KR790001639B1 - Method for preparation of new antifungal agent - Google Patents

Abstract

I(R = lower alkyl) was prepd. by treating dialkylphosphonites[CH3P (OR)2(R = lower alkyl) with ! d-acetamidoacrylic acid[H2C = C(CHCOCH3)COOH . The title agent II (α-amino-β-methylphosp- hinyl) propionic acid) was manufd. by hydrolysis of I.

Description

Preparation method of new antimicrobial substance

The present invention relates to a process for the preparation of a novel compound α-amino-β-methylphosphenyl propionic acid having anti-esthetic properties. The present invention is represented by the following equation

(Where R is a lower alkyl group)

Dialkyl methyl phosphonite (I) and α-acetamido acrylic acid (II) are reacted to give dialkyl-α-acetamido-β-methylphosphphenyl-propioate (III), which is then hydrolyzed. The present invention relates to a method for producing α-amino-β-methylphosphenyl propionic acid (IV).

Compound (I), a starting material of the present invention, is a known compound and can be prepared by various methods described in the literature. For example, phosphorus trichloride, anhydrous aluminum chloride, methyl chloride (or methyl iodide) is reacted, followed by heating with aluminum and salt (or potassium chloride) to obtain methylphosphorous dichloride represented by CH ₃ PCl ₂ and again Compound (I) is obtained by reacting lower alcohols such as methanol, ethanol and n-butanol in the presence of pyridine and triethylamine.

In addition, trialkyl phosphite (P (OR) ₃ ) is used as a raw material, and a Glia reagent is used to obtain compound (I), or trialkyl phosphite and phosphorus trichloride are reacted to form Cl P (OR) _2. The dialkyl chloro phosphite which is represented by the following, and the method of obtaining a compound (I) by acting Greenian reagent to this, etc. are mentioned.

Compound (II) can also be obtained as a known compound by the method described in Mounheon. For example, compound (II) can also be obtained by making aceramide and a pyrvinic acid react.

In the method for obtaining (III) from the compounds (I) and (II), (I) and (II) are mixed in the same equivalents, and gradually warmed up to avoid complete exotherm and reacted until completely dissolved. The homogeneous solution is preferably kept at 80 to 100 ° C. for 30 minutes to 1 hour to complete the reaction.

In addition, excessive addition of (I) in this reaction helps to accelerate the reaction, but after completion of the reaction, excess (I) must be distilled off under sufficient pressure. And this reaction proceeds even without the solvent mentioned above, and also in solvents, such as benzene and toluene. When the solvent is distilled off after the reaction is completed, dialkyl-α-acetamido-β-methylphosphenyl propionate (III) is obtained as an oily substance.

Subsequently, compound (III) is hydrolyzed by refluxing at 80 to 110 ° C. for 2 to 18 hours in hydrochloric acid or sulfuric acid having 3 to 6 rules, and then dried under reduced pressure to obtain crude hydrochloric acid (or sulfuric acid) salt of compound (IV). Get This is dissolved in a small amount of water to obtain a purified product of compound (IV) purified by chromatography using a cation exchange resin such as Dow X 50W or Amberlite IR-120. Compound (IV) can also be obtained by direct acid decomposition without isolating Compound (III) obtained by reacting Compound (I) and (II). In addition, the hydrolysis may be used in addition to the above strong acid, alkali such as sodium hydroxide, potassium hydroxide, barium hydroxide. It is 210-215 degreeC (foam decomposition) of melting | fusing point of compound (IV) obtained here.

Furthermore, compounds (III) and (IV) obtained by the present production method are novel compounds and are racemates of D and L. Compound (IV) obtained by the present invention, as shown in Table 1, had anti-aesthetic properties and exhibited a blocking effect of 90% or more against the heat-breaking disease at 200 mcg / ml even in an in vivo experiment.

TABLE 1

(Badge: glucose .sabec)

Next, the present invention will be described by way of Examples, but the present invention is not limited thereto. For example, as the raw material dialkylmethyl phosphonite, lower alkyl bodies other than diemethylmethylphosphonite may be used.

Example 1

1.5g of diemethylmethylphosphonite and 1g of α-acetanidoacrylic acid are mixed and put into a 100 ° C oil bath with a cooler to generate heat while dissolving α-acetamido and acrylic acid in a few seconds. Respond. Store at 100 ° C. for 30 minutes and then stop the reaction. The reaction solution was methanoled at 120 ° C. under 2-3 mm Hg. The dry ice trap is weighed and the excess diemethylmethylphosphonite is distilled off to obtain 2 g of diechyl-α-acetamido-β-methylphosphphenyl-propionate (III) on the syrup. Nuclear magnetic resonance absorption spectra δ = 2.0 (CH ₃ CO−) δ = 1.55 (CH ₃ P doublet J = 13 Hz). Mass spectra molecular ion m / e = 265.

Elemental Analysis Value: C: 44.98% H: 7.11% N = 5.03%

Theoretical: C ₁₀ H ₂₀ O ₅ NP as C: 45.28% H: 7.55% N: 5.28%

2 g of compound (III) is dissolved in 10 ml of 6 N hydrochloric acid, heated at reflux at 110 ° C. for about 3 hours, and after completion of the reaction, the reaction solution is concentrated to remove hydrochloric acid as much as possible.

The residue is then dissolved in about 10 ml of water and bleached through about 2 ml of activated carbon column, followed by chromatography by water development using a column of about 30 ml of Dow X 50 WX 2 (H ⁺ ). Concentrate and dry ninhydrin-positive cocci 15-31 in 10 g fractions to obtain 810 mg of target (IV). This was recrystallized from the heated methanol, and 620 mg of thing of melting | fusing point 210-215 degreeC (foam decomposition) was obtained.

Analytical Value: C: 28.21% H: 6.01% N: 8.55%

Theory C ₄ H ₁₀ O ₄ NP as C: 28.74% H: 5.99% N: 8.38%

Example 2

1.5 g of crude methylphosphonite and 1.3 g of acetamido acrylic acid are combined and gradually warmed from 50 ° C. in an oil bath. When the temperature reaches about 70 ° C., α-acetamido acrylicine gradually begins to dissolve and almost dissolves in about 5 minutes. Thereafter it is stored at 100 ° C. for about 15 minutes to complete the reaction. Next, about 15 ml of 4N hydrochloric acid is added to the reaction solution, and the mixture is refluxed for about 6 hours. Next, the reaction solution is concentrated to remove hydrochloric acid as much as possible, and then chromatographed in the same manner as in Example 1 using about 50 ml of Amberlite IR-120. The ninhydrin positive portion is collected and concentrated to obtain about 1.1 g of Compound (IV).

Example 3

1.6 g of methylmethylphosphonite is dissolved in about 10 ml of dry benzene. 1.3 g of α-acetamido acrylic acid was added thereto, and the mixture was refluxed at 90 ° C. under stirring. After about 1 hour, α-acetamido acrylic acid is completely dissolved but refluxed for 1 hour to complete the reaction. The reaction solution is concentrated under reduced pressure of 2-3 mgHg at 100 to 120 ° C for 1 hour, and benzene and excess diemethylmethylphosphonite are distilled off. 15 ml of 6N hydrochloric acid is added to the residue of about 2.5, and the mixture is refluxed at 100 to 110 ° C for about 2 hours for hydrolysis. Column after the completion of the reaction The reaction solution is concentrated as much as possible to remove hydrochloric acid and then using the activated carbon of the nokhyeo 2ml and the residue in water of from about 20ml to concentration again after bleaching and Dowex ^{50W × 2 (H +) (} 200-400 Mesh) 25 Thousands of chromatographies are performed using. Ninehydrin positive fractions from pages 7 to 25 were collected and concentrated in 10 g fraction to obtain 1.25 g of compound (IV).

Example 4

About 1.3 g of Compound (III) obtained in Example 1 is dissolved in 15 ml of 4 N sodium hydroxide and hydrolyzed at 110 ° C. for 6 hours. The reaction solution was neutralized in Ambalite IRC-50 (H ⁺ ), and then subjected to thousands of chromatographs using about 40 ml of DoeX 5W × 2 (H ⁺ ) to collect approximately 500 mg of compound (IV) by collecting positive ninhydrin fractions. Got it.

Claims (1)

Formula CH ₃ · P (OR) ₂ (Wherein R is a lower alkyl group) By reacting the dialkyl methyl phosphonite represented by the formula with α-acetamide acrylic acid represented by the formula H ₂ C = C (NHCOCH ₃ ) COOH General formula

(Where R is a lower alkyl group) To produce a dialkyl-α-acetamido-β-methyl phosphphenyl-propionate, which is then hydrolyzed to Formula

A method for producing α-amino-β-methylphosphphenylpropionic acid, characterized by preparing α-amino-β-methyl phosphphenylpropionic acid.