JPS596300B2 - Method for producing novel phenylalanine derivatives - Google Patents

Description

Detailed Description of the Invention The present invention is based on the general formula (■) A-CH2-SCONH-CH-COR (where A represents a substituted phenyl group, phenyl group, substituted naphthyl group, or naphthyl group, and R represents a hydroxyl group or an alkoxy The present invention relates to a method for producing a thiocarbonylphenylalanine derivative () represented by the general formula (I) (in which R has the same meaning as above). phenylalanine or a phenylalanine derivative represented by ) and carbonyl sulfide and a substituted or unsubstituted phenylalanine represented by the general formula ( ) (wherein A has the same meaning as above and X represents a halogen atom) The present invention relates to a method for producing a thiocarbonylphenylalanine derivative represented by the general formula (), which is characterized by reacting with halomethylbenzene or halomethylnaphthalene (hereinafter abbreviated as halomethyl compound).

The inventors of the present invention have previously shown that the water moiety of the compound represented by the above general formula () produced by the method of the present invention has a cholesterol-lowering effect and is a useful compound expected to be used as a pharmaceutical. Patent 1/Patent application (Patent application 1987-18)
871, 51-18872),
In the phenylalanine derivative represented by the general formula (), A is a para-nitrophenyl group, 2-5-dimethylphenyl group, 2,6-dimethylphenyl group, t-butylphenyl group or naphthyl group, and R is hydroxyl. Compounds in which A is a paranitrophenyl group, 2.5-dimethylphenyl group, 2,6-dimethylphenyl group, parafluorophenyl group, or naphthyl group, and R is a methoxy group, are This is the first new compound to be synthesized, and the first to discover that they have the medicinal effect of lowering cholesterol.

Conventionally, this type of compound has been synthesized by the method shown by the following reaction formula [Chemitsier Berichte, Vol. 89, p. 2293 (1956) and Nature, Vol. 177, p. 841 (1956).
956) is known. However, according to this conventional method, the mercaptans used as raw materials and the pendylthiocarbonyl chloride obtained by reacting with phosgene generally cause a bad working environment due to their bad and irritating odors. These materials are expensive, and phosgene is a highly toxic raw material, so it is not suitable for industrial production.

Furthermore, in addition to the target product, by-products such as dithiocarbonate esters and urea compounds are likely to be produced, making it extremely difficult to purify the target product. As described above, the conventional method cannot be said to be an industrially advantageous manufacturing method in terms of working environment, manufacturing cost, and manufacturing process. As a result of studies to improve the above-mentioned drawbacks, the inventors of the present invention have found that by using halomethyl compounds and carbonyl sulfides, which are inexpensive, easily available, and easy to handle, as raw materials, the work environment can be worsened due to the bad odor of mercaptans, etc. The present inventors have discovered that a chemically pure target product can be obtained in a high yield with virtually no by-products produced in one production process, and have completed the present invention.

The method of the present invention is illustrated by the following reaction formula.

(In the formula, A.R.X has the same meaning as above, and Base
indicates an inorganic or organic base.

Further, B represents an alkali metal ion of an inorganic base or an ammonium ion of an organic base. ), that is, general formula (1)
Phenylalanine or a phenylalanine derivative represented by and a base are allowed to coexist in a solvent, and reacted with carbonyl sulfide to prepare a thiol carbamate () as an intermediate, without isolating or purifying it. Add to this the general formula (
) is reacted to produce the desired thiocarbonylphenylalanine derivative represented by the general formula ().

The compound represented by the general formula (1) used as a raw material includes a compound in which the group R is a hydroxyl group, a lower alkoxy group, or a general formula -NRlR2 (wherein R1 and R2 are the same or different and are a hydrogen atom or a lower alkyl group). , or R1
and R2, together with the adjacent nitrogen atom, represents a piperidino group or a morpholino group). Among the raw materials, amide derivatives are obtained by condensing phenylalanine with a protected amino group with the corresponding amine using a known method commonly used in the field of amino acid and peptide synthetic chemistry. Carbonyl or t-butyloxycarbonyl) is used. Specific examples of the compound represented by general formula (1) include phenylalanine, phenylalanine methyl ester,
Phenylalanine ethyl ester, phenylalanine-n-butyl ester, phenylalanine-n-hexyl ester, phenylalanine amide, phenylalanine methylamide, phenylalanine ethylamide, phenylalanine-n-butylamide, enylalanine cyclohexylamide, phenylalanine dimethylamide,
Phenylalanine diethylamide, Phenylalanine dicyclohexylamide, Phenylalanine piperidide,
Examples include phenylalanine morpholide.

