Patent GB-1146021-A (GB)
Title: Production of substituted cyclohexylphenylacetic acids
IPC: C01B9/08
Filed: 1966-06-08
Abstract: 1,146,021. α-Alkyl-(3-halo-4-cyclohexylphenyl)-acetic acids. MERCK & CO. Inc. 8 June, 1966 [15 June, 1965], No. 25564/66. Heading C2C. α - (C 1-5  Alkyl) - (3 - halo - 4 - cyclohexylphenyl)-acetic acids are prepared by (1) acidic or basic hydrolysis of the corresponding acetonitriles or acetamides; (2) de-esterification of the corresponding esters; (3) oxidation of the corresponding aldehydes or alkyl ketones; (4) α-alkylation of the corresponding α- unsubstituted acids (this process may also be effected on the esters, and then these deesterified as in (3)); (5) decarboxylation of the corresponding malonic acid compounds or simultaneous hydrolysis and decarboxylation of the corresponding esters; (6) reduction of the corresponding α - (C 1-5  alkyl) - α - R<SP>1</SP> - (3- halo - 4 - cyclohexylphenyl) - acetic acids or their esters (wherein R<SP>1</SP> is C 1-5  alkoxy, aryl substituted C 1-5  alkoxy, NH 2 , Cl, Br, phenylsulphonyl or C 1-5  alkylsulphonyl, or, in the esters, hydroxy) followed, when required, by deesterification; (7) Wolff rearrangement of an appropriate diazoketone with water or an alcohol to form the free acid or the ester which is subsequently de-esterified, or reaction of the diazoketone with an amine to form the corresponding amide, and hydrolysis of this; (8) carboxylation with CO 2  of an α-(C 1-5  alkyl)-α- (3 - halo - 4 - cyclohexylphenyl) - α - R 3  - methane (wherein R 3  is MgY, Li, CdY, K, AlYR, ZnY or Na, in which Y is halogen and R is alkyl) and reaction of the product with aqueous acid; (9) reaction of an α-(3-halo-4-cyclohexylphenyl)- (C 2-6  alkyl) halide or the corresponding alcohol with CO under acid conditions; (10) dehydrohalogenation of an a-(3-halo-4-cyclohexylphenyl) - (C 2-6  alkyl) - halide or dehydration of the corresponding alcohol to form a substituted alkene and reaction of this with CO under acid conditions; (11) reaction of a 3-halo-4-cyclohexylphenyl magnesium halide with an ester of an α-halo-C 3-7  aliphatic acid to form an ester of the required acid and de-esterification of this; (12) hydrolysis of a corresponding acetyl halide; (13) cyclohexylation of a corresponding α - (C 1-5  alkyl) - α - (3 - halophenyl) - acetic acid or an ester thereof and, when required, deesterification; (14) reduction of a corresponding cyclohexenyl or cyclohexadienyl compound or an ester thereof followed, when required, by de-esterification; (15) dehydrogenation of an α - (C 1-5  alkyl) - α - (3 - halo - 4 - cyclohexylcyclohexenyl or -cyclohexadienyl)-acetic acid or an ester thereof followed, when required, by de-esterification; (16) reaction of a corresponding acid or ester containing a diazonium halide group instead of the 3-halo substituent with an inorganic halide followed, when required, by de-esterification; (17) halogenation of a corresponding 3-unsubstituted phenyl compound or an ester thereof followed, when required, by de-esterification; or (18) reaction of the corresponding 3-hydroxyphenyl compound or an ester thereof with PCl 5  followed, when required, by de-esterification. The starting materials may be racemates or resolved compounds (e.g. particularly the starting materials for process (6), which may be resolved by standard methods), leading to racemates or resolved products. Racemate products may subsequently be resolved, or resolution may be effected at an intermediate stage. dl - α - (3 - Chloro - 4 - cyclohexylphenyl)- ethyl bromide is prepared by brominating with HBr the corresponding alcohol (itself prepared by reduction of 3-chloro-4-cyclohexyl acetophenone) and is converted into the corresponding acetonitrile by reaction with sodium cyanide, this nitrile also being obtained by methylation of (3 - chloro - 4 - cyclohexylphenyl) - acetonitrile (prepared by chlorinating cyclohexyl benzene to give 2-cyclohexyl-chlorobenzene, reacting this with formaldehyde and HCl to give 3 - chloro - 4 - cyclohexylbenzyl chloride and reacting this with sodium cyanide) or from 2- cyclohexylchlorobenzene and α - chloropropionitrile or α-bromopropionitrile. dl-Ethyl α- methyl - (3 - chloro - 4 - cyclohexylphenyl) - acetate is prepared from α-chloroethyl propionate and 2- cyclohexyl chlorobenzene. (3-Chloro-4-cyclohexylphenyl)-acetic acid is prepared by hydrolysis of the nitrile or by the action of CO 2  on the Grignard reagent prepared from (3-chloro-4- cyclohexyl)-benzyl chloride. 