JP5347591B2 - Method for producing fluorine-containing epoxy ester - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for producing a fluorine-containing epoxy ester represented by general formula [2] in high yield under an industrially feasible easy reaction condition by using an inexpensive raw material while considerably suppressing the formation of byproducts. <P>SOLUTION: The method for producing the fluorine-containing epoxy ester represented by general formula [2] includes reacting fluorine-containing &alpha;,&beta;-unsaturated ester represented by general formula [1] and having a plurality of fluorine atoms with an oxidizing agent such as hypochlorous acid and hypochlorite. In the formulas [1] and [2], Rf is a substituent selected from 1-10C linear or branched perfluoroalkyl group, (CF<SB>3</SB>)<SB>2</SB>CH group, CHF<SB>2</SB>group, and CClF<SB>2</SB>group. The fluorine-containing epoxy ester can be produced in high productivity without environmental loading because the reaction proceeds well even in an absent condition of a catalyst. <P>COPYRIGHT: (C)2010,JPO&amp;INPIT

Description

  The present invention relates to a method for producing a fluorine-containing epoxy ester that is useful as an intermediate for pharmaceuticals or agricultural chemicals.

  Epoxy esters having fluorine-containing alkyl groups are highly versatile substances that can be derived from various physiologically active substances. For example, Non-Patent Document 1 and Non-Patent Document 2 report many application examples of epoxy esters such as an example in which epoxy is reduced to be converted into a physiologically active alcohol.

  As conventional examples of deriving a compound having a double bond site (olefin compound) to an epoxy compound, Non-patent Document 3 and Non-patent Document 4 include reactions using a peracid and reactions in which a hypohalide is reacted. It has been.

  On the other hand, in Patent Document 1, a method of reacting sodium hypochlorite with an olefin is used. In Patent Document 2, hypochlorous acid dissolved or suspended in an aqueous phase is used as an oxidizing agent, and an inorganic base is used. In epoxidizing a fluoroallyl compound in the presence or absence, a method of reacting in a two-phase system of an aqueous phase and an organic phase in the presence of a phase transfer catalyst such as a quaternary ammonium salt is disclosed in Patent Document 3, A method of reacting an α, β-unsaturated ketone with an oxidizing agent such as hypochlorite in the presence of a quaternary ammonium salt and water is disclosed in Patent Document 4 as a method for producing an optically active epoxy enone derivative. As a catalyst for α, β-unsaturated ketone, lanthanide triisopropoxide, (R) -1,1-bi-2-naphthol, triphenylphosphine oxide, and cumene hydroperoxide or How to asymmetric oxidation using a catalyst consisting of tert- butyl hydroperoxide is known.

  In Non-Patent Document 5 and Non-Patent Document 6, a method of oxidizing α, β-unsaturated ketone or olefin compound using silica or alumina as a catalyst and sodium hypochlorite is used. A method of oxidizing using nickel hypochlorite using nickel as a catalyst, and in Non-Patent Document 8, quaternary ammonium is used as a phase transfer catalyst when sodium hypochlorite is reacted with a fluoroolefin compound. The use of salts is disclosed.

  Moreover, as a synthesis example of the epoxy ester having these alkyl groups, Non-Patent Documents 9-10 disclose a method of synthesizing via cyclization using alkyl lithium or the like.

JP-A-4-108780 Japanese Patent Application Laid-Open No. 60-069077 JP-A-11-092466 JP 2004-137265 A

Tetrahedron, 52, 14631-14640, 1996. Tetrahedron Lett. 36, 2491-2492, 1995. Organic Functional Group Preparations, 110-111, 1968. Organic Functional Group Preparations, 110-111, 1968. Synthesis, 854-856, 1987. Synthesis, 787-789, 1990. J. et al. Org. Chem. 71, 9291-9296, 2006. J. et al. Fluorine Chem. , 125, 99-105, 2004. J. et al. Fluorine Chem. 44, 113-120, 1989. Tetrahedron Lett. , 34, 2469-2472, 1993.

  The methods of Non-Patent Document 3 and Non-Patent Document 4 use peracid, which is a very strong oxidant, requires very careful handling, and the post-treatment is complicated, waste is large, and the scale is large. It is somewhat difficult to adopt as a manufacturing method on an industrial scale because it is not suitable for production in Japan.

  The method of Non-Patent Document 9-10 is a method using alkyllithium and the like. Usually, since a reaction using alkyllithium or the like requires a cryogenic reactor at −78 ° C., it is industrially easy and safe. It is very difficult to produce.

  In addition, since the oxidation reaction is exothermic, it is intended to perform so-called “partial oxidation” in which only a specific site (for example, α, β-unsaturated ketone indicates an olefin site) is oxidized. However, the reaction temperature rises due to self-generated heat, and the reaction is often accelerated, and problems such as not only selective oxidation of double bonds but also unintended side reactions are likely to occur.

