Mallinckrodt, Inc.

Robert E Halvachs

Gary Lee Cantrell

Peter Xianqi Wang

Frank William Moser

Joseph P Haar, Jr

Kevin R Roesch

Henry J Buehler

Esa T Jarvi

Tao Jiang

Christopher W Grote

David W Berberich

Douglas C Miller

Gary A Nichols

Neile A Grayson

Joseph P Haar

An improved process for the N-alkylation of tertiary morphinan alkaloid bases to form the corresponding quaternary morphinan alkaloid derivatives.

Process for the preparation of quaternary N-alkyl morphinan alkaloid salts

The present invention provides 3-oxy-hydromorphone derivatives, and in particular, 3-ester, 3-carbonate, and 3-sulfonate derivatives of hydromorphone.

3-oxy-hydromorphone derivatives

The present invention relates to novel crystalline forms of naltrexone methobromide including hydrated and solvated forms. The invention also describes methods of preparing the various crystalline forms. The present invention also relates to pharmaceutical compositions containing crystalline forms of naltrexone methobromide, as well as methods of treating or preventing opioid induced side effects by administering the pharmaceutical compositions.

Crystalline forms of naltrexone methobromide

The invention generally provides processes and intermediate compounds useful for the production of normorphinans and derivatives of normorphinans.

Processes and compounds for the preparation of normorphinans

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 method of making a substituted pyrazolopyrimidine. The method comprises reacting a aminopyrazole compound or a salt thereof with a substituted 1-oxo-2-propenyl-arene(-heterocycle) or a salt thereof under acidic conditions in a reaction medium including a two-phase mixture of an aqueous solution and a water-immiscible organic liquid. Specific substituted pyrazolopyrimidines include N-[3-(3-cyanopyrazolo[1,5-a]pyrimidin-7-yl)phenyl]-N-ethylacetamide and N-methyl-N-(3-{3-[2-thienyl-carbonyl]-pyrazolo[1,5-a]-pyrimidin-7-yl}phenyl)acetamide.

Two-phase method for the synthesis of selected pyrazolopyrimidines

A process for the preparation of a quaternary derivative of the morphinan alkaloid, the process comprising contacting a tertiary N-substituted morphinan alkaloid with an alkyl halide in an anhydrous solvent system, wherein the solvent system comprises an aprotic dipolar solvent with the aprotic dipolar solvent constituting at least 25 wt. % of the solvent system.

(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.

Synthesis and purification of (r*,r*)-2-&lsqb; (dimethylamino) methyl&rsqb;-1-(3-methoxyphenyl) cyclohexanol hydrochloride

A process for producing 2-halofluorobenzene from 2,4-dihalofluorobenzenes comprises treating an aqueous slurry of 2,4-dihalofluorobenzene with hydrogen at an elevated temperature in the presence of a transition metal supported on a carbon catalyst. The process produces a mixture including fluorobenzene and 2-halofluorobenzene. The 2-halofluorobenzene can be separated from the mixture by conventional means such as distillation. Optionally, the fluorobenzene also can be recovered.

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Belleville, IL, United States of America

Robert E Halvachs