WO2012128265A1 - Process for producing cyanoacetic acid esters - Google Patents
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- WO2012128265A1 WO2012128265A1 PCT/JP2012/057099 JP2012057099W WO2012128265A1 WO 2012128265 A1 WO2012128265 A1 WO 2012128265A1 JP 2012057099 W JP2012057099 W JP 2012057099W WO 2012128265 A1 WO2012128265 A1 WO 2012128265A1
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- cyanoacetic acid
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
Definitions
- a cyanoacetic acid ester means a general formula NCCH 2 COOR (wherein R is a linear or branched saturated hydrocarbon group having 1 to 10 carbon atoms, a linear or branched non-cyclic group).
- R 1 is a linear or branched group having 1 to 8 carbon atoms
- Patent Document 1 describes that neopentyl ⁇ -cyanoacetate was produced by reacting cyanoacetic acid, neopentyl alcohol, sulfuric acid and toluene under reflux and removing the produced water azeotropically.
- Patent Document 2 a cyanoacetic acid and C 4 ⁇ C 10 alkanol in an aqueous medium in the presence of an acid catalyst, and reacted while separating the C 4 ⁇ C 10 alkanol / water azeotrope C 4 It describes a method of producing a ⁇ C 10 alkyl cyanoacetate. Furthermore, in Patent Document 3, in the esterification reaction in an aqueous medium, the esterification is performed in the presence of an inert entraining agent such as toluene, and water and the entraining agent are distilled off during the reaction. A method is described.
- Patent Documents 1 to 3 have a problem that the yield of cyanoacetate is low.
- the production methods disclosed in Patent Documents 1 and 3 since toluene is used as the organic solvent, there are problems that many by-products are generated and toxicity is strong. Further, the production method disclosed in Patent Document 2 has a problem that a large amount of alcohol needs to be used for esterification.
- the present invention has been made in view of the above problems, and an object of the present invention is to provide a method for producing a cyanoacetate having a high yield of cyanoacetate and less generation of by-products.
- the organic solvent has a solubility of cyanoacetic acid of a specific amount or more. It has been found that by using a certain first solvent in combination with a second solvent that is substantially insoluble in water, the esterification reaction proceeds efficiently and the yield of cyanoacetate is improved.
- Cyanoacetic acid and general formula ROH (wherein R is a linear or branched saturated hydrocarbon group having 1 to 10 carbon atoms, linear or branched unsaturated hydrocarbon group, alicyclic carbonization)
- a hydrogen group, an aromatic hydrocarbon group, and a formula —C 2 H 4 —O—R 1 (wherein R 1 is a linear or branched saturated hydrocarbon group having 1 to 8 carbon atoms, linear or An organic compound represented by a group selected from the group consisting of a branched unsaturated hydrocarbon group, an alicyclic hydrocarbon group or an aromatic hydrocarbon group) in an organic solvent other than the organic compound.
- the organic solvent includes a first solvent having a solubility of cyanoacetic acid at 25 ° C. of 1 [g / 100 g-solvent] or more, and substantially at 25 ° C. It is substantially composed of a second solvent that is insoluble in water.
- Method of manufacturing that cyanoacetic acid ester 2. 2. The method for producing a cyanoacetic acid ester according to 1 above, wherein the solubility parameter of the first solvent is 6.0 to 10.0. 3. 3. 3. The method for producing a cyanoacetic acid ester according to 1 or 2 above, wherein 20 to 300 parts by mass of the first solvent is used per 1 mol of the cyanoacetic acid.
- the method for producing a cyanoacetic acid ester according to the present invention is substantially insoluble in water and a first solvent having a solubility of cyanoacetic acid of a specific amount or more as an organic solvent other than the organic compound represented by the general formula ROH.
- An esterification reaction of cyanoacetic acid is performed in combination with a second solvent.
- the esterification reaction proceeds efficiently, and as a result, the yield of cyanoacetate is improved.
- production of by-products, such as malonic ester can also be suppressed.
- the method for producing a cyanoacetic acid ester according to the present invention comprises cyanoacetic acid and a general formula ROH (wherein R is a linear or branched saturated hydrocarbon group having 1 to 10 carbon atoms, linear or branched chain).
- An unsaturated hydrocarbon group, an alicyclic hydrocarbon group, an aromatic hydrocarbon group and a formula —C 2 H 4 —O—R 1 (wherein R 1 is a straight chain having 1 to 8 carbon atoms, or An organic group represented by a group selected from the group consisting of a branched saturated hydrocarbon group, a linear or branched unsaturated hydrocarbon group, an alicyclic hydrocarbon group or an aromatic hydrocarbon group)
- the esterification reaction with the compound is carried out in an organic solvent other than the organic compound.
- the organic solvent is substantially composed of a first solvent having a solubility of cyanoacetic acid at 25 ° C.
- the organic solvent is “substantially composed” of the first solvent and the second solvent, but the organic solvent is mainly composed of two components of the first solvent and the second solvent. It is acceptable to contain an amount of the third solvent component that does not affect the conversion reaction.
- the organic solvent used by this invention means a solvent inactive with respect to the compound of the raw material cyanoacetic acid and the said general formula ROH.
- aliphatic alcohols is selected from the group consisting of aliphatic alcohols, alicyclic alcohols, aromatic alcohols, and cellosolves, and serves as a raw material for the esterification reaction.
- the group represented by R has 1 to 10 carbon atoms.
- the group represented by R 1 has 1 to 8 carbon atoms.
- Specific examples of the organic compound include methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, t-butanol, 1-pentanol, 2-pentanol, 3-pentanol, neopentyl.
- Alcohol 1-hexanol, 2-hexanol, 3-hexanol, 2-ethylbutanol, 1-heptanol, 2-heptanol, 3-heptanol, 1-octanol, 2-octanol, 2-ethylhexanol, 1-decanol, 1- Nonanol, 2-methyl-2-butanol, 2-methyl-1-butanol, 3-methyl-1-butanol, 3-methyl-2-butanol, 4-methyl-2-pentanol, allyl alcohol, 2-methyl- 2-propen-1-ol, 3-buten-1-ol, 4- Nten-1-ol, 2-methyl-4-penten-1-ol, 2-ethyl-4-penten-1-ol, 2-ethyl-5-hexen-1-ol, 5-hexen-1-ol, Cyclohexanol, methylcyclohexanol, 2-methoxyethanol, 2-ethoxyethanol, 2-butoxyethanol,
- the solubility of cyanoacetic acid is high, it is methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, t-butanol, 2-methoxyethanol and 2-ethoxyethanol. Methanol, ethanol, 1-propanol and 2-propanol are more preferable.
- the reaction system becomes homogeneous, which is advantageous for the esterification reaction.
- the amount of the organic compound is preferably 1 to 2 times mol, more preferably 1.1 to 1.8 times mol, and 1.2 to 1.6 times mol per mol of cyanoacetic acid. More preferably it is. If the amount of organic compound is less than 1 mole, unreacted cyanoacetic acid remains, and the yield of cyanoacetic acid ester is not improved. On the other hand, when it exceeds 2 moles, the production cost may increase.
- the first solvent used in the present invention is an organic solvent other than the organic compound represented by the above general formula ROH, and the solubility of cyanoacetic acid at 25 ° C. is 1 [g / 100 g-solvent] or more. It is an organic solvent.
- the first solvent must have a solubility of cyanoacetic acid at 25 ° C. of 1 [g / 100 g-solvent] or more (usually 200 [g / 100 g-solvent] or less).
- the solubility is preferably 10 [g / 100 g-solvent] or more, and more preferably 20 [g / 100 g-solvent] or more.
- solubility When the solubility is less than 1 [g / 100 g-solvent], cyanoacetic acid is not substantially dissolved in the first solvent, and the reaction system becomes heterogeneous, resulting in an increase in the yield of cyanoacetate.
- the said solubility represents the mass of the cyanoacetic acid melt
- the solubility parameter (hereinafter also referred to as “SP value”) of the first solvent is preferably 6.0 to 10.0, more preferably 6.5 to 9.5, and 7.0 to More preferably, it is 9.5.
- SP value is less than 6, the solubility of cyanoacetic acid tends to be inferior, and the esterification reaction field becomes inhomogeneous. For example, it is good if the alcohol having high solubility of cyanoacetic acid is not used excessively. It becomes difficult to proceed with a simple esterification reaction.
- the SP value exceeds 10
- the affinity with the organic compound represented by the general formula ROH is improved, and a large amount of the organic compound is distilled together with water in the distilled water by dehydration reflux during esterification. Become. Therefore, the esterification reaction may be difficult to proceed.
- the SP value ( ⁇ ) in the present invention is calculated by the following equation.
- SP value ⁇ ⁇ ( ⁇ H ⁇ RT) / V ⁇ 1/2
- R Gas constant (1.9871 cal / mol ⁇ K)
- T Absolute temperature (K)
- V molar volume (ml / mol)
- the SP values of typical solvents shown in Table 1 are calculated from the numerical values of the heat of molar evaporation at 20 ° C. and the molar volume.
- the heat of molar evaporation and molar volume are based on “Physical properties of chemicals that can be used in Excel” written by Hiroyasu Fukui (published by Maruzen Publishing Co., Ltd.).
- the first solvent polar solvents such as ketone solvents, ester solvents, amide solvents and ether solvents
- polar solvents such as ketone solvents, ester solvents, amide solvents and ether solvents
- the ketone solvents include 1-octanone, 2-octanone, 1-nonanone, 2-nonanone, acetone (SP value 9.8), 4-heptanone, 1-hexanone, 2-hexanone, cyclohexanone.
- ester solvents include methyl acetate, ethyl acetate (SP value 9.0), isopropyl acetate, butyl acetate (SP value 8.7), amyl acetate, 2-ethylhexyl acetate, methyl formate, ethyl formate, butyl formate, formic acid
- Examples include propyl, ethyl lactate, butyl lactate, propyl lactate, diethyl adipate, triethyl acetylcitrate, ethyl benzoate, diethyl oxalate, diethyl carbonate, diethyl phthalate, and ethyl propionate.
- amide solvents include N-methyl-2-pyrrolidone, N, N-dimethylacetamide, N, N-dimethylformamide, hexamethylphosphoric triamide, 1,3-dimethyl-2-imidazolidinone and the like.
- Ether solvents include glycol solvents such as ethylene glycol (SP value 15.9), diethylene glycol and triethylene glycol, as well as ethyl isoamyl ether, ethyl t-butyl ether, ethyl benzyl ether, dimethyl ether, diethyl ether, and dipropyl.
- Examples include ether, diisopropyl ether (SP value 7.2), dibutyl ether, diisoamyl ether, diphenyl ether, dibenzyl ether, dioxane, tetrahydrofuran and the like. These may be used alone or in combination.
- the amount of the first solvent used is preferably 20 to 300 parts by mass, more preferably 30 to 250 parts by mass, and still more preferably 40 to 160 parts by mass with respect to 1 mol of cyanoacetic acid. If the amount used is less than 20 parts by mass, the reaction system is unlikely to be homogeneous, and the yield of cyanoacetate may not be improved. On the other hand, even if it is used in excess of 300 parts by mass, the yield of cyanoacetate is not improved and the production cost is increased.
- the second solvent used in the present invention is an organic solvent that is substantially insoluble in water at 25 ° C. and, of course, is an organic solvent other than the organic compound represented by the general formula ROH. Since the second solvent does not substantially dissolve in water, it becomes easy to separate water generated in the esterification reaction, and as a result, the yield of cyanoacetic acid ester is improved.
- substantially insoluble in water means that the solubility in water at 25 ° C. is less than 1% by mass.
- a hydrocarbon-based solvent may be mentioned.
- aromatic hydrocarbon solvents such as benzene, toluene and xylene; alicyclic hydrocarbon solvents such as cyclohexane and methylcyclohexane; aliphatic hydrocarbon solvents such as pentane, hexane, heptane, octane and decane Is mentioned.
- hexane, cyclohexane and heptane having a low boiling point and relatively low toxicity are preferable. When the boiling point is high, the temperature of the esterification reaction becomes high, and many byproducts such as malonic acid esters are generated.
- the amount of the second solvent used is preferably 20 to 150 parts by mass, more preferably 30 to 130 parts by mass, and still more preferably 40 to 120 parts by mass with respect to 1 mol of cyanoacetic acid.
- the amount used is less than 20 parts by mass, it is difficult to separate water produced by the esterification reaction, and the yield of cyanoacetate ester tends not to be improved.
- the yield of a cyanoacetate ester does not improve and production cost becomes high.
- the mass ratio between the first solvent and the second solvent is preferably 0.5 to 3.0, more preferably 0.8 to 2.5. 1.0 to 2.0 is more preferable. If the mass ratio is less than 0.5, the reaction system is unlikely to be homogeneous and the yield of cyanoacetate may not be improved. On the other hand, if it exceeds 3.0, it is difficult to separate water produced by the esterification reaction, and the yield of cyanoacetate ester tends not to be improved.
- Acid catalyst The esterification reaction of the present invention is carried out in the presence of an acid catalyst.
- an acid catalyst a strong inorganic acid or organic acid is used.
- sulfuric acid, hydrochloric acid, phosphoric acid, benzenesulfonic acid, o-toluenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid examples include fluoroacetic acid, monochloroacetic acid, dichloroacetic acid, and trichloroacetic acid.
- Sulfuric acid or p-toluenesulfonic acid is preferred from the viewpoint of availability and corrosion of the glass lining reaction vessel.
- the amount of the acid catalyst is preferably from 0.01 to 0.5 mol, more preferably from 0.05 to 0.3 mol, per 1 mol of cyanoacetic acid. After completion of the esterification reaction, it is desirable to remove the acid catalyst by washing with water or washing with an alkaline aqueous solution such as sodium carbonate. When the purification step of the cyanoacetate is carried out without the removal step of the acid catalyst, the cyano group is easily hydrolyzed and malonic acid mono- or diester is easily produced as a by-product.
