0% (w/w) in analysis.

Example 19: (S) -4- (cyclopropylethynyl) -6-methyl-4- (trifluoromethyl) -1, 4-dihydro-2H-3, 1-benzoxazin-2-one

(2S) -2- (2-amino-5-methylphenyl) -4-cyclopropyl-1, 1, 1-trifluorobut-3-yn-2-ol (CN46624) (97.0% (w/w), 10.0g, 36.0mmol) obtained according to example 18 in ethyl acetate/heptane (2:1 w/w, 30g) was charged together with caustic into a 150mL jacketed reactor with a stirrer and a vent gas scrubber. The reaction mixture was cooled to 7 ℃ and Na was added₂CO₃Aqueous solution (12% (w/w), 33.5 g). Triphosgene (3.67g, 12.4mmol) was added portionwise over a period of 25 minutes at 7 to 15 ℃. The reaction mixture was stirred at 8 ℃ for 15 minutes and sampled to control conversion (99.8% conversion according to method C). The precipitated solid was dissolved by adding ethyl acetate (25g) and the phases were separated. The organic phase was washed with water (10g) and over MgSO₄Dry, filter and concentrate to dryness under vacuum. The crude product (11.6g) was obtained as a white solid (purity 96.9% according to HPLC method C). Heptane (20mL) was added to the mixture at constant temperature (ct) and the mixture was stirred at room temperature for 1 hour. The product was filtered, washed with cold heptane (10mL) and dried under vacuum at 35 ℃. The product (compound of formula I, wherein R is¹Is trifluoromethyl, R²Is cyclopropyl, R⁸Is 6-methyl, R⁹Is hydrogen and R¹⁰Hydrogen) (9.76g, 32.9mmol, 91% yield), according to method C, the purity is 98.8%, and according to¹H-NMR showed 99.6% (w/w) of analysis.

Example 20: 2- (2-amino-5-chlorophenyl) -1,1, 1-trifluorooctan-3-yn-2-ol methanesulfonate (2:3mol/mol)

Example 20.1: (R) -2- (2-amino-5-chlorophenyl) -1,1, 1-trifluorooct-3-yn-2-ol methanesulfonate (2:3mol/mol)

Will be in THF/toluene (9: 1-w/w) at room temperatureAmount) (18.7% (w/w), 19.7g, 18.0mmol) of the (1S,2R) -PNE solution in (b/w) was charged into a container. A solution of diethylzinc in toluene (29.9% (w/w), 6.10g, 14.8mmol) was added at 17 to 25 deg.C and the mixture was aged at that temperature for 30 minutes, 1-hexyne (97% (w/w), 6.10g, 72.0mmol, a compound of formula III, where R is R, was added at 18 deg.C²N-butyl) and the resulting solution was aged at 20 c for 60 minutes. A BuLi solution in toluene (3.09mol/kg, 17.8g, 55.0mmol) and 1- (2-amino-5-chlorophenyl) -2,2, 2-trifluoroacetone (CN23315, compound of formula IV, where R is R, in toluene/THF (1:1 w/w) are added to the reaction mixture in parallel over 3 hours at 20 deg.C¹Is trifluoromethyl, R⁸Is 5-chloro, R⁹Is hydrogen and R¹⁰Hydrogen) solution (39.6% (w/w), 33.8g, 60 mmol). BuLi addition was started 10 minutes before CN23315 addition. After complete addition of CN23315, the reaction mixture was stirred at 20 ℃ for 30 minutes, then heated to 30 ℃ during 60 minutes and aged at 30 ℃ for 6 hours. The reaction mixture was stirred at 0 ℃ overnight. HPLC (method B) indicated 89.6% conversion. The reaction mixture was diluted with toluene (25.8g) and quenched by the addition of aqueous citric acid (1M, 44.1 g). After stirring for 15 min, the phases were separated and washed successively with water (9.1g), NaHCO₃The organic phase was washed with an aqueous solution (5% (w/w), 24.0g), and water (12.0 g). The organic phase is partially concentrated (51g of residual solution), diluted with toluene (30g) and partially concentrated again (58g of residue). The residue was diluted with toluene (59g) and isopropanol (1.50 g). Methanesulfonic acid (10.48g, 114mmol) was added over 30 minutes at 30 ℃ and the mixture was stirred for 30 minutes. A second portion of methanesulfonic acid (2.89g, 30mmol) was added over a period of 30 minutes at 30 ℃. The mixture was stirred at 30 ℃ for 30 minutes, cooled to 5 ℃ over a period of 60 minutes, and aged at 5 ℃ for 30 minutes. The crystals were filtered, washed with cold toluene (10g) and dried in vacuo at 40 ℃. The crude product (19.3g) was obtained as a yellowish solid with a purity of 93.3% and an ep of 99.6% according to method B. The product was further purified by slurrying it in a mixture of toluene (100mL) and isopropanol (2mL) for 3 hours at room temperature. The product (, (R) -MSA salt of CN47583, compound of formula II, wherein R¹Is trifluoromethyl, R²Is n-butyl, R⁸Is 5-chloro, R⁹Is hydrogen and R¹⁰Hydrogen), washed with toluene (10mL) and dried under vacuum at 40 ℃. The product was obtained as a white solid (17.1g, 35.3mmol, 59% yield) according to method B with a purity of 93.3% and an ep of 99.9%, and according to¹H-NMR, analysis showed 92.8% (w/w).

