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WO2006006183A2 - Procede ameliore de preparation de n-[(s)-ethoxycarbonyl-l-butyl]-(s)-alanine - Google Patents

Procede ameliore de preparation de n-[(s)-ethoxycarbonyl-l-butyl]-(s)-alanine Download PDF

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Publication number
WO2006006183A2
WO2006006183A2 PCT/IN2005/000225 IN2005000225W WO2006006183A2 WO 2006006183 A2 WO2006006183 A2 WO 2006006183A2 IN 2005000225 W IN2005000225 W IN 2005000225W WO 2006006183 A2 WO2006006183 A2 WO 2006006183A2
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WO
WIPO (PCT)
Prior art keywords
dioxane
filtering
alanine
hydrogen gas
crude product
Prior art date
Application number
PCT/IN2005/000225
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English (en)
Other versions
WO2006006183A3 (fr
Inventor
Satyanaryana Chava
Mohan Bandari
Kumar Sethi Mathuresh
Original Assignee
Matrix Laboratories Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Matrix Laboratories Ltd filed Critical Matrix Laboratories Ltd
Publication of WO2006006183A2 publication Critical patent/WO2006006183A2/fr
Publication of WO2006006183A3 publication Critical patent/WO2006006183A3/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/30—Preparation of optical isomers
    • C07C227/32—Preparation of optical isomers by stereospecific synthesis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/38—Separation; Purification; Stabilisation; Use of additives
    • C07C227/40—Separation; Purification
    • C07C227/42—Crystallisation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Definitions

