JP2010285350A - Method for producing 2-fluoroacrylic acid ester - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for industrially producing a 2-fluoroacrylic acid ester. <P>SOLUTION: The 2-fluoroacrylic acid ester can be produced by reacting 3-amino-2-fluoropropionic acid esters with a quaternary ammonium salt-forming agent in the presence of a base. The 3-amino-2-fluoropropionic acid esters of the raw material substrates can industrially more easily be produced in high position selectivity by reacting 3-hydroxy-2-aminopropionic acid esters with sulfuryl fluoride (SO<SB>2</SB>F<SB>2</SB>) in the presence of an organic base. <P>COPYRIGHT: (C)2011,JPO&INPIT

Description

  The present invention relates to a method for producing 2-fluoroacrylic acid ester which is important as an intermediate for medical and agricultural chemicals or a functional polymer monomer.

2-Fluoroacrylic acid ester is important as an intermediate for medical and agricultural chemicals or a functional polymer monomer. As a conventional technique related to the present invention, 2-fluoropropionic acid ester having a leaving group [X: iodine atom, hydroxyl group, bromine atom, tosylate group (CH ₃ C ₆ H ₄ SO ₃ )] at the 3-position is removed. A method based on the HX reaction is disclosed (see Scheme 1, Patent Document 1, Patent Document 2, Non-Patent Document 1, and Non-Patent Document 2).

Japanese Patent Laid-Open No. 60-78943 Japanese Patent Application Laid-Open No. 60-78942

Journal of Fluorine Chemistry (Netherlands), 2006, Vol. 127, p. 962-965 Journal of Fluorine Chemistry (Netherlands), 1993, Vol. 60, p. 179-183

  An object of the present invention is to provide an industrial production method of 2-fluoroacrylic acid ester. For that purpose, it is necessary to solve the problems of the prior art. The reason why the synthesis methods disclosed in Patent Document 1, Patent Document 2, Non-Patent Document 1, and Non-Patent Document 2 are difficult to adopt as an industrial production method is that the raw material substrate used for the de-HX reaction is obtained on a large scale. It is easy and inexpensive, or the yield of the de-HX reaction itself is low.

  On the other hand, a method for producing 2-fluoroacrylic acid ester, which is presumed to proceed by a Hoffman decomposition-like reaction mechanism via a quaternary ammonium salt disclosed in the present invention, has not yet been reported (see Scheme 2).

  Thus, an industrial production method of 2-fluoroacrylic acid ester has been strongly desired.

  As a result of intensive studies based on the above problems, the present inventors have reacted 2-amino-2-fluoropropionic acid esters with a quaternary ammonium chlorinating agent in the presence of a base. It has been found that acid esters can be produced. The important point of the present invention is that the reaction is carried out with a quaternary ammonium chlorinating agent in the presence of a base, and the reaction conditions that are much milder than in the absence of a base can be adopted. Therefore, it is convenient when the target compound is easily polymerizable as in the present invention.

As 3-amino-2-fluoropropionic acid esters, R ¹ and R ^{2 at the} amino moiety are each independently a methyl group, an ethyl group or a benzyl group, and R ^{3 at} the ester moiety is a methyl group, an ethyl group, or 2 , 2,2-trifluoroethyl group or 1,1,1,3,3,3-hexafluoroisopropyl group is preferable, and is easily available on a large scale, and the resulting 2-fluoroacrylic acid ester is Of particular importance.

As the quaternary ammonium chlorinating agent, R ^{4 at the} alkyl (benzyl) site is a methyl group, an ethyl group or a benzyl group, and Y at the elimination site is a bromine atom, an iodine atom or a mesylate group (CH ₃ SO ₃ ). Some are preferred, are readily available on a large scale, are inexpensive, and exhibit good reactivity.

  The base is preferably an alkali metal carbonate, easily available on a large scale, inexpensive and exhibits good reactivity.

  In the reaction and distillation purification, self-polymerization of 2-fluoroacrylic acid ester can be suppressed by performing it in the presence of a polymerization inhibitor. As such a polymerization inhibitor, phenothiazine, hydroquinone or 2,6-di-tert-butyl-4-methylphenol (BHT) is preferable, easily available on a large scale, inexpensive and excellent in inhibiting self-polymerization. ing.

