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An Improved Process For The Preparation Of N (Trans 4 Isopropylcyclohexylcarbonyl) D Phenyl Alanine And Intermediates Thereof

Abstract: The prsent invention relates to a process for the preparation of N-(trans-4-isopropyl cyclohexylcarbonyl)-D-phenylalanine commonly known as Nateglinide of general formula (I) and its intermediates. Also provided is a process for the preparation of chirally pure Nateglinide substantially in Form-B.

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Patent Information

Application #
Filing Date
05 December 2007
Publication Number
25/2009
Publication Type
INA
Invention Field
PHARMACEUTICALS
Status
Email
Parent Application

Applicants

UNICHEM LABORATORIES LIMITED
UNICHEM BHAVAN, PRABHAT ESTATE, S.V. ROAD, JOGESHWARI (WEST), MUMBAI

Inventors

1. AJIT MADHUKAR BHOBE
UNICHEM LABORATORIES LIMITED UNICHEM BHAVAN, PRABHAT ESTATE, S.V. ROAD, JOGESHWARI (WEST), MUMBAI-400102
2. AMIT CHANDRASHEKHAR KHANDEKAR
UNICHEM LABORATORIES LIMITED UNICHEM BHAVAN, PRABHAT ESTATE, S.V. ROAD, JOGESHWARI (WEST), MUMBAI-400102
3. MAHENDRA DINANATH SAWANT
UNICHEM LABORATORIES LIMITED UNICHEM BHAVAN, PRABHAT ESTATE, S.V. ROAD, JOGESHWARI (WEST), MUMBAI-400102
4. KAMLESH DIWAKAR PANGE
UNICHEM LABORATORIES LIMITED UNICHEM BHAVAN, PRABHAT ESTATE, S.V. ROAD, JOGESHWARI (WEST), MUMBAI-400102

