WO2003027072A1 - Process for the preparation of repaglinide - Google Patents

Process for the preparation of repaglinide Download PDF

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Publication number
WO2003027072A1
WO2003027072A1 PCT/IB2002/003943 IB0203943W WO03027072A1 WO 2003027072 A1 WO2003027072 A1 WO 2003027072A1 IB 0203943 W IB0203943 W IB 0203943W WO 03027072 A1 WO03027072 A1 WO 03027072A1
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Prior art keywords
process according
formula
repaglinide
reaction
protecting group
Prior art date
Application number
PCT/IB2002/003943
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French (fr)
Inventor
Purna Chandra Ray
Jayachandra Suresh Babu
Mohammad Salman
Naresh Kumar
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Ranbaxy Laboratories Limited
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Publication date
Application filed by Ranbaxy Laboratories Limited filed Critical Ranbaxy Laboratories Limited
Priority to DE60204334T priority Critical patent/DE60204334T2/en
Priority to EP02775017A priority patent/EP1432682B1/en
Priority to US10/490,275 priority patent/US7148355B2/en
Priority to CA002461087A priority patent/CA2461087A1/en
Priority to AT02775017T priority patent/ATE296287T1/en
Priority to JP2003530663A priority patent/JP2005521634A/en
Priority to BR0212772-5A priority patent/BR0212772A/en
Publication of WO2003027072A1 publication Critical patent/WO2003027072A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/135—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

  • the present invention relates to a cost effective and industrially advantageous process for the preparation of repaglinide.
  • repaglinide is S(+)-2-ethoxy-4-[N- ⁇ l-(2-piperidinophenyl)-3-methyl- 1 -butyl ⁇ aminocarbonylmethyl]benzoic acid having the Formula I,
  • FORMULA I and is known from U.S. Patent No. 5,312,924. It belongs to a new class of hypoglycemic benzoic acid derivatives. It offers significantly better biological profile as compared to sulphonylurea class of compounds for the treatment of non-insulin dependent diabetes mellitus (NIDDM).
  • NIDDM non-insulin dependent diabetes mellitus
  • the reaction of the (S)- amine of Formula II with a carboxylic acid of Formula III is carried out in the presence of N, N'-carbonyldimidazole, N, N'- dicyclohexylcarbodiimide or triphenylphosphine/carbon tetrachlori.de and triethylamine.
  • N,N'-carbonyldimidazole is expensive and gives low yields (50 to 55%) while the use of triphenylphosphine/carbon tetrachloride necessitates chromatographic purification to obtain repaglinide of desired purity.
  • N, N' -dicyclohexylcarbodiimide generates dicyclohexyl urea as a by-product which can only be removed by repeated crystallizations of the product resulting in increased cycle time and the cost of production. Furthermore, the N, N' -dicyclohexylcarbodiimide is toxic and its use on a commercial scale is undersirable.
  • the present invention provides a process for the preparation of repaglinide of Formula I comprising : -
  • R is a protecting group, in the presence of pivaloyl chloride and a base
  • the protecting group R in the compound of Formula IV is any carboxylic acid protecting group which is easily removed, such as methyl, ethyl, tert.-butyl, benzyl, p- nitrobenzyl,p-methoxybenzyl, and the like.
  • a suitable base which may be either organic or inorganic.
  • suitable organic bases include amines such as diisopropylamine, dicyclohexylamine, l,8-diazabicyclo[5.4.0] undec-7-ene, triethylamine, tributylamine, N, N-dimethylaniline, diisopropylethylamme, and the like.
  • suitable inorganic bases include potassium carbonate, sodium carbonate, and the like.
  • the reaction may be carried out in a suitable solvent such as dichloromethane, toluene, xylene, and the like.
  • the reaction is carried out at temperatures of between -25°C and 40°C, but preferably at temperatures of between -10 and 25°C.
  • Pivaloyl chloride (5.4g, 45 mmol) was added to a mixture of 3-ethoxy-4- ethoxycarbonyl phenylacetic acid (lO.Og, 40 mmol), toluene (50ml) and triethylamine (5.0g, 49 mmol) at -5°C and stirred for 1 hour.
  • a solution of (S)-3-methyl-l-(2- piperidinophenyl)-l-butylamine (9.8g, 40 mmol) in toluene (20ml) was then added at below 10°C. The temperature of the reaction mixture was raised to 30°C and the mixture stirred overnight. It was then washed with water and saturated sodium bicarbonate solution.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Diabetes (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Endocrinology (AREA)
  • Emergency Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Hydrogenated Pyridines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Steroid Compounds (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

The present invention relates to a cost effective and industrially advantageous process for the preparation of repaglinide.

