JP2008184410A - Method for producing 2,2-difluoro-phenylacetoacetate - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for producing ethyl 2,2-difluoro-phenylacetoacetate, suitable for the production in an industrial scale. <P>SOLUTION: This method for producing the 2,2-difluoro-phenylacetoacetate is characterized by reacting phenylacetyl chloride with chlorine (Cl<SB>2</SB>) to obtain 2,2-dichloro-phenylacetyl chloride, reacting the obtained 2,2-dichloro-phenylacetyl chloride with an alcohol to obtain a 2,2-dichloro-phenylacetoacetate, and then reacting the obtained 2,2-dichloro-phenylacetoacetate with hydrogen fluoride (HF) in a liquid phase to obtain the 2,2-difluoro-phenylacetoacetate. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

  The present invention relates to a process for producing 2,2-difluoro-phenylacetoacetate, which is an important intermediate of medicine.

  Methods for introducing fluorine atoms at specific sites for the purpose of enhancing the activity of drugs and reducing side effects are widely used in the development of new drugs, and 2,2-difluorophenylacetoacetate and its derivatives have specific medicinal properties. It is a promising pharmaceutical intermediate compound.

  As a conventional method for producing 2,2-difluorophenylacetoacetate ester, Non-Patent Document 1 discloses that dimethylaminosulfur trifluoride (DAST), which is a fluorinating agent, is added to a compound having a carbonyl group adjacent to the phenyl group. Method of reaction (Scheme 1)

However, Patent Document 1 discloses a method in which diphenyl selenide and 1-bromo-2,2-difluoroacetoacetate are reacted, and then the obtained α, α-difluoro-α-phenylselenoacetate is irradiated with light ( Scheme 2)

However, Non-Patent Document 2 discloses a nucleophilic fluorination method using a fluorination reagent such as N-fluorobenzenesulfonimide (NFBS).
JP 2005-145913 A M.M. Hudlicky, Org. Reac. 21, 1988, 513. Tsutomu Yokomatsu, Satoshi Shibuya, Journal of Synthetic Organic Chemistry, Vol. 60 NO. 8 2002, 12.

  The method of Non-Patent Document 1 is a method using DAST, but it needs to be used in a large excess in order to advance the reaction well. Furthermore, since it is very expensive and DAST itself is explosive, handling a large amount is very dangerous.

  The method of Patent Document 1 is a method for obtaining the target product by light irradiation, and is a very useful method because it easily proceeds even at room temperature. However, since the raw material diphenyl selenide is very expensive and requires a radical reaction, it is somewhat difficult in terms of industrial production.

  The method of Non-Patent Document 2 is somewhat unsuitable for large-scale synthesis because NFBS is expensive in the method using NFBS and the reaction needs to be performed at −78 ° C.

  For these reasons, regarding the production of 2,2-difluoro-phenylacetoacetate, it has been desired to establish a production method that is advantageous on the industrial scale and in production cost, safety, and simplicity. .

  The present inventors have intensively studied to solve the above problems. As a result, an inexpensive phenylacetyl chloride is used as a starting material, an inexpensive and stable raw material is used, and it is found that the above problems can be solved with a very high selectivity and high yield in a short process. completed.

The production method of the present invention is a method for producing 2,2-difluoro-phenylacetoacetic acid ester comprising the following steps.
First step: phenylacetyl chloride represented by the formula [1]

Is reacted with chlorine (Cl ₂ ) and 2,2-dichloro-phenylacetyl chloride represented by the formula [2]

Obtaining.
Second step: 2,2-dichloro-phenylacetyl chloride obtained in the first step is used as an alcohol represented by the formula [3]

(In the formula, n represents an integer of 1 to 10 carbon atoms.)
2,2-dichloro-phenylacetoacetate represented by the formula [4]

(Wherein n is the same as above)
Obtaining.
Third step: 2,2-Dichloro-phenylacetoacetate obtained in the second step is reacted with hydrogen fluoride (HF) in the liquid phase, and 2,2-difluoro-phenyl represented by the formula [5] Acetoacetate

(Wherein n is the same as above)
Obtaining.

When the present inventors reacted phenylacetyl chloride with chlorine (Cl ₂ ), 2,2-dichloro-phenylacetyl chloride was obtained (for example, with a selectivity of 95% or more and a yield of 90% or more). The knowledge that it was obtained (first step) was obtained.

  By reacting the obtained 2,2-dichloro-phenylacetyl chloride with an alcohol (details will be described later, for example, ethanol, etc.), 2,2-dichloro-phenylacetoacetate is obtained in a high yield (for example, 95 It was found that the second step was obtained with a selectivity of at least% and a yield of at least 90%.

  Further, when the obtained 2,2-dichloro-phenylacetoacetate was reacted with hydrogen fluoride (HF) in a liquid phase, 2,2-difluoro-phenylacetoacetate was obtained in good yield (for example, 85 It was found that it was obtained (with a yield of 78% or more even after distillation purification) with a selectivity of 3% or more (third step).

  Further, the present inventors have also found a knowledge that each step of the first step, the second step, and the third step can be particularly preferably achieved by certain specific conditions and operations.

  The present inventors have also made it possible to supply cheaply and easily compared with the conventional method for producing 2,2-difluoro-phenylacetoacetate ester by developing it by a simple method throughout this research. . This is a very excellent method for efficiently producing the target product on an industrial scale.

That is, the present invention is a method for producing 2,2-difluoro-phenylacetoacetate described in [Invention 1] to [Invention 6] below.
[Invention 1]
A process for producing 2,2-difluoro-phenylacetoacetate, comprising the following three steps.
First step: a step of reacting phenylacetyl chloride represented by the formula [1] with chlorine (Cl ₂ ) to obtain 2,2-dichloro-phenylacetyl chloride represented by the formula [2].
Second step: 2,2-dichloro-phenylacetyl chloride obtained in the first step is reacted with an alcohol represented by the formula [3], and 2,2-dichloro-phenyl represented by the formula [4] Obtaining acetoacetate.
Third step: 2,2-Dichlorophenylacetoacetate obtained in the second step is reacted with hydrogen fluoride (HF) in the liquid phase, and 2,2-difluoro-phenylacetoacetate represented by the formula [5] Obtaining an ester.
[Invention 2]
The method according to invention 1, wherein the alcohol represented by the formula [3] in the second step is methanol, ethanol, or propanol.
[Invention 3]
3. The method according to invention 1 or 2, wherein the reaction of 2,2-dichloro-phenylacetoacetate and hydrogen fluoride (HF) in the third step is carried out without solvent.
[Invention 4]
The method according to any one of Inventions 1 to 3, wherein the compound obtained after the first step is used as it is in the second step without purification.
[Invention 5]
The method according to any one of inventions 1 to 4, wherein the compound obtained after the second step is used as it is in the third step without purification.
[Invention 6]
6. The method according to any one of inventions 1 to 5, wherein the second step is carried out while allowing a dry inert gas to flow through the mixture obtained after the first step.

