CN111961018B - Preparation method of high-purity butylphthalide - Google Patents
Preparation method of high-purity butylphthalide Download PDFInfo
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- CN111961018B CN111961018B CN202010927412.5A CN202010927412A CN111961018B CN 111961018 B CN111961018 B CN 111961018B CN 202010927412 A CN202010927412 A CN 202010927412A CN 111961018 B CN111961018 B CN 111961018B
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Abstract
The invention relates to a preparation method of high-purity butylphthalide, which comprises the following steps: (1) preparing n-butyl magnesium bromide; (2) synthesizing 2-valeryl benzoic acid; (3) synthesizing butylphthalide; (4) and (5) refining butylphthalide. Due to the adoption of the technical scheme, the invention has the following advantages: in the step (1), n-butyl magnesium bromide is used as an initiator, so that the initiation condition is mild, and the safety performance is improved; the initiation temperature is 38-42 ℃, the reaction temperature is only 48-52 ℃, and the method is easy to realize in the large-scale production process. 2-valeryl benzoic acid is used as a raw material, and a sodium borohydride aqueous solution mode is adopted to reduce carbonyl, so that explosion caused by a solid feeding mode is avoided, and the production safety is ensured. The method for refining the butylphthalide by reduced pressure distillation is simple and feasible, and the purity of the obtained high-purity butylphthalide reaches 100%. The synthesis process of butylphthalide is stable, the preparation process is mild and controllable, and the method is suitable for batch production.
Description
Technical Field
The invention belongs to the field of chemical pharmacy, and particularly relates to a preparation method of butylphthalide.
Background
The butylphthalide is 3-n-butylphthalide chemically, apigenin, and is racemate extracted from celery seed, and is synthesized artificially, has the medicinal effect of resisting cerebral ischemia, is medicine with independent intellectual property right in China, and can reduce the infarction focus after focal cerebral ischemia, increase cerebral blood flow in ischemic area, improve microcirculation in cerebral ischemia area, protect mitochondrial function, reduce nerve function damage degree and improve function metabolism after cerebral ischemia.
CN 101962374A discloses a method for preparing apigenin, which takes phthalic anhydride as a raw material and is characterized in that an intermediate of o-valeryl benzoic acid is obtained by addition of the phthalic anhydride and a Grignard reagent of halogenated butane, and then the apigenin is obtained by reduction and acidic cyclization of sodium borohydride. Iodine is added as an initiator during preparation of the Grignard reagent, new impurities are introduced, the purity of the obtained product reaches 97-98%, the content of the impurities is 2-3%, and the product cannot be directly used for preparation of injection drugs.
CN 105130934A is a butyl phthalide bulk drug product and its preparation method, based on the method of preparing butyl phthalide from Lishao white, because the purity of the product is not enough, and some related impurities are controlled by the refining process, the main defect of the reaction is: (1) the method for preparing butylphthalide from Lipoxine uses phthalic anhydride as starting material, anhydrous sodium acetate and valeric anhydride to make reflux at 300 deg.C to obtain butenylphthalide intermediate, and said intermediate is catalytically hydrogenated in ethyl ether by using 10% Pd/C to obtain crude butylphthalide. The use of ether solvent and high temperature condition are not suitable for large-scale industrial production; (2) the reflux time in the ring-opening reaction in the refining process is too long (1.5 hours), which affects the production progress; (3) the temperature is high (35-40 ℃) in the ring-closing reaction, and the generation of byproducts is facilitated; (4) in the recrystallization process of the hydroxypentyl potassium benzoate, a water and ether system is used, which is not beneficial to industrial production; (5) in the ring-closing reaction, a methylene dichloride and a water system are adopted to dissolve hydroxyl amyl benzoic acid potassium salt, and the methylene dichloride is a second solvent; (6) and finally, the butylphthalide is refined by adopting a rectification mode, so that manpower and material resources are consumed, the maintenance cost is high, and the large-scale production is not facilitated.
CN 105859670A discloses a preparation method of high-purity butylphthalide, which is adopted to prepare butylphthalide with the purity improved to more than 99.0 percent, but the method has the following defects: (1) the synthesis process is only suitable for small batch processes, for example, column chromatography and rectification equipment are used; during the large-scale production, the separation and purification of column chromatography are difficult, and the cost of rectification equipment and the maintenance cost are not economical, so that the method should be carried out in a more reasonable, safe and efficient manner during the large-scale production.