  Also, complete oxidation is often caused, such as the formation of carbon dioxide and water. Therefore, it is generally difficult to selectively oxidize a desired site by controlling heat generation.

  As described above, all known methods for producing fluorine-containing epoxy esters that are useful as intermediates for pharmaceuticals or agricultural chemicals are suitable for obtaining a target product on a small scale, but are sufficient as a large-scale production method. It was not satisfactory.

  An object of the present invention is to efficiently synthesize useful epoxy esters from fluorine-containing α, β-unsaturated esters having good availability. That is, it is an object to avoid a cryogenic process that is not suitable for mass production and to selectively perform partial oxidation by controlling an exothermic oxidation reaction.

  As a result of intensive studies, the present inventors have made it possible to selectively form a double bond site by reacting a fluorine-containing α, β-unsaturated ester with an oxidizing agent such as hypochlorous acid or hypochlorite. Oxidized and found that the corresponding fluorine-containing epoxy ester can be synthesized with high selectivity and high yield, and the present invention has been completed.

That is, the invention described in [Invention 1]-[Invention 4] below is provided.
[Invention 1]
Fluorine-containing α, β-unsaturated ester represented by the formula [1]

And a fluorine-containing epoxy ester represented by the formula [2], characterized by reacting with an oxidizing agent

Manufacturing method.
[In the formulas [1] and [2], Rf is selected from the group consisting of a linear or branched perfluoroalkyl group having 1 to 10 carbon atoms, a (CF ₃ ) ₂ CH group, a CHF ₂ group, and a CClF ₂ group. R is a hydrogen atom or a linear or branched alkyl group having 1 to 9 carbon atoms, phenyl group, benzyl group, p-methoxyphenylmethyl group, methoxymethyl group, trimethylsilyl group, triethylsilyl group , A substituent selected from the group consisting of t-butyldimethylsilyl groups. ]
[Invention 2]
The method according to invention 1, wherein the oxidizing agent is hypochlorous acid or hypochlorite.
[Invention 3]
Fluorine-containing α, β-unsaturated ester represented by the formula [1]

And fluorine-containing epoxy ester represented by the formula [2], wherein hypochlorous acid or hypochlorite is reacted with

Manufacturing method.
[In the formula [1] and formula [2], Rf is selected from the group consisting of a linear or branched perfluoroalkyl group having 1 to 6 carbon atoms, a (CF ₃ ) ₂ CH group, a CHF ₂ group, and a CClF ₂ group. R is a hydrogen atom or a linear or branched alkyl group having 1 to 9 carbon atoms, phenyl group, benzyl group, p-methoxyphenylmethyl group, methoxymethyl group, trimethylsilyl group, triethylsilyl group , A substituent selected from the group consisting of t-butyldimethylsilyl groups. ]
[Invention 4]
4. The method according to any one of inventions 1 to 3, wherein the reaction is carried out under conditions in which no catalyst coexists in the system.

  The present invention is characterized in that an oxidation reaction is performed using a fluorine-containing α, β-unsaturated ester represented by the formula [1]. The ester has a carbon-carbon double bond (also referred to as “olefin”) moiety and a carbonyl moiety. Furthermore, a perfluoroalkyl group having a plurality of fluorine atoms, which are very strong electron withdrawing groups, is bonded to the carbon-carbon double bond site.

  As disclosed in Patent Document 2, in general, epoxidation of a fluoroolefin exhibits a very different chemical property compared to a hydrocarbon-based olefin such as propylene. It is known that it is very difficult to epoxidize electrophilically in the same manner as described above. From this, since the substrate used in the present invention has a plurality of fluorine atoms, it is expected that the substrate exhibits different reactivity as compared with a substrate having no fluorine atoms.

  In addition, since the epoxidation of α, β-unsaturated esters disclosed in the prior art is directed to a substrate having no fluorine atom, etc., even if an oxidation reaction is performed using the substrate of the present invention, It was completely unknown whether the compound could be obtained well.

  Therefore, the present inventors perform high oxidation selectivity by performing an oxidation reaction using hypochlorous acid or hypochlorite using the fluorine-containing α, β-unsaturated ester represented by the formula [1]. And it came to discover that the fluorine-containing epoxy ester represented by Formula [2] was obtained with a high yield.

  Further, in the present invention, even if the reaction is carried out under particularly preferable conditions, that is, the conditions in which the catalyst does not coexist in the reaction system, the target product can be obtained with a selectivity and yield equivalent to or higher than those of the prior art. We have obtained extremely useful knowledge in industrial production.

  The prior art discloses a method of obtaining a corresponding epoxy compound by reacting a hypochlorite with an α, β-unsaturated ketone compound having no fluorine atom. Further, it is also disclosed that a catalyst such as a quaternary ammonium salt or alumina coexists as a catalyst.

