Process for the preparation of anticancer drugs

Abstract

A process for preparing Anastrozole is provided. In the process the steps of a. combining 3,5-bis(2-cyanoisopropyl)toluene, a solvent selected from the group consisting of acetonitrile, dichloromethane and chlorobenzene, a brominating reagent selected from a group consisting of N-bromosuccinimide and 1,3-dibromo-5,5-dimethylhydantoin, and 2,2′-azobis(2-methylpropionitrile); b. heating; c. combining with 1,2,4-triazole, a solvent selected from a group consisting of N-methylpyrrolidine, dimethylformamide, mixtures of NMP and DMF, dimethylsulfoxide, mixtures of DMSO and toluene, acetone, ACN, and tetrahydrofuran, a base selected from a group consisting of NaOH, KOH, K 2 CO 3 , and Na 2 CO 3 , and 1,3-benzendiacetonitrile-5-(bromomethyl)-α,α,{acute over (α)},{acute over (α)}-tetramethyl, at a temperature below −20° C. are performed.

1 . A process for purifying anastrazole of the following formula: 
     
       
         
         
             
             
         
       
     
     comprising the steps of:
 a) extracting a quenched reaction mixture containing anastrazole with a mixture comprising toluene; a linear, branched or cyclic C 5-8  hydrocarbon; and water to form an organic phase and an aqueous phase; 
 b) extracting the aqueous phase with a mixture comprising toluene and a linear, branched or cyclic C 5-8  hydrocarbon; 
 c) adding water or an aqueous solution of NaCl to the extracted aqueous phase; 
 d) extracting the aqueous phase formed in step (c) with toluene; 
 e) washing the toluene extract obtained in step (d) with an aqueous solution of an acid; 
 f) adding a linear, branched, or cyclic C 5-8  hydrocarbon to the washed organic phase to precipitate Anastrozole. 
 
   
   
       2 . The process of  claim 1 , further comprising extracting the aqueous phase with a mixture comprising toluene; a linear, branched or cyclic C 5-8  hydrocarbon; and water prior to the step (d) extraction of the aqueous phase using toluene. 
   
   
       3 . The process of  claim 1 , wherein extracting the aqueous phase in step (d) comprises adding toluene and an aqueous solution of NaCl to the aqueous phase. 
   
   
       4 . The process of  claim 1 , further comprising washing the toluene extract obtained in step (d) with an aqueous solution of NaCl, prior to the step (e) washing with an aqueous solution of an acid. 
   
   
       5 . The process of  claim 1 , wherein the acid is an organic acid 
   
   
       6 . The process of  claim 5 , wherein the organic acid is tartaric acid or citric acid. 
   
   
       7 . The process of  claim 1 , wherein the acid is an inorganic acid. 
   
   
       8 . The process of  claim 7 , wherein the inorganic acid is sulfuric acid or hydrochloric acid. 
   
   
       9 . The process of  claim 1 , further comprising concentrating the washed toluene extract obtained in step (e), prior to adding a linear, branched, or cyclic C 5-8  hydrocarbon to precipitate Anastrozole in step (f). 
   
   
       10 . The process of  claim 9 , wherein the washed toluene extract is concentrated under reduced pressure. 
   
   
       11 . The process of  claim 10 , wherein the linear, branched, or cyclic C 5-8  hydrocarbon is added drop-wise to the concentrated toluene extract. 
   
   
       12 . The process of  claim 11 , wherein the drop-wise addition is done over a period of about 1 to about 1.5 hours, providing a suspension. 
   
   
       13 . The process of  claim 12 , further comprising cooling the suspension and then collecting a precipitate from the cooled suspension. 
   
   
       14 . The process of  claim 13 , wherein the suspension is cooled to a temperature of about 10° C. to about 0° C. 
   
   
       15 . The process of  claim 14 , wherein the suspension is cooled to a temperature of about 5° C. to about 0° C. 
   
