Book Details
The name of the invention: 2,2-improved method of difluoro acetaldehyde of storage stability
Technical field
[0001] The present invention provides 2,2-difluoro acetaldehyde (hereinafter, also referred to as DFAL) on Improvement method of preservation stability.
Background technique
[0002] 2,2-difluoro acetaldehyde represented by the formula (1) are useful compounds as intermediates for the material or pharmaceutical or agricultural advanced materials field.
[Formula 1]

In particular the difluoromethyl group (-CHF 2 ), although one fluorine atom 2 and the hydrogen atom with a high electronegativity, are 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. For this reason, 2,2-material was that using the difluoro acetaldehyde as a building block, in areas such as advanced materials field and pharmaceutical and agrochemical intermediates, have been the subject of active research and development.
[0003] For example, Patent Document 1, as one of the raw material for the production of useful halogenated hydroxy carbonyls as pharmaceutical and agrochemical intermediates, the use of 2,2-difluoro acetaldehyde has been proposed. In Patent Document 2, as a raw material for producing a novel insecticide, 2,2-difluoro acetaldehyde is used.
[0004] Conventionally, as a synthesizing means 2,2-difluoro acetaldehyde, alpha, .alpha.-difluoro acetic acid esters and methods for partial reduction by a hydride reducing agent such as lithium aluminum hydride was known (Non-Patent Document 1). In contrast, the applicant, alpha, .alpha.-difluoro acetic acid esters, and certain hydrogen ruthenium complex as a catalyst (H 2 by contacting with) a gas can be produced 2,2-difluoro-acetaldehyde catalytically to obtain a knowledge that has already been filed (Patent Document 3).
[0005] On the other hand, substances that aldehydes are unstable, gradually polymerized with other aldehydes molecules, it is known that the activity of the aldehyde loss (Non-Patent Document 2). Therefore, aldehyde and aqueous solution (Mizuwatai), specific surfactant thereto, pH adjusting agents, and by mixing the buffering agent, a method for preventing the polymerization of the aldehyde has been proposed (Patent Document 4) . Alternatively, by contacting the aldehyde with a large excess of alcohol, a method of converting into highly stable acetals are also known (Non-Patent Document 3).
CITATION
Patent literature
[0006] Patent Document 1: Laid-Open Publication No. 06-263684
Patent Document 2: Laid-open Publication No. 2010-209073
Patent Document 3: International Publication No. 2014/115801 Publication
Patent Document 4: Unexamined Publication No. 2010-523600

Non-patent literature
[0007] Non-Patent Document 1:.. J. Org Chem Volume 58 (1993), 2302 - 2312
2 Non-Patent Document: Synthetic Organic Chemistry No. (1961) Volume 3, No. 19, 254 - 260
Non-Patent Document 3 :.. Org Synth Volume 5 (1973) 303

Disclosure of the Invention
Problems that the Invention is to Solve
[0008] The method of Patent Document 4 described that in an aqueous solution of the aldehyde (Mizuwatai) is, 1 Tsutoieru of powerful method for storing the aldehyde stable. However, in this method, it is necessary to co-exist a plurality of substances such as surfactants, also if not tightly controlled the pH of the solution, there is a problem that it is difficult to prevent the "polymerization". Also it is necessary to perform a strong dehydrating immediately prior to use aldehyde as the reagent (see JP 50-12405 for example), when viewed overall, in many cases the operation becomes complicated.
[0009] On the other hand, a method for converting an aldehyde to a in contact with an alcohol acetal (chemical species alcohol 2 molecules react to aldehyde 1 molecule) are also excellent means as a method of stabilizing aldehyde.
[Formula 2]

In however this method, it is necessary to co-exist a large excess of the alcohol relative to the aldehyde. That is, when not allowed to coexist a large excess amount of alcohol in the system, can not be converted is always up to the acetal. Further, in order to save the generated acetal is also necessary to remove the strong water from the system, acetal and absorbs moisture is easily converted to hydrate and hemiacetal during storage, the liquid composition varies . Furthermore, since the acetal itself is stable species, when compared with the corresponding aldehyde or hemiacetal (species only alcohol 1 molecules react to aldehyde), it is quite low activity of the central carbon atom, as such often show no intrinsic activity aldehyde. That is, before subjected to use as a reagent, the operation to return the acetal by some means to "reactive species (e.g. free aldehyde)" that is required often, in that case, rather the operation is complicated.
[0010] Thus, as a method of the present invention to save difluoro acetaldehyde of interest stably, novel alternative to the above methods has been desired.
[0011] In view of the above circumstances, the present inventors have found that without generating an acetal, a method of stabilizing 2,2-difluoro-acetaldehyde with alcohol molecule relative to the aldehyde 1 molecule had reacted "hemiacetal" there are no, conducted various searches. As a result, 2,2-difluoro for acetaldehyde per molecule, alcohols represented by the general formula (2) is 1 molecule binding, hemiacetal stability represented by the formula (3) is considerably higher, this compound by converting into "polymerization" as described in non-Patent Document 2 (C-C bond linkage to generate a phenomenon that the molecular weight is increased), it was found to be able to sufficiently suppressed.
[Chemical formula 3]

[Formula 4]

(wherein, R 2 represents a hydrocarbon cyclic or chain-like or branched having 1 to 6 carbon atoms, a hydrogen atom may be substituted partially or entirely by fluorine atoms .)
[0012] However, a problem in the hemiacetal of formula (3), further on storage over a long period of time (several months or more), "dimer" in the compounds (herein this represented by the following formula (4) sometimes referred to as) is generated gradually in the system, the liquid composition resulting in gradual changes, a new problem has been found that.
[Chem 5 of 5]

R of the "dimer" 2 As, R alcohols are most abundant in the system 2 will often be. If "Ethanol" as in the Examples described below are the primary alcohol, R a "dimer" 2 become major ones ethyl. The "dimer", and is described in Non-Patent Document 2 "polymer of the aldehyde (compound C-C bond is gradually continuously)" is entirely different kind of material. That is, "2,2-difluoro-acetaldehyde stability equivalent of (hemiacetal)" is a type of, by an operation such as heating strongly by adding acid, it is possible to revert to the original aldehyde.
[0013] However, this "dimer", when compared to a hemiacetal of formula (3), are much more stable species, in remains in this species, as the aldehyde reagent to cause a desired reaction it is not easy. Moreover, when long-term storage, the liquid composition itself that will change, it can not be said that the management of the reagent preferred by progress of such a dimerization. Furthermore, even if this is possible to return to the "dimer" of the original aldehyde, heating by adding acid, working on is not always easy thing. Since the original "hemiacetal" is a compound that reaction activity is sufficient, without any special pre-treatment, if possible, it is desirable to directly used as a reaction reagent.
[0014] Thus, upon saving the 2,2-difluoro-acetaldehyde in the form of a hemiacetal, an effective way to improve the storage stability it has been desired.
[0015] Such a temporal product of a compound corresponding to "dimer", similar 2,2,2 acetaldehyde (the following formulas subject to 2,2-difluoro acetaldehyde and structure of the present invention (a ) in the case of the hemiacetal) (the following formulas (b)) is not significantly observed.
[Formula 6]

[Chemical Formula 7]

