阅读说明：本技术 一种吉非替尼中间体的电还原制备方法 (Electric reduction preparation method of gefitinib intermediate ) 是由 胡斯登 梁梓鹏 谢雯雪 何湘宁 于 2019-10-24 设计创作，主要内容包括：本发明公开了一种吉非替尼中间体的电还原制备方法,包括在隔膜电解槽中,以4-甲氧基-5-(3-吗啉基丙氧基)-2-硝基苯甲酸甲酯的酸性水溶液作为阴极电解液；酸性水溶液作为阳极电解液；相对于参比电极,阴极工作电极电压为1.00V～2.50V,阴极工作电极电流密度在25.0mA/cm<Sup>2</Sup>～250.0mA/cm<Sup>2</Sup>之间,电解槽的工作温度在25℃～80℃之间进行电解,制备得到吉非替尼中间体2-氨基-4-甲氧基-5-(3-吗啉基丙氧)苯甲酸甲酯。本发明在电还原过程中,不使用还原剂、有机溶剂,通过改变电极电位,就可以控制转化率和选择性,从而获得高纯度和高收率中间体。(The invention discloses an electroreduction preparation method of a gefitinib intermediate, which comprises the steps of taking an acidic aqueous solution of 4-methoxy-5- (3-morpholinylpropoxy) -2-nitrobenzoic acid methyl ester as a cathode electrolyte in a diaphragm electrolytic cell; an acidic aqueous solution is used as an anolyte; relative to a reference electrode, the voltage of the cathode working electrode is 1.00V-2.50V, and the current density of the cathode working electrode is 25.0mA/cm 2 ～250.0mA/cm 2 And electrolyzing at the working temperature of 25-80 ℃ in an electrolytic bath to prepare the gefitinib intermediate 2-amino-4-methoxyl-5- (3-morpholinyl propoxy) methyl benzoate. In the process of the electroreduction, the invention can control the conversion rate and the selectivity by changing the electrode potential without using a reducing agent and an organic solvent, thereby obtaining the intermediate with high purity and high yield.)

1. The method for preparing the gefitinib intermediate through electroreduction is characterized in that in a diaphragm electrolytic cell, acidic aqueous solution of 4-methoxy-5- (3-morpholinylpropoxy) -2-nitrobenzoic acid methyl ester is used as catholyte, the acidic aqueous solution is used as anolyte, and reduction product of gefitinib intermediate 2-amino-4-methoxy-5- (3-morpholinylpropoxy) methyl benzoate is obtained through electrolysis.

2. The process for the electroreductive preparation of gefitinib intermediate of claim 1, wherein said diaphragm cell and reference electrode are: a saturated potassium chloride calomel electrode; the cathode is: brass electrodes, red copper electrodes, titanium mesh electrodes, nickel, lead, platinum or graphite electrodes; the anode is: a DSA electrode or a titanium-based platinum electrode; the diaphragm is: a strong acid type cation exchange membrane.

3. The process for preparing gefitinib intermediate by electroreduction according to claim 1, wherein the concentration of methyl 4-methoxy-5- (3-morpholinopropoxy) -2-nitrobenzoate in said catholyte is 4.0g/L to 16.0 g/L.

4. The process for the electroreductive preparation of gefitinib intermediate of claim 1, wherein in said catholyte, the acidic aqueous solution is selected from the group consisting of: phosphoric acid solution, sulfuric acid solution or hydrochloric acid solution, and the acid concentration is 0.15 mol/L-1.00 mol/L.

5. The process for the electroreductive preparation of gefitinib intermediate of claim 1, wherein in said anolyte is selected the acidic aqueous solution: phosphoric acid solution, sulfuric acid solution or hydrochloric acid solution, and the acid concentration is 0.15 mol/L-1.00 mol/L.

6. The process for the electroreductive preparation of gefitinib intermediate of claim 1, wherein said cathode has an electrode working voltage of 1.00V-2.50V relative to a reference electrode.