Disclosure of Invention
The invention overcomes the defects in the prior art and provides a preparation method of high-purity butylphthalide, which has low impurity content and is suitable for large-scale production.
The specific technical scheme of the invention is as follows:
a preparation method of high-purity butylphthalide comprises the following steps:
(1) preparation of n-butyl magnesium bromide
Under the protection of nitrogen, adding anhydrous tetrahydrofuran, magnesium chips and n-butyl magnesium bromide into a reaction kettle, stirring and heating to 38-42 ℃, slowly dropwise adding a mixed solution of n-bromobutane and anhydrous tetrahydrofuran, controlling the reaction temperature to be 48-52 ℃ in the dropwise adding process, keeping the temperature for reacting for 25-35 minutes after the dropwise adding is finished, and removing the residual magnesium chips to prepare an n-butyl magnesium bromide Grignard reagent;
(2) synthesis of 2-valeryl benzoic acid
Under the protection of nitrogen, phthalic anhydride and n-butyl magnesium bromide in a Grignard reagent are used as raw materials, cuprous iodide is used as a catalyst, the raw materials react for 50-70 minutes in anhydrous tetrahydrofuran at the temperature of-30-5 ℃, and after the reaction is finished, 2-valeryl benzoic acid is prepared through post-treatment;
(3) synthesis of butylphthalide
Stirring 2-valeryl benzoic acid and a sodium hydroxide solution at 20-30 ℃ for reaction, cooling to below 10 ℃, slowly dropwise adding a sodium borohydride solution under the protection of nitrogen, after dropwise adding, heating to 20-30 ℃, reacting for 14-20 h, after the reaction is finished, cooling to-5 ℃, adding a hydrochloric acid solution to adjust the pH value to 2.4-2.6, then reacting for 14 h-20 h at 20-30 ℃, extracting the obtained product, washing and drying the extracted organic phase, and then concentrating under reduced pressure at-0.06-0.09 MPa and 35-45 ℃ to obtain a crude butylphthalide product; after the butyl phthalide crude product is post-treated, butyl phthalide is prepared;
(4) purification of butylphthalide
Transferring the butylphthalide prepared in the step (3) to a reduced pressure distillation device for reduced pressure distillation, heating the reduced pressure distillation device to 140-200 ℃, preserving the temperature, carrying out reduced pressure distillation under the condition that the vacuum degree is 100-450 Pa, discarding front fraction, and collecting main fraction at 140-150 ℃ to obtain high-purity butylphthalide.
Preferably, in the step (1), the molar ratio of the magnesium chips to the n-butyl magnesium bromide and the n-bromobutane is 245: 3-4: 225-240.
Preferably, in the step (2), the molar ratio of the cuprous iodide to the phthalic anhydride added is 0.04-0.08: 1, and the molar ratio of the n-butyl magnesium bromide to the phthalic anhydride in the grignard reagent is 0.9-2.0: 1.
Particularly preferably, the reaction temperature is controlled within the range of-25 to-5 ℃, most preferably, the reaction temperature is controlled within the range of-20 to-10 ℃, and preferably, the molar ratio of the added cuprous iodide to the phthalic anhydride is 0.06:1, and the molar ratio of the n-butyl magnesium bromide in the grignard reagent to the phthalic anhydride is 1.1 to 1.2: 1.
In order to further improve the purity of the product, preferably, in the step (2), the post-treatment step is as follows: after the reaction is finished, adding hydrochloric acid into a reaction system to adjust the pH value of the solution to 2-3, separating liquid, extracting a water layer by using methyl tert-butyl ether, combining organic layers, washing the organic layer, and concentrating the organic layer under reduced pressure at the temperature of 35-45 ℃ under the pressure of-0.08 to-0.1 MPa after liquid separation until no liquid drops flow out;
adding methyl tert-butyl ether into the obtained concentrated solution, adding a sodium hydroxide solution to adjust the pH value to 11-12, filtering, separating the filtrate, adding methyl tert-butyl ether into a water phase after liquid separation for washing, adjusting the pH value of an obtained water layer to 2-3 by hydrochloric acid, extracting by using methyl tert-butyl ether, combining organic phases, washing and drying the organic phases, filtering, and concentrating the obtained filtrate under reduced pressure at the temperature of 35-45 ℃ under the pressure of-0.08 to-0.1 MPa until no liquid drops flow out;
adding a mixed solution of ethyl acetate and n-heptane into the obtained concentrated solution, stirring, filtering, washing a filter cake by using the mixed solution of ethyl acetate and n-heptane, and concentrating the obtained filtrate under reduced pressure at the temperature of 35-45 ℃ under the pressure of-0.08 to-0.1 MPa until no liquid drops flow out to obtain a light yellow oily intermediate which is 2-valeryl benzoic acid.