(wherein, R 2 represents a hydrocarbon cyclic or chain-like or branched having 1 to 6 carbon atoms, a hydrogen atom may be substituted partially or entirely by fluorine atoms .)
[0016] That is, generation of such a "dimer" is a phenomenon peculiar to the hemiacetal of 2,2-difluoro-acetaldehyde (unique challenges).
Means for Solving the Problems
[0017] The present inventors have conducted extensive studies in order to solve the above problems. Excess Consequently, a 2,2-difluoro-acetaldehyde, occurring between the alcohol represented by the general formula (2), for hemiacetal represented by the formula (3), an alcohol represented by the above formula (2) coexist in, after a "2,2-difluoro-acetaldehyde alcohol complex", substantially neutral liquid property of the "2,2-difluoro-acetaldehyde alcohol complex", and the content of water It did on the 1000ppm or less, the total molar amount of the alcohol represented by the formula (2) (means the total molar amount of "free alcohol" "2,2-difluoro acetaldehyde hemiacetal". hereinafter the same.) of , 2,2 the total molar amount of difluoro acetaldehyde 1.15 ( "free of 2,2-difluoro-acetaldehyde" refers to the total molar amount of "2,2-difluoro-acetaldehyde hemiacetal". or less the same.) against by more than doubled and 4.00 times or less, it was found that the problems can be solved.
[Formula 8]

[Chem 9]

(wherein, R 2 represents a hydrocarbon cyclic or chain-like or branched having 1 to 6 carbon atoms, a hydrogen atom may be substituted partially or entirely by fluorine atoms .)
[0018] Specifically, for "2,2-difluoro-acetaldehyde alcohol complex" substantially neutral liquid of, and the content of water as a 1000ppm or less, 2,2-difluoro-acetaldehyde of the formula (2 ) in total molar amount of alcohol 1.15 times or more as represented, 4.00 times or less (that is, when the alcohol is adjusted to 15% excess to 300% excess), in the system, equation (3) in hemiacetal represented is the main product.
[Formula 10]

(wherein, R 2 meaning of as defined in the formula (2).)
Specifically, in this condition, free of 2,2-difluoro-acetaldehyde is not substantially detected, the alcohol was 2 molecules react "acetal" not detected nearly even. Within the clogging system, and the hemiacetal, surplus free alcohol is, to co-exist as a main component.
[0019] Here Surprisingly, in the total molar amount of less than 1.15 times the alcohol in the system, while not control time generation of "dimer" described above, the total molar amount of alcohol 1 When becomes .15 times, "dimer" is unlikely to remarkably generated, the specific phenomenon was found. Specifically, in this condition, that the hemiacetal represented by the formula (3) is likely to exist stably, the present inventors have found.
[0020] Here, as shown in the synthesis examples below, alpha as the starting compound for the synthesis of 2,2-difluoro-acetaldehyde, .alpha.-difluoro acetic ester is used.
[Chem 11]

(In the formula, A represents a hydrocarbon cyclic or chain-like or branched having 1 to 6 carbon atoms, a hydrogen atom may be substituted partially or entirely by a fluorine atom.)
Alpha, and subjecting the α- difluoro acetic acid ester to partial reduction, the above formula of the "-O-a" of the ester moiety, is almost as it is carried over, of the product 2,2-difluoro acetaldehyde of hemiacetal "-O- R 2 become. " (. When performing a reduction reaction in an alcohol solvent is caused transesterification part, in which case does not change the total amount of alcohol in the system) once is converted into hemiacetal, hemiacetal "- O-R 2 "is counted as" alcohol total "(by decomposition reactions, there is ability to produce alcohol). If attention is paid only to the chemical species called "2,2-difluoro-acetaldehyde hemiacetal of", regardless of its origin how, in the compound: the ratio of "aldehyde alcohol" is exactly 1: 1, "alcohols to aldehydes the amount for 1 mole "is exactly" 1 mole (1-fold molar) ".
[0021] That alpha, .alpha. when synthesizing the "2,2-Difluoro acetaldehyde hemiacetal" as difluoroacetic acid ester starting materials, in the reaction solution, already "alcohol component" derived from the raw material exist 1 moles there. After all, referred to in the present invention, "the total molar amount of alcohol in the system is, for the aldehyde 1 mole, 1.15 mole or more, 4.00 mol or less," and, alcohol to form a "hemiacetal binding component "except for the" free alcohol "is," 15% or more with respect to the aldehyde, 300% or less, "it refers to the present. A small amount of "free alcohol" coexisting in the system is inferred to be blocked for some reason the generation of the "dimer". Although the detailed mechanism is unknown, by the finding, 2,2-difluoro acetaldehyde in the form of "hemiacetal represented by the formula (3)", it is possible to stably stored over a long period of time It was.
[0022] In the present invention, "R in" Formula hemiacetal represented by formula (3) " 2 and" "R in the" alcohol represented by the formula (2) " 2 and" but has the same definition, within the framework of this definition, the "formula hemiacetal represented by formula (3)" "R 2 " R a "alcohol represented by the formula (2)" and " 2 " is a in the same group even it may be a different group. Further, "Equation (3) represented by hemiacetal by" "Equation (2) represented alcohol" both "R of the plurality of types 2 embodiment of no problem (described later also be a mixture of species" see example).
[0023] In the present invention, it is expressed as drives out to the state of the "hemiacetal represented by the formula (3)" can be stably stored, "improving the storage stability of the 2,2-difluoro-acetaldehyde" .
[0024] That is, the present invention includes
a first step: Formula (3), comprising a hemiacetal 2,2-difluoro acetaldehyde, and free of alcohol represented by the formula (2), a "2,2 preparing a difluoro acetaldehyde alcohol complex "
[Chem 12]

(wherein, R 2 represents a hydrocarbon cyclic or chain-like or branched having 1 to 6 carbon atoms, a hydrogen atom is part of a fluorine atom or a . all optionally substituted)
[formula 13]

