A kind of preparation method of carfilzomib
A carfilzomib and intermediate technology, applied in the field of medicinal chemistry, can solve the problems of less manganese complex catalysts, less side reactions, limited application and the like, and achieve the effects of low cost, simple operation and simple reaction conditions
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Embodiment 1
[0033]Add the compound of formula III (25.5g, 100 mmol), (2S)-2-[diphenyl[(trimethylsilyl ester)oxy]methyl]-pyrrolidine (3.7g, 10 mmol) to the reaction flask , Toluene (250 mL),N-Methylpyrrolidone (500 mL), stir well, cool to -3°C, slowly add hydrogen peroxide (34.0g, 30% aqueous solution, 300 mmol) dropwise at -5 to 0°C. After the dripping is completed, the reaction is kept for 4 hours.
[0034]TLC detection, after the reaction is complete, add sodium thiosulfate solution to quench (200 mL), add n-hexane (400 mL) for extraction and liquid separation, and then wash the organic phase with purified water (200 mL) and saturated brine (200 mL) , Dry the organic phase with anhydrous sodium sulfate, concentrate under reduced pressure to obtain an oily substance, and obtain a solid after recrystallization from n-hexane. The molar yield is 83%, the purity is 99.3%, and the chiral selectivity of the compound of formula I: the compound of formula II is 15:1.
[0035]1H NMR (400 MHz, CDCl3)δ 0.9 (d...
Embodiment 2
[0038]Add the compound of formula III (25.5g, 100 mmol), (2S)-2-[diphenyl[(triethylsilyl ester)oxy]methyl]-pyrrolidine (3.7g, 10 mmol) into the reaction flask , Toluene (250 mL),N-Methylpyrrolidone (500 mL), stir well, cool to -3°C, slowly add hydrogen peroxide (34.0g, 30% aqueous solution, 300 mmol) dropwise at -5 to 0°C. After the dropwise addition was completed, the reaction was kept for 4 hours.
[0039]TLC detection, after the reaction is complete, add sodium thiosulfate solution to quench (200 mL), add n-hexane (400 mL) for extraction and liquid separation, and then wash the organic phase with purified water (200 mL) and saturated brine (200 mL) , Dry the organic phase with anhydrous sodium sulfate, concentrate under reduced pressure to obtain an oily substance, and obtain a solid after recrystallization from n-hexane. The molar yield is 84%, the purity is 99.5%, and the chiral selectivity of the compound of formula I: the compound of formula II is 17:1.
[0040]The hydrogen spectru...
Embodiment 3
[0042]Add the compound of formula III (25.5g, 100 mmol), (2S)-2-[diphenyl[(triethylsilyl ester)oxy]methyl]-pyrrolidine (0.7g, 2 mmol) to the reaction flask , Toluene (250 mL),N -Methylpyrrolidone (500 mL), stir well, cool to -3°C, slowly add hydrogen peroxide (34.0g, 30% aqueous solution, 300 mmol) dropwise at -5 to 0°C. After the dropwise addition was completed, the reaction was kept for 4 hours.
[0043]TLC detection, after the reaction is complete, add sodium thiosulfate solution to quench (200 mL), add n-hexane (400 mL) for extraction and liquid separation, and then wash the organic phase with purified water (200 mL) and saturated brine (200 mL) , Dry the organic phase with anhydrous sodium sulfate, concentrate under reduced pressure to obtain an oily substance, and obtain a solid after recrystallization from n-hexane. The molar yield is 65%, the purity is 89%, and the chiral selectivity of the compound of formula I: the compound of formula II is 4.4:1.
[0044]The hydrogen spectrum a...
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