WO2008078340A1 - Procédé destiné à séparer des biphényles 4-bromométhyl-2'-substitués de biphényles 4,4-dibromométhyl-2'-substitués - Google Patents

Procédé destiné à séparer des biphényles 4-bromométhyl-2'-substitués de biphényles 4,4-dibromométhyl-2'-substitués Download PDF

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Publication number
WO2008078340A1
WO2008078340A1 PCT/IN2007/000613 IN2007000613W WO2008078340A1 WO 2008078340 A1 WO2008078340 A1 WO 2008078340A1 IN 2007000613 W IN2007000613 W IN 2007000613W WO 2008078340 A1 WO2008078340 A1 WO 2008078340A1
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WO
WIPO (PCT)
Prior art keywords
formula
stirring
substituted
bromomethyl
substituted biphenyls
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Application number
PCT/IN2007/000613
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English (en)
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WO2008078340B1 (fr
Inventor
Rohit Chaturvedi
Shrikrishna Vengurlekar
Yogesh Sonawane
Original Assignee
Calyx Chemicals And Pharmaceuticals Ltd.
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Publication date
Application filed by Calyx Chemicals And Pharmaceuticals Ltd. filed Critical Calyx Chemicals And Pharmaceuticals Ltd.
Publication of WO2008078340A1 publication Critical patent/WO2008078340A1/fr
Publication of WO2008078340B1 publication Critical patent/WO2008078340B1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C253/00—Preparation of carboxylic acid nitriles
    • C07C253/32—Separation; Purification; Stabilisation; Use of additives
    • C07C253/34—Separation; Purification

