CN118084678A - Preparation method of 2-bromo-6-fluoroaniline - Google Patents
Preparation method of 2-bromo-6-fluoroaniline Download PDFInfo
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- CN118084678A CN118084678A CN202410234111.2A CN202410234111A CN118084678A CN 118084678 A CN118084678 A CN 118084678A CN 202410234111 A CN202410234111 A CN 202410234111A CN 118084678 A CN118084678 A CN 118084678A
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- ALZFPYUPNVLVQM-UHFFFAOYSA-N 2-bromo-6-fluoroaniline Chemical compound NC1=C(F)C=CC=C1Br ALZFPYUPNVLVQM-UHFFFAOYSA-N 0.000 title claims abstract description 43
- 238000002360 preparation method Methods 0.000 title claims abstract description 35
- 238000000034 method Methods 0.000 claims abstract description 28
- 239000013067 intermediate product Substances 0.000 claims abstract description 27
- -1 2-acetamido-3-fluorobenzamide Chemical compound 0.000 claims abstract description 23
- DLNCZTUNEBLKRP-UHFFFAOYSA-N n-(2-amino-6-fluorophenyl)acetamide Chemical compound CC(=O)NC1=C(N)C=CC=C1F DLNCZTUNEBLKRP-UHFFFAOYSA-N 0.000 claims abstract description 14
- OMQMIKMVOINQQK-UHFFFAOYSA-N n-(2-bromo-6-fluorophenyl)acetamide Chemical compound CC(=O)NC1=C(F)C=CC=C1Br OMQMIKMVOINQQK-UHFFFAOYSA-N 0.000 claims abstract description 14
- LBOUEEMTFKPGKI-UHFFFAOYSA-N 2-amino-3-fluorobenzamide Chemical compound NC(=O)C1=CC=CC(F)=C1N LBOUEEMTFKPGKI-UHFFFAOYSA-N 0.000 claims abstract description 13
- 238000006243 chemical reaction Methods 0.000 claims description 47
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 27
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 21
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 20
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 16
- 239000007787 solid Substances 0.000 claims description 16
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 15
- 238000001816 cooling Methods 0.000 claims description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 14
- 239000012044 organic layer Substances 0.000 claims description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 13
- 239000003960 organic solvent Substances 0.000 claims description 12
- 239000007864 aqueous solution Substances 0.000 claims description 11
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 9
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 9
- 239000000706 filtrate Substances 0.000 claims description 9
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 8
- 239000005708 Sodium hypochlorite Substances 0.000 claims description 8
- 239000003153 chemical reaction reagent Substances 0.000 claims description 8
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 claims description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 7
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 claims description 7
- 239000012346 acetyl chloride Substances 0.000 claims description 7
- 238000001035 drying Methods 0.000 claims description 7
- 238000001914 filtration Methods 0.000 claims description 7
- 238000003756 stirring Methods 0.000 claims description 7
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- ODWXUNBKCRECNW-UHFFFAOYSA-M bromocopper(1+) Chemical compound Br[Cu+] ODWXUNBKCRECNW-UHFFFAOYSA-M 0.000 claims description 6
- 238000010438 heat treatment Methods 0.000 claims description 6
- 150000007522 mineralic acids Chemical class 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 5
- OWFXIOWLTKNBAP-UHFFFAOYSA-N isoamyl nitrite Chemical compound CC(C)CCON=O OWFXIOWLTKNBAP-UHFFFAOYSA-N 0.000 claims description 5
- IOGXOCVLYRDXLW-UHFFFAOYSA-N tert-butyl nitrite Chemical compound CC(C)(C)ON=O IOGXOCVLYRDXLW-UHFFFAOYSA-N 0.000 claims description 5
- 239000012414 tert-butyl nitrite Substances 0.000 claims description 5
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 4
- 230000000397 acetylating effect Effects 0.000 claims description 4
- 238000002156 mixing Methods 0.000 claims description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- 239000012345 acetylating agent Substances 0.000 claims description 2
- 239000012295 chemical reaction liquid Substances 0.000 claims description 2
- 238000009776 industrial production Methods 0.000 abstract description 6
- 239000007858 starting material Substances 0.000 abstract description 6
- 238000003786 synthesis reaction Methods 0.000 abstract description 4
- 239000002699 waste material Substances 0.000 abstract description 4
- 230000015572 biosynthetic process Effects 0.000 abstract description 3
- 239000000203 mixture Substances 0.000 description 21
