Method for continuously preparing trifluorobenzene pyrimidine

Abstract

The invention belongs to the field of pesticide intermediates and product preparation, and particularly relates to a method for continuously preparing trifluorobenzene pyrimidine. According to the method disclosed by the invention, pyrimidine-5-formaldehyde and 2-aminopyridine are used as starting substrates, and are subjected to Schiff base reaction, reductive amination reaction and cyclization reaction in sequence, and the target product trifluorobenzene pyrimidine is obtained after post-treatment. According to the invention, a multi-step continuous flow process for preparing trifluorobenzene pyrimidine through Schiff base reaction-reductive amination reaction-cyclization reaction based on a flow chemistry technology is found for the first time, the total retention time of the reaction is less than 30 minutes, the total conversion rate reaches 58%, and the total yield reaches 39%. Compared with the prior art, the method has the advantages that the reaction time is greatly shortened, meanwhile, through solvent compatibility and post-treatment simplification, the yield of three wastes in the reaction process is effectively reduced, the post-treatment operation frequency and reaction reagent consumption are greatly reduced, and efficient and green production is realized.

Description

Technical Field

[0001] The invention belongs to the field of pesticide intermediate and product preparation, and specifically relates to a method for continuously preparing trifluanidazole. Background Art

[0002] Triflumezopyrim (TFM) is a pyrido[1,2-α]pyrimidinone mesoionic insecticide developed by DuPont (now Corteva) and registered for marketing in 2017. The drug is a nicotinic acetylcholine receptor inhibitor that acts on the orthosteric site of insect nicotinic acetylcholine receptors (nAChRs) and can effectively inhibit their biological functions. The drug is mainly used to control rice-related pests such as rice planthoppers, brown planthoppers, white-backed planthoppers, leafhoppers, and has no cross-resistance with most insecticides currently on the market, and has good market prospects. In order to further reduce the cost of medication, it is of great significance to continuously optimize the synthesis process of the drug and reduce its production cost and the output of three wastes.

[0003]

[0004] The existing synthetic route of trifluorophenylpyrimidine mainly uses 2-(3-trifluoromethylphenyl)malonic acid derivatives and N-2-pyridine-5-pyrimidinemethylamine as key intermediates. Since 2-(3-trifluoromethylphenyl)malonyl chloride is not suitable for long-term storage, the cyclization reaction using it as a substrate requires low temperature and is easily affected by temperature, resulting in overreaction and low conversion rate. Therefore, it is only suitable for small-scale laboratory research and development. The existing intermittent production process often uses 2,4,6-trichlorophenol as a protective group, and its diester is refluxed with N-2-pyridine-5-pyrimidinemethylamine in toluene to obtain a crude trifluorophenylpyrimidine.

[0005]

[0006] For another key intermediate N-2-pyridine-5-pyrimidinemethylamine, WO2009099929A1 and WO2011017342A2 both disclose the preparation of Schiff base from 2-aminopyridine and pyrimidine-5-carboxaldehyde in chloroform, followed by reduction with sodium borohydride to generate N-2-pyridine-5-pyrimidinemethylamine. This route has the following shortcomings: 1. The Schiff base reaction is a reversible reaction, which requires strict anhydrous conditions, and the use of chloroform as a reaction solvent is more harmful to the environment; 2. The reductive amination reaction uses sodium borohydride as a reducing agent, which is costly and cumbersome to post-process, with a low conversion rate, usually only 65%; 3. The crude product prepared by the reaction needs to be purified before it can be used in the cyclization reaction, and the whole process post-processing uses a large number of solvents and the amount of waste liquid generated is relatively large.

[0007]

[0008] In addition, traditional intermittent processes mostly use kettle reactors, which have difficult-to-overcome defects, such as large liquid holding capacity, long reaction time, cumbersome operation, long process flow, poor production stability, low conversion rate, difficult to accurately control the reaction, and high safety risks. Therefore, it is of great value to develop an efficient, economical, environmentally friendly and continuous production process for the synthesis of trifluorophenylpyrimidine. Summary of the invention

[0009] The purpose of the present invention is to provide a green, safe and efficient continuous preparation method of trifluorobenzene. The present invention uses 2-aminopyridine and pyrimidine-5-carboxaldehyde as starting substrates, and optimizes and transforms the Schiff base reaction, reductive amination reaction and cyclization reaction respectively according to the technical characteristics of continuous flow synthesis, and the whole process can be connected in series, so as to realize the efficient and continuous preparation of trifluorobenzene. The continuous preparation method of the present invention can effectively reduce solvent consumption, reduce the cost of three wastes treatment and labor costs. In addition, compared with the kettle reactor, the microreactor used in the continuous preparation method has the characteristics of large specific surface area, small characteristic size and small liquid holding capacity, so that the heat and mass transfer efficiency can be greatly improved, and it has intrinsic safety characteristics. Based on the advantages of the microreactor in the reaction process such as efficient mixing, precise control, and external field enhancement, the continuous preparation method of the present invention can effectively reduce the generation of by-products, enhance the robustness of the production process, and realize the green, safe and efficient continuous preparation of trifluorobenzene.

[0010] The first aspect of the present invention provides a continuous synthesis method for preparing trifluorophenylpyrimidine, the method comprising the steps of:

[0011] (1) dissolving 2-aminopyridine and pyrimidine-5-carboxaldehyde in a first organic solvent to obtain a feed liquid A and a feed liquid B, respectively; mixing the feed liquid A and the feed liquid B in a first micromixer and then continuously pumping the feed liquid A and the feed liquid B into a first microreactor filled with a dehydrating agent to perform a Schiff base reaction to generate N-2-pyridine-5-pyrimidine imine;

[0012] (2) dissolving N-2-pyridine-5-pyrimidinemethoxyamine and a first base in a second organic solvent to obtain a feed liquid C, mixing the feed liquid C and hydrogen through a second micromixer, and continuously pumping the mixture into a second microreactor filled with a catalyst to carry out a reductive amination reaction to generate N-2-pyridine-5-pyrimidinemethoxyamine; or dissolving N-2-pyridine-5-pyrimidinemethoxyamine in a third organic solvent to obtain a feed liquid C', mixing the feed liquid C' and hydrogen through a second micromixer, and continuously pumping the mixture into a second microreactor filled with a catalyst to carry out a reductive amination reaction to generate N-2-pyridine-5-pyrimidinemethoxyamine;

[0013] (3) dissolving N-2-pyridine-5-pyrimidinemethylamine and a second base in a fourth organic solvent to obtain a feed liquid D, providing a feed liquid E containing 2-(3-trifluoromethylphenyl)malonyl chloride, mixing the feed liquid D and the feed liquid E in a third micromixer, and then continuously pumping them into a third microreactor for a cyclization reaction to obtain a reaction liquid containing trifluorophenylpyrimidine.

[0014] The second aspect of the present invention provides a continuous flow synthesis device for implementing the continuous synthesis method described in the first aspect of the present invention, the continuous flow synthesis device comprising a first micro mixer, a first micro reactor, a second micro mixer, a second micro reactor, a third micro mixer and a third micro reactor connected in sequence by a pipeline;

[0015] The continuous flow synthesis device also includes a first feed pump and a second feed pump for feeding the first microreactor, a third feed pump for feeding the second microreactor, and a fourth feed pump and a fifth feed pump for feeding the third microreactor;

[0016] The continuous flow synthesis device further comprises a hydrogen generator for continuously introducing hydrogen into the second micro mixer and a gas flow control device arranged on a pipeline connecting the hydrogen generator and the second micro mixer.

[0017] The present invention has the following beneficial effects:

[0018] (1) The advantages of the microreactor system, such as closed, low liquid holding volume, rapid reaction, and precise control, are utilized to realize a continuous process of production throughout the entire process, simplify the operation steps, reduce the generation of three wastes, and prevent the spillage of pungent odor materials and solvents from causing harm to personnel and the environment. This improves the reaction efficiency and safety of unit reactions such as Schiff base reaction, reductive amination reaction, and cyclization reaction.

[0019] (2) The method of the present invention uses a fixed bed microreactor for heterogeneous reactions such as continuous Schiff base reaction and continuous hydrogenation reaction (i.e., reductive amination reaction). Solid dehydrating agent and catalyst are filled into the fixed bed microreactor, providing a larger contact area between phases. The reaction liquid and gas can fully contact with the solid surface when flowing through the fixed bed microreactor, and the mass transfer limitation between phases is significantly improved, and the reaction speed is significantly accelerated. In addition, for the continuous hydrogenation reaction, hydrogen is produced by a high-pressure hydrogen generator and directly input into the microreactor, which effectively eliminates the safety hazard of hydrogen storage.

[0020] (3) The method of the present invention improves the yield and selectivity of each step of the unit reaction by optimizing each unit reaction process, strengthening the control of heat and mass transfer during the reaction process. Among them, the intermediate N-2-pyridine-5-pyrimidinemethylamine can be obtained with a total yield of more than 95%, which is much better than the 64% of the prior art process.

[0021] (4) The present invention is the first to discover a multi-step continuous flow process for preparing trifluorophenylpyrimidine based on flow chemistry technology, which includes Schiff base reaction-reductive amination reaction-cyclization reaction. The total reaction residence time is less than 30 minutes, the total conversion rate reaches 58%, and the total yield reaches 39%. Compared with the existing process, the reaction time is greatly shortened. At the same time, through solvent compatibility and simplified post-treatment, the output of three wastes during the reaction process is effectively reduced. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1 It is a schematic structural diagram of a continuous flow synthesis device used in one or more embodiments of the present invention; wherein, R1-first microreactor, R2-second microreactor, R3-third microreactor, R4-mixing coil, T1-first post-processing module, T2-second post-processing module, MS1-first membrane separator, P1-first feed pump, P2-second feed pump, P3-third feed pump, P4-fourth feed pump, P5-fifth feed pump, P6-sixth feed pump, M1-first micro mixer, M2-second micro mixer, M3-third micro mixer, M4-fourth micro mixer, MFC-gas flow control device, Wash 1-first device cleaning liquid, Wash 2-second device cleaning liquid, CP-TFM-trifluorobenzidine crude product, A-feed liquid A, B-feed liquid B, C-reaction liquid C, D-feed liquid D, E-feed liquid E. Figure 1 In the figure, the solid lines are necessary components of the continuous flow synthesis device; the dotted lines are non-essential components of the continuous flow synthesis device, and whether they are connected in series in the continuous flow synthesis device can be determined according to actual process requirements.

[0023] Figure 2 Schematic diagram of the first post-processing module and the second post-processing module in one or more embodiments of the present invention; wherein Ta-online extraction separation module, Tb-online solvent replacement module, MS2-second membrane separator, S1-first post-processing solvent, S2-second post-processing solvent, S3-replacement solvent, M5-fifth micro mixer, M6-sixth micro mixer, V1-first reversing valve, P7-seventh feed pump, P8-eighth feed pump, P9-ninth feed pump, P10-tenth feed pump, P11-eleventh feed pump, P12-twelfth feed pump, R in - Reaction liquid inlet, R out - Reaction liquid outlet. DETAILED DESCRIPTION

[0024] In order to enable those skilled in the art to understand the characteristics and effects of the present invention, the following is a general description and definition of the terms and expressions mentioned in the specification and claims. Unless otherwise specified, all technical and scientific terms used in the text are the common meanings understood by those skilled in the art for the present invention. In the event of a conflict, the definition in this specification shall prevail.

[0025] The theories or mechanisms described and disclosed herein, whether correct or incorrect, should not limit the scope of the present invention in any way, that is, the present invention can be implemented without being limited by any specific theory or mechanism.

[0026] Herein, “comprising”, “including”, “containing” and similar terms encompass the meanings of “consisting essentially of” and “consisting of”. For example, when “A comprises B and C” is disclosed herein, “A consists essentially of B and C” and “A consists of B and C” should be deemed to be disclosed herein.

[0027] In this article, all features such as values, quantities, contents and concentrations defined in the form of numerical ranges or percentage ranges are only for brevity and convenience. Accordingly, the description of numerical ranges or percentage ranges should be considered to have included and specifically disclosed all possible secondary ranges and individual values ​​within the range (including integers and fractions).

[0028] In this document, unless otherwise specified, percentage refers to mass percentage and ratio refers to mass ratio.

[0029] Herein, when describing embodiments or examples, it should be understood that they are not used to limit the present invention to these embodiments or examples. On the contrary, all substitutes, improvements and equivalents of the methods and materials described in the present invention can be included in the scope limited by the claims.

[0030] In this document, in order to make the description concise, not all possible combinations of various technical features in various embodiments or examples are described. Therefore, as long as there is no contradiction in the combination of these technical features, the various technical features in various embodiments or examples can be combined arbitrarily, and all possible combinations should be considered to be within the scope of this specification.

[0031] In the present invention, the continuous method for efficiently preparing trifluorobenzene adopts the following reaction route:

[0032]

[0033] The present invention provides a continuous synthesis method for preparing trifluorophenylpyrimidine, the method comprising the steps of:

[0034] (1) dissolving 2-aminopyridine and pyrimidine-5-carboxaldehyde in a first organic solvent to obtain a feed liquid A and a feed liquid B, respectively; mixing the feed liquid A and the feed liquid B in a first micromixer and then continuously pumping the feed liquid A and the feed liquid B into a first microreactor filled with a dehydrating agent to perform a Schiff base reaction to generate N-2-pyridine-5-pyrimidine imine;

[0035] (2) dissolving N-2-pyridine-5-pyrimidinemethoxyamine and a first base in a second organic solvent to obtain a feed liquid C, mixing the feed liquid C and hydrogen through a second micromixer, and continuously pumping the mixture into a second microreactor filled with a catalyst to carry out a reductive amination reaction to generate N-2-pyridine-5-pyrimidinemethoxyamine; or dissolving N-2-pyridine-5-pyrimidinemethoxyamine in a third organic solvent to obtain a feed liquid C', mixing the feed liquid C' and hydrogen through a second micromixer, and continuously pumping the mixture into a second microreactor filled with a catalyst to carry out a reductive amination reaction to generate N-2-pyridine-5-pyrimidinemethoxyamine;

[0036] (3) dissolving N-2-pyridine-5-pyrimidinemethylamine and a second base in a fourth organic solvent to obtain a feed liquid D, providing a feed liquid E containing 2-(3-trifluoromethylphenyl)malonyl chloride, mixing the feed liquid D and the feed liquid E in a third micromixer, and then continuously pumping them into a third microreactor for a cyclization reaction to obtain a reaction liquid containing trifluorophenylpyrimidine.

