Continuous flow synthesis method of zidovudine

Abstract

The invention provides a continuous flow synthesis method of zidovudine, which comprises the following steps: sequentially carrying out continuous hydroxyl protection (S1), continuous acylation (S2), continuous cyclization (S3), continuous azidation (S4) and continuous deprotection (S5) on a raw material compound beta-thymidine to obtain a zidovudine crude product. According to the technical scheme, a more efficient, safer and more flexible production mode and method are provided, hydroxyl protection, acylation, cyclization, azidation and deprotection reactions are continuously operated, the reaction efficiency and selectivity are improved, a large amount of separation and purification operation in the original production process is reduced, and the production cost is reduced. And the production time can be shortened from several weeks to several hours.

Description

Technical Field

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

[0002] Zidovudine (AZT), chemically named 3'-azido-3'-deoxythymidine, is an antiviral drug used to treat AIDS or AIDS-related syndrome and HIV. It was approved by the FDA for marketing in 1987. Zidovudine is the world's first anti-AIDS drug approved by the US FDA. Due to its definite efficacy, it has become the most basic component of the "cocktail" therapy. Zidovudine is highly active against retroviruses including human immunodeficiency virus (HIV) in vitro. Its mechanism of action is that in HIV-infected cells, through the phosphorylation of thymidine kinase and thymidylate kinase, it forms an activated triphosphate body, which can competitively inhibit HIV reverse transcriptase and terminate DNA chain growth, thereby preventing HIV replication. In order to further reduce the cost of medication for cancer patients, it is of great significance to continuously optimize the synthesis method of zidovudine API and reduce its production cost.

[0003]

[0004] The problems faced by the traditional zidovudine production method are: (1) The β-thymidine hydroxyl protection reaction takes several hours and the reaction time is long. (2) A large amount of heat is generated during the acylation reaction. The intermittent method requires strict control of the ice water bath conditions and the dripping rate of methanesulfonyl chloride to prevent the temperature from getting out of control during the reaction process. Low temperature leads to a decrease in reaction rate and production process efficiency. (3) The azide reaction has a high safety risk. The reaction rate is greatly restricted due to safety risk management and control, and the reaction time is as long as 60 hours. (4) There are large differences between different batches due to different mixing and mass transfer capabilities.

[0005] The traditional intermittent method has insurmountable defects, such as high safety risk, long reaction time, low yield, poor method repeatability, cumbersome operation, etc. Therefore, the synthesis of zidovudine requires a more efficient, safe and flexible production mode and method. Summary of the invention

[0006] The purpose of the present invention is to provide an efficient, safe and flexible continuous flow production method for zidovudine. Microreactors are suitable for continuous flow production of zidovudine due to their advantages such as high heat and mass transfer rate, precise controllable reaction parameters and intrinsic safety.

[0007] The first aspect of the present invention provides a continuous flow synthesis method of zidovudine, the method comprising the steps of:

[0008] S1: dissolving β-thymidine and triphenylmethane in a first organic solvent respectively to obtain a feed liquid A and a feed liquid B, mixing the feed liquid A and the feed liquid B in a first micromixer and then continuously pumping them into a first microreactor to perform a hydroxyl protection reaction to obtain a hydroxyl protected intermediate;

[0009] S2: dissolving the hydroxyl protected intermediate and trifluoromethanesulfonyl chloride in a second organic solvent to obtain feed liquid G and feed liquid C respectively, mixing the feed liquid G and feed liquid C in a second micro mixer and then continuously pumping them into a second microreactor to perform an acylation reaction to obtain a mesylate intermediate;

[0010] S3: dissolving the mesylate intermediate and sodium hydroxide in a second organic solvent and a third organic solvent respectively to obtain a feed liquid H and a feed liquid D, mixing the feed liquid H and the feed liquid D in a third micromixer and then continuously pumping them into a third microreactor to perform a cyclization reaction to obtain a cyclized intermediate;

[0011] S4: dissolving the cyclized intermediate and sodium azide in a fourth organic solvent to obtain a feed solution E, and continuously pumping the feed solution E into a fourth microreactor to perform an azidation reaction to obtain an azidation product;

[0012] S5: dissolving the azidation product and p-toluenesulfonic acid in a fifth organic solvent to obtain a feed liquid J and a feed liquid F, respectively; mixing the feed liquid J and the feed liquid F in a fourth micromixer and then continuously pumping them into a fifth microreactor to perform a deprotection reaction to obtain zidovudine;

[0013] Among them, the structural formulas of β-thymidine, hydroxyl protected intermediate, mesylate intermediate, cyclization intermediate, azidation product and zidovudine are:

[0014]

[0015] The second aspect of the present invention provides a continuous flow synthesis device for implementing the continuous flow synthesis method described in the first aspect of the present invention, wherein the continuous flow synthesis device comprises a first micro-mixer, a first micro-reactor, a second micro-mixer, a second micro-reactor, a third micro-mixer, a third micro-reactor, a continuous filtration and dissolution two-in-one device, a fourth micro-reactor, a fourth micro-mixer, and a fifth micro-reactor connected in sequence through a pipeline;

[0016] The continuous flow synthesis device also includes a first feed pump and a second feed pump for feeding the first micromixer, a third feed pump for feeding the second micromixer, a fourth feed pump for feeding the third micromixer, a fifth feed pump for feeding the fourth microreactor, and a sixth feed pump for feeding the fourth micromixer.

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

[0018] 1. The continuous method realized by using microreactor is simple to operate, has rapid reaction, can effectively simplify the experimental operation process, and realizes the full continuity of the production process. The azide reaction with potential explosion risk in the traditional intermittent operation mode is made continuous, which improves the harsh reaction conditions, improves the safety of the reaction, and greatly shortens the reaction time from 60 hours to 10 minutes.

[0019] 2. The method of the present invention protects the hydroxyl group of β-thymidine under continuous flow conditions. The reaction takes several hours in the traditional intermittent operation mode. Under continuous flow conditions, the reaction time is greatly shortened to 30 minutes, thereby improving production efficiency.

[0020] 3. The present invention continuously operates the hydroxyl protection, acylation, cyclization, azidation and deprotection reactions, strengthens the mixing process, improves the reaction efficiency and selectivity, and obtains the target product zidovudine with a total yield of 69.2% and a total residence time of 108 min. The synthesis speed and reaction yield are greatly improved.

[0021] 4. The method of the present invention provides a more efficient, safe and flexible production mode and method. The microreactor has efficient heat and mass transfer performance and no amplification effect, which effectively solves the large differences between different batches caused by different mixing and mass transfer capabilities. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1 It is a schematic diagram of the structure of the continuous synthesis device used in the present invention, wherein: a first injection pump-P1; a second injection pump-P2; a third injection pump-P3; a fourth injection pump-P4; a fifth injection pump-P5; a sixth injection pump-P6; a first microreactor-I; a second microreactor-II; a third microreactor-III; a fourth microreactor-IV; a fifth microreactor-V; a first micromixer-M1, a second micromixer-M2, a third micromixer-M3, and a fourth micromixer-M4; and a continuous filtration and dissolution two-in-one device-Q1. DETAILED DESCRIPTION

[0023] In order to enable those skilled in the art to understand the characteristics and effects of the present invention, the following is a general description and definition of the terms and expressions mentioned in the specification and claims. Unless otherwise specified, all technical and scientific terms used in the text are the common meanings understood by those skilled in the art for the present invention. In the event of a conflict, the definition in this specification shall prevail.

[0024] The theories or mechanisms described and disclosed herein, whether correct or incorrect, should not limit the scope of the present invention in any way, that is, the present invention can be implemented without being limited by any specific theory or mechanism.

[0025] Herein, “comprising”, “including”, “containing” and similar terms encompass the meanings of “consisting essentially of” and “consisting of”. For example, when “A comprises B and C” is disclosed herein, “A consists essentially of B and C” and “A consists of B and C” should be deemed to be disclosed herein.

[0026] In this article, all features such as values, quantities, contents and concentrations defined in the form of numerical ranges or percentage ranges are only for brevity and convenience. Accordingly, the description of numerical ranges or percentage ranges should be considered to have included and specifically disclosed all possible secondary ranges and individual values ​​within the range (including integers and fractions).

[0027] In this document, unless otherwise specified, percentage refers to mass percentage and ratio refers to mass ratio.

[0028] Herein, when describing embodiments or examples, it should be understood that they are not used to limit the present invention to these embodiments or examples. On the contrary, all substitutes, improvements and equivalents of the methods and materials described in the present invention can be included in the scope limited by the claims.

[0029] In this document, in order to make the description concise, not all possible combinations of various technical features in various embodiments or examples are described. Therefore, as long as there is no contradiction in the combination of these technical features, the various technical features in various embodiments or examples can be combined arbitrarily, and all possible combinations should be considered to be within the scope of this specification.

