Title of the invention: Practical method for producing fluorine-containing α-ketocarboxylic acid esters
Technical field

[0001]
　TECHNICAL FIELD The present invention relates to a practical production method of fluorine-containing α-ketocarboxylic acid esters which are important as intermediates for medicines and agricultural chemicals.
BACKGROUND ART

[0002]
　Fluorine-containing α-ketocarboxylic acid esters are important compounds as medicine and agricultural chemical intermediates. Representative methods for producing fluorine-containing α-ketocarboxylic acid esters include non-patent documents 1 to 4. Non-patent document 1 is a method for producing 3,3,3-trifluoropyruvic acid ester from hexafluoropropene-1,2-oxide. Non-Patent Document 2 is a method for producing 3,3-difluoropyruvic acid ester having key reaction of hydrogen fluoride and tautomerism of 3,3,3-trifluoro lactic acid ester derivative. Non-Patent Document 3 is a method for producing 3,3-difluoropyruvic acid ester in which reductive defluorination of a 2-trifluoroacetylfuran derivative and oxidative decomposition of a furan portion are key reactions. Non-Patent Document 4 is a method of oxidizing a fluorine-containing α-hydroxycarboxylic acid ester with a Dess-Martin reagent to produce a corresponding fluorine-containing α-ketocarboxylic acid ester.
[0003]
　On the other hand, Non-Patent Document 5 discloses a method of producing a corresponding trifluoromethyl ketone by oxidizing an alcohol having a trifluoromethyl group at the α-position with a Dess-Martin reagent, and further, Patent Document 1 Discloses a process for producing trifluoromethyl ketone by reacting an alcohol having a trifluoromethyl group at the α position with an aqueous solution of a hypohalous acid having a low content (1 to 20% by mass).
Prior Art Document

Patent literature

[0004]
Patent Document 1: National Publication of International Patent Application No. Hei 7-506337
Non-patent literature

[0005]
Non-patent document 1: Journal of Fluorine Chemistry (Netherlands), 2002, 115, p. 67-74
Non-Patent Document 2: Journal of Organic Chemistry (USA), 1996, 61, p. 7521-7528
Non-patent document 3: Journal of Fluorine Chemistry (Netherlands), 2009, 130, p. 682-683
Non-Patent Document 4: Journal of Organic Chemistry (USA), 1995, Vol. 60, p. 5174-5179
Non-Patent Document 5: Tetrahedron (UK), 1991, Vol. 47, p. 3207-3258
Disclosure of invention

Problem to be Solved by Invention

[0006]
　An object of the present invention is to provide a practical method for producing fluorine-containing α-ketocarboxylic acid esters which are important as intermediates for medicines and agricultural chemicals.
[0007]
　Non Patent Literature 1 is highly practical as a method for producing 3,3,3-trifluoropyruvic acid ester, but it is specialized only for the present compound, for example, 3,3-difluoropyruvic acid It was not successfully applied to analogous compounds like esters. In Non-Patent Document 2, tautomerism and side reaction became dominant and low yield was obtained. Non-Patent Document 3 required extremely low temperature conditions and it was difficult to scale up.
[0008]
　Considering the problem of the conventional production method, it is considered that the method of oxidizing the fluorine-containing α-hydroxycarboxylic acid ester which is relatively easily available is superior from the viewpoint of practicality. However, such an oxidizing agent which gives good results by oxidation of alcohol is limited to the Dess · Martin reagent which is expensive and pointed out the danger of handling, which is unsuitable for scale-up (Non-Patent Document 4).
[0009]
　The method described in Patent Document 1 is a remarkably practical manufacturing method as compared with the method described in Non-Patent Document 5 in which analogous raw materials are oxidized with Dess-Martin reagent. However, even if the fluorine-containing α-hydroxycarboxylic acid ester which is the raw material of the present invention is actually subjected to the typical reaction condition of Patent Document 1 (see Example 6 of said document), it is actually contained in the recovered organic layer It is found that there are few target substances and Patent Document 1 can not be a practical production method of the objective compound of the present invention (see Comparative Example 1). On the contrary, satisfactory results could not be obtained even if the raw materials and analogous materials claimed in Patent Document 1 were subjected to suitable reaction conditions of the present invention (see Comparative Examples 2 and 3).
[0010]
　Accordingly, a specific object of the present invention is to provide a novel fluorinated α-ketocarboxylic acid ester obtained by oxidizing a fluorine-containing α-hydroxycarboxylic acid ester with an oxidizing agent which is inexpensive and which is safe to handle even in scale-up It is to find a manufacturing method.
Means for solving the problem

[0011]
　As a result of intensive studies to solve the above problems, the present inventors have found that a fluorine-containing α-hydroxycarboxylic acid ester represented by the general formula [1] (hereinafter referred to as the compound [1]) is " (Hereinafter referred to as the compound [2]) by reacting the fluorine-containing α-ketocarboxylic acid ester represented by the general formula [2] with sodium hypochlorite or calcium hypochlorite having a concentration of 21% ) Can be produced by using the method of the present invention.
In the

formula, R 1 represents a hydrogen atom, a halogen atom or a haloalkyl group, and R 2 represents an alkyl group or a substituted alkyl group. ]
[Formula 2]

wherein, R 1 and R 2 has the general formula [1] R of 1 and R 2 are the same as. ]
[0012]
　In the present invention, hypochlorite disclosed in Patent Document 1 is used as an oxidizing agent, but the content of hypochlorite is clearly different, and the raw material substrate to be treated is clearly different.
[0013]
　The original oxidation product is considered to be a fluorine-containing α-ketocarboxylic acid ester represented by the general formula [3] (hereinafter referred to as the compound [3]), but water derived from the oxidizing agent or equivalent amount byproduct The α-keto group is obtained as a hydrated compound [2] by water to be treated. Therefore, in the present invention, a step of dehydrating the compound [2] into the compound [3] is also included.
[Chemical Formula 3]

[wherein, R 1 and R 2 are, R in the general formula [1] 1 and R 2 are the same as. ]
[0014]
　On the other hand, the fluorine-containing α-ketocarboxylic acid ester hemiketal (hereinafter referred to as the compound [5]) represented by the general formula [5] can be easily converted from the compound [2] (see Examples 5 and 6) , And can be recovered more efficiently via the compound [5] than the direct conversion from the compound [2] to the compound [3] (see also Examples 11 and 12 below).
[Formula 4]

[wherein, R 1 and R 2 are, R in the general formula [1] 1 and R 2 are the same as, R 3 represents an alkyl group having 1 to 4 carbon atoms. ] Further
　, the compound [5] has the same reactivity as the compound [3] (see Reference Examples 4 to 6), and the compound [5] is superior to the compound [3] also in long-term storage I found out. Thus, the compound [5] can effectively function as a synthetic equivalent of the compound [3].
[0015]
　The present invention is directed to the range shown in Scheme 1. Step A is an oxidation step for producing the compound [2] by reacting the compound [1] with "sodium hypochlorite or calcium hypochlorite having a mass percentage of composition of 21 mass% or more" B is a dehydration step for producing the compound [3] by reacting the compound [2] prepared in the step A with a dehydrating agent. Step C is a hemiketalization step for producing the compound [5] by reacting the compound [2] prepared in the step A with a lower alcohol or trialkyltin orthocarboxylate, the step D is a step And the compound [5] is reacted with a dealcoholizing agent to produce the compound [3]. Incidentally, when the compound [3] is brought into contact with water or a lower alcohol, it is immediately reverted back to the compound [2] and the compound [5], respectively. In addition, the compound [5] is easily reversed to the compound [2] by bringing it into contact with water.
[Chemical Formula 5]

[0016]
　Among the "sodium hypochlorite or calcium hypochlorite having a mass percentage of composition of 21 mass% or more" used in the step A, it is preferably 31 mass% or more, more preferably NaClO · 5 H 2 O or Ca (ClO) 2 · N H 2 O [n represents an integer of 0 to 3] is particularly preferable, and the desired reaction can be carried out with good yield.
[0017]
　Since the present invention can be suitably applied to the production of 3,3-difluoropyruvic acid esters in which the practical production method has been limited, as a preferred embodiment of the compound [1], 3,3-difluorolactate is preferably .
[0018]
　In the step A, a desired reaction can be smoothly carried out by reacting in the presence of a phase transfer catalyst. In addition, step A can be reacted without using a reaction solvent, which can contribute to high productivity and waste reduction from an industrial point of view.
[0019]
　It was also found that the compound [3] can be produced by reacting the compound [2] produced in the step A with a dehydrating agent.
[0020]
　Among the dehydrating agents, diphosphorous pentaoxide and concentrated sulfuric acid are preferable, and the compound [3] can be recovered with good yield.
[0021]
　It was also found that the compound [5] can be produced by reacting the compound [2] produced in the step A with a lower alcohol (hereinafter referred to as a step C-1).
[0022]
　Among the lower alcohols, methanol and ethanol are preferable, the boiling point of the obtained compound [5] can be kept low, and even a thermally unstable hemiketal structure can be purified by distillation.
[0023]
　Ester exchange {ester site (--CO 2 R 2 ) + lower alcohol (R 3 OH) → - CO 2 R 3 + R 2 OH} of compound [2] can occur as a side reaction in step C - 1, R 2] 2 with a lower alcohol R 3 a can be substantially avoided by aligning the same alkyl group, the preferred embodiments.
[0024]
　In Step C-1, a desired reaction can be carried out in a short time by reacting in the presence of an acid catalyst.
[0025]
　Further, by reacting the compound [2] prepared in the step A with trialkyl orthocarboxylate, a desired reaction can be reproduced well (hereinafter referred to as a step C-2). Equilibrium of Compound [2] ⇔ Compound [5] can be determined by consuming water existing in the reaction system [for example, R 4 C (OR 3 ) 3 + H 2 O → R 4 CO 2 R 3 + 2 R 3 OH] It can be greatly inclined to the side of the compound [5].
[0026]
　Among the trialkyl orthocarboxylates, trimethyl orthoformate, triethyl orthoformate, trimethyl orthoacetate and triethyl orthoacetate are preferable, the boiling point of the obtained compound [5] can be kept low, a thermally unstable hemiketal structure Even though it can be purified by distillation.
[0027]
　Ester exchange (ester site (--CO 2 R 2 ) of compound [2] + lower alcohol (R 3 OH) → - CO 2 R 3 + R 2 OH} formed in the reaction system → But it can be substantially avoided by aligning R 2 of the compound [2] and R 3 of the trialkyl orthocarboxylate to the same alkyl group, which is a preferred embodiment.
[0028]
　In step C-2, a desired reaction can be carried out in a short time by reacting in the presence of an acid catalyst.
[0029]
　It was also found that the compound [3] can be produced by reacting the compound [5] produced in the step C-2 with a dealcoholizing agent.
[0030]
　Of the dealcoholizing agents, diphosphorus pentoxide and concentrated sulfuric acid are preferable, and the compound [3] can be recovered with good yield.
[0031]
　That is, the present invention provides the following [invention 1] to [invention 17].
[0032]
　[Invention 1] By
　reacting the fluorine-containing α-hydroxycarboxylic acid ester represented by the general formula [1] with "sodium hypochlorite or calcium hypochlorite having a mass percentage of composition of 21 mass% or more" A method for producing a fluorine-containing α-ketocarboxylic acid ester hydrate represented by the general formula [2].
In the

formula, R 1 represents a hydrogen atom, a halogen atom or a haloalkyl group, and R 2 represents an alkyl group or a substituted alkyl group. ]
[Chemical Formula 7]

