CN111039845A - Preparation method of 4-fluoro-7-bromoisatin - Google Patents
Preparation method of 4-fluoro-7-bromoisatin Download PDFInfo
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- CN111039845A CN111039845A CN201911312966.8A CN201911312966A CN111039845A CN 111039845 A CN111039845 A CN 111039845A CN 201911312966 A CN201911312966 A CN 201911312966A CN 111039845 A CN111039845 A CN 111039845A
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- bromoisatin
- fluoro
- ethanol
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- water
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- OTHDRAOYSKYFRW-UHFFFAOYSA-N 7-bromo-4-fluoro-1h-indole-2,3-dione Chemical compound FC1=CC=C(Br)C2=C1C(=O)C(=O)N2 OTHDRAOYSKYFRW-UHFFFAOYSA-N 0.000 title claims abstract description 26
- 238000002360 preparation method Methods 0.000 title claims abstract description 7
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 claims abstract description 22
- -1 ethanol-sodium sulfate-water Chemical compound 0.000 claims abstract description 17
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 13
- FWTXFEKVHSFTDQ-UHFFFAOYSA-N 2-bromo-5-fluoroaniline Chemical compound NC1=CC(F)=CC=C1Br FWTXFEKVHSFTDQ-UHFFFAOYSA-N 0.000 claims abstract description 12
- RNFNDJAIBTYOQL-UHFFFAOYSA-N chloral hydrate Chemical compound OC(O)C(Cl)(Cl)Cl RNFNDJAIBTYOQL-UHFFFAOYSA-N 0.000 claims abstract description 11
- 229960002327 chloral hydrate Drugs 0.000 claims abstract description 11
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims abstract description 10
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 claims abstract description 4
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 20
- 238000010992 reflux Methods 0.000 claims description 16
- 239000002904 solvent Substances 0.000 claims description 7
- 150000003839 salts Chemical class 0.000 claims description 6
- 238000006482 condensation reaction Methods 0.000 claims description 5
- 238000001953 recrystallisation Methods 0.000 claims description 5
- 238000009833 condensation Methods 0.000 claims description 4
- 230000005494 condensation Effects 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims 7
- 238000000034 method Methods 0.000 abstract description 18
- 239000000543 intermediate Substances 0.000 abstract description 10
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 abstract description 8
- 239000012046 mixed solvent Substances 0.000 abstract description 7
- 239000002994 raw material Substances 0.000 abstract description 6
- 229910052938 sodium sulfate Inorganic materials 0.000 abstract description 5
- 235000011152 sodium sulphate Nutrition 0.000 abstract description 5
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- UFNDNNCDEFJCHU-RMKNXTFCSA-N (2e)-2-hydroxyimino-n-phenylacetamide Chemical compound O\N=C\C(=O)NC1=CC=CC=C1 UFNDNNCDEFJCHU-RMKNXTFCSA-N 0.000 abstract description 2
- 230000015572 biosynthetic process Effects 0.000 abstract description 2
- 230000003321 amplification Effects 0.000 abstract 1
- 238000003199 nucleic acid amplification method Methods 0.000 abstract 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 23
- JXDYKVIHCLTXOP-UHFFFAOYSA-N isatin Chemical compound C1=CC=C2C(=O)C(=O)NC2=C1 JXDYKVIHCLTXOP-UHFFFAOYSA-N 0.000 description 17
- 238000006243 chemical reaction Methods 0.000 description 13
- 238000001914 filtration Methods 0.000 description 12
- 239000007787 solid Substances 0.000 description 12
- 238000001035 drying Methods 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 6
- 238000010438 heat treatment Methods 0.000 description 6
- 238000010907 mechanical stirring Methods 0.000 description 6
- 238000003756 stirring Methods 0.000 description 5
- 239000005457 ice water Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 238000000297 Sandmeyer reaction Methods 0.000 description 3
- 239000007859 condensation product Substances 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 238000004821 distillation Methods 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 239000011259 mixed solution Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- 102000010909 Monoamine Oxidase Human genes 0.000 description 2
- 108010062431 Monoamine oxidase Proteins 0.000 description 2
- OATSQCXMYKYFQO-UHFFFAOYSA-N S-methyl thioacetate Chemical compound CSC(C)=O OATSQCXMYKYFQO-UHFFFAOYSA-N 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- IXLSBQAGQAGDIQ-UHFFFAOYSA-N 2-bromo-5-fluoroaniline;hydrochloride Chemical compound Cl.NC1=CC(F)=CC=C1Br IXLSBQAGQAGDIQ-UHFFFAOYSA-N 0.000 description 1
