Method for synthesizing 5-cyano-2-fluorophenyl compound based on continuous flow reaction technology

Abstract

The invention belongs to the technical field of compound synthesis, and discloses a method for synthesizing a 5-cyano-2-fluorophenyl compound based on a continuous flow reaction technology. The method adopts a continuous flow reaction device for synthesis, and comprises the following steps: carrying out lithium hydrogen exchange reaction on 4-fluorobenzonitrile and an organic lithium reagent in a first solvent to generate 5-cyano-2-fluorophenyl lithium; then carrying out nucleophilic substitution reaction on the 5-cyano-2-fluorophenyl lithium and an electrophilic reagent in a second solvent; after the reaction is finished, quenching is carried out, and the 5-cyano-2-fluorophenyl compound is prepared. According to the method provided by the invention, feeding and reaction are carried out under a controllable continuous condition, so that the reaction process is easier to control. According to the method, the production efficiency is improved, the danger coefficient existing in the amplification reaction of the organic lithium reagent is reduced, and the amplification reaction and industrial production are facilitated; and the purity and the yield of the target product are also greatly improved.

Description

Technical Field

[0001] The present invention belongs to the technical field of compound synthesis, and particularly relates to a method for synthesizing 5-cyano-2-fluorophenyl compounds based on continuous flow reaction technology. Background Art

[0002] Due to their special physical and chemical properties, fluorophenyl compounds are widely used in multiple industrial fields, especially in chemical synthesis, the electronics industry, and the pharmaceutical industry. The high electronegativity and chemical stability of fluorophenyl compounds make them precursors for certain special electronic materials. They can be used to manufacture organic electronic components, such as materials in organic optoelectronic devices, and some special insulating materials. Since the introduction of fluorine can greatly change the biological activity of molecules, fluorophenyl compounds are also important intermediates in drug synthesis and are widely used in the synthesis of fluorinated drugs, especially in the research of anti-cancer and antiviral drugs. As a common functional group, the cyano group exhibits diverse reaction characteristics in the field of organic synthesis. It can not only undergo hydrolysis, reduction, addition, and cyclization reactions, but is also one of the important means for increasing the carbon chain. Among fluorophenyl compounds, 5-cyano-2-fluorophenyl compounds are important intermediates for synthesizing numerous bioactive molecules, drugs, materials, etc. For example, 5-cyano-2-fluorophenylboronic acid is used as an intermediate for organic electroluminescent devices; 5-cyano-2-fluorobenzoic acid and its downstream 5-cyano-N-(3,4-difluorobenzyl)-2-fluorobenzamide are important building blocks for synthesizing PDK1 inhibitors; 5-cyano-2-fluorobenzaldehyde and its downstream 3-ethyl-4-fluorobenzonitrile can be used to prepare a class of heat shock protein 90 inhibitors, and so on.

[0003] The most economical synthetic route for 5-cyano-2-fluorophenyl compounds is to use 4-fluorobenzonitrile as a substrate, lithiate and deprotonate to prepare 5-cyano-2-fluorophenyllithium, and then carry out a nucleophilic substitution reaction. However, this synthetic route requires ultra-low temperature (-78 °C), which makes it difficult to scale up the production; moreover, the intermediate 5-cyano-2-fluorophenyllithium is extremely unstable and needs to be prepared at low temperature, and the reaction process is not easy to control. The structure temperature of o-fluorophenyllithium will form benzyne and release heat rapidly when it is higher than -50 °C, with the risk of material overflow or even explosion; in addition, in traditional methods, the reaction time for preparing 5-cyano-2-fluorophenyl compounds is long, the yield and purity are low, the yield is difficult to exceed 60%, and it is even impossible to reach 75%.

[0004] Therefore, researching a synthetic method with lower temperature requirements, high reaction efficiency, easier reaction process control, and capable of improving the product purity and yield is of great significance for the preparation and application of 5-cyano-2-fluorophenyl compounds. Summary of the Invention

[0005] The present invention aims to solve at least one of the technical problems existing in the above-mentioned prior art. To this end, the present invention establishes a method for synthesizing 5-cyano-2-fluorophenyl compounds based on continuous flow reaction technology. This method has lower temperature requirements, high reaction efficiency, easier control of the reaction process, and is safe and reliable, and can improve the purity and yield of the product.

[0006] The present invention provides a method for synthesizing 5-cyano-2-fluorophenyl compounds based on continuous flow reaction technology.

