A Synthetic Process of Tetraacetyl Gastrodin
By carrying out the condensation reaction of bromosugar and sodium phenolate under anhydrous conditions, the problem of bromosugar hydrolysis in the synthesis of gastrodin was solved, achieving high yield and high purity of tetraacetyl gastrodin, and reducing production pollution and corrosion risks.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- BAIYUN MOUNTAIN DONGTAI SHANGQIU PHARM CO LTD
- Filing Date
- 2023-09-25
- Publication Date
- 2026-05-26
AI Technical Summary
In the existing gastrodin synthesis process, the hydrolysis reaction of bromosaccharides affects the yield and results in high impurity content, leading to low product purity.
A single-phase reaction process was adopted to carry out the condensation reaction of bromosugars and sodium phenolate under anhydrous conditions. By using phosphorus tribromide instead of red phosphorus to pass hydrogen bromide, the reaction temperature and conditions were controlled to avoid the hydrolysis reaction of bromosugars and improve the purity of the product.
It improves the yield and purity of tetraacetyl gastrodin, reduces production pollution and pipeline corrosion, and the reaction conditions are mild and easy to control.
Smart Images
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Abstract
Description
Technical Field
[0001] This invention belongs to the field of pharmaceutical synthesis technology, specifically relating to a synthesis process for tetraacetyl gastrodin. Background Technology
[0002] Gastrodin is a sedative and sleep aid drug that can restore the balance between excitation and inhibition processes in the cerebral cortex. It has sedative, sleep-inducing, and analgesic effects and is mainly used clinically for insomnia, neurasthenia, headache, and migraine caused by anxiety, tension, excitement, and chronic fatigue.
[0003] Gastrodin is mainly produced through chemical synthesis. The traditional process involves first preparing bromosugars from acetic anhydride and glucose, and then reacting them in an aqueous reaction system in an alkaline environment (sodium hydroxide or potassium hydroxide). This reaction is a two-phase reaction, and the presence of water in the system introduces several drawbacks: firstly, it can cause partial hydrolysis of the bromosugar, affecting the yield; secondly, it results in a high impurity content. Summary of the Invention
[0004] In view of this, the purpose of the present invention is to provide a synthesis process for tetraacetyl gastrodin, in which the reaction of bromosugar with sodium phenolate is a single-phase reaction, and the reaction is carried out under anhydrous conditions, which can improve the yield and improve the purity of the product.
[0005] The technical solution adopted in this invention is as follows:
[0006] A process for synthesizing tetraacetyl gastrodin includes the following steps:
[0007] 1) Glucose and acetic anhydride undergo acetylation under the catalysis of aminosulfonic acid or perchloric acid. After the reaction is completed, phosphorus tribromide is added to the acetylation product and bromination is carried out to obtain tetraacetyl bromide glucose.
[0008] 2) Add an alcohol solution to p-hydroxybenzaldehyde, stir at room temperature, and then evaporate the solvent under reduced pressure to obtain sodium phenolate. Add a chloroform solution of bromosugar to sodium phenolate and react to obtain a condensation product.
[0009] 3) The condensation product was reduced with potassium borohydride to obtain tetraacetyl gastrodin;
[0010] In step 1), the acetylation reaction is carried out at a temperature of less than 40°C for 2 hours; the bromination reaction is carried out at a temperature of less than 30°C for 3 hours.
[0011] In step 2), the alcohol solution is an ethanol solution of sodium methoxide, a methanol solution of sodium methoxide, or an ethanol solution of sodium ethoxide.
[0012] The specific steps of step 1) are as follows: Glucose and acetic anhydride undergo acetylation reaction under the catalysis of aminosulfonic acid or perchloric acid, with the temperature controlled below 40°C; after the reaction, phosphorus tribromide is added to the acetylated product at a temperature controlled below 35°C, water is added dropwise, and the reaction is carried out at a temperature below 30°C. After the reaction, an appropriate amount of ice water is added, the mixture is filtered, the solid is washed with water and then dissolved in a solvent (dichloromethane or ethyl acetate / acetone / toluene / chloroform), washed with ice water and sodium bicarbonate, the organic layers are combined, dried, the solvent is evaporated under reduced pressure, petroleum ether or diethyl ether is added for recrystallization, the temperature is lowered to below 5°C and kept at that temperature for 1 hour, filtered, and dried under reduced pressure to obtain bromotetraacetyl glucose (bromosugar).
