Synthesis method of 2-fluoro-3-aminobenzoic acid and ester compound thereof

Abstract

The invention belongs to the field of organic synthesis, and particularly relates to a synthesis method of 2-fluoro-3-aminobenzoic acid and ester compounds thereof. The reaction formula is as follows: nitrating a compound I serving as a raw material under reaction conditions to obtain a compound II, and halogenating the obtained compound II under proper reaction conditions to obtain a compound III; fluorinating the obtained compound III under proper reaction conditions to obtain a compound IV; the obtained compound IV is subjected to catalytic hydrodehalogenation under proper reaction conditions to obtain 2-fluoro-3-aminobenzoic acid shown as a compound V and ester compounds thereof; the starting materials of the process route are cheap and easily available, the process flow is common unit operation in fine chemical engineering, the operation is convenient, the reaction conversion rate is high, and the selectivity is good. The completion of the invention provides an effective preparation method for industrial development of the compounds. # imgabs0 #

Description

Technical Field

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

[0002] 2-Fluoro-3-aminobenzoic acid and its ester compounds are important intermediates for organic synthesis and pharmaceutical pesticides. For example, methyl 2-fluoro-3-aminobenzoate is a new anticancer drug intermediate, CAS: 1195768-18-3, and its structural formula is as follows:

[0003]

[0004] The methods for synthesizing such compounds in the prior art literature mainly include the following:

[0005] Document WO2011059610 reports two methods for preparing methyl 2-fluoro-3-aminobenzoate, and the specific routes are as follows:

[0006]

[0007] Among them, the first route has expensive starting 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 a strong oxidant, has a high risk factor and great environmental pressure, and is not suitable for industrial production.

[0008] Document CN111320548 reports a method for preparing methyl 2-fluoro-3-aminobenzoate, and the specific route is as follows:

[0009]

[0010] The fluorination reaction selectivity of this route is poor (product: isomer = 30:1) and is difficult to purify, resulting in high production costs and is not suitable for industrial production.

[0011] Document CN114920661 reports a feasible method for preparing methyl 2-fluoro-3-aminobenzoate, and the specific route is as follows:

[0012]

[0013] Document CN113717053 reports a feasible method for preparing methyl 2-fluoro-3-aminobenzoate, and the specific route is as follows:

[0014]

[0015] This route uses the strong base lithium amide, and the operating conditions are relatively harsh, which is not suitable for industrial production.

[0016] Therefore, it is of great significance to use readily available starting materials, find a suitable synthesis process, and ultimately develop a method suitable for industrial production of 2-fluoro-3-aminobenzoic acid and its ester compounds. Summary of the invention

[0017] The purpose of the present invention is to provide a method for synthesizing 2-fluoro-3-aminobenzoic acid and its ester compounds.

[0018] To achieve the above object, the technical solution of the present invention is as follows:

[0019] A method for synthesizing 2-fluoro-3-aminobenzoic acid and its ester compounds, comprising: taking compound I as a raw material, nitrating under reaction conditions to obtain compound II, halogenating the obtained compound II under suitable reaction conditions to obtain compound III; fluorinating the obtained compound III under suitable reaction conditions to obtain compound IV; and catalytically hydrodehalogenating the obtained compound IV under suitable reaction conditions to obtain 2-fluoro-3-aminobenzoic acid and its ester compounds shown in compound V; wherein the reaction process is as follows:

[0020]

[0021] In the compound, X is selected from chlorine, bromine or iodine; Y is selected from chlorine, bromine or iodine; and R is selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, unsubstituted or optionally substituted benzyl.

[0022] 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.

[0023] The nitration reaction is to use compound I as a raw material in a mixed solution of sulfuric acid or glacial acetic acid and nitric acid, and react 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.

[0024] The above mixed solutions can be added after mixing, added sequentially, or a part of one of the solutions can be added first, and the remaining part can be mixed with the other solution and added.

[0025] The sulfuric acid is added into the system until the concentration of sulfuric acid in the system reaches 30%-90%.

[0026] The nitric acid is concentrated nitric acid or fuming nitric acid; wherein the concentration of nitric acid in the system reaches 10%-70%.

[0027] The halogenation reaction is to react the nitration reactant compound II in a suitable halogenation reagent 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, halogenation reagent and catalyst A is 1:1-50:0.1-10.

[0028] 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.;

[0029] 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.

[0030] The fluorination reaction is to react the halogenation reaction product compound III 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 VI; wherein the mass ratio of compound III, fluorination agent, reaction solvent A and catalyst B is 1:0.1-3:1-50:0-1.

[0031] 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; such as one or more of DMF, DMSO, sulfolane, benzene, toluene, xylene, etc.;

[0032] 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.

[0033] The catalytic hydrogenation dehalogenation reaction is to place the fluorination reaction product compound IV in a suitable reaction solvent B, in the presence of a suitable catalyst C, at a reaction temperature of 0-130° C., and a reaction pressure of 0.1-10.0 MPa to obtain 2-fluoro-3-aminobenzoic acid and its ester compounds, namely compound V; wherein the mass ratio of compound IV, reaction solvent B and catalyst C is 1:1-50:0.01-1.

[0034] The reaction solvent B is selected from one or more of 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.;

[0035] Suitable catalyst C is selected from one or more of the common supported metal catalysts, such as one or more of supported Raney nickel, supported metal palladium, supported metal platinum, supported metal molybdenum, supported metal cobalt, supported metal titanium, supported metal rhodium, etc.

[0036] The technical effects of the present invention are mainly reflected in the following aspects:

[0037] The starting materials of the process route of the present invention are easily available, the process flow is common unit operation in fine chemical industry, the operation is convenient, the yield is high and the cost is low. The completion of the present invention provides an effective preparation method for the industrial development of such compounds.

[0038] In the definitions of the compounds of the general formula given above, the terms used collectively generally represent the following substituents:

[0039] Halogen: refers to fluorine, chlorine, bromine or iodine.

[0040] Alkyl: a straight chain, branched chain or cyclic alkyl group, such as methyl, ethyl, n-propyl, isopropyl or cyclopropyl.

[0041] 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.

[0042] Alkenyl: a straight chain, branched chain or cyclic alkenyl group, such as vinyl, 1-propenyl, 2-propenyl and different butenyl, pentenyl and hexenyl isomers; alkenyl also includes polyenes such as 1,2-propadienyl and 2,4-hexadienyl.

[0043] Haloalkenyl: an alkenyl group in which at least one or more hydrogen atoms may be replaced by halogen atoms.

[0044] Alkynyl: includes straight-chain or branched alkynes, such as ethynyl, 1-propynyl and the different butynyl, pentynyl and hexynyl isomers; alkynyl also includes groups consisting of multiple triple bonds, such as 2,5-hexadiynyl.

[0045] Haloalkynyl: an alkynyl group in which at least one or more hydrogen atoms may be replaced by a halogen atom.

[0046] Alkoxy: a straight chain, branched chain or cyclic alkoxy group, such as methoxy, ethoxy, n-propoxy, isopropoxy, cyclopropyloxy or n-butoxy.

[0047] Haloalkoxy: a straight chain, branched or cyclic alkoxy group, in which the hydrogen atoms may be partially or completely substituted by halogen, for example chloromethoxy, dichloromethoxy, trichloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chlorofluoromethoxy, trifluoroethoxy, heptafluoroisopropyl, etc.

[0048] Alkylthio: A straight chain, branched or cyclic alkyl group connected to the structure via a sulfur atom bond, such as methylthio, ethylthio, etc.

[0049] Alkenylthio: a straight chain, branched or cyclic alkyl group connected to the structure via a sulfur atom bond, such as 1-propenyl-3-thio, 2-butenyl-4-thio, etc.

[0050] 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.

[0051] 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.

[0052] Alkylamino: A straight chain, branched or cyclic alkyl group bonded to the structure via a nitrogen atom, such as methylamino, ethylamino, n-propylamino, isopropylamino or the isomeric butylamino groups.

[0053] Dialkylamino: two identical or different straight-chain, branched or cyclic alkyl groups are connected to the structure via a nitrogen atom bond, such as dimethylamino, methylethylamino, cyclopropylamino, etc.

[0054] Alkoxycarbonyl: alkyl-O-CO-, for example CH3OCO-.

[0055] Alkylcarbonyl: alkyl-CO-, such as CH3CO-

[0056] Alkylsulfonyl: alkyl-S(O)2-, for example methylsulfonyl.

[0057] Alkylsulfinyl: alkyl-S(O)-, for example methylsulfinyl.

[0058] Alkylaminocarbonyl: alkyl-NH-CO-, for example CH3NHCO-.

[0059] Alkylaminosulfonyl: alkyl-NH-S(O)2-, for example CH3NH-S(O)2-. DETAILED DESCRIPTION

[0060] The following examples are used to further illustrate the present invention, but are not intended to limit the present invention.

[0061] Example 1

[0062] Preparation of 5-bromo-2-hydroxy-3-nitrobenzoic acid:

[0063]

[0064] 5-Bromo-2-hydroxybenzoic acid (43.5 g, 0.196 mol) was added to 250 g of glacial acetic acid and stirred thoroughly. 50 g of concentrated nitric acid was slowly added dropwise in an ice bath. After the addition was completed, the temperature was raised to room temperature for reaction. The reaction was monitored by HPLC until the reaction was complete. The reaction solution was poured into 1 L of ice water. A large amount of solid precipitated. The solid was filtered, and the filter cake was washed with saturated sodium bicarbonate aqueous solution and water in turn. After drying, 50.4 g of the target yellow solid was obtained. The purity was 98.7% by HPLC, and the yield was 96.9%.

[0065] The NMR data are as follows: 1 H NMR (600MHz, DMSO) δ (ppm): 8.29 (d, 1H), 8.12 (d, 1H).

[0066] Example 2

[0067] The difference from Example 1 is that 5-bromo-2-hydroxybenzoic acid (43.5 g, 0.196 mol) is added to 270 g of concentrated sulfuric acid and stirred thoroughly, 30 g of concentrated nitric acid is slowly added dropwise at -10°C, and after the addition is completed, the temperature is raised to 10°C for reaction, and HPLC is monitored until the reaction is complete. The reaction solution is poured into 1 L of ice water, and a large amount of solid is precipitated. The solid is filtered, and the filter cake is washed with saturated sodium bicarbonate aqueous solution and water in turn, and dried to obtain 50.5 g of the target yellow solid, with a purity of 98.3% and a yield of 96.6% as determined by HPLC.

[0068] Example 3

[0069] Preparation of 5-bromo-2-hydroxy-3-nitrobenzoic acid methyl ester:

[0070]

[0071] 5-bromo-2-hydroxybenzoic acid methyl ester (47.2g, 0.200mol) was added to 200g of concentrated sulfuric acid and stirred thoroughly. 25g of concentrated nitric acid was slowly added dropwise at -10°C. After the addition was complete, the mixture was heated to room temperature for reaction. HPLC was used to monitor the reaction until the reaction was complete. The reaction solution was poured into 800mL of ice water. A large amount of solid was precipitated. The solid was filtered, and the filter cake was washed with saturated sodium bicarbonate aqueous solution and water in turn. The target product was dried to obtain a light yellow solid of 54.3g. The purity was 98.5% and the yield was 96.8% as determined by HPLC.

[0072] The NMR data are as follows: 1 H NMR (600MHz, CDCl3) δ (ppm): 8.27 (d, 1H), 8.24 (d, 1H), 4.03 (s, 3H).

[0073] Example 4

[0074] Preparation of 2,5-dichloro-3-nitrobenzoic acid:

[0075]

[0076] 5-Chloro-2-hydroxy-3-nitrobenzoic acid (22.2 g, 0.100 mol) was added to 150 mL of phosphorus oxychloride and stirred thoroughly. Triethylamine (20.4 g, 0.200 mol) was slowly added dropwise in an ice bath. After the addition was completed, the temperature was raised to 110°C for reaction. The reaction was monitored by HPLC until the reaction was complete. The reaction solution was desolventized and the residue was poured into 200 mL of ice water. A large amount of solid precipitated. The solid was filtered and the filter cake was washed with saturated sodium bicarbonate aqueous solution and water in turn. After drying, 23.3 g of the target brown solid was obtained. The purity was 97.5% and the yield was 96.2% as determined by HPLC.

[0077] The NMR data are as follows: 1 H NMR (600MHz, DMSO) δ (ppm): 8.40 (d, 1H), 8.11 (d, 1H).

[0078] Example 5

[0079] Preparation of methyl 2-chloro-5-bromo-3-nitrobenzoate:

[0080]

[0081] The 5-bromo-2-hydroxy-3-nitrobenzoic acid methyl ester (28.0 g, 0.100 mol) obtained in Example 3 was added to 50 mL of oxalyl chloride and stirred thoroughly. DMF 150 mL was slowly added dropwise at -20 ° C. After the addition was completed, the temperature was raised to 80 ° C for reaction. HPLC was monitored until the reaction was complete. The reaction solution was decompressed and then the residue was poured into 200 mL of ice water. A large amount of solid was precipitated. The solid was filtered, and the filter cake was washed with saturated sodium bicarbonate aqueous solution and water in turn. The target product was dried to obtain a brown solid of 29.2 g. The purity was 97.4% and the yield was 96.6% as determined by HPLC.

[0082] The NMR data are as follows: 1 H NMR (600MHz, CDCl3) δ (ppm): 8.09 (d, 1H), 7.97 (d, 1H), 3.99 (s, 3H).

[0083] Example 6

[0084] The difference from Example 5 is that: 5-bromo-2-hydroxy-3-nitrobenzoic acid methyl ester (28.0 g, 0.100 mol) obtained in Example 3 is added to 100 mL of thionyl chloride and stirred thoroughly, and DMF 5 mL is slowly added dropwise under an ice bath. After the addition is completed, the temperature is raised to 100° C. for reaction, and HPLC is monitored until the reaction is complete. The reaction solution is desolventized, and the residue is poured into 200 mL of ice water. A large amount of solid is precipitated. The solid is filtered, and the filter cake is washed with a saturated sodium bicarbonate aqueous solution and water in turn, and dried to obtain 29.1 g of the target brown-yellow solid, with a purity of 97.6% and a yield of 96.4% as determined by HPLC.

[0085] Example 7

[0086] Preparation of 5-chloro-2-fluoro-3-nitrobenzoic acid:

[0087]

[0088] Anhydrous potassium fluoride (10g, 0.170mol) and tetrabutylammonium bromide (5g, 0.015mol) were added to 100mL toluene and stirred thoroughly. The temperature was raised to 120°C, and the temperature was lowered to room temperature after water separation for 1h. 2,5-dichloro-3-nitrobenzoic acid (21.8g, 0.090mol) was quickly added, and the temperature was raised to 120°C to continue the reaction. The reaction was monitored by HPLC until the reaction was complete. The reaction solution was brought to room temperature, and then 100mL of water was added. The reaction mixture was allowed to stand for stratification, and the organic phase was washed with saturated sodium bicarbonate and water respectively. 18.8g of brown-yellow residue was obtained by desolventizing. The purity was 93.1% and the yield was 88.6% as determined by HPLC.

[0089] The NMR data are as follows: 1H NMR (600MHz, DMSO) δ (ppm): 8.45-8.44 (m, 1H), 8.18-8.16 (m, 1H).

[0090] Example 8

[0091] The difference from Example 7 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. DMF is desolventized and a portion of DMF is desolventized and then cooled to room temperature. 2,5-dichloro-3-nitrobenzonitrile (21.8 g, 0.090 mol) is quickly added, and then the temperature is raised to 65°C for reaction. HPLC is monitored until the reaction is complete. DMF is desolventized 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. 19.1 g of brown-yellow residue is obtained by desolventization. The purity is 93.0% and the yield is 89.9% as determined by HPLC.

[0092] Example 9

[0093] The difference from Example 7 is that 2,5-dichloro-3-nitrobenzonitrile (22.3 g, 0.092 mol) and anhydrous potassium fluoride (6 g, 0.102 mol) are added to 52 g of dry DMSO and stirred thoroughly, and the temperature is raised to 60°C for reaction. After the reaction for 3 hours, the reaction solution is cooled to room temperature, desolventized until no solvent flows out, 60 ml of ethyl acetate is added, and the mixture is pulped and filtered. The ethyl acetate is desolventized to dryness to obtain 19.4 g of the target product. The purity is 92.9% and the yield is 89.2% as determined by HPLC.

[0094] Example 10

[0095] Preparation of 5-bromo-2-fluoro-3-nitrobenzoic acid methyl ester:

[0096]

[0097] 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 mixture was heated to 120 ° C. After 1 h of water separation, the mixture was cooled to room temperature. 2-chloro-5-bromo-3-nitrobenzoic acid methyl ester (30.2 g, 0.100 mol) was quickly added to Example 6. The mixture was then heated to 120 ° C. and the reaction was continued. The reaction was monitored by HPLC until the reaction was complete. The reaction solution was brought to room temperature, 100 mL of water was added, and the mixture was allowed to stand for stratification. The organic phase was washed with saturated sodium bicarbonate and water respectively, and 26.2 g of brown-yellow residue was obtained by desolventizing. The purity was 97.6% and the yield was 92.0% as determined by HPLC.

[0098] The NMR data are as follows: 1H NMR (600MHz, CDCl3) δ (ppm): 8.34-8.31 (m, 2H), 4.01 (s, 3H).

[0099] Embodiment 11

[0100] The difference from Example 10 is that anhydrous sodium fluoride (8.4g, 0.200mol) and tetrabutylammonium bromide (4g, 0.012mol) are added to 100mL toluene and stirred thoroughly, heated to 120°C, and cooled to room temperature after water separation for 1h, and methyl 2-chloro-5-bromo-3-nitrobenzoate (30.2g, 0.100mol) obtained in Example 6 is quickly added, and then heated to 120°C to continue the reaction, and HPLC is monitored until the reaction is complete. The reaction solution is brought to room temperature, and then 100mL of water is added, and the stratification is allowed to stand, and the organic phase is washed with saturated sodium bicarbonate and water respectively, and 26.1g of brown-yellow residue is obtained by precipitation. The purity is 97.5% and the yield is 91.5% as determined by HPLC.

[0101] Example 12

[0102] The difference from Example 10 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. DMF is desolventized and cooled to room temperature after a portion of DMF is desolventized. 2-chloro-5-bromo-3-nitrobenzoic acid methyl ester (27.2 g, 0.090 mol) is quickly added to Example 6, and then the temperature is raised to 65°C for reaction. HPLC is monitored until the reaction is complete. DMF is desolventized 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. 23.5 g of brown-yellow residue is obtained by desolventization. The purity is 97.7% and the yield is 91.8% as determined by HPLC.

[0103] Example 13

[0104] Preparation of 2-fluoro-3-aminobenzoic acid:

[0105]

[0106] 5-Chloro-2-fluoro-3-nitroformic acid (22.5 g, 0.100 mol), palladium carbon catalyst (wet palladium carbon with a content of 10 wt%) 2.0 g and methanol 100 mL were added to an autoclave, and then the temperature was raised to 35-40°C, and the pressure was 7-8 MPa of hydrogen pressure to react, and HPLC was monitored until the reaction was complete. After filtering the catalyst, the filtrate was desolvated under reduced pressure to obtain 15.1 g of a white solid. The purity was 97.2% and the yield was 94.6% as determined by HPLC.

[0107] The NMR data are as follows: 1H NMR (600MHz, DMSO) δ (ppm): 6.95-6.91 (m, 4H), 5.29 (brs, 2H).

[0108] Embodiment 14

[0109] Preparation of methyl 2-fluoro-3-aminobenzoate:

[0110]

[0111] The methyl 5-bromo-2-fluoro-3-nitroformate (28.5 g, 0.100 mol) obtained in Example 10, 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, and then the temperature was raised to 35-40° C., and the reaction was carried out under a hydrogen pressure of 5-6 MPa, and HPLC was monitored 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 a saturated sodium bicarbonate aqueous solution and water in turn, and the organic phase was desolvated to obtain 16.9 g of a light yellow liquid. The purity was 98.1% by HPLC, and the yield was 98.0%.

[0112] The NMR data are as follows: 1 H NMR (600MHz, CDCl3) δ (ppm): 7.22-7.19 (m, 1H), 6.93-6.89 (m, 2H), 3.94 (brs, 2H), 3.87 (s, 3H).

[0113] Embodiment 15

[0114] The difference from Example 14 is that: 5-bromo-2-fluoro-3-nitroformic acid methyl ester (28.5g, 0.100mol) obtained in Example 10, 2.0g of palladium carbon catalyst (wet palladium carbon with a content of 10wt%) and 100mL of ethyl acetate are added to an autoclave, and then the temperature is raised to 75-80°C, and the pressure is 3-4Mpa hydrogen pressure to react, and HPLC is monitored until the reaction is complete. After filtering the catalyst, the organic phase is washed with saturated sodium bicarbonate aqueous solution and water in turn, and the organic phase is desolvated to obtain 16.8g of light yellow liquid. HPLC determination purity is 98.5%, and the yield is 97.8%.