Description

PROCESS FORTHE PREPARATION OFREPAGLINIDE
Field of the Invention
The present invention relates to a cost effective and industrially advantageous process for the preparation of repaglinide.
Background of the Invention
Chemically, repaglinide is S(+)-2-ethoxy-4-[N-{l-(2-piperidinophenyl)-3-methyl- 1 -butyl} aminocarbonylmethyl]benzoic acid having the Formula I,
Figure imgf000002_0001
FORMULA I and is known from U.S. Patent No. 5,312,924. It belongs to a new class of hypoglycemic benzoic acid derivatives. It offers significantly better biological profile as compared to sulphonylurea class of compounds for the treatment of non-insulin dependent diabetes mellitus (NIDDM).
U.S. Patent No. 5,312,924 describes a process for the preparation of repaglinide which involves the reaction of (S)-amine of Formula II,
Figure imgf000002_0002
FORMULA H with a carboxylic acid of Formula III,
Figure imgf000003_0001
FORMULA III wherein W represents a (protected) carboxy group or a reactive derivative thereof, and cleaving the protecting group, if necessary, to obtain repaglinide of Formula I.
The reaction of the (S)- amine of Formula II with a carboxylic acid of Formula III is carried out in the presence of N, N'-carbonyldimidazole, N, N'- dicyclohexylcarbodiimide or triphenylphosphine/carbon tetrachlori.de and triethylamine. N,N'-carbonyldimidazole is expensive and gives low yields (50 to 55%) while the use of triphenylphosphine/carbon tetrachloride necessitates chromatographic purification to obtain repaglinide of desired purity. The use of N, N' -dicyclohexylcarbodiimide generates dicyclohexyl urea as a by-product which can only be removed by repeated crystallizations of the product resulting in increased cycle time and the cost of production. Furthermore, the N, N' -dicyclohexylcarbodiimide is toxic and its use on a commercial scale is undersirable.
Several variations of this method are known which involve the condensation of differently substituted amines and carboxylic acids, followed by suitable chemical modijEication of the substituents to obtain repaglinide. All of these variations involve additional number of synthetic steps and are therefore not suitable for commercial scale production of repaglinide.
It is, therefore desirable to solve the problems associated with the prior art and to provide an efficient process for the preparation of repaglinide which process improves the economics by employing less expensive and less hazardous raw materials and is more productive. The process avoids the tedious and cumbersome procedures of chromatography or special recrystallization techniques, is economical and convenient to operate on a commercial scale. The present invention provides a process for the preparation of repaglinide of Formula I comprising : -
a) reacting the (S)- amine of Formula II with a protected carboxylic acid of Formula IV,
Figure imgf000004_0001
FORMULA IV
wherein R is a protecting group, in the presence of pivaloyl chloride and a base, and
b) removing the protecting group to obtain repaglinide.
The protecting group R in the compound of Formula IV is any carboxylic acid protecting group which is easily removed, such as methyl, ethyl, tert.-butyl, benzyl, p- nitrobenzyl,p-methoxybenzyl, and the like.
The reaction is carried out in the presence of a suitable base which may be either organic or inorganic. Examples of suitable organic bases include amines such as diisopropylamine, dicyclohexylamine, l,8-diazabicyclo[5.4.0] undec-7-ene, triethylamine, tributylamine, N, N-dimethylaniline, diisopropylethylamme, and the like. Suitable inorganic bases include potassium carbonate, sodium carbonate, and the like.
The reaction may be carried out in a suitable solvent such as dichloromethane, toluene, xylene, and the like. The reaction is carried out at temperatures of between -25°C and 40°C, but preferably at temperatures of between -10 and 25°C.
The removal of a carboxylic acid protecting group is achieved by suitable methods known in the art such as acidic or basic hydrolysis or hydrogenolysis. Detailed Description of the Invention
In the following section one preferred embodiment has been described by way of example to illustrate the process of the invention. However, it is not intended in any way to limit the scope of the present invention.
EXAMPLE
Preparation of ethyl (S)-2-ethoxy-4-[N-{l-(2-piperidinophenyl)-3-methyl-l-butyl} aminocarbonylmethyl]benzoate
Pivaloyl chloride (5.4g, 45 mmol) was added to a mixture of 3-ethoxy-4- ethoxycarbonyl phenylacetic acid (lO.Og, 40 mmol), toluene (50ml) and triethylamine (5.0g, 49 mmol) at -5°C and stirred for 1 hour. A solution of (S)-3-methyl-l-(2- piperidinophenyl)-l-butylamine (9.8g, 40 mmol) in toluene (20ml) was then added at below 10°C. The temperature of the reaction mixture was raised to 30°C and the mixture stirred overnight. It was then washed with water and saturated sodium bicarbonate solution. Toluene was distilled off under reduced pressure to get the crude product. The crude product was dissolved in toluene (35ml), hexane (200ml) was added and the mixture cooled at 0°C. The solid product so obtained was filtered and dried to give 14.0g of the title compound (Yield: 73%, HPLC Purity 99%).
Preparation of (S)-2-ethoxy-4-[N-{l-(2-piperidinophenyl)-3-methyl-l-butyl} aminocarbonylmethyl]benzoic acid
A solution of ethyl (S)-2-ethoxy-4-[N-{l-(2-piperidinophenyl)-3 -methyl- 1 -butyl} - aminocarbonylmethyl]benzoate (20g, 41.6 mmol) in denatured spirit (200ml) was stirred at 60-65°C and IN sodium hydroxide solution (62ml) was added. After two hours of stirring at 60°C, the reaction mixture was cooled to 35°C and pH was adjusted to about 5.0 using IN hydrochloric acid (about 70ml). The solution was stirred for 30 minutes at 35- 40°C, cooled to 0°C and stirred at 0 to 5°C for one hour to get a crystalline product. The crystals were separated by filtration and washed with water. The product was dried at 60- 65°C under vacuum to get repaglinide (17.8g, Yield : 94%, Assay 99.5% by HPLC). While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

