Preparation method of Jardiance

A technology of exchanging empagliflozin and Grignard, which is applied in the field of preparation of empagliflozin for the treatment of diabetes, can solve the problems of selectivity, low yield, unfavorable process amplification, cumbersome route steps, etc., and achieve high product purity, Effect of reducing process cost and shortening reaction steps

Active Publication Date: 2017-06-30
山东科巢生物制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0014] Although the route of this method is slightly short, the docking of phenol and (R)-3-hydroxytetrahydrofuran needs to be reacted with Mitsunobu, which generates more urea compounds and triphenoxyphos, and the post-reaction treatment is cumbersome, which is not conducive to process amplification; the subsequent steps in the route The method is basically consistent with the above-mentioned patent, but the selectivity and yield are low, the route steps are cumbersome, and the overall efficiency is low

Method used

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  • Preparation method of Jardiance
  • Preparation method of Jardiance
  • Preparation method of Jardiance

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043]

[0044] Add polyphosphoric acid (94mL) into the three-necked flask, add compound formula 1a (23.55g, 100mmol), heat to an internal temperature of about 50°C and stir evenly, add phenol (18.82g, 200mmol), and heat up to 80-85°C after adding ℃ for 3 to 4 hours, after the reaction was completed, cool to 50℃ and slowly add water (235ml) dropwise to quench the reaction, then add dichloromethane (141mL) and stir for 20 minutes. Extracted twice, combined the organic phases, washed once with saturated sodium bicarbonate (141mL) solution, washed twice with saturated brine (70mL), dried over sodium sulfate, concentrated and recrystallized with a mixed solvent of dichloromethane and ethanol to obtain compound 2a (27.11g, 87%). ESI m / z = 311.0 (M+1).

Embodiment 2

[0046]

[0047] Add polyphosphoric acid (113mL) into the three-necked flask, add compound formula 1b (28.25g, 100mmol), heat to an internal temperature of about 50°C and stir evenly, add phenol (18.82g, 200mmol), and heat up to 80-85°C after adding ℃ for 3 to 4 hours, after the reaction was completed, cool to 50 ℃ and slowly add water (283mL) dropwise to quench the reaction, then add dichloromethane (169mL) and stir for 20 minutes, separate the organic phase, and then add dichloromethane (84mL) to the water phase Extracted twice, the combined organic phase was washed once with saturated sodium bicarbonate (169mL) solution, washed twice with saturated brine (84mL), dried over sodium sulfate, concentrated and recrystallized with a mixed solvent of dichloromethane and ethanol to obtain compound 2b (29.76g ,83%). ESI m / z = 358.9 (M+1).

Embodiment 3

[0049]

[0050]Add 2a (31.16g, 100mmol), R-3-chloro-tetrahydrofuran (11.73g, 110mmol), potassium carbonate (27.64g, 200mmol), potassium iodide (830mg, 5mmol) and acetonitrile (155mL) into a three-necked flask, stir well Heat to 50-55°C to react overnight. Concentrate directly to remove part of the acetonitrile after the reaction is completed, add water (155mL) and dichloromethane (155mL), extract the aqueous phase with dichloromethane (78mL) once, combine the organic phases and wash with saturated brine once (155mL), and dry over sodium sulfate , concentrated and then recrystallized from a mixed solvent of petroleum ether and ethyl acetate to obtain compound 4a (34.73 g, 91%).

[0051] Potassium carbonate in embodiment 3 can be replaced by sodium carbonate, cesium carbonate, potassium tert-butoxide, triethylamine or diisopropylethylamine; reaction solvent acetonitrile can be N,N-dimethylformamide, N,N-di Methylacetamide, tetrahydrofuran, 1,4-dioxane, toluene, isopropanol, ...

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Abstract

The invention discloses a preparation method of Jardiance. The preparation method comprises the following steps: (1) performing a Grignard exchange reaction on a compound 5, then enabling the compound 5 after the Grignard exchange reaction to react with a glucose lactone derivative 6 so as to obtain a compound 7 (as shown in the description), wherein X is bromine or iodine, LG is chlorine, bromine, mesyloxy or tosyl, and PG is acetyl, tert- butanoyl or benzoyl; (2) under the action of alkali, performing deprotection on the compound 7 so as to obtain a finished product namely an Jardiance type compound 8 (as shown in the description). The preparation route is simple to operate, the reaction steps are reduced, the yield is high, the obtained product is high in purity, and the preparation method is suitable for scaled production.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and in particular relates to a preparation method of empagliflozin, a drug for treating diabetes. Background technique [0002] Empagliflozin is a selective oral SGLT-2 inhibitor jointly developed by Boehringer Ingelheim and Eli Lilly and Company. It is a drug that can selectively inhibit the reabsorption of filtered glucose by the proximal tubules of the glomerulus, excrete excess glucose from the urine, and directly lower blood sugar. It is used to treat hyperglycemia in type II diabetes. The results of the study show that the efficacy is significant, and it has good safety and tolerance. It was approved by the US FDA in 2014 and has broad market prospects. [0003] The chemical name of Englie purification: (1S)-1,5-anhydro-1-C-[4-chloro-3-[[4-[[(3S)-tetrahydro-3-furyl]oxyl] Phenyl] methyl] phenyl] -D-glucitol, the structural formula is as follows: [0004] [0005] PCT paten...

Claims

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Application Information

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IPC IPC(8): C07D407/12
CPCC07D407/12Y02P20/55
Inventor 郑旭春张一平付晨晨
Owner 山东科巢生物制药有限公司
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