JP4727576B2 - Process for preparing alkyl esters of difluoroacetoacetic acid - Google Patents

Description

  The present invention relates to an alkyl ester of 4,4-difluoroacetoacetic acid (4,4-difluoro-3- (3)) from an alkyl ester of 4-chloro-4,4-difluoroacetoacetic acid obtained separately from an alkyl ester of 2-chlorodifluoroacetic acid. Relates to a novel process for the preparation of alkyl esters of oxobutanoic acid).

  It is already known that ethyl 4,4-difluoroacetoacetate can be obtained by reacting ethyl difluoroacetate with ethyl acetate in the presence of sodium hydride (see Tetrahedron 2001, 57, 2689-2700). However, the 25% yield obtained from this reaction is very unsatisfactory. Furthermore, the ethyl acetoacetate obtained as a by-product is difficult to separate from the desired product.

  It is also known that ethyl 4,4-difluoroacetoacetic acid can be obtained by reacting ethyl difluoroacetic acid with ethyl bromoacetate in the presence of zinc (see Tetrahedron 1996, 52, 119-130). However, the yield of this reaction is also far from the desired state.

  Furthermore, a common disadvantage of both processes mentioned above is that the ethyl difluoroacetate used is very expensive and therefore lacks attractiveness as a choice for large-scale industrial production.

  It is also known that chlorodifluoroacetyl groups as aromatic substituents can be reduced with sodium formaldehyde sulfoxylate dihydrate (see Tetrahedron Lett. 2001, 42, 4811-4814). However, this reaction cannot be converted to ethyl 4-chloro-4,4-difluoroacetoacetate.

  Accordingly, it is an object of the present invention to be able to utilize a new and economical method which can obtain alkyl esters of 4,4-difluoroacetoacetic acid in high overall yield and high purity.

  The subject of the present invention is therefore the structural formula (I)

［式中、Ｒはアルキルを表す。］の４，４−ジフルオロアセト酢酸のアルキルエステルを調製するための方法であり、この方法は、
ａ）第一段階において、構造式（ＩＩ）

[Wherein, R represents alkyl. For preparing an alkyl ester of 4,4-difluoroacetoacetic acid,
a) In the first step, the structural formula (II)

［式中、Ｒは上で説明されている意味を有している。］の４−クロロ−４，４−ジフルオロアセト酢酸のアルキルエステルを、構造式（ＩＩＩ）
Ｐ（ＯＲ^１）_３ （ＩＩＩ）
［式中、Ｒ^１はＣ_１−Ｃ_４アルキルを表し、ここで、残基Ｒ^１は出現毎に同じであってよく、または異なっていてもよい。］のトリアルキルホスファイトと反応させ、
このようにして得られた構造式（ＩＶ）

[Wherein R has the meaning described above. An alkyl ester of 4-chloro-4,4-difluoroacetoacetic acid of the formula (III)
P (OR ¹ ) ₃ (III)
[Wherein R ¹ represents C ₁ -C ₄ alkyl, wherein the residue R ¹ may be the same or different at each occurrence. With a trialkyl phosphite of
The structural formula (IV) thus obtained

［式中、ＲおよびＲ^１は上で説明されている意味を有している。］のアルキルホスホナートを、第二段階において、場合によって希釈剤の存在下において、構造式（Ｖ）

[Wherein R and R ¹ have the meanings described above. An alkyl phosphonate of the formula (V) in the second step, optionally in the presence of a diluent.

