CN114920661A - Synthetic method of 2-fluoro-3-aminobenzoic acid - Google Patents
Synthetic method of 2-fluoro-3-aminobenzoic acid Download PDFInfo
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- CN114920661A CN114920661A CN202210484605.7A CN202210484605A CN114920661A CN 114920661 A CN114920661 A CN 114920661A CN 202210484605 A CN202210484605 A CN 202210484605A CN 114920661 A CN114920661 A CN 114920661A
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- Prior art keywords
- bfl
- compound
- fluoro
- acid
- aminobenzoic acid
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- WZCZMWMNVHEBCK-UHFFFAOYSA-N 3-amino-2-fluorobenzoic acid Chemical compound NC1=CC=CC(C(O)=O)=C1F WZCZMWMNVHEBCK-UHFFFAOYSA-N 0.000 title claims abstract description 18
- 238000010189 synthetic method Methods 0.000 title claims abstract description 7
- 150000001875 compounds Chemical class 0.000 claims abstract description 46
- 238000006243 chemical reaction Methods 0.000 claims abstract description 17
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 14
- 239000000460 chlorine Substances 0.000 claims abstract description 12
- 229910052801 chlorine Inorganic materials 0.000 claims abstract description 12
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims abstract description 11
- 229910052794 bromium Inorganic materials 0.000 claims abstract description 11
- 125000001309 chloro group Chemical group Cl* 0.000 claims abstract description 9
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims abstract description 8
- 230000001546 nitrifying effect Effects 0.000 claims abstract description 5
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims abstract description 3
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical group II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims abstract description 3
- 239000011630 iodine Chemical group 0.000 claims abstract description 3
- 229910052740 iodine Chemical group 0.000 claims abstract description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 39
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 32
- 238000000034 method Methods 0.000 claims description 30
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 claims description 18
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 15
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 13
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 13
- 229910017604 nitric acid Inorganic materials 0.000 claims description 13
- 238000001914 filtration Methods 0.000 claims description 11
- 229910052739 hydrogen Inorganic materials 0.000 claims description 11
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 10
- 239000003054 catalyst Substances 0.000 claims description 10
- 239000001257 hydrogen Substances 0.000 claims description 10
- 238000006396 nitration reaction Methods 0.000 claims description 9
- 235000003270 potassium fluoride Nutrition 0.000 claims description 9
- 239000011698 potassium fluoride Substances 0.000 claims description 9
- 238000003682 fluorination reaction Methods 0.000 claims description 8
- 230000002829 reductive effect Effects 0.000 claims description 8
- PUZPDOWCWNUUKD-UHFFFAOYSA-M sodium fluoride Chemical compound [F-].[Na+] PUZPDOWCWNUUKD-UHFFFAOYSA-M 0.000 claims description 8
- 239000011259 mixed solution Substances 0.000 claims description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 6
- 238000010438 heat treatment Methods 0.000 claims description 6
- 238000002156 mixing Methods 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 5
- 238000005695 dehalogenation reaction Methods 0.000 claims description 5
- 239000000706 filtrate Substances 0.000 claims description 5
- 238000004537 pulping Methods 0.000 claims description 5
- XJHCXCQVJFPJIK-UHFFFAOYSA-M caesium fluoride Chemical compound [F-].[Cs+] XJHCXCQVJFPJIK-UHFFFAOYSA-M 0.000 claims description 4
