One-pot preparation of hydroxyproline

Abstract

The present invention provides a method for preparing hydroxypinacolone trimethylglycoside, comprising the following steps: (1) reacting β-acetonylxyloside with a hydroxyl protecting reagent to obtain intermediate 1; (2) subjecting intermediate 1 to catalytic hydrogenation to obtain a mixed solution of intermediate 2; (3) performing a deprotection treatment on the mixed solution of intermediate 2 to obtain hydroxypinacolone trimethylglycoside. The entire process of the method does not require excessive purification steps and can be prepared by a one-pot method; moreover, the yield is high and the proportion of the βS configuration is relatively large.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthesis, and particularly relates to the preparation of hydroxyprolisane by a one-pot method. Background Art

[0002] Hydroxyprolisane, also known as hydroxypropyltetrahydropyrantriol (CAS No. 439685-79-7), is a xylose derivative with anti-aging activity, which can induce the biosynthesis of GAGs (glycosaminoglycans) and PGs (proteoglycans) in the superficial epidermis. The deficiency of GAGs and PGs will lead to a decrease in skin water content and a reduction in defense ability. By inducing the biosynthesis of GAGs and PGs, hydroxyprolisane can effectively promote the tight connection between the epidermis and the dermis, better fix the dermis layer, make the skin stronger and more elastic, and long-term use can effectively improve facial and neck wrinkles and fine lines, and promote the regeneration of damaged tissues. Therefore, it is widely used in technical fields such as cosmetics, food, biology, and medicine.

[0003] The stereochemical characteristics of hydroxyprolisane have an important impact on its biological activity. The β-glycosidic bond is much more important for maintaining the biological activity of hydroxyprolisane than the α-glycosidic bond. At the same time, different diastereoisomer ratios caused by the different stereoconfigurations of the hydroxyl group (7-position chiral carbon) in the glycosyl ligand (hydroxypropane) will exhibit different biological activities. In the comparative study of the biological activities of different diastereoisomer ratios, it is considered that when the percentage of the compound with the β-configuration at the 1-position carbon and the S-configuration at the 7-position carbon is greater than the percentage of the compound with the β-configuration at the 1-position carbon and the R-configuration at the 7-position carbon, the efficacy of hydroxyprolisane is better.

[0004] In terms of the S / R configuration, the article (Bioorganic & Medicinal Chemistry Letters, 2009, 19, 845-849) has done a lot of research on the second-step reduction. Using a mixed solvent of isopropanol and acetic acid as the medium for the reduction reaction greatly improves the selectivity of the reaction, and the 7-position configuration ratio (S:R) can reach 9:1. The synthetic route of the method is as follows:

[0005]

[0006] In the literature, the residual acetic acid will bring a sour taste to hydroxyprolisane, and this literature uses NaBH4 as a reducing agent, while boric acid or borate has been listed in the prohibited addition catalog by the cosmetics specification, so the residual borate will cause the hydroxyprolisane product to be unqualified. In addition, metal salt ion catalysts such as NaBH4, LiAlH4, Red-Al, and DIBAL-H are used for reduction, and there is a problem of desalination of inorganic salts after reduction. At present, the existing ion exchange resin method is used for desalination, with low batch processing capacity, a large amount of wastewater for ion resin regeneration, high production cost for scale-up, and it is difficult to completely remove. Summary of the Invention

[0007] To solve one of the above-mentioned technical problems in the prior art, the present invention provides a one-pot method for preparing hydroxyprolisone, which has the advantages of short reaction time, high efficiency, high yield, low cost, few impurities generated in the last deprotection step, easy removal, and the percentage of β S / R configuration of the final product being greater than 1:1. Specifically as follows:

[0008] The present invention provides a method for preparing hydroxyprolisone by a one-pot method, comprising:

[0009] The method for preparing hydroxyprolisone by a one-pot method comprises the following steps: (1) reacting β - acetoxyl xyloside with a hydroxyl protecting reagent to obtain intermediate 1; (2) obtaining a mixed solution of intermediate 2 by catalytic hydrogenation of intermediate 1; (3) performing deprotection treatment on the mixed solution of intermediate 2 to obtain hydroxyprolisone,

[0010]

[0011] wherein, R1 and R2 are each independently H or a hydroxyl protecting group; or R1 and R2 are connected to form a cyclic hydroxyl protecting group; and PG is a hydroxyl protecting group.

