WO2004103983A1 - Process for the preparation of s(+)-2-ethoxy-4-[n-{1-(2-piperidinophelyl)-3-methyl-1- butyl} aminocarbonylmethyl]benzoic acid derivatives - Google Patents

Process for the preparation of s(+)-2-ethoxy-4-[n-{1-(2-piperidinophelyl)-3-methyl-1- butyl} aminocarbonylmethyl]benzoic acid derivatives Download PDF

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Publication number
WO2004103983A1
WO2004103983A1 PCT/IN2003/000197 IN0300197W WO2004103983A1 WO 2004103983 A1 WO2004103983 A1 WO 2004103983A1 IN 0300197 W IN0300197 W IN 0300197W WO 2004103983 A1 WO2004103983 A1 WO 2004103983A1
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WIPO (PCT)
Prior art keywords
formula
methyl
ethoxy
butyl
preparation
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PCT/IN2003/000197
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French (fr)
Inventor
Chandrashekar Aswathanarayanappa
Tom Thomas Puthiaparampil
Padudevastana Sathya Shanker
Madhavan Sridharan
Sambasivam Ganesh
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Biocon Limited
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Priority to AU2003237595A priority Critical patent/AU2003237595A1/en
Priority to PCT/IN2003/000197 priority patent/WO2004103983A1/en
Publication of WO2004103983A1 publication Critical patent/WO2004103983A1/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

Definitions

  • the present invention relates to a novel process for the preparation of S(+) 2-ethoxy-4-[N- ⁇ l-(2-piperidinophelyl)-3- methyl-1- butyl aminocarbonylmethyl]-benzoic acid derivatives.
  • EP 0 207 331 claims two polymorphous forms B and C of 2- ethoxy-4-[N- ⁇ l-(2-piperidinophelyl)-3- methyl-1-butyl aminocarbonylmethyl]-benzoic acid having the Formula IV and process for preparation thereof.
  • EP 0 589 874 claims S(+) 2-ethoxy-4-[N- ⁇ l-(2-piperidinophelyl)- 3- methyl- 1-butyl aminocarbonylmethyl]-benzoic acid having the Formula IV and process for preparation thereof.
  • the compound of formula (IV) is from a new class of hypoglycemic benzoic acid derivatives for the treatment of non-insulin dependent diabetes mellitus (NIDDM).
  • NIDDM non-insulin dependent diabetes mellitus
  • reaction of the 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 tetrachloride and triethylamine.
  • WO 2003/027072 claims process for preparation of compound of formula I by reacting an S(+) amine compound of formula II with a carboxylic acid of formula III in the presence of pivaloyl chloride and a base.
  • the reagents used here suffer from disadvantages like probable racemisation, expensiveness, additional reagents e.g. a base, low yields of the product, extra purification steps to obtain final product, repeated crystallization, hazardous and industrially impossible.
  • the present invention provides a process for the preparation of compound of formula I comprising, reacting the (S) amine of Formula II
  • the novel process employed in the instant invention has following definite advantages: a) Remarkably low risk of allergization compared to other reagents like DCC. b) Low toxicity of Propane phosphonic anhydride and its reaction products. c) Low racemization of products during reaction. d) By products are water soluble leading to simple work up and easy isolation of product. e) Reaction proceeds under ambient conditions. f) High yields.
  • the present invention provides a process for the preparation of compound of formula I comprising, reacting the (S) amine of Formula II
  • the protecting group P in the compound of Formula III is any carboxylic acid protecting group which can be easily removed, like ester groups.
  • the reaction may be carried out in any suitable solvent such as ethyl acetate, dichloromethane etc.
  • the reaction is carried out at temperatures of between -25°C and

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Hydrogenated Pyridines (AREA)

Abstract

The present invention relates to a novel process for the preparation of S(+)-2-ethoxy-4-[N-{1-(2-piperidinophelyl)-3-methyl-1-butyl} aminocarbonylmethyl]-benzoic acid derivatives.

