Octahydrobenzofuro[3,2-e]isoquinoline analgesic and narcotic antagonistic compounds which can be prepared by the process of this invention are disclosed in U.S. Pat. No. 4,243,668. In that patent are disclosed the compounds having the following formula: ##STR1## in which R.sup.1 is --H, C.sub.1-10 alkyl, --CH.sub.2 R.sup.6, ##STR2## or --CH.sub.2).sub.n CN in which n is 1-3; R.sup.2 is --H, --OH, C.sub.1-12 alkoxy or C.sub.2-12 acyloxy of an alkanoic acid;
R.sup.3 is --H, --OH, --CH.sub.3, C.sub.1-2 alkoxy, C.sub.2-12 acyloxy of an alkanoic acid, --F or --N.sub.3 ; PA1 R.sup.4 is --H or --F; PA1 R.sup.3-4 in combination are methylene or keto; PA1 R.sup.5 is --H, --OH, ##STR3## or --OCH.sub.3 ; R.sup.6 is ##STR4## --C.tbd.CH, C.sub.3-6 cycloalkyl, 2-thienyl, 2-furyl or tetrahydrofuryl; R.sup.7 is C.sub.1-3 alkyl, --OCH.sub.3, --Cl, --Br or --F; and PA1 R.sup.8 and R.sup.9 are, independently, --H, --CH.sub.3 or --Cl. PA1 R.sup.6 is C.sub.3-6 cycloalkyl, phenyl or 2-tetrahydrofuryl optionally substituted with a methyl group; and PA1 R.sup.7 is --H or C.sub.1-3 alkyl. PA1 R.sup.1 is as defined above; PA1 R.sup.2 is --H or C.sub.1-12 alkoxy or, in Compound XI, R.sup.2 may be --OH; PA1 R.sup.10 is C.sub.1-10 alkyl; PA1 R.sup.11 is --OH, C.sub.1-3 alkyl carbonyloxy, --Cl, --Br, --I, p-MeC.sub.6 H.sub.4 SO.sub.3 -- or MeSO.sub.3 ; PA1 R.sup.12 and R.sup.13 are --H or C.sub.1-3 alkyl and taken together may form a C.sub.2-5 alkylene group, optionally substituted with a methyl group, except that R.sup.12 and R.sup.13 may not both be --H; PA1 R.sup.14 is --OH, Me.sub.3 SiO-- or t-BuMe.sub.2 SiO--; PA1 R.sup.15 is C.sub.1-3 alkyl carbonyloxy or --OCH(R.sup.12)OR.sup.13, or, in Compounds IX and X, R.sup.15 may be R.sup.11, or, R.sup.11 or R.sup.14, respectively; PA1 L is --Cl, --Br, --I, p-MeC.sub.6 H.sub.4 SO.sub.3 -- or MeSO.sub.3 --; and PA1 a is -- or , ##STR7## PA1 R.sup.1 is --CH.sub.2).sub.n CN; PA1 R.sup.2 is C.sub.2-12 acyloxy; PA1 R.sup.5 is --OH, ##STR9## or --OCH.sub.3 ; R.sup.6 is ##STR10## --C.tbd.CH, 2-thienyl or 2-furyl, optionally substituted; R.sup.7 is --OCH.sub.3 or --Cl, --Br or --F; and PA1 R.sup.8 and R.sup.9 are, independently, --H, --CH.sub.3 or --Cl.
It is disclosed by way of example that R.sup.6 may also be phenyl.
A process for preparing the compounds is disclosed in the patent, as are utility, dosage formulations and preferred compounds.
It is an object of this invention to provide a new process for preparing the isoquinoline compounds disclosed in said patent.
Zimmerman, et al., U.S. Pat. No. 4,236,009, disclose the following process: reaction of phenyllithium, optionally substituted at the meta-position, with a 1-alkyl- or 1-benzyl-4-piperidone; dehydration of the product to yield a 1-alkyl- or 1-benzyl-4-aryl-1,2,3,6-tetrahydropyridine; metalation to form a carbanion; addition of a propylene or butylene dihalide at the 4-position; and cyclization of the 4-substituted product with, e.g., sodium iodide in acetonitrile. Zimmerman, U.K. Patent Application No. 2,010,806, discloses similar reactions.
Evans, et al., J. Am. Chem. Soc. 102, 5955 (1980) disclose addition of allyl bromide or 1-bromo-4-chlorobutane at the 4-position of a 1-methyl-4-aryl-1,2,3,6-tetrahydropyridine carbanion followed by cyclization of the latter adduct with sodium iodide in acetonitrile. Levine, et al., U.S. Pat. No. 3,824,242, disclose a similar metalation followed by addition of ethyl haloformate. Lewis, et al., J. Chem. Soc. (C), 1074 (1970) disclose lithium aluminum hydride reduction of the tetrahydropyridine substituted at the 4-position with ethoxycarbonyl to provide 2-methyl-5-phenyl-2-aza-7-oxabicyclo[3.2.1]octane.
USPTO Backgrounds
USPTO Backgrounds