[0030] The present invention provides a continuous flow synthesis method of zidovudine, which comprises sequentially performing hydroxyl protection (S1), acylation (S2), cyclization (S3), azidation (S4) and deprotection (S5) on a raw material compound β-thymidine to obtain a crude zidovudine product. Specifically, the method comprises the steps of:

[0031] S1: dissolving β-thymidine and triphenylmethane in a first organic solvent respectively to obtain a feed liquid A and a feed liquid B, mixing the feed liquid A and the feed liquid B in a first micromixer and then continuously pumping them into a first microreactor to perform a hydroxyl protection reaction to obtain a hydroxyl protected intermediate;

[0032] S2: dissolving the hydroxyl protected intermediate and trifluoromethanesulfonyl chloride in a second organic solvent to obtain feed liquid G and feed liquid C respectively, mixing the feed liquid G and feed liquid C in a second micro mixer and then continuously pumping them into a second microreactor to perform an acylation reaction to obtain a mesylate intermediate;

[0033] S3: dissolving the mesylate intermediate and sodium hydroxide in a second organic solvent and a third organic solvent respectively to obtain a feed liquid H and a feed liquid D, mixing the feed liquid H and the feed liquid D in a third micromixer and then continuously pumping them into a third microreactor to perform a cyclization reaction to obtain a cyclized intermediate;

[0034] S4: dissolving the cyclized intermediate and sodium azide in a fourth organic solvent to obtain a feed solution E, and continuously pumping the feed solution E into a fourth microreactor to perform an azidation reaction to obtain an azidation product;

[0035] S5: dissolving the azidation product and p-toluenesulfonic acid in a fifth organic solvent to obtain a feed liquid J and a feed liquid F, respectively; mixing the feed liquid J and the feed liquid F in a fourth micromixer and then continuously pumping them into a fifth microreactor to perform a deprotection reaction to obtain zidovudine;

[0036] Among them, the structural formulas of β-thymidine, hydroxyl protected intermediate, mesylate intermediate, cyclization intermediate, azidation product and zidovudine are:

[0037]

[0038] In S1, the first organic solvent is selected from one or more of N,N-dimethylformamide, dimethyl sulfoxide and pyridine; preferably, the first organic solvent is pyridine or a mixed solvent of pyridine and N,N-dimethylformamide. The concentration of β-thymidine in the feed liquid A is 0.1-0.75 mol / L, for example, 0.2 mol / L, 0.3 mol / L, 0.4 mol / L, 0.5 mol / L, 0.6 mol / L, 0.7 mol / L; preferably 0.4-0.75 mol / L. The concentration of triphenylmethane in the feed liquid B is 0.15-1.5 mol / L, for example, 0.3 mol / L, 0.5 mol / L, 0.8 mol / L, 1.0 mol / L, 1.3 mol / L, 1.5 mol / L; preferably 0.6-1.5 mol / L. The molar ratio of β-thymidine to triphenylmethane is 1:(1-3), such as 1:1.2, 1:1.5, 1:2, 1:2.5, preferably 1:(1.5-2). The reaction temperature may be 30-120°C, such as 50°C, 80°C, 100°C, 110°C; preferably 100-120°C. The residence time may be 15-120min, such as 20min, 30min, 40min, 50min, 60min, 80min, 100min; preferably 30-60min. The flow rate of the feed liquid A is 0.031-0.247mL / min; preferably 0.062-0.123mL / min. The flow rate of the feed liquid B is 0.031-0.247mL / min; preferably 0.062-0.123mL / min.

[0039] In S2, the second organic solvent is selected from one or more of N,N-dimethylformamide, dimethyl sulfoxide and pyridine; preferably N,N-dimethylformamide. In the feed liquid G, the concentration of the hydroxyl protected intermediate is 0.01-0.45 mol / L, such as 0.05 mol / L, 0.1 mol / L, 0.2 mol / L, 0.3 mol / L, 0.35 mol / L, 0.4 mol / L; preferably 0.3-0.45 mol / L. In the feed liquid C, the concentration of trifluoromethanesulfonyl chloride is 0.12-5.4 mol / L, such as 0.2 mol / L, 0.5 mol / L, 1 mol / L, 1.5 mol / L, 2.5 mol / L, 3.5 mol / L, 4.5 mol / L, 5 mol / L, preferably 3.6-5.4 mol / L. The molar ratio of the hydroxyl protected intermediate to trifluoromethanesulfonyl chloride is 1:(1-5), such as 1:1.2, 1:1.8, 1:2, 1:2.5, 1:3.5, preferably 1:(2-3). A base is also added to the feed liquid G and / or the feed liquid C, and the base is selected from one or more of triethylamine, pyridine, N,N-diisopropylethylamine, 4-dimethylaminopyridine, triethanolamine, tetrabutylammonium bromide, potassium carbonate, ammonium carbonate and sodium carbonate. Preferably, the molar ratio of the hydroxyl protected intermediate to the base is 1:(1-5), such as 1:1.2, 1:1.8, 1:2, 1:2.5, 1:3.5, preferably 1:(2-3). The reaction temperature can be 20-130°C, such as 30°C, 50°C, 80°C, 100°C, 120°C, 130°C; preferably 27-130°C. The residence time can be 1-60 min, such as 5 min, 10 min, 15 min, 20 min, 30 min; preferably 5-30 min. The flow rate of the feed liquid G is 0.029-1.76 mL / min; preferably 0.059-0.352 mL / min. The flow rate of the feed liquid C is 0.007-0.44 mL / min; preferably 0.015-0.088 mL / min.

[0040] In S3, the third organic solvent is selected from one or more of water, methanol, N,N-dimethylformamide, dimethyl sulfoxide and pyridine; preferably water. In the feed liquid H, the concentration of the mesylate intermediate is 0.01-0.45 mol / L, such as 0.05 mol / L, 0.1 mol / L, 0.2 mol / L, 0.3 mol / L, 0.4 mol / L, preferably 0.3-0.45 mol / L. The concentration of sodium hydroxide in the feed liquid D is 1-20 mol / L, such as 3 mol / L, 5 mol / L, 10 mol / L, 13 mol / L, 15 mol / L, 18 mol / L; preferably 10-15 mol / L. The molar ratio of sodium hydroxide to the mesylate intermediate can be 1:(1-5), such as 1:1.2, 1:1.8, 1:2, 1:2.5, 1:3.5, 1:4.5; preferably 1:(1-3). The reaction temperature may be 30-100°C, for example, 40°C, 50°C, 60°C, 70°C, 80°C; preferably 50-65°C. The residence time may be 1-30min, for example, 5min, 10min, 15min, 20min, 30min; preferably 15-30min. In some embodiments, the cyclization reaction liquid obtained after the reaction of step S3 is passed into water, and the cyclization intermediate is obtained by filtration. Herein, the cyclization reaction liquid is passed into a continuous filtration and dissolution two-in-one device. The continuous filtration and dissolution two-in-one device is used to separate the cyclization intermediate. In the present invention, the cyclization intermediate needs to be separated from the cyclization reaction liquid to remove the alkali (sodium hydroxide) in the system. The flow rate of the feed liquid H is 0.169-5.063mL / min; preferably 0.169-0.338mL / min. The flow rate of the feed liquid D is 0.011-0.338 mL / min; preferably 0.011-0.022 mL / min.

[0041] In S4, the fourth organic solvent is selected from one or more of N,N-dimethylformamide, dimethyl sulfoxide, water, methanol, acetonitrile, tetrahydrofuran, toluene and 1,4-dioxane; preferably dimethyl sulfoxide. In the feed liquid E, the concentration of the cyclized intermediate may be 0.1-0.5 mol / L, such as 0.1 mol / L, 0.2 mol / L, 0.3 mol / L, 0.4 mol / L, 0.5 mol / L; preferably 0.2-0.5 mol / L. The molar ratio of the cyclized intermediate to sodium azide may be 1:(1-3), preferably 1:(1.5-2). The reaction temperature may be 100-180°C, such as 120°C, 130°C, 150°C, 180°C; preferably 140-180°C. The residence time may be 1-45 min, such as 5 min, 15 min, 20 min, 35 min; preferably 10-30 min. The flow rate of the feed liquid E may be 0.024-1.1 mL / min, preferably 0.037-0.11 mL / min.

[0042] In S5, the fifth organic solvent is selected from one or more of N,N-dimethylformamide, dimethyl sulfoxide, water, methanol, acetonitrile, tetrahydrofuran, toluene and 1,4-dioxane; preferably dimethyl sulfoxide. In the feed liquid J, the concentration of the azidation product is 0.1-0.5 mol / L, such as 0.1 mol / L, 0.2 mol / L, 0.3 mol / L, 0.4 mol / L, 0.5 mol / L, preferably 0.2-0.5 mol / L. The concentration of p-toluenesulfonic acid in the feed liquid F is 0.1-0.5 mol / L, such as 0.2 mol / L, 0.3 mol / L, 0.4 mol / L, 0.5 mol / L; preferably 0.3-0.5 mol / L. The molar ratio of the azidation product to p-toluenesulfonic acid is 1:(0.25-2), such as 1:0.5, 1:1, 1:1.5, preferably 1:(1-1.25). The reaction temperature may be 60-120°C, such as 80°C, 90°C, 98°C, 110°C; preferably 90-120°C. The residence time may be 1-30min, such as 5min, 10min, 12min, 15min, 18min, 25min; preferably 5-15min. The flow rate of the feed liquid J is 0.067-2.0mL / min; preferably 0.133-0.4mL / min. The flow rate of the feed liquid F is 0.067-2.0mL / min; preferably 0.133-0.4mL / min.

[0043] In some embodiments, the deprotection reaction solution after the S5 reaction is completed enters the concentration, dissolution filtration, cooling and crystallization module to obtain crude zidovudine.

[0044] In some embodiments, in the method of the present invention, any two adjacent steps, any three adjacent steps, any four adjacent steps, or all five steps of steps S1, S2, S3, S4, and S5 are connected in series.

[0045] It should be understood that the series connection described herein means that the outlet of the reaction liquid of the previous step is directly connected to the inlet of the reaction material of the next step in the actual reaction, and the reaction liquid prepared in the previous step is directly used in the next step without purification or simple post-treatment. It should be understood that when connected in series, the solvents used in each step connected in series are usually the same solvent.

[0046] S1 and S2 are connected in series, that is, continuous hydroxyl protection and continuous acylation are connected in series to form S12, which can replace S1 and S2, and the mesylate intermediate obtained by S12 can enter S3 to participate in the reaction. Specifically, S12 includes: the feed liquid A and the feed liquid B are mixed in a first micro mixer and then continuously pumped into a first microreactor to perform a hydroxyl protection reaction to obtain a reaction liquid G; the reaction liquid G and the feed liquid C are mixed in a second micro mixer and then continuously pumped into a second microreactor to perform an acylation reaction to obtain a mesylate intermediate.

