Process for preparing a pharmaceutically active compound (granisetron)
View Patent ↗The invention relates to a process for preparing granisetron, or a pharmaceutically acceptable salt thereof, which comprises: a) cyclisation of a compound of formula (I) in an inert solvent and at a temperature between 0–100° C., in the presence of a strong acid, in order to yield the compound of formula (II); b) methylation of the compound of formula (II), with an alkylating agent, in the presence of a base, in an inert solvent and at a temperature between 0° C.–160° C., and with optional formation of a pharmaceutically acceptable salt. The process of the invention yields a granisetron of high purity, preventing impurities due to demethylation, by carrying out the methylation after rather than before cyclisation and with a higher yield.
1. Process for preparing granisetron, or a pharmaceutically acceptable salt thereof, which comprises:
a) cyclisation of a compound of formula (I):
in an inert solvent and at a temperature between 0–100° C., in the presence of a strong acid, in order to yield the compound of formula (II):
b) methylation of the compound of formula (II), with an alkylating agent, in the presence of a base, in an inert solvent and at a temperature between 0° C.–160° C. and optionally obtaining a pharmaceutically acceptable salt thereof.
2. Process as claimed in claim 1 , wherein step a) is carried out in a protic solvent or mixture of protic solvents.
3. Process as claimed in claim 1 , wherein step a) is carried out at a temperature between 10° C. and 40° C.
4. Process as claimed in claim 1 , wherein said alkylating agent is dimethyl sulphate.
5. Process as claimed in claim 1 , wherein said alkylating agent is dimethyl carbonate.
6. Process as claimed in claim 1 , wherein the solvent of step b) is selected from among methylene chloride, toluene or tetrahydrofuran.
7. Process as claimed in claim 1 , wherein said base is sodium or potassium hydroxide in concentrated aqueous solution or in solid form.
8. Process as claimed in claim 1 , wherein step b) is carried out in the presence of a phase transfer catalyst.
9. Process as claimed in claim 1 , wherein the solvent of step b) is a polar aprotic solvent selected from either dimethylformamide (DMF) or N-methyl-2-pyrrolidonone (NMP).
10. Process as claimed in claim 1 , wherein said base is an alkaline carbonate.