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Electroreduction preparation method of anticancer drug gefitinib and analogue intermediate thereof

A technology of electrodes and derivatives, applied in the direction of electrolysis process, electrolysis components, electrolysis organic production, etc., can solve the problems of large environmental pollution, environmental pollution, expensive catalyst palladium, etc., and achieve the effect of simplifying the process and reducing production costs

Active Publication Date: 2020-02-04
HUNAN UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0021] Nitro compounds adopt catalytic hydrogenation method: palladium catalyst is more expensive; palladium catalyst forms complexes that are difficult to separate from amino compound intermediates, the reduction product, which affects the purity of intermediates and heavy metals in anticancer drug products exceed the standard
Inorganic reducing agent hydrosulfite, Fe / HOAc, Fe / HCl and tin dichloride have great environmental pollution; FeCl 3 / C-hydrazine hydrate, hydrazine hydrate and other reductions cause serious environmental pollution

Method used

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  • Electroreduction preparation method of anticancer drug gefitinib and analogue intermediate thereof
  • Electroreduction preparation method of anticancer drug gefitinib and analogue intermediate thereof
  • Electroreduction preparation method of anticancer drug gefitinib and analogue intermediate thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0077] Electroreduction Preparation of Methyl 2-Amino-4-Methoxy-5-(3-Chloropropoxy)benzoate

[0078]

[0079] Install separate electrolyzers ( figure 1 ). A magnetic stirrer was added to the cathode (Cu) electrolyzer, and 0.45g of methyl 4-methoxy-5-(3-chloropropoxy)-2-nitrobenzoate was completely dissolved in 60mL of methanol, and then 60mL of 0.5 mol / L hydrochloric acid solution, or 6.0g ammonium chloride and 60mL water solution, add 120mL 0.25mol / L sulfuric acid solution to the anode (DSA) electrolyzer. The effective electrode area of ​​the cathode (Cu) and anode (DSA) is 4 cm each 2 , control the current at both ends of the anode and cathode to 0.3A, constant current electrolysis, the current density of the constant current is 75mA / cm 2 , the voltage between the cathode and the reference is between 1.1 and 1.4V; stir the electroreduction reaction in a water bath at 40°C for 4 hours, take out the cathode solution, adjust it to weak alkalinity with 10% NaOH solution, e...

Embodiment 2

[0080] Embodiment 2 (control experiment)

[0081] Preparation of methyl 2-amino-4-methoxy-5-(3-chloropropoxy)benzoate

[0082]

[0083] According to the method of literature [Bioorg Med Chem,2010,18(11):3812-3822], adopt iron powder and acetic acid to reduce 4-methoxy-5-(3-chloropropoxy)-2-nitrobenzoic acid methyl ester to obtain methyl 2-amino-4-methoxy-5-(3-chloropropoxy)benzoate, melting point: 96-98°C, yield 77%.

Embodiment 3

[0085] Preparation of 2-amino-4-methoxy-5-(3-morpholinopropoxy)methyl benzoate by electroreduction

[0086]

[0087] figure 1 Diaphragm type electrolyzer as shown, add magnetic stirrer bar, 0.50g 4-methoxy-5-(3-morpholinopropoxy)-2-methyl nitrobenzoate and 120mL 0.5mol / L hydrochloric acid solution, stir to dissolve it completely, add 120mL 0.25mol / L sulfuric acid solution into the anode (DSA) electrolyzer. The cathode uses a saturated calomel electrode (SCE) as a reference electrode, controls the constant voltage between the cathode and the reference to 2.0V, and the effective electrode area of ​​the cathode (Cu) and anode (DSA) is 4cm each 2 , current density at 60mA / cm 2 Stir the electroreduction reaction in a water bath at 40°C for 3.0 hours, take out the cathode solution, adjust it to weak alkalinity with 10% NaOH solution, extract it twice with dichloromethane, dry it with anhydrous sodium sulfate, filter it with suction, remove the solvent, and dry it to obtain 0.45...

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Abstract

The invention relates to an electroreduction preparation method of a 2-amino-4-methoxybenzoic acid derivative represented by a formula I, wherein the preparation reaction is defined in the specification, n is selected from 1, 2 and 3, X is selected from CO2H, CO2Me, CO2Et, CO2Bn, CONH2 and CN, Bn is benzyl, Y is selected from HO, Cl, Br, MsO, TsO and a group defined in the specification, M is selected from CH and N, and W is selected from CH2, O, S, NH, HOCH, MeN and EtN. The electroreduction preparation method is characterized in that in a diaphragm electrolytic cell, an acidic solution of a4-methoxy-2-nitrobenzoic acid derivative or a mixed solution of an inorganic ammonium salt, an organic solvent and water is used as a cathode electrolytic solution; relative to a reference electrode,the voltage of a cathode working electrode is 1.00-2.50 V; an anode electrolytic solution is an acidic solution, constant-current or constant-voltage electrolysis is carried out, the current density of the constant current is 20.0-250.0 mA / cm<2>, and the electrolysis temperature is 20-80 DEG C.

Description

technical field [0001] The present invention relates to the electroreduction preparation method of the anticancer drug gefitinib and its analog intermediates, specifically the preparation of 2-amino-4 by electroreduction of 4-methoxy-2-nitrobenzoic acid derivatives (A). - A method of methoxybenzoic acid derivatives. Background technique [0002] Gefitinib is a selective inhibitor of the epidermal growth factor receptor (EGFR) tyrosine kinase, which is overexpressed in certain types of human cancer cells -- for example, in solid cancers such as lung and breast. Inhibition of EGFR tyrosine kinase activity can hinder tumor growth, metastasis and angiogenesis, and increase tumor cell apoptosis. [0003] [0004] Li Xingshu, Zhang Aiqin et al. [A preparation method of gefitinib. CN 102030716A, 2011-04-27] described 3,4-dimethoxybenzoic acid, which was nitrated, demethylated, and methylated to obtain the intermediate Body 2-nitro-4-methoxy-5-hydroxybenzoic acid methyl ester, ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C25B3/04C25B3/25
CPCC25B3/25
Inventor 胡斯登谢雯雪陈伟胡艾希梁梓鹏
Owner HUNAN UNIV
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