| 摘要 |
A process for the manufacture of the (-) trans piperidine carbinol (1) by a process comprising contacting a racemic mixture of the piperidine carbinol in solution with (-)-ditoluoyltartaric acid, crystallising the (-) -ditoluoyltartaric acid salt of the piperidine carbinol, isolating the crystalline salt and neutralising the crystalline salt to regenerate the (-) trans isomer of the piperidine carbinol and the (-)-ditoluoyltartaric acid, which is characterised by one or more of the following steps: (1) combining solutions of the racemic piperidine carbinol and (-)-ditoluoyltartaric acid in acetone so that the combined solution contains 2-3 % wt/wt of water, (2) consolidating the chiral salt crystallisation at from 30 to 40° C., (3) cooling the crystallisation mixture to from 3 to 7° C. before isolating the chiral salt, (4) regenerating the (-) trans piperidine carbinol at a pH of from 10.5 to 11.5, (5) forming a concentrated solution of the (-) trans piperidine carbinol in toluene, contacting the solution with heptane at 60-65 ° C., and cooling stepwise to crystallise the (-) trans piperidine carbinol. Alternatively, a solution of the racemic piperidine carbinol in toluene, suitably from a previous stage in the manufacture of paroxetine, is combined with a solution of (-)- ditoluoyltartaic acid in acetone. The resultant (-) trans piperidine carbinol of structure (1) may be coupled with sesamol, then deprotected, to give paroxetine (2), with optional formation of a pharmaceutically acceptable salt of paroxetine.
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