  According to the present invention, 2,2-difluoro-phenylacetoacetic acid ester is easily produced with high selectivity and high yield, using phenylacetyl chloride, which is easily available industrially, as a raw material, at a lower cost than before. be able to.

Hereinafter, the present invention will be described in more detail. In the present invention, phenylacetyl chloride represented by the formula [1] is reacted with chlorine (Cl ₂ ) to obtain 2,2-dichloro-phenylacetyl chloride represented by the formula [2] (first step). 2,2-Dichloro-phenylacetyl chloride obtained in one step is reacted with an alcohol represented by the formula [3] to obtain a 2,2-dichloro-phenylacetoacetate ester represented by the formula [4]. (Second step), 2,2-Dichloro-phenylacetoacetate obtained in the second step is reacted with hydrogen fluoride (HF) in the liquid phase, and 2,2-difluoro represented by the formula [5] -It comprises a step of obtaining phenylacetoacetic acid ester (third step).

  In addition, about the phenylacetyl chloride represented by Formula [1] which is a starting material of this invention, those skilled in the art can obtain easily by a conventionally well-known method.

Hereinafter, the first step will be described in detail. The first step is a step of reacting phenylacetyl chloride with chlorine (Cl ₂ ) to obtain 2,2-dichloro-phenylacetyl chloride.

As the reaction vessel, glass, or a reaction vessel lined with glass, fluororesin or the like is suitably employed. On the other hand, in the case of a reaction vessel whose inner wall is made of stainless steel, iron, etc., the metal is converted into chloride (for example, in the case of iron (Fe), iron chloride (III) FeCl ₃ ), which becomes the Lewis acid catalyst and Friedel -It is not preferable because it causes a side reaction of the craft type and a compound in which a chlorine atom (Cl) is directly bonded to a benzene nucleus (phenyl group) is easily generated.

  In this step, the method for adding chlorine is not particularly limited, and can be carried out in a flow system, a batch system or a semi-batch system. For example, the reaction is generally carried out by blowing chlorine gas into phenylacetyl chloride previously charged in a reaction vessel, which is preferably employed. Hydrogen chloride (HCl) gas generated by the reaction can be discharged from the reaction region together with unreacted chlorine gas and trapped with water, an alkaline aqueous solution, or the like.

  In order to advance this reaction, the reaction temperature is set to 160 ° C. or higher to generate radicals in the system. Usually, the reaction temperature is 100 ° C to 300 ° C, preferably 130 to 250 ° C, and more preferably 150 to 220 ° C. If it is less than 100 ° C., water accumulates in the system and the catalyst is deactivated and the reaction hardly proceeds. If it exceeds 300 ° C., the reaction yield decreases due to decomposition or the like, which is not preferable.

  The amount of chlorine used in the reaction may be 2 mol or more per 1 mol of phenylacetyl chloride, but is about 2 to 4 mol, and about 2 to 3 mol by optimizing the reaction apparatus or reaction operation. be able to. Since optimization sets reaction conditions and the chlorination reaction is a gas-liquid contact reaction, conventional means for increasing contact efficiency, for example, adjustment of gas introduction speed, stirring device, gas blowing device, It is effective to use a method such as a sparger or a method using a multistage chlorination reactor as appropriate.

  Since the reaction pressure in the chlorination reaction in this step hardly affects the reaction, it is not necessary to pressurize in particular, and is usually 0.05 to 1 MPa (absolute pressure, hereinafter the same in the present specification), 0 .1 to 0.3 MPa.

  Moreover, this process can also be performed in presence of a solvent. In the case of using a solvent, it is preferable that the raw material and the product are dissolved as the solvent to be used, and the solvent is inert in the chlorination reaction, and further has a sufficient boiling point difference from the product. Carbon chloride, chloroform, tetrachloroethane, monochlorobenzene, o-, m-, p-dichlorobenzene, trichlorobenzene, monobromobenzene, dibromobenzene, 2,3-, 2,4-, 2,5-, 2,6 -, 3,4-, 3,5-dichlorobenzotrifluoride, 3,4,5-trichlorobenzotrifluoride, bistrifluoromethylbenzene and the like. However, the reaction raw material phenylacetyl chloride is a liquid, and the product 2,2-dichloro-phenylacetyl chloride is also a liquid under the reaction conditions, and sufficiently dissolves chlorine and serves as a solvent. However, it is not necessary to use a separate solvent, which is industrially not burdensome and economically preferable.

  In order to advance this reaction, radical initiators such as 2,2′-azobis (4-methoxy-2,4-dimethylvaleronitrile), 2,2′-azobis (2,4-dimethylvaleronitrile), (1-phenylethyl) azodiphenylmethane, 2,2′-azobisisobutyronitrile, dimethyl 2,2′-azobisisobutyrate, 1,1′-azobis (1-cyclohexanecarbonitrile), 2,2 ′ -Azo compounds such as azobis (2-methylpropane), 2,2'-azobis (2-amidinopropane) dihydrochloride, 4,4'-azobis (4-cyanopentanoic acid), benzoyl peroxide, peroxide Dodecanoyl, dilauroyl peroxide, t-butyl peroxypivalate, di-t-butyl hydroperoxide, t-butyl-cumyl-peroxide, 2,5-dimethyl-2,5-bi Radical initiators such as peroxides such as bis (t-butylperoxy) hexyne, isobutyryl peroxide, 3,5,5-trimethylhexanoyl peroxide, red phosphorus, phosphorus pentachloride, phosphorus trichloride, triphenyl Phosphine, phosphorous compounds such as triphenyl phosphite, and the like can be used, and can also be performed by irradiating light. Further, these radical initiation methods may be used in appropriate combination.

