WO2010106550A2

WO2010106550A2 - A process for the preparation of n-[[trans-4-(1-methylethyl)cyclohexyl]carbonyl]-d-phenylalanine

Info

Publication number: WO2010106550A2
Application number: PCT/IN2010/000131
Authority: WO
Inventors: Arul Ramkrishnana; Gobind Singh Kapkoti; Sanjay Kumar Dehury
Original assignee: Neuland Laboratories Ltd.
Priority date: 2009-03-09
Filing date: 2010-03-09
Publication date: 2010-09-23
Also published as: WO2010106550A3

Abstract

The present invention is directed to an novel, industrially viable and cost effective process for preparation of substantially pure N-[[trans-4-(l-methylethyl) cyclohexyl] carbonyl]-D- phenylalanine commonly known as Nateglinide.

Description

A PROCESS FOR THE PREPARATION OF N-[[TRANS-4-(l- METHYLETHYL)CYCLOHEXYLICARBONYL]-D-PHENYLALANINE

TECHNICAL FIELD OF THE INVENTION

The present invention is directed to a novel, industrially viable and cost effective process for manufacturing of N-[[trans-4-(l-methylethyl)cyclohexyl]carbonyl]-D- phenylalanine commonly known as Nateglinide and its polymorphic Form H.

BACKGROUND OF THE INVENTION

N-[[trans-4-(l-methylethyl) cyclohexyl]carbonyl]-D-phenylalanine commonly known as Nateglinide is represented by Formula I.

Nateglinide belongs to the class of blood glucose-lowering drugs. It is a derivative of unnatural amino acid D-phenyl alanine. It is known as hypoglycemic agent, an active ingredient of a composition for treating type 2 diabetes. It is a white powder and soluble in methanol, ethanol chloroform, ether, sparingly soluble in acetonitrile and octanol and practically insoluble in water.

US4816484, the product patent and its subsequent reissue US RE 34878 discloses the process as in scheme I comprising the reaction of 4-isopropylbenzoic acid of formula II with platinum oxide in acetic acid, undergoes hydrogenation to give cis:trans (3:1) of formula III and further gets converted to methyl ester of formula IV. Formula IV reacts with sodium hydride gives transxis (6:1) methyl ester of formula V. The trans cis ester is converted to the respective acid of formula VI which on coupling with compound of formula VII in presence of DCC gives compound VIII.

The compound VIII couples with methyl ester of D-phenylalanine of formula XI and hydrochloric acid to give methyl ester compound of formula X. Ester of formula X reacts with IN aqueous sodium hydroxide to give respective salt in presence of methanol and undergoes acidification by dilute aqueous hydrochloric acid giving Nateglinide of formula I. Drawbacks:

• Multistep, tedious, cumbersome and difficult to scale up

• DCC used is an acute irritant and a hygroscopic reagent.

EP0196222 and J. Med. Chem (1986) vol. 32 page 1436 elucidates the synthesis of Nateglinide as given in scheme II from trans 4-isopropyl cyclohexane carboxylic acid of formula VI which couples with N-hydroxy succinamide of formula VII to give succinamide derivative of formula VIII which on further reaction with methyl ester of D-phenylalanine gives the methyl ester of Nateglinide of formula X. The compound of formula X undergoes alkali Scheme II

hydrolysis in presence of sodium hydroxide and organic solvent such as methanol to give

Nateglinide of formula I.

Drawbacks:

• Multistep, tedious, cumbersome and difficult to scale up

• DCC used is acute irritant and a hygroscopic reagent.

• Purification of methyl ester by high vacuum distillation which is an additional and time consuming operation.

US4816484, USRE34878, EP 196222 describes other processes for the preparation of Nateglinide in which trans-4-isopropylcyclohexyl carboxylic acid is converted to its acid chloride salt and further reacted with D-phenyl alanine in acetone using 10% sodium hydroxide to give formula I. Scheme HI

A Chinese article Xue-yan Zhu, et.al., Hecheng Huaxue 9(6) 537-540 (2001) discloses a process as given in scheme III where isopropylbenzene of formula XII is chlorinated to give isopropylbenzyl chloride of formula XIII which is converted to isopropyl benzaldehyde. The aldehyde derivative is converted to the acid of formula XV having the cis and trans (3:1) ratio and is further transformed to cis :trans (6:1) ratio form of formula VI. The compound of formula VI is chlorinated to give the respective acylchloride of formula XVI. In the final step acyl chloride of formula XVI couples with phenylalanine to give nateglinide of formula I.

