Method of making piperidine derivatives
View Patent ↗The present invention relates to a process for the preparation of piperidine derivatives including sufentanil, and their pharmaceutically acceptable salts, such as the citrate salt in which a quaternary ammonium (nosylate) salt of an appropriate piperidine is reacted with a corresponding 4-NO 2 sulfonate ester to produce the desired piperidine derivative at a high purity.
1. A method of making a 4-anilido-piperidine derivative of formula (4) comprising:
reacting a piperidine ammonium salt of formula (2)
with a 4-NO 2 sulfonate ester of formula (3)
where R is selected from —COOMe or —CH 2 OMe, and where R1 is selected from the following formulae (a), (b), (c), or (d):
to produce the 4-anilido-piperidine derivative.
2. The method of claim 1 wherein the 4-NO 2 sulfonate ester of formula (3) is prepared by reacting an alcohol selected from formula (a1), (b1), (c1), or (d1) with 4-nitrobenzenesulfonyl chloride:
3. The method of claim 1 wherein the piperidine ammonium salt of formula (2) is prepared by debenzylating the intermediate of following formula (1), or a salt thereof:
and then reacting the deprotected intermediate with nitrobenzenesulfonic acid.
4. The method of claim 1 for making sufentanil wherein a piperidine ammonium salt of formula (2B)
is reacted with a 4-NO 2 sulfonate ester of formula (3B)
5. The method of claim 4 wherein the 4-NO 2 sulfonate ester of formula (3B) is prepared by reacting 2-(2-thienyl)ethanol with 4-nitrobenzenesulfonyl chloride.
6. The method of claim 4 wherein the wherein the piperidine ammonium salt of formula (2B) is prepared by debenzylating an intermediate of following formula (1B), or a salt thereof:
and then contacting the deprotected intermediate with nitrobenzenesulfonic acid.
7. The method of claim 5 wherein the wherein the piperidine ammonium salt of formula (2B) is prepared by debenzylating an intermediate of following formula (1B) or a salt thereof:
and then reacting the deprotected intermediate with nitrobenzenesulfonic acid.