  On the other hand, as disclosed in Patent Document 2, a quaternary ammonium salt such as tri-n-octylmethylammonium chloride is added to the olefin compound having a fluorine atom at the carbon-carbon double bond site in the reaction system. There is a description that when the reaction is carried out under conditions that do not coexist with the above, the production of the corresponding epoxy compound is a trace amount.

  From this, the oxidation reaction of the compound represented by the formula [1], in which a plurality of fluorine atoms are introduced into a fluorine-containing α, β-unsaturated ester, which is clearly lower in reactivity than α, β-unsaturated ketones. When performing the reaction, it is natural to expect that a catalyst such as a quaternary ammonium salt is preferably present in the reaction system, and the reaction is actually good when the reaction is performed under conditions where the catalyst is not present. It was completely unclear whether or not to proceed.

  However, when the present inventor conducted an oxidation reaction on the fluorine-containing α, β-unsaturated ester represented by the formula [1], a catalyst such as a quaternary ammonium salt was not allowed to coexist in the reaction system. However, the inventors have obtained a surprising finding that the reaction has proceeded sufficiently and the target product can be obtained with high selectivity and high yield.

  As described above, the present invention can produce the target compound under easy reaction conditions that can be carried out industrially, and the reaction proceeds well even under conditions where no catalyst coexists. The desired fluorine-containing epoxy ester can be produced in terms of productivity.

  Using fluorine-containing α, β-unsaturated esters that are inexpensive and easily available and relatively easy to handle as starting materials, it is possible to selectively produce fluorine-containing epoxy esters that are important as intermediates for pharmaceuticals and agricultural chemicals. There is an effect.

  Hereinafter, the present invention will be described in detail. The present invention is a method for producing a fluorine-containing epoxy ester represented by the formula [2], characterized by reacting a fluorine-containing α, β-unsaturated ester represented by the formula [1] with an oxidizing agent. is there. The fluorine-containing α, β-unsaturated ester represented by the formula [1], which is a starting material of the present invention, is a known compound in the literature, for example, by the method described in JP-A-2005-232096, Those skilled in the art can manufacture. In addition, the manufacturing method of a starting material is not limited to this patent document.

Among the fluorine-containing α, β-unsaturated esters represented by the formula [1], Rf is a linear or branched perfluoroalkyl group having 1 to 10 carbon atoms, (CF ₃ ) ₂ CH group, CHF ₂ group, CClF ₂ group. Examples of the perfluoroalkyl group include straight-chain or branched chain groups having 1 to 10 carbon atoms, and among these, straight-chain or branched chain groups having 1 to 6 carbon atoms are preferable.

  Since R is also a protecting group for the ester moiety, any commonly used carboxylic acid protecting group can be used for efficient protection and deprotection. For example, R is a hydrogen atom, or a linear or branched alkyl group having 1 to 9 carbon atoms, phenyl group, benzyl group, p-methoxyphenylmethyl group, methoxymethyl group, trimethylsilyl group, triethylsilyl group, t-butyl. Examples thereof include a substituent selected from the group consisting of dimethylsilyl groups.

  Examples of the oxidizing agent used in the present invention include hypochlorous acid or hypochlorite. Of these, alkali metal salts such as potassium hypochlorite and sodium hypochlorite are preferably used as the hypochlorite. The usage-amount of hypochlorous acid or hypochlorite is 0.05 mol-100 mol normally with respect to 1 mol of (alpha), (beta)-unsaturated ester, Preferably it is the range of 1-50 mol.

  Hypochlorous acid or hypochlorite which is an oxidizing agent is easy to use as an aqueous solution thereof. The amount of water is not particularly limited and can be appropriately adjusted by those skilled in the art.

When water is present in the reaction system, hypochlorous acid (HOCl) can also be generated in the reaction system by blowing chlorine (Cl ₂ ) as shown in the following scheme. If a base such as sodium hydroxide (NaOH) aqueous solution or potassium hydroxide (KOH) aqueous solution is present, sodium hypochlorite (NaOCl) and potassium hypochlorite (KOCl) are substantially generated. Then, the reaction of the present invention proceeds. This reaction can also be carried out under basic conditions, but if the basic stability of the raw material fluorine-containing α, β-unsaturated ester is low, dilute hydrochloric acid or the like is added to make the pH weakly alkaline, In general, the pH can be controlled to about 8 to 10.

  In the present invention, it is a simple method to use water as a solvent, but an organic solvent other than water can be used. The organic solvent here refers to an inert organic compound that does not directly participate in the reaction of the present invention. Further, those having excellent compatibility between the fluorine-containing α, β-unsaturated ester and the hypochlorite aqueous solution and strong base resistance are preferred.