[wherein, R 1 represents a hydrogen atom, a halogen atom or a haloalkyl group, R 2 represents an alkyl group or a substituted alkyl group. ]
[0033]
　[Inventive
　Aspect 2] The method according to Invention 1, characterized in that it is reacted with "sodium hypochlorite or calcium hypochlorite having a mass percentage of the composition of 31 mass% or more".
[0034]
　[Invention 3]
　NaClO · 5 H 2 O or Ca (ClO) 2 · n H 2 O [wherein n represents an integer of 0 to 3]. The process according to Invention 1, characterized in that it is reacted with a compound of the formula
[0035]
　[Invention 4] The method according to any one of Inventions 1 to 3, wherein
　R 1 of the fluorine-containing α-hydroxycarboxylic acid ester represented by the general formula [1] is a hydrogen atom.
[0036]
　[Invention 5]
　The method according to any one of Inventions 1 to 4, which comprises reacting in the presence of a phase transfer catalyst.
[0037]
　[Invention 6]
　The method according to any one of Inventions 1 to 5, wherein the reaction is carried out without using a reaction solvent.
[0038]
　[Invention 7]
　A method for producing a fluorine-containing α-ketocarboxylic acid ester hydrate represented by the general formula [2] by the method according to any one of the inventions 1 to 6, and then dehydrating the ester · hydrate To produce a fluorine-containing α-ketocarboxylic acid ester represented by the general formula [3].
In the

formula, R 1 represents a hydrogen atom, a halogen atom or a haloalkyl group, and R 2 represents an alkyl group or a substituted alkyl group. ]
[0039]
　[Invention 8]
　The method according to Invention 7, wherein the dehydrating agent is diphosphorus pentoxide or concentrated sulfuric acid.
[0040]
　[Invention 9]
　A method for producing a fluorine-containing α-ketocarboxylic acid ester hydrate represented by the general formula [2] by the method according to any one of the inventions 1 to 6, A method for producing a fluorine-containing α-ketocarboxylic acid ester · hemiketal represented by the general formula [5] by reacting with a lower alcohol represented by the general formula [4].
In the

formula, R 3 represents an alkyl group having 1 to 4 carbon atoms. ]
[Formula 10]

wherein, R 1 represents a hydrogen atom, a halogen atom or a haloalkyl group, R 2 represents an alkyl group or a substituted alkyl group, R 3 represents an alkyl group having 1 to 4 carbon atoms. ]
[0041]
　[Invention 10] The method according to Invention 9, wherein
　R 3 of the lower alcohol represented by the general formula [4] is a methyl group or an ethyl group.
[0042]
　[Invention 11] It is confirmed that
　R 2 of the fluorine-containing α-ketocarboxylic acid ester hydrate represented by the general formula [2] and R 3 of the lower alcohol represented by the general formula [4] are the same alkyl group A method according to invention 9 or 10 characterized in that it is characterized.
[0043]
　[Invention 12]
　A process for producing a fluorine-containing α-ketocarboxylic acid ester hydrate represented by the general formula [2] by a process according to any one of the inventions 1 to 6, A method for producing a fluorine-containing α-ketocarboxylic acid ester · hemiketal represented by the general formula [5] by reacting with a trialkyl orthocarboxylate represented by the general formula [6].
In the

formula, R 3 represents an alkyl group having 1 to 4 carbon atoms, and R 4 represents a hydrogen atom, a methyl group or an ethyl group. ]
[Formula 12]

wherein, R 1 represents a hydrogen atom, a halogen atom or a haloalkyl group, R 2 represents an alkyl group or a substituted alkyl group, R 3 represents an alkyl group having 1 to 4 carbon atoms. ]
[0044]
　[Invention 13] The method according to Invention 12, wherein
　R 3 of the trialkyl orthocarboxylate represented by the general formula [6] is a methyl group or an ethyl group.
[0045]
　[Invention 14]
　R 2 of the fluorine-containing α-ketocarboxylic acid ester hydrate represented by the general formula [2] and R 3 of the trialkyl orthocarboxylate represented by the general formula [6] are the same alkyl group A method according to invention 12 or 13, characterized in that it is characterized by being.
[0046]
　[Invention 15]
　The method according to any one of Inventions 9 to 14, wherein the reaction is carried out in the presence of an acid catalyst.
[0047]
　[Invention 16]
　A method for producing a fluorine-containing α-ketocarboxylic acid ester · hemiketal represented by the general formula [5] by the method according to any one of the inventions 9 to 15, then reacting the ester · hemiketal with the dealcoholizing agent To give a fluorine-containing α-ketocarboxylic acid ester represented by the general formula [3].
In the

formula, R 1 represents a hydrogen atom, a halogen atom or a haloalkyl group, and R 2 represents an alkyl group or a substituted alkyl group. ]
[0048]
　[Invention 17]
　The method according to Invention 16, wherein the dealcoholizing agent is diphosphorous pentoxide or concentrated sulfuric acid.
[0049]
　In the present invention, by suitably combining the raw materials and the reaction conditions, it is possible to produce the effect that the fluorine-containing α-hydroxycarboxylic acid ester can be efficiently produced with high yield.
MODE FOR CARRYING OUT THE INVENTION

[0050]
　Details of the present invention will be described below in order of oxidation step, dehydration step, hemiketalization step and dealcoholization step.
[0051]
　1. Oxidation Step
　This step is a step of reacting the fluorine-containing α-hydroxycarboxylic acid ester represented by the general formula [1] with "sodium hypochlorite or calcium hypochlorite having a mass percentage of composition of 21 mass% or more" Is a step of producing a fluorine-containing α-ketocarboxylic acid ester hydrate represented by the general formula [2].
[0052]
　R 1 of the fluorine-containing α-hydroxycarboxylic acid ester represented by the general formula [1] represents a hydrogen atom, a halogen atom or a haloalkyl group. The halogen atom is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. The haloalkyl group may be substituted with any number and any combination on any carbon atom of a straight or branched chain or cyclic (in the case of 3 or more carbon atoms) alkyl group having 1 to 12 carbon atoms And has the above-mentioned halogen atom. Among them, a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom and a haloalkyl group having 1 to 6 carbon atoms are preferable, and a hydrogen atom is particularly preferable.
[0053]
　R 2 of the fluorine-containing α-hydroxycarboxylic acid ester represented by the general formula [1] represents an alkyl group or a substituted alkyl group. The alkyl group is a linear or branched chain or cyclic (in the case of having 3 or more carbon atoms) having 1 to 8 carbon atoms. The substituted alkyl group has a substituent on any carbon atom of the alkyl group in any number and in any combination. Such a substituent is the above-mentioned halogen atom or an alkoxy group having 1 to 4 carbon atoms. The alkyl moiety of the alkoxy group is linear or branched chain or cyclic (in the case of having 3 or more carbon atoms). Among these, an alkyl group having 1 to 4 carbon atoms is preferable, and a methyl group and an ethyl group are particularly preferable.
[0054]
　The fluorine-containing α-hydroxycarboxylic acid esters represented by the general formula [1] are described in JP-A Nos. 1993-279314, 2004-018503, and 2014-078220 (hereinafter referred to as Patent Document 2) And Non-Patent Document 4 or the like (see Reference Example 1). Even if the substituent groups of R 1 and R 2 are somewhat different somewhat different novel compounds in a narrow sense, they can be prepared in the same manner. R Among them 1 and R 2 are preferred compounds of the preferred combinations of, R 1 and R 2 the compounds of the particularly preferred combination of particularly preferred.
[0055]
　The chemical formulas of sodium hypochlorite and calcium hypochlorite are represented by NaClO, Ca (ClO) 2 , respectively . Sodium hypochlorite and calcium hypochlorite are often used in the form of hydrates or aqueous solutions, and in some cases inorganic salts without oxidative activity may be included in production.
[0056]
　"Sodium hypochlorite or calcium hypochlorite having a mass percentage of composition of 21 mass% or more" means that the component as NaClO or Ca (ClO) 2 is contained in an amount of 21 mass% or more. Specific examples thereof include compounds exemplified by the following mass percentages. Among them, those having 31 mass% or more are preferable, and NaClO · 5H 2 O and Ca (ClO) 2 · nH 2 O are particularly preferable. N in Ca (ClO) 2 .nH 2 O represents an integer from 0 to 3. As an illustration of the mass percentage, NaClO · 5H 2 O is 45% by mass based on "molecular weight of NaClO (74.4) ÷ NaClO · 5H 2 O (164.5) × 100". Ca (ClO) 2 · H 2 O, Ca (ClO) 2 · 2H 2 O, Ca (ClO) 2 · 3H 2 O and Ca (ClO) 2 · CaCl 2 · 2H 2 O [CaCl (ClO) · H 2O] are 89 mass%, 80 mass%, 73 mass%, 49 mass%, respectively, from the same calculation. Naturally, the 12% by mass sodium hypochlorite aqueous solution and Ca (ClO) 2 are 12% by mass and 100% by mass, respectively. With respect to the content of sodium hypochlorite or calcium hypochlorite, an additive or the like which does not substantially affect the oxidation reaction itself (or has no oxidation activity) is deliberately added, and the apparent content of the oxidizing agent Is less than 21% by mass, it is treated as included in the claims of the present invention.
[0057]
　NaClO · 5H 2 O suitable as an oxidizing agent can be used in industrial grades and has long-term storage stability compared to a low content aqueous sodium hypochlorite solution, which is advantageous in industrial implementation.
[0058]
　The amount of sodium hypochlorite or calcium hypochlorite to be used is 0.7 mol or more as NaClO or Ca (ClO) 2 component with respect to 1 mol of the fluorine-containing α-hydroxycarboxylic acid ester represented by the general formula [1] May be used, preferably 0.8 to 7 mol, particularly preferably 0.9 to 5 mol.
[0059]
　Since this step is often a heterogeneous reaction, it can be reacted in the presence of a phase transfer catalyst, if necessary. Naturally, by adopting suitable reaction conditions, it is not always necessary to use a phase transfer catalyst.
[0060]
　The phase transfer catalyst is not particularly limited, and examples thereof include quaternary ammonium salt, phosphonium salt, polyether (polyethylene glycol, crown ether), and the like. Among these, quaternary ammonium salts are preferable, tetra n-butyl ammonium bromide and tetra n-butyl ammonium hydrogen sulfate are particularly preferable.
[0061]
　The quaternary ammonium salt is represented by the general formula [7].
[Formula 14]

