Alpha, method for producing α- difluoro acetaldehyde hemiacetal

Technical field

[0001]

　The present invention, alpha, a method for producing a α- difluoro acetaldehyde hemiacetal.

BACKGROUND

[0002]

　Α is expressed by the formula [1], alpha-difluoro acetaldehyde are compounds useful as intermediates for the material or medicines, agricultural chemicals advanced materials field.
[Formula 1]

　In particular the difluoromethyl group (-CHF 2 ) is one fluorine atom two and a hydrogen atom with a high electronegativity, it is attached to the same carbon atom. This unique structure is water-repellent, transparency synthesized various materials therewith, is believed to closely related to characteristics such as low dielectric property, specific bioactivity, mimic effects. Thus, alpha, alpha-material is that used difluoro acetaldehyde as building blocks, in the field of advanced materials field and pharmaceutical and agrochemical intermediates, have been the subject of active research and development.

[0003]

　alpha, alpha-As a method for producing difluoro acetaldehydes, the presence of a catalyst, to esters having a difluoromethyl group, a reduction reaction using a hydride reducing agent such as lithium aluminum hydride is known (Non-Patent Document 1 ). Further, the applicant, alpha, alpha-difluoro acetic acid esters to the presence of a ruthenium catalyst, hydrogen (H 2 discloses a method by reduction reaction with) (Patent Document 1).

[0004]

　On the other hand, substances that aldehydes are unstable, gradually is known to polymerize with other aldehydes molecules (Non-patent Document 2). Aldehydes that is an object of the invention is a strong electron withdrawing groups for difluoromethyl group are directly connected, self-polymer, Mizuwatai, hemiacetal, compounds acetal and these structural features are combined etc., it is also disclosed in Patent Document 1 can be obtained as a plurality of stable equivalents.

[0005]

　Thus, aldehydes difluoromethyl group are directly connected tended easily converted into a plurality of compounds. Therefore, the applicant, alpha, alpha-difluoro acetaldehyde presence of an alcohol represented by the general formula [2], represented by the general formula [3] alpha, to form a alpha-difluoro acetaldehyde hemiacetal, and , by adjusting the amount of alcohol coexisting, the hemiacetal is likely to exist stably in the system, i.e., the effect that storage stability is improved, are reported in the patent literature 2.
[Formula 2]

wherein, R 4 represents an alkyl group or a substituted alkyl group. ]
[Formula 3]

[wherein, R 1 is the general formula [2] R in 1 same as. ]

[0006]

　Incidentally, in the present applicant Patent Documents 1 and 2, alpha, alpha-upon-difluoro acetaldehyde hemiacetal purification, the general formula [4] with alpha represented, alpha-difluoro acetaldehyde dimer (hereinafter, herein in may be simply referred to as "dimer") have reported that the generate.
[Formula 4]

[wherein, R 3 is R in the general formula [2] 1 same as. ]
　This compound, alpha, is a stable species as compared to α- difluoro acetaldehyde hemiacetal and thus once formed, this remains in the alpha, in order to proceed the reaction of interest as α- difluoro acetaldehyde, dimeric body of alpha, so that the step of converging the α- difluoro acetaldehyde hemiacetal increases. Therefore, alpha, alpha-difluoro acetaldehyde hemi in the acetal dimer does not occur, or it is reduced as much it would be desirable advance.

[0007]

　However, alpha, alpha-order difluoro acetaldehyde hemiacetal is unstable compounds in the gas phase, after synthesis is performed distillation operation or the like in order to remove the neutralized salt and hydride reducing agent in the reaction solution, fixed dimer of the amount occurs. The present applicant has improved storage stability, also found a specific phenomenon that compounds other than the hemiacetal (dimer) becomes difficult to produce a remarkably, have reported that effect in Patent Document 2 .

CITATION

Patent Document

[0008]

Patent Document 1: International Publication 2014/115801 Patent
Patent Document 2: WO 2016/017318

Non-patent literature

[0009]

Non-Patent Document 1: The Journal of Organic Chemistry,1997, 62 (25), 8826-8833.
Non-Patent Document 2: Synthetic Organic Chemistry, Volume 19, No. 3 (1961), 254 - 260

Summary of the Invention

Problems that the Invention is to Solve

[0010]

　alpha, the α- difluoro acetaldehyde, self polymer, Mizuwatai, other stable equivalent of such hemiacetal, be dimers are obtained, which are known by the method described in Patent Document 2 described above. Furthermore, according to the literature, the operation such as strongly heated by the addition of acid relative to the dimer, alpha, it has been made according to the effect to be able to return to α- difluoro acetaldehyde.

[0011]

　However, as described in Patent Document 2, the dimer described above is once generated, the corresponding α by decomposing it, it is difficult to find a condition for obtaining the α- difluoro acetaldehyde hemiacetal stably. If so returning the dimer alpha, the α- difluoro acetaldehyde, even went heating or the like by adding an acid, in fact, alpha and dimer decomposes, converting rate in the α- difluoro acetaldehyde hemiacetal , it has been wide variation in the process conditions (Comparative examples). If also the conversion rate is low dimers even if a long time reaction was also not decrease from a predetermined ratio.

[0012]

　On the other hand, alpha, alpha-decomposition during storage difluoro acetaldehyde hemiacetal was sometimes progresses decomposed to difluoroacetate thus-produced. Once the difluoroacetate thus generated, this compound itself is a strong acid, since it affects the material of the reaction vessel by this amount is increased, alpha, not suitable for long-term storage of α- difluoro aldehyde Met.

[0013]

　Therefore, alpha, a by-product during the purification of alpha-difluoro acetaldehyde hemiacetal reduces the dimer contained in the hemiacetal, and capable of suppressing the by-production of difluoro acetic acid, efficient alpha, alpha- method for producing difluoro acetaldehyde hemiacetal has been demanded.

Means for Solving the Problems

[0014]

　The present inventors have, alpha, the mixture containing α- difluoro acetaldehyde hemiacetal and dimer are acidic state dimer is stabilized, in particular, pH of the mixture is less than 3.5 in some cases, stability is significantly higher, decomposition reaction of the dimer obtained a finding of a decrease.

[0015]

　Usually, alpha, as the potential acid present during the production of α- difluoro acetaldehyde hemiacetal, and the acid used for neutralization process hydride reducing agent and a base, alpha, by degradation of α- difluoro acetaldehyde hemiacetal considered occurs difluoroacetate. Of these, difluoro acetic acid is a strong acid, pH of the entire solution even content several tens ppm about a trace amount of the mixed solution is less than 3.5. When difluoro acetic acid present in the system, be reacted with an alcohol to dimers, decomposition reaction of the dimer, i.e., there is a problem that it becomes difficult to proceed to the hemiacetal.

[0016]

　Therefore the present inventors have conducted extensive studies, higher-purity alpha, as a condition for the production of α- difluoro acetaldehyde hemiacetal, by adopting the manufacturing method including three steps below, alpha, suppressing the generation of difluoro acetic acid is a degradation product from α- difluoro acetaldehyde hemiacetal, and a by-product during the purification of the hemiacetal alpha, and said can reduce the dimer of α- difluoro acetaldehyde hemiacetal, very give preferred findings, and completed the present invention.
　First Step:
　alpha represented by the general formula [5], alpha-difluoro acetic acid esters and the alcohol represented by the general formula [2] and a solvent in the presence of a base and a ruthenium catalyst, hydrogen (H 2 ) is reacted with, or to the general formula [5] alpha, the alpha-difluoro acetic acid esters, are reacted with a hydride reducing agent, by, alpha represented by the general formula [3], alpha-difluoro acetaldehyde step of preparing a mixture comprising a hemiacetal.
[Chemical Formula 5]

[wherein, R 2 is R in the general formula [3] 1 is the same as the '
　second step:
　to the mixture obtained in the first step, performed neutralization treatment, then, the mixture It was charged to the reaction vessel, under dark conditions, oxygen (O in the reaction vessel 2 ) to adjust the concentration so as to 5000ppm or less, by performing subsequently distillation, alpha, and α- difluoro acetaldehyde hemiacetal the general formula [4] with α represented, alpha-difluoro including dimer of acetaldehyde, steps pH to obtain a mixture between 3.5 and 10.0.
　Third Step:
　The mixture obtained in the second step is filled in a reaction vessel, under dark conditions, after the oxygen concentration in the gas phase portion of the reaction vessel was adjusted to be 5000ppm or less, relative to the mixture, by reacting the alcohol represented by the general formula [2], at least a portion of the dimer contained in the mixture is reduced, or substantially free of dimers contained in the mixture, alpha, to obtain a mixture containing α- difluoro acetaldehyde hemiacetal.

