CN107216298B - Preparation method of butylphthalide - Google Patents
Preparation method of butylphthalide Download PDFInfo
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Abstract
The invention provides a preparation method of butylphthalide, which comprises S1) taking Raney nickel as a catalyst, carrying out hydrogenation reaction on the butenyl phthalide in an alcohol solvent, removing the solvent under reduced pressure to obtain a intermediate, S2) mixing the intermediate, sodium hydroxide and water for reaction, then washing the reaction system with dichloromethane, adding the alcohol solvent, carrying out acid adjustment reaction to obtain a second intermediate, and S3) carrying out cyclization reaction on the second intermediate in an acidic organic solvent to obtain the butylphthalide.
Description
Technical Field
The invention belongs to the technical field of drug synthesis, and particularly relates to a preparation method of butylphthalide.
Background
The butylphthalide [ (+ -) -3-n-butylphthalide ] is a national new drug with independent intellectual property rights in China, has the same structure with levo apigenin [ (-) - (S) -3-n-butylphthalide ] extracted from celery seed oil, is an artificially synthesized racemate, has spectrum anticonvulsant activity, and clinical research results show that the butylphthalide has obvious treatment effect on patients with acute and convalescent cerebral apoplexy, can improve the metabolism of brain energy, increase the cerebral blood flow in an ischemic area, improve the cerebral blood supply, reduce the area of cerebral infarction and protect and repair cerebral nerve cells in the ischemic area, and has the following structural formula:
the butyl phthalide (3-butyl phthalide) soft capsule is sold in the market of Enbip pharmaceutical CoA new medicine with new chemical structure for treating cerebral ischemia and NO and PGI in cerebral blood vessel is disclosed, which can decrease the content of arachidonic acid and increase the content of NO and PGI in cerebral blood vessel2The level of the compound can inhibit the release of glutamic acid, reduce the calcium concentration in cells, inhibit free radicals, improve the activity of antioxidant enzyme and the like, thereby having the pharmacodynamic effect on a plurality of pathological links caused by cerebral ischemia. Can be clinically used for mild and moderate acute ischemic stroke.
In the prior art, Lishao white, Zhang Shaming and the like are published in the university of Lanzhou university Commission (Nature science edition) in 1990, crude butenylphthalide is prepared by heating and refluxing phthalic anhydride, sodium acetate and valeric anhydride at 300 ℃, and is refined by silica gel column chromatography, the yield is 25 percent, and the yield is obviously lower. Diethyl ether is used as a hydrogenation solvent, Pd/C is used as a catalyst, butylphthalide is prepared by reduction, and column chromatography is carried out to obtain the butylphthalide, wherein the yield of the step is 95%. However, the method involves the use of high temperature and diethyl ether, and column chromatography is adopted in the refining process, so that the method is not suitable for industrial production. The method comprises the following process routes:
the Jatropha doctor academic paper of China cooperative medical university mentions that the synthesis of butylphthalide is carried out by using phthalic anhydride, valeric anhydride and sodium valerate, and the yield is 60-65% after rectification; ethanol is used as a hydrogenation solvent, Pd/C is used as a catalyst to prepare a crude butylphthalide product, the yield after distillation is 90-95%, and the obtained fraction is rectified on a vacuum distillation column with a high reflux ratio, so that the rectification yield is 90-95%. The method adopts sodium valerate to replace sodium acetate, reduces the reaction temperature, and avoids the pollution of acetic acid steam to the environment in the reaction process; ethanol is used for catalysis instead of ether, so that the safety is greatly improved, but the ethanol still needs high rectification degree for multiple times of distillation, the energy consumption is high, the total cost is high, and the production is not facilitated. The method comprises the following process routes:
chinese patent with publication number CN105884726A discloses a synthesis method and a purification process of butylphthalide, which comprises the steps of taking o-formylbenzoic acid as a starting material, taking THF as a solvent to react with n-butyl magnesium chloride format reagents, adjusting acid to obtain a butylphthalide product, hydrolyzing a crude butylphthalide product by using an alkaline substance, precipitating solid by using acid, filtering to obtain a butylphthalide intermediate, wherein main impurities of the butylphthalide intermediate are unreacted starting material and phthalide, repeating the acid and alkali adjustment process, and finally performing ring closing and reduced pressure desolventization to obtain high-purity butylphthalide, wherein the purification yield is 48-52%.