  Specifically, water-soluble solvents such as ethers such as diethyl ether, dioxane, tetrahydrofuran and ethylene glycol dimethyl ether, ketones such as acetone, methyl ethyl ketone and methyl isobutyl ketone, and nitriles such as acetonitrile and propionitrile are used. Among them, nitriles such as acetonitrile are preferable, and acetonitrile is particularly preferable because of excellent compatibility between the fluorine-containing α, β-unsaturated ester and the hypochlorite aqueous solution and strong base resistance.

  Although there is no restriction | limiting in particular as the usage-amount of an organic solvent, What is necessary is just to use 0.1L (liter) or more with respect to 1 mol of fluorine-containing alpha, beta-unsaturated ester represented by Formula [1], and is normal. Is preferably 0.1 to 20 L, more preferably 0.1 to 10 L. In addition, these organic solvents can be used individually or in combination.

  In the present invention, a catalyst can be separately added to the reaction system in order to increase the compatibility.

  As specific examples of the catalyst, metal oxide, metal halide, activated carbon, and zeolite are preferably used. As the metal oxide, magnesium, aluminum, silicon, titanium, vanadium, chromium, manganese, iron, cobalt, nickel, copper, zinc, zirconium, niobium, molybdenum, tin, antimony, and tungsten oxides are preferable, and alumina, Silica, magnesia and titania are particularly preferred. As the metal halide, a metal fluoride, a metal chlorinated product, a metal brominated product, and a metal iodinated product can be used, and a metal chlorinated product is preferable. As metal species of the metal halide, magnesium, aluminum, silicon, titanium, vanadium, chromium, manganese, iron, cobalt, nickel, copper, zinc, zirconium, niobium, molybdenum, tin, antimony, and tungsten are preferable. Aluminum is more preferable. In addition, zinc chloride, iron chloride, and aluminum chloride are particularly preferable as these metal halides. Further, as the activated carbon or zeolite, activated carbon having a large specific surface area or zeolite which is a composite metal oxide can be used. A catalyst in which the above metal species are supported on activated carbon, zeolite, silica, alumina or the like generally used as a catalyst carrier can also be used.

  In addition, a phase transfer catalyst such as a quaternary ammonium salt or a quaternary phosphonium salt can be added for efficient contact with the fluorine-containing α, β-unsaturated ester represented by the formula [1]. It is. For example, quaternary ammonium salts include tetramethylammonium fluoride, tetramethylammonium chloride, tetramethylammonium bromide, tetramethylammonium iodide, tetraethylammonium fluoride, tetraethylammonium chloride, tetraethylammonium bromide, tetraethylammonium iodide, tetrapropyl. Ammonium fluoride, tetrapropylammonium chloride, tetrapropylammonium bromide, tetrapropylammonium iodide, tetrabutylammonium fluoride, tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium iodide, tri-n-octylmethylammonium fluoride And tri-n-octylmethyl Ammonium chloride, tri-n-octylmethylammonium bromide, tri-n-octylmethylammonium iodide, benzyltrimethylammonium fluoride, benzyltrimethylammonium chloride, benzyltrimethylammonium bromide, benzyltrimethylammonium iodide, benzyltriethylammonium fluoride, Examples thereof include benzyltriethylammonium chloride, benzyltriethylammonium bromide, and benzyltriethylammonium iodide.

  On the other hand, quaternary phosphonium salts include tetraphenylphosphonium fluoride, tetraphenylphosphonium chloride, tetraphenylphosphonium bromide, tetraphenylphosphonium iodide, tetrabutylphosphonium fluoride, tetrabutylphosphonium chloride, tetrabutylphosphonium bromide, tetrabutylphosphonium. Iodide, butyltriphenylphosphonium fluoride, butyltriphenylphosphonium chloride, butyltriphenylphosphonium bromide, butyltriphenylphosphonium iodide, trioctylethylphosphonium fluoride, trioctylethylphosphonium chloride, trioctylethylphosphonium bromide, trioctyl Ethylphosphonium iodide, benzyltriphenylphos Nitrofluoride, benzyltriphenylphosphonium chloride, benzyltriphenylphosphonium bromide, benzyltriphenylphosphonium iodide, ethyltriphenylphosphonium fluoride, ethyltriphenylphosphonium chloride, ethyltriphenylphosphonium bromide, ethyltriphenylphosphonium iodide, etc. Can be mentioned.

  The amount of the catalyst used is usually 0.1 to 50 mol%, preferably 1 to 25 mol%, based on 1 mol of the fluorine-containing α, β-unsaturated ester represented by the formula [1]. More preferably, it is 1-15 mol%.

  In the present invention, the reaction proceeds even when the above-described catalyst is used, but a favorable finding that the reaction proceeds satisfactorily even under the condition where the catalyst does not coexist in the reaction system was obtained.