Description

Process for the preparation of S(+)-2-ethoxy -4-|Η-{l-(2 iperidinophenyl)-3-methyl-l-butyl}arninocarbonylrnethyl]benzoic acid derivatives
FIELD OF THE INVENTION
The present invention relates to a novel process for the preparation of S(+) 2-ethoxy-4-[N-{l-(2-piperidinophelyl)-3- methyl-1- butyl aminocarbonylmethyl]-benzoic acid derivatives. BACKGROUND OF THE INVENTION EP 0 147850 claims racemate (forms A, B and C) of 2-ethoxy-4-
[N-{l-(2-piperidinophelyl)-3- methyl-1-butyl aminocarbonylmethyl]- benzoic acid having the Formula IV and process for preparation thereof. EP 0 207 331 claims two polymorphous forms B and C of 2- ethoxy-4-[N-{l-(2-piperidinophelyl)-3- methyl-1-butyl aminocarbonylmethyl]-benzoic acid having the Formula IV and process for preparation thereof.
EP 0 589 874 claims S(+) 2-ethoxy-4-[N-{l-(2-piperidinophelyl)- 3- methyl- 1-butyl aminocarbonylmethyl]-benzoic acid having the Formula IV and process for preparation thereof.
Figure imgf000002_0001
FORMULA IV
The compound of formula (IV) is from a new class of hypoglycemic benzoic acid derivatives for the treatment of non-insulin dependent diabetes mellitus (NIDDM).
The patents mentioned above also claim processes for the preparation of 2-ethoxy-4-[N-{l-(2-piperidinophelyl)-3- methyl- 1-butyl aminocarbonylmethyl]-benzoic acid which involves the reaction of an amine or S (+) amine of Formula II,
Figure imgf000003_0001
FORMULA II with a carboxylic acid of Formula III,
Figure imgf000003_0002
FORMULA III where P is a protecting group or a reactive derivative thereof to obtain compound of Formula I.
Figure imgf000004_0001
FORMULA I where P is a protecting group
The reaction of the 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 tetrachloride and triethylamine.
WO 2003/027072 claims process for preparation of compound of formula I by reacting an S(+) amine compound of formula II with a carboxylic acid of formula III in the presence of pivaloyl chloride and a base.
The reagents used here suffer from disadvantages like probable racemisation, expensiveness, additional reagents e.g. a base, low yields of the product, extra purification steps to obtain final product, repeated crystallization, hazardous and industrially impossible.
Thus, there is a need to solve the problems associated with the prior art and to provide an efficient process for the preparation of compounds of formula I. SUMMARY OF THE INVENTION
The present invention provides a process for the preparation of compound of formula I comprising, reacting the (S) amine of Formula II
Figure imgf000005_0001
FORMULA II with a carboxylic acid of Formula III,
Figure imgf000005_0002
FORMULA III where P is a protecting group in the presence of propane phosphonic acid anhydride to obtain compound of formula I.
Figure imgf000005_0003
FORMULA I where P is a protecting group
The novel process employed in the instant invention has following definite advantages: a) Remarkably low risk of allergization compared to other reagents like DCC. b) Low toxicity of Propane phosphonic anhydride and its reaction products. c) Low racemization of products during reaction. d) By products are water soluble leading to simple work up and easy isolation of product. e) Reaction proceeds under ambient conditions. f) High yields.
DETAILED DESCRIPTION OF THE INVENTION The present invention provides a process for the preparation of compound of formula I comprising, reacting the (S) amine of Formula II
Figure imgf000006_0001
FORMULA II
with a carboxylic acid of Formula III,
Figure imgf000007_0001
FORMULA III where P is a protecting group in the presence of Propane phosphonic acid anhydride to obtain compound of formula I.
Figure imgf000007_0002
FORMULA I where P is a protecting group
The protecting group P in the compound of Formula III is any carboxylic acid protecting group which can be easily removed, like ester groups. The reaction may be carried out in any suitable solvent such as ethyl acetate, dichloromethane etc.
The reaction is carried out at temperatures of between -25°C and
40°C, but preferably at ambient temperatures. The removal of a carboxylic acid protecting group is achieved by suitable methods known in the art like acidic or basic hydrolysis or hydrogenolysis. The following examples and scheme are used to illustrate the invention which are not to be considered as limiting. EXAMPLES EXAMPLE 1
2-ethoxy-4-- [3-methyl-l-(2-piperidin-l-yl-phenyl)- butyIcarbamoyl]-methyl>-benzoic acid ethyl ester: To a mixture of (15)-3-methyl-l-(2-piperidin-l-ylphenyl)butan-l-amine (49g, 0.2 mol), [3-ethoxy-4-(ethoxycarbonyl)phenyl]acetic acid (50 g, 0.2 mol) and triethylamine (100 g, 0.99 mol) in ethyl acetate (1.0 L), a solution (50% w/w) of propane phosphonic acid anhydride (278 g, 0.44 mol) in ethyl acetate was added dropwise over a period of 30 minutes, maintaining the temperature . at 0-5° C and stirred for 18 hours at ambient temperature. The reaction mixture was washed with 1.5 N HCI, 5% sodium bicarbonate solution and brine. The organic layer was concentrated to give title compound. Yield: 86 g, 89.5% EXAMPLE 2
S(+) ethoxy [N-{I-(2-piperidinophelyl) methyl 1-butylaminocarbonyl methyl] benzoic acid:
To a solution of 2-ethoxy-4-{[3-methyl-l-(2-piperidin-l-yl- phenyl)-butylcarbamoyl]-methyl}-benzoic acid ethyl ester (86 g, 0.18 mol) in ethanol (860 mL), a solution of sodium hydroxide (10.3 g, 0.26 mol) in water (260 mL) was added and stirred at 60-65° C for 2 h. Activated chrcoal (9 g) was added to the reaction mixture and filtered over celite bed. After adjusting the pH of the clear filtrate to 4.0 - 4.2, the mixture was stirred at 40-45° C for 30 minutes. The mixture further cooled to 0-5° C and stirred for 1 h. The product was filtered and dried. Yield: 66 g, 81%
SCHEME
Figure imgf000010_0001
Formula I
Figure imgf000010_0002
Formula IV where P is a protecting group