[0012] The method of the present invention can not only increase the proportion of β S configuration in the product, but also does not require specific purification steps in the middle, and hydroxyprolisone can be directly obtained in one pot, with high yield and short overall reaction time.

[0013] Further, in step (1), β - acetoxyl xyloside is dissolved in an aprotic water-miscible solvent and reacted with a hydroxyl protecting reagent under the condition of a base; after the reaction is completed, water at 0 - 5 °C is added to precipitate intermediate 1.

[0014] The amount of water added is for the purpose of precipitating intermediate 1 or making intermediate 1 in a solid state, which depends on the amount of the aprotic water-miscible solvent and the form of intermediate 1. According to specific circumstances, an ice-water mixture can also be used.

[0015] R1 and R2 of intermediate 1 are hydrogen or a protecting group, and R1 and R2 have little influence on the configuration ratio of the product. The main difference lies in the synthesis process, which affects the final yield;

[0016] When R1 and R2 are connected to form a cyclic hydroxyl protecting group, intermediate 1 can be the following non-limiting exemplary formula a:

[0017]

[0018] Further, the aprotic water-miscible solvent includes DMF or DMSO; the base includes one or more of potassium carbonate, cesium carbonate, sodium carbonate, imidazole or triethylamine.

[0019] Further, intermediate 1 is first subjected to catalytic hydrogenation with palladium / carbon in an alcohol or a mixed solution of alcohol and water, and then hydrochloric acid is added and stirred to obtain hydroxyproline.

[0020] Further, the hydroxy protecting group is benzyl, methyl ether methyl, propylene protecting group, or silyl group.

[0021] Further, the hydroxy protecting group is alkylsilyl, alkylarylsilyl, or arylsilyl.

[0022] Further, the hydroxy protecting group is trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, methyldiphenylsilyl, or triphenylsilyl.

[0023] Further, the molar ratio of β-acetoxyl xyloside to the hydroxy protecting reagent is (1:4)-(1:6).

[0024] Further, the reaction temperature of β-acetoxyl xyloside with the hydroxy protecting reagent is 60-90 °C.

[0025] Further, in step (1), β-acetoxyl xyloside is dissolved in DMF or DMSO, carbonate such as potassium carbonate is added, heated to 75-85 °C, such as 80 °C, a silane-based hydroxy protecting reagent is added dropwise, and after the reaction is completed, water at 0-5 °C is added and stirred to precipitate intermediate 1; in step (2), intermediate 1 is dissolved in ethanol or a mixed solution of ethanol and water, hydrogenated under the catalysis of palladium on carbon to obtain a mixed solution of intermediate 2; hydrochloric acid is added to remove the hydroxy protecting group to obtain hydroxyproline.

[0026] The method of the present invention can not only increase the proportion of βS configuration in the product, but also does not require specific purification steps in the middle, and hydroxyproline can be directly obtained in one pot, with high yield and short overall reaction time.

[0027] The present invention provides a method for preparing hydroxyproline. The whole method process does not require excessive purification steps and can be prepared by a one-pot method; moreover, the yield is high and the proportion of βS configuration is relatively large. Specific Embodiments

[0028] To make the purpose, technical solutions and advantages of the present invention more clear, the following examples are used to further elaborate on the present invention in detail. The specific examples described here are only used to explain the present invention and do not constitute any limitation to the present invention. In addition, in the following description, the description of well-known structures and technologies is omitted to avoid unnecessarily confusing the concepts of the present disclosure. Such structures and technologies are also described in many publications.

[0029] Definition

[0030] Unless otherwise defined, all technical and scientific terms used in this invention have the same meaning as commonly used in the field to which this invention belongs. For the purpose of interpreting this specification, the following definitions will apply, and where appropriate, terms used in the singular form will also include the plural form and vice versa.

[0031] As used herein, the term "about" means a range of ±20% of the value that follows. In some embodiments, the term "about" means a range of ±10% of the value that follows. In some embodiments, the term "about" means a range of ±5% of the value that follows.

