A method for the on-line synthesis of vitamin b4 acylated derivatives in a continuous flow reactor

Abstract

The application provides a method for synthesizing vitamin B4 acylated derivatives in a continuous flow reactor, vitamin B4 and fatty acid vinyl ester are used to synthesize vitamin B4 acylated derivatives in a microfluidic channel reactor by catalysis of lipase Lipozyme RM IM. The method not only greatly shortens the reaction time, but also has high conversion rate; meanwhile, the acylation reaction of vitamin B4 and fatty acid vinyl ester is catalyzed by economical lipase Lipozyme RM IM for the first time, the reaction cost is reduced, and the method has the advantages of economy and efficiency.

Description

Technical Field

[0001] This invention relates to a method for the online synthesis of vitamin B4 acylated derivatives in a continuous flow reactor. Background Technology

[0002] Vitamin B4, also known as adenine, is one of the five major bases of DNA and RNA, present in the nucleic acids of organisms. It is also an important component of adenosine triphosphate (ATP), coenzyme nicotinamide adenine dinucleotide (NAD), and flavin adenine dinucleotide (FAD). In recent years, vitamin B4 and its derivatives have been extensively studied, showing promising antibacterial, anti-HIV, and anticancer activities. The synthesis of vitamin B4 derivatives has become a focus of attention for medicinal chemists. However, the unique physicochemical properties of vitamin B4 hinder its preparation. First, the low solubility of vitamin B4 makes the reaction difficult to occur; second, the existence of isomers of vitamin B4 reduces the selectivity of the reaction due to multiple reaction sites. Therefore, developing a green, efficient, and highly selective method for synthesizing vitamin B4 derivatives has become a research hotspot in the field of medicinal chemistry.

[0003] Enzyme-catalyzed reactions have become a key focus of green chemistry research due to their high efficiency, green nature, and high specificity. Enzyme-catalyzed reactions have been widely applied in industrial biosynthesis, healthcare, and food industries due to their mild reaction conditions, high selectivity, and good product stability. However, enzyme-catalyzed reactions are limited by factors such as solvent solubility of substrates and solvent polarity inhibiting enzyme activity, often resulting in long reaction times (24h–96h) and relatively low conversion rates for specific substrates. Therefore, developing a novel microfluidic-based enzyme-catalyzed synthesis technology for vitamin B6 lipids, building upon traditional enzyme-catalyzed reactions, has become our research objective.

[0004] Compared to conventional chemical reactors, microfluidic reactors offer advantages such as high mixing efficiency, rapid mass and heat transfer, precise parameter control, high reaction selectivity, and good safety, leading to their widespread application in organic synthesis reactions. In continuous flow microreactors, many reactions can be rapidly screened under minute-scale conditions, allowing for safe reactions even under harsh experimental conditions. This significantly saves reaction materials, improves screening efficiency, and aligns more closely with the concept of green chemistry.

[0005] To develop a novel, efficient, and environmentally friendly technique for the synthesis of vitamin B4 acylated derivatives, we investigated a method for the online synthesis of vitamin B4 acylated derivatives using lipase catalysis in a continuous flow microreactor. Our aim was to find a new, highly efficient, and environmentally friendly method for synthesizing vitamin B4 acylated derivatives. Summary of the Invention

[0006] The present invention aims to provide a novel process for the online synthesis of vitamin B4 acylated derivatives in a microfluidic channel reactor, which has the advantages of short reaction time and high yield.

[0007] The technical solution of the present invention is as follows:

[0008] A method for online synthesis of vitamin B4 acylated derivatives, the method comprising:

[0009] The method employs a microfluidic channel reactor, which includes a syringe, a reaction channel, and a product collector connected in sequence. The syringe is installed in an injection pump and is connected to the inlet of the reaction channel via a first connecting pipe. The product collector is connected to the outlet of the reaction channel via a second connecting pipe. The inner diameter of the reaction channel is 1.6-2.2 mm (preferably 2.0 mm), and the length of the reaction channel is 0.8-1.2 m (preferably 1.0 m).