Specification

FORM 2 THE PATENTS ACT 1970 (39 OF 1970) COMPLETE SPECIFICATION (SECTION 10) AN IMPROVED PROCESS FOR THE PREPARATION OF N- (TRANS-4-ISOPROPYLCYCLOHEXYLCARBONYL)-D-PHENYL ALANINE AND INTERMEDIATES THEREOF UNICHEM LABORATORIES LIMITED, A COMPANY REGISTERED UNDER THE INDIAN COMPANY ACT, 1956, HAVING ITS REGISTERED OFFICE LOCATED AT MAHALAXMI CHAMBERS, 2nd FLOOR, 22, BHULABHAIDESAI ROAD, MUMBAI-400 026. MAHARASTRA, INDIA The following specification particularly describes the invention and the manner in which it is to be performed. AN IMPROVED PROCESS FOR THE PREPARATION OF N-(TRANS-4-ISOPROPYLCYCLOHEXYLCARBONYL)-D-PHENYL ALANINE AND INTERMEDIATES THEREOF TECHNICAL FIELD The present invention relates to an improved process for the preparation of Nateglinide and its intermediates thereof. It also relates to a process for the preparation of chirally pure Nateglinide substantially in the B-form. BACKGROUND OF THE INVENTION N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine commonly known as Nateglinide is an antidiabetic drug possessing hypoglycemic activity in patients with type-II diabetes. Nateglinide is represented by the following structural formula (I) HN' ^ V.„yCH3 COOH CH3 O Formula-I N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine is disclosed in Japanese Patent Application No. 63-54321 [equivalent to EP-A-196222 (1986, Toyoshima s, et al); US 4816484 (1989, Toyoshima s, et al); and its subsequent reissue RE34878 (1995, Toyoshima s, et al)]. The process for the preparation of Nateglinide described therein (EP-A-196222/ US 4816484) comprises a condensation employing dicyclohexylcarbodiimide to obtain the activated N-hydroxy succinimide ester of trans-4-isopropyl cyclohexane carboxylic acid; which is then reacted with D-phenyl alanine methyl ester hydrochloride to obtain Nateglinide methyl ester. The alkyl group acts as a protecting group thereby limiting the undesired side reactions. It has however been found that following the process described in US 4816484, the Nateglinide methyl ester is found to be present in an unacceptable amount in the final Nateglinide product. Also, crystallization of Nateglinide from aqueous methanol results in undesirable further esterification. Further that the product so obtained is chirally impure containing a substantial amount of the enantiomeric impurity, which value does not meet the tight requirements imposed either by the pharmacopoeia or by the health authorities and the quality directives, since the acceptable maxima for known impurities is 0.1 %. Consequently the product prepared by the process mentioned above needs further purification, which could be done by several recrystallization steps, thereby lowering the overall yield and also harboring the risk of re-esterification of the product already obtained if alcoholic solvents are employed. Journal of Medicinal Chemistry, 1989, Vol 32, No 7, page 1437, describes a similar process, wherein the trans-4-isopropylcyclohexane carboxylic acid is converted to an activated N-hydroxysuccinimide ester, which on acylation reaction with D-phenyl alanine methyl ester and subsequent hydrolysis gives Nateglinide. The processes mentioned above are low yielding and hence commercially not viable. PCT application WO2004018408 (2004, Naik S, et al) describes a process for nateglinide, wherein trans-4-isopropylcyclohexane carboxylic acid is converted to a mixed anhydride by reacting with an alkyl chloroformate. This acid anhydride is reacted with aqueous alkali salt solution of D-phenyl alanine to give Nateglinide. The process gives low yields and laborious purifications inorder to achieve the right quality material. EP 1535900 (2003, Vigano E et al) discloses a method for the preparation of nateglinide, preferably in the B-form, substantially free from the H-form. The process essentially involves the formation of mixed anhydrides by the reaction of trans-4-isopropylcyclohexane carboxylic acid with acyl chlorides like pivaloyl chloride or with carbonyldiimidazole. Reaction of these mixed anhydrides with D-phenyl alanine methyl ester gives nateglinide methyl ester, which is hydrolyzed to Nateglinide. PCT Application WO2004005240 (2004, Yahalomi, R et al) describes a process for the preparation of Nateglinide by reaction of trans-4-isopropylcyclohexane carboxylic acid chloride with a suitable salt of D-phenyl alanine. The process described therein give an undesirable impurity arising due to cross reactions, which therein is referred to as a dimer and the formation of which is as illustrated in Scheme-I below, coci H3C V-CH, «3C, )—CH3 COONa pH 99% (HPLC) Example 2 Trans-4-isopropyl cyclohexane carboxylic acid chloride: Method A) To a solution of Trans-4-isopropyl cyclohexane carboxylic acid (161 gm) in dichloromethane (161 mL) was added thionyl chloride (90 mL) dropwise and the reaction is continued at 30° to 35 °C. Progress of the reaction was monitored on GC. After completion of the reaction, solvent was removed under reduced pressure and the acid chloride so obtained, was used as such for the subsequent step Method B) To a solution of Trans-4-isopropyl cyclohexane carboxylic acid in dichloromethane containing a catalytic amount of dimethyl formamide was added oxalyl chloride dropwise and the reaction was continued at 30° to 35 °C. Progress of the reaction was monitored on GC. After completion of the reaction, solvent was removed under reduced pressure and the acid chloride was used as such for the subsequent step. Example 3 Preparation of Nateglinide methyl ester: D-phenyl alanine methyl ester hydrochloride (200 gm) was added to a solution of potassium carbonate (196 gm) in water and dichloromethane (1.6 lit) was then added to this at 25-30 °C. The biphasic mixture was cooled under stirring to 5 - 10 °C. Trans-4- isopropyl cyclohexane carboxylic acid chloride (obtained above eg method A) was added drop-wise over 1 - 1 Vi hr under vigorous stirring and maintaining the temperature below 10 °C. Stirring was continued for 5 - 10 mins after complete addition. The reaction was then allowed to attain room temperature and the layers were allowed to settle. The MDC layer was separated and washed sequentially with dilute HC1 and water before evaporating the solvent under atmospheric pressure till solid starts precipitating. Hexane was then added and residual MDC removed by continuing the distillation. The suspension was cooled to room temperature and was filtered under suction to give nateglinide methyl ester (296 gm; 96 %) as a white solid having purity > 99 %. The solid if desired was recrystallized from methanol by dissolution at 60 °C and gradual cooling to 10-15 °C, maintaining for 1 hr before filtering under suction Example 4 Preparation of Nateglinide: To a suspension of Nateglinide methyl ester (200 gm) in 50 % (v/v) aqueous THF (800 mL) at 18-22 °C, was added drop-wise, a solution of NaOH (29 gm) in water (800 mL), over a period of 1 - 1VS hr. The reaction mixture was stirred at 18-22 °C for further 4-6 hrs The solid suspension during the process dissolves in the solution and a clear solution was obtained. After completion of the reaction, (monitored on TLC/ HPLC) the reaction mixture was filtered to remove any suspended matter and solvent THF is removed under reduced pressure below 40 °C. The residue was diluted with water and pH of the mixture is adjusted to 2.5 - 2.7 using dil HCl maintaining the temperature between 18 - 22 °C. The precipitated solid was stirred for 15 - 30 mins and filtered under suction. The solid was washed with water, suck dried thoroughly and finally air dried using tray driers at 70 to 90 °C. Yield : 180 gm (94 % of theoretical) with no single impurity exceeding 0.1 %. Chiral purity 99.9-100%. We Claim: 1. A process for the preparation of Nateglinide of formula (I), which comprises a. a reaction between the alkyl ester of D-phenyl alanine or its the acid addition salt of formula (II) HX. R,N -COOR (ID wherein R represents CM alkyl, with trans-4-isopropylcyclohexanecarboxylic acid halide of formula (III) COX H3C CH3 (m) wherein X represents a halo, under biphasic conditions in the presence of a base to give Nateglinide alkyl ester of formula (IV), O COOR CH3 (IV) wherein R is as defined above. b. isolation of nateglinide alkyl ester (IV) c. hydrolyzing nateglinide alkyl ester (IV) to nateglinide of formula (I). O CH- CH, f COOH Ch 2. A process of claim 1, wherein the reaction of step a, is carried out in a solvent system which comprises of water and water immiscible organic solvent/s. 3. A process of claim 2, wherein the water immiscible organic solvents comprises of dichloromethane and ethyl acetate. 4. A process of claim 1, step a, wherein the base used is an organic base or an inorganic base like an alkali metal carbonate, bicarbonate, hydroxide or mixtures thereof. 5. A process of claim 1, wherein the alkyl ester of nateglinide in step b is isolated and optionally purified. 6. A process of claim 1, wherein the reaction step c comprises hydrolyzing the alkyl ester of Nateglinide in an aqueous-organic solvent system in the presence of a base, followed by acidification. 7. A process of claim 1 step c, wherein the organic solvent for hydrolysis comprises water miscible aprotic solvents like Tetrahydrofuran, 1,4-Dioxan and the base is an alkali metal hydroxide like sodium, potassium, lithium hydroxide, preferably sodium hydroxide. 8. A process for the preparation of nateglinide, which comprises hydrolyzing the alkyl ester of nateglinide in an aqueous-organic solvent system in the presence of a base, wherein the organic solvent comprises of water miscible aprotic solvents like Tetrahydrofuran or 1,4-Dioxan. 9. A process of claim 1, wherein the nateglinide obtained is chirally pure. 10. A process of claim 1, wherein drying of the solvated/ hydrated wet crystals is carried out at 70-100 °C in tray driers optionally employing reduced pressures. 11. A process of claim 1, wherein the nateglinide obtained is chirally pure and substantially in form-B. 12. A process of claim 1, wherein the trans-4-isopropylcyclohexane carboxylic acid halide (III) is prepared by using thionyl chloride; or oxalyl chloride optionally in the presence of an organic amide such as N,N-Dimethyl formamide, N,N-dimethylacetamide and N-methylprrrolidone, preferably N,N-Dimethylformamide. 13. Alkyl ester of Nateglinide by a process as per claim 5 , which comprises a reaction between the alkyl ester of D-phenyl alanine or its acid addition salt of formula (II) HX. H2N COOR (II) wherein R represents C1-4 alkyl, with trans-4-isopropylcyclohexanecarboxylic acid halide of formula (III) COX H3C CH3 (in) wherein X represents a halo, preferably CI, in a two phase system and in the presence of a base. 14. A process for the preparation of compounds of formula (I), substantially as herein described and illustrated with reference to the accompanying examples ABSTRACT: The present invention relates to a process for the preparation of Nateglinide and its intermediates. Also provided is a process for the preparation of chirally pure Nateglinide substantially in Form-B.