wherein, R 5 , R 6 , R 7 and R 8 represent each independently an alkyl group or an aralkyl group, X - is a halide ion or hydrogen sulfate ion (HSO 4 - represents a). The
　alkyl group is a linear or branched chain or cyclic (in the case of having 3 or more carbon atoms) having 1 to 12 carbon atoms. The aralkyl group has 1 to 12 carbon atoms, and the alkyl moiety is linear or branched chain or cyclic (in the case of having 9 or more carbon atoms). The halide ion is a fluoride ion, a chloride ion, a bromide ion or an iodide ion.
[0062]
　The amount of the phase transfer catalyst to be used may be 0.7 mol or less with respect to 1 mol of the fluorine-containing α-hydroxycarboxylic acid ester represented by the general formula [1], preferably 0.0001 to 0.5 mol, more preferably 0.0005 And particularly preferably 0.3 mol.
[0063]
　The reaction solvent is not particularly limited and examples thereof include aliphatic hydrocarbons such as n-hexane, cyclohexane and n-heptane, aromatic hydrocarbons such as toluene, xylene and mesitylene, aromatic hydrocarbons such as methylene chloride, chloroform, 1,2-dichloroethane and the like Ethers such as tetrahydrofuran, tert-butyl methyl ether and 1,2-dimethoxyethane, esters such as ethyl acetate, n-butyl acetate, propylene glycol monomethyl ether acetate and the like, N, N-dimethylformamide, Amide type such as N, N-dimethylacetamide and 1,3-dimethyl-2-imidazolidinone, nitrile type such as acetonitrile, propionitrile, benzonitrile and the like. Among them, aromatic hydrocarbon type, halogen type, ether type, ester type and nitrile type are preferable, and aromatic hydrocarbon type, ester type and nitrile type are particularly preferable. These reaction solvents can be used alone or in combination. This step can also be carried out without using a reaction solvent, and the reaction in neat may be a preferred embodiment in some cases.
[0064]
　The reaction solvent may be used in an amount of 0.01 L (liter) or more per 1 mol of the fluorine-containing α-hydroxycarboxylic acid ester represented by the general formula [1], preferably 0.02 to 7 L, more preferably 0.03 To 5 L is particularly preferable.
[0065]
　The reaction temperature may be carried out at + 150 ° C. or lower, preferably from + 125 to -50 ° C., particularly preferably from +100 to -25 ° C.
[0066]
　Since the reaction time may be carried out within 48 hours, depending on the raw material substrate and reaction conditions, the progress of the reaction is tracked by analysis means such as gas chromatography, liquid chromatography, nuclear magnetic resonance, and the decrease of the raw material substrate It is preferable to set the end point as the point where almost no recognition is made.
[0067]
　The post-treatment can obtain the fluorine-containing α-ketocarboxylic acid ester hydrate represented by the general formula [2] by adopting a general procedure in organic synthesis. If the boiling point of the object product obtained is sufficiently low, it is convenient to directly recover from the reaction finished liquid by distillation (see Example 4). If necessary, the recovered crude product can be purified to high purity by fractional distillation, recrystallization, column chromatography and the like.
[0068]
　This step and the hemiketalization step can also be performed as a one-pot reaction, which is a preferred embodiment of the present invention (see Example 8).
[0069]
　R fluorinated α- ketocarboxylic acid ester hydrate represented by the general formula [2] 1 and R 2 has the general formula [1] in the fluorine-containing α- hydroxy carboxylic acid ester represented R 1 and R 2 in It comes from.
[0070]
　In the compound [1] as the raw material of the present invention, there is an ester group which is easily hydrolyzed, and when it is hydrolyzed before the desired oxidation occurs, a fluorine-containing carboxylic acid (R 1 CF 2 CO 2 H) as a by-product (see Comparative Example 4). On the other hand, when the target substance is hydrolyzed after oxidation, it becomes a highly water-soluble α-ketocarboxylic acid hydrate [R 1 CF 2 C (OH) 2 CO 2 H] It is difficult to recover it in the organic layer. In the present invention, since a high content of hypochlorite is used, not only the reactivity of oxidation can be improved, but also the amount of water brought into the reaction system can be minimized, and addition of undesired ester groups Decomposition can be prevented. Further, the 12% by mass sodium hypochlorite aqueous solution which is frequently used in Patent Document 1 contains, as compared with NaClO · 5H 2 O or Ca (ClO) 2 · nH 2 O which is a preferable oxidizing agent of the present invention , A large amount of unnecessary alkali components are contained, and there is a strong tendency to promote hydrolysis of the ester group (see Comparative Example 1). In this way, by using the preferred oxidizing agent of the present invention, the desired compound [2] can be obtained with good yield. In the present invention, the desired compound [2] can be obtained with high selectivity. For example, an objective compound having a hydrogen atom at the α-position of a carbonyl group (or gem-diol group) (R 1 of the compound [2]Is a chlorine atom as a side reaction, it can be suitably applied to the production of high purity products of 3,3-difluoropyruvic acid esters (see Examples 3 and 4) .
[0071]
　Further, in the present invention, there is no need to necessarily use the phase transfer catalyst essential in Patent Document 1, which can contribute to cost reduction and waste reduction from an industrial point of view (see Example 1).
[0072]
　Furthermore, in the present invention, there is no need to necessarily use the reaction solvent essential in Patent Document 1, which is advantageous from an industrial point of view (see Example 4).
[0073]
　Finally, suitable oxidizing agents for use in the present invention are inexpensively available on an industrial scale and are safe to handle on an industrial scale. Given that oxidation of analogous materials was conventionally limited to oxidizing agents such as Dess-Martin reagent (see Non-Patent Document 4), the high practicality of the present invention can be easily understood .
[0074]
　2. Dehydration Step In
　this step, by reacting the fluorine-containing α-ketocarboxylic acid ester hydrate represented by the general formula [2] with a dehydrating agent produced in the oxidation step, a fluorine-containing compound represented by the general formula [3] thereby producing an α-ketocarboxylic acid ester.
[0075]
　The dehydrating agent may be selected from inorganic compounds such as diphosphorus pentaoxide, concentrated sulfuric acid, sodium sulfate, magnesium sulfate, calcium sulfate, calcium chloride, molecular sieves (synthetic zeolite), silica gel and the like, acetic anhydride, propionic anhydride, benzoic anhydride, succinic anhydride Acid, maleic anhydride, phthalic anhydride, trifluoroacetic anhydride, trifluoromethanesulfonic anhydride, and other organic systems. Among them, diphosphorus pentoxide, concentrated sulfuric acid, calcium chloride, acetic anhydride, benzoic anhydride, succinic anhydride, phthalic anhydride and trifluoroacetic anhydride are preferable, and diphosphorus pentoxide and concentrated sulfuric acid are particularly preferable.
[0076]
　The amount of the dehydrating agent other than the molecular sieve and the silica gel to be used may be 0.1 mol or more per 1 mol of the fluorine-containing α-ketocarboxylic acid ester hydrate represented by the general formula [2], preferably 0.2 to 50 mol , And particularly preferably 0.3 to 30 mol.
[0077]
　The amount of molecular sieve and silica gel to be used may be 0.01 g or more based on 1 g of fluorine-containing α-ketocarboxylic acid ester hydrate represented by the general formula [2], preferably 0.02 to 10 g, more preferably 0 Especially preferred is 03 to 7 g.
[0078]
　In the case of using an organic dehydrating agent, the desired reaction can be smoothly carried out by reacting in the presence of an organic base such as a tertiary amine or a pyridine. Naturally, by adopting suitable reaction conditions, it is not always necessary to use an organic base.
[0079]
　Among organic base, triethylamine, diisopropylethylamine, tri-n- propylamine, tri-n- butylamine, pyridine, lutidine (including all positional isomers) and collidine (including all positional isomers) are preferred, triethylamine, tri n-butylamine, pyridine and lutidine are particularly preferred.
[0080]
　The tertiary amine is represented by the general formula [8].
In the

