Claims
- 1. A compound selected from the compounds described and labeled in the specification as 2 CPT, 2G, 3 CPT, 3G, 4 CPT, 4G, 5a CPT and its bisulfite adduct, 5 CPT, 5G, 6 CPT, 6G, 7CPTA, 7 CPTG, 7GG, 7GA, 8 CPTA, 8 CPTB, 8 CPTG, 8GG, 8GA, 8GB, 9 CPTA, 9 CPTB, 9 CPTG, 9GG, 9GA, 10 CPT, 10 CPT(R), 10 CPT(S), 10G, 10G(S), 10G(R), 11 CPT, 11 CPT(R), 11 CPT(S), 11G, 11G(S), 11G(R), 12 CPT, 12 CPT(R), 12 CPT(S), 12 CPTA-1, 12 CPTA-1(R), 12 CPTA-1(S), 12 CPTB-1, 12 CPTB-1(R), 12 CPTB-1(S), 12 CPTA-2, 12 CPTA-2(R), 12 CPTA-2(S) 12GA-1, 12GA-1(S), 12GA-1(R), 12GA-2, 12GA-2(S), 12GA-2(R), 12GB-1, 12GB-1(S), 12GB-1(R), 12GB-2, 12GB-2(S), 12GB-2(R), 12G, 12G(S), 12G(R), 13 CPT, 13 CPT(R), 13 CPT(S), 13G, 13G(S), or 13G(R); where R.sub.1 is optionally substituted C.sub.1-8 alkyl, including lower alkyl, C.sub.3-10 cycloalkyl, lower alkyl-C.sub.3-10 cycloalkyl, alkenyl, aryl, substituted aryl, alkylaryl, or substituted alkylaryl, including benzyl and substituted benzyl;
- where R.sub.2 is
- a) H;
- b) --C(O)--R.sub.3 ; or
- c) --C(R.sub.7).sub.2 --O--R.sub.3 where each R.sub.7 is independent of the other;
- where R.sub.3 is H, optionally substituted C.sub.1-8 alkyl, including lower alkyl, cycloalkyl, alkenyl, aryl, substituted aryl, and alkylaryl, or substituted alkylaryl, including benzyl and substituted benzyl;
- where R.sub.4 is optionally substituted C.sub.1-8 alkyl, including lower alkyl, C.sub.3-10 cycloalkyl, lower alkyl-C.sub.3-10 cycloalkyl, alkenyl, aryl, substituted aryl, alkylaryl, or substituted alkylaryl, including benzyl and substituted benzyl;
- where R.sub.5 is H, optionally substituted C.sub.1-8 alkyl, including lower alkyl, aryl, substituted aryl, or two R.sub.5 groups may be combined to form cyclopentane or cyclohexane, or substituted derivatives thereof;
- where R.sub.6 is optionally substituted C.sub.1-8 alkyl, lower alkyl, including ethyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, including benzyl and substituted benzyl, C.sub.3-10 cycloalkyl, lower alkyl-C.sub.3-10 cycloalkyl, heteroaryl, or substituted heteroaryl,
- where R.sub.7 is independently H, optionally substituted C.sub.1-8 alkyl, including lower alkyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, or two R.sub.7 groups may be combined to form cyclopentane or cyclohexane or substituted derivatives thereof,
- where R.sub.8 is optionally substituted C.sub.1-8 alkyl, including lower alkyl, including t-butyl, C.sub.3-10 cycloalkyl, lower alkyl-C.sub.3-10 cycloalkyl, alkenyl, aryl, substituted aryl, alkylaryl, or substituted alkylaryl, including benzyl and substituted benzyl.
- 2. The process of making the compounds described in claim 1 and are of formula 2G, by either, 1) mixing 2,6-dichloroisonicotinic acid with a nucleophile that is either a Grignard Reagent or an alkyllithium and an ethereal solvent followed by exposing the reaction products to dilute acid or 2) by converting 2,6-dichloroisonicotinic acid into the acid chloride followed by conversion into the Weinreb amide followed by mixing with a nucleophile that is either a Grignard Reagent or an alkyllithium and an ethereal solvent followed by exposing the reaction products to dilute acid.
