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

Patent metadata

Field	Value
Publication number	US-9593124-B2
Application number	US-201514818199-A
Country	US
Kind code	B2
Filing date	Aug 4, 2015
Priority date	Jun 11, 2010
Publication date	Mar 14, 2017
Grant date	Mar 14, 2017

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 (57)

comprising contacting a compound of Formula (41)

with an allyl scavenger selected from the group consisting of sodium 2-ethylhexonate, morpholine, dimedone, 4-methylbenzensulfinic acid, sodium hydroxymethyl sulfinate, benzenesulfinic acid, sodium toluene sulfinate, sodium 2-thiophene sulfinate, tetrabutylammonium toluene sulfinate, N,N-dimethyl barbituric acid, sodium 4-chloro-3-nitrobenzene sulfinate, formic acid, diethyl amine, methanol, ethanol, and combinations of two or more thereof, and
a transition metal catalyst, to provide the compound of Formula (57);
wherein:
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; and
from about 1.0 equivalent to about 2.0 equivalents of the allyl scavenger is present per equivalent of the compound of Formula (41) provided that when the allyl scavenger is N,N-dimethyl barbituric acid or dimedone then from about 0.5 equivalents to about 1.0 equivalent of N,N-dimethyl barbituric acid or dimedone is present per equivalent of the compound of Formula (41).

2. The method of claim 1 , wherein the allyl scavenger is N,N-dimethyl barbituric acid.

3. 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], Mo[0], Ru[II], Rh[I], and combinations of two or more thereof.

4. The method of claim 3 , 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.

5. 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], Ru[II], and combinations of two or more thereof.

6. The method of claim 5 , 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.

7. The method of claim 5 , wherein the transition metal catalyst is Pd(PPh 3 ) 4 .

8. The method of claim 1 , wherein the contacting 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.

9. The method of claim 8 , wherein the solvent is selected from the group consisting of chloroform, dichloromethane, 1,2-dichloroethane, and combinations of two or more thereof.

10. 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.

11. The method of claim 10 , 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 .

12. The method of claim 1 , wherein:
R 14 and R 16 are each —OH; and
R 15 is ═O.

13. The method of claim 12 , wherein the allyl scavenger is N,N-dimethyl barbituric acid.

14. The method of claim 12 , 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.

15. The method of claim 14 , 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.

16. The method of claim 12 , 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.

17. The method of claim 16 , 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.

18. The method of claim 16 , wherein the transition metal catalyst is Pd(PPh 3 ) 4 .

19. The method of claim 12 , wherein the contacting 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.

20. The method of claim 19 , wherein the solvent is selected from the group consisting of chloroform, dichloromethane, 1,2-dichloroethane, and combinations of two or more thereof.

21. A method for making a compound of Formula (57)

comprising contacting a compound of Formula (42)

with an allyl scavenger selected from the group consisting of sodium 2-ethyl

Assignees

• Rhodes Tech

Inventors

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

Classifications

• C07C269/04

  from amines with formation of carbamate groups · CPC title

• B01J31/2295

  Cyclic compounds, e.g. cyclopentadienyls · CPC title

• B01J23/44

  Palladium · CPC title

• C07D265/30

  not condensed with other rings · CPC title

• B01J31/2414

  comprising aliphatic or saturated rings · CPC title