A method for preparing boson by continuous flow process

Abstract

The present invention relates to a method for preparing bosylamine by a continuous flow process, and belongs to the technical field of fine chemicals. The method is prepared using D-xylose and acetylacetone as raw materials, through a two-step continuous flow reaction, and the second step reaction uses methyldiphenylsilane as a reducing agent, and in the presence of catalyst poly-L-alanine, the carbonyl group is asymmetric reduced to obtain S-hydroxypropyl tetrahydropyrantriol. The technical solution of the present invention is compared with traditional kettle reaction, not only avoiding the use of boride harmful to the environment and human body, but also avoiding the safety risk problem caused by kettle reaction. After adopting the technical solution of the present invention, the yield of the second step reduction reaction is increased from 39% to more than 95%, and the content of S-configuration product is greater than 99%. Effectively reduce production costs and have environmental friendliness.

Description

Technical Field

[0001] The present invention relates to the technical field of fine chemicals, and in particular to a method for preparing bosense using a continuous flow process. Background Art

[0002] Pro-Xylane, also known as hydroxypropyl tetrahydropyrantriol, is a xylose derivative with anti-aging properties. It promotes the production of glycosaminoglycans (GAGs), which in turn promotes the production of proteoglycans. Furthermore, Pro-Xylane effectively promotes tight epidermal-dermal junctions, better anchoring the dermis for stronger, more elastic skin. Long-term use can improve fine lines on the neck and prevent aging. Furthermore, some studies have shown that Pro-Xylane can promote the regeneration of fibroblast growth factor (FGF, similar to EGF), effectively repairing damaged skin. Consequently, Pro-Xylane is widely used in cosmetics, primarily in high-end skincare products such as anti-wrinkle products.

[0003] Existing methods for synthesizing bosylamine mainly include chemical and enzymatic methods. Enzymatic methods, such as patent document CN2020010629023.4, disclose a one-pot method for preparing bosylamine using isopropyl alcohol dehydrogenase and bosylamine synthetase, with a yield of up to 89.5%. This method is relatively green compared to chemical methods, but product purification is difficult. Chemical methods, such as Chinese patent application CN111559998A, disclose a method for synthesizing hydroxypropyl tetrahydropyrantriol. The reduction step uses sodium borohydride, sodium cyanoborohydride, or sodium triacetylborohydride as a reducing agent to prepare bosylamine. The reaction is carried out in a kettle reactor and sodium borohydride is required to reduce the carbonyl group. The reaction generates a large amount of heat and releases hydrogen during the reaction, posing a significant safety risk. Furthermore, the use of sodium borohydride introduces borate into the product. According to cosmetic quality requirements, borate must not be detected in the product. Therefore, a complex process is required to remove the borate, which not only increases production costs but also often results in incomplete borate removal, leading to product quality issues. Patent document CN 201910785216.6 discloses a one-pot method for synthesizing bosine by using a rare earth metal complex to catalyze the Knoevenagel condensation of xylose and ethyl acetoacetate, followed by reduction with isopropanol. The yield reaches 80%, but the use of a homogeneous metal catalyst inevitably increases the metal residue in the product.

[0004] Continuous flow reaction technology, based on the principle of repeated impact driven by a high-pressure constant-flow pump, increases raw material conversion by over 20%, reduces side-reaction impurities by over 30%, and shortens reaction time to 1.3% of that of a batch reactor. This eliminates the amplification effect during the reaction process, enabling fully intelligent and automated chemical reactions suitable for large-scale continuous chemical production. Compared to conventional batch reactors, microreactors offer significant advantages, including high safety, continuously controllable reaction processes, compact size, low energy consumption, and environmental friendliness.

[0005] The present invention develops a set of continuous flow microreactors and applies the continuous flow microreaction technology to the preparation process of bosine, and optimizes the relevant process routes and process parameters to solve the problems of low yield, high residue, large amount of hazardous waste and high safety risks in conventional reaction processes. Summary of the Invention

[0006] Aiming at the problems of low yield, high residue, large amount of hazardous waste and high safety risk in the prior art process for preparing bosaicin in a tank reactor, the present invention uses D-xylose and acetylacetone as raw materials, carries out a two-step continuous flow reaction, and uses methyldiphenylsilane as a reducing agent in the second step to asymmetric reduce the carbonyl group in the presence of a catalyst poly-L-alanine to obtain S-hydroxypropyl tetrahydropyrantriol.

[0007] In order to solve the above technical problems, the present invention adopts the following technical solutions:

[0008] The present invention provides a method for preparing bosylamine using a continuous flow process, comprising: using a metering pump to pump D-xylose, i.e., a mixed solution of compound 1 and alkali solution, and acetylacetone into a microreactor respectively; after the reaction is complete, the feed liquid enters a post-processing system to obtain compound 2; then using a metering pump to dissolve compound 2 in a first solvent and a mixed solution of methyldiphenylsilane, a second solvent, and a catalyst, and pumping them into the microreactor respectively; after the reaction is complete, the feed liquid enters a post-processing system to obtain S-hydroxypropyl tetrahydropyrantriol, i.e., compound 3; the reaction process is shown below:

[0009]

[0010] A method for preparing bosonine by continuous flow process, the specific steps are as follows:

[0011] 1) Using a metering pump, D-xylose, a mixed solution of compound 1 and alkali solution, and acetylacetone are pumped into the microreactor respectively. After the reaction is complete, the feed solution enters the post-treatment system to obtain compound 2;

[0012] 2) Compound 2 dissolved in the first solvent and a mixture of methyldiphenylsilane, the second solvent, and the catalyst are pumped into the microreactor using a metering pump. After the reaction is complete, the feed liquid enters a post-processing system to obtain S-hydroxypropyl tetrahydropyrantriol.

[0013] The alkali in step 1) is selected from at least one of sodium hydroxide, potassium hydroxide, sodium bicarbonate, and sodium carbonate. Preferably, the alkali is sodium hydroxide. More preferably, the alkali solution is an aqueous sodium hydroxide solution.

[0014] The flow rate of the metering pump in step 1) is 3 ml / min-30 ml / min. Preferably, the flow rate is 5 ml / min-15 ml / min. More preferably, the flow rate is 10 ml / min.

[0015] In step 1), the flow rate ratio of the mixed solution of compound 1 and alkali solution to acetylacetone is 1:1 to 10:1. Preferably, the flow rate ratio of the two is 3:1 to 8:1. More preferably, the flow rate ratio of the two is 6:1.

[0016] In step 1), the molar ratio of acetylacetone to compound 1 is 1:1 to 3:1. Preferably, the molar ratio of acetylacetone to compound 1 is 1:1.2 to 2.5:1. More preferably, the molar ratio of acetylacetone to compound 1 is 1:1.5, 1:1.8, 1:2, or 1:2.4.

[0017] The reaction temperature in the microreactor in step 1) is 10° C. to 80° C. Preferably, the reaction temperature in the microreactor in step 1) is 30° C. to 60° C. More preferably, the reaction temperature in the microreactor in step 1) is 50° C.

[0018] The reaction residence time in the microreactor in step 1) is 10 seconds to 30 minutes. Preferably, the reaction residence time in the microreactor in step 1) is 2 minutes to 10 minutes. More preferably, the reaction residence time in the microreactor in step 1) is 3 minutes.

[0019] The operation of the post-treatment system in step 1) includes: performing continuous online extraction and separation, collecting the aqueous phase, and concentrating under reduced pressure. Preferably, the operation of the post-treatment system in step 1) includes: performing continuous online extraction and separation, wherein the extract is dichloromethane, collecting the aqueous phase, and concentrating under reduced pressure.

[0020] In step 2), the first solvent is a mixed solution of ethanol and tetrahydrofuran, a mixed solution of methanol and tetrahydrofuran, a mixed solution of isopropanol and tetrahydrofuran, a mixed solution of methanol and 1,4-dioxane, a mixed solution of isopropanol and 1,4-dioxane, a mixed solution of methanol and acetonitrile, or a mixed solution of isopropanol and acetonitrile.

[0021] In step 2), the second solvent is one of tetrahydrofuran, 1,4-dioxane and acetonitrile.

[0022] The catalyst in step 2) is poly-L-alanine.

[0023] The molar ratio of methyldiphenylsilane to compound 2 in step 2) is 1:1 to 3:1. Preferably, the molar ratio of methyldiphenylsilane to compound 2 is 1:1.2 to 2.5:1. More preferably, the molar ratio of methyldiphenylsilane to compound 2 is 1:1.5, 1:1.8, 1:2, or 1:2.4.

[0024] In step 2), the molar ratio of the catalyst to compound 2 is 0.01:1 to 1:1. Preferably, the molar ratio of the catalyst to compound 2 is 0.1:1 to 0.8:1. More preferably, the molar ratio of the catalyst to compound 2 is 0.2:1, 0.4:1, or 0.6:1.

[0025] The reaction temperature in the microreactor in step 2) is 10° C. to 60° C. Preferably, the reaction temperature in the microreactor in step 2) is 20° C. to 40° C. More preferably, the reaction temperature in the microreactor in step 2) is 25° C.

[0026] The flow rate of the metering pump in step 2) is 3 ml / min-30 ml / min. Preferably, the flow rate is 5 ml / min-15 ml / min. More preferably, the flow rate is 10 ml / min.

[0027] In step 2), the flow rate ratio of the first solvent mixture of compound 2 to the methyldiphenylsilane, second solvent, and catalyst mixture is 0.5:1 to 2:1. Preferably, the flow rate ratio is 0.8:1 to 1.8:1. More preferably, the flow rate ratio is 1:1.

[0028] The reaction residence time in the microreactor in step 2) is 10 seconds to 30 minutes. Preferably, the reaction residence time in the microreactor in step 2) is 1 minute to 10 minutes. More preferably, the reaction residence time in the microreactor in step 2) is 2 minutes.

[0029] The operation of the post-processing system in step 2) includes: performing a first continuous online extraction and separation, collecting an aqueous phase, performing a second online extraction and separation, collecting an aqueous phase, concentrating under reduced pressure, and recrystallizing to obtain S-hydroxypropyl tetrahydropyrantriol. Preferably, the operation of the post-processing system in step 2) includes: performing a first continuous online extraction and separation, collecting an aqueous phase, performing a second online extraction and separation, collecting an aqueous phase, concentrating under reduced pressure, and recrystallizing with ethanol to obtain S-hydroxypropyl tetrahydropyrantriol, wherein the solvent for the first extraction is ethyl acetate and the solvent for the second extraction is methyl tert-butyl ether.

[0030] In some embodiments, a method for preparing bosylamine by a continuous flow process comprises: using a metering pump to pump D-xylose, i.e., compound 1, an aqueous solution of sodium hydroxide, and acetylacetone into a microreactor respectively; after the reaction is complete, the feed liquid enters a post-processing system, undergoes continuous online extraction and separation, collects the aqueous phase, and concentrates under reduced pressure to obtain compound 2; then using a metering pump to pump a mixed solution of compound 2 dissolved in ethanol and tetrahydrofuran and a mixed solution of methyldiphenylsilane, tetrahydrofuran, and poly-L-alanine into a microreactor respectively; after the reaction is complete, the feed liquid enters a post-processing system, undergoes a first continuous online extraction and separation, collects the aqueous phase, then undergoes a second online extraction and separation, collects the aqueous phase, concentrates under reduced pressure, and recrystallizes with ethanol to obtain S-hydroxypropyl tetrahydropyrantriol, wherein the solvent for the first extraction is ethyl acetate and the solvent for the second extraction is methyl tert-butyl ether.

[0031] Compared with the prior art, the present invention has the following beneficial technical effects:

[0032] The technical solution of the present invention utilizes a continuous flow microreactor synthesis method. Compared to traditional autoclave reactions, the innovative feature of the present invention lies in the enantioselective reduction of the carbonyl group to the target product using methyldiphenylsilane as a reducing agent in the presence of a poly-L-alanine catalyst within a continuous microchannel reactor. This method not only avoids the use of boron compounds, which are harmful to the environment and human health, but also avoids the safety risks associated with autoclave reactions. Using the present technical solution, the yield of the second reduction step is increased from 39% to over 95%, with the content of the S-configuration product exceeding 99%. This effectively reduces production costs while also being environmentally friendly.

[0033] In the description of this specification, the reference terms "one embodiment", "some embodiments", "example", "specific example", or "some examples" mean that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described can be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art can combine and combine different embodiments or examples described in this specification and features of different embodiments or examples without contradiction.

[0034] In the present invention, expressions such as "Compound 1", "Compound represented by Formula 1" and "Formula 1" refer to the same compound.

[0035] In the present invention, "optional" means that the process may or may not be performed. For example, "optional post-treatment" means that the process may or may not be performed. DETAILED DESCRIPTION

[0036] In order to enable those skilled in the art to better understand the technical solutions of the present invention, some non-limiting embodiments are further disclosed below to further illustrate the present invention in detail.

[0037] The reagents used in the present invention can be purchased from the market or prepared by the method described in the present invention.

[0038] In the present invention, min means minute; h means hour; g means gram; and ml means milliliter.

[0039] In the present invention, HPLC means high performance liquid chromatography.

[0040] In the present invention, the completion of the reaction means that less than 5% of the reaction raw materials remain.

[0041] Example 1

[0042]

[0043] Prepare solution A with 30g of D-xylose, 180ml of water and 9.5g of sodium hydroxide, and prepare solution B with 38g of acetylacetone. Set the reaction temperature to 50 degrees. Use two plunger metering pumps to pump liquid A and liquid B into the micro-pain duct at a flow rate of 6:1. The residence time is 3 minutes. The reaction is controlled to be complete during sampling. After the reaction liquid flows out, it enters the post-processing system. After continuous online extraction and separation, 200ml of dichloromethane is added to extract and separate the liquid. The aqueous phase is collected and concentrated under reduced pressure. The residue is directly used for the next reaction.

[0044] Example 2

[0045]

[0046] The residue from the previous step was dissolved in a mixture of 100ml of ethanol and 60ml of tetrahydrofuran (THF) as solution A. 60g of methyldiphenylsilane and 3g of the catalyst poly-L-alanine were dissolved in 200ml of THF as solution B. The reaction temperature was set to 25°C. Liquids A and B were pumped into a microporous reaction system using two plunger-type metering pumps at a flow rate of 1:1. The residence time was 2 minutes. The reaction was sampled for completion. The effluent was fed to a post-processing system. After continuous online extraction and separation, 500ml each of water and ethyl acetate were added, and the aqueous phase was collected. Further continuous online extraction and separation was performed, and 300ml of methyl tert-butyl ether was added. The aqueous phase was collected and concentrated under reduced pressure to obtain a crude product. Ethanol was then added to the crude product for crystallization, yielding 29.8g of S-hydroxypropyl tetrahydropyrantriol (77.6% yield). Liquid chromatography analysis revealed a 99.6% S:R configuration:0.36%.

[0047] Example 3

[0048] According to the method in Example 2, the effects of the reducing agent and catalyst on the purity and yield of S-hydroxypropyl tetrahydropyrantriol in the second step reaction were investigated.

[0049] Table 1 Effect of reducing agent and catalyst on purity and yield of S-hydroxypropyl tetrahydropyrantriol

[0050]

[0051] As can be seen from Table 1, after screening, we selected methyldiphenylsilane as the reducing agent and poly-L-alanine as the catalyst. The S-configuration product can reach a purity of more than 99% and a yield of more than 77%.

[0052] Example 4

[0053] According to the method in Example 2, the fixed reducing agent is methyldiphenylsilane, the catalyst is poly-L-alanine, and other conditions remain unchanged. The effects of the reaction temperature in the microreactor in step 2, the flow rate of the metering pump, the molar ratio of methyldiphenylsilane to compound 2, and the mass ratio of the catalyst to compound 2 on the purity and yield of S-hydroxypropyl tetrahydropyrantriol are investigated.

[0054] Table 2 Effect of changing process parameters on the purity and yield of S-hydroxypropyl tetrahydropyrantriol

[0055]

[0056]

[0057] As can be seen from Table 2, after screening, the flow rate of the metering pump is 3 ml / min-30 ml / min, the molar ratio of the reducing agent to the compound 2 is 1:1 to 3:1, the mass ratio of the catalyst to the compound 2 is 0.1:1 to 0.2:1, the residence time is 10 seconds to 30 minutes, and the reaction temperature of the microreactor is 10°C-60°C, which is conducive to the reaction.

[0058] Comparative Example 1

[0059] Compound 2 prepared according to the method in Example 1 was added to a mixed solvent of ethanol and tetrahydrofuran. The reaction flask was placed in a magnetic stirrer and cooled to 0-5°C. 16 g of sodium borohydride was slowly added in batches. The reaction was carried out at 0-10°C for 6 hours, then the temperature was raised to 25°C and the reaction was carried out for 2 hours. The reaction was controlled for completion during sampling. The temperature was then lowered to 0-5°C, 1N hydrochloric acid was added dropwise, and the mixture was stirred for 1 hour. The mixture was concentrated and filtered. The mother liquor was added to ethanol for crystallization to obtain 19.2 g of S-hydroxypropyl tetrahydropyrantriol with a yield of 49.6%. Liquid chromatography analysis showed S configuration: R configuration = 94.2%:5.3%.

