Preparation method of potassium dehydroandrographolide succinate

Abstract

The invention belongs to the technical field of medicine production, and particularly provides a kalii dehydroandrographolide half ester preparation method which comprises the following steps: 1) taking andrographolide, succinic anhydride and pyridine, mixing and reacting, adding ethyl acetate after the reaction, stirring, adding a hydrochloric acid solution, stirring, and filtering to obtain a filter cake; and 2) adding a hydrochloric acid solution into the filter cake obtained in the step 1), stirring, filtering, adding a mixed solution of ethanol and dichloromethane into the filter cake, stirring, filtering, drying the filter cake, and collecting powder, thereby obtaining the product. According to the preparation method of the kalii dehydroandrograpolide succinate, the obtained kalii dehydroandrograpolide succinate is high in yield, the yield can reach 93.0% or above, the product quality is good, the single impurity content is within 0.3%, the total impurity content is within 0.7%, fat-soluble impurities are few, and pyridine residues are at the level of 0.01%.

Description

Technical Field

[0001] The invention belongs to the technical field of drug production, and particularly relates to a preparation method of succinate hemiester. Background Art

[0002] Chuanhuning, i.e., dehydroandrographolide succinate monopotassium salt, is produced by the reaction of andrographolide with succinic acid, and the resulting dehydroandrographolide succinate monopotassium salt is then salified. The main ingredient of Chuanhuning injection is dehydroandrographolide succinate monopotassium salt, which is widely used clinically, but its adverse reactions are also relatively common, including anaphylactic shock, drug rash, thrombocytopenia, dyspnea, chills, fever, etc. These adverse reactions are closely related to its impurity content.

[0003] The data of the production of chuansuning show that the process of preparing chuansuning by salting dehydroandrographolide succinic acid half ester basically does not produce impurities. The impurities of chuansuning are mainly introduced by its raw material dehydroandrographolide succinic acid half ester (chuansuning half ester). First, in the synthesis process of chuansuning half ester, pyridine is used as a solvent and catalyst in the synthesis of chuansuning half ester, which is easy to remain in the product. The Chinese Pharmacopoeia standard requires that the residual pyridine in the drug is ≤0.02%; secondly, due to the high temperature and long reaction time of the condensation reaction, it is easy to cause the molecular structure to open, oxidize, hydrolyze, etc. to generate new substances. The fat-soluble substances in these newly generated substances and the residual pyridine as fat-soluble impurities are difficult to remove because of their polarity and chuansuning half ester. In addition, improper removal methods have a great impact on the yield.

[0004] Hu Shigao et al. (Study on the Synthesis of Andrographis paniculatae [J] Pharmaceutical Research, 2007, 10 (24): 21) added distilled water to the crude product of Andrographis paniculatae half ester, stirred and crystallized, filtered, washed, and recrystallized with ethanol to obtain high-purity Andrographis paniculata half ester, but the yield was very low, only 41.7%. Yang Chengfu et al. (Synthesis Method of Andrographis paniculatae [P] CN: 2013100639237, 2013 0522) dissolved the crude product of half ester in hot water at 30°C to 70°C, and crystallized at low temperature at -10°C to 15°C to obtain refined half ester. This method has a high yield, but there are many impurities in the solid. Yao Gang et al. (Journal of PLA Pharmacy, 2012, 28(4): 325327) added ethanol to the crude half ester, and then dripped a hydrochloric acid solution, crystallized at low temperature, filtered, washed, and dried to obtain a refined half ester. However, this method is prone to agglomeration and inclusion of impurities. The method for preparing the half ester of succinic acid disclosed in CN 105732547A also failed to remove fat-soluble impurities in the crude half ester of succinic acid. Summary of the invention

[0005] In order to solve the above problems, the present invention provides a method for preparing succinate hemiester, which comprises the following steps:

[0006] 1) mixing andrographolide, succinic anhydride and pyridine for reaction, adding ethyl acetate and stirring after the reaction, then adding hydrochloric acid solution and stirring, filtering to obtain a filter cake;

[0007] 2) adding hydrochloric acid solution to the filter cake obtained in step 1), stirring, filtering, adding a mixed solution of ethanol and dichloromethane to the filter cake, stirring, filtering, drying the filter cake, and collecting powder to obtain.

[0008] Furthermore, the reaction conditions of step 1) are: stirring after nitrogen replacement, temperature 95±5° C., and time 6-10 hours.

[0009] Furthermore, in step 1), the temperature of adding ethyl acetate and stirring is 60±5° C., and the time is 0.5 to 1 hour.

[0010] Furthermore, the stirring time of adding the hydrochloric acid solution is 20 to 60 minutes.

[0011] Furthermore, the pH value of the hydrochloric acid solution is 4-6.

[0012] Furthermore, in step 2), the mixed solution of ethanol and dichloromethane is stirred for 20 to 60 minutes.

[0013] Furthermore, the mass ratio of ethanol to dichloromethane in the mixed solution is 10:1-2.

[0014] Furthermore, the mass ratio of ethanol to dichloromethane in the mixed solution is 10:1.

[0015] Furthermore, the ethanol is anhydrous ethanol.

[0016] Furthermore, in step 2), the drying temperature is 40-60° C., preferably 50° C., and the drying time is 5-6 hours.

[0017] Furthermore, the mass ratio of andrographolide, succinic anhydride, pyridine, ethyl acetate, the hydrochloric acid solution in step 1), the hydrochloric acid solution in step 2), and the mixed solution of ethanol and dichloromethane is 5-15:5-15:4-8:1-3:50-80:50-80:10-30, preferably 10:10:6:2:60:60:20.

[0018] The preparation method of succinate half ester of the present invention comprises the following steps: after the synthesis reaction of succinate half ester is completed, ethyl acetate solution is added to disperse the reactants, hydrochloric acid solution is added for crystallization, and the precipitated crystals are purified by hydrochloric acid solution and a mixed solution of ethanol and dichloromethane in sequence, so that the obtained succinate half ester has a high yield of more than 93.0%, good product quality, single impurities within 0.3%, total impurities within 0.7%, less fat-soluble impurities, and pyridine residue at a level of 0.01%.

[0019] In addition, the method of the present invention has a simple process, a short time step, a small amount of solvent used, a small environmental pressure, and a low cost, which is very conducive to commercial production.

[0020] Obviously, according to the above contents of the present invention, in accordance with common technical knowledge and customary means in the art, without departing from the above basic technical ideas of the present invention, other various forms of modification, replacement or change may be made.

[0021] The above contents of the present invention are further described in detail below through specific implementation methods in the form of embodiments. However, this should not be understood as the scope of the above subject matter of the present invention being limited to the following examples. All technologies realized based on the above contents of the present invention belong to the scope of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1 Chromatogram of succinate half-ester obtained by traditional preparation method;

[0023] Figure 2 The chromatogram of succinate half ester obtained by the preparation method of the present invention;

[0024] Figure 3 The parameters of the mixed solution of anhydrous ethanol + dichloromethane with a weight ratio of (10:0.5) penetrate the spectrum of succinate half ester;

[0025] Figure 4 The parameters of the mixed solution of anhydrous ethanol and dichloromethane with a weight ratio of (10:1.0) were used to pierce the half-ester spectrum of succinate. DETAILED DESCRIPTION

[0026] The raw materials and equipment used in the present invention are all known products, which are obtained by purchasing commercially available products. The high-performance liquid phase detection method of succinate hemiester involved is:

[0027] Take succinyl hemiester, add mobile phase to make a test solution containing 0.4 mg per 1 ml, inject 10 μl of the test solution into the liquid chromatograph, the chromatographic conditions are: chromatographic column: octadecylsilane bonded silica gel as filler (COSMOSIL5C18-MS-II, 4.6×250mm, 5μm chromatographic column applicable); mobile phase: 10mmol / L potassium dihydrogen phosphate solution (phosphoric acid adjusted to pH 2.8±0.2)-acetonitrile (50:50); detection wavelength: 245nm. Flow rate: 1.0mL / min column temperature: 35℃; record the chromatogram to 2.5 times the retention time of the main component peak. In the chromatogram of the test solution, if there are impurity peaks, deduct the pyridine peak and calculate by area normalization method. The area of ​​a single impurity peak shall not exceed 0.5%, and the sum of the areas of each impurity peak shall not exceed 1.0%. The peak of 0.05% of the main peak area in the chromatogram of the test solution is ignored.

[0028] In the liquid chromatogram of succinate half ester obtained by the above method, the retention time of the succinate half ester chromatographic peak is about 25 minutes, the peak before the retention time of about 25 minutes is the water-soluble impurity peak, and the peak at the retention time of 40-60 minutes is the fat-soluble impurity peak.

[0029] Example 1: Study on the removal process of fat-soluble impurities in succinate hemiester of the present invention

[0030] The fat-soluble impurities in succinate hemiester are difficult to remove because of their similar polarity to succinate hemiester. If the removal method is inappropriate, the yield of succinate hemiester will be affected. Therefore, the applicability of the method was investigated based on the chromatographic peaks of fat-soluble impurities in the HPLC spectrum of succinate hemiester, the yield and purity of succinate hemiester.

[0031] 1. Process

[0032] 1. Preliminary exploration of purification process

[0033] In the early stage, the literature was consulted and the method disclosed was used to prepare the succinate half ester. The HPLC detection showed that fat-soluble impurities were present. According to the preparation method of succinate half ester disclosed in Comparative Example 2 in CN 105732547A, succinate half ester that can well remove fat-soluble impurities could not be obtained. Therefore, a new purification method was tried to remove fat-soluble impurities in succinate half ester during the preparation of succinate half ester.

