Preparation method of crude drug for inhibiting release of platelet factors

Abstract

The invention discloses a preparation method of a crude drug for inhibiting release of platelet factors, which comprises the following steps: 1) reacting 2-[4-(1, 3-dioxo-2-isoindolyl) phenyl] butyric acid with glacial acetic acid, zinc powder and hydrochloric acid at a stirring speed of 120-140 r / min to obtain a wet solid; (2) refining the wet solid product obtained in the step (1) to obtain a medicine crude product for inhibiting the release of the platelet factors; the crude drug product for inhibiting the release of the platelet factors, which is obtained by the invention, has higher purity and yield.

Description

Technical Field

[0001] The present application belongs to the technical field of drug preparation, and in particular relates to a method for preparing a crude drug for inhibiting the release of platelet factors. Background Art

[0002] Indobufen, chemical name: (±) 2-[4-(1-oxo-2-isoindole)phenyl]butyric acid, molecular formula: C 18 H 17 NO3, relative molecular mass: 295.34. This product inhibits the release of platelet factors such as ADP, 5-hydroxytryptamine, platelet factor 4, and β-thromboglobulin, and plays an anti-platelet aggregation role. Indobufen does not affect the plasma parameters of blood coagulation, but only prolongs the bleeding time. Therefore, after achieving the therapeutic purpose, discontinuation of the drug can quickly restore the abnormal platelet function to normal. Indobufen is used for arteriosclerotic ischemic cardiovascular disease, ischemic cerebrovascular disease and peripheral arterial disease, lipid metabolism disorders, venous thrombosis and diabetes, and can also be used to prevent thrombosis during extracorporeal circulation surgery.

[0003] There are many synthetic routes of indobufen in the prior art, such as the route described in Zheng Gengxiu et al., "Preparation Process of Indobufen" (China Pharmaceutical Industry Journal, 1991, 22 (7)):

[0004]

[0005] Gao Xuemin et al., in "Synthesis of the anticoagulant indobufen" (China Pharmaceutical Industry Journal, 1989, 20(11)), the route is:

[0006]

[0007] Patent CN106631974A, the synthesis route is as follows:

[0008]

[0009] Patent CN117263842A synthesis route is:

[0010]

[0011] The above indobufen synthesis processes all involve the process of converting 2-[4-(1,3-dioxo-2-isoindolyl)phenyl]butyric acid (hereinafter referred to as compound II) into indobufen through a reduction reaction. This step is crucial. Given that indobufen API has not yet been included in domestic and foreign pharmacopoeias, in-depth research on its impurities is particularly important. Especially in the final stage of the reaction, impurities are easily generated and introduced due to the characteristics of the process. This reduction reaction is mainly divided into two stages: first, in an acidic environment, the carbonyl group on the isoindole ring of compound II is reduced to form an intermediate compound III; then, the hydroxyl group is removed under acidic conditions to finally obtain the target product indobufen. As shown in the following formula:

[0012]

[0013] Different reaction conditions may affect the conversion rate of the reaction, which in turn leads to differences in the residual level of compound III. It is worth noting that in the last step of the reaction, if there is too much residual compound III, it will directly affect the quality of indobufen as an impurity, especially since compound III has a similar structure to indobufen and the removal effect is poor. Therefore, in-depth research and optimization of this key step is particularly urgent. Summary of the invention

[0014] In order to solve the problems existing in the prior art, the present invention provides the following technical solution: a method for preparing a crude drug for inhibiting the release of platelet factors, comprising the following steps:

[0015] 1) 2-[4-(1,3-dioxo-2-isoindolyl)phenyl]butyric acid is reacted with glacial acetic acid, zinc powder and hydrochloric acid at a stirring speed of 120 r / min to 140 r / min to obtain a wet solid;

[0016] 2) Purifying the wet solid obtained in step 1) to obtain a crude drug for inhibiting the release of platelet factors.