- 3. The process of claim 2, where the reactants are maintained at a temperature of about -30.degree. to about +10.degree..
- 4. The process of claim 3, where the compound produced is formula 2CPT.
- 5. The process, for producing the compounds defined in claim 1 by formula 3G, by mixing the product of formula 2G with an alcohol or diol in the presence of trimethylchlorosilane.
- 6. The process of claim 5, where the alcohol or diol is ethylene glycol.
- 7. The process of claim 5, where the compound produced is represented by formula 3CPT.
- 8. The process of claim 5, where the the alcohol or diol is ethylene glycol and the temperature is maintained between about 0.degree. to about +60.degree..
- 9. The process for producing the compounds defined in claim 1 formula 4G, where R.sub.2 is H, by mixing the compound of formula 3G with a sodium or potassium alkoxide in a solvent.
- 10. The process of claim 9, where the reactants are maintained at a temperature between about 20.degree. and about about 80.degree..
- 11. The process for producing the compounds, defined in claim 1 as of formula 5G, by beginning with the compound of formula 4G, where R.sub.2 is H, and mixing it with a solvent and an alkyllithium or aryllithium base to form the pyridyl anion which is then mixed with electrophile, the product of which is then mixed with an acid and the end product is isolated.
- 12. The process of claim 11, where the solvent is selected from diethyl ether, tetrahydrofuran, or 1,2-dimethoxyethane or hydrocarbons such as toluene, hexane, heptane, cyclohexane, or isooctane, or mixtures of any of these.
- 13. The process of claim 11, where the alkyllithium is selected from methyllithium, n-butyllithium, sec-butyllithium or t-butyllithium, or mixtures of any of these.
- 14. The process of claim 11, where the electrophile is a formamide including dimethylformamide, N-formylpiperidine, or N formylmorpholine or N-methylformanilide or similar formamides or mixtures of any of these.
- 15. The process of claim 11, where the reactants are maintained at a temperature between about -40.degree. and about +50.degree..
- 16. The process of claim 15, where the reactants are maintained at a temperature between about -5.degree. and about +5.degree..
- 17. The process of claim 15, where the product is isolated with a dilute acid.
- 18. The process of claim 17, where the dilute acid is selected from a moderate to strong acids such as hydrochloric acid, acetic acid, or sulfuric acid, or mixtures of any of these.
- 19. The process of claim 17, where sodium bisulfite is mixed with the product of claim 14 and the compound produced is the bisulfite adduct.
- 20. The process of claim 18, where the compound produced is represented by formula 5aCPT.
- 21. The process of claim 19, where 5aCPT bisulfite adduct is further mixed with acid or base to produce the compound represented by formula 5aCPT.
- 22. The process for producing the compounds defined in claim 1 as of formula 5G, where R.sub.2 is CH.sub.2 OH, where R.sub.3 is H, by beginning with the corresponding aldehyde and mixing it with a reducing agent.
- 23. The process of claim 22, where the reducing agent is a hydride.
- 24. The process of claim 23, where the hydride is sodium borohydride.
- 25. The process of claim 22, where the reactants are mixed in an alcohol or under two-phase conditions.
- 26. The process of claim 25, where the alcohol is methanol or 2-propanol or the two phase condition is water and an organic phase.
- 27. The process of claim 26, where the organic phase is heptane, methylene chloride or methyl t-butyl ether, or mixtures of these solvents.
- 28. The process of claim 22, where the compound produced is represented by formula 5CPT.
- 29. The process for producing the compounds defined in claim 1 as of formula 6G, by beginning with the compound of formula 5G, and a) mixing it with a base and an alkylating agent in a solvent or b) mixing it under phase transfer conditions using water and an organic solvent.
- 30. The process of claim 29, where the base is a hydride such as sodium hydride or potassium hydride, or an alkoxide base such as potassium t-butoxide or mixtures of these bases.
