Claims
- 1. A process for preparing a compound of formula III
- 2. The process of claim 1 wherein R1 and R2 are each independently (C1-C10)alkyl, (C2-C10)alkenyl, (C2-C10)alkynyl, (C6-C10)aryl, (C1-C10)alkoxy, (C6-C10)aryl(C1-C10)alkyl, cycloalkyl, or cycloalkylalkyl; wherein any alkyl, alkoxy, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkylalkyl, or arylalkyl can be optionally substituted with one or more halo, nitro, cyano, trifluoromethyl, hydroxy, SR or NRR, wherein each R is independently H or (C1-C10)alkyl.
- 3. The process of claim 1 wherein the acylating comprises heating with an acid anhydride, a carboxylic acid, an acid chloride, or a combination thereof.
- 4. The process of claim 1 wherein the acylating comprises heating with acetic anhydride, benzoyl anhydride, maleic anhydride, phtalic anhydride, succinic anhydride, acetic acid, benzoic acid, acetyl chloride, pentanoyl chloride, or benzoyl chloride.
- 5. The process of claim 1 wherein the acylating comprises heating at a temperature above about 25° C.
- 6. The process of claim 1 wherein the acylating comprises heating in a solvent selected from acetone, methylene chloride, chloroform, carbon tetrachloride, THF, dicloromethane, pyridine, benzene, xylenes, toluene, trifluoromethylbenzene, o-chlorotrifluoromethylbenzene, m-chlorotrifluoromethylbenzene, and p-chlorotrifluoromethylbenzene.
- 7. The process of claim 1 wherein the acylating comprises heating in pyridine and benzoyl chloride at about 50° C. to about 60° C. for about 20 hours to about 30 hours.
- 8. The process of claim 1 wherein the acylating provides the compound of formula II in a yield greater than about 90%.
- 9. The process of claim 1 wherein the acylating provides the compound of formula II and a mono acylated compound in a ratio of at least about 90:10.
- 10. The process of claim 1 wherein the alcoholyzing is carried out employing an aluminum alkoxide
- 11. The process of claim 10 wherein the aluminum alkoxide is a compound of the formula Al(O—R)3 wherein R3 is (C1-C10)alkyl, (C2-C10)alkenyl, or (C2-C10)alkynyl.
- 12. The process of claim 10 wherein the aluminum alkoxide is aluminum methoxide, aluminum ethoxide, aluminum isopropoxide, aluminum n-propoxide, aluminum sec-butoxide, aluminum tert-butoxide, or a combination thereof.
- 13. The process of claim 1 wherein the alcoholyzing provides the compound wherein the primary acyl group, but not the secondary acyl group, is alcoholyzed and the compound wherein both the primary and secondary acyl groups are alcoholyzed, in a ratio of greater than about 80:20.
- 14. The process of claim 1 wherein the alcoholyzing employs an alcohol.
- 15. The process of claim 14 wherein the alcohol is methanol, ethanol, tert-butanol, iso-propanol, or a combination thereof.
- 16. The process of claim 14 wherein the alcohol is anhydrous.
- 17. The process of claim 1 wherein the alcoholyzing comprises heating in the presence of an aluminum alkoxide and an anhydrous alcohol.
- 18. The process of claim 17 wherein the alcohol is isopropanol.
- 19. The process of claim 1 wherein the alcoholyzing is carried out at a temperature above about 25° C.
- 20. The process of claim 1 wherein the alcoholyzing is carried out for about 0.5 to about 4 hours.
- 21. The process of claim 1 further comprising oxidizing the compound of formula III to provide a compound of formula VI
- 22. The process of claim 21 further comprising oxidizing the compound of formula VI to provide a compound of formula IV
- 23. The process of claim 22 further comprising deprotecting the compound of formula IV to provide a compound of formula V
- 24. The process of claim 21 further comprising deprotecting the compound of formula VI to provide a compound of formula VII:
- 25. The process of claim 24 further comprising oxidizing the compound of formula VII to provide a compound of formula V
- 26. The process of claim 1 further comprising oxidizing the compound of claim III to provide a compound of formula IV
- 27. The process of claim 26 further comprising deprotecting the compound of formula IV, or a pharmaceutically acceptable salt thereof, to provide a compound of formula V
- 28. A process for preparing a compound of formula V
- 29. The process of claim 28 wherein R1 and R2 are each independently (C1-C10)alkyl, (C2-C10)alkenyl, (C2-C10)alkynyl, (C6-C10)aryl, (C1-C10)alkoxy, (C6-C10)aryl(C1-C10)alkyl, cycloalkyl, or cycloalkylalkyl; wherein any alkyl, alkoxy, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkylalkyl, or arylalkyl can be optionally substituted with one or more halo, nitro, cyano, trifluoromethyl, hydroxy, SR or NRR, wherein each R is independently H or (C1-C10)alkyl.