formula, R 9 , R 10 and R 11 each independently represent an alkyl group or an aralkyl group. The
　alkyl group is a linear or branched chain or cyclic (in the case of having 3 or more carbon atoms) having 1 to 12 carbon atoms. The aralkyl group has 1 to 12 carbon atoms, and the alkyl moiety is linear or branched chain or cyclic (in the case of having 9 or more carbon atoms).
[0081]
　The amount of the organic base used may be 0.1 mol or more per 1 mol of the fluorine-containing α-ketocarboxylic acid ester hydrate represented by the general formula [2], preferably 0.2 to 50 mol, more preferably 0.3 To 30 mol is particularly preferable.
[0082]
　The reaction solvent is not particularly limited, and examples thereof include aliphatic hydrocarbons such as n-hexane, cyclohexane and n-heptane, aromatic hydrocarbons such as toluene, xylene and mesitylene, methylene chloride, chloroform, 1,2- dichloroethane and the like Ether type such as tetrahydrofuran, cyclopentyl methyl ether and diethylene glycol dimethyl ether, ester type such as ethyl acetate, n-butyl acetate, propylene glycol monomethyl ether acetate and the like, N, N-dimethylformamide, N, N-dimethylacetamide, 1 , 3-dimethyl-2-imidazolidinone and the like, nitriles such as acetonitrile, propionitrile, benzonitrile and the like, sulfur type such as dimethylsulfoxide, methylphenyl sulfoxide, sulfolane and the like. Among them, aromatic hydrocarbon type, halogen type, ether type, ester type and nitrile type are preferable, aromatic hydrocarbon type, halogen type and ether type are particularly preferable. These reaction solvents can be used alone or in combination. This step can also be carried out without using a reaction solvent, and the reaction in neat may be a preferred embodiment in some cases.
[0083]
　The reaction solvent may be used in an amount of 0.01 L or more per 1 mol of the fluorine-containing α-ketocarboxylic acid ester hydrate represented by the general formula [2], preferably 0.02 to 5 L, more preferably 0.03 To 3 L is particularly preferable.
[0084]
　The reaction temperature may be carried out at + 200 ° C. or lower, preferably from +175 to -50 ° C., particularly preferably from + 150 to -25 ° C.
[0085]
　Since the reaction time may be carried out within 24 hours, it varies depending on the raw material substrate and reaction conditions, so that the progress of the reaction is tracked by analysis means such as gas chromatography, liquid chromatography, nuclear magnetic resonance, etc., and the reduction of the raw material substrate It is preferable to set the end point as the point where almost no recognition is made.
[0086]
　The post-treatment can obtain the fluorine-containing α-ketocarboxylic acid ester represented by the general formula [3] by adopting a general operation in organic synthesis. If the reaction is carried out without using a reaction solvent and the boiling point of the object product obtained is sufficiently low, the operation of directly recovering from the reaction completion liquid by distillation is simple. In addition, for thermally unstable target substances, it is possible to suitably apply an operation of withdrawing raw materials to a heated dehydrating agent and withdrawing the produced target substances successively under reduced pressure to the outside of the reaction system 11). If necessary, the recovered crude product can be purified to high purity by fractional distillation, recrystallization, column chromatography and the like.
[0087]
　R 1 and R 2 of the fluorine-containing α-ketocarboxylic acid ester represented by the general formula [3] are derived from R 1 and R 2 of the fluorine-containing α-ketocarboxylic acid ester hydrate represented by the general formula [2] .
[0088]
　3. Hemiketalization
　This step is a step of converting the fluorine-containing α-ketocarboxylic acid ester hydrate represented by the general formula [2] produced in the oxidation step with a lower alcohol represented by the general formula [4] or a lower alcohol represented by the general formula [6] To produce a fluorine-containing α-ketocarboxylic acid ester · hemiketal represented by the general formula [5]. In particular, the case of reacting with a lower alcohol represented by the general formula [4] is referred to as a hemiketalization step-1, and a case of reacting with a trialkyl orthocarboxylate represented by the general formula [6] is referred to as a hemiketalization step-2.
[0089]
　(Relating to Hemiketalization Process-1)
　R 3 of the lower alcohol represented by the general formula [4] represents an alkyl group having 1 to 4 carbon atoms. The alkyl group is linear or branched chain or cyclic (in the case of having 3 or more carbon atoms). Among them, those having 1 to 3 carbon atoms are preferable, and methyl group and ethyl group are particularly preferable.
[0090]
　The amount of the lower alcohol represented by the general formula [4] to be used may be 0.7 mol or more per 1 mol of the fluorine-containing α-ketocarboxylic acid ester hydrate represented by the general formula [2], and 0.8 To 200 mol, particularly preferably 0.9 to 150 mol.
[0091]
　(Relating to Hemiketalization Process-2)
　R 3 of trialkyl orthocarboxylate represented by the general formula [6] represents an alkyl group having 1 to 4 carbon atoms. The alkyl group is linear or branched chain or cyclic (in the case of having 3 or more carbon atoms). Among them, those having 1 to 3 carbon atoms are preferable, and methyl group and ethyl group are particularly preferable.
[0092]
　R 4 of the trialkyl orthocarboxylate represented by the general formula [6] represents a hydrogen atom, a methyl group or an ethyl group. Among them, a hydrogen atom and a methyl group are preferable, and a hydrogen atom is particularly preferable.
[0093]
　Formula Among ortho carboxylic acid trialkyl represented by [6], R 3 and R 4 preferably is a compound of preferred combinations of, R 3 and R 4 particularly preferably compounds of the particularly preferred combination of trimethyl orthoformate is highly preferred .
[0094]
　The amount of trialkyl orthocarboxylate represented by the general formula [6] may be 0.3 mol or more per 1 mol of the fluorine-containing α-ketocarboxylic acid ester hydrate represented by the general formula [2] Preferably from 0.4 to 100 mol, particularly preferably from 0.5 to 75 mol. When water is contained in the fluorine-containing α-ketocarboxylic acid ester hydrate represented by the general formula [2], which is used as a starting material, water may be used in a multipurpose, taking account of the water content. The hemiketalization step-2 can also be reacted in the presence of a lower alcohol represented by the general formula [4].
[0095]
　(Common to the hemiketalization step-1 and the hemiketalization step-2)
　This step is a step of converting the gem-diol group of the fluorine-containing α-ketocarboxylic acid ester hydrate represented by the general formula [2] into a hemiketal group , But as a side reaction the transesterification described above can occur. Naturally, by adopting suitable reaction conditions, it is possible to control side reactions to the minimum, but R 2 of the fluorinated α-ketocarboxylic acid ester hydrate represented by the general formula [2] and general Can be substantially avoided by aligning the lower alcohol represented by the formula [4] or R 3 of the trialkyl orthocarboxylate represented by the general formula [6] to the same alkyl group, which is a preferred embodiment For example, referring to Examples 5 and 6 in which R 2 and R 3 are both methyl or ethyl groups).
[0096]
　Further, when the fluorine-containing α-ketocarboxylic acid ester hydrate represented by the general formula [2], which is produced in the oxidation step, is stored for a long period of time in a state of high moisture content, the compound represented by the general formula [9a] or [9b] It decomposes into fluorine-containing α-ketocarboxylic acid hydrate or hemiketal.
[Formula 16]

wherein, R 1 and R 2 are, R in the general formula [2] 1 and R 2 derived from. ]
　This decomposition product can be converted to the fluorine-containing α-ketocarboxylic acid ester · hemiketal represented by the general formula [10a], [10b], [10c] or [5] through this step.
[Formula 17]

