WO2018090670A1 - Method for preparing droxidopa and intermediate thereof - Google Patents

Abstract

The present invention relates to a method for preparing a droxidopa intermediate (2S,3R)-3-(3,4-dibenzyloxyphenyl)-2-dibenzylamino-3-hydroxypropionate, comprising carrying out asymmetric hydrogenation to 3-(3,4-dibenzyloxyphenyl)-2-dibenzylamino-3-oxo-propionate in an organic solvent under the catalysis of a ruthenium catalyst in the presence of a hydrogen donor reagent and an organic base. The reaction highly stereoselectively introduces two chiral centres of droxidopa in a high yield in one step. Furthermore, on the basis of the reaction, a method for preparing droxidopa is designed. The method has a simple and short process, and can stereoselectively synthesize droxidopa.

Description

Preparation method of dexcidopa and intermediate thereof Technical field

The present invention relates to the field of medicinal chemistry, and in particular to an improved method for preparing cexidopa and a novel intermediate of cixidol.

Background technique

Quxiedoba, also known as L-threo-3-(3,4-dihydroxyphenyl)serine, is a compound of formula (VIII), a synthetic amino acid that causes abnormally reduced noradrenal cells in the brain. The concentration of hormone returns to normal levels, thus improving various symptoms caused by norepinephrine deficiency, such as dizziness, dizziness and fatigue caused by orthostatic hypotension, gait stiffness in patients with Parkinson's disease, etc.

Patent US 3,920,728 (Route 1) discloses for the first time that 3,4-dibenzyloxybenzaldehyde and glycine are used as starting materials to react firstly to obtain racemic SU/Red-3-(3,4-dibenzyloxyphenyl). -N-benzyloxycarbonylserine, resolved by dicyclohexylamine to give racemic threo-3-(3,4-dibenzyloxyphenyl)-N-benzyloxycarbonylserine, further ephedrine Resolution of base or threon-3-nitrophenyl-2-amino-1,3-propanediol to give threo-3-(3,4-dibenzyloxyphenyl)-N-benzyloxycarbonylserine, and finally A method of hydrogenating a deprotecting group to give L-threo-3-(3,4-dihydroxyphenyl)serine.

EP0024210A1, EP0084928A1 have improved the sequence of the chiral resolving agent, protecting group and deprotecting group on the basis of this route. The biggest disadvantage of this type of method is that it requires two splits to obtain cexidopa, resulting in lower overall yield and higher cost.

WO2013142093A1 uses L-ephedrine as a resolving agent, and the serine derivative can obtain the L-threo serine derivative in one step, but the theoretical yield is still low due to the absence of configuration conversion in the resolution. And ephedrine is a controlled drug and is more difficult to obtain.

JPH01228946 discloses a novel method for synthesizing cixidol (Scheme 2) which uses (S)-2-amino-3-(3,4-dihydroxyphenyl)propionic acid as a starting material. The steps of esterification, reduction, acetylation, oxidation and the like form an oxazoline derivative substituted with an acetoxymethyl group at the 4-position, and the compound is subjected to ring opening, oxidation, and deprotection to obtain dicedopa. Although the method can obtain xicidoba in a stereoselective manner, the route is too long, the operation is cumbersome and complicated, and the starting material contains a chiral center, and the cost is high.

GB2300858 (Route 3) Although the improvement of Route 2, the four ester-substituted oxazoline derivatives can be formed in one step by reacting an N-carbonyl derivative with a halogen radical initiator or a tetravalent phosphonium salt. The product, dicedopa, can be directly obtained by ring-opening and deprotection, but there are still disadvantages in that the raw material is expensive and the post-treatment requires column chromatography.

WO2005085178 uses protected 3,4-dihydroxybenzaldehyde as starting material (Scheme 4), constructs a chiral center through a chiral metal coordination compound, and then deprotects to obtain dripopa. The chiral selectivity is not reported in the patent, but due to the use of an excessive amount of heavy metals such as nickel, copper, or zinc, a large amount of heavy metal ion wastewater is generated, and environmental pollution is severe.

Sang-Ho Baik [Biotechnology Letters (2010), 32(1), 143-149] starting with 3,4-dihydroxybenzaldehyde and glycine The material is directly catalyzed by an aldolase to construct a C-C bond. The reaction is catalyzed by an enzyme, and the advantage is that the route is short, the reaction is mild, and the cost is low. However, the enzymatic reaction requires strict conditions, and the current enzyme-catalyzed synthesis of dexcidopa has not been reported to have industrialized production, mostly in the laboratory research stage. And during the reaction of the enzyme, the selectivity of the hand is not high, and some impurity isomers still exist (route 5).

The route reported by JPH09249626 (Route 6) has a short reaction step, and the yield of each step is high. The chiral center is directly constructed during the reaction without disassembly. However, the reaction involved in the process uses highly toxic and explosive sodium azide, which poses a safety hazard and is therefore not suitable for industrial production.

WO2016147133A1 discloses a synthesis method of ceceidopa using a chiral sulfenamide as a chiral auxiliary (Scheme 7), which is expensive, and the three-membered ring intermediate is unstable and the reaction yield is low.

Summary of the invention

Summary of invention

In a first aspect, the present invention provides the preparation of (2S,3R)-3-(3,4-dibenzyloxyphenyl)-2-dibenzylamino-3-hydroxypropionate of formula (V). Methods,

Wherein R ¹ is C _1-4 alkyl or benzyl;

It comprises 3-(3,4-dibenzyloxyphenyl)-2-dibenzylamino-3-oxopropionate in an organic solvent, catalyzed by a rhodium catalyst, in a hydrogen donor reagent and organic An asymmetric hydrogenation reaction is carried out in the presence of a base.

In a second aspect, the present invention provides a method for preparing cixidol using the above method as a key step. The two methods have the advantages of high yield, high stereoselectivity, easy availability of raw materials, simple process, economical and environmental protection, and are suitable for industrial production.

Definition of Terms

The invention is intended to cover all alternatives, modifications, and equivalents, which are within the scope of the invention as defined by the appended claims. Those skilled in the art will recognize that many methods and materials similar or equivalent to those described herein can be used in the practice of the invention. The invention is in no way limited to the methods and materials described herein. In the event that one or more of the incorporated literature, patents, and similar materials are different or inconsistent with the present application (including but not limited to defined terms, terminology applications, described techniques, etc.), Prevail.

