CN108299137B

CN108299137B - Selective fluorination method of isatin hydrazone compound

Info

Publication number: CN108299137B
Application number: CN201810313338.0A
Authority: CN
Inventors: 唐真宇; 杨琼; 代国丽; 李佳威
Original assignee: Central South University
Current assignee: Central South University
Priority date: 2018-04-09
Filing date: 2018-04-09
Publication date: 2020-04-14
Anticipated expiration: 2038-04-09
Also published as: CN108299137A

Abstract

The invention discloses a selective fluorination method of isatin hydrazone compounds, which comprises the steps of enabling isatin hydrazone to react with 1-chloromethyl-4-fluoro-1, 4-diazabicyclo [2.2.2] octane bis (tetrafluoroborate) salt and an alkaline compound in one pot, and selectively synthesizing corresponding 3, 3-difluoroindolone and 3-fluoroindolone fluorination products; the method fills the technical blank of the prior art that the selectivity is in three-position mono-fluorination or di-fluorination starting from isatin, has simple operation, short flow and high product yield, and meets the requirements of industrial production.

Description

Selective fluorination method of isatin hydrazone compound

Technical Field

The invention relates to a method for selectively fluorinating an isatin hydrazone compound, and belongs to the field of synthesis of fluorine-containing drug intermediates.

Background

The fluorine-containing organic compound is the core skeleton of many drug molecules, and at least 20-35% of the drug molecules clinically existing so far contain a fluorine atom or a fluorine-containing group. In the field of treatment of various diseases, fluorine-containing compounds cover many aspects, such as anti-inflammation, anti-virus, sedation, anti-tumor, and the like. The introduction of fluorine atoms results in compounds with unique physical, chemical and physiological properties due to their most intense electronegativity, smaller atomic radius and lower polarizability. Indole derivatives are widely distributed in the nature, the structures of a plurality of natural compounds contain indole rings, some indole derivatives are closely related to life activities, and the indoles are important heterocyclic compounds. Fluorination of indoles has been a branch of great importance in the field of fluorine chemistry. The introduction of fluorine atoms into the indole ring changes the chemical and physical properties of the indole ring, so that the indole ring has biological activity. On the other hand, due to the characteristics of low price and easy availability of isatin, isatin is widely applied as a substrate in the field of organic synthesis to synthesize a drug intermediate containing an indole skeleton.

The prior indole fluorination reaction is shown as the following reaction equation:

in summary, the methods for directly obtaining 3-fluoroindolone and analogues thereof in the prior art are few, such as starting from indol-2-one, and obtaining a 3-position monofluorinated product under the action of an N-fluoro-bis-benzenesulfonamide (NFSI) reagent and sodium hydride. The substrates for this process are limited to indol-2-ones with protecting groups on the nitrogen and the harsh reaction conditions require the use of a strong base, sodium hydride. There are relatively many ways in which 3, 3-difluoroindolone and its analogs can be obtained, but generally there are some transition metal catalyzed intramolecular or intermolecular ring-forming reactions. The reactions for the direct fluorination of indole derivatives to give products difluorinated at the 3-position are mainly two: firstly, starting from isatin, under the action of a diethylamino sulfur trifluoride (DAST) reagent, corresponding 3, 3-difluoroindolone is obtained, the substrate adaptability of the method is poor, the used fluorination reagent diethylamino sulfur trifluoride (DAST) is explosive at the temperature of more than 50 ℃, the method needs low-temperature storage in a refrigerator, the toxicity is high, and during operation, the eyeshade, the gas mask and the gloves are well carried, and all-round protective measures are taken. Secondly, starting from indole, under the action of an N-fluoro-diphenyl sulfonamide (NFSI) reagent, a 3-position difluorinated product is obtained, and the reaction also has the characteristics of poor substrate adaptability, harsh reaction conditions and low yield. These deficiencies have largely limited the use of existing reactions in drug development and have made it impossible for chemists to meet the demand for indole fluorination products. Therefore, the development of a simple, cheap, green and environment-friendly and atom-economic method for the three-position monofluorination or difluorination of the indolone meets the requirement of the current sustainable development strategy.

Disclosure of Invention

Aiming at the technical blank of selective mono-fluorination or di-fluorination at 3-position from isatin in the prior art, the invention aims to provide a method for selectively synthesizing a 3-position mono-fluorination or 3-position di-fluorination product from isatin hydrazone.

A method for fluorinating an isatin hydrazone compound comprises the step of carrying out a fluorination reaction on an isatin hydrazone compound with a structural formula of a formula 1 and a fluorinating agent to obtain a fluorinated isatin product with a structural formula of a formula 2:

R₁～R₅independently H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C6-C10 aryl, benzyl, C5-C10 saturated or partially unsaturated cycloalkyl, C5-C10 saturated or partially unsaturated heterocyclic alkyl, C5-C10 heterocyclic aryl, halogen and nitro;

the alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclic alkyl and heterocyclic aryl are selectively provided with at least one substituent of halogen, C1-6 alkoxy and C1-6 alkyl;

said R₆Is H or F.

Wherein the fluorinating agent is 1-chloromethyl-4-fluorine-1, 4-diazabicyclo [2.2.2] octane bis (tetrafluoroborate) salt;

the reaction solvent of the fluorination reaction is dichloroethane, alkali is added in the reaction, and R is selectively obtained₆A fluorinated isatin product that is H;

the reaction solvent for the fluorination reaction is acetonitrile (CH)₃CN) is selectively obtained₆Is a fluorinated isatin product of F.

The inventors have found that the synthesis scheme of the present invention can obtain a 3-position monofluorinated product or a 3-position bifluorinated product with high selectivity by controlling the kind of the reaction solvent, and have found that a 3-position bifluorinated product (i.e., R) can be obtained with high selectivity by using acetonitrile as the reaction solvent₆As F), when dichloroethane is used as the reaction solvent, a 3-position monofluorinated product (i.e. R) can be obtained unexpectedly₆H), the method of the invention, through one potThe reaction can obtain fluorizating product with high selectivity, especially obtain monofluorizating product which is difficult to obtain in the field.

The method is simple, the process flow is short, the product selectivity is high, and the industrial scale-up production is facilitated.

In the present invention, the alkyl group having 1 to 10 is a linear or branched hydrocarbon group having the above-mentioned carbon number, and the alkylene group having 2 to 10 is a hydrocarbon group having at least one carbon-carbon double bond, for example, allyl group, propenyl group, etc.; the alkynyl of C2-C10 is a hydrocarbyl group having at least one carbon-carbon triple bond, such as propargyl; the aryl of C6-C10 is, for example, phenyl or a condensed ring group formed by combining a plurality of benzene rings, such as naphthyl.

The saturated or partially unsaturated cycloalkyl group having 5 to 10 carbon atoms may be saturated carbon or partially unsaturated carbon atoms, for example, a five-or six-membered cyclic group.

The saturated or partially unsaturated heterocyclic hydrocarbon group of C5-C10 is, for example, a five-membered or six-membered cyclic group, the carbon constituting the ring may be replaced by a hetero atom hybrid, and the carbon and/or the hetero atom constituting the ring may be saturated carbon or partially unsaturated carbon.

The heterocyclic aryl group having C5 to C10 is, for example, a five-or six-membered aromatic group having a hetero atom, such as pyridine, etc.

Preferably, the isatin hydrazone compound with the structural formula of formula 1 has the structural formula of formula 1-A, formula 1-B or formula 1-C:

preferably, R₁Is C1-C6 alkyl, allyl, propargyl, phenyl, benzyl or chloroethyl. R₂Is H, C1-C6 alkyl, halogen or nitro. R₃H and halogen. R₄Is H, halogen or trifluoromethyl. R₅Is H. The halogen is preferably F, Cl, Br or I.

More preferably, formula 1-A, formula 1-B, formula 1-In C, R₁Selected from methyl, isopropyl, allyl, propargyl, phenyl, benzyl or chloroethyl; r₂Selected from hydrogen, methyl, fluorine, chlorine or bromine; r₃Selected from fluorine; r₄Selected from fluorine, bromine, chlorine or trifluoromethyl.

Preferably, the molar concentration of the isatin hydrazone compound in the initial solution system of the fluorination reaction is 0.04-0.2 mol/L.

Controlling the molar concentration of the substrate helps to further improve the selectivity and yield of the product for the conditions in which dichloroethane is used as the reaction solvent to obtain the 3-position monofluorinated product.

Preferably, the substrate is represented by formula 1-A, and the initial molar concentration of formula 1-A in dichloroethane is 0.1-0.2 mol/L. A substrate having a protective group (formula 1-A) on nitrogen, and a higher substrate molar concentration (0.16mol/L) can further provide a 3-position monofluorinated product with high selectivity.

Preferably, the substrate is represented by formula 1-B, and the initial molar concentration of formula 1-B in dichloroethane is 0.04-0.1 mol/L. For substrates without protecting groups on nitrogen (e.g., formula 1-B), the reaction selectivity is poor at higher substrate molar concentrations, and it is desirable to obtain the 3-position monofluorinated product with unexpectedly high selectivity at lower substrate molar concentrations (at least 0.04 mol/L).

Under the condition of obtaining the 3-position double-fluorination product in acetonitrile, the influence of the substrate molar concentration is little, and the 3-position double-fluorination product can be obtained at high selectivity under the condition of higher substrate molar concentration.

Preferably, the fluorinating agent is 1-chloromethyl-4-fluoro-1, 4-diazabicyclo [2.2.2] octane bis (tetrafluoroborate) salt (Selectfluor). It was found that the desired product could not be obtained with a fluorinating agent commonly used in the art, such as 1-methyl-4-fluoro-1, 4-diazabicyclo [2.2.2] octane bis (tetrafluoroborate) salt (SelectfluorII), N-fluorobisbenzenesulfonamide (NFSI) reagent, diethylaminosulfur trifluoride (DAST) reagent, and N-pyridinium trifluoromethanesulfonate (NFPTf) reagent, and that only 1-chloromethyl-4-fluoro-1, 4-diazabicyclo [2.2.2] octane bis (tetrafluoroborate) salt (Selectfluor) was suitable for the reaction of the present invention, and the desired product could be obtained with unexpectedly high selectivity.