[0013] The specific steps of step 2) are as follows: An alcoholic solution is added to p-hydroxybenzaldehyde, stirred at room temperature, and then the solvent is evaporated under reduced pressure to obtain sodium phenolate. A chloroform solution of a bromosugar is added, and the mixture is heated under reflux for 3 hours. After the reaction is complete, the mixture is cooled to room temperature, filtered, and the organic phase is washed with water and sodium bicarbonate, dried over sodium sulfate, filtered, and the solvent is evaporated under reduced pressure to obtain a brown viscous substance. Then, an alcoholic solution is added to p-hydroxybenzaldehyde.
[0014] After cooling and crystallizing in methanol, the product is filtered to obtain the crude condensate. The crude product is then recrystallized in methanol to obtain the final condensate.
[0015] The specific steps of step 3) are as follows: dissolve the condensate obtained in the previous step in methanol (3 times the volume of the condensate), heat to 40°C until dissolved, slowly add 0.5 equivalents of potassium borohydride, after the reaction is complete, add dilute hydrochloric acid at room temperature to adjust the pH to neutral, filter, cool and crystallize to obtain tetraacetyl gastrodin.
[0016] In step 1), the molar ratio of glucose to acetic anhydride is 1:7.5; the molar ratio of the acetylated product to phosphorus tribromide is 1:0.75.
[0017] In step 2), the molar ratio of p-hydroxybenzaldehyde to sodium methoxide is 1:1; the molar ratio of sodium phenolate to bromotetraacetylglucose is 1.2:1.
[0018] Compared with the prior art, the beneficial technical effects of the present invention are:
[0019] 1. In the preparation of bromosaccharides, this invention adopts a one-pot process and uses phosphorus tribromide instead of the old process that uses acetic acid solution with hydrogen bromide in the form of red phosphorus. This brings the advantages of less production pollution, less corrosion to pipelines, mild reaction conditions, and easy control.
[0020] 2. In the condensation reaction of p-hydroxybenzaldehyde and bromosugar, the present invention first converts p-hydroxybenzaldehyde into sodium phenoxide, which then condenses with bromosugar to form a condensate and sodium bromide. The sodium bromide precipitates out later and can be removed as a byproduct. This allows the condensation reaction to be carried out under anhydrous conditions. Therefore, in an anhydrous environment, the bromosugar will not undergo hydrolysis, avoiding the loss of the bromosugar raw material and increasing the yield. Attached Figure Description
[0021] Figure 1 The NMR spectrum of bromotetraacetylglucose obtained in Example 1;
[0022] Figure 2 The NMR spectrum of the condensate obtained in Example 1 (condensate 1);
[0023] Figure 3 The NMR spectrum of the condensate obtained in Example 5 (condensate 2);
[0024] Figure 4 The NMR spectrum of tetraacetyl gastrodin obtained in Example 1 (tetraacetyl gastrodin 1);
[0025] Figure 5 The NMR spectrum of tetraacetyl gastrodin obtained in Example 2 (tetraacetyl gastrodin 2);
[0026] Figure 6 The NMR spectrum of tetraacetyl gastrodin obtained in Example 3 (tetraacetyl gastrodin 3);
[0027] Figure 7 The NMR spectrum of tetraacetyl gastrodin obtained in Example 4 (tetraacetyl gastrodin 4).
[0028] Figure 8 The NMR spectrum of tetraacetyl gastrodin obtained in Example 5 (tetraacetyl gastrodin 5). Detailed Implementation
[0029] The following examples illustrate specific implementations of the present invention. However, these examples are merely for illustrative purposes and do not limit the scope of the invention in any way.
[0030] Example 1:
[0031] A process for synthesizing tetraacetyl gastrodin includes the following steps:
[0032] 1) Weigh 382.5g acetic anhydride and 5g sulfamic acid. Add 90g glucose in portions at room temperature, controlling the temperature not to exceed 40℃. After 2 hours of reaction, monitor the reaction by TLC. Then, add 101.6g phosphorus tribromide in a water bath, controlling the temperature not to exceed 35℃. After the addition is complete, add 20g water dropwise, controlling the temperature not to exceed 30℃. After 3 hours of reaction, monitor the reaction by TLC. Once the reaction is complete, pour the solution into an appropriate amount of ice water, filter, wash with water, dissolve the filter cake in an appropriate amount of dichloromethane or toluene / n-hexane / benzene / chloroform, wash twice with 150ml sodium bicarbonate, wash with 100ml water, combine the organic layers, dry with sodium sulfate, filter, evaporate the solvent under reduced pressure, add 100ml petroleum ether, solidify, filter, and dry under reduced pressure to obtain 189g of bromotetraacetyl glucose. The NMR spectrum is shown below. Figure 1 As shown;
[0033] 2) Also weigh 67.3g of p-hydroxybenzaldehyde, and another 99.3g of a 30% sodium methoxide methanol solution. Stir at room temperature for 30 minutes, then evaporate the solvent under reduced pressure to obtain 79.5g of sodium phenolate; dissolve 189g of bromosugar in 150ml of chloroform, then add 79.5g of alcohol.
