JP5659658B2 - Process for producing α, α-difluoroesters - Google Patents

Description

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

α, α-Difluoroesters are important as intermediates for medicines and agricultural chemicals. In the α, α-difluoroesters targeted in the present invention, the β-position carbon atom takes an sp ³ hybrid orbital, and this carbon atom is substituted with at least one hydrogen atom. (Including body) is not replaced. The production method of such a difluoro compound is very limited. In particular, as a conventional technique related to the present invention, α-halogeno-α- using hexachloromelamine or chlorine fluoride (oxidant) and hydrogen fluoride is used. Oxidative fluorination reaction of fluoroesters (Non-Patent Documents 1 and 2) and oxidative decomposition reaction of double bond sites of 3,3-difluoro-2-chloro-1-butene using alkaline potassium permanganate ( Patent Document 1, and a method for synthesizing α, α-difluoropropionic acid ester, which is a preferred object of the present invention, are only mentioned.

  In addition, the preparation of “a salt or complex comprising 1,8-diazabicyclo [5.4.0] undec-7-ene and hydrogen fluoride” and a fluorination reaction using the salt or complex have been reported (non- Patent Document 3).

JP 55-69501 A

Zhurnal Organicheskoi Kimii (Russia), 1993, 29, p. 1746-1753 Zhurnal Organicheskoi Kimii (Russia), 1982, Vol. 18, p. 946-953 Tetrahedron Letters (UK), 1995, 36, p. 2611-2614

  An object of the present invention is to provide a practical method for producing α, α-difluoroesters.

  In Non-Patent Documents 1 and 2, it is not always easy to obtain an oxidizing agent on a large scale. Moreover, in patent document 1, there existed a problem in the acquisition of a raw material substrate and the waste of heavy metal. Therefore, with these conventional techniques, it has been difficult to practically produce the α, α-difluoroesters targeted by the present invention. Further, in Non-Patent Document 3, “a salt or complex comprising 1,8-diazabicyclo [5.4.0] undec-7-ene and hydrogen fluoride” is suitable for the fluorine substitution reaction targeted in the present invention. It was never reported whether it could be used as a fluoride ion source.

On the other hand, in the fluorine substitution reaction of α-halogeno group of α-halogeno-α-fluoroesters (raw material substrate) in which a hydrogen atom is substituted at β-position, as in the present invention, When a conventional fluoride ion source is used, the dehydrohalogenation of the side reaction occurs preferentially [α-fluoro-α, β-unsaturated ester (byproduct) is a byproduct], and the desired α, α -Difluoroesters (target product) could not be selectively obtained [Scheme 1 and Comparative Example 1 (potassium fluoride), Comparative Example 2 (potassium fluoride / 18-crown-6), Comparative Example 3 (Cesium fluoride), comparative example 4 (tetra-n-butylammonium fluoride), comparative example 5 (hydrogen fluoride), comparative example 6 (hydrogen fluoride / 5 antimony chloride) and comparative example 7 (hydrogen fluoride / 1 , 3-Dimethyl-2-imidazolide See down)]. Furthermore, since the boiling point of the target product and by-products is close, it has been difficult to purify with high purity by fractional distillation, which is a simple operation.

  Thus, a practical method for producing α, α-difluoroesters has been strongly desired.

  As a result of intensive studies based on the above problems, the present inventors have reacted α-halogeno-α-fluoroesters with “a salt or complex comprising an organic base and hydrogen fluoride” to obtain α, α- It has been found that difluoroesters can be produced.

  As a raw material substrate, a hydrogen atom is further substituted at the β-position (at least becomes a methylene group), the remaining one substituent is a hydrogen atom or an alkyl group, the substituent at the ester site is an alkyl group, and α Preferably, the halogeno group at the position is a chlorine atom or bromine atom, the β-position is a methyl group, the substituent at the ester site is a methyl group, an ethyl group or a propyl group, and the α-position halogeno group is a bromine atom Those are particularly preferred. These suitable raw material substrates are relatively easy to obtain on a large scale, and the obtained target product is particularly important as an intermediate for medical and agricultural chemicals.

  As a fluoride ion source, “a salt or complex composed of 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) and hydrogen fluoride” is preferable, and the molar ratio of DBU to hydrogen fluoride is A range of 1: 2.0 to 2.5 is particularly preferred. By using these suitable fluoride ion sources, the desired fluorine substitution reaction can be performed satisfactorily.

  As a purification method, after α-fluoro-α, β-unsaturated esters as by-products are polymerized or after Michael addition reaction of the by-products, the target α, α-difluoroesters are recovered. It is preferable to perform both the polymerization treatment and the Michael addition reaction treatment. By adopting these suitable purification methods, a high-purity product of the target product can be obtained efficiently.

  That is, the present invention includes [Invention 1] to [Invention 7] and provides a practical method for producing α, α-difluoroesters.

[Invention 1]
General formula [1]

[Wherein, R ¹ and R ² each independently represents a hydrogen atom, a halogen atom, an alkyl group, a substituted alkyl group, an aromatic ring group or a substituted aromatic ring group, R ³ represents an alkyl group or a substituted alkyl group, and Represents a chlorine atom, a bromine atom or an iodine atom. R ¹ and R ² , or R ¹ or R ² and R ³ may each take a cyclic structure by any bond between carbon atoms, or through a nitrogen atom, an oxygen atom or a sulfur atom. . ]
The α-halogeno-α-fluoroester represented by the general formula [2] is reacted with “a salt or complex comprising an organic base and hydrogen fluoride (HF)”.

[Wherein R ¹ , R ² and R ³ are the same as above. ]
A method for producing an α, α-difluoroester represented by the formula:

[Invention 2]
General formula [3]

[Wherein, R ⁴ represents a hydrogen atom or an alkyl group, R ⁵ represents an alkyl group, and Y represents a chlorine atom or a bromine atom. ]
The α-halogeno-α-fluoroester represented by the general formula [4] is reacted with a “salt or complex comprising an organic base and hydrogen fluoride (HF)”.

[Wherein, R ⁴ and R ⁵ are the same as above. ]
A method for producing an α, α-difluoroester represented by the formula:

[Invention 3]
General formula [5]

[Wherein, Me represents a methyl group, and R ⁶ represents a methyl group, an ethyl group, or a propyl group. ]
The α-halogeno-α-fluoroester represented by the general formula [6] is reacted with “a salt or complex comprising an organic base and hydrogen fluoride (HF)”.

[Wherein, Me and R ⁶ are the same as above. ]
A method for producing an α, α-difluoroester represented by the formula:

[Invention 4]
The organic base of the “salt or complex comprising an organic base and hydrogen fluoride (HF)” is 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), Invention 1 4. A method for producing an α, α-difluoroester according to any one of items 1 to 3.

[Invention 5]
The molar ratio of 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) to hydrogen fluoride (HF) is in the range of 1: 2.0 to 2.5, A method for producing an α, α-difluoroester according to the invention 4.

[Invention 6]
6. The invention according to any one of inventions 1 to 5, wherein the α-fluoro-α, β-unsaturated ester as a by-product is polymerized and then the target α, α-difluoroester is recovered. A method for producing α, α-difluoroesters.

[Invention 7]
Any one of inventions 1 to 6, wherein the α-fluoro-α, β-unsaturated ester as a by-product is subjected to a Michael addition reaction treatment, and then the target α, α-difluoroester is recovered. A method for producing the α, α-difluoroester described above.

  The advantages of the present invention over the prior art will be described below.

  Since the reaction of the present invention is not an oxidative fluorination reaction, it does not require an oxidant which has a problem in obtaining on a large scale. Furthermore, the acquisition of a raw material substrate and waste of heavy metals are not a problem (in the reaction of the present invention, a reagent containing heavy metals is not used).