Preferably, the fluorinating agent is in excess relative to the isatin hydrazone compound.

More preferably, the molar ratio of the fluorinating agent to the isatin hydrazone compound is 2 to 4: 1. When the molar ratio of the fluorinating reagent to the isatin hydrazone compound is 1:1, the fluorination yield can be obtained, but the reaction yield is low, and the optimal molar ratio of the fluorinating reagent to the isatin hydrazone compound is 2-4: 1. On the basis of this, if the amount of the fluorinating agent is further increased, the yield is rather decreased, and more by-products are easily produced (isatin hydrazone becomes isatin).

Preferably, in the conditions where dichloroethane is used as solvent to obtain 3-position monofluorination, the monofluorine product can be obtained with high selectivity only by adding a certain amount of base. However, in the conditions where acetonitrile is used as a solvent to obtain the difluoride product, the addition of a base reduces the yield, so it is preferred that the addition of a base is not required in the conditions where the difluoride product is obtained.

The base is preferably an alkali metal hydroxide, an organic base triethylamine, an acetate, a phosphate or a carbonate.

Preferably, the base is lithium acetate. Researches show that under the reaction system of the invention, the lithium acetate can be used for obtaining the 3-position monofluorine product with high selectivity.

Preferably, the molar ratio of the adding amount of the alkali to the isatin hydrazone compound is 5.5-6.5; most preferably 6: 1. in the case of conditions in which 3-position monofluorination is obtained using dichloroethane as a solvent, a base is necessary, but too much or too little base is detrimental to the reaction. For example, when the amount of the base is less than the lower limit of the ratio, the reaction yield is lowered. When the amount of alkali is more than the upper limit of the isatin hydrazone proportion, under the excessively strong alkaline condition, the isatin hydrazone is hydrazinolyzed, which is not beneficial to the reaction.

Preferably, the temperature of the fluorination reaction is 0 to 80 ℃.

Further preferably, the reaction solvent is dichloroethane, the isatin hydrazone compound shown in the formula 1-A is used as a substrate, and the reaction temperature is 70-80 ℃. In the conditions in which 3-position monofluorination is obtained using dichloroethane as a solvent, the reaction is facilitated at a high temperature of 80 ℃ with respect to a substrate having a protecting group on nitrogen (in the formula 1-A, R1 is not H, and is, for example, an alkyl group having 1 to 6, an allyl group, a propargyl group, a phenyl group, a benzyl group or a chloroethyl group).

Further preferably, the reaction solvent is dichloroethane, the isatin hydrazone compound shown in the formula 1-B is used as a substrate, and the reaction temperature is 70-75 ℃. For the substrate of the type of formula 1-B, a high temperature of 80 ℃ makes the reaction selectivity poor, and below 70 ℃ the substrate remains much, so that the optimum reaction state is reached when the temperature is 70 ℃.

Further preferably, the reaction solvent is acetonitrile, and the reaction temperature is 0-60 ℃. For conditions to obtain 3-position difluorinated product in acetonitrile, the general substrate can be reacted at room temperature to obtain the corresponding difluorinated product, but only the poorly soluble substrate, such as the substrate of formula 1-C, preferably heated to 50℃, is more favorable for higher difluorination yields.

Preferably, the fluorination reaction time is 12-18 h.

The isatin hydrazone compound can be prepared by an external purchase method or an existing method.

Preferably, the isatin hydrazone compound is obtained by reacting the isatin hydrazone compound shown in formula 3 with hydrazine hydrate:

R₁～R₅independently H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C6-C10 aryl, C5-C10 saturated or partially unsaturated cycloalkyl, C5-C10 saturated or partially unsaturated heterocyclic alkyl, C5-C10 heterocyclic aryl, halogen or nitro;

the alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclic alkyl and heterocyclic aryl are selectively provided with at least one substituent of halogen, C1-6 alkoxy and C1-6 alkyl.

The isatin compound has a structure shown in a formula 3-A or a formula 3-B:

wherein R is₁Is methyl, ethyl, propyl, isopropyl, allyl, propargyl, butyl, pentyl, hexyl, phenyl, benzyl, chloroethyl; r₂Hydrogen atom, methyl, fluorine atom, chlorine atom, bromine atom; r₃Is a fluorine atom; r₄Is fluorine atom, bromine atom, chlorine atom, trifluoromethyl.

Preferred synthetic methods of formula 1: isatin (1g,1eq) was added separately to a 100mL round bottom flask equipped with a magnetic stirrer, and 20mL methanol was added to dissolve the isatin completely. Then hydrazine hydrate (80%, 2eq) was added all at once and heated to methanol reflux. The progress of the reaction was monitored by Thin Layer Chromatography (TLC) and, after completion of the reaction, cooled to room temperature. After the crystals precipitated from the round bottom flask, the filtrate was filtered and the residue was washed with a small amount of cold methanol. And (4) carrying out suction filtration and drying on the cleaned filter residue to obtain the isatin hydrazone and the derivative substrate thereof.

The preferable method is that the isatin hydrazone compound reacts with 1-chloromethyl-4-fluoro-1, 4-diazabicyclo [2.2.2] octane bis (tetrafluoroborate) and alkaline compound in one pot to obtain monofluorination product (3-fluoroindolone compound) or bifluorination product (3, 3-difluoroindolone compound) of the isatin hydrazone and the derivative 3 site thereof;

for isatin hydrazones of formula 1-A, formula 1-B or formula 1-C, dichloroethane is used as the solvent with 1-chloromethyl-4-fluoro-1, 4-diazabicyclo [2.2.2]Octane bis (tetrafluoroborate) salt and an alkaline compound are reacted in one pot to obtain a corresponding 3-position monofluorinated indolone compound (R)₆Is H); using acetonitrile as solvent, with 1-chloromethyl-4-fluoro-1, 4-diazabicyclo [2.2.2]Octane bis (tetrafluoroborate) salt is reacted in one pot to obtain the corresponding 3, 3-bifluorinated indolone compound (R)₆Is F).

Preferably, taking formula 1-A as an example, the reaction equation is shown in formula 1 (preferred embodiment A):

preferably, in preferred embodiment A, 1-chloromethyl-4-fluoro-1, 4-diazabicyclo [2.2.2] is]The octane bis (tetrafluoroborate) salt and alkali are subjected to fluorination reaction in dichloroethane to prepare R₆Fluorinated isatin product as H: wherein the molar concentration of the formula 1-A in an initial solution system is 0.1-0.2mol/L, the reaction temperature is 70-80 ℃, and the adding amount of alkali is 5.5-6.5 of the molar ratio of the formula 1-A; the molar ratio of the fluorinating agent to the formula 1-A is 2-4: 1. Under the preferred conditions, the 3-position monofluoro product can be obtained with high yield;

preferably, the reaction equation is shown in equation 2 (preferred embodiment B) by taking formula 1-B as an example

Preferably, in variant B, the compound of formula 1-B, 1-chloromethyl-4-fluoro-1, 4-diazabicyclo [2.2.2]The octane bis (tetrafluoroborate) salt and alkali are subjected to fluorination reaction in dichloroethane to prepare R₆Fluorinated isatin product as H: wherein the molar concentration of the formula 1-B in an initial solution system is 0.04-0.1 mol/L, the reaction temperature is 70-75 ℃, and the adding amount of the alkali is 5.5-6.5 of the molar ratio of the formula 1-B; the molar ratio of the fluorinating agent to the formula 1-B is 2-4: 1. Under the preferred conditions, the 3-position monofluoro product can be obtained in high yield.

Preferably, in preferred embodiment C, a compound of formula 1-C, 1-chloromethyl-4-fluoro-1, 4-diazabicyclo [2.2.2]Octane bis (tetrafluoroborate) salt in CH₃Fluorination reaction in CN to obtain R₆Fluorinated isatin product as F: the molar concentration of the formula 1-C in an initial solution system is 0.1-0.2mol/L, and the reaction temperature is 50-60 ℃; the molar ratio of the fluorinating agent to the compound represented by the formula 1-C is 2-4: 1. Under the preferred conditions, the 3, 3-position difluoride product can be obtained in high yield.

Preferably, in the preferred embodiment D, at least one of the starting materials of the formula 1-A or the formula 1-B, 1-chloromethyl-4-fluoro-1, 4-diazabicyclo [2.2.2]Octane bis(tetrafluoroborate) in CH₃Fluorination reaction in CN to obtain R₆Fluorinated isatin product as F: the molar concentration of the raw materials in an initial solution system is 0.1-0.2mol/L, and the reaction temperature is 0-60 ℃; the molar ratio of the fluorinating agent to the raw material is 2-4: 1. Under the preferred conditions, the 3, 3-position difluoride product can be obtained in high yield.

The invention further comprises the following preferred technical scheme:

in a preferable scheme, the isatin hydrazone shown in the formula 1-A takes dichloroethane as a solvent, and the reaction molar concentration is 0.16 mol/L; reacting the intermediate product with 1-chloromethyl-4-fluoro-1, 4-diazabicyclo [2.2.2] octane bis (tetrafluoroborate) and lithium acetate according to the molar ratio of 1:2:6, wherein the reaction temperature is 80 ℃, and the reaction time is 18 hours, so as to obtain the corresponding 3-fluoroindolone.

In a preferable scheme, the isatin hydrazone shown in the formula 1-B takes dichloroethane as a solvent, and the reaction molar concentration is 0.04 mol/L; reacting the intermediate product with 1-chloromethyl-4-fluoro-1, 4-diazabicyclo [2.2.2] octane bis (tetrafluoroborate) and lithium acetate according to the molar ratio of 1:2:6 at the reaction temperature of 70 ℃ for 16 hours to obtain the corresponding 3-fluoroindolone.

