JPS641463B2 - - Google Patents

Description

[Detailed description of the invention]

This invention relates to a method for producing an amino acid ester, specifically, by reacting a cyanoformic acid ester and an active methylene compound in the presence of metal chloride, and then treating the resulting reaction product with water to produce an α,β-unsaturated α- The present invention relates to a method for producing an amino acid ester. The amino acid ester obtained by this invention is
It is a compound useful as an intermediate for pharmaceuticals, agricultural chemicals, and additives for polymeric compounds. For example, an amino acid ester (1-amino-
1,2,2-triethoxycarbonylethylene)
When reduced with sodium borohydride, α-ethoxycarbonyl-β-imino-γ-butyrolactone, which has a herbicidal effect, is obtained. Conventionally, methods for producing α,β-unsaturated α-amino acid esters have been based on the presence of metal halides such as aluminum chloride, aluminum chloride, titanium tetrachloride, stannic chloride, and iron trichloride, and bases such as pyridine and triethylamine. Below, a method has been proposed in which a cyanoformic acid ester is reacted with an active methylene compound, and then the resulting reaction product is treated with water [Ohno et al., Proceedings of the 21st Natural Organic Compounds Symposium,
128 (1978)] However, in the above method, zinc chloride is selected as the metal halide and triethylamine is selected as the base, and ethyl cyanoformate and ethyl acetoacetate are mixed in the presence of the metal halide and the base at room temperature for 6 hours. When reacting with ester and then treating the resulting reaction product with water, 1-amino-2-acetyl-1,2-diethoxycarbonylethylene could be synthesized in a relatively high yield (85%). However, if aluminum chloride, titanium tetrachloride, stannic chloride, or iron trichloride is used as the metal halide instead of zinc chloride, 1-amino-2-acetyl-1,2-diethoxycarbonylethylene It has the disadvantage that it is not produced at all, or even if it is produced, the yield is very low (14% or less). Furthermore, even if the combination of zinc chloride and triethylamine gives the desired product in high yield, if this is replaced with a combination of zinc chloride and pyridine, the yield of the desired product will be extremely low. (20%). Furthermore, even if the desired product can be produced by carrying out the reaction in the presence of a metal halide and a base according to the above method, the above method requires a complicated step of recovering the base after the reaction. There are drawbacks. In addition, imino compound metal halide complexes have conventionally been produced by reacting aliphatic or aromatic nitriles with active methylene compounds in the presence of stannic chloride or titanium tetrachloride (Japanese Patent Publication No. 1973-
7894), a method for producing β-iminocarboxylic acid ester (a tautomer of α,β-unsaturated-α-aminocarboxylic acid ester) by decomposing it with water or alcohol (Japanese Patent Publication No. 43 ―
17169 and Special Publication No. 44-29448) have been proposed. However, even if the imino compound metal halide complex is decomposed with water or alcohol, the yield of β-iminocarboxylic acid ester produced is low, so combining the above methods,
Even if an aliphatic or aromatic nitrile and an active methylene compound are reacted in the presence of stannic chloride or titanium tetrachloride and then decomposed with water, alcohol, etc., β-iminocarboxylic acid ester can be obtained in high yield. The disadvantage is that it cannot be manufactured. Therefore, the present inventors aimed to develop a method that can improve the drawbacks of the conventional methods and can produce α,β-unsaturated-α-amino acid esters in high yield. After various studies, it was found that in the presence of specific metal halides, especially tin or titanium halides, from which α,β-unsaturated α-amino acid esters could not be produced in high yield by conventional methods, By reacting a specific cyanoformic acid ester with an active methylene compound and then treating the reaction product with water, α,β-unsaturated α- can be easily obtained in high yield without using a base.
discovered that amino acid esters could be produced,
We have arrived at this invention. That is, this invention provides general formula (1) (However, in the formula, R ¹ is an alkyl group having 1 to 4 carbon atoms.) A cyanoformic acid ester represented by the formula (2) (However, in the formula, R ² is an alkyl group having 1 to 4 carbon atoms, Y is a CN group, COR ³ group or COOR ⁴ group,
R ³ represents an alkyl group having 1 to 4 carbon atoms or a phenyl group, and R ⁴ represents an alkyl group having 1 to 4 carbon atoms. Note that R ² and R ⁴ may be the same group or different groups. ) in the presence of a metal chloride represented by the general formula (3) MCl ₄ ...(3) (wherein M is titanium or tin), and then It is characterized in that the reaction product obtained by the reaction is treated with water or an acidic aqueous solution. General formula (4) (However, in the formula, R ¹ , R ² and Y have the same meanings as above.) The present invention relates to a method for producing an amino acid ester represented by the following. The cyanoformic acid ester used in this invention is represented by general formula (1). (However, in the formula, R ¹ is an alkyl group having 1 to 4 carbon atoms.) Examples of the cyanoformate represented by the general formula (1) include methyl cyanoformate, ethyl cyanoformate, propyl cyanoformate, and cyanoformate. Butyl is mentioned. Further, the active methylene compound is represented by the following general formula (2). (However, in the formula, R ² is an alkyl group having 1 to 4 carbon atoms, Y is a CN group, COR ³ group or COOR ⁴ group,