- 31. The process of claim 30, where the base is potassium t-butoxide.
- 32. The process of claim 30, where the solvent is selected from an ethereal solvent such as tetrahydrofuran (THF), methyl t-butyl ether (MTBE) or 1,2-dimethoxyethane or an alcohol such as t-butanol.
- 33. The process of claim 32, where the solvent is THF or MTBE and the temperature is between about 20.degree. and about 40.degree..
- 34. The process of claim 29, where the organic solvent is selected from methylene chloride, or a hydrocarbon such as hexane, heptane, or toluene and where the base is selected from a hydroxide such as sodium or potassium hydroxide, or a carbonate such as sodium or potassium carbonate.
- 35. The process of claim 29, where the compound produced is represented by formula 6CPT.
- 36. The process for producing the compounds defined in claim 1 as of formula 7G, or 7GG by beginning with the compound of formula 6G, and mixing it with carbon monoxide and an alcohol in the presence of a soluble palladium II salt, a phosphine ligand and a base in a polar aprotic solvent.
- 37. The process of claim 36, where the soluble palladium II salt is selected from palladium acetate.
- 38. The process of claim 37, where the phosphine ligand is selected from 1,3-bisdiphenylphosphinopropane.
- 39. The process of claim 38, where the base is selected from sodium or potassium acetate, sodium or potassium carbonate, triethylamine, or tri n-butylamine.
- 40. The process of claim 39, where the polar aprotic solvent is selected from dimethyl formamide or acetonitrile.
- 41. The process of claim 40, where the compound produced is represented by formula 7CPTG.
- 42. The process for producing the compounds defined in claim 1 as of formula 7GA, by beginning with the compound of formula 6G, and then removing the ketal by a) mixing that product with water in the presence of a strong acid or by b) using an exchange reaction to remove the ketal.
- 43. The process of claim 42, where the process temperature is between about 15.degree. to about 80.degree..
- 44. The process of claim 43, where the concentration of the acid is between about 50 and 90%.
- 45. The process of claim 44, where the strong acid is trifluoroacetic acid.
- 46. The process of claim 45, where the compound produced is represented by formula 7CPTA.
- 47. The process of claim 43, where the exchange reaction procedes with a ketone that is catalyzed by a strong acid or on an acidic ion exchange resin.
- 48. The process of claim 47, where the ketone is acetone or 2-butanone or where the acidic ion exchange resin is a resin such as amberlyst A-15 resin.
- 49. The process of claim 48, where the compound produced is represented by formula 7CPTA.
- 50. The process for producing the compounds defined in claim 1 as of formula 8GG, by beginning with the compound of formula 7G, or 7GG, and then removing the ketal by a) mixing that product with water in the presence of a strong acid or by b) using an exchange reaction to remove the ketal.
- 51. The process of claim 50, where the process temperature is between about 15.degree. to about 80.degree..
- 52. The process of claim 51, where the concentration of the acid is between about 50 and 90%.
- 53. The process of claim 52, where the strong acid is trifluoroacetic acid.
- 54. The process of claim 53, where the compound produced is represented by formula 8CPTG.
- 55. The process of claim 50, where the exchange reaction procedes with a ketone that is catalyzed by a strong acid or on an acidic ion exchange resin.
- 56. The process of claim 55, where the ketone is acetone or 2-butanone or where the acidic ion exchange resin is a resin such as amberlyst A-15 resin.
- 57. The process of claim 56, where the compound produced is represented by formula 8CPTG.
- 58. The process of, producing the compound as defined in claim 1 as formula 8GA, by beginning with the compound of formula 7GA, and dissolving it in a solvent and mixing it with vinyllithium or a vinylmagnesium halide.
- 59. The process of claim 58, where the solvent is selected from ethers such as diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, or MTBE, either alone or as mitures, or as mixtures with hydrocarbons such as toluene, heptane, or cyclohexane.
