Continuous preparation method for dolutegravir

Abstract

The present invention provides a continuous preparation method for dolutegravir, comprising the steps of: pumping a feed liquid A and a feed liquid B into a first microreactor, and carrying out an addition reaction to obtain a first addition product; pumping a feed liquid J and a feed liquid C into a second microreactor, and carrying out a cyclization reaction to obtain a first cyclization product; pumping a feed liquid K and a feed liquid D into a third microreactor, and carrying out an addition reaction to obtain a second addition product; pumping a feed liquid L and a feed liquid E into a fourth microreactor, and carrying out a hydrolysis reaction to obtain a hydrolysate; pumping a feed liquid M and a feed liquid F into a fifth microreactor, and carrying out a cyclization reaction to obtain a second cyclization product; pumping a feed liquid N and a feed liquid G into a sixth microreactor, and carrying out an amide reaction to obtain an amide product; and pumping a feed liquid O and hydrogen into a seventh microreactor, and carrying out a reduction reaction to obtain a dolutegravir crude product.

Description

A continuous preparation method of dolutegravir Technical Field

[0001] The present invention belongs to the field of flow chemistry, and in particular relates to a continuous preparation method of dolutegravir. Background Art

[0002] Dolutegravir is an anti-HIV drug developed by GlaxoSmithKline (GSK) and approved for marketing by the FDA on August 12, 2013. This drug is an integrase inhibitor that effectively inhibits HIV replication. Combining it with other antiretroviral drugs in a "cocktail therapy" can be even more effective in treating HIV infection. It can be used by a wide range of patients, including those undergoing HIV treatment for the first time as well as those who have developed drug resistance after previous treatment. To further reduce medication costs for cancer patients, continuous optimization of the synthesis process for dolutegravir's API and lowering its production costs are crucial.

[0003] The traditional dolutegravir production process faces the following challenges: 1) Due to the long hydrolysis reaction time, the product is prone to hydrolysis side reactions, generating diacid impurities. 2) The cyclization product during the synthesis step is prone to degradation and ring-opening side reactions, generating ring-opening impurities. 3) The dolutegravir production process uses lithium bromide to carry out the methoxylation reaction, which simultaneously produces dolutegravir and the toxic gas methyl bromide. The traditional production process uses batch reactors, which have high safety and security requirements and high risks. The exhaust gas treatment equipment is difficult to meet the rapidly increasing demand for methyl bromide gas absorption.

[0004] The traditional intermittent process mode has difficult-to-overcome defects, such as high safety risks, long reaction time, low yield, poor process repeatability, cumbersome operation, long process flow, complex handling operations, large environmental pollution, high production cost, and low efficiency. Therefore, it is very meaningful to develop a simple, economical and commercially viable continuous flow process for dolutegravir.

[0005] Summary of the Invention

[0006] The object of the present invention is to provide a green, safe and efficient continuous preparation method of dolutegravir. The present invention makes the treatment process continuous, which can save a large amount of organic solvent and labor costs. The microreactor has a large specific surface area and a small liquid holdup, which can greatly improve its mass transfer and heat transfer efficiency, reduce the risk in the production process, and has intrinsic safety characteristics. Secondly, based on the advantages of efficient mixing and precise control of the microreactor, the generation of by-products in the reaction can be effectively reduced, the product quality is improved, and the green, safe and efficient continuous preparation of high-purity dolutegravir is achieved.

[0007] The first aspect of the present invention provides a continuous preparation method of dolutegravir, comprising the steps of:

[0008] S1: Pumping feed liquid A containing methyl 4-benzyloxyacetoacetate and feed liquid B containing N,N-dimethylformamide dimethyl acetal into a first microreactor to carry out an addition reaction to obtain a first addition product;

[0009] S2: dissolving the first addition product and dimethyl oxalate in a second organic solvent to obtain feed solution J and feed solution C, respectively; pumping the feed solution J and feed solution C into a second microreactor to perform a cyclization reaction to obtain a first cyclized product;

[0010] S3: dissolving the first cyclization product and aminoacetaldehyde dimethyl acetal in a third organic solvent to obtain feed liquid K and feed liquid D, respectively, and pumping the feed liquid K and feed liquid D into a third microreactor to perform an addition reaction to obtain a second addition product;

[0011] S4: dissolving the second addition product in a fourth organic solvent to obtain a feed liquid L, and the second acid as a feed liquid E, and pumping the feed liquid L and the feed liquid E into a fourth microreactor to perform a hydrolysis reaction to obtain a hydrolyzed product;

[0012] S5: dissolving the hydrolyzate and (R)-3-aminobutanol in a fifth organic solvent to obtain a feed liquid M and a feed liquid F, respectively; and pumping the feed liquid M and the feed liquid F into a fifth microreactor to perform a cyclization reaction to obtain a second cyclized product;

[0013] S6: dissolving the second cyclized product and 2,4-difluorobenzylamine in a sixth organic solvent to obtain a feed liquid N and a feed liquid G, respectively, and pumping the feed liquid N and the feed liquid G into a sixth microreactor to perform an amide reaction to obtain an amide product;

[0014] S7: dissolving the amide product in a seventh organic solvent to obtain a feed liquid O, pumping the feed liquid O and hydrogen into a seventh microreactor to perform a reduction reaction to obtain a crude dolutegravir product.

[0015] A second aspect of the present invention provides a continuous preparation method of dolutegravir, wherein any two adjacent steps, any three adjacent steps, any four adjacent steps, any five adjacent steps, any six adjacent steps, or all seven steps of steps S1, S2, S3, S4, S5, S6, and S7 are connected in series.

[0016] In a third aspect of the present invention, a continuous synthesis device is provided, which includes a first microreactor, a second microreactor, a third microreactor, a fourth microreactor, a fifth microreactor, a sixth microreactor and a seventh microreactor fluidically connected in sequence, a first injection pump and a second injection pump fluidically connected to the first microreactor, a third injection pump fluidically connected to the second microreactor, a fourth injection pump fluidically connected to the third microreactor, a fifth injection pump fluidically connected to the fourth microreactor, a sixth injection pump fluidically connected to the fifth microreactor, a seventh injection pump fluidically connected to the sixth microreactor, a mass flowmeter fluidically connected to the seventh microreactor, pipelines connecting the reactors and the pumps, and control components for operating the device to implement the method described in the first or second aspect of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0017] Figure 1 is a schematic structural diagram of the continuous synthesis device used in the present invention; wherein A-first injection pump; B-second injection pump; C-third injection pump; D-fourth injection pump; E-fifth injection pump; F-sixth injection pump; G-seventh injection pump; H-mass flowmeter; J-first microreactor; K-second microreactor; L-third microreactor; M-fourth microreactor; N-fifth microreactor; O-sixth microreactor; P-seventh microreactor; I-dolutegravir crude product. DETAILED DESCRIPTION

[0018] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (such as embodiments) can be combined with each other to form a preferred technical solution.

[0019] Continuous preparation method

[0020] The continuous preparation method of dolutegravir of the present invention adopts the following reaction process:

[0021] The above reaction process includes continuous addition (S1), continuous cyclization (S2), continuous addition (S3), continuous hydrolysis (S4), continuous cyclization (S5), continuous amide (S6), and continuous reduction (S7) to the raw material compound 1 to obtain the crude dolutegravir product I.

[0022] The method of the present invention comprises the following steps:

[0023] S1: Pumping feed liquid A containing methyl 4-benzyloxyacetoacetate and feed liquid B containing N,N-dimethylformamide dimethyl acetal into a first microreactor to carry out an addition reaction to obtain a first addition product;

[0024] S2: dissolving the first addition product and dimethyl oxalate in a second organic solvent to obtain feed solution J and feed solution C, respectively; pumping the feed solution J and feed solution C into a second microreactor to perform a cyclization reaction to obtain a first cyclized product;

[0025] S3: dissolving the first cyclization product and aminoacetaldehyde dimethyl acetal in a third organic solvent to obtain feed liquid K and feed liquid D, respectively, and pumping the feed liquid K and feed liquid D into a third microreactor to perform an addition reaction to obtain a second addition product;

[0026] S4: dissolving the second addition product in a fourth organic solvent to obtain a feed liquid L, and the second acid as a feed liquid E, and pumping the feed liquid L and the feed liquid E into a fourth microreactor to perform a hydrolysis reaction to obtain a hydrolyzed product;

[0027] S5: dissolving the hydrolyzate and (R)-3-aminobutanol in a fifth organic solvent to obtain a feed liquid M and a feed liquid F, respectively; and pumping the feed liquid M and the feed liquid F into a fifth microreactor to perform a cyclization reaction to obtain a second cyclized product;

[0028] S6: dissolving the second cyclized product and 2,4-difluorobenzylamine in a sixth organic solvent to obtain a feed liquid N and a feed liquid G, respectively, and pumping the feed liquid N and the feed liquid G into a sixth microreactor to perform an amide reaction to obtain an amide product;

[0029] S7: dissolving the amide product in a seventh organic solvent to obtain a feed liquid O, pumping the feed liquid O and hydrogen into a seventh microreactor to perform a reduction reaction to obtain a crude dolutegravir product.

[0030] In S1, a feed liquid A containing 4-benzyloxy methyl acetoacetate and a feed liquid B containing N,N-dimethylformamide dimethyl acetal undergo an addition reaction in a first microreactor J to obtain a reaction liquid J of a first addition product (compound 2). Feed liquid A can be pure 4-benzyloxy methyl acetoacetate, or it can be a solution of 4-benzyloxy methyl acetoacetate dissolved in a first organic solvent. In some embodiments, feed liquid A is 4-benzyloxy methyl acetoacetate. Feed liquid B can be N,N-dimethylformamide dimethyl acetal, or it can be a solution of N,N-dimethylformamide dimethyl acetal dissolved in a first organic solvent. In some embodiments, feed liquid B is N,N-dimethylformamide dimethyl acetal. The first organic solvent is a commonly used organic solvent, as long as it has no adverse effect on the reaction. Exemplary first organic solvents include, but are not limited to, ethyl acetate, 1,3-dimethyl-2-imidazolidinone, N,N-dimethylformamide, acetonitrile, tetrahydrofuran, toluene, dichloromethane, 1,4-dioxane, or a combination thereof. When feed liquid A is a solution of methyl 4-benzyloxyacetoacetate dissolved in the first organic solvent, the concentration of methyl 4-benzyloxyacetoacetate may be 0.01-1.0 mol / L; preferably, 0.8-1.0 mol / L. When feed liquid B is a solution of N,N-dimethylformamide dimethyl acetal dissolved in the first organic solvent, the concentration of N,N-dimethylformamide dimethyl acetal may be 0.01-1.5 mol / L; preferably, 1.2-1.5 mol / L. The reaction temperature may be 20-100°C; preferably, 25-100°C; in some embodiments, 60-100°C; and in some embodiments, 80-100°C. The residence time may be 1-60 min; preferably, 15-30 min. In some embodiments, the feed liquid A and feed liquid B are pumped into the first microreactor J by a first syringe pump A and a second syringe pump B, respectively. The flow rate of the feed liquid A and feed liquid B pumped into the first microreactor may be 0.03-1 mL / min. The flow rate of the feed liquid A pumped into the first microreactor may be the same as or different from the flow rate of the feed liquid B pumped into the first microreactor.

[0031] In S2, feed liquid J and feed liquid C are pumped into the second microreactor K by the third syringe pump C for a cyclization reaction to obtain a reaction liquid K of the first cyclized product (compound 3). The second organic solvent includes, but is not limited to, methanol, 1,3-dimethyl-2-imidazolidinone, N,N-dimethylformamide, dichloromethane, acetonitrile, tetrahydrofuran, toluene, 1,4-dioxane, or a combination thereof. In a preferred embodiment, the second organic solvent is dichloromethane. In the feed liquid J, the concentration of the first addition product can be 0.1-0.7 mol / L; preferably, 0.4-0.5 mol / L. In the feed liquid C, the concentration of dimethyl oxalate can be 0.15-3.5 mol / L; preferably, 0.6-3.0 mol / L. The feed liquid C also includes a base, which can be one or more of sodium methoxide, potassium methoxide, sodium ethoxide, sodium tert-butoxide, and potassium tert-butoxide. In some embodiments, the base is sodium methoxide. In the feed liquid C, the molar ratio of the first addition product to the base can be 1:0.5-1:3.0; preferably, 1:1.5-1:2.0. The base can be mixed with dimethyl oxalate in the form of a solution, and the concentration of the base in the base solution can be 20-50%, such as 25-35%. The reaction temperature in S2 can be 30-100°C; preferably, 40-80°C; in some embodiments, 60-80°C. The residence time can be 5-60 minutes; preferably, 15-30 minutes. The flow rate of the feed liquid J and the feed liquid C pumped into the second microreactor can be 0.03-0.2 mL / min.

[0032] In S3, the feed liquid K and the feed liquid D are pumped into the third microreactor L by the fourth syringe pump D to undergo an addition reaction to obtain a reaction liquid L of the second addition product (compound 4). The third organic solvent includes but is not limited to: methanol, 1,3-dimethyl-2-imidazolidinone, N,N-dimethylformamide, dichloromethane, acetonitrile, tetrahydrofuran, toluene, 1,4-dioxane, or a combination thereof. In some embodiments, the third organic solvent is N,N-dimethylformamide. In the feed liquid K, the concentration of the first cyclization product can be 0.03-0.20 mol / L; preferably, 0.15-0.20 mol / L. In the feed liquid D, the concentration of aminoacetaldehyde dimethyl acetal can be 0.04-0.24 mol / L; preferably, 0.18-0.24 mol / L. The feed liquid D also includes a first acid, and the type of the first acid can be one or more of formic acid, acetic acid, hydrochloric acid, sulfuric acid and methanesulfonic acid. In some embodiments, the first acid is acetic acid. In the feed liquid D, the molar ratio of the first cyclized product to the first acid is 1:1.0-1:6.0; preferably, 1:3.0-1:4.0. The reaction temperature in S3 can be 80-140°C; preferably, 100-120°C. The residence time can be 5-40 minutes; preferably, 15-30 minutes. The flow rate of feed liquid D and feed liquid K pumped into the third microreactor can be 0.02-0.2 mL / min.