- BWWHTIHDQBHTHP-UHFFFAOYSA-N 2-nitrobenzoyl chloride Chemical compound [O-][N+](=O)C1=CC=CC=C1C(Cl)=O BWWHTIHDQBHTHP-UHFFFAOYSA-N 0.000 description 1
- IBLUVZHBUVLHSL-UHFFFAOYSA-N 3-methylsulfanyl-1H-indol-2-ol Chemical compound CSC1=C(NC2=CC=CC=C12)O IBLUVZHBUVLHSL-UHFFFAOYSA-N 0.000 description 1
- 206010006100 Bradykinesia Diseases 0.000 description 1
- 238000003512 Claisen condensation reaction Methods 0.000 description 1
- 238000003624 Gassman synthesis reaction Methods 0.000 description 1
- 208000006083 Hypokinesia Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- 229940124639 Selective inhibitor Drugs 0.000 description 1
- 229960001413 acetanilide Drugs 0.000 description 1
- OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical compound CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 description 1
- 229960004373 acetylcholine Drugs 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 150000004982 aromatic amines Chemical class 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000006114 decarboxylation reaction Methods 0.000 description 1
- DBKKFIIYQGGHJO-UHFFFAOYSA-N diethyl 2-oxopropanedioate Chemical compound CCOC(=O)C(=O)C(=O)OCC DBKKFIIYQGGHJO-UHFFFAOYSA-N 0.000 description 1
- 230000003467 diminishing effect Effects 0.000 description 1
- 229960003638 dopamine Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- XFBVBWWRPKNWHW-UHFFFAOYSA-N etodolac Chemical compound C1COC(CC)(CC(O)=O)C2=N[C]3C(CC)=CC=CC3=C21 XFBVBWWRPKNWHW-UHFFFAOYSA-N 0.000 description 1
- 229960005293 etodolac Drugs 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 210000001577 neostriatum Anatomy 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/32—Oxygen atoms
- C07D209/38—Oxygen atoms in positions 2 and 3, e.g. isatin
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a preparation method of 4-fluoro-7-bromoisatin, and belongs to the field of synthesis of medical intermediates. Condensing 2-bromo-5-fluoroaniline serving as a raw material with chloral hydrate and hydroxylamine hydrochloride in an ethanol-sodium sulfate-water system; then cyclizing in concentrated sulfuric acid, and recrystallizing with ethanol-water to obtain 4-fluoro-7-bromoisatin. According to the invention, an ethanol-water-sodium sulfate mixed solvent system is developed by improving experimental conditions, compared with a literature method, the yield is improved to a certain extent, the use amount of sodium sulfate is reduced, the purity requirement of next-step cyclization can be met without purifying the intermediate namely the isonitrosoacetanilide, and the product purity is up to more than 99%, so that the industrial amplification is easy.
Description
Technical Field
The invention relates to a method for preparing 4-fluoro-7-bromoisatin, and belongs to the technical field of synthesis of medical intermediates.
Background
Isatin (Isatin/ISA), also known as indolidione or 2, 3-indoloquinone, is an endogenous active substance present in mammalian tissues and fluids. Studies show that ISA is a monoamine oxidase (MAO) -B selective inhibitor, can improve the levels of acetylcholine and dopamine in striatum of mice with Parkinson's disease, and improves bradykinesia symptoms. 4-fluoro-7-bromoisatin as an organic synthesis intermediate, the structural formula of which is as follows:
the compound is used for synthesizing etodolac medicaments, and the medicaments have better application in the aspects of treating cancers, diminishing inflammation and relieving pain. The prior art has no published report on the preparation of 4-fluoro-7-bromoisatin.
Currently, the preparation method of isatin derivatives mainly comprises the following steps:
the first method is a Claisen synthesis method, which uses o-nitrobenzoyl chloride as a substrate to obtain isatin with high yield through three-step reaction.
The second method is a Martinet synthesis method, which takes aromatic amine and diethyl ketomalonate as substrates to carry out hydrolysis and decarboxylation under the conditions of acetic acid solvent and oxygen, and finally isatin is generated.
The third method is Gassman synthesis method, aniline and its derivative are reacted with methylthio acetate to produce 3-methylthio-2-hydroxy indole, which is oxidized into isatin.
