Processes for the preparation of normorphinan salts
AssigneeMallinckrodt Inc.
InventorsPeter X. Wang, Tao Jiang, Gary L. Cantrell, David W. Berberich, Jian Bao, Bobby N. Trawick
Life of this patent
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Abstract
The invention provides a process for the conversion of opioid derivatives into normorphinan compounds useful for making “nal” compound analgesics and antagonists. In particular, the process may be used for the production of pure normorphinan salts from crude opioid substrates.
Claims25
A process for the preparation of compound 2 from compound 1 according to the following reaction:
- wherein:
- R1 is selected from the group consisting of hydrogen, hydrocarbyl and substituted hydrocarbyl;
- R1a is an oxygen protecting group;
- R2 is selected from the group consisting of hydrocarbyl, and substituted hydrocarbyl;
- R3, R4, R5, and R6, are independently selected from the group consisting of hydrogen, halogen, hydroxyl, methoxy, {—}OR8, hydrocarbyl, and substituted hydrocarbyl;
- R8 is selected from the group consisting of hydrocarbyl, and substituted hydrocarbyl;
- and
- X is halogen selected from the group consisting of Cl, and Br.
A process for the preparation of compound 3 from compound 2 according to the following reaction:
- wherein:
- R1 is selected from the group consisting of hydrogen, hydrocarbyl and substituted hydrocarbyl;
- R1a is an oxygen protecting group;
- R2 is selected from the group consisting of hydrocarbyl, and substituted hydrocarbyl;
- R3, R4, R5, and R6, are independently selected from the group consisting of hydrogen, halogen, hydroxyl, {—}OR8, hydrocarbyl, and substituted hydrocarbyl;
- R7 is selected from the group consisting of proton donors having a pKa less than about 0;
- R8 is selected from the group consisting of hydrocarbyl, and substituted hydrocarbyl;
- and
- X is halogen selected from the group consisting of Cl, and Br.
A process for the preparation of compound 3, the process comprising a first reaction that comprises contacting compound 1 with a proton acceptor and XCO2R2 to form compound 2, and a second reaction that comprises contacting compound 2 with a proton donor to form compound 3 according to the following reaction scheme:
- wherein:
- R1 is selected from the group consisting of hydrogen, hydrocarbyl and substituted hydrocarbyl;
- R1a is an oxygen protecting group;
- R2 is selected from the group consisting of hydrocarbyl, and substituted hydrocarbyl;
- R3, R4, R5, and R6, are independently selected from the group consisting of hydrogen, halogen, hydroxyl, {—}OR8, hydrocarbyl, and substituted hydrocarbyl;
- R7 is selected from the group consisting of proton donors having a pKa less than about 0;
- R8 is selected from the group consisting of hydrocarbyl, and substituted hydrocarbyl;
- and
- X is halogen selected from the group consisting of Cl, and Br.
Dependencies are inferred from the claim text.