[0047] S2 and S3 are connected in series, that is, continuous acylation and continuous cyclization are connected in series to form S23, which can replace S2 and S3, and the cyclization intermediate obtained by S23 can enter S4 to participate in the reaction. Specifically, S23 includes: connecting S2 and S3 in series; mixing the feed liquid G and the feed liquid C through the second micro mixer and then continuously pumping them into the second micro reactor to perform an acylation reaction to obtain a reaction liquid H; mixing the reaction liquid H and the feed liquid D through the third micro mixer and then continuously pumping them into the third micro reactor to perform a cyclization reaction to obtain a cyclization intermediate.

[0048] S3 and S4 are connected in series, that is, continuous cyclization and continuous azidation are connected in series to form S34, which can replace S3 and S4, and the azidation intermediate obtained by S34 can enter S5 to participate in the reaction. Specifically, S34 includes: connecting S3 and S4 in series; mixing the feed liquid H and the feed liquid D through a third micro mixer and continuously pumping them into a third microreactor to perform a cyclization reaction to obtain a reaction liquid I; passing the reaction liquid I into a continuous filtration and dissolution two-in-one device to separate the cyclization intermediate; dissolving the cyclization intermediate and sodium azide in a fourth organic solvent to obtain a feed liquid E; continuously pumping the feed liquid E into a fourth microreactor to perform an azidation reaction to obtain an azidation product.

[0049] S4 and S5 are connected in series, that is, continuous azidation and continuous deprotection are connected in series to form S45, which can replace S4 and S5. Specifically, S45 includes: connecting S4 and S5 in series; continuously pumping the feed liquid E into the fourth microreactor to perform an azidation reaction to obtain a reaction liquid J; mixing the reaction liquid J and the feed liquid F in the fourth micro-mixer and continuously pumping them into the fifth microreactor to perform a deprotection reaction to obtain a crude zidovudine product. The deprotection reaction liquid obtained by S45 is concentrated, dissolved, filtered, and cooled and crystallized to obtain a crude zidovudine product.

[0050] S1, S2 and S3 are connected in series, that is, continuous hydroxyl protection, continuous acylation and continuous cyclization are connected in series to form S123, which can replace S1, S2 and S3. The cyclization reaction liquid obtained by S123 is passed into water, and the cyclization intermediate obtained by filtration can enter S4 to participate in the reaction. Specifically, the feed liquid A and the feed liquid B are mixed in the first micro mixer and continuously pumped into the first microreactor to carry out a hydroxyl protection reaction to obtain a reaction liquid G; the reaction liquid G and the feed liquid C are mixed in the second micro mixer and continuously pumped into the second microreactor to carry out an acylation reaction to obtain a reaction liquid H; the reaction liquid H and the feed liquid D are mixed in the third micro mixer and continuously pumped into the third microreactor to carry out a cyclization reaction to obtain a cyclization intermediate.

[0051] In some embodiments, the continuous flow synthesis method of the present invention comprises module 1 and module 2, wherein module 1 comprises step S123, and module 2 comprises step S45. Module 1 and module 2 are connected via a continuous filtration and dissolution two-in-one device.

[0052] The present invention provides a continuous synthesis device, which is composed of six injection pumps, five microreactors (capillary microreactors or glass chip microreactors), a continuous filtration and dissolution two-in-one device, three micromixers and various connecting pipelines. Figure 1 shown.

[0053] The present invention provides a continuous flow synthesis device for implementing the continuous flow synthesis method of the present invention. The continuous flow synthesis device comprises a first micro mixer M1, a first micro reactor I, a second micro mixer M2, a second micro reactor II, a third micro mixer M3, a third micro reactor III, a continuous filtration and dissolution two-in-one device Q1, a fourth micro reactor IV, a fourth micro mixer M4 and a fifth micro reactor V, which are sequentially connected through pipelines; the continuous flow synthesis device also comprises a first feed pump P1 and a second feed pump P2 for feeding the first micro mixer M1, a third feed pump P3 for feeding the second micro mixer M2, a fourth feed pump P4 for feeding the third micro mixer M3, a fifth feed pump P5 for feeding the fourth micro reactor IV, and a sixth feed pump P6 for feeding the fourth micro mixer M4.

[0054] The continuous flow synthesis device of the present invention comprises a continuous hydroxyl protection part, a continuous acylation part, a continuous cyclization part, a continuous azidation part, and a continuous deprotection part in order of the reaction process. In the continuous hydroxyl protection part, the first injection pump P1 and the second injection pump P2 respectively transport the feed liquid A and the feed liquid B into the first microreactor I through the first micromixer M1. In the continuous acylation part, the third injection pump P3 transports the feed liquid C and the reaction liquid G into the second microreactor II through the second micromixer M2. In the continuous cyclization part, the fourth injection pump P4 transports the feed liquid D and the reaction liquid H into the third microreactor III through the third micromixer M3, and a continuous filtration and dissolution two-in-one device Q1 is connected at the outlet. In the continuous azidation part, the fifth injection pump P5 transports the feed liquid E into the fourth microreactor IV. In the continuous deprotection part, the sixth injection pump P6 is used to pump the reaction liquid J and the feed liquid F into the fifth microreactor V through the fourth micromixer M4 to carry out the deprotection reaction. Preferably, the continuous flow synthesis device of the present invention further comprises a post-processing module, for example, one or more selected from the group consisting of a concentration, a dissolution filtration and a cooling crystallization module. The deprotection reaction solution obtained from the continuous deprotection part of the continuous flow synthesis device of the present invention is subjected to concentration, dissolution filtration and a cooling crystallization module to obtain a crude zidovudine product.

[0055] In some embodiments, the first microreactor I, the second microreactor II, the third microreactor III, the fourth microreactor IV and the fifth microreactor V are each independently a capillary microreactor or a glass chip microreactor. Preferably, the first microreactor I, the second microreactor II, the third microreactor III, the fourth microreactor IV and the fifth microreactor V are all capillary microreactors. Preferably, the second microreactor II and the fourth microreactor IV are glass chip microreactors.

[0056] In some embodiments, the first micromixer M1, the second micromixer M2, the third micromixer M3 and the fourth micromixer M4 are all T-type three-way mixers.

[0057] In some embodiments, the first feed pump P1, the second feed pump P2, the third feed pump P3, the fourth feed pump P4, the fifth feed pump P5 and the sixth feed pump P6 are each independently a syringe pump or a horizontal flow pump.

[0058] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental methods in the following examples without specifying specific conditions are usually based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0059] Herein, the first microreactor I, the third microreactor III and the fifth microreactor V are capillary microreactors; the second microreactor II and the fourth microreactor IV are glass chip microreactors.

[0060] Example 1 (Continuous Hydroxyl Protection Reaction)

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

[0062] Take 0.968g of β-thymidine (compound 1, 1 equivalent), add pyridine thereto, and dilute to 10mL, as feed liquid A for standby. Take 2.230g (2 equivalents) of triphenylmethane, add pyridine thereto, and dilute to 10mL, as feed liquid B for standby. Feed liquid A and feed liquid B are transported into the first microreactor I by the first injection pump P1 and the second injection pump P2 through the first micromixer M1, with a flow rate of 0.062mL / min, a residence time of 60min, and a microreactor temperature of 100°C, and a continuous hydroxyl protection reaction is carried out to obtain reaction liquid G. HPLC detection shows that the yield of the hydroxyl protection intermediate is 97.1%.

[0063] Example 2 (Continuous Hydroxyl Protection Reaction)

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

[0065] Take 0.968g of β-thymidine (compound 1, 1 equivalent), add pyridine thereto, and dilute to 10mL, as feed liquid A for standby. Take 2.230g (2 equivalents) of triphenylmethane, add pyridine thereto, and dilute to 10mL, as feed liquid B for standby. Feed liquid A and feed liquid B are transported into the first microreactor I by the first injection pump P1 and the second injection pump P2 through the first micromixer M1, with a flow rate of 0.123mL / min, a residence time of 30min, and a microreactor temperature of 100°C, and a continuous hydroxyl protection reaction is carried out to obtain reaction liquid G. HPLC detection shows that the yield of the hydroxyl protection intermediate is 94.3%.

[0066] Example 3 (Continuous Hydroxyl Protection Reaction)

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

[0068] Take 0.968g of β-thymidine (compound 1, 1 equivalent), add pyridine thereto, and dilute to 10mL, as feed liquid A for standby. Take 1.6725g of triphenylmethane (1.5 equivalents), add pyridine thereto, and dilute to 10mL, as feed liquid B for standby. Feed liquid A and feed liquid B are transported into the first microreactor I by the first injection pump P1 and the second injection pump P2 through the first micromixer M1, with a flow rate of 0.247mL / min, a residence time of 15min, and a microreactor temperature of 100°C, and a continuous hydroxyl protection reaction is carried out to obtain reaction liquid G. HPLC detection shows that the yield of the hydroxyl protection intermediate is 66.8%.

[0069] Example 4 (Continuous Hydroxyl Protection Reaction)

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

[0071] Take 0.968g of β-thymidine (compound 1, 1 equivalent), add pyridine thereto, and dilute to 10mL, as feed liquid A for standby. Take 1.6725g of triphenylmethane (1.5 equivalents), add pyridine thereto, and dilute to 10mL, as feed liquid B for standby. Feed liquid A and feed liquid B are transported into the first microreactor I by the first injection pump P1 and the second injection pump P2 through the first micromixer M1, with a flow rate of 0.123mL / min, a residence time of 30min, and a microreactor temperature of 100°C, and a continuous hydroxyl protection reaction is carried out to obtain reaction liquid G. HPLC detection shows that the yield of the hydroxyl protection intermediate is 77.5%.

