GB2065656A

GB2065656A - Preparing arylpropionic acids

Info

Publication number: GB2065656A
Application number: GB8040295A
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: FR2473507B1; NL8006488A; JPS5697246A; IT8050410A0; IT1128706B; GB2065656B; CH651288A5; DE3046523A1; FR2473507A1

Abstract

Arylpropionic acids such as ibuprofen and flurbiprofen are prepared by carboxylating 1-arylethylmagnesium halides. These Grignard reagents may be prepared by reacting the corresponding arylmagnesium halide with ethylene or by reacting a corresponding arylethylene with an ethylmagnesium halide, both reactions being conducted catalytically, preferably in an ethereal solvent.

Description

SPECIFICATION Preparing arylpropionic acids This invention relates to a process for preparing 2-arylpropionic acids. Such compounds, and in particular 2-(4-isobutylphenyl)propionic acid and 2-(2-fluoro-4-bi-phenylyl)propionic acid, respectively known as ibuprofen and flurbiprofen, are known to have valuable therapeutic properties, e.g. anti-inflammatory activity.

British Patent Specification No. 1,459,084 discloses reacting an arylmagnesium bromide with a salt of 2-bromopropionic acid, to prepare a 2-arylpropionic acid.

L. Farady et al. J. Organomet. Chem. '7(1969)107-116 disclose the reaction of various arylmagnesium bromides with ethylene in the presence of anhydrous nickel chloride to obtain a corresponding 1-arylethylmagnesium bromide. The given aryl groups are phenyl, methyiphenyl, ethylphenyl, mesityl and naphthyl.

The carboxylation of Grignard reagents by carbonation to form carboxylic acids is well known. Finkbeiner etal.,J. Org. Chem.27(1962) 3395 discioses reacting styrenewith propylmagnesium bromide, in the presence of titanium tetrachloride, to form a-phenethyl-magnesium bromide, which is reacted with CO2 to obtain hydratropic acid (2-phenylpropionic acid). L. Farady metal, J. Organomet. Chem 28(1971)159 discuss a similar reaction using nickel chloride (NiCL2).

2-Arylpropionic acids have been prepared from 2-aminobiphenyl compounds. However, these intermediates may be mutagenic.

In accordance with the invention, a 2-arylpropionic acid of the formula Ar-CH(CH3)-COOH may be prepared by carboxylating a 1-arylethylmagnesium halide of the formula Ar-CH(CH3)-MgHal wherein Hal is chlorine, bromine or iodine, preferably bromine, and Ar is defined below.

This Grignard reagent may be prepared by reacting the corresponding arylmagnesium halide with ethylene in the presence of a catalyst or by reacting the corresponding arylethene with an ethylmagnesium halide in the presence of a catalyst. It is particularly preferred that the formation of the 1 -arylethylmagnesium halide should be conducted in a solvent comprising an ether. It is particularly preferred that the solvent should additionally comprise a hydrocarbon cosolvent.

Ar is generally of the formula

wherein n is an integer of from 1 to 4 and Q is aralkyl, e.g. benzyl; cycloalkyl, e.g. of 3 to 7 carbon atoms, especially cyclohexyl; alky-substituted cycloalkyl, e.g. wherein alkyl is methyl, ethyl, propyl, butyl (especially isobutyl), pentyl, branched hexyl or heptyl; cycloalkenyl, e.g. cyclohexenyl; aryl, e.g. phenyl or phenyl substituted with, for example, 1 to 2 alkyl, alkoxy or alkylthio, e.g. methylthio groups or fluorine or chlorine atoms; alkoxy, e.g. methoxy or isopropoxy; aralkoxy, e.g. benzyloxy; cycloalkoxy, e.g. cyclohexyloxy; aryloxy, e.g. phenoxy or phenoxy substituted with, for example, 1 or 2 fluorine or chlorine atoms; alkylthio, e.g. methylthio, ethylthio, propylthio or n-butylthio; aralkylthio; cycloalkylthio, e.g. cyclohexylthio; arylthio, e.g. pheylpenylthio; aryl(dialkyloxy)methyl; aryl(alkylenedioxy)- methyl; N-alkyl-N-arylamino in which the aryl is e.g. phenyl or phenyl substituted with, for example, one or more fluorine or chlorine atoms; trifluoromethyl; fluorine, chlorine. dialkylamino; substituted and unsu bstituted pyridyl; piperidyl; furyl; N-alkyl-morpholino; N-aklylthiomorpholino; pyrrolinyl; pyrrolidinyl; pyrrolyl orthienyl; two Q groups taken together may form a heterocyclic ring or Q taken together with the benzene ring is 9H-carbazol-3-yl or optionally substituted naphthyl.