Chinese patent with publication number CN105130934A discloses butylphthalide bulk drug products and a preparation method thereof, wherein a butylphthalide crude product is hydrolyzed by potassium hydroxide in methanol, an ether solvent is added after the temperature is reduced, potassium hydroxypentyl benzoate is salted out, the potassium salt is dissolved in water, the ether solvent is added, the mixture is stirred and crystallized for refining, the refined potassium salt is added into the mixture of water and dichloromethane, the pH value is controlled to be 1.5-3.0, the reaction is acidified and ring-closed at the temperature of 30-45 ℃ to obtain the butylphthalide crude product, the vacuum degree is controlled to be 4-5 mmHg in a rectifying tower, the temperature is raised to 154-160 ℃, the reflux ratio is controlled to be 3-7: 1, and the butylphthalide bulk drug is obtained.
Chinese patent publication No. CN105859670A discloses a preparation method of high-purity butylphthalide, which comprises the steps of decompressing a crude butylphthalide product under the vacuum degree of 1-2mbar, collecting 130-140 ℃ fractions, adding the fractions into methanol, hydrolyzing by using inorganic base, concentrating to remove the methanol, adding dichloromethane, stirring to separate out solids to obtain hydroxypentyl benzoate, adding refined sylvite into water, acidifying and cyclizing at the temperature of 30-45 ℃ to obtain butylphthalide, wherein the HPLC purity is not less than 99.90%.
Disclosure of Invention
In view of the above, the technical problem to be solved by the present invention is to provide a preparation method of butylphthalide, which has high yield and high purity without rectification.
The invention provides a preparation method of butylphthalide, which comprises the following steps:
s1) taking Raney nickel as a catalyst, carrying out hydrogenation reaction on butenyl phthalide in an alcohol solvent, and removing the solvent under reduced pressure to obtain a intermediate;
s2) mixing the intermediate, sodium hydroxide and water for reaction, washing a reaction system by using dichloromethane, adding an alcohol solvent, and adjusting acid for reaction to obtain a second intermediate;
s3) carrying out cyclization reaction on the second intermediate in an acidic organic solvent to obtain butylphthalide.
Preferably, the temperature of the hydrogenation reaction in the step S1) is 15-50 ℃; the pressure of the hydrogenation reaction is 1-10 atm.
Preferably, the mass-to-volume ratio of the butenyl phthalide to the alcohol solvent in the step S1) is 1 g: (2-20) ml; the mass of the Raney nickel in the step S1) is 5-20% of that of the butenyl phthalide.
Preferably, the mass volume ratio of the th intermediate to water is 1g (2-20) ml, the mass volume ratio of the th intermediate to the alcohol solvent is 1g (0.1-1) ml, and the mass volume ratio of the butenyl phthalide to dichloromethane is 1g (2-20) ml.
Preferably, the temperature of the mixing reaction in the step S2) is 10-80 ℃, and the time of the mixing reaction is 1-3 h.
Preferably, glacial acetic acid is adopted for regulating acid in the step S2); adjusting the pH value to 4-6; the temperature of the acid adjusting reaction is 0-20 ℃.
Preferably, the temperature of the cyclization reaction in the step S3) is 20-40 ℃; the pH value of the cyclization reaction in the step S3) is 1-4.
Preferably, the butenyl phthalide is prepared according to the following method:
mixing valeric anhydride, phthalic anhydride and partial sodium valerate for reaction, and adding the rest sodium valerate for continuous reaction;
and after the reaction is finished, adjusting the pH value of the reaction system to be alkaline by using ammonia water, and extracting by using dichloromethane to obtain the butenyl phthalide.
Preferably, the step S2) is specifically:
mixing the th intermediate, sodium hydroxide and water at 10-80 ℃ for reaction, keeping the system temperature at 10-30 ℃ after the reaction is finished, washing the reaction system by using dichloromethane, adding an alcohol solvent, and adjusting acid for reaction to obtain a second intermediate.
Preferably, the step S3) is specifically:
performing a ring closing reaction on the second intermediate in an acidic organic solvent, separating an organic layer after the reaction is performed for 0.5-2 h, supplementing the organic solvent, continuing the reaction, and finally combining the organic layers to obtain an organic phase;
and (3) washing the organic phase with a weak alkaline solution, washing with water, drying with a drying agent, and recovering the solvent to obtain butylphthalide.
