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A kind of synthetic method of the impurity of c-glycoside derivative

A synthesis method, a technology of derivatives, applied in the direction of organic chemistry, organic chemistry, etc.

Active Publication Date: 2021-10-29
BEIJING HUIZHIHENG BIOTECHNOLOGY CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, there is no research on the related impurities of the C-glycoside derivatives shown in the formula (V) in the above-mentioned ZL201410004395.2 patent, and the compound shown in the formula (I) of the present invention is the applicant's research on the above-mentioned C-glycoside derivatives. An impurity found

Method used

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  • A kind of synthetic method of the impurity of c-glycoside derivative
  • A kind of synthetic method of the impurity of c-glycoside derivative
  • A kind of synthetic method of the impurity of c-glycoside derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] This example is used to illustrate the method for synthesizing the compound shown in formula (I) starting from the compound shown in formula (II), including the following steps:

[0039] (1) Synthesis of intermediate 1

[0040] Compound (125 g, 216.6 mmol) represented by formula (II) and AlCl 3 (144 g, 1083.0 mmol) was dissolved in dichloromethane (2.5 L), and 1-dodecylmercaptan (218.8 g, 1083.0 mmol) was added dropwise at a temperature of 10-15°C. After dropping, the temperature was raised to 25°C to react for 6 hours. Cool down to 0°C and add water (2 L) dropwise to quench the reaction. Add dichloromethane (1 L*2) to extract twice, add anhydrous sodium sulfate to the organic phase, and spin dry. The remaining solid was slurried with n-hexane (3 L), filtered, and dried to obtain intermediate 1 represented by formula (III) (80.1 g), yield: 67.4%.

[0041] (2) Synthesis of Intermediate 2

[0042] Intermediate 1 (70 g, 0.12 mol) and Cs 2 CO 3 (124.5 g, 0.38 mol) wa...

Embodiment 2

[0045] Example 2: Confirm the structure of the compound prepared in Example 1

[0046] The compound prepared in Example 1 is detected by mass spectrometry, proton nuclear magnetic spectrum and carbon nuclear magnetic spectrum, and the detection results are as follows:

[0047] LC-MS (Agilent 1200 / 6110 Quadrupole LC / MS, methanol): (ES, m / z): [M+NH 4 ] + :790.3.

[0048] 1 H-NMR (Bruker AVANCE Ⅲ 400 nuclear magnetic resonance spectrometer, 400 MHz, DMSO- d 6 , ppm): δ7.35 (d, J = 8.24 Hz, 1H), 7.32 (d, J = 1.12 Hz, 1H), 7.22 (dd, J = 1.40, 8.0Hz, 1H), 7.11 (d, J = 8.52 Hz, 2H), 6.97 (d, J = 8.52 Hz, 2H), 5.74 (s, 2H), 4.96 (s, 1H), 4.96 (s, 1H), 4.84 (s, 1H), 4.44 (s, 1H), 4.02-3.93(s, 2H) ,4.02-3.93 (m, 1H), 3.68(d, J = 11.36 Hz, 1H), 3.42 (dd, J = 5.32, 11.48 Hz,1H), 3.23-3.22 (m, 1H), 3.20-3.19 (m, 1H), 3.17-3.12 (m, 1H), 3.12-3.06 (m,1H).

[0049] 13 C-NMR (Bruker AVANCE Ⅲ 400 nuclear magnetic resonance spectrometer, 400 MHz, DMSO- d 6 , ppm): δ38.14, 61.81, 70...

Embodiment 3

[0052] Example 3: Qualitative and quantitative experiments of impurities represented by formula (I) in the crude compound represented by formula (V)

[0053] Reagent solution: diammonium hydrogen phosphate, phosphoric acid, methanol, acetonitrile, ultrapure water.

[0054] Instruments and equipment: electronic balance, high performance liquid chromatography, pH meter, centrifuge.

[0055] 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); the flow rate is 1.0mL / min; the detection wavelength is 2...

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Abstract

The invention relates to the technical field of medicinal chemistry, and specifically discloses a method for synthesizing impurities of C-glycoside derivatives. The impurity is a compound shown in formula (I), and its synthesis steps include: (1) combining the compound of formula (II) and AlCl 3 Dissolve in dichloromethane, add dropwise 1‑dodecylmercaptan, prepare intermediate 1; (2) intermediate 1 and Cs 2 CO 3 Dissolve in DMF, protect with nitrogen, add diiodomethane and heat up to 85-95°C to react; cool to 20-30°C, filter, add TEA and DMAP to the filtrate, add acetic anhydride dropwise, heat up to 22-28°C to react to prepare the intermediate 2; (3) Dissolve intermediate 2 in methanol, add KOH aqueous solution to react, spin to dry the solvent, add saturated sodium chloride, distill acetonitrile under reduced pressure to obtain a white solid. The method of the invention solves the problem of large-scale production required by the 10g grade of the reference substance, improves the reaction yield, and reduces the production cost.

Description

technical field [0001] The invention relates to the technical field of medicinal chemistry, in particular to a method for synthesizing impurities of 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 2 diabetes. Normalization of insulin can therefore be expected to improve blood glucose in patients with type 2 diabetes. 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 almos...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D309/10
CPCC07D309/10C07B2200/07
Inventor 曹海燕顾志强张洪强安丰伟
Owner BEIJING HUIZHIHENG BIOTECHNOLOGY CO LTD