Preparation method of microchannel inner-cycloprosulfuron and intermediate of microchannel inner-cycloprosulfuron

Abstract

The invention belongs to the field of organic chemical synthesis, and particularly provides a method for preparing cyprosulfuron and an intermediate thereof in a microchannel. According to the method, appropriate reaction conditions and materials are selected, and a microchannel synthesis technology is adopted in the whole process, so that compared with traditional kettle type synthesis, the yield of each step is improved, the reaction time is remarkably shortened, meanwhile, the use of non-green solvents difficult to treat is avoided, and waste generation is reduced. Furthermore, the intermediate 3-(N-(cyclopropylmethyl)-4-fluorobenzamido)-2-fluorobenzoic acid can be synthesized in series by adopting four steps, the time is only 48 minutes, the total yield is 87%, and the post-treatment process is remarkably simplified; in addition, the synthesis of the 4-(perfluoroisopropyl)-2-(trifluoromethyl) aniline through the water phase and the oil phase only takes 60 minutes, and the yield is 87%; the use of non-green solvents such as dichloroethane, N, N-dimethylformamide and the like is avoided through micro-channel bromination; the reaction time of condensation of the two segments into the cyprosulfuron is shortened from 6 hours to 7.5 minutes.

Description

Technical Field

[0001] The invention relates to the technical field of organic chemical synthesis, and in particular to a method for preparing ciprofloxacin and an intermediate thereof in a microchannel. Background Art

[0002] Cyproflanilide is a diamide insecticide with the characteristics of high efficiency, low toxicity, broad insecticide spectrum, good permeability, rapid onset and long lasting effect. It can effectively control lepidopteran pests such as beet armyworm, diamondback moth, cutworm, and striped stem borer; coleopteran pests such as longhorn beetles and leaf beetles; and thrips. Cyproflanilide is an allosteric modulator of γ-aminobutyric acid (GABA)-gated chloride ion channels. It blocks activated γ-aminobutyric acid chloride ion channels by allosteric blocking, causing pests to become overexcited and spasmodic, eventually leading to death. Although cyproflanilide has a diamide structure, it is not a traditional nicotinic acid receptor modulator. It is classified as Group 30 with bromofenac in the IRAC classification, and is in the same group as the most popular isoxazoline insecticides (isoxazolinamide, fluoxazolidinamide, and fluoxazolidinamide). Cyproflanilide has excellent stomach toxicity, contact toxicity and systemic activity.

[0003] CN109497062A discloses a method for synthesizing meta-diamide compounds, and CN116178198A discloses a method for synthesizing cycloflumizone. These methods are relatively simple to operate and have a high yield. However, as the cost is reduced and environmental protection requirements are further improved, it is necessary to find a more economical, efficient and environmentally friendly method for synthesizing cycloflumizone. Summary of the invention

[0004] In order to provide a green, environmentally friendly, low-energy, low-consumption and low-cost synthesis method of ciprofloxacin, the present invention studies the synthesis method of ciprofloxacin, and provides a method for preparing ciprofloxacin in a microchannel based on a microchannel. The method has a total of eight steps, and microchannel synthesis technology is used throughout the process. Compared with traditional kettle synthesis, the yield of each step is improved, and the reaction time is significantly shortened. At the same time, the use of non-green and difficult-to-treat solvents is avoided, and waste generation is reduced.

[0005] The method adopts microchannel synthesis technology, and compared with traditional kettle synthesis, it avoids the use of non-green difficult-to-treat solvents, reduces waste generation, and greatly shortens the reaction time. Avoid some non-green difficult-to-treat solvents. The present invention also provides a four-step combined microchannel reaction for the end-to-end synthesis of 3-(N-(cyclopropylmethyl)-4-fluorobenzamide)-2-fluorobenzoic acid, which only takes 48 minutes in total time and has a total yield of 87%, significantly simplifies the post-reaction processing link, and significantly shortens the reaction time. In addition, the present invention also provides a microchannel synthesis process for synthesizing 4-(perfluoroisopropyl)-2-(trifluoromethyl)aniline by dehalogenation sulfinization reaction, which uses microscale effects to increase the mass transfer of water and oil phases, thereby significantly improving the reaction rate and product yield, and the space-time yield can reach 1.5 kg / day, and the method can also be applied to the synthesis of other molecules containing perfluoro side chain alkyls. The microchannel bromination of 4-(perfluoroisopropyl)-2-(trifluoromethyl)aniline used acetonitrile as solvent, replacing N,N-dimethylformamide, which has significantly higher toxicity and health risks. The raw material was completely converted within a retention time of 30 minutes, and the product yield was 98%. In addition, for extremely electron-poor bromodecafluoroaniline, bis(trimethylsilyl)amide lithium was used as a base, and the amide coupling with 3-(N-(cyclopropylmethyl)-4-fluorobenzamido)-2-fluorobenzoyl chloride in the microchannel was completed within 7.5 minutes, with a two-step yield of 88%, effectively avoiding the decarboxylation side reaction of the carboxylic acid compound.

[0006] The present invention belongs to the field of organic chemical synthesis, and specifically provides a method for preparing ciprofloxacin in a microchannel. The present invention provides a method for preparing ciprofloxacin in a microchannel, comprising the steps of:

[0007] 1. Synthesis of 3-(N-(cyclopropylmethyl)-4-fluorobenzamido)-2-fluorobenzoic acid in microchannel

[0008] (1) Nitro reduction: In a micro-packed bed reactor, methyl 2-fluoro-3-nitrobenzoate and hydrogen react under the catalysis of palladium carbon or platinum carbon to obtain methyl 2-fluoro-3-aminobenzoate; the amount of the catalyst palladium carbon or platinum carbon is: the mass fraction of palladium carbon or platinum carbon (5-10w / w% loading) relative to the above methyl ester is 1% to 20%, and the device operates stably for 24 hours.

[0009] Preferably, in a micro-packed bed reactor with an inner diameter of 2 mm to 5 mm and a length of 10 to 30 cm, the flow rate of the hydrogen is 10 mL / min to 40 mL / min; the flow rate of the reaction solution of methyl 2-fluoro-3-nitrobenzoate is 0.1 mL / min to 0.5 mL / min, and the concentration is 0.2 mol / L to 1 mol / L.

[0010] Preferably, the pressure in the micro-packed bed reactor is 1.0 MPa to 2.0 MPa.

[0011] Preferably, the flow rate of the hydrogen is 10 mL / min, 20 mL / min, 30 mL / min or 40 mL / min.

[0012] Preferably, the flow rate of the hydrogen is 20 mL / min.

[0013] Preferably, the flow rate of the reaction solution of methyl 2-fluoro-3-nitrobenzoate is 0.1 mL / min to 0.3 mL / min.

[0014] Preferably, the concentration of the reaction solution of methyl 2-fluoro-3-nitrobenzoate is 0.2 mol / mL to 1 mol / mL.

[0015] Preferably, the concentration of the reaction solution of methyl 2-fluoro-3-nitrobenzoate is 0.2 mol / mL, 0.3 mol / mL, 0.4 mol / mL, 0.5 mol / mL, 0.6 mol / mL, 0.7 mol / mL, 0.8 mol / mL, 0.9 mol / mL, or 1 mol / mL.

[0016] Preferably, the concentration of the reaction solution of methyl 2-fluoro-3-nitrobenzoate is 1 mol / mL.

[0017] Preferably, the amount of palladium on carbon is 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15 or 20%.

[0018] Preferably, the reaction temperature is 60°C to 80°C.

[0019] Preferably, the reaction temperature is 60°C, 70°C or 80°C.

[0020] Preferably, the reaction temperature is 80°C.

[0021] Preferably, the solvent of the reaction is ethanol, acetonitrile or ethyl acetate.

[0022] Preferably, the solvent for the reaction is ethyl acetate.

[0023] Preferably, the reaction time is 6 min to 15 min.

[0024] Preferably, the reaction time is 6 min, 7 min, 8 min, 9 min, 10 min, 11 min, 12 min, 13 min, 14 min or 15 min.

[0025] Preferably, the reaction time is 15 min.

[0026] (2) Reductive amination: In a micro-packed bed reactor, methyl 2-fluoro-3-aminobenzoate, cyclopropanecarboxaldehyde and hydrogen react under the catalysis of platinum carbon to obtain methyl 3-((cyclopropylmethyl)amino)-2-fluorobenzoate; the amount of platinum carbon in the micro-packed bed: based on a methyl 2-fluoro-3-aminobenzoate concentration of 0.2 mol / L, a flow rate of 0.3 mL / min and continuous stable operation for 24 hours, the relative mass fraction of platinum carbon (5-10 w / w% loading) is 1% to 20%.

[0027] Preferably, in a micro-packed bed reactor with an inner diameter of 2 mm to 5 mm and a length of 10 to 30 cm, the flow rate of the hydrogen is 10 mL / min to 40 mL / min, the flow rate of the mixed reaction liquid of methyl 2-fluoro-3-aminobenzoate and cyclopropanecarboxaldehyde is 0.1 mL / min to 0.3 mL / min, and the concentrations are 0.1 mol / L to 0.2 mol / L and 0.2 mol / L to 0.6 mol / L, respectively.

[0028] Preferably, the pressure in the micro-packed bed reactor is 1.0 MPa to 2.0 MPa.

[0029] Preferably, the flow rate of the mixed reaction liquid of methyl 2-fluoro-3-aminobenzoate and cyclopropanecarboxaldehyde is 0.1 mL / min.

[0030] Preferably, the concentration of methyl 2-fluoro-3-aminobenzoate is 0.1 mol / L-0.2 mol / L.

[0031] Preferably, the concentration of methyl 2-fluoro-3-aminobenzoate is 0.2 mol / L.

[0032] Preferably, the concentration of cyclopropanecarboxaldehyde is 0.2 mol / L to 0.6 mol / L; preferably 0.3 mol / L

[0033] Preferably, the concentration of cyclopropanecarboxaldehyde is 0.2 mol / L, 0.3 mol / L, 0.4 mol / L, 0.5 mol / L or 0.6 mol / L.

[0034] Preferably, the molar ratio of methyl 2-fluoro-3-aminobenzoate to cyclopropanecarboxaldehyde is 1:(2-3).

[0035] Preferably, the molar ratio of methyl 2-fluoro-3-aminobenzoate to cyclopropanecarboxaldehyde is 1:2.

[0036] Preferably, the flow rate of the hydrogen is 10 mL / min, 20 mL / min, 30 mL / min, or 40 mL / min.

[0037] Preferably, the flow rate of the hydrogen is 20 mL / min.

[0038] Preferably, the amount of platinum carbon is 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15% or 20%.

[0039] Preferably, the reaction temperature is 80°C to 120°C, preferably 100°C.

[0040] Preferably, the solvent for the reaction is ethanol, methanol or toluene.

[0041] Preferably, the solvent for the reaction is toluene.

[0042] Preferably, the reaction time is 20 min to 40 min.

[0043] Preferably, the reaction time is 30 min.

[0044] (3) Amide coupling: In a micro-pipeline reactor, methyl 3-((cyclopropylmethyl)amino)-2-fluorobenzoate and p-fluorobenzoyl chloride react to obtain methyl 3-(N-(cyclopropylmethyl)-4-fluorobenzamido)-2-fluorobenzoate.