7. The process for the electroreductive preparation of gefitinib intermediate of claim 1, wherein said cathode, electrode current density is 25.0mA/cm ²～250.0mA/cm ²。

8. The process for the electroreductive preparation of gefitinib intermediate of claim 1, wherein said diaphragm electrolyzer operates at a temperature between 25 ℃ and 80 ℃.

9. The process for the electroreductive preparation of gefitinib intermediate of claim 1, wherein the level of catholyte and the level of anolyte are at the same level in said diaphragm cell.

Technical Field

The invention relates to an electroreduction reaction, in particular to a method for preparing gefitinib intermediate 2-amino-4-methoxyl-5- (3-morpholinyl propoxy) methyl benzoate by the electroreduction reaction.

Background

Gefitinib (gefitinib) is a selective Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibitor, which is overexpressed in certain types of human cancer cells-e.g., in solid cancers such as lung and breast cancer. Inhibition of EGFR tyrosine kinase activity can interfere with tumor growth, metastasis and angiogenesis, and increase apoptosis of tumor cells.

The relevant literature for gefitinib synthesis is summarized, and found that the gefitinib is synthesized by using veratraldehyde, 3, 4-dimethoxybenzoic acid, isovanillin, isovanillic acid and derivatives thereof as raw materials and passing through a gefitinib intermediate 2-amino-4-methoxy-5- (3-morpholinylpropoxy) methyl benzoate as shown in a formula I.

Zheng and jimin et al [ Zheng Y, Li M, Zhang S, et al. novel prediction of gefitinib. j Chem Research,2009,6: 388-; germin, Zhengyouguang, Limindong et al A process for preparing gefitinib WO101148439A1,2008-03-26 describes the synthesis of gefitinib intermediate methyl 2-amino-4-methoxy-5- (3-morpholinylpropoxy) benzoate with a yield of 90% using sodium dithionite as a reducing agent.

Shih et al [ Shih Kaeshyang, et al synthetic method for 6, 7-substitents-4-aniline quinazoline. WO101148439A1,2011-12-01] describe the synthesis of gefitinib intermediate methyl 2-amino-4-methoxy-5- (3-morpholinopropoxy) benzoate by catalytic hydrogenation under a pressure of 50psi using 10% Pd/C as a catalyst, although the reduction yield is high, the reaction pressure is high, and the requirements on equipment safety are high.

CN102030716A, 2011-04-27 describes a method for synthesizing gefitinib intermediate 2-amino-4-methoxy-5- (3-morpholinyl propoxy) methyl benzoate by catalytic hydrogenation under normal pressure by using 10% Pd/C as a catalyst, wherein the reaction is as follows:

a catalytic hydrogenation method is adopted: the catalyst palladium is expensive, and the catalyst palladium and the gefitinib intermediate form a complex which is difficult to separate, so that the purity of the gefitinib intermediate and the standard exceeding of heavy metals in gefitinib products are influenced; the sodium hydrosulfite of the inorganic reducing agent has great pollution to the environment.

Disclosure of Invention

In order to overcome the defects of the catalytic hydrogenation preparation method of the gefitinib intermediate, the invention provides the electroreduction preparation method, which is environment-friendly, mild in operation condition, controllable in process and improved in yield and purity of the gefitinib intermediate.

An electro-reduction preparation method of gefitinib intermediate has a reaction formula as follows:

the method for preparing the gefitinib intermediate through electroreduction comprises the steps of taking an acidic aqueous solution of 4-methoxy-5- (3-morpholinylpropoxy) -2-nitrobenzoic acid methyl ester as a cathode electrolyte and an acidic aqueous solution as an anode electrolyte in a diaphragm electrolytic cell, and electrolyzing to obtain a reduction product 2-amino-4-methoxy-5- (3-morpholinylpropoxy) benzoic acid methyl ester, namely gefitinib intermediate I.

In the diaphragm electrolytic cell, the reference electrode is a saturated potassium chloride calomel electrode, and the cathode is a brass electrode, a red copper electrode, a titanium mesh electrode, a nickel, lead, platinum or graphite electrode. The anode is DSA electrode or titanium-based platinum electrode, and the diaphragm is strong acid type cation exchange membrane.

