Microwave continuous flow debenzylation method
The continuous flow debenzylation reaction for biotin synthesis using a microwave-mediated microchannel reactor solves the complexity and safety issues of benzyl removal in existing technologies, and realizes an efficient, safe, and environmentally friendly biotin synthesis process.
Patent Information
- Application Number
- CN202511034846.1
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-07-25
- Publication Date
- 2025-11-07
AI Technical Summary
Existing methods for removing the benzyl group in biotin synthesis suffer from problems such as complex processes, difficulty in scale-up, high safety risks, and serious environmental pollution. There is a lack of green, efficient, mild, and continuously operable debenzylation methods.
A microwave-mediated microchannel reactor is used for continuous flow debenzylation reaction. The microwave continuous flow microchannel reactor is used for micro-mixing, mass transfer and heat transfer. Combined with an adjustable back pressure valve and separation and purification treatment, the continuous synthesis of raw material liquid is realized.
The reaction time is greatly shortened, the degree of automation is high, the safety is improved, the energy consumption is reduced, the product yield is increased, and it is suitable for industrial applications.
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Figure CN120904111A_ABST
Abstract
Description
TECHNICAL FIELD
[0001] The application belongs to the technical field of pharmaceutical engineering, and particularly relates to a microwave continuous flow debenzyl method. BACKGROUND
[0002] In the synthesis of biotin molecules, benzyl (Bn-) protecting groups are widely used for the protection of alcohol hydroxyl groups, carboxyl groups or amine groups because they are easy to introduce, have good stability, and can be selectively removed in the later stage. However, the removal of benzyl groups usually depends on the following methods:
[0003] Catalytic hydrogenation debenzyl (H2 / Pd-C): It is the most commonly used debenzyl method, but has the following problems:
[0004] It is extremely sensitive to catalysts and requires strict oxygen removal; it is not suitable for substrates with unsaturated bonds, nitrogen heterocyclic rings and other hydrogenated substances; high-pressure equipment has poor safety and is not suitable for continuous industrial scaling.
[0005] Lewis acid / Acid debenzyl: such as using trifluoroacetic acid (TFA), sulfuric acid, concentrated hydrochloric acid, etc., to remove Bn at high temperature, but often accompanied by side reactions (ester hydrolysis, condensation, etc.), especially in the final stage of synthesis, which has a great impact on the target structure, and the strong acidity corrodes the equipment and has poor environmental friendliness.
[0006] Oxidative debenzyl method: such as using DDQ (2,3-dichloro-5,6-dicyano-1,4-benzoquinone) or CAN (cerium ammonium nitrate), which is suitable for the removal of some benzyl ethers, but the reagent is expensive, the reaction selectivity is poor, and there are many by-products, which is difficult to apply to large-scale synthesis.
[0007] In summary, the removal of benzyl groups in the current biotin synthesis still relies on traditional kettle operation methods, which have complex processes, scaling difficulties, and problems such as long reaction time, high safety risk, and serious environmental pollution. Therefore, there is an urgent need for a green, efficient, mild and continuous debenzyl method to meet the modern industrial synthesis needs of biotin and its derivatives. SUMMARY
[0008] The purpose of the present application is to overcome the deficiencies in the prior art and provide a microwave continuous flow debenzyl method, which greatly shortens the reaction time, significantly improves the automation and efficiency of the process, avoids the generation of waste acid, greatly reduces energy consumption, greatly improves safety, and is easy to industrialize.
[0009] To achieve the above-mentioned purpose, the technical scheme adopted by the present application is as follows:
[0010] A microwave continuous flow debenzyl method using a microwave-mediated microchannel reactor, the specific steps are:
[0011] (1) pumping the benzyl-containing raw material solution and the benzyl-removing reagent into a micro-mixer for mixing;
[0012] (2) pumping the reaction solution in step (1) into a microwave continuous flow micro-channel reactor for microwave continuous benzyl-removing reaction;
[0013] (3) pumping the reaction solution in step (2) into an adjustable back pressure valve to collect the reaction mixture flowing out of the microwave continuous flow micro-channel reactor, and subjecting the reaction mixture to separation and purification treatment to obtain the target product after benzyl removal;
[0014] The reaction formula is as follows:
[0015]
[0016] In the formula, R1 is any one of hydrogen, alkyl, cycloalkyl, and substituted phenyl, and Ar is substituted phenylthiophenyl, biphenyl, or naphthyl.
