CN117700388A - Synthesis method of high-quality (beta, S) -configuration hydroxypropyl tetrahydropyran triol - Google Patents

Abstract

The invention relates to a method for synthesizing high-quality (beta, S) -configuration hydroxypropyl tetrahydropyran triol, which comprises the following steps: 1-C- (beta-D-xylopyranosyl) -acetone is used as a starting material, alkali is used as a catalyst, the starting material reacts with chlorosilane to form silyl ether, an intermediate I is prepared, the intermediate I is subjected to a silane reduction reaction to prepare an intermediate II, the intermediate II is subjected to a desilication protecting reagent reaction, and the intermediate II is subjected to activated carbon decolorization and ion resin exchange to obtain a hydroxypropyl tetrahydropyran triol solid with a single (beta, S) configuration and a high quality configuration, wherein the structural formula is shown below. The process method is simple and easy to operate, the water soluble salts are removed by washing the intermediate with better ester solubility, the yield of wastewater is reduced, the purity of the product is high, the property is good, and the process method is suitable for large-scale production.

Description

Synthesis method of high-quality (beta, S) -configuration hydroxypropyl tetrahydropyran triol

Technical Field

The invention relates to the technical field of organic synthesis, in particular to a method for synthesizing (beta, S) -configuration hydroxypropyl tetrahydropyran triol.

Background

The vitronectin (Pro-xylane) is a raw material group consisting of water, propylene glycol and hydroxypropyl tetrahydropyran triol, and INCI name is Hydroxypropyl Tetrahyclropyantiol, wherein the functional active ingredient is hydroxypropyl tetrahydropyran triol, and the substance is discovered by a lanokamara laboratory under the European Leya flag from beech tree, is a C-glycoside with biological activity in an aqueous medium, can stimulate the production of glycosaminoglycan (GAGs), promotes the production of hyaluronic acid and collagen, increases the content of mucopolysaccharide in a cell interstitial substance, improves the adhesiveness between dermis and epidermis, helps maintain the elasticity of skin and improves skin aging. Meanwhile, the natural plant is easy to biodegrade, can not accumulate in organisms, and is known as a green active raw material in the cosmetic industry.

The structural formula of the hydroxypropyl tetrahydropyran triol is shown in the specification, wherein International patent WO2002051828 of European Leya company, chinese patent CN100441588C and Bioorganic in 2009&Medicinal Chemistry Letters journal articles "Synthesis of Pro-Xylane ^TM The preparation route and the use in cosmetics of hydroxypropyl tetrahydropyran triol are described in A new biologically active C-glycoside in aqueous media ", where experimental data clearly demonstrate that the activity of the (beta, S) configuration is better than that of the (beta, R) and (beta, S) mixture.

The structural formula of the (beta, S) -configured hydroxypropyl tetrahydropyran triol shown above, which is chemically named C-beta-D-xylopyranoside-2- (S) -hydroxypropane (CAS No.: 868156-46-1), is a pale yellow to off-white solid, unlike the (beta, R) and (beta, S) mixtures which are viscous. However, since the (β, S) -configuration hydroxypropyl tetrahydropyran triol has a good solid moldability, and cannot simplify the purification difficulty, but a large amount of acetate, boric acid, borate and the like remain in the preparation process, and the hydroxypropyl tetrahydropyran triol has extremely high water solubility and cannot be purified by removing inorganic salts by conventional extraction and other means, desalting by column chromatography purification, ion resin desalting and other means are reported in the original patent and other patent documents to obtain a product, but the process is complicated, the batch amount is small, the wastewater amount is huge, and the production cost is high.

Boric acid and borates were listed in the catalogue of cosmetic banned raw materials by the national institute of food and drug testing in 2021, and therefore efficient removal of boric acid and borates was a key factor to obtain high quality, boron-free (β, S) configuration hydroxypropyl tetrahydropyran triol. The asymmetric reduction is carried out by metal catalysis, so that the (beta, S) configuration product content in the obtained product is higher, but the cost of the metal catalyst is higher, and the removal of the metal and the complex residues is still a difficult problem.

Therefore, the development of the preparation process of the (beta, S) -configuration hydroxypropyl tetrahydropyran triol raw material with high purity, no metal catalytic element impurity residue, no boric acid or borate residue, white product color and high product purity has important significance.

Disclosure of Invention

Aiming at the problems in the prior art, the invention provides a synthetic method for preparing high-quality (beta, S) configuration hydroxypropyl tetrahydropyran triol from the aspects of reducing production cost and improving quality. The synthesis method of the (beta, S) -configuration hydroxypropyl tetrahydropyran triol has the advantages of simple process, more than 99.5 percent of (beta, S) -configuration, no residual impurity of metal catalytic elements, no residual boric acid or borate, strong process operability, low production cost and industrial application potential.

In order to achieve the above purpose, the invention is realized by adopting the following technical scheme:

a method for synthesizing high-quality (beta, S) -configuration hydroxypropyl tetrahydropyran triol, which comprises the following steps:

(1) 1-C- (beta-D-xylopyranosyl) -acetone is used as a starting material, alkali is used as a catalyst, and the starting material reacts with chlorosilane to form silyl ether, so that an intermediate I is prepared, wherein the structural formula of the intermediate I is as follows:

wherein R1, R2 and R3 are any one of hydrogen, trimethylsilyl, tert-butyldimethylsilyl, triisopropylsilyl or tert-butyldiphenylsilyl respectively; r1, R2 and R3 are preferably tert-butyldimethylsilyl groups;

(2) The intermediate I is subjected to silane reduction reaction to prepare an intermediate II, and the structural formula is as follows:

wherein R1, R2 and R3 are any one of hydrogen, trimethylsilyl, tert-butyldimethylsilyl, triisopropylsilyl or tert-butyldiphenylsilyl respectively, and R4 is any one of triphenylsilyl, triethylsilyl, triethoxysilyl and trimethylsilyl;

(3) The intermediate II reacts by a desilication group protective reagent, and is decolorized by active carbon and exchanged by ion resin to obtain the hydroxypropyl tetrahydropyran triol solid with single (beta, S) configuration and high quality configuration, wherein the structural formula is as follows:

further, the specific preparation steps of the step (1) are as follows:

Taking 1-C- (beta-D-xylopyranosyl) -acetone as a starting material, adding a solvent, alkali and chlorosilane, controlling the temperature for reaction, monitoring the reaction by TLC, adding alkane after the reaction of the 1-C- (beta-D-xylopyranosyl) -acetone is finished, washing with water and saturated saline water in sequence, separating an organic phase, drying by anhydrous sodium sulfate, and concentrating to obtain an intermediate I;

further, in the step (1), 1-C- (β -D-xylopyranosyl) -acetone: alkali: the molar ratio of chlorosilane is 1:1 to 5:1 to 4; still further, 1-C- (β -D-xylopyranosyl) -acetone: alkali: the molar ratio of chlorosilane is preferably 1:4:3.3.

further, in the step (1),

the alkali used is: one or more of imidazole, pyridine, triethylamine, sodium carbonate or sodium bicarbonate; preferably imidazole;

the chlorosilane used was: one or more of trimethylchlorosilane, t-butyldimethylchlorosilane, triisopropylchlorosilane or t-butyldiphenylchlorosilane; preferably t-butyldimethylchlorosilane;

further, in the step (1),

the solvent is selected from one or more of dichloromethane, dichloroethane, N-dimethylformamide and tetrahydrofuran; (N, N-dimethylformamide) is preferred.

Further, in the step (1), the reaction temperature is 0-50 ℃; preferably from 10℃to 30 ℃.

Further, in the step (1), the alkane added after the reaction is completed is one or more of petroleum ether, cyclohexane, n-hexane and n-heptane; n-hexane is preferred.

Further, the specific preparation steps of the step (2) are as follows:

taking the intermediate I as a raw material, adding a solvent, silane and a catalyst, performing reduction reaction, monitoring the reaction by TLC, concentrating an organic phase of a reaction liquid, extracting with ethyl acetate, fully washing with water, and concentrating to obtain an intermediate II.

Further, in the step (2), the solvent used in the reaction is one or more of methanol, ethanol, isopropanol, tetrahydrofuran or dioxane, preferably one or more of isopropanol and tetrahydrofuran.

Further, in step (2), intermediate I, based on 1-C- (. Beta. -D-xylopyranosyl) -acetone molar amount: silane: the molar ratio of the catalyst is 1:1.0-1.5:0.01-0.1; preferably 1:1.1:0.05.

further, in the step (2), the silane is one of trimethylsilane, triphenylsilane, triethylsilane, triethoxysilane, and methylhydrosiloxane Polymer (PMHS); still further, trimethylsilane, triethylsilane or methylhydrosiloxane Polymers (PMHS) are preferred.

