Optically active 5H-pyrrolo[3,4-b] pyrazine derivative, its preparation and pharmaceutical compositions containing same
Dextrorotatory isomer of 6-(5-chloro-2-pyridyl)-5-[(4-methyl-1-piperazinyl)carbonyloxy]-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazine, its preparation and pharmaceutical compositions containing it which are usable as tranquillisers and hypnotics.
1. A method of making a dextrorotatory isomer of zopiclone, 6-(5-chloro-2-pyridyl)-5-[4-methyl-1-piperazinyl) carbonyloxy]-7-oxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazine, comprising the steps of:
a) forming a first reaction mixture by mixing a solution of an optically active acid in dichloromethane to a solution of zopiclone in dichloromethane;
b) concentrating the reaction mixture to dryness under reduced pressure to form a dry salt;
c) recrystallizing the salt in acetonitrile to form a first crystallized product;
d) dissolving the crystallized product in dichloromethane with reflux;
e) adding acetonitrile to form a second reaction mixture;
f) maintaining the second reaction mixture to form a second crystallized product and recrystallizing the second crystallized product to obtain a crystallized salt;
g) dissolving the crystallized salt in water in the presence of dichloromethane to form a third reaction mixture;
h) alkalinizing the third reaction mixture to pH 11, collecting a first organic phase, extracting a remaining aqueous phase at least once with dichloromethane to obtain a second organic phase, collecting the second organic phase, and recombining the first and second organic phases;
i) washing the recombined organic phases in water, then drying over magnesium sulfate, then filtering;
j) evaporating the solvent and recrystallizing the resulting product in acetonitrile to obtain the dextrorotatory zopiclone isomer.
2. The method according to claim 1 , wherein the first crystallized product has a melting temperature of 160–165° C. and a rotatory power of [α] 20 D =83° (c=0.5; acetone).
3. The method according to claim 1 , wherein the second reaction mixture is maintained for 1 hour at 5° C.
4. The method according to claim 1 , wherein the crystallized salt has a melting temperature of 160–165° C. and a rotary power of [α] 20 D =102° (c=0.5; acetone).
5. The method according to claim 1 , wherein the alkalinizing of the third reaction mixture is achieved by the slow addition of a basic aqueous solution.
6. The method according to claim 1 , wherein the dextrorotatory zopiclone isomer has a melting temperature of 206.5° C. and [α] 20 D =135°±3° (c=1.0; acetone).
7. The method according to claim 1 , wherein the optically active acid is D(+)-O,O′-dibenzoyltartaric acid.