A fully continuous flow preparation method for vitamin B1

Abstract

The present invention discloses a fully continuous flow preparation method for vitamin B1. The present invention transports a chloroester reaction solution, a 2-methyl-4-amino-5-aminomethylpyrimidine reaction solution and carbon disulfide into a continuous flow reactor for continuous addition reaction, and the resulting reaction mixture enters a continuous filtration and reaction device. After the filter cake continues to react with a hydrochloric acid solution, the mixture is transported to a micro mixer and a continuous flow reactor together with an inorganic alkali aqueous solution through a control valve, and the outflowing mixed reaction solution and hydrogen peroxide are transported to another reactor for continuous oxidation reaction to obtain thiamine sulfate; eventually, the reaction mixture enters a continuous filtration and reaction device; the filter cake reacts with an organic solution of hydrochloric acid to obtain a vitamin B1 product. Compared with the traditional intermittent reactor synthesis method, the method of the present invention has the advantages of short reaction time, high product yield, high degree of automation, high process continuous efficiency, high time-space yield, low energy consumption and easy industrial amplification application.

Description

Technical Field

[0001] The present invention belongs to the technical field of organic chemical engineering, and in particular relates to a fully continuous flow preparation method of vitamin B1 (thiamine hydrochloride). Background Art

[0002] Since Windaus isolated vitamin B1 from yeast in 1932, it has played a vital role in the growth and health of animals as an anti-neuritis vitamin, and has attracted increasing attention from academia and the pharmaceutical industry. So far, scientists have invested a lot of effort in synthesizing vitamin B1 using different strategies. The structural formula is shown in formula (1):

[0003] 1

[0005] Among the synthetic routes of vitamin B1, the synthetic route developed by Williams and Cline ( J. Am. Chem. Soc, 1936, 58, 1504) and the route developed by Todd and Bergel ( J. Chem. Soc, 1937, 364) is most suitable for industrial production. In the Williams-Cline route, 4-amino-5-bromomethyl-2-methylpyrimidine and thiazole components are condensed to produce thiamine hydrobromide, which is then ion exchanged to produce the required thiamine hydrochloride, i.e., vitamin B1. In the Todd–Bergel route, the key is to produce a thioformyl derivative of 2-methyl-4-amino-5-aminomethylpyrimidine, which is then condensed with an open-chain chloroketone to obtain vitamin B1. The Moine research group improved the first two routes ( Chim.Acta , 1990, 73, 1300), using Grewe diamine and mercapto ketone to undergo condensation cyclization reaction to obtain vitamin B1. The advantage of this route is that the synthesis steps are short, but it requires high equipment and production costs, which is not conducive to industrial production. Currently, the most widely used industrial route is the Matsukawa route ( Yakugaku Zasshi , 1951, 71, 1215). This route has the advantages of a short synthesis process and good atom economy. However, in traditional batch reactor processes, this method has a long reaction time, multiple intermediate product post-processing steps, cumbersome operation, and demanding temperature control, which is not conducive to industrial scale-up production. Summary of the Invention

[0006] In order to overcome the shortcomings of traditional intermittent reactor synthesis methods such as long reaction time, great safety hazards, high energy consumption and low efficiency, the present invention provides a fully continuous flow preparation method for vitamin B1 (thiamine hydrochloride). The reaction time of this method is greatly shortened, the yield and production efficiency of the product vitamin B1 are greatly improved, the degree of automation of the process is significantly improved, energy consumption is greatly reduced, safety is greatly improved, and it is easy to apply industrially.

[0007] The present invention provides a fully continuous flow preparation method for vitamin B1, which uses a continuous flow reaction system consisting of a feed pump, a continuous flow reactor, a micromixer, a continuous filtration and reaction device, and a control valve connected in sequence. The specific steps of the method are as follows:

[0008] (1) transporting the reaction solutions of chloroester, carbon disulfide and 2-methyl-4-amino-5-aminomethylpyrimidine into a continuous flow reactor in the presence of a base to carry out a continuous addition-substitution reaction to obtain a mixed reaction material;

[0009] (2) The mixed reaction material discharged from step (1) directly enters a continuous filtration and reaction device. After continuous filtration, the filter cake continues to undergo a cyclization reaction with a hydrochloric acid solution. The reaction liquid passes through a control valve and is transported by a feed pump together with an inorganic alkali aqueous solution to a micro-mixer and a continuous flow reactor for a continuous hydrolysis reaction to obtain thiothiamine;

[0010] (3) The mixed reaction material flowing out of the continuous flow reactor in step (2) is then transported to another continuous flow reactor together with hydrogen peroxide for continuous oxidation reaction to obtain thiamine sulfate;

[0011] (4) The mixed reaction material flowing out of another continuous flow reactor in step (3) enters a continuous filtration and reaction device for continuous filtration, and the filter cake continues to react with the hydrochloric acid organic solution. After filtration and drying, thiamine hydrochloride solid is obtained, i.e., vitamin B1 product;

[0012] The chemical reaction formula is:

[0013]

[0014] Among them, 2-methyl-4-amino-5-aminomethylpyrimidine is a compound represented by formula (2); chloroester is a compound represented by formula (3); thioammonium thioate is a compound represented by formula (5); thiamine sulfate is a compound represented by formula (6); and the compound represented by formula (1) is the target product, vitamin B1 (thiamine hydrochloride).