- the method for producing a cyanoacetic acid ester according to the present invention performs the esterification reaction in the organic solvent in the presence of an acid catalyst using the raw materials.
- the esterification reaction is performed while removing generated water while refluxing the organic solvent.
- the reflux temperature is determined by the type of the organic compound represented by the general formula ROH and the types of the first solvent and the second solvent, but is preferably 50 to 100 ° C., and preferably 55 to 90 ° C.
- the temperature is 60 to 80 ° C.
- the reflux temperature is out of the range of 50 to 100 ° C., it can be adjusted by pressurization or depressurization. However, reflux under the atmosphere is preferable from the viewpoint of ease of operation.
- the esterification reaction proceeds slowly and the yield of cyanoacetate may not be improved. On the other hand, when it exceeds 100 ° C., many byproducts such as malonic acid ester may be generated. The esterification reaction ends when the distillate no longer contains water. Next, after cooling the reaction solution, the acid catalyst is washed with water or neutralized with an alkaline aqueous solution to obtain a reaction solution separated into three phases. High purity cyanoacetate can be obtained by distilling the upper layer (organic solvent phase) and middle layer (cyanoacetate phase) of the separated reaction liquid.
- the solubility of cyanoacetic acid was measured as follows. 1. Measurement Method (1) Solubility of Cyanoacetic Acid The solubility of cyanoacetic acid was measured in a room controlled at 25 ° C. About 8 g of cyanoacetic acid (Wako Pure Chemicals special grade) is placed in a 100 ml beaker, and the amount charged is accurately measured until all the cyanoacetic acid dissolves as slowly as possible while stirring with a stirrer. Added. About 0.5 g was added in 10 minutes just before the end point.
- the solubility of cyanoacetic acid was calculated from the weight of the solvent charged up to the end point (unit: [g / 100 g-solvent]). During the addition of the solvent, the beaker was film-wrapped in order to suppress the volatilization of the solvent. On the other hand, in the case of a very low solubility solvent such as n-hexane, about 0.1 g (exact balance) of cyanoacetic acid is stirred in 50.0 g of solvent for 30 minutes, and then filtered and the residue is dried. Undissolved cyanoacetic acid was weighed to determine the amount dissolved. Table 1 shows the SP values of typical organic compounds, the first solvent and the second solvent, and the solubility of cyanoacetic acid.
- a Dean-Stark device (h-type) is installed between the Dimroth cooler and the 1-liter flask to trap the reflux distillate so that the lower layer does not overflow and return to the reaction vessel.
- the lower layer was extracted.
- water was not contained in the distillate, so the reaction vessel was cooled to room temperature.
- the amount of distilled water obtained was 31.3 g.
- the amount of ethanol in the distilled water was 12.5 g, and the amount of water was 16.1 g.
- 100 g of a 16% sodium carbonate aqueous solution was added and then transferred to a separatory funnel.
- Each layer was separated and collected to obtain a reaction solution of 75 g of the upper layer, 220 g of the middle layer, and 124 g of the lower layer.
- the mass% of ethyl cyanoacetate and diethyl malonate in each reaction solution was determined by gas chromatography.
- the content of ethyl cyanoacetate in the above three layers is 9.4% for the upper layer, 44.6% for the middle layer, and 1.9% for the lower layer.
- the combined yield of ethyl cyanoacetate is 105.2 g.
- the determined production amount of diethyl malonate was 1.8 g.
- the yield (mol%) was 93.1 mol% for ethyl cyanoacetate and 1.1 mol% for diethyl malonate relative to the charged cyanoacetic acid.
- Table 2 The mass% of ethyl cyanoacetate and diethyl malonate in each reaction solution was determined by gas chromatography.
- the method for producing a cyanoacetate according to the present invention can obtain a cyanoacetate in a high yield.
- generation of byproducts such as malonic acid esters can be suppressed. Therefore, it is useful as a method for producing cyanoacetate used as an intermediate for pharmaceuticals and agricultural chemicals and an intermediate for industrial products.
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Abstract
Provided is a process for producing cyanoacetic acid esters which achieves high-yield production of cyanoacetic acid esters and minimizes the generation of by-products. A process for producing cyanoacetic acid esters by esterifying cyanoacetic acid with an organic compound represented by the general formula ROH [wherein R is a C1-10 group selected from the group consisting of linear or branched saturated hydrocarbon groups, linear or branched unsaturated hydrocarbon groups, alicyclic hydrocarbon groups, aromatic hydrocarbon groups and -C2H4-O-R1 groups (wherein R1 is a linear or branched saturated hydrocarbon group, a linear or branched unsaturated hydrocarbon group, an alicyclic hydrocarbon group, or an aromatic hydrocarbon group, each group having 1 to 8 carbon atoms)] in an organic solvent other than the organic compound, wherein both a first solvent, the solubility of cyanoacetic acid in which is 1 [g/100g of solvent] or more at 25°C, and a second solvent which is substantially insoluble in water at 25°C are jointly used as the organic solvent.
Description
本発明は、医薬及び農薬の中間体、並びに工業製品の中間体として有用なシアノ酢酸エステルの製造方法に関する。本発明において、シアノ酢酸エステルとは、一般式ＮＣＣＨ2ＣＯＯＲ（式中、Ｒは炭素数１～１０の、直鎖状又は分岐鎖状の飽和炭化水素基、直鎖状又は分岐鎖状の不飽和炭化水素基、脂環式炭化水素基、芳香族炭化水素基及び式－Ｃ2Ｈ4－Ｏ－Ｒ1（式中、Ｒ1は炭素数１～８の、直鎖状又は分岐状の飽和炭化水素基、直鎖状又は分岐鎖状の不飽和炭化水素基、脂環式炭化水素基又は芳香族炭化水素基）からなる群より選ばれる基を示す）で表されるシアノ酢酸エステルを意味する。
The present invention relates to a method for producing cyanoacetate useful as an intermediate for pharmaceuticals and agricultural chemicals, and an intermediate for industrial products. In the present invention, a cyanoacetic acid ester means a general formula NCCH 2 COOR (wherein R is a linear or branched saturated hydrocarbon group having 1 to 10 carbon atoms, a linear or branched non-cyclic group). A saturated hydrocarbon group, an alicyclic hydrocarbon group, an aromatic hydrocarbon group and a formula —C 2 H 4 —O—R 1 (wherein R 1 is a linear or branched group having 1 to 8 carbon atoms) A cyanoacetate represented by a group selected from the group consisting of a saturated hydrocarbon group, a linear or branched unsaturated hydrocarbon group, an alicyclic hydrocarbon group or an aromatic hydrocarbon group) means.
従来、シアノ酢酸エステルの製造方法としては、シアノ酢酸とアルコールとを酸触媒存在下で、脱水エステル化反応させる方法が一般的である。例えば、特許文献１には、シアノ酢酸、ネオペンチルアルコール、硫酸及びトルエンを還流下に反応させ、生成水を共沸下に除去して、ネオペンチルα－シアノアセテートを製造したことが記載されている。また、特許文献２には、シアノ酢酸とＣ4～Ｃ10アルカノールとを水性媒体中で、酸触媒の存在下、Ｃ4～Ｃ10アルカノール／水共沸混合物を分離しながら反応させてＣ4～Ｃ10アルキルシアノアセテートを製造する方法が記載されている。更に、特許文献３には、水性媒体中のエステル化反応において、当該エステル化がトルエン等の不活性共留剤の存在下に行われ、反応の間に、水と共留剤を蒸留除去する方法が記載されている。
Conventionally, as a method for producing a cyanoacetic acid ester, a method in which cyanoacetic acid and an alcohol are subjected to dehydration esterification reaction in the presence of an acid catalyst is generally used. For example, Patent Document 1 describes that neopentyl α-cyanoacetate was produced by reacting cyanoacetic acid, neopentyl alcohol, sulfuric acid and toluene under reflux and removing the produced water azeotropically. . In Patent Document 2, and a cyanoacetic acid and C 4 ~ C 10 alkanol in an aqueous medium in the presence of an acid catalyst, and reacted while separating the C 4 ~ C 10 alkanol / water azeotrope C 4 It describes a method of producing a ~ C 10 alkyl cyanoacetate. Furthermore, in Patent Document 3, in the esterification reaction in an aqueous medium, the esterification is performed in the presence of an inert entraining agent such as toluene, and water and the entraining agent are distilled off during the reaction. A method is described.
しかしながら、特許文献１～３に開示されるようなシアノ酢酸エステルの製造方法では、シアノ酢酸エステルの収率が低いという問題がある。また、特許文献１及び３に開示されるような製造方法では、有機溶剤としてトルエンを使用することから、副生成物が多く発生することや、毒性が強いという問題がある。また、特許文献２に開示されるような製造方法では、エステル化のために多量のアルコールを使用する必要があるという問題がある。
However, the method for producing cyanoacetate disclosed in Patent Documents 1 to 3 has a problem that the yield of cyanoacetate is low. In addition, in the production methods disclosed in Patent Documents 1 and 3, since toluene is used as the organic solvent, there are problems that many by-products are generated and toxicity is strong. Further, the production method disclosed in Patent Document 2 has a problem that a large amount of alcohol needs to be used for esterification.
本発明は、上記問題点に鑑みなされたものであって、その目的は、シアノ酢酸エステルの収率が高く、副生成物の発生が少ないシアノ酢酸エステルの製造方法を提供することにある。
The present invention has been made in view of the above problems, and an object of the present invention is to provide a method for producing a cyanoacetate having a high yield of cyanoacetate and less generation of by-products.
本発明者らは、シアノ酢酸とＯＨ基を有する有機化合物とを有機溶剤中でエステル化反応させることによりシアノ酢酸エステルを製造する方法において、前記有機溶剤として、シアノ酢酸の溶解度が特定量以上である第一溶剤と、実質的に水に不溶である第二溶剤とを併用することにより、エステル化反応が効率的に進行し、シアノ酢酸エステルの収率が向上することを見出した。
In the method for producing a cyanoacetic acid ester by reacting cyanoacetic acid and an organic compound having an OH group in an organic solvent, the organic solvent has a solubility of cyanoacetic acid of a specific amount or more. It has been found that by using a certain first solvent in combination with a second solvent that is substantially insoluble in water, the esterification reaction proceeds efficiently and the yield of cyanoacetate is improved.
すなわち、本発明は以下の通りである。
１．シアノ酢酸と一般式ＲＯＨ（式中、Ｒは炭素数１～１０の、直鎖状又は分岐鎖状の飽和炭化水素基、直鎖状又は分岐鎖状の不飽和炭化水素基、脂環式炭化水素基、芳香族炭化水素基及び式－Ｃ2Ｈ4－Ｏ－Ｒ1（式中、Ｒ1は炭素数１～８の、直鎖状又は分岐状の飽和炭化水素基、直鎖状又は分岐鎖状の不飽和炭化水素基、脂環式炭化水素基又は芳香族炭化水素基）からなる群より選ばれる基を示す）で表わされる有機化合物とを、前記有機化合物以外の有機溶剤中でエステル化反応させることによりシアノ酢酸エステルを製造する方法において、前記有機溶剤は、２５℃におけるシアノ酢酸の溶解度が１［ｇ／１００ｇ－溶剤］以上である第一溶剤と、２５℃において実質的に水に不溶である第二溶剤から実質的に構成されることを特徴とするシアノ酢酸エステルの製造方法。
２．上記第一溶剤の溶解度パラメーターが、６．０～１０．０であることを特徴とする上記１に記載のシアノ酢酸エステルの製造方法。
３．上記シアノ酢酸１モルに対して、上記第一溶剤を２０～３００質量部用いることを特徴とする上記１又は２に記載のシアノ酢酸エステルの製造方法。
４．上記シアノ酢酸１モルに対して、上記第二溶剤を２０～１５０質量部用いることを特徴とする上記１～３のいずれかに記載のシアノ酢酸エステルの製造方法。
５．上記第一溶剤と第二溶剤の質量比（第一溶剤／第二溶剤）が、０．５～３．０であることを特徴とする上記１～４のいずれかに記載のシアノ酢酸エステルの製造方法。
６．上記有機化合物量が、シアノ酢酸１モルに対し、１～２倍モルであることを特徴とする上記１～５のいずれかに記載のシアノ酢酸エステルの製造方法。 That is, the present invention is as follows.
1. Cyanoacetic acid and general formula ROH (wherein R is a linear or branched saturated hydrocarbon group having 1 to 10 carbon atoms, linear or branched unsaturated hydrocarbon group, alicyclic carbonization) A hydrogen group, an aromatic hydrocarbon group, and a formula —C 2 H 4 —O—R 1 (wherein R 1 is a linear or branched saturated hydrocarbon group having 1 to 8 carbon atoms, linear or An organic compound represented by a group selected from the group consisting of a branched unsaturated hydrocarbon group, an alicyclic hydrocarbon group or an aromatic hydrocarbon group) in an organic solvent other than the organic compound. In the method for producing a cyanoacetic acid ester by an esterification reaction, the organic solvent includes a first solvent having a solubility of cyanoacetic acid at 25 ° C. of 1 [g / 100 g-solvent] or more, and substantially at 25 ° C. It is substantially composed of a second solvent that is insoluble in water. Method of manufacturing that cyanoacetic acid ester.
2. 2. The method for producing a cyanoacetic acid ester according to 1 above, wherein the solubility parameter of the first solvent is 6.0 to 10.0.
3. 3. The method for producing a cyanoacetic acid ester according to 1 or 2 above, wherein 20 to 300 parts by mass of the first solvent is used per 1 mol of the cyanoacetic acid.
4). 4. The method for producing a cyanoacetic acid ester according to any one of 1 to 3 above, wherein 20 to 150 parts by mass of the second solvent is used per 1 mol of the cyanoacetic acid.
5. 5. The cyanoacetate ester according to any one of 1 to 4 above, wherein the mass ratio of the first solvent to the second solvent (first solvent / second solvent) is 0.5 to 3.0. Production method.
