CN109776624B - Preparation method of tribenoside - Google Patents
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Abstract
The invention belongs to the technical field of medicines, and particularly relates to a preparation method of tribenoside. The method comprises the following specific steps: taking 3,5, 6-tribenzyloxy-1, 2-oxo-isopropylidene-alpha-D-glucopyranose as an initial reactant, carrying out deprotection reaction under an acidic condition to generate a crude product of the 3,5, 6-tribenzyloxy-D-glucopyranose, sequentially carrying out refining and purification twice to obtain a pure product of the 3,5, 6-tribenzyloxy-D-glucopyranose, and finally carrying out etherification reaction under an acidic condition to obtain the ethyl-3, 5, 6-tribenzyloxy-D-glucopyranoside. The method for preparing tribenoside has the advantages of simple and convenient synthesis, separation and purification operations of intermediates, avoidance of column chromatography operation, good quality of final products, higher purity and capability of obviously shortening the production period.
Description
Technical Field
The invention belongs to the technical field of medicinal chemistry, and particularly relates to a preparation method of tribenoside.
Background
Tribenoside (TBS), i.e. ethyl-3, 5, 6-tribenzyloxy-D-furanoside, compound CAS registry number: 10310-32-4, the specific structural formula is as follows:
the tribenoside is composed of two optical isomers, alpha and beta. It is a capillary vessel protectant, has antiinflammatory, antitoxin, wound tissue healing and weak analgesic effects, and can be used with sphingosine for preventively resisting gram-negative and gram-positive bacteria. The medicine is discovered and synthesized in the 50 th century, and is developed into an oral medicine for treating hemorrhoids in 1999 from Japan, and the clinical curative effect of the medicine is greatly improved compared with other similar medicines because the medicine has extremely strong fat solubility, is easy to be absorbed by small intestine and has higher medicine utilization rate. TBS products can be prepared by conventional low-pressure column chromatography methods, but the process is time-consuming, limited in throughput and of low purity.
The preparation methods of ethyl-3, 5, 6-tribenzyloxy-D-furanoside reported at present are few, wherein the synthetic route reported in the patent US3157634 is as follows:
the purity of the initial raw materials adopted in the route is low, so that more byproducts are mixed in the intermediate II, the purification difficulty of the target product is increased, and although the target product can be obtained through repeated recrystallization, distillation and other operations, the total yield of the target product is low, so that the method is not suitable for industrial production.
The synthetic route reported in patent GB1310382 is as follows:
the obtainment of the target product still requires multiple recrystallizations and distillation operations, with no significant advantages compared to the above route. In addition, there are patents which report the use of intermediate IV as a method for purifying intermediate II ', and the hydrolysis of intermediate IV under acidic conditions can be used directly as a donor for intermediate II'. Although the method can reduce the content of related substances in the process of synthesizing the target product, the target product needs to be obtained through complicated column chromatography operation. The intermediate IV has the following structural formula:
disclosure of Invention
Aiming at the problems of longer production period and low purity existing in the existing preparation process of tribenoside, a new method for purifying the intermediate I by adopting a two-step refining method so as to obtain a target compound is provided.
The specific technical scheme of the invention is as follows: taking 3,5, 6-tribenzyloxy-1, 2-oxo-isopropylidene-alpha-D-glucopyranose as an initial raw material, and sequentially carrying out deprotection and etherification two-step reaction to synthesize the ethyl-3, 5, 6-tribenzyloxy-D-glucopyranoside.
The method specifically comprises the following steps:
(1) under the acidic condition, 3,5, 6-tribenzyloxy-1, 2-oxo-isopropylidene-alpha-D-glucopyranose is subjected to deprotection reaction to obtain a crude product of 3,5, 6-tribenzyloxy-D-glucopyranose oil;
(2) then refining and solidifying the obtained oily crude product in an ether-hydrocarbon mixed solvent for one time to obtain a 3,5, 6-tribenzyloxy-D-glucopyranose solid crude product;
(3) sequentially refining the obtained solid crude product in an alcohol-hydrocarbon mixed solvent for the second time to obtain a pure product of 3,5, 6-tribenzyloxy-D-glucopyranose;
(4) and finally, carrying out an etherification reaction on the obtained pure 3,5, 6-tribenzyloxy-D-glucopyranose and ethanol under an acidic condition to obtain the target compound.