  • the present invention relates to an improved process for the synthesis of N-[(S)-ethoxy carbonyl-l-butyl]-(S)-alanine and its application in the industrial manufacturing of perindopril and its pharmaceutically acceptable salts
  • N-[(S)-ethoxycarbonyl-l-butyl]-(S)-alanine of the formula ( I ) is useful in the synthesis of (2S, 3aS, 7aS) - 1 - ⁇ 2 - [1- (ethoxycarbonyl) - (S) - butylamino] - (S)-propionyl ⁇ - octahydroindole - 2-caroxylic acid (Perindopril) is known to have therapeutic application as an angiotensin-converting enzyme (ACE) inhibitor.
  • ACE angiotensin-converting enzyme
  • R 1 and R 2 have the meaning given therein, with pyruvic acid in water by catalytic hydrogenation under pressure and with slight heating, the pressure being between 10-100 bars and the temperature being between 10 and 60°C.
  • stage B the above publication describes the synthesis of compound of formula (I) reported from the reaction of ethyl L-norvalinate hydrochloride and pyruvic acid under a hydrogenation pressure of 30 bars at ambient temperature for twenty four hours.
  • the isolation of the crude product is then carried out by evaporation of water, and then ethanol is added to precipitate the sodium chloride formed during the reaction. After filtration, the ethanol solution obtained is evaporated and the residue is crystallized from acetonitrile to obtain the (S, S)-diastereoisomer in good optical purity.
  • European patent EP 0 309 324 discloses a process for obtaining a compound of formula (I) by reacting alanine benzyl ester with ethyl [alpha] -bromo valerate in dimethylformamide in the presence of triethylamine.
  • the major drawbacks of that process are the large number of steps involved and the low yield of the required isomer.
  • US patent application 2003/0045744 discloses a process for the industrial synthesis of a compound of formula (I) by condensing ethyl L-norvalinate hydrochloride (IV) with sodium pyruvate (V) in water under catalytic hydrogenation at a pressure of 1 to 20 bars
  • the main object of the present invention is to provide a simple, economic and industrially feasible process for the preparation of N-[(S)-ethoxycarbonyl-l-butyl]-(S)-alanine without the use of high pressure / high pressure vessels during hydrogenation.
  • pyruvic acid is condensed with ethyl L-norvalinate hydrochloride in water with hydrogenation by bubbling hydrogen gas at atmospheric pressure or at slight negative pressure, catalysed by 5% palladium on carbon (50% wet) at a temperature of from -2 to 8 0 C, in presence of 1 to 5 mol equivalents of sodium hydroxide, preferably 2 to 3 equivalents per mol of ethyl L-norvalinate hydrochloride, removal of water by vacuum distillation and crystallizing the residue from 1,4-dioxane or THF to obtain N- [(S)-ethoxycarbonyl-l -butyl] -(S)-alanine of formula (I).
  • Ethyl L-norvalinate hydrochloride is dissolved in 1 to 10 volumes of water, preferably in 2-3 volumes of water at -2 to 8°C. This solution is neutralized using inorganic bases such as alkali hydroxide, carbonates & bicarbonates etc, preferably aqueous solution of sodium hydroxide at the same temperature.
  • Freshly distilled pyruvic acid 0.7 to 1.3 mol equivalents, preferably 1.0 mol equivalents, is added to above solution to obtain a pH of about 1.0.
  • the resulting solution is basified using inorganic bases such as alkali hydroxide, carbonates & bicarbonates, preferably aqueous solution of sodium hydroxide, at -2 to 8°C to a pH of 6.5 - 10.0, preferably 9 to 10.
  • inorganic bases such as alkali hydroxide, carbonates & bicarbonates, preferably aqueous solution of sodium hydroxide, at -2 to 8°C to a pH of 6.5 - 10.0, preferably 9 to 10.
  • reaction mass 5% palladium-on-carbon (50% wet) is added to the reaction mass and reaction is carried out by bubbling hydrogen gas at -2 to 8 0 C at atmospheric pressure or at slight negative pressure (by applying up to 500 millibar of vacuum) till reaction is completed.
  • the progress of the reaction is monitored by TLC or HPLC. The reaction may be completed over a period of 6 to 18 hours.
  • catalyst is filtered and the filtrate is neutralized and concentrated under reduced pressure below 45 0 C of mass temperature.
  • the water traces present in the residue are removed completely by co-distillation with 2-3 volumes of toluene under vacuum.
  • the residue is treated with 3 to 5 volumes of ethanol and the inorganic salts are removed by filtration.
  • the filtrate is concentrated under vacuum and the resulting mass is treated with 1,4-dioxane / THF at 15-25 0 C, filtered and dried to obtain the crude product.
  • the crude product is crystallized from 5 - 30 volumes of 1, 4-dioxane / THF, preferably 15-' 30 volumes of the solvent.
  • the reaction mass is subjected to hydrogenation in presence of 23 g of 5% palladium-on-carbon (50% wet) by bubbling hydrogen gas at -2 to 7 0 C for 12 hours.
  • the catalyst is filtered; the filtrate is neutralized and evaporated under vacuum at below a 45 0 C.
  • the residue is treated with 360ml of ethanol and the inorganic salts are removed by filtration and rinsed with 60ml of ethanol.
  • Ethanol is distilled off and the residue is treated with 500ml of 1, 4-dioxane, cooled to 15 to 20 0 C, filtered and dried to obtain 72.5g of crude product. Crystallization from 1300ml of 1, 4-dioxane provided 44 g of pure N-[(S)-ethoxycarbonyl-l-butyl]-(S)-alanine as white crystalline solid.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne un procédé amélioré de préparation de N-[(S)-éthoxycarbonyl-1-butyl]-(S)-alanine par simple barbotage d'hydrogène dans le mélange de réaction à la pression atmosphérique ou à une pression légèrement négative en présence de palladium-carbone à basse température.
PCT/IN2005/000225 2004-07-12 2005-07-04 Procede ameliore de preparation de n-[(s)-ethoxycarbonyl-l-butyl]-(s)-alanine WO2006006183A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN669CH2004 2004-07-12
IN669/CHE/2004 2004-07-12

Publications (2)

Publication Number Publication Date
WO2006006183A2 true WO2006006183A2 (fr) 2006-01-19
WO2006006183A3 WO2006006183A3 (fr) 2007-05-31

Family

ID=35784266

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IN2005/000225 WO2006006183A2 (fr) 2004-07-12 2005-07-04 Procede ameliore de preparation de n-[(s)-ethoxycarbonyl-l-butyl]-(s)-alanine

Country Status (1)

Country Link
WO (1) WO2006006183A2 (fr)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0308340A1 (fr) * 1987-09-17 1989-03-22 Adir Et Compagnie Procédé de synthèse d'alpha amino acides N alkyles et de leurs esters. Application à la synthèse de carboxyalkyl dipeptides
US20030045744A1 (en) * 2000-03-31 2003-03-06 Jean-Claude Souvie Novel method for synthesis of n-[(s)-1-carboxybutyl]-(s)-alanine esters and use in synthesis of perindopril

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0308340A1 (fr) * 1987-09-17 1989-03-22 Adir Et Compagnie Procédé de synthèse d'alpha amino acides N alkyles et de leurs esters. Application à la synthèse de carboxyalkyl dipeptides
US20030045744A1 (en) * 2000-03-31 2003-03-06 Jean-Claude Souvie Novel method for synthesis of n-[(s)-1-carboxybutyl]-(s)-alanine esters and use in synthesis of perindopril

Also Published As

Publication number Publication date
WO2006006183A3 (fr) 2007-05-31

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