Method for producing α-(mercaptomethyl)acrylic acid ester

Abstract

To provide a new method for producing α-(mercaptomethyl) acrylate that is useful as the raw material for pharmaceuticals and various resin compositions.SOLUTION: A method for producing α-(mercaptomethyl) acrylate includes hydrolyzing Bunte salt represented by general formula (2) (where R is a hydrocarbon group and M is Na, K, Li, 1 / 2Ca, 1 / 2Mg, 1 / 2Ba, 1 / 3Al or NH4).SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a method for producing an α-(mercaptomethyl)acrylic ester. [Background technology]

[0002] α-(mercaptomethyl)acrylic acid derivatives are known as intermediates for the production of α-(mercaptomethyl)acrylic acid prolylamide, which is useful as a pharmaceutical product (Patent Document 1). Some α-(mercaptomethyl)acrylic acid esters are also known as raw materials for actinic ray- or radiation-sensitive resin compositions and radiation-curable inkjet recording inks (Patent Documents 2 and 3).

[0003] As a method for producing an α-(mercaptomethyl)acrylic acid derivative, Patent Document 1 describes a method in which β,β'-dihalogenoisobutyric acid is treated with a base to form α-(halogenomethyl)acrylic acid, which is then reacted with hydrogen sulfide in the presence of a base to obtain the derivative. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] Japanese Patent Application Publication No. 57-46961 [Patent Document 2] International Publication No. 2020 / 129683 [Patent Document 3] JP 2007-177057 A Summary of the Invention [Problem to be solved by the invention]

[0005] However, Patent Document 1 does not disclose an example in which β,β'-dihalogenoisobutyric acid is treated with a base to form an α-(halogenomethyl)acrylic acid ester, and then hydrogen sulfide is reacted in the presence of a base. As a reference example, it only discloses that α-(bromomethyl)acrylic acid is reacted with potassium thioacetate to obtain α-(acetylthio)acrylic acid, and that β,β'-dibromoisobutyric acid is reacted with anhydrous potassium carbonate, and then potassium thiobenzoate is reacted in the presence of anhydrous potassium carbonate to obtain α-(benzoylthiomethyl)acrylic acid. Therefore, an object of the present invention is to provide a new method for producing an α-(mercaptomethyl)acrylic ester which is useful as a raw material for producing pharmaceuticals and various resin compositions. [Means for solving the problem]

[0006] The present inventors therefore investigated various methods for directly producing α-(mercaptomethyl)acrylic esters which have a mercaptomethyl group, rather than an acylthiomethyl group such as acetylthiomethyl, at the α-position of acrylic acid. As a result, they discovered that Bunte salts can be obtained by reacting readily available α-(halogenomethyl)acrylic esters as raw materials with thiosulfates, and that α-(mercaptomethyl)acrylic esters can be obtained in high yields by hydrolyzing the Bunte salts thus obtained, thus completing the present invention.

[0007] That is, the present invention provides the following inventions [1] to [7]. [1] The following general formula (2) [ka] (In the formula, R represents a hydrocarbon group, and M represents Na, K, Li, 1 / 2Ca, 1 / 2Mg, 1 / 2Ba, 1 / 3Al, or NH4.) A method for producing an α-(mercaptomethyl)acrylic ester, comprising hydrolyzing a Bunte salt represented by the following formula: [2] The method according to [1], wherein R is an alkyl group. [3] The method according to [1] or [2], wherein M is Na. [4] A method for producing an α-(mercaptomethyl)acrylic ester, comprising reacting an α-(halogenomethyl)acrylic ester with a thiosulfate, followed by hydrolysis. [5] The following general formula (2)

[0008] [ka]

[0009] (In the formula, R represents a hydrocarbon group, and M represents Na, K, Li, 1 / 2Ca, 1 / 2Mg, 1 / 2Ba, 1 / 3Al, or NH4.) Represented by Bunte salt. [6] The Bunte salt according to [5], wherein R is an alkyl group. [7] The Bunte salt according to [5] or [6], wherein M is Na. Effect of the Invention

[0010] According to the present invention, an α-(mercaptomethyl)acrylic ester useful as a raw material for producing pharmaceuticals and various resin compositions can be produced in high yield. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0011] The process for producing an α-(mercaptomethyl)acrylic ester of the present invention from a starting material, an α-(halogenomethyl)acrylic ester, is shown in the following reaction scheme.

