WO2018180610A1

WO2018180610A1 - PRODUCTION METHOD FOR α,α-DIFLUOROACETALDEHYDE HEMIACETAL

Info

Publication number: WO2018180610A1
Application number: PCT/JP2018/010510
Authority: WO
Inventors: 真人木村; 進也秋葉; 将彰武田; 一樹田中; 雅隆藤本
Original assignee: セントラル硝子株式会社
Priority date: 2017-03-31
Filing date: 2018-03-16
Publication date: 2018-10-04
Also published as: CN110520403B; JPWO2018180610A1; CN110520403A; JP7032666B2

Abstract

The production method for an α,α-difluoroacetaldehyde hemiacetal ("DFAL-ROH") according to the present invention comprises: a step in which a difluoroacid ester is reacted with hydrogen (H2) in a reactor in the presence of a base and a ruthenium catalyst to produce a mixture containing a DFAL-ROH; a step in which the mixture is neutralized, thereafter the oxygen concentration inside the reactor is regulated to 5,000 ppm or less under such conditions that the mixture is shielded from light, and then distillation is conducted to obtain a mixture comprising the DFAL-ROH and a dimer and having a pH of 3.5-10.0; and a step in which an alcohol is added to the mixture after the oxygen concentration inside the reactor is regulated under light-shielding conditions, thereby obtaining a DFAL-ROH-containing mixture from which at least some of the dimer contained in said mixture has been removed or substantially all the dimer contained in said mixture has been removed. By the method, a DFAL-ROH reduced in by-product content is efficiently obtained.

Description

Process for producing α, α-difluoroacetaldehyde hemiacetal

The present invention relates to a method for producing α, α-difluoroacetaldehyde hemiacetal.

Α, α-Difluoroacetaldehyde represented by the formula [1] is a compound useful as a material in the field of advanced materials or an intermediate for medical and agricultural chemicals.

In particular, in the difluoromethyl group (—CHF ₂ ), two fluorine atoms and one hydrogen atom having high electronegativity are bonded to the same carbon atom. This unique structure is considered to be deeply related to characteristics such as water repellency, transparency, low dielectric property, unique physiological activity, and mimic effect of various materials synthesized using the structure. For this reason, substances using α, α-difluoroacetaldehyde as a building block are subject to active research and development in the fields of advanced materials and intermediates for medical and agricultural chemicals.

As a method for producing α, α-difluoroacetaldehyde, a reduction reaction using a hydride reducing agent such as lithium aluminum hydride is known for esters having a difluoromethyl group in the presence of a catalyst (Non-patent Document 1). ). Further, the present applicant has disclosed a method of reducing α, α-difluoroacetic acid esters by hydrogen (H ₂ ) in the presence of a ruthenium catalyst (Patent Document 1).

On the other hand, it is known that a substance called aldehyde is unstable and gradually polymerizes with other aldehyde molecules (Non-patent Document 2). Since the aldehyde targeted in the present invention is directly linked to a difluoromethyl group which is a strong electron-attracting group, a self-polymer, a hydrate, a hemiacetal, an acetal and a compound in which these structural features are combined It is also disclosed in Patent Document 1 that it can be obtained as a plurality of stable equivalents.

As described above, the aldehyde to which the difluoromethyl group is directly linked tends to be easily converted into a plurality of compounds. Therefore, the applicant of the present invention forms α, α-difluoroacetaldehyde hemiacetal represented by the general formula [3] in the presence of α, α-difluoroacetaldehyde with the alcohol represented by the general formula [2], and Patent Document 2 reports that adjusting the amount of coexisting alcohol makes it easier for the hemiacetal to exist stably in the system, that is, the storage stability is improved.

[Wherein, R ⁴ represents an alkyl group or a substituted alkyl group. ]

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

By the way, the present applicants disclosed in Patent Documents 1 and 2 a dimer of α, α-difluoroacetaldehyde represented by the general formula [4] (hereinafter referred to as the present specification) when purifying α, α-difluoroacetaldehyde hemiacetal. (Sometimes referred to as “dimers”).

[Wherein R ³ is the same as R ¹ in the general formula [2]. ]
This compound is a stable chemical species compared to α, α-difluoroacetaldehyde hemiacetal, and once produced, in order to proceed the desired reaction as α, α-difluoroacetaldehyde, it is a dimer. This will increase the number of steps for converging to α, α-difluoroacetaldehyde hemiacetal. Therefore, it can be said that it is desirable not to generate a dimer in α, α-difluoroacetaldehyde hemiacetal, or to reduce it as much as possible.

However, α, α-difluoroacetaldehyde hemiacetal is a compound that is unstable in the gas phase. Therefore, after synthesis, if a distillation operation or the like is performed to remove the neutralized salt or hydride reducing agent in the reaction solution, it will be constant. An amount of dimer is generated. Therefore, the present applicant has also found a specific phenomenon that the storage stability is improved and the compound (dimer) other than the hemiacetal is much less likely to be produced, and this is reported in Patent Document 2. .

International Publication No. 2014/115801 International Publication No. 2016/017318

It is known by the method described in Patent Document 2 that α, α-difluoroacetaldehyde can be obtained as a dimer in addition to stable equivalents such as self-polymers, hydrates, and hemiacetals. Further, according to this document, there is a description that it can be returned to α, α-difluoroacetaldehyde by an operation such as adding an acid to the dimer and heating it strongly.

However, as described in Patent Document 2, once the above-mentioned dimer is formed, it is difficult to find a condition for decomposing it to stably obtain the corresponding α, α-difluoroacetaldehyde hemiacetal. Even if an acid is added to the dimer to return it to α, α-difluoroacetaldehyde, heating, etc., the conversion rate when the dimer is actually decomposed into α, α-difluoroacetaldehyde hemiacetal There were large variations depending on the processing conditions (comparative examples described later). When the conversion rate is low, the dimer may not be reduced from a predetermined ratio even if the reaction is performed for a long time.

On the other hand, during the storage of α, α-difluoroacetaldehyde hemiacetal, decomposition progressed and sometimes decomposed to produce difluoroacetic acid as a by-product. Once difluoroacetic acid is produced, this compound itself is a strongly acidic substance, and increasing this amount affects the material of the reaction vessel, so it is not suitable for long-term storage of α, α-difluoroaldehyde. Met.

Therefore, an efficient α, α- which can reduce the dimer contained in the hemiacetal, which is by-produced during the purification of α, α-difluoroacetaldehyde hemiacetal, and can suppress the by-product of difluoroacetic acid. There has been a demand for a method for producing difluoroacetaldehyde hemiacetal.

The inventors of the present invention can stabilize a dimer when a mixed solution containing α, α-difluoroacetaldehyde hemiacetal and a dimer is in an acidic state. In particular, the pH of the mixed solution is less than 3.5. In some cases, it has been found that the stability is significantly increased and the dimer decomposition reaction is reduced.

In general, acids that may be present in the production of α, α-difluoroacetaldehyde hemiacetal include acids used in hydride reducing agents and base neutralization processes, and decomposition of α, α-difluoroacetaldehyde hemiacetal. The resulting difluoroacetic acid is contemplated. Of these, difluoroacetic acid is a strong acid, and the pH of the whole liquid is less than 3.5 even if the content in the mixed liquid is as small as several tens of ppm. When difluoroacetic acid is present in the system, there is a problem that even if alcohol is reacted with the dimer, it is difficult to proceed to the decomposition reaction of the dimer, that is, to hemiacetal.

