Novel isoserine ester derivates and method for preparing same
An isoserine ester and acidic technology, which is applied in the field of preparing the anti-tumor drug docetaxel, can solve the problems of low yield, high price, and difficult separation, and achieve the effect of high yield and easy operation
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Embodiment 1
[0130] Example 1: Preparation of 2'-triethylsilyl-7,10-bis(trichloroacetyl)docetaxel
[0131] 7,10-bis(trichloroacetyl)baccatin (III) (20 g) was dissolved in THF, under nitrogen protection, the temperature was lowered to -65°C, 1.5N lithium bis(trimethylsilyl)amide was added dropwise, Then 1-tert-butoxycarbonyl-3-triethylsilyloxy-4-phenyl-azetidinone tetrahydrofuran solution (21 g, 100 ml) was added dropwise, the temperature was raised to -50° C., and the reaction was carried out for 40 min. Saturated brine (600ml) was added, and the aqueous layer was extracted with ethyl acetate (400ml×2). The organic layer was washed with water (300ml) and saturated brine (300ml), dried over anhydrous sodium sulfate, concentrated to dryness, and then dissolved in ethyl acetate and The product was crystallized in n-hexane mixture to obtain 28 g (yield 95%).
[0132] MS (m / z): 1232 (M+Na). 1 HNMR (500MHz) δ0.45(6H, t), 0.81(9H, m), 1.14(3H, s), 1.24(2H, m), 1.37(9H, s), 1.69(3H, s), 1.73( 2...
Embodiment 2
[0133] Example 2: Preparation of docetaxel from 2'-triethylsilyl-7,10-bis(trichloroacetyl)docetaxel
[0134] At room temperature, 2'-triethylsilyl-7,10-bis(trichloroacetyl)docetaxel (10 g) was dissolved in 200 ml of methanol / tetrahydrofuran, and 24 ml of 2N aqueous ammonia solution was added dropwise. After stirring the reaction for 3 hours, the reaction was concentrated in vacuo to a small volume, then diluted with water and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, and then crystallized in a mixture of ethyl acetate and n-hexane to obtain 6.2 g (94% yield).
[0135] MS (m / z): 808 (M+1). 1 HNMR (500MHz) δ1.25(3H, s), 2.14(1H, m), 2.42(2H, m), 2.46(3H, s), 2.69(1H, m), 3.97(1H, d), 4.21( 1H,d), 4.39(1H,d), 4.66(1H,d), 4.69(1H,m), 4.85(2H,s), 4.98(1H,d), 5.03(1H,m), 5.34(1H , bd), 5.51(1H, bd), 5.60(1H, dd), 5.75(1H, d), 6.27(1H, bt), 6.28(1H, s), 7.37~7.45(5...
Embodiment 3
[0136] Example 3: Preparation of 2'-(1-ethoxy)ethyl-7,10-bis(trichloroacetyl)docetaxel
[0137] Dissolve 7,10-bis(trichloroethoxycarbonyl)baccatin (III) (11g) in THF, under nitrogen protection, cool down to -65°C, add 1.5N sodium hexamethyldisilazide, and stir for 10min , a solution of 1-tert-butoxycarbonyl-3-triethylsilyloxy-4-phenyl-azetidinone in tetrahydrofuran (12 g, 50 ml) was started to be added dropwise. The temperature was raised to -50°C, and the reaction was continued for 30 minutes. Add saturated brine (300ml), extract the aqueous layer with ethyl acetate (200ml×2), wash the organic layer with water (150ml) and saturated brine (150ml), dry over anhydrous sodium sulfate, concentrate to dryness, and obtain the product by silica gel column chromatography 14g (91% yield).
[0138] MS (m / z): 1190 (M+Na). 1 HNMR (500MHz) δ1.13 (10H, m), 1.31 (4H, m), 1.36 (1H, m), 1.39 (9H, s), 1.62 (4H, m), 1.64 (1H, m), 1.75 ( 2H,m), 2.27(3H,s), 3.29(1H,m), 3.51(1H,m), 4.11(2H,m), ...
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