[0012] [ka]

[0013] (In the formula, R represents a hydrocarbon group, X represents a halogen atom, and M represents Na, K, Li, 1 / 2Ca, 1 / 2Mg, 1 / 2Ba, 1 / 3Al, or NH4.)

[0014] In the above reaction scheme, the Bunte salt represented by general formula (2) is a novel compound and is useful as a production intermediate for α-(mercaptomethyl)acrylic esters. The present invention is a method for producing an α-(mercaptomethyl)acrylic acid ester, which comprises hydrolyzing the Bunte salt represented by the following general formula (2): The present invention also provides a process for producing an α-(mercaptomethyl)acrylic ester, which comprises reacting an α-(halogenomethyl)acrylic ester with a thiosulfate, followed by hydrolysis.

[0015] In the formula, R represents a hydrocarbon group. Here, the hydrocarbon group is preferably an alkyl group, more preferably a linear, branched or cyclic alkyl group having 1 to 6 carbon atoms, and further preferably a methyl group, an ethyl group, a propyl group, an isopropyl group, an isobutyl group, a tert-butyl group, a cyclohexyl group or the like.

[0016] Examples of the halogen atom represented by X include a chlorine atom, a bromine atom, a fluorine atom, and an iodine atom. From the viewpoint of reactivity, a chlorine atom and a bromine atom are preferred, and a bromine atom is more preferred.

[0017] M may be Na, K, Li, 1 / 2Ca, 1 / 2Mg, 1 / 2Ba, 1 / 3Al or NH4, with Na being preferred.

[0018] The starting material, α-(halogenomethyl)acrylic ester (1), can be easily produced, for example, as described in Patent Document 1, by reacting β,β'-dibromoisobutyric acid with a base such as anhydrous potassium carbonate. Specific examples of the raw material include preferably α-(bromomethyl)acrylic acid alkyl ester and α-(chloromethyl)acrylic acid alkyl ester, and more preferably α-(bromomethyl)acrylic acid C1-6 alkyl ester and α-(chloromethyl)acrylic acid C1-6 alkyl ester.

[0019] The thiosulfate used in the initial reaction includes metal thiosulfates such as sodium thiosulfate, potassium thiosulfate, lithium thiosulfate, calcium thiosulfate, magnesium thiosulfate, barium thiosulfate, and aluminum thiosulfate, and ammonium thiosulfate. From the viewpoint of economy, sodium thiosulfate is particularly preferred.

[0020] The reaction of the α-(halogenomethyl)acrylic ester (1) with a thiosulfate can be carried out by reacting the α-(halogenomethyl)acrylic ester with 1 to 1.5 equivalents of the thiosulfate in a solvent. As the reaction solvent, water may be used, but a mixture of hydrocarbon solvents such as pentane, hexane, cyclohexane, heptane, octane, benzene, toluene, and xylene; halogen-based solvents such as dichloromethane, dichloroethane, trichloroethane, tetrachloroethane, chloroform, carbon tetrachloride, monochlorobenzene, and dichlorobenzene; and ether-based solvents such as ethyl methyl ether, diethyl ether, isopropyl ether, diphenyl ether, tetrahydrofuran, and dioxane may also be used.

[0021] The amount of thiosulfate used is preferably 1 to 1.5 equivalents, and more preferably 1 to 1.2 equivalents, per equivalent of the α-(halogenomethyl)acrylic acid ester. The reaction temperature is not particularly limited, but from the viewpoint of energy saving, it is preferably 5 to 50° C., more preferably 5 to 35° C. In addition, the reaction time is also not particularly limited, as long as the reaction is carried out until the corresponding Bunte salt is produced, and from the viewpoint of production efficiency and energy saving, it is more preferably within 10 hours.

[0022] This reaction produces the Bunte salt represented by the general formula (2). The resulting Bunte salt (2) is a novel compound. This Bunte salt (2) may be isolated, or may be used for the next reaction without isolation.

