CN112375110A - Preparation method of compound 3,4-DGE - Google Patents
Preparation method of compound 3,4-DGE Download PDFInfo
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Abstract
The invention belongs to the technical field of chemical pharmacy, and particularly relates to a preparation method of a compound 3,4-DGE, which comprises the following steps: (1) taking a sulfuric acid solution and adjusting the pH value to 4.5-5.5 as a solvent; (2) dissolving and diluting anhydrous glucose by using the solvent prepared in the step (1) to prepare a glucose solution; (3) and (3) heating the glucose solution obtained in the step (2) at 90-121 ℃ for reaction to obtain a compound 3, 4-DGE. The invention is a method for preparing 3,4-DGE only by a single raw material, the raw material is anhydrous glucose, is a necessary product in daily life, is one of the production raw materials of peritoneal dialysis solution, is easy to obtain and has stable property; the preparation process of the method is simple and easy to implement, no organic reagent is required to participate in the synthesis process, and the whole preparation process is non-toxic, safe and environment-friendly; the preparation method of the invention is simple to operate and can be used newly, thus avoiding the problem that the 3,4-DGE is extremely easy to degrade in the storage process to the maximum extent.
Description
Technical Field
The invention belongs to the technical field of chemical pharmacy, and particularly relates to a preparation method of a compound 3, 4-DGE.
Background
The peritoneal dialysis solution is prepared from anhydrous glucose, sodium chloride, sodium lactate, calcium chloride, magnesium chloride, dilute hydrochloric acid and water for injection according to a certain proportion. As a large amount of injection, the injection must meet the requirement of sterility, so the process must be sterilized at high temperature, while the anhydrous glucose can generate Maillard reaction and caramelization reaction in the high-temperature sterilization, but the Maillard reaction needs the participation of amino substances to be completed, and the peritoneal dialysis solution does not contain the amino substances, so the caramelization reaction is considered to be generated in the high-temperature sterilization process, and the possible degradation products are as follows: fructose, maltose, maltotriose, 3-deoxyglucurone (3-DG), 3, 4-dideoxyglucurone-3-ene (3,4-DGE), 5-hydroxymethylfurfural and the like. As the research data of 5-hydroxymethylfurfural toxicity are clear, the control method of 5-hydroxymethylfurfural has been set in the quality standard of peritoneal dialysis solution, and 3,4-DGE as the upper-level product of 5-hydroxymethylfurfural should be paid attention.
Since 3,4-DGE is present in the peritoneal dialysis solution product as an important degradation product, when the impurities in the peritoneal dialysis solution are measured, the 3,4-DGE is controlled, but the 3,4-DGE reference substance and the Chinese drug testing research institute reference substance catalog do not have the variety, and other manufacturers in China also have no source, therefore, the purchase can only be realized through foreign import channels, the current 3,4-DGE selling price of 10 mg/piece per piece is different from 1 ten thousand to 4 ten thousand (RMB), the price is quite expensive, the purchase period needs more than 2 months, 3,4-DGE is used as an intermediate product of anhydrous glucose and 5-hydroxymethyl furfural, the property is extremely unstable, degradation occurs very easily during transport, and therefore subsequent studies on 3,4-DGE in peritoneal dialysis solutions are difficult to perform by purchasing the control directly.
Disclosure of Invention
The invention aims to provide a preparation method of a compound 3, 4-DGE. The method is developed mainly aiming at the 3,4-DGE impurity analysis, and the preparation method of the simple and feasible compound 3,4-DGE is developed under the condition that a reference substance 3,4-DGE is difficult to obtain, so that the analysis requirement is met.
The realization process of the invention is as follows:
a preparation method of a compound 3,4-DGE comprises the following steps:
(1) taking a sulfuric acid solution and adjusting the pH value to 4.5-5.5 as a solvent;
(2) dissolving and diluting anhydrous glucose by using the solvent prepared in the step (1) to prepare a glucose solution;
(3) and (3) heating the glucose solution obtained in the step (2) at 100-121 ℃ for reaction to obtain a compound 3, 4-DGE.
Further, in the step (2), the glucose solution is a solution containing 15-90 mg of glucose per 1 mL.