[0115] Example 16

[0116] The difference from Example 14 is that: 5-bromo-2-fluoro-3-nitroformic acid methyl ester (28.5g, 0.100mol) obtained in Example 10, 1.0g of palladium carbon catalyst (wet palladium carbon with a content of 10wt%) and 100mL of ethanol are added to an autoclave, and then the temperature is raised to 90-95°C, and the pressure is 3-4Mpa hydrogen pressure to react, and HPLC is monitored until the reaction is complete. After the catalyst is filtered, the filtrate is desolventized, 100mL of ethyl acetate is added, and the organic phase is washed with saturated sodium bicarbonate aqueous solution and water in turn, and the organic phase is desolventized to obtain 16.8g of a light yellow liquid. HPLC determination purity is 98.3%, and the yield is 97.6%.

[0117] Embodiment 17

[0118] The difference from Example 14 is that: 5-bromo-2-fluoro-3-nitroformic acid methyl ester (28.5g, 0.100mol) obtained in Example 10, 2.0g of platinum carbon catalyst (10wt% platinum carbon) and 100mL of toluene are added to an autoclave, and then the temperature is raised to 110-115°C, and the pressure is 0.5-0.6Mpa hydrogen pressure to react, and HPLC is monitored until the reaction is complete. After filtering the catalyst, the organic phase is washed with saturated sodium bicarbonate aqueous solution and water in turn, and the organic phase is desolvated to obtain 16.8g of light yellow liquid. HPLC determination purity is 97.9%, and the yield is 97.3%.

[0119] Embodiment 18

[0120] The difference from Example 14 is that: 5-bromo-2-fluoro-3-nitroformic acid methyl ester (23.8 g, 0.100 mol) obtained in Example 10, 2.0 g of palladium carbon catalyst (recovered from Example 15) and 100 mL of ethyl acetate are added to an autoclave, then the temperature is raised to 75-80° C., and the pressure is 3-4 MPa of hydrogen pressure to react, and HPLC is monitored until the reaction is complete. After filtering the catalyst, the organic phase is washed with saturated sodium bicarbonate aqueous solution and water in turn, and the organic phase is desolvated to obtain 16.9 g of a light yellow liquid. HPLC determination purity is 97.7%, and the yield is 97.6%.

Claims

1. A method for synthesizing 2-fluoro-3-aminobenzoic acid and its ester compounds, characterized in that: Compound I is used as a raw material and nitrated under reaction conditions to obtain compound II; the obtained compound II is halogenated under suitable reaction conditions to obtain compound III; the obtained compound III is fluorinated under suitable reaction conditions to obtain compound IV; the obtained compound IV is catalytically hydrogenated and dehalogenated under suitable reaction conditions to obtain 2-fluoro-3-aminobenzoic acid and its ester compounds shown in compound V; wherein the reaction process is as follows: In the compound, X is selected from chlorine, bromine or iodine; Y is selected from chlorine, bromine or iodine; and R is selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, unsubstituted or optionally substituted benzyl.

2. The method for synthesizing 2-fluoro-3-aminobenzoic acid and its ester compounds according to claim 1, characterized in that: The nitration reaction is to use compound I as a raw material in a mixed solution of sulfuric acid or glacial acetic acid and nitric acid, and react 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 synthesizing 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 synthesizing 2-fluoro-3-aminobenzoic acid and its ester compounds according to claim 1, characterized in that: The halogenation reaction is to react the nitration reactant compound II in a suitable halogenation reagent 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, halogenation reagent and catalyst A is 1:1-50:0.1-10.

5. The method for synthesizing 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 synthesizing 2-fluoro-3-aminobenzoic acid and its ester compounds according to claim 1, characterized in that: The fluorination reaction is to react the halogenation reaction product compound III 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 VI; 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 synthesizing 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 synthesizing 2-fluoro-3-aminobenzoic acid and its ester compounds according to claim 1, characterized in that: The catalytic hydrogenation dehalogenation reaction is to place the fluorination reaction product compound IV in a suitable reaction solvent B, in the presence of a suitable catalyst C, at a reaction temperature of 0-130° C., and a reaction pressure of 0.1-10.0 MPa to obtain 2-fluoro-3-aminobenzoic acid and its ester compounds, namely compound V; wherein the mass ratio of compound IV, reaction solvent B and catalyst C is 1:1-50:0.01-1.

9. The method for synthesizing 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 common alcohol, ester or benzene solvents; the suitable catalyst C is selected from one or more of common supported metal catalysts.

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