It will be further appreciated that certain features of the invention are described in the various embodiments of the invention, and may be described in combination in a single embodiment. On the contrary, the various features of the invention are described in a single embodiment for the sake of brevity, but may be provided separately or in any suitable sub-combination.

Unless otherwise stated, all technical and scientific terms used in the present invention have the same meaning as commonly understood by those skilled in the art. All patents and publications related to the present invention are hereby incorporated by reference in their entirety.

The following definitions used herein should be applied unless otherwise stated. For the purposes of the present invention, the chemical elements are consistent with the CAS version of the Periodic Table of the Elements, and the 75th edition of the Handbook of Chemistry and Physics in 1994. The term "comprising" or "including" is an open-ended expression that includes the content of the invention, but does not exclude other aspects.

In each part of the specification, the substituents of the compounds disclosed herein are disclosed in terms of the type or range of groups. In particular, the invention includes each individual sub-combination of each member of the group and range of such groups. For example, the term "C1-6 alkyl" specifically refers to the independently disclosed methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl groups.

In various parts of the invention, linking substituents are described. When the structure clearly requires a linking group, the Markush variable recited for that group is understood to be a linking group. For example, if the structure requires a linking group and the definition of the Markush group for the variable is "alkyl" or "aryl", it should be understood that the "alkyl" or "aryl" respectively represent the attached An alkylene group or an arylene group.

The term "alkyl" as used herein, denotes a saturated straight or branched monovalent hydrocarbyl group containing from 1 to 20 carbon atoms, wherein the alkyl group may be optionally one or more Substituted by the substituents described in the invention.

The invention provides a novel preparation method of the intermediate (2S,3R)-3-(3,4-dibenzyloxyphenyl)-2-dibenzylamino-3-hydroxypropionate of cixidol, which The structure of the intermediate is as shown in formula (V):

The preparation method of the present invention comprises 3-(3,4-dibenzyloxyphenyl)-2-dibenzylamino-3-oxopropionate having the following structure in an organic solvent ( IV)

Catalytic amount of rhodium catalyst (VII)

Or catalytic amount of ruthenium catalyst (VIII)

Asymmetric hydrogenation reaction under catalysis;

The asymmetric hydrogenation reaction is carried out in the presence of a hydrogen donor reagent and an organic base.

among them,

R ¹ represents C _1-4 alkyl or benzyl; in some embodiments, R ¹ is methyl, ethyl, t-butyl or benzyl.

R ² represents C _1-6 alkyl, optionally substituted C _1-6 alkyl, phenyl or optionally substituted phenyl; in some embodiments, R ² is methyl, p-methylphenyl, p-trifluoro Methylphenyl, pentafluorophenyl, trifluoromethyl or perfluorobutyl.

R ³ and R ⁴ each represent a phenyl group or a substituted phenyl group, or R ³ and R ⁴ together represent a butylene group; in some embodiments, R ³ and R ⁴ are each a phenyl group.

Ar represents benzene, optionally substituted benzene, cyclopentadiene, optionally substituted cyclopentadiene; in some embodiments, the Ar is benzene or Isopropyltoluene or cyclopentadiene.

P represents oxygen, a chemical bond or CH ₂ .

Q represents hydrogen or an alkyl group; in some embodiments, Q is hydrogen or methyl.

The rhodium catalyst (VII) or the rhodium catalyst (VIII) may be any rhodium catalyst conforming to the above definition; for example, the rhodium catalyst (VII) or the rhodium catalyst (VIII) may be a rhodium catalyst of the following structure:

In some embodiments, the rhodium catalyst (VII) is catalyst VII-A, catalyst VII-B, catalyst VII-E, or catalyst VII-G; in some embodiments, rhodium catalyst (VIII) is catalyst VIII-A.

The asymmetric hydrogenation reaction can be carried out in any suitable organic solvent; for example, the organic solvent can be dichloromethane, toluene, N,N-dimethylformamide, tetrahydrofuran, or a combination thereof; In the embodiment, the organic solvent is dichloromethane, toluene, N,N-dimethylformamide or tetrahydrofuran.

The hydrogen donor reagent can be any suitable hydrogen donor reagent; in some embodiments, the hydrogen donor reagent is formic acid.

The organic base may be any suitable organic base; in some embodiments, the organic base is diethylamine, diisopropylamine, bicyclic Hexylamine, triethylamine, N,N-diisopropylethylamine, or a combination thereof.

The rhodium catalyst (VII) or the rhodium catalyst (VIII) may be used in an amount of any suitable catalyst; for example, relative to 1 mol of 3-(3,4-dibenzyloxyphenyl)-2-dibenzyl. The amide catalyst (VII) or the ruthenium catalyst (VIII) may be used in an amount of from 0.001 mole to 0.1 mole; in some embodiments, relative to 1 mole of 3-(3, 4-Dibenzyloxyphenyl)-2-dibenzylamino-3-oxopropionate, the rhodium catalyst (VII) or rhodium catalyst (VIII) is used in an amount of 0.015 mol.

The amount of the organic base may be any suitable amount of the organic base; for example, relative to 1 mole of 3-(3,4-dibenzyloxyphenyl)-2-dibenzylamino-3-oxopropionic acid The ester may be used in an amount of from 1 mole to 10 moles; in some embodiments, relative to 1 mole of 3-(3,4-dibenzyloxyphenyl)-2-dibenzylamino-3. An oxopropionate, the organic base being used in an amount of 7 moles.

The asymmetric hydrogenation reaction can be carried out at any suitable temperature; for example, the reaction is carried out at about 0 degrees Celsius or below; in some embodiments, the reaction is carried out at about 40 degrees Celsius, 60 degrees Celsius, or 80 degrees Celsius.

In the reaction of the present invention, the reaction end point is monitored by high performance liquid chromatography (HPLC), when the compound of formula (IV) is 3-(3,4-dibenzyloxyphenyl)-2-dibenzylamino-3. When the HPLC purity of the oxopropionate is less than or equal to 5%, the reaction is considered to be completed, and the reaction time is usually from 15 to 80 hours depending on the substrate and the catalyst.

After completion of the reaction, the reaction solution was washed with water, and the solvent was evaporated under reduced pressure to give the product (2S,3R)-3-(3,4-dibenzyloxyphenyl)-2-dibenzylamino-3-hydroxy Propionate (V).

