WO2012117410A1 - Procédé pour la préparation d'ester phénylméthylique de n-[2-[(acétylthio) méthyl]-1-oxo-3-phénylpropyl] glycine et d'intermédiaires de celui-ci - Google Patents

Procédé pour la préparation d'ester phénylméthylique de n-[2-[(acétylthio) méthyl]-1-oxo-3-phénylpropyl] glycine et d'intermédiaires de celui-ci Download PDF

Info

Publication number
WO2012117410A1
WO2012117410A1 PCT/IN2011/000132 IN2011000132W WO2012117410A1 WO 2012117410 A1 WO2012117410 A1 WO 2012117410A1 IN 2011000132 W IN2011000132 W IN 2011000132W WO 2012117410 A1 WO2012117410 A1 WO 2012117410A1
Authority
WO
WIPO (PCT)
Prior art keywords
formula
compound
preparation
racecadotril
mole
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/IN2011/000132
Other languages
English (en)
Inventor
Dodda Mohan Rao
Pingili Krishna Reddy
Tarnikanti PRAKASH
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Symed Labs Ltd
Original Assignee
Symed Labs 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 Symed Labs Ltd filed Critical Symed Labs Ltd
Priority to PCT/IN2011/000132 priority Critical patent/WO2012117410A1/fr
Publication of WO2012117410A1 publication Critical patent/WO2012117410A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C327/00—Thiocarboxylic acids
    • C07C327/20—Esters of monothiocarboxylic acids
    • C07C327/32—Esters of monothiocarboxylic acids having sulfur atoms of esterified thiocarboxyl groups bound to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C68/00—Preparation of esters of carbonic or haloformic acids
    • C07C68/02—Preparation of esters of carbonic or haloformic acids from phosgene or haloformates

