IP Library › Granted Patent US 8,921,556

Granted Patent B2

US 8,921,556 · App. 13/711,288 · Granted Dec 30, 2014

Process for N-dealkylation of tertiary amines

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

Assignee: Rhodes Technologies

C07D489/08 C07D489/12

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Quick Facts

Patent No.: US 8,921,556
App. No.: 13/711,288
Granted: Dec 30, 2014
Kind: B2

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Abstract

The present disclosure provides improved methods for N-dealkylation of tertiary amines, including methods for N-demethylation of alkaloids and opioids, in which the dealkylation reaction is carried out in a solvent comprising a tertiary alcohol. The present disclosure also provides improved processes for preparing semi-synthetic opioids that incorporate the disclosed methods for N-dealkylation of tertiary amines.

Claims (232)

1. A method for N-demethylating a compound of formula (6)

comprising

contacting the compound of formula (6) with a compound of formula (2)

in a solvent to provide a compound of formula (7)

wherein

the solvent comprises a tertiary alcohol;

the 7,8-bond is a single bond or a double bond;

R 9 and R 11 are each independently selected from the group consisting of —OH, —H, and —OR 15 ;

R 9′ and R 11′ are each independently selected from the group consisting of —OH, —H, —OR 15 , and —OC(O)OR 4 ;

R 10 is selected from the group consisting of ═O, —OH, ═CH 2 , —H, and —OR 15 ;

R 10′ is selected from the group consisting of ═O, —OH, ═CH 2 , —H, —OR 15 , and —OC(O)OR 4 ;

R 15 is an oxygen protecting group;

R 4 is selected from the group consisting of —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, aryl, and heteroaryl, each being unsubstituted or substituted with 1, 2, 3, 4, or 5 independently-selected R 5 groups;

each R 5 is independently selected from the group consisting of —OH, —Cl, Br, —I, —NH 2 , —CN, —O—(C 1 -C 6 ) alkyl, and phenyl; and

X is selected from the group consisting of —Cl, —Br, —I, mesylate, and tosylate.

2. The method of claim 1 , wherein the solvent consists essentially of a tertiary alcohol.

3. The method of claim 1 , wherein the tertiary alcohol is an alcohol of formula (5)

wherein R 6 , R 7 , and R 8 are each independently —(C 1 -C 6 )alkyl.

4. The method of claim 3 , wherein the tertiary alcohol is selected from the group consisting of tert-amyl alcohol, tert-butyl alcohol, 3-methyl-3-pentanol, 2,3-dimethyl-3-pentanol, 3-ethyl-3-pentanol, 2-methyl-2-hexanol, and mixtures of two or more thereof.

5. The method of claim 4 , wherein the tertiary alcohol is tert-amyl alcohol.

6. The method of claim 1 , wherein the 7,8-bond is a single bond.

7. The method of claim 6 , wherein R 9 and R 11 are each —OH and R 10 is ═O.

8. The method of claim 6 , wherein R 9 is —OCH 3 , R 11 is —OH, and R 10 is ═O.

9. The method of claim 1 , wherein said contacting is carried out in the presence of an iodide salt.

10. The method of claim 9 , wherein the iodide salt is NaI.

11. The method of claim 1 , wherein the compound of formula (6) is a compound of formula (19):

wherein

R 9 is selected from the group consisting of —OH, —H, and —OR 15 ; and

R 15 is an oxygen protecting group.

12. The method of claim 11 , further comprising hydrogenating the 7,8-double bond of a compound of formula (21)

to provide the compound of formula (19);

wherein

R 9 is selected from the group consisting of —OH, —H, and —OR 15 ; and

R 15 is an oxygen protecting group.

13. The method of claim 12 , further comprising oxidizing a compound of formula (20)

to provide the compound of formula (21);

wherein

R 9 is selected from the group consisting of —OH, —H, and —OR 15 ; and

R 15 is an oxygen protecting group.

14. A method for making a compound of formula (8)

comprising

contacting a compound of formula (6)

with a compound of formula (2)

in a solvent to provide a compound of formula (7)

and

converting the compound of formula (7) to the compound of formula (8);

wherein

the solvent comprises a tertiary alcohol;

the 7,8-bond is a single bond or a double bond;

R 9 and R 11 are each independently selected from the group consisting of —OH, —H, and —OR 15 ;

R 9′ and R 11′ are each independently selected from the group consisting of —OH, —H, —OR 15 , and —OC(O)OR 4 ;

R 10 is selected from the group consisting of ═O, —OH, ═CH 2 , —H, and —OR 15 ;

R 10′ is selected from the group consisting of ═O, —OH, ═CH 2 , —H, —OR 15 , and —OC(O)OR 4 ;

R 15 is an oxygen protecting group;

each R 5 is independently selected from the group consisting of —OH, —Cl, —Br, —I, —NH 2 , —CN, —O—(C 1 -C 6 ) alkyl, and phenyl; and

X is selected from the group consisting of —Cl, —Br, —I, mesylate, and tosylate.