[0045] Preferably, in a micro-tube reactor with an inner diameter of 0.5 mm to 5 mm, the flow rate of the reaction solution of methyl 3-((cyclopropylmethyl)amino)-2-fluorobenzoate is 0.3 mL / min to 0.8 mL / min; the flow rate of the reaction solution of p-fluorobenzoyl chloride is 0.3 mL / min to 0.8 mL / min.

[0046] Preferably, the flow rate of the reaction solution of methyl 3-((cyclopropylmethyl)amino)-2-fluorobenzoate is 0.5 mL / min.

[0047] Preferably, the flow rate of the reaction solution of p-fluorobenzoyl chloride is 0.5 mL / min.

[0048] Preferably, the concentration of methyl 3-((cyclopropylmethyl)amino)-2-fluorobenzoate is 0.2 mol / L-0.4 mol / L, preferably 0.2 mol / L.

[0049] Preferably, the concentration of p-fluorobenzoyl chloride is 0.2 mol / L-0.6 mol / L, preferably 0.2 mol / L-0.3 mol / L.

[0050] Preferably, the molar ratio of methyl 3-((cyclopropylmethyl)amino)-2-fluorobenzoate to p-fluorobenzoyl chloride is 1:(1-2), preferably 1:1.05.

[0051] Preferably, the reaction temperature is 80°C to 120°C, preferably 120°C.

[0052] Preferably, the solvent of the reaction is acetonitrile or 1,2-dichloroethane, preferably acetonitrile.

[0053] Preferably, the reaction time is 5-30 min, preferably 5 min.

[0054] (4) Ester hydrolysis: In a micro-pipeline reactor, methyl 3-(N-(cyclopropylmethyl)-4-fluorobenzamido)-2-fluorobenzoate is hydrolyzed under the action of sodium hydroxide to obtain 3-(N-(cyclopropylmethyl)-4-fluorobenzamido)-2-fluorobenzoic acid.

[0055] Preferably, in a micro-tube reactor with an inner diameter of 0.5 mm to 5 mm, the flow rate of the reaction solution of 3-(N-(cyclopropylmethyl)-4-fluorobenzamido)-2-fluorobenzoic acid methyl ester is 8 mL / min to 12 mL / min; the flow rate of the sodium hydroxide solution is 8 mL / min to 12 mL / min.

[0056] Preferably, the flow rate of the reaction solution of methyl 3-(N-(cyclopropylmethyl)-4-fluorobenzamido)-2-fluorobenzoate is 10 mL / min.

[0057] Preferably, the flow rate of the reaction solution sodium hydroxide is 10 mL / min.

[0058] Preferably, the concentration of methyl 3-(N-(cyclopropylmethyl)-4-fluorobenzamido)-2-fluorobenzoate is 0.1 mol / L to 0.2 mol / L, preferably 0.13 mol / L.

[0059] Preferably, the concentration of p-fluorobenzoyl chloride is 0.17 mol / L to 0.4 mol / L, preferably 0.4 mol / L.

[0060] Preferably, the molar ratio of methyl 3-((cyclopropylmethyl)amino)-2-fluorobenzoate to sodium hydroxide is 1:(1.3-3), preferably 1:3.

[0061] Preferably, the reaction temperature is 80°C to 85°C, preferably 85°C.

[0062] Preferably, the solvent of the reaction solution 3-(N-(cyclopropylmethyl)-4-fluorobenzamido)-2-fluorobenzoic acid methyl ester is acetonitrile.

[0063] Preferably, the solvent of the reaction solution sodium hydroxide is water.

[0064] Preferably, the reaction time is 10 min to 15 s, preferably 15 s.

[0065] In some embodiments, two adjacent microchannel reactors in step (1), step (2), step (3) and step (4) are directly connected or not directly connected to form a microchannel reaction system.

[0066] In some embodiments, the microchannel reaction system is selected from one of the following:

[0067] i. The microchannel reactors in step (1), step (2), step (3) and step (4) are not connected to each other;

[0068] ii. The microchannel reactors of step (1) and step (2) are directly connected; the microchannel reactors of step (3) and step (4) are directly connected; the microchannel reactors of step (2) and step (3) are not connected;

[0069] iii. The microchannel reactors of step (1), step (2), step (3) and step (4) are directly connected end to end in sequence.

[0070] 2. Preparation of ciprofloxacin in microchannels

[0071] The present invention also provides a method for preparing cycloflumizone in a microchannel, the method comprising starting from methyl 2-fluoro-3-nitrobenzoate, synthesizing 3-(N-(cyclopropylmethyl)-4-fluorobenzamido)-2-fluorobenzoic acid in four steps in series, comprising the steps of:

[0072] Reaction A (nitro reduction) in a micro-packed bed reactor: methyl 2-fluoro-3-nitrobenzoate and hydrogen react under the catalysis of palladium carbon or platinum carbon to obtain methyl 2-fluoro-3-aminobenzoate;

[0073] Reaction B (reductive amination) in a micro-packed bed reactor: methyl 2-fluoro-3-aminobenzoate, cyclopropanecarboxaldehyde and hydrogen react under platinum-carbon catalysis to obtain methyl 3-((cyclopropylmethyl)amino)-2-fluorobenzoate;

[0074] Reaction C (amide coupling) in a micro-pipeline reactor: methyl 3-((cyclopropylmethyl)amino)-2-fluorobenzoate reacts with p-fluorobenzoyl chloride to obtain methyl 3-(N-(cyclopropylmethyl)-4-fluorobenzamido)-2-fluorobenzoate;

[0075] Reaction D (ester hydrolysis) in a micro-channel reactor: methyl 3-(N-(cyclopropylmethyl)-4-fluorobenzamido)-2-fluorobenzoate is hydrolyzed in the presence of sodium hydroxide to give 3-(N-(cyclopropylmethyl)-4-fluorobenzamido)-2-fluorobenzoic acid;

[0076] Wherein, reactions A and B share a micro-packed bed reactor, which is connected end-to-end with the micro-pipe reactor of reaction C and the micro-pipe reactor of reaction D to continuously synthesize 3-(N-(cyclopropylmethyl)-4-fluorobenzamido)-2-fluorobenzoic acid; the flow rate of the hydrogen is 10mL / min to 40mL / min; the flow rate of the reaction solution of methyl 2-fluoro-3-nitrobenzoate and cyclopropanecarboxaldehyde is 0.05mL / min to 0.5mL / min; the relative mass fraction of platinum carbon (5-10w / w% loading) is 1% to 20%; the flow rate of the reaction solution of p-fluorobenzoyl chloride is 0.4mL / min to 0.6mL / min; the flow rate of the sodium hydroxide solution is preferably 0.8mL / min to 1.0mL / min;

[0077] Wherein, after methyl 3-(N-(cyclopropylmethyl)-4-fluorobenzamido)-2-fluorobenzoate is hydrolyzed under sodium hydroxide, an acidification step may be further included.

[0078] In reaction A and reaction B:

[0079] Preferably, the flow rate of the hydrogen is 10 mL / min, 20 mL / min, 30 mL / min, 40 mL / min, preferably 20 mL / min.

[0080] Preferably, the flow rate of the reaction solution of methyl 2-fluoro-3-nitrobenzoate and cyclopropanecarboxaldehyde is 0.075 mL / min.

[0081] Preferably, the amount of platinum carbon is 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15% or 20%.

[0082] Preferably, the concentration of methyl 2-fluoro-3-nitrobenzoate is 0.1 mol / L to 0.3 mol / L, preferably 0.1 mol / L.

[0083] Preferably, the concentration of cyclopropanecarboxaldehyde is 0.2 mol / L to 0.6 mol / L, preferably 0.3 mol / L.

[0084] Preferably, the reaction temperature is 80°C to 120°C, preferably 100°C.

[0085] Preferably, the solvent for the reaction is toluene.

[0086] Preferably, the reaction time is 30-40 min, preferably 40 min.

[0087] The two-step reaction of reaction A and reaction B uses 2-fluoro-3-nitrobenzoic acid methyl ester as a raw material and toluene as a solvent. After undergoing nitro reduction hydrogenation and reductive amination, the toluene solution of 3-((cyclopropylmethyl)amino)-2-fluorobenzoic acid methyl ester is obtained without purification. The obtained solution flows out of the tube and can be connected in series with the p-fluorobenzoyl chloride toluene solution required for reaction C, and then the solution of sodium hydroxide (e.g., aqueous solution) required for reaction D is connected in series. The flow rate of the p-fluorobenzoyl chloride toluene solution and the sodium hydroxide solution is preferably 0.4 mL / min.

[0088] In reaction C and reaction D:

[0089] Preferably, the reaction liquid flow rate of p-fluorobenzoyl chloride is preferably 0.4 mL / min.

[0090] Preferably, the flow rate of the reaction solution sodium hydroxide is preferably 0.8 mL / min.

[0091] Preferably, the concentration of p-fluorobenzoyl chloride is 0.08 mol / L to 0.15 mol / L, preferably 0.095 mol / L.

[0092] Preferably, the concentration of the sodium hydroxide is 0.1 mol / L to 0.6 mol / L, preferably 0.12 mol / L.

[0093] Preferably, the reaction temperature is 80-140°C, preferably C reaction temperature is 140°C, the coil inner diameter is 1.6mm, and the wall thickness is 0.8mm, preferably D reaction temperature is 90°C, the coil inner diameter is 1.6mm, and the wall thickness is 0.8mm.

[0094] Preferably, the solvent of the reaction is toluene, methanol or water, preferably the solvent of p-fluorobenzoyl chloride is toluene, and the solvent of sodium hydroxide is water and methanol in a volume ratio of 1:1.

[0095] Preferably, the reaction time is 5 min to 50 min, preferably the total retention time of the first two steps is 40 min, and the retention time of the last two coils is 6.25 min and 1.56 min.

[0096] In some embodiments, the method for preparing ciprofloxacin in a microchannel further comprises synthesizing brominated decafluoroaniline in a microchannel, comprising the steps of:

[0097] Synthesis of decafluoroaniline: Phase A: 2-trifluoromethylaniline, heptafluoroisopropyl iodide, dibenzo-18-crown-6, tetrabutylammonium bromide dissolved in a mixed solution of ethyl acetate and acetonitrile; Phase B: a mixed solution of sodium dithionite and sodium carbonate in water and acetonitrile; Phase C: a mixed solution of sodium hydroxide in water and acetonitrile; three-phase liquids are pumped in separately by double injection pumps, with a flow rate of 0.5 mL / min to 6 mL / min for phase A, a flow rate of 0.5 mL / min to 6 mL / min for phase B, and a flow rate of 1 mL / min to 9 mL / min for phase C, and enter a polytetrafluoroethylene coil with an inner diameter of 0.5 mm to 5 mm and a retention volume of 60 mL to 720 mL through a mixer, and the pressure of a back pressure valve is 0.6 MPa.

[0098] Preferably, the flow rate of phase A is 0.5 mL / min, the flow rate of phase B is 0.5 mL / min, and the flow rate of phase C is 1 mL / min.

[0099] Preferably, the reaction temperature is 100°C to 120°C, preferably 120°C.

[0100] Preferably, the reaction retention time is 30 min to 60 min, preferably 60 min.

[0101] Synthesis of bromodecafluoroaniline: Phase A: acetonitrile solution of decafluoroaniline; Phase B: acetonitrile solution of N-bromosuccinimide; pumped into a polytetrafluoroethylene coil with an inner diameter of 0.5 mm to 5 mm through a double syringe pump through a T-type mixer, the pumping speed of phase A is 0.1 mL / min, and the pumping speed of phase B is 0.1 mL / min.