[0032] The term "hydroxy protecting group" refers to a group that is easily removed and introduced on a hydroxyl group to block or protect the hydroxyl group while reactions are carried out on other functional groups of the compound. Non-limiting examples include: trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), tert-butyldimethylsilyl (TBS), tert-butyldiphenylsilyl (TBDPS), methyldiphenylsilyl, triphenylsilyl (TPS), methyl, tert-butyl, allyl, benzyl, methoxymethyl (MOM), ethoxyethyl, 2-tetrahydropyranyl (THP), formyl, acetyl, benzoyl, p-nitrobenzoyl, etc.

[0033] The present invention provides a one-pot method for preparing hydroxyproline, comprising the following steps: (1) reacting β-acetoxyl xyloside with a hydroxy protecting reagent to obtain intermediate 1; (2) subjecting intermediate 1 to catalytic hydrogenation to obtain a mixture of intermediate 2; (3) performing a deprotection treatment on the mixture of intermediate 2 to obtain hydroxyproline.

[0034]

[0035] Wherein, R1 and R2 are each independently H or a hydroxy protecting group; or R1 and R2 are linked to form a cyclic hydroxy protecting group; PG is a hydroxy protecting group.

[0036] The present invention provides a method for synthesizing stereospecific hydroxypropyltetrahydropyrantriol (Boschniakine). This method utilizes the steric and atomic effects of the special protection of the hydroxyl group at the 3-position, especially Si, and ingeniously uses the principle of palladium metal-catalyzed hydrogenation to efficiently and stereospecifically reduce β-acetonylxyloside to obtain relatively specific S-configured Boschniakine. This reaction has a high tolerance for whether there are substituents at the 4- and 5-positions. The present invention not only avoids the use of borane-based reducing agents but also avoids some precious metal catalysts. At the same time, in the previous steps of this application, catalysts or raw materials that have a great impact on the subsequent reaction steps are basically not used, and the same solvent can be used for the front and back solvents. Except that the upper protecting group has requirements for water content, the subsequent reaction has loose requirements for the water content of the solvent. During the reaction process, there is no need for special purification processes, and it can be obtained by a method similar to one-pot synthesis, which is more suitable for industrial production and has lower costs.

[0037] The position numbers in this application are as follows:

[0038]

[0039] Examples are provided below to help understand the present invention. However, it should be understood that these examples are only used to illustrate the present invention and do not constitute any limitation. The actual protection scope of the present invention is set forth in the claims. It should be understood that any modifications and changes can be made without departing from the spirit of the present invention.

[0040] Example 1:

[0041]

[0042] Add 100 g of raw material D-xylose, 40 g of sodium hydroxide, 80 g of acetylacetone, and 800 g of water to the reaction kettle, start stirring, and react at 80 - 100 °C for 2 h. After the reaction is completed, adjust the pH to 1 - 2 with solid sodium bisulfate, and extract with ethyl acetate (200 mL × 3). Discard the organic phase layer, and return the aqueous phase to be concentrated under reduced pressure to obtain the crude product of β-acetonylxyloside 1. MS (ESI + ) m / z 191.2 [(M + H) + .

[0043] Example 2:

[0044]

[0045] Dissolve compound 1 (20 mmol) in dry DMF (40 mL), add potassium carbonate (60 mmol), heat to 80 °C, dropwise add tert-butyldimethylchlorosilane (100 mmol). After the addition is complete, keep the reaction at the same temperature for 3 h. Quench the reaction with ice water, continue to add ice water and stir to precipitate solids. Filter under low temperature, wash the obtained solid once with ice water to obtain the crude product of intermediate 2-2. The obtained solid does not need to be further purified and can be directly used for the next feeding. Dissolve the crude product of intermediate 2-2 in ethanol / water in a hydrogenation kettle, add palladium-carbon, displace with nitrogen three times first, then displace with hydrogen once, introduce hydrogen and carry out hydrogenation reduction at 50 °C. After 4 h, the reaction is complete. Add 10% hydrochloric acid and stir for 1 h. Filter, extract the filtrate twice with ethyl acetate. Concentrate the aqueous phase, add isopropanol, heat to dissolve, then stir for 0.5 h, cool to -10 °C to crystallize, centrifuge to obtain the solid and dry it. The yield is 91.6%. The βS / βR configuration ratio detected by HPLC is 5.3:1.

