Method for continuously preparing canagliflozin by using microreactor one-pot method

A micro-reactor, canagliflozin technology, applied in the field of medicine, can solve the problems of large reaction risk factor, harsh operation requirements, hidden safety hazards, etc., achieve continuity and automation, reduce the generation of by-products, fully mixed Effect

Active Publication Date: 2017-06-20
山东安信制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The advantage of this route is that the reaction is simple and the idea of ​​constructing the skeleton is ingenious; the disadvantage is that the Grignard reagent needs to be self-made, and the use of butyllithium requires low temperature, which requires harsh operation and a high risk factor for the reaction.
[0022] The above several routes all have their own advantages, bu

Method used

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  • Method for continuously preparing canagliflozin by using microreactor one-pot method
  • Method for continuously preparing canagliflozin by using microreactor one-pot method
  • Method for continuously preparing canagliflozin by using microreactor one-pot method

Examples

Experimental program
Comparison scheme
Effect test

Example Embodiment

[0048] Example 1

[0049] Prepare 500ml 85g / L of the toluene solution of the main raw material M1 in a 1L three-necked flask, and flow it into the A unit of the microreactor at a flow rate of 100ml / min. In addition, the concentration of 1.8mol / L n-butyllithium at 20ml / min The flow rate flows into the A unit of the microreactor at the same time. The residence time of the reaction is 8.0 seconds, and the reaction temperature is controlled at -18℃. After the reaction liquid flows out of the A unit of the microreactor, the configured 320g / L M3 material The liquid flows into the B unit of the microreactor at the same time at a flow rate of 60 ml / min. The residence time of the reaction unit is 23.3 seconds, and the reaction temperature controlled by the reaction unit is -5°C.

[0050] Add 300ml of methanol and 100ml of methanesulfonic acid into a 500ml three-necked flask, stir and mix, and then lower to room temperature. After the reaction feed liquid flows out of the B unit of the micro...

Example Embodiment

[0052] Example 2

[0053] Prepare 500ml 85g / L toluene solution of the main raw material M1 in a 1L three-necked flask, and flow it into the A unit of the microreactor at a flow rate of 110ml / min. In addition, the concentration of 1.8mol / L n-butyllithium at 20ml / min The flow rate flows into unit A at the same time, the residence time of the reaction is 7.4 seconds, and the reaction temperature is controlled at -18°C. After the reaction solution flows out of unit A, the configured 320g / L M3 feed solution flows into unit B at a flow rate of 60ml / min at the same time. The residence time of the reaction unit is 22.1 seconds, and the reaction temperature controlled by the reaction unit is- 5°C.

[0054] Add 300ml of methanol and 100ml of methanesulfonic acid into a 500ml three-necked flask, stir and mix, and then lower to room temperature. After the reaction material flows out of unit B, the methanol solution of methanesulfonic acid will flow into C at a flow rate of 20ml / min. In the u...

Example Embodiment

[0056] Example 3

[0057] Prepare 500ml 85g / L of the toluene solution of the main raw material M1 in a 1L three-necked flask, and flow it into Unit A at a flow rate of 100ml / min, and flow into Unit A with a concentration of 1.8mol / L n-butyl lithium at a flow rate of 20ml / min. In the unit, the residence time of the reaction is 8 seconds, and the reaction temperature is controlled at -23°C. After the reaction liquid flows out of the A unit, the configured 320g / L M3 feed solution flows into the B unit at a flow rate of 60ml / min. The residence time of the reaction unit is 23 seconds, and the reaction temperature controlled by the reaction unit is -7°C.

[0058] Add 300ml of methanol and 100ml of methanesulfonic acid into a 500ml three-necked flask, stir and mix, and then lower to room temperature. After the reaction material flows out of unit B, the methanol solution of methanesulfonic acid will flow into C at a flow rate of 20ml / min. In the unit, the residence time of the reaction un...

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Abstract

The invention discloses a method for continuously preparing canagliflozin by using a microreactor one-pot method. The method is used for continuously preparing the canagliflozin by using the microreactor one-pot method, and microreactors are divided into a unit A, a unit B, a unit C and a unit D. The method comprises the steps of mixing a solution of M1 with n-butyl lithium in the unit A for carrying out a reaction; after the reaction is finished, enabling the reaction product to enter the unit B together with a solution of M3, and carrying out a reaction at the temperature of -15 to -5 DEG C to obtain an intermediate A; enabling reaction liquid containing the intermediate A to enter the unit C together with a methanol solution of methane sulfonic acid, and carrying out a reaction to obtain an intermediate B; enabling reaction liquid containing the intermediate B to directly react with boron trifluoride and triethyl silicane in the unit D to obtain the canagliflozin. The method greatly simplifies the operation steps, shortens the reaction time, greatly reduces the use of various solvents, lowers the production cost, improves the production safety, can realize continuous and automatic production, and is high in product purity and yield, thus being suitable for industrial production.

Description

technical field [0001] The invention relates to a method for preparing canagliflozin by using a microreactor one-pot continuous flow method, which belongs to the technical field of medicine. Background technique [0002] Canagliflozin, also known as canagliflozin, Chinese chemical name: (1S)-1,5-dehydro-1-{3-[(5-(4-fluorophenyl)-2-thienyl)methyl base]-4-methylphenyl}-D-glucitol, the structural formula is as follows: [0003] [0004] Canagliflozin is a novel SGLT-2 inhibitor for the treatment of type 2 diabetes in adult patients. Jointly developed by Mitsubishi Tanabe Pharmaceuticals and Johnson & Johnson Pharmaceuticals. On March 29, 2013, the U.S. Food and Drug Administration (FDA) approved canagliflozin for improving blood sugar control in adults with type II diabetes. This product is the first SGLT-2 inhibitor approved by the FDA. In November 2013 On March 25, it was approved by the European Commission (EC) for the treatment of adults with type 2 diabetes to improv...

Claims

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Application Information

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IPC IPC(8): C07D409/10
CPCY02P20/55C07D409/10
Inventor 常宝磊李德才陈中南周先国董廷华张兆珍吴柯李保勇
Owner 山东安信制药有限公司
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