[0072] Example 5 (Continuous Hydroxyl Protection Reaction)

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

[0074] Take 0.968g of β-thymidine (compound 1, 1 equivalent), add pyridine thereto, and dilute to 10mL, as feed liquid A for standby. Take 1.6725g (1.5 equivalents) of triphenylmethane, add pyridine thereto, and dilute to 10mL, as feed liquid B for standby. Feed liquid A and feed liquid B are transported into the first microreactor I by the first injection pump P1 and the second injection pump P2 through the first micromixer M1, with a flow rate of 0.031mL / min, a residence time of 120min, and a microreactor temperature of 100°C, and a continuous hydroxyl protection reaction is carried out to obtain reaction liquid G. HPLC detection shows that the yield of the hydroxyl protection intermediate is 75.3%.

[0075] Example 6 (Continuous Hydroxyl Protection Reaction)

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

[0077] Take 0.968g of β-thymidine (compound 1, 1 equivalent), add pyridine thereto, and dilute to 10mL, as feed liquid A for standby. Take 1.6725g (1.5 equivalents) of triphenylmethane, add pyridine thereto, and dilute to 10mL, as feed liquid B for standby. Feed liquid A and feed liquid B are transported into the first microreactor I by the first injection pump P1 and the second injection pump P2 through the first micromixer M1, with a flow rate of 0.041mL / min, a residence time of 90min, and a microreactor temperature of 100°C, and a continuous hydroxyl protection reaction is carried out to obtain reaction liquid G. HPLC detection shows that the yield of the hydroxyl protection intermediate is 79.8%.

[0078] Example 7 (Continuous Hydroxyl Protection Reaction)

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

[0080] Take 0.968g of β-thymidine (compound 1, 1 equivalent), add pyridine thereto, and dilute to 10mL, as feed liquid A for standby. Take 1.6725g of triphenylmethane (1.5 equivalents), add pyridine thereto, and dilute to 10mL, as feed liquid B for standby. Feed liquid A and feed liquid B are transported into the first microreactor I by the first injection pump P1 and the second injection pump P2 through the first micromixer M1, with a flow rate of 0.062mL / min, a residence time of 60min, and a microreactor temperature of 100°C, and a continuous hydroxyl protection reaction is carried out to obtain reaction liquid G. HPLC detection shows that the yield of the hydroxyl protection intermediate is 81.8%.

[0081] Example 8 (Continuous Hydroxyl Protection Reaction)

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

[0083] Take 0.968g of β-thymidine (compound 1, 1 equivalent), add pyridine thereto, and dilute to 10mL, as feed liquid A for standby. Take 1.6725g (1.5 equivalents) of triphenylmethane, add pyridine thereto, and dilute to 10mL, as feed liquid B for standby. Feed liquid A and feed liquid B are transported into the first microreactor I by the first injection pump P1 and the second injection pump P2 through the first micromixer M1, with a flow rate of 0.041mL / min, a residence time of 90min, and a microreactor temperature of 120°C, and a continuous hydroxyl protection reaction is carried out to obtain reaction liquid G. HPLC detection shows that the yield of the hydroxyl protection intermediate is 34.3%.

[0084] Example 9 (Continuous Hydroxyl Protection Reaction)

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

[0086] Take 0.968g of β-thymidine (compound 1, 1 equivalent), add pyridine thereto, and dilute to 10mL, as feed liquid A for standby. Take 1.6725g (1.5 equivalents) of triphenylmethane, add pyridine thereto, and dilute to 10mL, as feed liquid B for standby. Feed liquid A and feed liquid B are transported into the first microreactor I by the first injection pump P1 and the second injection pump P2 through the first micromixer M1, with a flow rate of 0.062mL / min, a residence time of 60min, and a microreactor temperature of 120°C, and a continuous hydroxyl protection reaction is carried out to obtain reaction liquid G. HPLC detection shows that the yield of the hydroxyl protection intermediate is 32.6%.

[0087] Example 10 (Continuous Hydroxyl Protection Reaction)

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

[0089] Take 0.968g of β-thymidine (compound 1, 1 equivalent), add pyridine thereto, and dilute to 10mL, as feed liquid A for standby. Take 1.6725g of triphenylmethane (1.5 equivalents), add pyridine thereto, and dilute to 10mL, as feed liquid B for standby. Feed liquid A and feed liquid B are transported into the first microreactor I by the first injection pump P1 and the second injection pump P2 through the first micromixer M1, with a flow rate of 0.123mL / min, a residence time of 30min, and a microreactor temperature of 120°C, and a continuous hydroxyl protection reaction is carried out to obtain reaction liquid G. HPLC detection shows that the yield of the hydroxyl protection intermediate is 32.5%.

[0090] Example 11 (Continuous Hydroxyl Protection Reaction)

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

[0092] Take 0.968g of β-thymidine (compound 1, 1 equivalent), add pyridine thereto, and dilute to 10mL, as feed liquid A for standby. Take 2.230g (2 equivalents) of triphenylmethane, add pyridine thereto, and dilute to 10mL, as feed liquid B for standby. Feed liquid A and feed liquid B are transported into the first microreactor I by the first injection pump P1 and the second injection pump P2 through the first micromixer M1, with a flow rate of 0.041mL / min, a residence time of 90min, and a microreactor temperature of 100°C, and a continuous hydroxyl protection reaction is carried out to obtain reaction liquid G. HPLC detection shows that the yield of the hydroxyl protection intermediate is 96.0%.

[0093] The reaction solution G is purified to obtain a hydroxyl-protected intermediate, the structure of which is:

[0094]

[0095] Example 12 (Continuous Acylation Reaction)

[0096] In the continuous acylation part of the above continuous synthesis device, the connecting pipe is a pipe made of PTFE material, and the feed pump is a syringe pump.

[0097] Take 3.874g (1 equivalent) of the hydroxyl protected intermediate and 1.898g (3 equivalents) of pyridine, add N,N-dimethylformamide to it, dilute to 20mL, and use it as feed liquid G. Take 4.044g (3 equivalents) of trifluoromethanesulfonyl chloride, add N,N-dimethylformamide to it, dilute to 5mL, and use it as feed liquid C. Feed liquid G and feed liquid C are transported into the second microreactor II by the second injection pump P2 and the third injection pump P3 through the second micro mixer M2. The flow rates of the second injection pump P2 and the third injection pump P3 are 0.059mL / min and 0.015mL / min, respectively, the residence time is 30min, and the temperature of the microreactor is 100°C. A continuous acylation reaction is carried out to obtain reaction liquid H. HPLC detection shows that the yield of the mesylate intermediate is 97.2%.

[0098] Example 13 (Continuous Acylation Reaction)

[0099] In the continuous acylation part of the above continuous synthesis device, the connecting pipe is a pipe made of PTFE material, and the feed pump is a syringe pump.

[0100] Take 3.874g (1 equivalent) of the hydroxyl protected intermediate and 1.898g (3 equivalents) of pyridine, add N,N-dimethylformamide to it, dilute to 20mL, and use it as feed liquid G. Take 4.044g (3 equivalents) of trifluoromethanesulfonyl chloride, add N,N-dimethylformamide to it, dilute to 5mL, and use it as feed liquid C. Feed liquid G and feed liquid C are transported into the second microreactor II by the second injection pump P2 and the third injection pump P3 through the second micromixer M2. The flow rates of the second injection pump P2 and the third injection pump P3 are 0.088mL / min and 0.022mL / min, respectively, the residence time is 20min, and the temperature of the microreactor is 100°C. Continuous acylation reaction is carried out to obtain reaction liquid H. HPLC detection shows that the yield of the mesylate intermediate is 91.7%.

[0101] Example 14 (Continuous Acylation Reaction)

[0102] In the continuous acylation part of the above continuous synthesis device, the connecting pipe is a pipe made of PTFE material, and the feed pump is a syringe pump.

[0103] Take 3.874g (1 equivalent) of the hydroxyl protected intermediate and 1.898g (3 equivalents) of pyridine, add N,N-dimethylformamide to it, dilute to 20mL, and use it as feed liquid G. Take 4.044g (3 equivalents) of trifluoromethanesulfonyl chloride, add N,N-dimethylformamide to it, dilute to 5mL, and use it as feed liquid C. Feed liquid G and feed liquid C are transported into the second microreactor II by the second injection pump P2 and the third injection pump P3 through the second micro mixer M2. The flow rates of the second injection pump P2 and the third injection pump P3 are 0.176mL / min and 0.044mL / min, respectively. The residence time is 10min, and the temperature of the microreactor is 100°C. A continuous acylation reaction is carried out to obtain reaction liquid H. HPLC detection shows that the yield of the mesylate intermediate is 69.8%.

[0104] Example 15 (Continuous Acylation Reaction)

[0105] In the continuous acylation part of the above continuous synthesis device, the connecting pipe is a pipe made of PTFE material, and the feed pump is a syringe pump.

[0106] Take 3.874g (1 equivalent) of the hydroxyl protected intermediate and 1.898g (3 equivalents) of pyridine, add N,N-dimethylformamide to it, and dilute to 20mL, as feed liquid G for standby. Take 4.044g (3 equivalents) of trifluoromethanesulfonyl chloride, add N,N-dimethylformamide to it, and dilute to 5mL, as feed liquid C for standby. Feed liquid G and feed liquid C are transported into the second microreactor II by the second injection pump P2 and the third injection pump P3 through the second micromixer M2. The flow rates of the second injection pump P2 and the third injection pump P3 are 0.088mL / min and 0.022mL / min, respectively, the residence time is 20min, the microreactor temperature is 120°C, and a continuous acylation reaction is carried out to obtain reaction liquid H. According to HPLC detection, the yield of the mesylate intermediate is 99.9%.