Definitions

  • the present invention relates to a novel process for the separation of 4-bromomethyl-2'- ⁇ siuihbstittiittiuittfteHd h biipnVhifiennvyilis n off F Fnorrmmiuillna T ITI
  • 4-Bromomethyl-2'-substitutedbiphenyls are known as useful intermediates for pharmaceutical products, such as a compound having an angiotensin II antagonist action.
  • the compound was first disclosed in EP0253310.
  • the bromomethyl biphenyls are prepared from the corresponding methyl biphenyls of Formula I by bromination reaction.
  • Patent applications JP 63-23868, EP 553879, and US 6177587 describe the bromination of o-tolylbenzonitrile (referred to herein below as OTBN) using brominating agents such as N-bromosuccinimide (referred to herein below as NBS), dibromodimethylhydantoin (DDH), N-bromophthalimide or bromine, in the presence of chemical initiator such as benzoyl peroxide, t-butyl peroxide, t-butyl perbenzoate or 2,2'-azobis(isobutyronitrile) (referred to herein below as AIBN) in solvents like C 5 -C 7 alkane, halogentated Ci -C 4 aliphatic hydrocarbons such as dicholoromethane or carbon tetrachloride, a C 1 -C 4 alkyl ester such as ethyl acetate, or a halogenated aromatic hydrocarbon such as chlorobenzene.
  • the present inventors have surprisingly found out a simple process for obtaining compound of Formula II, substantially free from compound of Formula III. Thus, increasing the yield and purity of the final product and reducing overall cost of production. Also, compound of formula II separated during the process can be further used to obtain OTBN or can be converted to aldehyde compound which is also a useful intermediate.
  • An object of the invention is to provide a process for the separation of 4-bromomethyl-2'- substituted biphenyls from 4,4,-dibromomethyl-2'-substituted biphenyls.
  • Another object of the invention is to provide an economical process to obtain 4- bromomethyl-2'-substituted biphenyls, substantially free from other impurities.
  • Yet another object of the invention is to provide a process for obtaining 4-bromomethyI- 2 '-substituted biphenyls in high purity.
  • R' is cyano, 1-H tetrazole or N-protected 1-H tetrazole.
  • the present invention particularly describes a process for the separation of 4- bromomethyl-2'-substitued biphenyl of Formula II from 4,4-dibromo-2'-substitued biphenyls of Formula HI in a crude reaction mixture obtained after brominating compounds of Formula I
  • R' is as specified above comprising: a) stirring the crude reaction mixture with an organic solvent at above 50°C; b) gradually cooling below 20°C and stirring; and c) filtering the crystals to obtain compound of Formula II with >97% purity.
  • 4-Bromomethylbiphenyl derivatives of Formula II substituted in the 2'position are very valuable as intermediate products in the production of pharmaceutically active substances, especially for the production of drugs, which are useful as angiotensin-II- antagonists.
  • R' is cyano , 1-H tetrazole or N-protected 1-H tetrazole
  • the present inventors have surprisingly found out a process for obtaining compound of Formula II substantially free from compound of Formula III.
  • the present invention particularly describes a process for the separation of 4- bromomethyl-2'-substitued biphenyl of Formula II from 4,4-dibromo-2'-substitued biphenyls of Formula III in a crude reaction mixture obtained after brominating compounds of Formula I
  • the bromination of compound of Formula I can be carried out by any of the methods reported in the prior art such as using N-bromoimides or DDH as brominating agent in a suitable solvent in the presence of a chemical initiator like benzoyl peroxide or AIBN or without the chemical initiator.
  • a chemical initiator like benzoyl peroxide or AIBN or without the chemical initiator.
  • the product was obtained as a cake with the composition as Compound of Formula II - 84%+ Compound of Formula III - 11% + Compound of Formula I - 5%
  • the crude reaction mixture containing a mixture of compounds of Formula II, compounds of Formula III and compounds of Formula I, obtained as a cake is further stirred with an organic solvent at a temperature of above 50° C.
  • Stirring temperature varies between 50° to 9O 0 C, preferably between 60 0 C to 90 0 C, more preferably between 60° to 70°C.
  • Stirring time varies from 10 to 90 minutes, preferably for 10 to 60 minutes, more preferably for 10 to 45 minutes.
  • the organic solvent is selected from esters and ethers; preferably esters, more preferably alkyl ester OfC 1 -C 4 carboxylic acid.
  • the solvent used is 1 to 5 times with respect to the crude reaction mixture, preferably 2 to 4 times.
  • the slurry obtained in step (a) is then cooled gradually to less than 20 0 C, preferably between 0 0 C to 15 0 C, more preferably between 0 0 C to 10 0 C and maintained the temperature with stirring. Stirring is continued for 1-3 hours, preferably for 1 hour.
  • Crystals thus obtained are collected by filtration and dried under vacuum to obtain compounds of the Formula II with HPLC purity >97%.
  • Purity of the compounds of Formula II can be further enhanced by repeating the above mentioned treatment.
  • Example- 1 The cake obtained in Example- 1 was transferred to a flask and slurried with 300 ml ethyl acetate. The reaction mixture was heated to 60° to 70° C. After stirring for 15 minutes, the mixture was gradually cooled to 3° to 5°C, maintained for 1 hour with stirring and filtered. Additional quantity of the product was obtained by concentrating the mother liquor, cooling it to O 0 C to 5°C and filtration.

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

Abstract

L'invention concerne un procédé destiné à séparer des biphényles 4-bromométhyl-2'-substitués de formule (II) de biphényles 4,4-dibromométhyl-2'-substitués de formule (III) et d'un biphényle 4-méthyl-2'-substitué de formule (I) par agitation d'un mélange de réaction brut comprenant les composés de formule (I), (II) et (III) dans des solvants organiques appropriés à une température supérieure à 50°C, et par refroidissement progressif du mélange de réaction jusqu'à une température inférieure à 20°C en vue de l'obtention de cristaux purs de formule (II) présentant une pureté supérieure à 97%.
PCT/IN2007/000613 2006-12-27 2007-12-27 Procédé destiné à séparer des biphényles 4-bromométhyl-2'-substitués de biphényles 4,4-dibromométhyl-2'-substitués WO2008078340A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN2151/MUM/2006 2006-12-27
IN2151MU2006 2006-12-27

Publications (2)

