Method for preparing 2-chloro-3-aminobenzoic acid and ester compound thereof

Abstract

A method for preparing 2-fluoro-3-aminobenzoic acid and an ester compound thereof. The reaction formula is as follows. Specifically, a compound I is nitrated under suitable reaction conditions to obtain a compound II; the compound II is halogenated under suitable reaction conditions to obtain a compound III; the compound III is fluorinated under suitable reaction conditions to obtain a compound IV; the compound IV is hydrolyzed or alcoholyzed under suitable reaction conditions to prepare a compound V; and the compound V is subjected to catalytic hydrogenation dehalogenation under suitable reaction conditions to obtain 2-fluoro-3-aminobenzoic acid and an ester compound thereof, namely a compound X. The starting material of the process route is cheap and easy to obtain, the procedures of the process are operated by common units in fine chemical industry, the operation is convenient, the reaction conversion rate is high, and the selectivity is good. The method provides an effective preparation method for industrial development of the compound.

Description

A method for preparing 2-fluoro-3-aminobenzoic acid and its ester compounds Technical Field

[0001] The invention belongs to the field of organic synthesis, and particularly relates to a method for preparing 2-fluoro-3-aminobenzoic acid and its ester compounds. Background Art

[0002] 2-Fluoro-3-aminobenzoic acid and its ester compounds are important intermediates in organic synthesis and pharmaceutical pesticides, and are key intermediates in the insecticide broflanilide.

[0003] Taking methyl 2-fluoro-3-aminobenzoate as an example, the methods for preparing this type of compound in the prior art are mainly as follows:

[0004] Document WO2011059610 reports two methods for preparing methyl 2-fluoro-3-aminobenzoate, the specific routes are as follows:

[0005] Among them, the first route has expensive starting raw materials and high costs; the second route has poor selectivity in the nitration reaction and is difficult to purify, with high yield and low cost. The oxidation reaction uses strong oxidants, which has a high risk factor and great environmental pressure, and is not suitable for industrial production.

[0006] Document CN111320548 reports a method for preparing methyl 2-fluoro-3-aminobenzoate, the specific route is as follows:

[0007] The fluorination reaction selectivity of this route is poor (product: isomer = 30:1) and purification is difficult, resulting in high production costs and is not suitable for industrial production.

[0008] Document WO2021070124 reports a feasible method for preparing methyl 2-fluoro-3-aminobenzoate, the specific route is as follows:

[0009] This route uses expensive starting materials and highly toxic sodium cyanide, and the operating conditions are relatively harsh, making it unsuitable for industrial production.

[0010] Document CN114920661 reports a feasible method for preparing methyl 2-fluoro-3-aminobenzoate, the specific route is as follows:

[0011] Document CN113717053 reports a feasible method for preparing methyl 2-fluoro-3-aminobenzoate, the specific route is as follows:

[0012] This route uses the strong base lithium amide, and the operating conditions are relatively harsh, making it unsuitable for industrial production.

[0013] Therefore, it is of great significance to use cheap and readily available starting materials, find a suitable synthesis process, and ultimately develop a method suitable for the industrial production of 2-fluoro-3-aminobenzoic acid and its ester compounds.

[0014] Summary of the Invention

[0015] The present invention aims to provide a method for preparing 2-fluoro-3-aminobenzoic acid and its ester compounds, which has the advantage of being suitable for industrial production.

[0016] To achieve the above object, the technical solution of the present invention is as follows:

[0017] A method for preparing 2-fluoro-3-aminobenzoic acid and its ester compounds, the reaction formula is:

[0018] 1) Compound I is nitrated under suitable reaction conditions to obtain Compound II;

[0019] 2) Compound II is halogenated under suitable reaction conditions to obtain Compound III;

[0020] 3) Compound III is fluorinated under suitable reaction conditions to obtain compound IV;

[0021] 4) Compound IV is hydrolyzed or alcoholyzed under suitable reaction conditions to prepare compound V;

[0022] 5) Compound V is subjected to catalytic hydrodehalogenation under suitable reaction conditions to obtain Compound X;

[0023] in:

[0024] X is selected from chlorine, bromine or iodine;

[0025] Y is selected from chlorine, bromine or iodine;

[0026] R is selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, and unsubstituted or optionally substituted benzyl.

[0027] The above unsubstituted or optionally substituted benzyl is benzyl or benzyl is optionally substituted by 1 to 5 of the following substituents: halogen, nitro, cyano, CONH2, CHO, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C2-C6 haloalkynyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio ... -C6 haloalkylthio, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyl, C1-C6 haloalkylcarbonyl, C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfonyl, C1-C6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, C1-C6 alkylaminocarbonyl or C1-C6 alkylaminosulfonyl.

[0028] The first step of the nitration reaction is to react compound I in a mixed solution of sulfuric acid or glacial acetic acid and nitric acid at a reaction temperature of -20-100°C to obtain compound II; wherein the mass ratio of compound I, sulfuric acid / glacial acetic acid and nitric acid is 1:1-10:1-5.

[0029] The mixed solutions can be added after mixing, added sequentially, or a portion of one solution can be added first and the remaining portion can be mixed with the other solution and added.

[0030] The sulfuric acid is added into the system until the concentration of sulfuric acid in the system reaches 30%-90%.

[0031] The nitric acid is concentrated nitric acid or fuming nitric acid; wherein the nitric acid concentration in the system reaches 10%-70%.

