KR890002010B1 - Manufacturing process of artificial sweetner - Google Patents

Abstract

Synthetic sweeteners (I)[A=cyano, halo, nitro, etc.; B=O,S; Z=benzyl, methyl, propyl, butyl, etc.; X=methyl, CH3COO were prepd.. Thus, 4- cyano phenyl isocyanide layer obtained from a mixt. contg. 1.18g 4- cyanophenyl amine, 3.36g KOH, and 30g chloroform was refluxed with 3.2g sulfur in 30g chloroform and recrystallized with hexane to give 1.28g 4-cyanophenyl isothiocyanate. 0.005M L-Aspartyl-L- phenylalanine methyl ester in 40ml H2O was adjusted to pH 9 with NaOH and reacted with 0.005 M 4-cyano phenyl isothiocyanate in 15ml EtOH to give 1.47g N-(4-cyanophenylthiocarbamoyl)-L-aspartyl-L-phenyl alanine methyl ester.

Description

Manufacturing method of synthetic sweetener

The present invention relates to a method for producing a synthetic seasoning. In more detail, the present invention relates to a method for preparing the compound of formula (I), which is a synthetic sweetener.

In the formula, A represents a group of electron donor such as cyano group, halogen, nitro group, CH ₃ CO group, CH ₃ OCO group, CH ₃ SO ₂ group, B represents oxygen or sulfur atom, Z represents benzyl, Cyclohexylmethyl, methyl, propyl, butyl, phenyl, cyclohexyl, CH ₂ OC (CH ₃ ) ₃ groups, COOCH ₃ groups, CF ₃ groups, COOC ₂ H ₅ groups, COOC ₃ H ₇ groups, CONHC ₃ H ₇ groups , (CH ₂ ) ₂ CH (CH ₃ ) ₂ group, COOCH (CH ₃ ) ₂ group, -CONHR group (wherein R represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms), X represents a methyl group or COOCH ₃ group .

Sweeteners are compounds that give sweet taste by mixing with various foods and medicines. Synthetic sweeteners are widely used as a substitute for sugar, mainly for diabetics and people with obesity. Among them, sodium cyclate and saccharin are known. There is a situation.

In order to solve this problem, an amino acid ester, that is, a substance commonly known as asapane, has been developed. The sweetness of this aspartame is intermediate between cicarine and sodium cyclate. However, since this aspartame has an expensive and unstable disadvantage, in order to solve this problem, Nofleclrod et al. Developed the same compound as the compound according to the present invention (see Japanese Patent Laid-Open No. 59-73559). It was found to be 300 to 50,000 times that of sugar. However, since this method uses extremely toxic substances such as phoskens and thiophosgenes in the preparation of the general formula (II) compounds described below as starting materials, there is a great risk of handling them, and after synthesis There is a risk that these toxic substances remain in live tablets.

The present inventors earnestly studied to remove the above drawbacks, and as a result, reacting chloroform and potassium hydroxide with an aniline derivative of the following general formula (III) to obtain an isocyanide derivative compound, and adding sulfur again and heating it to thioisocyanate The present invention was completed by finding that a derivative compound was obtained and oxygen was blown into the isocyanide derivative compound as needed to synthesize an isocyanate compound.

Hereinafter, the present invention will be described in detail.

In preparing the compound of the general formula (I), the aniline derivative of the following general formula (III) is reacted with chloroform in the presence of potassium hydroxide to obtain an isocyanide derivative, and sulfur is added thereto to heat the isothiocyanate derivative ( II ') was obtained. In addition, an isocyanate derivative (II ") was prepared by blowing oxygen into the isocyanide derivative compound.

Wherein A is as described above.

In the above formula, the general formulas (II ') and (II ") are included in the general formula (II) compound, that is, AC ₆ H ₄ -N = C = B (wherein A and B are as described above). The temperature conditions for preparing the (II ′) isothiocyanate derivative are from about 40 ° C. to boiling temperature, but preferably between 60 and 65 ° C. The starting material (II) thus obtained and the compound of formula (IV) The reaction was carried out according to a known method to prepare a target compound.

In the above formula, X and Z are as described above.

The target compound of the general formula (I) prepared according to the method of the present invention has the advantage of not only toxic substances remaining, but also a simple reaction process.

Hereinafter, the present invention will be described in detail by the following examples.

Example 1

Preparation of N- (4-shihanophenylthiocarbamoyl) -L-aspartyl-L-phenylalanine methyl ester.

