Process for the preparation of 3-hydroxymorphinan derivatives
View Patent ↗Processes are described for the synthesis of 3-hydroxymorphinan derivatives by hydrolysis of side products from the O-demethylation of 3-methoxymorphinan derivatives.
1. A process for the preparation of a morphinan compound (III) corresponding to the formula:
the process comprising hydrolyzing a compound (I) corresponding to the formula:
in a protic solvent to form an intermediate compound (II) corresponding to the formula:
and
heating a mixture comprising an aqueous solvent and the compound (II), at a pH of about 1 to about 6, to form compound (III), wherein
R is selected from the group consisting of hydrogen, alkyl, aryl, acyl, —SR 4 , —OR 4 , and —NR 4 R 5 ;
R 1 and R 2 are independently selected from the group consisting of hydrogen, alkyl, B(OH) 2 , and R 1 and R 2 , along with the atoms to which they are attached, form a 5-membered ring having a fifth ring member B(OH); provided, however, that at least one of R 1 and R 2 is B(OH) 2 or that R 1 and R 2 form the 5-membered ring;
R 3 is selected from the group consisting of hydrocarbyl, substituted hydrocarbyl, and a nitrogen protecting group;
R 4 and R 5 are independently selected from the group consisting of hydrogen, alkyl, aryl, and acyl;
R 6 and R 7 are independently selected from the group consisting of hydrogen, halogen, hydroxyl, NH 2 , SH, hydrocarbyl, and substituted hydrocarbyl, wherein R 6 and R 7 may together form a group selected from the group consisting of ═O and ═S;
R 8 and R 9 are independently selected from the group consisting of hydrogen, halogen, hydroxyl, NH 2 , CN, hydrocarbyl, and substituted hydrocarbyl; and
X is selected from the group consisting of chloro, bromo, and iodo.
2. The process of claim 1 , wherein R 3 is selected from the group consisting of alkyl, allyl, aryl, and acyl.
3. The process of claim 1 , wherein the protic solvent is selected from the group consisting of water, methanol, ethanol, isopropyl alcohol, and combinations thereof, the mixture is heated to a temperature of about 60° C. to about 90° C.; the mixture is adjusted to a pH of about 2 to about 4; X is bromo; R 3 is alkyl; R is selected from the group consisting of hydrogen and hydroxyl; R 7 is methyl; and R 8 is hydroxyl.
4. The process of claim 1 , wherein one of R 1 and R 2 is hydrogen and the other of R 1 and R 2 is B(OH) 2 or R 1 and R 2 , together with the atoms to which they are attached, form the 5-membered ring.
5. The process of claim 1 , wherein the optical activity of compounds (I), (II), and (III) is (−) or (+), and the configuration of C13, C14, and C9, respectively, of compounds (I) and (II) is selected from the group consisting of RRR, RRS, RSR, RSS, SRR, SRS, SSR, and SSS, and the configuration of C5, C13, C14, and C9, respectively, of compound (III) is selected from the group consisting of RRRR, RRSR, RRRS, RRSS, RSRR, RSSR, RSRS, RSSS, SRRR, SRSR, SRRS, SRSS, SSRR, SSSR, SSRS, and SSSS.
6. A process for the preparation of a morphinan compound (III) corresponding to the formula:
the process comprising heating a mixture comprising an aqueous solvent and a compound (II) corresponding to the formula:
at a pH of about 1 to about 6 to form compound (III), wherein:
R is selected from the group consisting of hydrogen, alkyl, aryl, acyl, —SR 4 , —OR 4 , and —NR 4 R 5 ;
R 3 is selected from the group consisting of hydrocarbyl, substituted hydrocarbyl, and a nitrogen protecting group;
R 4 and R 5 are independently selected from the group consisting of hydrogen, alkyl, aryl, and acyl;
R 6 and R7 are independently selected from the group consisting of hydrogen, halogen, hydroxyl, NH 2 , SH, hydrocarbyl, and substituted hydrocarbyl, wherein R 6 and R 7 may together form a group selected from the group consisting of ═O and ═S;
R 8 and R 9 are independently selected from the group consisting of hydrogen, halogen, hydroxyl, NH 2 , CN, hydrocarbyl, and substituted hydrocarbyl; and
X is selected from the group consisting of chloro, bromo, and iodo.
7. The process of claim 6 , wherein R 3 is selected from the group consisting of alkyl, allyl, aryl, and acyl.
8. The process of claim 6 , wherein the mixture is heated to a temperature of about 60° C. to about 90° C.; the mixture is adjusted to a pH of about 2 to about 4; X is bromo; R 3 is alkyl; and R is selected from the group consisting of hydrogen and hydroxyl.
9. The process of claim 6 , wherein the optical activity of compounds (I), (II), and (III) is (−) or (+), and the configuration of C13, C14, and C9, respectively, of compounds (I) and (II) is selected from the group consisting of RRR, RRS, RSR, RSS, SRR, SRS, SSR, and SSS, and the configuration of C5, C13, C14, and C9, respectively, of compound (III) is selected from the group consisting of RRRR, RRSR, RRRS, RRSS, RSRR, RSSR, RSRS, RSSS, SRRR, SRSR, SRRS, SRSS, SSRR, SSSR, SSRS, and SSSS.