When Ar is optionally substituted naphthyl, it is preferably optionally 6-substituted-2-naphthyl. Any substituent is preferably selected from alkyl, cycloalkyl, phenyl, alkoxy, fluorine and chlorine. 6-methoxy-2naphthyl and 6-fluoro-2-naphthyl are the most preferred groups of this type.

Alternatively, it is particularly preferred that Ar should be

wherein m is zero or 1 and R1, R2, R3 and R4 are independently selected from hydrogen, alkyl, cycloalkyl, phenyl, alkoxy, fluorine and chlorine. When m is one, the most preferred group of this type is 3-phenoxyphenyl. When m is zero, the most preferred group of this type is 2-fluoro-4-biphenylyl, so that the acid prepared by the process of the invention is flurbiprofen.

In accordance with a second aspect of the invention, a 2-arylpropionic acid of the formula Ar' -CH(CH3)-COOH may be prepared by a process of the type described above, starting from the corresponding arylmagnesium halide or the corresponding arylethene and in which the Grignard reagent of the formula Ar'-CH(CH3)-MgHal is formed in a solvent wih comprises tetrahydrofuran, tetrahydropyran, 2-methyltetrahydrofuran or a mixture of two or more thereof, preferably together with a hydro-carbon cosolvent. Again, Hal is preferably bromine.

Ar' is phenyl carrying zero to 4 substituents independently selected from CiA alkyl, cycloalkyl, alkyl-substituted cycloalkyl and cycloalkenyl. Preferably, Ar' is 4-substituted phenyl in which the substituent is alkyl, cycloalkyl, e.g. cyclohexyl, or cyclohexenyl. Ar' is most preferably 4-isobutylphenyl, so that the acid prepared is ibuprofen.

The starting materials for the processes of this invention are commercially available or may be prepared by known processes. For example, US Patent Specification No. 2,452,154 discloses a method for brominating organic compounds, which is particularly useful for preparing the arylmagnesium halides used in this invention as starting materials. The use of a mixture of bromine and chlorine in such a bromination is particularly advantageous.

When the starting material contains a functional group which is itself reactive with Grignard reagent, it is usually necessary to protect this functional group. Suitable protecting groups are well known, as are methods for their introduction and removal, e.g. by acidification.

4-halobiphenyl, and particularly 4-bromobiphenyl, compounds which can be used as starting materials for the preparation of biphenylmagnesium halides for use as starting materials in the process of the present invention, may suitably be prepared by the coupling reaction described and claimed in copending Application No. 80/40293 filed on even date herewith (Agents Reference: GJE 6180/199) claiming priority from US Patent Application No. 105,062. This process involves coupling a 4-haloaniline compound with a benzene compound in the presence of a metal or alkyl nitrite.However, the novel process conditions described therein are not essential for preparing biphenyl compounds for use as precursors to the starting materials of this invention and, for example, conditions as, or similar to those, described in US Patent Specification No. 3,992,459 may be used for a comparable coupling reaction. These conditions include the use of copper or a copper salt.

Accordingly, novel combinations of steps may be used to prepare 2-arylpropionic acids from readily available starting materials. For example, a 4-bromo-aniline compound may be reacted with a benzene compound to prepare a 4-bromobiphenyl compound which is then converted to a 4-biphenylylmagnesium halide which is then reacted with ethylene to form a 1-(4-biphenylyl)ethyl-magnesium halide which is then carboxylated. Any substituents on the rings throughout the reaction may be for example, as defined in claim 2 of Application No. 80140293 (GJE 6180/199) or as defined above for the preferred value of Ar when m is zero. More particularly, a novel combination of steps provides a total synthesis of flurbiprofen.In this synthesis, 2-fluoroaniline is brominated to form 4-bromo-2-fluoroaniline, e.g. by the method described and claimed in copending Application No. 80/40291 filed on even date herewith (Agents Reference GJE 6180/189) claiming priority from US Patent Application No. 105,064. The 4-bromo-2-fluoroaniline is then reacted with benzene to form 4-bromo-2-fluorobiphenyl. This product is then reacted with magnesium to form 2-fluoro-4-biphenylyImagnesium halide. This Grignard reagent is then reacted with ethylene in the presence of a catalyst to prepare 1-(2-fluoro-4-biphenylyl)ethylmagnesium halide which is then carboxylated to give flurbiprofen.

