FIELD: chemistry.
SUBSTANCE: invention relates to a method of producing dimethylaminomicheliolide fumarate hydrate, characterized by that the hydrate is in crystalline form D, the molar ratio of dimethylaminomicheliolide fumarate to water is 1:1, and the hydrate has molecular formula C17H27NO3⋅C4H4O4⋅H2O. Thermogravimetric analysis shows a weight loss of 3.97–4.22% before decomposition, a differential scanning calorimetry graph shows an endothermic peak of dehydration at 75±5°C and characteristic melting peak at 148±5°C. Hydrate has characteristic peaks at angles 2θ 7.8±0.2°, 11.1±0.2°, 11.4±0.2°, 12.6±0.2°, 12.9±0.2°, 14.4±0.2°, 15.3±0.2°, 17.0±0.2°, 18.7±0.2°, 19.7±0.2°, 20.6±0.2°, 21.0±0.2°, 22.5±0.2°, 23.7±0.2°, 24.3±0.2°, 25.5±0.2° and 26.2±0.2° in X-ray powder diffraction pattern using Cu-Kα radiation. Crystalline form D is in an orthorhombic crystallographic system and has space group P212121, cell parameter a = 8.8346(18) Å, b = 14.796(3) Å, c= 16.385(3) Å, α = 90°, β = 90° and γ = 90°; and cell volume 2141.8 (8) Å3.. The method is carried out by active crystallization, where dimethylaminomicheliolide and fumaric acid are added to a mixed solvent system consisting of solvent S1 and solvent S2 under the action of stirring, at a constant temperature of 30–70°C, wherein the weight ratio of the solvent S2 to the solvent S1 is (0–3):1, and the molar ratio of dimethylaminomicheliolide to fumaric acid is (1–1.6):1; after 5–10 hours of reaction, the reaction mixture is filtered and the residue is dried at 25–45°C at normal pressure for 6–10 hours to obtain dimethylaminomicheliolide fumarate in crystalline form D. Solvent S1 is a mixed solvent consisting of water and any of acetone, tetrahydrofuran, 1,4-dioxane, acetonitrile and methyl isobutyl ketone; solvent S2 is a mixed solvent consisting of an ester and an ether; ester solvent can be selected from any one or two of methyl acetate, ethyl acetate, hexyl acetate and isopropyl acetate; ether solvent can be selected from any one or two of diethyl ether, methyl-ethyl ether, methyl-tert-butyl ether, dipropyl ether, dibutyl ether, dimethyl ether of ethylene glycol, monomethyl ether of ethylene glycol, 1,4-dioxane, tetrahydrofuran and 2-methyltetrahydrofuran.
EFFECT: high output of dimethylamine cheliolide fumarate hydrate with high crystallinity, high bulk density, good fluidity and stability.
3 cl, 6 dwg, 2 tbl, 16 ex