And fourthly, a Stoll synthesis method, namely reacting aniline with oxalyl chloride, and closing a ring under the action of Lewis acid to obtain isatin, wherein the method is mainly used for preparing the isatin containing multiple rings.
The method five, Sandmeyer synthesis, using aniline as initial raw material, adding chloral hydrate and hydroxylamine hydrochloride into saturated aqueous solution of sodium sulfate to obtain isonitrosoacetoaniline, then purifying, adding concentrated sulfuric acid to catalyze and close ring to obtain isatin. The method has the advantages of easily available raw materials, high yield and certain economic value.
The applicant prepared 4-fluoro-7-bromoisatin according to the Sandmeyer synthesis method, and found that the defects of low product content, solid precipitation, difficult filtration and the like exist in the process of preparing the intermediate N- (2-bromo-5-fluorophenyl) -2- (hydroxyimine) acetamide during experiments.
Disclosure of Invention
In order to overcome the technical defects, the invention develops an ethanol-water-sodium sulfate mixed solvent system by improving experimental conditions, compared with a literature method, the yield is improved to a certain extent, the use amount of sodium sulfate is reduced, and the purity requirement of the next step of cyclization can be met without purifying the intermediate namely the isonitrosoacetanilide, so that the reaction can meet the requirement of industrial production.
The invention relates to a preparation method of 4-fluoro-7-bromoisatin, which comprises the following steps: condensing 2-bromo-5-fluoroaniline with chloral hydrate and hydroxylamine hydrochloride in a solvent/salt mixed system to obtain N- (2-bromo-5-fluorophenyl) -2- (hydroxyimine) acetamide; then cyclizing in concentrated sulfuric acid to obtain 4-fluoro-7-bromoisatin. The reaction equation is expressed as follows:
further, in the above technical scheme, in the condensation step, the molar ratio of 2-bromo-5-fluoroaniline to chloral hydrate is 1:1.1-1.3, and the molar ratio of reactant 2-bromo-5-fluoroaniline to hydroxylamine hydrochloride is 1: 1.3-1.8.
Further, in the above technical scheme, in the condensation step, the solvent/salt system is ethanol-sodium sulfate-water solution in a mass ratio of 1:0.2-0.5: 1.0-1.5.
Further, in the above technical scheme, the condensation reaction is performed under reflux in a solvent/salt system.
Further, in the technical scheme, in the cyclization reaction, the mass ratio of the N- (2-bromo-5-fluorophenyl) -2- (hydroxyimine) acetamide to the concentrated sulfuric acid is 1: 3.5-7.0.
Further, in the above technical scheme, the reaction temperature in the cyclization reaction is 60-90 ℃.
Further, in the above technical scheme, after the cyclization reaction is completed, the obtained crude product is recrystallized by using a mixed solvent of anhydrous ethanol and water, wherein the mixed solvent is prepared according to a mass ratio of ethanol/water of 1/1.6-1.8.
The invention typically operates optimally as follows: adding 2-bromo-5-fluoroaniline, chloral hydrate and hydroxylamine hydrochloride into an ethanol-water-sodium sulfate mixed solvent, refluxing and stirring for 8-12 hours, evaporating part of ethanol, filtering, and drying to obtain N- (2-bromo-5-fluorophenyl) -2- (hydroxyimine) acetamide; and then controlling the temperature to be 60-70 ℃, adding the mixture into concentrated sulfuric acid in batches, reacting for 30 minutes, slowly adding the reaction liquid into ice water, filtering and collecting a crude product of the 4-fluoro-7-bromoisatin, and recrystallizing by adopting an ethanol-water mixed solvent to obtain a pure product of the 4-fluoro-7-bromoisatin.
Advantageous effects of the invention
According to the invention, an ethanol-water-sodium sulfate mixed solvent system is developed by improving experimental conditions, compared with a literature method, the yield is improved to a certain extent, the use amount of sodium sulfate is reduced, and the purity requirement of next-step cyclization can be met without purifying the intermediate namely the isonitro-acetanilide.
The method has the advantages of simple operation, mild reaction conditions and stable product quality, and the purity of the 4-fluoro-7-bromoisatin prepared by the method reaches more than 99 percent after recrystallization, so the method is suitable for industrial production.
DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION
Example 1
The first step, condensation reaction:
14.2Kg of ethanol, 18Kg of water and 3.6Kg of anhydrous sodium sulfate are added into a 50L reaction kettle equipped with a mechanical stirring and oil bath kettle, a thermometer and a reflux condenser, and after uniform stirring, the temperature is raised to 40-50 ℃ to form a mixed solution. Then 4.44Kg of chloral hydrate, 2.33Kg of hydroxylamine hydrochloride and 4.25Kg of 2-bromo-5-fluoroaniline are added in turn, the temperature is slowly raised to 85 ℃, the reflux is maintained for 10 hours, the middle control raw material of 2-bromo-5-fluoroaniline is less than 5 percent, the ethanol is distilled, the distillation is stopped when the temperature of the kettle is raised to 105 ℃, the temperature is reduced, the filtration is carried out, and the drying is carried out, thus obtaining 4.8Kg of light yellow solid N- (2-bromo-5-fluorophenyl) -2- (hydroxyimine) acetamide with the yield of 82.3 percent.
Step two, ring closing reaction:
adding 21Kg of concentrated sulfuric acid into a 50L reaction kettle equipped with a mechanical stirring and oil bath kettle, a thermometer and a reflux condenser, heating to 70 ℃, adding the condensation product dried in the first step in batches, keeping the temperature below 90 ℃, keeping the temperature for 30 minutes at 90 ℃ after the feeding is finished, cooling, pouring into ice water, and separating out dark red solid. Filtering and washing, adding 9.1Kg of ethanol and 15.2Kg of water after drying the filter cake, heating to reflux for recrystallization, and filtering and drying to obtain 3.47Kg of red solid 4-fluoro-7-bromoisatin, wherein the yield is 77.0 percent and the HPLC purity is 99.3 percent.
Example 2
The first step, condensation reaction:
200g of ethanol, 210g of water and 45g of anhydrous sodium sulfate are added into a 1L reaction kettle provided with a mechanical stirring and oil bath kettle, a thermometer and a reflux condenser, and the temperature is raised to 40-50 ℃ under stirring to form a mixed solution. Then, 56.3g of chloral hydrate, 29.5g of hydroxylamine hydrochloride and 55.0g of 2-bromo-5-fluoroaniline are added in sequence, the temperature is slowly raised to 85 ℃, reflux is maintained for 10 hours, the medium control raw material 2-bromo-5-fluoroaniline is less than 5%, ethanol is distilled, the temperature is stopped from distillation and reduced, filtration and drying are carried out until the temperature of the kettle is raised to 105 ℃, and 57.9g of light yellow solid N- (2-bromo-5-fluorophenyl) -2- (hydroxyimine) acetamide is obtained with the yield of 78.0%.
Step two, ring closing reaction:
adding 420g of concentrated sulfuric acid into a 500mL reaction kettle provided with a mechanical stirring and oil bath kettle, a thermometer and a reflux condenser, heating to 70 ℃, adding the condensation product dried in the first step in batches, keeping the temperature below 90 ℃, keeping the temperature for 30 minutes at 90 ℃ after the feeding is finished, cooling, pouring into ice water, and separating out dark red solid. Filtering and washing, adding 107.0g of ethanol and 178.7g of water after drying a filter cake, heating to reflux for recrystallization, and filtering and drying to obtain 40.8g of red solid 4-fluoro-7-bromoisatin, wherein the yield is 75.4 percent and the HPLC purity is 99.7 percent.
Example 3
The first step, condensation reaction:
200g of ethanol, 300g of water and 80g of anhydrous sodium sulfate are added into a 1L reaction kettle which is provided with a mechanical stirring and oil bath kettle, a thermometer and a reflux condenser, and the temperature is raised to 40-50 ℃ under stirring to form a mixed solution. Then, 62.5g of chloral hydrate, 32.8g of hydroxylamine hydrochloride and 57.0g of 2-bromo-5-fluoroaniline are added in sequence, the temperature is slowly raised to 85 ℃, reflux is maintained for 10 hours, the medium control raw material 2-bromo-5-fluoroaniline is less than 5%, ethanol is distilled, the temperature is stopped from distillation and reduced, filtration and drying are carried out until the temperature of the kettle is raised to 105 ℃, 58.2g of light yellow solid N- (2-bromo-5-fluorophenyl) -2- (hydroxyimine) acetamide is obtained, and the yield is 74.3%.