6). 6. The method for producing a cyanoacetic acid ester according to any one of 1 to 5 above, wherein the amount of the organic compound is 1 to 2 moles per mole of cyanoacetic acid.
１．シアノ酢酸と一般式ＲＯＨ（式中、Ｒは炭素数１～１０の、直鎖状又は分岐鎖状の飽和炭化水素基、直鎖状又は分岐鎖状の不飽和炭化水素基、脂環式炭化水素基、芳香族炭化水素基及び式－Ｃ2Ｈ4－Ｏ－Ｒ1（式中、Ｒ1は炭素数１～８の、直鎖状又は分岐状の飽和炭化水素基、直鎖状又は分岐鎖状の不飽和炭化水素基、脂環式炭化水素基又は芳香族炭化水素基）からなる群より選ばれる基を示す）で表わされる有機化合物とを、前記有機化合物以外の有機溶剤中でエステル化反応させることによりシアノ酢酸エステルを製造する方法において、前記有機溶剤は、２５℃におけるシアノ酢酸の溶解度が１［ｇ／１００ｇ－溶剤］以上である第一溶剤と、２５℃において実質的に水に不溶である第二溶剤から実質的に構成されることを特徴とするシアノ酢酸エステルの製造方法。
２．上記第一溶剤の溶解度パラメーターが、６．０～１０．０であることを特徴とする上記１に記載のシアノ酢酸エステルの製造方法。
３．上記シアノ酢酸１モルに対して、上記第一溶剤を２０～３００質量部用いることを特徴とする上記１又は２に記載のシアノ酢酸エステルの製造方法。
４．上記シアノ酢酸１モルに対して、上記第二溶剤を２０～１５０質量部用いることを特徴とする上記１～３のいずれかに記載のシアノ酢酸エステルの製造方法。
５．上記第一溶剤と第二溶剤の質量比（第一溶剤／第二溶剤）が、０．５～３．０であることを特徴とする上記１～４のいずれかに記載のシアノ酢酸エステルの製造方法。
６．上記有機化合物量が、シアノ酢酸１モルに対し、１～２倍モルであることを特徴とする上記１～５のいずれかに記載のシアノ酢酸エステルの製造方法。 That is, the present invention is as follows.
1. Cyanoacetic acid and general formula ROH (wherein R is a linear or branched saturated hydrocarbon group having 1 to 10 carbon atoms, linear or branched unsaturated hydrocarbon group, alicyclic carbonization) A hydrogen group, an aromatic hydrocarbon group, and a formula —C 2 H 4 —O—R 1 (wherein R 1 is a linear or branched saturated hydrocarbon group having 1 to 8 carbon atoms, linear or An organic compound represented by a group selected from the group consisting of a branched unsaturated hydrocarbon group, an alicyclic hydrocarbon group or an aromatic hydrocarbon group) in an organic solvent other than the organic compound. In the method for producing a cyanoacetic acid ester by an esterification reaction, the organic solvent includes a first solvent having a solubility of cyanoacetic acid at 25 ° C. of 1 [g / 100 g-solvent] or more, and substantially at 25 ° C. It is substantially composed of a second solvent that is insoluble in water. Method of manufacturing that cyanoacetic acid ester.
2. 2. The method for producing a cyanoacetic acid ester according to 1 above, wherein the solubility parameter of the first solvent is 6.0 to 10.0.
3. 3. The method for producing a cyanoacetic acid ester according to 1 or 2 above, wherein 20 to 300 parts by mass of the first solvent is used per 1 mol of the cyanoacetic acid.
4). 4. The method for producing a cyanoacetic acid ester according to any one of 1 to 3 above, wherein 20 to 150 parts by mass of the second solvent is used per 1 mol of the cyanoacetic acid.
5. 5. The cyanoacetate ester according to any one of 1 to 4 above, wherein the mass ratio of the first solvent to the second solvent (first solvent / second solvent) is 0.5 to 3.0. Production method.
6). 6. The method for producing a cyanoacetic acid ester according to any one of 1 to 5 above, wherein the amount of the organic compound is 1 to 2 moles per mole of cyanoacetic acid.
本発明に係るシアノ酢酸エステルの製造方法は、上記一般式ＲＯＨで表される有機化合物以外の有機溶剤として、シアノ酢酸の溶解度が特定量以上の第一溶剤と、実質的に水に不溶である第二溶剤とを併用して、シアノ酢酸のエステル化反応を行う。この製造方法は、反応系内が均質であることや、エステル化により生成する水を分離し易いため、エステル化反応が効率的に進行し、結果としてシアノ酢酸エステルの収率が向上する。また、この製造方法によれば、マロン酸エステル等の副生成物の発生を抑制することもできる。
The method for producing a cyanoacetic acid ester according to the present invention is substantially insoluble in water and a first solvent having a solubility of cyanoacetic acid of a specific amount or more as an organic solvent other than the organic compound represented by the general formula ROH. An esterification reaction of cyanoacetic acid is performed in combination with a second solvent. In this production method, since the reaction system is homogeneous and water produced by esterification is easily separated, the esterification reaction proceeds efficiently, and as a result, the yield of cyanoacetate is improved. Moreover, according to this manufacturing method, generation | occurrence | production of by-products, such as malonic ester, can also be suppressed.
本発明の一実施形態について説明すると以下の通りであるが、本発明はこれに限定されるものではない。
本発明に係るシアノ酢酸エステルの製造方法は、シアノ酢酸と一般式ＲＯＨ（式中、Ｒは炭素数１～１０の、直鎖状又は分岐鎖状の飽和炭化水素基、直鎖状又は分岐鎖状の不飽和炭化水素基、脂環式炭化水素基、芳香族炭化水素基及び式－Ｃ2Ｈ4－Ｏ－Ｒ1（式中、Ｒ1は炭素数１～８の、直鎖状又は分岐状の飽和炭化水素基、直鎖状又は分岐鎖状の不飽和炭化水素基、脂環式炭化水素基又は芳香族炭化水素基）からなる群より選ばれる基を示す）で表される有機化合物とのエステル化反応を、該有機化合物以外の有機溶剤中で行う。詳しくは、この有機溶剤は、２５℃におけるシアノ酢酸の溶解度が１［ｇ／１００ｇ－溶剤］以上である第一溶剤と、２５℃において実質的に水に不溶である第二溶剤とから実質的に構成される。有機溶剤が上記第一溶剤と上記第二溶剤とから「実質的に構成される」とは、有機溶剤が上記第一溶剤と上記第二溶剤の２成分から大部分構成されるが、上記エステル化反応に影響を与えない量の第３の溶剤成分を含有することは許容されることを意味する。なお、本発明で使用する有機溶剤は、原料であるシアノ酢酸及び上記一般式ＲＯＨの化合物に対して不活性な溶剤を意味する。 An embodiment of the present invention will be described as follows, but the present invention is not limited to this.
The method for producing a cyanoacetic acid ester according to the present invention comprises cyanoacetic acid and a general formula ROH (wherein R is a linear or branched saturated hydrocarbon group having 1 to 10 carbon atoms, linear or branched chain). An unsaturated hydrocarbon group, an alicyclic hydrocarbon group, an aromatic hydrocarbon group and a formula —C 2 H 4 —O—R 1 (wherein R 1 is a straight chain having 1 to 8 carbon atoms, or An organic group represented by a group selected from the group consisting of a branched saturated hydrocarbon group, a linear or branched unsaturated hydrocarbon group, an alicyclic hydrocarbon group or an aromatic hydrocarbon group) The esterification reaction with the compound is carried out in an organic solvent other than the organic compound. Specifically, the organic solvent is substantially composed of a first solvent having a solubility of cyanoacetic acid at 25 ° C. of 1 [g / 100 g-solvent] or more and a second solvent substantially insoluble in water at 25 ° C. Configured. The organic solvent is “substantially composed” of the first solvent and the second solvent, but the organic solvent is mainly composed of two components of the first solvent and the second solvent. It is acceptable to contain an amount of the third solvent component that does not affect the conversion reaction. In addition, the organic solvent used by this invention means a solvent inactive with respect to the compound of the raw material cyanoacetic acid and the said general formula ROH.
本発明に係るシアノ酢酸エステルの製造方法は、シアノ酢酸と一般式ＲＯＨ（式中、Ｒは炭素数１～１０の、直鎖状又は分岐鎖状の飽和炭化水素基、直鎖状又は分岐鎖状の不飽和炭化水素基、脂環式炭化水素基、芳香族炭化水素基及び式－Ｃ2Ｈ4－Ｏ－Ｒ1（式中、Ｒ1は炭素数１～８の、直鎖状又は分岐状の飽和炭化水素基、直鎖状又は分岐鎖状の不飽和炭化水素基、脂環式炭化水素基又は芳香族炭化水素基）からなる群より選ばれる基を示す）で表される有機化合物とのエステル化反応を、該有機化合物以外の有機溶剤中で行う。詳しくは、この有機溶剤は、２５℃におけるシアノ酢酸の溶解度が１［ｇ／１００ｇ－溶剤］以上である第一溶剤と、２５℃において実質的に水に不溶である第二溶剤とから実質的に構成される。有機溶剤が上記第一溶剤と上記第二溶剤とから「実質的に構成される」とは、有機溶剤が上記第一溶剤と上記第二溶剤の２成分から大部分構成されるが、上記エステル化反応に影響を与えない量の第３の溶剤成分を含有することは許容されることを意味する。なお、本発明で使用する有機溶剤は、原料であるシアノ酢酸及び上記一般式ＲＯＨの化合物に対して不活性な溶剤を意味する。 An embodiment of the present invention will be described as follows, but the present invention is not limited to this.
The method for producing a cyanoacetic acid ester according to the present invention comprises cyanoacetic acid and a general formula ROH (wherein R is a linear or branched saturated hydrocarbon group having 1 to 10 carbon atoms, linear or branched chain). An unsaturated hydrocarbon group, an alicyclic hydrocarbon group, an aromatic hydrocarbon group and a formula —C 2 H 4 —O—R 1 (wherein R 1 is a straight chain having 1 to 8 carbon atoms, or An organic group represented by a group selected from the group consisting of a branched saturated hydrocarbon group, a linear or branched unsaturated hydrocarbon group, an alicyclic hydrocarbon group or an aromatic hydrocarbon group) The esterification reaction with the compound is carried out in an organic solvent other than the organic compound. Specifically, the organic solvent is substantially composed of a first solvent having a solubility of cyanoacetic acid at 25 ° C. of 1 [g / 100 g-solvent] or more and a second solvent substantially insoluble in water at 25 ° C. Configured. The organic solvent is “substantially composed” of the first solvent and the second solvent, but the organic solvent is mainly composed of two components of the first solvent and the second solvent. It is acceptable to contain an amount of the third solvent component that does not affect the conversion reaction. In addition, the organic solvent used by this invention means a solvent inactive with respect to the compound of the raw material cyanoacetic acid and the said general formula ROH.
１．一般式ＲＯＨで表される有機化合物
本発明に用いられる一般式ＲＯＨ（式中、Ｒは炭素数１～１０の、直鎖状又は分岐鎖状の飽和炭化水素基、直鎖状又は分岐鎖状の不飽和炭化水素基、脂環式炭化水素基、芳香族炭化水素基及び式－Ｃ2Ｈ4－Ｏ－Ｒ1（式中、Ｒ1は炭素数１～８の、直鎖状又は分岐状の飽和炭化水素基、直鎖状又は分岐鎖状の不飽和炭化水素基、脂環式炭化水素基又は芳香族炭化水素基）からなる群より選ばれる基を示す）で表される有機化合物は、具体的には、脂肪族アルコール類、脂環族アルコール類、芳香族アルコール類、及びセロソルブ類からなる群より選択されるものであり、エステル化反応の原料となるものである。上記Ｒで表わされる基の炭素数は１～１０である。また、上記Ｒ1で表わされる基の炭素数は１～８である。前記有機化合物の具体例としては、メタノール、エタノール、１－プロパノール、２－プロパノール、１－ブタノール、２－ブタノール、ｔ－ブタノール、１－ペンタノール、２－ペンタノール、３－ペンタノール、ネオペンチルアルコール、１－ヘキサノール、２－ヘキサノール、３－ヘキサノール、２－エチルブタノール、１－ヘプタノール、２－ヘプタノール、３－ヘプタノール、１－オクタノール、２－オクタノール、２－エチルヘキサノール、１－デカノール、１－ノナノール、２－メチル－２－ブタノール、２－メチル－１－ブタノール、３－メチル－１－ブタノール、３－メチル－２－ブタノール、４－メチル－２－ペンタノール、アリルアルコール、２－メチル－２－プロペン－１－オール、３－ブテン－１－オール、４－ペンテン－１－オール、２－メチル－４－ペンテン－１－オール、２－エチル－４－ペンテン－１－オール、２－エチル－５－ヘキセン－１－オール、５－ヘキセン－１－オール、シクロヘキサノール、メチルシクロヘキサノール、２－メトキシエタノール、２－エトキシエタノール、２－ブトキシエタノール、２－フェノキシエタノール、２－（ベンジルオキシ）エタノール、２－（シクロヘキシルオキシ）エタノール、２－プロポキシエタノール、２－イソプロポキシエタノール、２－イソブトキシエタノール、エチルブチルセロソルブ、２－ｔ－ブトキシエタノール、及びエチレングリコールモノヘキシルエーテル等が挙げられる。これらの中でも、シアノ酢酸の溶解度が高いことから、メタノール、エタノール、１－プロパノール、２－プロパノール、１－ブタノール、２－ブタノール、ｔ－ブタノール、２－メトキシエタノール及び２－エトキシエタノールであることが好ましく、メタノール、エタノール、１－プロパノール、２－プロパノールであることがより好ましい。シアノ酢酸の溶解度が高い有機化合物の場合は、反応系が均質になり、エステル化反応に有利となる。 1. Organic compound represented by general formula ROH General formula ROH used in the present invention (wherein R is a linear or branched saturated hydrocarbon group having 1 to 10 carbon atoms, linear or branched chain) An unsaturated hydrocarbon group, an alicyclic hydrocarbon group, an aromatic hydrocarbon group and a formula —C 2 H 4 —O—R 1 (wherein R 1 is a linear or branched group having 1 to 8 carbon atoms) A saturated hydrocarbon group, a linear or branched unsaturated hydrocarbon group, an alicyclic hydrocarbon group or an aromatic hydrocarbon group). Specifically, is selected from the group consisting of aliphatic alcohols, alicyclic alcohols, aromatic alcohols, and cellosolves, and serves as a raw material for the esterification reaction. The group represented by R has 1 to 10 carbon atoms. The group represented by R 1 has 1 to 8 carbon atoms. Specific examples of the organic compound include methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, t-butanol, 1-pentanol, 2-pentanol, 3-pentanol, neopentyl. Alcohol, 1-hexanol, 2-hexanol, 3-hexanol, 2-ethylbutanol, 1-heptanol, 2-heptanol, 3-heptanol, 1-octanol, 2-octanol, 2-ethylhexanol, 1-decanol, 1- Nonanol, 2-methyl-2-butanol, 2-methyl-1-butanol, 3-methyl-1-butanol, 3-methyl-2-butanol, 4-methyl-2-pentanol, allyl alcohol, 2-methyl- 2-propen-1-ol, 3-buten-1-ol, 4- Nten-1-ol, 2-methyl-4-penten-1-ol, 2-ethyl-4-penten-1-ol, 2-ethyl-5-hexen-1-ol, 5-hexen-1-ol, Cyclohexanol, methylcyclohexanol, 2-methoxyethanol, 2-ethoxyethanol, 2-butoxyethanol, 2-phenoxyethanol, 2- (benzyloxy) ethanol, 2- (cyclohexyloxy) ethanol, 2-propoxyethanol, 2-iso Examples thereof include propoxyethanol, 2-isobutoxyethanol, ethylbutyl cellosolve, 2-t-butoxyethanol, and ethylene glycol monohexyl ether. Among these, since the solubility of cyanoacetic acid is high, it is methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, t-butanol, 2-methoxyethanol and 2-ethoxyethanol. Methanol, ethanol, 1-propanol and 2-propanol are more preferable. In the case of an organic compound having a high solubility of cyanoacetic acid, the reaction system becomes homogeneous, which is advantageous for the esterification reaction.