[0010] The method includes: constructing a reaction system using DMSO as a reaction solvent, vitamin B4 of formula (I) and ethylene fatty acid ester of formula (II) as raw materials, and lipase Lipozyme RM IM as a catalyst; placing the raw materials and the reaction solvent in a syringe, uniformly filling the reaction channel of the microfluidic channel reactor with lipase Lipozyme RM IM, and continuously feeding the raw materials and the reaction solvent into the reaction channel under the synchronous push of the injection pump to carry out the acylation reaction, controlling the reaction temperature at 30-55℃ (preferably 45℃), and the reaction time for the reaction liquid to flow continuously in the reaction channel is 10-60 min (preferably 50 min), collecting the reaction liquid flowing out of the reaction channel online through a product collector, and post-processing the reaction liquid to obtain the vitamin B4 acylated derivative of formula (III);

[0011]

[0012] In equations (II) and (III), R is CH3 or (CH2)4COOC2H3 or C 11 H 23 Or C 15 H 31 (Preferred: (CH2)4COOC2H3);

[0013] The molar ratio of vitamin B4 shown in formula (I) to ethylene ester of fatty acid shown in formula (II) is 1:0.5 to 4 (particularly preferred 1:3); within the maximum extent that the reaction channel can accommodate the filled catalyst, the amount of catalyst added is 0.030 g / mL to 0.060 g / mL (preferably 0.043 g / mL) based on the volume of the reaction solvent; in the reaction system, the concentration of vitamin B4 shown in formula (I) is 0.1 mmol / mL to 0.4 mmol / mL (preferably 0.25 mmol / mL).

[0014] The lipase Lipozyme RM IM used is a commercial product manufactured by Novozymes. It is a food-grade lipase (EC 3.1.1.3) prepared by microorganisms, specifically for positions 1 and 3, on granular silica gel. It is produced by deep fermentation of a genetically modified Aspergillus oryzae microorganism obtained from Rhizomucor miehei. The lipase Lipozyme RM IM can be obtained by directly and uniformly immobilizing the granular catalyst in the reaction channel using a physical method. Within the maximum capacity of the reaction channel to accommodate the filled catalyst, the amount of catalyst added is 0.043 g / mL based on the volume of the reaction medium.

[0015] Furthermore, in the microfluidic channel reactor used in this invention, the number of syringes can be one or more, depending on the specific reaction requirements. This invention uses two reaction materials, preferably two syringes. Specifically, the syringes are a first syringe and a second syringe. The first connecting pipe is a Y-shaped or T-shaped pipe. The first syringe and the second syringe are respectively connected to the two ports of the Y-shaped or T-shaped pipe and connected in series with the reaction channel through the Y-shaped or T-shaped pipe. The increased probability of contact and collision between reactant molecules in the microchannel allows the two reaction streams to mix and react in the common reaction channel. That is, the microfluidic channel reactor of this invention includes a first syringe, a second syringe, a reaction channel, and a product collector; the first syringe and the second syringe are connected to the inlet of the reaction channel via Y-shaped or T-shaped pipes, and the product collector is connected to the outlet of the reaction channel via a pipe.

[0016] Furthermore, the vitamin B4 shown in formula (I) and the ethylene fatty acid ester shown in formula (II) are each dissolved in DMSO to obtain a vitamin B4 solution and a ethylene fatty acid ester solution, which are then introduced into the reaction channel through the first syringe and the second syringe, respectively. In the vitamin B4 solution, the concentration of vitamin B4 shown in formula (I) is 0.2 mmol / mL to 0.8 mmol / mL (preferably 0.5 mmol / mL), and in the ethylene fatty acid ester solution, the concentration of ethylene fatty acid ester shown in formula (II) is 0.25 to 2 mmol / mL (preferably 1.5 mmol / mL).