Therefore, as a result of intensive studies by the present inventors, by adopting a production method including the following three steps as a condition for producing α, α-difluoroacetaldehyde hemiacetal of higher purity, α, It is said that the production of difluoroacetic acid, which is a decomposition product from α-difluoroacetaldehyde hemiacetal, can be suppressed, and the dimer of α, α-difluoroacetaldehyde hemiacetal produced as a by-product during the purification of hemiacetal can be reduced. The present inventors have obtained preferable findings and completed the present invention.
First step:
Reacting α, α-difluoroacetate represented by the general formula [5] with hydrogen (H ₂ ) in the presence of a base and a ruthenium catalyst using the alcohol represented by the general formula [2] as a solvent; Alternatively, α, α-difluoroacetaldehyde hemiacetal represented by the general formula [3] is contained by reacting the α, α-difluoroacetic acid ester represented by the general formula [5] with a hydride reducing agent. Producing a mixture;

[Wherein R ² is the same as R ¹ in the general formula [3]]
Second step:
The mixture obtained in the first step is subjected to neutralization treatment, and then the mixture is filled into a reaction vessel so that the oxygen (O ₂ ) concentration in the reaction vessel is 5000 ppm or less under light shielding conditions. And then a distillation operation is performed, so that the pH is 3.5, which includes α, α-difluoroacetaldehyde hemiacetal and a dimer of α, α-difluoroacetaldehyde represented by the general formula [4]. Obtaining a mixture of ˜10.0.
Third step:
After filling the mixture obtained in the second step into a reaction vessel and adjusting the oxygen concentration in the gas phase in the reaction vessel to 5000 ppm or less under light-shielding conditions, the general formula [2 ], By which at least part of the dimer contained in the mixture is reduced or substantially free of the dimer contained in the mixture, α, α- Obtaining a mixture comprising difluoroacetaldehyde hemiacetal.

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

[Invention 1]
A method for producing α, α-difluoroacetaldehyde hemiacetal represented by the general formula [3], comprising the following steps.
First step:
Reacting α, α-difluoroacetate represented by the general formula [5] with hydrogen (H ₂ ) in the presence of a base and a ruthenium catalyst using the alcohol represented by the general formula [2] as a solvent; Alternatively, α, α-difluoroacetaldehyde hemiacetal represented by the general formula [3] is contained by reacting the α, α-difluoroacetic acid ester represented by the general formula [5] with a hydride reducing agent. Producing a mixture;
Second step:
The mixture obtained in the first step is neutralized, and then filled into a reaction vessel so that the oxygen concentration in the gas phase in the reaction vessel is 5000 ppm or less under light-shielding conditions. And a distillation operation is carried out to adjust the pH to 3 with α, α-difluoroacetaldehyde hemiacetal and a dimer of α, α-difluoroacetaldehyde represented by the general formula [4]. Obtaining a mixture of 5 to 10.0.
Third step:
The mixture obtained in the second step is filled in a reaction vessel, and after adjusting the oxygen concentration in the gas phase in the reaction vessel to be 5000 ppm or less under light-shielding conditions, the general formula [2] Is reduced in at least one part of the dimer contained in the mixture, or substantially free of the dimer contained in the mixture. Obtaining a mixture comprising acetal;

[Invention 2]
The production method according to invention 1, wherein in the first step, the ruthenium catalyst is a catalyst represented by formula [6] or formula [7].

[In the formula, each R independently represents a hydrogen atom, an alkyl group, a substituted alkyl group, an aromatic ring group or a substituted aromatic ring group, Ar represents each independently an aromatic ring group or a substituted aromatic ring group, and each X represents an independent group. Represents a ligand having a formal charge of −1 or 0 (provided that the sum of the three formal charges of X is −2), and n independently represents an integer of 1 or 2. ]

[Wherein, Ph represents a phenyl group. ]

[Invention 3]
The manufacturing method of the invention 1 or 2 whose ruthenium catalyst represented by Formula [6] is a catalyst represented by a following formula.

[Wherein, Ph represents a phenyl group. ]

[Invention 4]
The production method according to invention 1, wherein in the first step, the ruthenium catalyst is a catalyst having a ruthenium compound supported on a carrier.

[Invention 5]
The production method according to claim 4, wherein the carrier is a catalyst supported on a metal oxide or activated carbon.

[Invention 6]
The production method according to invention 4 or 5, wherein the ruthenium compound is at least one selected from the group consisting of ruthenium fluoride, chloride, fluorinated chloride, oxyfluoride, oxychloride, and oxyfluoride chloride. .

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

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

[Invention 9]
The production method according to any one of inventions 1 to 8, wherein in the second step, the pH of the mixture is adjusted by adding an acid.

[Invention 10]
The production method according to invention 9, wherein the acid is acetic acid, benzoic acid or para-toluenesulfonic acid.

[Invention 11]
The manufacturing method according to any one of Inventions 1 to 10, wherein in the third step, the alcohol is methanol or ethanol.

[Invention 12]
The manufacturing method according to any one of inventions 1 to 11, wherein in the second step or the third step, the oxygen concentration is adjusted by bubbling an inert gas into the container.

Note that the change over time in the production of the compound corresponding to such a “dimer” is represented by the general formula [8], which is a structure similar to 2,2-difluoroacetaldehyde which is the subject of the present invention. In the case of hemiacetal of α, α, α-trifluoroacetaldehyde, it is not significantly observed. That is, the formation of such a “dimer” is a unique phenomenon (inherent problem) in α, α-difluoroacetaldehyde hemiacetal.

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

According to the present invention, in the production of α, α-difluoroacetaldehyde hemiacetal, the dimer produced as a by-product during purification of the hemiacetal can be reduced, and the content of difluoroacetic acid can be reduced.

Hereinafter, the present invention will be described in detail. The scope of the present invention is not limited to these descriptions, and other than the following examples, the scope of the present invention can be appropriately changed and implemented without departing from the spirit of the present invention. It should be noted that all publications cited in the present specification, for example, prior art documents, publications, patent publications and other patent documents are incorporated herein by reference.

[First step]
First, the first step will be described. In the first step, the α, α-difluoroacetic acid ester represented by the general formula [5] is used as a solvent, the alcohol represented by the general formula [2] is used as a solvent, hydrogen (H _{2) in} the presence of a base and a ruthenium catalyst. ), Or α, α-difluoroacetate represented by the general formula [5] is reacted with a hydride reducing agent, whereby α, α-difluoro represented by the general formula [3] It is a process for producing a mixture containing acetaldehyde hemiacetal.

This step is a known method, and adopting the method described in Patent Document 1 is particularly advantageous in producing the hemiacetal on a large scale. Since adopting this step is important in carrying out the present invention, this manufacturing method will be described below.

The manufacturing method of α, α-difluoroacetic acid esters which are starting materials for this step can be easily manufactured by those skilled in the art with reference to known manufacturing methods.

R ² of the α, α-difluoroacetate ester represented by the general formula [5] used in this step represents an alkyl group or a substituted alkyl group. Note that R ³ in the dimer represented by the general formula [4] is also synonymous with R ² in the acetate esters.

An alkyl group (“alkyl group” in the present specification means an “unsubstituted alkyl group”) represents a linear or branched alkyl group having 1 to 10 carbon atoms. For example, methyl group, ethyl group, n-propyl group, i-propyl group, n-butyl group, i-butyl group, s-butyl group, t-butyl group, n-pentyl group, n-octyl group, n- Examples include decyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group and the like.

