Preparation of 10-keto morphinans by benzylic oxidation
View Patent ↗The present invention provides processes for the preparation of 10-keto and/or 10-hydroxy morphinans. In particular, the invention provides to processes for preparing a 10-keto morphinan by chromium-catalyzed benzylic oxidation of a morphinan with a periodic acid.
1. A process for preparing a 10-keto morphinan, the process comprising contacting a pentacyclic morphinan comprising hydrogen substituents on C-10 with an oxidizing system comprising a periodic acid and a chromium catalyst to form the 10-keto morphinan, wherein the yield of the 10-keto morphinan is at least about 40%.
2. The process of claim 1 , wherein the periodic acid is chosen from H 5 IO 6 , HIO 4 , H 4 I 2 O 9 , H 3 IO 5 , and H 8 I 2 O 11 .
3. The process of claim 1 , wherein chromium catalyst is chosen from CrO, Cr 2 O 3 , CrO 2 , CrO 3 , CrO 3 /3,5-dimethylpyrazole complex, pyridinium chlorochromate, pyridinium dichromate, pyridinium fluorochromate, CrO 5 , Na 2 CrO 7 , K 2 CrO 7 , Na 2 CrO 4 , K 2 CrO 4 , CrCl 3 , CrBr 3 , CrF 3 , CrI 3 , Cr(NO 2 ) 3 , Cr(OAc) 3 , CrO 2 (OAc) 2 , and Cr(CIO 4 ) 3 .
4. The process of claim 1 , wherein the periodic acid is H 5 IO 6 and the chromium catalyst is CrO 3 .
5. The process of claim 1 , wherein the 10-keto morphinan is contacted with a reducing agent to form a 10-hydroxy morphinan.
6. A process for preparing a compound of Formula (II):
the process comprising:
contacting a compound of Formula (I):
with an oxidizing system comprising a periodic acid and a chromium catalyst to form the compound of Formula (II),
wherein:
R is chosen from hydrogen, hydrocarbyl, and substituted hydrocarbyl;
R 1 and R 2 are independently chosen from hydrogen, hydrocarbyl, substituted hydrocarbyl, halogen, {—}OR 15 , and hydroxy protecting group;
R 3 , R 7 , and R 8 are independently chosen from hydrogen, hydrocarbyl, substituted hydrocarbyl, and {—}OR 15 ;
R 6 is chosen from hydrogen, hydrocarbyl, substituted hydrocarbyl, {═}O, carbonyl protecting group, {—}OR 15 , hydroxy protecting group, and {—}NR 16 R 17 ;
R 14 is chosen from hydrogen and {—}OR 16 ;
R 15 is chosen from hydrocarbyl and substituted hydrocarbyl; and
R 16 and R 17 are independently chosen from hydrogen, hydrocarbyl, and substituted hydrocarbyl,
and further wherein the yield of the compound of Formula (II) is at least about 40%.
7. The process of claim 6 , wherein R 1 , R 2 , R 7 , and R 8 are hydrogen; R 14 is hydrogen or hydroxy; R is chosen from hydrogen, alkyl, cycloalkyl, cycloalkylmethyl, alkenyl, aryl, and heterocyclo; R 3 is chosen from alkoxy, methoxy, and protected hydroxy; and R 6 is chosen from hydrogen, protected hydroxy, alkoxy, keto, protected keto, ketal, and amido.
8. The process of claim 6 , wherein the periodic acid is chosen from H 5 IO 6 , HIO 4 , H 4 I 2 O 9 , H 3 IO 5 , and H 8 I 2 O 11 ; the chromium catalyst is chosen from CrO, Cr 2 O 3 , CrO 2 , CrO 3 , CrO 3 /3,5-dimethylpyrazole complex, pyridinium chlorochromate, pyridinium dichromate, pyridinium fluorochromate, CrO 5 , Na 2 CrO 7 , K 2 CrO 7 , Na 2 CrO 4 , K 2 CrO 4 , CrCl 3 , CrBr 3 , CrF 3 , CrI 3 , Cr(NO 2 ) 3 , Cr(OAc) 3 , CrO 2 (OAc) 2 , and Cr(CIO 4 ) 3 ; the molar ratio of the compound of Formula (I) to the periodic acid to the chromium catalyst is from about 1:1:0.1 to about 1:20:20; and the reaction is conducted at a temperature from about −20° to about 120° C.
