Patent GB-1226344-A (GB)
IPC: C07C67/00
Filed: 1967-07-31
Abstract: 1,226,344. Phenylacetic acid derivatives. ALLEN & HANBURYS Ltd. 19 July, 1968 [31 July, 1967], No. 35166/67. Heading C2C. [Also in Division A5] The invention comprises novel phenylacetic acid derivative of the formula in which the group R 3 CO may only be meta or para orientated with respect to the side chain -CR 1 R 2 COR 4  and in which R 1  and R 2 , which may be the same or different, are H, or a straight or branched chain C 1-6  alkyl, which may be substituted by an aryl radical; R 3  is C 3-9  cycloalkyl, or an aryl radical which may be substituted by one or more halogen atoms or alkyl, NO 2 , OH, alkoxy, phenyl or CF 3  groups, or by a group -NRSR 6  in which R 5  and R 6 , which may be the same or different, are H or C 1-6  alkyl; R 4  is OH, aryloxy or C 1-6  alkoxy, which may be substituted by an aryl radical or the amine group -NR 5 R 6 , or R 4  may be -NR 7 R 8  in which R 7  and R 8 , which may be the same or different are H, OH, C 1-6  alkyl or aryl, or R 7  and R 8  together may form a heterocyclic ring which may contain additional heteroatoms; X, Y and Z may be the same or different and are H, halogen, C 1-6  alkyl, OH, C 1-6  alkoxy, or NH 2  with the following provisos: (a) when R 3 CO is para orientated to the group CR 1 R 2 COR 4 , R 1 , R 2 , X, Y, and Z are hydrogen and R 3  is phenyl then R 4  may not be OH, OCH 3 , or OC 2 H 5  or NH 2  and (b) when Z is OCH 3  in the 2-position to the group -CR 1 R 2 COR 4  and X, Y, R 1  and R 2  are H and R 3  is phenyl then the group R 3 CO- may not be in the 5-positions. The above compounds are prepared by hydrolysing the corresponding nitriles either with a mixture of acetic acid, water and sulphuric acid and with concentrated sulphuric acid, the latter method giving rise to compound wherein R 4  is NH 2 , or by subjecting an appropriately substituted acetophenone to the Willgerodt reaction, or by treating an appropriately substituted benzoyl chloride with diazomethane, reacting the thus obtained diazoketone with silver oxide and methanol, and if desired, hydrolysing the resulting methyl ester, or compounds of the above general formula in which R 1  and R 2  are alkyl or aralkyl by reacting the appropriate compound in which R 4  is alkoxy with a base, reacting the mono- and di-anion so formed with a suitable alkylating or aralkylating agent, and, if desired, hydrolysing the resulting ester. The acids so produced, if desired, may be converted to the corresponding esters, amides and salts by conventional methods, and any alkoxy or nitro groups present in the radical R 3  converted to hydroxy and amino groups respectively, and the amino groups alkylated. 4 - Cyclohexanoylphenylacetonitrile is made by reacting sodium cyanide with α - bromo - ptolylcyclohexyl ketone resulting from refluxing a mixture of N - bromosuccinimide, benzoyl peroxide and cyclohexyl - p - tolyl ketone in carbon tetrachloride. 3 - Cyanomethyl - 4,6 - dimethylbenzophenone is obtained in a similar manner from 3 - chloromethyl - 4,6 - dimethylbenzophenone, which is made by reacting a mixture of paraformaldehyde, fused zinc chloride, concentrated hydrochloric acid, acetic acid and 2,4-dimethylbenzophenone. 4[4 - (2,4 - Dimethylbenzoyl)phenylthioacetyl]- morpholide is prepared by refluxing morpholine and 4 - acetyl - 2<SP>1</SP>,4<SP>1</SP> - dimethylbenzophenone resulting from the reaction of 4 - acetylbenzoyl chloride with m-xylene in the presence of aluminium chloride. 5 - Benzoyl - 4 - methylbenzoic acid is made by hydrolysis of the 5 - cyano - 2 - methylbenzophenone, which is prepared by adding cuprous cyanide to diazotized 5 - amino - 2 - methylbenzophenone, obtained by reducing the corresponding nitro compound. 3 - Cyanomethylbenzophenone is made by reacting sodium cyanide with 3 - bromomethylbenzophenone obtained by brominating 3- methylbenzophenone which is in turn obtained by reacting a mixture of benzene, aluminium chloride and m - tolyl - chloride, resulting from the reaction of m - toluic acid with phenylchloride. 4 - Chloro - 31 - cyanomethylbenzophenone is obtained by reacting 3<SP>1 </SP>- bromomethyl - 4 - chlorobenzophenone with sodium cyanide.