In a preferable scheme, the isatin hydrazone shown in the formula 1-A or 1-B takes acetonitrile as a solvent, and the reaction molar concentration is 0.16 mol/L; reacting the intermediate product with 1-chloromethyl-4-fluoro-1, 4-diazabicyclo [2.2.2] octane bis (tetrafluoroborate) salt according to a molar ratio of 1:2, and reacting at room temperature for 16 hours to obtain the corresponding 3, 3-difluoroindolone.

In a preferable scheme, the isatin hydrazone shown in the formula 1-C takes acetonitrile as a solvent, and the reaction molar concentration is 0.16 mol/L; reacting the intermediate product with 1-chloromethyl-4-fluoro-1, 4-diazabicyclo [2.2.2] octane bis (tetrafluoroborate) salt according to a molar ratio of 1:2, wherein the reaction temperature is 50 ℃, and the reaction time is 16 hours, so as to obtain the corresponding 3, 3-difluoroindolone.

After the fluorination reaction is finished, the selective product is recovered by the existing method, and preferably the high-selectivity product is obtained by extraction and chromatographic purification.

In a preferred embodiment, after completion of the fluorination reaction, the reaction mixture is cooled to room temperature, extracted twice with 20mL of ethyl acetate, the organic phases are combined and washed with saturated brine, and then the organic phase is dried by adding anhydrous sodium sulfate. And (4) drying the organic phase after the drying is finished, and then carrying out decompression spin drying on the organic solvent to obtain a crude product. The crude product was purified using 9: and (3) carrying out column separation by using petroleum ether and ethyl acetate of the step 1 as eluent to obtain a final product.

Compared with the prior art, the technical scheme provided by the invention has the beneficial technical effects that:

1. the technical scheme disclosed by the invention is used for selectively synthesizing 3, 3-difluoroindolone (namely 3, 3-bifluorinated indolone compound) from isatin for the first time₆Is F)) and 3-fluoroindolone (3-position monofluorinated indolone compound (R)₆H)), fills the gap in the prior art.

2. The technical scheme of the invention adopts a one-pot reaction, has mild process conditions, short flow and simple steps, and meets the requirements of industrial production.

3. The technical scheme of the invention is to synthesize the corresponding 3, 3-difluoroindolone and 3-fluoroindolone fluorinated products from isatin, and the product yield is high.

4. The preference of the isatin hydrazone and the reaction parameters as described above can give a product with a yield of 97% or more, which the inventors have not intended at all at the beginning of their development.

The invention finally realizes the selective synthesis of 3, 3-difluoroindolone and 3-fluoroindolone from isatin by continuously optimizing and improving reaction conditions and parameters for different substrate types, and realizes very high yield. The method has simple scheme, can obtain high yield, can bring huge economic benefits and has very important practical significance.

Drawings

FIG. 1 shows the product obtained in example 1¹H NMR spectrum

FIG. 2 shows the product obtained in example 1¹³C NMR spectrum

FIG. 3 shows the product obtained in example 1¹⁹F NMR spectrum

FIG. 4 shows a result obtained in example 13Of the product¹H NMR spectrum

FIG. 5 shows the product obtained in example 13¹³C NMR spectrum

FIG. 6 shows the product obtained in example 13¹⁹F NMR spectrum

Detailed Description

The following examples are intended to illustrate the present invention, but not to further limit the scope of the claims.

The following examples, in analogy to the following methods, can be used to prepare the corresponding isatin hydrazones:

the method comprises the steps of utilizing the existing mode (adding isatin (1g,1eq) into a 100mL round bottom flask with a magnetic stirrer respectively, adding 20mL of methanol to completely dissolve the isatin, then adding hydrazine hydrate (80%, 2eq) at a time, heating until the methanol refluxes, monitoring the reaction process through Thin Layer Chromatography (TLC), cooling to room temperature after the reaction is finished, separating out crystals in the round bottom flask, filtering, washing filter residues with a small amount of cold methanol, and carrying out suction filtration and drying on the cleaned filter residues to obtain the isatin hydrazone and the derivative substrate thereof.

Example 1

3-fluoro-2-indolone synthesis, separation and purification: isatin hydrazone (0.5mmol,1eq), Selectfluor (354.3mg,1mmol,2eq), lithium acetate (197.8mg,3mmol,6eq) were added separately to a 100mL round bottom flask equipped with a magnetic stirrer and sealed with a rubber stopper; dichloroethane (13mL) was then added as solvent using a syringe; the reaction flask was placed in an oil bath at 70 ℃ and the reaction was stirred with heating for 18 hours, the progress of the reaction being monitored by Thin Layer Chromatography (TLC). After the reaction was completed, it was cooled to room temperature, the reaction mixture was extracted twice with 40mL of ethyl acetate, and the organic phases were combined and washed with saturated brine, followed by adding anhydrous sodium sulfate and drying the organic phase. And (4) drying the organic phase after the drying is finished, and then carrying out decompression spin drying on the organic solvent to obtain a crude product. The crude product was purified using 9: and (3) carrying out column separation by using petroleum ether and ethyl acetate of the step 1 as eluent to obtain a final product. 3-fluoro-2-indolone as a white solid in 68% yield (yield by¹⁹F NMR measurement).

¹H NMR(400MHz,DMSO-d₆):δ10.65(s,1H),7.45(d,J＝7.6Hz,1H),7.35(t,J＝7.6Hz,1H),7.04(t,J＝7.6Hz,1H),6.87(d,J＝7.6Hz,1H),5.88(d,J_H-F＝50.8Hz,1H).

¹³C NMR(100MHz,DMSO-d₆):δ172.9(d,J＝18.0Hz),143.8(d,J＝6.0Hz),131.8(d,J＝3.0Hz),126.6,123.8(d,J＝16.0Hz),122.7(d,J＝2.0Hz),110.8(d,J＝1.0Hz),86.5(d,J＝181.0Hz).

¹⁹F NMR(376MHz,DMSO-d₆):δ-192.1(d,J_H-F＝50.8Hz).

Example 2

3-fluoro-1-isopropyl-2-indolone synthesis, separation and purification: 1-isopropyl-isatin hydrazone (0.5mmol,1eq), Selectfluor (354.3mg,1mmol,2eq), lithium acetate (197.8mg,2mmol,6eq) were added separately to a 25mL round bottom flask equipped with a magnetic stirrer and sealed with a rubber stopper; dichloroethane (3mL) was then added as solvent using a syringe; the reaction flask was placed in an oil bath at 80 ℃ and the reaction was stirred with heating for 16 hours, and the progress of the reaction was monitored by Thin Layer Chromatography (TLC). After the reaction was completed, it was cooled to room temperature, the reaction mixture was extracted twice with 20mL of ethyl acetate, and the organic phases were combined and washed with saturated brine, followed by adding anhydrous sodium sulfate and drying. And (4) drying the organic phase after the drying is finished, and then carrying out decompression spin drying on the organic solvent to obtain a crude product. The crude product was purified using 9: and (3) carrying out column separation by using petroleum ether and ethyl acetate of the step 1 as eluent to obtain a final product. 3-fluoro-1-isopropyl-2-indolone as a white solid in 71% yield (yield by¹⁹F NMR measurement).

¹H NMR(400MHz,CDCl₃):δ7.46(d,J＝7.2Hz,1H),7.36(t,J＝7.8Hz,1H),7.09(t,J＝7.6Hz,1H),6.99(d,J＝8.0Hz,1H),5.60(d,J_H-F＝51.2Hz,1H),4.50-4.60(m,2H),1.48(q,J＝7.0Hz,6H).

¹³C NMR(125MHz,CDCl₃):δ170.8(d,J＝17.5Hz),143.5(d,J＝5.1Hz),131.2(d,J＝3.3Hz),126.3,123.2(d,J＝16.0Hz),122.7(d,J＝2.7Hz),110.4,85.5(d,J＝186.3Hz),44.2,19.2.

¹⁹F NMR(376MHz,CDCl₃):δ-192.9(d,J_H-F＝51.2Hz).

HRMS-ESI(m/z):Calcd for[M+H]⁺,194.0973.Found,194.0981.

Example 3

3-fluoro-1-allyl-2-indolone synthesis and separation purification: 1-allyl-isatin hydrazone (0.5mmol,1eq), Selectfluor (354.3mg,1mmol,2eq), lithium acetate (197.8mg,2mmol,6eq) were added separately to a 25mL round bottom flask equipped with a magnetic stirrer and sealed with a rubber stopper; dichloroethane (3mL) was then added as solvent using a syringe; the reaction flask was placed in an oil bath at 80 ℃ and the reaction was stirred with heating for 16 hours, and the progress of the reaction was monitored by Thin Layer Chromatography (TLC). After the reaction was completed, it was cooled to room temperature, the reaction mixture was extracted twice with 20mL of ethyl acetate, and the organic phases were combined and washed with saturated brine, followed by adding anhydrous sodium sulfate and drying. And (4) drying the organic phase after the drying is finished, and then carrying out decompression spin drying on the organic solvent to obtain a crude product. The crude product was purified using 9: and (3) carrying out column separation by using petroleum ether and ethyl acetate of the step 1 as eluent to obtain a final product. 3-fluoro-1-allyl-2-indolone as a white solid in 73% yield (yield by¹⁹F NMR measurement).

¹H NMR(500MHz,CDCl3):δ7.48(d,J＝7.0Hz,1H),7.37(t,J＝7.8Hz,1H),7.11(t,J＝7.5Hz,1H),6.84(d,J＝8.0Hz,1H),5.79-5.86(m,1H),5.71(d,J_H-F＝51.0Hz,1H),5.27(t,J＝9.3Hz,2H),4.26-4.37(m,2H).

¹³C NMR(125MHz,CDCl3):δ170.8(d,J＝18.7Hz),144.0(d,J＝5.0Hz),131.4(d,J＝3.7Hz),130.7,126.1,123.3(d,J＝2.5Hz),122.7(d,J＝16.3Hz),118.2,109.7,85.5(d,J＝187.5Hz),42.4.