  Further, by using the fluoride ion source newly disclosed in the present invention, dehydrohalogenation as a side reaction can be suppressed, and a desired fluorine substitution reaction can be selectively performed. Further, by-polymerization or Michael addition reaction treatment is performed only on the by-product α-fluoro-α, β-unsaturated ester contained in the reaction end solution or the crude product, thereby allowing the by-product to have a high boiling point. It can be converted into a polymer or an adduct (high boiling point treatment). Therefore, the boiling point difference from the target α, α-difluoroester can be markedly increased, and a high-purity product of the target can be efficiently obtained by fractional distillation, which is a simple operation.

  Thus, the present invention is a practical method for producing α, α-difluoroesters that solves the problems of the prior art.

  The production method of α, α-difluoroesters of the present invention will be described in detail.

R ¹ and R ² of the α-halogeno-α-fluoroester represented by the general formula [1] each independently represents a hydrogen atom, a halogen atom, an alkyl group, a substituted alkyl group, an aromatic ring group or a substituted aromatic ring group. Represent. The halogen atom is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. The alkyl group is a straight chain or branched chain group having 1 to 18 carbon atoms, or cyclic (in the case of 3 or more carbon atoms). The aromatic ring group is an aromatic hydrocarbon group having 1 to 18 carbon atoms such as a phenyl group, a naphthyl group, an anthryl group, or a pyrrolyl group (including a nitrogen-protected form), a pyridyl group, a furyl group, a thienyl group, an indolyl An aromatic heterocyclic group containing a nitrogen atom such as a group (including a nitrogen-protected form), a quinolyl group, a benzofuryl group, a benzothienyl group, a hetero atom such as an oxygen atom or a sulfur atom. The substituted alkyl group and the substituted aromatic ring group each have a substituent in any number and in any combination on any carbon atom or nitrogen atom of the above alkyl group and aromatic ring group. Such substituents include halogen atoms such as fluorine, chlorine and bromine, lower alkyl groups such as methyl, ethyl and propyl, lower haloalkyl groups such as fluoromethyl, chloromethyl and bromomethyl, methoxy Group, lower alkoxy group such as ethoxy group and propoxy group, lower haloalkoxy group such as fluoromethoxy group, chloromethoxy group and bromomethoxy group, lower alkoxycarbonyl such as cyano group, methoxycarbonyl group, ethoxycarbonyl group and propoxycarbonyl group Groups, phenyl groups, naphthyl groups, anthryl groups, pyrrolyl groups (including nitrogen-protected products), pyridyl groups, furyl groups, thienyl groups, indolyl groups (including nitrogen-protected products), quinolyl groups, benzofuryl groups, benzothienyl groups, etc. Aromatic ring group, protected group of carboxyl group, amino group Mamorukarada, and protection and the like of the hydroxyl groups. In this specification, “lower” means a straight chain or branched chain or cyclic group (in the case of 3 or more carbon atoms) having 1 to 6 carbon atoms. In addition, the above “aromatic group as the substituent” includes a halogen atom, a lower alkyl group, a lower haloalkyl group, a lower alkoxy group, a lower haloalkoxy group, a cyano group, a lower alkoxycarbonyl group, a protected group of a carboxyl group. In some cases, an amino group protector, a hydroxyl group protector and the like may be substituted. Furthermore, pyrrolyl, indolyl, carboxyl, amino and hydroxyl protecting groups are described in Protective Groups in Organic Synthesis, Third Edition, 1999, John Wiley & Sons, Inc. And the like.

R ³ of the α-halogeno-α-fluoroester represented by the general formula [1] represents an alkyl group or a substituted alkyl group. The alkyl group and the substituted alkyl group are the same as the alkyl group and the substituted alkyl group described in R ¹ and R ² of the α-halogeno-α-fluoroester represented by the general formula [1].

  X of the α-halogeno-α-fluoroester represented by the general formula [1] represents a chlorine atom, a bromine atom or an iodine atom.

In the α-halogeno-α-fluoroesters represented by the general formula [1], R ¹ and R ² , or R ¹ or R ² and R ³ are each an arbitrary carbon atom, or a nitrogen atom, A cyclic structure may be taken by a covalent bond through an oxygen atom or a sulfur atom.

R ⁴ of the α-halogeno-α-fluoroester represented by the general formula [3] represents a hydrogen atom or an alkyl group. The alkyl group is the same as the alkyl group described in R ¹ and R ² of the α-halogeno-α-fluoroester represented by the general formula [1].

R ⁵ of the α-halogeno-α-fluoroester represented by the general formula [3] represents an alkyl group. The alkyl group is the same as the alkyl group described in R ¹ and R ² of the α-halogeno-α-fluoroester represented by the general formula [1].

  Y of the α-halogeno-α-fluoroester represented by the general formula [3] represents a chlorine atom or a bromine atom.

  Me of the α-halogeno-α-fluoroester represented by the general formula [5] represents a methyl group.

R ⁶ of the α-halogeno-α-fluoroester represented by the general formula [5] represents a methyl group, an ethyl group or a propyl group.

  The α-halogeno-α-fluoroesters represented by the general formula [1], [3] or [5] should be produced in the same manner with reference to Japanese Patent Application Laid-Open No. 2001-139519, Japanese Patent Application No. 2010-041158, etc. Can do. At the time of filing this patent application, since the latter is not disclosed, the portions necessary for explaining the invention of this patent application are extracted and described. In Japanese Patent Application No. 2010-041158, 2-bromo-2-fluoropropionic acid ester is produced by reacting 2-fluoropropionic acid ester with “a brominating agent having a nitrogen-bromine bond” in the presence of a radical initiator. Reference Example 1 shows an example of a specific experimental operation.

  Examples of the organic base of the “salt or complex comprising an organic base and hydrogen fluoride” include triethylamine, diisopropylethylamine, tri-n-propylamine, tri-n-butylamine, pyridine, 2,6-lutidine, and 2,4,6-collidine. 4-dimethylaminopyridine, 1,5-diazabicyclo [4.3.0] non-5-ene, 1,8-diazabicyclo [5.4.0] undec-7-ene, and the like. Among them, triethylamine, tri-n-butylamine, pyridine, 4-dimethylaminopyridine, 1,5-diazabicyclo [4.3.0] non-5-ene and 1,8-diazabicyclo [5.4.0] undec-7 -Ene is preferred, and 1,8-diazabicyclo [5.4.0] undec-7-ene is particularly preferred. These organic bases can be used alone or in combination.

  The molar ratio of the organic base to hydrogen fluoride in the “salt or complex comprising an organic base and hydrogen fluoride” may be in the range of 1: 0.3 to 7, preferably 1: 0.5 to 5. : 0.7 to 3 is particularly preferable. The molar ratio of the organic base and hydrogen fluoride is not particularly limited. However, when the ratio of hydrogen fluoride is increased, the target α, α-difluoro with respect to the by-product α-fluoro-α, β-unsaturated esters is obtained. The production ratio of esters increases, but the reaction rate decreases. On the other hand, when the ratio of the organic base is increased, the reaction rate is increased, but the production ratio of the target product to by-products is decreased. Therefore, from the viewpoint of a practical production method, there is a suitable range for the molar ratio, and it varies slightly depending on the type of organic base used. When using 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), a preferred organic base of the present invention, the molar ratio of DBU to hydrogen fluoride is from 1: 1.8. It may be in the range of 2.7, preferably 1: 1.9 to 2.6, and particularly preferably 1: 2.0 to 2.5 (see Examples 4 to 8). It is easy to finely adjust the molar ratio by mixing DBU · 3HF (liquid) and DBU at an arbitrary ratio (DBU · 1HF is a hygroscopic solid and is not always easy to handle on a large scale. ).