9. The process of claim 6 , wherein the periodic acid is H 5 IO 6 and the chromium catalyst is CrO 3 .
10. The process of claim 6 , wherein the reaction is conducted in the presence of a solvent chosen from acetonitrile, a mixture of acetonitrile and water, t-butanol, dichloromethane, chloroform, chlorobenzene, ethyl acetate, acetone, methyl t-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, N,N-dimethylformamide, and acetic acid; and the weight ratio of the solvent to the compound of Formula (II) is from about 1:1 to about 100:1.
11. The process of claim 6 , wherein the periodic acid is H 5 IO 6 and the chromium catalyst is CrO 3 ; the molar ratio of the compound of Formula (I) to H 5 IO 6 to CrO 3 is from about 1:1:0.1 to about 1:10:1.5; the reaction is conducted in the presence of a solvent comprising acetonitrile and water; the weight ratio of the solvent to the compound of Formula (I) is about 20:1 to about 40:1; the reaction is conducted at temperature from about 10° to about 40° C.; and the yield of the compound of Formula (II) is at least about 40%.
12. The process of claim 6 , wherein the compound of Formula (II) is contacted with a reducing agent to form a compound of Formula (III):
wherein:
R is chosen from hydrogen, hydrocarbyl, and substituted hydrocarbyl;
R 1 and R 2 are independently chosen from hydrogen, hydrocarbyl, substituted hydrocarbyl, halogen, {—}OR 15 , and hydroxy protecting group;
R 3 , R 7 , and R 8 are independently chosen from hydrogen, hydrocarbyl, substituted hydrocarbyl, and {—}OR 15 ;
R 6 is chosen from hydrogen, hydrocarbyl, substituted hydrocarbyl, {═}O, carbonyl protecting group, {—}OR 15 , hydroxy protecting group, and {—}NR 16 R 17 ;
R 14 is chosen from hydrogen and {—}OR 16 ;
R 15 is chosen from hydrocarbyl and substituted hydrocarbyl; and
R 16 and R 17 are independently chosen from hydrogen, hydrocarbyl, and substituted hydrocarbyl.
13. The process of claim 12 , wherein R 1 , R 2 , R 7 , and R 8 are hydrogen; R 14 is hydrogen or hydroxyl; R is chosen from hydrogen, alkyl, cycloalkyl, cycloalkylmethyl, alkenyl, aryl, and heterocyclo; R 3 is chosen from alkoxy, methoxy, and protected hydroxy; and R 6 is chosen from hydrogen, protected hydroxy, alkoxy, keto, protected keto, ketal, amino, and amido.
14. The process of claim 12 , wherein the reducing agent is chosen from aluminum hydride, borane-tetrahydrofuran, catecholborane, diisobutylaluminum hydride, disiamylborane, lithium aluminum hydride, lithium borohydride, lithium tri-t-butoxyaluminum hydride, lithium triethylborohydride, potassium tri-s-butylborohydride, sodium borohydride, sodium cyanoborohydride, and sodium triacetoxyborohydride; and the molar ratio of the compound of Formula (II) to the reducing agent is from about 1:1 to about 1:10.
15. The process of claim 12 , wherein the reaction is conducted in the present of a solvent chosen from methanol, tetrahydrofuran, ether, and toluene.
16. The process of claim 12 , wherein the reaction is conducted at a temperature from about −80° C. to about 110° C.
17. The process of claim 12 , wherein the reducing agent is chosen from sodium borohydride and lithium borohydride; the molar ratio of the compound of Formula (II) to the reducing agent is from about 1:2 to about 1:5; the reaction is conducted in the presence of a solvent chosen from methanol and tetrahydrofuran and at a temperature from about 0° to about 40° C.; and the yield of the compound of Formula (III) is at least about 60%.
18. The process of claim 12 , wherein the optical activity of the compounds of Formulas (I), (II), or (III) is (−) or (+), and the configuration of C-5, C-13, C-14, and C-9, respectively, is chosen from RRRR, RRRS, RRSR, RSRR, SRRR, RRSS, RSSR, SSRR, SRRS, SRSR, RSRS, RSSS, SRSS, SSRS, SSSR, and SSSS, provided that C-15 and C-16 are both either on the alpha face or the beta face of the molecule.
19. The process of claim 12 , wherein the reaction product comprises 10-alpha-hydroxy epimers, 10-beta-hydroxy epimers, or a combination thereof.