As a method for producing 3-amino-2-fluoropropionic acid esters which are raw material substrates, 3-hydroxy-2-aminopropionic acid esters are reacted with sulfuryl fluoride (SO ₂ F ₂ ) in the presence of an organic base. It is preferable to make it easy to manufacture industrially with high position selectivity. Further, by using diisopropylethylamine as the organic base, the by-product of the quaternary ammonium salt can be effectively suppressed.

  Thus, the very useful manufacturing method of 2-fluoroacrylic acid ester was discovered and the present invention was reached.

That is, the present invention includes [Invention 1] to [Invention 9] and provides an industrial production method of 2-fluoroacrylic acid ester.
[Invention 1]
General formula [1]

In the presence of a base, a 3-amino-2-fluoropropionic acid ester represented by the general formula [2]

Is reacted with a quaternary ammonium chlorinating agent represented by the general formula [3]

The method to manufacture 2-fluoroacrylic acid ester shown by these.
[Wherein R ¹ , R ² and R ⁴ each independently represents an alkyl group or a benzyl group, R ³ represents an alkyl group or a fluorine-substituted alkyl group, and Y represents a halogen atom or a sulfonate group]
[Invention 2]
In Invention 1, R ¹ , R ² and R ⁴ are each independently a methyl group, an ethyl group or a benzyl group, and R ³ is a methyl group, an ethyl group, a 2,2,2-trifluoroethyl group or 1,1 , 1,3,3,3-hexafluoroisopropyl group, and Y is a bromine atom, an iodine atom or a mesylate group (CH ₃ SO ₃ ), Ester production method.
[Invention 3]
The method for producing a 2-fluoroacrylic acid ester according to Invention 1 or Invention 2, wherein the base is an alkali metal carbonate in Invention 1 or Invention 2.
[Invention 4]
The method for producing a 2-fluoroacrylic acid ester according to any one of inventions 1 to 3, wherein the reaction is carried out in the presence of a polymerization inhibitor in any one of inventions 1 to 3.
[Invention 5]
Production of 2-fluoroacrylic acid ester according to invention 4, characterized in that, in invention 4, the polymerization inhibitor is phenothiazine, hydroquinone or 2,6-di-tert-butyl-4-methylphenol (BHT). Method.
[Invention 6]
The invention according to any one of inventions 1 to 5, characterized in that in any one of inventions 1 to 5, the obtained 2-fluoroacrylic acid ester is purified by distillation in the presence of a polymerization inhibitor. A method for producing a fluoroacrylate ester.
[Invention 7]
Production of 2-fluoroacrylic acid ester according to invention 6, characterized in that the polymerization inhibitor in invention 6 is phenothiazine, hydroquinone or 2,6-di-tert-butyl-4-methylphenol (BHT). Method.
[Invention 8]
In any one of Inventions 1 to 7, the general formula [1]

3-amino-2-fluoropropionic acid ester represented by the general formula [4]

Any one of Inventions 1 to 7, characterized in that it is obtained by reacting 3-hydroxy-2-aminopropionic acid ester represented by the formula ( _II ) with sulfuryl fluoride (SO ₂ F ₂ ) in the presence of an organic base. A process for producing the 2-fluoroacrylic acid ester according to claim 1.
[Wherein, R ¹ and R ² each independently represents an alkyl group or a benzyl group, and R ³ represents an alkyl group or a fluorine-substituted alkyl group]
[Invention 9]
The method for producing a 2-fluoroacrylic acid ester according to claim 8, wherein the organic base is diisopropylethylamine in invention 8.

  In the present invention, the raw material substrate to be subjected to the de-HX reaction is easily available on a large scale and inexpensive, and the yield of the de-HX reaction itself is high.

  Thus, this invention provides the industrial manufacturing method of 2-fluoroacrylic acid ester which solved all the problems of the prior art.

  The production method of 2-fluoroacrylic acid ester of the present invention will be described in detail.

  The present invention comprises reacting 3-amino-2-fluoropropionic acid esters represented by the general formula [1] with a quaternary ammonium chlorinating agent represented by the general formula [2] in the presence of a base. This is a method for producing a 2-fluoroacrylic acid ester represented by the general formula [3]. The reaction mechanism presumed in the production method of the present invention is shown in Scheme 2, but the 3-amino-2-fluoropropionic acid ester is converted to a quaternary ammonium chloride (alkylating agent or benzylating agent) in the presence of a base. The reaction mechanism is not limited to the Hoffman decomposition-like reaction mechanism as long as a 2-fluoroacrylic acid ester can be obtained by reacting with (H).