Claims

1. A process for the preparation of repaglinide of Formula I,
Figure imgf000007_0001
FORMULA I comprising
a) reacting the (S)- amine of Formula IT,
Figure imgf000007_0002
FORMULA π with a protected carboxylic acid of Formula IV,
Figure imgf000007_0003
FORMULA IV wherein R is a protecting group, in the presence of pivaloyl chloride and a base, and b) removing the protecting group to obtain repaglinide.
2. The process according to claim 1 wherein the protecting group R is selected from the group consisting of methyl, ethyl, tert.-butyl, benzyl, p-nitrobenzyl, and p- methoxybenzyl.
3. The process according to claim 1 wherein the reaction is carried out in the presence of an organic or inorganic base.
4. The process according to claim 3 wherein the organic base is an amine.
5. The process according to claim 4 wherein the amine is selected from the group consisting of l,8-diazabicyclo[5.4.0]undec-7-ene, triethylamine, tributylamine, N, N-dimethylaniline, diisopropylethylamme diisopropylamine, and discyclohexylamine.
6. The process according to claim 3 wherein the inorganic base is potassium carbonate or sodium carbonate.
7. The process according to claim 1 wherein the reaction is carried out in a solvent.
8. The process according to claim 7 where the solvent is selected from the group consisting of dichloromethane, toluene and xylene.
9. The process according to claim 1 wherein the reaction is carried out temperatures of between -25°C and 40°C.
10. The process according to claim 9 wherein the temperature is -10° to 25°C.
PCT/IB2002/003943 2001-09-25 2002-09-24 Process for the preparation of repaglinide WO2003027072A1 (en)

Priority Applications (7)

Application Number Priority Date Filing Date Title
DE60204334T DE60204334T2 (en) 2001-09-25 2002-09-24 Process for the preparation of repaglinide
EP02775017A EP1432682B1 (en) 2001-09-25 2002-09-24 Process for the preparation of repaglinide
US10/490,275 US7148355B2 (en) 2001-09-25 2002-09-24 Process for the preparation of repaglinide
CA002461087A CA2461087A1 (en) 2001-09-25 2002-09-24 Process for the preparation of repaglinide
AT02775017T ATE296287T1 (en) 2001-09-25 2002-09-24 METHOD FOR PRODUCING REPAGLINIDE
JP2003530663A JP2005521634A (en) 2001-09-25 2002-09-24 Preparation of repaglinide
BR0212772-5A BR0212772A (en) 2001-09-25 2002-09-24 Process for the preparation of repaglinide

Applications Claiming Priority (2)

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IN983/DEL/2001 2001-09-25
IN983DE2001 IN192527B (en) 2001-09-25 2001-09-25

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EP (1) EP1432682B1 (en)
JP (1) JP2005521634A (en)
CN (1) CN1571769A (en)
AR (1) AR036623A1 (en)
AT (1) ATE296287T1 (en)
BR (1) BR0212772A (en)
CA (1) CA2461087A1 (en)
DE (1) DE60204334T2 (en)
ES (1) ES2242068T3 (en)
IN (1) IN192527B (en)
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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004018442A1 (en) * 2002-08-23 2004-03-04 Dr. Reddy's Laboratories Limited Crystalline and amorphous forms of (s) -repaglinide and the processes for preparation thereof
WO2004103983A1 (en) * 2003-05-26 2004-12-02 Biocon Limited Process for the preparation of s(+)-2-ethoxy-4-[n-{1-(2-piperidinophelyl)-3-methyl-1- butyl} aminocarbonylmethyl]benzoic acid derivatives
WO2009004485A2 (en) * 2007-06-06 2009-01-08 Actavis Group Ptc Ehf Repaglinide substantially free of dimer impurity
US8101769B2 (en) 2007-02-15 2012-01-24 Actavis Group Ptc Ehf Process for preparing ethyl (S)-2-ethoxy-4-[N-[1-(2-piperidinophenyl)-3-methyl-1-butyl]aminocarbonyl methyl]benzoate and use thereof for the preparation of Repaglinide
CN104557778A (en) * 2015-01-09 2015-04-29 蔡伦 Preparation method and application of repaglinide