[0007] Specifically, a method for synthesizing 5-cyano-2-fluorophenyl compounds based on continuous flow reaction technology, which is synthesized using a continuous flow reaction device, includes the following steps:

[0008] 4-Fluorobenzonitrile undergoes a lithiation reaction with an organolithium reagent in a first solvent to generate 5-cyano-2-fluorophenyllithium; then the 5-cyano-2-fluorophenyllithium and an electrophile undergo a nucleophilic substitution reaction in a second solvent; after the reaction is completed, a quenching agent is used for quenching to obtain 5-cyano-2-fluorophenyl compounds;

[0009] The reaction route of the method provided by the present invention is as follows:

[0010]

[0011] Among them, R = X, R1R2(OH) or Si(R3)3, X is one of Cl, Br, I, R1 is H or CH3, and R2 is C 2-9 a straight-chain or branched alkyl group, a C 4-9 cycloalkyl group, phenyl group, pyridyl group, furyl group, or thienyl group; R3 is one of methyl, ethyl, or isopropyl;

[0012] The organolithium reagent is at least one of butyllithium, lithium diisopropylamide, lithium hexamethyldisilazide, pentamethyldiethylenetriamine-butyllithium complex, and tetramethylpiperidine magnesium chloride lithium chloride;

[0013] The temperature of the lithiation reaction is -60 to -25 °C;

[0014] The temperature of the nucleophilic substitution reaction is -60 to -25 °C.

[0015] In some embodiments of the present invention, the first solvent and the second solvent are each independently selected from at least one of tetrahydrofuran, 2-methyltetrahydrofuran, toluene, diethyl ether, methyl tert-butyl ether, and ethylene glycol dimethyl ether; preferably, the first solvent and the second solvent are each independently selected from at least one of tetrahydrofuran, methyl tert-butyl ether, and ethylene glycol dimethyl ether; more preferably, the first solvent and the second solvent are tetrahydrofuran and ethylene glycol dimethyl ether. The mass ratio of the tetrahydrofuran to the ethylene glycol dimethyl ether is (2 - 5):1.

[0016] In some embodiments of the present invention, the electrophilic reagent is selected from one of iodine, hexachloroethane, bromine, 1,2-dibromo-1,1,2,2-tetrafluoroethane, carbonyl compounds, and alkylsilane compounds. Among them, the carbonyl compounds include heteroaromatic aldehydes, heteroaromatic ketones, C 3-10 alkyl and cycloalkyl aldehydes with 3-10 alkyl and cycloalkyl ketones with. The alkylsilane compounds include trimethylchlorosilane, triethylchlorosilane, triisopropylchlorosilane, etc.

[0017] In some embodiments of the present invention, the quenching agent is selected from at least one of water, saturated ammonium chloride, dilute hydrochloric acid, dilute sulfuric acid, formic acid, acetic acid, and citric acid.

[0018] In some embodiments of the present invention, the concentration of 4-fluorobenzonitrile is 0.5 mol / L - 3 mol / L; preferably, the concentration of 4-fluorobenzonitrile is 0.5 mol / L - 2 mol / L. Such as 0.8 mol / L - 1.5 mol / L.

[0019] In some embodiments of the present invention, the concentration of the organolithium reagent is 0.5 mol / L - 3 mol / L; preferably, the concentration of the organolithium reagent is 0.5 mol / L - 2 mol / L. Such as 0.8 mol / L - 1.5 mol / L.

[0020] In some embodiments of the present invention, the molar ratio of the 4-fluorobenzonitrile to the organolithium reagent is 1:(0.9 - 1.2).

[0021] In some embodiments of the present invention, the temperature of the lithiation reaction is -60 to -40 °C, and the time of the lithiation reaction is 0.5 - 2 min.

[0022] In some embodiments of the present invention, the concentration of the electrophilic reagent is 0.3 mol / L - 3 mol / L; preferably, the concentration of the electrophilic reagent is 0.5 mol / L - 2 mol / L. Such as 0.5 mol / L - 1 mol / L.

[0023] In some embodiments of the present invention, the molar ratio of the electrophilic reagent to the 4-fluorobenzonitrile is (0.9 - 2.0):1.

[0024] In some embodiments of the present invention, the temperature of the nucleophilic substitution reaction is -60 to -40 °C, and the time of the nucleophilic substitution reaction is 0.5 - 3 min.

[0025] In some embodiments of the present invention, the molar ratio of the quenching agent to the 4-fluorobenzonitrile is (1.1 - 5):1.

[0026] In some embodiments of the present invention, the temperature of the quenching is -30 to 10 °C.

