Preparation of saturated ketone morphinan compounds
View Patent ↗The present invention provides processes for the preparation of saturated ketone morphinan compounds. In particular, the invention provides processes for the conversion of a morphinan comprising an allyl alcohol ring moiety into a morphinan comprising a saturated ketone ring moiety by an isomerization reaction catalyzed by an inorganic salt of a late transition metal.
1. A one-pot process for the preparation of a morphinan comprising a saturated ketone ring moiety, the process comprising contacting a morphinan comprising an allyl alcohol ring moiety with an inorganic salt of a late transition metal in the presence of a protic solvent, wherein the allyl alcohol ring moiety is catalytically isomerized to the saturated ketone ring moiety, and wherein the weight:weight ratio of the protic solvent to the morphinan comprising an allyl alcohol ring moiety is from 2:1 to 4:1.
2. The process of claim 1 , wherein the late transition metal is a group VIIIB metal selected from the group consisting of ruthenium, rhodium, palladium, osmium, iridium, and platinum; and the inorganic salt is selected from the group consisting of halide, sulfate, phosphate, and nitrate.
3. The process of claim 1 , wherein the inorganic salt of the late transition metal is selected from the group consisting of RuCl 3 , RuBr 3 , Ru(CF 3 SO 3 ) 2 , Ru 2 (SO 4 ) 3 , Ru(NO 3 ) 3 , RhCl 3 , RhBr 3 , Rh 2 (SO 4 ) 3 , [Rh(CO 2 )Cl] 2 , IrCl 3 , OsCl 3 , and PdCl 2 .
4. The process of claim 1 , wherein the weight:weight ratio of the protic solvent to the morphinan comprising an allyl alcohol ring moiety is from 2:1 to 3.6.
5. The process of claim 1 , wherein the process comprises a single inorganic salt of a late transition metal.
6. The process of claim 1 , wherein the morphinan comprising a saturated ketone ring moiety is produced with a yield in excess of 85%.
7. The process of claim 1 , wherein the morphinan comprising a saturated ketone ring moiety is produced with a yield in excess of 95%.
8. A process for the preparation of a compound of Formula (III), the process comprising contacting a compound of Formula (II) with an inorganic salt of a late transition metal in the presence of a protic solvent to form the compound of Formula (III):
wherein:
A is a heteroatom selected from the group consisting of oxygen and sulfur;
R 1 , R 2 , and R 3 are independently selected from the group consisting of hydrogen, halogen, hydroxy, protected hydroxy, {—}SH, {—}SR 1611 , {—}OR 1611 , and {—}NR 1611 R 1612 hydrocarbyl, and substituted hydrocarbyl;
R 5 , R 7 , R 8 , R 9 , R 10a , R 10b , R 14 , R 15a R 15b , R 16a , R 16b , and R 17 are independently selected from the group consisting of hydrogen, halogen, hydroxy, {—}SH, {-}SR 1611 , {—}OR 1611 , and {—}NR 1611 R 1612 , hydrocarbyl, and substituted hydrocarbyl; provided that any of R 10a and R 10b , R 15a and R 15b , and R 16a and R 16b may together form a moiety selected from the group consisting of {═}O, {═}S, and {═}NR 1613 ;
R 1611 , R 1612 , and R 1613 are independently selected from the group consisting of hydrocarbyl, and substituted hydrocarbyl;
one or more of R 1 , R 2 , R 3 , R 5 , R 7 , R 8 , R 9 , R 10a , R 10b , R 14 , R 15a , R 15b , R 16a , and R 16b may form part of a ring or ring system chosen from carbocyclic, heterocyclic, aryl, heteroaryl, and combinations thereof; and
Z is an anion, and
wherein the weight:weight ratio of the protic solvent to the compound of Formula (II) is from 2:1 to 4:1.
9. The process of claim 8 , wherein A is oxygen; R 1 , R 2 , R 5 , R 7 , R 8 , R 9 , R 10a , R 10b , R 15a , R 15b , R 16a , and R 16b are hydrogen; R 3 is selected from the group consisting of hydroxy, protected hydroxy, alkyloxy, and acyloxy; R 14 is hydrogen or hydroxy; and R 17 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkylmethyl, allyl, and aryl.
10. The process of claim 9 , wherein R 3 is hydroxy or methyoxy; R 14 is hydrogen; R 17 is methyl; and Z is selected from the group consisting of hydrochloride, sulfate, and bitartrate.
11. The process of claim 8 , wherein the compound of Formula (III) is isolated as a free base of Formula (IV):
wherein:
A is a heteroatom selected from the group consisting of oxygen and sulfur;
R 1 , R 2 , and R 3 are independently selected from the group consisting of hydrogen, halogen, hydroxy, protected hydroxy, {—}SH, {—}SR 1611 , {—}OR 1611 , and {—}NR 1611 R 1612 , hydrocarbyl, and substituted hydrocarbyl;
R 5 , R 7 , R 8 , R 9 , R 10a , R 10b , R 14 , R 15a R 15b , R 16a , R 16b , and R 17 are independently selected from the group consisting of hydrogen, halogen, hydroxy, {—}SH, {—}SR 1611 , {—}OR 1611 , and {—}NR 1611 R 1612 , hydrocarbyl, and substituted hydrocarbyl; provided that any of R 10a and R 10b , R 15a and R 15b , and R 16a and R 16b may together form a moiety selected from the group consisting of {═}O, {═}S, and {—}NR 1613 ;
R 1611 , R 1612 , and R 1613 are independently selected from the group consisting of hydrocarbyl, and substituted hydrocarbyl; and
one or more of R 1 , R 2 , R 3 , R 5 , R 7 , R 8 , R 9 , R 10a , R 10b , R 14 , R 15a , R 15a , R 16a , and R 16b may form part of a ring or ring system selected from the group consisting of carbocyclic, heterocyclic, aryl, heteroaryl, and combinations thereof.