[0017] Furthermore, the mass molar ratio of the 2-[4-(1,3-dioxo-2-isoindolyl)phenyl]butyric acid to the zinc powder is 1:(2-5); the mass molar ratio of the 2-[4-(1,3-dioxo-2-isoindolyl)phenyl]butyric acid to the glacial acetic acid is 1:(30-35).

[0018] Furthermore, the operation process of step 1) is: adding glacial acetic acid to the reaction kettle, starting stirring, controlling the stirring speed, sequentially adding 2-[4-(1,3-dioxo-2-isoindolyl)phenyl]butyric acid and zinc powder to the reaction kettle, then dripping hydrochloric acid, controlling the temperature of the reaction solution to react until the reaction is complete, and obtaining the wet solid after filtering, concentration and crystallization.

[0019] Furthermore, in step 1), the temperature of the reaction solution is 75-85°C.

[0020] Furthermore, the crystallization conditions in step 1) are: cooling the reaction solution to 20-30° C. and stirring for crystallization for 30 min to 120 min.

[0021] Furthermore, the refining solvent in step 2) is ethyl acetate.

[0022] Furthermore, the operation process of step 2) is: adding ethyl acetate into the reaction kettle, starting stirring, adding the crude indobufen obtained in step 1), starting heating, heating and beating for 1 to 3 hours, and then cooling, crystallizing, centrifuging and drying to obtain the crude drug for inhibiting platelet factor release.

[0023] Furthermore, the heating temperature in step 2) is 50-60°C.

[0024] Furthermore, the crystallization conditions in step 2) are: cooling the reaction solution to 20-30° C. and stirring for crystallization for 30 min-60 min.

[0025] On the other hand, the present invention provides a drug for inhibiting the release of platelet factors obtained by the above method, wherein the drug is preferably indobufen.

[0026] Compared with the prior art, the preparation method of the crude drug for inhibiting the release of platelet factors (hereinafter referred to as crude indobufen) of the present invention has the following advantages: first, the method effectively reduces the content of compound III and other impurities by optimizing the reaction conditions, thereby reducing the influence of impurities on the quality of the final product. Secondly, the method of the present invention significantly improves the purity of the crude indobufen, so that the product is more in line with the pharmaceutical standards and meets the market demand. In addition, the method shows a higher yield in the experiment, which is conducive to reducing production costs and improving economic benefits. The crude indobufen obtained by the present invention only needs to be subjected to simple subsequent treatment, mainly to adjust the crystal morphology, and high-quality refined indobufen can be obtained. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1 This is the HPLC test result of related substances of crude indobufen in Example 1.

[0028] Figure 2 This is the HPLC test result of related substances of crude indobufen in Comparative Example 5.

[0029] Figure 3 This is the HPLC test result of related substances of crude indobufen in Comparative Example 6.

[0030] Figure 4 This is the HPLC test result of related substances of crude indobufen in Comparative Example 7.

[0031] Figure 5 This is the HPLC test result of related substances of crude indobufen in Comparative Example 8. DETAILED DESCRIPTION

[0032] The following will be combined with the drawings in the embodiments of the present application to clearly describe the technical solutions in the embodiments of the present application. Obviously, the described embodiments are part of the embodiments of the present application, rather than all the embodiments. All other embodiments obtained by ordinary technicians in this field based on the embodiments in the present application belong to the scope of protection of this application.

[0033] The terms "first", "second", etc. in the specification and claims of the present application are used to distinguish similar objects, and are not used to describe a specific order or sequence. It should be understood that the data used in this way can be interchangeable under appropriate circumstances, so that the embodiments of the present application can be implemented in an order other than those illustrated or described here, and the objects distinguished by "first", "second", etc. are generally of one type, and the number of objects is not limited. For example, the first object can be one or more. In addition, "and / or" in the specification and claims represents at least one of the connected objects, and the character " / " generally indicates that the objects associated with each other are in an "or" relationship.