[0027] In some embodiments of the present invention, the continuous flow reaction device includes:

[0028] Liquid delivery pumps, including a first liquid delivery pump, a second liquid delivery pump, and a third liquid delivery pump;

[0029] Mixers, the mixer includes a first mixer and a second mixer, the first liquid delivery pump and the second liquid delivery pump are respectively connected to the first mixer; the third liquid delivery pump is connected to the second mixer;

[0030] Reaction tubes, the reaction tube includes a first reaction tube and a second reaction tube, the first reaction tube is located between the first mixer and the second mixer;

[0031] Quenching device, the quenching device is connected to the second mixer, and the second reaction tube is located between the second mixer and the quenching device;

[0032] Temperature control system, the liquid delivery pumps, the mixers, the reaction tubes, and the quenching device are controlled by the temperature control system.

[0033] In some embodiments of the present invention, the continuous flow reaction device further includes raw material tanks, the raw material tanks include a 4-fluorobenzonitrile raw material tank, an organolithium reagent raw material tank, and an electrophilic reagent raw material tank. The 4-fluorobenzonitrile raw material tank, the organolithium reagent raw material tank, and the electrophilic reagent raw material tank are respectively connected to the first liquid delivery pump, the second liquid delivery pump, and the third liquid delivery pump.

[0034] In some embodiments of the present invention, the continuous flow reaction device further includes a product receiving device, the product receiving device is connected to the quenching device, and is used to receive the crude product of the synthesized 5-cyano-2-fluorophenyl compound.

[0035] More specifically, a method for synthesizing a 5-cyano-2-fluorophenyl compound based on continuous flow reaction technology includes the following steps:

[0036] Under a protective atmosphere, 4-fluorobenzonitrile and an organolithium reagent are respectively pumped into the first mixer of the continuous flow reaction device at a flow rate of 10 - 100 mL / min, and mixed at -60°C to -25°C to obtain a first mixed material. The first mixed material undergoes a lithium-hydrogen exchange reaction through a first reaction tube to generate 5-cyano-2-fluorophenyllithium; the 5-cyano-2-fluorophenyllithium further reacts with an electrophilic reagent pumped into a second mixer at a flow rate of 10 - 100 mL / min and is mixed at -60°C to -25°C to obtain a second mixed material; the second mixed material undergoes a nucleophilic substitution reaction through a second reaction tube. After the reaction is completed, it is quenched by the quenching agent in a quenching device to obtain a crude product of 5-cyano-2-fluorophenyl compound.

[0037] In some embodiments of the present invention, the flow rate of the pumped 4-fluorobenzonitrile is 10 - 40 mL / min; the flow rate of the pumped organolithium reagent is 15 - 40 mL / min; the flow rate of the pumped electrophilic reagent is 15 - 60 mL / min.

[0038] It should be understood that the time of the lithium-hydrogen exchange reaction is the residence time of the first mixed material in the first reaction tube, and the residence time is 0.5 - 2 min, such as 1 min or 2 min. The time of the nucleophilic substitution reaction is the residence time of the second mixed material in the second reaction tube, and the residence time is 0.5 - 3 min, such as 1 min or 2 min.

[0039] It should be noted that before the continuous flow reaction, it is necessary to ensure that the pipeline is filled with solvent under dry conditions, and measure and calibrate the flow rate of the liquid delivery pump.

[0040] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0041] The method for synthesizing 5-cyano-2-fluorophenyl compound provided by the present invention uses a continuous flow reaction device for synthesis, feeds materials and reacts under controllable continuous conditions, making the reaction process easier to control. This method not only simplifies the process flow, improves production efficiency, reduces the risk coefficient of the scale-up reaction of organolithium reagents, has a lower temperature requirement, reduces the energy consumption required for the reaction, and is beneficial to scale-up reaction and industrial production; but also greatly improves the purity and yield of 5-cyano-2-fluorophenyl compound. BRIEF DESCRIPTION OF THE DRAWINGS

[0042] Figure 1 It is a schematic diagram of the continuous flow reaction device for synthesizing 5-cyano-2-fluorophenyl compound in the embodiment of the present invention;

[0043] Description of the attached reference numerals: 1 is the raw material tank for 4-fluorobenzonitrile, 3 is the raw material tank for organolithium reagent, 5 is the raw material tank for electrophilic reagent, 2 is the first liquid transfer pump, 4 is the second liquid transfer pump, 6 is the third liquid transfer pump, 7 is the first mixer, 8 is the first reaction tube, 9 is the second mixer, 10 is the second reaction tube, 11 is the quenching device, and 12 is the product receiving device. Detailed implementation manners

[0044] In order to make those skilled in the art more clearly understand the technical solutions of the present invention, the following examples are listed for illustration. It should be noted that the following examples do not limit the scope of protection required by the present invention.