Example 20.2: (S) -2- (2-amino-5-chlorophenyl) -1,1, 1-trifluorooctan-3-yn-2-ol methanesulfonate (2:3mol/mol)

Example 20.1 was repeated with (1R,2S) -PNE as chiral ligand to obtain the (S) -enantiomer of CN 47583.

A solution of (1R,2S) -PNE (17.6% (w/w), 42.0g, 36.0mmol) in THF/toluene (9: 1-w/w) was charged to a vessel at room temperature. A solution of diethylzinc in toluene (29.9% (w/w), 12.0g, 29.05mmol) was added at 17 to 25 ℃ and the mixture was aged at said temperature for 30 minutes, 1-hexyne (97% (w/w), 13.21g, 156.0mmol, a compound of formula III, where R is R, was added at 18 ℃²N-butyl) and the resulting solution was aged at 20 c for 60 minutes. A BuLi solution in toluene (3.09mol/kg, 35.53g, 109.8mmol) and 1- (2-amino-5-chlorophenyl) -2,2, 2-trifluoroacetone (CN23315, compound of formula IV, where R is R, in toluene/THF (1:1 w/w) are added to the reaction mixture in parallel over 3 hours at 20 deg.C¹Is trifluoromethyl, R⁸Is 5-chloro, R⁹Is hydrogen and R¹⁰Hydrogen) solution (39.6% (w/w), 67.75g, 120.0 mmol). BuLi addition was started 10 minutes before CN23315 addition. After complete addition of CN23315, the reaction mixture was stirred at 20 ℃ for 30 minutes, then heated to 30 ℃ during 60 minutes and aged at 30 ℃ for 6 hours. The reaction mixture was stirred at 0 ℃ overnight. HPLC (method B) indicated 81.9% conversion. The reaction mixture was diluted with toluene (51.6g) and purified by addition of aqueous citric acid (1)M, 88.2 g). After stirring for 15 min, the phases were separated and washed successively with water (18.1g), NaHCO₃The organic phase was partially concentrated (110g residual solution), diluted with toluene (60g), and partially concentrated again (114g residue) diluted with toluene (120 g.) isopropanol (3.2g) was added, methanesulfonic acid (10.96g, 114mmol) was added during 30 minutes at 30 ℃ and the mixture was stirred for 30 minutes, a second portion of methanesulfonic acid (5.78g, 60mmol) was added during 30 minutes at 30 ℃, the mixture was stirred for 30 minutes at 30 ℃, cooled to 5 ℃ during 60 minutes and aged for 30 minutes at 5 ℃, the crystals were filtered, washed with cold toluene/isopropanol (98:1, 1 × 25mL, 2 × 120mL) and dried under vacuum at 40 ℃ to obtain the product as a micron-colored solid (MSA salt of formula II, where R is R¹Is trifluoromethyl, R²Is n-butyl, R⁸Is 5-chloro, R⁹Is hydrogen and R¹⁰Is hydrogen, 28.57g) (based on¹H-NMR, analysis result 96.5% (w/w)).