- 239000000047 product Substances 0.000 description 9
- 239000002994 raw material Substances 0.000 description 7
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 6
- 239000000243 solution Substances 0.000 description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 4
- 230000001105 regulatory effect Effects 0.000 description 4
- KEQGZUUPPQEDPF-UHFFFAOYSA-N 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione Chemical compound CC1(C)N(Cl)C(=O)N(Cl)C1=O KEQGZUUPPQEDPF-UHFFFAOYSA-N 0.000 description 3
- FTZQXOJYPFINKJ-UHFFFAOYSA-N 2-fluoroaniline Chemical compound NC1=CC=CC=C1F FTZQXOJYPFINKJ-UHFFFAOYSA-N 0.000 description 3
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 3
- 235000011114 ammonium hydroxide Nutrition 0.000 description 3
- 230000031709 bromination Effects 0.000 description 3
- 238000005893 bromination reaction Methods 0.000 description 3
- XTHPWXDJESJLNJ-UHFFFAOYSA-N chlorosulfonic acid Substances OS(Cl)(=O)=O XTHPWXDJESJLNJ-UHFFFAOYSA-N 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 238000012512 characterization method Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- HPJKCIUCZWXJDR-UHFFFAOYSA-N letrozole Chemical compound C1=CC(C#N)=CC=C1C(N1N=CN=C1)C1=CC=C(C#N)C=C1 HPJKCIUCZWXJDR-UHFFFAOYSA-N 0.000 description 2
- 229960003881 letrozole Drugs 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 230000004224 protection Effects 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000006277 sulfonation reaction Methods 0.000 description 2
- IPWBFGUBXWMIPR-UHFFFAOYSA-N 1-bromo-2-fluorobenzene Chemical compound FC1=CC=CC=C1Br IPWBFGUBXWMIPR-UHFFFAOYSA-N 0.000 description 1
- QDFKKJYEIFBEFC-UHFFFAOYSA-N 1-bromo-3-fluorobenzene Chemical compound FC1=CC=CC(Br)=C1 QDFKKJYEIFBEFC-UHFFFAOYSA-N 0.000 description 1
- MDAZJVAIZVUWDE-UHFFFAOYSA-N 2-bromo-6-fluorobenzoic acid Chemical compound OC(=O)C1=C(F)C=CC=C1Br MDAZJVAIZVUWDE-UHFFFAOYSA-N 0.000 description 1
- 241000701022 Cytomegalovirus Species 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 238000006105 Hofmann reaction Methods 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- IOVCWXUNBOPUCH-UHFFFAOYSA-M Nitrite anion Chemical compound [O-]N=O IOVCWXUNBOPUCH-UHFFFAOYSA-M 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000009435 amidation Effects 0.000 description 1
- 238000007112 amidation reaction Methods 0.000 description 1
- 229940124409 anti-cytomegalovirus drug Drugs 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 238000004880 explosion Methods 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- QWPPOHNGKGFGJK-UHFFFAOYSA-N hypochlorous acid Chemical compound ClO QWPPOHNGKGFGJK-UHFFFAOYSA-N 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- FWYSMLBETOMXAG-QHCPKHFHSA-N letermovir Chemical compound COC1=CC=CC(N2CCN(CC2)C=2N([C@@H](CC(O)=O)C3=CC=CC(F)=C3N=2)C=2C(=CC=C(C=2)C(F)(F)F)OC)=C1 FWYSMLBETOMXAG-QHCPKHFHSA-N 0.000 description 1
- 229950010668 letermovir Drugs 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 150000008060 phenylpyrroles Chemical class 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 230000006103 sulfonylation Effects 0.000 description 1
- 238000005694 sulfonylation reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000002351 wastewater Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/62—Preparation of compounds containing amino groups bound to a carbon skeleton by cleaving carbon-to-nitrogen, sulfur-to-nitrogen, or phosphorus-to-nitrogen bonds, e.g. hydrolysis of amides, N-dealkylation of amines or quaternary ammonium compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/14—Preparation of carboxylic acid amides by formation of carboxamide groups together with reactions not involving the carboxamide groups
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a preparation method of 2-bromo-6-fluoroaniline. The method takes 2-amino-3-fluorobenzamide as a starting material to prepare an intermediate product 2-acetamido-3-fluorobenzamide; then the intermediate product N- (2-amino-6-fluorophenyl) acetamide is prepared, the intermediate product N- (2-bromo-6-fluorophenyl) acetamide is prepared, and finally the 2-bromo-6-fluoroaniline is prepared. The starting material 2-amino-3-fluorobenzamide can be prepared from the cheap and easily available 7-fluoroindigo red in one step, and has wide sources and low cost; the method adopts a brand new synthesis process, and can obtain the 2-bromo-6-fluoroaniline with high yield; simple process, low cost, less three wastes and good selectivity, and is suitable for industrial production.