The step in which ethylene is reacted with a Grignard reagent is generally carried out in a conventional manner for Grignard reactions, e.g. in an anhydrous medium. The reaction is generally carried out at a temperature of 0 C to the boiling point of the solvent. However, generally the Grignard reagent mixture is cooled to about -20 C during addition of reactants and then allowed to warm to room temperature.

A catalyst is required to effect the reaction of ethylene with aryl Grignard reagent.

Ziegler-Natta type catalysts (when conditions are modified to inhibit polymerization) are efficaceous in this regard. Anhydrous salts of nickel are especially efficacious in the desired reaction. Although most nickel compounds will effect reaction to some extent, preferred nickel salts are nickel chloride or nickel bis(acetyl-acetonate). Nickel bromide can also be used.

It is further found that partial reduction of the nickel catalyst by pretreatment causes a surprising increase in the efficacy of the preferred nickel catalyst. Such a pretreated catalyst is especially preferred.

The pretreatment consists of the addition of from zero to 5 molar equivalents of an alkyl aluminium compound for example, triisobutylaluminium, diethylaluminium chloride or bromide, triethylaluminium, ethylaluminium dichloride, to the nickel salt in an ether or tetrahydrofuran solvent under an inert atmosphere for 0.5 to 3 hours. Other suitable conditions for pretreatment include the reaction of two molar equivalents of diisobutylaluminium hydride with anhydrous nickel bis(acetylacetonate) at -30" to 0 C.

particularly for Ar compounds.

Yields are greatly increased by the evacuation of ethylene gas after absorption of the ethylene in the Grignard. The absorption is accomplished by saturation of the reagent mixture with the gas under three to four atmospheres of pressure with vigorous shaking or stirring and is complete when the reaction mixture shows no further absorption of ethylene.

Yields are also advantageously affected by the addition of ethylmagnesium bromide to the reaction mixture as described above, also after the mixture shows no further absorption of ethylene.

It is found for Ar compounds that absorption of ethylene occurs in an ether solvent such as di-n-butyl ether or diethyl ether, preferably diethyl ether. On the other hand, essentially no reaction occurs in a reaction mixture having tetrahydrofuran, methylene dichloride, 1,2-dimethoxyethane, or a mixture of equivalent amounts of diethylether and toluene as the solvent therefrom.

To the contrary, it is found that, for Ar' compounds, absorption of ethylene unexpectedly produces a high yield in an ether solvent, such as tetrahydrofuran, tetrahydropyran, 2-methyltetrahydrofuran, mixtures thereof or preferably one of these ethers in combination with a hydrocarbon cosolvent such as toluene or hexane. In this reaction, on the other hand, only negligible yields are obtained in diethyl ether, dioxane, 2,5-dimethyltetrahydrofuran, di-n-butyl ether, diglyme, n-butyl ethyl ether, n-butyl methyl ether, dimethoxy methane, 2-methyltetrahydrofuran, or 4-methyldioxolane. Since 2-methyltetrahydrofuran is more expensive, the preferred ether component of the solvent system for this reaction is tetrahydrofuran.

However, it is particularly found that the use of the hydrocarbon cosolvent such as toluene or hexane advantageously reduces undesirable byproduct formation for Ar' compounds. Effective ratios of ether to hydrocarbon in a solvent-cosolvent mixture range from 1:1 to 1:0. Use of the hydrocarbon cosolvent causes an unexpected advantage by reducing the formation of dimers in the yield of the desired product and is therefore preferred in a ratio by volume of from 1:1 to 3.5:2 with 1:1 especially preferred.

The mixture resulting from the catalytic reaction of the aryl Grignard reagent with ethylene is cooled, for carboxylation, to between +10"C and -30 C. It is then treated with dry carbon dioxide (CO2) gas and thereafter acidified, for example with hydrochloric acid. A resulting organic phase is extracted with water and mild alkaline solutions, e.g., aqueous sodium or potassium bicarbonate. The desired product may be isolated and purified from the combined aqueous extracts by conventional methods, e.g. extraction, evaporation, distillation, crystallization or chromatography.

As indicated above, the 1-aryethylmagnesium halide may be prepared by reacting the corresponding aryl-ethene with an ethylmagnesium halide, preferably in the presence of a nickel catalyst of the type described above. Instead of the ethylmagnesium halide, magnesium and an ethyl halide may be used.

