Process for the preparation of l-mannose

Abstract

The application belongs to the technical field of sugar synthesis chemistry, and particularly relates to a preparation method of L-mannose. The method of the application uses 1,2,3,4,6-penta-O-acetyl-beta-L-glucopyranose as a raw material, and L-mannose is obtained through modification and inversion of L-glucose 2-OH. The raw material is easy to obtain, the method is simple in process, low in cost, high in yield, and suitable for large-scale production.

Description

TECHNICAL FIELD

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

[0002] The information disclosed in this background section is intended to provide an overview of the general background of the application and is not necessarily a complete description of the prior art. It is not intended to be used as an aid in determining the prior art.

[0003] L-mannose (CAS: 10030-80-5) is a mirror image isomer of natural D-mannose (CAS: 3458-28-4) and has a very low content in nature. L-mannose and its derivatives have important application value in the research of mirror biology and the development of active drugs. Due to the difficulty in obtaining, especially the high price of commercial L-mannose, the development and research of its application are limited.

[0004]

[0005] In the existing chemical synthesis technology, L-mannose can be synthesized from bispropyl-D-glucose as a raw material in 7 steps (Hung S C, Wang C C, Thopate S R. Efficient synthesis of L-altrose and L-mannose. Tetrahedron Letters [J]. 2000, 41(17): 3119-3122. DOI: 10.1016 / S0040-4039(00)00363-4), 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 (Draskovits, Markus, Stanetty, Christian, Baxendale, Ian R. 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, DOI: 10.1021 / acs.joc.7b03063), and it is also difficult to synthesize L-mannose in large quantities due to the complicated steps. SUMMARY

[0006] In order to solve the problems in the prior art, the application provides a preparation method of L-mannose, which is safe and simple to operate, easy to purify, low in cost and suitable for large-scale production.

[0007] To achieve the above object, the application adopts the following technical scheme.

[0008] A preparation method of L-mannose comprises the following steps:

[0009] (1) 1,2,3,4,6-penta-O-acetyl-beta-L-glucopyranose is mixed with PCl5 in an organic solvent at -10 ℃ to 0 ℃, and the reaction is carried out at room temperature. After the reaction is completed, the temperature is lowered to -10 ℃ to 0 ℃, and the intermediate 1 is separated.

[0010] (2) The intermediate 1, N,N-dimethylformamide (DMF) and water are reacted at room temperature in an organic solvent, and the intermediate 2 is separated after the reaction is completed.

[0011] (3) The intermediate 2 and trifluoromethanesulfonic anhydride (Tf2O) are reacted in the presence of pyridine in an organic solvent at -10 ℃ to 0 ℃, and the intermediate 3 is separated after the reaction is completed.

[0012] (4) The intermediate 3 and sodium nitrite are reacted at room temperature in an organic solvent, and the intermediate 4 is separated after the reaction is completed.

[0013] (5) The intermediate 4 and sodium methoxide are reacted at room temperature in methanol, and the product is separated and purified after the reaction is completed.

[0014] In step (1), the molar ratio of 1,2,3,4,6-penta-O-acetyl-beta-L-glucopyranose to PCl5 is 1:(1-2.5); preferably 1:(1.5-2.5); more preferably 1:(2-2.5).

[0015] In steps (1) and (3), the separation step is that a saturated sodium bicarbonate solution at not higher than 0 ℃ is added to the reaction system until the pH is greater than 7, the organic phase is separated by standing, and the solvent is removed.

[0016] In step (2), the mass ratio of water to 1,2,3,4,6-penta-O-acetyl-beta-L-glucopyranose is 2:5. The volume ratio of DMF to water is 1:4; and the volume ratio of DMF to the organic solvent is 1:100.

[0017] In step (2), the separation step is that after the reaction system is removed of the solvent, an equal amount of dichloromethane is added to the original volume, washed with saturated brine, the organic phase is separated by standing, and the solvent is removed.

[0018] In step (3), the molar ratio of 1,2,3,4,6-penta-O-acetyl-beta-L-glucopyranose to trifluoromethanesulfonic anhydride is 1:(1.5-3); preferably 1:(2-2.5). The molar ratio of pyridine to trifluoromethanesulfonic anhydride is (1-4):1; preferably (2.5-4):1; more preferably (3.5-4):1.

[0019] In step (4), the molar amount of sodium nitrite added is 2-3 times that of 1,2,3,4,6-penta-O-acetyl-beta-L-glucopyranose.

[0020] In step (4), the separation step is to pour the reaction system into a 1N hydrochloric acid solution at 0-4°C, and then extract with ethyl acetate, which can be performed 1-3 times; wherein the ratio of the hydrochloric acid solution to 1,2,3,4,6-penta-O-acetyl-beta-L-glucopyranose is 2 mL:1 g, and the ratio of ethyl acetate to 1,2,3,4,6-penta-O-acetyl-beta-L-glucopyranose is 5 mL:1 g; the ethyl acetate phase obtained by liquid separation is dried to remove the solvent.

[0021] In step (5), the molar ratio of 1,2,3,4,6-penta-O-acetyl-beta-L-glucopyranose to sodium methoxide is (25-30):1.

[0022] In step (5), the separation and purification step is to remove the solvent after the reaction system is neutralized, add methanol and methyl tert-butyl ether in a volume ratio of 1:2 to 0.5-1 times the volume of the reaction system, filter and dry to obtain the product.

[0023] In the above steps, the concentration of 1,2,3,4,6-penta-O-acetyl-beta-L-glucopyranose and each intermediate in the organic solvent is not higher than 0.5 mol / L; preferably 0.1-0.5 mol / L; more preferably 0.2-0.3 mol / L. The organic solvent is selected from at least one of dichloromethane, acetone and N,N-dimethylformamide (DMF).

[0024] The present application has the following advantages:

[0025] The present application uses readily available 1,2,3,4,6-penta-O-acetyl-beta-L-glucopyranose as a raw material, and L-mannose is obtained by modification and inversion of L-glucose 2-OH. The method is simple, low in cost and high in yield, and is suitable for large-scale production. BRIEF DESCRIPTION OF DRAWINGS

[0026] Figure 1 is L-mannose 1 H NMR spectrum;

[0027] Figure 2 is L-mannose 13 C NMR spectrum;

[0028] Figure 3 is L-mannose high resolution mass spectrum (HRMS) chart;

[0029] Figure 4 is L-mannose HPLC chart. DETAILED DESCRIPTION

[0030] The present application provides a preparation method of L-mannose, the reaction route is as follows:

[0031] .

[0032] Specifically, the above preparation method comprises the following steps:

[0033] (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 carried out at room temperature. After monitoring the disappearance of the raw material, the reaction is stopped, the reaction system is cooled to -10℃-0℃, and the intermediate 1 is separated and directly connected to the next step.

[0034] Specifically, the separation step is: saturated sodium bicarbonate ice water solution is added to the reaction system to be weakly basic (pH>7), and the organic phase is separated by standing. The organic phase is evaporated under reduced pressure to obtain oily intermediate 1.

[0035] (2) Intermediate 1 is dissolved in acetone, and 1:4 volume ratio of DMF and water is added. The volume ratio of DMF and acetone is 1:100, and the reaction is carried out at room temperature. After monitoring the disappearance of the raw material, the intermediate 2 is separated and directly connected to the next step.

[0036] 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, washed with saturated brine, and the organic phase is separated by standing. Wash once more, evaporate the solvent from the organic phase under reduced pressure to obtain oily intermediate 2.

[0037] (3) Intermediate 2 is dissolved in dichloromethane and pyridine, and trifluoromethanesulfonic anhydride is added dropwise at -10℃-0℃. The molar amount of trifluoromethanesulfonic anhydride is 1-1.5 times that of 1,2,3,4,6-penta-O-acetyl-beta-L-glucopyranose. The molar ratio of trifluoromethanesulfonic anhydride and pyridine is 1:3.8. After monitoring the disappearance of the raw material, the intermediate 3 is separated and directly connected to the next step.

[0038] Specifically, the separation step is: the reaction system is added with saturated sodium bicarbonate solution at not higher than 0 ℃ to pH greater than 7, the organic phase is separated, and the solvent is evaporated under reduced pressure to obtain the oily intermediate 3.

[0039] (4) The intermediate 3 and sodium nitrite are reacted in DMF at room temperature, the molar amount of sodium nitrite added is 2-3 times that of 1,2,3,4,6-penta-O-acetyl-beta-L-glucopyranose, after the disappearance of the raw material is monitored, the reaction system is separated to obtain the intermediate 4, which is directly used in the next step;

[0040] Specifically, the separation step is: the reaction system is poured into 1N hydrochloric acid solution at 0 ℃-4 ℃, then extracted with ethyl acetate for 3 times, the obtained ethyl acetate phase is combined and dried with anhydrous sodium sulfate, and the solvent is evaporated under reduced pressure to obtain the oily intermediate 4; wherein the ratio of the hydrochloric acid solution to 1,2,3,4,6-penta-O-acetyl-beta-L-glucopyranose is 2 mL:1 g, and the ratio of ethyl acetate to 1,2,3,4,6-penta-O-acetyl-beta-L-glucopyranose is 5 mL:1 g.

[0041] (5) The intermediate 4 and sodium methoxide are reacted in methanol at room temperature, the amount of sodium methoxide added is 1:(25-30) times the molar amount of 1,2,3,4,6-penta-O-acetyl-beta-L-glucopyranose; after the reaction is monitored to be completed, the product L-mannose is obtained by separation and purification;

[0042] Specifically, the separation and purification step is: an acidic resin is added to the reaction system to neutralize the system to neutral, the acidic resin is removed by filtration, then the residue is concentrated under reduced pressure until no distillate is obtained, then methanol and methyl tert-butyl ether are added to the residue in a volume ratio of 1:2 to 0.5-1 times the volume of the reaction system, the mixture is stirred, then cooled to 0 ℃ and continuously stirred, and then filtered, and the filter cake is dried to obtain the white powder product.

[0043] In the above steps, the concentration of 1,2,3,4,6-penta-O-acetyl-beta-L-glucopyranose and each intermediate in the organic solvent is not higher than 0.5 mol / L.

[0044] The application will be further described below in conjunction with the embodiments and the accompanying drawings, but the application is not limited by the following embodiments. Unless otherwise specified, room temperature refers to 10 ℃-30 ℃; low temperature refers to not higher than 5 ℃, especially -10 ℃-5 ℃; ice water refers to 0 ℃-4 ℃; and weakly basic pH refers to 7.1-8.5.

[0045] Example 1 Synthesis of L-mannose

[0046] (1) 10.0 g (25.6 mmol) of 1,2,3,4,6-penta-O-acetyl-beta-L-glucopyranose (CAS: 66966-07-2) was added to 100 mL of dichloromethane under stirring, and the system was cooled to below -5°C, then 11.7 g (56.4 mmol) of PCl5 was added in batches, and the temperature of the system was controlled to be below -5°C during the addition. After the addition was completed, the temperature of the system was increased to 25°C, and then the stirring reaction was continued for 6 hours. After the raw material was detected to disappear by TLC, the system was cooled to below -5°C, 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, then the organic phase was separated by standing. The obtained oil (intermediate 1) was directly used in the next step.

[0047] (2) Intermediate 1 was dissolved in 100 mL of acetone at room temperature, 4 mL of water and 1 mL of DMF were added to the system, then the stirring reaction was carried out at room temperature, and after about 6 hours, the raw material was detected to disappear by TLC. The system was concentrated under reduced pressure, and the obtained oil was dissolved in 100 mL of dichloromethane, washed twice with saturated brine, then the organic phase was separated, and concentrated under reduced pressure to obtain an oil which was directly used in the next step.

[0048] (3) The oil from step (2) was dissolved in 100 mL of dichloromethane and 20 mL (19.6 g, 247 mmol) of pyridine, and cooled to below -5°C, then 16.6 g (64.7 mmol) of triflic anhydride was slowly added dropwise under temperature control, and the system was stirred at below -5°C for about 2 hours after the addition was completed. The raw material was detected to disappear by TLC, then the system was poured into a saturated sodium bicarbonate ice water solution and stirred to neutralize to weak alkaline. The dichloromethane phase was separated by standing, and concentrated under reduced pressure to obtain an oil which was directly used in the next step.

[0049] (4) The oil from step (3) was dissolved in 100 mL of DMF, and 5.30 g (76.8 mmol) of sodium nitrite was added under stirring at room temperature, then the stirring reaction was carried out for about 6 hours until the raw material was detected to disappear by TLC. The system was poured into 20 mL of 1N hydrochloric acid ice water solution, and stirred for 30 minutes, then the water phase was extracted with 50 mL of ethyl acetate three times. The three ethyl acetate phases were combined, dried with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain an oil which was directly used in the next step.

[0050] (5) The oily substance from step (4) was dissolved in 50 mL of methanol, 50 mg (0.92 mmol) of sodium methoxide was added, and the reaction was stirred at room temperature for 1 hour. HPLC detection showed that there was no starting material and intermediate. The system was neutralized to neutral by adding an acid resin. After removing the acid resin by filtration, the system was concentrated under reduced pressure until there was no fraction. Then 10 mL of methanol and 20 mL of methyl tert-butyl ether were added to the concentrated residue and stirred for 1 hour until white insoluble substance was produced. The system was cooled to 0°C and continued to stir for 1 hour. After filtration, the filter was dried by hot air. The white powder product was weighed to obtain 2.58 g, with a total yield of 56%.

[0051] The above product 1 H NMR, 13 C NMR and HRMS spectra are shown in Figures 1-3 :

[0052] 1 H 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);

[0053] 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.

[0054] 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.

[0055] HRMS (ESI, m / z) calculated for C6H 12 ClO6[M+H] + : 215.0322, found 215.0327; molecular formula C6H 12 O6.

[0056] Optical rotation [a]20 / D = -14.1° (c = 1, H2O), the optical rotation [a]20 / D specification of commercially available L-mannose product: -15.5° ~ -13.5°.

[0057] The above L-mannose sample was prepared into a 50 mg / mL solution with acetonitrile / water (80:20 by volume) as the solvent for HPLC detection. The chromatographic conditions are as follows:

[0058] Chromatographic column: Durashell NH2, φ4.6x250mmx5μm;

[0059] Column temperature: 40°C;

[0060] Mobile phase: acetonitrile / water = 80:20;

[0061] Flow rate: 1.0 mL / min;

[0062] Detector: Evaporative Light Scattering Detector (ELSD).

[0063] The HPLC chart of the L-mannose sample is shown in Figure 4 , the peak time is 5.49 min, and the content is 100% according to the area normalization method.

[0064] Example 2 Synthesis of L-mannose

[0065] (1) Under stirring, 100 g of 1,2,3,4,6-penta-O-acetyl-beta-L-glucopyranose was added into 1 liter of dichloromethane, the system was stirred and cooled to below -5°C, then 110 g of PCl5 was added in batches, and the temperature of the system was controlled below -5°C during the addition. After the addition was completed, the temperature of the system was raised to 25°C, and then the stirring reaction was continued for 6 hours. After the raw material was detected to disappear by TLC, the system was cooled to below -5°C, 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 = 8.0), then the organic phase was separated by standing. The organic phase was concentrated under reduced pressure to obtain an oily substance (intermediate 1) which was directly used in the next step.

[0066] (2) The intermediate 1 was dissolved in 1 liter of acetone at room temperature, 40 ml of water and 10 ml of DMF were added into the system, then the stirring reaction was carried out at room temperature, and after about 6 hours, the raw material was detected to disappear by TLC. The system was concentrated under reduced pressure, the obtained oily substance was dissolved in 1 liter of dichloromethane, washed twice with saturated brine, then the organic phase was separated, and concentrated under reduced pressure to obtain an oily substance (intermediate 2) which was directly used in the next step.

[0067] (3) The intermediate 2 was dissolved in 1 liter of dichloromethane and 200 ml of pyridine, and cooled to below -5°C, then 166 g of triflic anhydride was slowly added dropwise under temperature control, and after the dropwise addition was completed, the system was stirred at below -5°C until the raw material was detected to disappear by TLC. The system was poured into a saturated sodium bicarbonate ice water solution, and stirred to neutralize to weak alkaline (pH = 8.0). The dichloromethane phase was separated by standing, and concentrated under reduced pressure to obtain an oily substance (intermediate 3) which was directly used in the next step.

[0068] (4) The intermediate 3 was dissolved in 1 liter of DMF, 53.0 g of sodium nitrite was added under stirring at room temperature, then the stirring reaction was carried out for about 6 hours, and after the raw material was detected to disappear by TLC, the system was poured into 200 ml of 1N hydrochloric acid ice water solution, stirred for 30 minutes, and then extracted with 500 ml of ethyl acetate three times. The three times of ethyl acetate phases were combined, dried with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain an oily substance which was directly used in the next step.

[0069] (5) The oily substance of step (4) was dissolved in 500 ml of methanol, 500 mg of sodium methoxide was added, and the stirring reaction was carried out at room temperature for 1 hour. After HPLC detection showed that there was no raw material and intermediate, the system was neutralized to neutral by adding an acidic resin. After the acidic resin was removed by filtration, the system was concentrated under reduced pressure until no fraction was left, then 100 ml of methanol and 200 ml of methyl tert-butyl ether were added into the concentrated residue, and stirred until the insoluble substance was generated. The system was cooled to 0°C and continued to stir for 1 hour, then filtered, and the filter residue was dried by hot air to obtain 26.7 g of white powder of L-mannose, with a total yield of 58% and a purity of 100% (HPLC method).

[0070] Example 3 Synthesis of L-mannose

[0071] (1) Under stirring, 1000 g of 1,2,3,4,6-penta-O-acetyl-beta-L-glucopyranose was added into 10.0 L of dichloromethane, and the system was stirred and cooled to about -10°C, then 1000 g of PCl5 was added in batches, and the temperature of the system was controlled at -10°C to -5°C during the addition. After the addition was completed, the temperature of the system was increased to 25°C, and then the reaction was continued under stirring until the raw material disappeared by TLC detection. Then the system was cooled to below -5°C, and then slowly poured into a vigorously stirred saturated sodium bicarbonate ice water solution until the system was weakly alkaline (pH = 7.5). Then the organic phase was separated by standing. The obtained oil (intermediate 1) was directly used in the next step.

[0072] (2) At room temperature, intermediate 1 was dissolved in 10.0 L of acetone, and 400 mL of water and 100 mL of DMF were added to the system. Then the system was stirred at room temperature until the raw material disappeared by TLC detection. The system was concentrated under reduced pressure, and the obtained oil was dissolved in 10.0 L of dichloromethane. After washing twice with saturated brine, the dichloromethane in the organic phase was evaporated, and the oil (intermediate 2) was concentrated to obtain an oil which was directly used in the next step.

[0073] (3) Intermediate 2 was dissolved in 10.0 L of dichloromethane and 2.00 L of pyridine, and the temperature was cooled to below -5°C. Then 1.66 kg (6.47 mol) of triflic anhydride was slowly added dropwise under temperature control, and the system was stirred at below -5°C until the raw material disappeared by TLC detection. Then the system was poured into a saturated sodium bicarbonate ice water solution and stirred until the system was weakly alkaline (pH = 7.5). The dichloromethane phase was separated by standing, and the oil (intermediate 3) was concentrated under reduced pressure, which was directly used in the next step.

[0074] (4) Intermediate 3 was dissolved in 10.0 L of DMF, and 530 g of sodium nitrite was added under stirring at room temperature. Then the system was stirred until the raw material disappeared by TLC detection. The system was poured into 2 L of 1N hydrochloric acid ice water solution, and then stirred until the reaction was completed. The water phase was extracted with 5 L of ethyl acetate three times, and then dried with anhydrous sodium sulfate. The three ethyl acetate phases were combined and concentrated under reduced pressure to obtain an oil (intermediate 4) which was directly used in the next step.

[0075] (5) Intermediate 4 was dissolved in 5 L of methanol, and 5.00 g of sodium methoxide was added. The system was stirred at room temperature until there was no raw material and intermediate by HPLC detection, and then the system was neutralized to neutral by adding an acid resin. After the acid resin was removed by filtration, the system was concentrated under reduced pressure until there was no distillate. Then 1 L of methanol and 2 L of methyl tert-butyl ether were added to the concentrated residue, and stirred for about 1 hour. Then the system was cooled to 0°C and continued to stir until a large amount of insoluble substance was produced. The insoluble substance was filtered and hot air dried to obtain 272 g of white powder L-mannose, with a total yield of 59% and a purity of 100% (HPLC method).