R ¹ and R ² of the 3-amino-2-fluoropropionic acid ester represented by the general formula [1] each independently represents an alkyl group or a benzyl group. The alkyl group can have a linear or branched chain structure having 1 to 8 carbon atoms, or a cyclic structure (when the number of carbon atoms is 3 or more). Among them, an alkyl group having 1 to 4 carbon atoms and a benzyl group are preferable, and a methyl group, an ethyl group, and a benzyl group are particularly preferable.

R ³ of the 3-amino-2-fluoropropionic acid ester represented by the general formula [1] represents an alkyl group or a fluorine-substituted alkyl group. The alkyl group is the same as that described in R ¹ and R ² of the 3-amino-2-fluoropropionic acid ester represented by the general formula [1]. In the fluorine-substituted alkyl group, any number of fluorine atoms can be substituted on any carbon atom of the alkyl group. Of these, alkyl groups and fluorine-substituted alkyl groups having 1 to 4 carbon atoms are preferred, and include methyl, ethyl, 2,2,2-trifluoroethyl, and 1,1,1,3,3,3-hexa. A fluoroisopropyl group is particularly preferred.

Although the 2-position carbon atom of the 3-amino-2-fluoropropionic acid ester represented by the general formula [1] is an asymmetric carbon, it is ultimately converted to the sp ² carbon, so that the optically active substance (R Or it is not limited to S) or a racemate, Both can be used equally. Of these, racemates that are easily available on a large scale and inexpensive are preferred. Of course, an optically active substance can also be used.

  The method for producing the 3-amino-2-fluoropropionic acid ester represented by the general formula [1] is not particularly limited, and Journal of the American Chemical Society (USA), 1982, vol. 104, p. 5836-5837, International Publication No. 2006/038872 pamphlet and the like can be used for the same production. However, an object of the present invention is to provide an industrial production method of 2-fluoroacrylic acid ester. Therefore, it is preferable that the method for producing 3-amino-2-fluoropropionic acid esters, which are raw material substrates, is also industrially endurable, and combining with the industrial method for producing raw material substrates is suitable for the present invention. This is one aspect.

  The present applicant has already filed a patent application for a method for producing a similar α-fluoro-β-amino acid conforming to such a viewpoint (Japanese Patent Application No. 2009-101506, 3-amino-2-fluoropropionic acid). (Part of the industrial production of esters). However, since the present patent application has not yet been published, the contents necessary for the disclosure of the present invention (method for producing 2-fluoroacrylic acid ester) are also described below.

By reacting 3-hydroxy-2-aminopropionic acid ester represented by the general formula [4] with sulfuryl fluoride (SO ₂ F ₂ ) in the presence of an organic base, 3 represented by the general formula [1] -Amino-2-fluoropropionic acid esters can be produced remarkably easily industrially with high regioselectivity. In this production method, the fluorosulfuric acid ester derivative derived from the raw material substrate is converted into an aziridinium intermediate, and the fluorine anion (F ⁻ ) by-produced in the reaction system causes the second carbon atom to undergo nucleophilic attack in a S _N 2 manner. As a result, a ring-opening fluorination reaction involving rearrangement of a nitrogen atom proceeds (see Scheme 3). In this dehydroxyfluorination reaction involving 1,2-rearrangement, the attack of the fluorine anion (F ⁻ ) on the aziridinium intermediate is highly regioselectively performed on the 2-position carbon atom (vs. 3-position carbon atom). [3-amino-2-fluoropropionic acid esters (major product) vs. 3-Fluoro-2-aminopropionic acid esters (minor products)], and the stereochemical inversion rate of the 2-position carbon atom is extremely high. On the other hand, if an organic base with a low steric bulk (for example, triethylamine) is used, an intramolecular ring closure reaction from a fluorosulfate ester to an aziridinium intermediate, or an opening from an aziridinium intermediate to the target compound is performed. In the ring fluorination reaction, an organic base (tertiary amine) is partially involved, and a quaternary ammonium salt (a 3-position adduct or a 2-position adduct, respectively) may be produced as a by-product. Therefore, using a sterically bulky organic base (such as diisopropylethylamine) can be one of the preferred embodiments of the present invention.