The conditions for this reaction are generally as described above for the alternative way of preparing the 1-arylethylmagnesium halide. In this second method, ethylene is eliminated in the reaction.

When it is desired to prepare an arylmagnesium halide in which the aryl group is Ar' as defined above, it is particularly preferred tha the aryl halide precursor should be prepared by reacting the corresponding Ar'H compound with a halogenating agent in liquid sulphur dioxide. The halogenating agent is preferably a brominating agent and most preferably bromine chloride.

The following Examples illustrate the invention.

The 2-fluoro-4-halobiphenyl compounds used as starting materials may be the products of any suitable Example of Application No.80/40293 (GJE 6180/199), and preferably of Example 1.

In the Examples, glc means gas-liquid chromatography, and g-at means gram atoms.

EXAMPLE 1 2-(2-fluoro.4-biphenylyl)propionic acid.

All operations conducted under nitrogen or a CH2= CH2 atmosphere in dry equipment To 12.2 grams (0.50 g-at.) of magnesium in 100 ml anhydrous ether are added dropwise 15.6 grams (0.083 mole) 1,2-dibromoethane. After a reduction in refluxing, there is added dropwise over 2 hours a solution of 104.4 grams (0.416 mole) of distilled 4-bromo-2-fluorobiphenyl in 300 ml of ether. The mixture is then refluxed for one hour to complete the preparation of the Grignard reagent. The mixture is cooled to -200 C., saturated with ethylene gas, and 1.08 grams (8.5 millimoles) of anhydrous nickel chloride (NiC12) is added and the mixture is allowed to warm to room temperature under an atmosphere of ethylene gas at a 3-4 atom pressure with vigorous shaking or stirring.After 1/2 to 2 hours at room temperature (gas-liquid chromatography shows no more change), excess ethylene is thoroughly removed from the system alternat(iv)ely evacuating to 10" vacuum with vigorous shaking or stirring for two to six cycles. The mixture is then cooled to -10 C and treated with C02 gas until there is no more exotherm. The mixture is warmed to room temperature and acidified with 150 ml 6N hydrochloric acid. The organic phase is washed twice with 100 ml water, then extracted with 4 portions of 100 ml 1 N potassium bicarbonate solution. The combined aqueous extracts are washed four times with 50 ml of methylene chloride, and then acidified with 40 ml of concentrated hydrochloric acid.The product is twice extracted with 50 ml of methylene chloride, which is passed through anhydrous sodium sulfate and evaporated to give crystalline crude 2-(2-fluoro-4 biphenylyl)propionic acid (flurbi-profen) in 50-80% yield, based on starting biphenyl.

The material is recrystallized several times from 4 times its weight (in ml) of 10-25% ethyl acetate in Skellysolve B hexanes (or heptane), using 5 weight percent Pittsburgh Cal-carbon for decolorization in the last crystallization, to obtain flurbiprofen in 34-54% yield, based on the biphenyl, of melting point 110-114"C.

In a preferred procedure, the mixed catalyst for the above reaction, on a 60 mMole scale, is prepared by adding dropwise, 0.83 ml (1.2 mMoles) of a 25% solution of triethylaluminium in hexane to a suspension of 164 mg (0.60 mMole) of anhydrous nickel bis(acetylacetonate) in 2 ml of anhydrous diethyl ether in a bath at -14 to -35 C under a nitrogen or ethylene atmosphere. The mixture is stirred at the same temperature for 2 hours, then added to the aryl Grignard solution at -20 C as described above. Ethylene uptake in this experiment is as rapid as the experiment using 3 mole percent nickel chloride, that is not treated to prior aikylaluminium reduction. The yield of flurbiprofen, as determined by glc assay, was 82% chemical.

EXAMPLE 2 2-(4-isobutylphenyllpropionic acid A. p-Bromoisobutylbenzene Variation a without catalyst To a solution of 67.1 grams (0.50 mole) of isobutyl-20 benzene in 125 ml of liquid sulfur dioxide, under a nitrogen atmosphere, and cooled to -32 C (-45"C bath), are added over 13 minutes 95.9 grams (0.60 mole) of liquid bromine. The mixture is kept at about -33 C for an hour, then treated with 25 ml of water and allowed to warm to room temperature, during which time sulfur dioxide and byproduct hydrogen bromide evaporated. The resultant organic phase is separated from the small aqueous phase. The aqueous phase is diluted with 75 ml of water and extracted with methylene chloride.The methylene chloride extract is combined with the original organic phase and washed with 25 ml of of 20% sodium hydroxide solution and then twice with half-saturated sodium chloride solution. The organic solution is dried over anhydrous calcium chloride, then concentrated under vacuum to give 107.5 g of light yellow-colored oil.