- 235000013024 sodium fluoride Nutrition 0.000 claims description 4
- 239000011775 sodium fluoride Substances 0.000 claims description 4
- 239000000243 solution Substances 0.000 claims description 4
- 239000007868 Raney catalyst Substances 0.000 claims description 2
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 claims description 2
- 229910000564 Raney nickel Inorganic materials 0.000 claims description 2
- 238000001035 drying Methods 0.000 claims description 2
- 239000012025 fluorinating agent Substances 0.000 claims description 2
- JCZMXVGQBBATMY-UHFFFAOYSA-N nitro acetate Chemical compound CC(=O)O[N+]([O-])=O JCZMXVGQBBATMY-UHFFFAOYSA-N 0.000 claims description 2
- 238000001556 precipitation Methods 0.000 claims description 2
- 238000005406 washing Methods 0.000 claims description 2
- 230000002194 synthesizing effect Effects 0.000 claims 6
- 230000000802 nitrating effect Effects 0.000 claims 2
- 239000002994 raw material Substances 0.000 abstract description 7
- 238000001308 synthesis method Methods 0.000 abstract description 2
- 239000000047 product Substances 0.000 description 20
- 238000004128 high performance liquid chromatography Methods 0.000 description 9
- 239000007787 solid Substances 0.000 description 9
- -1 1 H-NMR (400MHz Substances 0.000 description 7
- 238000005160 1H NMR spectroscopy Methods 0.000 description 7
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- 238000009776 industrial production Methods 0.000 description 4
- SXOKSXISBYNNQM-UHFFFAOYSA-N 5-bromo-2-fluoro-3-nitrobenzoic acid Chemical compound OC(=O)C1=CC(Br)=CC([N+]([O-])=O)=C1F SXOKSXISBYNNQM-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- 125000001246 bromo group Chemical group Br* 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- ZLXBCTDPBNEWRX-UHFFFAOYSA-N 2,5-dibromo-3-nitrobenzoic acid Chemical compound OC(=O)C1=CC(Br)=CC([N+]([O-])=O)=C1Br ZLXBCTDPBNEWRX-UHFFFAOYSA-N 0.000 description 2
- AUAXYMOBWXOEQD-UHFFFAOYSA-N 2,5-dichloro-3-nitrobenzoic acid Chemical compound OC(=O)C1=CC(Cl)=CC([N+]([O-])=O)=C1Cl AUAXYMOBWXOEQD-UHFFFAOYSA-N 0.000 description 2
- BLINULPTLDKOLO-UHFFFAOYSA-N 5-bromo-2-chloro-3-nitrobenzoic acid Chemical compound OC(=O)C1=CC(Br)=CC([N+]([O-])=O)=C1Cl BLINULPTLDKOLO-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- KXZJHVJKXJLBKO-UHFFFAOYSA-N chembl1408157 Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=CC=1C1=CC=C(O)C=C1 KXZJHVJKXJLBKO-UHFFFAOYSA-N 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 238000011031 large-scale manufacturing process Methods 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 239000012286 potassium permanganate Substances 0.000 description 2
- MMZYCBHLNZVROM-UHFFFAOYSA-N 1-fluoro-2-methylbenzene Chemical compound CC1=CC=CC=C1F MMZYCBHLNZVROM-UHFFFAOYSA-N 0.000 description 1
- SQQKOTVDGCJJKI-UHFFFAOYSA-N 2,5-dibromobenzoic acid Chemical compound OC(=O)C1=CC(Br)=CC=C1Br SQQKOTVDGCJJKI-UHFFFAOYSA-N 0.000 description 1
- QVTQYSFCFOGITD-UHFFFAOYSA-N 2,5-dichlorobenzoic acid Chemical compound OC(=O)C1=CC(Cl)=CC=C1Cl QVTQYSFCFOGITD-UHFFFAOYSA-N 0.000 description 1
- MRUDNSFOFOQZDA-UHFFFAOYSA-N 2,6-dichlorobenzoic acid Chemical compound OC(=O)C1=C(Cl)C=CC=C1Cl MRUDNSFOFOQZDA-UHFFFAOYSA-N 0.000 description 1
- XWBTZHDDWRNOQH-UHFFFAOYSA-N 3-chloro-2-fluoroaniline Chemical compound NC1=CC=CC(Cl)=C1F XWBTZHDDWRNOQH-UHFFFAOYSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- PBCJIPOGFJYBJE-UHFFFAOYSA-N acetonitrile;hydrate Chemical compound O.CC#N PBCJIPOGFJYBJE-UHFFFAOYSA-N 0.000 description 1