[0017]

　That is, the present invention provides the following [Invention 1] - to provide the invention 12.

[0018]

　[Invention 1]
　comprising the following steps, the general formula [3] with α represented method of α- difluoro acetaldehyde hemiacetal.
　First Step:
　alpha represented by the general formula [5], alpha-difluoro acetic acid esters and the alcohol represented by the general formula [2] and a solvent in the presence of a base and a ruthenium catalyst, hydrogen (H 2 ) is reacted with, or to the general formula [5] alpha, the alpha-difluoro acetic acid esters, are reacted with a hydride reducing agent, by, alpha represented by the general formula [3], alpha-difluoro acetaldehyde step of preparing a mixture comprising a hemiacetal.
　Second step:
　to the mixture obtained in the first step, performed neutralization treatment, then, filled with the mixture in the reaction vessel, 5000 ppm light shielding conditions, the oxygen concentration in the gas phase portion of the reaction vessel adjusted to below by performing subsequently distillation, including alpha, alpha-and-difluoro acetaldehyde hemiacetal, alpha represented by the general formula [4], a dimer of alpha-difluoro acetaldehyde, step the pH obtain a mixture between 3.5 and 10.0.
　Third Step:
　The mixture obtained in the second step is filled in a reaction vessel, under dark conditions, after the oxygen concentration in the gas phase portion of the reaction vessel was adjusted to be 5000ppm or less, typically to the mixture by reacting the alcohol represented by the formula [2], at least a portion of the dimer contained in the mixture is reduced, or substantially free of dimers contained in the mixture, alpha, alpha - to obtain a mixture containing difluoro acetaldehyde hemiacetal.

[0019]

　[Invention 2]
　In the first step, the ruthenium catalyst is a catalyst of the formula [6] or formula [7] The production method according to the invention 1.
[Formula 6]

[wherein, each R is independently a hydrogen atom, an alkyl group, a substituted alkyl group, an aromatic ring group or substituted aromatic ring group, Ar each independently represent an aromatic ring group or substituted aromatic ring group, X each independently formal charge of -1 or 0 ligand (the total formal charge of the three X is -2) represents, n represents represents an integer of 1 or 2 independently. ]
[Chemical Formula 7]

wherein, Ph represents a phenyl group. ]

[0020]

　[Invention 3]
　ruthenium catalyst of the formula [6] is a catalyst represented by the following formula, The process according to the invention 1 or 2.
[Formula 8]

wherein, Ph represents a phenyl group. ]

[0021]

　[Invention 4]
　In the first step, the ruthenium catalyst is a catalyst of the ruthenium compound supported on a carrier, the production method according to the invention 1.

[0022]

　[Invention 5]
　carrier is a catalyst supported on metal oxide or activated carbon, the manufacturing method according to the invention 4.

[0023]

　[Invention 6]
　ruthenium compounds, fluorides ruthenium, chloride, fluoride chloride, oxyfluoride, oxychloride, and at least one selected from the group consisting of oxyfluorides chloride, the invention 4 or 5 the method according.

[0024]

　[Invention 7]
　In the first step, a hydride reducing agent is a metal hydride, the production method according to the invention 1.

[0025]

　[Invention 8]
　metal hydride, lithium aluminum hydride, a lithium borohydride, sodium borohydride or sodium cyanoborohydride, production method according to the invention 7.

[0026]

　[Invention 9]
　In a second step, the adjustment of the pH of the mixture is carried out by adding an acid, the production method according to any one of Inventions 1 to 8.

[0027]

　[Invention 10]
　acid, acetic acid, benzoic acid or para - toluene sulfonic acid, the production method according to the invention 9.

[0028]

　[Invention 11]
　In the third step, the alcohol is methanol or ethanol, the production method according to any one of Inventions 1 to 10.

[0029]

　[Invention 12]
　In the second step or the third step, the adjustment of the oxygen concentration is carried out by bubbling an inert gas into the container, a manufacturing method according to any one of Inventions 1 to 11.

[0030]

　Note that changes over time in the production of compounds corresponding to such "dimer" is represented by a target 2,2-difluoro acetaldehyde similar structure of the present invention, the general formula [8] alpha, alpha, in the case of the hemiacetal of α- trifluoroacetaldehyde is significantly is not observed. That is, generation of such a "dimer" alpha, a peculiar in α- difluoro acetaldehyde hemiacetal phenomenon (unique challenges).
[Formula 9]

[wherein, R 5 represents an alkyl group or a substituted alkyl group. ]

The invention's effect

[0031]

　According to the present invention, alpha, in the production of α- difluoro acetaldehyde hemiacetal reduces the dimer by-produced during the purification of the hemiacetal, and an effect of reducing the content of difluoro acetic acid.

DESCRIPTION OF THE INVENTION

[0032]

　The present invention will be described in detail. The scope of the invention should not be restricted to these descriptions, even with the addition to the following examples, can be suitably changed and then practiced within a range not departing from the spirit of the present invention. Note that all of the publications cited herein, for example, prior art documents, and publications, patent publications and other patent documents, are incorporated herein by reference.

[0033]

　[First Step]
　First, a description will be given of the first step. The first step is represented by the general formula [5] alpha, alpha-difluoro acetic acid esters and the alcohol represented by the general formula [2] and a solvent in the presence of a base and a ruthenium catalyst, hydrogen (H 2 ) and reacted, or the general formula [5] in alpha represented, alpha-difluoro acetic acid esters is reacted with a hydride reducing agent, by, alpha represented by the general formula [3], alpha-difluoro it is a step for preparing a mixture comprising acetaldehyde hemiacetal.

[0034]

　This step is a known method, for adaptation of the methods described in Patent Document 1 are particularly advantageous for producing the hemiacetal in large scale. Employing the present process, since it is important in the practice of the present invention, it will be described below this manufacturing method.

[0035]

　Production method of the present process is a starting material of alpha, alpha-difluoro acetic esters, those skilled in reference to known production method can be easily manufactured.

[0036]

　Used in this step, alpha represented by the general formula [5], R of α- difluoro acetic acid esters 2 represents an alkyl group or a substituted alkyl group. Incidentally, R in the dimer represented by the general formula [4] 3 R in the acetic acid esters also 2 is synonymous with.

[0037]

　( "Alkyl group" referred to herein, it indicates that the "unsubstituted alkyl") alkyl group is a straight or branched alkyl group having 1 to 10 carbon atoms. For example, a methyl group, an ethyl group, n- propyl group, i- propyl, n- butyl group, i- butyl, s- butyl, t- butyl group, n- pentyl group, n- octyl group, n- decyl group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group.

[0038]

　Substituted alkyl groups, on any of the carbon atoms of the alkyl group, any number and any combination, you have a substituent. Substituents according a halogen atom, a lower alkoxy group, lower haloalkoxy group, cyano group or lower alkoxycarbonyl group. Specific examples thereof include fluorine, chlorine, bromine, methoxy, ethoxy, propoxy, fluoromethoxy group, chloromethoxy group, bromomethoxy group, a cyano group, a methoxycarbonyl group, an ethoxycarbonyl group and a propoxycarbonyl group is . In this specification, the term "lower", having 1 to 6 carbon atoms, means a straight-chain or branched chain or cyclic (in the case of 3 or more carbon atoms).

