Organic compounds -- part of the class 532-570 series – Organic compounds – Amino nitrogen containing
Patent
1999-07-27
2000-03-07
Killos, Paul J.
Organic compounds -- part of the class 532-570 series
Organic compounds
Amino nitrogen containing
564300, C06C21100
Patent
active
060342749
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to a novel process for preparing a naphtalenamine derivative, the compound of formula (I) (chemical name: cis-(1S)-N-methyl-4-(3,4-dichloroplenyl-1,2,3,4-tetrahydro-1-naphtalenamin e) hereinafter referred as to "sertraline" and its acid addition salts. ##STR1##
A novel intermedier used in this process, the compound of formula (II) is also disclosed. ##STR2##
It is known that sertraline hydrochloride is a valuable pharmaceutically active substance, and the pharmaceutical composition containing this compound is applicable in the treatment of depression and other dependence and anxiety-related disorders (See U.S. Pat. Nos. 4,536,518 and 5,248,699).
The preparation of sertraline is reported in the above mentioned U.S. Pat. No. 4,536,518 (or the equivalent Hungarian patent No. 182,224). The essence of the herein described process is, that 4-(3,4-diclorophenyl)-3,4-dihydro-1-(2H)-naplitalene-1-on, which can be prepared in a complicated reaction way of several steps is condensed with methylamine to the Schiff base in the presence of titane tetrachloride as catalyst. The Schiff base is hydrogenated in the presence of palladitun on carbon as catalyst, and a mixture of the cis/trans isomers of N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphtalenamine hydrochloride is obtained, where the cis/trans ratio is about 70:30. The mixture of cis/trans isomers is dissolved in a 40 times amount of hot methanol based on the starting tetralone, and the cis isomer in crystalline form can be obtained after the addition of a 30 times amount of diethyl ether. The primary yield is 48%, which is increased to 68% by working up the mother liquor obtaining a second crop of the title compound.
The disadvantages of the described process obviously appear from the above survey, namely, the appropriate diliydro-naphtalenone derivative can be prepared only in several steps with difficulties. Moreover, the hydrogenation of the Schiff-base derivative of this compound results in a mixture of cis/trans isomers. The desired cis-isomer from this mixture can be obtained only in large dilution and using big excess of solvents. The large-scale realization of this process is very disadvantageous, even without mentioning the working time, working power and energy excess made by the big solvent circulation and the work-up of the so-called secondary generation's mother liquor.
So the aim of the present invention is to produce a process which doesn't show the above disadvantages but at the same time gives sertraline or its acid addition salts in a simplier way and in better yield.
During our experiments, we found that reacting the appropriatly substituted 3,4-dihydro-naphtalenone derivative, that could be prepared in a simple way, with the commercially available N-methylhydroxylamine a so far in the literature not reported N-oxide derivative formed, which after isolation could give directly the desired cis-compound in catalytic hydrogenation, which was easily resolved and converted to sertraline.
This recognition is surprising because N-oxide derivatives similar to that compound of Formula (II) are unstable, and it was unexpected that exactly the desired stereoisoiner could be obtained by the hydrogenation.
According to the above, the invention relates to a process for preparing cis-(1S)-N--methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphtalenam ine of formula (I) and its acid addition salts, in the way, that N-methyl-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-naphtalene-1-en]-amine -N-oxide of formula (II) is hydrogenated in an inert solvent in the presence of a catalyst, then the resulting mixture is treated with alcanolic solution of a mineral acid, the resulting cis-racemic acid addition salt is converted to the free cis-base by standard techniques well-known to those skilled in the art, resolved, then in the required case the cis-(+)-base of formula (I) is converted to the acid addition salt.
According to a preferred version of the process disclosed in the invention, methanol is used as inert solvent, and
REFERENCES:
patent: 5248699 (1993-09-01), Sysko et al.
Tremaine, L et al, Drug Metab, Dispos. (1989) 17(5) 542-50.
Fellegvari Iren
Fischer Janos
Fodor Tamas
Levai Sandor
Vukics Krisztina
Killos Paul J.
Richter Gedeon
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