[0032] The operation of the second step halogenation reaction is that compound II reacts in a suitable halogenating agent in the presence of a suitable catalyst A at a reaction temperature of -20-200°C to obtain compound III; wherein the mass ratio of compound II, halogenating agent and catalyst A is 1:1-50:0.1-10.

[0033] The suitable halogenating agent is selected from one or more of a chlorinating agent, a brominating agent or an iodinating agent; such as one or more of chlorine, oxalyl chloride, thionyl chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, liquid bromine, hydrobromic acid, phosphorus oxybromide, elemental iodine, hydroiodic acid, etc.;

[0034] Suitable catalyst A is selected from one or more of DMF or organic bases, such as one or more of DMF, pyridine, triethylamine, N,N-diisopropylethylamine, etc.

[0035] The third step of fluorination reaction is to react compound III with a suitable fluorinating agent in a suitable reaction solvent A, in the presence or absence of a suitable catalyst B, at a reaction temperature of 0-200° C. to obtain compound IV; wherein the mass ratio of compound III, fluorinating agent, reaction solvent A and catalyst B is 1:0.1-3:1-50:0-1;

[0036] The fluorination agent is selected from one or more of lithium fluoride, potassium fluoride, sodium fluoride, ammonium fluoride or cesium fluoride;

[0037] The reaction solvent A is selected from one or more polar aprotic solvents or benzene solvents, such as one or more of DMF, DMSO, sulfolane, benzene, toluene, xylene, etc.

[0038] Suitable catalyst B is selected from one or more of common quaternary ammonium salts, quaternary phosphonium salts, cyclic crown ethers or polyether phase transfer catalysts, such as one or more of tetrabutylammonium bromide, tetraphenylphosphine bromide, 18-crown-6-ether, polyethylene glycol, etc.

[0039] The fourth step of hydrolysis or alcoholysis reaction is to react compound IV in a suitable reaction reagent B in the presence of a suitable catalyst C at a reaction temperature of 0-200° C. to obtain compound V; wherein the mass ratio of compound IV, reaction solvent B and catalyst C is 1:1-50:0.1-50.

[0040] The reaction solvent B is selected from one or more of water, common alcohols or benzyl alcohol solvents; such as one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, allyl alcohol, propargyl alcohol, cyclohexanol, cyclopentanol, benzyl alcohol, 2-methylbenzyl alcohol, 3-fluorobenzyl alcohol, 4-trifluoromethylbenzyl alcohol, etc.;

[0041] Suitable catalyst C is selected from one or more of hydrochloric acid, sulfuric acid, thionyl chloride, hydrogen chloride, trifluoromethanesulfonic acid, hydrobromic acid or hydrogen bromide.

[0042] In the fifth step, compound V can be directly subjected to catalytic hydrodehalogenation in the presence of a catalyst to obtain compound X, or the nitro group can be first reduced to an amine group and then directly subjected to catalytic hydrodehalogenation in the presence of a catalyst to obtain compound X.

[0043] The method for reducing the nitro group to an amino group is selected from commonly used nitro group reduction methods, such as metal reduction, stannous chloride reduction, sulfide reduction, metal hydride reduction, etc.

[0044] The compound X obtained by direct catalytic hydrogenation dehalogenation in the presence of the catalyst is compound V or the product of compound V after nitro reduction, which is respectively carried out in a suitable reaction solvent C in the presence of a suitable catalyst D, at a reaction temperature of 0-130° C., hydrogen is introduced, and the reaction pressure is 0.1-10.0 MPa to obtain 2-fluoro-3-aminobenzoic acid and its ester compounds, namely compound X; wherein the mass ratio of compound V, reaction solvent C and catalyst D is 1:1-50:0.01-1; the mass ratio of the product after nitro reduction of compound V, reaction solvent C and catalyst D is 1:1-50:0.01-1.

[0045] The reaction solvent C is selected from one or more common alcohol, ester or benzene solvents; such as one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, ethyl acetate, isopropyl acetate, butyl acetate, benzene, toluene, xylene, etc.;

[0046] Suitable catalyst D is selected from one or more common supported metal catalysts, such as one or more supported Raney nickel, supported metal palladium, supported metal platinum, supported metal molybdenum, supported metal cobalt, supported metal titanium, supported metal rhodium, etc.

[0047] The technical effects of the present invention are mainly reflected in the following aspects:

[0048] The process route of the present invention uses cheap and readily available starting materials, and the process flow comprises common unit operations in fine chemicals, is easy to operate, has a high yield, and good selectivity. The completion of the present invention provides an effective preparation method for the industrial development of such compounds.

[0049] In the definitions of the compounds of the general formula given above, the terms used collectively generally represent the following substituents:

[0050] Halogen: refers to fluorine, chlorine, bromine or iodine.

[0051] Alkyl: a straight-chain, branched or cyclic alkyl group, such as methyl, ethyl, n-propyl, isopropyl or cyclopropyl.

[0052] Haloalkyl: a straight-chain, branched or cyclic alkyl group, in which the hydrogen atoms may be partially or completely replaced by halogen, such as chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl or heptafluoroisopropyl.

[0053] Alkenyl: a straight-chain, branched or cyclic alkenyl group, such as ethenyl, 1-propenyl, 2-propenyl and different butenyl, pentenyl and hexenyl isomers; alkenyl also includes polyenes such as 1,2-propadienyl and 2,4-hexadienyl.

[0054] Haloalkenyl: an alkenyl group in which at least one or more hydrogen atoms may be replaced by a halogen atom.

[0055] Alkynyl: includes straight-chain or branched alkynes, such as ethynyl, 1-propynyl, and the different butynyl, pentynyl, and hexynyl isomers; alkynyl also includes groups composed of multiple triple bonds, such as 2,5-hexadiynyl.

[0056] Haloalkynyl: an alkynyl group in which at least one or more hydrogen atoms may be replaced by a halogen atom.

[0057] Alkoxy: a straight-chain, branched or cyclic alkoxy group, such as methoxy, ethoxy, n-propoxy, isopropoxy, cyclopropyloxy or n-butoxy.

[0058] Haloalkoxy: a straight-chain, branched or cyclic alkoxy group, in which the hydrogen atoms may be partially or completely replaced by halogen, for example, chloromethoxy, dichloromethoxy, trichloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chlorofluoromethoxy, trifluoroethoxy, heptafluoroisopropyl, etc.

[0059] Alkylthio: a straight-chain, branched, or cyclic alkyl group connected to the structure via a sulfur atom bond, such as methylthio, ethylthio, etc.

[0060] Alkenylthio: a straight-chain, branched, or cyclic alkyl group connected to the structure via a sulfur atom bond, for example, 1-propenyl-3-thio, 2-butenyl-4-thio, etc.

[0061] Alkynylthio: a straight-chain, branched, or cyclic alkyl group connected to the structure via a sulfur atom bond, for example, 1-propynyl-3-thio, 2-butynyl-4-thio, etc.

[0062] Haloalkylthio: a straight-chain, branched or cyclic alkylthio group, in which the hydrogen atoms may be partially or completely substituted by halogen, for example, difluoromethylthio, trifluoroethylthio and the like.

[0063] Alkylamino: a straight-chain, branched or cyclic alkyl group attached to the structure via a nitrogen atom, such as methylamino, ethylamino, n-propylamino, isopropylamino or the isomeric butylamino groups.

[0064] Dialkylamino: two identical or different straight-chain, branched or cyclic alkyl groups connected to the structure via a nitrogen atom bond, such as dimethylamino, methylethylamino, cyclopropylamino, etc.

[0065] Alkoxycarbonyl: alkyl-O-CO-, for example CH3OCO-.

[0066] Alkylcarbonyl: alkyl-CO-, such as CH3CO-

[0067] Alkylsulfonyl: alkyl-S(O)2-, for example methylsulfonyl.

[0068] Alkylsulfinyl: alkyl-S(O)-, for example methylsulfinyl.

[0069] Alkylaminocarbonyl: alkyl-NH-CO-, for example CH3NHCO-.

[0070] Alkylaminosulfonyl: alkyl-NH-S(O)2-, for example CH3NH-S(O)2-. DETAILED DESCRIPTION

[0071] The following examples are used to further illustrate the present invention, but are not intended to limit the present invention.

[0072] Example 1

[0073] Preparation of 5-chloro-2-hydroxy-3-nitrobenzamide:

[0074] 5-Chloro-2-hydroxybenzamide (50 g, 0.291 mol) was added to 200 g of glacial acetic acid and stirred thoroughly. 65% concentrated nitric acid (50 g) was slowly added dropwise in an ice bath. After completion of the addition, the temperature was raised to 25°C for reaction and monitored by HPLC until the reaction was complete. The reaction solution was poured into 1 L of ice water, whereupon a large amount of solid precipitated. The solid was filtered, and the filter cake was washed sequentially with saturated sodium bicarbonate aqueous solution and water. After drying, 62.2 g of the desired product as a yellow solid was obtained. The purity was 98.4% as determined by HPLC, and the yield was 97.1%.

[0075] The NMR data are as follows: 1H NMR (600 MHz, DMSO) δ (ppm): 8.33 (d, 1H), 8.22 (d, 1H).

[0076] Example 2

[0077] The difference from Example 1 is that

[0078] 5-Chloro-2-hydroxybenzamide (50 g, 0.291 mol) was added to 100 g of 95% sulfuric acid and stirred thoroughly. 25 g of 65% concentrated nitric acid was slowly added dropwise at -10°C. After completion of the addition, the temperature was raised to 10°C for reaction and monitored by HPLC until the reaction was complete. The reaction solution was poured into 1 L of ice water, whereupon a large amount of solid precipitated. The solid was filtered, and the filter cake was washed sequentially with saturated sodium bicarbonate aqueous solution and water. After drying, 62.5 g of the desired product as a yellow solid was obtained. The purity was 98.1% as determined by HPLC, and the yield was 97.3%.

[0079] Example 3

[0080] Preparation of 5-bromo-2-hydroxy-3-nitrobenzamide:

[0081] 5-Bromo-2-hydroxybenzamide (65.0 g, 0.300 mol) was added to 150 g of glacial acetic acid and stirred thoroughly. 100 g of 65% concentrated nitric acid was slowly added dropwise in an ice bath. After completion of the addition, the temperature was raised to 90°C for reaction and monitored by HPLC until the reaction was complete. The reaction solution was poured into 1 L of ice water, whereupon a large amount of solid precipitated. The solid was filtered, and the filter cake was washed sequentially with saturated sodium bicarbonate aqueous solution and water. After drying, 77.6 g of the desired product as a yellow solid was obtained. The purity was 98.3% as determined by HPLC, and the yield was 97.4%.

[0082] Example 4

[0083] Preparation of 2,5-dichloro-3-nitrobenzonitrile:

[0084] 5-Chloro-2-hydroxy-3-nitrobenzamide (32 g, 0.145 mol) obtained in Example 2 was added to 200 mL of phosphorus oxychloride and stirred thoroughly. Triethylamine (44.2 g, 0.435 mol) was slowly added dropwise in an ice bath. After completion of the addition, the temperature was raised to 110°C for reaction and monitored by HPLC until the reaction was complete. The reaction solution was desolvated under reduced pressure, and the residue was poured into 500 mL of ice water. A large amount of solid precipitated, which was filtered. The filter cake was washed sequentially with saturated sodium bicarbonate aqueous solution and water, and dried to obtain 31.4 g of the target product as a brownish-yellow solid. The purity was 97.5% as determined by HPLC, and the yield was 97.3%.

[0085] The NMR data are as follows: 1H NMR (600 MHz, CDCl 3 ) δ (ppm): 8.09 (d, 1H), 7.90 (d, 1H).

[0086] Example 5

[0087] The difference from Example 4 is that 5-chloro-2-hydroxy-3-nitrobenzamide (32 g, 0.145 mol) obtained in Example 2 was added to 100 mL of oxalyl chloride and stirred thoroughly. DMF (10.6 g, 0.145 mol) was slowly added dropwise at -20°C. After completion of the addition, the temperature was raised to 80°C for reaction and monitored by HPLC until the reaction was complete. The reaction solution was desolvated under reduced pressure and the residue was poured into 250 mL of ice water. A large amount of solid precipitated, which was filtered and the filter cake was washed with saturated sodium bicarbonate aqueous solution and water in sequence. After drying, 31.2 g of the target product was obtained as a brownish-yellow solid. The purity was 97.4% as determined by HPLC, and the yield was 96.6%.

[0088] Example 6

[0089] The difference from Example 4 is that 5-chloro-2-hydroxy-3-nitrobenzamide (22.1 g, 0.100 mol) obtained in Example 1 was added to 80 mL of thionyl chloride and stirred thoroughly. DMF (3.7 g, 0.050 mol) was slowly added dropwise in an ice bath. After completion of the addition, the temperature was raised to 100° C. for reaction and monitored by HPLC until the reaction was complete. The reaction solution was desolvated under reduced pressure and the residue was poured into 200 mL of ice water. A large amount of solid precipitated, which was filtered and the filter cake was washed with saturated sodium bicarbonate aqueous solution and water in sequence. After drying, 21.6 g of the target product was obtained as a brownish-yellow solid. The purity was 97.6% as determined by HPLC and the yield was 97.1%.

[0090] Example 7

[0091] Preparation of 2-bromo-5-chloro-3-nitrobenzonitrile:

[0092] 5-Chloro-2-hydroxy-3-nitrobenzamide (22.0 g, 0.100 mol) obtained in Example 1 was added to 150 mL of phosphorus oxybromide and stirred thoroughly. N,N-diisopropylethylamine (65.3 g, 0.500 mol) was slowly added dropwise in an ice bath. After completion of the addition, the temperature was raised to 160°C for reaction and monitored by HPLC until the reaction was complete. The reaction solution was desolvated under reduced pressure and the residue was poured into 500 mL of ice water. A large amount of solid precipitated, which was filtered and the filter cake was washed sequentially with saturated sodium bicarbonate aqueous solution and water. After drying, 25.9 g of the target product was obtained as a brownish-yellow solid. The purity was 97.3% as determined by HPLC, and the yield was 96.4%.

[0093] Example 8

[0094] Preparation of 5-chloro-2-fluoro-3-nitrobenzonitrile:

[0095] Anhydrous potassium fluoride (10 g, 0.170 mol) and tetrabutylammonium bromide (5 g, 0.015 mol) were added to 100 mL of toluene and stirred thoroughly. The temperature was raised to 120°C, and after removing water for 1 hour, the mixture was cooled to room temperature. 2,5-dichloro-3-nitrobenzonitrile (20 g, 0.090 mol) obtained in Example 6 was quickly added. The temperature was then raised to 120°C and the reaction was continued. HPLC monitoring was performed until the reaction was complete. The reaction solution was cooled to room temperature, and 100 mL of water was added. The mixture was allowed to stand for separation. The organic phase was washed with saturated sodium bicarbonate and water, respectively, and solvent removal was performed to obtain 17.8 g of a brownish-yellow residue. HPLC analysis showed a purity of 97.5% and a yield of 96.1%.

[0096] The NMR data are as follows: 1H NMR (600 MHz, CDCl 3 ) δ (ppm): 8.32-8.31 (m, 1H), 7.93-7.92 (m, 1H).

[0097] Example 9

[0098] The difference from Example 8 is that anhydrous cesium fluoride (26.1 g, 0.170 mol) and tetrabutylammonium bromide (5 g, 0.015 mol) were added to 100 mL of toluene and stirred thoroughly. The temperature was raised to 120°C, and the water was removed after 1 hour. The temperature was then cooled to room temperature. 2,5-dichloro-3-nitrobenzonitrile (20 g, 0.090 mol) obtained in Example 6 was quickly added. The temperature was then raised to 120°C and the reaction was continued. HPLC monitoring was performed until the reaction was complete. The reaction solution was cooled to room temperature, and 100 mL of water was added. The layers were allowed to stand and the organic phase was washed with saturated sodium bicarbonate and water, respectively. After desolventizing, 17.9 g of a brownish-yellow residue was obtained. The purity was 97.7% as determined by HPLC, and the yield was 96.8%.

[0099] Example 10

[0100] The difference from Example 8 is that anhydrous potassium fluoride (10 g, 0.170 mol) and tetrabutylammonium bromide (5 g, 0.015 mol) are added to 100 mL of DMF and stirred thoroughly. The DMF is desolvated under reduced pressure. After a portion of the DMF is desolvated, the temperature is cooled to room temperature. 2,5-dichloro-3-nitrobenzonitrile (20 g, 0.090 mol) obtained in Example 6 is quickly added. The temperature is then raised to 75°C for reaction and monitored by HPLC until the reaction is complete. The DMF is desolvated under reduced pressure, and then 50 mL of toluene and 50 mL of water are added. The mixture is allowed to stand for stratification, and the organic phase is washed with saturated sodium bicarbonate and water, respectively. Desolvation yields 17.8 g of a brownish-yellow residue. HPLC analysis shows a purity of 97.6% and a yield of 96.3%.

[0101] Example 11

[0102] The difference from Example 8 is that anhydrous potassium fluoride (9 g, 0.155 mol) and 18-crown-6-ether (2.7 g, 0.010 mol) were added to 90 mL of DMF and stirred thoroughly. The DMF was desolvated under reduced pressure. After desolvation of a portion of the DMF, the temperature was cooled to room temperature. 2,5-dichloro-3-nitrobenzonitrile (20 g, 0.090 mol) obtained in Example 6 was quickly added. The temperature was then raised to 65°C for reaction and monitored by HPLC until the reaction was complete. The DMF was desolvated under reduced pressure, and then 50 mL of toluene and 50 mL of water were added. The mixture was allowed to stand for stratification, and the organic phase was washed with saturated sodium bicarbonate and water, respectively. Desolvation afforded 17.7 g of a brownish-yellow residue. HPLC analysis showed a purity of 97.8% and a yield of 95.9%.

[0103] Example 12

[0104] The difference from Example 8 is that anhydrous potassium fluoride (10 g, 0.170 mol) and tetraphenylphosphonium bromide (8.4 g, 0.020 mol) were added to 100 mL of xylene and stirred thoroughly. The temperature was raised to 150° C., the water was removed, and the mixture was cooled to room temperature after 1 hour. 2,5-dichloro-3-nitrobenzonitrile (18.9 g, 0.085 mol) obtained in Example 6 was quickly added. The temperature was then raised to 150° C. and the reaction was continued. HPLC monitoring was performed until the reaction was complete. The reaction solution was cooled to room temperature, 100 mL of water was added, and the layers were allowed to stand. The organic phase was washed with saturated sodium bicarbonate and water, respectively, and desolventized to obtain 16.8 g of a brownish-yellow residue. HPLC analysis showed a purity of 97.3% and a yield of 95.9%.

[0105] Example 13

[0106] The difference from Example 8 was that 2,5-dichloro-3-nitrobenzonitrile (10 g, 0.045 mol) and anhydrous potassium fluoride (5 g, 0.085 mol) obtained in Example 6 were added to 30 mL of dry DMSO, stirred thoroughly, and then heated to 100°C for reaction. The reaction was monitored by HPLC until completion. The reaction solution was cooled to room temperature, and then 100 mL of toluene and 100 mL of water were added. The reaction mixture was allowed to stand for separation, and the organic phase was washed with saturated sodium bicarbonate and water, respectively. After desolventizing, 8.9 g of a brownish-yellow residue was obtained. HPLC analysis showed a purity of 97.0% and a yield of 95.6%.

[0107] Example 14

[0108] Preparation of 5-bromo-2-fluoro-3-nitrobenzonitrile:

[0109] Anhydrous potassium fluoride (11.7 g, 0.200 mol) and tetrabutylammonium bromide (4 g, 0.012 mol) were added to 100 mL of toluene and stirred thoroughly. The temperature was raised to 120°C, and the mixture was allowed to cool to room temperature after 1 hour of water removal. 5-Bromo-2-chloro-3-nitrobenzonitrile (26.9 g, 0.100 mol) was then quickly added. The temperature was then raised to 120°C and the reaction continued. HPLC monitoring was performed until the reaction was complete. The reaction solution was cooled to room temperature, and 100 mL of water was added. The layers were allowed to stand and the organic phase was washed with saturated sodium bicarbonate and water, respectively. After desolventizing, 24.1 g of a brownish-yellow residue was obtained. HPLC analysis showed a purity of 97.6% and a yield of 96.0%.

[0110] Example 15

[0111] The difference from Example 14 is that anhydrous sodium fluoride (8.4 g, 0.200 mol) and tetrabutylammonium bromide (4 g, 0.012 mol) were added to 100 mL of toluene and stirred thoroughly. The temperature was raised to 120° C., and after removing water for 1 hour, the temperature was lowered to room temperature. 5-bromo-2-chloro-3-nitrobenzonitrile (26.9 g, 0.100 mol) was quickly added, and the temperature was raised to 120° C. The reaction was continued and monitored by HPLC until the reaction was complete. The reaction solution was cooled to room temperature, and 100 mL of water was added. The layers were allowed to stand and the organic phase was washed with saturated sodium bicarbonate and water, respectively. After desolventizing, 24.0 g of a brownish-yellow residue was obtained. The purity was 97.4% by HPLC, and the yield was 95.4%.

