GB2087886A - Preparing biphenyl compounds by coupling - Google Patents

Preparing biphenyl compounds by coupling Download PDF

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Publication number
GB2087886A
GB2087886A GB8134869A GB8134869A GB2087886A GB 2087886 A GB2087886 A GB 2087886A GB 8134869 A GB8134869 A GB 8134869A GB 8134869 A GB8134869 A GB 8134869A GB 2087886 A GB2087886 A GB 2087886A
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process according
alkyl
benzene
compound
hydrogen
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GB2087886B (en
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Pharmacia and Upjohn Co
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Upjohn Co
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C17/00Preparation of halogenated hydrocarbons
    • C07C17/26Preparation of halogenated hydrocarbons by reactions involving an increase in the number of carbon atoms in the skeleton
    • C07C17/263Preparation of halogenated hydrocarbons by reactions involving an increase in the number of carbon atoms in the skeleton by condensation reactions

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

Abstract

Biphenyl compounds are prepared by coupling an aniline and a benzene in the presence of a C1-6 alkyl nitrite, preferably in the additional presence of copper. The process can be used to prepare 2-fluoro- 4-halobiphenyls which are useful in the preparation of the anti-inflammatory agent flurbiprofen.

Description

1
GB2087 886A 1
SPECIFICATION
Preparing biphenyl compounds by coupling
5 British Patent Application No. 8040295 (Serial No. 2065656) describes and claims a method for converting aromatic, including biphenyl, compounds to 2-arylpropionic acids. Such acids, and in particular 2-(2-fluoro-4-10 biphenylyl)propionic acid which is also known as flurbiprofen, have valuable therapeutic properties.
It is known to form diaryl compounds by the Gomberg or Gomberg-Bachmann reaction 1 5 discussed by March, Advanced Organic Chemistry (McGraw-Hill, 1968) 550-551. However, March noted that "yields are not high (usually under 40%) because of the many side-reations undergone by diazonium 20 salts" which are described as intermediates therein. Cadogan, J. Chem. Soc. (1962) 4257, discloses the use of pentyl nitrite as a diazotising agent, with increasing yields of the named biaryls. More recent references, such 25 as British Patent Specification No.
1,091,403; C.A. 64 (1 966) 5005e; and U.S. Patent Specification No. 3,992,459 disclose various coupling reactions, based on the Gomberg or Gomberg-Bachmann reaction. 30 According to the present invention, a process for preparing a biphenyl compound of the formula
„ 45 wherein R, and R2 are independently selected from hydrogen, halogen, C,^ alkoxy, (C,_4 alkoxy)carbonyl, nitro, C^,, alkyl, C4_7 cyclo-alkyl, phenyl, cyano and (T'OOC)xC(T)3_x wherein x is one or two, T is hydrogen or 50 C, _4 alkyl, the T's being the same or different when x is one, and either each T' is C,_4 alkyl or (COOT')2 forms a cyclic diester; and R3 and R4 are independently selected from hydrogen, hydroxyl, halogen, nitro, Ct_4 alkyl, C,_4 al-55 koxy, (C,^6 alkoxy)carbonyl, aryloxycarbonyl, phenyl, cyano and C4_7 cycloalkyl, which comprises simultaneously adding aC^j alkyl nitrite and an aniline compound of the formula
75 wherein R, and R2 are as defined above, to an excess of a benzene compound of the formula wherein R3 and R4 are as defined above.
85 Preferably, the products of the present invention have the formula
95 in which R1# R2, R3 and R4 are independently selected from hydrogen, chlorine, bromine and fluorine but are not all hydrogen.
The invention is of particular utility in preparing 4-bromo-2-fluorobiphenyl and 2,4-difl-100 uorobiphenyl for which the reactants are benzene and, respectively, 4-bromo-2-fluoroanil-ine and 2,4-difluoroaniline. The products can be used as starting materials for the preparation of flurbiprofen by the process of British 105 Patent Application No. 8040295 (Serial No. 2065656). 4-Bromo-2-fluoroaniline can be prepared by reacting 2-fluoroaniline with a brominating agent in a solvent comprising dimethylformamide or dimethylacetamide, by 110 the process described and claimed in British Patent Application No. 8040291 (Serial No. 2065654). If desired, however, such starting materials may also be prepared by a corresponding reaction in which the solvent is 115 formamide, N-methylformamide, dioxane, di-glyme in ethylene chloride or benzene. The use of benzene has the advantage that the reaction mixture may be used in the coupling reaction of this invention without further puri-120 fication.
The process of this invention may also be used to prepare other precursors of 2-arylpro-pionic acids, e.g. 2-(2-fluoro-4-biphenylyl)-2-methylmalonic acid alkyl esters, including cy-125 clic alkyl esters thereof. Cyclic diesters are 2, 2-di(C! _4 alkyl)-1,3-dioxane-4,6-diones; 2, 2-dimethyl-1,3-dioxane-4,6-dione is preferred.
The alkyl group in the alkyl nitrite may be methyl, ethyl, propyl, butyl, pentyl or hexyl, 1 30 or an isomer thereof. The preferred alkyl m-
2
GB2 087 886A
2