[0046] 1 HNMR (400 MHz, CD3OD) δ 4.93–4.88 (m, 3H), 4.25 (d, J = 4.3 Hz, 1H), 3.84–3.73 (m, 1H), 3.67 - 3.63 (m, 1H), 3.21 - 3.18 (m, 1H), 3.13–2.87 (m, 3H), 2.85 - 2.82 (m, 1H), 1.77 - 1.73 (m, 1H), 1.51 - 1.45 (m, 1H), 1.07 - 1.05 (d, J = 6.1 Hz, 3H).

[0047] Example 3:

[0048]

[0049]

[0050] Dissolve compound 1 (20 mmol) in dry DMF (40 mL), add potassium carbonate (60 mmol), heat at 80 °C, dropwise add tert-butyldiphenylchlorosilane (100 mmol). After the addition is complete, keep the reaction at a constant temperature for 4 h. Quench the reaction with ice water, continue to add ice water and stir to precipitate a solid. Filter the solid at low temperature. Wash the obtained solid once with ice water to obtain the crude product of intermediate 2-2. The obtained solid does not need to be further purified and is directly used for the next feeding. Dissolve the crude product of intermediate 2-2 in ethanol / water in a hydrogenation kettle, add palladium on carbon, displace with nitrogen three times first, then displace with hydrogen once, introduce hydrogen and carry out hydrogenation reduction at 50 °C. After 4 h, the reaction is complete. Add 10% hydrochloric acid and stir for 1 h. Filter by suction. Extract the filtrate twice with ethyl acetate. Concentrate the aqueous phase, add isopropanol, heat to dissolve, then stir for 0.5 h, cool to -10 °C to crystallize, centrifuge to obtain the solid and drain it. The yield is 95.3%: HPLC detects that the βS / βR configuration ratio is 8.9:1.

[0051] Example 4:

[0052]

[0053] Dissolve compound 1 (20 mmol) in dry DMF (40 mL), add potassium carbonate (60 mmol), heat at 80 °C, dropwise add phenyldimethylchlorosilane (100 mmol). After the addition is complete, keep the reaction at a constant temperature for 4 h. Quench the reaction with ice water, continue to add ice water and stir to precipitate a solid. Filter the solid at low temperature. Wash the obtained solid once with ice water to obtain the crude product of intermediate 4-2. The obtained solid does not need to be further purified and is directly used for the next feeding. Dissolve the crude product of intermediate 4-2 in ethanol / water in a hydrogenation kettle, add palladium on carbon, displace with nitrogen three times first, then displace with hydrogen once, introduce hydrogen and carry out hydrogenation reduction at 50 °C. After 4 h, the reaction is complete. Add 10% hydrochloric acid and stir for 1 h. Filter by suction. Extract the filtrate twice with ethyl acetate. Concentrate the aqueous phase, add isopropanol, heat to dissolve, then stir for 0.5 h, cool to -10 °C to crystallize, centrifuge to obtain the solid and drain it. The yield is 94.6%: HPLC detects that the βS / βR configuration ratio is 8.2:1.

[0054] Example 5:

[0055]

[0056] Dissolve compound 1 (20 mmol) in dry DMF (40 mL), add potassium carbonate (60 mmol), heat to 80 °C, dropwise add trimethylchlorosilane (100 mmol). After the addition is complete, keep the reaction at a constant temperature for 3 h. Quench the reaction with ice water, continue to add ice water and stir to precipitate a solid. Filter the solid at low temperature. Wash the obtained solid once with ice water to obtain the crude product of intermediate 5-2. The obtained solid does not need to be further purified and is directly used for the next feeding. Dissolve the crude product of intermediate 5-2 in ethanol / water in a hydrogenation kettle, add palladium-carbon. First, displace with nitrogen three times, then displace with hydrogen once. Introduce hydrogen and carry out hydrogenation reduction at 50 °C. After 4 h, the reaction is complete. Add 10% hydrochloric acid and stir for 1 h. Filter by suction. Extract the filtrate twice with ethyl acetate. Concentrate the aqueous phase, add isopropanol, heat to dissolve, then stir for 0.5 h, cool to -10 °C to crystallize, centrifuge to obtain a solid and dry it. The yield is 87.5%: HPLC detects that the βS / βR configuration ratio is 4.9:1.

