GB2065655A

GB2065655A - Preparing biphenyl compounds by coupling

Info

Publication number: GB2065655A
Application number: GB8040293A
Authority: GB
Original assignee: Upjohn Co
Current assignee: Pharmacia and Upjohn Co
Priority date: 1979-12-19
Filing date: 1980-12-16
Publication date: 1981-07-01
Also published as: NL8006497A; JPS5697236A; FR2471962A1; IT8050411A0; GB2065655B; DE3046512A1; GB2087886A; GB2087886B

Abstract

Biphenyl compounds are prepared by coupling an aniline and a benzene in the presence of a metal or 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

SPECIFICATION Preparing biphenyl compounds by coupling In our Patent Application No. 80/40295 filed on even date herewith (Agents Reference GJE 6180/198) claiming priority from U. S. Patent Application No. 105,061, we have described and claimed a method for converting aromatic, including biphenyl, compounds to 2-arylpropionic acids. Such acids, and in particular 2-(2-fluoro-4-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 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-reactions undergone by diazonium 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 as Dutch Patent Application No.6,500,865; C. A. 64 (1966) 5005e; and U. S. Patent Specification No.3,992,459 disclose various coupling reactions, based on the Gomberg or Gomberg-Bachmann reaction.

According to the present invention, a process for preparing a biphenyl compound comprises coupling an aniline compound and a benzene compound. In a first aspect, the reaction is conducted in the presence of a metal nitrite. In a second aspect, the reaction is conducted in the presence of an alkyl nitrite at 20 to 80"C over a period of 5 to 20 hours, and/or the aniline or the alkyl nitrite are separately and simultaneously added to the benzene.

The invention can be used to prepare biphenyl compounds of the formula

wherein R1 and R2 are independently selected from hydrogen, halogen, C1 6 alkoxy, (C1-4 alkoxy) carbonyl, nitro, C14 alkyl, C47 cycloalkyl, phenyl, cyano and (T'OOC)XC(T)3~x wherein xis 1 or 2, each T is hydrogen or C1-4 alkyl and each T' is C14 alkyl or (COOT')2 forms a cyclic diester; and R3 and R4 are independently selected from hydrogen, hydroxy, halogen, nitro, C14 alkyl, C1~4 alkoxy, (C1~6 alkoxy)carbonyl, aryloxycarbonyl, phenyl, cyano and C47 cycloalkyl.In preparing such compounds, the aniline compound may carry the R1 and R2 substituents and the benzene compound may carry the R3 and R4 substituents.

Preferably, the products of the present invention have the formula

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-difluorobiphenyl for which the reactants are benzene and, respectively, 4-bromo-2-fluoroaniline and 2,4-difluoroaniline. The products can be used as starting materials for the preparation of flurbiprofen by the process of copending Application No. 80/40295 (GJE 6180/198). 4-bromo-2-fluoroaniline can be prepared by reacting 2fluoroaniline with a brominating agent in a solvent comprising dimethylformamide or dimethylacetamide by the process described and claimed in copending Application No.80/40291 (Agents Reference GJE 6180/189) based on U. S.Patent Application No. 105,064. If desired, however, such starting materials may also be prepared by a corresponding reaction in which the solvent is formamide, N-methylformamide, dioxane, diglyme 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 purification.

The process of this invention may also be used to prepare other precursors of 2-arylpropionic acids, e.g.

2-(2-fluoro-4-biphenylyl)-2-methylmalonic acid alkyl esters, including cyclic alkyl esters thereof. Cyclic diesters are 2,2-di(C1 -4 a lkyl)-1 ,3-dioxane-4,6-diones 2,2-dimethyl-1 ,3-dioxane-4,6-dione is preferred.