[0034] 1.1 Methods

[0035] 10 g of andrographolide (molecular weight: 350.46), 10 g of succinic anhydride and 6 g of pyridine were added to a reaction flask, replaced with nitrogen three times, stirred, heated to 95±5°C, reacted for 6-10 hours, and after the reaction was completed, cooled by 60±5°C, and 60 g of hydrochloric acid solution with a pH value of 4-6 was added while hot, stirred and dispersed for 30 minutes, filtered, and the obtained filter cake was added to 60 g of hydrochloric acid solution with a pH value of 4-6 and slurried for 30 minutes, filtered, and the obtained filter cake was added to 20 g of anhydrous ethanol solution and slurried for 30 minutes, filtered, and the obtained filter cake was dried at 50 degrees for 5-6 hours to obtain 14.0 g of andrographolide half ester (molecular weight: 532.59), with a yield of 92.1%.

[0036] 1.2 Results

[0037] Take the half ester of succinic acid and use liquid chromatography to detect the result. Figure 1 .from Figure 1 It can be seen that there are more fat-soluble impurities after the retention time of 40-60MIN, accounting for about 2.96%, and the largest single impurity is 1.17%.

[0038] 2. Adjustment of purification process

[0039] 2.1 Methods

[0040] 10 g of andrographolide (molecular weight: 350.46), 10 g of succinic anhydride, and 6 g of pyridine were added to a reaction flask, replaced with nitrogen three times, stirred, heated to 95±5°C, reacted for 6-10 hours, and after the reaction was completed, cooled to 60±5°C, 2 g of ethyl acetate was added, stirred for 1 hour, 60 g of hydrochloric acid solution with a pH value of 4-6 was added while hot, stirred and dispersed for 30 minutes, filtered, the obtained filter cake was added to 60 g of hydrochloric acid solution with a pH value of 4-6 and slurried for 30 minutes, filtered, the obtained filter cake was added to 20 g of a mixed solution of anhydrous ethanol + dichloromethane (10:1) and slurried for 30 minutes, filtered, and the obtained filter cake was dried at 50 degrees for 5-6 hours to obtain 14.2 g of andrographolide half ester (molecular weight: 532.59), with a yield of 93.4%.

[0041] 2.2 Results

[0042] Take the half ester of succinic acid and use liquid chromatography to detect the result. Figure 2 .from Figure 2 It can be seen that the total proportion of fat-soluble impurities after the retention time of 25MIN is about 0.63%, the maximum single impurity is 0.16%, and the pyridine residue is at the level of 0.01%.

[0043] From the above results, it can be seen that the half-ester of succinic acid generated by the reaction of andrographolide, succinic anhydride and pyridine, without ethyl acetate dispersion, has poor crystallization effect by direct acid addition and low yield; during the purification process of adding anhydrous ethanol, dichloromethane is not introduced, and the fat-soluble impurities are not properly treated, and both single and total impurities exceed the standard. The half-ester of succinic acid generated by the reaction is dispersed with ethyl acetate, and the post-treatment is performed by beating a mixed solution of anhydrous ethanol + dichloromethane. The impurity control level is better, the yield is also higher, the amount of solvent used is less, and the cost is relatively low.

[0044] 2. Process parameters

[0045] Through preliminary experiments, it was found that among the process parameters for removing fat-soluble impurities in succinate hemiester, the ratio of anhydrous ethanol + dichloromethane has a greater influence on the removal effect and yield of fat-soluble impurities. Therefore, the ratio of anhydrous ethanol + dichloromethane was more precisely controlled.

[0046] 1. Methods

[0047] 10 g of andrographolide (molecular weight: 350.46), 10 g of succinic anhydride, and 6 g of pyridine were added to the reaction bottle, nitrogen was replaced three times, stirring was started, the temperature was raised to 95±5°C, the reaction was carried out for 6-10 hours, the reaction was completed, the temperature was lowered by 60±5°C, 2 g of ethyl acetate was added, the mixture was stirred for 1 hour, 60 g of hydrochloric acid solution with a pH value of 4-6 was added while hot, the mixture was stirred and dispersed for 30 minutes, and the filter cake was added to 60 g of hydrochloric acid solution with a pH value of 4-6 and beaten for 30 minutes, and the mixture was filtered, and the filter cake was added to a mixed solution of anhydrous ethanol + dichloromethane 20 g and beaten for 30 minutes, and the mixture was filtered, and the filter cake was dried at 50 degrees for 5-6 hours to obtain the half ester of andrographolide. The mixed solution of anhydrous ethanol + dichloromethane was set, and the weight ratios were 10:0.5, 10:1, 10:1.5, and 10:2, respectively.

