CN107235943B - Preparation method of high-purity butylphthalide - Google Patents

Abstract

The invention provides a preparation method of high-purity 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 first intermediate; s2) mixing the first intermediate, potassium hydroxide, tetrahydrofuran and water for reaction, and cooling and crystallizing after the reaction is finished to obtain a second intermediate; s3) carrying out cyclization reaction on the second intermediate in an acidic organic solvent to obtain butylphthalide. Compared with the prior art, the method adopts the alcohol solvent and the tetrahydrofuran as the reaction solvent, can effectively recover the solvent, has low price, and greatly reduces the production cost; meanwhile, through hydrolysis and refining, the requirement on a rectifying tower of production equipment is reduced, repeated rectification is not needed, and energy is saved.

Description

Preparation method of high-purity butylphthalide

Technical Field

The invention belongs to the technical field of drug synthesis, and particularly relates to a preparation method of high-purity butylphthalide.

Background

Butyl phthalide [ (+ -) -3-n-butyl phthalide ] is a new medicine for the state with independent intellectual property rights in China. It has the same structure as that of levo apigenin ((-) - (S) -3-n-butylphthalide) extracted from celery seed oil, is synthesized racemate, and has broad-spectrum anticonvulsive activity. The clinical research result shows that butylphthalide has obvious treatment effect on patients with acute and convalescent ischemic stroke; can improve brain energy metabolism, increase cerebral blood flow in ischemic region, improve cerebral blood supply, reduce cerebral infarction area, and protect and repair cerebral nerve cells in ischemic region. The structural formula is as follows:

the butyl phthalide (3-butyl phthalide) soft capsule is a new anti-cerebral ischemia drug with independent intellectual property right and brand new chemical structure sold in the market of Enbiprep pharmaceutical Co., Ltd, the trade name is Enbiprep, and the NO and PGI of cerebral vessel endothelium can be improved by reducing the content of arachidonic acid₂Inhibiting glutamate release, reducing intracellular calcium concentration, inhibitingFree radical production, improvement of antioxidant enzyme activity and other mechanisms, and has medicinal effect on various 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 method for synthesizing butylphthalide and a purification process, wherein o-formylbenzoic acid is used as a starting material, THF is used as a solvent to react with n-butyl magnesium chloride format reagent, and a butylphthalide product is prepared after acid adjustment; hydrolyzing the crude butylphthalide product with alkaline matter, separating solid with acid, and filtering to obtain butylphthalide intermediate with unreacted starting material and phthalide as main impurities; and repeating the acid and alkali adjusting process, and finally performing ring closing and decompression desolventizing to obtain the high-purity butylphthalide, wherein the purification yield is 48-52%. The method has simple purification process operation, does not need column chromatography and high-temperature and high-vacuum reduced pressure rectification, and is easy for industrial production; however, the intermediate plate precipitated from water in the acid adjusting process is not easy to be discharged from the reaction kettle, the butylphthalide intermediate is extremely unstable, self-cyclization can occur under the solid condition, and multiple acid and alkali adjustment can result in low yield and high total cost. The method comprises the following process routes:

chinese patent publication No. CN105130934A discloses a butylphthalide crude drug product and its preparation method, which comprises hydrolyzing butylphthalide crude product in methanol with potassium hydroxide, cooling, adding ether solvent to salt out potassium hydroxypentylphthalate; dissolving the potassium salt in water, adding an ether solvent, stirring, crystallizing and refining; and adding the refined potassium salt into a mixed solution of water and dichloromethane, controlling the pH value to be 1.5-3.0, acidifying and ring closing at the temperature of 30-45 ℃ to obtain a crude butylphthalide product, controlling the vacuum degree to be 4-5 mmHg in a rectifying tower, heating to 154-160 ℃, and controlling the reflux ratio to be 3-7: 1 to obtain the butylphthalide bulk drug. In the method, the hydroxyl amyl benzoate potassium salt has extremely high solubility in water, the ether solvent is used for crystallization, the yield is low, and the cost of the ether solvent is higher, so that the production cost is higher.