[0015] Preferably, the chloroester reaction liquid in step (1) is pure 3-chloro-4-oxoacetic acid pentyl ester liquid, or a solution of 3-chloro-4-oxoacetic acid pentyl ester dissolved in an organic solvent; the organic solvent is any one of an alcohol, ether, ester, and ketone solvent; preferably, the chloroester reaction liquid is 3-chloro-4-oxoacetic acid pentyl ester liquid. The 2-methyl-4-amino-5-aminomethylpyrimidine reaction liquid is prepared according to patent CN112341395B.

[0016] Preferably, the flow rate ratio of the reaction solution of chloroester, carbon disulfide and 2-methyl-4-amino-5-aminomethylpyrimidine transported to the continuous flow reactor in step (1) is controlled so that the molar ratio of the three raw materials is in the range of (0.9-5): (0.9-5): 1; more preferably, the molar ratio of the three raw materials is (1-3): (1-3): 1

[0017] Preferably, the temperature in the continuous flow reactor described in step (2) is controlled within the range of 0-80°C; the residence time of the mixed reaction materials in the continuous flow reactor is 0.5-60 minutes, and the reaction pressure is controlled within the range of 0-1 MPa; more preferably, the temperature in the continuous flow reactor is 20-60°C; the residence time of the mixed reaction materials in the continuous flow reactor is 10-40 minutes, and the reaction pressure is controlled within the range of 0-0.3 MPa.

[0018] Preferably, the filtration temperature of the continuous filtration and reaction device in step (2) is controlled within the range of -10 to 30°C, and the reaction temperature is within the range of 20 to 100°C; more preferably, the filtration temperature is within the range of -5 to 10°C, and the reaction temperature is within the range of 50 to 70°C.

[0019] Preferably, the control valve and the flow rate of the hydrochloric acid solution in step (2) are controlled so that the molar ratio of the reaction intermediate (4) to the hydrochloric acid contained in the filter cake is in the range of 1:0.5 to 6. More preferably, the molar ratio of the intermediate (4) to the hydrochloric acid is in the range of 1:1 to 3.

[0020] Preferably, the flow ratio of the mixed reaction liquid and the alkaline solution transported to the micromixer and the continuous flow reactor in step (2) is controlled so that the molar ratio of the intermediate product to the base is in the range of 1: (1-10), preferably, the molar ratio of the intermediate product to the base is 1: (1-4); the temperature of the micromixer in step (2) is controlled in the range of 0-40°C, the temperature in the continuous flow reactor is controlled in the range of 20-120°C, and the residence time of the mixed reaction material in the reactor is 0.1-60 minutes, preferably, the temperature of the micromixer is controlled in the range of 20-40°C, the temperature in the continuous flow reactor is controlled in the range of 30-80°C, and the residence time of the mixed reaction material in the reactor is 0.2-30 minutes.

[0021] Preferably, the temperature in the continuous flow reactor in step (2) is controlled within the range of -10 to 80 °C, and the reaction pressure is controlled within the range of 0 to 1 MPa; further preferably, the temperature in the continuous flow reactor is controlled within the range of 20 to 60 °C, and the reaction pressure is controlled within the range of 0 to 0.3 MPa.

[0022] Preferably, the mass fraction of the inorganic base in the aqueous solution of the inorganic base in step (2) is 5 to 50%, preferably, the mass fraction of the inorganic base is 10 to 30%; the inorganic base is at least one of lithium carbonate, sodium carbonate, potassium carbonate, lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, ammonia water, ammonium carbonate, ammonium chloride, ammonium bicarbonate, lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, lithium hydroxide, sodium hydroxide and potassium hydroxide, etc. Preferably, the inorganic base is sodium bicarbonate, sodium carbonate, sodium hydroxide and potassium hydroxide.

[0023] Preferably, the continuous filtration and reaction device in step (2) and step (4) is one or more of a continuous kettle filter, a continuous scraper filter, a continuous filter press and a continuous rotary disc filter connected in series with a reactor to perform the continuous filtration and reaction steps.