[0112] Example 16

[0113] The difference from Example 14 is that anhydrous potassium fluoride (10 g, 0.170 mol) and tetrabutylammonium bromide (4 g, 0.012 mol) are added to 150 mL of DMF and stirred thoroughly. The DMF is desolvated under reduced pressure. After desolvation of a portion of the DMF, the temperature is cooled to room temperature. 5-bromo-2-chloro-3-nitrobenzonitrile (24.2 g, 0.090 mol) is quickly added, and the temperature is raised to 60-65°C for reaction. HPLC monitoring is performed until the reaction is complete. The DMF is desolvated under reduced pressure, and then 50 mL of toluene and 50 mL of water are added. The mixture is allowed to stand for stratification, and the organic phase is washed with saturated sodium bicarbonate and water, respectively. Desolvation yields 24.2 g of a brownish-yellow residue. HPLC determination shows a purity of 97.5% and a yield of 96.3%.

[0114] Example 17

[0115] The difference from Example 14 is that 5-bromo-2-chloro-3-nitrobenzonitrile (122.2 g, 0.458 mol) and anhydrous potassium fluoride (30 g, 0.511 mol) were added to 260 g of dry DMSO and stirred thoroughly. The temperature was raised to 60°C for reaction. After 3 hours of reaction, the reaction solution was cooled to room temperature and desolvated under reduced pressure until no solvent was left. 300 ml of ethyl acetate was added, and the mixture was slurried and filtered. The ethyl acetate was desolvated under reduced pressure to dryness to obtain 110.1 g of the desired brown-yellow product. HPLC analysis showed a purity of 97.1% and a yield of 95.3%.

[0116] Example 18

[0117] Preparation of 5-chloro-2-fluoro-3-nitrobenzoic acid:

[0118] 5-Chloro-2-fluoro-3-nitrobenzonitrile (20.6 g, 0.100 mol) obtained in Example 12 was added to 100 mL of 60% aqueous sulfuric acid solution, then heated to 80°C for reaction. The reaction was monitored by HPLC until completion. The reaction solution was cooled to room temperature and then poured into 400 mL of ice water. A large amount of solid precipitated. The solid was filtered, and the filter cake was washed sequentially with saturated aqueous sodium bicarbonate solution and water, and dried to obtain 21.7 g of the target product as a light yellow solid. HPLC analysis showed a purity of 98.2% and a yield of 97.0%.

[0119] Example 19

[0120] The difference from Example 18 is that 5-chloro-2-fluoro-3-nitrobenzonitrile (20.6 g, 0.100 mol) obtained in Example 12 was added to 200 mL of 48% aqueous hydrobromic acid solution, then heated to 100°C for reaction, and monitored by HPLC until the reaction was complete. The reaction solution was cooled to room temperature and then poured into 600 mL of ice water. A large amount of solid precipitated, which was filtered. The filter cake was washed with saturated aqueous sodium bicarbonate solution and water, and dried to obtain 21.8 g of the target product as a light yellow solid. HPLC analysis showed a purity of 97.9% and a yield of 97.2%.

[0121] Example 20

[0122] Preparation of 5-chloro-2-fluoro-3-nitrobenzoic acid methyl ester:

[0123] 5-Chloro-2-fluoro-3-nitrobenzonitrile (15 g, 0.073 mol) obtained in Example 10 was added to 100 mL of methanol. Concentrated sulfuric acid (14.6 g, 0.146 mol) was slowly added dropwise in an ice bath. The reaction was then heated to 70°C and monitored by HPLC until completion. A portion of the methanol was removed under reduced pressure, resulting in the precipitation of a large amount of solid. The solid was filtered, and the filter cake was washed sequentially with saturated sodium bicarbonate aqueous solution and water, and dried to obtain 16.9 g of the desired product as a light yellow solid. HPLC analysis revealed a purity of 98.1% and a yield of 97.2%.

[0124] The NMR data are as follows: 1H NMR (600 MHz, CDCl 3 ) δ (ppm): 8.20-8.17 (m, 2H), 4.00 (s, 3H).

[0125] Example 21

[0126] The difference from Example 20 was that 5-chloro-2-fluoro-3-nitrobenzonitrile (15 g, 0.073 mol) obtained in Example 10 was added to 150 mL of methanol. Hydrogen chloride gas was introduced under an ice bath until saturation was achieved. The temperature was then raised to 45°C for reaction, and the reaction was monitored by HPLC until completion. A portion of the methanol was stripped off under reduced pressure, resulting in a large amount of precipitated solid. The solid was filtered, and the filter cake was washed sequentially with saturated sodium bicarbonate aqueous solution and water, and dried to obtain 17.0 g of the desired product as a light yellow solid. HPLC analysis showed a purity of 98.0% and a yield of 97.7%.

[0127] Example 22

[0128] The difference from Example 20 was that 5-chloro-2-fluoro-3-nitrobenzonitrile (15 g, 0.073 mol) obtained in Example 10 was added to 100 mL of methanol, and thionyl chloride (87.7 g, 0.73 mol) was slowly added dropwise in an ice bath. The temperature was then raised to 70°C for reaction, and the reaction was monitored by HPLC until completion. A portion of the methanol was removed under reduced pressure, resulting in a large amount of precipitated solid. The solid was filtered, and the filter cake was washed sequentially with saturated sodium bicarbonate aqueous solution and water, and dried to obtain 17.1 g of the target product as a light yellow solid. HPLC analysis showed a purity of 97.1% and a yield of 97.3%.