[0057] Example 6:

[0058]

[0059] Dissolve compound 1 (20 mmol) in dry DMF (40 mL), add potassium carbonate (60 mmol), heat to 80 °C, dropwise add triphenylchlorosilane (100 mmol). After the addition is complete, keep the reaction at a constant temperature for 4 h. Quench the reaction with ice water, continue to add ice water and stir to precipitate a solid. Filter the solid at low temperature. Wash the obtained solid once with ice water to obtain the crude product of intermediate 6-2. The obtained solid does not need to be further purified and is directly used for the next feeding. Dissolve the crude product of intermediate 6-2 in ethanol / water in a hydrogenation kettle, add palladium-carbon. First, displace with nitrogen three times, then displace with hydrogen once. Introduce hydrogen and carry out hydrogenation reduction at 50 °C. After 4 h, the reaction is complete. Add 10% hydrochloric acid and stir for 1 h. Filter by suction. Extract the filtrate twice with ethyl acetate. Concentrate the aqueous phase, add isopropanol, heat to dissolve, then stir for 0.5 h, cool to -10 °C to crystallize, centrifuge to obtain a solid and dry it. The yield is 95.2%: HPLC detects that the βS / βR configuration ratio is 9.1:1.

[0060] Example 7

[0061]

[0062] Dissolve compound 1 (20 mmol) in dry DMF (40 mL), add NaH (60%, 150 mmol) at 0 °C and stir for 5 min. Dropwise add benzyl bromide (100 mmol). After the addition is complete, react at room temperature for 3 h. Take a sample to detect that the reaction is complete. Return to room temperature. Add the reaction solution to ice water and stir for 1 h. A large amount of solid precipitates. Filter by suction. Wash the obtained solid once with water.

[0063] After draining, the product 7-2 in the obtained solid does not need to be further purified and can be directly used for the next feeding; dissolve the crude product of intermediate product 7-2 in ethanol / water in a hydrogenation kettle, add palladium-carbon, displace with nitrogen three times first, then displace with hydrogen once, introduce hydrogen for hydrogenation reduction at 50 °C, after 4 h the reaction is complete, add 10% hydrochloric acid and stir for 1 h, filter by suction, extract the filtrate twice with ethyl acetate, concentrate the aqueous phase, add isopropanol, heat to dissolve, then stir for 0.5 h, cool to -10 °C for crystallization, centrifuge to obtain the solid and drain, the yield is 92.1%: HPLC detects that the βS / βR configuration ratio is 2.5:1.

[0064] Example 8:

[0065]

[0066] Dissolve compound 1 (20 mmol) in dry dichloromethane (40 mL), cool to 0 °C, dropwise add diisopropylethylamine (120 mmol), after stirring evenly, add chloromethyl methyl ether (200 mmol), then add tetrabutylammonium iodide (40 mmol), stir evenly and then raise the temperature to room temperature and react in the dark for 20 h. After the reaction is completed, add saturated NH4Cl aqueous solution to quench the reaction, wash the organic phase with water and dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the crude product of intermediate product 8-2. Dissolve the crude product of intermediate product 8-2 in ethanol / water in a hydrogenation kettle, add palladium-carbon, displace with nitrogen three times first, then displace with hydrogen once, introduce hydrogen for hydrogenation reduction at 50 °C, after 4 h the reaction is complete, add 10% hydrochloric acid and stir for 1 h, filter by suction, extract the filtrate twice with ethyl acetate, concentrate the aqueous phase, add isopropanol, heat to dissolve, then stir for 0.5 h, cool to -10 °C for crystallization, centrifuge to obtain the solid and drain, the yield is 83.1%: HPLC detects that the βS / βR configuration ratio is 1.5:1.