[0024] Preferably, the flow rate ratio of the mixed reaction liquid and hydrogen peroxide transported to the continuous flow reactor in step (3) is controlled so that the molar ratio of the ammonium thiosulfate (5) obtained by the reaction to hydrogen peroxide is in the range of 1:(0.9~5), more preferably, the molar ratio of the ammonium thiosulfate (5) to hydrogen peroxide is 1:1.2~4; the temperature in the continuous flow reactor is controlled in the range of -10~50°C; the reaction residence time is 0.1~60 minutes, and the reaction pressure is controlled in the range of 0~1MPa, more preferably, the temperature in the continuous flow reactor is controlled in the range of 10~50°C; the reaction residence time is 1~40 minutes, and the reaction pressure is controlled in the range of 0~0.3MPa.

[0025] Preferably, the filtration temperature of the continuous filtration and reaction device in step (4) is controlled within the range of -5 to 25°C, the reaction temperature is 20 to 100°C, the reaction time is 0.1 to 60 minutes, and the reaction pressure is controlled within the range of 0 to 1 MPa; more preferably, the filtration temperature is controlled within the range of 0 to 10°C, the reaction temperature is 30 to 60°C, the reaction time is 1 to 40 minutes, and the reaction pressure is controlled within the range of 0 to 0.3 MPa.

[0026] Preferably, the control valve and the flow rate of the hydrochloric acid organic solution in step (4) are controlled so that the molar ratio of thiamine sulfate (6) to hydrochloric acid contained in the filter cake is in the range of 1:0.9 to 5. More preferably, the molar ratio of thiamine sulfate (6) to hydrochloric acid is in the range of 1:1 to 3.

[0027] Preferably, the hydrochloric acid organic solution in step (4) is one of the organic solutions such as hydrochloric acid methanol solution, hydrochloric acid ethanol solution, hydrochloric acid ethylene glycol solution, hydrochloric acid propanol solution, hydrochloric acid acetone solution, hydrochloric acid ethyl acetate solution or hydrochloric acid dioxane solution; further preferably, the hydrochloric acid organic solution is hydrochloric acid methanol solution, hydrochloric acid ethanol solution or hydrochloric acid ethylene glycol solution.

[0028] Preferably, the continuous flow reactor described in step (1), step (2), step (3) and step (4) is a microchannel continuous flow reactor, a static tubular continuous flow reactor, a dynamic oscillating tubular continuous flow reactor or a plate-type oscillating continuous flow reactor; the inner diameter of the tubular continuous flow reactor is 1 mm to 20 cm, preferably, the inner diameter is 2 mm to 10 cm; the inner diameter of the channel of the plate-type oscillating continuous flow reactor is 500 μm to 5 cm, preferably, the inner diameter is 1000 μm to 2.5 cm.

[0029] Preferably, the micromixer described in step (1), step (2), step (3) and step (4) is any one of a static mixer, a T-type micromixer, a Y-type micromixer, a cross mixer, a coaxial flow micromixer, a dynamic continuous stirring mixer and a flow focusing micromixer; the continuous flow reactor and the continuous filtration and reaction device can be composed of one or more units connected in series or in parallel.

[0030] As a preferred technical solution, steps (1) to (4) include a feed pump, a continuous flow reactor, a continuous filtration and reaction device, a control valve, a micro mixer, etc., the inlet of the continuous flow reactor is connected to three reaction liquid feed pumps, the outlet of the continuous flow reactor is connected to an inlet of the continuous filtration and reaction device, the other inlet of the continuous filtration and reaction device is connected to the feed pump through a control valve, the outlet of the continuous filtration and reaction device is connected to an interface of the control valve, the other interface of the control valve is connected to a filtrate collection pipeline, the third interface of the control valve is connected to the feed pump, the feed pump is connected to an inlet of the micro mixer, the other inlet of the micro mixer is connected to another feed pump, the outlet of the micro mixer is connected to the continuous flow reactor, the outlet of the continuous flow reactor is connected to the continuous filtration and reaction device through a control valve, the other interface of the continuous filtration and reactor is connected to the feed pump through a control valve, the outlet of the continuous filtration and reaction device is connected to an interface of the control valve, the other interface of the control valve is connected to the filtrate collection pipeline, which can be connected to a recovery system, and the third interface of the control valve is connected to a product collection pipeline.