[0129] Example 23

[0130] Preparation of methyl 2-fluoro-3-aminobenzoate:

[0131] Methyl 5-chloro-2-fluoro-3-nitroformate (23.8 g, 0.100 mol) obtained in Example 20, 2.0 g of palladium-carbon catalyst (wet palladium-carbon with a content of 10 wt%), and 100 mL of methanol were added to an autoclave. The temperature was then raised to 35-40° C. and the reaction was carried out under a hydrogen pressure of 7-8 MPa. The reaction was monitored by HPLC until completion. The catalyst was filtered, the filtrate was desolvated under reduced pressure, 100 mL of ethyl acetate was added, and the organic phase was washed sequentially with a saturated aqueous sodium bicarbonate solution and water. The organic phase was desolvated to obtain 16.9 g of the target product as a light yellow liquid. The purity was determined by HPLC to be 98.1%, and the yield was 98.0%.

[0132] The NMR data are as follows: 1H NMR (600 MHz, CDCl 3 ) δ (ppm): 7.22-7.19 (m, 1H), 6.93-6.89 (m, 2H), 3.94 (brs, 1H), 3.87 (s, 3H).

[0133] Example 24

[0134] The difference from Example 23 is that: methyl 5-chloro-2-fluoro-3-nitroformate (23.8 g, 0.100 mol) obtained in Example 20, 2.0 g of palladium-carbon catalyst (wet palladium-carbon content 10 wt%), and 100 mL of ethyl acetate were added to an autoclave, then heated to 80° C. and reacted under a hydrogen pressure of 5-6 MPa. HPLC monitoring was performed until the reaction was complete. After filtering the catalyst, the organic phase was washed with saturated sodium bicarbonate aqueous solution and water, and the organic phase was desolvated to obtain 16.8 g of the target product as a light yellow liquid. HPLC determination showed a purity of 98.5% and a yield of 97.9%.

[0135] Example 25

[0136] The difference from Example 23 is that: methyl 5-chloro-2-fluoro-3-nitroformate (23.8 g, 0.100 mol) obtained in Example 20, 1.0 g of palladium-carbon catalyst (wet palladium-carbon with a content of 10 wt%), and 100 mL of ethanol were added to an autoclave, then the temperature was raised to 90° C. and the reaction was carried out under a hydrogen pressure of 5-6 MPa. HPLC monitoring was performed until the reaction was complete. After filtering the catalyst, the filtrate was desolvated under reduced pressure, 100 mL of ethyl acetate was added, and the organic phase was washed with saturated sodium bicarbonate aqueous solution and water in sequence. The organic phase was desolvated to obtain 16.9 g of the target product as a light yellow liquid. The purity was determined by HPLC to be 98.3%, and the yield was 97.6%.

[0137] Example 26

[0138] The difference from Example 23 was that methyl 5-chloro-2-fluoro-3-nitroformate (23.8 g, 0.100 mol) obtained in Example 20, 2.0 g of a platinum-on-carbon catalyst (10 wt% platinum-on-carbon), and 100 mL of toluene were added to an autoclave. The temperature was then raised to 120°C and the reaction was carried out under a hydrogen pressure of 0.5-1 MPa. The reaction was monitored by HPLC until completion. After filtering the catalyst, the organic phase was washed sequentially with saturated sodium bicarbonate solution and water. The organic phase was desolvated to obtain 17.0 g of the target product as a light yellow liquid. HPLC analysis showed a purity of 97.9% and a yield of 98.4%.

[0139] Example 27

[0140] The difference from Example 23 is that: methyl 5-chloro-2-fluoro-3-nitroformate (23.8 g, 0.100 mol) obtained in Example 20, 2.0 g of palladium-carbon catalyst (recovered from Example 24), and 100 mL of ethyl acetate were added to an autoclave, then heated to 80°C and reacted under a hydrogen pressure of 5-6 MPa. HPLC monitoring was performed until the reaction was complete. After filtering the catalyst, the organic phase was washed with saturated sodium bicarbonate aqueous solution and water, and the organic phase was desolvated to obtain 16.9 g of the target product as a light yellow liquid. HPLC determination showed a purity of 97.7% and a yield of 97.6%.

[0141] Example 28

[0142] The difference from Example 23 is that 5-chloro-2-fluoro-3-nitroformate (23.8 g, 0.100 mol) obtained in Example 20 was added to 100 mL of glacial acetic acid, 28.0 g of iron powder was slowly added in batches at room temperature, and then the temperature was raised to 65 ° C for reaction. HPLC was used to monitor the reaction until the reaction was complete. The reaction solution was filtered, the filtrate was desolvated under reduced pressure, and the residue was dissolved in 100 mL of ethanol for standby use. 1.0 g of a standby ethanol solution and a palladium-carbon catalyst (10 wt% wet palladium-carbon) were added to an autoclave, then the temperature was raised to 80 ° C, and the pressure was 5-6 MPa of hydrogen pressure for reaction. HPLC was used to monitor the reaction until the reaction was complete. After the catalyst was filtered, the organic phase was washed with saturated sodium bicarbonate aqueous solution and water in sequence. The organic phase was desolvated to obtain 16.8 g of the target product as a light yellow liquid. HPLC determination showed a purity of 98.4% and a yield of 97.7%.

