GB2098610A - Iron-catalyzed coupling reaction - Google Patents

Abstract

A substituted biphenyl compound is prepared by coupling an optionally substituted benzene compound with either a substituted aniline in the presence of a nitrite, or a corresponding diazo compound, in the presence of an acid and an iron catalyst. For example, 4-bromo-2- fluorobiphenyl is prepared by reacting 4-bromo-2-fluoroaniline with benzene in the presence of sodium nitrite, trichloroacetic acid and iron powder.

Description

SPECIFICATION Iron-catalysed coupling reaction Biphenyl compounds are known, e.g. from US Patent Specifications Nos 3,755,427; 3,784,705 and 3,992,459, to be useful as analgesics, anti-pyretics and anti-inflammatory agents, and as intermediates in the preparation of other valuable pharmacological agents. Various processes for the preparation of such compounds, and in particular biphenyipropionic acids, have been developed and are disclosed in, for example, US Patent Specification No 3,992,459 and German Offenlegungsschrift 30 46 512 where copper catalysts are used. The use of copper, while it may facilitate the coupling reaction which is disclosed, can cause environmental problems in recovery and/or disposal.

According to a first aspect of the present invention, a process for the preparation of a substituted biphenyl (III) comprises reacting a substituted aniline (I) with an optionally substituted benzene (II) in the presence of a nitrite, an acid and an iron catalyst. This aspect of the invention is iliustrated in Chart A.

According to a second aspect of the invention, a process for the preparalion of a substituted biphenyl (III) comprises reacting a substituted diazo compounds (I') with an optionally substituted benzene (II) in the presence of an acid and an iron catalyst. This aspect of the invention is illustrated in Chart B.

In the given formulae, n is 1 or 2 and the or each R1 is selected from fluorine, chlorine, bromine, iodine, C14 alkyl, hydroxy, C14 alkoxy, (C14 alkoxv) carbonyl, nitro, phenyl in the 3- or 4-position on the benzene ring to which it is attached, cyano, -C(Q)COOZ)2 or -C(Q)2(COOZ) in which the or each Q is hydrogen or C14 alkyl and the or each Z is C14 alkyl or (COOZ)2 forms a cyclic diester; and m is 0, 1 or 2 and the or each R2, if present, is fluorine, chlorine, bromine, iodine, C14 alkyl, hydroxy, C14 alkoxy, (C14 alkoxy) carbonyl, phenyl in the 3- or 4-position on the benzene ring to which it is attached, cyano or C47 cycloalkyl. Any alkyl group may be in any isomeric form.

The starting materials, of formulae I, I' and II, are all well known or can be prepared by generally known processes. When n is 2, the R, groups can be the same or different, but it is preferred that one of them be para-bromo. It is preferred that R, is a bromine atom when only one R, is present. It is preferred that R, be in the para position when only one R, is present. It is preferred that the substituted aniline (I) be 4-bromo-2-fluoroaniline. When m is 2, the R2 groups can be the same or different. It is preferred that m be 0. It is preferred that R2, when present, be a fluorine or chlorine atom.

The substituted aniline (I) is contacted with the benzene (II) in the presence of a nitrite, an acid and an iron catalyst. The nitrite can be either an alkali metal nitrite such as sodium or potassium nitrite, or an alkyl nitrite where the alkyl group is from 2 thru 5 carbon atoms, such as i-amyl nitrite, i-propyl nitrite and n-pentyl nitrite. It is preferable to use 1-4 equivalents of nitrite/equivalent of substituted aniline (I). The acid should have a pKa less than or equal to 5.0.

The pKa of an acid is defined as the negative logarithm (to the base 10) of the dissociation constant, Ka, for the dissociation of the acid, HA.

HA= H++A [H+] [A-] Ka= [HA] pka=-log Ka See The Condensed Chemical Dictionary, Eighth Edition, G. G. Hawley, Van Nostrad Reinhold Co., 1972, p. 698 and Physical Chemistry, Second Edition, F. Daniels and R. A. Alberty, John Wiley s Sons, Inc., 1961, p. 428-9.

