Method for producing morphinan derivative

Patent metadata

Field	Value
Publication number	US-12202830-B2
Application number	US-202017626697-A
Country	US
Kind code	B2
Filing date	Jul 17, 2020
Priority date	Jul 19, 2019
Publication date	Jan 21, 2025
Grant date	Jan 21, 2025

Abstract

Provided is, for example, a method for producing a morphinan derivative represented by General Formula (II), including the step of: allowing metal sodium and ethylenediamine to act on a morphinan derivative represented by General Formula (I) in presence of an auxiliary solvent.

wherein R 1 represents a hydrogen atom, or a C 1-10 alkyl group, a C 3-6 cycloalkyl group, a C 2-6 alkenyl group, a C 6-10 aryl group, or a heteroaryl group optionally having a substituent, R 2 represents an amino protecting group, R 3 represents a methoxy group, R 4 and R 5 represent a hydrogen atom or a hydroxy group, R 6 and R 7 represent a hydrogen atom or an electron-donating group, wherein R 6 and R 7 are not simultaneously a hydrogen atom, and X represents O or CH 2 .

First claim

The invention claimed is:

1. A method for producing a morphinan derivative represented by Formula (II) below:

wherein R 1 represents a hydrogen atom, a C 1-10 alkyl group optionally having a substituent, a C 3-6 cycloalkyl group optionally having a substituent, a C 2-6 alkenyl group optionally having a substituent, a C 6-10 aryl group optionally having a substituent, or a heteroaryl group optionally having a substituent,
R 2 represents an amino protecting group,
R 3 represents a methoxy group,
R 4 and R 5 are same or different and represent a hydrogen atom or a hydroxy group, and
X represents O or CH 2 ,
said method comprising:
allowing metal sodium and ethylenediamine to act on a morphinan derivative represented by Formula (I) below:

wherein R 1 to R 5 and X have a meaning same as above,
R 6 and R 7 are same or different and represent a hydrogen atom or an electron-donating group,
wherein R 6 and R 7 are not simultaneously a hydrogen atom, and
in presence of an auxiliary solvent.

2. The method for producing a morphinan derivative according to claim 1 , wherein R 1 is a hydrogen atom.

3. The method for producing a morphinan derivative according to claim 1 , wherein R 1 is a C 1-10 alkyl group substituted with a C 3-6 cycloalkyl group optionally having a substituent.

4. The method for producing a morphinan derivative according to claim 1 , wherein R 1 is a cyclopropylmethyl group.

5. The method for producing a morphinan derivative according to claim 1 , wherein R 2 is a benzyl group.

6. The method for producing a morphinan derivative according to claim 1 , wherein R 3 is a C 1-10 alkoxy group.

7. The method for producing a morphinan derivative according to claim 1 , wherein R 3 is a methoxy group.

8. The method for producing a morphinan derivative according to claim 1 , wherein R 4 and R 5 are a hydrogen atom.

9. The method for producing a morphinan derivative according to claim 1 , wherein R 6 is a C 1-10 alkyl group, OR 8 (R 8 represents a hydrogen atom or a C 1-10 alkyl group optionally having a substituent), or NR 9 R 10 (R 9 and R 10 are same or different and represent a hydrogen atom or a C 1-10 alkyl group optionally having a substituent).

10. The method for producing a morphinan derivative according to claim 1 , wherein R 6 is a C 1-10 alkyl group optionally having a substituent.

11. The method for producing a morphinan derivative according to claim 1 , wherein R 6 is a tert-butyl group.

12. The method for producing a morphinan derivative according to claim 1 , wherein R 6 is a hydrogen atom.

13. The method for producing a morphinan derivative according to claim 1 , wherein R 7 is a hydrogen atom.

14. The method for producing a morphinan derivative according to claim 1 , wherein R 7 is a C 1-10 alkyl group optionally having a substituent, OR 11 (R 11 represents a hydrogen atom or a C 1-10 alkyl group optionally having a substituent), or NR 12 R 13 (R 12 and R 13 are same or different and represent a hydrogen atom or a C 1-10 alkyl group optionally having a substituent).

