Preparation method of hydroxypropyl tetrahydropyrantriol

Abstract

The invention discloses a preparation method of hydroxypropyl tetrahydropyrantriol, which comprises the following steps: dissolving D-xylose in an ethanol water solution, adding acetylacetone and a sodium hydroxide water solution, and finishing adding within 1-1.5 hours; adjusting the pH value of the system to 7-7.5, carrying out negative pressure external evaporation to remove water until the water content is less than or equal to 0.1%, adding isopropanol for dissolving, and filtering; adding a hydrogen transfer catalyst and a formic acid solution into the filtrate, heating to 50-60 DEG C, reacting for 6-8 hours, evaporating out part of liquid under negative pressure, filtering, and spin-drying the filtrate to obtain the (beta, S)-configuration hydroxypropyl tetrahydropyrantriol. According to the method, tedious steps of hydroxyl protection and deprotection and use and purification of various organic raw materials are avoided, the steps are simplified, and the cost is reduced; a hydrogen transfer method is used for replacing a hydrogenation reduction reaction, so that the use of high-pressure hydrogen is avoided, and the production intrinsic safety is improved; the proportion of the S configuration in the prepared glass color is larger than or equal to 95%, the product quality and the market competitiveness are improved, and industrial popularization is facilitated.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and particularly relates to a method for preparing hydroxypropyl tetrahydropyrantriol. Background Art

[0002] Hydroxypropyl tetrahydropyrantriol, also known as Bossain, is a bioactive substance that has the effects of fighting skin aging and dehydration. It is widely used in many fields such as food, biology, medicine, and cosmetics, especially in the field of cosmetics. Bossain promotes the production of polysaccharides through information transmission in cosmetics, increases the water content between extracellular matrices, and makes the matrix gel-like, thereby fully filling the gaps between matrices, increasing skin firmness, reducing wrinkles, and making the skin delicate; Bossain can also play a role in the epidermis-dermis junction, promoting the synthesis of integrins, laminin and collagen, making the epidermis and dermis tightly connected and full, making the skin more firm and elastic. At the same time, researchers found that the (β, S) configuration of hydroxypropyl tetrahydropyrantriol is the dominant configuration, and its biological activity is far greater than that of the (β, R) configuration. The higher the proportion of the (β, S) configuration in hydroxypropyl tetrahydropyrantriol, the higher the biological activity.

[0003] At present, the mainstream chemical synthesis method for producing bosone is to use xylose and acetylacetone to react to generate the intermediate 1-C-(β-D-pyranosyl)-acetone, and then catalytic hydrogenation reduction to obtain bosone. The core of this method is to select appropriate catalytic conditions for chiral hydrogenation reduction in order to obtain more active (β, S) configuration bosone. Researchers have also conducted corresponding research on this.

[0004] The L'Oreal team pointed out in an article on the synthesis of bosonine (Bioorganic & Medicinal Chemistry Letters, 2009, 19, 845-849) that the use of an isopropanol-acetic acid mixed solvent as a medium for the reduction reaction can significantly improve the selectivity of the S-configuration of bosonine. Studies have shown that the mechanism of action is that acetic acid first reacts with sodium borohydride to generate sodium triacetate borohydride, and then sodium triacetate borohydride is used as a hydrogenation reducing agent to selectively generate S-configuration bosonine in an isopropanol solvent environment with a selectivity of about 90%. This method will introduce a large amount of acetic acid / boron salt while improving chiral selectivity.

[0005] Patent CN114105922A discloses a method for synthesizing hydroxypropyl tetrahydropyrantriol. This method is a one-step synthesis, using (2-hydroxypropyl)boric acid or its dimethyl ester and bromine-substituted xylose as raw materials, in the presence of a metal catalyst and a chiral ligand, and coupling in an alkaline environment to prepare bosine. Although this method is a one-step method, the raw materials are not easy to purchase directly. If the order is added, the price is high, which increases the production cost. If it is prepared by itself, it requires multi-step reaction treatment, and the process is cumbersome. And from the nuclear magnetic carbon spectrum provided in the embodiment, it can be seen that the ratio of R configuration to S configuration is about 6:4, and the selectivity of S configuration is not increased due to the presence of chiral ligands.