  In the present specification, “does not coexist with the catalyst” means that these catalysts are not substantially present in the system. Specifically, the fluorine-containing α, β represented by the formula [1] -0.05 mol% or less with respect to 1 mol of unsaturated esters, Preferably it is 0.01 mol% or less, More preferably, it means the quantity of 0.001 mol% or less. As long as the reaction is carried out without positively adding these catalysts into the system, it is easy to achieve the condition that the catalysts do not coexist.

  Although the reaction of the present invention involves an oxidation reaction, since the oxidation reaction is generally an exothermic reaction, the reaction temperature rises frequently due to its own reaction heat, and a rapid oxidation reaction often occurs. In fact, in the case of industrial large scale, heat generation control is an important management item in terms of selectivity and safety. The notable point of the present invention is that it proceeds gently and selectively near room temperature. Therefore, the reaction temperature is preferably −50 ° C. to 150 ° C., particularly preferably 0 ° C. to 80 ° C. When the reaction temperature is lower than −50 ° C., the reaction rate may decrease and a problem such as a long time may be required until the completion of the reaction. When the reaction temperature exceeds 150 ° C., the oxidation reaction rapidly proceeds and partial oxidation occurs. By-products are likely to occur.

  The pressure condition is not particularly limited, but may be performed, for example, in the range of normal pressure (0.1 MPa (absolute pressure reference, hereinafter the same)) to 2 MPa. In this case, 0.1 MPa to 1.5 MPa is preferable. In particular, 0.1 MPa to 1 MPa is more preferable.

  The reactor used in this step can perform the reaction at normal pressure or under pressure. When the reaction is performed under pressure, the material is not particularly limited as long as it can withstand the pressure, and a reaction in which tetrafluoroethylene resin, chlorotrifluoroethylene resin, vinylidene fluoride resin, PFA resin, glass, etc. are lined inside. A glass container or a glass container can be used.

  As the reaction mode, both a flow type and a batch type can be used, but the batch type is simple. As an example of the reaction form, it is possible to charge all raw materials at once, but after adding a solvent, a catalyst, a fluorine-containing α, β-unsaturated ester in advance and stirring, hypochlorite Aqueous solutions can also be added sequentially. Of course, chlorine gas can be bubbled instead of the hypochlorite aqueous solution. If desired, a solvent, a hypochlorite aqueous solution, and a catalyst can be charged in advance, and the fluorine-containing α, β-unsaturated ester can be sequentially added.

  The reaction time is not particularly limited, but usually it may be performed within a range of 24 hours. Since it varies depending on various reactants and reaction conditions, the progress of the reaction by means of analysis such as gas chromatography, liquid chromatography, NMR, etc. It is preferable to set the end point when the raw material substrate is almost disappeared.

  The post-treatment method is not particularly limited, and the reaction product after completion of the reaction may be treated based on a usual organic synthesis treatment method (extraction, distillation, dehydration, etc.). The epoxy ester which is a target object can be obtained by a normal means.

  In addition to the fluorine-containing epoxy ester represented by the formula [2], which is the target product, a trace amount of carboxylic acid obtained by hydrolysis of the target product may be generated in the reaction system. At that time, the by-product can be removed by a simple operation (washing with water or a basic aqueous solution). For example, as shown in this Example, the operation of adding a saturated aqueous sodium hydrogen carbonate solution and washing improves the chemical purity of the fluorine-containing epoxy ester represented by the formula [2], which is the target product. It is mentioned as one of the preferable embodiments.

The present invention will be described in more detail with reference to examples below, but the present invention is not limited thereto.
[Example 1]
[Production of benzyl 2,3-epoxy-4,4,4-trifluorobutyrate]

Acetonitrile containing (E) -benzyl 4,4,4-trifluorobut-2-enoate (11.51 g, 50.0 mmol) and chlorite (ZnCl ₂ ) catalyst (1.33 g, 10 mmol) in a 300 mL three-necked glass flask (150 mL) To the solution was added 10.2% sodium hypochlorite aqueous solution (54.79 g, 75 mmol), and the mixture was stirred at room temperature for 9 hours. As a result, benzyl 2,3-epoxy-4,4,4-trifluorobutyrate Generation was confirmed. After filtration, the yield was determined by ¹⁹ F-NMR and found to be 64%.
¹ H NMR (reference material: TMS, solvent: CDCl ₃ ) δ (ppm): 3.74 (2H, m), 5.21 (1H, d, J = 12.3 Hz), 5.28 (1H, d, J = 12.3 Hz), 7.39-7.40 (5H, m).
¹⁹ F NMR (reference substance: CFCl ₃ , solvent: CDCl ₃ ) δ (ppm): -75.13 (d, J = 4.5 Hz).
¹³ C NMR (reference material: TMS, solvent: CDCl ₃ ) δ (ppm): 49.5 (q, J = 2.5 Hz), 52.8 (q, J = 42.2 Hz), 68.1, 121.4 (q, J = 275.4 Hz) , 128.6, 128.7, 128.9, 134.3, 165.6.
IR (neat) ν 3944, 3689, 3054, 2987, 2685, 2306, 1756, 1456, 1422, 1382, 1341, 1265, 1169, 1089, 988, 929, 896, 664 cm ^-1 .
Anal. Calcd for C ₁₁ H ₉ F ₃ O ₃ : C, 53.67; H, 3.68. Found: C, 53.54; H, 3.89.
[Example 2-4]
[Production of benzyl 2,3-epoxy-4,4,4-trifluorobutyrate]
Conducted using alumina (Al ₂ O ₃ ) catalyst (10 mmol), silica (SiO ₂ ) catalyst (10 mmol), and magnesia (MgO) catalyst (10 mmol) instead of chloride (ZnCl ₂ ) catalyst (10 mmol) The same experiment as in Example 1 was performed. The results are shown in Table 1.

