Transition metal-catalyzed processes for the preparation of N-allyl compounds and use thereof

Patent metadata

Field	Value
Publication number	US-9499557-B2
Application number	US-201514827132-A
Country	US
Kind code	B2
Filing date	Aug 14, 2015
Priority date	Jun 11, 2010
Publication date	Nov 22, 2016
Grant date	Nov 22, 2016

Abstract

The present disclosure provides processes for the N-dealkylation of tertiary amines and the use of transition metal catalysts to prepare tertiary N-allyl amine derivatives and secondary amine derivatives thereof. The tertiary amines can be alkaloids and, more particularly, the tertiary amines can be opioids. In specific embodiments, the present disclosure provides methods for use in processes for the synthesis of naloxone and naltrexone from oripavine.

First claim

What is claimed is:

1. A method for making a compound of Formula (41):

comprising:
(a) contacting a compound of Formula (45):

with a compound of Formula (10):

to provide a compound of Formula (60):

(b) contacting the compound of Formula (60) with an alkoxide of Formula (61):

to provide the compound of Formula (95):

and
(c) contacting the compound of Formula (95) with a transition metal catalyst to provide the compound of Formula (41),
wherein:
X is selected from —Cl, —Br, and —I;
R 9 is selected from phenyl and 4-nitro-phenyl;
R 14 and R 16 are each independently selected from —OH, —H, and —OR 17 ;
R 15 is selected from —OH, —H, —OR 17 , ═O, and ═CH 2 ;
R 17 is an oxygen protecting group;
R 14′ and R 16′ are each independently selected from —OH, —H, —OR 17 , and —OC(O)OR 9 ;
R 15′ is selected from —OH, —H, —OR 17 ,═O, ═CH 2 , and —OC(O)OR 9 ;
and
M is selected from the group consisting of Na, K, and Li.

2. The method of claim 1 , wherein R 14 and R 16 are each independently selected from —H and —OR 17 and R 15 is selected from —H, —OR 17 , ═O, and ═CH 2 .

3. The method of claim 1 , wherein:
the oxygen protecting group is selected from the group consisting of allyl, benzoyl, benzyl, β-methoxyethoxymethyl, dimethoxytrityl, methoxymethyl, para-methoxybenzyl, methylthiomethyl, pivaloyl, tetrahydropyranyl, trityl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldimethylsilyloxymethyl, tri-iso-propylsilyl, methyl, ethoxyethyl, —C(O)O—CH 2 —CH═CH 2 , tert-butyl-diphenylsilyl, [bis-(4-methoxyphenyl)phenylmethyl)], triphenylmethyl, —C(O)(C 1 -C 4 ) alkyl, —C(O)OR 18 , and —(C 1 -C 6 ) alkyl, each alkyl being unsubstituted or substituted with 1, 2, 3, 4, or 5 independently-selected R 21 groups;
each R 18 is independently selected from —(C 1 -C 6 ) alkyl, —(C 2 -C 6 ) alkenyl, and —(C 2 -C 6 ) alkynyl, each alkyl, alkenyl, and alkynyl being unsubstituted or substituted with 1, 2, 3, 4, or 5 independently-selected R 21 groups; and
each R 21 is independently selected from —Cl, —Br, —I, —NH 2 , —CN, and phenyl.

4. The method of claim 3 , wherein the oxygen protecting group is allyl, benzoyl, benzyl, β-methoxyethoxymethyl, dimethoxytrityl, methoxymethyl, para-methoxybenzyl, methylthiomethyl, pivaloyl, tetrahydropyranyl, trityl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldimethylsilyloxymethyl, tri-iso-propylsilyl, methyl, ethoxyethyl, or —C(O)O—CH 2 —CH═CH 2 .

5. The method of claim 2 , wherein:
the oxygen protecting group is selected from the group consisting of allyl, benzoyl, benzyl, β-methoxyethoxymethyl, dimethoxytrityl, methoxymethyl, para-methoxybenzyl, methylthiomethyl, pivaloyl, tetrahydropyranyl, trityl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldimethylsilyloxymethyl, tri-iso-propylsilyl, methyl, ethoxyethyl, —C(O)O—CH 2 —CH═CH 2 , tert-butyl-diphenylsilyl, [bis-(4-methoxyphenyl)phenylmethyl)], triphenylmethyl, —C(O)(C 1 -C 4 ) alkyl, —C(O)OR 18 , and —(C 1 -C 6 ) alkyl, each alkyl being unsubstituted or substituted with 1, 2, 3, 4, or 5 independently-selected R 21 groups;
each R 18 is independently selected from —(C 1 -C 6 ) alkyl, —(C 2 -C 6 ) alkenyl, and —(C 2 -C 6 ) alkynyl, each alkyl, alkenyl, and alkynyl being unsubstituted or substituted with 1, 2, 3, 4, or 5 independently-selected R 21 groups; and
each R 21 is independently selected from —Cl, —Br, —I, —NH 2 , —CN, and phenyl.

6. The method of claim 5 , wherein the oxygen protecting group is allyl, benzoyl, benzyl,β-methoxyethoxymethyl, dimethoxytrityl, methoxymethyl, para-methoxybenzyl, methylthiomethyl, pivaloyl, tetrahydropyranyl, trityl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldimethylsilyloxymethyl, tri-iso-propylsilyl, methyl, ethoxyethyl, or —C(O)O—CH 2 —CH═CH 2 .