[0023] The Bunte salt (2) is then hydrolyzed to give the α-(mercaptomethyl)acrylate ester (3). This hydrolysis reaction can be carried out in an aqueous solvent, but conditions that do not hydrolyze the alkyl ester are preferred. For example, it is preferred to carry out the reaction in a solvent in which water and alcohol are mixed in any ratio, or in an absolute alcohol solvent. The type of acid used for hydrolysis of Bunte salt (2) is not particularly limited, but an acid catalyst selected from hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, sulfonic acid, and p-toluenesulfonic acid, or a cationic ion exchange resin, etc., can be used, and hydrogen chloride gas or the like can be dissolved in a solvent such as alcohol. The reaction temperature and reaction time are not particularly limited, but in order to suppress the hydrolysis of the alkyl ester, it is preferable to carry out the reaction at 0°C to 100°C for 5 minutes to 30 hours.

[0024] After completion of the reaction, the α-(mercaptomethyl)acrylic ester can be isolated and purified by means of, but not limited to, extraction of the target product with any organic solvent, concentration under reduced pressure, column chromatography, or the like.

[0025] According to the method of the present invention, α-(mercaptomethyl)acrylic esters, which are useful as raw materials for the production of pharmaceuticals and various resin compositions, can be produced in high yield. EXAMPLES

[0026] The present invention will now be described in more detail with reference to examples, but the present invention is not limited to these examples in any way.

[0027] Example 1 (Synthesis of Bunte salt (2)-1)

[0028] [ka]

[0029] 54 g of water, 12.9 g of sodium thiosulfate pentahydrate (equivalent to 52 mmol of sodium thiosulfate), and 9.3 g (52 mmol) of methyl α-(bromomethyl)acrylate were placed in a 150 ml four-neck flask and stirred at room temperature for 1 hour. 40 g of toluene was added to the reaction solution, and after stirring, the aqueous layer (lower layer) was separated. After distilling off the solvent in the aqueous layer, the residue was washed with methanol to obtain 10 g of Bunte salt (2)-1 (yield: 82%). 1 H NMR(400MHz,DMSO-d6)δ6.15(s,1H,CH2=C),5.76(s,1H,CH2=C),3.69(s,3H,CH3),3.51(s,2H,CH2); 13 C NMR(100MHz,DMSO-d6)δ165.6,135.1,128.4,52.07,38.21;IR(KBr):ν~=1708,1231,1194,1141,1034cm ?1 ;HRMS-ESI:calcd for C5H7O5S2[M-Na] - :210.9735.Found:210.9731.

[0030] Example 2 (Synthesis of Bunte salt (2)-2)

[0031] [ka]

[0032] 54 g of water, 12.9 g of sodium thiosulfate pentahydrate (equivalent to 52 mmol of sodium thiosulfate), and 10 g (52 mmol) of ethyl α-(bromomethyl)acrylate were placed in a 150 ml four-neck flask and stirred at room temperature for 1 hour. 40 g of toluene was added to the reaction solution, and after stirring, the aqueous layer (lower layer) was separated. After distilling off the solvent in the aqueous layer, the residue was washed with methanol to obtain 12 g of Bunte salt (2)-2 (yield: 93%). 1H NMR(400MHz,CD3OD)δ6.26(d,J=0.8Hz,1 H,CH2=C),5.96(d,J=0.8Hz,1H,CH2=C),4.22(q,J=7.2Hz,2H,CH2-CH3),3.94(s,2H,CH2-S),1.30(t,J=7.2Hz,3H,CH3); 13 C NMR(100MHz,CD3OD)δ167.5,138.2,128.3,62.11,36.38,14.41;IR(KBr):ν~=1717,1200,1045cm ?1 ;HRMS-ESI:calcd for C6H9O5S2[M-Na] - :224.9891.Found:224.9898.