Description
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a preparation method of a drug intermediate, and especially relates to a preparation method of 2-bromo-6-fluoroaniline.
Background
Letrozole (letermovir, lmv for short) is a potent anti-cytomegalovirus drug. Clinical researches show that the letromycin has better safety and efficacy, after 28 days of treatment, cytomegalovirus is not detected in a patient, and compared with other approved medicines, the letromycin has no cross drug resistance and has good market prospect.
2-Bromo-6-fluoroaniline is an important synthesis intermediate for synthesizing letrozole, and has the following chemical structural formula:
At present, the preparation method of 2-bromo-6-fluoroaniline mainly uses 2-fluoroaniline or bromofluorobenzene as a starting material, such as:
Chinese patent document CN115784896A discloses a preparation method of 2-bromo-6-fluoroaniline, which uses 2-fluoroaniline as a starting material to obtain a target product through amino protection, sulfonylation, amidation/esterification reaction, bromination and desulfonamide/sulfonate in sequence. However, the reaction process has the defects of long steps and low yield, and the operation is dangerous because the sulfonation reagent such as chlorosulfonic acid is used in the reaction process, so that a large amount of acid wastewater is generated, and the environmental pollution is large.
Literature "Organic Letters,2009,vol.11,#5,p.1051–1054;Synthesis ofpyrrolnitrin and related halogenated phenylpyrroles,Morrison,Matthew D.;Hanthorn,Jason J.;Pratt,DerekA." discloses a preparation method of 2-fluoro-6-bromoaniline, the scheme uses 1-bromo-3-fluorobenzene as a starting material, step 1 needs to adopt LDA to pull hydrogen to generate carbanion and then react with carbon dioxide to generate 2-bromo-6-fluorobenzoic acid, step 2 uses sodium azide, the reaction temperature condition of the route is harsh, and flammable and explosive chemicals LDA (lithium diisopropylamide) and sodium azide used in the reaction process have larger explosion risks and are not suitable for industrial production.
The Chinese patent document CN116063184A also discloses a preparation method of 2-bromo-6-fluoroaniline, which simplifies the reaction process, takes 2-fluoroaniline as a starting material, firstly prepares 3-amino-5-bromo-4-fluorobenzenesulfonic acid hydrobromide, then uses concentrated sulfuric acid to replace chlorosulfonic acid for sulfonation to prepare 2-bromo-6-fluoroaniline, and can solve the problems of lower yield and higher cost caused by using chlorosulfonic acid, so that the product purity is still required to be further improved.
Therefore, the research and development of the preparation method of the 2-bromo-6-fluoroaniline, which has the advantages of high product purity, low cost, short reaction process and safe operation, is suitable for industrial production, and has important significance for reducing the production cost of related medicaments.
Disclosure of Invention
The invention aims to solve the technical problems that: aiming at the problems existing in the prior art, the preparation method of the 2-bromo-6-fluoroaniline is provided, and the preparation method has the advantages of high product purity, low cost, short reaction process, simple and safe operation, less three wastes and good selectivity, and is suitable for industrial production.
In order to solve the technical problems, the invention adopts the following technical scheme:
In a first aspect, the invention provides a preparation method of 2-bromo-6-fluoroaniline, which specifically comprises the following steps:
(1) Dissolving 2-amino-3-fluorobenzamide in a first organic solvent with the volume of 4-8 times, adding 1-2 mol equivalents of alkali, cooling to 5-10 ℃, adding 1-1.5 mol equivalents of acetylating reagent, keeping the temperature of 0-5 ℃ and stirring for 4-6 hours, separating an organic layer after the reaction is complete, and concentrating to obtain an intermediate product A, namely 2-acetamido-3-fluorobenzamide;
(2) Dissolving the intermediate product A in a second organic solvent with the volume of 4-8 times, cooling to below 10 ℃, dropwise adding 1-3 molar equivalents of sodium hypochlorite aqueous solution, stirring for 3-5 hours at room temperature after the addition, separating an organic layer after the reaction is finished, and concentrating at 40-60 ℃ under reduced pressure to obtain an intermediate product B, namely N- (2-amino-6-fluorophenyl) acetamide;
wherein, the sodium hypochlorite aqueous solution is a special reagent for Huffman reaction.