Further, in the step (2), the catalyst is one or more of ferric chloride, ferric bromide, cupric chloride or ferric acetylacetonate; still further, ferric chloride is preferred.

Further, in the step (2), the condition of the reduction reaction is that the materials are added at the temperature of 0-15 ℃, and the materials react at the temperature of 15-30 ℃ after the addition temperature is stable; further, the preferable condition of the reduction reaction is that the material is fed at 10-15 ℃, and the material is reacted at room temperature after the feeding temperature is stable.

Further, the specific preparation steps of the step (3) are as follows:

the intermediate II reacts with desilication protective reagent, purified water is added, the water phase is extracted by ethyl acetate to remove organic impurities, and the water phase is decolorized by active carbon, exchanged by ion resin, concentrated and crystallized to obtain the hydroxypropyl tetrahydropyran triol solid with single (beta, S) configuration and high quality configuration.

Further, in the step (3), the desilication-based protecting agent is one or more of hydrogen chloride alcohol solution, tetrabutylammonium fluoride, hexafluorosilicic acid, hydrofluoric acid or N-iodosuccinimide; still further, an alcohol solution of hydrogen chloride or tetrabutylammonium fluoride is preferable.

Further, in the step (3), after concentration, recrystallization is performed by ethanol, water and ethyl acetate.

Further, in step (3), intermediate II, based on 1-C- (. Beta. -D-xylopyranosyl) -acetone molar amount: the molar ratio of the desilication group protecting reagent is 1:4-12; further, intermediate ii: the molar ratio of the desilication group protecting reagent is 1:4-8.

Further, in the step (3), the intermediate II is added with a desilylation protecting agent at 0-30 ℃ to react for 1-6 hours, and further, the reaction is preferably carried out at 25 ℃ for 3 hours.

The beneficial effects are that:

1) The reaction step of the invention does not involve noble metal, and the production cost is low;

2) According to the invention, the product is subjected to reduction post-treatment under the action of the protecting group, the product is soluble in an organic phase, and inorganic salts can be removed by extraction and water washing, so that the separation of the product and the salts is realized;

3) The process route of the invention can realize no residual of boric acid, borate and other salts without using boron-containing reducing agents such as sodium borohydride, sodium triacetoxyborohydride and the like.

4) The white solid powdery product is obtained through deprotection, decolorization and ion resin exchange, and the (beta, S) -configuration hydroxypropyl tetrahydropyran triol liquid phase purity is more than 99.5 percent. Wherein, most of salts are washed by water phase in the first and second steps, so the ion resin consumption is small and the regeneration is easier in the third step of post-treatment.

Drawings

In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the following description will briefly explain the drawings needed in the embodiments or the prior art, and it is obvious that the drawings in the following description are some embodiments of the present invention and that other drawings can be obtained according to these drawings without inventive effort to a person skilled in the art.

FIG. 1 is a HPLC chromatogram of (beta, S) -configured hydroxypropyl tetrahydropyran triol of example 1 of the present invention

FIG. 2 is a HPLC chromatogram of (beta, S) -configured hydroxypropyl tetrahydropyran triol of example 2 of the present invention

FIG. 3 is a HPLC chromatogram of (beta, S) -configured hydroxypropyl tetrahydropyran triol of example 12 of the present invention

FIG. 4 shows a hydroxypropyl tetrahydropyran triol of the (beta, S) configuration of example 12 of the present invention ¹ H NMR spectrum

FIG. 5 is a hydroxypropyl tetrahydropyran triol of the (beta, S) configuration of example 12 of the present invention ¹³ C NMR spectrum

Detailed Description

Hereinafter, the present invention will be described in detail. Before the description, it is to be understood that the terms used in this specification and the appended claims should not be construed as limited to general and dictionary meanings, but interpreted based on the meanings and concepts corresponding to technical aspects of the present invention on the basis of the principle that the inventor is allowed to define terms appropriately for the best explanation. Accordingly, the description set forth herein is merely a preferred example for the purpose of illustration and is not intended to limit the scope of the invention, so that it should be understood that other equivalents or modifications may be made thereto without departing from the spirit and scope of the invention.

The following examples are merely illustrative of embodiments of the present invention and are not intended to limit the invention in any way, and those skilled in the art will appreciate that modifications may be made without departing from the spirit and scope of the invention. Unless otherwise specified, reagents and equipment used in the following examples are commercially available products.

In this document, the terms "comprising," "including," "having," "containing," or any other similar term are all open ended terms that are intended to cover a non-exclusive inclusion. For example, a composition or article comprising a plurality of elements is not limited to only those elements listed herein, but may include other elements not explicitly listed but typically inherent to such composition or article. In addition, unless explicitly stated to the contrary, the term "or" refers to an inclusive "or" and not to an exclusive "or". For example, any one of the following conditions satisfies the condition "a or B": a is true (or present) and B is false (or absent), a is false (or absent) and B is true (or present), a and B are both true (or present). Furthermore, the terms "comprising," "including," "having," "containing," and their derivatives, as used herein, are intended to be open ended terms that have been specifically disclosed and encompass both the closed and semi-closed terms, consisting of …, and consisting essentially of ….

All features or conditions defined herein in terms of numerical ranges or percentage ranges are for brevity and convenience only. Accordingly, the description of a numerical range or percentage range should be considered to cover and specifically disclose all possible sub-ranges and individual values within the range, particularly integer values. For example, a range description of "1 to 8" should be taken as having 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 should be taken as having specifically disclosed individual values such as 1, 2, 3, 4, 5, 6, 7, 8, etc. within the range. The foregoing explanation applies to all matters of the invention throughout its entirety unless indicated otherwise, whether or not the scope is broad.

If an amount or other numerical value or parameter is expressed as a range, preferred range, or a series of upper and lower limits, then it is understood that any range, whether or not separately disclosed, from any pair of the upper or preferred value for that range and the lower or preferred value for that range is specifically disclosed herein. Furthermore, where a range of numerical values is recited herein, unless otherwise stated, the range is intended to include the endpoints thereof, and all integers and fractions within the range.

In this context, numerical values should be understood to have the accuracy of the numerical significance of the numerical values provided that the objectives of the present invention are achieved. For example, the number 40.0 is understood to cover a range from 39.50 to 40.49.

The following examples are merely illustrative of embodiments of the present invention and are not intended to limit the invention in any way, and those skilled in the art will appreciate that modifications may be made without departing from the spirit and scope of the invention. Unless otherwise specified, reagents and equipment used in the following examples are commercially available products.

Example 1: preparation of (2S, 3R,4S, 5R) -2- ((S) -2-hydroxypropyl) tetrahydro-2H-pyran-3, 4, 5-triol ((beta, S) configuration hydroxypropyl tetrahydropyran triol).

In the TLC monitoring reaction employed in step 1 of the following example, the developing reagent was methanol/dichloromethane=1: developing with 4, 20% sulfuric acid ethanol solution; in the TLC monitoring reaction employed in step 2, the developing reagent was ethyl acetate/petroleum ether=1: developing with 3, 20% sulfuric acid ethanol solution; in the TLC monitoring reaction employed in step 3, the developing reagent was ethyl acetate/petroleum ether=1: 3, 20% sulfuric acid in ethanol developed, confirming the conversion of the starting material, and then methanol/dichloromethane=1: the color development of the 4, 20% sulfuric acid ethanol solution was confirmed to produce the product.

Step 1: preparation of 1- ((2S, 3S,4S, 5R) -3,4, 5-tris ((t-butyldimethylsilyl) oxy) tetrahydro-2H-pyran-2-yl) propan-2-one

1-C- (. Beta. -D-xylopyranosyl) -acetone (20.27 g,106.57 mmol) (CAS number 439685-73-1), t-butyldimethylchlorosilane (53 g,351.7 mmol), imidazole (29 g,426.3 mmol) were weighed into a 500ml round bottom flask, N-dimethylformamide (100 ml) was added and the reaction was stirred at 23 ℃. After the conversion of 1-C- (beta-D-xylopyranosyl) -acetone in the reaction is monitored by TLC, n-hexane (300 ml) is added and stirred for 1h, the reaction solution is washed with water (2X 200 ml) and saturated sodium chloride aqueous solution (1X 50 ml) in sequence, and the organic phase is dried by anhydrous sodium sulfate, filtered and distilled under reduced pressure to obtain a yellow oily crude product intermediate I, and the yellow oily product intermediate I is directly subjected to the next reaction for reduction.