(wherein, R 2 meaning of the formula (3) and the same) and a.
second step: the "2,2-difluoro-acetaldehyde alcohol complex" the includes a step of storing in the storage vessel, the,
and, the "2,2-difluoro-acetaldehyde-alcohol complex" at the time to start saving in the storage container is in a substantially neutral, and water content is at 1000ppm or less, the total molar amount of the alcohol in the "2,2-difluoro-acetaldehyde-alcohol complex" at the time to start saving in the storage container and the ( "free of alcohol," "2,2 It refers to the total molar amount of various hemiacetal "difluoro acetaldehyde. or less the same.) is, 2,2-total molar amount of difluoro-acetaldehyde (" free of 2,2-difluoro-acetaldehyde, "" 2,2-difluoro-acetaldehyde It refers to the total molar amount of the various hemiacetal ". hereinafter the same.) for 1.15 times or more, or less 4.00 times, improved method of storage stability of the 2,2-difluoro-acetaldehyde.
Effect of the invention
[0025] According to the present invention, in the form of the corresponding hemiacetal useful 2,2-difluoro acetaldehyde as pharmaceutical and agrochemical intermediates and can be stably stored over a long period of time. That is, the generated temporal change of the liquid composition according to the "dimer", can be suppressed by a simple method.
DESCRIPTION OF THE INVENTION
[0026] The following describes each of the elements that constitute the present invention. The present invention is not limited to the following embodiments, without departing from the spirit and scope of the present invention, based on ordinary knowledge of a person skilled in the art, appropriate modifications, improvements are added to the following embodiments also it goes without saying that within the scope of the present invention one has.
[0027] The present invention, as described above,
the first step: 2,2 difluoro acetaldehyde, coexist alcohol represented by the formula (2), containing a hemiacetal represented by the formula (3) "2,2 - preparing a difluoro acetaldehyde alcohol complex ",
a second step: a step of saving in the" 2,2-difluoro acetaldehyde alcohol complex "storage container, and
includes the two steps . For each, it will be described below.
[0028] [1] for the first step
the first step is a step for preparing a "2,2-Difluoro acetaldehyde alcohol complex".
[0029] [The amount of alcohol]
referred to in the present invention, "2,2-difluoro-acetaldehyde alcohol complex", a hemiacetal of 2,2-difluoro-acetaldehyde of the formula (3), apart from the formula from this ( alcohol represented by 2) was present in excess complex (composition) refers. And for the "2,2-difluoro total amount of acetaldehyde" is alcohol the total amount represented by the formula (2) "1.15 times mole or more, 4.00-fold molar or less" are present.
[0030] Alcohol represented by the formula (2) may be one kind, but may be a mixture of plural kinds of alcohols are encompassed by formula (2). In the latter case, the total value of the molar number of the plurality kinds of alcohol, 1.15 moles or more relative to 2,2-difluoro-acetaldehyde, to be equal to or less than 4.00 times by mole.
[0031] In this condition 2,2-difluoro acetaldehyde is converted to the hemiacetal of formula (3), and "acetal" is not generated effectively. That is, the inside of the system, so that the a hemiacetal, an excess of free alcohol coexist as a main component. Work-up condition after the reaction, a portion is sometimes made to the "dimer" of the formula (4), the amount of this at the start Save "dimer" minimal.
[0032] Incidentally, even when present at greater than 2.00 mol per mol of the total amount of the total amount of the alcohol is 2,2-difluoro acetaldehyde, hardly leads to a further improvement in the stability of the 2,2-difluoro-acetaldehyde. Almost no generation of "acetal" is also in the 2.00-fold molar excess of conditions, "2,2-difluoro acetaldehyde, while maintaining the original reactive aldehyde, to improve its storage stability" that the objects reach that can. However, too much use of a large amount of alcohol, wasted. Thus, more preferably the total amount of alcohol is 1.15 to 2.00 times by mole, and further 1.15 to 1.60-fold molar or even that preferably 1.15 to 1.30 times by mole, very small excess state (ie state free of alcohol are present 15% to 30%) is advantageous to the most economical, yet it is also ensure storage stability.
[0033] In the first step of the present invention, a method of making a "2,2-Difluoro acetaldehyde alcohol complex", a hemiacetal of 2,2-difluoro-acetaldehyde of the formula (3), the formula (2) it is sufficient as excess alcohol represented coexists is not particularly limited.
[0034] "2,2-a single difluoro acetaldehyde is mixed with a single alcohol" to the method that is also possible, after synthesizing a 2,2-difluoro-acetaldehyde "other than alcohol solvents, the formula in the reaction solution (2) alcohol with the addition of methods are possible that the solvent substitution ". "In a solvent moistened beforehand alcohol, to synthesize 2,2-difluoro acetaldehyde, leaving excess alcohol" methods are possible as.
[0035] Further, as described above, alpha, .alpha.-difluoro acetic acid ester in the case of synthesizing the "2,2-Difluoro acetaldehyde hemiacetal" as the starting material, the reaction solution, already "alcohol moiety (-OR derived from the raw material 2 ) "are present 1-fold molar (clogging mol). On the other hand, it may be adopted a method such as adding a surplus of alcohol.
[0036] About humoral]
In the present invention, the "2,2-difluoro-acetaldehyde alcohol complex" at the time supplied to the storage vessel must be substantially neutral. The term "substantially neutral", liquid which is recognized as "near neutral" in humoral (those skilled in the art knowledge as pH is 5-10 when immersed in pH test paper was collected liquid refers to sex), more preferably from 6-9. Becomes acidic side out of the range of these pH, because it may hemiacetal site is decomposed by an acid, it is not preferable. Conversely, when these become alkaline side is outside the range of the pH, it tends to occur a side reaction such as Cannizzaro reaction, since the stabilization of 2,2-difluoro acetaldehyde, which is the gist of the present invention is less likely aim, undesirable .
[0037] [Water content for]
In the present invention, it is also necessary the water content is below 1000 ppm (value of mass in the entire liquid "2,2-difluoro-acetaldehyde alcohol complex"). No more, and a lot of water is present, 2,2-difluoro acetaldehyde reacts with water to produce the following "Mizuwatai".
[Of 14]

the "Mizuwatai" is it on itself is not a less stable chemical species, for the aqueous solution of the hydrated body, for example, it would limit the nucleophilic reaction conditions to the carbonyl group. Also it decreased to cause unfavorable than even "2,2-difluoro-acetaldehyde-alcohol complex" for reactivity. Although it is possible further to convert the hemiacetal from the hydrated body, it must be distilled water from the excess presence of an alcohol operation is complicated. The water content this respect even more preferably at 500ppm or less, still preferably 200 ppm. Dehydration (reduction of water content), the dehydrating agent (magnesium chloride, anhydrous metal salts such as calcium chloride, zeolite, etc.) other can be performed by, concentrated using a evaporation - even achieved by solvent substitution. It is more effective when carried out dehydration by combining the plurality of means.
[0038] [2,2 synthesis Part 1 of difluoro acetaldehyde]
2,2-difluoro acetaldehyde, by the Non-Patent Document 1 method, alpha is expressed by the following equation, .alpha.-difluoro acetate lithium aluminum hydride, hydrogen and partial reduction in the "hydride reducing agent" such as sodium borohydride, site of the hemiacetal of formula (3) {(-O-a ) is (-O-R 2 corresponds to). The obtained as} is the commonly known synthetic methods.
[Formula 15]