The thermodynamic dissociation constant, Ka, is dependent on temperature and the solvent. See Daniels and Alberty, supra, p. 429. Therefore, in the present invention a pKa less than or equal to 5.0 refers to the pKa at 250 in distilled water.

The acid can be a mineral acid such as sulfuric, hydrochloric, phosphoric, hydrofluoric or fluboric acid or an organic acid such as trichloroacetic, dichloroacetic, chloroacetic, acetic, trifluoroacetic, benzoic, methanesulfonic or p-TSA. Trichloroacetic is the preferred organic acid. It is preferred that 14 equivalents of acid/equivalent of substituted aniline (I) are used. The iron catalyst can be iron powder (as a finely divided solid). The catalyst is present in 0.12 equivalent/equivalent of substituted aniline (I), or substituted diazo compound (I'). When iron powder is used, the reaction conditions must be adjusted to assure a timely preparation of the iron salt in situ.

The preferred starting materials are 4-bromo-2-fluoro aniline (I), see Chem. Abstra. 78, 43571 q (1973), and benzene (II).

The process of the present invention involves contacting the substituted aniline (I) with the benzene (II) in the presence of a nitrite, an acid, and the iron catalyst. Excess of the benzene (II) is utilized as the solvent. The reaction is conducted at about 0 to reflux and normally takes 1-20 hours, depending on temperature and other factors. The reaction can be monitored by GLC and is worked up by procedures well known to those skilled in the art.

The substituted aniline (I) and the acid are added to a mixture of the nitrite and benzene (11). It is preferred that the substituted aniline (I) and the acid be added simultaneously. The reaction medium can be aqueous or non-aqueous. It is preferred that excess benzene (II) be used as the solvent and that the substituted aniline (I) be added in the benzene (II) solvent. If the coupling reaction is carried out in a non-aqueous environment with a solid metal nitrite, it is advantageous to add an adsorbent such as anhydrous sodium or magnesium sulfate. When anhydrous conditions are used, potassium nitrite is preferred over sodium nitrite.

Following completion of the reaction, the desired substituted biphenyl (III) is isolated and purified as is well known to those skilled in the art. In the case where m is not 0 but 1 or 2 positional, isomeric substituted biphenyls (III) will be produced. The desired substituted biphenyl (III) is isolated and purified from the undesired positional isomeric products and reaction mixture as is well known to those skilled in the art. The problem of having positional isomeric products makes isolation more difficult than in the case where m is 0 and no isomeric products are produced, but this situation is handled routinely by those skilled in the art.

Instead of generating a substituted diazo compound (I') in situ by use of a substituted aniline (I), a nitrite and an acid, the reaction can be performed by starting with a substituted diazo compound (I') instead of a substituted aniline (I) and reacting it with a benzene (II) in the presence of an acid and an iron catalyst. Processes for preparation of the substituted diazo compound (I') are known, see U.S.

Patent 3,992,459, column 4, lines 44-63. It is preferred that the substituted diazo compound (I') be generated in situ such that the process starts with a substituted aniline (I) and a nitrite.

It has been reported, U.S. Patent 3,992,459, that a finely divided inert solid is useful in a coupling reaction such as that of the present invention. Finely divided inert solids include, for example, silica gel, diatomaceous earth, crushed glass, alumina, crushed molecular sieves, magnesium sulfate, etc. A finely divided inert solid can be used in the process of the present invention; however it is not necessary to do so, as the reaction proceeds very well without use of the finely divided inert solid, see Example 1.

Similar coupling reactions have used copper catalysts, see U.S. Patent 3,992,459 and German Offen. 3,046,512. However, copper catalysts have the disadvantage of recovery and/or disposal thereof. The processes of the present invention solve the problem of catalyst recovery and/or disposal.