[0060] Comparative Example 2

[0061] Compound 2 prepared according to the method in Example 1 was added to a mixed solvent of ethanol and tetrahydrofuran, and the reaction flask was placed in a magnetic stirrer. Methyldiphenylsilane and 0.3 g of poly-L-alanine were added as a catalyst, and the reaction was carried out at 25° C. for 5 hours. The reaction was controlled to be complete during sampling. 500 ml each of water and ethyl acetate were added, the aqueous phase was collected, and 300 ml of methyl tert-butyl ether was added for extraction. The aqueous phase was collected and concentrated under reduced pressure to obtain a crude product. Ethanol was then added to the crude product for crystallization to obtain 23.5 g of S-hydroxypropyltetrahydropyrantriol with a yield of 61.2%. Liquid chromatography analysis showed S configuration: R configuration = 98.1%:1.4%.

[0062] The methods of the present invention have been described through preferred embodiments. It is apparent that those skilled in the art will be able to modify or appropriately alter and combine the methods and applications described herein within the scope, spirit, and spirit of the present invention to implement and apply the technology of the present invention. Those skilled in the art may refer to the disclosure herein and appropriately modify the process parameters to achieve the desired effect. It is particularly important to note that all similar substitutions and modifications apparent to those skilled in the art are considered encompassed by the present invention.

Claims

1. A method for preparing boson by a continuous flow process, characterized in that: The steps include: 1) Using a metering pump, D-xylose, a mixed solution of compound 1 and alkali solution, and acetylacetone are pumped into the microreactor respectively. After the reaction is complete, the feed solution enters the post-treatment system to obtain compound 2; 2) using a metering pump to dissolve compound 2 in the first solvent and a mixture of methyldiphenylsilane, a second solvent, and a catalyst and pump them into the microreactor respectively. After the reaction is complete, the feed liquid enters a post-processing system to obtain S-hydroxypropyl tetrahydropyrantriol; Wherein, the base described in step 1) is selected from at least one of sodium hydroxide, potassium hydroxide, sodium bicarbonate, and sodium carbonate; In step 2), the first solvent is one of a mixed solution of ethanol and tetrahydrofuran, a mixed solution of methanol and tetrahydrofuran, a mixed solution of isopropanol and tetrahydrofuran, a mixed solution of methanol and 1,4-dioxane, a mixed solution of isopropanol and 1,4-dioxane, a mixed solution of methanol and acetonitrile, and a mixed solution of isopropanol and acetonitrile; In step 2), the second solvent is one of tetrahydrofuran, 1,4-dioxane, and acetonitrile; The catalyst in step 2) is poly-L-alanine.

2. The method according to claim 1, wherein In step 1), the reaction temperature in the microreactor is 10°C-80°C.

3. The method according to claim 1, wherein The operation of the post-treatment system in step 1) includes: continuous online extraction and separation, collecting the aqueous phase, and concentrating under reduced pressure; the reaction residence time in the microreactor in step 1) is 10 seconds to 30 minutes.

4. The method according to claim 1, wherein The molar ratio of acetylacetone to compound 1 in step 1) is 1:1 to 3:

1.

5. The method according to claim 1, wherein The molar ratio of methyldiphenylsilane to compound 2 in step 2) is 1:1 to 3:

1.

6. The method according to claim 1, wherein The molar ratio of the catalyst to compound 2 in step 2) is 0.01:1 to 1:

1.

7. The method according to claim 1, wherein The reaction temperature in the microreactor in step 2) is 10°C-60°C.

8. The method according to claim 1, wherein The operation of the post-treatment system in step 2) includes: a first continuous online extraction and separation, collecting the aqueous phase, a second online extraction and separation, collecting the aqueous phase, concentrating under reduced pressure, and recrystallizing to obtain S-hydroxypropyl tetrahydropyrantriol.

9. A method for preparing boson by a continuous flow process, characterized in that: include: D-xylose, i.e., an aqueous solution of compound 1 and sodium hydroxide, and acetylacetone are pumped into a microreactor using a metering pump. After the reaction is complete, the feed liquid enters a post-processing system, undergoes continuous online extraction and separation, collects the aqueous phase, and concentrates under reduced pressure to obtain compound 2; then, a mixed solution of compound 2 dissolved in ethanol and tetrahydrofuran and a mixed solution of methyldiphenylsilane, tetrahydrofuran, and poly-L-alanine are pumped into the microreactor using a metering pump. After the reaction is complete, the feed liquid enters a post-processing system, undergoes a first continuous online extraction and separation, collects the aqueous phase, and then undergoes a second online extraction and separation, collects the aqueous phase, concentrates under reduced pressure, and recrystallizes with ethanol to obtain S-hydroxypropyl tetrahydropyrantriol, wherein the solvent for the first extraction is ethyl acetate and the solvent for the second extraction is methyl tert-butyl ether;

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