Example 21: (R) -6-chloro-4- (hex-1-yn-1-yl) -4- (trifluoromethyl) -1, 4-dihydro-2H-3, 1-benzoxazin-2-one

(R) -2- (2-amino-5-chlorophenyl) -1,1, 1-trifluorozinc-3-yn-2-ol methanesulfonate ((R) -CN47583) (92.8% (w/w) as methanesulfonate, 2:3mol/mol, 15.0g, 30.9mmol) obtained according to example 20.1 in ethyl acetate/heptane (2:1 w/w, 30g) was charged with caustic in a 150mL jacketed reactor with stirrer and vent scrubber. The reaction mixture was cooled to 15 ℃ and Na was added₂CO₃An aqueous solution (12% (w/w), 27g, gas formed during addition!) and the mixture was then stirred for 5 minutes at 15 ℃. The aqueous phase was separated and removed. Adding Na to the organic phase₂CO₃Aqueous solution (12% (w/w), 33 g). Triphosgene (3.62g, 12.2mmol) was added portionwise over a period of 25 minutes at 7 to 15 ℃. The reaction mixture was stirred at 8 ℃ for 15 minutes and sampledTo control the conversion (according to method C, conversion is greater than 99%). The phases were allowed to separate. The organic phase was passed over MgSO₄Dry, filter and concentrate to dryness under vacuum. The crude product (11.4g) was obtained as a yellow oil (purity > 99.0% according to method C). The sample was cooled to 5 ℃ and it slowly solidified. The crude product was slurried in heptane (10mL) for 2 hours at room temperature. The product was filtered, washed with cold (about 5 ℃) heptane (5mL) and dried under vacuum at 30 ℃. The product ((R) -A Compound of formula I, wherein R is obtained as a white solid¹Is trifluoromethyl, R²Is n-butyl, R⁸Is 6-chloro, R⁹Is hydrogen and R¹⁰Hydrogen) (7.73g, 22.7mmol, 73% yield), according to method C, the purity is greater than 99.0%, and according to¹H-NMR showed 97.1% (w/w) in analysis. The mother liquor was concentrated to dryness under vacuum to yield additional product as a yellow solid (2.54g, 7.2mmol, 23% yield), 98% purity according to method C, and according to¹H-NMR showed 93.6% (w/w) in analysis.

Example 22: (S) -6-chloro-4- (hex-1-yn-1-yl) -4- (trifluoromethyl) -1, 4-dihydro-2H-3, 1-benzoxazin-2-one

