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Preparation method of sodium-glucose cotransporter 2 inhibitor

A compound and halogen technology, applied in the field of preparation of sodium-glucose cotransporter 2 inhibitors and their derivatives, can solve the problems of complex compound structure, long synthetic route, and great influence on process yield

Active Publication Date: 2018-02-13
JIANGSU HENGRUI MEDICINE CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] This type of compound has a complex structure and a long synthetic route, especially the method related to the structure of the five-membered heterocyclic ring and the removal of hydroxyl protection have a greater impact on the yield of the entire process

Method used

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  • Preparation method of sodium-glucose cotransporter 2 inhibitor
  • Preparation method of sodium-glucose cotransporter 2 inhibitor
  • Preparation method of sodium-glucose cotransporter 2 inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0051] Example 1: Compound III-1 was obtained by reaction under paraformaldehyde / potassium hydroxide conditions

[0052]

[0053] 10 g of compound IV-1, 56.5 g of 1, 4-dioxane was put into the reaction bottle, stirred and dissolved. Add 2.6g of paraformaldehyde and 3.9g of potassium hydroxide in turn under the protection of argon. After the addition is complete, raise the temperature to 20-30°C and keep it for 30 minutes, then raise the temperature to 50-55°C and keep it for 2 hours. Cool down to room temperature, filter, and concentrate the filtrate to dryness under reduced pressure, add 30g of purified water and 40g of dichloromethane, extract and separate the organic phase, wash with saturated brine (24g×2), separate layers, concentrate the organic layer under reduced pressure, and use Separation and purification on a silica gel column (eluent: petroleum ether / dichloromethane) gave compound III-1 as an oil, which was slurried by adding isopropyl ether to get 5.8 g of com...

Embodiment 2

[0054] Embodiment 2: "one pot method" synthetic compound I-1

[0055]

[0056] In the reaction bottle, put 50g of compound III-1, 300mL of tetrahydrofuran and 250mL of methanol, stir to dissolve, control the temperature below 30°C, add 8.8mL of hydrochloric acid and 2.5g of 10% palladium carbon, and then add 50mL of methanol to rinse the palladium carbon. After the addition is completed, the hydrogen gas is replaced three times, and the hydrogen gas is passed under normal pressure, and the temperature is controlled at 30±5°C for 8 hours, and the sampling is started and controlled until the reaction ends in accordance with the regulations. Filter the reaction solution through diatomaceous earth, wash the filter cake with 150mL of tetrahydrofuran until the washing solution meets the requirements, adjust the pH of the filtrate to neutral with saturated sodium bicarbonate solution, concentrate under reduced pressure, add 320mL of ethyl acetate to dissolve, add Stir and extract ...

Embodiment 3

[0057] Embodiment 3: "one pot method" synthetic compound I-1

[0058] 50 g of compound III-1, 237.5 g of methanol, and 267.5 g of tetrahydrofuran were put into the reaction flask, stirred and dissolved. Then add 50 g of 1,2-dichlorobenzene, and stir evenly. Add 10% palladium on carbon (25g, W:W=50%), after the addition is complete, replace with hydrogen three times, and react with hydrogen at normal pressure and temperature for 8h, monitor by TLC until the raw material point disappears, and terminate the reaction. Filter, wash with tetrahydrofuran (100g×3), concentrate the filtrate to dryness, dissolve the residue with 500g ethyl acetate, wash with water (400g×3), separate layers, concentrate the organic layer to dryness, and separate and purify on a silica gel column (eluent: dichloromethane / methanol) to obtain 26 g of compound I-1 with a yield of 86.6% and a purity of 99.0%.

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Abstract

The invention discloses a preparation method of a sodium-glucose cotransporter 2 inhibitor. The preparation method specifically relates to a reaction step for converting a compound of a formula III into a compound of a formula II by a 'one-pot method' in a palladium carbon / acid or 1,2-dichlorobenzene catalytic system, wherein the definition of each substituent in the formula II and the formula IIIare the same as that in the description. The method has simple operation and low cost, and is suitable for large-scale production.

Description

technical field [0001] The invention relates to a preparation method of sodium-glucose co-transporter 2 (SGLT-2) inhibitor and derivatives thereof. Background technique [0002] In recent years, in-depth research on the pathogenesis of diabetes has provided more and more ways for the treatment of type II diabetes. The discovery of sodium-glucose transporter 2 (SGLT-2) inhibitors provides another new idea for the treatment of diabetes. The function of SGLT-2 is to transport glucose. The therapeutic mechanism of SGLT-2 inhibitors is to lower blood sugar by selectively inhibiting the activity of SGLT-2. SGLT-2 was chosen as the target, on the one hand because of its absolute reabsorption of glucose, and on the other hand because it is only expressed in the kidney. Since SGLT-2 inhibitors do not intervene in glucose metabolism, this treatment is a novel approach to glycemic control. The current study also found that the mechanism of action of SGLT-2 does not depend on the ab...

Claims

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Application Information

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IPC IPC(8): C07H15/18C07H7/04C07H1/00C07D493/08
CPCC07D493/08C07H1/00C07H7/04C07H15/18Y02P20/55
Inventor 武乖利邱振均边林卢韵
Owner JIANGSU HENGRUI MEDICINE CO LTD
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