Process for the preparation of sufentanil base and related compounds
AssigneeMallinckrodt Inc.
InventorsBrian Orr, Joseph P. Haar, Jr., George H. Klemm, Keith G. Tomazi
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Abstract
The present disclosure generally related to an improved process for the preparation of various piperidine derivatives. More particularly, the present disclosure related to an improved process for preparing sufentanil base (1) and related compounds, which advantageously utilizes more cost effective and/or less hazardous reagents, including a dispersion comprising between about 50% and about 70% by weight (based on the total weight of the dispersion) of an alkali metal hydride, such as sodium hydride, as well as eliminates the need for expensive and/or time consuming purification techniques.
Claims14
A process for preparing a compound of Formula (3),
- the process comprising:
- (i) contacting a substituted 4-hydroxymethyl-4-aminopiperidine of Formula (2)
- with a dispersion comprising between about 50 and about 70% by weight (based on the total weight of the dispersion) alkali metal hydride in the presence of an alcohol catalyst and an organic solvent selected from the group consisting of N, N-dimethyl tormamide (DMF), 1methyl-2-pyrrolidinone (NMP), dimethoxy ethane (glyme), diethylene glycol diethyl ether (diglyme), dimethyl sulfoxide (DMSO), and combinations thereof, to deprotonate the hydroxyl group of the substituted 4-hydroxymethyl-4-aminopiperidine;
- and,
- (ii) reacting an alkylating agent with the deprotonated, substituted 4-hydroxymethyl-4 aminopiperidine to form the compound of Formula (3).
A process for preparing an amide of Formula (C) comprising:
- (i) contacting a compound of Formula (2) with a dispersion comprising between about 50% and about 70% by weight (based on the total weight of the dispersion) alkali metal hydride in the presence of an alcohol catalyst and an organic solvent to deprotonate the hydroxyl group of the compound of Formula (2);
- (ii) reacting an alkylating agent with the deprotonated compound of Formula (2) to form the compound of Formula (3);
- (iii) contacting the compound of Formula (3) with an alkyl acid halide in an organic solvent to form the amide of Formula (C);
- (iv) removing a portion of the organic solvent from the amide of Formula (C);
- and,
- (v) collecting the amide of Formula (C);
- wherein Formula (C), Formula (2), and Formula (3) are as follows:
- and wherein R1 is 2-thiophen-2-ylethyl;
- R2 is methoxymethyl;
- and R3 is a C1-C5 alkyl.
Dependencies are inferred from the claim text.