trite is isoamyl nitrite. The process may be conducted by reacting a solution of the aniline compound in excess benzene with the alkyl nitrite, e.g. isoamyl nitrite, in the presence of 5 the benzene compound. The reaction may be conducted at 20 to SOX over a period of 5 to 20 hours. Preferably, isoamyl nitrate and a solution of the aniline compound in benzene are each added dropwise separately but sub-1 0 stantially simultaneously over a period of about 20 hours to an excess amount of the benzene compound while maintaining the temperature at from 25°C to the boiling point of the solvent, preferably about 65°C. 1 5 The reaction may be modified by conducting it in the presence of copper, e.g. in the form of copper powder or a copper salt. If copper powder is chosen, reaction conditions are used which ensure a timely preparation of 20 copper salt in situ.
The biphenyl product is isolated by cooling the reaction mixture, washing, evaporating, distilling or other conventional procedures. A particularly simple and preferred work-up is 25 evaporation and extraction with hexane and washing with 85% sulfuric acid. Crude product is obtained and further purification may not be necessary for the use of the product in making the arylmagnesium bromides to be 30 reacted in the process of British Patent Application No. 8040295 (Serial No. 2065656). However, nitro compounds may be by-prod-ucts in this reaction, so it is advantageous to reduce the reaction mixture by adding iron/ 35 acetic acid mixtures or sodium dithionite, which converts these by-products to amines, such that these can be removed from the product simply by washing with acid. Conditions for the reduction of nitro compounds are 40 similar to those outlined by Faudler et a!.. Organic Functional Group Preparations, Vol. 1, (Academic Press, New York, 1968) 339.
Without wishing to be tied to any theory, it Is believed that the good results which can be 45 achieved by the process of the invention,
relative to conventional Gomberg-Bachman reactions, are the result of the restriction of the "ormation of intermediate diazonium salts and resultant side-reactions. This theory is sup-50 ported by the discovery that the processes of this invention provide an additional advantage in that no precautions are required to avoid explosive decompositions of diazonium salts while preparing and handling large amounts 55 of reaction mixtures.
The following Examples illustrate the invention. The starting material 4-bromo-2-fluoroan-iline can be prepared by the Example of British Patent Application No. 8040291 (Ser-60 .at No. 2065654).
Example 1 4-Bromo-2-fluorobiphenyl
Solutions of 375 ml (325 g, 2.8 moles) of .soamyl nitrite, and of 378 grams (2.0 moles) 65 of crude 4-bromo-2-fluoroaniline in 250 ml benzene are added separately and simultaneously dropwise over about 20 hours to 3500 ml of benzene vigorously stirred under a nitrogen atmosphere, and kept in a water bath at 70 65°C. The mixture is kept overnight at 65°C, and then cooled, washed twice with 250 ml of water and evaporated. The dark oily residue is dissolved in 750 ml methanol and 450 ml concentrated hydrochloric acid, and treated 75 with 138 grams (2.1 moles) of granular zinc, added in small portions over about 6 hours. In order to complete this "reductive upgrading", the solution is treated with 54 grams (1.0 mole) of fine iron filings over 0.5 hours. 80 Within one hour, the colour the mixture is visibly lighter. The solution is diluted with one litre of water and one litre of Skellysolve B (mixed isomeric hexanes), and the liquids are decanted from the remaining metals. The 85 aqueous phase is extracted twice with one litre of Skellysolve B and then one litre of water, one litre of 1N NaOH, and one litre of water. The solution is then passed through anhydrous sodium sulfate and evaporated to 90 provide 389 grams of 4-bromo-2-fluorobiphe-nyl.
This is distilled under vacuum to obtain a fraction of 282 grams (56%) of 2-fluoro-4-bromobiphenyl, b.p. 1 37-155°C./1 1 mm 95 Hg, which crystallises on standing.
Examples 2 and 3
Example 1 is repeated using 50 mmole of 4-bromo-2-fluoroaniline and 79 mmole of iso-100 amyl nitrite, and 76 mmole of trichloroacetic acid and 15 mmole Cu powder are added. The period of addition is 45 minutes and the temperature is 3-1 S°C. In Example 2, 83 mmole of anhydrous MgS04 are added and 105 the yield is 87%. In Example 4, without MgS04, the yield is 88%.
Example 4 4-Bromo-2-fluorobiphenyl
A slurry containing 1.0 grams (15 milli-110 moles) copper powder, 12.5 grams (76.5 millimoles) trichloroacetic acid and 125 millil-itres benzene is stirred at 23-26°C under a nitrogen blanket for 4^ hours. The slurry is cooled to 6°C and 10.5 millilitres (78.5 milli-115 moles) isoamyl nitrate are added. After waiting 90 seconds, a solution containing 9.5 grams (50 millimoles) 4-bromo-2-fluoroanili-ne in 50 millilitres benzene is added dropwise over 30 minutes to the slurry, keeping the 120 temperature of the slurry pot between 8 and 1 7°C. When the addition is complete, the green slurry is allowed to warm to 25°C and is stirred at 23-25°C overnight.
Analysis by gas liquid chromatography 125 shows a chemical yield of 88%.