The process of the invention is preferably conducted by adding, substantially simultaneously, the aniline compound and an acid to a mixture of a metal nitrite, e.g. sodium or potassium nitrite, and the benzene compound. For example, the process may be conducted by adding a benzene solution of the aniline compound simultaneously with an acid to a non-aqueous mixture of excess benzene compound and solid metal nitrite. Alternatively, a benzene solution of the aniline compound may be added simultaneously with an acid to a mixture of excess benzene compound and an aqueous solution of the metal nitrite. The ratio of the aniline to the benzene compound may be from 5:10 to 1:10. The acid may be a mineral acid such as sulfuric acid or an organic acid such as benzoic, chloroacetic, dichloroacetic, trichloracetic, methanesulfonic or acetic acid.The temperature of the reaction mixture is maintained between 25"C and boiling temperature of the mixture. Temperatures in the higher end of the range are preferred. Molar amounts of acid and sodium or potassium nitrite to that of the aniline compound are preferably each from 1:1 to 4:1; e.g. 2.5:1. In an especially preferred embodiment, the aniline compound and acetic acid are added dropwise to a mixture of the aqueous or non-aqueous metal nitrite in the benzene compound. Stirring from 2 to 18 hours after the addition is completed at the preferred temperatures of the reaction is advantageous. 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 evaporation and extraction with hexane and washing with 85% sulfuric acid. Crude product is obtained and further purification may not be necessaryforthe use of the product in making the arylmagnesium bromides to be reacted in the process of copending Application 80/40295 (GJE 6180/198. However, nitro compounds may be by-products in this reaction, so it is advantageous to reduce the reaction mixture by adding iron/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 similar to those outlined by Faudler et al., Organic Functional Group Preparations, Vol. 1, (Academic Press, New York, 1968)339.

If the coupling reaction is carried out in non-aqueous conditions with a solid metal nitrite, it is also advantageous to add an absorbent for water, such as anhydrous magnesium sulfate, silica gel or Celite (registered Trade Mark). Furthermore, the use of potassium nitrite rather than sodium nitrite in this reaction gives a higher yield and is therefore among the preferred conditions for the anhydrous coupling reaction.

In addition to the above-named acids for use in this reaction, it is found that in the two-phase aqueous reaction mixture, hydrofluoric and fluoboric acids are effective. However, fluorboric acid (HBF4) gives a particularly high and unexpected yield. If sulfuric acid is used, a 10% solution is preferred.

In preparing the especially preferred compound 4-bromo-2-fluorobiphenyl, the temperature of the coupling reaction is preferably 25 to 80"C and most preferably 60"C.

The alternative coupling reaction employs an alkyl nitrite, e.g. a C16 alkyl nitrite, and is conducted in the absence of water. In this reaction, a solution of the aniline compound in excess benzene is reacted with an alkyl nitrite such as isoamyl nitrite in the presence of the benzene compound at 20 to 800C over a period of 5 to 20 hours.Preferably, in this embodiment of the invention, isoamyl nitrite and a solution of the aniline compound in benzene are each added dropwise separately but substantially 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. The product may be treated with a reducing agent and isolated in a manner analogous to that described above for the coupling reaction using metal nitrite.

Each of the coupling reactions may be modified by conducting the reaction in the presence of copper. For example, it is especially preferred to use copper in a non-aqueous medium with sodium or potassium nitrite.

The copper may be in the form of a copper powder or a copper salt. However, if a copper powder is chosen, reaction conditions are used which ensure a timely preparation of copper salt in situ.

Without wishing to be tied to any theory, it is believed that the good results which can be achieved by the process of the invention, relative to conventional Gomberg-Bachmann reactions, are the result of the restriction of the formation of intermediate diazonium salts and resultant side-reactions. This theory is supported 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 of reaction mixtures.

The following Examples illustrate the invention. The starting material 4-bromo-24luoroaniline can be prepared by the Example of Application No.80/40291. (GJE 6180/189).

Example 1 4-bromo-2-fluorobiphenyl A solution of 96 grams (0.50 mole) of crude 4-bromo-2-fluoroaniline and 60.0 grams (1.0 mole) of glacial acetic acid in 100 ml of benzene is added dropwise over 7 hours to a mixture of 69.0 grams (1.0 mole) of sodium nitrite, 69 ml water, and 700 ml of benzene kept at 65"C. The mixture is then allowed to stir at 65"C.

overnight (12 hours) under a nitrogen atmosphere. The cooled mixture is washed twice with 400 ml of 1N hydrochloric acid, then heated under reflux overnight (13 hours) with 20 grams (0.36 mole) of iron powder, 250 ml of methanol, and 150 ml (1.8 moles) of concentrated hydrochloric acid. The resultant solution is cooled and the benzene layer is washed with 490 ml of water, and evaporated at 40 C/40 mm Hg. The resultant dark oil is distilled at 10 mm Hg pressure to obtain 64.6 grams (51.5%) of 4-bromo-2-fluorobiphenyl 3s the entire distillate, boiling point mostly 132 --141" c./8 mm. The product crystallizes on seeding.