[0037] In some embodiments, the first organic solvent is selected from one or more of n-hexane, n-heptane, petroleum ether, cyclohexane, carbon tetrachloride, methyl tert-butyl ether, isopropyl ether, toluene, xylene, dichloromethane, dichloroethane, tetrahydrofuran, ethyl acetate, chloroform, dioxane, ethanol, methanol, isopropanol and acetonitrile, preferably toluene.

[0038] In order to make the feed liquid B in a clear state, the feed liquid B can be kept warm during the whole process from preparation to the end of feeding to avoid precipitation of solids in the feed liquid B. Preferably, the insulation temperature can be 50 to 90°C, such as 50°C, 60°C, 70°C, 80°C, 90°C, more preferably 50 to 70°C.

[0039] In some embodiments, the concentration of 2-aminopyrimidine in the feed liquid A is 0.05-2.0 mol / L, for example, 0.08 mol / L, 0.1 mol / L, 0.3 mol / L, 0.5 mol / L, 0.8 mol / L, 1.0 mol / L, 1.3 mol / L, 1.5 mol / L, 1.8 mol / L, preferably 0.1-0.5 mol / L.

[0040] In some embodiments, the concentration of pyrimidine-5-carboxaldehyde in the feed liquid B is 0.05 to 2.0 mol / L, for example, 0.08 mol / L, 0.1 mol / L, 0.3 mol / L, 0.5 mol / L, 0.8 mol / L, 1.0 mol / L, 1.3 mol / L, 1.5 mol / L, 1.8 mol / L, preferably 0.1 to 0.5 mol / L.

[0041] In some embodiments, in step (1), the reaction temperature is 20-140°C, for example, 20°C, 30°C, 50°C, 80°C, 90°C, 100°C, 120°C, 130°C, preferably 60-110°C.

[0042] In some embodiments, in step (1), the residence time is 1 to 60 min, for example, 5 min, 8 min, 10 min, 15 min, 20 min, 30 min, 40 min, 50 min, preferably 5 to 30 min.

[0043] In some embodiments, the feed rate of the feed liquid A is 10.0 to 500.0 μL / min, for example, 12.0 μL / min, 15.0 μL / min, 20.0 μL / min, 30.0 μL / min, 50.0 μL / min, 80.0 μL / min, 100.0 μL / min, 150.0 μL / min, 200.0 μL / min, 300.0 μL / min, and 400.0 μL / min.

[0044] In some embodiments, the feed rate of the feed liquid B is 10.0 to 500.0 μL / min, for example, 12.0 μL / min, 15.0 μL / min, 20.0 μL / min, 30.0 μL / min, 50.0 μL / min, 80.0 μL / min, 100.0 μL / min, 150.0 μL / min, 200.0 μL / min, 300.0 μL / min, and 400.0 μL / min.

[0045] The dewatering agent is selected from one or more of molecular sieve, anhydrous sodium sulfate, anhydrous magnesium sulfate and color-changing silica gel, preferably molecular sieve. In the present invention, any shape of the above-mentioned dewatering agent can be used to implement the present invention, for example, the dewatering agent can be granular or powdery. In some embodiments, the dewatering agent is a granular molecular sieve. The dewatering agent can be loaded in the first microreactor in the manner of the art, for example, the dewatering agent is filled in the reactor, or the dewatering agent is quantitatively loaded according to the amount of water produced during the reaction and the dewatering ability of the dewatering agent. The dewatering agent can be mixed with an inert filler and loaded together in the first microreactor. Exemplary fillers include, but are not limited to, one or more of quartz sand, glass beads, ceramic beads, stainless steel beads and zeolite.

[0046] The second organic solvent can be selected from one or more of n-hexane, n-heptane, petroleum ether, cyclohexane, carbon tetrachloride, toluene, xylene, dichloromethane and dichloroethane, preferably toluene.

[0047] The third organic solvent may be selected from one or more of tetrahydrofuran, ethanol, methanol, isopropanol and acetonitrile, and is preferably selected from one or two of tetrahydrofuran and methanol.

[0048] The first base can be an acid binding agent commonly used in the art, as long as it has no adverse effect on the reaction of step (2). Exemplary first bases are selected from one or more of triethylamine, ethylenediamine, pyridine and N,N-diisopropylethylamine, preferably triethylamine.

[0049] In some embodiments, in the feed liquid C, the molar ratio of the first base to N-2-pyridine-5-pyrimidinemethamine is (0.5-3):1, for example, 0.8:1, 1:1, 1.2:1, 1.5:1, 1.8:1, 2:1, 2.3:1, preferably (1-2.5):1.

[0050] In order to make the feed liquid C or the feed liquid C' in a clear state, the feed liquid C or the feed liquid C' can be kept warm during the whole process from preparation to the end of feeding to avoid precipitation of solids from the feed liquid C or the feed liquid C'. Preferably, the insulation temperature can be 40 to 100°C, such as 50°C, 60°C, 70°C, 80°C, 90°C, more preferably 50 to 70°C.

[0051] In some embodiments, the concentration of N-2-pyridine-5-pyrimidinemethamine in the feed liquid C or the feed liquid C' is 0.01 to 1.0 mol / L, for example, 0.05 mol / L, 0.08 mol / L, 0.1 mol / L, 0.2 mol / L, 0.3 mol / L, 0.5 mol / L, 0.8 mol / L, preferably 0.05 to 0.20 mol / L.

[0052] In some embodiments, the flow rate of the feed liquid C or feed liquid C' is 0.1-1 mL / min, for example, 0.1 mL / min, 0.2 mL / min, 0.3 mL / min, 0.5 mL / min, 0.8 mL / min.

[0053] In some embodiments, the flow rate of hydrogen pumped into the second microreactor is 0.2 to 30.0 mL / min, for example, 0.5 mL / min, 0.8 mL / min, 1 mL / min, 2 mL / min, 3 mL / min, 5 mL / min, 8 mL / min, 10 mL / min, 15 mL / min, 20 mL / min, 25 mL / min, preferably 5.0 to 30.0 mL / min.

[0054] In some embodiments, the back pressure at the outlet of the second microreactor is 1-4 MPa, such as 1 MPa, 2 MPa, 3 MPa, 4 MPa, and preferably 1-3 MPa.

[0055] In some embodiments, in step (2), the reaction temperature is 50-140°C, for example 60°C, 70°C, 80°C, 90°C, 100°C, 120°C, 130°C, preferably 70-100°C.

[0056] In some embodiments, in step (2), the residence time is 10 s to 10 min, for example, 30 s, 1 min, 3 min, 5 min, 6 min, 7 min, 8 min, 9 min, 10 min, preferably 5 to 10 min.

[0057] In some embodiments, the catalyst is selected from one or more of 5-20wt% Pd(OH)2 / C, 5-20wt% Pd / C, 5wt% Pd / Al2O3 / C, Pd(OCOCH3)2, PdCl2, Ranney Ni, NiCl2, Ni(OH)2, Al-Ni and Ni / Al2O3 / SiO2, preferably 5-20wt% Pd(OH)2 / C. Herein, the mass fraction contained in the name of the catalyst refers to the mass fraction of the metal element in the catalyst, for example, "5-20wt%" in "5-20wt% Pd(OH)2 / C" refers to the mass fraction of the metal element Pd in ​​the catalyst Pd(OH)2 / C, for example 5wt%, 8wt%, 10wt%, 13wt%, 15wt%, 18wt%, 20wt%.

[0058] The catalyst can be mixed with an inert filler and loaded into the second microreactor. Exemplary fillers include, but are not limited to, one or more of quartz sand, glass beads, ceramic beads, stainless steel beads, alumina, molecular sieves, montmorillonite, and zeolite.

[0059] In step (2), in order to prevent the reaction material from remaining in the second microreactor, the first device cleaning liquid can be passed into the second microreactor after the reaction in step (2) is completed. The first device cleaning liquid can be selected from one or more of toluene, dichloromethane, ethyl acetate, acetonitrile, tetrahydrofuran, ethanol and methanol, preferably selected from one or two of dichloromethane and methanol. Preferably, the first device cleaning liquid flowing out of the outlet of the second microreactor is combined with the reaction liquid flowing out of the outlet of the second microreactor to avoid the loss of the reaction product. Preferably, the first device cleaning liquid is the same as the reaction solvent of step (2).

[0060] The fourth organic solvent may be selected from one or more of n-hexane, n-heptane, petroleum ether, cyclohexane, carbon tetrachloride, toluene, xylene, dichloromethane, dichloroethane and tetrahydrofuran, preferably one or more of toluene, dichloromethane and tetrahydrofuran.

[0061] The second base can be an acid binding agent commonly used in the art, as long as it has no adverse effect on the reaction of step (3). The second base can be selected from one or more of triethylamine, ethylenediamine, pyridine and N,N-diisopropylethylamine, preferably triethylamine. In some embodiments, the second base is the same as the first base.

[0062] The feed liquid E is 2-(3-trifluoromethylphenyl)malonyl chloride or a mixture of 2-(3-trifluoromethylphenyl)malonyl chloride in a fifth organic solvent. The fifth organic solvent can be selected from one or more of n-hexane, n-heptane, petroleum ether, cyclohexane, carbon tetrachloride, toluene, xylene, dichloromethane, dichloroethane and tetrahydrofuran, preferably one or more of toluene, dichloromethane and tetrahydrofuran. In the mixture of 2-(3-trifluoromethylphenyl)malonyl chloride in the fifth organic solvent, the concentration of 2-(3-trifluoromethylphenyl)malonyl chloride is 0.01 to 5.0 mol / L, for example, 0.03 mol / L, 0.05 mol / L, 0.1 mol / L, 0.2 mol / L, 0.3 mol / L, 0.5 mol / L, 0.8 mol / L, 1.0 mol / L, 1.5 mol / L, preferably 0.1 to 2.0 mol / L.

[0063] In the feed liquid D, the concentration of N-2-pyridine-5-pyrimidinemethylamine can be 0.01-1.0 mol / L, for example, 0.03 mol / L, 0.05 mol / L, 0.08 mol / L, 0.1 mol / L, 0.2 mol / L, 0.3 mol / L, 0.5 mol / L, 0.8 mol / L, preferably 0.05-0.20 mol / L.

[0064] In some embodiments, in the feed solution D, the molar ratio of the second base to N-2-pyridine-5-pyrimidinemethylamine is (1-4):1, for example, 1:1, 2:1, 3:1, 4:1, preferably (2-3):1.

[0065] In some embodiments, in step (3), the reaction temperature is -10 to 50°C, for example, -5°C, 0°C, 5°C, 10°C, 15°C, 20°C, 25°C, preferably 0 to 30°C.

[0066] In some embodiments, in step (3), the residence time is 1 to 60 min, for example, 5 min, 8 min, 10 min, 15 min, 20 min, 30 min, 40 min, preferably 5 to 30 min.

[0067] In some embodiments, the flow rate at which the feed liquid D is pumped into the third microreactor is 10.0 to 500.0 μL / min, for example, 20 μL / min, 50 μL / min, 80 μL / min, 100 μL / min, 150 μL / min, 180 μL / min, 220 μL / min, 250 μL / min, 350 μL / min, and 400 μL / min.

[0068] In some embodiments, the flow rate at which the feed liquid E is pumped into the third microreactor is 10.0 to 500.0 μL / min, for example, 20 μL / min, 50 μL / min, 80 μL / min, 100 μL / min, 150 μL / min, 180 μL / min, 220 μL / min, 250 μL / min, 350 μL / min, and 400 μL / min.

[0069] In step (3), in order to prevent the reaction material from remaining in the third microreactor, the second device cleaning liquid can be passed into the third microreactor after the reaction in step (3) is completed. The second device cleaning liquid can be selected from one or more of toluene, dichloromethane, ethyl acetate, acetonitrile, tetrahydrofuran, ethanol and methanol, preferably selected from one or both of dichloromethane and methanol. Preferably, the second device cleaning liquid flowing out of the outlet of the third microreactor is combined with the reaction liquid flowing out of the outlet of the third microreactor to avoid the loss of the reaction product. Preferably, the second device cleaning liquid is the same as the reaction solvent of step (3).

[0070] In some embodiments, the method further comprises the steps of: washing impurities in the reaction solution containing trifluorobenzoic acid with water, separating to obtain an organic phase, and removing the solvent to obtain a crude trifluorobenzoic acid product.

[0071] In some embodiments, in the method of the present invention, any two adjacent steps or all three steps in step (1), step (2) and step (3) are connected in series.

[0072] It should be understood that the series connection described in this article means that the reaction liquid outlet of the previous step reaction is directly connected to the reaction liquid inlet of the next step reaction or is connected to the reaction liquid inlet of the next step reaction through a buffer bottle in the actual reaction, and no offline post-processing operation is involved in the whole process.

[0073] In some embodiments, step (12) is used to replace step (1) and step (2), and step (12) includes: connecting step (1) and step (2) in series; mixing the feed liquid A and the feed liquid B through the first micromixer and continuously pumping them into the first microreactor for Schiff base reaction to obtain reaction liquid C; optionally performing solvent replacement on the reaction liquid C and adding the first base to obtain feed liquid C; mixing the feed liquid C and hydrogen through a second micromixer and continuously pumping them into the second microreactor for reductive amination reaction to generate N-2-pyridine-5-pyrimidinemethylamine.