[0102] Preferably, the concentration of decafluoroaniline is 0.1 mol / L to 0.3 mol / L.

[0103] Preferably, the concentration of N-bromosuccinimide (NBS) is 0.3-0.9 mol / L.

[0104] Preferably, the reaction temperature is 80°C to 120°C, preferably 120°C.

[0105] Preferably, the reaction retention time is 15 min to 30 min, preferably 30 min.

[0106] In some embodiments, the method for preparing ciprofloxacin in a microchannel further comprises the synthesis of ciprofloxacin in a microchannel:

[0107] (1) Synthesis of acyl chloride: 3-(N-(cyclopropylmethyl)-4-fluorobenzamido)-2-fluorobenzoic acid reacts with thionyl chloride to generate 3-(N-(cyclopropylmethyl)-4-fluorobenzamido)-2-fluorobenzoyl chloride;

[0108] Phase A: toluene solution of 3-(N-(cyclopropylmethyl)-4-fluorobenzamido)-2-fluorobenzoic acid; Phase B: toluene solution of dichlorothionyl; both phases were pumped through a dual syringe pump at a flow rate of 0.5 mL / min, through a T-type mixer, a polytetrafluoroethylene coil with an inner diameter of 0.5 mm to 5 mm, a retention volume of 30 mL, a retention time of 30 min, a temperature of 130°C, and a back pressure valve pressure of 0.8 MPa;

[0109] Preferably, the concentration of 3-(N-(cyclopropylmethyl)-4-fluorobenzamido)-2-fluorobenzoic acid is 0.2 mol / L to 0.6 mol / L.

[0110] Preferably, the concentration of 3-(N-(cyclopropylmethyl)-4-fluorobenzamido)-2-fluorobenzoic acid is 0.2 mol / L.

[0111] Preferably, the concentration of thionyl chloride is 1 mol / L to 3 mol / L.

[0112] Preferably, the concentration of thionyl chloride is 1 mol / L.

[0113] Preferably, the reaction temperature is between 100°C and 130°C, preferably 130°C.

[0114] Preferably, the reaction retention time is between 15 min and 30 min, preferably 30 min.

[0115] (2) Condensation of acyl chloride with bromodecafluoroaniline: Bromodecafluoroaniline reacts with 3-(N-(cyclopropylmethyl)-4-fluorobenzamido)-2-fluorobenzoyl chloride in the presence of lithium bis(trimethylsilyl)amide to obtain cyclohexanil;

[0116] Phase A: toluene solution of 3-(N-(cyclopropylmethyl)-4-fluorobenzamido)-2-fluorobenzoyl chloride and bromodecafluoroaniline; Phase B: lithium bis(trimethylsilyl)amide (1 mol / L toluene solution); the two phases were pumped in through a double syringe pump with a flow rate of 2.0 mL / min, mixed through a T-type mixer, and entered a polytetrafluoroethylene coil with an inner diameter of 0.5 mm to 5 mm, with a back pressure valve pressure of 0.8 MPa.

[0117] Preferably, the concentration of 3-(N-(cyclopropylmethyl)-4-fluorobenzamido)-2-fluorobenzoyl chloride is 0.05 mol / L to 0.2 mol / L.

[0118] Preferably, the concentration of brominated decafluoroaniline is 0.075 mol / L to 0.3 mol / L.

[0119] Preferably, the reaction temperature is 50°C to 130°C, preferably 90°C.

[0120] Preferably, the reaction time (retention time) is 5 min to 30 min, preferably 7.5 min.

[0121] Preferably, the solvent for the reaction is tetrahydrofuran and toluene, preferably toluene.

[0122] 3. Synthesis of perfluoropropyl-substituted aniline in microchannels

[0123] The present invention provides a method for synthesizing perfluoropropyl substituted aniline in a microchannel.

[0124]

[0125] R1 is independently hydrogen, halogen, alkyl, haloalkyl, alkoxy or haloalkoxy; R2 is hydrogen, alkyl or acyl; n is 1, 2, 3 or 4;

[0126] Phase A: Compound I, heptafluoroisopropyl iodide, dibenzo-18-crown ether-6, and tetrabutylammonium bromide are dissolved in a mixed solution of ethyl acetate and acetonitrile; Phase B: a mixed solution of sodium dithionite and sodium carbonate in water and acetonitrile; Phase C: a mixed solution of sodium hydroxide in water and acetonitrile; the three-phase liquids are pumped in separately using a double injection pump, with a flow rate of 0.5 mL / min to 1 mL / min for phase A, 0.5 mL / min to 1 mL / min for phase B, and 0.5 mL / min to 1 mL / min for phase C, and then enter a polytetrafluoroethylene coil with an inner diameter of 0.5 mm to 5 mm through a mixer; the reaction temperature is 80°C to 120°C.

[0127] In some embodiments, the concentration of Compound I is 0.1 mol / L to 0.6 mol / L, the concentration of heptafluoroisopropyl iodide is 0.3 mol / L to 1.2 mol / L, the concentration of dibenzo-18-crown-6 is 0.01 mol / L to 0.02 mol / L, the concentration of tetrabutylammonium bromide is 0.01 mol / L to 0.05 mol / L; the concentration of sodium dithionite is 0.5 mol / L to 1.0 mol / L, the concentration of sodium carbonate is 0.03 mol / L to 0.05 mol / L; the concentration of sodium hydroxide is 0.03 mol / L to 0.1 mol / L; and the reaction pressure is 0.5 MPa to 0.8 MPa.

[0128] In some embodiments, the concentration of Compound I is 0.2 mol / L, the concentration of heptafluoroisopropyl iodide is 0.4 mol / L, the concentration of dibenzo-18-crown-6 is 0.015 mol / L, the concentration of tetrabutylammonium bromide is 0.015 mol / L; the concentration of sodium dithionite is 0.6 M, the concentration of sodium carbonate is 0.04 mol / L; the concentration of sodium hydroxide is 0.1 mol / L; and the reaction pressure is 0.6 MPa.

[0129] In some embodiments, Compound I is selected from: aniline, o-difluoromethoxyaniline, p-anisidine, o-methylaniline, or o-chloroaniline.

[0130] Terminology

[0131] Certain embodiments of the present invention are now described in detail, examples of which are illustrated by the accompanying structural formulas and chemical formulae. The present invention is intended to encompass all substitutions, modifications, and equivalent technical solutions, which are all included within the scope of the present invention as defined in the claims. It should be appreciated by those skilled in the art that many methods and materials similar or equivalent to those described herein can be used to practice the present invention. The present invention is in no way limited to the methods and materials described herein. In the event that one or more of the combined documents, patents, and similar materials differ from or contradict the present application (including but not limited to defined terms, term applications, described technologies, etc.), the present application shall prevail.

[0132] It should be further appreciated that certain features of the invention, which for clarity are described in multiple separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which for brevity are described in a single embodiment, may also be provided separately or in any suitable sub-combination.

[0133] Unless otherwise specified, all technical terms used in the present invention have the same meaning as commonly understood by those skilled in the art to which the present invention belongs. All patents and publications related to the present invention are incorporated herein by reference in their entirety.

[0134] In the description of this specification, the description with reference to the terms "one embodiment", "some embodiments", "example", "specific example", or "some examples" etc. means that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described may be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art may combine and combine the different embodiments or examples described in this specification and the features of the different embodiments or examples, without contradiction.

[0135] In the following, all numbers disclosed herein are approximate, regardless of whether the words "about" or "approximately" are used. The value of each number may vary by 1%, 2%, 5%, 7%, 8%, 10%, 15% or 20%. Whenever a number having a value of N is disclosed, any number having a value of N+ / -1%, N+ / -2%, N+ / -3%, N+ / -5%, N+ / -7%, N+ / -8%, N+ / -10%, N+ / -15% or N+ / -20% is explicitly disclosed, where "+ / -" means plus or minus. BRIEF DESCRIPTION OF THE DRAWINGS

[0136] Figure 1 This is the flow chart of the microchannel synthesis of decafluoroaniline.

[0137] Figure 2 This is the microchannel synthesis flow chart of brominated decafluoroaniline.

[0138] Figure 3 The microchannel synthesis flow chart of methyl 2-fluoro-3-aminobenzoate.

[0139] Figure 4 The microchannel synthesis flow chart of methyl 3-((cyclopropylmethyl)amino)-2-fluorobenzoate.

[0140] Figure 5 The microchannel synthesis flow chart of methyl 3-(N-7(cyclopropylmethyl)-4-fluorobenzamido)-2-fluorobenzoate.

[0141] Figure 6 The microchannel synthesis flow chart of 3-(N-(cyclopropylmethyl)-4-fluorobenzamido)-2-fluorobenzoic acid.

[0142] Figure 7 The figure is a two-step combined microchannel synthesis flow chart of methyl 3-((cyclopropylmethyl)amino)-2-fluorobenzoate.

[0143] Figure 8 The figure is a two-step combined microchannel synthesis flow chart of 3-(N-(cyclopropylmethyl)-4-fluorobenzamido)-2-fluorobenzoic acid.

[0144] Fig. 9 The figure is a four-step combined microchannel synthesis flow chart of 3-(N-(cyclopropylmethyl)-4-fluorobenzamido)-2-fluorobenzoic acid.

[0145] Fig.10 The microchannel synthesis flow chart of 3-(N-(cyclopropylmethyl)-4-fluorobenzamido)-2-fluorobenzoyl chloride.

[0146] Fig.11 This is the microchannel synthesis flow chart of ciprofloxacin.

[0147] Fig.12 The overall flow chart of the microchannel synthesis of ciprofloxacin

[0148] Fig.13 For ciprofloxacin 1 H NMR spectra.

[0149] Fig.14 For ciprofloxacin 19 F NMR spectrum. DETAILED DESCRIPTION

[0150] In order to make the purpose, technical scheme and advantages of the present invention clearer, the present invention is further described in detail below in conjunction with embodiments. The specific embodiments described herein are only used to explain the present invention and are not intended to constitute any limitation of the present invention. In addition, in the following description, the description of known structures and technologies is omitted to avoid unnecessary confusion of the concepts of the present disclosure. Such structures and technologies are also described in many publications.

[0151] The reagents used in the present invention can be purchased from the market or prepared by the method described in the present invention. 1. Synthesis of bromodecafluoroaniline:

[0152] Step 1) Synthesis of decafluoroaniline

[0153] Pump: Double plunger pump.

[0154] Mixers and accessories: 1 / 16 inch mixer, 1 / 8 inch mixer, 1 / 8 inch nut front and rear ferrules, 1 / 16 inch nut front and rear ferrules.

[0155] Reaction Coil: One-sixteenth inch Teflon tubing.

[0156] Back pressure device.

[0157] Heating module: stirrer.

[0158] Method 1

[0159] Organic phase (phase A), aqueous phase containing sodium dithionite (phase B), aqueous phase containing sodium hydroxide (phase C).

[0160] The solvent of the reaction is as follows: phase A is ethyl acetate and acetonitrile in a ratio of 1:1; phase B is water and acetonitrile in a ratio of 4:1; and phase C is water and acetonitrile in a ratio of 1:1.

