Method for preparing ticagrelor key intermediate
A technology of ticagrelor and intermediates, applied in the field of drug synthesis, can solve problems that have not been seen yet, and achieve the effect of reducing environmental pressure
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Embodiment 1
[0057] Example 1 Preparation of Compound I
[0058] Add 300g of D-ribose, 1040ml of acetone, 1040ml of methanol, and 30ml of concentrated hydrochloric acid into a 3000ml three-neck flask, stir and heat to reflux. Keep reflux reaction for 3h, cool to room temperature, add 450ml purified water, saturated Na 2 CO 3 The pH of the solution was adjusted to about 8, and extracted with 600ml ethyl acetate and 1200ml ethyl acetate successively. The ethyl acetate layers were combined, washed once with saturated saline and water, dried over anhydrous sodium sulfate for 1 h, filtered with suction, and distilled to dryness under reduced pressure to obtain 208.1 g of light yellow oily compound Ⅰ with a yield of 51.1%. 1 H NMR (400 MHz, CDCl 3 )δ:4.94(s,1H),4.97(d, J =6.0 Hz,1H),4.55(d, J =6.0 Hz,1H),4.38(d, J =3.2 Hz,1H),3.6-3.5(m,2H),3.4(s,3H),3.0(s,1H),1.4(s,3H),1.3(s,3H).
Embodiment 2
[0059] Example 2 Preparation of Compound II
[0060] Add 426g of compound Ⅰ and 342ml of pyridine into a 2000ml three-necked flask, cool down in a salt ice water bath to below 0°C, add p-toluenesulfonyl chloride dichloromethane solution (422g: 933ml) dropwise, and drop it in about 30 minutes. Then move the three-neck flask to room temperature, stir and react for 5 hours, add 311ml of water dropwise, continue stirring for 30min, then transfer the reaction system to a 2000ml separating funnel, take the organic layer, and distill to dryness under reduced pressure to obtain 732g of beige solid compound Ⅱ Crude product, the yield is 98%. Put the crude compound II above in 2928ml (4V) ethanol, stir and heat to reflux, dissolve completely, decolorize with 60g activated carbon for 15min, filter with suction, cool, crystallize, filter with suction, and dry to obtain 666g of pure compound II (>99 %). m.p.83.3-85.2°C (document: 84-84°C).
[0061] 1 H NMR (400 MHz, CDCl 3 )δ: 7.81(d,...
Embodiment 3
[0062] Example 3 Preparation of Compound III
[0063] Add 359g of compound II, 300.8g of NaI, 1330ml of toluene, and 332ml of DMF into a 3000ml three-neck flask, stir and heat to reflux, and keep reflux for 2h. After cooling, the reaction solution was washed successively with water (500ml×2) and saturated brine (500ml×2), dried over anhydrous magnesium sulfate, filtered with suction, and concentrated to dryness under reduced pressure to obtain a light yellow oily substance, which was compound Ⅲ. >98%, purity 99.3%. MS: m / z =315(MH) + .
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