¹⁹F NMR(376MHz,CDCl3):δ-192.8(d,J_H-F＝51.0Hz).

HRMS-ESI(m/z):Calcd for[M+H]⁺,192.0816.Found,192.0825.

Example 4

3-fluoro-1-propargyl-2-indolone synthesis, separation and purification: 1-propargyl-isatin hydrazone (0.5mmol,1eq), Selectfluor (354.3mg,1mmol,2eq), lithium acetate (197.8mg,2mmol,6eq) were added separately to a 25mL round bottom flask equipped with a magnetic stirrer and sealed with a rubber stopper; dichloroethane (3mL) was then added as solvent using a syringe; will be reversedThe flask was placed in an oil bath at 80 ℃ and the reaction was stirred with heating for 16 hours, the progress of the reaction being monitored by Thin Layer Chromatography (TLC). After the reaction was completed, it was cooled to room temperature, the reaction mixture was extracted twice with 20mL of ethyl acetate, and the organic phases were combined and washed with saturated brine, followed by adding anhydrous sodium sulfate and drying. And (4) drying the organic phase after the drying is finished, and then carrying out decompression spin drying on the organic solvent to obtain a crude product. The crude product was purified using 9: and (3) carrying out column separation by using petroleum ether and ethyl acetate of the step 1 as eluent to obtain a final product. 3-fluoro-1-propargyl-2-indolone as a white solid in 76% yield (yield by¹⁹F NMR measurement).

¹H NMR(400MHz,CDCl₃):δ7.49(s,1H),7.43(s,1H),7.16(s,1H),7.08(s,1H),5.72(d,J_H-F＝51.2Hz,1H),4.38-4.59(m,2H),2.71(s,1H).

¹³C NMR(100MHz,CDCl₃):δ170.1(d,J＝18.0Hz),142.8(d,J＝5.0Hz),131.5(d,J＝4.0Hz),126.2(d,J＝1.0Hz),123.7(d,J＝3.0Hz),122.6(d,J＝17.0Hz),109.9(d,J＝2Hz),85.4(d,J＝188.0),76.1,72.9,29.4.

¹⁹F NMR(376MHz,CDCl₃):δ-193.1(d,J_H-F＝51.2Hz).

Example 5

3-fluoro-1-hexyl-2-indolone synthesis, separation and purification: 1-hexyl-isatin hydrazone (0.5mmol,1eq), Selectfluor (354.3mg,1mmol,2eq), lithium acetate (197.8mg,2mmol,6eq) were added separately to a 25mL round bottom flask equipped with a magnetic stirrer and sealed with a rubber stopper; dichloroethane (3mL) was then added as solvent using a syringe; the reaction flask was placed in an oil bath at 80 ℃ and the reaction was stirred with heating for 16 hours, and the progress of the reaction was monitored by Thin Layer Chromatography (TLC). After the reaction was completed, it was cooled to room temperature, the reaction mixture was extracted twice with 20mL of ethyl acetate, and the organic phases were combined and washed with saturated brine, followed by adding anhydrous sodium sulfate and drying. And (4) drying the organic phase after the drying is finished, and then carrying out decompression spin drying on the organic solvent to obtain a crude product. The crude product was purified using 9: and (3) carrying out column separation by using petroleum ether and ethyl acetate of the step 1 as eluent to obtain a final product. 3-fluoro-1-hexyl-2-indolone as a white solid in 79% yield (yield by¹⁹F NMR measurement).

¹H NMR(400MHz,CDCl₃):δ7.47(d,J＝7.2Hz,1H),7.38(t,J＝7.8Hz,1H),7.10(t,J＝7.6Hz,1H),6.84(d,J＝8.0Hz,1H),5.65(d,J_H-F＝50.8Hz,1H),3.60-3.72(m,2H),1.64-1.70(m,2H),1.29-1.34(m,6H),0.88(t,J＝7.0Hz,3H).

¹³C NMR(100MHz,CDCl₃):δ171.0(d,J＝17.9Hz),144.2(d,J＝5.0Hz),131.4(d,J＝3.0Hz),126.2,123.0(d,J＝3.0Hz),122.9(d,J＝16.0Hz),109.1,85.5(d,J＝187.0Hz),40.1,27.2,22.5,14.0.

¹⁹F NMR(376MHz,CDCl₃):δ-193.2(d,J_H-F＝50.8Hz).

HRMS-ESI(m/z):Calcd for[M+H]⁺,236.1442.Found,236.1451.

Example 6

3-fluoro-1-benzyl-2-indolone synthesis, separation and purification: 1-benzyl-isatin hydrazone (0.5mmol,1eq), Selectfluor (354.3mg,1mmol,2eq), lithium acetate (197.8mg,2mmol,6eq) were added separately to a 25mL round bottom flask equipped with a magnetic stirrer and sealed with a rubber stopper; dichloroethane (3mL) was then added as solvent using a syringe; the reaction flask was placed in an oil bath at 80 ℃ and the reaction was stirred with heating for 16 hours, and the progress of the reaction was monitored by Thin Layer Chromatography (TLC). After the reaction was completed, it was cooled to room temperature, the reaction mixture was extracted twice with 20mL of ethyl acetate, and the organic phases were combined and washed with saturated brine, followed by adding anhydrous sodium sulfate and drying. And (4) drying the organic phase after the drying is finished, and then carrying out decompression spin drying on the organic solvent to obtain a crude product. The crude product was purified using 9: and (3) carrying out column separation by using petroleum ether and ethyl acetate of the step 1 as eluent to obtain a final product. 3-fluoro-1-benzyl-2-indolone as a white solid in 83% yield (yield by¹⁹F NMR measurement).

¹H NMR(400MHz,CDCl₃):δ7.48(d,J＝8.0Hz,1H),7.28-7.36(m,6H),7.08(t,J＝7.6Hz,1H),6.73(d,J＝7.6Hz,1H),5.77(d,J_H-F＝51.2Hz,1H),4.88(q,J＝24.8Hz,2H).

¹³C NMR(100MHz,CDCl₃):δ171.2(d,J＝18.0Hz),143.9(d,J＝5.0Hz),135.0,131.4(d,J＝3.0Hz),128.9,127.9,127.4,126.2,123.3(d,J＝3.0Hz),122.8(d,J＝16.0Hz),109.8,85.5(d,J＝188.0Hz),43.9.

¹⁹F NMR(376MHz,CDCl₃):δ-192.6(d,J_H-F＝51.2Hz).

Example 7

3-fluoro-1-chloroethyl-2-indolone synthesis, separation and purification: 1-chloroethyl-isatin hydrazone (0.5mmol,1eq), Selectfluor (354.3mg,1mmol,2eq), lithium acetate (197.8mg,2mmol,6eq) were added separately to a 25mL round bottom flask equipped with a magnetic stirrer and sealed with a rubber stopper; dichloroethane (3mL) was then added as solvent using a syringe; the reaction flask was placed in an oil bath at 80 ℃ and the reaction was stirred with heating for 16 hours, and the progress of the reaction was monitored by Thin Layer Chromatography (TLC). After the reaction was completed, it was cooled to room temperature, the reaction mixture was extracted twice with 20mL of ethyl acetate, and the organic phases were combined and washed with saturated brine, followed by adding anhydrous sodium sulfate and drying. And (4) drying the organic phase after the drying is finished, and then carrying out decompression spin drying on the organic solvent to obtain a crude product. The crude product was purified using 9: and (3) carrying out column separation by using petroleum ether and ethyl acetate of the step 1 as eluent to obtain a final product. 3-fluoro-1-chloroethyl-2-indolone as a white solid in 81% yield (yield by¹⁹F NMR measurement).

¹H NMR(400MHz,CDCl₃):δ7.49(d,J＝7.2Hz,1H),7.41(t,J＝7.6Hz,1H),7.14(t,J＝7.4Hz,1H),6.94(d,J＝8Hz,1H),5.70(d,J_H-F＝50.8Hz,1H),3.93-4.12(m,2H),3.76(t,J＝6.4Hz,2H).

¹³C NMR(100MHz,CDCl₃):δ171.3(d,J＝18.0Hz),143.7(d,J＝5.0Hz),131.5(d,J＝3.0Hz),126.4(d,J＝1.0Hz),123.6(d,J＝2.0Hz),122.7(d,J＝16.0Hz),109.1(d,J＝1.0Hz),86.2(d,J＝188.0Hz),42.0,40.3.

¹⁹F NMR(376MHz,CDCl₃):δ-192.9(d,J_H-F＝50.8Hz).

HRMS-ESI(m/z):Calcd for[M+H]⁺,214.0428.Found,214.0435.

Example 8

Synthesizing, separating and purifying 5-bromo-3-fluoro-2-indolone: 5-bromine was added to 100mL round-bottomed flasks equipped with a magnetic stirrerIsatin hydrazone (0.5mmol,1eq), Selectfluor (354.3mg,1mmol,2eq), lithium acetate (197.8mg,3mmol,6eq) and sealed with a rubber stopper; dichloroethane (13mL) was then added as solvent using a syringe; the reaction flask was placed in an oil bath at 70 ℃ and the reaction was stirred with heating for 18 hours, the progress of the reaction being monitored by Thin Layer Chromatography (TLC). After the reaction was completed, it was cooled to room temperature, the reaction mixture was extracted twice with 40mL of ethyl acetate, and the organic phases were combined and washed with saturated brine, followed by adding anhydrous sodium sulfate and drying the organic phase. And (4) drying the organic phase after the drying is finished, and then carrying out decompression spin drying on the organic solvent to obtain a crude product. The crude product was purified using 9: and (3) carrying out column separation by using petroleum ether and ethyl acetate of the step 1 as eluent to obtain a final product. 5-bromo-3-fluoro-2-indolone as a white solid in 45% yield (yield by¹⁹F NMR measurement).