  When using a radical initiator, the radical initiator is usually added in an amount of 0.0001 to 1 mol per mol of the raw material, preferably 0.001 to 0.1 mol, more preferably 0.001 to 0.05 mol. . The radical initiator can be added as appropriate by observing the progress of the reaction. If the amount of the radical initiator is less than 0.0001 mol with respect to 1 mol of the raw material, the reaction is likely to stop in the middle, and the yield may be lowered. Moreover, a radical initiator can also be added in the middle of reaction as needed.

  When performing light irradiation, the light source is at least one selected from the group consisting of a high-pressure mercury lamp, a low-pressure mercury lamp, various halogen lamps, a tungsten lamp, a light-emitting diode, etc. Among them, a high-pressure mercury lamp and a tungsten lamp are preferable. .

  However, when carrying out this chlorination reaction, the same radical reaction can be caused by heating to a high temperature (approximately 160 ° C. or higher) without adding the above-described radical initiator or irradiating light. There are few (it is estimated that radicals are generated in the system), and therefore there are few merits that require radical initiators and the like in consideration of operational convenience and selectivity of the reaction.

  In this step, in addition to the target 2,2-dichloro-phenylacetyl chloride, a positional isomer in which a chlorine atom is substituted at another site (for details, refer to Examples described later), and a mixture containing other compounds May be obtained (Scheme 3).

  Although it is possible to purify at this point, these regioisomers are very difficult to separate by purification operations such as distillation because of their close boiling points, and the purification operation is very burdensome in terms of manufacturing. . Therefore, the present inventors generally do not carry out purification of these mixtures, which are generally very difficult to be separated, at the time of the first step, and leave the mixture obtained in the first step as described below. By using it as a starting material in the second step, it was found that the second step proceeds well without impairing the yield.

  Also from this, it is preferable from the viewpoint of productivity that 2,2-dichloro-phenylacetyl chloride obtained after the reaction is used as it is as a raw material for the second step (esterification) without purification. It is.

  Next, the second step will be described. In the second step, 2,2-dichloro-phenylacetyl chloride represented by the formula [2] obtained in the first step is reacted with an alcohol represented by the formula [3], and represented by the formula [4]. To obtain 2,2-dichloro-phenylacetoacetic acid ester.

  Examples of the alcohol represented by the formula [3] used in this step include linear, branched or cyclic alkyl groups having 1 to 10 carbon atoms.

  Of these, linear, branched or cyclic alcohols having 1 to 6 carbon atoms are preferred because the usefulness of the product and the effect of coexistence are particularly remarkable, and more preferably 1 to 1 carbon atoms. 4 linear, branched or cyclic alcohols.

  Specific examples include methanol, ethanol, n-propyl alcohol, iso-propyl alcohol, n-butyl alcohol, iso-butyl alcohol, sec-butyl alcohol, tert-butyl alcohol, and preferably methanol. , Ethanol, n-propyl alcohol, and n-butyl alcohol, more preferably methanol and ethanol.

  The reaction in this step may be performed without a solvent or in a solvent. When a solvent is used, the reaction substrate itself can be used as the solvent, for example, aliphatic hydrocarbons such as pentane, hexane, heptane, and octane, aromatic hydrocarbons such as benzene, toluene, xylene, diethyl ether, and the like. , Ethers such as dioxane, tetrahydrofuran (THF), ethylene glycol dimethyl ether, ketones such as acetone, methyl ethyl ketone and methyl isobutyl ketone, nitriles such as acetonitrile, tertiary amines such as pyridine, N, N-dimethylformamide (DMF) ), Acid amides such as N, N-dimethylacetamide (DMAC), sulfur-containing compounds such as dimethyl sulfoxide (DMSO) and sulfolane, and the like can be used. In the present invention, as described above, alcohol is used as a reaction reagent, and since these can function as a solvent, it is usually unnecessary to use another solvent. The amount of the solvent used is usually 1 to 10 times, preferably 1 to 6 times, more preferably 2 times the volume of 2,2-dichloro-phenylacetyl chloride represented by the formula [2]. It is appropriately selected from the range of ˜4 times capacity.

This step may be performed in the presence of a base. In the case of using a base, those having a strength that gives a pH of 8 or more when dissolved in water at a concentration of 1 mol · dm ⁻³ are preferable. There are no restrictions on the base used, either an inorganic base or an organic base. When an inorganic base is used as the base, specifically, ammonia, sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate and the like can be used. Of these, sodium carbonate or potassium carbonate is preferred because the reaction proceeds smoothly. When using an organic base as the base, specifically, as the organic base, trimethylamine, triethylamine, diisopropylethylamine, tri-n-propylamine, pyridine, 2,3-lutidine, 2,4-lutidine, 2,5-lutidine, 2,6-lutidine, 3,4-lutidine, 3,5-lutidine, 2,3,4-collidine, 2,4,5-collidine, 2,5,6-collidine, 2,4,6-collidine, 3,4,5-collidine, 3,5,6-collidine and the like can be mentioned. Among them, triethylamine, diisopropylethylamine, tri-n-propylamine, pyridine, 2,3-lutidine, 2,4-lutidine, 2,6-lutidine, 3,4-lutidine, 3,5-lutidine, 2,4,6 -Colidine and 3,5,6-collidine are preferred, especially triethylamine, diisopropylethylamine, pyridine, 2,4-lutidine, 2,6-lutidine, 3,5-lutidine and 2,4,6-collidine. The amount of the base is usually equimolar or more with respect to 1 mol of 2,2-dichloro-phenylacetyl chloride, preferably 1 to 2 times mol, more preferably 1 to 1.5 times mol.

In this step, although it is also an esterification reaction, hydrogen chloride (HCl) gas is generated as it reacts. This generated hydrogen chloride is usually neutralized using a base coexisting in the reaction system, but in this step, the reaction is carried out while removing hydrogen chloride from the system using an inert gas such as nitrogen. It is also possible to make it. As a result, it was found that the reaction can proceed satisfactorily without requiring a base. Examples of the inert gas include nitrogen (N ₂ ), helium (He), and argon (Ar). For example, in Example 5 to be described later, it is one of the particularly preferred embodiments that nitrogen gas is introduced into the reaction system at 100 ml / min from the blowing tube.