Further, in the step (3), the heating mode is water bath heating or electric heating.
Further, in the step (3), the heating reaction time is 0.5-5 hours.
Further, in the step (1), the concentration of the sulfuric acid solution was 0.005 mol/L.
Further, in the step (1), sodium hydroxide or potassium hydroxide is used to adjust the pH value.
The invention has the following positive effects:
(1) the invention is a method for preparing 3,4-DGE by only needing a single raw material, the raw material is anhydrous glucose, is a necessary product in daily life, is one of the production raw materials of peritoneal dialysis solution, is easy to obtain and has stable property.
(2) The preparation process of the method is simple and easy to implement, organic reagents are not required to be added to participate in the synthesis process, and the whole preparation process is non-toxic, safe and environment-friendly.
(3) The preparation method of the invention is simple to operate and can be used newly, thus avoiding the problem that the 3,4-DGE is extremely easy to degrade in the storage process to the maximum extent.
Drawings
FIG. 1 is a high performance liquid chromatogram of a reaction solution obtained by subjecting an anhydrous glucose solution having a concentration of 15mg/ml to a water bath at 60 ℃ for 2 hours according to the conditions of the method of the present invention;
FIG. 2 is a high performance liquid chromatogram of a reaction solution obtained by subjecting an anhydrous glucose solution having a concentration of 30mg/ml to a water bath at 60 ℃ for 2 hours according to the conditions of the method of the present invention;
FIG. 3 is a high performance liquid chromatogram of a reaction solution obtained by subjecting an anhydrous glucose solution having a concentration of 60mg/ml to a water bath at 60 ℃ for 2 hours according to the conditions of the method of the present invention;
FIG. 4 is a high performance liquid chromatogram of a reaction solution obtained by subjecting an anhydrous glucose solution having a concentration of 90mg/ml to a water bath at 60 ℃ for 2 hours according to the conditions of the method of the present invention;
FIG. 5 is a high performance liquid chromatogram of a reaction solution obtained by subjecting an anhydrous glucose solution having a concentration of 90mg/ml to 100 ℃ water bath for 1 hour according to the conditions of the method of the present invention;
FIG. 6 is a high performance liquid chromatogram of a reaction solution obtained by subjecting an anhydrous glucose solution having a concentration of 90mg/ml to a water bath at 100 ℃ for 2 hours according to the conditions of the method of the present invention;
FIG. 7 is a high performance liquid chromatogram of a reaction solution obtained by subjecting an anhydrous glucose solution having a concentration of 90mg/ml to a water bath at 100 ℃ for 3 hours according to the conditions of the method of the present invention;
FIG. 8 is a high performance liquid chromatogram of a reaction solution obtained under the conditions of the method of the present invention in a water bath at 100 ℃ for 4 hours under the concentration of an anhydrous glucose solution of 90 mg/ml;
FIG. 9 is a high performance liquid chromatogram of a reaction solution obtained under the conditions of the method of the present invention in a water bath at 100 ℃ for 5 hours under the concentration of an anhydrous glucose solution of 90 mg/ml;
FIG. 10 is a high performance liquid chromatogram of a reaction solution obtained under the conditions of the method of the present invention in a water bath at 100 ℃ for 5 hours under anhydrous glucose solution concentration of 15 mg/ml;
FIG. 11 is a high performance liquid chromatogram of a reaction solution obtained by subjecting an anhydrous glucose solution having a concentration of 30mg/ml to a water bath at 100 ℃ for 5 hours according to the conditions of the method of the present invention;
FIG. 12 is a high performance liquid chromatogram of a first parallel test reaction solution obtained by subjecting an anhydrous glucose solution having a concentration of 15mg/ml to a water bath of pH4.5 at 100 ℃ for 5 hours under the conditions of the method of the present invention;
FIG. 13 is a high performance liquid chromatogram of a second parallel test reaction solution obtained by subjecting an anhydrous glucose solution having a concentration of 15mg/ml to 100 ℃ water bath for 5 hours in a solvent having a pH of 4.5 according to the method of the present invention;
FIG. 14 is a high performance liquid chromatogram of a third parallel test reaction solution obtained by subjecting an anhydrous glucose solution having a concentration of 15mg/ml to 100 ℃ water bath for 5 hours in a solvent having a pH of 4.5 according to the method of the present invention;
FIG. 15 is a high performance liquid chromatogram of a first parallel test reaction solution obtained by subjecting an anhydrous glucose solution having a concentration of 15mg/ml to water bath at 100 ℃ for 5 hours in a solvent having a pH of 5.0 according to the method of the present invention;
