Preparation method of sofosbuvir intermediate isomer

Abstract

The invention provides a preparation method of a sofosbuvir intermediate isomer as shown in a formula (I), which comprises the following steps: S4, carrying out dihydroxylation reaction on a compound 4 in the presence of a first oxidant to obtain a compound 3; s5, carrying out condensation reaction on the compound 3 and thionyl chloride in the presence of alkali; then carrying out oxidation reaction in the presence of a second oxidant to obtain a compound 2; s6, carrying out fluorination reaction on the compound 2 and a fluorinating agent in the presence of alkali; then, under an acidic condition, hydrolysis is carried out, a cyclization reaction is further carried out, and a compound 1 is obtained; s7, the compound 1 and benzoyl chloride are subjected to an esterification reaction in the presence of alkali, and the compound shown in the formula (I) is obtained. The oriented preparation of the sofosbuvir can realize accurate qualitative and quantitative analysis of isomer impurities in the medicine, and by strengthening the control of the impurities, the risk of adverse reaction of the medicine can be reduced, and the guarantee is provided for the medication safety of sofosbuvir.

Description

Technical Field

[0001] This invention relates to the preparation of a pharmaceutical intermediate, specifically to a method for preparing a sofosbuvir intermediate isomer. Background Technology

[0002] Sofosbuvir is an antiviral drug developed by Pharmasset for the treatment of chronic hepatitis C virus (HCV) infection. In December 2013, sofosbuvir was approved by the U.S. FDA under the brand name Sovaldi. Sofosbuvir is indicated for the treatment of chronic hepatitis C virus (HCV) infection in adults aged 18 years and older, showing significant efficacy against HCV genotypes 1-6. This drug can be used alone or in combination with ribavirin (RBV) or pegylated interferon (PEG-IFN) to create a personalized treatment regimen.

[0003] The existing synthetic route for sofosbuvir is as follows.

[0004]

[0005] As shown in the above synthetic route, methyl ((2R,3R,4R)-3-(benzoyloxy)-4-fluoro-4-methyl-5-oxotetrahydrofuran-2-yl)benzoate (SFB-6) is a key intermediate in the synthesis of sofosbuvir, containing a chiral quaternary carbon center in its structure. During the synthesis of sofosbuvir intermediate SFB-6, stereoisomers are easily generated as impurities. These are difficult to distinguish from the main component due to their highly similar structure (only the chiral center configuration differs). Patent WO2014196491A1 discloses various impurity isomers of sofosbuvir intermediate SFB-6. The synthesis and research of SFB-6 impurity isomers are crucial for ensuring the quality control and clinical safety of sofosbuvir. Summary of the Invention

[0006] To address the aforementioned problems in the prior art, a method for preparing a sofosbuvir intermediate isomer is provided. This method can obtain the sofosbuvir intermediate impurity isomer shown in formula (I), which can be used for the quality control of sofosbuvir.

[0007] This invention provides a method for preparing the sofosbuvir intermediate isomer shown in formula (I), comprising the following steps:

[0008]

[0009] S4: Compound 4 undergoes a dihydroxylation reaction in the presence of the first oxidant to give compound 3;

[0010] S5: Compound 3 undergoes a condensation reaction with thionyl chloride in the presence of a base; then it undergoes an oxidation reaction in the presence of a second oxidizing agent to give compound 2;

[0011] S6: Compound 2, in the presence of a base, undergoes a fluorination reaction with a fluorinating agent; then, under acidic conditions, it undergoes hydrolysis and further cyclization to yield compound 1;

[0012] S7: Compound 1, in the presence of a base, undergoes an esterification reaction with benzoyl chloride to give compound (I).

[0013] Preferably, in step S4, the first oxidant is selected from one or more of AD-mix-α, osmium tetroxide-potassium ferrocyanide oxide system and RuCl3-sodium periodate oxide system.

[0014] Preferably, in step S5, the alkali is selected from organic alkali or inorganic alkali.

[0015] Preferably, the organic base is selected from one or more of pyridine, triethylamine, N,N-dimethylamine and quinoline.

[0016] Preferably, in step S5, the second oxidant is selected from one or more of sodium hypochlorite, potassium periodate, and sodium periodate.

[0017] Preferably, in step S6, the alkali is selected from organic or inorganic alkalis.

[0018] Preferably, the organic base is selected from one or more of pyridine, triethylamine, N,N-dimethylamine and quinoline.