[0074] In some embodiments, step (12) is used to replace step (1) and step (2), and step (12) includes: connecting step (1) and step (2) in series; mixing the feed liquid A and the feed liquid B through the first micromixer and continuously pumping them into the first microreactor for Schiff base reaction to obtain reaction liquid C, optionally performing solvent replacement on the reaction liquid C to obtain feed liquid C', mixing the feed liquid C' and hydrogen through a second micromixer and continuously pumping them into the second microreactor for reductive amination reaction to generate N-2-pyridine-5-pyrimidinemethylamine.

[0075] In some embodiments, step (23) is used to replace step (2) and step (3), and step (23) includes: connecting step (2) and step (3) in series; mixing the feed liquid C or feed liquid C' with hydrogen through a second micromixer and continuously pumping the mixture into the second microreactor for a reduction amination reaction to obtain a reaction liquid D; optionally performing solvent replacement on the reaction liquid D and adding a second base to obtain feed liquid D; mixing the feed liquid D and feed liquid E through a third micromixer and continuously pumping the mixture into the third microreactor for a cyclization reaction to obtain a reaction liquid containing trifluorobenzoic acid.

[0076] In some embodiments, step (123) is used to replace step (1), step (2) and step (3), and step (123) includes: connecting step (1), step (2) and step (3) in series; mixing the feed liquid A and the feed liquid B through the first micromixer and continuously pumping them into the first microreactor for Schiff base reaction to obtain reaction liquid C, optionally performing solvent replacement on the reaction liquid C and adding a first base to obtain feed liquid C, mixing the feed liquid C and hydrogen through a second micromixer and continuously pumping them into the second microreactor for reductive amination reaction to obtain reaction liquid D, optionally performing solvent replacement on the reaction liquid D and adding a second base to obtain feed liquid D, mixing the feed liquid D and feed liquid E through a third micromixer and continuously pumping them into the third microreactor for cyclization reaction to obtain a reaction liquid containing trifluorophenylpyrimidine.

[0077] In some embodiments, step (123) is used to replace step (1), step (2) and step (3), and step (123) includes: connecting step (1), step (2) and step (3) in series; mixing the feed liquid A and the feed liquid B through the first micromixer and continuously pumping them into the first microreactor for Schiff base reaction to obtain reaction liquid C, optionally performing solvent replacement on the reaction liquid C to obtain feed liquid C', mixing the feed liquid C' and hydrogen through a second micromixer and continuously pumping them into the second microreactor for reductive amination reaction to obtain reaction liquid D, optionally performing solvent replacement on the reaction liquid D and adding a second base to obtain feed liquid D, mixing the feed liquid D and feed liquid E through a third micromixer and continuously pumping them into the third microreactor for cyclization reaction to obtain a reaction liquid containing trifluorophenylpyrimidine.

[0078] The present invention also provides a continuous flow synthesis device for implementing the continuous synthesis method of the present invention. The continuous flow synthesis device comprises a first micro mixer M1, a first micro reactor R1, a second micro mixer M2, a second micro reactor R2, a third micro mixer M3 and a third micro reactor R3 which are sequentially connected by pipelines;

[0079] The continuous flow synthesis device further comprises a first feed pump P1 and a second feed pump P2 for feeding the first microreactor R1, a third feed pump P3 for feeding the second microreactor R2, and a fourth feed pump P4 and a fifth feed pump P5 for feeding the third microreactor R3;

[0080] The continuous flow synthesis device further comprises a hydrogen generator for continuously feeding hydrogen into the second micro mixer M2 and a gas flow control device MFC arranged on a pipeline connecting the hydrogen generator and the second micro mixer. In some embodiments, the gas flow control device is a mass flow meter.

[0081] In some embodiments, the continuous flow synthesis device includes a fourth micromixer M4 connected to the outlet of the third microreactor R3, a mixing coil R4 connected to the outlet of the fourth micromixer M4, a first membrane separator MS1 connected to the outlet of the mixing coil R4, and a sixth feed pump P6 for feeding the fourth micromixer M4. Figure 1 As shown, the reaction system flows from the outlet of the third microreactor R3 to the fourth micromixer M4, and water is pumped into the fourth micromixer M4 by the sixth feed pump P6 to quench the reaction and dissolve the solid matter generated by the reaction. Then the mixed materials are fully mixed and extracted in the mixing coil R4, and separated by the first membrane separator MS1 to obtain an aqueous phase and an organic phase. The organic phase is collected and the organic solvent is removed to obtain a crude trifluorophenylpyrimidine CP-TFM.

[0082] In some embodiments, the hydrogen generator is a high pressure hydrogen generator.

[0083] The continuous flow synthesis device also optionally includes a first post-processing module T1 arranged between the outlet of the first microreactor R1 and the third feed pump P3. The continuous flow synthesis device also optionally includes a second post-processing module T2 arranged between the outlet of the second microreactor R2 and the fourth feed pump P4. In some embodiments, the first post-processing module T1 and the second post-processing module T2 include an online extraction separation module Ra and / or an online solvent replacement module Rb. Preferably, the first post-processing module and the second post-processing module include an online extraction separation module Ra and an online solvent replacement module Rb in series.

[0084] The first post-processing module T1 and the second post-processing module T2 can be connected in series in the continuous flow synthesis device according to the actual process conditions. When the continuous flow synthesis device of the present invention includes the first post-processing module T1, in step (12) and / or step (123), the reaction liquid C is subjected to online extraction separation and online solvent replacement in the first post-processing module T1, thereby replacing the solvent with the feed liquid C or the feed liquid C'. When the continuous flow synthesis device of the present invention includes the second post-processing module T2, in step (23) and / or step (123), the reaction liquid D is subjected to online extraction separation and online solvent replacement in the second post-processing module, thereby replacing the solvent with the feed liquid D.

[0085] In this article, the first post-processing module T1 and the second post-processing module T2 can be used separately according to actual conditions. Figure 2 The online extraction and separation module Ta or the online solvent replacement module Tb shown can also be used in series with the online extraction and separation module Ta and the online solvent replacement module Tb to achieve the online extraction-separation-solvent replacement function.

[0086] When only the online extraction separation module Ta is used, the reaction liquid is introduced into the reaction liquid inlet R in The organic phase is mixed with the first post-treatment solvent S1 delivered by the eighth feed pump P8 in the fifth micro-mixer M5 through the seventh feed pump P7, and the mixed liquid is mixed with the second post-treatment solvent S2 delivered by the ninth feed pump P9 in the sixth micro-mixer M6, and then separated by the second membrane separator MS2. The organic phase can be input into the online solvent replacement module Tb by the tenth feed pump P10 or enter the subsequent reaction system as a feed liquid.

[0087] When only the online solvent replacement module Tb is used, the reaction liquid can be fed into the rotary evaporator by the tenth feed pump P10 for online rotary evaporation. After the solvent is removed, the eleventh feed pump P11 delivers the replacement solvent S3 to the rotary evaporator through the first reversing valve V1 to dissolve the residue. Then, the reaction liquid in the rotary evaporator is extracted by the twelfth feed pump P12 through the first reversing valve V1 again, and finally the reaction liquid is discharged through the reaction liquid outlet Rout Output, which can be used as feed liquid for subsequent reactions.

[0088] When the online extraction separation module Ta and the online solvent replacement module Tb are used together, the reaction liquid is introduced into the reaction liquid inlet R in The first post-treatment solvent S1 delivered by the seventh feed pump P7 and the eighth feed pump P8 is mixed in the fifth micro mixer M5, and the mixed liquid is mixed with the second post-treatment solvent S2 delivered by the ninth feed pump P9 in the sixth micro mixer M6, and then separated by the second membrane separator MS2. The organic phase is continuously fed into the rotary evaporator by the tenth feed pump P10 for solvent removal. After the solvent removal is completed, the replacement solvent S3 is fed into the rotary evaporator by the eleventh feed pump P11 through the first reversing valve V1 to dissolve the residue, and then passes through the first reversing valve V1 again, and is extracted by the twelfth feed pump P12 and discharged from the reaction liquid outlet R out The feed solution for subsequent reaction is obtained.

[0089] The first post-processing solvent S1 is an organic solvent commonly used in the art that is easy to separate from the reaction product, preferably an organic solvent that is easy to remove by rotary evaporation, preferably the same as the solvent of the reaction solution. An exemplary first post-processing solvent S1 can be selected from one or more of dichloromethane, toluene and ethyl acetate. The second post-processing solvent S2 is water or an aqueous solution, which can be selected from saturated saline, saturated ammonium chloride aqueous solution, sodium hydroxide aqueous solution, dilute hydrochloric acid, etc. The replacement solvent S3 should be selected according to the type of solvent required for the subsequent reaction, for example, selected from toluene, methanol, tetrahydrofuran, etc.

[0090] In order to prevent the reaction material from remaining in the second microreactor R2, the continuous flow synthesis device is provided with a cleaning device before the third feed pump P3, and the first device cleaning liquid Wash 1 is stored in the cleaning device. In order to prevent the reaction material from remaining in the third microreactor R3, the continuous flow synthesis device is provided with a cleaning device before the fourth feed pump P4 and / or the fifth feed pump P5, and the second device cleaning liquid Wash 2 is stored in the cleaning device.

[0091] In some embodiments, the continuous flow synthesis apparatus further comprises a control component for operating the continuous flow synthesis apparatus to implement the continuous synthesis method of the present invention.

[0092] In some embodiments, the first feed pump P1, the second feed pump P2, the third feed pump P3, the fourth feed pump P4, the fifth feed pump P5, and the sixth feed pump P6 are each independently a syringe pump, a peristaltic pump, or a plunger pump.

[0093] In some embodiments, the first microreactor R1 and the second microreactor R2 are fixed bed microreactors.

[0094] In some embodiments, the third microreactor R3 is a PTFE capillary microreactor.

[0095] In some embodiments, the mixing coil R4 is a PTFE capillary coil.

[0096] In some embodiments, the first micromixer M1, the second micromixer M2, the third micromixer M3, and the fourth micromixer M4 are each independently a T-type mixer or a cross-type mixer.

[0097] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental methods in the following examples without specifying specific conditions are usually based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0098] Based on the attempts in the art, the above-mentioned preferred conditions can be combined arbitrarily to obtain the preferred embodiments of the present invention.

[0099] The reagents and raw materials used in the present invention are commercially available.

[0100] All reagents used in the experiments were of AR grade.

[0101] The dehydrating agents involved in the experiment should be activated before use. The typical operation is to place the dehydrating agent in a muffle furnace, heat it to 450°C and keep it warm for 2 hours, then cool it naturally and store it in a sealed container.

[0102] In the present invention, the gas reading is the mass flow meter display number, which is the gas state under the standard state (273.15K, 101.325kPa). When calculating the residence time, it needs to be converted according to the ideal gas state equation.

[0103] In the present invention, the conversion rate is calculated based on GC-MS or HPLC analysis; the yield is calculated based on the mass of the product after separation and purification; NR means no reaction.

[0104] Herein, the first microreactor R1 and the second microreactor R2 are fixed bed microreactors, the first microreactor R1 is filled with dehydrating agent, and the second microreactor R2 is filled with catalyst. The third microreactor R3 is a PTFE capillary microreactor. The mixing coil R4 is a PTFE capillary coil. The first micromixer M1, the second micromixer M2, the third micromixer M3 and the fourth micromixer M4 are T-type mixers or cross-type mixers.

[0105] Example 68 (Schiff base reaction, reaction step 1)

[0106] Fill the first microreactor R1 with a dehydrating agent Granular molecular sieve, multiple oscillations to ensure no obvious gaps. Toluene is used as the weighing solvent, and the volume of the reactor is calculated using the differential weight method. PTFE capillary tubes are used as connecting tubes, and the first feed pump P1 and the second feed pump P2 are injection pumps.

[0107] Take 2-aminopyridine (0.475g, 5.0mmol) and place it in a 25mL volumetric flask, use toluene to make up the volume, and use it as feed liquid A. Take pyrimidine-5-carboxaldehyde (0.550g, 5.0mmol) and place it in a 25mL volumetric flask, use toluene to make up the volume, and use it as feed liquid B. Transfer feed liquid B to a glass airtight syringe, wrap the glass airtight syringe and temperature control probe with a silicone heating pad, set the heating temperature to 60℃, keep warm to avoid substrate precipitation, and stop heating after the feeding is completed. Feed liquid A and feed liquid B are mixed by the first feed pump P1 and the second feed pump P2 through the first micromixer M1 and then enter the first microreactor R1. The flow rate is 12.5μL / min, the residence time is 20min, and the temperature of the microreactor is set to 60℃. Continuous Schiff base reaction is carried out to obtain reaction liquid C. GC-MS detection shows that the conversion rate is 94.83%. The solvent of the reaction solution C was removed by rotary evaporation to obtain a crude imine product as a yellow to light yellow solid.

[0108] Examples 69 to 85 (Schiff base reaction, reaction step 1)

[0109] The operation is similar to that of Example 68, except that the feed liquid flow rate, reactor temperature, and residence time are different. The conversion rates are shown in Table 6 below.

[0110] Table 6

[0111] Example Flow rate [μL / min] Residence time [min] Temperature [℃] Conversion rate [%] 69 25 10 60 78.02 70 50 5 60 68.06 71 12.5 20 70 97.47 72 25 10 70 91.72 73 50 5 70 88.97 74 12.5 20 80 95.75 75 25 10 80 94.65 76 50 5 80 83.21 77 12.5 20 90 96.59 78 25 10 90 95.52 79 50 5 90 88.83 80 12.5 20 100 96.60 81 25 10 100 94.62 82 50 5 100 89.10 83 12.5 20 110 95.73 84 25 10 110 92.92 85 50 5 110 90.52

[0112] Example 86 (Reductive amination reaction, reaction step 2)

[0113] The stainless steel reaction column of the second microreactor R2 was filled with 5 wt% Pd(OH)2 / C granular catalyst, and the mixture was shaken several times to ensure that there were no obvious gaps. The filled catalyst was weighed by differential weight method to weigh about 3.5 g. Methanol was used as the weighing solvent, and the reactor internal volume was calculated by differential weight method.

