JPS58164566A - Production of cystine - Google Patents

Abstract

PURPOSE:After the reaction of a specific beta-hydroxyaminoacid with hydrogen sulfide in the presence of a Lewis acid, the reaction product is oxidized and deprotected to produce the titled compound of optical activity readily with high stereoselectivity. CONSTITUTION:Hydrogen sulfide is made to act on the compound of formulaI (R<1> is H, lower alkyl; R<2> is N-protecting group; R<3> is protected carboxyl group) in a solvent such as methylene chloride in the presence of a Lewis acid such as boron trifluoride to give a reaction product of formula II. Preferably without separation of the reaction product, the product is oxidized to give the compound of formula III. Then, protecting groups are removed to give a cystine of formula IV. As an oxidizing agent, is used chromic acid, a halogen such as bromine or iodine. Especially the use of iodine achieves high yield of the compound of formula III. A beta-hydroxyaminoacid with the same configuration as a desired cystine is used as a raw material to give readily a cystine.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel method for producing cystines.

Conventionally, optically active cystines have been obtained by extracting L-cystine from natural products, by protecting the functional group of D-cystine, or by optically resolving L-cystine.
It is known that it can be obtained by removing the protecting group and then oxidizing it, but these methods have drawbacks such as difficulty in obtaining raw materials and complicated reactions. This invention has been made to overcome these drawbacks.

The method of this invention is shown in the following reaction formula.

1 (wherein, R is a hydrogen atom or a lower argyl group, R2 is N
- protecting group and R3 each mean a protected carboxy group) In each of the above general formulas, examples of the lower alkyl group represented by R include methyl, ethyl, propyl, isopropyl, and the like.

The N-protecting group represented by B may be one that is normally used as an amino protecting group, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, methoxycarbonyl, 6th-butoxycarbonyl,
Substituted or unsubstituted alkoxycarbonyl groups such as chloromethoxycarbonyl, bromoethoxycarbonyl, trichloroethoxycarbonyl, trichloroethoxycarbonyl, benzyloxycarbonyl, phenethyloxycarbonyl, diphenylmethoxycarbonyl, nitrobenzyloxycarbonyl, bromobenzyloxycarbonyl, methoxypene, Substituted or unsubstituted aralkoxycarbonyl groups such as zyloxycarbonyl, dinitrobenzyloxycarbonyl, etc., halogen-substituted alkanoyl groups such as trifluoroacetyl, substituted or unsubstituted aralkoxycarbonyl groups such as benzyl, diphenylmethyl, trityl, bromobenzyl, nitrobenzyl, etc. Examples include an unsubstituted aralkyl group and an O-nitrophenylsulfenyl group.

Further, examples of the carboxy protecting group for the protected carboxy group represented by R include aliphatic esters and esters or amides containing aromatic rings or heterocycles.

Aliphatic esters include linear, branched or cyclic, saturated or unsaturated aliphatic esters, such as evaporative methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, tertiary butyl ester, octyl ester, etc. esters, alkyl esters such as nonyl esters, alkenyl esters such as vinyl esters, 1-propenyl esters, allyl esters, 6-butynyl esters, alkynyl esters such as 3-butynyl esters and 4-butynyl esters, cyclobentyl esters, Examples include cycloalkyl esters such as cyclohexyl esters. Examples of esters containing an aromatic ring include aryl esters such as phenyl ester, tolyl ester, xylyl ester, naphthyl ester, and indanyl ester, aralkyl esters such as benzyl ester and phenethyl ester, phenoxymethyl ester, phenoxymethyl ester, and phenoxypus ester. Aroyl alkyl esters such as

Esters containing heterocycles include saturated or unsaturated monocyclic or fused heterocycle-containing esters having oxygen, sulfur or nitrogen atoms as heteroatoms; such esters include, for example, tetrahydropyrani. Examples include heterocyclic esters such as esters, and heterocyclic-substituted alkyl esters in which these heterocycles are bonded to an alkyl group.

Amide-type protecting groups include N-alkylamides such as N-unsubstituted amide, N-methylamide, N-ethylamide, N,N-dimethylamide, N,N diethylamide, N-
Examples include N,N-dialkylamides such as -ethyl-N-methylamide, N-arylamides such as N-phenylamide, acid amides with pyrazole, imidazole, or 4-alkylimidazole, and the like.