(3) Dissolving the intermediate product B in acetonitrile with the volume of 3-8 times, adding 1-2 molar equivalents of copper bromide, heating to 60-70 ℃, then dropwise adding 1-2.5 molar equivalents of nitrous acid ester, and preserving the heat for reacting for 5-8 hours at 60-70 ℃ after the addition is finished; after the reaction is finished, cooling to room temperature, filtering, and concentrating filtrate at 35-40 ℃ under reduced pressure to obtain an intermediate product C, namely N- (2-bromo-6-fluorophenyl) acetamide;
(4) Adding 3-6 times of inorganic acid into the intermediate product C, uniformly mixing and heating to 80-90 ℃ for reaction for 6-12 h, cooling to room temperature after the reaction is finished, and drying the filtered solid at 35-40 ℃ under reduced pressure to obtain 2-bromo-6-fluoroaniline.
The reaction equation of the preparation method is as follows:
Further, the first organic solvent in the step (1) is any one of toluene, methylene dichloride, tetrahydrofuran, ethyl acetate, dichloroethane and methyl tertiary butyl ether. Toluene is preferred.
Further, the base in the step (1) is any one of triethylamine, diisopropylethylamine, sodium carbonate and sodium bicarbonate. Preferably triethylamine.
Further, the acetylating agent in the step (1) is acetyl chloride or acetic anhydride. Acetyl chloride is preferred.
Further, in the step (2), the temperature is reduced to 0-10 ℃, and then 1-3 equivalent of sodium hypochlorite aqueous solution is added dropwise.
Further, the second organic solvent in the step (2) is any one of toluene, methylene dichloride, ethyl acetate and dichloroethane. Preferably dichloromethane.
Further, the nitrous acid ester in the step (3) is isoamyl nitrite or tert-butyl nitrite. Tert-butyl nitrite is preferred.
Further, the inorganic acid in step (4) is hydrochloric acid or sulfuric acid. Hydrochloric acid is preferred, and 10 to 15% hydrochloric acid is more preferred.
Further, the step (3) further comprises a post-treatment method after the reaction is finished: the residue obtained after concentrating the filtered filtrate is slurried with an aqueous ethanol solution (preferably an aqueous ethanol solution having a volume concentration of 80%) and then dried to obtain intermediate C.
Further, the post-treatment method after the reaction in the step (4) is finished specifically comprises the following steps: cooling the reaction liquid to room temperature, adding 2 times of volume of water, adjusting the pH value to 8-9, filtering the solid, and drying under reduced pressure at 35-40 ℃ to obtain 2-bromo-6-fluoroaniline. Preferably, ammonia is used to adjust the pH to 8-9.
The invention has the beneficial effects that:
1. According to the preparation method provided by the invention, 2-amino-3-fluorobenzamide is used as a starting raw material, and the raw material 2-amino-3-fluorobenzamide can be prepared from cheap and easily available 7-fluoroindigo red in one step, so that the raw material source is wide and the cost is low.
2. The invention adopts a brand new production process, and can obtain the 2-bromo-6-fluoroaniline with high yield. The purity of the product prepared by the preparation method is high and can reach more than 99 percent; the method has the advantages of low cost, simple process, short reaction process, simple and safe operation and less three wastes; and the selectivity is good, the generation of bromination at other positions of the benzene ring can be avoided, and the method is suitable for industrial production.
Drawings
FIG. 1 is a diagram showing the nuclear magnetic resonance spectrum of 1 HNMR of the product obtained in the example of the present invention.
Detailed Description
The term as used herein:
"prepared from … …" is synonymous with "comprising". The terms "comprising," "including," "having," "containing," or any other variation thereof, as used herein, are intended to cover a non-exclusive inclusion. For example, a composition, step, method, article, or apparatus that comprises a list of elements is not necessarily limited to only those elements but may include other elements not expressly listed or inherent to such composition, step, method, article, or apparatus.
The conjunction "consisting of … …" excludes any unspecified element, step or component. If used in a claim, such phrase will cause the claim to be closed, such that it does not include materials other than those described, except for conventional impurities associated therewith. When the phrase "consisting of … …" appears in a clause of the claim body, rather than immediately following the subject, it is limited to only the elements described in that clause; other elements are not excluded from the stated claims as a whole.
When an equivalent, concentration, or other value or parameter is expressed as a range, preferred range, or a range bounded by a list of upper preferable values and lower preferable values, this is to be understood as specifically disclosing all ranges formed from any pair of any upper range limit or preferred value and any lower range limit or preferred value, regardless of whether ranges are separately disclosed. For example, when ranges of "1 to 5" are disclosed, the described ranges should be construed to include ranges of "1 to 4", "1 to 3", "1 to 2 and 4 to 5", "1 to 3 and 5", and the like. When a numerical range is described herein, unless otherwise indicated, the range is intended to include its endpoints and all integers and fractions within the range.
In these examples, the parts and percentages are by mass unless otherwise indicated.
"Parts by weight"/"parts by mass" means a basic unit of measurement indicating a mass ratio relationship of a plurality of components, and 1 part may indicate an arbitrary unit mass, for example, 1g may be indicated, 2g may be indicated, or the like. If we say that the mass part of the a component is a part and the mass part of the B component is B part, the ratio a of the mass of the a component to the mass of the B component is represented as: b. or the mass of the A component is aK, the mass of the B component is bK (K is any number and represents a multiple factor). It is not misunderstood that the sum of the parts by mass of all the components is not limited to 100 parts, unlike the parts by mass.
"And/or" is used to indicate that one or both of the illustrated cases may occur, e.g., a and/or B include (a and B) and (a or B).
In order that the invention may be readily understood, a more complete description of the invention will be rendered by reference to the appended drawings. Preferred embodiments of the present invention are shown in the drawings. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used herein in the description of the invention is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. The specific conditions are not noted in the examples and are carried out according to conventional conditions or conditions recommended by the manufacturer. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention.
1. Preparation of 2-bromo-6-fluoroaniline
The invention provides a preparation method of 2-bromo-6-fluoroaniline, which specifically comprises the following steps:
(1) Preparation of 2-acetamido-3-fluorobenzamide: dissolving 2-amino-3-fluorobenzamide in a first organic solvent with the volume of 4-8 times, taking 2-amino-3-fluorobenzamide as a reference, adding 1-2 molar equivalents of alkali, cooling to 5-10 ℃, adding 1-1.5 molar equivalents of acetylating reagent, keeping the temperature of 0-5 ℃ and stirring for 4-6 hours, separating an organic layer after the reaction is complete, and concentrating to obtain an intermediate product A, namely 2-acetamido-3-fluorobenzamide. As a preferred embodiment, the first organic solvent is selected from any one of toluene, methylene chloride, tetrahydrofuran, ethyl acetate, dichloroethane and methyl tert-butyl ether. The alkali is any one of triethylamine, diisopropylethylamine, sodium carbonate and sodium bicarbonate. The acetylating reagent is acetyl chloride or acetic anhydride.
(2) Preparation of N- (2-amino-6-fluorophenyl) acetamide: dissolving the intermediate product A in a second organic solvent with the volume of 4-8 times, cooling to below 10 ℃, taking the intermediate product A as a reference, dropwise adding an aqueous solution of sodium hypochlorite (Hofmann reaction reagent) with the molar equivalent of 1-3, stirring for 3-5 hours at room temperature after the addition, separating an organic layer after the reaction is finished, and concentrating at the temperature of 40-60 ℃ under reduced pressure to obtain an intermediate product B, namely N- (2-amino-6-fluorophenyl) acetamide. As a preferred embodiment, the second organic solvent is selected from any one of toluene, methylene chloride, ethyl acetate and dichloroethane. The temperature is preferably 0 to 10 ℃.
(3) Preparation of N- (2-bromo-6-fluorophenyl) acetamide: dissolving the intermediate product B in acetonitrile with the volume of 3-8 times, taking the intermediate product B as a reference, firstly adding 1-2 molar equivalents of copper bromide, heating to 60-70 ℃, then dropwise adding 1-2.5 molar equivalents of nitrous acid ester, and preserving heat for reacting for 5-8 hours at 60-70 ℃ after the addition is finished; after the reaction is finished, cooling to room temperature, filtering, and concentrating filtrate at 35-40 ℃ under reduced pressure to obtain an intermediate product C, namely N- (2-bromo-6-fluorophenyl) acetamide. As a preferred embodiment, the nitrite is isoamyl nitrite or tert-butyl nitrite. Step (3) further comprises a post-treatment method after the reaction is finished: the residue obtained after concentrating the filtered filtrate is slurried with an aqueous ethanol solution (preferably an aqueous ethanol solution having a volume concentration of 80%) and then dried to obtain intermediate C.
(4) Preparation of 2-bromo-6-fluoroaniline: adding 3-6 times of inorganic acid into the intermediate product C, uniformly mixing, heating to 80-90 ℃ for reaction for 6-12 h, cooling to room temperature after the reaction is finished, and drying the filtered solid at 35-40 ℃ under reduced pressure to obtain 2-bromo-6-fluoroaniline. As a preferred embodiment, the inorganic acid is hydrochloric acid or sulfuric acid. The post-treatment method after the reaction in the step (4) is specifically as follows: the reaction solution is cooled to room temperature, added with 2 times of volume of water, pH is regulated to 8-9, filtered, decompressed and dried under vacuum at 35-40 ℃ to obtain 2-bromo-6-fluoroaniline. Preferably, ammonia is used to adjust the pH to 8-9.
