CN109678741A - The preparation method of 4- amino -3- fluobenzoic acid - Google Patents
The preparation method of 4- amino -3- fluobenzoic acid Download PDFInfo
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- CN109678741A CN109678741A CN201910085012.1A CN201910085012A CN109678741A CN 109678741 A CN109678741 A CN 109678741A CN 201910085012 A CN201910085012 A CN 201910085012A CN 109678741 A CN109678741 A CN 109678741A
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- difluorobenzonilyile
- fluoro
- aminobenzonitrile
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- 239000002253 acid Substances 0.000 title claims abstract description 59
- 238000002360 preparation method Methods 0.000 title claims abstract description 58
- 238000006243 chemical reaction Methods 0.000 claims abstract description 77
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims abstract description 63
- FDUGOYTWYJZNNP-UHFFFAOYSA-N 4-amino-2-fluorobenzonitrile Chemical compound NC1=CC=C(C#N)C(F)=C1 FDUGOYTWYJZNNP-UHFFFAOYSA-N 0.000 claims abstract description 48
- 229910021529 ammonia Inorganic materials 0.000 claims abstract description 32
- 239000000463 material Substances 0.000 claims abstract description 25
- 239000002994 raw material Substances 0.000 claims abstract description 24
- 230000007062 hydrolysis Effects 0.000 claims abstract description 10
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 63
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 56
- 238000000034 method Methods 0.000 claims description 51
- 239000002904 solvent Substances 0.000 claims description 44
- 238000001953 recrystallisation Methods 0.000 claims description 24
- 238000000605 extraction Methods 0.000 claims description 19
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 18
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 15
- 239000012074 organic phase Substances 0.000 claims description 15
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 12
- 238000009835 boiling Methods 0.000 claims description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 10
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 claims description 10
- 239000007864 aqueous solution Substances 0.000 claims description 9
- 238000005406 washing Methods 0.000 claims description 9
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 8
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 8
- 239000003513 alkali Substances 0.000 claims description 8
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical group COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 7
- 239000012043 crude product Substances 0.000 claims description 6
- 238000010792 warming Methods 0.000 claims description 6
- 238000011033 desalting Methods 0.000 claims description 4
- 125000003944 tolyl group Chemical group 0.000 claims description 4
- YFNKIDBQEZZDLK-UHFFFAOYSA-N triglyme Chemical compound COCCOCCOCCOC YFNKIDBQEZZDLK-UHFFFAOYSA-N 0.000 claims description 4
- 238000004090 dissolution Methods 0.000 claims description 3
- -1 methyl tertbutyl Chemical group 0.000 claims description 3
- YBAZINRZQSAIAY-UHFFFAOYSA-N 4-aminobenzonitrile Chemical compound NC1=CC=C(C#N)C=C1 YBAZINRZQSAIAY-UHFFFAOYSA-N 0.000 claims description 2
- 238000010612 desalination reaction Methods 0.000 claims description 2
- 239000003814 drug Substances 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 claims 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims 4
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 claims 2
- UQXKXGWGFRWILX-UHFFFAOYSA-N ethylene glycol dinitrate Chemical compound O=N(=O)OCCON(=O)=O UQXKXGWGFRWILX-UHFFFAOYSA-N 0.000 claims 1
- 238000002156 mixing Methods 0.000 claims 1
- 239000000575 pesticide Substances 0.000 claims 1
- 238000003912 environmental pollution Methods 0.000 abstract description 7
- 238000004176 ammonification Methods 0.000 abstract description 4
- 238000009776 industrial production Methods 0.000 abstract description 2
- 239000007788 liquid Substances 0.000 description 34
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 23
- 239000012065 filter cake Substances 0.000 description 23
- 238000001914 filtration Methods 0.000 description 23
- 239000000047 product Substances 0.000 description 22
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 16
- 238000012544 monitoring process Methods 0.000 description 10
- 239000000843 powder Substances 0.000 description 9
- 238000005070 sampling Methods 0.000 description 9
- 235000011121 sodium hydroxide Nutrition 0.000 description 9
- 239000007787 solid Substances 0.000 description 9
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical group COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 8
- 238000001291 vacuum drying Methods 0.000 description 8
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 238000010828 elution Methods 0.000 description 6
- 238000010606 normalization Methods 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 239000003960 organic solvent Substances 0.000 description 4
- FTZQXOJYPFINKJ-UHFFFAOYSA-N 2-fluoroaniline Chemical compound NC1=CC=CC=C1F FTZQXOJYPFINKJ-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 238000004321 preservation Methods 0.000 description 3
- BTBFCBQZFMQBNT-UHFFFAOYSA-N 3,4-difluorobenzonitrile Chemical compound FC1=CC=C(C#N)C=C1F BTBFCBQZFMQBNT-UHFFFAOYSA-N 0.000 description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 2
- KRZCOLNOCZKSDF-UHFFFAOYSA-N 4-fluoroaniline Chemical compound NC1=CC=C(F)C=C1 KRZCOLNOCZKSDF-UHFFFAOYSA-N 0.000 description 2
- DDFHBQSCUXNBSA-UHFFFAOYSA-N 5-(5-carboxythiophen-2-yl)thiophene-2-carboxylic acid Chemical compound S1C(C(=O)O)=CC=C1C1=CC=C(C(O)=O)S1 DDFHBQSCUXNBSA-UHFFFAOYSA-N 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- 206010054949 Metaplasia Diseases 0.000 description 2
- 150000001342 alkaline earth metals Chemical class 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- WVDDGKGOMKODPV-UHFFFAOYSA-N benzyl alcohol Substances OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 125000004802 cyanophenyl group Chemical group 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- 230000015689 metaplastic ossification Effects 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 230000000630 rising effect Effects 0.000 description 2
- 239000002351 wastewater Substances 0.000 description 2
- GOYDNIKZWGIXJT-UHFFFAOYSA-N 1,2-difluorobenzene Chemical compound FC1=CC=CC=C1F GOYDNIKZWGIXJT-UHFFFAOYSA-N 0.000 description 1