[0033] In S4, feed liquid L and feed liquid E are pumped into the fourth microreactor M by a fifth syringe pump E for a hydrolysis reaction, yielding a reaction liquid M containing the hydrolysis product (Compound 5). The fourth organic solvent includes, but is not limited to, N,N-dimethylformamide, formic acid, dichloromethane, acetonitrile, tetrahydrofuran, toluene, 1,4-dioxane, or a combination thereof. In some embodiments, the fourth organic solvent is formic acid. The concentration of the second addition product in the feed liquid L may be 0.1-0.5 mol / L, preferably 0.2-0.5 mol / L. The second acid may be one or more of formic acid, acetic acid, p-toluenesulfonic acid, sulfuric acid, and methanesulfonic acid. In some embodiments, the second acid is formic acid. The molar amount of the second acid may be at least twice the molar amount of the second addition product. In some embodiments, the molar ratio of the second addition product to the second acid is 1:5-1:30, preferably 1:20-1:30. Excessive amounts of the second acid have no adverse effects on S4. In some embodiments, a highly soluble second acid can be selected as the fourth organic solvent. The reaction temperature in S4 can be 70-130°C, preferably 90-130°C. The residence time can be 5-45 minutes, preferably 5-30 minutes. The flow rate of feed liquid L and feed liquid E pumped into the fourth microreactor can be 0.03-0.4 mL / min.

[0034] In S5, feed liquid M and feed liquid F are pumped into the fifth microreactor N by a sixth syringe pump F for a cyclization reaction, yielding reaction liquid N containing the second cyclized product (Compound 6). The fifth organic solvent includes, but is not limited to, N,N-dimethylformamide, methanol, dichloromethane, acetonitrile, tetrahydrofuran, toluene, 1,4-dioxane, or a combination thereof. In some embodiments, the fifth organic solvent is acetonitrile. The concentration of the hydrolyzed product in the feed liquid M may be 0.1-1.0 mol / L, preferably 0.15-1.0 mol / L. The concentration of (R)-3-aminobutanol in the feed liquid F may be 0.15-1.50 mol / L, preferably 0.25-1.5 mol / L. The reaction temperature in S5 may be 80-140°C, preferably 110-130°C. The residence time may be 10-50 min, preferably 20-40 min. The flow rate of the feed liquid M and the feed liquid F pumped into the fifth microreactor can be 0.02-0.1 mL / min.

[0035] In S6, feed liquid N and feed liquid G are pumped into the sixth microreactor O by the seventh syringe pump G to undergo an amide reaction, thereby obtaining a reaction liquid O containing the amide product (Compound 7). The sixth organic solvent includes, but is not limited to, N,N-dimethylformamide, methanol, dichloromethane, acetonitrile, tetrahydrofuran, toluene, 1,4-dioxane, or a combination thereof. In some embodiments, the sixth organic solvent is toluene. In the feed liquid N, the concentration of the second cyclization product is 0.1-0.8 mol / L; preferably, 0.18-0.80 mol / L. The feed liquid N also includes a third acid, which may be one or more of formic acid, acetic acid, p-toluenesulfonic acid, sulfuric acid, and methanesulfonic acid. In some embodiments, the third acid is acetic acid. In the feed liquid G, the concentration of 2,4-difluorobenzylamine may be 0.1-1.6 mol / L; preferably, 0.36-1.6 mol / L. The molar ratio of the second cyclized product to the third acid can be 0.8:1-1.3:1. The reaction temperature in S6 can be 80-160°C, preferably 100-140°C. The residence time can be 10-120 min, preferably 45-90 min. The flow rate of feed liquid N and feed liquid G pumped into the sixth microreactor can be 0.008-0.1 mL / min, preferably 0.01-0.05 mL / min.

[0036] In S7, the feed liquid O and hydrogen undergo a reduction reaction in the seventh microreactor P to obtain a reaction liquid I of the reduction product (dolutegravir crude product I). The seventh organic solvent includes but is not limited to: N,N-dimethylformamide, methanol, dichloromethane, acetonitrile, tetrahydrofuran, toluene, 1,4-dioxane, or a combination thereof. In some embodiments, it is tetrahydrofuran. In the feed liquid O, the concentration of the amide product can be 0.01-0.05 mol / L; preferably, 0.026-0.050 mol / L. The flow rate at which the feed liquid O is pumped into the seventh microreactor can be 0.02-0.50 mL / min, preferably, 0.03-0.30 mL / min. The flow rate at which hydrogen is pumped into the seventh microreactor can be 0.2-3.0 mL / min; preferably, 0.3-2.5 mL / min. The reaction temperature can be 25-160°C; preferably, 25-140°C. The residence time can be 0.5-10 min, preferably, 0.7-2.0 min. A Pd / C catalyst can also be added to the seventh microreactor P to catalyze the reduction reaction of S7. The palladium content of the Pd / C catalyst can be 5wt%-15wt%; preferably, 8wt%-12wt%. In some embodiments, the palladium content of the Pd / C catalyst is 10wt%. Preferably, the Pd / C catalyst can be first mixed with a filler and then added to the seventh microreactor P. Exemplary fillers include, but are not limited to, silica, alumina, molecular sieves, montmorillonite, zeolite, or a combination thereof.

[0037] In some embodiments, any two, three, four, five, six, or all seven of the seven reaction steps may be connected in series. It should be understood that the term "series" as used herein, in actual reactions, refers to the direct connection of the reaction liquid outlet of the previous reaction with the raw material inlet of the next reaction, and the reaction liquid prepared in the previous step is used directly in the next reaction without purification. It should be understood that when connected in series, the solvents used in each of the steps connected in series are typically the same solvent.

[0038] In some embodiments, S1 and S2 are connected in series, S1, S2, and S3 are connected in series, S4 and S5 are connected in series, S4, S5, and S6 are connected in series, or S4, S5, S6, and S7 are connected in series.

[0039] S1 and S2 are connected in series, that is, the first continuous addition and the first continuous cyclization are connected in series to form S12, which can replace S1 and S2. The first cyclization product obtained from S12 can enter S3 to participate in the reaction.

[0040] S1, S2 and S3 are connected in series, that is, the first continuous addition, the first continuous cyclization and the second continuous addition are connected in series to form S123, which can replace S1, S2 and S3. The second addition product obtained from S123 can enter S4 to participate in the reaction.

[0041] S4 and S5 are connected in series, that is, continuous hydrolysis and the second continuous cyclization are connected in series to form S45, which can replace S4 and S5. The second cyclization product obtained from S45 can enter S6 to participate in the reaction.

[0042] S4, S5 and S6 are connected in series, that is, continuous hydrolysis, second continuous cyclization and continuous amide are connected in series to form S456, which can replace S4, S5 and S6. The amide product obtained from S456 can enter S7 to participate in the reaction.

[0043] S4, S5, S6 and S7 are connected in series, i.e., continuous hydrolysis, second continuous cyclization, continuous amide and continuous reduction are connected in series to form S4567, which can replace S4, S5, S6 and S7 to obtain crude dolutegravir.

[0044] In some embodiments, the continuous preparation method of the present invention includes module 1 and module 2, wherein module 1 includes step S123 and module 2 includes step S4567. Preferably, DMI (1,3-dimethyl-2-imidazolidinone) is used as a solvent in module 1 and acetonitrile is used as a solvent in module 2.

[0045] Continuous synthesis device

[0046] [Corrected 09.08.2024 according to Rule 91] The present invention provides a continuous synthesis apparatus comprising seven syringe pumps, six PTFE capillary microreactors, a fixed-bed microreactor, a mass flowmeter, and various connecting pipelines. The detailed connections are shown in Figure 1. The continuous synthesis apparatus of the present invention comprises, in order of reaction process, a first continuous addition section, a first continuous cyclization section, a second continuous addition section, a continuous hydrolysis section, a second continuous cyclization section, a continuous amide section, and a continuous reduction section. In the first continuous addition section, first syringe pumps A and B are used to deliver feed liquids A and B, respectively, into the first microreactor J. In the first continuous cyclization section, a third syringe pump C is used to deliver a mixture of dimethyl oxalate and feed liquid J into the second microreactor K. In the second continuous addition section, a fourth syringe pump D delivers a mixture of aminoacetaldehyde dimethyl acetal and feed liquid K into the third microreactor L. In the continuous hydrolysis section, a fifth syringe pump E is used to deliver a mixture of formic acid and feed liquid L into the fourth microreactor M. In the second continuous cyclization section, the sixth syringe pump F is used to mix (R)-3-aminobutanol and feed liquid M and deliver them to the fifth microreactor N. In the continuous amide section, the seventh syringe pump G is used to mix 2,4-difluorobenzylamine and feed liquid N and deliver them to the sixth microreactor O. In the continuous reduction section, hydrogen enters the seventh microreactor P via a mass flow meter.

[0047] In the continuous addition, continuous cyclization, continuous hydrolysis, and continuous amide steps, a capillary microreactor is used, which can be made of PTFE. In the continuous reduction step, a fixed bed microreactor is used, which can be made of stainless steel. The seventh microreactor P can be filled with a corresponding catalyst according to the reaction requirements. In some embodiments, in the continuous reduction step of the present invention, the seventh microreactor P is filled with a Pd / C catalyst. The filled catalyst can be first mixed with a filler and then added to the seventh microreactor P.

[0048] Advantages of the present invention include:

[0049] (1) The continuous process realized by using microreactor is simple to operate, has rapid reaction, effectively simplifies the experimental operation process, reduces the generation of three wastes, effectively improves the addition, cyclization, hydrolysis, amide and reduction reactions, and effectively prevents the irritating odor caused by the overflow of acetic acid and solvents, as well as the damage to human body and environment.

[0050] (2) Fixed-bed microreactors are used for continuous hydrogenation reduction reactions. The fixed bed is filled with a Pd / C catalyst. Reactants and gases react as they flow through the fixed bed. High catalyst concentration and large interphase contact area result in a rapid reaction rate, significantly shortening the reaction time. Hydrogen is generated and consumed in situ via a hydrogen generator directly connected to the reaction feed port, avoiding safety concerns associated with hydrogen storage.

[0051] (3) The present invention performs addition, cyclization, hydrolysis, amide and reduction reactions in a continuous manner, strengthens the mixing process, and improves selectivity. The target product, dolutegravir, is obtained with a total yield of more than 34.4% and a total residence time of no more than 1 hour and 46 minutes. Compared with the batch synthesis route, the total yield is 5.6% and the total reaction time is 56 hours, which is significantly improved.

[0052] (4) Based on continuous flow technology, it has high operational safety. The use of a microreactor to prepare dolutegravir simplifies the experimental operation process. The microreactor has efficient heat and mass transfer performance and no amplification effect. It is a green, environmentally friendly, economical and efficient method for producing dolutegravir.

[0053] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present invention only and are not intended to limit the scope of the invention. The experimental methods in the following examples, for which specific conditions are not specified, are generally based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0054] Based on the attempts in this field, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

[0055] The reagents and raw materials used in the present invention are commercially available.

[0056] All reagents used in the experiments were of AR grade.

[0057] Example 1 (first continuous addition reaction)

[0058] In the continuous addition part of the above-mentioned continuous synthesis device, the connecting pipe is a PTFE pipe, and the feed pump is a syringe pump.

[0059] 2.7 g of methyl 4-benzyloxyacetoacetate (Compound 1) was added with dichloromethane and the volume was adjusted to 15 mL, which was used as Feed Liquid A. 2.17 g of N,N-dimethylformamide dimethyl acetal (DMF-DMA) was added with dichloromethane and the volume was adjusted to 15 mL, which was used as Feed Liquid B. Feed Liquids A and B were pumped into the first microreactor J via a first syringe pump A and a second syringe pump B at a flow rate of 0.033 mL / min, a residence time of 30 min, and a microreactor temperature of 25°C for continuous addition reactions to obtain Reaction Liquid J. The yield was 47% as determined by HPLC.

[0060] Example 2 (first continuous addition reaction)

[0061] In the continuous addition part of the above-mentioned continuous synthesis device, the connecting pipe is a PTFE pipe, and the feed pump is a syringe pump.

[0062] 2.7 g of methyl 4-benzyloxyacetoacetate (Compound 1) was added with ethyl acetate and the volume was adjusted to 15 mL, which was used as Feed Liquid A. 2.17 g of N,N-dimethylformamide dimethyl acetal was added with ethyl acetate and the volume was adjusted to 15 mL, which was used as Feed Liquid B. Feed Liquids A and B were pumped into the first microreactor J via a first syringe pump A and a second syringe pump B at a flow rate of 0.033 mL / min, a residence time of 30 min, and a microreactor temperature of 25°C for continuous addition reaction to obtain Reaction Liquid J. HPLC analysis revealed a yield of 30%.

[0063] Example 3 (first continuous addition reaction)

[0064] In the continuous addition part of the above-mentioned continuous synthesis device, the connecting pipe is a PTFE pipe, and the feed pump is a syringe pump.

[0065] Acetonitrile was added to 2.7 g of methyl 4-benzyloxyacetoacetate (Compound 1) to obtain 15 mL of feed solution A. Acetonitrile was added to 2.17 g of N,N-dimethylformamide dimethyl acetal to obtain 15 mL of feed solution B. Feed solutions A and B were pumped into the first microreactor J via a first syringe pump A and a second syringe pump B at a flow rate of 0.033 mL / min, a residence time of 30 min, and a microreactor temperature of 25°C for continuous addition reaction to obtain reaction solution J. HPLC analysis revealed a yield of 33%.

[0066] Example 4 (first continuous addition reaction)

[0067] In the continuous addition part of the above-mentioned continuous synthesis device, the connecting pipe is a PTFE pipe, and the feed pump is a syringe pump.

[0068] 2.7 g of methyl 4-benzyloxyacetoacetate (Compound 1) was added to 1,3-dimethyl-2-imidazolidinone, and the volume was adjusted to 15 mL. This was used as Feed Liquid A. 2.17 g of N,N-dimethylformamide dimethyl acetal was added to 1,3-dimethyl-2-imidazolidinone, and the volume was adjusted to 15 mL. This was used as Feed Liquid B. Feed Liquids A and B were pumped into the first microreactor J via a first syringe pump A and a second syringe pump B at a flow rate of 0.033 mL / min, a residence time of 30 min, and a microreactor temperature of 25°C. A continuous addition reaction was carried out to obtain Reaction Liquid J. The yield was 36% as determined by HPLC.