Examples2to 10 Example 1 is repeated using 50 mmole of 4-bromo-2-fluoroaniline, but otherwise under various conditions to give various yields of 4-bromo-2-fluorobiphenyl, as shown in the following Table. In each of Examples 6 and 7,72 mmole of anhydrous MgSO4 are added. In Example 10, 15 mmole Cu powder and 83 mmole of anhydrous MgSO4 are added.

NaN020 H20 Acid Temp. Addn. Yield Time Example /NO,O (mmole) (ml) (mmole) ( C) (hrs.) (%) 2 1250 6.9 105 (acetic) 60 3 55 3 1250 6.9 105 (benzoic) 60 2 52 4 1250 6.9 100(dichloro- 60 3 53 acetic) 5 125 None 105 (acetic) 60 3.5 53 6 125 6.9 100 (methane- 60 2 53 sulphonic) 7 1250 None 100 (acetic) 60 3 59 8 1250 6.9 100 (BFlH) 60 2 61 9 100 6.9 40 (10%H2SO4) 70 2.5 55 10 79 None 152 (trichloro- 5to13 1/2 82 acetic) Example 11 4-Bromo-2-chlorobiphenyl To a solution of 304 g (4.41 moles) of sodium nitrite and 244 ml of water in 2.5 litres of benzene, under a nitrogen atmosphere and in a water bath at 62"C is added dropwise over 8 hours a solution of 365 g (1.77 moles) of 4-bromo-2-chloroaniline and 212 ml (3.71 moles) of gl acetic acid in 212 ml benzene. The dark mixture is stirred overnight. The lower aqueous layer is removed and benzene is distilled at atmospheric pressure. The residue is mixed with 600 ml methanol and 81.4 g of iron power, then 1.093 litres of concentrated hydrochloric acid is slowly added. The mixture is refluxed for 5.5 hours, then diiuted with 1.4 1 of hexane and 1.41 of water and allowed to cool. The resultant slurry is filtered through Celite, which is rinsed well with hexane.The hexane phase is washed with water, dried over anhydrous magnesium sulfate, stirred with 40 g of Pittsburgh activated carbon, filtered again, and concentrated to constant weight (355 g). The Celite cake is extracted with acetone and treated separately.

The crude evaporated acetone extract is stirred with a mixture of 200 ml methylene chloride, 200 ml 85% sulfuric acid, and 300 ml hexane. The organic phase is washed with 3 x 200 ml of 85% sulfuric acid, each washing is back-extracted with the same 200 ml portion of hexane. The organic phases are finally washed with water and concentrated to obtain 28 g of oil containing a substantial amount of the product.

This is combined with the above 355 g crude product and chromatographed on 3 kg of silica gel with hexane. Fractions containing the product are collected, combined, and evaporated to constant weight to obtain a total of 292.9 g (62%) of 4-bromo-2-chlorobiphenyl as a colorless oil. Gc-ms (gas chromatographymass spectrometry) confirmed the structure: the mass spectrum consists of a typical BrCI (bromochloride) triad at 266 (M+), 268 (base peak) and 270.

Example 12 4-Bromo-2-fluorobiphenyl Solutions of 375 ml (325 g, 2.8 moles) of isoamyl nitrite and of 378 grams (2.0 moles) 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 65"C. The mixture is kept over-night at 650C., 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 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. 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 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 provide 389 grams of 4-bromo-2-fluorobiphenyl.

This is distilled under vacuum to obtain a fraction of 282 grams (56%) of 24luoro-4-bromobiphenyl, b.p.

137-155 C./11 mm Hg, which crystallizes on standing.

Examples 13 and 14 Example 12 is repeated using 50 mmole of 4-bromo-2-fluoroaniline and 79 mmole of isoamyl nitrite, and 76 mmole of trichloroacetic acid and 15 mmole Cu powder were added. The period of addition was 45 minutes and the temperature was 3-1 80C. In Example 1383 mmole of anhydrous MgSO4 were added and the yield was 87%. In Example 14, without MgSO4, the yield was 88%.