FIG. 16 is a high performance liquid chromatogram of a second parallel test reaction solution obtained by subjecting an anhydrous glucose solution having a concentration of 15mg/ml to 100 ℃ water bath for 5 hours in a solvent having a pH of 5.0 according to the method of the present invention;
FIG. 17 is a high performance liquid chromatogram of a third parallel test reaction solution obtained by subjecting an anhydrous glucose solution having a concentration of 15mg/ml to 100 ℃ water bath in a solvent having a pH of 5.0 for 5 hours according to the method of the present invention;
FIG. 18 is a high performance liquid chromatogram of a first parallel test reaction solution obtained by subjecting an anhydrous glucose solution having a concentration of 15mg/ml to water bath at 100 ℃ for 5 hours in a solvent having a pH of 5.5 according to the method of the present invention;
FIG. 19 is a high performance liquid chromatogram of a second parallel test reaction solution obtained by subjecting an anhydrous glucose solution having a concentration of 15mg/ml to 100 ℃ water bath for 5 hours in a solvent having a pH of 5.5 according to the method of the present invention;
FIG. 20 is a high performance liquid chromatogram of a third parallel test reaction solution obtained by subjecting an anhydrous glucose solution having a concentration of 15mg/ml to 100 ℃ water bath for 5 hours in a solvent having a pH of 5.5 according to the method of the present invention;
FIG. 21 is a high performance liquid chromatogram of a first parallel test reaction solution obtained by electrically heating an anhydrous glucose solution having a concentration of 15mg/ml in a solvent having a pH of 4.5 at 121 ℃ for 0.5h according to the method of the present invention;
FIG. 22 is a high performance liquid chromatogram of a second parallel test reaction solution obtained by electrically heating an anhydrous glucose solution having a concentration of 15mg/ml in a solvent having a pH of 4.5 at 121 ℃ for 0.5h according to the method of the present invention;
FIG. 23 is a high performance liquid chromatogram of a third parallel test reaction solution obtained by electrically heating an anhydrous glucose solution having a concentration of 15mg/ml at 121 ℃ for 0.5h in a solvent having a pH of 4.5 according to the method of the present invention;
FIG. 24 is a high performance liquid chromatogram of a first parallel test reaction solution obtained by electrically heating an anhydrous glucose solution having a concentration of 15mg/ml in a solvent having a pH of 5.0 at 121 ℃ for 0.5h according to the method of the present invention;
FIG. 25 is a high performance liquid chromatogram of a second parallel test reaction solution obtained by electrically heating an anhydrous glucose solution having a concentration of 15mg/ml at 121 ℃ for 0.5h in a solvent having a pH of 5.0 according to the method of the present invention;
FIG. 26 is a high performance liquid chromatogram of a third parallel test reaction solution obtained by electrically heating an anhydrous glucose solution having a concentration of 15mg/ml at 121 ℃ for 0.5h in a solvent having a pH of 5.0 according to the method of the present invention;
FIG. 27 is a high performance liquid chromatogram of a first parallel test reaction solution obtained by electrically heating an anhydrous glucose solution having a concentration of 15mg/ml in a solvent having a pH of 5.5 at 121 ℃ for 0.5h according to the method of the present invention;
FIG. 28 is a high performance liquid chromatogram of a second parallel test reaction solution obtained by electrically heating an anhydrous glucose solution having a concentration of 15mg/ml at 121 ℃ for 0.5h in a solvent having a pH of 5.5 according to the method of the present invention;
FIG. 29 is a high performance liquid chromatogram of a third parallel test reaction solution obtained by electrically heating an anhydrous glucose solution having a concentration of 15mg/ml at 121 ℃ for 0.5h in a solvent having a pH of 5.5 according to the method of the present invention;
FIG. 30 is a high performance liquid chromatogram of a fourth parallel test reaction solution obtained by electrically heating an anhydrous glucose solution having a concentration of 15mg/ml at 121 ℃ for 0.5h in a solvent having a pH of 5.5 according to the method of the present invention;
FIG. 31 is a high performance liquid chromatogram of a fifth parallel test reaction solution obtained by electrically heating an anhydrous glucose solution having a concentration of 15mg/ml at 121 ℃ for 0.5h in a solvent having a pH of 5.5 according to the method of the present invention;
FIG. 32 is a high performance liquid chromatogram of a sixth parallel test reaction solution obtained by electrically heating an anhydrous glucose solution having a concentration of 15mg/ml at 121 ℃ for 0.5h in a solvent having a pH of 5.5 according to the method of the present invention;
FIG. 33 is a high performance liquid chromatogram of a 3,4-DGE control solution.