[0161] The concentration of the reaction is

[0162] Phase A: 2-trifluoromethylaniline 0.2 mol / L, heptafluoroisopropyl iodide 0.4 mol / L, tetrabutylammonium bromide 0.015 mol / L, dibenzo-18-crown-6 0.015 mol / L.

[0163] Phase B: Sodium dithionite: 0.6 mol / L, Sodium carbonate: 0.04 mol / L.

[0164] Phase C: a mixed solution of sodium hydroxide in water and acetonitrile: 0.1 mol / L.

[0165] The reaction time is 1 h.

[0166] The temperature of the reaction was 120°C.

[0167] The flow rates of the reaction were 0.5 mL / min for phase A, 0.5 mL / min for phase B, and 1 mL / min for phase C.

[0168] The reaction pressure is 0.6 MPa.

[0169] Method 2 (Zoom in)

[0170] Except for the concentration, flow rate and reaction apparatus, other conditions are the same as those in step 1 of method 1 for synthesizing bromodecafluoroaniline.

[0171] The reaction process is as follows Figure 1 .

[0172] The concentrations of the reaction were:

[0173] Phase A: 2-trifluoromethylaniline 0.6 mol / L, heptafluoroisopropyl iodide 1.2 mol / L, tetrabutylammonium bromide 0.05 mol / L, dibenzo-18-crown ether-6 0.015 mol / L.

[0174] Phase B: Sodium dithionite: 0.1 mol / L, Sodium carbonate: 0.04 mol / L.

[0175] Phase C: a mixed solution of sodium hydroxide in water and acetonitrile: 0.1 mol / L.

[0176] The flow rates of the reaction were 6 mL / min for phase A, 6 mL / min for phase B, and 9 mL / min for phase C.

[0177] Synthesis of Perfluoropropyl Substituted Aniline Derivatives

[0178] Organic phase (phase A), aqueous phase containing sodium dithionite (phase B), aqueous phase containing sodium hydroxide (phase C).

[0179] The solvent of the reaction is as follows: phase A is ethyl acetate and acetonitrile in a ratio of 1:1; phase B is water and acetonitrile in a ratio of 4:1; and phase C is water and acetonitrile in a ratio of 1:1.

[0180] The concentrations of the reaction were:

[0181] Phase A: 0.2 mol / L of aniline, o-difluoromethoxyaniline, p-anisidine, o-methylaniline or o-chloroaniline, 0.4 mol / L of heptafluoroisopropyl iodide, 0.015 mol / L of tetrabutylammonium bromide, and 0.015 mol / L of dibenzo-18-crown-6.

[0182] Phase B: Sodium dithionite: 0.6 mol / L, Sodium carbonate: 0.04 mol / L.

[0183] Phase C: a mixed solution of sodium hydroxide in water and acetonitrile: 0.1 mol / L.

[0184] The reaction time is 1 h.

[0185] The reaction temperature is 80-120°C.

[0186] The flow rates of the reaction were 0.5 mL / min for phase A, 0.5 mL / min for phase B, and 1 mL / min for phase C.

[0187] The reaction pressure is 0.6 MPa.

[0188] Step 2) Synthesis of bromodecafluoroaniline

[0189] Pump: Double plunger pump.

[0190] Mixer and accessories: 1 / 16 inch mixer, 1 / 8 inch nut front and rear ferrules, 1 / 16 inch nut front and rear ferrules.

[0191] Reaction Coil: One-sixteenth inch Teflon tubing.

[0192] Back pressure device.

[0193] Heating module: stirrer.

[0194] The reaction process is as follows Figure 2 .

[0195] Contains decafluoroaniline (phase A), contains NBS (phase B).

[0196] The solvent for the reaction is acetonitrile.

[0197] The concentrations of the reaction are: decafluoroaniline 0.1 mol / L, NBS 0.3 mol / L.

[0198] The reaction time is 30 min.

[0199] The temperature of the reaction was 120°C.

[0200] The flow rates of the reaction were 0.1 mL / min for phase A and 0.1 mL / min for phase B.

[0201] The reaction pressure is 0.3 MPa.

[0202] 2. Synthesis of 3-(N-(cyclopropylmethyl)-4-fluorobenzamido)-2-fluorobenzoic acid

[0203] Method 1: Step-by-step reaction

[0204] Step 1) Synthesis of methyl 2-fluoro-3-aminobenzoate

[0205]

[0206] A commercial high-pressure hydrogen generator (Ou Shi Sheng, packed bed retention volume 3 ml) and a microchannel hydrogenator (Ou Shi Sheng) were used. The reaction process is as follows: Figure 3 .

[0207] The reaction is carried out in a reaction bottle, the reaction time is 2 hours, and the yield is 96%. The reaction time of this reaction is 6-15 minutes, the yield is 97%, and the use of a high-pressure reactor is avoided, the online material is small, and the process is inherently safe.

[0208] The flow rate of the hydrogen is 10 mL / min to 40 mL / min, for example, 10 mL / min, 20 mL / min, 30 mL / min, 40 mL / min, preferably 20 mL / min.

[0209] The flow rate of the reaction solution of methyl 2-fluoro-3-nitrobenzoate is 0.1 mL / min to 0.5 mL / min, preferably 0.2 mL / min. The concentration of the reaction solution is 0.2 mol / L to 1 mol / L, for example, 0.2 mol / L, 0.3 mol / L, 0.4 mol / L, 0.5 mol / L, 0.6 mol / L, 0.7 mol / L, 0.8 mol / L, 0.9 mol / L, 1 mol / L, preferably 1 mol / L.

[0210] The dosage of the palladium carbon is 1-2 g; based on the raw material concentration of 1 mol / L, the flow rate of 0.2 mL / min (6 min) and continuous stable operation for 24 hours, the relative raw material mass fraction of the palladium carbon (5-10 w / w% loading amount) is 0.0017%-0.014%; the reaction temperature is 60-80°C, for example, it can be 60°C, 70°C, 80°C, preferably 80°C.

[0211] The solvent for the reaction is ethanol, acetonitrile or ethyl acetate, preferably ethyl acetate.

[0212] The reaction time is 6 min to 15 min, for example, it can be 6 min, 7 min, 8 min, 9 min, 10 min, 11 min, 12 min, 13 min, 14 min, 15 min, preferably 15 min.

[0213] Step 2) Synthesis of methyl 3-((cyclopropylmethyl)amino)-2-fluorobenzoate

[0214]

[0215] A commercial high-pressure hydrogen generator (Ou Shi Sheng, packed bed retention volume 3 ml) and a microchannel hydrogenator (Ou Shi Sheng) were used. The reaction process is as follows: Figure 4 .

[0216] The reaction time is 16 hours in a reaction bottle, but in the present continuous flow reaction, it only takes 30 minutes, and the yield is 97%, which is also improved. At the same time, the use of a high-pressure reactor is avoided, and the safety is greatly improved.

[0217] The flow rate of the hydrogen is 10 mL / min to 40 mL / min, for example, 10 mL / min, 20 mL / min, 30 mL / min, 40 mL / min, preferably 20 mL / min.

[0218] The flow rate of the mixed reaction liquid of methyl 2-fluoro-3-aminobenzoate and cyclopropanecarboxaldehyde is 0.1 mL / min to 0.3 mL / min, preferably 0.1 mL / min.

[0219] The amount of the platinum carbon used is 1-2 g; based on a raw material concentration of 0.2 mol / L, a flow rate of 0.3 mL / min and continuous stable operation for 24 hours, the mass fraction of the platinum carbon (5-10 w / w% loading) relative to the above methyl ester is 6.8%-13.6%.

[0220] The concentration of the methyl 2-fluoro-3-aminobenzoate is 0.1 mol / L-0.2 mol / L, preferably 0.2 mol / L.

[0221] The molar ratio of the methyl 2-fluoro-3-aminobenzoate to cyclopropanecarboxaldehyde is 1:(2-3), preferably 1:2.

[0222] The reaction temperature is 80-120°C, preferably 100°C.

[0223] The solvent for the reaction is ethanol, methanol or toluene, preferably toluene.

[0224] The reaction time is 20-40 min, preferably 30 min.

[0225] Step 3) Synthesis of methyl 3-(N-7(cyclopropylmethyl)-4-fluorobenzamido)-2-fluorobenzoate

[0226]

[0227] Pump: Double plunger pump.

[0228] Mixer and accessories: 1 / 16 inch mixer, 1 / 8 inch nut front and rear ferrules, 1 / 16 inch nut front and rear ferrules.

[0229] Reaction Coil: One-sixteenth inch Teflon tubing.

[0230] Back pressure device.

[0231] Heating module: stirrer.

[0232] The reaction process is as follows Figure 5 .

[0233] The reaction time is 5 min, the yield is 97%, and the use of toxic and difficult-to-degrade solvent DCE is avoided, and the low-toxic green solvent acetonitrile is used.

[0234] The reaction liquid flow rate of the methyl 3-((cyclopropylmethyl)amino)-2-fluorobenzoate was 0.5 mL / min.

[0235] The reaction liquid flow rate of the p-fluorobenzoyl chloride is 0.5 mL / min.

[0236] The concentration of methyl 3-((cyclopropylmethyl)amino)-2-fluorobenzoate is 0.2 mol / L-0.4 mol / L, preferably 0.2 mol / L.

[0237] The concentration of p-fluorobenzoyl chloride is 0.2 mol / L-0.6 mol / L, preferably 0.21 mol / L

[0238] The molar ratio of methyl 3-((cyclopropylmethyl)amino)-2-fluorobenzoate to p-fluorobenzoyl chloride is 1:(1-2), preferably 1:1.05.

[0239] The reaction temperature is 80-120°C, preferably 120°C.

[0240] The solvent of the reaction is acetonitrile or 1,2-dichloroethane, preferably acetonitrile.

[0241] The reaction time is 5-30 min, preferably 5 min.

[0242] Step 4) Synthesis of 3-(N-(cyclopropylmethyl)-4-fluorobenzamido)-2-fluorobenzoic acid

[0243]

[0244] Pump: Double plunger pump.

[0245] Mixer and accessories: 1 / 16 inch mixer, 1 / 8 inch nut front and rear ferrules, 1 / 16 inch nut front and rear ferrules.

[0246] Reaction Coil: One-sixteenth inch Teflon tubing.

[0247] Back pressure device.

[0248] Heating module: stirrer.

[0249] The reaction process is as follows Figure 6 .

[0250] The reaction time is 15s and the yield is 97%. Compared with methanol, water, which is cheaper and greener, is introduced as a solvent.

[0251] The flow rate of the reaction solution of methyl 3-(N-(cyclopropylmethyl)-4-fluorobenzamido)-2-fluorobenzoate was 10 mL / min.

[0252] The flow rate of the sodium hydroxide in the reaction solution is preferably 10 mL / min.

[0253] The concentration of the methyl 3-(N-(cyclopropylmethyl)-4-fluorobenzamido)-2-fluorobenzoate is 0.1 mol / L to 0.2 mol / L, preferably 0.13 mol / L.

[0254] The molar ratio of methyl 3-((cyclopropylmethyl)amino)-2-fluorobenzoate to sodium hydroxide is 1:(1.3-3), preferably 1:1.3.

[0255] The reaction temperature is 80-85°C, preferably 85°C.

[0256] The solvent of the reaction solution 3-(N-(cyclopropylmethyl)-4-fluorobenzamido)-2-fluorobenzoic acid methyl ester is acetonitrile.

[0257] The solvent of the sodium hydroxide in the reaction solution is water.