[0045] The raw materials, reagents or devices used in the following examples and comparative examples can be obtained from conventional commercial channels or can be obtained by existing known methods without special instructions.

[0046] A method for synthesizing 5-cyano-2-fluorophenyl compounds based on continuous flow reaction technology provided by an embodiment of the present invention is synthesized using a continuous flow reaction device. As Figure 1 shown, the continuous flow reaction device includes: a raw material tank, a liquid transfer pump, a mixer, a reaction tube, a quenching device 11, a product receiving device 12, and a temperature control system. Among them, the raw material tank specifically includes a raw material tank 1 for 4-fluorobenzonitrile, a raw material tank 3 for organolithium reagent, and a raw material tank 5 for electrophilic reagent; the liquid transfer pump specifically includes a first liquid transfer pump 2, a second liquid transfer pump 4, and a third liquid transfer pump 6; the raw material tank 1 for 4-fluorobenzonitrile, the raw material tank 3 for organolithium reagent, and the raw material tank 5 for electrophilic reagent are respectively connected to the first liquid transfer pump 2, the second liquid transfer pump 4, and the third liquid transfer pump 6. The mixer specifically includes a first mixer 7 and a second mixer 9, and the first liquid transfer pump 2 and the second liquid transfer pump 4 are respectively connected to the first mixer 7; the third liquid transfer pump 6 is connected to the second mixer 9. The reaction tube includes a first reaction tube 8 and a second reaction tube 10, and the first reaction tube 8 is located between the first mixer 7 and the second mixer 9. The reaction tube is selected from PTFE Teflon tube or 316 stainless steel tube. The quenching device 11 is connected to the second mixer 9, and the second reaction tube 10 is located between the second mixer 9 and the quenching device 11. The product receiving device 12 is connected to the quenching device 11 for receiving the crude product of the synthesized 5-cyano-2-fluorophenyl compound. The liquid transfer pump, the mixer, the reaction tube, and the quenching device 11 are controlled by a temperature control system.

[0047] The method for synthesizing 5-cyano-2-fluorophenyl compounds based on continuous flow reaction technology provided by an embodiment of the present invention uses the above continuous flow reaction device to prepare 5-cyano-2-fluorophenyl compounds, balances the system pressure with a protective atmosphere (such as nitrogen), and uses a liquid transfer pump for continuous feeding and discharging to achieve continuous production. The specific synthesis process is as follows in the following examples.

[0048] Example 1

[0049] A method for synthesizing 3-iodo-4-fluorobenzonitrile based on continuous flow reaction technology, and its structural formula is: It includes the following steps:

[0050] 4-Fluorobenzonitrile is diluted with tetrahydrofuran to form a 1.0 mol / L solution and loaded into the 4-fluorobenzonitrile raw material tank 1; the organolithium reagent is commercially available 1.0 mol / L lithium diisopropylamide, which is loaded into the organolithium reagent raw material tank 3; the electrophilic reagent iodine is diluted with tetrahydrofuran to form a 0.5 mol / L solution and loaded into the electrophilic reagent raw material tank 5.

[0051] The first liquid delivery pump 2 pumps 4-fluorobenzonitrile at a flow rate of 20 ml / min, and the second liquid delivery pump 4 pumps lithium diisopropylamide at a flow rate of 22 mL / min into the first mixer 7 at the same time. The temperature of the first mixer 7 is controlled at -50°C, and the first mixed material is obtained by mixing. The first mixed material passes through the first reaction tube 8 and undergoes a lithium-hydrogen exchange reaction at -50°C, and the residence time is controlled at 1 min to generate 5-cyano-2-fluorophenyllithium. 5-Cyano-2-fluorophenyllithium further mixes with 0.5 mol / L iodine pumped into the second mixer 9 at a flow rate of 44 mL / min at -50°C to obtain a second mixed material; the second mixed material passes through the second reaction tube 10 for a nucleophilic substitution reaction, and the residence time is controlled at 1 min. To ensure the experimental results, the reaction liquid in the early stage is discarded for 1 minute, and the stabilized reaction liquid is collected for 3 minutes. The reaction liquid is pumped into the quenching device 11 and quenched in 10% hydrochloric acid to obtain the crude product of 3-iodo-4-fluorobenzonitrile, which is received by the product receiving device 12. The crude product of 3-iodo-4-fluorobenzonitrile is separated by liquid separation. The obtained aqueous phase is extracted with ethyl acetate, and the obtained organic phase is washed with an aqueous solution of sodium thiosulfate. Finally, the organic phases are combined, dried, concentrated, and purified by column chromatography to obtain 9.9 g of white solid. After testing, the GC purity is 98.2%, the yield is 67.3%, and the GCMS m / z is 247 (all the following results are measured by Agilent 5975 inert MSD).