  Although there is no restriction | limiting in particular in the reaction temperature of this process, Preferably it is 0-220 degreeC, More preferably, it is 50-120 degreeC. If it is less than 0 ° C., the reaction is slow. On the other hand, when the temperature exceeds 120 ° C., by-products are likely to be generated, and excessive heating is inferior in energy efficiency and is not preferable from the viewpoint of economy. When the temperature is lower than this range, the reaction does not proceed sufficiently, resulting in a decrease in yield, which is economically disadvantageous, or the reaction rate decreases and it takes a long time to complete the reaction. It may cause problems and is not preferred. The reaction time is preferably 1 to 48 hours.

  The 2,2-dichloro-phenylacetoacetate obtained in the reaction is treated in the usual way. That is, washing with water and an acidic aqueous solution (aqueous hydrochloric acid solution) is performed to remove ethyl alcohol, salt, and base. Thereafter, by removing moisture with a desiccant or the like, 2,2-dichloro-phenylacetoacetate represented by the formula [4] is obtained with high purity.

  In this step, in addition to the target 2,2-dichloro-phenylacetoacetate, a mixture containing the positional isomers derived from the previous step (first step) contained in the starting material of this step (described above) The mixture obtained by subjecting the esterification reaction to Scheme 3) is accompanied by impurities. These impurities can be separated by a purification treatment such as column chromatography, but the boiling points of these target products and impurities are very high, and purification by distillation is usually difficult and requires complicated operations. Therefore, although details will be described later, since it is possible to sufficiently purify by distillation operation in the next third step, the reaction mixture after the end of the second step is not purposely purified in order to take advantage of this step. Further, it is preferable to use it as it is as a raw material for the third step (fluorination reaction).

  Hereinafter, the third step will be described. In the third step, 2,2-dichloro-phenylacetoacetate obtained in the second step is reacted with hydrogen fluoride (HF) in the liquid phase, and 2,2-difluoro- represented by the formula [5] is used. In this step, phenylacetoacetic acid ester is obtained.

  As a reaction vessel, it is carried out using a stirrer in a pressure-resistant reaction vessel lined with fluorine resin such as Monel, Hastelloy, nickel or these metals, polytetrafluoroethylene, perfluoropolyether resin, batch reaction, A continuous or semi-continuous reaction is used.

  Metal halides commonly used in liquid phase fluorination reactions, such as antimony pentachloride and tin tetrachloride, can be used as a catalyst, but they may be non-catalyzed.

  In the case of no catalyst, the reaction temperature is usually 40 to 80 ° C, preferably 50 to 70 ° C. If it is less than 40 ° C., the reaction is slow, and if it exceeds 80 ° C., tarring occurs and the yield and purity of 2,2-difluoro-phenylacetoacetate are lowered, which is not preferable. For example, it is one of the particularly preferred embodiments that the reaction is carried out at 55 ° C. in this example.

  The fluorination reaction in this process is reversible, and the progress of the reaction depends on the equilibrium, so if there is an excessive amount of by-produced hydrogen chloride, fluorination will not proceed, so the hydrogen chloride in the system will be adjusted while adjusting the reaction pressure. It is necessary to exhaust outside the system. The reaction pressure is usually 0.2 MPa to 0.8 MPa, preferably 0.4 MPa to 0.6 MPa.

  The amount of hydrogen fluoride is usually 8-30 mol, preferably 10-25 mol, more preferably 15-23 mol, per mol of 2,2-dichloro-phenylacetoacetic acid ethyl ester. If the amount is less than 8 moles, the yield is unfavorable, and if it is used in excess of 30 moles, there is no problem in terms of reactivity, but the productivity increases due to an increase in the amount of hydrogen fluoride. This is not preferable because it causes serious problems.

  In this step, an inert solvent can also be used. Examples of the solvent include toluene, fluorobenzene, difluorobenzene, benzotrifluoride, 1,4-bistrifluoromethylbenzene, and the like. However, since the raw material and product of this step are both liquid and the reaction proceeds smoothly even if no solvent is present, the absence of solvent is preferred from the viewpoint of economy and operability.

  The 2,2-difluoro-phenylacetoacetic acid ethyl ester obtained in the reaction is treated in the usual manner. That is, unreacted hydrogen fluoride is separated and removed, then washed with water, and hydrogen fluoride and moisture are removed from the system with calcium chloride. Washing with water or an alkaline aqueous solution (sodium carbonate aqueous solution, sodium hydrogen carbonate aqueous solution, etc.) is performed to remove hydrogen fluoride from the system. Thereafter, moisture can be removed with a desiccant or the like.

  Distillation is particularly preferred as a purification operation of 2,2-difluoro-phenylacetoacetate.

  When distillation is performed, normal pressure (0.1 MPa) may be used, but reduced pressure is preferable. Usually, the one after removing the hydrogen fluoride by the post-treatment is used. In this case, the material of the distillation column is not limited, and glass, stainless steel, tetrafluoroethylene resin, chlorotrifluoroethylene resin, vinylidene fluoride resin, PFA resin, glass, etc. are lined inside. Things can be used. During distillation or the like, a filler can be packed. Distillation is preferred because it can be achieved at a relatively low temperature when performed under reduced pressure. Although there is no restriction | limiting in the number of stages of the distillation tower | column requested | required for this distillation, 5-100 stages are preferable, More preferably, it is 10-50 stages.

  By this distillation operation, colorless and transparent 2,2-difluoro-phenylacetoacetate is obtained with high purity.

  In addition, although this process is a process for producing 2,2-difluoro-phenylacetoacetate, in addition to the target product, the mixture derived from the first process and the second process contained in the starting material of this process. Alternatively, a compound in which the mixture derived from the first step and the second step is fluorinated by this step may accompany as an impurity (see Examples described later). However, since 2,2-difluoro-phenylacetoacetate containing these impurities can be easily separated by performing a distillation operation in this step, the object can be easily obtained without taking time for purification operations in the previous step. The product can be supplied with high purity and high yield. This is an excellent method for producing the target product on an industrial scale.

  The present invention will be described in more detail with reference to examples below, but the present invention is not limited thereto. Here, “%” of the composition analysis value represents “area%” of the composition obtained by directly measuring the reaction mixture by gas chromatography (GC; unless otherwise specified, the detector is FID).