R ¹ , R ² and R ³ of the 3-hydroxy-2-aminopropionic acid esters represented by the general formula [4] are the same as those of the 3-amino-2-fluoropropionic acid esters represented by the general formula [1]. The same as described for R ¹ , R ² and R ³ .

  The 2-position carbon atom of the 3-hydroxy-2-aminopropionic acid ester represented by the general formula [4] is also an asymmetric carbon, and if the optically active substance (R or S) is used, the general formula [1] The optically active form of the 3-amino-2-fluoropropionic acid ester shown can be obtained without impairing the optical purity. However, in the present invention, a racemic body can be used equally, so that it is not necessary to dare to use an optically active substance (R or S).

Sulfuryl fluoride (SO ₂ F ₂ ) is widely used as a fumigant and is easily available on a large scale and inexpensive. Furthermore, from the viewpoint of waste treatment [can be easily treated with an inorganic salt such as fluorite (CaF ₂ ) or calcium sulfate], it is suitable as a reactant in an industrial production method.

The amount of sulfuryl fluoride (SO ₂ F ₂ ) used may be 0.7 mol or more relative to 1 mol of 3-hydroxy-2-aminopropionic acid esters represented by the general formula [4]. 8 to 10 mol is preferred, and 0.9 to 5 mol is particularly preferred.

  Organic bases include trimethylamine, dimethylethylamine, diethylmethylamine, triethylamine, di-n-propylmethylamine, diisopropylethylamine, tri-n-propylamine, diisopropylisobutylamine, dimethyl n-nonylamine, tri-n-butylamine, di-n-hexyl. Methylamine, dimethyl n-dodecylamine, tri-n-pentylamine, pyridine, 2,3-lutidine, 2,4-lutidine, 2,6-lutidine, 3,4-lutidine, 3,5-lutidine, 2,4 , 6-collidine, 3,5,6-collidine and the like. Among them, tertiary amines having 2 to 2 alkyl groups having 8 to 12 carbon atoms and 3 or more carbon atoms are preferable, and diisopropylethylamine is particularly preferable. In addition, since the organic base having 8 or more carbon atoms has high fat solubility, it can be easily recovered even in a post-treatment using water, and can be reused without lowering the reactivity. Therefore, it is suitable as a reactant for an industrial production method. In the present specification, the tertiary amine means an amine in which all three hydrogen atoms of ammonia are substituted with alkyl groups. The number of carbons means the total number of carbon atoms of three alkyl groups.

  The amount of the organic base used may be 0.7 mol or more, preferably 0.8 to 10 mol, relative to 1 mol of 3-hydroxy-2-aminopropionic acid ester represented by the general formula [4]. 0.9 to 5 mol is particularly preferred.

  This dehydroxyfluorination reaction involving 1,2-rearrangement can be carried out in the presence of “a salt or complex comprising the above organic base and hydrogen fluoride” as a new fluorine source. However, since the desired reaction proceeds satisfactorily without adding the salt or complex, it is not necessary to carry out the reaction in the presence.

  As the reaction solvent, aliphatic systems such as n-hexane, cyclohexane and n-heptane, aromatic systems such as benzene, toluene, ethylbenzene, xylene and mesitylene, halogen systems such as methylene chloride, chloroform and 1,2-dichloroethane, Ether type such as diethyl ether, tetrahydrofuran, diisopropyl ether, tert-butyl methyl ether, ester type such as ethyl acetate, n-butyl acetate, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, 1 Amides such as 3-dimethyl-2-imidazolidinone, nitriles such as acetonitrile and propionitrile, sulfur oxides such as dimethyl sulfoxide, and the like. Among them, n-hexane, n-heptane, toluene, xylene, mesitylene, methylene chloride, tetrahydrofuran, diisopropyl ether, tert-butyl methyl ether, ethyl acetate, N, N-dimethylformamide, N, N-dimethylacetamide, acetonitrile, pro Pionitrile and dimethyl sulfoxide are preferred, and toluene, xylene, methylene chloride, tetrahydrofuran, diisopropyl ether, ethyl acetate, N, N-dimethylformamide and acetonitrile are more preferred. These reaction solvents can be used alone or in combination. In addition, this dehydroxyfluorination reaction involving 1,2-rearrangement can be carried out without a solvent.