¹H NMR(400MHz,DMSO-d₆):δ10.79(s,1H),7.67(s,1H),7.53(d,J＝7.6Hz,1H),6.84(d,J＝7.6Hz,1H),5.89(d,J_H-F＝50.0Hz,1H).

¹³C NMR(100MHz,DMSO-d₆):δ177.1(d,J＝18.0Hz),147.9(d,J＝5.0Hz),139.2(d,J＝3.0Hz),134.2,130.8(d,J＝15.0Hz),118.9(d,J＝3.0Hz),117.6,90.9(d,J＝183.0Hz).

¹⁹F NMR(376MHz,DMSO-d₆):δ-192.7(d,J_H-F＝50.0Hz).

Example 9

Synthesizing, separating and purifying 7-fluoro-3-fluoro-2-indolone: in a 100mL round bottom flask equipped with a magnetic stirrer were added 7-fluoro-isatin hydrazone (0.5mmol,1eq), Selectfluor (354.3mg,1mmol,2eq), lithium acetate (197.8mg,3mmol,6eq), respectively, and sealed with a rubber stopper; dichloroethane (13mL) was then added as solvent using a syringe; the reaction flask was placed in an oil bath at 70 ℃ and the reaction was stirred with heating for 18 hours, the progress of the reaction being monitored by Thin Layer Chromatography (TLC). After the reaction was completed, it was cooled to room temperature, the reaction mixture was extracted twice with 40mL of ethyl acetate, and the organic phases were combined and washed with saturated brine, followed by adding anhydrous sodium sulfate and drying the organic phase. And (4) drying the organic phase after the drying is finished, and then carrying out decompression spin drying on the organic solvent to obtain a crude product. The crude product was purified using 9: 1 petroleum ether and ethyl acetate as eluentAnd (5) performing column separation to obtain a final product. 7-fluoro-3-fluoro-2-indolone as a white solid in 60% yield (yield by¹⁹F NMR measurement).

¹H NMR(400MHz,DMSO-d₆):δ11.17(s,1H),7.27-7.34(m,2H),7.05-7.10(m,1H),5.95(d,J_H-F＝50.0Hz,1H).

¹³C NMR(100MHz,DMSO-d₆):δ172.6(d,J＝17.0Hz),146.9(d,J＝242.0Hz),130.8(q,J＝6.0Hz),126.5-126.7(m),123.7(q,J＝3.0Hz),122.7(d,J＝3.0Hz),118.7-118.9(m),86.2(d,J＝183.0Hz).

¹⁹F NMR(376MHz,DMSO-d₆):δ-132.3,-192.0(d,J_H-F＝50.0Hz).

HRMS-FIA(m/z):Calcd for[M+H]+,170.0409.Found,170.0417.

Example 10

Synthesizing, separating and purifying 7-chloro-3-fluoro-2-indolone: in a 100mL round bottom flask equipped with a magnetic stirrer were added 7-chloro-isatin hydrazone (0.5mmol,1eq), Selectfluor (354.3mg,1mmol,2eq), lithium acetate (197.8mg,3mmol,6eq), respectively, and sealed with a rubber stopper; dichloroethane (13mL) was then added as solvent using a syringe; the reaction flask was placed in an oil bath at 70 ℃ and the reaction was stirred with heating for 18 hours, the progress of the reaction being monitored by Thin Layer Chromatography (TLC). After the reaction was completed, it was cooled to room temperature, the reaction mixture was extracted twice with 40mL of ethyl acetate, and the organic phases were combined and washed with saturated brine, followed by adding anhydrous sodium sulfate and drying the organic phase. And (4) drying the organic phase after the drying is finished, and then carrying out decompression spin drying on the organic solvent to obtain a crude product. The crude product was purified using 9: and (3) carrying out column separation by using petroleum ether and ethyl acetate of the step 1 as eluent to obtain a final product. 7-chloro-3-fluoro-2-indolone as a white solid in 54% yield (yield by¹⁹F NMR measurement).

¹H NMR(400MHz,DMSO-d₆):δ11.10(s,1H),7.44(d,J＝8.0Hz 2H),7.08(t,J＝7.8Hz,1H)5.96(d,J_H-F＝50.0Hz,1H).

¹³C NMR(100MHz,DMSO-d₆):δ172.7(d,J＝17.0Hz),141.5(d,J＝6.0Hz),131.6(q,J＝3.0Hz),121.6(q,J＝16.0Hz),125.3,124.0(d,J＝3.0Hz),114.9,86.7(d,J＝183.0Hz).

¹⁹F NMR(376MHz,DMSO-d₆):δ-191.8(d,J_H-F＝50.0Hz).

HRMS-ESI(m/z):Calcd for[M+H]⁺,186.0113.Found,186.0122.

Example 11

Synthesizing, separating and purifying 5, 6-difluoro-3-fluoro-2-indolone: 5, 6-difluoro-isatin hydrazone (0.5mmol,1eq), Selectfluor (354.3mg,1mmol,2eq), lithium acetate (197.8mg,3mmol,6eq) were added separately to a 100mL round bottom flask equipped with a magnetic stirrer and sealed with a rubber stopper; dichloroethane (13mL) was then added as solvent using a syringe; the reaction flask was placed in an oil bath at 70 ℃ and the reaction was stirred with heating for 18 hours, the progress of the reaction being monitored by Thin Layer Chromatography (TLC). After the reaction was completed, it was cooled to room temperature, the reaction mixture was extracted twice with 40mL of ethyl acetate, and the organic phases were combined and washed with saturated brine, followed by adding anhydrous sodium sulfate and drying the organic phase. And (4) drying the organic phase after the drying is finished, and then carrying out decompression spin drying on the organic solvent to obtain a crude product. The crude product was purified using 9: and (3) carrying out column separation by using petroleum ether and ethyl acetate of the step 1 as eluent to obtain a final product. 5, 6-difluoro-3-fluoro-2-indolone as a white solid in 51% yield (yield by¹⁹F NMR measurement).

¹H NMR(400MHz,DMSO-d₆):δ10.78(s,1H),7.69(t,J＝8.0Hz,1H),6.92-6.96(m,1H),5.86(d,J_H-F＝50.4Hz,1H).

¹³C NMR(100MHz,DMSO-d₆):δ172.8(d,J＝17.0Hz),150.4-153.1(m),144.7-147.2(m),140.8-141.0(m),119.6-119.8(m),116.7(d,J＝21.0Hz),101.0(q,J＝22.0Hz),85.9(d,J＝184.0Hz).

¹⁹F NMR(376MHz,DMSO-d₆):δ-133.6,-147.2,-192.0(d,J_H-F＝50.4Hz).

HRMS-ESI(m/z):Calcd for[M+H]⁺,188.0314.Found,188.0323.

Example 12

And (3) synthesizing, separating and purifying 7-trifluoromethyl-3-fluoro-2-indolone: 7-trifluoromethyl-isatin hydrazone (0.5 mm) was added to a 100mL round-bottomed flask equipped with a magnetic stirrerol, eq), Selectfluor (354.3mg,1mmol,2eq), lithium acetate (197.8mg,3mmol,6eq) and sealed with a rubber stopper; dichloroethane (13mL) was then added as solvent using a syringe; the reaction flask was placed in an oil bath at 70 ℃ and the reaction was stirred with heating for 18 hours, the progress of the reaction being monitored by Thin Layer Chromatography (TLC). After the reaction was completed, it was cooled to room temperature, the reaction mixture was extracted twice with 40mL of ethyl acetate, and the organic phases were combined and washed with saturated brine, followed by adding anhydrous sodium sulfate and drying the organic phase. And (4) drying the organic phase after the drying is finished, and then carrying out decompression spin drying on the organic solvent to obtain a crude product. The crude product was purified using 9: and (3) carrying out column separation by using petroleum ether and ethyl acetate of the step 1 as eluent to obtain a final product. 7-trifluoromethyl-3-fluoro-2-indolone as a white solid in 56% yield (yield by¹⁹F NMR measurement).

¹H NMR(400MHz,DMSO-d₆):δ11.14(s,1H),7.77(d,J＝7.2Hz,1H),7.66(d,J＝8.0Hz,1H),7.24(t,J＝7.8Hz,1H),5.97(d,J_H-F＝50.4Hz,1H).

¹³C NMR(125MHz,DMSO-d₆):δ173.2(d,J＝17.5Hz),141.2(d,J＝2.5Hz),130.6,127-128.0(m),125.7(d,J＝16.25Hz),122.9(d,J＝1.2Hz),123.7(q,J＝270.6Hz),111.9(q,J＝31.9Hz),85.1(d,J＝182.5Hz).

¹⁹F NMR(376MHz,DMSO-d₆):δ-60.2,-193.2(d,J_H-F＝50.4Hz).

HRMS-ESI(m/z):Calcd for[M+H]⁺,220.0379.Found,220.0386.

Example 13

3, 3-difluoro-2-indolone synthesis, separation and purification: isatin hydrazone (0.5mmol,1eq), Selectfluor (354.3mg,1mmol,2eq) were added to a 25mL round bottom flask equipped with a magnetic stirrer and sealed with a rubber stopper; then acetonitrile (3mL) was added as a solvent with a syringe; the reaction flask was left to stir at room temperature for 16 hours and the progress of the reaction was monitored by Thin Layer Chromatography (TLC). After the reaction was completed, the reaction mixture was extracted twice with 20mL of ethyl acetate, and the organic phases were combined and washed with saturated brine, and then the organic phase was dried by adding anhydrous sodium sulfate. And (4) drying the organic phase after the drying is finished, and then carrying out decompression spin drying on the organic solvent to obtain a crude product.The crude product was purified using 9: and (3) carrying out column separation by using petroleum ether and ethyl acetate of the step 1 as eluent to obtain a final product. 3, 3-difluoro-2-indolone as a white solid in 76% yield (yield by¹⁹FNMR assay).

¹H NMR(400MHz,CDCl₃):δ7.55-7.60(m,2H),7.45(t,J＝8.0Hz,1H),7.17(t,J＝7.4Hz,1H),6.92(d,J＝8.0Hz,1H).

