Synthetic method of L-mannose

Abstract

The invention discloses a synthesis method of L-mannose, and belongs to the technical field of sugar chemistry. The synthesis method comprises the following steps: by taking 1, 2, 3, 4, 6-penta-O-acetyl-beta-L-glucopyranose as a raw material, carrying out five-step continuous feeding reaction, sequentially using PCl5, DMF (Dimethyl Formamide), water, acetic anhydride, sodium borohydride and sodium methoxide, and separating after monitoring that the raw material disappears, thereby finally obtaining the L-mannose. The method overcomes the difficulty of preparing the L-mannose by a traditional method, and promotes the development and application of the functions of the L-mannose. According to the method disclosed by the invention, commercialized beta-pentaacetyl-L-glucopyranose which is easy to obtain is taken as a starting raw material, and the L-mannose is efficiently obtained through five-step continuous feeding conversion. The method is safe and simple to operate, easy to purify, low in cost and suitable for large-scale production, so that application and development of the L-mannose can be promoted.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of sugar chemistry, and particularly relates to a synthesis method of L-mannose. BACKGROUND

[0002] L-mannose (I) is a mirror image isomer of natural D-mannose (II) and has a very low content in nature. L-mannose and its derivatives have important application values in the research of mirror image biology and the development of active drugs. Due to the great difficulty in obtaining, especially the high price of commercial L-mannose, the development and research of the application thereof are limited.

[0003] In the existing chemical synthesis technology, L-mannose can be synthesized from bispropyl-D-glucose as a raw material in 7 steps (Tetrahedron Letters, 2000, 41, 3119-3122), and the total yield is less than 30%, and it is difficult to scale up the preparation. In addition, there are other total synthesis methods (J. Org. Chem. 2018, 83, 2647-2659), and it is also difficult to synthesize L-mannose in large quantities due to the complicated steps. SUMMARY

[0004] The purpose of the present application is to provide a synthesis method of L-mannose, which solves the problem of complicated steps in the prior art for preparing L-mannose. The present application uses commercially available beta-pentaacetyl-L-glucopyranose (CAS: 66966-07-2) as a starting material, and L-mannose is obtained through 5 steps of continuous conversion with high efficiency. The method is safe and simple to operate, easy to purify, low in cost, and suitable for scale-up production, so as to promote the application and development of L-mannose. The present application provides a synthesis method of L-mannose, comprising the following steps: Step 1, 1, 2, 3, 4, 6-penta-O-acetyl-beta-L-glucopyranose is mixed with PCl5 in dichloromethane at a molar ratio of 1:1-2.5 at-10℃-0℃, and the reaction is warmed to room temperature, and the reaction is stopped after the disappearance of the raw material is monitored, and the reaction system is cooled to-10℃-0℃, and the intermediate 1 is separated and obtained, and directly connected to the next step; Step 2, the intermediate 1 is dissolved in acetone, 1:4 volume ratio of DMF and water is added, the volume ratio of DMF to acetone is 1:100, and the reaction is carried out at room temperature, and the intermediate 2 is separated and obtained after the disappearance of the raw material is monitored, and directly connected to the next step; Step 3, the intermediate 2 is reacted with acetic anhydride in DMSO, and the amount of acetic anhydride added is 5-10 times the molar amount of 1, 2, 3, 4, 6-penta-O-acetyl-beta-L-glucopyranose; the intermediate 3 is separated and obtained after the disappearance of the raw material is monitored, and directly connected to the next step; Step 4, intermediate 3 is reacted with sodium borohydride in methanol, the amount of sodium borohydride added is 1-5 times the molar amount of 1,2,3,4,6-penta-O-acetyl-beta-L-glucopyranose; after monitoring the disappearance of the raw material, intermediate 4 is separated and directly connected to the next step; Step 5, intermediate 4 is reacted with sodium methoxide in methanol at room temperature, the molar ratio of sodium methoxide to 1,2,3,4,6-penta-O-acetyl-beta-L-glucopyranose is 1:10-20; after monitoring the end of the reaction, L-mannose is obtained by separation and purification; The reaction scheme is as follows: .

