Process for the preparation of epothilone analogs

Abstract

The present invention relates to a process for the preparation of epothilone analogs by initially forming novel ring-opened epothilones and carrying out a macrolactamization reaction thereon. The subject process is amenable to being carried out in a single reaction vessel without isolation of the intermediate compound and provides at least about a three-fold increase in yield over prior processes for preparing the desired epothilone analogs.

1. A compound represented by the formula 
                 
 
       wherein:
 Q is selected from the group consisting of 
                 
 M is selected from the group consisting of oxygen, sulfur, NR 8 , and CR 9 R 10 ;  
 Z is selected from the group consisting of: 
                 
 R 1 -R 5 , R 7 , and R 11 -R 15  are selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl and heterocyclo, and wherein R 1  and R 2  are alkyl, they can be joined to form a cycloalkyl;  
 R 6  is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, heterocyclo and substituted heterocyclo;  
 R 8  is selected from the group consisting of hydrogen, alkyl, substituted alkyl, R 11 C═O, R 12 OC═O and R 13 SO 2 ;  
 R 9  and R 10  are selected from the group consisting of hydrogen, halogen, alkyl, substituted alkyl, aryl, heterocyclo, hydroxy, R 14 C═O, and R 15 OC═O; and 
 R 16 , R 17 , and R 18  are independently selected from the group consisting of alkyl, aryl, and aralkyl;  
 
 
 
       and any salts, solvants, or hydrates thereof . 
     
     
       2. A compound in accordance with  claim 1  wherein said compound has the formula:
                 
 
     
     
       3. A compound in accordance with  claim 2  wherein said compound has the structure:
                 
 
     
     
       4. A process for preparing a compound represented by the formula:
                 
 
       wherein:
 Q is selected from the group consisting of:
                 
 M is selected from the group consisting of oxygen, sulfur, NR 8 , and CR 9 R 10 ;  
 Z is selected from the group consisting of: 
                 
 R 1 -R 5 , R 7 , and R 11 -R 15  are selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl and heterocyclo, and wherein R 1  and R 2  are alkyl, they can be joined to form a cycloalkyl;  
 R 6  is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, heterocyclo and substituted heterocyclo;  
 R 8  is selected from the group of hydrogen, alkyl, substituted alkyl, R 11 C═O, R 12 OC═O and R 13 SO 2 ;  
 R 9  and R 10  are selected from the group consisting of hydrogen, halogen, alkyl, substituted alkyl, aryl, heterocyclo, hydroxy, R 14 C═O, and R 15 OC═O;  
 R 16 , R 17 , and R 18  are independently selected from the group consisting of alkyl, aryl, and aralkyl;  
 comprising reacting an epothilone starting material represented by the formula:
                 
 
  wherein Q, and R 1  through R 6  are as defined above, with an azide donor agent and a reducing agent in the presence of a phase transfer catalyst and a palladium catalyst.  
 
 
 
     
     
       5. A process in accordance with  claim 4 , for preparing a compound represented by the formula:
                 
 
     
     
       6. A process in accordance with  claim 5 , wherein said epothilone starting material is epothilone B, and said compound of formula IV is represented by the structure 
                 
 
     
     
       7. A process for preparing a compound represented by the formula: 
                 
  wherein: 
 Q is selected from the group consisting of 
                 
 M is selected from the group consisting of oxygen, sulfur, NR 8 , and CR 9 R 10 ;  
 Z is selected from the group consisting of 
                 
 R 1 -R 5 , R 7 , and R 11 -R 15  are selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl and heterocyclo, and wherein R 1  and R 2  are alkyl, they can be joined to form a cyclalkyl;  
 R 6  is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, heterocyclo and substituted heterocyclo;  
 R 8  is selected from the group consisting of hydrogen, alkyl, substituted alkyl, R 11 C═O, R 12 OC═O and R 13  SO 2 ;  
 R 9  and R 10  are selected from the group consisting of hydrogen, halogen, alkyl, substituted alkyl, aryl, heterocyclo, hydroxy, R 14 C═O, and R 15 OC═O;  
 R 16 , R 17 , and R 18  are independently selected from the group consisting of alkyl, aryl, and aralkyl;  
 comprising reacting an epothilone starting material represented by the formula: 
                 
 
  wherein Q is selected from the group consisting of 
                 
 
 
 
   M is selected from the group consisting of oxygen, sulfur, NR   8   , and CR   9   R   10 ; and R 1  through R 6  are as defined above 
 R 1   —R   5   , R   7   , and R   11   —R   13    are selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl and heterocyclo, and wherein R   1    and R   2    are alkyl, they can be joined to form a cycloalkyl;    
 R 6    is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, heterocyclo and substituted heterocyclo;    
   R   8    is selected from the group consisting of hydrogen, alkyl, substituted alkyl, R   11   C═O, R   12   OC═O and R   13   SO   2   ;    
   R   9    and R   10    are selected from the group consisting of hydrogen, halogen, alkyl, substituted alkyl, aryl, heterocyclo, hydroxy, R   14   C═O, and R   15   OC═O;    
 with an azide donor agent and a buffering agent in the presence of a palladium catalyst and a reducing agent.  
 