Among the methods of this invention, the reaction in which hydrogen sulfide acts on compound 6(1) in the presence of a Lewis acid usually involves the use of methylene chloride, chloroform, tetracyclic compounds (tJL acetone, dimethylformamide, ether, etc.) that have an adverse effect on this reaction. Dissolve the compound [:] in an unintelligible organic solvent, and add the solution to room temperature to
This is carried out by heating F and introducing hydrogen sulfide gas into the presence F of a Lewis acid. Examples of Lewis acids include organic or inorganic acids, metal halides, and nonmetals. Preferred examples of such Lewis acids include boron trifluoride, boron trichloride, and boron tribromide. Trihalogenated borides such as borine (including coordination compounds of boronic trihalides and solvents such as ethers (e.g. evadimethyl ether, diethyl ether, etc.)), halogens such as aluminum chloride, aluminum bromide, etc. Examples include aluminum chloride, zinc halides such as zinc chloride, tin halides such as tin chloride, iron halides, titanium halides, silicon tetrahalides, and mineral acids such as hydrochloric acid and sulfuric acid. Among these Lewis acids, the most preferred is trifluoride diethyl etherate. The compound produced by this reaction [L may be isolated by a conventional method and subjected to the next oxidation reaction, but it is usually preferable to subject the compound CI to the oxidation reaction without isolating it. As the oxidizing agent in this oxidation reaction, chromium-halosulfonamide, oxygen, hydrogen peroxide, organic peracid, peroxosulfuric acid, dimethyl sulfoxide, iron (1) salts such as iron chloride and potassium hexacyanoferrate I), etc. Any oxidizing agent that oxidizes a thiol group to provide a disulfide compound may be used. Among these oxidizing agents,
When a halogen, particularly iodine, is used, the desired product can often be obtained in good yield.

This oxidation reaction easily proceeds by stirring the compound [sulfuric acid] and the oxidizing agent in an alcohol such as methanol, ethanol, propatool, or a solvent such as water, acetic acid, or chloroform under cooling to heating. Compound (1) thus obtained is isolated by a conventional method, but in particular, it may be subjected to a reaction for removing the protecting groups of the amino group and the carboxy group, without isolation.

The elimination reaction of this protecting group depends on the type of protecting group. [1 Hydrolysis, reduction, metal halide, metal mercaptide,
It is carried out by methods using metal salts such as metal cyanide and metal cyanate, among which hydrolysis, such as hydrochloric acid, hydrobromic acid, sulfuric acid, diic acid, trifluoroacetic acid,
Acid decomposition using propionic acid, benzenesulfone Ll)-)luenesulfonic acid, etc. is particularly preferred. If the amino protecting group and the carboxy protecting group are different, the protecting group may be removed in two steps, but if the amine protecting group is a substituted or unsubstituted alkoxycarbonyl group, a substituted or unsubstituted aralkoxycarbonyl group, a substituted or If it is an unsubstituted aralkyl group and the carboxy protecting group is an aralkyl ester, it is more preferable because both protecting groups are simultaneously eliminated by hydrolysis to give the target compound (IV).

The compounds obtained in this reaction (If containing (■) and (IV
] can be purified by conventional methods such as column chromatography, recrystallization, treatment with activated carbon, treatment with Celite, etc.

According to the method of the present invention, cystines having desired optical activity can be easily obtained because the reaction proceeds stereoselectively. That is, β-hydroxyamino acids that are easily available and easy to handle can be obtained using known methods, such as the method described in Pretin Op the Chemical Society of Japan, Vol. 51, pp. 1577-1578 (1978). Similar to the enrichment method, a starting material [1] in which only the β-position configuration was inverted while retaining the 0-position configuration was used, and by subjecting it to the method of this invention, the 0-position configuration was retained. Optically active cystines (IV) in which only the configuration at the β position is further inverted can be obtained.

Therefore, cystines with the desired configuration (IV
By selecting a β-hydroxyamino acid having the same configuration as , 1 as a starting material, the desired cystine (IV) can be easily obtained.

Next, the present invention will be explained with reference to examples.

Example 1 (1) A dry methylene chloride solution of 1-benzyloxycarbonyl-6-methyl-(28,3R)-aziridine-2-carboxylic acid pencil ester (340~) is saturated with dry hydrogen sulfide gas at room temperature. It can be understood by sword. After adding a catalytic amount of boron trifluoride etherate to this solution, hydrogen sulfide gas was passed through it again for 15 minutes. After leaving the reaction mixture at room temperature for 6 hours, it was concentrated under reduced pressure, and the resulting oily residue was dissolved in methanol (30xt). To this solution was added a 0.2M iodine-methanol solution (13s+/) at 0°C with stirring.
Dry it dropwise over 45 minutes and stir for another 45 minutes at the same temperature.

Reaction 1' (re-heated and cooled to 0°C, then thio Ik
Add sodium chloride bath solution until it turns brown or disappears. The reaction solution was extracted with ethyl acetate under reduced pressure until it reached a density of about 10 m/s. After washing the extract with water and drying, the solvent was distilled off under reduced pressure.
By condensing the resulting residue with a mixed solvent of methanol-ether-hexa7, N,N'-cybensyloxyluponylutrel ester (295'1
1 g) as an oil.

