阅读说明：本技术 凡德他尼及其类似物中间体电还原制备方法 (Vantanib and analogue intermediate electro-reduction preparation method thereof ) 是由 胡斯登 陈伟 蹇湘鄂 谢雯雪 胡艾希 梁梓鹏 于 2019-11-15 设计创作，主要内容包括：本发明涉及式Ⅰ所示2-氨基-5-甲氧基苯甲酸衍生物的电还原制备方法,其制备反应如下：<Image he="184" wi="700" file="DDA0002274088600000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>其中,n选自：1,2或3；R选自：氢,甲基,乙基或苄基；Y选自：C<Sub>6</Sub>H<Sub>5</Sub>,HO,Cl,Br,甲磺酰氧基,对甲苯磺酰氧基或<Image he="103" wi="149" file="DDA0002274088600000012.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>M选自：CH或N；W选自：CH<Sub>2</Sub>,O,S,NH,HOCH,BocN,MeN,EtN,C<Sub>6</Sub>H<Sub>5</Sub>N,4-ClC<Sub>6</Sub>H<Sub>4</Sub>N或4-HOC<Sub>6</Sub>H<Sub>4</Sub>N。本发明的2-氨基-5-甲氧基苯甲酸衍生物Ⅰ的电还原制备方法,其特点是,在隔膜电解槽中,以5-甲氧基-2-硝基苯甲酸衍生物的酸性溶液作为阴极电解液；相对于参比电极,阴极工作电极电压为1.00V～2.50V；阳极电解液为酸性溶液,恒电流或恒电压电解,恒电流的电流密度在25.0mA/cm<Sup>2</Sup>～250.0mA/cm<Sup>2</Sup>之间,电解的温度15℃～80℃。(The invention relates to an electroreduction preparation method of a 2-amino-5-methoxybenzoic acid derivative shown in a formula I, which comprises the following preparation reactions: wherein n is selected from: 1, 2 or 3; r is selected from: hydrogen, methyl, ethyl or benzyl; y is selected from: c 6 H 5 HO, Cl, Br, methanesulfonyloxy, p-toluenesulfonyloxy or M is selected from: CH or N; w is selected from: CH (CH) 2 ，O，S，NH，HOCH，BocN，MeN，EtN，C 6 H 5 N，4‑ClC 6 H 4 N or 4-HOC 6 H 4 And N is added. The invention relates to an electroreduction preparation method of a 2-amino-5-methoxybenzoic acid derivative I, which is characterized in that in a diaphragm electrolytic cell, an acid solution of a 5-methoxy-2-nitrobenzoic acid derivative is used as a cathode electrolyte; relative to each otherThe voltage of the cathode working electrode on the reference electrode is 1.00V-2.50V; the anolyte is acidic solution, and is electrolyzed at constant current or constant voltage, and the current density of the constant current is 25.0mA/cm 2 ～250.0mA/cm 2 The temperature of electrolysis is 15-80 ℃.)

1. The electro-reduction preparation method of the 2-amino-5-methoxybenzoic acid derivative shown in the structural formula I is characterized in that the preparation reaction is as follows:

wherein n is selected from: 1, 2 or 3; r is selected from: hydrogen, methyl, ethyl or benzyl;

y is selected from: c₆H₅HO, Cl, Br, methanesulfonyloxy, p-toluenesulfonyloxy orM is selected from: CH or N; w is selected from: CH (CH)₂，O，S，NH，HOCH，BocN，MeN，EtN，C₆H₅N，4-ClC₆H₄N or 4-HOC₆H₄N。

The electroreduction preparation method of the 2-amino-5-methoxybenzoic acid derivative is characterized in that in a diaphragm electrolytic cell, an acidic solution of the 5-methoxy-2-nitrobenzoic acid derivative (A) is used as a catholyte, or the acidic solution of the 5-methoxy-2-nitrobenzoic acid derivative (A) and an organic solvent form the catholyte; the acid aqueous solution is an anolyte; obtaining a cathode electrolysis product containing the 2-amino-5-methoxybenzoic acid derivative through an electro-reduction reaction.

2. The process for preparing 2-amino-5-methoxybenzoic acid derivatives by electroreduction according to claim 1, wherein the reference electrode of the diaphragm electrolyzer is: 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: DSA electrode, platinum mesh electrode or titanium-based platinum electrode; the diaphragm is: a strong acid type cation exchange membrane.

3. The process for producing 2-amino-5-methoxybenzoic acid derivative by electroreduction according to claim 1 or 2, characterized in that the working voltage of the cathode of the diaphragm electrolyzer is 1.00V to 2.50V relative to a reference electrode; the electrode current density of the cathode is 25.0mA/cm²～250.0mA/cm²To (c) to (d); the working temperature of the diaphragm electrolytic cell is 15-80 ℃.

4. The process for preparing 2-amino-5-methoxybenzoic acid derivatives by electroreduction according to claim 1, wherein the organic solvent in the catholyte is one or more of ethyl acetate, C1-C5 straight-chain alcohol, C2-C5 branched-chain alcohol, and acetonitrile.

5. The process for preparing 2-amino-5-methoxybenzoic acid derivatives by electroreduction according to claim 1, wherein the acidic solution in the catholyte is selected from the group consisting of: phosphoric acid solution, sulfuric acid solution or hydrochloric acid solution; the anolyte is selected from: phosphoric acid solution, sulfuric acid solution, or hydrochloric acid solution.

6. The process for producing 2-amino-5-methoxybenzoic acid derivative by electroreduction according to claim 1, wherein the concentration of the 5-methoxy-2-nitrobenzoic acid derivative (a) in the catholyte is 3.0g/L to 15.0 g/L.

7. The process for producing a 2-amino-5-methoxybenzoic acid derivative by electroreduction according to claim 1, wherein the 2-amino-5-methoxybenzoic acid derivative (i) is selected from the group consisting of compounds represented by the formula ii:

wherein n is selected from: 1, 2 or 3; r is selected from: hydrogen, methyl, ethyl or benzyl; y is selected from: c₆H₅HO, Cl, Br, methanesulfonyloxy or p-toluenesulfonyloxy.

8. The process for producing a 2-amino-5-methoxybenzoic acid derivative by electroreduction according to claim 1, wherein the 2-amino-5-methoxybenzoic acid derivative (i) is selected from the group consisting of compounds represented by the formula iii:

wherein n is selected from: 1, 2 or 3; r is selected from: hydrogen, methyl, ethyl or benzyl; m is selected from: CH or N; w is selected from: CH (CH)₂，O，S，NH，HOCH，BocN，MeN，EtN，C₆H₅N，4-ClC₆H₄N or 4-HOC₆H₄N。

9. The process for producing 2-amino-5-methoxybenzoic acid derivatives by electroreduction according to claim 1, wherein the 2-amino-5-methoxybenzoic acid derivative (i) is selected from the group consisting of the following compounds:

10. the process for producing 2-amino-5-methoxybenzoic acid derivatives by electroreduction according to claim 1, wherein the 2-amino-5-methoxybenzoic acid derivative (i) is selected from the group consisting of the following compounds:

Technical Field

The invention relates to an electroreduction preparation method of an intermediate of an anticancer drug vandetanib and an analogue thereof, in particular to a method for preparing a 2-amino-5-methoxybenzoic acid derivative by electroreduction of a 5-methoxy-2-nitrobenzoic acid derivative (A).

Background

Vandetanib (Vandetanib, 4- (4-bromo-2-fluoroanilino) -6-methoxy-7- [ (1-methylpiperidin-4-yl) methoxy ] quinazoline), a kinase inhibitor, is indicated for the treatment of unresectable, locally advanced or metastatic symptomatic or progressive medullary thyroid cancer.

Vandetanib (Vandetanib) is prepared by taking vanillic acid as a raw material through a protection and deprotection process [ Chemical process. WO.2007/036713A2.2005 ]: wherein, sodium hydrosulfite [ US20100075916A1] is selected for reduction reaction of the 5-methoxy-4-benzyloxy-2-benzyl nitrobenzoate, and the yield is 71%; tin dichloride reduction [ J Med Chem,2002,45(17):3772-3793] was selected in ethyl acetate solvent in 95% yield.

Zhao Ling et al (Vandini's synthetic process research. Wuhan academy of industry, 2012, 31(2): 35-38).]Also describes that the vandetanib is prepared by adopting the vanillic acid methyl ester as the raw material through a similar process; wherein the reduction of the methyl 5-methoxy-4-benzyloxy-2-nitrobenzoate is catalyzed by potassium carbonate, and sodium hydrosulfite (Na)₂S₂O₄) As a reducing agent, the yield is 93% [ CN102603718A,2012-07-25]](ii) a Selecting iron powder-ammonium chloride [ med.chem.commun.,2017, 8: 1069-1092]Reduction; selecting ethanol solvent, and reducing by iron powder [ CN101835375A,2010-09-15 ]]The yield is 85%; selecting ethanol, glacial acetic acid and water as a mixed solvent, and reducing by iron powder [ ChemMedChem,2016,11(20): 2327-2338)](ii) a Selecting iron powder-ammonium formate (Hangzhou university journal (Nature science edition), 2010,9(4):248-]Reduction, yield 93.12%; selectively armorAlcohol solvent, zinc powder-glacial acetic acid [ Eur Med Chem,2017,125:245-]Reducing and refluxing for 3h, wherein the yield is 84.7%.

Liuyu et al [ Synthesis of anticancer drug vandetanib, J. China antibiotic 2011, 36(12):917-920] describe the synthetic route of vandetanib: selecting 4-hydroxymethyl piperidine tert-butyl formate, and carrying out mesylation, etherification with vanillic acid methyl ester, N-methylation, nitration, reduction, cyclization, acyl chlorination and amination reaction to obtain vandetanib. Wherein, the reduction selective catalytic hydrogenation of 5-methoxy-4- [ (1-methylpiperidin-4-yl) methoxy-2-nitrobenzoic acid methyl ester:

scholars of Beijing university of teachers [ Euro J Med Chem 2017, 138: 669-688 ] describes a preparation method of 2-amino-5-methoxy-4- (3-chloropropoxy) methyl benzoate as an intermediate of anticancer active compound: iron powder is adopted to reduce 5-methoxy-4- (3-chloropropoxy) -2-nitrobenzoic acid methyl ester in acetic acid at 80 ℃ to obtain 2-amino-5-methoxy-4- (3-chloropropoxy) benzoic acid methyl ester with the yield of 82 percent.

Teliez et al [ ChemMedChem 2007, 2: 318-332 describes a preparation method of 2-amino-5-methoxy-4- (3-morpholinylpropoxy) methyl benzoate as an intermediate of an anticancer active compound: the 5-methoxy-4- (3-morpholinylpropoxy) -2-nitrobenzoic acid methyl ester is reduced by tin dichloride to obtain the 2-amino-5-methoxy-4- (3-morpholinylpropoxy) benzoic acid methyl ester with the yield of 40 percent.

By the use of nitro compoundsThe hydrogenation method comprises the following steps: the catalyst palladium is relatively expensive; the palladium catalyst and the reduction product amino compound intermediate form a complex which is difficult to separate, and the purity of the intermediate and the standard exceeding of heavy metals in anticancer drug products are influenced. Inorganic reducing agent sodium hydrosulfite, 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; FeCl₃The reduction of/C-hydrazine hydrate, hydrazine hydrate and the like seriously pollutes the environment.

Disclosure of Invention

The technical problem to be solved by the invention is to provide an electroreduction preparation method of an intermediate 2-amino-5-methoxybenzoic acid derivative of vandetanib and an analogue thereof as an anticancer drug; to overcome the problems of the classical reduction reaction.

In order to solve the technical problem, the invention provides the following technical scheme:

the technical scheme of the invention provides an electroreduction preparation method of a 2-amino-5-methoxybenzoic acid derivative (I) as an intermediate of vandetanib and an analogue thereof, which is characterized in that the 2-amino-5-methoxybenzoic acid derivative (I) is prepared from a 5-methoxy-2-nitrobenzoic acid derivative (A) through an electroreduction method; the preparation reaction is as follows:

wherein n is selected from: 1, 2 or 3; r is selected from: hydrogen, methyl, ethyl or benzyl;

y is selected from: c₆H₅HO, Cl, Br, methanesulfonyloxy, p-toluenesulfonyloxy orM is selected from: CH or N; w is selected from: CH (CH)₂，O，S，NH，HOCH，BocN，MeN，EtN，C₆H₅N，4-ClC₆H₄N or 4-HOC₆H₄N。

Further, a process for producing a 2-amino-5-methoxybenzoic acid derivative (I) by electroreduction, wherein the 2-amino-5-methoxybenzoic acid derivative (I) is selected from the group consisting of compounds represented by the formula II:

wherein n is selected from: 1, 2 or 3; r is selected from: hydrogen, methyl, ethyl or benzyl; y is selected from: c₆H₅HO, Cl, Br, methanesulfonyloxy or p-toluenesulfonyloxy.

Further, a process for producing a 2-amino-5-methoxybenzoic acid derivative (I) by electroreduction, wherein the 2-amino-5-methoxybenzoic acid derivative (I) is selected from the group consisting of compounds represented by the following formula III:

wherein n is selected from: 1, 2 or 3; r is selected from: hydrogen, methyl, ethyl or benzyl; m is selected from: CH or N; w is selected from: CH (CH)₂，O，S，NH，HOCH，BocN，MeN，EtN，C₆H₅N，4-ClC₆H₄N or 4-HOC₆H₄N。

Further, a process for producing a 2-amino-5-methoxybenzoic acid derivative (I) by electroreduction, wherein the 2-amino-5-methoxybenzoic acid derivative (I) is selected from the group consisting of the following compounds:

further, a process for producing a 2-amino-5-methoxybenzoic acid derivative (I) by electroreduction, wherein the 2-amino-5-methoxybenzoic acid derivative (I) is selected from the group consisting of the following compounds:

in order to achieve the above object, the electro-reduction preparation method of the 2-amino-5-methoxybenzoic acid derivative of the present invention comprises:

in a diaphragm electrolytic cell, an acid solution of the 5-methoxy-2-nitrobenzoic acid derivative (A) is taken as a cathode electrolyte, or the acid solution of the 5-methoxy-2-nitrobenzoic acid derivative (A) and an organic solvent form the cathode electrolyte; the acid aqueous solution is an anolyte; obtaining a cathode electrolysis product containing the 2-amino-5-methoxybenzoic acid derivative through an electro-reduction reaction.

The voltage of the cathode working electrode is 1.00V-2.50V relative to the reference electrode; the current density of the cathode working electrode is 25.0mA/cm²～250.0mA/cm²To (c) to (d); the electrolysis temperature is between 15 and 80 ℃.

The principle of the electro-reduction reaction of the 5-methoxy-2-nitrobenzoic acid derivative (A) is that the reaction formula of a cathode under an acidic condition is as follows:

the stepwise reaction formula is as follows:

in the step reaction formula, the structural formula (1) is taken as a raw material, and the structural formulas (2) to (5) are intermediate products or byproducts; the structural formula I is a main product, namely a 2-amino-5-methoxybenzoic acid derivative.

The reaction formula of the anode under the acidic condition is as follows:

6H₂O→12H⁺+3O₂+12e^-

the overall reaction formula is:

after the electrolysis is completed, a cathode electrolysis product containing the 2-amino-5-methoxybenzoic acid derivative shown as I is obtained.

Preferably, the reference electrode of the diaphragm electrolyzer is: a saturated potassium chloride calomel electrode.

The cathode of the diaphragm electrolytic cell is as follows: brass electrodes, red copper electrodes, titanium mesh electrodes, nickel, lead, platinum or graphite electrodes.

The anode of the diaphragm electrolytic cell is: DSA electrode, platinum mesh electrode or titanium-based platinum electrode; the DSA electrode and the metal oxide anode are mainly oxides of titanium, manganese, cobalt, noble metals such as ruthenium and iridium, and the matrix is titanium.

The diaphragm of the diaphragm electrolytic cell is as follows: HF-101 strong acid cation exchange membrane.

The organic solvent in the catholyte is any one or more of ethyl acetate, C1-C5 straight-chain alcohol, C2-C5 branched-chain alcohol or acetonitrile.

Preferably, the concentration of the 5-methoxy-2-nitrobenzoic acid derivative (A) in the catholyte is between 3.0g/L and 15.0 g/L.

The acidic aqueous solution serves as an electrolyte for the electro-reduction reaction, and the catholyte has suitable conductivity in this concentration range.

Preferably, the acid solution in the catholyte is selected from: phosphoric acid solution, sulfuric acid solution or hydrochloric acid solution; the acidic solution facilitates the supply and migration of protons.

Preferably, the anolyte is selected from the group consisting of: phosphoric acid solution, sulfuric acid solution or hydrochloric acid solution, the acid solution being favorable for the supply and migration of protons.

Preferably, the liquid levels of the catholyte and the anolyte are at the same level.

The beneficial technical effects are as follows:

the invention relates to an electroreduction preparation method of an intermediate I of vandetanib and an analogue thereof serving as an anticancer drug, and the electroreduction preparation method of the 2-amino-5-methoxybenzoic acid derivative has the following advantages:

(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 5-methoxy-2-nitrobenzoic acid derivative (A) may not require the use of an organic solvent.

Toxic or dangerous reducing agents are not needed in the electro-reduction reaction, and the method is an important component for developing the green pharmaceutical industry; by varying the electrode potential, the conversion and selectivity can be controlled, thereby obtaining high purity and high yield intermediates.

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.