Example 15 4-Bromo-2-fluorobiphenyl A slurry containing 1.0 grams (15 millimoles) copper powder, 12.5 grams (76.5 millimoles) trichloroacetic acid and 125 millilitres benzene is stirred at 23-26"C under a nitrogen blanket for 421 hours. The slurry is cooled to 60C and 10.5 millilitres (78.5 millimoles) isoamyl nitrite are added. After waiting 90 seconds, a solution containing 9.5 grams (50 miliimoles) 4-bromo-2-fluoroaniline in 50 millilitres benzene is added dropwise over 30 minutes to the slurry, keeping the temperature of the slurry pot between 8 and 17"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 shows a chemical yield of 88%.

Claims

1. A process for preparing a biphenyl compound, which comprises coupling an aniline compound and a benzene compound in the presence of a metal nitrite.

2. A process for preparing a biphenyl compound of the formula

wherein R1 and R2 are independently selected from hydrogen, halogen, C16 alkoxy, (C14 alkoxy)carbonyl, nitro, Cur ~4 alkyl, C47 cycloalkyl, phenyl, cyano and (T'OOC)xC(T)3~x wherein xis one or two, T is hydrogen or C14 alkyl, the T's being the same or different when xis one, and each T' is C14 alkyl or (COOT)2 forms a cyclic diester; and R3 and R4 are independently selected from hydrogen, hydroxyl, halogen, nitro, C14 alkyl, C14 alkoxy, (C1--6 alkoxy)carbonyl, aryloxycarbonyl, phenyl, cyano and C47 cycloalkyl, which comprises coupling aniline and benzene compounds of the formulae

and wherein R1, R2, R3 andR4 are as defined above, with a metal nitrite.

3. A process according to claim 2 wherein the biphenyl compound has the formula

in which R1, R2, R3 and R4 are independently selected from hydrogen, chlorine, bromine and fluorine, but is not biphenyl itself.

4. A process according to claim 2 for preparing 4-bromo-2-fluorobiphenyl which comprises coupling 4-bromo-2-fluoroaniline and benzene.

5. A process according to claim 4 wherein the 4-bromo-2-fluoroaniline has been prepared by reacting 2-fluoroaniline with a brominating agent in a solvent comprising dimethylformamide or dimethylacetamide.

6. A process according to claim 2 for preparing 2,4-difluorobiphenyl which comprises coupling 2,4-difluoroaniline and benzene.

7. A process according to any preceding claim which is conducted in the presence of copper powder.

8. A process according to any preceding claim wherein the aniline compound is reacted with aqueous metal nitrite in the presence of the benzene compound and an acid.

9. A process according to claim 8 wherein the aniline compound and an acid are simultaneously added to a mixture of aqueous sodium nitrite in an excess of the benzene compound and the ratio of acid to the aniline compound is from 1:1 to 4:1.

10. A process according to claim 8 or claim 9 wherein the acid is sulfuric or acetic acid.

11. A process according to claim 8 or claim 9 wherein the acid is fluoroboric acid.

12. A process according to claim 7 wherein the aniline compound is reacted with non-aqueous metal nitrite in the presence of the benzene compound, an acid and magnesium sulfate.

13. A process according to claim 12 wherein the compound and an acid are simultaneously added to finely divided potassium nitrite in an excess of the benzene compound, the ratio of potassium nitrite to the aniline compound is from 1:1 to 4:1 and the ratio of acid to the aniline compound is from 1:1 to 4:1.

14. A process according to claim 12 or claim 13 wherein the acid is fluoroboric acid.

15. A process according to claim 12 or claim 13 wherein the acid is acetic acid.

16. A process according to any of claims 7 to 15 wherein the aniline compound contains no more than one, and preferably no, alkyl, cycloalkyl, phenyl or cyano substituent in the ortho-position.

17. A process according to claim 1 substantially as described in any of Examples 1 to 11.

18. A process for preparing a biphenyl compound, which comprises coupling an aniline compound and a benzene compound in the presence of an alkyl nitrite at 20 to 80"C.

19. A process according to claim 18 wherein the aniline compound and a C3-8 alkyl nitrite are added separately and substantially simultaneously to an excess of the benzene compound.

20. A process for preparing a biphenyl compound, which comprises adding, separately and substantially simultaneously, an aniline compound and an alkyl nitrite to a benzene compound.

21. A process according to any of claims 18 to 20 which is conducted in the absence of water.

22. A process according to any of claims 18 to 21 in which from 0.1 to 0.5 moles of the aniline compound are used per mole of the benzene compound.

23. A process according to any of claims 18 to 22 having the characteristics of any of claims 2 to 7.

24. A process according to claim 18 substantially as described in any of Examples 12 to 15.