[0067] Example 9:

[0068]

[0069] Dissolve compound 1 (20 mmol) in dry DMF (40 mL), add potassium carbonate (60 mmol), and dropwise add triphenylchlorosilane (100 mmol) at room temperature. After the addition is complete, monitor the reaction by TLC, keep the reaction at a constant temperature for 25 h. After the reaction is completed, quench the reaction with ice water, continue to add ice water and stir to precipitate a solid. Filter the solid at low temperature, wash the obtained solid once with ice water to obtain the crude product of intermediate 9-2. The obtained solid does not need to be further purified and can be directly used for the next feeding. Dissolve the crude product of intermediate 9-2 in ethanol / water in a hydrogenation kettle, add palladium-carbon, displace with nitrogen three times first, then displace with hydrogen once, and introduce hydrogen for hydrogenation reduction at 50 °C. After 4 h, the reaction is complete. Add 10% hydrochloric acid and stir for 1 h, filter by suction. Extract the filtrate twice with ethyl acetate, concentrate the aqueous phase, add isopropanol, heat to dissolve, then stir for 0.5 h, cool to -10 °C to crystallize, centrifuge to obtain the solid and drain it. The yield is 76.1%: HPLC detects that the βS / βR configuration ratio is 8.8:1.

[0070] Example 10:

[0071]

[0072] Dissolve compound 1 (20 mmol) in dry DMF (40 mL), add potassium carbonate (60 mmol), and dropwise add triphenylchlorosilane (100 mmol) at 80 °C. After the addition is complete, monitor the reaction by TLC, keep the reaction at a constant temperature for 3 - 4 h. After the reaction is completed, quench the reaction with ice water, continue to add ice water and stir to precipitate a solid. Filter the solid at low temperature, wash the obtained solid once with ice water to obtain the crude product of intermediate 10-2. The obtained solid does not need to be further purified and can be directly used for the next feeding. Dissolve the crude product of intermediate 10-2 in ethanol, add sodium borohydride (26 mmol), and react at 35 °C for 4 h. After the reaction is completed, quench the reaction with ice water, add 10% hydrochloric acid and stir for 1 h, filter by suction. Extract the filtrate twice with ethyl acetate, concentrate the aqueous phase, add isopropanol, heat to dissolve, then stir for 0.5 h, cool to -10 °C to crystallize, centrifuge to obtain the solid and drain it. The yield is 92.8%: HPLC detects that the βS / βR configuration ratio is 1:1.3.

[0073] Example 11:

[0074]

[0075] Dissolve compound 1 (20 mmol) in dry DMF (40 mL), add 2,2 - dimethoxypropane (0.1 mmol) and p - toluenesulfonic acid (0.2 mmol). Stir the reaction mixture at room temperature for 5 hours, then cool it to - 5°C. Add imidazole (70 mmol) and stir for 10 min, then dropwise add tert - butyldimethylchlorosilane (100 mmol). After the addition is complete, stir at room temperature and monitor the reaction by TLC. Keep the reaction warm for 3 - 4 h. After the reaction is complete, quench the reaction with ice - water, continue to stir with ice - water until a solid precipitates, filter under low temperature. Wash the obtained solid once with ice - water to get the crude product of intermediate 11 - 2. The obtained solid does not need further purification and is directly used for the next feeding. Dissolve the crude product of intermediate 11 - 2 in ethanol / water in a hydrogenation kettle, add palladium - carbon. First, displace with nitrogen three times, then displace with hydrogen once. Pass in hydrogen and carry out hydrogenation reduction at 50°C. After 4 h, the reaction is complete. Add 10% hydrochloric acid and stir for 1 h, filter. Extract the filtrate twice with ethyl acetate. Concentrate the aqueous phase, add isopropanol, heat to dissolve, then stir for 0.5 h, cool to - 10°C to crystallize, centrifuge to obtain the solid and dry it. The yield is 84.6%: HPLC detects that the βS / βR configuration ratio is 5.5:1.

[0076] Example 12:

[0077]