15. The method of claim 14 , wherein the solvent consists essentially of a tertiary alcohol.

16. The method of claim 14 , wherein the tertiary alcohol is tert-amyl alcohol.

17. The method of claim 14 , wherein the 7,8-bond is a single bond.

18. The method of claim 17 , wherein R 9 and R 11 are —OH and R 10 is ═O.

19. The method of claim 17 , wherein R 9 is —OCH 3 , R 11 is —OH, and R 10 is ═O.

20. The method of claim 14 , wherein said contacting is carried out in the presence of sodium iodide.

21. The method of claim 14 , wherein the compound of formula (6) is a compound of formula (19):

wherein

R 9 is selected from the group consisting of —OH, —H, and —OR 15 ; and

R 15 is an oxygen protecting group.

22. The method of claim 21 , further comprising hydrogenating the 7,8-double bond of a compound of formula (21)

to provide the compound of formula (19);

wherein

R 9 is selected from the group consisting of —OH, —H, and —OR 15 ; and

R 15 is an oxygen protecting group.

23. The method of claim 22 , further comprising oxidizing a compound of formula (20)

to provide the compound of formula (21);

wherein

R 9 is selected from the group consisting of —OH, —H, and —OR 15 ; and

R 15 is an oxygen protecting group.

24. A method for making a compound of formula (9)

comprising

(a) contacting a compound of formula (6)

with a compound of formula (2)

in a solvent to provide a compound of formula (7)

(b) converting the compound of formula (7) to a compound of formula (8)

and

X′—R 16

to provide the compound of formula (9);

wherein

the solvent comprises a tertiary alcohol;

the 7,8-bond is a single bond or a double bond;

R 9 and R 11 are each independently selected from the group consisting of —OH, —H, and —OR 15 ;

R 9′ are each independently selected from the group consisting of —OH, —H, —OR 15 , and —OC(O)OR 4 ;

R 10 is selected from the group consisting of ═O, —OH, ═CH 2 , —H, and —OR 15 ;

R 10′ is selected from the group consisting of ═O, —OH, ═CH 2 , —H, —OR 15 , and —OC(O)OR 4 ;

R 15 is an oxygen protecting group;

R 16 is selected from the group consisting of allyl, methylcyclopropyl, methylcyclobutyl, and propargyl;

each R 5 is independently selected from the group consisting of —OH, —Cl, —Br, —I, —NH 2 , —CN, —O—(C 1 -C 6 ) alkyl, and phenyl; and

X and X′ are each independently selected from the group consisting of —Cl, —Br, —I, mesylate, and tosylate.

25. The method of claim 24 , wherein the solvent consists essentially of a tertiary alcohol.

26. The method of claim 24 , wherein the tertiary alcohol is tert-amyl alcohol.

27. The method of claim 24 , wherein step (a) is carried out in the presence of an NaI.

28. The method of claim 24 , wherein said converting step (b) comprises contacting the compound of formula (7) with a base to provide the compound of formula (8).

29. The method of claim 28 , wherein the base is selected from the group consisting of Na 2 CO 3 , K 2 CO 3 , Cs 2 CO 3 , Na 3 PO 4 , Na 2 HPO 4 , and combinations of two or more thereof.

30. The method of claim 24 , wherein the compound of formula (6) is a compound of formula (19):

wherein

R 9 is selected from the group consisting of —OH, —H, and —OR 15 ; and

R 15 is an oxygen protecting group.

31. The method of claim 30 , further comprising hydrogenating the 7,8-double bond of a compound of formula (21)

to provide the compound of formula (19);

wherein

R 9 is selected from the group consisting of —OH, —H, and —OR 15 ; and

R 15 is an oxygen protecting group.

32. The method of claim 31 , further comprising oxidizing a compound of formula (20)

to provide the compound of formula (21);

wherein

R 9 is selected from the group consisting of —OH, —H, and —OR 15 ; and

R 15 is an oxygen protecting group.