Chinese patent publication No. CN1136209C reports that racemic-butylphthalide is subjected to hydrolytic ring-opening using an alkaline substance such as one of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium methoxide and sodium ethoxide, and the solvent used in the dissociation reaction includes one of methanol, ethanol, water or alcohol-water mixture. After acidification, acid-base neutralization is carried out on the obtained product and optically active amine to prepare salt for resolution, and after crystallization and purification, the optically active ammonium salt of a single isomer is re-acidified and cyclized at the temperature of 0-40 ℃ and the pH value of 1.0-4.0 to obtain high-purity optically active (-) -n-butylphthalide and (+) -n-butylphthalide. However, the patent mentions that the hydrolysis is performed by using one of methanol, ethanol, water or alcohol-water mixture, and the solubility of the solvent to potassium salt is high, so that the potassium salt is difficult to precipitate.

Disclosure of Invention

In view of this, the technical problem to be solved by the present invention is to provide a method for preparing high-purity butylphthalide, which has high yield and high purity.

The invention provides a preparation method of high-purity 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 first intermediate;

s2) mixing the first intermediate, potassium hydroxide, tetrahydrofuran and water for reaction, and cooling and crystallizing after the reaction is finished 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-to-volume ratio of the first intermediate, tetrahydrofuran and water is 1 g: (2-20) ml: (0.03-2.0) 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, the temperature for crystallization in the step S2) is-10 ℃ to 35 ℃.

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:

and mixing tetrahydrofuran, water and potassium hydroxide, then adding the first intermediate for mixing reaction, cooling and crystallizing after the reaction is received, filtering, and washing with tetrahydrofuran 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, recovering the solvent, and finally rectifying to obtain butylphthalide.

The invention provides a preparation method of high-purity 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 first intermediate; s2) mixing the first intermediate, potassium hydroxide, tetrahydrofuran and water for reaction, and cooling and crystallizing after the reaction is finished to obtain a second intermediate; s3) carrying out cyclization reaction on the second intermediate in an acidic organic solvent to obtain butylphthalide. Compared with the prior art, the method adopts the alcohol solvent and the tetrahydrofuran as the reaction solvent, can effectively recover the solvent, has low price, and greatly reduces the production cost; meanwhile, through hydrolysis and refining, the requirement on a rectifying tower of production equipment is reduced, repeated rectification is not needed, and energy is saved.

Drawings

FIG. 1 is an HPLC chromatogram of butylphthalide obtained in example 2 of the present invention;

FIG. 2 is an HPLC chromatogram of the first intermediate obtained in example 4 of the present invention;

FIG. 3 is an HPLC chromatogram of the second intermediate obtained in example 4 of the present invention;

FIG. 4 is an HPLC chromatogram of crude butylphthalide obtained in example 6 of the present invention;

FIG. 5 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 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 provides a preparation method of high-purity 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 first intermediate; s2) mixing the first intermediate, potassium hydroxide, tetrahydrofuran and water for reaction, and cooling and crystallizing after the reaction is finished to obtain a second intermediate; s3) carrying out cyclization reaction on the second intermediate in an acidic organic solvent to obtain 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 is obtained as a first intermediate, namely a crude butylphthalide product.

Mixing the first intermediate, potassium hydroxide, tetrahydrofuran and water for reaction, preferably mixing tetrahydrofuran, water and potassium hydroxide firstly, then adding the first intermediate for reaction, more preferably mixing tetrahydrofuran and water firstly, then adding potassium hydroxide in batches under the condition of stirring, and then dropwise adding the first intermediate for reaction; the temperature of the mixing reaction is preferably 10-80 ℃, more preferably 35-reflux, and further preferably reflux; the mixing reaction time is preferably 1-3 h, more preferably 1.5-2.5 h, and further preferably 2 h; the mass-to-volume ratio of the first intermediate, tetrahydrofuran and water is preferably 1 g: (2-20) ml: (0.03-2.0) ml, more preferably 1 g: (2-15) ml: (0.03-1.5) ml, more preferably 1 g: (2-10) ml: (0.05-1.0) ml, more preferably 1 g: (3-8) ml: (0.05-0.5) ml, most preferably 1 g: (3-8) ml: (0.05-0.2) ml.

