Process for production of delta-9- tetrahydrocannabinol

• US 20070093665A1
• Filed: 09/28/2006
• Published: 04/26/2007
• Est. Priority Date: 09/29/2005
• Status: Active Grant

• Current Assignee: Albany Molecular Research Incorporated
• Original Assignee: AMR Technology Incorporated
• Inventors: Paul, Bernhard, Meckler, Harold, Biolatto, Betina, Burdick, David, Habershaw, Alicia, Jos, Frederic, Collier, Steven, Helle, Mark
• Granted Patent: US 7,674,922 B2
• Time in Patent Office: Days
• US Class Current: 549/390
• CPC Class Codes: C07C 2601/16 the ring being unsaturated
• CPC Class Codes: C07C 29/00 Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
• CPC Class Codes: C07C 35/16 Inositols
• CPC Class Codes: C07C 37/16 by condensation involving hydroxy groups of phenols or alcohols or the ether or mineral ester group derived therefrom
• CPC Class Codes: C07C 39/23 polycyclic, containing six-membered aromatic rings and other rings, with unsaturation outside the aromatic rings
• CPC Class Codes: C07C 67/343 by increase in the number of carbon atoms
• CPC Class Codes: C07C 69/94 of polycyclic hydroxy carboxylic acids, the hydroxy groups and the carboxyl groups of which are bound to carbon atoms of six-membered aromatic rings

Abstract

The present invention relates to a process for preparation of a delta-9-tetrahydrocannabinol compound or derivative thereof involving treating a first intermediate compound with an organoaluminum-based Lewis acid catalyst, under conditions effective to produce the delta-9-tetrahydrocannabinol compound or derivative thereof. Another aspect of the present invention relates to a process for preparation of a cannabidiol or cannabidiolate compound involving reacting a first starting compound with a second starting compound in the presence of a metal triflate catalyst, under conditions effective to form the cannabidiol or cannabidiolate compound. The present invention also relates to a compound of the formula:
where R₈, R₉, and R₁₀ are the same or different and independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or halo, with R₁, R₂, and R₃ defined herein.

Claims

1. A process for preparation of a product compound of the formula:

2. The process according to claim 1, wherein the organoaluminum-based Lewis acid catalyst is selected from the group consisting of a trialkyl- or triarylaluminum, dialkyl- or diarylaluminum halide, alkylarylaluminum halide, dialkyl- or alkylaryl- or diarylaluminum alkoxide or aryloxide, dialkyl- or alkylaryl- or diarylaluminum thioalkoxide or thioarylate, dialkyl- or alkylaryl- or diarylaluminum carboxylate, alkyl- or arylaluminum dihalide, alkyl- or arylaluminum dialkoxide or diaryloxide or alkylaryloxide, alkyl- or arylaluminum dithioalkoxide or dithioarylate, alkyl- or arylaluminum dicarboxylate, aluminum trialkoxide or triaryloxide or mixed alkylaryloxide, aluminum triacylcarboxylate, and mixtures thereof.

3. The process according to claim 2, wherein the organoaluminum-based Lewis acid catalyst is a C₁-C₃₀ alkylaluminum-based catalyst.

4. The process according to claim 2, wherein the organoaluminum-based Lewis acid catalyst is ethyl aluminum dichloride, diethylaluminum chloride, diethylaluminum sesquichloride, isobutylaluminum dichloride, diisobutylaluminum chloride, or mixtures thereof.

5. The process according to claim 2, wherein the trialkylaluminum is trimethylaluminum, triethylaluminum, triisopropylaluminum, triisobutylaluminum, trioctylaluminum, or tridecylaluminum.

6. The process according to claim 2, wherein the organoaluminum-based Lewis acid catalyst is diisobutylaluminum acetate, diisobutylaluminum benzoate, diisobutylaluminum trifluoroacetate, diisobutylaluminum isopropoxide, diisobutylaluminum 2,6-di-t-butyl-4-methylphenoxide, or isobutylaluminum bis-(2,6-di-t-butyl-4-methylphenoxide).

7. The process according to claim 1, wherein said treating is carried out with the organoaluminum-based Lewis acid catalyst in an amount of from about 0.5 mol % to about 100 mol % with respect to the first intermediate compound.

8. The process according to claim 7, wherein said treating is carried out with the organoaluminum-based Lewis acid catalyst in an amount of from about 5 mol % to about 15 mol % with respect to the first intermediate compound.

9. The process according to claim 1, wherein said treating is carried out in an organic solvent.

10. The process according to claim 9, wherein the solvent is aprotic.

11. The process according to claim 9, wherein the organic solvent is hexane, heptane, toluene, xylene, dichloromethane, or mixtures thereof.