wherein, R 1 and R 2 are R in the general formula [2] 1 and R 2 is derived from, R 3 of the general formula [4] lower alcohol or represented by the general formula [6 ] Of the trialkyl orthocarboxylate represented by R 3 . ]
　The fluorine-containing α-ketocarboxylic acid hydrate or hemiketal represented by the general formula [9a] or [9b] ​​can not be used as a raw material substrate in the dehydration step or the dealcoholation step, but the compounds represented by the general formulas [10a] and [10b] , [10c] or [5] can be used as a raw material substrate in the dealcoholation step. In such a case, R 2 of the fluorine-containing α-ketocarboxylic acid ester hydrate represented by the general formula [2] and a lower alcohol represented by the general formula [4] or represented by the general formula [6] The α-ketocarboxylic acid ester · hemiketal represented by the general formulas [10a], [10b], [10c] and [5] can be synthesized by aligning R 3 of trialkyl orthocarboxylate to the same alkyl group It can converge on the compound. Accordingly, by passing through the compound, the recovery rate of the fluorine-containing α-ketocarboxylic acid ester represented by the general formula [3] can be improved (as described above), which is a preferred embodiment (for example, R 2 and R 3 Are aligned with methyl groups, see Example 7).
[0097]
　The acid catalyst is not particularly limited and examples thereof include inorganic acids such as boric acid, phosphoric acid, hydrogen chloride, hydrogen bromide, nitric acid, sulfuric acid and the like, organic acids such as formic acid, acetic acid, oxalic acid, benzoic acid, benzenesulfonic acid, It is an organic acid. Among them, phosphoric acid, hydrogen chloride, sulfuric acid, benzenesulfonic acid and paratoluenesulfonic acid are preferable, and hydrogen chloride, sulfuric acid and paratoluenesulfonic acid are particularly preferable. Naturally, by adopting suitable reaction conditions, it is not always necessary to use an acid catalyst (see Example 5).
[0098]
　The amount of the acid catalyst used may be 0.7 mol or less with respect to 1 mol of the fluorine-containing α-ketocarboxylic acid ester hydrate represented by the general formula [2], preferably 0.0001 to 0.5 mol, more preferably 0 .0005 to 0.3 mol is particularly preferable.
[0099]
　The reaction solvent is not particularly limited and examples thereof include aliphatic hydrocarbons such as n-hexane, cyclohexane and n-heptane, aromatic hydrocarbons such as toluene, xylene and mesitylene, aromatic hydrocarbons such as methylene chloride, chloroform, 1,2-dichloroethane and the like Ethers such as tetrahydrofuran, tert-butyl methyl ether and 1,2-dimethoxyethane, esters such as ethyl acetate, n-butyl acetate, propylene glycol monomethyl ether acetate and the like, N, N-dimethylformamide, Amide type such as N, N-dimethylacetamide and 1,3-dimethyl-2-imidazolidinone, nitrile type such as acetonitrile, propionitrile, benzonitrile and the like. Among them, aromatic hydrocarbon type, halogen type, ether type, ester type and nitrile type are preferable, and aromatic hydrocarbon type, halogen type and nitrile type are particularly preferable. These reaction solvents can be used alone or in combination. This step can also be carried out without using a reaction solvent, and the reaction in neat may be a preferred embodiment in some cases.
[0100]
　The reaction solvent may be used in an amount of 0.01 L or more per 1 mol of the fluorine-containing α-ketocarboxylic acid ester hydrate represented by the general formula [2], preferably 0.02 to 5 L, more preferably 0.03 To 3 L is particularly preferable.
[0101]
　The reaction temperature may be carried out at + 150 ° C. or lower, preferably from + 125 to -50 ° C., particularly preferably from +100 to -25 ° C.
[0102]
　The reaction time may be carried out within 72 hours, depending on the raw material substrate and the reaction conditions, so that the progress of the reaction is tracked by analysis means such as gas chromatography, liquid chromatography, nuclear magnetic resonance, etc., and the reduction of the raw material substrate It is preferable to set the end point as the point where almost no recognition is made.
[0103]
　In the post treatment, fluorine-containing α-ketocarboxylic acid ester · hemiketal represented by the general formula [5] can be obtained by adopting a general operation in organic synthesis. If the boiling point of the object product obtained is sufficiently low, it is convenient to carry out the reaction directly from the reaction completion liquid by distillation (see Examples 5 and 6). If necessary, the recovered crude product can be purified to high purity by fractional distillation, recrystallization, column chromatography and the like.
[0104]
　Formula [5] R fluorinated α- keto carboxylic ester hemiketal represented by 1 and R 2 are fluorine-containing α- ketocarboxylic acid ester hydrate represented by the general formula [2] R 1 and R 2 .
[0105]
　Further, R 3 of the fluorine-containing α-ketocarboxylic acid ester hemiketal represented by the general formula [5] is a lower alcohol represented by the general formula [4] or a trialkyl orthocarboxylate represented by the general formula [6] R 3 .
[0106]
　In the above-mentioned distillation recovery or fractional distillation, dealcoholation of the fluorine-containing α-ketocarboxylic acid ester · hemiketal represented by the general formula [5] takes place partially, and the fluorine-containing α-ketocarboxylic acid ester represented by the general formula [3] And may be collected as a mixture. Such cases are also treated as being included in the claims of the present invention.
[0107]
　4.
　Dealcoholization Step This step is a step of reacting a fluorine-containing α-ketocarboxylic acid ester · hemiketal represented by the general formula [5] with a dealcoholation agent, which is produced in a hemiketalization step, to obtain a dealcoholated Thereby producing a fluorine α-ketocarboxylic acid ester.
[0108]
　This step can be carried out in the same way for all the items described in "2. Dehydration step" (see Example 11). However, the terms "dehydrating agent", "fluorine-containing α-ketocarboxylic acid ester hydrate represented by the general formula [2]" and "prepared by the oxidizing step" are referred to as "dealcoholizing agent", " ], "Prepared by a hemiketalization step", and "fluorine-containing α-ketocarboxylic acid ester hemiketal represented by a hemiketalization step". The preferred embodiment is also the same for all items.
Example
[0109]
　Hereinafter, embodiments of the present invention will be specifically described, but the present invention is not limited to these examples.
[0110]
　Example 1 Preparation of ethyl 3,3,3-trifluoropyruvate hydrate ( oxidation of ethyl 3,3,3-trifluoro lactate with NaClO 5 H 2 O)
　58 mL (1.0 mL / mmol ) of acetonitrile ) Was dissolved by adding 10 g (58 mmol, 1.0 eq) of ethyl 3,3,3-trifluoro lactate. Further, 11 g (67 mmol, 1.2 eq) of NaClO · 5 H 2 O was added and the mixture was stirred at 20 ° C. for 30 minutes. Analysis of the reaction-terminated liquid by 19 F-NMR revealed that the conversion was 100% and the selectivity was 98%. To the reaction completion solution, 0.38 g (1.5 mmol, 0.026 eq) of sodium thiosulfate pentahydrate was added and stirred to quench the remaining oxidizing agent. Further, 0.33 g (3.9 mmol, 0.067 eq) of sodium hydrogencarbonate and 10 g (70 mmol, 1.2 eq) of sodium sulfate were added and stirred, and the solid content was removed by filtration. The filtrate was quantified with an internal standard method (internal standard substance; α, α, α-trifluorotoluene) by 19 F-NMR, and as a result, 56 mmol of ethyl 3,3,3-trifluoropyruvate hydrate (quantitative yield The rate was 97%) was included. By simple distillation (-48 ° C./0.5 kPa) of the filtrate, 7.6 g of ethyl 3,3,3-trifluoropyruvate hydrate was obtained. The 19 F-NMR purity was 99% (40 mmol), and the total yield was 69%. 1 H-NMR and 19 F-NMR of
　3,3,3-trifluoropyruvic acid hydrate are shown below. 1
　H-NMR (reference material; tetramethylsilane, solvent; deuterochloroform), δ ppm; 1.38 (t, 3H), 4.41 (q, 2H), protons of gem-diol group can not be assigned.
　19 F-NMR (reference substance; hexafluorobenzene, solvent; deuterochloroform), δ ppm; 78.6 (s, 3 F).
　In this example, no by-products in which the target ester group was hydrolyzed were observed, and the amount of by-produced trifluoroacetic acid was less than 1%.
[0111]
　Example 2 Preparation of ethyl 3,3,3-trifluoropyruvate hydrate ( oxidation of ethyl 3,3,3-trifluoro lactate with Ca (ClO) 2. 3H 2 O)
　Ethyl acetate 6. 1.0 g (5.8 mmol, 1.0 eq) of ethyl 3,3,3-trifluoro lactate and 0.098 g (0.29 mmol, 0 eq) tetra n-butylammonium hydrogen sulfate were added to 0 mL (1.0 mL / mmol) .050 eq) was added and dissolved. Further, 1.2 g (6.1 mmol, 1.1 eq) of Ca (ClO) 2 .3H 2 O was added and the mixture was stirred overnight at room temperature. Analysis of the reaction-terminated liquid by 19 F-NMR revealed that the conversion was 98% and the selectivity was 93%. 1 H-NMR and 19 F-NMR of
　3,3,3-trifluoropyruvic acid hydrate were identical to those of Example 1. 　In this example, no by-products in which the target ester group was hydrolyzed were observed, and the amount of by-produced trifluoroacetic acid was 3%.
[0112]
　Example 3 Preparation of methyl 3,3-difluoropyruvate hydrate ( oxidation of methyl 3,3-difluorolactate with NaClO 5 H 2 O) To
　270 mL (1.0 mL / mmol) of ethyl acetate was added 3, 38 g (270 mmol, 1.0 eq) of methyl 3-difluorolactate and 4.6 g (14 mmol, 0.052 eq) of tetra n-butylammonium hydrogen sulfate were added and dissolved. Further, 49 g (300 mmol, 1.1 eq) of NaClO · 5 H 2 O was added and the mixture was stirred at 15 ° C. for 3 hours. Analysis of the reaction-terminated liquid by 19 F-NMR revealed that the conversion was 100% and the selectivity was 95%. To the reaction completion solution, 69 g (55 mmol, 0.20 eq) of 10% sodium sulfite aqueous solution was added and stirred to quench the remaining oxidizing agent. The organic layer thus recovered was quantitated with an internal standard method (internal standard substance; α, α, α-trifluorotoluene) by 19 F-NMR. As a result, 200 mmol of 3,3-difluoropyruvate hydrate (quantitative yield The rate was 74%). 1 H-NMR and 19 F-NMR of
　3,3-difluoropyruvate hydrate were consistent with those of Non-Patent Document 3. 　In this example, no by-products in which the target ester group was hydrolyzed were observed, and the by-product amount of difluoroacetic acid was 2%. In addition, no by-products in which the hydrogen atom at the α position was chlorinated was observed at all.
[0113]
　Example 4 Preparation of ethyl 3,3-difluoropyruvate hydrate ( Oxidation of ethyl 3,3-difluoro lactate with NaClO 5 H 2 O)
　Ethyl 3,3-difluoro lactate 1.0 g (6.5 mmol , 1.0 eq), 0.11 g (0.32 mmol, 0.049 eq) of tetra n-butylammonium hydrogen sulfate and 1.2 g (7.3 mmol , 1.1 eq) of NaClO · 5 H 2 O were added and the mixture was stirred at 30 ° C. And the mixture was stirred for 30 minutes. Analysis of the reaction-terminated liquid by 19 F-NMR revealed that the conversion was 96% and the selectivity was 97%. 0.93 g of ethyl 3,3-difluoropyruvate hydrate was obtained by Kugelrohr distillation (-130 ° C./0.8 kPa) of the reaction completion solution. The 19 F-NMR purity was 94% (5.1 mmol), and the total yield was 78%. 1 H-NMR and 19 F-NMR of
　ethyl 3,3-difluoropyruvate hydrate are shown below. 1 H-NMR (reference material; tetramethylsilane, solvent; deuterochloroform), δ ppm; 1.34 (t, 3 H), 4.18 (br, 2 H), 4.35 (q, 2 H), 5. 88 (t, 1 H). 19 F-NMR (reference material; hexafluorobenzene, solvent: deuterochloroform), δ ppm; 26.5 (d, 2 F).
　
　
　In this example, no by-products in which the target ester group was hydrolyzed were observed, and the by-product amount of difluoroacetic acid was 1%. In addition, no by-products in which the hydrogen atom at the α position was chlorinated was observed at all.
[0114]
　Example 5 Preparation of Ethyl 3, 3, 3-trifluoropyruvate Ethyl
　Hemiketal (Hemiketaration of ethyl 3,3,3-trifluoropyruvate hydrate with ethanol) Ethanol 25 g (540 mmol, 20 eq ), 5.0 g (27 mmol, 1.0 eq) of ethyl 3,3,3-trifluoropyruvate hydrate was added and the mixture was stirred at room temperature for 2 days. 3.9 g of ethyl 3,3,3-trifluoropyruvate / ethyl hemiketal was obtained by simple distillation (-44 ° C./1.5 kPa) of the reaction-terminated liquid. The molar ratio of the target product and ethanol by 1 H-NMR was 10: 1, 19 F-NMR purity was 98% (19 mmol), and the total yield was 70%. 19 F-NMR of
　3,3,3-trifluoropyruvic acid ethyl-ethyl hemiketal is shown below. 19 F-NMR (reference material; trichlorofluoromethane, solvent; deuterochloroform), δ ppm; -81.9 (s, 3 F).
　
[0115]
　Example 6 Preparation of methyl 3,3-difluoropyruvate.methyl hemiketal
　( hemiketalization of methyl 3,3-difluoropyruvate hydrate with trimethyl orthoformate) 2.7 g (25 mmol, 0 (trimethyl orthoformate ) of trimethyl orthoformate (26 mmol, 1.0 eq) of 3,3-difluoropyruvate hydrate and 0.25 g (2.5 mmol, 0.096 eq) of sulfuric acid were added, and the mixture was stirred at room temperature for 2 hours . The reaction-terminated liquid was analyzed by 19 F-NMR, and the conversion was 100%. By simple distillation (~ 59 ° C / 2.1 kPa) of the reaction finished solution, 2.8 g of methyl 3,3-difluoropyruvate · methylhemiketal was obtained. The molar ratio of the target product and methanol by 1 H-NMR was 55: 8, the 19 F-NMR purity was 97% (18 mmol), and the total yield was 69%. 19 F-NMR of
　methyl 3,3-difluoropyruvate · methyl hemiketal was consistent with that of non-patent document 3.
[0116]
　Example 7 Preparation of methyl 3,3-difluoropyruvate · methyl hemiketal (hemiketalization of long-term stored 3,3-difluoropyruvate hydrate with trimethyl orthoformate / see Scheme 2)
　Water 59 mmol Difluorobenzoic acid hydrate containing 32.3 mmol (1.0 eq in total, containing difluoroacetic acid as a by-product) containing methyl 3,3-difluoropyruvate hydrate (measured by the Karl Fischer method), 9.9 g of trimethyl orthoformate (93 mmol, 2.9 eq) and 0.74 g (7.5 mmol, 0.23 eq) of sulfuric acid, and the mixture was stirred overnight at room temperature. The reaction-terminated solution was quantified with an internal standard method (internal standard substance; α, α, α-trifluorotoluene) by 19 F-NMR, and it was found that methyl 3,3-difluoropyruvate · methyl hemiketal and methyl difluoroacetate 26 mmol, 1.1 mmol (total 27 mmol) were contained. Also, 0.39 mmol of water was contained in the reaction terminated liquid. 19 mmol and 4.7 mmol of 3,3-difluoropyruvic acid methyl methyl hemiketal and methyl 3,3-difluoropyruvate respectively were obtained by simple distillation (-60 ° C./0.6 kPa) of the reaction finished solution. The distillate contained 0.12 mmol of water. In addition, methyl difluoroacetate could be removed by simple distillation. 19 F-NMR of
　methyl 3,3-difluoropyruvate · methyl hemiketal was equivalent to that of Example 6. In addition, 1 H-NMR and 19 F-NMR of 3,3-difluoropyruvate matched those of Non-Patent Document 3. [Chemical Formula 18]