The substituted alkyl group has a substituent in any number and in any combination on any carbon atom of the alkyl group. Such a substituent is a halogen atom, a lower alkoxy group, a lower haloalkoxy group, a cyano group, a lower alkoxycarbonyl group, or the like. Specific examples include fluorine, chlorine, bromine, methoxy group, ethoxy group, propoxy group, fluoromethoxy group, chloromethoxy group, bromomethoxy group, cyano group, methoxycarbonyl group, ethoxycarbonyl group and propoxycarbonyl group. . In this specification, “lower” means a linear or branched chain or cyclic group (in the case of 3 or more carbon atoms) having 1 to 6 carbon atoms.

Bases used in this step are alkali metal hydrogen carbonate, alkali metal carbonate, alkali metal hydroxide, tetraalkylammonium hydroxide, alkali metal alkoxide, organic base, alkali metal bis (trialkylsilyl) Amides, alkali metal borohydrides, and the like. Specifically, lithium hydrogen carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, lithium carbonate, sodium carbonate and potassium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, tetramethylammonium hydroxide, tetraethylammonium hydroxide, water Tetra n-propyl ammonium oxide, tetra n-butyl ammonium 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-dimethylaminopi Gin, 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. Among these, alkali metal alkoxides (alkoxides having 1 to 6 carbon atoms) are preferable, and lithium methoxide, sodium methoxide, and potassium methoxide are particularly preferable. As described in Examples below, sodium methoxide is usually available as a methanol solution. For this reason, methanol remains in the reaction system. That is, methanol plays at least part of the role as the alcohol represented by the general formula [2] described above.

Among the alcohols represented by the general formula [2], R ⁴ has the same meaning as R ^{1 of} α, α-difluoroacetaldehyde hemiacetal represented by the general formula [3]. Specific examples of the alcohol include methanol, ethanol, n-propanol, isopropanol, butanol, tert-butanol, and benzyl alcohol. Among these, methanol, ethanol, n-propanol, and isopropanol are preferable. And ethanol are particularly preferred because anhydrous reagents can be easily obtained on a large scale, and the effect of improving the stability of α, α-difluoroacetaldehyde alkyl hemiacetal is great.

The amount of alcohol used may be 0.001 mol or more, preferably 0.005 to 5 mol, particularly preferably 0.01 to 3 mol, relative to 1 mol of α, α-difluoroacetate as a raw material.

The 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 [7].

[Wherein, Ph represents a phenyl group. ]

Further, as the ruthenium catalyst, a catalyst in which a ruthenium compound is supported on a carrier can be used. Details will be described later.

The definition of the alkyl group of the ruthenium catalyst represented by the general formula [6] is synonymous with R ¹ in the general formula [4] or the general formula [5]. The aromatic ring group of the ruthenium catalyst is an aromatic hydrocarbon group or an aromatic heterocyclic group containing a hetero atom such as a nitrogen atom, an oxygen atom or a sulfur atom. Specific examples of the aromatic hydrocarbon group include a phenyl group, a naphthyl group, and an anthryl group having 6 to 18 carbon atoms, and specific examples of the aromatic heterocyclic group containing a hetero atom include a pyrrolyl group (also a nitrogen-protected substance). A pyridyl group, a furyl group, a thienyl group, an indolyl group (including a nitrogen protector), a quinolyl group, a benzofuryl group, a benzothienyl group, and the like.

The “substituent” in the substituted alkyl group and the substituted aromatic ring group of the ruthenium catalyst represented by the general formula [6] is an arbitrary number and an arbitrary number on an arbitrary carbon atom of the alkyl group or aromatic ring group. Exists in combination. Such substituents include halogen atoms, lower alkyl groups, lower haloalkyl groups, lower alkoxy groups, lower haloalkoxy groups, cyano groups, lower alkoxycarbonyl groups, aromatic ring groups, carboxyl groups, carboxyl group protectors, amino groups, amino groups Group protectors, hydroxyl groups, and hydroxyl group protectors. Specifically, fluorine, chlorine, bromine, methyl group, ethyl group, propyl group, fluoromethyl group, chloromethyl group, bromomethyl group, methoxy group, ethoxy group, propoxy group, fluoromethoxy group, chloromethoxy group, bromomethoxy Group, methoxycarbonyl group, ethoxycarbonyl group, propoxylbonyl group, phenyl group, naphthyl group, anthryl group, pyrrolyl group (including nitrogen protected form), pyridyl group, furyl group, thienyl group, indolyl group (including nitrogen protected form) ), Quinolyl group, benzofuryl group, benzothienyl group and the like.

Furthermore, the substituted alkyl group of the ruthenium catalyst represented by the general formula [6] is a carbon-carbon double bond or carbon in which any carbon-carbon single bond of the alkyl group is in any number and in any combination. It can also be replaced by carbon triple bonds (of course, alkyl groups replaced by these unsaturated bonds can likewise have the aforementioned substituents). Depending on the type of the substituent, the substituent itself may be involved in the side reaction, but it can be minimized by employing suitable reaction conditions.

The “aromatic ring group” in the “substituent” is a halogen atom, lower alkyl group, lower haloalkyl group, lower alkoxy group, lower haloalkoxy group, cyano group, lower alkoxycarbonyl group, carboxyl group, A protected group of a carboxyl group, an amino group, a protected group of an amino group, a hydroxyl group, a protected group of a hydroxyl group, and the like can be substituted. Further, pyrrolyl group, indolyl group, carboxyl group, amino group and hydroxyl protecting group are protecting groups described in Protective Group in Organic Synthesis, Third Edition, 1999, John Wiley & Sons, Inc.

Among the ruthenium catalysts represented by the general formula [6], a ruthenium catalyst represented by the following formula {(commercially available as “Ru-MACHO”, manufactured by Takasago International Corporation)} has high activity, Particularly preferred.

[Wherein, Ph represents a phenyl group. ]

When reacting with hydrogen, it is necessary to perform the reaction in the presence of a base. When at least one of the three X ligands of the ruthenium catalyst adopts BH ₄ , the reaction is performed in the absence of a base. It can also be done.

On the other hand, the ruthenium catalyst represented by the general formula [7] can be prepared by a known method, but is commercially available under the trade name “Ru-SNS” (manufactured by Sigma-Aldrich Sakai Japan LLC). It is convenient to use.

In addition to the ruthenium catalyst described 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, 1113-1115 and the like. A typical example (homogeneous ruthenium catalyst) is shown in FIG. 1 (abbreviation / Et: ethyl group, t-Bu; tert-butyl group, Ph: phenyl group, i-Pr: isopropyl group). It is not limited to these. These ruthenium catalysts can be used under similar reaction conditions.

Next, as the ruthenium catalyst, a catalyst in which a ruthenium compound is supported on a carrier can be used. The ruthenium compound referred to here is at least one selected from the group consisting of ruthenium fluoride, chloride, fluorinated chloride, oxyfluoride, oxychloride, and oxyfluorinated chloride. Oxide or activated carbon. The metal oxide is at least one selected from the group consisting of alumina, zirconia, titania, silica, and magnesium.

The activated carbon can be selected from commercially available ones. For example, activated carbon manufactured from bituminous coal (for example, Calgon granular activated carbon CAL (manufactured by Toyo Calgon Co., Ltd.), coconut shell charcoal (for example, Nippon Enviro Chemicals). (Made by Co., Ltd.), etc., but of course not limited to these types.