[0034] After heating to reflux for 2 hours and monitoring the reaction to completion by TLC, the mixture was cooled to room temperature, filtered, and the organic phase was washed twice with 150 ml of sodium bicarbonate and then with 150 ml of water. The mixture was dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain a brown viscous substance. 300 ml of methanol was added, and the mixture was cooled and crystallized for 2 hours, followed by filtration to obtain 128 g of crude condensate. Recrystallization with three times the amount of methanol yielded 115 g of refined condensate. The NMR spectrum is shown below. Figure 2 As shown. (Yield 61%, based on brominated sugars.)
[0035] 3) The condensate was reduced by potassium borohydride / sodium borohydride to obtain 103g of tetraacetyl gastrodin.
[0036] The total yield of tetraacetylgastrodin was calculated to be 45.4% (based on glucose, total molar yield). The purity of tetraacetylgastrodin was determined to be 99.8%, as shown in the NMR spectrum. Figure 4 As shown. Figure 1 , Figure 2 , Figure 4 The intermediates, condensates, and tetraacetylglucose obtained in Example 1 are shown. It can be seen that the structures of the obtained brominated product, condensate, and tetraacetyl product are correct and the purity is high.
[0037] Example 2
[0038] A process for synthesizing tetraacetyl gastrodin includes the following steps:
[0039] 1) Same as Example 1.
[0040] 2) Another batch of 67.3g of p-hydroxybenzaldehyde and 99.5g of sodium methoxide in ethanol (30% concentration) were stirred at room temperature for 30 min, and the solvent was evaporated under reduced pressure to obtain 80g of sodium phenolate. 189g of bromosugar was dissolved in 150ml of chloroform and then added to 80g of sodium phenolate. The mixture was heated under reflux for 3 h, and the reaction was monitored by TLC until it was complete. The mixture was then cooled to room temperature, filtered, and the organic phase was washed with 150ml of sodium bicarbonate and 150ml of water. The mixture was dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain a brown viscous substance. 300ml of methanol was added, and the mixture was cooled and crystallized for 2 h. After filtration, 125g of crude condensate was obtained. Recrystallization with 3 times the amount of methanol yielded 110g of refined condensate. (Yield 61%, based on bromosugar.)
[0041] 3) The condensate concentrate was reduced by potassium borohydride / sodium borohydride to obtain 100g of tetraacetyl gastrodin.
[0042] The total yield of tetraacetylgastrodin was calculated to be 44.1% (based on glucose, total molar yield). The purity of tetraacetylgastrodin was determined to be 99.5%, as shown in the NMR spectrum. Figure 5 As shown.
[0043] Example 3
[0044] A process for synthesizing tetraacetyl gastrodin includes the following steps:
[0045] 1) Same as Example 1.
[0046] 2) 67.5g of p-hydroxybenzaldehyde and 125g of sodium ethoxide ethanol solution (30% concentration) were stirred at room temperature for 30 minutes, and the solvent was evaporated under reduced pressure to obtain 79g of sodium phenolate. 189g of bromosugar was dissolved in 150g of chloroform and then added to 79g of sodium phenolate. The mixture was heated under reflux for 2 hours, and the reaction was monitored by TLC until complete. The mixture was then cooled to room temperature, filtered, and the organic phase was washed with 150ml of sodium bicarbonate and 150ml of water. After drying with sodium sulfate, the mixture was filtered, and the solvent was evaporated under reduced pressure to obtain a brown viscous substance. 300ml of methanol was added, and the mixture was cooled and crystallized for 2 hours. After filtration, 121g of crude condensate was obtained. Recrystallization with 3 times the amount of methanol yielded 109g of refined condensate. (Yield 59%, based on bromosugar.)
[0047] 3) The condensate concentrate was reduced by potassium borohydride / sodium borohydride to obtain 98.5g of tetraacetyl gastrodin.
[0048] The total yield of tetraacetylgastrodin was calculated to be 43.4% (based on glucose, total molar yield). The purity of tetraacetylgastrodin was determined to be 99.6%, as shown in the NMR spectrum. Figure 6 As shown.
