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

Patent metadata

Field	Value
Publication number	US-9657030-B2
Application number	US-201514827085-A
Country	US
Kind code	B2
Filing date	Aug 14, 2015
Priority date	Jun 11, 2010
Publication date	May 23, 2017
Grant date	May 23, 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 (54)

comprising
contacting a compound of Formula (55)

with a compound of Formula (56)

in a solvent containing an additional base and a transition metal catalyst to provide the compound of Formula (54);
wherein:
R 14 is selected from —OH and —OR 17 ;
R 16 is selected from —OH, —H, and —OR 17 ;
the 6,7 bond, the 7,8 bond, and the 8,14 bond are each independently a single bond or a double bond, with the provisos that (1) if the 6,7 bond is a double bond, then the 7,8 bond is a single bond, (2) if the 7,8 bond is a double bond, then the 6,7 and 8,14 bonds are each a single bond, and (3) if the 8,14 bond is a double bond, then the 7,8 bond is a single bond and R 16 is not present;
R 15 is selected from —OH, —H, —OR 17 , ═O, and ═CH 2 with the proviso that if the 6,7 bond is a double bond, then R 15 is selected from —OH, —H, and —OR 17 ;
R 22 is —OC(O)X;
X is selected from —Cl, —Br, and —I; and
R 17 is an oxygen protecting group.

2. 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.

3. 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 , ((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.

4. The method of claim 1 , wherein the additional 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-1-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.

5. The method of claim 4 , wherein the additional base is selected from the group consisting of 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.

6. The method of claim 1 , wherein:
the R 17 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 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.

7. The method of claim 6 , wherein the R 17 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 .

8. The method of claim 1 , wherein the 6,7 and 8,14 bonds are each a double bond and R 15 is —OCH 3 .

9. The method of claim 2 , wherein R 14 and R 16 are each —OH, R 15 is ═O, and the 6,7 , 7,8 , and 8,14 bonds are each a single bond.

10. The method of claim 8 , wherein R 14 is —OCH 3 .

11. The method of claim 1 , wherein R 14 and R 16 are each —OH, R 15 is ═O, and the 6,7 , 7,8 , and 8,14 bonds are each a single bond.

12. The method of claim 1 , wherein R 14 is —OCH 3 .

13. The method of claim 1 , 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.

14. The method of claim 13 , wherein the solvent comprises dichloromethane, toluene, tetrahydrofuran, tert-amyl alcohol, acetonitrile, N,N-dimethylformamide, or combinations of two or more thereof.

15. The method of claim 13 , wherein the solvent comprises dichloromethane, toluene, tert-amyl alcohol, N,N-dimethylformamide, or combinations of two or more thereof.

16. The method of claim 2 , 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.

17. The method of claim 16 , wherein the solvent comprises dichloromethane, toluene, tetrahydrofuran, tert-amyl alcohol, acetonitrile, N,N-dimethylformamide, or combinations of two or more thereof.

18. The method of claim 16 , wherein the solvent comprises dichloromethane, toluene, tert-amyl alcohol, N,N-dimethylformamide, or combinations of two or more thereof.

19. The method of claim 4 , 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 comprises dichloromethane, toluene, tetrahydrofuran, tert-amyl alcohol, acetonitrile, N,N-dimethylformamide, or combinations of two or more thereof.

21. The method of claim 19 , wherein the solvent comprises dichloromethane, toluene, tert-amyl alcohol, N,N-dimethylformamid

Assignees

• Rhodes Tech

Inventors

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

Classifications

• B01J2531/64

  Molybdenum · CPC title

• C07D265/30

  not condensed with other rings · CPC title

• C07D295/03

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

• B01J23/44

  Palladium · CPC title

• C07D295/205

  Radicals derived from carbonic acid · CPC title