The method for preparing the catalyst used in the present invention is not limited, but for example, it can be adjusted by dissolving a ruthenium compound in a solution, impregnating the solution with a support, and then reducing with hydrogen while heating. Alternatively, it can be prepared by impregnating or spraying a solution in which a soluble compound of a ruthenium compound is dissolved in a compound in which a carrier is modified with a halogen in advance by hydrogen fluoride, hydrogen chloride, chlorinated fluorinated hydrocarbon or the like. Examples of the soluble compound include nitrates, phosphates, chlorides, oxides, oxychlorides, oxyfluorides, and the like of ruthenium compounds that dissolve in a solvent such as water, hydrochloric acid, aqueous ammonia, ethanol, and acetone. . The amount of the ruthenium compound supported on the carrier is suitably 0.1 to 80% by mass, preferably 1 to 40% by mass, based on the total amount with the carrier.

As described above, various catalysts prepared by supporting a ruthenium compound on a carrier can be prepared by the above-mentioned method, but commercially available catalysts can also be used. For example, it is convenient to use heterogeneous catalysts such as A type, B type, K type, and R type, which are ruthenium activated carbon powders (dehydrated products) manufactured by N. chemcat.

The ruthenium catalyst may be used in an amount of 0.000001 mol or more per 1 mol of α, α-difluoroacetic acid ester when the ruthenium catalyst represented by the general formula [6] or formula [7] is used. 0.00001 to 0.005 mol is preferable, and 0.00002 to 0.002 mol is particularly preferable.

On the other hand, when a catalyst having a ruthenium compound supported on a carrier is used as the ruthenium catalyst, 0.00001 mol% or more is used with respect to 1 mol of α, α-difluoroacetic acid ester, and 0.001 to 10 mol% is preferable. 0.01 to 5 mol% is particularly preferable.

The amount of hydrogen gas used may be 1 mol or more per 1 mol of α, α-difluoroacetic acid ester, a large excess is preferred, and a large excess under pressure (hydrogen pressure will be described later) is particularly preferred.

The hydrogen pressure is not particularly limited, but is usually 0.01 to 10 MPa (absolute pressure standard, hereinafter the same in the present specification), preferably 0.1 to 6 MPa, and more preferably 0.3 to 5 MPa.

In addition, examples of the hydride reducing agent used in this step include aluminum hydride and boron hydride. Specific examples include (i-Bu) ₂ AlH, LiAlH ₄ , NaAlH ₂ (OCH ₂ CH ₂ OCH ₃ ) ₂ , diborane, BH ₃ · THF, BH ₃ · SMe ₂ , BH ₃ · NMe ₃ , BH ₃ · NPhEt ₂ , NaBH ₄ , LiBH _{4 and the} like (Bu represents a butyl group, THF represents a tetrahydrofuran, Me represents a methyl group, Ph represents a phenyl group, and Et represents an ethyl group).

The amount of hydride reducing agent used is preferably 0.3 to 2.0 equivalents, particularly preferably 0.7 to 1.3 equivalents, per mole of α, α-difluoroacetate. When the hydride reducing agent is less than 0.3 equivalent, the addition rate of the reaction is not sufficient. On the other hand, when the hydride reducing agent exceeds 2.0 equivalent, the overreduction of side reaction increases, and the yield of the target product is greatly reduced. is there.

When using a hydride reducing agent, a reaction solvent may be used. Examples of the reaction solvent include aliphatic hydrocarbons, aromatic hydrocarbons, halogenated hydrocarbons, nitriles, acid amides, ethers, and alcohols. Specific compounds include n-pentane, n-hexane, n-heptane, benzene, toluene, xylene, methylene chloride, chloroform, 1,2-dichloroethaneacetonitrile, propionitrile, phenylacetonitrile, isobutyronitrile, benzone. Nitrile, dimethylformamide, dimethylacetamide, methylformamide, formamide, hexamethylphosphoric triamide, N-methylpyrrolidone, diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, 1,2-epoxyethane, 1 4-dioxane, dibutyl ether, t-butyl methyl ether, substituted tetrahydrofuran, methanol, ethanol, n-propanol, isopropanol, butanol, tert-butanol, benzil Alcohol and the like. These reaction solvents can be used alone or in combination.

The reaction solvent may be used in an amount of 0.03 L (liter) or more, preferably 0.05 to 10 L, particularly preferably 0.07 to 7 L with respect to 1 mol of α, α-difluoroacetic acid ester as a raw material. .

The reaction time may be within 72 hours, and varies depending on the raw material substrate and reaction conditions. Therefore, the progress of the reaction is traced by analytical means such as gas chromatography, liquid chromatography, nuclear magnetic resonance, etc. The end point should be the point at which almost no recognition is possible. Thereby, a mixture containing α, α-difluoroacetaldehyde hemiacetal represented by the general formula [3] can be obtained.

The reaction in this step once generates α, α-difluoroacetaldehyde (corresponding to the general formula [1]), but reacts with the alcohol present in the system to form a stable alkyl hemiacetal (general formula [1] 3], which is quickly converted to α, α-difluoroacetaldehyde hemiacetal. In addition to the α, α-difluoroacetaldehyde alkyl hemiacetal represented by the general formula [3], the starting material in this step includes an alcohol represented by the general formula [2], and two compounds represented by the general formula [4]. Although a monomer may be contained (an example described later), even such a starting material can be suitably used as a starting material in the subsequent second step.

[Second step]
Next, the second step will be described. In the second step, the mixture obtained in the first step is neutralized, and then the reaction vessel is filled with the mixture, and the oxygen concentration in the gas phase in the reaction vessel is reduced under light-shielding conditions. The dimer of α, α-difluoroacetaldehyde hemiacetal and α, α-difluoroacetaldehyde represented by the general formula [4] is contained by adjusting to 5000 ppm or less and performing a distillation operation under light-shielding conditions. In this step, a mixture having a pH of 3.5 to 10.0 is obtained.

The mixture obtained in the first step is a reaction solution containing a base regardless of whether hydrogenation using a ruthenium catalyst or reduction with a hydride reducing agent is used, and has a strong basicity (pH 11.0 or higher). In this step, neutralization is performed in order to make the reaction solution for purification operation neutral to weakly basic. The term “neutral to weakly basic” as used herein means that a liquid is collected and immersed in a pH test paper, but the liquid has a pH of 3.5 to 10.0 when measured with a pH meter (ie, , "Liquidity that can be defined as" neutral to weakly basic vicinity "), more preferably 6 to 10. If the pH falls outside the pH range and becomes acidic, the liquid used in the third step becomes acidic, and the produced dimer is stabilized, which is not preferable. On the other hand, if the pH is out of the pH range, the side reaction such as the Cannizzaro reaction is likely to occur and the yield of α, α-difluoroacetaldehyde hemiacetal is reduced, which is not preferable.

In this step, in order to adjust the pH to the range of 3.5 to 10.0, acetic acid, benzoic acid, para-toluenesulfonic acid or the like may be used (see Examples described later).

This step is performed under light-shielding conditions. As a light shielding condition, a material that blocks all wavelengths by an opaque outer wall is most desirable, but any material that can block a short wavelength, specifically, a wavelength of less than 450 nm, can be used by a brown light shielding glass or the like.

Furthermore, in this process, it is necessary to control the oxygen concentration in the gas phase portion. The oxygen concentration can be measured using a general oxygen concentration meter.