[0033] Example 3 (Synthesis of Bunte salt (2)-3)

[0034] [ka]

[0035] 54 g of water, 12.9 g of sodium thiosulfate pentahydrate (equivalent to 52 mmol of sodium thiosulfate), and 10.8 g (52 mmol) of isopropyl α-(bromomethyl)acrylate were placed in a 150 ml four-neck flask and stirred at room temperature for 1 hour. 40 g of toluene was added to the reaction solution, and after stirring, the aqueous layer (lower layer) was separated. After distilling off the solvent in the aqueous layer, the residue was washed with methanol to obtain 11.5 g of Bunte salt (2)-3 (yield: 84%). 1 H NMR(400MHz,CD3OD)δ6.92(d,J=1.2Hz,1 H,CH2=C),6.54(d,J=1.2Hz,1H,CH2=C),5.76(sep,J=6.2Hz,1H,CH),4.31(s,2H,CH2),2.02(d,J=6.2Hz,6H,CH3); 13 C NMR(100MHz,CD3OD)δ174.1,145.3,137.2,77.68,48.05,31.02(2C);IR(KBr):ν~=1715,1234,1219,1191,1048,1032cm ?1;HRMS-ESI:calcd for C7H 11 O5S2[M-Na] - :239.0048.Found:239.0052.

[0036] Example 4 (Synthesis of Bunte salt (2)-2)

[0037] [ka]

[0038] 54 g of water, 12.9 g of sodium thiosulfate pentahydrate (equivalent to 52 mmol of sodium thiosulfate), and 7.7 g (52 mmol) of ethyl α-(chloromethyl)acrylate were placed in a 150 ml four-neck flask and stirred at room temperature for 1 hour. 40 g of toluene was added to the reaction solution, and after stirring, the aqueous layer (lower layer) was separated. After distilling off the solvent in the aqueous layer, the residue was washed with methanol to obtain 11.7 g of Bunte salt (2)-2 (yield: 91%). The physical property data of Bunte salt (2)-2 was the same as in Example 2.

[0039] Example 5 (Synthesis of ethyl α-(mercaptomethyl)acrylate)

[0040] [ka]

[0041] 15 g (60 mmol) of Bunte salt (2)-2 and 90 g of 3% hydrogen chloride-ethanol solution were placed in a 300 ml three-neck flask and stirred at 65° C. for 6 hours. 100 g of toluene was added to the reaction solution, and the ethanol was distilled off. Then, 50 g of water was added, and after stirring, the organic layer (upper layer) was separated. The separated organic layer was washed with water, and the solvent was distilled off under reduced pressure to obtain 6.2 g of ethyl α-(mercaptomethyl)acrylate (yield: 70%).

[0042] Example 6 (Synthesis of ethyl α-(mercaptomethyl)acrylate)

[0043] [ka]

[0044] 54 g of water, 14.2 g of sodium thiosulfate pentahydrate (equivalent to 57 mmol of sodium thiosulfate), and 10 g (52 mmol) of ethyl α-(bromomethyl)acrylate were placed in a 150 ml four-neck flask and stirred at room temperature for 1 hour. 50 g of toluene was added to the reaction solution, and then 5.7 g of concentrated hydrochloric acid was added dropwise and stirred at 85°C for 6 hours. After the reaction, the organic layer (upper layer) was separated. The separated organic layer was washed with water, and the solvent was distilled off under reduced pressure to obtain 3.4 g of ethyl α-(mercaptomethyl)acrylate (yield: 45%).

Claims

1. The following general formula (2) 【Chemistry 1】 (In the formula, R represents a hydrocarbon group, and M represents Na, K, Li, 1 / 2Ca, 1 / 2Mg, 1 / 2Ba, 1 / 3Al, or NH 4 (Indicates A method for producing an α-(mercaptomethyl)acrylic ester, comprising hydrolyzing a Bunte salt represented by the following formula:

2. 2. The process according to claim 1, wherein R is an alkyl group.

3. 3. The process according to claim 1 or 2, wherein M is Na.

4. A method for producing an α-(mercaptomethyl)acrylic ester, which comprises reacting an α-(halogenomethyl)acrylic ester with a thiosulfate and then hydrolyzing the ester.

5. The following general formula (2) 【Chemistry 2】 (In the formula, R represents a hydrocarbon group, and M represents Na, K, Li, 1 / 2Ca, 1 / 2Mg, 1 / 2Ba, 1 / 3Al, or NH 4 (Indicates Represented by Bunte salt.

6. The Bunte salt of claim 5, wherein R is an alkyl group.

7. 7. The Bunte salt according to claim 5 or 6, wherein M is Na.

Images