Synthesis of piperidine and piperazine compounds as CCR5 antagonists

Abstract

In its several embodiments, this invention discloses novel processes to prepare the compounds of formula II and formula IV:

1 . A process for preparing a piperidine of formula (I):  
       
         
           
           
               
               
           
         
       
       said process comprising: 
 (a) reacting a compound of formula V:  
                     
 with a base to liberate the free base of the formula VI:  
                     
 (b) reacting the compound of formula VI with the compound of formula VIII:  
                     
 and a cyanating compound, to prepare the compound of formula VIII:  
                     
 and  
 (c) reacting the compound of formula VIII with a methyl-metal and an organometallic reagent to yield the compound of formula I.  
 
     
     
         2 . The process of  claim 1 , wherein said base in step (a) is selected from the group consisting of (i) a metal hydroxide, oxide, carbonate and a bicarbonate, wherein the metal is selected from the group consisting of lithium, sodium, potassium, rubidium, cesium, beryllium, magnesium, calcium, strontium, barium, aluminum, indium, thallium, titanium, zirconium, cobalt, copper, silver, zinc, cadmium, mercury and cerium; or (ii) a metal salt of a C 1 -C 12  alkanol, a C 3 -C 12  cycloalkanol, a (C 3 -C 8  cycloalkyl)C 1 -C 6  alkanol; ammonia; a C 1 -C 12  alkylamine; a di(C 1 -C 12  alkyl)amine; a C 3 -C 8  cycloalkylamine; a N-(C 3 -C 8  cycloalkyl)-N-(C 1 -C 12  alkyl)amine; a di(C 3 -C 8  cycloalkyl)amine; a (C 3 -C 8  cycloalkyl)C 1 -C 6  alkylamine; a N-(C 3 -C 8 -cycloalkyl)C 1 -C 6 -alkyl-N-(C 1 -C 12  alkyl)amine; a N-(C 3 -C 8  cycloalkyl)C 1 -C 6  alkyl-N-(C 3 -C 8  cycloalkyl)amine; a di[(C 1 -C 6  cycloalkyl)C 1 -C 6  alkyl]amine; and a heterocyclic amine selected from the group consisting of imidazole, triazole, pyrrolidine, piperidine, heptamethyleneimine, morpholine, thiomorpholine and a 1-(C 1 -C 4  alkyl)piperazine, and mixtures thereof.  
     
     
         3 . The process of  claim 2 , wherein said base is K 2 CO 3 .  
     
     
         4 . The process of  claim 1 , wherein said cyanating compound in step (b) is selected from the group consisting of HCN; acetone cyanohydrin; cyclohexanone cyanohydrin; a mixture of (C 2 H 5 ) 2 AlCN and Ti(OPr) 4 , a mixture of acetic acid, H 2 SO 4 ; NaHSO 4 , KHSO 3  or Na 2 S 2 O 5  with NaCN or KCN; NaCN and acid; KCN and acid; trimethylsilylcyanide; glycolonitrile; mandelonitrile; glycinonitrile; acetone amino nitrile; dimethylaminoacetonitrile; and mixtures thereof.  
     
     
         5 . The process of  claim 4 , wherein said cyanating compound is acetone cyanohydrin.  
     
     
         6 . The process of  claim 1 , wherein said cyanating compound is used in about 0.9 to about 3 molar equivalents.  
     
     
         7 . The process of  claim 1 , wherein step (b) contains a solvent, said solvent being an ester, nitrile, ether, hydrocarbon or mixtures thereof.  
     
     
         8 . The process of  claim 7 , wherein said solvent is ethyl acetate.  
     
     
         9 . The process of  claim 1 , wherein said organometallic reagent in step (c) is selected from the group consisting of trimethylaluminum, triethylaluminum, triethylborane, methyl zinc and tetramethyl tin.  
     
     
         10 . The process of  claim 9 , wherein said trialkylaluminum is trimethylaluminum.  
     
     
         11 . The process of  claim 10 , wherein said trimethylaluminum is used in about 0.9 to about 6 molar equivalents with respect to the compound of formula VI.  
     
     
         12 . The process of  claim 1 , wherein said methyl-metal in step (c) is selected from the group consisting of methyl magnesium chloride, methyl magnesium bromide, methyl magnesium iodide and methyl lithium.  
     
     
         13 . The process of  claim 12 , wherein said methyl-metal is methyl magnesium chloride.  
     
     
         14 . The process of  claim 1 , wherein said step (c) is performed in a solvent, said solvent being an ether, hydrocarbon or mixtures thereof.  
     
     
         15 . The process of  claim 1 , wherein said compound of formula I is further reacted with an acid to form an acid salt of the-formula II:  
       
         
           
           
               
               
           
         
       
     
     
         16 . The process of  claim 1 , wherein in step (c), said organometallic reagent and said compound of formula VIII are combined first and then said methyl-metal is added to the combination.  
     
     
         17 . The process of  claim 1 , wherein in step (c), a portion of said organometallic reagent and said compound of formula VIII are combined to form a first mixture, said methyl-metal and remaining portion of said organometallic reagent are combined to form a second mixture, and said first mixture and said second mixture are then combined.  
     
     
         18 . The process of  claim 1 , wherein said compound of formula VII is prepared by a process comprising: 
 (a) reacting 2,4-dimethylnicotinic acid with oxalyl chloride to form the acid chloride:                          (b) reacting the acid chloride of step (a) with 4-piperidone hydrochloride monohydrate to form the compound of formula XIV:                          and    (c) oxidizing the compound of formula XIV with an oxidant to form the compound of formula VII.    
     
     
         19 . The process of  claim 18 , wherein said oxidant in step (c) is selected from the group consisting of m-chloroperbenzoic acid; phthalic anhydride/urea-H 2 O 2 ; KMnO4; oxone; ozone; inorganic peracid; peracetic acid; Na 2 WO 4 ; a mixture of benzonitrile, H 2 O 2  and methanol; and a mixture of trifluoroacetic acid, H 2 O 2  and H 2 SO 4 .  
     
     
         20 . The process of  claim 19 , wherein said oxidant is oxone.  
     
     
         21 . The process of  claim 20 , wherein said oxidation in step (c) is performed in a solvent.  
     
     
         22 - 32 . (canceled)  
     
     
         33 . A compound of formula II prepared by the process of  claim 15 .  
     
     
         34 . (canceled)  
     
     
         35 . A compound of the formula:  
       
         
           
           
               
               
           
         
       
     
     
         36 . A compound of the formula:  
       
         
           
           
               
               
           
         
       
     
     
         37 . A compound of the formula:  
       
         
           
           
               
               
           
         
       
     
     
         38 . (canceled)  
     
     
         39 . A compound of the formula:  
       
         
           
           
               
               
           
         
       
     
     
         40 . A compound of the formula:  
       
         
           
           
               
               
           
         
       
     
     
         41 . A compound of the formula:  
       
         
           
           
               
               
           
         
       
     
     
         42 . A pharmaceutical composition comprising the compound of formula II of  claim 33 .  
     
     
         43 . (canceled)  
     
     
         44 - 45 . (canceled)