Synthetic process for the manufacture of an ecteinaschidin compound

Abstract

Processes are provided for preparing compounds with a fused ring structure of formula (XIV). Such products include ecteinascidins and have a spiroamine-1,4-bridge. The process involving forming a 1,4 bridge using a 1-labile, 10-hydroxy, 18-protected hydroxy, di-6,8-en-5-one fused ring compound. After formation of the 1,4 bridge, C-18 protection is removed before spiroamine introduction.

1 . A process for preparing an ecteinascidin product with a spiroamine-1,4-bridge, the process involving forming a 1,4 bridge using a 1-labile, 10-hydroxy, 18-protected hydroxy, di-6,8-en-5-one fused ring compound, wherein C-18 protection is removed before spiroamine introduction.  
     
     
         2 . A process according to  claim 1 , wherein the ecteinascidin product has a 21-hydroxy group, the process including converting a 21-cyano group to the 21-hydroxy group.  
     
     
         3 . A process according to  claim 1  or  2 , wherein the spiroamine is a spiroquinoline.  
     
     
         4 . A process according to any preceding claim, wherein the 18-protected group of the 1-labile, 10-hydroxy, 18-protected hydroxy, di-6,8-en-5-one fused ring compound is protected with: MOM, methoxymethyl; or MEM, methoxyethoxymethyl group.  
     
     
         5 . A process according to any preceding claim, wherein the 1-labile group is an N-protected cysteinyloxymethylene group of the formula  
       —CH 2 —O—CO—CNHProt 1 —CH 2 —S—H.  
     
     
         6 . A process according to  claim 5 , where Prot 1  is: Boc, t-butyloxycarbonyl; Troc, 2,2,2-trichloroethyloxycarbonyl; Cbz, benzyloxycarbonyl; or Alloc, allyloxycarbonyl.  
     
     
         7 . A process according to  claim 5  or  6 , wherein Prot 1  is removed in the same step as C-18 protection.  
     
     
         8 . A process according to  claim 5 ,  6  or  7 , wherein the 1-labile group is generated from a 1-substituent of the formula:  
       —CH 2 —O—CO—CNHProt 1 —CH 2 —S-Prot 2 .  
     
     
         9 . A process according to  claim 8 , wherein Prot 2  is Fm, 9-fluorenylmethyl.  
     
     
         10 . A process according to  claim 8  or  9 , wherein the 1-substituent of the formula:  
       —CH 2 —O—CO—CNHProt 1 —CH 2 —S-Prot 2 .  
       is formed by esterification of a —CH 2 —O—H substituent.  
     
     
         11 . A process according to  claim 10 , wherein the esterification is carried out before formation of the 10-hydroxy, di-6,8-en-5-one structure.  
     
     
         12 . A process according to  claim 10 , wherein the esterification is carried out after introduction of the 10-hydroxy, di-6,8-en-5-one structure.  
     
     
         13 . A process according to any preceding claim, which starts from a 1-aminomethylene, 5-protected hydroxy, 7,8-dioxymethylene, 18-hydroxy, 21-cyano fused ring compound  
     
     
         14 . A process according to  claim 13 , where the 1-aminomethylene group is temporarily protected to allow protection at the 18-hydroxy group, and the temporary protection is removed.  
     
     
         15 . A process according to  claim 13 , wherein the C-18 hydroxy group is protected after formation of a 1-ester function.  
     
     
         16 . A process according to  claim 13 , wherein the 1-aminomethylene group is converted to a 1-hydroxymethylene group and the 1-hydroxymethylne group is temporarily protected, to allow protection at the 18-hydroxy group, and the temporary protection is removed.  
     
     
         17 . A process according to  claim 1 , wherein the 1-labile, 10-hydroxy, 18-protected hydroxy, di-6,8-en-5-one fused ring compound is prepared by steps starting from a 21-Nuc compound with a structure of formula (XIV):  
       
         
           
           
               
               
           
         
       
       where at least one ring A or E is quinolic, and where Nuc indicates the residue of a nucleophilic agent.  
     
     
         18 . A process according to  claim 17 , wherein the compound of formula (XIV) is cyanosafracin B.  
     
     
         19 . A process according to any preceding claim, wherein the product is of formula (XXIIb):  
       
         
           
           
               
               
           
         
       
       where: 
 R 1  and R 4  together form a group of formula (IV), (V), (VI) or (VII):  
                     
 R 5  is —OH or a protected or derivatised version of such a group;  
 R 14a  and R 14b  are both —H or one is —H and the other is —OH or a protected or derivatised version of such a group, —OCH3 or —OCH 2 CH 3 , or R 14a  and R 14b  together form a keto group;  
 R 12  is —NCH 3 —;  
 R 15  is —OH or a protected or derivatised version of such a group; and  
 R 18  is —OH or a protected or derivatised version of such a group.  
 
     
     
         20 . A process according to  claim 19 , wherein R 5  is alkanoyloxy of 1 to 5 carbon atoms.  
     
     
         21 . A process according to  claim 20 , wherein R 5  is acetyloxy.  
     
     
         22 . A process according to  claim 19 ,  20  or  21 , wherein R 14a  and R 14b  are hydrogen.  
     
     
         23 . A process according to any of  claims 19  to  22 , wherein R 15  is hydrogen.  
     
     
         24 . A process according to any of  claims 19  to  23 , wherein R 21  is —OH or —CN.  
     
     
         25 . A process according to  claim 11 , wherein R 7  and R B  together form a group —O—CH 2 —O—.  
     
     
         26 . A process according to any of  claims 19  to  25 , wherein R 1  and R 4  together form a group of formula (IV):  
       
         
           
           
               
               
           
         
       
     
     
         27 . A process according to any preceding claim, wherein the ecteinascidin product is ecteinascidin 743.  
     
     
         28 . A process step in the manufacture of an ecteinascidin comopund, the step comprising removing both protecting groups in a single step, in accordance with the following scheme:  
       
         
           
           
               
               
           
         
       
       where Prot NH  is amino protecting group, and Prot OH  is a hydroxy protecting group.  
     
     
         29 . A process according to any of  claims 1  to  27 , which includes the process step according to  claim 28.