[0117]
　Example 8 Production of methyl 3,3-difluoropyruvate · methyl hemiketal ( Oxidation of methyl 3,3-difluorolactate with NaClO · 5H 2 O → methyl 3,3-difluoropyruvate · hydrate Orthorhi
　Hemiketalization with acid trimethyl / one-pot reaction) To 330 mL (350 mL / mol) of acetonitrile, 300 g (2.1 mol, 1.0 eq) of methyl 3,3-difluorolactate and 37 g (0.11 mol, 0.052 eq) was added and dissolved. Further, 390 g (2.4 mol, 1.1 eq) of NaClO · 5H 2 O was added under ice cooling and the mixture was stirred at room temperature for 30 minutes. Analysis of the reaction-terminated liquid by 19 F-NMR revealed that the conversion was 100% and the selectivity was 96%. Acetonitrile was distilled off by concentration of the reaction completion solution under reduced pressure. To the concentrated residue, 1600 g (15 mol, 7.1 eq) of trimethyl orthoformate and 11 g (0.11 mol, 0.052 eq) of sulfuric acid were added under ice cooling and the mixture was stirred at room temperature for 4 hours and 30 minutes. The reaction-terminated liquid was analyzed by 19 F-NMR, and the conversion was 100%. 270 g of a mixture of methyl 3,3-difluoropyruvate · methyl hemiketal and 3,3-difluoropyruvate was obtained by simple distillation (-60 ° C. / 0.6 kPa) of the reaction finished solution. The molar ratio of the target product and the dealcohol according to 1 H-NMR was 86: 14, the 19 F-NMR purity was 98% or more (1.6 mol), and the total yield was 76%.
　Methyl 3, 3-difluoropyruvate · methyl hemiketal19 F-NMR was equivalent to that of Example 6. Also, 1 H-NMR and 19 F-NMR of methyl 3,3-difluoropyruvate agreed with those of Example 7.
[0118]
　Example 9 Preparation of methyl 3-chloro-3,3-difluoropyruvate hydrate ( Oxidation of methyl 3-chloro-3,3-difluorolactate with NaClO 5 H 2 O) To a
　solution of 4.7 mL of acetonitrile / Mol), 0.83 g (4.7 mmol, 1.0 eq) of methyl 3-chloro-3,3-difluorolactate and 0.08 g (0.24 mmol, 0.05 eq) of tetra n-butylammonium hydrogen sulfate In addition, it was dissolved. Further, 0.94 g (5.7 mmol, 1.2 eq) of NaClO · 5H 2 O was added under ice cooling and the mixture was stirred at room temperature for 1 hour. When the reaction-terminated liquid was analyzed by 19 F-NMR, the conversion was 100%. 1.2 g (0.95 mmol, 0.20 eq) of a 10% sodium sulfite aqueous solution was added to the reaction completion liquid, and the mixture was stirred to quench the remaining oxidizing agent. The reaction solution was quantitated with an internal standard method (internal standard substance; α, α, α-trifluorotoluene) by 19 F-NMR. As a result, methyl 3-chloro-3,3-difluoropyruvate hydrate was found to be 4. 5 mmol (quantitative yield: 95%) was contained. 1 H-NMR and 19 F-NMR of
　3-chloro-3,3-difluoropyruvate hydrate are shown below. 1 H-NMR (reference material; tetramethylsilane, solvent; deuterated chloroform), δ ppm; 3.96 (s, 3H), protons of gem-diol group can not be attributed. 19
　
　F-NMR (reference material; hexafluorobenzene, solvent; deuterochloroform), δ ppm; 93.8 (s, 3 F).
[0119]
　Example 10 Preparation of Methyl 3,3,4,4,4-pentafluoro-2,2-dihydroxybutanoate (Methyl 3,3,4,4,4-pentafluoro-2-hydroxybutanoate NaClO · Oxidation with 5 H 2 O
　0.39 g (1.9 mmol, 1.0 eq) of methyl 3,3,4,4,4-methylpentafluoro-2-hydroxybutanoate and 1.9 mL (1 mmol / 0.032 g (0.091 mmol, 0.05 eq) of tetra n-butylammonium hydrogen sulfate was added and dissolved. Further, 0.68 g (4.2 mmol, 2.2 eq) of NaClO · 5H 2 O was added under ice cooling and the mixture was stirred at room temperature for 30 minutes. When the reaction-terminated liquid was analyzed by 19 F-NMR, the conversion was 100%. 0.48 g (0.38 mmol, 0.20 eq) of a 10% sodium sulfite aqueous solution was added to the reaction terminated liquid, and the mixture was stirred to quench the remaining oxidizing agent. The reaction solution was quantified with an internal standard method (internal standard substance; α, α, α-trifluorotoluene) by 19 F-NMR to find that 3,3,4,4,4-pentafluoro-2,2-dihydroxybutane 1.3 mmol of methyl acid (quantitative yield: 71%) was contained. 1 H-NMR and 19 F-NMR of
　methyl 3,3,4,4,4-pentafluoro-2,2-dihydroxybutanoate are shown below. 1 H-NMR (reference material; tetramethylsilane, solvent; deuterated chloroform), δ ppm; 3.87 (s, 3 H), protons of the gem-diol group can not be assigned. 19
　
　F-NMR (reference material; hexafluorobenzene, solvent; deuterochloroform), δ ppm; 36.8 (s, 2 F), 82.6 (s, 3 F).
[0120]
　[Example 11] Preparation of ethyl 3,3,3-trifluoropyruvate (dehydration of ethyl 3,3,3-trifluoropyruvate hydrate by concentrated sulfuric acid)
　5.2 g of concentrated sulfuric acid (53 mmol, 0 eq) was heated to 97 ° C. While dropping 5.0 g (27 mmol, 1.0 eq) of 3,3,3-trifluoropyruvic acid hydrate in a reduced pressure (13.5 to 3.3 kPa), the distillate was withdrawn to obtain 3 , 1.7 g of ethyl 3,3-trifluoropyruvate was obtained. 19 F-NMR purity was 100% (10 mmol), and the yield was 37%. 1 H-NMR and 19 F-NMR of
　ethyl 3,3,3-trifluoropyruvate agreed with those disclosed in JP-A-63-035538.
[0121]
　Example 12 Preparation of Ethyl 3,3,3-Trifluoropyruvate
　(Deethanolation of Ethyl 3,3,3-Trifluoropyruvate Ethyl Hemiketal with Concentrated Sulfuric Acid ) Concentrated sulfuric acid 5.7 g (58 mmol, 4 . 1 eq) was heated to 97 ° C. 3.1 g (14 mmol, 1.0 eq) of ethyl 3, 3, 3-trifluoropyruvate / ethyl hemiketal was dropped under reduced pressure (6.6 to 2.2 kPa) to extract the distillate, whereby 3 , 1.6 g of ethyl 3,3-trifluoropyruvate was obtained. 19 F-NMR purity was 100% (9.4 mmol), and the yield was 67%. 1 H-NMR and 19 F-NMR of
　ethyl 3,3,3-trifluoropyruvate were identical to those of Example 11.
[0122]
　Example 13 Preparation of methyl 3,3-difluoropyruvate (dehydration of methyl 3,3-difluoropyruvate hydrate with trifluoroacetic anhydride)
　2.0 mL (0.31 mL / mmol) of cyclopentyl methyl ether was added, , 1.0 g (6.4 mmol, 1.0 eq) of methyl 3,3-difluoropyruvate hydrate was added and dissolved. Further, 1.1 g (14 mmol, 2.2 eq) of pyridine and 1.5 g (7.1 mmol, 1.1 eq) of trifluoroacetic anhydride were added and stirred at 10 ° C. for 1 hour. Analysis of the reaction-terminated liquid by 19 F-NMR revealed that the conversion was 100% and the selectivity was 76%. 1 H-NMR and 19 F-NMR of
　methyl 3,3-difluoropyruvate agreed with those of Example 7.
[0123]
　[Example 14] Preparation of methyl 3,3-difluoropyruvate (dehydration of methyl 3,3-difluoropyruvate hydrate and 3,3-difluoropyruvate methyl methyl hemiketal mixture by diphosphorus pentoxide)
　To a mixture of 0.5 g (3.3 mmol) of 3,3-difluoropyruvate hydrate and 74.5 g (438 mmol) of methyl 3,3-difluoropyruvate / methyl hemiketal, diphosphorus pentoxide 31 (221 mmol, 0.5 eq) was slowly added at room temperature. The internal temperature rose to 43 ° C due to heat generation at the time of addition. Thereafter, the mixture was further stirred at 80 ° C. for 6 hours, and then simple distillation (81 ° C./10 kPa) was carried out to obtain 54.7 g of methyl 3,3-difluoropyruvate. 19 F-NMR purity was 100% (396 mmol), and the yield was 90%. 1 H-NMR and 19 F-NMR of
　methyl 3,3-difluoropyruvate agreed with those of Example 7.
[0124]
　Comparative Example 1 Oxidation of methyl 3,3-difluoro lactate (Reaction Condition of Example 6 of Patent Document 1 was Adopted)
　To 18 mL (2.5 mL / mmol) of methylene chloride was added 1.0 g of methyl 3,3-difluorolactate 7.1 mmol, 1.0 eq) and 0.11 g (0.34 mmol, 0.048 eq) of tetra n-butylammonium bromide were added and dissolved. Further, 8.8 g (14 mmol, 2.0 eq) of a 12% by mass sodium hypochlorite aqueous solution was added and the mixture was vigorously stirred at 28 ° C. for 4 hours (reaction is a two-phase system). The reaction completed solution was separated, and the aqueous layer was extracted with methylene chloride and combined with the separated organic layer. The recovered organic layer was quantitated with an internal standard method (internal standard substance: α, α, α-trifluorotoluene) by 19 F-NMR, and it was found that 1.1 mmol of 3,3-difluoropyruvate hydrate was contained It was. The quantitative yield was 15%. Incidentally, when the recovered aqueous layer was quantified with an internal standard method (internal standard substance; potassium trifluoromethanesulfonate) by 19 F-NMR, it was confirmed that 3,3-difluoropyruvic acid · hydrate and difluoroacetic acid were 1.6 mmol , 0.6 mmol was contained. 1 H-NMR and 19 F-NMR of
　3,3-difluoropyruvate hydrate were identical to those of Example 3. 19 F-NMR of 3,3-difluoropyruvic acid · hydrate is shown below. 19 F-NMR (reference material; trichlorofluoromethane, solvent: heavy water), δ ppm; -134.9 (d, 2 F).
　
[0125]
　Comparative Example 2 Oxidation of 1,1,1-trifluoro-2-propanol (Adoption of Preferred Reaction Conditions of the
　Present Invention ) To 4.4 mL (1.0 mL / mmol) of acetonitrile, 1,1,1-tri 0.50 g (4.4 mmol, 1.0 eq) of fluoro-2-propanol and 0.074 g (0.22 mmol, 0.050 eq) of tetra n-butylammonium hydrogen sulfate were added and dissolved. Further, 0.86 g (5.2 mmol, 1.2 eq) of NaClO · 5H 2 O was added and the mixture was stirred overnight at room temperature. When the reaction-terminated liquid was analyzed by 19 F-NMR, 1,1,1-trifluoroacetone or the hydrate thereof was not observed at all.
[0126]
　Comparative Example 3 Oxidation of 1,1-difluoro-2-propanol (Adoption of Suitable Reaction Conditions of the
　Present Invention) To 5.2 mL (1.0 mL / mmol) of acetonitrile, 1,1-difluoro-2-propanol 0 (5.2 mmol, 1.0 eq) was added and dissolved. Further, 1.0 g (6.1 mmol, 1.2 eq) of NaClO · 5 H 2 O was added and the mixture was stirred overnight at room temperature. When the reaction-terminated liquid was analyzed by 19 F-NMR, 1,1-difluoroacetone or the hydrate thereof was not observed at all.
[0127]
　Comparative Example 4 Oxidation of 3,3,3-trifluoro lactic acid (by-production of trifluoroacetic acid by reduction of charcoal) To
　0.85 g (5.9 mmol, 1.0 eq) of 3,3,3-trifluoro lactic acid, 5.9 g (9.5 mmol, 1.6 eq) of a 12% by mass sodium hypochlorite aqueous solution was added and the mixture was vigorously stirred at room temperature for 2 hours. Analysis of the reaction-terminated liquid by 19 F-NMR revealed that the conversion was 45%, and 27% of trifluoroacetic acid was by-produced. No 3,3,3-trifluoropyruvic acid hydrate, which is considered to be the original oxidation product, was observed.
[0128]
　Reference Example 1 Preparation of methyl 3,3-difluorolactate and ethyl 3,3-difluoro lactate (Preparation of 3,3-difluoro lactic acid amide with reference to Patent Document 2) To
　190 mL (1.2 mL / mmol) of water , 20 g (160 mmol, 1.0 eq) of 3,3-difluoro lactic acid amide and 78 g (800 mmol, 5.0 eq) of sulfuric acid were added and the mixture was stirred at 100 ° C. for 20 hours. The reaction completed solution was extracted with 2-methyltetrahydrofuran, and the recovered organic layer was concentrated under reduced pressure to obtain 16 g (130 mmol) of 3,3-difluorolactic acid. The yield was 81%.
　(79 mmol, 1.0 eq) of 3,3-difluorolactic acid, 13 g (120 mmol, 1.5 eq) of trimethyl orthoformate and 1.2 g (12 mmol, 0.15 eq) of sulfuric acid were added to 3.8 g (120 mmol, 1.5 eq) ) Was added and the mixture was stirred overnight at room temperature. 9.7 g (69 mmol) of methyl 3,3-difluoro lactate was obtained by simple distillation (-44 ° C./0.6 kPa) of the reaction terminated liquid. The yield was 87%. 1 H-NMR and 19 F-NMR of
　methyl 3,3-difluoro lactate are shown below. 1 H-NMR (reference material; tetramethylsilane, solvent; deuterated chloroform), δ ppm; 3.87 (s, 3 H), 4.40 (ddd, 1 H), 5.96 (dt, 1 H), hydroxyl group Protons can not be attributed. 19 F-NMR (reference material; hexafluorobenzene, solvent; deuterochloroform), δ ppm; 31.3 (ddd, 1 F), 32.7 (ddd, 1 F). 　By ethyl esterification in the same manner, ethyl 3,3-difluoro lactate could be prepared.
　
　