[0017] The specific process of the separation and purification treatment is as follows: the reaction mixture is poured into water, stirred at 0°C for 1 hour, and the crystal-like solid is collected to obtain the crude product. Then 5% NaOH solution is added, and after the crude product is dissolved, toluene is used for extraction, the water phase is separated, 18% HCl aqueous solution is used to adjust the pH to 2.0-3.0, the formed crystals are collected, and then dissolved in deionized water with activated carbon to reflux for 1 hour. After cooling to room temperature, the white solid is completely precipitated at 10°C to obtain the target product after benzyl removal.
[0018] Further, the benzyl-removing reagent in step (1) is any one of CH3SO3H, H2SO4, HBr, H3PO4, H3PO2, CH3CO2H, and CF3CO2H, or a mixture of two or more thereof in any ratio.
[0019] Further, the solvent of the benzyl-containing raw material solution in step (1) is any one of ethyl acetate, dichloromethane, toluene, o-xylene, m-xylene, p-xylene, mesitylene, anisole dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether, acetonitrile, and acetone, or a mixture of two or more thereof in any ratio.
[0020] Further, the concentration of the raw material solution in step (1) is 0.05-5.0 M.
[0021] Further, the micro-mixer of the reaction material in step (1) is any one of a T-shaped, Y-shaped, cross-shaped, and screen-shaped mixer.
[0022] Further, the micro-channel reactor in step (2) is a tubular micro-channel reactor, and the inner diameter of the tubular micro-channel reactor is 0.1-50 mm.
[0023] Further, the reaction temperature of the reaction solution pumped into the microwave continuous flow reactor in step (2) is 100-260 °C, and the microwave continuous flow reaction time is 0.1-30 min.
[0024] Further, the material of the micro-channel reactor in step (2) is any one of polyethylene, polypropylene, glass fiber reinforced polypropylene, polytetrafluoroethylene or a mixture of two or more thereof in any ratio.
[0025] Further, the output power of the microwave continuous flow micro-channel reactor in step (2) is 200-1000 W.
[0026] Further, the back pressure value of the adjustable back pressure valve in step (3) is 2.5-30 bar.
[0027] As a preferred technical solution, the microwave continuous flow reaction system comprises a feeding pump, a micro-mixer, a microwave continuous flow micro-channel reactor and a back pressure valve; the inlet of the feeding pump is connected with a benzyl-containing raw material solution and a debenzylation reagent respectively, the mixed solution is pumped into the inlet of the microwave continuous flow micro-channel reactor after being mixed by the micro-mixer, the outlet of the microwave continuous flow micro-channel reactor is connected with the inlet of the adjustable back pressure valve, the pressure of the back pressure valve can be adjusted in the range of 2.5-30 bar, the reaction mixture is guided out of the outlet of the adjustable back pressure valve and collected in a storage tank, and the target product is obtained after separation, purification and decolorization.
[0028] The present application has the following advantages:
[0029] Compared with the existing synthesis method using a traditional batch reaction kettle, the present application has the following advantages:
[0030] 1. The continuous synthesis from raw materials to products is realized, the process is continuously carried out without interruption, the degree of automation is high, the corrosion of organic acid or inorganic acid to the reaction kettle during the long reaction process is avoided, various safety hazards existing in the kettle production process are avoided, the time-space efficiency is high, a large amount of by-products are avoided, the number of operating workers and the labor intensity are greatly reduced, and the production cost is significantly reduced.
[0031] 2. The debenzylation reaction of the benzyl-containing raw material is completed in the microwave continuous flow reactor channel, the total volume of the reaction fluid channel is small, the on-line liquid holding capacity is small, the reaction process is safe, and the yield per unit time is increased by 50% under the same liquid holding capacity compared with the traditional kettle reactor.
[0032] 3. The microwave continuous flow microchannel reactor has excellent mass transfer, heat transfer and material mixing performance, so that the debenzyl reaction time is greatly shortened, from several hours of traditional batch kettle reaction to several minutes of reaction interval.
[0033] 4. The continuous flow process based on the microwave continuous flow microchannel reactor, the reaction system can be continuously operated for a long time, greatly improving the process efficiency and space-time yield, and the product yield is high.
[0034] 5. The mixing of one or more solvents, mass transfer and reaction process in the reaction fluid channel of the microwave continuous flow microchannel reactor are completed, without stirring device, and the energy consumption of the process is greatly reduced.
[0035] DRAWINGS
[0036] Figure 1 The reaction flow diagram of Example 1 of the present application is shown. DETAILED DESCRIPTION
[0037] In order to better illustrate the purpose, technical scheme and advantages of the present application, the present application will be further described below in combination with specific examples.
[0038] Example 1
[0039] Reference Figure 1 The raw material double benzyl-substituted substrate (R1 is hydrogen, Ar is phenyl) (0.10 mol) was dissolved in 200 mL of toluene and placed in a substrate liquid storage tank, 250 mL of methyl sulfonic acid was placed in substrate liquid storage tank 4, the raw material liquid and methyl sulfonic acid solution were respectively fed into a Y-type microchannel mixer (the flow ratio of the two liquids was controlled to be 1:1.2) by a feed pump, and then pumped into a microwave continuous flow microchannel reactor (an inner diameter of 1.6 mm PTFE tube, an output power of 500 W), the retention volume in the microchannel reactor was 20 mL, the reaction temperature was controlled to be 200℃, the back pressure value of the back pressure valve was set to be 20 bar, the reaction retention time was 5 minutes, and the reaction material flowed out of the microchannel reactor outlet, the product liquid was collected from the storage tank, and after separation, purification and decolorization treatment, the yield of the obtained product was 96%, and the purity was greater than 98%.
[0040] The specific process of separation and purification treatment is as follows: the reaction mixture is poured into water, stirred at 0℃ for 1 hour, the crystal-like solid is collected to obtain a crude product, 5% NaOH solution is added, after the crude product is dissolved, toluene is extracted, the water phase is separated, 18% HCl aqueous solution is used to adjust the pH to 2.0-3.0, the formed crystals are collected, and then dissolved in deionized water with activated carbon to reflux for 1 h, cooled to room temperature, and then placed at 10℃ to completely precipitate white solid to obtain the debenzylated target product.
[0041] Example 2
[0042] The raw material of the double benzyl-substituted substrate (R1 is hydrogen, and Ar is a p-methoxyphenyl group) (0.15 mol) was dissolved in 300 mL of toluene and placed in a substrate liquid storage tank. 300 mL of a mixed acid solution of sulfuric acid and trifluoroacetic acid (1:1) was placed in the substrate liquid storage tank. The raw material liquid and the mixed acid solution were respectively fed into a Y-shaped microchannel mixer 6 (the flow ratio of the two liquids was controlled to be 1:1.4) by using a feed pump, and then pumped into a microwave continuous flow microchannel reactor (an inner diameter of 1.6 mm PTFE tube, an output power of 650 W). The retention volume in the microchannel reactor was 20 mL, the reaction temperature was controlled to be 220°C, the back pressure value of the back pressure valve was set to be 25 bar, the reaction retention time was 3 minutes, and the reaction material flowed out of the outlet of the microchannel reactor. The product liquid was collected from the storage tank, and then separated, purified, and decolorized. The yield of the obtained product was 97%, and the purity was greater than 98%.
[0043] Example 3
[0044] The raw material of the double benzyl-substituted substrate (R1 is hydrogen, and Ar is a p-methoxyphenyl group) (0.20 mol) was dissolved in 300 mL of p-xylene and placed in a substrate liquid storage tank. 250 mL of hypophosphorous acid was placed in the substrate liquid storage tank. The raw material liquid and the hypophosphorous acid were respectively fed into a Y-shaped microchannel mixer (the flow ratio of the two liquids was controlled to be 1:1.3) by using a feed pump, and then pumped into a microwave continuous flow microchannel reactor (an inner diameter of 1.6 mm PTFE tube, an output power of 800 W). The retention volume in the microchannel reactor was 30 mL, the reaction temperature was controlled to be 210°C, the back pressure value of the back pressure valve was set to be 25 bar, the reaction retention time was 5 minutes, and the reaction material flowed out of the outlet of the microchannel reactor. The product liquid was collected from the storage tank, and then separated, purified, and decolorized. The yield of the obtained product was 95%, and the purity was greater than 98%.
[0045] Example 4
[0046] The raw material of the double benzyl-substituted substrate (R1 is hydrogen, and Ar is a p-methoxyphenyl group) (0.20 mol) was dissolved in 400 mL of anisole and placed in a substrate liquid storage tank. 400 mL of a mixed acid solution of sulfuric acid and phosphoric acid (1:1.5) was placed in the substrate liquid storage tank. The raw material liquid and the mixed acid solution were respectively fed into a Hastelloy mesh microchannel mixer (the flow ratio of the two liquids was controlled to be 1:1.1) by using a feed pump, and then pumped into a microwave continuous flow microchannel reactor (an inner diameter of 1.6 mm PTFE tube, an output power of 900 W). The retention volume in the microchannel reactor was 30 mL, the reaction temperature was controlled to be 200°C, the back pressure value of the back pressure valve was set to be 30 bar, the reaction retention time was 3 minutes, and the reaction material flowed out of the outlet of the microchannel reactor. The product liquid was collected from the storage tank, and then separated, purified, and decolorized. The yield of the obtained product was 98%, and the purity was greater than 99%.