本発明に用いられる一般式ＲＯＨ（式中、Ｒは炭素数１～１０の、直鎖状又は分岐鎖状の飽和炭化水素基、直鎖状又は分岐鎖状の不飽和炭化水素基、脂環式炭化水素基、芳香族炭化水素基及び式－Ｃ2Ｈ4－Ｏ－Ｒ1（式中、Ｒ1は炭素数１～８の、直鎖状又は分岐状の飽和炭化水素基、直鎖状又は分岐鎖状の不飽和炭化水素基、脂環式炭化水素基又は芳香族炭化水素基）からなる群より選ばれる基を示す）で表される有機化合物は、具体的には、脂肪族アルコール類、脂環族アルコール類、芳香族アルコール類、及びセロソルブ類からなる群より選択されるものであり、エステル化反応の原料となるものである。上記Ｒで表わされる基の炭素数は１～１０である。また、上記Ｒ1で表わされる基の炭素数は１～８である。前記有機化合物の具体例としては、メタノール、エタノール、１－プロパノール、２－プロパノール、１－ブタノール、２－ブタノール、ｔ－ブタノール、１－ペンタノール、２－ペンタノール、３－ペンタノール、ネオペンチルアルコール、１－ヘキサノール、２－ヘキサノール、３－ヘキサノール、２－エチルブタノール、１－ヘプタノール、２－ヘプタノール、３－ヘプタノール、１－オクタノール、２－オクタノール、２－エチルヘキサノール、１－デカノール、１－ノナノール、２－メチル－２－ブタノール、２－メチル－１－ブタノール、３－メチル－１－ブタノール、３－メチル－２－ブタノール、４－メチル－２－ペンタノール、アリルアルコール、２－メチル－２－プロペン－１－オール、３－ブテン－１－オール、４－ペンテン－１－オール、２－メチル－４－ペンテン－１－オール、２－エチル－４－ペンテン－１－オール、２－エチル－５－ヘキセン－１－オール、５－ヘキセン－１－オール、シクロヘキサノール、メチルシクロヘキサノール、２－メトキシエタノール、２－エトキシエタノール、２－ブトキシエタノール、２－フェノキシエタノール、２－（ベンジルオキシ）エタノール、２－（シクロヘキシルオキシ）エタノール、２－プロポキシエタノール、２－イソプロポキシエタノール、２－イソブトキシエタノール、エチルブチルセロソルブ、２－ｔ－ブトキシエタノール、及びエチレングリコールモノヘキシルエーテル等が挙げられる。これらの中でも、シアノ酢酸の溶解度が高いことから、メタノール、エタノール、１－プロパノール、２－プロパノール、１－ブタノール、２－ブタノール、ｔ－ブタノール、２－メトキシエタノール及び２－エトキシエタノールであることが好ましく、メタノール、エタノール、１－プロパノール、２－プロパノールであることがより好ましい。シアノ酢酸の溶解度が高い有機化合物の場合は、反応系が均質になり、エステル化反応に有利となる。 1. Organic compound represented by general formula ROH General formula ROH used in the present invention (wherein R is a linear or branched saturated hydrocarbon group having 1 to 10 carbon atoms, linear or branched chain) An unsaturated hydrocarbon group, an alicyclic hydrocarbon group, an aromatic hydrocarbon group and a formula —C 2 H 4 —O—R 1 (wherein R 1 is a linear or branched group having 1 to 8 carbon atoms) A saturated hydrocarbon group, a linear or branched unsaturated hydrocarbon group, an alicyclic hydrocarbon group or an aromatic hydrocarbon group). Specifically, is selected from the group consisting of aliphatic alcohols, alicyclic alcohols, aromatic alcohols, and cellosolves, and serves as a raw material for the esterification reaction. The group represented by R has 1 to 10 carbon atoms. The group represented by R 1 has 1 to 8 carbon atoms. Specific examples of the organic compound include methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, t-butanol, 1-pentanol, 2-pentanol, 3-pentanol, neopentyl. Alcohol, 1-hexanol, 2-hexanol, 3-hexanol, 2-ethylbutanol, 1-heptanol, 2-heptanol, 3-heptanol, 1-octanol, 2-octanol, 2-ethylhexanol, 1-decanol, 1- Nonanol, 2-methyl-2-butanol, 2-methyl-1-butanol, 3-methyl-1-butanol, 3-methyl-2-butanol, 4-methyl-2-pentanol, allyl alcohol, 2-methyl- 2-propen-1-ol, 3-buten-1-ol, 4- Nten-1-ol, 2-methyl-4-penten-1-ol, 2-ethyl-4-penten-1-ol, 2-ethyl-5-hexen-1-ol, 5-hexen-1-ol, Cyclohexanol, methylcyclohexanol, 2-methoxyethanol, 2-ethoxyethanol, 2-butoxyethanol, 2-phenoxyethanol, 2- (benzyloxy) ethanol, 2- (cyclohexyloxy) ethanol, 2-propoxyethanol, 2-iso Examples thereof include propoxyethanol, 2-isobutoxyethanol, ethylbutyl cellosolve, 2-t-butoxyethanol, and ethylene glycol monohexyl ether. Among these, since the solubility of cyanoacetic acid is high, it is methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, t-butanol, 2-methoxyethanol and 2-ethoxyethanol. Methanol, ethanol, 1-propanol and 2-propanol are more preferable. In the case of an organic compound having a high solubility of cyanoacetic acid, the reaction system becomes homogeneous, which is advantageous for the esterification reaction.
上記有機化合物量は、シアノ酢酸１モルに対し、１～２倍モルであることが好ましく、１．１～１．８倍モルであることがより好ましく、１．２～１．６倍モルであることが更に好ましい。有機化合物量が、１倍モル未満では、未反応のシアノ酢酸が残存することとなり、シアノ酢酸エステルの収率が向上しない。一方、２倍モルを超えると、製造コストが高くなる場合がある。
The amount of the organic compound is preferably 1 to 2 times mol, more preferably 1.1 to 1.8 times mol, and 1.2 to 1.6 times mol per mol of cyanoacetic acid. More preferably it is. If the amount of organic compound is less than 1 mole, unreacted cyanoacetic acid remains, and the yield of cyanoacetic acid ester is not improved. On the other hand, when it exceeds 2 moles, the production cost may increase.
２．第一溶剤
本発明に用いられる第一溶剤は、上記一般式ＲＯＨで表される有機化合物以外の有機溶剤であり、かつ、２５℃におけるシアノ酢酸の溶解度が１［ｇ／１００ｇ－溶剤］以上である有機溶剤である。
上記第一溶剤は、２５℃におけるシアノ酢酸の溶解度が１［ｇ／１００ｇ－溶剤］以上（通常２００［ｇ／１００ｇ－溶剤］以下）であることが必要である。当該溶解度は１０［ｇ／１００ｇ－溶剤］以上であることが好ましく、２０［ｇ／１００ｇ－溶剤］以上であることがより好ましい。溶解度が１［ｇ／１００ｇ－溶剤］未満では、シアノ酢酸が実質的に第一溶剤に溶解せず、反応系が不均質となるため、結果としてシアノ酢酸エステルの収率が向上しない。
なお、上記溶解度は、溶剤１００ｇに溶解するシアノ酢酸の質量を表しており、測定方法は後述する。 2. First Solvent The first solvent used in the present invention is an organic solvent other than the organic compound represented by the above general formula ROH, and the solubility of cyanoacetic acid at 25 ° C. is 1 [g / 100 g-solvent] or more. It is an organic solvent.
The first solvent must have a solubility of cyanoacetic acid at 25 ° C. of 1 [g / 100 g-solvent] or more (usually 200 [g / 100 g-solvent] or less). The solubility is preferably 10 [g / 100 g-solvent] or more, and more preferably 20 [g / 100 g-solvent] or more. When the solubility is less than 1 [g / 100 g-solvent], cyanoacetic acid is not substantially dissolved in the first solvent, and the reaction system becomes heterogeneous, resulting in an increase in the yield of cyanoacetate.
In addition, the said solubility represents the mass of the cyanoacetic acid melt | dissolved in 100 g of solvents, and a measuring method is mentioned later.
本発明に用いられる第一溶剤は、上記一般式ＲＯＨで表される有機化合物以外の有機溶剤であり、かつ、２５℃におけるシアノ酢酸の溶解度が１［ｇ／１００ｇ－溶剤］以上である有機溶剤である。
上記第一溶剤は、２５℃におけるシアノ酢酸の溶解度が１［ｇ／１００ｇ－溶剤］以上（通常２００［ｇ／１００ｇ－溶剤］以下）であることが必要である。当該溶解度は１０［ｇ／１００ｇ－溶剤］以上であることが好ましく、２０［ｇ／１００ｇ－溶剤］以上であることがより好ましい。溶解度が１［ｇ／１００ｇ－溶剤］未満では、シアノ酢酸が実質的に第一溶剤に溶解せず、反応系が不均質となるため、結果としてシアノ酢酸エステルの収率が向上しない。
なお、上記溶解度は、溶剤１００ｇに溶解するシアノ酢酸の質量を表しており、測定方法は後述する。 2. First Solvent The first solvent used in the present invention is an organic solvent other than the organic compound represented by the above general formula ROH, and the solubility of cyanoacetic acid at 25 ° C. is 1 [g / 100 g-solvent] or more. It is an organic solvent.
The first solvent must have a solubility of cyanoacetic acid at 25 ° C. of 1 [g / 100 g-solvent] or more (usually 200 [g / 100 g-solvent] or less). The solubility is preferably 10 [g / 100 g-solvent] or more, and more preferably 20 [g / 100 g-solvent] or more. When the solubility is less than 1 [g / 100 g-solvent], cyanoacetic acid is not substantially dissolved in the first solvent, and the reaction system becomes heterogeneous, resulting in an increase in the yield of cyanoacetate.
In addition, the said solubility represents the mass of the cyanoacetic acid melt | dissolved in 100 g of solvents, and a measuring method is mentioned later.
上記第一溶剤の溶解度パラメーター（以下、「ＳＰ値」ともいう）は、６．０～１０．０であることが好ましく、６．５～９．５であることがより好ましく、７．０～９．５であることが更に好ましい。ＳＰ値が６未満では、シアノ酢酸の溶解性が劣る傾向にあるため、エステル化の反応の場が不均質となり、例えば、シアノ酢酸の溶解度が高いアルコール等をより過剰に使用するなどしないと良好なエステル化反応を進めることが難しくなる。一方、ＳＰ値が１０を超えると、一般式ＲＯＨで表される有機化合物との親和性がよくなり、エステル化の際の脱水還流による留出水に、水と共に前記有機化合物の留出が多くなる。よって、エステル化反応が進みにくくなる場合がある。
The solubility parameter (hereinafter also referred to as “SP value”) of the first solvent is preferably 6.0 to 10.0, more preferably 6.5 to 9.5, and 7.0 to More preferably, it is 9.5. When the SP value is less than 6, the solubility of cyanoacetic acid tends to be inferior, and the esterification reaction field becomes inhomogeneous. For example, it is good if the alcohol having high solubility of cyanoacetic acid is not used excessively. It becomes difficult to proceed with a simple esterification reaction. On the other hand, when the SP value exceeds 10, the affinity with the organic compound represented by the general formula ROH is improved, and a large amount of the organic compound is distilled together with water in the distilled water by dehydration reflux during esterification. Become. Therefore, the esterification reaction may be difficult to proceed.