[0017] Furthermore, this invention recommends a method for online synthesis of vitamin B4 acylated derivatives. The method employs a microfluidic channel reactor, which includes a syringe, a reaction channel, and a product collector connected in sequence. The syringe is installed in an injection pump and is connected to the inlet of the reaction channel via a first connecting pipe. The product collector is connected to the outlet of the reaction channel via a second connecting pipe. The inner diameter of the reaction channel is 1.6–2.2 mm (preferably 2.0 mm), and the length of the reaction channel is 0.8–1.2 m (preferably 1.0 m). The syringes are a first syringe and a second syringe. The first connecting pipe is a Y-type or T-type pipe. The first syringe and the second syringe are respectively connected to two ports of the Y-type or T-type pipe and connected in series with the reaction channel via the Y-type or T-type pipe.

[0018] The method is as follows: Vitamin B4 of Formula (I) and ethylene fatty acid ester of Formula (II) are dissolved in DMSO to obtain a vitamin B4 solution of Formula (I) with a concentration of 0.2 mmol / mL to 0.8 mmol / mL (preferably 0.5 mmol / mL) and a ethylene fatty acid ester solution of Formula (II) with a concentration of 0.25 to 2 mmol / mL (preferably 1.5 mmol / mL); the vitamin B4 solution of Formula (I) and the ethylene fatty acid ester solution of Formula (II) are respectively loaded into the first syringe and the second syringe, and the first syringe and the second syringe are loaded into the same injection pump; lipase Lipozyme RM is then added. After IM is uniformly filled into the reaction channel of the microfluidic channel reactor, the vitamin B4 solution shown in formula (I) and the fatty acid ethylene ester solution shown in formula (II) are continuously and synchronously introduced into the reaction channel under the synchronous push of the injection pump to carry out the Michael addition reaction. The reaction temperature is controlled at 30-55°C (preferably 45°C), and the reaction time in which the reaction solution flows continuously in the reaction channel is 10-60 min (preferably 50 min). The reaction solution flowing out of the reaction channel is collected online by a product collector. The reaction solution is post-processed to obtain the vitamin B4 acylated derivative shown in formula (III). The concentration ratio of the vitamin B4 solution shown in formula (I) to the fatty acid ethylene ester solution shown in formula (II) is 1:0.5-4 (particularly preferred 1:3). Within the maximum limit that the reaction channel can accommodate the filled catalyst, the amount of catalyst added is 0.03 g / mL to 0.06 g / mL (preferably 0.043 g / mL) based on the volume of the reaction solvent.

[0019] Further, the post-processing is as follows: after removing the solvent from the reaction solution under reduced pressure, silica gel column chromatography is performed using a mixed solution of ethyl acetate and petroleum ether in a volume ratio of 2:3 as the eluent, the eluent containing the target compound is collected, evaporated to dryness, and the vitamin B4 acylated derivative shown in formula (III) is obtained.

[0020] Specifically, the post-processing method is as follows: the reaction solution is removed by vacuum distillation to remove the solvent, and silica gel column chromatography is performed. The column is packed with 200-300 mesh silica gel by wet packing. The elution reagent is a mixture of ethyl acetate and petroleum ether = 2:3. The elution process is tracked by TLC. The eluent containing the target compound is collected, the solvent is removed by evaporation and dried to obtain the product vitamin B4 acylated derivative (III).

[0021] The method of the present invention employs a microfluidic channel reactor, which includes: a first syringe, a second syringe, a reaction channel, and a product collector; the first syringe and the second syringe are connected to the inlet of the reaction channel via Y-shaped or T-shaped pipes, and the product collector is connected to the outlet of the reaction channel via a pipe;

[0022] The first syringe and the second syringe are installed in the injection pump and are synchronously driven by the injection pump;

[0023] The reaction channel has an inner diameter of 2.0 mm and a length of 1.0 m. The material of the reaction channel is not limited, but green and environmentally friendly materials, such as silicone tubes, are recommended. The shape of the reaction channel is preferably curved to ensure that the reaction liquid flows through at a uniform and stable speed.