- PWKNBLFSJAVFAB-UHFFFAOYSA-N 1-fluoro-2-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1F PWKNBLFSJAVFAB-UHFFFAOYSA-N 0.000 description 1
- KUHAYJJXXGBYBW-UHFFFAOYSA-N 2-amino-3-fluorobenzoic acid Chemical compound NC1=C(F)C=CC=C1C(O)=O KUHAYJJXXGBYBW-UHFFFAOYSA-N 0.000 description 1
- CBXKVIFVKCNVGJ-UHFFFAOYSA-N 2-amino-4-fluorobenzonitrile Chemical compound NC1=CC(F)=CC=C1C#N CBXKVIFVKCNVGJ-UHFFFAOYSA-N 0.000 description 1
- JHWIEAWILPSRMU-UHFFFAOYSA-N 2-methyl-3-pyrimidin-4-ylpropanoic acid Chemical compound OC(=O)C(C)CC1=CC=NC=N1 JHWIEAWILPSRMU-UHFFFAOYSA-N 0.000 description 1
- RLMBRRQWBTWGMB-UHFFFAOYSA-N 4-amino-3-fluorobenzonitrile Chemical compound NC1=CC=C(C#N)C=C1F RLMBRRQWBTWGMB-UHFFFAOYSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- JCTRYKLXXYJFJF-UHFFFAOYSA-N C(=O)O.NC1=C(C=CC=C1)F Chemical compound C(=O)O.NC1=C(C=CC=C1)F JCTRYKLXXYJFJF-UHFFFAOYSA-N 0.000 description 1
- PWHULOQIROXLJO-UHFFFAOYSA-N Manganese Chemical compound [Mn] PWHULOQIROXLJO-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical class ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 1
- ZCDOYSPFYFSLEW-UHFFFAOYSA-N chromate(2-) Chemical compound [O-][Cr]([O-])(=O)=O ZCDOYSPFYFSLEW-UHFFFAOYSA-N 0.000 description 1
- 150000001844 chromium Chemical class 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000007599 discharging Methods 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 238000004043 dyeing Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 229910052748 manganese Inorganic materials 0.000 description 1
- 239000011572 manganese Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- JKQOBWVOAYFWKG-UHFFFAOYSA-N molybdenum trioxide Chemical compound O=[Mo](=O)=O JKQOBWVOAYFWKG-UHFFFAOYSA-N 0.000 description 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Substances [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 1
- 229910000510 noble metal Inorganic materials 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- KMUONIBRACKNSN-UHFFFAOYSA-N potassium dichromate Chemical compound [K+].[K+].[O-][Cr](=O)(=O)O[Cr]([O-])(=O)=O KMUONIBRACKNSN-UHFFFAOYSA-N 0.000 description 1
- 239000012286 potassium permanganate Substances 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 1
- KKCBUQHMOMHUOY-UHFFFAOYSA-N sodium oxide Chemical compound [O-2].[Na+].[Na+] KKCBUQHMOMHUOY-UHFFFAOYSA-N 0.000 description 1
- 229910001948 sodium oxide Inorganic materials 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 238000006561 solvent free reaction Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
-
- 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
- C07C227/26—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing carboxyl groups by reaction with HCN, or a salt thereof, and amines, or from aminonitriles
-
- 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
- C07C227/38—Separation; Purification; Stabilisation; Use of additives
- C07C227/40—Separation; Purification
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention relates to a kind of preparation methods of 4- amino -3- fluobenzoic acid, which is characterized in that with 3,4- difluorobenzonilyile is prepared for raw material, it preferably includes following step: (1) after reacting 3,4- difluorobenzonilyile with ammonia, obtaining the fluoro- 4- aminobenzonitrile of intermediate 3-；(2) reaction is hydrolyzed in the fluoro- 4- aminobenzonitrile of intermediate 3- under alkaline condition, obtains 4- amino -3- fluobenzoic acid.The present invention, for main material, has the advantages that easy to operate, price economy, environmental pollution are small, it can be achieved that large-scale industrial production through ammonification and two steps of hydrolysis with cheap 3,4- difluorobenzonilyile to synthesize 4- amino -3- fluobenzoic acid with high-purity in high yield.
Description
Technical field
The present invention relates to the preparation technical fields of compound, and in particular to a kind of preparation side of 4- amino -3- fluobenzoic acid
Method.
Background technique
The method of existing synthesis 4- amino -3- fluobenzoic acid includes following three kinds of methods: 1) from 4- nitro -3- toluene fluoride
For raw material, through strong oxidizer such as potassium permanganate (US20080139619；US20090270372), potassium bichromate
(J.Med.Chem.2005,48(6),729；) or sodium dichromate (Bio.Med.Chem.Lett.2007,17 PCT2009130481
(4),1043；Bio.Med.Chem.Lett.2009,19 (5), 1386) oxidation preparation 4- nitro -3- fluobenzoic acid, then warp
The reduction of Pd/C catalytic hydrogenation nitro (Bio.Med.Chem.2016,24 (12), 2697；PCT2000016769) 4- ammonia is prepared
Base -3- fluobenzoic acid.Wherein raw material 4- nitro -3- toluene fluoride is by 3- toluene fluoride nitrification preparation (dyestuff and dyeing
.2004,41(5),271；Shangrao Normal University journal .2006,26 (3), 49).2) equally with 4- nitro -3- toluene fluoride be original
Material generates benzyl bromine through free radical bromination, is then hydrolyzed to benzylalcohol, then through NaClO or NaClO2Benzylalcohol is oxidized to acid, most
By the also original preparation (PCT2004058764 of Pd/C catalysis；PCT2003037898).It 3) is raw material through alkane using o-fluoronitrobenzene
The baseization preparation fluoro- 4- alkyl nitro benzene of 2- (Tetrahedron, 2001,57 (22), 4753；J.Org.Chem.2002,67(2),
394) it, then through the identical step of method (1) synthesizes.
Method1:
Method2:
Method3:
Summary of the invention
Technical problem solved by the present invention is it is above-mentioned in the prior art, first method generate two kinds of isomers, to target
The selectivity of product is lower than 20%, causes the price of raw material higher, and denitrification step and oxidation step belong to strong exothermal reaction, safety
Hidden danger is big, and generates a large amount of acid waste water and contain manganese or chromate waste water, and environmental pollution is big.Reduction step is needed with valuableness
Noble metal catalyst palladium Pd, it is at high cost；Although second method avoids chromium/manganese salt using high price, but significantly increase anti-
Answer step；The third method is as first two method, all with cost of material is more expensive, synthesis step is long and at high cost, operation
Trouble, the disadvantage that security risk is big and environmental pollution is big.