[0006] Patent CN115093386A discloses a method for producing colorless, tasteless and borate-free bosonine, which first uses xylose and acetylacetone to react to generate an intermediate 1-C-(β-D-pyranose xyloyl)-acetone, then uses benzyl bromide or p-nitrophenyl chloroformate to protect the hydroxyl group of the intermediate and desalt it, then uses metal ruthenium as a catalyst, a chiral ligand as a chiral inducer, and hydrogen gas high pressure reaction, direct hydrogenation and deprotection to obtain S-configuration bosonine, and the S-configuration selectivity reaches up to 99.5%. This method changes the water solubility of the intermediate by introducing aromatic groups to protect the hydroxyl group, making it easy to separate the salt water and eliminating the purification step of the ion exchange resin; and this method introduces a large volume group through hydroxyl protection, and then greatly increases the selectivity of S-configuration bosonine under the joint action of the chiral ligand. However, this method has complicated steps. After the protection and deprotection of aromatic compounds, the protective agent becomes ineffective and needs to be chlorinated or brominated again before it can be reused, which increases production costs. At the same time, hydrogenation requires a high-pressure hydrogen environment, which is not conducive to inherently safe production. Summary of the invention

[0007] In view of the problems of low selectivity of S configuration, high production cost and low safety in the process of synthesizing bosone in the prior art, the present invention provides a preparation method of hydroxypropyl tetrahydropyrantriol, which avoids the cumbersome steps of hydroxyl protection and deprotection and the use and purification of various organic raw materials, simplifies the steps, reduces costs, improves production safety, and the proportion of S configuration in bosone is ≥95%, thereby improving product quality and market competitiveness, and is conducive to industrial promotion.

[0008] The present invention is achieved through the following technical solutions: A method for preparing hydroxypropyl tetrahydropyrantriol comprises the following steps: (1) Dissolve D-xylose in ethanol aqueous solution, add acetylacetone and sodium hydroxide aqueous solution, and add them over 1-1.5 hours; (2) Adjust the pH of the system to 7-7.5, remove water by negative pressure evaporation until the water content is ≤ 0.1%, add isopropanol to dissolve, and filter; (3) Add a hydrogen transfer catalyst and a formic acid solution to the filtrate of step (2), raise the temperature to 50-60°C, react for 6-8 hours, evaporate part of the liquid under negative pressure, filter, and spin-dry the filtrate to obtain (β, S)-configuration hydroxypropyl tetrahydropyrantriol.

[0009] Furthermore, in step (1), the mass percentage concentration of ethanol is 40-60%, and the mass ratio of D-xylose to ethanol aqueous solution is 1:1-1.2 times.

[0010] Furthermore, in step (1), the molar ratio of D-xylose, acetylacetone and sodium hydroxide is 1:1.1-1.3:1.2-1.5; and the mass percentage concentration of the sodium hydroxide aqueous solution is 10-15%.

[0011] Furthermore, in step (2), acetic acid is used to adjust the pH of the system to 7-7.5.

[0012] Furthermore, in step (2), the mass ratio of isopropanol to D-xylose is 2-3:1; and in step (3), the hydrogen transfer catalyst is a complex product of a metal ruthenium compound and a diamine chiral ligand.

[0013] Furthermore, the metal ruthenium compound is RuCl[(S,S)-Tsdpen](mesitylene) or RuCl[(S,S)-Tsdpen](p-cymene).

[0014] Furthermore, in step (3), the amount of hydrogen transfer catalyst is 0.1-0.5% of the mass of D-xylose.

[0015] Furthermore, the vacuum degree of the negative pressure external evaporation in step (2) and step (3) is -90~-80KPa.

[0016] Furthermore, in step (3), the formic acid solution is a mixed solution of formic acid and triethylamine, wherein the mass ratio of formic acid to triethylamine is 90-100:1; and the molar ratio of formic acid solution to D-xylose is 1-1.5.

[0017] Furthermore, in step (3), the mass ratio of water to hydrogen transfer catalyst is 1-2:1.

[0018] The structural formula of the hydrogen transfer catalyst RuCl[(S,S)-Tsdpen](mesitylene) is:

[0019] The structural formula of the hydrogen transfer catalyst RuCl[(S,S)-Tsdpen](p-cymene) is: Beneficial Effects

[0020] The present invention uses D-xylose and acetylacetone to react to generate an intermediate 1-C-(β-D-pyranose xyloyl)-acetone, and then the intermediate is subjected to a hydrogen transfer reaction of formic acid to obtain bosine. This method avoids the cumbersome steps of hydroxyl protection and deprotection and the use and purification of various organic raw materials, simplifies the steps, and reduces costs; the use of a hydrogen transfer method to replace a hydrogenation reduction reaction avoids the use of high-pressure hydrogen, and improves the inherent safety of production; the present invention uses a diamine chiral catalyst RuCl[(S,S)-Tsdpen](mesitylene) or RuCl[(S,S)-Tsdpen](p-cymene) to perform hydrogen transfer of the intermediate, significantly improving the selectivity of the product S configuration, and the proportion of the S configuration in the prepared bosine is ≥95%, which improves product quality and market competitiveness, and is conducive to industrial promotion. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 This is a chiral analysis chromatogram of (β, S)-configuration hydroxypropyl tetrahydropyrantriol prepared in Example 1; Figure 2 This is the C NMR spectrum of (β, S)-configuration hydroxypropyl tetrahydropyrantriol prepared in Example 1; Figure 3 This is a chiral analysis chromatogram of (β, S)-configuration hydroxypropyl tetrahydropyrantriol prepared in Comparative Example 1; Figure 4 This is the C NMR spectrum of (β, S)-configuration hydroxypropyl tetrahydropyrantriol prepared in Comparative Example 1. DETAILED DESCRIPTION

[0022] The specific details of the present invention are further described for a full understanding of the present invention. The terms used in the description of the present invention are only used to illustrate the advantages and features of the present invention and are not intended to limit the present invention.

[0023] Unless otherwise defined, all professional and scientific terms used in the present invention have the same meanings as those understood by technicians in the technical field of the present invention. Unless otherwise specified, the drugs or reagents used in the present invention are used in accordance with the product instructions or the conventional methods of use in the field. The technical solution of the present invention is now further described according to the specific implementation methods.

[0024] The formic acid solution in the following examples and comparative examples is prepared by mixing 10 g of triethylamine and 950 g of formic acid and set aside. Example 1

[0025] (1) Add 150 g of D-xylose and 150 g of ethanol aqueous solution (mass percentage concentration 40%) to the reactor, start stirring, and heat to 30-35 °C. After the xylose is completely dissolved, add 110 g of acetylacetone at a rate of 1.83 g / min and 480 g of 10% sodium hydroxide aqueous solution at a rate of 8 g / min. The addition is completed after 1 hour. (2) The reactor was stirred continuously, and acetic acid was added dropwise to adjust the pH value of the system to 7.21. Stirring was stopped, and water was distilled under a vacuum pressure of -90 KPa. The water content was measured to be 0.07%. 300 g of isopropanol was added, and stirring was started for 10 min. The filtrate was then filtered and the filtrate was transferred to the reactor; (3) Add 0.3 g of RuCl[(S,S)-Tsdpen](mesitylene) and 56 g of formic acid solution to the filtrate of step (2), start stirring, raise the temperature to 52±2°C, keep warm for 6 h, evaporate 289 g of isopropanol, formic acid and triethylamine under vacuum pressure of -90 KPa, separate and reuse, add 3 g of water and let stand for 30 min, filter with suction, add 300 g of isopropanol to dissolve the filter cake, filter with suction again, and spin dry the filtrate to obtain 180.6 g of (β,S)-configuration hydroxypropyl tetrahydropyrantriol; After testing, the product purity was 99.57%, the yield was 93.96%, the S and R configuration ratio was 97.4:2.6, and the acetate ion content was 1496ppm. Example 2

[0026] (1) Add 150 g of D-xylose and 180 g of ethanol aqueous solution (mass percentage concentration 60%) to the reactor, start stirring, and heat to 30-35 °C. After the xylose is completely dissolved, add 130 g of acetylacetone at a rate of 2.17 g / min and 400 g of 15% sodium hydroxide aqueous solution at a rate of 6.67 g / min. The addition is completed after 1 hour. (2) The reactor was stirred continuously, and acetic acid was added dropwise to adjust the pH value of the system to 7.24. Stirring was stopped, and water was distilled under a vacuum pressure of -80 KPa. The water content was measured to be 0.05%. 450 g of isopropanol was added, and stirring was started for 10 min. The filtrate was then filtered and the filtrate was transferred to the reactor; (3) Add 0.45 g of RuCl[(S,S)-Tsdpen](mesitylene) and 60 g of formic acid solution to the filtrate of step (2), start stirring, raise the temperature to 58±2°C, keep warm for 8 h, evaporate 433 g of isopropanol, formic acid and triethylamine under vacuum pressure of -80 KPa, separate and reuse, add 6 g of water and let stand for 30 min, filter with suction, add 300 g of isopropanol to dissolve the filter cake, filter with suction again, and spin dry the filtrate to obtain 178.5 g of (β,S)-configuration hydroxypropyl tetrahydropyrantriol; After testing, the product purity was 99.48%, the yield was 92.87%, the S and R configuration ratio was 97.1:2.9, and the acetate ion content was 1758ppm. Example 3

[0027] (1) Add 150 g of D-xylose and 150 g of ethanol aqueous solution (mass percentage concentration 40%) to the reactor, start stirring, and heat to 30-35 °C. After the xylose is completely dissolved, add 110 g of acetylacetone at a rate of 1.83 g / min and 320 g of 15% sodium hydroxide aqueous solution at a rate of 5.33 g / min. The addition is completed after 1 hour. (2) The reactor was stirred continuously, and acetic acid was added dropwise to adjust the pH value of the system to 7.18. Stirring was stopped, and water was distilled under a vacuum pressure of -90 KPa. The water content was measured to be 0.06%. 300 g of isopropanol was added, and stirring was started for 10 min. The filtrate was then filtered and transferred to the reactor. (3) Add 0.3 g of RuCl[(S,S)-Tsdpen](p-cymene) and 56 g of formic acid solution to the filtrate of step (2), start stirring, raise the temperature to 52±2°C, keep warm for 6 h, evaporate 290 g of isopropanol, formic acid and triethylamine under vacuum pressure of -90 KPa, separate and reuse, add 3 g of water and let stand for 30 min, filter with suction, add 300 g of isopropanol to dissolve the filter cake, filter with suction again, and spin dry the filtrate to obtain 181.1 g of (β,S)-configuration hydroxypropyl tetrahydropyrantriol; After testing, the product purity was 99.60%, the yield was 94.22%, the S and R configuration ratio was 97.5:2.5, and the acetate ion content was 1513ppm. Example 4

[0028] (1) Add 150 g of D-xylose and 180 g of ethanol aqueous solution (mass percentage concentration 60%) to the reactor, start stirring, and heat to 30-35 °C. After the xylose is completely dissolved, add 130 g of acetylacetone at a rate of 2.17 g / min and 600 g of 10% sodium hydroxide aqueous solution at a rate of 10 g / min. The addition is completed after 1 hour. (2) The reactor was stirred continuously, and acetic acid was added dropwise to adjust the pH value of the system to 7.26. Stirring was stopped, and water was distilled under vacuum pressure of -80 KPa. The water content was measured to be 0.08%. 450 g of isopropanol was added, and stirring was started for 10 min. The filtrate was filtered and transferred to the reactor; (3) Add 0.45 g of RuCl[(S,S)-Tsdpen](p-cymene) and 60 g of formic acid solution to the filtrate of step (2), start stirring, raise the temperature to 58±2°C, keep warm for 8 h, evaporate 430 g of isopropanol, formic acid and triethylamine under vacuum pressure of -80 KPa, separate and reuse, add 6 g of water and let stand for 30 min, filter with suction, add 300 g of isopropanol to dissolve the filter cake, filter with suction again, and spin dry the filtrate to obtain 177.8 g of (β,S)-configuration hydroxypropyl tetrahydropyrantriol; After testing, the product purity was 99.57%, the yield was 92.50%, the S and R configuration ratio was 96.9:3.1, and the acetate ion content was 1722ppm.

[0029] Comparative Example 1 (1) Add 150 g of D-xylose and 150 g of ethanol aqueous solution (mass percentage concentration 40%) to the reactor, start stirring, and heat to 30-35 °C. After the xylose is completely dissolved, add 110 g of acetylacetone at a rate of 1.83 g / min and 480 g of 10% sodium hydroxide aqueous solution at a rate of 8 g / min. The addition is completed after 1 hour. (2) The reactor was stirred continuously, and acetic acid was added dropwise to adjust the pH value of the system to 7.21. Stirring was stopped, and water was distilled under a vacuum pressure of -90 KPa. The water content was measured to be 0.07%. 300 g of isopropanol was added, and stirring was started for 10 min. The filtrate was then filtered and the filtrate was transferred to the reactor; (3) Add 0.3 g [RuCl(cymene)(S-Binap)]Cl and 56 g formic acid solution to the filtrate of step (2), start stirring, raise the temperature to 52±2°C, keep warm for 6 h, evaporate 289 g of isopropanol, formic acid and triethylamine under vacuum pressure of -90 KPa, separate and reuse, add 3 g of water and let stand for 30 min, filter with suction, add 300 g of isopropanol to dissolve the filter cake, filter with suction again, and spin dry the filtrate to obtain 102.2 g of (β, S)-configuration hydroxypropyl tetrahydropyrantriol; After testing, the product purity was 99.47%, the yield was 53.17%, the S and R configuration ratio was 81.7:18.3, and the acetate ion content was 1521ppm.

