Patent ID: 6414156
Filing Date: 2002-07-02
Classification: A61K,A61P,C07D

Abstract:
A process for the preparation of a compound having the formula I or a pharmaceutically acceptable salt thereof, wherein:R is alkyl, aryl or heteroaryl; R1, R2, R3, R4 and R5 are each independently hydrogen, alkyl, aryl or heteroaryl; R6 and R7 are each independently hydrogen, alkyl, aryl, heteroaryl, halogen, hydroxy or alkoxy; R8 is hydrogen, alkyl, aryl, heteroaryl, CONR9R10, COR11 or COOR12; R9, R10, R11 and R12 are each independently hydrogen, alkyl or aryl; m equals 0 to 5; and n equals 0 to 5; which comprises the steps of:(a) reacting an &agr;-substituted ketone having the formula II wherein:R and R1 are as described hereinabove; and L is halogen or sulfonate; with a cyclic alkylenetetramine in a suitable solvent or solvent mixture to form a quaternary ammonium salt;(b) reacting the quaternary ammonium salt with an acid in a suitable solvent or solvent mixture to form an &agr;-amino ketone; (c) reacting the &agr;-amino ketone with an &agr;-substituted acyl derivative having the formula V wherein:R2, R3 and L are as described hereinabove; and X is hydroxy, halogen or acyloxy; in the presence of a base in a suitable solvent or solvent mixture to form an amide; or, alternatively, reacting the &agr;-amino ketone with an &agr;-substituted acid in the presence of a coupling reagent to form the corresponding amide;(d) reacting the amide with a dehydrating reagent in a suitable solvent or solvent mixture to give a 2-oxazolylalkyl derivative; (e) reacting the 2-oxazolylalkyl derivative with a sulfur-containing reagent in a suitable solvent or solvent mixture to give a 2-oxazolylalkyl sulfide compound; (f) reacting the 2-oxazolylalkyl sulfide with a 5-halo-2-aminothiazole compound in the presence of a base in a suitable solvent or solvent mixture to give a 5-(2-oxazolylmethylthio)-2-aminothiazole compound; (g) reacting the 5-(2-oxazolylmethylthio)-2-aminothiazole with an azacycloalkanoic acid derivative having the formula XII wherein:R6, R7 and X are as described hereinabove; P is a nitrogen-protecting group; m equals 0 to 5; and n equals 0 to 5; in the presence of a coupling reagent in a suitable solvent or solvent mixture to form a thiazolyl amide; and (h) reacting the thiazolyl amide with a deprotecting reagent in a suitable solvent or solvent mixture to form the compound of formula I.