One pot process for producing 6-hydroxyl nal-opiate

1. A one pot process for preparing a 6-hydroxyl nal-opiate from a 6-keto nor-opiate, the process comprising:

(a) contacting the 6-keto nor-opiate with an alkylating reagent to form a 6-keto nal-opiate, wherein the 6-keto nal-opiate is not isolated; and

(b) contacting the 6-keto nal-opiate with a reducing agent and a proton acceptor to form the 6-hydroxyl nal-opiate;

wherein the reducing agent is selected from the group consisting of a sulfinic acid reducing agent, a hydrosulphite, a borohydride reagent, an aluminum hydride reagent, and a catalytic hydrogen transfer reduction reagent;

wherein the catalytic hydrogen transfer reduction reagent comprises a transition metal and a hydrogen donor, the transition metal being selected from the group consisting of palladium and platinum; and

wherein the process further comprises addition of a protic solvent after step (a).

2. The process of claim 1 , wherein the alkylating reagent comprises an alkyl halide and the reducing agent is chosen from a hydrosulphite, a sulfinic acid reducing agent, a borohydride reagent, and a catalytic hydrogen transfer reduction regent.

3. The process of claim 1 , wherein a 6-β-epimer of 6-hydroxyl nal-opiate is produced in a ratio of greater than 75:25 to a 6-α-epimer.

4. The process of claim 1 , wherein a 6-α-epimer of 6-hydroxyl nal-opiate is produced in a ratio of greater than 75:25 to a 6-β-epimer.

5. A one pot process for producing a compound comprising Formula (I) from a compound comprising Formula (II), the process comprising:

(a) contacting the compound comprising Formula (II) with an alkylating reagent comprising R 17 to form an intermediate comprising Formula (III), wherein the intermediate comprising Formula Op is not isolated; and

(b) contacting the intermediate comprising Formula (III) with a reducing agent and a proton acceptor to form the compound comprising Formula (I) according to the following reaction scheme:

wherein,

R 1 , R 2 , and R 3 are independently chosen from hydrogen, hydrocarbyl, substituted hydrocarbyl, halogen, hydroxyl, SH, SR 1811 , OR 1811 , and NR 1811 R 1812 ;

R 5 , R 7a , R 7b , R 8a , R 8b , R 9 , R 10a , R 10b , R 14 , R 15a , R 16a , and R 16b are independently chosen from hydrogen, hydrocarbyl, substituted hydrocarbyl, halogen, hydroxyl, SH, SR 1811 , OR 1811 , and NR 1811 R 1812 , wherein any pair of R #a and R #b where # is chosen from 7, 8, 10, 15, and 16 may be optionally linked by groups chosen from ═O, ═S, and ═NR 1813 ;

R 17 is chosen from hydrocarbyl or substituted hydrocarbyl;

R 1811 , R 1812 , and R 1813 are independently chosen from hydrogen, hydrocarbyl, and substituted hydrocarbyl;

the dashed lines between the C-7 and C-8 carbons represent a carbon-carbon double bond or a carbon-carbon single bond, provided that if there is a double bond between the C-7 and C-8 carbons then only one of R 7a and R 7b is present and only one of R 8a or R 8b is present; and

provided that one or more of R 1 , R 2 , R 3 , R 5 , R 7a , R 7b , R 8a , R 8b , R 9 , R 10a , R 10b , R 14 , R 15a , R 15b , R 16a , and R 16b may be linked to form carbocyclic or heterocyclic rings;

wherein the reducing agent is selected from the group consisting of a sulfinic acid reducing agent, a hydrosulphite, a borohydride reagent, an aluminum hydride reagent, and a catalytic hydrogen transfer reduction reagent;

wherein the catalytic hydrogen transfer reduction reagent comprises a transition metal and a hydrogen donor, the transition metal being selected from the group consisting of palladium and platinum; and

wherein the process further comprises addition of a protic solvent after step (a).

6. The process of claim 5 , wherein the alkylating reagent comprises R 17 and a leaving group.

7. The process of claim 5 , wherein the alkylating reagent comprises allyl bromide.

8. The process of claim 5 , wherein R 17 is chosen from methyl, allyl, methanecyclopropyl, and methanecyclobutyl.

9. The process of claim 5 , wherein R 1 , R 2 , R 5 , R 7a , R 7b , R 8a , R 8b , R 9 , R 10a , R 10b , R 15a , R 15b , R 16a , and R 16b are hydrogen.

10. The process of claim 5 , wherein R 3 and R 14 are chosen from hydrogen, hydroxyl and OR 1811 .

11. The process of claim 5 , wherein the reducing agent is chosen from a hydrosulphite, a sulfinic acid reducing agent, a borohydride reagent, and a catalytic hydrogen transfer reduction regent.

12. The process of claim 11 , wherein the sulfinic acid reducing agent is chosen from formamidine sulfinic acid and hydroxymethane sulfinic acid.

13. The process of claim 11 , wherein the reducing agent comprises sodium hydrosulphite.

14. The process of claim 5 , wherein the C-5, C-6, C-9, C-13, and C-14 stereocenters of the compound comprising Formula (I) are chosen from RRRRR, RSRRR, RRRRS, RSRRS, RRRSR, RSRSR, RRSRR, RSSRR, SRRRR, SSRRR, RRRSS, RSRSS, RRSSR, RSSSR, SRSRR, SSSRR, SRRRS, SSRRS, SRRSR, SSRSR, RRSRS, RSSRS, RRSSS, RSSSS, SRRSS, SSRSS, SRSRS, SSSRS, SRSSR, SSSSR, SRSSS, and SSSSS, respectively, 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.

15. The process of claim 5 , wherein a 6-β-epimer of the compound comprising Formula (I) is produced in a ratio of greater than 75:25 to a 6-α-epimer.

16. The process of claim 5 , wherein a 6-β-epimer of the compound comprising Formula (I) is produced in a ratio of greater than 95:5 to a 6-α-epimer.

17. The process of claim 5 , wherein a 6-α-epimer of the compound comprising Formula (I) is produced in a ratio of greater than 75:25 to a 6-β-epimer.

18. The process of claim 5 , wherein a 6-α-epimer of the compound comprising Formula (I) is produced in a ratio of greater than 95:5 to a 6-β-epimer.

19. The process of claim 5 , wherein the compound comprising Formula (II) is contacted with the alkylating reagent in an organic solvent chosen from dimethylformamide, N-methylpyrrolidinone, dimethylacetamide, and mixtures thereof.

20. The process of claim 5 , wherein the yield of the compound comprising Formula (I) is above 75%.