Documents

Application Documents

# Name Date
1 2380-MUM-2007- WO- PCT DOCUMENTS.pdf 2022-02-17
1 abstract1.jpg 2018-08-09
2 2380-MUM-2007_EXAMREPORT.pdf 2018-08-09
3 2380-mum-2007-form-5.pdf 2018-08-09
3 2380-mum-2007-abstract.pdf 2018-08-09
4 2380-mum-2007-form-3.pdf 2018-08-09
5 2380-mum-2007-form-2.pdf 2018-08-09
7 2380-mum-2007-form-1.pdf 2018-08-09
8 2380-mum-2007-form 2(title page)-(5-12-2007).pdf 2018-08-09
9 2380-MUM-2007-FORM 18(18-8-2009).pdf 2018-08-09
11 2380-mum-2007-description (complete).pdf 2018-08-09
12 2380-mum-2007-correspondence-received.pdf 2018-08-09
13 2380-MUM-2007-CORRESPONDENCE(IPO)-(11-6-2013).pdf 2018-08-09
14 2380-MUM-2007-CORRESPONDENCE(18-8-2009).pdf 2018-08-09
15 2380-mum-2007-claims.pdf 2018-08-09
17 2380-mum-2007-abstract.pdf 2018-08-09
19 2380-MUM-2007- WO- PCT DOCUMENTS.pdf 2022-02-17