Claims

1. A method for preparing 2-fluoro-3-aminobenzoic acid and its ester compounds, characterized in that: The reaction formula is: 1) Compound I is nitrated under appropriate reaction conditions to obtain Compound II; 2) Compound II is halogenated under appropriate reaction conditions to obtain compound III; 3) Compound III is fluorinated under appropriate reaction conditions to obtain compound IV; 4) Compound IV is hydrolyzed or alcoholyzed under appropriate reaction conditions to prepare compound V; 5) Compound V is subjected to catalytic hydrodehalogenation under suitable reaction conditions to obtain compound X; in: X is selected from chlorine, bromine or iodine; Y is selected from chlorine, bromine or iodine; R is selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, and unsubstituted or optionally substituted benzyl.

2. The method for preparing 2-fluoro-3-aminobenzoic acid and its ester compounds according to claim 1, characterized in that: The operation of the first step of the nitration reaction is that compound I reacts in a mixed solution of sulfuric acid or glacial acetic acid and nitric acid at a reaction temperature of -20-100°C to obtain compound II; wherein the mass ratio of compound I, sulfuric acid / glacial acetic acid and nitric acid is 1:1-10:1-5.

3. The method for preparing 2-fluoro-3-aminobenzoic acid and its ester compounds according to claim 2, characterized in that: The nitric acid is concentrated nitric acid or fuming nitric acid.

4. The method for preparing 2-fluoro-3-aminobenzoic acid and its ester compounds according to claim 1, characterized in that: The operation of the second step halogenation reaction is that compound II reacts in a suitable halogenating agent in the presence of a suitable catalyst A at a reaction temperature of -20-200°C to obtain compound III; wherein the mass ratio of compound II, halogenating agent and catalyst A is 1:1-50:0.1-10.

5. The method for preparing 2-fluoro-3-aminobenzoic acid and its ester compounds according to claim 4, characterized in that: The suitable halogenating agent is selected from one or more of a chlorinating agent, a brominating agent or an iodinating agent; the suitable catalyst A is selected from one or more of DMF or an organic base.

6. The method for preparing 2-fluoro-3-aminobenzoic acid and its ester compounds according to claim 1, characterized in that: The operation of the third step fluorination reaction is that compound III reacts with a suitable fluorination agent in a suitable reaction solvent A, in the presence or absence of a suitable catalyst B, at a reaction temperature of 0-200° C. to obtain compound IV; wherein the mass ratio of compound III, fluorination agent, reaction solvent A and catalyst B is 1:0.1-3:1-50:0-1; 7. The method for preparing 2-fluoro-3-aminobenzoic acid and its ester compounds according to claim 6, characterized in that: The fluorination agent is selected from one or more of lithium fluoride, potassium fluoride, sodium fluoride, ammonium fluoride or cesium fluoride; the reaction solvent A is selected from one or more of polar aprotic solvents or benzene solvents; and the suitable catalyst B is selected from one or more of common quaternary ammonium salts, quaternary phosphonium salts, cyclic crown ethers or polyether phase transfer catalysts.

8. The method for preparing 2-fluoro-3-aminobenzoic acid and its ester compounds according to claim 1, characterized in that: The operation of the fourth step hydrolysis or alcoholysis reaction is that compound IV is reacted in a suitable reaction solvent B in the presence of a suitable catalyst C at a reaction temperature of 0-200° C. to obtain compound V; wherein the mass ratio of compound IV, reaction solvent B and catalyst C is 1:1-50:0.1-50.

9. The method for preparing 2-fluoro-3-aminobenzoic acid and its ester compounds according to claim 8, characterized in that: The reaction solvent B is selected from one or more of water, common alcohols or benzyl alcohol solvents; the suitable catalyst C is selected from one or more of hydrochloric acid, sulfuric acid, thionyl chloride, hydrogen chloride, trifluoromethanesulfonic acid, hydrobromic acid or hydrogen bromide.

10. The method for preparing 2-fluoro-3-aminobenzoic acid and its ester compounds according to claim 1, characterized in that: In the fifth step, compound V can be directly subjected to catalytic hydrodehalogenation in the presence of a catalyst to obtain compound X, or the nitro group can be first reduced to an amine group and then directly subjected to catalytic hydrodehalogenation in the presence of a catalyst to obtain compound X.

11. The method for preparing 2-fluoro-3-aminobenzoic acid and its ester compounds according to claim 10, characterized in that: The compound X obtained by direct catalytic hydrogenation dehalogenation in the presence of the catalyst is compound V or the product of compound V after nitro reduction, respectively, in a suitable reaction solvent C, in the presence of a suitable catalyst D, hydrogen is introduced at a reaction temperature of 0-130° C., and the reaction pressure is 0.1-10.0 MPa to obtain 2-fluoro-3-aminobenzoic acid and its ester compounds, namely compound X; wherein the mass ratio of compound V, reaction solvent C and catalyst D is 1:1-50:0.01-1; the mass ratio of the product after nitro reduction of compound V, reaction solvent C and catalyst D is 1:1-50:0.01-1.

12. The method for preparing 2-fluoro-3-aminobenzoic acid and its ester compounds according to claim 11, characterized in that: The reaction solvent C is selected from one or more of common alcohol, ester or benzene solvents; the suitable catalyst D is selected from one or more of common supported metal catalysts.

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