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Method for preparing sodium-glucose co-transport enzyme inhibitor intermediate through utilization of micro-reactor

A kind of technology of microreactor and glucose is applied in the field of intermediate I preparing antidiabetic drug Sotagliflozin, and achieves the effect of reducing loss, shortening production time and improving reaction yield

Inactive Publication Date: 2017-01-04
CHANGZHOU FANGNAN MEDICINE TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] The technical problem to be solved by the present invention is to provide a method for preparing sodium-glucose cotransportase inhibitor intermediate I using a microreactor to overcome various defects in the existing preparation methods

Method used

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  • Method for preparing sodium-glucose co-transport enzyme inhibitor intermediate through utilization of micro-reactor
  • Method for preparing sodium-glucose co-transport enzyme inhibitor intermediate through utilization of micro-reactor
  • Method for preparing sodium-glucose co-transport enzyme inhibitor intermediate through utilization of micro-reactor

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034]

[0035] Compound IV (150.3 g, 0.55 mol) was dissolved in THF (150 mL), and 1.3 mol / L tert-butylmagnesium chloride solution (44.6 mL) was added dropwise at room temperature, and stirred for 30 minutes to form a THF solution of Compound IIa.

[0036] Prepare 163 ml (162.8 g, 0.5 mol) of 1 g / mL compound IIIa in tetrahydrofuran, and pass the above tetrahydrofuran solution into material channel A, and control the flow rate to 0.1 ml / min. At the same time, 200 milliliters of 2.5 mol / liter n-butyllithium solutions were passed into the material channel B, and the control flow rate was 0.12 milliliters / minute, wherein the preset temperature T1 of the micro-reaction unit L was minus 80 ~ minus 75 ° C . Subsequently, the tetrahydrofuran solution of the above-mentioned compound IIa is passed into the material channel C, and the flow rate is controlled at 0.3 ml / min, wherein the preset temperature T2 of the micro-reaction unit H is minus 80 ~ minus 70 ° C. After the reaction is...

Embodiment 2

[0038]

[0039] Prepare 932 ml (186.3 g, 0.5 mol) of THF solution of compound IIIb at 0.2 g / mL, and pass the above THF solution into material channel A, and control the flow rate at 1 ml / min. Simultaneously feed 250 milliliters of isopropyl lithium chloride magnesium chloride solution of 2 mol / liter in material passage B, control flow rate to be 0.25 milliliters / minute, wherein the preset temperature T1 of micro reaction unit L is 0~minus 5 ℃ . Subsequently, 693 milliliters (277 grams, 0.55 moles) of the 0.4 g / ml toluene solution of the above-mentioned compound IIb was passed into the material channel C, and the control flow rate was 0.4 ml / min, wherein the preset temperature T2 of the micro-reaction unit H was 0~ 5°C. After the reaction is completed, pass the reaction liquid flowing out of outlet D into saturated ammonium chloride solution (1 liter), control the temperature at 15-25 °C, and when the system is completely passed through, stir for 1 hour, extract with toluen...

Embodiment 3

[0041]

[0042] Compound V (239.0 g, 0.55 mol) was dissolved in toluene (1500 ml), and thionyl chloride (77.3 g, 0.65 mol) was added dropwise at room temperature, stirred at 60-65 °C for 2 hours, and concentrated under reduced pressure to The total volume was 650 mL, resulting in a solution of compound IIc in toluene.

[0043] Prepare 932 ml (186.3 g, 0.5 mol) of THF solution of compound IIIc at 0.2 g / mL, and pass the above THF solution into material channel A, and control the flow rate at 1 ml / min. Simultaneously feed 250 milliliters of isopropyl lithium chloride magnesium chloride solution of 2 mol / liter in material passage B, control flow rate to be 0.25 milliliters / minute, wherein the preset temperature T1 of micro reaction unit L is 0~minus 5 ℃ . Subsequently, 693 milliliters (277 grams, 0.55 moles) of the 0.4 g / ml toluene solution of the above-mentioned compound IIb was passed into the material channel C, and the control flow rate was 0.4 ml / min, wherein the preset t...

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Abstract

The invention discloses a method for preparing a sodium-glucose co-transport enzyme inhibitor intermediate through utilization of a micro-reactor. The method comprises: mixing a solution formed from a compound III and an organic solvent with a metal organic reagent in a micro-reactor unit (L) through material pipes, and allowing the mixed solution to flow to a micro-reactor unit (H) through (L); mixing a solution formed from a compound II and an organic solvent with the solution obtained in the first step in the micro-reactor unit (H) at a pre-set temperature (T2) through a material pipe, allowing the mixed solution to pass through the micro-reactor unit (H) and to flow out from an outlet after a reaction is over; post-treating the reaction liquid flowing out of the outlet to obtain a target product, which is sodium-glucose co-transport enzyme inhibitor intermediate I. The intermediate I is prepared through the micro-reactor, and the problem in heat release of such reaction is solved. The safety of the reaction is improved, the reaction yield is increased, the reaction time is shortened, and the reaction efficiency is improved. An amplification effect hardly exists in a micro-reactor, and therefore, compared with conventional batch-type technology, the method is more suitable for industrial production.

Description

technical field [0001] The present invention relates to a method for preparing a novel sodium-glucose cotransporter 2 (SGLT2) inhibitor intermediate using a microreactor, in particular to an intermediate for preparing an antidiabetic drug Sotagliflozin using a microreactor as shown in Figure 1 I method. Background technique [0002] Sodium-glucose cotransporter is a recently discovered new target for diabetes treatment. The use of SGLT2 inhibitors is beneficial to the regulation of blood sugar in patients with type 2 diabetes and provides a new mechanism to improve diabetes and its complications by excreting excess glucose. At present, many pharmaceutical companies and R&D institutions around the world are continuously increasing investment and actively developing SGLT2 inhibitors as new drugs for the treatment of diabetes. At present, several products have been launched, such as canagliflozin, dapagliflozin and empagliflozin . Sotagliflozin developed by Lexicon Pharmaceu...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D493/04C07H15/18
CPCY02P20/55C07D493/04C07H15/18
Inventor 张席妮熊志刚资春鹏
Owner CHANGZHOU FANGNAN MEDICINE TECH CO LTD
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