[0114] Take N-2-pyridine-5-pyrimidine azomethine (0.937g, 5.0mmol) and place it in a 100mL volumetric flask, add anhydrous methanol to the fixed volume, shake and dissolve it, and use it as feed liquid C'. Feed liquid C' is heated by high-pressure constant flow pump P3 through the preheating section and pumped into the mixer. High-pressure hydrogen is prepared by a high-pressure hydrogen generator, and the pressure reducing valve adjusts the inlet pressure. The flow rate is controlled by the mass flow meter MFC and passed into the mixer. After the feed liquid C' and hydrogen are mixed in the mixer, they enter the second microreactor R2 for continuous reduction amination reaction. The reaction pressure is controlled by the back pressure valve. After the material is separated by the gas-liquid separator, the reaction liquid D is obtained. The flow rate of feed liquid C' is 0.2mL / min, the temperature of the preheating section is 70℃, the gas pressure is 3.1MPa, and the gas flow rate is 10mL / min. The temperature of the microreactor is 70℃, the pressure of the back pressure valve is 3.0MPa, and the residence time is about 6.5min. The reaction solution D was detected by GC-MS, and the conversion rate was 86.92%. After the reaction solution D was evaporated under reduced pressure to remove the solvent, the reduction product N-2-pyridine-5-pyrimidinemethylamine was obtained as a crude yellow to light yellow solid.

[0115] Examples 87-95 (Reductive amination reaction, reaction step 2)

[0116] The operation is similar to that of Example 86. The difference is that the feed liquid flow rate, hydrogen flow rate, and back pressure valve pressure are different. The conversion rate is shown in Table 7 below. The hydrogen pressure is 0.1 MPa higher than the back pressure to ensure the stability of the gas supply.

[0117] Table 7

[0118] Example Feed liquid flow rate Hydrogen flow rate [mL / min] Back pressure [MPa] Conversion rate [%] 87 0.2 5 2.0 39.40 88 0.2 10 2.0 72.05 89 0.2 15 2.0 76.54 90 0.2 20 2.0 77.81 91 0.2 5 3.0 77.10 92 0.2 15 3.0 87.03 93 0.2 20 3.0 88.06 94 0.4 20 3.0 89.33 95 0.6 30 3.0 90.97

[0119] Example 96 (Reductive amination reaction, reaction step 2)

[0120] The stainless steel reaction column of the second microreactor R2 was filled with 5 wt% Pd(OH)2 / C granular catalyst, and the mixture was shaken several times to ensure that there were no obvious gaps. The filled catalyst was weighed by differential weight method to weigh about 3.5 g. Anhydrous tetrahydrofuran was used as the weighing solvent, and the reactor internal volume was calculated by differential weight method.

[0121] Take N-2-pyridine-5-pyrimidine azomethine (0.937g, 5.0mmol) and place it in a 100mL volumetric flask, add anhydrous tetrahydrofuran to the volume, shake and dissolve it, and use it as feed liquid C'. Feed liquid C' is heated by high-pressure constant flow pump P3 through the preheating section and pumped into the mixer. High-pressure hydrogen is prepared by a high-pressure hydrogen generator, and the pressure reducing valve adjusts the inlet pressure. The flow rate is controlled by the mass flow meter MFC and passed into the mixer. After the feed liquid C' and hydrogen are mixed in the mixer, they enter the second microreactor R2 for continuous reduction amination reaction. The reaction pressure is controlled by the back pressure valve. After the material is separated by the gas-liquid separator, the reaction liquid D is obtained. The flow rate of feed liquid C' is 0.2mL / min, the temperature of the preheating section is 70℃, the gas pressure is 3.1MPa, and the gas flow rate is 10mL / min. The temperature of the microreactor is 70℃, the pressure of the back pressure valve is 3.0MPa, and the residence time is about 6.5min. The reaction solution D was detected by GC-MS, and the conversion rate was 70.42%. After the reaction solution D was evaporated under reduced pressure to remove the solvent, the reduction product N-2-pyridine-5-pyrimidinemethylamine was obtained as a crude yellow to light yellow solid.

[0122] Examples 97-104 (reductive amination reaction, reaction step 2)

[0123] The operation is similar to that of Example 96. The difference is that the feed liquid flow rate, hydrogen flow rate, reaction residence time, and back pressure valve pressure are different. The conversion rate is shown in Table 8 below. The hydrogen pressure reducing valve pressure is 0.1 MPa higher than the back pressure valve pressure to ensure the stability of gas supply.

[0124] Table 8

[0125] Example Feed liquid flow rate Hydrogen flow rate [mL / min] Back pressure [MPa] Conversion rate [%] 97 0.2 5 2.0 64.23 98 0.2 10 2.0 68.73 98 0.2 15 2.0 67.61 99 0.2 20 2.0 68.06 100 0.2 5 3.0 71.67 101 0.2 15 3.0 73.81 102 0.2 20 3.0 72.42 103 0.4 20 3.0 72.72 104 0.6 30 3.0 70.05

[0126] Example 105 (Reductive amination reaction, reaction step 2)

[0127] The stainless steel reaction column of the second microreactor R2 was filled with 5 wt% Pd(OH)2 / C granular catalyst, and the mixture was shaken several times to ensure that there were no obvious gaps. The filled catalyst was weighed by differential weight method to weigh about 3.5 g. Anhydrous tetrahydrofuran was used as the weighing solvent, and the reactor internal volume was calculated by differential weight method.

[0128] Take N-2-pyridine-5-pyrimidine azomethine (0.937g, 5.0mmol) and triethylamine (1.022g, 10.0mmol) in a 100mL volumetric flask, dilute with toluene, shake in a 60℃ water bath to dissolve, and use as feed liquid C. Use a silica gel heating pad to cover the glass bottle containing feed liquid C, and maintain the feed liquid temperature at 60℃ to avoid substrate precipitation until the feed liquid is fed, and is heated by a high-pressure constant flow pump P3 through the preheating section and pumped into the mixer. High-pressure hydrogen is prepared by a high-pressure hydrogen generator, the pressure reducing valve adjusts the inlet pressure, and the mass flow meter MFC controls the flow rate and passes into the mixer. After the feed liquid C and hydrogen are mixed in the mixer, they enter the second microreactor R2 for continuous reduction amination reaction. The reaction pressure is controlled by a back pressure valve. After the material is separated by a gas-liquid separator, a reaction liquid D is obtained. The flow rate of feed liquid C is 0.2mL / min, the temperature of preheating section is 70°C, the gas pressure is 3.1MPa, and the gas flow rate is 10mL / min. The temperature of microreactor is 70°C, the back pressure valve pressure is 3.0MPa, and the residence time is about 6.5min. The reaction liquid D is detected by GC-MS, and the conversion rate is 87.92%. After the reaction liquid D is evaporated under reduced pressure to remove the solvent, the reduction product N-2-pyridine-5-pyrimidinemethylamine crude product is obtained, which is a yellow to light yellow solid.

[0129] Examples 106-123 (Reductive amination reaction, reaction step 2)

[0130] The operation is similar to that of Example 105. The difference is that the catalyst type, hydrogen flow rate, and back pressure valve pressure are different. The conversion rate is shown in Table 9 below. The pressure of the hydrogen pressure reducing valve is 0.1 MPa higher than the pressure of the back pressure valve to ensure the stability of the gas supply.

[0131] Table 9

[0132] Example Catalyst type Hydrogen flow rate [mL / min] Back pressure [MPa] Conversion rate [%] 106 <![CDATA[5wt%Pd(OH)2 / C]]> 5 2.0 81.31 107 <![CDATA[5wt%Pd(OH)2 / C]]> 10 2.0 81.13 108 <![CDATA[5wt%Pd(OH)2 / C]]> 20 2.0 65.87 109 <![CDATA[5wt%Pd(OH)2 / C]]> 5 3.0 87.35 110 <![CDATA[5wt%Pd(OH)2 / C]]> 10 3.0 87.92 111 <![CDATA[5wt%Pd(OH)2 / C]]> 20 3.0 86.96 112 <![CDATA[5wt%Pd(OH)2 / C]]> 5 4.0 86.24 113 <![CDATA[5wt%Pd(OH)2 / C]]> 10 4.0 87.83 114 <![CDATA[5wt%Pd(OH)2 / C]]> 20 4.0 87.52 115 <![CDATA[10wt%Pd(OH)2 / C]]> 5 2.0 87.53 116 <![CDATA[10wt%Pd(OH)2 / C]]> 10 2.0 87.04 117 <![CDATA[10wt%Pd(OH)2 / C]]> 20 2.0 86.02 118 <![CDATA[10wt%Pd(OH)2 / C]]> 5 3.0 88.75 119 <![CDATA[10wt%Pd(OH)2 / C]]> 10 3.0 88.86 120 <![CDATA[10wt%Pd(OH)2 / C]]> 20 3.0 87.96 121 <![CDATA[10wt%Pd(OH)2 / C]]> 5 4.0 86.87 122 <![CDATA[10wt%Pd(OH)2 / C]]> 10 4.0 88.16 123 <![CDATA[10wt%Pd(OH)2 / C]]> 20 4.0 87.70

[0133] Example 124 (Cyclization reaction, reaction step 3)

[0134] The tetrafluoroethylene capillary was rectified into a long straight column as the third microreactor R3.

[0135] Add 2-(3-trifluoromethylphenyl)malonic acid (0.552g, 2.0mmol), N,N-dimethylformamide (1 drop), and dichloromethane (10.0mL) to a 25mL flask and stir for 15min in an ice-water bath; slowly add oxalyl chloride (1.27g, 10.0mmol) to the reaction bottle, and continue to stir for 30min in an ice-water bath, then slowly warm to room temperature and stir at room temperature for 1h; after the reaction is completed, use a rotary evaporator to remove all solvents and unreacted oxalyl chloride. The residue is placed in a 10mL volumetric flask, fixed to volume with toluene, shaken to dissolve, and used as feed liquid E. Take N-2-pyridine-5-pyrimidinemethylamine (0.372g, 2.0mmol) and triethylamine (0.408g, 4.0mmol) and place them in a 10mL volumetric flask, fixed to volume with toluene, shaken to dissolve, and used as feed liquid D.

[0136] Feed liquid D and feed liquid E are mixed by syringe pump P4 and syringe pump P5 through T-type mixer and then pumped into the third microreactor R3. The feed flow rate is 100 μL / min, the reaction residence time is about 2.5 min, and the temperature of the microreactor is 20 ° C. The reaction liquid flows into a flask containing 10 mL of purified water from the outlet of the third microreactor R3 for quenching. After oscillation, standing, and separation, the organic phase is dried over anhydrous sodium sulfate, filtered, and the solvent is evaporated under reduced pressure to obtain a crude trifluorophenylpyrimidine. According to HPLC detection, the conversion rate is 63.82%. The crude product is separated and purified by column chromatography, and the eluent is ethyl acetate → ethyl acetate: methanol = 20: 1 to 5: 1. After separation and purification, it is vacuum dried for 24 hours and sealed for storage, with a yield of 41%.

[0137] Example 125 (Cyclization reaction, reaction step 3)

[0138] The tetrafluoroethylene capillary was rectified into a long straight column as the third microreactor R3.

[0139] Add 2-(3-trifluoromethylphenyl)malonic acid (0.552g, 2.0mmol), N,N-dimethylformamide (1 drop), and dichloromethane (10.0mL) to a 25mL flask and stir for 15min in an ice-water bath; slowly add oxalyl chloride (1.27g, 10.0mmol) to the reaction bottle, and continue to stir for 30min in an ice-water bath, then slowly warm to room temperature and stir at room temperature for 1h; after the reaction is completed, use a rotary evaporator to remove all solvents and unreacted oxalyl chloride. The residue is placed in a 10mL volumetric flask, fixed to volume with toluene, shaken to dissolve, and used as feed liquid E. Take N-2-pyridine-5-pyrimidinemethylamine (0.372g, 2.0mmol) and triethylamine (0.408g, 4.0mmol) and place them in a 10mL volumetric flask, fixed to volume with toluene, shaken to dissolve, and used as feed liquid D.

[0140] Feed liquid D and feed liquid E are mixed by injection pump P4 and injection pump P5 through T-type mixer and then pumped into the third microreactor R3. The feed flow rate is 100 μL / min, the microreactor temperature is 20°C, and the reaction residence time is about 2.5 min. After the reaction liquid flows out of the outlet of the third microreactor R3, it is mixed with purified water (flow rate 100 μL / min) delivered by pump P6 through a T-type mixer and then quenched and extracted online in a PTFE capillary, and then the water-oil two-phase separation is achieved through a membrane separator. The organic phase is dried over anhydrous sodium sulfate, filtered, and the solvent is evaporated under reduced pressure to obtain a crude trifluorophenylpyrimidine. According to HPLC detection, the conversion rate is 65.73%. The crude product is separated and purified by column chromatography, and the eluent is ethyl acetate → ethyl acetate: methanol = 20:1~5:1. After separation and purification, it is vacuum dried for 24 hours and sealed for storage, with a yield of 38%.

[0141] Example 126 (Cyclization reaction, reaction step 3)

[0142] The tetrafluoroethylene capillary was rectified into a long straight column as the third microreactor R3.

[0143] Add 2-(3-trifluoromethylphenyl)malonic acid (0.552g, 2.0mmol), N,N-dimethylformamide (1 drop), and dichloromethane (10.0mL) to a 25mL flask and stir for 15min in an ice-water bath; slowly add oxalyl chloride (1.27g, 10.0mmol) to the reaction bottle, and continue to stir for 30min in an ice-water bath, then slowly warm to room temperature and stir at room temperature for 1h; after the reaction is completed, use a rotary evaporator to remove all solvents and unreacted oxalyl chloride. The residue is placed in a 10mL volumetric flask, fixed to volume with toluene, shaken to dissolve, and used as feed liquid E. Take N-2-pyridine-5-pyrimidinemethylamine (0.372g, 2.0mmol) and triethylamine (0.408g, 4.0mmol) and place them in a 10mL volumetric flask, fixed to volume with toluene, shaken to dissolve, and used as feed liquid D.

