Method for preparing everolimus intermediate and ethylated impurities thereof
A technology for everolimus and intermediates, which is applied in the field of preparation of everolimus intermediates and their ethylated impurities, which can solve the problems of difficult degradation, separation, limited structural stability of the reaction degree, and no compound synthesis reports and other problems, to achieve the effect of simple preparation process and high yield
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Embodiment 1
[0033] In a 100ml single-necked flask, add 4.50g of rapamycin and 9.50g of 2-(tert-butyldiphenylsilyl)oxyethyl trifluoromethanesulfonate respectively, then add 150ml of dichloromethane, Stirring at room temperature, the solution was a milky white suspension. Then add methylamine and sodium bicarbonate, stir at room temperature, and react for 4 to 5 hours. Concentrate under reduced pressure to obtain a white foamy solid, which is washed with a small amount of petroleum ether, filtered with suction, and dried in vacuo to obtain 4.89 g of a white solid intermediate with a yield of 81%.
Embodiment 2
[0035] Dissolve everolimus (0.2g) in absolute ethanol (20ml), add 0.1N hydrochloric acid (10ml), stir at 20°C-30°C for 24 hours, add 200ml of water, extract with ethyl acetate (150ml×3) , combined the organic phases, washed once with saturated sodium bicarbonate, and washed twice with saturated brine. Anhydrous Na 2 SO 4 Dry, filter, and concentrate the filtrate to dryness in vacuo at 25°C. The crude product was purified by preparative liquid phase to obtain the target product ethylated impurity (102mg, white solid), the yield was 51%, and the high-resolution mass spectrum of the obtained product was as follows: figure 1 Shown, the HPLC collection of illustrative plates of product is as figure 2 shown.
[0036] Preparation conditions:
[0037] Chromatographic column: Phenomenex Luna C18(2) 10u 250mm×50mm
[0038] Wavelength: 275nm
[0039] Flow rate: 100ml / min
[0040] Mobile phase: 0.002M potassium dihydrogen phosphate-acetonitrile (30:70)
[0041] Example 2:
[00...
Embodiment 3
[0049] Dissolve everolimus (0.2g) in absolute ethanol (20ml), add trifluoroacetic acid (0.5ml) dropwise, stir at 20°C-30°C for 9 hours, add 200ml of water, extract with ethyl acetate (150ml×3 ), combined the organic phases, washed once with saturated sodium bicarbonate, and washed twice with saturated brine. Anhydrous Na 2 SO 4 Dry, filter, and concentrate the filtrate to dryness in vacuo at 25°C. The crude product was purified by preparative liquid phase to obtain the target ethylated impurity (97 mg, white solid) with a yield of 49%.
[0050] Preparation conditions:
[0051] Chromatographic column: Phenomenex Luna C18(2) 10u 250mm×50mm
[0052] Wavelength: 275nm
[0053] Flow rate: 100ml / min
[0054] Mobile phase: 0.002M potassium dihydrogen phosphate-acetonitrile (30:70).
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