本発明におけるＳＰ値（δ）は、次式によって計算したものである。
ＳＰ値 δ＝｛（△Ｈ－ＲＴ）／Ｖ｝1/2
δ ：ＳＰ値（（ｃａｌ／ｍｌ）1/2）
△Ｈ：モル蒸発熱（ｃａｌ／ｍｏｌ）
Ｒ ：気体定数（１．９８７１ｃａｌ／ｍｏｌ・Ｋ）
Ｔ ：絶対温度（Ｋ）
Ｖ ：モル体積（ｍｌ／ｍｏｌ）
また、混合系のＳＰ値は、
δmix＝Σ（φi・Ｖi・δi）／Σ（φi・Ｖi）
δi ：溶剤ｉのＳＰ値
φi ：溶剤ｉの容積分率 （ここで、Σφi＝１）
Ｖi ：溶剤ｉのモル容積
によって求められる。
表１に示した代表的な溶剤のＳＰ値は、２０℃におけるモル蒸発熱とモル体積の数値から算出したものである。尚、モル蒸発熱とモル体積は、『Ｅｘｃｅｌで使える化学物質の物性』福井弘康著（丸善出版社発行）による。 The SP value (δ) in the present invention is calculated by the following equation.
SP value δ = {(ΔH−RT) / V} 1/2
δ: SP value ((cal / ml) 1/2 )
ΔH: heat of vaporization (cal / mol)
R: Gas constant (1.9871 cal / mol · K)
T: Absolute temperature (K)
V: molar volume (ml / mol)
The SP value of the mixed system is
δ mix = Σ (φ i · V i · δ i ) / Σ (φ i · V i )
δ i : SP value of solvent i φ i : Volume fraction of solvent i (where Σφ i = 1)
V i : determined by the molar volume of solvent i.
The SP values of typical solvents shown in Table 1 are calculated from the numerical values of the heat of molar evaporation at 20 ° C. and the molar volume. The heat of molar evaporation and molar volume are based on “Physical properties of chemicals that can be used in Excel” written by Hiroyasu Fukui (published by Maruzen Publishing Co., Ltd.).
ＳＰ値 δ＝｛（△Ｈ－ＲＴ）／Ｖ｝1/2
δ ：ＳＰ値（（ｃａｌ／ｍｌ）1/2）
△Ｈ：モル蒸発熱（ｃａｌ／ｍｏｌ）
Ｒ ：気体定数（１．９８７１ｃａｌ／ｍｏｌ・Ｋ）
Ｔ ：絶対温度（Ｋ）
Ｖ ：モル体積（ｍｌ／ｍｏｌ）
また、混合系のＳＰ値は、
δmix＝Σ（φi・Ｖi・δi）／Σ（φi・Ｖi）
δi ：溶剤ｉのＳＰ値
φi ：溶剤ｉの容積分率 （ここで、Σφi＝１）
Ｖi ：溶剤ｉのモル容積
によって求められる。
表１に示した代表的な溶剤のＳＰ値は、２０℃におけるモル蒸発熱とモル体積の数値から算出したものである。尚、モル蒸発熱とモル体積は、『Ｅｘｃｅｌで使える化学物質の物性』福井弘康著（丸善出版社発行）による。 The SP value (δ) in the present invention is calculated by the following equation.
SP value δ = {(ΔH−RT) / V} 1/2
δ: SP value ((cal / ml) 1/2 )
ΔH: heat of vaporization (cal / mol)
R: Gas constant (1.9871 cal / mol · K)
T: Absolute temperature (K)
V: molar volume (ml / mol)
The SP value of the mixed system is
δ mix = Σ (φ i · V i · δ i ) / Σ (φ i · V i )
δ i : SP value of solvent i φ i : Volume fraction of solvent i (where Σφ i = 1)
V i : determined by the molar volume of solvent i.
The SP values of typical solvents shown in Table 1 are calculated from the numerical values of the heat of molar evaporation at 20 ° C. and the molar volume. The heat of molar evaporation and molar volume are based on “Physical properties of chemicals that can be used in Excel” written by Hiroyasu Fukui (published by Maruzen Publishing Co., Ltd.).
第一溶剤としては、ケトン系溶剤、エステル系溶剤、アミド系溶剤及びエーテル系溶剤等の極性溶剤を用いることができる。
具体的に例示すると、ケトン系溶剤としては、１－オクタノン、２－オクタノン、１－ノナノン、２－ノナノン、アセトン（ＳＰ値９．８）、４－ヘプタノン、１－ヘキサノン、２－ヘキサノン、シクロヘキサノン、メチルシクロヘキサノン、フェニルアセトン、メチルエチルケトン（ＳＰ値９．２）、メチルイソブチルケトン、メチル－ｎ－アミルケトン、メチル－ｎ－ブチルケトン、メチル－ｎ－プロピルケトン、メチル－ｎ－ヘキシルケトン、メチル－ｎ－ヘプチルケトン、エチル－ｎ－ブチルケトン、ジエチルケトン、ジ－ｎ－プロピルケトン、ジイソプロピルケトン、ジイソブチルケトン、アセチルアセトン、アセトニルアセトン、ジアセトニルアルコール、アセチルカービノール、アセトフェノン、メチルナフチルケトン、イソホロン、プロピレンカーボネート等が挙げられる。
エステル系溶剤としては、酢酸メチル、酢酸エチル（ＳＰ値９．０）、酢酸イソプロピル、酢酸ブチル（ＳＰ値８．７）、酢酸アミル、酢酸２－エチルヘキシル、蟻酸メチル、蟻酸エチル、蟻酸ブチル、蟻酸プロピル、乳酸エチル、乳酸ブチル、乳酸プロピル、アジピン酸ジエチル、アセチルクエン酸トリエチル、安息香酸エチル、シュウ酸ジエチル、炭酸ジエチル、フタル酸ジエチル、プロピオン酸エチル等が挙げられる。
アミド系溶剤としては、Ｎ－メチル－２－ピロリドン、Ｎ，Ｎ－ジメチルアセトアミド、Ｎ，Ｎ－ジメチルホルムアミド、ヘキサメチルホスホリックトリアミド、１，３－ジメチル－２－イミダゾリジノン等が挙げられる。
エーテル系溶剤としては、エチレングリコール（ＳＰ値１５．９）、ジエチレングリコール、トリエチレングリコール等のグリコール系溶剤の他、エチルイソアミルエーテル、エチル－ｔ－ブチルエーテル、エチルベンジルエーテル、ジメチルエーテル、ジエチルエーテル、ジプロピルエーテル、ジイソプロピルエーテル（ＳＰ値７．２）、ジブチルエーテル、ジイソアミルエーテル、ジフェニルエーテル、ジベンジルエーテル、ジオキサン、テトラヒドロフラン等が挙げられる。これらは、単独で用いてもよいし、複数を混合して使用してもよい。 As the first solvent, polar solvents such as ketone solvents, ester solvents, amide solvents and ether solvents can be used.
Specifically, the ketone solvents include 1-octanone, 2-octanone, 1-nonanone, 2-nonanone, acetone (SP value 9.8), 4-heptanone, 1-hexanone, 2-hexanone, cyclohexanone. , Methylcyclohexanone, phenylacetone, methyl ethyl ketone (SP value 9.2), methyl isobutyl ketone, methyl-n-amyl ketone, methyl-n-butyl ketone, methyl-n-propyl ketone, methyl-n-hexyl ketone, methyl-n- Heptyl ketone, ethyl-n-butyl ketone, diethyl ketone, di-n-propyl ketone, diisopropyl ketone, diisobutyl ketone, acetylacetone, acetonylacetone, diacetonyl alcohol, acetylcarbinol, acetophenone, methylnaphthylketone, iso Ron and propylene carbonate.
Examples of ester solvents include methyl acetate, ethyl acetate (SP value 9.0), isopropyl acetate, butyl acetate (SP value 8.7), amyl acetate, 2-ethylhexyl acetate, methyl formate, ethyl formate, butyl formate, formic acid Examples include propyl, ethyl lactate, butyl lactate, propyl lactate, diethyl adipate, triethyl acetylcitrate, ethyl benzoate, diethyl oxalate, diethyl carbonate, diethyl phthalate, and ethyl propionate.
Examples of amide solvents include N-methyl-2-pyrrolidone, N, N-dimethylacetamide, N, N-dimethylformamide, hexamethylphosphoric triamide, 1,3-dimethyl-2-imidazolidinone and the like. .
Ether solvents include glycol solvents such as ethylene glycol (SP value 15.9), diethylene glycol and triethylene glycol, as well as ethyl isoamyl ether, ethyl t-butyl ether, ethyl benzyl ether, dimethyl ether, diethyl ether, and dipropyl. Examples include ether, diisopropyl ether (SP value 7.2), dibutyl ether, diisoamyl ether, diphenyl ether, dibenzyl ether, dioxane, tetrahydrofuran and the like. These may be used alone or in combination.
具体的に例示すると、ケトン系溶剤としては、１－オクタノン、２－オクタノン、１－ノナノン、２－ノナノン、アセトン（ＳＰ値９．８）、４－ヘプタノン、１－ヘキサノン、２－ヘキサノン、シクロヘキサノン、メチルシクロヘキサノン、フェニルアセトン、メチルエチルケトン（ＳＰ値９．２）、メチルイソブチルケトン、メチル－ｎ－アミルケトン、メチル－ｎ－ブチルケトン、メチル－ｎ－プロピルケトン、メチル－ｎ－ヘキシルケトン、メチル－ｎ－ヘプチルケトン、エチル－ｎ－ブチルケトン、ジエチルケトン、ジ－ｎ－プロピルケトン、ジイソプロピルケトン、ジイソブチルケトン、アセチルアセトン、アセトニルアセトン、ジアセトニルアルコール、アセチルカービノール、アセトフェノン、メチルナフチルケトン、イソホロン、プロピレンカーボネート等が挙げられる。
エステル系溶剤としては、酢酸メチル、酢酸エチル（ＳＰ値９．０）、酢酸イソプロピル、酢酸ブチル（ＳＰ値８．７）、酢酸アミル、酢酸２－エチルヘキシル、蟻酸メチル、蟻酸エチル、蟻酸ブチル、蟻酸プロピル、乳酸エチル、乳酸ブチル、乳酸プロピル、アジピン酸ジエチル、アセチルクエン酸トリエチル、安息香酸エチル、シュウ酸ジエチル、炭酸ジエチル、フタル酸ジエチル、プロピオン酸エチル等が挙げられる。
アミド系溶剤としては、Ｎ－メチル－２－ピロリドン、Ｎ，Ｎ－ジメチルアセトアミド、Ｎ，Ｎ－ジメチルホルムアミド、ヘキサメチルホスホリックトリアミド、１，３－ジメチル－２－イミダゾリジノン等が挙げられる。
エーテル系溶剤としては、エチレングリコール（ＳＰ値１５．９）、ジエチレングリコール、トリエチレングリコール等のグリコール系溶剤の他、エチルイソアミルエーテル、エチル－ｔ－ブチルエーテル、エチルベンジルエーテル、ジメチルエーテル、ジエチルエーテル、ジプロピルエーテル、ジイソプロピルエーテル（ＳＰ値７．２）、ジブチルエーテル、ジイソアミルエーテル、ジフェニルエーテル、ジベンジルエーテル、ジオキサン、テトラヒドロフラン等が挙げられる。これらは、単独で用いてもよいし、複数を混合して使用してもよい。 As the first solvent, polar solvents such as ketone solvents, ester solvents, amide solvents and ether solvents can be used.
Specifically, the ketone solvents include 1-octanone, 2-octanone, 1-nonanone, 2-nonanone, acetone (SP value 9.8), 4-heptanone, 1-hexanone, 2-hexanone, cyclohexanone. , Methylcyclohexanone, phenylacetone, methyl ethyl ketone (SP value 9.2), methyl isobutyl ketone, methyl-n-amyl ketone, methyl-n-butyl ketone, methyl-n-propyl ketone, methyl-n-hexyl ketone, methyl-n- Heptyl ketone, ethyl-n-butyl ketone, diethyl ketone, di-n-propyl ketone, diisopropyl ketone, diisobutyl ketone, acetylacetone, acetonylacetone, diacetonyl alcohol, acetylcarbinol, acetophenone, methylnaphthylketone, iso Ron and propylene carbonate.
Examples of ester solvents include methyl acetate, ethyl acetate (SP value 9.0), isopropyl acetate, butyl acetate (SP value 8.7), amyl acetate, 2-ethylhexyl acetate, methyl formate, ethyl formate, butyl formate, formic acid Examples include propyl, ethyl lactate, butyl lactate, propyl lactate, diethyl adipate, triethyl acetylcitrate, ethyl benzoate, diethyl oxalate, diethyl carbonate, diethyl phthalate, and ethyl propionate.
Examples of amide solvents include N-methyl-2-pyrrolidone, N, N-dimethylacetamide, N, N-dimethylformamide, hexamethylphosphoric triamide, 1,3-dimethyl-2-imidazolidinone and the like. .
Ether solvents include glycol solvents such as ethylene glycol (SP value 15.9), diethylene glycol and triethylene glycol, as well as ethyl isoamyl ether, ethyl t-butyl ether, ethyl benzyl ether, dimethyl ether, diethyl ether, and dipropyl. Examples include ether, diisopropyl ether (SP value 7.2), dibutyl ether, diisoamyl ether, diphenyl ether, dibenzyl ether, dioxane, tetrahydrofuran and the like. These may be used alone or in combination.
第一溶剤の使用量は、シアノ酢酸１モルに対して、２０～３００質量部用いることが好ましく、３０～２５０質量部であることがより好ましく、４０～１６０質量部であることが更に好ましい。当該使用量が２０質量部未満であると、反応系が均質に成りにくく、シアノ酢酸エステルの収率が向上しない場合がある。一方、３００質量部を超えて用いてもシアノ酢酸エステルの収率は向上せず、生産コストが高くなる。
The amount of the first solvent used is preferably 20 to 300 parts by mass, more preferably 30 to 250 parts by mass, and still more preferably 40 to 160 parts by mass with respect to 1 mol of cyanoacetic acid. If the amount used is less than 20 parts by mass, the reaction system is unlikely to be homogeneous, and the yield of cyanoacetate may not be improved. On the other hand, even if it is used in excess of 300 parts by mass, the yield of cyanoacetate is not improved and the production cost is increased.
