USRE38408EExpiredUtility

Methods of preparing and purifying 9-nitro-20-camptothecin

70
Assignee: STEHLIN FOUNDATION FOR CANCERPriority: Aug 5, 1997Filed: Jun 9, 2000Granted: Jan 27, 2004
Est. expiryAug 5, 2017(expired)· nominal 20-yr term from priority
Inventors:Zhisong Cao
C07D 491/22
70
PatentIndex Score
4
Cited by
10
References
42
Claims

Abstract

A method is disclosed for the preparation of 9-nitrocamptothecin which involves reacting 20-camptothecin with at least one inorganic nitrate salt and at least one acid effective in catalyzing the formation of a nitronium ion, where the reaction occurs at a temperature and for a time sufficient to form the 9-nitrocamptothecin. Also, methods of further purifying the 9-nitrocamptothecin by column chromatography or by reprecipitation is also disclosed.

Claims

exact text as granted — not AI-modified
What is claimed is:  
     
       1. A method for the preparation of 9-nitrocamptothecin comprising: 
       reacting 20-camptothecin with at least one inorganic nitrate salt capable of forming a nitrobium ion and at least one acid effective in catalyzing the formation of a nitronium ion, at a temperature and for a time sufficient to form said 9-nitrocamptothecin.  
     
     
       2. The method of  claim 1 , wherein said 20-camptothecin is racemic 20-camptothecin or 20(S)-camptothecin. 
     
     
       3. The method of  claim 2 , wherein said 20-camptothecin is 20(S)-camptothecin, and said 9-nitrocamptothecin is 9-nitro-20(S)-camptothecin. 
     
     
       4. The method of  claim 1 , wherein said acid is concentrated sulfuric acid, trifluoroacetic acid, or trifluoroacetic acid anhydride. 
     
     
       5. The method of  claim 4 , wherein said acid is concentrated sulfuric acid. 
     
     
       6. The method of  claim 1 , wherein said inorganic nitrate salt is KNO 3 ; NH 4 NO 3 ; LiNO 3 ; AgNO 3 ; TiNO 3 ; BiONO 3 ; Cu(NO 3 ) 2 2.5.H 2 O; Hg(NO 3 ) 2  4.H 2 O; Ba(NO 3 ) 2 ; Zn(NO 3 ) 2  6.H 2 O; Mg(NO 3 ) 2  6.H 2 O; Co(NO 3 ) 2  6.H 2 O; Sr(NO 3 ) 2 ; Pb(NO 3 ) 2 ; Al(NO 3 ) 3  9.H 2 O; Fe(NO 3 ) 2  9.H 2 O; Cr(NO 3 ) 3  9.H 2 O; La(NO 3 ) 3  6.H 2 O; or mixtures thereof. 
     
     
       7. The method of  claim 1 , wherein said inorganic nitrate salt is a mixture of at least two inorganic nitrate salts. 
     
     
       8. The method of  claim 7 , wherein said inorganic nitrate salt comprises KNO 3  and at least one other inorganic nitrate salt. 
     
