JPS6284059A - Disulfide compound and preparation thereof - Google Patents

Abstract

NEW MATERIAL:A compound of formula I (R<1>, R<2> are divalent organic groups). EXAMPLE:Bis-[2-(N-maleimide)ethyl]disulfide. USE:A cross-linking agent between polymeric substances. PREPARATION:The reaction between a diamine of formula II and maleic anhydride in an inert solvent such as halogenated hydrocarbon, ether or ester or in the absence of solvent, at 0-50 deg.C for 10min to 2 days is followed by heating the product in acetic anhydride at 80-120 deg.C for 30min-5hr to give the objective substance.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to disulfide compounds. More specifically, the present invention relates to a disulfide compound having a structure containing one maleimide group on different sides of a disulfide bond in its molecular structure.

It has been known that bis-maleimide compounds containing 21 bonds in their molecular structures can serve as intramolecular or intermolecular crosslinking agents for polymeric substances. That is, N, N'-(1
,2-phenylene)-bisumareimide Q[D (J
, E. Moore and W. H. Ward.

J, Am, Cham, Soc,, 78, 2414 (1
956)).

N,N'-hexamethylene-bis-maleimide (IV)
(Peter Kovacic and Rlcha
rd W, He1nJ, Am, Chsm, Soc, ,
81.1187 (see 1959).

Bis-(N-maleimidomethyl) ether (P, O,
Tawney, R.H., 5nyder, at al.
J,Org,Chem,.

26.15 (1961) and Donna J, Arnd.
t, 5anfard R.

Simon, et al., J. Biol, Chem.
, 246, 2602 (1971)) are serum albumin.

Wool keratin, gelatin, urethane polymer.

It is known that it can act as an intramolecular or intermolecular crosslinking agent for polymeric substances such as hemoglobin.

These compounds are useful crosslinking agents, especially for thiol group-containing polymers, or, depending on the reaction conditions, for 7 min-based polymers, but they can be used satisfactorily for all purposes. isn't it. For example, once a polymer has been crosslinked, if it is necessary to remove the crosslinks and regenerate the polymer again, these compounds cannot be used for this purpose.

In order to develop a crosslinking agent for realizing reversible crosslinking between polymeric substances, the present inventors have conducted intensive research and found that a bis- It was discovered that maleimide compounds are not only efficient cross-linking agents, but also that the cross-links formed thereby are reversible cross-links that can be cleaved by chemical or biological reduction reactions, and the present invention It was completed.

That is, the present invention is a novel disulfide compound containing bis-maleimide represented by formula 5 and a method for producing the same.

The raw materials for producing the disulfide compound of the present invention are:
(contains a disulfide in its molecular structure represented by formula 2)'12N-'i;2. '-E! -Fl'-t'eH>
... (II (in the formula, the definitions of R1 and R2 are the same as in the case of substitute seals)), such as cystamine (R'=R"=4CH, +2), which are industrially used. It is easily available.The reaction between diamines and maleic anhydride is achieved by mixing them in a solvent or without a solvent.Maleic anhydride is used in an equivalent amount of 2 to 3 times that of the diamine. Although it is preferable to use a larger amount, it is also possible to use a larger amount.Solvents that can be used include primary or secondary amines and lower alcohols that have the property of reacting with maleic anhydride, and also A wide range of inert solvents can be used, excluding acids that reduce the oxidation of the solvent, such as halogenated hydrocarbons such as xyloform, methylene chloride, and dioxane.

Ethers such as THF, esters such as ethyl acetate and methyl acetate, and dimethylformamide.

Polar solvents such as dimethylacetamide and dimethylsulfoxide can be mentioned as preferred reaction solvents. When the raw material diamine is obtained as a monohydrochloride or other salt, the diamine can be reacted with maleic anhydride while being liberated by the action of a base such as triethylamine in a reaction solvent. The appropriate reaction temperature is 0° to 50" and the reaction time is 10 minutes to 2 days. After the reaction is completed,
After distilling off the solvent under reduced pressure, the resulting product can be used in the next reaction by simply performing a simple purification by solvent extraction.