[0034] The present invention studies the process of preparing crude indobufen from compound II and finds that the preparation conditions and refining conditions have a great influence on the purity and yield of the final crude indobufen. The specific process is as follows:

[0035] 1) Compound II reacts with glacial acetic acid, zinc powder and hydrochloric acid at a stirring speed of 120 r / min to 140 r / min to obtain a wet solid, wherein the wet solid is a crude indobufen; chemical reaction formula:

[0036]

[0037] The stirring speed may be 120 r / min, 130 r / min or 140 r / min, but is not limited to the listed values, and other values ​​not listed within the numerical range are also applicable.

[0038] In a reaction system involving the use of metal catalyst zinc powder, especially in the experimental process under acidic conditions, it is very common that the zinc powder is easy to agglomerate and settle to the bottom. This not only hinders the generation of hydrogen, but also further affects the conversion efficiency of the reactants, resulting in an increase in the residual amount of reaction intermediates. In order to solve this problem, the inventors conducted a detailed investigation on the stirring rate in the reaction system, aiming to prevent the agglomeration and sedimentation of zinc powder by increasing the stirring speed. However, the experimental results show that when the stirring rate is too high, the conversion rate and efficiency of the reaction are reduced. This may be due to the excessively intense stirring action causing local overheating in the reaction system, affecting the overall uniformity and conversion efficiency of the reaction medium; at the same time, the excessively high stirring rate may also cause the zinc powder to be too dispersed, thereby affecting the effective generation of hydrogen and the efficiency of the entire reaction system, and ultimately adversely affecting the purity of the target product indobufen.

[0039] In one embodiment of the present invention, the mass molar ratio of the compound II to the zinc powder is 1: (2-5), preferably 1: (3-4); the mass molar ratio of the compound II to the glacial acetic acid is 1: (30-35), preferably 1: (32-33). The amount of zinc powder and glacial acetic acid used will directly affect the reaction and the related substances and yields of subsequent products.

[0040] In one embodiment of the present invention, the operation is to add glacial acetic acid into the reactor, start stirring, control the stirring speed, add compound II and zinc powder into the reactor in sequence, then dropwise add hydrochloric acid, control the temperature of the reaction solution to react until the reaction is complete, and obtain the wet solid after filtering, concentration and crystallization.

[0041] In one embodiment of the present invention, the temperature of the reaction liquid is 75-85°C, for example, it can be lower than 80°C, for example, 75°C, 76°C, 77°C, 78°C, 79°C, but not limited to the listed values. It can also be above 80°C, for example, 80°C, 81°C, 82°C, 83°C, 84°C or 85°C, but not limited to the listed values, and other values ​​not listed in the numerical range are also applicable.

[0042] In one embodiment of the present invention, the crystallization conditions are: cooling the reaction solution to 20-30°C and stirring for crystallization for 30 min to 120 min. The cooling temperature can be 20°C, 21°C, 22°C, 23°C, 24°C, 25°C, 26°C, 27°C, 28°C, 29°C or 30°C, but is not limited to the listed values, and other values ​​not listed within the numerical range are also applicable; the stirring time can be 30 min, 60 min, 90 min or 120 min, but is not limited to the listed values, and other values ​​not listed within the numerical range are also applicable.

[0043] The inventors investigated the existing step 1) various reaction systems with different reactions, including the hydrogen chloride gas / glacial acetic acid / zinc powder reaction system disclosed in patent CN106631974A, and found that different reaction systems and temperatures had a significant effect on the level of impurity residues, and using hydrochloric acid / glacial acetic acid / zinc powder or hydrogen chloride gas / glacial acetic acid / zinc powder reaction systems at 75 to 85 ° C, both can obtain a higher purity of crude indobufen. However, further comparison found that the effect of using hydrochloric acid is better than hydrogen chloride, and hydrogen chloride gas is difficult to control in industrial production, and is not suitable for production equipment due to its large corrosiveness. Therefore, choosing hydrochloric acid / glacial acetic acid / zinc powder to react at 75 to 85 ° C can have a better effect. Although patent CN106631974A can obtain crude indobufen with higher purity and yield, it is poor in the control of key impurity compound III.