The chemical reaction formula is as follows:
the invention firstly provides an embodiment of a method for preparing 2-acetamido-3-fluorobenzamide in the step (1) by taking 7-fluoroindigo red as a raw material, which comprises the following steps:
10 kg of 7-fluoroindigo red and 40 kg of ammonia water are mixed and stirred, 5kg of 28% hydrogen peroxide is added dropwise, the mixture is heated to 70 ℃ for 4 hours, the mixture is cooled to room temperature, filtered, washed with water and dried to obtain 8.9 kg of 2-acetamido-3-fluorobenzamide product with the yield of 95% and the purity of 99.1%.
The chemical reaction formula is as follows:
The following is a further description of the present invention with reference to specific examples:
example 1
(1) Preparation of 2-acetamido-3-fluorobenzamide: 5 kg of 2-amino-3-fluorobenzamide is dissolved in 25 kg of toluene, 3.4 kg of triethylamine is added, the temperature is reduced to 5-10 ℃, 2.64 kg of acetyl chloride is added dropwise, the mixture is kept at 0-5 ℃ for stirring for 6 hours after the addition, an organic layer is separated after the reaction is finished, 10 kg of water is added, and the mixture is concentrated and dried to obtain 6 kg of 2-acetamido-3-fluorobenzamide (intermediate A) with the yield of 95%.
(2) Preparation of N- (2-amino-6-fluorophenyl) acetamide: 6kg of 2-acetamido-3-fluorobenzamide is dissolved in 50 kg of dichloroethane, the temperature is reduced to 0-10 ℃, 25 kg of hypochlorous acid aqueous solution is added dropwise, and the mixture is stirred for 3 hours at room temperature after the addition is completed. After the reaction, an organic layer is separated, washed with water and concentrated under reduced pressure at 40-60 ℃ to obtain 4.63 kg of N- (2-amino-6-fluorophenyl) acetamide (intermediate B) with a yield of 90%.
(3) Preparation of N- (2-bromo-6-fluorophenyl) acetamide: 6 kg of N- (2-amino-6-fluorophenyl) acetamide is dissolved in 50 kg of acetonitrile, 7.5 kg of copper bromide is added, the temperature is raised to 60 ℃, 4kg of tert-butyl nitrite is added dropwise, the reaction is carried out for 5 hours after the completion of the addition, the temperature is reduced to room temperature, the filtration and the reduced pressure concentration of the filtrate at 40 ℃ are carried out, the residue is pulped and purified by 80% ethanol to obtain 7.5 kg of N- (2-bromo-6-fluorophenyl) acetamide (intermediate product C) with the yield of 91%.
(4) Preparation of 2-bromo-6-fluoroaniline: 7.5 kg of N- (2-bromo-6-fluorophenyl) acetamide and 40 kg of 10% hydrochloric acid are mixed and heated to 80 ℃ for reaction for 6 hours, after the reaction is finished, the mixture is cooled to room temperature, the mixture is filtered, 30 kg of water is added into the obtained solid, the pH value of the obtained solid is regulated to 8-9 by ammonia water, the mixture is filtered, and the obtained solid is dried at a reduced pressure of 40 ℃ to obtain 5.9 kg of 2-bromo-6-fluoroaniline, wherein the purity of the 2-bromo-6-fluoroaniline is more than 99%.
Example 2
(1) Preparation of 2-acetamido-3-fluorobenzamide: 5 kg of 2-amino-3-fluorobenzamide is dissolved in 25 kg of dichloroethane, then 4.2 kg of diisopropylethyl is added, the temperature is reduced to 5-10 ℃, 2.85 kg of acetyl chloride is added dropwise, the mixture is kept at 0-5 ℃ for 5 hours after the addition, an organic layer is separated after the reaction, 12 kg of water is added, and the mixture is concentrated and dried to obtain 5.7 kg of 2-acetamido-3-fluorobenzamide (intermediate A) with the yield of 90%.
(2) Preparation of N- (2-amino-6-fluorophenyl) acetamide: 6 kg of 2-acetamido-3-fluorobenzamide is dissolved in 50 kg of dichloromethane, the temperature is reduced to 0-10 ℃, 28 kg of sodium hypochlorite aqueous solution is added dropwise, and the mixture is stirred for 4 hours at room temperature after the addition is finished. After the reaction, an organic layer is separated, washed with water and concentrated under reduced pressure at 40-60 ℃ to obtain 4.37 kg of N- (2-amino-6-fluorophenyl) acetamide (intermediate B) with a yield of 85%.