[0031] As a preferred technical solution, steps (1) to (4) include a feed pump, a continuous flow reactor, a continuous filtration and reaction device, a control valve, a micro mixer and a buffer tank, etc., the inlet of the continuous flow reactor is connected to three reaction liquid feed pumps, the outlet of the continuous flow reactor is connected to an inlet of the continuous filtration and reaction device, the other inlet of the continuous filtration and reaction device is connected to the feed pump through the control valve, the outlet of the continuous filtration and reaction device is connected to an interface of the control valve, the other interface of the control valve is connected to the filtrate collection pipeline, the third interface of the control valve is connected to the inlet of the buffer tank, the outlet of the buffer tank is connected to the feed pump, the feed pump is connected to an inlet of the micro mixer, the other inlet of the micro mixer is connected to another feed pump, the outlet of the micro mixer is connected to the continuous flow reactor, the outlet of the continuous flow reactor is connected to the continuous filtration and reaction device through the control valve, the other interface of the continuous filtration and reactor is connected to the feed pump through the control valve, the outlet of the continuous filtration and reaction device is connected to an interface of the control valve, the other interface of the control valve is connected to the filtrate collection pipeline, and the third interface of the control valve is connected to the product collection pipeline.

[0032] The method of the present invention for continuously preparing vitamin B1 (1) using a micro-reaction system can conveniently realize industrial large-scale production of vitamin B1 (1) by fully continuous flow chemistry through a multi-channel parallel amplification strategy.

[0033] Beneficial effects

[0034] The method for preparing vitamin B1 proposed in the present invention uses a fully continuous flow chemical reaction system including a feed pump, a continuous flow reactor, a continuous filtration and reaction device, a control valve, a micromixer and other equipment connected in sequence. Compared with the synthesis method using a traditional batch reactor, it has the following advantages:

[0035] 1. The continuous flow reaction technology system has excellent mass transfer, heat transfer and material molecular mixing properties, which greatly shortens the reaction time and greatly improves the reaction efficiency. It can be completed quantitatively from several days of traditional batch reactor reactions to several hours or even tens of minutes. At the same time, side reactions are suppressed to the greatest extent. The yield of the product vitamin B1 is comparable to that of the traditional batch reactor synthesis method, but the intermediate processing process is greatly reduced.

[0036] 2. Achieve continuous synthesis from raw materials to products. The process is continuous and uninterrupted with a high degree of automation. No external intervention is required in the middle. It has high time and space efficiency, greatly reduces the number of operators and labor intensity, and significantly reduces production costs.

[0037] 3. The reaction of 2-methyl-4-amino-5-aminomethylpyrimidine, chloroester, and carbon disulfide can be completed in a relatively closed continuous channel, and the amount of raw materials can be precisely controlled. The continuous oxidation reaction of ammonium thiosulfate and hydrogen peroxide is completed in the reaction fluid channel of the continuous flow reactor. The total reaction volume is small, resulting in low online liquid holdup and an inherently safe reaction process.

[0038] 4. The multiphase mixing, mass transfer and reaction processes of the reaction process are completed in a micro-mixer, continuous filtration and reaction device and continuous flow reactor. The operation is simple and the process is efficient, which greatly reduces the energy consumption of the process and greatly saves production time and equipment costs.

[0039] 5. The full continuous flow preparation process can conveniently realize industrial amplification of the synthesis method of the present invention through a multi-channel parallel amplification strategy, and can quickly achieve industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0040] Figure 1 Schematic diagram of the fully continuous flow synthesis process used in one embodiment of the present invention.

[0041] Figure 2 Schematic diagram of the fully continuous flow synthesis process used in one embodiment of the present invention.

[0042] Reference numerals in the figure: 1 is a chloroester reaction liquid feed pump, 2 is a carbon disulfide feed pump, 3 is a 2-methyl-4-amino-5-aminomethylpyrimidine reaction liquid feed pump, 4 is a continuous flow reactor, 5 is a hydrochloric acid solution feed pump, 6 is a control valve, 7 is a continuous filtration and reaction device, 8 is a filtrate collection line, 9 is a control valve, 10 is a feed pump, 11 is an inorganic alkali aqueous solution feed pump, 12 is a micro mixer, 13 is a continuous flow reactor, 14 is a hydrogen peroxide feed pump, 15 is a continuous flow reactor, 16 is a control valve, 17 is a hydrochloric acid organic solution feed pump, 18 is a control valve, 19 is a continuous filtration and reaction device, 20 is a filtrate collection line, 21 is a product collection line, 22 is a continuous filtration and reaction device, 23 is a continuous filtration and reaction device, 24 is a control valve, 25 is a control valve, and 26 is a buffer tank. DETAILED DESCRIPTION

[0043] To explain the technical content, structural features, achieved objectives, and effects of the technical solution in detail, the following is a further description of the specific embodiments and accompanying drawings. This embodiment is implemented based on the technical solution of the present invention, and provides a detailed implementation method and specific operation process, but the scope of protection of the present invention is not limited to the following embodiments.

