Process for preparing arylacetylaminothiazoles

A process for the preparation of a compound having the formula I

• 14
• or a pharmaceutically acceptable salt thereof, wherein:
• R1, R2, R4, R5, R6, R8, R9, R12 and R13 are each independently hydrogen, alkyl, aryl or heteroaryl;
• R3, R7, R10 and R11 are each independently hydrogen, alkyl, aryl, heteroaryl, halogen, hydroxy or alkoxy;
• and
• X is CH or N;
• which comprises the steps of:
• (a) reacting an alkylarylacetate or alkylarylacetic acid compound having the formula VIII
• 15
• 10 wherein:
• R1, R2, R3, R4, R5 and X are as described hereinabove;
• R is hydrogen, alkyl, aryl or heteroaryl;
• and
• W is halogen or sulfonate;
• with a 5-(2-oxazolylalkylthio)-2-aminothiazole compound having the formula VI
• 16
• 10 wherein:
• R6, R7, R8, R9, R10 and R11 are as described hereinabove;
• in the presence of a coupling reagent and in a suitable solvent or solvent mixture to form an amide;
• and
• (b) reacting the amide with an amine in a suitable solvent or solvent mixture to form the compound of formula I.

A process for the preparation of a compound having the formula I

• 17
• or a pharmaceutically acceptable salt thereof, wherein:
• R1, R2, R4, R5, R6, R8, R9, R12 and R13 are each independently hydrogen, alkyl, aryl or heteroaryl;
• R3, R7, R10 and R11 are each independently hydrogen, alkyl, aryl, heteroaryl, halogen, hydroxy or alkoxy;
• and
• X is CH or N;
• which comprises the steps of:
• (a) reacting an aldehyde having the formula VII
• 18
• 10 wherein:
• R1, R2, R3, R4, R6, R7, R8, R9, R10, R11 and X are as described hereinabove;
• with an organometallic reagent in a suitable solvent or solvent mixture to form an alcohol derivative;
• (b) reacting the alcohol derivative with a halide;
• and
• (c) reacting the halide compound with an excess of a primary amine or a secondary amine in a suitable solvent, or solvent mixture to form the compound of formula I.

A process for the preparation of a formylarylacetate or formylarylacetic acid which comprises the following steps:

• (a) reacting a haloarylacetate or haloarylacetic acid having formula II
• 19
• 10 wherein:
• R is hydrogen, alkyl, aryl or heteroaryl;
• R1 and R2 are each independently hydrogen, alkyl, aryl or heteroaryl;
• R3 is hydrogen, alkyl, aryl, heteroaryl, halogen, hydroxy or alkoxy;
• W is halogen or sulfonate;
• and
• X is CH or N;
• with an olefin having the formula III
• 20
• 10 wherein:
• R4 is hydrogen, alkyl, aryl or heteroaryl;
• Y is CHO, C(O)R, COOR, CONRR1, CN, NO2, SO2OR or SO2NRR1;
• Z is hydrogen, CHO, C(O)R, COOR, CONRR1, CN, NO2, SO2OR or SO2NRR1;
• and
• R and R1 are as described hereinabove;
• in the presence of a palladium catalyst in a suitable solvent or solvent mixture to form a vinyl-substituted arylacetate or vinyl-substituted arylacetic acid;
• and
• (b) reacting the vinyl-substituted arylacetate or vinyl-substituted arylacetic acid with an oxidizing reagent in a suitable solvent or solvent mixture to form the formylarylacetate or formylarylacetic acid compound.