Process for preparing heteroaryl and unsaturated heterocycloalkylmagnesium reagents and uses thereof

Abstract

The present invention is directed to a novel process for preparing heteroaryl and unsaturated heterocycloalkylmagnesium reagents that are useful in the synthesis of a variety of pharmaceuticals, in particular certain cysteine protease inhibitors.

1 .- 7 . (canceled)  
   
   
       8 . A process of preparing a compound of formula (VIIa):  
     
       
         
         
             
             
         
       
     
     wherein: 
 R 30  is isopropylmethyl or cyclopropylmethyl which process comprises:  
 (i) reacting benzoxazole with a Grignard reagent in a suitable solvent to provide a benzoxazolyl Grignard reagent;  
 (ii) reacting benzoxazolyl Grignard reagent obtained in Step (i) above with an aldehyde of formula (IIa):  
                     
 where PG is an amino-protecting group to provide a compound of formula (IIIa):  
                     
 (iii) deprotecting the amino group in (IIIa) to provide a compound of formula (IVa) and optionally converting the free base to an acid addition salt;  
                     
 (iv) reacting (IVa) or its acid addition salt with a compound of formula (Va):  
                     
 where R 30  is cyclopropylmethyl or isopropylmethyl, under coupling reaction conditions to provide a compound of formula (VIa):  
                     
 and;  
 (v) oxidizing (VIa) with a suitable oxidizing agent to provide a compound of formula (VIIa);  
 (vi) optionally converting a compound of formula (VIIa) to an acid addition salt; and  
 (vii) optionally converting a salt form of a compound of formula (VIIa) to a free base.  
 
   
   
       9 . The process of  claim 8  wherein step (i) is carried out at about −10° to about 10° C.  
   
   
       10 . The process of  claim 8  wherein the Grignard reagent in Step (i) is isopropylmagnesium chloride and the reaction is carried out in a mixture of tetrahydrofuran and toluene.  
   
   
       11 . The process of  claim 8  wherein the amino protecting group is tert-butoxycarbonyl, benzyl or benzyloxycarbonyl.  
   
   
       12 . The process of  claim 8  wherein the amino protecting group is tert-butoxycarbonyl and is removed by treating (IIIa) with trimethylsilyl chloride in an ethanolic solvent.  
   
   
       13 . The process of  claim 12  wherein the coupling reaction is carried out with a coupling agent selected from the group consisting of benzotriazole-1-yloxytrispyrrolidino-phosphonium hexafluorophosphate, O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate, O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate, or 1-hydroxybenzotriazole, in the presence of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, or 1,3-dicyclohexylcarbodiimide, and an organic base.  
   
   
       14 . The process of  claim 13  wherein the reaction is carried out with catalytic amount of 1-hydroxybenzotriazole, in the presence of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and triethylamine in dichloromethane.