Preparation of saturated ketone morphinan compounds by catalytic isomerization
View Patent ↗The present invention provides processes for the preparation of saturated ketone morphinan compounds by catalytic isomerization. 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 allyl-transition metal catalyst.
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 a bis(allyl)-ruthenium (IV) complex catalyst under acidic conditions such that the allyl alcohol ring moiety is catalytically isomerized to the saturated ketone ring moiety.
2. The process of claim 1 , wherein the reaction is conducted in the presence of a solvent, the solvent being chosen from a protic solvent, an aprotic solvent, and combinations thereof; and wherein the reaction is conducted at a temperature from about 10° to about 120° C.
3. A one-pot process for the preparation of a pharmaceutically acceptable salt of a morphinan comprising a saturated ketone ring moiety, the process comprising contacting a pharmaceutically acceptable salt of a morphinan comprising an allyl alcohol ring moiety with a bis(allyl)-ruthenium (IV) complex under acidic conditions such that the allyl alcohol ring moiety is catalytically isomerized to the saturated ketone ring moiety.
4. The process of claim 3 , wherein the morphinan comprising the saturated ketone ring moiety is a compound having Formula (IIa) and the morphinan comprising an allyl alcohol ring moiety is a compound having Formula (Ia), wherein Formulas (IIa) and (Ia) correspond to the following structures:
wherein:
A is a heteroatom chosen from oxygen and sulfur;
R 1 , R 2 , and R 3 are independently chosen from 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 chosen from 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 chosen from {═}O, {═}S, and {═}NR 1613 ;
R 1611 , R 1612 , and R 1613 are independently chosen from 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 a pharmaceutically acceptable salt.
5. The process of claim 4 , wherein the reaction is conducted in the presence of a solvent, the solvent being chosen from a protic solvent, an aprotic solvent, and combinations thereof; and wherein the reaction is conducted at a temperature from about 10° to about 120° C.
6. A process for the preparation of a compound comprising Formula (II) or a pharmaceutically acceptable salt thereof, the process comprising contacting a compound comprising Formula (I) with a bis(ally)-ruthenium (IV) complex catalyst and a proton donor to form the compound comprising Formula (II):
wherein:
A is a heteroatom chosen from oxygen and sulfur;
R 1 , R 2 , and R 3 are independently chosen from hydrogen, halogen, hydroxy, protected hydroxy, {—}SH, {—}SR 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 chosen from 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 chosen from {═}O, {═}S, and {═}NR 1613 ;
R 1611 , R 1612 , and R 1613 are independently chosen from hydrocarbyl, and substituted hydrocarbyl; and
one or more of R 1 , R 2 , R 3 , R 6 , R 7 , R 6 , 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.
7. The process of claim 6 , 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 chosen from hydroxy, protected hydroxy, alkyloxy, and acyloxy; R 14 is hydrogen or hydroxy; and R 17 is chosen from hydrogen, alkyl, cycloalkyl, cycloalkylmethyl, allyl, and aryl.
8. The process of claim 7 , wherein R 3 is hydroxy or methyoxy; R 14 is hydrogen; and R 17 is methyl.
9. The process of claim 6 , wherein the catalyst is a bis-η 3 -bonded ruthenium complex.
10. The process of claim 9 , wherein the bis-η 3 -bonded ruthenium complex is chosen from:
(a) a complex comprising Formula (III):
wherein:
R 811 , R 812 , R 813 , R 814 , R 815 , and R 816 are independently chosen from hydrocarbyl and substituted hydrocarbyl; provided one or more of R 811 , R 812 , R 813 , R 814 , R 818 , and R 816 may form part of a ring or ring system chosen from carbocyclic, heterocyclic, aryl, heteroaryl, and combinations thereof; provided two or more of R 811 , R 813 , R 814 , and R 816 may link together to form a longer chain; and
L 1 and L 2 are independently chosen from anion, hydrocarbyl, and substituted hydrocarbyl; provided L 1 and L 2 together may form the anion, a hydrocarbyl moiety, or a substituted hydrocarbyl moiety;
(b) a complex comprising Formula (IV):
R 811 , R 812 , R 813 , R 814 , R 815 , and R 816 are independently chosen from hydrocarbyl and substituted hydrocarbyl; provided one or more of R 811 , R 812 , R 813 , R 814 , R 815 , and R 816 may form part of a ring or ring system chosen from carbocyclic, heterocyclic, aryl, heteroaryl, and combinations thereof; provided two or more of R 811 , R 813 , R 814 , and R 816 may link together to form a longer chain; and
X is halogen; and
(c) a complex comprising Formula (V):
wherein:
R 811 , R 812 , R 813 , R 814 , R 815 , and R 816 are independently chosen from hydrocarbyl and substituted hydrocarbyl; provided one or more of R 811 , R 812 , R 813 , R 814 , R 815 , and R 816 may form part of a ring or ring system chosen from carbocyclic, heterocyclic, aryl, heteroaryl, and combinations thereof; provided two or more of R 811 , R 813 , R 814 , and R 816 may link together to form a longer chain;
L 1 and L 2 are independently chosen from an anion, hydrocarbyl, and substituted hydrocarbyl; provided L 1 and L 2 together may form the anion, a hydrocarbyl moiety, or a substituted hydrocarbyl moiety; and
L 3 is a coordinated ligand chosen from water, alcohol, acetonitrile, acetone, carbon monoxide, ether, N,N-dimethylformamide, N-methylpyrrolidone, propylamine, pyridine, triphenylphosphine, and tetrahydrofuran.