In addition, these compounds have free amino groups or acid salts,
For example, inorganic hydrochloric acids such as hydrochloric acid, sulfuric acid, and hydrobromic acid, or organic acid salts such as acetic acid and trifluoroacetic acid can also be used in the reaction. On the other hand, the halomethyl compound represented by the general formula () is obtained by halomethylating substituted or unsubstituted benzene or naphthalene.

The compound represented by the general formula () includes benzyl chloride or bromide and 2 as a substituent of the phenyl group.
-Methyl, 3-methyl, 4-methyl, 2,5-dimethyl, 2,6-dimethyl, 3,4-dimethyl, 2,3,4-
Triethyl, 2, 3, 4, 5, 6-pentamethyl, 4-
Ethyl, 4-n-butyl, 4-Tert-butyl, 2-methoxy, 4-methoxy, 2,3-dimethoxy, 2-fluoro, 3-fluoro, 4-fluoro, 2-chloro, 3-
Benzyl chloride or bromide having chloro, 4-chloro, 4-bromo, 3-chloro-4-methoxy, 4-methoxy-3,5-dichloro, 4-hydroxy, 2-nitro, 4-nitro, etc.; 1-(chloromethyl)naphthalene 1-(bromomethyl)naphthalene, 2-
Examples include (chloromethyl)naphthalene and 2-(bromomethyl)naphthalene.

As the reaction solvent, water, an organic solvent, or a mixed solvent of water and an organic solvent is used.

As the organic solvent, any inert organic solvent that does not participate in the reaction can be used, but aromatic hydrocarbons such as benzene, toluene, and xylene, and halogens such as methylene chloride, chloroform, ethane dichloride, and carbon tetrachloride are preferred. Hydrogens, esters such as methyl acetate and ethyl acetate, ethers such as diethyl ether, dioxane and tetrahydrofuran, ketones such as acetone, methyl ethyl ketone and diethyl ketone, acetonitrile, dimethylformamide, etc. alone or in combination. used. When using a mixed solvent of these organic solvents and water, the amount of water contained in the organic solvent is not particularly limited, but if the amount is at least enough to dissolve the raw material phenylalanine or phenylalanine derivative, the reaction will be rapid. It is preferable to proceed, and usually water is optionally mixed in an amount of 1/4 to 4 times the amount of the organic solvent. Examples of the base include inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, and sodium bicarbonate, and organic bases such as triethylamine, N-methylmorpholine, dimethylaniline, and pyridine. Furthermore, it is also possible to use the phenylalanine derivative itself as the base, which has a free amino group. The reaction is carried out in a solvent in the presence of phenylalanine or a phenylalanine derivative represented by general formula (1) and a base at 50°C or lower, preferably in the temperature range of -5°C to 20°C, with stirring. Blow in,
A thiol carbamate () is generated as an intermediate, and then a reaction with a halomethyl compound represented by the general formula () is carried out in a range of 0 to 50
It is carried out in the temperature range of ℃.

These reactions usually proceed almost simultaneously with the completion of addition of the halomethyl compound, but stirring is continued for an additional 30 minutes to 3 hours to complete the reaction. The carbonyl sulfide used at this time may be added after being absorbed in a solvent in advance.
It is also possible to react carbonyl sulfide in a solvent in the presence of phenylalanine or a phenylalanine derivative, a methyl compound, and a base. Further, the amount of carbonyl sulfide to be used is equal to or less than the same mole, preferably in the range of 1 to 0.8 mole per mole of phenylalanine or phenylalanine derivative, so that the desired product can be obtained in good yield. . If carbonyl sulfide is used in excess of equimolar or more, the thiol carbamate () formed as an intermediate becomes significantly unstable, producing by-products and causing a decrease in yield. The amount of base used is
Basically, equivalent moles of phenylalanine or phenylalanine derivatives are required to form these thiol carbamates, but when used in the form of acid salts, free amino groups are required. An additional equimolar amount of base is required to form the mold.