The amount of the “salt or complex comprising an organic base and hydrogen fluoride” is fluoride relative to 1 mol of α-halogeno-α-fluoroesters represented by the general formula [1], [3] or [5]. The ion (F ⁻ ) may be 0.7 mol or more, preferably 0.8 to 30 mol, particularly preferably 0.9 to 20 mol.

  This fluorine substitution reaction can also be carried out in the presence of a polymerization inhibitor. For example, when the reaction is carried out under high concentration conditions with the expectation of high productivity, the reaction system may not be smoothly stirred due to polymerization of by-produced α-fluoro-α, β-unsaturated esters. In such a case, the addition of a polymerization inhibitor is effective. However, by adopting suitable reaction conditions, the reaction can be carried out satisfactorily in the absence of a polymerization inhibitor even at high concentration conditions. The polymerization inhibitor is not essential for the present fluorine substitution reaction, but is extremely effective for mass production.

  Such polymerization inhibitors include phenothiazine, hydroquinone, 2,6-di-tert-butyl-4-methylphenol, methoquinone, tert-butylhydroquinone, 2,5-di-tert-butylhydroquinone, 1,2,4- Trihydroxybenzene, leucoquinizarin, nonflex F, nonflex H, nonflex DCD, 2,2'-methylene-bis (4-methyl-6-tert-butylphenol), ozonone 35, tetraethylthiuram disulfide, Q-1300, Q -1301, chloranil, sulfur and the like. These polymerization inhibitors are commercially available products, are easily available on a large scale, and are inexpensive. Among them, phenothiazine, hydroquinone and 2,6-di-tert-butyl-4-methylphenol are preferable, and phenothiazine and 2,6-di-tert-butyl-4-methylphenol are particularly preferable.

  When the polymerization inhibitor is used, the amount used is 0.00001 mol or more with respect to 1 mol of the α-halogeno-α-fluoroester represented by the general formula [1], [3] or [5]. 0.0001 to 0.1 mol is preferable, and 0.0003 to 0.05 mol is particularly preferable.

  Examples of the reaction solvent include aliphatic hydrocarbons such as n-hexane and n-heptane, aromatic hydrocarbons such as toluene and xylene, halogens such as methylene chloride and 1,2-dichloroethane, tetrahydrofuran, and tert-butylmethyl. Ethers such as ether, esters such as ethyl acetate and n-butyl acetate, N, N-dimethylformamide, N, N-dimethylacetamide, 1-methyl-2-pyrrolidinone, 1,3-dimethyl-2-imidazolid Examples thereof include amides such as non, nitriles such as acetonitrile and propionitrile, and dimethyl sulfoxide. Among them, n-heptane, toluene, methylene chloride, tetrahydrofuran, ethyl acetate, N, N-dimethylformamide, N, N-dimethylacetamide, 1-methyl-2-pyrrolidinone, 1,3-dimethyl-2-imidazolidinone, Acetonitrile and dimethyl sulfoxide are preferred, and toluene, tetrahydrofuran, N, N-dimethylformamide, N, N-dimethylacetamide, 1-methyl-2-pyrrolidinone, 1,3-dimethyl-2-imidazolidinone, acetonitrile and dimethyl sulfoxide are preferred. Particularly preferred. These reaction solvents can be used alone or in combination.

  The reaction solvent may be used in an amount of 0.01 L or more with respect to 1 mol of the α-halogeno-α-fluoroester represented by the general formula [1], [3] or [5]. 20L is preferable, and 0.03 to 10L is particularly preferable. This fluorine substitution reaction can also be performed without using a reaction solvent in expectation of high productivity.

  The reaction temperature may be in the range of −20 to + 150 ° C., preferably −10 to + 125 ° C., particularly preferably 0 to + 100 ° C.

  The reaction time may be in the range of 240 hours or less, and varies depending on the raw material substrate, the fluoride ion source and the reaction conditions. Therefore, the reaction time is determined by an analytical means such as gas chromatography, thin layer chromatography, liquid chromatography, or nuclear magnetic resonance. It is preferable to track the progress of the process and set the end point when the consumption of the raw material substrate is almost stopped.

The post-treatment can obtain α, α-difluoroesters represented by the general formula [2], [4] or [6] by employing general operations in organic synthesis. R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ of the α-halogeno-α-fluoroesters represented by the general formulas [1], [3] and [5] are passed through this fluorine substitution reaction. It does not change before and after. The crude product can be purified to a higher chemical purity by operations such as activated carbon treatment, distillation, recrystallization, column chromatography and the like, if necessary. In addition, crude products or refined products (processed products obtained by high-boiling treatment, fractional distillation products, etc.) can be used as required by anhydrous sodium sulfate, anhydrous magnesium sulfate, calcium chloride, diphosphorus pentoxide, silica gel, synthetic zeolite. It can be dehydrated with a desiccant such as various water removal filters. Furthermore, the crude product or the purified product was listed as a defluorinating agent such as sodium fluoride, calcium chloride, silica gel or the like, an organic base (an organic base of a “salt or complex comprising an organic base and hydrogen fluoride” if necessary) It can be defluorinated by contact distillation or the like.

  As a suitable post-treatment, a crude product can be obtained by directly collecting and distilling the reaction end solution. In the present fluorine substitution reaction, the amount of by-produced α-fluoro-α, β-unsaturated esters in the reaction completion liquid or the crude product can be significantly reduced. However, because the target α, α-difluoroesters and the by-product α-fluoro-α, β-unsaturated esters are close in boiling point, it is difficult to purify to high purity by fractional distillation, which is a simple operation. Met. Therefore, paying attention to the reactivity of the by-product double bond site, it is easy to increase the boiling point difference from the target product by increasing the boiling point of the by-product only (high boiling point treatment). It has been found that high purity products can be efficiently obtained by fractional distillation, which is a simple operation. This technique is a preferred embodiment in the method for purifying the target product of the present invention.

  Examples of the high boiling point treatment include polymerization treatment and Michael addition reaction treatment.

  The former polymerization process will be specifically described.

  In the polymerization treatment, only the by-product in the presence of the polymerization initiator is applied to the reaction end solution or crude product containing the by-product α-fluoro-α, β-unsaturated ester obtained by the fluorine substitution reaction. Polymerization is performed to recover the target α, α-difluoroester from the high boiling point completion liquid, and further fractional distillation is performed as necessary, whereby a high-purity product of the target can be obtained.

  When the fluorine substitution reaction is performed in the presence of a polymerization inhibitor, the polymerization treatment is preferably performed after removing the polymerization inhibitor in advance.

  As a polymerization initiator, 2,2′-azobis (4-methoxy-2,4-dimethylvaleronitrile), 2,2′-azobis (2,4-dimethylvaleronitrile), 2,2′-azobis (2 -Methylpropionitrile), 2,2′-azobis (2-methylbutyronitrile), 1,1′-azobis (cyclohexane-1-carbonitrile) and other azo compounds, benzoyl peroxide, tert-butylperoxy Pivalate, di-tert-butyl peroxide, i-butyryl peroxide, lauroyl peroxide, succinic acid peroxide, dicinnamyl peroxide, di-n-propyl peroxydicarbonate, tert-butylperoxyallyl monocarbonate, peroxy Examples thereof include peroxides such as hydrogen oxide and ammonium persulfate. Among them, 2,2′-azobis (4-methoxy-2,4-dimethylvaleronitrile), 2,2′-azobis (2,4-dimethylvaleronitrile), 2,2′-azobis (2-methylpropio) Nitrile), 2,2′-azobis (2-methylbutyronitrile), 1,1′-azobis (cyclohexane-1-carbonitrile), benzoyl peroxide, tert-butyl peroxypivalate and di-tert-butyl Peroxides are preferred, 2,2′-azobis (4-methoxy-2,4-dimethylvaleronitrile), 2,2′-azobis (2,4-dimethylvaleronitrile), 2,2′-azobis (2- Methylpropionitrile), 2,2′-azobis (2-methylbutyronitrile) and 1,1′-azobis (cyclohexane-1-carbonitone) Le) is particularly preferred. These polymerization initiators are commercially available products, are easily available on a large scale, and are inexpensive. For selection of the polymerization initiator, it is necessary to consider the ease of separation of the decomposition product derived from the polymerization initiator and the target product in distillation. From this point of view, among the particularly preferred ones, 2,2′-azobis (4-methoxy-2,4-dimethylvaleronitrile), 2,2′-azobis (2,4-dimethylvaleronitrile) and 1,1 ′ -Azobis (cyclohexane-1-carbonitrile) is very particularly preferred.

