阅读说明：本技术 一种高稳定性3-丁基-1(3h)-异苯并呋喃酮的制备方法 (Preparation method of high-stability 3-butyl-1 (3H) -isobenzofuranone ) 是由 石江涛 梁云科 刘翠环 兰文杰 汪飞 姜召红 于 2020-05-13 设计创作，主要内容包括：本发明涉及一种高稳定性3-丁基-1(3H)-异苯并呋喃酮的制备方法,所述方法包括在3-丁基-1(3H)-异苯并呋喃酮粗品蒸馏/精馏结束泄压时充入保护气体,制得高稳定性3-丁基-1(3H)-异苯并呋喃酮产品,解决了3-丁基-1(3H)-异苯并呋喃酮作为原料药在储存中易降解的难题,保证临床用药的安全性。(The invention relates to a preparation method of high-stability 3-butyl-1 (3H) -isobenzofuranone, which comprises the steps of filling protective gas when the distillation/rectification of a crude product of the 3-butyl-1 (3H) -isobenzofuranone is finished and the pressure is relieved, so that a high-stability 3-butyl-1 (3H) -isobenzofuranone product is prepared, the problem that the 3-butyl-1 (3H) -isobenzofuranone as a raw material medicine is easy to degrade in storage is solved, and the safety of clinical medication is ensured.)

1. A preparation method of high-stability 3-butyl-1 (3H) -isobenzofuranone is characterized by comprising the following steps: and (3) introducing protective gas after the rectification or distillation of the crude 3-butyl-1 (3H) -isobenzofuranone.

2. The method of claim 1, wherein: and filling protective gas when the pressure is released after the rectification or the distillation is finished.

3. The production method according to claim 1 or 2, characterized in that: the protective gas includes, but is not limited to, one or more of nitrogen, helium, neon, argon, krypton and xenon, and preferably argon.

4. The method according to claim 3, characterized by comprising the steps of:

A. optionally, checking the performance of the vacuum system of the device before rectification or distillation;

B. adding the crude product of 3-butyl-1 (3H) -isobenzofuranone into a rectification or distillation still;

C. slowly heating the crude product of the 3-butyl-1 (3H) -isobenzofuranone, and collecting fractions at 100-130 ℃ under the vacuum degree of 100-400 Pa;

D. after the rectification or the distillation is finished, the heating equipment is closed, the vacuum pipeline valve is closed, the protective gas pipeline valve is opened, and the protective gas is discharged to normal pressure or positive pressure;

E. and (4) maintaining the pressure in the tower, opening a valve of the movable storage tank, and discharging to the inerted movable storage tank.

5. The preparation method according to claim 4, wherein the performance of the device is checked before the distillation or rectification, and after the system is stabilized, the vacuum degree is less than or equal to 400Pa, the vacuum system is closed, and the pressure increase of the distillation or rectification system is less than or equal to 2000Pa within 5 min.

6. The method of claim 4, wherein: after the rectification or the distillation is finished, the pressure is released, the protective gas is filled to normal pressure or positive pressure, and the pressure in the tower is 0.0-0.1 MPa, preferably 0.001-0.003 MPa.

7. The preparation method according to claim 4, wherein in the step E, the container is discharged to a movable storage tank and then transferred to a packaging procedure, and the packaging material used in the packaging procedure is a glass bottle, a stainless steel bottle, an aluminum bottle, a fluoropolymer packaging material, preferably a glass bottle.

8. The production method according to claims 1 to 7, characterized in that: the purity of the obtained 3-butyl-1 (3H) -isobenzofuranone product is not less than 99.0%, preferably not less than 99.5%, and more preferably not less than 99.7%.

Technical Field

The invention belongs to the technical field of medicines, and particularly relates to a high-stability 3-butyl-1 (3H) -isobenzofuranone product prepared by filling protective gas during pressure relief of a 3-butyl-1 (3H) -isobenzofuranone crude product in the rectification or distillation purification process, which effectively solves the problem that 3-butyl-1 (3H) -isobenzofuranone as a raw material medicine is easy to degrade in production and storage.

Background

3-butyl-1 (3H) -isobenzofuranone, also known as butylphthalide, was first discovered in southern Water celery seed, also known as apigenin, as a pale yellow clear oily liquid with a specific aroma. The chemical structural formula is as follows:

the butylphthalide acts on a plurality of pathological links caused by cerebral ischemia through mechanisms such as improving the level of cerebrovascular endothelial NO and PGI2, reducing the concentration of intracellular calcium, inhibiting the release of glutamic acid, reducing the content of arachidonic acid, inhibiting oxygen free radicals, improving the activity of antioxidant enzyme and the like, and clinical research results show that: the butylphthalide has significant improvement effect on light and moderate acute ischemic stroke, and can promote the functional recovery of patients.