- 60. The process of claim 59, where the process temperature is between about -78.degree. and about 25.degree..
- 61. The process of claim 60, where the product is isolated after reaction with a dilute acid.
- 62. The process of claim 61, where the dilute acid is hydrochloric, sulfuric, or acetic acids.
- 63. The process of claim 62, where the compound produced is represented by formula 8CPTA.
- 64. The process for producing the compounds defined in claim 1 as of formula 8GB, by beginning with the compound of formula 7GA, and mixing it in a ylide solution and solvent as a Wittig reaction.
- 65. The process of claim 64, where the ylide solution is prepared from a methyl triphenylphosphonium salt, and a strong base, in a solvent.
- 66. The process of claim 65, where the solvent is as diethyl ether, terahydrofuran, 1,2-dimethoxyethane, or DMF.
- 67. The process of claim 66, where the strong base is selected from n-butyllithium, potassium t-butoxide, or potassium bis trimethylsilylamide.
- 68. The process of claim 67, where the methyl triphenylphosphonium salt is the bromide salt, the base is potassium bis trimethylsilylamide, the solvent is DMF.
- 69. The process of claim 68, where the process temperature is between about -5.degree. and about 25.degree. and the reaction is run for anytime from about 5 minutes to about 2 hours.
- 70. The process of claim 69, where the compound produced is represented by formula 8CPTB.
- 71. The process for producing the compounds defined in claim 1 as of formula 9GG, by beginning with the compound of formula 8GG, and mixing it in a ylide solution and solvent as a Wittig reaction.
- 72. The process of claim 71, where the ylide solution is prepared from a methyl triphenylphosphonium salt, and a strong base, in a solvent.
- 73. The process of claim 72, where the solvent is as diethyl ether, terahydrofuran, 1,2-dimethoxyethane, or DMF.
- 74. The process of claim 73, where the strong base is selected from n-butyllithium, potassium t-butoxide, or potassium bis trimethylsilylamide.
- 75. The process of claim 74, where the methyl triphenylphosphonium salt is the bromide salt, the base is potassium bis trimethylsilylamide, the solvent is DMF.
- 76. The process of claim 75, where the process temperature is between about -5.degree. and about 25.degree. and the reaction is run for anytime from about 5 minutes to about 2 hours.
- 77. The process of claim 76, where the compound produced is represented by formula 9CPTG.
- 78. The process for producing the compounds defined in claim 1 as of formula 9GA, by beginning with the compound of formula 8GA, and mixing it with a solvent and ozone to produce an intermediate that is reduced either directly or through an intermediate to 9GA.
- 79. The process of claim 78, where the solvents are selected from chlorinated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, 1,2-dichloroethane, or other multiply chlorinated ethane or ethylene derivatives, either alone, as mixture, or as mixtures with alcohols such as methanol.
- 80. The process of claim 79, where the process is at a temperature from about -78.degree. to about -25.degree..
- 81. The process of claim 80, where the reducing agent is sodium borohydride.
- 82. The process of claim 81, where the solvent is selected from a mixture of methylene chloride and methanol, and where the temperature is from about -78.degree. to about -40.degree. for the initial reaction with ozone, and a temperature of about 0.degree. to 25.degree. for the reduction of the intermediate.
- 83. The process of claim 82, where the compound produced is represented by formula 9CPTA.
- 84. The process for producing the compounds defined in claim 1 as of formula 10GG, by beginning with the compound of formula 9GG, and converting the diol by osmylation under standard conditions.
- 85. The process of claim 84, where the process temperature is from about 15.degree. to about 50.degree..
- 86. The process of claim 85, where the compound produced is represented by formula 10 CPT.
- 87. The process for producing the compounds defined in claim 1 as of formula 10GG, by beginning with the compound of formula 9GA, and mixing it with carbon monoxide and an alcohol in the presence of a soluble palladium II salt, a phosphine ligand and a base in a polar aprotic solvent.
- 88. The process of claim 87, where the soluble palladium II salt is selected from palladium acetate.