Further, when phenylalanine is used as a raw material, it is necessary to further add an equimolar excess of a base because the carboxyl group forms a salt. In addition, although a molar ratio of thiol carbamate () to halomethyl compound of 1:1 is sufficient, by using a slight excess of the former within an economically acceptable range, a highly pure target product can be obtained. You can get it.

Next, isolation and purification of the target product from the reaction solution can be achieved by performing isolation and purification operations that are commonly performed in the field of organic synthetic chemistry.

To describe a very general method, in the general formula (), R
When is a hydroxyl group, water alone or a mixed solvent of water and an organic solvent is usually used for the reaction, and a hydrophilic solvent is generally used as the organic solvent to perform a homogeneous reaction with water. Therefore, after the reaction is complete, unreacted halomethyl compounds can be removed in advance by distilling off the organic solvent under reduced pressure in the case of water alone or a mixed solvent, and then directly into the reaction solution or by washing with an appropriate organic solvent. After removal, the reaction solution is made acidic by adding acids and extracted with a suitable organic solvent. The extracted organic solvent layer is washed with water and dried with a dehydrating agent. The organic solvent is then distilled off under reduced pressure to obtain a syrup or solid. The pure target product can be obtained by recrystallizing this from an appropriate solvent. On the other hand, when R in the general formula () is other than a hydroxyl group, the reaction is often carried out in an organic solvent, and after the reaction is completed, the reaction solution is washed with water, dilute acids, and then water, and then treated with a dehydrating agent. dry. Then, the pure target product can be obtained by the same operation as above. Suitable organic solvents for washing the reaction solution and extracting the target product from the reaction solution include organic solvents that easily dissolve the halomethyl compound or the reaction product and are difficult to miscible with water, such as ethyl acetate, diethyl ether, and benzene. , toluene, methylene chloride, chloroform, etc., and are appropriately selected from these.

Hydrochloric acid, sulfuric acid, etc. are used as the acids. As the dehydrating agent, anhydrous sodium sulfate, magnesium sulfate, calcium chloride, etc. are used. Ethyl acetate, diethyl ether, methanol, ethanol, etc. are used as suitable recrystallization solvents. When recrystallizing, the combined use of n-hexane, petroleum ether, etc. is effective in reducing the crystallization by -1 if it is easy. Next, among the compounds obtained by the method of the present invention, Triton (
Table 1 shows the results confirmed by the effect on TritOn)-induced hyperlipidemia.

Test method Male Dd mice (20 ± 1V) 1 group of 9 mice
On (WR-1339) 600η/Kg was administered intravenously, immediately after which the drug 100119/Kg was orally administered, and after another 20 hours the same amount of drug was orally administered, and after another 20 hours the same amount of drug was orally administered. administered.

43 hours after TritOn administration, the animals were decapitated and blood was collected. The blood cells are removed from the blood by centrifugation, and the cholesterol in the serum obtained is extracted using a modified ZurkOwski-Shibata method (color development with sulfosalicylic acid, acetic acid, and sulfuric acid,
The absorbance was measured at 20 mμ). Next, the present invention will be explained by giving examples.

Example 1 Preparation of N-benzylthiocarbonyl-L-phenylalanine 9.97 (0.06 mol) of L-phenylalanine and 5.8 V (0.055 mol) of sodium carbonate were dissolved in 15 mol of water.
Carbonyl sulfide 3,0 dissolved in 0ml at 10-15℃
f7 (0.05 mol) was injected over 30 minutes.