[0069] Example 5 (first continuous addition reaction)

[0070] In the continuous addition part of the above-mentioned continuous synthesis device, the connecting pipe is a PTFE pipe, and the feed pump is a syringe pump.

[0071] 2.7 g of methyl 4-benzyloxyacetoacetate (Compound 1) was added to N,N-dimethylformamide and the volume was adjusted to 15 mL, which was used as Feed Liquid A. 2.17 g of N,N-dimethylformamide dimethyl acetal was added to N,N-dimethylformamide and the volume was adjusted to 15 mL, which was used as Feed Liquid B. Feed Liquids A and B were pumped into the first microreactor J via a first syringe pump A and a second syringe pump B at a flow rate of 0.033 mL / min, a residence time of 30 min, and a microreactor temperature of 25°C for continuous addition reaction to obtain Reaction Liquid J. The yield was 40% as determined by HPLC.

[0072] Example 6 (first continuous addition reaction)

[0073] In the continuous addition part of the above-mentioned continuous synthesis device, the connecting pipe is a PTFE pipe, and the feed pump is a syringe pump.

[0074] 2.7 g of methyl 4-benzyloxyacetoacetate (Compound 1) was added to tetrahydrofuran, and the volume was adjusted to 15 mL. This was used as Feed Liquid A. 2.17 g of N,N-dimethylformamide dimethyl acetal was added to tetrahydrofuran, and the volume was adjusted to 15 mL. This was used as Feed Liquid B. Feed Liquids A and B were pumped into the first microreactor J via a first syringe pump A and a second syringe pump B at a flow rate of 0.033 mL / min, a residence time of 30 min, and a microreactor temperature of 25°C. A continuous addition reaction was carried out to obtain Reaction Liquid J. The yield was 25% as determined by HPLC.

[0075] Example 7 (first continuous addition reaction)

[0076] In the continuous addition part of the above-mentioned continuous synthesis device, the connecting pipe is a PTFE pipe, and the feed pump is a syringe pump.

[0077] 2.7 g of methyl 4-benzyloxyacetoacetate (Compound 1) was used as feed solution A. 2.17 g of N,N-dimethylformamide dimethyl acetal was used as feed solution B. Feed solutions A and B were pumped into the first microreactor J via a first syringe pump A and a second syringe pump B at a flow rate of 0.033 mL / min, a residence time of 30 min, and a microreactor temperature of 25°C. A continuous addition reaction was carried out to obtain reaction solution J. The yield was 80% as determined by HPLC.

[0078] Example 8 (first continuous addition reaction)

[0079] In the continuous addition part of the above-mentioned continuous synthesis device, the connecting pipe is a PTFE pipe, and the feed pump is a syringe pump.

[0080] 2.7 g of methyl 4-benzyloxyacetoacetate (Compound 1) was added with dichloromethane and the volume was adjusted to 15 mL. This was used as Feed Liquid A. 2.17 g of N,N-dimethylformamide dimethyl acetal was added with dichloromethane and the volume was adjusted to 15 mL. This was used as Feed Liquid B. Feed Liquids A and B were pumped into the first microreactor J via a first syringe pump A and a second syringe pump B at a flow rate of 0.049 mL / min, a residence time of 20 min, and a microreactor temperature of 25°C. A continuous addition reaction was carried out to obtain Reaction Liquid J. The yield was 39% as determined by HPLC.

[0081] Example 9 (first continuous addition reaction)

[0082] In the continuous addition part of the above-mentioned continuous synthesis device, the connecting pipe is a PTFE pipe, and the feed pump is a syringe pump.

[0083] 2.7 g of methyl 4-benzyloxyacetoacetate (Compound 1) was added with dichloromethane and the volume was adjusted to 15 mL, which was used as Feed Liquid A. 2.17 g of N,N-dimethylformamide dimethyl acetal was added with dichloromethane and the volume was adjusted to 15 mL, which was used as Feed Liquid B. Feed Liquids A and B were pumped into the first microreactor J via a first syringe pump A and a second syringe pump B at a flow rate of 0.098 mL / min, a residence time of 10 min, and a microreactor temperature of 25°C for continuous addition reactions to obtain Reaction Liquid J. The yield was 30% as determined by HPLC.

[0084] Example 10 (First Continuous Addition Reaction)

[0085] In the continuous addition part of the above-mentioned continuous synthesis device, the connecting pipe is a PTFE pipe, and the feed pump is a syringe pump.

[0086] 2.7 g of methyl 4-benzyloxyacetoacetate (Compound 1) was added with dichloromethane and the volume was adjusted to 15 mL. This was used as Feed Liquid A. 2.17 g of N,N-dimethylformamide dimethyl acetal was added with dichloromethane and the volume was adjusted to 15 mL. This was used as Feed Liquid B. Feed Liquids A and B were pumped into the first microreactor J via a first syringe pump A and a second syringe pump B at a flow rate of 0.98 mL / min, a residence time of 1 min, and a microreactor temperature of 25°C. A continuous addition reaction was carried out to obtain Reaction Liquid J. The yield was 10% as determined by HPLC.

[0087] Example 11 (First Continuous Addition Reaction)

[0088] In the continuous addition part of the above-mentioned continuous synthesis device, the connecting pipe is a PTFE pipe, and the feed pump is a syringe pump.

[0089] 2.7 g of methyl 4-benzyloxyacetoacetate (Compound 1) was used as feed solution A. 2.17 g of N,N-dimethylformamide dimethyl acetal was used as feed solution B. Feed solutions A and B were pumped into the first microreactor J via a first syringe pump A and a second syringe pump B at a flow rate of 0.098 mL / min, a residence time of 10 min, and a microreactor temperature of 60°C for continuous addition reactions to obtain reaction solution J. HPLC analysis revealed an 89% yield.

[0090] Example 12 (First Continuous Addition Reaction)

[0091] In the continuous addition part of the above-mentioned continuous synthesis device, the connecting pipe is a PTFE pipe, and the feed pump is a syringe pump.

[0092] 2.7 g of methyl 4-benzyloxyacetoacetate (Compound 1) was used as feed solution A. 2.17 g of N,N-dimethylformamide dimethyl acetal was used as feed solution B. Feed solutions A and B were pumped into the first microreactor J via a first syringe pump A and a second syringe pump B at a flow rate of 0.098 mL / min, a residence time of 10 min, and a microreactor temperature of 80°C for continuous addition reactions to obtain reaction solution J. The yield, as determined by HPLC, was 95%.

[0093] Example 13 (First Continuous Addition Reaction)

[0094] In the continuous addition part of the above-mentioned continuous synthesis device, the connecting pipe is a PTFE pipe, and the feed pump is a syringe pump.

[0095] 2.7 g of methyl 4-benzyloxyacetoacetate (Compound 1) was used as feed solution A. 2.17 g of N,N-dimethylformamide dimethyl acetal was used as feed solution B. Feed solutions A and B were pumped into the first microreactor J via a first syringe pump A and a second syringe pump B at a flow rate of 0.098 mL / min, a residence time of 10 min, and a microreactor temperature of 100°C for continuous addition reactions to obtain reaction solution J. HPLC analysis revealed a yield of 92%.

[0096] Example 14 (First Continuous Addition Reaction)

[0097] In the continuous addition part of the above-mentioned continuous synthesis device, the connecting pipe is a PTFE pipe, and the feed pump is a syringe pump.

[0098] 2.7 g of methyl 4-benzyloxyacetoacetate (Compound 1) was used as feed solution A. 2.17 g of N,N-dimethylformamide dimethyl acetal was used as feed solution B. Feed solutions A and B were pumped into the first microreactor J via a first syringe pump A and a second syringe pump B at a flow rate of 0.196 mL / min, a residence time of 5 min, and a microreactor temperature of 100°C for continuous addition reactions to obtain reaction solution J. HPLC analysis revealed a yield of 92%.

[0099] The reaction solution J was purified to obtain the addition product compound 2, whose structure is:

[0100] Example 15 (First Continuous Cyclization Reaction)

[0101] In the continuous cyclization part of the above-mentioned continuous synthesis device, the connecting pipe is a PTFE pipe, and the feed pump is a syringe pump.

[0102] 0.7 g of the addition product from Example 12 was added with dichloromethane, and the volume was adjusted to 25 mL. This was used as feed solution J. 0.88 g of dimethyl oxalate and 1.13 g of 30% sodium methoxide were added with dichloromethane, and the volume was adjusted to 25 mL. This was used as feed solution C. Feed solutions J and C were pumped into the second microreactor K via a third syringe pump C at a flow rate of 0.196 mL / min, a residence time of 5 min, and a microreactor temperature of 40°C. Continuous cyclization reactions were carried out to obtain reaction solution K. The yield was 4% as determined by HPLC.

[0103] Example 16 (First Continuous Cyclization Reaction)

[0104] In the continuous cyclization part of the above-mentioned continuous synthesis device, the connecting pipe is a PTFE pipe, and the feed pump is a syringe pump.

[0105] 0.7 g of the addition product from Example 12 was added with dichloromethane, and the volume was adjusted to 25 mL. This was used as feed solution J. 0.88 g of dimethyl oxalate and 1.13 g of 30% sodium methoxide were added with dichloromethane, and the volume was adjusted to 25 mL. This was used as feed solution C. Feed solutions J and C were pumped into the second microreactor K via a third syringe pump C at a flow rate of 0.098 mL / min, a residence time of 10 min, and a microreactor temperature of 40°C. Continuous cyclization reactions were carried out to obtain reaction solution K. The yield was 10% as determined by HPLC.

[0106] Example 17 (First Continuous Cyclization Reaction)

[0107] In the continuous cyclization part of the above-mentioned continuous synthesis device, the connecting pipe is a PTFE pipe, and the feed pump is a syringe pump.

[0108] 0.7 g of the addition product from Example 12 was added with dichloromethane, and the volume was adjusted to 25 mL. This was used as feed solution J. 0.88 g of dimethyl oxalate and 1.13 g of 30% sodium methoxide were added with dichloromethane, and the volume was adjusted to 25 mL. This was used as feed solution C. Feed solutions J and C were pumped into the second microreactor K via a third syringe pump C at a flow rate of 0.049 mL / min, a residence time of 20 min, and a microreactor temperature of 40°C. Continuous cyclization reactions were carried out to obtain reaction solution K. The yield was 12% as determined by HPLC.

[0109] Example 18 (First Continuous Cyclization Reaction)

[0110] In the continuous cyclization part of the above-mentioned continuous synthesis device, the connecting pipe is a PTFE pipe, and the feed pump is a syringe pump.

[0111] 0.7 g of the addition product from Example 12 was added with dichloromethane and the volume was adjusted to 25 mL. This was used as Feed Liquid J. 0.88 g of dimethyl oxalate and 1.13 g of 30% sodium methoxide were added with dichloromethane and the volume was adjusted to 25 mL. This was used as Feed Liquid C. Feed Liquids J and C were pumped into the second microreactor K using a third syringe pump C at a flow rate of 0.033 mL / min, a residence time of 30 min, and a microreactor temperature of 40°C for continuous cyclization reaction to obtain Reaction Liquid K. The yield was 18% as determined by HPLC.

[0112] Example 19 (First Continuous Cyclization Reaction)

[0113] In the continuous cyclization part of the above-mentioned continuous synthesis device, the connecting pipe is a PTFE pipe, and the feed pump is a syringe pump.

[0114] 0.7 g of the addition product from Example 12 was added with dichloromethane, and the volume was adjusted to 25 mL. This was used as feed solution J. 0.36 g of dimethyl oxalate and 0.91 g of 30% sodium methoxide were added with dichloromethane, and the volume was adjusted to 10 mL. This was used as feed solution C. Feed solutions J and C were pumped into the second microreactor K via a third syringe pump C at a flow rate of 0.196 mL / min, a residence time of 5 min, and a microreactor temperature of 40°C. Continuous cyclization reactions were carried out to obtain reaction solution K. The yield was 20% as determined by HPLC.

[0115] Example 20 (First Continuous Cyclization Reaction)

[0116] In the continuous cyclization part of the above-mentioned continuous synthesis device, the connecting pipe is a PTFE pipe, and the feed pump is a syringe pump.

[0117] 0.7 g of the addition product from Example 12 was added with dichloromethane, and the volume was adjusted to 25 mL. This was used as feed solution J. 0.36 g of dimethyl oxalate and 0.91 g of 30% sodium methoxide were added with dichloromethane, and the volume was adjusted to 10 mL. This was used as feed solution C. Feed solutions J and C were pumped into the second microreactor K via a third syringe pump C at a flow rate of 0.049 mL / min, a residence time of 20 min, and a microreactor temperature of 40°C. Continuous cyclization reactions were carried out to obtain reaction solution K. The yield was 43% as determined by HPLC.

[0118] Example 21 (First Continuous Cyclization Reaction)

[0119] In the continuous cyclization part of the above-mentioned continuous synthesis device, the connecting pipe is a PTFE pipe, and the feed pump is a syringe pump.

[0120] 0.7 g of the addition product from Example 12 was added with dichloromethane, and the volume was adjusted to 25 mL. This was used as feed solution J. 0.71 g of dimethyl oxalate and 0.91 g of 30% sodium methoxide were added with dichloromethane, and the volume was adjusted to 10 mL. This was used as feed solution C. Feed solutions J and C were pumped into the second microreactor K via a third syringe pump C at a flow rate of 0.049 mL / min, a residence time of 20 min, and a microreactor temperature of 40°C. Continuous cyclization reactions were carried out to obtain reaction solution K. The yield was 88% as determined by HPLC.

[0121] Example 22 (First Continuous Cyclization Reaction)

[0122] In the continuous cyclization part of the above-mentioned continuous synthesis device, the connecting pipe is a PTFE pipe, and the feed pump is a syringe pump.