R ³ represents an alkyl group having 1 to 4 carbon atoms or a phenyl group, and R ⁴ represents an alkyl group having 1 to 4 carbon atoms. Note that R ² and R ⁴ may be the same group or different groups. Examples of the active methylene compound represented by the general formula (2) include methyl cyanoacetate, ethyl cyanoacetate, propyl cyanoacetate, butyl cyanoacetate, methyl acetoacetate, ethyl acetoacetate, ethyl propionyl acetate, ethyl butyryl acetate, and ethyl valeryl acetate. , methyl benzoylacetate, ethyl benzoylacetate, dimethyl malonate, diethyl malonate, dipropyl malonate, and dibutyl malonate. The amount of the active methylene compound used is an equimolar amount to the amount of the cyanoformate ester used, but is not limited thereto, and may be an amount equal to or more than the amount of the cyanoformate ester used. The metal chloride used in this invention is represented by general formula (3). MCl ₄ ...(3) (However, in the formula, M is titanium or tin.) The amount of metal chloride used is an equimolar amount with the amount of the cyanoformate or the active methylene compound, whichever is smaller. , without limitation,
The amount may be equal to or more than the amount of the cyanoformate or active methylene compound used. Note that even if an excessive amount of metal chloride is used, there is no particular effect thereof. The reaction between the cyanoformic acid ester and the active methylene compound in this invention can be carried out with or without a solvent, but it is preferable to use a solvent in terms of removal of reaction heat and the like. Any solvent may be used as long as it is inert to the reaction in this invention, such as aromatic hydrocarbons such as benzene, toluene, chlorobenzene, and dichlorobenzene, as well as methylene chloride, ethylene chloride, chloroform, and tetrachlorobenzene. Examples include halogenated hydrocarbons such as carbon chloride. Note that the solvent is preferably sufficiently dehydrated prior to the reaction. The reaction between the cyanoformate ester and the active methylene compound may be carried out by any method as long as the cyanoformate ester, the active methylene compound, and the metal chloride can be brought into contact with each other under substantially anhydrous conditions. Furthermore, the three components may be mixed in any order. The reaction temperature between the cyanoformic acid ester and the active methylene compound varies depending on the type and combination of the active methylene compound and metal chloride used, but if the reaction is carried out at too high a temperature, the yield of the final target product will decrease. , generally a temperature in the range of -10 to 100°C is preferred. The reaction time between the cyanoformic acid ester and the active methylene compound varies depending on the type and combination of the active methylene compound and the metal chloride. For example, when using ethylene chloride as the solvent, titanium tetrachloride as the metal halide, and diethyl malonate as the active methylene compound, the final target product can be obtained in good yield in a reaction time of about 30 minutes under reflux.
In the above case, if ethyl cyanoacetate is used in place of diethyl malonate, the final desired product can be obtained in good yield in a reaction time of about 8 hours under reflux. The reaction product obtained after the end of the reaction of the cyanoformic acid ester with the active methylene compound in the presence of metal chloride is treated with water or an aqueous acid solution. As a treatment operation, it is sufficient to simply add water to the reaction product obtained by reacting the cyanoformic acid ester and the active methylene compound and thoroughly shake (mix) the mixture.
There is no difference in the yield of the desired product even if a dilute acidic aqueous solution such as hydrochloric acid, sulfuric acid, para-toluenesulfonic acid, etc. is used instead of water. Treatment with water or an acidic aqueous solution yields a reaction mixture containing the desired product, ie the α,β-unsaturated-α-amino acid ester. As a processing operation, a mixture containing α,β-unsaturated-α-amino acid ester is separated into an aqueous layer and an organic layer, the resulting organic layer is distilled or concentrated, and the resulting residue is subjected to a process such as recrystallization. When treated with this process, it is possible to isolate the amino acid ester, in particular the α,β-unsaturated-α-amino acid ester, which is the target product of the invention. The amino acid ester obtained by this invention is represented by general formula (4). (However, in the formula, R ¹ , R ² and Y have the same meanings as above.) As the amino acid ester represented by the general formula (4), 1-amino-2-cyano-1,2-dimethoxycarbonylethylene , 1-amino-2-cyano-1-ethoxycarbonyl-2-methoxycarbonylethylene, 1-amino-2-cyano-1
-butoxycarbonyl-2-ethoxycarbonylethylene, 1-amino-2-cyano-1,2-diethoxycarbonylethylene, 1-amino-2-
Cyano-2-butoxycarbonyl-1-ethoxycarbonylethylene, 1-amino-2-cyano-
1-ethoxycarbonyl-2-propyloxycarbonylethylene, 1-amino-2-acetyl-
1,2-dimethoxycarbonylethylene, 1-amino-2-acetyl-1,2-diethoxycarbonylethylene, 1-amino-2-propionyl-
1,2-diethoxycarbonylethylene, 1-amino-2-valeryl-1,2-diethoxycarbonylethylene, 1-amino-2-benzoyl-1,
2-dimethoxycarbonylethylene, 1-amino-2-benzoyl-1,2-diethoxycarbonylethylene, 1-amino-1,2,2-trimethoxycarbonylethylene, 1-amino-1,2,
2-triethoxycarbonylethylene, 1-amino-1,2,2-tripropyloxycarbonylethylene, 1-amino-1,2,2-tributoxycarbonylethylene and 1-amino-1-butoxycarbonyl-2,2 -Diethoxycarbonylethylene, etc. can be mentioned. Next, examples of this invention will be shown. Example 1 While stirring a solution obtained by dissolving 5.91 g of stannic chloride in 40 ml of methylene chloride, 2.29 g of ethyl cyanoformate was added dropwise thereto, and then 4.33 g of ethyl benzoylacetate was added dropwise, mixed, and stirred. 2 at below 21.5℃
Allowed time to react. After the reaction, add 40℃ of water to the reaction product while cooling it with ice water so that the temperature of the reaction product does not exceed 10℃.
ml was added dropwise and mixed for 1 hour to obtain a reaction mixture. The reaction mixture is then separated into an aqueous layer and an organic layer,
The aqueous layer was extracted three times with 40 ml of chloroform. A solution of this extract and the organic layer separated from the reaction mixture was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 6.21 g of pale yellow crystals. When this slightly yellow crystal was washed with 50 ml of n-hexane, 6.00 g of slightly yellow-orange needle-shaped crystals (yield 93%)
was gotten. The melting point of the slightly yellowish-orange needle-shaped crystal obtained by recrystallizing this crystal from cyclohexane is 138 to 139°C. From the spectrum analysis results, the new compound 1-
It was confirmed to be amino-2-benzoyl-1,2-diethoxycarbonylethylene.