¹³C NMR(100MHz,CDCl₃)δ166.2(t,J＝29.0Hz),143.0(t,J＝8.0Hz),134.7,125.3,119.6(t,J＝23.0Hz),112.3,111.7(t,J＝247.0Hz).

¹⁹F NMR(376MHz,CDCl₃)δ-111.3(s,2F).

Example 14

3, 3-difluoro-1-isopropyl-2-indolone synthesis, separation and purification: 1-isopropyl-isatin hydrazone (0.5mmol,1eq), Selectfluor (354.3mg,1mmol,2eq) were added to a 25mL round bottom flask equipped with a magnetic stirrer and sealed with a rubber stopper; then acetonitrile (3mL) was added as a solvent with a syringe; the reaction flask was left to stir at room temperature for 16 hours and the progress of the reaction was monitored by Thin Layer Chromatography (TLC). After the reaction was completed, the reaction mixture was extracted twice with 20mL of ethyl acetate, and the organic phases were combined and washed with saturated brine, and then the organic phase was dried by adding anhydrous sodium sulfate. And (4) drying the organic phase after the drying is finished, and then carrying out decompression spin drying on the organic solvent to obtain a crude product. The crude product was purified using 9: and (3) carrying out column separation by using petroleum ether and ethyl acetate of the step 1 as eluent to obtain a final product. 3, 3-difluoro-1-isopropyl-2-indolone as a white solid in 60% yield (yield by¹⁹F NMR measurement).

¹H NMR(400MHz,CDCl₃):δ7.55(d,J＝7.6Hz,1H),7.46(t,J＝8.0Hz,1H),7.15(t,J＝7.6Hz,1H),7.03(d,J＝8.0Hz,1H),4.46-4.56(m,1H),1.50(d,J＝7.2Hz,6H).

¹³C NMR(125MHz,CDCl₃):δ165.0(t,J＝29.3Hz),142.9(t,J＝7.5Hz),133.4,124.9,123.4,120.5(t,J＝22.5Hz),111.0,110.5(t,J＝2Hz),120.2(t,J＝23.0Hz),110.5(t,J＝247.5Hz),44.8,19.2.

¹⁹F NMR(376MHz,CDCl₃):δ-112.4(s,2F).

Example 15

3, 3-difluoro-1-allyl-2-indolone synthesis, separation and purification: 1-allyl-isatin hydrazone (0.5mmol,1eq), Selectfluor (354.3mg,1mmol,2eq) were added to a 25mL round bottom flask equipped with a magnetic stirrer and sealed with a rubber stopper; then acetonitrile (3mL) was added as a solvent with a syringe; the reaction flask was left to stir at room temperature for 16 hours and the progress of the reaction was monitored by Thin Layer Chromatography (TLC). After the reaction was completed, the reaction mixture was extracted twice with 20mL of ethyl acetate, and the organic phases were combined and washed with saturated brine, and then the organic phase was dried by adding anhydrous sodium sulfate. And (4) drying the organic phase after the drying is finished, and then carrying out decompression spin drying on the organic solvent to obtain a crude product. The crude product was purified using 9: and (3) carrying out column separation by using petroleum ether and ethyl acetate of the step 1 as eluent to obtain a final product. 3, 3-difluoro-1-allyl-2-indolone as a white solid in 60% yield (yield by¹⁹F NMR measurement).

¹H NMR(500MHz,CDCl₃):δ7.56(d,J＝7.5Hz,1H),7.46(t,J＝7.7Hz,1H),7.17(t,J＝7.7Hz,1H),6.89(d,J＝7.5Hz,1H),5.79-5.87(m,1H),5.29(d,J＝12.0Hz,2H),4.33(d,J＝5.5Hz,2H).

¹³C NMR(100MHz,CDCl₃):δ165.1(t,J＝31.0Hz),143.2(t,J＝6.9Hz),133.5,130.1,124.73,123.9(t,J＝1.5Hz),120.1(t,J＝22.5Hz),118.6,110.8(t,J＝248.5Hz),110.4,42.5.

¹⁹F NMR(376MHz,CDCl₃):δ-112.0(s,2F).

HRMS-ESI(m/z):Calcd for[M+H]⁺,210.0730.Found,210.0720.

Example 16

3, 3-difluoro-1-propargyl-2-indolone synthesis, separation and purification: 1-propargyl-isatin hydrazone (0.5mmol,1eq), Selectfluor (354.3mg,1mmol,2eq) were added to a 25mL round bottom flask equipped with a magnetic stirrer and sealed with a rubber stopper; then acetonitrile (3mL) was added as a solvent with a syringe; the reaction flask was left to stir at room temperature for 16 hours and the progress of the reaction was monitored by Thin Layer Chromatography (TLC). After the reaction is finished, extracting the reaction mixed system by 20mL ethyl acetate twice, and combiningThe organic phase was washed with saturated brine, and then the organic phase was dried by adding anhydrous sodium sulfate. And (4) drying the organic phase after the drying is finished, and then carrying out decompression spin drying on the organic solvent to obtain a crude product. The crude product was purified using 9: and (3) carrying out column separation by using petroleum ether and ethyl acetate of the step 1 as eluent to obtain a final product. 3, 3-difluoro-1-propargyl-2-indolone as a white solid in 95% yield (yield by¹⁹F NMR measurement).

¹H NMR(400MHz,CDCl₃):δ7.58(d,J＝7.2Hz,1H),7.54(t,J＝8.0Hz,1H),7.22(t,J＝7.6Hz,1H),7.13(d,J＝7.6Hz,1H),4.50(d,J＝2.4Hz,2H),2.31(t,J＝2.6Hz,1H).

¹³C NMR(125MHz,CDCl₃):δ164.3(t,J＝30.6Hz),142.1(t,J＝6.8Hz),133.6,124.7,124.3,120.0(t,J＝23.1Hz),110.8(t,J＝248.7Hz),110.6,75.4,73.5,29.5.

¹⁹F NMR(376MHz,CDCl₃):δ-111.4(s,2F).

HRMS-ESI(m/z):Calcd for[M+H]⁺,208.0564.Found,208.0674.

Example 17

3, 3-difluoro-1-hexyl-2-indolone synthesis, separation and purification: 1-hexyl-isatin hydrazone (0.5mmol,1eq), Selectfluor (354.3mg,1mmol,2eq) were added to a 25mL round bottom flask equipped with a magnetic stirrer and sealed with a rubber stopper; then acetonitrile (3mL) was added as a solvent with a syringe; the reaction flask was left to stir at room temperature for 16 hours and the progress of the reaction was monitored by Thin Layer Chromatography (TLC). After the reaction was completed, the reaction mixture was extracted twice with 20mL of ethyl acetate, and the organic phases were combined and washed with saturated brine, and then the organic phase was dried by adding anhydrous sodium sulfate. And (4) drying the organic phase after the drying is finished, and then carrying out decompression spin drying on the organic solvent to obtain a crude product. The crude product was purified using 9: and (3) carrying out column separation by using petroleum ether and ethyl acetate of the step 1 as eluent to obtain a final product. 3, 3-difluoro-1-hexyl-2-indolone as a white solid in 67% yield (yield by¹⁹F NMR measurement).

¹H NMR(400MHz,CDCl₃):δ7.55(d,J＝7.2Hz,1H),7.48(t,J＝7.4Hz,1H),7.16(t,J＝7.6Hz,1H),6.90(d,J＝8.0Hz,1H),3.68(t,J＝7.4Hz,2H),1.64-1.72(m,2H),1.30-1.34(m,6H),0.88(t,J＝7Hz,3H).

¹³C NMR(100MHz,CDCl₃):δ165.2(t,J＝30.0Hz),143.5(t,J＝7.0Hz),133.6,124.7,123.7(t,J＝2Hz),120.2(t,J＝23.0Hz),110.9(t,J＝248.0Hz),109.8,40.3,31.3,27.0,26.4,22.5,13.9.

¹⁹F NMR(376MHz,CDCl₃):δ-112.4(s,2F).

HRMS-FIA(m/z):Calcd for[M+H]+,254.1346.Found,254.1356.

Example 18

3, 3-difluoro-1-benzyl-2-indolone synthesis, separation and purification: 1-benzyl-isatin hydrazone (0.5mmol,1eq), Selectfluor (354.3mg,1mmol,2eq) were added to a 25mL round bottom flask equipped with a magnetic stirrer and sealed with a rubber stopper; then acetonitrile (3mL) was added as a solvent with a syringe; the reaction flask was left to stir at room temperature for 16 hours and the progress of the reaction was monitored by Thin Layer Chromatography (TLC). After the reaction was completed, the reaction mixture was extracted twice with 20mL of ethyl acetate, and the organic phases were combined and washed with saturated brine, and then the organic phase was dried by adding anhydrous sodium sulfate. And (4) drying the organic phase after the drying is finished, and then carrying out decompression spin drying on the organic solvent to obtain a crude product. The crude product was purified using 9: and (3) carrying out column separation by using petroleum ether and ethyl acetate of the step 1 as eluent to obtain a final product. 3, 3-difluoro-1-benzyl-2-indolone as a white solid in 89% yield (yield by¹⁹F NMR measurement).

¹H NMR(400MHz,CDCl₃):δ7.56(d,J＝7.2Hz,1H),7.28-7.39(m,6H),7.14(t,J＝7.6Hz,1H),6.77(d,J＝7.6Hz,1H),4.90(s,2H).

¹³C NMR(100MHz,CDCl₃):δ165.5(t,J＝30.0Hz),143.1(t,J＝7.0Hz),134.3,133.5,129.1,128.2,127.3,124.7,124.0(t,J＝2.0Hz),120.2(t,J＝23.0Hz),110.0(t,J＝248.0Hz),110.6,44.0.

¹⁹F NMR(376MHz,CDCl₃):δ-111.7(s,2F).