33. A method for making a compound of formula (11)

comprising

(a) contacting a compound of formula (12)

with a compound of formula (2)

in a solvent to provide a compound of formula (13)

(b) converting the compound of formula (13) to a compound of formula (14)

and

X′—R 16

to provide the compound of formula (11);

wherein

the solvent comprises a tertiary alcohol;

the bond is a single bond or a double bond;

R 9 is selected from the group consisting of —OH, —H, and —OR 15 ;

R 9′ is selected from the group consisting of —OH, —H, —OR 15 , and —OC(O)OR 4 ;

R 19 is selected from the group consisting of —H, —CH 3 , —OH, and —OR 15 ;

R 15 is an oxygen protecting group;

R 16 is selected from the group consisting of allyl, methylcyclopropyl, methylcyclobutyl, and propargyl;

each R 5 is independently selected from the group consisting of —OH, —Cl, —Br, —I, —NH 2 , —CN, —O—(C 1 -C 6 ) alkyl, and phenyl; and

X and X′ are each independently selected the group consisting of —Cl, —Br, —I, mesylate, and tosylate.

34. The method of claim 33 , wherein the solvent consists essentially of a tertiary alcohol.

35. The method of claim 33 , wherein the tertiary alcohol is tert-amyl alcohol.

36. The method of claim 33 , wherein said converting step (b) comprises contacting the compound of formula (13) with a base to provide the compound of formula (14).

37. The method of claim 36 , wherein the base is selected from the group consisting of Na 2 CO 3 , K 2 CO 3 , Cs 2 CO 3 , Na 3 PO 4 , Na 2 HPO 4 , and combinations of two or more thereof.

38. A method for making a compound of formula (15)

comprising

(a) contacting the compound of formula (16)

with a compound of formula (2)

in a solvent to provide a compound of formula (17)

(b) converting the compound of formula (17) to a compound of formula (18)

and

X′—R 16

to provide the compound of formula (15);

wherein

the solvent comprises a tertiary alcohol;

the bond is a single bond or a double bond;

R 9 is selected from the group consisting of —OH, —H, and —OR 15 ;

R 9′ is selected from the group consisting of —OH, —H, —OR 15 , and —OC(O)OR 4 ,

R 19 is selected from the group consisting of —H, —OH, —CH 3 , and —OR 15 ;

R 15 is an oxygen protecting group;

R 16 is selected from the group consisting of allyl, methylcyclopropyl, methylcyclobutyl, and propargyl;

each R 5 is independently selected from the group consisting of OH, —Cl, —Br, —I, —NH 2 , —CN, —O—(C 1 -C 6 ) alkyl, and phenyl; and

X and X′ are each independently selected the group consisting of —Cl, —Br, —I, mesylate, and tosylate.

39. The method of claim 38 , wherein the solvent consists essentially of a tertiary alcohol.

40. The method of claim 38 , wherein the tertiary alcohol is tert-amyl alcohol.

41. The method of claim 38 , wherein R 16 is methylcyclopropyl, the bond is a single bond, R 9 is —OH, and R 19 is —OCH 3 .

42. The method of claim 38 , wherein step (a) is carried out in the presence of an NaI.

43. The method of claim 38 , wherein step (c) is carried out in the presence of NaI.

44. A composition prepared by combining a compound of formula (1)

a compound of formula (2)

and

a tertiary alcohol;

wherein

R 1 , R 2 , and R 3 are each independently selected from the group consisting of —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, aryl, and heteroaryl, each being unsubstituted or substituted with 1, 2, 3, 4, or 5 independently-selected R 5 groups, or R 1 and R 2 are taken together with the nitrogen atom to which they are bound to form a heterocyclic or heteroaryl ring of formula (4)

n is an integer selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, and 11;

the heterocyclic or heteroaryl ring of formula (4) is a monocyclic ring that is saturated, unsaturated non-heteroaryl, or heteroaryl, which is unsubstituted or substituted with 1, 2, 3, 4, or 5 independently-selected R 20 groups, or is a subunit of a polycyclic ring system comprising any combination of 1, 2, 3, 4, 5, or 6 carbocyclic, heterocyclic, aryl, or heteroaryl rings, each of which is unsubstituted or substituted with 1, 2, 3, 4, or 5 independently-selected R 20 groups;

each R 20 is independently selected from the group consisting of ═O, ═CH 2 , —OR 21 , —O(C 1 -C 6 )alkyl, —C(═O)(C 1 -C 6 ) alkyl, and —(C 1 -C 6 )alkyl, each said alkyl being either unsubstituted or substituted with 1, 2, 3, 4, or 5 independently-selected —OR 21 groups;

R 21 is H or an oxygen protecting group;

each R 5 is independently selected from the group consisting of OH, —Cl, —Br, —I, —NH 2 , —CN, —O—(C 1 -C 6 ) alkyl, and phenyl; and

X is selected from the group consisting of —Cl, —Br, —I, mesylate, and tosylate.