The present invention also provides a method for synthesizing cixidol with the asymmetric hydrogenation reaction as a key step. The method includes the following steps:

(a) 3-(3,4-Dibenzyloxyphenyl)-2-dibenzylamino-3-oxopropionate of the formula (IV) in an organic solvent

Catalytic amount of ruthenium catalyst (VII)

Or catalytic amount of ruthenium catalyst (VIII)

Asymmetric hydrogenation in the presence of a hydrogen donor reagent and an organic base,

among them,

R ¹ represents C _1-4 alkyl or benzyl;

R ² represents C _1-6 alkyl, optionally substituted C _1-6 alkyl, phenyl, or optionally substituted phenyl;

R ³ and R ⁴ each independently represent a phenyl group or a substituted phenyl group, or R ³ and R ⁴ together represent a butylene group;

Ar is a ligand selected from the group consisting of benzene, optionally substituted benzene, cyclopentadiene, and optionally substituted cyclopentadiene;

P represents oxygen, chemical bond or CH ₂ ;

Q represents hydrogen or an alkyl group.

(b) The compound of the formula (V) is hydrolyzed by an inorganic base in a mixed solvent of an organic solvent and water to obtain (2S,3R)-3-(3,4- represented by the formula (VI). Dibenzyloxyphenyl)-2-dibenzylamino-3-hydroxypropionic acid,

(c) The compound represented by the formula (VI) is hydrogenated with hydrogen in a water-soluble organic solvent under the action of aqueous hydrochloric acid and Pd/C to prepare cexidopa of the formula (IX).

among them,

The organic solvent described in the step (b) may be any suitable organic solvent; in some embodiments, the organic solvent is tetrahydrofuran;

The inorganic base in the step (b) may be any suitable inorganic base; for example, the inorganic base may be an alkali metal hydroxide or a hydrate thereof; in some embodiments, the inorganic base is sodium hydroxide;

The organic solvent in the step (c) may be any suitable organic solvent; for example, the organic solvent may be methanol, ethanol, isopropanol, tetrahydrofuran, or a combination thereof; in some embodiments, the organic solvent is ethanol or isopropanol. ;

In step (c), the aqueous hydrochloric acid solution may be any suitable concentration; for example, the concentration of aqueous hydrochloric acid may be 0-12 mol / L; in some embodiments, the concentration of aqueous hydrochloric acid solution is 3mol / L, 5mol / L;

The hydrogen pressure in step (c) may be any suitable pressure; for example, the hydrogen pressure may be from 1 to 50 atm; in some embodiments, the hydrogen pressure is from 1 atm, 30 atm.

In some embodiments, 3-(3,4-dibenzyloxyphenyl)-2-dibenzylamino-3-oxopropionate of formula (IV) as described in step (a)

The preparation method thereof can include the following steps:

(a) Preparation of the intermediate 3-(3,4-dibenzyloxyphenyl)-3-oxopropionate (II);

The intermediate 3-(3,4-dibenzyloxyphenyl)-3-oxopropionate (II) can be obtained by the method of the following step (a1) or (a2);

(a1) The compound 3,4-dibenzyloxybenzoic acid (I) forms the intermediate 3,4-dibenzyloxybenzoyl chloride (Ia) under the action of thionyl chloride, and the intermediate (Ia) in the base Reaction with Methic acid to form the intermediate 5-(3,4-dibenzyloxybenzoyl)-2,2-dimethyl-1,3-dioxane-4,6-dione ( Ib), intermediate (Ib) is reacted with an alcohol of the structure R ¹ OH to prepare the intermediate 3-(3,4-dibenzyloxyphenyl)-3-oxopropionate (II), and the reaction formula is as follows:

(a2) The compound 3,4-dibenzyloxybenzoic acid (I) is formed under the action of thionyl chloride to form the intermediate 3,4-dibenzyloxybenzoyl chloride (Ia), intermediate (Ia) in magnesium chloride and The intermediate 3-(3,4-dibenzyloxyphenyl)-3-oxopropionate (II) is prepared by the reaction of triethylamine with potassium malonate monoester. The reaction formula is as follows:

(b) The intermediate 3-(3,4-dibenzyloxyphenyl)-3-oxopropionate (II) is reacted with a halogenating reagent to prepare the intermediate 3-(3,4-dibenzyl) Oxyphenyl)-2-halo-3-oxopropionate (III)

(c) The intermediate 3-(3,4-dibenzyloxyphenyl)-2-halo-3-oxopropionate (III) is reacted with dibenzylamine under the action of an acid binding agent to have the following The structure intermediate 3-(3,4-dibenzyloxyphenyl)-2-dibenzylamino-3-oxopropionate (IV)

Wherein R ¹ is as defined above; and X is a halogen selected from chlorine, bromine or iodine.

among them,

The halogenating agent described in step (b) may be any suitable halogenating agent; for example, the halogenating agent may be sulfonyl chloride, N-chlorosuccinimide, N-bromosuccinimide, Dibromohydantoin, bromine or N-iodosuccinimide; in certain embodiments, the halogenating agent is sulfonyl chloride, N-bromosuccinimide, dibromohydantoin, N-iodine Desuccinimide

The acid binding agent described in the step (c) may be any suitable organic or inorganic base; for example, the acid binding agent may be an inorganic base such as sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, potassium acetate, phosphoric acid. Dipotassium hydrogen, disodium hydrogen phosphate, or a combination thereof, an organic base such as triethylamine, pyridine, N,N-diisopropylethylamine, N-methylmorpholine, or a combination thereof; in some embodiments, The acid binding agent is potassium carbonate, sodium hydrogencarbonate, triethylamine, pyridine, potassium acetate, diisopropylethylamine;

Step (c) can be carried out at any suitable temperature; for example, the reaction temperature can be 0 ° C ~ 150 ° C; in some embodiments, the reaction temperature is room temperature, 58 ° C, 76 ° C, 100 ° C;

Step (c) can be carried out in any suitable organic solvent; in some embodiments, the reaction solvent is N,N-dimethylformamide, dimethyl sulfoxide, acetonitrile, acetone, ethanol or a combination thereof.