[Table] Example of calculated values 2 Titanium tetrachloride 4 instead of 5.91 g of stannic chloride
Example 1 was carried out in the same manner as in Example 1, except that the amount of ethyl cyanoformate used was changed from 2.29 g to 2.17 g, and the amount of ethyl benzoylacetate was changed from 4.33 g to 3.79 g. Amino-2-benzoyl-1,2-diethoxycarbonylethylene5.29
g (yield 88%). Example 3 While stirring a solution obtained by dissolving 3.96 g of titanium tetrachloride in 40 ml of ethylene chloride, 2.02 g of ethyl cyanoformate was added dropwise, and then 3.37 g of diethyl malonate was added dropwise, mixed, and refluxed. The reaction was allowed to take place for 30 minutes. After the reaction, 40 ml of water was added dropwise to the reaction product (brown) while cooling with ice water so that the temperature of the reaction product did not exceed 10°C, and the mixture was mixed for 1 hour to obtain a reaction mixture. Then, the reaction mixture was separated into an aqueous layer and an organic layer,
The aqueous layer was extracted three times with 40 ml of chloroform. A solution of this extract and the organic layer separated from the reaction mixture was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 5.13 g of yellow crystals. The yellow crystals were washed with 50 ml of n-hexane to obtain 4.47 g of yellow crystals (yield: 84%). The melting point of colorless prismatic crystals obtained by recrystallizing these crystals from isopropyl ether is 69.5-70℃.
This result is the elemental analysis value shown in Table 2,
From the analysis results of IR spectrum, NMR spectrum, and mass spectrum, it was confirmed that it was a new compound, 1-amino-1,2,2-triethoxycarbonylethylene.