[0039]

　Base used in this step, alkali metal hydrogen carbonates, alkali metal carbonates, alkali metal hydroxides, tetraalkylammonium hydroxide, alkali metal alkoxides, organic bases, alkali metal bis (trialkylsilyl) amides, and borohydride, such as the alkali metal. Specifically, lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, lithium carbonate, sodium and potassium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, tetramethylammonium hydroxide, tetraethylammonium hydroxide, water oxidation tetra n- propyl ammonium, tetra-n- butylammonium hydroxide, lithium methoxide, sodium methoxide, potassium methoxide, lithium ethoxide, sodium ethoxide, potassium ethoxide, lithium isopropoxide, sodium isopropoxide, potassium isopropoxide, lithium tert- butoxide, sodium tert- butoxide, potassium tert- butoxide, triethylamine, diisopropylethylamine, 4-dimethylaminopyridine pin Jin, 1,8-diazabicyclo [5.4.0] undec-7-ene, lithium bis (trimethylsilyl) amide, sodium bis (trimethylsilyl) amide, potassium bis (trimethylsilyl) amide, lithium borohydride, sodium borohydride and potassium borohydride and the like. Among these alkali metal alkoxides (carbon number of alkoxide 1-6) are preferred, lithium methoxide, sodium methoxide and potassium methoxide particularly preferred. Incidentally, as described later in Examples, sodium methoxide is available as a normal methanol solution. Therefore, in the reaction system, so that the methanol remains. That is, methanol, at least a portion would serve as the alcohol represented by the general formula [2] described above.

[0040]

　Of the alcohols represented by the general formula [2] here, R 4 is represented by the general formula [3] alpha, R of α- difluoro acetaldehyde hemiacetal 1 is synonymous with. Specific compounds of the alcohol is methanol, ethanol, n- propanol, isopropanol, butanol, tert- butanol, although benzyl alcohol and the like, among these, methanol, ethanol, n- propanol, isopropanol are preferable, and among them, methanol ethanol are readily available anhydrous reagents in large scale, moreover alpha, for even greater effect of improving the stability of α- difluoro acetaldehyde alkyl hemiacetal, particularly preferred.

[0041]

　The amount of the alcohol, the raw alpha, alpha-difluoro acetic acid esters 1 may be used more than 0.001 mol per mol, preferably 0.005 to 5 mol, particularly preferably 0.01 to 3 mol.

[0042]

　Ruthenium catalyst used in this step is not particularly limited, for example, it is preferable to use a ruthenium catalyst represented by the following general formula [6] or formula [7].
[Formula 10]

wherein, each R is independently a hydrogen atom, an alkyl group, a substituted alkyl group, an aromatic ring group or substituted aromatic ring group, Ar each independently represent an aromatic ring group or substituted aromatic ring group, X each independently formal charge of -1 or 0 ligand (the total formal charge of the three X is -2) represents, n represents represents an integer of 1 or 2 independently. ]
[Chemical Formula 11]

wherein, Ph represents a phenyl group. ]

[0043]

　Further, as the ruthenium catalyst is a ruthenium compound may be used a catalyst supported on a carrier, it will be described in detail later.

[0044]

　Alkyl group as defined ruthenium catalyst represented by the general formula [6], R in the general formula [4] or the general formula [5] 1 is synonymous with. Aromatic ring group of the ruthenium catalyst is an aromatic heterocyclic group containing an aromatic hydrocarbon group or a nitrogen atom, a hetero atom such as an oxygen atom or a sulfur atom. Having 6 to 18 carbon atoms Specific examples of the aromatic hydrocarbon group, a phenyl group, a naphthyl group and an anthryl group, also aromatic heterocyclic group a pyrrolyl group (a nitrogen protecting body Specific examples of heteroatom-containing including), pyridyl group, furyl group, including also a thienyl group, indolyl group (the nitrogen-protected form), quinolyl group, a benzofuryl group and benzothienyl group.

[0045]

　Ruthenium catalyst represented by the general formula [6], "substituent" in the substituted alkyl group and substituted aromatic ring group, an alkyl group or an aromatic ring group of the, on any of the carbon atoms, any number and a combination of, exist. Substituents according a halogen atom, a lower alkyl group, lower haloalkyl group, a lower alkoxy group, lower haloalkoxy group, cyano group, lower alkoxycarbonyl group, aromatic ring group, a carboxyl group, protected carboxyl group, an amino group, an amino protection of groups is a protecting member such as a hydroxyl group, and a hydroxyl group. Specifically, fluorine, chlorine, bromine, methyl group, ethyl group, propyl group, fluoromethyl group, chloromethyl group, bromomethyl group, a methoxy group, an ethoxy group, a propoxy group, fluoromethoxy group, chloromethoxy group, bromomethoxy containing group, a methoxycarbonyl group, an ethoxycarbonyl group, polypropoxylated isobornyl group, a phenyl group, a naphthyl group, an anthryl group, (including nitrogen-protected form) a pyrrolyl group, a pyridyl group, a furyl group, a thienyl group, also an indolyl group (the nitrogen-protected form ), quinolyl group, a benzofuryl group, etc. benzothienyl group.

[0046]

　Further, the substituted alkyl group of ruthenium catalyst represented by the general formula [6], any carbon atoms in the alkyl group of the - carbon single bond, in any number and any combination, carbon - carbon double bond or carbon - it is also possible to replace the carbon triple bond (of course, an alkyl group substituted with these unsaturated bonds may also have a similar said substituent). Depending on the kind of substituents in some cases a substituent is itself involved in side reactions, but can be minimized by adopting suitable reaction conditions.

[0047]

　Further, "according substituent" of the the "aromatic ring group" of a halogen atom, a lower alkyl group, lower haloalkyl group, a lower alkoxy group, lower haloalkoxy group, cyano group, lower alkoxycarbonyl group, a carboxyl group, protection of carboxyl group, amino group, protected amino group, protected, etc. hydroxyl groups and hydroxyl groups can also be substituted. Furthermore, a pyrrolyl group, an indolyl group, a carboxyl group, an amino-protecting group and hydroxyl group, Protective Groups in Organic Synthesis, Third Edition, 1999, John Wiley & Sons, a protecting group as described in Inc. or the like.

[0048]

　Of the ruthenium catalyst represented by the general formula [6], a ruthenium catalyst represented by the following formula {(trade name "Ru-MACHO", manufactured by Takasago International Corporation) is commercially available as} has high activity, particularly preferred.
[Formula 12]

wherein, Ph represents a phenyl group. ]

[0049]

　When reacting with hydrogen, it is necessary to carried out in the presence of a base, of the three X ligand of the ruthenium catalyst, at least one BH 4 when taking the reaction in the absence of a base It can also be carried out.

[0050]

　Meanwhile, the ruthenium catalyst represented by the general formula [7], it is also possible to prepare in a known manner, which is commercially available under the trade name of "Ru-SNS" (manufactured by Sigma-Aldrich Japan LLC) it is convenient to use.

[0051]

　Furthermore, in addition to the ruthenium catalyst mentioned above, for example, Angew. Chem. Int. Ed . 2013, 52, 2538-2542, Organometallics 2012, 31, 5239-5242, Angew. Chem. Int. Ed. 2012, 51, 2772 -2775 and Angew. Chem. Int. Ed. 2006, 45, include a ruthenium catalyst according to 1113-1115 and the like. Its typical show (ruthenium homogeneous catalyst) in FIG. 1 (abbreviations / Et; ethyl, t-Bu; tert-butyl group, Ph; phenyl, i-Pr; isopropyl), naturally but it is not limited thereto. Even these ruthenium catalysts can be used under the same reaction conditions.
[Of 13]

[0052]

　Next, as a ruthenium catalyst, it is also possible to use a catalyst supporting ruthenium compound on a carrier. Here, the ruthenium compound to say, fluorides of ruthenium, chloride, fluoride chloride, oxyfluoride, oxychloride, and at least one selected from the group consisting of oxyfluorides chloride, carriers, metal an oxide or activated carbon. As the kind of the metal oxide is at least one of alumina, zirconia, selected from the group consisting of titania, silica, and magnesium.