Detailed Description
The process of the present invention is further illustrated by the following examples.
The design concept of the method of the invention is as follows: selecting proper anhydrous glucose solvent, selecting high-temperature heating condition, determining solvent and heating condition, heating glucose solution at high temperature to degrade to generate 3,4-DGE, detecting by the following analysis method, confirming the product by using 3,4-DGE reference substance and developed 3,4-DGE preparation method, and finally repeating the method. The method of the invention saves the cost, and the method is simple and easy to operate by using the 3,4-DGE prepared by the method under the condition that the 3,4-DGE reference substance is expensive and easy to degrade.
The analysis method used in the research process of the method of the invention comprises the following steps: calcium-based resin particles were used as a filler [ Agilent Hi-Plex Ca column (7.7 mm. times.300 mm, 8 μm) ] as measured by high performance liquid chromatography (China pharmacopoeia 2015 edition rules 0512); taking 0.005mol/L sulfuric acid solution as a mobile phase; measured with a differential refractometer (e2695-2414, waters), the cell temperature was 40 deg.C, the column temperature was 85 deg.C, and the flow rate was 0.3 ml/min.
Example 1
The preparation method of the compound 3,4-DGE comprises the following steps:
(1) taking a sulfuric acid solution with the concentration of 0.005mol/L, and using sodium hydroxide to adjust the pH value to 5.5 to be used as a solvent;
(2) dissolving anhydrous glucose by using the solvent prepared in the step (1) and diluting to prepare glucose solution containing 15mg of glucose per 1 mL;
(3) and (3) electrically heating the glucose solution obtained in the step (2) at 121 ℃ for reaction for 0.5 hour to obtain the compound 3, 4-DGE.
Example 2
The preparation method of the compound 3,4-DGE comprises the following steps:
(1) taking a sulfuric acid solution with the concentration of 0.005mol/L, and using sodium hydroxide to adjust the pH value to 5.0 to serve as a solvent;
(2) dissolving anhydrous glucose by using the solvent prepared in the step (1) and diluting to prepare glucose solution containing 90mg of glucose per 1 mL;
(3) and (3) heating the glucose solution obtained in the step (2) in a water bath at 100 ℃ for 1 hour to react to obtain the compound 3, 4-DGE.
Example 3
The preparation method of the compound 3,4-DGE comprises the following steps:
(1) taking a sulfuric acid solution with the concentration of 0.005mol/L, and using sodium hydroxide to adjust the pH value to 5.0 to serve as a solvent;
(2) dissolving anhydrous glucose by using the solvent prepared in the step (1) and diluting to prepare glucose solution containing 90mg of glucose per 1 mL;
(3) and (3) heating the glucose solution obtained in the step (2) in a water bath at 100 ℃ for 2 hours to react to obtain the compound 3, 4-DGE.
Example 4
The preparation method of the compound 3,4-DGE comprises the following steps:
(1) taking a sulfuric acid solution with the concentration of 0.005mol/L, and using sodium hydroxide to adjust the pH value to 5.0 to serve as a solvent;
(2) dissolving anhydrous glucose by using the solvent prepared in the step (1) and diluting to prepare glucose solution containing 90mg of glucose per 1 mL;
(3) and (3) heating the glucose solution obtained in the step (2) in a water bath at 100 ℃ for 3 hours to react to obtain the compound 3, 4-DGE.
Example 5
The preparation method of the compound 3,4-DGE comprises the following steps:
(1) taking a sulfuric acid solution with the concentration of 0.005mol/L, and using sodium hydroxide to adjust the pH value to 5.0 to serve as a solvent;
(2) dissolving anhydrous glucose by using the solvent prepared in the step (1) and diluting to prepare glucose solution containing 90mg of glucose per 1 mL;
(3) and (3) heating the glucose solution obtained in the step (2) in a water bath at 100 ℃ for 4 hours to react to obtain the compound 3, 4-DGE.
Example 6
The preparation method of the compound 3,4-DGE comprises the following steps:
(1) taking a sulfuric acid solution with the concentration of 0.005mol/L, and using sodium hydroxide to adjust the pH value to 5.0 to serve as a solvent;
(2) dissolving anhydrous glucose by using the solvent prepared in the step (1) and diluting to prepare glucose solution containing 90mg of glucose per 1 mL;
(3) and (3) heating the glucose solution obtained in the step (2) in a water bath at 100 ℃ for 5 hours to react to obtain the compound 3, 4-DGE.
Example 7
The preparation method of the compound 3,4-DGE comprises the following steps:
(1) taking a sulfuric acid solution with the concentration of 0.005mol/L, and using sodium hydroxide to adjust the pH value to 5.0 to serve as a solvent;
(2) dissolving anhydrous glucose by using the solvent prepared in the step (1) and diluting to prepare glucose solution containing 15mg of glucose per 1 mL;
(3) and (3) heating the glucose solution obtained in the step (2) in a water bath at 100 ℃ for 5 hours to react to obtain the compound 3, 4-DGE.
Example 8
The preparation method of the compound 3,4-DGE comprises the following steps:
(1) taking a sulfuric acid solution with the concentration of 0.005mol/L, and using sodium hydroxide to adjust the pH value to 5.0 to serve as a solvent;
(2) dissolving anhydrous glucose by using the solvent prepared in the step (1) and diluting to prepare a glucose solution containing 30mg of glucose per 1 mL;
(3) and (3) heating the glucose solution obtained in the step (2) in a water bath at 100 ℃ for 5 hours to react to obtain the compound 3, 4-DGE.
Example 9
The preparation method of the compound 3,4-DGE comprises the following steps:
(1) taking a sulfuric acid solution with the concentration of 0.005mol/L, and using sodium hydroxide to adjust the pH value to 4.5 to be used as a solvent;
(2) dissolving anhydrous glucose by using the solvent prepared in the step (1) and diluting to prepare glucose solution containing 15mg of glucose per 1 mL;
(3) and (3) heating the glucose solution obtained in the step (2) in a water bath at 100 ℃ for 5 hours to react to obtain the compound 3, 4-DGE.
Example 10
The preparation method of the compound 3,4-DGE comprises the following steps:
(1) taking a sulfuric acid solution with the concentration of 0.005mol/L, and using sodium hydroxide to adjust the pH value to 5.5 to be used as a solvent;
(2) dissolving anhydrous glucose by using the solvent prepared in the step (1) and diluting to prepare glucose solution containing 15mg of glucose per 1 mL;
(3) and (3) heating the glucose solution obtained in the step (2) in a water bath at 100 ℃ for 5 hours to react to obtain the compound 3, 4-DGE.
Example 11
The preparation method of the compound 3,4-DGE comprises the following steps:
(1) taking a sulfuric acid solution with the concentration of 0.005mol/L, and using sodium hydroxide to adjust the pH value to 5.5 to be used as a solvent;
(2) dissolving anhydrous glucose by using the solvent prepared in the step (1) and diluting to prepare glucose solution containing 15mg of glucose per 1 mL;
(3) and (3) electrically heating the glucose solution obtained in the step (2) at 121 ℃ for reaction for 0.5 hour to obtain the compound 3, 4-DGE.
Example 12
The preparation method of the compound 3,4-DGE comprises the following steps:
(1) taking a sulfuric acid solution with the concentration of 0.005mol/L, and using sodium hydroxide to adjust the pH value to 5.0 to serve as a solvent;
(2) dissolving anhydrous glucose by using the solvent prepared in the step (1) and diluting to prepare glucose solution containing 15mg of glucose per 1 mL;
(3) and (3) electrically heating the glucose solution obtained in the step (2) at 121 ℃ for reaction for 0.5 hour to obtain the compound 3, 4-DGE.
Example 13
The preparation method of the compound 3,4-DGE comprises the following steps:
(1) taking a sulfuric acid solution with the concentration of 0.005mol/L, and using sodium hydroxide to adjust the pH value to 4.5 to be used as a solvent;
(2) dissolving anhydrous glucose by using the solvent prepared in the step (1) and diluting to prepare glucose solution containing 15mg of glucose per 1 mL;
(3) and (3) electrically heating the glucose solution obtained in the step (2) at 121 ℃ for reaction for 0.5 hour to obtain the compound 3, 4-DGE.
Example 14
The preparation method of the compound 3,4-DGE comprises the following steps:
(1) taking a sulfuric acid solution with the concentration of 0.005mol/L, and using potassium hydroxide to adjust the pH value to 5.5 to be used as a solvent;
(2) dissolving anhydrous glucose by using the solvent prepared in the step (1) and diluting to prepare glucose solution containing 15mg of glucose per 1 mL;
(3) and (3) electrically heating the glucose solution obtained in the step (2) at 121 ℃ for reaction for 0.5 hour to obtain the compound 3, 4-DGE.
The main research process of the method of the invention is as follows:
1 research on preparation method of compound 3,4-DGE
As the 3,4-DGE belongs to the high-temperature degradation product of the anhydrous glucose, the preparation method adopts a method of destroying the anhydrous glucose solution at high temperature.
1.1 Change in concentration and heating Condition of Anhydrous glucose solution
The preparation method of the anhydrous glucose solution comprises the following steps: 150mg, 300mg, 600mg and 900mg of D-glucose anhydride (SLBZ9363, Sigma) are respectively taken and placed in a 10ml measuring flask, dissolved by 0.005mol/L sulfuric acid solution and diluted to the scale as 15mg/ml, 30mg/ml, 60mg/ml and 90mg/ml glucose solutions respectively.
Test of heating condition change: taking the glucose solutions with different concentrations, carrying out high-temperature destruction in a 60 ℃ water bath for 2 hours, a 100 ℃ water bath for 1 hour, a 100 ℃ water bath for 2 hours, a 100 ℃ water bath for 3 hours, a 100 ℃ water bath for 4 hours and a 100 ℃ water bath for 5 hours, injecting the destroyed solution into a high performance liquid chromatograph, and observing the generation condition of the 3, 4-DGE.
The analysis method comprises the following steps: measuring by high performance liquid chromatography (0512 according to the general rules of the national Pharmacopeia 2015), using calcium-based resin particles as filler [ Agilent Hi-Plex Ca column (7.7mm × 300mm, 8 μm) ]; taking 0.005mol/L sulfuric acid solution as a mobile phase; measured with a differential refractometer (e2695-2414, waters), the cell temperature was 40 deg.C, the column temperature was 85 deg.C, and the flow rate was 0.3 ml/min.
The experimental results are as follows: as can be seen from Table 1 (see FIGS. 1 to 11), 3,4-DGE was not produced when anhydrous glucose solutions of different concentrations were subjected to a 60 ℃ water bath for 2 hours; when the temperature of the water bath is 100 ℃, the glucose solutions with different concentrations generate the compound 3,4-DGE, and the amount of the generated 3,4-DGE increases along with the increase of the length of the water bath. The glucose solution adopts a mobile phase as a solvent, the concentration is 15mg/ml, 30mg/ml, when the concentration is 90mg/ml, the water bath is carried out for 5 hours at 100 ℃, and the percentage area of the generated 3,4-DGE is 0.04-0.07, so that when the concentration of the glucose solution is 15mg/ml, the cost is saved and the effect is ensured.