The prior art reports on the study of butylphthalide products are as follows:

the synthesis of (+/-) apigenin, Leshao white, etc., 1990, 26(1), filed by Lanzenbai university of Lanzhou (Nature science edition) discloses a butylphthalide product and a preparation method thereof: phthalic anhydride 2 is used as a raw material, the phthalic anhydride, anhydrous sodium acetate and valeric anhydride are subjected to heating reflux reaction at 300 ℃, the butenylphthalide 3 is prepared by ether extraction column chromatography purification, the butenylphthalide is dissolved in ether and is subjected to catalytic hydrogenation by 10 percent Pd/C to obtain the butenylphthalide 1, and the reaction formula is shown as follows:

the butylphthalide product prepared by the method has the following defects: the product content can only reach about 95 percent; the stability is poor, the content is obviously reduced in the standing process, the impurity growth is rapid, the preparation cannot be directly used for research of the preparation, and the research data is detailed in table 1 (see patent CN 105130934B).

TABLE 1 Butylphthalide stability study data (40 deg.C, 75% RH)

With the above problems, the prior art has been improved on butylphthalide products:

chinese patent CN101962374 discloses a butylphthalide product and a preparation method thereof, phthalic anhydride 2 is used as a raw material, an intermediate product o-valeryl benzoic acid 4 is obtained by addition reaction with a Grignard reagent of halogenated butane, and butylphthalide 1 is obtained by reduction and acid cyclization of sodium borohydride, wherein the reaction route is as follows:

the butylphthalide product prepared by the method has improved content, impurity level and the like, the butylphthalide content is about 97%, the impurity content is about 3.0%, but the product has poor stability, the impurities are obviously increased and obviously reduced in the standing process, and the research data is shown in table 2 (see patent CN 105130934B):

TABLE 2 Butylphthalide stability study data (40 deg.C, 75% RH)

The Chinese patent CN102716121B controls the degradation of the butylphthalide raw material by controlling the content of a component II in the butylphthalide, wherein the component II is a butylphthalide process impurity. The research shows that: the total content of the component II is less than or equal to 2.0 percent, and when the content of the single components such as phthalide, propenylphthalide, butenylphthalide, pentenylphthalide and the like in the component II is less than 0.5 percent, and the content of the single components such as phthalide, methylphthalide, ethylphthalide, propylphthalide, pentylphthalide and the like is less than 1.0 percent, the quality stability of the butylphthalide product is good. When the content of any impurity component in the component II is more than 1.0 percent, the quality stability of the butylphthalide medicinal active composition is obviously influenced. The disadvantages of this method are: the component II has various types and high initial content, brings certain safety risk and hidden danger to the product quality, and the research data is shown in table 3 (see patent CN 102716121B).

TABLE 3 Butylphthalide stability study data (40 deg.C, 75% RH)

Note: "-" indicates no detection

Chinese patent CN105968077B adopts molecular distillation method to separate all process impurities of phthalide, propenylphthalide, butenylphthalide, pentenylphthalide, phthalide, methylphthalide, ethylphthalide, propylphthalide and pentylphthalide in component II to obtain high-content raw material medicine for improving the stability of raw materials. However, the method has high requirements on equipment and harsh production conditions (the vacuum degree is required to be 1-5 pa), and the commercial production is not easy to realize.

The inventor finds that the butylphthalide still has a degradation phenomenon under a refrigeration condition, the butylphthalide standard product is placed at the temperature of 2-8 ℃ for 9 months, the degradation impurity is 0.48%, and relevant substance detection is shown in figure 1. Chromatographic conditions are as follows: octadecylsilane chemically bonded silica is used as a filling agent, methanol/water (65: 35) is used as a mobile phase, the detection wavelength is 228nm, and the peak of degraded impurities in a chromatogram is calculated according to an area normalization method.

In conclusion, the butylphthalide product has unstable quality and is easy to degrade in the placement process, thereby bringing great hidden danger to the clinical curative effect and the medication safety of the preparation. Therefore, the prior art needs to be improved to obtain a high-stability butylphthalide product as a raw material drug.

Disclosure of Invention

The present inventors have conducted extensive studies on the preparation process of 3-butyl-1 (3H) -isobenzofuranone and the stability of product quality according to the prior art.

At present, a 3-butyl-1 (3H) -isobenzofuranone purification method mostly adopts a rectification or distillation mode, generally operates to cool and discharge air after rectification or distillation is finished, and then discharges and stores the air, and during the storage process of a 3-butyl-1 (3H) -isobenzofuranone product, degraded impurities grow rapidly, the quality of the product is greatly influenced, and even the curative effect and the medication safety of a preparation can be influenced.

The invention aims to provide a preparation method of high-stability 3-butyl-1 (3H) -isobenzofuranone.

Another object of the present invention is to provide a method for increasing the purity of 3-butyl-1 (3H) -isobenzofuranone.

In order to realize the purpose, the invention adopts the following technical scheme:

a preparation method of high-stability 3-butyl-1 (3H) -isobenzofuranone comprises the following steps: and (3) introducing protective gas into the crude product of the 3-butyl-1 (3H) -isobenzofuranone after the rectification or distillation is finished.

Preferably, the protective gas is introduced at the end of the pressure release at the end of the rectification or distillation.

The protective gas comprises one or more of nitrogen, helium, neon, argon, krypton and xenon; argon is preferred.

And (3) filling protective gas to normal pressure or positive pressure when the pressure relief is finished during the rectification or distillation, wherein the positive pressure in the tower is 0.0-0.1 MPa, and preferably 0.001-0.003 MPa.

Preferably, after the rectification or distillation is finished, the pressure is firstly released, the protective gas is filled, and then the fraction is transferred.

More preferably, the preparation method of the high-stability 3-butyl-1 (3H) -isobenzofuranone comprises the following steps: checking the performance of a vacuum system of the device before rectification or distillation, after the system is stable, the vacuum degree should be less than or equal to 400Pa, closing the vacuum system, and increasing the pressure of the rectification or distillation system for 5min to be less than or equal to 2000 Pa; adding the crude product of 3-butyl-1 (3H) -isobenzofuranone into a rectifying or distilling still; slowly heating the crude product of the 3-butyl-1 (3H) -isobenzofuranone, and collecting fractions at 100-130 ℃ under the vacuum degree of 100-400 Pa; after the rectification or the distillation is finished, the heating equipment is closed, the vacuum pipeline valve is closed, the protective gas pipeline valve is opened, and the protective gas is decompressed and filled to normal pressure or positive pressure; maintaining the pressure in the tower, opening a valve of the movable storage tank, and discharging to the inerted movable storage tank; and transferring to a packaging program.

The purity of the obtained 3-butyl-1 (3H) -isobenzofuranone product is not less than 99.0%, preferably not less than 99.5%, and more preferably not less than 99.7%.

The inventor discovers a preparation method of high-stability 3-butyl-1 (3H) -isobenzofuranone by improving a preparation process of 3-butyl-1 (3H) -isobenzofuranone, and the method is suitable for 3-butyl-1 (3H) -isobenzofuranone with different purities.

The invention aims to provide a preparation process of high-stability 3-butyl-1 (3H) -isobenzofuranone.

A preparation method of high-stability 3-butyl-1 (3H) -isobenzofuranone comprises the following steps:

A. optionally, checking the device vacuum system performance;

B. adding the crude product of 3-butyl-1 (3H) -isobenzofuranone into a rectification or distillation still;

C. slowly heating the crude product of the 3-butyl-1 (3H) -isobenzofuranone, and collecting fractions at the temperature of 100-130 ℃ under the vacuum degree of 100-400 Pa;

D. after distillation and rectification, closing the heating equipment, closing the vacuum pipeline valve, opening the protective gas pipeline valve, and discharging the protective gas to normal pressure or positive pressure;

E. maintaining the pressure in the tower, opening a valve of the movable storage tank, and discharging to the inerted movable storage tank;

in the preparation method, the protective gas includes nitrogen, helium, neon, argon, krypton and xenon, and preferably argon;

in the preparation method, the step A is carried out to check the performance of a vacuum system of the device if necessary, after the system is stable, the vacuum degree is less than or equal to 400Pa, the vacuum system is closed, and the pressure intensity of the rectification or distillation system is increased by less than or equal to 2000Pa within 5 min;

in the preparation mode, in the step D, the pressure in the tower is 0.0-0.1 MPa, preferably 0.001-0.003 MPa;

in the preparation method, in the step E, the storage tank is moved to be transferred to a packaging procedure, and the packaging material used in the packaging procedure is a glass bottle, a stainless steel bottle, an aluminum bottle, a fluorine-containing polymer packaging material, preferably a glass bottle.