(3) Preparation of N- (2-bromo-6-fluorophenyl) acetamide: 600 g of N- (2-amino-6-fluorophenyl) acetamide is dissolved in 5000 ml of acetonitrile, 750 g of copper bromide is added, the temperature is raised to 60 ℃, 450 g of isoamyl nitrite is added dropwise, the reaction is carried out for 8 hours after the completion of the addition, the temperature is reduced to room temperature, the filtration and the concentration of filtrate at 40 ℃ under reduced pressure are carried out, the residue is pulped and purified by 80% ethanol to obtain 651 g of N- (2-bromo-6-fluorophenyl) acetamide (intermediate product C), and the yield is 79%.
(4) Preparation of 2-bromo-6-fluoroaniline: 75 g of N- (2-bromo-6-fluorophenyl) acetamide and 400 g of 10% sulfuric acid are mixed and heated to 80 ℃ for reaction for 12 hours, after the reaction is finished, the mixture is cooled to room temperature and filtered, 300 g of water is added into the obtained solid, the pH value of the solid is regulated to 8-9, the solid is filtered, and 55 g of 2-bromo-6-fluoroaniline is obtained after drying under reduced pressure at 40 ℃, and the purity is more than 99%.
Example 3
(1) Preparation of 2-acetamido-3-fluorobenzamide: 50g of 2-amino-3-fluorobenzamide is dissolved in 250 ml of ethyl acetate, 250g of saturated sodium bicarbonate aqueous solution is added, the temperature is reduced to 5-10 ℃, 30 g of acetyl chloride is added dropwise, the mixture is kept at 0-5 ℃ after the addition is finished and stirred for 4 hours, an organic layer is separated, 120 g of water is used for washing the organic layer, and 54 g of 2-acetamido-3-fluorobenzamide (intermediate A) is obtained after concentration and drying, and the yield is 85%.
(2) Preparation of N- (2-amino-6-fluorophenyl) acetamide: 50 g of 2-acetamido-3-fluorobenzamide is dissolved in 200 g of toluene, the temperature is reduced to 0-10 ℃, 240 g of sodium hypochlorite aqueous solution is added dropwise, and the mixture is stirred for 4 hours at room temperature after the addition is finished. After the reaction, an organic layer was separated, washed with water, and concentrated under reduced pressure at 40 to 60℃to give 34.3 g of N- (2-amino-6-fluorophenyl) acetamide (intermediate B) in 80% yield.
(3) Preparation of N- (2-bromo-6-fluorophenyl) acetamide: 30 g of N- (2-amino-6-fluorophenyl) acetamide is dissolved in 270 ml of acetonitrile, 37 g of copper bromide is added, the mixture is heated to 60 ℃, 23 g of isoamyl nitrite is added dropwise, the mixture is reacted for 6 hours after the addition, the mixture is cooled to room temperature, filtered, the filtrate is concentrated to dryness under reduced pressure at 40 ℃, and the residue is pulped and purified by 80% ethanol to obtain 31 g of N- (2-bromo-6-fluorophenyl) acetamide (intermediate product C) with the yield of 77%.
(4) Preparation of 2-bromo-6-fluoroaniline: 31 g of N- (2-bromo-6-fluorophenyl) acetamide and 60 g of concentrated hydrochloric acid are mixed and heated to 90 ℃ for reaction for 6 hours, after the reaction is finished, the mixture is cooled to room temperature, the mixture is filtered, 50 g of water is added into the obtained solid, the pH value of the solid is regulated to 8-9 by ammonia water, the solid is filtered, and the solid is dried at a reduced pressure of 40 ℃ to obtain 21 g of 2-bromo-6-fluoroaniline, wherein the purity of the solid is more than 99%.
To verify the feasibility and effectiveness of the present invention, the present invention also performed 1 HNMR structural characterization of the products prepared in the above examples, the results of which are shown in fig. 1. The specific characterization results are as follows:
1HNMR(500MHz，CDCl3)：δ7.5ppm(dd,1H，ArH)；δ7.38ppm(m,1H,ArH)；δ7.26ppm(dd,1H,ArH)。
In conclusion, the 2-amino-3-fluorobenzamide is taken as the initial raw material, the raw material 2-amino-3-fluorobenzamide can be prepared from cheap and easily available 7-fluoroindigo red in one step, and the raw material has wide sources and low cost; the method adopts a brand new production process, and can obtain the 2-bromo-6-fluoroaniline with high yield; the method has the advantages of simple process, low cost, less three wastes, good selectivity, capability of avoiding generating bromination at other positions of the benzene ring, and suitability for industrial production.