[0049] Example 4
[0050] A process for synthesizing tetraacetyl gastrodin includes the following steps:
[0051] 1) Weigh 42.5 kg of acetic anhydride and 150 ml of perchloric acid and put them into a reactor. Add 10 kg of glucose in batches at room temperature, keeping the temperature below 40°C. After the reaction is complete for 2 hours, monitor the reaction by TLC. Then add 11.3 kg of phosphorus tribromide under ice bath conditions, keeping the temperature below 35°C. After the addition is complete, add 3.8 kg of water dropwise, keeping the temperature below 30°C. After the addition is complete, monitor the reaction for 5 hours. Once the reaction is complete, pour the solution into an appropriate amount of ice water, filter, wash with water, dissolve the filter cake in 20 kg of dichloromethane, wash with 40 kg of ice water and 30 kg of sodium bicarbonate, combine the organic layers, dry with sodium sulfate, filter, evaporate the solvent under reduced pressure, add 40 kg of petroleum ether, solidify, filter, and dry under reduced pressure to obtain 18.8 kg of bromotetraacetyl glucose.
[0052] 2) Another batch of 6.7 kg of p-hydroxybenzaldehyde and 9.9 kg of a 30% methanol solution of sodium methoxide were stirred at room temperature for 30 min and the solvent was evaporated under reduced pressure to obtain approximately 7.9 kg of sodium phenolate. 18.8 kg of bromosugar was dissolved in 10 kg of chloroform and then added to the sodium phenolate. After heating under reflux for 2 h and monitoring the reaction to complete by TLC, the mixture was cooled to room temperature, filtered, and the organic phase was washed with 30 kg of sodium bicarbonate and 30 kg of water. The mixture was dried with sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain a brown viscous substance. Three times the amount of methanol was added, and the mixture was cooled and crystallized for 2 h. After filtration, 12.2 kg of crude condensate was obtained. Three times the amount of methanol was recrystallized to obtain 11.5 kg of refined condensate (yield 61%, based on bromosugar).
[0053] 3) The condensate concentrate was reduced by potassium borohydride / sodium borohydride to obtain 9.9 kg of tetraacetyl gastrodin.
[0054] The total yield of tetraacetylgastrodin was calculated to be 43.6% (based on glucose, total molar yield). The purity of tetraacetylgastrodin was determined to be 99.3%, as shown in the NMR spectrum. Figure 7 As shown.
[0055] Example 5
[0056] 1) Weigh 382.5g acetic anhydride and 5g sulfamic acid. Add 90g glucose in portions at room temperature, keeping the temperature below 40℃. After 2 hours of reaction, monitor the reaction by TLC. After the reaction is complete, add 101g phosphorus tribromide in a water bath, keeping the temperature below 35℃. After the addition is complete, add 20g water dropwise, keeping the temperature below 30℃. After the addition is complete, monitor the reaction by TLC for 3 hours. Once the reaction is complete, pour the solution into an appropriate amount of ice water, filter, wash with water, dissolve the filter cake in an appropriate amount of dichloromethane or toluene / n-hexane / benzene / chloroform, wash with 150ml sodium bicarbonate, wash with 100ml water, combine the organic layers, dry with sodium sulfate, filter, evaporate the solvent under reduced pressure, add 100ml petroleum ether, solidify, filter, and dry under reduced pressure to obtain 188g of bromotetraacetyl glucose.
[0057] 2) Add 61.6g of p-hydroxybenzaldehyde, 70.1g of potassium carbonate, and 44.3g of tetrabutylammonium bromide sequentially, along with 200ml of water and 100ml of chloroform. Stir to dissolve and heat to 40-50℃. Dissolve the bromosugar in chloroform and add it dropwise to the above solution at 40-50℃. Maintain the reaction temperature for about 5 hours, and monitor the reaction until the endpoint is reached using TLC. After the reaction is complete, cool to room temperature, allow to separate into layers, discard the aqueous layer, and wash the chloroform layer sequentially with 10% sodium hydroxide solution and saturated sodium chloride solution. Dry with sodium sulfate, concentrate under reduced pressure (rotary evaporation), until no chloroform drips out, forming a thick paste. Add 200ml of ethanol, stir thoroughly at room temperature to disperse, and crystallize by cooling in an ice bath for about 2 hours. Filter, wash with anhydrous ethanol, filter under vacuum, and dry to obtain 85g of the condensate, yield 41% (based on bromosugar). Figure 3 The NMR spectrum of the obtained condensate is shown below.
