Method for producing difluoro-acetyl-acetic acid alkylesters
View Patent ↗The present invention relates to a three-step method for the preparation of alkyl esters of 4,4-difluoroacetoacetic acid in which in the first step alkyl esters of 4-chloro-4,4-difluoroacetic acid are reacted with trialkylphosphites of formula (III) P(OR 1 ) 3 (III) in which R 1 stands for C 1 -C 4 -alkyl, whereby the residues R 1 can in each case be the same or different, to form alkyl phosphonates of formula (IV) which in the next step are reacted with an amine of formula (V), in which R 2 and R 3 independent of each other stand for hydrogen or C 1 -C 4 -alkyl or together form —CH 2 —CH 2 —O—CH 2 —CH 2 —, to form enamines of formula (VI), in which R 2 and R 3 have the meanings described above, which in the third step are hydrolyzed in the presence of an acid.
1. 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(OR 1 ) 3 (III)
in which each R 1 independently of the others represents C 1 -C 4 -alkyl, to give a alkylphosphonate of formula (IV)
in which R and R 1 have the meanings described above,
(b) in a second step, reacting the alkylphosphonate of formula (IV) with an amine of formula (V)
in which
R 2 and R 3 independently of each other represent hydrogen or C 1 -C 8 -alkyl, or R 2 and R 3 together represent —CH 2 —CH 2 —O—CH 2 —CH 2 —, —CH 2 —CH 2 —S—CH 2 —CH 2 —, or —CH 2 —CH 2 —N(R 4 )—CH 2 —CH 2 —, and
R 4 stands for hydrogen or C 1 -C 8 -alkyl,
optionally in the presence of a diluent,
to give an enamine of formula (VI)
in which R, R 2 , and R 3 have the meanings described above, and
(c) in a third step, condensing the enamine of formula (VI) in the presence of an acid.
2. A method according to claim 1 , in which the alkyl 4-chloro-4,4-difluoroacetoacetate of formula (II) used in the first step is prepared by reacting an alkyl chlorodifluoroacetate of formula (VII)
in which R represents alkyl, with an alkyl acetate of formula (VIII)
in which R represents alkyl, in the presence of a base and in the presence of a diluent.
3. A method according to claim 1 , in which, for compounds of formula (II), R represents C 1 -C 8 -alkyl.
4. A method according to claim 1 , in which, for compounds of formula (II), R represents C 1 -C 6 -alkyl.
5. A method according to claim 1 , in which
for compounds of formula (II), R represents methyl, ethyl, n- or iso-propyl, or n-, iso-, sec-, or tert-butyl,
for compounds of formula (III), each R 1 independently of the others represents methyl, ethyl, n- or iso-propyl, or n-, iso-, sec-, or tert-butyl, and
for compounds of formula (V), R 2 and R 3 independently of each other represent hydrogen, methyl, ethyl, n- or iso-propyl, or n-, iso-, sec-, or tert-butyl, or R 2 and R 3 together represent —CH 2 —CH 2 —O—CH 2 —CH 2 —.
6. A method according to claim 1 , in which the first step is carried out without diluent.
7. A method according to claim 1 , in which the hydrolysis in the third step is carried out in the presence of sulphuric acid, phosphoric acid, or hydrochloric acid, each of which is acids optionally diluted with water.
8. An alkyl phosphonate of formula (IV)
in which
R represents alkyl, and
each R 1 independently represents C 1 -C 4 -alkyl.
9. An enamine of formula (VI)
in which
R represents alkyl,
R 2 and R 3 independently of each other represent hydrogen or C 1 -C 8 -alkyl, or R 2 and R 3 together represent —CH 2 —CH 2 —O—CH 2 —CH 2 —, —CH 2 —CH 2 —S—CH 2 —CH 2 —, or —CH 2 —CH 2 —N(R 4 )—CH 2 —CH 2 —, and
R 4 stands for hydrogen or C 1 -C 8 -alkyl.