Glc analysis of the product showed 1.4% starting isobutylbenzene, 5.1% o-bromoisobutylbenzene, and 94.

0% p-bromoisobutylbenzene. This calculates out to a yield (% of thoery) of 5% o-bromoisobutvlbenzene and 95% p-bromoisobutylbenzene.

Variation b using iron powder as catalyst This experiement is very similar to the uncatalyzed reaction, except that the reaction was run at -50 to -600 C after preforming the catalyst at -7 C.

Bromine (2 ml) is added to a slurry of 1.39 grams (0.025 grams-atoms, 5 mole-1%) iron powder in 125 ml of liquid sulfur dioxide kept at -7 C. After 0.5 hours at -7 C, the mixture is cooled to -660C and the isobutylbenzene (67.1 grams, 0.5 mole) is added. The reaction mixture is kept at -52 to -600C during the addition of the remainder of a total of 101.9 grams (0.64 mole) of bromine during 6.5 minutes. The mixture is kept at -53 to 57"C for 50 minutes, then treated with 49 ml of water and worked up essentially as in the above experiment a. The crude yield is 106.7 grams, which assayed 0.16 grams isobutylbenzene, 5.9 grams ortho-, and 91.3 grams para-bromoisobutylbenzene.This calculates out to a yield of 6% o-bromoisobutylbenzene and 93% p-bromoisobutylbenzene.

The major difference between this experiment and the preceding one is the rate of bromination at the low temperature. Glc analysis of the reactions showed about 5% starting material after one hour reaction at -33 C in the preceding reaction, but only 0.3% after one hour at -57 C in the present one, indicating that preformed ferric bromide speeds the bromination at low temperatures.

Variation c using antimony trichloride as catalyst A mixture of liquid sulfur dioxide (20 ml), antimony trichloride (149 milligrams), and bromine (0.52 ml, 1.52 grams, 9.5 milliMoles) at -30" C is cooled to -72 C (some solids) and treated in less than 3 seconds with 1.57 ml (10.0 milliMoles) of isobutylbenzene. The mixture, which contained considerable solids, is stirred at -69 to -72 C for 70 minutes, at which point the reaction is quenched with 1.2 g (10.9 milliMoles) of resorcinol. The mixture is then warmed to room temperature (sulfur dioxide evaporated) and the product is extracted with hexane. The hexane solution is washed with aqueous sodium hydroxide and water, dried over anhydrous sodium sulfate, and diluted with hexane to a volume of 100 ml for glc analysis. Based on the assays, the yields are isobutylbenzene 16% o-bromoisobutylbenzene 4%, and p-bromoisobutylbenzene 79%.

This and the following two experiments were competitive experiments, in an effort to determine relative reaction rates at 700C over 65-70 minutes. The reactions are quenched by adding resorcinol, which reacts almost instantly with the remaining bromine. A standard run without catalyst gave 22% isobutylbenzene, 2% ortho-, and 74%para-bromoisobutylbenzene. The higher conversion in the present experiment indicates that antimonytrichloride increases the rate of the reaction.

Variation d using bromine chloride as brominating agent Bromine chloride (Dow, 1.12 g, 9.7 milliMoles) is condensed in a tube using Dry Ice cooling, then it is diluted with 20 ml of liquid sulfur dioxide and the resultant solution is cooled to -72"C. Isobutylbenzene (1.57 ml, 10.0 milliMoles) is added, and the resultant mixture is stirred at -70 C for 65 minutes before quenching with 1.2 grams (10.9 milliMoles) of resorcinol. Workup and analysis as above gives 8% isobutylbenzene, 6% ortho-, and 83% para-bromoisobutylbenzene. This result indicates that the bromination with bromine chloride is faster than that with molecular bromine, and the extent of ortho-bromination is somewhat higher.

A similar experiment, but in which the BrCI solution in liquid sulfur dioxide is added to the isobutylbenzene in liquid SO2 at -70 C gives yields, respectively, of 16%, 5%, and 80%.

