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Eutectic preparation method of sodium-glucose cotransporter 2 bulk pharmaceutical chemicals

A technology for glucose and raw materials, which is applied in the field of co-crystal preparation of sodium-glucose cooperating protein-2 raw materials, can solve the problems of low yield of the main product in beta configuration, many reaction steps, and high demethoxylation conditions. It achieves the effects of simple and economical demethoxyl conditions and reagents, shortened reaction steps and high selectivity

Inactive Publication Date: 2011-08-31
SHANGHAI HUISI BIOTECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] The purpose of the present invention is to improve a co-crystal preparation method of a sodium-glucose cooperating protein-2 raw material drug, which mainly solves the problem that the existing preparation method has many reaction steps, high demethoxylation conditions, and low yield of the main product in the beta configuration. technical issues

Method used

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  • Eutectic preparation method of sodium-glucose cotransporter 2 bulk pharmaceutical chemicals
  • Eutectic preparation method of sodium-glucose cotransporter 2 bulk pharmaceutical chemicals
  • Eutectic preparation method of sodium-glucose cotransporter 2 bulk pharmaceutical chemicals

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0020] Add 4 grams of N-3, 50 milliliters of methanol, and 5 milliliters of water into a 250 milliliter three-necked flask, and raise the temperature to 70° C. under stirring to make the suspension gradually transparent. Add 5 g of L-proline and continue stirring for 2 h. Sodium cyanoborohydride was added in batches until all reactions of N-3 were detected by HPLC, and hydrochloric acid was added to adjust the pH value to 7. Then the temperature was lowered and stirred overnight, and a precipitate was precipitated. Filtrate, beat with n-hexane, and dry the solid in vacuum for 24 hours to obtain 5 g of the final product as a white solid (purity 99.62%, yield 85%). 1H NMR (400MHz, DMSO), d12.05 (s, 2H), 7.34 (d, 1H, J=6Hz), 7.32 (m, 2H), 7.08 (d, 2H, J=8.6Hz), 6.78 (d , 2H, J=8.8Hz), 4.10-3.83 (m, 8H), 3.69-3.60 (m, 3H), 3.30 (m, 4H), 3.05 (b, 2H), 2.82 (m, 4H), 1.90- 1.55 (m, 8H), 1.34 (t, 3H, J=7Hz).

Embodiment 2

[0022] In a 250 ml three-neck flask, add 4.4 g of N-3, 60 ml of ethanol, and 6 ml of water, and raise the temperature to 80° C. under stirring to make the suspension gradually transparent. Add 5.5 g of L-proline and continue stirring for 2 h. Sodium acetate borohydride was added in batches until all reactions of N-3 were detected by HPLC, and hydrochloric acid was added to adjust the pH value to 7. Then the temperature was lowered and stirred overnight, and a precipitate was precipitated. After filtration, it was slurried with n-hexane, and the solid was vacuum-dried for 24 hours to obtain 5.8 g of a white solid final product (purity 99.36%, yield 89%).

Embodiment 3

[0024] In a 100 ml three-necked flask, add 2.2 g of N-3, 30 ml of ethanol, and 3 ml of water, and raise the temperature to 80° C. under stirring, so that the suspension becomes gradually transparent. Add 3.4 g of L-tryptophan and continue stirring for 2 h. Sodium cyanoborohydride was added in batches until all reactions of N-3 were detected by HPLC, and hydrochloric acid was added to adjust the pH value to 7. Then the temperature was lowered and stirred overnight, and a precipitate was precipitated. After filtration, it was slurried with n-hexane, and the solid was vacuum-dried for 24 hours to obtain 3.6 g of a white solid final product (purity 99.45%, yield 88%). 1H NMR (400MHz, DMSO), 12.45 (s, 2H), 10.53(s, 2H), 8.33(m, 4H), 7.60 (d, 2H, J=5.5Hz), 7.30-7.06(m, 13H), 6.78 (d, 2H, J=8.8Hz), 4.14-3.90 (m, 9H), 3.85-3.65 (m, 2H), 3.42-3.06 (m, 8H), 1.43(t, 3H, J=6.8Hz) .

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Abstract

The invention relates to a preparation method of bulk pharmaceutical chemicals used for curing the type 2 diabete, in particular to a eutectic preparation method of sodium-glucose cotransporter 2 bulk pharmaceutical chemicals. In the invention, the technical problems of the existing preparation method that reaction steps are more, the methoxy-removing condition is strict and the yield of the obtained main product with beta configuration is low are solved. The technical scheme in the invention is as follows: the eutectic preparation comprises the following steps: adding chiral component (X) inN-3((3R,4S,5S,6R)-2-(4-chloro-3-(4-ethoxylbenzyl)phenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol, performing selective complexation with reductant to remove methoxy, then reducing the temperature to perform eutectic preparation, and adopting the one-pot method to obtain dapagliflozin-X. The eutectic preparation method is mainly used to prepare the sodium-glucose cotransporter 2bulk pharmaceutical chemicals.

Description

technical field [0001] The invention relates to a preparation method of a raw material drug for treating type II diabetes, in particular to a method for preparing a co-crystal of a sodium-glucose cooperating protein-2 raw material drug. Background technique [0002] Type 2 diabetes is a chronic progressive disease characterized by dysfunction of the beta cells of the pancreas, resulting in reduced insulin secretion and elevated glucose levels. Over time, this persistent polysaccharide triggers worsening insulin resistance and further beta cell dysfunction. Many people with type 2 diabetes have co-morbidities, such as obesity and high blood pressure. About half of the treated patients are not well controlled by the current hypoglycemic therapy, and the number of patients whose multiple parameters have been controlled is even less. The market demand is huge and has not yet been met. In the past, treatment of type 2 diabetes has focused primarily on insulin-dependent mechanis...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H7/04C07H1/00C07D207/16C07D209/20C07C229/36C07C227/42
Inventor 卓碧钦邢溪娟
Owner SHANGHAI HUISI BIOTECH
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