[0044] The structure of the full continuous flow preparation technology used in the embodiment is shown in the attached Figure 1As shown, it includes a chloroester reaction liquid feed pump 1, a carbon disulfide feed pump 2, a 2-methyl-4-amino-5-aminomethylpyrimidine reaction liquid feed pump 3, a continuous flow reactor 4, a hydrochloric acid solution feed pump 5, a control valve 6, a continuous filtration and reaction device 7, a filtrate collection pipeline 8, a control valve 9, a feed pump 10, an inorganic alkali aqueous solution feed pump 11, a micro mixer 12, a continuous flow reactor 13, a hydrogen peroxide feed pump 14, a continuous flow reactor 15, a control valve 16, a hydrochloric acid organic solution feed pump 17, a control valve 18, a continuous filtration and reaction device 19, a filtrate collection pipeline 20, a product collection pipeline 21, a continuous filtration and reaction device 22, a continuous filtration and reaction device 23, a control valve 24, a controllable valve 25, and a buffer tank 26.

[0045] The inlet of the continuous flow reactor 4 is connected to three reaction liquid feed pumps 1 to 3 respectively, the outlet of the continuous flow reactor 4 is connected to the control valve 24, the outlet of the control valve 24 is connected to the continuous filtration and reaction device 7 and an inlet of the parallel continuous filtration and reaction device 23, the other inlets of the continuous filtration and reaction devices 7 and 23 are connected to the feed pump 5 through the control valve 6, the outlet of the continuous filtration and reaction device 7 is connected to an interface of the control valve 9, the other interface of the control valve 9 is connected to the filtrate collection pipeline 8, the third interface of the control valve 9 is connected to the feed pump 10, and the feed pump 10 is connected to the micro mixer 12 , the other inlet of the micromixer 12 is connected to another feed pump 11, the outlet of the micromixer 12 is connected to the continuous flow reactor 13, the outlet of the continuous flow reactor 13 is connected to the continuous filtration and reaction device 19 through the control valve 16, another interface of the continuous filtration and reactor 19 is connected to the feed pump 17 through the control valve 18, the outlet of the continuous filtration and reaction device 19 is connected to an interface of the control valve 25, the other interface of the control valve 25 is connected to the filtrate collection pipeline 20, which can be connected to the recovery system, and the third interface of the control valve is connected to the product collection pipeline 21.

[0046] Its working process is:

[0047] (A) Feed pumps 1 to 3 are used to simultaneously deliver the chloroester reaction solution, carbon disulfide, and 2-methyl-4-amino-5-aminomethylpyrimidine to a continuous flow reactor 4 for continuous addition-substitution reaction. The mixture flowing out of the continuous flow reactor 4 then enters a continuous filtration and reaction device 7. The filtrate enters a filtrate collection line 8 through a second interface of a control valve 9. In the continuous filtration and reaction device 7, a filter cake undergoes a cyclization reaction with a hydrochloric acid solution delivered by a feed pump 5.

[0048] (B) The mixed reaction materials are connected to the feed pump 10 through the third interface of the control valve 9 and enter the micro mixer 12 at the same time as the inorganic alkaline aqueous solution delivered by the feed pump 11. The mixed materials then enter the continuous flow reactor 13 for continuous hydrolysis reaction.

[0049] (C) The reaction liquid material flowing out of the continuous flow reactor 13 directly enters the continuous flow reactor 15. At the same time, the feed pump 14 is used to transport hydrogen peroxide into the continuous flow reactor 15 to carry out a continuous oxidation reaction.

[0050] (D) The reaction liquid flowing out of continuous flow reactor 15 enters continuous filtration and reaction unit 19 through control valve 16. The filtrate enters filtrate collection line 20 through the second port of control valve 25. In continuous filtration and reaction unit 19, the filter cake reacts with the hydrochloric acid organic solution delivered by feed pump 17. The reaction liquid then enters the product collection line through control valve 25 for collection. After filtration and drying, solid thiamine hydrochloride, i.e., vitamin B1 product, is obtained.

[0051] In order to better illustrate the purpose, technical solutions and advantages of the present invention, the present invention will be further described below in conjunction with specific embodiments.