Drawbacks:

• The reaction results in contamination of the final product with Nateglinide' s corresponding cis impurity.

• Phosphorous pentachloride is extremely corrosive, hygroscopic, and difficult to handle in the scale up operation.

• Hydrogen peroxide is a strong oxidizing agent and thus is not suitable from industrial view.

• Moreover it is a long step process which is time consuming.

CN1517334 expounds the process for the synthesis of Nateglinide which involves the condensation reaction of anti-isopropylcyclohexaformyl chloride and D-phenylpropanoic acid in presence of dimethylformamide- water system. Pd/C is used as a catalyst for the hydrogenating reduction reaction to prepare 4-isopropylcyclohexaformic acid from p- isopropyl benzoic acid. The anti 4-isopropylcyclohexaformic acid is directly prepared by isomerization of the mixture of 4-isopropylcyclohexaformic acid's bis- and anti- isomers under the action of potassium hydroxide.

CNl 517335 set froths the process as given in scheme IV comprising the conversion of 4-isopropyl toluene to 4-isopropylbenzoic acid which is reduced to the respective cis and trans isomers of 4-isopropyl cyclohexane carboxylic acid of formula VI and further gets converted to one form of 4-isopropylcyclohexane carboxylic acid. The compound of formula VI is converted to the respective acid chloride

Scheme IV

of formula XVIII which on coupling with D-phenylalanine gives Nateglinide of formula I.

EP 1651591 as in scheme V elucidates the conversion of R-substituted Nateglinide where R is a lower alkyl group (C₁-C₄) group or hydrogen in presence of base such as sodium hydroxide, potassium hydroxide, lithium hydroxide to yield an alkali salt and further undergoes acidification by hydrochloric acid or sulphuric acid to give Nateglinide of formula I. Scheme V

EP1765769 (WO2005121071, CA2570041, US20070259955) as given in scheme VI discloses the one pot synthesis where D-phenylalanine is acylated to give methyl ester of D- phenylalanine hydrochloride salt which gets converted in situ to the free base of formula XI. The compound of formula XI reacts with

Schems VI

trans -4-isopropylcyclohexane carboxylic acid or trans-4-isopropylcyclo hexane carboxylic acid chloride in presence of dehydrating agent to give the ester of formula X. The ester is washed with water miscible organic solvent such as methanol and then undergoes alkali hydrolysis in presence of sodium hydroxide giving Nateglinide sodium salt and on simultaneous acidification by acid such as hydrochloric acid gives Nateglinide. Drawbacks:

• DMAP is a hazardous reagent and is not useful for industrial scale up.

• DCC is a corrosive and high moisture sensitive reagent. WO2004018408 describes the process by scheme VII whrere trans- isopropylcyclohexyl carboxylic acid of formula VI reacts with alkylchloroformate (where R is methyl, ethyl, propyl, isopropyl, amyl, isoamyl, isobutyl) in presence of solvent and base to give an anhydride intermediate of formula XX which on further reaction with salt solution of D-phenylalanine, aqueous alkali and base such as triethylamine, tripropylamine, tributylamine in combination

Scheme VU

with catalytic amount of N-ethyl morpholine, N-methyl morpholine, N-propyl morpholine to give Nateglinide of formula I.

Drawback:

• This process gives the low overall yield (44%), too many purification and use of mixtures of solvents making the process less useful for commercial production.

JP07017899 equivalent to JP4008794 reports in scheme VIII the process which comprises the single and one pot synthetic reaction of trans-4-isopropylcyclohexane carboxylic acid with D-phenyl alanine in presence of 1,1-dichloroethane and phosphorous pentachloride to give Nateglinide. Scheme VIE

Drawbacks:

• DCE is a class II solvent and is to be avoided in the manufacture of pharmaceutical ingredients.

• Phosphorous pentachloride is extremely corrosive, hygroscopic, difficult to handle in the scale up operation.

WO0232853 [equivalent to US20040024219, EP1334962, CN1481355, CA2425533] discloses in the scheme IX the process comprising the coupling of trans-4-isopropyl cyclohexyl carbonyl chloride with D-phenylalanine in a biphasic solvent system where one solvent is organic solvent and other solvent is water in presence of base to give formula I.