The substituted biphenyls (III) are useful as intermediates in the production of compounds which are pharmacologically useful as analgesics, antipyretics, and anti-inflammatory agents. For example, 4bromo-2-fluorobiphenyl, a product of the present invention (Example 1), is transformed to 2-(2-fluoro4-biphenyl)propionic acid by the process of U.S. Patent 3,959,364. U.S. Patent 3,725,427 discloses the utility of 2-(2-fluoro-4-biphenyl)propionic acid. U.S. Patent 3,784,705 discloses the transformation of 4-chlorobiphenyl, produced by the processes of the present invention, to 2-(4'chloro-4-biphenyl)propionic acid, and its utility as an analgesic, antipyretic and anti-inflammatory agent. U.S.Patent 3,992,459 discloses the transformation of 2,4-difluorobiphenyl, produced by the processes of the present invention, to 5-(2,4-difluorophenyl)salicylic acid and its utility as an analgesic, antipyretic and anti-inflammatory agent.

The definitions and explanations below are for the terms as used throughout the entire specification.

Ali temperatures are in degrees Centigrade.

TLC refers to thin-layer chromatography.

GLC refers to gas-liquid chromatography.

DMF refers to dimethylformamide.

SSB refers to an isomeric mixture of hexanes.

p-TSA refers to p-toluenesulfonic acid.

Without further elaboration, it is believed that one skilled in the art can, using the preceding description, practice the present invention to its fullest extent. The following preferred specific embodiments are, therefore, to be construed as merely illustrative, and not limiting of the preceding disclosure in any way whatsoever.

Preparation 1 4-Bromo-2-fluoroaniline (I) DMF (37.5 ml) is added to 1 ,3-dibromo-5,5-dimethylhydantoin (97.7%, 36.5 g) under nitrogen in a dropping funnel. The mixture is stirred until the solids dissolve and then the solution is added dropwise over 55 min. to a mixture of 2-fluoroaniline (24.1 ml) in DMF (30 ml) which is kept at -34 to 230 in a dry ice-acetone bath. The dropping funnel is rinsed with methylene chloride (5 ml), which is added to the reaction mixture. The reaction mixture is poured into a separating funnel containing methylene chloride (27 ml), heptane (128 ml), sodium hydroxide (50%,11 g) and water (120 ml). After phase separation, the aqueous layer is extracted with methylene chloride (20%) in heptane (50 ml).

The organic extracts are combined, washed with water (3x 100 ml), dried and concentrated under reduced pressure to give 4-bromo-2-fluroaniline (94.0%).

Preparation 2 4-Bromo-2-chloroaniline (I) A solution of 1 ,3-dibromo-5,5-dimethylhydantoin (286 g) in DMF (300 ml) is added dropwise over 3 hrs. to a solution of 2-chloroaniline (250 g) in DMF (235 ml) kept at -30 to 400 in a dry ice acetone bath and under a nitrogen atmosphere. The mixture is stored in a refrigerator overnight at 00, then assayed for the starting 2-chloroaniline by GLC. There is a small amount of 2-chloroaniline left (approximately 2%); therefore, additional 1 ,3-dibromo-5,5-dimethylhydantoin (2.86 g) in DMF (3 ml) is added over 3 min. to the reaction mixture, which is cooled to --250. Reactions then warmed to 200, diluted with DMF (1,000 ml). GLC assay indicates 4-bromo-2-chloroaniline present in 99% yield.The DMF solution is shaken in a separatory funnel with a mixture of sodium hydroxide (50%), methylene chloride in hexane (20%, 1.25 1) and water (500 ml). The aqueous phase is extracted with methylene chloride and hexane (20%, 200 ml), the organic phases are combined and washed with water (500 ml) and then combined and diluted with methylene chloride (300 ml) when the product begins to crystallize during tbe removal of the DMF. The solution is washed with water (500 ml) and then concentrated under reduced pressure to a thick slurry. The slurry is diluted with heptane (450 ml), heated to dissolve the crystals, and allowed to cool with seeding. The mixture is re-heated, water (250 ml) is added, and the mixture then cooled.The product crystallizes and is washed with water (300 ml) and hexane (250 ml) cooled to 200 to obtain the title compound.