In order to solve the above technical problems, the present invention provides a kind of method for preparing 4- amino -3- fluobenzoic acid.Just with price
Suitable 3,4- difluorobenzonilyile is main material, through two steps of ammonification and hydrolysis, to synthesize 4- amino -3- fluorobenzene first with high-purity in high yield
Acid has the advantages that easy to operate, price economy, environmental pollution are small, it can be achieved that large-scale industrial production.
Specifically, in view of the deficiencies of the prior art, the present invention provides the following technical scheme that
A kind of preparation method of 4- amino -3- fluobenzoic acid, which is characterized in that be prepared into 3,4- difluorobenzonilyile for raw material
It arrives.
Preferably, in above-mentioned preparation method, the 4- amino -3- fluobenzoic acid is with the raw material system comprising 3,4- difluorobenzonilyile
It is standby to obtain.
In above-mentioned preparation method, 3,4- difluorobenzonilyiles are the parent compound that reaction is participated in raw material.
Preferably, above-mentioned preparation method includes the following steps:
(1) after reacting 3,4- difluorobenzonilyile with ammonia, the fluoro- 4- aminobenzonitrile of intermediate 3- is obtained；
(2) reaction is hydrolyzed in the fluoro- 4- aminobenzonitrile of intermediate 3- under alkaline condition, obtains 4- amino -3- fluorobenzene
Formic acid.
Preferably, in above-mentioned preparation method, the molar ratio of 3, the 4- difluorobenzonilyile and ammonia is 1:(2-10), preferably
1:(4-10).
Preferably, in above-mentioned preparation method, the reaction temperature of 3, the 4- difluorobenzonilyile and ammonia is 60-150 DEG C, preferably
It is 90-110 DEG C.
Preferably, in above-mentioned preparation method, the reaction time of 3, the 4- difluorobenzonilyile and ammonia is 20-40h.
Preferably, in above-mentioned preparation method, the step (1) includes the following steps:
After 3,4- difluorobenzonilyile is reacted with ammonia, 10-35 DEG C is adjusted the temperature to, resulting material is passed through into recrystallization process
Afterwards, the fluoro- 4- aminobenzonitrile of intermediate 3- is obtained.
Preferably, described before recrystallization process in above-mentioned preparation method, it further include with water and organic extraction solvent pair
Material obtains the process of organic phase after carrying out extraction or washing and desalting.
Preferably, described before recrystallization process in above-mentioned preparation method, it is further comprising the steps of: directly to aggravate knot
Brilliant solvent, cool down after rising temperature for dissolving crystallization again, filtering, after filter cake is washed with water, dry the fluoro- 4- aminobenzonitrile of sterling 3-.
Preferably, in above-mentioned preparation method, the extraction process includes the following steps: to mix in water and organic extraction solvent
Afterwards, material is extracted, the water, organic extraction solvent and 3, the mass ratio of 4- difluorobenzonilyile is preferably (5-15): (2-
6):1。
Preferably, in above-mentioned preparation method, the process of the washing and desalting includes the following steps:
It discharges after organic extraction solvent dissolution is added into material, adds desalination after water washing, separate organic phase.
Preferably, in above-mentioned preparation method, the organic extraction solvent is selected from methyl tertiary butyl ether(MTBE), 2- methyl tetrahydro furan
It mutters, the one or more of ethyl acetate or methylene chloride.
Preferably, in above-mentioned preparation method, the process of the recrystallization includes the following steps: that weight is added in resulting material
After recrystallisation solvent, first it is warming up to 60-80 DEG C and is cooled to 0-5 DEG C again.
Preferably, in above-mentioned preparation method, the recrystallization solvent is selected from one or both of benzene, toluene or dimethylbenzene
More than.It preferably, further include to 3,4- difluorobenzene before reacting 3,4- difluorobenzonilyile with ammonia in above-mentioned preparation method
The process of reaction dissolvent is added in nitrile；The reaction dissolvent is selected from toluene, glycol dimethyl ether, diethylene glycol dimethyl ether, three second
One or more of glycol dimethyl ether, 2- methyltetrahydrofuran, n,N-Dimethylformamide or dimethyl sulfoxide, preferably
, the reaction dissolvent includes diethylene glycol dimethyl ether.
Preferably, in above-mentioned preparation method, when reaction dissolvent is not soluble in water, the step (1) include the following steps: by
3,4- difluorobenzonilyiles are added in reaction dissolvent, after after reacting with ammonia, resulting material is washed with water, separates organic phase, concentration
Crude product is obtained, after recrystallization process, obtains the fluoro- 4- aminobenzonitrile of intermediate 3-, the reaction dissolvent choosing not soluble in water
From toluene or 2- methyltetrahydrofuran；
When reaction dissolvent is the low boiling point solvent for being dissolved in water, the step (1) includes the following steps: 3,4- difluorobenzene
Nitrile is added in reaction dissolvent, after reacting with ammonia, resulting material is concentrated into no fraction and is shuffled with water, by recrystallization process
Afterwards, the fluoro- 4- aminobenzonitrile of intermediate 3- is obtained；The low boiling point solvent for being dissolved in water is preferably glycol dimethyl ether；
When reaction dissolvent is the high boiling solvent for being dissolved in water, the step (1) includes the following steps: 3,4- difluorobenzene
Nitrile is added in reaction dissolvent, after reacting with ammonia, be obtained by extraction to material with the mixture of water and organic extraction solvent
Machine phase obtains the fluoro- 4- aminobenzonitrile of intermediate 3- after recrystallization process；The high boiling solvent for being dissolved in water is selected from two
One or more of glycol dimethyl ether, triethylene glycol dimethyl ether, n,N-Dimethylformamide or dimethyl sulfoxide, preferably
, the high boiling solvent for being dissolved in water includes diethylene glycol dimethyl ether.
Preferably, in above-mentioned preparation method, molar concentration of 3, the 4- difluorobenzonilyile in reaction dissolvent is greater than
0.5mol/L, preferably 1-5mol/L.
It preferably, further include the process of filtering in above-mentioned preparation method, after the recrystallization process.
Preferably, in above-mentioned preparation method, the step (2) includes the following steps:
The fluoro- 4- aminobenzonitrile of intermediate 3- is mixed with alkaline aqueous solution, reaction is hydrolyzed, after acid for adjusting pH value is added
Obtain 4- amino -3- fluobenzoic acid.
Preferably, in above-mentioned preparation method, the temperature of the hydrolysis in the step (2) is 50-100 DEG C.When reaction
Between be 1-10h.