[0107] Example 16 (Continuous Acylation Reaction)

[0108] In the continuous acylation part of the above continuous synthesis device, the connecting pipe is a pipe made of PTFE material, and the feed pump is a syringe pump.

[0109] Take 3.874g (1 equivalent) of the hydroxyl protected intermediate and 1.898g (3 equivalents) of pyridine, add N,N-dimethylformamide to it, dilute to 20mL, and use it as feed liquid G. Take 4.044g (3 equivalents) of trifluoromethanesulfonyl chloride, add N,N-dimethylformamide to it, dilute to 5mL, and use it as feed liquid C. Feed liquid G and feed liquid C are transported into the second microreactor II by the second injection pump P2 and the third injection pump P3 through the second micro mixer M2. The flow rates of the second injection pump P2 and the third injection pump P3 are 0.176mL / min and 0.044mL / min, respectively. The residence time is 10min, and the temperature of the microreactor is 120°C. A continuous acylation reaction is carried out to obtain reaction liquid H. HPLC detection shows that the yield of the mesylate intermediate is 99.9%.

[0110] Example 17 (Continuous Acylation Reaction)

[0111] In the continuous acylation part of the above continuous synthesis device, the connecting pipe is a pipe made of PTFE material, and the feed pump is a syringe pump.

[0112] Take 3.874g (1 equivalent) of the hydroxyl protected intermediate and 1.898g (3 equivalents) of pyridine, add N,N-dimethylformamide to it, dilute to 20mL, and use it as feed liquid G. Take 4.044g (3 equivalents) of trifluoromethanesulfonyl chloride, add N,N-dimethylformamide to it, dilute to 5mL, and use it as feed liquid C. Feed liquid G and feed liquid C are transported into the second microreactor II by the second injection pump P2 and the third injection pump P3 through the second micro mixer M2. The flow rates of the second injection pump P2 and the third injection pump P3 are 0.176mL / min and 0.044mL / min, respectively. The residence time is 10min, and the temperature of the microreactor is 130°C. A continuous acylation reaction is carried out to obtain reaction liquid H. HPLC detection shows that the yield of the mesylate intermediate is 99.9%.

[0113] Example 18 (Continuous Acylation Reaction)

[0114] In the continuous acylation part of the above continuous synthesis device, the connecting pipe is a pipe made of PTFE material, and the feed pump is a syringe pump.

[0115] Take 3.874g (1 equivalent) of the hydroxyl protected intermediate and 1.898g (3 equivalents) of pyridine, add N,N-dimethylformamide to it, dilute to 20mL, and use it as feed liquid G. Take 4.044g (3 equivalents) of trifluoromethanesulfonyl chloride, add N,N-dimethylformamide to it, dilute to 5mL, and use it as feed liquid C. Feed liquid G and feed liquid C are transported into the second microreactor II by the second injection pump P2 and the third injection pump P3 through the second micro mixer M2. The flow rates of the second injection pump P2 and the third injection pump P3 are 0.029mL / min and 0.007mL / min, respectively. The residence time is 60min, and the temperature of the microreactor is 70°C. A continuous acylation reaction is carried out to obtain reaction liquid H. According to HPLC detection, the yield of the mesylate intermediate is 99.9%.

[0116] Example 19 (Continuous Acylation Reaction)

[0117] In the continuous acylation part of the above continuous synthesis device, the connecting pipe is a pipe made of PTFE material, and the feed pump is a syringe pump.

[0118] Take 3.874g (1 equivalent) of the hydroxyl protected intermediate and 1.898g (3 equivalents) of pyridine, add N,N-dimethylformamide to it, dilute to 20mL, and use it as feed liquid G. Take 4.044g (3 equivalents) of trifluoromethanesulfonyl chloride, add N,N-dimethylformamide to it, dilute to 5mL, and use it as feed liquid C. Feed liquid G and feed liquid C are transported into the second microreactor II by the second injection pump P2 and the third injection pump P3 through the second micro mixer M2. The flow rates of the second injection pump P2 and the third injection pump P3 are 0.352mL / min and 0.088mL / min, respectively, the residence time is 5min, the microreactor temperature is 120°C, and a continuous acylation reaction is carried out to obtain reaction liquid H. According to HPLC detection, the yield of the mesylate intermediate is 99.9%.

[0119] Example 20 (Continuous Acylation Reaction)

[0120] In the continuous acylation part of the above continuous synthesis device, the connecting pipe is a pipe made of PTFE material, and the feed pump is a syringe pump.

[0121] Take 3.874g (1 equivalent) of the hydroxyl protected intermediate and 1.898g (3 equivalents) of pyridine, add N,N-dimethylformamide to it, dilute to 20mL, and use it as feed liquid G. Take 4.044g (3 equivalents) of trifluoromethanesulfonyl chloride, add N,N-dimethylformamide to it, dilute to 5mL, and use it as feed liquid C. Feed liquid G and feed liquid C are transported into the second microreactor II by the second injection pump P2 and the third injection pump P3 through the second micro mixer M2. The flow rates of the second injection pump P2 and the third injection pump P3 are 0.352mL / min and 0.088mL / min, respectively, the residence time is 5min, and the temperature of the microreactor is 130°C. Continuous acylation reaction is carried out to obtain reaction liquid H. HPLC detection shows that the yield of the mesylate intermediate is 99.9%.

[0122] Example 21 (Continuous Acylation Reaction)

[0123] In the continuous acylation part of the above continuous synthesis device, the connecting pipe is a pipe made of PTFE material, and the feed pump is a syringe pump.

[0124] Take 3.874g (1 equivalent) of the hydroxyl protected intermediate and 1.898g (3 equivalents) of pyridine, add N,N-dimethylformamide to it, dilute to 20mL, and use it as feed liquid G. Take 2.696g (2 equivalents) of trifluoromethanesulfonyl chloride, add N,N-dimethylformamide to it, dilute to 5mL, and use it as feed liquid C. Feed liquid G and feed liquid C are transported into the second microreactor II by the second injection pump P2 and the third injection pump P3 through the second micro mixer M2. The flow rates of the second injection pump P2 and the third injection pump P3 are 0.029mL / min and 0.007mL / min, respectively, the residence time is 60min, the microreactor temperature is 27°C, and continuous acylation reaction is carried out to obtain reaction liquid H. According to HPLC detection, the yield of the mesylate intermediate is 63.4%.

[0125] Example 22 (Continuous Acylation Reaction)

[0126] In the continuous acylation part of the above continuous synthesis device, the connecting pipe is a pipe made of PTFE material, and the feed pump is a syringe pump.

[0127] Take 3.874g (1 equivalent) of the hydroxyl protected intermediate and 1.898g (3 equivalents) of pyridine, add N,N-dimethylformamide to it, dilute to 20mL, and use it as feed liquid G. Take 2.696g (2 equivalents) of trifluoromethanesulfonyl chloride, add N,N-dimethylformamide to it, dilute to 5mL, and use it as feed liquid C. Feed liquid G and feed liquid C are transported into the second microreactor II by the second injection pump P2 and the third injection pump P3 through the second micro mixer M2. The flow rates of the second injection pump P2 and the third injection pump P3 are 0.029mL / min and 0.007mL / min, respectively. The residence time is 60min, and the temperature of the microreactor is 70°C. A continuous acylation reaction is carried out to obtain reaction liquid H. According to HPLC detection, the yield of the mesylate intermediate is 84.8%.

[0128] The reaction solution H is purified to obtain a mesylate intermediate, the structure of which is:

[0129]

[0130] Example 23 (Continuous Cyclization Reaction)

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

[0132] Take 20 mL of the effluent of Example 19 (i.e., reaction liquid H) as feed liquid H, prepare 5 mL of 15 mol / L NaOH aqueous solution, and use it as feed liquid D. Feed liquid H and feed liquid D are transported into the third microreactor III by the third injection pump P3 and the fourth injection pump P4 and through the third micro mixer M3. The flow rates of the third injection pump P3 and the fourth injection pump P4 are 0.169 mL / min and 0.011 mL / min, respectively, and the residence time is 30 min. The microreactor is placed in ultrasound at a temperature of 65° C. to perform continuous cyclization reaction to obtain reaction liquid I. HPLC detection shows that the yield of the cyclized intermediate is 91.5%.

[0133] Example 24 (Continuous Cyclization Reaction)

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

[0135] Take 20 mL of the effluent of Example 19 (i.e., reaction liquid H) as feed liquid H, prepare 5 mL of 15 mol / L NaOH aqueous solution, and use it as feed liquid D. Feed liquid H and feed liquid D are transported into the third microreactor III by the third injection pump P3 and the fourth injection pump P4 and through the third micro mixer M3. The flow rates of the third injection pump P3 and the fourth injection pump P4 are 0.338 mL / min and 0.022 mL / min, respectively, and the residence time is 15 min. The microreactor is placed in ultrasound at a temperature of 65° C. to perform continuous cyclization reaction to obtain reaction liquid I. HPLC detection shows that the yield of the cyclized intermediate is 91.5%.

[0136] The reaction solution I is passed into water and filtered to obtain a cyclized intermediate, the structure of which is:

[0137]

[0138] Example 25 (Continuous Azide Reaction)

[0139] In the continuous azidation part of the above-mentioned continuous synthesis device, the connecting pipe is a pipe made of PTFE material, and the feed pump is a syringe pump.

[0140] Take the effluent of Example 24 (i.e., reaction solution I), pour it into a large amount of ice water (volume ratio 10:1), solid precipitates, and filter to obtain a cyclized intermediate. Take 4.66g (1 equivalent) of the cyclized intermediate and 0.975g (1.5 equivalents) of sodium azide, add 20mL of dimethyl sulfoxide thereto, dissolve at high temperature, and use as feed solution E. Feed solution E is transported into the fourth microreactor IV by the fifth syringe pump P5, the flow rate of the fifth syringe pump P5 is 0.11mL / min, the residence time is 10min, the temperature of the microreactor is 170°C, and a continuous azidation reaction is carried out to obtain a reaction solution J. HPLC detection shows that the yield of the azidation product is 78.6%.

[0141] Example 26 (Continuous Azide Reaction)

[0142] In the continuous azidation part of the above-mentioned continuous synthesis device, the connecting pipe is a pipe made of PTFE material, and the feed pump is a syringe pump.

[0143] Take the effluent of Example 24 (i.e., reaction solution I), pour it into a large amount of ice water (volume ratio 10:1), solid precipitates, and filter to obtain a cyclized intermediate. Take 2.33g (1 equivalent) of the cyclized intermediate and 0.488g (1.5 equivalents) of sodium azide, add 20mL of dimethyl sulfoxide thereto, dissolve at high temperature, and use as feed solution E. Feed solution E is transported into the fourth microreactor IV by the fifth syringe pump P5, the flow rate of the fifth syringe pump P5 is 0.11mL / min, the residence time is 10min, the temperature of the microreactor is 170°C, and a continuous azidation reaction is carried out to obtain a reaction solution J. HPLC detection shows that the yield of the azidation product is 39.1%.

[0144] Example 27 (Continuous Azide Reaction)

[0145] In the continuous azidation part of the above-mentioned continuous synthesis device, the connecting pipe is a pipe made of PTFE material, and the feed pump is a syringe pump.

[0146] Take the effluent of Example 24 (i.e., reaction solution I), pour it into a large amount of ice water (volume ratio 10:1), solid precipitates, and filter to obtain a cyclized intermediate. Take 4.66g (1 equivalent) of the cyclized intermediate and 0.975g (1.5 equivalents) of sodium azide, add 20mL of dimethyl sulfoxide thereto, dissolve at high temperature, and use as feed solution E. Feed solution E is transported into the fourth microreactor IV by the fifth syringe pump P5, the flow rate of the fifth syringe pump P5 is 0.11mL / min, the residence time is 10min, the temperature of the microreactor is 140°C, and a continuous azidation reaction is carried out to obtain a reaction solution J. HPLC detection shows that the yield of the azidation product is 28.1%.

[0147] Example 28 (Continuous Azide Reaction)

[0148] In the continuous azidation part of the above-mentioned continuous synthesis device, the connecting pipe is a pipe made of PTFE material, and the feed pump is a syringe pump.

[0149] Take the effluent of Example 24 (i.e., reaction solution I), pour it into a large amount of ice water (volume ratio 10:1), solid precipitates, and filter to obtain a cyclized intermediate. Take 4.66g (1 equivalent) of the cyclized intermediate and 0.975g (1.5 equivalents) of sodium azide, add 20mL of dimethyl sulfoxide thereto, dissolve at high temperature, and use as feed solution E. Feed solution E is transported into the fourth microreactor IV by the fifth syringe pump P5, the flow rate of the fifth syringe pump P5 is 0.11mL / min, the residence time is 10min, the microreactor temperature is 150°C, and a continuous azidation reaction is carried out to obtain a reaction solution J. HPLC detection shows that the yield of the azidation product is 48.9%.

[0150] Example 29 (Continuous Azide Reaction)

[0151] In the continuous azidation part of the above-mentioned continuous synthesis device, the connecting pipe is a pipe made of PTFE material, and the feed pump is a syringe pump.

[0152] Take the effluent of Example 24 (i.e., reaction solution I), pour it into a large amount of ice water (volume ratio 10:1), solid precipitates, and filter to obtain a cyclized intermediate. Take 4.66g (1 equivalent) of the cyclized intermediate and 0.975g (1.5 equivalents) of sodium azide, add 20mL of dimethyl sulfoxide thereto, dissolve at high temperature, and use as feed solution E. Feed solution E is transported into the fourth microreactor IV by the fifth syringe pump P5, the flow rate of the fifth syringe pump P5 is 0.11mL / min, the residence time is 10min, the microreactor temperature is 180°C, and a continuous azidation reaction is carried out to obtain a reaction solution J. HPLC detection shows that the yield of the azidation product is 89.0%.

[0153] The reaction solution J is purified to obtain an azidation product, the structure of which is:

[0154]

[0155] Example 30 (Continuous Deprotection Reaction)

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

[0157] Take 20 mL of the effluent of Example 29 (i.e., reaction solution J) as feed solution J, take p-toluenesulfonic acid (1.72 g, 1 equivalent), add 20 mL of dimethyl sulfoxide thereto, and use as feed solution F. Feed solution J and feed solution E are respectively transported into the fifth microreactor V by the fifth syringe pump P5 and the sixth syringe P6 through the fourth micromixer M4, the flow rate of the fifth syringe pump P5 and the sixth syringe P6 are both 0.186 mL / min, the residence time is 10.75 min, the microreactor temperature is 90° C., and continuous deprotection reaction is carried out to obtain reaction solution K. HPLC detection shows that the yield of zidovudine is 78.8%.

[0158] Example 31 (Continuous Deprotection Reaction)

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

[0160] Take 20 mL of the effluent of Example 29 (i.e., reaction solution J) as feed solution J, take p-toluenesulfonic acid (0.86 g, 0.5 equivalent), add 20 mL of dimethyl sulfoxide thereto, and use as feed solution F. Feed solution J and feed solution E are respectively transported into the fifth microreactor V by the fifth syringe pump P5 and the sixth syringe P6 through the fourth micromixer M4, the flow rate of the fifth syringe pump P5 and the sixth syringe P6 are both 0.186 mL / min, the residence time is 10.75 min, the microreactor temperature is 90° C., and continuous deprotection reaction is carried out to obtain reaction solution K. HPLC detection shows that the yield of zidovudine is 41.4%.

[0161] Example 32 (Continuous Deprotection Reaction)

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

[0163] Take 20 mL of the effluent of Example 29 (i.e., reaction solution J) as feed solution J, take p-toluenesulfonic acid (2.187 g, 1.25 equivalents), add 20 mL of dimethyl sulfoxide thereto, and use as feed solution F. Feed solution J and feed solution E are respectively transported into the fifth microreactor V by the fifth syringe pump P5 and the sixth syringe P6 through the fourth micromixer M4, the flow rate of the fifth syringe pump P5 and the sixth syringe P6 are both 0.186 mL / min, the residence time is 10.75 min, the microreactor temperature is 90° C., and continuous deprotection reaction is carried out to obtain reaction solution K. HPLC detection shows that the yield of zidovudine is 83.3%.

[0164] Example 33 (Continuous Deprotection Reaction)

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

[0166] Take 20 mL of the effluent of Example 29 (i.e., reaction solution J) as feed solution J, take p-toluenesulfonic acid (1.72 g, 1 equivalent), add 20 mL of dimethyl sulfoxide thereto, and use as feed solution F. Feed solution J and feed solution E are respectively transported into the fifth microreactor V by the fifth syringe pump P5 and the sixth syringe P6 through the fourth micromixer M4, the flow rate of the fifth syringe pump P5 and the sixth syringe P6 are both 0.25 mL / min, the residence time is 8 min, the microreactor temperature is 110° C., and continuous deprotection reaction is carried out to obtain reaction solution K. HPLC detection shows that the yield of zidovudine is 97.6%.

[0167] Example 34 (Continuous Deprotection Reaction)

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

[0169] Take 20 mL of the effluent of Example 29 (i.e., reaction solution J) as feed solution J, take p-toluenesulfonic acid (1.72 g, 1 equivalent), add 20 mL of dimethyl sulfoxide thereto, and use as feed solution F. Feed solution J and feed solution E are respectively transported into the fifth microreactor V by the fifth syringe pump P5 and the sixth syringe P6 through the fourth micromixer M4, the flow rate of the fifth syringe pump P5 and the sixth syringe P6 are both 0.25 mL / min, the residence time is 8 min, the microreactor temperature is 120° C., and continuous deprotection reaction is carried out to obtain reaction solution K. HPLC detection shows that the yield of zidovudine is 97.9%.

[0170] The reaction solution K is concentrated, dissolved in water, filtered to remove impurities, cooled and crystallized to purify, and the deprotected product zidovudine is obtained, the structure of which is:

[0171]

[0172] Example 35 (Continuous hydroxyl protection reaction and continuous acylation reaction in series)

[0173] In the above-mentioned continuous synthesis device, the continuous hydroxyl protection reaction is connected in series with the continuous acylation reaction, the connecting pipe is a PTFE pipe, and the feed pumps are all horizontal flow pumps.

[0174] Take 9.68g of β-thymidine (compound 1, 1 equivalent) and 9.49g of pyridine (3 equivalents), add N,N-dimethylformamide to it, and adjust the volume to 100mL, which is used as feed liquid A. Take 22.30g of triphenylmethane (2 equivalents) and 9.49g of pyridine (3 equivalents), add N,N-dimethylformamide to it, and adjust the volume to 100mL, which is used as feed liquid B. Feed liquid A and feed liquid B are transported into the first microreactor I by the first horizontal flow pump P1 and the second horizontal flow pump P2 through the first micro mixer M1, with a flow rate of 0.0825mL / min, a residence time of 45min, and a microreactor temperature of 100°C, and a continuous hydroxyl protection reaction is carried out to obtain reaction liquid G. Take 20.16g of trifluoromethanesulfonyl chloride (3 equivalents), add N,N-dimethylformamide to it, and adjust the volume to 25mL, which is used as feed liquid C. The outlet of the first microreactor I was connected to the second micromixer M2, and the other end was connected to the third advection pump P3, and the feed liquid C was transported into the second microreactor II by the third advection pump P3, the flow rate of the third advection pump P3 was 0.041 mL / min, the residence time was 10.7 min, the temperature of the microreactor was 120° C., and a continuous acylation reaction was performed to obtain a reaction liquid H. HPLC detection showed that the yield of the mesylate intermediate was 96.3%.

