Mallinckrodt, Inc.

Frank William Moser

Gary Lee Cantrell

Peter Xianqi Wang

Christopher W Grote

Tao Jiang

David W Berberich

Jian Bao

Catherine E Thomasson

Robert E Halvachs

Joseph P McClurg

Daniel P Magparangalan

Joseph P Mcclurg

Dan P Magparangalan

Bobby N Trawick

Subo Liao

Esa T Jarvi

John E Johnson, Jr

Douglas C Miller

Todd Osiek

Robert Edward Halvachs

The present invention provides processes for the synthesis of substituted berbine compounds. Also provided are intermediates used in the synthesis of substituted berbine compounds.

Substituted berbines and processes for their synthesis

The present invention provides an efficient process for the preparation of hexahydroisoquinolines from amides. In particular, the invention provides a good yielding, one-pot process for the synthesis of hexahydroisoquinolines.

One-pot preparation of hexahydroisoquinolines from amides

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 is directed to the preparation of 6-hydroxy morphinans having formula (II) or N-alkylated 6-hydroxy morphinans having formula (III).

Process for the preparation of 6-alpha-hydroxy-N-alkylated opiates

The present invention provides processes for the stereoselective synthesis of 6-alpha-amino N-substituted morphinans. In particular, the invention provides processes for the reductive amination of 6-keto N-substituted morphinans by catalytic hydrogen transfer.

Preparation of 6-alpha-amino N-substituted morphinans by catalytic hydrogen transfer

The present invention provides processes for the stereoselective synthesis of 6-alpha-amino morphinans. In particular, the invention provides processes for the reductive amination of 6-keto normorphinans by catalytic transfer hydrogenation.

Reductive amination of 6-keto normorphinans by catalytic hydrogen transfer

The present invention is directed to processes for the synthesis of morphinans. In particular, a process for coupling a carboxylic acid compound with an amine compound to form an amide product that can then be isolated or the crude amide product can be cyclized to form a 3,4-dihydroisoquinoline. In one embodiment, the carboxylic acid contains a phenol moiety protected with a labile protecting group. The protected phenol reduces reaction times, simplifies work-up of the product, and reduces the amount of cyclizing agent, POClthat is necessary to form the 3,4-dihydroisoquinoline.

Preparation of amides from an acid and amine for intermediates in the synthesis of morphinans

Preparation of 3,4-dihydroisoquinolines from an acid and an amine

The present invention provides an efficient process for the preparation of hexahydroisoquinolines from dihydroisoquinolines. In particular, the invention provides a good yielding, one-pot process for the synthesis of hexahydroisoquinolines.

One-pot preparation of hexahydroisoquinolines from dihydroisoquinolines

The present invention is directed to the preparation of 6-keto morphinans.

The invention generally provides processes and intermediate compounds useful for the production of (+)-opiates. Non-limiting examples of (+) opiates that may be derived from one or more compounds of the invention include (+)-noroxymorphone, (+)-naltrexone, (+)-naloxone, (+)-N-cyclopropylmethylnorhydrocodone, (+)-N-cycloproylmethylnorhydromorphone, (+)-N-allylnorhydrocodone, (+)-N-allylnorhydromorphone, (+)-noroxycodone, (+)-naltrexol, (+)-naloxol, and (+)-3-O-methyl-naltrexone.

Process and compounds for the production of (+)opiates

The present invention is directed to processes for the synthesis of morphinans. In particular, a process for the asymmetric reduction of an imine moiety in a 3,4-dihydroisoquinoline to produce a tetrahydroisoquinoline, followed by a Birch reduction to produce a hexahydroisoquinoline. In various embodiments, the 3,4-dihydroisoquinoline contains a phenol moiety protected with a labile protecting group. In other embodiments, the imine reduction reaction mixture contains silver tetrafluoroborate.

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Arnold, MO, United States of America

Frank William Moser