(In the formula, A represents a hydrocarbon cyclic or chain-like or branched having 1 to 6 carbon atoms, a hydrogen atom may be substituted partially or entirely by fluorine atoms, particularly preferably , it can be suitably adopted an ethyl group or a methyl group.)
[0039] The reduction reaction is as "Synthesis Example 1" below, anhydrous ethereal solvent, preferably, can be carried out at -70 ℃ ~ -100 ℃. Such reactions by performing a cryogenic, can suppress the generation of an excessive reducing compound 2,2-difluoro-ethanol.
[0040] Note that the excess reducing compound 2,2-difluoro-ethanol also belong to the alcohol represented by the formula (2), also referred to hemiacetal (which between the target compound 2,2-difluoro-acetaldehyde as "DFAL-DFOL" ) is formed. In this case, (- O-CH 2 -CF 2 ) is (-O-R 2 corresponds to). In other words, it can be said that the 2,2-difluoro-ethanol also contribute to the stabilization of the 2,2-difluoro-acetaldehyde substance. Then, in the post-processing described above, for example an excess of ethanol is added to the system, even as solvent replacement by evaporation, is in the system is often may remain "DFAL-DFOL" Ganao (later see example). In this way it is often a plurality of types of hemiacetal coexist in the system.
[0041] However, the fact that "2,2-difluoro-ethanol is produced," is by the reduction reaction, which means that "the yield of 2,2-difluoro-acetaldehyde in the hydride reduction is reduced." Then 2,2-difluoro-acetaldehyde improving storage stability of the are sufficiently achieved even cheaper unsubstituted alcohols. Therefore, in the reduction reaction, very expensive 2,2-difluoro ethanol dare not-produced, and it by necessity to stabilize the 2,2-difluoro-acetaldehyde is low. That, alpha, when reducing the α- difluoro acetic acid ester by lithium aluminum hydride is carried out and the reaction temperature was low (e.g., -70 ~ -100 ° C.), (while controlling the temperature) slowly mixing of the reagent etc., it is preferably reacted as over-reduction is not possible occurs.
[0042] Since the reaction solution is exhibiting strong basicity, after completion of the reaction immediately brought into contact with ice water, neutralized with an acid, it is preferable to substantially neutral (above). Specifically, as described above, pH 5-10 (preferably 6-9) until performs neutralized by addition of acid, substantially in a neutral state. In this case, in order to prevent the liquid beyond the point of neutralization is to change to the acidic side, such as acetic acid, carbonic acid, is preferable to the neutralization with a weak acid such as boric acid (acetic acid are particularly preferred). This of whether or not "substantially neutral" determination, for example, the reaction solution was taken, I'll be dipped in a commercially available pH paper, it can be performed.
[0043] Then, the reaction solution Was this substantially neutral, the addition of alcohol (e.g. ethanol) of formula (2), going exchange of hemiacetal site, the main component hemiacetal of the last alcohol was added can do. However, this operation is not essential (even complex solution in which a plurality kinds of hemiacetal is present, since the improvement of the stabilization of 2,2-difluoro-acetaldehyde can be achieved).
[0044] The "hemiacetal" can extract the water-insoluble organic solvent (such as diethyl ether), it can be separated remove water-soluble substances contained in a large amount in the reaction solution of the hydrogenation reaction in the aqueous phase. On The organic layers were dried over drying agent (water removed), by performing the solvent was distilled off by evaporation, the water content of the reaction solution can be reduced to 1000ppm or less, hemi represented by the formula (3) acetal (1-alkoxy-2,2-difluoro-ethanol) can be obtained. However, the material obtained through the above post-treatment, is a hemiacetal represented by the formula (3), since the through solvent extraction, excess alcohol is almost non-existent. In other words, in this state, the present invention can not be achieved in long-term storage stability improvement of which is an object. Therefore, it is necessary to convert it to "2,2-difluoro acetaldehyde alcohol complex" present invention given. Therefore, the addition of alcohol represented by the formula (2) again, 2,2 relative to the total amount of difluoro acetaldehyde, Equation (2) the total amount of alcohol represented by the 1.15-fold mole or more, 4. it can be adjusted so as to be 00-fold molar. After the addition of alcohol, do the evaporation also serves as a dehydration, leaving only in the system (a very effective amount but improvement of storage stability) a small excess of alcohol such as, for example, 1.15 times by mole to 1.60-fold molar , it is also possible to recover the other alcohols.
[0045] Incidentally, extracts the acetal in water-insoluble organic solvent, immediately after dehydrated with a dehydrating agent, added in excess an alcohol of the formula (2), followed by carrying out the evaporation, the water-insoluble solvent distilled and removed by, it may be subjected to a distillation of the alcohol at the same time.
[0046] Further, if when it is desired to remove the high boiling components, separate from the process of performing distillation of alcohol, by increasing the degree of vacuum, it is also possible to recover the hemiacetal itself as a fraction. At this time, keep the less without increasing the number of stages, the excess of alcohol can also at the same time and recovery hemiacetal as a fraction (that can be recovered as a temporary fraction "2,2-difluoro-acetaldehyde-alcohol complex") as to be convenient.
[0047] As the alcohol represented by the formula (2), unsubstituted alcohol having 1 to 6 carbon atoms, on inexpensive, particularly preferable because it has a sufficient stabilizing effect of the present invention. Among them, methanol and ethanol are readily available anhydride reagent in large scale, yet because even a large effect of improving the stability, especially preferable.
[0048] [Synthesis method that 2 of 2,2-difluoro-acetaldehyde]
On the other hand, α, α- difluoro acetic acid esters (the same material as the synthesis method 1), specific hydrogen ruthenium complex as a catalyst (H 2 is brought into contact with) gas also by, it can produce 2,2-difluoro-acetaldehyde (Patent Document 3) (synthesis example 2). Direct reaction of hydrogen to the ruthenium catalyst and the catalyst, although requires a catalyst of ruthenium, since it is not necessary to deal with difficult hydride reducing agent of a large amount of handling, particularly advantageous in carrying out the synthesis of a mass scale is there.
[0049] Ruthenium catalysts which can be used in this reaction are complexes of the following.
[Formula 16]

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 -1 or 0 of the ligand (provided that the total formal charge of three X -2) represent, n represents represents an integer of 1 or 2 independently. ]
Above, substituted alkyl groups, the term "substituent" of the substituted aromatic ring group, an alkyl group or aromatic ring group mentioned above, on any carbon atom, in any number and any combination of those present point. Substituents according to fluorine, chlorine and halogen atom such as bromine, lower alkyl group such as a methyl group, an ethyl group and a propyl group, fluoromethyl group, chloromethyl group and a lower haloalkyl group such as bromomethyl group, a methoxy group, an ethoxy group and lower alkoxy groups such as a propoxy group, fluoromethoxy group, chloromethoxy group and a lower haloalkoxy group such as bromo methoxy group, a cyano group, a methoxycarbonyl group, a lower alkoxycarbonyl group such as ethoxycarbonyl group, and polypropoxylated isobornyl group, a phenyl group , naphthyl group, anthryl group, (including nitrogen protected compound) pyrrolyl group, a pyridyl group, a furyl group, a thienyl group, (including nitrogen protected compound) indolyl group, a quinolyl group, an aromatic ring group such as a benzofuryl group and a benzothienyl group , carboxyl group, protected carboxyl group, an amino group, protected amino group, a protected form such as a hydroxyl group, and a hydroxyl group. Further, the substituted alkyl group, any carbon of the alkyl groups of the - carbon single bond, in any number and any combination carbon-carbon double bond or carbon - may be replaced by carbon triple bond (of course these alkyl groups replaced by an unsaturated bond may also have the same manner the above substituents). Depending on the kind of substituents in some cases the substituents themselves are involved in side reactions, but can be minimized by adopting suitable reaction conditions. In the present 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). Further, "according substituents" of the the "aromatic ring group" of a halogen atom, a lower alkyl group, a lower haloalkyl group, a lower alkoxy group, lower haloalkoxy group, cyano group, lower alkoxycarbonyl group, a carboxyl group, protection of the carboxyl group, amino group, protected amino group, protected or 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 are Protective Groups in Organic Synthesis, Third Edition , 1999, John Wiley & Sons, protecting groups described in Inc., And the like.
[0050] Among them, (Ru-MACHO ruthenium catalyst represented by the following formula TM is known as) the activity is particularly high, especially preferable.
[Of 17]