     
     
       8. A process in accordance with  claim 7  for preparing a compound represented by the formula:
                 
 
     
     
       9. A process in accordance with  claim 8 , wherein said epothilone starting material is epothilone B, and said compound of formula IV is represented by the structure:
                 
 
     
     
       10. A process in accordance with claim  7   9 , wherein said azide donor agent is tetrabutylammonium azide. 
     
     
       11. A process for the preparation of an epothilone a compound represented by the formula II:
                 
 
       wherein:
 Q is selected from the group consisting of 
                 
 M is selected from the group consisting of oxygen, sulfur, NR 8 , and CR 9 R 10 ;  
 R 1 -R 5 , R 7 , and R 11 -R 15  are selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl and heterocyclo, and wherein R 1  and R 2  are alkyl, they can be joined to form a cycloalkyl;  
 R 6  is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, heterocyclo and substituted heterocyclo;  
 R 8  is selected from the group consisting of hydrogen, alkyl, substituted alkyl, R 11 C═O, R 12 OC═O and R 13 SO 2 ;  
 R 9  and R 10  are selected from the group consisting of hydrogen, halogen, alkyl, substituted alkyl, aryl, heterocyclo, hydroxy, R 14 C═O, and R 15 OC═O;  
 which comprises carrying out a macrolactamization reaction of an intermediated compound represented by the formula I:
                 
 
 
 
       wherein
 Q, and R 1  through R 6  are as defined above;  
 Z is selected from the group consisting of 
                 
 
  and  
 R 16 , R 17 , and R 18  are independently selected from the group consisting of alkyl, aryl, and aralkyl;  
 
       in the presence of a suitable coupling agent for such reaction. 
     
     
       12. A process in accordance with  claim 11  wherein said intermediate compound is represented by the formula IV:
                 
 
     
     
       13. A process in accordance with  claim 12  wherein said epothilone compound represented by formula II has the structure:
                 
 
       and said macrolactamization reaction is carried out on an intermediate compound represented by the structure:                   
     
     
       14. A process in accordance with claim  11   13  wherein said coupling agent comprises 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 1-hydroxy-7-benzotriazole hydrate. 
     
     
       15. A process for the preparation of an epothilone a compound represented by the formula:
                 
 
       wherein:
 Q is selected from the group consisting of 
                 
 M is selected from the group consisting of oxygen, sulfur, NR 8 , and CR 9 R 10 ;  
 R 1 -R 5 , R 7 , and R 11 -R 15  are selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl and heterocyclo, and wherein R 1  and R 2  are alkyl, they can be joined to form a cycloalkyl;  
 
 R 6  is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, heterocyclo and substituted heterocyclo;  
 R 8  is selected from the group consisting of hydrogen, alkyl, substituted alkyl, R 11 C═O, R 12 OC═O and R 13 SO 2 ;  
 R 9  and R 10  are selected from the group consisting of hydrogen, halogen, alkyl, substituted alkyl, aryl, heterocyclo, hydroxy, R 14 C═O, and R 15 OC═O;  
 comprising reacting an epothilone starting material represented by the formula 
                 
 
  wherein Q, and R 1  through R 6  are as defined above, with an azide donor agent and a reducing agent in the presence of a phase transfer catalyst and a palladium catalyst to form an intermediate compound represented by the formula 
                 
 
 
       wherein:
 Q, and R 1  through R 6  are as defined above;  
 Z is selected from the group consisting of 
                 
 
  and 
 R 16 , R 17 , and R 18  are independently selected from the group consisting of alkyl, aryl, and aralkyl; and  
 
 
       carrying out a macrolactamization reaction on said intermediate compound in the presence of a suitable coupling agent for such reaction. 
     