[0052] Example 2

[0053] This example provides a method for synthesizing 3-iodo-4-fluorobenzonitrile based on continuous flow reaction technology. The difference between this example and Example 1 is that 1.0 mol / L lithium diisopropylamide as the organolithium reagent is replaced with a 1.0 mol / L solution of magnesium chloride lithium tetramethylpiperidine chloride. And to ensure the experimental results, the reaction liquid in the early stage is discarded for 1 minute, and the stabilized reaction liquid is collected for 3 minutes. The other steps are the same as those in Example 1. Finally, 8.9 g of white solid product is obtained. After testing, the GC purity is 98.1%, and the yield is 60.3%.

[0054] Example 3

[0055] This example provides a method for synthesizing 3-iodo-4-fluorobenzonitrile using continuous flow reaction technology. This example differs from Example 1 in that 1.0 mol / L of the organolithium reagent lithium diisopropylamide is replaced with 1.0 mol / L pentamethyldiethylenetriamine-butyllithium complex. The remaining steps are the same as in Example 1. The resulting product is a white solid (9.6 g), with a GC purity of 98.5% and a yield of 64.9%.

[0056] Example 4

[0057] This example provides a method for synthesizing 3-iodo-4-fluorobenzonitrile using a continuous flow reaction technique. This example differs from Example 1 in that the tetrahydrofuran solvent used to dissolve 4-fluorobenzonitrile and elemental iodine is replaced with a 3:1 mass ratio of tetrahydrofuran to ethylene glycol dimethyl ether. The remaining steps are the same as in Example 1. The resulting product is a white solid (10.4 g), with a GC purity of 99.0% and a yield of 70.3%.

[0058] As shown in Example 4, when other conditions are the same, when tetrahydrofuran (THF) and ethylene glycol dimethyl ether (EGDE) are used as common solvents, the GC purity of the synthesized 3-iodo-4-fluorobenzonitrile is increased from 98.2% to 99.0%, and the yield is increased from 67.3% to 70.3%. Research has found that when tetrahydrofuran (THF) and EGDE are selected as common solvents and the mass ratio of the two is controlled to be (2-5): 1, the purity and yield of the synthesized 5-cyano-2-fluorophenyl compound can be further improved. The EGDE with two ether oxygen atoms and the tetrahydrofuran with a cyclic structure and a monoether oxygen atom act together, not only can dissolve the reactants and reaction products well, but also can better stabilize the intermediate, reduce the generation of by-products, and can improve the purity and yield of the 5-cyano-2-fluorophenyl compound in a continuous flow reaction.

[0059] Example 5

[0060] A method for synthesizing 4-fluoro-3-hydroxybenzylbenzonitrile based on continuous flow reaction technology, the structural formula of which is: The difference from Example 1 was that the 0.5 mol / L iodine solution was replaced with a 1.0 mol / L benzaldehyde solution (the solvent was the same as in Example 1), and the flow rate into the second mixer 9 was reduced to 18 mL / min. The remaining steps were the same as in Example 1. The product was finally obtained as a white solid (10.1 g). GC purity was 99.3%, yield was 82.3%, and GCMS m / z was 227.

[0061] Example 6

[0062] This example provides a method for synthesizing 4-fluoro-3-hydroxybenzyl benzonitrile based on continuous flow reaction technology. The difference between this example and Example 5 is that the solvent for dissolving 4-fluorobenzonitrile and benzaldehyde, tetrahydrofuran, is replaced with a mixture of tetrahydrofuran and ethylene glycol dimethyl ether with a mass ratio of 3:1. The remaining steps are the same as those in Example 5. Finally, 10.7 g of white solid product is obtained. After testing, the GC purity is 99.4% and the yield is 87.2%.