When reducing the oxygen concentration, the hemiacetal reaction liquid is supplied to the container and then filled with an inert gas such as nitrogen or argon, but there is no particular limitation on the method of filling the container with the inert gas. . For example, as described in the examples below,
After supplying the container containing the α, α-difluoroacetaldehyde hemiacetal mixture obtained in the first step into the container, the inert gas is bubbled through the liquid phase in the container, and then the container is sealed. Or
After supplying the mixture into the container, the inside of the container is sealed, and after performing a pressure reducing operation to such an extent that the mixture is not discharged out of the container, an inert gas is blown onto the liquid phase part in the container, or the liquid phase part is Bubbling inert gas,
Etc. In either case, the dissolved oxygen concentration in the liquid phase part is lowered, and at the same time, the gas phase part in the container is gradually replaced with an inert gas.

In addition, in order to increase the removal efficiency of dissolved oxygen, it is preferable to use a stirring operation or a degassing operation in the liquid phase part in combination with these methods. Depending on the scale of preservation of the hemiacetal, it is possible to efficiently reduce the oxygen concentration by appropriately combining these methods.

¡As the type of inert gas, a gas that does not affect the reaction, such as nitrogen or argon, is used.

Next, in this step, the oxygen in the container is adjusted so that the oxygen concentration in the gas phase is 5000 ppm or less, preferably 1000 ppm or less, particularly preferably 300 ppm or less. There is no limitation on the specific method for adjusting the oxygen concentration, for example,
(1) Adjust the oxygen concentration range to be within the above-mentioned range by introducing an inert gas into the container, or
(2) A mixed gas of oxygen and an inert gas such as nitrogen or argon is blown to reduce the oxygen concentration in the container to an appropriate range, or
(3) The inside of the container containing α, α-difluoroacetaldehyde hemiacetal is sealed, and the inside of the container is depressurized.
And the like.

In addition, when blowing the mixed gas of oxygen and inert gas, such as nitrogen and argon, each ratio in the mixed gas of oxygen and an inert gas does not have a restriction | limiting in particular.

By adopting these conditions, reactions such as polymerization and oxidation of α, α-difluoroacetaldehyde hemiacetal can be sufficiently prevented. Among these, the adjustment method of (1) or (2) is Since it is easy to adjust the oxygen concentration of a gaseous phase part to 5000 ppm or less, it is preferably used.

In order to remove by-products (difluoroethanol, etc.) in addition to the normal distillation operation, the distillation operation in this step is a fractional distillation (in addition, in explaining “precision distillation” here, For convenience, chemical purity can be increased by combining “fractional distillation” or “distillation”.

There are no particular restrictions on the conditions and apparatus for the distillation operation referred to herein, and conditions can be set as appropriate in light of the common general knowledge of those skilled in the art. For example, in the case of precision distillation, the number of stages of the distillation column may be, for example, 2 or more and 50 or less.

As the packing packed in the distillation column, either regular packing or irregular packing can be used. The regular packing may be those usually used, and examples thereof include sulzer packing, mela pack, techno pack, and flexi pack. The irregular packing may be those usually used, and examples thereof include helipac, Raschig ring, and Dixon packing. The reflux ratio is 0.5 to 8.0, preferably 0.5 to 7.0, more preferably 0.5 to 6.0.

The pressure and temperature during distillation are not particularly limited as long as α, α-difluoroacetaldehyde hemiacetal is vaporized. Also, the reaction time is not particularly limited.

By passing through this step, the pH of the reaction system containing a dimer of α, α-difluoroacetaldehyde hemiacetal and α, α-difluoroacetaldehyde is 3.5 to 10. without forming difluoroacetic acid in the reaction system. A zero mixture will be obtained.

Since the hemiacetal is an aldehyde having a difluoromethyl group directly bonded thereto, as described above, the fraction after distillation includes a self-polymer, a hydrate, an acetal, a hemiacetal, and a structure thereof. In many cases, it is obtained as a stable equivalent such as a compound having a combination of specific characteristics. Also in this step, a dimer of the general formula [4] is produced in addition to α, α-difluoroacetaldehyde hemiacetal, as shown in Examples described later. Therefore, the dimer can be efficiently converted to the hemiacetal by passing through the subsequent third step.

[Third step]
Next, the third step will be described. For the third step, the mixture containing α, α-difluoroacetaldehyde hemiacetal and dimer obtained in the second step is filled into a reaction vessel, and the oxygen in the gas phase in the reaction vessel is filled under a light-shielding condition. After adjusting the concentration to be 5000 ppm or less, by adding an alcohol represented by the general formula [2] to the mixture, at least a part of the dimer contained in the mixture is reduced, or the mixture Is a step of obtaining a mixture containing α, α-difluoroacetaldehyde hemiacetal substantially free of the dimer contained in

In this step, the oxygen concentration in the reaction vessel is adjusted to 5000 ppm or less under light-shielding conditions with respect to the mixture introduced into the reaction vessel, but the reaction vessel used and the conditions for introducing oxygen are as described above. Since it can be carried out under the same conditions as described in the two steps, repeated description of the oxygen introduction conditions is omitted in this step.

In addition, this step is preferably performed when the alcohol represented by the general formula [2] is added to the mixture obtained in the second step so that the pH of the mixture is in the range of 3.5 to 10.0. . Here, when an acid or the like is added to the mixture to adjust the pH to be out of the range of 3.5 to 10.0, a part of the dimer contained in the mixture decreases, but α, α-difluoro The amount of acetaldehyde hemiacetal may decrease (Comparative Examples 4 to 8 described later). Accordingly, in this step, as in the second step, it is preferable that the alcohol is reacted with the mixture at a pH in the range of 3.5 to 10.0 (note that this step is the second step). Since the obtained mixture having a pH of 3.5 to 10.0 is used as it is, it is not always necessary to positively add acid).

The alcohol used in this step is represented by the general formula [2] (note that it is not necessarily the same as the alcohol used as necessary in the first step). Among these, methanol and ethanol are more preferable because anhydrous reagents can be easily obtained on a large scale and the effect of improving the stability of α, α-difluoroacetaldehyde alkyl hemiacetal is large.

Although this step uses alcohol, even in an embodiment in which water and other organic solvents are added to the reaction system to such an extent that the reaction described in the present invention is not substantially affected, Treat as included in the range.

The addition of alcohol in this step may be added all at once at the time of preparation, while it may be added sequentially while monitoring the progress of the reaction, and there is no particular limitation. For example, the dimer is added to α, α-difluoroacetaldehyde hemiacetal by adding at least 1.0 equivalent, preferably 1.5 equivalents or more, of alcohol to the dimer with respect to the number of moles of the dimer. It is gradually decomposed, and as a result, the selectivity to the hemiacetal is improved. In addition, it is not economical to add 5 equivalents or more of alcohol to the dimer because it uses more reagents than necessary.

The reaction temperature in this step is not particularly limited, but it is preferable to perform the reaction at room temperature of 5 ° C. to 35 ° C. because no load is applied.

The reaction time of this step is not particularly limited, but the end point of the reaction is the time when almost no decrease in the dimer as a starting material can be confirmed using an analytical instrument such as gas chromatography or nuclear magnetic resonance (NMR). It is preferable to do.

The second step and the third step can be performed, for example, in an inert gas atmosphere such as nitrogen or argon. The reactor or the storage container may be made of any material that is made of a material having corrosion resistance to an organic solvent or α, α-difluoroacetaldehyde hemiacetal and can sufficiently react under normal pressure or pressure. 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 Can be used.

