A kind of convenient preparation method of palbociclib
A compound and solvent technology, applied in the field of simple preparation of Palbociclib, can solve the problems of increasing synthesis cost, difficult industrialized operation, etc., and achieve the effects of less waste water and waste liquid, low cost, high purity and total yield
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Embodiment 1
[0052] Embodiment 1: the preparation of palbociclib (Ⅰ)
[0053] Step (1): Preparation of 3-acetyl-1-cyclopentyl-4-methylpyridine-2,6-(1H,5H)-dione (Ⅲ)
[0054] In the 500 milliliter four-necked flask that is connected with stirring, thermometer, water separator, reflux condenser and dropping funnel, add 220 gram toluene, 0.2 gram methylbenzenesulfonic acid, 26.0 gram (0.2 moles) ethyl acetoacetate, 110 to 115 ° C stirring and reflux dehydration reaction for 5 hours. Cool to 50°C, add 10.0 g (0.12 moles) of cyclopentylamine, stir and react at 90 to 95°C for 4 hours, while distilling off the ethanol generated. The solvent was recovered by distillation under reduced pressure, and the residue was recrystallized with 50 g of methyl tert-butyl ether to obtain 21.7 g of white solid 3-acetyl-1-cyclopentyl-4-methylpyridine-2,6-(1H,5H) - diketone, yield 92.5%, liquid phase purity 99.8%.
[0055] Step (2): Preparation of Boc-protected palbociclib (Ⅵ)
[0056] In a 500 ml four-necked...
Embodiment 2
[0063] Embodiment 2: the preparation of palbociclib (Ⅰ)
[0064] Step (1): Preparation of 3-acetyl-1-cyclopentyl-4-methylpyridine-2,6-(1H,5H)-dione (Ⅲ)
[0065] In the 500 milliliter four-necked flask that is connected with stirring, thermometer, water separator, reflux condenser and dropping funnel, add 220 gram toluene, 0.15 gram 98wt% sulfuric acid, 23.2 gram (0.2 moles) methyl acetoacetate, 110 to Stir and reflux dehydration reaction at 115°C for 5 hours. Cool to 50° C., add 10.0 g (0.12 moles) of cyclopentylamine, stir and react at 100 to 105° C. for 3 hours, and simultaneously distill off the generated methanol. The solvent was recovered by distillation under reduced pressure, and the residue was recrystallized with 50 g of methyl tert-butyl ether to obtain 21.3 g of white solid 3-acetyl-1-cyclopentyl-4-methylpyridine-2,6-(1H,5H) - diketone, yield 90.6%, liquid phase purity 99.3%.
[0066] Step (2): Preparation of Boc-protected palbociclib (Ⅵ)
[0067] In a 500 ml fo...
Embodiment 3
[0070] Embodiment 3: the preparation of palbociclib (I)
[0071] Step (1): Preparation of 3-acetyl-1-cyclopentyl-4-methylpyridine-2,6-(1H,5H)-dione (Ⅲ)
[0072] In the 500 milliliter four-necked flask that is connected with stirring, thermometer, water separator, reflux condenser and dropping funnel, add 220 grams of toluene, 0.25 grams of p-toluenesulfonic acid, 23.2 grams (0.2 moles) of methyl acetoacetate , 110 to 115 ° C stirring reflux dehydration reaction for 5 hours. Cool to 50° C., add 10.0 g (0.12 moles) of cyclopentylamine, stir and react at 100 to 105° C. for 3 hours, and simultaneously distill off the generated methanol. The solvent was recovered by distillation under reduced pressure, and the residue was recrystallized with 50 g of methyl tert-butyl ether to obtain 21.6 g of white solid 3-acetyl-1-cyclopentyl-4-methylpyridine-2,6-(1H,5H) - diketone, yield 91.9%, liquid phase purity 99.5%.
[0073] Step (2): Preparation of Boc-protected palbociclib (Ⅵ)
[0074]...
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