After the reaction is finished, cooling and crystallizing to obtain a second intermediate; the temperature for cooling and crystallization is preferably-10-35 ℃, more preferably 5-30 ℃, further preferably 15-25 ℃, and most preferably 20 ℃; the cooling crystallization time is preferably 0.5-3 h, and more preferably 1-2 h; and (4) preferably filtering after cooling and crystallization, and washing a filter cake by using tetrahydrofuran to obtain a second intermediate. The mixed solution of tetrahydrofuran and water is used as a reaction solvent and also used as a refining solvent, potassium salt can be directly separated out after temperature reduction, further refining is not needed, and the purity of the second intermediate obtained by the step is more than 99.5 percent, and the maximum single impurity is less than 0.1 percent (HPLC area normalization method).

Performing a cyclization reaction on the second intermediate in an acidic organic solvent, preferably dissolving the second intermediate in water, and then adding the second intermediate into the acidic organic solvent to perform the cyclization reaction; 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; in the present invention, it is preferable that the organic solvent is first adjusted to be acidic, heated to the temperature of the cyclization reaction, and then the second intermediate dissolved in water is dropped; 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. 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 dissolved in water and is dripped, and the second intermediate, namely the potassium hydroxypentylbenzoate is neutralized into hydroxypentylbenzoate to directly close the ring because the reaction is always in an acid environment, so that the stirring is not influenced by a large amount of hydroxypentylbenzoate.

After recovering the solvent under reduced pressure, a pale yellow oily liquid is obtained, and preferably, the distillation is carried out to obtain butylphthalide. The rectification method is a method well known by the technical personnel in the field, and is not limited in particular, in the invention, reduced pressure rectification is preferably carried out, 154 ℃/4-5 mmHg fractions are collected, and colorless oily liquid, namely butylphthalide, is obtained; the vacuum rectification preferably adopts a thorn-shaped rectification column, and more preferably adopts a 40cm long thorn-shaped rectification column.

The invention adopts the alcohol solvent and the tetrahydrofuran as the reaction or extraction solvent, can be effectively recycled, has low solvent price and greatly reduces the production cost; meanwhile, through hydrolysis and refining, the requirement on a rectifying tower of production equipment is reduced, repeated rectification is not needed, and energy is saved.

The preparation process of butylphthalide provided by the invention comprises the following steps:

according to the invention, tetrahydrofuran and water are used as hydrolysis solvents, potassium hydroxypentyl benzoate can be directly separated out, and simultaneously, the refining effect is achieved, further refining is not needed, the purity of acidification cyclization or the obtained crude butylphthalide product can reach more than 99.5%, and high-purity butylphthalide meeting the preparation requirements can be obtained in a high yield through simple rectification once, the operation is simple, and impurities in butylphthalide can be removed without a high-reflux ratio rectifying column or repeated rectification. 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 describe the present invention, the following will describe the preparation and refining method of butylphthalide in detail with reference to the following examples.

The reagents used in the following examples are all commercially available.

Example 1: preparation and distillation of Butylene phthalide (DBT-1)

Adding 46.56g of valeric anhydride, 40.73g of phthalic anhydride and 12.41g of sodium valerate into a 500ml reaction bottle, stirring and mixing uniformly, heating to about 170 ℃ and reacting for 1 h; then adding 12.41g of sodium valerate, then heating to about 190 ℃, and continuing to perform heat preservation reaction for 3 hours; after the reaction is finished, cooling the system to about 100 ℃, dropwise adding 95.0ml of deionized water, continuously heating until 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 using 186.0 dichloromethane, washing twice by adopting 124.0ml of dilute ammonia water (1 percent), washing twice by adopting 124.0ml of deionized water, and drying by adopting a proper amount of anhydrous calcium chloride; and (3) carrying out suction filtration, removing the drying agent, concentrating and recovering dichloromethane to obtain deep red oily liquid, and carrying out reduced pressure distillation on a 20cm long thorn type rectifying column to obtain yellow oily liquid, namely the butylphthalide.

The butenylphthalide obtained in example 1 was analyzed by high performance liquid chromatography to obtain an HPLC spectrogram result, wherein the purity of the butenylphthalide (Z/E) was 99.154%, the larger impurities were arranged from large to small as 0.563%, 0.117%, 0.056%, and the yield of this step was 70.0%.