     
       16. A process in accordance with  claim 15  wherein said intermediate compound is represented by the formula 
                 
 
     
     
       17. A process in accordance with  claim 16  wherein said epothilone starting material is epothilone B, said intermediate compound represented by formula I has the structure 
                 
 
       and said epothilone compound represented by formula II has the structure 
                 
 
     
     
       18. A process for the preparation of an epothilone a compound represented by the formula II:
                 
 
       wherein:
 Q is selected from the group consisting of 
                 
 M is selected from the group consisting of oxygen, sulfur, NR 8 , and CR 9 R 10 ;  
 R 1 -R 5 , R 7 , and R 11 -R 15  are selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl and heterocyclo, and wherein R 1  and R 2  are alkyl, they can be joined to form a cycloalkyl;  
 R 6  is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, heterocyclo and substituted heterocyclo;  
 R 8  is selected from the group consisting of hydrogen, alkyl, substituted alkyl, R 11 C═O, R 12 OC═O and R 13 SO 2 ;  
 R 9  and R 10  are selected from the group consisting of hydrogen, halogen, alkyl, substituted alkyl, aryl, heterocyclo, hydroxy, R 14 C═O, and R 15 OC═O;  
 comprising reacting an epothilone starting material represented by the formula 
                 
 
  wherein Q, and R 1  through R 6  are as defined above, with an azide donor agent and a buffering agent in the presence of a pallidium catalyst and a reducing agent to form an intermediate compound represented by the formula 
                 
 
 wherein:  
 Q, and R 1  through R 6  are as defined above;  
 Z is selected from the group consisting of a cation of the azide donor agent; 
                 
 R 16 , R 17 , and R 18  are independently selected from the group consisting of alkyl, aryl, and aralkyl; 
 
 
 
       and carrying out a macrolactamization reaction on said intermediate compound in the presence of a suitable coupling agent for such reaction. 
     
     
       19. A process in accordance with  claim 18  wherein said intermediate compound is represented by the formula 
                 
 
     
     
       20. A process in accordance with  claim 19  wherein said epothilone starting material is epothilone B, said intermediate compound represented by formula IV has the structure 
                 
 
       and said epothilone compound represented by formula II has the structure 
                 
 
     
     
       21. A process in accordance with claim  15   17  wherein said azide donor agent is selected from the group consisting of lithium azide, sodium azide, tetraalkylammonium azide, and trialkylsilyl azide, said reducing agent is selected from the group consisting of a trialkylphosphine, triarylphosphine, trialkylarsine, triarylarsine, and mixtures thereof, said phase transfer catalyst is selected from the group consisting of tetraalkylonium, tetraarylonium, tetraaralkylonium salts and mixtures thereof, and said palladium catalyst is selected from the group consisting of pallidium acetate, palladium chloride, palladium tetrakis-(triphenylphosphine), palladium tetrakris-(triphenylarsine), and tris-(dibenzylidenaecetone)-dipalladium(0)chloroform adduct, and tris-(dibenzylideneacetone)-dipalladium. 
     
     
       22. A process in accordance with  claim 21  wherein the azide donor agent is sodium azide or tetrabutylammonium azide, the reducing agent is trimethylphosphine, the phase transfer catalyst is tetrabutylammonium chloride, benzyltriethylammonium chloride, and/or tetrabutylonium, and the palladium catalyst is tris-(dibenzylideneacetone)-dipalladium(0)chloroform adduct or tris-(dibenzylideneacetone)-dipalladium. 
     
     
       23. A process in accordance with claim  15   17  wherein said macrolactamization coupling agent comprises one or more members selected from the group consisting of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 1-hydroxy-7-benzotriazole hydrate, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 1-hydroxy-7-azabenzotriazole hydrate, dicyclohexylcarbodiimide, diisopropylcarboniimide, diphenylphosphoryl azide, O-benzotriazol-1-yl-N,N,N′,N′-bis(tetramethylene)uronium hexafluorophosphate, O-(7-azabenzotriazol)-1-yl-N,N,N′,N′-bis(tetramethylene)uronium hexafluorophosphate, benzotriazol-1-yloxy-tris(bimethylamino)phosphonium hexafluorophosphate, N,N-dimethyl-4-aminopyridine, K 2 CO 3 , diisopropylamine, and triethylamine. 
     
     
       24. A process in accordance with  claim 23  where said coupling agent is 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 1-hydroxy-7-benzotriazole hydrate. 
     
     
       25. A process in accordance with claim  18   20  wherein said azide donor agent is selected from the group consisting of lithium azide, sodium azide, tetraalkylammonium azide and trialkylsilyl azide, said buffering agent is selected from the group consisting of mild acids and acidic salts, said palladium catalyst is selected from the group consisting of palladium acetate, palladium chloride, palladium tetrakis-(triphenylphosphine), palladium tetrakris-(triphenylarsine) and tris-(dibenzylideneacetone)-dipallidium(0)chloroform adduct, and tris-(dibenzylideneacetone)-dipallidium, and said reducing agent is selected from the group consisting of a trialkyphosphine, triarylphosphine, trialkylarsine, triarylarsine, and mixtures thereof. 
     