［式中、
Ｒ^２およびＲ^３は相互に独立して水素もしくはＣ_１−Ｃ_８−アルキルを表し、または共に−ＣＨ_２−ＣＨ_２−Ｏ−ＣＨ_２−ＣＨ_２−、ＣＨ_２−ＣＨ_２−Ｓ−ＣＨ_２−ＣＨ_２−または−ＣＨ_２−ＣＨ_２−Ｎ（Ｒ^４）−ＣＨ_２−ＣＨ_２−を表し、
Ｒ^４は水素またはＣ_１−Ｃ_８−アルキルを表す。］のアミンと反応させ、
このようにして得られた構造式（ＶＩ）

[Where:
R ² and R ³ each independently represent hydrogen or C ₁ -C ₈ -alkyl, or both —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 - represents,
R ⁴ represents hydrogen or C ₁ -C ₈ -alkyl. ] With an amine of
The structural formula (VI) thus obtained

［式中、Ｒ、Ｒ^２およびＲ^３は上で説明されている意味を有している。］のエナミンを、第三段階において、酸の存在下において加水分解される
ことを特徴とする。

[Wherein R, R ² and R ³ have the meanings described above. In the third stage, the enamine is hydrolyzed in the presence of an acid.

  Surprisingly, the alkyl phosphonate of structural formula (IV) cannot be converted directly to the desired end product by acid hydrolysis, rather, degradation is observed under these conditions. Also surprising is the fact that in the second stage of the process of the invention, from the alkyl phosphonate of structural formula (IV) and the amine of structural formula (V) the desired alkyl 4,4-difluoroacetoacetate and the corresponding phosphones. The amide is not obtained, and the ammonium salt of the enamine of structural formula (VI) and the phosphoric diester is obtained. This enamine is surprisingly easily converted to 4,4-difluoro-acetoacetate of structural formula (I) by acid hydrolysis. For this reason, no enamine isolation is required.

  Thus, the process of the present invention overcomes the drawbacks of the known preparation procedures described above and gives alkyl esters of 4,4-difluoroacetoacetic acid in high yield and high purity. Furthermore, this method has the advantage that esters of acetoacetic acid that may be present as impurities in the alkyl ester of 4-chloro-4-difluoroacetoacetate of structural formula (II) can be easily removed from the reaction mixture. is doing. During the conversion, the ester of acetoacetic acid does not react with the trialkyl phosphite of structural formula (III) and by distillation the alkyl of structural formula (IV)

  Starting from ethyl 4-chloro-4,4-difluoroacetoacetate, trimethyl phosphite and diisoproprylamine, the process of the present invention can be illustrated by the following reaction scheme.

  The alkyl 4,4-difluoroacetoacetates obtained by the process of the present invention can also exist in the enol form as well as the keto form shown in structural formula (I):

  In addition to alkyl 4,4-difluoroacetoacetates, hydrates of these compounds are also obtained by the process of the present invention.

  Thus, it is understood that the individual hydrates, as well as alkyl 4,4-difluoroacetoacetates (in keto and enol forms) are also products of the process of the present invention. Depending on the subsequent chemistry, all three forms of the product can be further reacted, or individually, only specific forms can be further reacted (see below).

The alkyl 4-chloro-4,4-difluoroacetoacetates of the structural formula (II) used as starting materials in the first stage (a) of the invention are known (Journal of Fluorine Chemistry 1992, 56, 271- 284; Huaxue Xuebao 1983, 41, 729-729 and Chemical Abstracts 1984, 100, Abstract No. 22308; EP-A 0 082 252). This compound is, for example,
b) Structural formula (VII)

［式中、Ｒは上で述べられている意味を有している。］のアルキルクロロジフルオロアセタートを、塩基の存在下において、および希釈剤の存在下において、構造式（ＶＩＩＩ）

[Wherein R has the meaning described above. An alkylchlorodifluoroacetate of the formula (VIII) in the presence of a base and in the presence of a diluent.

［式中、Ｒは上で述べられている意味を有している。］のアルキルアセタートと反応させる
ことにおいて調製されてよい。

[Wherein R has the meaning described above. And may be prepared by reacting with an alkyl acetate.

  The alkyl phosphonates of structural formula (IV) and the enamines of structural formula (VI) are novel. These compounds can be prepared by the method (a) of the present invention.