Example 1 4-Bromo-2-fluorobiphenyl (III) Iron powder (M-1 grade, Iron Specialties Co., Muskegon, Ml, 5.0 g) trichloroacetic acid (125 g) and benzene (11, 300 ml) are stirred in a cold water bath. 4-Bromo-2-fluoroaniline (I, Preparation 1, 47.5 g, 87% purity) is dissolved in benzene (100 ml) in an addition funnel. The aniline solution is added continuously over 2 hr with stirring to the trichloroacetic acid mixture. Sodium nitrite (27.0 g) is added in nine 3-9 portions every 1 5 min. to the trichloroacetic acid solution during the addition of the 4bromo-2-fluoroaniline. The temperature is kept between 1820 by means of a cold water bath and stirred overnight at that temperature. The reaction mixture is filtered and the resulting cake washed with benzene (200 ml).The first filtrate is washed with water (2x 125 ml) and the resulting aqueous layer is back extracted with the benzene which was ued to wash the filter cake. The two benzene fractions are combined, Celite 545 (5 g) is added and the mxiture concentrated to an oil under reduced pressure while heating to 800. To the oil, n-heptane is added and the mixture reconcentrated to drive off the benzene. The resulting oil is mixed with n-heptane (375 ml) to obtain a thin slurry which is filtered and the resulting cake is washed with n-heptane (2x200 ml). The first filtrate is extracted with sulfuric acid (85%, 2x50 ml) and the resulting sulfuric acid phase is backwashed with the n-heptane which was ued to wash the filter cake. The first n-heptane layer is washed with water (2x200 ml) and the resulting water layer is back extracted with the second n-heptane layer.The two n-heptane layers are combined and washed with sodium hydroxide (25%, 2 xl 00 ml), followed by a water wash (3 x200 mi). The aqueous layers are back extracted with heptane (200 ml). The two heptane layers are combined and concentrated under reduced pressure in an 800 bath to give the title compound as an oil.

Example 2 2-(2-fluoro-4-biphenyl)propionic acid All operations are conducted under nitrogen or in an ethylene atmosphere in dry equipment.

To magnesium (12.2 g) in anhydrous ether (100 ml) is added dropwise 1,2-dibromoethane (15.6 g). After the reaction subsides refluxing, there is added dropwise over 2 hr. a solution of distilled 4 brnmo-2-fiuornbiphenyl (III, Example 1, 104.4 g) in ether (300 ml). The mixture is then refluxed for 1 hour to complete the preparation of the Grignard reagent. The mixture is cooled to 200, saturated with ethylene gas and anhydrous nickel chloride (1.08 g) is added and the mixture is allowed to warm to 2025 under an atmosphere of ethylene at 3---4 atmospheres pressure with vigorous shaking or stirring.After 0.5-2 hr at 2025 , GLC shows no more change, excess ethylene is thoroughly removed from the system by alternately evacuating to 10" vacuum with vigorous shaking or stirring or 2-6 cycles. The mixture is then cooled to --100 and treated with carbon dioxide gas until there is no more exotherm. The. mixture is warmed to 2025 and acidified with hydrochloric acid (6 N, 150 ml). The organic phase is washed twice with water (100 ml) and extracted with potassium bicarbonate (1 N, 4x 100 ml). The combined aqueous extracts are washed with methylene chloride (4x50 ml) and acidified with concentrated hydrochloric acid (40 ml). The product is twice extracted with methylene chloride (50 ml) which is passed through anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound. The material is recrystallized from ethyl acetate in SSB or heptane using a decolorizing agent such as charcoal in the last crystallization.

In a preferred procedure, the mixed catalyst for the above reaction is prepared by adding dropwise a solution of triethylaluminum in hexane (25%, 0.83 ml) to suspension of 1 64 mg anhydrous nickel bis(acetylacetonate) in 2 ml of anhydrous diethyl ether in a bath at -14 to --300 under a nitrogen or ethylene atmosphere. The mixture is stirred at the same temperature for 2 hrs., then added to the aryl Grignard solution at --200 as described above.

Example 3 4-Bromo-2-chlorobiphenyl (III) Following the general procedure of Example 1 and making non-critical variations but starting with 4-bromo-2-chloroaniline (I, Preparation 2), the title compound is obtained.