[0019] Preferably, in step S6, the fluorinating agent is selected from one or more of triethylamine trihydrofluoride, triethylamine hydrofluoride, pyridinium hydrofluoride, and diethylaminosulfur trifluoride.

[0020] Preferably, in step S6, the hydrolysis is carried out with barium chloride in water.

[0021] Preferably, in step S6, the acidic reagent is selected from one or more of concentrated hydrochloric acid, concentrated sulfuric acid, and concentrated nitric acid.

[0022] Preferably, in step S7, the alkali is selected from organic or inorganic alkalis.

[0023] Preferably, the organic base is selected from one or more of pyridine, triethylamine, N,N-dimethylamine and quinoline.

[0024] Preferably, in step S7, the condensing agent for the esterification reaction is selected from one or more of 4-dimethylaminopyridine and 4-pyrrolidinylpyridine.

[0025] Preferably, the preparation method further includes the following steps:

[0026]

[0027] S3: Compound 5 reacts with phosphorus ylide reagent in a Wittig reaction to give compound 4.

[0028] Preferably, the preparation method further includes the following steps:

[0029]

[0030] S2: Compound 6 undergoes an oxidation reaction under alkaline conditions and in the presence of a third oxidizing agent to yield compound 5.

[0031] Preferably, in step S2, the reagent for the alkaline condition is selected from one or more of sodium bicarbonate, sodium sesquicarbonate, disodium hydrogen phosphate, sodium triphosphate, tetrasodium pyrophosphate, sodium citrate, calcium citrate, calcium carbonate, magnesium oxide, sodium gluconate, sodium lactate, sodium acetate, dipotassium hydrogen phosphate, tetrapotassium pyrophosphate, potassium bicarbonate, calcium lactate, calcium glycerophosphate, calcium gluconate, magnesium lactate, magnesium gluconate, and magnesium hydroxide.

[0032] Preferably, in step S2, the third oxidant is selected from one or more of potassium periodate and sodium periodate.

[0033] Preferably, the preparation method further includes the following steps:

[0034]

[0035] S1: Mannitol, in the presence of a catalyst, undergoes a condensation reaction with 2,2-dimethoxypropane to give compound 6.

[0036] Preferably, in step S1, the catalyst is selected from one or more of methanesulfonic acid, toluenesulfonic acid, p-toluenesulfonic acid, and trifluoromethanesulfonic acid.

[0037] The beneficial effects of this invention are as follows: It provides a method for preparing methyl benzoate ((2R,3S,4S)-3-(benzoyloxy)-4-fluoro-4-methyl-5-oxotetrahydrofuran-2-yl)benzoate, an intermediate isomer of sofosbuvir. This method allows for precise qualitative and quantitative analysis of isomeric impurities in the drug. By strengthening the control of this impurity, the risk of adverse drug reactions can be reduced, ensuring the safety of sofosbuvir. Simultaneously, this impurity reference standard can be used to study the mechanism of its influence on drug activity and toxic side effects, providing a basis for process optimization. Furthermore, the synthetic route of this invention is simple in design and the reaction steps are streamlined. The use of inexpensive and readily available materials, solvents, and reagents significantly reduces production costs and increases the yield of the final product, conforming to the principles of green chemistry. Attached Figure Description

[0038] Figure 1 This is a schematic diagram of the single-crystal structure of the compound of formula I prepared in this invention. Detailed Implementation

[0039] To make the technical solutions and beneficial effects of this disclosure more apparent and understandable, a detailed description is provided below by citing specific embodiments. The accompanying drawings are not necessarily drawn to scale, and local features may be enlarged or reduced to more clearly show the details of the local features; unless otherwise defined, the technical and scientific terms used herein have the same meanings as those in the technical field to which this application pertains.

[0040] This invention provides a method for preparing the sofosbuvir intermediate isomer shown in formula (I), comprising the following steps:

[0041]

[0042] S4: Compound 4 undergoes a dihydroxylation reaction in the presence of the first oxidant to give compound 3;

[0043] S5: Compound 3 undergoes a condensation reaction with thionyl chloride in the presence of a base; then it undergoes an oxidation reaction in the presence of a second oxidizing agent to give compound 2;

[0044] S6: Compound 2, in the presence of a base, undergoes a fluorination reaction with a fluorinating agent; then, under acidic conditions, it undergoes hydrolysis and further cyclization to yield compound 1;

[0045] S7: Compound 1, in the presence of a base, undergoes an esterification reaction with benzoyl chloride to give compound (I).

[0046] In some embodiments, in step S4, the first oxidant is selected from one or more of AD-mix-α, osmium tetroxide-potassium ferrocyanide oxide system, and RuCl3-sodium periodate oxide system.

[0047] In some embodiments, in step S4, the first oxidant is selected from AD-mix-α; AD-mix-α, through its specific cis-oxidation mechanism, has high selectivity and can yield compound 3.

[0048] In some embodiments, in step S5, the base is selected from organic or inorganic bases.

[0049] In some embodiments, the organic base is selected from one or more of pyridine, triethylamine, N,N-dimethylamine, and quinoline.

[0050] In some embodiments, the organic base is selected from triethylamine.

[0051] In some embodiments, in step S5, the second oxidant is selected from one or more of sodium hypochlorite, potassium periodate, and sodium periodate.

[0052] In some embodiments, in step S5, the second oxidant is selected from sodium hypochlorite.

[0053] In some embodiments, in step S6, the base is selected from organic or inorganic bases.

[0054] In some embodiments, the organic base is selected from one or more of pyridine, triethylamine, N,N-dimethylamine, and quinoline.

[0055] In some embodiments, the organic base is selected from triethylamine.

[0056] In some embodiments, in step S6, the fluorinating agent is selected from one or more of triethylamine trihydrofluoride, triethylamine fluoride, pyridinium hydrofluoride, and diethylaminosulfur trifluoride.

[0057] In some embodiments, in step S6, the fluorinating agent is selected from triethylamine trihydrofluoride.

[0058] In some embodiments, in step S6, the hydrolysis is carried out with barium chloride in water.

[0059] In some embodiments, in step S6, the acidic reagent is selected from one or more of concentrated hydrochloric acid, concentrated sulfuric acid, and concentrated nitric acid.

[0060] In some embodiments, in step S6, the acidic reagent is selected from concentrated hydrochloric acid.

[0061] In some embodiments, in step S7, the base is selected from organic or inorganic bases.

[0062] In some embodiments, the organic base is selected from one or more of pyridine, triethylamine, N,N-dimethylamine, and quinoline.

[0063] In some embodiments, the organic base is selected from triethylamine.

[0064] In some embodiments, in step S7, the condensing agent for the esterification reaction is selected from one or more of 4-dimethylaminopyridine and 4-pyrrolidinylpyridine.

[0065] In some embodiments, in step S7, the condensing agent for the esterification reaction is selected from 4-dimethylaminopyridine.

[0066] In some embodiments, in step S7, the condensing agent for the esterification reaction is selected from 4-pyrrolidinylpyridine.

[0067] In some embodiments, the preparation method further includes the following steps:

[0068]

[0069] S3: Compound 5 reacts with phosphorus ylide reagent in a Wittig reaction to give compound 4.

[0070] In some embodiments, the preparation method further includes the following steps:

[0071]

[0072] S2: Compound 6 undergoes an oxidation reaction under alkaline conditions and in the presence of a third oxidizing agent to yield compound 5.

[0073] In some embodiments, in step S2, the reagent for the alkaline condition is selected from one or more of sodium bicarbonate, sodium sesquicarbonate, disodium hydrogen phosphate, sodium triphosphate, tetrasodium pyrophosphate, sodium citrate, calcium citrate, calcium carbonate, magnesium oxide, sodium gluconate, sodium lactate, sodium acetate, dipotassium hydrogen phosphate, tetrapotassium pyrophosphate, potassium bicarbonate, calcium lactate, calcium glycerophosphate, calcium gluconate, magnesium lactate, magnesium gluconate, and magnesium hydroxide.

[0074] In some embodiments, in step S2, the reagent for the alkaline condition is selected from sodium bicarbonate.

[0075] In some embodiments, in step S2, the third oxidant is selected from one or more of potassium periodate and sodium periodate.

[0076] In some embodiments, in step S2, the third oxidant is selected from sodium periodate.

[0077] In some embodiments, the preparation method further includes the following steps:

[0078]

[0079] S1: Mannitol, in the presence of a catalyst, undergoes a condensation reaction with 2,2-dimethoxypropane to give compound 6.

[0080] In some embodiments, in step S1, the catalyst is selected from one or more of methanesulfonic acid, toluenesulfonic acid, p-toluenesulfonic acid, and trifluoromethanesulfonic acid.

[0081] In some embodiments, in step S1, the catalyst is selected from p-toluenesulfonic acid.

[0082] In some embodiments, the preparation method is carried out in an organic solvent.

[0083] In some embodiments, the organic solvent is selected from one or more of acetonitrile, dichloromethane, 2-methyltetrahydrofuran, acetone, methanol, toluene, ethylene glycol, tetrahydrofuran, anhydrous ethanol, 1,4-dioxane, ethyl acetate, isopropyl acetate, ethylene glycol dimethyl ether, isopropanol, n-hexane, and methyl tert-butyl ether.

[0084] The method of the present invention will be described below through specific embodiments. It should be understood that these embodiments are used to illustrate the basic principles, main features and advantages of the present invention, and the present invention is not limited to the scope of the following embodiments. The implementation conditions used in the embodiments can be further adjusted according to specific requirements, and the implementation conditions not specified are usually the conditions in conventional experiments.

[0085] In the following examples, unless otherwise specified, all temperatures are in Celsius, and unless otherwise specified, all starting materials and reagents are commercially available or synthesized according to known methods. Commercially available materials and reagents are used directly without further purification.

[0086] Unless otherwise specified in the examples, the solution in the reaction refers to an aqueous solution.

[0087] Unless otherwise specified in the examples, the reaction temperature is room temperature, which is 20℃~30℃.

[0088] The following embodiments are provided to better understand the present invention and are not limited to the preferred embodiments described. They do not constitute a limitation on the content and scope of protection of the present invention. Any product that is the same as or similar to the present invention, derived by any person under the guidance of the present invention or by combining the features of the present invention with other prior art, falls within the protection scope of the present invention.

[0089] Main instruments

[0090] Waters Q-TOF micro mass spectrometer; Bruker TENSOR 27 infrared spectrometer (KBr pellet method); BRUKER AV-500 nuclear magnetic resonance spectrometer (CDCl3 as solvent, TMS as internal standard); Bruker Smart Apex II X-ray single crystal diffractometer.

[0091] Example 1: Synthesis of 1,2-bis(2,2-dimethyl-1,3-dioxapentan-4-yl)ethane-1,2-diol (compound 6)

[0092]

[0093] 110 g of dimethyl sulfoxide was added to a 500 mL reaction flask and stirred. Then, 100 g (0.55 mol) of mannitol, 0.5 g of p-toluenesulfonic acid, and 135.5 g of 2,2-dimethoxypropane were added. The reaction was allowed to proceed to completion at room temperature. The reaction solution was neutralized with 0.4 g of triethylamine and stirred. 200 g of water was added, and the mixture was extracted with 400 mL of ethyl acetate. The extract was separated, and then extracted with 200 mL of ethyl acetate. The extracts were combined and washed successively with 200 mL of water and 200 mL of saturated sodium chloride solution. The mixture was separated, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure at 50 °C to obtain a white solid. 216 g of methyl tert-butyl ether was added, and the mixture was stirred at 50 °C for 1 h. The temperature was lowered to 30 °C, and 297 g of n-hexane was added dropwise. The mixture was stirred for 1 h, and then cooled to 10 °C to crystallize. The crystals were filtered and dried under blast at 50 °C to obtain 50.3 g of white solid compound 6.

[0094] Example 2: Synthesis of (S,E)-3-(2,2-dimethyl-1,3-dioxapentan-4-yl)-2-methylacrylate (compound 4)

[0095]

[0096] Add 250 mL of dichloromethane and 50 g of compound 6 to a 500 mL reaction flask, stir, add 25 mL of saturated sodium bicarbonate solution, cool to 2 °C, add 49 g of sodium periodate in portions, maintain the temperature at 15-20 °C, after the addition is complete, control the temperature and react for 2 hours. After the reaction is complete, add 31 g of anhydrous sodium sulfate, stir and dry for 10 min, filter, wash the filter cake with a small amount of dichloromethane, dry under vacuum, combine the filtrates and add to the reaction flask, stir, add 145.2 g of phosphorus ylide, react at room temperature and pass through the solution, after the reaction is complete, concentrate under reduced pressure at 40 °C, distill twice with 100 mL of n-hexane, concentrate, then wash twice with 400 mL of n-hexane, filter, combine the filtrates and concentrate under reduced pressure at 50 °C to obtain 73.8 g of oily compound 4.

[0097] Example 3: Synthesis of (4R,5S)-5-((R)-2,2-dimethyl-1,3-dioxolane-4-yl)-4-methyl-1,3,2-dioxothiacyclopentane-4-carboxylic acid ethyl ester 2,2-dioxide (compound 2)

[0098]

[0099] Add 28g of AD-mix-α to 100mL of tert-butanol, add 100mL of water, cool to 0℃, add 21g of compound 4, keep the reaction at this temperature until complete, stop the reaction, add 400mL of ethyl acetate and 200mL of purified water, stir at room temperature for 10min, let stand and separate the layers, extract the aqueous phase with 100mL*3 ethyl acetate, separate the layers, combine the organic layers, dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure at 50℃ to dryness, and obtain compound 3. To concentrate compound 3, add 30 mL of isopropyl acetate and 6 mL of acetonitrile, stir, add 8.58 g of triethylamine, cool to 0–5 °C, add 5.7 g of thionyl chloride dropwise, and after the addition is complete, keep the reaction at this temperature for 30 min. After the reaction is complete, add 30 mL of purified water, stir for 30 min, let stand and separate the layers. Extract the aqueous layer once with 50 mL of isopropyl acetate, separate the layers, combine the organic layers, wash successively with 50 mL of saturated sodium bicarbonate solution and saturated sodium chloride solution, separate the layers, add 6 mL of acetonitrile and 3 g of sodium bicarbonate to the organic layer, stir, add 50 mL of sodium hypochlorite solution dropwise, stir and react for 1 hour, after the reaction is complete, quench the reaction with 5 mL of saturated sodium sulfite solution, let stand and separate the layers, wash with 5 mL of saturated sodium bicarbonate solution, separate the layers, dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure at 50 °C to dryness, and obtain 6.4 g of oily compound 2.

[0100] Example 4: Synthesis of methyl benzoate ((2R,3S,4S)-3-(benzoyloxy)-4-fluoro-4-methyl-5-oxotetrahydrofuran-2-yl)benzoate (compound of formula (I))

[0101]

[0102] Add 2.5g of triethylamine, 6.4g of triethylamine trihydrofluoride, and 6.4g of compound 2 to a 100mL reaction flask, stir, and heat to 85℃. After the reaction is complete, add 2mL of concentrated hydrochloric acid, stir for 30min, and concentrate to dryness under reduced pressure at 50℃. Add 6g of barium chloride and 15mL of purified water to the residue, heat to 85-90℃, and stir to maintain the temperature until the reaction is complete. Stop heating, concentrate to dryness under reduced pressure at 50℃ to obtain compound 1. To the concentrated compound 1, 100 mL of acetonitrile and 0.2 g of 4-dimethylaminopyridine were added, stirred, and 8.5 g of benzoyl chloride was added. The mixture was cooled to 0–5 °C, and 8.5 g of triethylamine was added dropwise. After the addition was complete, the mixture was allowed to react at room temperature until complete. 300 mL of isopropyl acetate was added, and the mixture was stirred for 1 h. The mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure at 50 °C. 300 mL of isopropyl acetate was added, and the mixture was washed successively with 200 mL of saturated sodium bicarbonate solution and saturated sodium chloride solution. The mixture was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure at 50 °C to obtain the crude product. After purification by column chromatography, the product was purified by pre-liquid chromatography to obtain 1.28 g of white solid compound (I).

[0103] 1H NMR (CDCl3, 500MHz) δ: 8.09~8.01 (m, 2H), 8.01~7.94 (m, 2H), 7.61~7.52 (m, 2H), 7.52~7.35 (m, 4H), 5.90~5.69 (t, J=4.3Hz, 1H,), 5.09~4.94 (q, J=5.25Hz, 1H), 4.78~4.61 (d, J=5.30Hz, 2H), 1.89~1.70 (d, J=22.25Hz, 3H).

[0104] 13 C NMR (CDCl3, 500MHz) δ: 170.79, 170.59, 165.92, 164.94, 134.07, 133.51, 130.00, 129.78, 129.02, 12 8.70, 128.48, 128.10, 91.11, 89.49, 77.25, 77.00, 76.75, 75.98, 72.77, 72.65, 61.85, 19.53, 19.32.

[0105] Example 5: Identification of the structure of compound (I)

[0106] The obtained compound of formula (I) was subjected to X-ray single-crystal diffraction test, and the Flack constant was measured to be 0.06 (8), and its absolute configuration was determined to be 9R, 10S, 13S, as shown in the figure. Figure 1 The specific crystal data is shown in Table 1 below.