In order to further improve the purity of the product, in the step (3), preferably, the molar ratio of the 2-valerylbenzoic acid to the sodium hydroxide in the sodium hydroxide solution is 1: 1-1.3, and the molar ratio of the 2-valerylbenzoic acid to the sodium borohydride in the sodium borohydride solution is 1: 1.2-1.6.
In order to further improve the purity of the product, preferably, in the step (3), the post-treatment step is as follows: mixing potassium hydroxide and methanol, heating, refluxing and dissolving, then transferring a crude butylphthalide product to a mixed solution of potassium hydroxide and methanol, refluxing and stirring, adding methyl tert-butyl ether when the temperature is reduced to 50 ℃, separating out a large amount of solids, washing the separated solids, adding methanol, heating to 65-75 ℃, refluxing, after the solids are completely dissolved, adding methyl tert-butyl ether when the temperature is reduced to 50 ℃, performing suction filtration, washing a filter cake, adding water for dissolving, and cooling to-5 ℃; adding a hydrochloric acid solution to adjust the pH value to 2.4-2.6, then reacting for 14-20 h at 20-30 ℃, extracting the obtained product, washing and drying the extracted organic phase, and concentrating under reduced pressure at-0.06-0.09 MPa at 35-45 ℃ until no liquid drops flow out to obtain colorless or light yellow oily butylphthalide.
In order to further improve the purity of the product, preferably, in the step (4), the butylphthalide prepared in the step (3) is transferred to a reduced pressure distillation device for reduced pressure distillation, the reduced pressure distillation device is heated to 188-192 ℃ and is kept warm, reduced pressure distillation is carried out under the condition that the vacuum degree is 200-300 Pa, front fractions are discarded, and main fractions at 142-144 ℃ are collected to obtain the high-purity butylphthalide.
And (3) during reduced pressure distillation, the temperature of the fraction has a certain relation with the vacuum degree, preferably, in order to further improve the purity of the product, the butylphthalide prepared in the step (3) is transferred to a reduced pressure distillation device for reduced pressure distillation, the reduced pressure distillation device is heated to 188-192 ℃ for heat preservation, reduced pressure distillation is carried out under the condition that the vacuum degree is 230Pa, the front fraction is discarded, and the main fraction at 142-144 ℃ is collected to obtain the high-purity butylphthalide.
Due to the adoption of the technical scheme, the invention has the following advantages:
1. when the n-butyl magnesium bromide Grignard reagent is prepared, n-butyl magnesium bromide is used as an initiator, the initiation condition is mild, and the safety performance is improved; the initiation temperature is 38-42 ℃, the reaction temperature is only 48-52 ℃, and the method is easy to realize in the large-scale production process.
2. When the butylphthalide is synthesized, 2-valeryl benzoic acid is used as a raw material, and a sodium borohydride aqueous solution is used for reducing carbonyl, so that explosion caused by a solid feeding mode is avoided, and the production safety is ensured. In addition, the purity of the butylphthalide obtained by adopting the post-treatment condition of the invention reaches more than 99.5 percent, and the maximum single impurity is less than 0.05 percent.
3. The method for refining the butylphthalide by reduced pressure distillation is simple and feasible, and the purity of the obtained high-purity butylphthalide reaches 100.00 percent.
4. The method has the advantages of stable synthesis process of butylphthalide, mild and controllable preparation process, environmental protection, high yield, low impurity content of products and suitability for batch production.
Drawings
FIG. 1 is an HPLC chromatogram of high purity butylphthalide prepared in example 1.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention. The invention is not mentioned in part as prior art.
The invention provides a preparation method of high-purity butylphthalide, which comprises the following reaction processes:
the HPLC described in the examples was measured using area normalization.