[0144] Feed liquid D and feed liquid E are mixed by injection pump P4 and injection pump P5 through T-type mixer and then pumped into the third microreactor R3. The feed flow rate is 50 μL / min, the temperature of the microreactor is 20 ° C, and the reaction residence time is about 5 min. The reaction liquid flows into a flask containing 10 mL of purified water from the outlet of the third microreactor R3 for quenching. After oscillation, standing, and separation, the organic phase is dried over anhydrous sodium sulfate, filtered, and the solvent is evaporated under reduced pressure to obtain a crude trifluorophenylpyrimidine. According to HPLC detection, the conversion rate is 84.83%. The crude product is separated and purified by column chromatography, and the eluent is ethyl acetate → ethyl acetate: methanol = 20: 1 to 5: 1. After separation and purification, it is vacuum dried for 24 hours and sealed for storage, with a yield of 47%.

[0145] Example 127 (Cyclization reaction, reaction step 3)

[0146] The tetrafluoroethylene capillary was rectified into a long straight column as the third microreactor R3.

[0147] Add 2-(3-trifluoromethylphenyl)malonic acid (0.552g, 2.0mmol), N,N-dimethylformamide (1 drop), and dichloromethane (10.0mL) to a 25mL flask and stir for 15min in an ice-water bath; slowly add oxalyl chloride (1.27g, 10.0mmol) to the reaction bottle, and continue to stir for 30min in an ice-water bath, then slowly warm to room temperature and stir at room temperature for 1h; after the reaction is completed, use a rotary evaporator to remove all solvents and unreacted oxalyl chloride. The residue is placed in a 10mL volumetric flask, fixed to volume with toluene, shaken to dissolve, and used as feed liquid E. Take N-2-pyridine-5-pyrimidinemethylamine (0.372g, 2.0mmol) and triethylamine (0.408g, 4.0mmol) and place them in a 10mL volumetric flask, fixed to volume with toluene, shaken to dissolve, and used as feed liquid D.

[0148] Feed liquid D and feed liquid E are mixed by syringe pump P4 and syringe pump P5 through T-type mixer and then pumped into the third microreactor R3. The feed flow rate is 25 μL / min, the microreactor temperature is 20°C, and the reaction residence time is about 10 min. The reaction liquid flows into a flask containing 10 mL of purified water from the outlet of the third microreactor R3 for quenching. After oscillation, standing, and separation, the organic phase is dried over anhydrous sodium sulfate, filtered, and the solvent is evaporated under reduced pressure to obtain a crude trifluorophenylpyrimidine. According to HPLC detection, the conversion rate is 85.55%. The crude product is separated and purified by column chromatography, and the eluent is ethyl acetate → ethyl acetate: methanol = 20:1~5:1. After separation and purification, it is vacuum dried for 24 hours and sealed for storage, with a yield of 49%.

[0149] Examples 128 to 133 (Cyclization reaction, reaction step 3)

[0150] The operation is similar to Example 124, Example 126, and Example 127, except that the reaction temperature and material flow rate are different. The conversion rate is shown in Table 10 below.

[0151] Table 10

[0152]

[0153]

[0154] Example 134 (Cyclization reaction, reaction step 3)

[0155] The operation is similar to that of Example 124, Example 126, and Example 127, except that N-2-pyridine-5-pyrimidinemethylamine (0.372 g, 2.0 mmol) and triethylamine (0.408 g, 4.0 mmol) are placed in a 20 mL volumetric flask, fixed to volume with toluene, shaken to dissolve, and then divided into two equal volumes as feed liquid D for standby use. Feed liquid D and feed liquid E are respectively mixed by a dual-channel syringe pump P4 and a single-channel syringe pump P5 through a cross-type mixer and pumped into the third microreactor R3. The material flow rate is 16.67 μL / min, the microreactor temperature is 20 ° C, and the reaction residence time is about 10 min. The reaction solution flows from the outlet of the third microreactor R3 into a flask containing 10 mL of purified water for quenching. After shaking, standing, and liquid separation, the organic phase is dried by anhydrous sodium sulfate, filtered, and the solvent is evaporated under reduced pressure to obtain a crude trifluorophenylpyrimidine. Detected by HPLC, the conversion rate was 67.81%. The crude product was separated and purified by column chromatography, and the eluent was ethyl acetate→ethyl acetate:methanol=20:1-5:1. After separation and purification, it was vacuum dried for 24 hours and sealed for storage, and the yield was 30%.

[0156] Example 135 (Cyclization reaction, reaction step 3)

[0157] The operation is similar to that of Example 134, except that the material flow rate is 33.33 μL / min, the microreactor temperature is 20°C, and the reaction residence time is about 5 min. The reaction solution flows from the outlet of the third microreactor R3 into a flask containing 10 mL of purified water for quenching. After oscillation, standing, and separation, the organic phase is dried over anhydrous sodium sulfate, filtered, and the solvent is evaporated under reduced pressure to obtain a crude trifluorophenylpyrimidine. HPLC detection showed a conversion rate of 72.71%. The crude product was separated and purified by column chromatography, and the eluent was ethyl acetate → ethyl acetate: methanol = 20: 1 to 5: 1. After separation and purification, it was vacuum dried for 24 h and sealed for storage, with a yield of 33%.

[0158] Example 135 (Cyclization reaction, reaction step 3)

[0159] The operation is similar to that of Example 134, except that the material flow rate is 66.66 μL / min, the microreactor temperature is 20°C, and the reaction residence time is about 2.5 min. The reaction solution flows from the outlet of the third microreactor R3 into a flask containing 10 mL of purified water for quenching. After oscillation, standing, and separation, the organic phase is dried over anhydrous sodium sulfate, filtered, and the solvent is evaporated under reduced pressure to obtain a crude trifluorophenylpyrimidine. HPLC detection showed a conversion rate of 81.47%. The crude product was separated and purified by column chromatography, and the eluent was ethyl acetate → ethyl acetate: methanol = 20: 1 to 5: 1. After separation and purification, it was vacuum dried for 24 hours and sealed for storage, with a yield of 39%.

[0160] Example 136 (Schiff base reaction-reductive amination reaction, reaction step 12)

[0161] Fill the first microreactor R1 with Granular molecular sieve, oscillate multiple times to ensure that there are no obvious gaps. Use toluene as the weighing solvent and use the differential weight method to calculate the reactor volume. Fill the stainless steel reaction column of the second microreactor R2 with 10wt% Pd(OH)2 / C catalyst and oscillate multiple times to ensure that there are no obvious gaps. Use toluene as the weighing solvent and use the differential weight method to calculate the reactor volume. Use a PTFE capillary as the connecting tube of the first microreactor R1, and a stainless steel capillary as the connecting tube of the second microreactor R2.

[0162] Take 2-aminopyridine (0.475g, 5.0mmol) and place it in a 25mL volumetric flask, use toluene to make up the volume, and use it as feed liquid A. Take pyrimidine-5-carboxaldehyde (0.550g, 5.0mmol) and place it in a 25mL volumetric flask, use toluene to make up the volume, and use it as feed liquid B. After the feed liquid B is made up, it is transferred into a gas-tight glass syringe, heated and coated with a silica gel pad, and the insulation temperature is set to 60°C to avoid low-temperature precipitation of the substrate until the feed liquid is transported. Feed liquid A and feed liquid B are mixed by pump P1 and pump P2 respectively through a T-type mixer and enter the first microreactor R1. The flow rate is 12.5μL / min, the residence time is 20min, and the temperature of the microreactor is set to 70°C. A continuous Schiff base reaction is carried out to obtain reaction liquid C.

[0163] The reaction liquid C was mixed with 50 mL of toluene solution containing triethylamine (1.022 g, 10.0 mmol) as feed liquid C. The container containing feed liquid C was covered with a heating silica gel pad, and the insulation temperature was set to 60 ° C to avoid low-temperature precipitation of the substrate until the feed liquid was transported. The feed liquid C was heated by a high-pressure constant flow pump P3 through the preheating section and pumped into the mixer. High-pressure hydrogen was prepared by a high-pressure hydrogen generator, the pressure reducing valve adjusted the inlet pressure, and the flow was controlled by the mass flow meter MFC and passed into the mixer. After the feed liquid C and hydrogen were mixed in the mixer, they entered the second microreactor R2 for continuous reduction amination reaction. The reaction pressure was controlled by a back pressure valve. After the material was separated by a gas-liquid separator, the reaction liquid D was obtained. The flow rate of the feed liquid C was 0.2 mL / min, the temperature of the preheating section was 70 ° C, the gas pressure was 3.1 MPa, and the gas flow rate was 10 mL / min. The temperature of the microreactor is 70°C, the back pressure valve pressure is 3.0MPa, and the residence time is about 20s. The reaction solution D is detected by GC-MS, and the conversion rate is 86.61%. After the reaction is completed, anhydrous methanol is used as a cleaning liquid to clean the microreactor R2. After the cleaning liquid is combined with the reaction solution D, the solvent is evaporated under reduced pressure to obtain the reduction product N-2-pyridine-5-pyrimidinemethylamine crude product, which is a yellow to light yellow solid. The crude product is purified by column chromatography, and the eluent is dichloromethane: methanol = 30: 1 to 20: 1, and a small amount of ammonia or triethylamine is added at the same time. The pure product is a light yellow solid with a yield of 75%.

[0164] Example 137 (Schiff base reaction-reductive amination reaction, reaction step 12)

[0165] Fill the first microreactor R1 with Granular molecular sieve, oscillate multiple times to ensure that there are no obvious gaps. Use toluene as the weighing solvent and use the differential weight method to calculate the reactor volume. Fill the stainless steel reaction column of the second microreactor R2 with 10wt% Pd(OH)2 / C granular catalyst and oscillate multiple times to ensure that there are no obvious gaps. Use toluene as the weighing solvent and use the differential weight method to calculate the reactor volume. Use a PTFE capillary as the connecting tube of the first microreactor R1, and a stainless steel capillary as the connecting tube of the second microreactor R2.

[0166] Take 2-aminopyridine (0.475g, 5.0mmol) and place it in a 25mL volumetric flask, use toluene to make up the volume, and use it as feed liquid A. Take pyrimidine-5-carboxaldehyde (0.550g, 5.0mmol) and place it in a 25mL volumetric flask, use toluene to make up the volume, and use it as feed liquid B. Subsequently, transfer feed liquid B to a glass airtight syringe, cover it with a silica gel heating pad, and keep it warm at 60°C to avoid substrate precipitation until feed liquid B is delivered. Feed liquid A and feed liquid B are mixed by pump P1 and pump P2 respectively through a T-type mixer and enter the first microreactor R1. The flow rate is 12.5μL / min, the residence time is 20min, and the temperature of the microreactor is set to 70°C. Continuous Schiff base reaction is carried out to obtain reaction liquid C.

[0167] After the solvent is removed by online reduced pressure evaporation of the reaction liquid C by the post-treatment module T1, 100 mL of anhydrous methanol is used as the replacement solvent to redissolve the rotary evaporation residue to obtain the feed liquid C'. The feed liquid C' is heated by the high-pressure constant flow pump P3 through the preheating section and pumped into the mixer. High-pressure hydrogen is prepared by a high-pressure hydrogen generator, the pressure reducing valve adjusts the inlet pressure, and the flow is controlled by the mass flow meter MFC and passed into the mixer. After the feed liquid C' and hydrogen are mixed in the mixer, they enter the second microreactor R2 for continuous reduction amination reaction. The reaction pressure is controlled by the back pressure valve. After the material is separated by the gas-liquid separator, the reaction liquid D is obtained. The flow rate of the feed liquid C' is 0.2 mL / min, the temperature of the preheating section is 70°C, the gas pressure is 3.1 MPa, and the gas flow rate is 10 mL / min. The temperature of the microreactor is 70°C, the pressure of the back pressure valve is 3.0 MPa, and the residence time is about 6.5 min. The reaction liquid D is detected by GC-MS, and the conversion rate is 87.73%. After the reaction is completed, anhydrous methanol is used as a cleaning liquid to clean the microreactor R2. After the cleaning liquid is combined with the reaction liquid D, the solvent is evaporated under reduced pressure to obtain the reduction product N-2-pyridine-5-pyrimidinemethylamine crude product, which is a yellow to light yellow solid. The crude product is purified by column chromatography, and the eluent is dichloromethane: methanol = 30:1 to 20:1, and a small amount of ammonia or triethylamine is added at the same time. The pure product is a light yellow solid, and the yield is 77%.

[0168] Example 138 (Schiff base reaction-reductive amination reaction, reaction step 12)

[0169] The first microreactor R1 is filled with granular Molecular sieve, oscillate multiple times to ensure that there are no obvious gaps. Toluene is used as the weighing solvent, and the reactor volume is calculated using the differential weight method. 10wt% Pd(OH)2 / C granular catalyst is filled in the stainless steel reaction column of the second microreactor R2, and oscillates multiple times to ensure that there are no obvious gaps. Anhydrous tetrahydrofuran is used as the weighing solvent, and the reactor volume is calculated using the differential weight method. A PTFE capillary is used as the connecting tube of the first microreactor R1, and a stainless steel capillary is used as the connecting tube of the second microreactor R2.

[0170] Take 2-aminopyridine (0.475g, 5.0mmol) and place it in a 25mL volumetric flask, use toluene to make up the volume, and use it as feed liquid A. Take pyrimidine-5-carboxaldehyde (0.550g, 5.0mmol) and place it in a 25mL volumetric flask, use toluene to make up the volume, and use it as feed liquid B. Subsequently, transfer feed liquid B to a glass airtight syringe, cover it with a silica gel heating pad, and keep it warm at 60°C to avoid substrate precipitation until feed liquid B is delivered. Feed liquid A and feed liquid B are mixed by pump P1 and pump P2 respectively through a T-type mixer and enter the first microreactor R1. The flow rate is 12.5μL / min, the residence time is 20min, and the temperature of the microreactor is set to 70°C. Continuous Schiff base reaction is carried out to obtain reaction liquid C.

