Taxane compounds, compositions and methods

Abstract

The present invention provides a method for the preparation of orally available pentacyclic taxane compounds, as well as intermediates useful in their preparation.

1 - 17 . (canceled) 
     
     
         18 . A method of producing an acid salt of tesetaxel, comprising:
 adding an acid selected from a monobasic acid, a dibasic acid, a tribasic acid, or a polybasic acid to a solution of tesetaxel in an organic solvent, thereby forming a mixture; and   crystallizing the acid salt of tesetaxel from the mixture;   provided that either:   (a) the solvent is isopropyl alcohol, or   (b) the acid is selected from benzoic acid, ortho-toluic acid, meta-toluic acid, para-toluic acid, ethane sulphonic acid, camphor sulphonic acid, (S)-(+)-mandelic acid, (R)-(−)-mandelic acid, gentisic acid, hippuric acid, glycolic acid, 2-hydroxyethanesulfonic acid, 2-naphthalenesulfonic acid, gluconic acid, malic acid, oxalic acid, succinic acid, tartaric acid, malonic acid, adipic acid, itaconic acid, cyclohexane dicarboxylic acid, phthalic acid, edisylate, phenyl phosphonic acid, digluconic acid, dibasic natural amino acids, or phosphoric acid.   
     
     
         19 . The method of  claim 18 , wherein the acid is selected from benzoic acid, ortho-toluic acid, meta-toluic acid, para-toluic acid, ethane sulphonic acid, camphor sulphonic acid, (S)-(+)-mandelic acid, (R)-(−)-mandelic acid, gentisic acid, hippuric acid, glycolic acid, 2-hydroxyethanesulfonic acid, 2-naphthalenesulfonic acid, gluconic acid, malic acid, oxalic acid, succinic acid, tartaric acid, malonic acid, adipic acid, itaconic acid, cyclohexane dicarboxylic acid, phthalic acid, edisylate, phenyl phosphonic acid, digluconic acid, dibasic natural amino acids, or phosphoric acid. 
     
     
         20 . The method of  claim 18 , wherein the acid is selected from benzoic acid, ortho-toluic acid, meta-toluic acid, para-toluic acid, ethane sulphonic acid, camphor sulphonic acid, (S)-(+)-mandelic acid, (R)-(−)-mandelic acid, gentisic acid, hippuric acid, glycolic acid, 2-hydroxyethanesulfonic acid, 2-naphthalenesulfonic acid, and gluconic acid. 
     
     
         21 . The method of  claim 18 , wherein the acid is selected from malic acid, oxalic acid, succinic acid, tartaric acid, malonic acid, adipic acid, itaconic acid, cyclohexane dicarboxylic acid, phthalic acid, edisylate, phenyl phosphonic acid, digluconic acid, and dibasic natural amino acids. 
     
     
         22 . The method of  claim 18 , wherein the acid is phosphoric acid. 
     
     
         23 . The method of  claim 18 , wherein the organic solvent is selected from acetone, methanol, ethanol, propanol, butanol, acetonitrile, tetrahydrofuran, isopropyl alcohol, toluene and N,N-dimethylformamide. 
     
     
         24 . The method of  claim 23 , wherein the organic solvent is isopropyl alcohol. 
     
     
         25 . A method of producing an acid salt of tesetaxel, comprising:
 adding an acid selected from a monobasic acid, a dibasic acid, a tribasic acid, or a polybasic acid to a first mixture comprising an organic solvent and a compound represented by formula (Ia):   
       
         
           
           
               
               
           
         
         linking the compound of Formula (Ia) with a taxane side chain precursor, thereby producing a second mixture comprising 2′-O protected tesetaxel; 
         deprotecting the 2′-O protected tesetaxel group, thereby producing a third mixture comprising tesetaxel; and 
         crystallizing the acid salt of tesetaxel from the third mixture. 
       
     
     
         26 . The method of  claim 25 , wherein the acid is selected from benzoic acid, ortho-toluic acid, meta-toluic acid, para-toluic acid, ethane sulphonic acid, camphor sulphonic acid, (S)-(+)-mandelic acid, (R)-(−)-mandelic acid, gentisic acid, hippuric acid, glycolic acid, 2-hydroxyethanesulfonic acid, 2-naphthalenesulfonic acid, gluconic acid, malic acid, oxalic acid, succinic acid, tartaric acid, malonic acid, adipic acid, itaconic acid, cyclohexane dicarboxylic acid, phthalic acid, edisylate, phenyl phosphonic acid, digluconic acid, dibasic natural amino acids, or phosphoric acid. 
     
     
         27 . The method of  claim 25 , wherein the acid is selected from benzoic acid, ortho-toluic acid, meta-toluic acid, para-toluic acid, ethane sulphonic acid, camphor sulphonic acid, (S)-(+)-mandelic acid, (R)-(−)-mandelic acid, gentisic acid, hippuric acid, glycolic acid, 2-hydroxyethanesulfonic acid, 2-naphthalenesulfonic acid, and gluconic acid. 
     
     
         28 . The method of  claim 25 , wherein the acid is selected from malic acid, oxalic acid, succinic acid, tartaric acid, malonic acid, adipic acid, itaconic acid, cyclohexane dicarboxylic acid, phthalic acid, edisylate, phenyl phosphonic acid, digluconic acid, and dibasic natural amino acids. 
     
     
         29 . The method of  claim 25 , wherein the acid is phosphoric acid. 
     
     
         30 . The method of  claim 25 , wherein the organic solvent is selected from acetone, methanol, ethanol, propanol, butanol, acetonitrile, tetrahydrofuran, isopropyl alcohol, toluene and N,N-dimethylformamide. 
     
     
         31 . The method of  claim 30 , wherein the organic solvent is isopropyl alcohol.