[0107] Table 1 Crystal data for compound (I)

[0108]

[0109] It should be understood that the above embodiments are exemplary and are not intended to encompass all possible implementations included in the claims. Various modifications and changes can be made to the above embodiments without departing from the scope of this disclosure. Similarly, the various technical features of the above embodiments can be arbitrarily combined to form other embodiments of the present invention that may not be explicitly described. Therefore, the above embodiments only illustrate several implementations of the present invention and do not limit the scope of protection of this patent.

Claims

1. A method for preparing a sofosbuvir intermediate isomer as shown in formula (I), characterized in that, Includes the following steps: S4: Compound 4 undergoes a dihydroxylation reaction in the presence of the first oxidant to give compound 3; S5: Compound 3 undergoes a condensation reaction with thionyl chloride in the presence of a base; then it undergoes an oxidation reaction in the presence of a second oxidizing agent to give compound 2; S6: Compound 2, in the presence of a base, undergoes a fluorination reaction with a fluorinating agent; then, under acidic conditions, it undergoes hydrolysis and further cyclization to yield compound 1; S7: Compound 1, in the presence of a base, undergoes an esterification reaction with benzoyl chloride to give compound (I).

2. The preparation method according to claim 1, characterized in that, In step S4, the first oxidant is selected from one or more of AD-mix-α, osmium tetroxide-potassium ferrocyanide oxide system and RuCl3-sodium periodate oxide system.

3. The preparation method according to claim 1, characterized in that, In step S5, the base is selected from organic or inorganic bases; and / or, The organic base is selected from one or more of pyridine, triethylamine, N,N-dimethylamine, and quinoline; and / or, In step S5, the second oxidant is selected from one or more of sodium hypochlorite, potassium periodate, and sodium periodate.

4. The preparation method according to claim 1, characterized in that, In step S6, the base is selected from organic or inorganic bases; and / or, The organic base is selected from one or more of pyridine, triethylamine, N,N-dimethylamine, and quinoline; and / or, In step S6, the fluorinating agent is selected from one or more of triethylamine trifluoride, triethylamine hydrofluoric acid, pyridinium hydrofluoric acid, and diethylaminosulfur trifluoride; and / or, In step S6, the hydrolysis is carried out with barium chloride in water; and / or, In step S6, the acidic reagent is selected from one or more of concentrated hydrochloric acid, concentrated sulfuric acid, and concentrated nitric acid.

5. The preparation method according to claim 1, characterized in that, In step S7, the base is selected from organic or inorganic bases; and / or, The organic base is selected from one or more of pyridine, triethylamine, N,N-dimethylamine, and quinoline; and / or, In step S7, the condensing agent for the esterification reaction is selected from one or more of 4-dimethylaminopyridine and 4-pyrrolidinylpyridine.

6. The preparation method according to claim 1, characterized in that, The preparation method further includes the following steps: S3: Compound 5 reacts with phosphorus ylide reagent in a Wittig reaction to give compound 4.

7. The preparation method according to claim 6, characterized in that, The preparation method further includes the following steps: S2: Compound 6 undergoes an oxidation reaction under alkaline conditions and in the presence of a third oxidizing agent to yield compound 5.

8. The preparation method according to claim 7, characterized in that, In step S2, the reagent for the alkaline condition is selected from one or more of sodium bicarbonate, sodium sesquicarbonate, disodium hydrogen phosphate, sodium triphosphate, tetrasodium pyrophosphate, sodium citrate, calcium citrate, calcium carbonate, magnesium oxide, sodium gluconate, sodium lactate, sodium acetate, dipotassium hydrogen phosphate, tetrapotassium pyrophosphate, potassium bicarbonate, calcium lactate, calcium glycerophosphate, calcium gluconate, magnesium lactate, magnesium gluconate, and magnesium hydroxide; and / or, In step S2, the third oxidant is selected from one or more of potassium periodate and sodium periodate.

9. The preparation method according to claim 7, characterized in that, The preparation method further includes the following steps: S1: Mannitol, in the presence of a catalyst, undergoes a condensation reaction with 2,2-dimethoxypropane to give compound 6.

10. The preparation method according to claim 9, characterized in that, In step S1, the catalyst is selected from one or more of methanesulfonic acid, toluenesulfonic acid, p-toluenesulfonic acid, and trifluoromethanesulfonic acid.

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