IP Library › Granted Patent US 9,499,557

Granted Patent B2

US 9,499,557 · App. 14/827,132 · Granted Nov 22, 2016

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

Inventors: Joshua Robert Giguere (Sharon, MA); Keith Edward McCarthy (Old Lyme, CT); Helge Alfred Reisch (Westerly, RI); Sergio Sandoval (West Warwick, RI); Jake Larry Stymiest (Foster, RI)

Assignee: Rhodes Technologies

C07D489/08 B01J23/42 B01J23/44 B01J31/1855 B01J31/20 B01J31/2295 B01J31/2414 C07C209/00 C07C209/44 C07C269/04 C07D265/30 C07D295/03 C07D295/205 B01J2231/40 B01J2531/64 B01J2531/821 B01J2531/824 B01J2531/828 B01J2531/847 Y02P20/55

View Patent ↗

Loading inventors, assignments & file history…

Monitor This Case

Get email alerts when status or documents change.

Order Certified Copies

Most orders are placed with the USPTO same day — all within 24 business hours.

Order via The Patent Place →

Pre-filled with this patent's details

Quick Facts

Patent No.: US 9,499,557
App. No.: 14/827,132
Granted: Nov 22, 2016
Kind: B2

External Links

USPTO Patent Center↗ Full Patent PDF↗

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.

Claims (53)

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

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:

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 , Ni[P(OEt) 3 ] 4 , and combinations of two or more thereof.

17. The method of claim 6 , 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.

18. The method of claim 17 , 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.

19. The method of claim 1 , wherein the contacting in step (c) 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 comprises tert-amyl alcohol, dichloromethane, tetrahydrofuran, or combinations of two or more thereof.

21. The method of claim 19 , 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.

22. The method of claim 21 , 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.

23. The method of claim 2 , 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.

24. The method of claim 23 , wherein the solvent comprises tert-amyl alcohol, dichloromethane, tetrahydrofuran, or combinations of two or more thereof.

25. The method of claim 2 , 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.

26. The method of claim 25 , wherein the solvent comprises tert-amyl alcohol, dichloromethane, tetrahydrofuran, or combinations of two or more thereof.

27. The method of claim 2 , wherein the contacting in step (c) 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.

28. The method of claim 27 , wherein the solvent comprises tert-amyl alcohol, dichloromethane, tetrahydrofuran, or combinations of two or more thereof.

29. The method of claim 1 , wherein R 15′ is selected from —OH, —H, —OR 17 , ═CH 2 , and —OC(O)OR 9 .

Assignments (3)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Mar 17, 2021

From: RHODES TECHNOLOGIES

To: NORAMCO, LLC

Reel/Frame 055627/0662 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Nov 4, 2015

From: GIGUERE, JOSHUA R.; MCCARTHY, KEITH E.; REISCH, HELGE A.; SANDOVAL, SERGIO; STYMIEST, JAKE L.

To: PURDUE PHARMA L.P.

Reel/Frame 036960/0605 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Nov 4, 2015

From: PURDUE PHARMA L.P.