Step 2: preparation of ((2S, 3S,4S, 5R) -2- ((S) -2- (triethylsiloxy) propyl) tetrahydro-2H-pyran-3, 4, 5-tris (oxy)) tris (t-butyldimethylsilane)

Intermediate I of the previous reaction (calculated as the amount of material charged from the complete conversion to product in the previous step) was dissolved in dry isopropanol (250 ml), stirred at 10℃and added with ferric trichloride (864 mg,5.33 mmol), triethylsilane (13.63 g,117.23 mmol) was added dropwise, reaction was maintained at room temperature, TLC confirmed complete conversion of intermediate I, the reaction was stopped, insoluble material was removed by filtration, the remaining filtrate was concentrated to dryness under reduced pressure, EA (200 ml) was added for dispersion, washed successively with 10% aqueous sodium hydrogen carbonate (100 ml), water (100 ml) and saturated aqueous sodium chloride (1X 50 ml), and the organic phase was dried over anhydrous sodium sulfate, filtered and distilled under reduced pressure to give crude intermediate II as a yellow oil, which was used directly in the next reaction.

Step 3: preparation of (2S, 3R,4S, 5R) -2- ((S) -2-hydroxypropyl) tetrahydro-2H-pyran-3, 4, 5-triol ((beta, S) configuration hydroxypropyl tetrahydropyran triol).

The crude intermediate II from step 2 was added with tetrabutylammonium fluoride (TBAF; 426ml of 1M tetrahydrofuran solution), stirred at 20℃for 3 hours, the complete conversion of intermediate II was confirmed by TLC, the reaction was stopped, the solvent was concentrated to dryness, purified water (100 ml) was added, stirred, extracted with EA (3X 80 ml), the aqueous phase was decolorized with activated carbon, anion-cation resin exchanged, concentrated, and recrystallized from ethanol, water and ethyl acetate to give 14.57g of a white solid, in terms of 1-C- (. Beta. -D-xylopyranosyl) -acetone, in a three-step reaction yield of 71.1% (calculated as the molar amount of 1-C- (. Beta. -D-xylopyranosyl) -acetone charged, in the same manner as in the following example), and liquid phase test was performed with an evaporation detector, with purity of (beta, S) -configuration hydroxypropyl tetrahydropyran triol of 99.8% (see FIG. 1), and conductivity of a 30% aqueous solution of 16. Mu.S/cm.

Example 2: preparation of (2S, 3R,4S, 5R) -2- ((S) -2-hydroxypropyl) tetrahydro-2H-pyran-3, 4, 5-triol ((beta, S) configuration hydroxypropyl tetrahydropyran triol).

In the TLC monitoring reaction employed in step 1 of the following example, the developing reagent was methanol/dichloromethane=1: developing with 4, 20% sulfuric acid ethanol solution; in the TLC monitoring reaction employed in step 2, the developing reagent was ethyl acetate/petroleum ether=1: developing with 3, 20% sulfuric acid ethanol solution; in the TLC monitoring reaction employed in step 3, the developing reagent was ethyl acetate/petroleum ether=1: 3, 20% sulfuric acid in ethanol developed, confirming the conversion of the starting material, and then methanol/dichloromethane=1: the color development of the 4, 20% sulfuric acid ethanol solution was confirmed to produce the product.

Step 1: preparation of 1- ((2S, 3S,4S, 5R) -3,4, 5-tris ((t-butyldimethylsilyl) oxy) tetrahydro-2H-pyran-2-yl) propan-2-one

1-C- (. Beta. -D-xylopyranosyl) -acetone (19.02 g,100 mmol), t-butyldimethylchlorosilane (52.75 g,350 mmol), pyridine (31.64 g,400 mmol) were weighed into a 500ml round bottom flask, N-dimethylformamide (100 ml) was added and reacted under stirring at 20 ℃. TLC monitors that 1-C- (beta-D-xylopyranosyl) -acetone is converted, petroleum ether (300 ml) is added and stirred for 1h, the reaction liquid is washed with water (2X 200 ml) and saturated sodium chloride aqueous solution (1X 50 ml) in sequence, the organic phase is dried by anhydrous sodium sulfate and filtered, and reduced pressure distillation is carried out to obtain yellow oily crude product, and the yellow oily product is directly subjected to the next reaction for reduction.

Step 2: preparation of ((2S, 3S,4S, 5R) -2- ((S) -2- (triethylsiloxy) propyl) tetrahydro-2H-pyran-3, 4, 5-tris (oxy)) tris (t-butyldimethylsilane)

The crude product of the previous reaction (calculated as the amount of material charged from the complete conversion to product in the previous step) was dissolved in dry methanol (250 ml), stirred at 10 ℃, ferric bromide (1.48 g,5.0 mmol) was added dropwise, the reaction was maintained at room temperature, TLC monitoring confirmed complete conversion of intermediate I, the reaction was stopped, the insoluble material was removed by filtration, the remaining filtrate was concentrated to dryness under reduced pressure, EA ethyl acetate (200 ml) was added to disperse, washed successively with 10% aqueous sodium bicarbonate (100 ml), aqueous solution (100 ml), saturated aqueous sodium chloride (1×50 ml) and the organic phase was dried over anhydrous sodium sulfate, filtered and distilled under reduced pressure to give a crude yellow oil which was used directly in the next step.

Step 3: preparation of (2S, 3R,4S, 5R) -2- ((S) -2-hydroxypropyl) tetrahydro-2H-pyran-3, 4, 5-triol ((beta, S) configuration hydroxypropyl tetrahydropyran triol).

The crude product of step 2 was added with a methanol solution of hydrogen chloride (containing 4mol/L HCl, 150 ml) and stirred at 10℃for 4 hours, the complete 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 (3X 80 ml), the aqueous phase was decolorized by activated carbon, ion-exchanged, concentrated, and recrystallized from ethanol, water and ethyl acetate to give 13.37g of a white solid, the yield of the three-step reaction was 70.29% by 1-C- (. Beta. -D-xylopyranosyl) -acetone, the purity of the (beta, S) -configuration hydroxypropyl tetrahydropyran triol was 100% (see FIG. 2) and the conductivity of the 30% aqueous solution was 8. Mu.S/cm by liquid phase test using an evaporation detector.

Example 3: preparation of (2S, 3R,4S, 5R) -2- ((S) -2-hydroxypropyl) tetrahydro-2H-pyran-3, 4, 5-triol ((beta, S) -configured hydroxypropyl tetrahydropyran triol)

In the TLC monitoring reaction employed in step 1 of the following example, the developing reagent was methanol/dichloromethane=1: developing with 4, 20% sulfuric acid ethanol solution; in the TLC monitoring reaction employed in step 2, the developing reagent was ethyl acetate/petroleum ether=1: developing with 3, 20% sulfuric acid ethanol solution; in the TLC monitoring reaction employed in step 3, the developing reagent was ethyl acetate/petroleum ether=1: 3, 20% sulfuric acid in ethanol developed, confirming the conversion of the starting material, and then methanol/dichloromethane=1: the color development of the 4, 20% sulfuric acid ethanol solution was confirmed to produce the product.

Step 1: preparation of 1- ((2S, 3S,4S, 5R) -3,4, 5-tris ((t-butyldimethylsilyl) oxy) tetrahydro-2H-pyran-2-yl) propan-2-one

1-C- (. Beta. -D-xylopyranosyl) -acetone (19.02 g,100 mmol), t-butyldimethylchlorosilane (49.74 g,330 mmol), triethylamine (40.48 g,400 mmol) were weighed into a 500ml round bottom flask, tetrahydrofuran (100 ml) was added and the reaction stirred at room temperature. After confirming completion of conversion of 1-C- (. Beta. -D-xylopyranosyl) -acetone in the reaction by TLC, cyclohexane (250 ml) was added and stirred for 1 hour, the reaction mixture was washed successively with water (3X 170 ml) and a saturated aqueous sodium chloride solution (1X 50 ml), and the organic phase was dried over anhydrous sodium sulfate, filtered and distilled under reduced pressure to obtain a crude yellow oily product.

Step 2: preparation of ((2S, 3S,4S, 5R) -2- ((S) -2- (trimethylsiloxy) propyl) tetrahydro-2H-pyran-3, 4, 5-tris (oxy)) tris (t-butyldimethylsilane)

The oily substance was dissolved in tetrahydrofuran (200 ml), stirred at 10℃and copper chloride (672 mg,5.0 mmol) was added dropwise, trimethylsilane (8.9 g,120 mmol) was added and the reaction was kept at room temperature, TLC confirmed complete conversion of intermediate I, the reaction was stopped, insoluble substances were removed by filtration, the remaining filtrate was concentrated to dryness under reduced pressure, EA (200 ml) was added to disperse, and washing was carried out sequentially with 10% aqueous sodium hydrogencarbonate (100 ml), aqueous solution (100 ml) and saturated aqueous sodium chloride (1X 50 ml), and the organic phase was dried over anhydrous sodium sulfate, filtered and distilled under reduced pressure to obtain a crude yellow oily substance which was used directly in the next step.

Step 3: preparation of (2S, 3R,4S, 5R) -2- ((S) -2-hydroxypropyl) tetrahydro-2H-pyran-3, 4, 5-triol ((beta, S) configuration hydroxypropyl tetrahydropyran triol).

The crude product was added with an ethanol solution of hydrogen chloride (containing 4mol/L HCl, 120 ml) and stirred at 25℃for 4 hours, the progress of the reaction 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 (3X 60 ml), the aqueous phase was decolorized by activated carbon, anion-cation resin exchanged, concentrated, and recrystallized from ethanol, water and ethyl acetate to give 13.86g of a white solid, calculated as 1-C- (. Beta. -D-xylopyranosyl) -acetone, the three-step reaction yield was 72.11%, the purity of the (beta, S) configuration hydroxypropyl tetrahydropyran triol was 100% and the conductivity of the 30% aqueous solution was 7.8. Mu.S/cm by liquid phase test with an evaporative light detector.

Example 4: preparation of (2S, 3R,4S, 5R) -2- ((S) -2-hydroxypropyl) tetrahydro-2H-pyran-3, 4, 5-triol ((beta, S) -configured hydroxypropyl tetrahydropyran triol)

In the TLC monitoring reaction employed in step 1 of the following example, the developing reagent was methanol/dichloromethane=1: developing with 4, 20% sulfuric acid ethanol solution; in the TLC monitoring reaction employed in step 2, the developing reagent was ethyl acetate/petroleum ether=1: developing with 3, 20% sulfuric acid ethanol solution; in the TLC monitoring reaction employed in step 3, the developing reagent was ethyl acetate/petroleum ether=1: 3, 20% sulfuric acid in ethanol developed, confirming the conversion of the starting material, and then methanol/dichloromethane=1: the color development of the 4, 20% sulfuric acid ethanol solution was confirmed to produce the product.

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

1-C- (. Beta. -D-xylopyranosyl) -acetone (19.02 g,100 mmol), triisopropylchlorosilane (63.63 g,330 mmol), imidazole (27.23 g,400 mmol) were weighed into a 500ml round bottom flask, N-dimethylformamide (100 ml) was added and the reaction stirred at room temperature. After confirming that 1-C- (. Beta. -D-xylopyranosyl) -acetone was converted by TLC, n-hexane (300 ml) was added and stirred for 1 hour, the reaction mixture was washed successively with water (2X 200 ml) and a saturated aqueous sodium chloride solution (1X 50 ml), and the organic phase was dried over anhydrous sodium sulfate, filtered and distilled under reduced pressure to obtain a crude yellow oily product.

Step 2: ((2S, 3S,4S, 5R) -2- ((S) -2- (triethylsiloxy) propyl) tetrahydro-2H-pyran-3, 4, 5-tris (oxy)) tris (triisopropylsilane)

The oily substance was dissolved in tetrahydrofuran (200 ml), stirred at 10℃and ferric trichloride (811 mg,5 mmol) was added dropwise, triethylsilane (13.95 g,120 mmol) was added dropwise and the reaction was kept at room temperature, TLC confirmed complete conversion of intermediate I, the reaction was stopped, insoluble matter was removed by filtration, the remaining filtrate was concentrated to dryness under reduced pressure, EA (200 ml) was added to disperse it, and washing was carried out sequentially with 10% aqueous sodium hydrogencarbonate (100 ml), aqueous solution (100 ml) and saturated aqueous sodium chloride (1X 50 ml), and the organic phase was dried over anhydrous sodium sulfate, filtered and distilled under reduced pressure to give a crude yellow oily substance which was used directly in the next step.

Step 3: preparation of (2S, 3R,4S, 5R) -2- ((S) -2-hydroxypropyl) tetrahydro-2H-pyran-3, 4, 5-triol ((beta, S) configuration hydroxypropyl tetrahydropyran triol).

The intermediate of the above step 2 was added with tetrabutylammonium fluoride (TBAF; 1M tetrahydrofuran solution 440 ml), stirred at 25℃for 3 hours, the complete conversion of intermediate II was confirmed by TLC, the reaction was stopped, the solvent was concentrated to dryness, purified water (120 ml) was added, stirred, extracted with EA (3X 80 ml), the aqueous phase was decolorized with activated carbon, anion-cation resin exchanged, concentrated, and recrystallized from ethanol, water and ethyl acetate to give 11.93g of a white solid, the yield of the three-step reaction was 62.07% in terms of 1-C- (. Beta. -D-xylopyranosyl) -acetone, the purity of the (beta, S) -configuration hydroxypropyl tetrahydropyran triol was 99.62% by liquid phase test by an evaporation detector, and the conductivity of a 30% aqueous solution was 14.3. Mu.S/cm.

Example 5: preparation of (2S, 3R,4S, 5R) -2- ((S) -2-hydroxypropyl) tetrahydro-2H-pyran-3, 4, 5-triol ((beta, S) -configured hydroxypropyl tetrahydropyran triol)

In the TLC monitoring reaction employed in step 1 of the following example, the developing reagent was methanol/dichloromethane=1: developing with 4, 20% sulfuric acid ethanol solution; in the TLC monitoring reaction employed in step 2, the developing reagent was ethyl acetate/petroleum ether=1: developing with 3, 20% sulfuric acid ethanol solution; in the TLC monitoring reaction employed in step 3, the developing reagent was ethyl acetate/petroleum ether=1: 3, 20% sulfuric acid in ethanol developed, confirming the conversion of the starting material, and then methanol/dichloromethane=1: the color development of the 4, 20% sulfuric acid ethanol solution was confirmed to produce the product.

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

1-C- (. Beta. -D-xylopyranosyl) -acetone (19.02 g,100 mmol), trimethylchlorosilane (35.85 g,330 mmol), imidazole (27.23 g,400 mmol) were weighed into a 500ml round bottom flask, N-dimethylformamide (100 ml) was added and the reaction stirred at room temperature. After confirming that 1-C- (. Beta. -D-xylopyranosyl) -acetone was converted by TLC, n-hexane (300 ml) was added and stirred for 1 hour, the reaction mixture was washed successively with water (2X 200 ml) and a saturated aqueous sodium chloride solution (1X 50 ml), and the organic phase was dried over anhydrous sodium sulfate, filtered and distilled under reduced pressure to obtain a crude yellow oily product.

Step 2: preparation of ((2S, 3S,4S, 5R) -2- ((S) -2- (trimethylsiloxy) propyl) tetrahydro-2H-pyran-3, 4, 5-triyl) tris (oxy) tris (trimethylsilane)

The oily substance was dissolved in ethanol (200 ml), stirred at room temperature, ferric acetylacetonate (1.70 g,5.0 mmol) was added, trimethylsilane (7.79 g,105 mmol) was added dropwise, room temperature reaction was maintained, TLC confirmed that intermediate I was complete, the reaction was stopped, the reaction solution was concentrated to dryness under reduced pressure, EA (200 ml) was added to disperse, and washing was performed sequentially with 10% aqueous sodium bicarbonate solution (100 ml), aqueous solution (100 ml) and saturated aqueous sodium chloride solution (1X 50 ml), and the organic phase was dried over anhydrous sodium sulfate, filtered, distilled under reduced pressure to obtain a crude yellow oily substance, which was used directly in the next step.

Step 3: preparation of (2S, 3R,4S, 5R) -2- ((S) -2-hydroxypropyl) tetrahydro-2H-pyran-3, 4, 5-triol ((beta, S) configuration hydroxypropyl tetrahydropyran triol).

The intermediate of the above step 2 was added with 146g of methanol, followed by addition of hydrofluoric acid (48% -52% aqueous solution, 16g,400 mmol) at 0 ℃ and stirring at a temperature for 2 hours, complete 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, EA was used for extraction (3×80 ml), the aqueous phase was decolorized with activated carbon, anion-cation resin was exchanged, concentrated, and 11.89g of a white solid was obtained by recrystallization from ethanol, water and ethyl acetate, and the three-step reaction yield was 61.92% in terms of 1-C- (. Beta. -D-xylopyranosyl) -acetone, and liquid phase test was performed with an evaporation detector, with purity of (β, S) -configuration hydroxypropyl tetrahydropyran triol being 99.54%, and conductivity of 30% aqueous solution being 23.2 μs/cm.

Example 6: preparation of (2S, 3R,4S, 5R) -2- ((S) -2-hydroxypropyl) tetrahydro-2H-pyran-3, 4, 5-triol ((beta, S) -configured hydroxypropyl tetrahydropyran triol)

In the TLC monitoring reaction employed in step 1 of the following example, the developing reagent was methanol/dichloromethane=1: developing with 4, 20% sulfuric acid ethanol solution; in the TLC monitoring reaction employed in step 2, the developing reagent was ethyl acetate/petroleum ether=1: developing with 3, 20% sulfuric acid ethanol solution; in the TLC monitoring reaction employed in step 3, the developing reagent was ethyl acetate/petroleum ether=1: 3, 20% sulfuric acid in ethanol developed, confirming the conversion of the starting material, and then methanol/dichloromethane=1: the color development of the 4, 20% sulfuric acid ethanol solution was confirmed to produce the product.

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

1-C- (. Beta. -D-xylopyranosyl) -acetone (19.02 g,100 mmol) was weighed, methylene chloride (100 ml) was added, and the mixture was stirred and dispersed in a 500ml round bottom flask, pyridine (27.69 g,350 mmol) was added, tert-butyldiphenylchlorosilane (90.71 g,330 mmol) was added dropwise at 0℃and reacted at 0℃for 1 hour, and then transferred to room temperature and stirred for 3 hours. After completion of conversion of 1-C- (. Beta. -D-xylopyranosyl) -acetone in the reaction was monitored by TLC, n-hexane (300 ml) was added and stirred for 1 hour, the reaction mixture was washed successively with water (3X 200 ml) and a saturated aqueous sodium chloride solution (1X 50 ml), and the organic phase was dried over anhydrous sodium sulfate, filtered and distilled under reduced pressure to give a crude yellow oily product.

Step 2: preparation of ((2S, 3S,4S, 5R) -2- ((S) -2- (di-tert-Butoxy (methyl) silyl) oxy) propyl) tetrahydropyran-3, 4, 5-tris (oxy) tris (tert-butyldiphenylsilane)

The oil was dissolved in dioxane (200 ml), stirred at 10 ℃, copper chloride (672 mg,5.0 mmol) was added dropwise, methyl hydrogen siloxane Polymer (PMHS) (24.48 g,110 mmol) was added dropwise, reaction was kept at room temperature, intermediate I was completely converted in TLC monitoring, the reaction was stopped, insoluble matter was removed by filtration, the remaining filtrate was concentrated to dryness under reduced pressure, EA (200 ml) was added to disperse, washing was carried out sequentially with 10% aqueous sodium hydrogencarbonate (100 ml), aqueous solution (100 ml) and saturated aqueous sodium chloride solution (1X 50 ml), and the organic phase was dried over anhydrous sodium sulfate, filtered and distilled under reduced pressure to obtain crude yellow oil which was directly used for the next reaction.

Step 3: preparation of (2S, 3R,4S, 5R) -2- ((S) -2-hydroxypropyl) tetrahydro-2H-pyran-3, 4, 5-triol ((beta, S) configuration hydroxypropyl tetrahydropyran triol).

The intermediate of the above step 2 was stirred and reacted for 4 hours at 10℃with an ethanol solution of hydrogen chloride (containing 4mol/L of HCl, 130 ml), the reaction was monitored by TLC to complete the reaction of intermediate II, the reaction was stopped, the solvent was concentrated to dryness, purified water (100 ml) was added and stirred, extracted with EA (3X 80 ml), the aqueous phase was decolorized by activated carbon, anion-cation resin, concentrated, and recrystallized from ethanol, water and ethyl acetate to give 9.76g of a white solid, calculated as 1-C- (. Beta. -D-xylopyranosyl) -acetone, in three steps with a yield of 50.78%, and liquid phase test was performed with an evaporation detector, the purity of the (beta, S) -configuration hydroxypropyl tetrahydropyran triol was 99.63%, and the conductivity of the 30% aqueous solution was 26. Mu.S/cm.

Example 7: preparation of (2S, 3R,4S, 5R) -2- ((S) -2-hydroxypropyl) tetrahydro-2H-pyran-3, 4, 5-triol ((beta, S) -configured hydroxypropyl tetrahydropyran triol)

In the TLC monitoring reaction employed in step 1 of the following example, the developing reagent was methanol/dichloromethane=1: developing with 4, 20% sulfuric acid ethanol solution; in the TLC monitoring reaction employed in step 2, the developing reagent was ethyl acetate/petroleum ether=1: developing with 3, 20% sulfuric acid ethanol solution; in the TLC monitoring reaction employed in step 3, the developing reagent was ethyl acetate/petroleum ether=1: 3, 20% sulfuric acid in ethanol developed, confirming the conversion of the starting material, and then methanol/dichloromethane=1: the color development of the 4, 20% sulfuric acid ethanol solution was confirmed to produce the product.

Step 1: preparation of 1- ((2S, 3S,4S, 5R) -3,4, 5-tris ((t-butyldimethylsilyl) oxy) tetrahydro-2H-pyran-2-yl) propan-2-one

1-C- (. Beta. -D-xylopyranosyl) -acetone (19.02 g,100 mmol), t-butyldimethylchlorosilane (49.74 g,330 mmol), imidazole (23.83 g,350 mmol) were weighed into a 500ml round bottom flask, tetrahydrofuran (100 ml) was added and the reaction was stirred at 20 ℃. After the conversion of 1-C- (beta-D-xylopyranosyl) -acetone in the reaction is monitored by TLC, n-hexane (300 ml) is added and stirred for 1h, the reaction solution is washed with water (2X 200 ml) and saturated sodium chloride aqueous solution (1X 50 ml) in sequence, and the organic phase is dried by anhydrous sodium sulfate, filtered and distilled under reduced pressure to obtain a yellow oily crude product, and the yellow oily crude product is directly subjected to the next reaction for reduction.

Step 2: preparation of ((2S, 3S,4S, 5R) -2- ((S) -2- (trimethylsiloxy) propyl) tetrahydro-2H-pyran-3, 4, 5-tris (oxy)) tris (t-butyldimethylsilane)

The crude product of the previous reaction (calculated as the amount of material charged in the previous step to be completely converted into the product) was dissolved in dry tetrahydrofuran (250 ml), stirred at 10℃and added with ferric trichloride (1.62 mg,10 mmol), trimethylsilane (8.35 g,115 mmol) was added dropwise, the reaction was kept at room temperature, TLC monitored for complete reaction of intermediate I, the reaction was stopped, the insoluble matter was removed by filtration, the remaining filtrate was concentrated to dryness under reduced pressure, EA (200 ml) was added for dispersion, washed successively with 10% aqueous sodium hydrogen carbonate (100 ml), aqueous solution (100 ml) and saturated aqueous sodium chloride (1X 50 ml), and the organic phase was dried over anhydrous sodium sulfate, filtered and distilled under reduced pressure to give a crude yellow oil which was directly used in the next reaction.

Step 3: preparation of (2S, 3R,4S, 5R) -2- ((S) -2-hydroxypropyl) tetrahydro-2H-pyran-3, 4, 5-triol ((beta, S) configuration hydroxypropyl tetrahydropyran triol).

The crude product of step 2 was added with tetrabutylammonium fluoride (TBAF; 1M tetrahydrofuran solution 440 ml), stirred at 25℃for 3 hours, the complete conversion of intermediate II was confirmed by TLC, the reaction was stopped, the solvent was concentrated to dryness, purified water (100 ml) was added, stirred, extracted with EA (3X 80 ml), the aqueous phase was decolorized with activated carbon, anion-cation resin exchanged, concentrated, and recrystallized from ethanol, water and ethyl acetate to give 12.59g of a white solid, the yield of the three-step reaction was 65.50% in terms of 1-C- (. Beta. -D-xylopyranosyl) -acetone, and the purity of the (beta, S) -configuration hydroxypropyl tetrahydropyran triol was 99.59% by liquid phase test with an evaporation detector.

Example 8: preparation of (2S, 3R,4S, 5R) -2- ((S) -2-hydroxypropyl) tetrahydro-2H-pyran-3, 4, 5-triol ((beta, S) -configured hydroxypropyl tetrahydropyran triol)

In the TLC monitoring reaction employed in step 1 of the following example, the developing reagent was methanol/dichloromethane=1: developing with 4, 20% sulfuric acid ethanol solution; in the TLC monitoring reaction employed in step 2, the developing reagent was ethyl acetate/petroleum ether=1: developing with 3, 20% sulfuric acid ethanol solution; in the TLC monitoring reaction employed in step 3, the developing reagent was ethyl acetate/petroleum ether=1: 3, 20% sulfuric acid in ethanol developed, confirming the conversion of the starting material, and then methanol/dichloromethane=1: the color development of the 4, 20% sulfuric acid ethanol solution was confirmed to produce the product.

Step 1: preparation of 1- ((2S, 3S,4S, 5R) -3,4, 5-tris ((t-butyldimethylsilyl) oxy) tetrahydro-2H-pyran-2-yl) propan-2-one

1-C- (. Beta. -D-xylopyranosyl) -acetone (19.02 g,100 mmol), t-butyldimethylchlorosilane (49.74 g,330 mmol), imidazole (24.51 g,360 mmol) were weighed into a 500ml round bottom flask, N-dimethylformamide (100 ml) was added and reacted under stirring at 35℃for 5 hours. After TLC monitoring the disappearance of the raw material 1-C- (beta-D-xylopyranosyl) -acetone, n-hexane (300 ml) is added and stirred for 1h, the reaction solution is washed with water (2X 200 ml) and saturated sodium chloride aqueous solution (1X 50 ml) in sequence, and the organic phase is dried by anhydrous sodium sulfate, filtered and distilled under reduced pressure to obtain a yellow oily crude product, and the yellow oily crude product is directly subjected to the next reaction for reduction.

Step 2: preparation of ((2S, 3S,4S, 5R) -2- ((S) -2- ((triphenylsilyl) oxy) propyl) tetrahydro-2H-pyran-3, 4, 5-tris (oxy)) tris (t-butyldimethylsilane)

The crude product of the previous reaction (calculated as the amount of material charged from the complete conversion to product in the previous step) was dissolved in dry ethanol (250 ml), stirred at 10 ℃, ferric trichloride (1.62 g,10 mmol) was added dropwise, the reaction was maintained at room temperature, TLC confirmed complete conversion of intermediate I, the reaction was stopped, the insoluble matter was removed by filtration, the remaining filtrate was concentrated to dryness under reduced pressure, EA (300 ml) was added to disperse it, washed successively with 10% aqueous sodium bicarbonate (100 ml), aqueous solution (100 ml) and saturated aqueous sodium chloride (1X 50 ml), the organic phase was dried over anhydrous sodium sulfate, filtered and distilled under reduced pressure to give a crude yellow oil which was used directly in the next reaction.

Step 3: preparation of (2S, 3R,4S, 5R) -2- ((S) -2-hydroxypropyl) tetrahydro-2H-pyran-3, 4, 5-triol ((beta, S) configuration hydroxypropyl tetrahydropyran triol).

The crude product of step 2 was added with an ethanol solution of hydrogen chloride (containing 4mol/L HCl, 110 ml) and stirred at 25℃for 3 hours, the reaction of intermediate II was monitored by TLC to completion, the reaction was stopped, the solvent was concentrated to dryness, purified water (100 ml) was added and stirred, extracted with EA (3X 100 ml), the aqueous phase was decolorized with activated carbon, anion-cation resin exchanged, concentrated, and recrystallized from ethanol, water and ethyl acetate to give 7.65g of a white solid, the yield of the three-step reaction was 39.80% in terms of 1-C- (. Beta. -D-xylopyranosyl) -acetone, and the purity of the (beta, S) -configuration hydroxypropyl tetrahydropyran triol was 99.68% by liquid phase test with an evaporation detector.

Example 9: preparation of (2S, 3R,4S, 5R) -2- ((S) -2-hydroxypropyl) tetrahydro-2H-pyran-3, 4, 5-triol ((beta, S) -configured hydroxypropyl tetrahydropyran triol)

In the TLC monitoring reaction employed in step 1 of the following example, the developing reagent was methanol/dichloromethane=1: developing with 4, 20% sulfuric acid ethanol solution; in the TLC monitoring reaction employed in step 2, the developing reagent was ethyl acetate/petroleum ether=1: developing with 3, 20% sulfuric acid ethanol solution; in the TLC monitoring reaction employed in step 3, the developing reagent was ethyl acetate/petroleum ether=1: 3, 20% sulfuric acid in ethanol developed, confirming the conversion of the starting material, and then methanol/dichloromethane=1: the color development of the 4, 20% sulfuric acid ethanol solution was confirmed to produce the product.

Step 1: preparation of 1- ((2S, 3S,4S, 5R) -3,4, 5-tris ((t-butyldimethylsilyl) oxy) tetrahydro-2H-pyran-2-yl) propan-2-one

1-C- (. Beta. -D-xylopyranosyl) -acetone (19.02 g,100 mmol), t-butyldimethylchlorosilane (52 g,345 mmol), imidazole (24.51 g,360 mmol) were weighed into a 500ml round bottom flask, N-dimethylformamide (100 ml) was added and the reaction stirred at 25℃for 10 hours. After TLC monitoring the disappearance of the raw material 1-C- (beta-D-xylopyranosyl) -acetone, n-hexane (300 ml) is added and stirred for 1h, the reaction solution is washed with water (2X 200 ml) and saturated sodium chloride aqueous solution (1X 50 ml) in sequence, and the organic phase is dried by anhydrous sodium sulfate, filtered and distilled under reduced pressure to obtain a yellow oily crude product, and the yellow oily crude product is directly subjected to the next reaction for reduction.

Step 2: preparation of ((2S, 3S,4S, 5R) -2- ((S) -2- ((triethylsilyl) oxy) propyl) tetrahydro-2H-pyran-3, 4, 5-tris (oxy)) tris (t-butyldimethylsilane)

The crude product of the previous reaction (calculated as the amount of material charged from the complete conversion to product in the previous step) was dissolved in dry tetrahydrofuran (250 ml), stirred at 10 ℃, ferric trichloride (1.3 g,8 mmol) was added dropwise, reaction was maintained at room temperature, TLC monitored for substantial conversion of reaction intermediate I, the reaction was stopped, the insoluble matter was removed by filtration, the remaining filtrate was concentrated to dryness under reduced pressure, EA (300 ml) was added for dispersion, washed successively with 10% aqueous sodium hydrogen carbonate (100 ml), aqueous solution (100 ml) and saturated aqueous sodium chloride (1X 50 ml), the organic phase was dried over anhydrous sodium sulfate, filtered and distilled under reduced pressure to give crude yellow oil which was used directly in the next reaction.

Step 3: preparation of (2S, 3R,4S, 5R) -2- ((S) -2-hydroxypropyl) tetrahydro-2H-pyran-3, 4, 5-triol ((beta, S) configuration hydroxypropyl tetrahydropyran triol).

The crude product of step 2 was added with a methanol solution of hydrogen chloride (containing 4mol/L HCl, 130 ml) and stirred at 20℃for 3 hours, reaction intermediate II was monitored by TLC to completion, the reaction was stopped, the solvent was concentrated to dryness, purified water (100 ml) was added and stirred, extracted with EA (3X 80 ml), the aqueous phase was decolorized with activated carbon, anion-cation resin exchanged, concentrated, and recrystallized from ethanol, water and ethyl acetate to give 12.67g of a white solid, the three-step reaction yield was 65.92% as 1-C- (. Beta. -D-xylopyranosyl) -acetone, and the (beta, S) configuration hydroxypropyl tetrahydropyran triol purity was 99.73% as measured by liquid phase with an evaporation detector.

Example 10: preparation of (2S, 3R,4S, 5R) -2- ((S) -2-hydroxypropyl) tetrahydro-2H-pyran-3, 4, 5-triol ((beta, S) -configured hydroxypropyl tetrahydropyran triol)

In the TLC monitoring reaction employed in step 1 of the following example, the developing reagent was methanol/dichloromethane=1: developing with 4, 20% sulfuric acid ethanol solution; in the TLC monitoring reaction employed in step 2, the developing reagent was ethyl acetate/petroleum ether=1: developing with 3, 20% sulfuric acid ethanol solution; in the TLC monitoring reaction employed in step 3, the developing reagent was ethyl acetate/petroleum ether=1: 3, 20% sulfuric acid in ethanol developed, confirming the conversion of the starting material, and then methanol/dichloromethane=1: the color development of the 4, 20% sulfuric acid ethanol solution was confirmed to produce the product.

Step 1: preparation of 1- ((2S, 3S,4S, 5R) -3,4, 5-tris ((t-butyldimethylsilyl) oxy) tetrahydro-2H-pyran-2-yl) propan-2-one

1-C- (. Beta. -D-xylopyranosyl) -acetone (19.02 g,100 mmol), t-butyldimethylchlorosilane (47.48 g,315 mmol), imidazole (23.83 g,350 mmol) were weighed into a 500ml round bottom flask, N-dimethylformamide (100 ml) was added and the reaction was stirred at 30℃for 6 hours. After TLC monitoring the disappearance of the raw material 1-C- (beta-D-xylopyranosyl) -acetone, n-hexane (300 ml) is added and stirred for 1h, the reaction solution is washed with water (2X 200 ml) and saturated sodium chloride aqueous solution (1X 50 ml) in sequence, and the organic phase is dried by anhydrous sodium sulfate, filtered and distilled under reduced pressure to obtain a yellow oily crude product, and the yellow oily crude product is directly subjected to the next reaction for reduction.

Step 2: preparation of ((2S, 3S,4S, 5R) -2- ((S) -2- ((triethylsilyl) oxy) propyl) tetrahydro-2H-pyran-3, 4, 5-tris (oxy)) tris (t-butyldimethylsilane)

The crude product of the previous reaction (calculated as the amount of material charged in the previous step to be completely converted into the product) was dissolved in dry tetrahydrofuran (250 ml), stirred at 10℃and copper chloride (1.34 g,10 mmol) was added dropwise, triethylsilane (13.95 g,120 mmol) was added and kept at room temperature for reaction, TLC monitored intermediate I reaction, the reaction was stopped, the insoluble matter was removed by filtration, the remaining filtrate was concentrated to dryness under reduced pressure, EA (300 ml) was added for dispersion, and washed successively with 10% aqueous sodium hydrogen carbonate (100 ml), aqueous solution (100 ml) and saturated aqueous sodium chloride (1X 50 ml), and the organic phase was dried over anhydrous sodium sulfate, filtered and distilled under reduced pressure to give a crude yellow oil which was directly used for the next reaction.

Step 3: preparation of (2S, 3R,4S, 5R) -2- ((S) -2-hydroxypropyl) tetrahydro-2H-pyran-3, 4, 5-triol ((beta, S) configuration hydroxypropyl tetrahydropyran triol).

Adding 100ml of methanol into the crude product obtained in the step 2, stirring to dissolve, adding a methanol solution of hexafluorosilicic acid (40% aqueous solution, 36 g), stirring at 5 ℃ for reaction for 3 hours, monitoring the completion of the reaction of the intermediate II by TLC, stopping the reaction, concentrating the solvent to dryness, adding purified water (100 ml), stirring, extracting by EA (3X 80 ml), decolorizing the water phase by activated carbon, exchanging anion-cation resin, concentrating, recrystallizing by ethanol, water and ethyl acetate to obtain 8.48g of white solid, and carrying out liquid phase test by an evaporation detector with the three-step reaction yield of 44.12 percent and the purity of (beta, S) configuration hydroxypropyl tetrahydropyran triol of 99.66 percent.

Example 11: preparation of (2S, 3R,4S, 5R) -2- ((S) -2-hydroxypropyl) tetrahydro-2H-pyran-3, 4, 5-triol ((beta, S) -configured hydroxypropyl tetrahydropyran triol)

In the TLC monitoring reaction employed in step 1 of the following example, the developing reagent was methanol/dichloromethane=1: developing with 4, 20% sulfuric acid ethanol solution; in the TLC monitoring reaction employed in step 2, the developing reagent was ethyl acetate/petroleum ether=1: developing with 3, 20% sulfuric acid ethanol solution; in the TLC monitoring reaction employed in step 3, the developing reagent was ethyl acetate/petroleum ether=1: 3, 20% sulfuric acid in ethanol developed, confirming the conversion of the starting material, and then methanol/dichloromethane=1: the color development of the 4, 20% sulfuric acid ethanol solution was confirmed to produce the product.

Step 1: preparation of 1- ((2S, 3S,4S, 5R) -3,4, 5-tris ((t-butyldimethylsilyl) oxy) tetrahydro-2H-pyran-2-yl) propan-2-one

1-C- (. Beta. -D-xylopyranosyl) -acetone (19.02 g,100 mmol), t-butyldimethylchlorosilane (49.74 g,330 mmol), imidazole (27.23 g,400 mmol) were weighed into a 500ml round bottom flask, N-dimethylformamide (110 ml) was added and the reaction was stirred at 5℃for 10 hours. After TLC monitoring the disappearance of the raw material 1-C- (beta-D-xylopyranosyl) -acetone, normal hexane (300 ml) is added and stirred for 1h, the reaction solution is washed with water (2X 200 ml) and saturated sodium chloride aqueous solution (50 ml) in sequence, and the organic phase is dried by anhydrous sodium sulfate, filtered and distilled under reduced pressure to obtain a yellow oily crude product, and the yellow oily crude product is directly subjected to the next reaction for reduction.

Step 2: preparation of ((2S, 3S,4S, 5R) -2- ((S) -2- ((triethylsilyl) oxy) propyl) tetrahydro-2H-pyran-3, 4, 5-tris (oxy)) tris (t-butyldimethylsilane)

The crude product of the previous reaction (calculated as the amount of material charged to the complete conversion to product in the previous step) was dissolved in dry isopropanol (250 ml), stirred at 10 ℃, ferric chloride (811 mg,5 mmol) was added dropwise, the reaction was maintained at room temperature, TLC monitored for substantial conversion of reaction intermediate I, the reaction stopped, the insoluble material was removed by filtration, the remaining filtrate was concentrated to dryness under reduced pressure, EA (300 ml) was added for dispersion, washed successively with 10% aqueous sodium bicarbonate (100 ml), aqueous solution (100 ml) and saturated aqueous sodium chloride (1X 50 ml), the organic phase was dried over anhydrous sodium sulfate, filtered and distilled under reduced pressure to give a crude yellow oil which was used directly in the next step.

Step 3: preparation of (2S, 3R,4S, 5R) -2- ((S) -2-hydroxypropyl) tetrahydro-2H-pyran-3, 4, 5-triol ((beta, S) configuration hydroxypropyl tetrahydropyran triol).

Adding 150ml of methanol into the crude product obtained in the step 2, stirring and clearing, adding N-iodosuccinimide (90 g,0.4 mol), stirring and reacting for 3 hours at 30 ℃ under the protection of nitrogen, concentrating the solvent to dryness, adding purified water (100 ml), stirring, extracting (3X 80 ml) by EA, decoloring the water phase by activated carbon, exchanging anion-cation resin, concentrating, recrystallizing by ethanol, water and ethyl acetate to obtain 3.12g of white solid, and carrying out liquid phase test on the 3.23% yield by an evaporation light detector according to 1-C- (beta-D-xylopyranosyl) -acetone, wherein the purity of the hydroxypropyl tetrahydropyran triol with the (beta, S) configuration is 99.81%.

Example 12: amplified preparation of (2S, 3R,4S, 5R) -2- ((S) -2-hydroxypropyl) tetrahydro-2H-pyran-3, 4, 5-triol ((beta, S) -configured hydroxypropyl tetrahydropyran triol)

In the TLC monitoring reaction employed in step 1 of the following example, the developing reagent was methanol/dichloromethane=1: developing with 4, 20% sulfuric acid ethanol solution; in the TLC monitoring reaction employed in step 2, the developing reagent was ethyl acetate/petroleum ether=1: developing with 3, 20% sulfuric acid ethanol solution; in the TLC monitoring reaction employed in step 3, the developing reagent was ethyl acetate/petroleum ether=1: 3, 20% sulfuric acid in ethanol developed, confirming the conversion of the starting material, and then methanol/dichloromethane=1: the color development of the 4, 20% sulfuric acid ethanol solution was confirmed to produce the product.

Step 1:

1-C- (. Beta. -D-xylopyranosyl) -acetone (1.902 kg,10 mol), t-butyldimethylchlorosilane (4.97 kg,33 mol), imidazole (2.72 kg,40 mol) were weighed into a 100L reaction vessel, N-dimethylformamide (9.5 kg) was added, the low-temperature circulation was started, and the reaction temperature was controlled at about 25 ℃. After completion of conversion of 1-C- (. Beta. -D-xylopyranosyl) -acetone in the reaction was monitored by TLC, n-hexane (15 kg) was added to the reaction mixture and stirred for 1 hour, the reaction mixture was dried over water (3X 15 kg), and the organic phase was dried over anhydrous sodium sulfate, filtered and distilled under reduced pressure to give a crude yellow oily product.

Step 2:

the crude oil of the previous reaction (calculated as product charge for complete conversion in the previous step) was dissolved in dry isopropanol (20L), stirred at 15℃and ferric trichloride (81.1 g,0.5 mol) was added dropwise, triethylsilane (1.279 kg,11 mol) was added, the reaction was maintained at room temperature, TLC monitored for complete conversion of reaction intermediate I, insoluble material was removed by filtration, the remaining filtrate was concentrated to dryness under reduced pressure, EA (12.5 kg) was added for dispersion, water (3X 10 kg) was used and the organic phase was distilled under reduced pressure to give crude yellow oil.

Step 3:

adding hydrogen chloride in methanol solution (containing 4mol/L HCl and 11L) to react for 3 hr at 25deg.C, confirming intermediate II reaction completion by TLC, stopping reaction, concentrating solvent to dryness, adding purified water (8 kg), stirring, extracting with EA (3×4.5 kg), decolorizing the water phase with active carbon, exchanging anion-cation resin, concentrating, recrystallizing with ethanol, water and ethyl acetate to obtain white solid 1.387kg, measuring with 1-C- (beta-D-xylopyranosyl) -acetone, measuring with evaporation detector to obtain three steps with yield of 72.16%, and testing with liquid phase detector to obtain hydroxypropyl tetrahydropyran triol with (beta, S) configuration of 100% (see figure 3) Data: ¹ H NMR(500MHz,D ₂ O)δ4.06-4.01(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). ¹³ C NMR(500MHz,D ₂ O)δ78.39,77.30,73.62,69.46,68.78,65.65,39.93,21.43.( ¹ h NMR is shown in figure 4), nuclear magnetic carbon spectrum [ (] ¹³ C NMR is shown in FIG. 5), the conductivity of the 30% aqueous solution was 6. Mu.S/cm.

Summarizing the preparation of (2S, 3R,4S, 5R) -2- ((S) -2-hydroxypropyl) tetrahydro-2H-pyran-3, 4, 5-triol ((beta, S) configuration hydroxypropyl tetrahydropyran triol) in the above examples, in which in step 1 in order to obtain a different degree of protection even complete for the 3 hydroxyl groups in 1-C- (. Beta. -D-xylopyranosyl) -acetone, more than 1 equivalent of chlorosilane is required, complete protection is necessary, while more than 3 equivalents of base are necessary than the amount of chlorosilane to neutralize the hydrogen chloride produced by the reaction. Meanwhile, under the condition that the reduction of the silicane reduced ketocarbonyl in the step 2 is ensured to be thorough, the silicon base is removed in the step 3, impurities in an organic phase are removed through the distribution of the product in a water phase, the active carbon is used for decoloring, the residual anions and cations are removed through the ion resin, the product with the purity of more than 99.5% can be obtained, and the correct structure is confirmed through nuclear magnetism.

The foregoing is merely illustrative of the present invention, and the present invention is not limited thereto, and any person skilled in the art will readily recognize that variations or substitutions are within the scope of the present invention. Therefore, the protection scope of the present invention shall be subject to the protection scope of the claims.

Claims (8)

1. A method for synthesizing high-quality (beta, S) -configuration hydroxypropyl tetrahydropyran triol, which is characterized by comprising the following steps of:

(1) 1-C- (beta-D-xylopyranosyl) -acetone is used as a starting material, alkali is used as a catalyst, and the starting material reacts with chlorosilane to form silyl ether, so that an intermediate I is prepared, wherein the structural formula of the intermediate I is as follows:

wherein R is ₁ ，R ₂ ，R ₃ Respectively hydrogen, trimethylsilyl, tert-butyldimethylsilyl, triisopropylsilyl or tert-butyldiphenylsilyl; r is R ₁ ，R ₂ ，R ₃ Preferably t-butyldimethylsilyl;

(2) The intermediate I is subjected to silane reduction reaction to prepare an intermediate II, and the structural formula is as follows:

wherein R is ₁ ，R ₂ ，R ₃ Is respectively any one of hydrogen, trimethylsilyl, tert-butyldimethylsilyl, triisopropylsilyl or tert-butyldiphenylsilyl, R ₄ Is any one of triphenylsilyl, triethylsilyl, triethoxysilyl and trimethylsilyl;

(3) The intermediate II reacts by a desilication group protective reagent, and is decolorized by active carbon and exchanged by ion resin to obtain the hydroxypropyl tetrahydropyran triol solid with single (beta, S) configuration and high quality configuration, wherein the structural formula is as follows:

2. the method for synthesizing the high-quality (beta, S) -configured hydroxypropyl tetrahydropyran triol according to claim 1, wherein the specific preparation step of the step (1) is as follows:

1-C- (beta-D-xylopyranosyl) -acetone is taken as a starting material, a solvent, alkali and chlorosilane are added, the temperature is controlled to react, TLC is adopted to monitor the reaction, alkane is added after the reaction of the 1-C- (beta-D-xylopyranosyl) -acetone is finished, water and saturated saline water are sequentially added for washing, and an organic phase is separated, dried through anhydrous sodium sulfate and concentrated to obtain an intermediate I.

3. The method for synthesizing high-quality (β, S) -configured hydroxypropyl tetrahydropyran triol according to claim 2, wherein in said step (1), 1-C- (β -D-xylopyranosyl) -acetone: alkali: the molar ratio of chlorosilane is 1:1 to 5:1 to 4; preferably, 1-C- (β -D-xylopyranosyl) -acetone: alkali: the molar ratio of chlorosilane is preferably 1:4:3.3.

4. the method for synthesizing high-quality (β, S) -configured hydroxypropyl tetrahydropyran triol according to claim 2, wherein in the step (1), at least one of the following features (a) to (e) is included:

(a) The alkali used is: one or more of imidazole, pyridine, triethylamine, sodium carbonate or sodium bicarbonate; preferably imidazole;

(b) The chlorosilane used was: one or more of trimethylchlorosilane, t-butyldimethylchlorosilane, triisopropylchlorosilane or t-butyldiphenylchlorosilane; preferably t-butyldimethylchlorosilane;

(c) The solvent is selected from one or more of dichloromethane, dichloroethane, N-dimethylformamide and tetrahydrofuran; preferably N, N-dimethylformamide;

(d) The alkane added after the reaction is one or more of petroleum ether, cyclohexane, n-hexane and n-heptane; preferably n-hexane;

(e) The reaction temperature is 0-50 ℃; preferably from 10℃to 30 ℃.

5. The method for synthesizing the high-quality (beta, S) -configured hydroxypropyl tetrahydropyran triol according to claim 1, wherein the specific preparation step of the step (2) is as follows:

taking the intermediate I as a raw material, adding a solvent, silane and a catalyst, performing reduction reaction, monitoring the reaction by TLC, concentrating an organic phase of a reaction liquid, extracting with ethyl acetate, fully washing with water, and concentrating to obtain an intermediate II.

6. The method for synthesizing high-quality (β, S) -configured hydroxypropyl tetrahydropyran triol according to claim 5, wherein in said step (2), at least one of the following features (f) to (j) is included:

(f) The solvent used in the reaction is one or more of methanol, ethanol, isopropanol, tetrahydrofuran or dioxane, preferably one or two of isopropanol and tetrahydrofuran;

(g) Intermediate I, based on 1-C- (β -D-xylopyranosyl) -acetone molar amount: silane: the molar ratio of the catalyst is 1:1.0-1.5:0.01-0.1; preferably 1:1.1:0.05;

(h) The silane is one of trimethylsilane, triphenylsilane, triethylsilane, triethoxysilane and methylhydrosiloxane Polymer (PMHS); preferably trimethylsilane, triethylsilane or methylhydrosiloxane Polymers (PMHS);

(i) The catalyst is one or more of ferric chloride, ferric bromide, cupric chloride or ferric acetylacetonate; still further, ferric chloride is preferred;

(j) The reduction reaction is carried out under the condition of 0-15 ℃, and after the feeding temperature is stable, the reaction is carried out at 15-30 ℃; further, the preferable condition of the reduction reaction is that the material is fed at 10-15 ℃, and the material is reacted at room temperature after the feeding temperature is stable.

7. The method for synthesizing the high-quality (beta, S) -configured hydroxypropyl tetrahydropyran triol according to claim 1, wherein the specific preparation step of the step (3) is as follows:

the intermediate II reacts with desilication protective reagent, purified water is added, the water phase is extracted by ethyl acetate to remove organic impurities, and the water phase is decolorized by active carbon, exchanged by ion resin, concentrated and crystallized to obtain the hydroxypropyl tetrahydropyran triol solid with single (beta, S) configuration and high quality configuration.

8. The method for synthesizing high-quality (β, S) -configured hydroxypropyl tetrahydropyran triol according to claim 7, wherein in said step (3), at least one of the following features (k) to (n) is included:

(k) The desilication protecting reagent is one or more of hydrogen chloride alcohol solution, tetrabutylammonium fluoride, hexafluorosilicic acid, hydrofluoric acid or N-iodo succinimide; still further, an alcohol solution of hydrogen chloride or tetrabutylammonium fluoride is preferable;

(l) Concentrating, and recrystallizing with ethanol, water and ethyl acetate;

(m) intermediate II, based on 1-C- (β -D-xylopyranosyl) -acetone molar amount: the molar ratio of the desilication group protecting reagent is 1:4-12; still further, intermediate II: the molar ratio of the desilication group protecting reagent is 1:4-8;

(n) intermediate II is reacted at 0-30℃with the addition of a desilylation protecting reagent for 1-6 hours, more preferably at 25℃for 3 hours.