- 239000003905 agrochemical Substances 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- QSLZKWPYTWEWHC-UHFFFAOYSA-N broflanilide Chemical compound C=1C=CC(C(=O)NC=2C(=CC(=CC=2Br)C(F)(C(F)(F)F)C(F)(F)F)C(F)(F)F)=C(F)C=1N(C)C(=O)C1=CC=CC=C1 QSLZKWPYTWEWHC-UHFFFAOYSA-N 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- DXPIZCZNFUTPEI-UHFFFAOYSA-N diphenylphosphane;azide Chemical compound [N-]=[N+]=[N-].C=1C=CC=CC=1PC1=CC=CC=C1 DXPIZCZNFUTPEI-UHFFFAOYSA-N 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 239000002917 insecticide Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000010606 normalization Methods 0.000 description 1
- 230000005311 nuclear magnetism Effects 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 231100000167 toxic agent Toxicity 0.000 description 1
- 239000003440 toxic substance Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/04—Formation of amino groups in compounds containing carboxyl groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
- C07C201/06—Preparation of nitro compounds
- C07C201/08—Preparation of nitro compounds by substitution of hydrogen atoms by nitro groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
- C07C201/06—Preparation of nitro compounds
- C07C201/12—Preparation of nitro compounds by reactions not involving the formation of nitro groups
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/584—Recycling of catalysts
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The application discloses a synthetic method of 2-fluoro-3-aminobenzoic acid, which comprises the following steps: (1) nitrifying the compound BFL-0 to obtain a compound BFL-1; (2) fluorinating the compound BFL-1 to obtain a compound BFL-2; (3) reducing and dehalogenating the compound BFL-2 to obtain a compound BFL-3;
Description
Technical Field
The invention relates to a synthetic method of 2-fluoro-3-aminobenzoic acid.
Background
The 2-fluoro-3-aminobenzoic acid is an important intermediate for organic synthesis and medical and agricultural chemicals, and is a key intermediate of broflanilide insecticide.
The prior art mainly comprises the following four methods for preparing 2-fluoro-3-aminobenzoic acid:
(1) method A, reference US200614761/WO202170124, the synthetic route is:
the method A uses 2-fluoro-3-chloroaniline as a raw material, and sodium cyanide is used for replacing hydrolysis to obtain a target product; the method has expensive starting raw materials, uses sodium cyanide which is a highly toxic substance, has harsh operating conditions and is not suitable for industrial production;
(2) method B, reference WO2009137391, the synthetic route is:
the method B takes 2-fluorotoluene as a raw material, and a target product is obtained through nitration, potassium permanganate oxidation and palladium carbon hydrogenation reduction; the method has poor selectivity of the nitration step, difficult separation of zero-position and para-position nitration products, high risk coefficient and serious environmental pollution because potassium permanganate is used as an oxidation reagent, and is not suitable for large-scale production process;
(3) method C, reference US2008188450, the synthetic route is:
the method C uses diphenylphosphine azide, has expensive and explosive raw materials and harsh industrial operation conditions, and is not suitable for large-scale production process;
(4) method D, reference CN111320548A, the synthetic route is:
the method D takes 2, 6-dichlorobenzoic acid as a raw material, and prepares a target product through nitration, fluorination and dehalogenation; the method has high nitration selectivity, but poor fluorination selectivity (product: isomer: 30: 1), and difficult removal of the generated isomer impurities, so that the production cost is high, and the method is not suitable for industrial production.
Therefore, the development of a method suitable for industrial production of 2-fluoro-3-aminobenzoic acid is of great significance.
Disclosure of Invention
The invention aims to provide a synthetic method of 2-fluoro-3-aminobenzoic acid, which has the advantage of being suitable for industrial production.