[0044] 2) Purifying the wet solid obtained in step 1) to obtain crude indobufen.

[0045] The crude indobufen of the present invention can be transformed into the final fine indobufen by further refining.

[0046] In one embodiment of the present invention, the operation process is: add ethyl acetate into the reaction kettle, start stirring, add the wet solid obtained in step 1), start heating, heat up and slurry and purify for 1 to 3 hours, then cool down, crystallize, centrifuge and dry to obtain the crude indobufen.

[0047] In one embodiment of the present invention, the heating temperature is 50-60°C, for example 50°C, 51°C, 52°C, 53°C, 54°C, 55°C, 56°C, 57°C, 58°C, 59°C or 60°C, but is not limited to the listed values, and other unlisted values ​​within the numerical range are also applicable.

[0048] In one embodiment of the present invention, the crystallization conditions are: cooling the reaction solution to 20-30°C and stirring for crystallization for 30 min to 120 min. The cooling temperature can be 20°C, 21°C, 22°C, 23°C, 24°C, 25°C, 26°C, 27°C, 28°C, 29°C or 30°C, but is not limited to the listed values, and other values ​​not listed within the numerical range are also applicable; the stirring time can be 30 min, 60 min, 90 min or 120 min, but is not limited to the listed values, and other values ​​not listed within the numerical range are also applicable.

[0049] The inventors screened different refining solvents, such as dichloromethane, isopropanol, acetonitrile, activated carbon, 75% ethanol / water, and methanol / water, and found that in the refining step of the indobufen crude product preparation process, ethyl acetate can make the final indobufen crude product have better yield and purity than other solvents.

[0050] The following are specific examples of the present invention and comparative examples, but the present invention is not limited to the following examples.

[0051] Example 1

[0052] Preparation method:

[0053] 1) Add glacial acetic acid (720.0 kg) to the reactor, start stirring and control the stirring speed to 120 r / min, add compound II (114.0 kg) and zinc powder (92.0 kg) to the reactor in turn, start dripping hydrochloric acid (255.0 kg), after the hydrochloric acid is dripped, the reaction liquid is controlled at 80-85 ° C to react, and HPLC monitors the reaction until the reaction is complete. Turn off the heating, and inject the reaction liquid into the glass-lined reactor through a bag filter, start stirring, and reduce the pressure and concentrate the filtrate. After the concentration is completed, control the temperature between 20 and 30 ° C, add purified water (715.0 kg) to the concentrated residue, add it, control the temperature at 20-30 ° C, and stir and crystallize for 1 hour. Centrifuge, collect the wet solid and mix it with purified water (715.0 kg), control the temperature at 20-30 ° C, and stir and beat for 30 minutes. Centrifuge again, rinse the filtered solid with purified water (114.0 kg) to obtain a wet solid.

[0054] 2) Add ethyl acetate (515.0 kg) into the reactor, start stirring, add the wet solid from step 1), start heating, raise the temperature to 50-60°C and slurry and purify for 2 hours. Turn off heating, cool to 20-30°C, stir and crystallize for 30 minutes. Centrifuge, put the wet solid obtained by centrifugation into a vacuum dryer, and dry to obtain 93.28 kg of crude indobufen.

[0055] Example 2

[0056] The stirring speed in step 1) was adjusted from 120 r / min to 140 r / min, and the remaining process steps and conditions were the same as those in Example 1. 90.56 kg of crude indobufen was obtained.

[0057] Example 3

[0058] The temperature of the reaction solution in step 1) was controlled from 80 to 85°C to 75 to 80°C, and the remaining process steps and conditions were the same as those in Example 1. 86.64 kg of crude indobufen was obtained.

