Synthesis method of helicid

Abstract

The invention discloses a synthesis method of helicid, and relates to the technical field of compound synthesis, glucose is taken as an initial raw material, allose is obtained through a series of reactions, pentaacetyl allose is prepared from allose through acetylation reaction, tetraacetyl alloside is prepared through selective deacetylation reaction, substitution reaction and nucleophilic substitution reaction, and the helicid is synthesized through a one-step method. And finally, carrying out a deacetylation reaction on the tetraacetyl alloside to prepare helicid. Helicid has the effects of calming, sleeping, easing pain and resisting inflammation, and can be applied to preparation of medicaments with corresponding effects. The preparation method of the helicid provided by the invention is simple to operate, can be used for large-scale industrial production, and overcomes the defect of insufficient yield of naturally extracted helicid.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of compound synthesis, and particularly relates to a synthesis method of helicid. BACKGROUND

[0002] β-D-allopyranose p-formylphenyl glycoside, also known as helicid, is a natural active ingredient extracted from Helicia nilagirica in the family of Meliaceae, and its chemical structure is 4-formylphenyl-β-D-allopyranoside. In recent years, due to its significant pharmacological effects, helicid has attracted widespread attention in the medical field. Helicid has various pharmacological effects, such as sedation, sleep and analgesia, and has a unique treatment potential for relieving neurasthenia, headache and other symptoms, which makes its demand in the medical market continue to rise.

[0003] At present, the main way to obtain helicid is to extract it from natural plants. This extraction method has many limitations, which makes it difficult to meet the growing market demand for helicid. On the one hand, the growth cycle of natural plants is long, the yield is limited, and the supply is unstable, which greatly restricts the total amount of helicid obtained by extraction; on the other hand, the extraction process is complex and the cost is high, which further limits its large-scale production and application. Therefore, developing a method for mass production of helicid has become a technical problem to be solved. SUMMARY

[0004] The purpose of the present application is to provide a preparation method of helicid to solve the above-mentioned problems existing in the prior art, so that helicid can be synthesized simply, efficiently and in large quantities.

[0005] In order to achieve the above-mentioned purpose, the present application provides the following technical scheme:

[0006] The present application provides a synthesis method of helicid, comprising the following steps:

[0007] (1) taking glucose as a starting material, reacting with acetone under the catalysis of concentrated sulfuric acid to obtain diacetyl glucose; oxidizing the hydroxyl group at C3 to a carbonyl group by a TEMPO (tetramethylpiperidine oxide) / sodium hypochlorite / sodium bromide oxidation system to obtain compound 1-3; then reducing compound 1-3 by sodium borohydride to obtain compound 1-4; removing the acetone fork protection of compound 1-4 to obtain allose;

[0008] Among them, the structural formula of compound 1-3 and 1-4 are respectively:

[0009]

[0010] (2) the allose is prepared by acetylation to obtain a beta configuration pentacetyl allose;

[0011] (3) the pentacetyl allose is prepared by selective deacetylation in an ammonia / methanol mixed system, and then substituted by trichloroacetonitrile to obtain compound 1-8;

[0012] The structural formula of the compound 1-8 is as follows:

[0013]

[0014] (4) the compound 1-8 is prepared by a nucleophilic substitution reaction of glycosylation to obtain tetraacetyl alloside;

[0015] (5) the tetraacetyl alloside is prepared by deacetylation to obtain helicid.

[0016] Preferably, the process for synthesizing diacetone glucose comprises the following steps: under stirring, concentrated sulfuric acid is added dropwise into acetone, and then glucose is added in batches, and the reaction is carried out at room temperature for 10 hours, and then the filtrate is neutralized, concentrated, extracted, and concentrated again to obtain diacetone glucose.

[0017] Preferably, the process for synthesizing the compound 1-3 comprises the following steps: diacetone glucose is dissolved in dichloromethane, and then sodium bromide, TEMPO and sodium hypochlorite solution are added in sequence under ice bath, the whole process is adjusted to pH=9-10 by sodium bicarbonate solution, after the reaction is completed, sodium iodide equivalent to sodium bromide is added, and then sodium thiosulfate is added and stirred until the solution is clear, dichloromethane is used for extraction, and then concentrated to obtain the compound 1-3.