- 30. The process of claim 28 wherein the acylating comprises heating with an acid anhydride, a carboxylic acid, an acid chloride, or a combination thereof.
- 31. The process of claim 28 wherein the acylating comprises heating with acetic anhydride, benzoyl anhydride, maleic anhydride, phtalic anhydride, succinic anhydride, acetic acid, benzoic acid, acetyl chloride, pentanoyl chloride, or benzoyl chloride.
- 32. The process of claim 28 wherein the acylating comprises heating at a temperature above about 25° C.
- 33. The process of claim 1 wherein the acylating comprises heating in a solvent selected from acetone, methylene chloride, chloroform, carbon tetrachloride, THF, dicloromethane, pyridine, benzene, xylenes, toluene, trifluoromethylbenzene, o-chlorotrifluoromethylbenzene, m-chlorotrifluoromethylbenzene, and p-chlorotrifluoromethylbenzene.
- 34. The process of claim 28 wherein the acylating comprises heating in pyridine and benzoyl chloride at about 50° C. to about 60° C. for about 20 hours to about 30 hours.
- 35. The process of claim 28 wherein the acylating provides the compound of formula II in a yield greater than about 90%.
- 36. The process of claim 28 wherein the acylating provides the compound of formula II and a mono acylated compound in a ratio of at least about 90:10.
- 37. The process of claim 28 wherein the alcoholyzing is carried out employing an aluminum alkoxide
- 38. The process of claim 37 wherein the aluminum alkoxide is a compound of the formula Al(O—R)3 wherein R3 is (C1-C10)alkyl, (C2-C10)alkenyl, or (C2-C10)alkynyl.
- 39. The process of claim 37 wherein the aluminum alkoxide is aluminum methoxide, aluminum ethoxide, aluminum isopropoxide, aluminum n-propoxide, aluminum sec-butoxide, aluminum tert-butoxide, or a combination thereof.
- 40. The process of claim 28 wherein the alcoholyzing provides the compound wherein the primary acyl group, but not the secondary acyl group, is alcoholyzed and the compound wherein both the primary and secondary acyl groups are alcoholyzed, in a ratio of greater than about 80:20.
- 41. The process of claim 28 wherein the alcoholyzing employs an alcohol.
- 42. The process of claim 41 wherein the alcohol is methanol, ethanol, tert-butanol, iso-propanol, or a combination thereof.
- 43. The process of claim 41 wherein the alcohol is anhydrous.
- 44. The process of claim 28 wherein the alcoholyzing comprises heating in the presence of an aluminum alkoxide and an anhydrous alcohol.
- 45. The process of claim 44 wherein the anhydrous alcohol is isopropanol.
- 46. The process of claim 28 wherein the alcoholyzing is carried out at a temperature above about 25° C.
- 47. The process of claim 28 wherein the alcoholyzing is carried out for about 0.5 to about 4 hours.
- 48. The process of claim 28 wherein the oxidizing of compound III to compound VI comprises palladium acetate, molecular sieves, and oxygen in trifluoromethylbenzene and pyridine at about 80° C. to about 85° C. for about 0.5 hour to about 4 hours.
- 49. The process of claim 28 wherein the oxidizing of compound VI to compound IV comprises oxygen and Cobalt (III) acetylacetonate in trifluoromethylbenzene at 60-65° C. for about 0.5 hour to about 2 hours.
- 50. The process of claim 28 wherein the deprotecting comprises heating to reflux in methanol, water and sodium hydroxide.
- 51. A process for preparing a compound of formula V
- 52. The process of claim 51 wherein R1 and R2 are each independently (C1-C10)alkyl, (C2-C10)alkenyl, (C2-C10)alkynyl, (C6-C10)aryl, (C1-C10)alkoxy, (C6-C10)aryl(C1-C10)alkyl, cycloalkyl, or cycloalkylalkyl; wherein any alkyl, alkoxy, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkylalkyl, or arylalkyl can be optionally substituted with one or more halo, nitro, cyano, trifluoromethyl, hydroxy, SR or NRR, wherein each R is independently H or (C1-C10)alkyl.
- 53. The process of claim 51 wherein the acylating comprises heating with an acid anhydride, a carboxylic acid, an acid chloride, or a combination thereof.
- 54. The process of claim 51 wherein the acylating comprises heating with acetic anhydride, benzoyl anhydride, maleic anhydride, phtalic anhydride, succinic anhydride, acetic acid, benzoic acid, acetyl chloride, pentanoyl chloride, or benzoyl chloride.