[0258] The reaction time is 10 min-15 s, preferably 15 s.

[0259] Method 2: Two-step combined reaction

[0260] Step 1) Synthesis of methyl 3-((cyclopropylmethyl)amino)-2-fluorobenzoate

[0261] The reaction flow chart is as follows Figure 7 .

[0262] The flow rate of the hydrogen is 10 mL / min to 40 mL / min, for example, 10 mL / min, 20 mL / min, 30 mL / min, 40 mL / min, preferably 20 mL / min.

[0263] The flow rate of the reaction solution (mixed solution of methyl 2-fluoro-3-nitrobenzoate and cyclopropanecarboxaldehyde) is 0.05 mL / min-0.5 mL / min, preferably 0.075 mL / min.

[0264] The amount of platinum carbon in the micro-packed bed: the relative mass fraction of the 5% platinum carbon is 1% to 10%;

[0265] The concentration of the methyl 2-fluoro-3-nitrobenzoate is 0.1 mol / L to 0.2 mol / L, preferably 0.1 mol / L.

[0266] The concentration of the cyclopropanecarboxaldehyde is 0.2 mol / L to 0.4 mol / L, preferably 0.3 mol / L.

[0267] The reaction temperature is 80°C to 120°C, preferably 100°C.

[0268] The solvent for the reaction is toluene, preferably toluene.

[0269] The reaction time is 40 min.

[0270] Step 2) Synthesis of 3-(N-(cyclopropylmethyl)-4-fluorobenzamido)-2-fluorobenzoic acid

[0271] The reaction flow chart is as follows Figure 8 .

[0272] The flow rate of the reaction solution methyl 3-((cyclopropylmethyl)amino)-2-fluorobenzoate is preferably 0.5 mL / min.

[0273] The flow rate of the reaction solution p-fluorobenzoyl chloride is preferably 0.5 mL / min.

[0274] The flow rate of the sodium hydroxide in the reaction solution is preferably 0.5 mL / min.

[0275] The concentration of the methyl 3-((cyclopropylmethyl)amino)-2-fluorobenzoate is 0.1 mol / L to 0.3 mol / L, preferably 0.13 mol / L.

[0276] The concentration of p-fluorobenzoyl chloride is 0.1 mol / L to 0.3 mol / L, preferably 0.14 mol / L.

[0277] The concentration of the sodium hydroxide is 0.1 mol / L to 0.6 mol / L, preferably 0.4 mol / L.

[0278] The reaction temperature is 80°C to 130°C, preferably the first reaction coil temperature is 130°C, and the second reaction coil temperature is 85°C.

[0279] The solvent for the reaction is acetonitrile, water, preferably 3-((cyclopropylmethyl)amino)-2-fluorobenzoic acid methyl ester, 4-fluorobenzoyl chloride is acetonitrile, and the solvent for sodium hydroxide is water.

[0280] The reaction time is 5 min to 30 min, preferably the first coil retention time is 5 min and the second coil retention time is 1.3 min.

[0281] Method 3: Four-step combined reaction

[0282] Synthesis of 3-(N-(cyclopropylmethyl)-4-fluorobenzamido)-2-fluorobenzoic acid

[0283] Commercial high-pressure hydrogen generator (Ou Shi Sheng, packed bed retention volume 3 ml), microchannel hydrogenator (Ou Shi Sheng).

[0284] Pump: Double plunger pump.

[0285] Mixer and accessories: 1 / 16 inch mixer, 1 / 8 inch nut front and rear ferrules, 1 / 16 inch nut front and rear ferrules.

[0286] Reaction Coil: One-sixteenth inch Teflon tubing.

[0287] Back pressure device.

[0288] Heating module: stirrer.

[0289] The reaction flow chart is as follows Fig. 9 .

[0290] When the reaction is carried out in a reaction bottle, the total reaction time of the four steps is more than 24 hours, and the yield is 78%; while in the continuous flow, the total time of the four steps is 48 minutes, and the yield is 87%. The continuous flow reaction of the present invention has a huge advantage.

[0291] The flow rate of the hydrogen is 10 mL / min-40 mL / min, for example, 10 mL / min, 20 mL / min, 30 mL / min, 40 mL / min, preferably 20 mL / min.

[0292] The flow rate of the reaction solution (mixed solution of methyl 2-fluoro-3-nitrobenzoate and cyclopropanecarboxaldehyde) is 0.05 mL / min to 0.5 mL / min, preferably 0.075 mL / min.

[0293] Based on a raw material concentration of 0.1 mol / L, a flow rate of 0.075 mL / min and continuous stable operation for 120 hours, the mass fraction of the platinum carbon (5-10 w / w% loading) relative to the methyl ester is 9.3% to 18.6%.

[0294] The concentration of the methyl 2-fluoro-3-nitrobenzoate is 0.1 mol / L.

[0295] The concentration of the cyclopropanecarboxaldehyde is 0.3 mol / L.

[0296] The reaction temperature is 80-120°C, preferably 100°C.

[0297] The solvent for the reaction is toluene.

[0298] The reaction time is 40 min.

[0299] The solution of the above two-step reaction is a toluene solution of pure 3-((cyclopropylmethyl)amino)-2-fluorobenzoic acid methyl ester after the two-step reaction of nitro reduction hydrogenation and reductive amination of the raw material 2-fluoro-3-nitrobenzoic acid methyl ester, which is connected to the pump of the next two-step reaction as the raw material solution, and the flow rate is preferably 0.4 mL / min.

[0300] The flow rate of the reaction solution p-fluorobenzoyl chloride is 0.4 mL / min.

[0301] The flow rate of the sodium hydroxide in the reaction solution is 0.8 mL / min.

[0302] The concentration of p-fluorobenzoyl chloride is 0.08 mol / L to 0.2 mol / L, preferably 0.095 mol / L.

[0303] The concentration of the sodium hydroxide is 0.1 mol / L to 0.6 mol / L, preferably 0.12 mol / L.

[0304] The reaction temperature is 80°C to 140°C, preferably the first reaction coil temperature is 140°C, and the second reaction coil temperature is 90°C.

[0305] The solvent of the reaction is acetonitrile or water, preferably the solvent of p-fluorobenzoyl chloride is acetonitrile, and the solvent of sodium hydroxide is water to methanol in a ratio of 1:1.

[0306] The reaction time is 5 to 50 minutes, preferably the total retention time of the first two steps is 40 minutes, and the retention time of the last two coils is 6.25 minutes and 1.56 minutes.

[0307] 3. Synthesis of cyprofenamide by amidation

[0308] Step 1) Synthesis of 3-(N-(cyclopropylmethyl)-4-fluorobenzamido)-2-fluorobenzoyl chloride

[0309] Pump: Double plunger pump, HPLC pump.

[0310] Mixer and accessories: 1 / 16 inch mixer, 1 / 8 inch nut front and rear ferrules, 1 / 16 inch nut front and rear ferrules.

[0311] Reaction Coil: 1 / 16 inch PFA tubing.

[0312] Back pressure device.

[0313] Heating module: stirrer.

[0314] The reaction flow chart is as follows Fig.10 .

[0315] Contains 3-(N-(cyclopropylmethyl)-4-fluorobenzamido)-2-fluorobenzoic acid (phase A) and contains thionyl chloride (phase B).

[0316] The solvent for the reaction is toluene.

[0317] The concentrations of the reaction are: 0.2 mol / L 3-(N-(cyclopropylmethyl)-4-fluorobenzamido)-2-fluorobenzoic acid and 1 mol / L thionyl chloride.

[0318] The reaction time is 30 min.

[0319] The temperature of the reaction was 130°C.

[0320] The flow rates of the reaction were 0.5 mL / min for phase A and 0.5 mL / min for phase B.

[0321] The reaction pressure is 0.8 MPa.

[0322] Step 2) Synthesis of cyprodinilfluanid

[0323] Pump: Double plunger pump (Oushisheng), HPLC pump (Oushisheng).

[0324] Mixer and accessories: 1 / 16 inch mixer, 1 / 8 inch nut front and rear ferrules, 1 / 16 inch nut front and rear ferrules.

[0325] Reaction Coil: One-sixteenth inch Teflon tubing.

[0326] Back pressure device.

[0327] Heating module: stirrer.

[0328] The reaction flow chart is as follows Fig.11 .

[0329] Contains 3-(N-(cyclopropylmethyl)-4-fluorobenzamido)-2-fluorobenzoyl chloride, bromodecafluoroaniline (phase A), and LiHMDS (phase B).

[0330] The solvent for the reaction is toluene.

[0331] The reaction concentration is: 0.05M 3-(N-(cyclopropylmethyl)-4-fluorobenzamido)-2-fluorobenzoyl chloride (the acyl chloride solution prepared in step 1 above is diluted four times by replacing the solvent), 0.075mol / L bromodecafluoroaniline, and 0.2mol / L NaHMDS (or LiHMDS).

[0332] The reaction time is 7.5 min.

[0333] The temperature of the reaction was 90°C.

[0334] The flow rates of the reaction were 2 mL / min for phase A and 2 mL / min for phase B.

[0335] The reaction pressure is 0.8 MPa.

[0336] Preparation Example 1: Preparation of methyl 2-fluoro-3-aminobenzoate in continuous flow

[0337] 39.83 g (200 mmol) of methyl 2-fluoro-3-nitrobenzoate was dissolved in 200 mL of ethyl acetate. 1 gram of palladium carbon (5-10 w / w% loading) was loaded in the packed bed of the gas-liquid reactor. The temperature was set to 60°C, the back pressure was set to 1 MPa, the hydrogen flow rate was set to 40 mL / min, the reaction liquid flow rate was set to 0.2 mL / min, the retention time was 15 min, the yield was 91%, and the space-time yield was 1840 mg / h.

[0338] Structural testing: 1 H NMR (600 MHz, CDCl 3 ) data are as follows (δ [ppm]): 7.23 (m, 1H), 6.93 (m, 2H), 3.89 (s, 3H), 3.60 (br s, 2H).

[0339] Preparation Example 2: Preparation of methyl 3-((cyclopropylmethyl)amino)-2-fluorobenzoate in continuous flow

[0340] 6.77g (40mmol) 2-fluoro-3-aminobenzoic acid methyl ester and 5.61g (80mmol) cyclopropylcarboxaldehyde were dissolved in 200mL toluene. 1.7 grams of platinum carbon (5-10w / w% loading) were loaded in the packed bed of the gas-liquid reactor. The temperature was set at 100°C, the back pressure was set at 1.6MPa, the hydrogen flow rate was set at 20mL / min, the reaction solution flow rate was set at 0.1mL / min, the retention time was 30min, the yield was 97%, and the space-time yield was 196.7mg / h.

[0341] Structural detection: LC / MS: m / z=223; 1H NMR (600MHz, CDCl3) data are as follows (δ[ppm]): 7.08 (m, 1H),

[0342] 6.93(m,1H),6.73(m,1H),4.15(br s,1H),3.83(s,3H),2.91(t,2H),1.03(m,1H),0.50(m,2H),0.18(m,2H).