[0052] Example 1

[0053] 3-Chloro-4-oxoacetic acid pentyl ester liquid, carbon disulfide and 2-methyl-4-amino-5-aminomethylpyrimidine were simultaneously transported to a tubular continuous flow reactor (reaction volume: 10 ml, microchannel diameter: 2.5 cm). The flow ratio of 3-chloro-4-oxoacetic acid pentyl ester liquid, carbon disulfide and 2-methyl-4-amino-5-aminomethylpyrimidine was adjusted to make the molar ratio of the three to be 1.2:1.3:1. The back pressure value inside the reactor was set to 0 MPa, and the temperature inside the continuous flow reactor was controlled to 50°C. After 10 minutes of reaction (i.e., the residence time of the mixed reaction materials in the microchannel reactor was 10 minutes), the mixed reaction materials flowed out from the outlet of the continuous flow reactor and entered the continuous filtration and reaction device for continuous filtration. The conversion rate of 2-methyl-4-amino-5-aminomethylpyrimidine was 100% and the purity of the intermediate product (4) was greater than 99%. Then, the control valve is used to transport the hydrochloric acid solution to the continuous kettle filter to react with the filter cake. At this time, the reaction material flowing out of the continuous flow reactor enters the parallel continuous kettle filter through the control valve for continuous filtration. The filtration temperature is set to 20°C, the reaction temperature is 78°C, the reaction time is 15 minutes, and the flow rate of the feed pump is adjusted so that the molar ratio of the intermediate product (4) to hydrochloric acid is 1:1.5. After the reaction is completed, the feed pump and the sodium hydroxide aqueous solution are simultaneously fed into the T-type micro mixer and the microchannel continuous flow reactor. The flow rate of the reaction liquid and the sodium hydroxide solution is adjusted so that the molar ratio of the intermediate product to sodium hydroxide is 1:1.1. The temperature in the T-type micro mixer is set to 25°C, the temperature in the reactor is set to 25°C, the reaction time is 2 minutes, and the reaction pressure is 0.2MPa. The purity of the intermediate product (5) is greater than 98% when sampled and tested. The mixed reaction liquid continued to enter the tubular oscillating continuous flow reactor to undergo oxidation reaction with hydrogen peroxide. The flow rate of the feed pump was adjusted so that the molar ratio of 5 to hydrogen peroxide was 1:1.05, the reaction temperature was 25°C, the reaction time was 30 minutes, and the reaction pressure was 0 MPa. The conversion rate was greater than 98% when sampling was performed. The mixed reaction liquid entered the continuous kettle filter, and the filtration temperature was set to 0°C. Then, the control valve was used to transport the hydrochloric acid ethanol solution to the continuous kettle filter to react with the filter cake. At this time, the reaction material flowing out of the continuous flow reactor passed through the control valve and entered the parallel continuous kettle filter for continuous filtration. The reaction temperature was 60°C, the reaction time was 15 minutes, and the flow rate of the feed pump was adjusted so that the molar ratio of the intermediate product (6) to hydrochloric acid was 1:1.15. After the reaction was completed, filtration was continued in the continuous kettle filter at a filtration temperature of 0°C. The filtrate was collected through the filtrate collection pipeline for subsequent recycling. After drying, the purity of the product, vitamin B1, was detected to be 98.8%, and the total separation yield was 70.2%.

[0054] Example 2

[0055] This example is identical to Example 1, except that the continuous flow reactor in this example is a plate-type continuous oscillating reactor with a volume of 90 ml and a channel inner diameter of 2 mm. The addition reaction temperature in the plate-type continuous oscillating reactor is 60°C for 45 minutes, and the continuous oxidation reaction temperature is 40°C for 20 minutes. In this example, the substrate 2-methyl-4-amino-5-aminomethylpyrimidine is also substantially completely converted, resulting in a vitamin B1 product with a purity of 99% and an overall isolated yield of 68.5%.

[0056] Example 3

[0057] This example is identical to Example 1, except that the reaction liquid after continuous cyclization is not directly subjected to hydrolysis. Instead, it is collected in a buffer tank. It is then pumped via a feed pump to a continuous flow reactor for reaction with sodium hydroxide solution. In this example, the substrate, 2-methyl-4-amino-5-aminomethylpyrimidine, is also completely converted, resulting in a vitamin B1 product with a purity of 98.9% and a total isolated yield of 72%.

[0058] Example 4

[0059] This example is the same as Example 1, except that the molar ratio of liquid 3-chloro-4-oxoacetate, carbon disulfide, and 2-methyl-4-amino-5-aminomethylpyrimidine in the addition reaction is 1.1:1:1, and the temperature in the continuous flow reactor is controlled at 40°C. In this example, the conversion of the substrate 2-methyl-4-amino-5-aminomethylpyrimidine is 92%, the purity of the resulting vitamin B1 product is 98%, and the total isolated yield is 40.2%.

[0060] Example 5

[0061] This example is the same as Example 1, except that the temperature of the cyclization reaction is controlled at 85°C, the reaction time is 30 minutes, and the molar ratio of the intermediate product (4) to hydrochloric acid is 1:2. In this example, the conversion rate of the substrate 2-methyl-4-amino-5-aminomethylpyrimidine is 99%, the purity of the obtained product vitamin B1 is 98.7%, and the total isolated yield is 72.4%.