- 89. The process of claim 88, where the phosphine ligand is selected from 1,3-bisdiphenylphosphinopropane.
- 90. The process of claim 89, where the base is selected from sodium or potassium acetate, sodium or potassium carbonate, triethylamine, or tri n-butylamine.
- 91. The process of claim 90, where the polar aprotic solvent is selected from dimethyl formamide or acetonitrile.
- 92. The process of claim 91, where the compound produced is represented by formula 10CPT.
- 93. The process of resolving the compounds described in claim 1 as of formula 10G, by treating the racemic diol with an acetylating reagent in an organic solvent with an appropriate lipase.
- 94. The process of claim 93, where the acetylating reagent is selected from vinyl acetate, isopropenyl acetate, acetic anhydride or ethyl acetate in an organic solvent.
- 95. The process of claim 94, where the organic solvent is ether, or hexane and the lipase is Pseudomonas.
- 96. The process of claim 94, where the lipase is Pseudomonas cepaica.
- 97. The process of claim 93, where the lipase is Pseudomonas cepaica and the process is conducted between 25.degree. to 45.degree. at a concentration of 15-40 mg/mL. and the resolved compounds are represented by formula 10CPT(R) or 10CPT(S).
- 98. The process of making the compounds defined in claim 1 as of formula 11G, by oxidizing the compounds of formula 10G, to the hydroxy aldehyde under either a) Swern type conditions or b) a two phase system comprising water and an aprotic solvent.
- 99. The process of claim 98, where the Swern type conditions are DMSO, oxalyl chloride and triethylamine in an aprotic solvent and the temperature ranges from about -78.degree. to about 25.degree..
- 100. The process of claim 99, where the aprotic solvent is methylene chloride.
- 101. The process of claim 98, where the two phase system comprising water and an aprotic solvent is a sodium hypochlorite solution catalyzed by TEMPO or a substituted TEMPO such as 4-acetoxy-TEMPO and where the other phase is methylene chloride.
- 102. The process of claim 101, where the process temperature is between about -5.degree. and about +25.degree. and the time allowed for reaction may be anytime from about 30 minutes to about 2 hours.
- 103. The process for producing the compounds defined in claim 1 as of formula 11CPT, 11CPT(R) or 11CPT(S).
- 104. The process for producing the compounds defined in claim 1 as of formula 12GA-1, by oxidizing the compound of formula 11G.
- 105. The process of claim 102, where the temperature is about 10.degree. or 20.degree. and the reaction time is about an hour.
- 106. The process of claim 102, where the oxidizing agent is sodium chlorite.
- 107. The process of claim 104 , to produce the compound of formula 12 CPTA-1, of formula 12 CPTA-1(R) or of formula 12 CPTA-1(S).
- 108. The process for producing the compounds defined in claim 1 as of formula 12GB-1 ,12CPTB-1, 12CPTB-1(R) or 12CPTB-1(S), by removing the leaving group from the compound of formula 11G.
- 109. The process of claim 108, where the leaving group is removed by hydrogenation over a catalyst.
- 110. The process of claim 109, where the catalyst is palladium.
- 111. The process of claim 108, where the compound produced is represented by formula 12CPTB-1, formula 12CPTB-1(R) or formula 12CPTB-1(S).
Parent Case Info
This application is the (national phase) of International Application No. PCT/US96/04163, International Filing Date Apr. 1, 1996, which was a continuation-in-part of U.S. patent application Ser. No. 08/419,643, filed Apr. 7, 1995, now abandoned.
PCT Information
Filing Document |
Filing Date |
Country |
Kind |
102e Date |
371c Date |
PCT/US96/04163 |
4/1/1996 |
|
|
10/2/1997 |
10/2/1997 |
Publishing Document |
Publishing Date |
Country |
Kind |
WO96/31513 |
10/10/1996 |
|
|
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Number |
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EPX |
Continuation in Parts (1)
|
Number |
Date |
Country |
Parent |
419643 |
Apr 1995 |
|