TABLE 1 summary of the results of selecting the concentration and heating conditions of glucose solutions
1.2 Change of solvent pH and heating conditions of Anhydrous glucose solution
Quality standard WS due to peritoneal dialysis solution1XG-001-2007 specifies a pH value of 4.5 to 6.5, and the pH value of the peritoneal dialysis solution used in the present invention is about 5.0 under the process conditions, so that the formation of 3,4-DGE is considered when the solvent pH is 4.5, 5.0, 5.5.
The preparation method of the solvent comprises the following steps: three portions of 500ml of 0.005mol/L sulfuric acid solution (mobile phase) are taken, and the pH is adjusted to 4.5, 5.0 and 5.5 respectively by sodium hydroxide solution, and the pH is respectively taken as a solvent pH4.5, a solvent pH5.0 and a solvent pH 5.5.
The preparation method of the anhydrous glucose solution comprises the following steps: three aliquots of 150mg of D-anhydroglucose (SLBZ9363, Sigma) were taken, and placed in 10ml volumetric flasks, dissolved and diluted to the mark with solvent pH4.5, solvent pH5.0, solvent pH5.5, respectively, as three glucose solutions.
Heating condition selection research method: the three glucose solutions are taken respectively, water bath is carried out at 100 ℃ for 5 hours, electric heating is carried out at 121 ℃ for 30min for high-temperature destruction, the solution after destruction is injected into a high performance liquid chromatograph, and the generation condition of 3,4-DGE is inspected.
The analysis method comprises the following steps: measuring by high performance liquid chromatography (0512 according to the general rules of the national Pharmacopeia 2015), using calcium-based resin particles as filler [ Agilent Hi-Plex Ca column (7.7mm × 300mm, 8 μm) ]; taking 0.005mol/L sulfuric acid solution as a mobile phase; measured with a differential refractometer (e2695-2414, waters), the cell temperature was 40 deg.C, the column temperature was 85 deg.C, and the flow rate was 0.3 ml/min.
The experimental results are as follows: as is clear from Table 2 (see FIGS. 12 to 29), the results of heating a 15mg/ml anhydrous glucose solution at 121 ℃ for 30 minutes using a solution having a pH of 5.5 as a solvent were consistently stable in triplicate, and the amount of 3,4-DGE produced was relatively stable, which is the optimum condition for preparing 3, 4-DGE.
TABLE 2 summary table of pH and heating conditions of glucose solutions
1.3 comparison of 3,4-DGE prepared with a control
The preparation method of the reference solution comprises the following steps:
3,4-DGE control solution: a 3,4-DGE control (ZZS19092612,
) An appropriate amount is precisely weighed and diluted by a mobile phase into a solution containing about 5 mu g of 3,4-DGE in each 1 ml.
Anhydrous glucose control solution: an appropriate amount of an anhydrous glucose reference substance (110833-.
3,4-DGE preparation solution: precisely weighing a proper amount of anhydrous glucose reference substance, adding a pH5.5 solution (taking a proper amount of 0.005mol/L sulfuric acid solution, adjusting the pH to 5.5 with sodium hydroxide solution) to dissolve and dilute to prepare a solution containing about 15mg of anhydrous glucose per 1ml, heating at 121 ℃ for 30 minutes, and cooling to room temperature.
The analysis method comprises the following steps: measuring by high performance liquid chromatography (0512 according to the general rules of the national Pharmacopeia 2015), using calcium-based resin particles as filler [ Agilent Hi-Plex Ca column (7.7mm × 300mm, 8 μm) ]; taking 0.005mol/L sulfuric acid solution as a mobile phase; measured with a differential refractometer (e2695-2414, waters), the cell temperature was 40 deg.C, the column temperature was 85 deg.C, and the flow rate was 0.3 ml/min.
The experimental results are as follows: in the chromatogram, the retention time of 3,4-DGE in a 3,4-DGE control solution is 25.120min (see figure 33), the retention time of the compound 3,4-DGE prepared by the method is 25.56-25.58 min (see figure 27-32), and the retention time of the compound 3,4-DGE prepared by the method is basically consistent with that of the 3,4-DGE in the control solution, so that the compound is confirmed to be the same substance.