  The amount of the polymerization initiator used may be 1 mol or less with respect to 1 mol of the by-product α-fluoro-α, β-unsaturated ester contained, preferably 0.00001 to 0.7 mol, 0 0.0001 to 0.5 mole is particularly preferred.

  The treatment solvent and treatment temperature of the main polymerization treatment are the same as the reaction solvent and reaction temperature in the fluorine substitution reaction.

  The amount of the solvent used for the polymerization treatment may be 0.01 volume or more with respect to 1 volume of the reaction end solution or crude product containing α-fluoro-α, β-unsaturated ester as a by-product. 0.03 to 10 volumes is preferred, and 0.05 to 5 volumes is particularly preferred. This polymerization treatment can also be carried out without using a treatment solvent in anticipation of high productivity.

  The polymerization treatment time may be within a range of 120 hours or less, and varies depending on the content of α-fluoro-α, β-unsaturated esters as a by-product, the polymerization initiator, and the polymerization conditions. It is preferable that the progress of the polymerization is followed by analysis means such as layer chromatography, liquid chromatography, nuclear magnetic resonance, etc., and the end point is when the consumption of by-products is almost stopped.

  The recovery of the target α, α-difluoroesters in the polymerization treatment can obtain a high-purity product of the target by employing a general operation in organic synthesis. For recovery of the target product in a suitable polymerization treatment, a high-boiling crude product can be obtained by directly collecting and distilling the high-boiling point completion liquid. The high-boiling crude product can be purified to a higher chemical purity by an operation such as fractional distillation, if necessary.

In raising the boiling point of by-product α-fluoro-α, β-unsaturated esters by polymerization, general formula [7]

^[Wherein, R 1, ^{R 2} and ^{R 3,} the general formula [1] alpha-halogeno -α- fluoroester represented by the the same as ^R 1, ^{R 2} and ^{R 3,} n is 2 or more Represents an integer. At both terminal sites, α-halogeno-α-fluoroesters (raw material substrate), “salt or complex consisting of organic base and hydrogen fluoride” (fluoride ion source), polymerization inhibitor, reaction in fluorine substitution reaction Atoms, functional groups or parts of functional groups derived from solvents, α, α-difluoroesters (target product), α-fluoro-α, β-unsaturated esters (by-products), polymerization initiation in polymerization process An atom, a functional group or a part of a functional group derived from an agent, a processing solvent or the like, or an atom, a functional group or a part of a functional group derived from water (H ₂ O) or oxygen (O ₂ ) is introduced. ]
Is converted into a polymer represented by

  The latter Michael addition reaction will be specifically described.

  In the Michael addition reaction treatment, a by-product is obtained by using a nucleophilic agent on the reaction end solution or crude product containing α-fluoro-α, β-unsaturated esters as a by-product obtained by the fluorine substitution reaction. Is subjected to Michael addition reaction, and the target α, α-difluoroester is recovered from the high boiling point completion liquid, and further subjected to fractional distillation as necessary, whereby a high-purity product of the target product can be obtained.

As the nucleophile, the general formula [8]

[Wherein, R ⁷ and R ⁸ each independently represents a hydrogen atom, an alkyl group, a substituted alkyl group, an aromatic ring group or a substituted aromatic ring group. R ⁷ and R ⁸ may each have an arbitrary carbon atom, or may adopt a cyclic structure by a covalent bond via a nitrogen atom, an oxygen atom, or a sulfur atom. ]
Or a nitrogen nucleophile represented by the general formula [9]

[Wherein R ⁹ represents a hydrogen atom, an alkyl group, a substituted alkyl group, an aromatic ring group or a substituted aromatic ring group. ]
The sulfur nucleophile shown by these is mentioned. Among them, sulfur nucleophiles are preferable, and sulfur nucleophiles in which R ⁹ is an alkyl group or an aromatic ring group are particularly preferable. In selecting a nucleophile, it is necessary to consider the ease of separation in distillation of the nucleophile remaining unreacted and the target product. From such a viewpoint, among those particularly preferable, a sulfur nucleophile having an aromatic ring group as R ⁹ is extremely preferable.

R ⁷ and R ⁸ of the nitrogen nucleophile represented by the general formula [8] each independently represent a hydrogen atom, an alkyl group, a substituted alkyl group, an aromatic ring group or a substituted aromatic ring group. The alkyl group, substituted alkyl group, aromatic ring group and substituted aromatic ring group are the alkyl group and substituted alkyl group described in R ¹ and R ² of the α-halogeno-α-fluoroester represented by the general formula [1]. The same as the aromatic ring group and the substituted aromatic ring group.

R ⁷ and R ⁸ of the nitrogen nucleophile represented by the general formula [8] may each take a cyclic structure with any carbon atom or covalent bond via a nitrogen atom, oxygen atom or sulfur atom. is there.

R ^{9 of the} sulfur nucleophile represented by the general formula [9] represents a hydrogen atom, an alkyl group, a substituted alkyl group, an aromatic ring group or a substituted aromatic ring group. The alkyl group, substituted alkyl group, aromatic ring group and substituted aromatic ring group are the alkyl group and substituted alkyl group described in R ¹ and R ² of the α-halogeno-α-fluoroester represented by the general formula [1]. The same as the aromatic ring group and the substituted aromatic ring group.

  The amount of the nucleophilic agent used may be 0.7 mol or more, preferably 0.8 to 700 mol, per mol of by-product α-fluoro-α, β-unsaturated ester contained, .9 to 500 mol is particularly preferred.

  By performing this Michael addition reaction treatment in the presence of a base, the treatment time may be shortened. However, by adopting suitable treatment conditions, the treatment can be performed satisfactorily in the absence of a base. In addition, a base is not essential for the present Michael addition reaction treatment, but is extremely effective for purification on a large scale.

  Examples of such bases include inorganic bases such as lithium hydrogen carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, lithium carbonate, sodium carbonate, and potassium carbonate, and organic bases of “salts or complexes comprising an organic base and hydrogen fluoride” in a fluorine substitution reaction. And the like. Among them, organic bases are preferable, and triethylamine, diisopropylethylamine, tri-n-butylamine, pyridine, 2,6-lutidine, 4-dimethylaminopyridine and 1,8-diazabicyclo [5.4.0] undec-7-ene are particularly preferable. preferable. These bases can be used alone or in combination.

  In the case of using a base, the amount used may be 0.7 mol or more, preferably 0.8 to 700 mol, relative to 1 mol of by-product α-fluoro-α, β-unsaturated ester. 0.9 to 500 moles is particularly preferred.

  The processing solvent of this Michael addition reaction treatment, the amount used, the processing temperature, the processing time, and the recovery of the target α, α-difluoroesters in the Michael addition reaction processing are the processing solvent in the polymerization processing, the amount used, the processing The temperature, processing time, and recovery of the target product in the polymerization process are the same. However, regarding the processing time, the term “polymerization initiator and polymerization conditions” is read as “nucleophilic agent and Michael addition reaction conditions”.