[0018] Preferably, the reaction time of the reduction reaction is 3 hours, and the reaction temperature is 0°C.

[0019] Preferably, the process for synthesizing the allose comprises the following steps: compound 1-4 is dissolved in a mixed solvent of tetrahydrofuran (THF) and water, trifluoroacetic acid is dissolved in tetrahydrofuran, and then added dropwise into the reaction system containing compound 1-4 at room temperature, and then reacted at 60°C for 10 hours, extracted with water, concentrated, and then washed by ethanol grinding to obtain the allose.

[0020] Preferably, in the step (2), the acetylation reaction is carried out at a temperature of 90°C for 4 hours.

[0021] Preferably, the step (3) comprises the following steps: under ice bath, ammonia gas is introduced into a mixed system of methanol and tetrahydrofuran for 10 minutes, and then pentacetyl allose is added, and then stirred for 1.5 hours, and then the reaction product is dissolved in an organic solvent DCM (dichloromethane) after removing the solvent, anhydrous potassium carbonate is added, trichloroacetonitrile is slowly added under nitrogen protection, and then reacted at room temperature for 15 hours, and then the filtrate is concentrated under reduced pressure, and then recrystallized to obtain the compound 1-8.

[0022] Further preferably, the volume ratio of methanol to tetrahydrofuran is 1:7.

[0023] Preferably, the compound 1-8 is mixed with p-hydroxybenzaldehyde and added into anhydrous dichloromethane, protected by nitrogen, and then trifluoroboron ether is added under ice bath, stirred overnight, extracted, and then tetraacetylallose glycoside is obtained.

[0024] Preferably, in the step (5), ammonia is introduced into the mixed system of methanol and tetrahydrofuran under ice bath condition for 10 minutes, and then the tetraacetylallose glycoside is added, stirred at room temperature for 2.5 hours, the solvent is removed, and ethanol / water is crystallized to obtain the helicid.

[0025] Further preferably, the volume ratio of methanol to tetrahydrofuran in the mixed solvent of methanol and tetrahydrofuran is 1:6.

[0026] The present application discloses the following beneficial effects:

[0027] 1. The present application uses glucose as a starting material, which is widely available and has low preparation cost.

[0028] 2. The present application has mild chemical reaction conditions in each step of synthesizing helicid, simple reaction operation and purification, and is easy to realize industrialized production.

[0029] 3. The present application has high yield, short path, and is easy to obtain in large quantities. BRIEF DESCRIPTION OF DRAWINGS

[0030] In order to more clearly illustrate the technical solutions in the embodiments of the present application or the prior art, the drawings needed in the embodiments will be briefly introduced below. Obviously, the drawings in the following description are only some embodiments of the present application, and other drawings can also be obtained by those skilled in the art without creative labor.

[0031] Figure 1 The allose nuclear magnetic resonance hydrogen spectrum prepared in Example 1 of the present application;

[0032] Figure 2 The allose nuclear magnetic resonance carbon spectrum prepared in Example 1 of the present application;

[0033] Figure 3 The nuclear magnetic resonance hydrogen spectrum of beta configuration of pentaacetylallose prepared in Example 1 of the present application;

[0034] Figure 4 The nuclear magnetic resonance carbon spectrum of beta configuration of pentaacetylallose prepared in Example 1 of the present application;

[0035] Figure 5NMR hydrogen spectrum of compound 1-8 prepared for Example 1 of the present application;

[0036] Figure 6 NMR carbon spectrum of compound 1-8 prepared for Example 1 of the present application;

[0037] Figure 7 NMR hydrogen spectrum of tetraacetyl-allose prepared for Example 1 of the present application;

[0038] Figure 8 NMR carbon spectrum of tetraacetyl-allose prepared for Example 1 of the present application

[0039] Figure 9 NMR hydrogen spectrum of helicidin prepared for Example 1 of the present application;

[0040] Figure 10 NMR carbon spectrum of helicidin prepared for Example 1 of the present application. DETAILED DESCRIPTION

[0041] Various exemplary embodiments of the present application will now be described in detail, which should be considered to be illustrative of the present application and should not be construed to limit the scope of the present application.

[0042] It is to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the present application.

[0043] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. Although preferred methods and materials are described herein, any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present application. All documents mentioned herein are incorporated by reference to disclose and describe in further detail the methods and / or materials associated with the documents. In the case of conflict between the present specification and any document incorporated by reference, the present specification will control.

[0044] Various modifications and changes can be made to the specific embodiments of the present application described herein without departing from the scope or spirit of the application. Other embodiments of the application will be apparent to those of ordinary skill in the art from the description and examples presented herein. The description and examples are illustrative of the application and are not intended to limit the scope of the application.

[0045] The present application provides a synthetic method of helicidin, comprising the following steps:

[0046] (1) Synthesis of allose: glucose as starting material, concentrated sulfuric acid catalysis and reaction with acetone to obtain diacetyl glucose 1-2, oxidation of C3 hydroxyl to carbonyl by TEMPO / sodium hypochlorite / sodium bromide oxidation system to obtain compound 1-3, then reduction of carbonyl by sodium borohydride to realize inversion of C3 hydroxyl configuration to obtain compound 1-4, compound 1-4 removes acetone to obtain allose 1-5, the reaction route is as follows:

[0047]

[0048] (2) The β configuration of pentaacetyl allose is prepared by acetylation reaction, and the reaction route is as follows:

[0049]

[0050] (3) Pentaacetyl allose is subjected to selective deacetylation by ammonia / methanol, and then subjected to substitution reaction with trichloroacetonitrile to prepare compound 1-8, and the reaction route is as follows:

[0051]

[0052] (4) Compound 1-8 is prepared by glycosidation of nucleophilic substitution reaction to prepare tetraacetyl alloside 1-9, and the reaction route is as follows:

[0053]

[0054] (5) Tetraacetyl alloside is subjected to deacetylation to obtain helicid 1-10, and the reaction route is as follows:

[0055]

[0056] In some preferred embodiments of the present application, the step (1) comprises:

[0057] Add acetone to the container, slowly drop concentrated sulfuric acid under vigorous stirring, then weigh glucose and add it in batches slowly, keep stirring at room temperature for 10 hours, then neutralize the filtrate, concentrate, extract, and concentrate again to obtain diacetyl glucose, i.e. compound 1-2;

[0058] Add compound 1-2 to the container, add dichloromethane to dissolve, stir in ice bath, add sodium bromide, then add TEMPO and drop sodium hypochlorite solution, adjust pH to 9-10 with sodium bicarbonate solution throughout the process, add sodium iodide equivalent to sodium bromide after the reaction is completed, stir, then add sodium thiosulfate and stir until the solution is clear, extract with dichloromethane, and concentrate to obtain compound 1-3;

[0059] Compound 1-3 is added into a container, dissolved in a solution of ethanol / water with a volume ratio of 6:4, and sodium borohydride (NaBH4) is added under stirring in an ice bath. After the addition is completed, the reaction system is continuously stirred for 3 hours. After the reaction is completed, saturated ammonium chloride solution is added and stirred until no gas bubbles are generated. Most of the ethanol is removed under reduced pressure, and dichloromethane is used for extraction to obtain compound 1-4.

[0060] Compound 1-4 is dissolved in a mixed solvent of tetrahydrofuran and water with a volume ratio of 1:8. Trifluoroacetic acid is dissolved in tetrahydrofuran, and then added dropwise into the above reaction system at room temperature. After the dropwise addition is completed, the reaction liquid is heated to 60℃ and continuously reacted for 10 hours. Water is used for extraction, and then concentrated and washed by ethanol grinding to obtain allose.

[0061] In some preferred embodiments of the present application, step (2) comprises: adding allose and sodium acetate into a container, adding acetic anhydride, then heating to 90℃ and reacting for 4 hours, stirring with ice water to separate, and recrystallizing with ethanol to obtain β configuration pentacetyl allose.

[0062] In some preferred embodiments of the present application, step (3) comprises: bubbling ammonia gas into a mixed solution of tetrahydrofuran and methanol (THF / MeOH) with a ratio of 7:1 for 10 minutes under ice bath, then adding pentacetyl allose, stirring and reacting for about 1.5 hours, directly drying the solvent under reduced pressure, then dissolving in anhydrous dichloromethane (DCM), adding anhydrous potassium carbonate, slowly adding trichloroacetonitrile into the reaction system under nitrogen protection, reacting at room temperature for 15 hours, concentrating the filtrate under reduced pressure, and recrystallizing to obtain compound 1-8.