[In the formula, Ph represents a phenyl group. ]
[0051] Other of the ruthenium complex, Ru-MACHO TM can be produced in the same manner with reference to the manufacturing method and the like of. Also included are organic solvents such as water, toluene can also be used equally, the purity may be any at least 70%, preferably at least 80%, particularly preferably 90% or more.
[0052] The amount of the ruthenium complex on the starting alpha, may be used more 0.000001mol against α- difluoro acetic acid esters 1 mol, preferably from 0.00001 ~ 0.005 mol, particularly preferably 0.00002 ~ 0.002 mol .
[0053] The catalytic reduction reaction in the presence of a base, it is necessary to carry out, among the three X ligand in the ruthenium complex, at least one BH 4 when taking the reaction in the absence of a base It can also be carried out.
[0054] Base is lithium hydrogen carbonate, alkali metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate, lithium carbonate, alkali metal carbonates such as sodium carbonate and potassium carbonate, lithium hydroxide, sodium hydroxide and potassium hydroxide alkali metal hydroxides like tetramethylammonium hydroxide, tetraethylammonium hydroxide, tetra-alkyl ammonium hydroxide such as tetramethylammonium n- propyl ammonium hydroxide, and tetra n- butyl ammonium, lithium methoxide, sodium methoxide , potassium methoxide, lithium ethoxide, sodium ethoxide, potassium ethoxide, lithium isopropoxide, sodium isopropoxide, potassium isopropoxide, alkali metal such as lithium tert- butoxide, sodium tert- butoxide and potassium tert- butoxide alkoxide, triethylamine, diisopropylethylamine, 4-dimethylaminopyridine and 1,8-diazabicyclo [5.4.0] organic bases include lithium bis (trimethylsilyl) amide, such as undec-7-ene, sodium bis (trimethylsilyl) amide and potassium bis (trimethylsilyl) an alkali metal bis (trialkylsilyl) amide such as amide, and lithium borohydride, borohydride or the like of alkali metals such as sodium borohydride and potassium borohydride. Alkali metal alkoxides (carbon number of alkoxide 1-6) are preferable among them, lithium methoxide, sodium methoxide and potassium methoxide particularly preferred. It should be noted that, as of synthetic examples below, sodium methoxide is available as a normal methanol solution. Therefore, in the reaction system, so that the methanol remains (i.e., methanol, at least in part serve as the alcohol of formula (2).).
[0055] Amount of use when a base is used, the raw material alpha, may be used more than 0.001mol against α- difluoro acetic acid esters 1 mol, preferably from 0.005 ~ 5 mol, particularly preferably 0.01 ~ 3 mol.
[0056] The amount of hydrogen gas, alpha, .alpha.-difluoro acetic acid esters may be used more than 1mol against 1mol, preferably large excess, a large excess is especially preferred under pressure.
[0057] The hydrogen pressure is not particularly limited, is preferably 2 ~ 0.001MPa, 1 ~ 0.01MPa is more preferred.
[0058] The reaction solvent, n- hexane, cyclohexane and n- heptane and aliphatic hydrocarbons, toluene, xylene, and aromatic hydrocarbons such mesitylene, methylene chloride, 1,2-dichloroethane and alpha, alpha, .alpha. tri halogen system such as fluoro toluene, diethyl ether, 1,2-dimethoxyethane, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, diisopropyl ether, diethylene glycol dimethyl ether and ether such as anisole, methanol, ethanol, n- propanol, isopropanol, n- butanol, tert-butanol, n- pentanol, n- hexanol and cyclohexanol alcohol-based, N, N-dimethylformamide, N, N-dimethylacetamide and 1,3 dimethyl-2-imidazolidinone or the like amide-based, acetonitrile, propionitrile and nitrile such as benzonitrile, dimethyl sulfoxide, and water. Aliphatic hydrocarbon Among them, aromatic hydrocarbons, halogen-containing, preferably ether and alcohol, aliphatic hydrocarbon, aromatic hydrocarbon, ether and alcohol is particularly preferred. These reaction solvents may be used alone or in combination.
[0059] The reaction solvent (hereinafter, the A) of alcohol in this has the accelerating effect of the reaction rate, aliphatic hydrocarbon, aromatic hydrocarbon, the reaction solvent of the halogen-based and ether-based (hereinafter, B) is , β, it has an inhibitory effect of excess reduction to β- difluoroethanol. To maximize the utility of the present invention is preferably mode of using a mixed solvent of A and B (mode 1), the capacitive ratio (A: Bs, and 100 the sum of A and B) are 60 or more: it may be used to 40 or less, more than 70: preferably 30 or less, 80 or more: particularly preferably 20 or less.
[0060] The amount of the reaction solvent, the raw alpha, may be used more than 0.03 L (liter) with respect to α- difluoro acetic acid esters 1 mol, preferably 0.05 ~ 10 L, particularly preferably 0.07 ~ 7L.
[0061] The reaction temperature is, in the case of using a reaction solvent of alcohol-based, may be carried out at + 30 ℃ or less, preferably from + 25 ~ -50 ℃, particularly preferably + 20 ~ -40 ℃, is very preferably + 15 ~ -30 ℃, aliphatic hydrocarbons hydrogen-based, an aromatic hydrocarbon, in the case of using a reaction solvent of the halogen-based or ether-based, may be carried out at + 50 ℃ or less, preferably from + 45 ~ -30 ℃, particularly preferably + 40 ~ -20 ℃, + 35 ~ -10 ℃ is highly preferred. In the case of mixed solvent, the most busy content solvent, it may be the reaction is carried out at the above temperature range.
[0062] To maximize the utility of the present invention uses a reaction solvent of alcohol type, the reaction temperature is preferably performed at 20 ° C. or less, or an aliphatic hydrocarbon, an aromatic hydrocarbon , using the reaction solvent of the halogen-based or ether-based, it is preferably performed at 40 ° C. or less.
[0063] If the reaction is carried out at a temperature in excess of the above temperature, over-reduction is likely to proceed, 2,2-difluoro-ethanol selectivity of rise is, because the yield of the desired product is reduced, which is not preferable.
[0064] In any case, according to the reduction reaction using the ruthenium catalyst, compared with reduction (above) using a hydride reducing agent, at much higher temperatures (mild conditions of around room temperature), the desired product in good yield 2,2-difluoro acetaldehyde can be obtained.
[0065] The reaction time, may be carried out in less than 72 hours, in order to vary depending on the raw material substrate and the reaction conditions, gas chromatography, liquid chromatography, to track the progress of the reaction by an analytical means of nuclear magnetic resonance, etc., reduction of raw material substrate the time when not recognized most may be the end point.
[0066] Work-up of the catalytic reduction reaction, in principle the same as the post-processing "hydride reduction". That is, after the reaction solution exhibiting basicity, and neutralized with an acid (preferably a weak acid), was added an alcohol (e.g. ethanol) of formula (2), the product 2,2-difluoro-acetaldehyde, the corresponding hemiacetal to convert to. The hemiacetal, and extracted into a water-insoluble organic solvent, while drying the organic layer with a desiccant (water removed), by performing the solvent was distilled off by evaporation, the water content of the reaction solution 1000ppm or less It is reduced to the formula (3) hemiacetal represented by (1-alkoxy-2,2-difluoro-ethanol) is obtained. After such, be added the excess alcohol, can be obtained "2,2-Difluoro acetaldehyde alcohol complex" of the present invention.
[0067] Alternatively, extract the hemiacetal water-insoluble organic solvent, which after drying treatment with a drying agent, the addition of excess alcohol by evaporation, can be distilled off water-insoluble organic solvent.
[0068] In contrast, the "case where a metal alcoholate and a reduction reaction was performed as base", it is possible to perform a simple work-up than the above. First, the reaction solution, glacial acetic acid, the "acid free of water" such as acetic anhydride was added, and the substantially neutral liquid property. Wherein when the "metal alcoholate" with a base, the by-product by neutralization with an acid is exclusively "alcohol represented by the formula (2)" (water does not by-product). Therefore, by performing even separation of by-product salt material, otherwise, it is not necessary to perform processes such as "solvent extraction". That is, the solvent which has dissolved "metal alkoxide (usually alcohol) together, a state in which the alcohol of the formula (2) is already present in the system. Therefore, a state that allows the conventional distillation. may be distilled off the free of alcohol is as it is a low-boiling substances, for the purpose of removing the high boiling point substances, to obtain the present invention given the "2,2-difluoro-acetaldehyde-alcohol complex" as a fraction also it can. Thus with respect to the extracted fraction, optionally, an alcohol of the formula (2) was additionally added, may be repeated and concentrated. By doing so, it is possible to obtain low-boiling substance, the "2,2-difluoro-acetaldehyde-alcohol complex" of high-quality, high-boiling substances have been removed together. Even when adopting such a post-processing method, as appropriate, in contact with the desiccant, thereby further reducing the water content is not hindered in any way.
[0069] As the alcohol represented by the formula (2), unsubstituted alcohol having 1 to 6 carbon atoms, on inexpensive, particularly preferable because it has a sufficient stabilizing effect of the present invention. Among them, methanol and ethanol are readily available anhydride reagent in large scale, yet because even a large effect of improving the stability, especially preferable.
[0070] [Method of determining the liquid composition]
in the case of obtaining a 2,2-difluoro-acetaldehyde in either of the synthesis method described above is also, in the course of performing a post-treatment after the reaction, or after one through the post-processing, supplied to the storage vessel at the time of, determining the composition of the reaction solution is preferred. Although there is no limitation to the method for obtaining the composition of the reaction mixture, 1 H-NMR is a particularly advantageous method. Depending on the species 19 is better quantified by using the F-NMR, it may be accurate (as discussed below examples, quantifying the example of DFAL-DFOL). Therefore, 1 1 H-NMR while the basic 19 to perform a quantitative in combination with the F-NMR is an effective method.
[0071] Specifically, each compound from a chemical shift of protons or fluorine (free alcohol, hemiacetal, dimer) can identify peaks, further in view of the number of protons with the respective compounds, of the internal standard from comparison, the number of moles of each chemical species, can be determined in a short time. If wanted the composition can be calculated the "2,2-Difluoro acetaldehyde total moles of the total number of moles of alcohol."
[0072] By performing this analysis, it should be added how much alcohol further becomes easy to determine. If the total amount of the alcohol has not reached the predetermined range of the present invention, it is preferable to immediately perform additional alcohol. Conversely, if the alcohol is too large, it is sufficient to remove the alcohol by evaporation.
[0073] [2] The second step
The second step is a step of saving the "2,2-Difluoro acetaldehyde alcohol complex" prepared in the first step in storage vessel.
[0074] As already described, the "2,2-difluoro-acetaldehyde alcohol complex" at the time of starting the preservation is by (a) a substantially neutral, and at 1000ppm or less the content of (b) water, and ( c) the total molar amount of the alcohol (which refers to the total molar amount of "various hemiacetal of 2,2-difluoro-acetaldehyde" "free of alcohol," said. hereinafter the same.) is the total molar amount of 2,2-difluoro-acetaldehyde (refers to the total molar amount of "free of 2,2-difluoro-acetaldehyde" and "2,2-difluoro-acetaldehyde of various hemiacetal". or less the same.) to 1.15 times or more, 4.00 times or less, it is necessary satisfy the condition that. These conditions are met, "2,2-difluoro-acetaldehyde-alcohol complex", stored at storage vessel.
[0075] As the second step, to introduce the storage vessel was prepared as previously described "2,2-difluoro-acetaldehyde alcohol complex", which is the most usual means. However, for example - alone was placed in the storage vessel "2,2-difluoro acetaldehyde hemiacetal", there by adding free alcohol predetermined amount, "2,2-difluoro-acetaldehyde alcohol in preservation container method of, forming a complex ", or conversely, firstly," 2,2-difluoro-acetaldehyde after the introduction of free alcohol in the storage container - adding single hemiacetal ", a method that, what is excluded not (in this case, the first step and the second step becomes the form which takes place partially at the same time).
[0076] As already mentioned, the 2,2-difluoro acetaldehyde reacts with water to form a "Mizuwatai". As the "Mizuwatai" as already mentioned, less on not stable, since the reactivity is significantly lower than the "2,2-difluoro-acetaldehyde alcohol complex", handling in an aqueous solution limited reaction conditions Resulting in. Therefore, "2,2-difluoro-acetaldehyde alcohol complex" as it is not possible to absorb the moisture in the air, it is preferably stored in a sealed container.
[0077] Or coexist dehydrating agent, for example nitrogen, it may be or the addition of an inert gas such as argon. However, "2,2-difluoro-acetaldehyde-alcohol complex" of the present invention for has a high enough stability, usually may not be performed strict management up there.
[0078] The "2,2-difluoro-acetaldehyde alcohol complex", (including glass lining) glass container, can be suitably conserved in any of stainless steel containers.
[0079] There is no particular limit on the storage temperature, it is possible to save in a wide range of temperature of -40 ~ + 70 ℃. It is preferred to save in this one for example -30 ~ + 50 ℃, room temperature near the (10 ~ 45 ℃, especially 20 ~ 35 ℃) is particularly preferred. With respect to the generation of dimerization body, sometimes higher the temperature, it is suppressed, rather. However, other, considering the overall stability of the substance, at about room temperature, it is most preferably stored in a hard environment of lighting. However, not hindered at all be transported in a state of being stored in a storage container. Even exposed to conditions which are departing from the very temporary temperature listed here, it does not immediately become a problem I than.
[0080] When performing stored over a long period of time, performs re-sampling immediately prior to the use as a reagent, it is preferable to measure the composition of the liquid. However, as already mentioned, the liquid composition of the saved "2,2-difluoro-acetaldehyde alcohol complex" in this way, hardly vary greatly as compared with the saving start of the liquid composition, and activity as aldehyde reagent since the remains kept easy to high, it can be used immediately as it is for the reaction.
Example [0081] The following examples illustrate the present invention in detail. However, the present invention is not limited to the following examples.
[0082] [Synthesis Example 1] DFAL-EtOH of synthesis
in diethyl ether 30mL α, α- difluoro ethyl acetate (CHF 2 COOC 2 H 5 ) 2.5G (20 mmol) was dissolved, lithium aluminum hydride, which was cooled to -78 ℃ 1.9g was added dropwise to (50 mmol) and tetrahydrofuran 50 mL. After stirring for 3 hours, and the temperature was raised to room temperature ethanol was added 5mL. The reaction solution was concentrated sulfuric acid 15mL was poured into ice water, and the mixture was extracted with diethyl ether. The organic layer was dried over anhydrous magnesium sulfate and distilling off the diethyl ether distillation, 1-ethoxy-2,2-difluoro ethanol (DFAL-EtOH) was obtained in 60% yield.
[0083] [Synthesis Example 2] Synthesis of EtOH-DFAL
alpha in stainless steel autoclave, α- difluoro ethyl acetate (CHF 2 COOC 2 H 5 ) 450G (3.6 mol), Rutenirumu complex 470mg represented by the following formula, (730 micro mol), 910 mmol of 28% sodium methoxide methanol solution 170 g (sodium methoxide), methanol was added 1.2 L.
[Of 18]