[0005] By the above technical solutions, the beneficial effects of the present application are as follows: The present application uses easily available commercial 1,2,3,4,6-penta-O-acetyl-beta-L-glucopyranose as the starting material, and through 5-step continuous conversion, the modification of L-glucose 2-OH is completed with high efficiency to obtain L-mannose product, overcoming the difficulties in preparing L-mannose by traditional methods. The method of the present application is simple, low in cost and high in yield, and is suitable for large-scale production. BRIEF DESCRIPTION OF DRAWINGS

[0006] Figure 1 The chemical structure diagram of L-mannose (I) and D-mannose (II) provided for the embodiments of the present application; Figure 2 The synthesis route diagram of L-mannose provided for the embodiments of the present application; Figure 3 The nuclear magnetic hydrogen spectrum diagram of L-mannose provided for the embodiments of the present application; Figure 4 The nuclear magnetic carbon spectrum diagram of L-mannose provided for the embodiments of the present application; Figure 5 The high-performance liquid chromatogram of L-mannose (sample number: 2207-28) provided for the embodiments of the present application; Figure 6 The high-resolution mass spectrum detection diagram of L-mannose (sample number: 2207-28) provided for the embodiments of the present application; Figure 7 The chemical structure diagram of L-mannose (I) and L-mannose (III) being mutual tautomers (the same compound), and D-mannose (II) and D-mannose (IV) being mutual tautomers (the same compound). DETAILED DESCRIPTION

[0007] In order to fully illustrate the preparation idea of the present application, the process of the present application is described below in combination with specific examples, and the examples are only for illustration, and should not be interpreted or understood as a limitation on the protection of the present application. In addition, all materials used in the experiments of the present application are commercially available products unless otherwise specified.

[0008] In the examples of the present application, continuous feeding refers to that the intermediate does not need to be purified and is directly used in the next step reaction.

[0009] As shown in the following formula, L-mannose (I) and L-mannose (III) are tautomers of each other, and both belong to the same compound; D-mannose (II) and D-mannose (IV) are tautomers of each other, and both belong to the same compound. Figure 7

[0010] As shown in the following formula, L-mannose (I) and L-mannose (III) are tautomers of each other, and both belong to the same compound; D-mannose (II) and D-mannose (IV) are tautomers of each other, and both belong to the same compound. Figure 2

[0011] The above preparation method comprises the following steps: (1) 1,2,3,4,6-penta-O-acetyl-beta-L-glucopyranose and PCl5 are mixed in dichloromethane at a molar ratio of 1:1-2.5 at -10°C-0°C, and the reaction is carried out at room temperature. The reaction is stopped after the disappearance of the raw material is monitored, the reaction system is cooled to -10°C-0°C, and the intermediate 1 is separated and obtained, which is directly continuously fed into the next step reaction; Specifically, the separation step is: saturated sodium bicarbonate ice water solution is added to the reaction system to be weakly alkaline, the organic phase is separated by standing, and the solvent is distilled out of the organic phase under reduced pressure to obtain the oily intermediate 1.

[0012] (2) The intermediate 1 is dissolved in acetone, 1:4 volume ratio of DMF and water is added, and the volume ratio of DMF and acetone is 1:100, and the reaction is carried out at room temperature. After the disappearance of the raw material is monitored, the intermediate 2 is separated and obtained, which is directly continuously fed into the next step reaction; Specifically, the separation step is: the reaction system is removed under reduced pressure to obtain an oily substance, which is then dissolved in an equal volume of dichloromethane as the reaction solvent, washed with saturated brine, and the organic phase is separated by standing. The organic phase is washed once more, and the solvent is distilled out of the organic phase under reduced pressure to obtain the oily intermediate 2.

[0013] (3) The intermediate 2 and acetic anhydride are reacted in DMSO, and the molar amount of acetic anhydride is 5-10 times that of 1,2,3,4,6-penta-O-acetyl-beta-L-glucopyranose; After the disappearance of the raw material is monitored, the intermediate 3 is separated and obtained, which is directly continuously fed into the next step reaction; Specifically, the separation step is: the reaction system is diluted with 4-5 times the volume of dichloromethane, then adjusted to weak alkalinity with saturated sodium bicarbonate solution, and the organic phase is separated by standing. The solvent is removed.

[0014] ​​(4) intermediate 3 and sodium borohydride are reacted in methanol, the molar amount of sodium borohydride is 1-5 times of 1,2,3,4,6-penta-O-acetyl-beta-L-glucopyranose; after monitoring the disappearance of raw materials, intermediate 4 is separated and directly connected to the next step; Specifically, the separation step is: pouring the reaction system into 0-4°C, 1N hydrochloric acid solution, then extracting with dichloromethane, separating the dichloromethane phase to obtain a dry dichloromethane phase, and removing the solvent; wherein the ratio of hydrochloric acid solution to 1,2,3,4,6-penta-O-acetyl-beta-L-glucopyranose is 2 mL:1 g, and the ratio of dichloromethane to 1,2,3,4,6-penta-O-acetyl-beta-L-glucopyranose is 5 mL:1 g.