As described above, by adopting the conditions of the first step to the third step, the content of the dimer in α, α-difluoroacetaldehyde hemiacetal is, for example, less than 10% by mass as shown in the examples described later. Can be reduced. Furthermore, the production of difluoroacetic acid is, for example, less than 200 ppm (not detected in the examples described later), and is a useful method as an efficient production method of α, α-difluoroacetaldehyde hemiacetal.

Hereinafter, the present invention will be specifically described by way of examples, but the present invention is not limited to these examples. Here, the quantification (composition ratio and yield) of the product was calculated based on “mol%” of the composition obtained by measuring the reaction mixture with a nuclear magnetic resonance analyzer (NMR). The pH is a value obtained by measuring a mixture of a solution and ultrapure water at a weight ratio of 1: 1 with a pH meter.

[Example 1]
First step:
In a stainless steel pressure-resistant reaction vessel, 109 g (0.88 mol) of ethyl α, α-difluoroacetate, 0.107 g (0.18 mmol) of a ruthenium catalyst represented by the following formula, 42 g of sodium methoxide 28% methanol solution (sodium) 0.22 mol as methoxide) and 290 mL of methanol were added, the inside of the reactor was replaced with hydrogen gas five times, the hydrogen pressure was set to 1.0 MPa, and the reaction was stirred at 15 ° C. for 8 hours.

After completion of the reaction, the conversion of ethyl α, α-difluoroacetate was 65% and the selectivity for α, α-difluoroacetaldehyde ethyl hemiacetal was 91% from ¹⁹ F-NMR analysis. ¹⁹ F-NMR was quantified with an internal standard (α, α, α-trifluorotoluene).
Second step:
When 13.2 g (0.22 mol) of acetic acid was added to the reaction completed solution, the pH reached 8 and the addition was terminated. The reaction solution was bubbled with nitrogen gas. It was confirmed by bubbling operation that the oxygen concentration in the container was 3000 ppm. By subjecting this liquid to direct distillation under a light-shielding condition (bottom temperature; room temperature (25 ° C.) to 66 ° C., reduced pressure; normal pressure (0.1 MPa) to 2.0 kPa), α, α-difluoroacetaldehyde ethyl A solution containing hemiacetal, difluoroethanol, and methanol was obtained (the yield as α, α-difluoroacetaldehyde ethyl hemiacetal was 90%).
Next, the obtained solution was bubbled again with nitrogen gas, and after confirming that the oxygen concentration in the gas phase was 2000 ppm, the liquid was subjected to precision distillation (theoretical plate number: 35 plates) under light shielding conditions. Distillation temperature; room temperature (25 ° C.) to 92 ° C., degree of vacuum; normal pressure (0.1 MPa) to 35 kPa) was used to separate difluoroethanol and most of methanol.
The fraction obtained after precision distillation contains ethanol, α, α-difluoroacetaldehyde ethyl hemiacetal, and a “dimer” derived from the hemiacetal represented by the following formula, each having a composition ratio of ethanol Was 6.3 wt%, α, α-difluoroacetaldehyde ethyl hemiacetal was 72.1 wt%, and the dimer was 21.6 wt%.

The yield of difluoroacetaldehyde ethyl hemiacetal through the first step and the second step considering the composition ratio was 51%, and the pH of the solution was 4.5.
Third step:
A stirrer is placed in a 100 ml light-shielded glass container, and 50 g of the solution after the precision distillation obtained in the second step is filled in a nitrogen atmosphere. The solution is then filled with nitrogen gas as in the second step. Bubbling operation was performed. When the oxygen concentration in the container reached 3000 ppm, 1.8 equivalents of ethanol was added to the dimer, and the mixture was stirred at room temperature of 25 ° C. for 1 hour.
After 1 hour, the solution was measured by ¹⁹ F-NMR. The composition of the solution was 7.5 wt% ethanol, 84.2 wt% α, α-difluoroacetaldehyde ethyl hemiacetal, and 8.3 wt% dimer, and no difluoroacetic acid was detected by ¹⁹ F-NMR.

[Comparative Example 1]
First step:
In a stainless steel pressure-resistant reaction vessel, 109 g (0.88 mol) of ethyl α, α-difluoroacetate, 0.107 g (0.18 mmol) of a ruthenium catalyst represented by the following formula, 42 g of sodium methoxide 28% methanol solution (sodium) 0.22 mol as methoxide) and 290 mL of methanol were added, the inside of the reactor was replaced with hydrogen gas five times, the hydrogen pressure was set to 1.0 MPa, and the reaction was stirred at 15 ° C. for 8 hours.

After 8 hours, the reaction solution was analyzed by ¹⁹ F-NMR. As a result, the conversion rate of ethyl α, α-difluoroacetate was 64%, and the selectivity of α, α-difluoroacetaldehyde ethyl hemiacetal was 90%. ¹⁹ F-NMR was quantified with an internal standard (α, α, α-trifluorotoluene).
Second step:
When 7.5 g (0.13 mol) of acetic acid was added to the reaction-terminated liquid, the pH was 12, so the addition was terminated. The neutralized solution was bubbled with nitrogen gas, and it was confirmed that the oxygen concentration in the container was 3000 ppm. By subjecting this liquid to direct distillation under light-shielding conditions (bottom temperature; room temperature (25 ° C.) to 66 ° C., degree of vacuum; normal pressure (0.1 MPa) to 2.1 kPa), α, α-difluoroacetaldehyde ethyl A solution containing hemiacetal, difluoroethanol and methanol was obtained (5% yield as α, α-difluoroacetaldehyde ethyl hemiacetal, 40% yield as raw material ethyl difluoroacetate, yield as difluoroethanol Was 38%).
As described above, in Comparative Example 1, the yield of α, α-difluoroacetaldehyde ethyl hemiacetal was significantly reduced as compared with Example 1. This is because the side reaction (Canizzaro reaction) progressed because the pH in the second step was too high. Accordingly, it can be said that the reaction solution used for the purification operation in the second step needs to maintain neutral to weak basicity.

[Comparative Example 2]
First step:
In a stainless steel pressure-resistant reaction vessel, 109 g (0.88 mol) of ethyl α, α-difluoroacetate, 0.107 g (0.18 mmol) of a ruthenium catalyst represented by the following formula, 42 g of sodium methoxide 28% methanol solution (sodium) 0.22 mol as methoxide) and 290 mL of methanol were added, the inside of the reactor was replaced with hydrogen gas five times, the hydrogen pressure was set to 1.0 MPa, and the reaction was stirred at 15 ° C. for 8 hours.

After 8 hours, the reaction solution was analyzed by ¹⁹ F-NMR. As a result, the conversion rate of ethyl α, α-difluoroacetate was 64%, and the selectivity of α, α-difluoroacetaldehyde ethyl hemiacetal was 90%. ¹⁹ F-NMR was quantified with an internal standard (α, α, α-trifluorotoluene).
Second step:
When 13.2 g (0.22 mol) of acetic acid was added to the reaction completed solution, the pH reached 8 and the addition was terminated. The neutralized solution was bubbled with nitrogen gas, and it was confirmed that the oxygen concentration in the container was 3000 ppm. By subjecting this liquid to distillation (bottom temperature; room temperature (25 ° C.) to 67 ° C., reduced pressure; normal pressure (0.1 MPa) to 1.9 kPa) directly under fluorescent lamp irradiation conditions, α, α-difluoro A methanol solution containing acetaldehyde ethyl hemiacetal was obtained in 90% yield of difluoroacetaldehyde ethyl hemiacetal.
Next, the solution thus obtained was bubbled again with nitrogen gas, and after confirming that the oxygen concentration in the gas phase was 2000 ppm, this liquid was subjected to precision distillation (theoretical plate number) under fluorescent lamp irradiation conditions. Most of the methanol was separated by 35 stages, distillation temperature; room temperature (25 ° C.) to 92 ° C., reduced pressure; normal pressure (0.1 MPa) to 36 kPa).
The fraction contains ethanol, α, α-difluoroacetaldehyde ethyl hemiacetal, and a “dimer” derived from the hemiacetal represented by the following formula, each having a composition ratio of 6.6 wt% ethanol, The α, α-difluoroacetaldehyde alkyl hemiacetal was 71.9 wt%, and the dimer was 21.5 wt%.