  Trialkyl phosphites of structural formula (III), amines of structural formula (V), alkyl chlorodifluoroacetates of structural formula (VII) (see preparation examples for possible preparation methods) and structural formulas (VIII ) Is a known synthetic chemical.

In the first step of the process (a) according to the invention, alkyl-4-chloro-4,4-difluoroacetoacetate of the structural formula (II) is used, wherein R is preferably C ₁ -C _8. -Alkyl, more preferably C ₁ -C ₆ -alkyl, most preferably methyl, ethyl, n-, iso-propyl, n-, iso-, sec-, tert-butyl, especially Most preferably it represents methyl or ethyl.

In the first step of the process (a) according to the invention, a trialkyl phosphite of the structural formula (III) is used, wherein R ¹ may be the same for each occurrence or may be different. Good. R ¹ preferably represents methyl, ethyl, n-, iso-propyl, n-, iso-, sec-, tert-butyl, more preferably methyl or ethyl.

Preferred alkyl phosphonates are compounds such as structural formula (IV), where each R is given as preferred, more preferred, most preferred and particularly preferred. R ^{1 in} the formula may be the same for each occurrence or may be different and is given as preferred or more preferred above. It has meaning.

In the second step of the process (a) according to the invention, an amine of the structural formula (V) is used, wherein R ² and R ³ are independently of each other preferably hydrogen, —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 — is represented and more preferred. hydrogen, methyl, ethyl, the n-, iso - propyl, n-, iso -, sec-, represents tert- butyl, or together _{-CH 2 -CH 2 -O-CH 2} -CH 2 - represents, most preferably, independently of one another, iso - propyl, iso -, sec-, tert-butyl represent, or together _{-CH 2 -CH 2 -O-CH 2} -CH 2 - represents, in particular, most preferred Represents iso-propyl for each occurrence. In Structural Formula (V), R ⁴ preferably represents hydrogen or C ₁ -C ₆ -alkyl, more preferably hydrogen, methyl, ethyl, n-, iso-propyl, n-, iso-, sec -Or tert-butyl.

Preferred enamines are compounds such as structural formula (VI), wherein each R is given as preferred, more preferred, most preferred and particularly preferred. Wherein R ² and R ³ have the meanings given as being preferred, more preferred and most preferred, respectively.

First stage of the process (a) according to the invention The first stage of the process (a) according to the invention is usually carried out without the use of further diluents. However, it is also possible to use an additional diluent (eg methylene chloride).

  The first stage of the method (a) according to the invention can be carried out within a relatively wide temperature range. Generally, it is carried out at a temperature from 10 ° C to 50 ° C, preferably from 20 ° C to 40 ° C, more preferably from 20 ° C to 30 ° C. Most preferably, the reaction of the reaction components in the first stage is initiated at a temperature from 25 ° C to 30 ° C. The further reaction is carried out at a temperature from 40 ° C. to 45 ° C. and then cooled to room temperature.

  The reaction time is not critical and can be selected within a wide range depending on the size of the batch. Generally, the reactants are mixed for a time of up to 150 minutes, preferably up to 120 minutes, more preferably up to 90 minutes. The time for further reaction is usually 3 hours with overnight (ie about 16 hours) cooling.

  Post-processing is performed by a normal method. In the first stage of the process (a) according to the invention, evaporation is first carried out under reduced pressure and the product of this stage is isolated by distillation.

  In carrying out the first stage of the process (a) according to the invention, generally from 0.5 mol to 1 mol alkyl 4-chloro-4,4-difluoroacetoacetate of the structural formula (II) Between 5 moles, preferably between 0.5 moles and 3 moles, more preferably between 1 moles and 2 moles, most preferably between 1.2 moles and 1.7 moles. A trialkyl phosphite of structural formula (III) is used.