In raising the boiling point of by-product α-fluoro-α, β-unsaturated esters by Michael addition reaction treatment, the general formula [10]

^[Wherein, R 1, ^{R 2} and ^{R 3} are the same as the general formula ^[R 1 of α- halogeno -α- fluoroester represented by 1], ^{R 2} and ^{R 3, R 7} and ^{R 8} Is the same as nitrogen nucleophiles R ⁷ and R ⁸ . ]
And general formula [11]

^[Wherein, R 1, ^{R 2} and ^{R 3} are the same as the general formula ^[R 1 of α- halogeno -α- fluoroester represented by 1], ^{R 2} and ^{R 3, R 8} is nitrogen Same as R ⁸ for nucleophile. This compound may be adopted when the nitrogen nucleophile is a primary amine (R ⁸ NH ₂ , R ⁸ represents an alkyl group, a substituted alkyl group, an aromatic ring group or a substituted aromatic ring group). As shown. ]
Or the general formula [12]

^[Wherein, R 1, ^{R 2} and ^{R 3} are the same as the general formula ^[R 1 of α- halogeno -α- fluoroester represented by 1], ^{R 2} and ^{R 3.} This compound is shown as a possible structural formula when the nitrogen nucleophile is ammonia (NH ₃ ). ]
Or a nitrogen adduct represented by the general formula [13]

^[Wherein, R 1, ^{R 2} and ^{R 3} are the same as the general formula ^[R 1 of α- halogeno -α- fluoroester represented by 1], ^{R 2} and ^{R 3, R 9} is sulfur Same as R ⁹ for nucleophile. ]
Or the general formula [14]

^[Wherein, R 1, ^{R 2} and ^{R 3} are the same as the general formula ^[R 1 of α- halogeno -α- fluoroester represented by 1], ^{R 2} and ^{R 3.} This compound is shown as a possible structural formula when the sulfur nucleophile is hydrogen sulfide (H ₂ S). ]
Is converted to a sulfur adduct represented by

  In the high boiling point treatment of the by-product α-fluoro-α, β-unsaturated ester, by performing both the polymerization treatment and the Michael addition reaction treatment, the purity of the target α, α-difluoroester is further increased. Goods can be obtained. In this case, there is no restriction on the order in which they are performed, and they can be performed simultaneously. Of course, these processes can be repeated.

[Example]
Embodiments of the present invention will be specifically described by way of examples, but the present invention is not limited to these examples. Me and Et are abbreviations for methyl group and ethyl group, respectively.

1,3-Dimethyl-2-imidazolidinone (DMI) 140 mL (0.519 L / mol) was added to 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) .multifluorohydrogen 97. .6 g (460 mmol, 1.70 eq), DBU 24.7 g (162 mmol, 0.600 eq) and 2,6-di-tert-butyl-4-methylphenol 250 mg (1.13 mmol, 0.00419 eq) were added, and ice-cooled. (Mole ratio of organic base to hydrogen fluoride 1: 2.2, fluoride ion 5.10 eq). In this homogeneous solution, the following formula

50.0 g (270 mmol, 1.00 eq) of α-halogeno-α-fluoroesters (raw material substrate) represented by the formula (II) was added under ice cooling, and the mixture was stirred at 50 ° C. for 2 days. The conversion rate was 87% from ¹⁹ F-NMR analysis of the reaction completed liquid, and the following formula

Α, α-difluoroesters (target product), hydrolysates of α, α-difluoroesters (target product hydrolysates) and α-fluoro-α, β-unsaturated esters (by-products) The production ratio of was 73: 4: 23. By directly recovering and distilling the reaction completion liquid (degree of vacuum ~ 2 kPa, oil bath temperature ~ 100 ° C),

As a result, 60.0 g of a crude product containing the target product, by-products and raw material substrate was obtained (the target hydrolyzate was not distilled by recovery distillation). From the ¹⁹ F-NMR analysis of the crude product, the composition ratio of the target product, by-product and raw material substrate was 73: 20: 7, and quantified by the internal standard method (internal standard substance α, α, α-trifluorotoluene). However, 165 mmol of the target product was contained (most of the remaining was DMI), and the yield was 61%.

Produced in the same manner with reference to the above [2 runs (total 3.24 mol) on 300 g raw material substrate], crude product containing target product, by-product and raw material substrate (recovered and distilled directly from reaction end solution) ) To 710 g [dried molecular sieve 4A, target product, by-product and raw material substrate composition ratio 70: 23: 7, containing 246 g (1.98 mol) of target product, yield 61%], 2,2′-azobis ( 4-methoxy-2,4-dimethylvaleronitrile) 8.00 g [25.9 mmol, 0.0569 eq vs. Side product (455 mmol)] was added and stirred at 50 ° C. overnight. The composition ratio was 89: 2: 9 from ¹⁹ F-NMR analysis of the high boiling point completion liquid by polymerization. By directly collecting and distilling the high-boiling point-end liquid (decompression degree to 2 kPa, distillation temperature to 90 ° C.), 411 g of a high-boiling crude product was obtained [same composition ratio 90: 1: 9, target product 246 g. (1.98 mol) contained]. The gas chromatographic purity of the target product, by-product, raw material substrate, and DMI in the high-boiling crude product was 56.3%, 0.6%, 5.6%, and 32.6%, respectively. By subjecting the high-boiling crude product to fractional distillation (theoretical plate number: 20 plates, degree of vacuum: 60 kPa, distillation temperature: 79 ° C.), 223 g (1.80 mol) of the desired product was obtained. The recovery from the crude product was 91% and the total yield from the reaction was 56%. The gas chromatographic purity of the target product and by-product in the purified product was 98.9 to 99.2% and 1.1 to 0.6%, respectively.

  To 10.0 g (80.6 mmol, 1.00 eq) of the purified product obtained above, 444 mg of thiophenol [4.03 mmol, 5.88 eq vs. Byproduct (685 μmol)] was added and stirred at room temperature overnight. By directly fractionally distilling the high boiling point completion liquid by the Michael addition reaction, 9.30 g of a re-refined product of the target product was obtained. The recovery rate was 93%. The gas chromatographic purity of the target product and by-product in the re-refined product was 99.8% and 0.2%, respectively.

¹ H-NMR, ¹⁹ F-NMR and mass chromatography (MS) of α, α-difluoroesters are shown below.

¹ H-NMR [reference material; (CH ₃ ) ₄ Si, deuterated solvent; CDCl ₃ ], δ ppm; 1.81 (t, 18.8 Hz, 3H), 3.88 (s, 3H).

¹⁹ F-NMR (reference material; C ₆ F ₆ , deuterated solvent; CDCl ₃ ), δ ppm; 62.90 (q, 18.3 Hz, 2F).

MS; EI / 124 (M +), 81, 65, 59, CI / 125 (M + H).

To 50.0 mL of acetonitrile (0.463 L / mol), 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) .31.7 g of hydrogen trifluoride (149 mmol, 1.38 eq), DBU10 0.1 g (66.3 mmol, 0.614 eq) and 2,6-di-tert-butyl-4-methylphenol 100 mg (454 μmol, 0.00420 eq) were added and stirred under ice cooling (organic base and hydrogen fluoride). Molar ratio 1: 2.1, fluoride ion 4.14 eq). In this homogeneous solution, the following formula

20.0 g (108 mmol, 1.00 eq) of α-halogeno-α-fluoroester represented by the formula (1) was added under ice cooling, and the mixture was stirred at 50 ° C. for 3 days. The conversion rate is 70% from ¹⁹ F-NMR analysis of the reaction completed solution, and the following formula

Α, α-difluoroesters (target product), hydrolysates of α, α-difluoroesters (target product hydrolysates) and α-fluoro-α, β-unsaturated esters (by-products) The production ratio was 77: 5: 18, and it was quantified by an internal standard method (internal standard substance α, α, α-trifluorotoluene). As a result, 57.2 mmol of the target product was contained, and the yield was 53%. Met.