   
       16 . The process of  claim 1 , wherein the linear, branched, or cyclic C 5-8  hydrocarbon is hexane, heptane or cyclohexane. 
   
   
       17 . The process of  claim 16 , wherein the linear, branched, or cyclic C 5-8  hydrocarbon is heptane. 
   
   
       18 . The process of  claim 1 , further comprising crystallizing the Anastrazole. 
   
   
       19 . The process of  claim 18 , wherein the crystallization is from a mixture of a solvent and an anti-solvent. 
   
   
       20 . The process of  claim 19 , wherein the solvent is selected from acetone, ethanol, 2-propanol, methanol, dichloromethane, n-butanol, acetonitrile, ethyl acetate and toluene; and the anti-solvent is selected from heptane, diisopropyl ether, water and cyclohexane. 
   
   
       21 . The process of  claim 20 , wherein the mixtures of a solvent and an anti-solvent are selected from acetone and heptane, ethanol and heptane, ethanol and diisopropyl ether, ethanol and water, methanol and water, dichloromethane and diisopropyl ether, 2-propanol and heptane, n-butanol and heptane, 2-propanol and diisopropyl ether, 2-propanol and water, n-butanol and diisopropyl ether, acetonitrile and water, 2-propanol and heptane, and toluene and heptane. 
   
   
       22 . The process of  claim 21 , wherein the mixtures of a solvent and an anti-solvent are selected from 2-propanol and heptane, toluene and heptane, and methanol and water. 
   
   
       23 . The process of  claim 19 , wherein the crystallization is done by the following steps:
 a) dissolving Anastrozole in the solvent;   b) adding the anti-solvent to the solution formed in step (a), in a drop-wise manner to form a suspension; and   c) cooling the suspension formed in step (b) to a temperature of about 10° C. to about 0° C.   
   
   
       24 . The process of  claim 23 , wherein step (a) of dissolving Anastrozole in the solvent, is done by heating a mixture of Anastrozole and the solvent to a temperature of about 20° C. to about 55° C. 
   
   
       25 . The process of  claim 24 , wherein the addition in step (b) is carried out with stirring. 
   
   
       26 . The process of  claim 23 , wherein the Anastrozole in step (a) is crude Anastrozole. 
   
   
       27 . The process of  claim 26 , wherein the crude Anastrazole contains at least one of the impurities selected from isoanastrozole, 3,5-bis(2-cyanoisopropyl)toluene and 1,1-dibromomethyl-3,5-bis(2-cyanoisopropyl)benzene. 
   
   
       28 . The process of  claim 23 , wherein the solvent is methanol, and the dissolution temperature range is about 20° C. to about 30° C. 
   
   
       29 . The process of  claim 28 , wherein the dissolution temperature range is about 20° C. to about 25° C. 
   
   
       30 . The process of  claim 23 , wherein the solvent is 2-propanol or toluene, and the dissolution temperature range is about 40° C. to about 50° C. 
   
   
       31 . The process of  claim 23 , wherein the anti-solvent is added slowly over a period of about 15 minutes to about 2 hours. 
   
   
       32 . The process of  claim 31 , wherein the solvent is 2-propanol or toluene, and the anti-solvent is heptane and the addition is done over a period of about 0.5 hours to about 2 hours. 
   
   
       33 . The process of  claim 32 , wherein the addition is done over a period of about an hour to about 1.2 hours. 
   
   
       34 . The process of  claim 31 , wherein the anti-solvent is water and the solvent is methanol, and the addition is done over a period of about 1 hour to about 2 hours. 
   
   
       35 . The process of  claim 34 , wherein the addition is done over a period of about 75 to about 100 minutes. 
   
   
       36 . The process of  claim 23 , wherein the suspension in step (c) is cooled to a temperature of about 5° C. to about 0° C. 
   
   
       37 . The process of  claim 36 , wherein the suspension is cooled to about 2° C. to about 0° C.