(S) -2- (2-amino-5-chlorophenyl) -1,1, 1-trifluorooct-3-yn-2-ol methanesulfonate ((S) -CN47583) (96.5% (weight/weight) as a methanesulfonate, 2:3mol/mol, 15.0g, 32.2mmol) obtained according to example 20.2 in ethyl acetate/heptane (2:1 weight/weight, 30g) was charged with caustic in a 150mL jacketed reactor with stirrer and vent scrubber. The reaction mixture was cooled to 15 ℃ and Na was added₂CO₃An aqueous solution (12% (w/w), 27g, gas formed during addition!) and the mixture was then stirred for 5 minutes at 15 ℃. The aqueous phase was removed. And adding Na to the organic phase₂CO₃Aqueous solution (12% (w/w), 33 g). To the reaction mixture was added a solution of triphosgene (0.73g, 2.5mmol) in diphosgene (2.90g, 14.7mmol) over a period of 30 minutes at 7 to 11 ℃. The reaction mixture was heated at 8 deg.CStirred for 20 minutes. The reaction mixture was sampled to control conversion until greater than 99% conversion was achieved (according to method C). Allowing phase separation. The aqueous phase was removed. The organic phase was passed over MgSO₄Dried, filtered and concentrated to dryness. The crude product was obtained as a yellow solid (10.5g, 31.1mmol, 97% yield) (> 99.0% purity, HPLC method C, by¹H-NMR, analysis result 98.6% (w/w)). The crude product was slurried in heptane (10mL) for 3 hours at room temperature. The product was filtered, washed with cold (about 5 ℃) heptane (5mL) and dried under vacuum at 30 ℃. The product ((S) -Compound of formula I, wherein R is obtained as a white solid¹Is trifluoromethyl, R²Is n-butyl, R⁸Is 6-chloro, R⁹Is hydrogen and R¹⁰Is hydrogen) (8.25g, 24.6mmol, 77% yield), has a purity of more than 99.0% (according to method C) and is according to¹H-NMR showed 99.1% (w/w) of the result of analysis. The mother liquor was concentrated to dryness under vacuum to give additional product (1.58g) as a yellow solid with a purity of 97% (according to method C).

Example 23: cyclization of SD573 (free base) with diphosgene in triphosgene

Triphosgene (5.12g, 17mmol) was added to diphosgene (20.16g, 101mmol) at 8 ℃ and the mixture was aged for 30 minutes with vigorous stirring (until all triphosgene was dissolved).

In another container, Na is added at 8 DEG C₂CO₃Aqueous solution (12% (w/w), 235g, 266mmol) was charged with SD573 free base (compound of formula II, wherein R is R) in heptane (68.3g) and ethyl acetate (136.1g)¹Is trifluoromethyl, R²Is cyclopropyl, R⁸Is 5-chloro, R⁹Is hydrogen and R¹⁰Hydrogen, 67.0g, 0.231 mol). Then, a solution of triphosgene in diphosgene was added over 90 minutes at 8 to 11 ℃. The mixture was aged at 8 ℃ for an additional 45 minutes. The mixture was warmed to 15 ℃ in about 30 minutes and aged at 15 ℃ for another 30 minutes to reach complete conversion according to method C. At 15 ℃ addingHeptane (137g) was added and the mixture was aged at 15 ℃ for a further 60 minutes. The mixture was warmed to 19 ℃ and water (80g) was added. The phases were allowed to separate and the aqueous phase was removed. The organic phase was distilled and heptane was added continuously until 5.4% (w/w) ethyl acetate remained (concentration of heptane solution was about 9.5mL/gSD 573). The mixture was seeded with DMP-266(0.8g) at 58 ℃ and the suspension was stirred at 58 ℃ for an additional 120 minutes, cooled to 25 ℃ over 120 minutes, cooled to-13 ℃ over 120 minutes and stirred at-13 ℃ for an additional about 30 minutes and filtered. The wet cake was washed twice with heptane (pre-cooled at-8 ℃, 50mL) at-8 ℃. The filter cake was dried under vacuum at 80 ℃ for 8 hours. The product (DMP-266, a compound of formula I, wherein R is methyl) was obtained in a yield of 90.2% (65.99g, 209mmol)¹Is trifluoromethyl, R²Is cyclopropyl, R⁸Is 6-chloro, R⁹Is hydrogen and R¹⁰Hydrogen) according to method D, the purity is 100% (w/w). According to X-ray analysis, crystalline form I was obtained.

Comparative example 1: homogeneous cyclization of SD573 with triphosgene

In a 500mL reactor, Na was added at 25 deg.C₂CO₃The aqueous solution (10.6g, 0.126mol) was charged to SD573 free base (25.13g, 0.087mol) in acetonitrile (25 mL). The mixture was cooled to-12 ℃ and a solution of triphosgene in acetonitrile (19.7 w/w%, 63.63g, 42mmol) was added over 40 minutes at-10 to-5 ℃. According to method C, complete conversion was achieved after 90 minutes. The reaction mixture was heated to 25 ℃ with Na at 20 ℃ to 25 ℃₂CO₃Neutralized, washed with water and then filtered. The mixture was cooled to-10 ℃ and water (7.5g) was then added dropwise. The slurry was filtered and the product isolated. The wet cake was dried under vacuum to give the final product in 5% yield (1.89g, 6 mmol). According to method D, the purity was 97.3% (w/w).

