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WO2000026169A1 - PROCEDE POUR LA PRODUCTION INDUSTRIELLE D'ACIDE 4'- CHLORO- α- METHYLEN- η-OXO- (1.1'-BIPHENYL)- 4'- BUTANOIQUE - Google Patents

PROCEDE POUR LA PRODUCTION INDUSTRIELLE D'ACIDE 4'- CHLORO- α- METHYLEN- η-OXO- (1.1'-BIPHENYL)- 4'- BUTANOIQUE Download PDF

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Publication number
WO2000026169A1
WO2000026169A1 PCT/EP1999/008010 EP9908010W WO0026169A1 WO 2000026169 A1 WO2000026169 A1 WO 2000026169A1 EP 9908010 W EP9908010 W EP 9908010W WO 0026169 A1 WO0026169 A1 WO 0026169A1
Authority
WO
WIPO (PCT)
Prior art keywords
acid
water
hydrolysis
salt solution
dilute
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/EP1999/008010
Other languages
German (de)
English (en)
Inventor
Thomas Schmidt
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.)
Bayer AG
Original Assignee
Bayer AG
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 Bayer AG filed Critical Bayer AG
Priority to AU11532/00A priority Critical patent/AU1153200A/en
Publication of WO2000026169A1 publication Critical patent/WO2000026169A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides

Definitions

  • the present invention relates to a new process for the pure preparation of the known 4'-chloro- ⁇ -methylene- ⁇ -oxo- (l .1 '-biphenyl) -4'-butanoic acid (biphenylacrylic acid), which serves as an intermediate for the synthesis of active pharmaceutical ingredients .
  • the mass can neither be pumped with technically customary pumps, nor can a liquid / liquid phase separation be carried out with it.
  • On a laboratory scale it is possible to stir the organic slurry with water to remove the aluminum salts and to decant the rinse water.
  • an analogous procedure cannot be implemented in normal technical systems.
  • the biphenylacrylic acid prepared by the literature process described above only has a content of 86.6% before recrystallization.
  • the additional cleaning step required in the technical process is associated with complex solids handling and solvent recovery as well as a loss of yield.
  • the addition of alcohol or acetone to the reaction mixture obtained to improve the filtration properties proposed in CA-1 152 103 represents an additional technical effort because of the need to recover a second solvent.
  • WO 96/15096 describes a process for the preparation of biphenylacrylic acid 1, in which the reaction of 4-chlorobiphenyl 1 with itaconic anhydride 2 in the presence of A1C1 3 in 1JJJ-tetrachloroethane is carried out and the reaction mixture obtained by adding a 10% HCl Solution with ice cooling, immediate extraction with chloroform, washing the organic phase with saturated sodium bicarbonate solution, acidifying with concentrated hydrochloric acid, extracting the aqueous phase with chloroform, washing with brine, drying over magnesium sulfate, stripping off the solvent in vacuo and recrystallizing the remaining residue from hexane / ethyl acetate is worked up (Example 30).
  • the work-up of the reaction mixture obtained is comparatively complex and has the same disadvantages as the process by Cousse et al. afflicted.
  • the organic suspension is separated from the water phase by liquid / liquid phase separation, and it is repeatedly separated with water and / or dilute acid and / or salt solution and then the crystalline biphenyl acrylic acid is separated from the methylene chloride by filtration, the filter cake is washed with methylene chloride and dried.
  • the method according to the invention has a number of advantages.
  • the aluminum salts obtained can be removed in a technically simple manner by liquid / liquid stirring and phase separation.
  • the desired one also falls Product in high purity as a crystalline solid immediately after stirring with water and / or dilute acid and / or salt solution, so that the steps of the removal of the solvent in vacuo and recrystallization which are necessary in the conventional processes but are problematic on an industrial scale as described above the residue thus obtained is eliminated.
  • the biphenylacrylic acid 1 obtained by the process according to the invention can be used as a starting material for pharmaceutical production without additional recrystallization.
  • the yield of biphenylacrylic acid 1 in the process according to the invention is 75 to 85%, which is significantly higher than in the conventional processes (52% in the process by Cousse et al., About 33% in the process described in WO 96/15096 ).
  • the starting materials 4-chlorobiphenyl 1 and itaconic anhydride 2 are well-known, commercially available chemicals and can be obtained, for example, from Sigma-Aldrich GmbH.
  • inert organic solvents and their mixtures are suitable as solvents and diluents for the reaction and workup.
  • solvents and diluents include halogenated aliphatic and aromatic hydrocarbons such as chlorobenzene, di- chlorobenzene, chloroform, 1 J-dichloroethane and particularly preferably methylene chloride.
  • the organic phase is freed from the aluminum salts by liquid / liquid washing.
  • Water and / or dilute aqueous acid such as, for example, dilute hydrochloric acid or dilute sulfuric acid or aqueous salt solutions such as e.g. Saline.
  • the workup according to the invention is normally carried out at temperatures between -5 ° and + 40 ° C, preferably at + 10 ° C to + 25 ° C.
  • the work-up according to the invention can be carried out under normal pressure, but also under increased or reduced pressure.
  • pressures between 0.01 and 10.0 bar, preferably between 0.01 and 6.0 bar, are used.
  • the concentration of the dilute hydrochloric acid or saline solution used for the laundry is between 0.01 and 3.0 percent by weight, preferably between 0J and 2.0 percent by weight.
  • the subsequent stirring time of the hydrolysis mixture is generally 1 to 10 hours, preferably 2.5 to 5 hours.
  • the stirring time for stirring the organic phase with water and / or dilute acid and / or salt solution is between 5 and 15 minutes.
  • wash the organic phase with water or dilute acid or salt solution can be done continuously or discontinuously.
  • the order of addition of both components is arbitrary, they can also be mixed synchronously.
  • water and hydrochloric acid are initially introduced for the hydrolysis and the reaction mixture obtained from the Friedel-Crafts reaction is metered in.
  • the biphenylacrylic acid prepared according to the invention can be used as an intermediate for the synthesis of pharmaceuticals, for example those from WO96 / 15096.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne un nouveau procédé pour la production d'acide biphénylacrylique pur de la formule (1). Ce procédé est caractérisé en ce que l'on obtient, par réaction de 4-chlorobiphényle avec de l'anhydride d'acide itaconique dans un solvant organique inerte ou un mélange de solvants organiques inertes, avec du chlorure d'aluminium comme catalyseur, et par hydrolyse subséquente avec de la glace/de l'acide chlorhydrique, un mélange que l'on soumet à une agitation à des températures entre 0 et 45 DEG C et pendant 1 à 10 heures. La suspension organique est séparée de la phase aqueuse par séparation de phases liquide/liquide. Ladite suspension organique est soumise à une agitation répétée avec de l'eau et/ou de l'acide dilué et/ou une solution saline. L'acide biphénylacrylique cristallin est séparé du chlorure de méthylène par filtration, le gâteau de filtration est lavé avec du chlorure de méthylène et est séché.
PCT/EP1999/008010 1998-11-04 1999-10-22 PROCEDE POUR LA PRODUCTION INDUSTRIELLE D'ACIDE 4'- CHLORO- α- METHYLEN- η-OXO- (1.1'-BIPHENYL)- 4'- BUTANOIQUE Ceased WO2000026169A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU11532/00A AU1153200A (en) 1998-11-04 1999-10-22 Method for the technological production of 4'- chloro- alpha- methylene- gamma- oxo-(1,1'- biphenyl)- 4'-butane acid

