Method for preparing 2-fluoro-3-aminobenzoic acid and ester compounds thereof

Abstract

The invention belongs to the field of organic synthesis, and particularly relates to a method for preparing 2-fluoro-3-aminobenzoic acid and ester compounds thereof. The reaction formula is as follows, substituent groups in the formula are shown in the specification, and specifically, a compound I is nitrified under proper reaction conditions to obtain a compound II, the compound II is halogenated under proper reaction conditions to obtain a compound III, the compound III is fluorinated under proper reaction conditions to obtain a compound IV, and the compound IV is hydrolyzed or alcoholyzed under proper reaction conditions to prepare a compound V. And performing catalytic hydrogenation dehalogenation on the compound V under proper reaction conditions to obtain 2-fluoro-3-aminobenzoic acid and ester compounds thereof, namely a compound X. 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 preparing 2-fluoro-3-aminobenzoic acid and ester compounds thereof. Background Art

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

[0003]

[0004] 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:

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

[0012]

[0013] This route has expensive starting materials and uses highly toxic sodium cyanide. The operating conditions are relatively harsh and it is not suitable for industrial production.

[0014] Document CN114920661 reports a feasible method for preparing methyl 2-fluoro-3-aminobenzoate, and the specific route is as follows:

[0015]

[0016] Document CN113717053 reports a feasible method for preparing methyl 2-fluoro-3-aminobenzoate, and the specific route is as follows:

[0017]

[0018] This route uses the strong base lithium amide, and the operating conditions are relatively harsh, which is not suitable for industrial production.

[0019] 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 industrial production of 2-fluoro-3-aminobenzoic acid and its ester compounds. Summary of the invention

[0020] The object of the present invention is 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.

[0021] To achieve the above object, the technical solution of the present invention is as follows:

[0022] A method for preparing 2-fluoro-3-aminobenzoic acid and its ester compounds, the reaction formula is:

[0023]

[0024] 1) Compound I is nitrated under appropriate reaction conditions to obtain Compound II;

[0025] 2) Compound II is halogenated under appropriate reaction conditions to obtain compound III;

[0026] 3) Compound III is fluorinated under appropriate reaction conditions to obtain compound IV;

[0027] 4) Compound IV is hydrolyzed or alcoholyzed under appropriate reaction conditions to prepare compound V;

[0028] 5) Compound V is subjected to catalytic hydrodehalogenation under suitable reaction conditions to obtain compound X;

[0029] in:

[0030] X is selected from chlorine, bromine or iodine;

[0031] Y is selected from chlorine, bromine or iodine;

[0032] R is selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, and unsubstituted or optionally substituted benzyl.

[0033] 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.

[0034] 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.

[0035] 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.

[0036] The sulfuric acid is added into the system until the concentration of sulfuric acid in the system reaches 30%-90%.

[0037] The nitric acid is concentrated nitric acid or fuming nitric acid; wherein the concentration of nitric acid in the system reaches 10%-70%.

[0038] 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.

[0039] 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.;

[0040] 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.

[0041] 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;

[0042] The fluorination agent is selected from one or more of lithium fluoride, potassium fluoride, sodium fluoride, ammonium fluoride or cesium fluoride;

[0043] 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.

[0044] 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.

[0045] The operation of the fourth step of hydrolysis or alcoholysis reaction is that compound IV is reacted 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.

[0046] 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.;

[0047] 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.

[0048] 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.

[0049] The method for reducing the nitro group to an amine group is selected from commonly used nitro group reduction methods, such as metal reduction, stannous chloride reduction, sulfide reduction, metal hydride salt reduction, and the like.

[0050] 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.

[0051] The reaction solvent C 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.;

[0052] Suitable catalyst D 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.

[0053] The technical effects of the present invention are mainly reflected in the following aspects:

[0054] The starting materials of the process route of the present invention are cheap and easily available, and the process flow is common unit operation in fine chemical industry, which is easy to operate, has high yield and good selectivity. The completion of the present invention provides an effective preparation method for the industrial development of such compounds.

[0055] In the definitions of the compounds of the general formula given above, the terms used collectively generally represent the following substituents:

[0056] Halogen: refers to fluorine, chlorine, bromine or iodine.

[0057] Alkyl: a straight chain, branched chain or cyclic alkyl group, such as methyl, ethyl, n-propyl, isopropyl or cyclopropyl.

[0058] 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.

[0059] 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.

[0060] Haloalkenyl: an alkenyl group in which at least one or more hydrogen atoms may be replaced by halogen atoms.

[0061] 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.

[0062] Haloalkynyl: an alkynyl group in which at least one or more hydrogen atoms may be replaced by a halogen atom.

[0063] Alkoxy: a straight chain, branched chain or cyclic alkoxy group, such as methoxy, ethoxy, n-propoxy, isopropoxy, cyclopropyloxy or n-butoxy.

[0064] 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.

[0065] Alkylthio: A straight chain, branched or cyclic alkyl group connected to the structure via a sulfur atom bond, such as methylthio, ethylthio, etc.

[0066] 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.

[0067] 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.

[0068] 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.

[0069] 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.

[0070] 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.

[0071] Alkoxycarbonyl: alkyl-O-CO-, for example CH3OCO-.

[0072] Alkylcarbonyl: alkyl-CO-, such as CH3CO-

[0073] Alkylsulfonyl: alkyl-S(O)2-, for example methylsulfonyl.

[0074] Alkylsulfinyl: alkyl-S(O)-, for example methylsulfinyl.

[0075] Alkylaminocarbonyl: alkyl-NH-CO-, for example CH3NHCO-.

[0076] Alkylaminosulfonyl: alkyl-NH-S(O)2-, for example CH3NH-S(O)2-. DETAILED DESCRIPTION

[0077] The following examples are used to further illustrate the present invention, but are not intended to limit the present invention.

[0078] Example 1

[0079] Preparation of 5-chloro-2-hydroxy-3-nitrobenzamide:

[0080]

[0081] 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 the addition was completed, the temperature was raised to 25°C 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, 62.2 g of the target yellow solid was obtained. The purity was 98.4% by HPLC, and the yield was 97.1%.

[0082] The NMR data are as follows: 1 H NMR (600MHz, DMSO) δ (ppm): 8.33 (d, 1H), 8.22 (d, 1H).

[0083] Example 2

[0084] The difference from Example 1 is

[0085] 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 the addition was completed, the temperature was raised to 10°C 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, 62.5 g of the target yellow solid was obtained. The purity was 98.1% by HPLC and the yield was 97.3%.

[0086] Example 3

[0087] Preparation of 5-bromo-2-hydroxy-3-nitrobenzamide:

[0088]

[0089] 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 the addition was completed, the temperature was raised to 90°C 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, 77.6 g of the target yellow solid was obtained. The purity was 98.3% by HPLC and the yield was 97.4%.

[0090] Example 4

[0091] Preparation of 2,5-dichloro-3-nitrobenzonitrile:

[0092]

[0093] 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 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 500 mL of ice water. A large amount of solid precipitated. The solid was filtered and the filter cake was washed with a saturated sodium bicarbonate aqueous solution and water in turn. After drying, 31.4 g of the target brown-yellow solid was obtained. The purity was 97.5% and the yield was 97.3% as determined by HPLC.

[0094] The NMR data are as follows: 1 H NMR (600MHz, CDCl3) δ (ppm): 8.09 (d, 1H), 7.90 (d, 1H).

[0095] Example 5

[0096] The difference from Example 4 is that: 5-chloro-2-hydroxy-3-nitrobenzamide (32 g, 0.145 mol) obtained in Example 2 is added to 100 mL of oxalyl chloride and stirred thoroughly, and DMF (10.6 g, 0.145 mol) is slowly added dropwise at -20°C. After the addition is completed, the temperature is raised to 80°C for reaction, and HPLC is monitored until the reaction is complete. The reaction solution is decompressed and then the residue is poured into 250 mL of ice water. 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. After drying, 31.2 g of the target brown-yellow solid is obtained. The purity is 97.4% and the yield is 96.6% as determined by HPLC.

[0097] Example 6

[0098] The difference from Example 4 is that: 5-chloro-2-hydroxy-3-nitrobenzamide (22.1 g, 0.100 mol) obtained in Example 1 is added to 80 mL of thionyl chloride and stirred thoroughly, DMF (3.7 g, 0.050 mol) is slowly added dropwise in an ice bath, and 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, where a large amount of solid precipitates. 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 21.6 g of the target brown-yellow solid, with a purity of 97.6% and a yield of 97.1% as determined by HPLC.

[0099] Example 7

[0100] Preparation of 2-bromo-5-chloro-3-nitrobenzonitrile:

[0101]

[0102] 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 the addition was completed, the temperature was raised to 160°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 500 mL of ice water. A large amount of solid precipitated. The solid was filtered and the filter cake was washed with a saturated sodium bicarbonate aqueous solution and water in turn. After drying, 25.9 g of the target brown-yellow solid was obtained. The purity was 97.3% and the yield was 96.4% as determined by HPLC.

[0103] Example 8

[0104] Preparation of 5-chloro-2-fluoro-3-nitrobenzonitrile:

[0105]

[0106] 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 mixture was heated to 120°C, and the mixture was cooled to room temperature after 1 hour of water separation. 2,5-dichloro-3-nitrobenzonitrile (20 g, 0.090 mol) obtained in Example 6 was quickly added, and the mixture was heated to 120°C to continue the reaction. The reaction was monitored by HPLC 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 stratification, and the organic phase was washed with saturated sodium bicarbonate and water, respectively. The residue was desolventized to obtain 17.8 g of brown-yellow residue. The purity was 97.5% and the yield was 96.1% as determined by HPLC.

[0107] The NMR data are as follows: 1H NMR (600MHz, CDCl3) δ (ppm): 8.32-8.31 (m, 1H), 7.93-7.92 (m, 1H).

[0108] Example 9

[0109] The difference from Example 8 is that anhydrous cesium fluoride (26.1 g, 0.170 mol) and tetrabutylammonium bromide (5 g, 0.015 mol) are added to 100 mL of toluene and stirred thoroughly, heated to 120°C, and cooled to room temperature after water separation for 1 hour, and 2,5-dichloro-3-nitrobenzonitrile (20 g, 0.090 mol) obtained in Example 6 is quickly added, and then heated to 120°C to continue the reaction, and HPLC monitoring is performed until the reaction is complete. The reaction solution is cooled to room temperature, and then 100 mL of water is added, and the layers are allowed to stand, and the organic phase is washed with saturated sodium bicarbonate and water respectively, and 17.9 g of brown-yellow residue is obtained by desolventizing. The purity is 97.7% and the yield is 96.8% as determined by HPLC.

[0110] Example 10

[0111] 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. DMF is desolventized under reduced pressure. After a portion of DMF is desolventized, the temperature is lowered to room temperature, and 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 HPLC is monitored until the reaction is complete. DMF is desolventized 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. 17.8 g of a brown-yellow residue is obtained by desolventizing. The purity is 97.6% and the yield is 96.3% as determined by HPLC.

[0112] Embodiment 11

[0113] 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) are added to 90 mL of DMF and stirred thoroughly. DMF is desolventized under reduced pressure. After a portion of DMF is desolventized, the temperature is lowered to room temperature, and 2,5-dichloro-3-nitrobenzonitrile (20 g, 0.090 mol) obtained in Example 6 is quickly added. The temperature is then raised to 65°C for reaction, and HPLC is monitored until the reaction is complete. DMF is desolventized 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. 17.7 g of a brown-yellow residue is obtained by desolventizing. The purity is 97.8% and the yield is 95.9% as determined by HPLC.

[0114] Example 12

[0115] The difference from Example 8 is that anhydrous potassium fluoride (10 g, 0.170 mol) and tetraphenylphosphine bromide (8.4 g, 0.020 mol) are added to 100 mL of xylene and stirred thoroughly, heated to 150° C., separated for 1 hour and then cooled to room temperature, 2,5-dichloro-3-nitrobenzonitrile (18.9 g, 0.085 mol) obtained in Example 6 is quickly added, and then heated to 150° C. to continue the reaction, and HPLC monitoring is performed until the reaction is complete. The reaction solution is cooled to room temperature, and then 100 mL 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 16.8 g of brown-yellow residue is obtained by desolventizing. The purity is 97.3% and the yield is 95.9% as determined by HPLC.

[0116] Embodiment 13

[0117] The difference from Example 8 is that: 2,5-dichloro-3-nitrobenzonitrile (10 g, 0.045 mol) and anhydrous potassium fluoride (5 g, 0.085 mol) obtained in Example 6 are added to 30 mL of dry DMSO and stirred thoroughly, and the temperature is raised to 100°C for reaction, and HPLC is monitored until the reaction is complete. The reaction solution is cooled to room temperature, and then 100 mL of toluene and 100 mL of water are added, and the reaction is allowed to stand for stratification, and the organic phase is washed with saturated sodium bicarbonate and water respectively, and 8.9 g of brown-yellow residue is obtained by desolventizing. The purity is 97.0% and the yield is 95.6% as determined by HPLC.

[0118] Embodiment 14

[0119] Preparation of 5-bromo-2-fluoro-3-nitrobenzonitrile:

[0120]

[0121] 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 temperature was lowered to room temperature after water separation for 1 hour. 5-bromo-2-chloro-3-nitrobenzonitrile (26.9 g, 0.100 mol) 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 lowered to room temperature, and then 100 mL 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. The solution was desolvated to obtain 24.1 g of brown-yellow residue. The purity was 97.6% and the yield was 96.0% as determined by HPLC.

[0122] Embodiment 15

[0123] The difference from Example 14 is that anhydrous sodium fluoride (8.4 g, 0.200 mol) and tetrabutylammonium bromide (4 g, 0.012 mol) are added to 100 mL of toluene and stirred thoroughly, heated to 120°C, and cooled to room temperature after water separation for 1 hour, and 5-bromo-2-chloro-3-nitrobenzonitrile (26.9 g, 0.100 mol) 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 cooled to room temperature, and then 100 mL of water is added, and the layers are allowed to stand, and the organic phase is washed with saturated sodium bicarbonate and water respectively, and 24.0 g of brown-yellow residue is obtained by desolventizing. The purity is 97.4% and the yield is 95.4% as determined by HPLC.

[0124] Example 16

[0125] 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. DMF is desolventized under reduced pressure. After a portion of DMF is desolventized, the temperature is lowered to room temperature, and 5-bromo-2-chloro-3-nitrobenzonitrile (24.2 g, 0.090 mol) is quickly added. The temperature is then raised to 60-65°C for reaction, and HPLC is monitored until the reaction is complete. DMF is desolventized 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. 24.2 g of a brown-yellow residue is obtained by desolventization. The purity is 97.5% and the yield is 96.3% as determined by HPLC.

[0126] Embodiment 17

[0127] 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) are added to 260 g of dry DMSO and stirred thoroughly, and the temperature is raised to 60°C for reaction. After reacting for 3 hours, the reaction solution is cooled to room temperature, desolventized until no solvent flows out, 300 ml of ethyl acetate is added, and the mixture is pulped and filtered. Desolventized ethyl acetate is dried to obtain 110.1 g of a brown-yellow target product. The purity is 97.1% and the yield is 95.3% as determined by HPLC.

[0128] Embodiment 18

[0129] Preparation of 5-chloro-2-fluoro-3-nitrobenzoic acid:

[0130]

[0131] 5-Chloro-2-fluoro-3-nitrobenzonitrile (20.6 g, 0.100 mol) obtained in Example 12 was added to 100 mL of 60% sulfuric acid aqueous solution, and then heated to 80°C for reaction. The reaction was monitored by HPLC until the reaction was complete. 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 with saturated sodium bicarbonate aqueous solution and water in turn. After drying, 21.7 g of the target product was obtained as a light yellow solid. The purity was 98.2% as determined by HPLC, and the yield was 97.0%.

[0132] Embodiment 19

[0133] The difference from Example 18 is that: 5-chloro-2-fluoro-3-nitrobenzonitrile (20.6 g, 0.100 mol) obtained in Example 12 is added to 200 mL of 48% hydrobromic acid aqueous solution, then the temperature is raised to 100°C for reaction, and HPLC is monitored until the reaction is complete. The reaction solution is cooled to room temperature and then poured into 600 mL of ice water, where a large amount of solid precipitates. The solid is filtered, and the filter cake is washed with saturated sodium bicarbonate aqueous solution and water in turn, and dried to obtain 21.8 g of the target product as a light yellow solid. The purity is 97.9% and the yield is 97.2% as determined by HPLC.

[0134] Embodiment 20

[0135] Preparation of 5-chloro-2-fluoro-3-nitrobenzoic acid methyl ester:

[0136]

[0137] 5-Chloro-2-fluoro-3-nitrobenzonitrile (15 g, 0.073 mol) obtained in Example 10 was added to 100 mL of methanol, and concentrated sulfuric acid (14.6 g, 0.146 mol) was slowly added dropwise in an ice bath, and then the temperature was raised to 70°C for reaction, and HPLC was monitored until the reaction was complete. A portion of methanol was desolventized and a large amount of solid precipitated. The solid was filtered, and the filter cake was washed with a saturated sodium bicarbonate aqueous solution and water in turn, and dried to obtain 16.9 g of the target product as a light yellow solid. The purity was 98.1% and the yield was 97.2% as determined by HPLC.

[0138] The NMR data are as follows: 1 H NMR (600MHz, CDCl3) δ (ppm): 8.20-8.17 (m, 2H), 4.00 (s, 3H).

[0139] Embodiment 21

[0140] The difference from Example 20 is that: 5-chloro-2-fluoro-3-nitrobenzonitrile (15 g, 0.073 mol) obtained in Example 10 is added to 150 mL of methanol, hydrogen chloride gas is introduced under an ice bath until saturation is reached, and then the temperature is raised to 45°C for reaction, and HPLC is monitored until the reaction is complete. A portion of methanol is desolventized and 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 17.0 g of the target product as a light yellow solid. The purity is 98.0% and the yield is 97.7% as determined by HPLC.

[0141] Embodiment 22

[0142] The difference from Example 20 is that: 5-chloro-2-fluoro-3-nitrobenzonitrile (15 g, 0.073 mol) obtained in Example 10 is added to 100 mL of methanol, and thionyl chloride (87.7 g, 0.73 mol) is slowly added dropwise in an ice bath, and then the temperature is raised to 70°C for reaction, and HPLC is monitored until the reaction is complete. A portion of methanol is desolventized and 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 17.1 g of the target light yellow solid. The purity is 97.1% and the yield is 97.3% as determined by HPLC.

[0143] Embodiment 23

[0144] Preparation of methyl 2-fluoro-3-aminobenzoate:

[0145]

[0146] The 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, and then the temperature was raised to 35-40°C, and the reaction was carried out under a hydrogen pressure of 7-8 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. The organic phase was desolvated to obtain 16.9 g of the target product as a light yellow liquid. The purity was 98.1% and the yield was 98.0% as determined by HPLC.

[0147] 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, 1H), 3.87 (s, 3H).

[0148] Embodiment 24

[0149] The difference from Example 23 is that: 5-chloro-2-fluoro-3-nitroformic acid methyl ester (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 ethyl acetate are added to an autoclave, then the temperature is raised to 80°C, and the reaction is carried out under a hydrogen pressure of 5-6 MPa, and HPLC is monitored until the reaction is complete. After filtering the catalyst, the organic phase is washed with a saturated sodium bicarbonate aqueous solution and water in turn, and the organic phase is desolvated to obtain 16.8 g of the target light yellow liquid. The purity is 98.5% and the yield is 97.9% as determined by HPLC.

[0150] Embodiment 25

[0151] The difference from Example 23 is that: 5-chloro-2-fluoro-3-nitroformic acid methyl ester (23.8g, 0.100mol) obtained in Example 20, 1.0g of palladium carbon catalyst (wet palladium carbon with a content of 10wt%) and 100mL of ethanol are added to an autoclave, then the temperature is raised to 90°C, and the pressure is 5-6Mpa hydrogen pressure to react, and HPLC is monitored until the reaction is complete. After filtering the catalyst, the filtrate is desolventized, 100mL of ethyl acetate is added, and the organic phase is washed with a saturated sodium bicarbonate aqueous solution and water in turn. The organic phase is desolventized to obtain 16.9g of the target light yellow liquid. HPLC determination purity is 98.3%, and the yield is 97.6%.

[0152] Embodiment 26

[0153] The difference from Example 23 is that: 5-chloro-2-fluoro-3-nitroformic acid methyl ester (23.8 g, 0.100 mol) obtained in Example 20, 2.0 g of platinum carbon catalyst (10 wt% platinum carbon) and 100 mL of toluene are added to an autoclave, then the temperature is raised to 120°C, and the reaction is carried out under a hydrogen pressure of 0.5-1 MPa, and HPLC is monitored until the reaction is complete. After filtering the catalyst, the organic phase is washed with a saturated sodium bicarbonate aqueous solution and water in turn, and the organic phase is desolvated to obtain 17.0 g of the target light yellow liquid. The purity is 97.9% and the yield is 98.4% as determined by HPLC.

[0154] Embodiment 27

[0155] The difference from Example 23 is that: 5-chloro-2-fluoro-3-nitroformic acid methyl ester (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 are added to an autoclave, then the temperature is raised to 80°C, and the reaction is carried out under a hydrogen pressure of 5-6 MPa, and HPLC is monitored until the reaction is complete. After filtering the catalyst, the organic phase is washed with a saturated sodium bicarbonate aqueous solution and water in turn, and the organic phase is desolvated to obtain 16.9 g of the target light yellow liquid. The purity is 97.7% and the yield is 97.6% as determined by HPLC.

[0156] Embodiment 28

[0157] The difference from Example 23 is that: 5-chloro-2-fluoro-3-nitroformic acid methyl ester (23.8g, 0.100mol) obtained in Example 20 is added to 100mL glacial acetic acid, 28.0g of iron powder is slowly added in batches at room temperature, and then the temperature is raised to 65°C for reaction, and HPLC is monitored until the reaction is complete. The reaction solution is filtered, the filtrate is desolventized, and the residue is dissolved in 100mL ethanol for standby use. The standby ethanol solution and 1.0g of palladium carbon catalyst (wet palladium carbon with a content of 10wt%) are added to an autoclave, and then the temperature is raised to 80°C, and the pressure is 5-6Mpa 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 desolventized to obtain 16.8g of the target light yellow liquid. HPLC determination purity is 98.4%, and the yield is 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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