12. The process according to claim 1, wherein said treating is carried out at a temperature of from about −

20°

C. to about 100°

C.

13. The process according to claim 12, wherein said treating is carried out at a temperature of from about −

20°

C. to about 50°

C.

14. The process according to claim 13, wherein said treating is carried out at a temperature of from about 0°

C. to about 30°

C.

15. The process according to claim 1, wherein R₂ is n-C₅H₁₁ and R₁=R₃=R₄=H.

16. The process according to claim 1 further comprising:

reacting the product compound, wherein R₄=H, with a substituted or unsubstituted alkylsulfonyl halide, alkylsulfonyl anhydride, alkylsulfonyl mixed anhydride, alkylsulfonyl ester, or alkylsulfonic acid, under conditions effective to produce a second product compound of the formula;

wherein;

R₁ is H, substituted or unsubstituted alkyl, carboxylic ester, or acyl;

R₂ is H, OH, protected hydroxyl, substituted or unsubstituted alkyl, alkenyl, alkynyl, acyl, aryl, or heteroaryl;

R₃ is H, substituted or unsubstituted alkyl, carboxylic ester, or acyl; and

R₄″

′

is SO₂R₅, wherein R₅ is substituted or unsubstituted alkyl.

17. The process according to claim 16, wherein the product compound is a totally synthetic substance or a naturally derived substance.

18. The process according to claim 16 further comprising:

carrying out a method selected from the group consisting of chromatography, countercurrent extraction, and distillation on the second product compound under conditions effective to produce a purified second product compound.

19. The process according to claim 16 further comprising:

crystallizing the second product compound under conditions effective to produce a purified second product compound.

20. The process according to claim 19 further comprising:

hydrolyzing the purified second product compound under conditions effective to produce the purified product compound in a desired isomer form.

21. The process according to claim 20, wherein said hydrolyzing is carried out in the presence of an organic or inorganic base in a solvent.

22. The process according to claim 21, wherein the base is sodium hydroxide, potassium t-butoxide, or mixtures thereof.

23. The process according to claim 21, wherein the solvent is methanol, ethanol, isopropanol, t-butanol, acetonitrile, or mixtures thereof.

24. The process according to claim 16, wherein R₁=R₃=H and R₂ is H, OH, protected hydroxyl, substituted or unsubstituted alkyl, alkenyl, alkynyl, acyl, aryl, or heteroaryl.

25. The process according to claim 24, wherein R₁=R₃=H and R₂ is n-C₅H₁₁.

26. The process according to claim 16, wherein the second product compound is of the formula:

27. The compound according to claim 26, wherein the compound is a straight chain alkylsulfonate selected from the group consisting of methanesulfonate, ethanesulfonate, propanesulfonate, butanesulfonate, pentanesulfonate, hexanesulfonate, heptanesulfonate, octanesulfonate, nonanesulfonate, decanesulfonate, undecanesulfonate, dodecanesulfonate, tridecanesulfonate, tetradecanesulfonate, pentadecanesulfonate, hexadecanesulfonate, heptadecanesulfonate, octadecanesulfonate, nonadecanesulfonate, and icosanesulfonate.

28. The compound according to claim 26, wherein the compound is a branched chain alkylsulfonate selected from the group consisting of cyclopropylsulfonate, isopropylsulfonate, isobutylsulfonate, tert-octylsulfonate, adamantly sulfonate, and 10-camphorsulfonate.

29. The compound according to claim 26, wherein the compound is a substituted alkylsulfonate selected from the group consisting of chloromethylsulfonate, 2-chloroethylsulfonate, trifluoromethylsulfonate, trifluorethylsulfonate, perfluoroethylsulfonate, perfluorobutylsulfonate, perfluorooctanesulfonate, 2-aminoethylsulfonate, 2-dimethylaminoethylsulfonate, 2-phthalimidoethylsulfonate, 2-morpholinoethylsulfonate, 3-morpholinopropylsulfonate, 4-morpholinobutylsulfonate, 2-N-piperidinylethylsulfonate, 3-N-piperidylpropylsulfonate, 2-pyrrolidinylmethylsulfonate, 2-methoxyethylsulfonate, (1R)-3-bromocamphor-8-sulfonate, (1S)-3-bromocamphor-8-sulfonate, (1S)-3-bromo-camphor-10-sulfonate, (1R)-10-camphorsulfonate, and (1S)-10-camphorsulfonate.

