Processes for the production of (+)- "NAL" morphinan compounds
AssigneeMallinckrodt Inc.
InventorsPeter X. Wang, Tao Jiang, Gary L. Cantrell, David W. Berberich, Bobby N. Trawick, Subo Liao
Life of this patent
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Abstract
The invention generally provides processes and intermediate compounds useful for the production of (+) nal morphinan compounds. In particular, the process encompasses synthetic routes for the production of (+) nal morphinan compounds or derivatives of (+) nal morphinan compounds from (+)-morphinan substrates such as (+)-hydrocodone, (+)-norhydrocodone or derivatives of either compound.
Claims25
A process for preparing compound 2-1, the process comprising contacting compound 2-1(a) with a halogen, X, to form compound 2-1(b), and contacting compound 2-1(b) with a proton acceptor to form compound 2-1 according to the reaction scheme:
- wherein:
- R1 and R2 are independently selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, and a protecting group;
- R5, and R6 are independently selected from the group consisting of hydrogen, halogen, hydroxyl, NH2, CN, hydrocarbyl, and substituted hydrocarbyl;
- R7 is selected from the group consisting of hydrogen and hydroxyl;
- and
- Y is selected from the group consisting of oxygen, sulfur, and nitrogen.
A process for preparing a compound, the process comprising contacting compound 2 with (R0CO)2O in the presence of R7CO2M to form compound 3 according to the reaction scheme:
- wherein:
- R0 is selected from the group consisting of alkyl, substituted alkyl, aryl, and substituted aryl;
- R1 and R2 are independently selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, and a protecting group;
- R3, and R4 are independently selected from the group consisting of hydrogen, halogen, hydroxyl, NH2, SH, hydrocarbyl, and substituted hydrocarbyl, wherein R3, and R4 may together form a group selected from the group consisting of ═O, and ═S;
- R6 is selected from the group consisting of hydrogen, halogen, hydroxyl, NH2, CN, hydrocarbyl, and substituted hydrocarbyl;
- R7 is selected from the group consisting of hydrocarbyl or substituted hydrocarbyl;
- M is a metal atom selected from the group consisting of Li, Na, and K;
- X is selected from the group consisting of halogen and hydrogen;
- and
- Y is selected from the group consisting of oxygen, sulfur, and nitrogen.
A process for preparing a compound, the process comprising contacting compound 3 with an oxidizing agent to form compound 4, and then reducing compound 4 to form compound 5 according to the reaction scheme:
- wherein:
- R0 is selected from the group consisting of alkyl, substituted alkyl, aryl, and substituted aryl;
- R1 and R2 are independently selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, and a protecting group;
- R3, and R4 are independently selected from the group consisting of hydrogen, halogen, hydroxyl, NH2, SH, hydrocarbyl, and substituted hydrocarbyl, wherein R3, and R4 may together form a group selected from the group consisting of ═O, and ═S;
- R6 is selected from the group consisting of hydrogen, halogen, hydroxyl, NH2, CN, hydrocarbyl, and substituted hydrocarbyl;
- X is selected from the group consisting of halogen and hydrogen;
- and
- Y is selected from the group consisting of oxygen, sulfur and nitrogen.
A process for preparing a compound, the process comprising contacting compound 5a with a N-demethylation agent in the presence of a proton acceptor to form compound 6 according to the reaction scheme:
- wherein:
- R1a is {—}OCOR3a;
- R1 is methyl;
- R2 is selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, and a protecting group;
- R3a is selected from the group consisting of hydrocarbyl, and substituted hydrocarbyl;
- R3, and R4 are independently selected from the group consisting of hydrogen, halogen, hydroxyl, NH2, SH, hydrocarbyl, and substituted hydrocarbyl, wherein R3, and R4 may together form a group selected from the group consisting of ═O, and ═S;
- R6 is selected from the group consisting of hydrogen, halogen, hydroxyl, NH2, CN, hydrocarbyl, and substituted hydrocarbyl;
- and
- Y is selected from the group consisting of oxygen, sulfur, and nitrogen.
A process for preparing a compound, the process comprising contacting compound 6a with a proton donor to form compound 7 according to the reaction scheme:
- wherein:
- R1a is {—}OCOR3a;
- R2a is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, and acyl;
- R3a is hydrocarbyl, and substituted hydrocarbyl;
- R3, and R4 are independently selected from the group consisting of hydrogen, halogen, hydroxyl, NH2, SH, hydrocarbyl, and substituted hydrocarbyl, wherein R3, and R4 may together form a group selected from the group consisting of ═O, and ═S;
- R6 is selected from the group consisting of hydrogen, halogen, hydroxyl, NH2, CN, hydrocarbyl, and substituted hydrocarbyl;
- and
- Y is selected from the group consisting of oxygen, sulfur, and nitrogen.
A process for preparing a compound, the process comprising contacting compound 6a with an agent selected from the group consisting of a proton donor, and an O-demethylating agent;
- to form compound 7a according to the reaction scheme:
- wherein:
- R1a is {—}OCOR3a;
- R2a is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, and acyl;
- R3a is hydrocarbyl, and substituted hydrocarbyl;
- R3, and R4 are independently selected from the group consisting of hydrogen, halogen, hydroxyl, NH2, SH, hydrocarbyl, and substituted hydrocarbyl, wherein R3, and R4 may together form a group selected from the group consisting of ═O, and ═S;
- R6 is selected from the group consisting of hydrogen, halogen, hydroxyl, NH2, CN, hydrocarbyl, and substituted hydrocarbyl;
- and
- Y is selected from the group consisting of oxygen, sulfur, and nitrogen.
A process for preparing a compound, the process comprising contacting compound 7 with R1X to form compound 8 according to the reaction scheme:
- wherein:
- R1 is selected from the group consisting of hydrocarbyl, and substituted hydrocarbyl;
- R2a is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, and acyl;
- R3, and R4 are independently selected from the group consisting of hydrogen, halogen, hydroxyl, NH2, SH, hydrocarbyl, and substituted hydrocarbyl, wherein R3, and R4 may together form a group selected from the group consisting of ═O, and ═S;
- R6 is selected from the group consisting of hydrogen, halogen, hydroxyl, NH2, CN, hydrocarbyl, and substituted hydrocarbyl;
- X is a halogen;
- and
- Y is selected from the group consisting of oxygen, sulfur, and nitrogen.
A process for the preparation of compound 8-1 according to the following reaction scheme:
- wherein:
- R1 and R2 are independently selected from the group consisting of hydrogen and methyl;
- R1a is selected from the group consisting of hydrocarbyl, and substituted hydrocarbyl;
- R3 is alkyl, substituted alkyl, aryl, and substituted aryl;
- R4 is hydrocarbyl, and substituted hydrocarbyl;
- R5, and R6 are independently selected from the group consisting of hydrogen, halogen, hydroxyl, NH2, SH, hydrocarbyl, and substituted hydrocarbyl, wherein R5, and R6 may together form a group selected from the group consisting of ═O, and ═S;
- R7 is selected from the group consisting of hydrogen, halogen, hydroxyl, NH2, CN, hydrocarbyl, and substituted hydrocarbyl;
- X is selected from the group consisting of halogen and hydrogen;
- and
- Y is selected from the group consisting of oxygen, sulfur, and nitrogen.
Dependencies are inferred from the claim text.