３．第二溶剤
本発明に用いられる第二溶剤は、２５℃において実質的に水に不溶である有機溶剤であり、当然ながら、上記一般式ＲＯＨで表される有機化合物以外の有機溶剤である。第二溶剤は、実質的に水に溶解しないため、エステル化反応において生成する水を分離し易くなり、結果としてシアノ酢酸エステルの収率が向上する。
ここで、本発明において、実質的に水に不溶とは、２５℃における水に対する溶解度が１質量％未満であることを意味する。 3. Second Solvent The second solvent used in the present invention is an organic solvent that is substantially insoluble in water at 25 ° C. and, of course, is an organic solvent other than the organic compound represented by the general formula ROH. Since the second solvent does not substantially dissolve in water, it becomes easy to separate water generated in the esterification reaction, and as a result, the yield of cyanoacetic acid ester is improved.
Here, in the present invention, “substantially insoluble in water” means that the solubility in water at 25 ° C. is less than 1% by mass.
本発明に用いられる第二溶剤は、２５℃において実質的に水に不溶である有機溶剤であり、当然ながら、上記一般式ＲＯＨで表される有機化合物以外の有機溶剤である。第二溶剤は、実質的に水に溶解しないため、エステル化反応において生成する水を分離し易くなり、結果としてシアノ酢酸エステルの収率が向上する。
ここで、本発明において、実質的に水に不溶とは、２５℃における水に対する溶解度が１質量％未満であることを意味する。 3. Second Solvent The second solvent used in the present invention is an organic solvent that is substantially insoluble in water at 25 ° C. and, of course, is an organic solvent other than the organic compound represented by the general formula ROH. Since the second solvent does not substantially dissolve in water, it becomes easy to separate water generated in the esterification reaction, and as a result, the yield of cyanoacetic acid ester is improved.
Here, in the present invention, “substantially insoluble in water” means that the solubility in water at 25 ° C. is less than 1% by mass.
第二溶剤としては、炭化水素系溶剤が挙げられる。具体的には、ベンゼン、トルエン、キシレン等の芳香族炭化水素系溶剤；シクロヘキサン、メチルシクロヘキサン等の脂環族炭化水素系溶剤；ペンタン、ヘキサン、ヘプタン、オクタン、デカン等の脂肪族炭化水素系溶剤が挙げられる。これらの中でも、沸点が低く、比較的毒性の低いヘキサン、シクロヘキサン及びヘプタンが好ましい。沸点が高い場合は、エステル化反応の温度が高くなり、マロン酸エステル等の副生成物が多く発生する。
As the second solvent, a hydrocarbon-based solvent may be mentioned. Specifically, aromatic hydrocarbon solvents such as benzene, toluene and xylene; alicyclic hydrocarbon solvents such as cyclohexane and methylcyclohexane; aliphatic hydrocarbon solvents such as pentane, hexane, heptane, octane and decane Is mentioned. Among these, hexane, cyclohexane and heptane having a low boiling point and relatively low toxicity are preferable. When the boiling point is high, the temperature of the esterification reaction becomes high, and many byproducts such as malonic acid esters are generated.
第二溶剤の使用量は、シアノ酢酸１モルに対して、２０～１５０質量部用いることが好ましく、３０～１３０質量部であることがより好ましく、４０～１２０質量部であることが更に好ましい。当該使用量が２０質量部未満であると、エステル化反応で生成する水の分離がしにくく、シアノ酢酸エステルの収率が向上しない傾向にある。一方、１５０質量部を超えて用いてもシアノ酢酸エステルの収率は向上せず、生産コストが高くなる。
The amount of the second solvent used is preferably 20 to 150 parts by mass, more preferably 30 to 130 parts by mass, and still more preferably 40 to 120 parts by mass with respect to 1 mol of cyanoacetic acid. When the amount used is less than 20 parts by mass, it is difficult to separate water produced by the esterification reaction, and the yield of cyanoacetate ester tends not to be improved. On the other hand, even if it uses exceeding 150 mass parts, the yield of a cyanoacetate ester does not improve and production cost becomes high.
上記第一溶剤と、第二溶剤との質量比（第一溶剤／第二溶剤）は、０．５～３．０であることが好ましく、０．８～２．５であることがより好ましく、１．０～２．０であることが更に好ましい。当該質量比が、０．５未満であると、反応系が均質に成りにくく、シアノ酢酸エステルの収率が向上しない場合がある。一方、３．０を超えると、エステル化反応で生成する水の分離がしにくく、シアノ酢酸エステルの収率が向上しない傾向にある。
The mass ratio between the first solvent and the second solvent (first solvent / second solvent) is preferably 0.5 to 3.0, more preferably 0.8 to 2.5. 1.0 to 2.0 is more preferable. If the mass ratio is less than 0.5, the reaction system is unlikely to be homogeneous and the yield of cyanoacetate may not be improved. On the other hand, if it exceeds 3.0, it is difficult to separate water produced by the esterification reaction, and the yield of cyanoacetate ester tends not to be improved.
４．酸触媒
本発明のエステル化反応は、酸触媒の存在下で行われる。酸触媒としては、強い無機酸又は有機酸が用いられ、例えば、硫酸、塩酸、リン酸、ベンゼンスルホン酸、ｏ－トルエンスルホン酸、ｐ－トルエンスルホン酸、メタンスルホン酸、トリフルオロメタンスルホン酸、トリフルオロ酢酸、モノクロロ酢酸、ジクロロ酢酸及びトリクロロ酢酸等が挙げられる。入手の容易さやガラスライニング反応容器への腐食の点から、硫酸又はｐ－トルエンスルホン酸が好ましい。
酸触媒量は、シアノ酢酸１モルに対して、０．０１～０．５モルであることが好ましく、０．０５～０．３モルであることがより好ましい。
エステル化反応終了後は、水洗又は炭酸ナトリウムなどのアルカリ水溶液での洗浄で、酸触媒を除去することが望ましい。酸触媒の除去工程を省いてシアノ酢酸エステルの精製蒸留を行うとシアノ基が容易に加水分解し、マロン酸モノあるいはジエステルなどが副生し易くなる。 4). Acid catalyst The esterification reaction of the present invention is carried out in the presence of an acid catalyst. As the acid catalyst, a strong inorganic acid or organic acid is used. For example, sulfuric acid, hydrochloric acid, phosphoric acid, benzenesulfonic acid, o-toluenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid, Examples include fluoroacetic acid, monochloroacetic acid, dichloroacetic acid, and trichloroacetic acid. Sulfuric acid or p-toluenesulfonic acid is preferred from the viewpoint of availability and corrosion of the glass lining reaction vessel.
The amount of the acid catalyst is preferably from 0.01 to 0.5 mol, more preferably from 0.05 to 0.3 mol, per 1 mol of cyanoacetic acid.
After completion of the esterification reaction, it is desirable to remove the acid catalyst by washing with water or washing with an alkaline aqueous solution such as sodium carbonate. When the purification step of the cyanoacetate is carried out without the removal step of the acid catalyst, the cyano group is easily hydrolyzed and malonic acid mono- or diester is easily produced as a by-product.
本発明のエステル化反応は、酸触媒の存在下で行われる。酸触媒としては、強い無機酸又は有機酸が用いられ、例えば、硫酸、塩酸、リン酸、ベンゼンスルホン酸、ｏ－トルエンスルホン酸、ｐ－トルエンスルホン酸、メタンスルホン酸、トリフルオロメタンスルホン酸、トリフルオロ酢酸、モノクロロ酢酸、ジクロロ酢酸及びトリクロロ酢酸等が挙げられる。入手の容易さやガラスライニング反応容器への腐食の点から、硫酸又はｐ－トルエンスルホン酸が好ましい。
酸触媒量は、シアノ酢酸１モルに対して、０．０１～０．５モルであることが好ましく、０．０５～０．３モルであることがより好ましい。
エステル化反応終了後は、水洗又は炭酸ナトリウムなどのアルカリ水溶液での洗浄で、酸触媒を除去することが望ましい。酸触媒の除去工程を省いてシアノ酢酸エステルの精製蒸留を行うとシアノ基が容易に加水分解し、マロン酸モノあるいはジエステルなどが副生し易くなる。 4). Acid catalyst The esterification reaction of the present invention is carried out in the presence of an acid catalyst. As the acid catalyst, a strong inorganic acid or organic acid is used. For example, sulfuric acid, hydrochloric acid, phosphoric acid, benzenesulfonic acid, o-toluenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid, Examples include fluoroacetic acid, monochloroacetic acid, dichloroacetic acid, and trichloroacetic acid. Sulfuric acid or p-toluenesulfonic acid is preferred from the viewpoint of availability and corrosion of the glass lining reaction vessel.
The amount of the acid catalyst is preferably from 0.01 to 0.5 mol, more preferably from 0.05 to 0.3 mol, per 1 mol of cyanoacetic acid.
After completion of the esterification reaction, it is desirable to remove the acid catalyst by washing with water or washing with an alkaline aqueous solution such as sodium carbonate. When the purification step of the cyanoacetate is carried out without the removal step of the acid catalyst, the cyano group is easily hydrolyzed and malonic acid mono- or diester is easily produced as a by-product.
５．エステル化反応
本発明に係るシアノ酢酸エステルの製造方法は、上記原料を用いて酸触媒の存在下、上記有機溶剤中でエステル化反応を行う。エステル化反応は、有機溶剤を還流させながら、生成した水を除去しつつ行う。還流温度は、一般式ＲＯＨで表される有機化合物の種類、並びに第一溶剤及び第二溶剤の種類により決定されるが、５０～１００℃であることが好ましく、５５～９０℃であることが好ましく、６０～８０℃であることが更に好ましい。還流温度が５０～１００℃の範囲から外れるときは、加圧あるいは減圧で調整することも可能であるが、大気下で還流することが、操作の容易さから好ましい。還流温度が５０℃未満ではエステル化反応の進行が遅く、シアノ酢酸エステルの収率も向上しない場合がある。一方、１００℃を超えると、マロン酸エステル等の副生成物が多く発生する場合がある。
エステル化反応は、留出液がもはや水を含有しなくなった時点で終了する。次に、反応液を冷却後、酸触媒を水洗、又はアルカリ性水溶液を用いて中和し、３相に分離した反応液を得る。分離した反応液のうち、上層（有機溶剤相）及び中層（シアノ酢酸エステル相）を蒸留精製することにより、高純度のシアノ酢酸エステルを得ることができる。 5. Esterification Reaction The method for producing a cyanoacetic acid ester according to the present invention performs the esterification reaction in the organic solvent in the presence of an acid catalyst using the raw materials. The esterification reaction is performed while removing generated water while refluxing the organic solvent. The reflux temperature is determined by the type of the organic compound represented by the general formula ROH and the types of the first solvent and the second solvent, but is preferably 50 to 100 ° C., and preferably 55 to 90 ° C. Preferably, the temperature is 60 to 80 ° C. When the reflux temperature is out of the range of 50 to 100 ° C., it can be adjusted by pressurization or depressurization. However, reflux under the atmosphere is preferable from the viewpoint of ease of operation. If the reflux temperature is less than 50 ° C., the esterification reaction proceeds slowly and the yield of cyanoacetate may not be improved. On the other hand, when it exceeds 100 ° C., many byproducts such as malonic acid ester may be generated.
The esterification reaction ends when the distillate no longer contains water. Next, after cooling the reaction solution, the acid catalyst is washed with water or neutralized with an alkaline aqueous solution to obtain a reaction solution separated into three phases. High purity cyanoacetate can be obtained by distilling the upper layer (organic solvent phase) and middle layer (cyanoacetate phase) of the separated reaction liquid.
本発明に係るシアノ酢酸エステルの製造方法は、上記原料を用いて酸触媒の存在下、上記有機溶剤中でエステル化反応を行う。エステル化反応は、有機溶剤を還流させながら、生成した水を除去しつつ行う。還流温度は、一般式ＲＯＨで表される有機化合物の種類、並びに第一溶剤及び第二溶剤の種類により決定されるが、５０～１００℃であることが好ましく、５５～９０℃であることが好ましく、６０～８０℃であることが更に好ましい。還流温度が５０～１００℃の範囲から外れるときは、加圧あるいは減圧で調整することも可能であるが、大気下で還流することが、操作の容易さから好ましい。還流温度が５０℃未満ではエステル化反応の進行が遅く、シアノ酢酸エステルの収率も向上しない場合がある。一方、１００℃を超えると、マロン酸エステル等の副生成物が多く発生する場合がある。
エステル化反応は、留出液がもはや水を含有しなくなった時点で終了する。次に、反応液を冷却後、酸触媒を水洗、又はアルカリ性水溶液を用いて中和し、３相に分離した反応液を得る。分離した反応液のうち、上層（有機溶剤相）及び中層（シアノ酢酸エステル相）を蒸留精製することにより、高純度のシアノ酢酸エステルを得ることができる。 5. Esterification Reaction The method for producing a cyanoacetic acid ester according to the present invention performs the esterification reaction in the organic solvent in the presence of an acid catalyst using the raw materials. The esterification reaction is performed while removing generated water while refluxing the organic solvent. The reflux temperature is determined by the type of the organic compound represented by the general formula ROH and the types of the first solvent and the second solvent, but is preferably 50 to 100 ° C., and preferably 55 to 90 ° C. Preferably, the temperature is 60 to 80 ° C. When the reflux temperature is out of the range of 50 to 100 ° C., it can be adjusted by pressurization or depressurization. However, reflux under the atmosphere is preferable from the viewpoint of ease of operation. If the reflux temperature is less than 50 ° C., the esterification reaction proceeds slowly and the yield of cyanoacetate may not be improved. On the other hand, when it exceeds 100 ° C., many byproducts such as malonic acid ester may be generated.