Scheme IX

WO2004005240 provides a process as in scheme X for the preparation of a dimer intermediate where trans-4-isopropylcyclohexane acid chloride is formed by reacting 4- isopropyl cyclohexane carboxylic acid with thionyl chloride in the presence of organic amide such as dimethylacetamide, methylpyrrolidinone, dimethylformamide. Acylation of phenyl alanine is done in presence of base such as sodium hydroxide, potassium hydroxide, lithium hydroxide, magnesium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, The process also comprises acylation of salt of D-phenylalanine with trans-4- isopropylcyclohexane acid chloride in single as well as biphasic system and in water free of cosolvent. When water is used without a cosolvent in conjuction of strong base such as sodium or potassium hydroxide the product is free of undesirable dimer.

WO2007113650 defines the process as in scheme XII which comprises the coupling of trans -4-isopropyl cyclohexane carboxylic acid chloride of formula XVIII with N,O- , bistrimethyl silyl D-phenylalanine of formula XXI at -4 to 0⁰C for 3 hrs and quenched with ice water to give crude Nateglinide, which is further refluxed with cyclohexane and ethylacetate to give Pure Nateglinide of form H.

Figure 1 Drawback:

• HMDS is a highly flammable liquid and is not preferred to use in large industrial scale up.

Scheme XIV

followed by the adjustment of pH to 1.0-4.0 using mineral acid such as hydrochloric acid; filtering and drying to obtain Nateglinide. The drawback of this process is that it uses Lithium hydroxide, which is corrosive in nature and not preferred to use in scale up.

It's apparent from most of the prior art that the preparation of Nateglinide has certain disadvantages such as

• need of extra purification step

• the use of pivolyl anhydride makes the reaction exothermic

• the addition of pivolyl anhydride is very slow and needs 0-5 ⁰C to carry out.

• involves work up with sodium carbonate at high temperature at 70 to 80 ⁰C.

• The processes involves chromatographic purification techniques which is not viable at commercial scale

• Involves more reaction steps and lengthy work-up

• Overall higher cost of production

• Low yields and purity

Therefore, there is a continuing need for developing a new process for the manufacturing of Nateglinide which is cost effective, industrially viable and eco-friendly.

SUMMARY OF THE INVENTION The principal aspect of present invention is to provide a novel process for the manufacturing of N-[[trans-4-(l-methylethyl)cyclohexyl]carbonyl]-D-phenylalanine or Nateglinide of formula I comprising: a) coupling of trans-4-(l-methylethyl)cyclohexanecarboxylic acid of formula VI with substituted / unsubstituted aryl or substituted / unsubstituted alkyl sulphonyl chloride in presence of a base and a solvent to render a mixed anhydride of formula VF;

Where R is substituted / unsubstituted aryl or substituted / unsubstituted alkyl b) further reacting the mixed anhydride of formula VF formed in situ with D- phenylalanine methyl ester of formula XI to give N-[[trans-4-(l-methylethyl) cyclohexyl]carbonyl]-D-phenylalanine methyl ester of formula X;

c) purifying N-[[trans-4-(l-methylethyl)cyclohexyl]carbonyl]-D-phenylalanine methyl ester of formula X by recrystallization from a solvent or a mixture of solvents selected from cyclohexane, methylene dichloride, ethyl acetate methanol and toluene;

d) conversion of N-[[trans-4-(l-methylethyl)cyclohexyl]carbonyl]-D-phenylalanine methylester of formula X to N-[[trans-4-(l-methylethyl) cyclohexyl] carbonyl]-D- phenylalanine of formula I;

e) Alternatively, reacting the mixed anhydride of formula VF formed in situ in step (a) with D-phenylalanine of formula FX to obtain N-[[trans-4-(l-methylethyl) cyclohexyl] carbonyl] -D-phenylalanine of formula I; and f) optional purification of N-[[trans-4-(l-methylethyl) cyclohexyl] carbonyl]-D- phenylalanine to give Nateglinide.

