Patent GB-1447611-A (GB)
Title: Isoquinoline derivatieves and processes for their preparation
IPC: C07D217/26
Filed: 1974-12-09
Abstract: 1447611 Isoquinoline derivatives MERCK PATENT GmbH 9 Dec 1974 [10 Dec 1973] 53191/74 Heading C2C Novel compounds of the Formula I wherein R<SP>1</SP> is H or together with R<SP>2</SP> is a C-N bond, R<SP>2</SP> is H, R<SP>8</SP> or together with R<SP>1</SP> is a C-N bond, R<SP>3</SP> is H, methyl or ethyl, R<SP>4</SP> and R<SP>5</SP> are each H or together are a C-C bond, R<SP>6</SP> and R<SP>7</SP> are each H or methoxy, R<SP>8</SP> is C 1-10  acyl or alkyl which is optionally mono or polysubstituted by phenyl, OH, ArCOO,- ArCONH-, piperidino, 3,4-dehydropiperidino, morpholino, carboxy, carbomethoxy and/or carboethoxy said alkyl and any substituent(s) present therein having a total of 1 to 17 carbon atoms and Ar is 3,4,5- trimethoxyphenyl and their physiologically acceptable acid addition and quaternary ammonium salts may be prepared by (1) reacting a compound in which R<SP>9</SP> is R<SP>2</SP> or a NH 2 -substituted alkyl group with 1 to 4C atoms, with 3,4,5- trimethoxybenzoic acid or a functional derivative thereof, (2) for compounds I in which R<SP>1</SP>, R<SP>2</SP>, R<SP>4</SP> and R<SP>5</SP> are all H, reducing a compound (3) for compounds I in which R<SP>2</SP> is H or R<SP>8</SP> other than C 1-10 -acyl, and R<SP>4</SP> and R<SP>5</SP> are both H, reacting a compound in which R<SP>10</SP> is H or R<SP>8</SP> other than C 1-10  acyl, and R<SP>4</SP> and R<SP>5</SP> are both H, with 3,4,5-trimethoxybenzamidoacetaldehyde or a function derivative thereof, (3) for compounds I in which R<SP>1</SP> together with R<SP>2</SP> is a C-N bond and R<SP>4</SP> together with R<SP>5</SP> is a C-C bond, cyclizing a compound R<SP>11</SP>CH 2 NHCOAr wherein R<SP>11</SP> is R<SP>12</SP> is C 1-4  alkyl, R<SP>13</SP> is H, OH or OCH 3 , Z is O or S and R<SP>1</SP>, R<SP>2</SP>, R<SP>4</SP> and R<SP>5</SP> are all H, (4) for compounds I in which R<SP>1</SP> and R<SP>2</SP> together form a C-N bond, reacting a compound in which X is halogen or a reactively esterified OH group, with 3,4,5-trimethoxy benzamidoacetonitrile in the presence of a catalyst, (5) for compounds I in which R<SP>2</SP> is H, hydrolysing or hydrogenolysing a compound I in which R<SP>2</SP> is R<SP>8</SP>, (6) for compounds I in which R<SP>2</SP> is R<SP>8</SP>, reacting a compound I in which R<SP>2</SP> is hydrogen with a compound R<SP>8</SP>OH or a functional derivative thereof, (7) for compounds I in which R<SP>1</SP>, R<SP>2</SP>, R<SP>4</SP> and R<SP>5</SP> are all hydrogen, reducing a compound I in which R<SP>1</SP> together with R<SP>2</SP> is a C-N bond and/or R<SP>4</SP> together with R<SP>5</SP> is a C-C bond, (8) forming an acid addition or quaternary ammonium salt of I or (9) for compounds I in which R<SP>2</SP> is R<SP>8</SP> other than C 1-10  acyl and R<SP>1</SP>, R<SP>2</SP>, R<SP>4</SP> and R<SP>5</SP> are all H, reducing an appropriate quaternary isoquinolinium salt. 1 - Aminomethyl - 2 - (2 - piperidinoethyl)- 1,2,3,4 - tetrahydroisoquinoline and 1 - aminomethyl - 2 - [2 - (3,4 - dehydropiperidino)ethyl]- 1,2,3,4 - tetrahydroisoquinoline are prepared by formation of the quaternary salt from 1- benzamidomethyl - 2 - (2 - chloroethyl) - 1,2,3,4- tetrahydroisoquinoline and pyridine followed by complete or partial reduction of the salt to yield 1 - benzamido - 2 - (2 - piperidinoethyl)- 1,2,3,4 - tetrahydroisoquinoline and 1 - benzamido - 2[2 - (3,4 - dehydropiperidino)ethyl]- 1,2,3,4 - tetrahydroisoquinoline respectively followed in each case by hydrolysis of the amide group to amine. 1 - Aminomethyl - 2 - (3 - carbethoxypropyl)- 1,2,3,4 - tetrahydroisoquinoline is prepared by reaction of 1 - benzamidomethyl - 2 - (2- chloroethyl) - 1,2,3,4 - tetrahydroisoquinoline with malonic acid diethyl ester in presence of strong base followed by saponification, decarboxylation and esterificaton. 1 - Aminomethyl - 2 - (2 - hydroxy - 3 - morpholinopropyl) - 1,2,3,4 - tetrahydroisoquinoline is prepared by reacting 1-benzamidomethyl-2- (2 - hydroxy - 3 - chloropropyl) - 1,2,3,4 - tetrahydroisoquinoline with morpholine and hydrolysis of the resulting 1-benzamidomethyl-2- (2 - hydroxy - 3 - morpholinopropyl) - 1,2,3,4- tetrahydroisoquinoline. Optical isomers of 1-aminomethyl-3-methyl- 1,2,3,4 - tetrahydroisoquinoline are separated using tartaric acid. 1 - Cyano - 2 - (3,4,5 - trimethoxybenzoyl) - 3- methyl 1,2 - dihydroisoquinoline is prepared by reaction of 3-methylisoquinoline with sodium cyanide followed by reaction with 3,4,5-trimethoxybenzoyl chloride. 3,4,5 - Trimethoxybenzamido - acetaldehydediethylacetal is obtained by reaction of 3,4,5- trimethoxybenzoyl chloride with aminoacetaldehyde diethylacetal. α - (3,4,5 - Trimethoxybenzamido)- N - [2- hydroxy - 2 - (3,4 - dimethoxyphenyl)ethyl]- acetamide is prepared from 2-(3,4-dimethoxyphenyl) - 2 - hydroxy - ethylamine and 3,4,5- trimethoxybenzamidoacetyl chloride. 3,4,5 - Trimethoxybenzamidoacetonitrile is prepared from aminoacetonitrile and 3,4,5- trimethoxybenzoyl chloride. Pharmaceutical compositions of the compounds I with the usual excipients show cardiac and circulatory activity and are effective antiarrhythmic and analgesic agents when administered orally, parenterally or topically.