Publication Number Publication Date
WO2008078340A1 true WO2008078340A1 (fr) 2008-07-03
WO2008078340B1 WO2008078340B1 (fr) 2008-09-12

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PCT/IN2007/000613 WO2008078340A1 (fr) 2006-12-27 2007-12-27 Procédé destiné à séparer des biphényles 4-bromométhyl-2'-substitués de biphényles 4,4-dibromométhyl-2'-substitués

Country Status (1)

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WO (1) WO2008078340A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103626677A (zh) * 2013-12-05 2014-03-12 天津大学 制备高纯度溴代沙坦联苯的结晶方法

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5231094A (en) * 1992-02-24 1993-07-27 Societe Anonyme: Laboratoires Upsa Triazolopyrimidines which are angiotensin II receptor antagonists and pharmaceutical compositions in which they are present
EP0553879A2 (fr) * 1992-01-31 1993-08-04 Takeda Chemical Industries, Ltd. Procédé pour la préparation de composés 4-bromométhylbiphényl
WO1995017396A1 (fr) * 1993-12-23 1995-06-29 Merck & Co., Inc. Polymorphes de losartane et procede de preparation de la forme ii du losartane
EP0709369A1 (fr) * 1994-10-27 1996-05-01 SUMIKA FINE CHEMICALS Co., Ltd. Procédé pour la préparation de 4'-bromométhyl-2-cyanobiphényle
WO1998046562A1 (fr) * 1997-04-11 1998-10-22 Istituto Luso Farmaco D'italia S.P.A. Procede pour la preparation de composes de 4-bromomethyle diphenyle
DE19757995A1 (de) * 1997-12-29 1999-07-08 Great Lakes Chem Konstanz Gmbh Verfahren zur Herstellung von aromatischen Brommethyl-Verbindungen
US6214999B1 (en) * 1997-11-17 2001-04-10 Sanofi-Synthelabo Method for preparing bromomenthyl-biphenyl derivatives
US20020095042A1 (en) * 1999-04-15 2002-07-18 Heinrich Schneider Process for brominating the side chain of 4-methylbiphenyl derivatives substituted in the 2' position

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0553879A2 (fr) * 1992-01-31 1993-08-04 Takeda Chemical Industries, Ltd. Procédé pour la préparation de composés 4-bromométhylbiphényl
US5231094A (en) * 1992-02-24 1993-07-27 Societe Anonyme: Laboratoires Upsa Triazolopyrimidines which are angiotensin II receptor antagonists and pharmaceutical compositions in which they are present
WO1995017396A1 (fr) * 1993-12-23 1995-06-29 Merck & Co., Inc. Polymorphes de losartane et procede de preparation de la forme ii du losartane
EP0709369A1 (fr) * 1994-10-27 1996-05-01 SUMIKA FINE CHEMICALS Co., Ltd. Procédé pour la préparation de 4'-bromométhyl-2-cyanobiphényle
WO1998046562A1 (fr) * 1997-04-11 1998-10-22 Istituto Luso Farmaco D'italia S.P.A. Procede pour la preparation de composes de 4-bromomethyle diphenyle
US6214999B1 (en) * 1997-11-17 2001-04-10 Sanofi-Synthelabo Method for preparing bromomenthyl-biphenyl derivatives
DE19757995A1 (de) * 1997-12-29 1999-07-08 Great Lakes Chem Konstanz Gmbh Verfahren zur Herstellung von aromatischen Brommethyl-Verbindungen
US20020095042A1 (en) * 1999-04-15 2002-07-18 Heinrich Schneider Process for brominating the side chain of 4-methylbiphenyl derivatives substituted in the 2' position

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
ULRICH BEUTLER ET AL: "A High-Throughput Process for Valsartan", ORGANIC PROCESS RESEARCH AND DEVELOPMENT, vol. 11, 28 July 2007 (2007-07-28), pages 892 - 898, XP002479424 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103626677A (zh) * 2013-12-05 2014-03-12 天津大学 制备高纯度溴代沙坦联苯的结晶方法

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