[0024] The microfluidic channel reactor may also include a constant temperature chamber, in which the reaction channel is placed to effectively control the reaction temperature. The constant temperature chamber can be selected according to the reaction temperature requirements, such as a water bath constant temperature chamber.

[0025] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0026] This invention enables the online synthesis of vitamin B4 acylated derivatives in a microfluidic channel reactor. This method not only significantly shortens the reaction time but also achieves a high conversion rate. Furthermore, it is the first to utilize the economical lipase Lipozyme RM IM to catalyze the acylation reaction of vitamin B4 with ethylene fatty acids, thereby reducing reaction costs and demonstrating economic and high efficiency. Attached Figure Description

[0027] Figure 1 This is a schematic diagram of the microfluidic channel reactor used in an embodiment of the present invention.

[0028] In the diagram, 1-first syringe, 2-second syringe, 3-reaction channel, 4-product collector, 5-water bath thermostat. Detailed Implementation

[0029] The present invention will be further described below with reference to specific embodiments, but the scope of protection of the present invention is not limited thereto:

[0030] Structural reference of the microfluidic channel reactor used in the embodiments of the present invention Figure 1 The system includes a syringe pump (not shown), two syringes 1 and 2, a reaction channel 3, a water bath thermostat (5, only its plan view is shown), and a product collector 4. The two syringes 1 and 2 are installed in the syringe pump and connected to the inlet of the reaction channel 3 through a Y-type interface. The reaction channel 3 is placed in the water bath thermostat 5, and the reaction temperature is controlled by the water bath thermostat 5. The inner diameter of the reaction channel 3 is 2.0 mm, and the tube length is 1.0 m. The outlet of the reaction channel 3 is connected to the product collector 4 through an interface.

[0031] Example 1: Synthesis of vinyl 6-((9H-purin-6-yl)amino)-6-oxohexanoate

[0032]

[0033] Device Reference Figure 1 Vitamin B4 (5.0 mmol, 0.675 g) and diethylene adipate (15.0 mmol, 2.970 g) were dissolved in 10 mL of DMSO, and then each was placed into a 10 mL syringe for later use. 0.87 g of Lipozyme RM IM was uniformly filled into the reaction channel. Using a PHD 2000 syringe pump, the two reaction solutions were dispensed at a rate of 6.3 μL / min. -1 The flow rate is introduced into the reaction channel through the "Y" connector to carry out the reaction. The reactor temperature is controlled at 45℃ by a water bath constant temperature box. The reaction solution flows continuously in the reaction channel for 50 minutes. The reaction results are tracked and detected by thin-layer chromatography (TLC).

[0034] The reaction solution was collected online using a product collector. The solvent was removed by vacuum distillation. The solution was then packed into a column using a wet method with 200-300 mesh silica gel. The eluent was ethyl acetate:petroleum ether (v / v) = 2:3. The column height was 35 cm and the column diameter was 4.5 cm. The sample was dissolved in a small amount of the eluent and then loaded onto the column using a wet method. The eluent was collected at a flow rate of 2 mL / min. -1 Meanwhile, TLC was used to track the elution process, and the eluents containing a single product were combined and evaporated to dryness to obtain a white solid, yielding 1.185 g of vitamin B6 acylated derivative with a separation yield of 82%.

[0035] The NMR characterization results are as follows:

[0036] White powder, yield 82%. 1 H NMR(500MHz,DMSO-d6)δ11.95(s,1H),8.61(s,1H),8.28(s,1H),7.50(s,1H),7.25(t,J=10.3Hz,1H),4 .89(dd,J=14.0,1.6Hz,1H),4.65(dd,J=6.3,1.6Hz,1H),2.45(m,2H),2.36(m,2H),1.57–1.50(m,4H).; 13 C NMR (126MHz, DMSO) δ171.01,170.25,156.35,153.83,148.60,141.24,138.39,119.56,98.02,35.98,32.76,23.80,23.33.

[0037] Examples 2-4

[0038] The solvent in the microfluidic microchannel reactor was changed, and the temperature was controlled at 45°C. Other aspects were the same as in Example 1. The results are shown in Table 1.