[0053]

　Incidentally, the activated carbon may be used to select from those commercially available, for example, activated carbon produced from bituminous coal (e.g., Calgon granular activated carbon CAL (manufactured by Toyo Calgon Co.), coconut shell charcoal (e.g., Japan EnviroChemicals Chemicals and the like can be mentioned Co., Ltd.), is not of course limited to these types.

[0054]

　Methods of preparing the catalyst used in the present invention is not limited, for example, dissolving a ruthenium compound in the solution, the solution was impregnated in the support it can be adjusted by reducing treatment with heating while hydrogen. Or, pre hydrogen fluoride carrier, the compound modification treatment with halogen hydrogen chloride, and the like chlorinated fluorinated hydrocarbon, or impregnated with a solution of soluble compounds of ruthenium compounds can be prepared by spraying. The soluble compounds referred to herein, water, hydrochloric acid, ammonia water, ethanol, nitrate ruthenium compound soluble in a solvent such as acetone, phosphates, chlorides, oxides, oxychlorides, oxyfluorides, and the like . Supported amount to the carrier of the ruthenium compound, a percentage of the total amount of the carrier is 0.1 to 80 wt%, preferably from 1 40% by weight suitable.

[0055]

　Thus, catalyst supporting ruthenium compound on a carrier, which may be various prepared by the method may be used those commercially available. For example, N. Lee - Chemcat Co. A type is ruthenium activated carbon powder (dehydrated product), B-type, K type, and to utilize a heterogeneous catalyst such as R-type which is convenient.

[0056]

　The amount of the ruthenium catalyst is represented by the general formula [6] or when using a ruthenium catalyst represented by the formula [7], alpha, alpha-difluoro acetic acid esters may be used 0.000001 mol or more with respect to 1 mol, preferably 0.00001 to 0.005 mol, particularly preferably from 0.00002 to 0.002 mol.

[0057]

　On the other hand, when using a catalyst of the ruthenium compound supported on a carrier as a ruthenium catalyst, alpha, alpha-difluoro acetic acid esters may be used more than 0.00001 mol% relative to 1 mol, 0.001 to 10 mol% are preferred , particularly preferably 5 mol% 0.01.

[0058]

　The amount of hydrogen gas, alpha, alpha-difluoro acetic acid esters may be used more than 1 mol per 1 mol, preferably large excess, a large excess particularly preferred under pressure (hydrogen pressure will be described later).

[0059]

　Hydrogen pressure is not particularly limited, usually, 0.01 ~ 10 MPa (absolute pressure reference. Hereinafter, in this specification the same), and preferably 0.1 ~ 6 MPa, more preferably 0.3 ~ 5 MPa.

[0060]

　Incidentally, hydride reducing agent used in this step include aluminum hydride type, boron hydride systems. Specific examples (i-Bu) 2 AlH, LiAlH 4 , NaAlH 2 (OCH 2 CH 2 OCH 3 ) 2 , diborane, BH3 · THF, BH 3 · SMe 2 , BH 3 · NMe 3 , BH 3 · NPhEt 2 , NaBH 4 , LiBH 4 (representing each Bu is butyl group, THF is tetrahydrofuran, Me is methyl, Ph is phenyl, Et is an ethyl group) and the like.

[0061]

　The amount of the hydride reducing agent alpha, alpha-difluoro acetates hydride reducing agent to one mole of preferably 0.3 to 2.0 equivalents, particularly preferably 0.7 to 1.3 equivalents. If hydride reducing agent is less than 0.3 equivalents not sufficient addition rate of the reaction, whereas, 2.0 and over-reduced side reactions exceeds equivalent increase, that yield of the desired product is significantly reduced is there.

[0062]

　When using a hydride reducing agent, preferably used a reaction solvent. The reaction solvent is aliphatic hydrocarbons, aromatic hydrocarbons, halogenated hydrocarbons, nitriles, acid amides, ethers, and alcohols. Specific compounds, n- pentane, n- hexane, n- heptane, benzene, toluene, xylene, methylene chloride, chloroform, 1,2-dichloroethane acetonitrile, propionitrile, phenylacetonitrile, isobutyronitrile, benzo nitrile, dimethylformamide, dimethylacetamide, methylformamide, formamide, hexamethylphosphoric triamide, N- methylpyrrolidone, diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, 1,2-epoxy ethane, 1 , 4-dioxane, dibutyl ether, t- butyl methyl ether, substituted tetrahydrofuran, methanol, ethanol, n- propanol, isopropanol, butanol, tert- butanol, benzyl Alcohol and the like. These reaction solvents can be used alone or in combination.

[0063]

　The amount of the reaction solvent, the raw alpha, alpha-difluoro acetic acid esters 1 mole may be used 0.03 L (liter) or more with respect to, preferably 0.05 ~ 10L, particularly preferably 0.07 ~ 7L .

[0064]

　The reaction time may be performed within 72 hours, because it varies from a source substrate and the reaction conditions, gas chromatography, liquid chromatography to follow the progress of the reaction by an analytical means nuclear magnetic resonance, etc., decrease in the raw material substrate the point at which no longer observed almost the end point should be set. Thus, represented by the general formula [3] alpha, it is possible to obtain a mixture containing α- difluoro acetaldehyde hemiacetal.

[0065]

　Incidentally, the reaction of this step, once, alpha, alpha-difluoro acetaldehyde (corresponding to the general formula [1]) is generated, and reacts with alcohol present in the system, a stable alkyl hemiacetal (formula [ 3] α represented, is rapidly converted into α- difluoro acetaldehyde hemiacetal). Further, the starting material in this step, the general formula [3] with α represented, other α- difluoro acetaldehyde alkyl hemiacetal, an alcohol represented by the general formula [2], and the general formula [4] two there may contain mer (examples below), even in such a starting material, it can be suitably used as starting material in the subsequent second step.

[0066]

　[Second Step]
　The following describes a second step. The second step, relative to the mixture obtained in the first step, performed neutralization treatment, then, filled with the mixture in the reaction vessel, under dark conditions, the oxygen concentration in the gas phase portion of the reaction vessel 5000ppm adjusted to become less, by performing the distillation in shading conditions, including alpha, alpha-difluoro acetaldehyde hemiacetal of the general formula [4] with alpha represented, the dimer of alpha-difluoro acetaldehyde a step of pH to obtain a mixture between 3.5 and 10.0.

[0067]

　The mixture obtained in the first step, hydrogenated with ruthenium catalyst, be adopted either method of reduction with a hydride reducing agent has a reaction solution containing a base, strongly basic (pH 11.0 or higher) to indicate the, in this process, since the reaction solution to perform a purification operation is a weakly basic neutral, performing neutralization treatment. The term "weakly basic neutral" is to collect the liquid immersion in pH test paper, pH when measured by a pH meter 3.5 to 10.0 is such humoral (i.e. refers to liquid that can be defined as "weakly basic near neutral"), more preferably 6-10. Becomes acidic side outside the scope of these pH, the liquid to be subjected to the third process becomes acidic, the resulting dimer is not preferable because the thus stabilized. Conversely, when these become alkaline side out of the range of pH, tends to occur side reactions such as Cannizzaro reaction, alpha, undesirably reduced yield of α- difluoro acetaldehyde hemiacetal is produced.

[0068]

　In the present process, to adjust the pH range of the 3.5 to 10.0, the acetic acid, benzoic acid or para - may be performed in-toluenesulfonic acid (see Examples below).