The method for synthesizing cixidol provided by the present invention has the following advantages compared with the prior art:

1. Using asymmetric catalytic technology, high yield and high stereoselectivity of two chiral centers of cixidoba are introduced in one step, making the enantioselectivity (>98.5% ee) and non-pair of the target product The selectivity is very high (dr>99:1), and the theoretical yield is increased from 25% of the original splitting process to 100%;

2. The raw materials are cheap and easy to obtain, the reaction operation is simple, and the reaction is not harsh;

3. The phenolic hydroxyl group and the protecting group of the amino group are unified into a benzyl group, which can be completely removed at one time, saving operation and improving production efficiency. At the same time, this protection method is also a key factor for ensuring high stereoselectivity, and the amino protecting group is benzyl. If the base is replaced, the asymmetric hydrogenation reaction cannot be made to have higher stereoselectivity. Therefore, the technology is more green and efficient, and more in line with the needs of industrial production.

DRAWINGS

Figure 1 is a synthetic route diagram of cixidoba.

detailed description

In order to make those skilled in the art better understand the technical solutions of the present invention, the present invention will be further described in detail below by way of non-limiting embodiments.

The reagents used in the present invention are all commercially available or can be prepared by the methods described herein.

In the present invention, mmol means millimolar, h means hour, g means gram, ml means liter, atm means standard atmospheric pressure, PE means petroleum ether, EA means ethyl acetate, DCM means dichloromethane, ¹ H NMR means nuclear magnetic resonance spectrum , LCMS refers to liquid chromatography, HPLC refers to high performance liquid chromatography, CDCl ₃ refers to deuterated chloroform.

Example 1 Preparation of methyl 3-(3,4-dibenzyloxyphenyl)-3-oxopropanoate (II-A)

To the reaction flask was added 200 g of the compound 3,4-dibenzyloxybenzoic acid (I), which was dissolved in 1000 mL of dichloromethane, and 120 g of thionyl chloride was added dropwise at room temperature; and the mixture was stirred at 40 ° C to reflux to give a clear solution. Another reaction flask was charged with 87 g of N,N-dimethylaminopyridine and 76.3 g of malic acid, dissolved in 500 mL of dichloromethane, and the above solution was added dropwise at 30 ° C. After the addition, the reaction was carried out at 30 ° C for 24 h. After washing with 2000 mL of 1 mol/L dilute hydrochloric acid, the organic phase was concentrated under reduced pressure to remove dichloromethane, and the residue was added to 1000 mL of methanol, and the mixture was warmed to reflux for 5 h. After completion of the reaction, the temperature was lowered to 0 ° C, and a solid was precipitated, which was washed with suction to give a white solid (131 g, yield: 56%).

Example 2 Preparation of ethyl 3-(3,4-bis(benzyloxy)phenyl)-3-oxopropanoate (II-B)

50 g of the compound 3,4-dibenzyloxybenzoic acid (I) was added to the reaction flask, and it was dissolved in 300 mL of tetrahydrofuran, and 40 g of thionyl chloride was added dropwise at room temperature; and the mixture was stirred at 40 ° C to obtain a clear acid chloride solution. In a separate reaction flask, 50 g of monoethyl malonate potassium salt and 500 mL of tetrahydrofuran were added. Further, 35 g of anhydrous magnesium chloride and 40 g of triethylamine were added, and the mixture was stirred at 30 ° C for 2 hours, and the above acid chloride solution was added dropwise. After the addition, the reaction was carried out at 30 ° C for 24 hours. After the completion of the reaction, 500 mL of 1 mol/L of dilute hydrochloric acid was added, and 200 mL of ethyl acetate was used. The organic phase was concentrated under reduced pressure to give a pale yellow oil.

Example 3 Preparation of Benzyl 3-(3,4-bis(benzyloxy)phenyl)-3-oxopropionate (II-C)

10 g of the compound 3,4-dibenzyloxybenzoic acid (I) was added to the reaction flask, and the mixture was dissolved in 100 mL of tetrahydrofuran, and 10 g of thionyl chloride was added dropwise at room temperature; and the mixture was stirred at 40 ° C to obtain a clear acid chloride solution. Another reaction flask was charged with 15 g of monobenzyl malonate potassium salt and 100 mL of tetrahydrofuran. Further, 7 g of anhydrous magnesium chloride and 10 g of triethylamine were added, and the mixture was stirred at 30 ° C for 2 hours, and the above acid chloride solution was added dropwise. After the addition, the reaction was carried out at 30 ° C for 2 hours. After the reaction was completed, 100 mL of 1 mol/L of dilute hydrochloric acid was added, and 100 mL of ethyl acetate was used. The organic phase was concentrated under reduced pressure to give a pale yellow oil (11.2 g).

Example 4 Preparation of tert-butyl 3-(3,4-bis(benzyloxy)phenyl)-3-oxopropanoate (II-D)

33 g of Compound I was added to the reaction flask, and the mixture was dissolved in 120 mL of tetrahydrofuran, and 20 g of thionyl chloride was added dropwise at room temperature; and the mixture was stirred at 40 ° C to obtain a clear acid chloride solution, which was concentrated under reduced pressure to give tetrahydrofuran, and the residue was dissolved in 50 mL of tetrahydrofuran. Another reaction flask was charged with 23 g of t-butyl acetate and 100 mL of tetrahydrofuran. 120 mL of lithium diisopropylamide in tetrahydrofuran solution was added dropwise at -20 ° C, and the mixture was stirred for 0.5 hour. The above acid chloride solution was added dropwise. After the addition, the temperature was raised to 30 ° C for 8 hours. After the reaction was completed, 200 mL of 1 mol/L was added. The diluted hydrochloric acid was extracted with ethyl acetate (200 mL).

Example 5 Preparation of Methyl 3-(3,4-bis(benzyloxy)phenyl)-2-chloro-3-oxopropanoate (III-A)

80 g of the compound methyl 3-(3,4-dibenzyloxyphenyl)-3-oxopropanoate (II-A) was added to the reaction flask, dissolved in 250 mL of dichloromethane, and 29 g of sulfonyl chloride was added at room temperature. The reaction was stirred for 10 h. After completion of the reaction, 200 mL of a saturated aqueous solution of sodium hydrogencarbonate was added and the mixture was separated.

Example 6 Preparation of ethyl 3-(3,4-bis(benzyloxy)phenyl)-2-bromo-3-oxopropanoate (III-B)

57 g of the compound ethyl 3-(3,4-bis(benzyloxy)phenyl)-3-oxopropanoate (II-B) was added to the reaction flask, and dissolved in 150 mL of dichloromethane, and 36 g of N was added at room temperature. - Bromosuccinimide, stirred for 24 h. After completion of the reaction, 500 mL of a saturated aqueous solution of sodium hydrogensulfite was added, and the organic layer was concentrated under reduced pressure to give 63.1 g of III-B.

