C-14 oxidation of morphine derivatives
View Patent ↗The present invention relates to process for the preparation of a 14-hydroxynormorphinone derivative of formula IV comprising reacting the compound of formula III, with a cobalt (II) oxidant in the presence of a mild base and air or oxygen as the cooxidant; wherein R 1 is (1C-7C)alkyl optionally substituted with one or more chlorines, butenyl, vinyl, benzyl, phenyl or naphthyl; and R 2 is benzyl or benzyl substituted with one or more (1C-6C)alkoxy group or benzyl substituted with one or more halogen. The process is very suitable in the production of noroxymorphone.
1. A process for the preparation of a 14-hydroxynormorphinone compound of formula IV
comprising reacting the compound of formula III,
with a cobalt (II) oxidant in the presence of a mild base and air or oxygen as the cooxidant;
wherein
R 1 is (1C-7C)alkyl optionally substituted with one or more chlorines, butenyl, vinyl, benzyl, phenyl or naphthyl; and
R 2 is benzyl or benzyl substituted with one or more (1C-6C)alkoxy group or benzyl substituted with one or more halogen.
2. The process of claim 1 , wherein the oxidant is Co(OAc) 2 .
3. The process of claim 1 , wherein the cooxidant is oxygen.
4. The process of claim 1 , wherein the mild base is sodium acetate, potassium acetate, sodium phosphate or potassium phosphate.
5. The process of claim 4 , wherein the mild base is sodium acetate.
6. The process of claim 1 , wherein R 1 is (1-7C)alkyl.
7. The process of claim 6 , wherein R 1 is ethyl.
8. The process of claim 1 , wherein R 2 is benzyl.
9. A 14-hydroxynormorphinone compound of the formula IV
wherein
R 1 is (1C-7C)alkyl optionally substituted with one or more chlorines, butenyl, vinyl, benzyl, phenyl or naphthyl; and
R 2 is benzyl or benzyl substituted with one or more (1C-6C)alkoxy group or benzyl substituted with one or more halogen.
10. The 14-hydroxynormorphinone compound of claim 9 , wherein R 1 is ethyl.
11. The 14-hydroxynormorphinone compound of claim 9 , wherein R 2 is benzyl.
12. A morphinone compound of the formula III
wherein
R 1 is (1C-7C)alkyl optionally substituted with one or more chlorines, butenyl, vinyl, benzyl, phenyl or naphthyl; and
R 2 is benzyl or benzyl substituted with one or more (1C-6C)alkoxy group or benzyl substituted with one or more halogen.
13. The morphinone compound of claim 12 , wherein R 1 is ethyl.
14. The morphinone compound of claim 12 , wherein R 2 is benzyl.
15. A process for the preparation of a compound of formula III
wherein
R 1 is (1C-7C)alkyl optionally substituted with one or more chlorines, butenyl, vinyl, benzyl, phenyl or naphthyl; and
R 2 is benzyl or benzyl substituted with one or more (1C-6C)alkoxy group or benzyl substituted with one or more halogen,
comprising: reactively contacting a morphine compound of formula II
wherein R 1 and R 2 are as defined above,
with an oxidizing agent effective for oxidizing allylic hydroxy groups to form keto groups, to form the compound of formula III.
16. The process of claim 15 , wherein the oxidizing agent is sodium dichromate.
17. The process of claim 15 , wherein R 1 is ethyl.
18. A process for the production of noroxymorphone, comprising: a reaction step wherein a morphinone compound of formula III
is oxidized into a 14-hydroxynormorphinone compound of formula IV
with a cobalt (II) oxidant in the presence of a mild base and air or oxygen as the cooxidant;
wherein
R 1 is (1C-7C)alkyl optionally substituted with one or more chlorines, butenyl, vinyl, benzyl, phenyl or naphthyl; and
R 2 is benzyl or benzyl substituted with one or more (1C-6C)alkoxy group or benzyl substituted with one or more halogen.
19. The process of claim 18 , further comprising reactively contacting a compound of formula II
wherein R 1 is (1C-7C)alkyl optionally substituted with one or more chlorines, butenyl, vinyl, benzyl, phenyl or naphthyl; and
R 2 is benzyl or benzyl substituted with one or more (1C-6C)alkoxy group or benzyl substituted with one or more halogen,
with an oxidizing agent effective for oxidizing allylic hydroxy groups to form keto groups, to form a morphinone compound of formula III
wherein R 1 and R 2 are as defined above.
20. A process for the production of noroxymorphone, wherein morphine having the formula I
is converted into noroxymorphone, comprising:
(a) converting morphine having the formula I
by reaction with a haloformate ester of the formula X—C(=O)OR 1 , wherein R 1 is (1C-7C)alkyl optionally substituted with one or more chlorines, butenyl, vinyl, benzyl, phenyl or naphthyl and X is a halogen, followed by a reaction with R 2 —X, wherein X is as previously defined and R 2 is benzyl or benzyl substituted with one or more (1C-6C)alkoxy group or benzyl substituted with one or more halogen, to form a morphine compound of formula II
wherein R 1 and R 2 are as defined above,
(b) oxidizing the morphine of formula II to form a morphinone compound of formula III
wherein R1 and R2 are as defined above,
wherein the process is reactively contacting a morphine compound of formula II with an oxidizing agent effective for oxidizing allylic hydroxy groups to form keto groups;
(c) oxidizing the morphinone compound of formula III with a cobalt (II) oxidant in the presence of a mild base and air or oxygen as the cooxidant to form a 14-hydroxynormorphinone compound of formula IV
wherein R 1 and R 2 are as defined above;
(d) deprotecting the 3-position and reducing the double bond at the 7,8-position of the 14-hydroxynormorphinone compound of formula IV to form a 3,14-hydroxynormorphinone compound of formula V,
wherein R 1 is as defined above;
(e) and hydrolyzing the 3,14-hydroxynormorphinone compound of formula V into noroxymorphone of formula VI,
21. The process of claim 1 , wherein the cooxidant is air.
22. The process of claim 15 , wherein R 2 is benzyl.