A tenofovir prodrug or pharmaceutically acceptable salt and its application in medicine
A technology for medicinal salts and medicines, which can be applied to tenofovir prodrugs or medicinally acceptable salts and their application fields in medicine, and can solve problems such as technical barriers and the like
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Embodiment 1
[0032] step 1:
[0033] .
[0034] The mixture of tenofovir (70.5 g), triethylamine, DMAP, triphenyl phosphite and acetonitrile was refluxed at 80°C for 48 hours, then the heating was stopped, the acetonitrile was removed by rotary evaporation, and the fractions were extracted with water, ethyl acetate and acetonitrile respectively. liquid. Concentrated hydrochloric acid (30%) was added dropwise to the aqueous phase at low temperature (≤25°C) until the pH was 3, and the stirring was continued until solids were precipitated. Continue to add concentrated hydrochloric acid dropwise until the pH is less than 2. After filtering and drying, 73.1 g of white powdery solid IIA was obtained, with a yield of 81.57%. MS(m / z):364.1(M+H) + .
[0035] Step 2:
[0036] .
[0037] Thionyl chloride (336 mg) was added to IIA (513 mg) in acetonitrile mixture, stirred at 80°C for 5 h, a solid was precipitated, the acetonitrile was distilled off under reduced pressure, the solid was adde...
Embodiment 2
[0043] .
[0044] Thionyl chloride (336 mg) was added to IIA (513 mg) in acetonitrile mixture, stirred at 80°C for 5 h, a solid was precipitated, the acetonitrile was distilled off under reduced pressure, the solid was added with toluene and then spin-dried. The solid was then dissolved in dichloromethane, and a mixed solution of IIIA (337 mg) and dichloromethane was added dropwise at -30°C. After dropping, continue to add triethylamine dropwise until the pH is 6-7 after stirring for 5 minutes. After dropping, continue to react for 1 hour. Raise the temperature to -5°C, wash with sodium dihydrogen phosphate dihydrate solution, sodium bicarbonate solution, and saturated brine successively, dry with anhydrous sodium sulfate, spin dry, and obtain 482 mg of light yellow oil after column chromatography, yield 71.5% .
[0045] 1 H-NMR (400MHz, CDCl 3 )δ8.35(s, 1H), 7.94(m, 1H), 7.30~7.43(m, 1H), 7.21~7.35(m, 1H), 7.0~7.21(m, 2H), 6.80~6.99(m, 1H), 5.50~5.65(m, 2H), 4.58~4.92(...
Embodiment 3
[0048] Example 3: Compounds D and D1 were synthesized in a similar manner to compounds C and C1.
[0049] .
[0050] D: 1 H-NMR (400MHz, CDCl 3 ( m, 4H), 4.38~4.48(m, 1H), 4.01~4.20(m, 4H), 3.60~3.74(m, 2H), 1.28~1.50(m, 9H).
[0051] D1: MS(m / z):523.2(M+H) + .
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