[0343] Preparation Example 3: Preparation of methyl 3-(N-(cyclopropylmethyl)-4-fluorobenzamido)-2-fluorobenzoate in continuous flow

[0344] 5.80 g (26 mmol) of methyl 3-((cyclopropylmethyl)amino)-2-fluorobenzoate was dissolved in 200 mL of acetonitrile and pumped into the reaction coil from pump A through a T-type mixer at a flow rate of 0.5 mL / min; 4.44 g (28 mmol) of p-fluorobenzoyl chloride was dissolved in 200 mL of acetonitrile and pumped into the reaction coil from pump B through a T-type mixer at a flow rate of 0.5 mL / min. The reaction retention time was 6 min, the temperature was 130° C., the back pressure was 0.6 MPa, the yield was 88%, and the space-time yield was 1.18 g / h.

[0345] Structure detection: LC / MS [M+1]: m / z = 345; 1 H NMR (400 MHz, CDCl3) data are as follows (δ [ppm]):

[0346] 7.75(t,1H),7.28(m,3H),7.05(t,1H),6.80(t,2H),3.82(s,3H),3.69(d,2H),0.99(m,1H),0.36(m,2H),0.03(m,2H); 19 F NMR (600 MHz, CDCl3) data are as follows (δ [ppm]): -110.06 (s, 1F), -119.55 (s, 1F). Preparation Example 4: Preparation of 3-(N-(cyclopropylmethyl)-4-fluorobenzamido)-2-fluorobenzoic acid in continuous flow

[0347] 13.81g (40mmol) of methyl 3-(N-7(cyclopropylmethyl)-4-fluorobenzamido)-2-fluorobenzoate was dissolved in 200mL of acetonitrile and pumped into the reaction coil from pump A through a T-type mixer at a flow rate of 10mL / min; 2.08g (52mmol) of sodium hydroxide was dissolved in 200mL of water and pumped into the reaction coil from pump B through a T-type mixer at a flow rate of 10mL / min. The reaction retention time was 15s, the temperature was 85°C, the back pressure was 0.5MPa, the yield was 94%, and the space-time yield was 37.45g / h.

[0348] Structural testing: 1 H NMR (600 MHz, CDCl3) data are as follows (δ [ppm]): 7.88 (t, 1H), 7.34 (m, 3H), 7.13 (t, 1H), 6.87 (t, 2H), 3.75 (d, 2H), 1.05 (m, 1H), 0.44 (m, 2H), 0.10 (m, 2H).

[0349] Preparation Example 5: Preparation of methyl 3-((cyclopropylmethyl)amino)-2-fluorobenzoate from methyl 2-fluoro-3-nitrobenzoate in two steps in a continuous flow end-to-end reaction

[0350] 3.98 g (20 mmol) of methyl 2-fluoro-3-nitrobenzoate and 4.21 g (60 mmol) of cyclopropylcarboxaldehyde were dissolved in 200 mL of toluene. 1.7 g of 5% platinum carbon was loaded in the packed bed of the gas-liquid reactor. The temperature was set at 100° C., the back pressure was set at 1.6 MPa, the hydrogen flow rate was set at 20 mL / min, the reaction liquid flow rate was set at 0.075 mL / min, the retention time was 40 min, the two-step total yield was 93%, and the space-time yield was 93.03 mg / h.

[0351] Preparation Example 6: Preparation of 3-(N-(cyclopropylmethyl)-4-fluorobenzamido)-2-fluorobenzoic acid from methyl 3-((cyclopropylmethyl)amino)-2-fluorobenzoate in two steps in a continuous flow

[0352] Pump A is used to transport 3-((cyclopropylmethyl)amino)-2-fluorobenzoic acid methyl ester solution, pump B is used to transport p-fluorobenzoyl chloride solution, and pump C is used to transport sodium hydroxide solution. 5.80g (26mmol) 3-((cyclopropylmethyl)amino)-2-fluorobenzoic acid methyl ester is dissolved in 200mL acetonitrile and transported into the first reaction coil via pump A, and the flow rate of pump A is 0.5mL / min; 4.44g (28mmol) p-fluorobenzoyl chloride is dissolved in 200mL acetonitrile and transported into the first reaction coil via pump B, and the flow rate of pump B is 0.5mL / min; 3.20g (80mmol) sodium hydroxide is dissolved in 200mL water and transported into the second reaction coil via pump C, and the flow rate of pump C is 0.5mL / min. The temperature of the first reaction coil is 130℃, and the retention time is 5min; the temperature of the second reaction coil is 85℃, and the retention time is 1.3min; the pressure is 0.6MPa. The total yield of the two steps was 88.3%, and the space-time yield was 1.14 g / h.

[0353] Preparation Example 7: Synthesis of 3-(N-(cyclopropylmethyl)-4-fluorobenzamido)-2-fluorobenzoic acid from methyl 2-fluoro-3-nitrobenzoate in four steps in a continuous flow end-to-end reaction

[0354] 3.98g (20mmol) of methyl 2-fluoro-3-nitrobenzoate and 4.21g (60mmol) of cyclopropylcarboxaldehyde were dissolved in 200mL of toluene. 1.7g of 5% platinum carbon was loaded in the packed bed of the gas-liquid reactor. The temperature was set to 100°C, the back pressure was set to 1.6MPa, the hydrogen flow rate was set to 20mL / min, the reaction liquid flow rate was set to 0.075mL / min, the retention time was 40min, and the outflowing reaction liquid was directly transported to the first reaction coil by pump A, and the flow rate of pump A was set to 0.4mL / min. Pump B transported p-fluorobenzoyl chloride solution at a flow rate of 0.4mL / min; pump C transported sodium hydroxide solution at a flow rate of 0.4mL / min. 3.01g (19mmol) of p-fluorobenzoyl chloride was dissolved in 200mL of acetonitrile and input into the first reaction coil via pump B. 1.12g (28mmol) of sodium hydroxide solution was dissolved in 200mL of water and fed into the second reaction coil via pump C. The temperature of the first reaction coil was 140°C, and the retention time was 6.25min; the temperature of the second reaction coil was 90°C, and the retention time was 1.56min; the back pressure was 0.6MPa. The total yield of the four steps was 87%, and the space-time yield was 662mg / h.

[0355] Preparation Example 8: Preparation of decafluoroaniline in continuous flow

[0356] 16.11 g (100 mmol) of 2-trifluoromethylaniline, 59.2 g (20 mmol) of heptafluoroisopropyl iodide, 2.73 g (7.5 mmol) of dibenzo-18-crown-6, and 2.22 g (7.5 mmol) of tetrabutylammonium bromide were dissolved in a mixed solution of 250 mL of ethyl acetate and 250 mL of acetonitrile. This is phase A.

[0357] 52.23 g (300 mmol) of sodium dithionite and 2.12 g (20 mmol) of sodium carbonate were dissolved in a mixed solution of 400 mL of water and 100 mL of acetonitrile. This is phase B.

[0358] 1.6 g (40 mmol) of sodium hydroxide was dissolved in a mixed solution of 500 mL of water and 500 mL of acetonitrile to obtain phase C.

[0359] The three phases were pumped in separately by double syringe pumps, with the flow rate of phase A at 0.5 mL / min, the flow rate of phase B at 0.5 mL / min, and the flow rate of phase C at 1 mL / min, and then passed through the mixer into the reaction coil with a retention volume of 60 mL. The reaction temperature was 120°C, the retention time was 60 min, the pressure was 0.6 MPa, and the yield was 87%. The space-time yield was 1627 mg / h.

[0360] Structural testing: 1 H NMR (600 MHz, CDCl3) data are as follows (δ [ppm]): 7.43 (d, 1H), 7.37 (s, 1H), 6.98 (d, 1H), 6.28 (s, 2H); 19 F NMR (600MHz, CDCl3) data are as follows (δ [ppm]): -61.01 (s, 3F), -74.89 (d, 6F),

[0361] -180.95(m,1F).

[0362] Preparation Example 9: Preparation of Bromodecafluoroaniline in Continuous Flow

[0363] Decafluoroaniline (3.29 g, 10 mmol) was dissolved in 100 mL of acetonitrile as phase A, and N-bromosuccinimide (5.34 g, 30 mmol) was dissolved in 100 mL of acetonitrile as phase B. The phases were pumped into the reaction coil via a double syringe pump through a T-type mixer. The pumping speed of phase A was 0.1 mL / min, and the pumping speed of phase B was 0.1 mL / min. The retention time was 30 min, the temperature was 120° C., the pressure was 0.3 MPa, and the yield was 98%.

[0364] Structural detection: 1H NMR (600 MHz, CDCl3) data are as follows (δ [ppm]): 7.81 (s, 1H), 7.71 (s, 1H), 5.85 (s, 2H).

[0365] Preparation Example 10: Scale-up of the preparation of decafluoroaniline in a continuous flow

[0366] 72.5 g (450 mmol) of 2-trifluoromethylaniline, 177.6 g (600 mmol) of heptafluoroisopropyl iodide, 4.05 g (11.23 mmol) of dibenzo-18-crown-6, and 12.1 g (38 mmol) of tetrabutylammonium bromide were dissolved in a mixed solution of 375 mL of ethyl acetate and 375 mL of acetonitrile. This is phase A.

[0367] 104.4 g (600 mmol) of sodium dithionite and 3.2 g (30 mmol) of sodium carbonate were dissolved in a mixed solution of 600 mL of water and 150 mL of acetonitrile. This is phase B.

[0368] 4 g (100 mmol) of sodium hydroxide was dissolved in a mixed solution of 500 mL of water and 500 mL of acetonitrile to obtain phase C.

[0369] The three phases were pumped in separately by double syringe pumps, with the flow rate of phase A being 6 mL / min, the flow rate of phase B being 6 mL / min, and the flow rate of phase C being 9 mL / min, and then passed through the mixer into the reaction coil with a retention volume of 720 mL. The reaction temperature was 120°C, the retention time was 60 min, the pressure was 0.6 MPa, and the yield was 68%. The space-time yield was 48.06 g / h.

[0370] Preparation Example 11: Preparation of 4-(perfluoropropan-2-yl)-2-difluoromethoxyaniline in continuous flow

[0371] 3.2 g (20 mmol) of o-difluoromethoxyaniline, 12 g (40 mmol) of heptafluoroisopropyl iodide, 0.36 g (0.2 mmol) of dibenzo-18-crown-6, and 1 g (3 mmol) of tetrabutylammonium bromide were dissolved in a mixed solution of 50 mL of ethyl acetate and 50 mL of acetonitrile. This is phase A.

[0372] 10.5 g (60 mmol) of sodium dithionite and 0.21 g (0.4 mmol) of sodium carbonate were dissolved in a mixed solution of 80 mL of water and 20 mL of acetonitrile. This is phase B.

[0373] 0.8 g (20 mmol) of sodium hydroxide was dissolved in a mixed solution of 100 mL of water and 100 mL of acetonitrile to obtain phase C.

[0374] The three phases were pumped in separately by double syringe pumps, with the flow rate of phase A at 0.5 mL / min, the flow rate of phase B at 0.5 mL / min, and the flow rate of phase C at 1 mL / min, and passed through the mixer into the reaction coil with a retention volume of 60 mL. The reaction temperature was 90°C, the retention time was 60 min, the pressure was 0.6 MPa, and the yield was 76%.

[0375] Structural testing: 1 H NMR (600 MHz, CDCl 3 ) data are as follows (δ [ppm]): 7.25 (d, 2H), 6.82 (d, 1H), 6.48 (t, 1H), 4.09 (d, 2H).