Preferably, in above-mentioned preparation method, the molar ratio of the fluoro- 4- aminobenzonitrile of the 3- and alkali is 1:(1-5), preferably
1:(1-3).
Preferably, in above-mentioned preparation method, the pH value is 1.0-4.0, preferably 2.0-3.0.
Preferably, in above-mentioned preparation method, the alkali is selected from the hydroxide or carbonate of alkali or alkaline earth metal, institute
State one or more of the acid selected from hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, formic acid or acetic acid.
Preferably, in above-mentioned preparation method, the concentration of the alkaline aqueous solution is 5-30wt%, and the concentration of the acid is 5-
30wt%.
The present invention also provides 4- amino -3- fluobenzoic acids, are prepared by above-mentioned preparation method.
The present invention also provides above-mentioned 4- amino -3- fluobenzoic acid field of medicaments application.
The invention has the advantages that 1) raw material is easy to get, it is at low cost；2) synthesis step is simple to operation, with high purity, high income,
Environmental pollution is small, easy to industrialized production.
Detailed description of the invention
Fig. 1 is liquid phase-mass spectrogram of the 1 fluoro- 4- aminobenzonitrile of gained intermediate 3- of embodiment.
Fig. 2 is liquid phase-mass spectrogram of 1 products obtained therefrom 4- amino -3- fluobenzoic acid of embodiment.
Specific embodiment
For solve that cost of material existing for current 4- amino -3- fluobenzoic acid preparation method is more expensive, synthesis step is long and at
This height, the disadvantage that troublesome in poeration, security risk is big and environmental pollution is big, the present invention, which provides, a kind of prepares 4- amino -3- fluorobenzene first
The method of acid.With cheap 3,4- difluorobenzonilyile for main material, through ammonification and two steps of hydrolysis to be synthesized in high yield with purity
4- amino -3- fluobenzoic acid has the advantages that easy to operate, price economy, environmental pollution are small, it can be achieved that large-scale industry metaplasia
It produces.
In a kind of preferred embodiment, the present invention provides a kind of preparation method of 4- amino -3- fluobenzoic acid, synthesizes road
Line is mainly comprised the steps that as shown in following reaction equations
(1) ammonification: 3,4- difluorobenzonilyile and ammonia are reacted in autoclave, obtain the fluoro- 4- aminobenzonitrile of intermediate 3-；
(2) hydrolyze: hydrolysis occurs under alkaline condition for the fluoro- 4- aminobenzonitrile of the intermediate 3- that step (1) obtains, raw
At 4- amino -3- fluobenzoic acid.
Preferably, aminating reaction described in step (1) are as follows: 3,4- difluorobenzonilyile and solvent is added into autoclave first
(or not solubilizer), then passes to ammonia, is warming up to 60-150 DEG C of reaction, negates and control in material liquid chromatogram (LC) is answered to react extremely
Completely.After cooling the temperature to 10-30 DEG C of pressure release in the presence of solvent, according to the difference of solvent type, select that following certain is suitable
Mode is post-processed: 1) when solvent and water are immiscible, adding water washing organic phase, be concentrated to give crude product, recrystallized to obtain sterling；
2) when solvent is low boiling point solvent reaction miscible with water, it is concentrated into no fraction, adds water to shuffle filtering, filter cake is through recrystallizing
The fluoro- 4- aminobenzonitrile of sterling 3-；3) when solvent is high boiling solvent miscible with water, water and organic extraction solvent is added, point
After separating out organic phase, recrystallization solvent is added, cool down crystallization, obtains the fluoro- 4- aminobenzonitrile of intermediate 3-.When solvent-free reaction,
After cooling the temperature to 10-30 DEG C of pressure release, it can choose and select a kind of post-processed from following mode: 1) organic solvent is added
Dissolution discharging, adds water washing, separates organic phase, be concentrated to give crude product, recrystallized to obtain the fluoro- 4- aminobenzonitrile of sterling 3-；2) directly
Recrystallisation solvent is aggravated, cool down after rising temperature for dissolving crystallization again, filtering, after filter cake is washed with water, dry the fluoro- 4- aminobenzene of sterling 3-
Nitrile.Wherein organic solvent is selected from methyl tertiary butyl ether(MTBE), ethyl acetate, methylene chloride etc. and the immiscible solvent of water.
Preferably, step (1) aminating reaction: can carry out under solvent-free conditions, can also be carried out with solubilizer.React molten
Agent is selected from toluene, glycol dimethyl ether, diethylene glycol dimethyl ether, triethylene glycol dimethyl ether, 2- methyltetrahydrofuran, N, N- diformazan
One of base formamide or dimethyl sulfoxide are a variety of, wherein it is preferred that diethylene glycol dimethyl ether.The quality of 3,4- difluorobenzonilyile with
The volume ratio of solvent is 1:0-100.
Preferably, step (1) aminating reaction: the molar ratio of 3,4- difluorobenzonilyiles and ammonia is 1:2-10, wherein with 1:4-
10 effects are more preferable.
Preferably, step (1) aminating reaction: reaction temperature is 90-110 DEG C.
Preferably, step (1) aminating reaction: organic solvent (extractant) is selected from methyl tertiary butyl ether(MTBE), ethyl acetate, two
Chloromethanes etc. and the immiscible solvent of water.
Preferably, step (1) aminating reaction: recrystallization solvent is selected from one of benzene, toluene or dimethylbenzene or a variety of.
Preferably, 3,4- difluorobenzonilyile carries out under liquid chromatogram control with reacting for ammonia in the step (1), until
Fully reacting, and the method for middle control reaction is not limited to liquid chromatogram, other modes are good, such as: TLC or GC.
In the present invention, organic solvent is added in the feed, helps to discharge.
Preferably, step (2) hydrolysis: the fluoro- 4- aminobenzonitrile of 3- and alkaline aqueous solution are mixed, anti-at 50-100 DEG C
It answers, is reacted with liquid chromatogram control to complete；Acid for adjusting pH=1.0-4.0 is added dropwise, is cooled to room temperature filtering, filter cake is mixed with water
It washes, it is dry, obtain 4- amino -3- fluobenzoic acid.
Preferably, step (2) hydrolysis: alkali is selected from the hydroxide or carbonate of alkali or alkaline earth metal, such as hydrogen
Sodium oxide molybdena, potassium hydroxide；Acid is selected from hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, formic acid or acetic acid.