The above process can be illustrated by the below scheme XV:

Scheme XV

The another aspect of present invention is to provide a novel process for the manufacturing of N-[[trans-4-(l-methylethyl)cyclohexyl]carbonyl]-D-phenylalanine methyl ester of formula X comprising: a) coupling of trans-4-(l-methylethyl)cyclohexanecarboxylic acid of formula VI with p- toluenesulphonyl chloride in presence of a base and a solvent to render a mixed anhydride of formula VF b) further reacting the mixed anhydride of formula VF formed in situ with D- phenylalanine methyl ester of formula XI to give N-[[trans-4-(l- methylethyl)cyclohexyl]carbonyl]-d-phenylalanine methyl ester of formula X;

In yet another aspect, the present invention provides a novel compound of formula VI'

Where R is substituted / unsubstituted aryl or substituted / unsubstituted alkyl

BRIEF DESCRIPTION OF THE ACCOMPANYING DRAWINGS

Fig 1 : XRD of Nateglinide Form H of the present invention

Fig 2: DSC thermogram of Nateglinide Form H of the present invention.

DETAIL DESCRIPTION OF THE INVENTION

Accordingly in an embodiment of the invention, the coupling of trans-4-(l- methylethyl)cyclohexanecarboxylic acid of formula VI with substituted / unsubstituted aryl or substituted / unsubstituted alkyl sulphonyl chloride, preferably with p-toluenesulphonyl chloride in presence of a base selected from the group consisting of alkyl amine, aryl amine and arylalkyl amine preferably the base is triethylamine and a solvent selected from methylene dichloride, ethylene dichloride, xylene, toluene and the like to render a mixed anhydride of formula VF followed by reacting the mixed anhydride of formula VF formed in situ with D-phenylalanine methyl ester of formula XI to give N-[[trans-4-(l- methylethyl)cyclohexyl]carbonyl]-D-phenylalanine methyl ester of formula X. In another embodiment of the invention, N-[[trans-4-(l-methylethyl)cyclohexyl]carbonyl]-D- phenylalanine methyl ester of formula X is purified by recrystallizing from a solvent selected from cyclohexane, methylene dichloride, ethyl acetate, methanol, toluene and mixture thereof.

In another embodiment of the invention, N-[[trans-4-(l-methylethyl)cyclohexyl] carbonyl]-D-phenylalanine methyl ester of formula X is converted to N-[[trans-4-(l- methylethyl) cyclohexyl] carbonyl]-D-phenylalanine of formula I in presence of a base selected from sodium hydroxide, potassium hydroxide, preferably sodium hydroxide and organic solvent like toluene, xylene, methanol, ethanol, ethylacetate and the like. The solvent is preferably methanol.

Alternatively, the mixed anhydride of formula VF formed in situ in step (a) is reacted with D-phenylalanine of formula IX to obtain N-[[trans-4-(l-methylethyl) cyclohexyl] carbonyl]-D-phenylalanine of formula I. hi another embodiment of the invention, the obtained Nateglinide of formula I is purified by a solvent selected from the group methanol, ethanol, propanol, cyclohexane, ethyl acetate, water or the mixture thereof. The preferred solvent for the purification is mixture of cyclohexane and ethyl acetate. hi yet another embodiment of the invention, the obtained Nateglinide of formula I is Form H characterised by a powder X-Ray diffraction pattern with peaks at 2.9340, 3.9137, 4.5325, 5.5862, 5.8204, 6.3517, 8.2743, 8.6273, 9.1045, 10.472110.8705, 11.6868, 12.1187, 13.2890, 14.5606, 15.3526, 15.9610, 16.1780, 16.3797, 16.5152, 17.1537, 17.4380, 18.2812, 18.7295, 19.7374, 20.0796, 21.1323, 21.5880, 22.1378, 23.1337, 23.6496, 24.4567, 25.6737, 26.1745, 27.2552, 28.8185, 29.9000, 31.0993, 32.8137, 33.6732, 34.6343, 35.0210, 38.4179, 40.7908, ± 0.2 degree 2Θ or substantially as indicated in figure 1.

This invention can be clearly illustrated by the following examples, which should not be construed to limit the scope of invention in anyway. Examples:

Example 1: Preparation of D-Phenylalanine methyl ester hydrochloride

Methanol (1200 mL) and D-phenylalanine (200 g) were taken in a round bottom flask at 25-30 ⁰C and cooled to 0 ± 5 ⁰C. Thionyl chloride (172.8 mL) was added to the above reaction mixture over 2 hours and the temperature was raised to 25-3O⁰C. The contents were maintained for 12 hours at 40 ± 5°C. The contents were cooled to 25-3O⁰C and maintained for 8 hours. Methanol was completely distilled out under vacuum condition at below 45⁰C. To the above crude, 1200 mL of acetone was added and the mixture was cooled slowly to 0-5⁰C in 2 hours. The compound was filtered and washed with 100 mL of acetone. The material was dried for 8 hours at 45-50⁰C under vacuum to obtain the title compound (244g, 93.85% ), HPLC purity : 99.80%. Example 2: Preparation of Methyl ester of Nateglinide

