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Diacerhein aminophosphonate derivatives, and synthetic method and applications thereof

A kind of technology of acid amino phosphonate and diacetyl rhubarb is applied in the field of diacetyl rhein acid amino phosphonate derivative and its synthesis, and can solve the problems such as no public report of α-amino phosphonate

Inactive Publication Date: 2014-01-22
GUANGXI NORMAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, there are no public reports on the introduction of α-aminophosphonate functional groups into rhein and the anti-tumor effects of such derivatives.

Method used

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  • Diacerhein aminophosphonate derivatives, and synthetic method and applications thereof
  • Diacerhein aminophosphonate derivatives, and synthetic method and applications thereof
  • Diacerhein aminophosphonate derivatives, and synthetic method and applications thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0058] Example 1: O,O'diethyl{[2-(4,5-Diacetyl-9,10-dioxo-9,10-dihydroanthracenylamino)acetamido](4-bromophenyl ) Synthesis of methyl} phosphonic acid diethyl ester (a)

[0059] 1) Synthesis of diethyl α-O, O'diethylamino(4-bromophenyl)methylphosphonate

[0060] Add p-bromobenzaldehyde, ammonium acetate and diethyl phosphite (2:1:1 molar ratio) in a round bottom flask, stir and react at 80°C for 10 hours, then add the amount of diethyl ether into the round bottom flask is 1.2 times the amount of p-bromobenzaldehyde), concentrated hydrochloric acid was added under ice bath to make the reaction system acidic (pH=6) and stirred for 3h, the reaction system was extracted with water, the aqueous layer was collected and extracted with ether to remove organic impurities, Collect the water layer again, and in the water layer of collection, add the sodium hydroxide solution that mass concentration is 10% and adjust its pH to be 9, extract with ethyl acetate, collect the organic layer, ...

Embodiment 2

[0067] Example 2: O, O'diethyl{[2-(4,5-Diacetyl-9,10-dioxo-9,10-dihydroanthracenylamino)acetamido](2-bromophenyl ) Synthesis of methyl} phosphonic acid diethyl ester (b)

[0068] 1) Synthesis of diethyl α-O, O'diethylamino(2-bromophenyl)methylphosphonate

[0069] Synthesize according to the method and conditions described in step 1) in Example 1, except that p-bromobenzaldehyde is replaced with o-bromobenzaldehyde.

[0070] 2) Synthesis of target product:

[0071] In a round-bottomed flask, dissolve 1 mmol diacetylrhein in 10 mL N,N-dimethylformamide, add 0.05 mmol catalyst 1-hydroxybenzotriazole dropwise under ice-cooling, stir at room temperature for 13 min, and then add 1.2 mmol condensing agent 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, continue stirring for 13 min; then add 1 mmol α-O, O'diethylamino (2-Bromophenyl)methylphosphonic acid diethyl ester, stir the reaction at room temperature until complete (about 4h), then add chloroform to the reaction ...

Embodiment 3

[0076] Example 3: O, O'diethyl{[2-(4,5-Diacetyl-9,10-dioxo-9,10-dihydroanthraceneamino)acetamido](3-bromophenyl ) Synthesis of methyl} phosphonic acid diethyl ester (c)

[0077] 1) Synthesis of diethyl α-O, O'diethylamino(3-bromophenyl)methylphosphonate

[0078] Synthesize according to the method and conditions described in step 1) in Example 1, except that m-bromobenzaldehyde is used instead of p-bromobenzaldehyde.

[0079] 2) Synthesis of target product:

[0080]In a round bottom flask, dissolve 1mmol diacetylrhein in 10mL methanol, add 0.5mmol catalyst 1-hydroxybenzotriazole dropwise under ice bath, stir at room temperature for 10min, then add 2mmol condensing agent 1-(3-di Methylaminopropyl)-3-ethylcarbodiimide hydrochloride, continue to stir for 5 minutes; then add 1mmol α-O, O'diethylamino(3-bromophenyl)methyl dropwise to the round bottom flask Diethyl phosphonate (dissolved in 20mL ethanol to form a solution, added as a solution), stirred at room temperature until th...

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Abstract

The invention discloses a series of diacerhein aminophosphonate derivatives, and a synthetic method and applications thereof. The synthetic method of the diacerhein aminophosphonate derivatives comprises: taking diacerhein and an alpha-aminophosphonate as raw materials, dissolving in a polar solvent, in the presence of a catalyst HOBT and a condensing agent EDAC, reacting completely; and adding trichloromethane into the reaction liquid, washing with water, applying the organic layer to silica gel for column chromatography, eluting with a mixed solvent of ethyl acetate and petroleum ether with a volume ratio of 1:6-100 to obtain the corresponding derivative. The diacerhein aminophosphonate derivatives have the structural general formula (I) as shown in the description, wherein R is p-bromophenyl, o-bromophenyl, m-bromophenyl, p-fluorophenyl, o-fluorophenyl, p-chlorophenyl, m-chlorophenyl, o-chlorophenyl, m-methoxyphenyl, o-methoxyphenyl, phenyl, naphthyl, p-methoxyphenyl, m-methylphenyl, p-methylphenyl, m-fluorophenyl or anthryl.

Description

technical field [0001] The invention relates to rhein derivatives, in particular to diacetylrhein aminophosphonate derivatives and their synthesis method and application. Background technique [0002] Diacetylrhein (Diacerhein, chemical name is 4,5-diacetyl-9,10-dihydro-9,10-dioxo-2-anthracene carboxylic acid), also known as diacerein, is a derivative of rhein The compound adds two acetyl groups to the 4 and 5 positions of the anthraquinone ring of rhein, thereby avoiding the complication that rhein is prone to diarrhea when administered orally. Clinically, it is mainly used to treat osteoarthritis and delayed arthritis. Recent studies have found that it has a good effect on rheumatoid arthritis, osteoporosis, adult acute respiratory syndrome and emphysema. [0003] α-Aminophosphonate is an intermediate compound with biological activity and pharmaceutical activity, and has been widely used in antibiotics, fungicides, enzyme inhibitors and herbicides. However, there are no...

Claims

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Application Information

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IPC IPC(8): C07F9/40A61K31/662A61P35/00
Inventor 王恒山黄日镇潘英明姚贵阳戴伟龙叶鳗仪陈振峰
Owner GUANGXI NORMAL UNIV
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