Novel process for the preparation of roflumilast

Abstract

The invention relates to novel processes for the preparation of high-purity roflumilast.

1 - 21 . (canceled) 
   
   
       22 . Roflumilast prepared by reacting an anion of 4-amino-3,5-dichloropyridine (1) 
     
       
         
         
             
             
         
       
     
     in which A +  is a potassium cation, with an activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2), 
     
       
         
         
             
             
         
       
     
     in which LG is a suitable leaving group selected from a chlorine atom, a bromine atom or a radical of the formula OC(O)-1-4C-alkyl, wherein
 (a) the molar ratio of the employed anion of 4-amino-3,5-dichloropyridine (1) to the activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is at least 1.8 and at most 2.7, 
 (b) the reaction of the anion of 4-amino-3,5-dichloropyridine (1) with the activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is carried out in dimethylformamide, 
 (c) the reaction of the anion of 4-amino-3,5-dichloropyridine (1) with the activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is carried out at a temperature between 0° C. and the boiling point of the solvent used, 
 (d) KOtBu is used to prepare the anion of 4-amino-3,5-dichloropyridine (1), and 
 (e) the roflumilast is recrystallized in a mixture of isopropanol and water, 
 
     wherein the ratio of isopropanol/water is between 85:15 and 100:0% by volume; 
     wherein said roflumilast has a purity level of greater than or equal to 99.8% by weight. 
   
   
       23 . Roflumilast according to  claim 22 , wherein the molar ratio of the employed anion of 4-amino-3,5-dichloropyridine (1) to the activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is at least 2 and at most 2.5. 
   
   
       24 . Roflumilast according to  claim 22 , wherein the molar ratio of the employed anion of 4-amino-3,5-dichloropyridine (1) to the activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is 2.2. 
   
   
       25 . Roflumilast according to  claim 22 , wherein the reaction of the anion of 4-amino-3,5-dichloropyridine (1) with an activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is carried out at a temperature between 15° C. and 40° C. 
   
   
       26 . Roflumilast according to  claim 22 , wherein the reaction of the anion of 4-amino-3,5-dichloropyridine (1) with an activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is carried out at a temperature between 20° C. and 30° C. 
   
   
       27 . Roflumilast according to  claim 22 , wherein the activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is 3-cyclopropylmethoxy-4-difluoromethoxybenzoyl chloride. 
   
   
       28 . Roflumilast according to  claim 22 , wherein the activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is 3-cyclopropylmethoxy-4-difluoromethoxybenzoyl bromide. 
   
   
       29 . Roflumilast according to  claim 22 , wherein the activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is a 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid 1-4C-alkyl-ester. 
   
   
       30 . Roflumilast according to  claim 23 , wherein the reaction of the anion of 4-amino-3,5-dichloropyridine (1) with an activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is carried out at a temperature between 15° C. and 40° C. 
   
   
       31 . Roflumilast according to  claim 23 , wherein the reaction of the anion of 4-amino-3,5-dichloropyridine (1) with an activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is carried out at a temperature between 20° C. and 30° C. 
   
   
       32 . Roflumilast according to  claim 23 , wherein the activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is 3-cyclopropylmethoxy-4-difluoromethoxybenzoyl chloride. 
   
   
       33 . Roflumilast according to  claim 23 , wherein the activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is 3-cyclopropylmethoxy-4-difluoromethoxybenzoyl bromide. 
   
   
       34 . Roflumilast according to  claim 23 , wherein the activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is a 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid 1-4C-alkyl-ester. 
   
   
       35 . Roflumilast according to  claim 24 , wherein the reaction of the anion of 4-amino-3,5-dichloropyridine (1) with an activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is carried out at a temperature between 15° C. and 40° C. 
   
   
       36 . Roflumilast according to  claim 24 , wherein the reaction of the anion of 4-amino-3,5-dichloropyridine (1) with an activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is carried out at a temperature between 20° C. and 30° C. 
   
   
       37 . Roflumilast according to  claim 24 , wherein the activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is 3-cyclopropylmethoxy-4-difluoromethoxybenzoyl chloride. 
   
   
       38 . Roflumilast according to  claim 24 , wherein the activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is 3-cyclopropylmethoxy-4-difluoromethoxybenzoyl bromide. 
   
   
       39 . Roflumilast according to  claim 24 , wherein the activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is a 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid 1-4C-alkyl-ester. 
   
   
       40 . Roflumilast according to  claim 27 , wherein the reaction of the anion of 4-amino-3,5-dichloropyridine (1) with 3-cyclopropyl-methoxy-4-difluoromethoxybenzoyl chloride is carried out at a temperature between 15° C. and 40° C. 
   
   
       41 . Roflumilast according to  claim 32 , wherein the reaction of the anion of 4-amino-3,5-dichloropyridine (1) with 3-cyclopropyl-methoxy-4-difluoromethoxybenzoyl chloride is carried out at a temperature between 15° C. and 40° C. 
   
   
       42 . Roflumilast according to  claim 37 , wherein the reaction of the anion of 4-amino-3,5-dichloropyridine (1) with 3-cyclopropyl-methoxy-4-difluoromethoxybenzoyl chloride is carried out at a temperature between 15° C. and 40° C.