CN110747489B - Electroreduction preparation method of intermediate of anticancer drug gefitinib and analogue thereof - Google Patents
Electroreduction preparation method of intermediate of anticancer drug gefitinib and analogue thereof Download PDFInfo
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Abstract
The invention relates to an electroreduction preparation method of a 2-amino-4-methoxybenzoic acid derivative shown in a formula I, which comprises the following preparation reactions:
wherein n is selected from: 1, 2 or 3; x is selected from: CO 22H，CO2Me，CO2Et，CO2Bn，CONH2Or CN; bn is benzyl; y is selected from: HO, Cl, Br, MsO, TsO or
M is selected from: CH or N; w is selected from: CH (CH)2O, S, NH, HOCH, Men or EtN. The invention relates to an electroreduction preparation method of a 2-amino-4-methoxybenzoic acid derivative I, which is characterized in that in a diaphragm electrolytic cell, an acidic solution or a mixed solution of inorganic ammonium salt, an organic solvent and water of the 4-methoxy-2-nitrobenzoic acid derivative is used as a catholyte; the voltage of the cathode working electrode is 1.00V-2.50V relative to the reference electrode; the anolyte is acidic solution, and is electrolyzed at constant current or constant voltage, and the current density of the constant current is 20.0mA/cm2～250.0mA/cm2The electrolysis temperature is between 20 and 80 ℃.
Description
Technical Field
The invention relates to an electroreduction preparation method of an anticancer drug gefitinib and an analogue intermediate thereof, in particular to a method for preparing a 2-amino-4-methoxybenzoic acid derivative by electroreduction of a 4-methoxy-2-nitrobenzoic acid derivative (A).
Background
Gefitinib is a selective Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibitor, EGFR 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.
Dawn, zhangeiqin and the like [ a preparation method of gefitinib, CN 102030716a, 2011-04-27] describe that 3, 4-dimethoxybenzoic acid is subjected to nitration, demethylation and methyl esterification to obtain an intermediate 2-nitro-4-methoxy-5-hydroxybenzoic acid methyl ester, and then alkyl side chain is introduced for reaction to obtain gefitinib. Wherein 4-methoxy-5- (3-morpholinylpropoxy) -2-nitrobenzoic acid methyl ester is subjected to catalytic hydrogenation to prepare 2-amino-4-methoxy-5- (3-morpholinylpropoxy) benzoic acid methyl ester:
xuzhou's right et al (gefitinib synthesis research, chemical and biological engineering, 2011(1): 20-22.) describe 3-hydroxy-4-methoxybenzaldehyde, which is first converted into 3-hydroxy-4-methoxybenzonitrile, then condensed with N- (3-chloropropyl) morpholine, and then nitrated, reduced, reacted with DMF-DMA, and reacted with 3-chloro-4-fluoroaniline to synthesize gefitinib. Wherein, the reduction of 4-methoxy-5- (3-morpholinylpropoxy) -2-nitrobenzonitrile selects sodium hydrosulfite (sodium hydrosulfite) as a chemical reducing agent:
tengwei [ Gefitinib and erlotinib synthesis process research, Shenyang pharmaceutical university Master thesis, 2008] describes that 3-hydroxy-4-methoxybenzoic acid is subjected to cyanidation, etherification and nitration to generate a key intermediate 4-methoxy-5- (3-morpholinylpropoxy) -2-nitrobenzonitrile, 4-methoxy-5- (3-morpholinylpropoxy) -2-nitrobenzonitrile is reduced by sodium hydrosulfite, and then Gefitinib is obtained through two-step reaction:
chen ren macro and the like [ research on Gefitinib synthesis process, China journal of pharmacy 2012, 47(13):1084-1087] describe that veratraldehyde is subjected to nitration, selective demethylation, nucleophilic substitution, reduction, amination, ring closure and other reactions to obtain Gefitinib. Wherein, the reduction of 4-methoxy-5- (3-morpholinylpropoxy) -2-nitrobenzonitrile selects sodium hydrosulfite as a chemical reducing agent:
zheng and jimin et al [ Novel prediction of gefitinib. J Chem Research, 2009, 6: 388-; WO101148439A1, 2008-03-26 describes that sodium hydrosulfite is used as a reducing agent, and the yield is 90%. Shih et al [ Shih Kaeshyang, et al synthetic method for 6, 7-substitents-4-aniline quinazoline, WO101148439A1, 2011-12-01] describe catalytic hydrogenation at 50psi pressure with 10% Pd/C as catalyst. Although the reduction yield is high, the pressure is high, and the equipment safety requirement is high. Li-Astro et al [ A preparation method of Gefitinib, CN 102030716A, 2011-04-27] describe catalytic hydrogenation with 10% Pd/C as catalyst under normal pressure.
Sunjin and the like [ the research on a synthetic method of an anti-tumor drug gefitinib, the chemical research and the application thereof, 2013, (8) 1180-1184] takes isovanillin as a raw material, and prepares the gefitinib through reactions such as cyanation, chloropropylation, nitration, reduction, rearrangement, introduction of morpholinyl and the like. Wherein, the reduction of 4-methoxy-5- (3-chloropropoxy) -2-nitrobenzonitrile selects sodium hydrosulfite as a chemical reducing agent:
xujiankang et al (Gefitinib synthesis research. Wash. J. Pharmacology, 2012, 27(4): 362-364.) describe veratraldehyde, which was reacted in the following 10 steps to obtain Gefitinib. Wherein 4-methoxy-5- (3-hydroxy propoxy) -2-nitrobenzoic acid methyl ester is subjected to catalytic hydrogenation to prepare 2-amino-4-methoxy-5- (3-hydroxy propoxy) benzoic acid methyl ester:
the university of southeast university scholars [ Bioorg Med Chem,2010,18(11):3812-3822] describes a preparation method of 2-amino-4-methoxy-5- (3-chloropropoxy) methyl benzoate as an intermediate of an anticancer active compound, and the 4-methoxy-5- (3-chloropropoxy) -2-nitrobenzoic acid methyl ester is reduced by iron powder and acetic acid to obtain the 2-amino-4-methoxy-5- (3-chloropropoxy) methyl benzoate with the yield of 77 percent.
Chongzhang et al [4- (3-chloro-4-fluorophenylamino) -7-methoxy-6- (3-morpholinopropoxy) quinazoline preparation method CN1773738A, 2006-02-15] adopts 3, 4-dimethoxybenzoic acid as a raw material, and gefitinib is prepared through reactions such as nitration, demethylation, reduction, ring closure, chlorination, substitution, etherification and the like. Wherein the reduction of 5-hydroxy-4-methoxy-2-nitrobenzoic acid selects iron powder as a metal reducing agent:
the nitro compound adopts a catalytic hydrogenation method: 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. The inorganic reducing agent sodium hydrosulfite, Fe/HOAc, Fe/HCl 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 invention solves the technical problem of providing an electroreduction preparation method of an anticancer drug gefitinib and an analogue intermediate thereof, namely a 2-amino-4-methoxybenzoic acid derivative (I).
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-4-methoxybenzoic acid derivative (I), which is characterized in that the 4-methoxy-2-nitrobenzoic acid derivative (A) is subjected to electroreduction to prepare the 2-amino-4-methoxybenzoic acid derivative (I), and the preparation reaction is as follows:
wherein n is selected from: 1, 2 or 3; x is selected from: CO 22H，CO2Me，CO2Et，CO2Bn，CONH2Or CN; bn is benzyl;
y is selected from: HO, Cl, Br, MsO, TsO or
Ms is methylsulfonyl; ts is p-toluenesulfonyl; w is selected from: CH (CH)2O, S, NH, HOCH, Men or EtN; m is selected from: CH or N.
Further, a process for producing a 2-amino-4-methoxybenzoic acid derivative (I) by electroreduction, wherein the 2-amino-4-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: HO, Cl, Br, MsO or TsO.
Further, a process for producing a 2-amino-4-methoxybenzoic acid derivative (I) by electroreduction, wherein the 2-amino-4-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; w is selected from: CH (CH)2O, S, NH, HOCH, Men or EtN; m is selected from: CH or N.
Further, a process for producing a 2-amino-4-methoxybenzoic acid derivative (I) by electroreduction, wherein the following compounds are preferred as the 2-amino-4-methoxybenzoic acid derivative:
further, a process for producing 2-amino-4-methoxybenzoic acid derivative (I) by electroreduction, wherein the following compounds are preferred for 4-methoxy-2-nitrobenzoic acid derivative (A):
further, a process for producing 2-amino-4-methoxybenzoic acid derivative (I) by electroreduction, wherein the following compounds are preferred for 4-methoxy-2-aminobenzoic acid derivative (I):
further, a process for producing 2-amino-4-methoxybenzoic acid derivative (I) by electroreduction, wherein the following compounds are preferred for 4-methoxy-2-nitrobenzoic acid derivative (A):
in order to achieve the purpose, the electro-reduction preparation method of the 2-amino-4-methoxybenzoic acid derivative (I) comprises the following steps:
in a diaphragm electrolytic cell, an acid solution of the 4-methoxy-2-nitrobenzoic acid derivative (A) is taken as a catholyte, or a mixed solution of inorganic ammonium salt, an organic solvent and water of the 4-methoxy-2-nitrobenzoic acid derivative (A) is taken as the catholyte; the acid aqueous solution is an anolyte; the cathode electrolysis product containing the 2-amino-4-methoxybenzoic acid derivative is obtained through the electro-reduction reaction.
The principle of the electro-reduction reaction of the 4-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 target product, namely a 2-amino-4-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:
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 20.0mA/cm2～250.0mA/cm2To (c) to (d); the electrolysis temperature is between 20 ℃ and 80 ℃.
After the electrolysis is completed, a cathode electrolysis product containing the 2-amino-4-methoxybenzoic acid derivative shown as I is obtained.
Within the range of the working voltage and the current density of the electrode, the structural formula I is a main product, namely the 2-amino-4-methoxybenzoic acid derivative, the selectivity of the main product is highest, and the yield of the intermediate products or byproducts of the structural formulas (2) to (5) is lowest.
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: a DSA electrode or a 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 and acetonitrile.
Preferably, the concentration of the 4-methoxy-2-nitrobenzoic acid derivative (A) in the catholyte is between 2.0g/L and 16.0 g/L. In the cathode electrolyte, the concentration of the 4-methoxy-2-nitrobenzoic acid derivative (A) is too high, the dissolution is not good, and the reduction reaction is not favorably carried out; if the concentration is too low, the equipment utilization rate and the reduction reaction efficiency are lowered. The concentration of the acid within the range can ensure the dissolution of the 4-methoxy-2-nitrobenzoic acid derivative (A), provide good conductivity of the electrolyte and sufficient proton and electron generation, and facilitate the post-treatment of the electric reduction product.
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 catholyte is a phosphoric acid solution, a sulfuric acid solution or a hydrochloric acid solution containing the 4-methoxy-2-nitrobenzoic acid derivative (A), and the acid solution is favorable for supplying and transferring protons.
Preferably, the catholyte is a mixed solution of inorganic ammonium salt containing the 4-methoxy-2-nitrobenzoic acid derivative (A), an organic solvent and water; the inorganic ammonium salt in the catholyte is: ammonium chloride, ammonium sulfate, ammonium nitrate, ammonium carbonate, ammonium bromide, or ammonium iodide; ammonium ions have good conductivity.
Preferably, the anolyte is a phosphoric acid solution, a sulfuric acid solution or a hydrochloric acid solution, and the acidic solution is favorable for supplying and transferring 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 anticancer drug gefitinib and an analogue intermediate 2-amino-4-methoxybenzoic acid derivative (I), and the electroreduction preparation method of the 2-amino-4-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 4-methoxy-2-nitrobenzoic acid derivative (A) in part does not require the use of organic solvents.
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.
Example 1
Preparation of 2-amino-4-methoxy-5- (3-chloropropoxy) methyl benzoate by electroreduction
A separate electrolytic cell was installed (fig. 1). A magnetic stirrer is added into a cathode (Cu) electrolytic tank, 0.45g of 4-methoxy-5- (3-chloropropoxy) -2-nitrobenzoic acid methyl ester is completely dissolved in 60mL of methanol, 60mL of a 0.5mol/L hydrochloric acid solution or a solution prepared from 6.0g of ammonium chloride and 60mL of water is added, and 120mL of a 0.25mol/L sulfuric acid solution is added into an anode (DSA) electrolytic tank. The effective electrode areas of the cathode (Cu) and the anode (DSA) were each 4cm2Controlling the current at two ends of the anode and the cathode to be 0.3A, and carrying out constant current electrolysis with the constant current density of 75mA/cm2The voltage between the cathode and the reference is 1.1-1.4V; stirring the mixture in a water bath at 40 ℃ for an electro-reduction reaction for 4 hours, taking out a cathode solution, adjusting the cathode solution to be alkalescent by using a 10% NaOH solution, extracting the mixture for 2 times by using dichloromethane, drying the mixture by using anhydrous sodium sulfate, carrying out suction filtration, carrying out solvent desolventization, and drying the mixture to obtain 0.38g of 2-amino-4-methoxy-5- (3-chloropropoxy) methyl benzoate, wherein the melting point is 97-99 ℃, and the yield is 93.8%;1H NMR(400MHz，CDCl3)δ：7.36(s，1H，C6H2 6-H)，6.15(s，1H，C6H2 3-H)，4.08(t，J＝6.0Hz，2H，OCH2)，3.85(s，3H，COOCH3)，3.84(s，3H，OCH3)，3.77(t，J＝6.4Hz，2H，ClCH2)，2.21～2.27(m，2H，CH2)。1H NMR(400MHz，DMSO-D6)δ：7.17(s，1H，C6H26-H)，6.50(s，1H，NH2)，6.37(s，1H，C6H2 3-H)，3.92(t，J＝6.0Hz，2H，OCH2)，3.78(t，J＝6.4Hz，2H，ClCH2)，3.75(s，3H，COOCH3)，3.74(s，3H，OCH3)，2.07～2.13(m，2H，CH2)。
example 2 (control experiment)
Preparation of methyl 2-amino-4-methoxy-5- (3-chloropropoxy) benzoate
Reduction of methyl 4-methoxy-5- (3-chloropropoxy) -2-nitrobenzoate using iron powder and acetic acid to give methyl 2-amino-4-methoxy-5- (3-chloropropoxy) benzoate, melting point: 96-98 ℃ and the yield is 77%.
Example 3
Preparation of 2-amino-4-methoxy-5- (3-morpholinylpropoxy) methyl benzoate by electroreduction
In the diaphragm type electrolytic cell shown in FIG. 1, a magnetic stirrer, 0.50g of 4-methoxy-5- (3-morpholinopropoxy) -2-nitrobenzoic acid methyl ester and 120mL of a 0.5mol/L hydrochloric acid solution were added to a cathode (Cu) electrolytic cell, and stirred to be completely dissolved, and 120mL of a 0.25mol/L sulfuric acid solution was added to an anode (DSA) electrolytic cell. The cathode uses Saturated Calomel Electrode (SCE) as reference electrode, constant voltage between cathode and reference is controlled to be 2.0V, and effective electrode areas of cathode (Cu) and anode (DSA) are respectively 4cm2The current density is 60mA/cm2(ii) a Stirring the mixture in a water bath at 40 ℃ for an electro-reduction reaction for 3.0h, taking out a cathode solution, adjusting the mixture to be alkalescent by using a 10% NaOH solution, extracting the mixture for 2 times by using dichloromethane, drying the mixture by using anhydrous sodium sulfate, carrying out suction filtration, carrying out solvent desolventization, and drying the mixture to obtain 0.45g of 2-amino-4-methoxy-5- (3-morpholinylpropoxy) methyl benzoate, wherein the melting point is 90-92 ℃, and the yield is 98.3%;1H NMR(400MHz，CDCl3)δ：1.97～2.02(m，2H，CH2)，2.48(t，J＝4.6Hz，4H，CH2NCH2)，2.54(t，J＝7.2Hz，2H，NCH2)，3.73(t，J＝4.6Hz，4H，CH2OCH2)，3.84(s，3H，OCH3)，3.85(s，3H，COOCH3)，4.01(t，J＝6.4Hz，2H，OCH2)，5.60(s，2H，NH2)，6.14(s，1H，C6H2 3-H)，7.34(s，1H，C6H2 6-H)。
example 4 (control experiment)
Preparation of methyl 2-amino-4-methoxy-5- (3-morpholinylpropoxy) benzoate
The compound is prepared by a method of a document [ Novel preparation of gefitinib. J Chem Res,2009: 388-390 ], and sodium hydrosulfite (sodium hydrosulfite) is adopted to reduce 4-methoxy-5- (3-morpholinylpropoxy) -2-nitrobenzoic acid methyl ester to obtain 2-amino-4-methoxy-5- (3-morpholinylpropoxy) benzoic acid methyl ester, the melting point is 89-90 ℃, and the yield is 90%.
Example 5
Preparation of ethyl 2-amino-4-methoxy-5- (3-morpholinylpropoxy) benzoate by electroreduction
Ethyl 4-methoxy-5- (3-morpholinopropoxy) -2-nitrobenzoate was electroreduced as in example 3 to give ethyl 2-amino-4-methoxy-5- (3-morpholinopropoxy) carboxylate.
Example 6 (use or application)
Preparation of gefitinib
Referring to [ a preparation method of gefitinib, CN 102030716a, 2011-04-27], gefitinib is prepared according to the following route:
example 7
Preparation of 2-amino-4-methoxy-5- (3-morpholinylpropoxy) benzamide by electroreduction
4-methoxy-5- (3-morpholinopropoxy) -2-nitrobenzamide was electroreduced as in example 3 to give 2-amino-4-methoxy-5- (3-morpholinopropoxy) benzamide.
Wherein the 4-methoxy-5- (3-morpholinylpropoxy) -2-nitrobenzamide is prepared according to a method of a document [ the research of the gefitinib synthesis process, China journal of pharmacy 2012, 47(13):1084-1087 ].
Example 8
Preparation of 2-amino-4-methoxy-5- (3-morpholinylpropoxy) benzonitrile by electroreduction
4-methoxy-5- (3-morpholinopropoxy) -2-nitrobenzonitrile was electroreduced as in example 3 to give 2-amino-4-methoxy-5- (3-morpholinopropoxy) benzonitrile.
Wherein, the 4-methoxy-5- (3-morpholinylpropoxy) -2-nitrobenzonitrile is prepared according to the method of the literature [ the synthesis process research of gefitinib and erlotinib, Shenyang pharmaceutical university Master thesis, 2008 ].
The electro-reduction preparation method of the 2-amino-4-methoxybenzoic acid derivative simplifies the process flow and reduces the production cost in industrial production, basically has no pollution to the environment, and is suitable for large-scale popularization and application.
In the present specification, the invention has been described with reference to specific embodiments thereof. It will, however, be evident that various modifications and changes may be made thereto without departing from the broader spirit and scope of the invention. The specification and drawings are, accordingly, to be regarded in an illustrative rather than a restrictive sense.
Claims (8)
1. The electro-reduction preparation method of the 2-amino-4-methoxybenzoic acid derivative shown in the structural formula I is characterized in that the preparation reaction is as follows:
n is selected from: 1, 2 or 3; x is selected from: CO 22H，CO2Me，CO2Et，CO2Bn or CONH2(ii) a Bn is benzyl;
y is selected from: HO, Cl, Br, MsO, TsO or
Ms is methylsulfonyl; ts is p-toluenesulfonyl; w is selected from: CH (CH)2O, S, NH, HOCH, Men or EtN; m is selected from: CH or N;
wherein: the compounds of formula I do not include compounds of the following structure:
in a diaphragm electrolytic cell, taking an acidic solution of a 4-methoxy-2-nitrobenzoic acid derivative A or a mixed solution of inorganic ammonium salt, an organic solvent and water as a catholyte; the acid aqueous solution is an anolyte; obtaining a cathode electrolysis product containing the 2-amino-4-methoxybenzoic acid derivative through an electroreduction reaction;
the reference electrode of the diaphragm electrolyzer was: 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;
the working voltage of the cathode of the diaphragm electrolytic cell is 1.00V-2.50V relative to the reference electrode; the electrode current density of the cathode is 20.0mA/cm2～250.0mA/cm2To (c) to (d); the working temperature of the diaphragm electrolytic cell is between 20 and 80 ℃.
2. The process for preparing 2-amino-4-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.
3. The process for producing 2-amino-4-methoxybenzoic acid derivatives by electroreduction according to claim 1, wherein the catholyte is a phosphoric acid solution, a sulfuric acid solution or a hydrochloric acid solution containing 4-methoxy-2-nitrobenzoic acid derivatives; the anolyte is a phosphoric acid solution, a sulfuric acid solution or a hydrochloric acid solution.
4. The process for preparing 2-amino-4-methoxybenzoic acid derivatives by electroreduction according to claim 1, wherein the inorganic ammonium salt in the catholyte is: ammonium chloride, ammonium sulfate, ammonium nitrate, ammonium carbonate, ammonium bromide, or ammonium iodide.
5. The process for producing a 2-amino-4-methoxybenzoic acid derivative by electroreduction according to claim 1, wherein the 2-amino-4-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: HO, Cl, Br, MsO or TsO.
6. The process for producing a 2-amino-4-methoxybenzoic acid derivative by electroreduction according to claim 1, wherein the 2-amino-4-methoxybenzoic acid derivative i is selected from the group consisting of compounds represented by the formula iii:
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)2O, S, NH, HOCH, Men or EtN;
wherein: the compounds of formula iii do not include compounds of the following structure:
7. the process for producing 2-amino-4-methoxybenzoic acid derivatives by electroreduction as claimed in claim 1, wherein the 2-amino-4-methoxybenzoic acid derivative I is selected from the group consisting of the following compounds:
8. the process for producing 2-amino-4-methoxybenzoic acid derivatives by electroreduction as claimed in claim 1, wherein the 2-amino-4-methoxybenzoic acid derivative I is selected from the group consisting of the following compounds:
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