The technical route is as follows:
according to the preparation method of the ethyl-3, 5, 6-tribenzyloxy-D-furan glucoside, the acidic environment in the step (1) is a sulfuric acid-acetic acid system; in a sulfuric acid-acetic acid system, 3,5, 6-tribenzyloxy-1, 2-oxo-isopropylidene- α -D-glucopyranose: acetic acid: the mass ratio of the sulfuric acid is 1: 1.0-12.0: 0.2 to 5.0.
The preparation method of the ethyl-3, 5, 6-tribenzyloxy-D-glucopyranoside has the advantages that the reaction temperature in the step (1) is 65-100 ℃, and the reaction time is 10-120 min.
According to the preparation method of the ethyl-3, 5, 6-tribenzyloxy-D-furan glucoside, in the ether-hydrocarbon mixed solvent in the step (2), the ether solvent is diethyl ether, isopropyl ether, methyl tert-butyl ether or a combination of the diethyl ether, the isopropyl ether and the methyl tert-butyl ether, the hydrocarbon solvent is n-pentane, cyclohexane and n-heptane or a combination of the n-pentane, the cyclohexane and the n-heptane, and the ether-hydrocarbon mixed solvent is preferably an isopropyl ether-cyclohexane system.
The preparation method of the ethyl-3, 5, 6-tribenzyloxy-D-furan glucoside comprises the following steps of (2) preparing ether in an ether-hydrocarbon mixed solvent: hydrocarbon volume ratio of 1: 1.0 to 10.0.
The preparation method of the ethyl-3, 5, 6-tribenzyloxy-D-furan glucoside comprises the following steps of (3) using an alcohol solvent in an alcohol-hydrocarbon mixed solvent, wherein the alcohol solvent is methanol, ethanol, isopropanol, n-butanol or a combination of the methanol, the ethanol, the isopropanol and the n-butanol, and using a hydrocarbon solvent which is n-pentane, cyclohexane, n-heptane or a combination of the n-pentane, the cyclohexane and the n-heptane; the alcohol-hydrocarbon mixed solvent is preferably an isopropanol-n-heptane system; alcohol: hydrocarbon volume ratio of 1: 2.0 to 10.0.
According to the preparation method of the ethyl-3, 5, 6-tribenzyloxy-D-glucopyranoside, the acid system in the step (4) is a hydrochloric acid-ethanol system; the reaction temperature is-10 to 25 ℃; the molar ratio of the 3,5, 6-tribenzyloxy-D-glucopyranose to the hydrogen chloride is 1: 1.0 to 10.5; the mass fraction of the hydrogen chloride in the hydrochloric acid-ethanol solution is 2.00-25.00%; the water content of the hydrochloric acid-ethanol is 1 to 5 percent.
According to the preparation method of the ethyl-3, 5, 6-tribenzyloxy-D-glucopyranoside, the reaction time in the step (4) is 0.5-10.0 h.
Compared with the prior art, the invention has the following remarkable progress:
the tribenzyl glycoside, namely ethyl-3, 5, 6-tribenzyloxy-D-glucopyranoside, prepared by the method has the advantages of simple and convenient synthesis, separation and purification operations of intermediates, avoidance of column chromatography operation, good quality of final products, higher purity and capability of obviously shortening the production period.
Detailed Description
The following examples may further illustrate the present invention, however, these examples should not be construed as limiting the scope of the present invention. Variations of those skilled in the art in light of the teachings of this invention are intended to be within the scope of the claims appended hereto.
The reagents used in the present invention are either commercially available or prepared by the methods described herein.