  The amount of the reaction solvent used may be 0.05 L (liter) or more per mole of 3-hydroxy-2-aminopropionic acid ester represented by the general formula [4], preferably 0.1 to 10 L. 0.15 to 5 L is particularly preferable.

The temperature condition may be in the range of −100 to + 100 ° C., preferably −60 to + 60 ° C., particularly preferably −50 to + 50 ° C. In the case where the reaction is performed at a temperature condition higher than the boiling point of sulfuryl fluoride (SO ₂ F ₂ ) (−49.7 ° C.), a pressure resistant reactor can be used.

The pressure condition may be in the range from atmospheric pressure to 2 MPa, preferably from atmospheric pressure to 1.5 MPa, particularly preferably from atmospheric pressure to 1 MPa. Therefore, it is preferable to perform the reaction using a pressure-resistant reaction vessel made of a material such as stainless steel (SUS) or glass (glass lining). In addition, as a method for charging sulfuryl fluoride (SO ₂ F ₂ ) on a large scale, it is effective to first introduce a pressure-resistant reaction vessel into a negative pressure and introduce it as a gas or a liquid under reduced pressure while restoring pressure.

  The reaction time may be within 72 hours and varies depending on the raw material substrate, reactants, reaction aids, and reaction conditions. Therefore, the progress of the reaction by means of analysis such as gas chromatography, liquid chromatography, nuclear magnetic resonance, etc. It is preferable that the end point is a time point when almost no decrease in the raw material substrate is observed.

  In the post-treatment, the target 3-amino-2-fluoropropionic acid ester represented by the general formula [1] can be obtained by performing a general operation in organic synthesis on the reaction end solution. Preferably, the reaction completion liquid is concentrated, the residue is diluted with an organic solvent, washed with an aqueous solution of an inorganic base, and the precipitated solid is filtered if necessary, washed with water, and the recovered organic layer is concentrated. Is effective. By performing such post-treatment, a target compound having a quality sufficient for the reaction in the next step can be obtained. The target compound can be purified to a high purity by operations such as activated carbon treatment, fractional distillation, recrystallization, column chromatography and the like as necessary.

R ^{4 of the} quaternary ammonium chlorinating agent represented by the general formula [2] represents an alkyl group or a benzyl group. The alkyl group and the benzyl group are the same as those described for R ¹ and R ² of the 3-amino-2-fluoropropionic acid ester represented by the general formula [1].

Y of the quaternary ammonium chlorinating agent represented by the general formula [2] represents a halogen atom or a sulfonate group. Among them, a chlorine atom, a bromine atom, an iodine atom, a mesylate group (CH ₃ SO ₃ ) and a tosylate group (CH ₃ C ₆ H ₄ SO ₃ ) are preferable, and a bromine atom, an iodine atom and a mesylate group (CH ₃ SO ₃ ) are preferable. Particularly preferred. The amount of the quaternary ammonium chlorinating agent represented by the general formula [2] is 0.7 mol or more per 1 mol of the 3-amino-2-fluoropropionic acid ester represented by the general formula [1]. 0.8 to 15 mol is preferable, and 0.9 to 10 mol is particularly preferable.

  Bases include trimethylamine, triethylamine, diisopropylethylamine, tri-n-propylamine, tri-n-butylamine, tri-n-pentylamine, tri-n-hexylamine, pyridine, 2,3-lutidine, 2,4-lutidine, 2, 5-lutidine, 2,6-lutidine, 3,4-lutidine, 3,5-lutidine, 2,3,4-collidine, 2,4,5-collidine, 2,5,6-collidine, 2,4 6-collidine, 3,4,5-collidine, 3,5,6-collidine, 4-dimethylaminopyridine (DMAP), 1,5-diazabicyclo [4.3.0] non-5-ene (DBN), 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), N, N, N ′, N ′, N ″ -pentamethylguanidine, 1,5,7-triazabici (B) Organic bases such as [4.4.0] dec-5-ene (TBD), BEMP, tert-Bu-P4, lithium hydrogen carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, cesium hydrogen carbonate, lithium carbonate, sodium carbonate Inorganic bases such as potassium carbonate and cesium carbonate. Among them, triethylamine, diisopropylethylamine, tri-n-butylamine, 2,6-lutidine, 2,4,6-collidine, 4-dimethylaminopyridine (DMAP), 1,8-diazabicyclo [5.4.0] undec-7 -Ene (DBU) and alkali metal carbonates (lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate) are preferred, and alkali metal carbonates (lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate) are particularly preferred. These bases can be used alone or in combination. On the other hand, alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide, and cesium hydroxide are not preferable because they involve hydrolysis of the ester moiety of the target compound.