[0030] From the comparison between the examples and the comparative examples, it can be seen that in the hydrogen transfer reaction, the catalytic activity of the phosphine-based chiral catalyst is not high, the product conversion rate is low, and the selectivity of the diamine chiral catalyst in the product S configuration is higher than that of the phosphine-based chiral catalyst.

[0031] The preferred embodiments of the present invention are described in detail above, but the present invention is not limited thereto. Within the technical concept of the present invention, the technical solution of the present invention can be subjected to a variety of simple modifications, including the combination of various technical features in any other suitable manner, and these simple modifications and combinations should also be regarded as the contents disclosed by the present invention and belong to the protection scope of the present invention.

Claims

1. A method for preparing hydroxypropyl tetrahydropyrantriol, characterized in that: The following steps are involved: (1) Dissolve D-xylose in ethanol aqueous solution, add acetylacetone and sodium hydroxide aqueous solution, and add them over 1-1.5 hours; (2) Adjust the pH of the system to 7-7.5, remove water by negative pressure evaporation until the water content is ≤ 0.1%, add isopropanol to dissolve, and filter; (3) Add a hydrogen transfer catalyst and a formic acid solution to the filtrate of step (2), raise the temperature to 50-60°C, react for 6-8 hours, evaporate part of the liquid under negative pressure, filter, and spin-dry the filtrate to obtain (β, S)-configuration hydroxypropyl tetrahydropyrantriol.

2. The preparation method of hydroxypropyl tetrahydropyrantriol according to claim 1, characterized in that, In step (1), the mass percentage concentration of ethanol is 40-60%, and the mass ratio of D-xylose to ethanol aqueous solution is 1:1-1.2 times.

3. The preparation method of hydroxypropyl tetrahydropyrantriol according to claim 1, characterized in that, In step (1), the molar ratio of D-xylose, acetylacetone and sodium hydroxide is 1:1.1-1.3:1.2-1.5; and the mass percentage concentration of the sodium hydroxide aqueous solution is 10-15%.

4. The preparation method of hydroxypropyl tetrahydropyrantriol according to claim 1, characterized in that, In step (2), acetic acid is used to adjust the pH of the system to 7-7.

5.

5. The method for preparing hydroxypropyl tetrahydropyrantriol according to claim 1, characterized in that, In step (2), the mass ratio of isopropanol to D-xylose is 2-3:1; in step (3), the hydrogen transfer catalyst is a complex product of a metal ruthenium compound and a diamine chiral ligand.

6. The method for preparing hydroxypropyl tetrahydropyrantriol according to claim 5, characterized in that: The metal ruthenium compound is RuCl[(S,S)-Tsdpen](mesitylene) or RuCl[(S,S)-Tsdpen](p-cymene).

7. The method for preparing hydroxypropyl tetrahydropyrantriol according to claim 1, characterized in that: In step (3), the amount of hydrogen transfer catalyst is 0.1-0.5% of the mass of D-xylose.

8. The method for preparing hydroxypropyl tetrahydropyrantriol according to claim 1, characterized in that: The vacuum degree of negative pressure external evaporation in step (2) and step (3) is -90~-80KPa.

9. The method for preparing hydroxypropyl tetrahydropyrantriol according to claim 1, characterized in that: In step (3), the formic acid solution is a mixed solution of formic acid and triethylamine, wherein the mass ratio of formic acid to triethylamine is 90-100:1; and the molar ratio of formic acid solution to D-xylose is 1-1.

5.

10. The method for preparing hydroxypropyl tetrahydropyrantriol according to claim 1, characterized in that: In step (3), the mass ratio of water to hydrogen transfer catalyst is 1-2:1.

Images