Example 4 2-(2-chloro-4-biphenyl)propionic acid To a slurry'of magnesium chips (3.8 g) in anhydrous diethyl ether (50 ml) is added a solution of 1,2-dibromoethane (2.1 ml) under a nitrogen atmosphere. When the reaction subsides there is added slowly over 2 hrs a solution of 4-bromo-2-chlorobiphenyl (III, Example 3,32.4 g) in anhydrous diethyl ether (40 ml). The reaction is kept near the reflux during the addition and is completed by refluxing the mixture for 1 5 min. after the end of the addition.The mixture in a Parr bottle is cooled to less than --200, anhydrous nickel chloride t470 mg) is added, the bottles placed in the Parr apparatus and shaken under an atmosphere of ethylene gas at 60 Ib/in2. The mixture is shaken vigorously without heating for 1 5 min., by which time the temperature of the contents rises to 260. Water is circulated in the jacket to maintain a temperature of 2830 . After a total of 38 min., the uptake of ethylene ceases. The pressure is released and the mixture is shaken with occasional evacuation to maintain a pressure below atmosphere (1-8 in. of vacuum) for about 0.5 hr. The mixture is then cooled to about --130 by circulating --350 coolant in the jacket.The bottle is pressurized to 20 Ib/in2 with dry carbon dioxide gas the mixture is shaken for about 0.5 hrs. during which time the temperature rises to 200.

The pressure is released and the reaction mixture is acidified with excess 1 N hydrochloric acid. The ether layer is separated, washed with water (2x25 ml) and extracted with sufficient 1 N potassium hydroxide to obtain a pH of 10 in the aqueous layer. The organic phase is extracted with water (25 ml) and the combined aqueous phases are washed with diethyl ether (50 ml). the aqueous extracts are acidified with sulfuric acid (10%) and extracted with two portions of ether (150 ml and 25 ml). The two ether extracts are combined, washed with water (50 ml) and passed through a slug of cotton into a dry flask. The ether solution is diluted with anhydrous diethyl ether (250 ml) and stirred under an ammonia atmosphere for 0.5 hr. to precipitate the ammonium salt.After cooling the slurry in ice, the salt is collected, washed with ether and dried in a stream of nitrogen to obtain the ammonium salt in the granular solid. The ammonium salt is recrystallized from water containing a small amount of ammonia.

The free acid obtained on acidification of the ammonium salt is recrystallized from heptane-ethyl acetate to give the title compound.

Examples 5-12 Following the general procedures of Example 1 and making non-critical variations but starting with the substituted aniline (I) of Column A and the benzene (II) of column B, the substituted biphenyl (III) of Column C is obtained.

Example Column A Column B Column C 5 4-Bromoaniline Fluorobenzene 4-Bromo-2'-fluoro biphenyl 6 4-Bromo-2- Fluorobenzene 4-Bromo-2,2'-difluoro fluoroaniline biphenyl 7 4-Bromoaniline Chlorobenzene 4-Bromo-4'-chlorobi phenyl 8 4-Bromoaniline Isobutylbenzene 4-Bromo-4'-isobutyl biphenyl 9 4-Bromo-2- Methoxybenzene 4-Bromo-2-fluoro-4' fluoroaniline methoxybiphenyl 10 4-Bromo-2- m-Difluorobenzene 4-Bromo-2,2',4' fluoroaniline trifluorobiphenyl 11 2,4-Difluoroaniline Benzene 2,4-Difluorobiphenyl 12 4-Bromoaniline m-Difluorobenzene 4-Bromo-2',4'-di fluorobiphenyl CHART A

Claims (34)

Claims

1. A process for the preparation of a substituted biphenyl of the formula

wherein n is 1 or 2 and the or each Ri is selected from fluorine, chlorine, bromine, iodine, C14 alkyl, hydroxy, C14 alkoxy, (C14 alkoxy) carbonyl, nitro, phenyl in the 3- or 4-position on the benzene ring to which it is attached, cyano, -C(Q)(COOZ)2 or -C(Q)2(COOZ) in which the or each Q is hydrogen or C14 alkyl and the or each Z is C14 alkyl or (COOZ)2 forms a cyclic diester; and m is 0, 1 or 2 and the or each R2, if present, is fluorine, chlorine, bromine, iodine, C14 alkyl, hydroxy, C14 alkoxy, (C,~4 alkoxy) carbonyl phenyl in the 3- or 4-position on the benzene ring to which it is attached, cyano or C47 cycloalkyl; which comprises reacting a substituted aniline of the formula

wherein n and R, are as defined above, with an optionally substituted benzene of the formula

wherein n and R2 are as defined above, in the presence of a nitrite, an acid and an iron catalyst.