- 55. The process of claim 51 wherein the acylating comprises heating at a temperature above about 25° C.
- 56. The process of claim 51 wherein the acylating comprises heating in a solvent selected from acetone, methylene chloride, chloroform, carbon tetrachloride, THF, dicloromethane, pyridine, benzene, xylenes, toluene, trifluoromethylbenzene, o-chlorotrifluoromethylbenzene, m-chlorotrifluoromethylbenzene, and p-chlorotrifluoromethylbenzene.
- 57. The process of claim 51 wherein the acylating comprises heating in pyridine and benzoyl chloride at about 50° C. to about 60° C. for about 20 hours to about 30 hours.
- 58. The process of claim 51 wherein the acylating provides the compound of formula II in a yield greater than about 90%.
- 59. The process of claim 51 wherein the acylating provides the compound of formula II and a mono acylated compound in a ratio of at least about 90:10.
- 60. The process of claim 51 wherein the alcoholyzing is carried out employing an aluminum alkoxide
- 61. The process of claim 60 wherein the aluminum alkoxide is a compound of the formula Al(O-R)3 wherein R3 is (C1-C10)alkyl, (C2-C10)alkenyl, or (C2-C10)alkynyl.
- 62. The process of claim 60 wherein the aluminum alkoxide is aluminum methoxide, aluminum ethoxide, aluminum isopropoxide, aluminum n-propoxide, aluminum sec-butoxide, aluminum tert-butoxide, or a combination thereof.
- 63. The process of claim 51 wherein the alcoholyzing provides the compound wherein the primary acyl group, but not the secondary acyl group, is alcoholyzed and the compound wherein both the primary and secondary acyl groups are alcoholyzed, in a ratio of greater than about 80:20.
- 64. The process of claim 51 wherein the alcoholyzing employs an alcohol.
- 65. The process of claim 64 wherein the alcohol is methanol, ethanol, tert-butanol, iso-propanol, or a combination thereof.
- 66. The process of claim 64 wherein the alcohol is anhydrous.
- 67. The process of claim 51 wherein the alcoholyzing comprises heating in the presence of an aluminum alkoxide and an anhydrous alcohol.
- 68. The process of claim 51 wherein the alcohol is isopropanol.
- 69. The process of claim 51 wherein the alcoholyzing is carried out at a temperature above about 25° C.
- 70. The process of claim 51 wherein the alcoholyzing is carried out for about 0.5 to about 4 hours.
- 71. A process for preparing a compound of formula V
- 72. The process of claim 71 wherein R1 and R2 are each independently (C1-C10)alkyl, (C2-C10)alkenyl, (C2-C10)alkynyl, (C6-C10)aryl, (C1-C10)alkoxy, (C6-C10)aryl(C1-C10)alkyl, cycloalkyl, or cycloalkylalkyl; wherein any alkyl, alkoxy, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkylalkyl, or arylalkyl can be optionally substituted with one or more halo, nitro, cyano, trifluoromethyl, hydroxy, SR or NRR, wherein each R is independently H or (C1-C10)alkyl.
- 73. The process of claim 71 wherein the acylating comprises heating with an acid anhydride, a carboxylic acid, an acid chloride, or a combination thereof.
- 74. The process of claim 71 wherein the acylating comprises heating with acetic anhydride, benzoyl anhydride, maleic anhydride, phtalic anhydride, succinic anhydride, acetic acid, benzoic acid, acetyl chloride, pentanoyl chloride, or benzoyl chloride.
- 75. The process of claim 71 wherein the acylating comprises heating at a temperature above about 25° C.
- 76. The process of claim 71 wherein the acylating comprises heating in a solvent selected from acetone, methylene chloride, chloroform, carbon tetrachloride, THF, dicloromethane, pyridine, benzene, xylenes, toluene, trifluoromethylbenzene, o-chlorotrifluoromethylbenzene, m-chlorotrifluoromethylbenzene, and p-chlorotrifluoromethylbenzene.
- 77. The process of claim 71 wherein the acylating comprises heating in pyridine and benzoyl chloride at about 50° C. to about 60° C. for about 20 hours to about 30 hours.
- 78. The process of claim 71 wherein the acylating provides the compound of formula II in a yield greater than about 90%.
- 79. The process of claim 71 wherein the acylating provides the compound of formula II and a mono acylated compound in a ratio of at least about 90:10.
- 80. The process of claim 71 wherein the alcoholyzing is carried out employing an aluminum alkoxide
- 81. The process of claim 80 wherein the aluminum alkoxide is a compound of the formula Al(O—R)3 wherein R3 is (C1-C10)alkyl, (C2-C10)alkenyl, or (C2-C10)alkynyl.