[0069]

　This step is carried out in the dark conditions. Things as the light-shielding condition to block all wavelengths of an opaque outer wall is most desirable, but the short wavelength, specifically the brown shading glass can be used as long as the material can block the wavelengths below 450nm.

[0070]

　Further in this process, it is necessary to manage the oxygen concentration in the gas phase portion. Oxygen concentration can be measured using common oximeter.

[0071]

　After fed to the vessel the reaction mixture of the hemiacetal when reducing the oxygen concentration, nitrogen, is carried out by filling an inert gas such as argon, is not particularly limited method of filling inert gas into the container . For example, as described in the Examples below,
　alpha obtained in the first step to the container, alpha-after mixture comprising difluoro acetaldehyde hemiacetal was supplied into the vessel, the liquid phase portion of the inert gas in the container after bubbling, to seal the vessel, or,
　after supplying the mixture into a container, sealing the container, after the mixture was subjected to pressure reduction operation so as not to be discharged out of the vessel, the inert gas the blown to the liquid phase portion of the vessel, or bubbling an inert gas into the liquid phase portion,
include like. In either case, as well as reducing the dissolved oxygen concentration in the liquid phase portion, at the same time the gas phase of the vessel will be gradually replaced with the inert gas.

[0072]

　Incidentally, to increase the removal efficiency of dissolved oxygen, it is preferable to use a stirring operation, or degassing operations the liquid phase portion to those methods. Depending on the size of the storage of the hemiacetal, it is possible to reduce efficiently the oxygen concentration by combining these methods appropriately.

[0073]

　The type of inert gas used nitrogen, the gas which does not adversely influence the reaction such as argon.

[0074]

　Then, in this step, the oxygen concentration in the gas phase portion, 5000 ppm or less, preferably 1000ppm or less, particularly preferably to adjust the oxygen in the container so that the 300ppm or less. Limited to a specific method of how to adjust the oxygen concentration is not, for example,
　be adjusted to the oxygen concentration range by introducing into the vessel (1) inert gases, or
　(2) oxygen , nitrogen, a mixed gas of an inert gas such as argon blowing, to lower the oxygen concentration in the container to the appropriate range or,
　(3) alpha, sealed vessel containing α- difluoro acetaldehyde hemiacetal, depressurizing the vessel,
method and the like.

[0075]

　In the case of blowing the oxygen, nitrogen, a mixed gas of an inert gas such as argon, each ratio in the mixed gas of oxygen and inert gas is not particularly limited.

[0076]

　By adopting these conditions, alpha, alpha-polymerization difluoro acetaldehyde hemiacetal, although the reaction such as oxidation can be sufficiently prevented, among these, the adjustment method of (1) or (2), the oxygen concentration in the gas phase, for easily adjusted to 5000ppm or less is preferably used.

[0077]

　Upon distillation operation in this step, in addition to the conventional distillation operation, to remove the by-product (difluoro ethanol), precision distillation (fractional Distillation) (Note that a description of the "rectification" as referred to herein, for convenience, the combination of Sometimes referred to as "fractional distillation" or "distilling"), it is possible to increase the chemical purity.

[0078]

　Distillation conditions here, for apparatus are not particularly limited, against the skill of the art can set appropriate conditions. For example, if a precision distillation, the number of stages of the distillation column, for example, 2 or more, may be at 50 or less.

[0079]

　The filler to be filled in the distillation column, ordered packings, any irregularities packing available. The ordered packings may be those generally used, for example, Sulzer packing, Mellapak, Technopack, Flexipac and the like. The irregularities filler may be those generally used, for example, Helipack, Raschig rings, Dixon packing, and the like. Reflux ratio is 0.5-8.0, preferably 0.5-7.0, more preferably 0.5-6.0.

[0080]

　Pressure during the distillation is not particularly limited with respect to temperature, alpha, alpha-difluoro acetaldehyde hemiacetal may be a condition to be vaporized. Also, with respect to the reaction time is not particularly limited.

[0081]

　Through this step, without generating difluoroacetate in the reaction system, alpha, alpha-and-difluoro acetaldehyde hemiacetal, alpha, alpha-difluoro including dimer of acetaldehyde, pH is 3.5-10. and thus to obtain a mixture of 0.

[0082]

　Incidentally, since the hemiacetal are aldehydes difluoromethyl group directly bonded, as mentioned above, the fraction after distillation, self polymer, Mizuwatai, acetals, hemiacetals, and their structures characteristics are often obtained as a stable equivalent of compounds having associated therewith. For even this step, as shown in Examples below, alpha, other α- difluoro acetaldehyde hemiacetal, dimer of the general formula [4] is produced. Thus, by way of the subsequent third step, it is possible to convert the dimer efficiently the hemiacetal.

[0083]

　[Third Step]
　The following describes a third step. For the third step, alpha obtained in the second step, alpha-difluoro acetaldehyde hemiacetal and mixture containing dimer was charged to the reaction vessel, under dark conditions, the oxygen in the vapor phase in the reaction vessel after adjusting to a concentration of between 5000ppm or less, the mixture to, the addition of alcohol represented by the general formula [2], at least a portion of the dimer contained in the mixture is reduced, or the mixture substantially free of dimer contained, alpha, is a step of obtaining a mixture containing α- difluoro acetaldehyde hemiacetal.

[0084]

　In this step, relative to the mixture introduced into the reaction vessel, is to adjust the oxygen concentration in the reaction vessel so as to be 5000ppm or less in the dark conditions, the reaction vessel used, conditions for introducing oxygen, the first because that can be performed under the same conditions as described in two steps, in the present step thereof will not be repeated description about the oxygen delivery conditions.

[0085]

　The present process, compared mixture obtained in the second step, in adding an alcohol represented by the general formula [2], it is preferable that the pH of the mixture is in a range of 3.5 to 10.0 . Here the acid added to the mixture, when the pH was adjusted to outside the range 3.5 to 10.0, although reduced some dimer contained in the mixture, alpha, alpha-difluoro the amount of acetaldehyde hemiacetal may be decreased (Comparative examples 4 to 8 below). Thus, the present process is similar to the second step, pH with a range from 3.5 to 10.0, it is a preferred embodiment to react the alcohol with respect to the mixture (Note that this step is the second step obtained, because pH is used as it is the mixture between 3.5 and 10.0, need not necessarily be added actively acid).

[0086]

　Alcohols used in this step is represented by the general formula [2] (Note that not necessarily the same as the alcohol used as necessary in the first step). Among them, methanol and ethanol are readily available anhydrous reagents in large scale, and, alpha, because even a great effect of improving the stability of α- difluoro acetaldehyde alkyl hemiacetal, and more preferred.

[0087]

　The present process is an alcohol, but even the embodiment was added to an extent that does not substantially affect the water or other organic solvents for the reaction according to the present invention in the reaction system, it the present invention treated as intended to be included within the scope.

[0088]

　Addition of alcohol in this step may be added at once at the time of charging, while may be added sequentially while Mihakarai the progress of the reaction is not particularly limited. For example, with respect to dimers, alcohol at least two relative dimer moles of 1.0 equivalent or more, preferably by adding 1.5 equivalents or more, dimers alpha, the α- difluoro acetaldehyde hemiacetal It is gradually degraded, as a result, the selectivity to the hemiacetal is improved. Note that adding 5 equivalents or more of alcohol against dimer will be used more than necessary reagents, not economical.

[0089]

　The reaction temperature of this step is not particularly limited, be carried out at a room temperature of 5 ° C. ~ 35 ° C. is not applied load is preferred.

[0090]

　The reaction time in this step is not particularly limited, gas chromatography, using analytical equipment such as nuclear magnetic resonance (NMR), and the end point of the reaction time the decrease in dimer as a starting material is no longer minimal, it is preferable to.

