The preparation method of Epagliflozin and its intermediate
A technology for an intermediate and a synthesis method, which is applied in the preparation method of a diabetes drug SGLT-2 inhibitor Epagliflozin and its intermediate field, can solve the problem of low yield of key reactions, low total route yield, troublesome exhaust gas treatment, etc. problems, to avoid ultra-low temperature reaction conditions, high product purity, and reduce process costs.
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Embodiment 1
[0044] (2R,3S,4S)-2,3,4-Tribenzyloxy-4-(4-((benzyloxy)methyl)-2,2-dimethyl-1,3-dioxane Pent-4-yl)-1-(4-chloro-3-(4-ethoxybenzyl)phenyl)butan-1-one
[0045]
[0046]Add compound formula 1a (32.56g, 110mmol) and tetrahydrofuran (162mL) into the three-necked flask, stir and dissolve, then cool in an ice-salt bath to -5~0°C, and add dropwise 2.0M isopropylmagnesium chloride tetrahydrofuran solution (120mmol, 60.0 mL), keep the inner temperature -5~0℃ and react for 1 hour. Dissolve compound 2 (70.89g, 100mmol) in tetrahydrofuran (81mL) under the protection of nitrogen and slowly drop it into the reaction flask, then raise the temperature to 20-30°C to react for 4-6 hours, and slowly add saturated ammonium chloride solution after the reaction is completed (162mL) to quench the reaction, the mixture was extracted twice with ethyl acetate (162mL), the combined organic phases were washed twice with water (162mL), dried over sodium sulfate, filtered, concentrated and recrystallized ...
Embodiment 2
[0050] (2R,3S,4S)-2,3,4-Tribenzyloxy-4-(4-((benzyloxy)methyl)-2,2-dimethyl-1,3-dioxane Pent-4-yl)-1-(4-chloro-3-(4-ethoxybenzyl)phenyl)butan-1-one
[0051]
[0052] Add compound formula 1b (37.26g, 110mmol) and tetrahydrofuran (186mL) into the three-necked flask, stir and dissolve, cool to -5~0°C in an ice-salt bath, add dropwise 1.0M n-butylmagnesium chloride tetrahydrofuran solution (120mmol, 120.0 mL), keep the inner temperature -5~0℃ and react for 1 hour. Dissolve compound 2 (70.89g, 100mmol) in tetrahydrofuran (93mL) under the protection of nitrogen and slowly drop it into the reaction flask, then raise the temperature to 20-30°C to react for 4-6 hours, and slowly add saturated ammonium chloride solution after the reaction is completed (186mL) to quench the reaction, the mixture was extracted twice with ethyl acetate (186mL), the combined organic phases were washed twice with water (186mL), dried over sodium sulfate, filtered, concentrated and recrystallized with ethy...
Embodiment 3
[0055] Epagliflozin crude compound 4
[0056]
[0057] Add intermediate 3 (85.54g, 100mmol) to the hydrogenation bottle, add methanol (428mL) to dissolve, add acetic acid (86mL) and palladium carbon (5%, 8.55g), switch hydrogen in vacuum three times, pressurize to about 0.2Mpa and keep React at an internal temperature of 40-50°C for 20-24 hours. At the end of the reaction, cool the diatomaceous earth to filter off the palladium carbon, concentrate and spin off part of the methanol, add dichloromethane (856mL) to dissolve, the solution is washed with saturated sodium bicarbonate and saturated brine (428mL each), dried over anhydrous sodium sulfate, and filtered The crude product 4 of epagliflozin was concentrated and directly used for the next reaction. MS(ESI)m / z=459.1[M+Na] +
[0058] In the embodiment, the catalyst palladium carbon can be replaced by palladium hydroxide or palladium oxide; acetic acid can also be replaced by propionic acid or trifluoroacetic acid, etc....
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