[0039] Table 1 Effect of solvent on reaction

[0040] Example solvent Conversion rate [%) Production [g] 1 DMSO 82 1.184 2 tert-amyl alcohol <5 0.029 3 DMF 52 0.751 4 methanol <5 0.058

[0041] The results in Table 1 show that when the molar ratio of vitamin B4 to diethylene adipate is 1:3 and the flow rate is 12.6 μL·min, the optimal concentration of vitamin B4 and diethylene adipate is achieved. -1 The reaction time was 50 min and the reaction temperature was 45 °C. The conversion rate was optimal when DMSO was used as the organic solvent. Therefore, DMSO is the optimal solvent in the microfluidic microchannel reactor of this invention.

[0042] Examples 5-9

[0043] The temperature of the microfluidic channel reactor was changed, and other aspects remained the same as in Example 1. The reaction results are shown in Table 2.

[0044] Table 2: Effect of temperature on the reaction

[0045] Example Temperature [°C] Conversion rate [%) Production [g] 5 30 45 0.651 6 35 53 0.766 7 40 66 0.954 1 45 82 1.185 8 50 68 0.983 9 55 51 0.737

[0046] The results in Table 2 show that when the flow rate is 12.6 μL·min -1 The reaction time was 50 min for all reactions, with DMSO as the organic solvent and a molar ratio of vitamin B4 to diethylene adipate of 1:3. The conversion rate was optimal at a reaction temperature of 45°C; temperatures that were too high or too low would affect enzyme activity. Therefore, the optimal temperature in the microfluidic microchannel reactor of this invention was 45°C.

[0047] Examples 10-13

[0048] Using vitamin B4 dosage as a baseline, the molar ratio of vitamin B4 to diethylene adipate in the microfluidic microchannel reactor was varied, and the temperature was controlled at 30°C. Other parameters were the same as in Example 1. The results are shown in Table 3.

[0049] Table 3 Effect of substrate molar ratio on the reaction

[0050] Example Vitamin B4 and diethylene adipate Conversion rate [%) Production [g] 10 1:0.5(5.0mmol:2.5mmol,0.675g:0.495g) 36 0.520 11 1:1(5.0mmol:5.0mmol,0.675g:0.990g) 58 0.838 12 1:2(5.0mmol:10.0mmol,0.675g:1.980g) 65 0.939 1 1:3(5.0mmol:15.0mmol,0.675g:2.970g) 82 1.185 13 1:4(5.0mmol:20.0mmol,0.675g:3.960g) 71 1.026

[0051] The results in Table 3 show that when the flow rate is 12.6 μL·min -1 The reaction time was 50 min and the reaction temperature was 45 °C. DMSO was used as the organic solvent. As the reactant diethylene adipate increased, the conversion rate also increased. The conversion rate was optimal when the substrate-to-vitamin B4-to-diethylene adipate ratio was 1:3. Therefore, the optimal substrate-to-substrate ratio in the microfluidic microchannel reactor of this invention is 1:3.

[0052] Examples 14-18

[0053] The reaction time of the microfluidic channel reactor was changed, while other aspects remained the same as in Example 1. The reaction results are shown in Table 4.

[0054] Table 4. Effect of reaction time on the reaction

[0055] Example Time [min] Conversion rate [%) Production [g] 14 10 31 0.448 15 20 47 0.679 16 30 69 0.997 17 40 75 1.083 1 50 82 1.185 18 60 77 1.113

[0056] The results in Table 4 show that when DMSO is used as the organic solvent in the reactor, the molar ratio of vitamin B4 to diethylene adipate is 1:4, the reaction temperature is 45℃, and the reaction time is 50 min, the conversion rate is 82%. Therefore, the optimal reaction time in the microfluidic microchannel reactor of this invention is 50 min.

[0057] Comparative Examples 1-3

[0058] The types of ethylene fatty acid esters in the microfluidic channel reactor were changed, with diethylene adipate replaced by vinyl acetate, vinyl laurate, and vinyl palmitate, while other aspects remained the same as in Example 1. The reaction results are shown in Table 5.