45. A composition prepared by combining a compound of formula (6)

a compound of formula (2)

and

a tertiary alcohol;

wherein

the 7,8-bond is a single bond or a double bond;

R 9 and R 11 are each independently selected from the group consisting of —OH, —H, and —OR 15 ;

R 10 is selected from the group consisting of ═O, ═CH 2 , —H, and —OR 15 ;

R 15 is an oxygen protecting group;

each R 5 is independently selected from the group consisting of —OH, —Cl, —Br, —I, —NH 2 , —CN, —O—(C 1 -C 6 ) alkyl, and phenyl; and

X is selected from the group consisting of —Cl, —Br, —I, mesylate, and tosylate.

46. The composition of claim 45 , wherein

the oxygen protecting group is selected from the group consisting of acetyl, benzoyl, benzyl, β-methoxyethoxymethyl, dimethoxytrityl, methoxymethyl, p-methoxybenzyl, methylthiomethyl, pivaloyl, tetrahydropyranyl, trityl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldimethylsilyloxymethyl, triisopropylsilyl, —C(O)O—CH 2 —CH═CH 2 ), tert-butyl-diphenylsilyl, tert-butyl-dimethylsilyl, tri-iso-propylsilyl, [bis-(4-methoxyphenyl)phenylmethyl)], methoxymethyl, ethoxyethyl, triphenylmethyl, —C(O)(C 1 -C 6 )alkyl, —C(O)OR 18 , and —(C 1 -C 6 )alkyl, each said alkyl being unsubstituted or substituted with 1, 2, 3, 4, or 5 independently-selected R 50 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 said alkyl, alkenyl, and alkynyl being unsubstituted or substituted with 1, 2, 3, 4, or 5 independently-selected R 50 groups; and

each R 50 is independently selected from —Cl, —Br, —I, —NH 2 , —CN, and phenyl.

47. The method of claim 1 , wherein

each R 50 is independently selected from —Cl, —Br, —I, —NH 2 , —CN, and phenyl.

48. The method of claim 12 , wherein R 9 is —OH or —OCH 3 .

49. The method of claim 18 , wherein R 9 is —OH or —OCH 3 .

50. The method of claim 14 , wherein

each R 50 is independently selected from —Cl, —Br, —I, —NH 2 , —CN, and phenyl.

51. The method of claim 22 , wherein R 9 is —OH or —OCH 3 .

52. The method of claim 23 , wherein R 9 is —OH or —OCH 3 .

53. The method of claim 24 , wherein

each R 50 is independently selected from —Cl, —Br, —I, —NH 2 , —CN, and phenyl.

54. The method of claim 24 , wherein the 7,8-bond is a single bond.

55. The method of claim 54 , wherein R 9 and R 11 are each —OH and R 10 is ═O.

56. The method of claim 54 , wherein R 9 is —OCH 3 , R 10 is ═O, and R 11 is —OH.

57. The method of claim 31 , wherein R 9 is —OH or —OCH 3 .

58. The method of claim 32 , wherein R 9 is —OH or —OCH 3 .

59. The method of claim 33 , wherein

each R 50 is independently selected from —Cl, —Br, —I, —NH 2 , —CN, and phenyl.

60. The method of claim 38 , wherein

each R 50 is independently selected from —Cl, —Br, —I, —NH 2 , —CN, and phenyl.

61. The composition of claim 44 , wherein

each R 50 is independently selected from —Cl, —Br, —I, —NH 2 , —CN, and phenyl.

62. The composition of claim 44 , wherein R 3 is methyl.

Assignments (4)

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 Oct 6, 2014

From: GIGUERE, JOSHUA ROBERT

To: RHODES TECHNOLOGIES

Reel/Frame 033891/0136 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Mar 7, 2013

From: REISCH, HELGE A.; SANDOVAL, SERGIO; STYMIEST, JAKE L.

To: PURDUE PHARMA L.P.

Reel/Frame 029939/0717 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Mar 7, 2013

From: PURDUE PHARMA L.P.

To: RHODES TECHNOLOGIES

Reel/Frame 029939/0791 →

Continuity (3)

Continuation PCTIB2011001328 · Jun 10, 2011

Provisional Application 61354017 · Jun 11, 2010

Related Publication 20130102784A1 · Apr 25, 2013