[0123] 0.7 g of the addition product from Example 12 was added with dichloromethane, and the volume was adjusted to 25 mL. This was used as feed solution J. 0.71 g of dimethyl oxalate and 0.91 g of 30% sodium methoxide were added with dichloromethane, and the volume was adjusted to 10 mL. This was used as feed solution C. Feed solutions J and C were pumped into the second microreactor K via a third syringe pump C at a flow rate of 0.049 mL / min, a residence time of 20 min, and a microreactor temperature of 60°C. Continuous cyclization reactions were carried out to obtain reaction solution K. The yield was 90% as determined by HPLC.

[0124] Example 23 (First Continuous Cyclization Reaction)

[0125] In the continuous cyclization part of the above-mentioned continuous synthesis device, the connecting pipe is a PTFE pipe, and the feed pump is a syringe pump.

[0126] 0.7 g of the addition product from Example 12 was added with dichloromethane, and the volume was adjusted to 25 mL. This was used as feed solution J. 0.71 g of dimethyl oxalate and 0.91 g of 30% sodium methoxide were added with dichloromethane, and the volume was adjusted to 10 mL. This was used as feed solution C. Feed solutions J and C were pumped into the second microreactor K via a third syringe pump C at a flow rate of 0.049 mL / min, a residence time of 20 min, and a microreactor temperature of 80°C. Continuous cyclization reactions were carried out to obtain reaction solution K. The yield, as determined by HPLC, was 91%.

[0127] Example 24 (First Continuous Cyclization Reaction)

[0128] In the continuous cyclization part of the above-mentioned continuous synthesis device, the connecting pipe is a PTFE pipe, and the feed pump is a syringe pump.

[0129] 2.8 g of the addition product from Example 12 was added with dichloromethane, and the volume was adjusted to 25 mL. This was used as feed solution J. 2.84 g of dimethyl oxalate and 3.64 g of 30% sodium methoxide were added with dichloromethane, and the volume was adjusted to 10 mL. This was used as feed solution C. Feed solutions J and C were pumped into the second microreactor K via a third syringe pump C at a flow rate of 0.049 mL / min, a residence time of 20 min, and a microreactor temperature of 80°C. Continuous cyclization reactions were carried out to obtain reaction solution K. The yield, as determined by HPLC, was 97%.

[0130] Example 25 (First Continuous Cyclization Reaction)

[0131] In the continuous cyclization part of the above-mentioned continuous synthesis device, the connecting pipe is a PTFE pipe, and the feed pump is a syringe pump.

[0132] 3.5 g of the addition product from Example 12 was added with dichloromethane, and the volume was adjusted to 25 mL. This was used as feed solution J. 3.55 g of dimethyl oxalate and 4.55 g of 30% sodium methoxide were added with dichloromethane, and the volume was adjusted to 10 mL. This was used as feed solution C. Feed solutions J and C were pumped into the second microreactor K via a third syringe pump C at a flow rate of 0.049 mL / min, a residence time of 20 min, and a microreactor temperature of 80°C. Continuous cyclization reactions were carried out to obtain reaction solution K. The yield, as determined by HPLC, was 98%.

[0133] Example 26 (First Continuous Cyclization Reaction)

[0134] In the continuous cyclization part of the above-mentioned continuous synthesis device, the connecting pipe is a PTFE pipe, and the feed pump is a syringe pump.

[0135] 0.7 g of the addition product from Example 12 was added with methanol, and the volume was adjusted to 25 mL. This was used as feed solution J. 0.71 g of dimethyl oxalate and 0.91 g of 30% sodium methoxide were added with methanol, and the volume was adjusted to 10 mL. This was used as feed solution C. Feed solutions J and C were pumped into the second microreactor K via a third syringe pump C at a flow rate of 0.049 mL / min, a residence time of 20 min, and a microreactor temperature of 60°C. Continuous cyclization reactions were carried out to obtain reaction solution K. The yield was 69% as determined by HPLC.

[0136] Example 27 (First Continuous Cyclization Reaction)

[0137] In the continuous cyclization part of the above-mentioned continuous synthesis device, the connecting pipe is a PTFE pipe, and the feed pump is a syringe pump.

[0138] Toluene was added to 0.7 g of the addition product from Example 12, and the volume was adjusted to 25 mL to serve as Feed Solution J. Toluene was added to 0.71 g of dimethyl oxalate and 0.91 g of 30% sodium methoxide, and the volume was adjusted to 10 mL to serve as Feed Solution C. Feed Solution J and Feed Solution C were pumped into the second microreactor K via a third syringe pump C at a flow rate of 0.049 mL / min, a residence time of 20 min, and a microreactor temperature of 60°C for continuous cyclization reaction to obtain Reaction Solution K. The yield was 40% as determined by HPLC.

[0139] Example 28 (First Continuous Cyclization Reaction)

[0140] In the continuous cyclization part of the above-mentioned continuous synthesis device, the connecting pipe is a PTFE pipe, and the feed pump is a syringe pump.

[0141] 0.7 g of the addition product from Example 12 was added with acetonitrile and the volume was adjusted to 25 mL, which was used as feed solution J. 0.71 g of dimethyl oxalate and 0.91 g of 30% sodium methoxide were added with acetonitrile and the volume was adjusted to 10 mL, which was used as feed solution C. Feed solutions J and C were pumped into the second microreactor K via a third syringe pump C at a flow rate of 0.049 mL / min, a residence time of 20 min, and a microreactor temperature of 60°C for continuous cyclization reactions to obtain reaction solution K. The yield was 55% as determined by HPLC.

[0142] Example 29 (First Continuous Cyclization Reaction)

[0143] In the continuous cyclization part of the above-mentioned continuous synthesis device, the connecting pipe is a PTFE pipe, and the feed pump is a syringe pump.

[0144] 0.7 g of the addition product from Example 12 was added to 1,3-dimethyl-2-imidazolidinone, and the volume was adjusted to 25 mL to serve as feed solution J. 0.71 g of dimethyl oxalate and 0.91 g of 30% sodium methoxide were added to 1,3-dimethyl-2-imidazolidinone, and the volume was adjusted to 10 mL to serve as feed solution C. Feed solutions J and C were pumped into the second microreactor K via a third syringe pump C at a flow rate of 0.049 mL / min, a residence time of 20 min, and a microreactor temperature of 60°C for continuous cyclization reactions to obtain reaction solution K. The yield, as determined by HPLC, was 78%.

[0145] The reaction solution K was purified to obtain the cyclized product compound 3, whose structure is:

[0146] Example 30 (Second Continuous Addition Reaction)

[0147] In the continuous addition part of the above-mentioned continuous synthesis device, the connecting pipe is a PTFE pipe, and the feed pump is a syringe pump.

[0148] 0.2 g of the cyclized product from Example 25 was added to 1,3-dimethyl-2-imidazolidinone, and the volume was adjusted to 10 mL. This was used as feed liquid K. 0.08 g of aminoacetaldehyde dimethyl acetal and 0.07 g of acetic acid were added to 1,3-dimethyl-2-imidazolidinone, and the volume was adjusted to 10 mL. This was used as feed liquid D. Feed liquids K and D were pumped into the third microreactor L by a fourth syringe pump D at a flow rate of 0.094 mL / min, a residence time of 5 min, and a microreactor temperature of 100° C. A continuous addition reaction was carried out to obtain reaction liquid L. The yield was 10% as determined by HPLC.

[0149] Example 31 (Second Continuous Addition Reaction)

[0150] In the continuous addition part of the above-mentioned continuous synthesis device, the connecting pipe is a PTFE pipe, and the feed pump is a syringe pump.

[0151] 0.4 g of the cyclized product from Example 25 was added to 1,3-dimethyl-2-imidazolidinone, and the volume was adjusted to 10 mL. This was used as feed liquid K. 0.16 g of aminoacetaldehyde dimethyl acetal and 0.14 g of acetic acid were added to 1,3-dimethyl-2-imidazolidinone, and the volume was adjusted to 10 mL. This was used as feed liquid D. Feed liquids K and D were pumped into the third microreactor L via a fourth syringe pump D at a flow rate of 0.094 mL / min, a residence time of 5 min, and a microreactor temperature of 100°C for continuous addition reaction to obtain reaction liquid L. The yield was 15% as determined by HPLC.

[0152] Example 32 (Second Continuous Addition Reaction)

[0153] In the continuous addition part of the above-mentioned continuous synthesis device, the connecting pipe is a PTFE pipe, and the feed pump is a syringe pump.

[0154] 0.6 g of the cyclized product from Example 25 was added to 1,3-dimethyl-2-imidazolidinone, and the volume was adjusted to 10 mL. This was used as feed liquid K. 0.24 g of aminoacetaldehyde dimethyl acetal and 0.21 g of acetic acid were added to 1,3-dimethyl-2-imidazolidinone, and the volume was adjusted to 10 mL. This was used as feed liquid D. Feed liquids K and D were pumped into the third microreactor L by a fourth syringe pump D at a flow rate of 0.094 mL / min, a residence time of 5 min, and a microreactor temperature of 100°C. A continuous addition reaction was carried out to obtain reaction liquid L. The yield was 18% as determined by HPLC.

[0155] Example 33 (Second Continuous Addition Reaction)

[0156] In the continuous addition part of the above-mentioned continuous synthesis device, the connecting pipe is a PTFE pipe, and the feed pump is a syringe pump.

[0157] 0.6 g of the cyclized product from Example 25 was added with acetonitrile and the volume was adjusted to 10 mL to serve as feed liquid K. 0.24 g of aminoacetaldehyde dimethyl acetal and 0.21 g of acetic acid were added with acetonitrile and the volume was adjusted to 10 mL to serve as feed liquid D. Feed liquids K and D were pumped into the third microreactor L via a fourth syringe pump D at a flow rate of 0.094 mL / min, a residence time of 5 min, and a microreactor temperature of 100°C for continuous addition reaction to obtain reaction liquid L. The yield was 13% as determined by HPLC.

[0158] Example 34 (Second Continuous Addition Reaction)

[0159] In the continuous addition part of the above-mentioned continuous synthesis device, the connecting pipe is a PTFE pipe, and the feed pump is a syringe pump.

[0160] 0.6 g of the cyclized product from Example 25 was added with dichloromethane and the volume was adjusted to 10 mL. This was used as feed liquid K. 0.24 g of aminoacetaldehyde dimethyl acetal and 0.21 g of acetic acid were added with dichloromethane and the volume was adjusted to 10 mL. This was used as feed liquid D. Feed liquids K and D were pumped into the third microreactor L via a fourth syringe pump D at a flow rate of 0.094 mL / min, a residence time of 5 min, and a microreactor temperature of 100°C for continuous addition reaction to obtain reaction liquid L. The yield was 15% as determined by HPLC.

[0161] Example 35 (Second Continuous Addition Reaction)

[0162] In the continuous addition part of the above-mentioned continuous synthesis device, the connecting pipe is a PTFE pipe, and the feed pump is a syringe pump.

[0163] 0.6 g of the cyclized product from Example 25 was added with methanol and the volume was adjusted to 10 mL to serve as feed liquid K. 0.24 g of aminoacetaldehyde dimethyl acetal and 0.21 g of acetic acid were added with methanol and the volume was adjusted to 10 mL to serve as feed liquid D. Feed liquids K and D were pumped into the third microreactor L via a fourth syringe pump D at a flow rate of 0.094 mL / min, a residence time of 5 min, and a microreactor temperature of 100°C for continuous addition reaction to obtain reaction liquid L. The yield was 9% as determined by HPLC.

[0164] Example 36 (Second Continuous Addition Reaction)

[0165] In the continuous addition part of the above-mentioned continuous synthesis device, the connecting pipe is a PTFE pipe, and the feed pump is a syringe pump.

[0166] 0.6 g of the cyclized product from Example 25 was added toluene, and the volume was adjusted to 10 mL. This was used as feed liquid K. 0.24 g of aminoacetaldehyde dimethyl acetal and 0.21 g of acetic acid were added toluene, and the volume was adjusted to 10 mL. This was used as feed liquid D. Feed liquids K and D were pumped into the third microreactor L via a fourth syringe pump D at a flow rate of 0.094 mL / min, a residence time of 5 min, and a microreactor temperature of 100°C for continuous addition reaction to obtain reaction liquid L. The yield was 11% as determined by HPLC.

[0167] Example 37 (Second Continuous Addition Reaction)

[0168] In the continuous addition part of the above-mentioned continuous synthesis device, the connecting pipe is a PTFE pipe, and the feed pump is a syringe pump.

[0169] 0.6 g of the cyclized product from Example 25 was added to N,N-dimethylformamide, and the volume was adjusted to 10 mL. This was used as feed liquid K. 0.24 g of aminoacetaldehyde dimethyl acetal and 0.21 g of acetic acid were added to N,N-dimethylformamide, and the volume was adjusted to 10 mL. This was used as feed liquid D. Feed liquids K and D were pumped into the third microreactor L via a fourth syringe pump D at a flow rate of 0.094 mL / min, a residence time of 5 min, and a microreactor temperature of 100°C for continuous addition reaction to obtain reaction liquid L. The yield was 22% as determined by HPLC.

[0170] Example 38 (Second Continuous Addition Reaction)

[0171] In the continuous addition part of the above-mentioned continuous synthesis device, the connecting pipe is a PTFE pipe, and the feed pump is a syringe pump.

[0172] 0.6 g of the cyclized product from Example 254 was added to N,N-dimethylformamide, and the volume was adjusted to 10 mL. This was used as feed liquid K. 0.24 g of aminoacetaldehyde dimethyl acetal and 0.21 g of acetic acid were added to N,N-dimethylformamide, and the volume was adjusted to 10 mL. This was used as feed liquid D. Feed liquids K and D were pumped into the third microreactor L via a fourth syringe pump D at a flow rate of 0.067 mL / min, a residence time of 7 min, and a microreactor temperature of 100°C for continuous addition reaction to obtain reaction liquid L. The yield was 25% as determined by HPLC.

[0173] Example 39 (Second Continuous Addition Reaction)

[0174] In the continuous addition part of the above-mentioned continuous synthesis device, the connecting pipe is a PTFE pipe, and the feed pump is a syringe pump.