     
       26. A process in accordance with  claim 25  wherein the azide donor agent is tetrabutylammonium azide, the buffering agent is ammonium chloride, the palladium catalyst is tris-(dibenzylideneacetone)-dipalladium(0)chloroform adduct, and the reducing agent is trimethylphosphine. 
     
     
       27. A process in accordance with claim  18   20  wherein said macrolactamization coupling agent comprises one or more members selected from the group consisting of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 1-hydroxy-7-benzotriazole hydrate, 1-(3-demethylaminopropyl)-3-ethylcarbodimmide hydrochloride and 1-hydroxy-7-azabenzotriazole hydrate, dicyclohexylcarbodiimide, diisopropylcarboniimide, diphenylphosporyl azide, O-benzotriazol-1-yl-N,N,N′,N′-bis(tetramethylene)uronium hexafluorophosphate, O-(7-azabenzotriazol)-1-yl-N,N,N′,N′-bis(tetramethylene)uronium hexafluorophosphate, benzotriazol-1-yloxy-tris(bimethylamino)phosphonium hexafluorophosphate, N,N-dimethyl-4-aminopyridine, K 2 CO 3 , diisopropylamine, and triethylamine. 
     
     
       28. A process in accordance with  claim 27  where said coupling agent is 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 1-hydroxy-7-benzotriazole hydrate. 
     
     
       29. The process according to  claim 6 , wherein said azide donor agent is tetraalkylammonium azide, and said phase transfer catalyst is the cation of the azide donor agent. 
     
     
       30. The process according to  claim 6 , further comprising reacting the epothilone starting material with the azide donor agent and reducing agent in the presence of a buffering agent. 
     
     
       31. The process according to  claim 30 , wherein the buffering agent is selected from ammonium salts. 
     
     
       32. The process according to  claim 11 , wherein the step of macrolactamization comprises a reverse addition wherein the intermediate compound is added to the coupling agent. 
     
     
       33. The process according to  claim 13 , wherein the step of macrolactamization comprises a reverse addition wherein the intermediate compound is added to the coupling agent. 
     
     
       34. The process according to  claim 14 , wherein the step of macrolactamization comprises a reverse addition wherein the intermediate compound is added to the coupling agent. 
     
     
       35. The process according to  claim 17 , wherein the step of macrolactamization comprises a reverse addition wherein the intermediate compound is added to the coupling agent. 
     
     
       36. The process according to  claim 20 , wherein the step of macrolactamization comprises a reverse addition wherein the intermediate compound is added to the coupling agent. 
     
     
       37. A process for making the compound having the formula II,                   
       comprising reacting epothilone B starting material with an azide donor agent in the presence of palladium catalyst and reducing agent and optionally either or both of a phase transfer catalyst and/or buffering agent, to obtain an optionally- isolated and/or purified intermediate and carrying out a macrolactamization reaction of said intermediate in the presence of a suitable coupling agent to obtain the compound of formula II.   
     
     
       38. The process of  claim 37  performed in essentially two steps without isolation and/or purification of the intermediate. 
     
     
       39. An intermediate compound having the formula, 
                   
         wherein Z   +    is a cation of an azide donor agent and/or phase transfer catalyst wherein the azide donor agent is selected from the group consisting of lithium azide, sodium azide, tetraalkyl - ammonium azide and trialkylsilyl azide, and the phase transfer catalyst is selected from the group consisting of tetraalkylonium, tetraarylonium, and tetraaralkyonium salts.   
     
     
       40. [ 1 S- [ 1 R*, 3 R* ( E ) , 7 R*, 10 S*, 11 R*, 12 R*, 16 S*]] -   7 , 11   - dihydroxy -   8 , 8 , 10 , 12 , 16   - pentamethyl -   3   - [ 1   - methyl -   2   -(   2   - methyl -   4   - thiazolyl ) ethenyl] -   4   - aza -   17   - oxabicyclo[ 14 . 1 . 0 ]heptadecane -   5 , 9   - dione, in crystalline form substantially free of amorphous material.   
     
     
       41. [ 1 S- [ 1 R*, 3 R* ( E ) , 7 R*, 10 S*, 11 R*, 12 R*, 16 S*]] -   7 , 11   - dihydroxy -   8 , 8 , 10 , 12 , 16   - pentamethyl -   3   - [ 1   - methyl -   2   -(   2   - methyl -   4   - thiazolyl ) ethenyl] -   4   - aza -   17   - oxabicyclo[ 14 . 1 . 0 ]heptadecane -   5 , 9   - dione, in crystalline form having a purity of at least  93   % .