[0171] The reaction liquid C was mixed with 50 mL of toluene solution containing triethylamine (1.022 g, 10.0 mmol) as feed liquid C. Subsequently, a silica gel heating pad was used to cover the container containing feed liquid C, and the temperature was kept at 60 ° C to avoid substrate precipitation until the feed liquid C was transported. The feed liquid C was heated by a high-pressure constant flow pump P3 through the preheating section and pumped into the mixer. High-pressure hydrogen was prepared by a high-pressure hydrogen generator, the pressure reducing valve adjusted the inlet pressure, and the flow was controlled by a mass flow meter MFC and passed into the mixer. After the feed liquid C and hydrogen were mixed in the mixer, they entered the second microreactor R2 for continuous reduction amination reaction. The reaction pressure was controlled by a back pressure valve. After the material was separated by a gas-liquid separator, the reaction liquid D was obtained. The flow rate of the feed liquid C was 0.2 mL / min, the temperature of the preheating section was 70 ° C, the gas pressure was 3.1 MPa, and the gas flow rate was 10 mL / min. The temperature of the microreactor is 70°C, the back pressure valve pressure is 3.0MPa, and the residence time is about 6.5min. The reaction solution D is detected by GC-MS, and the conversion rate is 66.36%. After the reaction is completed, anhydrous methanol is used as a cleaning liquid to clean the microreactor R2. After the cleaning liquid is combined with the reaction solution D, the solvent is evaporated under reduced pressure to obtain the reduction product N-2-pyridine-5-pyrimidinemethylamine crude product, which is a yellow to light yellow solid. The crude product is purified by column chromatography, and the eluent is dichloromethane: methanol = 30: 1 to 20: 1, and a small amount of ammonia or triethylamine is added at the same time. The pure product is a light yellow solid with a yield of 45%.

[0172] Example 139 (Schiff base reaction-reductive amination reaction, reaction step 12)

[0173] The first microreactor R1 is filled with granular Molecular sieve, oscillate multiple times to ensure that there are no obvious gaps. Toluene is used as the weighing solvent, and the reactor volume is calculated using the differential weight method. 10wt% Pd(OH)2 / C granular catalyst is filled in the stainless steel reaction column of the second microreactor R2, and oscillates multiple times to ensure that there are no obvious gaps. Toluene is used as the weighing solvent, and the reactor volume is calculated using the differential weight method. A capillary made of PTFE is used as the connecting tube of the first microreactor R1, and a capillary made of stainless steel is used as the connecting tube of the second microreactor R2.

[0174] Take 2-aminopyridine (0.475g, 5.0mmol) and place it in a 25mL volumetric flask, use toluene to make up the volume, and use it as feed liquid A. Take pyrimidine-5-carboxaldehyde (0.550g, 5.0mmol) and place it in a 25mL volumetric flask, use toluene to make up the volume, and use it as feed liquid B. Subsequently, transfer feed liquid B to a glass airtight syringe, cover it with a silica gel heating pad, and keep it warm at 60°C to avoid substrate precipitation until feed liquid B is delivered. Feed liquid A and feed liquid B are mixed by pump P1 and pump P2 respectively through a T-type mixer and enter the first microreactor R1. The flow rate is 12.5μL / min, the residence time is 20min, and the temperature of the microreactor is set to 70°C. Continuous Schiff base reaction is carried out to obtain reaction liquid C.

[0175] After the solvent is removed by online reduced pressure evaporation of the reaction liquid C in the post-treatment module T1, 100 mL of anhydrous tetrafuran is used to redissolve the reaction liquid C'. The reaction liquid C' is heated by the high-pressure constant flow pump P3 through the preheating section and pumped into the mixer. High-pressure hydrogen is prepared by a high-pressure hydrogen generator, the pressure reducing valve adjusts the inlet pressure, and the mass flow meter MFC controls the flow rate and passes into the mixer. After the reaction liquid C' and hydrogen are mixed in the mixer, they enter the second microreactor R2 for continuous reduction amination reaction. The reaction pressure is controlled by the back pressure valve. After the material is separated by the gas-liquid separator, the reaction liquid D is obtained. The flow rate of the reaction liquid C' is 0.2 mL / min, the temperature of the preheating section is 70 ° C, the gas pressure is 3.1 MPa, and the gas flow rate is 10 mL / min. The temperature of the microreactor is 70 ° C, the pressure of the back pressure valve is 3.0 MPa, and the residence time is about 6.5 min. The reaction liquid D is detected by GC-MS, and the conversion rate is 72.27%. After the reaction is completed, anhydrous methanol is used as a cleaning liquid to clean the microreactor R2. After the cleaning liquid is combined with the reaction liquid D, the solvent is evaporated under reduced pressure to obtain the reduction product N-2-pyridine-5-pyrimidinemethylamine crude product, which is a yellow to light yellow solid. The crude product is purified by column chromatography, and the eluent is dichloromethane: methanol = 30:1 to 20:1, and a small amount of ammonia water or triethylamine is added at the same time. The pure product is a light yellow solid, and the yield is 56%.

[0176] Example 140 (Schiff base reaction-reductive amination reaction, reaction step 12)

[0177] The first microreactor R1 is filled with granular Molecular sieve, oscillate multiple times to ensure that there are no obvious gaps. Toluene is used as the weighing solvent, and the reactor volume is calculated using the differential weight method. 5wt% Pd(OH)2 / C granular catalyst is filled in the stainless steel reaction column of the second microreactor R2, and oscillates multiple times to ensure that there are no obvious gaps. Toluene is used as the weighing solvent, and the reactor volume is calculated using the differential weight method. A capillary made of PTFE is used as the connecting tube of the first microreactor R1, and a capillary made of stainless steel is used as the connecting tube of the second microreactor R2.

[0178] Take 2-aminopyridine (0.475g, 5.0mmol) and place it in a 25mL volumetric flask, use toluene to make up the volume, and use it as feed liquid A. Take pyrimidine-5-carboxaldehyde (0.550g, 5.0mmol) and place it in a 25mL volumetric flask, use toluene to make up the volume, and use it as feed liquid B. Subsequently, transfer feed liquid B to a glass airtight syringe, cover it with a silica gel heating pad, and keep it warm at 60°C to avoid substrate precipitation until feed liquid B is delivered. Feed liquid A and feed liquid B are mixed by pump P1 and pump P2 respectively through a T-type mixer and enter the first microreactor R1. The flow rate is 12.5μL / min, the residence time is 20min, and the temperature of the microreactor is set to 70°C. Continuous Schiff base reaction is carried out to obtain reaction liquid C.

[0179] The reaction liquid C was mixed with 50 mL of toluene solution containing triethylamine (1.022 g, 10.0 mmol) as feed liquid C. The container containing feed liquid C was covered with a silica gel heating pad and kept warm at 60 ° C to avoid substrate precipitation until the feed liquid C was delivered. The feed liquid C was heated by a high-pressure constant flow pump P3 through the preheating section and pumped into the mixer. High-pressure hydrogen was prepared by a high-pressure hydrogen generator, the pressure reducing valve adjusted the inlet pressure, and the flow was controlled by a mass flow meter MFC and passed into the mixer. After the feed liquid C and hydrogen were mixed in the mixer, they entered the second microreactor R2 for continuous reduction amination reaction. The reaction pressure was controlled by a back pressure valve. After the material was separated by a gas-liquid separator, the reaction liquid D was obtained. The flow rate of the feed liquid C was 0.2 mL / min, the temperature of the preheating section was 70 ° C, the gas pressure was 3.1 MPa, and the gas flow rate was 10 mL / min. The temperature of the microreactor is 70°C, the back pressure valve pressure is 3.0MPa, and the residence time is about 6.5min. The reaction solution D is detected by GC-MS, and the conversion rate is 86.04%. After the reaction is completed, anhydrous methanol is used as a cleaning liquid to clean the microreactor R2. After the cleaning liquid is combined with the reaction solution D, the solvent is evaporated under reduced pressure to obtain the reduction product N-2-pyridine-5-pyrimidinemethylamine crude product, which is a yellow to light yellow solid. The crude product is purified by column chromatography, and the eluent is dichloromethane: methanol = 30: 1 to 20: 1, and a small amount of ammonia or triethylamine is added. The pure product is a light yellow solid with a yield of 72%.

[0180] Example 141 (Schiff base reaction-reductive amination reaction, reaction step 12)

[0181] The first microreactor R1 is filled with granular Molecular sieve, oscillate multiple times to ensure that there are no obvious gaps. Toluene is used as the weighing solvent, and the reactor volume is calculated using the differential weight method. 5wt% Pd(OH)2 / C granular catalyst is filled in the stainless steel reaction column of the second microreactor R2, and oscillates multiple times to ensure that there are no obvious gaps. Toluene is used as the weighing solvent, and the reactor volume is calculated using the differential weight method. A capillary made of PTFE is used as the connecting tube of the first microreactor R1, and a capillary made of stainless steel is used as the connecting tube of the second microreactor R2.

[0182] Take 2-aminopyridine (0.475g, 5.0mmol) and place it in a 25mL volumetric flask, use toluene to make up the volume, and use it as feed liquid A. Take pyrimidine-5-carboxaldehyde (0.550g, 5.0mmol) and place it in a 25mL volumetric flask, use toluene to make up the volume, and use it as feed liquid B. Subsequently, transfer feed liquid B to a glass airtight syringe, cover it with a silica gel heating pad, and keep it warm at 60°C to avoid substrate precipitation until feed liquid B is delivered. Feed liquid A and feed liquid B are mixed by pump P1 and pump P2 respectively through a T-type mixer and enter the first microreactor R1. The flow rate is 12.5μL / min, the residence time is 20min, and the temperature of the microreactor is set to 70°C. Continuous Schiff base reaction is carried out to obtain reaction liquid C.

[0183] The reaction liquid C was mixed with 50 mL of toluene solution containing triethylamine (1.150 g, 11.25 mmol) as feed liquid C. The container containing feed liquid C was covered with a silica gel heating pad and kept warm at 60 ° C to avoid substrate precipitation until the feed liquid C was delivered. The feed liquid C was heated by a high-pressure constant flow pump P3 through the preheating section and pumped into the mixer. High-pressure hydrogen was prepared by a high-pressure hydrogen generator, the pressure reducing valve adjusted the inlet pressure, and the flow was controlled by a mass flow meter MFC and passed into the mixer. After the feed liquid C and hydrogen were mixed in the mixer, they entered the second microreactor R2 for continuous reduction amination reaction. The reaction pressure was controlled by a back pressure valve. After the material was separated by a gas-liquid separator, the reaction liquid D was obtained. The flow rate of the feed liquid C was 0.2 mL / min, the temperature of the preheating section was 70 ° C, the gas pressure was 3.1 MPa, and the gas flow rate was 10 mL / min. The temperature of the microreactor is 70°C, the back pressure valve pressure is 3.0MPa, and the residence time is about 6.5min. The reaction solution D is detected by GC-MS, and the conversion rate is 88.24%. After the reaction is completed, anhydrous methanol is used as a cleaning liquid to clean the microreactor R2. After the cleaning liquid is combined with the reaction solution D, the solvent is evaporated under reduced pressure to obtain the reduction product N-2-pyridine-5-pyrimidinemethylamine crude product, which is a yellow to light yellow solid. The crude product is purified by column chromatography, and the eluent is dichloromethane: methanol = 30: 1 to 20: 1, and a small amount of ammonia or triethylamine is added. The pure product is a light yellow solid with a yield of 76%.

[0184] Example 142 (Schiff base reaction-reductive amination reaction-cyclization reaction, reaction step 123)

[0185] Fill the first microreactor R1 with Granular molecular sieve, oscillate multiple times to ensure that there are no obvious gaps. Use toluene as the weighing solvent and use the differential weight method to calculate the reactor volume. Fill the stainless steel reaction column of the second microreactor R2 with 5wt% Pd(OH)2 / C granular catalyst and oscillate multiple times to ensure that there are no obvious gaps. Use toluene as the weighing solvent and use the differential weight method to calculate the reactor volume. Use PTFE capillaries as the reaction tubes of the first microreactor R1 and the third microreactor R3, and use stainless steel capillaries as the connecting tubes of the second microreactor R2.

[0186] Add 2-(3-trifluoromethylphenyl)malonic acid (1.380 g, 5.0 mmol), N,N-dimethylformamide (1 drop), and dichloromethane (25.0 mL) into a 100 mL flask and stir for 30 min in an ice-water bath; slowly drop oxalyl chloride (3.175 g, 25.0 mmol) into the reaction flask, continue to stir for 60 min in an ice-water bath, then slowly warm to room temperature and stir for 2 h at room temperature; after the reaction is complete, use a rotary evaporator to remove all solvents and unreacted oxalyl chloride. Place the residue in a 50 mL volumetric flask, dilute to volume with toluene, shake to dissolve, and use as feed liquid E.

[0187] Take 2-aminopyridine (0.475g, 5.0mmol) and place it in a 25mL volumetric flask, use toluene to make up the volume, and use it as feed liquid A. Take pyrimidine-5-carboxaldehyde (0.550g, 5.0mmol) and place it in a 25mL volumetric flask, use toluene to make up the volume, and use it as feed liquid B. Subsequently, transfer feed liquid B to a glass airtight syringe, cover it with a silica gel heating pad, and keep it warm at 60°C to avoid substrate precipitation until feed liquid B is delivered. Feed liquid A and feed liquid B are mixed by pump P1 and pump P2 respectively through a T-type mixer and enter the first microreactor R1. The flow rate is 12.5μL / min, the residence time is 20min, and the temperature of the microreactor is set to 70°C. Continuous Schiff base reaction is carried out to obtain reaction liquid C.