Second stage of the process (a) according to the invention The second stage of the process (a) according to the invention is optionally carried out in the presence of a diluent. Any conventional organic solvent that is inert to such reactions is suitable. Preferably, optionally halogenated aliphatic, cycloaliphatic or aromatic hydrocarbons such as petroleum ether, hexane, heptane, cyclohexane, methylcyclohexane, benzene, toluene, xylene, decalin, chlorobenzene, dichlorobenzene or dichloromethane Ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, methyl tert-amyl ether, dioxane, tetrahydrofuran, 1,2-dimethoxyethane, 1,2-diethoxyethane or anisole; nitriles such as acetonitrile, pro Pionitrile, n- or iso-butyronitrile or benzonitrile; amides such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl Rumuanirido, N- methylpyrrolidone or hexamethylphosphoramide; sulfoxides such as dimethyl sulfoxide; or sulfone, for example, sulfolane is used.

  The second stage of the process (a) according to the invention can be carried out within a wide temperature range. In general, temperatures from 10 ° C. to 100 ° C. are used, preferably the reaction components are mixed at a temperature from 20 ° C. to 30 ° C. and then from 30 ° C. to 100 ° C., preferably from 50 ° C. to 75 ° C. It is made to react at the temperature of.

  The reaction time is not critical and can be selected over a wide range depending on the size of the batch. In general, the reactants are mixed within a time period of a few minutes to 60 minutes, preferably within a range of 10 minutes to 30 minutes, and then allowed to react for a few hours, preferably up to 24 hours. The reaction is preferably carried out for up to 20 hours.

  Post-processing is performed by a normal method. In the second stage, the reaction mixture is cooled to room temperature, washed with sodium chloride solution and water, the crude product is dried and evaporated under reduced pressure. The enamine of structural formula (VI) is then freed of further impurities by distillation.

  In carrying out the second stage of the process (a) according to the invention, generally between 2.5 and 5 moles, preferably between 2 and 5 moles, per mole of alkylphosphonate of structural formula (IV) Between 3 and 5 moles, more preferably between 2 and 4 moles of the amine of structural formula (V) is used.

The third stage of the process (a) according to the invention The hydrolysis in the third stage of the process (a) according to the invention is carried out in the presence of an acid, preferably sulfuric acid, phosphoric acid or optionally diluted with water. It is carried out in the presence of hydrochloric acid, more preferably in the presence of hydrochloric acid, most preferably in the presence of a mixture of hydrochloric acid and water.

  The third stage of the process (a) according to the invention can be carried out over a wide temperature range. In general, temperatures from 10 ° C. to 50 ° C. are used, preferably temperatures from 20 ° C. to 30 ° C. are used.

  The reaction time is not critical and a wide range can be selected depending on the size of the batch. In general, the reactants are mixed for a time from a few minutes to 60 minutes, preferably mixed for a time from 10 minutes to 30 minutes and allowed to react for several hours, preferably up to 24 hours, more preferably Is allowed to react for up to 20 hours.

  Post-processing is performed by a normal method. In the third stage, the reaction mixture is usually extracted with a suitable solvent, washed with sodium chloride solution and sodium bicarbonate solution, the crude product is dried and evaporated under reduced pressure. The alkyl 4,4-difluoroacetoacetate of structural formula (I) is then freed of further impurities by distillation.

  In the implementation of the third stage of the process (a) according to the invention, generally between 0.5 and 5 mol, preferably between 1 and 5 mol, relative to 1 mol of enamine of structural formula (VI) More preferably, between 1 and 2.5 moles of acid are used.

Method (b) of the present invention
In the process (b) according to the invention, an alkyl chlorodifluoroacetate of the structural formula (VII) and an alkyl acetate of the structural formula (VIII) are used, wherein R is preferably C ₁ -C ₈ -alkyl. More preferably C ₁ -C ₆ -alkyl, most preferably methyl, ethyl, n-, iso-propyl, n-, iso-, sec-, tert-butyl, most particularly preferably methyl or Represents ethyl.

