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Method for continuously synthesizing benzyl-substituted glucolactone by adopting microchannel reaction device

A technology of gluconolactone and microchannel reaction, which is applied in the direction of organic chemistry, can solve the problems of difficult purification of reaction products, complex reaction conditions, cumbersome post-processing, etc., and achieve simple and convenient post-processing, simple synthesis process, and short reaction time Effect

Active Publication Date: 2021-06-15
安庆奇创药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0007] Purpose of the invention: In view of the deficiencies in the existing synthesis of dapagliflozin intermediates, provide a method for continuously synthesizing the benzyl-substituted gluconolactone intermediate of the hypoglycemic drug Dapagliflozin using a microchannel reaction device. With the help of a new microchannel reaction device, Through unification of solvent, on-line post-processing, coordination of flow field parameters, etc., to solve the existing problems of high cost, complicated reaction conditions, long reaction time, cumbersome post-processing, difficult purification of reaction products, low purity and other problems in the prior art, thus Realize continuous flow preparation, improve reaction efficiency, and further realize industrial production

Method used

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  • Method for continuously synthesizing benzyl-substituted glucolactone by adopting microchannel reaction device
  • Method for continuously synthesizing benzyl-substituted glucolactone by adopting microchannel reaction device
  • Method for continuously synthesizing benzyl-substituted glucolactone by adopting microchannel reaction device

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] (1) In the microchannel reaction device, the tetrahydrofuran solution (50mL) of methyl-α-D-mannopyranoside (0.025mol) and the tetrahydrofuran solution (50mL) of benzyl chloride (0.125mol) are respectively pumped from pump A1, Pump B2, pumping into the first microstructure mixer 3, the flow rate of pump A1 is 0.25mL / min, and the flow rate of pump B2 is 1.25mL / min. Enter the first microreactor 4 after fully mixing, the volume of the first microreactor 4 is 25mL, and the reaction residence time is 20min. The reaction temperature was 55°C, and the yield was 93.2%.

[0045] (2) Along with the reaction liquid that step (1) obtains flows into the second microstructure mixer, the tetrahydrofuran solution (25mL) of hydrochloric acid (0.025mol) is pumped into the second Microstructure mixer 6, pump C5 flow rate is 0.39mL / min; After fully mixing, pump into the second microreactor 7 in the second section of continuous microchannel reaction device to react, the second microreactor ...

Embodiment 2

[0053] The operation is the same as in Example 1, the only difference is:

[0054] (1) In step (1), the flow rate of pump A 1 is 0.21 mL / min, and the flow rate of pump B 2 is 1.11 mL / min. The volume of the first microreactor 4 is 20mL, and the reaction residence time is 18min. The reaction temperature was 50°C, and the yield was 86.2%.

[0055] (2) The flow rate of the pump C5 is 0.31 mL / min, the volume of the second microreactor 7 is 20 mL, the residence time is 12 min, the heating temperature is 0° C., and the yield is 84.9%.

[0056](3) The flow velocity of the pump D8 is 0.675mL / min, the flow velocity of the pump E9 is 0.04mL / min, the volume of the third microreactor 11 is 20mL, the reaction temperature is 50° C., the residence time is 9min, and the productive rate is 81.8%. , with a purity of 97.5%.

Embodiment 3

[0058] The operation is the same as in Example 1, the only difference is:

[0059] (1) In step (1), the flow rate of pump A1 is 0.29mL / min, and the flow rate of pump B2 is 1.53mL / min. The volume of the first microreactor 4 is 30mL, and the reaction residence time is 22min. The reaction temperature was 75°C, and the yield was 87.5%.

[0060] (2) The flow rate of the pump C5 is 0.42mL / min, the volume of the second microreactor 7 is 30mL, the residence time is 16min, the heating temperature is 25° C., and the yield is 85.8%.

[0061] (3) The flow velocity of pump D8 is 0.70mL / min, the flow velocity of pump E9 is 0.105mL / min, the volume of the third microreactor 11 is 30mL, reaction temperature is 75 ℃, residence time is 14min, productive rate is 82.4% , with a purity of 96.8%.

[0062] This application is based on the difficulty of synthesizing the intermediate benzyl gluconolactone through the above-mentioned traditional route. Through the study of reaction kinetics and the i...

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Abstract

The invention discloses a method for continuously synthesizing benzyl-substituted glucolactone by adopting a microchannel reaction device. The method comprises the following steps: taking methyl-alpha-D-mannopyranoside as an initial raw material, preparing the methyl-alpha-D-mannopyranoside into an old organic solvent solution, and reacting the old organic solvent solution with an organic solvent solution of benzyl chloride in a first microreactor to generate methyl glucose with hydroxyl protected by benzyl; reacting a homogeneous solution formed by mixing a reaction solution of benzyl-substituted gluconic acid and a small amount of hydrochloric acid solution in a second microreactor for demethylation to generate hydroxyl benzyl-substituted glucose; and finally, reacting the reaction solution with an aqueous solution of hydrogen peroxide and sodium hydroxide and an organic solvent solution of tetramethylpiperidine nitrogen oxide in a third microreactor to generate the high-purity hypoglycemic drug Dapagliflozin intermediate benzyl substituted glucolactone. The method disclosed by the invention is higher in heat and mass transfer efficiency and easier to industrially amplify, the initial materials are simple, cheap and easily available, the process is simple, the obtained intermediate is high in purity and high in yield, the production cost can be effectively reduced, and the method is suitable for industrial production.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry and continuous flow, and in particular relates to a method for continuously synthesizing the benzyl-substituted gluconolactone of the hypoglycemic drug Dapagliflozin intermediate by using a microchannel reaction device. Background technique [0002] In recent years, diabetes has posed a serious threat to us, and SGLT2 inhibitors lead us to the root of diabetes, using the inhibition of glucose reabsorption in renal tubules as the target, can continuously and stably lower blood sugar in patients, and open up a new era A new chapter in the history of diabetes treatment. [0003] Dapagliflozin is the first pharmaceutically important sodium-dependent glucose transporter (SGLT2) inhibitor jointly developed by Bristol-Myers Squibb of the United States and AstraZeneca of Sweden. It is currently the first choice for the treatment of type 2 diabetes drug. As a representative drug of SGLT2 inhibitor, Dap...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D309/30
CPCC07D309/30
Inventor 吴学平时珠勇
Owner 安庆奇创药业有限公司
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