[0175] Example 36 (Continuous hydroxyl protection reaction, continuous acylation reaction and continuous cyclization reaction in series)

[0176] In the above-mentioned continuous synthesis device, the continuous hydroxyl protection reaction, the continuous acylation reaction and the continuous cyclization reaction are connected in series, the connecting pipe is a PTFE pipe, and the feed pumps are all horizontal flow pumps.

[0177] Take 9.68g of β-thymidine (compound 1, 1 equivalent) and 9.49g of pyridine (3 equivalents), add N,N-dimethylformamide to it, and adjust the volume to 100mL, which is used as feed liquid A. Take 22.30g of triphenylmethane (2 equivalents) and 9.49g of pyridine (3 equivalents), add N,N-dimethylformamide to it, and adjust the volume to 100mL, which is used as feed liquid B. Feed liquid A and feed liquid B are transported into the first microreactor I by the first horizontal flow pump P1 and the second horizontal flow pump P2 through the first micro mixer M1, with a flow rate of 0.0825mL / min, a residence time of 45min, and a microreactor temperature of 100°C, and a continuous hydroxyl protection reaction is carried out to obtain reaction liquid G. Take 20.16g of trifluoromethanesulfonyl chloride (3 equivalents), add N,N-dimethylformamide to it, and adjust the volume to 25mL, which is used as feed liquid C. The outlet of the first microreactor I is connected to the second micromixer M2, and the other end is connected to the third advection pump P3. The feed liquid C is transported into the second microreactor II by the third advection pump P3. The flow rate of the third advection pump P3 is 0.041 mL / min, the residence time is 10.7 min, and the temperature of the microreactor is 120 ° C. A continuous acylation reaction is performed to obtain a reaction liquid H. 20 mL of a 15 mol / L sodium hydroxide aqueous solution is configured as a feed liquid D for standby. The outlet of the second microreactor II is connected to the third micromixer M3, and the other end is connected to the fourth advection pump P4. The feed liquid D is transported into the third microreactor III by the fourth advection P4. The flow rate of the fourth advection pump P4 is 0.013 mL / min, and the residence time is 24.7 min. The third microreactor III is placed in ultrasound at a temperature of 65 ° C. A continuous cyclization reaction is performed to obtain a reaction liquid I. HPLC detection shows that the yield of the cyclized intermediate is 82.0%.

[0178] Example 37 (Continuous azidation reaction and continuous deprotection reaction in series)

[0179] In the above-mentioned continuous synthesis device, the continuous azidation reaction is connected in series with the continuous deprotection reaction, the connecting pipe is a PTFE pipe, and the feed pumps are all horizontal flow pumps.

[0180] Take 23.3 g (1 equivalent) of the cyclized intermediate and 4.875 g (1.5 equivalents) of sodium azide, add 100 mL of dimethyl sulfoxide, dissolve at high temperature, and use as feed liquid E. Feed liquid E is transported into the fourth microreactor IV by the fifth horizontal flow pump P5, the flow rate of the fifth horizontal flow pump P5 is 0.11 mL / min, the residence time is 10 min, the temperature of the microreactor is 180°C, and a continuous azidation reaction is carried out to obtain reaction liquid J. Take p-toluenesulfonic acid (19.78 g, 2.5 equivalents), add 100 mL of dimethyl sulfoxide, and use as feed liquid F. The outlet of the fourth microreactor IV was connected to the fourth micromixer M4, and the other end was connected to the sixth advection pump P6, and the feed liquid F was transported into the fifth microreactor V by the sixth advection pump P6, the flow rate of the sixth advection pump P6 was 0.11 mL / min, the residence time was 18.3 min, the temperature of the microreactor was 120° C., and a continuous deprotection reaction was performed to obtain a reaction liquid K. According to HPLC detection, the yield of zidovudine was 84.4%.

[0181] Example 38 (Continuous hydroxyl protection reaction, continuous acylation reaction, continuous cyclization reaction, continuous azidation reaction and continuous deprotection reaction in series)

[0182] In the above-mentioned continuous synthesis device, the continuous hydroxyl protection reaction, the continuous acylation reaction, the continuous cyclization reaction, the continuous azidation reaction and the continuous deprotection are all connected in series, the connecting pipe is a PTFE pipe, the feed pumps are all horizontal flow pumps, and the continuous synthesis device is as follows: Figure 1 described.

[0183] Take 9.68g of β-thymidine (compound 1, 1 equivalent) and 9.49g of pyridine (3 equivalents), add N,N-dimethylformamide to it, and adjust the volume to 100mL, which is used as feed liquid A. Take 22.30g of triphenylmethane (2 equivalents) and 9.49g of pyridine (3 equivalents), add N,N-dimethylformamide to it, and adjust the volume to 100mL, which is used as feed liquid B. Feed liquid A and feed liquid B are transported into the first microreactor I by the first horizontal flow pump P1 and the second horizontal flow pump P2 through the first micro mixer M1, with a flow rate of 0.0825mL / min, a residence time of 45min, and a microreactor temperature of 100°C, and a continuous hydroxyl protection reaction is carried out to obtain reaction liquid G. Take 20.16g of trifluoromethanesulfonyl chloride (3 equivalents), add N,N-dimethylformamide to it, and adjust the volume to 25mL, which is used as feed liquid C. The outlet of the first microreactor I is connected to the second micromixer M2, and the other end is connected to the third horizontal flow pump P3. The feed liquid C is transported into the second microreactor II by the third horizontal flow pump P3. The flow rate of the third horizontal flow pump P3 is 0.041 mL / min, the residence time is 10.7 min, and the temperature of the microreactor is 120 ° C. A continuous acylation reaction is performed to obtain a reaction liquid H. 20 mL of a 15 mol / L sodium hydroxide aqueous solution is configured as a feed liquid D for standby. The outlet of the second microreactor II is connected to the third micromixer M3, and the other end is connected to the fourth horizontal flow pump P4. The feed liquid D is transported into the third microreactor III by the fourth horizontal flow P4. The flow rate of the fourth horizontal flow pump P4 is 0.013 mL / min, and the residence time is 24.7 min. The third microreactor III is placed in ultrasound at a temperature of 65 ° C. A continuous cyclization reaction is performed to obtain a reaction liquid I. The obtained cyclization reaction liquid was passed through a continuous filtration and dissolution two-in-one device to obtain a cyclization intermediate; 2.33 g (1 equivalent) of the cyclization intermediate and 0.4875 g (1.5 equivalents) of sodium azide were taken, 10 mL of dimethyl sulfoxide was added thereto, dissolved at high temperature, and used as feed liquid E. Feed liquid E was transported into the fourth microreactor IV by the fifth horizontal flow pump P5, the flow rate of the fifth horizontal flow pump P5 was 0.11 mL / min, the residence time was 10 min, the temperature of the microreactor was 180°C, and a continuous azidation reaction was carried out to obtain reaction liquid J. p-Toluenesulfonic acid (1.978 g, 2.5 equivalents) was taken, 10 mL of dimethyl sulfoxide was added thereto, and used as feed liquid F. The outlet of the fourth microreactor IV is connected to the fourth micromixer M4, and the other end is connected to the sixth advection pump P6, and the feed liquid F is transported into the fifth microreactor V by the sixth advection pump P6, the flow rate of the sixth advection pump P6 is 0.11mL / min, the residence time is 18.3min, the temperature of the microreactor is 120°C, and a continuous deprotection reaction is performed to obtain a reaction liquid K. According to HPLC detection, the yield of zidovudine is 69.2%. The obtained reaction liquid is concentrated, dissolved in water, filtered to remove impurities, and purified by cooling crystallization to obtain a crude zidovudine product.

Claims

1. A continuous flow synthesis method of zidovudine, characterized in that: The method comprises the steps of: S1: dissolving β-thymidine and triphenylmethane in a first organic solvent respectively to obtain a feed liquid A and a feed liquid B, mixing the feed liquid A and the feed liquid B in a first micromixer and then continuously pumping them into a first microreactor to perform a hydroxyl protection reaction to obtain a hydroxyl protected intermediate; S2: dissolving the hydroxyl protected intermediate and trifluoromethanesulfonyl chloride in a second organic solvent to obtain feed liquid G and feed liquid C respectively, mixing the feed liquid G and feed liquid C in a second micro mixer and then continuously pumping them into a second microreactor to perform an acylation reaction to obtain a mesylate intermediate; S3: dissolving the mesylate intermediate and sodium hydroxide in a second organic solvent and a third organic solvent respectively to obtain a feed liquid H and a feed liquid D, mixing the feed liquid H and the feed liquid D in a third micromixer and then continuously pumping them into a third microreactor to perform a cyclization reaction to obtain a cyclized intermediate; S4: dissolving the cyclized intermediate and sodium azide in a fourth organic solvent to obtain a feed solution E, and continuously pumping the feed solution E into a fourth microreactor to perform an azidation reaction to obtain an azidation product; S5: dissolving the azidation product and p-toluenesulfonic acid in a fifth organic solvent to obtain a feed liquid J and a feed liquid F, respectively; mixing the feed liquid J and the feed liquid F in a fourth micromixer and then continuously pumping them into a fifth microreactor to perform a deprotection reaction to obtain zidovudine; Among them, the structural formulas of β-thymidine, hydroxyl protected intermediate, mesylate intermediate, cyclization intermediate, azidation product and zidovudine are:

2. The continuous flow synthesis method according to claim 1, characterized in that: Step S1 has one or more of the following features: The first organic solvent is selected from one or more of N,N-dimethylformamide, dimethyl sulfoxide and pyridine; preferably, the first organic solvent is pyridine or a mixed solvent of pyridine and N,N-dimethylformamide; The concentration of β-thymidine in the feed solution A is 0.1-0.75 mol / L, preferably 0.4-0.75 mol / L; The concentration of triphenylmethane in the feed liquid B is 0.15-1.5 mol / L, preferably 0.6-1.5 mol / L; The molar ratio of β-thymidine to triphenylmethane is 1:(1-3), preferably 1:(1.5-2); The reaction temperature is 30-120°C, preferably 100-120°C; The residence time is 15-120 min, preferably 30-60 min; The flow rate of the feed liquid A is 0.031-0.247 mL / min, preferably 0.062-0.123 mL / min; The flow rate of the feed liquid B is 0.031-0.247 mL / min, preferably 0.062-0.123 mL / min.

