Process for the preparation of 2-trifluoromethyl-5-(1-substituted)alkylpyridines
View Patent ↗2-Trifluoromethyl-5-(1-substituted)alkylpyridines of formula (I) wherein R 1 and R 2 independently represent H, C 1 -C 4 alkyl, or either of R 1 or R 2 taken together with R 3 represent a 4- to 6-membered saturated ring, or R 1 taken together with R 2 represents a 3- to 6-membered saturated ring optionally substituted with an O or a N atom, R 3 represents C 1 -C 4 alkyl or R 3 taken together with either of R 1 or R 2 represent a 4- to 6-membered saturated ring, and X represents CH 2 , O or S, are produced efficiently and in high yield from an 4-alkoxy-1,1,1-trifluorobut-3-en-2-one (II) wherein R represents a C 1 -C 4 alkyl by condensation with an enamine (III) wherein R 1 , R 2 , R 3 and X are as previously defined, and R 4 and R 5 independently represent C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 1 -C 8 arylalkyl, C 1 -C 8 haloalkyl, C 1 -C 8 alkoxyalkyl, C 1 -C 8 alkylaminoalkyl, aryl or heteroaryl or R 4 and R 5 taken together with N represent a 5- or 6-membered saturated or unsaturated ring, to provide an intermediate of the formula (IV) wherein R 1 , R 2 , R 3 , R 4 , R 5 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.
1. A process for the preparation of a 2-trifluoromethyl-5-(1-substituted)-alkylpyridine (I),
wherein
R 1 and R 2 independently represent H, C 1 -C 4 alkyl, or either of R 1 or R 2 taken together with R 3 represent a 4- to 6-membered saturated ring, or R 1 taken together with R 2 represents a 3- to 6-membered saturated ring optionally substituted with an O or a N atom,
R 3 represents C 1 -C 4 alkyl or R 3 taken together with either of R 1 or R 2 represent a 4- to 6-membered saturated ring, and
X represents CH 2 , 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 C 1 -C 4 alkyl
is condensed with an enamine (III)
wherein
R 1 , R 2 , R 3 and X are as previously defined, and
R 4 and R 5 independently represent C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 1 -C 8 arylalkyl, C 1 -C 8 haloalkyl, C 1 -C 8 alkoxyalkyl, C 1 -C 8 alkylaminoalkyl, aryl or heteroaryl or R 4 and R 5 taken together with N represent a 5- or 6-membered saturated or unsaturated ring,
to provide an intermediate of the formula (IV)
wherein
R 1 , R 2 , R 3 , R 4 , R 5 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.
2. A process according to claim 1 wherein R 1 and R 2 independently represent H or methyl, R 3 represents methyl and X represents S.
3. A process according to claim 1 wherein the molecule of formula (II) is condensed with an enamine (III) at a temperature from about −20° C. to about 35° C.
4. A process according to claim 1 wherein the molecule of formula (II) is condensed with an enamine (III) at a temperature from about −5° C. to about 20° C.
5. A process according to claim 1 wherein said non-polar solvent is toluene.
6. A process according to claim 2 , 3 , or 4 , wherein said non-polar solvent is toluene.