  The amount of the base used may be 0.6 mol or more, preferably 0.7 to 7 mol, based on 1 mol of the 3-amino-2-fluoropropionic acid ester represented by the general formula [1]. .8 to 5 mol is particularly preferred.

  As polymerization inhibitors, phenothiazine, hydroquinone, 2,6-di-tert-butyl-4-methylphenol (BHT), methoquinone, tert-butylhydroquinone (TBH), 2,5-di-tert-butylhydroquinone, 1 , 2,4-trihydroxybenzene, leucoquinizarin, nonflex F, nonflex H, nonflex DCD, nonflex MBP [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, 2,6-di-tert-butyl-4-methylphenol (BHT), methoquinone and nonflex MBP [2,2′-methylene-bis (4-methyl-6-tert-butylphenol)] Are preferred, with phenothiazine, hydroquinone and 2,6-di-tert-butyl-4-methylphenol (BHT) being particularly preferred.

  The polymerization inhibitor may be used in an amount of 0.00001 mol or more per mol of 3-amino-2-fluoropropionic acid ester represented by the general formula [1], and 0.0001 to 0.2 mol. Is preferable, and 0.001 to 0.1 mol is particularly preferable. The polymerization inhibitor is not essential for this step (reaction and distillation purification), but is extremely effective for mass production.

  Reaction solvents include aliphatic systems such as n-hexane and n-heptane, aromatic systems such as toluene and xylene, halogen systems such as methylene chloride and 1,2-dichloroethane, and ethers such as tetrahydrofuran and tert-butyl methyl ether. System, ester systems such as ethyl acetate, n-butyl acetate, amide systems such as N, N-dimethylformamide, N, N-dimethylacetamide, 1,3-dimethyl-2-imidazolidinone, acetonitrile, propionitrile, etc. Nitriles, sulfur oxides such as dimethyl sulfoxide, sulfolane and the like. Among them, n-heptane, toluene, methylene chloride, tetrahydrofuran, ethyl acetate, N, N-dimethylformamide, N, N-dimethylacetamide, 1,3-dimethyl-2-imidazolidinone, acetonitrile and dimethyl sulfoxide are preferable. , N-dimethylformamide, N, N-dimethylacetamide, 1,3-dimethyl-2-imidazolidinone and dimethyl sulfoxide are particularly preferred. These reaction solvents can be used alone or in combination.

  The used amount of the reaction solvent may be 0.05 L (liter) or more with respect to 1 mol of 3-amino-2-fluoropropionic acid ester represented by the general formula [1], preferably 0.1 to 5 L 0.15 to 4 L is particularly preferable.

  The reaction temperature may be in the range of −30 to + 120 ° C., preferably −20 to + 110 ° C., particularly preferably −10 to + 100 ° C. In the case where the reaction is carried out at a temperature not lower than the boiling point of the quaternary ammonium chlorinating agent represented by the general formula [2] (for example, methyl iodide has a boiling point of 42.5 ° C.), a pressure-resistant reaction vessel can be used. .

  The pressure condition may be in the range from atmospheric pressure to 2 MPa, preferably from atmospheric pressure to 1.5 MPa, particularly preferably from atmospheric pressure to 1 MPa. Therefore, it is preferable to perform the reaction using a pressure-resistant reaction vessel made of a material such as stainless steel (SUS) or glass (glass lining).

  The reaction time may be in the range of 24 hours or less, and varies depending on the raw material substrate, reactants, reaction aids, and reaction conditions. Therefore, the progress of the reaction by means of analysis such as gas chromatography, liquid chromatography, or nuclear magnetic resonance It is preferable that the end point is a time point when almost no decrease in the raw material substrate is observed.