[0376] Preparation Example 12: Preparation of 2-(perfluoropropan-2-yl)-4-methoxyaniline in continuous flow

[0377] 2.46 g (20 mmol) of p-anisidine, 12 g (40 mmol) of heptafluoroisopropyl iodide, 0.36 g (0.2 mmol) of dibenzo-18-crown-6, and 1 g (3 mmol) of tetrabutylammonium bromide were dissolved in a mixed solution of 50 mL of ethyl acetate and 50 mL of acetonitrile. This is phase A.

[0378] 10.5 g (60 mmol) of sodium dithionite and 0.21 g (0.4 mmol) of sodium carbonate were dissolved in a mixed solution of 80 mL of water and 20 mL of acetonitrile. This is phase B.

[0379] 0.8 g (20 mmol) of sodium hydroxide was dissolved in a mixed solution of 100 mL of water and 100 mL of acetonitrile to obtain phase C.

[0380] The three phases were pumped in separately by double syringe pumps, with the flow rate of phase A at 0.5 mL / min, the flow rate of phase B at 0.5 mL / min, and the flow rate of phase C at 1 mL / min, and passed through the mixer into the reaction coil with a retention volume of 60 mL. The reaction temperature was 120°C, the retention time was 60 min, the pressure was 0.6 MPa, and the yield was 83%.

[0381] Structural testing: 1 H NMR (600 MHz, CDCl 3 ) data are as follows (δ [ppm]): 6.89 (m, 1H), 6.85 (s, 1H), 6.69 (d, 1H), 3.89 (s, 2H), 3.74 (d, 3H).

[0382] Preparation Example 13: Preparation of 4-(perfluoropropan-2-yl)-2-methylaniline in continuous flow

[0383] 2.15 g (20 mmol) of o-methylaniline, 12 g (40 mmol) of heptafluoroisopropyl iodide, 0.36 g (0.2 mmol) of dibenzo-18-crown-6, and 1 g (3 mmol) of tetrabutylammonium bromide were dissolved in a mixed solution of 50 mL of ethyl acetate and 50 mL of acetonitrile. This is phase A.

[0384] 10.5 g (60 mmol) of sodium dithionite and 0.21 g (0.4 mmol) of sodium carbonate were dissolved in a mixed solution of 80 mL of water and 20 mL of acetonitrile. This is phase B.

[0385] 0.8 g (20 mmol) of sodium hydroxide was dissolved in a mixed solution of 100 mL of water and 100 mL of acetonitrile to obtain phase C.

[0386] The three phases were pumped in separately by double syringe pumps, with the flow rate of phase A at 0.5 mL / min, the flow rate of phase B at 0.5 mL / min, and the flow rate of phase C at 1 mL / min, and passed through the mixer into the reaction coil with a retention volume of 60 mL. The reaction temperature was 100°C, the retention time was 60 min, the pressure was 0.6 MPa, and the yield was 88%.

[0387] Structural testing: 1 H NMR (600 MHz, CDCl3) data are as follows (δ [ppm]): 7.28 (d, 2H), 6.72 (d, 1H), 3.78 (d, 2H), 2.19 (s, 3H); 19 F NMR (600 MHz, CDCl3) data are as follows (δ [ppm]): -75.96 (d, 6F), -181.49 (m, 1F). Preparation Example 14: Preparation of 4-(perfluoropropan-2-yl)-aniline in continuous flow

[0388] 3.7 g (40 mmol) of aniline, 24 g (80 mmol) of heptafluoroisopropyl iodide, 0.72 g (0.4 mmol) of dibenzo-18-crown-6, and 2 g (6 mmol) of tetrabutylammonium bromide were dissolved in a mixed solution of 100 mL of ethyl acetate and 100 mL of acetonitrile. This is phase A.

[0389] 21 g (120 mmol) of sodium dithionite and 0.42 g (0.8 mmol) of sodium carbonate were dissolved in a mixed solution of 160 mL of water and 40 mL of acetonitrile. This is phase B.

[0390] 1.6 g (40 mmol) of sodium hydroxide was dissolved in a mixed solution of 200 mL of water and 200 mL of acetonitrile to obtain phase C.

[0391] The three phases were pumped in separately by double syringe pumps, with the flow rate of phase A being 0.5 mL / min, the flow rate of phase B being 0.5 mL / min, and the flow rate of phase C being 1 mL / min, and then passed through the mixer into the reaction coil with a retention volume of 60 mL. The reaction temperature was 100°C, the retention time was 60 min, the pressure was 0.6 MPa, and the yield was 85%.

[0392] Structural testing: 1The H NMR (600 MHz, CDCl 3 ) data are as follows (δ [ppm]): 7.37 (m, 2H), 6.73 (d, 2H), 3.81 (s, 3H).

[0393] Preparation Example 15: Preparation of 4-(perfluoropropan-2-yl)-2-chloroaniline in continuous flow

[0394] 2.55 g (20 mmol) of o-chloroaniline, 12 g (40 mmol) of heptafluoroisopropyl iodide, 0.36 g (0.2 mmol) of dibenzo-18-crown-6, and 1 g (3 mmol) of tetrabutylammonium bromide were dissolved in a mixed solution of 50 mL of ethyl acetate and 50 mL of acetonitrile. This is phase A.

[0395] 10.5 g (60 mmol) of sodium dithionite and 0.21 g (0.4 mmol) of sodium carbonate were dissolved in a mixed solution of 80 mL of water and 20 mL of acetonitrile. This is phase B.

[0396] 0.8 g (20 mmol) of sodium hydroxide was dissolved in a mixed solution of 100 mL of water and 100 mL of acetonitrile to obtain phase C.

[0397] The three phases were pumped in separately by double syringe pumps, with the flow rate of phase A being 0.5 mL / Min, the flow rate of phase B being 0.5 mL / Min, and the flow rate of phase C being 1 mL / Min, and then passed through the mixer into the reaction coil with a retention volume of 60 mL. The reaction temperature was 100°C, the retention time was 60 min, the pressure was 0.6 MPa, and the yield was 79%.

[0398] Structural testing: 1 H NMR (600 MHz, CDCl 3 ) data are as follows (δ [ppm]): 7.46 (d, 1H), 7.26 (d, 1H), 6.81 (d, 1H), 3.29 (s, 3H).

[0399] The results of the microchannel reaction of Preparation Examples 11-15 were compared with the corresponding autoclave reaction, as shown in Table 1:

[0400] Table 1:

[0401]

[0402] The reaction conditions of the autoclave are referred to patent CN 116178198 A.

[0403] Preparation Example 16: Preparation of 3-(N-(cyclopropylmethyl)-4-fluorobenzamido)-2-fluorobenzoyl chloride in continuous flow

[0404] 2.8 g (8 mmol) of 3-(N-(cyclopropylmethyl)-4-fluorobenzamido)-2-fluorobenzoic acid was dissolved in 40 mL of redistilled toluene as phase A, and 4.8 g (40 mmol) of thionyl chloride was dissolved in 40 mL of redistilled toluene as phase B. The two phases were passed through a double syringe pump at a flow rate of 0.5 mL / min, passed through a T-type mixer, and entered the reaction coil with a retention volume of 30 mL, a retention time of 30 min, a temperature of 130° C., and a pressure of 0.8 MPa. The mixture was spin-dried and directly used for the next step of the synthesis of cyclohexanil.

[0405] Preparation Example 17: Preparation of ciprofloxacin in continuous flow

[0406] The above-mentioned acyl chloride was dissolved in 160 mL of redistilled toluene as phase A, 4.9 g (12 mmol) of bromodecafluoroaniline was added to phase A, 40 mL of lithium bistrimethylsilylamide (1 M toluene solution) was dissolved in 160 mL of toluene as phase B, and the two phases passed through a dual syringe pump at a flow rate of 2 mL / min, passed through a T-type mixer, and entered the reaction coil with a retention volume of 30 mL, a retention time of 7.5 min, a temperature of 90° C., a pressure of 0.8 MPa, and a total yield of 88% in two steps. 1 H NMR images Fig.13 , 19 F NMR images Fig.14 .

[0407] The method of the present invention has been described through preferred embodiments, and relevant personnel can obviously modify or appropriately change and combine the methods and applications described herein within the content, spirit and scope of the present invention to implement and apply the technology of the present invention. Those skilled in the art can refer to the content of this article and appropriately improve the process parameters. It is particularly important to point out that all similar replacements and modifications are obvious to those skilled in the art, and they are all considered to be included in the present invention.

Claims

1. A method for preparing a high value-added intermediate of 3-(N-(cyclopropylmethyl)-4-fluorobenzamido)-2-fluorobenzoic acid in a microchannel, characterized in that: Contains steps: (1) In a micro-packed bed reactor, methyl 2-fluoro-3-nitrobenzoate and hydrogen react under the catalysis of palladium carbon or platinum carbon to obtain methyl 2-fluoro-3-aminobenzoate; according to the concentration of methyl 2-fluoro-3-nitrobenzoate being 1 mol / L, the flow rate being 0.2 mL / min, and the continuous stable operation for 24 hours, the palladium carbon or platinum carbon is 5-10 w / w% loading, and the mass fraction relative to methyl 2-fluoro-3-nitrobenzoate is 1% to 20%; the reaction temperature is 50° C. to 60° C.; optionally, in a micro-packed bed reactor having an inner diameter of 2 mm to 5 mm and a length of 10 to 30 cm, the flow rate of the hydrogen is 10 mL / min to 40 mL / min; the flow rate of the reaction solution of methyl 2-fluoro-3-nitrobenzoate is 0.1 mL / min to 0.5 mL / min, and the concentration is 0.2 mol / L to 1 mol / L; (2) In a micro-packed bed reactor, methyl 2-fluoro-3-aminobenzoate, cyclopropanecarboxaldehyde and hydrogen react under the catalysis of platinum carbon to obtain methyl 3-((cyclopropylmethyl)amino)-2-fluorobenzoate; based on the concentration of methyl 2-fluoro-3-aminobenzoate being 0.2 mol / L, the flow rate being 0.3 mL / min and the continuous stable operation for 24 hours, the platinum carbon is loaded with 5-10 w / w%, and the mass fraction relative to methyl 2-fluoro-3-aminobenzoate is 0. 1% to 20%; optionally, in a micro-packed bed reactor with an inner diameter of 2 mm to 5 mm and a length of 10 to 30 cm, the flow rate of the hydrogen is 10 mL / min to 40 mL / min, the flow rate of the mixed reaction liquid of 2-fluoro-3-aminobenzoic acid methyl ester and cyclopropanecarboxaldehyde is 0.1 mL / min to 0.3 mL / min, and the concentrations are 0.1 mol / L to 0.2 mol / L and 0.2 mol / L to 0.6 mol / L, respectively; (3) in a micro-channel reactor, reacting methyl 3-((cyclopropylmethyl)amino)-2-fluorobenzoate with p-fluorobenzoyl chloride to obtain methyl 3-(N-(cyclopropylmethyl)-4-fluorobenzoylamino)-2-fluorobenzoate; optionally, in a micro-channel reactor having an inner diameter of 0.5 mm to 5 mm, the flow rate of the reaction solution of methyl 3-((cyclopropylmethyl)amino)-2-fluorobenzoate is 0.3 mL / min to 0.8 mL / min; the flow rate of the reaction solution of p-fluorobenzoyl chloride is 0.3 mL / min to 0.8 mL / min; (4) In a micro-channel reactor, 3-(N-(cyclopropylmethyl)-4-fluorobenzamido)-2-fluorobenzoic acid methyl ester is hydrolyzed under the action of sodium hydroxide to obtain 3-(N-(cyclopropylmethyl)-4-fluorobenzamido)-2-fluorobenzoic acid; optionally, in a micro-channel reactor with an inner diameter of 0.5 mm to 5 mm, the flow rate of the reaction solution of 3-(N-(cyclopropylmethyl)-4-fluorobenzamido)-2-fluorobenzoic acid methyl ester is 8 mL / min to 12 mL / min; the flow rate of the sodium hydroxide solution is 8 mL / min to 12 mL / min.

