Production and purification methods for efinaconazole

Abstract

The present invention provides efinaconazole producing and purifying methods adapted to industrial scale that provide high-purity efinaconazole in high yield by simple operations using specific impurities as indices. The efinaconazole producing method comprises: step A of forming a toluene solution comprising compound (II), compound (III), an inorganic base, and toluene in a volume (L) which is 2 to 5 times the mass (kg) of compound (II); step B of subjecting the toluene solution to reaction under heating; step C of washing the reaction mixture from step B to obtain a toluene solution of crude efinaconazole in which the residual amount of 4-MP is not more than 5 wt % of efinaconazole.

1 . A method of producing efinaconazole comprising:
 (A) forming a primary toluene solution comprising:
 a compound represented by formula (II): 
   
       
         
           
           
               
               
           
         
         
           hereinafter sometimes referred to as epoxytriazole; 
           a compound represented by formula (III): 
         
       
       
         
           
           
               
               
           
         
         
           where X is Cl, Br or I, and the compound (III) is hereinafter sometimes referred to as 4-MP.HX salt, which is a HX salt of 4-MP; 
           an inorganic base; and 
           toluene in a volume (L), which is from 2 to 5 times mass (kg) of the epoxytriazole; 
         
         (B) subjecting the primary toluene solution to a reaction under heating; 
         (C) washing the resulting reaction mixture from (B), which is:
 (C)-(i) washing the resulting reaction mixture from (B) more than once, or 
 (C)-(ii) washing the resulting reaction mixture from (B) so that pH of an aqueous layer after the washing of the reaction mixture is in a range from 3 to 5, thereby obtaining a secondary toluene solution of crude efinaconazole in which a residual amount of the 4-MP is not more than 5 wt % of efinaconazole; 
 
         (D) mixing the secondary toluene solution of crude efinaconazole with 2-propanol andp-toluenesulfonate or a hydrate thereof so as to precipitate p-toluenesulfonate of efinaconazole; 
         (E) isolating the precipitated p-toluenesulfonate of efinaconazole; and 
         (F) neutralizing the isolated p-toluenesulfonate of efinaconazole. 
       
     
     
         2 . The method according to  claim 1 , wherein the compound (III) is a compound represented by formula (III-A): 
       
         
           
           
               
               
           
         
         where the compound (III-A) is hereinafter sometimes referred to as 4-MP.HBr salt, wherein the compound (III-A) is contained in an amount in a range from 1 to 1.6 moles relative to one mole of the epoxytriazole, and 
         the inorganic base is lithium hydroxide or a hydrate thereof and contained in an amount in a range from 1 to 1.6 moles relative to one mole of the epoxytriazole. 
       
     
     
         3 . The method according to  claim 1 , wherein a reaction time in (B) is in a range from 1 to 15 hours. 
     
     
         4 . The method according to  claim 1 ,
 wherein the washing (C)-(ii) is performed as the washing (C), and   a content of a compound represented by formula (IV):   
       
         
           
           
               
               
           
         
       
       in the efinaconazole as obtained by (F) is no more than 0.50% as a HPLC area percentage detected with UV light at a wavelength of 262 nm. 
     
     
         5 . The method according to  claim 1 , further comprising, after (F):
 (G) forming a solution of the obtained efinaconazole in an ethanol-water mixed solvent and crystallizing the efinaconazole; and   (H) further adding water to the ethanol-water mixed solvent solution from (G) and isolating the efinaconazole that has precipitated out,   wherein a content of a compound represented by formula (IV) in the obtained efinaconazole is no more than 0.10% as a HPLC area percentage detected with UV light at a wavelength of 262 nm,   
       
         
           
           
               
               
           
         
       
     
     
         6 . The method according to  claim 5 , wherein the solution of the ethanol-water mixed solvent in (G) is a solution in which ethanol is mixed with water in a range from 50 to 65% by volume-relative to the solution. 
     
     
         7 . The method according to  claim 5 , wherein an amount of the water added to the solution of the ethanol-water mixed solvent in (H) is such that an ethanol concentration in the resulting solution after the adding of the water is in a range of 35-45% by volume relative to the resulting solution. 
     
     
         8 . The method according to  claim 5 , wherein a content of a compound represented by formula (V): 
       
         
           
           
               
               
           
         
       
       hereinafter sometimes referred to as compound (V), 
       in the obtained efinaconazole is no more than 0.50% as a HPLC area percentage detected with UV light at a wavelength of 262 nm. 
     
     
         9 . The method according to  claim 8 , wherein the content of the compound (V) in the obtained efinaconazole is no more than 0.15% as the HPLC area percentage. 
     
     
         10 . The method according to  claim 5 , wherein a content of a compound represented by formula (XIII): 
       
         
           
           
               
               
           
         
       
       hereinafter sometimes referred to as compound (XIII), in the obtained efinaconazole is no more than 0.10% as a HPLC area percentage detected with UV light at a wavelength of 262 nm. 
     
     
         11 . The method according to  claim 10 , wherein the content of the compound (XIII) in the obtained efinaconazole is no more than 0.05% as the HPLC area percentage. 
     