  In the post-treatment, the target 2-fluoroacrylic acid ester represented by the general formula [3] can be obtained by performing a general operation in organic synthesis on the reaction end solution. Preferably, the reaction product is diluted with an organic solvent, the solid is filtered, a polymerization inhibitor is added to the washing solution, and the product is directly distilled to recover the crude product in a simple operation with good yield. Can do. Fluorine ions or moisture contained in the reaction completion liquid, filter washing liquid, or crude product are respectively defluorinating agents such as calcium carbonate, calcium hydroxide, calcium chloride, silica gel, magnesium sulfate, diphosphorus pentoxide, molecular sieves. It can be appropriately treated with a dehydrating agent such as a dewatering filter. The crude product can be purified to a high purity by operations such as activated carbon treatment, fractional distillation, recrystallization, column chromatography, etc., if necessary. Also in these purifications, self-polymerization of 2-fluoroacrylic acid ester can be suppressed by carrying out in the presence of a polymerization inhibitor.

When a suitable alkali metal carbonate is used as the base, since the boiling point of the target 2-fluoroacrylic acid ester represented by the general formula [3], particularly the methyl ester, is close to the boiling point of water, Shows a tendency to increase. However, the amount of water can be effectively reduced by treating with the above dehydrating agent. In this way, when an alkali metal carbonate is used as the base, water is by-produced to neutralize the protonic acid (HY) as the reaction proceeds. It is an important finding found in the present invention that the ester site of the target compound is hardly hydrolyzed despite the presence of water in the reaction system under basic conditions.
[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 represents a methyl group, and Bn represents a benzyl group.

  With reference to the International Publication No. 2006/038872 pamphlet, the following formula

The 3-hydroxy-2-aminopropionic acid ester shown by these was manufactured. The total yield of methyl esterification (hydrochloric acid chloride) and N, N-dibenzylation from the racemate of serine (commercial product) was quantitative.

In a pressure resistant reaction vessel made of stainless steel (SUS), 285 g (952 mmol, 1.00 eq) of 3-hydroxy-2-aminopropionic acid esters represented by the above formula, 147 g (1.14 mol, 1.20 eq) of diisopropylethylamine and acetonitrile 316 mL was added, immersed in a −78 ° C. refrigerant bath, 194 g (1.90 mol, 2.00 eq) of sulfuryl fluoride (SO ₂ F ₂ ) was blown from the bomb and stirred at room temperature overnight. The conversion rate was 100% from the gas chromatography of the reaction completed liquid. The reaction-terminated liquid is concentrated under reduced pressure, the residue is diluted with 300 mL of toluene, washed twice with 100 mL of saturated aqueous potassium carbonate solution, the precipitated solid is filtered, washed with 100 mL of water, and the recovered organic layer is concentrated under reduced pressure. By drying, the following formula

As a result, 286 g of 3-amino-2-fluoropropionic acid ester represented by the formula (1) was obtained. The yield was quantitative. The gas chromatography purity was 98.7%.

¹ H-NMR and ¹⁹ F-NMR are shown below.
¹ H-NMR [reference substance; (CH ₃ ) ₄ Si, deuterated solvent; CDCl ₃ ]; δ ppm / 2.97 (ddd, 24.4 Hz, 14.6 Hz, 3.2 Hz, 1 H), 3.04 ( ddd, 24.4 Hz, 14.6 Hz, 6.0 Hz, 1 H), 3.52 (d, 13.6 Hz, 2 H), 3.69 (s, 3 H), 3.83 (d, 13.6 Hz, 2 H) ), 5.04 (ddd, 51.9 Hz, 6.0 Hz, 3.2 Hz, 1H), 7.20-7.40 (Ar-H, 10H).
¹⁹ F-NMR (reference material; C ₆ F ₆ , heavy solvent; CDCl ₃ ); δ ppm / −28.76 (dt, 51.9 Hz, 24.4 Hz, 1F).

