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Method for preparing Invokana medicine intermediate by using micro-reactor

A micro-reactor and micro-reaction technology, which is applied in chemical instruments and methods, chemical/physical/physical chemical reactors, preparation of sugar derivatives, etc., to achieve high safety performance, shorten reaction time, and improve reaction efficiency

Active Publication Date: 2014-12-31
SHANGHAI FANGNAN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] The technical problem to be solved by this invention is to provide a kind of method that utilizes micro-reactor to prepare the intermediate I of phenazine drug, to overcome the various defects existing in the existing preparation method

Method used

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  • Method for preparing Invokana medicine intermediate by using micro-reactor
  • Method for preparing Invokana medicine intermediate by using micro-reactor
  • Method for preparing Invokana medicine intermediate by using micro-reactor

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0027] Example 1 Dapagliflozin Intermediate Ia--(3R,4S,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(hydroxymethyl) - Synthesis of 2-methoxytetrahydro-2H-pyran-3,4,5-triol.

[0028]

[0029] method 1

[0030] Prepare 163mL (163g, 0.5mol) of the ether solution of 4-bromo-1-chloro-2-(4-ethoxybenzyl)benzene of 1g / mL, feed the above ether solution into material channel A, and control the flow rate to be 0.1 mL / min. At the same time, a total of 200 mL of 2.5M n-butyllithium solution was passed into the material channel B, and the flow rate was controlled to be 0.12 mL / min, wherein the preset temperature T1 of the micro-reaction unit L was -80~-75°C. Then, 0.5 g / mL of (3R,4S,5R,6R)-3,4,5-tris(trimethylsiloxy)-6-((trimethylsiloxy) was passed into material channel C The ether solution of methyl) tetrahydro-2H-pyran-2-one 514mL (257g, 0.55mol), the control flow rate is 0.3mL / min, wherein the preset temperature T2 of the micro reaction unit H is -80~-70 ℃ . After the completio...

example 2

[0035] Example 2 Canagliflozin Intermediate Ib--(3R,4S,5R,6R)-6-(acetylmethyl)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl) )Methyl)-4-methylphenyl)-2-tetrahydro-2H-pyran-3,4,5-triacetate synthesis.

[0036]

[0037] Prepare 2040mL (204g, 0.5mol) of a toluene solution of 2-(2-methyl-5-iodobenzyl)-5-(4-fluorophenyl)thiophene at 0.1g / mL, and feed the above into material channel A Toluene solution, control flow rate 2mL / min. At the same time, a total of 250 mL of 2M isopropyl Grignard reagent and lithium chloride solution (the molar ratio of Grignard reagent and lithium chloride is 1:1) was passed into the material channel B, and the control flow rate was 0.23 mL / min. The preset temperature T1 of L is -10~0℃. Then, 0.2 g / mL of (2R,3R,4S,5R)-2-(acetoxymethyl)-6-carbonyltetrahydro-2H-pyran-3,4,5-tris was passed into material channel C The tetrahydrofuran solution of acetate was 952 mL (190 g, 0.55 mol), and the flow rate was controlled to be 0.9 mL / min, and the preset temperature ...

example 3

[0039] Example 3 Canagliflozin Intermediate Ic--(3R,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)-2-(3-(( Synthesis of 5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)tetrahydro-2H-pyran-2-oxane.

[0040]

[0041] Prepare 2040mL (204g, 0.5mol) of a toluene solution of 2-(2-methyl-5-iodobenzyl)-5-(4-fluorophenyl)thiophene at 0.1g / mL, and feed the above into material channel A Toluene solution, control speed 2mL / min. At the same time, a total of 250 mL of 2M ethyl Grignard reagent and lithium chloride solution (the molar ratio of Grignard reagent to lithium chloride is 1:1.2) was passed into channel B, and the flow rate was controlled to 0.23 mL / min. The temperature T1 is -10 to 0°C. Then 0.2 g / mL of (3R,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)tetrahydro-2H-pyridine was passed into feed channel C 1480 mL (296 g, 0.55 mol) of the tetrahydrofuran solution of furan-2-one, the flow rate was controlled to be 1.4 mL / min, and the preset temperature T2 of t...

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Abstract

The invention discloses a method for preparing an Invokana medicine intermediate by using a micro-reactor, which is characterized in that a compound III dissolved in an organic solvent and an organometallic reagent respectively passes through a material channel and are mixed in a micro-reactor unit (L), and passes through (L) and flow to the micro-reactor unit (H); a compound II dissolved in the organic solvent passes through the material channel and then is mixed with the above mixed liquor in the micro-reactor unit (H) at preset temperature, then a mixture passes through the micro-reactor unit (H), flow out from an outlet after a reaction is completed, a reaction solution is subjected to post treatment to obtain the target compound-Invokana medicine intermediate I. According to the invention, the Invokana medicine intermediate (I) is synthesized by the micro-reactor, so that heat transfer problem of the reactions can be effectively solved, the reaction objects in the micro-reactor can be fully mixed, reaction time is shortened, reaction efficiency is increased, almost no amplification effect is generated on the micro-reactor, the method has high safety performance, and is suitable for industrial production.

Description

technical field [0001] The present invention relates to a kind of method that utilizes microreactor to prepare Liejing class medicine intermediate, is specifically related to a kind of method utilizing such as figure 1 The microreactors shown were used to prepare new anti-type II diabetes drugs--Dapagliflozin, Canagliflozin and (1S)-1,5-anhydro-1-C-[4-chloro-3 -[[4-[[(3S)-tetrahydro-3-furanyl]oxy]phenyl]methyl]phenyl]-D-glucitol (Empagliflozin) and other methods for the intermediate I of the class of drugs. Background technique [0002] Sodium-glucose cotransporter 2 (SGLT2) is a recently discovered new target for diabetes treatment. The use of SGLT2 inhibitors is beneficial for glycemic regulation in patients with type 2 diabetes and provides a novel mechanism to ameliorate diabetes and its complications by excreting excess glucose. At present, many pharmaceutical companies and R&D institutions around the world are increasing their investment and actively developing SGLT2...

Claims

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Application Information

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IPC IPC(8): C07H15/04C07H1/00B01J19/00
CPCC07H1/00B01J19/0093B01J2219/00792B01J2219/00867B01J2219/00873B01J2219/00889B01J2219/00894B01J2219/00961C07D309/10C07D407/12C07D409/10C07H7/04C07H15/04
Inventor 郑勤龙
Owner SHANGHAI FANGNAN PHARMA
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