Torasemide phosphate prodrug, preparation method of torasemide phosphate prodrug and composition
A technology of torasemide phosphate and torasemide phosphate, which is applied in the field of biomedicine, can solve problems such as hidden dangers of injection drug safety, and achieve the effect of good druggability and excellent solubility
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Embodiment 1
[0025] Embodiment 1: the preparation of N-hydroxymethyl-torasemide phosphate (I)
[0026] Step 1: Preparation of N-hydroxymethyl-torsemide (2)
[0027] Add absolute ethanol (300mL), torasemide (34.8g, 0.1mol, 1eq), sodium carbonate (15.9g, 0.15mol, 1.5eq) into a 500mL reaction flask, and add paraformaldehyde (15g, 1.5eq) in batches under stirring. 0.5mol, 5eq). After the addition, the temperature was raised to an internal temperature of 80-85°C for 2 hours, and then slowly lowered to an internal temperature of 20-25°C. A white solid precipitated, filtered and washed with water. The filter cake was vacuum-dried (40° C.) to obtain N-hydroxymethyl-torsemide (2) (32.5 g, yield 86%), MS: 379 [M+1].
[0028] Step 2: Preparation of N-chloromethyl-torasemide (3)
[0029] Dichloromethane (200mL), N,N-dimethylformamide (2mL), compound 2 (30g, 79.3mmol, 1eq) were added to a 500mL reaction flask, and thionyl chloride (28.3g, 237.8mmol , 3eq). After the addition, heat up to an interna...
Embodiment 2
[0034] Embodiment 2: the preparation of N-hydroxymethyl-torasemide phosphate disodium (Ia)
[0035] Add absolute ethanol (50mL), N-hydroxymethyl-torsemide phosphate (I) (10g, 21.8mol, 1eq) in the 100mL reaction flask, and add dropwise 25% sodium hydroxide solution (1.83g, 45.8mol, 2.1eq), after the addition was completed, the reaction was stirred for 1h. Add acetone (50 mL) to the reaction solution, continue to stir for 30 min, and filter to obtain the crude disodium salt. Gained crude product was added acetone (50mL) / H 2 O (5mL) system was recrystallized, filtered, and the filter cake was vacuum-dried (50°C) to obtain N-hydroxymethyl-torsemide phosphate disodium (Ia) (7.6g, yield 69%), HPLC purity 99.90% . MS:503[M+1], 1 H NMR (400MHz, D 2 O)δ:8.55(s,1H),7.99(d,J=4.0Hz,1H),7.25(m,1H),6.98-7.05(m,3H),6.92(m,1H),5.92(s, 2H), 3.56(m, 1H), 2.24(s, 3H), 0.94(s, 3H), 0.93(s, 3H). Sodium content: 9.19%.
Embodiment 3
[0036] Embodiment 3 Preparation of N-hydroxymethyl-torasemide phosphate dipotassium (Ib)
[0037] Add absolute ethanol (50mL), N-hydroxymethyl-torsemide phosphate (I) (10g, 21.8mol, 1eq) in the 100mL reaction flask, and add dropwise 20% sodium hydroxide solution (2.57g, 45.8mol, 2.1eq), after the addition was completed, the reaction was stirred for 1h. Add acetone (50 mL) to the reaction liquid, continue to stir for 30 min, and filter to obtain the crude product of dipotassium salt. Gained crude product was added acetone (50mL) / H 2 O (5mL) system was recrystallized, filtered, and the filter cake was vacuum-dried (50°C) to obtain N-hydroxymethyl-torsemide phosphate dipotassium (Ib) (7.6g, yield 65%), HPLC purity 99.92% . MS:535[M+1], 1 H NMR (400MHz, D 2 O)δ:8.57(s,1H),7.99(d,J=4.0Hz,1H),7.27(m,1H),6.99-7.04(m,3H),6.94(m,1H),5.91(s, 2H), 3.55(m, 1H), 2.23(s, 3H), 0.94(s, 6H). Potassium content: 14.58%.
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