- 82. The process of claim 80 wherein the aluminum alkoxide is aluminum methoxide, aluminum ethoxide, aluminum isopropoxide, aluminum n-propoxide, aluminum sec-butoxide, aluminum tert-butoxide, or a combination thereof.
- 83. The process of claim 71 wherein the alcoholyzing provides the compound wherein the primary acyl group, but not the secondary acyl group, is alcoholyzed and the compound wherein both the primary and secondary acyl groups are alcoholyzed, in a ratio of greater than about 80:20.
- 84. The process of claim 71 wherein the alcoholyzing employs an alcohol.
- 85. The process of claim 84 wherein the alcohol is methanol, ethanol, tert-butanol, iso-propanol, or a combination thereof.
- 86. The process of claim 84 wherein the alcohol is anhydrous.
- 87. The process of claim 71 wherein the alcoholyzing comprises heating in the presence of an aluminum alkoxide and an anhydrous alcohol.
- 88. The process of claim 84 wherein the alcohol is isopropanol.
- 89. The process of claim 71 wherein the alcoholyzing is carried out at a temperature above about 25° C.
- 90. The process of claim 71 wherein the alcoholyzing is carried out for about 0.5 to about 4 hours.
- 91. A process for preparing a compound of formula III
- 92. The process of claim 91 wherein R1 and R2 are each independently (C1-C10)alkyl, (C2-C10)alkenyl, (C2-C10)alkynyl, (C6-C10)aryl, (C1-C10)alkoxy, (C6-C10)aryl(C1-C10)alkyl, cycloalkyl, or cycloalkylalkyl; wherein any alkyl, alkoxy, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkylalkyl, or arylalkyl can be optionally substituted with one or more halo, nitro, cyano, trifluoromethyl, hydroxy, SR or NRR, wherein each R is independently H or (C1-C10)alkyl.
- 93. The process of claim 91 wherein the alcoholyzing is carried out employing an aluminum alkoxide
- 94. The process of claim 93 wherein the aluminum alkoxide is a compound of the formula Al(O—R)3 wherein R3 is (C1-C10)alkyl, (C2-C10)alkenyl, or (C2-C10)alkynyl.
- 95. The process of claim 93 wherein the aluminum alkoxide is aluminum methoxide, aluminum ethoxide, aluminum isopropoxide, aluminum n-propoxide, aluminum sec-butoxide, aluminum tert-butoxide, or a combination thereof.
- 96. The process of claim 91 wherein the alcoholyzing provides the compound wherein the primary acyl group, but not the secondary acyl group, is alcoholyzed and the compound wherein both the primary and secondary acyl groups are alcoholyzed, in a ratio of greater than about 80:20.
- 97. The process of claim 91 wherein the alcoholyzing employs an alcohol.
- 98. The process of claim 97 wherein the alcohol is methanol, ethanol, tert-butanol, iso-propanol, or a combination thereof.
- 99. The process of claim 97 wherein the alcohol is anhydrous.
- 100. The process of claim 91 wherein the alcoholyzing comprises heating in the presence of an aluminum alkoxide and an anhydrous alcohol.
- 101. The process of claim 100 wherein the alcohol is isopropanol.
- 102. The process of claim 91 wherein the alcoholyzing is carried out at a temperature above about 25° C.
- 103. The process of claim 91 wherein the alcoholyzing is carried out for about 0.5 to about 4 hours.
- 104. The process of claim 91 further comprising oxidizing the compound of formula III to provide a compound of formula VI
- 105. The process of claim 104 further comprising deprotecting the compound of formula VI to provide a compound of formula VII:
- 106. The process of claim 105 further comprising oxidizing the compound of formula VII to provide a compound of formula V
- 107. The process of claim 104 further comprising oxidizing the compound of formula VI to provide a compound of formula IV
- 108. The process of claim 107 further comprising deprotecting the compound of formula IV to provide a compound of formula V
- 109. The process of claim 107 further comprising oxidizing the compound of formula III to provide a compound of formula IV
- 110. The process of claim 109 further comprising deprotecting the compound of formula IV to provide a compound of formula V
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation under 35 USC 111(a) of PCT/US01/00991 filed Jan. 11, 2001 (WO01/51451),which claimed priority from U.S. patent application Ser. No. 09/480,406, filed Jan. 11, 2000, which applications are incorporated by reference.
Continuations (1)
|
Number |
Date |
Country |
Parent |
PCT/US01/00991 |
Jan 2001 |
US |
Child |
10194924 |
Jul 2002 |
US |