Novel rosaxostat intermediate and novel preparation method of rosaxostat
A technology for roxadustat and intermediates, which is applied in the field of synthesis of pharmaceutical intermediates, can solve the problems of long production cycle, complicated reaction operation, increased cost and the like, and achieves high product purity and yield, mild reaction conditions and easy operation. Effect
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Embodiment 1
[0040] Preparation of methyl 2-acetamido-3-oxo-3-(4-phenoxyphenyl) propionate (Ⅲ-a)
[0041] 20.0 g (0.063 mol) of methyl 2-acetamido-3-(4-phenoxyphenyl) propionate (II-a) was dissolved in 200 ml of acetone, and the temperature was lowered to -78°C with stirring. 30.1g (3.0e.q.) of potassium permanganate and 25.5g (2.5e.q.) of ferric chloride were sequentially added, and the reaction was incubated for 2 hours. The temperature was then slowly raised to room temperature and stirring was continued for 12 hours. The reaction solution was diluted with 100 ml of dichloromethane and filtered, the filter cake was rinsed with 100 ml of dichloromethane, the dichloromethane phases were combined, dried over anhydrous magnesium sulfate, decolorized with activated carbon, filtered and concentrated to obtain an off-white solid 2-acetylamino -18.7 g of methyl 3-oxo-3-(4-phenoxyphenyl) propionate (III-a), yield: 89.5%.
[0042] 1H NMR (400MHz DMSO): δ=1.920(s,3H); 3.662(s,3H); 5.932(d,1H); ...
Embodiment 2
[0044] Preparation of ethyl 2-acetamido-3-oxo-3-(4-phenoxyphenyl)propanoate (Ⅲ-b)
[0045] 10.2 g of potassium bromate and 3.2 g of cerium dioxide were dissolved in 100 ml of dioxane solution and stirred at room temperature for five minutes, and ethyl 2-acetamido-3-(4-phenoxyphenyl) propionate (II-b) was added. After 20.0 g (0.061 mol), the temperature was raised to 95° C., and the reaction was maintained for 1 hour. After cooling to room temperature, the reaction solution was filtered, and extracted with dichloromethane and water. The dichloromethane phase was separated, washed with saturated brine, the dichloromethane phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a pale yellow solid 2-acetamido-3-oxo-3-(4- Ethyl phenoxyphenyl)propionate (III-b) 19.0 g, yield: 91.1%.
[0046] 1 H NMR (400MHz DMSO): δ=1.236(t,3H); 1.928(s,3H); 4.219(q,2H); 5.934(d,1H); 7.066(d,2H); 7.176(d,2H) ; 7.188 (d, 1H); 7.429 (t, 2H); 8.652 (s, 1H). ...
Embodiment 3
[0048] Preparation of isopropyl 2-acetamido-3-oxo-3-(4-phenoxyphenyl) propionate (Ⅲ-c)
[0049] Dissolve 20.0 g (0.059 mol) of isopropyl 2-acetamido-3-(4-phenoxyphenyl) propionate (II-c) in 100 ml of tert-butanol, and stir 15.9 g of tert-butyl hydroperoxide. g, the temperature was raised to reflux (85° C.), after the reaction was completed, the tert-butanol was evaporated under reduced pressure to obtain a yellow oil. Add 200ml to dissolve, wash twice with saturated brine (100ml×2), separate the dichloromethane phase, dry with anhydrous magnesium sulfate, and concentrate under pressure to obtain a pale yellow solid 2-acetamido-3-oxo- Isopropyl 3-(4-phenoxyphenyl)propanoate (III-c) 18.5 g, yield: 88.2%.
[0050] 1 H NMR (400MHz DMSO): δ=1.20(d,6H); 1.945(s,3H); 4.944(m,1H); 5.947(d,1H); 7.074(d,2H); 7.183(d,2H) ; 7.192 (d, 1H); 7.431 (t, 2H); 8.660 (s, 1H).
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