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE1998150695 DE19850695A1 (de) 1998-11-04 1998-11-04 Verfahren zur technischen Herstellung von 4'-Chlor-alpha-methylen-gamma-oxo-(1.1'-biphenyl)-4'-butansäure
DE19850695.3 1998-11-04

Publications (1)

Publication Number Publication Date
WO2000026169A1 true WO2000026169A1 (fr) 2000-05-11

Family

ID=7886574

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1999/008010 Ceased WO2000026169A1 (fr) 1998-11-04 1999-10-22 PROCEDE POUR LA PRODUCTION INDUSTRIELLE D'ACIDE 4'- CHLORO- α- METHYLEN- η-OXO- (1.1'-BIPHENYL)- 4'- BUTANOIQUE

Country Status (3)

Country Link
AU (1) AU1153200A (fr)
DE (1) DE19850695A1 (fr)
WO (1) WO2000026169A1 (fr)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2466450A1 (fr) * 1979-10-01 1981-04-10 Fabre Sa Pierre Procede industriel de purification et d'obtention d'itanoxone de qualite pharmaceutique
WO1996015096A1 (fr) * 1994-11-15 1996-05-23 Bayer Corporation Acides 4-biarylbutyrique ou 5-biarylpentanoique substitues et leurs derives en tant qu'inhibiteurs de metalloproteases matrices

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2466450A1 (fr) * 1979-10-01 1981-04-10 Fabre Sa Pierre Procede industriel de purification et d'obtention d'itanoxone de qualite pharmaceutique
WO1996015096A1 (fr) * 1994-11-15 1996-05-23 Bayer Corporation Acides 4-biarylbutyrique ou 5-biarylpentanoique substitues et leurs derives en tant qu'inhibiteurs de metalloproteases matrices

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
RIEU J P ET AL: "Secondary products of itanoxone", JOURNAL OF PHARMACEUTICAL SCIENCES, vol. 69, no. 1, January 1980 (1980-01-01), pages 49 - 53, XP002130272 *

Also Published As

Publication number Publication date
DE19850695A1 (de) 2000-05-11
AU1153200A (en) 2000-05-22

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