[0063] In some preferred embodiments of the present application, step (4) comprises: mixing compound 1-8 and p-hydroxybenzaldehyde, dissolving in anhydrous dichloromethane, protecting under nitrogen, then adding boron trifluoride ether under ice bath and stirring overnight, extracting, concentrating, and column chromatography to obtain tetraacetyl alloside.

[0064] In some preferred embodiments of the present application, step (5) comprises: adding a mixed solution of methanol and tetrahydrofuran with a volume ratio of 1:6 into a container, bubbling ammonia gas into the mixed solution for 10 minutes under ice bath, adding tetraacetyl alloside into the above reaction liquid, stirring at room temperature for 2.5 hours, drying the solvent under reduced pressure, and crystallizing with ethanol / water to obtain helicid.

[0065] It should be noted that the raw materials and reagents used in the embodiments of the present application are obtained by purchasing through a conventional route.

[0066] Embodiment 1

[0067] A synthesis method of helicid, comprising the following steps:

[0068] (1) Synthesis of allose: Take 2L single mouth bottle, room temperature, add acetone (1L, 12.19mol), slowly drop the concentrated sulfuric acid (16mL, 289.75mmol, 18mol / L) under stirring, then take glucose (36.00g, 200mmol) and slowly add it in batches, keep the temperature and stirring for 10 hours, then filter the unreacted glucose, adjust the pH to neutral with sodium hydroxide solution, filter the residue, concentrate the filtrate, then dissolve it in dichloromethane (100mL) and saturated brine (100mL), continue to extract the water phase with dichloromethane (100mL x 2), dry the combined organic phase with anhydrous sodium sulfate, filter and concentrate, then evaporate to dryness, recrystallize the crude product with ethyl acetate / petroleum ether = 1:10 to obtain white compound 39.20g (diacetone glucose 1-2), the crystallization yield is 76%.

[0069] Add diacetone glucose 1-2 (30.00g, 115.26mmol) to a 1L single mouth bottle, dissolve it in dichloromethane (120mL), stir under ice bath, then add sodium bromide (1.19g, 11.53mmol), then add TEMPO (90.4mg, 0.57mmol), and drop sodium hypochlorite solution (300ml, 11-14% effective chlorine content) dropwise, adjust the pH to 9-10 with sodium bicarbonate solution, and monitor the reaction with TLC at any time, after the reaction is completed, add sodium iodide equivalent to sodium bromide, stir for a while, then add sodium thiosulfate and stir until the solution is clear, extract with dichloromethane (150mL x 3), dry the combined organic phase with anhydrous sodium sulfate, filter, and evaporate to dryness under reduced pressure to obtain white solid compound 24.61g (compound 1-3), the yield is 83%. It is directly used in the next step reaction without purification.

[0070] Add compound 1-3 (24.00g, 92.93mmol) to a 500mL single mouth bottle, dissolve it in 300mL mixed solution of ethanol / water (6:4), stir under ice bath, then slowly add NaBH4 (3.87g, 102.22mmol), continue to stir the reaction system for 3 hours after the addition is completed, then slowly add saturated ammonium chloride solution after the reaction is completed by TLC detection, stir until no bubbles are generated, remove most of the ethanol under reduced pressure, extract with dichloromethane (150mL x 3), dry the combined organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain white solid compound 22.80g (compound 1-4), the yield is 94%. It is directly used in the next step reaction without purification.

[0071] Into a 500 mL single neck flask was added compound 1-4 (15.00 g, 57.63 mmol), followed by a mixture of tetrahydrofuran and water (1:10 by volume) (180 mL) to dissolve, then trifluoroacetic acid (4.38 mL, 1.5 g / mL, 57.63 mmol) was dissolved in tetrahydrofuran (40 mL) to dilute, and then slowly added into the above reaction system at room temperature. After the addition was completed, the reaction liquid was warmed to 60°C and reacted for 10 h. TLC was used to monitor the completion of the reaction. After the reaction was completed, the reaction liquid was extracted with distilled water (80 mL x 3, i.e. 80 mL of distilled water was used to extract 3 times), and the water phase was combined and concentrated under reduced pressure. Ethanol (100 mL) was added to grind the white solid, the filtrate was removed, and the residue was washed with ethanol 3 times and then evaporated under reduced pressure to obtain white compound allose 10.00 g (compound 1-5), yield: 96% (α:β = 1:8).

[0072] 1 H NMR (400 MHz, D2O) δ 4.85 (d, J = 8.2 Hz, 1H), 4.13 (t, J = 2.6 Hz, 1H), 3.84 (dd, J = 12.1, 1.7 Hz, 1H), 3.78-3.71 (m, 1H), 3.69-3.56 (m, 2H), 3.37 (dd, J = 8.2, 2.9 Hz, 1H);

[0073] [β configuration]: 13 C NMR (101 MHz, D2O) δ 93.37, 73.56, 71.21, 71.12, 66.76, 61.14;

[0074] [α configuration]: 13 C NMR (101 MHz, D2O) δ 92.80, 72.42, 71.66, 66.98, 66.03, 60.65.

[0075] The product allose nuclear magnetic resonance hydrogen spectrum is as shown in Figure 1 , and the allose nuclear magnetic resonance carbon spectrum is as shown in Figure 2 .

[0076] (2) Into a 250 mL single neck flask was added allose (10.00 g, 55.51 mmol) and sodium acetate (4.55 g, 55.51 mmol), followed by acetic anhydride (52.47 mL, 1.08 g / mL, 555.07 mmol), and then warmed to 90°C and reacted for 4 h. TLC was used to monitor the reaction. After the reaction was completed, the reaction liquid was cooled to room temperature, and then poured into a large amount of ice to stir until white sticky material was precipitated. Filtration was performed, and acetic acid was washed out with ice water. The residue was collected and dried. Ethanol recrystallization was performed to obtain pentacetyl allose of β configuration 15.24 g (compound 1-6), yield: 70%.

[0077] [β configuration]:1 H NMR (400 MHz, CDC13) δ 6.03 - 5.81 (m, 1H), 5.73 - 5.53 (m, 1H), 4.96 (td, J = 8.3, 5.6, 3.0 Hz, 2H), 4.30 - 4.02 (m, 3H), 2.13 (s, 3H), 2.09 (s, 3H), 2.04 (s, 3H), 1.97 (s, 6H);

[0078] 13 C NMR (101 MHz, CDC13) δ 170.71, 169.85, 169.29, 169.14, 169.07, 90.09, 71.10, 68.25, 68.15, 65.71, 61.90, 20.96, 20.78, 20.72, 20.55.

[0079] The product, pentaacetyl-allose, has a nuclear magnetic resonance hydrogen spectrum in the beta configuration as shown in Figure 3 and a nuclear magnetic resonance carbon spectrum in the beta configuration as shown in Figure 4 .

[0080] (3) A 500 mL single-neck flask was charged with a mixed solvent of tetrahydrofuran and methanol (THF / MeOH) in a ratio of 7:1 (400 mL), and ammonia gas was bubbled into the mixed solution for 10 minutes in an ice bath. Then, pentaacetyl-allose (30.00 g, 76.8 mmol) was added, and the reaction was stirred for about 1.5 hours. After the completion of the reaction was confirmed by TLC, the solvent was directly distilled off under reduced pressure, and the residue was dissolved in anhydrous DCM (350 mL). Anhydrous potassium carbonate (15.90 g, 115.0 mmol) was added, and the reaction system was slowly added with trichloroacetonitrile (15.40 mL, 153.3 mmol) under nitrogen protection. The reaction was performed at room temperature for 15 hours, and after the completion of the reaction was confirmed by TLC, the reaction mixture was directly filtered, concentrated under reduced pressure, and recrystallized with a mixed solvent of n-hexane / ethyl acetate = 8:1 to obtain 36.8 g (compound 1-8) of a white solid, with a crystallization yield of 97%.

[0081] 1 H NMR (400 MHz, CDC13) δ 8.70 (s, 1H), 6.11 (d, J = 8.5 Hz, 1H), 5.73 (t, J = 2.8 Hz, 1H), 5.21 (dd, J = 8.5, 3.0 Hz, 1H), 5.07 (dd, J = 9.8, 2.7 Hz, 1H), 4.50 - 4.11 (m, 3H), 2.18 (s, 3H), 2.09 (s, 3H), 2.02 (s, 3H), 2.01 (s, 3H).

[0082] 13C NMR (101 MHz, CDCI3) δ 170.85, 169.91, 169.21, 168.97, 161.28, 94.39, 90.63, 71.27, 68.46, 68.11, 65.86, 61.95, 20.89, 20.85, 20.65, 20.61.

[0083] The product compound 1-8 has a nuclear magnetic resonance hydrogen spectrum as shown in Figure 5 The product compound 1-8 has a nuclear magnetic resonance carbon spectrum as shown in Figure 6 .

[0084] (4) Compound 1-8 (200 mg, 405.94 mmol) and p-hydroxybenzaldehyde (49.57 mg, 405.94 mmol) were added to a 50 mL two-necked flask, dissolved in anhydrous dichloromethane (20 mL), protected by nitrogen, and then trifluoroboron ether (51.44 μL, 1.12 g / mL, 405.94 mmol) was added under ice bath and stirred overnight. TLC monitoring showed that the reaction was complete. Saturated sodium bicarbonate solution (10 mL) was added and stirred for 10 minutes. The organic phase was separated, the aqueous phase was extracted with dichloromethane (2 x 15 mL), the combined organic phases were washed with water (15 mL) and saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain a white solid compound 1-9 (tetraacetylallosucrose) 151 mg, with a yield of 82%.

[0085] 1H NMR (400 MHz, CDCI3) δ 9.92 (s, 1H), 7.85 (d, J = 8.6 Hz, 2H), 7.13 (d, J = 8.6 Hz, 2H), 5.75 (t, J = 2.9 Hz, 1H), 5.48 (d, J = 8.1 Hz, 1H), 5.19 (dd, J = 8.1, 3.0 Hz, 1H), 5.05 (dd, J = 9.7, 2.7 Hz, 1H), 4.41 - 4.14 (m, 3H), 2.17 (s, 3H), 2.07 (s, 3H), 2.04 (s, 3H), 2.03 (s, 3H);

[0086] 13 C NMR (101 MHz, CDCI3) δ 190.87, 170.70, 169.79, 169.19, 169.13, 161.60, 131.89, 131.79, 116.89, 96.40, 70.80, 68.75, 68.38, 66.14, 62.34, 20.85, 20.81, 20.69, 20.65.

[0087] The product tetraacetylallosucrose has a nuclear magnetic resonance hydrogen spectrum as shown inFigure 7 , tetraacetyl-allose nucleomagnetic resonance carbon spectrum is as Figure 8 .

[0088] (5) take 50 mL single mouth bottle, add methanol and tetrahydrofuran volume ratio 1:6 mixed solution (20 mL), ice bath to the mixed solution into ammonia gas 10 minutes, weighed tetraacetyl-allose 1-9 (100 mg, 0.228 mmol) is added to the above reaction liquid, stirring at room temperature 2.5 h after TLC detection reaction is completed, directly under reduced pressure to dry the solvent to obtain white sticky tofu fruit 62 mg, the yield 96%, again by ethanol water mixed solvent recrystallization to obtain white solid tofu fruit glycoside 46 mg, the yield 73%.

[0089] 1 H NMR (400 MHz, MeOD) δ 9.85 (s, 1H), 8.28-7.81 (m, 3H), 7.45-7.02 (m, 2H), 5.38 (d, J = 7.9 Hz, 1H), 4.14 (t, J = 3.1 Hz, 1H), 3.89 (tt, J = 10.3, 2.9 Hz, 2H), 3.82-3.48 (m, 3H).

[0090] 13 C NMR (101 MHz, MeOD) δ 191.51, 162.93, 131.45, 131.05, 116.41, 98.16, 74.47, 71.60, 70.59, 67.14, 61.37.

[0091] The product tofu fruit nucleomagnetic resonance hydrogen spectrum is as Figure 9 , tofu fruit nucleomagnetic resonance carbon spectrum is as Figure 10 .

[0092] The above described embodiments are only to describe the preferred mode of the present application, and not to limit the scope of the present application, without departing from the design spirit of the present application, the person skilled in the art to the technical scheme of the present application makes various modifications and improvements, all should fall within the scope of the present application claim book determines the protection range.