[Example 5]
[Production of benzyl 2,3-epoxy-4,4,4-trifluorobutyrate]
Acetonitrile containing (E) -benzyl 4,4,4-trifluorobut-2-enoate (11.51 g, 50.0 mmol) and chlorite (ZnCl ₂ ) catalyst (1.33 g, 10 mmol) in a 300 mL three-necked glass flask To the (150 mL) solution was added 10.2% aqueous sodium hypochlorite solution (73.05 g, 100 mmol), and the mixture was stirred at room temperature for 9 hours. After filtration, extraction with methylene chloride (CH ₂ Cl ₂ ), washing with saturated aqueous sodium bicarbonate (NaHCO ₃ ) solution to remove by-product carboxylic acid, and drying with sodium sulfate (Na ₂ SO ₄ ) And concentrated. By-products were removed from the resulting crude product by distillation to obtain benzyl 2,3-epoxy-4,4,4-trifluorobutyrate in an isolated yield of 85%.
[Example 6]
[ Production of benzyl 2,3-epoxy-4,4,4-trifluorobutyrate ]
In a 10 mL three-necked glass flask, an acetonitrile (4.5 mL) solution containing (E) -benzyl 4,4,4-trifluorobut-2-enoate (0.233 g, 1.01 mmol) was added to an aqueous sodium hypochlorite solution (5%; 2.233 g, 1.50 mmol) was added, and the mixture was stirred at room temperature (25 ° C.) for 1 hour. After filtration, extraction with methylene chloride (CH ₂ Cl ₂ ), washing with saturated aqueous sodium bicarbonate (NaHCO ₃ ) solution to remove by-product carboxylic acid, and drying with sodium sulfate (Na ₂ SO ₄ ) And concentrated to obtain 77% NMR yield of benzyl 2,3-epoxy-4,4,4-trifluorobutyrate.
[Example 7]
[ Production of benzyl 2,3-epoxy-4,4,5,5,5-pentafluoropentanoate ]

In a 10 mL three-necked glass flask, (E) -benzyl 4,4,5,5,5-pentafluoropent-2-enoate (0.084 g, 0.30 mmol) and chlorite (ZnCl ₂ ) catalyst (0.01 g, 0.070 mmol) 5% Aqueous sodium hypochlorite solution (0.91 g, 0.61 mmol) was added to the acetonitrile solution (1.80 mL) added, and the mixture was stirred at room temperature for 4.5 hours. After filtration, extraction with methylene chloride (CH ₂ Cl ₂ ), washing with saturated aqueous sodium bicarbonate (NaHCO ₃ ) solution to remove by-product carboxylic acid, and drying with sodium sulfate (Na ₂ SO ₄ ) And concentrated. As a result, benzyl 2,3-epoxy-4,4,5,5,5-pentafluoropentanoate was obtained with a ¹⁹ F-NMR yield of 49%.
¹ H NMR (reference material: TMS, solvent: CDCl ₃ ) δ (ppm): 3.73 (2H, m), 5.22 (1H, d, J = 12.0 Hz), 5.29 (1H, d, J = 12.0 Hz), 7.34-7.40 (5H, m).
¹⁹ F NMR (reference substance: CFCl ₃ , solvent: CDCl ₃ ) δ (ppm): -85.23 (3F, s), -127.13 (1F, dd, J = 7.1, 275.9 Hz), -129.05 (1F, dd, J = 11.5, 276.0 Hz).
¹³ C NMR (reference material: TMS, solvent: CDCl ₃ ) δ (ppm): 48.6 (dd, J = 1.9, 5.0 Hz), 51.7 (dd, J = 26.0, 32.2 Hz), 68.2, 110.2 (qdd, J = 38.7, 254.3, 257.4 Hz), 118.5 (tq, J = 35.0, 286.0 Hz), 128.6, 128.7, 128.9, 134.2, 165.7.
IR (neat) ν 3069, 3037, 2962, 1758, 1457, 1357, 1327, 1287, 1200, 1149, 1044, 974, 923, 833, 745, 698 cm ^-1 .
[Example 8]
[ Production of benzyl 2,3-epoxy-4,4-difluorobutanoate ]