To 50.0 mL of toluene (0.463 L / mol), 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) · 31.7 g of hydrogen trifluoride (149 mmol, 1.38 eq), DBU10 0.1 g (66.3 mmol, 0.614 eq) and 2,6-di-tert-butyl-4-methylphenol 100 mg (454 μmol, 0.00420 eq) were added and stirred under ice cooling (organic base and hydrogen fluoride). Molar ratio 1: 2.1, fluoride ion 4.14 eq). In this heterogeneous solution,

20.0 g (108 mmol, 1.00 eq) of α-halogeno-α-fluoroester represented by the formula (1) was added under ice cooling, and the mixture was stirred at 50 ° C. for 3 days. According to ¹⁹ F-NMR analysis of the reaction completed liquid, the conversion rate is 75%,

Α, α-difluoroesters (target product), hydrolysates of α, α-difluoroesters (target product hydrolysates) and α-fluoro-α, β-unsaturated esters (by-products) The production ratio was 72: 4: 24, and it was quantified by an internal standard method (internal standard substance α, α, α-trifluorotoluene). As a result, 57.9 mmol of the target product was contained, and the yield was 54%. Met.

To 140 mL (0.519 L / mol) of 1,3-dimethyl-2-imidazolidinone, 97.6 g of 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) · hydrogen trifluoride ( 460 mmol, 1.70 eq), DBU 53.3 g (350 mmol, 1.30 eq) and 2,6-di-tert-butyl-4-methylphenol 250 mg (1.13 mmol, 0.00419 eq) were added and stirred under ice cooling. (Mole ratio of organic base to hydrogen fluoride 1: 1.7, fluoride ion 5.10 eq). In this homogeneous solution, the following formula

The α-halogeno-α-fluoroester represented by the formula (50.0 g, 270 mmol, 1.00 eq) was added under ice cooling, and the mixture was stirred at 40 ° C. overnight. The conversion rate is 100% from ¹⁹ F-NMR analysis of the reaction completed solution, and the following formula

Α, α-difluoroesters (target product), hydrolysates of α, α-difluoroesters (target product hydrolysates) and α-fluoro-α, β-unsaturated esters (by-products) The production ratio of was 42: 8: 50.

To 140 mL (0.519 L / mol) of 1,3-dimethyl-2-imidazolidinone, 97.6 g of 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) · hydrogen trifluoride ( 460 mmol, 1.70 eq), DBU 32.9 g (216 mmol, 0.800 eq) and 2,6-di-tert-butyl-4-methylphenol 250 mg (1.13 mmol, 0.00419 eq) were added and stirred under ice cooling. (Molar ratio of organic base to hydrogen fluoride 1: 2.0, fluoride ion 5.10 eq). In this homogeneous solution, the following formula

The α-halogeno-α-fluoroester represented by the formula (50.0 g, 270 mmol, 1.00 eq) was added under ice cooling, and the mixture was stirred at 40 ° C. overnight. According to ¹⁹ F-NMR analysis of the reaction completed liquid, the conversion rate is 90%.

Α, α-difluoroesters (target product), hydrolysates of α, α-difluoroesters (target product hydrolysates) and α-fluoro-α, β-unsaturated esters (by-products) The production ratio of was 60: 3: 37.

To 140 mL (0.519 L / mol) of 1,3-dimethyl-2-imidazolidinone, 97.6 g of 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) · hydrogen trifluoride ( 460 mmol, 1.70 eq), DBU 24.7 g (162 mmol, 0.600 eq) and 2,6-di-tert-butyl-4-methylphenol 250 mg (1.13 mmol, 0.00419 eq) were added and stirred under ice cooling. (Mole ratio of organic base to hydrogen fluoride 1: 2.2, fluoride ion 5.10 eq). In this homogeneous solution, the following formula

50.0 g (270 mmol, 1.00 eq) of α-halogeno-α-fluoroesters represented by the above was added under ice cooling, and the mixture was stirred at 50 ° C. for 2 days. The conversion rate was 87% from ¹⁹ F-NMR analysis of the reaction completed liquid, and the following formula

Α, α-difluoroesters (target product), hydrolysates of α, α-difluoroesters (target product hydrolysates) and α-fluoro-α, β-unsaturated esters (by-products) The production ratio of was 73: 4: 23.

To 140 mL (0.519 L / mol) of 1,3-dimethyl-2-imidazolidinone, 97.6 g of 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) · hydrogen trifluoride ( 460 mmol, 1.70 eq), DBU 20.6 g (135 mmol, 0.50 eq) and 2,6-di-tert-butyl-4-methylphenol 250 mg (1.13 mmol, 0.00419 eq) were added and stirred under ice cooling. (Molar ratio of organic base to hydrogen fluoride 1: 2.3, fluoride ion 5.10 eq). In this homogeneous solution, the following formula

50.0 g (270 mmol, 1.00 eq) of α-halogeno-α-fluoroesters represented by the above was added under ice cooling, and the mixture was stirred at 50 ° C. for 2 days. The conversion rate is 80% from ¹⁹ F-NMR analysis of the reaction completed solution, and the following formula

Α, α-difluoroesters (target product), hydrolysates of α, α-difluoroesters (target product hydrolysates) and α-fluoro-α, β-unsaturated esters (by-products) The production ratio of was 77: 2: 21.

To 140 mL (0.519 L / mol) of 1,3-dimethyl-2-imidazolidinone, 97.6 g of 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) · hydrogen trifluoride ( 460 mmol, 1.70 eq), DBU 12.3 g (80.8 mmol, 0.300 eq) and 2,6-di-tert-butyl-4-methylphenol 250 mg (1.13 mmol, 0.00419 eq) were added, and the mixture was cooled with ice. (Molar ratio of organic base to hydrogen fluoride 1: 2.6, fluoride ion 5.10 eq). In this homogeneous solution, the following formula

50.0 g (270 mmol, 1.00 eq) of α-halogeno-α-fluoroester represented by the formula (1) was added under ice cooling, and the mixture was stirred at 40 ° C. overnight, and further stirred at 50 ° C. for 5 days. According to ¹⁹ F-NMR analysis of the reaction completed liquid, the conversion rate is 78%.

Α, α-difluoroesters (target product), hydrolysates of α, α-difluoroesters (target product hydrolysates) and α-fluoro-α, β-unsaturated esters (by-products) The production ratio was 85: very small amount: 15.

Regarding the “salt or complex consisting of an organic base and hydrogen fluoride” of the fluoride ion source, the results of Examples 4 to 8 (see Table 1) are similar to the “suitable organic bases of the invention described in the fluorine substitution reaction. When a certain 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) is used, the molar ratio of DBU to hydrogen fluoride is in the range of 1: 1.8 to 2.7. It clearly shows that "1: 1.9 to 2.6 is preferred, and 1: 2.0 to 2.5 is particularly preferred". In Example 4 in which the molar ratio of DBU to hydrogen fluoride was 1: 1.7, the reaction rate was increased, but the target α, α-to the by-product α-fluoro-α, β-unsaturated ester was obtained. The production ratio of difluoroesters is low. On the other hand, in Example 8 in which the molar ratio of DBU to hydrogen fluoride is 1: 2.6, the production ratio of the target product to the by-product is increased, but the reaction rate is decreased. Therefore, a molar ratio of DBU to hydrogen fluoride of 1: 2.0 to 2.5 is strongly recommended from the viewpoint of a practical production method.