[0059] Comparative Example 1

[0060] Adjust the reaction system and temperature. The specific operations are as follows:

[0061] 1) Add glacial acetic acid to the reactor, start stirring and control the stirring speed to 120r / min, add compound II and zinc powder to the reactor in turn, control the temperature of the reaction solution to 110-120℃, and monitor the reaction until the reaction is complete. Turn off the heating, and inject the reaction solution into the glass-lined reactor through a bag filter, start stirring, and reduce the pressure and concentrate the filtrate. After concentration, control the temperature between 20 and 30℃, add purified water to the concentrated residue, control the temperature at 20-30℃, and stir and crystallize for 1h. Centrifuge, collect the wet solid and mix with purified water, control the temperature at 20-30℃, and stir and slurry for 30min. Centrifuge again, rinse the filtered solid with purified water to obtain a wet solid.

[0062] The operation and conditions of step 2) are the same as those of Example 1. 73.15 kg of crude indobufen was obtained.

[0063] Comparative Example 2

[0064] The hydrochloric acid in step 1) was adjusted to hydrogen chloride gas, and the remaining process steps and conditions were the same as those in Example 1. 76.52 kg of crude indobufen was obtained.

[0065] Comparative Example 3

[0066] The stirring speed in step 1) was adjusted from 120 r / min to 80 r / min, and the remaining process steps and conditions were the same as those in Example 1. 71.19 kg of crude indobufen was obtained.

[0067] Comparative Example 4

[0068] The stirring speed in step 1) was adjusted from 120 r / min to 160 r / min, and the remaining process steps and conditions were the same as those in Example 1. 85.88 kg of crude indobufen was obtained.

[0069] Comparative Example 5 (unrefined)

[0070] The operation and conditions of step 1) are the same as those of Example 1.

[0071] 2) The wet solid obtained in step 1) was placed in a vacuum dryer and dried to obtain 98.29 kg of crude indobufen.

[0072] Comparative Example 6

[0073] The wet solid obtained in step 1) is purified using dichloromethane, and the specific operation is as follows:

[0074] The operation and conditions of step 1) are the same as those of Example 1.

[0075] 2) Add dichloromethane to the reactor, start stirring, add the wet solid obtained in step 1), start heating, raise the temperature to 50-60°C and slurry and purify for 2 hours. Turn off the heating, cool to 20-30°C, stir and crystallize for 30 minutes. Centrifuge, put the wet solid obtained by centrifugation into a vacuum dryer, and dry to obtain 71.62 kg of crude indobufen.

[0076] Comparative Example 7

[0077] The wet solid obtained in step 1) is purified using isopropanol, and the specific operation is as follows:

[0078] The operation and conditions of step 1) are the same as those of Example 1.

[0079] 2) Add isopropanol to the reaction kettle, start stirring, add the wet solid obtained in step 1), start heating, raise the temperature to 50-60°C and slurry and purify for 2 hours. Turn off the heating, cool to 20-30°C, stir and crystallize for 30 minutes. Centrifuge, put the wet solid obtained by centrifugation into a vacuum dryer, and dry to obtain 74.56 kg of crude indobufen.

[0080] Comparative Example 8

[0081] The wet solid obtained in step 1) is purified using acetonitrile, and the specific operation is as follows:

[0082] The operation and conditions of step 1) are the same as those of Example 1.

[0083] 2) Add acetonitrile to the reaction kettle, start stirring, add the wet solid obtained in step 1), start heating, raise the temperature to 50-60°C and slurry and purify for 2 hours. Turn off the heating, cool to 20-30°C, stir and crystallize for 30 minutes. Centrifuge, put the wet solid obtained by centrifugation into a vacuum dryer, and dry to obtain 67.81 kg of crude indobufen.

[0084] Comparative Example 9

[0085] The wet solid obtained in step 1) is purified using activated carbon, and the specific operation is as follows:

[0086] The operation and conditions of step 1) are the same as those of Example 1.

[0087] 2) Add acetonitrile to the reaction kettle, start stirring, add the wet solid obtained in step 1) and activated carbon, start heating, raise the temperature to 50-60°C for refining for 2h, filter the reaction solution hot, cool it to 20-30°C, stir and crystallize for 30min. Centrifuge, put the wet solid obtained by centrifugation into a vacuum dryer, and dry to obtain 65.74kg of crude indobufen.