6.4 optimal method confirmation for preparation of 3,4-DGE by the method of the invention
Precisely weighing a proper amount of anhydrous glucose reference substance, adding a pH5.5 solution (taking a proper amount of 0.005mol/L sulfuric acid solution, adjusting the pH to 5.5 with sodium hydroxide solution) to dissolve and dilute to prepare a solution containing about 15mg of anhydrous glucose per 1ml, heating at 121 ℃ for 30 minutes, and cooling to room temperature. (Co-parallel preparation 6 parts)
The experimental results are as follows: as can be seen from Table 3,4-DGE was produced in all of the 6 replicates, and the reproducibility was good (see FIGS. 27 to 32).
TABLE 36 summary of the results of the parallel test preparation of 3,4-DGE
The invention develops a simple and feasible preparation method of the compound 3,4-DGE through a plurality of tests and grops, and plays a key role in controlling and measuring the 3, 4-DGE. The 3,4-DGE prepared in a laboratory can be directly used in the experimental operation process, so that the purchase cost of the 3,4-DGE reference substance is saved, the reference substance can be quickly obtained, the conditions that the experimental progress is delayed and the 3,4-DGE of the reference substance is degraded due to long shelf life of the reference substance are avoided, and the method research of the 3,4-DGE plays a role in saving time, labor and cost. The preparation method is simple and easy to operate, and can be used for preparing the 3,4-DGE when required by an experiment, so that the degradation caused by long standing time of the 3,4-DGE is avoided, the purity of the 3,4-DGE is ensured, and the smooth operation of the experiment is also ensured. The reliability is proved by comparing the prepared 3,4-DGE with a reference substance purchased through foreign import.
The foregoing is a more detailed description of the invention in connection with specific preferred embodiments and is not intended to limit the invention to the particular forms disclosed. For those skilled in the art to which the invention pertains, several simple deductions or substitutions can be made without departing from the spirit of the invention, and all shall be considered as belonging to the protection scope of the invention.
Claims (6)
1. A preparation method of a compound 3,4-DGE is characterized by comprising the following steps:
(1) taking a sulfuric acid solution and adjusting the pH value to 4.5-5.5 as a solvent;
(2) dissolving and diluting anhydrous glucose by using the solvent prepared in the step (1) to prepare a glucose solution;
(3) and (3) heating the glucose solution obtained in the step (2) at 100-121 ℃ for reaction to obtain a compound 3, 4-DGE.
2. A process for the preparation of the compound 3,4-DGE according to claim 1, characterized in that: in the step (2), the glucose solution is a solution containing 15-90 mg of glucose per 1 mL.
3. A process for the preparation of the compound 3,4-DGE according to claim 1, characterized in that: in the step (3), the heating mode is water bath heating or electric heating.
4. A process for the preparation of the compound 3,4-DGE according to claim 1, characterized in that: in the step (3), the heating reaction time is 0.5-5 hours.
5. A process for the preparation of the compound 3,4-DGE according to claim 1, characterized in that: in the step (1), the concentration of the sulfuric acid solution is 0.005 mol/L.
6. A process for the preparation of the compound 3,4-DGE according to claim 1, characterized in that: in the step (1), sodium hydroxide or potassium hydroxide is used for adjusting the pH value.
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| CN1312813A (en) * | 1998-06-09 | 2001-09-12 | 宝酒造株式会社 | Therapeutic agents |
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| WO2014002039A1 (en) * | 2012-06-27 | 2014-01-03 | Shire Ag | Amphetamine prodrugs |
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| CN1312813A (en) * | 1998-06-09 | 2001-09-12 | 宝酒造株式会社 | Therapeutic agents |
| EP1254902A1 (en) * | 2000-01-13 | 2002-11-06 | Takara Bio Inc. | Agents correcting gene expression regulatory error |
| WO2012095793A2 (en) * | 2011-01-11 | 2012-07-19 | Universidade De Lisboa | (n-alkylcarbamoyl)methyl enulosides and related pyranoside containing an alfa, beta, gama, delta - unsaturated ester, their preparation and their efficacy as antibacterial agents |
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