[0091]

　The second and third steps, for example, nitrogen, can be carried out in an inert gas atmosphere such as argon. Reactor or storage vessel, the organic solvent, also alpha, alpha-made of a material having corrosion resistance against difluoro acetaldehyde hemiacetal, and atmospheric pressure or as long as it can perform sufficient reaction under pressure, stainless steel, Monel TM , Hastelloy TM , or metal containers, such as nickel, tetrafluoroethylene resin, chlorotrifluoroethylene resin, vinylidene fluoride resin, PFA resin, polypropylene resin, and polyethylene, typical materials in the chemical industry it is possible to use.

[0092]

　Above, by employing the conditions of the first to third steps, alpha, the content of dimers in the α- difluoro acetaldehyde hemiacetal, as shown in Examples described later, for example, to less than 10 wt% It can be reduced. Furthermore, for the generation of difluoro acetic acid, for example less than 200 ppm (not detected in the examples below), alpha, is a useful method as a method for efficiently producing α- difluoro acetaldehyde hemiacetal.
Example

[0093]

　Hereinafter, a detailed explanation of the present invention through examples, the present invention is not limited to these examples. Here, the determination of product (composition ratio and yield), and the reaction mixture was calculated based on the "mole%" of compositions obtained by measuring the nuclear magnetic resonance spectrometer (NMR). pH 1 solution and ultrapure water: a value measured by the pH meter a mixture in a weight ratio.

[0094]

　[Example 1]
　First Step:
　stainless steel pressure reaction vessel alpha, alpha-difluoro-ethyl acetate 109 g (0.88 mol), ruthenium catalyst 0.107 g (0.18 mmol) represented by the following formula, sodium methoxide 28% methanol solution 42 g (0.22 mol as sodium methoxide), methanol 290mL was added, the reaction vessel was replaced five times with hydrogen gas, and a hydrogen pressure of 1.0 MPa, 8 hours at 15 ℃ and the mixture was stirred to react.
[Chemical Formula 14]

　After the reaction was completed 19 than F-NMR analysis, alpha, converting 65% of the α- ethyl difluoroacetate, alpha, selectivity of α- difluoro acetaldehyde ethyl hemiacetal was 91%. 19 F-NMR internal standard (α, α, α- trifluorotoluene) was determined by.
　Second step:
　When acetic acid was added 13.2 g (0.22 mol) to the reaction-terminated liquid, because the pH became 8, to complete the addition. It was blown into operation with nitrogen gas to the reaction mixture. By bubbling operation, the oxygen concentration in the container it was confirmed that a 3000 ppm. Directly in the liquid under dark conditions, the distillation (bottom temperature: room temperature (25 ℃) ~ 66 ℃, vacuum degree; atmospheric pressure (0.1 MPa) ~ 2.0 kPa) by subjecting to, alpha, alpha-difluoro-acetaldehyde ethyl hemiacetal, difluoroethanol, and to obtain a solution containing methanol (alpha, the yield of the α- difluoro acetaldehyde ethyl hemiacetal was 90%).
　Then, the obtained solution, again subjected to bubbling operation with nitrogen gas, after the oxygen concentration in the gas phase was confirmed to be 2000 ppm, the liquid under dark conditions, precision distillation (35 theoretical plates , distillation temperature: room temperature (25 ℃) ~ 92 ℃, vacuum degree; difluoroethanol, and most of the methanol was separated by normal pressure (0.1MPa) ~ 35kPa).
　After rectification, the resulting fraction, ethanol, alpha, alpha-difluoro-acetaldehyde ethyl hemiacetal, and include "dimer" derived from the hemiacetal represented by the following formula, each of the composition ratios of ethanol but 6.3wt%, α, α- difluoro acetaldehyde ethyl hemiacetal 72.1wt%, dimer was 21.6wt%.
[Formula 15]

　The first step and the yield of difluoromethyl acetaldehyde ethyl hemiacetal through second step in consideration of the composition ratio is 51%, pH of the solution was 4.5.
　Step 3:
　Put the stirrer is light-resistant glass container of 100 ml, after the solution 50g after precision distillation obtained in the second step was charged under a nitrogen atmosphere, to the solution, similarly to the second step It was blown into operation with nitrogen gas. When the oxygen concentration in the container became 3000 ppm, and stirred 1.8 hour at room temperature of equivalents added to 25 ° C. relative to ethanol dimers.
　After one hour, the solution 19 was measured by F-NMR. The composition of the solution of ethanol 7.5wt%, α, α- difluoro acetaldehyde ethyl hemiacetal 84.2wt%, dimer is 8.3 wt%, difluoro acetic acid 19 was detected by F-NMR.

[0095]

　[Comparative Example 1]
　First Step:
　stainless steel pressure reaction vessel alpha, alpha-difluoro-ethyl acetate 109 g (0.88 mol), ruthenium catalyst 0.107 g (0.18 mmol) represented by the following formula, sodium methoxide 28% methanol solution 42 g (0.22 mol as sodium methoxide), methanol 290mL was added, the reaction vessel was replaced five times with hydrogen gas, and a hydrogen pressure of 1.0 MPa, 8 hours at 15 ℃ and the mixture was stirred to react.
[Chemical Formula 16]

　After 8 hours, the reaction mixture 19 was analyzed by F-NMR, alpha, alpha-conversion rate of the difluoro ethyl acetate 64%, alpha, the selectivity of alpha-difluoro acetaldehyde ethyl hemiacetal in 90% there were. 19 F-NMR internal standard (α, α, α- trifluorotoluene) was determined by.
　Second step:
　When acetic acid was added 7.5 g (0.13 mol) to the reaction-terminated liquid, because the pH became 12, to complete the addition. Perform bubbling operation with nitrogen gas to neutralization with liquid, the oxygen concentration in the container it was confirmed that a 3000 ppm. The liquid directly distilled under dark conditions (bottom temperature: room temperature (25 ℃) ~ 66 ℃, vacuum degree; atmospheric pressure (0.1 MPa) ~ 2.1 kPa) by subjecting to, alpha, alpha-difluoro-acetaldehyde ethyl hemiacetal, to obtain a solution containing difluoro ethanol and methanol (alpha, alpha-yield 5% as difluoro acetaldehyde ethyl hemiacetal, the yield of the ethyl difluoroacetate ingredients 40% yield as difluoroethanol It was 38%).
　Thus, in Comparative Example 1, alpha, as compared yield of α- difluoro acetaldehyde ethyl hemiacetal in Example 1 is substantially reduced. This is because the pH in the second step was too high, side reactions (Cannizzaro reaction) is resulted from the proceeds. Thus, it can be said that the reaction liquid to be subjected to purification in the second step is required to maintain a weakly basic neutral.

[0096]

　[Comparative Example 2]
　First step:
　stainless steel pressure reaction vessel alpha, alpha-difluoro-ethyl acetate 109 g (0.88 mol), ruthenium catalyst 0.107 g (0.18 mmol) represented by the following formula, sodium methoxide 28% methanol solution 42 g (0.22 mol as sodium methoxide), methanol 290mL was added, the reaction vessel was replaced five times with hydrogen gas, and a hydrogen pressure of 1.0 MPa, 8 hours at 15 ℃ and the mixture was stirred to react.
[Formula 17]

