Large scale synthesis of 1,2,4- and 1,3,4- oxadiazole carboxylates

Abstract

Disclosed are efficient and scalable processes for preparing 1,2,4- and 1,3,4-oxadiazole carboxylates from readily available starting materials.

1 . A method for preparing a 1,3,4-oxadiazole carboxylate comprising: 
 A) reacting the N-protected acylhydrazide with a chloro-oxo-acetic acid ester in the presence of a first base to afford an N-protected diacylhydrazide;    B) cyclizing the N-protected diacylhydrazide in the presence of a phosphorous reagent, a per-halogenated methane and a second base to afford the N-protected 1,3,4-oxadiazole;    C) deprotecting the N-protected 1,3,4-oxadiazole to form the product.    
     
     
         2 . A method according to  claim 1 , wherein the 1,3,4-oxadiazole is  
       
         
           
           
               
               
           
         
       
       wherein 
 z is 1 to 6;  
 each R 4  is independently selected from hydrogen, a suitably protected amino acid residue, or heterocycloalkyl optionally substituted with C 1 -C 6  alkyl, or 
 C 1 -C 6  alkyl optionally substituted with one or two groups independently selected from thioalkyl, hydroxy, C 1 -C 6  alkoxy, carboxamido, mono or di(C 1 -C 6  alkyl)carboxamido, heterocycloalkyl, amidinyl, mono or di(C 1 -C 6 )amino, protected amino, protected carboxyl, and phenyl, optionally substituted with one or two groups independently selected from C 1 -C 6  alkoxy and C 1 -C 6  alkyl;  
 
 R 5  is C 1 -C 6  alkyl or arylalkyl, where each aryl is optionally substituted with one, two or three groups independently selected from C 1 -C 6  alkyl, C 1 -C 6  alkoxy, halogen, nitro, trifluoromethyl, and trifluoromethoxy; and  
 R 6  is a suitable amino acid protecting group.  
 
     
     
         3 . A method according to  claim 1  wherein the tertiary-butoxycarbonyl protected-amino acid is selected from N-tertiary-butoxycarbonyl glycine, N-tertiary-butoxycarbonyl alanine, N-tertiary-butoxycarbonyl valine, N-tertiary-butoxycarbonyl leucine, N-tertiary-butoxycarbonyl methionine, N-tertiary-butoxycarbonyl isoleucine, N-tertiary-butoxycarbonyl serine, N-tertiary-butoxycarbonyl threonine, N-tertiary-butoxycarbonyl cysteine, N-tertiary-butoxycarbonyl proline, N-tertiary-butoxycarbonyl asparagine, N-tertiary-butoxycarbonyl glutamine, N-tertiary-butoxycarbonyl phenylalanine, N-tertiary-butoxycarbonyl tyrosine, N-tertiary-butoxycarbonyl tryptophan, N-tertiary-butoxycarbonyl lysine, N-tertiary-butoxycarbonyl arginine, N-tertiary-butoxycarbonyl histidine, N-tertiary-butoxycarbonyl aspartine, and N-tertiary-butoxycarbonyl glutamine, 
 wherein if the protected-amino acid has further reactive sidechains, such sidechains are protected with a suitable protecting group.    
     
     
         4 . A method according to  claim 1  wherein the first base is selected from sodium bicarbonate, sodium carbonate, potassium carbonate, calcium carbonate, barium carbonate, cesium carbonate, and strontium carbonate.  
     
     
         5 . A method according to  claim 4  wherein the first base is sodium bicarbonate.  
     
     
         6 . A method according to  claim 1  wherein R5 is a C 1 -C 4  alkyl group.  
     
     
         7 . A method according to  claim 6  wherein the C 1 -C 6  alkyl group is ethyl.  
     
     
         8 . A method according to  claim 1  wherein the N-protected acylhydrazide is treated with a chloro-oxo-acetic acid ester in the presence of at least one solvent.  
     
     
         9 . A method according to  claim 8  wherein the solvent is aprotic.  
     
     
         10 . A method according to  claim 9  wherein the solvent is tetrahydrofuran.  
     
     
         11 . A method according to  claim 1  wherein the diacylhydrazide is formed at temperatures between −10° C. and 40° C.  
     
