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Electroreduction preparation method of vandetanib and analog intermediates

A technology of electrodes and derivatives, which is applied in the direction of electrolysis process, electrolysis components, electrolysis organic production, etc., can solve the problems of environmental pollution, large environmental pollution, and excessive heavy metals affecting the purity of intermediates and anticancer drug products, so as to reduce production costs, The effect of simplifying the process flow

Active Publication Date: 2019-12-31
HUNAN UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] 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 sodium hydrochloride, iron powder / ammonium chloride, iron powder / ethanol, iron powder / ammonium formate, Fe / HOAc, Fe / HCl, zinc powder / glacial acetic acid and tin dichloride have great environmental pollution; FeCl 3 The reduction of / C-hydrazine hydrate and hydrazine hydrate seriously pollutes the environment

Method used

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  • Electroreduction preparation method of vandetanib and analog intermediates
  • Electroreduction preparation method of vandetanib and analog intermediates
  • Electroreduction preparation method of vandetanib and analog intermediates

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0063] Electroreduction Preparation of Methyl 2-Amino-5-methoxy-4-(3-chloropropoxy)benzoate

[0064]

[0065] Install the diaphragm electrolyzer ( figure 1 ), separated by HF-101 strong acid cation exchange membrane. Add 0.61g of 5-methoxy-4-(3-chloropropoxy)-2-nitrobenzoic acid methyl ester to the cathode (Cu) electrolyzer of the diaphragm electrolyzer, add 30ml of acetonitrile, and then add 1mol / L 30ml of aqueous hydrochloric acid solution; add 60ml of 0.25mol / L sulfuric acid aqueous solution to the anode (DSA) electrolyzer, and stir in a 40°C constant temperature water bath; power reduction: the voltage of the reference electrode relative to the working electrode is 2.0V, and the power supply voltage is 25V , current 0.65A, cathode electrode (brass 2cm × 2cm), anode electrode (platinum mesh 1cm × 1cm) electrolytic reduction 3.0h. After the reaction was completed, neutralize with potassium carbonate, extract with dichloromethane, combine the organic layers, dry over anh...

Embodiment 2

[0066] Embodiment 2 (control experiment)

[0067] Preparation of methyl 2-amino-5-methoxy-4-(3-chloropropoxy)benzoate

[0068]

[0069] Prepared according to [Euro J Med Chem 2017, 138:669~688], using iron powder to reduce 5-methoxy-4-(3-chloropropoxy)-2-nitrobenzoic acid in acetic acid at 80°C Methyl ester to obtain methyl 2-amino-5-methoxy-4-(3-chloropropoxy)benzoate with a yield of 82% and a melting point of 97-99°C.

Embodiment 3

[0071] Electroreduction Preparation of Methyl 2-Amino-5-methoxy-4-(3-morpholinopropoxy)benzoate

[0072]

[0073] Install the diaphragm electrolyzer ( figure 1 ), separated by HF-101 strong acid cation exchange membrane. Add a magnetic stirrer bar, 0.36g 5-methoxy-4-(3-morpholinopropoxy)-2-nitrobenzoic acid methyl ester and 60mL0.5mol / L hydrochloric acid solution in the cathode (Cu) electrolyzer, Stir to dissolve, add 60mL 0.25mol / L sulfuric acid solution in the anode (DSA) electrolytic cell; the cathode uses a saturated calomel electrode as a reference electrode, and conducts constant current electrolysis with a current density of 200mA / cm 2 , the voltage between the cathode and the reference is between 1.2 and 1.6V; stir at 40°C for 4.0h, after the reaction is complete, the catholyte is adjusted to weak alkaline with 10% NaOH solution, extracted twice with dichloromethane, dried over anhydrous sodium sulfate , suction filtration, solvent precipitation, recrystallization...

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Abstract

The invention relates to an electroreduction preparation method of 2-amino-5-methoxybenzoic acid derivatives represented by a formula I shown in the specification. A preparation reaction is shown in the specification, wherein n is selected from 1, 2 or 3; R is selected from hydrogen, methyl, ethyl or benzyl; Y is selected from C6H5, HO, Cl, Br, mesyloxy, p-toluenesulfonyloxy or M is selected fromCH or N; and W is selected from CH2, O, S, NH, HOCH, BocN, MeN, EtN, C6H5N, 4-ClC6H4N or 4-HOC6H4N. The electroreduction preparation method for the 2-amino-5-methoxybenzoic acid derivatives represented by the formula provided by the invention is characterized by comprising the step of performing constant-current or constant-voltage electrolysis in a diaphragm electrolytic cell by using an acid solution of a 5-methoxy-2-nitrobenzoic acid derivative as a catholyte and an acidic solution as an anolyte, wherein the voltage of a cathode working electrode is 1.00-2.50 V relative to that of a reference electrode, the current density of constant-current electrolysis is 25.0-250.0 mA / cm<2>, and the electrolysis temperature is 15-80 DEG C.

Description

technical field [0001] The present invention relates to the electroreduction preparation method of the anticancer drug vandetanib and its analog intermediates, specifically 2-amino-5 - A method of methoxybenzoic acid derivatives. Background technique [0002] Vandetanib (4-(4-bromo-2-fluoroanilino)-6-methoxy-7-[(1-methylpiperidin-4-yl)methoxy]quinazoline) , vandetanib is a kinase inhibitor indicated for the treatment of unresectable, locally advanced or metastatic symptomatic or progressive medullary thyroid cancer. [0003] Using vanillic acid as raw material, prepare Vandetanib through protection and deprotection process [Chemical Process.WO.2007 / 036713A2.2005]: 5-methoxy-4-benzyloxy-2-nitro The reduction reaction of benzyl benzoate selects hydrosulfite [US20100075916A1] for reduction, and the yield is 71%; in ethyl acetate solvent, tin dichloride is selected for reduction [J Med Chem,2002,45(17):3772-3793], Yield 95%. [0004] [0005] Zhao Ling et al. [Research on...

Claims

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Application Information

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IPC IPC(8): C25B3/04C25B3/25
CPCC25B3/25
Inventor 胡斯登陈伟蹇湘鄂谢雯雪胡艾希梁梓鹏
Owner HUNAN UNIV
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