Example 1
A preparation method of high-purity butylphthalide comprises the following steps:
step 1: preparation of n-butyl magnesium bromide
1.192kg (49mol) of magnesium chips and 10.2kg (141.7mol) of anhydrous tetrahydrofuran were charged into a 50L reactor, and after nitrogen gas was replaced three times with stirring, the whole reaction and post-treatment was protected with nitrogen gas. Stirring and raising the temperature to ensure that the temperature in the reaction kettle reaches 40 ℃ and is stable. Stopping stirring, adding 350mL of a prepared mixed solution of n-butyl magnesium bromide with the molar concentration of 2mol/L and anhydrous tetrahydrofuran into a reaction kettle, starting stirring, dropwise adding a mixed solution of 6.4kg (46.7mol) of n-bromobutane and 6.4kg (88.9mol) of anhydrous tetrahydrofuran, observing the temperature rise in the reaction kettle, indicating that the solution is accompanied by bubbles, continuing to slowly dropwise add the mixed solution of the n-bromobutane and the anhydrous tetrahydrofuran, and controlling the temperature in the reaction kettle to be 50 ℃ through the external temperature and the dropwise adding speed. After the dropwise addition, the reaction system was maintained at 50 ℃ for further reaction for 30 min. Connecting a filter and a storage kettle, carrying out vacuum filtration, removing residual magnesium chips, preparing an n-butyl magnesium bromide Grignard reagent, and transferring the Grignard reagent into a 30L storage kettle to keep the temperature at 50-60 ℃ for later use. Sampling and titrating the concentration of the Grignard reagent, and then diluting the Grignard reagent to 2.0-2.2 mol/L by using anhydrous tetrahydrofuran, wherein the product amount is about 23L.
Step 2: synthesis of 2-valeryl benzoic acid
6.0kg (37.81mol) of phthalic anhydride, 60L (691.17mol) of tetrahydrofuran and 463g (2.27mol) of cuprous iodide are added into a 200L reaction kettle, nitrogen is introduced, the temperature is reduced to minus 15 +/-5 ℃ under the protection of the nitrogen, about 23L of Grignard reagent (containing 41.6mol of n-butyl magnesium bromide) is slowly dripped, the temperature of a dripping tank and a dripping pipeline is required to be kept at 50-60 ℃, and the temperature of a reaction system is controlled at minus 15 +/-5 ℃. TLC detection was completed by dropwise addition (developing solvent: ethyl acetate: petroleum ether: 1:3, UV254 was not reacted completely and additional Grignard reagent was added). Controlling the temperature to be minus 15 +/-5 ℃ after the reaction is finished, reacting for 2 hours, and stopping introducing nitrogen after the reaction is finished.
Adding 1mol/L hydrochloric acid of about 45L into a reaction kettle, adjusting the pH value to be 2-3 (the internal temperature is less than 5 ℃), separating, vacuumizing a water layer into a 150L reaction kettle, extracting (stirring for 10min) the water layer by using 12.6L of methyl tert-butyl ether, vacuumizing the water layer into a 100L reaction kettle, extracting (stirring for 10min) the water layer by using 12.6L of methyl tert-butyl ether, and discarding the water layer. The organic phases in the 150L reactor and the 100L reactor were combined in a 200L reactor, and 25.2L of saturated saline was added to the 200L reactor and washed 1 time (stirred for 10min), followed by separation and removal of the aqueous layer. About 100L of organic layer is decompressed and concentrated under the conditions of-0.06 to-0.1 MPa and 40 +/-5 ℃ until no solvent flows out.
Adding 13.5L of methyl tert-butyl ether into the concentrated solution, stirring for dissolving, adding about 36L of 5% sodium hydroxide solution, adjusting the pH value to be 11-12, stirring for 10min, filtering with diatomite (about 1kg), pumping the filtrate into a 150L reaction kettle, separating, discarding the organic layer, pumping the water layer into a 100L reaction kettle, heating to 65 +/-5 ℃, stirring for 2h, cooling to room temperature (30 +/-5 ℃), adding 9.5L of methyl tert-butyl ether into the 100L reaction kettle, washing the aqueous phase (stirring for 10min), separating, and discarding the organic layer. The aqueous layer was taken out into a 150L reactor, 8.4L of methyl t-butyl ether was added to the 150L reactor to wash the aqueous layer (stirred for 10min) for separation, and the organic layer was discarded.