3-Chloro-4-cyclohexylstyrene is prepared by dehydration of α- (3 - chloro - 4 - cyclohexylphenyl) - ethanol. dl - α - Methyl - (3 - chloro - 4 - cyclohexylphenyl)- acetaldehyde is prepared by reacting 3-chloro-4- cyclohexylacetophenone with ethyl chloracetate to give ethyl #-methyl-#-(3-chloro-4-cyclohexylphenyl)-glycidate, converting this to the sodium salt of the acid, and heating this in acetic acid. 3 - (3<SP>1</SP> - Chloro - 4<SP>1</SP> - cyclohexylphenyl) - butan - 2- one is prepared similarly. α-Methyl-(3-chloro-4- cyclohexylphenyl)-acetaldehyde is also prepared (1) by reacting 3-chloro-4-cyclohexylphenyl magnesium bromide (prepared by reacting cyclohexanol, cyclohexene or cyclohexyl chloride with 3-bromochlorobenzene to give 3 - chloro - 4 - cyclohexylbromobenzene and converting this to the Grignard reagent) with monochloroacetone to give dl - α - methyl - α- (3 - chloro - 4 - cyclohexylphenyl) - # chloroethanol (also prepared from methyl magnesium bromide and 3-chloro-4-cyclohexylphenacyl chloride, prepared in turn, inter alia, from 3-chloro- 4-cyclohexyl-acetophenone and ethyl hypochlorite, or from 2-cyclohexylchlorobenzene and chloroacetyl chloride), reacting this with sodium ethoxide in ethanol to give 2-(3<SP>1</SP>-chloro- 41 - cyclohexylphenyl) - propylene oxide and heating this with HCl in a bomb at 180‹ C.; or (2) by reacting 3-chloro-4-cyclohexyl-acetophenone with methoxymethylenetriphenylphosphorane, and hydrolysing the enol ether with perchloric acid. dl-Ethyl α-methyl-(3- chloro - 4 - cyclohexylphenyl) - acetate is prepared by α-methylation of ethyl (3-chloro-4- cyclohexylphenyl) -acetate, prepared in turn by heating 3 - chloro - 4 - cyclohexylacetophenone with sulphur and morpholine and heating the product with aq. KOH to give 3-chloro-4-cyclohexylphenylacetic acid and esterifying this. The 3-bromo compounds are prepared similarly, as are other α-alkyl compounds. Ethyl α-methyl- α - (3 - chloro - 4 - cyclohexylphenyl) - malonate is prepared by methylation of ethyl α-(3-chloro-4- cyclohexylphenyl) - malonate, and is hydrolysed to α - methyl - α - (3 - chloro - 4 - cyclohexylphenyl) - malonate. dl - Ethyl α-hydroxy- α - methyl - (3 - chloro - 4 - cyclohexylphenyl)- acetate is prepared from ethyl (3 - chloro - 4- cyclohexylphenyl) - glyoxalate (prepared from ethyl oxalyl chloride and 2-cyclohexyl-chlorobenzene) and methyl magnesium bromide, or from ethyl pyruvate and 3-chloro-4-cyclohexylphenyl magnesium bromide, and is hydrolysed to dl - α - methyl - α - hydroxy - (3 - chloro- 4 - cyclohexylphenyl)-acetic acid. dl - α - Methyl- α - methoxy - (3 - chloro - 4 - cyclohexylphenyl)- acetic acid is prepared from 3-chloro-4-cyclohexylacetophenone and CHCl 3  in methanolic KOH followed by acidification; if water replaces the methanol the α-hydroxy compound is obtained. dl - t - Butyl α - methyl - (3 - chloro- 4 - cyclohexylphenyl) acetate is prepared from t-butyl α-bromopropionate and 3-chloro-4- cyclohexylphenyl magnesium bromide; on heating it gives the free acid. dl-Benzyl α- methyl - (3 - chloro - 4 - cyclohexylphenyl) - acetate is prepared by reacting 3-chloro-4-cyclohexylphenyl magnesium bromide with CO 2  to give 3 - chloro - 4 - cyclohexyl benzoic acid (also prepared from 3-chloro-4-cyclohexyl-acetophenone), converting this to the acid chloride, reacting this with diazoethane to give 3-chloro- 4 - cyclohexyl - α - diazo - propiophenone and converting this by Wolff rearrangement and reaction with benzyl alcohol to the desired product. The preparation of the above and other starting materials is also referred to in general terms.