the reactor was replaced five times with hydrogen gas, a hydrogen pressure of 1.0MPa, was followed by stirring for 8 hours at 15 ℃. After completion of the reaction 19 from F-NMR analysis, alpha, converting 49% of the α- difluoromethyl methyl acetate, the selectivity of DFAL- hemiacetal (total methyl hemiacetal thereof and ethyl hemiacetal form) was 95%. . 19 F-NMR internal standard substance α, α, was quantified with α- trifluorotoluene.
When the reaction solution was added acetic acid 51.9 g (860 mmol), the pH became 8, and determines as it becomes substantially neutral, was discontinued added. This liquid directly, distillation (bottom temperature ~ 66 ℃, the degree of reduced pressure ~ 2.1kPa) by subjecting to, to give a methanol solution containing DFAL- hemiacetal. This solution precision distillation (35 theoretical plates, distillation temperature 92 ℃, the degree of reduced pressure ~ 35kPa) to separate the majority of the methanol by. The distillation still (bottom) was added to ethanol 850 g (. 19 mol) was continued distillation to obtain 450g difluoro acetaldehyde ethyl hemiacetal the (DFAL-EtOH) as a fraction.
The fraction, methanol, ethanol, β, β- difluoroethanol, methyl hemiacetal body (DFAL-MeOH), ethyl hemiacetal body (DFAL-EtOH), represented by the following formula (i), β, β- difluoro It was found to contain "dimer" from ethyl hemiacetal represented by the ethyl hemiacetal thereof and the following formula (ii).
[Of 19]