Step two, ring closing reaction:
adding 250g of concentrated sulfuric acid into a 500mL reaction kettle provided with a mechanical stirring and oil bath kettle, a thermometer and a reflux condenser, heating to 70 ℃, adding the condensation product obtained after the first step of reaction and drying in batches, keeping the temperature below 90 ℃, keeping the temperature for 30 minutes at 90 ℃ after the feeding is finished, cooling, pouring into ice water, and separating out dark red solid. Filtering and washing, adding 107.0g of ethanol and 178.7g of water after drying a filter cake, heating to reflux for recrystallization, and filtering and drying to obtain 38.9g of red solid 4-fluoro-7-bromoisatin, wherein the yield is 71.5 percent and the HPLC purity is 99.0 percent.
Comparative example 1
According to the common method of Sandmeyer reaction, chloral hydrate, hydroxylamine hydrochloride and 2-bromo-5-fluoroaniline hydrochloride are added into a large amount of sodium sulfate aqueous solution, the temperature is raised and the reflux is carried out, as the reaction proceeds, a brown solid begins to be separated out, the solid is more viscous and is easy to wind on a stirring paddle, the content of the intermediate N- (2-bromo-5-fluorophenyl) -2- (hydroxyimine) acetamide obtained after the temperature is reduced and the intermediate is filtered, and the next ring closing reaction can be carried out only after the intermediate is subjected to alkali-soluble acidification purification.
The foregoing shows and describes the general principles, essential features, and advantages of the invention. It will be understood by those skilled in the art that the present invention is not limited to the embodiments described above, and the preferred embodiments of the present invention are described in the above embodiments and the description, and are not intended to limit the present invention. The scope of the invention is defined by the appended claims and equivalents thereof.
Claims (8)
1. The preparation method of the 4-fluoro-7-bromoisatin is characterized by comprising the following steps of: condensing 2-bromo-5-fluoroaniline with chloral hydrate and hydroxylamine hydrochloride in a solvent/salt mixed system to obtain N- (2-bromo-5-fluorophenyl) -2- (hydroxyimine) acetamide; then cyclizing in concentrated sulfuric acid to obtain 4-fluoro-7-bromoisatin.
2. The method for producing 4-fluoro-7-bromoisatin according to claim 1, characterized in that: in the condensation step, the mol ratio of the 2-bromine-5-fluoroaniline, the chloral hydrate and the hydroxylamine hydrochloride is 1:1.1-1.3: 1.3-1.8.
3. The method for producing 4-fluoro-7-bromoisatin according to claim 2, characterized in that: in the condensation step, the solvent/salt system is ethanol-sodium sulfate-water solution, and the mass ratio is 1:0.2-0.5: 1.0-1.5.
4. The method for producing 4-fluoro-7-bromoisatin according to claim 3, characterized in that: the condensation reaction is carried out under reflux in a solvent/salt system.
5. The method for producing 4-fluoro-7-bromoisatin according to claim 1, characterized in that: in the cyclization reaction, the mass ratio of the N- (2-bromo-5-fluorophenyl) -2- (hydroxyimine) acetamide to concentrated sulfuric acid is 1: 3.5-7.0.
6. The method for producing 4-fluoro-7-bromoisatin according to claim 5, wherein: the temperature of the cyclization reaction is 60-90 ℃.
7. The method for producing 4-fluoro-7-bromoisatin according to any one of claims 1 to 6, characterized in that: after cyclization reaction, ethanol-water is adopted for recrystallization to obtain the 4-fluoro-7-bromoisatin.
8. The method for producing 4-fluoro-7-bromoisatin according to claim 7, wherein: the ethanol-water is prepared according to the mass ratio of 1: 1.6-1.8.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN115260079A (en) * | 2022-08-08 | 2022-11-01 | 湖北可赛化工有限公司 | Synthetic method of isatin and derivatives thereof |
| CN115784966A (en) * | 2022-12-19 | 2023-03-14 | 上海泰坦科技股份有限公司 | Preparation method of 6-bromo-5-fluoroindole-2-ketone |
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| WO2011148922A1 (en) * | 2010-05-24 | 2011-12-01 | 田辺三菱製薬株式会社 | Novel quinazoline compound |
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|---|---|---|---|---|
| CN115260079A (en) * | 2022-08-08 | 2022-11-01 | 湖北可赛化工有限公司 | Synthetic method of isatin and derivatives thereof |
| CN115784966A (en) * | 2022-12-19 | 2023-03-14 | 上海泰坦科技股份有限公司 | Preparation method of 6-bromo-5-fluoroindole-2-ketone |
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