  Process (b) according to the invention is carried out in the presence of a suitable base. Any conventional inorganic and organic base is suitable. These bases preferably include alkaline earth and alkali metal hydrides, amides, alcoholates such as sodium hydride, sodium amide, lithium diisopropylamide (LDA), sodium methylate, sodium ethylate, potassium tert-butylate. More preferred are lithium diisopropylamide (LDA) and sodium hydride.

  Process (b) according to the invention is carried out in the presence of a diluent. Any conventional organic solvent that is inert to such reactions is suitable. Preferably, optionally halogenated aliphatic, cycloaliphatic or aromatic hydrocarbons such as petroleum ether, hexane, heptane, cyclohexane, methylcyclohexane, benzene, toluene, xylene, decalin, chlorobenzene, dichlorobenzene or dichloromethane Ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, methyl tert-amyl ether, dioxane, tetrahydrofuran, 1,2-dimethoxyethane, 1,2-diethoxyethane or anisole; nitriles such as acetonitrile, pro Pionitrile, n- or iso-butyronitrile or benzonitrile; amides such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl Rumuanirido, N- methylpyrrolidone or hexamethylphosphoramide; sulfoxides such as dimethyl sulfoxide; or sulfone, for example, sulfolane is used.

  The method (b) of the present invention can be carried out over a wide temperature range. In general, temperatures from -80 ° C to + 100 ° C are used, preferably temperatures from -70 ° C to 0 ° C are used.

  The reaction time is not critical and a wide range can be selected depending on the size of the batch. In general, the reactants are mixed for a time from several minutes to 180 minutes, preferably mixed for a time from 10 minutes to 90 minutes and allowed to react for several hours, preferably up to 24 hours, more preferably 16 Allow time to react.

  Post-processing is performed by a normal method. Usually, the reaction mixture is neutralized, the phases are separated, washed with sodium chloride solution, the crude product is dried and evaporated under reduced pressure. The alkyl 4-chloro-difluoroacetoacetate of structural formula (II) is then freed of further impurities by distillation.

  In carrying out the process (b) according to the invention, it is generally between 0.5 and 5 mol, preferably 1 to 5 mol, relative to 1 mol of alkylchlorodifluoroacetate of structural formula (VII). And more preferably between 1 and 2.5 moles of alkyl acetate of structural formula (VIII) is used.

  All steps of the methods (a) and (b) of the present invention are usually carried out at normal pressure. However, it is also possible to carry out the individual stages or all stages under high pressure or reduced pressure-generally between 0.1 bar and 50 bar and under pressure between 1 bar and 10 bar.

  Alkyl 4,4-difluoroacetoacetate obtained by the method (a) of the present invention is a valuable intermediate for the preparation of difluoromethyl-substituted pyrazolylcarboxylic acid and thiazolylcarboxylic acid derivatives. , A precursor of compounds having antifungal activity (see, for example, WO 02/08197 and DE-A 102 15 292).

  For example, alkyl 4,4-difluoroacetoacetate is first used in acetic anhydride and trialkyl orthoformate to produce high yields (with ethyl esters) of alkyl 2- (difluoroacetyl) -3-alkoxyacrylates. 90% or more, see Preparation Examples). Cyclization with methyl hydrazine gives 1-methyl-3-difluoromethyl-pyrazole-4-carboxylic acid (in the case of ethyl ester, with a yield of over 65%). Inappropriate isomers (1-methyl-5-difluoromethyl-pyrazole-4-carboxylic acid) can be separated by crystallization. This transformation can be illustrated by the following reaction scheme.

  Alternatively, the alkyl 4,4-difluoroacetoacetate can be first chlorinated, with mono and dichlorinated products (alkyl 2,2-dichloro-4,4-difluoro-3-oxobutanoate and Alkyl 2-chloro-4,4-difluoro-3-oxobutanoate), both of these compounds being thioacetamide to form alkyl 3-methyl-4-difluoromethylthiazole-5-carboxylate (See the following reaction scheme).