[0175] 0.6 g of the cyclized product from Example 25 was added to N,N-dimethylformamide, and the volume was adjusted to 10 mL. This was used as feed liquid K. 0.24 g of aminoacetaldehyde dimethyl acetal and 0.21 g of acetic acid were added to N,N-dimethylformamide, and the volume was adjusted to 10 mL. This was used as feed liquid D. Feed liquids K and D were pumped into the third microreactor L via a fourth syringe pump D at a flow rate of 0.047 mL / min, a residence time of 10 min, and a microreactor temperature of 100°C for continuous addition reaction to obtain reaction liquid L. The yield was 39% as determined by HPLC.

[0176] Example 40 (Second Continuous Addition Reaction)

[0177] In the continuous addition part of the above-mentioned continuous synthesis device, the connecting pipe is a PTFE pipe, and the feed pump is a syringe pump.

[0178] 0.6 g of the cyclized product from Example 25 was added to N,N-dimethylformamide, and the volume was adjusted to 10 mL. This was used as feed liquid K. 0.24 g of aminoacetaldehyde dimethyl acetal and 0.21 g of acetic acid were added to N,N-dimethylformamide, and the volume was adjusted to 10 mL. This was used as feed liquid D. Feed liquids K and D were pumped into the third microreactor L via a fourth syringe pump D at a flow rate of 0.031 mL / min, a residence time of 15 min, and a microreactor temperature of 100°C for continuous addition reaction to obtain reaction liquid L. The yield was 42% as determined by HPLC.

[0179] Example 41 (Second Continuous Addition Reaction)

[0180] In the continuous addition part of the above-mentioned continuous synthesis device, the connecting pipe is a PTFE pipe, and the feed pump is a syringe pump.

[0181] 0.6 g of the cyclized product from Example 25 was added to N,N-dimethylformamide, and the volume was adjusted to 10 mL. This was used as feed liquid K. 0.24 g of aminoacetaldehyde dimethyl acetal and 0.21 g of acetic acid were added to N,N-dimethylformamide, and the volume was adjusted to 10 mL. This was used as feed liquid D. Feed liquids K and D were pumped into the third microreactor L via a fourth syringe pump D at a flow rate of 0.023 mL / min, a residence time of 20 min, and a microreactor temperature of 100°C for continuous addition reaction to obtain reaction liquid L. The yield was 45% as determined by HPLC.

[0182] Example 42 (Second Continuous Addition Reaction)

[0183] In the continuous addition part of the above-mentioned continuous synthesis device, the connecting pipe is a PTFE pipe, and the feed pump is a syringe pump.

[0184] 0.6 g of the cyclized product from Example 25 was added to N,N-dimethylformamide, and the volume was adjusted to 10 mL. This was used as feed liquid K. 0.24 g of aminoacetaldehyde dimethyl acetal and 0.32 g of acetic acid were added to N,N-dimethylformamide, and the volume was adjusted to 10 mL. This was used as feed liquid D. Feed liquids K and D were pumped into the third microreactor L via a fourth syringe pump D at a flow rate of 0.031 mL / min, a residence time of 15 min, and a microreactor temperature of 100°C for continuous addition reaction to obtain reaction liquid L. The yield was 60% as determined by HPLC.

[0185] Example 43 (Second Continuous Addition Reaction)

[0186] In the continuous addition part of the above-mentioned continuous synthesis device, the connecting pipe is a PTFE pipe, and the feed pump is a syringe pump.

[0187] 0.6 g of the cyclized product from Example 25 was added to N,N-dimethylformamide, and the volume was adjusted to 10 mL. This was used as feed liquid K. 0.24 g of aminoacetaldehyde dimethyl acetal and 0.32 g of acetic acid were added to N,N-dimethylformamide, and the volume was adjusted to 10 mL. This was used as feed liquid D. Feed liquids K and D were pumped into the third microreactor L via a fourth syringe pump D at a flow rate of 0.023 mL / min, a residence time of 20 min, and a microreactor temperature of 100°C for continuous addition reaction to obtain reaction liquid L. The yield was 65% as determined by HPLC.

[0188] Example 44 (Second Continuous Addition Reaction)

[0189] In the continuous addition part of the above-mentioned continuous synthesis device, the connecting pipe is a PTFE pipe, and the feed pump is a syringe pump.

[0190] 0.6 g of the cyclized product from Example 25 was added to N,N-dimethylformamide, and the volume was adjusted to 10 mL. This was used as feed liquid K. 0.24 g of aminoacetaldehyde dimethyl acetal and 0.42 g of acetic acid were added to N,N-dimethylformamide, and the volume was adjusted to 10 mL. This was used as feed liquid D. Feed liquids K and D were pumped into the third microreactor L via a fourth syringe pump D at a flow rate of 0.023 mL / min, a residence time of 20 min, and a microreactor temperature of 100°C for continuous addition reaction to obtain reaction liquid L. The yield was 66% as determined by HPLC.

[0191] Example 45 (Second Continuous Addition Reaction)

[0192] In the continuous addition part of the above-mentioned continuous synthesis device, the connecting pipe is a PTFE pipe, and the feed pump is a syringe pump.

[0193] 0.6 g of the cyclized product from Example 25 was added to N,N-dimethylformamide, and the volume was adjusted to 10 mL. This was used as feed liquid K. 0.24 g of aminoacetaldehyde dimethyl acetal and 0.32 g of acetic acid were added to N,N-dimethylformamide, and the volume was adjusted to 10 mL. This was used as feed liquid D. Feed liquids K and D were pumped into the third microreactor L via a fourth syringe pump D at a flow rate of 0.023 mL / min, a residence time of 20 min, and a microreactor temperature of 120°C for continuous addition reaction to obtain reaction liquid L. The yield was 89% as determined by HPLC.

[0194] The reaction solution L was purified to obtain the addition product compound 4, whose structure is:

[0195] Example 46 (Continuous Hydrolysis Reaction)

[0196] In the continuous hydrolysis part of the above-mentioned continuous synthesis device, the connecting pipe is a PTFE pipe, and the feed pump is a syringe pump.

[0197] 1.0 g of the addition product from Example 45 was taken, and formic acid was added to the mixture, and the volume was adjusted to 10 mL. This was used as feed liquid L. 10 mL of formic acid was taken, and this was used as feed liquid E. Feed liquid L and feed liquid E were pumped into the fourth microreactor M via a fifth syringe pump E at a flow rate of 0.196 mL / min, a residence time of 10 min, and a microreactor temperature of 70°C. Continuous hydrolysis reaction was carried out to obtain reaction liquid M. The yield, as determined by HPLC, was 15%.

[0198] Example 47 (Continuous Hydrolysis Reaction)

[0199] In the continuous hydrolysis part of the above-mentioned continuous synthesis device, the connecting pipe is a PTFE pipe, and the feed pump is a syringe pump.

[0200] 1.0 g of the addition product from Example 45 was taken, and formic acid was added thereto, and the volume was adjusted to 10 mL. This was used as feed liquid L. 10 mL of formic acid was taken and used as feed liquid E. Feed liquid L and feed liquid E were pumped into the fourth microreactor M via a fifth syringe pump E at a flow rate of 0.098 mL / min, a residence time of 20 min, and a microreactor temperature of 70°C. Continuous hydrolysis reaction was carried out to obtain reaction liquid M. The yield, as determined by HPLC, was 16%.

[0201] Example 48 (Continuous Hydrolysis Reaction)

[0202] In the continuous hydrolysis part of the above-mentioned continuous synthesis device, the connecting pipe is a PTFE pipe, and the feed pump is a syringe pump.

[0203] 1.0 g of the addition product from Example 45 was taken, and formic acid was added to the mixture, and the volume was adjusted to 10 mL. This was used as feed liquid L. 10 mL of formic acid was taken, and this was used as feed liquid E. Feed liquid L and feed liquid E were pumped into the fourth microreactor M via a fifth syringe pump E at a flow rate of 0.065 mL / min, a residence time of 30 min, and a microreactor temperature of 70°C. Continuous hydrolysis reactions were carried out to obtain reaction liquid M. The yield, as determined by HPLC, was 22%.

[0204] Example 49 (Continuous Hydrolysis Reaction)

[0205] In the continuous hydrolysis part of the above-mentioned continuous synthesis device, the connecting pipe is a PTFE pipe, and the feed pump is a syringe pump.

[0206] 1.0 g of the addition product from Example 45 was taken, and formic acid was added to the mixture, and the volume was adjusted to 10 mL. This was used as feed liquid L. 10 mL of formic acid was taken, and this was used as feed liquid E. Feed liquid L and feed liquid E were pumped into the fourth microreactor M via a fifth syringe pump E at a flow rate of 0.196 mL / min, a residence time of 10 min, and a microreactor temperature of 90°C. Continuous hydrolysis reactions were carried out to obtain reaction liquid M. The yield, as determined by HPLC, was 63%.

[0207] Example 50 (Continuous Hydrolysis Reaction)

[0208] In the continuous hydrolysis part of the above-mentioned continuous synthesis device, the connecting pipe is a PTFE pipe, and the feed pump is a syringe pump.

[0209] 1.0 g of the addition product from Example 45 was added with formic acid, and the volume was adjusted to 10 mL. This was used as feed liquid L. 10 mL of formic acid was used as feed liquid E. Feed liquids L and E were pumped into the fourth microreactor M via a fifth syringe pump E at a flow rate of 0.065 mL / min, a residence time of 30 min, and a microreactor temperature of 90°C. Continuous hydrolysis reactions were carried out to obtain reaction liquid M. The yield, as determined by HPLC, was 98%.

[0210] Example 51 (Continuous Hydrolysis Reaction)

[0211] In the continuous hydrolysis part of the above-mentioned continuous synthesis device, the connecting pipe is a PTFE pipe, and the feed pump is a syringe pump.

[0212] 1.0 g of the addition product from Example 45 was taken, and formic acid was added to the mixture, and the volume was adjusted to 10 mL. This was used as feed liquid L. 10 mL of formic acid was taken, and this was used as feed liquid E. Feed liquids L and E were pumped into the fourth microreactor M via a fifth syringe pump E at a flow rate of 0.392 mL / min, a residence time of 5 min, and a microreactor temperature of 110°C. Continuous hydrolysis reactions were carried out to obtain reaction liquid M. The yield, as determined by HPLC, was 92%.

[0213] Example 52 (Continuous Hydrolysis Reaction)

[0214] In the continuous hydrolysis part of the above-mentioned continuous synthesis device, the connecting pipe is a PTFE pipe, and the feed pump is a syringe pump.

[0215] 1.0 g of the addition product from Example 45 was taken, and formic acid was added to the mixture, and the volume was adjusted to 10 mL. This was used as feed liquid L. 10 mL of formic acid was taken, and this was used as feed liquid E. Feed liquid L and feed liquid E were pumped into the fourth microreactor M via a fifth syringe pump E at a flow rate of 0.280 mL / min, a residence time of 7 min, and a microreactor temperature of 110°C. Continuous hydrolysis reaction was carried out to obtain reaction liquid M. The yield, as determined by HPLC, was 98%.

[0216] Example 53 (Continuous Hydrolysis Reaction)

[0217] In the continuous hydrolysis part of the above-mentioned continuous synthesis device, the connecting pipe is a PTFE pipe, and the feed pump is a syringe pump.

[0218] 1.0 g of the addition product from Example 45 was taken, and formic acid was added thereto, and the volume was adjusted to 10 mL. This was used as feed liquid L. 10 mL of formic acid was taken and used as feed liquid E. Feed liquid L and feed liquid E were pumped into the fourth microreactor M via a fifth syringe pump E at a flow rate of 0.196 mL / min, a residence time of 10 min, and a microreactor temperature of 110°C. Continuous hydrolysis reaction was carried out to obtain reaction liquid M. The yield, as determined by HPLC, was 98%.

[0219] The reaction solution M was purified to obtain the hydrolyzed product compound 5, whose structure is:

[0220] Example 54 (Second Continuous Cyclization Reaction)

[0221] In the continuous cyclization part of the above-mentioned continuous synthesis device, the connecting pipe is a PTFE pipe, and the feed pump is a syringe pump.

[0222] 3.5 g of the hydrolyzate from Example 53 was added with acetonitrile and the volume was adjusted to 50 mL, which was used as feed liquid M. 1.3 g of (R)-3-aminobutanol was added with acetonitrile and the volume was adjusted to 50 mL, which was used as feed liquid F. Feed liquids M and F were pumped into the fifth microreactor N via the sixth syringe pump F at a flow rate of 0.032 mL / min, a residence time of 30 min, and a microreactor temperature of 90°C for continuous cyclization reaction to obtain reaction liquid N. The yield was 73% as determined by HPLC.

[0223] Example 55 (Second Continuous Cyclization Reaction)

[0224] In the continuous cyclization part of the above-mentioned continuous synthesis device, the connecting pipe is a PTFE pipe, and the feed pump is a syringe pump.

[0225] Acetonitrile was added to 3.5 g of the hydrolyzate from Example 53, and the volume was adjusted to 50 mL to serve as feed liquid M. Acetonitrile was added to 1.3 g of (R)-3-aminobutanol, and the volume was adjusted to 50 mL to serve as feed liquid F. Feed liquids M and F were pumped into the fifth microreactor N via a sixth syringe pump F at a flow rate of 0.032 mL / min, a residence time of 30 min, and a microreactor temperature of 100°C for continuous cyclization reaction to obtain reaction liquid N. HPLC analysis revealed a yield of 78%.

[0226] Example 56 (Second Continuous Cyclization Reaction)

[0227] In the continuous cyclization part of the above-mentioned continuous synthesis device, the connecting pipe is a PTFE pipe, and the feed pump is a syringe pump.

[0228] Acetonitrile was added to 3.5 g of the hydrolyzate from Example 53, and the volume was adjusted to 50 mL to serve as Feed Liquid M. Acetonitrile was added to 1.3 g of (R)-3-aminobutanol, and the volume was adjusted to 50 mL to serve as Feed Liquid F. Feed Liquids M and F were pumped into the fifth microreactor N via a sixth syringe pump F at a flow rate of 0.032 mL / min, a residence time of 30 min, and a microreactor temperature of 110°C for continuous cyclization reaction to obtain Reaction Liquid N. The yield, as determined by HPLC, was 87%.

