Production of 6-hydroxy morphinans without the isolation of intermediates
View Patent ↗The present invention provides a process for preparing a saturated 6,14-dihydroxy morphinan. The process comprises contacting an unsaturated 6-O-hydrocarbyl morphinan with hydrogen peroxide and an organic acid to form an unsaturated 6-keto-14-hydroxy morphinan. The unsaturated 6-keto-14-hydroxy morphinan is contacted with a first reducing agent to form an unsaturated 6,14-dihydroxy morphinan, and the unsaturated 6,14-dihydroxy morphinan is contacted with a second reducing agent to form the saturated 6,14-dihydroxy morphinan.
1. A process for preparing a compound of Formula (IV) from a compound of Formula (I), comprising:
(a) contacting the compound of Formula (I) with hydrogen peroxide and a compound of formula HOOCR 18 to form a compound of Formula (II);
(b) contacting the compound of Formula (II) with a first reducing agent to form a compound of Formula (III); and
(c) contacting the compound of Formula (III) with a second reducing agent to form the compound of Formula (IV) according to the following reaction scheme:
wherein:
A is oxygen;
R is selected from the group consisting of hydrogen, hydrocarbyl, and substituted hydrocarbyl;
R 1 , R 2 , and R 3 are independently selected from the group consisting of hydrogen, amino, halogen, {—}OH, {—}OR 1611 , {—}SH, {—}SR 1611 , {—}NHR 1611 , {—}NR 1611 R 1612 , hydrocarbyl, and substituted hydrocarbyl;
R 5 , R 7 ,R 8 , R 9 , R 10a ,R 10b , R 15a , R 15b ,R 16a , and R 16b are independently selected from the group consisting of hydrogen, amino, halogen, {—}OH, {—}OR 1611 , {—}SH, {—}SR 1611 , {—}NHR 1611 , {—}NR 1611 R 1612 , hydrocarbyl, and substituted hydrocarbyl; wherein any pair of R #a and R #b wherein # is any one of 10, 15, and 16, optionally together form a moiety chosen from the group consisting of {═}O, {═}S, {=}CH 2 , and {═}NR 1612 ;
R 6 , R 1611 , and R 1612 are independently selected from the group consisting of hydrocarbyl and substituted hydrocarbyl; and
R 18 is selected from the group consisting of hydrogen, hydrocarbyl and substituted hydrocarbyl.
2. The process of claim 1 , wherein
R is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, substituted alkyl, substituted alkenyl, substituted alkynyl, and substituted aryl;
R 1 and R 2 are independently selected from the group consisting of hydrogen, amino, amine, halo, hydroxy, alkoxy, alkyl, alkenyl, alkynyl, aryl, substituted alkyl, substituted alkenyl, substituted alkynyl, and substituted aryl;
R 3 is selected from the group consisting of hydroxy, alkoxy, hydrocarbyloxy, and substituted hydrocarbyloxy;
R 6 is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, substituted alkyl, substituted alkenyl, substituted alkynyl, and substituted aryl;
R 5 , R 7 , R 8 , R 9 , R 10a , R 15a , R 15b ,R 16a , and R 16b are independently selected from the group consisting of hydrogen, amino, amine, halo, hydroxy, alkoxy, alkyl, alkenyl, alkynyl, aryl, substituted alkyl, substituted alkenyl, substituted alkynyl, and substituted aryl; and
R 18 is selected from the group consisting of hydrogen, alkyl, aryl, substituted alkyl, and substituted aryl.
3. The process of claim 2 , wherein; R is selected from the group consisting of hydrogen, methyl, cyclopropyl methyl, cyclobutyl methyl, and allyl; 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 if present, are hydrogen; R 3 is selected from the group consisting of hydroxy, alkoxy, aryloxy, substituted aryloxy, and protected hydroxy; R 6 is selected from the group consisting of alkyl and aryl; and R 18 is selected from the group consisting of hydrogen, methyl, phenyl, and substituted phenyl.
4. The process of claim 1 , wherein the mole to mole ratio of the compound of Formula (I) to hydrogen peroxide to the compound comprising formula HOOCR 18 is from about 1:0.1:0.2 to about 1:11:40.
5. The process of claim 1 , wherein the first reducing agent comprises a borohydride.
6. The process of claim 5 , wherein the mole to mole ratio of the compound of Formula (II) to hydride from the first reducing agent is from about 1:0.15 to about 1:25.
7. The process of claim 1 , wherein the second reducing agent is selected from the group consisting of a hydrogen transfer reagent, a combination of a hydrogen transfer reagent and a metal catalyst, and hydrogen and a metal catalyst.
8. The process of claim 1 , wherein the second reducing agent is a hydrogen transfer reagent, and the hydrogen transfer reagent is used in the presence of a transition metal catalyst.
9. The process of claim 8 , wherein the mole to mole ratio of the compound of Formula (III) to the hydrogen transfer reagent to the transition metal catalyst is from about 1:0.5:0.0004 to about 1:10:0.08.
10. The process of claim 1 , wherein the process is conducted in the presence of at least one polar protic solvent; and the volume to mass ratio of the solvent to the compound of Formula (I) is from about 0.5:1 to about 100:1.
11. The process of claim 1 , wherein the process is conducted at a temperature from about 0° C. to about 100° C.
12. The process of claim 1 , wherein steps (a), (b), and (c) are conducted in a single reaction pot without isolation of the compounds of Formula (II) or Formula (III).
13. The process of claim 1 , further comprising, after step (c), adjusting the pH to greater than about 8.7 to precipitate the compound of Formula (IV).
14. The process of claim 1 , further comprising removing the hydroxyl group from C-14 of the compound of Formula (IV).
15. The process of claim 1 , wherein the compounds of Formulas (I), (II), (III), and (IV) independently have an optical activity of (−) or (+); and the configuration of C-5, C-13, C-14, and C-9, respectively, is RRRR, RRSR, RRRS, RRSS, RSRR, RSSR, RSRS, RSSS, SRRR, SRSR, SRRS, SRSS, SSRR, SSSR, SSRS, or 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 1 , wherein the hydroxy group on C-6 of the compounds of Formulas (III) or (IV) has an alpha isomer to beta isomer ratio of at least 90:10.
17. The process of claim 3 , wherein R 18 is hydrogen; the first reducing agent is sodium borohydride or sodium triacetoxyborohydride; the second reducing agent is a hydrogen transfer agent which is used in the presence of a transition metal catalyst, and the hydrogen transfer agent is formic acid.
18. The process of claim 17 , wherein the mole to mole ratio of the compound of Formula (I) to hydrogen peroxide to the compound of formula HOOCR 18 is from about 1:0.6:1 to about 1:2.2:8; the mole to mole ratio of the compound of Formula (II) to hydride from the first reducing agent is from about 1:0.7 to about 1:5; the mole to mole ratio of the compound of Formula (III) to the hydrogen transfer reagent to the transition metal catalyst is from about 1:0.1:0.002 to about 1:1:0.02.
19. The process of claim 18 , wherein the process is conducted in the presence of at least one polar protic solvent; and the volume to mass ratio of the solvent to the compound of Formula (I) is from about 1:1 to about 20:1, and the process is conducted at a temperature from about 0° C. to about 70° C.
20. The process of claim 19 , further comprising removing the hydroxyl group from C-14 of the compound of Formula (IV).