(First step: Chlorination)
A 500 ml four-necked flask equipped with a Dimroth tube, a thermometer, and a chlorine blowing tube was charged with 154.5 g (1.0 mol) of phenylacetyl chloride, the internal temperature was raised to 160 ° C. while stirring, and chlorine gas was supplied. The reaction was started at a rate of about 0.5 mol / Hr. While maintaining the internal temperature at 160 ° C., chlorine gas was supplied for 6 hours. As a result, the composition of the reaction solution was 97.6% (selectivity) of 2,2-dichloro-phenylacetyl chloride, which was the target product, as analyzed by gas chromatography. Other by-products include 2,2-dichloro- (2-chloro-phenyl) acetyl chloride and 2,2-dichloro- (3-chloro-phenyl) acetyl chloride and 2,2-dichloro which are perchlorates The total of-(4-chloro-phenyl) acetyl chloride was 1.8% and benzoyl chloride was 0.2%. The weight of the reaction solution was 223.5 g. This reaction solution (chlorination mixture) was used for the subsequent second step (esterification) without purification.
(Second step: esterification)
In a 1000 ml four-necked flask equipped with a Dimroth condenser, thermometer and dropping funnel, ethanol: 90.2 g (1.96 mol) and pyridine: 116.3 g (1.47 mol) and a dropping funnel were obtained in the first step. 2,2-dichloro-phenylacetyl chloride: 218.0 g (0.98 mol) was charged, and the internal temperature was cooled to 5 ° C. with stirring. The dropping from the dropping funnel was started and the reaction was started. While maintaining the internal temperature at 30 ° C. or lower, 218.0 g of 2,2-dichloro-phenylacetyl chloride was added dropwise over 40 minutes. The composition of the reaction liquid after completion of the dropwise addition of 2,2-dichloro-phenylacetyl chloride is 96.1% (selectivity) of 2,2-dichloro-phenylacetoacetic acid ethyl ester, which is the target product, based on analysis by gas chromatography. there were. As other by-products, 2,2-dichloro- (2-chloro-phenyl) acetoacetic acid ethyl ester and 2,2-dichloro- (3-chloro-phenyl), which are compounds in which perchlorinated compounds are esterified The total of acetoacetic acid ethyl ester and 2,2-dichloro- (4-chloro-phenyl) acetoacetic acid ethyl ester was 2.1%, and benzoyl acetic acid ethyl ester was 0.5%.

After completion of the reaction, the collected reaction solution was washed once with water and once with 10% -HCl. Magnesium sulfate was added to the reaction solution after washing, followed by filtration after stirring. The weight of the reaction solution obtained from the filtrate was 212.2. This reaction solution was used in the subsequent third step (fluorination) without purification.
(Third step: fluorination)
2,2-dichloro-phenylacetoacetic acid ethyl ester obtained in the second step in a metal 1 L pressure-resistant reaction vessel equipped with a stirrer, a cooling reflux tube equipped with a pressure control valve, a thermocouple, a pressure gauge, and a sampling tube: 212.2 g (0.91 mol) and anhydrous hydrogen fluoride: 364.3 g (18.2 mol) were charged and sealed, and the internal temperature was raised to 55 ° C. while stirring to initiate the reaction. The pressure regulating valve was adjusted so that the internal pressure became 0.4 MPa, and the reaction was performed for 3 hours while releasing hydrogen chloride generated with the progress of the reaction out of the system. The composition of the reaction solution after 3 hours was 89.46% (selectivity) of 2,2-difluoro-phenylacetoacetic acid ethyl ester, which was the target product, as analyzed by gas chromatography. The other fluorinated compound, 2-chloro-2-fluoro-phenylacetoacetic acid ethyl ester, was 2.0%, and unreacted 2,2-dichloro-phenylacetoacetic acid ethyl ester was 0%. It was. After completion of the reaction, the recovered reaction solution was washed with water. Calcium chloride was added to the reaction solution after washing, followed by filtration after stirring. The weight of the reaction solution obtained from the filtrate was 158.2.

  The resulting fluorination reaction solution was purified by distillation in a 45 cm distillation column packed with Dixon packing. By fractionating a fraction at 1600 Pa and a temperature of 95 to 96 ° C. by this distillation, 108.0 g of the desired product having a purity of 99.5% was obtained. The overall yield from the raw material phenylacetyl chloride was 56.4%.

(First step: Chlorination)
A 500 ml four-necked flask equipped with a Dimroth tube, a thermometer, and a chlorine blowing tube was charged with 154.5 g (1.0 mol) of phenylacetyl chloride, the internal temperature was raised to 180 ° C. while stirring, and chlorine gas was supplied. The reaction was started at a rate of about 0.5 mol / Hr. While maintaining the internal temperature at 180 ° C., chlorine gas was supplied for 5 hours. As a result, the composition of the reaction solution was found to be 96.3% (selectivity) for 2,2-dichloro-phenylacetyl chloride, which was the target product, from gas chromatography analysis. Other by-products include 2,2-dichloro- (2-chloro-phenyl) acetyl chloride and 2,2-dichloro- (3-chloro-phenyl) acetyl chloride and 2,2-dichloro which are perchlorates The total of-(4-chloro-phenyl) acetyl chloride was 2.3% and benzoyl chloride was 0.3%. The weight of the reaction solution was 221.5 g. This reaction solution (chlorination mixture) was used for the subsequent second step (esterification) without purification.
(Second step: esterification)
In a 1000 ml four-necked flask equipped with a Dimroth condenser, thermometer and dropping funnel, ethanol: 181.1 g (3.94 mol) and triethylamine: 148.5 g (1.47 mol) and a dropping funnel were obtained in the first step. 2,2-Dichloro-phenylacetyl chloride: 220.0 g (0.98 mol) was charged, and the internal temperature was cooled to 10 ° C. with stirring. The dropping of 2,2-dichloro-phenylacetyl chloride was started from the dropping funnel, and the reaction was started. While maintaining the internal temperature at 30 ° C. or lower, 2,2-dichloro-phenylacetyl chloride: 220.0 g was added dropwise over 40 minutes. The composition of the reaction solution after the completion of the dropwise addition of 2,2-dichloro-phenylacetyl chloride is 96.3% (selectivity) of 2,2-dichloro-phenylacetoacetic acid ethyl ester, which is the target product, as analyzed by gas chromatography. there were. As other by-products, 2,2-dichloro- (2-chloro-phenyl) acetoacetic acid ethyl ester and 2,2-dichloro- (3-chloro-phenyl), which are compounds in which perchlorinated compounds are esterified The total of acetoacetic acid ethyl ester and 2,2-dichloro- (4-chloro-phenyl) acetoacetic acid ethyl ester was 2.4%, and benzoylacetic acid ethyl ester was 0.3%.