[0015] (5) intermediate 4 and sodium methoxide are reacted in methanol at room temperature, the amount of sodium methoxide added is 1:10-20 times of the molar amount of 1,2,3,4,6-penta-O-acetyl-beta-L-glucopyranose; after monitoring the end of the reaction, the product L-mannose is separated and purified.

[0016] The present application is further described below in conjunction with examples and drawings, but the present application is not limited by the following examples. Unless otherwise specified, room temperature refers to 10-30°C; low temperature refers to not higher than 5°C, especially -10-5°C; ice water is 0-4°C; weakly basic pH is 7.1-8.5.

[0017] Example 1 Synthesis of L-mannose (1) 10.0 g (25.6 mmol) of beta-pentaacetyl-L-glucopyranose is added to 100 mL of dichloromethane under stirring, the system is uniformly cooled to below -5°C, then 11.7 g (56.4 mmol) of PCl5 is added in batches, the temperature of the system is controlled below -5°C during the addition process. After the addition is completed, the temperature of the system is raised to 25°C, then the stirring reaction is continued for 6 hours. After the disappearance of the raw material point is detected by TLC (developing agent 1 / 1 ethyl acetate / petroleum ether), the system is cooled to below -5°C, then slowly poured into a vigorously stirred saturated sodium bicarbonate ice water solution, stirred for 30 minutes, the system is detected to be weakly alkaline (pH=7.1-8.5), then allowed to stand to separate the organic phase. After the solvent is removed by reduced pressure concentration, the obtained oily intermediate 1 is directly connected to the next step.

[0018] (2) The oily intermediate 1 of step 1 is dissolved in 100 mL of acetone at room temperature, 4 mL of water and 1 mL of DMF are added to the system, then the system is stirred and reacted at room temperature, after about 6 hours, the disappearance of the raw material point is detected by TLC (developing agent 1 / 1 ethyl acetate / petroleum ether), the system is concentrated by reduced pressure to remove the solvent, the obtained oily substance is dissolved in 100 mL of dichloromethane, washed with saturated brine twice, then the organic phase is separated, concentrated by reduced pressure to remove the solvent to obtain oily intermediate 2 which is directly connected to the next step.

[0019] (3) Dissolve the oily intermediate 2 from step 2 in 10 mL of DMSO and 10 mL of acetic anhydride, stir the reaction at room temperature until TLC (1 / 1 ethyl acetate / petroleum ether) shows no starting material. Dilute the reaction with 100 mL of dichloromethane and pour into a stirred saturated aqueous sodium bicarbonate solution until the solution is weakly basic (pH = 7.1-8.5). Separate the dichloromethane layer and concentrate under reduced pressure to remove the solvent to give the oily intermediate 3 which is used in the next step without further purification.

[0020] (4) Dissolve the oily intermediate 3 from step 3 in 100 mL of methanol and stir the solution while cooling to below -5°C. Add 4.91 g (130 mmol) of sodium borohydride in portions and stir the reaction at below -5°C for 30 minutes and then at room temperature for about 6 hours. TLC (1 / 1 ethyl acetate / petroleum ether) shows no starting material. Pour the reaction into a stirred solution of 1 N aqueous hydrochloric acid in ice water and stir for 30 minutes. Extract the aqueous layer with 100 mL of dichloromethane three times. Combine the dichloromethane layers and concentrate under reduced pressure to remove the solvent to give the oily intermediate 4 which is used in the next step without further purification.

[0021] (5) Dissolve the oily intermediate 4 from step 4 in 50 mL of methanol and add 50 mg (0.92 mmol) of sodium methoxide. Stir the reaction at room temperature for 1 hour. HPLC shows no starting material or intermediates. Neutralize the reaction with Dowex 50W-X8 acid resin. Filter the acid resin and concentrate the filtrate under reduced pressure until no distillate is collected. Add 10 mL of methanol and 20 mL of tert-butyl methyl ether to the residue and stir the mixture for 1 hour. White insoluble material is formed. Cool the mixture to 0°C and stir for 1 hour. Filter the white powder and dry the product at 40-50°C with a hot air stream until the mass is constant. Weigh the product to give 2.58 g of product (sample number: 2207-28) with a total yield of 56%. The product has a HPLC purity of 100% (ELSD).