[Table] Example of calculated values 4 While stirring a solution obtained by dissolving 5.67 g of stannic chloride in 40 ml of benzene, 3.58 g of diethyl malonate was added, followed by ethyl cyanoformate.
2.23 g was added dropwise and the reaction was carried out under reflux for 1 hour. After the reaction, the reaction product was treated in the same manner as in Example 3 to obtain 5.15 g (yield: 91%) of 1-amino-1,2,2-triethoxycarbonylethylene. Example 5 While stirring a solution obtained by dissolving 3.58 g of titanium tetrachloride in 40 ml of ethylene chloride, 1.83 g of ethyl cyanoformate was added dropwise to the solution, followed by ethyl acetoacetate.
2.52 g was added dropwise, mixed, and the reaction was carried out at 60° C. for 15 minutes. After the reaction, 40 ml of water was added dropwise to the reaction product (brown) while cooling with ice water so that the temperature of the reaction product did not exceed 10°C, and the mixture was mixed for 1 hour to obtain a reaction mixture. The reaction mixture was separated into an aqueous layer and an organic layer, and the aqueous layer was extracted three times with 40 ml of chloroform. A solution of this extract and the organic layer separated from the reaction mixture was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 4.10 g of brown crystals. When the brown crystals were washed with n-hexane, 3.39 g (yield: 80%) of yellow-orange crystals were obtained. The melting point of colorless massive crystals obtained by recrystallizing these crystals from benzene is 88-89℃, and these crystals are
Elemental analysis values and IR spectrum shown in Table 3,
From the analysis results of NMR spectrum and mass spectrum, it was confirmed to be 1-amino-2-acetyl-1,2-diethoxycarbonylethylene.

[Table] Calculated Value Example 6 While stirring a solution obtained by dissolving 5.06 g of stannic chloride in 40 ml of methylene chloride, add acetoacetic acid while cooling the solution so that the temperature does not rise above -3°C. 2.50 g of ethyl was added dropwise, and then 1.91 g of ethyl cyanoacetate was added and mixed. While cooling the mixture so that the temperature did not rise above -3°C,
A time reaction was performed. After the reaction, the reaction product solution was treated in the same manner as in Example 5 to obtain 3.61 g (yield: 82%) of 1-amino-2-acetyl-1,2-diethoxycarbonylethylene. Example 7 While stirring a solution obtained by dissolving 3.98 g of titanium tetrachloride in 40 ml of ethylene chloride, 2.22 g of ethyl acenoformate was added dropwise, followed by ethyl cyanoacetate.
2.31 g was added dropwise, mixed, and the reaction was carried out under reflux for 8.5 hours. After the reaction, the temperature of the reaction product is 10
40 ml of water while cooling with ice water so as not to exceed ℃.
was added dropwise and mixed for 1 hour to obtain a reaction mixture. The reaction mixture was separated into an aqueous layer and an organic layer, and the aqueous layer was extracted twice with 40 ml of chloroform. A solution of this extract and the organic layer separated from the reaction mixture was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give 3.81 g of brown crystals (crude yield: 88
%) was obtained. The brown crystals were recrystallized from a mixed solvent of isopropyl ether and cyclohexane to obtain 2.93 g (yield: 68%) of colorless needle crystals. The melting point of this crystal is 76 to 77°C, and the elemental analysis values shown in Table 4, as well as the analysis results of IR spectrum, NMR spectrum, and mass spectrum, indicate that 1-amino-2-cyano-1,2-
It was confirmed to be diethoxycarbonylethylene.

[Table] Calculated values

Claims (1)

[Claims] 1 General formula (1) (However, in the formula, R ¹ is an alkyl group having 1 to 4 carbon atoms.) A cyanoformic acid ester represented by the formula (2) (However, in the formula, R ² is an alkyl group having 1 to 4 carbon atoms, Y is a CN group, COR ³ group, COOR ⁴ group, R ³ is an alkyl group having 1 to 4 carbon atoms or a phenyl group, and R ⁴ represents an alkyl group having 1 to 4 carbon atoms.
Note that R ³ and R ⁴ may be the same group or different groups. is reacted with an active methylene compound represented by the general formula (3) MC1 ₄ ...(3) (wherein, M is tin or titanium) in the presence of a metal chloride represented by the following: It is characterized by treating the reaction product with water or an acidic aqueous solution. General formula (4) (However, in the formula, R ¹ , R ² and Y have the same meanings as above.) A method for producing an amino acid ester represented by the following.