Process for the preparation of 2-trifluoromethyl-5-(1-substituted)alkylpyridines

摘要

2-Trifluoromethyl-5-(1-substituted)alkylpyridines of formula (I);whereinR1 and R2 independently represent H, C1-C4 alkyl, or either of R1 or R2 taken together with R3 represent a 4- to 6-membered saturated ring, or R1 taken together with R2 represents a 3- to 6-membered saturated ring optionally substituted with an O or a N atom,R3 represents C1-C4 alkyl or R3 taken together with either of R1 or R2 represent a 4- to 6-membered saturated ring, andX represents CH2, O or S,

are produced efficiently and in high yield from an 4-alkoxy-1,1,1-trifluorobut-3-en-2-one (II)
;whereinR represents a C1-C4 alkyl by condensation with an enamine (III);wherein
R1, R2, R3 and X are as previously defined, andR4 and R5 independently represent C1-C8 alkyl, C2-C8 alkenyl, C1-C8 arylalkyl, C1-C8 haloalkyl, C1-C8 alkoxyalkyl, C1-C8 alkylaminoalkyl, aryl or heteroaryl or R4 and R5 taken together with N represent a 5- or 6-membered saturated or unsaturated ring,

to provide an intermediate of the formula (IV)
;wherein
R1, R2, R3, R4, R5 and X are as previously defined followed by cyclization in the presence of ammonia or a reagent capable of generating ammonia. Both reactions are performed in the same nonpolar solvent without isolation and purification of intermediates.

主权项

1. A process for the preparation of a 2-trifluoromethyl-5-(1-substituted)-alkylpyridine (I), wherein R1 and R2 independently represent H, C1-C4 alkyl, or either of R1 or R2 taken together with R3 represent a 4- to 6-membered saturated ring, or R1 taken together with R2 represents a 3- to 6-membered saturated ring optionally substituted with an O or a N atom, R3 represents C1-C4 alkyl or R3 taken together with either of R1 or R2 represent a 4- to 6-membered saturated ring, and X represents CH2, O or S,in which:
i) an 4-alkoxy-1,1,1-trifluorobut-3-en-2-one of the formula (II) in which R represents a C1-C4 alkylis condensed with an enamine (III) wherein
R1, R2, R3 and X are as previously defined, andR4 and R5 independently represent C1-C8 alkyl, C2-C8 alkenyl, C1-C8 arylalkyl, C1-C8 haloalkyl, C1-C8 alkoxyalkyl, C1-C8 alkylaminoalkyl, aryl or heteroaryl or R4 and R5 taken together with N represent a 5- or 6-membered saturated or unsaturated ring,to provide an intermediate of the formula (IV) wherein
R1, R2, R3, R4, R5 and X are as previously defined, and ii) the intermediate of the formula (IV) is cyclized in the presence of ammonia or a reagent capable of generating ammonia,the improvement comprising conducting both steps in a nonpolar solvent without isolation or purification of the condensation intermediate IV.