10. A morphinan compound, or pharmaceutically acceptable salt thereof, the compound corresponding to the formula:
wherein:
R is selected from the group consisting of hydrogen, alkyl, aryl, acyl, —SR 4 , —OR 4 , and —NR 4 R 5 ;
R 3 is selected from the group consisting of alkyl, aryl, acyl, and a nitrogen protecting group;
R 4 and R 5 are independently selected from the group consisting of hydrogen, alkyl, aryl, and acyl;
R 6 and R 7 are independently selected from the group consisting of hydrogen, halogen, hydroxyl, NH 2 , SH, hydrocarbyl, and substituted hydrocarbyl, wherein R 6 and R 7 may together form a group selected from the group consisting of ═O and ═S;
R 8 and R 9 are independently selected from the group consisting of hydrogen, halogen, hydroxyl, NH 2 , CN, hydrocarbyl, and substituted hydrocarbyl; and
X is selected from the group consisting of chloro, bromo, and iodo.
11. The compound of claim 10 , wherein X is bromo; R 3 is alkyl; and R is selected from the group consisting of hydrogen and hydroxyl.
12. The compound of claim 11 , wherein R 3 is selected from the group consisting of methyl, cyclopropyl, isobutyl, and cyclobutyl.
13. The compound of claim 10 comprising the structure:
wherein:
R 6 and R 7 are independently selected from the group consisting of hydrogen, halogen, hydroxyl, NH 2 , SH, hydrocarbyl, and substituted hydrocarbyl, wherein R 6 and R 7 may together form a group selected from the group consisting of ═O and ═S; and
R 8 and R 9 are independently selected from the group consisting of hydrogen, halogen, hydroxyl, NH 2 , CN, hydrocarbyl, and substituted hydrocarbyl.
14. The compound of claim 10 , wherein the optical activity of the compound is (−) or (+), and the configuration of C13, C14, and C9, respectively, is selected from the group consisting of RRR, RRS, RSR, RSS, SRR, SRS, SSR, and SSS.
15. A morphinan compound, or pharmaceutically acceptable salt thereof, the compound corresponding to the formula:
wherein:
R is selected from the group consisting of hydrogen, alkyl, aryl, acyl, —SR 4 , —OR 4 , and —NR 4 R 5 ;
R 1 and R 2 are independently selected from the group consisting of hydrogen, alkyl, B(OH) 2 , and R 1 and R 2 , along with the atoms to which they are attached, form a 5-membered ring having a fifth ring member B(OH); provided, however, that at least one of R 1 and R 2 is B(OH) 2 or that R 1 and R 2 form the 5-membered ring;
R 3 is selected from the group consisting of alkyl, aryl, acyl, and a nitrogen protecting group;
R 4 and R 5 are independently selected from the group consisting of hydrogen, alkyl, aryl, and acyl;
R 6 and R 7 are independently selected from the group consisting of hydrogen, halogen, hydroxyl, NH 2 , SH, hydrocarbyl, and substituted hydrocarbyl, wherein R 6 and R 7 may together form a group selected from the group consisting of ═O and ═S;
R 8 and R 9 are independently selected from the group consisting of hydrogen, halogen, hydroxyl, NH 2 , CN, hydrocarbyl, and substituted hydrocarbyl; and
X is selected from the group consisting of chloro, bromo, and iodo.
16. The compound of claim 15 , wherein X is bromo; R 3 is alkyl; and R is selected from the group consisting of hydrogen and hydroxyl.
17. The compound of claim 16 , wherein R 3 is selected from the group consisting of methyl, cyclopropyl, isobutyl, and cyclobutyl.
18. The compound of claim 15 having the structure:
wherein:
R 6 and R 7 are independently selected from the group consisting of hydrogen, halogen, hydroxyl, NH 2 , SH, hydrocarbyl, and substituted hydrocarbyl, wherein R6 and R 7 may together form a group selected from the group consisting of ═O and ═S; and
R 8 and R 9 are independently selected from the group consisting of hydrogen, halogen, hydroxyl, NH 2 , CN, hydrocarbyl, and substituted hydrocarbyl.
19. The compound of claim 15 having the structure:
wherein:
R 6 and R 7 are independently selected from the group consisting of hydrogen, halogen, hydroxyl, NH 2 , SH, hydrocarbyl, and substituted hydrocarbyl, wherein R 6 and R7 may together form a group selected from the group consisting of ═O and ═S; and
R 8 and R 9 are independently selected from the group consisting of hydrogen, halogen, hydroxyl, NH 2 , CN, hydrocarbyl, and substituted hydrocarbyl.
20. The compound of claim 15 , wherein the optical activity of the compound is (−) or (+), and the configuration of C13, C14, and C9, respectively, is selected from the group consisting of RRR, RRS, RSR, RSS, SRR, SRS, SSR, and SSS.