Acetonitrile (3.015 g, 0.10 mmol) with (E) -benzyl 4,4-difluorobut-2-enoate (0.105 g, 0.50 mmol) and chlorite (ZnCl ₂ ) catalyst (0.015 g, 0.10 mmol) added to a 10 mL three-necked glass flask To the solution was added 5% aqueous sodium hypochlorite solution (1.49 g, 1.00 mmol), and the mixture was stirred at room temperature for 4 hours. After filtration, extraction with methylene chloride (CH ₂ Cl ₂ ), washing with saturated aqueous sodium bicarbonate (NaHCO ₃ ) solution to remove by-product carboxylic acid, and drying with sodium sulfate (Na ₂ SO ₄ ) And concentrated. By removing by-products from the resulting crude product by distillation, benzyl 2,3-epoxy-4,4-difluorobutanoate was thereby obtained in a ¹⁹ F-NMR yield of 71%.
¹ H NMR (reference material: TMS, solvent: CDCl ₃ ) δ (ppm): 3.56 (1H, dddd, J = 1.8, 3.6, 6.3, 7.2 Hz), 3.64 (1H, m), 5.19 (1H, d, J = 12.0 Hz), 5.25 (1H, d, J = 12.0 Hz), 5.68 (1H, dt, J = 3.6, 54.7 Hz), 7.39 (5H, m).
¹⁹ F NMR (reference substance: CFCl ₃ , solvent: CDCl ₃ ) δ (ppm): -125.04 (1F, ddd, J = 6.8, 54.8, 303.3 Hz), -126.91 (1F, ddd, J = 6.8, 54.8, 303.3 Hz).
¹³ C NMR (reference material: TMS, solvent: CDCl ₃ ) δ (ppm): 49.2 (t, J = 4.4 Hz), 54.4 (t, J = 32.6 Hz), 67.9, 112.3 (t, J = 242.6 Hz) , 128.6, 128.7, 128.8, 134.4, 166.6.
IR (neat) ν 3067, 3036, 2964, 1753, 1456, 1389, 1321, 1295, 1243, 1200, 1146, 1107, 1065, 1001, 910, 753, 698 cm ^-1 .
[Example 9]
[ Production of benzyl 4-chloro-2,3-epoxy-4,4-difluorobutanoate ]

To a 10 mL three-necked glass flask, add (E) -benzyl 4-chloro-4,4-difluorobut-2-enoate (0.125 g, 0.51 mmol) and chlorite (ZnCl ₂ ) catalyst (0.015 g, 0.10 mmol) To a solution of acetonitrile (3.0 mL) was added 5% aqueous sodium hypochlorite solution (1.49 g, 1.00 mmol), and the mixture was stirred at room temperature for 8.5 hours. After filtration, extraction with methylene chloride (CH ₂ Cl ₂ ), washing with saturated aqueous sodium bicarbonate (NaHCO ₃ ) solution to remove by-product carboxylic acid, and drying with sodium sulfate (Na ₂ SO ₄ ) And concentrated. By removing by-products from the resulting crude product by distillation, benzyl 4-chloro-2,3-epoxy-4,4-difluorobutanoate was obtained in a ¹⁹ F-NMR yield of 55%. .
¹ H NMR (reference material: TMS, solvent: CDCl ₃ ) δ (ppm): 3.76 (1H, dd, J = 0.3, 1.2 Hz), 3.85 (1H, dt, J = 1.4, 6.6 Hz), 5.19 (1H , d, J = 12.3 Hz), 5.26 (1H, d, J = 12.0 Hz), 7.39 (5H, m).
¹⁹ F NMR (reference substance: CFCl ₃ , solvent: CDCl ₃ ) δ (ppm): -63.2 (dd, J = 6.8, 168.7 Hz), -65.23 (dd, J = 6.8, 168.7 Hz).
¹³ C NMR (reference material: TMS, solvent: CDCl ₃ ) δ (ppm): 50.6 (dd, J = 1.8, 3.1 Hz), 57.6 (dd, J = 34.1, 36.0 Hz), 68.1, 123.8 (t, J = 291.5 Hz), 128.6, 128.7, 128.9, 134.2, 165.7.
IR (neat) ν 3490, 3068, 3036, 2960, 1956, 1756, 1456, 1380, 1330, 1291, 1197, 1127, 1042, 983, 924, 752, 698, 608 cm ^-1 .
[Example 10]
[ Production of benzyl 4-chloro-2,3-epoxy-4,4-difluorobutanoate ]
In a 10 mL three-necked glass flask, add (E) -benzyl 4-chloro-4,4-difluorobut-2-enoate (0.124 g, 0.50 mmol) to an acetonitrile (3.0 mL) solution, and add 5% hypochlorous acid. A sodium aqueous solution (1.49 g, 1.00 mmol) was added, and the mixture was stirred at room temperature for 1.5 hours. After filtration, extraction with methylene chloride (CH ₂ Cl ₂ ), washing with saturated aqueous sodium bicarbonate (NaHCO ₃ ) solution to remove by-product carboxylic acid, and drying with sodium sulfate (Na ₂ SO ₄ ) After drying, it concentrated. By removing by-products from the resulting crude product by distillation, benzyl 4-chloro-2,3-epoxy-4,4-difluorobutanoate was obtained in a ¹⁹ F-NMR yield of 59%. .
[Example 11]
[ Production of benzyl 4-chloro-2,3-epoxy-4,4-difluorobutanoate ]
(E) -benzyl 4-chloro-4,4-difluorobut-2-enoate (0.121 g, 0.50 mmol) and n-Bu ₄ NHSO ₄ catalyst (0.018 g, 0.05 mmol) were added to a 10 mL three-necked glass flask. To a solution of acetonitrile (3.0 mL) was added 5% aqueous sodium hypochlorite solution (1.49 g, 1.00 mmol), and the mixture was stirred at room temperature for 1.5 hours. After filtration, extraction with methylene chloride (CH ₂ Cl ₂ ), washing with saturated aqueous sodium bicarbonate (NaHCO ₃ ) solution to remove by-product carboxylic acid, and drying with sodium sulfate (Na ₂ SO ₄ ) After drying, it concentrated. By removing by-products from the resulting crude product by distillation, benzyl 4-chloro-2,3-epoxy-4,4-difluorobutanoate was thereby obtained in a ¹⁹ F-NMR yield of 50%. .
[Example 12]
[ Production of ethyl 2,3-epoxy-4,4,5,5,6,6,7,7,8,8,9,9,9-tridecafluorononanoate ]