Adjusting pH to 2-3 with 4mol/L hydrochloric acid (about 8L) (temperature controlled < 20 deg.C), extracting with 12.6L methyl tert-butyl ether (stirring for 10min), separating, collecting organic layer, pumping water layer into 100L reaction kettle, extracting with 12.6L methyl tert-butyl ether (stirring for 10min), separating, and discarding water layer. Combining the organic phases into a 100L reaction kettle, adding 12.6L saturated salt solution, washing once (stirring for 10min), separating liquid, removing a water layer, adding 2.2kg of anhydrous sodium sulfate into the organic layer, stirring and drying for 0.5h, filtering, pumping the filtrate into a 50L glass reaction kettle, and concentrating under reduced pressure at-0.08 to-0.1 MPa and 40 +/-5 ℃ until no liquid drops flow out.
A 50L reactor was charged with ethyl acetate: pulping a 1:4 mixture (about 21L) of n-heptane at 20 + -5 deg.C for 1h, and filtering; the molar ratio of the filter cake to ethyl acetate is: washing twice with a 1:4 mixed solution (100 mL); the obtained filtrate is concentrated under reduced pressure at the temperature of between 0.08 and 0.1mPa below zero and 40 +/-5 ℃ until no liquid drops flow out to obtain 5.02kg of an oily intermediate DBT2 (2-valeryl benzoic acid), the yield is 60.09%, and the purity is as follows: 85.31 percent.
And step 3: preparation of butylphthalide semi-finished product
Adding 25.4L of purified water into a 100L reaction kettle, adding 1.17kg (30.5mol) of NaOH, stirring and dissolving, adding 25.02kg (26.18mol) of DBT25 when the temperature is reduced to 25 +/-5 ℃, stirring for 30min at 25 +/-5 ℃, opening a refrigerant, starting to reduce the temperature to 0 +/-5 ℃, completely dissolving 1.29kg (35.42mol) of sodium borohydride with 6.5L of purified water, slowly dropwise adding the sodium borohydride into the kettle, controlling the temperature to be below 10 ℃, and stirring for 30min after the addition. Heating to room temperature of 25 +/-5 ℃, reacting for 14-16 h, cooling the reaction kettle to 0 +/-5 ℃ after the reaction is finished, adding 4mol/L hydrochloric acid of about 12.8L to adjust the pH value to 2.5 (slowly dropwise adding hydrochloric acid, controlling the temperature T to be less than 10 ℃), adding a proper amount of methyl tert-butyl ether if stirring is difficult in the dropwise adding process, and stirring for 14-16 h at 25 +/-5 ℃. After the reaction is finished, adding 10.5L of methyl tert-butyl ether to extract twice (stirring for 10min), combining organic layers, transferring the organic phase to a 50L reaction kettle, adding 10.5L of 12.5% ammonia water to wash for 3 times (stirring for 30min each time), separating, discarding a water layer, pumping the organic phase back to the kettle, washing twice with 10.5L of saturated saline water (stirring for 10min each time), separating, discarding a water layer, pumping the organic layer back to the kettle, adding 4.2kg of anhydrous sodium sulfate, stirring and drying for 30min, discharging and filtering, concentrating the filtrate under reduced pressure of-0.08 to-0.1 mPa at 40 +/-5 ℃ until no liquid drops flow out, and obtaining a DBT1 (butylphthalide) crude product.
Opening a ring of lactone: 1.66kg (28.52mol) of potassium hydroxide was added to a 100L reactor, and 4.7L of methanol was slowly added (the internal temperature was raised from 20 ℃ C. to 71 ℃ C., and the solvent was refluxed); refluxing and stirring until potassium hydroxide is completely dissolved, adding the obtained DBT1 crude product under a refluxing state, refluxing and stirring for 30min, and cooling; when the internal temperature is reduced to 50 ℃, 47L of methyl tert-butyl ether is slowly added, and after the dropwise addition is finished, the mixture is stirred for 2 hours. And after the reaction is finished, carrying out suction filtration, treating filtrate as waste liquid, washing a filter cake by using methyl tert-butyl ether, and carrying out suction filtration until the filter cake is dry.
Potassium salt recrystallization: transferring the obtained filter cake into a 100L reaction kettle, adding 6.0L of methanol, heating to 70 +/-5 ℃ for refluxing, and cooling after the solid is completely dissolved; when the internal temperature is reduced to 50 ℃, slowly adding 54L of methyl tert-butyl ether, stirring for 2h, carrying out suction filtration, directly discarding the filtrate, and washing the filter cake with methyl tert-butyl ether.