  The preparation of alkyl 4,4-difluoroacetoacetates according to the present invention as well as the use of these alkyl 4,4-difluoroacetoacetates to prepare difluoromethyl substituted heterocyclic compounds further illustrates the above explanation. Considered in the following examples. However, these examples should not be construed in a limiting manner.

  Preparation examples

Stage 1:
Preparation of ethyl 3-[(dimethoxyphosphoryl) oxy] -4,4-difluorobut-3-enoate (IV-1)

  Trimethyl phosphite (232.0 g, 1.87 mol) was cooled to ethyl 4-chloro-4,4-difluoroacetoacetate (305.1 g, content 77.0%, 1.17 mol) with ice, and the gas was While generating, add dropwise at 90 ° C. over 90 minutes. Stirring is first continued for 1 hour at 30 ° C. and then for 3 hours at 40 to 45 ° C. For workup, the reaction mixture is cooled to room temperature (about 16 hours) and evaporated under reduced pressure. The crude product is further purified by distillation.

  302.0 g (97%, 91% of theory) of ethyl 3-[(dimethoxyphosphoryl) oxy] -4,4-difluorobut-3-enoate (bp 92-95 ° C. at 0.4 hPa) are obtained. .

Stage 2:
Preparation of ethyl 3- (diisopropylamino) -4,4-difluorobut-3-enoate (VI-1)

  Diisopropylamine (15.2 g, 0.15 mol) in 100 ml methyl-tert-butyl ether ethyl 3-[(dimethoxyphosphoryl) oxy] -4,4-difluorobut-3-enoate (IV-1) (14. 2 g, 97%, 0.05 mol) is added dropwise over 10 minutes. After heating for 19 hours under reflux, the reaction mixture is cooled to room temperature, washed twice with 10 ml of 10% sodium chloride solution each time, dried over sodium sulfate, filtered and evaporated under reduced pressure. This residue was distilled for further use.

  8.8 g (95%, 67.4% of theory) of ethyl 3- (diisopropylamino) -4,4-difluorobut-3-enoate are obtained (boiling point at 55-57 ° C. at 0.5 hPa).

Stages 2 and 3:
Preparation of ethyl 4,4-difluoroacetoacetate (I) without isolation of ethyl 3- (diisopropylamino) -4,4-difluorobut-3-enoate (VI-1)

  Diisopropylamine (2811.6 g, 27.8 mol) was added at 20 ° C. with ethyl 3-[(dimethoxyphosphoryl) oxy] -4,4-difluorobut-3-enoate in methyl-tert-butyl ether (18.5 l). Add dropwise to a solution of (IV-1) (2570 g, 98.8%, 9.26 mol) over 10 minutes. Continue stirring at reflux (57 ° C.) for 20 hours. Then, a solution of 2037 g of concentrated hydrochloric acid in 4080 ml of water is added dropwise at 20-25 ° C. with cooling and stirring is continued for 20 hours. Two phases are formed and then these phases are separated. The aqueous phase is extracted twice with 2.3 l of methyl-tert-butyl ether each time. The combined organic phases are washed with 2.8 l of 10% sodium chloride solution, 10% sodium hydrogen carbonate solution and again with 10% sodium chloride solution, dried over sodium sulfate, filtered and evaporated under reduced pressure. . The crude product is purified by distillation.

  1179 g (92%, 76.6% of theory) of ethyl 4,4-difluoroacetoacetate are obtained.

