Manufacture of 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4h-1,2,4-triazol-3-ylthio)acetic acid

Abstract

Described herein are certain processes for the synthesis of compounds of Formula (I):

1 .- 9 . (canceled) 
     
     
         10 . A process for preparing Compound 3 or Compound 3-A 
       
         
           
           
               
               
           
         
         comprising contacting a compound of Formula (II): 
       
       
         
           
           
               
               
           
         
         
           wherein R is methyl or ethyl; 
         
         with N-bromosuccinimide (NBS) and a solvent. 
       
     
     
         11 . A process for preparing Compound 4 comprising:
 (4-i) preparing a compound of formula (III):   
       
         
           
           
               
               
           
         
         comprising contacting a compound of Formula (II): 
       
       
         
           
           
               
               
           
         
         
           wherein R is —C 1 -C 20  alkyl, —C 1 -C 20  alkenyl, —C 3 -C 10  cycloalkyl, or —C 3 -C 10  cycloalkenyl; 
         
         with N-bromosuccinimide (NBS) and a solvent; 
         (4-ii) stirring the compound of Formula (II), the NB S and the solvent for at least 12 hours; and at a temperature of between about room temperature and about 32° C.; 
         (4-iii) contacting the compound of Formula (III) with a sodium hydroxide solution to provide Compound 4: 
       
       
         
           
           
               
               
           
         
       
     
     
         12 . A process for preparing Compound 1 comprising:
 (1-i) preparing a compound of formula (III):   
       
         
           
           
               
               
           
         
         comprising contacting a compound of Formula (II): 
       
       
         
           
           
               
               
           
         
         wherein R is —C 1 -C 20  alkyl, —C 1 -C 20  alkenyl, —C 3 -C 10  cycloalkyl, or —C 3 -C 10  cycloalkenyl; with N-bromosuccinimide (NBS) and a solvent; 
         (1-ii) stirring the compound of Formula (II), the NBS and the solvent for at least 12 hours; and at a temperature of between about room temperature and about 32° C.; 
         (1-iii) contacting the compound of Formula (III) with a sodium hydroxide solution to provide Compound 4: 
       
       
         
           
           
               
               
           
         
         (1-iv) crystallizing Compound 4 from the aqueous sodium hydroxide solution; 
         (1-v) contacting Compound 4 with an acid to provide Compound 1: 
       
       
         
           
           
               
               
           
         
       
     
     
         13 . Compound 1 of  claim 12 , which is a crystalline polymorph characterized by peaks at 10.46, 18.76, and 19.83°2θ±0.1°2θ. 
     
     
         14 . Compound 1 of  claim 12 , which is the crystalline polymorph form 2. 
     
     
         15 . A reaction mixture comprising a compound of Formula (II): 
       
         
           
           
               
               
           
         
         wherein R is —C 1 -C 20  alkyl, —C 1 -C 20  alkenyl, —C 3 -C 10  cycloalkyl, or —C 3 -C 10  cycloalkenyl; 
         a brominating agent; and 
         a solvent. 
       
     
     
         16 . The reaction mixture of  claim 15 , wherein the brominating agent is N-bromosuccinimide (NBS). 
     
     
         17 . A reaction mixture comprising a compound of formula (III) 
       
         
           
           
               
               
           
         
         wherein R is —C 1 -C 20  alkyl, —C 1 -C 20  alkenyl, —C 3 -C 10  cycloalkyl, or —C 3 -C 10  cycloalkenyl; 
         a base; and 
         a solvent. 
       
     
     
         18 . The reaction mixture of  claim 17 , wherein the base is sodium hydroxide. 
     
     
         19 . A reaction mixture comprising Compound 4: 
       
         
           
           
               
               
           
         
         an acid; and 
         a solvent. 
       
     
     
         20 . The reaction mixture of  claim 19 , wherein the acid is hydrobromic acid. 
     
     
         21 . A process for preparing a compound of Formula (II) comprising contacting compound 5: 
       
         
           
           
               
               
           
         
         with:
 a base; 
 a solvent; and 
 a compound of Formula (IV): 
 
       
       
         
           
           
               
               
           
         
         
           
             wherein X is halo, tosylate, mesylate, triflate, or besylate; and
 R is —C 1 -C 20  alkyl, —C 1 -C 20  alkenyl, —C 3 -C 10  cycloalkyl, or —C 3 -C 10  cycloalkenyl. 
 
           
         
       
     
     
         22 . The process of  claim 21 , wherein the compound of Formula (IV) is selected from methyl bromoacetate, ethyl bromoacetate, methyl chloroacetate, and ethyl chloroacetate. 
     
     
         23 . The process of  claim 21 , wherein a crude reaction product comprising a compound of Formula (II) is washed with a cooled mixture of ethyl acetate and isopropanol. 
     
     
         24 . Compound 2 or Compound 2-A: 
       
         
           
           
               
               
           
         
       
     
     
         25 . Compound 2 or Compound 2-A, which are represented by the structures: 
       
         
           
           
               
               
           
         
         and are obtained by the process of  claim 21 . 
       
     
     
         26 . A reaction mixture comprising Compound 5: 
       
         
           
           
               
               
           
         
         a compound of Formula (IV): 
       
       
         
           
           
               
               
           
         
         
           wherein:
 X is a leaving group; and 
 R is —C 1 -C 20  alkyl, —C 1 -C 20  alkenyl, —C 3 -C 10  cycloalkyl or —C 3 -C 10  cycloalkenyl; 
 
         
         a base; and 
         a solvent. 
       
     
     
         27 . The reaction mixture of  claim 26 , wherein the compound of Formula (IV) is methyl bromoacetate, ethyl bromoacetate, methyl chloroacetate, or ethyl chloroacetate. 
     
     
         28 . The process of  claim 21 , wherein Compound 5 is prepared by a process comprising:
 (5-i) contacting Compound 6:   
       
         
           
           
               
               
           
         
         
           with nitric acid, water and a solvent to provide compound 7: 
         
       
       
         
           
           
               
               
           
         
         (5-ii) contacting Compound 7 with hydrogen, palladium on charcoal, and one or more solvents to provide Compound 8: 
       
       
         
           
           
               
               
           
         
         (5-iii) contacting Compound 8 with an acid to provide a salt of Compound 8; 
         (5-iv) contacting the salt of Compound 8 of step (5-iii) with a base, thiophosgene and a solvent to provide Compound 9: 
       
       
         
           
           
               
               
           
         
         (5-v) contacting Compound 9 with formyl hydrazine and a solvent to provide Compound 10: 
       
       
         
           
           
               
               
           
         
       
       and
 (5-vi) contacting Compound 10 with a base, water and a solvent to provide Compound 5: