JPS5829789B2 - Novel phenylalanine derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel phenylalanine derivative, N-benzylthiocarbonyl-L-phenylalanine methyl ester.

The object compound of the present invention has a cholesterol-lowering effect,
It is a useful compound that is expected to be used as a medicine.

As a related compound of N-benzylthiocarbonyl-L-phenylalanine methyl ester, pendylthiocarbonylphenylalanine Kachemissier Berichte No. 89
Volume, 2293 pages (1956) and Nature No. 177
Volume 841 (1956) and N-benzylthiocarbonylphenylalanine ethyl ester are described in Chemical Abstracts Vol. 74, 23, 116J (1971), but N-benzylthiocarbonyl-L-phenylalanine methyl ester is described in There is no description.

Furthermore, it is a completely newly discovered fact that N-benzylthiocarbonyl-L-phenylalanine methyl ester has a cholesterol-lowering effect.

Regarding the above-mentioned two known compounds, there is no mention of any cholesterol-lowering effect.

Next, the methods for synthesizing the target compound of the present application can be roughly divided into two methods, A and B, as follows.

A) A method in which the reaction is carried out in an organic solvent.

This method is a method in which benzylthiohalide represented by the general formula (1) 0CH2-8co-X (the middle represents a halogen atom) and phenylalanine methyl ester are reacted in an organic solvent, and the reaction is shown by the following formula. .

Specifically, the reaction is carried out by dissolving or suspending phenylalanine methyl ester in an organic solvent, and then gradually adding benzylthiocarbonyl halide represented by the general formula (1) with or without addition of a base. Let's do it.

Although it is not necessary to add a base, the reaction proceeds more smoothly and the yield is also better.

The entire amount of the base to be added may be added at once, or may be added simultaneously with the addition of the substituted benzylthiocarbonyl halide.

Phenylalanine methyl ester can be used in the reaction in the free form or in the form of an acid salt, such as an inorganic acid salt such as hydrochloride or hydrobromide, or an organic acid salt such as acetate or trifluoroacetate.

When using an acid salt in the reaction, it is preferable to carry out the reaction using a base.

As the solvent used in the reaction, any inert organic solvent that does not participate in the reaction can be used, but aromatic hydrocarbons such as benzene, toluene, and xylene, methylene chloride, and chloroform are preferred.

Halogenated hydrocarbons such as ethane dichloride and carbon tetrachloride, esters such as methyl acetate and ethyl acetate.

Ethers such as diethyl ether, dioxane, and tetrahydrofuran, ketones such as acetone and methyl ethyl ketone, acetonitrile, dimethylformamide, and the like are used alone or in combination.

Preferably used bases include organic bases such as triethylamine, dimethylaniline, N-methylmorpholine, and pyridine.

The reaction is usually carried out at a concentration of 0.05 mol/l (solvent amount) to 3 mol/l (solvent amount), and the reaction temperature is in the range of -50°C to 50°C, preferably 5°C to +25°C. It will be held in

Further, the reaction usually completes in 30 minutes to 3 hours.

Starting material used benzylthiocarbonyl halide,
It is preferable to use equal moles of each phenylalanine methyl ester in order to suppress the formation of by-products. Even when using a base, benzylthiocarbonyl halide,
It is preferable to use equimolar amounts of phenylalanine methyl ester and the base.

However, when the acid salt of phenylalanine methyl ester is used as a raw material, the base is used in an equimolar excess in order to free it.

Regarding the method of adding the raw materials to the reaction system, it is also possible to add benzylthiocarbonyl halide and phenylalanine methyl ester to an organic solvent, and then gradually add a base under the above reaction conditions to cause the reaction.

The raw material or base to be added to the reaction system can also be diluted with the solvent used in the reaction before being added.

Next, the method for isolating the target product from the reaction solution will be described. After the reaction is complete, the reaction solution is washed with water, then with a dilute acid such as dilute hydrochloric acid, and then with water to remove unreacted raw materials, residual salts, side reaction products, etc. Then, the reaction solution is dehydrated using a dehydrating agent.

Preferably used dehydrating agents include anhydrous sodium sulfate, anhydrous magnesium sulfate, calcium chloride, and the like.

When the solvent is distilled off from the dehydrated reaction solution under reduced pressure, a slag or solid substance is obtained.

This is recrystallized from a suitable solvent.

Suitable recrystallization solvents include ethyl acetate, ethyl ether, and methanol.

Ethanol etc. are used.

In this manner, a novel phenylalanine derivative, which is the purified target compound, can be obtained.

When recrystallizing, the combined use of n-hexane, petroleum ether, etc. is effective in facilitating crystallization.

3) A method in which the reaction is carried out in water or a water-containing organic solvent.

This method uses the same raw materials as Method A, and the reaction is also the same.

More specifically, the reaction is carried out by suspending or dissolving phenylalanine methyl ester in water or a water-containing organic solvent, and then adding benzylthiocarbonyl halide with or without the addition of a base.

Although the addition of a base is not always necessary, the reaction proceeds more smoothly and the yield is also better.

The base to be added may be added in its entirety at once, or may be added simultaneously with the addition of benzylthiocarbonyl halide.

Phenylalanine methyl ester can be present in free form or as an acid salt, such as an inorganic acid salt such as hydrochloride, hydrobromide,
It can be used in the reaction in the form of organic acid salts such as acetate and trifluoroacetate.

When using an acid salt in a reaction, it is preferable to use an equimolar amount of a base to free it before the reaction.

The solvent preferably used in the reaction is water or a water-containing organic solvent, and examples of the organic solvent include dioxane, tetrahydrofuran, N,N-dimethylformamide, acetonitrile, acetone, dimethyl sulfoxide, methyl acetate, ethyl acetate, etc. alone or in combination. Used in combination.

The amount of water contained in the organic solvent is not particularly limited, but it is preferable that the amount of water contained in the organic solvent is at least the amount that dissolves the phenylalanine methyl ester, as the reaction proceeds smoothly.
It can be mixed arbitrarily between 1/4 volume and 4 times the volume.

The base used is sodium hydroxide.

Examples include inorganic bases such as potassium hydroxide, sodium carbonate, potassium carbonate, and sodium hydrogen carbonate, and organic bases such as triethylamine, dimethylaniline, N-methylmorpholine, and pyridine.

The reaction is usually carried out at a concentration of 0.01 mol/l (solvent amount) to 3 mol/l (solvent amount), and the reaction temperature is -50°C to
It is carried out between 50°C, particularly preferably between -5°C and 25°C.

Further, the reaction usually completes in 30 minutes to 3 hours.

Regarding the method of adding raw materials to the reaction system, benzylthiocarbonyl halide may be added to a solvent, and then phenylalanine methyl ester dissolved in an alkali may be added.

In addition, when adding raw materials to the suspension or solution of phenylalanine methyl ester as described above, the raw materials can be added as they are, or in order to carry out the reaction smoothly, they can be dissolved in the solvent used for the reaction before being added. You can also do it.

The starting material used, benzylthiocarbonyl halide, is 0.05 to 0 relative to phenylalanine methyl ester.
, it is preferable to use an excess of about 2 times the mole.

It is preferable to use the base in an amount of about 0.05 to 1 mole in excess of the raw material benzylthiocarbonyl halide.

When phenylalanine methyl ester is used in the reaction in the form of an acid salt, an additional 1
Used in two-fold molar excess.

Next, the isolation and purification method will be described. After the reaction is completed, the reaction solution is extracted with an organic solvent.

Next, the extracted organic solvent is washed with an acid such as hydrochloric acid and then with water.

After dehydration with a dehydrating agent, the organic solvent is distilled off under reduced pressure to obtain the desired product in the form of a slag or a solid.

When this is recrystallized from a suitable organic solvent, the purified target product is obtained.

Suitable organic solvents used for extracting the target product from the reaction solution include ethyl acetate, ethyl ether, benzene, toluene, xylene, chloroform, methylene dichloride, and ethane dichloride.

Suitable acids for washing the extracted organic solvent include hydrochloric acid and sulfuric acid.

Examples of the dehydrating agent used next include anhydrous sodium sulfate, anhydrous magnesium sulfate, calcium chloride, and the like.

Suitable organic solvents to be used for recrystallizing the target benzylthiocarbonylphenylalanine methyl ester that has become solid or solidified include ethyl acetate, methanol, ethanol, isopropanol, and the like.

Further, during recrystallization, the combined use of n-hexane, petroleum ether, etc. is effective in making crystallization easier.

Next, the compound of the present invention, N-benzylthiocarbonyl-
Table 1 shows the results of confirming that L-phenylalanine methyl ester has a cholesterol-lowering effect based on its effect on Triton-induced hyperlipidemia.

Test method Triton (WR-1339) 600 μ/ky was administered intravenously to a group of 9 male DD mice (20 ± 1 g). Immediately thereafter, 100 μ/ky of the drug was administered orally, and the same amount was administered 20 hours later. of the drug was administered orally.

43 hours after administration of Triton, the animals were decapitated and blood was collected. Cholesterol in serum obtained by removing blood cells from blood by centrifugation was collected using a modified Zurkowsk 1-8hibata method (color development with sulfosalicylic acid, acetic acid and sulfuric acid, 620 m
quantification was performed by measuring the absorbance of μ).

Next, a method for synthesizing the target compound of the present application will be specifically explained with reference to Examples.

Example 1 L-phenylalanine methyl ester hydrochloride 8.6
g (0.04 mol) was suspended in 100 ml of ooform, and 11.1 ml (O, OS mol) of triethylamine was added over 5 minutes while cooling with water.

Further, 7.5 g (0.04 mol) of benzylthiocarbonyl chloride was added over 30 minutes while cooling with water (5-10°C).

After the addition, the reaction solution was further stirred for 1 hour at room temperature, and the reaction solution was poured with water (Lo
oml, 2N-hydrochloric acid 100ml. It was washed with 100 ml of water, and then dehydrated with anhydrous sodium sulfate.

The solvent was distilled off under reduced pressure to obtain a slag-like residue.

This is 20mA! of ethyl acetate and 507711 of n-
Recrystallization from hexane gave 8.19 white crystals (yield: 61.6%) with m-p-46-47°C.

Elemental analysis value As Cl8H19NO3S Calculated value (%) Actual value (%) C65,6365,87 H5,815,89 N4゜25 4.30

Claims (1)

[Claims] 1 N-benzylthiocarbonyl-L-phenylalanine methyl ester