Process for the preparation of opioid compounds
The present invention is directed to a process for the preparation of opioid compounds such as buprenorphine, naltrexone, naloxone, nalbuphone, nalbuphine, and the like.
1. A process for the preparation of a compound of formula (I)
or a pharmaceutically acceptable salt thereof; comprising
reacting a compound of formula (V) with a compound of formula (VI), wherein L 1 is a leaving group; in the presence of an inorganic base; wherein the inorganic base does not form water when reacted with or contacted with an acid; in a first organic solvent; at a temperature in the range of from about 40° C. to about 70° C.; to yield the corresponding compound of formula (VII); and
reacting the compound of formula (VII) with a demethylating agent; in the presence of a base; in a second organic solvent; at a temperature in the range of from about 110° C. to about 150° C.; under an inert atmosphere; to yield the corresponding compound of formula (I).
2. A process as in claim 1 , wherein L 1 is bromo.
3. A process as in claim 1 , wherein the compound of formula (VI) is present in an amount in the range of from about 1.1 to about 2.5 molar equivalents.
4. A process as in claim 1 , wherein the compound of formula (VI) is present in an amount in the range of from about 1.25 to about 1.75 molar equivalents.
5. A process as in claim 1 , wherein the inorganic base is an anhydrous inorganic base.
6. A process as in claim 1 , wherein the inorganic base is anhydrous K 2 HPO 4 .
7. A process as in claim 1 , wherein the inorganic base is present in an amount in the range of from about 2 to about 4 molar equivalents.
8. A process as in claim 1 , wherein the inorganic base is present in an amount of in the range of from about 2.25 to about 3.25 molar equivalents.
9. A process as in claim 1 , wherein the first organic solvent is DMF.
10. A process as in claim 1 , wherein the compound of formula (VII) is not isolated.
11. A process as in claim 1 , wherein the demethylating agent is tert-dodecyl mercaptan and wherein the base is an alkoxide base.
12. A process as in claim 10 , wherein the alkoxide base is NaOtBu.
13. A process as in claim 1 , wherein the demethylating agent is present in an amount in the range of from about 2.5 to about 4 molar equivalents.
14. A process as in claim 1 , wherein the demethylating is present in an amount of in the range of from about 2.8 to about 3.4 molar equivalents.
15. A process as in claim 1 , wherein the base is present in an amount in the range of from about 2.5 to about 4 molar equivalents.
16. A process as in claim 1 , wherein the base is present in an amount of in the range of from about 2.8 to about 3.4 molar equivalents.
17. A process as in claim 1 , wherein the compound of formula (V) is reacted with the compound (VI) in the presence of a promoter.
18. A process as in claim 17 , wherein the promoter is NaI; and wherein the NaI is present in an amount in the range of from about 5 mole % to about 10 mole %.
19. A process as in claim 1 , further comprising reacting the compound of formula (I) with HCl to yield the corresponding hydrochloride salt of the compound of formula (I).
20. A process for the preparation of a compound of formula (I)
or a pharmaceutically acceptable salt thereof; comprising
reacting a compound of formula (V) with a compound of formula (VI), wherein L 1 is bromo; wherein the compound of formula (VI) is present in an amount of about 1.4 molar equivalents;
in the presence of anhydrous K 2 HPO 4 ; wherein the anhydrous K 2 HPO 4 is present in an amount of in the range of from about 2.4 to about 3 molar equivalents;
in DMF; at a temperature of about 60° C.; to yield the corresponding compound of formula (VII); and
reacting the compound of formula (VII) with tert-dodecylmercaptan; wherein the tert-dodecyl mercaptan is present in an amount of about 3.1 molar equivalents;
in the presence of NaOtBu; wherein the NaOtBu is present in amount of about 3.1 molar equivalents;
in DMF; at a temperature of about 131° C.; under an inert atmosphere; to yield the corresponding compound of formula (I).
21. A process for the preparation of a compound of formula (VII)
or a pharmaceutically acceptable salt thereof; comprising
reacting a compound of formula (V) with a compound of formula (VI), wherein L 1 is a leaving group; in the presence of an inorganic base; wherein the inorganic base does not form water when reacted with or contacted with an acid; in a first organic solvent; at a temperature in the range of from about 40° C. to about 70° C.; to yield the corresponding compound of formula (VII).
22. A process as in claim 21 , wherein L 1 is bromo; wherein the compound of formula (VI) is present in an amount of about 1.4 molar equivalents; wherein the inorganic base is anhydrous K 2 HPO 4 ; wherein the anhydrous K 2 HPO 4 is present in an amount of in the range of from about 2.4 to about 3 molar equivalents; wherein the first organic solvent is DMF; and wherein the compound of formula (V) is reacted with the compound of formula (VI) at a temperature of about 60° C.
23. A process as in claim 21 , further comprising
reacting the compound of formula (VII) with a demethylating agent; in the presence of a base; in a second organic solvent; at a temperature in the range of from about 110° C. to about 150° C.; under an inert atmosphere; yield the corresponding compound of formula (I).
24. A process for the preparation of a compound of formula (I)
or a pharmaceutically acceptable salt thereof; comprising
reacting a compound of formula (V) with a compound of formula (VI), wherein L1 is a leaving group; in the presence of an inorganic base; wherein the inorganic base does not form water when reacted with or contacted with an acid; in a first organic solvent; at a temperature in the range of from about 40° C. to about 70° C.; to yield the corresponding compound of formula (VII); and
reacting the compound of formula (VII) with a demethylating agent to yield the corresponding compound of formula (I).