Process to prepare camptothecin derivatives

Abstract

A process is provided for the preparation of camptothecin derivatives, such as irinotecan, in a one-pot operation.

1 . A process for adding a sidechain to a starting material comprising reacting together: 
 (i) a compound of formula I:                          wherein each of the ring atoms may be carbon, or any one, two or three of the ring atoms may be nitrogen, and R a , R b  and R c  are the same or different and independently represent one or more optional non-hydrogen substituents on each of rings A, B and C;    (ii) an amine of formula R 1 R 2 NH wherein R 1  and R 2  are the same or different and independently represent organic groups; and    (iii) phosgene or a reactive equivalent thereof,    to provide a solution comprising a compound of formula III:                          
     
     
         2 . The process of  claim 1  wherein R a , R b  and R c  have, in total, no more than 30 carbon atoms and no more than 5 oxygen atoms.  
     
     
         3 . The process of  claim 1  wherein the compound of formula I has the structure:  
       
         
           
           
               
               
           
         
       
       wherein R 3  is an alkyl group.  
     
     
         4 . The process of  claim 3  wherein the compound of formula I has the structure:  
       
         
           
           
               
               
           
         
       
       or a partially or completely purified stereoisomer thereof, or a salt thereof.  
     
     
         5 . The process of  claim 1  wherein the amine of formula R 1 R 2 NH is piperidinopiperidine.  
     
     
         6 . The process of  claim 5  wherein the compound of formula I has the structure:  
       
         
           
           
               
               
           
         
       
       wherein R 3  is an alkyl group.  
     
     
         7 . The process of  claim 1  wherein the phosgene or a reactive equivalent thereof is phosgene trihydrate.  
     
     
         8 . The process of  claim 1  wherein the phosgene or reactive equivalent thereof and the amine of formula R 1 R 2 NH are combined to provide an intermediate solution, and the compound of formula I is added to the intermediate solution.  
     
     
         9 . The process of  claim 8  further comprising adding pyridine or a tertiary amine to the intermediate solution along with the compound of formula I.  
     
     
         10 . The process of  claim 1  further comprising a step wherein the solution comprising a compound of formula III is filtered and then freed from solvent to provide a residue.  
     
     
         11 . The process of  claim 10  wherein the residue is purified by column chromatography, filtration, precipitation or crystallization.  
     
     
         12 . The process of  claim 1  wherein the molar yield of the compound of formula III is at least 50% based on the moles of the compound of formula I used in the process.  
     
     
         13 . The process of  claim 1  wherein the molar yield of the compound of formula III is at least 75% based on the moles of the compound of formula I used in the process.  
     
     
         14 . The process of  claim 1  wherein the molar yield of the compound of formula III is at least 90% based on the moles of the compound of formula I used in the process.  
     
     
         15 . The process of  claim 1  wherein the molar yield of the compound of formula III is 94% based on the moles of the compound of formula I used in the process.  
     
     
         16 . The process of  claim 1  wherein the compound of formula I is SN-38, the amine of formula R 1 R 2 NH is piperidinopiperidine, and the compound of formula III is irinotecan, and wherein the process is a one-pot operation.  
     
     
         17 . The process of  claim 16  wherein the phosgene or reactive equivalent thereof is phosgene trihydrate, and the phosgene trihydrate and piperidinopiperidine are combined in a solvent and allowed to react together to form an intermediate solution, and the SN-38 and an organic base are added to the intermediate solution to form the solution comprising irinotecan.  
     
     
         18 . The process of  claim 17  wherein the phosgene trihydrate is dissolved in a chlorinated solvent and then cooled to a temperature in the range of −40° C. to 25° C. followed by addition of piperidinopiperidine to the cooled solution.  
     
     
         19 . The process of  claim 18  wherein the phosgene trihydrate is cooled to a temperature in the range of −10° C. to 0° C.  
     
     
         20 . The process of  claim 18  wherein, subsequent to the addition of piperidinopiperidine, N,N-diisopropylethylamine, triethylamine or an equivalent base is added to the cooled solution.  
     
     
         21 . The process of  claim 20  further comprising adding a catalyst to the intermediate solution along with the SN-38 and the organic base.  
     
     
         22 . The process of  claim 21  wherein the organic base is pyridine or the like.  
     
     
         23 . The process of  claim 21  wherein the catalyst is DMAP, DCC or the like.  
     
     
         24 . A composition comprising a solvent and the reaction product of: 
 (i) a compound of formula I:                          wherein each of the ring atoms may be carbon, or any one, two or three of the ring atoms may be nitrogen, and R a , R b  and R c  are the same or different and independently represent one or more optional non-hydrogen substituents on each of rings A, B and C,    (ii) an amine of formula R 1 R 2 NH wherein R 1  and R 2  are the same or different and independently represent organic groups, and    (iii) phosgene or a reactive equivalent thereof.    
     
     
         25 . The composition of  claim 24  wherein the compound of formula I is SN-38 and the amine of formula R 1 R 2 NH is piperidinopiperidine.