Method for preparing vorapaxar sulfate intermediate
An intermediate and sulfuric acid technology, applied in the field of preparation of Vorapaxa sulfate intermediates, can solve the problems of high preparation cost and high cost of butynol raw materials, achieve high yield, reduce synthesis cost, and high selectivity. Effect
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Embodiment 1
[0076] The preparation method of embodiment 1 compound III
[0077] In a 2L three-necked flask, add D-methyl lactate (104g, 1mol), dichloromethane (208ml) and imidazole (102g, 1.5mol), cool the reaction solution to 0-5°C, protect it with nitrogen, and add TBSCl dropwise (150g, 1mol) and dichloromethane (300ml) solution, keep the temperature at 0-5°C, add dropwise for about 1h, stir at 0-5°C for 1h, raise the temperature to 20-30°C, stir for 18h, and add the reaction solution Water (500ml), stirred for 10min, the aqueous layer was extracted with dichloromethane (300ml), the organic phase was combined, washed with saturated sodium chloride solution (50mlx3), the organic phase was collected, dried with anhydrous magnesium sulfate for 1h, filtered, and the filtrate was collected , concentrated under reduced pressure to obtain a crude product, which was distilled under reduced pressure to obtain 197 g of the product, with a yield of 90%.
Embodiment 2
[0078] The first preparation method of embodiment 2 compound IV
[0079] Add compound III (65.4g, 0.3mol) and n-hexane (600ml) into a 2L three-necked flask, cool to -78°C, and protect with nitrogen; take another DIBAL-H (220ml, 1.5M toluene solution, 0.33mol), pre Cool to -78°C, add DIBAL-H dropwise to the solution of compound III, control the temperature at -78°C, take about 30min, after the addition is complete, stir and react at -78°C for 1h, then add methanol (30ml) to the reaction solution , Quench the reaction, after the addition is complete, stir at -78°C for 15min. Take another 2L three-necked bottle, use mechanical stirring instead, add saturated potassium sodium tartrate solution (600ml), add the above reaction solution into potassium sodium tartrate solution, heat up to 20-30°C, stir for 2-3h, stand still, separate The organic phase and the aqueous phase were extracted with n-hexane (200ml), the organic phases were combined, washed with saturated sodium chloride so...
Embodiment 3
[0080] The second preparation method of embodiment 3 compound IV
[0081] Lithium chloride (7.8g, 183mmol) and tetrahydrofuran (200ml) were added into a 500ml three-necked flask, sodium borohydride (6.9g, 183mmol) was added, under nitrogen protection, stirred at 20-25°C for 3h, compound III (20g, 91.7 mmol), under nitrogen protection, stirred and reacted at 20-25°C for 48h. After the reaction was completed, it was quenched with 1N HCl (50ml), extracted with ethyl acetate (200ml), and the organic phase was collected, washed with saturated brine, anhydrous sulfuric acid Dried over magnesium, concentrated to dryness to obtain a crude product, and distilled under reduced pressure at 40-45°C to obtain 15.2 g of the product, with a yield of 87.2%.
[0082] DCM (50ml) and oxalyl chloride (27.8g, 276mmol) were added to a 500ml three-necked flask, protected by nitrogen, cooled to -78°C, a solution of DMSO (27.9g, 276mmol) in DCM (50ml) was added dropwise, and the temperature was contro...
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