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Preparation method of empagliflozin intermediate

A system and inert gas technology, applied in the direction of organic chemistry, bulk chemical production, etc., can solve the problems of unsuitable industrial production and cumbersome operation, and achieve the effect of less impurities, lower impurity content, and less impurities

Active Publication Date: 2021-01-08
TONGHUA DONGBAO PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, during the actual reaction, a large amount of heat is released during the dropping process. In order to ensure the low temperature of the system, the equipment must reach at least -30°C or even lower.
Obviously, such harsh conditions are not suitable for industrial production
In addition, when preparing the compound of structural formula 3, the reaction is quenched with 10% citric acid solution at the end of the reaction, and then the methyl ketal reaction is carried out to obtain the compound of structural formula 4, and the system must be removed with toluene before the methyl ketal reaction. The water in the water, the operation is cumbersome

Method used

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  • Preparation method of empagliflozin intermediate
  • Preparation method of empagliflozin intermediate
  • Preparation method of empagliflozin intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0074] Example 1 The preparation of the compound of structural formula 4

[0075] (1) In a 150ml three-neck flask, add 2.00g of the compound of structural formula 1, and then add 4g of 2-methyltetrahydrofuran and stir to dissolve. The reaction system was protected by nitrogen gas, and 1.20 g of magnesium chips and 2.25 g of lithium chloride were added.

[0076] (2) The temperature of the system is raised to 45°C, a grain of iodine is added, and it is allowed to stand for automatic initiation.

[0077] (3) After the reaction is initiated, the temperature is controlled at 45-55°C, and 18g of the compound of structural formula 1 is dissolved in 36g of 2-methyltetrahydrofuran, and added dropwise to the reaction system; after dropping, keep stirring at 45-55°C for 1 hour; take a sample of 1ml, Add 1ml of 10% citric acid solution to quench, take the organic phase for HPLC measurement, the relative area of ​​the main peak is greater than or equal to 98%, and when the relative area...

Embodiment 2

[0088] Example 2 The preparation of the compound of structural formula 4

[0089] (1) In a 30L reactor, add 300g of the compound of structural formula 1 and 600g of 2-methyltetrahydrofuran. The reaction system was protected by nitrogen gas, and 179.36 g of magnesium chips and 337.38 g of lithium chloride were added.

[0090] (2) The temperature of the system is raised to 45° C., 1 g of iodine is added, and the system is allowed to stand still for automatic initiation.

[0091] (3) After the reaction is initiated, the temperature is controlled at 45-55°C, and 2.7kg of the compound of structural formula 1 is dissolved in 5.4kg of 2-methyltetrahydrofuran, and added dropwise to the reaction system; after dropping, keep stirring at 45-55°C for 1 hour; Sampling 1ml, add 1ml10% citric acid solution to quench, take the organic phase HPLC measurement, the relative area of ​​the main peak is greater than or equal to 98%, the relative area of ​​the chromatographic peak of the compound...

Embodiment 3

[0105] Example 3 Preparation of Empagliflozin

[0106] (1) Take 10.00 g of the compound of structural formula 4 prepared in Example 1, put it into a 100 mL Erlenmeyer flask with a stopper, add 15.00 g of acetonitrile and 15.00 g of dichloromethane, shake to dissolve, and set aside.

[0107] (2) Add 5.82g of anhydrous aluminum trichloride and 20.00g of dichloromethane to a 250mL three-necked flask, cool down to 0-10°C, and add 20.00g of acetonitrile dropwise through a constant pressure dropping funnel to make the system temperature between 0-30°C. ℃. After the dropwise addition, 6.53 g of triethylsilane was added to equilibrate the temperature to 15-25°C.

[0108](3) Add the compound solution of structural formula 4 prepared in step 1) dropwise through a constant pressure dropping funnel, and stir for 1 to 2 hours after the addition, and control the temperature at 15 to 25° C. in this step.

[0109] (4) When HPLC shows that the compound of structural formula 4 remains less ...

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Abstract

The invention relates to a preparation method of an empagliflozin intermediate with a structural formula 4, which comprises the following steps of by using a compound with a structural formula 1 as astarting raw material, dissolving the compound with the structural formula 1 in 2-methyl tetrahydrofuran, adding 10% of the compound with the structural formula 1 under the protection of inert gas, and adding magnesium chips and lithium chloride, initiating a reaction by using a small amount of iodine at 40-50 DEG C, then adding the rest of the compound shown in the structural formula 1, and afterthe addition is finished, carrying out heat preservation reaction until the reaction is complete, then reacting with a glucolactone derivative with a structural formula 6 at -10 to 0 DEG C, finally,dropwise adding a hydrogen chloride-methanol solution, and reacting at 10-20 DEG C until the reaction is complete, and finally, adding triethylamine into the reaction solution to adjust the pH value to 7-8, thereby obtaining the compound with the structural formula 4. According to the method, low-temperature reaction in the prior art is avoided, and the prepared compound with the structural formula 4 is low in impurity content.

Description

technical field [0001] The invention belongs to the field of organic chemistry, and in particular relates to a preparation method of a key intermediate of Empagliflozin. Background technique [0002] Empagliflozin, the chemical name is 1-chloro-4-(β-D-glucopyranose-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl] -Benzene, structural formula as shown in I, is developed by Boehringer Ingelheim Company of Germany. Empagliflozin is a sodium-glucose co-transporter 2 (sodium-glucose co-transporter 2, SGLT-2) inhibitor, mainly by inhibiting the expression of SGLT-2 in the kidney, reducing the reabsorption of glucose in the kidney and increasing the amount of glucose in the urine. Excretion of glucose, thereby reducing plasma glucose levels. The hypoglycemic effect of Empagliflozin is not dependent on β-cell function and insulin resistance, and it is a new type of non-insulin-dependent hypoglycemic drug. It was first approved for marketing in Europe on May 3, 2014, for the treat...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D407/12
CPCC07D407/12Y02P20/55
Inventor 李晓朋邱红雨毕文博陈秋实傅彦评蔡瑜姜鹏冷春生
Owner TONGHUA DONGBAO PHARMA