Comparative example 2: homogeneous cyclization of SD573 with triphosgene

To SD573 free base (25.04g, 0.086mol) in acetone (25mL) at 25 ℃ in a 500mL reactorCharging Na₂CO₃(10.6g, 0.126mol) and water (50 mL). The mixture was cooled to-12 ℃ and a solution of triphosgene (24% (w/w), 52g, 42mmol) in acetonitrile was added over 55 minutes at-10 to-5 ℃. According to method C, a conversion of 98.1% (w/w) was achieved after 60 minutes. The reaction mixture was heated to 25 ℃. According to method C, after a further 100 minutes, a conversion of 98.8% (w/w) is achieved. Triphosgene (0.69g) was added. According to method C, complete conversion is achieved after 180 minutes. At 20-25 deg.C with Na₂CO₃The reaction mixture was neutralized and then filtered. The filter was washed with water (12.5 g). Water (100mL) was added to the filtrate at 25 ℃. Since no product precipitated after 15 hours, the mixture was cooled to-10 ℃ and filtered to obtain batch 1 product. To the filtrate was added water (200mL) at-10 ℃ and the suspension was filtered again to obtain batch 2 of product. The precipitation was repeated to obtain batch 3 with additional water (100mL) added to the filtrate of batch 2. The combined batches (1 to 3) of wet product were dried in vacuo to give 84.5% yield (22.39g, 71 mmol). According to method D, the purity was 96.9% (w/w).

Comparative example 3: homogeneous cyclization of SD573 with triphosgene

In a 500mL reactor at 25 deg.C, SD573 free base (25.11g, 0.087mol) in THF (25mL) was charged with Na₂CO₃(10.6g, 0.126mol) and water (50 mL). The mixture was cooled to-12 ℃ and a solution of triphosgene (22.1% (w/w), 56.5g, 42mmol) in THF was added over 36 minutes between-10 and-5 ℃. According to method C, a conversion of 96.2% (w/w) was achieved after 120 minutes. The reaction mixture was heated to 25 ℃. According to method C, after a further 100 minutes, a conversion of 97.7% (w/w) is achieved. Triphosgene (0.68g) was added. An additional small portion of phosgene was added until 99.6% (w/w) conversion was reached. At a temperature of between 20 ℃ and 25 ℃ with Na₂CO₃The reaction mixture was neutralized and then filtered. Water (325g) was added to the mixture at 25 ℃. The mixture was cooled to 0 ℃ and filtered (batch 1 product). Adding to the product remaining in the vessel at 5 deg.CWater (200mL) was added; and the mixture was filtered (batch 2 product). Additional water (100mL) was added to the product remaining in the vessel at 5 ℃; and the mixture was filtered (batch 3 product). The combined batches (1 to 3) of wet product were dried in vacuo to give 56.5% yield (15.53g, 49 mmol). According to method D, the purity is 98.1% (w/w).