[0048] 1.2 Results

[0049] The specific results are shown in Table 1 and Figures 3-4 .

[0050] Table 1 Effect of different ratios of anhydrous ethanol + dichloromethane on purified succinic acid hemiester

[0051] Weight ratio of anhydrous ethanol + dichloromethane mixed solution 10：0.5 10：1.0 10：1.5 10：2.0 Overall yield 93.6％ 93.4％ 89.5％ 85.7％ content 98.1％ 99.3％ 99.4％ 99.4％

[0052] From the above results, it can be seen that as the proportion of dichloromethane increases, the removal effect of fat-soluble impurities is better and the purity is higher, but the yield gradually decreases. Considering the product content, yield and the removal effect of fat-soluble impurities, the weight ratio of anhydrous ethanol + dichloromethane in the purification of succinic acid hemiester is best when it is 10:1.0.

[0053] 3. Determination of the final preparation and purification process

[0054] According to the screened purification process steps and parameters, the preparation method that can ensure the yield of succinate hemiester and effectively remove the fat-soluble impurities in succinate hemiester is determined as follows:

[0055] Take andrographolide, succinic anhydride and pyridine, mix them, add them to a reaction bottle, replace with nitrogen three times, start stirring, heat to 95±5°C, react for 6-10 hours, cool to 60±5°C, add ethyl acetate, keep warm and stir for 1 hour, add hydrochloric acid solution with a pH value of 4-6 while hot, stir and disperse for 30 minutes, filter with suction, add the obtained filter cake to the hydrochloric acid solution with a pH value of 4-6 and beat for 30 minutes, filter with suction, add the obtained filter cake to a mixed solution of anhydrous ethanol + dichloromethane (10:1) and beat for 30 minutes, filter with suction, and dry the obtained filter cake at 50°C for 5-6 hours to obtain;

[0056] The mass ratios of andrographolide, succinic anhydride, pyridine, ethyl acetate, the hydrochloric acid solution added for the first time, the hydrochloric acid solution added for the second time, and the mixed solution of anhydrous ethanol + dichloromethane (10:1) are 10:10:6:2:60:60:20.

[0057] In summary, the present invention is to add ethyl acetate solution to disperse the reactants after the synthesis reaction of succinate half ester is completed, then add hydrochloric acid solution for crystallization, and the precipitated crystals are purified by hydrochloric acid solution and a mixed solution of anhydrous ethanol + dichloromethane in sequence, so that the obtained succinate half ester has a high yield of more than 93.0%, a good product quality, a single impurity within 0.3%, a total impurity within 0.7%, and a pyridine residue at a level of 0.01%.

Claims

1. A method for preparing succinic acid half ester, characterized in that: It includes the following steps: 1) mixing andrographolide, succinic anhydride and pyridine for reaction, adding ethyl acetate and stirring after the reaction, then adding hydrochloric acid solution and stirring, filtering to obtain a filter cake; 2) adding hydrochloric acid solution to the filter cake obtained in step 1), stirring, filtering, adding a mixed solution of ethanol and dichloromethane to the filter cake, stirring, filtering, drying the filter cake, and collecting powder to obtain.

2. The preparation method according to claim 1, characterized in that Step 1) The reaction conditions are: nitrogen replacement followed by stirring, temperature 95±5° C., and time 6-10 hours.

3. The preparation method according to claim 1, characterized in that: In step 1), the temperature of adding ethyl acetate and stirring is 60±5° C. and the time is 0.5 to 1 hour.

4. The preparation method according to claim 1, characterized in that: The stirring time of adding the hydrochloric acid solution is 20 to 60 minutes.

5. The preparation method according to claim 4, characterized in that: The pH value of the hydrochloric acid solution is 4-6.

6. The preparation method according to claim 1, characterized in that: Step 2) the mixed solution of ethanol and dichloromethane is stirred for 20 to 60 minutes.

7. The preparation method according to claim 6, characterized in that: The mass ratio of ethanol to dichloromethane in the mixed solution is 10:1-2, preferably 10:

1.

8. The preparation method according to claim 7, characterized in that: The ethanol is anhydrous ethanol.

9. The preparation method according to claim 1, characterized in that: Step 2) The drying temperature is 40-60°C, preferably 50°C, and the drying time is 5-6 hours.

10. The preparation method according to claim 1, characterized in that: The mass ratio of andrographolide, succinic anhydride, pyridine, ethyl acetate, the hydrochloric acid solution in step 1), the hydrochloric acid solution in step 2), and the mixed solution of ethanol and dichloromethane is 5-15:5-15:4-8:1-3:50-80:50-80:10-30, preferably 10:10:6:2:60:60:20.

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