25021-08-3

Pale Yellow Solid

Maleimidoacetic Acid (CAS# 25021-08-3) is a heterocyclic organic compound that has a variety of uses in organic synthesis. It contains both a maleimide and carboxylic acid functional group, making it a versatile reagent for coupling reactions with amine-containing compounds.

2-Maleimido acetic acid is a maleimide-containing ligand that could be used to produce the cisplatin-based Pt(IV) complexes (OC-6-44)-diamminedichlorido(ethanolato)(2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)acetato)platinum(IV) and (OC-6-44)-acetatodiamminedichlorido(2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)acetato)platinum(IV). The Pt(IV) complexes are considered to act as antitumor prodrugs and their in vivo activity can be improved by exploiting drug targeting and delivery strategies[1]. In this case,  conjugation between maleimide-containing Pt(IV) prodrugs and furan or furan-containing drug delivery vectors via Diels-Alder cycloaddition.

In a 1000 mL three-necked flask, compound (II) (162 g, 0.94 mol, X = 1) and 400 mL of dichloromethane were added, followed by triethylamine (284.8 g, 2.82 mol). The reaction mixture was cooled in an ice-salt bath and the temperature was maintained at -2 °C with stirring. Phenyl 4-nitrilotrifluoroacetate (353.4 g, 1.5 mol) dissolved in 300 mL of dichloromethane was then added slowly dropwise, with the rate of dropwise acceleration controlled to maintain the reaction temperature between -5 and 10 °C. After titration was completed, the reaction mixture was continued to be stirred at the same temperature for 3 hours. After completion of the reaction, the reaction solution was concentrated to dryness. To the residue was added 400 mL of water and the pH was adjusted to 3-4 with concentrated hydrochloric acid under stirring. the resulting 4-nitrophenol was removed by filtration and the filtrate was extracted three times with dichloromethane. The organic phases were combined, washed with water and dried with anhydrous magnesium sulfate. The dried organic phase was concentrated to give 129 g of a pale yellow solid. The solid was recrystallized with a mixed solvent of ethyl acetate and petroleum ether to give 107 g of white solid. After drying, it was weighed as 94 g. The purity was determined by HPLC to be 98.2% and the yield was 64.5%.

[1] Gabano E, et al. Conjugation between maleimide-containing Pt(IV) prodrugs and furan or furan-containing drug delivery vectors via Diels-Alder cycloaddition. Inorganica Chimica Acta, 2019; 488: 195-200.