11. The process of claim 10 , wherein the anion, if present, is chosen from hydride, halogen, MeSO 3− , p-MeC 6 H 4 SO 3− , H 2 PO 4− , CF 3 SO 3− , CIO 4− , PF 6− , BF 4− , CF 3 SO 3− , HSO 4− , and hydrocarbyl or substituted hydrocarbyl anion chosen from RO—, RCO 2− , and RSO 3− , wherein R is hydrocarbyl or substituted hydrocarbyl.
12. The process of claim 6 , wherein the bis(allyl)-ruthenium(IV) complex is chosen from {Ru(η 3 :η 3 -C 10 H 16 )(μ-Cl)Cl} 2 , Ru(η 3 :η 2 :η 3 -C 12 H 18 )Cl 2 , and {Ru(η 3 :η 3 -C 12 H 20 )(μ-Cl)Cl} 2 .
13. The process of claim 6 , wherein the proton donor has a pKa of less than 5 and is chosen from HOAc, HCO 2 H, H 2 CO 3 , MeSO 3 H, poly H 3 PO 4 , H 3 PO 4 , H 2 SO 4 , HCl, HBr, HClO 4 , HI, HNO 3 , CF 3 SO 3 H, p-methyltoluenesulfonic acid, HClO 3 , HBrO 4 , HIO 3 , HIO 4 , and combinations thereof.
14. The process of claim 6 , wherein the weight:weight ratio of the compound comprising Formula (I) to the catalyst is from about 1:0.0001 to about 1:0.05, the mole:mole ratio of the compound comprising Formula (I) to the proton donor is from about 1:0.1 to about 1:5; the reaction is conducted in the presence of a solvent; the weight:weight ratio of the solvent to the compound comprising Formula (I) is from about 0.5:1 to about 10:1; the solvent is chosen from a protic solvent, an aprotic solvent, and combinations thereof; and the reaction is conducted at a temperature from about 10° to about 120° C.
15. The process of claim 6 , wherein the optical activity of the compounds comprising Formulas (I) and (II) is (−) or (+), and the configuration of C-5, C-13, C-14, and C-9, respectively, is chosen from 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.
16. The process of claim 8 , wherein the bis(allyl)-ruthenium(IV) complex catalyst is a bis-η 3 -bonded ruthenium complex chosen from {Ru(η 3 :η 3 -C 10 H 16 )(μ-Cl )Cl} 2 , Ru(η 3 :η 2 :η 3 -C 12 H 18 )Cl 2 , and {Ru(η 3 :η 3 -C 12 H 20 )(μ-Cl)Cl} 2 ; the weight:weight ratio of the compound comprising Formula (I) to the bis-η 3 -bonded ruthenium complex is from about 1:0.005 to about 1:0.02; the proton donor has a pKa of less than 5; the mole:mole ratio of the compound comprising Formula (I) to the proton donor is from about 1:1 to about 1:2; the reaction is conducted in the presence of a protic solvent; and the reaction is conducted at a temperature from about 65° to about 100° C.
17. The process of claim 16 , wherein the optical activity of the compounds comprising Formulas (I) and (II) is (−), and the configuration of C-5, C-13, C-14, and C-9, respectively, is RSRR.
18. The process of claim 16 , wherein the optical activity of the compounds comprising Formula (I) and (II) is (+), and the configuration of C-5, C-13, C-14, and C-9, respectively, is SRSS.
19. The process of claim 6 , wherein the compound of Formula (II) is a pharmaceutically acceptable salt chosen from hydrochloride, sulfate, and bitartrate.