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Betulinic acid derivative and synthesis method and application thereof

A technology of betulinic acid and derivatives, applied in medicine and its preparation and application fields, can solve the problems of low bioavailability, in vivo transport, metabolism, poor solubility, etc., achieve good application value, make up for poor water solubility, and improve the effects of solubility

Active Publication Date: 2018-09-07
河南省医药科学研究院 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, due to its poor solubility in water, it leads to low bioavailability and shortcomings in in vivo transmission and metabolism.

Method used

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  • Betulinic acid derivative and synthesis method and application thereof
  • Betulinic acid derivative and synthesis method and application thereof
  • Betulinic acid derivative and synthesis method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] The synthesis of embodiment 1 compound ii

[0033] The synthesis path is as follows:

[0034]

[0035] in

[0036] Synthesis of Compound 2: Add betulin (20.0 g, 45.2 mmol) and acetone (400 mL) into a 1000 mL three-necked flask, then add the newly prepared Jones reagent (100 mL) dropwise under ice bath, and continue the reaction for 30 Minutes later, remove the ice bath, stir at room temperature for 8 hours, add methanol (250mL) and water (250mL) to terminate the reaction, evaporate the solvent, add water, extract with ethyl acetate, combine the organic phases, dry and concentrate, and separate by column chromatography to obtain a white solid 2 (12.2 g, 26.8 mmol, 59.3%). 1 H NMR (DMSO-d 6 ,400MHz) δ: 12.08(s,1H),4.70(s,1H),4.57(s,1H),2.90~2.99(m,1H),2.46~2.30(m,2H),2.25(dt,J= 12.7, 3.5Hz, 1H), 2.15~2.08(m, 1H), 1.87~1.73(m, 3H), 1.65(s, 3H), 1.62(s, 1H), 1.54(t, J=11.3Hz, 1H ),1.48~1.00(m,15H),0.98(s,3H),0.95(s,3H),0.93(s,3H),0.90(s,3H),0.85(s,3H).

[0037] S...

Embodiment 2

[0041] The synthesis of embodiment 2 compound ii

[0042] The synthesis path is as follows:

[0043]

[0044] That

[0045] Synthesis of Compound 2: Add betulin (20.0 g, 45.2 mmol) and acetone (400 mL) into a 1000 mL three-necked flask, then add the newly prepared Jones reagent (100 mL) dropwise under ice bath, and continue the reaction for 30 Minutes later, remove the ice bath, stir at room temperature for 8 hours, add methanol (250mL) and water (250mL) to terminate the reaction, evaporate the solvent, add water, extract with ethyl acetate, combine the organic phases, dry and concentrate, and separate by column chromatography to obtain a white solid 2 (12.2 g, 26.8 mmol, 59.3%). 1 H NMR (DMSO-d 6 ,400MHz) δ: 12.08(s,1H),4.70(s,1H),4.57(s,1H),2.90~2.99(m,1H),2.46~2.30(m,2H),2.25(dt,J= 12.7, 3.5Hz, 1H), 2.15~2.08(m, 1H), 1.87~1.73(m, 3H), 1.65(s, 3H), 1.62(s, 1H), 1.54(t, J=11.3Hz, 1H ),1.48~1.00(m,15H),0.98(s,3H),0.95(s,3H),0.93(s,3H),0.90(s,3H),0.85(s,3H).

[0046]...

Embodiment 3

[0050] The synthesis of embodiment 3 compound i

[0051] The synthesis path is as follows:

[0052]

[0053] in

[0054] Synthesis of Compound 2: Add betulin (20.0 g, 45.2 mmol) and acetone (400 mL) into a 1000 mL three-necked flask, then add the newly prepared Jones reagent (100 mL) dropwise under ice bath, and continue the reaction for 30 Minutes later, remove the ice bath, stir at room temperature for 8 hours, add methanol (250mL) and water (250mL) to terminate the reaction, evaporate the solvent, add water, extract with ethyl acetate, combine the organic phases, dry and concentrate, and separate by column chromatography to obtain a white solid 2 (12.2 g, 26.8 mmol, 59.3%). 1 H NMR (DMSO-d 6 ,400MHz) δ: 12.08(s,1H),4.70(s,1H),4.57(s,1H),2.90~2.99(m,1H),2.46~2.30(m,2H),2.25(dt,J= 12.7, 3.5Hz, 1H), 2.15~2.08(m, 1H), 1.87~1.73(m, 3H), 1.65(s, 3H), 1.62(s, 1H), 1.54(t, J=11.3Hz, 1H ),1.48~1.00(m,15H),0.98(s,3H),0.95(s,3H),0.93(s,3H),0.90(s,3H),0.85(s,3H).

[0055] Sy...

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Abstract

The invention discloses a betulinic acid derivative shown by the formula (I) and a synthesis method and application thereof, the betulinic acid derivative comprises a betulinic acid part which is in covalent binding with a 1,2,3-triazole linker in the C-2 position the betulinic acid part, and the linker is in covalent binding with the fludarabine part. According to the compound, the problem of lowwater solubility of the betulinic acid is solved by medical method design, and the betulinic acid is connected with a nucleoside compound by the stable 1,2,3-triazole liker.

Description

technical field [0001] The invention belongs to the technical field of medicine and its preparation and application, and in particular relates to a betulinic acid derivative and its synthesis method and application. Background technique [0002] Betulinic acid (BA) is a pentacyclic triterpenoid compound that exists in many plants such as birch, Prunella vulgaris, and papaya. Studies have found that betulinic acid has a wide range of physiological activities, such as anti-HIV, anti-tumor, and anti-inflammatory effects. Compared with betulinic acid, its derivatives have better activity in anti-HIV, anti-tumor, etc. For example, RPR103611 and PA457 (bevirimat) are in the clinical trial stage of anti-HIV, and NVX-207 is in the clinical trial of anti-tumor . However, due to its poor solubility in water, it leads to low bioavailability and shortcomings in in vivo transportation and metabolism. Contents of the invention [0003] The main purpose of the present invention is to ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J63/00A61P35/00A61P31/20A61P31/18
CPCA61P31/18A61P31/20A61P35/00C07J63/008
Inventor 郑立运王强李玉江方先珍赵志鸿郝佳张壮丽马芳徐丽萍苗良郑果
Owner 河南省医药科学研究院
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