ALICYCLIC CARBOXAMIDES HAVING PHYSIOLOGICAL COOLING ACTIVITY

摘要

1489359 Cycloalkane-carboxamides WILKINSON SWORD Ltd 11 Dec 1974 [12 Dec 1973] 50801/76 Divided out of 1471894 Heading C2C Novel compounds I n is 0 or an integer of from 2-6 inclusive; R is C 1 -C 5 alkyl; x is an integer of from 1-3, with the proviso that at least one R group is in a 1-, 2- or 3-position relative to the carboxamide group, the values of R, n and x being such that the total number of carbon atoms provided by the R groups and the carbocycle to which they are attached is from 8-14, preferably 8-12 and that when x is 2 or 3, each R is the same or different; and R11, when taken separately, is H or C 1 -C 10 alkyl; R111, when taken separately, is H, C 1 -C 10 alkyl, hydroxy C 1 -C 10 alkyl, or alkoxycarbonylalkyl of up to 8 carbon atoms, with the proviso that when R11 is H, R111 may also be cycloalkyl of up to 8 carbon atoms, phenyl or substituted phenyl containing alkyl, hydroxy or methoxy substituents and a total of up to 10 carbon atoms; and R11 and R111, when taken together represent an alkylene group of up to 8 carbon atoms, the carbon atom chain of which may optionally be interrupted by an oxygen atom; with the provisos that: (i) where n is 0 and x is 2, with one R group being isopropyl in the 1-position and the other R group being in the 2-position, then said other R group contains at least 2 carbon atoms, when R11 is H and R111 is phenyl; and (ii) where n is 0 and x is 2, with one R group being isopropyl in the 3-position and the other R group being in the 1-position, then said other R group contains at least 2 carbon atoms, when R11 and R111 are both ethyl, are prepared by conversion of the corresponding acid to the amide by conventional procedures. 2 - Isopropylcycloheptone - carboxylic acid is prepared by reacting a Schiffs base of cycloheptanone with isoPrI and acid hydrolysis to give 2-isopropylcycloheptanone which undergoes a Grignard reaction with EtOCH 2 MgCl followed by treatment with Ag 2 O/HCOOH; 2,6,6 - trimethylcycloheptane-carboxylic acid is similarly prepared from 2,6,6-trimethylcycloheptanone. 1-Ethyl-cyclooctanecarboxylic acid is prepared by ethylation of cyclooctane nitrile followed by hydrolysis. 1-Isopropyl-2-methylcyclopentonecarboxylic acid is prepared by hydrolysis of the corresponding ethyl ester which is obtained by hydrogenation of the corresponding cyclopentene prepared by dehydration of ethyl 2 - hydroxyl - 1 - iso - propyl- 2 - methyl - cyclopentane - carboxylate which in turn is prepared by a Grignard reaction between MeMgI and 2 - isopropyl - 2 - carbethoxycyclopentanone.