Claims (1)

1. A process for preparing a biphenyl compound of the formula
3
GB2 087 886A
3
wherein R-, and R2 are independently selected *15 from hydrogen, halogen, alkoxy, (C,_4 alkoxy)carbonyl, nitro, alkyl, C4_7 cycloal-kyl, phenyl, cyano and (T'OOC)xC(T)3_:,
wherein x is one or two, T is hydrogen or C,_4 alkyl, the T's being the same or different 20 when x is one, and either each T' is C,_4 alkyl or (COOT')2 forms a cyclic diester, and R3 and R4 are independently selected from hydrogen, hydroxyl, halogen, nitro, C.,_4 alkyl, C,_4 alkoxy, (C, _ 6 alkoxy)carbonyl, aryloxycarbonyl 25 phenyl, cyano and C4_7 cycloalkyl, which comprises simultaneously adding a alkyl nitrite and an aniline compound of the formula wherein R, and R2 are as defined above, to an excess of a benzene compound of the formula wherein R3 and R4 are as defined above.
2. A process according to claim 1 wherein the biphenyl compound has the formula
50
55 \
R 3 Rz
4. A process according to claim 3 wherein the 4-bromo-2-fluoroaniline has been prepared by reacting 2-fluoroaniline with a brominating agent in a solvent comprising dimethylfor-
70 mamide or dimethylacetamide.
5. A process according to claim 1 for preparing 2,4-difluorobiphenyl, in which the aniline compound is 2,4-difluoroaniline and the benzene compound is benzene.
75 6. A process according to any preceding claim wherein the nitrite is isoamyl nitrite.
7. A process according to any preceding claim which is conducted at from 20 to 80°C.
8. A process according to any preceding
80 claim which is conducted in the absence of water.
9. A process according to any preceding claim which is conducted in the presence of copper.
85 10. A process according to claim 1 substantially as described in any of the Examples.
Printed for Her Majesty's Stationery Office by Burgess & Son (Abingdon) Ltd.—1982.
Published at The Patent Office, 25 Southampton Buildings,
London, WC2A 1AY, from which copies may be obtained.
p~
in which R,, R2, R3 and R4 are independently 60 selected from hydrogen, chlorine, bromine and fluorine, but is not biphenyl itself.
3. A process according to claim 1 for preparing 4-bromo-2-fluorobiphenyl, in which the aniline compound is 4-bromo-2-fluoroanil-65 ine and the benzene compound is benzene.
GB8134869A 1979-12-19 1980-12-16 Preparing biphenyl compounds by coupling Expired GB2087886B (en)