Preferably, step (2) hydrolysis: the molar ratio of the fluoro- 4- aminobenzonitrile of 3- and alkali is 1:1.0-5.0 in reaction,
Preferably 1:1.0-3.0；The concentration of the aqueous solution of alkali is 5-30%；The concentration of acid is 5-30%.
Preferably, step (2) hydrolysis: the optimal pH=2.0-3.0 that acid adding is adjusted.
The preparation method of 4- amino -3- fluobenzoic acid of the present invention is further illustrated below by specific embodiment.
In the following embodiments, the information of each reagent used and instrument is as follows:
3,4- difluorobenzonilyile: Zhejiang Ying Xin Chemical Co., Ltd., content 99%.
Autoclave: Dalian Run Chang petrochemical equipment Co., Ltd, model: KCF-250 bears pressure >=4Mpa.
Liquid chromatogram: Agilent, model: 1260.
Liquid chromatograph-mass spectrometer: Agilent, model: 6120.
Differential scanning calorimeter: Shimadzu DSC-60.
Embodiment 1
Step 1: 3,4- difluorobenzonilyile (30g, 0.22mol) being added in 500mL autoclave, ammonia 7.5g is passed through
(0.44mol).90 DEG C of reactions (maximum pressure is 4.0Mpa in reaction process) for 24 hours is then heated to, sampling is supervised with liquid chromatogram
It surveys reaction to raw material and normalizes content≤0.5%.After being cooled to room temperature pressure release, methyl tertiary butyl ether(MTBE) (90mL) dissolved matter is added
Material；The ammonium fluoride that (150mL × 3) are washed with water to generate except dereaction, separates organic phase, is concentrated under reduced pressure into not flow liquid and obtains slightly
Product.It is recrystallized with toluene (120mL), is cooled to 0 DEG C of filtering, filter cake is primary with (0-5 DEG C) of cold toluene elution, and 40 DEG C of vacuum are dry
It is dry, obtain the fluoro- 4- aminobenzonitrile 8.8g (yield: 30% of 3-；Purity > 99%；Off-white powder, 70-72 DEG C of fusing point).
Wherein, the calculation formula of yield are as follows: product quality ÷ (3,4- difluorobenzonilyile molal quantitys × molecular weight of product) ×
100%
The detection method of purity are as follows: Agilent liquid chromatogram 1260, area normalization.
The detection method of fusing point are as follows: detect to obtain with differential scanning calorimeter.
Step 2: by the fluoro- 4- aminobenzonitrile (13.6g, 0.1mol) of 3-, the room sodium hydrate aqueous solution (0.1mol, 5wt%)
The lower charging of temperature, then heats to 50 DEG C of reaction 10h, samples, with liquid chromatogram monitoring reaction to raw material normalize content≤
0.5%, 20 DEG C are then cooled to, 15wt% hydrochloric acid is added dropwise at this temperature and adjusts pH=2, filtering, filter cake is mixed with water (70mL)
Wash it is primary, 50 DEG C be dried in vacuo 4- amino -3- fluobenzoic acid 14.7g (yield 95%, purity > 99%, white solid melt
Point: 215-216 DEG C).
The detection method of the fluoro- 4- aminobenzonitrile of intermediate 3- and product 4- amino -3- fluobenzoic acid are as follows: Agilent liquid phase color
Spectrum 1260, area normalization.Target product is accredited as through liquid chromatography mass spectrometric (LC-MS).
Wherein, the calculation formula of yield are as follows: product quality ÷ (the fluoro- 4- aminobenzonitrile molal quantity × molecular weight of product of 3-) ×
100%
The present embodiment gained intermediate and product, the testing result of intermediate are detected with liquid chromatograph-mass spectrometer are as follows:
LC-MS(m/z):137[M+H]+, C7H5FN2.The testing result of product are as follows: LC-MS (m/z): 156 [M+H]+, C7H6FNO2.Specifically
Such as Fig. 1-Fig. 2, shown in table 1- table 2.
Fig. 1 be intermediate liquid phase-mass spectrogram (LC-MS figure), table 1 for Fig. 1 testing result, from Fig. 1 and table 1 it is found that
Ion mass-to-charge ratio 137.0514,138.054 and corresponding molecular formula C7H5FN2Show synthesis is the fluoro- 4- aminobenzene of intermediate 3-
Nitrile, Fig. 2 be product 4- amino -3- fluobenzoic acid liquid phase-mass spectrogram, table 2 be Fig. 2 testing result, from Fig. 2 and table 2 it is found that
Ion mass-to-charge ratio 156.0461,157.0491 and corresponding molecular formula C7H6FNO2The product for showing synthesis is 4- amino -3- fluorobenzene first
Acid.
The testing result of 1 intermediate LC-MS figure of table
The testing result of 2 product LC-MS figure of table
Embodiment 2
Step 1: 3,4- difluorobenzonilyile (30g, 0.22mol) being added in 500mL autoclave, ammonia 15g is passed through
(0.88mol).90 DEG C of reactions (maximum pressure is 4.0Mpa in reaction process) for 24 hours is then heated to, sampling is supervised with liquid chromatogram
It surveys reaction to raw material and normalizes content≤0.5%.After being cooled to room temperature pressure release, ethyl acetate (90mL) dissolved material is added；With
Water washing (150mL × 3) is separated organic phase, is concentrated under reduced pressure into not flow liquid and obtains crude product with the ammonium fluoride generated except dereaction.Use first
Benzene (120mL) recrystallization is cooled to 0 DEG C of filtering, and filter cake is primary with (0-5 DEG C) of cold toluene elution, and 40 DEG C of vacuum drying obtain 3-
Fluoro- 4- aminobenzonitrile 27.9g (yield: 95%；Purity > 99%；Off-white powder, 70-72 DEG C of fusing point), it is identical with embodiment 1
Method detects that intermediate is the fluoro- 4- aminobenzonitrile of 3-.
Step 2: by the fluoro- 4- aminobenzonitrile (13.6g, 0.1mol) of 3-, the room sodium hydrate aqueous solution (0.1mol, 5wt%)
The lower charging of temperature, then heats to 50 DEG C of reaction 10h, samples, with liquid chromatogram monitoring reaction to raw material normalize content≤
0.5%, 20 DEG C are then cooled to, 15wt% hydrochloric acid is added dropwise at this temperature and adjusts pH=2, filtering, filter cake is mixed with water (70mL)
Wash it is primary, 50 DEG C be dried in vacuo 4- amino -3- fluobenzoic acid 14.7g (yield 95%, purity > 99%, white solid melt
Point: 215-216 DEG C), detect that product is 4- amino -3- fluobenzoic acid with 1 same procedure of embodiment.