Drawings

FIG. 1 shows the detection spectra of the substances related to butylphthalide standard

FIG. 2 liquid phase detection chromatogram of substances related to 0 day of 3-butyl-1 (3H) -isobenzofuranone prepared in comparative example 1

FIG. 3 liquid phase detection pattern of substances related to 3-butyl-1 (3H) -isobenzofuranone prepared in comparative example 1 for a long period of 30 days

FIG. 4 liquid phase detection chromatogram of substances related to 0 day of 3-butyl-1 (3H) -isobenzofuranone product prepared in example 4

FIG. 5 liquid phase detection chromatogram of substances related to acceleration of 6 months for 3-butyl-1 (3H) -isobenzofuranone product prepared in example 4

Related substance determination method: taking a proper amount of 3-butyl-1 (3H) -isobenzofuranone, precisely weighing, adding a solvent [ mobile phase A-methanol (50: 50) ] for dissolving and diluting to prepare a solution containing about 1mg in each 1ml, and taking the solution as a test solution; taking phthalic anhydride, methylphthalide, ethylphthalide, propylphthalide, pentylphthalide, butylphthalide, hydrogenated impurities, degraded impurities 1, degraded impurities 2 and the like, precisely weighing, dissolving and diluting by using a solvent to prepare a solution containing 1 mu g of impurities in each 1ml, taking the solution as a mixed reference solution, performing a high performance liquid chromatography (the general regulation 0512 of the 2015 edition of Chinese pharmacopoeia) test, taking octadecylsilane chemically bonded silica as a filler, taking a 0.01% glacial acetic acid aqueous solution as a mobile phase A, taking acetonitrile as a mobile phase B, performing gradient elution, detecting the wavelength of 228nm, the column temperature of 30 ℃ and the flow rate of 1.0 ml/min; precisely measuring 10 μ l of the test solution, injecting into a liquid chromatograph, and recording chromatogram. If an impurity peak exists in the chromatogram of the test solution, calculating according to an area normalization method.

Detailed Description

The invention is further illustrated by the following examples. It should be understood that the method described in the examples is only for illustrating the present invention and not for limiting the present invention, and that simple modifications of the preparation method of the present invention based on the concept of the present invention are within the scope of the claimed invention. The crude 3-butyl-1 (3H) -isobenzofuranone is prepared by referring to a doctor thesis method of Jatropha, university of medical science, but is not limited to the method. All the raw materials and solvents used in the examples are commercially available products unless otherwise specified.

Comparative example 1

Assembling rectification equipment, opening a vacuum pump, keeping the vacuum degree of 350Pa after a system is stabilized, closing a vacuum valve, increasing the pressure of a rectification system by 1220Pa for 5min, adding 516.0g of a crude product of 3-butyl-1 (3H) -isobenzofuranone into a rectification bottle, heating and raising the temperature, and starting a reflux ratio controller to receive front fraction when the temperature of feed liquid steam reaches 80 ℃. When the temperature is stabilized at 122 ℃, the vacuum degree is 360Pa, the fraction receiving valve is closed, the decompressed receiving bottle is taken down, the pure product receiving bottle is connected, the vacuum pumping is carried out, when the vacuum degree of the receiving bottle is consistent with that of the rectifying tower, the receiving valve is opened to collect the fraction at 100-126 ℃, when the steam temperature is reduced to 100 ℃, the heating is stopped, the temperature is reduced to the room temperature, the rectifying system is decompressed and filled with air to the normal pressure, the receiving bottle is taken down, the receiving bottle is poured into a 500ml mobile storage tank, and 315.0g of colorless oily liquid is obtained. The purity of the sample was tested to 99.879%, and the product was subjected to stability studies with the results shown in Table 4.

Comparative example 2

Assembling rectification equipment, opening a vacuum pump, keeping the vacuum degree of 310Pa after the system is stabilized, closing a vacuum valve, increasing the pressure of a rectification system to 1020Pa after 5min, adding 1.22kg of the crude product of the 3-butyl-1 (3H) -isobenzofuranone into a rectification bottle, heating and raising the temperature, and starting a reflux ratio controller to receive front fraction when the temperature of feed liquid steam reaches 90 ℃. When the temperature is stabilized at 118 ℃, the vacuum degree is 340Pa, the receiving valve is closed, the receiving bottle after pressure relief is taken down, the pure product receiving bottle is connected, the vacuum pumping is carried out, when the vacuum degree of the receiving bottle is consistent with that of the rectifying tower, the receiving valve is opened to collect the fraction at the temperature of 100-123 ℃, when the temperature is reduced to 100 ℃, the heating is closed, the temperature is reduced to the room temperature, the rectifying system is decompressed and filled with air to the normal pressure, the receiving bottle is taken down, the receiving bottle is poured into a 1000ml mobile storage tank, and 894.0g of colorless oily liquid is obtained. And introducing argon into the mobile storage tank for 0.5h at the speed of 1-2 bubbles/second. The purity of the sample was tested to 99.882%, and the product was subjected to stability studies with the results shown in Table 4.