After completion of the reaction, the collected reaction solution was washed once with water and once with 10% -HCl. Magnesium sulfate was added to the reaction solution after washing, followed by filtration after stirring. The weight of the reaction solution obtained from the filtrate was 214.3 g. This reaction solution was used in the subsequent third step (fluorination) without purification.
(Third step: fluorination)
2,2-dichloro-phenylacetate obtained in the second step in a metal 1 L pressure-resistant reaction vessel equipped with a stirrer, a cooling reflux tube equipped with a pressure control valve, a thermocouple, a pressure gauge, and a sampling tube Acetic acid ethyl ester: 214.3 g (0.92 mol) and anhydrous hydrogen fluoride: 147.0 g (7.35 mol) were charged and sealed, and the internal temperature was raised to 45 ° C. while stirring to initiate the reaction. The pressure control valve was adjusted so that the internal pressure became 0.5 MPa, and the reaction was carried out for 17 hours while releasing hydrogen chloride generated with the progress of the reaction out of the system. The composition of the reaction solution after 17 hours was found to be 62.7% (selectivity) of 2,2-difluoro-phenylacetoacetic acid ethyl ester as a target product from gas chromatography analysis. In addition to this, one fluorinated compound, 2-chloro-2-fluoro-phenylacetoacetic acid ethyl ester, 15.3%, unreacted 2,2-dichloro-phenylacetoacetic acid ethyl ester, 12.8% Met. After completion of the reaction, the recovered reaction solution was washed with water. Calcium chloride was added to the reaction solution after washing, followed by filtration after stirring. The weight of the reaction solution obtained from the filtrate was 154.7 g.

  The resulting fluorination reaction solution was purified by distillation in a 45 cm distillation column packed with Dixon packing. When the fraction having a temperature of 1333 Pa and a temperature of 92 to 93 ° C. was collected by this distillation, 52.1 g of a target product having a purity of 99.7% was obtained. The overall yield from the raw material phenylacetyl chloride was 27.2%.

(First step: Chlorination)
A 500 ml four-necked flask equipped with a Dimroth tube, a thermometer, and a chlorine blowing tube was charged with 154.5 g (1.0 mol) of phenylacetyl chloride, the internal temperature was raised to 200 ° C. while stirring, and chlorine gas was supplied. The reaction was started at a rate of about 0.5 mol / Hr. While maintaining the internal temperature at 200 ° C., chlorine gas was supplied for 4.5 hours. As a result, the composition of the reaction solution was 91.1% (selectivity) of 2,2-dichloro-phenylacetyl chloride, which was the target product, as analyzed by gas chromatography. Other by-products include 2,2-dichloro- (2-chloro-phenyl) acetyl chloride and 2,2-dichloro- (3-chloro-phenyl) acetyl chloride and 2,2-dichloro which are perchlorates The total of-(4-chloro-phenyl) acetyl chloride was 4.1% and benzoyl chloride was 0.1%. The weight of the reaction solution was 220.0 g. This reaction solution (chlorination mixture) was used for the subsequent second step (esterification) without purification.
(Second step: esterification)
In a 1000 ml four-necked flask equipped with a Dimroth condenser, thermometer and dropping funnel, ethanol: 181.1 g (3.94 mol) and lutidine: 157.4 g (1.47 mol) and a dropping funnel were obtained in the first step. 2,2-Dichloro-phenylacetyl chloride: 220.0 g (0.98 mol) was charged, and the internal temperature was cooled to 10 ° C. with stirring. The dropping of 2,2-dichloro-phenylacetyl chloride obtained in the first step from the dropping funnel was started, and the reaction was started. While maintaining the internal temperature at 30 ° C. or lower, 2,2-dichloro-phenylacetyl chloride: 220.0 g was added dropwise over 30 minutes. The composition of the reaction solution after completion of the dropwise addition of 2,2-dichloro-phenylacetyl chloride is 97.0% (selectivity) of 2,2-dichloro-phenylacetoacetic acid ethyl ester as the target product, as determined by gas chromatography analysis. there were. As other by-products, 2,2-dichloro- (2-chloro-phenyl) acetoacetic acid ethyl ester and 2,2-dichloro- (3-chloro-phenyl), which are compounds in which perchlorinated compounds are esterified The total of acetoacetic acid ethyl ester and 2,2-dichloro- (4-chloro-phenyl) acetoacetic acid ethyl ester was 2.5%, and benzoylacetic acid ethyl ester was 0.3%.

  After completion of the reaction, the collected reaction solution was washed once with water and once with 10% -HCl. Magnesium sulfate was added to the reaction solution after washing, followed by filtration after stirring. The weight of the reaction solution obtained from the filtrate was 211.2 g. This reaction solution was used in the subsequent third step (fluorination) without purification.

(Third step: fluorination)
2,2-dichloro-phenylacetoacetic acid ethyl ester obtained in the second step in a metal 1 L pressure-resistant reaction vessel equipped with a stirrer, a cooling reflux tube equipped with a pressure control valve, a thermocouple, a pressure gauge, and a sampling tube: 210.0 g (0.90 mol) and anhydrous hydrogen fluoride: 360.5 g (18.0 mol) were charged and sealed, and the internal temperature was raised to 55 ° C. while stirring to initiate the reaction. The pressure control valve was adjusted so that the internal pressure became 0.5 MPa, and the reaction was performed for 3 hours while releasing hydrogen chloride generated with the progress of the reaction out of the system. The composition of the reaction solution after 3 hours was found to be 86.2% (selectivity) of 2,2-difluoro-phenylacetoacetic acid ethyl ester as a target product from gas chromatography analysis. The other fluorinated compound, 2-chloro-2-fluoro-phenylacetoacetic acid ethyl ester, was 5.1%, and unreacted 2,2-dichloro-phenylacetoacetic acid ethyl ester was 0%. It was. After completion of the reaction, the recovered reaction solution was washed with water. Calcium chloride was added to the reaction solution after washing, followed by filtration after stirring. The weight of the reaction solution obtained from the filtrate was 145.8 g.