     
         12 . The method according to  claim 10 , wherein a content of a compound represented by formula (V): 
       
         
           
           
               
               
           
         
       
       hereinafter sometimes referred to as compound (V), in the obtained efinaconazole is no more than 0.15% as a HPLC area percentage detected with UV light at a wavelength of 262 nm, and
 wherein the content of the compound (XIII) in the obtained efinaconazole is no more than 0.05% as the HPLC area percentage. 
 
     
     
         13 . The method according to  claim 12 , wherein purity of the obtained efinaconazole is no less than 98.0% as a HPLC area percentage detected with UV light at a wavelength of 262 nm. 
     
     
         14 . The method according to  claim 12 , wherein purity of the obtained efinaconazole is no less than 99.0% as a HPLC area percentage detected with UV light at a wavelength of 262 nm. 
     
     
         15 . The method according to  claim 5 , wherein the obtained efinaconazole has purity of 99.99% or more as a HPLC area percentage detected with UV light at a wavelength of 262 nm. 
     
     
         16 . Efinaconazole having purity of 99.99% or more as a HPLC area percentage detected with UV light at a wavelength of 262 nm. 
     
     
         17 . The efinaconazole according to  claim 16 , wherein presence of a compound represented by formula (IV): 
       
         
           
           
               
               
           
         
       
       in the efinaconazole is not detected as a HPLC area percentage with UV light at a wavelength of 262 nm. 
     
     
         18 . The efinaconazole according to  claim 16 , wherein presence of a compound represented by formula (V): 
       
         
           
           
               
               
           
         
       
       in the efinaconazole is not detected as a HPLC area percentage with UV light at a wavelength of 262 nm. 
     
     
         19 . The efinaconazole according to  claim 16 , wherein presence of a compound represented by formula (VI): 
       
         
           
           
               
               
           
         
       
       in the efinaconazole is not detected as a HPLC area percentage with UV light at a wavelength of 262 nm. 
     
     
         20 . The efinaconazole according to  claim 16 , wherein presence of a compound represented by formula (VII): 
       
         
           
           
               
               
           
         
       
       in the efinaconazole is not detected as a HPLC area percentage with UV light at a wavelength of 262 nm. 
     
     
         21 . The efinaconazole according to  claim 16 , wherein presence of a compound represented by formula (VIII): 
       
         
           
           
               
               
           
         
       
       in the efinaconazole is not detected as a HPLC area percentage with UV light at a wavelength of 262 nm. 
     
     
         22 . The efinaconazole according to  claim 16 , wherein presence of a compound represented by formula (IX): 
       
         
           
           
               
               
           
         
       
       in the efinaconazole is not detected as a HPLC area percentage with UV light at a wavelength of 262 nm. 
     
     
         23 . The efinaconazole according to  claim 16 , wherein presence of a compound represented by formula (X): 
       
         
           
           
               
               
           
         
       
       in the efinaconazole is not detected as a HPLC area percentage with UV light at a wavelength of 262 nm. 
     
     
         24 . The efinaconazole according to  claim 16 , wherein presence of a compound represented by formula (XI): 
       
         
           
           
               
               
           
         
       
       in the efinaconazole is not detected as a HPLC area percentage with UV light at a wavelength of 262 nm. 
     
     
         25 . The efinaconazole according to  claim 16 , wherein presence of a compound represented by formula (XII): 
       
         
           
           
               
               
           
         
       
       in the efinaconazole is not detected as a HPLC area percentage with UV light at a wavelength of 262 nm. 
     
     
         26 . The efinaconazole according to  claim 16 , wherein a content of a compound represented by formula (XIII): 
       
         
           
           
               
               
           
         
       
       in the efinaconazole is no more than 0.01% as a HPLC area percentage detected with UV light at a wavelength of 262 nm. 
     
     
         27 . The efinaconazole according to  claim 16 ,
 wherein presence of a compound (IV) and presence of a compound (V) in the efinaconazole are not detected as a HPLC area percentage with UV light at a wavelength of 262 nm, and   a content of a compound (XIII) in the efinaconazole is no more than 0.01% as a HPLC area percentage detected with UV light at a wavelength of 262 nm,   where the compound (IV), the compound (V), and the compound (XIII) are represented by respective formulae below:   
       
         
           
           
               
               
           
         
       
     
     
         28 . The efinaconazole according to  claim 16 ,
 wherein presence of a compound (IV), a compound (V), a compound (VI), a compound (VII), a compound (VIII), a compound (IX), a compound (X), a compound (XI), and a compound (XII) in the efinaconazole is not detected as a HPLC area percentage with UV light at a wavelength of UV 262 nm, and   a content of a compound (XIII) in the efinaconazole is no more than 0.01% as a HPLC area percentage detected with UV light at a wavelength of 262 nm, and   where the compound (IV), the compound (V), the compound (VI), the compound (VII), the compound (VIII), the compound (IX), the compound (X), the compound (XI), the compound (XII), and the compound (XIII) are represented by respective formulae below:   
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         29 . Efinaconazole having purity of 99.99% or more as a HPLC area percentage detected with UV light at a wavelength of 262 nm, wherein efinaconazole is obtained by the method according to  claim 5 .