Preparation method of SGLT2 inhibitor intermediate

A technology of inhibitors and intermediates, which is applied in the field of preparation of SGLT2 inhibitor intermediates, can solve the problems of unsuitability for industrial application and production, more time required, and small reactor volume, etc., and achieve easy recycling, simple treatment, The effect of high purity

Pending Publication Date: 2021-08-03
ASTATECH CHENGDU BIOPHARM CORP
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

In the above-mentioned patent, the condition of reacting at room temperature for 12 hours was adopted, which resulted in too long reaction time and was not suitable for industrial application and production.
However, if the Claisen rearrangement reaction is carried out under high temperature conditions, there are also the following disadvantages: it generally takes 1 to 2 hours to rise from room temperature to 200 degrees Celsius in the reactor, and more time is required to cool down.
[0009] However, although continuous flow reaction has the advantages of small reactor volume, large specific surface area, high heat exchange efficiency, easy and precise control of reaction temperature and material ratio compared with traditional tank reaction, not all reactions can be carried out with continuous flow Optimization, continuous flow reaction requires precise control, and various factors such as material volume, reaction temperature, time, etc. will affect the reaction result. Therefore, there are still difficulties when the conventional tank reaction is applied to the continuous flow reaction
At present, the use of continuous flow reaction technology for Claisen rearrangement has not been reported

Method used

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  • Preparation method of SGLT2 inhibitor intermediate
  • Preparation method of SGLT2 inhibitor intermediate
  • Preparation method of SGLT2 inhibitor intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] 1) Preparation of raw material solution: Stir and mix 500g (1.636mol) of methyl 3-(allyloxy)-5-bromo-2-chlorobenzoate and 250g of diphenyl ether, and connect to metering pump P1;

[0034] 2) Set the continuous flow reactor I, the circulation temperature is 220°C, and reach stability; set the continuous flow reactor II, the circulation temperature is 40°C, and reach stability.

[0035] 3) Add 1500 g of n-heptane into the collection kettle, and install a mechanical stirring device.

[0036] 4) Set the flow rate of metering pump P1 to 50.0ml / min, turn on metering pump P1, run in reactor I for 5 minutes, and run in reactor II for 10 minutes, then collect the reaction solution.

[0037] 5) After pumping all the raw materials, the collected reaction solution was cooled to 5 degrees Celsius, stirred for 1 hour, filtered, and dried to obtain 475 g of the target product, with a yield of 95% and an HPLC of 98%.

Embodiment 2

[0039] 1) Preparation of raw material solution: Stir and mix 500g (1.636mol) of methyl 3-(allyloxy)-5-bromo-2-chlorobenzoate and 250g of simethicone oil, and connect to metering pump P1;

[0040] 2) Set the continuous flow reactor I, the circulation temperature is 220°C, and reach stability; set the continuous flow reactor II, the circulation temperature is 40°C, and reach stability.

[0041] 3) Add 1500 g of n-heptane into the receiving container, and install a mechanical stirring device.

[0042] 4) Set the flow rate of metering pump P1 to 50.0ml / min, turn on metering pump P1, run in reactor I for 5 minutes, and run in reactor II for 10 minutes, then collect the reaction solution.

[0043] 5) After pumping all the raw materials, the collected reaction solution was cooled to 5 degrees Celsius, stirred for 1 hour, filtered, and dried to obtain 465 g of the target product, with a yield of 93% and an HPLC of 98%.

Embodiment 3

[0045] 1) Preparation of raw material liquid: Stir and mix 500g (1.636mol) of methyl 3-(allyloxy)-5-bromo-2-chlorobenzoate and 250g of paraffin oil, and connect to metering pump P1;

[0046] 2) Set the continuous flow reactor I, the circulation temperature is 220°C, and reach stability; set the continuous flow reactor II, the circulation temperature is 40°C, and reach stability.

[0047]3) Add 1500 g of n-heptane into the receiving container, and install a mechanical stirring device.

[0048] 4) Set the flow rate of metering pump P1 to 50.0ml / min, turn on metering pump P1, run in reactor I for 5 minutes, and run in reactor II for 10 minutes, then collect the reaction solution.

[0049] 5) After pumping all the raw materials, cool the collected reaction solution to 5 degrees Celsius, stir for 1 hour, filter, and dry to obtain 480 g of the target product, with a yield of 96% and an HPLC of 98%.

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PUM

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Abstract

The invention provides a method for preparing an SGLT2 inhibitor intermediate through a continuous flow reaction. The SGLT2 inhibitor intermediate shown in the formula II is obtained by performing a a Claisen rearrangement reaction on 4-allyl-5-bromine-2-chloro-3-methyl hydroxybenzoate as a raw material for 5-20 minutes in a continuous flow tubular reactor I at the temperature of 180-250 DEG C, and then carrying out cooling, crystallization and filtering. The method for synthesizing the key intermediate of the SGLT2 inhibitor through the continuous flow reaction is stable and feasible in process, low in cost, high in yield, high in reaction rate, simple and convenient to operate, safe and environment-friendly, and has a huge practical value in the aspect of improving the production efficiency.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis, and in particular relates to a preparation method of an SGLT2 inhibitor intermediate. Background technique [0002] Co., Ltd. Green Cross and Korea Daewoo Pharmaceutical have reported methods for preparing diphenylmethane derivatives in patents CN109311861A and CN103596564B. The diphenylmethane derivatives can be effectively used as sodium-dependent glucose cotransporters ( SGLT2) inhibitors for the prevention or treatment of metabolic diseases, especially diabetes. [0003] Among the 243 diphenylmethane derivatives reported, the E172 compound: (2S,3R,4R,5S,6R)-2-(7-chloro-6-(4-cyclopropylbenzyl)-2 , 3-dihydrobenzofuran-4-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol, in the test of inhibiting human SGLT2 activity, IC50 is only 0.463nM, with good specificity. Compared with other diphenylmethane derivatives with the same efficacy, such as E110, E098, E113, E114, etc., it has no...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C69/88C07C67/333
CPCC07C67/333C07C69/88
Inventor 郭安勇王银胡林强张华东周家焱郭鹏
Owner ASTATECH CHENGDU BIOPHARM CORP
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