     
       9. The method of  claim 7 , wherein said inorganic nitrate salt comprises KNO 3  and Cu(NO 3 ) 2  2.5.H 2 O. 
     
     
       10. The method of  claim 7 , wherein said inorganic nitrate salt comprises KNO 3  and TiNO 3 . 
     
     
       11. The method of  claim 7 , wherein said inorganic nitrate salt comprises KNO 3  and Hg(NO 3 ) 2  H 2 O. 
     
     
       12. The method of  claim 7 , wherein said inorganic nitrate salt comprises KNO 3  and Ca(NO 3 ) 2  4.H 2 O. 
     
     
       13. The method of  claim 7 , wherein said inorganic nitrate salt comprises KNO 3  and Ba(NO 3 ) 2 . 
     
     
       14. The method of  claim 7 , wherein said inorganic nitrate salt comprises KNO 3  and Zn(NO 3 ) 2  6.H 2 O. 
     
     
       15. The method of  claim 7 , wherein said inorganic nitrate salt comprises KNO 3  and Sr(NO 3 ) 2 . 
     
     
       16. The method of  claim 7 , wherein said inorganic nitrate salt comprises KNO 3  and Pb(NO 3 ) 2 . 
     
     
       17. The method of  claim 7 , wherein said inorganic nitrate salt comprises KNO 3  and Al(NO 3 ) 3  9.H 2 O. 
     
     
       18. The method of  claim 7 , wherein said inorganic nitrate salt comprises KNO 3  and Fe(NO 3 ) 3  9.H 2 O. 
     
     
       19. The method of  claim 7 , wherein said inorganic nitrate salt comprises LiNO 3  and Hg(NO 3 ) 2 .H 2 O. 
     
     
       20. The method of  claim 7 , wherein said inorganic nitrate salt comprises LiNO 3  and Cu(NO 3 ) 2  2.5.H 2 O. 
     
     
       21. The method of  claim 7 , wherein said inorganic nitrate salt comprises LiNO 3  and Co(NO 3 ) 2  6.H 2 O. 
     
     
       22. The method of  claim 7 , wherein said inorganic nitrate salt comprises AgNO 3  and Cr(NO 3 ) 3  9.H 2 O. 
     
     
       23. The method of  claim 7 , wherein said inorganic nitrate salt comprises Cu(NO 3 ) 2  2.5.H 2 O and Fe(NO 3 ) 3  9.H 2 O. 
     
     
       24. The method of  claim 7 , wherein said inorganic nitrate salt comprises Hg(NO 3 ) 2  .H 2 O; and Fe(NO 3 ) 3  9.H 2 O. 
     
     
       25. The method of  claim 7 , wherein said inorganic nitrate salt comprises NH 4 NO 3  and Cu(NO 3 ) 2  2.5.H 2 O. 
     
     
       26. The method of  claim 7 , wherein said inorganic nitrate salt comprises KNO 3 ; TiNO 3 ; and Cu(NO 3 ) 2  2.5.H 2 O. 
     
     
       27. The method of  claim 7 , wherein said inorganic nitrate salt comprises KNO 3 ; TiNO 3 ; and Zn(NO 3 ) 2  6.H 2 O. 
     
     
       28. The method of  claim 7 , wherein said inorganic nitrate salt comprises KNO 3 ; TiNO 3 ; and Pb(NO 3 ) 2 . 
     
     
       29. The method of  claim 7 , wherein said inorganic nitrate salt comprises KNO 3 ; Cu(NO 3 ) 2  2.5.H 2 O; and Fe(NO 3 ) 3  9.H 2 O. 
     
     
       30. The method of  claim 7 , wherein said inorganic nitrate salt comprises KNO 3 ; Cu(NO 3 ) 2  2.5.H 2 O; Hg(NO 3 ) 2 .H 2 O; and Zn(NO 3 ) 2  6.H 2 O. 
     
     
       31. The method of  claim 7 , wherein said inorganic nitrate salt comprises KNO 3 ; LiNO 3 ; Cu(NO 3 ) 2 2.5.H 2 O; Hg(NO 3 ) 2 .H 2 O; and Fe(NO 3 ) 3  9.H 2 O. 
     
     
       32. The method of  claim 7 , wherein said inorganic nitrate salt comprises KNO 3 ; LiNO 3 ; AgNO 3 ; Cu(NO 3 ) 2  2.5.H 2 O; Hg(NO 3 ) 2 .H 2 O; and Fe(NO 3 ) 3  9.H 2 O. 
     
     
       33. The method of  claim 7 , wherein said inorganic nitrate salt comprises KNO 3 ; LiNO 3 ; Zn(NO 3 ) 2  6.H 2 O; Cu(NO 3 ) 2  2.5 H 2 O; Hg(NO 3 ) 2 .H 2 O; and Fe(NO 3 ) 3  9.H 2 O. 
     
     
       34. The method of  claim 7 , wherein said inorganic nitrate salt comprises KNO 3 ; Zn(NO 3 ) 2  6.H 2 O; Cu(NO 3 ) 2  2.5.H 2 O; Hg(NO 2 ) 2 .H 2 O; and Fe(NO 3 ) 3  9.H 2 O. 
     
     
       35. The method of  claim 1 , further comprising the step of purifying the 9-nitrocamptothecin by column chromatography. 
     
     
       36. The method of  claim 35 , wherein said column chromatography is conducted with an element comprising tetrahydrofuran and methylene chloride. 
     
     
       37. The method of  claim 1 , further comprising purifying the 9-nitrocamptothecin by reprecipitation from ethanol. 
     
     
       38. The method of  claim 1 , wherein said inorganic nitrate salt comprises thallium nitrate. 
     
     
       39. The method of  claim 1 , wherein said inorganic nitrate salt comprises potassium nitrate and thallium nitrate. 
     
     
       40. The method of  claim 1 , wherein said inorganic nitrate salt is thallium nitrate and said acid is sulfuric acid. 
     
     
       41.  9 - nitrocamptothecin in crystalline form wherein the crystalline form has a melting point of at least  268 ° C.    
     
     
       42. A method of crystallizing  9 - nitrocamptothecin comprising:    
         performing a crystallization process on  9   - nitrocamptothecin wherein ethanol is employed as the primary solvent to form crystalline  9   - nitrocaptothecin having a yellow color and a melting point of at least  268 ° C.

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