12. The process of claim 8 , wherein the compound of Formula (II) is formed in situ by contacting an acid with a compound of Formula (I):
wherein:
A is a heteroatom selected from the group consisting of oxygen and sulfur;
R 1 , R 2 , and R 3 are independently selected from the group consisting of hydrogen, halogen, hydroxy, protected hydroxy, {—}SH, {—}SR 1611 , {—}OR 1611 and {—}NR 1611 , R 1612 , hydrocarbyl, and substituted hydrocarbyl;
R 5 , R 7 , R 8 , R 9 , R 10a , R 10b , R 14 , R 15a , R 15b , R 16a , R 16b , and R 17 are independently selected from the group consisting of hydrogen, halogen, hydroxy, {—}SH, {—}SR 1611 , {—}OR 1611 , and {—}NR 1611 R 1612 , hydrocarbyl, and substituted hydrocarbyl; provided that any of R 10a and R 10b , R 15a and R 15b , and R 16a and R 16b may together form a moiety selected from the group consisting of {═}O, {═}S, and {═}NR 1613;
R 1611 , R 1612 , and R 1613 are independently selected from the group consisting of hydrocarbyl, and substituted hydrocarbyl; and
one or more of R 1 , R b 2 ,R 3 , R 5 , R 7 , R 8 , R 9 , R 10a , R 10b , R 14 , R 15a , R 15b , R 16a , and R 16b may form part of a ring or ring system selected from the group consisting of carbocyclic, heterocyclic, aryl, heteroaryl, and combinations thereof.
13. The process of claim 12 , wherein the acid is selected from the group consisting of sulfuric acid, hydrochloric acid, and tartaric acid.
14. The process of claim 8 , wherein the late transition metal is a group VIIIB metal selected from the group consisting of ruthenium, rhodium, palladium, osmium, iridium, and platinum; and the inorganic salt is selected from the group consisting of halide, sulfate, phosphate, and nitrate.
15. The process of claim 8 , wherein the inorganic salt of the late transition metal is selected from the group consisting of RuCl 3 , RuBr 3 , Ru(CF 3 SO 3 ) 2 , Ru 2 (SO 4 ) 3 , Ru(NO 3 ) 3 , RhCl 3 , RhBr 3 , Rh 2 (SO 4 ) 3 , [Rh(CO 2 )Cl] 2 , IrCl 3 , OsCl 3 , and PdCl 2 .
16. The process of claim 8 , wherein the weight:weight ratio of the compound of Formula (II) to the late transition metal salt is from about 1:0.0001 to about 1:0.1; the protic solvent is selected from the group consisting of methanol, ethanol, isopropanol, n-propanol, isobutanol, n-butanol, s-butanol, t-butanol, formic acid, acetic acid, water, and combinations thereof; and the reaction is conducted at a temperature from about 10° C. to about 120° C.
17. The process of claim 16 , wherein the protic solvent comprises a mixture of alcohol and water.
18. The process of claim 8 , further comprising a co-reactant selected from the group consisting of acetone, acetonitrile, 1-hexene, cyclohexene, H 3 PO 2 , NaH 2 PO 2 , and combinations thereof.
19. The process of claim 8 , wherein the optical activity of the compounds of Formulas (II) and (III) is (−) or (+), and the configuration of C-5, C-13, C-14, and C-9, respectively, is selected from the group consisting of RRRR, RRSR, RRRS, RRSS, RSRR, RSSR, RSRS, RSSS, SRRR, SRSR, SRRS, SRSS, SSRR, SSSR, SSRS, and SSSS, provided that the C-15 and the C-16 carbons are both either on the alpha face of the molecule or the beta face of the molecule.
20. The process of claim 10 , wherein the late transition metal salt is RuCl 3 ; the weight:weight ratio of the compound of Formula (II) to RuCl 3 is from about 1:0.01 to about 1:0.2; the protic solvent comprises ethanol and water; the reaction is conducted at a temperature from about 65° C. to about 90° C.; and the compound of Formula (III) has a yield of at least about 60%.
21. The process of claim 17 , further comprising a co-reactant selected from the group consisting of acetone, acetonitrile, 1-hexene, cyclohexene, H 3 PO 2 , NaH 2 PO 2 , and combinations thereof; and the weight:weight ratio of the compound of Formula (II) to the co-reactant is from about 1:0.005 to about 1:0.05.
22. The process of claim 20 , wherein the optical activity of the compounds of Formulas (II) and (III) is (−), and the configuration of C-5, C-13, C-14, and C-9, respectively, is RSRR.
23. The process of claim 20 , wherein the optical activity of the compounds of Formulas (II) and (III) is (+), and the configuration of C-5, C-13, C-14, and C-9, respectively, is SRSS.