Example 7 Preparation of Benzyl 3-(3,4-bis(benzyloxy)phenyl)-2-bromo-3-oxopropionate (III-C)

75 mL of toluene and 9.3 g of the compound 3-(3,4-bis(benzyloxy)phenyl)-3-oxopropionate (II-C) were added to the reaction flask, stirred and dissolved, and 2.57 g was added at room temperature. Dibromohydantoin, heat preservation reaction for 16 hours. After completion of the reaction, 100 mL of a saturated aqueous solution of sodium hydrogensulfite was added, and the organic layer was concentrated under reduced pressure to give 10.6 g of III-C (yield: 97.2%).

Example 8 Preparation of tert-butyl 3-(3,4-bis(benzyloxy)phenyl)-2-iodo-3-oxopropionate (III-D)

Add 120 ml of toluene and 22 g of compound tert-butyl 3-(3,4-bis(benzyloxy)phenyl)-3-oxopropionate (II-D) to the reaction flask, stir to dissolve, and add 11 g of N at room temperature. - Iodobutylimide, and the reaction was kept for 4 hours. After completion of the reaction, 200 mL of a saturated aqueous solution of sodium hydrogensulfite was added, and the mixture was separated, and the organic layer was concentrated under reduced pressure to yield 20.9 g of III-D.

Example 9 Preparation of methyl 3-(3,4-bis(benzyloxy)phenyl)-2-dibenzylamino-3-oxopropanoate (IV-A)

Add 500 mL of N,N-dimethylformamide and 80 g of methyl 3-(3,4-bis(benzyloxy)phenyl)-2-chloro-3-oxopropionate (III-A) to the reaction flask. 40 g of dibenzylamine, stirred and dissolved, 28 g of potassium carbonate was added at room temperature, and the reaction was kept for 48 hours. After completion of the reaction, 500 mL of water was added, and the mixture was extracted twice with ethyl acetate (300 mL).

Example 10 Preparation of ethyl 3-(3,4-bis(benzyloxy)phenyl)-2-dibenzylamino-3-oxopropanoate (IV-B)

Add 350 mL of acetonitrile, 50 g of ethyl 3-(3,4-bis(benzyloxy)phenyl)-2-bromo-3-oxopropionate (III-B), 40 mL of dibenzylamine, and stir. After the dissolution, 12.6 g of sodium hydrogencarbonate was added at room temperature, and the mixture was heated to reflux for 24 hours. After completion of the reaction, the mixture was cooled to room temperature, and then added with 500 mL of EtOAc.

Example 11 Preparation of (IV-B) ethyl 3-(3,4-bis(benzyloxy)phenyl)-2-dibenzylamino-3-oxopropanoate

Add 50 mL of acetonitrile, 5 g of ethyl 3-(3,4-bis(benzyloxy)phenyl)-2-bromo-3-oxopropionate (III-B), 4 mL of dibenzylamine, and stir to dissolve in the reaction flask. After adding 1 mL of triethylamine at room temperature, the temperature was raised to reflux for 5 hours. After the reaction was completed, the mixture was cooled to room temperature, 50 mL of water was added, and the mixture was extracted twice with ethyl acetate (25 mL). 5.9 g of compound IV-B was obtained in a yield of 95%.

Example 12 Preparation of Benzyl 3-(3,4-bis(benzyloxy)phenyl)-2-dibenzylamino-3-oxopropanoate (IV-C)

50 mL of DMSO, 4 g of benzyl 3-(3,4-bis(benzyloxy)phenyl)-2-bromo-3-oxopropionate (III-C), 2.4 mL of dibenzylamine were added to the reaction flask. After stirring and dissolving, 3 mL of pyridine was added at room temperature, and the mixture was heated to 100 ° C for 5 hours. After completion of the reaction, the mixture was cooled to room temperature, and 50 mL of water was added, and the mixture was extracted twice with 25 mL of ethyl acetate. The combined organics were evaporated to dryness <RTI ID=0.0> The yield of -C was 74.8%.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.52 - 7.18 (m, 23H), 7.18 - 7.08 (m, 4H), 6.83 (d, J = 8.5 Hz, 1H), 5.36 (d, J = 12.2 Hz, 1H), 5.22 (s, 2H), 5.19 (d, J = 12.3 Hz, 1H), 5.05 (q, J = 11.7 Hz, 2H), 4.94 (s, 1H), 3.89 (q, J = 13.6 Hz, 4H).

Example 13 Preparation of tert-butyl 3-(3,4-bis(benzyloxy)phenyl)-2-dibenzylamino-3-oxopropanoate (IV-D)

120 ml of 95 ethanol, 20 g of tert-butyl 3-(3,4-bis(benzyloxy)phenyl)-2-iodo-3-oxopropionate (III-D), 15 mL of dibenzylamine were added to the reaction flask. After stirring and dissolving, 7.0 g of potassium acetate was added at room temperature, and the temperature was raised to 78 ° C for 2 hours. After completion of the reaction, the mixture was cooled to room temperature, and 120 mL of water was added thereto to precipitate a solid, which was filtered, and the obtained solid was washed with 50 mL of a 1:1 aqueous solution of ethanol to obtain 17.5 g of IV-D, yield 78%.

Example 14 Preparation of ethyl 3-(3,4-bis(benzyloxy)phenyl)-2-dibenzylamino-3-oxopropanoate (IV-B)

Add 50 mL of acetone, 10 g of ethyl 3-(3,4-bis(benzyloxy)phenyl)-2-bromo-3-oxopropionate (III-B), 6 mL of dibenzylamine, and stir. After the dissolution, 5 mL of diisopropylaminoethylamine was added at room temperature, and the temperature was raised to 56 ° C for 8 hours. After completion of the reaction, the mixture was cooled to room temperature, and 100 mL of water was added thereto to precipitate a solid, which was filtered with suction, and the obtained solid was washed with water to give 8.9 g of Compound IV-B.

Example 15 Preparation of (2S,3R)-3-(3,4-bis(benzyloxy)phenyl)-2-dibenzylamino-3-hydroxypropanoic acid methyl ester (V-A)

4-Methylisopropylphenylphosphonium dichloride [RuCl ₂ (p-Cymene)] ₂ (250 mg), N-((1R,2R)-2-amino-1,2- was added sequentially to a Schlenk bottle. Diphenylethyl)methanesulfonamide MsDPEN (270 mg), 0.5 ml of triethylamine and 10 mL of isopropanol, the whole reaction system was replaced with nitrogen three times, the reaction was heated to 80 ° C, and the reaction was carried out for 1 hour to obtain a catalyst VII-A solution. Cool down to room temperature for use.