Variation e using N-bromosuccinimide To a mixture of 1.78 g (10 milliMoles) of N-bromosuccinimide in 20 ml of liquid sulfur dioxide at -30 C is added 1.57 ml (10.0 mMoles) of isobutylbenzene. The mixture is stirred at -30 to -18" for 65 minutes, then worked up as above. Assay gives only 2%,p-bromoisobutylbenzene and 88% recovered starting isobutylbenzene, indicating that the reaction with N BS is very slow at this temperature.

Variation fusing N-bromoacetamide catalyzed by BrCI To a mixture of 1.39 grams (10 milliMoles) of N-bromoacetamide in 19 ml of liquid sulfur dioxide at -700C is added 1.57 ml (10.0 milliMoles) of isobutylbenzene. The mixture is treated with a solution of 0.05 ml of BrCI in 1.5 ml of SO2 and then stirred at -70 C for 65 minutes, after which it is worked up as above. Glc analysis shows 62% isobutylbenzene, 1.5% ortho-bromoisobutylbenzene, and 35%para-bromoisobutylbenzene. This result shows that N-bromo compounds function as brominating agents if an acid catlyst (equivalent to HCI) is added.The low-temperature reaction in liquid SO2 is catalyzed by iron powder or antimonytrichloride, but these are not necessary for efficient bromination. Bromine chloride is also an effective catalyst to the brominating agent, giving as high as 90% conversion to thep-bromo isomer.

B. A solution of 1.0 ml of 1,2-dibromoethane in 10 milliliter of anhydrous tetrahydrofuran (THF) is added dropwise over 5 minutes to a mixture of 1.90 grams (78 grams atoms) of magnesium chips in 10 ml of THF.

The mixture is refluxed for 2 minutes, then treated by dropwise addition, over 50 mintes, with a solution of 12.85 grams (60 mMoles) of p-bromoisobutylbenzene in 20 ml of TH F. The resultant mixture is refluxed for 15 minutes to complete the reaction. The mixture is then cooled to -20"C, 240 mg of anhydrous NiCI2 are added, and the mixture is allowed to warm to room temperature, with vigorous stirring or shaking, under an atmosphere of ethylene gas at a pressure of 3-4 atmospheres. After 0.5 to 2 hours at up to 30"C, the ethylene uptake ceases and the mixture is evacuated to -10 inches mercury, and shaken at this pressure for 20 minutes (bath temperature 45"C) to completely remove excess ethylene from the solution.The mixture is then cooled to -15 C and treated with excess carbon dioxide gas. The product is isolated by acidification, extraction of the acidic product from ether with 1N potassium hydroxide, then acidification of the latter solution to obtain crude ibuprofen. Based on gic assay of the crude product, the chemical yield is 47%. Pure ibuprofen, m.p.

73-74"C, is obtained with 91% recovery via recrystallization of the sodium salt from water, followed by acidification.

The wide range of hydratropic acids which can be prepared by the present invention are well known as therapeutic agents. For example, see Wong, "Chapter 18. Non Steroidal Anti-inflammatory Agents" Annual Reports in Medicinal Chemistry Vol. 10, Utility ofHydratropicAcids, Section IV - Metabolic Diseases and Endrocrine Function Ed: Morland pp. 172-181(1975); U.S. Patent Specification Nos. 3,624,1423,755,427; 3,865,949; 3,784,705 and 4,052,514.

The following procedure illustrates a preferred method of purifying flurbiprofen by distillation.

A toluene extract of crude acids from hydrolysis and extraction of Grignard carboxylation, containing 51.3 g of flurbiprofen by gic assay, is evaporated, and the residue is distilled under vacuum. The fraction which boils at 119-176"C (mostly at 172-176"C) at a pressure of 0.4-0.5 mm is collected (49.2 g, which solidified) and recrystallised from a mixture of 25 ml of ethyl acetate and 170 ml heptane (decolorisation with 0.5 g of Darco G-60) ("Darco" is a registered Trade Mark). The dried product weighs 44.6 g (87% recovery of available product). Glc assay indicates a purity of 98.4%.

