Method for producing difluoro-acetyl-acetic acid alkylesters

A method of preparing alkyl esters of 4,4-difluoroacetoacetic acid of formula (I)

• in which R represents alkyl,
• comprising
• (a) in a first step, reacting an alkyl ester 4-chloro-4,4-difluoroacetoacetic acid of formula (II)
• in which R represents alkyl,
• with a trialkylphosphite of formula (III)
• P(OR1)3 (III)
• in which each R1 independently of the others represents C1-C4-alkyl, to give a alkylphosphonate of formula (IV)
• in which R and R1 have the meanings described above,
• (b) in a second step, reacting the alkylphosphonate of formula (IV) with an amine of formula (V)
• in which
• R2 and R3 independently of each other represent hydrogen or C1-C8-alkyl, or R2 and R3 together represent —CH2—CH2—O—CH2—CH2—, —CH2—CH2—S—CH2—CH2—, or —CH2—CH2—N(R4)—CH2—CH2—, and
• R4 stands for hydrogen or C1-C8-alkyl,
• optionally in the presence of a diluent, to give an enamine of formula (VI)
• in which R, R2, and R3 have the meanings described above, and
• (c) in a third step, condensing the enamine of formula (VI) in the presence of an acid.

A method of preparing a difluoromethyl-substituted pyrazolylcarboxylic acid comprising

• (a) reacting an alkyl 4,4-difluoroacetoacetate of formula (I)
• in which R represents alkyl,
• with acetic anhydride or a trialkyl orthoformate, to form a corresponding alkyl 2-(difluoracetyl)-3-alkoxy acrylate, and
• (b) cyclizing the alkyl 2-(difluoracetyl)-3-alkoxy acrylate with an alkyl hydrazine to give a 1-alkyl-3-difluoromethyl-pyrazole-4-carboxylic acid.

A method of preparing a difluoromethyl-substituted thiazolylcarboxylic acid comprising

• (a) chlorinating an alkyl 4,4-difluoroacetoacetate of formula (I)
• in which R represents alkyl,
• to form a corresponding alkyl 2,2-dichloro-4,4-difluoro-3-oxobutanoate or alkyl 2-chloro-4,4-difluoro-3-oxobutanoate, and
• (b) reacting the alkyl 2,2-dichloro-4,4-difluoro-3-oxobutanoate or alkyl 2-chloro-4,4-difluoro-3-oxobutanoate with thioalkanamide to give an alkyl 3-alkyl-4-difluoromethylthiazole-5-carboxylate.

An enamine of formula (VI)

• in which
• R represents alkyl,
• R2 and R3 independently of each other represent hydrogen or C1-C8-alkyl, or R2 and R3 together represent —CH2—CH2—O—CH2—CH2—, —CH2—CH2—S—CH2—CH2—, or —CH2—CH2—N(R4)—CH2—CH2—, and
• R4 represents hydrogen or C1-C8-alkyl.