IE35027L - Aryloxy-and alkylthio-alkanoic acids. - Google Patents

Abstract

1331839 Aryloxy and aryl thioalkanoic acids, amides and esters CIBA-GEIGY AG 19 April 1971 [20 March 1970] 24671/71 Heading C2C Novel aryloxy- and arylthioalkanoic acids, amides and esters of the Formula I wherein R 1 is a C 1-14 alkyl or C 5-7 cycloalkyl; R 2 is hydrogen or methyl; R 3 is OH, OM, C 1-3 alkoxy or unsubstituted amino; X and Y are independently oxygen or sulphur and M is an alkali or alkaline earth metal may be prepared by (a) condensing an alkali metal salt of II with a compound III wherein A is halogen, alkylsulphonyloxy or arylsulphonyloxy; (b) forming the free acid I by hydrolysing a functional derivative of I to form a carboxyl group at COR 3 ; (c) forming I in which R 2 is hydrogen and R 3 hydroxy by heating under hydrolysing conditions a compound IV wherein Z 1 and Z 2 are independently C 1-6 alkoxycarbonyl or nitrile, until one Z group is hydrolysed and the other is replaced by hydrogen; (d) I in which R 2 is hydrogen, heating to remove a mole of carbon dioxide from V (e), for I in which R 3 is NH 2 , reacting a compound VI wherein B is halogen or alkoxy, with ammonia; (f), for I in which R 3 is NH 2 , partially hydrolysing a nitrile group of VII to CONH 2 ; (g), for I in which R 3 is a C 1-3 alkoxy, reacting VII with a C 1-3 alkanol in the presence of water and mineral acid; (h) forming an alkali metal derivative of an alkali metal salt or a halomagnesium derivative of a halo-magnesium salt of acid VIII and reacting the organo metallic compound with a mole of R 1 A wherein A is as above; (i), for I in which R 2 is methyl and R 3 is hydroxy, reacting a compound II with a methane tri- or tetra-substituted by chlorine and/or bromine and a ketone R 1 COCH 3 or the reaction product of the latter two compounds, i.e. XI wherein Hal is chlorine or bromine, in the presence of at least a fourfold excess molar amount of a strong base and; (j) optionally converting free acids to salts with alkali- or alkaline earth metals and vice versa. The intermediates II may be formed by reacting a sodium m- or p-methoxy phenolate or thiophenolate with 2-bromo cyclohexanone to form the 2(m or p-methoxy phenoxy or phenylthiol)-cyclohexanone cyclizing the product with ortho-phosphoric acid to give 2 or 3 methoxy - 6,7,8,9 - tetrahydrodibenzo - furan or thiophene, followed by demethylation with pyridine hydrochloride. The compound II in which X is oxygen may be converted to those in which X is sulphur by forming the dimethyl thiocarbamic acid ester at the 2- or 3-position of the ring, rearranging the ester to a dimethyl carbamic acid 5-ester and hydrolysing to give II in which X is sulphur. The intermediates IV, V, VII and VIII may be prepared by processes similar to (a) above. Pharmaceutical compositions of the compounds I show hypolipaemic activity when administered orally or parenterally with the usual excipients. [GB1331839A]