Patent ID: 7276611

Claim:
A process for the preparation of bicyclic heteroaryl carboxaldehydes of Formula I wherein: Y is (CH 2 ) n ; n is 1 or 2; X is CH 2 ; which process comprises the steps of: a. nitrosating an amino acid 1 of the formula wherein X and Y are defined as above with a nitrosating reagent to form a nitroso compound of formula 2 wherein X and Y are defined as above b. reacting the nitroso compound 2 with a dehydrating agent and neutralizing with an inorganic base to form the ylide of formula 3 wherein X and Y are defined as above c. reacting the ylide of formula 3 with a propiolate ester of formula 4 HC≡CCO 2 R 1 4 where R 1 is alkyl of 1 to 6 carbon atoms, in aprotic solvents to form a mixture of bicyclic-heteroaryl-3-carboxylate ester of formula 5 and bicyclic-heteroaryl-2-carboxylate ester of formula 6 wherein R 1 , X and Y are defined as above d. reacting the mixture of bicyclic-heteroaryl-3-carboxylate ester 5 and bicyclic-heteroaryl-2-carboxylate ester 6 with a hydrolyzing reagent MOR 5 where M is an alkali metal or R 4 N where R 4 is straight or branched alkyl of 1 to 6 carbon atoms when R 5 is H, in an alcohol solvent, or when M is an alkali metal and R 5 is alkyl of 1 to 6 carbon atoms in an aqueous alcohol solvent to preferentially form a salt 7 of the formula wherein X, Y and M are defined as above e. isolating the salt 7; f. reacting the salt 7 with acid to form bicyclic-heteroaryl-2-carboxylic acid 8 of formula wherein X and Y are defined as above g. reacting the bicyclic-heteroaryl-2-carboxylic acid 8 or salts thereof with an acid halide reagent or coupling reagent to form an activated intermediate of formula 9 where Q is a leaving group formed from the coupling reagent or acid halide reagent wherein X and Y are defined as above h. reacting an activated intermediate of formula 9 or the bicyclic-heteroaryl carboxylic acid 8 with a substituted hydroxylamine of the formula R 3 NHOR 2 10 where R 2 and R 3 are independently alkyl of 1 to 6 carbon atoms in the presence of an organic base or inorganic base to provide an amide of formula 11 wherein X, Y, R 2 and R 3 are defined as above i. reducing the amide of formula 11 with a reducing agent to provide a bicyclic heteroaryl carboxaldehyde of Formula I wherein X and Y are defined as above and isolating the heteroaryl carboxaldehyde of Formula I.