Comparative example 4: cyclization of SD573 with triphosgene

In a 1L reactor, Na was added at 25 deg.C₂CO₃Aqueous solution (21.5g, 0.256mol in 100mL water) was charged to SD573 free base (50.1g, 174mmol) in acetonitrile (50 mL). After adding Na₂CO₃Thereafter, the apparatus used containing SD573 free base was rinsed with 10mL of water. The mixture was cooled to-12 ℃ and a solution of triphosgene (24.3% (w/w), 103.3g, 84mmol) in acetonitrile was added over 30 minutes at-10 to-5 ℃. Since the triphosgene solution in acetonitrile was too concentrated as in example 1 of WO2010/032259a, the triphosgene did not all dissolve, and therefore the apparatus used containing the triphosgene was flushed with 5mL of acetonitrile after the addition of the triphosgene. After 60 minutes at-12 ℃, the mixture was warmed to 25 ℃ and complete conversion was achieved according to method C. Water (65mL) was added at 25 ℃ to achieve the same dilution as described in WO2010/032259 a. In contrast to the teaching of WO2010/032259a, no precipitation occurred at 10 ℃, so the mixture was cooled to-5 ℃ and then filtered. To completely remove the product, the reactor was flushed with water (200mL), after which the water was used to wash the wet cake. The filter cake was dried under vacuum to give the final product in 34.2% yield (18.63g, 6 mmol). According to method D, the purity is 100% (w/w).

The analysis method comprises the following steps:

the method A comprises the following steps: (HPLC method for determining enantiomeric purity)

Column:AD, 250 × 4.6.6 mm, temperature 40 ℃, flow rate 1.0mL/min, mobile phase Hexane/Isopropanol 75:25 (volume)Volume/volume); and (4) UV detection: 260nm

The method B comprises the following steps: (HPLC methods for conversion, purity and enantiomeric purity)

Column:AD-H250 × 4.6.6 mm, temperature 40 deg.C, flow rate 1.0mL/min, mobile phase hexane/isopropanol 89:11 (volume/volume), UV detection 260nm

The method C comprises the following steps: (HPLC method for detecting purity)

Column:RX-C18, 250 × 4.6.6 mm, 5 μm, temperature 40 ℃, flow rate 1.5mL/min, mobile phase A50% (w/w) buffer/50% (w/w) MeCN, mobile phase B MeCN, buffer 0.1% (w/w) H in water₃PO₄Adjusting the pH value to 3.6; gradient: 0min 0% (w/w) B to 30min 90% (w/w) B; and (4) UV detection: 250nm

The method D comprises the following steps: (HPLC method for detecting purity)

Column:SB-CN 150 × 4.6.6 mm, temperature 40 ℃, flow rate 1.5mL/min, mobile phase A90% (w/w) water/10% (w/w) MeOH + 0.05% (w/w) TFA (v/v), mobile phase B90% water/10% (w/w) MeOH + 0.05% (w/w) TFA (v/v), gradient 16min 40% (w/w) B to 50% B, 7min to 65% (w/w) B, 5min to 70% B, 1min to 80% B, 2min hold 80% (w/w) B, 1min to 40% (w/w) B, UV detection 250 nm.

Claims (30)

1. A process for the preparation of a compound of formula I and/or a suitable salt thereof,

wherein

R¹Selected from: hydrogen, straight-chain or branched C_1-6-alkyl or (C)_1-6-alkoxy) carbonyl, and any alkyl group substituted with one or more halogen atoms or any alkoxy group optionally substituted with one or more halogen atoms,

R²selected from: straight-chain or branched C_1-6Alkyl radicals, (C)_1-6-alkoxy) carbonyl, C_3-6-alkenyl, C_3-6-alkynyl and C_3-6Cycloalkyl, wherein each alkyl, alkoxy, alkenyl, alkynyl and cycloalkyl can carry an alkyl radical selected from aryl, aralkyl, C_1-6Alkyl and (1' -R)³)-C_3-6-another substituent in cycloalkyl, wherein R³Is hydrogen, methyl or ethyl, and any of the alkyl, cycloalkyl, aryl and aralkyl radicals in said further substituent which may be carried are optionally substituted by one or more halogen atoms, cyano, C_1-6Alkyl radical, C_3-6-cycloalkyl, -NR⁴R⁵、-SR⁶、S(O)R⁶Or S (O)₂)R⁶and/OR-OR⁷Is substituted, and R⁶Is C_1-6-an alkyl group, optionally substituted with one or more halogen atoms,