Preferably, the DSA electrode is a metal oxide anode comprising oxides of titanium, manganese, cobalt, noble metals ruthenium or iridium, and the substrate is titanium.

In the catholyte, the concentration of the 4-methoxy-5- (3-morpholinylpropoxy) -2-nitrobenzoic acid methyl ester is between 4.0g/L and 16.0 g/L; in the catholyte, selecting an acidic aqueous solution: phosphoric acid solution, sulfuric acid solution or hydrochloric acid solution, and the acid concentration is between 0.15mol/L and 1.00 mol/L.

In the catholyte, the concentration of the 4-methoxy-5- (3-morpholinylpropoxy) -2-nitrobenzoic acid methyl ester is too high to be beneficial to the reduction reaction; if the concentration is too low, the equipment utilization rate and the reduction reaction efficiency are lowered. The concentration of the acid is in the range, so that the dissolution of the 4-methoxy-5- (3-morpholinylpropoxy) -2-nitrobenzoic acid methyl ester can be ensured, the good conductivity of the electrolyte and the sufficient generation of protons and electrons can be provided, and the post-treatment of the electro-reduction product is convenient.

In the anolyte, selecting an acidic aqueous solution: phosphoric acid solution, sulfuric acid solution or hydrochloric acid solution, and the acid concentration is between 0.15mol/L and 1.00 mol/L. The acid concentration in this range provides good conductivity of the electrolyte and sufficient proton and electron generation.

Under acidic conditions, the cathode reaction formula is:

gefitinib intermediate and by-product that may occur in the cathode reaction:

in the reaction formula, the structural formula (1) is taken as a raw material, and the structural formulas (2) to (5) are taken as byproducts; the structural formula I is a main product intermediate, namely 2-amino-4-methoxyl-5- (3-morpholinyl propoxy) methyl benzoate.

Anode: under acidic conditions

6H ₂O→12H ⁺+30 ₂+12e ^-

And (3) total reaction:

preferably, the working voltage of the cathode and the electrode is 1.00V-2.50V relative to the reference electrode.

Preferably, the cathode and the electrodeThe current density is 25.0mA/cm ²～250.0mA/cm ²。

Within the electrode working voltage and current density ranges, the structural formula I is a main product, namely 2-amino-4-methoxy-5- (3-morpholinylpropoxy) methyl benzoate, the selectivity of the main product is highest, and the yield of byproducts of the structural formulas (2) to (5) is lowest.

The temperature of the diaphragm electrolytic cell for the electro-reduction reaction is between 25 and 80 ℃. Within the temperature range, the reaction is mild, and the conversion rate and the selectivity are easy to control.

In the diaphragm electrolytic cell, the liquid levels of the catholyte and the anolyte are at the same level.

The reaction end point of the electrolytic reduction is judged by adopting a Thin Layer Chromatography (TLC); after thin layer chromatography, stopping electrolysis when the raw material point basically disappears; the developing agent is V _{Petroleum ether}：V _{Ethyl acetate}4:1, color development with ultraviolet lamp.

The beneficial technical effects of the invention are as follows:

(1) no toxic or dangerous reducing agent is needed in the reduction reaction, and the 'electron' is a clean reaction reagent and is an important component for developing the 'green pharmaceutical industry'.

(2) During the electroreduction process, the conversion rate and selectivity can be controlled by changing the electrode potential; thereby obtaining the intermediate with high purity and high yield.

(3) In industrial production, the process flow is simplified, the production cost is reduced, and the method is safe and environment-friendly and is suitable for large-scale popularization and application.

(4) The electro-reduction of the 4-methoxy-5- (3-morpholinylpropoxy) -2-nitrobenzoic acid methyl ester does not need to use an organic solvent, and the subsequent treatment is simple and has less pollution.

Drawings

FIG. 1 is a schematic view of a diaphragm electrolyzer.

Detailed Description

The following examples are intended to illustrate the invention without further limiting it.