Process for the preparation of morphinan-6-one compounds
View Patent ↗The present invention provides processes for preparing morphinan-6-one compounds, in particular oxymorphone and salts thereof, having improved impurity profiles.
1. A process for preparing a compound of formula (3), comprising:
treating an aqueous acidic solution comprising a compound of formula (1) and a compound of formula (2), wherein the compound of formula (2) dehydrates to form a compound of formula (1) and the compound of formula (1) is reduced to form the compound of formula (3),
wherein:
the process is carried out at one or more temperatures greater than ambient in the presence of a hydrogenation catalyst and hydrogen gas; and
the aqueous acidic solution is heated to a temperature above ambient before it is exposed to the hydrogen gas; and
wherein for the compounds of formulae (1), (2) and (3):
i) R 1 is —OH, R 2 is —OH and R 3 —H; or
ii) R 1 is —OCH 3 , R 2 is —H and R 3 —CH 3 ; or
iii) R 1 is —OH, R 2 is —H and R 3 —CH 3 ; or
iv) R 1 is —OCH 3 , R 2 is —H and R 3 —H; or
v) R 1 is —OH, R 2 is —H and R 3 —H; or
vi) R 1 is —OCH 3 , R 2 is —OH and R 3 —H.
2. The process according to claim 1 , wherein R 1 is —OH, R 2 is —OH and R 3 —H.
3. The process according to claim 1 , wherein the acid in the aqueous acidic solution is acetic acid, phosphoric acid, citric acid, tartaric acid, oxalic acid, hydrochloric acid, hydrobromic acid, or a mixture thereof.
4. The process according to claim 1 , wherein the treating is carried out at about 75° C. to about 100° C.
5. The process according to claim 1 , wherein the hydrogenation catalyst is a heterogeneous catalyst.
6. The process according to claim 5 , wherein the heterogeneous catalyst is a heterogeneous platinum group metal (PGM) catalyst.
7. The process according to claim 1 , wherein the aqueous acidic solution of the compound of formula (3) comprises about 0.05 area % or less of the compound of formula (1) as determined by HPLC.
8. The process according to claim 1 , further comprising treating the aqueous acidic solution of the compound of formula (3) to form solid a salt of compound (3).
9. The process according to claim 8 , wherein the solid salt of the compound of formula (3) comprises about 0.05 area % or less of the compound of formula (1) as determined by HPLC.
10. The process according to claim 8 , further comprising converting the solid salt of the compound of formula (3) to a free alkaloid of the compound of formula (3).
11. A The process according to claim 1 , further comprising treating the aqueous acidic solution of the compound of formula (3) at about 45-50° C. with a base to form the alkaloid of the compound of formula (3).
12. The process according to claim 10 , wherein the alkaloid of the compound of formula (3) comprises about 0.05 area % or less of the compound of formula (1) as determined by HPLC.
13. A process for preparing a compound of formula (3), comprising:
(I) hydrogenating an aqueous acidic solution comprising a compound of formula (1) and a compound of formula (2), wherein the hydrogenation is carried out at ambient temperature in the presence of a hydrogenation catalyst and hydrogen gas; and
(II) hydrogenating the product of step (I) at a temperature greater than ambient temperature in the presence of a hydrogenation catalyst and hydrogen gas to form an aqueous acidic solution of the compound of formula (3) comprising 0.05 area % or less of the compound of formula (1) as determined by HPLC and 2.00 area % or less of a compound of formula (4) as determined by HPLC,
wherein:
i) R 1 is —OH, R 2 is —OH and R 3 —H;
ii) R 1 is —OCH 3 , R 2 is —H and R 3 —CH 3 ;
iii) R 1 is —OH, R 2 is —H and R 3 —CH 3 ;
iv) R 1 is —OCH 3 , R 2 is —H and R 3 —H;
v) R 1 is —OH, R 2 is —H and R 3 —H; or
vi) R 1 is —OCH 3 , R 2 is —OH and R 3 —H.
14. The process according to claim 13 , wherein R 1 is —OH, R 2 is —OH, and R 3 —H.
15. The process according to claim 13 , wherein the acid in the aqueous acidic solution is acetic acid, phosphoric acid, citric acid, tartaric acid, oxalic acid, hydrochloric acid, hydrobromic acid, or a mixture thereof.
16. The process according to claim 1 , wherein the hydrogenation catalysts of step (I) and step (II) are, independently, a heterogeneous or homogenous catalyst.
17. The process according to claim 16 , wherein the heterogeneous catalyst is a heterogeneous platinum group metal (PGM) catalyst.
18. The process according to claim 13 , wherein the hydrogenation of step (II) is carried out at about 75° C. to about 100° C.
19. The process according to claim 13 , further treating the aqueous acidic solution of the compound of formula (3) to form a solid salt of compound (3).
20. The process according to claim 19 , wherein the solid salt of the compound of formula (3) comprises about 0.05 area % or less of the compound of formula (1) as determined by HPLC.
21. The process according to claim 19 , further comprising converting the solid salt of the compound of formula (3) to a free alkaloid of formula (3).
22. The process according to claim 13 , further comprising treating the aqueous acidic solution of the compound of formula (3) at 45-50° C. with a base to form the alkaloid of the compound of formula (3).
23. The process according to claim 21 , wherein the alkaloid of the compound of formula (3) comprises about 0.05 area % or less of the compound of formula (1) as determined by HPLC.
24. The process according to claim 6 , wherein the heterogeneous catalyst is a heterogeneous palladium catalyst.
25. The process according to claim 16 , wherein the catalyst is a heterogeneous catalyst.
26. The process according to claim 17 , wherein the PGM catalyst is a heterogeneous palladium catalyst.