[0063] Example 7

[0064] A method for synthesizing 4-fluoro-3-((3-bromophenyl)hydroxymethyl)benzonitrile based on continuous flow reaction technology, and its structural formula is:

[0065] The difference from Example 5 is that the 1.0 mol / L benzaldehyde solution is replaced with a 1.0 mol / L 3-bromobenzaldehyde solution (the solvent is the same as that in Example 5). The remaining steps are the same as those in Example 5. Finally, 10.8 g of white solid product is obtained. After testing, the GC purity is 99.1% and the yield is 65.7%.

[0066] 1 H NMR(400MHz,CDCl3)δ=7.93(dd,J=6.7,2.1,1H),7.63-7.57(m,1H),7.54(s,1H),7.44(d,J=7.9,1H),7.31(d,J=7.7,1H),7.23(t,J=7.8,1H),7.16-7.10(m,1H),6.08(s,1H),2.55(s,1H).

[0067] Example 8

[0068] A method for synthesizing 4-fluoro-3-((4-fluorophenyl)hydroxymethyl)benzonitrile based on continuous flow reaction technology, and its structural formula is: The difference from Example 5 is that the 1.0 mol / L benzaldehyde solution is replaced with a 1.0 mol / L 4-fluorobenzaldehyde solution (the solvent is the same as that in Example 5). The remaining steps are the same as those in Example 5. Finally, 8.1 g of white solid product is obtained. After testing, the GC purity is 99.2% and the yield is 61.2%.

[0069] 1 H NMR(400MHz,CDCl3)δ=7.96(dd,J=6.7,2.1,1H),7.58(ddd,J=8.5,4.8,2.2,1H),7.35(dd,J=8.6,5.3,2H),7.11(dd,J=9.5,8.6,1H),7.08-7.00(m,2H),6.10(s,1H),2.51(s,1H).

[0070] Example 9

[0071] A method for synthesizing 4-fluoro-3-hydroxy(thiophene-2-methyl)benzonitrile based on continuous flow reaction technology, and its structural formula is: It is different from Example 5 in that the 1.0 mol / L benzaldehyde solution is replaced with a 1.0 mol / L 2-thiophenealdehyde solution (the solvent is the same as that in Example 5). The remaining steps are the same as those in Example 5. Finally, 11.5 g of solid product is obtained. After testing, the GC purity is 97.9%, the yield is 55.0%, and the GCMS, m / z is 233.

[0072] 1 H NMR(400MHz,CDCl3)δ=8.01(dd,J=6.7,2.1,1H),7.64-7.57(m,1H),7.31-7.28(m,1H),7.17-7.11(m,1H),6.99-6.94(m,2H),6.35(s,1H),2.73(s,1H).

[0073] Example 10

[0074] A method for synthesizing 4-fluoro-3-(trimethylsilyl)benzonitrile based on continuous flow reaction technology, and its structural formula is: It is different from Example 5 in that the 1.0 mol / L benzaldehyde solution is replaced with a 1.2 mol / L trimethylchlorosilane solution (the solvent is the same as that in Example 5). The reaction solution is taken for 3 minutes, quenched with water, the organic phase is dried and concentrated, and purified by column chromatography. The remaining steps are the same as those in Example 5. Finally, 7.2 g of white solid product of 4-fluoro-3-trimethylsilylbenzonitrile is obtained, the GC purity is 98.1%, the yield is 62.1%, and the GCMS m / z is 193.

[0075] Example 11

[0076] A method for synthesizing 4-fluoro-3-(isopropylhydroxymethyl)benzonitrile based on continuous flow reaction technology, and its structural formula is: It is different from Example 5 in that the 1.0 mol / L benzaldehyde solution is replaced with a 1.5 mol / L isobutyraldehyde (the solvent is the same as that in Example 5). The reaction solution is taken for 3 minutes, quenched with 10% hydrochloric acid, the organic phase is dried and concentrated, and purified by column chromatography. The remaining steps are the same as those in Example 5. Finally, 8.2 g of light yellow liquid product is obtained, the GC purity is 98.7%, the yield is 71.1%, and the GCMS m / z is 193.

[0077] Example 12

[0078] A method for synthesizing 4-fluoro-3-(cyclohexylhydroxy)benzonitrile based on continuous flow reaction technology, and its structural formula is: The difference from Example 5 is that the 1.0 mol / L benzaldehyde solution is replaced with 1.5 mol / L cyclohexanone (the solvent is the same as in Example 5). The reaction solution is collected for 3 minutes, quenched with saturated ammonium chloride, the organic phase is dried and concentrated, and purified by column chromatography. The remaining steps are the same as in Example 5. Finally, 8.5 g of a pale yellow solid product is obtained, with a GC purity of 98.3%, a yield of 64.6%, and a GCMS m / z of 219.