Mass spectrum ms (esi) of intermediate i: 451.2115(M + H)+)。
Mass Spectrometry MS (ESI) of Ethyl-3, 5, 6-tribenzyloxy-D-furanoside: 465.2272(M + H)+)。
Example 1
Synthesis of intermediate I
At room temperature, 8.40kg of purified water was added to a three-necked flask, and 0.22kg of concentrated sulfuric acid was slowly added thereto with stirring, and after stirring uniformly, 1.10kg of acetic acid was added thereto. After the temperature of the reaction solution is raised to 65 ℃, 1.10kg of 3,5, 6-tribenzyloxy-1, 2-oxo-isopropylidene-alpha-D-glucopyranose is added at one time, and the temperature is controlled to 65 ℃ for reaction for 10min after the addition is finished. Stirring, pouring 2.60kg of crushed ice into the reaction solution, adding 10.60L of dichloromethane, stirring for 30min, and separating an organic phase; the aqueous phase is extracted with 2.30L of dichloromethane, the organic phases are combined and washed with 10.60X 2kg of purified water; washing the dichloromethane phase with a solution prepared by 0.12kg of sodium bicarbonate and 8.60kg of purified water in advance until the pH value is 7-8; and washing the dichloromethane phase with 10.60kg of purified water, adding 3.00kg of anhydrous sodium sulfate into the dichloromethane phase, stirring and drying at room temperature for 2.5h, filtering, and evaporating the filtrate at 40-50 ℃ under reduced pressure to obtain yellow oily matter, namely a crude product of the intermediate I, wherein the mass yield is 109.10%. The purity is 96.41%.
Example 2
Synthesis of intermediate I
At room temperature, 8.40kg of purified water was added to a three-necked flask, and 5.5kg of concentrated sulfuric acid was slowly added thereto with stirring, and after stirring uniformly, 13.2kg of acetic acid was added thereto. After the reaction solution is heated to 100 ℃, 1.10kg of 3,5, 6-tribenzyloxy-1, 2-oxo-isopropylidene-alpha-D-glucopyranose is added at one time, and the temperature is controlled to 100 ℃ for reaction for 120min after the addition is finished. Stirring, pouring 2.60kg of crushed ice into the reaction solution, adding 10.60L of dichloromethane, stirring for 30min, and separating an organic phase; the aqueous phase is extracted with 2.30L of dichloromethane, the organic phases are combined and washed with 10.60X 2kg of purified water; washing the dichloromethane phase with a solution prepared by 1.2kg of sodium bicarbonate and 8.60kg of purified water in advance until the pH value is 7-8; and washing the dichloromethane phase with 10.60kg of purified water, adding 3.00kg of anhydrous sodium sulfate into the dichloromethane phase, stirring and drying at room temperature for 2.5h, filtering, and evaporating the filtrate at 40-50 ℃ under reduced pressure to obtain yellow oily matter, namely a crude product of the intermediate I, wherein the mass yield is 105.21%. The purity is 96.12%.
Example 3
Synthesis of intermediate I
At room temperature, 8.40kg of purified water was added to a three-necked flask, and 0.22kg of concentrated sulfuric acid was slowly added thereto with stirring, and after stirring uniformly, 1.1kg of formic acid was added. After the temperature of the reaction solution is raised to 65 ℃, 1.10kg of 3,5, 6-tribenzyloxy-1, 2-oxo-isopropylidene-alpha-D-glucopyranose is added at one time, and the temperature is controlled to 65 ℃ for reaction for 10min after the addition is finished. Stirring, pouring 2.60kg of crushed ice into the reaction solution, adding 10.60L of dichloromethane, stirring for 30min, and separating an organic phase; the aqueous phase is extracted with 2.30L of dichloromethane, the organic phases are combined and washed with 10.60X 2kg of purified water; washing the dichloromethane phase with a solution prepared by 0.12kg of sodium bicarbonate and 8.60kg of purified water in advance until the pH value is 7-8; and washing the dichloromethane phase with 10.60kg of purified water, adding 3.00kg of anhydrous sodium sulfate into the dichloromethane phase, stirring and drying at room temperature for 2.5h, filtering, and evaporating the filtrate at 40-50 ℃ under reduced pressure to obtain yellow oily matter, namely a crude product of the intermediate I, wherein the mass yield is 95.20%. The purity was 95.81%.
Example 4
One-step refining of intermediate I
Adding 1.10kg of crude intermediate I and 1.10L of isopropyl ether into a three-necked bottle at room temperature, heating to 30-40 ℃ under stirring until the raw materials are completely dissolved, controlling the temperature to be 20-25 ℃, continuously stirring for 1.5h, adding 1.10L of cyclohexane, cooling to 10-15 ℃, stirring for 2.0h, filtering, drying a filter cake at 35 ℃ under reduced pressure for 10.0-15.0 h to obtain a white solid, namely a primary refined intermediate I product, wherein the mass yield is 83.00%. The purity is 98.21%.
Example 5
One-step refining of intermediate I
Adding 1.10kg of crude intermediate I and 1.10L of isopropyl ether into a three-necked bottle at room temperature, heating to 30-40 ℃ under stirring until the raw materials are completely dissolved, controlling the temperature to be 20-25 ℃, continuously stirring for 1.5h, adding 11.0L of n-pentane, cooling to 10-15 ℃, stirring for 2.0h, filtering, drying a filter cake at 35 ℃ under reduced pressure for 10.0-15.0 h to obtain a white solid, namely a primary refined intermediate I product, wherein the mass yield is 86.00%. Purity 98.34.
Example 6
Secondary refining of intermediate I
Adding 825.00g of the primary refined product of the intermediate I, 2.65L of isopropanol, 5.3L of n-heptane and 41.30g of activated carbon into a three-necked bottle at room temperature, heating to 70 ℃ under stirring, refluxing for 50min, cooling the reaction solution to 30-40 ℃, filtering, cooling to 10-15 ℃, stirring for 3.0h, filtering, adding 10.60L of n-heptane into the filter cake, stirring for 1.5h at room temperature, filtering, drying the filter cake at 35 ℃ under reduced pressure for 10.0-15.0 h to obtain a white solid, namely the secondary refined product of the intermediate I, wherein the mass yield is 63.00%. The purity is 99.53%.
Example 7
Secondary refining of intermediate I
Adding 825.00g of the primary refined product of the intermediate I, 2.65L of isopropanol, 26.5L of n-heptane and 41.30g of activated carbon into a three-necked bottle at room temperature, heating to 70 ℃ under stirring, refluxing for 50min, cooling the reaction solution to 30-40 ℃, filtering, cooling to 10-15 ℃, stirring for 3.0h, filtering, adding 10.60L of n-heptane into the filter cake, stirring for 1.5h at room temperature, filtering, drying the filter cake at 35 ℃ under reduced pressure for 10.0-15.0 h to obtain a white solid, namely the secondary refined product of the intermediate I, wherein the mass yield is 71.00%. The purity is 99.54%.
Example 8
Preparation of ethyl-3, 5, 6-tribenzyloxy-D-furanoside
450.6g of the secondary refined product of the intermediate I and 2.60kg of ethanol are added into a three-necked flask at room temperature, stirred and dissolved, then cooled to-10 ℃, and 1825.0g of 2.0% hydrochloric acid-ethanol solution is dropwise added at the temperature of-10 ℃. After the dripping is finished, the temperature is controlled to be minus 10 ℃ for reaction for 0.5 h. The prepared mixture of 187.80g sodium bicarbonate solution (15.20 kg) and 8.64L dichloromethane was cooled to 10 deg.C for further use. Dropwise adding the reaction solution into the mixed solution, stirring for 45min after dropwise adding, filtering, separating an organic layer, extracting a water layer by 2.56X 2L of dichloromethane, combining the organic layers, washing the organic layer by 3.60kg of aqueous solution of 16.00g of sodium bicarbonate, washing the organic layer by 2.56X 2L of purified water, stirring and drying 276.00g of anhydrous sodium sulfate at room temperature for 1.5h, filtering, and concentrating the filtrate under reduced pressure to dryness to obtain yellowish transparent liquid, namely the target product, wherein the mass yield is 95.00 percent, and the purity is 99.41 percent (HPLC external standard method). 0.007% of benzyl alcohol, 0.012% of benzaldehyde and very small other known impurities, and the total content of other impurities is about 0.075%.
