Sinomenine derivatives and processes for their synthesis
AssigneeMallinckrodt Inc.
InventorsPeter X. Wang, Tao Jiang, Gary L. Cantrell, David W. Berberich, Bobby N. Trawick, Subo Liao, John Brandt
Life of this patent
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Abstract
The invention generally provides processes and intermediate compounds useful for the production of sinomenine derivatives. In particular, the process may encompass synthetic routes for the production of (+)-sinomenine derivatives and their intermediates.
Claims24
A compound comprising Formula (I):
- wherein:
- R1 is selected from the group consisting of hydrocarbyl and substituted hydrocarbyl;
- R2 and R3 are independently selected from the group consisting of hydrogen, halogen, OH, NH2, CN, hydrocarbyl, and substituted hydrocarbyl;
- R4 is selected from the group consisting of hydrogen, halogen, NH2, CN, hydrocarbyl, substituted hydrocarbyl, and OR4a;
- R4a is selected from the group consisting of hydrogen and a bond that forms part of an ether-containing ring;
- R5 and R6 are independently selected from the group consisting of hydrogen, OH, NH2, SH, hydrocarbyl, and substituted hydrocarbyl, wherein R5 and R6 together may form a group selected from the group consisting of ═O, ═NOH, ═S, ═CHR5a, and —O(CH2)2O—;
- R5a is selected from the group consisting of hydrogen, halogen, hydrocarbyl, and substituted hydrocarbyl;
- R7 is selected from the group consisting of hydrogen and OR7a;
- R7a is selected from the group consisting of hydrocarbyl and substituted hydrocarbyl;
- R8 is selected from the group consisting of hydrogen, hydrocarbyl, and substituted hydrocarbyl;
- R9 and R10 are independently selected from the group consisting of hydrogen, OH, NH2, SH, hydrocarbyl, and substituted hydrocarbyl, wherein R9 and R10 together may form a group selected from the group consisting of ═O and ═S;
- R11 and R12 are independently selected from the group consisting of hydrogen, OH, halogen, hydrocarbyl, and substituted hydrocarbyl;
- Y is selected n is from the group consisting of alkyl, substituted alkyl, carbonyl, and alkyl carbonyl;
- m is an integer from 0 to 8;
- and
- is a single bond or a double bond.
A process for preparing a compound, the process comprising contacting a compound comprising Formula 2 with a compound selected from the group consisting of vinyl chloroformate and 1-chloroethyl chloroformate, followed by hydrolysis of the reaction mixture in the presence of a proton donor or a proton acceptor to form a compound comprising Formula 3 according to the reaction scheme:
- wherein
- R1, R2, R3, and R4 are independently selected from the group consisting of hydrogen, halogen, OH, NH2, CN, hydrocarbyl, and substituted hydrocarbyl;
- R5 and R6 are independently selected from the group consisting of hydrogen, OH, NH2, SH, hydrocarbyl, and substituted hydrocarbyl, wherein R5 and R6 together may form a group selected from the group consisting of ═O, ═NOH, ═S, ═CHR5a, and —O(CH2)2O—;
- and
- R5a is selected from the group consisting of hydrogen, halogen, hydrocarbyl, and substituted hydrocarbyl;
- and
- R8 and R9 are independently selected from the group consisting of hydrogen, OH, NH2, SH, hydrocarbyl, and substituted hydrocarbyl, wherein R8 and R9 together may form a group selected from the group consisting of ═O and ═S.
A process for preparing a compound, the process comprising contacting a compound having Formula 3 with a compound selected from the group consisting of R7YX and R7Y to form a compound comprising Formula 4 according to the reaction scheme:
- wherein
- R1, R2, R3, and R4 are independently selected from the group consisting of hydrogen, halogen, OH, NH2, CN, hydrocarbyl, and substituted hydrocarbyl;
- R5 and R6 are independently selected from the group consisting of hydrogen, OH, NH2, SH, hydrocarbyl, and substituted hydrocarbyl, wherein R5 and R6 together may form a group selected from the group consisting of ═O, ═NOH, ═S, ═CHR5a, and —O(CH2)2O—;
- R5a is selected from the group consisting of hydrogen, halogen, hydrocarbyl, and substituted hydrocarbyl.