　After 8 hours, the reaction mixture 19 was analyzed by F-NMR, alpha, alpha-conversion rate of the difluoro ethyl acetate 64%, alpha, the selectivity of alpha-difluoro acetaldehyde ethyl hemiacetal in 90% there were. 19 F-NMR internal standard (α, α, α- trifluorotoluene) was determined by.
　Second step:
　When acetic acid was added 13.2 g (0.22 mol) to the reaction-terminated liquid, because the pH became 8, to complete the addition. Perform bubbling operation with nitrogen gas to neutralization with liquid, the oxygen concentration in the container it was confirmed that a 3000 ppm. Direct the liquid with a fluorescent lamp irradiation conditions, the distillation (bottom temperature: room temperature (25 ℃) ~ 67 ℃, vacuum degree; atmospheric pressure (0.1 MPa) ~ 1.9 kPa) by subjecting to, alpha, alpha-difluoro the methanol solution containing acetaldehyde ethyl hemiacetal in 90% yield difluoro acetaldehyde ethyl hemiacetal.
　Then, the obtained solution, again subjected to bubbling operation with nitrogen gas, after the oxygen concentration in the gas phase was confirmed to be 2000 ppm, precision distillation (theoretical plate number of the liquid with a fluorescent lamp irradiation conditions 35-stage, distillation temperature: room temperature (25 ℃) ~ 92 ℃, vacuum degree; to separate most of the methanol by normal pressure (0.1MPa) ~ 36kPa).
　The fraction, ethanol, alpha, alpha-difluoro-acetaldehyde ethyl hemiacetal, and derived from the hemiacetal represented by the following formula are included "dimer", each of the composition ratios of ethanol 6.6 wt%, alpha, alpha-difluoro acetaldehyde alkyl hemiacetal 71.9wt%, dimer was 21.5 wt%.
[Formula 18]

　The first step and the yield of difluoromethyl acetaldehyde ethyl hemiacetal through second step in consideration of the purity of 51%, pH of the solution was 2.7.
　Step 3:
　the light-shielding glass-made container of 100 ml, put a stirrer, after the solution 50g obtained in the second step was charged under a nitrogen atmosphere, to a mixture, as in the second step, the nitrogen gas in was blown into operation. When the oxygen concentration in the container became 3000 ppm, and stirred 1.8 for 24 hours at room temperature under equivalent added to 25 ° C. relative to ethanol dimers.
　After 24 hours, the solution 19 was measured by F-NMR. Composition ethanol 6.4 wt% solution, alpha, alpha-difluoro-acetaldehyde ethyl hemiacetal 73.0wt%, dimer is 20.6 wt%, difluoromethyl acetate was contained 710 ppm.
　Thus, pH is lowered by was carried out in a non-light-shielding condition in the second step, decomposition of the dimer in the third step can be suppressed, alpha-difluoro-acetic acid after rectification at the same time by-products, It remained in the α- difluoro acetaldehyde alkyl hemiacetal.

[0097]

　[Comparative Example 3]
　First step:
　stainless steel pressure reaction vessel alpha, alpha-difluoro-ethyl acetate 109 g (0.88 mol), ruthenium catalyst 0.107 g (0.18 mmol) represented by the following formula, sodium methoxide 28% methanol solution 42 g (0.22 mol as sodium methoxide), methanol 290mL was added, the reaction vessel was replaced five times with hydrogen gas, and a hydrogen pressure of 1.0 MPa, 8 hours at 15 ℃ and the mixture was stirred to react.
[Formula 19]

　After 8 hours, the reaction mixture 19 was analyzed by F-NMR, alpha, alpha-conversion rate of the difluoro ethyl acetate 66%, alpha, the selectivity of alpha-difluoro acetaldehyde ethyl hemiacetal in 90% there were. 19 F-NMR internal standard (α, α, α- trifluorotoluene) was determined by.
　Second step:
　When acetic acid was added 13.2 g (0.22 mol) to the reaction-terminated liquid, pH became 8. Perform bubbling operation with nitrogen gas to neutralization with liquid, the oxygen concentration in the container it was confirmed that a 7000 ppm. The liquid directly distilled under dark conditions (bottom temperature: room temperature (25 ℃) ~ 66 ℃, vacuum degree; atmospheric pressure (0.1 MPa) ~ 2.1 kPa) by subjecting to, alpha, alpha-difluoro-acetaldehyde ethyl to obtain a methanol solution containing hemiacetal. Precision distillation in the solution under dark conditions (35 theoretical plates, distillation temperature: room temperature (25 ℃) ~ 92 ℃, vacuum degree; atmospheric pressure (0.1 MPa) ~ 35 kPa) separating most of the methanol by did.
　The fraction, ethanol, alpha, alpha-difluoro-acetaldehyde ethyl hemiacetal, and include "dimer" derived from the hemiacetal represented by the following formula, each of the composition ratios of ethanol 6.3 wt%, alpha, α- difluoro acetaldehyde ethyl hemiacetal 72.1wt%, dimer was 21.6wt%.
[Formula 20]

　yields the difluoro acetaldehyde ethyl hemiacetal considering purity of 51%, pH of the solution was 3.2.
　Step 3:
　Put the stirrer is light-resistant glass container of 100 ml, after the solution 50g after precision distillation obtained in the second step was charged under a nitrogen atmosphere, to a mixture, as in the second step It was blown into operation with nitrogen gas. When the oxygen concentration in the container became 2000 ppm, it was stirred ethanol 1.8 at room temperature eq added to 25 ° C. relative to the dimers 24 hours. After 24 hours, the solution 19 was measured by F-NMR. The composition of the solution of ethanol 7.8wt%, α, α- difluoro acetaldehyde ethyl hemiacetal 76.9wt%, the dimer is 15.3wt%, difluoromethyl acetate was contained 530 ppm.
　Thus, pH is lowered to the oxygen concentration in the gas phase was carried out under conditions exceeding 5000ppm in the second step, decomposition of the dimer in the subsequent third step resulted to be suppressed. Further, after rectification alpha, also remained difluoro acetic acid by-product in α- difluoro acetaldehyde alkyl hemiacetal.

[0098]

　[Example 2-5, Comparative Example 4-8]
　First step:
　stainless steel pressure reaction vessel alpha, alpha-difluoro-ethyl acetate 218 g (1.76 mol), ruthenium catalyst 0.214g of the following formula (0.36 mmol), 28% sodium methoxide methanol solution 84 g (0.44 mol as sodium methoxide), methanol 580mL was added, the reaction vessel was replaced five times with hydrogen gas, the hydrogen pressure at 1.0MPa set, and then stirred for 8 hours at 15 ° C..
[Formula 21]

　After 8 hours, the reaction mixture 19 was analyzed by F-NMR, alpha, alpha-conversion rate of the difluoro ethyl acetate 64%, alpha, selectivity of alpha-difluoro acetaldehyde ethyl hemiacetal in 91% there were. 19 F-NMR internal standard (α, α, α- trifluorotoluene) was determined by.
　Second step:
　When acetic acid was added 26.4 g (0.44 mol) to the reaction-terminated liquid, the pH became 8, it is determined to have become weakly basic neutral, the addition was complete. Perform bubbling operation with nitrogen gas to neutralization with liquid, the oxygen concentration in the container it was confirmed that a 3000 ppm. Directly in the liquid under dark conditions, the distillation (bottom temperature: room temperature (25 ℃) ~ 67 ℃, vacuum degree; atmospheric pressure (0.1 MPa) ~ 2.0 kPa) by subjecting to, alpha, alpha-difluoro-acetaldehyde ethyl hemiacetal, difluoroethanol, and to obtain a solution containing methanol (alpha, the yield of the α- difluoro acetaldehyde ethyl hemiacetal was 90%).
　Then, the obtained solution, again subjected to bubbling operation with nitrogen gas, after the oxygen concentration in the gas phase was confirmed to be 2000 ppm, precision distillation (35 theoretical plates of this liquid in shading conditions , distillation temperature: room temperature (25 ℃) ~ 91 ℃, vacuum degree; difluoroethanol, and most of the methanol was separated by normal pressure (0.1MPa) ~ 38kPa).
　The fraction, ethanol, alpha, alpha-difluoro acetaldehyde alkyl hemiacetal, and dimers of the following formula are included, each of the composition ratios ethanol 4.5 wt%, alpha, alpha-difluoro acetaldehyde ethyl hemiacetal 78.4wt%, dimer was 15.3wt%.
Formula 22]

　yields the difluoro acetaldehyde ethyl hemiacetal through first and second steps in consideration of the composition ratio is 51%, pH of the solution was 5.0.
　Step 3:
　the light-shielding glass-made container of 30 ml, were placed a stirrer, the solution 20 g (liquid composition after precision distillation obtained in the second step is ethanol 4.5 wt%, alpha, alpha-difluoro-acetaldehyde ethyl hemiacetal 78.4wt%, dimers filled with 15.3wt%) under a nitrogen atmosphere. Subsequently, by adding various acids to adjust the pH of the liquid (adjustment of the pH was carried out for Examples 3-5 and Comparative Example 4-8). Thereafter, to the mixture was subjected to bubbling operation with nitrogen gas. By bubbling operation, where the oxygen concentration in the container becomes 4000 ppm, ethanol was added a predetermined amount with respect to dimers was stirred for 24 hours at a predetermined temperature, pH of the solution during the second step is completed the third It confirmed the effect on dimer conversion of the process. After 72 hours, the content liquid 19 was measured by F-NMR. The following are shown in Table 1.