Example 2: preparation and distillation of Butylene phthalide (DBT-1)

Adding 2.40kg of valeric anhydride, 2.10kg of phthalic anhydride and 0.64kg of sodium valerate into a 20L reaction bottle, stirring and mixing uniformly, heating to about 170 ℃ and reacting for 1 h; then 0.64kg of sodium valerate is added, then 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 4.8L 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 9.6L dichloromethane, washing twice by adopting 6.4L diluted ammonia water (1 percent), washing twice by adopting 6.4L deionized water, and drying 300g of 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 yellow oily liquid, namely the butylphthalide.

The high performance liquid chromatography is used for analyzing the butylphthalide obtained in the example 2, and an HPLC spectrogram is shown in figure 1. As shown in FIG. 1, the purity of the butylphthalide (Z/E) is 98.058%, the larger impurities are arranged from large to small as 1.259%, 0.367%, 0.123% and 0.078%, and the yield of the step is 72.3%.

Example 3: preparation of Potassium hydroxypentylbenzoate (DBT-2)

Adding 100.0ml of absolute ethyl alcohol and 25.00g of butenyl phthalide (DBT-1) into a hydrogenation kettle, adding 3.75g of Raney nickel (wet), performing nitrogen exchange for 3 times to remove air, performing hydrogen exchange for 3 times, controlling the reaction temperature to be 25-35 ℃, and controlling the pressure to be 2.5 atmospheric pressures (2.5 kg/cm)²) Carrying out hydrogenation reaction for about 3 hours until hydrogen is not absorbed; the catalyst was removed and ethanol was concentrated under reduced pressure to give a pale yellow oily liquid, which gave the first intermediate. HPLC analysis of the first intermediate by high performance liquid chromatography shows that the purity of the hydrogenated crude butylphthalide is 97.555%, and the larger impurities are 0.524%, 0.480%, 0.420%, 0.202% and 0.143% from large to small.

Adding 125.0ml of tetrahydrofuran and 2.5ml of deionized water into a 250ml three-necked flask, adding 9.0g of 82% flaky potassium hydroxide in batches under stirring, and dropwise adding the light yellow oily liquid; heating to reflux, gradually dissolving potassium hydroxide, and then separating out a large amount of solid to react for about 2 hours; after the reaction is finished, the temperature is reduced to about 20 ℃, the mixture is stirred and crystallized for 1h, the mixture is filtered, 25.0ml of tetrahydrofuran is used for washing a filter cake, and the filter cake is decompressed and dried at the temperature of 45 ℃ to obtain 29.35g of a second intermediate, namely, hydroxyl amyl potassium benzoate (DBT-2) and an off-white solid.

HPLC analysis of the second intermediate by high performance liquid chromatography revealed that the purity of DBT-2 is 98.480%, wherein 1.349% of butylphthalide (potassium salt is generated by ring closure in a solvent), and the impurities are 0.075%, 0.065% and 0.032% from large to small. The yield thereof was found to be 89.7%.

Example 4: preparation of Potassium hydroxypentylbenzoate (DBT-2)

Adding 6.8L of absolute ethyl alcohol and 1.70kg of butenyl phthalide (DBT-1) into a hydrogenation kettle, adding 204.0g of Raney nickel (wet), performing nitrogen exchange for 3 times to remove air, performing hydrogen exchange for 3 times, controlling the reaction temperature to be 25-35 ℃, and controlling the pressure to be 2.5 atmospheric pressures (2.5 kg/cm)²) Carrying out hydrogenation reaction for about 3 hours until hydrogen is not absorbed; the catalyst was removed and ethanol was concentrated under reduced pressure to give a pale yellow oily liquid, which gave the first intermediate.

Adding 8.5L of tetrahydrofuran into a 20L reaction kettle, adding 170ml of deionized water, stirring, adding 636.4g of 82% flaky potassium hydroxide in batches, and dropwise adding the light yellow oily liquid; heating to reflux, gradually dissolving potassium hydroxide, and then separating out a large amount of solid to react for about 2 hours; after the reaction is finished, the temperature is reduced to about 20 ℃, the mixture is stirred and crystallized for 1 hour, the mixture is filtered, 1.7L of tetrahydrofuran is used for washing a filter cake, and the filter cake is decompressed and dried at the temperature of 45 ℃ to obtain a second intermediate, namely, hydroxyl amyl potassium benzoate (DBT-2), and 2.01kg of off-white solid.