[0062] Example 6

[0063] This example is the same as Example 1, except that the micromixer in this example is a Y-type mixer, the mixing temperature is set to 30°C, the temperature of the continuous flow reactor in the continuous hydrolysis reaction is set to 35°C, the reaction time is 0.5 minutes, and the reaction pressure is 0 MPa. In this example, the conversion rate of the substrate 2-methyl-4-amino-5-aminomethylpyrimidine is 100%, the purity of the resulting vitamin B1 product is 99.4%, and the total isolated yield is 70.2%.

[0064] Example 7

[0065] This example is the same as Example 1, except that an aqueous solution of potassium bicarbonate with a mass fraction of 15% is used in the continuous hydrolysis reaction. The purity of the vitamin B1 product obtained in this example is 98%, and the total separation yield is 70.3%.

[0066] Example 8

[0067] This example is the same as Example 1, except that the hydrochloric acid organic solution in this example is a hydrochloric acid ethylene glycol solution, the molar ratio of the intermediate product sulfuric acid amide to the hydrochloric acid organic solution is adjusted to 1:3, the reaction temperature is controlled at 80°C, and the filtration temperature is -15°C. In this example, the conversion rate of the substrate 2-methyl-4-amino-5-aminomethylpyrimidine is 99%, the purity of the resulting vitamin B1 product is 99%, and the total isolated yield is 68.0%.

[0068] Example 9

[0069] This example is the same as Example 1, with the only difference being that the continuous filtration and reaction apparatus in this example is a combination of a continuous rotary disc filter and a kettle reactor. The purity of the vitamin B1 product obtained in this example is 95%, and the total separation yield is 53%.

[0070] Example 10

[0071] This example is the same as Example 1, except that the molar ratio of liquid 3-chloro-4-oxoacetate, carbon disulfide, and 2-methyl-4-amino-5-aminomethylpyrimidine in this example is 2:1.5:1. In this example, the conversion rate of the substrate 2-methyl-4-amino-5-aminomethylpyrimidine is 100%, the purity of the obtained product vitamin B1 is 98%, and the total isolated yield is 71.2%.

[0072] Example 11

[0073] This example is the same as Example 1, except that a methanol solution of a chloroester is used in the substitution reaction. In this example, the conversion rate of the substrate 2-methyl-4-amino-5-aminomethylpyrimidine is 100%, the purity of the obtained product vitamin B1 is 99%, and the total isolated yield is 69.7%.

[0074] It should be noted that although the above embodiments have been described herein, this does not limit the scope of patent protection of the present invention. Therefore, based on the innovative concept of the present invention, changes and modifications to the embodiments described herein, or equivalent structural or equivalent process transformations made using the contents of the present invention's specification and drawings, and direct or indirect application of the above technical solutions to other related technical fields, are all included in the scope of patent protection of the present invention.

Claims

1. A fully continuous flow preparation method for vitamin B1, characterized in that: The specific steps of preparation are: (1) using feed pumps 1 to 3 to simultaneously deliver the chloroester reaction liquid, carbon disulfide and 2-methyl-4-amino-5-aminomethylpyrimidine to the first continuous flow reactor (4) for continuous addition-substitution reaction, the mixed material flowing out of the first continuous flow reactor (4) then enters the first continuous filtration and reaction device (7), the filtrate enters the filtrate collecting pipeline (8) through the second interface of the second control valve (9), and the filter cake in the first continuous filtration and reaction device (7) undergoes a cyclization reaction with the hydrochloric acid solution delivered by the hydrochloric acid solution feed pump (5); (2) The mixed reaction materials are connected to the feed pump (10) through the third interface of the second control valve (9), and enter the first micro mixer (12) at the same time as the inorganic alkali aqueous solution delivered by the inorganic alkali aqueous solution feed pump (11). The mixed materials then enter the second continuous flow reactor (13) for continuous hydrolysis reaction to obtain thiothiamine; (3) The reaction liquid material flowing out of the second continuous flow reactor (13) directly enters the third continuous flow reactor (15), and at the same time, the hydrogen peroxide is transported to the third continuous flow reactor (15) by a hydrogen peroxide feed pump (14) to carry out a continuous oxidation reaction to obtain thiamine sulfate; (4) The reaction liquid material flowing out of the third continuous flow reactor (15) enters the second continuous filtration and reaction device (19) through the third control valve (16), and the filtrate enters the filtrate collection pipeline (20) through the second interface of the fifth control valve (25). After the filter cake in the second continuous filtration and reaction device (19) reacts with the hydrochloric acid organic solution transported by the hydrochloric acid organic solution feed pump (17), the reaction liquid enters the product collection pipeline through the fifth control valve (25) for collection; after filtration and drying, thiamine hydrochloride solid, i.e., vitamin B1 product, is obtained; The chloroester reaction liquid in step (1) is a pure 3-chloro-4-oxoacetic acid pentyl ester liquid, or a solution of 3-chloro-4-oxoacetic acid pentyl ester dissolved in an organic solvent; the organic solvent is any one of an alcohol, ether, ester and ketone solvent.