Claims

1. A method for preparing L-mannose, characterized in that, Includes the following steps: (1) 1,2,3,4,6-penta-O-acetyl-beta-L-pyranose was mixed with PCl5 in an organic solvent at -10℃ to 0℃ and reacted at room temperature. After the reaction was completed, the temperature was lowered to -10℃ to 0℃, and intermediate 1 was obtained by separation. ; (2) Intermediate 1 reacts with DMF and water in an organic solvent at room temperature. After the reaction is complete, intermediate 2 is obtained by separation: ; (3) Intermediate 2 and trifluoromethanesulfonic anhydride were reacted in an organic solvent in the presence of pyridine at -10℃ to 0℃. After the reaction was completed, intermediate 3 was obtained by separation: ; (4) Intermediate 3 and sodium nitrite react in an organic solvent at room temperature. After the reaction is complete, intermediate 4 is obtained by separation: ; (5) Intermediate 4 and sodium methoxide react in methanol at room temperature. After the reaction is complete, the product is separated and purified.

2. The preparation method according to claim 1, characterized in that, In step (1), the molar ratio of 1,2,3,4,6-penta-O-acetyl-beta-L-pyranose to PCl5 is 1:(1~2.5); In step (2), the mass ratio of water to 1,2,3,4,6-penta-O-acetyl-beta-L-pyranose is 2:5; the volume ratio of DMF to water is 1:4; and the volume ratio of DMF to organic solvent is 1:

100. In step (3), the molar ratio of 1,2,3,4,6-penta-O-acetyl-beta-L-pyranose to trifluoromethanesulfonic anhydride is 1:(1.5~3); the molar ratio of pyridine to trifluoromethanesulfonic anhydride is (1~4):

1. In step (4), the molar amount of sodium nitrite added is 2-3 times that of 1,2,3,4,6-penta-O-acetyl-beta-L-pyranose. In step (5), the molar ratio of 1,2,3,4,6-penta-O-acetyl-beta-L-pyranose to sodium methoxide is (25~30):1; The concentration of 1,2,3,4,6-penta-O-acetyl-beta-L-pyranose and its intermediates in organic solvents shall not exceed 0.5 mol / L; The organic solvent is selected from at least one of dichloromethane, acetone, and DMF.

3. The preparation method according to claim 1, characterized in that, In step (1), the molar ratio of 1,2,3,4,6-penta-O-acetyl-beta-L-pyranose to PCl5 is 1:(1.5~2.5); In step (3), the molar ratio of 1,2,3,4,6-penta-O-acetyl-beta-L-pyranose to trifluoromethanesulfonic anhydride is 1:(2~2.5); the molar ratio of pyridine to trifluoromethanesulfonic anhydride is (2.5~4):1; The concentrations of 1,2,3,4,6-penta-O-acetyl-beta-L-pyranose and its intermediates in organic solvents range from 0.1 mol / L to 0.5 mol / L. In step (1), the organic solvent is dichloromethane; in step (2), the organic solvent is acetone; in step (3), the organic solvent is dichloromethane; and in step (4), the organic solvent is DMF.

4. The preparation method according to claim 1, characterized in that, In step (1), the molar ratio of 1,2,3,4,6-penta-O-acetyl-beta-L-pyranose to PCl5 is 1:(2~2.5); In step (3), the molar ratio of pyridine to trifluoromethanesulfonic anhydride is (3.5~4):1; The concentrations of 1,2,3,4,6-penta-O-acetyl-beta-L-pyranose and its intermediates in organic solvents range from 0.2 mol / L to 0.3 mol / L.

5. The preparation method according to claim 1, characterized in that, In steps (1) and (3), the separation step is to add a saturated sodium bicarbonate solution at a temperature not higher than 0°C to the reaction system until the pH is greater than 7, let it stand to separate the organic phase, and remove the solvent; In step (2), the separation step is to remove the solvent from the reaction system, add an equal amount of dichloromethane to the original volume, wash with saturated brine, let stand to separate the organic phase, and remove the solvent. In step (4), the separation step involves pouring the reaction system into a 1N hydrochloric acid solution at 0℃~4℃, and then extracting it with ethyl acetate. The extraction is performed 1-3 times. The ratio of hydrochloric acid solution to 1,2,3,4,6-penta-O-acetyl-beta-L-pyranose is 2mL:1g, and the ratio of ethyl acetate to 1,2,3,4,6-penta-O-acetyl-beta-L-pyranose is 5mL:1g. The ethyl acetate phase obtained by separation is dried to remove the solvent. In step (5), the separation and purification steps are as follows: after neutralizing the reaction system, the solvent is removed, and methanol and methyl ether with a volume ratio of 1:2 are added to the residue to 0.5 to 1 volume times the reaction system. The product is then obtained by filtration and drying.

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