Embodiment 3
Step 1: 3,4- difluorobenzonilyile (30g, 0.22mol) being added in 500mL autoclave, ammonia 37.4g is passed through
(2.2mol).Then heat to 110 DEG C reaction for 24 hours, sampling, with liquid chromatogram monitoring reaction to raw material normalization content≤
0.5%.It after being cooled to room temperature pressure release, is added toluene (120mL), is warming up to 60 DEG C of heat preservation 0.5h and is then cooled to 0 DEG C, filter,
Filter cake is shuffled (150mL × 3) with water, filtering, and 40 DEG C of filter cake vacuum drying obtain the fluoro- 4- aminobenzonitrile 27.9g (yield 95% of 3-；
Purity > 99%, off-white powder, 70-72 DEG C of fusing point), detect that intermediate is the fluoro- 4- amino of 3- with 1 same procedure of embodiment
Cyanophenyl.
Step 2: by the fluoro- 4- aminobenzonitrile (13.6g, 0.1mol) of 3-, sodium hydroxide (0.18mol, 10wt%) and water chamber
The lower charging of temperature, then heats to 100 DEG C of reaction 1.5h, samples, with liquid chromatogram monitoring reaction to raw material normalize content≤
0.5%, 30 DEG C are then cooled to, 15wt% hydrochloric acid is added dropwise at this temperature and adjusts pH=2, filtering, filter cake is mixed with water (70mL)
Wash it is primary, 55 DEG C be dried in vacuo 4- amino -3- fluobenzoic acid 15.2g (yield 98%, purity > 99%, white solid melt
Point: 215-216 DEG C), detect that product is 4- amino -3- fluobenzoic acid with 1 same procedure of embodiment.
Embodiment 4
Step 1: 3,4- difluorobenzonilyile (30g, 0.22mol) being added in 500mL autoclave, ammonia 15g is passed through
(0.88mol).Then heat to 110 DEG C reaction for 24 hours, sampling, with liquid chromatogram monitoring reaction to raw material normalization content≤
0.5%.It after being cooled to room temperature pressure release, is added toluene (120mL), is warming up to 80 DEG C of heat preservation 0.5h and is then cooled to 0 DEG C, filter,
Filter cake is shuffled (150mL × 3) with water, filtering, and 40 DEG C of filter cake vacuum drying obtain the fluoro- 4- aminobenzonitrile 27.3g (yield 93% of 3-；
Purity > 99%, off-white powder, 70-72 DEG C of fusing point), detect that intermediate is the fluoro- 4- amino of 3- with 1 same procedure of embodiment
Cyanophenyl.
Step 2: by the fluoro- 4- aminobenzonitrile (13.6g, 0.1mol) of 3-, sodium hydroxide (0.18mol, 10wt%) and water chamber
The lower charging of temperature, then heats to 100 DEG C of reaction 1.5h, samples, with liquid chromatogram monitoring reaction to raw material normalize content≤
0.5%, 30 DEG C are then cooled to, 15wt% hydrochloric acid is added dropwise at this temperature and adjusts pH=2, filtering, filter cake is mixed with water (70mL)
Wash it is primary, 55 DEG C be dried in vacuo 4- amino -3- fluobenzoic acid 15.2g (yield 98%, purity > 99%, white solid melt
Point: 215-216 DEG C), detect that product is 4- amino -3- fluobenzoic acid with 1 same procedure of embodiment.
Embodiment 5
Step 1: 3,4- difluorobenzonilyile (30g, 0.22mol) and diethylene glycol dimethyl ether (150mL) are added to 500mL high
It presses in kettle, is passed through ammonia 22.5g (1.32mol).Then heat to 100 DEG C of reactions for 24 hours, sampling is monitored with liquid chromatogram and reacted
Content≤0.5% is normalized to raw material.After being cooled to room temperature pressure release, it is added water (180mL, 180g), is extracted with ethyl acetate
(60g × 3) merge organic phase, are concentrated under reduced pressure into not flow liquid, residue re crystallization from toluene (120mL), 5 DEG C of filterings, filter in kettle
Cake is primary with (5 DEG C) of toluene elution, and 40 DEG C of vacuum drying obtain the fluoro- 4- aminobenzonitrile 26.4g (yield 90% of 3-；Purity >
99%, off-white powder, 70-72 DEG C of fusing point), detect that intermediate is the fluoro- 4- aminobenzonitrile of 3- with 1 same procedure of embodiment.
Step 2: by the fluoro- 4- aminobenzonitrile (13.6g, 0.1mol) of 3-, sodium hydroxide (0.18mol, 20wt%) and water chamber
The lower charging of temperature, then heats to 90 DEG C of reaction 2h, samples, and normalizes content≤0.5% with liquid chromatogram monitoring reaction to raw material,
Then 30 DEG C are cooled to, 15wt% sulfuric acid is added dropwise at this temperature and adjusts pH=2, filtering, filter cake is shuffled once with water (70mL),
55 DEG C are dried in vacuo to obtain 4- amino -3- fluobenzoic acid 14.7g (yield 95%, purity > 99%, white solid, fusing point: 215-
216 DEG C), detect that product is 4- amino -3- fluobenzoic acid with 1 same procedure of embodiment.
Embodiment 6
Step 1: 3,4- difluorobenzonilyile (30g, 0.22mol) and diethylene glycol dimethyl ether (150mL) are added to 500mL high
It presses in kettle, is passed through ammonia 22.5g (1.32mol).Then heat to 100 DEG C of reactions for 24 hours, sampling is monitored with liquid chromatogram and reacted
Content≤0.5% is normalized to raw material.After being cooled to room temperature pressure release, it is added water (150mL, 150g), is extracted with dichloromethane
(20g × 3) merge organic phase, are concentrated under reduced pressure into not flow liquid, residue re crystallization from toluene (120mL), 5 DEG C of filterings, filter in kettle
Cake is primary with (5 DEG C) of toluene elution, and 40 DEG C of vacuum drying obtain the fluoro- 4- aminobenzonitrile 26.4g (yield 90% of 3-；Purity >
99%, off-white powder, 70-72 DEG C of fusing point), detect that intermediate is the fluoro- 4- aminobenzonitrile of 3- with 1 same procedure of embodiment.