Definitions

  • the present invention relates to a process for the preparation of N-[2-[(acetylthio) methyl]- l-oxo-3-phenylpropyl] glycine phenyl methyl ester and intermediates thereof.
  • the present invention relates to a process for the preparation of intermediate compound 2-(benzyl acrylolyl amino) acetic acid benzyl ester.
  • Racecadotril is a neutral endopeptidase inhibitor used as antidiarrheal in the treatment of chronic cardiac insufficiency and is available under the brand names Hidrasec and Tiorfan. Racecadotril is chemically known as N-[2-[(acetylthio) methyl] -l-oxo-3-phenylpropyl] glycine phenyl methyl ester, (herein after referred by its generic name racecadotril) and represented by the formula (I).
  • HOBT hydroxyl benzotriazole
  • DCC dicyclohexyl amine carbodiimide
  • the process of present invention is simple, cost effective, eco-friendly, reproducible, robust and is well suited on commercial scale.
  • the present invention relates to a process for the preparation of N-[2-[(acetylthio) methyl]- l-oxo-3-phenylpropyl] glycine phenyl methyl ester and intermediates thereof.
  • the present invention relates to a process for the preparation of intermediate compound 2-(benzyl acrylolyl amino) acetic acid benzyl ester.
  • the present invention relates to a process for the preparation of 2-(benzyl acrylolyl amino) acetic acid benzyl ester of formula (la)
  • R is C1-C6 alkyl branched or straight chain or aryl.
  • HX is acid addition salts, such as those made with hydrochloric, hydrobromic, hydroiodic, methylsulfonic, perchloric, sulfuric, nitric, phosphoric, acetic, propionic, glycolic lactic pyruvic, malonic, succinic, maleic, fumaric, maleic, tartaric, citric, benzoic, carbonic cinnamic, mandelic, methanesulfonic, ethanesulfonic, benezenesulfonic,
  • Fig. 1 is a schematic representation of an embodiment of the process of present invention.
  • the present invention is directed to a process for the preparation of N-[2-[(acetylthio) methyl] -l-oxo-3-phenylpropyl] glycine phenyl methyl ester and intermediates thereof.
  • the present invention relates to a process for the preparation of intermediate compound 2-(benzyl acrylolyl amino) acetic acid benzyl ester.
  • R is C1-C6 alkyl branched or straight chain or aryl.
  • HX is acid addition salts, such as those made with hydrochloric, hydrobromic, hydroiodic, methylsulfonic, perchloric, sulfuric, nitric, phosphoric, acetic, propionic, glycolic, lactic pyruvic, malonic, succinic, maleic, fumaric, maleic, tartaric, citric, benzoic, carbonic cinnamic, mandelic, methanesulfonic, ethanesulfonic, benezenesulfonic,
  • the suitable base that can be used in step a) include inorganic or organic base.
  • Inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, ammonia and the like; and the organic bases such as triethylamine, tripropylamine, pyridine, dimethyl amino pyridine, diisopropylamine, diisopropylethylamine and the like, or mixture thereof, preferably triethylamine.
  • the organic solvents that can be used in step a) is selected from the group consisting of halogenated solvents such as dichloromethane, ethylene dichloride , chloroform, chlorobenzene, and the like; hydrocarbon solvents such as toluene, xylene, cyclohexane, n- hexane and the like; esters such as ethyl acetate, isopropyl acetate and the like: or mixtures thereof in various proportions without limitation.
  • halogenated solvents such as dichloromethane, ethylene dichloride , chloroform, chlorobenzene, and the like
  • hydrocarbon solvents such as toluene, xylene, cyclohexane, n- hexane and the like
  • esters such as ethyl acetate, isopropyl acetate and the like: or mixtures thereof in various proportions without limitation.
  • dichloromethane is being used.
  • the reaction temperature and time should be suitable to bring the reaction to completion at a minimum time, without the production of unwanted side products.
  • the reaction temperature is from about -20°C to about 40°C. Preferably at about -5°C to about 10 °C.
  • the time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagent and solvent(s) employed. The time period is from about 1 hour to about 10 hours, preferably from about 1 hour to 5 hours.
  • the molar equivalent of base used can be from about 0.5 mole to about 10 moles on weight of the compound of formula V taken. Preferably, 1 mole is being used.
  • the molar equivalent of formula IV used can be from about 0.5 mole to about 5 moles on weight of the compound of formula V taken. Preferably, 1 mole is being used.
  • step b) the compound of formula II is being used in acid addition salt form that can be organic or inorganic acid salt namely hydrobromic acid salt, iodic acid salt, hydrogen sulfate salt, besylate salt, paratoluene sulfonate salt, mesylate salt, tartarate salt and the like.
  • acid addition salt form can be organic or inorganic acid salt namely hydrobromic acid salt, iodic acid salt, hydrogen sulfate salt, besylate salt, paratoluene sulfonate salt, mesylate salt, tartarate salt and the like.
  • paratoluene sulfonate is being prepared.
  • the R groups in the compounds of formula III and IV can be Ci-C 6 alkyl straight chain or branched or aryl namely methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, isobutyl, allyl, cyclohexyl, benzyl, phenyl, para nitro phenyl etc. preferably the R- group is ethyl.
  • the preferable compounds suitable for the preparation of compounds of formula III and IV include but are limited to ethyl chloro formate, benzyl chloro formate, isobutyl chloro formate, allyl chloro formate, phenyl chloro formate, paranitro phenyl chloro formate or mixtures thereof.
  • ethyl chloro formate Preferably ethyl chloro formate.
  • the reaction temperature is from about -20°C to about 40°C. preferably at about -5°C to about 10 °C.
  • the time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagent and solvent(s) employed. The time period is from about 1 hour to about 10 hours, preferably from about 1 hour to 5 hours.
  • the intermediate compound of formula III is optionally isolated as and when needed.
  • reaction mixture can be carried out by common operation, but in consideration of the physical properties of the desired compound, crystallization, extraction, washing, column chromatography, etc. may be combined.
  • the processes of present invention can be carried out by one pot synthesis.
  • the intermediate compounds can be optionally purified by recrystallisation, using a solvent or mixture of solvents; or by converting into their corresponding acid addition salt and then processed back to the respective free base or free acid compounds.
  • the process of present invention provides the intermediates with higher yields and purities thus leading to higher yields and purities of final product.
  • a process according to the present invention by using the intermediates prepared by the processes of present invention preferably yields racecadotril (I) substantially pure form.
  • the racecadotril obtained by the process of present invention has purity at least about 98 area % by HPLC , preferably at least about 99 area%. More preferably at least about 99.5 area % by HPLC.
  • the intermediate compound of formula (la) obtained by the above described process of present invention can be further converted into Racecadotril of formula I by processes described in the art. Illustratively, by the process described in U.S. Patent No. US 6,835,851 B2.
  • the present invention provides a simple, ecofriendly, inexpensive, reproducible, robust processes for preparation intermediates of racecadotril, which forthwith are viably adaptable on a commercial scale.
  • reaction mass was brought to about 25 °C and stirred for 30min. he reaction mass was washed with 250ml. of water followed by 250ml. of 4% sodium bicarbonate solution and again with 250ml. of water. The organic layer was separated and washed with 4 gms of carbon. The resulted reaction solution was distilled ordinarily and then finally under vacuum. Then charged 75ml. of isopropyl alcohol and distilled under vacuum upto 80°C to obtain 2-(benzylacryloyl amino)acetic acid benzyl ester as the residue.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Emergency Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention concerne un procédé pour la préparation d'ester phénylméthylique de N-[2-[(acétylthio) méthyl]-1-oxo-3-phénylpropyl] glycine et d'intermédiaires de celui-ci. Plus particulièrement, la présente invention concerne un procédé pour la préparation du composé intermédiaire ester benzylique d'acide 2-(benzyl acryloyl amino) acétique.
PCT/IN2011/000132 2011-03-02 2011-03-02 Procédé pour la préparation d'ester phénylméthylique de n-[2-[(acétylthio) méthyl]-1-oxo-3-phénylpropyl] glycine et d'intermédiaires de celui-ci Ceased WO2012117410A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/IN2011/000132 WO2012117410A1 (fr) 2011-03-02 2011-03-02 Procédé pour la préparation d'ester phénylméthylique de n-[2-[(acétylthio) méthyl]-1-oxo-3-phénylpropyl] glycine et d'intermédiaires de celui-ci