[0058] 3) The condensate concentrate was reduced with Raney nickel / hydrogen to yield 68 g of tetraacetylgastrodin. The total yield of tetraacetylgastrodin was 30% (total molar yield based on glucose), and the purity was 95%. Figure 8 The image shows the NMR spectrum of the obtained tetraacetylgastrodin. Figure 3 and Figure 8 It is evident that when using the old process, the solution environment in which the bromosugar is added contains water, leading to the hydrolysis of some of the bromosugar and a loss of some of the bromosugar raw material. The condensate produced by this method has significant impurities, and the yield of tetraacetylgastrodin is low. Finally, it should be noted that the above embodiments are only used to illustrate the technical solution of the present invention and not to limit it. Other modifications or equivalent substitutions made by those skilled in the art to the technical solution of the present invention, as long as they do not depart from the spirit and scope of the technical solution of the present invention, should be covered within the scope of the claims of the present invention.
Claims
1. A process for synthesizing tetraacetylgastrodin, characterized in that, Includes the following steps: 1) Glucose and acetic anhydride undergo acetylation under the catalysis of aminosulfonic acid or perchloric acid. After the reaction is completed, phosphorus tribromide and water are added to the acetylation product and bromination is carried out to obtain tetraacetyl bromide glucose. 2) Add an alcohol solution to p-hydroxybenzaldehyde, stir at room temperature, and then evaporate the solvent under reduced pressure to obtain sodium phenolate. Add a chloroform solution of tetramethyl bromide glucose to the sodium phenolate and react to obtain a condensation product. The alcohol solution is an ethanol solution of sodium methoxide, a methanol solution of sodium methoxide, or an ethanol solution of sodium ethoxide. 3) The condensation product was reduced with potassium borohydride to obtain tetraacetyl gastrodin.
2. The synthesis process according to claim 1, characterized in that: In step 1), the acetylation reaction temperature is less than 40℃ and the reaction time is 2 hours; the bromination reaction temperature is less than 30℃ and the reaction time is 3 hours.
3. The synthesis process according to claim 1, characterized in that: The specific steps of step 1) are as follows: Glucose and acetic anhydride undergo acetylation reaction under the catalysis of aminosulfonic acid or perchloric acid, and the temperature is controlled below 40°C; after the reaction is completed, phosphorus tribromide is added to the acetylated product at a temperature controlled below 35°C, water is added dropwise, and the reaction is carried out at a temperature below 30°C. After the reaction is completed, an appropriate amount of ice water is added, the mixture is filtered, the solid is washed with water and dissolved in a solvent, washed with ice water and sodium bicarbonate, the organic layers are combined, dried, the solvent is evaporated under reduced pressure, petroleum ether or diethyl ether is added for recrystallization, the temperature is lowered to below 5°C and kept at that temperature for 1 hour, filtered, and dried under reduced pressure to obtain bromotetraacetyl glucose.
4. The synthesis process according to claim 1, characterized in that: The specific steps of step 2) are as follows: an alcohol solution is added to p-hydroxybenzaldehyde, stirred at room temperature, and then the solvent is evaporated under reduced pressure to obtain sodium phenolate. A chloroform solution of bromotetraacetyl glucose is added, and the mixture is heated under reflux. After the reaction is completed, the mixture is cooled to room temperature, filtered, and the organic phase is washed with water and sodium bicarbonate, dried with sodium sulfate, filtered, and the solvent is evaporated under reduced pressure to obtain a brown viscous substance. Methanol is added, the mixture is cooled and crystallized, and then filtered to obtain the crude condensate. The crude condensate is then recrystallized with methanol to obtain the condensation product.
5. The synthesis process according to claim 1, characterized in that: The specific steps of step 3) are as follows: dissolve the condensate obtained in the previous step in methanol, heat it to 40°C until it is completely dissolved, slowly add 0.5 equivalents of potassium borohydride, after the reaction is complete, add dilute hydrochloric acid at room temperature to adjust the pH to neutral, filter, cool and crystallize to obtain tetraacetyl gastrodin.
6. The synthesis process according to claim 3, characterized in that: In step 1), the molar ratio of glucose to acetic anhydride is 1:7.5, and the molar ratio of the acetylated product to phosphorus tribromide is 1:0.
75. In step 2), the molar ratio of p-hydroxybenzaldehyde to sodium methoxide or sodium ethoxide is 1:1, and the molar ratio of sodium phenolate to bromotetraacetyl glucose is 1.2:1.