New methods for the synthesis of alfentanil, sufentanil, and remifentanil
AssigneeMallinckrodt Inc.
InventorsJacob Mathew, J. Killgore
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Abstract
Synthetic pathways are disclosed for synthesizing derivatives or analogs of fentanyl. Specifically set out are pathways for synthesizing alfentanil, sufentanil and remifentanil. The disclosed methods require fewer steps and produce a greater yield of product than methods reported in the prior art.
Claims10
A process for preparing an intermediate compound from which fentanyl analogs and derivatives can be synthesized, the intermediate compound having the structure
- wherein the process comprises:
- (a) hydrolyzing the ester group of an alkylated 4-amino-4-carboxyamino-piperidine compound having the formula
- to form a piperidine hydrolysis product having the formula
- (b) treating said piperidine hydrolysis product with a hydride to produce a 4-hydroxymethyl-piperidine having the structure
- wherein R is C1-6 alkyl.
A method for preparing a piperidine derivative which comprises reacting a 4-amino-4-hydroxyalkyl-piperidine with a mesylate (methanesulfonyl) of the formula R—(CH2)m—O-MS, wherein R is phenyl, thienyl or 4-ethyl-4,5-dihydro-5-oxo-1H-tetrazol-1-yl, m is an integer from 1 to about 10 and Ms is methanesulfonyl, so as to form an N-substituted R—(CH2)m-piperidine product.
A compound of the formula selected from the group consisting of:
- wherein R1 is COO—(CH2)nCH3 wherein n is an integer from 0 to about 10, R2 is alkyl, and R3 is H or alkyl;
- and
- wherein R1 is alkyl, and R2 is H or alkyl.
A process for preparing a piperidine derivative which comprises condensing a piperidone with a primary amine so as to form a 4-amino-4-carboxyamino-piperidine, wherein N of said piperidone and N of the piperidine portion of said 4-amino-4-carboxyamino-piperidine is a —N—COO—(CH2)nCH3, wherein n is an integer of from 0 to about 10, further including a step of alkylating an N of the carboxyamino group of said 4-amino-4-carboxyamino-piperidone thereby producing an N-alkyl-anilide, further including a step of hydrolyzing said —COO—(CH2)nCH3 group of said 4-amino-4-carboxyamino-piperidine following the condensation reaction so as to form a piperidine hydrolysis product, further including a step of treating said piperidine hydrolysis product with a hydride to produce a 4-hydroxymethyl-piperidine, wherein said 4-hydroxymethyl-piperidine is reacted with a haloalkyl-tetrazole so as to form an N-substituted tetrazole-pyridine product.
Dependencies are inferred from the claim text.