Example 9
Preparation of ethyl-3, 5, 6-tribenzyloxy-D-furanoside
450.6g of the secondary refined product of the intermediate I and 2.60kg of ethanol are added into a three-necked flask at room temperature, stirred and dissolved, then cooled to 25 ℃, and 1533.0g of 25% hydrochloric acid-ethanol solution is added dropwise at the temperature of 25 ℃. After the dripping is finished, the temperature is controlled to be 25 ℃ for reaction for 10.0 h. The prepared mixture of 187.80g sodium bicarbonate solution (15.20 kg) and 8.64L dichloromethane was cooled to 25 deg.C for further use. Dropwise adding the reaction solution into the mixed solution, stirring for 45min after dropwise adding, filtering, separating an organic layer, extracting a water layer by 2.56X 2L of dichloromethane, combining the organic layers, washing the organic layer by 3.60kg of aqueous solution of 16.00g of sodium bicarbonate, washing the organic layer by 2.56X 2L of purified water, stirring and drying 276.00g of anhydrous sodium sulfate at room temperature for 1.5h, filtering, and concentrating the filtrate under reduced pressure to dryness to obtain yellowish transparent liquid, namely the target product, wherein the mass yield is 97.00 percent, and the purity is 99.72 percent (HPLC external standard method). 0.007% of benzyl alcohol, 0.011% of benzaldehyde and small other known impurities, and the other impurities are not excessive and are about 0.075% in total.
When ethyl-3, 5, 6-tribenzyloxy-D-furanoside was prepared using intermediate I without purification, the final yield was 84.00% and the purity was 90.24% (HPLC external standard method). 0.57% of benzyl alcohol, 0.59% of benzaldehyde and other known impurities are out of limits, and the sum of the other impurities is about 2.144%. Attached: TB quality standard: the determination method comprises dissolving appropriate amount of the product in solvent, and diluting to obtain solution containing TB 40mg/ml as test solution; taking a proper amount of BJQ, adding a solvent to dissolve and dilute the BJQ to prepare a solution containing 0.1mg/ml of BJQ as a control solution 1; an appropriate amount of BJC, TB-2ZB, LHB, TB-2, TB-1ZB, 2BM and TB-1 was dissolved in a solvent and diluted to give a solution containing about 0.12mg/ml of BJC, 0.2mg/ml of TB-2ZB, 0.12mg/ml of LHB, 20.2mg/ml of TB-20, 0.12mg/ml of TB-1ZB, 10.12 mg/ml of TB-2 BM and 0.12mg/ml of 2BM as control solution 2. Precisely measuring 20 μ l of each of the test solution and the control solutions 1 and 2, respectively, injecting into a liquid chromatograph, and recording chromatogram. If an impurity peak exists in a chromatogram of a test solution, if BJQ, 2BM and TB-1 are calculated by a peak area according to an external standard method, the BJQ is not more than 0.50 percent, the TB-1 is not more than 0.50 percent, and the 2BM is not more than 0.30 percent; the peak area of the remaining individual impurities should not be greater than the peak area of TB-1 in control solution 1 (0.30%), the sum of the peak areas of the remaining individual impurities should not be greater than 6.7 times the peak area of TB-1 in control solution 1 (2.00%), and the peak area of any impurity should be negligibly less than 0.17 times the peak area of TB-1 in control solution 1 (0.05%).
Comparative example 1
Synthesis of intermediate I
At room temperature, 8.40kg of purified water was added to a three-necked flask, and 0.22kg of phosphoric acid was slowly added thereto with stirring, and after stirring uniformly, 1.10kg of acetic acid was added thereto. After the temperature of the reaction solution is raised to 65 ℃, 1.10kg of 3,5, 6-tribenzyloxy-1, 2-oxo-isopropylidene-alpha-D-glucopyranose is added at one time, and the temperature is controlled to 65 ℃ for reaction for 10min after the addition is finished. Stirring, pouring 2.60kg of crushed ice into the reaction solution, adding 10.60L of dichloromethane, stirring for 30min, and separating an organic phase; the aqueous phase is extracted with 2.30L of dichloromethane, the organic phases are combined and washed with 10.60X 2kg of purified water; washing the dichloromethane phase with a solution prepared by 0.12kg of sodium bicarbonate and 8.60kg of purified water in advance until the pH value is 7-8; and washing the dichloromethane phase with 10.60kg of purified water, adding 3.00kg of anhydrous sodium sulfate into the dichloromethane phase, stirring and drying at room temperature for 2.5h, filtering, and evaporating the filtrate at 40-50 ℃ under reduced pressure to obtain yellow oily matter, namely a crude product of the intermediate I, wherein the mass yield is 80.12%. The purity is 90.25%.
Comparative example 2
Synthesis of intermediate I
At room temperature, 8.40kg of purified water was added to a three-necked flask, and 7.26kg of sulfuric acid was slowly added thereto with stirring, and after stirring uniformly, 15.4kg of acetic acid was added thereto. After the temperature of the reaction solution is raised to 65 ℃, 1.10kg of 3,5, 6-tribenzyloxy-1, 2-oxo-isopropylidene-alpha-D-glucopyranose is added at one time, and the temperature is controlled to 65 ℃ for reaction for 10min after the addition is finished. Stirring, pouring 2.60kg of crushed ice into the reaction solution, adding 10.60L of dichloromethane, stirring for 30min, and separating an organic phase; the aqueous phase is extracted with 2.30L of dichloromethane, the organic phases are combined and washed with 10.60X 2kg of purified water; washing the dichloromethane phase with a solution prepared by 0.12kg of sodium bicarbonate and 8.60kg of purified water in advance until the pH value is 7-8; and washing the dichloromethane phase with 10.60kg of purified water, adding 3.00kg of anhydrous sodium sulfate into the dichloromethane phase, stirring and drying at room temperature for 2.5h, filtering, and evaporating the filtrate at 40-50 ℃ under reduced pressure to obtain yellow oily matter, namely a crude product of the intermediate I, wherein the mass yield is 85.23%. 92.27 percent.
Comparative example 3
One-step refining of intermediate I
Adding 1.10kg of crude product of the intermediate I and 1.10L of isopropyl ether into a three-necked bottle at room temperature, heating to 30-40 ℃ under stirring until the raw materials are completely dissolved, controlling the temperature to be 20-25 ℃, continuously stirring for 1.5h, adding 11.0L of petroleum ether, cooling to 10-15 ℃, stirring for 2.0h, filtering, drying a filter cake at 35 ℃ under reduced pressure for 10.0-15.0 h to obtain a white solid, namely a primary refined product of the intermediate I, wherein the mass yield is 78.25%. The purity is 94.49%.
Comparative example 4
One-step refining of intermediate I
Adding 1.10kg of crude intermediate I and 1.10L of isopropyl ether into a three-necked bottle at room temperature, heating to 30-40 ℃ under stirring until the raw materials are completely dissolved, controlling the temperature to be 20-25 ℃, continuously stirring for 1.5h, adding 14.0L of n-pentane, cooling to 10-15 ℃, stirring for 2.0h, filtering, drying a filter cake at 35 ℃ under reduced pressure for 10.0-15.0 h to obtain a white solid, namely a primary refined intermediate I product, wherein the mass yield is 79.91%. The purity is 95.24%.
Comparative example 5
Secondary refining of intermediate I
Adding 825.00g of the primary refined product of the intermediate I, 2.65L of isopropanol, 5.3L of n-heptane and 41.30g of activated carbon into a three-necked bottle at room temperature, heating to 70 ℃ under stirring, refluxing for 50min, cooling the reaction solution to 30-40 ℃, filtering, cooling to 10-15 ℃, stirring for 3.0h, filtering, adding 10.60L of petroleum ether into the filter cake, stirring for 1.5h at room temperature, filtering, drying the filter cake at 35 ℃ under reduced pressure for 10.0-15.0 h to obtain a white solid, namely the secondary refined product of the intermediate I, wherein the mass yield is 58.32%. The purity was 97.28%.
Comparative example 6
Secondary refining of intermediate I
Adding 825.00g of the primary refined product of the intermediate I, 2.65L of isopropanol, 5.3L of n-heptane and 41.30g of activated carbon into a three-necked bottle at room temperature, heating to 70 ℃ under stirring, refluxing for 50min, cooling the reaction solution to 30-40 ℃, filtering, cooling to 10-15 ℃, stirring for 3.0h, filtering, adding 31.8L of n-heptane into the filter cake, stirring for 1.5h at room temperature, filtering, drying the filter cake at 35 ℃ under reduced pressure for 10.0-15.0 h to obtain a white solid, namely the secondary refined product of the intermediate I, wherein the mass yield is 59.42%. The purity is 97.94%.
Comparative example 7
Preparation of ethyl-3, 5, 6-tribenzyloxy-D-furanoside
450.6g of the secondary refined product of the intermediate I and 2.60kg of ethanol are added into a three-necked flask at room temperature, stirred and dissolved, then cooled to-10 ℃, and 1573.3g of 12.80 percent hydrobromic acid-ethanol solution is added dropwise at the temperature of-5 ℃. After the dripping is finished, the temperature is controlled to be minus 10 ℃ for reaction for 0.5 h. The prepared mixture of 187.80g sodium bicarbonate solution (15.20 kg) and 8.64L dichloromethane was cooled to 10 deg.C for further use. Dropwise adding the reaction solution into the mixed solution, stirring for 45min after dropwise adding, filtering, separating an organic layer, extracting a water layer by 2.56X 2L of dichloromethane, combining the organic layers, washing the organic layer by 3.60kg of aqueous solution of 16.00g of sodium bicarbonate, washing the organic layer by 2.56X 2L of purified water, stirring and drying 276.00g of anhydrous sodium sulfate at room temperature for 1.5h, filtering, and concentrating the filtrate under reduced pressure to dryness to obtain yellowish transparent liquid, namely the target product, wherein the yield is 68.30%, and the purity is 97.38% (HPLC external standard method). 0.137 percent of benzyl alcohol, 0.109 percent of benzaldehyde and other known impurities are all very small and do not contain excessive impurities, and the total content of other impurities is about 0.225 percent.
Comparative example 8
Preparation of ethyl-3, 5, 6-tribenzyloxy-D-furanoside
450.6g of the secondary refined product of the intermediate I and 2.60kg of ethanol are added into a three-necked flask at room temperature, stirred and dissolved, then cooled to 25 ℃, and 3504.0g of 1.25% hydrochloric acid-ethanol solution is added dropwise at the temperature of 25 ℃. After the dripping is finished, the temperature is controlled to be 25 ℃ for reaction for 10.0 h. The prepared mixture of 187.80g sodium bicarbonate solution (15.20 kg) and 8.64L dichloromethane was cooled to 25 deg.C for further use. Dropwise adding the reaction solution into the mixed solution, stirring for 45min after dropwise adding, filtering, separating an organic layer, extracting a water layer by 2.56X 2L of dichloromethane, combining the organic layers, washing the organic layer by 3.60kg of aqueous solution of 16.00g of sodium bicarbonate, washing the organic layer by 2.56X 2L of purified water, stirring and drying 276.00g of anhydrous sodium sulfate at room temperature for 1.5h, filtering, and concentrating the filtrate under reduced pressure to dryness to obtain yellowish transparent liquid, namely the target product, wherein the mass yield is 97.00 percent, and the purity is 98.03 percent (HPLC external standard method). 0.119% of benzyl alcohol, 0.074% of benzaldehyde, no overproof impurities and about 0.197% of other impurities.