[0229] Example 57 (Second Continuous Cyclization Reaction)

[0230] In the continuous cyclization part of the above-mentioned continuous synthesis device, the connecting pipe is a PTFE pipe, and the feed pump is a syringe pump.

[0231] Acetonitrile was added to 3.5 g of the hydrolyzate from Example 53, and the volume was adjusted to 50 mL to serve as feed liquid M. Acetonitrile was added to 1.3 g of (R)-3-aminobutanol, and the volume was adjusted to 50 mL to serve as feed liquid F. Feed liquids M and F were pumped into the fifth microreactor N via a sixth syringe pump F at a flow rate of 0.032 mL / min, a residence time of 30 min, and a microreactor temperature of 120°C for continuous cyclization reaction to obtain reaction liquid N. HPLC analysis revealed a yield of 74%.

[0232] Example 58 (Second Continuous Cyclization Reaction)

[0233] In the continuous cyclization part of the above-mentioned continuous synthesis device, the connecting pipe is a PTFE pipe, and the feed pump is a syringe pump.

[0234] Acetonitrile was added to 3.5 g of the hydrolyzate from Example 53, and the volume was adjusted to 50 mL to serve as feed liquid M. Acetonitrile was added to 1.3 g of (R)-3-aminobutanol, and the volume was adjusted to 50 mL to serve as feed liquid F. Feed liquids M and F were pumped into the fifth microreactor N via a sixth syringe pump F at a flow rate of 0.049 mL / min, a residence time of 20 min, and a microreactor temperature of 110°C for continuous cyclization reaction to obtain reaction liquid N. HPLC analysis revealed a yield of 68%.

[0235] Example 59 (Second Continuous Cyclization Reaction)

[0236] In the continuous cyclization part of the above-mentioned continuous synthesis device, the connecting pipe is a PTFE pipe, and the feed pump is a syringe pump.

[0237] Acetonitrile was added to 3.5 g of the hydrolyzate from Example 53, and the volume was adjusted to 50 mL to serve as Feed Liquid M. Acetonitrile was added to 1.3 g of (R)-3-aminobutanol, and the volume was adjusted to 50 mL to serve as Feed Liquid F. Feed Liquids M and F were pumped into the fifth microreactor N via a sixth syringe pump F at a flow rate of 0.098 mL / min, a residence time of 10 min, and a microreactor temperature of 110°C for continuous cyclization reaction to obtain Reaction Liquid N. The yield was 44% as determined by HPLC.

[0238] Example 60 (Second Continuous Cyclization Reaction)

[0239] In the continuous cyclization part of the above-mentioned continuous synthesis device, the connecting pipe is a PTFE pipe, and the feed pump is a syringe pump.

[0240] Acetonitrile was added to 3.5 g of the hydrolyzate from Example 53, and the volume was adjusted to 50 mL to serve as Feed Liquid M. Acetonitrile was added to 1.3 g of (R)-3-aminobutanol, and the volume was adjusted to 50 mL to serve as Feed Liquid F. Feed Liquids M and F were pumped into the fifth microreactor N via a sixth syringe pump F at a flow rate of 0.025 mL / min, a residence time of 40 min, and a microreactor temperature of 110°C for continuous cyclization reaction to obtain Reaction Liquid N. HPLC analysis revealed a yield of 73%.

[0241] The reaction solution N was purified to obtain the cyclized product compound 6, whose structure is:

[0242] Example 61 (Continuous Amide Reaction)

[0243] In the continuous amide part of the above-mentioned continuous synthesis device, the connecting pipe is a PTFE pipe, and the feed pump is a syringe pump.

[0244] Toluene was added to 3.5 g of the cyclized product from Example 56 and 0.49 g of acetic acid, and the volume was adjusted to 15 mL to serve as Feed Liquid N. Toluene was added to 0.79 g of 2,4-difluorobenzylamine, and the volume was adjusted to 15 mL to serve as Feed Liquid G. Feed Liquids N and G were pumped into the sixth microreactor O via the seventh syringe pump G at a flow rate of 0.008 mL / min, a residence time of 60 min, and a microreactor temperature of 100°C for continuous amide reaction to obtain Reaction Liquid O. HPLC analysis revealed an 80% yield.

[0245] Example 62 (Continuous Amide Reaction)

[0246] In the continuous amide part of the above-mentioned continuous synthesis device, the connecting pipe is a PTFE pipe, and the feed pump is a syringe pump.

[0247] Toluene was added to 3.5 g of the cyclized product from Example 56 and 0.49 g of acetic acid, and the volume was adjusted to 15 mL to serve as Feed Liquid N. Toluene was added to 0.79 g of 2,4-difluorobenzylamine, and the volume was adjusted to 15 mL to serve as Feed Liquid G. Feed Liquids N and G were pumped into the sixth microreactor O via the seventh syringe pump G at a flow rate of 0.008 mL / min, a residence time of 60 min, and a microreactor temperature of 120°C for continuous amide reaction to obtain Reaction Liquid O. HPLC analysis revealed an 81% yield.

[0248] Example 63 (Continuous Amide Reaction)

[0249] In the continuous amide part of the above-mentioned continuous synthesis device, the connecting pipe is a PTFE pipe, and the feed pump is a syringe pump.

[0250] Toluene was added to 3.5 g of the cyclized product from Example 56 and 0.49 g of acetic acid, and the volume was adjusted to 15 mL to serve as Feed Liquid N. Toluene was added to 0.79 g of 2,4-difluorobenzylamine, and the volume was adjusted to 15 mL to serve as Feed Liquid G. Feed Liquids N and G were pumped into the sixth microreactor O via the seventh syringe pump G at a flow rate of 0.008 mL / min, a residence time of 60 min, and a microreactor temperature of 130°C for continuous amide reaction to produce Reaction Liquid O. The yield was 80% as determined by HPLC.

[0251] Example 64 (Continuous Amide Reaction)

[0252] In the continuous amide part of the above-mentioned continuous synthesis device, the connecting pipe is a PTFE pipe, and the feed pump is a syringe pump.

[0253] Toluene was added to 3.5 g of the cyclized product from Example 56 and 0.49 g of acetic acid, and the volume was adjusted to 15 mL to serve as Feed Liquid N. Toluene was added to 0.79 g of 2,4-difluorobenzylamine, and the volume was adjusted to 15 mL to serve as Feed Liquid G. Feed Liquids N and G were pumped into the sixth microreactor O via the seventh syringe pump G at a flow rate of 0.008 mL / min, a residence time of 60 min, and a microreactor temperature of 140°C for continuous amide reaction to produce Reaction Liquid O. HPLC analysis revealed a yield of 79%.

[0254] Example 65 (Continuous Amide Reaction)

[0255] In the continuous amide part of the above-mentioned continuous synthesis device, the connecting pipe is a PTFE pipe, and the feed pump is a syringe pump.

[0256] Toluene was added to 3.5 g of the cyclized product from Example 56 and 0.49 g of acetic acid, and the volume was adjusted to 15 mL to serve as Feed Liquid N. Toluene was added to 0.79 g of 2,4-difluorobenzylamine, and the volume was adjusted to 15 mL to serve as Feed Liquid G. Feed Liquids N and G were pumped into the sixth microreactor O via the seventh syringe pump G at a flow rate of 0.016 mL / min, a residence time of 30 min, and a microreactor temperature of 140°C for continuous amide reaction to produce Reaction Liquid O. The yield was 70% as determined by HPLC.

[0257] Example 66 (Continuous Amide Reaction)

[0258] In the continuous amide part of the above-mentioned continuous synthesis device, the connecting pipe is a PTFE pipe, and the feed pump is a syringe pump.

[0259] Toluene was added to 3.5 g of the cyclized product from Example 56 and 0.49 g of acetic acid, and the volume was adjusted to 15 mL to serve as Feed Liquid N. Toluene was added to 0.79 g of 2,4-difluorobenzylamine, and the volume was adjusted to 15 mL to serve as Feed Liquid G. Feed Liquids N and G were pumped into the sixth microreactor O via the seventh syringe pump G at a flow rate of 0.011 mL / min, a residence time of 45 min, and a microreactor temperature of 140°C for continuous amide reaction to produce Reaction Liquid O. The yield, as determined by HPLC, was 84%.

[0260] Example 67 (Continuous Amide Reaction)

[0261] In the continuous amide part of the above-mentioned continuous synthesis device, the connecting pipe is a PTFE pipe, and the feed pump is a syringe pump.

[0262] Toluene was added to 3.5 g of the cyclized product from Example 56 and 0.49 g of acetic acid, and the volume was adjusted to 15 mL to serve as Feed Liquid N. Toluene was added to 0.79 g of 2,4-difluorobenzylamine, and the volume was adjusted to 15 mL to serve as Feed Liquid G. Feed Liquids N and G were pumped into the sixth microreactor O via the seventh syringe pump G at a flow rate of 0.05 mL / min, a residence time of 90 min, and a microreactor temperature of 140°C for continuous amide reaction to produce Reaction Liquid O. The yield was 82% as determined by HPLC.

[0263] Example 68 (Continuous Amide Reaction)

[0264] In the continuous amide part of the above-mentioned continuous synthesis device, the connecting pipe is a PTFE pipe, and the feed pump is a syringe pump.

[0265] 3.5 g of the cyclized product from Example 56 and 0.49 g of acetic acid were added to N,N-dimethylformamide and the volume was adjusted to 15 mL, which was used as feed liquid N. 0.79 g of 2,4-difluorobenzylamine was added to N,N-dimethylformamide and the volume was adjusted to 15 mL, which was used as feed liquid G. Feed liquids N and G were pumped into the sixth microreactor O via the seventh syringe pump G at a flow rate of 0.011 mL / min, a residence time of 45 min, and a microreactor temperature of 140°C for continuous amide reaction to obtain reaction liquid O. The yield was 75% as determined by HPLC.

[0266] The reaction solution O was purified to obtain the amide product compound 7, whose structure is:

[0267] Example 66 (Continuous Reduction Reaction)

[0268] In the continuous reduction part of the above-mentioned continuous synthesis device, the connecting pipe is a PTFE pipe, and the feed pump is a syringe pump.

[0269] 0.2 g of the amide product from Example 63 was added to tetrahydrofuran, and the volume was adjusted to 15 mL. This was used as feed liquid O. Hydrogen was passed through mass flowmeter H and entered the reactor, where it was used as feed H. Feed liquid O and feed H were pumped into the seventh fixed-bed microreactor P at flow rates of 0.032 mL / min and 0.32 mL / min, respectively, with a residence time of 10 min. The microreactor was heated at 25°C for continuous reduction to obtain reaction liquid P. The yield was 96% as determined by HPLC.

[0270] Example 67 (Continuous Reduction Reaction)

[0271] In the continuous reduction part of the above-mentioned continuous synthesis device, the connecting pipe is a PTFE pipe, and the feed pump is a syringe pump.

[0272] 0.2 g of the amide product from Example 63 was added to tetrahydrofuran, and the volume was adjusted to 15 mL. This was used as feed liquid O. Hydrogen was introduced into the reactor through mass flowmeter H and used as feed H. Feed liquid O and feed H were pumped into the seventh fixed-bed microreactor P at flow rates of 0.064 mL / min and 0.64 mL / min, respectively, with a residence time of 5 min. The microreactor was heated at 25°C for continuous reduction to obtain reaction liquid P. The yield was 95% as determined by HPLC.

[0273] Example 68 (Continuous Reduction Reaction)

[0274] In the continuous reduction part of the above-mentioned continuous synthesis device, the connecting pipe is a PTFE pipe, and the feed pump is a syringe pump.

[0275] 0.2 g of the amide product from Example 63 was added to tetrahydrofuran, and the volume was adjusted to 15 mL. This was used as feed liquid O. Hydrogen was passed through mass flowmeter H and entered the reactor, where it was used as feed H. Feed liquid O and feed H were pumped into the seventh fixed-bed microreactor P at flow rates of 0.107 mL / min and 1.07 mL / min, respectively, with a residence time of 2 min. The microreactor was heated at 25°C for continuous reduction to obtain reaction liquid P. The yield was 95% as determined by HPLC.

[0276] Example 69 (Continuous Reduction Reaction)

[0277] In the continuous reduction part of the above-mentioned continuous synthesis device, the connecting pipe is a PTFE pipe, and the feed pump is a syringe pump.

[0278] 0.2 g of the amide product from Example 63 was added to tetrahydrofuran, and the volume was adjusted to 15 mL. This was used as feed liquid O. Hydrogen was passed through mass flowmeter H and entered the reactor, where it was used as feed H. Feed liquid O and feed H were pumped into the seventh fixed-bed microreactor P at flow rates of 0.214 mL / min and 2.14 mL / min, respectively, with a residence time of 1 min. The microreactor was heated at 25°C for continuous reduction to obtain reaction liquid P. The yield was 95% as determined by HPLC.

[0279] Example 70 (Continuous Reduction Reaction)

[0280] In the continuous reduction part of the above-mentioned continuous synthesis device, the connecting pipe is a PTFE pipe, and the feed pump is a syringe pump.

[0281] 0.2 g of the amide product from Example 63 was added to tetrahydrofuran, and the volume was adjusted to 15 mL. This was used as feed liquid O. Hydrogen was introduced into the reactor through mass flowmeter H and used as feed H. Feed liquid O and feed H were pumped into the seventh fixed-bed microreactor P at flow rates of 0.214 mL / min and 1.07 mL / min, respectively, with a residence time of 1 min. The microreactor was heated at 25°C for continuous reduction to obtain reaction liquid P. The yield was 95% as determined by HPLC.

[0282] Example 71 (Continuous Reduction Reaction)

[0283] In the continuous reduction part of the above-mentioned continuous synthesis device, the connecting pipe is a PTFE pipe, and the feed pump is a syringe pump.