EXAMPLE 4 2-(2-chloro-4-biphenylyl)propionic acid To a slurry of 3.8 g (0.156 g-at) magnesium chips in 50 ml of anhydrous ether is added a solution of 2.1 ml (24 mmoles) of 1 ,2-dibromoethane, under a nitrogen atmosphere. When the reaction subsides there is added, slowly over 2 hours, a solution of 32.4 g (121 mmoles) of 4-bromo-chlorobiphenyl in 40 ml of anhydrous ether. The reaction is kept near the boiling point during the addition, and is completed by refluxing the mixture for 15 minutes after the end of the addition. The mixture, in a Parr bottle, is cooled to < -20"C, 470 mg of anhydrous nickel chloride are added, the bottle is placed in the Parr apparatus, and shaken under an atmosphere of ethylene gas at 60 psig. (pounds per square inch gauge).The mixture is shaken vigorously without heating for 15 minutes, by which time the temperature of the contents rise to 260C. Water is circulated in the jacket to maintain a temperature of 28-30"C. After a total of 38 minutes, the uptake of ethylene ceases. Pressure is released, and the mixture is shaken, with occasional evacuation to maintain a pressure below atmospheric (1-8" vacuum) for about 0.5 hours. The mixture is then cooled to ~ -130C by circulating -35 C coolant in the jacket. The bottle is pressurized to 20 pounds per square inch gauge with dry carbon dioxide gas, and the mixture is shaken for about 0.5 hours, during which time the temperature rises to 200C.

Pressure is released, and the reaction mixture is acidified with excess 1N HCI. The ether layer is separated, washed with 2 x 25 ml of water, and extracted with sufficient 1M KOH to obtain a pH of 10 in the aqueous layer. The organic phase is extracted with 25 ml of water, and the combined aqueous phases are washed with 50 ml of ether. The aqueous extracts are acidifed with excess 10% sulfuric acid and extracted with 150 and 25 ml portions of ether. The two ether extracts are combined, washed with 50 ml of water, and passed through a plug of cotton into a dry flask.

The ether solution is diluted to 250 ml with anhydrous ether and stirred under an ammonia atmosphere for 0.5 hours 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 26.4 g (79%) of the ammonium salt as a granular off-white 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 18.4 g (58%) of "chlorobiprofen", m.p. 134-6"C.

Claims

1. A process for preparing a 1 -arylethylmagnesium halide of the formula Ar-CH(CH3)-MgHal where Hal is chlorine, bromine or iodine and Ar is of the formula

in which n is an integer of from 1 to 4 and each Q is independently selected from aralkyl, cycloalkyl, alkyl-substituted cycloalkyl, cycloalkenyl, aryl, alkoxy, aralkoxy, cycloalkoxy, aryloxy, alkylthio, aralkylthio, cyclo-alkylthio, arylthio, aryl(dialkoxy) methyl, aryl(alkylene-dioxy)methyl, N-alkyl-N-arylamino, trifluoromethyl, fluorine, chlorine, dialkylamine, substituted and unsubstituted pyridyl, piperidyl, furyl, N-alkyl-morpholino, N-alkyl-thiamorpholino, pyrrolinyl, pyrrolidinyl, pyrrolyl, thienyl or two Q groups taken together form a heterocyclic ring, or Q together with the phenyl group is 9H-carbazol-3-yl or optionally substituted naphthyl, which comprises reacting an arylmagnesium halide of the formula ArMgHal wherein Ar and Hal are as defined above, with ethylene in the presence of a catalyst.

2. A process for preparing a 1-arylethylmagnesium halide as defined in claim 1, which comprises reacting an arylethene of the formula Ar-CH=CH2 wherein Ar is as defined in claim 1, with ethylmagnesium chloride, bromide or iodide in the presence of a catalyst

3. A process according to claim 1 or claim 2 wherein Ar is 6-methoxy-2-naphthyl.

4. A process acording to claim 1 or claim 2 wherein Ar is

wherein m is 0 or 1 and R1, R2, R3 and R4 are independently selected from hydrogen, alkyl, cycloalkyl, phenyl, alkoxy, fluorine and chlorine.

5. A process according to claim 4 wherein m is 1.

6. A process according to claim 5 wherein Ar is 3-phenoxyphenyl.

7. A process according to claim 4 wherein m is0.

8. A process according to claim 7 wherein Ar is 2-fluoro-4-biphenyl.

9. A process according to claim 7 or claim 8 when appendantto claim 1 wherein the biphenylmagnesium halide has been prepared by coupling a R1, R2-substituted 4-haloaniline with a R3, R4-substituted benzene and converting the resultant biphenyl halide to the magnesium derivative in known manner.