To 17.0 mL (0.499 L / mol) of 1,3-dimethyl-2-imidazolidinone, 18.6 g (108 mmol) of 1,8-diazabicyclo [5.4.0] undec-7-ene · hydrogen monofluoride. , 2.00 eq), 13.3 g (54.2 mmol, 1.00 eq) of tri-n-butylamine · hydrogen trifluoride and 50.0 mg (227 μmol, 0.003 mol) of 2,6-di-tert-butyl-4-methylphenol. (00420eq) was added, and the mixture was stirred under ice-cooling (molar ratio of organic base to hydrogen fluoride was 1: 1.7, fluoride ion was 5.00 eq). In this homogeneous solution, the following formula

Then, 10.0 g (54.1 mmol, 1.00 eq) of α-halogeno-α-fluoroester represented by the formula (1) was added under ice cooling, and the mixture was stirred at 40 ° C. for 2 days. According to ¹⁹ F-NMR analysis of the reaction completed liquid, the conversion rate is 72%, and the following formula

Α, α-difluoroesters (target product), hydrolysates of α, α-difluoroesters (target product hydrolysates) and α-fluoro-α, β-unsaturated esters (by-products) The production ratio of was 68: 5: 27.

To 5.00 mL (0.996 L / mol) of 1,3-dimethyl-2-imidazolidinone, 2.60 g of 1,8-diazabicyclo [5.4.0] undec-7-ene · hydrogen fluoride (15 .1 mmol, 3.01 eq), 138 mg of 70% hydrogen fluoride pyridine [96.6 mg (4.83 mmol, 0.962 eq) of hydrogen fluoride, 41.4 mg (523 μmol, 0.104 eq)] of pyridine and 2,6-di -Tert-butyl-4-methylphenol 5.00 mg (22.7 μmol, 0.00452 eq) was added and stirred under ice-cooling (molar ratio of organic base to hydrogen fluoride 1: 1.3, fluoride ion 3 .97 eq). In this homogeneous solution, the following formula

1.00 g (5.02 mmol, 1.00 eq) of α-halogeno-α-fluoroesters represented by the above was added under ice cooling and stirred at room temperature for 2 days. According to ¹⁹ F-NMR analysis of the reaction completed liquid, the conversion rate is 75%,

Α, α-difluoroesters (target product), hydrolysates of α, α-difluoroesters (target product hydrolysates) and α-fluoro-α, β-unsaturated esters (by-products) The production ratio was 64: 9: 27.

[Comparative Example 1]
To 5.40 mL (0.998 L / mol) of dimethyl sulfoxide,

Α-halogeno-α-fluoroesters represented by the formula: 1.00 g (5.41 mmol, 1.00 eq), 376 mg (6.47 mmol, 1.20 eq) of potassium fluoride (spray-dried product) and 2,6-di- 10.0 mg (45.4 μmol, 0.00839 eq) of tert-butyl-4-methylphenol was added, and the mixture was stirred at 80 ° C. for 3 hours. The conversion rate is 60% from ¹⁹ F-NMR analysis of the reaction completed liquid, and the following formula

Α, α-difluoroesters (target product), hydrolysates of α, α-difluoroesters (target product hydrolysates) and α-fluoro-α, β-unsaturated esters (by-products) The production ratio of was 16: not detected: 84.

[Comparative Example 2]
To 5.40 mL (0.998 L / mol) of dimethyl sulfoxide,

Α-halogeno-α-fluoroesters represented by the formula: 1.00 g (5.41 mmol, 1.00 eq), potassium fluoride (spray-dried product) 376 mg (6.47 mmol, 1.20 eq), 18-crown-6 285 mg (1.08 mmol, 0.200 eq) and 10.0 mg (45.4 μmol, 0.00839 eq) of 2,6-di-tert-butyl-4-methylphenol were added and stirred at 40 ° C. overnight. According to ¹⁹ F-NMR analysis of the reaction completed liquid, the conversion rate is 49%.

Α, α-difluoroesters (target product), hydrolysates of α, α-difluoroesters (target product hydrolysates) and α-fluoro-α, β-unsaturated esters (by-products) The production ratio was 12: not detected: 88.

[Comparative Example 3]
To 6.00 mL (1.11 L / mol) of dimethyl sulfoxide,

1.00 g (5.41 mmol, 1.00 eq) and 984 mg (6.48 mmol, 1.20 eq) of cesium fluoride were added, and the mixture was stirred at 60 ° C. overnight. The conversion rate was 89% from ¹⁹ F-NMR analysis of the reaction completed liquid, and the following formula

Α, α-difluoroesters (target product), hydrolysates of α, α-difluoroesters (target product hydrolysates) and α-fluoro-α, β-unsaturated esters (by-products) The production ratio of was 25: not detected: 75.

[Comparative Example 4]
To 1.00 mL (1.85 L / mol) of tetrahydrofuran,

100 mg (541 μmol, 1.00 eq) of α-halogeno-α-fluoroester represented by the above and 1.08 mL (1.08 mmol, 2.00 eq) of 1.0 M tetrahydrofuran solution of tetra-n-butylammonium fluoride were added, and room temperature was added. And stirred overnight. The conversion rate is 100% from ¹⁹ F-NMR analysis of the reaction completed solution, and the following formula

Α, α-difluoroesters (target product), hydrolysates of α, α-difluoroesters (target product hydrolysates) and α-fluoro-α, β-unsaturated esters (by-products) As for the production ratio, only by-products were detected (two other large impurities were by-produced).

[Comparative Example 5]
To 6.48 g (324 mmol, 20.0 eq) of hydrogen fluoride,

Was added with 3.00 g (16.2 mmol, 1.00 eq) of α-halogeno-α-fluoroester, and the mixture was stirred at room temperature overnight. The conversion rate was 0% from ¹⁹ F-NMR analysis of the reaction completed liquid (the reaction did not proceed at all).

[Comparative Example 6]
To 203 g (10.1 mol, 10.1 eq) of hydrogen fluoride,

185 g (1.00 mol, 1.00 eq) and 150 g (502 mmol, 0.502 eq) antimony pentachloride were added, and the mixture was added at 40 ° C. for 2 hours, at 60 ° C. for 2 hours, and further The mixture was stirred at 80 ° C. for 2 hours (the internal pressure was controlled to 1.00 MPa or less). From the gas chromatographic analysis of the reaction finished liquid, the conversion rate is 50%.

Α, α-difluoroesters (target product), α-bromo-α, β-unsaturated esters (impurities) and α-halogeno-α-fluoroesters hydrolyzates (raw material substrate hydrolysates) ) Gas chromatographic purity was 2.8%, 23.3%, and 9.1%, respectively.

[Comparative Example 7]
To 30.0 g (263 mmol, 1.00 eq) of 1,3-dimethyl-2-imidazolidinone, 83.2 g (4.16 mol, 15.8 eq) of hydrogen fluoride was added under ice cooling, and the mixture was stirred at room temperature for 2 hours. did. In this homogeneous solution, the following formula

48.6 g (263 mmol, 1.00 eq) of α-halogeno-α-fluoroesters represented by the above was added, and the mixture was stirred at room temperature overnight and further at 50 ° C. for 2 days. The conversion rate was 4% from ¹⁹ F-NMR analysis of the reaction completed solution, and the following formula

Α, α-difluoroesters (target product), hydrolysates of α, α-difluoroesters (target product hydrolysates) and α-fluoro-α, β-unsaturated esters (by-products) The product hydrolyzate was the main product (a trace amount of the product and by-products were detected). Although this comparative example was performed using a pressure resistant reaction vessel made of stainless steel (SUS), significant corrosion was observed [all examples were performed using a reaction vessel made of glass (glass lining), but corrosion was not observed. Was hardly recognized]. Comparative Example 7 was produced in the same manner with reference to Japanese Patent Application Laid-Open No. 2001-072608. However, the target product targeted by the present invention could hardly be obtained.