7. The method of claim 1 , wherein the contacting in step (a) occurs in a solvent, wherein the solvent is selected from the group consisting of chloroform, dichloromethane, 1,2-dichloroethane, toluene, tetrahydrofuran, ethyl acetate, acetone, tert-amyl alcohol, tert-butyl alcohol, 3-methyl-3-pentanol, 2,3-dimethyl-3-pentanol, 3-ethyl-pentanol, 2-methyl-2-hexanol, acetonitrile, benzene, carbon tetrachloride, chlorobenzene, 1,2-dichlorobenzene, N,N-dimethylformamide, trifluorotoluene, 1,4-dioxane, 1,2-dimethoxyethane, xylene, and combinations of two or more thereof.

8. The method of claim 7 , wherein the solvent comprises tert-amyl alcohol, dichloromethane, tetrahydrofuran, or combinations of two or more thereof.

9. The method of claim 1 , wherein the contacting in step (b) occurs in a solvent, wherein the solvent is selected from the group consisting of chloroform, dichloromethane, 1,2-dichloroethane, toluene, tetrahydrofuran, ethyl acetate, acetone, tert-amyl alcohol, tert-butyl alcohol, 3-methyl-3-pentanol, 2,3-dimethyl-3-pentanol, 3-ethyl-pentanol, 2-methyl-2-hexanol, acetonitrile, benzene, carbon tetrachloride, chlorobenzene, 1,2-dichlorobenzene, N,N-dimethylformamide, trifluorotoluene, 1,4-dioxane, 1,2-dimethoxyethane, xylene, and combinations of two or more thereof.

10. The method of claim 9 , wherein the solvent comprises tert-amyl alcohol, dichloromethane, tetrahydrofuran, or combinations of two or more thereof.

11. The method of claim 1 , wherein the transition metal catalyst comprises a transition metal selected from the group consisting of Pd[0], Pd[II], Ni[0], Ni[II], Mo[0], Ru[II], Rh[I], and combinations of two or more thereof.

12. The method of claim 11 , wherein the transition metal catalyst is selected from the group consisting of Pd(PPh 3 ) 4 , Pd(Ph 2 P(CH 2 ) 4 PPh 2 ) 2 , Ni(PPh 3 ) 4 , Ni(Ph 2 P(CH 2 ) 4 PPh 2 ) 2 , ((pentamethylcyclopentadienyl)RuCl) 4 , [Pd(DBA) 2 ]/PPh 3 , [Pd(OAc) 2 ]/PPh 3 , [Ni(COD) 2 ]/PPh 3 , NiCl 2 /PPh 3 , Ni[P(OEt) 3 ] 4 , [Mo(CO) 6 -DPPE], RhH(PPh 3 ) 4 —P(n-Bu) 3 , and combinations of two or more thereof.

13. The method of claim 2 , wherein the transition metal catalyst comprises a transition metal selected from the group consisting of Pd[0], Pd[II], Ni[0], Ni[II], Ru[II], and combinations of two or more thereof.

14. The method of claim 13 , wherein the transition metal catalyst is selected from the group consisting of Pd(PPh 3 ) 4 , Pd(Ph 2 P(CH 2 ) 4 PPh 2 ) 2 , Ni(PPh 3 ) 4 , Ni(Ph 2 P(CH 2 ) 4 PPh 2 ) 2 , ((pentamethylcyclopentadienyl)RuCl) 4 , [Pd(DBA) 2 ]/PPh 3 , [Pd(OAc) 2 ]/PPh 3 , [Ni(COD) 2 ]/PPh 3 , NiCl 2 /PPh 3 , Ni[P(OEt) 3 ] 4 , and combinations of two or more thereof.

15. The method of claim 4 , wherein the transition metal catalyst comprises a transition metal selected from the group consisting of Pd[0], Pd[II], Ni[0], Ni[II], Ru[II], and combinations of two or more thereof.

16. The method of claim 15 , wherein the transition metal catalyst is selected from the group consisting of Pd(PPh 3 ) 4 , Pd(Ph 2 P(CH 2 ) 4 PPh 2 ) 2 , Ni(PPh 3 ) 4 , Ni(Ph 2 P(CH 2 ) 4 PPh 2 ) 2 , ((pentamethylcyclopentadienyl)RuCl) 4 , [Pd(DBA) 2 ]/PPh 3 , [Pd(OAc) 2 ]/PPh 3 , [Ni(COD) 2 ]/PPh 3 , NiCl 2 /PPh 3

Assignees

• Rhodes Tech

Inventors

• Giguere Joshua Robert
• Mccarthy Keith Edward
• Reisch Helge Alfred
• Sandoval Sergio
• Stymiest Jake Larry

Classifications

• B01J23/42

  Platinum · CPC title

• C07D295/205

  Radicals derived from carbonic acid · CPC title

• C07C269/04

  from amines with formation of carbamate groups · CPC title

• B01J31/2414

  comprising aliphatic or saturated rings · CPC title

• C07D295/03

  with the ring nitrogen atoms directly attached to acyclic carbon atoms · CPC title