Methods for the preparation of 1,3-benzodioxole heterocyclic compounds

Abstract

The present invention relates to novel methods for the preparation of 1,3-benzodioxole heterocyclic compounds and intermediates for the same. The compounds are useful as PDE4 inhibitors.

1 .- 15 . (canceled) 
     
     
         16 . A method for the preparation of a compound of formula (I) 
       
         
           
           
               
               
           
         
         wherein R 1  is selected from CHF 2  and CF 3 , Q is selected from chloro, bromo and fluoro, comprising the following steps: 
         (2b+3) reacting the compound of formula (VI), 
       
       
         
           
           
               
               
           
         
         with a difluorocarbene source reagent in a polar solvent in the presence of a base to obtain the compound of formula (IX), 
       
       
         
           
           
               
               
           
         
         wherein R 21  is C(O)CH 3 , and wherein R 1  is as defined above; 
         (4) reacting the compound of formula (IX) with a pyridine compound of formula (X) 
       
       
         
           
           
               
               
           
         
         wherein Q is as defined above and Q x  is selected from chloro, bromo, fluoro, and iodo, to form a compound of formula (XI); 
       
       
         
           
           
               
               
           
         
         wherein R 1  and Q are as defined above; and 
         (5) oxidizing the resulting compound of formula (XI) to obtain the compound of formula (I). 
       
     
     
         17 . The method according to  claim 16 , wherein the difluorocarbene source is selected from sodium chlorodifluoroacetate, diethyl bromodifluoromethylphosphonate, chlorodifluoromethyl phenyl sulfone, and 2-chloro-2,2-difluoroacetophenone. 
     
     
         18 . The method according to  claim 17 , wherein the difluorocarbene source is sodium chlorodifluoroacetate. 
     
     
         19 . The method according to  claim 16 , wherein the reaction in step (2b+3) is performed in a solvent selected from NMP (N-methylpyrolidone), DMI (1,3-dimethyl-2-imidazolidinone), DMSO (dimethyl sulfoxide), EtOAc (ethyl acetate), MeCN (acetonitrile), THF (tetrahydrofuran), ethanol, methanol, and water, or mixtures thereof. 
     
     
         20 . The method according to  claim 16 , wherein the reaction in step (2b+3) is performed in a mixture of water and DMF (N,N-dimethylformamide). 
     
     
         21 . The method according to  claim 16 , wherein the base in the reaction in step (2b+3), is selected from K 2 CO 3 , Na 2 CO 3 , KHCO 3 , NaHCO 3 , CsCO 3 , TEA (triethylamine), tert-BuOLi (lithium tert-butoxide), sodium methoxide, sodium ethoxide, DIPEA (N,N-diisopropylethylamine), KOH, NaOH, and LiOH. 
     
     
         22 . The method according to  claim 21 , wherein the base is K 2 CO 3 . 
     
     
         23 . The method according to  claim 16 , wherein the reaction in step (2b+3) is performed in the temperature range of 6-115° C. 
     
     
         24 . The method according to  claim 16 , wherein, in the reaction in step (2b+3) the difluoromethylating reagent is sodium chlorodifluoroacetate, the polar solvent is a mixture of N,N-dimethylformamide and water, and the base is K 2 CO 3 . 
     
     
         25 . The method according to  claim 16 , wherein the reaction in step (4) is conducted in a polar solvent selected from DMF (N,N-dimethylformamide), NMP (N-methylpyrrolidone), DMI (1,3-dimethyl-2-imidazolidinone), DMSO (dimethyl sulfoxide), MeCN (acetonitrile), and THF (tetrahydrofuran), or mixtures thereof, in the presence of a base selected from tert-BuOK (potassium tert-butoxide), tert-BuOLi (lithium tert-butoxide), tert-BuONa (sodium tert-butoxide), sodium or potassium methoxide, sodium or potassium ethoxide, K 2 CO 3 , Na 2 CO 3 , KHCO 3 , NaHCO 3 , Et 3 N (triethylamine) and DIPEA (N,N-diisopropylethylamine). 
     
     
         26 . The method according to  claim 25 , wherein the reaction in step (4) is conducted in DMF and the base is tert-BuOK. 
     
     
         27 . The method according to  claim 25 , wherein the molar ratio of the base to the compound of formula (IX) is from 5:1 to 2:1. 
     
     
         28 . The method according to  claim 16 , wherein the reaction in step (4) is conducted at a temperature of 0-40° C. 
     
     
         29 . The method according to  claim 16 , wherein, in the reaction in step (4), the compound of formula (XI) is crystalised from a solvent selected from dimethylformamide (DMF), ethanol, methanol, ethyl acetate, hexane, and heptane, or a mixture thereof. 
     
     
         30 . The method according to  claim 29 , wherein the solvent is a mixture of ethyl acetate and ethanol. 
     
     
         31 . The method according to  claim 16 , wherein, in the reaction in step (5) the oxidizing agent is selected from PAA (peracetic acid) in AcOH (acetic acid), H 2 O 2  (aq) in formic acid, and H 2 O 2  in acetic acid. 
     
     
         32 . The method according to  claim 31 , wherein the oxidizing agent is PAA in AcOH. 
     
     
         33 . The method according to  claim 16 , wherein R 1  is CHF 2 . 
     
     
         34 . The method according to  claim 16 , wherein each Q and each Q x  are chloro.