10. A process according to claim 9 wherein the coupling reaction is conducted in the presence of copper.

11. A process according to claim 9 or claim 10 wherein the coupling comprises reacting the 4-haloaniline with aqueous metal nitrite in the presence of the benzene and an acid.

12. A process according to claim 11 wherein the 4-haloaniline and an acid are simultaneously added to aqueous sodium nitrite in an excess of the benzene such that the ratio of sodium nitrite to the 4-haloaniline is from 1:1 to 4:1 and the ratio of acid to the 4-haloaniline is from 1:1 to 4:1.

13. A process according to claim 11 or claim 12 wherein the acid is sulfuric or acetic acid.

14. A process according to claim 11 or claim 12 wherein the acid is fluoboric acid.

15. A process according to claim 10 wherein the coupling comprises reacting the 4-haloaniline with non-aqueous metal nitrite in the presence of the benzene, an acid and copper.

16. A process according to claim 15 wherein the 4-haloaniline and an acid are simultaneously added to finely divided potassium nitrite in an excess of the benzene such that the ratio of potassium nitrite to the 4-haloaniline is from 1:1 to 4:1 and the ratio of acid to the 4-haloaniline is from 1:1 to 4:1.

17. A process according to claim 16 wherein the acid is acetic acid.

18. A process according to claim 9 or claim 10 wherein the coupling comprises adding the 4-haloaniline and a C38 alkyl nitrite separately and simultaneously to the benzene.

19. A process according to any of claims 9 to 18 wherein 4-bromo-2-fluoroaniline is coupled with benzene.

20. A process according to claim 19 wherein the 4-bromo-2-fluoroaniline is prepared by reacting 2-fluoroaniline with a brominating agent in a solvent comprising dimethylformamide or dimethylacetamide.

21. A process according to any preceding claim wherein the 1-arylethylmagnesium halide is prepared in a solvent comprising tetrahydrofuran, tetrahydropyran, 2-methyltetrahydrofuran or a mixture of two or more thereof.

22. A process for preparing a 1 -arylethylmagnesium halide of the formula Ar'-CH(CH3)-MgHal wherein Hal is as defined in claim 1 and Ar' is phenyl optionally substituted up to 4times bysubstituents independently selected from C14 alkyl, cycloalkyl, alkyl-substituted cycloalkyl and cycloalkenyl, which comprises reacting an arylmagnesium halide of the formula Ar'MgHal wherein Ar' and Hal are as defined above, with ethylene in the presence of a catalyst in a solvent comprising tetrahydrofuran, tetrahydropyran, 2-methyltetrahydrofuran or a mixture of two or more thereof.

23. A process according to claim 22 wherein the arylmagnesium halide is a bromide which has been prepared by reacting a compound of the formula Ar'H with a brominating agent in liquid sulphur dioxide.

24. A process according to claim 23 wherein the brominating agent is bromine chloride.

25. A process for preparing a 1 -arylethylmagnesium halide as defined in claim 22, which comprises reacting an arylethene of the formula Ar'-CH=CH2 wherein Ar' is as defined in claim 22, with ethylmagnesium chloride, bromide or iodide in the presence of a catalyst in a solvent comprising tetrahydrofuran, tetrahydropyran, 2-methyltetrahydrofuran or a mixture of two or more thereof.

26. A process according to any of claims 22 to 25 wherein Ar' is alkylphenyl.

27. A process according to claim 26 wherein Ar' is 4-isobutylphenyl.

28. A process according to any of claims 21 to 27 wherein the solvent comprises tetrahydrofuran.

29. A process according to any of claims 21 to 28 wherein the solvent additionally comprises a hydrocarbon cosolvent.

30. A process according to any preceding claim wherein the catalyst is an anhydrous nickel salt selected from nickel chloride, nickel bis(acetylacetonate) and nickel bromide.

31. A process according to claim 30 wherein the nickel salt is nickel chloride or nickel bis(acetylacetonate).

32. A process according to claim 30 or claim 31 wherein the nickel salt has been pretreated with a reducing agent.

33. A process according to claim 32 wherein the reducing agent is an alkylaluminium compound.

34. A process according to any preceding claim wherein the halide is a bromide.

35. A process for preparing a 2-arylpropionic acid of the formula Ar"-CH(CH3)-COOH wherein Ar" is Ar as defined in claim 1 or Ar' as defined in claim 22, which comprises carboxylating a 1-arylethyl-magnesium halide prepared by a process according to any preceding claim.

36. A process substantiallyas described in any of the Examples.