Synthesis method of C-glycoside derivative

A synthesis method and a technology of derivatives, which are applied in the field of synthesis of C-glycoside derivatives, can solve the problems of unfavorable large-scale industrial production, boron trifluoride ether is flammable and explosive, and difficult to store, so as to avoid the growth of impurities, The effect of short quenching time and easy handling

Active Publication Date: 2021-08-13
BEIJING HUIZHIHENG BIOTECHNOLOGY CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] Patent ZL201410004395.2 discloses the compound represented by formula (I) and its synthesis process, but the process requires the use of boron trifluoride ether, which is flammable and explosive, difficult to store, and has serious safety hazards
Moreover, the reaction conditions involved in this patent will lead to difficult-to-remove isomer impurities and by-product impurities in the preparation process, requiring additional steps to further control the impurities, resulting in complex processes and high costs, which are not conducive to the application of large-scale industrial production

Method used

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  • Synthesis method of C-glycoside derivative
  • Synthesis method of C-glycoside derivative
  • Synthesis method of C-glycoside derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0049] This example is used to illustrate the method of synthesizing and purifying the compound of formula (I) starting from the compound of formula (II), and further synthesizing the L-proline co-crystal complex of the compound of formula (I).

[0050] 1. Under the protection of nitrogen, add dichloromethane (364.1 kg) into a 500 L cryogenic reaction kettle, start stirring, and add triethylsilane (20.3 kg) and compound of formula (II) (28.1 kg). Cool down to -40°C. 20% boron trifluoride acetonitrile complex (69.1 kg) was added dropwise under temperature control for about 2 hours. After dropping, keep warm for 3 hours to synthesize the compound of formula (I).

[0051] 2. Add 5% sodium bicarbonate aqueous solution (313.73kg) into the 1000 L cryogenic reaction kettle. The feed liquid in the 500 L cryogenic reactor kept at -40°C was directly dropped into the 1000 L cryogenic reactor to quench the reaction (dropping for about 1 hour), and the temperature in the 1000 L cryogenic...

Embodiment 2

[0059] In this example, the content of impurity (X) in the L-proline eutectic complex of the compound of formula (I) prepared in Example 1 was detected by HPLC.

[0060] The detection method is as follows:

[0061] Reagent solution: diammonium hydrogen phosphate, phosphoric acid, methanol, acetonitrile, ultrapure water.

[0062] Instruments and equipment: electronic balance, high performance liquid chromatography, pH meter, centrifuge.

[0063] Chromatographic conditions: determined according to high-performance liquid chromatography (Chinese Pharmacopoeia 2020 Edition Sibu General Rules 0512), using octadecylsilane-bonded silica gel as a filler column (Agilent Eclipse XDB-C18, 150mm×4.6mm, 5μm); Mobile phase A is 0.01mol / L diammonium hydrogen phosphate solution (take 1.32g of diammonium hydrogen phosphate, add 1000mL of water to ultrasonically dissolve, adjust the pH value to 5.00±0.05 with phosphoric acid)-acetonitrile (90:10), mobile phase B is Water-acetonitrile (10:90);...

Embodiment 3

[0068] In this example, according to the synthesis method described in Example 1, three batches of samples were respectively prepared with different amounts of starting materials, and the samples were subjected to high-efficiency liquid phase detection, and the results are as follows:

[0069]

[0070] Experimental results prove that the synthetic method provided by the present invention has good repeatability.

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Abstract

The invention relates to the technical field of medicinal chemistry, and particularly discloses a synthesis method of a C-glycoside derivative. The method comprises the following steps: adding a compound shown in formula (II) and triethyl silane into dichloromethane, carrying out nitrogen protection, carrying out dry ice acetonitrile bath cooling to-35 DEG C to -45 DEG C, dropwise adding a 20% boron trifluoride acetonitrile complex, and carrying out heat preservation at -35 DEG C to -45 DEG C to carry out a synthesis reaction of the C-glycoside derivative shown in formula (I); and then, dropwise adding the reaction system into a sodium bicarbonate aqueous solution for quenching reaction; The quenching reaction mode in the existing synthesis process is improved, the reaction can be rapidly quenched, the quenching time is short, the operation is easy, and the problem of impurity III growth caused by reaction system temperature rise can be effectively avoided.

Description

technical field [0001] The invention relates to the technical field of medicinal chemistry, in particular to a method for synthesizing C-glycoside derivatives. Background technique [0002] Hyperglycemia is considered a major risk factor for the development of diabetic complications and may be directly related to impaired insulin secretion in advanced type II diabetes. Normalization of insulin can therefore be expected to improve blood glucose in type 2 diabetic patients. Most of the existing diabetes drugs are insulin secretory drugs or insulin sensitizers, such as sulfonylureas, glinides, thiazolidinediones, and metformin, which have potential side effects, such as easy to cause weight gain , hypoglycemia, lactic acidosis, etc. Therefore, there is an urgent need to develop novel, safe and effective antidiabetic drugs with a mechanism of action. [0003] In the kidney, glucose is freely filtered from the glomerulus (approximately 180 g / day), but is almost reabsorbed by ac...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D309/10C07D207/16
CPCC07D207/16C07D309/10
Inventor 曹海燕顾志强张洪强王田园安丰伟张世野
Owner BEIJING HUIZHIHENG BIOTECHNOLOGY CO LTD
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