In a 10 mL three-neck glass flask, (E) -ethyl 4,4,5,5,6,6,7,7,8,8,9,9,9-tridecafluoronon-2-enoate (0.125 g, 0.30 mmol) And 5% aqueous sodium hypochlorite solution (2.23 g, 1.50 mmol) were added to a solution of acetonitrile (4.5 mL) containing chlorite and chlorite (ZnCl ₂ ) catalyst (0.010 g, 0.06 mmol) for 43 hours at room temperature. Stir. After filtration, extraction with methylene chloride (CH ₂ Cl ₂ ), washing with saturated aqueous sodium bicarbonate (NaHCO ₃ ) solution to remove by-product carboxylic acid, and drying with sodium sulfate (Na ₂ SO ₄ ) After drying, it concentrated. By removing by-products from the resulting crude product by distillation, ethyl 2,3-epoxy-4,4,5,5,6,6,7,7,8,8,9, 9,9-tridecafluorononanoate was obtained with a ¹⁹ F-NMR yield of 71%.
¹ H NMR (reference material: TMS, solvent: CDCl ₃ ) δ (ppm): 1.26 (3H, t, J = 7.2 Hz), 3.64 (1H, d, J = 1.5 Hz), 3.69 (1H, t, J = 9.8 Hz), 4.23 (2H, dq, J = 1.4, 7.2 Hz).
¹⁹ F NMR (reference material: CFCl ₃ , solvent: CDCl ₃ ) δ (ppm): -82.03 (3F, m), -123.32 (2F, m), -124.11 (2F, m), -124.52 (2F, m ), -124.97 (2F, m), -127.43 (2F, m).
¹³ C NMR (reference material: TMS, solvent: CDCl ₃ ) δ (ppm): 14.0, 48.6 (t, J = 3.7 Hz), 52.0 (t, J = 28.5 Hz), 62.7, 108.1-119.5 (m), 165.8.
IR (neat) ν 2990, 2945, 1759, 1451, 1339, 1242, 1147, 1026, 927, 850, 744, 721, 708, 653 cm ^-1 .

Claims (4)

Fluorine-containing α, β-unsaturated ester represented by the formula [1]
Fluorine-containing epoxy ester represented by the formula [2], characterized by reacting hypochlorite with
Manufacturing method.
[In the formulas [1] and [2], Rf is selected from the group consisting of a linear or branched perfluoroalkyl group having 1 to 10 carbon atoms, a (CF ₃ ) ₂ CH group, a CHF ₂ group, and a CClF ₂ group. R is an ethyl group or a benzyl group . ] The method according to claim 1, wherein the hypochlorite is an aqueous solution of sodium hypochlorite. The production method according to claim 1 or 2, wherein the reaction is carried out in the presence of a water-soluble organic solvent. Zinc chloride, alumina, silica, magnesia and n-Bu ₄ NHSO ₄ The production method according to any one of claims 1 to 3, wherein the reaction is performed in the presence of at least one catalyst selected from the group consisting of: