A continuous flow method for the synthesis of a boscalid derivative

Abstract

The application provides a continuous flow synthesis method of a Bose factor derivative, which comprises flowing reaction of D-glucose and dimethyl barbituric acid under alkaline conditions in a micro-channel reactor to synthesize 2,4(1H,3H)-pyrimidine dione-5-D-glucopyranosyl-6-hydroxy-1,3-dimethyl sodium salt, and flowing reaction of the reaction product with an oxidizing agent in another micro-channel reactor to obtain the Bose factor derivative (2ξ,3ξ)-3,7-dehydrated-N-methyl-D-glucosinamide. The continuous synthesis method of the Bose factor derivative has the advantages of short reaction time, simple operation, high automation degree, cheap and easily obtained reagent, high purity of the obtained product, and few impurities. Meanwhile, the preparation method has the advantages of high safety, large production capacity, high yield, reduced environmental pollution, and good application prospect.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, specifically relating to a continuous flow synthesis method for Bosein derivatives. Background Technology

[0002] In 2019, the international patent application "Method for Treating Keratin Materials with Amide C-Glucoside Derivatives and Cosmetic Compositions Containing Them" (WO2016 / 177908A1) first disclosed the preparation method and cosmetic potential of amide C-glucoside derivatives, namely Pro-Xylane derivatives. Pro-Xylane derivatives, when added to cosmetics, have whitening, anti-aging, and moisturizing effects. They are mainly used for non-therapeutic cosmetic treatments such as decolorizing, brightening, and bleaching keratin materials, as well as combating skin aging and dryness. They do not contain any unpleasant odor, color, or appearance, are safe and non-toxic, and are suitable for topical application to the skin and epidermis.

[0003] The aforementioned patent application discloses a series of methods for synthesizing amide C-glycoside derivatives, namely Bosein derivatives. When the starting material is D-glucose, the route for synthesizing the Bosein derivative (IC) glue is as follows:

[0004] ;

[0005] (LA)gluc is one of the Bosein derivatives. A series of (IC)gluc are synthesized through alkalization, esterification protection, lactone formation, reaction with amine R1R2NH, and deprotection. However, the synthesis of (LA)gluc involves hydrogen peroxide and an oxidation process, and the synthesis of (IV)gluc requires further concentration, posing an explosion risk. In 2022, my country's Ministry of Emergency Management issued the "Guidelines for Safety Risk Prevention and Control of Hazardous Chemical Production Construction Projects (Trial)" (Emergency Management

[2022] No. 52), which lists oxidation processes as one of the key hazardous processes under supervision. For newly constructed fine chemical production projects involving hazardous chemical processes, continuous production processes should be prioritized if the process conditions meet the requirements for continuous technologies such as micro-reaction, tubular, and circulating flow after evaluation. Summary of the Invention

[0006] To address the problems existing in the prior art, this invention provides a continuous flow synthesis method for Bosein derivatives. This flow synthesis method consists of two steps: first, D-glucose and dimethylbarbituric acid are reacted in a microchannel reactor under alkaline conditions to synthesize 2,4(1H,3H)-pyrimidinidone-5-D-pyranoglucosyl-6-hydroxy-1,3-dimethyl sodium salt; then, the above substance is reacted with an oxidant in another microchannel reactor to obtain (2ξ,3ξ)-3,7-dehydro-N-methyl-D-glucosinolate, one of the Bosein derivatives. The continuous synthesis method for Bosein derivatives provided by this invention has a short reaction time, simple operation, high degree of automation, inexpensive and readily available reagents, high purity of the obtained product, and few impurities. At the same time, the preparation method has high safety, high production capacity, high yield, and can reduce environmental pollution, showing good application prospects.

[0007] Subsequently, using a traditional synthetic approach, a series of bosine derivatives can be obtained by alkalization, esterification protection and lactone formation, reaction with amine R1R2NH and deprotection of (2ξ,3ξ)-3,7-dehydro-N-methyl-D-glucosinolate.

[0008] The continuous flow synthesis method of the Bosein derivative of this invention is as follows:

[0009] (1) Dissolve D-glucose in water to prepare reaction phase A, dissolve dimethylbarbituric acid and base in water to prepare reaction phase B, and use a plunger pump to pump reaction phase A and reaction phase B into the first mixer at a set constant flow rate. After mixing, the mixture enters the microchannel reactor I and reacts at 80~100℃ for 200~400s to obtain compound 3.

[0010] ;

[0011] The molar ratio of D-glucose to dimethylbarbituric acid is 1:1~3, and the molar ratio of D-glucose to base is 1:1~3; the base is selected from sodium bicarbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, and potassium carbonate; the concentration of D-glucose in reaction phase A is 0.5~1.5 mmol / mL, and the flow rate of reaction phase A or reaction phase B is 0.5~1 mL / min.

[0012] (2) The reaction product and oxidant of step (1) are pumped into the second mixer respectively. After being held at 20~80℃ for 100~150s, they are introduced into the microchannel reactor II and reacted at 20~80℃ for 200~400s. The reaction product is transferred to the reaction flask, a reducing agent is added, and the mixture is stirred at room temperature for 0.5~2h. Then, it is recrystallized to obtain the Bosein derivative.

[0013] .

[0014] The molar ratio of D-glucose to oxidant is 1:1.5~2, the molar ratio of D-glucose to reducing agent is 1:0.2~0.3, the oxidant is a 20~40% H2O2 solution, and the reducing agent is a 15~25% sodium metabisulfite aqueous solution; the pump flow rate of the reaction product or oxidant is 0.5~1 mL / min.

[0015] The advantages and technical effects of this invention are as follows:

[0016] The continuous synthesis method for Bosein derivatives provided by this invention utilizes a microchannel reactor and a continuous flow synthesis method to prepare Bosein derivatives, avoiding the risk of explosion, eliminating the post-processing of (IV)gluc, and increasing the yield from 61.7% to 78%. This method is simple, highly automated, has a short reaction time, is safe, green and efficient, and uses readily available raw materials. It does not require complex purification and impurity removal processes, greatly saving costs and improving yield. The obtained product has high purity and few impurities, and the preparation method has a large production capacity and high yield, which can reduce environmental pollution and has good application prospects. Attached Figure Description

[0017] Figure 1 This is a schematic diagram of the apparatus and process used in the method of the present invention. Detailed Implementation

[0018] The present invention will be further described below with reference to embodiments. However, the scope of the present invention is not limited to the following examples. Those skilled in the art will understand that various changes and modifications can be made to the present invention without departing from the spirit and scope thereof. Unless otherwise specified, the instruments, reagents, and materials involved in the following embodiments are all conventional instruments, reagents, and materials already existing in the prior art and can be obtained through legitimate commercial channels. Unless otherwise specified, the experimental methods and detection methods involved in the following examples are all conventional experimental methods and detection methods already existing in the prior art.

[0019] The synthesis reaction formula for the bosine derivative in the examples is as follows:

[0020] ; Example 1

[0021] 1. For example Figure 1As shown, 5g of D-glucose was dissolved in 30mL of water and stirred for 5 minutes until the D-glucose was completely dissolved, obtaining reaction phase A. 4.33g of dimethyl barbituric acid and 2.33g of sodium bicarbonate were dissolved in 30mL of water, obtaining reaction phase B. The flow rates of reaction phase A and reaction phase B were set to 0.5mL / min using a plunger pump. The mixture was pumped into the first mixer at a constant flow rate and then into microchannel reactor I. The mixture was reacted at 80℃ for 300s.

[0022] 2. The reaction product from step 1 and 5 mL of 30% H2O2 solution were pumped into the second mixer at a flow rate of 0.5 mL / min using a plunger pump. After being held at 40°C for 120 s, the mixture was transferred into microchannel reactor II and reacted at 40°C for 300 s. The reaction product was then transferred to a 250 mL flask, and 20% sodium metabisulfite aqueous solution was added (the molar ratio of D-glucose to sodium metabisulfite was 1:0.3). After stirring at room temperature for 1 h, the reaction product was recrystallized in 100 mL of anhydrous ethanol. A white solid precipitated out. The solid was filtered and dried under vacuum to obtain compound 4, 5.41 g, with a yield of 78%.

[0023] 3. Compound 4 (2.56 g, 10 mmol) was added to 50 mL of NaOH (4 g, 100 mmol) aqueous solution. After stirring at 110 °C for 5 hours, the reaction mixture was cooled to room temperature. Amberlite IR-120 strong acid cation exchange resin was added to adjust the pH to 4. The resin was then removed by filtration, and the filtrate was concentrated to obtain compound 5, 2.3 g.

[0024] ;

[0025] 4. Compound 5 (2.5 g, 10 mmol), NaOAc (2 g, 10 mmol), and 20 mL Ac₂O were mixed and stirred at 110 °C for 16 hours. The mixture was then concentrated to dryness. The residue was dissolved in 200 mL of saturated NaHCO₃ aqueous solution and extracted three times with ethyl acetate. The organic phases were combined and concentrated under vacuum. The concentrate was purified by silica gel chromatography (petroleum ether:ethyl acetate = 2:1) to give compound 6, 1.9 g, in 50% yield.

[0026]

[0027] 5. Compound 6 (1.50 g, 3.86 mmol), L-glycine ethyl ester hydrochloride (0.54 g, 3.86 mmol), and DIEA (1.50 g, 11.59 mmol) were added to THF (50 mL), mixed well, and stirred at 80 °C for 14 hours. After removing the solvent by evaporation, 5 mL of ethyl acetate was added to dissolve the residue. The residue was washed twice with (0.1 M) HCl aqueous solution, and the aqueous phase was extracted with ethyl acetate. The organic phases were collected and combined, dried over MgSO4, filtered and evaporated, and the residue was purified by silica gel chromatography (ethyl acetate: n-heptane = 2:1) to obtain compound 7, with a mass of 1.15 g and a yield of 61%.

[0028] ;

[0029] 6. Product 7 (569 mg, 1.16 mmol) was dissolved in 15 mL of 7 M ammonia solution. The mixture was stirred at room temperature for 17 hours. After evaporating the solvent, 5 mL of methanol was added to dissolve the residue. After adding 50 mL of ethyl acetate, a precipitate was formed. The precipitate was filtered, washed with ethyl acetate and n-heptane, and dried under vacuum to give compound 8, with a mass of 333 mg and a yield of 98%.

[0030] . Example 2

[0031] The method in this embodiment is the same as in embodiment 1, except that sodium bicarbonate in step (a) is replaced with sodium hydroxide. The mass of compound 4 obtained is 4.16 g, with a yield of 60%. Example 3

[0032] The method in this embodiment is the same as in Example 1, except that the reaction temperature of microchannel reactor I in step (a) is 100°C, and the mass of compound 4 obtained is 5.82g, with a yield of 84%. Example 4

[0033] The method in this embodiment is the same as in embodiment 3, except that the reaction temperature of microchannel reactor II in step (b) is 80°C, the mass of compound 4 obtained is 4.44 g, and the yield is 64%. Example 5

[0034] The method in this embodiment is the same as in embodiment 3, except that the flow rate of the plunger pump in steps (a) and (b) is 1.0 mL / min, the mass of compound 4 obtained is 5.55 g, and the yield is 80%.

Claims

1. A continuous flow synthesis method for a Bosein derivative, characterized in that, The steps are as follows: (1) Dissolve D-glucose in water to prepare reaction phase A, dissolve dimethylbarbituric acid and base in water to prepare reaction phase B, and use a plunger pump to pump reaction phase A and reaction phase B into the first mixer at a set constant flow rate. After mixing, the mixture enters the microchannel reactor I and reacts at 80~100℃ for 200~400s to obtain compound 3. ； (2) The reaction product and oxidant of step (1) are pumped into the second mixer respectively. After being held at 20~80℃ for 100~150s, they are introduced into the microchannel reactor II and reacted at 20~40℃ for 200~400s. The reaction product is transferred to the reaction flask, a reducing agent is added, and the mixture is stirred at room temperature for 0.5~2h. Then, it is recrystallized to obtain the Bosein derivative. ； The alkali is selected from sodium bicarbonate, sodium carbonate, and potassium carbonate; the flow rate of reaction phase A or reaction phase B is 0.5~1 mL / min; the molar ratio of D-glucose to oxidant is 1:1.5~2, the molar ratio of D-glucose to reducing agent is 1:0.2~0.3, the oxidant is a 20~40% H2O2 solution, and the reducing agent is a 15~25% sodium metabisulfite aqueous solution. In step (2), the reaction product or oxidant is pumped in at a flow rate of 0.5~1 mL / min.

2. The continuous flow synthesis method for Bosein derivatives according to claim 1, characterized in that: The molar ratio of D-glucose to dimethylbarbituric acid is 1:1~3, and the molar ratio of D-glucose to base is 1:1~3.

3. The continuous flow synthesis method for Bosein derivatives according to claim 1, characterized in that: The concentration of D-glucose in phase A of the reaction solution is 0.5~1.5 mmol / mL.

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