The first intermediate obtained in example 4 was analyzed by high performance liquid chromatography, and its HPLC spectrum was shown in fig. 2. From fig. 2, it can be seen that the purity of the hydrogenated crude butylphthalide is 95.864%, and the larger impurities are 1.907%, 1.001%, 0.318%, 0.276%, and 0.169% from large to small.

The second intermediate obtained in example 4 was analyzed by high performance liquid chromatography, and its HPLC spectrum was shown in fig. 3. From FIG. 3, it can be seen that the purity of DBT-2 is 99.794%, and the impurities are arranged from large to small as 0.062%, 0.052%, 0.037%, 0.028%, and 0.027%. The yield thereof was found to be 90.5%.

Example 5: preparation of butylphthalide (DBT)

Adding hydrochloric acid and dichloromethane into a 250ml reaction bottle, and heating to 25-35 ℃; dissolving 25.00g of hydroxyl amyl benzoate (DBT-2) in deionized water to be dissolved, dropwise adding the solution into a reaction system, and controlling the temperature of the system to be 25-35 ℃; after the dropwise addition is finished, keeping the pH value between 1 and 2, and continuing the reaction for 30 min. And (3) separating a dichloromethane layer, continuously adding 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, i.e. crude butylphthalide 19.06 g. The purity of the product is 99.794%, and the impurities are 0.102%, 0.051% and 0.027% from large to small.

Example 6: preparation and rectification of butylphthalide (DBT)

Adding hydrochloric acid and dichloromethane into a 20L reaction bottle, and heating to 25-35 ℃; dissolving hydroxyl amyl benzoate potassium (DBT-2) in deionized water to be dissolved, dropwise adding the solution into a reaction system, and controlling the temperature of the system to be 25-35 ℃; after the dropwise addition is finished, keeping the pH value between 1 and 2, and continuing the reaction for 30 min. And (3) separating a dichloromethane layer, continuously adding 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; decompressing, concentrating and recovering the solvent to obtain light yellow oily liquid, namely crude butylphthalide.

Vacuum rectification is carried out by adopting a 40cm long-thorn type rectification column, 154 ℃/4-5 mmHg fractions are collected, colorless oily liquid, namely butylphthalide, is obtained, and the ring closing and distillation yield is 82.2%.

The crude butylphthalide (DBT-CP) obtained in example 6 was analyzed, and its HPLC spectrum was shown in fig. 4. As can be seen from FIG. 4, the purity was 99.853%, and the impurities were 0.055%, 0.048% and 0.044% from large to small.

The butylphthalide obtained in example 6 was analyzed, and its HPLC spectrum was shown in fig. 5. As shown in fig. 5, the purity was 99.903%, and the impurities were 0.040%, 0.037%, and 0.012% from large to small. (by HPLC area normalization).

Claims (6)

1. A preparation method of high-purity 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 first intermediate; the mass volume ratio of the butenyl phthalide to the alcohol solvent 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;

s2) mixing the first intermediate, potassium hydroxide, tetrahydrofuran and water for reaction, and cooling and crystallizing after the reaction is finished to obtain a second intermediate; the mass volume ratio of the first intermediate to the tetrahydrofuran to the water is 1 g: 2-20 ml: 0.03-2.0 ml; the temperature of the mixing reaction is 10-80 ℃, and the time of the mixing reaction is 1-3 h; the crystallization temperature is-10 ℃ to 35 ℃;

s3), firstly, adjusting the organic solvent to be acidic, heating to the temperature of the cyclization reaction, and then dropwise adding a second intermediate dissolved in water to carry out the cyclization reaction to obtain butylphthalide.

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 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.

4. 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.

5. The preparation method according to claim 1, wherein the step S2) is specifically:

and mixing tetrahydrofuran, water and potassium hydroxide, then adding the first intermediate for mixing reaction, cooling and crystallizing after the reaction is finished, filtering, and washing with tetrahydrofuran to obtain a second intermediate.

6. 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, recovering the solvent, and finally rectifying to obtain butylphthalide.

Images