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WO1998006688A1 - Liaison par catalyse d'halogenures d'arylmagnesium et de composes d'acides bromo-arylcarboxyliques pour la fabrication d'acides biphenylcarboxyliques - Google Patents

Liaison par catalyse d'halogenures d'arylmagnesium et de composes d'acides bromo-arylcarboxyliques pour la fabrication d'acides biphenylcarboxyliques Download PDF

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Publication number
WO1998006688A1
WO1998006688A1 PCT/EP1997/004380 EP9704380W WO9806688A1 WO 1998006688 A1 WO1998006688 A1 WO 1998006688A1 EP 9704380 W EP9704380 W EP 9704380W WO 9806688 A1 WO9806688 A1 WO 9806688A1
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WO
WIPO (PCT)
Prior art keywords
carboxylic acid
compound
aryl
reaction
acid
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/EP1997/004380
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German (de)
English (en)
Inventor
Bernd Köhler
Manfred Langer
Thomas Mosandl
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.)
Great Lakes Chemical Konstanz GmbH
Original Assignee
Great Lakes Chemical Konstanz GmbH
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 Great Lakes Chemical Konstanz GmbH filed Critical Great Lakes Chemical Konstanz GmbH
Priority to AU44543/97A priority Critical patent/AU4454397A/en
Publication of WO1998006688A1 publication Critical patent/WO1998006688A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B37/00—Reactions without formation or introduction of functional groups containing hetero atoms, involving either the formation of a carbon-to-carbon bond between two carbon atoms not directly linked already or the disconnection of two directly linked carbon atoms
    • C07B37/04—Substitution
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups

Definitions

  • the invention relates to a process by which asymmetrically substituted biphenylcarboxylic acids can be obtained in high yields.
  • the invention relates to a method for producing liquid crystals and pharmaceutically active substances which contain a biphenyl skeleton.
  • Angiotensin II inhibitors in particular contain biphenyl as a structural component.
  • the use of asymmetrically substituted biphenyls as a starting or intermediate product is therefore appropriate, from which the target compound is finally completely synthesized.
  • a high selectivity with a high yield is particularly required for this.
  • the biphenyl derivatives functionalized with a carboxyl group are of particular importance.
  • asymmetrically substituted biphenyl or biaryl compounds are also particularly suitable as liquid-crystalline compounds or as a component of electro-optical components, particularly in the field of non-linear optics.
  • Classic methods for the construction of asymmetrically substituted biphenyls include, among others, the Gomberg-Bachmann (J. Org. Chem. 49 (1984) 1594) and the Ullmann reaction (Synthesis 1974. 9.). They are regularly characterized by poor yields and selectivities.
  • the introduction of synthetic methods using organometallic coupling reagents has significantly improved the availability of a number of biphenyl derivatives in recent years. However, this only applies to a limited extent to the production of biphenylcarboxylic acids.
  • the ortho-linked biphenylcarboxylic acids can, like the biphenyl derivatives with carboxyl functions in the meta and para positions which cannot be synthesized by means of the Meyers coupling above, by saponification of the corresponding biphenyl nitriles (EP-A-299789), - carboxamides (Angew. Chem. 61 ( 1949) 183), or carboxylic acid ester (US-A-4242121). According to the prior art, these in turn can be catalyzed by nickel or palladium-coupled coupling of a bromophenyl nitrile, amide or ester with a suitable boron (Tetrahedron Lett. 26 (1985) 5997), zinc (J. Organomet.
  • the invention has for its object to provide an easy to carry out process by which asymmetrically substituted biphenyl or biarylcarboxylic acids can be obtained in high selectivity with high yield.
  • a primary aim of the invention is, however, to enable an overall process by which compounds can be obtained which contain a biphenyl or biaryl structural component.
  • a highly selective, simple and, above all, economical synthesis of the asymmetrically substituted biphenylcarboxylic acids enables simple synthesis of such target compounds as, for example, some angiotensin II inhibitors.
  • bromobenzoic acids can be converted into magnesium salts of biphenylcarboxylic acids by treatment with more than one equivalent of an aryl-Grignard compound in a reaction catalyzed by a palladium complex. In the course of the working up, the desired free biphenylcarboxylic acids are liberated therefrom.
  • This reaction is to be understood in such a way that after generation of the halogen magnesium salt of bromobenzoic acid, this reacts with further Grignard reagent in the sense of a Heck or Suzuki coupling and the central C-C bond of the biphenyl skeleton is built up in the process.
  • salts of bromobenzoic acids prepared in another way also react in the sense of building up a biphenyl skeleton and thus forming the salt of a biphenylcarboxylic acid.
  • These salts can either be used as an isolated substance or else be prepared in situ and then subjected to the palladium-catalyzed coupling reaction. If the salt of a carboxylic acid is used as the coupling component, the synthesis can be brought to complete conversion with one equivalent of the Grignard compound.
  • the manufacturing process described here represents an unprecedentedly simple and economical access to biphenylcarboxylic acids.
  • the invention thus relates to a process for the preparation of biphenylcarboxylic acids, an aryl-Grignard compound of the general formula OAlkyl, F, Cl
  • M hydrogen, tetraalkylammonium, alkali or alkaline earth metal. (Tetraalkylammonium means that the nitrogen here carries C 1 to C, alkyl groups.) Further embodiments of the invention are specified in the claims. It has proven particularly useful to carry out the reaction with a Pd complex catalyst. It is also possible to carry out the catalyzed reaction with cocatalysis of a zinc salt.
  • reaction solutions can be worked up particularly easily after the reaction has ended in order to obtain the product.
  • the asymmetrically substituted biphenylcarboxylic acid obtained can easily be separated from the reaction mixture (precipitation / crystallization from the organic phase).
  • the product is obtained in high purity.
  • aryl-Grignard compound to be used according to the invention corresponds to the following general formula
  • alkyl here in principle encompasses any type of substituted or unsubstituted alkyl or cycloalkyl radicals having 1 or 3 to 20 carbon atoms. As investigations by the applicant have now shown, linear or branched alkyl substituents with a higher number of carbon atoms are entirely feasible, although an upper limit is probably around 25 to 30 carbon atoms.
  • Tetraalkylammonium means an ammonium group which is substituted by 4 C 1 - C g alkyl groups.
  • the broraarylcarboxylic acid compound can also carry further substituents which correspond to the definitions given above. Here too, reasonable limits are set at most by an undesirable reactivity or steric hindrance of the additional substituents. All functionalities that are compatible with a Grignard functionality can be selected as the third substituent in the bromoarylcarboxylic acid compound.
  • the invention also relates to a process for the preparation of compounds which contain a biphenyl skeleton.
  • processes are based on asymmetrically substituted biphenylcarboxylic acids which are obtained by the process explained above.
  • All Pd complexes (such as, for example, Pd (PPh 3 ) 4 ) which are known to be catalytically active in the reaction on which this invention is based (often called Suzuki or Heck coupling) are suitable as catalysts.
  • the catalytically active Pd ° species can also be prepared in situ from palladiu (II) compounds.
  • the catalytically active species is generated in situ by using a mixture of PdCl 2 and triphenylphosphine (in a molar ratio of 1: 2) under the influence of the Grignard compound.
  • the palladium compound used as a catalyst can be in a molar concentration of 0.01 to 20% (based on the bromoarylcarboxylic acid compound) can be used expediently. Larger amounts of catalyst used do not adversely affect the course of the reaction, but are not meaningful in the sense of an economical synthesis.
  • the amount of catalyst used is preferably on the order of one to a few mol%.
  • the course of the reaction is favorably influenced by the use of a zinc salt as a cocatalyst in terms of reproducibility, product quality and yield.
  • the zinc compound used as cocatalyst can be used in a molar concentration of 0.01 to 20% (based on the bromoarylcarboxylic acid compound). Larger amounts of cocatalyst do not adversely affect the course of the reaction, but are not sensible in the sense of an economical synthesis and with regard to the disposal of the synthesis residues.
  • the amount of cocatalyst used is preferably of the order of one to a few mol%.
  • the use of zinc chloride as a cocatalyst has proven particularly useful.
  • Solvents which are inert to aryl Grignard compounds, such as tetrahydrofuran, other cyclic ethers, acyclic ethers or acetals, are suitable as the reaction medium.
  • the reaction is preferably carried out in tetrahydrofuran or 2-methyltetrahydrofuran.
  • the reaction temperature can be selected in the range from 10 ° C to 100 ° C.
  • the reactions are preferably carried out in the temperature range between 20 ° and 80 ° C.