[0088] Comparative Example 10

[0089] The wet solid obtained in step 1) is purified using 75% ethanol / water, and the specific operation is as follows:

[0090] The operation and conditions of step 1) are the same as those of Example 1.

[0091] 2) Add 75% ethanol / water to the reactor, start stirring, add the wet solid obtained in step 1), start heating, raise the temperature to 50-60°C and slurry refine for 2 hours. Turn off the heating, cool to 20-30°C and stir to crystallize for 30 minutes. Centrifuge, put the wet solid obtained by centrifugation into a vacuum dryer, and dry to obtain 73.58 kg of crude indobufen.

[0092] Comparative Example 11

[0093] The wet solid obtained in step 1) is purified using methanol / water, and the specific operation is as follows:

[0094] The operation and conditions of step 1) are the same as those of Example 1.

[0095] 2) Add methanol / water to the reactor, start stirring, add the wet solid obtained in step 1), start heating, raise the temperature to 50-60°C and slurry and purify for 2 hours. Turn off the heating, cool to 20-30°C, stir and crystallize for 30 minutes. Centrifuge, put the wet solid obtained by centrifugation into a vacuum dryer, and dry to obtain 76.08 kg of crude indobufen.

[0096] Determination of related substances, purity and yield of crude indobufen obtained in Examples 1 to 3 and Comparative Examples 1 to 11

[0097] The determination methods of relevant substances and purity are as follows:

[0098] Related substances were determined according to the high performance liquid chromatography method (Chinese Pharmacopoeia 2020 Edition Part IV General Rules 0512) Solvent acetonitrile-water (60:40)

[0099] Test solution Take an appropriate amount of the product, dissolve it in solvent and dilute it to make a solution containing about 0.5 mg per 1 ml as the test solution;

[0100] System suitability solution: Take appropriate amounts of compound III, compound II and indobufen, place them in the same volumetric flask, add solvent to dissolve and dilute to prepare a mixed solution containing about 0.5 mg of indobufen and about 0.75 μg of other impurities per 1 ml, as the system suitability solution;

[0101] Chromatographic conditions: Use octadecylsilane bonded silica gel as filler (YMC-Pack ODS-AQ 4.6mm×250mm, 5μm or other chromatographic columns with equivalent performance); 0.01mol / L potassium dihydrogen phosphate buffer-acetonitrile (90:10) as mobile phase A, acetonitrile as mobile phase B; gradient elution according to the table below; column temperature is 30°C; detection wavelength is 205nm; injection volume is 5μl.

[0102] Table 1

[0103] Time (minutes) Mobile phase A (%) Mobile phase B (%) 0 95 5 10 95 5 20 62 38 35 62 38 40 45 55 60 45 55

[0104] System suitability requirements: 5 μl of system suitability solution was accurately measured and injected into the high performance liquid chromatograph to record the chromatogram. The peak order of each component was compound III, indobufen and compound II. The separation degree between the main peak and each impurity peak should meet the requirements.

[0105] Determination method: Accurately measure 5 μl of blank solvent and test solution, inject them into liquid chromatograph respectively, and record the chromatogram.

[0106] If there are impurity peaks in the chromatogram of the limit test solution, after deducting the blank solvent peak, according to the area normalization method, the impurity compound II shall not exceed 0.15%, the compound III shall not exceed 0.15%, the other individual impurities shall not exceed 0.15%, and the sum of all impurities shall not exceed 2.0%.