30. The compound according to claim 26, wherein the compound has the following formula:

31. The compound according to claim 26, wherein the compound has the following formula:

32. The compound according to claim 26, wherein the compound is a diastereomeric mixture of the following two formulae:

33. The compound according to claim 26, wherein the compound is an aryl or heteroaryl substituted alkylsulfonate selected from the group consisting of benzylsulfonate, 2-nitrobenzylsulfonate, 3-nitrobenzylsulfonate, 4-nitrobenzylsulfonate, 2-chlorobenzylsulfonate, 3-chlorobenzylsulfonate, 4-chlorobenzylsulfonate, 2-trifluoromethybenzylsulfonate, 3-trifluoromethylbenzylsulfonate, 4-trifluoromethylbenzylsulfonate, 3,5-dichlorobenzylsulfonate, 3,5-di-trifluoromethylbenzylsulfonate, 4-methylbenzylsulfonate, 4-t-butylbenzylsulfonate, 1-napthylethylsulfonate, 2-pyridylmethylsulfonate, 3-pyridylmethylsulfonate, 4-pyridylmethylsulfonate, 2-(2-pyridyl)ethylsulfonate, and diphenylmethanesulfonate.

34. The process according to claim 26 further comprising:

carrying out a method selected from the group consisting of chromatography, countercurrent extraction, and distillation on the second product compound under conditions effective to produce a purified second product compound.

35. The process according to claim 26 further comprising:

crystallizing the second product compound under conditions effective to produce a purified second product compound.

36. The process according to claim 35 further comprising:

hydrolyzing the purified second product compound under conditions effective to produce the purified product compound in a desired isomer form.

37. The process according to claim 1 further comprising:

reacting a second intermediate compound of the formula;

wherein;

R₆ is H, substituted or unsubstituted alkyl, silyl, hetero-substituted or unsubstituted acyl, alkylsulfonyl, arylsulfonyl, alkylphosphoryl, or arylphosphoryl;

with a second compound of the formula;

wherein X=H, alkyl, acyl, silyl, aryl, heteroaryl, sulfinyl, sulfonyl, phosphoryl, or phosphinyl,

in the presence of a metal triflate catalyst, under conditions effective to form the first intermediate compound.

38. The process according to claim 37, wherein said reacting is carried out under conditions effective to achieve preferential formation of the first intermediate compound over undesired stereochemical and regiochemical isomers and undesired compounds.

39. The process according to claim 37, wherein R₁ is H or COOR₇, R₂ is n-C₅H₁₁, and R₃ is H or COOR₇, wherein R₇ is C₁-C₂₀ alkyl.

40. The process according to claim 39, wherein R₁ is COOR₇, where R₇ is ethyl, R₄=H and X=H.

41. The process according to claim 39, wherein R₁=R₃=R₄=H and X=H.

42. The process according to claim 37, wherein the metal triflate catalyst is a transition metal triflate or lanthanide triflate.

43. The process according to claim 42, wherein the transition metal triflate is selected from the group consisting of zinc triflate, ytterbium triflate, yttrium triflate, and scandium triflate.

44. The process according to claim 43, wherein the transition metal triflate is zinc triflate or scandium triflate.

45. The process according to claim 37, wherein said reacting is carried out with the metal triflate catalyst in an amount of from about 0.5 mol % to about 100 mol % with respect to the second intermediate compound.

46. The process according to claim 45, wherein said reacting is carried out with the metal triflate catalyst in an amount of from about 0.5 mol % to about 10 mol % with respect to the second intermediate compound.

47. The process according to claim 37, wherein said reacting is carried out in an organic solvent.

48. The process according to claim 47, wherein the organic solvent is a hydrocarbon, aromatic hydrocarbon, halogenated hydrocarbon, ether, ester, amide, nitrile, carbonate, alcohol, carbon dioxide, or mixtures thereof.

49. The process according to claim 48, wherein the organic solvent is dichloromethane.

50. The process according to claim 37, wherein said reacting is carried out at a temperature of from about −

20°

C. to about 150°

C.

51. The process according to claim 50, wherein said reacting is carried out under pressure at a temperature above the normal atmospheric boiling point of the organic solvent or where temperatures are above boiling point and pressure is above atmosphere.

52. The process according to claim 37, wherein said reacting is carried out with a less than about one equivalent of the second compound to the second intermediate compound.

53. A process for preparation of a product compound of the formula:

54. The process according to claim 53, wherein said reacting is carried out under conditions effective to achieve preferential formation of the first intermediate compound over undesired isomers.

55. The process according to claim 53, wherein R₁ is H or COOR₇, R₂ is n-C₅H₁₁, and R₃ is H or COOR₇, wherein R₇ is C₁-C₂₀ alkyl.

56. The process according to claim 55, wherein R₁ is COOR₇, where R₇ is ethyl, R₄=H and X=H.

57. The process according to claim 55, wherein R₁=R₃=R₄=H and X=H.

58. The process according to claim 53, wherein the metal triflate catalyst is a transition metal triflate or lanthanide triflate.