[α] also 'knee 42. da(C1,0,methanol)NM
R (CDCd5.δ): 1.23 (6H, d), 3.5
0 (2H, m).

4.60 (2H, m), 5.07 (4H, s), 5.
61 (4H, s).

5.68 (2H,,d), 7.28 (20H,S)
.

(2) The target compound (141q) from (1) above is suspended in a saturated hydrogen bromide acetic acid solution (5+g/) and stirred for 60 minutes at room temperature. After the reaction solution was left to stand for one day, the solvent was distilled off under reduced pressure. Dry ether is added to the oily residue obtained, the pencil bromide is removed by decanting, the residue is concentrated under reduced pressure and the oil obtained is dissolved in a small amount of water. This solution was used to obtain 1N hydrogen carbonate (401f). mp 175°C (decomposition) [α] A5 knee 362° (CI, 0.1N hydrochloric acid) Example 2 (1) In the same manner as in Example 1-(1), 1-benzyloxycarbonyl-6-methyl 128. 3S)-aziridine-2-carboxylic acid pencil ester dibenzyl ester (2s oq) is converted into an oil.

[a″ID: 1,42.3′″ (C1,0,) Tough-tV) NMR (CDC/!,, δ): 1.15 (3H
, d), 1.20 (3H, d).

3.2-3.6 (28, m), 4.4-4.7 (2H,
m), 5.08 (4H, S), 5.12 (4H, S),
5.70 (2H, (1).

7.31(20H,S) L-cystine (50'%') is obtained. mp177.
5-17El (decomposition) [α) D: +3i, 5° (C0,9,IN hydrochloric acid) Example 6 (1) 1-benzyloxycarbonyl-D-aziridine in the same manner as in Example 1-(1) -2-Carboxylic acid pencil ester (320q) to obtain N,N'-cybenzyloxycarbonyl-D-synutin cybenzyl ester (285111F). mp85.7-87.
0℃ [α]'D': -39,8(Ci, 1,0HC7
! 3) NMFi (CD0g3.δ): 3.05 (4H,
d), 4.62 (2H, m).

5.05 (4H, 8), 5.11 (4H, s), 5.8
0(!H,d).

7.28 (20H, 5) (2) In the same manner as in Example 1-(2), D-cystine (55,8■) was obtained from the target compound (200q) of (1) above.
get. mp206°C (decomposition) [α]D-+21 di(C1,[1,IN hydrochloric acid) Example 4 (1) In the same manner as in Example 1-(1), 1-benzyloxycarbonyl-L-aziridine-2 -N,N'-dibenzyloxycarbonyl-L-cystine dibenzyl ester (250q) is obtained from carboxylic acid benzyl ester (0,32y). mp85.5-86.7°C NMR (CDCl, , δC3,10(4H,d), 4
．． 62 (2H, m).

5.05 (4H, s), 5.12 (4H, s), 570
(2H, d).

7.35 (20H, 5) (2) In the same manner as in Example 1-(2), the target compound of (1) above (200~) mustard-cystine (57,8~)
get. mp2o4't; (disassembly) Procedural amendment (voluntary) Director of the Japan Patent Office Kazuo Wakasugi 1, Indication of the case, Special Agreement No. 37655 of 1982, 2 Title of the invention: Process for producing cystines 5, Patent application by the person making the amendment Kenji Okawa 4, 5-7 Izumigaoka, Hitotakarazuka City, Agent 21-1-6 No. 5, Kashima, Yodoyou-ku, Osaka 532, Subject of amendment 6, Contents of amendment (1) Specification page 12 [2] Insert the following sentence before "Example 2" on the line.

[After further dissolving this target compound in water, ethanol is added to precipitate crystals to obtain a purified crystal product.

[α] Ro 3 knee 406.8° (C1,1,IN hydrochloric acid)”
(2) Insert the following sentence before "Example 3" in the 4th line from the bottom of page 13.

[After further dissolving this target compound in water, ethanol is added to precipitate crystals to obtain a purified crystal product.

((Z)1): +412.9 Bought CD, 6. IN Hydrochloric acid monthly payment, slip-

Claims (1)

[Claims] General formula: (In the formula, R1 means a hydrogen atom or a lower alkyl group, R2 means an N-protecting group, and R3 means a protected carboxy group, respectively):; A compound represented by ~hydrogen sulfide is reacted in the presence of a Lewis acid, the reaction product is subjected to an oxidation reaction, and then to an elimination reaction of the protecting group to form a product represented by the general formula (wherein R1 has the same meaning as before). A method for producing cystines, characterized by obtaining cystines.