[0047] Example 5
[0048] The raw material of the double benzyl-substituted substrate (R1 is hydrogen, Ar is p-methoxyphenyl) (0.30 mol) was dissolved in 300 mL of acetonitrile and placed in a substrate liquid storage tank. 300 mL of methanesulfonic acid and acetic acid (2.5:1) was placed in a substrate liquid storage tank. The raw material liquid and the mixed acid liquid were respectively fed into a T-shaped channel mixer (the flow ratio of the two liquids was controlled to be 1:1.5) by a feed pump, and then pumped into a microwave continuous flow microchannel reactor (an inner diameter of 1.6 mm PTFE tube, an output power of 700 W). The retention volume in the microchannel reactor was 40 mL, the reaction temperature was controlled at 200°C, the back pressure value of the back pressure valve was set to 25 bar, the reaction retention time was 5 minutes, and the reaction material flowed out of the microchannel reactor outlet. The product liquid was collected from the storage tank, separated, purified, and decolorized, and analyzed. The yield of the obtained product was 96%, and the purity was greater than 98%.
[0049] The continuous flow microchannel reaction does not require a stirring device, which greatly reduces energy consumption, and the process is continuous, easy to operate, highly automated, and greatly improves efficiency. In addition, the online liquid holdup of the micro-reaction continuous flow synthesis method is small, and the excellent mass transfer and heat transfer characteristics of the microchannel reactor make the process intrinsically safe, effectively solving the problem of large safety hazards in the catalytic hydrogenation of traditional batch kettle synthesis methods.
[0050] Finally, it should be noted that the above examples are only used to illustrate the technical solutions of the present application and not to limit the scope of protection of the present application. Although the present application has been described in detail with reference to the preferred embodiments, those skilled in the art should understand that the technical solutions of the present application can be modified or replaced by equivalents without departing from the essence and scope of the technical solutions of the present application.
Claims
1. A method for microwave continuous flow debenzylations, characterized by: The specific steps are as follows: (1) pumping the benzyl-containing raw material liquid and the debenzylating reagent into a micro-mixer for mixing; (2) pumping the reaction liquid in step (1) into a microwave continuous flow micro-channel reactor for microwave continuous debenzylating reaction; (3) pumping the reaction liquid in step (2) into an adjustable back pressure valve, collecting the reaction mixture flowing out of the microwave continuous flow micro-channel reactor, and obtaining the target product after debenzylating through separation and purification treatment; The reaction formula is as follows: In the formula, R1 is any one of hydrogen, alkyl, cycloalkyl, and substituted phenyl, and Ar is substituted phenylthiophenyl, biphenyl, or naphthyl.
2. The process for debenzylating in continuous flow under microwave according to claim 1, characterized in that, The debenzylating reagent in step (1) is any one of CH3SO3H, H2SO4, HBr, H3PO4, H3PO2, CH3CO2H, and CF3CO2H, or a mixture of two or more thereof in any ratio.
3. The process for debenzylating in continuous flow under microwave according to claim 1, characterized in that, The solvent of the benzyl-containing raw material liquid in step (1) is any one of ethyl acetate, dichloromethane, toluene, o-xylene, m-xylene, p-xylene, mesitylene, anisole dichloromethane, trichloromethane, carbon tetrachloride, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether, acetonitrile, and acetone, or a mixture of two or more thereof in any ratio.
4. The process for debenzylating in continuous flow under microwave according to claim 1, characterized in that, The concentration of the raw material liquid in step (1) is 0.05-5.0 M.
5. The process for debenzylating in continuous flow according to claim 1, characterized in that, The micro-mixer of the reaction material in step (1) is any one of a T-shaped, Y-shaped, cross-shaped, and screen-shaped mixer.
6. The process for debenzylating in continuous flow according to claim 1, characterized in that, The micro-channel reactor in step (2) is a tubular micro-channel reactor, and the inner diameter of the tubular micro-channel reactor is 0.1-50 mm.
7. The process for debenzylating in continuous flow under microwave according to claim 1, characterized by, The reaction temperature of the reaction liquid pumped into the microwave continuous flow reactor in step (2) is 100-260 ℃, and the microwave continuous flow reaction time is 0.1-30 min.
8. The process for debenzylating in continuous flow under microwave according to claim 1, characterized by, The material of the micro-channel reactor in step (2) is any one of polyethylene, polypropylene, glass fiber reinforced polypropylene, and polytetrafluoroethylene, or a mixture of two or more thereof in any ratio.
9. The process for debenzylating in continuous flow under microwave according to claim 1, characterized by, The output power of the microwave continuous flow micro-channel reactor in step (2) is 200-1000 W.
10. The process for debenzylating in continuous flow under microwave according to claim 1, characterized by, The back pressure value of the adjustable back pressure valve in step (3) is 2.5-30 bar.