2. The method according to claim 1, characterized in that In step (1), the concentration of the reaction solution of methyl 2-fluoro-3-nitrobenzoate is 0.2 mol / L to 1 mol / L; and / or, the reaction temperature is 60° C. to 80° C.; and / or, the reaction solvent is ethanol, acetonitrile or ethyl acetate; and / or, the reaction time is 6 min to 15 min; In step (2), the concentration of methyl 2-fluoro-3-aminobenzoate is 0.1 mol / L to 0.2 mol / L; and / or, preferably, the concentration of cyclopropanecarboxaldehyde is 0.2 mol / L to 0.6 mol / L; and / or, the molar ratio of methyl 2-fluoro-3-aminobenzoate to cyclopropanecarboxaldehyde is 1:(2-3); and / or, the reaction temperature is 80°C to 120°C; and / or, the reaction solvent is ethanol, methanol or toluene; and / or, the reaction time is 20 min to 40 min; In step (3), the concentration of methyl 3-((cyclopropylmethyl)amino)-2-fluorobenzoate is 0.2 mol / L to 0.4 mol / L; and / or the concentration of p-fluorobenzoyl chloride is 0.2 mol / L to 0.6 mol / L; and / or the molar ratio of methyl 3-((cyclopropylmethyl)amino)-2-fluorobenzoate to p-fluorobenzoyl chloride is 1:(1-2); and / or the reaction temperature is 80°C to 120°C; and / or the reaction time is 5 min to 30 min; In step (4), the concentration of methyl 3-(N-(cyclopropylmethyl)-4-fluorobenzamido)-2-fluorobenzoate is 0.1 mol / L to 0.2 mol / L; and / or the molar ratio of methyl 3-((cyclopropylmethyl)amino)-2-fluorobenzoate to sodium hydroxide is 1:(1.3-3); and / or the reaction temperature is 80°C to 85°C; and / or the solvent of the sodium hydroxide solution is water; and / or the reaction time is 10 min to 15 s.

3. The method according to claim 1 or 2, characterized in that: Two adjacent microchannel reactors in step (1), step (2), step (3) and step (4) are directly connected or not directly connected to form a microchannel reaction system.

4. The method according to claim 3, characterized in that The microchannel reaction system is selected from one of the following: i. The microchannel reactors in step (1), step (2), step (3) and step (4) are not connected to each other; ii. The microchannel reactors of step (1) and step (2) are directly connected; the microchannel reactors of step (3) and step (4) are directly connected; the microchannel reactors of step (2) and step (3) are not connected; iii. The microchannel reactors of step (1), step (2), step (3) and step (4) are directly connected end to end in sequence.

5. A method for preparing ciprofloxacin in a microchannel, characterized in that: The method comprises four steps of tandem synthesis of 3-(N-(cyclopropylmethyl)-4-fluorobenzamido)-2-fluorobenzoic acid: Reaction A in a micro-packed bed reactor: methyl 2-fluoro-3-nitrobenzoate and hydrogen react under the catalysis of palladium carbon or platinum carbon to obtain methyl 2-fluoro-3-aminobenzoate; Reaction B in a micro-packed bed reactor: methyl 2-fluoro-3-aminobenzoate, cyclopropylcarboxaldehyde and hydrogen react under the catalysis of platinum-carbon to obtain methyl 3-((cyclopropylmethyl)amino)-2-fluorobenzoate; Reaction C in a micro-pipeline reactor: methyl 3-((cyclopropylmethyl)amino)-2-fluorobenzoate reacts with p-fluorobenzoyl chloride to obtain methyl 3-(N-(cyclopropylmethyl)-4-fluorobenzamideamino)-2-fluorobenzoate; Reaction D in a micro-channel reactor: 3-(N-(cyclopropylmethyl)-4-fluorobenzamido)-2-fluorobenzoic acid methyl ester is hydrolyzed in the presence of sodium hydroxide and then acidified to obtain 3-(N-(cyclopropylmethyl)-4-fluorobenzamido)-2-fluorobenzoic acid; Among them, reactions A and B share a micro-packed bed reactor, which is connected end-to-end with the micro-pipe reactor of reaction C and the micro-pipe reactor of reaction D to continuously synthesize 3-(N-(cyclopropylmethyl)-4-fluorobenzamido)-2-fluorobenzoic acid; the flow rate of the hydrogen is 10mL / min~40mL / min; the flow rate of the reaction solution of methyl 2-fluoro-3-nitrobenzoate and cyclopropanecarboxaldehyde is 0.05mL / min~0.5mL / min; the platinum carbon has a loading amount of 5-10w / w%, and the mass fraction relative to methyl 2-fluoro-3-aminobenzoate is 1%~20%; the flow rate of the reaction solution of p-fluorobenzoyl chloride is 0.4mL / min~0.6mL / min; the flow rate of the sodium hydroxide solution is 0.8mL / min~1.0mL / min.

6. The method according to claim 5, characterized in that Reaction A and reaction B occur successively in a micro-packed bed reactor, the concentration of methyl 2-fluoro-3-nitrobenzoate is 0.1 mol / L to 0.3 mol / L; and / or, the concentration of cyclopropanecarboxaldehyde is 0.3 mol / L to 0.6 mol / L; and / or, the reaction temperature is 80° C. to 120° C.; and / or, the reaction solvent is toluene; and / or, the reaction time is 30 min to 40 min; In the micro-channel reactor reaction C and the micro-channel reactor reaction D, the concentration of p-fluorobenzoyl chloride is 0.08 mol / L to 0.15 mol / L; and / or, the concentration of sodium hydroxide is 0.1 mol / L to 0.6 mol / L; and / or, the reaction temperature is 80° C. to 140° C.; and / or, the reaction solvent is acetonitrile or water; and / or, the reaction time is 5 min to 50 min.

7. The method according to any one of claims 5-6, characterized in that: The invention also includes a method for synthesizing brominated decafluoroaniline in a microchannel, comprising the steps of: (1) Synthesis of decafluoroaniline: Phase A: 2-trifluoromethylaniline, heptafluoroisopropyl iodide, dibenzo-18-crown-6, tetrabutylammonium bromide dissolved in a mixed solution of ethyl acetate and acetonitrile; Phase B: a mixed solution of sodium dithionite and sodium carbonate in water and acetonitrile; Phase C: a mixed solution of sodium hydroxide in water and acetonitrile; The three phases were pumped into the mixture using a double injection pump, with a flow rate of 0.5 mL / min to 6 mL / min for phase A, 0.5 mL / min to 6 mL / min for phase B, and 1 mL / min to 9 mL / min for phase C, and then passed through a mixer into a polytetrafluoroethylene coil with an inner diameter of 0.5 mm to 5 mm and a total volume of 60 mL to 720 mL; The reaction temperature was 100°C to 120°C, the retention time was 30 min to 60 min, and the back pressure valve pressure was 0.6 MPa; (2) Synthesis of bromodecafluoroaniline: Phase A: acetonitrile solution of decafluoroaniline; Phase B: acetonitrile solution of N-bromosuccinimide; pumped into a polytetrafluoroethylene coil with an inner diameter of 0.5 mm to 5 mm through a double syringe pump through a T-type mixer, the pumping rate of phase A is 0.1 mL / min, the pumping rate of phase B is 0.1 mL / min, the retention time is 15 min to 30 min, and the temperature is 80°C to 120°C.

8. The method according to any one of claims 5-6, characterized in that: Also included is the synthesis of cyprodinil in a microchannel, comprising the steps of: (1) 0.2 mol / L to 0.6 mol / L of 3-(N-(cyclopropylmethyl)-4-fluorobenzamido)-2-fluorobenzoic acid reacts with 1 mol / L to 3 mol / L of thionyl chloride to generate 3-(N-(cyclopropylmethyl)-4-fluorobenzamido)-2-fluorobenzoyl chloride; Phase A: toluene solution of 3-(N-(cyclopropylmethyl)-4-fluorobenzamido)-2-fluorobenzoic acid; Phase B: toluene solution of dichlorothionyl; both phases are pumped through a dual syringe pump at a flow rate of 0.5 mL / min, through a T-type mixer, and enter a polytetrafluoroethylene coil with an inner diameter of 0.5 mm to 5 mm, with a retention volume of 30 mL, a retention time of 30 min, a temperature of 130°C, and a pressure of 0.8 MPa; (2) Bromodecafluoroaniline reacts with 3-(N-(cyclopropylmethyl)-4-fluorobenzamido)-2-fluorobenzoyl chloride in the presence of lithium bis(trimethylsilyl)amide to obtain cyclohexanil; Phase A: toluene solution of 0.05 mol / L to 0.2 mol / L 3-(N-(cyclopropylmethyl)-4-fluorobenzamido)-2-fluorobenzoyl chloride and 0.075 mol / L to 0.3 mol / L bromodecafluoroaniline; Phase B: 0.2 mol / L to 0.8 mol / L toluene solution of lithium bis(trimethylsilyl)amide; the two phases pass through a dual syringe pump at a flow rate of 2.0 mL / min, through a T-type mixer, and enter a polytetrafluoroethylene coil with an inner diameter of 0.5 mm to 5 mm, with a retention volume of 30 mL and a pressure of 0.8 MPa.

9. A method for synthesizing perfluoropropyl substituted aniline in a microchannel, characterized in that: R1 is independently hydrogen, halogen, alkyl, haloalkyl, alkoxy or haloalkoxy; R2 is hydrogen, alkyl or acyl; n is 1, 2, 3 or 4; Phase A: Compound I, heptafluoroisopropyl iodide, dibenzo-18-crown ether-6, and tetrabutylammonium bromide are dissolved in a mixed solution of ethyl acetate and acetonitrile; Phase B: a mixed solution of sodium dithionite and sodium carbonate in water and acetonitrile; Phase C: a mixed solution of sodium hydroxide in water and acetonitrile; the three-phase liquids are pumped in separately using a double injection pump, with a flow rate of 0.5 mL / min to 1 mL / min for phase A, 0.5 mL / min to 1 mL / min for phase B, and 0.5 mL / min to 1 mL / min for phase C, and then enter a polytetrafluoroethylene coil with an inner diameter of 0.5 mm to 5 mm through a mixer; the reaction temperature is 80°C to 120°C.

10. The synthesis method according to claim 7, characterized in that: The concentration of compound I is 0.1mol / L~0.6mol / L, the concentration of heptafluoroisopropyl iodide is 0.3mol / L~1.2mol / L, the concentration of dibenzo-18-crown-6 is 0.01mol / L~0.02mol / L, the concentration of tetrabutylammonium bromide is 0.01mol / L~0.02mol / L; the concentration of sodium dithionite is 0.5mol / L-1mol / L, the concentration of sodium carbonate is 0.03mol / L~0.05mol / L; the concentration of sodium hydroxide is 0.03mol / L~0.1mol / L; the reaction pressure is 0.5MPa~0.8MPa.

Images