[0099]

[Table 1]

[0100]

　From Table 1, in Examples 2-5, in the composition after 72 hours, the two content of dimer has become less than 10 wt%, as long pH3.5 more, dimers regardless of the type of acid but alpha, it can be seen that are efficiently converted to α- difluoro acetaldehyde hemiacetal. In Examples 2-5, difluoro acetic acid was not detected.

[0101]

　In contrast, in Comparative Examples 4-8, compared with the previous addition of the acid, the two although dimer is reduced, it was found that remaining dimer least 10 mass% in the composition after 72 hours . Adjustment of pH of the liquid in the third step of the present invention, in order to convert the dimeric alpha, the α- difluoro acetaldehyde hemiacetal, it can be said that one particularly preferred embodiment.

[0102]

　[Comparative Example 9-11]
　The first step to the second step, carried out under the same conditions as in Example 1 to obtain a fraction after rectification (see below). Using the fractions were subjected to the following third step.
　Step
　3: In a glass vessel 100 ml, after putting a stirrer alpha, alpha-composition ratio of difluoro acetaldehyde ethyl hemiacetal 72.1wt%, ethanol 6.3 wt% and alpha, alpha-difluoro-acetaldehyde ethyl hemiacetal dimers of 21.6wt%, and the mixture 50g is pH4.0 filled under nitrogen atmosphere. Ethanol was added 1.8 equivalents with respect to the dimer, to the mixture was subjected to bubbling operation with nitrogen gas. By bubbling operation, where the oxygen concentration in the container becomes 10000 ppm, a mixed gas of nitrogen, after the oxygen concentration in the container was filled to a value shown in Table 2 below was sealed, at 25 ° C. 24 time and the mixture was stirred.
　After 24 hours, the content liquid 19 was measured by F-NMR. The following are shown in Table 2. As for Example 6, difluoro acetic acid 19 was detected by F-NMR. In Table 2, "N.D.." Indicates a non-detection.

[0103]

[Table 2]

[0104]

　From Table 2, in Example 6, in the composition after 72 hours, the two content-mer is less than 10 wt%, dimers alpha, is efficiently converted to α- difluoro acetaldehyde hemiacetal, and difluoro acetic acid 19 was detected by F-NMR.

[0105]

　On the other hand, when the content in Comparative Example 9-11, compared with the previous addition of the acid, although dimer is reduced, in the composition after 72 hours, the dimer may remain above 10 wt%, difluoro acetic acid 300ppm more it can be seen that is.

[0106]

　From the above experimental results, defining method of the oxygen concentration and the light-shielding conditions of the present invention is a dimeric alpha, alpha-converted into difluoro acetaldehyde hemiacetal seen to be effective as a manufacturing method.

Industrial Applicability

[0107]

　α is an object of the present invention, alpha-difluoro acetaldehyde hemiacetal can be utilized as intermediates for the material or medicines, agricultural chemicals advanced materials field.

The scope of the claims

[Requested item 1]

　Comprising the steps of the general formula [3] with α represented method of α- difluoro acetaldehyde hemiacetal.
Formula 23]

wherein, R 1 represents an alkyl group or a substituted alkyl group. ]
　First step:
　represented by the general formula [5] alpha, alpha-difluoro acetic acid esters and the alcohol represented by the general formula [2] and a solvent in the presence of a base and a ruthenium catalyst, is reacted with hydrogen or the general formula [5] in alpha represented, alpha-difluoro acetic acid esters is reacted with a hydride reducing agent, by the general formula [3] alpha, the alpha-difluoro acetaldehyde hemiacetal step of preparing a mixture comprising.
Formula 24]

[wherein, R 2 is the general formula [3] in R 1 is the same as]
[Formula 25]

wherein, R 4 R in the general formula [3] 1 is the same as the '
　second step:
　to the mixture obtained in the first step, performed neutralization treatment, then, filled with the mixture in the reaction vessel, adjusting shielding conditions, the oxygen concentration in the reaction vessel so as to 5000ppm or less and, subsequently by performing a distillation operation, alpha, alpha-and-difluoro acetaldehyde hemiacetal represented by the general formula [4] alpha, including dimers of alpha-difluoro acetaldehyde, pH is 3.5-10 to obtain a mixture of 2.0.
[Chemical Formula 26]

wherein, R 3 represents an alkyl group or a substituted alkyl group. ]
　Third Step:
　The mixture obtained in the second step is filled in a reaction vessel, under dark conditions, after the oxygen concentration in the gas phase portion of the reaction vessel was adjusted to be 5000ppm or less, the mixture to , by adding an alcohol represented by the general formula [2], at least a portion of the dimer contained in the mixture is reduced, or substantially free of dimers contained in the mixture, alpha, to obtain a mixture containing α- difluoro acetaldehyde hemiacetal.

[Requested item 2]

　In the first step, a catalyst ruthenium catalyst is represented by the formula [6] or formula [7] The method according to claim 1.
[Formula 27]

In the formula, each R is independently a hydrogen atom, an alkyl group, a substituted alkyl group, an aromatic ring group or substituted aromatic ring group, Ar each independently represent an aromatic ring group or substituted aromatic ring group, X each independently formal charge of -1 or 0 ligand (the total formal charge of the three X is -2) represents, n represents represents an integer of 1 or 2 independently. ]
[Formula 28]

wherein, Ph represents a phenyl group. ]

[Requested item 3]

　Ruthenium catalyst represented by the formula [6] is a catalyst represented by the following formula, The process according to claim 1 or 2.
Chemical Formula 29]

wherein, Ph represents a phenyl group. ]

[Requested item 4]

　In the first step, the ruthenium catalyst is a catalyst of the ruthenium compound supported on a carrier, the production method according to claim 1.

[Requested item 5]

　Carrier is a catalyst supported on metal oxide or activated carbon The process of claim 4.

[Requested item 6]

　Ruthenium compounds, fluorides of ruthenium, chloride, fluoride chloride, oxyfluoride, oxychloride, and at least one selected from the group consisting of oxyfluorides chloride, prepared according to claim 4 or 5 Method.

[Requested item 7]

　In the first step, a hydride reducing agent is a metal hydride, the production method according to claim 1.

[Requested item 8]

　Metal hydride, lithium aluminum hydride, lithium borohydride, sodium borohydride or sodium cyanoborohydride method according to claim 7.

[Requested item 9]

　In a second step, the adjustment of the pH of the mixture is carried out by adding an acid, the production method according to any one of claims 1 to 8.

[Requested item 10]

　Acid, acetic acid, benzoic acid or para - toluene sulfonic acid The process of claim 9.

[Requested item 11]

　In the third step, the alcohol is methanol or ethanol, the production method according to any one of claims 1 to 10.

[Requested item 12]

　In the second step or the third step, the adjustment of the oxygen concentration is carried out by bubbling an inert gas into the container, a manufacturing method according to any one of claims 1 to 11.