The invention provides a preparation method of butylphthalide, which comprises S1) taking Raney nickel as a catalyst, carrying out hydrogenation reaction on the butenyl phthalide in an alcohol solvent, removing the solvent under reduced pressure to obtain a intermediate, S2) mixing the intermediate, sodium hydroxide and water for reaction, then washing the reaction system with dichloromethane, adding the alcohol solvent, carrying out acid adjustment reaction to obtain a second intermediate, and S3) carrying out cyclization reaction on the second intermediate in an acidic organic solvent to obtain the butylphthalide.
Drawings
FIG. 1 is an HPLC chromatogram of butylphthalide obtained in example 4 of the present invention;
FIG. 2 is an HPLC chromatogram of the th intermediate obtained in example 5 of the present invention;
FIG. 3 is an HPLC chromatogram of butylphthalide obtained in example 6 of the present invention.
Detailed Description
The technical solutions in the embodiments of the present invention will be described clearly and completely below with reference to the embodiments of the present invention, and it is obvious that the described embodiments are only partial embodiments of of the present invention, rather than all embodiments.
The invention provides a preparation method of butylphthalide, which comprises S1) taking Raney nickel as a catalyst, carrying out hydrogenation reaction on the butenyl phthalide in an alcohol solvent, removing the solvent under reduced pressure to obtain a intermediate, S2) mixing the intermediate, sodium hydroxide and water for reaction, washing the reaction system with dichloromethane, adding the alcohol solvent, carrying out acid adjustment reaction to obtain a second intermediate, and S3) carrying out cyclization reaction on the second intermediate in an acidic organic solvent to obtain the butylphthalide.
The invention has no special limitation on the sources of all raw materials, and the raw materials are available on the market or can be prepared by self.
In the present invention, the butenyl phthalide is preferably prepared by the following method: mixing valeric anhydride, phthalic anhydride and partial sodium valerate for reaction, and adding the rest sodium valerate for continuous reaction; and after the reaction is finished, adjusting the pH value of the reaction system to be alkaline by using ammonia water, and extracting by using dichloromethane to obtain the butenyl phthalide.
The method takes valeric anhydride, phthalic anhydride and sodium valerate as raw materials to synthesize the butylphthalide, and adds the sodium valerate in batches, thereby reducing the danger that a large amount of gas is suddenly and severely released to flush out of a reaction kettle in the heating process; wherein the mole ratio of valeric anhydride, phthalic anhydride and sodium valerate is preferably 1: (0.8-1.2): (0.8 to 1.2), more preferably 1: (0.9-1.1): (0.8-1), and more preferably 1: (1-1.1): (0.8 to 0.9), most preferably 1: 1.1: 0.8.
mixing sodium valerate and phthalic anhydride with part of sodium valerate to react, wherein the reaction temperature is preferably 160-180 ℃, more preferably 165-175 ℃, and still more preferably 170 ℃; the reaction time is preferably 0.5-2 h, more preferably 1-1.5 h, and further preferably 1 h; then adding the rest sodium valerate to continue the reaction; the mass ratio of the partial sodium valerate to the rest sodium valerate is preferably (1-2): (1-2), more preferably 1: 1; the temperature of the continuous reaction is preferably 170-200 ℃, more preferably 180-200 ℃, further preferably 185-195 ℃, and most preferably 190 ℃; the continuous reaction time is preferably 2-5 h, more preferably 2-4 h, and still more preferably 3 h.
After the reaction is continued, the temperature of the reaction system is preferably lowered to 90 to 110 ℃, more preferably to 95 to 105 ℃, further preferably to 100 ℃, water is added, and the reflux reaction is continued by heating. The volume of the added water is preferably 1-4 times, more preferably 2-3 times and even more preferably 2 times of the mass of the valeric anhydride; the time of the reflux reaction is preferably 0.5-2 h, more preferably 1-1.5 h, and still more preferably 1 h.
After the reaction is finished, preferably reducing the temperature to 20-40 ℃, more preferably reducing the temperature to 20-35 ℃, further preferably reducing the temperature to 25-30 ℃, most preferably reducing the temperature to 25 ℃, and adjusting the pH value of the reaction system to be alkaline by using ammonia water, more preferably 8-10, further preferably 8.5-9.5, and most preferably 9; then extracting with dichloromethane; the number of times of extraction is preferably 2-4 times, and more preferably 3 times.
After extraction, preferably washing with dilute ammonia water, washing with deionized water and drying with a drying agent in sequence, and recovering dichloromethane to obtain butenyl phthalide; the washing times of the dilute ammonia water are preferably 2-3 times; the number of washing times of the deionized water is preferably 2-3; the drying agent is not particularly limited as long as it is known to those skilled in the art, and anhydrous calcium chloride is preferable in the present invention.
The obtained butenyl phthalide can be directly subjected to hydrogenation reaction without rectification; and carrying out reduced pressure distillation, and collecting 140-145 ℃/2-3 mmHg fractions to obtain yellow oily liquid with the purity of about 98% and the yield of 70-75%.
Taking Raney nickel as a catalyst, and carrying out hydrogenation reaction on butenyl phthalide in an alcohol solvent, preferably mixing the butenyl phthalide with the alcohol solvent, and then adding Raney nickel to carry out hydrogenation reaction; the alcohol solvent is an alcohol solvent well known to those skilled in the art, and is not particularly limited, and in the present invention, ethanol is preferable, and absolute ethanol is more preferable; the mass volume ratio of the butenyl phthalide to the alcohol solvent is preferably 1 g: (2-20) ml, more preferably 1 g: (3-15) ml, more preferably 1 g: (3-10 ml), more preferably 1 g: (3-8 ml), most preferably 1 g: (4-6 ml); the mass of the Raney nickel is preferably 5-20% of that of butenyl phthalide, and more preferably 10-15%; the temperature of the hydrogenation reaction is preferably 15-50 ℃, more preferably 20-40 ℃, and further preferably 25-35 ℃; the pressure of the hydrogenation reaction is preferably 1-10 atm (1-10 kg/cm)2) More preferably 1 to 8atm, still more preferably 1.5 to 6atm, still more preferably 1.5 to 5atm, still more preferably 1.5 to 3.5atm, and most preferably 2.5 atm; and finishing the reaction until hydrogen is not absorbed.
After the reaction is finished, the catalyst is preferably removed, and after the solvent is removed under reduced pressure, a light yellow oily liquid which is an intermediate, namely a crude butylphthalide is obtained.
The th intermediate, sodium hydroxide and water are mixed for reaction, preferably, the sodium hydroxide and the water are mixed firstly, then the th intermediate is dripped under the condition of stirring, the mass volume ratio of the th intermediate to the water is preferably 1g (2-20) ml, more preferably 1g (3-15) ml, more preferably 1g (3-10 ml), more preferably 1g (3-8 ml), and most preferably 1g (4-6 ml), the temperature of the mixing reaction is preferably 10-80 ℃, more preferably 35-80 ℃, more preferably 50-60 ℃, and the time of the mixing reaction is preferably 1-3 h, more preferably 2-3 h, and more preferably 2 h.
After the reaction is finished, preferably enabling the temperature of the reaction system to be 10-30 ℃, more preferably 20-30 ℃, still more preferably 20-25 ℃, washing the reaction system with dichloromethane to obtain a yellow clear liquid, adding an alcohol solvent, and adjusting acid to carry out the reaction, wherein the alcohol solvent is well known to those skilled in the art, and is not particularly limited, ethanol is preferably used in the invention, anhydrous ethanol is more preferably used, the mass volume ratio of the th intermediate to the alcohol solvent is preferably 1g (0.1-1) ml, more preferably 1g (0.2-0.8) ml, still more preferably 1g (0.3-0.5) ml, the acid adjustment is preferably carried out by using an organic acid, more preferably glacial acetic acid, the acid adjustment is preferably carried out so that the pH value of the reaction system is 4-6, more preferably 5-6, still more preferably 6, the temperature of the acid adjustment reaction is preferably 0-20 ℃, more preferably 0-15 ℃, still more preferably 0-10 ℃, the temperature of the acid adjustment reaction is preferably carried out, filtration is preferably carried out, and the second intermediate, namely hydroxypentanoic acid is obtained.
Carrying out a cyclization reaction on the second intermediate in an acidic organic solvent; wherein, the organic solvent is any one known to those skilled in the art, and is not particularly limited, and dichloromethane is preferred in the present invention; the acidic organic solvent preferably provides acidic conditions using a mineral acid, more preferably hydrochloric acid; the temperature of the cyclization reaction is preferably 20-40 ℃, and more preferably 25-35 ℃; the pH value of the cyclization reaction is preferably 1-4, more preferably 1-3, and further preferably 1-2; in the present invention, the step is preferably embodied as follows: carrying out a ring closing reaction on the second intermediate in an acidic organic solvent, after the reaction is carried out for 0.5-2 h, preferably for 0.5-1 h, separating an organic layer, supplementing the organic solvent, continuing the reaction, and finally combining the organic layers to obtain an organic phase; and (3) washing the organic phase with a weak alkaline solution, washing with water, drying with a drying agent, and recovering the solvent to obtain butylphthalide. The continuous reaction time is preferably 0.5-2 h, and more preferably 0.5-1 h; the weak alkaline solution is a weak alkaline solution well known to those skilled in the art, and is not particularly limited, and in the present invention, dilute ammonia water is preferred; the drying agent is not particularly limited as long as it is known to those skilled in the art, and in the present invention, anhydrous calcium chloride is preferable; the method for recovering the solvent is not particularly limited as long as it is a method known to those skilled in the art, and it is preferable to recover the solvent by concentration under reduced pressure in the present invention. In the step, the second intermediate is added in batches, and the second intermediate is directly closed because the reaction is always in an acidic environment, so that the stirring is not influenced.
The invention takes water as a hydrolysis reaction solvent, removes impurities by extraction of dichloromethane, separates out a second intermediate by adjusting acid with ethanol, performs a refining function by filtration and purification, does not need to be refined by steps, and can obtain the butylphthalide bulk drug which meets the preparation requirements after acidification and cyclization.
The preparation process of butylphthalide provided by the invention comprises the following steps:
the method adopts the alcohol solvent and the dichloromethane as the reaction or extraction solvent, the alcohol solvent and the dichloromethane can be effectively recovered and have low price, the production cost is greatly reduced, and the high-purity butylphthalide meeting the preparation requirement can be obtained with high yield through hydrolysis purification and acid adjustment filtration purification, without the step of reduced pressure rectification, and the operation is simple. Moreover, the invention can ensure that the quality of the produced product meets the requirements of the raw material medicaments through the process verification of a pilot plant test and a pilot plant test, and the process has high yield and good reproducibility and feasibility.
In order to further the present invention, the following examples are provided to describe the preparation method of butylphthalide in detail.
The reagents used in the following examples are all commercially available.
EXAMPLE 1 preparation and distillation of Butylphthalide (DBT-1)
Adding 93.12g of valeric anhydride, 111.09g of phthalic anhydride and 24.82g of sodium valerate into a 1L reaction bottle, stirring and mixing uniformly, and heating to about 170 ℃ for reaction for 1 h; then 24.82g of sodium valerate is added, the temperature is raised to about 190 ℃, and the heat preservation reaction is continued for 3 hours; after the reaction is finished, cooling the system to about 100 ℃, dropwise adding 186mL of deionized water, continuously heating to reflux, continuously refluxing for 1h, cooling, and cooling to room temperature; controlling the temperature of the system to be about 25 ℃, adjusting the pH value to 9 by adopting concentrated ammonia water, extracting for three times by adopting dichloromethane of 450mL, washing twice by adopting 150mL of dilute ammonia water (1%), washing twice by adopting 150mL of deionized water, and drying anhydrous calcium chloride; and (3) carrying out suction filtration, removing the drying agent, concentrating and recovering dichloromethane to obtain deep red oily liquid, carrying out reduced pressure distillation on a 20cm long thorn type rectifying column, and collecting 140-145 ℃/2-3 mmHg fractions to obtain 62.88g of yellow oily liquid, namely, the butenephthalein (DBT-1).
The butenylphthalide (DBT-1) obtained in example 1 was analyzed by high performance liquid chromatography, and the (Z/E) purity was about 98.196% (HPLC), the larger impurities were arranged from large to small as 1.083%, 0.449%, 0.058%, and the yield of this step was 74.8%.
EXAMPLE 2 preparation of Hydroxypentylbenzoic acid (DBT-2)
To a 1L hydrogenation reactor were added 240mL of absolute ethanol, 60.00g of butenyl phthalide (DBT-1), and 9.00g of Raney nickel (wet), and air was purged by 4 times of hydrogen exchange. Heating to 25-35 deg.C, and controlling pressure to 2.5 atmospheric pressure (2.5 kg/cm)2) Hydrogenation reaction is carried out for about 2 hours until no hydrogen is absorbed, the catalyst is removed, and the ethanol is concentrated under reduced pressure to obtain light yellow oily liquid which is intermediate with the purity of 96.324 percent.
Adding 300ml of deionized water and 13.20g of sodium hydroxide into a 1L reaction bottle, stirring for dissolving, adding the light yellow oily liquid, controlling the temperature to be 50-60 ℃, and reacting for about 2 hours; after the reaction is finished, the temperature is reduced to about 20 ℃, 300mL of dichloromethane is used for extraction for three times, 30mL of absolute ethyl alcohol is added into a water phase, the pH value is adjusted to be 6 by glacial acetic acid, the filtration is carried out, and the filter cake is washed by 30mL of water to obtain a second intermediate (DBT-2).
EXAMPLE 3 preparation and rectification of butylphthalide (DBT)
Adding 120ml of 2N hydrochloric acid and 120ml of dichloromethane into a 1L reaction bottle, adjusting the pH value to 1-2, and controlling the temperature to be 25-35 ℃; and (3) adding hydroxyl amyl benzoic acid, namely a second intermediate (DBT-2), into the reaction system in batches, and controlling the temperature of the system to be 25-35 ℃ for reaction for 30 min. And (3) separating a dichloromethane layer, continuously adding 120ml of dichloromethane, controlling the temperature of the system to be 25-35 ℃, controlling the pH to be 1-2, and continuously reacting for 30 min. Combining the organic layers, washing with dilute ammonia water, washing with deionized water, and drying with anhydrous calcium chloride; vacuum concentrating to recover solvent to obtain 26.43g pale yellow oily liquid, i.e. butylphthalide.
The butylphthalide obtained in example 3 was analyzed by high performance liquid chromatography to obtain 99.718% purity and 0.070% maximum single impurity. Refining yield: 43.6 percent.
EXAMPLE 4 preparation and distillation of Butylphthalide (DBT-1)
Adding 441.41g of valeric anhydride, 386.59g of phthalic anhydride and 117.81g of sodium valerate into a 5L reaction bottle, stirring and mixing uniformly, and heating to about 170 ℃ for reaction for 1 h; then, 118.00g of sodium valerate is added, the temperature is raised to about 190 ℃, and the heat preservation reaction is continued for 3 hours; after the reaction is finished, cooling the system to about 100 ℃, dropwise adding 1L of deionized water, continuously heating to reflux, continuously refluxing for 1h, cooling, and cooling to room temperature; controlling the temperature of the system to be about 25 ℃, adjusting the pH value to 9 by adopting concentrated ammonia water, extracting for three times by adopting dichloromethane 2.5L, washing twice by adopting 1L of dilute ammonia water (1%), washing twice by adopting 1L of deionized water, and drying 100g of anhydrous calcium chloride; and (2) carrying out suction filtration, removing a drying agent, concentrating and recovering dichloromethane to obtain a deep red oily liquid, carrying out reduced pressure distillation on a 20cm long thorn type rectifying column, and collecting a distillate at 140-145 ℃/2-3 mmHg to obtain 339.66g of a yellow oily liquid, namely, the butenephthalein (DBT-1).
The butenylphthalide (DBT-1) obtained in example 1 was analyzed by high performance liquid chromatography to obtain an HPLC profile thereof, as shown in fig. 1. As can be seen from FIG. 1, the purity (Z/E) is about 98.367% (HPLC), the larger impurities are 0.870%, 0.116% and 0.471% from large to small, and the yield in this step is 76.1%.
EXAMPLE 5 preparation of Hydroxypentylbenzoic acid (DBT-2)
1300mL of absolute ethanol, 325.00g of butenyl phthalide (DBT-1), and 48.75g of Raney nickel (wet) were added to the hydrogenation reactor, and hydrogen exchange was performed 4 times to remove air. Heating to 25-35 deg.C, and controlling pressure to 2.5 atmospheric pressure (2.5)kg/cm2) Hydrogenation reaction is carried out for about 3 hours until no hydrogen is absorbed, the catalyst is removed, and the ethanol is concentrated under reduced pressure to obtain light yellow oily liquid which is intermediate with the purity of 97.893 percent.
Adding 1600ml of deionized water and 71.20g of sodium hydroxide into a 3L reaction bottle, stirring for dissolving, adding the light yellow oily liquid, controlling the temperature to be 50-60 ℃, and reacting for about 2 hours; after the reaction is finished, the temperature is reduced to about 20 ℃, 1600mL dichloromethane is used for extraction for three times, 160mL absolute ethyl alcohol is added into a water phase, the pH value is adjusted to 6 by glacial acetic acid, the filtration is carried out, and 160mL water is used for washing a filter cake to obtain a second intermediate (DBT-2).
The th intermediate obtained in example 2 was analyzed by high performance liquid chromatography to obtain an HPLC profile, as shown in FIG. 2.
Example 6 preparation and rectification of butylphthalide (DBT)
Adding 650ml of 2N hydrochloric acid and 650ml of dichloromethane into a 2L reaction bottle, adjusting the pH value to 1-2, and controlling the temperature to be 25-35 ℃; and (3) adding hydroxyl amyl benzoic acid, namely a second intermediate (DBT-2), into the reaction system in batches, and controlling the temperature of the system to be 25-35 ℃ for reaction for 30 min. And (3) separating a dichloromethane layer, continuously adding 325ml of dichloromethane, controlling the temperature of the system to be 25-35 ℃, controlling the pH to be 1-2, and continuously reacting for 30 min. Combining the organic layers, washing with dilute ammonia water, washing with deionized water, and drying with anhydrous calcium chloride; vacuum concentrating to recover solvent to obtain pale yellow oily liquid 190.2g, i.e. butylphthalide.
The butylphthalide obtained in example 3 was analyzed by high performance liquid chromatography to obtain its HPLC profile, as shown in fig. 3. As can be seen from FIG. 3, the purity was 99.823%, maximum single impurity was 0.088%, and total impurity was 0.177%. Refining yield: 57.9 percent.
Claims (8)
- The preparation method of 1 and butylphthalide is characterized by comprising the following steps:s1) taking Raney nickel as a catalyst, carrying out hydrogenation reaction on butenyl phthalide in an alcohol solvent, and removing the solvent under reduced pressure to obtain a intermediate;s2) mixing the intermediate, sodium hydroxide and water for reaction, washing a reaction system with dichloromethane, adding an alcohol solvent, adjusting the acid for reaction, and filtering to obtain a second intermediate, wherein the mass volume ratio of the intermediate to water is 1g (2-20) ml, the mass volume ratio of the intermediate to the alcohol solvent is 1g (0.1-1) ml, the mass volume ratio of the butenyl phthalide to dichloromethane is 1g (2-20) ml, glacial acetic acid is adopted for adjusting the acid in the step S2), the pH value is adjusted to be 6, and the temperature of the acid adjusting reaction is 0-20 ℃;s3) carrying out cyclization reaction on the second intermediate in an acidic organic solvent to obtain butylphthalide; the pH value of the cyclization reaction is 1-2.
- 2. The method according to claim 1, wherein the temperature of the hydrogenation reaction in the step S1) is 15 to 50 ℃; the pressure of the hydrogenation reaction is 1-10 atm.
- 3. The preparation method according to claim 1, wherein the mass-to-volume ratio of the butenyl phthalide to the alcohol solvent in the step S1) is 1 g: (2-20) ml; the mass of the Raney nickel in the step S1) is 5-20% of that of the butenyl phthalide.
- 4. The preparation method according to claim 1, wherein the temperature of the mixing reaction in the step S2) is 10-80 ℃, and the time of the mixing reaction is 1-3 h.
- 5. The method as claimed in claim 1, wherein the temperature of the cyclization reaction in step S3) is 20 to 40 ℃.
- 6. The method according to claim 1, wherein the butenyl phthalide is prepared by:mixing valeric anhydride, phthalic anhydride and partial sodium valerate for reaction, and adding the rest sodium valerate for continuous reaction;and after the reaction is finished, adjusting the pH value of the reaction system to be alkaline by using ammonia water, and extracting by using dichloromethane to obtain the butenyl phthalide.
- 7. The preparation method according to claim 1, wherein the step S2) is specifically:mixing the th intermediate, sodium hydroxide and water at 10-80 ℃ for reaction, controlling the system temperature at 10-30 ℃ after the reaction is finished, washing the reaction system by using dichloromethane, adding an alcohol solvent, adjusting acid for reaction, and filtering to obtain a second intermediate.
- 8. The preparation method according to claim 1, wherein the step S3) is specifically:performing a ring closing reaction on the second intermediate in an acidic organic solvent, separating an organic layer after the reaction is performed for 0.5-2 h, supplementing the organic solvent, continuing the reaction, and finally combining the organic layers to obtain an organic phase;and (3) washing the organic phase with a weak alkaline solution, washing with water, drying with a drying agent, and recovering the solvent to obtain butylphthalide.
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