2. The preparation method according to claim 1, characterized in that The flow rate ratio of the reaction solution of chloroester, carbon disulfide and 2-methyl-4-amino-5-aminomethylpyrimidine transported to the first continuous flow reactor (4) in step (1) is controlled so that the molar ratio of the three raw materials is (0.9~5):(0.9~5):

1.

3. The preparation method according to claim 1, characterized in that The temperature in the first continuous flow reactor (4) described in step (1) is controlled to be 0-80°C; the residence time of the mixed reaction materials in the first continuous flow reactor (4) is 0.5-60 minutes, and the reaction pressure is controlled to be 0-1 MPa.

4. The preparation method according to claim 1, characterized in that The filtration temperature of the continuous filtration and reaction device in step (1) is controlled to be -10~30°C, and the reaction temperature is 20~100°C; the molar ratio of the reaction intermediate contained in the filter cake in step (1) to hydrochloric acid is 1:0.5~6.

5. The preparation method according to claim 1, characterized in that In step (2), the flow ratio of the mixed reaction material and the inorganic alkali aqueous solution transported to the first micro-mixer (12) and the second continuous flow reactor (13) is controlled so that the molar ratio of the intermediate product to the inorganic alkali is 1: (1-10); the temperature of the first micro-mixer (12) in step (2) is controlled to be 0-40°C, the temperature in the second continuous flow reactor (13) is controlled to be 20-120°C, and the residence time of the mixed reaction material in the second continuous flow reactor (13) is 0.1-60 minutes.

6. The preparation method according to claim 1, characterized in that The mass fraction of the inorganic base in the aqueous solution of the inorganic base described in step (2) is 5 to 50%; the inorganic base is at least one of lithium carbonate, sodium carbonate, potassium carbonate, lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, ammonia water, ammonium carbonate, ammonium bicarbonate, lithium hydroxide, sodium hydroxide and potassium hydroxide.

7. The preparation method according to claim 1, characterized in that The continuous filtration and reaction device is one or more of a continuous kettle filter, a continuous scraper filter, a continuous filter press and a continuous rotary disc filter connected in series with a reactor to perform continuous filtration and reaction steps.

8. The preparation method according to claim 1, characterized in that In step (3), the flow rate ratio of the mixed reaction liquid and hydrogen peroxide transported into the continuous flow reactor is controlled so that the molar ratio of ammonium thiothionate and hydrogen peroxide obtained by the reaction is 1:(0.9~5); the temperature in the continuous flow reactor is controlled to be -10~50°C; the reaction residence time is 0.1~60 minutes, and the reaction pressure is controlled to be 0~1MPa.

9. The preparation method according to claim 1, characterized in that The filtration temperature of the continuous filtration and reaction device described in step (4) is controlled to be -15~30°C, the reaction temperature is 20~100°C, the reaction time is 0.1~60 minutes, and the reaction pressure is controlled to be 0~1MPa; the molar ratio of thiamine sulfate to hydrochloric acid contained in the filter cake in step (4) is 1:0.9~5.

10. The preparation method according to claim 1, characterized in that The hydrochloric acid organic solution described in step (4) is one of hydrochloric acid methanol solution, hydrochloric acid ethanol solution, hydrochloric acid ethylene glycol solution, hydrochloric acid propanol solution, hydrochloric acid acetone solution, hydrochloric acid ethyl acetate solution or hydrochloric acid dioxane solution.

11. The preparation method according to any one of claims 1 to 10, characterized in that: The continuous flow reactor is a microchannel continuous flow reactor, a static tubular continuous flow reactor, a dynamic oscillating tubular continuous flow reactor or a plate-type oscillating continuous flow reactor; the inner diameter of the tubular continuous flow reactor is 1 mm to 20 cm; the inner diameter of the channel of the plate-type oscillating continuous flow reactor is 500 μm to 5 cm.

12. The preparation method according to any one of claims 1 to 10, characterized in that: The micro mixer is any one of a static mixer, a T-type micro mixer, a Y-type micro mixer, a cross mixer, a coaxial flow micro mixer, a dynamic continuous stirring mixer and a flow focusing micro mixer; the continuous flow reactor and the continuous filtration and reaction device can be composed of one or more units connected in series or in parallel.

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