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.
Claims20
A process for preparing a piperidine derivative, the process comprising:
- (i) contacting a substituted 4-hydroxymethyl-4-aminopiperidine with a dispersion comprising between about 50% and about 70% by weight (based on the total weight of the dispersion) alkali metal halide 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 an ether derivative thereof.
A process for preparing sufentanil base, the process comprising:
- (i) preparing a purified 4-(methoxymethyl)-N-phenyl-1-(2-(thiophen-2-yl)ethyl)piperidin-4-amine, the process comprising:
- (a) combining (4-phenylamino)-1-(2-(thiophen-2-yl)ethyl-piperidin-4-yl)methanol with a dispersion comprising about 60% by weight sodium hydride or about 60% by weight potassium hydride in the presence of an alcohol catalyst to form a first reaction mixture;
- (b) heating the first reaction mixture to a temperature between about 65° C. and about 70° C. for about 2 hours to deprotonate the (4-phenylamino)-1-(2-(thiophen-2-yl)ethyl-piperidin-4-yl)methanol;
- (c) adjusting the temperature of the resulting mixture containing the deprotonated (4-phenylamino)-1-(2-(thiophen-2-yl)ethyl-piperidin-4-yl)methanol to between about 5° C. and about 10° C.;
- (d) adding an alkylating agent to the temperature adjusted solution, while maintaining the temperature thereof between about 5° C. and about 10° C., to form a crude 4-(methoxymethyl)-N-phenyl-1-(2-(thiophen-2-yl)ethyl)piperidin-4-amine;
- (e) isolation of the crude 4-(methoxymethyl)-N-phenyl-1-(2-(thiophen-2-yl)ethyl)piperidin-4-amine by the addition of water and filtering the product;
- (f) purifying the isolated crude 4-(methoxymethyl)-N-phenyl-1-(2-(thiophen-2-yl)ethyl)piperidin-4-amine by liquid-liquid extraction in a solvent system comprising an organic phase and an aqueous phase at a pH between about 5.0 and about 5.2, the organic phase soluble 4-(methoxymethyl)-N-phenyl-1-(2-(thiophen-2-yl)ethyl)piperidin-4-amine being partitioned into the aqueous phase by adjusting the pH thereof to between about 2.0 and about 2.7;
- and,
- (g) isolating the 4-methoxymethyl)-N-phenyl-1-(2-(thiophen-2-yl)piperidin-4-amine by adjusting the pH of the partitioned aqueous phase to a pH of greater than about 12 by the addition of a base thereto;
- and,
- (ii) converting of the purified 4-(methoxymethyl)-N-phenyl-1-(2-(thiophen-2-yl)ethyl)piperidin-4-amine to sufentanil base, the process comprising:
- (a) reacting the purified 4-(methoxymethyl)-N-phenyl-1-(2-(thiophen-2-yl)ethyl)piperidin-4-amine in a second reaction mixture comprising propionyl chloride and an organic solvent, to form an amide derivative thereof;
- (b) subjecting the resulting reaction mixture to distillation to remove between about 70% and about 80% (by weight) of the organic solvent therefrom;
- (c) adding HU to the distilled mixture to form sufentanil HCl;
- (d) subjecting the resulting sufentanil HCl mixture to distillation to remove additional organic solvent;
- and,
- (e) adding base to the distilled sufentanil HCl mixture to form sufentanil base.
Dependencies are inferred from the claim text.