1 H-NMR and 19 F-NMR of 　ethyl 3,3-difluoro lactate are shown below.
　1 H-NMR (reference material; tetramethylsilane, solvent; deuterochloroform), δ ppm; 1.28 (t, 3 H), 4.28 (dq, 2 H), 4.35 (ddd, 1 H), 5. 92 (dt, 1 H), protons of the hydroxyl group can not be attributed.
　19 F-NMR (reference material; hexafluorobenzene, solvent; deuterochloroform), δ ppm; 31.3 (ddd, 1 F), 32.8 (ddd, 1 F).
[0129]
　Reference Example 2 Preparation of methyl 3-chloro-3,3
　-difluorolactate 4.5 g of 2-chloro-2,2-difluoroacetaldehyde ethyl hemiacetal (product of Mitsui Chemicals, Inc.) was added in the same manner as in Reference Example 1 28 mmol), 3-chloro-3,3-difluoro lactic acid amide was prepared. To this was added 32 mL (1.1 mL / mmol) of water and 13.6 g (135 mmol, 4.8 eq) of sulfuric acid, and the mixture was stirred under reflux for 80 hours. The reaction completed solution was extracted with 2-methyltetrahydrofuran, and the recovered organic layer was dehydrated with sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. 10.3 g (321 mmol) of methanol, 4.9 g (46.1 mmol) of trimethyl orthoformate and 0.2 g (2 mmol) of sulfuric acid were added to the obtained concentrated residue, and the mixture was stirred at room temperature for 22 hours. By a simple distillation of the reaction-terminated liquid (-48 ° C./2.8 kPa), 1.7 g (9.7 mmol) of methyl 3-chloro-3,3-difluorolactate was obtained. The yield was 35%. 1 H-NMR and 19 F-NMR of
　methyl 3,3-difluoro lactate are shown below. 1 H-NMR (reference material; tetramethylsilane, solvent; deuterated chloroform), δ ppm; 3.93 (s, 3 H), 4.56 (dd, 1 H), protons of the hydroxyl group can not be attributed. 19 F-NMR (reference substance; hexafluorobenzene, solvent; deuterochloroform), δ ppm: 99.5 (dd, 1 F), 101. (Dd, 1 F).
　
　
[0130]
　Reference Example 3 Preparation of methyl 3,3,4,4,4-pentafluoro-2-hydroxybutanoate In the same
　manner as in Reference Example 2, 2,2,3,3,3 -pentafluoro-1-methoxy 3-pentafluoro-2-hydroxybutanoic acid was synthesized from 9.0 g (49.8 mmol) of 1-propanol. To this was added 23.8 g (741 mmol) of methanol, 10.6 g (99.6 mmol) of trimethyl orthoformate and 0.5 g (5.1 mmol) of sulfuric acid, and the mixture was stirred overnight at room temperature. Thereafter, 5.0 g (47.1 mmol) of trimethyl orthoformate was added and the mixture was heated to 50 ° C. with an oil bath and stirred for 2.5 hours. 5.8 g (target substance content 22.0 mmol) of methyl 3,3,4,4,4-pentafluoro-2-hydroxybutanoate was obtained by simple distillation (-43 ° C./4.0 kPa) of the reaction completed solution. The yield was 44%. 1 H-NMR and 19 F-NMR of
　methyl 3,3,4,4,4-pentafluoro-2-hydroxybutanoate are shown below. 1 H-NMR (reference material: tetramethylsilane, solvent: heavy chloroform), δ ppm; 3.93 (s , 3H), 4.56 (dd, 1H), protons of hydroxyl groups can not be assigned. 19 F-NMR (reference material: hexafluorobenzene, solvent: heavy chloroform), δ ppm; 80.1 (s , 3F), 41.2 (ddd, 1F), 34.5 (ddd, 1F).
　
　
[0131]
　Reference Example 4 Reactivity of ethyl 3,3,3-trifluoropyruvate · methyl hemiketal was investigated.
　83 mL (1.4 mL / mmol) of toluene was charged with ethyl 3,3,3-trifluoropyruvate · methylmaleimide 12 g (59 mmol, 1.0 eq) of ketal and 3.5 g (58 mmol, 0.98 eq) of ethylenediamine were added under ice cooling and the mixture was stirred at room temperature for 15 hours (crystal precipitation). The reaction-terminated liquid was analyzed by 19 F-NMR, and the conversion was 100%. A part of the toluene was distilled off by concentration under reduced pressure of the reaction terminated liquid. The precipitated crystals were filtered, washed with toluene and dried to obtain 11 g (60 mmol) of a trifluorohemiaminal amido-closed ring compound represented by the following formula. Yield was quantitative.
[Formula 19]