Methylene chloride (6000 mL), trans-4-isopropylcyclohexane (200 g) followed by para toluene sulfonyl chloride (208.38 g) and triethyl amine (409 mL) were added in a round bottom flask at 25-30⁰C. The contents were maintained for 8 hours. Meanwhile D-Phenyl alanine methyl ester solution was prepared by adding 200.22 g of D-Phenylalanine methyl ester hydrochloride (as described in example 1) followed by 1066.66 mL of 20 % sodium carbonate solution and methylene dichloride (200 mL) and the mixture was stirred for 30 minutes at 25-30⁰C. To the aqueous layer 400 mL of methylene dichloride was added and the mixture was stirred for 30 minutes. The methylene dichloride layer was dried over 10 g of sodium sulphate and filtered. D-Phenylalanine methyl ester solution as obtained was added to the above reaction mass over 30 minutes at 25— 30⁰C. The contents were maintained for 18 hours. 778 mL of 10% HCL solution was added to the reaction mass and stirred for 30 minutes. Methylene dichloride layer was taken and 1500 mL of 10% sodium carbonate solution was added and the mixture was stirred for 30 minutes. The organic layer was dried with sodium sulphate (5 g), filtered and distilled off completely at 35-40⁰C. Methylene chloride (400 mL) of followed by 1600 mL of cyclohexane was added into above crude at 25- 30⁰C. The contents were heated to 60-65⁰C (minimum 3 to 4 hours), and then maintained the contents for 1 hour at 0-5⁰C. It was filtered, washed with chilled cyclohexane (200 mL) and dried under vacuum for 8-10 hours at 50-55⁰C to get the title compound (270.3 g, 87.25%).HPLC purity : 99.7%.

Example 3: Hydrolysis of Methyl ester of Nateglinide Methanol (1500 mL) and methyl ester of nateglinide (200 g) (as described in example 2) were taken in round bottom flask at 25-3O⁰C and stirred for 15 minutes. Sodium hydroxide solution (36.24 g in 1080 mL of DM water) was added and contents were stirred for 5 hours. The reaction mass was filtered and 4000 mL of DM water was added and stirred for 15 minutes. Aqueous layer was taken and pH adjusted to 2.00-2.5 with 20% HCl solution. The contents were maintained for 1 hour. The material was filtered and washed with DM water (200 mL). Sodium carbonate (96.02 g) followed by 6000 mL of DM water was taken in another flask and stirred for 15 minutes. The above prepared wet material and ethyl acetate (1000 mL) were added to it and stirred for 30 minutes at 40-45⁰C. The layers were separated and aqueous layer was taken with 1000 mL of ethyl acetate and stirred for 30 minutes. The aqueous layer was taken and pH adjusted to 2.0-2.5 using 20% HCL solution at 25-30 ⁰C. The contents were maintained for 1 hour. The material was filtered and washed with DM water (200 mL). The wet material was dissolved in ethyl acetate (1000 mL) and washed twice with 300 mL with 10% HCL solution. Ethyl acetate layer was taken and washed twice with 600 mL (DM water). Sodium sulphate (50 g) was added to the reaction mass and filtered. The ethyl acetate layer was distilled out completely under vacuum at below 45⁰C. It was followed by addition of 500 mL water and the reaction mixture was stirred for 1 hour. The solid compound was isolated by filtration and then dried at 50-55⁰C to get the title compound. (155.00 g, 80.80%). HPLC purity : 99.89%

Example 4: Preparation of Nateglinide

Methylene chloride (6000 mL), trans-4-isopropylcyclohexane (200 g) followed by para toluene sulfonyl chloride (208.38 g) and triethyl amine (409 mL) were added in a round bottom flask at 25-3O⁰C. The contents were maintained for 8 hours. D-Phenylalanine (150 g) was added to the above reaction mass over 30 minutes at 25-30⁰C. The contents were maintained for 18 hours. 778 mL of 10% HCL solution was added to the reaction mass and stirred for 30 minutes. Methylene dichloride layer was taken and 1500 mL DM water was added and the mixture was stirred for 30 minutes repeatedly twice. The organic layer was dried with sodium sulphate (5 g), filtered and distilled off completely at 35— 40⁰C. Methylene chloride (400 mL) and 1600 mL of cyclohexane was added into above crude at 25-30⁰C. The contents were heated to 60-65⁰C (minimum 3 to 4 hours), and then maintained the contents for 1 hour at 0-5⁰C. Filtered, washed with chilled cyclohexane (200 mL) and dried under vacuum for 8-10 hours at 50-55⁰C to get the title compound (216 g, 75%). Example 5: Purification of Nateglinide