3. The continuous flow synthesis method according to claim 1, characterized in that: Step S2 has one or more of the following features: The second organic solvent is selected from one or more of N,N-dimethylformamide, dimethyl sulfoxide and pyridine, preferably N,N-dimethylformamide; In the feed liquid G, the concentration of the hydroxyl protected intermediate is 0.01-0.45 mol / L, preferably 0.3-0.45 mol / L; In the feed liquid C, the concentration of trifluoromethanesulfonyl chloride is 0.12-5.4 mol / L, preferably 3.6-5.4 mol / L; The molar ratio of the hydroxyl protected intermediate to trifluoromethanesulfonyl chloride is 1:(1-5), preferably 1:(2-3); A base is also added to the feed liquid G and / or the feed liquid C, and the base is selected from one or more of triethylamine, pyridine, N,N-diisopropylethylamine, 4-dimethylaminopyridine, triethanolamine, tetrabutylammonium bromide, potassium carbonate, ammonium carbonate and sodium carbonate; preferably, the molar ratio of the hydroxyl protected intermediate to the base is 1:(1-5), preferably 1:(2-3); The reaction temperature is 20-130°C, preferably 27-130°C; The residence time is 1-60 min, preferably 5-30 min; The flow rate of the feed liquid G is 0.029-1.76 mL / min; preferably 0.059-0.352 mL / min; The flow rate of the feed liquid C is 0.007-0.44 mL / min; preferably 0.015-0.088 mL / min.

4. The continuous flow synthesis method according to claim 1, characterized in that: Step S3 has one or more of the following features: The third organic solvent is selected from one or more of water, methanol, N,N-dimethylformamide, dimethyl sulfoxide and pyridine, preferably water; In the feed liquid H, the concentration of the mesylate intermediate is 0.01-0.45 mol / L, preferably 0.3-0.45 mol / L; The concentration of sodium hydroxide in the feed liquid D is 1-20 mol / L, preferably 10-15 mol / L; The molar ratio of sodium hydroxide to the mesylate intermediate is 1:(1-5), preferably 1:(1-3); The reaction temperature is 30-100°C, preferably 50-65°C; The residence time is 1-30 min, preferably 15-30 min; The cyclization reaction solution obtained after the reaction in step S3 is passed into water, and filtered to obtain a cyclization intermediate; The flow rate of the feed liquid H is 0.169-5.063 mL / min, preferably 0.169-0.338 mL / min; The flow rate of the feed liquid D is 0.011-0.338 mL / min, preferably 0.011-0.022 mL / min.

5. The continuous flow synthesis method according to claim 1, characterized in that: Step S4 has one or more of the following features: The fourth organic solvent is selected from one or more of N,N-dimethylformamide, dimethyl sulfoxide, water, methanol, acetonitrile, tetrahydrofuran, toluene and 1,4-dioxane, preferably dimethyl sulfoxide; In the feed liquid E, the concentration of the cyclized intermediate is 0.1-0.5 mol / L, preferably 0.2-0.5 mol / L; The molar ratio of the cyclized intermediate to sodium azide is 1:(1-3), preferably 1:(1.5-2); The reaction temperature is 100-180°C, preferably 140-180°C; The residence time is 1-45 min, preferably 10-30 min; The flow rate of the feed liquid E is 0.024-1.1 mL / min, preferably 0.037-0.11 mL / min.

6. The continuous flow synthesis method according to claim 1, characterized in that: Step S5 has one or more of the following features: The fifth organic solvent is selected from one or more of N,N-dimethylformamide, dimethyl sulfoxide, water, methanol, acetonitrile, tetrahydrofuran, toluene and 1,4-dioxane, preferably dimethyl sulfoxide; In the feed solution J, the concentration of the azidation product is 0.1-0.5 mol / L, preferably 0.2-0.5 mol / L; The concentration of p-toluenesulfonic acid in the feed liquid F is 0.1-0.5 mol / L, preferably 0.3-0.5 mol / L; The molar ratio of the azidation product to p-toluenesulfonic acid is 1:(0.25-2), preferably 1:(1-1.25); The reaction temperature is 60-120°C, preferably 90-120°C; The residence time is 1-30 min, preferably 5-15 min; The flow rate of the feed liquid J is 0.067-2.0 mL / min, preferably 0.133-0.4 mL / min; The flow rate of the feed liquid F is 0.067-2.0 mL / min, preferably 0.133-0.4 mL / min.

7. The method according to any one of claims 1 to 6, characterized in that In the method, any two adjacent steps, any three adjacent steps, any four adjacent steps or all five steps of steps S1, S2, S3, S4 and S5 are connected in series.

8. The continuous flow synthesis method according to claim 7, characterized in that: S12 is used to replace S1 and S2, and S12 comprises: connecting S1 and S2 in series; mixing the feed liquid A and the feed liquid B through a first micromixer and then continuously pumping them into a first microreactor to perform a hydroxyl protection reaction to obtain a reaction liquid G; mixing the reaction liquid G and the feed liquid C through a second micromixer and then continuously pumping them into a second microreactor to perform an acylation reaction to obtain a mesylate intermediate; or S23 is used to replace S2 and S3, and S23 comprises: connecting S2 and S3 in series; mixing the feed liquid G and the feed liquid C in a second micro mixer and then continuously pumping them into a second micro reactor to perform an acylation reaction to obtain a reaction liquid H; mixing the reaction liquid H and the feed liquid D in a third micro mixer and then continuously pumping them into a third micro reactor to perform a cyclization reaction to obtain a cyclization intermediate; or S34 is used to replace the S3 and S4, and S34 comprises: connecting S3 and S4 in series; mixing the feed liquid H and the feed liquid D in a third micro-mixer and then continuously pumping them into a third micro-reactor to perform a cyclization reaction to obtain a reaction liquid I; passing the reaction liquid I into a continuous filtration and dissolution two-in-one device to separate the cyclization intermediate; dissolving the cyclization intermediate and sodium azide in a fourth organic solvent to obtain a feed liquid E; continuously pumping the feed liquid E into a fourth micro-reactor to perform an azidation reaction to obtain an azidation product; or S45 is used to replace S4 and S5, and S45 comprises: connecting S4 and S5 in series; continuously pumping the feed liquid E into the fourth microreactor to perform an azidation reaction to obtain a reaction liquid J; mixing the reaction liquid J and the feed liquid F in the fourth micromixer and continuously pumping them into the fifth microreactor to perform a deprotection reaction to obtain a crude zidovudine product; or S123 is used to replace the S1, S2 and S3, and S123 comprises: connecting S1, S2 and S3 in series; mixing the feed liquid A and the feed liquid B through a first micromixer and then continuously pumping them into a first microreactor to perform a hydroxyl protection reaction to obtain a reaction liquid G; mixing the reaction liquid G and the feed liquid C through a second micromixer and then continuously pumping them into a second microreactor to perform an acylation reaction to obtain a reaction liquid H; mixing the reaction liquid H and the feed liquid D through a third micromixer and then continuously pumping them into a third microreactor to perform a cyclization reaction to obtain a cyclization intermediate; Preferably, the continuous flow synthesis method comprises module one and module two, wherein module one comprises S123, module two comprises S45, and module one and module two are connected via a continuous filtration and dissolution two-in-one device.

9. A continuous flow synthesis device for implementing the continuous flow synthesis method according to any one of claims 1 to 8, characterized in that: The continuous flow synthesis device comprises a first micro mixer, a first micro reactor, a second micro mixer, a second micro reactor, a third micro mixer, a third micro reactor, a continuous filtration and dissolution two-in-one device, a fourth micro reactor, a fourth micro mixer, and a fifth micro reactor which are sequentially connected through pipelines; The continuous flow synthesis device also includes a first feed pump and a second feed pump for feeding the first micromixer, a third feed pump for feeding the second micromixer, a fourth feed pump for feeding the third micromixer, a fifth feed pump for feeding the fourth microreactor, and a sixth feed pump for feeding the fourth micromixer.

10. The continuous flow synthesis device according to claim 9, characterized in that: The continuous flow synthesis device has one or more of the following features: The first microreactor, the second microreactor, the third microreactor, the fourth microreactor and the fifth microreactor are each independently a capillary microreactor or a glass chip microreactor; The first micro mixer, the second micro mixer, the third micro mixer and the fourth micro mixer are all T-type three-way mixers; The first feed pump, the second feed pump, the third feed pump, the fourth feed pump, the fifth feed pump and the sixth feed pump are each independently a syringe pump or a horizontal flow pump.

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