  The resulting fluorination reaction solution was purified by distillation in a 45 cm distillation column packed with Dixon packing. By fractionating a fraction at 1467 Pa and a temperature of 89 to 91 ° C. by this distillation, 90.8 g of the desired product having a purity of 99.5% was obtained. The overall yield from the raw material phenylacetyl chloride was 47.4%.

(First step: Chlorination)
A 500 ml four-necked flask equipped with a Dimroth tube, a thermometer, and a chlorine blowing tube was charged with 154.5 g (1.0 mol) of phenylacetyl chloride, the internal temperature was raised to 180 ° C. while stirring, and chlorine gas was supplied. The reaction was started at a rate of about 0.5 mol / Hr. While maintaining the internal temperature at 180 ° C., chlorine gas was supplied for 5 hours. As a result, the composition of the reaction solution was found to be 96.3% (selectivity) for 2,2-dichloro-phenylacetyl chloride, which was the target product, from gas chromatography analysis. Other by-products include 2,2-dichloro- (2-chloro-phenyl) acetyl chloride and 2,2-dichloro- (3-chloro-phenyl) acetyl chloride and 2,2-dichloro which are perchlorates The total of-(4-chloro-phenyl) acetyl chloride was 2.3% and benzoyl chloride was 0.3%. The weight of the reaction solution was 221.5 g. This reaction solution (chlorination mixture) was used for the subsequent second step (esterification) without purification.
(Second step: esterification)
In a 1000 ml four-necked flask equipped with a Dimroth condenser, thermometer and dropping funnel, ethanol: 181.1 g (3.94 mol) and potassium carbonate: 101.6 g (0.74 mol) were obtained in the dropping funnel in the first step. 2,2-dichloro-phenylacetyl chloride: 220.0 g (0.98 mol) was charged, and the internal temperature was cooled to 10 ° C. with stirring. The dropping of 2,2-dichloro-phenylacetyl chloride was started from the dropping funnel, and the reaction was started. While maintaining the internal temperature at 30 ° C. or lower, 2,2-dichloro-phenylacetyl chloride: 220.0 g was added dropwise over 45 minutes. The composition of the reaction solution after the completion of the dropwise addition of 2,2-dichloro-phenylacetyl chloride is 95.3% (selectivity) of 2,2-dichloro-phenylacetoacetic acid ethyl ester as the target product from gas chromatography analysis. there were. As other by-products, 2,2-dichloro- (2-chloro-phenyl) acetoacetic acid ethyl ester and 2,2-dichloro- (3-chloro-phenyl), which are compounds in which perchlorinated compounds are esterified The total of acetoacetic acid ethyl ester and 2,2-dichloro- (4-chloro-phenyl) acetoacetic acid ethyl ester was 2.3%, and benzoyl acetic acid ethyl ester was 0.3%.

  After completion of the reaction, the collected reaction solution was washed once with water and once with 10% -HCl. Magnesium sulfate was added to the reaction solution after washing, followed by filtration after stirring. The weight of the reaction solution obtained from the filtrate was 198.2 g. This reaction solution was used in the subsequent third step (fluorination) without purification.

(Third step: fluorination)
2,2-dichloro-phenylacetoacetic acid ethyl ester obtained in the second step in a metal 1 L pressure-resistant reaction vessel equipped with a stirrer, a cooling reflux tube equipped with a pressure control valve, a thermocouple, a pressure gauge, and a sampling tube: 198.0 g (0.85 mol) and anhydrous hydrogen fluoride: 340.3 g (17.0 mol) were charged and sealed, the internal temperature was raised to 55 ° C. while stirring, and the reaction was started. The pressure control valve was adjusted so that the internal pressure became 0.5 MPa, and the reaction was performed for 3 hours while releasing hydrogen chloride generated with the progress of the reaction out of the system. The composition of the reaction solution after 3 hours was found to be 86.2% (selectivity) of 2,2-difluoro-phenylacetoacetic acid ethyl ester as a target product from gas chromatography analysis. The other fluorinated compound, 2-chloro-2-fluoro-phenylacetoacetic acid ethyl ester, was 5.1%, and unreacted 2,2-dichloro-phenylacetoacetic acid ethyl ester was 0%. It was. After completion of the reaction, the recovered reaction solution was washed with water. Calcium chloride was added to the reaction solution after washing, followed by filtration after stirring. The weight of the reaction solution obtained from the filtrate was 137.7 g.

  The resulting fluorination reaction solution was purified by distillation in a 45 cm distillation column packed with Dixon packing. A fraction having a concentration of 1467 Pa and a temperature of 89 to 91 ° C. was collected by this distillation, whereby 85.7 g of a target product having a purity of 99.5% was obtained. The overall yield from the raw material phenylacetyl chloride was 42.9%.