Lactone ring closure: transferring the filter cake obtained in the previous step to a 50L reaction kettle, adding 25L of water for dissolving, and cooling to 0 +/-5 ℃; slowly adding 4mol/L hydrochloric acid about 4.2L to adjust pH to 2.5, and controlling the temperature below 10 ℃; and (3) adding a proper amount of methyl tert-butyl ether for stirring when the stirring is difficult in the dropwise adding process, and stirring for 14-16 h at the temperature of 25 +/-5 ℃. Extracting with 11.0L of methyl tert-butyl ether for 2 times (stirring for 10min), discarding water layer, mixing organic phases, pumping back into the kettle, washing with 11.0L of saturated sodium bicarbonate for 3 times, discarding water layer, and washing organic layer with 11.0L of saturated saline solution for three times; separating, discarding the water layer, returning the organic layer to the kettle, adding 2.0kg of anhydrous sodium sulfate, drying and stirring for 2h, carrying out suction filtration, discarding the solid, concentrating the filtrate at-0.08-0.1 mPa and 40 +/-5 ℃ under reduced pressure until no liquid drops flow out, and obtaining about 3.16kg of a colorless or light yellow oily semi-finished product DBT1 (butylphthalide), the yield is 68.2%, the purity is 99.99%, and the maximum single impurity content is 0.01%.
(4) Refining of high-purity butylphthalide
Adding 13.16kg of the semi-finished product DBT13 into a 5L distillation kettle, installing a reduced pressure distillation device, and simultaneously providing a Mach vacuum gauge, slowly raising the temperature outside the distillation kettle to 190 +/-2 ℃, carrying out reduced pressure distillation under the condition that the vacuum degree is 230Pa, distilling the product in a liquid state, collecting a main fraction of 142-.
The results of the analysis of the butylphthalide obtained in example 1 in comparison with the methods mentioned in the respective reference documents are shown in the following table:
Claims (4)
1. the preparation method of the high-purity butylphthalide is characterized by comprising the following steps:
(1) preparation of n-butyl magnesium bromide
Under the protection of nitrogen, adding anhydrous tetrahydrofuran, magnesium chips and n-butyl magnesium bromide into a reaction kettle, stirring and heating to 38-42 ℃, slowly dropwise adding a mixed solution of n-bromobutane and anhydrous tetrahydrofuran, controlling the reaction temperature to be 48-52 ℃ in the dropwise adding process, keeping the temperature for reacting for 25-35 minutes after the dropwise adding is finished, and removing the residual magnesium chips to prepare an n-butyl magnesium bromide Grignard reagent; the molar ratio of the magnesium chips to the n-butyl magnesium bromide to the n-bromobutane is 245: 3-4: 225-240;
(2) synthesis of 2-valeryl benzoic acid
Under the protection of nitrogen, phthalic anhydride and n-butyl magnesium bromide in a Grignard reagent are used as raw materials, cuprous iodide is used as a catalyst, the raw materials react for 50-70 minutes in anhydrous tetrahydrofuran at the temperature of-30-5 ℃, and after the reaction is finished, 2-valeryl benzoic acid is prepared through post-treatment; the molar ratio of the added cuprous iodide to the phthalic anhydride is 0.04-0.08: 1, and the molar ratio of the n-butyl magnesium bromide in the Grignard reagent to the phthalic anhydride is 0.9-2.0: 1;
(3) synthesis of butylphthalide
Stirring 2-valeryl benzoic acid and a sodium hydroxide solution at 20-30 ℃ for reaction, cooling to below 10 ℃, slowly dropwise adding a sodium borohydride solution under the protection of nitrogen, after dropwise adding, heating to 20-30 ℃, reacting for 14-20 h, after the reaction is finished, cooling to-5 ℃, adding a hydrochloric acid solution to adjust the pH value to 2.4-2.6, then reacting for 14-20 h at 20-30 ℃, extracting the obtained product, washing and drying the extracted organic phase, and concentrating under reduced pressure at-0.06-0.09 MPa and 35-45 ℃ to obtain a crude butylphthalide product; after the butyl phthalide crude product is post-treated, butyl phthalide is prepared; the molar ratio of the 2-valeryl benzoic acid to the sodium hydroxide in the sodium hydroxide solution is 1: 1-1.3: 1, and the molar ratio of the 2-valeryl benzoic acid to the sodium borohydride in the sodium borohydride solution is 1: 1.2-1.6;
(4) purification of butylphthalide