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/IN2011/000132 WO2012117410A1 (fr) 2011-03-02 2011-03-02 Procédé pour la préparation d'ester phénylméthylique de n-[2-[(acétylthio) méthyl]-1-oxo-3-phénylpropyl] glycine et d'intermédiaires de celui-ci

Publications (1)

Publication Number Publication Date
WO2012117410A1 true WO2012117410A1 (fr) 2012-09-07

Family

ID=46757408

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IN2011/000132 Ceased WO2012117410A1 (fr) 2011-03-02 2011-03-02 Procédé pour la préparation d'ester phénylméthylique de n-[2-[(acétylthio) méthyl]-1-oxo-3-phénylpropyl] glycine et d'intermédiaires de celui-ci

Country Status (1)

Country Link
WO (1) WO2012117410A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107129450A (zh) * 2017-06-05 2017-09-05 山东裕欣药业有限公司 一种消旋卡多曲晶体化合物及其制备方法
CN107486096A (zh) * 2016-06-12 2017-12-19 景津环保股份有限公司 一种圆筒式药粉速溶混合搅拌装置
CN110272363A (zh) * 2019-06-11 2019-09-24 扬子江药业集团江苏海慈生物药业有限公司 一种消旋卡多曲的合成方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2736728A (en) * 1954-12-06 1956-02-28 Lilly Co Eli Preparation of lysergic acid amides
US20020055645A1 (en) * 2000-11-09 2002-05-09 Thierry Monteil Process for synthesizing N-(mercaptoacyl) amino acid derivatives from alpha-substituted acrylic acids
US20020077481A1 (en) * 1996-12-11 2002-06-20 Martin Karpf Process for the preparation of mixed anhydrides
US6610880B1 (en) * 1999-10-13 2003-08-26 Akzo Nobel Nv Process for preparing peroxides using mixed anhydrides