2. A process for the preparation of a substituted biphenyl as defined in claim 1, which comprises reacting a substituted diazo compound of the formula

wherein n and R1 are as defined in claim 1, with an optionally substituted benzene as defined in claim 1 , in the presence of an acid an an iron catalyst.

3. A process according to claim 1, wherein the nitrite is an alkali metal nitrite.

4. A process according to claim 3, wherein the alkali metal nitrite is sodium or potassium nitrite.

5. A process according to claim 4, wherein the alkali metal nitrite is sodium nitrite.

6. A process according to claim 1, wherein the nitrite is a C25 alkyl nitrite.

7. A process according to claim 6, wherein the alkyl nitrite is isoamyl, isopropyl or m-pentyl nitrite.

8. A process according to any of claims 1 and 3 to 7, wherein from 1 to 4 equivalents of the nitrite are used per equivalent of the substituted aniline.

9. A process according to any of claims 1 and 3 to 8, wherein from 1 to 4 equivalents of the acid are used per equivalent of the substituted aniline.

1 0. A process according to claim 2, wherein from 1 to 4 equivalents of the substituted diazo compound are used.

11. A process according to any preceding claim, wherein the acid has a pKa of no more than 5.

12. A process according to claim 11 , wherein the acid is a mineral acid.

1 3. A process according to claim 12, wherein the mineral acid is sulfuric, hydrochloric, phosphoric, hydrofluoric or fluoroboric acid.

14. A process according to claim 11, wherein the acid is an organic acid.

1 5. A process according to claim 14, wherein the acid is trichloroacetic, dichloroacetic, chloroacetic, acetic, trifluoroacetic, benzoic, methanesulfonic or p-toluenesulfonic acid.

1 6. A process according to claim 1 5, wherein the acid is trichloroacetic acid.

1 7. A process according to any preceding claim, wherein the iron catalyst is in the form of a finely divided solid.

1 8. A process according to any preceding claim, wherein n is 1 and R1 is in the 4-position.

1 9. A process according to claim 18, wherein R1 is bromine.

20. A process according to any of claims 1 to 17, wherein n is 2 and the Ri groups are in the 2 and 4-positions.

21. A process according to claim 20, wherein the R1 group in the 4-position is bromine.

22. A process according to any preceding claim, wherein the optionally substituted benzene is unsubstituted benzene.

23. A process according to any of claims 1 to 17, wherein the substituted biphenyl is 4-bromo-2fluorobiphenyl.

24. A process according to any of claims 1 to 17, wherein the substituted biphenyl is 4-bromo 2'-fluorobiphenyl.

25. A process according to any of claims 1 to 17, wherein the substituted biphenyl is 4-bromo 2,2'-difluorobiphenyl.

26. A process according to any of claims 1 to 17, wherein the substituted biphenyl is 2,4 difluorobiphenyl.

27. A process according to any of claims 1 to 17, wherein the substituted biphenyl is 4-bromo 2',4'-difluorobiphenyl.

28. A process according to any of claims 1 to 17, wherein the substituted biphenyl is 4-bromo 4'-chlorobiphenyl.

29. A process according to any of claims 1 fo 17, wherein the substituted biphenyl is 4-bromo-2 chlorobiphenyl.

30. A process according to any of claims 1 to 17, wherein the substituted biphenyl is 4-bromo 4'-isobutylbiphenyl.

31. A process according to any of claims 1 to 17, wherein the substituted biphenyl is 4-bromo-2fluoro-4'-methoxybiphenyl.

32. A process according to any of claims 1 to 17, wherein the substituted biphenyl is 4-bromo 2,2',4'-trifluorobiphenyl.

33. A process for the preparation of 4-bromo-2-fluorobiphenyl, which comprises reacting 4 bromo-2-fluoroaniline with benzene in the presence of sodium nitrite, trichloroacetic acid and iron powder.

34. A process according to claim 1 or claim 2, substantially as described in any of the Examples.