Step 2: by the fluoro- 4- aminobenzonitrile (13.6g, 0.1mol) of 3-, sodium hydroxide (0.5mol, 20wt%) and water chamber temperature
Lower charging then heats to 90 DEG C of reaction 2h, sampling, normalizes content≤0.5% with liquid chromatogram monitoring reaction to raw material, so
After be cooled to 30 DEG C, 15wt% sulfuric acid is added dropwise at this temperature and adjusts pH=1, filtering, filter cake shuffles once with water (70mL), 55
DEG C it is dried in vacuo to obtain 4- amino -3- fluobenzoic acid 12.4g (yield 80%, purity > 99%, white solid, fusing point: 215-216
DEG C), detect that product is 4- amino -3- fluobenzoic acid with 1 same procedure of embodiment.
Embodiment 7
Step 1: 3,4- difluorobenzonilyile (30g, 0.22mol) and 2- methyltetrahydrofuran (150mL) are added to 500mL high
It presses in kettle, is passed through ammonia 15.0g (0.88mol).60 DEG C of reaction 40h are then heated to, are reacted with liquid chromatogram control to complete.
After being cooled to room temperature pressure release, (150mL × 3) are washed with water in reaction solution, separate organic phase, are concentrated under reduced pressure into not flow liquid, with benzene weight
It crystallizes (120mL), is cooled to 5 DEG C of filterings, filter cake is primary with (5 DEG C) of toluene elution, and 40 DEG C of vacuum drying obtain the fluoro- 4- amino of 3-
Cyanophenyl 21.0g (yield: 70%；Purity > 99%；Off-white powder, 70-72 DEG C of fusing point), it is detected with 1 same procedure of embodiment
It is the fluoro- 4- aminobenzonitrile of 3- to intermediate.
Step 2: by the fluoro- 4- aminobenzonitrile (13.6g, 0.1mol) of 3-, the room sodium hydrate aqueous solution (0.3mol, 30wt%)
The lower charging of temperature, then heats to 60 DEG C of reaction 6h, is then cooled to 20 DEG C, 10wt% hydrochloric acid is added dropwise at this temperature and adjusts pH=
3, filtering, filter cake shuffles once with water (70mL), 50 DEG C be dried in vacuo 4- amino -3- fluobenzoic acid 14.3g (yield 92%,
Purity > 99%, white solid, fusing point: 215-216 DEG C), detect that product is 4- amino -3- fluorine with 1 same procedure of embodiment
Benzoic acid.
Embodiment 8
Step 1: 3,4- difluorobenzonilyile (30g, 0.22mol) and glycol dimethyl ether (150mL) are added to 500mL high pressure
In kettle, it is passed through ammonia 20g (1.18mol).95 DEG C of reaction 40h are then heated to, are reacted with liquid chromatogram control to complete.Cooling
To room temperature pressure release, it is concentrated into not flow liquid, residue in (150mL × 3) kettle, the crude product being obtained by filtration toluene weight is washed with water
It crystallizes (120mL), is cooled to 5 DEG C of filterings, filter cake is primary with (5 DEG C) of toluene elution, and 40 DEG C of vacuum drying obtain the fluoro- 4- amino of 3-
Cyanophenyl 25.5g (yield: 85%；Purity > 99%；Off-white powder, 70-72 DEG C of fusing point), it is detected with 1 same procedure of embodiment
It is the fluoro- 4- aminobenzonitrile of 3- to intermediate.
Step 2: by the fluoro- 4- aminobenzonitrile (13.6g, 0.1mol) of 3-, sodium hydrate aqueous solution (0.14mol, 20wt%)
It feeds at room temperature, then heats to 60 DEG C of reaction 6h, be then cooled to 20 DEG C, 10wt% salt acid for adjusting pH is added dropwise at this temperature
=4, filtering, filter cake is shuffled once with water (70mL), and 50 DEG C are dried in vacuo to obtain 4- amino -3- fluobenzoic acid 12.5g (yield
80%, purity > 99%, white solid, fusing point: 215-216 DEG C), detect that product is 4- amino-with 1 same procedure of embodiment
3- fluobenzoic acid.
Embodiment 9
Step 1: 3,4- difluorobenzonilyile (30g, 0.22mol) being added in 500mL autoclave, ammonia 45g is passed through
(2.7mol).Then heat to 150 DEG C reaction for 24 hours, sampling, with liquid chromatogram monitoring reaction to raw material normalization content≤
0.5%.It after being cooled to room temperature pressure release, is added dimethylbenzene (120mL), is warming up to 80 DEG C of heat preservation 0.5h and then is cooled to 0 DEG C, mistake
Filter, filter cake are shuffled (150mL × 3) with water, are filtered, and 40 DEG C of filter cake vacuum drying obtain the fluoro- 4- aminobenzonitrile 26.4g (yield of 3-
90%；Purity > 99%, off-white powder, 70-72 DEG C of fusing point), detect that intermediate is 3- fluoro- with 1 same procedure of embodiment
4- aminobenzonitrile.
Step 2: by the fluoro- 4- aminobenzonitrile (13.6g, 0.1mol) of 3-, sodium hydroxide (0.8mol, 10wt%) and water chamber temperature
Lower charging then heats to 100 DEG C of reaction 1.5h, sampling, with liquid chromatogram monitoring reaction to raw material normalization content≤
0.5%, 30 DEG C are then cooled to, 15wt% hydrochloric acid is added dropwise at this temperature and adjusts pH=5, filtering, filter cake is mixed with water (70mL)
Wash it is primary, 55 DEG C be dried in vacuo 4- amino -3- fluobenzoic acid 10.9g (yield 70%, purity > 99%, white solid melt
Point: 215-216 DEG C), detect that product is 4- amino -3- fluobenzoic acid with 1 same procedure of embodiment.
In conclusion preparation method of the present invention is at low cost, step is simple, high income, pollution are small, it is easy to industrial metaplasia
It produces.
The foregoing is only a preferred embodiment of the present invention, but scope of protection of the present invention is not limited thereto,
Anyone skilled in the art within the technical scope of the present disclosure, according to the technique and scheme of the present invention and its
Inventive concept is subject to equivalent substitution or change, should all be included within the scope of the present invention.
Claims (20)
1. a kind of preparation method of 4- amino -3- fluobenzoic acid, which is characterized in that be prepared into 3,4- difluorobenzonilyile for raw material
It arrives.