The yield of difluoroacetaldehyde ethyl hemiacetal through the first step and the second step in consideration of purity was 51%, and the pH of the solution was 2.7.
Third step:
A stirrer is placed in a 100 ml light-shielded glass container, and 50 g of the solution obtained in the second step is filled in a nitrogen atmosphere. Then, the liquid mixture is bubbled with nitrogen gas as in the second step. went. When the oxygen concentration in the container reached 3000 ppm, 1.8 equivalents of ethanol was added to the dimer and stirred at room temperature of 25 ° C. for 24 hours.
After 24 hours, the solution was measured by ¹⁹ F-NMR. The composition of the solution was 6.4 wt% ethanol, 73.0 wt% α, α-difluoroacetaldehyde ethyl hemiacetal, 20.6 wt% dimer, and 710 ppm ethyl difluoroacetate.
As described above, the pH was lowered by carrying out the non-light-shielding condition in the second step, the decomposition of the dimer in the third step was suppressed, and at the same time, difluoroacetic acid as a by-product was α, It remained in the α-difluoroacetaldehyde alkyl hemiacetal.

[Comparative Example 3]
First step:
In a stainless steel pressure-resistant reaction vessel, 109 g (0.88 mol) of ethyl α, α-difluoroacetate, 0.107 g (0.18 mmol) of a ruthenium catalyst represented by the following formula, 42 g of sodium methoxide 28% methanol solution (sodium) 0.22 mol as methoxide) and 290 mL of methanol were added, the inside of the reactor was replaced with hydrogen gas five times, the hydrogen pressure was set to 1.0 MPa, and the reaction was stirred at 15 ° C. for 8 hours.

After 8 hours, the reaction solution was analyzed by ¹⁹ F-NMR. As a result, the conversion rate of ethyl α, α-difluoroacetate was 66%, and the selectivity of α, α-difluoroacetaldehyde ethyl hemiacetal was 90%. ¹⁹ F-NMR was quantified with an internal standard (α, α, α-trifluorotoluene).
Second step:
When 13.2 g (0.22 mol) of acetic acid was added to the reaction completed solution, the pH became 8. The neutralized solution was bubbled with nitrogen gas, and it was confirmed that the oxygen concentration in the container was 7000 ppm. By subjecting this liquid to direct distillation under light-shielding conditions (bottom temperature; room temperature (25 ° C.) to 66 ° C., degree of vacuum; normal pressure (0.1 MPa) to 2.1 kPa), α, α-difluoroacetaldehyde ethyl A methanol solution containing hemiacetal was obtained. This solution is subjected to precision distillation under light-shielded conditions (35 theoretical plates, distillation temperature: room temperature (25 ° C.) to 92 ° C., reduced pressure; normal pressure (0.1 MPa) to 35 kPa) to separate most of the methanol. did.
The fraction includes ethanol, α, α-difluoroacetaldehyde ethyl hemiacetal, and a “dimer” derived from the hemiacetal represented by the following formula, each having a composition ratio of ethanol 6.3 wt%, α, The α-difluoroacetaldehyde ethyl hemiacetal was 72.1 wt% and the dimer was 21.6 wt%.

In consideration of purity, the yield of difluoroacetaldehyde ethyl hemiacetal was 51%, and the pH of the liquid was 3.2.
Third step:
A stirrer is placed in a 100 ml light-shielded glass container, and 50 g of the precision-distilled solution obtained in the second step is filled in a nitrogen atmosphere. The mixture is then filled with nitrogen gas in the same manner as in the second step. Bubbling operation was performed. When the oxygen concentration in the container reached 2000 ppm, 1.8 equivalents of ethanol was added to the dimer and stirred at room temperature of 25 ° C. for 24 hours. After 24 hours, the solution was measured by ¹⁹ F-NMR. The composition of the solution was 7.8 wt% ethanol, 76.9 wt% α, α-difluoroacetaldehyde ethyl hemiacetal, 15.3 wt% dimer, and 530 ppm ethyl difluoroacetate.
Thus, since it implemented on the conditions which exceeded the oxygen concentration of gaseous-phase in 5000 steps | paragraph in the 2nd process, pH became low, and it resulted in the decomposition | disassembly of the dimer in the following 3rd process being suppressed. Further, difluoroacetic acid as a by-product remained in the α, α-difluoroacetaldehyde alkyl hemiacetal after rectification.

[Example 2-5, Comparative Example 4-8]
First step:
In a pressure resistant reaction vessel made of stainless steel, 218 g (1.76 mol) of ethyl α, α-difluoroacetate, 0.214 g (0.36 mmol) of a ruthenium catalyst represented by the following formula, 84 g of sodium methoxide 28% methanol solution (sodium) 0.44 mol) as methoxide) and 580 mL of methanol were added, the inside of the reactor was replaced with hydrogen gas five times, the hydrogen pressure was set to 1.0 MPa, and the reaction was stirred at 15 ° C. for 8 hours.

After 8 hours, the reaction mixture was analyzed by ¹⁹ F-NMR. As a result, the conversion rate of ethyl α, α-difluoroacetate was 64%, and the selectivity of α, α-difluoroacetaldehyde ethyl hemiacetal was 91%. ¹⁹ F-NMR was quantified with an internal standard (α, α, α-trifluorotoluene).
Second step:
When 26.4 g (0.44 mol) of acetic acid was added to the reaction-terminated liquid, the pH was 8. Therefore, it was judged that the reaction was neutral to weakly basic, and the addition was terminated. The neutralized solution was bubbled with nitrogen gas, and it was confirmed that the oxygen concentration in the container was 3000 ppm. By subjecting this liquid to direct distillation under a light-shielding condition (bottom temperature; room temperature (25 ° C.) to 67 ° C., degree of vacuum; normal pressure (0.1 MPa) to 2.0 kPa), α, α-difluoroacetaldehyde ethyl A solution containing hemiacetal, difluoroethanol, and methanol was obtained (the yield as α, α-difluoroacetaldehyde ethyl hemiacetal was 90%).
Next, the solution thus obtained was bubbled again with nitrogen gas, and after confirming that the oxygen concentration in the gas phase was 2000 ppm, this liquid was subjected to precision distillation (theoretical plate number: 35 plates) under light-shielding conditions. Distillation temperature; room temperature (25 ° C.) to 91 ° C., degree of vacuum; normal pressure (0.1 MPa) to 38 kPa) was used to separate difluoroethanol and most of methanol.
The fraction contains ethanol, α, α-difluoroacetaldehyde alkyl hemiacetal, and a dimer represented by the following formula, each having a composition ratio of 4.5 wt% ethanol, α, α-difluoro. Acetaldehyde ethyl hemiacetal was 78.4 wt%, and the dimer was 15.3 wt%.

