Patent GB-488423-A (GB)
Title: Manufacture of isoquinoline compounds and derivatives thereof
IPC: C07D217/02
Filed: 1937-01-04
Abstract: Isoquinoline compounds containing a hydroaromatic radical in 1-position and derivatives thereof hydrogenated in the pyridine ring are formed by ring closure, with acid condensing agents such as phosphorus oxychloride, of condensation products of 1-aryl-2-aminoethanes or their 1-oxo, 1-hydroxy, or 1-methoxy or other 1-ether derivatives with a hydroaromatic acid, acid derivative or aldehyde, and, if necessary, hydrogenating or dehydrogenating the isoquinoline compound so obtained.  When starting from amines of the formula R-CH2-CH2-NH2 (R = aryl), the corresponding 3 : 4-dihydroisoquinoline compounds are obtained which may be hydrogenated to the corresponding tetrahydro compounds or dehydrogenated to the isoquinoline compounds.  When starting from amino-alcohols of the formula R-CHOH-CH2-NH2 or their ethers, on the other hand, the isoquinolines are formed directly.  The products have therapeutic properties.  In examples: (1) and (4) 1-cyclohexyl-6 : 7-dimethoxyisoquinoline is formed by heating N - hexahydrobenzoyl - b - (3 : 4 - dimethoxyphenyl)-b -methoxyethylamine with phosphorus oxychloride in dry chloroform; the parent material is formed by reacting 3 : 4-dimethoxyphenyl-methoxyethylamine with hexahydrobenzoyl chloride in dry benzene; the corresponding diethoxyisoquinoline is similarly obtained; (2) 1-D 1-cyclohexyl-6 : 7-dimethoxyisoquinoline is similarly formed from N-tetrahydrobenzoyl - b  - (3 : 4- dimethoxyphenyl) - b -methoxyethylamine; it may also be obtained by adding phosphorus oxychloride to a boiling chloroform solution of N-hexahydro-2-hydroxybenzoyl-b -(3 : 4-dimethoxyphenyl)-b -methoxyethylamine obtained by heating hexahydrosalicylic acid methyl ester and b -(3 : 4-dimethoxyphenyl) - b  - methoxyethylamine; (3) 1 - hexahydrobenzyl - 6 : 7 - dimethoxyisoquinoline is formed from N-hexahydrophenylacetyl-b -(3 : 4-dimethoxyphenyl)-b -methoxyethylamine; (5) 1 - cyclohexyl - 6 : 7 - ethylenedioxyisoquinoline is formed from N-hexahydrobenzoyl - b  - (3 : 4 - ethylenedioxyphenyl) - b -methoxyethylamine made by condensing 3 : 4-ethylenedioxybenzaldehyde with nitromethane, adding methyl alcohol to produce b -(3 : 4-ethylenedioxyphenyl) - b  - methoxynitroethane, and catalytic reduction; (6) 1-cyclohexyl-3 : 4-dihydro-6 : 7-dimethoxyisoquinoline is formed from N - hexahydrobenzoyl - 3 : 4 - dimethoxyphenylethylamine; (7) 1 - cyclohexyl - 3 : 4-dihydro - 6 : 7 - ethylenedioxyisoquinoline is formed from N - hexahydrobenzoylethylenedioxyphenylethylamine, which is itself prepared from 3 : 4 - ethylenedioxyphenylethylamine made by the catalytic reduction of o -nitrostyrene; (8) 1 - cyclohexyl - 3 : 4 - dihydro - 6 - methoxy-7-hydroxyisoquinoline is formed from N-hexahydrobenzoyl-b -(3-methoxy-4-hydroxyphenyl)-ethylamine; (9) the product of example (1) may be prepared from the product of example (6) by boiling with xylene and palladium black until evolution of hydrogen has ceased; (10) 1 - cyclohexyl - 1 : 2 : 3 : 4 - tetrahydro-6 : 7-dimethoxyisoquinoline is prepared by hydrogenating the product of example (6) in presence of palladium and dilute hydrochloric acid; it may also be prepared by hydrogenating the product of example (1) in the presence of nickel and dilute hydrochloric acid; (11) 1-D 1-cyclohexenyl-3-methyl-6 : 7-dimethoxyisoquinoline is formed from N-D 1-tetrahydrobenzoyl - 1 - (3 : 4 - dimethoxyphenyl) - 2 - aminopropanol; (12) 1 - D 1 - cyclohexenyl - 3-cyclohexyl - 6 : 7 - dimethoxyisoquinoline is p formed from N - tetrahydrobenzoyl - b  - (3 : 4-dimethoxyphenyl) - b - hydroxy - a  - cyclohexylethylamine which is prepared from 3 : 4-dimethoxyphenylhexahydrobenzoyl ketone (made by the Friedel-Crafts reaction from veratrol and hexahydrophenylacetyl chloride) by treatment with butyl nitrite to give the isonitroso compound and subsequent reduction with palladium and hydrogen in alcoholic hydrochloric acid; (13) the tetrahydro derivative of example (10) may be converted into the isoquinoline of example (1) by boiling with xylene and palladium; (14) 1-cyclohexyl-3 : 4-dihydroisoquinoline is formed from the amide obtained by condensing hexahydrobenzoic acid methyl ester with phenylethylamine; (15) 1-hexahydrobenzyl-3-methyl-6 : 7-ethylenedioxyisoquinoline is formed from N-hexahydrophenylacetyl-a -methyl - b  - 3 : 4 - ethylenedioxyphenyl - b -hydroxyethylamine made by condensing 3 : 4-ethylenedioxy - a  - amino - propiophenone with hexahydrophenylacetyl chloride and reduction of the keto group to the corresponding hydroxy body.