Process for preparing pyridyl-substituted pyrazoles
View Patent ↗The present invention relates to a process for preparing 1-pyridyl-substituted pyrazoles, comprising the reaction of acetyleneketones with pyridylhydrazine derivatives to give 1-pyridyl-substituted dihydro-1H-pyrazoles, the further reaction thereof with elimination of water to give 1-pyridyl-substituted trihalomethylpyrazoles, and the further processing thereof.
1. A process for preparing a pyridyl substituted pyrazole derivative of formula (I)
in which
R 1 is alkoxy, hydroxyl, aryloxy, alkylaryloxy, alkyl, cycloalkyl, or halogen,
R 2 is hydroxyl, alkoxy, arylalkoxy, alkylthio, chlorine, bromine, fluorine, iodine, O—(C═O)alkyl, O—(C═O)O-alkyl, OSO 2 alkyl, OSO 2 Ph, OSO 2 -haloalkyl, or OSO 2 -aryl, and
R 3 is halogen, CN, NO 2 , alkyl, cycloalkyl, haloalkyl, halocycloalkyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, or cycloalkylamino,
comprising
(A) reacting an acetylketone of formula (II)
in which
R 4 is a protecting group selected from the group consisting of (C 1 -C 6 )-alkyl, aryl, benzyl, tetrahydropyran, (C═O)-alkyl, (C═O)-Oalkyl, and Si(alkyl) 3 , and
X is halogen,
with a hydrazinopyridine of formula (III)
in which R 3 is defined as above,
in the presence of a solvent, to give a 1-pyridyl-substituted dihydro-1H-pyrazole of formula (IV)
in which X, R 3 , and R 4 are each as defined above;
(B) optionally without isolating, in the presence of a solvent, reacting the compound of formula (IV) by eliminating water, to give a 1-pyridyl-substituted trihalomethylpyrazole of formula (V)
in which X, R 3 , and R 4 are each as defined above;
(C) reacting the compound of formula (V) under an acidic or basic condition, optionally in the presence of a catalyst, to give a pyrazolecarboxylic acid of formula (VI)
in which R 3 , and R 4 are each as defined above;
(D) removing the protecting group R 4 to give a hydroxymethylpyrazole acid of formula (VII)
in which R 3 is as defined above;
(E) reacting the compound of formula (VII) with a halogenating agent, in the presence of a solvent, to give an acid halide; and
optionally further reacting the halide with an alcohol to give the compound of formula (I).
2. The process for preparing a compound of formula (I) according to claim 1 , wherein
R 1 is (C 1 -C 6 )-alkoxy, or halogen,
R 2 is (C 1 -C 6 )-alkoxy, aryl(C 1 -C 6 )-alkoxy, fluorine, chlorine, bromine, or iodine, and
R 3 is halogen, CN, NO 2 , (C 1 -C 6 )-alkyl, halo(C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkoxy, or halo(C 1 -C 6 )alkoxy.
3. The process for preparing a compound of formula (I) according to claim 1 , comprising
(A) reacting an acetylketone of formula (II)
in which
R 4 is a protecting group selected form the group consisting of (C 1 -C 6 )-alkyl, aryl, benzyl, tetrahydropyran, (C═O)-alkyl(C═O)—Oalkyl, and Si(alkyl) 3 , and
X is halogen,
with a hydrazinopyridine of formula (III)
in which
R 3 is halogen CN, NO 2 , alkyl, cycloalkyl, haloalkyl, halocycloalkyl, alkoxy, haloalkoxy, alkylamino: dialkylamino, or cycloalkylamino
in the presence of a solvent, to give a compound of formula (IV)
in which X, R 3 , and R 4 are each as defined above; and
(B) optionally without isolating, in the presence of a solvent, reacting the compound of formula (IV) by eliminating water, to give a compound of formula (V)
in which X, R 3 , and R 4 are each as defined above.
4. The process for preparing a compound of formula (I) according to claim 3 , further comprising removing the protecting group R 4 from the compound of formula (V)
in which
X is halogen,
R 4 is a protecting group selected from the group consisting of (C 1 -C 6 )-allyl, aryl, benzyl, tetrahydropyran, (C═O)-alkyl, (C═O)—Oalkyl, and Si(alkyl) 3 ,
R 3 is halogen, CN, NO 2 , alkyl, cycloalkyl, haloalkyl, halocycloalkyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, or cycloalkylamino, to give a compound of formula (VIII)
in which X, and R 3 are each as defined above;
reacting the compound of formula (VIII) under an acidic or basic condition, optionally in the presence of a catalyst, to give a compound of formula (VII)
in which R 3 is as defined above;
reacting the compound of formula (VII) with a halogenating agent, in the presence of a solvent to give an acid halide; and
reacting the halide with an alcohol, in the presence of a solvent, to give the compound of formula (I).
5. The process for preparing a compound of the formula (I) according to claim 3 , further comprising reacting the compound of formula (V)
in which
X is halogen,
R 4 is a (C 1 -C 6 )-alkyl, or benzyl,
R 3 is halogen, CN, NO 2 , alkyl, cycloalkyl, haloalkyl, halocycloalkyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, or cycloalkylamino,
with an alcohol to directly give the compound of formula (I).
6. The process according to claim 1 , wherein the halogenating agent is selected from the group consisting of SOCl 2 , POCl 3 , oxalyl chloride, phosgene, diphosgene, POBr 3 , PBr 3 , SF 4 , HCF 2 CF 2 N(Me) 2 , and PI 3 .
7. The process according to claim 4 , wherein the halogenating agent is selected from the group consisting of SOCl 2 , POCl 3 , oxalyl chloride, phosgene, diphosgene, POBr 3 , PBr 3 , SF 4 , HCF 2 CF 2 N(Me) 2 , and PI 3 .