[0059] Table 6: Effect of different acrylates on reaction conversion rate

[0060] Comparative Example Ethylene esters of fatty acids Conversion rate [%) Production [g] 1 Vinyl acetate (15.0 mmol, 1.290 g) 32 0.462 2 Vinyl lauryl (15.0 mmol, 3.390 g) 15 0.217 3 Vinyl palmitate (15.0 mmol, 4.230 g) 9 0.130 Example 1 Divinyl adipate (15.0mmol, 2.970g) 82 1.185

[0061] The results showed that the structure of different fatty acid vinyl esters had a significant impact on the conversion rate of vitamin B4 lipids. In vinyl palmitate, the conversion rate of vitamin B4 was only 9%, while in divinyl adipic acid, the conversion rate of vitamin B4 reached 82%.

[0062] Comparative Examples 4-7

[0063] The catalyst in the microfluidic microchannel reactor was changed to porcine pancreatic lipase PPL, lipase Novozym435, Bacillus subtilis alkaline protease, and lipase TM IM, respectively. Other aspects were the same as in Example 1. The results are shown in Table 6.

[0064] Table 6. Effects of different enzymes on reaction conversion rate and selectivity

[0065]

[0066]

[0067] The results showed that different catalysts had a significant impact on the reaction. Using lipase™ IM to catalyze the reaction, the conversion rate of vitamin B4 was 25%. However, using Bacillus subtilis alkaline protease to catalyze the reaction, the conversion rate of vitamin B4 was less than 5%. Therefore, the optimal enzyme source in the microfluidic microchannel reactor of this invention is lipase RM IM.

Claims

1. A method for the on-line synthesis of acylated derivatives of vitamin B4 in a continuous flow reactor, characterized in that: The method employs a microfluidic channel reactor, which includes a syringe, a reaction channel, and a product collector connected in sequence. The syringe is installed in an injection pump and is connected to the inlet of the reaction channel via a first connecting pipe. The product collector is connected to the outlet of the reaction channel via a second connecting pipe. The inner diameter of the reaction channel is 1.6-2.2 mm, and the length of the reaction channel is 0.8-1.2 m. The method includes: A reaction system was constructed using DMSO as the reaction solvent, vitamin B4 as shown in formula (I) and ethylene fatty acid ester as shown in formula (II) as raw materials, and lipase Lipozyme RM IM as the catalyst. The raw materials and the reaction solvent were placed in a syringe, and lipase Lipozyme RM IM was uniformly filled into the reaction channel of a microfluidic channel reactor. Under the synchronous push of the injection pump, the raw materials and the reaction solvent were continuously introduced into the reaction channel to carry out the acylation reaction. The reaction temperature was controlled at 45°C, and the reaction time of the reaction liquid flowing continuously in the reaction channel was 50 min. The reaction liquid flowing out of the reaction channel was collected online by a product collector. The reaction liquid was post-treated to obtain the vitamin B4 acylated derivative shown in formula (III). (I) (II) (III) In equations (II) and (III), R is (CH2)4COOC2H3; The molar ratio of vitamin B4 shown in formula (I) to ethylene ester of fatty acid shown in formula (II) is 1:3; within the maximum extent that the reaction channel can accommodate the filled catalyst, the amount of catalyst added is 0.030 g / mL to 0.060 g / mL based on the volume of the reaction solvent; in the reaction system, the concentration of vitamin B4 shown in formula (I) is 0.1 mmol / mL to 0.4 mmol / mL.

2. The method for online synthesis of vitamin B4 acylated derivatives in a continuous flow reactor as described in claim 1, characterized in that: The amount of catalyst added was 0.043 g / mL based on the volume of the reaction solvent.

3. The process for the on-line synthesis of acylated derivatives of vitamin B4 in a continuous flow reactor as claimed in claim 1, characterized in that: In the reaction system, the concentration of vitamin B4 shown in formula (I) is 0.25 mmol / mL.