[0284] 0.2 g of the amide product from Example 63 was added to tetrahydrofuran, and the volume was adjusted to 15 mL. This was used as feed liquid O. Hydrogen was passed through mass flowmeter H and entered the reactor, where it was used as feed H. Feed liquid O and feed H were pumped into the seventh fixed-bed microreactor P at flow rates of 0.3 mL / min and 1.5 mL / min, respectively, with a residence time of 0.7 min. The microreactor was heated at 25°C for continuous reduction to obtain reaction liquid P. The yield was 95% as determined by HPLC.

[0285] The reaction solution P is purified to obtain the reduction product compound dolutegravir, whose structure is:

[0286] Example 72 (First Continuous Addition Reaction and First Continuous Cyclization Reaction in Series)

[0287] The first continuous addition part of the above-mentioned continuous synthesis device is connected in series with the first continuous cyclization part, the connecting pipe is a PTFE pipe, and the feed pumps are all syringe pumps.

[0288] 0.8 g of methyl 4-benzyloxyacetoacetate (Compound 1) was added to 1,3-dimethyl-2-imidazolidinone, and the volume was adjusted to 10 mL. This was used as Feed Liquid A. 0.47 g of N,N-dimethylformamide dimethyl acetal (DMF-DMA) was added to 1,3-dimethyl-2-imidazolidinone, and the volume was adjusted to 10 mL. This was used as Feed Liquid B. Feed Liquids A and B were pumped into the first microreactor J via a first syringe pump A and a second syringe pump B at a flow rate of 0.094 mL / min, a residence time of 5 min, and a microreactor temperature of 60°C for continuous addition reactions to obtain Reaction Liquid J. 1.275 g of dimethyl oxalate and 1.633 g of 30% sodium methoxide were added to 1,3-dimethyl-2-imidazolidinone, and the volume was adjusted to 10 mL. This was used as Feed Liquid C. The reaction solution J and feed solution C were directly pumped into the second microreactor K at a flow rate of 0.188 mL / min, a residence time of 15 min, and a microreactor temperature of 80° C. for continuous cyclization reaction to obtain reaction solution K. The yield was 85% as determined by HPLC.

[0289] Example 73 (First Continuous Addition Reaction and First Continuous Cyclization Reaction in Series)

[0290] The first continuous addition part of the above-mentioned continuous synthesis device is connected in series with the first continuous cyclization part, the connecting pipe is a PTFE pipe, and the feed pumps are all syringe pumps.

[0291] 0.8 g of methyl 4-benzyloxyacetoacetate (Compound 1) was added to 1,3-dimethyl-2-imidazolidinone, and the volume was adjusted to 10 mL. This was used as Feed Liquid A. 0.47 g of N,N-dimethylformamide dimethyl acetal (DMF-DMA) was added to 1,3-dimethyl-2-imidazolidinone, and the volume was adjusted to 10 mL. This was used as Feed Liquid B. Feed Liquids A and B were pumped into the first microreactor J via a first syringe pump A and a second syringe pump B at a flow rate of 0.067 mL / min, a residence time of 7 min, and a microreactor temperature of 60°C for continuous addition reactions to obtain Reaction Liquid J. 1.275 g of dimethyl oxalate and 1.633 g of 30% sodium methoxide were added to 1,3-dimethyl-2-imidazolidinone, and the volume was adjusted to 10 mL. This was used as Feed Liquid C. The reaction solution J and feed solution C were directly pumped into the second microreactor K at a flow rate of 0.134 mL / min, a residence time of 15 min, and a microreactor temperature of 80°C for continuous cyclization reaction to obtain reaction solution K. The yield was 89% as determined by HPLC.

[0292] Example 74 (First Continuous Addition Reaction and First Continuous Cyclization Reaction in Series)

[0293] The first continuous addition part of the above-mentioned continuous synthesis device is connected in series with the first continuous cyclization part, the connecting pipe is a PTFE pipe, and the feed pumps are all syringe pumps.

[0294] 0.8 g of methyl 4-benzyloxyacetoacetate (Compound 1) was added to 1,3-dimethyl-2-imidazolidinone, and the volume was adjusted to 10 mL. This was used as Feed Liquid A. 0.47 g of N,N-dimethylformamide dimethyl acetal (DMF-DMA) was added to 1,3-dimethyl-2-imidazolidinone, and the volume was adjusted to 10 mL. This was used as Feed Liquid B. Feed Liquids A and B were pumped into the first microreactor J via a first syringe pump A and a second syringe pump B at a flow rate of 0.047 mL / min, a residence time of 10 min, and a microreactor temperature of 60°C for continuous addition reactions to obtain Reaction Liquid J. 1.275 g of dimethyl oxalate and 1.633 g of 30% sodium methoxide were added to 1,3-dimethyl-2-imidazolidinone, and the volume was adjusted to 10 mL. This was used as Feed Liquid C. The reaction solution J and feed solution C were directly pumped into the second microreactor K at a flow rate of 0.094 mL / min, a residence time of 21 min, and a microreactor temperature of 80°C for continuous cyclization reaction to obtain reaction solution K. The yield was 94% as determined by HPLC.

[0295] Example 75 (First Continuous Addition Reaction, First Continuous Cyclization Reaction, and Second Continuous Addition Reaction in Series)

[0296] In the above-mentioned continuous synthesis device, the first continuous addition part is connected in series with the first continuous cyclization part and the second continuous addition reaction part. The connecting pipe is a PTFE pipe, and the feed pumps are all syringe pumps.

[0297] 0.8 g of methyl 4-benzyloxyacetoacetate (Compound 1) was added to 1,3-dimethyl-2-imidazolidinone, and the volume was adjusted to 10 mL. This was used as Feed Liquid A. 0.47 g of N,N-dimethylformamide dimethyl acetal (DMF-DMA) was added to 1,3-dimethyl-2-imidazolidinone, and the volume was adjusted to 10 mL. This was used as Feed Liquid B. Feed Liquids A and B were pumped into the first microreactor J via a first syringe pump A and a second syringe pump B at a flow rate of 0.047 mL / min, a residence time of 10 min, and a microreactor temperature of 60°C for continuous addition reactions to obtain Reaction Liquid J. 1.275 g of dimethyl oxalate and 1.633 g of 30% sodium methoxide were added to 1,3-dimethyl-2-imidazolidinone, and the volume was adjusted to 10 mL. This was used as Feed Liquid C. Reaction solution J and feed solution C were directly pumped into the second microreactor K at a flow rate of 0.094 mL / min, a residence time of 21 min, and a microreactor temperature of 80°C for continuous cyclization reaction to obtain reaction solution K. 1,3-dimethyl-2-imidazolidinone was added to 0.26 g of aminoacetaldehyde dimethyl acetal and 0.675 g of acetic acid, and the volume was adjusted to 25 mL to be used as feed solution D. Reaction solution K and feed solution D were directly pumped into the third microreactor L at a flow rate of 0.188 mL / min, a residence time of 15 min, and a microreactor temperature of 80°C for continuous addition reaction to obtain reaction solution L. The yield was 80% as determined by HPLC.

[0298] Example 76 (Continuous Hydrolysis Reaction and Second Continuous Cyclization Reaction in Series)

[0299] The continuous hydrolysis part of the above-mentioned continuous synthesis device is connected in series with the second continuous cyclization part, the connecting pipe is a PTFE pipe, and the feed pumps are all syringe pumps.

[0300] 0.8 g of the addition product from Example 45, 1.86 g of formic acid, and 0.1 g of methanesulfonic acid were added to acetonitrile and the volume was adjusted to 15 mL to serve as feed liquid E. Feed liquid E was pumped into the fourth microreactor M via a fifth syringe pump E at a flow rate of 0.047 mL / min, a residence time of 20 min, and a microreactor temperature of 120°C for continuous hydrolysis to obtain reaction liquid M. 0.26 g of (R)-3-aminobutanol was added to acetonitrile and the volume was adjusted to 15 mL to serve as feed liquid F. Reaction liquid M and feed liquid F were directly mixed and pumped into the fifth microreactor N at a flow rate of 0.047 mL / min, a residence time of 33 min, and a microreactor temperature of 120°C for continuous cyclization to obtain reaction liquid N. The yield was 71% as determined by HPLC.

[0301] Example 77 (Continuous Hydrolysis Reaction and Second Continuous Cyclization Reaction in Series)

[0302] The continuous hydrolysis part of the above-mentioned continuous synthesis device is connected in series with the second continuous cyclization part, the connecting pipe is a PTFE pipe, and the feed pumps are all syringe pumps.

[0303] 0.8 g of the addition product from Example 45, 1.86 g of formic acid, and 0.1 g of methanesulfonic acid were added to acetonitrile and the volume was adjusted to 15 mL to prepare Feed Liquid E. Feed Liquid E was pumped into the fourth microreactor M via a fifth syringe pump E at a flow rate of 0.038 mL / min, a residence time of 25 min, and a microreactor temperature of 120°C for continuous hydrolysis to obtain Reaction Liquid M. 0.26 g of (R)-3-aminobutanol was added to acetonitrile and the volume was adjusted to 15 mL to prepare Feed Liquid F. Reaction Liquid M and Feed Liquid F were directly mixed and pumped into the fifth microreactor N at a flow rate of 0.038 mL / min, a residence time of 42 min, and a microreactor temperature of 120°C for continuous cyclization to obtain Reaction Liquid N. The yield was 85% as determined by HPLC.

[0304] Example 78 (Continuous Hydrolysis Reaction and Second Continuous Cyclization Reaction in Series)

[0305] The continuous hydrolysis part of the above-mentioned continuous synthesis device is connected in series with the second continuous cyclization part, the connecting pipe is a PTFE pipe, and the feed pumps are all syringe pumps.

[0306] 0.8 g of the addition product from Example 45, 1.86 g of formic acid, and 0.1 g of methanesulfonic acid were added to acetonitrile and the volume was adjusted to 15 mL to be used as feed liquid E. Feed liquid E was pumped into the fourth microreactor M via a fifth syringe pump E at a flow rate of 0.031 mL / min, a residence time of 30 min, and a microreactor temperature of 120°C for continuous hydrolysis reaction to obtain reaction liquid M. 0.26 g of (R)-3-aminobutanol was added to acetonitrile and the volume was adjusted to 15 mL to be used as feed liquid F. Reaction liquid M and feed liquid F were directly mixed and pumped into the fifth microreactor N at a flow rate of 0.031 mL / min, a residence time of 50 min, and a microreactor temperature of 120°C for continuous cyclization reaction to obtain reaction liquid N. The yield was 85% as determined by HPLC.

[0307] Example 79 (Continuous Hydrolysis Reaction, Second Continuous Cyclization Reaction, and Continuous Amide Reaction in Series)

[0308] The continuous hydrolysis part of the above-mentioned continuous synthesis device is connected in series with the second continuous cyclization part and the continuous amide part. The connecting pipe is a PTFE pipe, and the feed pumps are all syringe pumps.

[0309] 0.8 g of the addition product from Example 45, 1.86 g of formic acid, and 0.1 g of methanesulfonic acid were added to acetonitrile and the volume was adjusted to 15 mL to be used as feed liquid E. Feed liquid E was pumped into the fourth microreactor M by the fifth syringe pump E at a flow rate of 0.038 mL / min, a residence time of 25 min, and a microreactor temperature of 120°C for continuous hydrolysis reaction to obtain reaction liquid M. 0.26 g of (R)-3-aminobutanol was added to acetonitrile and the volume was adjusted to 15 mL to be used as feed liquid F. Reaction liquid M and feed liquid F were directly mixed and pumped into the fifth microreactor N at a flow rate of 0.038 mL / min, a residence time of 42 min, and a microreactor temperature of 120°C for continuous cyclization reaction to obtain reaction liquid N. 0.95 g of 2,4-difluorobenzylamine was added to acetonitrile and the volume was adjusted to 50 mL to be used as feed liquid G. The reaction solution N and the feed solution G were pumped into the sixth microreactor O by the seventh syringe pump G at a flow rate of 0.076 mL / min, a residence time of 45 min, and a microreactor temperature of 130° C. for continuous amide reaction to obtain reaction solution O. The yield was 69% as determined by HPLC.

[0310] Example 80 (Continuous hydrolysis reaction, second continuous cyclization reaction, continuous amide reaction and continuous reduction reaction in series)

[0311] The continuous hydrolysis part of the above-mentioned continuous synthesis device is connected in series with the second continuous cyclization part, the continuous amide part and the continuous reduction part. The connecting pipe is a PTFE pipe, and the feed pumps are all syringe pumps.

[0312] 0.8 g of the addition product from Example 45, 1.86 g of formic acid, and 0.1 g of methanesulfonic acid were added to acetonitrile and the volume was adjusted to 15 mL to be used as feed liquid E. Feed liquid E was pumped into the fourth microreactor M by the fifth syringe pump E at a flow rate of 0.038 mL / min, a residence time of 25 min, and a microreactor temperature of 120°C for continuous hydrolysis reaction to obtain reaction liquid M. 0.26 g of (R)-3-aminobutanol was added to acetonitrile and the volume was adjusted to 15 mL to be used as feed liquid F. Reaction liquid M and feed liquid F were directly mixed and pumped into the fifth microreactor N at a flow rate of 0.038 mL / min, a residence time of 42 min, and a microreactor temperature of 120°C for continuous cyclization reaction to obtain reaction liquid N. 0.95 g of 2,4-difluorobenzylamine was added to acetonitrile and the volume was adjusted to 50 mL to be used as feed liquid G. Reaction liquid N and feed liquid G were pumped into the sixth microreactor O via a seventh syringe pump G at a flow rate of 0.076 mL / min, a residence time of 45 minutes, and a microreactor temperature of 130°C for continuous amide reaction to produce reaction liquid O. Hydrogen, whose flow rate was controlled by a mass flowmeter H, was used as feed H. Reaction liquid O and feed H were directly mixed and pumped into the seventh fixed-bed microreactor P at flow rates of 0.152 mL / min and 1.52 mL / min, respectively, with a residence time of 1 minute and a microreactor temperature of 25°C for continuous reduction reaction to produce reaction liquid P. The yield, as determined by HPLC, was 66%.

