Estradiol-4-aminomethyl pyridine conjugate as well as synthetic method and application thereof
A technology of aminomethylpyridine and a synthesis method, applied in the field of estradiol-4-aminomethylpyridine conjugates, can solve the problems such as the inability of continuous medication for patients and the influence of drug treatment effect and the like
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Embodiment 1
[0054] 1) Synthesis of Compound 2:
[0055] Take estradiol (1.000g, 3.67mmol) in a place with CaCl 2 In the round bottom flask of the drying tube, dissolve with DMF (8.0mL), add benzyl chloride (0.7mL, 6.08mmol) and NaOH (0.265g, 6.63mmol), and react at room temperature for 12h; the reaction solution is suction filtered, and the filter residue is washed with DMF , combined the filtrates, poured the filtrate into ice water, and precipitated a white solid, separated the white solid, and dried to obtain 1.251 g of compound 2 (white solid, yield 94%).
[0056] The above-mentioned compound 2 is detected by proton nuclear magnetic resonance spectrum, and the spectral data are as follows:
[0057] 1H NMR (500MHz, CDCl 3 )δ0.78(s,3H,H-18),1.15-2.32(m,13H,3×CH,5×CH 2 ),2.86(m,2H,H-6),3.73(t,1H,J=8.4Hz,H-17),5.03(s,2H,PhCH 2 0),6.72(d,1H,J=2.2Hz,H-4),6.78(dd,1H,J=2.5,8.5Hz,H-2),7.21(d,1H,J=8.6Hz,H- 1),7.32-7.44(m,5H,Ar-H).
[0058] Therefore, it can be determined that the above-me...
Embodiment 2
[0077] Repeat embodiment 1, difference is, replace step 3) with following step 3a), described step 3a) is as follows:
[0078] 3a) Synthesis of Compound 4:
[0079] Take compound 3 (2.500g, 4.76mmol) and dissolve in CH 3 Add 10%Pd / C (0.05g) to OH (5.0mL), and hydrogenate under normal pressure at room temperature for 12h; 3 After washing with OH, the filtrates were combined, and the obtained filtrate was spin-dried under reduced pressure to obtain 1.346 g of compound 4 (light yellow oil, yield 65%).
[0080] The obtained compound 4 is detected by proton nuclear magnetic resonance spectroscopy, and the obtained spectral data are the same as in Example 1. Therefore, it can be determined that compound 4 is 3-hydroxyl-17β-(6-bromohexyl)oxygen-1,3,5(10)- Triene-Estrogen.
Embodiment 3
[0082] 1) Synthesis of Compound 2:
[0083] Take estradiol (1.000g, 3.67mmol) in a place with CaCl 2 In the round bottom flask of the drying tube, dissolve with pyridine (15.0 mL), add benzyl chloride and NaOH (the molar ratio of estradiol, benzyl chloride and NaOH is 1:3:4), and react at 40°C for 8 h; The reaction solution was suction-filtered, the filter residue was washed with pyridine, the filtrates were combined, and the filtrate was poured into ice water to precipitate a white solid, which was separated and dried to obtain 1.304 g of compound 2 (white solid, yield 98%).
[0084] 2) Synthesis of Compound 3:
[0085] Compound 2 (1.109g, 3.06mmol) was dissolved in THF (5.0mL), NaH was added at 0°C, and after reacting for 90min, 1,6-dibromohexane was added at 0°C (the compound 2 , NaH and 1,6-dibromohexane in a molar ratio of 1:15:3), reacted at room temperature for 15h. The reaction solution was diluted with water, extracted with ethyl acetate, washed with saturated brin...
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