  Preparation of ethyl 4-chloro-4,4-difluoroacetoacetate (II)

  312.6 g (3.09 mol) of diisopropylamine is dissolved in 1.55 l of tetrahydrofuran and cooled to -70 ° C. To this solution 852.9 g (3.08 mol) of n-butyllithium (2.5 mol in n-hexane) is added dropwise at −60 ° C. over 80 minutes and stirring is continued at −70 ° C. for 45 minutes. The temperature is briefly raised to -20 ° C and immediately cooled again to -70 ° C. Next, at −60 ° C., 264.3 g (3.0 mol) of ethyl acetate is added dropwise over 50 minutes. At the same temperature, 242.7 g of ethyl chlorodifluoroacetate is added dropwise over 30 minutes, stirring is continued for 3 hours at −65 ° C. to −70 ° C., then the temperature is raised to room temperature. When −5 ° C. is reached, 1500 ml of 4N HCl are added and the reaction mixture is left for 16 hours. The aqueous phase (pH 6-7) is separated and the organic phase is washed with 750 ml 2N HCl and 1200 ml saturated sodium chloride solution. These organic phases are dried over sodium sulfate, filtered and evaporated under reduced pressure. The crude product is distilled for further purification.

  282.9 g (92%, 86.3% of theory) of ethyl 4-chloro-4,4-difluoroacetoacetate are obtained.

  Preparation of ethyl chlorodifluoroacetate (VII)

  504.3 g (3.87 mol) of chlorodifluoroacetic acid and 5.0 g of p-toluenesulfonic acid are dissolved in 775 ml of methylene chloride and at room temperature with 311.6 g (6.76 mol) of ethanol for 30 minutes. (Temperature rises to 33 ° C.). Continue to stir for 38 hours under reflux with water trap and then cool to room temperature. For workup, wash with water (200 ml), saturated sodium bicarbonate solution (200 ml) and again with water (200 ml), dry over sodium sulfate, filter and remove the solvent by distillation. Finally, further purification is carried out by fractional distillation.

  488.9 g (98%, 78.5% of theory) of ethyl chlorodifluoroacetate (bp 94-96 ° C.) are obtained.

Preparation of 1-methyl-5-difluoromethyl-pyrazole-4-carboxylic acid A solution of 527.8 g (11.45 mol) of methylhydrazine in 0.7 l of ethanol was added at −15 ° C. to −5 ° C. Add dropwise to a solution of 2394 g (10.35 mol) of ethyl 2- (difluoroacetyl) -3-ethoxyacrylate in 4 l of ethanol over 3.5 hours and continue stirring for 16 hours. 560 g (14 mol) of sodium hydroxide and 3.5 l of water are then added and stirring is continued at 50 ° C. for 7 hours. The reaction mixture is cooled and evaporated under reduced pressure. The residue is taken up in 6 l of water and 7 kg of ice and washed with dichloromethane (1 × 3 l, 1 × 2 l). The ice-cold aqueous phase is adjusted to pH 2 with concentrated hydrochloric acid and the precipitated product is filtered off and dried in a drying cabinet. This crude product is dissolved under reflux in 8 l isopropanol (hot), cooled, stirred at 0-5 ° C. for 30 minutes, filtered, washed with 1.4 l isopropanol (5 ° C.) and dried in a cabinet. Inside and dried at 40 ° C.

  1226.4 g (99.8%, 67.1% of theory) of 1-methyl-5-difluoromethylpyrazole-4-carboxylic acid [Log P (pH 2.3) = 0.52] are obtained.

Preparation of ethyl 3-methyl-4-difluoromethylthiazole-5-carboxylic acid Ethyl 2-chloro-4,4-difluoro-3-oxobutanoate (50.4%) and 2,2-dichloro- in 500 ml of dichloroethane To a mixture of ethyl 4,4-difluoro-3-oxobutanoate (68.2 g, 0.2 mol, 50.4% monochloro compound, 19.2% dichloro compound) was added 28 g (0.27 mol) thioacetamide. Heat at reflux for 2 hours, then let stand for 16 hours. After this, 300 ml of saturated sodium bicarbonate solution are slowly added with stirring and the phases are separated. The organic solution is dried over sodium sulfate and evaporated under reduced pressure. The remaining solution is filtered, washed with 20 ml of methylene chloride and evaporated under reduced pressure.