- R7 is selected from the group consisting of hydrocarbyl and substituted hydrocarbyl;
- R8 and R9 are independently selected from the group consisting of hydrogen, OH, NH2, SH, hydrocarbyl, and substituted hydrocarbyl, wherein R8 and R9 together may form a group selected from the group consisting of ═O and ═S;
- X is halogen;
- and
- Y is selected n is from the group consisting of alkyl, substituted alkyl, carbonyl, and alkyl carbonyl.
A process for preparing a compound, the process comprising contacting a compound having Formula 4a with X to form a compound comprising Formula 5 according to the reaction scheme:
- wherein
- R1, R2, R3, and R4 are independently selected from the group consisting of hydrogen, halogen, OH, NH2, CN, hydrocarbyl, and substituted hydrocarbyl;
- R7 is selected from the group consisting of hydrocarbyl and substituted hydrocarbyl;
- R8 and R9 are independently selected from the group consisting of hydrogen, OH, NH2, SH, hydrocarbyl, and substituted hydrocarbyl, wherein R8 and R9 together may form a group selected from the group consisting of ═O and ═S;
- X is halogen;
- and
- Y is selected n is from the group consisting of alkyl, substituted alkyl, carbonyl, and alkyl carbonyl.
A process for preparing a compound, the process comprising contacting a compound having Formula 5a with a proton acceptor to form a compound comprising Formula 6 according to the reaction scheme:
- wherein
- R1, R2, and R3 are independently selected from the group consisting of hydrogen, halogen, OH, NH2, CN, hydrocarbyl, and substituted hydrocarbyl;
- R4 is selected from the group consisting of OH and NH2;
- R7 is selected from the group consisting of hydrocarbyl and substituted hydrocarbyl;
- R8 and R9 are independently selected from the group consisting of hydrogen, OH, NH2, SH, hydrocarbyl, and substituted hydrocarbyl, wherein R8 and R9 together may form a group selected from the group consisting of ═O and ═S;
- and
- X is halogen;
- Y is selected from the group consisting of alkyl, substituted alkyl, carbonyl, and alkyl carbonyl;
- and
- Z is selected from the group consisting of {—}O{—} and {—}NH{—}.
A process for preparing a compound, the process comprising contacting a compound having Formula 6 with a scavenger and a proton donor to form a compound comprising Formula 7 according to the reaction scheme:
- wherein
- R1, R2, and R3 are independently selected from the group consisting of hydrogen, halogen, OH, NH2, CN, hydrocarbyl, and substituted hydrocarbyl;
- R7 is selected from the group consisting of hydrocarbyl and substituted hydrocarbyl;
- R8 and R9 are independently selected from the group consisting of hydrogen, OH, NH2, SH, hydrocarbyl, and substituted hydrocarbyl, wherein R8 and R9 together may form a group selected from the group consisting of ═O and ═S;
- Y is selected from the group consisting of alkyl, substituted alkyl, carbonyl, and alkyl carbonyl;
- and
- Z is selected from the group consisting of {—}O{—} and {—}NH{—}.
A process for preparation of compound 7 according to the following reaction scheme:
- wherein:
- R1 is selected from the group consisting of hydrocarbyl and substituted hydrocarbyl;
- R2 and R3 are independently selected from the group consisting of hydrogen, halogen, OH, NH2, CN, hydrocarbyl, and substituted hydrocarbyl;
- R4 and R5 are independently selected from the group consisting of hydrogen, OH, NH2, SH, hydrocarbyl, and substituted hydrocarbyl, wherein R4 and R5 together may form a group selected from the group consisting of ═O, ═NOH, ═S, ═CHR5a, and —O(CH2)2O—;
- R5a is selected from the group consisting of hydrogen, halogen, hydrocarbyl, and substituted hydrocarbyl;
- R6 is selected from the group consisting of hydrogen, hydrocarbyl, and substituted hydrocarbyl;
- R7 and R8 are independently selected from the group consisting of hydrogen, OH, NH2, SH, hydrocarbyl, and substituted hydrocarbyl, wherein R8 and R9 together may form a group selected from the group consisting of ═O and ═S;
- X is halogen;
- Y is selected n is from the group consisting of alkyl, substituted alkyl, carbonyl, and alkyl carbonyl;
- and
- Z is selected from the group consisting of {—}O{—} and {—}NH{—}.
Dependencies are inferred from the claim text.