Families Citing this family (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004101540A2 (en) * 2003-05-14 2004-11-25 Cilag Ag Method for the production of phenylacetic acid derivatives
CN100445275C (en) * 2006-06-21 2008-12-24 浙江大学 Repaglinide synthesis process
CN101481363B (en) * 2008-01-10 2011-05-04 江苏豪森药业股份有限公司 Method for preparing repaglinide
CN101220007B (en) * 2008-01-16 2010-09-15 浙江耐司康药业有限公司 Method for producing repaglinide
CN102267959B (en) * 2011-07-06 2013-05-01 海南锦瑞制药股份有限公司 Repaglinide crystal, preparation method thereof, and solid oral preparation containing same
CN103012319B (en) * 2011-09-20 2015-06-10 浙江九洲药业股份有限公司 Repaglinide intermediate synthesis process improvement
CN102633750A (en) * 2012-03-26 2012-08-15 浙江昂利康制药有限公司 One-pot method for synthesizing repaglinide for treating diabetes
CN102731436A (en) * 2012-04-09 2012-10-17 海南中化联合制药工业股份有限公司 Preparation and refining method of repaglinide
CN105198838A (en) * 2015-10-21 2015-12-30 河南普瑞制药有限公司 Preparation method of repaglinide
CN105906583B (en) * 2015-12-23 2018-03-09 嘉实（湖南）医药科技有限公司 A kind of preparation technology of repaglinide intermediate

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Patent Citations (2)

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US5312924A (en) * 1983-12-30 1994-05-17 Dr. Karl Thomae Gmbh Phenylacetic acid benzylamides

Non-Patent Citations (3)

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Title
GRELL W ET AL: "REPAGLINIDE AND RELATED HYPOGLYCEMIC BENZOIC ACID DERIVATIVES", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY. WASHINGTON, US, vol. 41, 1998, pages 5219 - 5246, XP000872800, ISSN: 0022-2623 *
GUAY D R P: "REPAGLINIDE, A NOVEL, SHORT-ACTING HYPOGLYCEMIC AGENT FOR TYPE 2 DIABETES MELLITUS", PHARMACOTHERAPY, BOSTON, US, vol. 18, no. 6, 1998, pages 1195 - 1204, XP000874581, ISSN: 0277-0008 *
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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004018442A1 (en) * 2002-08-23 2004-03-04 Dr. Reddy's Laboratories Limited Crystalline and amorphous forms of (s) -repaglinide and the processes for preparation thereof
WO2004103983A1 (en) * 2003-05-26 2004-12-02 Biocon Limited Process for the preparation of s(+)-2-ethoxy-4-[n-{1-(2-piperidinophelyl)-3-methyl-1- butyl} aminocarbonylmethyl]benzoic acid derivatives
US8101769B2 (en) 2007-02-15 2012-01-24 Actavis Group Ptc Ehf Process for preparing ethyl (S)-2-ethoxy-4-[N-[1-(2-piperidinophenyl)-3-methyl-1-butyl]aminocarbonyl methyl]benzoate and use thereof for the preparation of Repaglinide
WO2009004485A2 (en) * 2007-06-06 2009-01-08 Actavis Group Ptc Ehf Repaglinide substantially free of dimer impurity
WO2009004485A3 (en) * 2007-06-06 2009-03-19 Actavis Group Ptc Ehf Repaglinide substantially free of dimer impurity
CN104557778A (en) * 2015-01-09 2015-04-29 蔡伦 Preparation method and application of repaglinide

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ATE296287T1 (en) 2005-06-15
AR036623A1 (en) 2004-09-22
EP1432682B1 (en) 2005-05-25
JP2005521634A (en) 2005-07-21
DE60204334D1 (en) 2005-06-30
CN1571769A (en) 2005-01-26
ES2242068T3 (en) 2005-11-01
IN192527B (en) 2004-04-24
US7148355B2 (en) 2006-12-12
CA2461087A1 (en) 2003-04-03
PT1432682E (en) 2005-09-30
BR0212772A (en) 2004-10-13
EP1432682A1 (en) 2004-06-30
US20050107614A1 (en) 2005-05-19
DE60204334T2 (en) 2006-03-23

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