[0188] After the solvent is removed by online reduced pressure evaporation of the reaction liquid C in the post-treatment module T1, 100 mL of anhydrous methanol is used to redissolve the reaction liquid C'. The reaction liquid C' is heated by the high-pressure constant flow pump P3 through the preheating section and pumped into the mixer. High-pressure hydrogen is prepared by a high-pressure hydrogen generator, the pressure reducing valve adjusts the inlet pressure, and the mass flow meter MFC controls the flow rate and passes into the mixer. After the reaction liquid C' and hydrogen are mixed in the mixer, they enter the second microreactor R2 for continuous reduction amination reaction. The reaction pressure is controlled by the back pressure valve. After the material is separated by the gas-liquid separator, the reaction liquid D is obtained. The flow rate of the reaction liquid C' is 0.2 mL / min, the temperature of the preheating section is 70 ° C, the gas pressure is 3.1 MPa, and the gas flow rate is 10 mL / min. The temperature of the microreactor is 70 ° C, the pressure of the back pressure valve is 3.0 MPa, and the residence time is about 6.5 min.

[0189] After the reaction liquid D was decompressed and desolventized online by the post-treatment module T2, 50 mL of toluene solution containing triethylamine (1.022 g, 10.0 mmol) was used as the replacement solvent to redissolve the rotary evaporation residue to obtain the feed liquid D. The feed liquid D and the feed liquid E were mixed by the syringe pump P4 and the syringe pump P5 through the T-type mixer and then pumped into the third microreactor R3. The feed flow rate was 50 μL / min, the microreactor temperature was 20 ° C, and the reaction residence time was about 5 min. After the reaction liquid flowed out of the outlet of the third microreactor R3 and was mixed with purified water (flow rate 100 μL / min) delivered by pump P6 through the T-type mixer, it was quenched and extracted online in the PTFE capillary, and then the water-oil two-phase separation was achieved by the membrane separator. The organic phase was dried with anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the crude trifluorophenylpyrimidine. According to HPLC detection, the conversion rate was 68.12%. The crude product was separated and purified by column chromatography, and the eluent was ethyl acetate→ethyl acetate:methanol=20:1-5:1. After separation and purification, it was vacuum dried for 24 hours and sealed for storage, and the yield was 37%.

[0190] Example 143 (Schiff base reaction-reductive amination reaction-cyclization reaction, reaction step 123)

[0191] The first microreactor R1 is filled with granular Molecular sieve, oscillate multiple times to ensure that there are no obvious gaps. Toluene is used as the weighing solvent, and the volume of the reactor is calculated using the differential weight method. 5wt% Pd(OH)2 / C granular catalyst is filled in the stainless steel reaction column of the second microreactor R2, and oscillates multiple times to ensure that there are no obvious gaps. Toluene is used as the weighing solvent, and the volume of the reactor is calculated using the differential weight method. PTFE capillaries are used as the column tubes of the first micropacked bed reactor R1 and the reaction tubes of the third microreactor R3, and stainless steel capillaries are used as the connecting tubes of the second microreactor R2.

[0192] Add 2-(3-trifluoromethylphenyl)malonic acid (1.380 g, 5.0 mmol), N,N-dimethylformamide (1 drop), and dichloromethane (25.0 mL) into a 100 mL flask and stir for 30 min in an ice-water bath; slowly drop oxalyl chloride (3.175 g, 25.0 mmol) into the reaction flask, continue to stir for 60 min in an ice-water bath, then slowly warm to room temperature and stir for 2 h at room temperature; after the reaction is complete, use a rotary evaporator to remove all solvents and unreacted oxalyl chloride. Place the residue in a 50 mL volumetric flask, dilute to volume with toluene, shake to dissolve, and use as feed liquid E.

[0193] Take 2-aminopyridine (0.475g, 5.0mmol) and place it in a 25mL volumetric flask, use toluene to make up the volume, and use it as feed liquid A. Take pyrimidine-5-carboxaldehyde (0.550g, 5.0mmol) and place it in a 25mL volumetric flask, use toluene to make up the volume, and use it as feed liquid B. Transfer feed liquid B to a glass airtight syringe, cover it with a silica gel heating pad, and keep it warm at 60°C to avoid substrate precipitation until feed liquid B is delivered. Feed liquid A and feed liquid B are mixed by pump P1 and pump P2 respectively through a T-type mixer and enter the first microreactor R1. The flow rate is 12.5μL / min, the residence time is 20min, and the temperature of the microreactor is set to 70°C. Continuous Schiff base reaction is carried out to obtain reaction liquid C.

[0194] 50 mL of toluene solution containing triethylamine (1.022 g, 10.0 mmol) was added to the reaction liquid C to obtain the feed liquid C. The feed liquid C was heated by the high-pressure constant flow pump P3 through the preheating section and pumped into the mixer. High-pressure hydrogen was prepared by a high-pressure hydrogen generator, the pressure reducing valve adjusted the inlet pressure, and the mass flow meter MFC controlled the flow rate and passed into the mixer. After the feed liquid C and hydrogen were mixed in the mixer, they entered the second microreactor R2 for continuous reduction amination reaction. The reaction pressure was controlled by the back pressure valve. After the material was separated by the gas-liquid separator, the reaction liquid D was obtained. The flow rate of the feed liquid C was 0.2 mL / min, the temperature of the preheating section was 70°C, the gas pressure was 3.1 MPa, and the gas flow rate was 10 mL / min. The temperature of the microreactor was 70°C, the pressure of the back pressure valve was 3.0 MPa, and the residence time was about 6.5 min. Dichloromethane was used as a cleaning liquid and injected alternately with the feed liquid C into the second microreactor R2. After most of the dichloromethane was removed online by the post-treatment module T2, triethylamine was added according to the central control results until the equivalent ratio of triethylamine to N-2-pyridine-5-pyrimidinemethylamine was 2:1 to 2.2:1, which was used as the feed liquid D.

[0195] Feed liquid D and feed liquid E are mixed by injection pump P4 and injection pump P5 through T-type mixer and then pumped into the third microreactor R3. The feed flow rate is 50 μL / min, the microreactor temperature is 20°C, and the reaction residence time is 5min. After the reaction liquid flows out of the outlet of the third microreactor R3, it is mixed with purified water (flow rate 100 μL / min) delivered by pump P6 through a T-type mixer and then quenched and extracted online in a PTFE capillary, and then the water-oil two-phase separation is achieved through a membrane separator. The organic phase is dried over anhydrous sodium sulfate, filtered, and the solvent is evaporated under reduced pressure to obtain a crude trifluorophenylpyrimidine. According to HPLC detection, the conversion rate is 58.12%. The crude product is separated and purified by column chromatography, and the eluent is ethyl acetate → ethyl acetate: methanol = 20:1~5:1. After separation and purification, it is vacuum dried for 24 hours and sealed for storage, with a yield of 36%.

[0196] Example 144 (Schiff base reaction-reductive amination reaction-cyclization reaction, reaction step 123)

[0197] The first microreactor R1 is filled with granular Molecular sieve, oscillate multiple times to ensure that there are no obvious gaps. Toluene is used as the weighing solvent, and the volume of the reactor is calculated using the differential weight method. 5wt% Pd(OH)2 / C granular catalyst is filled in the stainless steel reaction column of the second microreactor R2, and oscillates multiple times to ensure that there are no obvious gaps. Toluene is used as the weighing solvent, and the volume of the reactor is calculated using the differential weight method. PTFE capillaries are used as the column tubes of the first micropacked bed reactor R1 and the reaction tubes of the third microreactor R3, and stainless steel capillaries are used as the connecting tubes of the second microreactor R2. Add 2-(3-trifluoromethylphenyl)malonic acid (1.380 g, 5.0 mmol), N,N-dimethylformamide (1 drop), and dichloromethane (25.0 mL) into a 100 mL flask and stir for 30 min in an ice-water bath; slowly drop oxalyl chloride (3.175 g, 25.0 mmol) into the reaction flask, continue to stir for 60 min in an ice-water bath, then slowly warm to room temperature and stir for 2 h at room temperature; after the reaction is complete, use a rotary evaporator to remove all solvents and unreacted oxalyl chloride. Place the residue in a 50 mL volumetric flask, dilute to volume with toluene, shake to dissolve, and use as feed liquid E.

[0198] Take 2-aminopyridine (0.475g, 5.0mmol) and place it in a 25mL volumetric flask, use toluene to make up the volume, and use it as feed liquid A. Take pyrimidine-5-carboxaldehyde (0.550g, 5.0mmol) and place it in a 25mL volumetric flask, use toluene to make up the volume, and use it as feed liquid B. Transfer feed liquid B to a glass airtight syringe, cover it with a silica gel heating pad, and keep it warm at 60°C to avoid substrate precipitation until feed liquid B is delivered. Feed liquid A and feed liquid B are mixed by pump P1 and pump P2 respectively through a T-type mixer and enter the first microreactor R1. The flow rate is 12.5μL / min, the residence time is 20min, and the temperature of the microreactor is set to 70°C. Continuous Schiff base reaction is carried out to obtain reaction liquid C.

[0199] 50 mL of toluene solution containing triethylamine (1.2775 g, 12.5 mmol) was added to the reaction liquid C to obtain the feed liquid C. The container containing the feed liquid C was covered with a silica gel heating pad and kept warm at 60 ° C to avoid the precipitation of the substrate until the feed liquid C was transported. The feed liquid C was heated by the high-pressure constant flow pump P3 through the preheating section and pumped into the mixer. High-pressure hydrogen was prepared by a high-pressure hydrogen generator, the pressure reducing valve adjusted the inlet pressure, and the mass flow meter MFC controlled the flow rate and passed into the mixer. After the feed liquid C and hydrogen were mixed in the mixer, they entered the second microreactor R2 for continuous reduction amination reaction. The reaction pressure was controlled by the back pressure valve. After the material was separated by the gas-liquid separator, the reaction liquid D was obtained. The flow rate of the feed liquid C was 0.2 mL / min, the temperature of the preheating section was 70 ° C, the gas pressure was 3.1 MPa, and the gas flow rate was 10 mL / min. The temperature of the microreactor was 70°C, the back pressure valve pressure was 3.0 MPa, and the residence time was about 6.5 min.

[0200] The obtained feed liquid D is divided into two equal volumes, which are respectively loaded into two syringes and controlled by a dual-channel syringe pump P4. Feed liquid D and feed liquid E are symmetrically mixed in a cross-type mixer by dual-channel syringe pump P4 and syringe pump P5, respectively, and then pumped into the third microreactor R3. The single-stream material flow rate of feed liquid D and feed liquid E is 33.33μL / min, the microreactor temperature is 20°C, and the reaction residence time is 5min. After the reaction liquid flows out of the outlet of the third microreactor R3, it is mixed with purified water (flow rate 100μL / min) delivered by pump P6 through a T-type mixer, and then online quenching and online extraction are carried out in a PTFE capillary, and then water-oil two-phase separation is achieved through a membrane separator. The organic phase is dried by anhydrous sodium sulfate, filtered, and the solvent is evaporated under reduced pressure to obtain a crude trifluorophenylpyrimidine. HPLC detection shows that the conversion rate is 56.35%. The crude product was separated and purified by column chromatography, and the eluent was ethyl acetate→ethyl acetate:methanol=20:1-5:1. After separation and purification, it was vacuum dried for 24 hours and sealed for storage, and the yield was 32%.

[0201] Example 145 (Schiff base reaction-reductive amination reaction-cyclization reaction, reaction step 123)

[0202] The first microreactor R1 is filled with granular Molecular sieve, oscillate multiple times to ensure that there are no obvious gaps. Toluene is used as the weighing solvent, and the volume of the reactor is calculated using the differential weight method. 5wt% Pd(OH)2 / C granular catalyst is filled in the stainless steel reaction column of the second microreactor R2, and oscillates multiple times to ensure that there are no obvious gaps. Toluene is used as the weighing solvent, and the volume of the reactor is calculated using the differential weight method. PTFE capillaries are used as the column tubes of the first micropacked bed reactor R1 and the reaction tubes of the third microreactor R3, and stainless steel capillaries are used as the connecting tubes of the second microreactor R2.

[0203] Add 2-(3-trifluoromethylphenyl)malonic acid (1.380 g, 5.0 mmol), N,N-dimethylformamide (1 drop), and dichloromethane (25.0 mL) into a 100 mL flask and stir for 30 min in an ice-water bath; slowly drop oxalyl chloride (3.175 g, 25.0 mmol) into the reaction flask, continue to stir for 60 min in an ice-water bath, then slowly warm to room temperature and stir for 2 h at room temperature; after the reaction is complete, use a rotary evaporator to remove all solvents and unreacted oxalyl chloride. Place the residue in a 50 mL volumetric flask, dilute to volume with toluene, shake to dissolve, and use as feed liquid E.

[0204] Take 2-aminopyridine (0.475g, 5.0mmol) and place it in a 25mL volumetric flask, use toluene to make up the volume, and use it as feed liquid A. Take pyrimidine-5-carboxaldehyde (0.550g, 5.0mmol) and place it in a 25mL volumetric flask, use toluene to make up the volume, and use it as feed liquid B. Transfer feed liquid B to a glass airtight syringe, cover it with a silica gel heating pad, and keep it warm at 60°C to avoid substrate precipitation until feed liquid B is delivered. Feed liquid A and feed liquid B are mixed by pump P1 and pump P2 respectively through a T-type mixer and enter the first microreactor R1. The flow rate is 12.5μL / min, the residence time is 20min, and the temperature of the microreactor is set to 70°C. Continuous Schiff base reaction is carried out to obtain reaction liquid C.

[0205] After the solvent is removed by online reduced pressure evaporation of the reaction liquid C by the post-treatment module T1, 100 mL of anhydrous tetrahydrofuran is used to redissolve the reaction liquid C'. The reaction liquid C' is heated by the high-pressure constant flow pump P3 through the preheating section and pumped into the mixer. High-pressure hydrogen is prepared by a high-pressure hydrogen generator, the pressure reducing valve adjusts the inlet pressure, and the mass flow meter MFC controls the flow rate and passes into the mixer. After the reaction liquid C' and hydrogen are mixed in the mixer, they enter the second microreactor R2 for continuous reduction amination reaction. The reaction pressure is controlled by the back pressure valve. After the material is separated by the gas-liquid separator, the reaction liquid D is obtained. The flow rate of the reaction liquid C' is 0.2 mL / min, the temperature of the preheating section is 70 ° C, the gas pressure is 3.1 MPa, and the gas flow rate is 10 mL / min. The temperature of the microreactor is 70 ° C, the pressure of the back pressure valve is 3.0 MPa, and the residence time is about 6.5 min.

