Process for N-dealkylation of tertiary amines
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.
1. A composition prepared by combining a compound of formula (12)
a compound of formula (2)
and
a tertiary alcohol;
wherein
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 19 is selected from the group consisting of —H, —OH, —CH 3 , and —OR 15 ;
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 composition of claim 1 , further comprising an iodide salt.
3. The composition of claim 2 , wherein the iodide salt is selected from the group consisting of NaI, KI, LiI, CsI, RuI, MgI 2 , CaI 2 , NH 4 I, tetrabutylammonium iodide, and combinations of two or more thereof.
4. The composition of claim 3 , 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.
5. The composition of claim 4 , wherein R 16 is methylcyclopropyl, the bond is a single bond, R 9 is —OH, and R 19 is —OCH 3 .
6. A composition prepared by combining a compound of formula (16)
a compound of formula (2)
and
a tertiary alcohol;
wherein
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 19 is selected from the group consisting of —H, —OH, —CH 3 , and —OR 15 ;
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, —CI, —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.
7. The composition of claim 6 , further comprising an iodide salt.
8. The composition of claim 7 , wherein the iodide salt is selected from the group consisting of NaI, KI, LiI, CsI, RuI, MgI 2 , CaI 2 , NH 4 I, tetrabutylammonium iodide, and combinations of two or more thereof.
9. The composition of claim 8 , 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.
10. The composition of claim 9 , wherein R 16 is methylcyclopropyl, the bond is a single bond, R 9 is —OH, and R 19 is —OCH 3 .
11. A composition comprising a tertiary alcohol and a compound of formula (2)
wherein
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.
12. The composition of claim 11 , further comprising an iodide salt.
13. The composition of claim 12 , wherein the tertiary alcohol is a compound of formula (5)
wherein R 6 , R 7 , and R 8 are each independently —(C 1 -C 6 )alkyl.
14. The composition of claim 13 , 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.
15. The composition of claim 14 , wherein the tertiary alcohol is tert-amyl alcohol.
16. The composition of claim 11 , further comprising a compound of formula (6)
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, —OH, ═CH 2 , —H, and —OR 15 ; and
R 15 is an oxygen protecting group.
17. The composition of claim 16 , further comprising an iodide salt.
18. The composition of claim 17 , wherein the tertiary alcohol is a compound of formula (5)
wherein R 6 , R 7 , and R 8 are each independently —(C 1 -C 6 )alkyl.
19. The composition of claim 18 , 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.
20. The composition of claim 19 , wherein the tertiary alcohol is tert-amyl alcohol.
21. The composition of claim 16 , 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 59 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 59 groups; and
each R 50 is independently selected from —Cl, —Br, —I, —NH 2 , —CN, and phenyl.
22. The composition of claim 21 , wherein the 7,8-bond is a single bond.
23. The composition of claim 22 , wherein R 9 and R 11 are —OH and R 10 is ═O.
24. The composition of claim 11 , further comprising a compound of formula (12)
wherein
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 19 is selected from the group consisting of —H, —CH 3 , —OH, and —OR 15 ; and
R 15 is an oxygen protecting group.
25. The composition of claim 24 , further comprising an iodide salt.
26. The composition of claim 25 , wherein the tertiary alcohol is a compound of formula (5)
wherein R 6 , R 7 , and R 8 are each independently —(C 1 -C 6 )alkyl.
27. The composition of claim 26 , 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.
28. The composition of claim 27 , wherein the tertiary alcohol is tert-amyl alcohol.
29. The composition of claim 24 , 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 —CI, —Br, —I, —NH 2 , —CN, and phenyl.
30. The composition of claim 29 , wherein R 16 is methylcyclopropyl, the bond is a single bond, R 9 is —OH, and R 19 is —OCH 3 .
31. The composition of claim 11 , further comprising a compound of formula (16)
wherein
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 19 is selected from the group consisting of —H, —OH, —CH 3 , and —OR 15 ; and
R 15 is an oxygen protecting group.
32. The composition of claim 31 , further comprising an iodide salt.
33. The composition of claim 32 , wherein the tertiary alcohol is a compound of formula (5)
wherein R 6 , R 7 , and R 8 are each independently —(C 1 -C 6 )alkyl.
34. The composition of claim 33 , 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.
35. The composition of claim 34 , wherein the tertiary alcohol is tert-amyl alcohol.
36. The composition of claim 31 , 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.
37. The composition of claim 36 , wherein R 16 is methylcyclopropyl, the bond is a single bond, R 9 is —OH, and R 19 is —OCH 3 .