Patent GB-1188349-A (GB)
Title: Tartranilic Acid Derivatives, their preparation and their use as Resolving Agents
Inventor: MONTZKA THOMAS ALFRED
IPC: C07D217/14
Filed: 1967-04-28
Abstract: 1,188,349. Tartranilic acid derivatives. BRISTOL-MYERS CO. 28 April, 1967 [29 April, 1966], No. 19693/67. Heading C2C. Novel optically active tartranilic acid derivatives having the general formula wherein R<SP>1</SP> is hydrogen, chloro, bromo or nitro and R<SP>2</SP> is hydrogen, chloro or bromo, but R<SP>1</SP> and R<SP>2</SP> are not both hydrogen, and acid addition salts thereof are prepared by heating a mixture of an optically active isomer of 2,3-diacetoxy succinic anhydride or a corresponding mono-acid halide or mono-mixed anhydride and an aniline derivative of the general formula to produce a diacetyl-tartranilic acid derivative which is deacetylated by treatment with alkali. (+)-2,3-Diacetoxysuccinic anhydride is prepared by reacting (+)-tartaric acid and acetic anhydride. Racemic organic amines are resolved by (a) forming a mixture of the two enantiomeric salts of the amine with an optically active tartranilic acid derivative of the first general formula above, (b) separating said enantiomeric salts by fractional crystallization and (c) converting said separated enantiomeric salts to the respective optical isomers of the organic amine. Examples of amines which can be resolved are (Œ)-6,7- dimethoxy - 1 - # - hydroxyethyl - 2 - methyl- 1,2,3,4 - tetrahydroisoquinoline (A), (Œ) - 1- (# - p - chlorothiophenoxy - ethyl) - 6,7 - dimethoxy - 2 - methyl - 1,2,3,4 - tetrahydroisoquinoline (B) and (Œ)-6,7-dimethoxy-1,2,3,4- tetrahydroisoquinoline - 1 - acetic acid ethyl ester (C). The optical isomers of amine (A) may be reacted with p-bromobenzene sulphonyl chloride in the presence of chloroform and sodium carbonate to give the optical isomers of [2,1-a] - azetidino - 6,7 - methoxy - 2 - methyl- 1,2,3,4 - tetrahydroisoquinolium p - bromobenzenesulphonate, which may be treated with pchlorothiophenol to form the optical isomers of amine (B). Racemic amine (B) is prepared (i) by reaction of #-p-chlorothiophenoxypropionic and homoveratrylamine, treatment of the resulting # - (p - chlorothiophenoxy) - propionic homoveratrylamide with phosphoryl chloride, reduction of the 1 -(#-p-chlorothiophenoxyethyl)-6,7- dimethoxy - 3,4 - dihydroisoquinoline so produced with sodium borohydride or lithium aluminium hydride and treatment of the 1-(#-pchlorothiophenoxyethyl) - 6,7 - dimethoxy- 1,2,3,4- tetrahydroisoquinoline thus obtained with formaldehyde and formic acid; or (ii) by reaction of homoveratrylamine with diethyl ethoxymethylene-malonate, followed by treatment with hydrochloric acid and then oxalic acid, reaction of the resulting 6,7 - dimethoxy-1,2,3,4-tetrahydroisoquinoline - 1 - acetic acid ethyl ester oxalate, i.e. the oxalate of amine (C), with formaldehyde and formic acid, followed by hydrochloric acid, reduction of the free base corresponding to the 6,7-dimethoxy-2-methyl-1,2,3,4- tetrahydroisoquinoline - 1 - acetic acid ethyl ester hydrochloride so obtained with lithium aluminium hydride, reaction of the free base corresponding to the resulting 6,7-dimethoxy-1-#- hydroxyethyl - 2 - methyl - 1,2,3,4 - tetrahydroisoquinoline hydrochloride with p-bromobenzenesulphonyl chloride in the presence of chloroform and sodium carbonate and reaction of the [2,1-a] - azetidino - 6,7 - dimethoxy - 2 - methyl- 1,2,3,4 - tetrahydroisoquinolinium p - bromobenzenesulphonate thus produced with p-chlorothiophenol.