　trifluoroacetic hemiaminal amide ring closed form 1 H-NMR and 19 to F-NMR are shown below.
　1 H-NMR (standard substance; tetramethylsilane, solvent; deuterated dimethylsulfoxide), δ ppm; 2.81 (m, 1 H), 3.04 (m, 2 H), 3.19 (m, 1 H), 3 . 36 (br, 1 H), 7.00 (br, 1 H), 8.12 (s, 1 H).
　19 F-NMR (standard substance; hexafluorobenzene, solvent; heavy dimethylsulfoxide), δ ppm; 82.8 (s, 3 F).
[0132]
　Reference Example 5 Reactivity of methyl 3,3-difluoropyruvate · methyl hemiketal was investigated.
　83 mL (1.4 mL / mmol) of toluene was charged with 10 g of methyl 3,3-difluoropyruvate · methyl hemiketal (59 mmol, 1 .0 eq) and 3.5 g (58 mmol, 0.98 eq) of ethylenediamine were added under ice cooling, and the mixture was stirred at room temperature for 15 hours (crystal precipitation). The reaction-terminated liquid was analyzed by 19 F-NMR, and the conversion was 100%. A part of the toluene was distilled off by concentration under reduced pressure of the reaction terminated liquid. The precipitated crystals were filtered, washed with toluene and dried to obtain 9.8 g (59 mmol) of a difluorohemienal amide closed cyclic compound represented by the following formula. Yield was quantitative.
[Formula 20]

　difluoro hemiaminal amide ring closed form 1 H-NMR and 19 show the F-NMR below.
　1 H-NMR (standard substance; tetramethylsilane, solvent; deuterated dimethylsulfoxide), δ ppm; 2.81 (m, 1 H), 3.11 (m, 4 H), 5.94 (t, 1 H), 6 . 50 (s, 1 H), 7.96 (s, 1 H).
　19 F-NMR (standard substance; hexafluorobenzene, solvent; deuterated dimethylsulfoxide), δ ppm; 17.7 (dd, 1 F), 36.1 (dd, 1 F).
[0133]
　Reference Example 6 Reactivity of methyl 3,3-difluoropyruvate · methyl hemiketal was investigated.
　14 mL (1.5 mL / mmol) of toluene was charged with 1.6 g (9 mmol) of methyl 3,3-difluoropyruvate · methyl hemiketal (4 mmol, 1.0 eq) and 0.58 g (9.7 mmol, 1.0 eq) of ethylenediamine were added under ice cooling and stirred at room temperature for 15 hours (crystal precipitation). Further, 0.17 g (0.89 mmol, 0.095 eq) of p-toluenesulfonic acid monohydrate was added and azeotropically dehydrated at 130 ° C. for 3 hours using Dean-Stark. The reaction-terminated solution was homogeneously dissolved with acetonitrile and quantitated with an internal standard method (internal standard substance; α, α, α-trifluorotoluene) by 19 F-NMR. As a result, it was confirmed that the closed loop diffluoroiminoamide represented by the following formula was 0 .99 g (6.7 mmol) was contained. The quantitative yield was 71%.
[Formula 21]

　difluoro imino amide closed body 19 the F-NMR are shown below.
　19 F-NMR (standard substance; hexafluorobenzene, solvent; deuterochloroform), δ ppm; 38.0 (d, 2 F).
Industrial applicability

[0134]
　The fluorine-containing α-ketocarboxylic acid ester to be treated in the present invention can be used as an intermediate for medical and agricultural chemicals.
The scope of the claims

[Claim 1]
By reacting the fluorine-containing α-hydroxycarboxylic acid ester represented by the general formula [1] with "sodium hypochlorite or calcium hypochlorite having a mass percentage of 21 mass% or more in the composition" 2] to produce a fluorine-containing α-ketocarboxylic acid ester hydrate.
In the

formula, R 1 represents a hydrogen atom, a halogen atom or a haloalkyl group, and R 2 represents an alkyl group or a substituted alkyl group. ]
[Chemical Formula 23]

wherein, R 1 represents a hydrogen atom, a halogen atom or a haloalkyl group, R 2 represents an alkyl group or a substituted alkyl group. ]
[Claim 2]
2. A process according to claim 1, characterized in that it is reacted with "sodium hypochlorite or calcium hypochlorite having a mass percentage of composition of 31% by mass or more".
[Claim 3]
NaClO 5 H 2 O or Ca (ClO) 2 .nH 2 O wherein n represents an integer from 0 to 3. 2. A process according to claim 1, wherein the reaction is carried out with a reducing agent.
[Claim 4]
The method according to any one of claims 1 to 3, wherein R 1 of the fluorine-containing α-hydroxycarboxylic acid ester represented by the general formula [1] is a hydrogen atom.
[Claim 5]
The method according to any one of claims 1 to 4, characterized in that it is reacted in the presence of a phase transfer catalyst.
[Claim 6]
6. The method according to any one of claims 1 to 5, wherein the reaction is carried out without using a reaction solvent.
[7]
A method for producing a fluorine-containing α-ketocarboxylic acid ester hydrate represented by the general formula [2] by the method according to any one of claims 1 to 6, and then reacting the ester · hydrate with the dehydrating agent To give a fluorine-containing α-ketocarboxylic acid ester represented by the general formula [3].
In the

formula, R 1 represents a hydrogen atom, a halogen atom or a haloalkyl group, and R 2 represents an alkyl group or a substituted alkyl group. ]
[Claim 8]
8. The method according to claim 7, wherein the dehydrating agent is diphosphorus pentoxide or concentrated sulfuric acid.
[Claim 9]
A method for producing a fluorine-containing α-ketocarboxylic acid ester hydrate represented by the general formula [2] by the method according to any one of claims 1 to 6, and then reacting the ester · hydrate with a compound represented by the general formula [ 4] to produce a fluorine-containing α-ketocarboxylic acid ester · hemiketal represented by the general formula [5].
In the

formula, R 3 represents an alkyl group having 1 to 4 carbon atoms. ]
[Chemical Formula 26]

wherein, R 1 represents a hydrogen atom, a halogen atom or a haloalkyl group, R 2 represents an alkyl group or a substituted alkyl group, R 3 represents an alkyl group having 1 to 4 carbon atoms. ]
[Claim 10]
10. The method according to claim 9, wherein R 3 of the lower alcohol represented by the general formula [4] is a methyl group or an ethyl group.
[Claim 11]
R 2 of the fluorine-containing α-ketocarboxylic acid ester hydrate represented by the general formula [2] and R 3 of the lower alcohol represented by the general formula [4] are the same alkyl group. Wherein the method of claim 9 or 10.
[Claim 12]
A method for producing a fluorine-containing α-ketocarboxylic acid ester hydrate represented by the general formula [2] by the method according to any one of claims 1 to 6, and then reacting the ester · hydrate with a compound represented by the general formula [ 6], thereby producing a fluorine-containing α-ketocarboxylic acid ester · hemiketal represented by the general formula [5].
In the

formula, R 3 represents an alkyl group having 1 to 4 carbon atoms, and R 4 represents a hydrogen atom, a methyl group or an ethyl group. ]
[Formula 28]

wherein, R 1 represents a hydrogen atom, a halogen atom or a haloalkyl group, R 2 represents an alkyl group or a substituted alkyl group, R 3 represents an alkyl group having 1 to 4 carbon atoms. ]
[Claim 13]
13. The method according to claim 12, wherein R 3 of the trialkyl orthocarboxylate represented by the general formula [6] is a methyl group or an ethyl group.
[Claim 14]
Characterized by that R 2 of the fluorine-containing α-ketocarboxylic acid ester hydrate represented by the general formula [2] and R 3 of the trialkyl orthocarboxylate represented by the general formula [6] are the same alkyl group The method according to claim 12 or 13.
[Claim 15]
A process according to any of claims 9 to 14, characterized in that it is reacted in the presence of an acid catalyst.
[Claim 16]
A method for producing a fluorine-containing α-ketocarboxylic acid ester · hemiketal represented by the general formula [5] by the method according to any one of claims 9 to 15, and reacting the ester · hemiketal with a dealcoholizing agent A process for producing a fluorine-containing α-ketocarboxylic acid ester represented by the formula [3].
In the

formula, R 1 represents a hydrogen atom, a halogen atom or a haloalkyl group, and R 2 represents an alkyl group or a substituted alkyl group. ]
[Claim 17]
17. The method according to claim 16, characterized in that the dealcoholing agent is diphosphorus pentoxide or concentrated sulfuric acid.