Water-soluble derivants containing 10-hydroxycamptothecine and preparation method thereof
A technology of hydroxycamptothecin and its derivatives, applied in the field of water-soluble derivatives and its preparation
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Embodiment 1
[0035] Preparation of Hydroxycamptothecin 10-(γ-N,N-Diethylamino)butyrate Hydrochloride
[0036] Under a dry nitrogen flow, add 80 mg of 10-hydroxycamptothecin and 4 ml of anhydrous pyridine into a 25 ml dry three-necked flask, and stir at room temperature until completely dissolved. Dissolve 300 mg (γ-N, N-diethylamino) butyryl chloride hydrochloride in 5 ml of dry dichloromethane, slowly add it dropwise, and react at room temperature for 2-3 hours. After the reaction is complete, add a few drops of water to the reaction solution, stir for 5 minutes, add 15ml of ether, and precipitate a solid, filter it, and rinse the solid with ether. Dissolve the solid in methanol, add diethyl ether dropwise until it becomes turbid, static crystallize, suction filter, rinse with diethyl ether; recrystallize according to the above method, dry under reduced pressure to obtain 60 mg of light yellow solid, m.p221-223°C, harvested rate 54%. IR (KBr, cm -1 ): 3559, 3435, 2942, 2646, 1774, 1743...
Embodiment 2
[0040] Preparation of Hydroxycamptothecin 10-(γ-Amino)butyrate Acetate
[0041] Dissolve 280 mg of CBZ-protected GABA and 250 mg of DCC in 10 ml of CH 2 Cl 2 In, add 40mg DMAP, stir at room temperature for 10min, then add 0.5ml pyridine and 150mg HCPT. After reacting for more than 10 hours, filter, and wash the filtrate with pH3 acid water until the water layer is acidic. NaHCO 3 Wash until the aqueous layer is alkaline, and finally wash with saturated brine until neutral. The organic layer was washed with anhydrous Na 2 SO 4 Dry and evaporate the organic solvent. Dissolve in THF, add 0.5ml of acetic acid, a little 10% palladium-carbon, pass through hydrogen for hydrogenolysis, react for about 1 hour, filter, add ether to crystallize, and obtain 100mg of light yellow solid, yield 46%. IR (KBr, cm -1 ): 3428, 2927, 1745, 1657, 1623, 1591, 1504, 1235, 1193, 1162, 1109, 1047. ESI-MS: 450 (M + -AcOH)
Embodiment 3
[0043] Preparation of HCPT-γ-aminobutyrate hydrochloride
[0044] Dissolve 230 mg Boc-protected GABA and 250 mg DCC in 10 ml CH 2 Cl 2 In, add 40mg DMAP, stir 10min. Add 0.5ml of pyridine and 150mg of HCPT, and react for more than 10 hours. After the reaction is completed, wash with pH3 acidic water until the water layer is acidic, then wash with saturated NaHCO3 until the water layer is alkaline, and finally wash with saturated saline until the water layer To be neutral, the organic layer was dried with anhydrous NaSO4. The organic solvent was evaporated to obtain 200 mg of a light yellow solid with a yield of 85%. Dissolve the solid in a mixture of ethyl acetate and dichloromethane, add HCl-saturated ethyl acetate solution dropwise under ice-bath cooling, filter after the reaction is complete, dissolve the filter cake in water, add acetone, crystallize, and filter 20 mg of HCPT-γ-aminobutyrate hydrochloride was obtained. Yield 11%. ESI-MS: 450 (M + -AcOH)
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