Process for the preparation of morphinan-6-one compounds

Patent metadata

Field	Value
Publication number	US-9908891-B2
Application number	US-201414909573-A
Country	US
Kind code	B2
Filing date	Feb 5, 2014
Priority date	Aug 2, 2013
Publication date	Mar 6, 2018
Grant date	Mar 6, 2018

Abstract

The present invention provides processes for preparing morphinan-6-one compounds, in particular oxymorphone and salts thereof, having improved impurity profiles.

First claim

The invention claimed is:

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.

Assignees

• Johnson Matthey Plc

Inventors

• Archer Nicolas
• Davies Timothy
• Price Amy
• Young Maureen

Classifications

• C07D489/08 Primary

  Oxygen atom · CPC title

• C07D498/08

  Bridged systems · CPC title

• C07D498/02 Primary

  in which the condensed system contains two hetero rings · CPC title

• C07D489/02

  with oxygen atoms attached in positions 3 and 6, e.g. morphine, morphinone · CPC title