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

Patent metadata

Field	Value
Publication number	US-9624232-B2
Application number	US-201514827104-A
Country	US
Kind code	B2
Filing date	Aug 14, 2015
Priority date	Jun 11, 2010
Publication date	Apr 18, 2017
Grant date	Apr 18, 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 (200)

comprising
contacting a compound of Formula (45)

with a compound of Formula (23)

and a base in a first solvent to provide a compound of Formula (211)

 and contacting the compound of Formula (211) with a transition metal catalyst and a second solvent to provide the compound of Formula (200);
wherein:
X is selected from —Cl, —Br, and —I;
R 4 , R 5 , R 6 , and R 7 are each hydrogen;
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 ; and
R 17 is an oxygen protecting group;
V is a leaving group; and
the transition metal catalyst comprises a transition metal selected from the group consisting of Pd[0],Pd[II], Ni[0], and combinations of two or more thereof.

2. The method of claim 1 , wherein V is selected from —Cl, —Br, —I, —OS(O) 2 C 4 F 9 , —OS(O) 2 CF 3 , —OS(O) 2 F, -para-toluene sulfonate, —OS(O) 2 CH 3 , and —B(O(C 1 —C 4 ) alkyl) 2 .

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], and combinations thereof.

4. The method of claim 1 , 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 , [Pd(DBA) 2 ]/PPh 3 , [Pd(OAc) 2 ]/PPh 3 ,[Ni(COD) 2 ]/PPh 3 , NiC1 2 /PPh 3 , Ni[P(OEt) 3 ] 4 , and combinations of two or more thereof.

5. The method of claim 2 , wherein the transition metal catalyst comprises a transition metal selected from the group consisting of Pd[0], Pd[II], and combinations thereof.

6. The method of claim 2 , 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 ,[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 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.

8. The method of claim 1 , wherein the oxygen protecting group is allyl, benzoyl, benzyl, β-methoxyethoxymethyl, dimethoxytrityl, methoxymethyl, para -methoxybenzyl, methylthiomethyl, pivaloyl, tetrahydropyranyl, trityl, trimethylsilyl, tert-butyldimethylsilyl, tertbutyldimethylsilyloxymethyl, tri-iso-propylsilyl, methyl, ethoxyethyl, or —C(O)O—CH 2 —CH═CH 2 .

9. The method of claim 1 , wherein the first 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 1 , wherein the second solvent comprises tert-amyl alcohol, 1,4-dioxane, tetrahydrofuran, or combinations thereof.

11. The method of claim 1 , wherein the base is selected from the group consisting of NaBO 3 , Na 2 HPO 4 , Na 3 PO 4 , K 2 HPO 4 , K 3 PO 4 , NaHCO 3 , KHCO 3 , NaOH, KOH, Na 2 CO 3 , K 2 CO 3 , Cs 2 CO 3 , pyridine, triethylamine, di-iso-propylethylamine, N-methylmorpholine, N,N-dimethylaminopyridine, N-(2-acetamido)-2-aminoethane sulfonic acid, N-(2-acetamido)-iminodiacetic acid, N,N-bis(2-hydroxyethyl)glycine, 3-(cyclohexylamino)-1-propanesulfonic acid, 2-(cyclohexylamino) ethanesulfonic acid, 4-(2-hydroxyethyl)-1-piperazinepropanesulfonic acid, 4-(2-hydroxyethyl)piperazine-l-ethanesulfonic acid, 2-(4-morpholinyl) ethanesulfonic acid, 4-morpholinepropanesulfonic acid, 1,4-piperazinediethanesulfonic acid, [(2-hydroxy-1,1 -bis(hydroxymethyl) ethyl)amino]-1-propanesulfonic acid, 2-[(2-hydroxy-1,1-bis(hydroxymethyl)ethyl)amino]ethanesulfonic acid, and combinations of two or more thereof.

12. The method of claim 1 , wherein the base is selected from the group consisting of K 3 PO 4 , Na 3 PO 4 , NaHCO 3 , KHCO 3 , Na 2 CO 3 , K 2 CO 3 , Cs 2 CO 3 , triethylamine, di-iso-propylethylamine, and combinations of two or more thereof.

13. 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.

14. The method of claim 2 , 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 .

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

16. The method of claim 2 , wherein:
R 14 and R 16 are each —OH; and
R 15 is ═O.

17. The method of claim 1 , wherein the second 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 combi

Assignees

• Rhodes Tech

Inventors

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

Classifications

• B01J2231/40

  Substitution reactions at carbon centres, e.g. C-C or C-X, i.e. carbon-hetero atom, cross-coupling, C-H activation or ring-opening reactions · CPC title

• C07D295/205

  Radicals derived from carbonic acid · CPC title

• B01J31/1855

  Triamide derivatives thereof · CPC title

• C07C209/44

  by reduction of carboxylic acids or esters thereof in presence of ammonia or amines, or by reduction of nitriles, carboxylic acid amides, imines or imino-ethers · CPC title

• C07C269/04

  from amines with formation of carbamate groups · CPC title