Claims (9)
1. A preparation method of tribenoside is characterized in that 3,5, 6-tribenzyloxy-1, 2-oxo-isopropylidene-alpha-D-glucopyranose is used as an initial raw material, and ethyl-3, 5, 6-tribenzyloxy-D-glucopyranoside is obtained through two-step reactions of deprotection and etherification, and the preparation method specifically comprises the following steps:
(1) under the acidic condition, 3,5, 6-tribenzyloxy-1, 2-oxo-isopropylidene-alpha-D-glucopyranose is subjected to deprotection reaction to obtain a crude product of 3,5, 6-tribenzyloxy-D-glucopyranose oil;
(2) then refining and solidifying the obtained oily crude product in an ether-hydrocarbon mixed solvent for one time to obtain a 3,5, 6-tribenzyloxy-D-glucopyranose solid crude product;
(3) sequentially refining the obtained solid crude product in an alcohol-hydrocarbon mixed solvent for the second time to obtain a pure product of 3,5, 6-tribenzyloxy-D-glucopyranose;
(4) finally, carrying out an etherification reaction on the obtained pure 3,5, 6-tribenzyloxy-D-glucopyranose and ethanol under an acidic condition to obtain a target compound;
wherein the acidic environment in the step (1) is a sulfuric acid-acetic acid system; in a sulfuric acid-acetic acid system, 3,5, 6-tribenzyloxy-1, 2-oxo-isopropylidene- α -D-glucopyranose: acetic acid: the mass ratio of the sulfuric acid is 1: 1.0-12.0: 0.2 to 5.0.
2. The method according to claim 1, wherein the reaction temperature in the step (1) is 65 to 100 ℃ and the reaction time is 10 to 120 min.
3. The method according to claim 1, wherein the ether solvent in the ether-hydrocarbon mixed solvent of step (2) is diethyl ether, isopropyl ether, methyl tert-butyl ether or a combination thereof, and the hydrocarbon solvent is n-pentane, cyclohexane, n-heptane or a combination thereof.
4. The production method according to claim 1, wherein the ratio of ether in the ether-hydrocarbon mixed solvent in the step (2): hydrocarbon volume ratio of 1: 1.0 to 10.0.
5. The method according to claim 1, wherein the mixed ether-hydrocarbon solvent of step (2) is an isopropyl ether-cyclohexane system.
6. The method according to claim 1, wherein the alcohol solvent in the alcohol-hydrocarbon mixed solvent of step (3) is methanol, ethanol, isopropanol, n-butanol or a combination thereof, and the hydrocarbon solvent is n-pentane, cyclohexane, n-heptane or a combination thereof; alcohol: hydrocarbon volume ratio of 1: 2.0 to 10.0.
7. The production method according to claim 1, wherein the alcohol-hydrocarbon mixed solvent of step (3) is an isopropanol-n-heptane system.
8. The method according to claim 1, wherein the acidic system in step (4) is a hydrochloric acid-ethanol system; the reaction temperature is-10 to 25 ℃; the molar ratio of the 3,5, 6-tribenzyloxy-D-glucopyranose to the hydrogen chloride is 1: 1.0 to 10.5; the mass fraction of the hydrogen chloride in the hydrochloric acid-ethanol solution is 2.00-25.00%; the water content of the hydrochloric acid-ethanol is 1 to 5 percent.
9. The preparation method according to claim 1, wherein the reaction time in the step (4) is 0.5-10.0 h.
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| CN112138015B (en) * | 2020-10-22 | 2022-08-05 | 合肥博思科创医药科技有限公司 | Application of tribenoside in treating skin diseases caused by microcirculation disturbance |
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