(First step: Chlorination)
A 500 ml four-necked flask equipped with a Dimroth tube, a thermometer, and a chlorine blowing tube was charged with 154.5 g (1.0 mol) of phenylacetyl chloride, and the internal temperature was raised to 180 ° C. while stirring to supply chlorine gas. The reaction was started at a rate of about 0.5 mol / Hr. While maintaining the internal temperature at 180 ° C., chlorine gas was supplied for 5 hours. As a result, the composition of the reaction solution was found to be 96.3% (selectivity) for 2,2-dichloro-phenylacetyl chloride, which was the target product, from gas chromatography analysis. Other by-products include 2,2-dichloro- (2-chloro-phenyl) acetyl chloride and 2,2-dichloro- (3-chloro-phenyl) acetyl chloride and 2,2-dichloro which are perchlorates The total of-(4-chloro-phenyl) acetyl chloride was 2.3% and benzoyl chloride was 0.3%. The weight of the reaction solution was 221.5 g. This reaction solution (chlorination mixture) was used for the subsequent second step (esterification) without purification.
(Second step: esterification)
In a 1000 ml four-necked flask equipped with a Dimroth condenser, thermometer, blowing tube and dropping funnel, ethanol: 180.3 g (3.92 mol) and 2,2-dichloro-phenyl obtained in the first step in the dropping funnel Acetyl chloride: 220.0 g (0.98 mol) was charged, and the internal temperature was cooled to 7 ° C. while stirring. While introducing nitrogen gas from the blowing tube at 100 ml / min, the dropping of 2,2-dichloro-phenylacetyl chloride was started from the dropping funnel, and the reaction was started. While maintaining the internal temperature at 30 ° C. or lower, 2,2-dichloro-phenylacetyl chloride: 220.0 g was added dropwise over 40 minutes. The composition of the reaction solution after completion of the dropwise addition of 2,2-dichloro-phenylacetyl chloride is 96.5% (selectivity) of 2,2-dichloro-phenylacetoacetic acid ethyl ester, which is the target product, from gas chromatography analysis. there were. As other by-products, 2,2-dichloro- (2-chloro-phenyl) acetoacetic acid ethyl ester and 2,2-dichloro- (3-chloro-phenyl), which are compounds in which perchlorinated compounds are esterified The total of acetoacetic acid ethyl ester and 2,2-dichloro- (4-chloro-phenyl) acetoacetic acid ethyl ester was 2.2%, and benzoyl acetic acid ethyl ester was 0.3%.

  After completion of the reaction, the collected reaction solution was washed once with water and once with 10% -HCl. Magnesium sulfate was added to the reaction solution after washing, followed by filtration after stirring. The weight of the reaction solution obtained from the filtrate was 212.4 g. This reaction solution was used in the subsequent fluorination step (third step) without purification.

(Third step: fluorination)
2,2-dichloro-phenylacetoacetic acid ethyl ester obtained in the second step in a metal 1 L pressure-resistant reaction vessel equipped with a stirrer, a cooling reflux tube equipped with a pressure control valve, a thermocouple, a pressure gauge, and a sampling tube: 210.0 g (0.90 mol) and anhydrous hydrogen fluoride: 360.5 g (18.0 mol) were charged and sealed, and the internal temperature was raised to 55 ° C. while stirring to initiate the reaction. The pressure control valve was adjusted so that the internal pressure became 0.5 MPa, and the reaction was performed for 3 hours while releasing hydrogen chloride generated with the progress of the reaction out of the system. The composition of the reaction solution after 3 hours was found to be 86.2% (selectivity) of 2,2-difluoro-phenylacetoacetic acid ethyl ester as a target product from gas chromatography analysis. The other fluorinated compound, 2-chloro-2-fluoro-phenylacetoacetic acid ethyl ester, was 5.1%, and unreacted 2,2-dichloro-phenylacetoacetic acid ethyl ester was 0%. It was. After completion of the reaction, the recovered reaction solution was washed with water. Calcium chloride was added to the reaction solution after washing, followed by filtration after stirring. The weight of the reaction solution obtained from the filtrate was 145.8 g.

The resulting fluorination reaction solution was purified by distillation in a 45 cm distillation column packed with Dixon packing. By fractionating a fraction at 1467 Pa and a temperature of 89 to 91 ° C. by this distillation, 90.8 g of the desired product having a purity of 99.5% was obtained. The overall yield from the raw material phenylacetyl chloride was 47.4%.
<Physical property data of 2,2-dichloro-phenylacetyl chloride>
¹ H-NMR (reference material: TMS, solvent: CDCl ₃ ) δ (ppm): 7.58 (mlut, 1H).
GC-MS m / z (rel. Intensity): 222 (M ⁺ , 0.8), 163 (10.4), 161 (63.6), 159 (100.0), 124 (10.5), 89 (27.1), 63 (14.8).
<Physical property data of 2,2-dichloro-phenylacetoacetic acid ethyl ester>
¹ H-NMR (reference material: TMS, solvent: CDCl ₃ ) δ (ppm) 7.54 (mlut, 1H), 4.31 (q, 7.13, 2H), 1.28 (t, 7.13) 3H).
GC-MS m / z (rel. Intensity): 232 (M ⁺ , 1.2), 163 (10.4), 161 (62.5), 159 (100.0), 124 (11.7), 89 (32.3), 63 (14.9).
<Physical property data of 2,2-difluoro-phenylacetoacetic acid ethyl ester>
¹ H-NMR (reference material: TMS, solvent: CDCl ₃ ) δ (ppm): 7.51 (mlut, 1H), 4.29 (q, 7.13, 2H), 1.29 (t, 7. 13, 3H).
¹⁹ F-NMR (reference material: CCl ₃ F, solvent: CDCl ₃ ) δ (ppm): −104.34 (s, 2F).
GC-MS m / z (rel. Intensity): 200 (M ⁺ , 8.0), 127 (100.0) 107 (2.0), 77 (9.5).

Claims (6)

A process for producing 2,2-difluoro-phenylacetoacetic acid ester comprising the following three steps.
First step: phenylacetyl chloride represented by the formula [1]

Is reacted with chlorine (Cl ₂ ) and 2,2-dichloro-phenylacetyl chloride represented by the formula [2]
Obtaining.
Second step: 2,2-dichloro-phenylacetyl chloride obtained in the first step is used as an alcohol represented by the formula [3]
(In the formula, n represents an integer of 1 to 10 carbon atoms.)
2,2-dichloro-phenylacetoacetate represented by the formula [4]
(Wherein n is the same as above)
Obtaining.
Third step: 2,2-Dichloro-phenylacetoacetate obtained in the second step is reacted with hydrogen fluoride (HF) in the liquid phase, and 2,2-difluoro-phenyl represented by the formula [5] Acetoacetate
(Wherein n is the same as above)
Obtaining. The method according to claim 1, wherein the alcohol represented by the formula [3] in the second step is methanol, ethanol, or propanol.   The process according to claim 1 or 2, wherein the reaction of 2,2-dichloro-phenylacetoacetate and hydrogen fluoride (HF) in the third step is carried out without a solvent.   The method according to any one of claims 1 to 3, wherein the compound obtained after the first step is used as it is in the second step without purification.   The method according to any one of claims 1 to 4, wherein the compound obtained after the second step is used as it is in the third step without purification.   The method according to any one of claims 1 to 5, wherein the second step is performed while a dry inert gas is allowed to flow through the mixture obtained after the first step.