1.18 g (0.01 mol) of 4-cyanophenyl amine and 3.36 g (0.06 mol) of potassium hydroxide are added to 30 g of chloroform and heated at a boiling temperature. The oil layer is separated and steam distilled. A suspension of 3.2 g (0.01 mol) of sulfur in 30 g of chloroform was added to the oil layer of 4-cyanophenyl isocyanide obtained above, and a reflux cooler was attached and refluxed to obtain crude 4-cyanophenyl isothiocyanide. Get After filtration and vacuum drying at room temperature, the mixture was recrystallized with hexane to obtain 1.28 g of 4-cyanophenyl isothiocyanate. Melting Point: 117-118 ℃ Yield: about 80%

1.47 g (0.005 mol) of L-aspartyl-L-phenylalanine methyl ester was added to 40 ml of water and dissolved by adjusting the pH to 9 with sodium hydroxide solution, followed by 0.8 g of 4-cyanophenyl isothiocyanate obtained above. 0.005 mole) is dissolved in 15 ml of ethanol and a small amount of the solution is stirred to form a white precipitate. After stirring for 1 hour at room temperature, the vacuum was concentrated at 45 ℃. After cooling, 100 ml of ethyl acetate was added to dissolve the precipitate. The lower aqueous layer was separated, and the pH was adjusted to 4.5 with 1 N hydrochloric acid solution to produce a white precipitate. The precipitate was filtered off, washed with water and dried in vacuo to afford 1.47 g of the titled title compound. Melting Point 172-173 ℃ Yield: 65%

Example 2

Preparation of N- (4-nitrophenyl carbamoyl) -L-aspartyl-L-phenylalanine ethyl ester.

1.38 g (0.01 mol) of 4-nitrophenylalanine and 3.36 g (0.06 mol) of potassium hydroxide are added to 30 g of chloroform and heated at a boiling temperature. The oil layer is separated and steam distilled. 30 g of chloroform is added thereto, and oxygen is added to reflux with vigorous stirring to form crude 4-nitro phenyl cyanate. It was filtered, dried in vacuo and recrystallized with hexane to obtain 1.08 g of 4-nitrophenyl isocyanate. Yield 75%

1.47 g (0.005 mol) of L-aspartyl-L-phenylalanine methyl ester was added to 40 ml of water, dissolved by adjusting the pH to 9 with sodium hydroxide, and then 0.72 g (0.005) of 4-nitrophenyl isocyanate obtained above. Mole) is dissolved in 15 ml of ethanol, and a small amount of the solution is added while stirring to generate a white precipitate. The mixture was stirred at room temperature for 1 hour and then concentrated in vacuo. After stirring, 100 ml of ethyl acetate was added, the precipitate was dissolved, the aqueous layer was separated, and 1N was adjusted to 4.5 with hydrochloric acid solution to produce a white precipitate. The precipitate was washed with water after filtration and dried in vacuo to yield 1.4 g of the crude title compound. Melting Point: 196-198 ℃ Yield: 62%

EXAMPLES 3-12

The following compounds were synthesized in the same manner as in Examples 1 and 2, and the results are as follows.

Claims (1)

The aniline derivative of the following general formula (III) is reacted with chloroform in the presence of potassium hydroxide to obtain an isocyanite derivative, which is heated with sulfur to obtain a thiisothiocyanate derivative of the general formula (II '), or iso A method for producing a compound of the general formula (I), characterized by reacting a derivative of cyanide with oxygen to obtain an isocyanate derivative (II "), followed by reaction with a compound of the general formula (IV) or a derivative thereof.

Wherein X represents a group of an electron donor such as a cyano group, a natro group, a halogen, a CH ₃ CO group, a CH ₃ OCO group, a C ₂ H ₅ OCO group, a CH ₃ SO ₂ group, and B is an oxygen or sulfur atom Z represents benzyl, cyclohexylmethyl, methyl, propyl, butyl, phenyl, cyclohexyl 2 CH ₂ OC (CH ₃ ) ₃ group, COOCH ₃ group, CF ₃ group, COOC ₂ H ₅ group, COOC ₃ H ₇ Group, CONHC ₃ H ₇ group, (CH ₂ ) ₂ CH (CH ₃ ) ₂ group, COOCH (CH ₃ ) ₂ group, CONHR (R is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms), X is a methyl group or COOCH ₃ group.