Patent GB-681358-A (GB)
Title: Preparation of isoquinoline derivatives
IPC: C07D217/22
Filed: 1949-05-04
Abstract: Compounds of the formula <FORM:0681358/IV (b)/1> where R is an alkylene group CnH2n (n not greater than 16), Y is a primary, secondary or tertiary amino group (in the latter cases the other groups attached to the nitrogen atom being aliphatic or aralkyl)-Y may be a heterocyclic nitrogen residue and this may also include R, provided that the oxygen atom is attached to a carbon atom of R-R1 is hydrogen, alkyl, aralkyl or aryl and R11 and R111 are hydrogen, methyl, alkoxy, benzyloxy, halogen, amino or acylamino, are prepared by reacting the alkali metal derivative of YROH with the appropriate 1-chloro-isoquinoline.  The latter may be obtained by treating the corresponding 1-hydroxy-derivative (or isoquinolone) with phosphorus oxychloride.  If Y is benzylamino or dibenzylamino it may be converted into a primary amino group by catalytic hydrogenation in the presence of 2 mols. of hydrochloric acid. The products of the above formula yield salts with acids, e.g. hydrochloric, hydrobromic, sulphuric, phosphoric, succinic, tartaric and benzoic.  In the examples, 1-chlorisoquinoline, 1 - chlor - 3 - methylisoquinoline, 1 - 1 - chlor - 3 - ethylisoquinoline, 1 - chlor - 3 - propylisoquinoline and 1 - chlor - 3 - butyl - isoquinoline are reacted with the sodium derivatives of b  - dimethylaminoethanol, b - diethylaminoethanol, b -dibutylaminoethanol, b -benzylaminoethanol, b  - piperidinoethanol and b  - diethylaminopropanol.  Details are given of the preparation of the above 1-chlorisoquinolines and of 1-chlor-6 : 7-dimethoxy-3-ethylisoquinoline.  In other compounds mentioned, R1 is pentyl, benzyl and phenyl, R11 and R111 are dimethyl, dimethoxy, monoethoxy, dibenzyloxy, mono- and di-chloro and bromo and mono-acetylamino and Y is dipropylamino, diamylamino, diheptylamino, dioctylamino, methylamino, ethylamino, propylamino, butylamino, amylamino, hexylamino, heptylamino, octylamino, cyclopentylamino, cyclohexylamino, amylmethylamino, benzylmethylamino, benzylethylamino, cyclopentylethylamino, cyclohexylethylamino and morpholino; in addition YROH may be tropine, 4-hydroxy-N-methylpiperidine or 1-(b -hydroxyethyl)-piperidine. Samples have been furnished under Sect. 2 (5) of (1) 1-(b -dimethylaminoethoxy)-3-phenylisoquinoline prepared by treating 3-phenylisocarbostyril with phosphorus oxychloride, and reacting the resulting 1-chlor-3-phenylisoquinoline with the sodium derivative of b -dimethyl aminoethanol; it is purified via its hydrochloride; and (2) 1-(b -dimethylaminoethoxy)-3-benzylisoquinoline prepared similarly from 3-benzyl-isocarbostyril via 1-chlor-3-benzylisoquinoline.  In the Specification as open to inspection under Sect. 91 it is stated that R11 and/or R111 may be fluorine, and that if Y is a secondary or tertiary amino group there may be an aryl radical attached to the nitrogen atom.  It is also stated that the starting material may be the corresponding 1-chloro or 1-bromo-isoquinoline, prepared by treating the appropriate isocarbostyril with a chlorinating or brominating agent.  This subject-matter does not appear in the Specification as accepted.