22.5 g of methyl 3-(3,4-bis(benzyloxy)phenyl)-2-dibenzylamino-3-oxopropionate (IV-A), 200 ml of LDCM, and 38 mL of triethylamine were added to the above. In the reaction flask, the temperature was lowered to 0 ° C, and then 45 mL of formic acid was slowly added. After the addition, the temperature was raised to 40 ° C under a nitrogen atmosphere to start the reaction. The reaction was controlled for about 60 hours and the reaction was complete. The reaction solution was washed twice with water, and the solvent was evaporated under reduced pressure to give the product V-A. The residue was purified by column chromatography to yield white solid, yield: 75%.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.44 - 7.32 (m, 20H), 6.83 (d, J = 8.0, 1H), 6.75 - 6.72 (m, 2H), 5.10 (s, 2H), 5.02-4.95 ( m, 2H), 4.92 (d, J = 8.1, 1H), 4.24 (s, 1H), 4.18 (s, 1H), 4.09-4.03 (m, 1H), 3.68 (s, 3H), 3.54 (d, J=11.9, 2H), 3.42 (d, J=11.9, 1H).

[M+H] ⁺ (LCMS)=588.3

Example 16 Preparation of (2S,3R)-3-(3,4-bis(benzyloxy)phenyl)-2-dibenzylamino-3-hydroxypropionic acid ethyl ester (V-B)

4-Methylisopropylphenylphosphonium dichloride [RuCl ₂ (p-Cymene)] ₂ (1.38 g), N-((1R,2R)-2-amino-1,2 was added sequentially to a Schlenk bottle. -diphenylethyl)trifluoromethanesulfonamide TfDPEN (1.55g), 3ml of triethylamine and 30mL of isopropanol, the whole reaction system was replaced with nitrogen three times, the reaction was heated to 80 degrees Celsius, and the reaction was carried out for 1 hour to obtain catalyst VII. -B solution, cooled to room temperature for use.

50g of ethyl 3-(3,4-bis(benzyloxy)phenyl)-2-dibenzylamino-3-oxopropionate (IV-B), 500mLDCM and 140 mL of triethylamine was added to the above reaction flask, and the temperature was lowered to 0 ° C. Then, 100 mL of formic acid was slowly added, and after the addition, the temperature was raised to 40 ° C under a nitrogen atmosphere to start the reaction. The reaction was controlled for about 35 hours and the reaction was complete. The reaction solution was washed twice with water, and the solvent was evaporated under reduced pressure to give a brown solid V-B (yield: 85%). The product V-B had a diastereoselectivity of 99:1 and ee >98.5%.

^{1 H-NMR (400MHz, CDCl} 3) δ7.45-7.31 (m, 20H), 6.83 (d, J = 8.0,1H), 6.76-6.73 (m, 2H), 5.12 (s, 2H), 5.04- 4.95 (m, 2H), 4.90 (d, J = 8.0, 1H), 4.24 (s, 1H), 4.21-4.14 (m, 3H), 4.09-4.03 (m, 1H), 3.52 (d, J = 12.0) , 2H), 3.40 (d, J = 12.0, 1H), 1.21 (t, J = 8.0, 3H).

[M+H] ⁺ (LCMS)=602.3

Example 17 Preparation of (2S,3R)-3-(3,4-bis(benzyloxy)phenyl)-2-dibenzylamino-3-hydroxypropionic acid ethyl ester (V-B)

Phenylphosphonium dichloride [RuCl ₂ (benzene)] ₂ (118 mg), N-((1R,2R)-2-amino-1,2-diphenylethyl)trifluoromethyl was added sequentially in a Schlenk bottle. Sulfonamide TfDPEN (150 mg), 0.5 mL of diisopropylethylamine and 5 mL of isopropanol, the whole reaction system was replaced with nitrogen three times, the reaction was heated to 80 ° C, and the reaction was carried out for 1 hour to obtain a catalyst VII-G solution, and the temperature was lowered to room temperature. spare.

2.5 g of ethyl 3-(3,4-bis(benzyloxy)phenyl)-2-dibenzylamino-3-oxopropionate (IV-B), 50 mL of toluene and 8 mL of diisopropyl B The amine was added to the above reaction flask, and the temperature was lowered to 0 ° C. Then, 10 mL of formic acid was slowly added, and after the addition, the temperature was raised to 80 ° C under a nitrogen atmosphere to start the reaction. The reaction was controlled for about 40 hours and the reaction was complete. The reaction solution was washed twice with water, and the solvent was evaporated evaporated evaporated. mjjjjjjj

Example 18 Preparation of (2S,3R)-3-(3,4-bis(benzyloxy)phenyl)-2-dibenzylamino-3-hydroxypropanoic acid ethyl ester (V-B)

10.0 g of ethyl 3-(3,4-bis(benzyloxy)phenyl)-2-dibenzylamino-3-oxopropanoate (IV-B), 552 mg of catalyst VIII-A, 80 mL of dichloro Methane and 1.6 g of diethylamine were added to a 250 mL reaction flask, and the temperature was lowered to 0 ° C. Then, 2.5 g of formic acid was slowly added. After the addition, the reaction was started by heating to 40 ° C under nitrogen atmosphere. The reaction was controlled for about 39 hours and the conversion was 100%. The reaction solution was washed twice with water, and the solvent was evaporated under reduced pressure to give a brown solid V-B (yield: 99%). The product V-B had a diastereoselectivity of 99:1, ee = 99.1%.

Example 19 Preparation of (2S,3R)-3-(3,4-bis(benzyloxy)phenyl)-2-dibenzylamino-3-hydroxypropanoic acid benzyl ester (V-C)

4-Methylisopropylphenylphosphonium dichloride [RuCl ₂ (p-Cymene)] ₂ (2.5 mg), N-((1R,2R)-2-amino-1,2 was added sequentially to a Schlenk bottle. -diphenylethyl)-2,3,4,5,6-pentafluorobenzenesulfonamide pentaF-DPEN (3.5 mg), 0.1 mL of triethylamine and 1 mL of isopropanol, the entire reaction system was replaced with nitrogen three times The reaction was heated to 80 ° C and reacted for 1 hour to obtain a catalyst VII-E solution, which was cooled to room temperature for use.

