A method for continuously preparing piceatannol by micro-tube reaction

Abstract

The present application relates to the technical field of chemical pharmacy, disclose a kind of micro-tube type reaction continuous preparation of piceatannol method, including the step (1) carried out in micro-tube type reactor and the step (2) carried out in kettle type reactor: (1) using the way of two feed, A stock solution and B stock solution are punched into micro-tube type reactor and are reacted, reaction temperature is-5~0 ℃, pressure is 0.15~0.3Mpa, reactor residence time is 40~100s;The A stock solution is the mixed solution of piceid and organic solvent I;The B stock solution is the mixed solution of DMP and organic solvent II;(2) after reaction, discharge to kettle type reactor and carry out reduction reaction with the aqueous solution of reducing agent, then aftertreatment, obtain piceatannol.The present application can be continuously oxidized under the condition close to 0 ℃ by the combined application of DMP and micro-tube type reaction, effectively inhibit the generation of side reaction, improve product quality and yield.

Description

Technical Field

[0001] This invention relates to the technical field of medicinal chemistry, and in particular to a method for the continuous preparation of paclitaxel via a microtubule reaction. Background Technology

[0002] The chemical formula of paclitaxel is C 14 H 12 O4 is a natural small molecule compound with anti-leukemia activity, capable of inhibiting non-receptor activating enzymes, spleen tyrosine kinase, and lymphocyte-specific protein tyrosine kinase. Paclitaxel is a compound with a chemical structure similar to resveratrol, widely found in fruits and vegetables such as grapes, blueberries, and passion fruit. It can inhibit the growth and development of immature fat cells, thereby achieving weight loss. In addition, paclitaxel may also help prevent cancer, heart disease, and neurological disorders.

[0003] Currently, direct extraction of leucopicrin from plants is costly and yields very low. However, leucopicrin has a chemical structure similar to resveratrol, and its sources are widely available (such as peanuts, grapes (red wine), Japanese knotweed, and mulberries). Extraction from plants is now a mature and inexpensive process. Numerous studies have reported the use of artificial chemical synthesis to prepare leucopicrin. The key to its synthesis lies in the coupling reaction of two benzene rings, i.e., the synthesis of the stilbene skeleton. However, the preparation process involves the issue of cis-trans isomerism.

[0004] Patent CN201110253242.8 reports a method for producing leucopicrin using dimethylformamide as a solvent and potassium tert-butoxide as a catalyst. 3,5-Dimethoxybenzyl phosphate undergoes a condensation reaction with 3,5-dimethoxybenzaldehyde to produce 3,4,3',5'-tetramethoxystilbene. Then, using dichloromethane as a solvent and boron tribromide as a catalyst, 3,4,3',5'-tetramethoxystilbene undergoes a demethylation reaction to produce leucopicrin. However, this method yields a low leucopicrin yield, only 45-50%.

[0005] Li Xiaoxia, Yan Ri'an, and Duan Hanying reported a method for synthesizing leucopicrin using the Wittig-Horne reaction in the 5th issue of *Fine Chemicals* in 2011. This synthetic route uses expensive starting materials and involves the use of the toxic substance PBr3, resulting in a low yield. This method is not well-suited for the commercial production of leucopicrin.

[0006] Additionally, a literature report (Plant Catechols and Their S-Glutathionyl Conjugates as Antiinitrosating Agents: Expedient Synthesis and Remarkable Potency of 5-S-Glutathionylpiceatannol, Chemical Research in Toxicology, 21, 12, 2407-2413) reports the use of resveratrol as a raw material and methanol as a solvent, oxidized with o-iodobenzoic acid (IBX) at a low temperature of -78℃ for 70 min. The oxidized intermediate was then reduced with the reducing agent Na2S2O4 to obtain piceatannol. The reaction equation is as follows: However, the oxidation of resveratrol using IBX reagent requires very low reaction temperatures to achieve high yields, resulting in high energy consumption. Furthermore, as the amount of reactants increases, the amount of byproducts also increases, leading to a decrease in product yield. Summary of the Invention

[0007] To address the problems in the prior art, this invention provides a method for the continuous preparation of paclitaxel using a microtubule reaction. DMP is used as the oxidant, and the paclitaxel is continuously oxidized via a microtubule reaction to achieve product production. Compared to IBX, DMP has better solubility in solvents, which is beneficial for implementing microtubule reactions. By combining DMP and microtubule reactions, resveratrol can be continuously oxidized at relatively high temperatures (close to 0°C). Furthermore, through research on reducing agents, reagents such as Na2S2O4, NaBH4, and KBH4 have been screened for reducing intermediate quinones to obtain the final product. Experiments have shown that the above process can effectively reduce side reactions and obtain high-quality, high-yield paclitaxel. At the same time, it also significantly reduces energy consumption, making it suitable for the commercial production of paclitaxel.

[0008] The objective of this invention is achieved through the following technical solution: a method for the continuous preparation of paclitaxel via a microtubule reaction, comprising step (1) in a microtubule reactor and step (2) in a batch reactor: (1) (2)

[0009] As a preferred option, the specific steps include the following: (1) A two-pronged feeding method is used to feed the A-pronged solution and the B-pronged solution into a microtube reactor for reaction. The reaction temperature is -5 to 0℃, the pressure is 0.15 to 0.3 MPa, and the residence time in the reactor is 40 to 100 s. The A-pronged solution is a mixed solution of resveratrol and organic solvent I. The B-pronged solution is a mixed solution of DMP and organic solvent II. (2) After the reaction is completed, the material is discharged into a batch reactor to undergo a reduction reaction with an aqueous solution of reducing agent, and then post-processed to obtain taurine.

[0010] The preparation method reported in the literature (Plant Catechols and Their S-Glutathionyl Conjugates as Antiinitrosating Agents: Expedient Synthesis and Remarkable Potency of 5-S-Glutathionylpiceatannol, Chemical Research in Toxicology, 21, 12, 2407-2413) has been found in our small-scale studies to require very low reaction temperatures (below -60°C) when oxidizing resveratrol using IBX reagents; otherwise, the yield is low. Furthermore, with increasing feed amounts, byproducts also increase, leading to a decrease in product yield. It is speculated that the intermediate quinone formed during the reaction may have undergone self-polymerization or other reactions, and the increased byproducts are due to the poorer mass and heat transfer in the batch reactor. The applicant attempted to eliminate the scale-up effect using continuous microchannel reaction. However, due to the poor solubility of IBX oxidant in solvent, even if continuous microchannel reaction is used to promote the reaction and improve the reaction efficiency, it is impossible to react at a high temperature. Not only is pipeline blockage easy to occur, but there are still many side reactions, which makes it impossible to realize continuous microchannel process and the yield is low.

[0011] The oxidation reaction of resveratrol to the intermediate quinone is affected by the reactants and reaction conditions. Conventional oxidants (such as KMnO4, K2Cr2O7, NaClO3, etc.) cannot achieve good reaction results and produce many byproducts, resulting in unsatisfactory effects. Studies have found that DMP (Dale Martin reagent) has an oxidation effect similar to IBX and can adapt to the reaction conditions for the oxidation of resveratrol to the intermediate quinone. However, the reaction in a batch reactor requires a very low reaction temperature, and the increase in side reactions leads to a decrease in yield. This invention uses a combination of DMP and microchannel reaction to continuously oxidize resveratrol at higher temperatures (close to 0°C). Increasing the reaction temperature will reduce the solubility of DMP in organic solvents, but by adjusting the reaction parameters of the microchannel reaction, including solution concentration, reactant ratio, and microchannel parameters, the high-efficiency oxidation effect of DMP at higher temperatures can be achieved, realizing a continuous oxidation reaction in the microchannel. Furthermore, the intermediate quinones obtained after oxidation by DMP oxidant have high activity and are easily reduced by reducing agents. Moreover, the activation energy required for the reduction reaction is very low, which can shorten the reduction reaction time and improve the reaction efficiency.

[0012] Preferably, the molar ratio of resveratrol to DMP in the microtubular reactor is 1:1 to 1.5.

[0013] Preferably, the resveratrol concentration in the A-strand solution is 5-15%, more preferably 5-10%.

[0014] Preferably, the mass concentration of DMP in the B-strand solution is 3-15%, more preferably 5-10%, and DMP is a Des Martin oxidant.

[0015] Reducing the amount of organic solvent I and organic solvent II can improve reaction efficiency, but the mass concentration of the solution cannot be too high, otherwise the raw materials will not dissolve easily, the pipeline will be easily blocked, and it will be difficult to carry out microchannel reactions.

[0016] Preferably, the reducing agent is NaBH4, KBH4, or Na2S2O4.

[0017] Preferably, the mass concentration of the reducing agent in the aqueous solution is 10-30%; and the temperature of the aqueous solution is controlled at 0-20°C.

[0018] The temperature of the reducing agent aqueous solution should be controlled between 0-20℃. If the temperature is too high, the product yield will decrease and the color will be poor.

[0019] Preferably, the molar ratio of the reducing agent to resveratrol is 1 to 3:1.

[0020] Preferably, the reduction reaction is a mixing and stirring reaction for 10 to 20 minutes.

[0021] Preferably, the organic solvent I is one or more of methanol, ethanol, acetone, and acetonitrile.

[0022] Preferably, the organic solvent II is one or more of methanol, ethanol, acetone, acetonitrile, and tetrahydrofuran.

[0023] Preferably, the post-processing includes: concentrating the reaction solution under reduced pressure, adding ethyl acetate and allowing it to stand for separation, washing the organic layer with water and drying it with anhydrous sodium sulfate, concentrating it under reduced pressure, adding dichloromethane to the concentrate for crystallization, filtering and recrystallizing to obtain leucopicrin.

[0024] Preferably, the solvent used for recrystallization is methanol, ethanol, isopropanol, acetone, acetonitrile, or a mixture thereof with water.

[0025] Preferably, the microtube reactor is made of 316L stainless steel; the interior of the microtube reactor has a spiral coil structure and uses stainless steel tubes with an inner diameter of 0.5 to 1.0 mm.

[0026] Compared with existing technologies, this invention has the following advantages: By combining DMP and microtubule reactors, resveratrol can be continuously oxidized at relatively high temperatures (close to 0°C). Replacing the reaction vessel with a microtubule reactor results in a stable process, requires less space, improves mass and heat transfer, shortens reaction time, increases reaction temperature, and effectively suppresses side reactions such as intermediate quinone polymerization, leading to high-quality, high-yield leucine. Simultaneously, it significantly reduces energy consumption, making it suitable for the commercial production of leucine. Detailed Implementation

[0027] The technical solution of the present invention is illustrated below with specific embodiments, but the scope of protection of the present invention is not limited thereto: A method for the continuous preparation of leucopicrin via a microtubule reaction includes the following steps: (1) Prepare A-strand solution and B-strand solution respectively. A-strand solution is a mixed solution of resveratrol and organic solvent I (the mass concentration of resveratrol is 5-15%). Organic solvent I is one or more of methanol, ethanol, acetone and acetonitrile. B-strand solution is a mixed solution of DMP oxidant and organic solvent II (the mass concentration of DMP is 3-15%). Organic solvent II is one or more of methanol, ethanol, acetone, acetonitrile and tetrahydrofuran. A-strand solution and B-strand solution are fed into a microtube reactor for reaction using a two-stream feeding method. By adjusting the flow rate of A-strand solution and B-strand solution, the molar ratio of resveratrol to DMP is 1:1-1.5, the reaction temperature is -5-0℃, the pressure is 0.15-0.3 MPa, and the residence time in the reactor is 40-100 s. The reaction equations for the above steps are as follows: (2) After the reaction is completed, the material is discharged into a batch reactor and mixed with an aqueous solution of reducing agent (the mass concentration of reducing agent in the aqueous solution of reducing agent is 10-30%, the reducing agent is NaBH4, KBH4 or Na2S2O4, and the temperature of the aqueous solution of reducing agent is controlled at 0-20℃) and stirred for 10-20 min. The molar ratio of reducing agent to resveratrol is 1-3:1. After the reduction reaction is completed, the reaction solution is obtained. The reaction equations for the above steps are as follows: (3) After the reaction, the liquid was concentrated under reduced pressure, and then ethyl acetate was added and allowed to stand for separation. The organic layer was washed with water and dried with anhydrous sodium sulfate. The solution was then concentrated under reduced pressure. The concentrate was crystallized by adding dichloromethane. After filtration, methanol, ethanol, isopropanol, acetone, acetonitrile or a mixture of solvents with water were added for recrystallization to obtain white paclitaxel.

[0028] Example 1 The microtube reactor uses a stainless steel tube with an inner diameter of 0.5 mm and a spiral coil. The microtube reactor is immersed in glacial ethylene glycol, the outlet pipe is connected to the liquid-liquid separator, and the inlet pipe is connected to the feed pump.

[0029] (1) Solution A (methanol solution of resveratrol): Dissolve 100g of resveratrol in 1900g of methanol to prepare a 5% resveratrol methanol solution; Solution B (methanol solution of DMP oxidant): Dissolve 223g of DMP in 4237g of methanol to prepare a 5% DMP methanol solution. A two-stream feeding method, A and B, is used. The A-stream solution and the B-stream solution are fed into the microtube reactor at a certain flow rate. The flow rate is adjusted so that the molar ratio of resveratrol to DMP is 1:1.2. The reaction temperature is controlled at -2.5±2.5℃ and the residence time in the reactor is 80s.

[0030] (2) Solution C: Dissolve 200g of Na2S2O4 in 1800g of water to prepare an aqueous solution of Na2S2O4 with a mass concentration of 10%. Add solution C to a 10L batch reactor and control the temperature at 10±10℃ for later use. After the material has reacted in the microtube reactor, discharge it into the batch reactor to undergo a reduction reaction with solution C. After discharge, continue mixing and stirring for 10 minutes.

[0031] (3) The liquid was concentrated under reduced pressure to about 1500g, 600g of ethyl acetate was added, and the mixture was allowed to stand for separation. The organic layer was washed with water and dried with anhydrous sodium sulfate, and then concentrated under reduced pressure. 500g of dichloromethane was added to the concentrate, and the mixture was stirred for 1h and filtered to obtain the crude wet product of leucopicrin. The crude leucopicrin was added to a mixture of 600g of ethanol and water (volume ratio 1:1) and recrystallized to obtain 75g of purified leucopicrin with a purity of 98% and a molar yield of 70%.

[0032] Example 2 The microtube reactor uses a stainless steel tube with an inner diameter of 0.5 mm and a spiral coil. The microtube reactor is immersed in glacial ethylene glycol, the outlet pipe is connected to the liquid-liquid separator, and the inlet pipe is connected to the feed pump.

[0033] (1) A-component solution (acetone solution of resveratrol): Dissolve 100g of resveratrol in 900g of acetone to prepare a resveratrol acetone solution with a mass concentration of 10%; B-component solution (methanol solution of DMP oxidant): Dissolve 223g of DMP in 2565g of methanol to prepare a DMP methanol solution with a mass concentration of 8%. A two-stream feeding method, A and B, is used. The A-stream solution and the B-stream solution are fed into the microtube reactor at a certain flow rate. The flow rate is adjusted so that the molar ratio of resveratrol to DMP is 1:1.2. The reaction temperature is controlled at -2.5±2.5℃ and the residence time in the reactor is 100s.

[0034] (2) Solution C: Dissolve 200g of Na2S2O4 in 1800g of water to prepare an aqueous solution of Na2S2O4 with a mass concentration of 10%. Add solution C to a 10L batch reactor and control the temperature at 5±5℃ for later use. After the material has reacted in the microtube reactor, discharge it into the batch reactor to undergo a reduction reaction with solution C. After discharge, continue mixing and stirring for 10 minutes.

[0035] (3) The liquid was concentrated under reduced pressure to about 1500g, 600g of ethyl acetate was added, and the mixture was allowed to stand for separation. The organic layer was washed with water and dried with anhydrous sodium sulfate, and then concentrated under reduced pressure. 500g of dichloromethane was added to the concentrate, and the mixture was stirred for 1h and filtered to obtain the crude wet product of leucopicrin. The crude leucopicrin was added to a mixture of 600g of ethanol and water (volume ratio 1:1) and recrystallized to obtain 72g of purified leucopicrin with a purity of 98% and a molar yield of 67%.

[0036] Example 3 The microtube reactor uses a stainless steel tube with an inner diameter of 0.5 mm and a spiral coil. The microtube reactor is immersed in glacial ethylene glycol, the outlet pipe is connected to the liquid-liquid separator, and the inlet pipe is connected to the feed pump.

[0037] (1) Solution A (ethanol solution of resveratrol): Dissolve 100g of resveratrol in 1900g of ethanol to prepare a 5% resveratrol ethanol solution; Solution B (methanol solution of DMP oxidant): Dissolve 223g of DMP in 4237g of methanol to prepare a 5% DMP methanol solution. A two-stream feeding method, A and B, is used. The A-stream solution and the B-stream solution are fed into the microtube reactor at a certain flow rate. The flow rate is adjusted so that the molar ratio of resveratrol to DMP is 1:1.2. The reaction temperature is controlled at -2.5±2.5℃ and the residence time in the reactor is 80s.

[0038] (2) Solution C: Dissolve 45g of NaBH4 in 800g of water to prepare an aqueous solution of NaBH4 with a mass concentration of 5.3%; Add solution C to a 10L batch reactor and control the temperature at 2.5±2.5℃ for later use. After the material has reacted in the microtube reactor, it is discharged into the batch reactor to undergo a reduction reaction with solution C. After the discharge is complete, continue mixing and stirring for 20 minutes.

[0039] (3) The liquid was concentrated under reduced pressure to about 1500g, 600g of ethyl acetate and 1000g of water were added, and the mixture was allowed to stand for separation. The organic layer was washed with water and dried with anhydrous sodium sulfate, and then concentrated under reduced pressure. 500g of dichloromethane was added to the concentrate, and the mixture was stirred for 1h and filtered to obtain the crude wet product of leucopicrin. The crude leucopicrin was added to a mixture of 600g of ethanol and water (volume ratio 1:1) and recrystallized to obtain 73g of purified leucopicrin with a purity of 98% and a molar yield of 68%.

[0040] Example 4 The microtube reactor uses a stainless steel tube with an inner diameter of 0.5 mm and a spiral coil. The microtube reactor is immersed in glacial ethylene glycol, the outlet pipe is connected to the liquid-liquid separator, and the inlet pipe is connected to the feed pump.

[0041] (1) A-strand solution (methanol solution of resveratrol): Dissolve 100g of resveratrol in 1500g of methanol to prepare a resveratrol methanol solution with a mass concentration of 6.3%; B-strand solution (tetrahydrofuran solution of DMP oxidant from Dysmart): Dissolve 223g of DMP in 4237g of tetrahydrofuran to prepare a DMP tetrahydrofuran solution with a mass concentration of 5%; Using a two-stream feeding method, A-strand solution and B-strand solution are fed into the microtube reactor at a certain flow rate. The flow rate is adjusted so that the molar ratio of resveratrol to DMP is 1:1.2; the reaction temperature is controlled at -2.5±2.5℃ and the residence time in the reactor is 80s.

[0042] (2) Solution C: Dissolve 45g of NaBH4 in 800g of water to prepare an aqueous solution of NaBH4 with a mass concentration of 5.3%; Add solution C to a 10L batch reactor and control the temperature at 2.5±2.5℃ for later use. After the material has reacted in the microtube reactor, it is discharged into the batch reactor to undergo a reduction reaction with solution C. After the discharge is complete, continue mixing and stirring for 20 minutes.

[0043] (3) The liquid was concentrated under reduced pressure to about 1500g, 600g of ethyl acetate and 1000g of water were added, and the mixture was allowed to stand for separation. The organic layer was washed with water and dried with anhydrous sodium sulfate, and then concentrated under reduced pressure. 500g of dichloromethane was added to the concentrate, and the mixture was stirred for 1h and filtered to obtain the crude wet product of leucopicrin. The crude product of leucopicrin was added to a mixture of 600g of ethanol and water (volume ratio 1:1) and recrystallized to obtain 77g of purified leucopicrin with a purity of 98% and a molar yield of 72%.

[0044] Comparative Example 1 This comparative example replicates the preparation method of piceatannol reported in the literature (Plant Catechols and Their S-GlutathionylConjugates as Antinitrosating Agents: Expedient Synthesis and Remarkable Potency of 5-S-Glutathion-ylpiceatannol, Chemical Research in Toxicology, 21, 12, 2407-2413).

[0045] Specifically, 15 g (66 mmol) of resveratrol was dissolved in 900 ml of methanol and cooled to -78 °C. 45 g (160 mmol) of IBX was added under vigorous stirring. After 3 hours, the reaction mixture was added to 1000 ml of an aqueous solution containing 30 g of Na₂S₂O₄. The solution was acidified with hydrochloric acid to pH 3, and then extracted three times with 500 ml of chloroform and 500 ml of ethyl acetate, respectively. The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 6.9 g of solid. The yield was 43%, and the product purity was 95%.

[0046] Comparative Example 2 Comparative Example 1 was modified to use a microchannel reactor for the reaction.

[0047] (1) A-share solution (methanol solution of resveratrol): Dissolve 100g of resveratrol in 1900g of methanol to prepare a 5% resveratrol methanol solution; B-share solution (methanol solution of IBX): Dissolve 147g of DMP in 2793g of methanol to prepare a 5% IBX methanol solution. A two-stream feeding method, A and B, is used. The A-stream solution and the B-stream solution are fed into the microtube reactor at a certain flow rate. The flow rate is adjusted so that the molar ratio of resveratrol to IBX is 1:2.4. The reaction temperature is controlled at -2.5±2.5℃ and the residence time in the reactor is 80s.

[0048] (2) Solution C: Dissolve 200g of Na2S2O4 in 1800g of water to prepare an aqueous solution of Na2S2O4 with a mass concentration of 10%. Add solution C to a 10L batch reactor and control the temperature at 10±10℃ for later use. After the material has reacted in the microtube reactor, discharge it into the batch reactor to undergo a reduction reaction with solution C. After discharge, continue mixing and stirring for 10 minutes.

[0049] (3) The liquid was concentrated under reduced pressure to about 1500g, 600g of ethyl acetate was added, and the mixture was allowed to stand for separation. The organic layer was washed with water and dried with anhydrous sodium sulfate, and then concentrated under reduced pressure. 500g of dichloromethane was added to the concentrate, and the mixture was stirred for 1h and filtered to obtain the crude wet product of leucopicrin. The crude leucopicrin was added to a mixture of 600g of ethanol and water (volume ratio 1:1) and recrystallized to obtain 50g of purified leucopicrin with a purity of 97% and a molar yield of 47%.

[0050] Comparative Example 3 The difference from Example 1 is that step (1) uses a batch reactor.

[0051] (1) Dissolve 10g of resveratrol in 500g of methanol, cool to below -70℃, and prepare a 5% resveratrol methanol solution. Add 22.3g of DMP while stirring and react for 3h.

[0052] (2) Add the reaction solution obtained in step (1) to an aqueous solution containing 20g Na2S2O4 (180g) and stir for 10min.

[0053] (3) The liquid obtained in step (2) was concentrated under reduced pressure to about 150g, 100g of ethyl acetate was added, and the mixture was allowed to stand for separation. The organic layer was washed with water and dried with anhydrous sodium sulfate, then concentrated under reduced pressure. 500g of dichloromethane was added to the concentrate, and the mixture was stirred for 1h. The solution was filtered to obtain the crude wet product of leucopicrin. The crude leucopicrin was added to a mixture of 80g of ethanol and water (volume ratio 1:1) and recrystallized to obtain 4.8g of purified leucopicrin with a purity of 98% and a molar yield of 45%.

[0054] Comparative Example 4 The difference from Example 1 is that the mass concentrations of the A-strand solution and the B-strand solution are too high (exceeding the scope defined in the claims).

[0055] (1) Solution A (methanol solution of resveratrol): Dissolve 100g of resveratrol in 525g of methanol to prepare a resveratrol methanol solution with a mass concentration of 16%; Solution B (methanol solution of DMP oxidant): Dissolve 223g of DMP in 1171g of methanol to prepare a DMP methanol solution with a mass concentration of 16%. A two-stream feeding method, A and B, is used. The A-stream solution and the B-stream solution are fed into the microtube reactor at a certain flow rate. The flow rate is adjusted so that the molar ratio of resveratrol to DMP is 1:1.2. The reaction temperature is controlled at -2.5±2.5℃ and the residence time in the reactor is 80s.

[0056] (2) Solution C: Dissolve 200g of Na2S2O4 in 1800g of water to prepare an aqueous solution of Na2S2O4 with a mass concentration of 10%. Add solution C to a 10L batch reactor and control the temperature at 10±10℃ for later use. After the material has reacted in the microtube reactor, discharge it into the batch reactor to undergo a reduction reaction with solution C. After discharge, continue mixing and stirring for 10 minutes.

[0057] (3) The liquid was concentrated under reduced pressure to about 1500g, 600g of ethyl acetate was added, and the mixture was allowed to stand for separation. The organic layer was washed with water and dried with anhydrous sodium sulfate, and then concentrated under reduced pressure. 500g of dichloromethane was added to the concentrate, and the mixture was stirred for 1h and filtered to obtain the crude wet product of leucopicrin. The crude leucopicrin was added to a mixture of 600g of ethanol and water (volume ratio 1:1) and recrystallized to obtain 59g of purified leucopicrin with a purity of 98% and a molar yield of 55%.

[0058] Comparative Example 5 The difference from Example 1 is that the molar ratio of resveratrol to DMP is 1.7.

[0059] (1) Solution A (methanol solution of resveratrol): Dissolve 100g of resveratrol in 1900g of methanol to prepare a resveratrol methanol solution with a mass concentration of 5%; Solution B (methanol solution of DMP oxidant): Dissolve 316g of DMP in 4237g of methanol to prepare a DMP methanol solution with a mass concentration of 6.9%; A two-stream feeding method, A and B, is used. The A-stream solution and the B-stream solution are fed into the microtube reactor at a certain flow rate. The flow rate is adjusted so that the molar ratio of resveratrol to DMP is 1:1.7. The reaction temperature is controlled at -2.5±2.5℃ and the residence time in the reactor is 80s.

[0060] (2) Solution C: Dissolve 200g of Na2S2O4 in 1800g of water to prepare an aqueous solution of Na2S2O4 with a mass concentration of 10%. Add solution C to a 10L batch reactor and control the temperature at 10±10℃ for later use. After the material has reacted in the microtube reactor, discharge it into the batch reactor to undergo a reduction reaction with solution C. After discharge, continue mixing and stirring for 10 minutes.

[0061] (3) The liquid was concentrated under reduced pressure to about 1500g, 600g of ethyl acetate was added, and the mixture was allowed to stand for separation. The organic layer was washed with water and dried with anhydrous sodium sulfate, and then concentrated under reduced pressure. 500g of dichloromethane was added to the concentrate, and the mixture was stirred for 1h and filtered to obtain the crude wet product of leucopicrin. The crude leucopicrin was added to a mixture of 600g of ethanol and water (volume ratio 1:1) and recrystallized to obtain 58g of purified leucopicrin with a purity of 96% and a molar yield of 54%.

[0062] Table 1 Example 1 98 70 Example 2 98 67 Example 3 98 68 Example 4 98 72 Comparative Example 1 95 43 Comparative Example 2 97 47 Comparative Example 3 98 45 Comparative Example 4 98 55 Comparative Example 5 96 54 Note: The molar yield is calculated as follows: (Taxodium production / Taxodium molecular weight) / (Resveratrol feed amount / Resveratrol molecular weight) × 100%.

[0063] As shown in Table 1, comparing Examples 1-4 and Comparative Example 1, the yield obtained by the combined process of DMP oxidant and microtube reactor is more than 20% higher than that of existing technologies. Comparing Example 1 and Comparative Example 3, the yield obtained by the microchannel continuous process is more than 20% higher than that obtained using a batch reactor, and the combination of DMP oxidant and microtube reactor significantly increases the reaction temperature and shortens the reaction time. Comparing Example 1 and Comparative Example 2, it was found that when the technology in Comparative Example 1 was modified to use a microchannel process, DMP performed significantly better than IBX, with a yield increase of more than 20%. This indicates that not all oxidants are suitable for microchannel processes, and the parameters of the microchannel process in this invention are not applicable to all oxidants. Only under the limited conditions of the combined process of DMP oxidant and microchannel reactor in this invention can high yields and high purity products be obtained. Comparing Example 1 and Comparative Example 4, it was found that when using the microchannel process, if the feed concentrations of resveratrol and DMP exceed the limits, the product yield is more than 10% lower. A comparison of Example 1 and Comparative Example 5 revealed that when using the microchannel process, if the molar equivalent of DMP exceeds the limit, the product yield is more than 10% lower.

[0064] The above are merely preferred embodiments of the present invention and do not limit the patent scope of the present invention. Any equivalent structural or procedural transformations made using the present invention specification, or direct or indirect applications in other related technical fields, are similarly included within the patent protection scope of the present invention.

Claims

1. A method for the continuous preparation of paclitaxel via a microtubule reaction, characterized in that, include: （1） ； A two-pronged feeding method is used, with solution A and solution B fed into a microtube reactor for reaction. The reaction temperature is -5 to 0°C, the pressure is 0.15 to 0.3 MPa, and the residence time in the reactor is 40 to 100 s. Solution A is a mixed solution of resveratrol and organic solvent I, with a resveratrol mass concentration of 5% to 15%. Solution B is a mixed solution of DMP and organic solvent II, with a DMP mass concentration of 3% to 15%, and DMP is a Dysmart oxidant. The molar ratio of resveratrol to DMP in the microtube reactor is 1:1 to 1.

5. （2） ； After the reaction is complete, the product is discharged into a batch reactor to undergo a reduction reaction with an aqueous solution of reducing agent. After post-processing, taurine is obtained.

2. The method for continuous preparation of paclitaxel via microtubule reaction according to claim 1, characterized in that, The resveratrol concentration in the A-share solution is 5-10%.

3. The method for continuous preparation of paclitaxel via microtubule reaction according to claim 1, characterized in that, The mass concentration of DMP in the B-strand solution is 5-10%.

4. The method for continuous preparation of paclitaxel via microtubule reaction according to any one of claims 1-3, characterized in that, The reducing agent is NaBH4, KBH4, or Na2S2O4; the mass concentration of the reducing agent in the aqueous solution is 10-30%; and the temperature of the aqueous solution is controlled at 0-20℃.

5. The method for continuous preparation of paclitaxel via microtubule reaction according to any one of claims 1-3, characterized in that, The reduction reaction is a mixing and stirring reaction for 10-20 minutes; the molar ratio of the reducing agent to resveratrol is 1-3:

1.

6. The method for continuous preparation of paclitaxel via microtubule reaction according to claim 1, characterized in that, The organic solvent I is one or more of methanol, ethanol, acetone, and acetonitrile.

7. The method for continuous preparation of paclitaxel via microtubule reaction according to claim 1, characterized in that, The organic solvent II is one or more of methanol, ethanol, acetone, acetonitrile, and tetrahydrofuran.

8. The method for continuous preparation of paclitaxel via microtubule reaction according to claim 1 or 7, characterized in that, The post-processing includes: concentrating the reaction solution under reduced pressure, adding ethyl acetate and allowing it to stand for separation, washing the organic layer with water and drying it with anhydrous sodium sulfate, concentrating it under reduced pressure, adding dichloromethane to the concentrate for crystallization, filtering and recrystallizing to obtain leucopicrin.

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