The above prepared compound $50 g) and cyclohexane (350 mL) and 125 mL of ethyl acetate were taken in round bottom flask at 25-3O⁰C. The contents were heated to 35-4O⁰C, maintained for 15 minutes at 65-7O⁰C. It was followed by addition of 2 g charcoal. The mixture was filtered and the filtrate was taken and heated to 75-80°C and maintained for 15 minutes. The contents were cooled slowly to 48-50⁰C over 6 hours and maintained for 18-20 hours at 48 - 50 ⁰C temperature. The contents were cooled to 35— 40⁰C. The compound was filtered and washed twice with cyclohexane (150 mL). The compound was dried under vacuum at 80-85⁰C for 10-12 hours to get the title compound. (105.0 g, 70.00%). HPLC purity : 99.95%

Claims

We claim:

1. A process for the manufacturing of N-[[trans-4-(l-methylethyl)cyclohexyl]carbonyl]- d-phenylalanine or Nateglinide of formula I comprising: a) coupling of trans-4-(l-methylethyl)cyclohexanecarboxylic acid of formula VI

with substituted or unsubstituted aryl or substituted or unsubstituted alkyl sulphonyl chloride in presence of a base and a solvent to render a mixed anhydride of formula VT;

Where R is substituted or unsubstituted aryl or substituted or unsubstituted alkyl b) further reacting the mixed anhydride of formula VF formed in situ with D- phenylalanine methyl ester of formula XI

to give N-[[trans-4-(l-methylethyl)cyclohexyl]carbonyl]-D-phenylalanine methyl ester of formula X;

c) purifying N-[[trans-4-(l-methylethyl)cyclohexyl]carbonyl]-D-phenylalanine methyl ester of formula X by recrystallization from a solvent selected from cyclohexane, methylene dichloride, ethyl acetate methanol, toluene and mixture thereof;

e) Alternatively, reacting the mixed anhydride of formula VF formed in situ in step (a) with D-phenylalanine of formula EX to obtain N-[[trans-4-(l-methylethyi) cyclohexyl] carbonyl]-D-phenylalanine of formula I; and

f) optional purification of N-[[trans-4-(l-methylethyl) cyclohexyl] carbonyl]-D- phenylalanine to give Nateglinide.

2. A process according to claim 1, wherein the sulphonyl chloride used in step (a) is p- toluenesulphonyl chloride.

3. A process according to claim 1, wherein the solvent is selected from the group consisting of methylene dichloride, ethylene dichloride, xylene, toluene, cyclohexane, ethyl acetate and mixture thereof.

4. A process according to claim 1, wherein the solvent used in step (a) is methylene dichloride and the solvent used in step (c) is mixture of methylene dichloride and cyclohexane.

5. A process according to claim 1, wherein the base is selected from the group consisting of alkyl amine, aryl amine and arylalkyl amine.

6. A process according to claim 1, wherein the base is triethylamine.

7. A process for the manufacturing of N-[[trans-4-(l-methylethyl)cyclohexyl]carbonyl]- d-phenylalanine methylester of formula X comprising; a) coupling of trans-4-(l-methylethyl)cyclohexanecarboxylic acid of formula VI

with substituted or unsubstituted aryl or substituted or unsubstituted alkyl sulphonyl chloride in presence of a base and a solvent to render a mixed anhydride of formula VI" ; and

Where R is substituted or unsubstituted aryl or substituted or unsubstituted alkyl b) further reacting the mixed anhydride of formula VT formed in situ with D- phenylalanine methyl ester of formula XI

8. A process according to claim 7, wherein the sulphonyl chloride used in step (a) is p- toluenesulphonyl chloride.

9. A process according to claim 7, wherein the solvent is selected from the group consisting of methylene dichloride, ethylene dichloride, xylene, toluene, cyclohexane, ethyl acetate and mixture thereof.

10. A compound of formula VI'

11. A compound according to claim 10 where R is 4-methylphenyl.