The technical purpose of the invention is realized by the following technical scheme:
a synthetic method of 2-fluoro-3-aminobenzoic acid comprises the following steps:
(1) nitrifying the compound BFL-0 to obtain a compound BFL-1;
(2) fluorinating the compound BFL-1 to obtain a compound BFL-2;
(3) reducing and dehalogenating the compound BFL-2 to obtain a compound BFL-3;
wherein X is selected from chlorine, bromine or iodine, and Y is selected from chlorine, bromine or iodine.
Further, the nitration reagent used in the nitration process in the step (1) is selected from a nitric acid/sulfuric acid system, an acetyl nitrate or a nitric acid/acetic anhydride system.
Further, a nitrification reagent used in the nitrification process in the step (1) is a nitric acid/sulfuric acid system, and the step (1) comprises the following steps: mixing a compound BFL-0 and part of sulfuric acid to obtain a mixed solution, cooling to 10 ℃, dropwise adding mixed acid of sulfuric acid and nitric acid into the mixed solution, heating to 85 ℃ after dropwise adding is finished, reacting for 2 hours, performing ice precipitation, filtering, washing with water, and drying; the mass ratio of the compound BFL-0 to the sulfuric acid to the nitric acid is 1: 2-3.
Further, the fluorinating agent used in the fluorination process in the step (2) is potassium fluoride, sodium fluoride or cesium fluoride.
Further, potassium fluoride is selected as a fluorinating reagent used in the fluorination process in the step (2), and the step (2) comprises the following steps: mixing a compound BFL-1, dimethyl sulfoxide and potassium fluoride, heating to 60 ℃, reacting for 3 hours, distilling under reduced pressure until no solvent flows out, adding ethyl acetate, pulping, filtering, and concentrating filtrate; the mass ratio of the compound BFL-1 to the dimethyl sulfoxide to the potassium fluoride is 1: 1.5-2: 0.2-0.25.
Further, the reagent used in the reductive dehalogenation process in the step (3) is selected from a palladium carbon/hydrogen system or a raney nickel/hydrogen system.
Further, the reagent used in the reductive dehalogenation process in the step (3) is selected from a palladium carbon/hydrogen system, and the step (3) comprises the following steps: adding a compound BFL-2, methanol and a palladium-carbon catalyst into a pressurized reactor, mixing, introducing hydrogen into the pressurized reactor, raising the temperature to 25 ℃ under the pressure of 0.2MPa, reacting for 4 hours, filtering, recovering the catalyst, and concentrating a reaction solution; the mass ratio of the compound BFL-2 to the methanol to the palladium-carbon catalyst is 1: 2-5: 0.08-0.10.
The technical effects of the invention are mainly reflected in the following aspects:
the synthesis method has the advantages of simple and easy operation, cheap and easily obtained raw materials, high reaction yield and low cost, avoids expensive reaction reagents, and is suitable for industrial popularization and application.
Detailed Description
In the present application, the nuclear magnetic test method: BRUKER 400MHz, and DMSO as solvent.
HPLC purity determination method:
1. instrument and appliance
1.1 high performance liquid chromatograph: agilent1200 equipped with uv detector or equivalent. 1.2 chromatographic column: ODS-34.6X 250mm, 5 um. 1.3 data processing system: a chromatographic workstation.
2. Reagent:
the phosphoric acid is analyzed and purified; purifying acetonitrile by chromatography; purified water
3. Chromatographic conditions
Mobile phase: acetonitrile-0.1% H 3 PO 4 Aqueous solution (30: 70); flow rate: 1.0 mL/min; detection wavelength: 210nm
Column temperature: 30 ℃; sample injection amount: 10 uL; running for 20 min; diluent agent: acetonitrile-water (30: 70).
4. And (4) calculating a result: (area normalization method)
In the formula:
a: main peak or each impurity peak area;
Σ Ai: sum of peak areas for all components.
Example 1: preparing a compound BFL-1 by nitrifying a compound BFL-0, wherein X and Y are chlorine, adding 130g of 2, 5-dichlorobenzoic acid and 200g of sulfuric acid with the mass concentration of 50% into a reactor, cooling to 10 ℃, and then dropwise adding 638g of mixed acid (374 g of sulfuric acid and 264g of nitric acid) into the mixed solution. After the dropwise addition, the temperature is raised to 80 ℃ for reaction for 2 hours. The reaction was then ice-precipitated, filtered, washed with an appropriate amount of water and dried to yield 145g of a yellow crystalline solid.
Performing nuclear magnetic identification on the yellow crystalline solid, 1 H-NMR (400MHz, DMSO). delta.: 8.52-8.56(d, 1H, J ═ 2.5Hz), 8.71-8.73(d, 1H, J ═ 2.5Hz), 12.2(s, 1H), and the yellow crystalline solid was identified by nuclear magnetic resonance as 2, 5-dichloro-3-nitrobenzoic acid. Purity by HPLC 98.9%. The yield thereof was found to be 90.63%.
Example 2: and (2) nitrifying the compound BFL-0 to prepare a compound BFL-1, wherein X is bromine, Y is chlorine, adding 125g of 5-bromine-2-chlorobenzoic acid and 200g of sulfuric acid with the mass concentration of 50% into a reactor, cooling to 10 ℃, and then dropwise adding 638g of mixed acid (374 g of sulfuric acid and 264g of nitric acid) into the mixed solution. After the dropwise addition, the temperature is raised to 85 ℃ for reaction for 2 hours. The reaction was then iced out, filtered, washed with an appropriate amount of water and dried to give 131g of a yellow crystalline solid.
Performing nuclear magnetic identification on the yellow crystalline solid, 1 H-NMR (400MHz, DMSO). delta.: 8.52-8.54(d, 1H, J ═ 2.6Hz), 8.72-8.74(d, 1H, J ═ 2.6Hz), 12.2(s, 1H), and the yellow crystalline solid was identified by nuclear magnetic resonance as 5-bromo-2-chloro-3-nitrobenzoic acid. Purity by HPLC 98.8%. The yield thereof was found to be 88.03%.
Example 3: compound BFL-0 is nitrified to prepare compound BFL-1, X and Y are bromine, 130g of 2, 5-dibromobenzoic acid and 200g of sulfuric acid with the mass concentration of 50% are added into a reactor, the temperature is reduced to 10 ℃, and then 600g of mixed acid (340 g of sulfuric acid and 260g of nitric acid) is added into the mixed solution dropwise. After the dropwise addition, the temperature is raised to 80 ℃ for reaction for 2 h. The reaction was then ice-precipitated, filtered, washed with an appropriate amount of water and dried to yield 138.52g of a yellow crystalline solid.
Subjecting the yellow crystalline solid to nuclear magnetic identificationAnd then the step of determining the number of the first time, 1 H-NMR (400MHz, DMSO). delta.: 8.54-8.56(d, 1H, J-2.5 Hz), 8.71-8.73(d, 1H, J-2.5 Hz), 12.2(s, 1H), and the yellow crystalline solid is 2, 5-dibromo-3-nitrobenzoic acid identified by nuclear magnetism. Purity 98.5% by HPLC and yield 92.05%.
Example 4: fluorination of compound BFL-1 to prepare compound BFL-2, wherein X and Y are bromine, 138.52g of 2, 5-dibromo-3-nitrobenzoic acid, 270g of dimethyl sulfoxide and 19.62g of sodium fluoride are added into a reactor, the temperature is raised to 60 ℃, and the reaction is carried out for 3 hours. Vacuum distilling until no solvent flows out, adding 300ml ethyl acetate, pulping and filtering. The filtrate was concentrated to dryness to give 107g of the desired product.
Performing nuclear magnetic identification on the target product, 1 H-NMR (400MHz, DMSO). delta.: 8.54-8.58(d, 1H, J ═ 2.5Hz), 8.74-8.76(d, 1H, J ═ 2.5Hz), 12.3(s, 1H), and the product was identified by nuclear magnetic resonance as 5-bromo-2-fluoro-3-nitrobenzoic acid. Purity by HPLC 95.6%. The yield was 95.54%.
Example 5: fluorinating a compound BFL-1 to prepare a compound BFL-2, adding 131g of 5-bromo-2-chloro-3-nitrobenzoic acid, 260g of dimethyl sulfoxide and 30g of potassium fluoride into a reactor, heating to 60 ℃, and reacting for 3 hours, wherein X is bromine, and Y is chlorine. Vacuum distilling until no solvent flows out, adding 300ml ethyl acetate, pulping and filtering. The filtrate was concentrated to dryness to obtain 117g of the objective product.
Performing nuclear magnetic identification on the target product, 1 H-NMR (400MHz, DMSO). delta.: 8.64-8.66(d, 1H, J ═ 2.5Hz), 8.84-8.86(d, 1H, J ═ 2.5Hz), 12.3(s, 1H), and the product was identified by nuclear magnetic resonance as 5-bromo-2-fluoro-3-nitrobenzoic acid. Purity by HPLC 99.5%. The yield was 94.54%.
Example 6: preparing a compound BFL-2 by fluorination of a compound BFL-1, adding 145g of 2, 5-dichloro-3-nitrobenzoic acid, 260g of tetrahydrofuran and 29.5g of potassium fluoride into a reactor when X and Y are chlorine, heating to 60 ℃, and reacting for 3 hours. Vacuum distilling until no solvent flows out, adding 300ml ethyl acetate, pulping and filtering. The filtrate was concentrated to dryness to give 129g of product.
Performing nuclear magnetic identification on the target product, 1 HNMR (400MHz, DMSO) δ: 8.66-8.68(d, 1H, J ═ 2.5Hz), 8.83-8.85(d, 1H, J ═ 2.5Hz), 12.2(s, 1H), nuclear magnetic assay product 5-chloro-2-fluoro-3-nitroAnd (5) benzoic acid. Purity by HPLC 99.5%. The yield was 96.13%.
Example 7: the compound BFL-2 is reduced and dehalogenated to prepare a compound BFL-3, wherein X and Y are chlorine, 129g of 5-chlorine-2-fluorine-3-nitrobenzoic acid, 200g of methanol and 10g of palladium carbon catalyst (wet palladium carbon with the content of 10 wt%) are added into a pressurized reactor, hydrogen is introduced into the pressurized reactor, the pressure is 0.2MPa, the temperature is raised to 45 ℃, and the reaction is carried out for 4 hours. Filtering, recovering the catalyst, and concentrating the reaction solution to be dry to obtain 100g of a target product.
Performing nuclear magnetic identification on the target product, 1 H-NMR (400MHz, DMSO). delta.: 5.32(s, 2H), 6.93-6.96(t, J ═ 9Hz, 1H), 7.00-7.02(t, J ═ 8Hz, 1H), 7.13-7.15(t, J ═ 9Hz, 1H), 12.3(s, 1H), nuclear magnetic identification product 2-fluoro-3-aminobenzoic acid. Purity by HPLC 99.8%. The yield was 98%.
Example 8: the compound BFL-2 is deoxidized and dehalogenated to prepare a compound BFL-3, wherein X is bromine, Y is chlorine, 117g of 5-bromo-2-fluoro-3-nitrobenzoic acid, 200g of methanol and 10g of palladium-carbon catalyst (wet palladium-carbon with the content of 10 wt%) are added into a pressurized reactor, hydrogen is introduced into the pressurized reactor, the pressure is 0.2MPa, the temperature is raised to 25 ℃, and the reaction is carried out for 4 hours. Filtering, recovering the catalyst, and concentrating the reaction solution to dryness to obtain 66g of a target product.
Performing nuclear magnetic identification on the target product, 1 H-NMR (400MHz, DMSO). delta.: 5.32(s, 2H), 6.93-6.96(t, J ═ 9Hz, 1H), 7.00-7.02(t, J ═ 8Hz, 1H), 7.13-7.15(t, J ═ 9Hz, 1H), 12.3(s, 1H), nuclear magnetic identification product 2-fluoro-3-aminobenzoic acid. Purity by HPLC 99.6%. The yield was 96%.