Transferring the butylphthalide prepared in the step (3) into a reduced pressure distillation device for reduced pressure distillation, heating the reduced pressure distillation device to 140-200 ℃, preserving the temperature, carrying out reduced pressure distillation under the condition that the vacuum degree is 100-450 Pa, discarding front fraction, collecting main fraction at 140-150 ℃ to obtain high-purity butylphthalide;
in the step (3), the post-treatment step is as follows: mixing potassium hydroxide and methanol, heating, refluxing and dissolving, then transferring a crude butylphthalide product to a mixed solution of potassium hydroxide and methanol, refluxing and stirring, adding methyl tert-butyl ether when the temperature is reduced to 50 ℃, separating out a large amount of solids, washing the separated solids, adding methanol, heating to 65-75 ℃, refluxing, after the solids are completely dissolved, adding methyl tert-butyl ether when the temperature is reduced to 50 ℃, performing suction filtration, washing a filter cake, adding water for dissolving, and cooling to-5 ℃; adding a hydrochloric acid solution to adjust the pH value to 2.4-2.6, then reacting for 14-20 h at 20-30 ℃, extracting the obtained product, washing and drying the extracted organic phase, and concentrating under reduced pressure at-0.06-0.09 MPa at 35-45 ℃ until no liquid drops flow out to obtain colorless or light yellow oily butylphthalide.
2. The method according to claim 1, wherein in the step (2), the post-treatment step is as follows: after the reaction is finished, adding hydrochloric acid into a reaction system to adjust the pH value of the solution to 2-3, separating liquid, extracting a water layer by using methyl tert-butyl ether, combining organic layers, washing the organic layer, and concentrating the organic layer under reduced pressure at the temperature of 35-45 ℃ under the pressure of-0.08 to-0.1 MPa after liquid separation until no liquid drops flow out;
adding methyl tert-butyl ether into the obtained concentrated solution, adding a sodium hydroxide solution to adjust the pH value to 11-12, filtering, separating the filtrate, adding methyl tert-butyl ether into a water phase after liquid separation for washing, adjusting the pH value of an obtained water layer to 2-3 by hydrochloric acid, extracting by using methyl tert-butyl ether, combining organic phases, washing and drying the organic phases, filtering, and concentrating the obtained filtrate under reduced pressure at the temperature of 35-45 ℃ under the pressure of-0.08 to-0.1 MPa until no liquid drops flow out;
adding a mixed solution of ethyl acetate and n-heptane into the obtained concentrated solution, stirring, filtering, washing a filter cake by using the mixed solution of ethyl acetate and n-heptane, and concentrating the obtained filtrate under reduced pressure at the temperature of 35-45 ℃ under the pressure of-0.08 to-0.1 MPa until no liquid drops flow out to obtain a light yellow oily intermediate which is 2-valeryl benzoic acid.
3. The preparation method according to claim 1, wherein in the step (4), the butylphthalide prepared in the step (3) is transferred to a reduced pressure distillation device for reduced pressure distillation, the reduced pressure distillation device is heated to 188-192 ℃ and is kept warm, reduced pressure distillation is carried out under the condition that the vacuum degree is 200-300 Pa, front fractions are discarded, and a main fraction at 142-144 ℃ is collected to obtain high-purity butylphthalide.
4. The preparation method of claim 1, wherein the butylphthalide prepared in the step (3) is transferred to a reduced pressure distillation device for reduced pressure distillation, the reduced pressure distillation device is heated to 188-192 ℃ and is kept warm, reduced pressure distillation is performed under the condition that the vacuum degree is 230Pa, front fractions are discarded, and a main fraction at 142-144 ℃ is collected to obtain high-purity butylphthalide.
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| CN101962374A (en) * | 2010-10-21 | 2011-02-02 | 上海应用技术学院 | Preparation method of butylphthalide |
| CN105130934A (en) * | 2015-08-15 | 2015-12-09 | 石药集团恩必普药业有限公司 | Butyl phthalide raw material drug product and preparation method thereof |
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| CN105130934A (en) * | 2015-08-15 | 2015-12-09 | 石药集团恩必普药业有限公司 | Butyl phthalide raw material drug product and preparation method thereof |
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