     
         12 . A method according to  claim 1  wherein the cyclization of the N-protected diacylhydrazide is performed in the presence of at least one solvent.  
     
     
         13 . A method according to  claim 12  wherein the solvent is a halogenated hydrocarbon.  
     
     
         14 . A method according to  claim 13  wherein the solvent is dichloromethane.  
     
     
         15 . A method according to  claim 1  wherein the second base is selected from triethylamine, diisopropylethylamine, pyridine, and lutidine.  
     
     
         16 . A method according to  claim 15  wherein the second base is triethylamine.  
     
     
         17 . A method according to  claim 1  wherein the dehydrating agent is a phosphorous reagent combined with a perhalogenated methane.  
     
     
         18 . A method according to  claim 17  wherein the phosphorous reagent is triphenylphosphine and the perhalogenated methane is carbon tetrachloride.  
     
     
         19 . A method according to  claim 1  wherein the dehydration is performed at temperature of about 15° C. to about 90° C.  
     
     
         20 . A method according to  claim 1  wherein the N-protected 1,3,4-oxadiazole is deprotected using a protic reagent.  
     
     
         21 . A method according to  claim 20  wherein the protic reagent is hydrogen chloride gas.  
     
     
         22 . A method according to  claim 20  wherein the protic reagent is hydrogen chloride gas dissolved in 1,4-dioxane.  
     
     
         23 . A method according to  claim 1  wherein the N-protected 1,3,4-oxadiazole is deprotected in the presence of at least one solvent.  
     
     
         24 . A method according to  claim 23  wherein the solvent is aprotic.  
     
     
         25 . A method according to  claim 24  wherein the solvent is ethyl acetate.  
     
     
         26 . A method according to  claim 25  wherein the deprotection is performed at temperature of about −10° C. to about 15° C.  
     
     
         27 . A method according to  claim 20  wherein the deprotection is performed without the addition of any additional solvent.  
     
     
         28 . A method according to  claim 27  wherein the deprotection is performed at temperature of about −10° C. to about 30° C.  
     
     
         29 . A method for preparing compounds of the formula:  
       
         
           
           
               
               
           
         
       
       wherein 
 z is 1 to 6;  
 each R 4  is independently selected from hydrogen, a suitably protected amino acid residue, or heterocycloalkyl optionally substituted with C 1 -C 6  alkyl, or 
 C 1 -C 6  alkyl optionally substituted with one or two groups independently selected from thioalkyl, hydroxy, C 1 -C 6  alkoxy, carboxamido, mono or di(C 1 -C 6  alkyl)carboxamido, heterocycloalkyl, amidinyl, mono or di(C 1 -C 6 )amino, protected amino, protected carboxyl, and 
 phenyl, optionally substituted with one or two groups independently selected from C 1 -C 6  alkoxy and C 1 -C 6  alkyl;  
 
 
 R 5  is C 1 -C 6  alkyl or arylalkyl, where each aryl is optionally substituted with one, two or three groups independenly selected from C 1 -C 6  alkyl, C 1 -C 6  alkoxy, halogen, nitro, trifluoromethyl, and trifluoromethoxy; and 
 R 6  is a suitable amino acid protecting group; the method comprising  
 A) reacting an intermediate of the structure  
                     
 wherein z, R 4  and R 6  are defined above, with  
                     
 in the presence of a first base and isolating a diacylhydrazide intermediate of the formula:  
                     
 wherein z, R 4 , R 5 , and R 6  are defined above;  
 B) cyclizing the diacylhydrazide intermediate in the presence of a phosphorous reagent, a per-halogenated methane and a second base to afford an intermediate of the formula:  
                     
 wherein z, R 4 , R 5 , and R 6  are defined above;  
 C) deprotecting the cyclized intermediate to form a compound of the formula:  
                     
 
 
     
     
         30 . A method according to  claim 29  wherein the phosphorous reagent is triphenylphosphine and the perhalogenated methane is carbon tetrachloride.  
     
     
         31 . A method according to  claim 29  wherein R 6  is tertiary-butoxy carbonyl.  
     
     
         32 . A method according to  claim 29  wherein R 5  is C 1 -C 6  alkyl.