Example 19

3, 3-difluoro-1-chloroethyl-2-indolone synthesis, separation and purification: the substrate 1-chloroethyl-indigo was added separately to a 25mL round-bottomed flask equipped with a magnetic stirrerRed hydrazone (0.5mmol,1eq), Selectfluor (354.3mg,1mmol,2eq) and sealed with a rubber stopper; then acetonitrile (3mL) was added as a solvent with a syringe; the reaction flask was left to stir at room temperature for 16 hours and the progress of the reaction was monitored by Thin Layer Chromatography (TLC). After the reaction was completed, the reaction mixture was extracted twice with 20mL of ethyl acetate, and the organic phases were combined and washed with saturated brine, and then the organic phase was dried by adding anhydrous sodium sulfate. And (4) drying the organic phase after the drying is finished, and then carrying out decompression spin drying on the organic solvent to obtain a crude product. The crude product was purified using 9: and (3) carrying out column separation by using petroleum ether and ethyl acetate of the step 1 as eluent to obtain a final product. 3, 3-difluoro-1-chloroethyl-2-indolone as a white solid in 91% yield (yield by¹⁹F NMR measurement).

¹H NMR(400MHz,CDCl₃):δ7.57(d,J＝7.6Hz,1H),7.51(t,J＝7.8Hz,1H),7.20(t,J＝7.6Hz,1H),7.00(d,J＝8.0Hz,1H),4.05(t,J＝6.4Hz,2H),3.77(t,J＝6.4Hz,1H).

¹³C NMR(100MHz,CDCl₃):δ165.5(t,J＝26.0Hz),143.1(t,J＝7.0Hz),133.7,125.0,124.2,120.0(t,J＝22.5Hz),110.6(t,J＝247.5Hz),109.9,42.1,40.1.

¹⁹F NMR(376MHz,CDCl₃):δ-111.8(s,2F).

HRMS-ESI(m/z):Calcd for[M+H]⁺,232.0331.Found,232.0341.

Example 20

Synthesizing, separating and purifying 5-bromo-3, 3-difluoro-2-indolone: 5-bromo-isatin hydrazone (0.5mmol,1eq), Selectfluor (354.3mg,1mmol,2eq) were added to a 25mL round bottom flask equipped with a magnetic stirrer and sealed with a rubber stopper; then acetonitrile (3mL) was added as a solvent with a syringe; the reaction flask was left to stir at room temperature for 16 hours and the progress of the reaction was monitored by Thin Layer Chromatography (TLC). After the reaction was completed, the reaction mixture was extracted twice with 20mL of ethyl acetate, and the organic phases were combined and washed with saturated brine, and then the organic phase was dried by adding anhydrous sodium sulfate. And (4) drying the organic phase after the drying is finished, and then carrying out decompression spin drying on the organic solvent to obtain a crude product. The crude product was purified using 9: and (3) carrying out column separation by using petroleum ether and ethyl acetate of the step 1 as eluent to obtain a final product. 5-bromo-33-difluoro-2-indolone as a white solid in 80% yield (yield by¹⁹F NMR measurement).

¹H NMR(400MHz,DMSO-d₆):δ11.36(s,1H),7.96(s,1H),7.72(d,J＝8.4Hz,1H),6.96(d,J＝8.4Hz,1H).

¹³C NMR(100MHz,DMSO-d₆):δ166.2(t,J＝17.0Hz),139.9(t,J＝7.0Hz),136.6,128.4,122.0(t,J＝23.0Hz),116.6,113.1,110.1(t,J＝250.5Hz).

¹⁹F NMR(376MHz,DMSO-d₆):δ-111.0(s,2F).

Example 21

Synthesizing, separating and purifying 7-fluoro-3, 3-difluoro-2-indolone: 7-fluoro-isatin hydrazone (0.5mmol,1eq), Selectfluor (354.3mg,1mmol,2eq) were added to a 25mL round bottom flask equipped with a magnetic stirrer and sealed with a rubber stopper; then acetonitrile (3mL) was added as a solvent with a syringe; the reaction flask was left to stir at room temperature for 16 hours and the progress of the reaction was monitored by Thin Layer Chromatography (TLC). After the reaction was completed, the reaction mixture was extracted twice with 20mL of ethyl acetate, and the organic phases were combined and washed with saturated brine, and then the organic phase was dried by adding anhydrous sodium sulfate. And (4) drying the organic phase after the drying is finished, and then carrying out decompression spin drying on the organic solvent to obtain a crude product. The crude product was purified using 9: and (3) carrying out column separation by using petroleum ether and ethyl acetate of the step 1 as eluent to obtain a final product. 7-fluoro-3, 3-difluoro-2-indolone as a white solid in 91% yield (yield by¹⁹F NMR measurement).

¹H NMR(400MHz,DMSO-d₆):δ11.82(s,1H),7.47-7.55(m,2H),7.18-7.23(m,1H).

¹³C NMR(100MHz,DMSO-d₆):δ166.0(t,J＝29.0Hz),147.35(d,J＝243.0Hz),130.2-130.5(m),125.0(d,J＝6.0Hz),121.8-122.3(m),121.7(d,J＝7.0Hz),121.3(d,J＝4.0Hz),108.5-113.5(m).

¹⁹F NMR(376MHz,DMSO-d₆):δ-110.7,-131.1(s,2F).

HRMS-ESI(m/z):Calcd for[M+H]⁺,188.0316.Found,188.0323.

Example 22

7-chloro-3And 3, synthesis, separation and purification of 3-difluoro-2-indolone: 7-chloro-isatin hydrazone (0.5mmol,1eq), Selectfluor (354.3mg,1mmol,2eq) were added to a 25mL round bottom flask equipped with a magnetic stirrer and sealed with a rubber stopper; then acetonitrile (3mL) was added as a solvent with a syringe; the reaction flask was left to stir at room temperature for 16 hours and the progress of the reaction was monitored by Thin Layer Chromatography (TLC). After the reaction was completed, the reaction mixture was extracted twice with 20mL of ethyl acetate, and the organic phases were combined and washed with saturated brine, and then the organic phase was dried by adding anhydrous sodium sulfate. And (4) drying the organic phase after the drying is finished, and then carrying out decompression spin drying on the organic solvent to obtain a crude product. The crude product was purified using 9: and (3) carrying out column separation by using petroleum ether and ethyl acetate of the step 1 as eluent to obtain a final product. 7-chloro-3, 3-difluoro-2-indolone as a white solid in 97% yield (yield by¹⁹F NMR measurement).

¹H NMR(400MHz,DMSO-d₆):δ11.73(s,1H),7.62-7.68(m,2H),7.20(t,J＝7.8Hz,1H).

¹³C NMR(100MHz,DMSO-d₆):δ166.3(t,J＝29.0Hz),140.8(t,J＝7.5Hz),134.5,125.2,124.0,121.4(t,J＝23.0Hz),116.4,111.3(t,J＝248.0Hz).

¹⁹F NMR(376MHz,DMSO-d₆):δ-110.2(s,2F).

HRMS-ESI(m/z):Calcd for[M+H]⁺,205.9834.Found,225.9847.

Example 23

Synthesizing, separating and purifying 5, 6-difluoro-3, 3-difluoro-2-indolone: 5, 6-difluoro-isatin hydrazone (0.5mmol,1eq), Selectfluor (354.3mg,1mmol,2eq) were added separately to a 25mL round bottom flask equipped with a magnetic stirrer and sealed with a rubber stopper; then acetonitrile (3mL) was added as a solvent with a syringe; the reaction flask was left to stir at room temperature for 16 hours and the progress of the reaction was monitored by Thin Layer Chromatography (TLC). After the reaction was completed, the reaction mixture was extracted twice with 20mL of ethyl acetate, and the organic phases were combined and washed with saturated brine, and then the organic phase was dried by adding anhydrous sodium sulfate. And (4) drying the organic phase after the drying is finished, and then carrying out decompression spin drying on the organic solvent to obtain a crude product. The crude product was purified using 9: 1 petroleum ether and ethyl acetate as eluent to carry out column chromatographySeparating to obtain the final product. 5, 6-difluoro-3, 3-difluoro-2-indolone as a white solid in 66% yield (yield by¹⁹F NMR measurement).

¹H NMR(500MHz,DMSO-d₆):δ11.39(s,1H),8.03(t,J＝8.5Hz,1H),7.09-7.13(m,1H).

¹³C NMR(100MHz,DMSO-d₆):δ166.2(t,J＝29.0Hz),152.2-154.9(m),145.3-147.8(m),140.3-140.6(m),115.8(d,J＝21.0Hz),115.0-115.5(m),110.9(t,J＝248.0Hz),102.8(d,J＝23.0Hz).

¹⁹F NMR(376MHz,DMSO-d₆):δ-110.5(s,2F),-128.7,-144.8.

HRMS-ESI(m/z):Calcd for[M+H]⁺,206.0220.Found,206.0229.

Example 24

Synthesizing, separating and purifying 7-trifluoromethyl-3, 3-difluoro-2-indolone: 7-trifluoromethyl-isatin hydrazone (0.5mmol,1eq), Selectfluor (354.3mg,1mmol,2eq) were added to a 25mL round bottom flask equipped with a magnetic stirrer and sealed with a rubber stopper; then acetonitrile (3mL) was added as a solvent with a syringe; the reaction flask was left to stir at room temperature for 16 hours and the progress of the reaction was monitored by Thin Layer Chromatography (TLC). After the reaction was completed, the reaction mixture was extracted twice with 20mL of ethyl acetate, and the organic phases were combined and washed with saturated brine, and then the organic phase was dried by adding anhydrous sodium sulfate. And (4) drying the organic phase after the drying is finished, and then carrying out decompression spin drying on the organic solvent to obtain a crude product. The crude product was purified using 9: and (3) carrying out column separation by using petroleum ether and ethyl acetate of the step 1 as eluent to obtain a final product. 7-trifluoromethyl-3, 3-difluoro-2-indolone as a white solid in 95% yield (yield by¹⁹F NMR measurement).