[0079] Example 13

[0080] A method for synthesizing 4-fluoro-3-(1-hydroxy-1-thiophen-2-yl)benzonitrile based on a continuous flow reaction technology, and its structural formula is: The difference from Example 5 is that the 1.0 mol / L benzaldehyde solution is replaced with 0.9 mol / L 2-acetylthiophene (the solvent is the same as in Example 5). The reaction solution is collected for 3 minutes, quenched with 10% hydrochloric acid, the organic phase is dried and concentrated, and purified by column chromatography. The remaining steps are the same as in Example 5. Finally, 8.7 g of a pale yellow liquid product is obtained, with a GC purity of 98.3%, a yield of 65.4%, and a GCMS m / z of 247.

[0081] Comparative Example 1

[0082] This comparative example provides a method for synthesizing 3-iodo-4-fluorobenzonitrile based on a continuous flow reaction technology. The difference between this comparative example and Example 1 is that the temperature of the first mixer 7 is controlled at -70 °C to obtain a first mixed material. The first mixed material passes through the first reaction tube 8 and undergoes a lithium-hydrogen exchange reaction at -70 °C, and the residence time is controlled at 1 min to generate 5-cyano-2-fluorophenyllithium. The remaining steps are the same as in Example 1. Finally, 7.7 g of a white solid product is obtained. After testing, the GC purity is 98.4% and the yield is 52.2%.

[0083] It can be seen from Comparative Example 1 that although the synthesis temperature is reduced to -70 °C, the purity and yield of the synthesized 3-iodo-4-fluorobenzonitrile also have certain advantages, but its reaction temperature is too low, which not only consumes high energy, but also has higher requirements for equipment, and is not conducive to industrial production.

[0084] Comparative Example 2

[0085] This comparative example provides a method for synthesizing 3-iodo-4-fluorobenzonitrile based on a continuous flow reaction technology. The difference between this comparative example and Example 1 is that the temperature of the first mixer 7 is controlled at -20 °C to obtain a first mixed material. The first mixed material passes through the first reaction tube 8 and undergoes a lithium-hydrogen exchange reaction at -20 °C, and the residence time is controlled at 1 min to generate 5-cyano-2-fluorophenyllithium for Comparative Example 3. The remaining steps are the same as in Example 1. Finally, 5.7 g of a white solid product is obtained. After testing, the GC purity is 98.3% and the yield is 23.1%.

[0086] Comparative Example 3

[0087] This comparative example provides a method for synthesizing 3-iodo-4-fluorobenzonitrile based on continuous flow reaction technology. The difference between this comparative example and Example 1 is that the 1.0 mol / L organolithium reagent lithium diisopropylamide is replaced with a 1.0 mol / L complex of tetramethylethylenediamine-lithium butyl. And to ensure the experimental results, the initial reaction solution was discarded for 1 minute, and the stabilized reaction solution was collected for 3 minutes. The remaining steps are the same as those in Example 1. Finally, 4.3 g of white solid product was obtained. After testing, the GC purity was 98.2%, and the yield was 29.1%.

[0088] Comparative Example 4

[0089] This comparative example provides a method for synthesizing 3-iodo-4-fluorobenzonitrile based on continuous flow reaction technology. The difference between this comparative example and Example 1 is that the 1.0 mol / L organolithium reagent lithium diisopropylamide is replaced with 1.0 mol / L lithium 2,2,6,6-tetramethylpiperidine. And to ensure the experimental results, the initial reaction solution was discarded for 1 minute, and the stabilized reaction solution was collected for 3 minutes. The remaining steps are the same as those in Example 1. Finally, 6.5 g of white solid product was obtained. After testing, the GC purity was 97.6%, and the yield was 43.9%.

[0090] The above-described embodiments merely represent several implementation manners of the present invention. The description is relatively specific and detailed, but it should not be construed as a limitation on the scope of the present invention patent. It should be noted that for those of ordinary skill in the art, without departing from the concept of the present invention, several modifications and improvements can still be made, and these all belong to the protection scope of the present invention. Therefore, the protection scope of the present invention patent shall be subject to the appended claims.