[0078] Dissolve compound 1 (20 mmol) in dry DMF (40 mL), add 2,2 - dimethoxypropane (0.1 mmol) and p - toluenesulfonic acid (0.2 mmol). Stir the reaction mixture at room temperature for 5 hours, then cool it to - 5°C. Add imidazole (70 mmol) and stir for 10 min, then dropwise add triphenylchlorosilane (100 mmol). After the addition is complete, stir at 50°C and monitor the reaction by TLC. Keep the reaction warm for 5 - 6 h. After the reaction is complete, quench the reaction with ice - water, continue to stir with ice - water until a solid precipitates, filter under low temperature. Wash the obtained solid once with ice - water to get the crude product of intermediate 12 - 2. The obtained solid does not need further purification and is directly used for the next feeding. Dissolve the crude product of intermediate 12 - 2 in ethanol / water in a hydrogenation kettle, add palladium - carbon. First, displace with nitrogen three times, then displace with hydrogen once. Pass in hydrogen and carry out hydrogenation reduction at 50°C. After 4 h, the reaction is complete. Add 10% hydrochloric acid and stir for 1 h, filter. Extract the filtrate twice with ethyl acetate. Concentrate the aqueous phase, add isopropanol, heat to dissolve, then stir for 0.5 h, cool to - 10°C to crystallize, centrifuge to obtain the solid and dry it. The yield is 80.2%: HPLC detects that the βS / βR configuration ratio is 9.2:1.

[0079] In summary, the present invention provides a method for synthesizing stereospecific hydroxypropyltetrahydropyrantriol (Boschniakine). This method utilizes the steric effect and atomic effect of special protecting groups, and ingeniously uses the principle of palladium-catalyzed hydrogenation to efficiently and stereospecifically reduce β-acetoxyxyloside, obtaining the specific S-configured Boschniakine. The synthesis method of the present invention has the advantages of simple operation steps, mild reaction conditions, easy post-treatment, good safety, etc. The S-configured Boschniakine prepared has a high yield and high purity, and has the potential for industrial production of S-configured Boschniakine.

[0080] The technical solution of the present invention is not limited to the limitations of the above specific embodiments. Any technical deformation made according to the technical solution of the present invention falls within the protection scope of the present invention.

Claims

1. A method for preparing hydroxyprolisane by a one-pot process, comprising the following steps: (1) reacting β-acetoxyxyloside with a hydroxyl protecting reagent to obtain intermediate 1; (2) subjecting intermediate 1 to catalytic hydrogenation to obtain a mixture of intermediate 2; (3) performing deprotection treatment on the mixture of intermediate 2 to obtain hydroxyprolisane, wherein, R1 and R2 are each independently H or a hydroxyl protecting group; or R1 and R2 are linked to form a cyclic hydroxyl protecting group; PG is a hydroxyl protecting group; Intermediate 1 is first subjected to catalytic hydrogenation with palladium / carbon in an alcohol or a mixed solution of alcohol and water to obtain a mixed solution of Intermediate 2, and the mixed solution of Intermediate 2 is treated with hydrochloric acid for deprotection to obtain boswellic acid; The hydroxyl protecting group is an alkylsilyl group, an alkylarylsilyl group or an arylsilyl group.

2. The method according to claim 1, characterized in that, In step (1), β-acetoxyl xyloside is dissolved in an aprotic water-miscible solvent and reacted with a hydroxyl protecting reagent under alkaline conditions; after the reaction is completed, water at 0-5 °C is added to precipitate Intermediate 1.

3. The method according to claim 2, characterized in that, The aprotic water-miscible solvent includes DMF or DMSO; the base includes one or more of potassium carbonate, cesium carbonate, sodium carbonate, imidazole or triethylamine.

4. The method according to any one of claims 1-3, characterized in that, The hydroxyl protecting group is trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, methyldiphenylsilyl, triphenylsilyl.

5. The method according to any one of claims 1-3, characterized in that, The molar ratio of β-acetoxyl xyloside to the hydroxyl protecting reagent is (1:4)-(1:6).

6. The method according to any one of claims 1-3, characterized in that, The reaction temperature of β-acetoxyl xyloside with the hydroxyl protecting reagent is 60-90 °C.

7. The method according to any one of claims 1-3, characterized in that, In step (1), β-acetoxyl xyloside is dissolved in DMF or DMSO, carbonate is added, heated to 75-85 °C, and a silane-based hydroxyl protecting reagent is added dropwise. After the reaction is completed, water at 0-5 °C is added and stirred to precipitate Intermediate 1; in step (2), Intermediate 1 is dissolved in ethanol or a mixed solution of alcohol and water, and hydrogenated under the catalysis of palladium-carbon to obtain a mixed solution of Intermediate 2; Hydrochloric acid is added to remove the hydroxyl protecting group to obtain boswellic acid.

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