After stirring for 30 minutes, 1 lb of benzyl chloride 6.3f7 (0.05 mol) dissolved in 90 ml of acetone was added.
The mixture was added dropwise over 5 minutes and further stirred at room temperature for 2 hours. After the reaction was completed, acetone was distilled off under reduced pressure, the resulting reaction solution was washed with 100 ml of benzene, the aqueous layer was acidified with concentrated hydrochloric acid, and the liberated oily substance was extracted twice with 100 ml of ethyl acetate. The ethyl acetate layer was washed twice with water 150111 and then dried over anhydrous sodium sulfate. Ether 207f11 and n-hexane 5 are added to the syrup-like substance obtained by distillation under reduced pressure.
After adding 0 ml of the mixture and leaving it in a cool place, a white powdery substance 11.6V (yield 73.7%) with an Mp of 63 to 65°C was obtained.
Elemental analysis value No. 1 as C, 7Hl7NO3S
]●l11 Spout. l
1 1 Example 2 Preparation of N-benzylthiocarbonyl-L-phenylalanine methyl ester 10.8 f7 (0.05 mol) of L-phenylalanine methyl ester hydrochloride was suspended in 100 ml of chloroform, and triethylamine 13 was added under ice cooling. .9 ml (0.1 mol) was added all at once.

3.07 (0.05 mol) of carbonyl sulfide was bubbled into the solution with stirring at 5-10° C. over 15 minutes. After aeration and stirring at the same temperature for 15 minutes, 20 ml of a chloroform solution containing 6.37 (0.05 mol) of benzyl chloride was added dropwise at 10 to 15°C over 10 minutes, and then stirred at room temperature for 3 minutes.
Stir for hours. After the reaction, 100ml of water, 100m
After washing twice each in the order of 1 part of 2N monohydrochloric acid and 150 ml of water, it was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting syrup was mixed with 30 mL of ethyl acetate.
1 and crystallized from n-hexane 50d, Mp46~
11.27 (yield: 68.1%) of white crystals at 47°C were obtained. Elemental analysis value as Cl8Hl9NO3S Example 3 Process for producing N-(4-methylbenzylthiocarbonyl)-L-phenylalanine L-phenylalanine 16.51 (
0.1 mol) and 27.8 ml (0.1 mol) of triethylamine.
2 mol) was dissolved in 100 d of water, and a dioxane solution 1507!11 in which carbonyl sulfide 6.07 (0.1 mol) was dissolved was added dropwise over 15 minutes at 5 to 10°C under ice cooling.

Lard 14.17 (0.1 mol) was added dropwise over 10 minutes at 10°C, and the mixture was further stirred at room temperature for 1 hour.

After the reaction was completed, the slag-like substance obtained by the same operation as in Example 1 was mixed with 60 ml of ethyl acetate and 300 ml of petroleum ether.
Crystallized from m1, white crystals with Mp of 92-93°C 25
．． 7V (yield 78.1%) was obtained. Elemental analysis value Cl8
Example 4 as Hl9NO3S Method for producing N-(4-chlorobenzylthiocarbonyl) L-phenylalanine ethylamide 3.4 t (0.015 mol) of L-phenylalanine ethylamide hydrochloride was added to 80 ml of chloroform under ice cooling. N-methylmorpholine 3
．． 3 ml (0.03 mol) was added thereto, and further, 20 ml of a chloroform solution containing 0.97 (0.015 mol) carbonyl sulfide was added dropwise at 5 to 10°C over 20 minutes.

After further stirring at the same temperature for 30 minutes, 30 ml of a chloroform solution in which 2.4 t (0.015 mol) of 4-chlorobenzyl chloride was dissolved was added dropwise over 30 minutes. After the dropwise addition, the solid was further stirred at room temperature for 1 hour, and then the solid obtained by the same operation as in Example 2 was recrystallized from 50 ml of ethyl acetate and 50 ml of n-hexane to give Mpl of 58.5 to 159.
．． 4.17 (yield 72.6%) of white crystals at 5° C. were obtained.
Elemental analysis value Cl, H2lN2O2SCl Example 5N-(4-nitrobenzylthiocarbonyl)-L-
Production method of phenylalanine L-phenylalanine 8.3f
7 (0.05 mol) and triethylamine 13.9 mI
! (0.1 mol) was dissolved in 50 ml of water, and 100 ml of a dioxane solution in which 8.6 t (0.5 mol) of 4-nitrobenzyl chloride was dissolved was added.

