A method for synthesizing high-quality (beta, s) configuration hydroxypropyl tetrahydropyran triol

Abstract

The application relates to a synthesis method of high-quality (beta, S) configuration hydroxypropyl tetrahydropyran triol, which comprises the following steps: taking 1-C-(beta-D-pyranosyl xylose)-propanone as a starting material, reacting with chlorosilane to form a silyl ether with an alkali as a catalyst to prepare an intermediate I, preparing an intermediate II through a silane reduction reaction of the intermediate I, and obtaining a single (beta, S) configuration high-quality configuration hydroxypropyl tetrahydropyran triol solid through desilyl protection reagent reaction, decolorization with activated carbon and ion resin exchange, and the structure formula is as follows. The process method is simple and easy to operate, the intermediate with good ester solubility is prepared, water-soluble salts are removed through water washing, the generation amount of waste water is reduced, the product is high in purity and good in property, and is suitable for large-scale production.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of organic synthesis, in particular to a synthesis method of (β, S) configuration hydroxypropyl tetrahydropyran triol. BACKGROUND

[0002] Pro-xylane, originally a raw material group composed of water + propylene glycol + hydroxypropyl tetrahydropyran triol, with the INCI name of Hydroxypropyl Tetrahyclropyantiol, wherein the functional active ingredient is hydroxypropyl tetrahydropyran triol, which is a C-glycoside with biological activity in aqueous media, discovered by Lancome Laboratory under L'Oreal, is a C-glycoside with biological activity in aqueous media, which can stimulate the production of glucosaminoglycans (GAGs), promote the generation of hyaluronic acid and collagen, increase the content of mucopolysaccharide in intercellular substance, improve the adhesion between dermis and epidermis, help maintain the elasticity of skin, and improve skin aging. At the same time, because it is easily biodegradable and does not accumulate in the body, it is praised as the "green active raw material" in the cosmetics industry.

[0003]

[0004] The structure of the above hydroxypropyl tetrahydropyran triol, wherein the preparation route and application in cosmetics of hydroxypropyl tetrahydropyran triol are introduced in the international patent WO2002051828 of L'Oreal, the authorized patent CN100441588C of China, and the article "Synthesis of Pro-Xylane: a new biologically active C-glycoside in aqueous media" published in the journal Bioorganic & Medicinal Chemistry Letters in 2009, wherein the experimental data clearly shows that the activity of (β, S) configuration is better than that of (β, R) and (β, S) mixture. TM :A new biologically active C-glycosidein aqueous media" in which the preparation route and application in cosmetics of hydroxypropyl tetrahydropyran triol are introduced, wherein the experimental data clearly shows that the activity of (β, S) configuration is better than that of (β, R) and (β, S) mixture.

[0005]

[0006] As shown above, the structural formula of (beta, S) configuration hydroxypropyl tetrahydropyran triol, its chemical name is C-beta-D-xylopyranoside-2-(S)-hydroxy propane (CAS NO.: 868156-46-1), which is a light yellow to white solid, unlike (beta, R) and (beta, S) mixture is viscous. However, the good solid formability of (beta, S) configuration hydroxypropyl tetrahydropyran triol cannot simplify its purification difficulty, but there will be a large amount of acetate, boric acid and borate salt residues in the preparation process. Because the water solubility of hydroxypropyl tetrahydropyran triol is very large, inorganic salts cannot be removed by conventional extraction methods for purification, therefore, column chromatography purification or ion resin desalting method is reported in the original patent and other patent documents to obtain the product, but this process is complex, the batch size is small, the wastewater is huge and the production cost is high.

[0007] In 2021, the Chinese Food and Drug Inspection Research Institute listed boric acid and borate in the cosmetic prohibited raw material directory, so to obtain high quality, boron-free (beta, S) configuration hydroxypropyl tetrahydropyran triol, the effective removal of boric acid and borate is a key factor. Asymmetric reduction by metal catalysis can obtain a product with high (beta, S) configuration product content, but the cost of metal catalyst is high, and the removal of metal and its complex is still a problem.

[0008] Therefore, it is of great significance to develop a preparation process of (beta, S) configuration hydroxypropyl tetrahydropyran triol raw material with high purity, no metal catalytic element impurity residue, no boric acid or borate residue, and white product color and high product purity. SUMMARY

[0009] In view of the problems existing in the prior art, the present application provides a synthesis method for preparing high-quality (beta, S) configuration hydroxypropyl tetrahydropyran triol. The synthesis method for preparing (beta, S) configuration hydroxypropyl tetrahydropyran triol has the advantages of simple process, (beta, S) configuration > 99.5%, no metal catalytic element impurity residue, no boric acid or borate residue, strong process operability, low production cost and industrial application potential.

[0010] To achieve the above object, the following technical scheme is adopted in the present application:

[0011] A synthesis method for preparing high-quality (beta, S) configuration hydroxypropyl tetrahydropyran triol, comprising the following steps:

[0012] (1) taking 1-C-(beta-D-xylopyranosyl)-propanone as a starting material, taking a base as a catalyst, and reacting with chlorosilane to form a silyl ether to prepare an intermediate I, the structural formula is:

[0013]

[0014] wherein R1, R2, R3are any one of hydrogen, trimethylsilyl, tert-butyldimethylsilyl, triisopropylsilyl or tert-butyldiphenylsilyl, respectively; R1, R2, R3are preferably tert-butyldimethylsilyl;

[0015] (2) the intermediate I is prepared into intermediate II by a silane reduction reaction, and the structural formula is:

[0016]

[0017] wherein R1, R2, R3are any one of hydrogen, trimethylsilyl, tert-butyldimethylsilyl, triisopropylsilyl or tert-butyldiphenylsilyl, respectively, and R4is any one of triphenylsilyl, triethylsilyl, triethoxysilyl or trimethylsilyl;

[0018] (3) the intermediate II is reacted with a desilyl protective reagent, decolorized by activated carbon, and ion resin exchanged to obtain a high-quality configuration hydroxypropyl tetrahydropyranetriol solid with a single (β, S) configuration, and the structural formula is:

[0019]

[0020] Further, the specific preparation steps of the step (1) are as follows:

[0021] 1-C-(β-D-xylopyranosyl)-propanone is used as a starting material, a solvent, a base and chlorosilane are added, the temperature is controlled, the reaction is monitored by TLC, after the reaction of 1-C-(β-D-xylopyranosyl)-propanone is completed, an alkane is added, and the organic phase is washed with water and saturated brine in sequence, dried by anhydrous sodium sulfate, concentrated, and then the intermediate I is obtained;

[0022] Further, in the step (1), the molar ratio of 1-C-(β-D-xylopyranosyl)-propanone: base: chlorosilane is 1:1-5:1-4; more preferably, the molar ratio of 1-C-(β-D-xylopyranosyl)-propanone: base: chlorosilane is 1:4:3.3.

[0023] Further, in the step (1),

[0024] The base used is one or more of imidazole, pyridine, triethylamine, sodium carbonate or sodium bicarbonate; preferably, the base is imidazole;

[0025] The chlorosilane used is one or more of trimethylchlorosilane, tert-butyldimethylchlorosilane, triisopropylchlorosilane or tert-butyldiphenylchlorosilane; preferably, the chlorosilane is tert-butyldimethylchlorosilane;

[0026] Further, in the step (1),

[0027] The solvent is selected from one or more of dichloromethane, dichloroethane, N,N-dimethylformamide, tetrahydrofuran; preferably (N,N-dimethylformamide).

[0028] Further, in the step (1), the reaction temperature is 0-50°C; preferably 10-30°C.

[0029] Further, in the step (1), the alkane added after the reaction is complete is one or more of petroleum ether, cyclohexane, n-hexane, n-heptane; preferably n-hexane.

[0030] Further, the specific preparation step of the step (2) is:

[0031] The intermediate I is used as a raw material, a solvent, silane and a catalyst are added to perform a reduction reaction, the reaction liquid is concentrated, extracted with ethyl acetate, washed with water, and concentrated to obtain the intermediate II.

[0032] Further, in the step (2), the solvent used for the reaction is one or more of methanol, ethanol, isopropanol, tetrahydrofuran or dioxane, preferably one or a mixture of two of isopropanol and tetrahydrofuran.

[0033] Further, in the step (2), the molar ratio of intermediate I: silane: catalyst is 1: 1.0-1.5: 0.01-0.1, preferably 1: 1.1: 0.05, according to the molar amount of 1-C-(β-D-xylopyranosyl)-propanone.

[0034] Further, in the step (2), the silane is one of trimethylsilane, triphenylsilane, triethylsilane, triethoxysilane, methyl hydrogen siloxane polymer (PMHS); further preferably, it is trimethylsilane, triethylsilane or methyl hydrogen siloxane polymer (PMHS).

[0035] Further, in the step (2), the catalyst is one or more of ferric chloride, ferric bromide, copper chloride or acetylacetone iron; further preferably, it is ferric chloride.

[0036] Further, in the step (2), the reduction reaction conditions are to add at 0-15°C, and after the temperature of the addition is stable, to react at 15-30°C; further preferably, the reduction reaction conditions are to add at 10-15°C, and after the temperature of the addition is stable, to react at room temperature.

[0037] Further, the specific preparation step of the step (3) is:

[0038] The intermediate II is reacted with a desilyl protecting agent, purified water is added, the aqueous phase is extracted with ethyl acetate to remove organic impurities, the aqueous phase is decolorized with activated carbon and ion resin is exchanged, and after concentration and crystallization, a single (β, S) configuration high-quality configuration hydroxypropyl tetrahydropyran triol solid is obtained.

[0039] Further, in the step (3), the desilyl protecting agent is one or more of hydrogen chloride alcohol solution, tetrabutylammonium fluoride, hexafluorosilicic acid, hydrofluoric acid, or N-iodosuccinimide; and more preferably, hydrogen chloride alcohol solution or tetrabutylammonium fluoride.

[0040] Further, in the step (3), after concentration, recrystallization is performed with ethanol, water and ethyl acetate.

[0041] Further, in the step (3), the molar ratio of intermediate II to desilyl protecting agent is 1:4-12, based on the molar amount of 1-C-(β-D-xylopyranosyl)-propanone; and more preferably, the molar ratio of intermediate II to desilyl protecting agent is 1:4-8.

[0042] Further, in the step (3), the intermediate II is added to the desilyl protecting agent and reacted at 0-30°C for 1-6 hours, and more preferably, the reaction is performed at 25°C for 3 hours.

[0043] Beneficial effects:

[0044] 1) The reaction steps of the present application do not involve noble metals, and the production cost is low;

[0045] 2) The present application uses a protecting group to treat the product after reduction, and the product is soluble in an organic phase, so that inorganic salts can be removed by extraction and water washing, thereby achieving separation of the product and the salt;

[0046] 3) The process route described in the present application does not use a boron-containing reducing agent such as sodium borohydride or sodium triacetoxyborohydride, and can achieve no residue of boric acid, borate and other salts.

[0047] 4) The white solid powder product (β, S) configuration hydroxypropyl tetrahydropyran triol with a liquid phase purity of >99.5% is obtained by deprotection, decolorization, ion resin exchange and crystallization. Since most of the salts are removed by water washing in the first and second reaction processes, the amount of ion resin used in the third reaction post-treatment is small, and it is easier to regenerate and utilize. BRIEF DESCRIPTION OF DRAWINGS

[0048] In order to more clearly illustrate the technical solutions in the specific embodiments of the present application or the prior art, the drawings needed to be used in the description of the specific embodiments or the prior art will be briefly introduced as follows. Obviously, the drawings described in the following description are some embodiments of the present application, and other drawings can be obtained by those skilled in the art without creative effort on the basis of these drawings.

[0049] Figure 1 HPLC spectrum of (β, S) configuration hydroxypropyl tetrahydropyran triol of Example 1 of the present application

[0050] Figure 2 HPLC spectrum of (β, S) configuration hydroxypropyl tetrahydropyran triol of Example 2 of the present application

[0051] Figure 3 HPLC spectrum of (β, S) configuration hydroxypropyl tetrahydropyran triol of Example 12 of the present application

[0052] Figure 4 HPLC spectrum of (β, S) configuration hydroxypropyl tetrahydropyran triol of Example 12 of the present application 1 H NMR spectrum

[0053] Figure 5 H NMR spectrum of (β, S) configuration hydroxypropyl tetrahydropyran triol of Example 12 of the present application 13 C NMR spectrum DETAILED DESCRIPTION

[0054] Hereinafter, the present application will be described in detail. Before proceeding with the description, it should be understood that the terms used in the specification and the appended claims should not be construed as limiting to the general and dictionary meanings and should be construed as carrying the meaning and concepts that are consistent with the technical aspects of the present application based on the principles that the inventor is allowed to define the terms in order to best explain the technical idea of the present application. Therefore, the description presented herein is merely a preferred example for the purpose of illustration and is not intended to limit the scope of the present application and it should be understood that other equivalent ways or modifications can be obtained from the technical idea of the present application without departing from the spirit and scope of the present application.

[0055] The following examples are merely set forth as examples of embodiments of the present application and are not intended to limit the present application in any way. Those skilled in the art will appreciate that modifications can be made without departing from the spirit and scope of the present application. Unless otherwise specifically defined herein, all reagents and instruments used in the following examples are commercially available.

[0056] As used herein, the terms "comprises," "comprising," "includes," "including," "has," "having," "contains," "containing," or any other similar words, are intended to be open-ended, and to mean including, but not limited to. In other words, use of these terms indicates that the named element is an element that is encompassed by the phrase, but not that the phrase is limited to the named element. For example, a composition or article that comprises a list of elements is not necessarily limited to only those elements but can include other elements not expressly listed or inherent to such composition or article. Further, unless otherwise specified, the use of "or" is to be treated as a disjunctive term that means "and / or," unless otherwise indicated by context. For example, a list of items joined by "or" means any one of the items can be present or each of the items can be present and used together. In addition, unless expressly stated to the contrary, the term "or" as used herein refers to an inclusive "or" and not to an exclusive "or." For example, a condition "A or B" is satisfied by any one of the following: A is true (or present) and B is false (or not present), A is false (or not present) and B is true (or present), and both A and B are true (or present). Also, the use of the terms "comprise," "comprising," "comprises," "include," "including," "includes," "have," "has," "having," or variants thereof are not to be limited to consisting only of the recited elements but can include other elements not explicitly listed or inherent to such composition or article.

[0057] As used herein, all features or conditions of a range or a percentage range are intended to be merely for convenience and brevity in providing the disclosure. Accordingly, the description of a range or a percentage range should be considered to have specifically disclosed and encompassed all possible sub-ranges and individual numerical values within the range, particularly integer values. For example, a range of "1 to 8" should be considered to have specifically disclosed all sub-ranges such as 1 to 7, 2 to 8, 2 to 6, 3 to 6, 4 to 8, 3 to 8, etc., particularly sub-ranges defined by all integer values, and to have specifically disclosed individual values within the range such as 1, 2, 3, 4, 5, 6, 7, 8, etc. The foregoing interpretation applies to all aspects of the disclosure, whether broad or narrow, unless otherwise indicated.

[0058] If a range or other numerical value or parameter is expressed herein as comprising an upper value or limit and a lower value or limit, then it is intended that an inclusive range between any stated upper value or limit and any stated lower value or limit comprises all values and / or parameters falling within the range, whether or not such values and / or parameters are expressly disclosed. In addition, if a range of values is stated herein, unless otherwise stated, the range is to be construed as including the endpoints and all integers and fractions within the range.

[0059] As used herein, numerical values are to be construed in a range of values having the precision of the number of significant figures in the numerical value. For example, the number 40.0 is to be construed to encompass a range of 39.50 to 40.49.

[0060] The following examples are set forth to illustrate the embodiments of the present application and are not intended to limit the scope of the application. Those skilled in the art will readily understand that modifications can be made to the present application without departing from the spirit and scope of the application. Unless otherwise indicated, the reagents and materials used in the following examples were obtained from commercial suppliers and used without further purification.

[0061] Example 1: Preparation of (2S,3R,4S,5R)-2-((S)-2-hydroxypropyl)tetrahydro-2H-pyran-3,4,5-triol ((β,S) configuration hydroxypropyl tetrahydro pyran triol).

[0062] The developing agent used in the reaction monitored by TLC in the following example step 1 is methanol / dichloromethane = 1:4, 20% sulfuric acid ethanol solution for coloration; the developing agent used in the reaction monitored by TLC in step 2 is ethyl acetate / petroleum ether = 1:3, 20% sulfuric acid ethanol solution for coloration; the developing agent used in the reaction monitored by TLC in step 3 is first ethyl acetate / petroleum ether = 1:3, 20% sulfuric acid ethanol solution for coloration to confirm the conversion of raw materials, and then methanol / dichloromethane = 1:4, 20% sulfuric acid ethanol solution for coloration to confirm the generation of product.

[0063] Step 1: Preparation of 1-((2S,3S,4S,5R)-3,4,5-tri((tert-butyldimethylsilyl)oxy)tetrahydro-2H-pyran-2-yl)propan-2-one

[0064]

[0065] 1-C-(β-D-xylopyranosyl)-propanone (20.27 g, 106.57 mmol) (CAS No.: 439685-73-1), tert-butyldimethylchlorosilane (53 g, 351.7 mmol), imidazole (29 g, 426.3 mmol) were weighed into a 500 ml round bottom flask, N,N-dimethylformamide (100 ml) was added, and the reaction was stirred at 23°C. After the conversion of 1-C-(β-D-xylopyranosyl)-propanone was completed in the reaction monitored by TLC, n-hexane (300 ml) was added and stirred for 1 h, and the reaction liquid was washed with water (2 x 200 ml) and saturated aqueous sodium chloride solution (1 x 50 ml) in sequence. The organic phase was dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure to obtain a yellow oily crude intermediate I, which was directly subjected to the next step of reduction.

[0066] Step 2: Preparation of ((2S,3S,4S,5R)-2-((S)-2-(triethylsilyloxy)propyl)tetrahydro-2H-pyran-3,4,5-trioxy))tris(tert-butyldimethylsilane)

[0067]

[0068] The intermediate I of the previous step (calculated on the amount of material used in the previous step to be fully converted into the product) was dissolved in dry isopropanol (250 ml) and stirred at 10°C. Iron trichloride (864 mg, 5.33 mmol) was added and triethylsilane (13.63 g, 117.23 mmol) was added dropwise. The reaction was maintained at room temperature until the complete conversion of intermediate I was confirmed by TLC. The reaction was stopped, the insoluble material was removed by filtration and the remaining filtrate was concentrated under reduced pressure until dryness. EA (200 ml) was added and the mixture was washed with 10% aqueous sodium bicarbonate solution (100 ml), water (100 ml) and saturated aqueous sodium chloride solution (1 x 50 ml). The organic phase was dried over anhydrous sodium sulfate, filtered and distilled under reduced pressure to obtain crude intermediate II as a yellow oil, which was used directly in the next step.

[0069] Step 3: Preparation of (2S,3R,4S,5R)-2-((S)-2-hydroxypropyl)tetrahydro-2H-pyran-3,4,5-triol ((β,S) configuration hydroxypropyltetrahydropyrantriol).

[0070]

[0071] The crude intermediate II of step 2 was added to Tetrabutylammonium fluoride (TBAF; 1 M solution in tetrahydrofuran 426 ml) and stirred at 20°C for 3 hours. The complete conversion of intermediate II was confirmed by TLC and the reaction was stopped. The solvent was concentrated until dryness and purified water (100 ml) was added and stirred. The aqueous phase was extracted with EA (3 x 80 ml) and the aqueous phase was decolorized with activated carbon and exchanged with cation and anion resins. The product was obtained as a white solid after recrystallization from ethanol, water and ethyl acetate. The yield of the three steps was 71.1% based on the amount of 1-C-(β-D-xylopyranosyl)-propanone used (calculated on the moles of 1-C-(β-D-xylopyranosyl)-propanone used, the same method was used in the following examples). The purity of the (β,S) configuration hydroxypropyltetrahydropyrantriol was 99.8% (see Figure 1) and the conductivity of a 30% aqueous solution was 16 μS / cm. Figure 1

[0072] Example 2: Preparation of (2S,3R,4S,5R)-2-((S)-2-hydroxypropyl)tetrahydro-2H-pyran-3,4,5-triol ((β,S) configuration hydroxypropyltetrahydropyrantriol).

[0073] ​The developing agent used in the TLC monitoring reaction in Step 1 of the following example was methanol / dichloromethane = 1:4, and the developing agent used in the TLC monitoring reaction in Step 2 was ethyl acetate / petroleum ether = 1:3, and the developing agent used in the TLC monitoring reaction in Step 3 was first ethyl acetate / petroleum ether = 1:3, 20% sulfuric acid ethanol solution was used for color development to confirm the conversion of the raw material, and then methanol / dichloromethane = 1:4, 20% sulfuric acid ethanol solution was used for color development to confirm the generation of the product.

[0074] Step 1: Preparation of 1-((2S,3S,4S,5R)-3,4,5-tris((tert-butyldimethylsilyl)oxy)tetrahydro-2H-pyran-2-yl)propan-2-one

[0075]

[0076] 1-C-(β-D-xylopyranosyl)-propanone (19.02 g, 100 mmol), tert-butyldimethylsilyl chloride (52.75 g, 350 mmol), pyridine (31.64 g, 400 mmol) were weighed into a 500 ml round-bottom flask, N,N-dimethylformamide (100 ml) was added, and the reaction was stirred at 20°C. The conversion of 1-C-(β-D-xylopyranosyl)-propanone was monitored by TLC, petroleum ether (300 ml) was added and stirred for 1 h, and the reaction solution was washed with water (2 x 200 ml), saturated aqueous sodium chloride solution (1 x 50 ml), and then dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure to obtain a yellow oil, which was directly used in the next step.

[0077] Step 2: Preparation of ((2S,3S,4S,5R)-2-((S)-2-(triethylsilyloxy)propyl)tetrahydro-2H-pyran-3,4,5-tris(oxy))tris(tert-butyldimethylsilane)

[0078]

[0079] The crude product of the previous step (calculated on the basis of complete conversion of the product of the previous step) was dissolved in dry methanol (250 ml) and stirred at 10°C. Iron tribromide (1.48 g, 5.0 mmol) was added, and triethylsilane (12.79 g, 110 mmol) was added dropwise. The reaction was maintained at room temperature until complete conversion of the intermediate I was confirmed by TLC. The reaction was then stopped, the insoluble material was removed by filtration, and the remaining filtrate was concentrated under reduced pressure to dryness. Ethyl acetate (200 ml) was added, and the mixture was washed with 10% aqueous sodium bicarbonate solution (100 ml), water (100 ml), and saturated aqueous sodium chloride solution (1 x 50 ml). The organic phase was dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure to give the crude product as a yellow oil, which was used directly in the next step.

[0080] Step 3: Preparation of (2S, 3R, 4S, 5R)-2-((S)-2-hydroxypropyl)tetrahydro-2H-pyran-3,4,5-triol ((β, S) configuration hydroxypropyl tetrahydro pyran triol).

[0081]

[0082] The crude product of Step 2 was dissolved in a methanolic solution of hydrogen chloride (containing HCl at 4 mol / L, 150 ml) and stirred at 10°C for 4 hours. Complete conversion of the intermediate II was confirmed by TLC, and the reaction was then stopped. The solvent was concentrated to dryness, and purified water (100 ml) was added and stirred. The mixture was extracted with EA (3 x 80 ml), and the aqueous phase was decolorized with activated carbon and ion-exchanged. After concentration, recrystallization from ethanol, water, and ethyl acetate gave white solid 13.37 g. The yield of the three steps was 70.29% based on 1-C-(β-D-xylopyranosyl)-propanone. The purity of the (β, S) configuration hydroxypropyl tetrahydro pyran triol was 100% as determined by liquid chromatography with an evaporative light detector (see Figure 1). Figure 2

[0083] Example 3: Preparation of (2S, 3R, 4S, 5R)-2-((S)-2-hydroxypropyl)tetrahydro-2H-pyran-3,4,5-triol ((β, S) configuration hydroxypropyl tetrahydro pyran triol)

[0084] In the TLC monitoring reaction used in Step 1 of the following example, the developing agent was methanol / dichloromethane = 1:4, and 20% sulfuric acid ethanol solution was used for color development. In the TLC monitoring reaction used in Step 2, the developing agent was ethyl acetate / petroleum ether = 1:3, and 20% sulfuric acid ethanol solution was used for color development. In the TLC monitoring reaction used in Step 3, the developing agent was first ethyl acetate / petroleum ether = 1:3, and 20% sulfuric acid ethanol solution was used for color development to confirm the conversion of the starting material. Then, methanol / dichloromethane = 1:4, and 20% sulfuric acid ethanol solution was used for color development to confirm the generation of the product.​

[0085] Step 1: Preparation of 1-((2S,3S,4S,5R)-3,4,5-tris((tert-butyldimethylsilyl)oxy)tetrahydro- 2H-pyran-2-yl)propan-2-one

[0086]

[0087] Weigh 1-C-(β-D-xylopyranosyl)-propanone (19.02 g, 100 mmol), tert-butyldimethylsilyl chloride (49.74 g, 330 mmol), triethylamine (40.48 g, 400 mmol) into a 500 ml round bottom flask, add tetrahydrofuran (100 ml), stir the reaction at room temperature. After confirming the completion of the reaction of 1-C-(β-D-xylopyranosyl)-propanone by TLC, add cyclohexane (250 ml) and stir for 1 h. Wash the reaction liquid with water (3 x 170 ml), saturated aqueous sodium chloride solution (1 x 50 ml) in sequence, dry the organic phase with anhydrous sodium sulfate, filter, and distill under reduced pressure to obtain a yellow oil crude product.

[0088] Step 2: Preparation of ((2S,3S,4S,5R)-2-((S)-2-(trimethylsilyloxy)propyl)tetrahydro-2H-pyran- 3,4,5-trioxy))tris(tert-butyldimethylsilyl)

[0089]

[0090] Dissolve the oil in tetrahydrofuran (200 ml), stir at 10°C, add copper chloride (672 mg, 5.0 mmol), dropwise add trimethylsilyl (8.9 g, 120 mmol), keep the reaction at room temperature, confirm the complete conversion of intermediate I by TLC, stop the reaction, remove the insoluble material by filtration, and concentrate the remaining filtrate to dryness under reduced pressure. Disperse in EA (200 ml), wash with 10% aqueous sodium bicarbonate solution (100 ml), aqueous solution (100 ml), saturated aqueous sodium chloride solution (1 x 50 ml) in sequence, dry the organic phase with anhydrous sodium sulfate, filter, and distill under reduced pressure to obtain a yellow oil crude product, which is directly used in the next step reaction.

[0091] Step 3: Preparation of (2S,3R,4S,5R)-2-((S)-2-hydroxypropyl)tetrahydro-2H-pyran-3,4,5-triol ((β, S) configuration hydroxypropyl tetrahydropyran triol).

[0092]

[0093] The above crude product was added to a solution of hydrogen chloride in ethanol (containing HCl 4 mol / L, 120 ml), stirred at 25°C for 4 hours, the reaction progress was monitored by TLC, the reaction was stopped, the solvent was concentrated to dryness, purified water (80 ml) was added and stirred, extracted with EA (3 x 60 ml), the aqueous phase was decolorized with activated carbon and exchanged with cation and anion resins, concentrated, and recrystallized with ethanol, water and ethyl acetate to obtain a white solid 13.86 g, the yield of the three-step reaction was 72.11% based on 1-C-(β-D-xylopyranosyl)-propanone, the purity of (β, S) configuration hydroxypropyl tetrahydropyrane triol was 100% by liquid phase test with an evaporative light detector, and the conductivity of a 30% aqueous solution was 7.8 μS / cm.

[0094] Example 4: Preparation of (2S, 3R, 4S, 5R)-2-((S)-2-hydroxypropyl)tetrahydro-2H-pyran-3, 4, 5-triol ((β, S) configuration hydroxypropyl tetrahydropyrane triol)

[0095] In the reaction monitoring by TLC in the following Example Step 1, the developing agent was methanol / dichloromethane = 1:4, and 20% sulfuric acid ethanol solution was used for color development; in the reaction monitoring by TLC in Step 2, the developing agent was ethyl acetate / petroleum ether = 1:3, and 20% sulfuric acid ethanol solution was used for color development; in the reaction monitoring by TLC in Step 3, the developing agent was first ethyl acetate / petroleum ether = 1:3, 20% sulfuric acid ethanol solution was used for color development to confirm the conversion of the raw material, and then methanol / dichloromethane = 1:4, 20% sulfuric acid ethanol solution was used for color development to confirm the generation of the product.

[0096] Step 1: Preparation of 1-(2S, 3S, 4S, 5R)-3, 4, 5-tris((triisopropylsilyl)oxy)tetrahydro-2H-pyran-2-yl)propan-2-one

[0097]

[0098] 1-C-(β-D-xylopyranosyl)-propanone (19.02 g, 100 mmol), triisopropylsilyl chloride (63.63 g, 330 mmol) and imidazole (27.23 g, 400 mmol) were weighed into a 500 ml round-bottom flask, N,N-dimethylformamide (100 ml) was added, and the reaction was stirred at room temperature. After the conversion of 1-C-(β-D-xylopyranosyl)-propanone in the reaction was confirmed by TLC, n-hexane (300 ml) was added and stirred for 1 h, the reaction liquid was washed with water (2 x 200 ml) and saturated sodium chloride aqueous solution (1 x 50 ml) in sequence, the organic phase was dried with anhydrous sodium sulfate, filtered, and distilled under reduced pressure to obtain a yellow oily crude product.

[0099] Step 2: ((2S, 3S, 4S, 5R)-2-((S)-2-(triethylsilyloxy)propyl)tetrahydro-2H-pyran-3,4,5- triol) tris(triisopropylsilane)

[0100]

[0101] The oil was dissolved in tetrahydrofuran (200 ml) and stirred at 10°C. Iron trichloride (811 mg, 5 mmol) was added and triethylsilane (13.95 g, 120 mmol) was added dropwise. The reaction was maintained at room temperature until the conversion of intermediate I was complete, as determined by TLC. The reaction was stopped, the insoluble material was removed by filtration and the remaining filtrate was concentrated under reduced pressure until dryness. The residue was dispersed in EA (200 ml) and washed sequentially with 10% aqueous sodium bicarbonate solution (100 ml), water (100 ml) and saturated aqueous sodium chloride solution (1 x 50 ml). The organic phase was dried over anhydrous sodium sulfate, filtered and distilled under reduced pressure to obtain a yellow oil, which was used directly in the next step.

[0102] Step 3: Preparation of (2S, 3R, 4S, 5R)-2-((S)-2-hydroxypropyl)tetrahydro-2H-pyran-3,4,5- triol ((β, S) configuration hydroxypropyl tetrahydro pyran triol).

[0103]

[0104] The intermediate from step 2 above was added to Tetrabutylammonium fluoride (TBAF; 1 M solution in tetrahydrofuran, 440 ml) and stirred at 25°C for 3 hours. The conversion of intermediate II was complete, as determined by TLC. The reaction was stopped, the solvent was concentrated until dryness and purified water (120 ml) was added and stirred. The aqueous phase was extracted with EA (3 x 80 ml), decolorized with activated carbon and exchanged with cation and anion resins. The product was obtained as a white solid by recrystallization from ethanol, water and ethyl acetate. The yield of the three steps was 62.07% based on 1-C-(β-D-xylopyranosyl)-propanone. The purity of the (β, S) configuration hydroxypropyl tetrahydro pyran triol was 99.62% as determined by liquid chromatography with an evaporative light detector. The conductivity of a 30% aqueous solution was 14.3 μS / cm.

[0105] Example 5: Preparation of (2S, 3R, 4S, 5R)-2-((S)-2-hydroxypropyl)tetrahydro-2H-pyran-3,4,5- triol ((β, S) configuration hydroxypropyl tetrahydro pyran triol).

[0106] The developing solvent used in the TLC monitoring reaction in the following Example Step 1 is methanol / dichloromethane = 1:4, 20% sulfuric acid ethanol solution for color development; the developing solvent used in the TLC monitoring reaction in Step 2 is ethyl acetate / petroleum ether = 1:3, 20% sulfuric acid ethanol solution for color development; the developing solvent used in the TLC monitoring reaction in Step 3 is first ethyl acetate / petroleum ether = 1:3, 20% sulfuric acid ethanol solution for color development to confirm the conversion of the raw material, and then methanol / dichloromethane = 1:4, 20% sulfuric acid ethanol solution for color development to confirm the generation of the product.

[0107] Step 1: Preparation of 1-(2S,3S,4S,5R)-3,4,5-tris((trimethylsilyl)oxy)tetrahydro-2H-pyran-2-yl)propan-2-one

[0108]

[0109] The 1-C-(β-D-xylopyranosyl)-propanone (19.02 g, 100 mmol), trimethylsilyl chloride (35.85 g, 330 mmol), and imidazole (27.23 g, 400 mmol) were weighed into a 500 ml round-bottom flask, and N,N-dimethylformamide (100 ml) was added. The reaction was stirred at room temperature. After the TLC confirmed that the conversion of 1-C-(β-D-xylopyranosyl)-propanone was complete, n-hexane (300 ml) was added and stirred for 1 h. The reaction solution was washed with water (2 x 200 ml), saturated aqueous sodium chloride solution (1 x 50 ml), and then dried over anhydrous sodium sulfate. After filtration, the crude product was obtained as a yellow oil by distillation under reduced pressure.

[0110] Step 2: Preparation of ((2S,3S,4S,5R)-2-((S)-2-(trimethylsilyloxy)propyl)tetrahydro-2H-pyran-3,4,5-triyl)tris(oxy)tris(trimethylsilane)

[0111]

[0112] The oil was dissolved in ethanol (200 ml) and stirred at room temperature. Iron acetylacetonate (1.70 g, 5.0 mmol) was added, and trimethylsilyl chloride (7.79 g, 105 mmol) was added dropwise. The reaction was maintained at room temperature. The TLC confirmed that the reaction of the intermediate I was complete, and the reaction was stopped. The reaction solution was concentrated to dryness under reduced pressure, dispersed in EA (200 ml), and washed with 10% aqueous sodium bicarbonate solution (100 ml), aqueous solution (100 ml), and saturated aqueous sodium chloride solution (1 x 50 ml). The organic phase was dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure to obtain a yellow oil as a crude product, which was directly used in the next step.

[0113] Step 3: Preparation of (2S, 3R, 4S, 5R)-2-((S)-2-hydroxypropyl)tetrahydro-2H-pyran-3,4,5-triol ((β, S) configuration hydroxypropyl tetrahydro pyran triol).

[0114]

[0115] The above Step 2 intermediate was added to 146 g of methanol, at 0°C, hydrofluoric acid (48-52% aqueous solution, 16 g, 400 mmol) was added, the temperature was maintained and the reaction was stirred for 2 hours, the conversion of intermediate II was confirmed by TLC, the reaction was stopped, the solvent was concentrated to dryness, purified water (100 ml) was added and stirred, extracted with EA (3 x 80 ml), the aqueous phase was decolorized with activated carbon, cation and anion resin exchange, concentrated, recrystallized with ethanol, water and ethyl acetate to obtain 11.89 g of white solid, the yield of the three-step reaction was 61.92% based on 1-C-(β-D-xylopyranosyl)-propanone, the purity of the (β, S) configuration hydroxypropyl tetrahydro pyran triol was 99.54% by liquid phase test with an evaporative light detector, and the conductivity of a 30% aqueous solution was 23.2 μS / cm.

[0116] Example 6: Preparation of (2S, 3R, 4S, 5R)-2-((S)-2-hydroxypropyl)tetrahydro-2H-pyran-3,4,5-triol ((β, S) configuration hydroxypropyl tetrahydro pyran triol)

[0117] The following examples were monitored by TLC in Step 1, the developing agent was methanol / dichloromethane = 1:4, 20% sulfuric acid ethanol solution was used for color development; in Step 2, the developing agent was ethyl acetate / petroleum ether = 1:3, 20% sulfuric acid ethanol solution was used for color development; in Step 3, the developing agent was first ethyl acetate / petroleum ether = 1:3, 20% sulfuric acid ethanol solution was used for color development to confirm the conversion of the raw material, then methanol / dichloromethane = 1:4, 20% sulfuric acid ethanol solution was used for color development to confirm the generation of the product.

[0118] Step 1: Preparation of 1-(2S, 3S, 4S, 5R)-3,4,5-tris((tert-butyldiphenylsilyl)oxy)tetrahydro-2H-pyran-2-yl)propan-2-one

[0119]

[0120] To a stirred solution of 1-C-(β-D-xylopyranosyl)-propanone (19.02 g, 100 mmol) in dichloromethane (100 ml) was added pyridine (27.69 g, 350 mmol) and the mixture was stirred at 0 °C. To this was added tert-butyldiphenylsilyl chloride (90.71 g, 330 mmol) dropwise and the reaction mixture was stirred at 0 °C for 1 h and then at room temperature for 3 h. The reaction was monitored by TLC. After completion of the reaction, the reaction mixture was washed with water (3 x 200 ml) and saturated aqueous NaCl solution (1 x 50 ml). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to obtain the crude product as a yellow oil.

[0121] Step 2: Preparation of ((2S,3S,4S,5R)-2-((S)-2-(di-tert-butoxy(methyl)silyl)oxy)propyl)tetrahydro- pyran-3,4,5-triol tris(tert-butyldiphenylsilane)

[0122]

[0123] The oil was dissolved in dioxane (200 ml) and stirred at 10 °C. To this was added copper chloride (672 mg, 5.0 mmol) and methylhydrogensiloxane polymer (PMHS) (24.48 g, 110 mmol) dropwise. The reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered to remove the insoluble material and the filtrate was concentrated under reduced pressure. The residue was dissolved in EA (200 ml) and washed with 10% aqueous NaHCO3solution (100 ml), water (100 ml) and saturated aqueous NaCl solution (1 x 50 ml). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to obtain the crude product as a yellow oil which was used as such in the next step.

[0124] Step 3: Preparation of (2S,3R,4S,5R)-2-((S)-2-hydroxypropyl)tetrahydro-2H-pyran-3,4,5-triol ((β,S) configuration hydroxypropyl tetrahydropyran triol).

[0125]

[0126] The intermediate of step 2 above, the crude product, was added into hydrogen chloride ethanol solution (containing HCl 4 mol / L, 130 ml), stirred at 10 °C for 4 h, the reaction was monitored by TLC, and the intermediate II was completely reacted, the reaction was stopped, the solvent was concentrated to dryness, purified water (100 ml) was added and stirred, extracted with EA (3 x 80 ml), the water phase was decolorized with activated carbon and exchanged with cation and anion resins, concentrated, and recrystallized with ethanol, water and ethyl acetate to obtain a white solid 9.76 g, the yield of the three-step reaction was 50.78% based on 1-C-(β-D-xylopyranosyl)-propanone, the purity of (β, S) configuration hydroxypropyl tetrahydropyrane triol was 99.63% by liquid chromatography with an evaporative light detector, and the conductivity of 30% aqueous solution was 26 μS / cm.

[0127] Example 7: Preparation of (2S, 3R, 4S, 5R)-2-((S)-2-hydroxypropyl)tetrahydro-2H-pyran-3, 4, 5-triol ((β, S) configuration hydroxypropyl tetrahydropyrane triol)

[0128] In the reaction monitoring of the following example step 1, the developing agent was methanol / dichloromethane = 1:4, and 20% sulfuric acid ethanol solution was used for color development; in the reaction monitoring of step 2, the developing agent was ethyl acetate / petroleum ether = 1:3, and 20% sulfuric acid ethanol solution was used for color development; in the reaction monitoring of step 3, the developing agent was first ethyl acetate / petroleum ether = 1:3, 20% sulfuric acid ethanol solution was used for color development to confirm the conversion of the raw material, and then methanol / dichloromethane = 1:4, 20% sulfuric acid ethanol solution was used for color development to confirm the generation of the product.

[0129] Step 1: Preparation of 1-((2S, 3S, 4S, 5R)-3, 4, 5-tri((tert-butyldimethylsilyl)oxy)tetrahydro-2H-pyran-2-yl)propan-2-one

[0130]

[0131] 1-C-(β-D-xylopyranosyl)-propanone (19.02 g, 100 mmol), tert-butyldimethylsilyl chloride (49.74 g, 330 mmol) and imidazole (23.83 g, 350 mmol) were weighed into a 500 ml round-bottom flask, and tetrahydrofuran (100 ml) was added, and the reaction was stirred at 20 °C. After the conversion of 1-C-(β-D-xylopyranosyl)-propanone was completed in the reaction monitoring, n-hexane (300 ml) was added and stirred for 1 h, and the reaction liquid was washed with water (2 x 200 ml) and saturated sodium chloride aqueous solution (1 x 50 ml) in sequence, and the organic phase was dried with anhydrous sodium sulfate, filtered, and distilled under reduced pressure to obtain a yellow oily crude product, which was directly used in the next step for reduction.

[0132] Step 2: Preparation of ((2S, 3S, 4S, 5R)-2-((S)-2-(trimethylsilyloxy)propyl)tetrahydro- 2H-pyran-3, 4, 5-triol) tris (tert-butyldimethylsilane)

[0133]

[0134] The crude product of the previous reaction (calculated on the basis of the amount of material charged for complete conversion to product in the previous step) was dissolved in dry tetrahydrofuran (250 ml) and stirred at 10°C. Iron trichloride (1.62 mg, 10 mmol) was added and trimethylsilane (8.35 g, 115 mmol) was added dropwise. The reaction was maintained at room temperature and the complete conversion of the intermediate I was monitored by TLC. The reaction was stopped, the insoluble material was removed by filtration and the remaining filtrate was concentrated to dryness under reduced pressure. The residue was dispersed in EA (200 ml) and washed with 10% aqueous sodium bicarbonate solution (100 ml), water (100 ml) and saturated aqueous sodium chloride solution (1 x 50 ml). The organic phase was dried over anhydrous sodium sulfate, filtered and distilled under reduced pressure to obtain the crude product as a yellow oil, which was used directly in the next step.

[0135] Step 3: Preparation of (2S, 3R, 4S, 5R)-2-((S)-2-hydroxypropyl)tetrahydro-2H-pyran-3, 4, 5-triol ((β, S) configuration hydroxypropyl tetrahydro pyran triol).

[0136]

[0137] The crude product of step 2 was added with tetrabutylammonium fluoride (TBAF; 1 M solution in tetrahydrofuran 440 ml) and stirred at 25°C for 3 hours. The complete conversion of the intermediate II was confirmed by TLC and the reaction was stopped. The solvent was concentrated to dryness and water (100 ml) was added and stirred. The aqueous phase was extracted with EA (3 x 80 ml) and the aqueous phase was decolored with activated carbon and exchanged with cation and anion resins. The product was obtained as a white solid (12.59 g) by recrystallization from ethanol, water and ethyl acetate. The yield of the three steps was 65.50% based on 1-C-(β-D-xylopyranosyl)-propanone and the purity of the hydroxypropyl tetrahydro pyran triol was 99.59% based on the β, S) configuration by liquid chromatography with an evaporative light detector.

[0138] Example 8: Preparation of (2S, 3R, 4S, 5R)-2-((S)-2-hydroxypropyl)tetrahydro-2H-pyran-3, 4, 5-triol ((β, S) configuration hydroxypropyl tetrahydro pyran triol).

[0139] The developing agent used in the TLC monitoring reaction in Step 1 of the following example was methanol / dichloromethane = 1:4, and the developing agent used in the TLC monitoring reaction in Step 2 was ethyl acetate / petroleum ether = 1:3, and the developing agent used in the TLC monitoring reaction in Step 3 was first ethyl acetate / petroleum ether = 1:3, 20% sulfuric acid ethanol solution was used for color development to confirm the conversion of the starting material, and then methanol / dichloromethane = 1:4, 20% sulfuric acid ethanol solution was used for color development to confirm the formation of the product.

[0140] Step 1: Preparation of 1-((2S,3S,4S,5R)-3,4,5-tri((tert-butyldimethylsilyl)oxy)tetrahydro-2H-pyran-2-yl)propan-2-one

[0141]

[0142] 1-C-(β-D-xylopyranosyl)-propanone (19.02 g, 100 mmol), tert-butyldimethylsilyl chloride (49.74 g, 330 mmol), and imidazole (24.51 g, 360 mmol) were weighed into a 500 ml round-bottom flask, and N,N-dimethylformamide (100 ml) was added. The reaction was stirred at 35°C for 5 hours. After the starting material 1-C-(β-D-xylopyranosyl)-propanone disappeared as monitored by TLC, n-hexane (300 ml) was added and stirred for 1 hour. The reaction solution was washed with water (2 x 200 ml) and saturated aqueous sodium chloride solution (1 x 50 ml) in sequence. The organic phase was dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure to obtain a yellow oil as a crude product, which was directly subjected to the next step of reduction.

[0143] Step 2: Preparation of ((2S,3S,4S,5R)-2-((S)-2-((triphenylsilyl)oxy)propyl)tetrahydro-2H-pyran-3,4,5-tri(oxy))tris(tert-butyldimethylsilane)

[0144]

[0145] The crude product of the previous step (calculated on the basis of complete conversion of the product of the previous step) was dissolved in dry ethanol (250 ml) and stirred at 10°C. Iron trichloride (1.62 g, 10 mmol) was added, and triphenylsilane (31.25 g, 120 mmol) was added dropwise. The reaction was maintained at room temperature until the complete conversion of the intermediate I, as determined by TLC. The reaction was then stopped, the insoluble material was removed by filtration, and the remaining filtrate was concentrated under reduced pressure until dryness. Ethyl acetate (300 ml) was then added, and the mixture was washed with 10% aqueous sodium bicarbonate solution (100 ml), water (100 ml), and saturated aqueous sodium chloride solution (1 x 50 ml). The organic phase was then dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure to obtain the crude product as a yellow oil, which was used directly in the next step.

[0146] Step 3: Preparation of (2S,3R,4S,5R)-2-((S)-2-hydroxypropyl)tetrahydro-2H-pyran-3,4,5-triol ((β,S) configuration hydroxypropyl tetrahydro pyran triol).

[0147]

[0148] The crude product of step 2 was dissolved in a solution of hydrogen chloride in ethanol (4 mol / L, 110 ml) and stirred at 25°C for 3 hours. The reaction was monitored by TLC until the complete conversion of the intermediate II. The reaction was then stopped, the solvent was concentrated until dryness, and purified water (100 ml) was added. The mixture was stirred and extracted with EA (3 x 100 ml). The aqueous phase was then decolorized with activated carbon and exchanged with cation and anion resins. After concentration, recrystallization from ethanol, water, and ethyl acetate gave a white solid (7.65 g). The yield of the three steps was 39.80% based on 1-C-(β-D-xylopyranosyl)-propanone. The purity of the (β,S) configuration hydroxypropyl tetrahydro pyran triol was 99.68% as determined by liquid chromatography with an evaporative light detector.

[0149] Example 9: Preparation of (2S,3R,4S,5R)-2-((S)-2-hydroxypropyl)tetrahydro-2H-pyran-3,4,5-triol ((β,S) configuration hydroxypropyl tetrahydro pyran triol).

[0150] In the reactions monitored by TLC in the following example step 1, the developing solvent was methanol / dichloromethane = 1:4, and 20% sulfuric acid in ethanol was used for color development. In the reactions monitored by TLC in step 2, the developing solvent was ethyl acetate / petroleum ether = 1:3, and 20% sulfuric acid in ethanol was used for color development. In the reactions monitored by TLC in step 3, the developing solvent was first ethyl acetate / petroleum ether = 1:3, and 20% sulfuric acid in ethanol was used for color development to confirm the conversion of the starting material. Then, methanol / dichloromethane = 1:4, and 20% sulfuric acid in ethanol was used for color development to confirm the formation of the product.

[0151] Step 1: Preparation of 1-((2S,3S,4S,5R)-3,4,5-tris((tert-butyldimethylsilyl)oxy)tetrahydro- 2H-pyran-2-yl)propan-2-one

[0152]

[0153] Weigh 1-C-(β-D-xylopyranosyl)-propanone (19.02 g, 100 mmol), tert-butyldimethylsilyl chloride (52 g, 345 mmol), imidazole (24.51 g, 360 mmol) into a 500 ml round bottom flask, add N,N-dimethylformamide (100 ml), stir the reaction at 25 °C for 10 hours. After TLC monitoring of the disappearance of the raw material 1-C-(β-D-xylopyranosyl)-propanone, add n-hexane (300 ml) and stir for 1 h. Wash the reaction liquid with water (2 x 200 ml), saturated aqueous sodium chloride solution (1 x 50 ml) in sequence. Dry the organic phase with anhydrous sodium sulfate, filter, and distill under reduced pressure to obtain a yellow oil crude product, which is directly used for the next step of reduction.

[0154] Step 2: Preparation of ((2S,3S,4S,5R)-2-((S)-2-((triethylsilyl)oxy)propyl)tetrahydro-2H-pyran- 3,4,5-trioxy))tris(tert-butyldimethylsilyl)

[0155]

[0156] Dissolve the crude product of the previous step (calculated on the basis of the amount of material charged for complete conversion to product) in dry tetrahydrofuran (250 ml), stir at 10 °C, add ferric chloride (1.3 g, 8 mmol), and drop triethylsilyl (13.95 g, 120 mmol). Keep the reaction at room temperature, and monitor the reaction intermediate I by TLC until it is basically converted. Stop the reaction, remove the insoluble material by filtration, and concentrate the remaining filtrate to dryness under reduced pressure. Disperse in EA (300 ml), and wash with 10% aqueous sodium bicarbonate solution (100 ml), aqueous solution (100 ml), and saturated aqueous sodium chloride solution (1 x 50 ml) in sequence. Dry the organic phase with anhydrous sodium sulfate, filter, and distill under reduced pressure to obtain a yellow oil crude product, which is directly used for the next step of reaction.

[0157] Step 3: Preparation of (2S,3R,4S,5R)-2-((S)-2-hydroxypropyl)tetrahydro-2H-pyran-3,4,5-triol ((β, S) configuration hydroxypropyl tetrahydropyran triol).

[0158]

[0159] The crude product of Step 2 was added to a solution of hydrogen chloride in methanol (containing HCl 4 mol / L, 130 ml) and stirred at 20°C for 3 hours. The reaction was monitored by TLC until the intermediate II was completely consumed. The reaction was stopped and the solvent was concentrated to dryness. Purified water (100 ml) was added and stirred. The aqueous phase was extracted with EA (3 x 80 ml), decolorized with activated carbon and exchanged with cation and anion resins. After concentration, recrystallization was performed with ethanol, water and ethyl acetate to obtain a white solid (12.67 g) with a yield of 65.92% based on 1-C-(β-D-xylopyranosyl)-propanone. The purity of the (β, S) configuration hydroxypropyl tetrahydropyrane triol was 99.73% as determined by liquid chromatography with an evaporative light detector.

[0160] Example 10: Preparation of (2S, 3R, 4S, 5R)-2-((S)-2-hydroxypropyl)tetrahydro-2H-pyran-3, 4, 5-triol ((β, S) configuration hydroxypropyl tetrahydropyrane triol)

[0161] In the TLC monitoring reaction used in the following Example Step 1, the developing agent was methanol / dichloromethane = 1:4 and 20% sulfuric acid ethanol solution was used for color development. In the TLC monitoring reaction used in Step 2, the developing agent was ethyl acetate / petroleum ether = 1:3 and 20% sulfuric acid ethanol solution was used for color development. In the TLC monitoring reaction used in Step 3, the developing agent was first ethyl acetate / petroleum ether = 1:3 and 20% sulfuric acid ethanol solution was used for color development to confirm the conversion of the starting material, and then methanol / dichloromethane = 1:4 and 20% sulfuric acid ethanol solution was used for color development to confirm the generation of the product.

[0162] Step 1: Preparation of 1-((2S, 3S, 4S, 5R)-3, 4, 5-tri((tert-butyldimethylsilyl)oxy)tetrahydro-2H-pyran-2-yl)propan-2-one

[0163]

[0164] 1-C-(β-D-xylopyranosyl)-propanone (19.02 g, 100 mmol), tert-butyldimethylsilyl chloride (47.48 g, 315 mmol) and imidazole (23.83 g, 350 mmol) were weighed into a 500 ml round-bottom flask, and N,N-dimethylformamide (100 ml) was added. The reaction was stirred at 30°C for 6 hours. After the disappearance of the starting material 1-C-(β-D-xylopyranosyl)-propanone was confirmed by TLC, n-hexane (300 ml) was added and stirred for 1 hour. The reaction solution was washed with water (2 x 200 ml) and saturated aqueous sodium chloride solution (1 x 50 ml) in sequence. The organic phase was dried over anhydrous sodium sulfate, filtered and distilled under reduced pressure to obtain a yellow oily crude product, which was directly used in the next step for reduction.

[0165] Step 2: Preparation of ((2S, 3S, 4S, 5R)-2-((S)-2-((triethylsilyl)oxy)propyl)tetrahydro- 2H-pyran-3, 4, 5-triol) tris (tert-butyldimethylsilyl)

[0166]

[0167] The crude product of the previous reaction (calculated on the basis of the amount of material charged for complete conversion to product in the previous step) was dissolved in dry tetrahydrofuran (250 ml) and stirred at 10°C. Copper chloride (1.34 g, 10 mmol) was added and triethylsilane (13.95 g, 120 mmol) was added dropwise. The reaction was allowed to proceed at room temperature and the progress of the reaction was monitored by TLC. The reaction was stopped and the insoluble material was removed by filtration. The remaining filtrate was concentrated to dryness under reduced pressure and dispersed in EA (300 ml). The organic phase was washed successively with 10% aqueous sodium bicarbonate solution (100 ml), water (100 ml) and saturated aqueous sodium chloride solution (1 x 50 ml). The organic phase was dried over anhydrous sodium sulphate, filtered and distilled under reduced pressure to obtain the crude product as a yellow oil which was used directly in the next step.

[0168] Step 3: Preparation of (2S, 3R, 4S, 5R)-2-((S)-2-hydroxypropyl)tetrahydro-2H-pyran-3, 4, 5-triol ((β, S) configuration hydroxypropyl tetrahydro pyran triol).

[0169]

[0170] The crude product of step 2 was dissolved in methanol (100 ml) and stirred to dissolve. Hexafluorosilicic acid in methanol solution (40% aqueous solution, 36 g) was added and the reaction was stirred at 5°C for 3 hours. The progress of the reaction was monitored by TLC. The reaction was stopped and the solvent was concentrated to dryness. Purified water (100 ml) was added and stirred. The aqueous phase was extracted with EA (3 x 80 ml). The aqueous phase was decolourised using activated carbon and exchanged using cation and anion resins. The product was obtained as a white solid by recrystallisation from ethanol, water and ethyl acetate. The yield of the three steps was 44.12% based on 1-C-(β-D-xylopyranosyl)-propanone. The purity of the product ((β, S) configuration hydroxypropyl tetrahydro pyran triol) was 99.66% as determined by liquid chromatography using an evaporative light detector.

[0171] Example 11: Preparation of (2S, 3R, 4S, 5R)-2-((S)-2-hydroxypropyl)tetrahydro-2H-pyran- 3, 4, 5-triol ((β, S) configuration hydroxypropyl tetrahydro pyran triol).

[0172] The developing agent used in the reaction monitored by TLC in the following Example Step 1 is methanol / dichloromethane = 1:4, and the color reagent is 20% sulfuric acid ethanol solution; the developing agent used in the reaction monitored by TLC in Step 2 is ethyl acetate / petroleum ether = 1:3, and the color reagent is 20% sulfuric acid ethanol solution; the developing agent used in the reaction monitored by TLC in Step 3 is ethyl acetate / petroleum ether = 1:3, and the color reagent is 20% sulfuric acid ethanol solution, which is used to confirm the conversion of the raw material; then methanol / dichloromethane = 1:4, and the color reagent is 20% sulfuric acid ethanol solution, which is used to confirm the generation of the product.

[0173] Step 1: Preparation of 1-((2S,3S,4S,5R)-3,4,5-tri((tert-butyldimethylsilyl)oxy)tetrahydro-2H-pyran-2-yl)propan-2-one

[0174]

[0175] 1-C-(β-D-xylopyranosyl)-propanone (19.02 g, 100 mmol), tert-butyldimethylsilyl chloride (49.74 g, 330 mmol), and imidazole (27.23 g, 400 mmol) were weighed into a 500 ml round-bottom flask, and N,N-dimethylformamide (110 ml) was added. The reaction was stirred at 5°C for 10 hours. After the raw material 1-C-(β-D-xylopyranosyl)-propanone disappeared as monitored by TLC, n-hexane (300 ml) was added and stirred for 1 hour. The reaction solution was washed with water (2×200 ml) and saturated aqueous sodium chloride solution (50 ml) in sequence. The organic phase was dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure to obtain a yellow oil crude product, which was directly used in the next step for reduction.

[0176] Step 2: Preparation of ((2S,3S,4S,5R)-2-((S)-2-((triethylsilyl)oxy)propyl)tetrahydro-2H-pyran-3,4,5-trioxy))tris(tert-butyldimethylsilane)

[0177]

[0178] The crude product of the previous step (calculated on the basis of complete conversion of the product of the previous step) was dissolved in dry isopropanol (250 ml) and stirred at 10°C. Iron chloride (811 mg, 5 mmol) was added and triethylsilane (13.95 g, 120 mmol) was added dropwise. The reaction was maintained at room temperature and the conversion of the intermediate I was monitored by TLC. The reaction was stopped, the insoluble material was filtered off and the remaining filtrate was concentrated under reduced pressure to dryness. EA (300 ml) was added and the mixture was washed with 10% aqueous sodium bicarbonate solution (100 ml), water (100 ml) and saturated aqueous sodium chloride solution (1 x 50 ml). The organic phase was dried over anhydrous sodium sulfate, filtered and distilled under reduced pressure to give the crude product as a yellow oil which was used directly in the next step.

[0179] Step 3: Preparation of (2S,3R,4S,5R)-2-((S)-2-hydroxypropyl)tetrahydro-2H-pyran-3,4,5-triol ((β,S) configuration hydroxypropyl tetrahydro pyran triol).

[0180]

[0181] The crude product of step 2 was dissolved in methanol (150 ml) and stirred. N-iodosuccinimide (90 g, 0.4 mol) was added and the reaction was stirred at 30°C under nitrogen for 3 hours. The solvent was concentrated to dryness and purified water (100 ml) was added. The mixture was stirred and extracted with EA (3 x 80 ml). The aqueous phase was decolored with activated carbon and exchanged with cation and anion resins. The product was recrystallized from ethanol, water and ethyl acetate to give a white solid (3.12 g). The yield of the three steps was 16.23% based on 1-C-(β-D-xylopyranosyl)-propanone. The purity of the (β,S) configuration hydroxypropyl tetrahydro pyran triol was 99.81% as determined by liquid chromatography with an evaporative light detector.

[0182] Example 12: Preparation of (2S,3R,4S,5R)-2-((S)-2-hydroxypropyl)tetrahydro-2H-pyran-3,4,5-triol ((β,S) configuration hydroxypropyl tetrahydro pyran triol) on a large scale

[0183] The following TLC monitoring reagents were used in the examples: in step 1, the developing solvent was methanol / dichloromethane = 1:4 and the reagent was 20% sulfuric acid in ethanol; in step 2, the developing solvent was ethyl acetate / petroleum ether = 1:3 and the reagent was 20% sulfuric acid in ethanol; in step 3, the developing solvent was first ethyl acetate / petroleum ether = 1:3 and the reagent was 20% sulfuric acid in ethanol to confirm the conversion of the starting material, and then methanol / dichloromethane = 1:4 and the reagent was 20% sulfuric acid in ethanol to confirm the formation of the product.

[0184] Step 1:

[0185] Weigh 1-C-(β-D-xylopyranosyl)-propanone (1.902 kg, 10 mol), tert-butyldimethylsilyl chloride (4.97 kg, 33 mol), imidazole (2.72 kg, 40 mol) into a 100 L reactor, add N,N-dimethylformamide (9.5 kg), start the low temperature cycle, control the reaction temperature at about 25°C. After TLC monitoring of the reaction of 1-C-(β-D-xylopyranosyl)-propanone is complete, add n-hexane (15 kg) to the reaction solution and stir for 1 h, then dry the organic phase with anhydrous sodium sulfate, filter, and distill under reduced pressure to obtain a yellow oily crude product.

[0186] Step 2:

[0187] Dissolve the crude oily product of the previous step (calculated on the basis of complete conversion to the product in the previous step) in dry isopropanol (20 L) and stir at 15°C. Add ferric chloride (81.1 g, 0.5 mol) and dropwise add triethylsilane (1.279 kg, 11 mol). Maintain the room temperature and monitor the reaction by TLC until the intermediate I is completely converted. Filter to remove the insoluble material, concentrate the remaining filtrate under reduced pressure to dryness, disperse with EA (12.5 kg), wash with water (3 x 10 kg), and distill the organic phase under reduced pressure to obtain a yellow oily crude product.

[0188] Step 3:

[0189] Add hydrogen chloride in methanol solution (containing HCl 4 mol / L, 11 L) to the above crude product and stir at 25°C for 3 hours. Confirm the complete reaction of the intermediate II by TLC, stop the reaction, concentrate the solvent to dryness, add purified water (8 kg) and stir, extract with EA (3 x 4.5 kg), decolorize the aqueous phase with activated carbon, exchange with cation and anion resins, concentrate, and recrystallize from ethanol, water, and ethyl acetate to obtain a white solid 1.387 kg. The yield of the three-step reaction is 72.16% based on 1-C-(β-D-xylopyranosyl)-propanone. The purity of the (β, S) configuration hydroxypropyl tetrahydropyrane triol is 100% as determined by liquid chromatography with an evaporative light detector (see Figure 1 Figure 3 ), and the nuclear magnetic resonance data are as follows: 1 H NMR (500 MHz, D2O) δ 4.06-4.01 (m, 1H), 3.93 (dd, 1H), 3.60-3.56 (m, 1H), 3.40-3.39 (t, 1H), 3.33 (td, 1H), 3.25 (t, 1H), 3.18 (t, 1H), 1.92 (ddd, 1H), 1.68-1.63 (m, 1H), 1.20 (d, 3H). 13C NMR (500 MHz, D20) δ 78.39, 77.30, 73.62, 69.46, 68.78, 65.65, 39.93, 21.43. 1 H NMR see attached Figure 4 ), carbon magnetic resonance spectrum ( 13 C NMR see attached Figure 5 ), the conductivity of 30% aqueous solution is 6 μS / cm.

[0190] Summarize the preparation of (2S,3R,4S,5R)-2-((S)-2-hydroxypropyl)tetrahydro-2H-pyran-3,4,5-triol ((β,S) configuration hydroxypropyl tetrahydropyran triol) in the above-mentioned examples, wherein in step 1, in order to obtain different degrees of protection or even complete protection of the three hydroxyl groups in 1-C-(β-D-xylopyranosyl)-propanone, the amount of chlorosilane required is more than 1 equivalent, complete protection requires more than 3 equivalents, and the amount of base is more than the amount of chlorosilane to neutralize the hydrogen chloride produced in the reaction. At the same time, in step 2, the reduction of the ketone carbonyl group by silane ensures complete reduction, and in step 3, the silicon group is removed, the impurities in the organic phase are removed by distributing the product in the aqueous phase, the product is decolorized by activated carbon, and the remaining anions and cations are removed by ion exchange resin, to obtain a product with a purity of > 99.5%, and the structure is confirmed by nuclear magnetic resonance to be correct.

[0191] The above merely provides a specific implementation of the present application, but the protection scope of the present application is not limited thereto, any person skilled in the art can easily think of changes or replacements within the technical range disclosed by the present application, which should be covered within the protection scope of the present application. Therefore, the protection scope of the present application should be subject to the protection scope of the claims.

Claims

1. A method for synthesizing high-quality (β,S)-configured hydroxypropyltetrahydropyranotriol, characterized in that, Includes the following steps: (1) Starting with 1-C-(β-D-xylanosyl)-acetone and using a base as a catalyst, an intermediate I was prepared by reacting with chlorosilane to form a silyl ether, with the following structural formula: R1, R2, and R3 are any one of trimethylsilyl, tert-butyldimethylsilyl, triisopropylsilyl, or tert-butyldiphenylsilyl, respectively. (2) Intermediate I was prepared into intermediate II by silane reduction reaction, with the following structural formula: R1, R2, and R3 are any one of trimethylsilyl, tert-butyldimethylsilyl, triisopropylsilyl, or tert-butyldiphenylsilyl, respectively; R4 is any one of triphenylsilyl, triethylsilyl, triethoxysilyl, or trimethylsilyl; and the catalyst is one or more of ferric chloride, ferric bromide, copper chloride, or ferric acetylacetone. (3) Intermediate II was reacted with a desilication protecting agent, then decolorized with activated carbon and exchanged with an ion exchange resin to obtain a high-quality solid of hydroxypropyltetrahydropyranotriol with a single (β,S) configuration, the structural formula of which is:

2. The method for synthesizing a high-quality (β,S) configuration hydroxypropyltetrahydropyranotriol according to claim 1, characterized in that, In step (1), R1, R2, and R3 are tert-butyldimethylsilyl groups.

3. The method for synthesizing a high-quality (β,S) configuration hydroxypropyltetrahydropyranotriol according to claim 1, characterized in that, The specific preparation steps of step (1) are as follows: Starting with 1-C-(β-D-xylanopyranosyl)-acetone, a solvent, alkali, and chlorosilane were added, and the reaction was carried out under controlled temperature. The reaction was monitored by TLC. After the 1-C-(β-D-xylanopyranosyl)-acetone had reacted completely, petroleum ether or an alkane was added, and the mixture was washed successively with water and saturated brine. After separation of the organic phase, the mixture was dried with anhydrous sodium sulfate and concentrated to obtain intermediate I, wherein the alkane was one or more of cyclohexane, n-hexane, and n-heptane.

4. The method for synthesizing high-quality (β,S)-configuration hydroxypropyltetrahydropyranotriol according to claim 3, characterized in that, In step (1), the molar ratio of 1-C-(β-D-xylanosyl)-acetone:base:chlorosilane is 1:1~5:1~4.

5. The method for synthesizing a high-quality (β,S) configuration hydroxypropyltetrahydropyranotriol according to claim 4, characterized in that, The molar ratio of 1-C-(β-D-xylanosyl)-acetone:base:chlorosilane is 1:4:3.

3.

6. The method for synthesizing high-quality (β,S)-configuration hydroxypropyltetrahydropyranotriol according to claim 3, characterized in that, Step (1) includes at least one of the following features (a) to (e): (a) The base used is one or more of the following: imidazole, pyridine, triethylamine, sodium carbonate, or sodium bicarbonate; (b) The chlorosilane used is one or more of the following: trimethylchlorosilane, tert-butyldimethylchlorosilane, triisopropylchlorosilane or tert-butyldiphenylchlorosilane; (c) The solvent is selected from one or more of dichloromethane, dichloroethane, N,N-dimethylformamide, and tetrahydrofuran; (d) The alkane is n-hexane; (e) The reaction temperature is 0℃-50℃.

7. The method for synthesizing a high-quality (β,S) configuration hydroxypropyltetrahydropyranotriol according to claim 6, characterized in that, (a) The base used is imidazole; (b) The chlorosilane used is tert-butyldimethylchlorosilane; (c) The solvent is N,N-dimethylformamide; (e) Reaction temperature 10℃-30℃.

8. The method for synthesizing high-quality (β,S)-configuration hydroxypropyltetrahydropyranotriol according to claim 1, characterized in that, The specific preparation steps of step (2) are as follows: Using intermediate I as a raw material, a solvent, silane, and a catalyst were added to carry out a reduction reaction. The reaction was monitored by TLC. After the organic phase of the reaction solution was concentrated, it was extracted with ethyl acetate, washed thoroughly with water, and concentrated to obtain intermediate II.

9. The method for synthesizing a high-quality (β,S) configuration hydroxypropyltetrahydropyranotriol according to claim 8, characterized in that, Step (2) includes at least one of the following features (f) to (j): (f) The solvent used in the reaction is one or more of methanol, ethanol, isopropanol, tetrahydrofuran or dioxane; (g) Based on the molar amount of 1-C-(β-D-xylanosyl)-acetone, the molar ratio of intermediate I:silane:catalyst is 1:1.0-1.5:0.01-0.1; (h) The silane is one of trimethylsilane, triphenylsilane, triethylsilane, and triethoxysilane; (i) The catalyst is ferric chloride; (j) The conditions for the reduction reaction are to add the material at 0-15℃, and after the temperature of the material is stable, to react at 15-30℃.

10. The method for synthesizing a high-quality (β,S) configuration hydroxypropyltetrahydropyranotriol according to claim 9, characterized in that, (f) The solvent used in the reaction is one of isopropanol, tetrahydrofuran, or a mixture of both; (g) Based on the molar amount of 1-C-(β-D-xylanosyl)-acetone, the molar ratio of intermediate I:silane:catalyst is 1:1.1:0.05; (h) The silane is trimethylsilane or triethylsilane; (j) The conditions for the reduction reaction are to add the material at 10-15℃, and after the temperature of the material addition stabilizes, to react at room temperature.

11. The method for synthesizing high-quality (β,S)-configuration hydroxypropyltetrahydropyranotriol according to claim 1, characterized in that, The specific preparation steps of step (3) are as follows: Intermediate II was reacted with a desilication protecting agent, purified water was added, the aqueous phase was extracted with ethyl acetate to remove organic impurities, the aqueous phase was decolorized with activated carbon, exchanged with ion exchange resin, concentrated and crystallized to obtain high-quality solid hydroxypropyltetrahydropyranotriol with a single (β,S) configuration.

12. The method for synthesizing a high-quality (β,S) configuration hydroxypropyltetrahydropyranotriol according to claim 11, characterized in that, Step (3) includes at least one of the following features (k) to (n): (k) The desilication protecting agent is one or more of the following: hydrochloric acid solution, tetrabutylammonium fluoride, hexafluorosilicic acid, hydrofluoric acid, or N-iodosuccinimide; (l) After concentration, recrystallize by ethanol, water and ethyl acetate; (m) The molar ratio of intermediate II to the desilication protecting agent is 1:4-12, based on the molar amount of 1-C-(β-D-xylanosyl)-acetone. (n) Intermediate II is reacted with a desilication protecting agent at 0-30℃ for 1-6 hours.

13. The method for synthesizing a high-quality (β,S) configuration hydroxypropyltetrahydropyranotriol according to claim 12, characterized in that, (k) The desilication protecting agent is a hydrochloric acid solution or tetrabutylammonium fluoride; (m) The molar ratio of intermediate II to the desilication protecting agent is 1:4-8, based on the molar amount of 1-C-(β-D-xylanosyl)-acetone. (n) Intermediate II was reacted with a desilication protecting agent at 25°C for 3 hours.

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