Claims

1. A method for synthesizing 5-cyano-2-fluorophenyl compounds based on continuous flow reaction technology, characterized in that, Synthesis is carried out using a continuous flow reaction device, including the following steps: 4-Fluorobenzonitrile undergoes a lithium-hydrogen exchange reaction with an organolithium reagent in a first solvent to form 5-cyano-2-fluorophenyllithium; then the 5-cyano-2-fluorophenyllithium and an electrophilic reagent undergo a nucleophilic substitution reaction in a second solvent; after the reaction is completed, a quenching agent is used for quenching to obtain a 5-cyano-2-fluorophenyl compound; The reaction route of the method provided by the present invention is as follows: Wherein, R = X, R1R2(OH) or Si(R3)3, X is one of Cl, Br, and I, R1 is H or CH3, and R2 is C 2-9 a linear or branched alkyl group, C 4-9 a cycloalkyl group, phenyl group, pyridyl group, furyl group, or thienyl group; R3 is one of methyl, ethyl, and isopropyl; The organolithium reagent is at least one of butyllithium, lithium diisopropylamide, lithium hexamethyldisilazide, pentamethyldiethylenetriamine-butyllithium complex, and tetramethylpiperidine magnesium chloride lithium chloride; The temperature of the lithium-hydrogen exchange reaction is -60 to -25 °C; The temperature of the nucleophilic substitution reaction is -60 to -25 °C.

2. The method according to claim 1, characterized in that, The first solvent and the second solvent are each independently selected from at least one of tetrahydrofuran, 2-methyltetrahydrofuran, toluene, diethyl ether, methyl tert-butyl ether, and ethylene glycol dimethyl ether.

3. The method according to claim 1, wherein The electrophilic reagent is selected from one of iodine, hexachloroethane, bromine, 1,2-dibromo-1,1,2,2,-tetrafluoroethane, carbonyl compounds, and alkylsilane compounds.

4. The method according to claim 1 or 3, characterized in that, The concentration of the 4-fluorobenzonitrile is 0.5 mol / L - 3 mol / L; the concentration of the organolithium reagent is 0.5 mol / L - 3 mol / L; the concentration of the electrophilic reagent is 0.3 mol / L - 3 mol / L.

5. The method according to claim 4, wherein The molar ratio of the organolithium reagent to the 4-fluorobenzonitrile is (0.9 - 1.2):

1.

6. The method according to claim 4, characterized in that The molar ratio of the electrophilic reagent to the 4-fluorobenzonitrile is (0.9 - 2.0):1; the molar ratio of the quenching agent to the 4-fluorobenzonitrile is (1.1 - 5):

1.

7. The method according to claim 1, wherein The temperature of the lithium-hydrogen exchange reaction is -60 to -40 °C, and the time of the lithium-hydrogen exchange reaction is 0.5 - 2 min.

8. The method according to claim 1, characterized in that The temperature of the nucleophilic substitution reaction is -60 to -40 °C, and the time of the nucleophilic substitution reaction is 0.5 - 3 min.

9. The method according to claim 7 or 8, characterized in that, The continuous flow reaction device includes: Liquid delivery pumps, including a first liquid delivery pump, a second liquid delivery pump, and a third liquid delivery pump; Mixers, the mixers include a first mixer and a second mixer, the first liquid delivery pump and the second liquid delivery pump are respectively connected to the first mixer; the third liquid delivery pump is connected to the second mixer; Reaction tubes, the reaction tubes include a first reaction tube and a second reaction tube, the first reaction tube is located between the first mixer and the second mixer; Quenching device, the quenching device is connected to the second mixer, and the second reaction tube is located between the second mixer and the quenching device; Temperature control system, the liquid delivery pumps, the mixers, the reaction tubes, and the quenching device are controlled by the temperature control system.

10. The method according to claim 9, wherein Including the following steps: Under a protective atmosphere, 4-fluorobenzonitrile and an organolithium reagent are respectively pumped into the first mixer of the continuous flow reaction device at a flow rate of 10 - 100 mL / min, and mixed at -60 °C to -25 °C to obtain a first mixed material. The first mixed material undergoes a lithium-hydrogen exchange reaction through a first reaction tube to generate 5-cyano-2-fluorophenyllithium; the 5-cyano-2-fluorophenyllithium further reacts with an electrophilic reagent pumped into a second mixer at a flow rate of 10 - 100 mL / min and is mixed at -60 °C to -25 °C to obtain a second mixed material; the second mixed material undergoes a nucleophilic substitution reaction through a second reaction tube. After the reaction is completed, it is quenched by the quenching agent in a quenching device to obtain a crude product of 5-cyano-2-fluorophenyl compound.

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