[0022] The above product has 1 H NMR, 13 C NMR and HRMS spectra as shown in Figure 3 , 4 , 6, respectively: 1H NMR (400 MHz, D2O) δ: 5.15 (d, 0.63 H, J = 0.8 Hz), 4.87 (s, 0.38 H), 3.91-3.86 (m, 1 H), 3.86-3.85 (d, 0.43 H, J = 2 Hz), 3.83-3.82 (m, 0.65 H), 3.80-3.76 (m, 1.08 H), 3.74-3.67 (m, 1 H), 3.64-3.59 (m, 1 H), 3.56-3.51 (t, 0.38 H, J = 9.6 Hz), 3.37-3.32 (m, 0.35 H); 13 C NMR (101 MHz, D2O) δ: 94.11, 93.75, 76.24, 73.13, 72.47, 71.30, 70.76, 70.71, 70.31, 66.94, 66.69, 61.05.

[0023] The hydrogen and carbon spectra are consistent with the literature Indium- and Zinc-Mediated Acyloxyallylation of Protected and Unprotected Aldotetroses-Revealing a Pronounced Diastereodivergence and a Fundamental Difference in the Performance of the Mediating Metal. Journal of Organic Chemistry, 2018, 83(5), 2647-2659.

[0024] HRMS (ESI, m / z) calculated for C6H 12 ClO6 [M+H] + : 215.0322, found 215.0327; molecular formula C6H 12 O6. (Table 2 is the mass spectrum report.) Specific optical rotation [a]20 / D = -14.1° (c = 1, H2O), the specific optical rotation [a]20 / D of the commercially available L-mannose product specification: -15.5° ~ -13.5°.

[0025] The above L-mannose sample was prepared into a 50 mg / mL solution with acetonitrile / water as solvent in a volume ratio of 80:20 for HPLC detection. The chromatographic conditions are as follows: Column: Durashell NH2, φ4.6x250mmx5μm; Column temperature: 40℃; Mobile phase: acetonitrile / water = 80:20; Flow rate: 1.0 mL / min; Detector: Evaporative light scattering detector (ELSD).

[0026] The HPLC chart of L-mannose sample is shown in Figure 1, and the peak time is about 5.49 min. According to the area normalization method, the content is 100% (Table 1 is the liquid phase detection method). Figure 5 Example 2 Synthesis of L-mannose (1) 500 grams (1.28 mol) of beta-pentaacetyl-L-glucopyranose was added to 5 liters of dichloromethane under stirring, and the system was uniformly cooled to below -5℃, then 585 grams (2.82 mol) of PCl5 was added in batches, and the system temperature was controlled below -5℃ during the addition. After the addition was completed, the system temperature was raised to 25℃, then the stirring reaction was continued for 6 hours. After the raw material point disappeared by TLC detection (developing agent 1 / 1 ethyl acetate / petroleum ether), the system was cooled to below -5℃, then slowly poured into a vigorously stirred saturated sodium bicarbonate ice water solution, stirred for 30 minutes, and the system was detected to be weakly alkaline (pH = 7.1-8.5), then the organic phase was separated by standing. After the solvent was removed by reduced pressure concentration, the obtained oily intermediate 1 was directly used in the next step.

[0027] (2) The oily intermediate 1 of step 1 was dissolved in 5 liters of acetone at room temperature, 200 ml of water and 50 ml of DMF were added to the system, then the system was stirred at room temperature for about 6 hours, and the raw material point disappeared by TLC detection (developing agent 1 / 1 ethyl acetate / petroleum ether). The system was concentrated by reduced pressure to remove the solvent, and the obtained oily substance was dissolved in 5 liters of dichloromethane, washed twice with saturated brine, then the organic phase was separated, and the solvent was removed by reduced pressure concentration to obtain oily intermediate 2 which was directly used in the next step.

[0028] (3) The oily intermediate 2 of step 2 was dissolved in 500 ml of DMSO and 500 ml of acetic anhydride, and the stirring reaction was carried out at room temperature until the raw material point disappeared by TLC detection (developing agent 1 / 1 ethyl acetate / petroleum ether), then the system was diluted with 5 liters of dichloromethane, poured into a saturated sodium bicarbonate aqueous solution, and stirred to neutralize to weak alkaline (pH = 7.1-8.5). The dichloromethane phase was separated by standing, and the solvent was removed by reduced pressure concentration to obtain oily intermediate 3 which was directly used in the next step.

[0029] ​(4) Dissolve the oily intermediate 3 from step 3 in 5 liters of methanol, cool the mixture to below -5°C with stirring, then add 245.5 grams (6.5 moles) of sodium borohydride powder in portions, stir the reaction at below -5°C for 30 minutes, then allow the reaction to proceed at room temperature for about 6 hours. When the starting material spot disappears by TLC test (developing agent 1 / 1 ethyl acetate / petroleum ether), pour the mixture into 1 N hydrochloric acid solution in ice water, stir the mixture for 30 minutes, then extract the aqueous phase with dichloromethane three times, each time using 5 liters of dichloromethane. Combine the three dichloromethane phases, and concentrate under reduced pressure to remove the solvent to obtain the oily intermediate 4, which is directly used in the next step.

[0030] (5) Dissolve the oily intermediate 4 from step 4 in 2.5 liters of methanol, add 2.5 grams (46 mmol) of sodium methoxide, and stir the mixture at room temperature for 1 hour. When there is no starting material or intermediate by HPLC test, add Dowex 50W-X8 acidic resin to neutralize the mixture to neutral. After removing the acidic resin by filtration, concentrate the mixture under reduced pressure until no fraction is left, then add 500 milliliters of methanol and 1 liter of methyl tert-butyl ether to the concentrated residue, and stir the mixture for 1 hour. White insoluble substances are produced. Cool the mixture to 0°C, continue stirring for 1 hour, then filter to obtain the white powder product. Dry the product at 40-50°C with hot air until the weight is constant (i.e., the mass is constant), then weigh to obtain 129.0 grams of product, with a total yield of 56%. The product has a purity of 100% by HPLC test (ELSD).

[0031] Example 3 Synthesis of L-mannose (1) Add 1000 grams (2.56 moles) of beta-pentaacetyl-L-glucopyranose to 10 liters of dichloromethane with stirring, cool the mixture to below -5°C, then add 1170 grams (5.64 moles) of PCl5 in portions, controlling the temperature of the mixture below -5°C during the addition. After the addition is completed, allow the temperature of the mixture to rise to 25°C, then continue stirring the reaction for 6 hours. When the starting material spot disappears by TLC test (developing agent 1 / 1 ethyl acetate / petroleum ether), cool the mixture to below -5°C, then slowly pour the mixture into a vigorously stirred saturated sodium bicarbonate solution in ice water. Stir the mixture for 30 minutes, and test the mixture to be weakly alkaline (pH = 7.1-8.5), then allow the mixture to stand to separate the organic phase. Concentrate the mixture under reduced pressure to remove the solvent to obtain the oily intermediate 1, which is directly used in the next step.

[0032] (2) Dissolve the oily intermediate 1 from step 1 in 10 liters of acetone at room temperature, add 400 milliliters of water and 100 milliliters of DMF to the mixture, then stir the mixture at room temperature for about 6 hours. When the starting material spot disappears by TLC test (developing agent 1 / 1 ethyl acetate / petroleum ether), concentrate the mixture under reduced pressure to remove the solvent. Dissolve the obtained oily substance in 10 liters of dichloromethane, wash the mixture with saturated brine twice, then separate the organic phase. Concentrate the mixture under reduced pressure to remove the solvent to obtain the oily intermediate 2, which is directly used in the next step.

[0033] (3) Dissolve the oily intermediate 2 from step 2 in 1 liter of DMSO and 1 liter of acetic anhydride, stir the reaction at room temperature until TLC (1 / 1 ethyl acetate / petroleum ether) shows no starting material. Dilute the reaction with 10 liters of dichloromethane and pour into a stirred solution of saturated aqueous sodium bicarbonate until the solution is weakly basic (pH = 7.1-8.5). Separate the dichloromethane layer and concentrate under reduced pressure to remove the solvent to give oily intermediate 3 which is used in the next step.

[0034] (4) Dissolve the oily intermediate 3 from step 3 in 10 liters of methanol and stir the solution while cooling to below -5°C. Add 491 grams (13 moles) of sodium borohydride in portions while maintaining the temperature below -5°C. Stir the reaction at -5°C for 30 minutes and then at room temperature for about 6 hours. TLC (1 / 1 ethyl acetate / petroleum ether) shows no starting material. Pour the reaction into a stirred solution of 1 N aqueous hydrochloric acid and stir for 30 minutes. Extract the aqueous layer with 10 liters of dichloromethane three times. Combine the dichloromethane layers and concentrate under reduced pressure to remove the solvent to give oily intermediate 4 which is used in the next step.