Next, excess acetic anhydride is added to the reaction mixture and heated to obtain the desired disulfide containing bis-(maleimide) in its structure.

In this reaction, more favorable results can be obtained by coexisting sodium acetate. The reaction temperature is 806-12
0'(:. The reaction time is 30 minutes to 5 hours. After the reaction, the target product, a disulfide containing bis-(maleimide) in its structure, is extracted by conventional methods such as solvent extraction and chromatography crystallization. The compound can be purified.As described above, the substance of the present invention is a substance that can be easily produced and supplied industrially.

The special feature of the compounds of the present invention as crosslinking agents is their reversibility. For example, bovine serum albumin (monomer) has bis-
When 2-(N-maleimido)ethyl fudisulfide was applied, a dimer of albumin was obtained by cross-linking between fulpmin molecules. What the body has produced
Confirmed by gel electrophoresis.

Example 1 4501 q of cystamine hydrochloride was added to 2° of dioxane, and 404 q of triethylamine was added thereto to form a mixed solution. A solution obtained by dissolving 420 μm of maleic anhydride in 10 μM dioxane was added dropwise to the above mixture while stirring, and after continued stirring for an additional 23 hours, the solvent was distilled off under reduced pressure to form a solid. A mold residue was obtained. This residual 5% sodium carbonate solution 60
The resulting solution was washed three times with 30 ml of ether and once with 30 ml of ethyl acetate.

Aqueous layer K was cooled with ice, and NHCJ was added to adjust the pH to 2.
After cooling with water for an hour, the resulting precipitate was collected. After drying this material in vacuum, 9 mK of acetic anhydride was dissolved in it, 90011 g of sodium acetate was added to the resulting solution, and 100 mK of sodium acetate was added under a nitrogen atmosphere.
The mixture was stirred while heating at 10°C for 2 hours. The temperature of the solution was returned to room temperature, 15 d of ice water was added thereto, and the mixture was stirred for 2 hours while being cooled. Excessive amounts of water and ether were added to extract the reaction product into an ether layer. The ether layer was washed with 5% sodium carbonate solution, dried over anhydrous sodium sulfate, and the ether was distilled off under reduced pressure to obtain a product oil. Separation and purification was performed by silica gel chromatography (Merck Kieselgel 60, 30.9, elution was carried out using benzene-ethyl acetate 5:1-1), and the solvent was distilled off under reduced pressure using the equivalent 7 lactate solution. , 140 crystals of bis-[2-(N-maleimido)ethyl fudisulfide, the target substance, were obtained.

Physical properties of bis-(z-(N-maleimido)ethyl fudisulfide
J, a value 2.90 from medium TMS (4H, t, 6.5H
z) 3.83 (4H, t, 6.5Hz) 6.70 (4H, 8).

OIRKBr.

3100, 1700 (sl, 1450.1433
, 1410 , 1400 .

1325.1130 Equipment-1.

＼-Ichinino

Claims (1)

[Claims] 1. The following formula [I] ▲There are mathematical formulas, chemical formulas, tables, etc.▼[I] [In the formula, R^1 and R^2 are the same or different and represent a divalent organic group . ] A disulfide compound represented by 2. The disulfide compound according to claim 1, wherein in formula [I], R^1 and R^2 represent a divalent alkyl group, an aryl group, or an aralkyl group. 3. The disulfide compound according to claim 1, wherein R^1 and R^2 in formula [I] are the same and represent -(CH_2)n- (n represents an integer from 2 to 5) . 4. The following formula [II] H_2N-R^1-SS-R^2-NH_2...
...[II] [Definition of R^1 and R^2 in the formula [I
] is the same as the case. ] A method for producing a disulfide compound represented by the above formula [I], which comprises reacting a diamine represented by the above with maleic anhydride and heating the obtained product in acetic anhydride.