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JP (1) JPS5697236A (en)
DE (1) DE3046512A1 (en)
FR (1) FR2471962A1 (en)
GB (2) GB2065655B (en)
IT (1) IT8050411A0 (en)
NL (1) NL8006497A (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101704723B (en) * 2009-11-02 2013-04-24 上海万溯化学有限公司 Preparation method of hydroxymethyl substitutent o-alkyl biphenyl and intermediate thereof

Families Citing this family (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NL8006496A (en) * 1979-12-19 1981-07-16 Upjohn Co PROCESS FOR PREPARING ARYL-PROPIONIC ACIDS.
DE3216851A1 (en) * 1981-05-18 1982-12-02 The Upjohn Co., 49001 Kalamazoo, Mich. METHOD FOR PRODUCING SUBSTITUTED BIPHENYL COMPOUNDS
IT1210910B (en) * 1982-07-23 1989-09-29 Blaschim Spa IMPROVEMENT OF THE PROCEDURE TO PREPARE BIARYL COMPOUNDS BY COPULATION OF AN ARILAMINE WITH AN ARENE.
US4482502A (en) * 1983-04-25 1984-11-13 Ethyl Corporation Preparation of biaryl compounds
US4539397A (en) * 1983-04-25 1985-09-03 Ethyl Corporation (Alkoxydiazo)halobenzeneacetonitriles
US4544509A (en) * 1983-08-15 1985-10-01 Ethyl Corporation Aryl coupling process
FR2811664B1 (en) * 2000-07-17 2002-09-13 Rhodia Chimie Sa PROCESS FOR THE PREPARATION OF A POLYAROMATIC COMPOUND
CN103936551B (en) * 2013-01-21 2015-10-28 北京交通大学 A kind of method preparing 3-bromo biphenyl
CN113620774A (en) * 2021-08-17 2021-11-09 上海应用技术大学 Method for synthesizing biphenyl compounds by adopting microchannel reactor
CN116003216B (en) * 2023-01-17 2024-08-06 沈阳药科大学 Preparation method of ibuprofen

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101704723B (en) * 2009-11-02 2013-04-24 上海万溯化学有限公司 Preparation method of hydroxymethyl substitutent o-alkyl biphenyl and intermediate thereof

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GB2065655A (en) 1981-07-01
GB2065655B (en) 1983-07-06
GB2087886B (en) 1983-06-08
NL8006497A (en) 1981-07-16
JPS5697236A (en) 1981-08-05
IT8050411A0 (en) 1980-12-18
FR2471962A1 (en) 1981-06-26
DE3046512A1 (en) 1981-08-27

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