[0035] (5) Dissolve the oily intermediate 4 from step 4 in 5 liters of methanol and add 5.0 grams (92 mmol) of sodium methoxide. Stir the reaction at room temperature for 1 hour. HPLC shows no starting material or intermediates. Neutralize the reaction with Dowex 50W-X8 acid resin. Filter the acid resin and concentrate the filtrate under reduced pressure until no distillate is collected. Add 1 liter of methanol and 2 liters of methyl tert-butyl ether to the residue and stir for 1 hour. White insoluble material forms. Cool the reaction to 0°C and stir for 1 hour. Filter the white powder and dry at 40-50°C with a hot air stream until the weight is constant. Weigh the product to give 258 grams in 56% overall yield. The product has a HPLC purity of 100% (ELSD).

[0036] High Performance Liquid Chromatography (HPLC) Table 1: Mobile Phase Table 2: Chromatographic Conditions Table 3: Mass Spectrometry Report for Sample 2207-28

Claims

1. A method for the synthesis of L-mannose, characterized in that, Comprise the following steps: Step 1, 1, 2, 3, 4, 6-penta-O-acetyl-beta-L-glucopyranose is mixed with PCl5 in dichloromethane at a molar ratio of 1:1-2.5 at-10℃-0℃, and the reaction is warmed to room temperature, and the reaction is stopped after the raw material disappears, and the reaction system is cooled to-10℃-0℃, and the intermediate 1 is separated and obtained, and directly connected to the next step; Step 2, the intermediate 1 is dissolved in acetone, and 1:4 volume ratio of DMF and water is added, and the volume ratio of DMF and acetone is 1:100, and the reaction is carried out at room temperature, and after the raw material disappears, the intermediate 2 is separated and obtained, and directly connected to the next step; Step 3, the intermediate 2 is reacted with acetic anhydride in DMSO, and the amount of acetic anhydride added is 5-10 times the molar amount of 1, 2, 3, 4, 6-penta-O-acetyl-beta-L-glucopyranose; after the raw material disappears, the intermediate 3 is separated and obtained, and directly connected to the next step; Step 4, the intermediate 3 is reacted with sodium borohydride in methanol, and the amount of sodium borohydride added is 1-5 times the molar amount of 1, 2, 3, 4, 6-penta-O-acetyl-beta-L-glucopyranose; after the raw material disappears, the intermediate 4 is separated and obtained, and directly connected to the next step; Step 5, the intermediate 4 is reacted with sodium methoxide in methanol at room temperature, and the molar ratio of sodium methoxide to 1, 2, 3, 4, 6-penta-O-acetyl-beta-L-glucopyranose is 1:10-20; after the reaction is completed, L-mannose is obtained by separation and purification; The reaction scheme is as follows: 。 2. The method of synthesis of claim 1, wherein, The separation step in step 1 is: saturated sodium bicarbonate ice water solution is added to the reaction system, the pH is adjusted to 7-8, and after standing, the organic phase is separated, the organic phase is evaporated under reduced pressure to obtain the intermediate 1.

3. The method of synthesis of claim 1, wherein, The separation step in step 2 is: the reaction system is removed under reduced pressure to obtain an oil, the oil is dissolved in dichloromethane with the same volume of reaction solvent, washed with saturated brine, and the organic phase is separated after standing, and the organic phase is washed once more, and the solvent is evaporated under reduced pressure to obtain the intermediate 2.

4. The method of synthesis of claim 1, wherein, The separation step in step 3 is: the reaction system is diluted with 4-5 times the volume of dichloromethane, and then the pH of the system is adjusted to 7.1-8.5 with saturated sodium bicarbonate solution, and after standing, the organic phase is separated, and the organic phase is evaporated under reduced pressure to obtain the intermediate 3.

5. The method of synthesis of claim 1, wherein, The separation step in step 4 is: the reaction system is poured into 0℃-4℃ 1N hydrochloric acid solution, extracted with dichloromethane, and then separated, and the obtained dichloromethane phase is dried, and then the solvent is evaporated under reduced pressure to obtain the intermediate 4.

6. The method of synthesis of claim 5, wherein, The amount of 1N hydrochloric acid solution to 1, 2, 3, 4, 6-penta-O-acetyl-beta-L-glucopyranose is 2mL:1g.

7. The method of synthesis of claim 6, wherein, The amount of dichloromethane to 1, 2, 3, 4, 6-penta-O-acetyl-beta-L-glucopyranose is 5mL:1g.

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