[of 20]

each of purity (mol%) is "less than 0.1%, 5.6%, 3.3%, 1.8%, 87.3%, 0.6%, 1. It was 5%. " The yield in consideration of the purity was about 30%.
[0084] [Measurement
Method for determine the time course of DFAL-EtOH more accurately, 1 H-NMR and 19 was a quantitative method using the F-NMR as follows.
[0085] Sample 0.15mL, as an internal standard para trifluoromethyl trifluoromethyl benzene (PTF-TFM) 50μL accurately weighed, respectively, liquid transfer the 0.55mL after adding and dissolving a heavy chloroform 1.0mL in NMR sample tube to. NMR: by (JNM-ECA400 manufactured by JEOL), 1 H, 19 were measured F. Each of the chemical shifts are shown below.
TFM-PTF:
7.53-7.93Ppm
(4H), DFAL-EtOH: 4.50-4.71Ppm (1H), DFAL-MeOH: 3.51-3.53Ppm
(3H), DFAL-DFOL [CF 2 HCH (OH) OCH 2 CF 2 H]: - 125 ～ -126Ppm (2F)
dimer: 4.92-5.11ppm (1H),
ethanol: 3.65-3.73ppm (2H)
methanol: 3 .41-3.45ppm (3H)
free DFOL: -128 ～ -127Ppm (2F)
(It should be noted, DFAL-EtOH, DFAL-MeOH as well as, in-DFOL DFAL, 1 was used as a measurement target of H is, first place is a H. in addition, the free methanol, acetal was detected.)
[0086] Samples used in the following examples were prepared by the same manner as in "Synthesis Example 2". However unlike the sample of "Synthesis Example 2", the abundance of "dimer" of the initial stage, as compared to the "Synthesis Examples", which is slightly more. However, this is timing of post-treatment, it is caused by slight differences. And once "dimer" is produced, the "dimer", or return to the original hemiacetal, may be or further converted into another chemical species, usually not. Therefore, in the present invention, the initial amount of "abundance of dimers" of (storage start time) is not a problem, the storage period (1 year), DFAL- hemiacetal is decreased much, dimer whether the body has been newly generated, attention is focused on that.
[0087] Incidentally, was used in the following Examples and Comparative Examples of "2,2-difluoro-acetaldehyde alcohol complex", pH during storage at the start, the result measured by the method of immersing a pH test paper, both 8 met It was. Also was measured the amount of water in storage start time by Karl Fischer moisture meter, it was 180 ~ 200ppm.
[0088] EXAMPLE 1] DFAL- storage stability test of the hemiacetal
"total amount of alcohol / total aldehyde" (molar ratio) = 1.50 in this embodiment
the total amount of alcohol, 1-ethoxy-2,2-difluoro-ethanol (DFAL-EtOH), 2,2- difluoro-1-methoxy ethanol, β, β- difluoroethyl hemiacetal (DFAL-DFOL), is a difluoroethanol, the total number of moles of ethyl alcohol.
The total aldehyde amount, 1-ethoxy-2,2-difluoro-ethanol (DFAL-EtOH), 2,2- difluoro-1-methoxy ethanol, β, the total number of moles of β- difluoroethyl hemiacetal (DFAL-DFOL) it is.
[0089] 1-ethoxy-2,2-difluoro-ethanol (DFAL-EtOH) 62.1 mol%, 2,2-difluoro-1-methoxy-ethanol 1.4% mole, difluoroethanol 1.4 mol%, β, β- difluoro ethyl hemiacetal body (DFAL-DFOL) 0.5 mol%, dimer 4.0 mole%, where a solution containing 30.6 mol% ethyl alcohol was stored at room temperature, after one year 1-ethoxy -2, 2-difluoroethanol (DFAL-EtOH) 60.8 mol%, 2,2-difluoro-1-methoxy-ethanol 1.3 mol, difluoroethanol 1.4 mol%, DFAL-DFOL0.4 mol%, dimer 4 .3 mol%, was 31.8 mole% ethyl alcohol. Below, we put a table of change over time.
[0090] [Table 1]

[0091] In this way "the surplus of alcohol" is, in the case of "Example 1" present 50 mol% with respect to the aldehyde, even after the lapse of one year, remains in the dimer is a slight increase, is a hemiacetal DFAL- EtOH, DFAL-MeOH, DFAL-DFOL is almost unchanged. Compared to the "Comparative Example" described later, it can be seen that the storage stability is remarkably improved.
[0092] [Example 2] DFAL- storage stability test of hemiacetal
the total amount of alcohol / total aldehyde = 1.23
The total amount of alcohol, 1-ethoxy-2,2-difluoro-ethanol (DFAL-EtOH), 2,2- difluoro-1-methoxy ethanol, β, β- difluoroethyl hemiacetal (DFAL-DFOL), is a difluoroethanol, the total number of moles of ethyl alcohol.
The total aldehyde amount, 1-ethoxy-2,2-difluoro-ethanol (DFAL-EtOH), 2,2- difluoro-1-methoxy ethanol, β, the total number of moles of β- difluoroethyl hemiacetal (DFAL-DFOL) it is.
[0093] 1-ethoxy-2,2-difluoro-ethanol (DFAL-EtOH) 75.8 mol%, 2,2-difluoro-1-methoxy-ethanol 1.5% mole, difluoroethanol 1.4 mol%, β, β- difluoro ethyl hemiacetal body (DFAL-DFOL) 0.6 mol%, dimer 4.0 mole%, where a solution containing 16.7 mol% ethyl alcohol was stored at room temperature, after one year 1-ethoxy -2, 2-difluoroethanol (DFAL-EtOH) 71.9 mol%, 2,2-difluoro-1-methoxy-ethanol 1.3 mol, difluoroethanol 1.3 mol%, DFAL-DFOL0.4 mol%, dimer 4 .8 mole%, 19.7 mole% ethyl alcohol. Below, we put a table of change over time.
[0094] [Table 2]

[0095] Thus "excess alcohol" is also present 23 mole% relative to the aldehyde in "Example 2", it can be seen that is excellent storage stability Following Example 1.
[0096] [Example 3] DFAL- storage stability test of hemiacetal
the total amount of alcohol / total aldehyde = 1.19
The total amount of alcohol, 1-ethoxy-2,2-difluoro-ethanol (DFAL-EtOH), 2,2- difluoro-1-methoxy ethanol, β, β- difluoroethyl hemiacetal (DFAL-DFOL), is a difluoroethanol, the total number of moles of ethyl alcohol.
The total aldehyde amount, 1-ethoxy-2,2-difluoro-ethanol (DFAL-EtOH), 2,2- difluoro-1-methoxy ethanol, β, the total number of moles of β- difluoroethyl hemiacetal (DFAL-DFOL) it is.
[0097] 1-ethoxy-2,2-difluoro-ethanol (DFAL-EtOH) 78.1 mol%, 2,2-difluoro-1-methoxy-ethanol 1.6% mole, difluoroethanol 1.4 mol%, β, β- difluoro ethyl hemiacetal body (DFAL-DFOL) 0.6 mol%, dimer 4.1 mol%, a solution containing 14.2 mol% ethyl alcohol was stored at room temperature, after one year 1-ethoxy -2, 2-difluoroethanol (DFAL-EtOH) 74.4 mol%, 2,2-difluoro-1-methoxy-ethanol 1.3 mol, difluoroethanol 1.3 mol%, DFAL-DFOL0.4 mol%, dimer 5 .4 mole%, was 17.1 mol% ethyl alcohol. Below, we put a table of change over time.
[0098] [table 3]