2. preparation method according to claim 1, wherein the method includes the following steps:
(1) after reacting 3,4- difluorobenzonilyile with ammonia, the fluoro- 4- aminobenzonitrile of intermediate 3- is obtained；
(2) reaction is hydrolyzed in the fluoro- 4- aminobenzonitrile of intermediate 3- under alkaline condition, obtains 4- amino -3- fluobenzoic acid.
3. preparation method according to claim 2, wherein the molar ratio of 3, the 4- difluorobenzonilyile and ammonia is 1:(2-
10), preferably 1:(4-10).
4. the preparation method according to Claims 2 or 3, wherein the reaction temperature of 3, the 4- difluorobenzonilyile and ammonia is 60-
150 DEG C, preferably 90-110 DEG C.
5. according to any one of the claim 2-4 preparation method, wherein the step (1) includes the following steps:
After 3,4- difluorobenzonilyile is reacted with ammonia, 10-35 DEG C is adjusted the temperature to, by resulting material after recrystallization process,
Obtain the fluoro- 4- aminobenzonitrile of intermediate 3-.
6. preparation method according to claim 5, wherein it is described before recrystallization process, it further include with water and organic extraction
The process of organic phase is obtained after taking solvent to carry out extraction or washing and desalting to material.
7. preparation method according to claim 6, wherein the extraction process includes the following steps: water and organic extraction
After solvent mixing, material is extracted, the water, organic extraction solvent and 3, the mass ratio of 4- difluorobenzonilyile is preferably (5-
15):(2-6):1。
8. preparation method according to claim 6, wherein the process of the washing and desalting includes the following steps:
It discharges after organic extraction solvent dissolution is added into material, adds desalination after water washing, separate organic phase.
9. according to any one of the claim 6-8 preparation method, wherein the organic extraction solvent is selected from methyl tertbutyl
The one or more of ether, 2- methyltetrahydrofuran, ethyl acetate or methylene chloride.
10. according to any one of the claim 5-8 preparation method, wherein the process of the recrystallization includes the following steps:
After recrystallization solvent is added in resulting material, first it is warming up to 60-80 DEG C and is cooled to 0-5 DEG C again.
11. preparation method according to claim 10, wherein the recrystallization solvent is in benzene, toluene or dimethylbenzene
It is one or more kinds of.
12. according to any one of the claim 2-10 preparation method, wherein 3,4- difluorobenzonilyile is being reacted it with ammonia
Before, it further include the process that reaction dissolvent is added into 3,4- difluorobenzonilyile；The reaction dissolvent is selected from toluene, glycol dinitrate
In ether, diethylene glycol dimethyl ether, triethylene glycol dimethyl ether, 2- methyltetrahydrofuran, N,N-dimethylformamide or dimethyl sulfoxide
One or more, it is preferred that the reaction dissolvent includes diethylene glycol dimethyl ether.
13. preparation method according to claim 12, wherein
When reaction dissolvent is not soluble in water, the step (1) includes the following steps: 3,4- difluorobenzonilyile reaction dissolvent is added
In, after being reacted with ammonia, resulting material is washed with water, separate organic phase, concentration after obtain crude product, by recrystallization process
Afterwards, the fluoro- 4- aminobenzonitrile of intermediate 3- is obtained；The reaction dissolvent not soluble in water is selected from toluene or 2- methyltetrahydrofuran；
When reaction dissolvent is the low boiling point solvent for being dissolved in water, the step (1) includes the following steps: to add 3,4- difluorobenzonilyile
Enter in reaction dissolvent, after being reacted with ammonia, resulting material is concentrated into no fraction and is shuffled with water, after recrystallization process,
Obtain the fluoro- 4- aminobenzonitrile of intermediate 3-；The low boiling point solvent for being dissolved in water is preferably glycol dimethyl ether；
When reaction dissolvent is the high boiling solvent for being dissolved in water, the step (1) includes the following steps: to add 3,4- difluorobenzonilyile
Enter in reaction dissolvent, after reacting with ammonia, material carried out with the mixture of water and organic extraction solvent organic phase is obtained by extraction,
After recrystallization process, the fluoro- 4- aminobenzonitrile of intermediate 3- is obtained；The high boiling solvent for being dissolved in water is selected from diethylene glycol
One or more of dimethyl ether, triethylene glycol dimethyl ether, n,N-Dimethylformamide or dimethyl sulfoxide, it is preferred that institute
State that be dissolved in the high boiling solvent of water include diethylene glycol dimethyl ether.
14. 2 or 13 preparation method according to claim 1, wherein mole of 3, the 4- difluorobenzonilyile in reaction dissolvent
Concentration is greater than 0.5mol/L, preferably 1-5mol/L.
15. according to any one of the claim 2-14 preparation method, wherein the step (2) includes the following steps:
The fluoro- 4- aminobenzonitrile of intermediate 3- is mixed with alkaline aqueous solution, reaction is hydrolyzed, is obtained after acid for adjusting pH value is added
4- amino -3- fluobenzoic acid.
16. according to any one of the claim 2-15 preparation method, wherein the temperature of the hydrolysis in the step (2)
It is 50-100 DEG C.
17. according to any one of the claim 2-16 preparation method, wherein mole of 3- fluoro- the 4- aminobenzonitrile and alkali
Than for 1:(1-5), preferably 1:(1-3).
18. any one of 5-17 preparation method according to claim 1, wherein the pH value is 1.0-4.0, preferably 2.0-
3.0。
19.4- amino -3- fluobenzoic acid, is prepared by any one of the claim 1-18 preparation method.
20. application of the 4- amino -3- fluobenzoic acid in field of medicaments or pesticide field described in claim 19.
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| CN111978209A (en) * | 2020-09-07 | 2020-11-24 | 成都美域高制药有限公司 | Synthetic method of tedizolid phosphate intermediate 3-fluoro-4-bromoaniline |
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| CN1194634A (en) * | 1995-08-30 | 1998-09-30 | 拜尔公司 | 4-cyano-2,5-difluoraniline preparation process |
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| CN1194634A (en) * | 1995-08-30 | 1998-09-30 | 拜尔公司 | 4-cyano-2,5-difluoraniline preparation process |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN111978209A (en) * | 2020-09-07 | 2020-11-24 | 成都美域高制药有限公司 | Synthetic method of tedizolid phosphate intermediate 3-fluoro-4-bromoaniline |
| CN111978209B (en) * | 2020-09-07 | 2023-05-30 | 成都美域高制药有限公司 | Synthesis method of tedizolid phosphate intermediate 3-fluoro-4-bromoaniline |
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