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

Abstract

Procédé de fabrication d'acides biphénylcarboxyliques par réaction catalytique d'un composé aryl de Grignard avec un composé d'acide bromo-arylcarboxylique.
PCT/EP1997/004380 1996-08-13 1997-08-12 Liaison par catalyse d'halogenures d'arylmagnesium et de composes d'acides bromo-arylcarboxyliques pour la fabrication d'acides biphenylcarboxyliques Ceased WO1998006688A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU44543/97A AU4454397A (en) 1996-08-13 1997-08-12 Catalysed coupling of aryl magnesium halogenides and bromaryl carboxylic acid compounds for preparing biphenyl carboxylic acids

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19632643.5 1996-08-13
DE1996132643 DE19632643C1 (de) 1996-08-13 1996-08-13 Katalysierte Kopplung von Arylmagnesiumhalogeniden und Bromarylcarbonsäureverbindungen zur Herstellung von Biphenylcarbonsäuren

Publications (1)

Publication Number Publication Date
WO1998006688A1 true WO1998006688A1 (fr) 1998-02-19

Family

ID=7802545

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1997/004380 Ceased WO1998006688A1 (fr) 1996-08-13 1997-08-12 Liaison par catalyse d'halogenures d'arylmagnesium et de composes d'acides bromo-arylcarboxyliques pour la fabrication d'acides biphenylcarboxyliques

Country Status (3)

Country Link
AU (1) AU4454397A (fr)
DE (1) DE19632643C1 (fr)
WO (1) WO1998006688A1 (fr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE19908504C2 (de) * 1999-02-26 2003-04-30 Boehringer Ingelheim Pharma Großtechnisches Verfahren zur Herstellung von Derivaten der Biphenyl-2-carbonsäure durch Verseifen eines (2-Oxazolinyl)-2-biphenyl-Derivats mit Salzsäure

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1990004577A1 (fr) * 1988-10-25 1990-05-03 Eastman Kodak Company Preparation de composes biaryle

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1990004577A1 (fr) * 1988-10-25 1990-05-03 Eastman Kodak Company Preparation de composes biaryle

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
TETSUTARO HATTORI ET AL.: "CONVENIENT SYNTHESIS OF BIPHENYL-2-CARBOXYLIC ACIDS VIA THE NUCLEOPHILIC AROMATIC SUBSTITUTION REACTION OF 2-METHOXYBENZOATES BY ARYL GRIGNARD REAGENTS", BULLETIN OF THE CHEMICAL SOCIETY OF JAPAN, vol. 66, no. 10, 1993, pages 3034 - 3040, XP002050908 *

Also Published As

Publication number Publication date
AU4454397A (en) 1998-03-06
DE19632643C1 (de) 1998-01-22

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