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Ester pentaacetyl geniposide derivative obtained through esterification reaction as well as preparation method and application of ester pentaacetyl geniposide derivative

A technology of pentaacetyl geniposide and geniposide, which is applied in the field of new compound preparation, can solve the problems of inability to directly apply clinically and have low activity, and achieve the effects of improving kidney damage activity, reducing inflammatory response and reducing levels

Active Publication Date: 2022-07-12
VEGETABLE RES INST OF SHANDONG ACADEMY OF AGRI SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Geniposide has anti-inflammatory, uric acid-lowering, blood-sugar-lowering, and blood-pressure-lowering activities, but due to its low activity, it cannot be directly used clinically

Method used

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  • Ester pentaacetyl geniposide derivative obtained through esterification reaction as well as preparation method and application of ester pentaacetyl geniposide derivative
  • Ester pentaacetyl geniposide derivative obtained through esterification reaction as well as preparation method and application of ester pentaacetyl geniposide derivative
  • Ester pentaacetyl geniposide derivative obtained through esterification reaction as well as preparation method and application of ester pentaacetyl geniposide derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0045] Example 1 Synthesis of Geniposide Lead Compound - Geniposide

[0046] (1) Synthesis of Geniposide (1a)

[0047]

[0048] Geniposide (100.0 mg, 0.257 mmol) and 10 mL of 4 % NaOH solution were added to the round-bottomed flask in turn, and the reaction was stirred under reflux at 65 °C, and the reaction was followed by TLC until the starting point disappeared (developing agent v / v: Dichloromethane / methanol=5 / 1). After the reaction is completed, use 1M hydrochloric acid to neutralize to pH=7, purify, and concentrate the obtained reaction solution to dryness under reduced pressure, pass through the column (eluent v / v: dichloromethane / methanol=8 / 1-1 / 1), 61.5 mg of white powder was obtained, mp. 250.9-251.6 °C, yield 91.3%, which was determined to be geniposide (1a) by NMR, HR-MS and other analysis. Spectrum such as figure 1 shown.

[0049] 1 H NMR (400 MHz, CD 3 OD) δ 7.19 (d, J = 11.5 Hz, 1H), 5.01 (dd, J =9.1, 5.4 Hz, 1H), 4.64 (dd,J = 12.4, 8.4 Hz, 1H),...

Embodiment 2

[0050] Example 2 Synthesis of Geniposide Derivative Pentaacetyl Geniposide (2a)

[0051] (1) Synthesis of pentaacetylgeniposide (2a)

[0052]

[0053] Geniposide derivative 1a (100.0 mg, 0.026 mmol) and 5 mL of triethylamine were added to the round-bottomed flask in turn, cooled in an ice-water bath, and 5 mL of acetic anhydride was slowly added dropwise with stirring. After the dropwise addition, the ice-water bath was removed. , the reaction was carried out at room temperature, and TLC was traced to the disappearance of the starting material point (developing solvent v / v: petroleum ether / ethyl acetate=1 / 1, 1 drop of formic acid). After the reaction, the reaction solution was washed with saturated NaHCO 3 The solution (20 mL) was neutralized to pH=7.0, washed with deionized water (20 mL × 3), the organic phases were combined, anhydrous Na 2 SO 4 Dry overnight and remove Na by suction filtration 2 SO 4 After distillation under reduced pressure, passed through the colum...

Embodiment 3 5

[0056] Example 3 Synthesis of pentaacetylgeniposide-3''-benzonitrile ester (5a)

[0057]

[0058] Geniposide derivative 2a (200.0 mg, 0.34 mmol) DMF (3 mL), EDCI (78.0 mg, 0.41 mmol) in a stirred solution, HOBT (55.0 mg, 0.41 mmol) and DIPEA (0.2 mL, 1.02 mmol) were added ), stirred at room temperature for 2 h, then added 3-hydroxybenzonitrile (44.0 mg, 0.37 mmol) and DMAP (63.0 mg, 0.51 mmol), and continued stirring at room temperature overnight. After the reaction was over, the solution used was added to ice water (30 mL) and extracted with dichloromethane (20 mL x 3). The combined organic solvent was washed with 1 M water diluted hydrochloric acid (20 mL × 3) and saturated brine (20 mL × 3). The organic phase is in anhydrous anhydrous Na 2 SO 4 It was dried overnight, distilled under reduced pressure, and purified by column chromatography (eluent v / v: petroleum ether / ethyl acetate=8 / 1-1 / 1) to obtain pale yellow powder 79.7 mg, mp.172.6-173.3 ℃, the yield was 34.1%, a...

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Abstract

The invention belongs to the technical field of novel compound preparation, and particularly relates to an ester pentaacetyl geniposide derivative obtained through esterification reaction and a preparation method and application thereof. The amide penta-acetyl geniposide derivative provided by the invention is prepared by the following steps: firstly, hydrolyzing lipid groups at C-4 sites of iridoid in geniposide to obtain geniposidic acid, then acetylating five hydroxyl groups at 2 ', 3', 4 ', 6' and 11 sites on sugar to obtain penta-acetyl geniposidic acid (2a), and finally reacting with ROH to obtain the penta-acetyl geniposide derivative. The geniposide derivative prepared by the invention has remarkable XOD inhibitory activity and kidney injury improvement activity, and can effectively reduce the accumulation of uric acid in the kidney. The inflammatory reaction is reduced, so that the level of inflammatory factors is reduced; renal fibrosis of a mouse with hyperuricemia can be reduced by inhibiting expression of an inflammatory factor TGF-beta.

Description

technical field [0001] The invention belongs to the technical field of preparation of new compounds, and in particular relates to an ester pentaacetylgeniposide derivative obtained by esterification, a preparation method and application thereof. Background technique [0002] Hyperuricemia is a metabolic disease caused by the disorder of purine metabolism in the body. In recent years, the number of patients with hyperuricemia has been increasing, and it has become the second largest metabolic disease. Long-term hyperuricemia can lead to many complications, especially kidney inflammation, and in severe cases, renal fibrosis, which can seriously damage kidney function. Xanthine oxidase (XOD) plays an important role in uric acid metabolism in vivo and is a key enzyme regulating uric acid production. Therefore, most of the current uric acid-lowering drugs target XOD, such as allopurinol, febuxostat, etc. However, most of these XOD inhibitors have obvious toxic side effects, wh...

Claims

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Application Information

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IPC IPC(8): C07H17/04C07H1/00A61P19/06A61P13/12
CPCC07H17/04C07H1/00A61P19/06A61P13/12Y02P20/55
Inventor 孙金月刘超陈家树陈莹莹张梦启郭溆王目旋王青
Owner VEGETABLE RES INST OF SHANDONG ACADEMY OF AGRI SCI
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