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Semisynthetic method of staurosporine derivative

A technology of staurosporine and derivatives, applied in the field of semi-synthesis of staurosporine derivatives, to achieve the effect of cheap and easy-to-obtain raw materials and high yield

Inactive Publication Date: 2013-02-13
SHANDONG LUBEI PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

About 30,000 people around the world suffer from bile duct cancer, a rare disease, and there is no approved effective therapy before; in 2004, the US Food and Drug Administration (FDA) announced that XL119 was designated as a rare disease for the treatment of bile duct cancer medication

Method used

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  • Semisynthetic method of staurosporine derivative
  • Semisynthetic method of staurosporine derivative
  • Semisynthetic method of staurosporine derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] Take 5g of fermented staurosporine products as raw material, dissolve it in a mixture of 120ml of methanol and 120ml of dichloromethane, add 0.5g of sodium tungstate dihydrate and 4ml of 30% aqueous hydrogen peroxide solution, and keep it away from light at room temperature Stir for 20 h, cool to 0°C, add 150 ml of saturated aqueous sodium bisulfite solution to terminate the reaction, evaporate the solvent under reduced pressure to obtain a yellow oil. The substance was dissolved in a mixture of 80ml methanol and 80ml dichloromethane, stirred at 0°C, added 1.5g hydroxylamine hydrochloride and 12ml pyridine, diluted with water, added 120ml dichloromethane, extracted twice, the organic layer was washed with water, anhydrous sodium sulfate Drying, concentration under reduced pressure, methanol crystallization to obtain light yellow crystals, recrystallization in ethyl acetate-methanol (5:1) to obtain colorless crystals, staurosporine derivative 1, yield 75.3%.

[0029] Der...

Embodiment 2

[0031] Take 5g of fermented staurosporine products as raw materials, dissolve it in a mixture of 120ml ethanol and 120ml dichloromethane, add 0.5g sodium tungstate dihydrate and 4ml 30% hydrogen peroxide aqueous solution, and keep it away from light at room temperature Stir for 20 h, cool to 0°C, add 150 ml of saturated aqueous sodium bisulfite solution to terminate the reaction, evaporate the solvent under reduced pressure to obtain a yellow oil. The substance was dissolved in a mixture of 80ml ethanol and 80ml dichloromethane, stirred at 0°C, added 1.5g hydroxylamine hydrochloride and 12ml pyridine, diluted with water, added 120ml dichloromethane, extracted twice, the organic layer was washed with water, anhydrous sodium sulfate Drying, concentration under reduced pressure, methanol crystallization to obtain light yellow crystals, recrystallization in ethyl acetate-methanol (5:1) to obtain colorless crystals, staurosporine derivative 1, yield 76.6%.

[0032] Derivative 1 was...

Embodiment 3

[0034] Take 5g of fermented staurosporine as raw material, dissolve it in a mixture of 120ml of methanol and 120ml of chloroform, add 0.5g of sodium tungstate dihydrate and 4ml of 30% aqueous hydrogen peroxide solution, and keep it away from light at room temperature Stir for 20 h, cool to 0°C, add 150 ml of saturated aqueous sodium bisulfite solution to terminate the reaction, evaporate the solvent under reduced pressure to obtain a yellow oil. The substance was dissolved in a mixture of 80ml methanol and 80ml chloroform, stirred at 0°C, added 1.5g hydroxylamine hydrochloride and 12ml pyridine, diluted with water, added 120ml dichloromethane, extracted twice, the organic layer was washed with water, anhydrous sodium sulfate Drying, concentration under reduced pressure, methanol crystallization to obtain light yellow crystals, recrystallization in ethyl acetate-methanol (5:1) to obtain colorless crystals, staurosporine derivative 1, yield 76.8%.

[0035] Derivative 1 was disso...

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Abstract

The invention discloses a semisynthetic method of staurosporine derivatives, which comprises the following steps: dissolving raw materials of fermented staurosporine products in a mixed solution of methanol and dichloromethane, adding sodium tungstate dihydrate and an aqueous hydrogen peroxide solution, stirring away from light, adding saturated sodium bisulfite to terminate the reaction, adding hydroxylamine hydrochloride and pyridine, performing extraction, concentration, and recrystallization to obtain a staurosporine derivative 1; dissolving the staurosporine derivative 1 with DMF, adding a TiCl3 aqueous solution, extracting with ethyl acetate for 3 times, washing the organic layer, performing drying by distillation, separation, elution, and crystallization to obtain a staurosporine derivative 2. The invention has cheap and easily available raw materials, and a high yield, and the obtained staurosporine derivatives have important application value in the anti-tumor aspect.

Description

technical field [0001] The invention belongs to organic synthesis and provides a semi-synthetic method of staurosporine derivatives. Background technique [0002] Staurosporine is an indole[2,3-a]carbazole alkaloid originally extracted from the metabolites of the microorganism Streptomyces sp. in 1977. It is a protein kinase C (PKC) and most other Potent inhibitor of kinases, including tyrosine-protein kinases, directly inhibits the activity of topoisomerase II by blocking the transfer of phosphodiester bonds from DNA to activated tyrosine sites, and can be used to induce apoptosis . Studies have shown that the compound has various biological activities such as treating diabetic complications and anti-tumor. However, due to the weak selectivity and high toxicity of staurosporine, searching for PKC inhibitors with better selectivity from fermented products has aroused widespread interest. [0003] Many scholars at home and abroad have carried out a lot of structural modifi...

Claims

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Application Information

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IPC IPC(8): C07D498/22A61P35/00
Inventor 王克柳
Owner SHANDONG LUBEI PHARMA
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