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2736728A (en) * 1954-12-06 1956-02-28 Lilly Co Eli Preparation of lysergic acid amides
US20020077481A1 (en) * 1996-12-11 2002-06-20 Martin Karpf Process for the preparation of mixed anhydrides
US6610880B1 (en) * 1999-10-13 2003-08-26 Akzo Nobel Nv Process for preparing peroxides using mixed anhydrides
US20020055645A1 (en) * 2000-11-09 2002-05-09 Thierry Monteil Process for synthesizing N-(mercaptoacyl) amino acid derivatives from alpha-substituted acrylic acids

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107486096A (zh) * 2016-06-12 2017-12-19 景津环保股份有限公司 一种圆筒式药粉速溶混合搅拌装置
CN107486096B (zh) * 2016-06-12 2023-05-02 景津装备股份有限公司 一种圆筒式药粉速溶混合搅拌装置
CN107129450A (zh) * 2017-06-05 2017-09-05 山东裕欣药业有限公司 一种消旋卡多曲晶体化合物及其制备方法
CN107129450B (zh) * 2017-06-05 2019-05-03 山东裕欣药业有限公司 一种消旋卡多曲晶体化合物及其制备方法
CN110272363A (zh) * 2019-06-11 2019-09-24 扬子江药业集团江苏海慈生物药业有限公司 一种消旋卡多曲的合成方法

Similar Documents

Publication Publication Date Title
US20130041180A1 (en) Process for preparing (r)-2-acetamido-n-benzyl-3-methoxy-propionamide
CA2476022C (fr) Procede de preparation d'un derive de la phenylalanine, et d'un intermediaire
US20170226047A1 (en) Process for the purification of melphalan
CN107810189B (zh) 用于制备氮芥衍生物的方法
WO2016024284A2 (fr) Processus de préparation du mirabegron et de ses produits intermédiaires
EP2970102B1 (fr) Procédé perfectionné pour la synthèse de melphalan et de son sel chlorhydrate
WO2012117410A1 (fr) Procédé pour la préparation d'ester phénylméthylique de n-[2-[(acétylthio) méthyl]-1-oxo-3-phénylpropyl] glycine et d'intermédiaires de celui-ci
US20110039937A1 (en) Novel process for the preparation of vorinostat
TWI634100B (zh) 製備拉科醯胺的方法
WO2007112613A1 (fr) Préparation de dérivés d'isothiazolinone n-substitués
US9790170B2 (en) Method for preparing lacosamide
US20240262805A1 (en) Method for producing compound or pharmaceutically acceptable salt thereof
IT201800006337A1 (it) Procedimento per la preparazione di lifitegrast
US12077484B2 (en) Process for the synthesis of melphalan
JP5704763B2 (ja) トランス−４−アミノシクロペンタ−２−エン−１−カルボン酸誘導体の製造
WO2013098826A1 (fr) Procédé de préparation d'un ester de n-[2-[(acétylthio)méthyl]-1-oxo- 3-phénylpropyl]glycine-phénylméthyle et de ses intermédiaires
US9630909B2 (en) Process for the preparation of nepafenac
JP5709101B2 (ja) ヒドロキシプロリン誘導体の製造法
EP3260442B1 (fr) Procédé de préparation de dérivés de l'acide n-substitué-3-méthoxypropionique optiquement pur
JP2024117554A (ja) 新規脱水縮合剤
US20110144346A1 (en) Method for producing n-phenyl-n-(4-piperidinyl) amide salts
WO2026033359A1 (fr) Procédé de préparation de salcaprozate de sodium
US20180237377A1 (en) Process for the Synthesis of Melphalan and the Hydrochloride Salt
WO2015031595A1 (fr) Procédé de préparation de saxagliptine et de son sel chlorhydrate
CN111247127A (zh) 用于合成药物的中间体化合物的生产方法

Legal Events

Date Code Title Description
WWE Wipo information: entry into national phase

Ref document number: 1327/CHENP/2012

Country of ref document: IN

121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 11859828

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 11859828

Country of ref document: EP

Kind code of ref document: A1