4. The process for the in-line synthesis of acylated derivatives of vitamin B4 in a continuous flow reactor as claimed in claim 1, wherein: The number of syringes is two.

5. The process for the in-line synthesis of acylated derivatives of vitamin B4 in a continuous flow reactor according to claim 4, characterized by the fact that: The syringes are a first syringe and a second syringe. The first connecting tube is a Y-shaped or T-shaped tube. The first syringe and the second syringe are respectively connected to two ports of the Y-shaped or T-shaped tube and connected in series with the reaction channel through the Y-shaped or T-shaped tube.

6. The process for the in-line synthesis of vitamin B4 acylated derivatives in a continuous flow reactor according to claim 5, characterized by the fact that: Vitamin B4 as shown in Formula (I) and ethylene fatty acid ester as shown in Formula (II) are each dissolved in DMSO to obtain a vitamin B4 solution and a ethylene fatty acid ester solution, which are then introduced into the reaction channel through the first syringe and the second syringe, respectively. In the vitamin B4 solution, the concentration of vitamin B4 as shown in Formula (I) is 0.2 mmol / mL to 0.8 mmol / mL, and in the ethylene fatty acid ester solution, the concentration of ethylene fatty acid ester as shown in Formula (II) is 0.25 to 2 mmol / mL.

7. The method for online synthesis of vitamin B4 acylated derivatives in a continuous flow reactor as described in claim 4, characterized in that: The method employs a microfluidic channel reactor, which includes a syringe, a reaction channel, and a product collector connected in sequence. The syringe is installed in an injection pump and is connected to the inlet of the reaction channel via a first connecting pipe. The product collector is connected to the outlet of the reaction channel via a second connecting pipe. The inner diameter of the reaction channel is 1.6~2.2mm, and the length of the reaction channel is 0.8~1.2m. The syringes are a first syringe and a second syringe. The first connecting pipe is a Y-type or T-type pipe. The first syringe and the second syringe are respectively connected to two ports of the Y-type or T-type pipe and connected in series with the reaction channel through the Y-type or T-type pipe. The method is as follows: Vitamin B4 of Formula (I) and ethylene ester of fatty acid of Formula (II) are dissolved in DMSO to obtain a vitamin B4 solution of Formula (I) with a concentration of 0.2 mmol / mL to 0.8 mmol / mL and an ethylene ester solution of Formula (II) with a concentration of 0.25 to 2 mmol / mL. The vitamin B4 solution of formula (I) and the fatty acid ethylene ester solution of formula (II) are respectively loaded into the first syringe and the second syringe, and the first syringe and the second syringe are loaded into the same injection pump; after uniformly filling the reaction channel of the microfluidic channel reactor with lipase Lipozyme RM IM, under the synchronous push of the injection pump, the vitamin B4 solution of formula (I) and the fatty acid ethylene ester solution of formula (II) are continuously and synchronously introduced into the reaction channel to carry out the Michael addition reaction. The reaction temperature is controlled at 30~55℃, and the reaction time of the reaction solution flowing continuously in the reaction channel is 10~60min. The reaction solution flowing out of the reaction channel is collected online by the product collector. The reaction solution is post-processed to obtain the vitamin B4 acylated derivative of formula (III); the concentration ratio of the vitamin B4 solution of formula (I) to the fatty acid ethylene ester solution of formula (II) is 1:0.5~4; within the maximum limit that the reaction channel can accommodate the filled catalyst, the amount of catalyst added is 0.03g / mL~0.06g / mL based on the volume of the reaction solvent.

8. The process for the on-line synthesis of acylated derivatives of vitamin B4 in a continuous flow reactor according to any one of claims 1 to 7, characterized in that: The post-processing is as follows: after removing the solvent from the reaction solution under reduced pressure, silica gel column chromatography is performed using a mixed solution of ethyl acetate and petroleum ether in a volume ratio of 2:3 as the eluent. The eluent containing the target compound is collected, evaporated to dryness, and the vitamin B4 acylated derivative shown in formula (III) is obtained.

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