The yield of difluoroacetaldehyde ethyl hemiacetal through the first step and the second step considering the composition ratio was 51%, and the pH of the solution was 5.0.
Third step:
A stirrer was placed in a 30 ml light-shielded glass container, and 20 g of the solution after the precision distillation obtained in the second step (the liquid composition was 4.5 wt% ethanol and 78 α-α-difluoroacetaldehyde ethyl hemiacetal). .4 wt%, dimer 15.3 wt%) was filled in a nitrogen atmosphere. Subsequently, various acids were added to adjust the pH of the solution (this pH was adjusted for Example 3-5 and Comparative Example 4-8). Thereafter, the mixture was bubbled with nitrogen gas. When the oxygen concentration in the container reached 4000 ppm by the bubbling operation, a predetermined amount of ethanol was added to the dimer and stirred at a predetermined temperature for 24 hours, and the pH of the solution at the end of the second step was third. The effect of the process on the dimer conversion was confirmed. After 72 hours, the contents were measured by ¹⁹ F-NMR. The following is shown in Table 1.

From Table 1, in Examples 2 to 5, in the composition after 72 hours, the content of the dimer is less than 10% by mass, and the pH is 3.5 or more, regardless of the type of acid. Is efficiently converted to α, α-difluoroacetaldehyde hemiacetal. In Examples 2 to 5, difluoroacetic acid was not detected.

On the other hand, in Comparative Examples 4 to 8, it was found that although the dimer was decreased as compared with before addition of the acid, the dimer remained at 10% by mass or more in the composition after 72 hours. . The adjustment of the pH of the liquid in the third step of the present invention can be said to be one of the particularly preferred embodiments for converting the dimer into α, α-difluoroacetaldehyde hemiacetal.

[Comparative Example 9-11]
The first step to the second step were carried out under the same conditions as in Example 1 to obtain a fraction after precision distillation (described later). The following 3rd process was performed using the fraction.
Third step:
The composition ratio of α, α-difluoroacetaldehyde ethyl hemiacetal is 72.1 wt%, ethanol 6.3 wt% and α, α-difluoroacetaldehyde ethyl hemiacetal dimer after putting a stir bar in a 100 ml glass container 21.6 wt% of a liquid mixture having a pH of 4.0 was charged in a nitrogen atmosphere. Ethanol was added in an equivalent amount of 1.8 with respect to the dimer, and the mixture was bubbled with nitrogen gas. When the oxygen concentration in the container reached 10000 ppm by the bubbling operation, the mixed gas of nitrogen was filled so that the oxygen concentration in the container became the value shown in Table 2 below, and then sealed and sealed at 25 ° C. at 24 ° C. Stir for hours.
After 24 hours, the contents were measured by ¹⁹ F-NMR. The following is shown in Table 2. As for Example 6, difluoroacetate was detected by ¹⁹ F-NMR. In Table 2, “ND” indicates no detection.

From Table 2, in Example 6, in the composition after 72 hours, the dimer content was less than 10% by mass, and the dimer was efficiently converted to α, α-difluoroacetaldehyde hemiacetal, and Difluoroacetic acid was not detected by ¹⁹ F-NMR.

On the other hand, in Comparative Example 9-11, the dimer decreased compared to before addition of the acid, but in the composition after 72 hours, the dimer remained at 10% by mass or more and difluoroacetic acid contained at 300 ppm or more. You can see that

From the above experimental results, it can be seen that the method for defining the oxygen concentration and light shielding conditions of the present invention is effective as a production method for converting a dimer into α, α-difluoroacetaldehyde hemiacetal.

The α, α-difluoroacetaldehyde hemiacetal targeted in the present invention can be used as a material in the field of advanced materials or as an intermediate for medical and agricultural chemicals.

Claims

A process for producing α, α-difluoroacetaldehyde hemiacetal represented by the general formula [3], comprising the following steps:

[Wherein, R 1 represents an alkyl group or a substituted alkyl group. ]
First step:
The α, α-difluoroacetic acid ester represented by the general formula [5] is reacted with hydrogen in the presence of a base and a ruthenium catalyst using the alcohol represented by the general formula [2] as a solvent, or the general formula The mixture containing α, α-difluoroacetaldehyde hemiacetal represented by the general formula [3] is produced by reacting α, α-difluoroacetate represented by [5] with a hydride reducing agent. Process.

[Wherein R 2 is the same as R 1 in the general formula [3]]

[Wherein R 4 is the same as R 1 in the general formula [3]]
Second step:
The mixture obtained in the first step is subjected to a neutralization treatment, and then the mixture is filled in a reaction vessel, and the oxygen concentration in the reaction vessel is adjusted to 5000 ppm or less under light shielding conditions, Subsequently, by performing distillation operation, the pH is 3.5 to 10.0 including a dimer of α, α-difluoroacetaldehyde hemiacetal and α, α-difluoroacetaldehyde represented by the general formula [4]. Obtaining a mixture of

[Wherein R 3 represents an alkyl group or a substituted alkyl group. ]
Third step:
After filling the mixture obtained in the second step into a reaction vessel and adjusting the oxygen concentration in the gas phase in the reaction vessel to 5000 ppm or less under light-shielding conditions, the general formula [2 ], At least a part of the dimer contained in the mixture is reduced, or the dimer contained in the mixture is substantially free of α, α-difluoroacetaldehyde hemi Obtaining a mixture comprising acetal;
The manufacturing method of Claim 1 whose ruthenium catalyst is a catalyst represented by Formula [6] or Formula [7] in a 1st process.

[In the formula, each R independently represents a hydrogen atom, an alkyl group, a substituted alkyl group, an aromatic ring group or a substituted aromatic ring group, Ar represents each independently an aromatic ring group or a substituted aromatic ring group, and each X represents an independent group. Represents a ligand having a formal charge of −1 or 0 (provided that the sum of the three formal charges of X is −2), and n independently represents an integer of 1 or 2. ]

[Wherein, Ph represents a phenyl group. ]
The manufacturing method of Claim 1 or 2 whose ruthenium catalyst represented by Formula [6] is a catalyst represented by a following formula.

[Wherein, Ph represents a phenyl group. ]
The production method according to claim 1, wherein in the first step, the ruthenium catalyst is a catalyst having a ruthenium compound supported on a carrier.
The production method according to claim 4, wherein the carrier is a catalyst supported on a metal oxide or activated carbon.
The production according to claim 4 or 5, wherein the ruthenium compound is at least one selected from the group consisting of ruthenium fluoride, chloride, fluorinated chloride, oxyfluoride, oxychloride, and oxyfluoride chloride. Method.
The manufacturing method according to claim 1, wherein in the first step, the hydride reducing agent is a metal hydride.
The production method according to claim 7, wherein the metal hydride is lithium aluminum hydride, lithium borohydride, sodium borohydride or sodium cyanoborohydride.
The production method according to any one of claims 1 to 8, wherein in the second step, the pH of the mixture is adjusted by adding an acid.
The production method according to claim 9, wherein the acid is acetic acid, benzoic acid or para-toluenesulfonic acid.
The manufacturing method according to any one of claims 1 to 10, wherein in the third step, the alcohol is methanol or ethanol.
The manufacturing method according to any one of claims 1 to 11, wherein in the second step or the third step, the oxygen concentration is adjusted by bubbling an inert gas into the container.