Convenient preparation of N-substituted morphinan-6-ols from morphinan-6-ones
View Patent ↗Described herein are methods of preparing 6-hydroxy N-alkyl morphinan-6-ols from morphinan-6-ones, as illustrated below: wherein the variables R 1 , R 2 , R 3 , R 10 , R 11 , R 14 , and are as defined herein and wherein the reactions occur in a one-pot procedure using a boron based reducing agent.
1. A method for preparing a compound of formula (I)
the method comprising,
(a) contacting a compound of formula (II)
with a carbonyl compound having formula:
to form an intermediate compound; and
(b) contacting the intermediate compound with a boron based reducing agent at a temperature of 0° C. or greater to form the compound of formula (I);
wherein:
is a single or double bond;
R 1 is H, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, OH, or —O-Pro;
R 2 is H, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, OH, or —O-Pro;
R 3 is H, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, OH, or —O-Pro, wherein
Pro, at each occurrence, is independently a hydroxyl protecting group;
R 10 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, —C 1 -C 6 alkyl-C 3 -C 8 cycloalkyl, -C 2 -C 6 alkenyl-C 3 -C 8 cycloalkyl, -C 2 -C 6 alkynyl-C 3 -C 8 cycloalkyl, or C 1 -C 6 alkoxy-C 1 -C 6 alkyl;
R 11 is H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, —C 1 -C 6 alkyl-C 3 -C 8 cycloalkyl, -C 2 -C 6 alkenyl-C 3 -C 8 cycloalkyl, -C 2 -C 6 alkynyl-C 3 -C 8 cycloalkyl, or C 1 -C 6 alkoxy-C 1 -C 6 alkyl; and
R 14 is H or OH.
2. The method of claim 1 , wherein R 1 is H; R 2 is H; and R 3 is OH, methoxy or OPro.
3. The method of claim 1 , wherein the compound of formula (I) comprises a mixture of 6-α-hydroxy and 6-β-hydroxy epimers, the mixture of epimers having an epimeric ratio of 6-α-hydroxy to 6-α-hydroxy epimers of greater than or equal to 9:1.
4. The method of claim 1 , wherein the boron reducing agent comprises MBH n R 4-n , wherein M is Li, Na, or K; n is 1 or 2; and each R is independently —O 2 C—(C 1 -C 5 alkyl).
5. The method of claim 1 , wherein
R 10 is C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, —C 1 -C 6 alkyl-C 3 -C 6 cycloalkyl, or allyl; and
R 11 is H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, —C 1 -C 6 alkyl-C 3 -C 6 cycloalkyl, or allyl.
6. The method of claim 5 , wherein the boron reducing agent comprises MBH n R 4-n , wherein M is Li, Na, or K; n is 1 or 2; and each R is independently —O 2 C—(C 1 -C 5 alkyl).
7. The method of claim 6 , the contacting is conducted in a solvent chosen from DMF, DMA, NMP, or combinations thereof.
8. The method of claim 7 , wherein the solvent further comprises an acid.
9. The method of claim 1 , wherein the compound of formula (II) is noroxymorphone and the compound of formula (I) is nalbuphine or 6-α-naltrexol.
10. A method for preparing a compound of Formula (Ia) from a compound of formula (IIa), the method comprising:
(a) contacting the compound of formula (IIa) with a carbonyl compound having formula
to form an intermediate compound; and
(b) contacting the intermediate compound with a boron based reducing agent at a temperature of 0° C. or greater to form the compound of formula (Ia), according to the following reaction scheme:
wherein:
is a single or double bond;
R 3 is C 1 -C 6 alkoxy, OH, or O-Pro; wherein Pro is a hydroxyl protecting group;
R 10 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, or C- 1 -C 6 alkyl-C 3 -C 8 cycloalkyl;
R 11 is H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, or C 1 -C 6 alkyl-C 3 -C 8 cycloalkyl; and
R 14 is H or OH.
11. The method of claim 10 , wherein the boron reducing agent comprises MBH n R 4−n , wherein M is Li, Na, or K; n is 1 or 2; and each R is independently —O 2 C—(C 1 -C 5 alkyl).
12. The method of claim 10 , wherein R 3 is OH or methoxy.
13. The method of claim 12 , wherein R 10 is C 3 -C 6 cycloalkyl and R 11 is H.
14. The method of claim 13 , wherein the boron based reducing agent is a triacetoxyborohydride.
15. The method of claim 14 , wherein the contacting is conducted in a solvent chosen from DMF, DMA, NMP, or combinations thereof.
16. The method of claim 15 , wherein the solvent further comprises an acid.
17. The method of claim 10 , wherein the compound of formula (Ia) comprises a mixture of 6-α-hydroxy and 6-β-hydroxy epimers, the mixture of epimers having an epimeric ratio of 6-α-hydroxy to 6-βhydroxy epimers of greater than or equal to 9:1.
18. The method of claim 10 , wherein the compound of formula (IIa) and the compound of formula (Ia) independently have an optical activity of (−) or (+), and carbons C-5, C-13, C-14, and C-9, respectively, have a configuration of RRRR, RRSR, RRRS, RRSS, RSRR, RSSR, RSRS, RSSS, SRRR, SRSR, SRRS, SRSS, SSRR, SSSR, SSRS, or SSSS, provided that carbons C-15 and C-16 are both either on the alpha face of the molecule or the beta face of the molecule.