  In the pressure resistant reaction vessel made of stainless steel (SUS), the following formula obtained above

20.0 g (66.4 mmol, 1.00 eq), methyl iodide 47.1 g (332 mmol, 5.00 eq), potassium carbonate 18.4 g (133 mmol, 2 .00 eq), 2,6-di-tert-butyl-4-methylphenol (BHT) 200 mg (0.908 mmol, 0.01 eq) and N, N-dimethylformamide 33 mL were added and stirred at 70 ° C. overnight. The conversion rate was 96% from ¹⁹ F-NMR of the reaction completed liquid. The reaction solution was diluted with 50 mL of N, N-dimethylformamide and 50 mL of methanol, the solid was filtered, and 200 mg (0.908 mmol) of 2,6-di-tert-butyl-4-methylphenol (BHT) was added to the filtrate. , 0.01 eq), and by direct simple distillation (flash distillation, boiling point 30 to 85 ° C., degree of vacuum 25 kPa),

71.2 g of a mixed solution of N, N-dimethylformamide and methanol containing 2-fluoroacrylic acid ester represented by the formula (1) was obtained. The content of 2-fluoroacrylic acid ester contained in this mixed solution was 5.08 g (48.8 mmol) from ¹⁹ F-NMR (quantified by internal standard method). The yield was 73%.

  The N, N-dimethylformamide solution containing the 2-fluoroacrylic acid ester represented by the above formula, produced in the same manner, is a polymerization inhibitor 2,6-di-tert-butyl-4-methylphenol (BHT). Can be recovered with good yield (fractional distillation is disclosed in JP-A No. 2001-172223) by fractional distillation (theoretical plate number: 30) in the presence of water. Can be done with reference to).

¹ H-NMR and ¹⁹ F-NMR of the high-purity product are shown below.
¹ H-NMR [reference material; (CH ₃ ) ₄ Si, heavy solvent; CDCl ₃ ]; δ ppm / 3.85 (s, 3 H), 5.36 (dd, 13.2 Hz, 3.2 Hz, 1 H) 5.69 (dd, 3.2 Hz, 44.0 Hz, 1H).
¹⁹ F-NMR (reference material; C ₆ F ₆ , heavy solvent; CDCl ₃ ); δ ppm / 44.67 (dd, 42.7 Hz, 13.7 Hz, 1F).

Claims (9)

General formula [1]

In the presence of a base, a 3-amino-2-fluoropropionic acid ester represented by the general formula [2]

Is reacted with a quaternary ammonium chlorinating agent represented by the general formula [3]

The method to manufacture 2-fluoroacrylic acid ester shown by these.
[Wherein R ¹ , R ² and R ⁴ each independently represents an alkyl group or a benzyl group, R ³ represents an alkyl group or a fluorine-substituted alkyl group, and Y represents a halogen atom or a sulfonate group] According to claim 1, R ^1, R ² and R ⁴ are each independently a methyl group, an ethyl group or a benzyl group, R ³ is a methyl group, an ethyl group, a 2,2,2-trifluoroethyl group or a 1, The 2-fluoro group according to claim 1, which is a 1,1,3,3,3-hexafluoroisopropyl group, and Y is a bromine atom, an iodine atom or a mesylate group (CH ₃ SO ₃ ). A method for producing an acrylic ester. The method for producing a 2-fluoroacrylic acid ester according to claim 1 or 2, wherein the base is an alkali metal carbonate according to claim 1 or 2. The method for producing a 2-fluoroacrylic acid ester according to any one of claims 1 to 3, wherein the reaction is performed in the presence of a polymerization inhibitor according to any one of claims 1 to 3. . 5. The 2-fluoroacrylic acid ester according to claim 4, wherein the polymerization inhibitor is phenothiazine, hydroquinone or 2,6-di-tert-butyl-4-methylphenol (BHT). Manufacturing method. In any one of Claims 1 to 5, distillation purification of the obtained 2-fluoroacrylic acid ester is performed in the presence of a polymerization inhibitor. The manufacturing method of 2-fluoroacrylic acid ester of description. The 2-fluoroacrylic acid ester according to claim 6, wherein the polymerization inhibitor is phenothiazine, hydroquinone, or 2,6-di-tert-butyl-4-methylphenol (BHT). Manufacturing method. The general formula [1] according to any one of claims 1 to 7.

3-amino-2-fluoropropionic acid ester represented by the general formula [4]

It is obtained by reacting 3-hydroxy-2-aminopropionic acid esters represented by the formula ( _II ) with sulfuryl fluoride (SO ₂ F ₂ ) in the presence of an organic base. The manufacturing method of 2-fluoroacrylic acid ester in any one of.
[Wherein, R ¹ and R ² each independently represents an alkyl group or a benzyl group, and R ³ represents an alkyl group or a fluorine-substituted alkyl group] 9. The method for producing a 2-fluoroacrylic acid ester according to claim 8, wherein the organic base is diisopropylethylamine.