  53.4 g (72%, 86.7% of theory) of ethyl 3-methyl-4-difluoromethyl-thiazole-5-carboxylate [Log P (pH 2.3) = 2.18] are obtained.

  The measurement of log P values reported in the table above and in the preparative examples is based on EEC Directive 79/831 Annex V. on a reverse phase column (C18). Performed according to 8A by HPLC (High Performance Liquid Chromatography). Temperature: 43 ° C.

  This measurement is performed in the acidic region at pH 2.3 using 0.1% aqueous phosphoric acid and acetonitrile as the eluent; a linear gradient from 10% acetonitrile to 90% acetonitrile.

  Calibration consists of unbranched alkane-2-ones (from 3 to 16) with known log P values (measurement of log P values based on retention time by linear interpolation between two subsequently used alkanones) With carbon atoms).

Claims (9)

Structural formula (I)

[Wherein, R represents alkyl. For preparing an alkyl ester of 4,4-difluoroacetoacetic acid
In the first step, the structural formula (II)

[Wherein R has the meaning described above. An alkyl ester of 4-chloro-4,4-difluoroacetoacetic acid of the formula (III)
P (OR ¹ ) ₃ (III)
[Wherein R ¹ represents C ₁ -C ₄ alkyl, wherein the residue R ¹ may be the same or different at each occurrence. With a trialkyl phosphite of
The structural formula (IV) thus obtained

[Wherein R and R ¹ have the meanings described above. An alkyl phosphonate of the formula (V) in the second step, optionally in the presence of a diluent

[Where:
R ² and R ³ independently of _one another represent C ₁ -C ₈ -alkyl. ] With an amine of
The structural formula (VI) thus obtained

[Wherein R, R ² and R ³ have the meanings described above. The enamine, in a third stage, characterized Rukoto is hydrolyzed in the presence of an acid, said method. The alkyl 4-chloro-4,4-difluoroacetoacetate of structural formula (II) used in the first step as starting material is structural formula (VII)

[Wherein R has the meaning described above. An alkylchlorodifluoroacetate of the formula (VIII) in the presence of a base and in the presence of a diluent.

[Wherein R has the meaning described above. The method according to claim 1, which is prepared by reacting with an alkyl acetate of the formula: R is C ₁ -C 8 _-, characterized in that the compound of formula according to claim 1 represents an alkyl (II) is used, the method according to claim 1 or 2. R is C ₁ -C ₆ -, characterized in that the compound of formula according to claim 1 represents an alkyl (II) is used, the method according to claim 1 or 2. A compound of structural formula (II) according to claim 1 is used, wherein R represents methyl, ethyl, n-, iso-propyl, n-, iso-, sec-, tert-butyl,
The compound of structural formula (III) according to claim 1 is used, wherein R ¹ represents methyl, ethyl, n-, iso-propyl, n-, iso-, sec-, tert-butyl,
The compound of structural formula (V) according to claim 1, wherein R ² and R ³ independently of one another represent methyl, ethyl, n-, iso-propyl, n-, iso-, sec-, or tert-butyl. The method according to claim 1 or 2, characterized in that is used.   6. A method according to claim 1, 2, 3, 4 or 5, characterized in that the first stage is carried out without a diluent.   The hydrolysis in the third stage is carried out in the presence of sulfuric acid, phosphoric acid or hydrochloric acid, the acid being in each case optionally diluted with water, characterized in that The method according to 4, 5, or 6. Structural formula (IV)

[Where:
R represents alkyl,
R ¹ represents C ₁ -C ₄ -alkyl, wherein the residue R ¹ may be the same or different for each occurrence. ]
Alkyl phosphonates. Structural formula (VI)

[Where:
R represents alkyl,
R ² and R ³ independently of _one another represent C ₁ -C ₈ -alkyl. ]
Enamine.