Synthesis of quetiapine and pharmaceutically acceptable salts thereof
AssigneeTeva Pharmaceutical Industries Ltd.
InventorsDov Diller, Ben-Zion Dolitzky
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Abstract
Provided is a novel synthesis of quetiapine employing phase transfer catalyst.
Claims34
A process for making quetiapine comprising the step of reacting 11-piperazinyl dibenzo[b,f]-[1,4]thiazepine hydrochloride and 2-(2-chloroethoxy) ethanol in a solvent in the presence of a base, and a phase transfer catalyst.
A process for making quetiapine hemifumarate comprising the steps of:
- a) reacting 11-piperazinyl dibenzo[b,f]-[1,4]thiazeine hydrochloride and 2-(2-chloroethoxy)ethanol in a solvent in the presence of a base, and a phase transfer catalyst, whereby a first slurry is obtained,
- b) separating the solid from the first slurry whereby a liquid filtrate is obtained,
- c) combining the liquid filtrate with fumaric acid, whereby a second slurry is obtained, and
- d) isolating quetiapine hemifumarate from the second slurry.
In a process for making quetiapine or a pharmaceutically acceptable salt thereof, the step of reacting 11-piperazinyl dibenzo[b,f]-[1,4]thiazepine hydrochloride and 2-(2-chloroethoxy)ethanol in a solvent that is a lower alkanol, an aromatic hydrocarbon, or a dipolar aprotic solvent, in the presence of sodium carbonate, sodium iodide, and tetrabutylammonium bromide.
A process for making quetiapine comprising the step of reacting, at reflux, 11-piperazinyl dibenzo [b,f]-[1,4]thiazepine hydrochloride and 2-(2-chloroethoxy)ethanol in a solvent selected from n-butanol, toluene, and dimethyl formamide, in the presence of sodium carbonate, sodium iodide, and tetrabutylammonium bromide.
A process for making quetiapine hemifumarate comprising the steps of:
- a) reacting, at reflux, 11-piperazinyl dibenzo[b,f]-[1,4]thiazapine hydrochloride and 2-(2-chloroethoxy)ethanol in a solvent selected from n-butanol, toluene, and dimethyl formamide in the presence of sodium carbonate, and tetrabutyl ammonium bromide, whereby a first slurry is obtained,
- b) separating the solid from the first slurry whereby a liquid filtrate is obtained,
- c) combining the liquid filtrate with fumaric acid,
- d) heating the combination to a temperature of about 100° C. or higher,
- e) subsequently cooling the combination to <100° C., whereby a second slurry is obtained, and
- f) isolating quetiapine hemifumarate from the second slurry.
Dependencies are inferred from the claim text.