[0099] In this way a "surplus of alcohol", even if it exists 19 mole% with respect to the aldehyde of "Example 3", it can be seen that is excellent storage stability next to the first and second embodiments.
[0100] [Example 4] DFAL- storage stability test of hemiacetal
the total amount of alcohol / total aldehyde = 1.17
The total amount of alcohol, 1-ethoxy-2,2-difluoro-ethanol (DFAL-EtOH), 2,2- difluoro-1-methoxy ethanol, β, β- difluoroethyl hemiacetal (DFAL-DFOL), is a difluoroethanol, the total number of moles of ethyl alcohol.
The total aldehyde amount, 1-ethoxy-2,2-difluoro-ethanol (DFAL-EtOH), 2,2- difluoro-1-methoxy ethanol, β, the total number of moles of β- difluoroethyl hemiacetal (DFAL-DFOL) it is.
[0101] 1-ethoxy-2,2-difluoro-ethanol (DFAL-EtOH) 79.5 mol%, 2,2-difluoro-1-methoxy-ethanol 1.9% mole, difluoroethanol 0.9 mol%, β, β- difluoro ethyl hemiacetal body (DFAL-DFOL) 1.1 mol%, dimer 3.7 mol%, a solution containing 13.0 mol% ethyl alcohol was stored at room temperature, after one year 1-ethoxy -2, 2-difluoroethanol (DFAL-EtOH) 74.6 mol%, 2,2-difluoro-1-methoxy-ethanol 1.6 mol, difluoroethanol 1.1 mol%, DFAL-DFOL0.8 mol%, dimer 5 .8 mol%, was 16.1 mole% ethyl alcohol. Below, we put a table of change over time.
[0102] [Table 4]

[0103] In this way "the surplus of alcohol" is, even if it exists 17 mol% with respect to the aldehyde of "Example 4", over one year, no significant compositional variations, are observed excellent storage stability.
[0104] [Comparative Example 1] DFAL- storage stability test of hemiacetal
the total amount of alcohol / total aldehyde = 1.11
the total amount of alcohol and is, 1-ethoxy-2,2-difluoro-ethanol (DFAL-EtOH), 2,2- difluoro-1-methoxy ethanol, β, β- difluoroethyl hemiacetal (DFAL-DFOL), is a difluoroethanol, the total number of moles of ethyl alcohol.
The total aldehyde amount, 1-ethoxy-2,2-difluoro-ethanol (DFAL-EtOH), 2,2- difluoro-1-methoxy ethanol, β, the total number of moles of β- difluoroethyl hemiacetal (DFAL-DFOL) it is.
[0105] 1-ethoxy-2,2-difluoro-ethanol (DFAL-EtOH) 83.5 mol%, 2,2-difluoro-1-methoxy-ethanol 1.6% mole, difluoroethanol 0.6 mol%, β, β- difluoro ethyl hemiacetal body (DFAL-DFOL) 1.0 mol%, the dimer 4.3 mol%, a solution containing 9.0 mole% ethyl alcohol was stored at room temperature, after one year 1-ethoxy -2, 2-difluoroethanol (DFAL-EtOH) 74.7 mol%, 2,2-difluoro-1-methoxy-ethanol 1.4 mol, difluoroethanol 0.8 mol%, β, β- difluoroethyl hemiacetal body (DFAL- DFOL) 0.7 mol%, the dimer 9.7 mol%, 12.8 mol% ethyl alcohol. Below, we put a table of change over time.
[0106] [table 5]

[0107] In this way "the surplus of alcohol" is, even if it exists 11 mole% with respect to the aldehyde of "Comparative Example 1", after a lapse of one year, an increase of dimer was 5% or more. The amount of free ethanol is also increased clearly. This is considered to correspond to the phenomenon DFAL-EtOH bimolecular react to form a "dimer", was released ethanol extra one molecule.
[0108] [Comparative Example 2] DFAL- storage stability test of hemiacetal
the total amount of alcohol / total aldehyde = 1.07
The total amount of alcohol, 1-ethoxy-2,2-difluoro-ethanol (DFAL-EtOH), 2,2- difluoro-1-methoxy ethanol, β, β- difluoroethyl hemiacetal (DFAL-DFOL), is a difluoroethanol, the total number of moles of ethyl alcohol.
The total aldehyde amount, 1-ethoxy-2,2-difluoro-ethanol (DFAL-EtOH), 2,2- difluoro-1-methoxy ethanol, β, the total number of moles of β- difluoroethyl hemiacetal (DFAL-DFOL) it is.
[0109] 1-ethoxy-2,2-difluoro-ethanol (DFAL-EtOH) 86.7 mol%, 2,2-difluoro-1-methoxy-ethanol 0.9% mole, difluoroethanol 1.5 mol%, β, β- difluoro ethyl hemiacetal body (DFAL-DFOL) 0.7 mol%, dimer 4.7 mol%, a solution containing 5.7 mole% ethyl alcohol was stored at room temperature, after one year 1-ethoxy -2, 2-difluoroethanol (DFAL-EtOH) 71.2 mol%, 2,2-difluoro-1-methoxy-ethanol 0.7 mol, difluoroethanol 1.3 mol%, β, β- difluoroethyl hemiacetal body (DFAL- DFOL) 0.8 mol%, the dimer 12.5 mol%, was ethyl alcohol 13.4 mol%. Below, we put a table of change over time.
[0110] [Table 6]

[0111] In this way a "surplus of alcohol", even if it exists 7 mol% with respect to the aldehyde of "Comparative Example 2", after a lapse of one year, an increase of the dimer, the increase in free of ethanol, both prominent there were. In such a composition, (although the stability of short duration is ensured), not necessarily suitable for the storage of several months to a year. In turn, of the present invention, excellent effects of configuration to be present dare surplus of alcohol more than 15 percent, was supported.
Industrial applicability
[0112] A method for stabilizing 2,2-difluoro acetaldehyde present invention are those expected as a method storage and distribution of pharmaceutical and agrochemical intermediates.
The scope of the claims
[Claim 1] First step: formula represented by (3), 2,2-and-difluoro acetaldehyde hemiacetal, including a free alcohol represented by the formula (2), a "2,2-difluoro-acetaldehyde alcohol complex preparing a ",
the second step: includes the steps of: storing in the" 2,2-difluoro-acetaldehyde-alcohol complex "save for the vessel, and the, and,
to start saving in the storage container time the in in the "2,2-difluoro-acetaldehyde-alcohol complex" is in a substantially neutral, and is the content of the water is 1000ppm or less, at the time to start saving in the storage container, "2,2 the total molar amount of the alcohol in difluoro acetaldehyde alcohol complex "is 2,2 1.15 times or more relative to the total molar amount of difluoro acetaldehyde is less than or equal 4.00 times, 2,2-difluoro acetaldehyde method for improving the storage stability.
[Formula 21]

(In the formula, R 2 represents a hydrocarbon cyclic or chain-like or branched having 1 to 6 carbon atoms, a hydrogen atom may be substituted partially or entirely by a fluorine atom.)
[Formula 22]

(in the formula, R 2 meaning of is the same as the equation (3).)
[Claim 2] The total molar amount of the alcohol, 2,2-1.15 times or more with respect to the total molar amount of difluoro acetaldehyde, which is 1.60 times or less, the storage stability of the 2,2-difluoro-acetaldehyde as claimed in claim 1 method of improving sex.
[Claim 3] Alcohol represented by the formula (2) it is at least is methanol or ethanol, according to claim 1 or improved method of 2,2-difluoro acetaldehyde storage stability according to claim 2.
[Claim 4] Storage temperature in the second step is characterized in that a -30 ~ + 50 ℃, claim 1 to improve the method of 2,2-difluoro-acetaldehyde storage stability according to any of claims 3.