The esterification reaction ends when the distillate no longer contains water. Next, after cooling the reaction solution, the acid catalyst is washed with water or neutralized with an alkaline aqueous solution to obtain a reaction solution separated into three phases. High purity cyanoacetate can be obtained by distilling the upper layer (organic solvent phase) and middle layer (cyanoacetate phase) of the separated reaction liquid.
本発明について、実施例及び比較例に基づいて具体的に説明するが、本発明はこれに限定されるものではない。尚、本発明において、シアノ酢酸の溶解度、各種有機化合物の定量、及び水分量は、以下のようにして測定した。
１．測定方法
（１）シアノ酢酸の溶解度
シアノ酢酸の溶解度は、全て２５℃で管理された室内にて測定した。
１００ｍｌビーカーに、約８ｇのシアノ酢酸（和光純薬特級品）を取り分け、その投入量を正確に計量し、攪拌子を用いて撹拌しながら測定する溶剤をできるだけゆっくりとシアノ酢酸が全て溶解するまで添加した。終点間際では１０分間に０．５ｇ程度の添加とした。終点までに投入した溶剤重量からシアノ酢酸の溶解度を算出した（単位；［ｇ／１００ｇ－溶剤］）。尚、溶剤添加中は、溶剤の揮発を抑えるためにビーカーにはフィルムラップを施した。
一方、ｎ－ヘキサンなどの極めて溶解性が低い溶剤の場合は、約０．１ｇ（精秤）のシアノ酢酸を５０．０ｇの溶剤中で３０分間攪拌した後にろ過分別し、ろ過残渣を乾燥して未溶解のシアノ酢酸を計量して溶解量を求めた。
表１に、代表的な有機化合物、第一溶剤及び第二溶剤のＳＰ値及びシアノ酢酸の溶解度を示す。
（２）有機化合物等の定量
有機化合物、各種溶剤、シアノ酢酸エステル及びマロン酸エステルの定量分析は、ガスクロマトグラフィーを用いて行った。定量にあたり、ジオキサンを内部標準液として、予め検量線を作成した。
＜ガスクロマトグラフィーの測定条件＞
カラム； ＤＢ－１、膜厚５μｍ、長さ３０ｍ、ＩＤ ０．３２０ｍｍ、
スプリット比＝１／３０、ＩＮＪ ２４０℃、 ＤＥＴ ２６０℃、
カラム温度 ６０℃×３分＋７．５℃／ｍｉｎ×２７分＋２６０℃×１５分
検出器； ＦＩＤ
内標； ジオキサン（ＲＴ＝５．９ｍｉｎ．）
試料量； ０．４μＬ
（３）水分量
カールフィッシャー法にて水分量を測定した。 The present invention will be specifically described based on Examples and Comparative Examples, but the present invention is not limited thereto. In the present invention, the solubility of cyanoacetic acid, the quantification of various organic compounds, and the amount of water were measured as follows.
1. Measurement Method (1) Solubility of Cyanoacetic Acid The solubility of cyanoacetic acid was measured in a room controlled at 25 ° C.
About 8 g of cyanoacetic acid (Wako Pure Chemicals special grade) is placed in a 100 ml beaker, and the amount charged is accurately measured until all the cyanoacetic acid dissolves as slowly as possible while stirring with a stirrer. Added. About 0.5 g was added in 10 minutes just before the end point. The solubility of cyanoacetic acid was calculated from the weight of the solvent charged up to the end point (unit: [g / 100 g-solvent]). During the addition of the solvent, the beaker was film-wrapped in order to suppress the volatilization of the solvent.
On the other hand, in the case of a very low solubility solvent such as n-hexane, about 0.1 g (exact balance) of cyanoacetic acid is stirred in 50.0 g of solvent for 30 minutes, and then filtered and the residue is dried. Undissolved cyanoacetic acid was weighed to determine the amount dissolved.
Table 1 shows the SP values of typical organic compounds, the first solvent and the second solvent, and the solubility of cyanoacetic acid.
(2) Quantification of organic compounds, etc. Quantitative analysis of organic compounds, various solvents, cyanoacetic esters and malonic esters was performed using gas chromatography. For quantification, a calibration curve was prepared in advance using dioxane as an internal standard solution.
<Measurement conditions for gas chromatography>
Column; DB-1, film thickness 5 μm, length 30 m, ID 0.320 mm,
Split ratio = 1/30, INJ 240 ° C., DET 260 ° C.,
Column temperature 60 ° C. × 3 minutes + 7.5 ° C./min×27 minutes + 260 ° C. × 15 minutes Detector; FID
Internal standard: Dioxane (RT = 5.9 min.)
Sample volume: 0.4 μL
(3) Water content The water content was measured by the Karl Fischer method.
１．測定方法
（１）シアノ酢酸の溶解度
シアノ酢酸の溶解度は、全て２５℃で管理された室内にて測定した。
１００ｍｌビーカーに、約８ｇのシアノ酢酸（和光純薬特級品）を取り分け、その投入量を正確に計量し、攪拌子を用いて撹拌しながら測定する溶剤をできるだけゆっくりとシアノ酢酸が全て溶解するまで添加した。終点間際では１０分間に０．５ｇ程度の添加とした。終点までに投入した溶剤重量からシアノ酢酸の溶解度を算出した（単位；［ｇ／１００ｇ－溶剤］）。尚、溶剤添加中は、溶剤の揮発を抑えるためにビーカーにはフィルムラップを施した。
一方、ｎ－ヘキサンなどの極めて溶解性が低い溶剤の場合は、約０．１ｇ（精秤）のシアノ酢酸を５０．０ｇの溶剤中で３０分間攪拌した後にろ過分別し、ろ過残渣を乾燥して未溶解のシアノ酢酸を計量して溶解量を求めた。
表１に、代表的な有機化合物、第一溶剤及び第二溶剤のＳＰ値及びシアノ酢酸の溶解度を示す。
（２）有機化合物等の定量
有機化合物、各種溶剤、シアノ酢酸エステル及びマロン酸エステルの定量分析は、ガスクロマトグラフィーを用いて行った。定量にあたり、ジオキサンを内部標準液として、予め検量線を作成した。
＜ガスクロマトグラフィーの測定条件＞
カラム； ＤＢ－１、膜厚５μｍ、長さ３０ｍ、ＩＤ ０．３２０ｍｍ、
スプリット比＝１／３０、ＩＮＪ ２４０℃、 ＤＥＴ ２６０℃、
カラム温度 ６０℃×３分＋７．５℃／ｍｉｎ×２７分＋２６０℃×１５分
検出器； ＦＩＤ
内標； ジオキサン（ＲＴ＝５．９ｍｉｎ．）
試料量； ０．４μＬ
（３）水分量
カールフィッシャー法にて水分量を測定した。 The present invention will be specifically described based on Examples and Comparative Examples, but the present invention is not limited thereto. In the present invention, the solubility of cyanoacetic acid, the quantification of various organic compounds, and the amount of water were measured as follows.
1. Measurement Method (1) Solubility of Cyanoacetic Acid The solubility of cyanoacetic acid was measured in a room controlled at 25 ° C.
About 8 g of cyanoacetic acid (Wako Pure Chemicals special grade) is placed in a 100 ml beaker, and the amount charged is accurately measured until all the cyanoacetic acid dissolves as slowly as possible while stirring with a stirrer. Added. About 0.5 g was added in 10 minutes just before the end point. The solubility of cyanoacetic acid was calculated from the weight of the solvent charged up to the end point (unit: [g / 100 g-solvent]). During the addition of the solvent, the beaker was film-wrapped in order to suppress the volatilization of the solvent.
On the other hand, in the case of a very low solubility solvent such as n-hexane, about 0.1 g (exact balance) of cyanoacetic acid is stirred in 50.0 g of solvent for 30 minutes, and then filtered and the residue is dried. Undissolved cyanoacetic acid was weighed to determine the amount dissolved.
Table 1 shows the SP values of typical organic compounds, the first solvent and the second solvent, and the solubility of cyanoacetic acid.
(2) Quantification of organic compounds, etc. Quantitative analysis of organic compounds, various solvents, cyanoacetic esters and malonic esters was performed using gas chromatography. For quantification, a calibration curve was prepared in advance using dioxane as an internal standard solution.
<Measurement conditions for gas chromatography>
Column; DB-1, film thickness 5 μm, length 30 m, ID 0.320 mm,
Split ratio = 1/30, INJ 240 ° C., DET 260 ° C.,
Column temperature 60 ° C. × 3 minutes + 7.5 ° C./min×27 minutes + 260 ° C. × 15 minutes Detector; FID
Internal standard: Dioxane (RT = 5.9 min.)
Sample volume: 0.4 μL
(3) Water content The water content was measured by the Karl Fischer method.
２．シアノ酢酸エステルの製造
（１）実施例１
ジムロート冷却器、温度計及び攪拌翼を備えた１リットルの４つ口フラスコに、シアノ酢酸８５ｇ、エタノール６４ｇ、酢酸エチル１００ｇを投入し、シアノ酢酸が溶解するまでよく撹拌した。次に、ｎ－ヘキサン１００ｇを加え、内温が３０℃になるようにウォーターバスで調整した。更に、９８％硫酸１０ｇを加え、還流温度（６２℃）まで１～２℃／分の速度で昇温した。
還流が始まってから１時間後に、ディーン・スターク装置（ｈ型）をジムロート冷却器と１リットルフラスコの間に設置して還流留出液をトラップし、下層がオーバーフローして反応容器に戻らないように下層を抜き取った。
還流が始まってから４時間後には留出液に水が含まれなくなったため、反応容器を室温まで冷却した。留出水の取得量は３１．３ｇであった。その留出水中のエタノール量は１２．５ｇ、水分量は１６．１ｇであった。
内温を室温に戻した後、１６％炭酸ソーダ水溶液１００ｇを投入してから、分液ロートに移し替えた。３層になっており、それぞれを分別回収し、上層７５ｇ、中層２２０ｇ、下層１２４ｇの反応液を得た。
それぞれの反応液のシアノ酢酸エチル及びマロン酸ジエチルの質量％をガスクロマトグラフィーにて求めた。上記３層におけるシアノ酢酸エチルの含有量は、上層９．４％、中層４４．６％、下層１．９％であり、上層と中層を合わせたシアノ酢酸エチルの収量は１０５．２ｇ、同様に求めたマロン酸ジエチルの生成量は１．８ｇであった。仕込みシアノ酢酸に対して、収率（モル％）は、シアノ酢酸エチルが９３．１モル％、マロン酸ジエチルは１．１モル％であった。
各種の評価結果は、表２にまとめて示した。 2. Preparation of cyanoacetate ester (1) Example 1
85 g of cyanoacetic acid, 64 g of ethanol and 100 g of ethyl acetate were put into a 1 liter four-necked flask equipped with a Dimroth cooler, a thermometer and a stirring blade, and stirred well until the cyanoacetic acid was dissolved. Next, 100 g of n-hexane was added and adjusted with a water bath so that the internal temperature was 30 ° C. Further, 10 g of 98% sulfuric acid was added, and the temperature was raised to the reflux temperature (62 ° C.) at a rate of 1 to 2 ° C./min.
One hour after the start of reflux, a Dean-Stark device (h-type) is installed between the Dimroth cooler and the 1-liter flask to trap the reflux distillate so that the lower layer does not overflow and return to the reaction vessel. The lower layer was extracted.
Four hours after the start of reflux, water was not contained in the distillate, so the reaction vessel was cooled to room temperature. The amount of distilled water obtained was 31.3 g. The amount of ethanol in the distilled water was 12.5 g, and the amount of water was 16.1 g.
After returning the internal temperature to room temperature, 100 g of a 16% sodium carbonate aqueous solution was added and then transferred to a separatory funnel. Each layer was separated and collected to obtain a reaction solution of 75 g of the upper layer, 220 g of the middle layer, and 124 g of the lower layer.
The mass% of ethyl cyanoacetate and diethyl malonate in each reaction solution was determined by gas chromatography. The content of ethyl cyanoacetate in the above three layers is 9.4% for the upper layer, 44.6% for the middle layer, and 1.9% for the lower layer. The combined yield of ethyl cyanoacetate is 105.2 g. The determined production amount of diethyl malonate was 1.8 g. The yield (mol%) was 93.1 mol% for ethyl cyanoacetate and 1.1 mol% for diethyl malonate relative to the charged cyanoacetic acid.
Various evaluation results are summarized in Table 2.
（１）実施例１
ジムロート冷却器、温度計及び攪拌翼を備えた１リットルの４つ口フラスコに、シアノ酢酸８５ｇ、エタノール６４ｇ、酢酸エチル１００ｇを投入し、シアノ酢酸が溶解するまでよく撹拌した。次に、ｎ－ヘキサン１００ｇを加え、内温が３０℃になるようにウォーターバスで調整した。更に、９８％硫酸１０ｇを加え、還流温度（６２℃）まで１～２℃／分の速度で昇温した。
還流が始まってから１時間後に、ディーン・スターク装置（ｈ型）をジムロート冷却器と１リットルフラスコの間に設置して還流留出液をトラップし、下層がオーバーフローして反応容器に戻らないように下層を抜き取った。
還流が始まってから４時間後には留出液に水が含まれなくなったため、反応容器を室温まで冷却した。留出水の取得量は３１．３ｇであった。その留出水中のエタノール量は１２．５ｇ、水分量は１６．１ｇであった。
内温を室温に戻した後、１６％炭酸ソーダ水溶液１００ｇを投入してから、分液ロートに移し替えた。３層になっており、それぞれを分別回収し、上層７５ｇ、中層２２０ｇ、下層１２４ｇの反応液を得た。
それぞれの反応液のシアノ酢酸エチル及びマロン酸ジエチルの質量％をガスクロマトグラフィーにて求めた。上記３層におけるシアノ酢酸エチルの含有量は、上層９．４％、中層４４．６％、下層１．９％であり、上層と中層を合わせたシアノ酢酸エチルの収量は１０５．２ｇ、同様に求めたマロン酸ジエチルの生成量は１．８ｇであった。仕込みシアノ酢酸に対して、収率（モル％）は、シアノ酢酸エチルが９３．１モル％、マロン酸ジエチルは１．１モル％であった。
各種の評価結果は、表２にまとめて示した。 2. Preparation of cyanoacetate ester (1) Example 1
85 g of cyanoacetic acid, 64 g of ethanol and 100 g of ethyl acetate were put into a 1 liter four-necked flask equipped with a Dimroth cooler, a thermometer and a stirring blade, and stirred well until the cyanoacetic acid was dissolved. Next, 100 g of n-hexane was added and adjusted with a water bath so that the internal temperature was 30 ° C. Further, 10 g of 98% sulfuric acid was added, and the temperature was raised to the reflux temperature (62 ° C.) at a rate of 1 to 2 ° C./min.