¹H NMR(400MHz,DMSO-d₆):δ11.74(s,1H),8.00(d,J＝7.6Hz,1H),7.85(d,J＝8.0Hz,1H),7.37(d,J＝7.8Hz,1H).

¹³C NMR(100MHz,DMSO-d₆):δ166.6(t,J＝29.0Hz),140.6(t,J＝7.5Hz),130.9(d,J＝4.0Hz),129.4,123.2(q,J＝270.0Hz),124.1,121.3(t,J＝23.0Hz),113.3(q,J＝33.5Hz),109.9(t,J＝246.5Hz).

¹⁹F NMR(376MHz,DMSO-d₆):δ-60.3(s,3F),-110.2(s,2F).

HRMS-ESI(m/z):Calcd for[M+H]⁺,238.0285.Found,238.0291.

Example 25

Synthesizing, separating and purifying 5-nitro-3, 3-difluoro-2-indolone: 5-Nitro-isatin hydrazone (0.5mmol,1eq), Selectfluor (354.3mg,1mmol,2eq) were added to a 25mL round bottom flask equipped with a magnetic stirrer and sealed with a rubber stopper; then acetonitrile (3mL) was added as a solvent with a syringe; the reaction flask was left to stir at room temperature for 16 hours and the progress of the reaction was monitored by Thin Layer Chromatography (TLC). After the reaction was completed, the reaction mixture was extracted twice with 20mL of ethyl acetate, and the organic phases were combined and washed with saturated brine, and then the organic phase was dried by adding anhydrous sodium sulfate. And (4) drying the organic phase after the drying is finished, and then carrying out decompression spin drying on the organic solvent to obtain a crude product. The crude product was purified using 9: and (3) carrying out column separation by using petroleum ether and ethyl acetate of the step 1 as eluent to obtain a final product. 5-Nitro-3, 3-difluoro-2-indolone as a white solid in 70% yield (yield by¹⁹F NMR measurement).

¹H NMR(400MHz,DMSO-d₆):δ11.92(s,1H),8.60(s,1H),8.44(d,J＝8.8Hz,1H),7.18(d,J＝13.6Hz,1H).

¹³C NMR(125MHz,DMSO-d₆):δ166.4(t,J＝28.7Hz),149.1(t,J＝7.5Hz),143.6,131.1,121.5,120.2(t,J＝23.1Hz),112.9,110.4(t,J＝248.7Hz).

¹⁹F NMR(376MHz,DMSO-d₆):δ-111.6(s,2F).

Compared with example 1, the present invention also screens the ranges of the materials and parameters as described in table 1, specifically as follows:

TABLE 1

As can be seen from experiments 1-5 of Table 1, dichloroethane is the best solvent to obtain monofluorinated products and acetonitrile is the best solvent to obtain difluorinated products. From experiments 5-9, it is clear that lithium acetate is the most preferred base and that the best results are obtained under the same conditions. Experiments 10 and 11 found that other fluorinating agents, such as SelectflurII and NFSI, did not yield fluorinated products. The optimum material ratio of the isatin hydrazone to obtain the monofluoro product is found by experiments 12 and 13 as follows: isatin hydrazone: selectflour lithium acetate ═ 1:2: 6. It is shown by experiment 14 that a lower initial reaction concentration favors a high selectivity towards the monofluoro product. From experiments 15 to 18, it is found that the reaction proceeds favorably under room temperature conditions without adding a base in the conditions for obtaining a difluoride product from an acetonitrile solution. By optimizing the conditions of the monofluorination and the bifluorination of the isatin hydrazone, the optimal conditions of the monofluorination of the isatin hydrazone are as follows: 0.5mmol of isatin hydrazone, 13mL of dichloroethane as a solvent, Selectflur (2eq), lithium acetate (6eq) at 70 ℃ for 16 hours; the optimal conditions for obtaining the isatin hydrazone bifluoride are as follows: 0.5mmol of isatin hydrazone, 3mL of acetonitrile as a solvent, Selectflur (2eq), was reacted at room temperature for 16 hours. Subsequently, the optimal conditions obtained by condition screening are applied to different substrates, wherein part of the substrates need to be subjected to fine adjustment on the optimal conditions. For example, the initial concentration of the reaction can be increased for a substrate with a protective group on nitrogen, (0.5mmol of isatin hydrazone, 3mL of dichloroethane as a solvent) can also obtain high yield of monofluorine; in the case of a substrate having a nitro group substituted at the 5-position, it is necessary to heat the substrate to 50 ℃ or the like because of poor solubility.

Claims

1. The method for selectively fluorinating the isatin hydrazone compound is characterized in that the isatin hydrazone compound with the structural formula of formula 1 and a fluorinating agent are subjected to a fluorination reaction to prepare a fluorinated isatin product with the structural formula of formula 2:

R₁~R₅independently H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C6-C10 aryl, benzylC5-C10 saturated or partially unsaturated cycloalkyl, C5-C10 saturated or partially unsaturated heterocyclic alkyl, C5-C10 heterocyclic aryl, halogen or nitro;

the alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclic alkyl and heterocyclic aryl are selectively provided with at least one substituent of halogen, C1-C6 alkoxy and C1-C6 alkyl;

said R₆Is H or F;

the reaction solvent of the fluorination reaction is dichloroethane, alkali is added in the reaction, and R is selectively obtained₆A fluorinated isatin product that is H; the alkali is lithium acetate;

the reaction solvent of the fluorination reaction is acetonitrile, and R is selectively obtained₆Is a fluorinated isatin product of F.

2. The method for selectively fluorinating an isatin hydrazone compound according to claim 1, wherein the molar concentration of the isatin hydrazone compound in the initial solution system of the fluorination reaction is 0.04 to 0.2 mol/L.

3. The method for selectively fluorinating an isatin hydrazone compound according to claim 1, wherein the molar ratio of the fluorinating agent to the isatin hydrazone compound is 2 to 4: 1.

4. The method of selectively fluorinating an isatin hydrazone compound according to claim 1, wherein the amount of the base added is 5.5 to 6.5 times the molar amount of the isatin hydrazone compound.

5. The selective fluorination method of an isatin hydrazone compound according to claim 1, wherein the fluorination reaction is carried out at a temperature of 0 to 80 ℃.

6. The selective fluorination method of an isatin hydrazone compound according to claim 5, wherein the fluorination reaction time is 12 to 18 hours.

7. The method of selectively fluorinating an isatin hydrazone compound according to claim 1, wherein the isatin hydrazone compound of formula 1 has the formula 1-a, formula 1-B, or formula 1-C:

R₁is C1-C6 alkyl, allyl, propargyl, phenyl, benzyl or chloroethyl;

R₂is alkyl of H, C1-C6, halogen or nitro;

R₃is H or halogen;

R₄is H, halogen or trifluoromethyl.

8. The selective fluorination process of isatin hydrazone compounds of claim 7 wherein R is₁Selected from methyl, isopropyl, allyl, propargyl, phenyl, benzyl or chloroethyl;

R₂selected from hydrogen, methyl, fluorine, chlorine or bromine;

R₃selected from fluorine; r₄Selected from fluorine, bromine, chlorine or trifluoromethyl.

9. The selective fluorination process of an isatin hydrazone compound according to claim 7,

reacting a compound of formula 1-A, 1-chloromethyl-4-fluoro-1, 4-diazabicyclo [2.2.2]The octane bis (tetrafluoroborate) salt and alkali are subjected to fluorination reaction in dichloroethane to prepare R₆Fluorinated isatin product as H: wherein the molar concentration of the formula 1-A in an initial solution system is 0.1-0.2mol/L, the reaction temperature is 70-80 ℃, and the molar ratio of alkali to the formula 1-A is 5.5-6.5; the molar ratio of the fluorinating agent to the formula 1-A is 2-4: 1;

or, 1-B, 1-chloromethyl-4-fluoro-1, 4-diazabicyclo [2.2.2]The octane bis (tetrafluoroborate) salt and alkali are subjected to fluorination reaction in dichloroethane to prepare R₆Fluorinated isatin product as H: wherein, formulaThe molar concentration of the 1-B in an initial solution system is 0.04-0.1 mol/L, the reaction temperature is 70-75 ℃, and the molar ratio of alkali to the formula 1-B is 5.5-6.5; the molar ratio of the fluorinating agent to the formula 1-B is 2-4: 1.

10. The method of selectively fluorinating an isatin hydrazone compound according to claim 7, wherein the isatin hydrazone compound is prepared by reacting

1-chloromethyl-4-fluoro-1, 4-diazabicyclo [2.2.2] starting material of at least one of the formulae 1-A or 1-B]Octane bis (tetrafluoroborate) salt in CH₃Fluorination reaction in CN to obtain R₆Fluorinated isatin product as F: the molar concentration of the raw materials in an initial solution system is 0.1-0.2mol/L, and the reaction temperature is 0-60 ℃; the molar ratio of the fluorinating agent to the raw material is 2-4: 1;

or, reacting a compound of formula 1-C, 1-chloromethyl-4-fluoro-1, 4-diazabicyclo [2.2.2]Octane bis (tetrafluoroborate) salt in CH₃Fluorination reaction in CN to obtain R₆Fluorinated isatin product as F: the molar concentration of the formula 1-C in an initial solution system is 0.1-0.2mol/L, and the reaction temperature is 50-60 ℃; the molar ratio of the fluorinating agent to the compound represented by the formula 1-C is 2-4: 1.

11. The method for selectively fluorinating an isatin hydrazone compound according to any one of claims 1 to 10, wherein the isatin hydrazone compound is obtained by reacting an isatin hydrazone compound of formula 3 with hydrazine hydrate:

R₁~R₅independently H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C6-C10 aryl, C5-C10 saturated or partially unsaturated cycloalkyl, C5-C10 saturated or partially unsaturated heterocyclic alkyl, C5-C10 heterocyclic aryl, halogen and nitro;

the alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclic alkyl and heterocyclic aryl are selectively provided with at least one substituent of halogen, C1-C6 alkoxy and C1-C6 alkyl.