Claims

1. A method for synthesizing tofu glycosides, characterized in that: The following steps are involved: (1) Glucose is used as a starting material and reacted with acetone in the presence of concentrated sulfuric acid to obtain diacetone glucose; the C3 hydroxyl group is oxidized to a carbonyl group using a TEMPO / sodium hypochlorite / sodium bromide oxidation system to obtain compound 1-3; then, compound 1-4 is reduced using sodium borohydride; and compound 1-4 is deprotected from the acetone formate to obtain allose; Among them, the structural formulas of compounds 1-3 and 1-4 are: (2) subjecting the allose to an acetylation reaction to prepare pentaacetyl allose with a β configuration; (3) The pentaacetyl allose is subjected to a selective deacetylation reaction with ammonia / methanol, and then subjected to a substitution reaction with trichloroacetonitrile to prepare compound 1-8; Among them, the structural formula of compound 1-8 is: (4) preparing tetraacetyl alloside by reacting the compound 1-8 with p-hydroxybenzaldehyde through a glycosylation nucleophilic substitution reaction; (5) The tetraacetyl alloside is subjected to a deacetylation reaction to obtain tofu fruit glycoside.

2. The method for synthesizing tofu glycoside according to claim 1, wherein The process of synthesizing diacetone glucose includes the following steps: adding concentrated sulfuric acid dropwise to acetone under stirring, then adding glucose in batches, reacting for 10 hours under stirring at room temperature, filtering to remove residue, neutralizing the filtrate, concentrating, extracting, and then concentrating again to obtain diacetone glucose.

3. The method for synthesizing tofu glycoside according to claim 1, wherein The process for synthesizing compound 1-3 comprises the following steps: dissolving diacetone glucose in dichloromethane, sequentially adding sodium bromide, TEMPO, and sodium hypochlorite solution under ice bath conditions, adjusting the pH to 9-10 with sodium bicarbonate solution throughout the process, adding sodium iodide in an amount equivalent to sodium bromide after the reaction is complete, and then adding sodium thiosulfate and stirring until the solution is clear, extracting with dichloromethane, and concentrating to obtain compound 1-3.

4. The method for synthesizing tofu glycoside according to claim 1, wherein The reduction reaction time is 3 hours and the reaction temperature is 0°C.

5. The method for synthesizing tofu glycoside according to claim 1, wherein The process for synthesizing the allose comprises the following steps: dissolving compound 1-4 in a mixed solvent of tetrahydrofuran and water, dissolving trifluoroacetic acid in tetrahydrofuran, adding the solution dropwise to a reaction system containing compound 1-4 at room temperature, reacting at 60° C. for 10 hours, extracting with water, concentrating, and then grinding and washing with ethanol to obtain allose.

6. The method for synthesizing tofu glycoside according to claim 1, wherein In the step (2), the acetylation reaction is carried out at a temperature of 90° C. and for 4 hours.

7. The method for synthesizing tofu glycoside according to claim 1, wherein The step (3) comprises: introducing ammonia gas into a mixture of methanol and tetrahydrofuran for 10 minutes under an ice bath, then adding pentaacetyl allose, stirring and reacting for 1.5 hours, removing the solvent from the reaction product, dissolving it in an organic solvent, adding anhydrous potassium carbonate, slowly adding trichloroacetonitrile dropwise under nitrogen protection, reacting at room temperature for 15 hours, and concentrating the filtrate under reduced pressure to obtain compound 1-8 through crystallization.

8. The method for synthesizing tofu glycoside according to claim 7, wherein: The volume ratio of methanol to tetrahydrofuran in the methanol and tetrahydrofuran mixed solvent is 1:

7.

9. The method for synthesizing tofu glycoside according to claim 1, wherein The step (4) comprises: mixing the compound 1-8 with p-hydroxybenzaldehyde, adding anhydrous dichloromethane to dissolve, protecting with nitrogen, then adding boron trifluoride ether under ice bath, stirring overnight, extracting, concentrating, and column chromatography to obtain tetraacetyl alloside.

10. The method for synthesizing tofu glycoside according to claim 1, characterized in that: The step (5) comprises: introducing ammonia gas into a mixture of methanol and tetrahydrofuran for 10 minutes under an ice bath, adding tetraacetyl alloside, stirring at room temperature for 2.5 hours, removing the solvent, and crystallizing with ethanol / water to obtain the tofu glycoside; the volume ratio of methanol to tetrahydrofuran in the methanol and tetrahydrofuran mixed solvent is 1:6.

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