59. The process according to claim 58, wherein the transition metal triflate is selected from the group consisting of zinc triflate, ytterbium triflate, yttrium triflate, and scandium triflate.

60. The process according to claim 59, wherein the transition metal triflate is zinc triflate or scandium triflate.

61. The process according to claim 60, wherein said reacting is carried out with the metal triflate catalyst in an amount of from about 0.5 mol % to about 100 mol % with respect to the second intermediate compound.

62. The process according to claim 61, wherein said reacting is carried out with the metal triflate catalyst in an amount of from about 0.5 mol % to about 10 mol % with respect to the second intermediate compound.

63. The process according to claim 53, wherein said reacting is carried out in an organic solvent.

64. The process according to claim 63, wherein the organic solvent is a hydrocarbon, aromatic hydrocarbon, halogenated hydrocarbon, ether, ester, amide, nitrile, carbonate, alcohol, carbon dioxide, or mixtures thereof.

65. The process according to claim 64, wherein the organic solvent is dichloromethane.

66. The process according to claim 53, wherein said reacting is carried out at a temperature of from about −

20°

C. to about 150°

C.

67. The process according to claim 66, wherein said reacting is carried out under pressure at a temperature above the normal atmospheric boiling point of the organic solvent or where temperatures are above boiling point and pressure is above atmosphere.

68. The process according to claim 53, wherein said reacting is carried out with a less than about one equivalent of the second compound to the second intermediate compound.

69. A process for preparation of a product compound of the formula:

70. A compound of the formula:

71. The compound according to claim 70, wherein the compound is a straight chain alkylsulfonate selected from the group consisting of methanesulfonate, ethanesulfonate, propanesulfonate, butanesulfonate, pentanesulfonate, hexanesulfonate, heptanesulfonate, octanesulfonate, nonanesulfonate, decanesulfonate, undecanesulfonate, dodecanesulfonate, tridecanesulfonate, tetradecanesulfonate, pentadecanesulfonate, hexadecanesulfonate, heptadecanesulfonate, octadecanesulfonate, nonadecanesulfonate, and icosanesulfonate.

72. The compound according to claim 70, wherein the compound is a branched chain alkylsulfonate selected from the group consisting of cyclopropylsulfonate, isopropylsulfonate, isobutylsulfonate, tert-octylsulfonate, adamantly sulfonate, and 10-camphorsulfonate.

73. The compound according to claim 70, wherein the compound is a substituted alkylsulfonate selected from the group consisting of chloromethylsulfonate, 2-chloroethylsulfonate, trifluoromethylsulfonate, trifluorethylsulfonate, perfluoroethylsulfonate, perfluorobutylsulfonate, perfluorooctanesulfonate, 2-aminoethylsulfonate, 2-dimethylaminoethylsulfonate, 2-phthalimidoethylsulfonate, 2-morpholinoethylsulfonate, 3-morpholinopropylsulfonate, 4-morpholinobutylsulfonate, 2-N-piperidinylethylsulfonate, 3-N-piperidylpropylsulfonate, 2-pyrrolidinylmethylsulfonate, 2-methoxyethylsulfonate, (1R)-3-bromocamphor-8-sulfonate, (1S)-3-bromocamphor-8-sulfonate, (1S)-3-bromo-camphor-10-sulfonate, (1R)-10-camphorsulfonate, and (1S)-10-camphorsulfonate.

74. The compound according to claim 73, wherein the compound has the following formula:

75. The compound according to claim 73, wherein the compound has the following formula:

76. The compound according to claim 73, wherein the compound is a diastereomeric mixture of the following two formulae:

77. The compound according to claim 70, wherein the compound is an aryl or heteroaryl substituted alkylsulfonate selected from the group consisting of benzylsulfonate, 2-nitrobenzylsulfonate, 3-nitrobenzylsulfonate, 4-nitrobenzylsulfonate, 2-chlorobenzylsulfonate, 3-chlorobenzylsulfonate, 4-chlorobenzylsulfonate, 2-trifluoromethybenzylsulfonate, 3-trifluoromethylbenzylsulfonate, 4-trifluoromethylbenzylsulfonate, 3,5-dichlorobenzylsulfonate, 3,5-di-trifluoromethylbenzylsulfonate, 4-methylbenzylsulfonate, 4-t-butylbenzylsulfonate, 1-napthylethylsulfonate, 2-pyridylmethylsulfonate, 3-pyridylmethylsulfonate, 4-pyridylmethylsulfonate, 2-(2-pyridyl)ethylsulfonate, and diphenylmethanesulfonate.