[0206] The obtained feed liquid D is divided into two equal volumes, which are respectively loaded into two syringes and controlled by a dual-channel syringe pump P4. Feed liquid D and feed liquid E are symmetrically mixed in a cross-type mixer by dual-channel syringe pump P4 and syringe pump P5, respectively, and then pumped into the third microreactor R3. The total flow rate of feed liquid D is 66.67μL / min, the flow rate of feed liquid E is 33.33μL / min, the temperature of the microreactor is 20°C, and the reaction stay time is 5min. After the reaction liquid flows out from the outlet of the third microreactor R3, it is mixed with purified water (flow rate 100μL / min) delivered by pump P6 through a T-type mixer, and then quenched and extracted online in a PTFE capillary, and then water-oil two-phase separation is achieved through a membrane separator. The organic phase is dried over anhydrous sodium sulfate, filtered, and the solvent is evaporated under reduced pressure to obtain a crude trifluorophenylpyrimidine. The crude product was separated and purified by column chromatography, and the eluent was ethyl acetate→ethyl acetate:methanol=20:1-5:1. After separation and purification, it was vacuum dried for 24 hours and sealed for storage, and the yield was 26%.

[0207] Related compound analysis data

[0208]

Claims

1. A continuous synthesis method for preparing trifluorophenylpyrimidine, characterized in that: The method comprises the steps of: (1) dissolving 2-aminopyridine and pyrimidine-5-carboxaldehyde in a first organic solvent to obtain a feed liquid A and a feed liquid B, respectively; mixing the feed liquid A and the feed liquid B in a first micromixer and then continuously pumping the feed liquid A and the feed liquid B into a first microreactor filled with a dehydrating agent to perform a Schiff base reaction to generate N-2-pyridine-5-pyrimidine imine; (2) dissolving N-2-pyridine-5-pyrimidinemethoxyamine and a first base in a second organic solvent to obtain a feed liquid C, mixing the feed liquid C and hydrogen through a second micromixer, and continuously pumping the mixture into a second microreactor filled with a catalyst to carry out a reductive amination reaction to generate N-2-pyridine-5-pyrimidinemethoxyamine; or dissolving N-2-pyridine-5-pyrimidinemethoxyamine in a third organic solvent to obtain a feed liquid C', mixing the feed liquid C' and hydrogen through a second micromixer, and continuously pumping the mixture into a second microreactor filled with a catalyst to carry out a reductive amination reaction to generate N-2-pyridine-5-pyrimidinemethoxyamine; (3) dissolving N-2-pyridine-5-pyrimidinemethylamine and a second base in a fourth organic solvent to obtain a feed liquid D, providing a feed liquid E containing 2-(3-trifluoromethylphenyl)malonyl chloride, mixing the feed liquid D and the feed liquid E in a third micromixer, and then continuously pumping them into a third microreactor for a cyclization reaction to obtain a reaction liquid containing trifluorophenylpyrimidine.

2. The continuous synthesis method according to claim 1, characterized in that Step (1) has one or more of the following characteristics: The first organic solvent is selected from one or more of n-hexane, n-heptane, petroleum ether, cyclohexane, carbon tetrachloride, methyl tert-butyl ether, isopropyl ether, toluene, xylene, dichloromethane, dichloroethane, tetrahydrofuran, ethyl acetate, chloroform, dioxane, ethanol, methanol, isopropanol and acetonitrile, preferably toluene; In the feed liquid A, the concentration of 2-aminopyrimidine is 0.05 to 2.0 mol / L, preferably 0.1 to 0.5 mol / L; In the feed liquid B, the concentration of pyrimidine-5-carboxaldehyde is 0.05 to 2.0 mol / L, preferably 0.1 to 0.5 mol / L; The reaction temperature is 20 to 140°C, preferably 60 to 110°C; The residence time is 1 to 60 minutes, preferably 5 to 30 minutes; The feed rate of the feed liquid A is 10.0-500.0 μL / min; The feed rate of the feed liquid B is 10.0-500.0 μL / min; The dehydrating agent is selected from one or more of molecular sieves, anhydrous sodium sulfate, anhydrous magnesium sulfate and color-changing silica gel, and is preferably a molecular sieve.

3. The continuous synthesis method according to claim 1, characterized in that Step (2) has one or more of the following characteristics: The second organic solvent is selected from one or more of n-hexane, n-heptane, petroleum ether, cyclohexane, carbon tetrachloride, toluene, xylene, dichloromethane and dichloroethane, preferably toluene; The third organic solvent is selected from one or more of tetrahydrofuran, ethanol, methanol, isopropanol and acetonitrile, preferably one or two of tetrahydrofuran and methanol; The first base is selected from one or more of triethylamine, ethylenediamine, pyridine and N,N-diisopropylethylamine, preferably triethylamine; In the feed liquid C, the molar ratio of the first base to N-2-pyridine-5-pyrimidinemethoxyimine is (0.5-3):1, preferably (1-2.5):1; In the feed liquid C or feed liquid C', the concentration of N-2-pyridine-5-pyrimidinemethoxyimine is 0.01 to 1.0 mol / L, preferably 0.05 to 0.20 mol / L; The flow rate of the feed liquid C or feed liquid C' is 0.1-1 mL / min; The flow rate of hydrogen pumped into the second microreactor is 0.2 to 30.0 mL / min, preferably 5.0 to 30.0 mL / min; The back pressure at the outlet of the second microreactor is 1-4 MPa, preferably 1-3 MPa; The reaction temperature is 50 to 140°C, preferably 70 to 100°C; The residence time is 10s to 10min, preferably 5min to 10min; The catalyst is selected from one or more of 5-20wt% Pd(OH)2 / C, 5-20wt% Pd / C, 5wt% Pd / Al2O3 / C, Pd(OCOCH3)2, PdCl2, Ranney Ni, NiCl2, Ni(OH)2, Al-Ni and Ni / Al2O3 / SiO2, preferably 5-20wt% Pd(OH)2 / C.

4. The continuous synthesis method according to claim 1, characterized in that Step (3) has one or more of the following characteristics: The fourth organic solvent is selected from one or more of n-hexane, n-heptane, petroleum ether, cyclohexane, carbon tetrachloride, toluene, xylene, dichloromethane, dichloroethane and tetrahydrofuran, preferably selected from one or more of toluene, dichloromethane and tetrahydrofuran; The second base is selected from one or more of triethylamine, ethylenediamine, pyridine and N,N-diisopropylethylamine, preferably triethylamine; The feed liquid E is 2-(3-trifluoromethylphenyl)malonyl chloride or a mixture of 2-(3-trifluoromethylphenyl)malonyl chloride in a fifth organic solvent; preferably, the fifth organic solvent is selected from one or more of n-hexane, n-heptane, petroleum ether, cyclohexane, carbon tetrachloride, toluene, xylene, dichloromethane, dichloroethane and tetrahydrofuran, preferably selected from one or more of toluene, dichloromethane and tetrahydrofuran; preferably, in the mixture of 2-(3-trifluoromethylphenyl)malonyl chloride in the fifth organic solvent, the concentration of 2-(3-trifluoromethylphenyl)malonyl chloride is 0.01 to 5.0 mol / L, preferably 0.1 to 2.0 mol / L; In the feed liquid D, the concentration of N-2-pyridine-5-pyrimidinemethylamine is 0.01 to 1.0 mol / L, preferably 0.05 to 0.20 mol / L; In the feed liquid D, the molar ratio of the second base to N-2-pyridine-5-pyrimidinemethylamine is (1-4):1, preferably (2-3):1; The reaction temperature is -10 to 50°C, preferably 0 to 30°C; The residence time is 1 to 60 minutes, preferably 5 to 30 minutes; The flow rate of the feed liquid D pumped into the third microreactor is 10.0-500.0 μL / min; The flow rate of the feed liquid E pumped into the third microreactor is 10.0-500.0 μL / min.

5. The continuous synthesis method according to claim 1, characterized in that The method further comprises the steps of: washing impurities in the reaction solution containing trifluorophenylamine with water, separating to obtain an organic phase, and removing the solvent to obtain a crude trifluorophenylamine product.

6. The continuous synthesis method according to claim 1, characterized in that: In the method, any two adjacent steps or all three steps in step (1), step (2) and step (3) are connected in series.

7. The continuous synthesis method according to claim 1, characterized in that: Step (12) is used to replace step (1) and step (2), and step (12) comprises: connecting step (1) and step (2) in series; mixing the feed liquid A and the feed liquid B in the first micromixer and continuously pumping them into the first microreactor for Schiff base reaction to obtain reaction liquid C; optionally performing solvent replacement on the reaction liquid C and adding a first base to obtain feed liquid C; mixing the feed liquid C and hydrogen in a second micromixer and continuously pumping them into the second microreactor for reductive amination reaction to generate N-2-pyridine-5-pyrimidinemethylamine; or Step (12) is used to replace step (1) and step (2), and step (12) comprises: connecting step (1) and step (2) in series; mixing the feed liquid A and the feed liquid B in the first micromixer and continuously pumping them into the first microreactor for Schiff base reaction to obtain reaction liquid C; performing optional solvent replacement on the reaction liquid C to obtain feed liquid C'; mixing the feed liquid C' and hydrogen in a second micromixer and continuously pumping them into the second microreactor for reductive amination reaction to generate N-2-pyridine-5-pyrimidinemethylamine; or Step (23) is used to replace step (2) and step (3), and step (23) comprises: connecting step (2) and step (3) in series; mixing the feed liquid C or feed liquid C' with hydrogen through a second micromixer and continuously pumping the mixture into the second microreactor for reductive amination reaction to obtain a reaction liquid D; optionally performing solvent replacement on the reaction liquid D and adding a second base to obtain feed liquid D; mixing the feed liquid D and feed liquid E through a third micromixer and continuously pumping the mixture into the third microreactor for cyclization reaction to obtain a reaction liquid containing trifluorophenylamine; or Step (123) is used to replace step (1), step (2) and step (3), and step (123) comprises: connecting step (1), step (2) and step (3) in series; mixing the feed liquid A and the feed liquid B through the first micromixer and continuously pumping them into the first microreactor for Schiff base reaction to obtain reaction liquid C; optionally performing solvent replacement on the reaction liquid C and adding a first base to obtain feed liquid C; mixing the feed liquid C and hydrogen through a second micromixer and continuously pumping them into the second microreactor for reductive amination reaction to obtain reaction liquid D; optionally performing solvent replacement on the reaction liquid D and adding a second base to obtain feed liquid D; mixing the feed liquid D and feed liquid E through a third micromixer and continuously pumping them into the third microreactor for cyclization reaction to obtain a reaction liquid containing trifluorophenylpyrimidine; or Step (123) is used to replace step (1), step (2) and step (3), and step (123) comprises: connecting step (1), step (2) and step (3) in series; mixing the feed liquid A and the feed liquid B through the first micromixer and continuously pumping them into the first microreactor for Schiff base reaction to obtain reaction liquid C; performing optional solvent replacement on the reaction liquid C to obtain feed liquid C'; mixing the feed liquid C' and hydrogen through a second micromixer and continuously pumping them into the second microreactor for reductive amination reaction to obtain reaction liquid D; performing optional solvent replacement on the reaction liquid D and adding a second base to obtain feed liquid D; mixing the feed liquid D and feed liquid E through a third micromixer and continuously pumping them into the third microreactor for cyclization reaction to obtain a reaction liquid containing trifluorophenylpyrimidine.

8. A continuous flow synthesis device for implementing the continuous synthesis method according to any one of claims 1 to 7, characterized in that: The continuous flow synthesis device comprises a first micro-mixer, a first micro-reactor, a second micro-mixer, a second micro-reactor, a third micro-mixer and a third micro-reactor which are sequentially connected by a pipeline; The continuous flow synthesis device also includes a first feed pump and a second feed pump for feeding the first microreactor, a third feed pump for feeding the second microreactor, and a fourth feed pump and a fifth feed pump for feeding the third microreactor; The continuous flow synthesis device further comprises a hydrogen generator for continuously introducing hydrogen into the second micro mixer and a gas flow control device arranged on a pipeline connecting the hydrogen generator and the second micro mixer.

9. The continuous flow synthesis device according to claim 8, characterized in that: The continuous flow synthesis device comprises a fourth micromixer connected to the outlet of the third microreactor, a mixing coil connected to the outlet of the fourth micromixer, a first membrane separator connected to the outlet of the mixing coil, and a sixth feed pump for feeding the fourth micromixer; The continuous flow synthesis device may further include a first post-processing module disposed between the outlet of the first microreactor and the third feed pump; The continuous flow synthesis device further optionally includes a second post-processing module disposed between the outlet of the second microreactor and the fourth feed pump; Preferably, the first post-processing module and the second post-processing module include an online extraction separation module and / or an online solvent replacement module.

10. The continuous flow synthesis device according to claim 8, characterized in that: The continuous flow synthesis device has one or more of the following features: The continuous flow synthesis device further comprises a control component for operating the continuous flow synthesis device to implement the continuous synthesis method according to any one of claims 1 to 7; The first feed pump, the second feed pump, the third feed pump, the fourth feed pump, the fifth feed pump, and the sixth feed pump are each independently a syringe pump, a peristaltic pump, or a plunger pump; The first microreactor and the second microreactor are fixed bed microreactors; The third microreactor is a PTFE capillary microreactor; The mixing coil is a PTFE capillary coil; The first micromixer, the second micromixer, the third micromixer and the fourth micromixer are each independently a T-type mixer or a cross-type mixer.

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