The foregoing description is only a preferred embodiment of the present invention, and the present invention is not limited thereto, but it is to be understood that modifications and equivalents of some of the technical features described in the foregoing embodiments may be made by those skilled in the art, although the present invention has been described in detail with reference to the foregoing embodiments. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. The preparation method of the 2-bromo-6-fluoroaniline is characterized by comprising the following steps of:
(1) Dissolving 2-amino-3-fluorobenzamide in a first organic solvent with the volume of 4-8 times, adding 1-2 mol equivalents of alkali, cooling to 5-10 ℃, adding 1-1.5 mol equivalents of acetylating reagent, keeping the temperature of 0-5 ℃ and stirring for 4-6 hours, separating an organic layer after the reaction is complete, and concentrating to obtain an intermediate product A, namely 2-acetamido-3-fluorobenzamide;
(2) Dissolving the intermediate product A in a second organic solvent with the volume of 4-8 times, cooling to below 10 ℃, dropwise adding 1-3 molar equivalents of sodium hypochlorite aqueous solution, stirring for 3-5 hours at room temperature after the addition, separating an organic layer after the reaction is finished, and concentrating at 40-60 ℃ under reduced pressure to obtain an intermediate product B, namely N- (2-amino-6-fluorophenyl) acetamide;
(3) Dissolving the intermediate product B in acetonitrile with the volume of 3-8 times, adding 1-2 molar equivalents of copper bromide, heating to 60-70 ℃, then dropwise adding 1-2.5 molar equivalents of nitrous acid ester, and preserving the heat for reacting for 5-8 hours at 60-70 ℃ after the addition is finished; after the reaction is finished, cooling to room temperature, filtering, and concentrating filtrate at 35-40 ℃ under reduced pressure to obtain an intermediate product C, namely N- (2-bromo-6-fluorophenyl) acetamide;
(4) Adding 3-6 times of inorganic acid into the intermediate product C, uniformly mixing and heating to 80-90 ℃ for reaction for 6-12 h, cooling to room temperature after the reaction is finished, and drying the filtered solid at 35-40 ℃ under reduced pressure to obtain 2-bromo-6-fluoroaniline.
2. The process for producing 2-bromo-6-fluoroaniline according to claim 1, wherein,
The first organic solvent in the step (1) is any one of toluene, methylene dichloride, tetrahydrofuran, ethyl acetate, dichloroethane and methyl tertiary butyl ether.
3. The process for producing 2-bromo-6-fluoroaniline according to claim 1, wherein,
The alkali in the step (1) is any one of triethylamine, diisopropylethylamine, sodium carbonate and sodium bicarbonate.
4. The process for producing 2-bromo-6-fluoroaniline according to claim 1, wherein,
The acetylating agent in the step (1) is acetyl chloride or acetic anhydride.
5. The process for producing 2-bromo-6-fluoroaniline according to claim 1, wherein,
And (3) cooling to 0-10 ℃ in the step (2), and then dropwise adding 1-3 equivalent of sodium hypochlorite aqueous solution.
6. The process for producing 2-bromo-6-fluoroaniline according to claim 1, wherein,
The second organic solvent in the step (2) is any one of toluene, methylene dichloride, ethyl acetate and dichloroethane.
7. The process for producing 2-bromo-6-fluoroaniline according to claim 1, wherein,
The nitrous acid ester in the step (3) is isoamyl nitrite or tert-butyl nitrite.
8. The process for producing 2-bromo-6-fluoroaniline according to claim 1, wherein,
The inorganic acid in the step (4) is hydrochloric acid or sulfuric acid.
9. The process for producing 2-bromo-6-fluoroaniline according to claim 1, wherein,
Step (3) further comprises a post-treatment method after the reaction is finished: the residue obtained after concentrating the filtered filtrate is pulped and purified by adopting an aqueous solution of ethanol, and then is dried to obtain an intermediate product C.
10. The process for producing 2-bromo-6-fluoroaniline according to claim 1, wherein,
The post-treatment method after the reaction in the step (4) is specifically as follows: cooling the reaction liquid to room temperature, adding 2 times of volume of water, adjusting the pH value to 8-9, filtering the solid, and drying under reduced pressure at 35-40 ℃ to obtain 2-bromo-6-fluoroaniline.
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