It is understood that the above are only exemplary embodiments of the present invention, and other embodiments of the present invention may be made by using equivalent or equivalent alternatives, which fall within the scope of the present invention.
Claims (7)
1. A synthetic method of 2-fluoro-3-aminobenzoic acid is characterized by comprising the following steps:
(1) nitrifying the compound BFL-0 to obtain a compound BFL-1;
(2) fluorinating the compound BFL-1 to obtain a compound BFL-2;
(3) reducing and dehalogenating the compound BFL-2 to obtain a compound BFL-3;
wherein X is selected from chlorine, bromine or iodine, and Y is selected from chlorine, bromine or iodine.
2. The method for synthesizing 2-fluoro-3-aminobenzoic acid according to claim 1, wherein the nitrating reagent used in the nitration in step (1) is selected from a nitric acid/sulfuric acid system, an acetyl nitrate or a nitric acid/acetic anhydride system.
3. The method for synthesizing 2-fluoro-3-aminobenzoic acid according to claim 2, wherein the nitrating reagent used in the nitration in the step (1) is a nitric acid/sulfuric acid system, and the step (1) comprises the following steps: mixing a compound BFL-0 and partial sulfuric acid to obtain a mixed solution, reducing the temperature to 10 ℃, dropwise adding a sulfuric acid and nitric acid mixed acid into the mixed solution, heating to 85 ℃ after dropwise adding, reacting for 2 hours, performing ice precipitation, filtering, washing with water, and drying; the mass ratio of the compound BFL-0 to the sulfuric acid to the nitric acid is 1: 2-5: 2-3.
4. The method for synthesizing 2-fluoro-3-aminobenzoic acid according to claim 1, wherein the fluorinating agent used in the fluorination in the step (2) is selected from potassium fluoride, sodium fluoride or cesium fluoride.
5. The method for synthesizing 2-fluoro-3-aminobenzoic acid according to claim 4, wherein the fluorinating reagent used in the fluorination in the step (2) is potassium fluoride, and the step (2) comprises the following steps: mixing a compound BFL-1, dimethyl sulfoxide and sodium fluoride, heating to 60 ℃, reacting for 3 hours, distilling under reduced pressure until no solvent flows out, adding ethyl acetate, pulping, filtering, and concentrating filtrate; the mass ratio of the compound BFL-1 to the dimethyl sulfoxide to the potassium fluoride is 1: 1.5-2.5: 0.2-0.3.
6. The method for synthesizing 2-fluoro-3-aminobenzoic acid according to claim 1, wherein the reagent used in the reductive dehalogenation in the step (3) is selected from palladium carbon/hydrogen system or Raney nickel/hydrogen system.
7. The method for synthesizing 2-fluoro-3-aminobenzoic acid according to claim 6, wherein the reagent used in the reductive dehalogenation process of the step (3) is selected from palladium carbon/hydrogen system, and the step (3) comprises the following steps: adding a compound BFL-2, methanol and a palladium-carbon catalyst into a pressurized reactor, mixing, introducing hydrogen into the pressurized reactor, raising the temperature to 25 ℃ under the pressure of 0.2MPa, reacting for 4 hours, filtering, recovering the catalyst, and concentrating a reaction solution; the mass ratio of the compound BFL-2 to the methanol to the palladium-carbon catalyst is 1: 2-5: 0.05-0.15.
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| CN111320548A (en) * | 2020-04-24 | 2020-06-23 | 浦拉司科技（上海）有限责任公司 | Synthesis method of anticancer drug intermediate 2-fluoro-3-methyl aminobenzoate |
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| CN102617360A (en) * | 2012-03-01 | 2012-08-01 | 江西吉翔医药化工有限公司 | Synthetic method of 3, 5-dichloro-2, 4-difluoroaniline |
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