R⁷is hydrogen or C_1-6-an alkyl group, optionally substituted with one or more halogen atoms,

wherein

(a)R⁴And R⁵Independently selected from hydrogen or C_1-6-alkyl, or

(b)R⁴Is hydrogen and R⁵Is C_2-7-acyl or (C)_1-6-alkoxy) carbonyl, wherein R⁵Each of the acyl and alkoxy groups in turn being optionally substituted with one or more halogen atoms, or

(c)R⁴And R⁵Together with the nitrogen atom form a 5-to 7-membered heterocyclic ring, or

(d)R⁴And R⁵Together being ═ CH-aryl, the aryl moiety optionally being substituted with a group selected from halogen atoms, -NH₂、-NH(C_1-6-alkyl), -N (C)_1-6-alkyl groups)₂Or C_1-6-one or more substituents in the alkyl group, or

(e)R⁴And R⁵Together being CH-N (C)_1-6-alkyl groups)₂，

R⁶Is C_1-6-alkyl, optionally substituted with one or more halogen atoms, and

R⁷is hydrogen or C_1-6-an alkyl group, optionally substituted with one or more halogen atoms,

R⁸and R⁹Independently selected from hydrogen, halogen atoms, and C optionally substituted with one or more halogen atoms_1-6-an alkyl group,

R¹⁰is hydrogen or a group selected from: aryl, aralkyl, C_1-6-alkyl and (C)_1-6-alkoxy) carbonyl, wherein the aryl moiety in any aryl and aralkyl group is optionally one or more selected from C_1-6Alkyl radical, C_1-6-alkoxy or C_3-8Substituents in cycloalkyl, each alkyl, alkoxy or cycloalkyl substituent being optionally substituted with one or more halogen atoms,

said process comprising reacting a compound of formula II and/or a suitable salt thereof with a cyclisation agent selected from phosgene, diphosgene, triphosgene and mixtures thereof,

wherein R is¹、R²、R⁸、R⁹And R¹⁰As defined above, the above-mentioned,

wherein the reaction is carried out in the presence of an aqueous base and a water-immiscible organic solvent, wherein at least 90% of the organic solvent is selected from the group consisting of at least one C_2-5-carboxylic acid C_2-5Alkyl esters with at least one C_5-8-mixture of alkanes and C_2-5-carboxylic acid C_2-5-at least one member of the group consisting of alkyl esters.

2. The method of claim 1, wherein the cyclizing agent is provided in gaseous form.

3. The method of claim 1, wherein the cyclizing agent is provided in liquid form.

4. The process of claim 1, wherein the cyclizing agent is provided in solid form.

5. The process of any one of claims 1 to 4, wherein the molar ratio of the cyclizing agent to the compound of formula II is in the range of 1:1 to 4:1 based on the molar equivalents of phosgene.

6. The process of claim 5, wherein the molar ratio of the cyclizing agent to the compound of formula II is in the range of 1:1 to 2.5:1 based on the molar equivalents of phosgene.

7. The method of any one of claims 1 to 4, wherein the weight ratio of water to the organic solvent is in the range of 1:1 to 5: 1.

8. The method according to any one of claims 1 to 4, wherein at least 90% of the organic solvent consists of at least one member selected from the group consisting of C_2-5-carboxylic acid C_2-5Alkyl esters with at least one C_5-8-mixture of alkanes and C_2-5-carboxylic acid C_2-5-at least one member of the group consisting of alkyl esters.

9. The method of any one of claims 1 to 4, wherein C is_2-5-carboxylic acid C_2-5-alkyl ester is selected from acetic acid C_2-5Alkyl esters, propionic acid C_2-5-alkyl esters, and butyric acid C_2-5-an alkyl ester.

10. The method of any one of claims 1 to 4, wherein C is_2-5-carboxylic acid C_2-5-alkyl ester is selected from acetic acid C_2-5Alkyl esters and propionic acid C_2-5-an alkyl ester.

11. The method of any one of claims 1 to 4, wherein C is_5-8-the alkane is selected from pentane, cyclopentane, hexane, cyclohexane, heptane, cycloheptane and octane.

