Patent GB-1235002-A (GB)
Title: Improvements in or relating to oxazoloisoquinoline derivatives
Inventor: HOULIHAN WILLIAM JOSEPH
IPC: C07D217/02
Filed: 1968-08-09
Abstract: 1,235,002. 1 - Phenyl - 3 - imino - 1,5,6,10btetrahydro - 3H - oxazolo[4,3-a]isoquinolines. SANDOZ Ltd. 9 Aug., 1968 [25 Aug., 1967; 21 May, 1968], No. 38266/68. Heading C2C. Novel 1 - phenyl - 3 - imino - 1,5,6,10b - tetrahydro - 3H - oxazolo[4,3-a]isoquinolines of the general formula wherein R, R 1 , R 2  and R 3  are each a hydrogen, fluorine or chlorine atom or a trifluoromethyl group, R 4  and R 5  are each a hydrogen, fluorine or chlorine atom or a straight chain C 1-4  alkyl group and R 6  is a hydrogen atom or a straight chain C 1-4  alkyl group, with the provisos (i) that no more than three of R, R 1 , R 2 , R 3 , R 4  and R 5  are other than a hydrogen atom and. (ii) R, R 1 , R 2  and R 3  are such that there is never a trifluoromethyl group on each of two adjacent carbon atoms, the compounds being in free base or acid addition salt form when R 6  is a hydrogen atom and in acid addition salt form when R 6  is an alkyl group, are prepared as follows: (a) obtaining a hydrochloride by reaction of a 1-(α- hydroxybenzyl) - 1,2,3,4 - tetrahydroisoquinoline-2-carboxamide of the general formula with thionyl chloride; (b) obtaining a mixed salt of a compound of the first general formula above wherein R 6  is a hydrogen atom by reaction of an α-phenyl-1,2,3,4-tetrahydroisoquinoline-1-methanol of the general formula with cyanogen bromide and lithium, sodium, potassium or calcium acetate in the presence of an inert organic solvent; (c) obtaining an acid addition salt of a compound of the first general formula above wherein R 6  is a straight chain C 1-4  alkyl group by reaction of an α-phenyl- 1, 2, 3,4-tetrahydroisoquinoline-1-methanol of the general formula wherein R<SP>1</SP> 6  is a straight chain C 1-4  alkyl group, with cyanogen bromide and the acetate of lithium, sodium, potassium or calcium, and reaction of the resulting 1-(α-hydroxybenzyl)- 1,2,3,4 - tetrahydroisoquinoline - 2 - carbonitrile of the general formula with an acid; (d) obtaining a compound of the first general formula above wherein R 6  is a hydrogen atom or an acid addition salt thereof by basifying an acid addition salt of the general formula wherein A is a chlorine or bromine atom or an acetate group, and, when an acid addition salt is required, reacting the resulting compound of the first general formula above wherein R 6  is a hydrogen atom with an acid; and (e) obtaining an acid addition salt of a compound of the first general formula above wherein R 6  is a straight chain C 1-4  alkyl group by basifying and then acidifying the corresponding hydrochloride salt. Pharmaceutical compositions having antidepressant and anorexic activity comprise, as active ingredient, a 1-phenyl-3-imino-1,5,6,10btetrahydro - 3H - oxazolo[4,3-a]isoquinoline of the first general formula above or a pharmaceutically acceptable acid addition salt thereof, the compound being in the form of a said acid addition salt unless R 6  is a hydrogen atom, in association with a pharmaceutically acceptable carrier or diluent, and may be administered orally or parenterally. 1 - (α - Hydroxybenzyl) - 1,2,3,4 - tetrahydroisoquinoline-2-carboxamides of the second general formula above are prepared by treatment of an α - phenyl - 1,2,3,4 - tetrahydroisoquinoline- 1-methanol of the general formula under acidic conditions with an alkali metal isocyanate in an inert organic solvent. α - Phenyl - 1,2,3,4 - tetrahydroisoquinoline- 1 -methanols of the general formula immediately above are prepared (a) by cyclization of an N- phenethyl - 2 - phenyl - acetamide of the general formula with phosphorus pentoxide in an inert solvent at 75-150 C., treatment of the resulting 1 - benzyl - 3,4 - dihydroisoquinoline of the general formula with air or oxygen and reduction of the obtained 1 - benzoyl - 3,4 - dihydroisoquinoline of the general formula at 20-50 C. in an inert solvent with hydrogen in the presence of a platinum catalyst; or (b) by reaction of a 1-cyano-2-benzoyl-1,2-dihydroisoquinoline with a lithium compound and a benzaldehyde derivative, followed by catalytic hydrogenation.