Claims

1. A continuous preparation method of dolutegravir, characterized in that: The method comprises the steps of: S1: pumping a feed liquid A containing methyl 4-benzyloxyacetoacetate and a feed liquid B containing N,N-dimethylformamide dimethyl acetal into a first microreactor to perform an addition reaction to obtain a first addition product; S2: dissolving the first addition product and dimethyl oxalate in a second organic solvent to obtain a feed liquid J and a feed liquid C, respectively, and pumping the feed liquid J and the feed liquid C into a second microreactor to perform a cyclization reaction to obtain a first cyclization product; S3: dissolving the first cyclization product and aminoacetaldehyde dimethyl acetal in a third organic solvent to obtain a feed liquid K and a feed liquid D, respectively, and pumping the feed liquid K and the feed liquid D into a third microreactor to perform an addition reaction to obtain a second addition product; S4: dissolving the second addition product in a fourth organic solvent to obtain a feed liquid L, and using the second acid as a feed liquid E, and pumping the feed liquid L and the feed liquid E into a fourth microreactor to perform a hydrolysis reaction to obtain a hydrolyzate; S5: dissolving the hydrolyzate and (R)-3-aminobutanol in a fifth organic solvent to obtain a feed liquid M and a feed liquid F, respectively, and pumping the feed liquid M and the feed liquid F into a fifth microreactor to perform a cyclization reaction to obtain a second cyclization product; S6: dissolving the second cyclization product and 2,4-difluorobenzylamine in a sixth organic solvent to obtain a feed liquid N and a feed liquid G, respectively, and pumping the feed liquid N and the feed liquid G into a sixth microreactor to perform an amide reaction to obtain an amide product; S7: dissolving the amide product in a seventh organic solvent to obtain a feed liquid O, pumping the feed liquid O and hydrogen into a seventh microreactor to perform a reduction reaction to obtain a crude dolutegravir product.

2. The continuous preparation method according to claim 1, characterized in that: In S1: The feed liquid A is 4-benzyloxy methyl acetoacetate or a solution of 4-benzyloxy methyl acetoacetate dissolved in a first organic solvent; preferably, the feed liquid A is 4-benzyloxy methyl acetoacetate; And / or, the feed liquid B is N,N-dimethylformamide dimethyl acetal or a solution of N,N-dimethylformamide dimethyl acetal dissolved in a first organic solvent; preferably, the feed liquid B is N,N-dimethylformamide dimethyl acetal; and / or, the first organic solvent is selected from the group consisting of ethyl acetate, 1,3-dimethyl-2-imidazolidinone, N,N-dimethylformamide, acetonitrile, tetrahydrofuran, toluene, dichloromethane, 1,4-dioxane, or a combination thereof; And / or, the feed liquid A is a solution of methyl 4-benzyloxyacetoacetate dissolved in a first organic solvent, and the concentration of methyl 4-benzyloxyacetoacetate is 0.01-1.0 mol / L; preferably, 0.8-1.0 mol / L; And / or, the feed liquid B is a solution of N,N-dimethylformamide dimethyl acetal dissolved in a first organic solvent, and the concentration of N,N-dimethylformamide dimethyl acetal is 0.01-1.5 mol / L; preferably, 1.2-1.5 mol / L; And / or, the reaction temperature is 20-100°C; preferably, 80-100°C; And / or, the residence time is 1-60 min; preferably, 5-30 min; And / or, the feed liquid A and the feed liquid B are pumped into the first microreactor at a flow rate of 0.03-1 mL / min.

3. The continuous preparation method according to claim 1, characterized in that: In S2: The second organic solvent is selected from the group consisting of methanol, 1,3-dimethyl-2-imidazolidinone, N,N-dimethylformamide, dichloromethane, acetonitrile, tetrahydrofuran, toluene, 1,4-dioxane, or a combination thereof; preferably, dichloromethane; And / or, the feed liquid C further comprises a base, and the base is one or more of sodium methoxide, potassium methoxide, sodium ethoxide, sodium tert-butoxide and potassium tert-butoxide; preferably, sodium methoxide; And / or, in the feed solution J, the concentration of the first addition product is 0.1-0.7 mol / L; preferably, 0.4-0.5 mol / L; And / or, in the feed liquid C, the concentration of dimethyl oxalate is 0.15-3.5 mol / L; preferably, 0.6-3.0 mol / L; And / or, in the feed liquid C, the molar ratio of the first addition product to the base is 1:0.5-1:3.0; preferably, 1:1.5-1:2.0; And / or, the reaction temperature is 30-100°C; preferably, 60-80°C; And / or, the residence time is 5-60 min; preferably, 15-30 min; And / or, the feed liquid J and the feed liquid C are pumped into the second microreactor at a flow rate of 0.03-0.2 mL / min.

4. The continuous preparation method according to claim 1, characterized in that: In S3: The third organic solvent is selected from the group consisting of methanol, 1,3-dimethyl-2-imidazolidinone, N,N-dimethylformamide, dichloromethane, acetonitrile, tetrahydrofuran, toluene, 1,4-dioxane, or a combination thereof; preferably, N,N-dimethylformamide; And / or, the feed liquid D further includes a first acid, which is one or more of formic acid, acetic acid, hydrochloric acid, sulfuric acid and methanesulfonic acid; preferably, acetic acid; And / or, in the feed solution K, the concentration of the first cyclization product is 0.03-0.20 mol / L; preferably, 0.15-0.20 mol / L; And / or, in the feed liquid D, the concentration of aminoacetaldehyde dimethyl acetal is 0.04-0.24 mol / L; preferably, 0.18-0.24 mol / L; And / or, in the feed liquid D, the molar ratio of the first cyclization product to the first acid is 1:1.0-1:6.0; preferably, 1:3.0-1:4.0; And / or, the reaction temperature is 80-140°C; preferably, 100-120°C; And / or, the residence time is 5-40 min; preferably, 15-30 min; And / or, the feed liquid D and the feed liquid K are pumped into the third microreactor at a flow rate of 0.02-0.2 mL / min.

5. The continuous preparation method according to claim 1, characterized in that: In S4: The fourth organic solvent is selected from the group consisting of N,N-dimethylformamide, formic acid, dichloromethane, acetonitrile, tetrahydrofuran, toluene, 1,4-dioxane, or a combination thereof; preferably, formic acid; and / or, the second acid is one or more of formic acid, acetic acid, p-toluenesulfonic acid, sulfuric acid and methanesulfonic acid; preferably, formic acid; And / or, in the feed liquid L, the concentration of the second addition product is 0.1-0.5 mol / L; preferably, 0.2-0.5 mol / L; and / or, in the feed liquid E, the molar number of the second acid is more than twice the molar number of the second addition product; preferably, the molar ratio of the second addition product to the second acid is 1:5-1:30, preferably 1:20-1:30; And / or, the reaction temperature is 70-130°C; preferably, 90-130°C; And / or, the residence time is 5-45 min; preferably, 5-30 min; And / or, the feed liquid L and the feed liquid E are pumped into the fourth microreactor at a flow rate of 0.03-0.4 mL / min.

6. The continuous preparation method according to claim 1, characterized in that: In S5: The fifth organic solvent is selected from the group consisting of N,N-dimethylformamide, methanol, dichloromethane, acetonitrile, tetrahydrofuran, toluene, 1,4-dioxane, or a combination thereof; preferably, acetonitrile; And / or, in the feed liquid M, the concentration of the hydrolyzate is 0.1-1.0 mol / L; preferably, 0.15-1.0 mol / L; And / or, in the feed liquid F, the concentration of (R)-3-aminobutanol is 0.15-1.50 mol / L; preferably, 0.25-1.5 mol / L; And / or, the reaction temperature is 80-140°C; preferably, 110-130°C; And / or, the residence time is 10-50 min; preferably, 20-40 min; And / or, the feed liquid M and the feed liquid F are pumped into the fifth microreactor at a flow rate of 0.02-0.1 mL / min.

7. The continuous preparation method according to claim 1, characterized in that: In S6: The sixth organic solvent is selected from the following group: N,N-dimethylformamide, methanol, dichloromethane, acetonitrile, tetrahydrofuran, toluene, 1,4-dioxane, or a combination thereof; preferably, toluene; And / or, the feed liquid N further includes a third acid, which is one or more of formic acid, acetic acid, p-toluenesulfonic acid, sulfuric acid and methanesulfonic acid; preferably, acetic acid; And / or, in the feed liquid N, the concentration of the second cyclization product is 0.1-0.8 mol / L; preferably, 0.18-0.80 mol / L; And / or, in the feed liquid G, the concentration of 2,4-difluorobenzylamine is 0.1-1.6 mol / L; preferably, 0.36-1.6 mol / L; and / or, the molar ratio of the second cyclization product to the third acid is 0.8:1-1.3:1; And / or, the reaction temperature is 80-160°C; preferably, 100-140°C; And / or, the residence time is 10-120 min; preferably, 45-90 min; And / or, the feed liquid N and the feed liquid G are pumped into the sixth microreactor at a flow rate of 0.008-0.1 mL / min.

8. The continuous preparation method according to claim 1, characterized in that: In S7: The seventh organic solvent is selected from the following group: N,N-dimethylformamide, methanol, dichloromethane, acetonitrile, tetrahydrofuran, toluene, 1,4-dioxane, or a combination thereof; preferably, tetrahydrofuran; And / or, in the feed liquid O, the concentration of the amide product is 0.01-0.05 mol / L; preferably, 0.026-0.050 mol / L; And / or, the flow rate of the feed liquid O pumped into the seventh microreactor is 0.02-0.50 mL / min, preferably, 0.03-0.30 mL / min; And / or, the flow rate of hydrogen pumped into the seventh microreactor is 0.2-3.0 mL / min; preferably, 0.3-2.5 mL / min; And / or, the reaction temperature is 25-160°C; preferably, 25-140°C; And / or, the residence time is 0.5-10 min; preferably, 0.7-2.0 min.

9. The continuous preparation method according to claim 1, characterized in that: In S7, a Pd / C catalyst is added to the seventh microreactor, wherein the palladium content of the Pd / C catalyst is 5wt%-15wt%; preferably, 10wt%; Preferably, the Pd / C catalyst is first mixed with a filler and then added to the seventh microreactor; the filler is selected from the group consisting of silicon dioxide, aluminum oxide, molecular sieves, montmorillonite, zeolite, or a combination thereof.

10. The continuous preparation method according to any one of claims 1 to 9, characterized in that: In the method, any two adjacent steps, any three adjacent steps, any four adjacent steps, any five adjacent steps, any six adjacent steps or all seven steps of steps S1, S2, S3, S4, S5, S6 and S7 are connected in series.

11. The continuous preparation method according to claim 10, characterized in that: S12 is used to replace S1 and S2, and S12 comprises: connecting S1 and S2 in series; pumping a feed liquid A containing 4-benzyloxyacetoacetate and a feed liquid B containing N,N-dimethylformamide dimethyl acetal into a first microreactor to perform an addition reaction to obtain a reaction liquid J; pumping a mixed solution of the reaction liquid J and the feed liquid C into a second microreactor to perform a cyclization reaction to obtain a first cyclization product; or S123 is used to replace S1, S2 and S3, and S123 comprises: connecting S1, S2 and S3 in series; pumping a feed liquid A containing 4-benzyloxyacetoacetate and a feed liquid B containing N,N-dimethylformamide dimethyl acetal into a first microreactor for addition reaction to obtain a reaction liquid J; pumping a mixture of the reaction liquid J and the feed liquid C into a second microreactor for cyclization reaction to obtain a reaction liquid K; pumping a mixture of the reaction liquid K and the feed liquid D into a third microreactor for addition reaction to obtain a second addition product; or S45 is used to replace S4 and S5, and S45 comprises: connecting S4 and S5 in series; pumping the feed liquid L and the feed liquid E into a fourth microreactor to perform a hydrolysis reaction to obtain a reaction liquid M; pumping a mixed solution of the reaction liquid M and the feed liquid F into a fifth microreactor to perform a cyclization reaction to obtain a second cyclization product; or S456 is used to replace the S4, S5 and S6, and S456 includes: connecting S4, S5 and S6 in series; pumping the feed liquid L and the feed liquid E into the fourth microreactor to perform a hydrolysis reaction to obtain a reaction liquid M; pumping the mixture of the reaction liquid M and the feed liquid F into the fifth microreactor to perform a cyclization reaction to obtain a reaction liquid N; pumping the mixture of the reaction liquid N and the feed liquid G into the sixth microreactor to perform an amide reaction to obtain an amide product; or S4567 is used to replace the S4, S5, S6 and S7, and S4567 includes: connecting S4, S5, S6 and S7 in series; pumping the feed liquid L and the feed liquid E into the fourth microreactor to perform a hydrolysis reaction to obtain a reaction liquid M; pumping the mixture of the reaction liquid M and the feed liquid F into the fifth microreactor to perform a cyclization reaction to obtain a reaction liquid N; pumping the mixture of the reaction liquid N and the feed liquid G into the sixth microreactor to perform an amide reaction to obtain a reaction liquid O; pumping the reaction liquid O and hydrogen into the sixth microreactor to perform a reduction reaction to obtain a crude dolutegravir product; Preferably, the continuous preparation method includes module one and module two, wherein module one includes S123 and module two includes S4567; preferably, 1,3-dimethyl-2-imidazolidinone is used as a solvent in module one and acetonitrile is used as a solvent in module two.

12. A continuous synthesis device, comprising a first microreactor, a second microreactor, a third microreactor, a fourth microreactor, a fifth microreactor, a sixth microreactor and a seventh microreactor in fluid communication in sequence, a first injection pump and a second injection pump in fluid communication with the first microreactor, a third injection pump in fluid communication with the second microreactor, a fourth injection pump in fluid communication with the third microreactor, a fifth injection pump in fluid communication with the fourth microreactor, a sixth injection pump in fluid communication with the fifth microreactor, a seventh injection pump in fluid communication with the sixth microreactor, a mass flow meter in fluid communication with the seventh microreactor, pipelines connecting the reactors and the pumps, and control components for operating the device to implement the method according to any one of claims 1 to 11; Preferably, the seventh microreactor is a fixed bed microreactor; and the first microreactor, the second microreactor, the third microreactor, the fourth microreactor, the fifth microreactor and the sixth microreactor are PTFE capillary microreactors.

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