12. The method of any one of claims 1 to 4, wherein C is_5-8-the alkane is selected from hexane, cyclohexane, heptane and cycloheptane.

13. The method of claim 12, wherein said C_5-8-the alkane is heptane.

14. The process according to any one of claims 1 to 4, wherein the reaction is carried out at a temperature of-30 to +40 ℃.

15. The process according to any one of claims 1 to 4, wherein the reaction is carried out at a temperature of from 0 to +20 ℃.

16. The process according to any one of claims 1 to 4, wherein the compound of formula II is obtained by a process comprising the following steps

Wherein R is¹、R²、R⁸、R⁹、R¹⁰As defined in claim 1, the method further comprising the step of,

the steps are as follows:

(i) reacting a protic chiral auxiliary with a diorganozinc (II) compound in the presence of an aprotic solvent at a temperature in the range from 0 to 40 ℃, and

(ii) (ii) maintaining the mixture of step (i) in a first maturation period until the reaction is complete, but for at least 20 minutes, and

(iii) (III) reacting the mixture obtained after step (ii) with a compound of formula III,

wherein R is²As defined above, and

(iv) (iv) maintaining the mixture of step (iii) for a second maturation period until the reaction is complete, but for at least 10 minutes, and

(v) (iii) reacting the mixture obtained after step (IV) with a compound of formula IV, and an organolithium base and/or other organoalkali metal at a temperature in the range of from 0 to 40 ℃,

wherein R is¹、R⁸、R⁹And R¹⁰As defined above, and

(vi) (vi) maintaining the mixture obtained in step (v) at 0 to 50 ℃ until the reaction is complete to obtain said compound of formula II.

17. The method of claim 16, wherein steps (ii) and (iv) are carried out separately under agitation.

18. The method of claim 16, wherein the protic chiral auxiliary is selected from N, N-disubstituted ephedrine derivatives.

19. The process of claim 16, wherein the molar ratio of protic chiral auxiliary agent to diorganozinc (II) compound is in the range of 1.5:1 to 1:1.

20. The method of claim 16, wherein the diorgano of the diorganozinc (II) compound is selected from di (C)_1-8-alkyl) and di (C)_3-6-cycloalkyl radicals),wherein the alkyl moiety is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl, pentyl, hexyl, heptyl, and octyl, and wherein the cycloalkyl moiety is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

21. The process of claim 16, wherein the molar ratio of the protic chiral auxiliary agent to the compound of formula IV is in the range of 1:1 to 1: 10.

22. The process of claim 21, wherein the molar ratio of the protic chiral auxiliary agent to the compound of formula IV is in the range of 1:2 to 1: 6.

23. The process of claim 21, wherein the molar ratio of the protic chiral auxiliary agent to the compound of formula IV is in the range of 1:3 to 1: 6.

24. The method of claim 16, wherein the compound of formula III is used in a molar ratio of 1:0.6 to 1:1.3 with the compound of formula IV.

25. The process of claim 16, wherein the organolithium base and/or other organoalkali metal and the compound of formula IV are added in a molar ratio of 1:0.8 to 1: 1.5.

26. The process of claim 16, wherein the organolithium base is selected from (C)_1-6-alkyl) lithium, lithium diisopropylamide, lithium hexamethyldisilazide, phenyllithium, and lithium napthyl.

27. The method of claim 26, wherein said (C)_1-6-alkyl) lithium is selected from methyllithium, n-butyllithium, sec-butyllithium, tert-butyllithium and hexyllithium.

28. The method of claim 16, wherein the other organo alkali metal is selected from C_1-6Sodium alkoxide or C_1-6-potassium alcoholate, sodium or potassium diisopropylamine, and sodium or potassium hexamethyldisilazide.

29. The method of claim 16, wherein the temperature during the addition of the base is from +10 to +30 ℃.

30. The method of claim 16, wherein the aprotic solvent is selected from the group consisting of aprotic non-polar solvents, aprotic polar solvents, and mixtures thereof.