2-methoxyestradiol-17β-prolineamide analogue, synthesis method and application thereof
A technology of methoxyestradiol and prolineamide, which is applied in the directions of drug combination, steroids, organic chemistry, etc., can solve the problems of irregular absorption in vivo, difficult clinical application, low bioavailability, etc., and achieves good water solubility. performance and bioavailability, improved bioavailability, simple method of preparation
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example 1
[0038] Example 1: The preparation method of compound 2-methoxy-3-hydroxyl-17β-(L-prolinamido)-estra-1,3,5,(10)-triene (A-1)
[0039] Accurately weigh 400 mg of 2-methoxy-3-benzyloxy-estra-1,3,5,(10)-triene-17β-amine and add it to a three-necked flask, add 15 ml of dichloromethane and stir to dissolve at room temperature, Then add 329 mg of N-tert-butoxycarbonyl-L-proline, 422 mg of dicyclohexylcarbodiimide, 235 mg of N-hydroxysuccinimide and 0.55 ml of N, N-diisopropylethylamine, at room temperature The reaction was complete after stirring for 6 hours. The reaction liquid was filtered, and then extracted once with 10% hydrochloric acid, saturated sodium carbonate, and saturated sodium chloride respectively. The organic phase was dried over anhydrous sodium sulfate and purified by column chromatography (eluent: petroleum ether: ethyl acetate = 4:1 by volume) to obtain 477 mg of condensation product with a yield of 80%.
[0040] In a three-necked flask, add 426 mg of the above...
example 2
[0041] Example 2: Compound 2-methoxy-3-sulfamate-17β-(L-prolinamido)-estra-1,3,5,(10)-triene (B-1) Preparation
[0042] In a 50ml polytetrafluoroethylene pressure bottle, 200mg of the proline condensation product obtained in Example 1 was dissolved in 20mL of ethanol, then 30mg of 10% palladium-carbon catalyst was added, the hydrogenation device was fed with a hydrogen pressure of 0.3MPa, and the oil bath React at 60°C for 3h until the hydrogenation reaction is complete. Then filtered, the filtrate was evaporated to dryness, and recrystallized with an appropriate amount of ethanol to obtain 156 mg of hydrogenated crude product with a yield of 92%.
[0043] Under ice bath and nitrogen protection, 156 mg hydrogenated crude product was dissolved in 5 mL of anhydrous N,N-dimethylformamide solution, then 0.1 mL of sulfamoyl chloride was slowly added dropwise, and stirred under ice bath for 2 h until the reaction was complete. Then, 8 times the volume of distilled water was slowly...
example 3
[0045] Example 3: The preparation method of the compound 2-methoxyl-3-hydroxyl-17β-(L-2-piperidine amido)-estra-1,3,5,(10)-triene (A-7)
[0046] Accurately weigh 540 mg of 2-methoxy-3-benzyloxy-estra-1,3,5,(10)-triene-17β-amine and add it to a three-necked flask, then add 30 mL of toluene and stir to dissolve at room temperature , add 483mg N-benzyloxycarbonyl-L-2 pipecolic acid, then add benzotriazole-N,N,N',N',-tetramethyluronium hexafluorophosphate 847mg and triethylamine 0.7ml , TLC detection, the reaction was complete after 4 h at room temperature. The filtered reaction solution was washed once with mass percent 10% hydrochloric acid aqueous solution, saturated sodium carbonate solution and saturated brine respectively, and the organic phase was dried with an appropriate amount of anhydrous sodium sulfate, concentrated and purified by column chromatography (eluent was volume ratio of petroleum Ether: ethyl acetate = 6: 1) to obtain 648 mg of condensation product, yield 7...
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