One hour after the start of reflux, a Dean-Stark device (h-type) is installed between the Dimroth cooler and the 1-liter flask to trap the reflux distillate so that the lower layer does not overflow and return to the reaction vessel. The lower layer was extracted.
Four hours after the start of reflux, water was not contained in the distillate, so the reaction vessel was cooled to room temperature. The amount of distilled water obtained was 31.3 g. The amount of ethanol in the distilled water was 12.5 g, and the amount of water was 16.1 g.
After returning the internal temperature to room temperature, 100 g of a 16% sodium carbonate aqueous solution was added and then transferred to a separatory funnel. Each layer was separated and collected to obtain a reaction solution of 75 g of the upper layer, 220 g of the middle layer, and 124 g of the lower layer.
The mass% of ethyl cyanoacetate and diethyl malonate in each reaction solution was determined by gas chromatography. The content of ethyl cyanoacetate in the above three layers is 9.4% for the upper layer, 44.6% for the middle layer, and 1.9% for the lower layer. The combined yield of ethyl cyanoacetate is 105.2 g. The determined production amount of diethyl malonate was 1.8 g. The yield (mol%) was 93.1 mol% for ethyl cyanoacetate and 1.1 mol% for diethyl malonate relative to the charged cyanoacetic acid.
Various evaluation results are summarized in Table 2.
（２）実施例２～６
エステル化反応に用いる第一溶剤及び第二溶剤を表２に示すように変更する以外は、実施例１と同様の方法でシアノ酢酸エチルを製造した。得られたシアノ酢酸エチルについて、上記の方法にしたがって、評価した。それらの結果を表２に示す。 (2) Examples 2 to 6
Ethyl cyanoacetate was produced in the same manner as in Example 1 except that the first solvent and the second solvent used in the esterification reaction were changed as shown in Table 2. The obtained ethyl cyanoacetate was evaluated according to the method described above. The results are shown in Table 2.
エステル化反応に用いる第一溶剤及び第二溶剤を表２に示すように変更する以外は、実施例１と同様の方法でシアノ酢酸エチルを製造した。得られたシアノ酢酸エチルについて、上記の方法にしたがって、評価した。それらの結果を表２に示す。 (2) Examples 2 to 6
Ethyl cyanoacetate was produced in the same manner as in Example 1 except that the first solvent and the second solvent used in the esterification reaction were changed as shown in Table 2. The obtained ethyl cyanoacetate was evaluated according to the method described above. The results are shown in Table 2.
（３）比較例１
ジムロート冷却器、温度計、窒素ガス吹き込み管及び攪拌翼を備えた１リットルの４つ口フラスコに、シアノ酢酸８５ｇ、エタノール６４ｇを投入し、シアノ酢酸が溶解するまでよく撹拌した。次に、ｎ－ヘプタン１００ｇを加え、その後は実施例１と同様に操作してシアノ酢酸エチルを製造した。
その評価結果は、表２に示した。 (3) Comparative Example 1
85 g of cyanoacetic acid and 64 g of ethanol were put into a 1 liter four-necked flask equipped with a Dimroth cooler, thermometer, nitrogen gas blowing tube and stirring blade, and stirred well until the cyanoacetic acid was dissolved. Next, 100 g of n-heptane was added, and then the same operation as in Example 1 was performed to produce ethyl cyanoacetate.
The evaluation results are shown in Table 2.
ジムロート冷却器、温度計、窒素ガス吹き込み管及び攪拌翼を備えた１リットルの４つ口フラスコに、シアノ酢酸８５ｇ、エタノール６４ｇを投入し、シアノ酢酸が溶解するまでよく撹拌した。次に、ｎ－ヘプタン１００ｇを加え、その後は実施例１と同様に操作してシアノ酢酸エチルを製造した。
その評価結果は、表２に示した。 (3) Comparative Example 1
85 g of cyanoacetic acid and 64 g of ethanol were put into a 1 liter four-necked flask equipped with a Dimroth cooler, thermometer, nitrogen gas blowing tube and stirring blade, and stirred well until the cyanoacetic acid was dissolved. Next, 100 g of n-heptane was added, and then the same operation as in Example 1 was performed to produce ethyl cyanoacetate.
The evaluation results are shown in Table 2.
（４）比較例２、３
エステル化反応に用いる第一溶剤及び第二溶剤を表２に示すように変更する以外は、比較例１と同様の方法でシアノ酢酸エチルを製造した。得られたシアノ酢酸エチルについて、上記の方法にしたがって、評価した。それらの結果を表２に示す。 (4) Comparative Examples 2 and 3
Ethyl cyanoacetate was produced in the same manner as in Comparative Example 1 except that the first solvent and the second solvent used in the esterification reaction were changed as shown in Table 2. The obtained ethyl cyanoacetate was evaluated according to the method described above. The results are shown in Table 2.
エステル化反応に用いる第一溶剤及び第二溶剤を表２に示すように変更する以外は、比較例１と同様の方法でシアノ酢酸エチルを製造した。得られたシアノ酢酸エチルについて、上記の方法にしたがって、評価した。それらの結果を表２に示す。 (4) Comparative Examples 2 and 3
Ethyl cyanoacetate was produced in the same manner as in Comparative Example 1 except that the first solvent and the second solvent used in the esterification reaction were changed as shown in Table 2. The obtained ethyl cyanoacetate was evaluated according to the method described above. The results are shown in Table 2.
表２に示すように、実施例１～６の製造方法では、シアノ酢酸エチルを高収率で得ることができた。また、副生成物であるマロン酸ジエチルの生成も抑制することができた。この程度のマロン酸ジエチル量であれば、蒸留精製により、十分に除去することが可能であり、最終的に高純度のシアノ酢酸エチルを得ることができる。
一方、第一溶剤を使用せず、第二溶剤のみを用いた比較例１及び２では、シアノ酢酸エチルの収率が低い。また、副生成物であるマロン酸ジエチルの生成率が高い結果となった。第一溶剤のみを用いた比較例３でも、シアノ酢酸エチルの収率は低かった。 As shown in Table 2, in the production methods of Examples 1 to 6, ethyl cyanoacetate could be obtained in high yield. Moreover, the production | generation of diethyl malonate which is a by-product was also able to be suppressed. With this amount of diethyl malonate, it can be sufficiently removed by distillation purification, and finally high-purity ethyl cyanoacetate can be obtained.
On the other hand, in Comparative Examples 1 and 2 using only the second solvent without using the first solvent, the yield of ethyl cyanoacetate is low. Further, the production rate of by-product diethyl malonate was high. Even in Comparative Example 3 using only the first solvent, the yield of ethyl cyanoacetate was low.
一方、第一溶剤を使用せず、第二溶剤のみを用いた比較例１及び２では、シアノ酢酸エチルの収率が低い。また、副生成物であるマロン酸ジエチルの生成率が高い結果となった。第一溶剤のみを用いた比較例３でも、シアノ酢酸エチルの収率は低かった。 As shown in Table 2, in the production methods of Examples 1 to 6, ethyl cyanoacetate could be obtained in high yield. Moreover, the production | generation of diethyl malonate which is a by-product was also able to be suppressed. With this amount of diethyl malonate, it can be sufficiently removed by distillation purification, and finally high-purity ethyl cyanoacetate can be obtained.
On the other hand, in Comparative Examples 1 and 2 using only the second solvent without using the first solvent, the yield of ethyl cyanoacetate is low. Further, the production rate of by-product diethyl malonate was high. Even in Comparative Example 3 using only the first solvent, the yield of ethyl cyanoacetate was low.
本発明に係るシアノ酢酸エステルの製造方法は、シアノ酢酸エステルを高収率で得ることができる。加えて、マロン酸エステル等の副生成物の発生を抑制することができる。よって、医薬及び農薬の中間体、並びに工業製品の中間体として用いられるシアノ酢酸エステルの製造方法として有用である。
The method for producing a cyanoacetate according to the present invention can obtain a cyanoacetate in a high yield. In addition, generation of byproducts such as malonic acid esters can be suppressed. Therefore, it is useful as a method for producing cyanoacetate used as an intermediate for pharmaceuticals and agricultural chemicals and an intermediate for industrial products.
Claims (6)
- シアノ酢酸と一般式ＲＯＨ（式中、Ｒは炭素数１～１０の、直鎖状又は分岐鎖状の飽和炭化水素基、直鎖状又は分岐鎖状の不飽和炭化水素基、脂環式炭化水素基、芳香族炭化水素基及び式－Ｃ2Ｈ4－Ｏ－Ｒ1（式中、Ｒ1は炭素数１～８の、直鎖状又は分岐状の飽和炭化水素基、直鎖状又は分岐鎖状の不飽和炭化水素基、脂環式炭化水素基又は芳香族炭化水素基）からなる群より選ばれる基を示す）で表わされる有機化合物とを、前記有機化合物以外の有機溶剤中でエステル化反応させることによりシアノ酢酸エステルを製造する方法において、前記有機溶剤は、２５℃におけるシアノ酢酸の溶解度が１［ｇ／１００ｇ－溶剤］以上である第一溶剤と、２５℃において実質的に水に不溶である第二溶剤とから実質的に構成されることを特徴とするシアノ酢酸エステルの製造方法。 Cyanoacetic acid and general formula ROH (wherein R is a linear or branched saturated hydrocarbon group having 1 to 10 carbon atoms, linear or branched unsaturated hydrocarbon group, alicyclic carbonization) A hydrogen group, an aromatic hydrocarbon group, and a formula —C 2 H 4 —O—R 1 (wherein R 1 is a linear or branched saturated hydrocarbon group having 1 to 8 carbon atoms, linear or An organic compound represented by a group selected from the group consisting of a branched unsaturated hydrocarbon group, an alicyclic hydrocarbon group or an aromatic hydrocarbon group) in an organic solvent other than the organic compound. In the method for producing a cyanoacetic acid ester by an esterification reaction, the organic solvent includes a first solvent having a solubility of cyanoacetic acid at 25 ° C. of 1 [g / 100 g-solvent] or more, and substantially at 25 ° C. It is substantially composed of a second solvent that is insoluble in water. Method for producing a cyanoacetic acid ester.
- 上記第一溶剤の溶解度パラメーターが、６．０～１０．０であることを特徴とする請求項１に記載のシアノ酢酸エステルの製造方法。 The method for producing a cyanoacetate according to claim 1, wherein the solubility parameter of the first solvent is 6.0 to 10.0.
- 上記シアノ酢酸１モルに対して、上記第一溶剤を２０～３００質量部用いることを特徴とする請求項１又は２に記載のシアノ酢酸エステルの製造方法。 The method for producing a cyanoacetic acid ester according to claim 1 or 2, wherein 20 to 300 parts by mass of the first solvent is used per 1 mol of the cyanoacetic acid.
- 上記シアノ酢酸１モルに対して、上記第二溶剤を２０～１５０質量部用いることを特徴とする請求項１～３のいずれか１項に記載のシアノ酢酸エステルの製造方法。 The method for producing a cyanoacetic acid ester according to any one of claims 1 to 3, wherein 20 to 150 parts by mass of the second solvent is used per 1 mol of the cyanoacetic acid.
- 上記第一溶剤と第二溶剤の質量比（第一溶剤／第二溶剤）が、０．５～３．０であることを特徴とする請求項１～４のいずれか１項に記載のシアノ酢酸エステルの製造方法。 The cyano according to any one of claims 1 to 4, wherein a mass ratio of the first solvent to the second solvent (first solvent / second solvent) is 0.5 to 3.0. Method for producing acetate ester.
- 上記有機化合物量が、シアノ酢酸１モルに対し、１～２倍モルであることを特徴とする請求項１～５のいずれか１項に記載のシアノ酢酸エステルの製造方法。 The method for producing a cyanoacetic acid ester according to any one of claims 1 to 5, wherein the amount of the organic compound is 1 to 2 moles per mole of cyanoacetic acid.
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| JPH0491069A (en) * | 1990-08-07 | 1992-03-24 | Three Bond Co Ltd | New alpha-cyanoacrylate and adhesive composition |
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| JPH09188657A (en) * | 1995-10-23 | 1997-07-22 | Basf Ag | Production of alkycyano acetate |
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| JP2002536352A (en) * | 1999-02-03 | 2002-10-29 | ビーエーエスエフ アクチェンゲゼルシャフト | Method for producing ester |
-
2012
- 2012-03-20 TW TW101109546A patent/TW201238940A/en unknown
- 2012-03-21 JP JP2013505972A patent/JP5794296B2/en active Active
- 2012-03-21 WO PCT/JP2012/057099 patent/WO2012128265A1/en active Application Filing
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| JPH0491069A (en) * | 1990-08-07 | 1992-03-24 | Three Bond Co Ltd | New alpha-cyanoacrylate and adhesive composition |
| JPH06157446A (en) * | 1992-08-20 | 1994-06-03 | Basf Ag | Method of preparing 4-10 c alkyl cyanoacetate |
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| JPWO2012128265A1 (en) | 2014-07-24 |
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