Carbonyl sulfide 3.0r (
0.05 mol) was bubbled in for 15 minutes. After ventilation, the reaction was further carried out at room temperature for 2 hours, and after the reaction was completed, the solid obtained by the same operation as in Example 1 was recrystallized from 50 ml of ethyl acetate and 20 ml of n-hexane to give light yellow crystals with an Mpl of 49 to 150°C.9. 4t (yield 52.2%) was obtained. Elemental analysis value Cl7Hl6N2O, Example 6N-(2.
5-dimethylbenzylthiocarbonyl)-L-phenylalanine methyl ester 10.8f7 (0.05 mol) of L-phenylalanine methyl ester hydrochloride was added to 100 ml of chloroform, and 13.9 ml of triethylamine was added under ice cooling. (0.1 mol) of carbonyl sulfide was added, and while stirring into this solution, the carbonyl sulfide 3.0
20 ml of a chloroform solution containing 7 (0.05 mol) was added dropwise over 20 minutes.

After further stirring at the same temperature for 30 minutes, 30 d of a chloroform solution in which 7.7 y (0.05 mol) of 2,5-dimethylbenzylchloride was dissolved was added dropwise over 30 minutes. After the addition, the mixture was further stirred at room temperature for 1 hour. After the reaction was completed in the same manner as in Example 2, the reaction mixture was washed twice each in the following order: 100 ml of water, 100 ml of 2N monohydrochloric acid, and 150 ml of water, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting syrup was mixed with 30 ml of ethyl acetate and n
-Crystallized from 50ml of hexane, Mp63.5-64
10.8y of white crystals (yield 60.5%) were obtained. Elemental analysis value C2OH23NO,S as Example 7 N-(d-naphthylmethylthiocarbonyl)-L-phenylalanine production method L-phenylalanine 8.37 (0
．． 05 mol) and triethylamine 13.9d (0.1 mol) and triethylamine 13.9d (0.1
mol) was dissolved in 100 d of water, and 100 ml of dioxane in which 3.0 mol (0.05 mol) of carbonyl sulfide was dissolved was added dropwise at 5 to 10°C under ice cooling over 15 minutes.

After stirring at 10°C for 15 minutes, 1-(chloromethyl)
The mixture was further stirred at room temperature for 1 hour.

After the reaction was completed, the syrup-like substance obtained by the same operation as in Example 6 was mixed with ether 807J! l and n-hexane 10
It was crystallized from 0 ml to obtain 14.8 f (yield: 81.1%) of white crystals having a temperature of Mpl3O to 132°C. Elemental analysis value C
Table 2 shows the compounds synthesized as 2lH,,NO3S according to the examples.

Claims (1)

[Claims] 1 General formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, R is a hydroxyl group, a lower alkoxy group, or a general formula -
NR_1R_2 (wherein R_1 and R_2 are the same or different and are a hydrogen atom or a lower alkyl group, or R_1 and R_2 together with the adjacent nitrogen atom represent a piperidino group or a morpholino group)] phenylalanine or phenylalanine derivative, carbonyl sulfide and general formula (II) A-CH
_2-X [wherein A is an unsubstituted or substituted phenyl group (substituents are 2-methyl, 3-methyl, 4-methyl, 2,5-dimethyl, 2,6-dimethyl, 3,4-dimethyl, 2・3・4
-triethyl, 2,3,4,5,6-pentamethyl, 4
-ethyl, 4-n-butyl, 4-tert-butyl, 2
-methoxy, 4-methoxy, 2,3-dimethoxy, 2-
Fluoro, 3-fluoro, 4-fluoro, 2-chloro,
3-chloro, 4-chloro, 4-bromo, 3-chloro-4
-methoxy, 4-methoxy-3,5-dichloro, 4-hydroxy, 2-nitro, 4-nitro) or an unsubstituted or substituted naphthyl group (the substituents are 1-chloromethyl, 1-bromomethyl, 2- Chloromethyl, 2-
bromomethyl), and X represents a halogen atom] General formula (III) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, A and R are A method for producing a phenylalanine derivative represented by (having the same meaning as above).