[0107] Table 2 Impurity information

[0108]

[0109] The related substances and purity test results of the crude indobufen obtained in Examples 1 to 3 and Comparative Examples 1 to 11 are shown in Table 3

[0110] Table 3

[0111]

[0112] According to Table 3 and Appendix Figures 1 to 5The data show that after being treated by a specific process system and a refining method (such as Examples 1 to 3), the content of related substances in the crude indobufen obtained by compound II is significantly reduced, especially the content of impurity compound III is greatly reduced. In the reaction system using glacial acetic acid and zinc powder (Comparative Example 1), when other conditions remain the same, the purity of the obtained crude indobufen is 99.097%, wherein the maximum unknown single impurity content is 0.500%, which exceeds the prescribed limit value of 0.15%. In the system using glacial acetic acid, zinc powder and hydrogen chloride gas (Comparative Example 2), although other conditions are the same, the purity of the crude indobufen is increased to 99.258%, and the maximum unknown single impurity content is reduced to 0.230%, but it still exceeds the limit value of 0.15%. In addition, the content of compound III is 0.32%, which is significantly higher than 0.016% in Example 1, and also exceeds the limit value.

[0113] Comparative Examples 3 and 4 further explored the effect of stirring speed under the hydrochloric acid, glacial acetic acid and zinc powder system. When other conditions remain unchanged, the stirring speed is too low (as shown in Comparative Example 3), the purity of the obtained crude indobufen is only 89.31%, and the content of each impurity is high. In Comparative Example 4 where the stirring speed is increased to 160r / min, the content of the largest unknown impurity is significantly increased compared with Examples 1 and 2, resulting in a decrease in product purity.

[0114] The refining process is also crucial. The unrefined sample, such as Comparative Example 5, has a compound III content of up to 0.43%, a maximum unknown single impurity of 0.59%, and a total impurity content of 5.102%, all significantly higher than Example 1. Comparative Examples 6 to 11 further compare the effects of different refining solvents. Although the content of all impurities (including compound III) is reduced compared to the unrefined sample (such as Comparative Example 5), effective control has not been achieved overall, and there are still problems of exceeding the limit requirements or low purity.

[0115] In summary, compound III is easy to generate during the preparation of crude indobufen, and it is difficult to remove due to its similar structure to API. The content of compound III and other impurities can be effectively controlled by precisely controlling the reaction parameters and refining conditions. High-purity crude indobufen can ensure that the final product meets regulatory requirements after a subsequent refining.

[0116] The determination method of the crude yield of indobufen is as follows:

[0117]

[0118] Note: 309.32 is the molecular weight of intermediate compound II, and 295.34 is the molecular weight of indobufen.

[0119] The yield results of crude indobufen in Examples 1 to 3 and Comparative Examples 1 to 11 are shown in Table 4.

[0120] Table 4

[0121]

[0122]

[0123] According to the data in Table 3 and Table 4, after being treated by a specific process system and a refining method (such as Examples 1 to 3), the crude indobufen obtained by Compound II can not only maintain a high purity, but also ensure a high yield. In contrast, when other process systems are used, not only the content of related substances will be affected, but also the yield will be negatively affected. For example, when using the glacial acetic acid and zinc powder system (Comparative Example 1) and the glacial acetic acid, zinc powder and hydrogen chloride gas system (Comparative Example 2), the yield of the obtained crude indobufen is lower than that of Example 1.

[0124] Further studies have shown that, in a system consisting of hydrochloric acid, glacial acetic acid and zinc powder, the choice of stirring speed has a significant effect on the yield of crude indobufen. When the stirring speed is set to 120r / min (as shown in Example 1), crude indobufen can achieve the highest yield while keeping other reaction conditions unchanged. In contrast, when the stirring speed is increased to 140r / min (as shown in Example 2), although the yield remains at a high level, it is slightly lower than the condition of 120r / min. And when the stirring speed is too low, for example, under the conditions in Comparative Example 3, even in the same reaction environment, the yield of crude indobufen is significantly reduced to 65.4%. In addition, even if the reaction conditions are improved by increasing the stirring speed to 160r / min (as shown in Comparative Example 4), the results show that the yield has decreased instead. Therefore, selecting an appropriate stirring speed is crucial for optimizing the synthesis yield of indobufen.

[0125] In the refining process, although the sample without refining treatment (such as comparative example 5) showed a higher yield, its purity and impurity control were far inferior to those of the refined samples. Comparative examples 6 to 11 further explored the effect of different refining solvents, and the results showed that the yield of the refined crude indobufen decreased and was lower than that of Example 1.

[0126] In summary, the crude indobufen preparation process provided by the present invention not only significantly improves the purity of the crude indobufen, but also does not cause excessive loss of the active ingredient indobufen while improving the purity, and the yield is still maintained at a relatively high level. This shows that the preparation process of the present invention not only ensures product quality, but also takes into account production efficiency.

[0127] The conditions of the embodiment and the comparative example are compared as follows:

[0128]

[0129] The embodiments of the present application are described above in conjunction with the accompanying drawings, but the present application is not limited to the above-mentioned specific implementation methods. The above-mentioned specific implementation methods are merely illustrative and not restrictive. Under the guidance of the present application, ordinary technicians in this field can also make many forms without departing from the purpose of the present application and the scope of protection of the claims, all of which are within the protection of the present application.

Claims

1. A method for preparing a crude drug for inhibiting the release of platelet factors, characterized in that: The steps include: 1) 2-[4-(1,3-dioxo-2-isoindolyl)phenyl]butyric acid is reacted with glacial acetic acid, zinc powder and hydrochloric acid at a stirring speed of 120 r / min to 140 r / min to obtain a wet solid; 2) Purifying the wet solid obtained in step 1) to obtain a crude drug for inhibiting the release of platelet factors.

2. The method for preparing a crude drug for inhibiting the release of platelet-derived factors according to claim 1, characterized in that: The mass molar ratio of the 2-[4-(1,3-dioxo-2-isoindolyl)phenyl]butyric acid to the zinc powder is 1:(2-5); the mass molar ratio of the 2-[4-(1,3-dioxo-2-isoindolyl)phenyl]butyric acid to the glacial acetic acid is 1:(30-35).

3. The method for preparing a crude drug for inhibiting the release of platelet factors according to claim 2, characterized in that: The operation process of step 1) is: adding glacial acetic acid to the reaction kettle, starting stirring, controlling the stirring speed, sequentially adding 2-[4-(1,3-dioxo-2-isoindolyl)phenyl]butyric acid and zinc powder to the reaction kettle, then dripping hydrochloric acid, controlling the temperature of the reaction liquid to react until the reaction is complete, and obtaining the wet solid after filtering, concentration and crystallization.

4. The method for preparing a crude drug for inhibiting the release of platelet factors according to claim 3, characterized in that: Step 1) The reaction liquid temperature is 75-85°C.

5. The method for preparing a crude drug for inhibiting the release of platelet factors according to claim 4, characterized in that: The crystallization conditions in step 1) are: cooling the reaction solution to 20-30° C. and stirring for crystallization for 30-120 min.

6. The method for preparing a crude drug for inhibiting the release of platelet factors according to claim 1, characterized in that: The refining solvent in step 2) is ethyl acetate.

7. The method for preparing a crude drug for inhibiting the release of platelet factors according to claim 6, characterized in that: The operation process of step 2) is: add ethyl acetate into the reaction kettle, start stirring, add the wet solid obtained in step 1), start heating, heat up and slurry and purify for 1 to 3 hours, then cool down, crystallize, centrifuge and dry to obtain a crude drug for inhibiting the release of platelet factors.

8. The method for preparing a crude drug for inhibiting the release of platelet factors according to claim 7, characterized in that: The temperature of the heating in step 2) is 50-60°C.

9. The method for preparing the crude drug for inhibiting the release of platelet factors according to claim 8, characterized in that: The crystallization conditions in step 2) are: cooling the reaction solution to 20-30° C. and stirring for crystallization for 30-60 minutes.

10. The crude drug for inhibiting the release of platelet factors obtained by the method according to any one of claims 1 to 9, wherein the drug is preferably indobufen.

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