Patent GB-1013233-A (GB)
Title: 3-aryl-5-cycloaliphatic-3-pyrrolidinols and their preparation
Inventor: GOULD WILLIAM ANDREW
IPC: C07D207/24
Filed: 1963-08-21
Abstract: The invention comprises compounds of formula <FORM:1013233/C2/1> where Y is a hydrogen atom, one or two halogen atoms, one or two hydroxy radicals, one or two alkyl radicals, or an alkoxy, phenoxy, halophenoxy, phenyl, halophenyl, benzhydryloxy, trifluoromethyl, methylmercapto, or isopropylidenedioxy radical, or <FORM:1013233/C2/2> where Z is a hydrogen atom, one or two halogen atoms, or an alkoxy or alkyl radical, each of said alkyl and alkoxy radicals having 1-4 carbon atoms, R2 is hydrogen, or an aliphatic hydrocarbon group having 1-4 carbon atoms, and R5 is a cycloaliphatic hydrocarbon radical having at least 5 carbon atoms, and their pharmaceutically acceptable acid-addition salts, which are prepared by hydrolysis or alcoholysis of the corresponding 1-carbalkoxy or 1-acyl compounds of the general formula <FORM:1013233/C2/3> where R1 is an alkyl or alkoxy group, in the presence of a strong base. Suitable strong bases include sodium methoxide or hydroxide, potassium hydroxide or t-butoxide, or calcium oxide, alkoxide or hydroxide.  In Formula III where Y represents a hydroxyl group the products may be prepared by hydrogenolysis of the corresponding benzyloxy compound.  The dihydroxy substances may also be prepared by dilute acid hydrolysis of the corresponding isopropylidenedioxy compounds.  Where Y represents a substituted benzyloxy or benzyhydroloxy group the products may be prepared by reaction of the corresponding 1-acyl or 1-carbalkoxy-3-(hydroxyphenyl) - 3 - pyrrolidinol with the desired benzyl or benzhydryl halide.  Compounds in which R5 is a saturated cycloaliphatic group may be prepared by catalytic hydrogenation of the corresponding unsaturated compound. In order to prepare compounds in which R5 represents an olefinically unsaturated cycloaliphatic group and in which Y represents an -OH group, which is normally prepared by hydrogenolysis of a corresponding benzyloxy compound, the debenzylation is preferably effected by chemical methods, e.g. with sodium and butanol or sodium and liquid ammonia.  Therapeutic compositions which are useful as smooth muscle depressants, vasodilators and vasoconstrictors, and which may be administered orally or parenterally (e.g. as tablets, capsules, elixirs, solutions or suspensions), contain as active ingredient compounds of the first general formula above. 1-Carbalkoxy or 1-acyl compounds of the third formula above are prepared by reacting an N-carbethoxy-a -amino acid ester or N-acyl-a -amino acid ethyl ester with the ester of an a ,b -unsaturated carboxylic acid to form a 1,4-dicarbalkoxy - 3 - pyrrolidinone or 1 - acyl - 4 -carbalkoxy-3-pyrrolidinone appropriately substituted in the 2 and 5 positions, which is then partially hydrolysed and decarboxylated to give a 1-carbalkoxy or 1-acyl 3-pyrrolidinone and this compound is reacted with an appropriate Grignard reagent, and hydrolysed.  The 3-cycloalkyl and 3-cycloalkenyl substituted acrylic esters are prepared from the corresponding cycloalkyl or cycloalkenyl carboxaldehyde and malonic acid.