15. The method for producing a morphinan derivative according to claim 1 , wherein R 7 is a C 1-10 alkoxy group optionally having a substituent.

16. The method for producing a morphinan derivative according to claim 1 , wherein R 7 is a methoxy group.

17. The method for producing a morphinan derivative according to claim 1 , wherein the metal sodium is used in an amount of 1 to 10 equivalents relative to the morphinan derivative of the Formula (I).

18. The method for producing a morphinan derivative according to claim 1 , wherein the metal sodium is a metal sodium dispersion.

19. The method for producing a morphinan derivative according to claim 1 , wherein the auxiliary solvent is an aromatic hydrocarbon solvent or an ether solvent.

20. The method for producing a morphinan derivative according to claim 1 , wherein a reaction temperature is −30° C. to 150° C.

21. The method for producing a morphinan derivative according to claim 1 , wherein a reaction temperature is 0° C. to 30° C.

22. A morphinan derivative represented by Formula (I) below:

wherein R 1 represents a hydrogen atom, a C 1-10 alkyl group optionally having a substituent, a C 3-6 cycloalkyl group optionally having a substituent, a C 2-6 alkenyl group optionally having a substituent, a C 6-10 aryl group optionally having a substituent, or a heteroaryl group optionally having a substituent,
R 2 represents an amino protecting group,
R 3 represents a methoxy group,
R 4 and R 5 are same or different and represent a hydrogen atom or a hydroxy group,
R 6 and R 7 are same or different and represent a hydrogen atom or an electron-donating group,
wherein R 6 and R 7 are not simultaneously a hydrogen atom, and
X represents O or CH 2 .

23. The morphinan derivative according to claim 22 , wherein R 1 is a hydrogen atom.

24. The morphinan derivative according to claim 22 , wherein R 1 is a C 1-10 alkyl group substituted with a C 3-6 cycloalkyl group optionally having a substituent.

25. The morphinan derivative according to claim 22 , wherein R 1 is a cyclopropylmethyl group.

26. The morphinan derivative according to claim 22 , wherein R 2 is a benzyl group.

27. The morphinan derivative according to claim 22 , wherein R 3 is a C 1-10 alkoxy group.

28. The morphinan derivative according to claim 22 , wherein R 3 is a methoxy group.

29. The morphinan derivative according to claim 22 , wherein R 4 and R 5 are a hydrogen atom.

30. The morphinan derivative according to claim 22 , wherein R 6 is a C 1-10 alkyl group, OR 8 (R 8 represents a hydrogen atom or a C 1-10 alkyl group optionally having a substituent), or NR 9 R 10 (R 9 and R 10 are same or different and represent a hydrogen atom or a C 1-10 alkyl group optionally having a substituent).

31. The morphinan derivative according to claim 22 , wherein R 6 is a C 1-10 alkyl group optionally having a substituent.

32. The morphinan derivative according to claim 22 , wherein R 6 is a tert-butyl group.

33. The morphinan derivative according to claim 22 , wherein R 6 is a hydrogen atom.

34. The morphinan derivative according to claim 22 , wherein R 7 is a hydrogen atom.

35. The morphinan derivative according to claim 22 , wherein R 7 is a C 1-10 alkyl group optionally having a substituent, OR 11 (R 11 represents a hydrogen atom or a C 1-10 alkyl group optionally having a substituent), or NR 12 R 13 (R 12 and R 13 are same or different and represent a hydrogen atom or a C 1-10 alkyl group optionally having a substituent).

36. The morphinan derivative according to claim 22 , wherein R 7 is a C 1-10 alkoxy group optionally having a substituent.

37. The mor

Assignees

• Nippon Chemiphar Co

Inventors

• Saito Daisuke
• Hayashida Kohei

Classifications

• C07D471/22

  in which the condensed systems contains four or more hetero rings · CPC title

• Y02P20/55

  Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups · CPC title

• C07D471/08 Primary

  Bridged systems · CPC title

• C07D491/18 Primary

  Bridged systems · CPC title