[Reference Example 1]
α, α, α-Trifluorotoluene (BTF) 170L has the following formula:

(R) -2-fluoropropionate methyl represented by 85.0 kg (801 mol, 1.00 eq), N-bromosuccinimide (NBS) 171 kg (961 mol, 1.20 eq) and 1,1′-azobis (cyclohexane-1) -Carbonitrile) (V-40) 1.17 kg (4.79 mol, 0.006 eq) was added, and the mixture was stirred at 85 to 93 ° C. for 35 hours. After 1, 5 hours, 10 hours, 15 hours and 20 hours, 1.17 kg (4.79 mol, 0.006 eq) of 1,1′-azobis (cyclohexane-1-carbonitrile) (V-40) was added. (Total amount used 0.03 eq). The conversion rate of the reaction completed liquid was 92% from ¹⁹ F-NMR. The reaction finished solution was cooled to room temperature, and 20.0 kg (81.2 mol, 0.10 eq) of diallyl phthalate was added to treat the oxidizing substance. The succinimide in the treatment liquid is filtered, washed with 30 L of α, α, α-trifluorotoluene (BTF), and the filtrate is directly subjected to simple distillation (flash distillation) to obtain the following formula.

As a result, 341 kg of an α, α, α-trifluorotoluene (BTF) solution containing methyl 2-bromo-2-fluoropropionate represented by the formula (1) was obtained. The content of methyl 2-bromo-2-fluoropropionate contained in the α, α, α-trifluorotoluene (BTF) solution was 115 kg (620 mol) from ¹⁹ F-NMR (quantitative determination by internal standard method). The yield was 77%.

  The total amount (341 kg) of the α, α, α-trifluorotoluene (BTF) solution containing methyl 2-bromo-2-fluoropropionate obtained above was fractionally distilled (theoretical plate number 30, boiling point 71 ° C., degree of vacuum 9). .1 kPa, reflux ratio 2: 1) to obtain 103 kg of the main distillation. The recovery rate was 90%. The main chromatography had a gas chromatography purity of 99.9%. Unreacted methyl (R) -2-fluoropropionate and the reaction solvent α, α, α-trifluorotoluene (BTF) can be recovered in a good yield in the form of a mixture as the first fraction of fractional distillation. Can be reused after drying with molecular sieves.

The ¹ H-NMR and ¹⁹ F-NMR of methyl 2-bromo-2-fluoropropionate are shown below.

¹ H-NMR [reference material; (CH ₃ ) ₄ Si, deuterated solvent; CDCl ₃ ], δ ppm; 2.27 (d, 19.6 Hz, 3H), 3.90 (s, 3H).

¹⁹ F-NMR (reference material; C ₆ F ₆ , deuterated solvent; CDCl ₃ ), δ ppm; 53.34 (q, 19.3 Hz, 1F).

  The methyl (R) -2-fluoropropionate which is the raw material substrate of Reference Example 1 is similarly described with reference to JP-A-2005-236405, JP-A-2007-212495, JP-A-2008-191444, and the like. Can be manufactured. Of course, a racemic body can be similarly used instead of an optically active body.

[Reference Example 2]
Under a nitrogen atmosphere, 45.7 g (1.20 mol, 0.580 eq) of lithium aluminum hydride was added to 1.80 L (0.870 L / mol) of tetrahydrofuran, and the mixture was stirred under ice cooling. In this heterogeneous solution,

A tetrahydrofuran solution (solvent use amount: 300 mL) of 257 g (2.07 mol, 1.00 eq) of α, α-difluoroesters represented by the above was added under ice-cooling and stirred at room temperature overnight. The conversion rate was 100% from ¹⁹ F-NMR analysis of the reaction completed liquid. To the reaction end solution, 220 g (12.2 mol, 5.89 eq) of water in tetrahydrofuran (solvent usage amount: 220 mL) was added under ice cooling, the temperature was gradually raised to 60 ° C., and the mixture was stirred at the same temperature for 3 hours (hanging). Cloudy solution). This suspension solution was filtered through Celite and washed with 300 mL of tetrahydrofuran to obtain the following formula.

2.40 kg of a tetrahydrofuran solution containing β, β-difluoroalcohol represented by the following formula was obtained. The tetrahydrofuran solution was quantified by ¹⁹ F-NMR internal standard method (internal standard substance α, α, α-trifluorotoluene) and found to contain 1.66 mol of the desired compound. The water content was 5.1% from Karl Fischer analysis of the tetrahydrofuran solution.

To the tetrahydrofuran solution obtained above, 630 mL of tetrahydrofuran is added and subjected to azeotropic dehydration by atmospheric distillation (distillation temperature to 66 ° C.), followed by recovery distillation (degree of vacuum to 16 kPa, distillation temperature to 64 ° C. ) To obtain 693 g of a crude product of β, β-difluoroalcohols represented by the above formula (including a considerable amount of tetrahydrofuran). When the crude product was quantified by ¹⁹ F-NMR internal standard method (internal standard substance α, α, α-trifluorotoluene), 1.59 mol of the desired compound was contained and the yield was 77%. there were. The water content was 1.6% from Karl Fischer analysis of the crude product.

  By subjecting the crude product obtained above to fractional distillation (theoretical plate number: 30, vacuum degree: 32 kPa, distillation temperature: 72 ° C.), 129 g of a purified product of β, β-difluoroalcohol represented by the above formula was obtained. . The recovery rate was 84%, and the total yield was 65%. The purified product had a gas chromatography purity of 99.9% or more. The purified product had a water content of 950 ppm by Karl Fischer analysis.

¹ H-NMR and ¹⁹ F-NMR of β, β-difluoroalcohols are shown below.

¹ H-NMR [reference material; (CH ₃ ) ₄ Si, deuterated solvent; CDCl ₃ ], δ ppm; 1.65 (t, 3H), 2,45 (br, 1H), 3.72 (t, 2H ).

¹⁹ F-NMR (reference material; C ₆ F ₆ , heavy solvent; CDCl ₃ ), δ ppm; 61.97 (m, 2F).

  Thus, the α, α-difluoroesters that are the object of the present invention can be converted into β, β-difluoroalcohols that are extremely important as intermediates for pharmaceuticals and agricultural chemicals.

  The α, α-difluoroesters targeted in the present invention are important as intermediates for medicines and agricultural chemicals.

Claims (4)

General formula [5]

[Wherein, Me represents a methyl group, and R ⁶ represents a methyl group, an ethyl group, or a propyl group. ]
The α-halogeno-α- fluoroester represented by the formula (1) is reacted with “a salt or complex composed of 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) and hydrogen fluoride (HF)”. Therefore, the general formula [6]

[Wherein, Me and R ⁶ are the same as above. ]
A method for producing an α, α-difluoroester represented by the formula: The molar ratio of 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) to hydrogen fluoride (HF) is in the range of 1: 2.0 to 2.5, The manufacturing method of (alpha), (alpha)-difluoroester of Claim 1 . Byproducts α- fluoro-.alpha., beta-unsaturated ester after polymerization treatment, the desired product alpha, and recovering the α- difluoro esters, according to claim 1 or 2 alpha, A method for producing α-difluoroesters. 3. The target α, α-difluoroester is recovered after Michael addition reaction of the byproduct α-fluoro-α, β-unsaturated ester, according to claim 1 or 2 . A method for producing α, α-difluoroesters.