Claims

We claim:
1. A process for the preparation of S(+) 2-ethoxy-4-[N-{l-(2- piperidinophelyl)-3- methyl- 1-butyl aminocarbonylmethylj-benzoic acid derivatives of FORMULA I,
Figure imgf000011_0001
FORMULA I where P is a protecting group comprising, reacting the (S) amine of FORMULA II,
Figure imgf000011_0002
FORMULA II
with a protected carboxylic acid of Formula III,
Figure imgf000012_0001
FORMULA III where P is a protecting group in the presence of propane phosphonic acid anhydride to get a compound of formula I.
Figure imgf000012_0002
FORMULA I
2. The process according to claim 1 wherein the protecting group P is selected from the group consisting of methyl, ethyl, t-butyl, benzyl or any suitable group protecting carboxylic acid.
3. The process according to claim 1 wherein the reaction is carried out in a water immiscible solvent.
4. The process according to claim 3, wherein the water immiscible solvent Is selected from the group consisting of dichloromethane or ethyl acetate.
5. The process according to claim 1, wherein the reaction is carried out temperature of between -25°C and 40°C.
6. A process as in claim 1 - 5, wherein the compound of formula I is deprotected to get Formula IV.
Figure imgf000013_0001
FORMULA IV
PCT/IN2003/000197 2003-05-26 2003-05-26 Process for the preparation of s(+)-2-ethoxy-4-[n-{1-(2-piperidinophelyl)-3-methyl-1- butyl} aminocarbonylmethyl]benzoic acid derivatives WO2004103983A1 (en)

Priority Applications (2)

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AU2003237595A AU2003237595A1 (en) 2003-05-26 2003-05-26 Process for the preparation of s(+)-2-ethoxy-4-(n-{1-(2-piperidinophelyl)-3-methyl-1- butyl} aminocarbonylmethyl)benzoic acid derivatives
PCT/IN2003/000197 WO2004103983A1 (en) 2003-05-26 2003-05-26 Process for the preparation of s(+)-2-ethoxy-4-[n-{1-(2-piperidinophelyl)-3-methyl-1- butyl} aminocarbonylmethyl]benzoic acid derivatives

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN100445275C (en) * 2006-06-21 2008-12-24 浙江大学 Repaglinide synthesis process
WO2009004485A2 (en) * 2007-06-06 2009-01-08 Actavis Group Ptc Ehf Repaglinide substantially free of dimer impurity
CN102002021A (en) * 2010-12-07 2011-04-06 合肥华方医药科技有限公司 Novel method for synthesizing repaglinide
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
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
FR3016880A1 (en) * 2014-01-29 2015-07-31 Guillaume Laconde PROCESS FOR THE PREPARATION OF N-ACYL BENZOTRIAZOLE
CN105198838A (en) * 2015-10-21 2015-12-30 河南普瑞制药有限公司 Preparation method of repaglinide

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AU3721084A (en) * 1983-12-30 1985-08-01 Dr. Karl Thomae Gmbh Phenyl acetic acid amides
AU8078191A (en) * 1991-06-21 1993-01-25 Novo Nordisk A/S (s)(+)-2-ethoxy-4-(n-(1-(2-piperidinophenyl)-3-methyl-1- butyl)aminocarbonylmethyl)benzoic acid
DE19503325A1 (en) * 1995-02-02 1996-08-08 Hoechst Ag Economic prepn. of 3-hydroxy-N-aryl-naphtho-amide(s) on technical scale
US5945543A (en) * 1995-07-28 1999-08-31 Basf Aktiengesellschaft Process for producing α-(N,N dialkyl)-amino carboxlic acid amides
EP1031575A1 (en) * 1999-02-26 2000-08-30 Pfizer Products Inc. Process for preparing growth hormone secretagogues
WO2003027072A1 (en) * 2001-09-25 2003-04-03 Ranbaxy Laboratories Limited Process for the preparation of repaglinide

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US5945543A (en) * 1995-07-28 1999-08-31 Basf Aktiengesellschaft Process for producing α-(N,N dialkyl)-amino carboxlic acid amides
EP1031575A1 (en) * 1999-02-26 2000-08-30 Pfizer Products Inc. Process for preparing growth hormone secretagogues
WO2003027072A1 (en) * 2001-09-25 2003-04-03 Ranbaxy Laboratories Limited Process for the preparation of repaglinide

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN100445275C (en) * 2006-06-21 2008-12-24 浙江大学 Repaglinide synthesis process
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
CN102002021A (en) * 2010-12-07 2011-04-06 合肥华方医药科技有限公司 Novel method for synthesizing repaglinide
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
FR3016880A1 (en) * 2014-01-29 2015-07-31 Guillaume Laconde PROCESS FOR THE PREPARATION OF N-ACYL BENZOTRIAZOLE
FR3016879A1 (en) * 2014-01-29 2015-07-31 Guillaume Laconde PROCESS FOR THE PREPARATION OF N-ACYL BENZOTRIAZOLE
CN105198838A (en) * 2015-10-21 2015-12-30 河南普瑞制药有限公司 Preparation method of repaglinide

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