Mallinckrodt, Inc.

Esa T Jarvi

Robert E Halvachs

James R Meyer

Douglas C Miller

Peter Xianqi Wang

Frank William Moser

Dennis J Kalota

Subo Liao

Keith G Tomazi

Anthony Mannino

Brian Orr

Edmund C Hudson

John Brandt

Brenda E Allen

Michael Schaefer

Neile A Grayson

The present invention provides processes for preparing normorphinans from N-substituted morphinans. In particular, the invention provides methods for removing the N-substituent from the N-substituted morphinan to from a normorphinan carbamate, and then removing the carbamate functionality from the normorphinan carbamate to form the normorphinan.

Preparation of normorphinans

The invention provides processes for the production of opiate alkaloids. In particular, the present invention provides processes for the formation of buprenorphine and derivatives of buprenorphine that minimizes the formation of impurities.

Processes for the alkylation of norbuprenorphine with reduced impurity formation

The present invention provides process for the production of opiate alkaloids. In particular, the present invention provides processes for the production of buprenorphine or a derivative of buprenorphine that minimizes the formation of impurities.

Processes for the production of buprenorphine with reduced impurity formation

An improved process for the preparation of a heteroaryl acetamide from a heteroaryl &#x3b1;-hydroxyacetamide is provided. The process comprises directly hydrogenating the heteroaryl &#x3b1;-hydroxyacetamide in the presence of a strong acid, a halide and a catalyst wherein the molar ratio of the starting heteroaryl &#x3b1;-hydroxyacetamide to water at the initiation of hydrogenolysis is at least about 2:1. In one embodiment, the heteroaryl acetamide is zolpidem and the heteroaryl &#x3b1;-hydroxyacetamide is &#x3b1;-hydroxyzolpidem.

Synthesis of heteroaryl acetamides from reaction mixtures having reduced water content

An improved process for the preparation of a heteroaryl acetamide from a heteroaryl &#x3b1;-hydroxyacetamide is provied. The process comprises directly hydrogenating the heteroaryl &#x3b1;-hydroxyacetamide in the presence of a strong acid, a halide and a catalyst. In one embodiment, the heteroaryl acetamide is zolpidem and the heteroaryl &#x3b1;-hydroxyacetamide is &#x3b1;-hydroxyzolpidem.

Synthesis of heteroaryl acetamides

(R*,R*)-2-&lsqb;(dimethylamino)methyl&rsqb;-1-(3-methoxyphenyl)cyclohexanol (Tramadol) is synthesized in a Grignard reaction in the presence of an additive resulting in a higher trans:cis ratio of product than is obtained in the absence of the additive. The Grignard reaction between 3 bromoanisole and the appropriate Mannich base in the presence of an amine or ether additive gives the amine product in an improved trans/cis ratio. The base is converted to its hydrochloride and recrystallized from a low molecular weight nitrile such as acetonitrile until a greater than 98% trans/cis ratio is obtained. Recrystallization from isopropanol gives (R*,R*)2-&lsqb;(dimethylamino)methyl&rsqb;-1-(3-metboxyphenyl)cyclohexanol hydrochloride free of the nitrile solvent. A hydrochloride of Tramadol can be synthesized without increasing a ratio of trans:cis by including a step in which HCl is added to Tramadol base in the presence of toluene.

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Ballwin, MO, United States of America

Esa T Jarvi