3-Maleimidobenzoic acid succinimidyl ester_Kain Industrial Additive

Background and overview^[1]

3-Maleimidobenzoic acid succinimidyl ester is a widely used intermediate in pharmaceuticals, agricultural chemicals, dyes and polymer compounds. Yoshio Igarashi et al. reported that N-substituted benzyl maleimide compounds have antimicrobial activity. In particular, this compound contains an imide ring and a relatively active terminal ester group. The polymer compound obtained by reacting it as a monomer with other compounds is very useful in the research and development of insulating materials and heat-resistant polymer materials. prominent role. The acetone method is used, that is, acetone is used as the solvent to react to generate the intermediate product amic acid. After separation and drying, the amic acid is heated and dehydrated under the action of anhydrous acetic acid and sodium acetate to obtain maleimidobenzene. Formic acid is finally condensed with N-hydroxysuccinimide to form an ester to obtain the product. This method is cumbersome to operate, has a long reaction cycle, consumes a lot of solvents and materials, and the overall yield is not high. The three-step yield is only about 40%. In order to avoid the separation of the intermediate product amic acid, the highly polar solvent dimethylformamide (DMF) can also be used, such as the DMF method reported by Liang Guozheng et al. This method uses DMF as the solvent to generate the intermediate product amic acid, then directly adds a dehydrating agent without separation, and then heats and dehydrates to obtain the product maleimido benzoic acid, which is finally combined with N-hydroxysuccinimide Condensate to form ester to obtain the product. This method is improved over the acetone method, but the intermediate after ring closure in DMF is very difficult to purify, and the yield after condensation is only about 45%.

Preparation^[1]

A method for preparing 3-maleimidobenzoic acid succinimide ester: add 692g of m-aminobenzoic acid and 3.5L of DMF in sequence to a 10L three-necked flask (the concentration should not exceed 20%). Stir to dissolve, lower the temperature to about 15°C, add 497g of maleic anhydride to it, the heat is relatively obvious, control the temperature of the system at about 20°C, complete the addition, remove the ice, and react at room temperature for about 2 hours. Add 599g N-hydroxysuccinimide HOSU to the system, then lower the temperature to about 15°C, and add dropwise a mixture of 2060g DCC and 500ml DMF. The reaction is exothermic. The temperature is controlled at about 20°C and added dropwise. There is a large amount of dicyclohexylurea in the process. DCU precipitates. After the dropwise addition is completed, the reaction takes place at room temperature for about 8 hours. Stop the reaction, cool the system to about 5°C, and stir for 2 hours. Filter with suction, and wash the filter cake with a small amount of DMF. The obtained filtrate was evaporated to dryness under reduced pressure, and DMF was recovered. A large amount of solid precipitated. Add acetonitrile and stir evenly before suction filtration. The wet solid obtained was heated and dissolved with about 2 L of methylene chloride, cooled and crystallized, and a large amount of solid was precipitated. Stir and beat in an ice bath for 1-2 hours, suction filtered, and vacuum dried to obtain 1030g of off-white solid (molar yield: 65.0% , liquid content: 98.9%, melting point: 176-179°C). Conduct nuclear magnetic resonance experiments on the reaction products. The data are as follows: HNMR (400MHz, DMSO): δ2.78-2.92 (m, 4H, CH2CH2), δ6.9 (m, 2H, CHCH), δ7.62-8.18 (m, 4H, CH).

Main reference materials

[1] Preparation method of CN201910043250.63-maleimidobenzoic acid succinimide ester