3 g of benzyl 3-(3,4-bis(benzyloxy)phenyl)-2-dibenzylamino-3-oxopropionate (IV-C), 20 ml of LDCM, and 7 mL of triethylamine were added to the above reaction. In the bottle, the temperature was lowered to 0 ° C, and then 5 mL of formic acid was slowly added. After the addition, the temperature was raised to 40 ° C under a nitrogen atmosphere to start the reaction. The reaction was controlled for about 80 hours and the conversion was 33%. The reaction solution was washed twice with water, and the solvent was evaporated under reduced pressure, and then purified by column chromatography to give a brown solid V-C. The product V-C had a diastereoselectivity of >99:1, ee >99%.

_{^{1 H NMR (400MHz, CDCl 3}} ) δ7.49-7.11 (m, 25H), 6.79-6.61 (m, 3H), 5.17-5.03 (m, 3H), 5.01-4.79 (m, 4H), 4.08 (t , J = 11.4 Hz, 2H), 3.80 (s, 1H), 3.40 (t, J = 11.4 Hz, 3H).

[M+H] ⁺ (LCMS)=663.3

Example 20 Preparation of (2S,3R)-3-(3,4-bis(benzyloxy)phenyl)-2-dibenzylamino-3-hydroxypropionic acid (VI)

Add 41g of (2S,3R)-3-(3,4-bis(benzyloxy)phenyl)-2-dibenzylamino-3-hydroxypropanoic acid ethyl ester (VB) to the reaction flask and dissolve in 400mL The tetrahydrofuran was dissolved, 54 g of NaOH and 500 mL of water were added, and the mixture was stirred at room temperature for 6 hours; after the reaction was completed, the pH was adjusted to 6-7 with dilute hydrochloric acid, extracted twice with 300 ml of dichloromethane, and the organic phase was combined and evaporated. A yellow solid 35 g VI was obtained in a yield of 91.4%.

^{1 H NMR (400MHz, CDCl3)} δ7.41-7.15 (m, 20H), 6.73 (t, J = 10.5Hz, 3H), 5.00 (s, 3H), 4.89 (dd, J = 22.6,11.8Hz, 2H ), 4.00 (d, J = 13.1 Hz, 2H), 3.67 (d, J = 13.2 Hz, 2H), 3.46 (d, J = 8.4 Hz, 1H).

[M+H] ⁺ (LCMS)=574.3

Example 21 Preparation of dexcidopa (IX)

To a stainless steel autoclave, add 4.2 g of (2S,3R)-3-(3,4-bis(benzyloxy)phenyl)-2-dibenzylamino-3-hydroxypropionic acid (VI), 50 mL of ethanol. 3M HCl solution, the reaction solution was stirred at room temperature, and then 1 g of Pd/C was added, and H _{2 was} replaced 3 times. The reaction was stirred at room temperature of 30 atm H ₂ for 2 hours, the reaction was completed, and palladium carbon was removed by filtration, using Et ₃ N. The pH was adjusted to about 6, and a solid was precipitated, and 1.5 g of dripopa was obtained by filtration, and the yield was 96%.

^{1 H NMR (400MHz, DMSO)} δ8.72 (s, 1H), 6.76 (s, 1H), 6.62 (dd, J = 23.2,7.4Hz, 2H), 4.86 (d, J = 3.5Hz, 1H), 3.23 (d, J = 3.7 Hz, 1H).

[M+H] ⁺ (LCMS)=214.1

Example 22 Preparation of dexcidopa (IX)

Into a stainless steel autoclave, 20 g of (2S,3R)-3-(3,4-bis(benzyloxy)phenyl)-2-dibenzylamino-3-hydroxypropionic acid (VI), 200 mL of isopropyl Alcohol, 5M HCl solution, the reaction solution was stirred at room temperature, and 5 g of Pd/C was added, and H _{2 was} replaced 3 times. The reaction was stirred at room temperature for 1 hour under 1 atm H ₂ atmosphere; the reaction was completed, and palladium carbon was removed by filtration. The pH was adjusted to about ₃ N 6, and the precipitated solid was filtered to give 7.0g droxidopa, yield 94.2%.

The method of the present invention has been described by the preferred embodiments, and it is obvious that those skilled in the art can make modifications and/or changes and combinations of the methods and applications described herein to implement and apply the present technology. . Those skilled in the art can learn from the contents of this document and appropriately improve the process parameters. It is to be understood that all such alternatives and modifications are obvious to those skilled in the art and are considered to be included in the present invention.

Claims (24)

A process for preparing (2S,3R)-3-(3,4-dibenzyloxyphenyl)-2-dibenzylamino-3-hydroxypropionate represented by formula (V),

Wherein R ¹ is C _1-4 alkyl or benzyl; It is characterized in that it comprises the following steps: 3-(3,4-Dibenzyloxyphenyl)-2-dibenzylamino-3-oxopropionate of formula (IV) in an organic solvent

Wherein R ^{1 is} as defined above; Catalytic amount of rhodium catalyst (VII)

Or catalytic amount of ruthenium catalyst (VIII)

Asymmetric hydrogenation in the presence of a hydrogen donor reagent and an organic base, among them, R ^{1 is} defined as previously described; R ² represents a C _1-6 alkyl group, an optionally substituted C _1-6 alkyl group, a phenyl group, or an optionally substituted phenyl group; R ^3, R ⁴ each independently represent a phenyl or substituted phenyl, or R ^3, R ⁴ together represent tetramethylene; Ar is a ligand selected from the group consisting of benzene, optionally substituted benzene, cyclopentadiene, and optionally substituted cyclopentadiene; P represents oxygen, chemical bond or CH ₂ ; Q represents hydrogen or an alkyl group. The method of claim 1 wherein R ¹ is methyl, ethyl, tert-butyl or benzyl. The method of claim 1 wherein R ² is methyl, p-methylphenyl, p-trifluoromethylphenyl, pentafluorophenyl, trifluoromethyl or perfluorobutyl. The method of claim 1 wherein said R ³ and R ^{4 are} simultaneously phenyl. The method of claim 1 wherein said Ar is benzene or p-isopropyltoluene. The method of claim 1 wherein said Q is hydrogen or methyl. The method according to claim 1, wherein the ruthenium catalyst has a structure of one of the following:

The method of claim 1 wherein said organic solvent is selected from the group consisting of dichloromethane, toluene, N,N-dimethylformamide, tetrahydrofuran, or a combination thereof. The method of claim 1 wherein said hydrogen donor reagent is formic acid. The method of claim 1 wherein the organic base is diethylamine, diisopropylamine, dicyclohexylamine, triethylamine, N,N-diisopropylethylamine, or a combination thereof. The method according to claim 1, wherein said hydrazine is relative to 1 mole of 3-(3,4-dibenzyloxyphenyl)-2-dibenzylamino-3-oxopropionate (V). The catalyst is used in an amount of from 0.1 mole to 0.001 mole. The method according to claim 1, wherein said organic is relative to 1 mole of 3-(3,4-dibenzyloxyphenyl)-2-dibenzylamino-3-oxopropionate (V) The base is used in an amount of from 1 mole to 10 moles. A method of preparing cixidol, comprising the steps of: (a) Preparation according to the method of claim 1 to obtain (2S,3R)-3-(3,4-dibenzyloxyphenyl)-2-dibenzylamino-3- represented by formula (V) Hydroxypropionate

Wherein R ¹ is C _1-4 alkyl or benzyl; (b) The compound of the formula (V) is hydrolyzed by an inorganic base in a mixed solvent of an organic solvent and water to obtain (2S,3R)-3-(3,4- represented by the formula (VI). Dibenzyloxyphenyl)-2-dibenzylamino-3-hydroxypropionic acid,

(c) a compound represented by the formula (VI) is hydrogenated with hydrogen in an aqueous solution of water and Pd/C in a water-soluble organic solvent to prepare a cexidopa of the formula (IX)

The method according to claim 13, wherein the organic solvent in the step (b) is tetrahydrofuran. The method according to claim 13, wherein the inorganic base in the step (b) is an alkali metal hydroxide or a hydrate thereof. The method according to claim 13, wherein the water-soluble organic solvent in the step (c) is selected from the group consisting of methanol, ethanol, isopropanol, tetrahydrofuran, or a combination thereof. A method of preparing cixidol, comprising the steps of: (a) The compound 3,4-dibenzyloxybenzoic acid (I) forms the intermediate 3,4-dibenzyloxybenzoyl chloride (II-a) under the action of thionyl chloride, and the intermediate (Ia) Reaction with maltetic acid under the action of a base to form the intermediate 5-(3,4-dibenzyloxybenzoyl)-2,2-dimethyl-1,3-dioxane-4,6-di The ketone (II-b), intermediate (Ib) is reacted with an alcohol of the structure R ¹ OH to obtain the intermediate 3-(3,4-dibenzyloxyphenyl)-3-oxopropionate (II) The reaction formula is as follows:

(b) The intermediate 3-(3,4-dibenzyloxyphenyl)-3-oxopropionate (II) is reacted with a halogenating reagent to give the intermediate 3-(3,4-dibenzyloxy). Phenyl)-2-halo-3-oxopropionate (III),

(c) The intermediate 3-(3,4-dibenzyloxyphenyl)-2-halo-3-oxopropionate (III) is reacted with dibenzylamine under the action of an acid binding agent to obtain intermediate 3-(3,4-Dibenzyloxyphenyl)-2-dibenzylamino-3-oxopropionate (IV),

(d) using the intermediate 3-(3,4-dibenzyloxyphenyl)-2-dibenzylamino-3-oxopropionate (IV) as a substrate, according to the method of claim 13. Preparation of cexidopa; Wherein X is chlorine, bromine or iodine; and R ¹ is C _1-4 alkyl or benzyl. A method of preparing cixidol, comprising the steps of: (a) The compound 3,4-dibenzyloxybenzoic acid (I) is formed under the action of thionyl chloride to form the intermediate 3,4-dibenzyloxybenzoyl chloride (Ia), intermediate (Ia) in magnesium chloride and The intermediate 3-(3,4-dibenzyloxyphenyl)-3-oxopropionate (II) is obtained by the reaction of triethylamine with potassium malonate monoester. The reaction formula is as follows:

(b) The intermediate 3-(3,4-dibenzyloxyphenyl)-3-oxopropionate (II) is reacted with a halogenating reagent to give the intermediate 3-(3,4-dibenzyloxy). Phenyl)-2-halo-3-oxopropionate (III),

(c) The intermediate 3-(3,4-dibenzyloxyphenyl)-2-halo-3-oxopropionate (III) is reacted with dibenzylamine under the action of an acid binding agent to obtain intermediate 3-(3,4-Dibenzyloxyphenyl)-2-dibenzylamino-3-oxopropionate (IV),

(d) using the intermediate 3-(3,4-dibenzyloxyphenyl)-2-dibenzylamino-3-oxopropionate (IV) as a substrate, according to the method of claim 13. Preparation of cexidopa; Wherein X is chlorine, bromine or iodine; and R ¹ is C _1-4 alkyl or benzyl. The method according to claim 17 or 18, wherein the halogenating agent in the step (b) is selected from the group consisting of sulfonyl chloride, N-chlorosuccinimide, N-bromosuccinimide, and dibromo- sea. Or bromine, N-iodosuccinimide, or a combination thereof. The method according to claim 17 or 18, wherein the acid binding agent in the step (c) is selected from the group consisting of an organic base or an inorganic base, wherein the inorganic base is selected from the group consisting of sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, and acetic acid. Potassium, dipotassium hydrogen phosphate, disodium hydrogen phosphate, or a combination thereof, the organic base is selected from the group consisting of triethylamine, pyridine, N,N-diisopropylethylamine, N-methylmorpholine, or a combination thereof. The method according to claim 17 or 18, wherein the solvent of the step (c) is selected from the group consisting of N,N-dimethylformamide, dimethyl sulfoxide, acetonitrile, acetone, ethanol, or a combination thereof. A compound of the formula (V) (2S,3R)-3-(3,4-dibenzyloxyphenyl)-2-dibenzylamino-3-hydroxypropionate,

Wherein R ¹ is C _1-4 alkyl or benzyl. a compound of the formula (VI) (2S, 3R)-3-(3,4-dibenzyloxyphenyl)-2-dibenzylamino-3-hydroxypropionic acid,

A compound of the formula (I-b): 5-(3,4-dibenzyloxybenzoyl)-2,2-dimethyl-1,3-dioxane-4,6-dione,

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