Method for preparing pyroglutamic acid tigorasone

Abstract

The invention discloses a method for preparing tegorasone pyroglutamate, and the prepared tegorasone pyroglutamate product has the advantages of reduced residual solvent content, good stability, and facilitation of the improvement of the product quality and the guarantee of the medication safety. The preparation method is simple and rapid in preparation process, beneficial to saving of production cost and suitable for industrial production.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical synthesis, and particularly relates to a method for preparing tegolanthrin pyroglutamate. Background Art

[0002] Tegolasan pyroglutamate is a pharmaceutical ingredient used to prevent and treat diseases mediated by acid pump antagonist activity, including but not limited to gastrointestinal diseases such as gastroesophageal reflux disease (GERD), peptic ulcer, gastric ulcer and duodenal ulcer, ulcer induced by NSAID, gastritis, Helicobacter pylori infection, dyspepsia and functional dyspepsia, Zollinger-Ellison syndrome, non-erosive reflux disease (NERD), visceral pain, heartburn, nausea, esophagitis, dysphagia, drooling, airway lesions and asthma.

[0003] The existing technology usually uses the solvent crystallization method to prepare raw materials, but the solvent residual solvent produced by the solvent crystallization method is relatively high, and the residual solvent will further form a solvate with tegrasen pyroglutamate. Affected by the intermolecular force, the residual solvent wrapped in the solvate is difficult to remove, affecting the product quality. Summary of the invention

[0004] The object of the present invention is to provide a method for preparing tigolasan pyroglutamate, which solves the quality problem of high residual solvent in the solvent crystallization process of tigolasan pyroglutamate, which affects the purity and stability of the product.

[0005] The invention provides a method for preparing teigolan pyroglutamate, wherein the method adopts spray drying for preparation.

[0006] Preferably, the method of the present invention is to prepare tigolasan and L-pyroglutamic acid by spray drying.

[0007] Preferably, the preparation method of the present invention comprises the following steps:

[0008] 1) dissolving tigolasan in an alcohol solvent, adding L-pyroglutamic acid, and stirring until dissolved;

[0009] 2) decolorizing with activated carbon, filtering with a membrane, and collecting the filtrate;

[0010] 3) spray drying the filtrate in step 2) and transferring it into a vacuum drying oven to prepare tegolanthrin pyroglutamate.

[0011] Preferably, the alcohol solvent in step 1) is at least one of methanol, ethanol or isopropanol, the reaction molar ratio of tigolasan to L-pyroglutamic acid is 1:1-1.2, and the mass volume ratio of tigolasan to the alcohol solvent is 1:20-85 g / mL, and more preferably 1:55-80 g / mL.

[0012] Preferably, in step 3), the spray drying temperature is 10-60°C, more preferably 30-60°C; the spray pressure is 0.01-1MPa, more preferably 0.2-0.5MPa; the vacuum drying temperature is 40-50°C, and the vacuum drying time is 10-12h.

[0013] Compared with the prior art, the beneficial technical effects of the present invention are:

[0014] (1) The residual solvent content of the product prepared by spray drying is low, which improves the product quality;

[0015] (2) The product prepared by the present invention has a short dissolution time in water, which can avoid product degradation, is conducive to maintaining product quality, and is more suitable for use as an injection;

[0016] (3) The clarity of the product prepared by the present invention is maintained for a long time, indicating that the product has better stability;

[0017] (4) The preparation process of the present invention is simple and rapid, which is beneficial to saving production costs and is suitable for industrial production. DETAILED DESCRIPTION

[0018] The content of the present invention is further described in detail below through specific embodiments, but the content of the present invention is not limited thereto.

[0019] Source of Tegolasen raw materials: selected from products of Shandong Luoxin Pharmaceutical Group Hengxin Pharmaceutical Co., Ltd.

[0020] Example 1

[0021] 100 mL of ethanol was added to the reaction bottle, and 5.0 g of tigolasan was added. After stirring until the solid was completely dissolved, 1.7 g of L-pyroglutamic acid was added, and the mixture was stirred at room temperature for 1-2 h. Activated carbon was added and stirred for decolorization for 30 minutes. The mixture was filtered with a membrane, and the filtrate was collected to obtain a reaction solution. The reaction solution was added to the material hopper of the spray dryer, and the spray pressure was set to 0.5 MPa and the spray temperature was set to 30°C for spray drying. The spray-dried material was transferred to a vacuum drying oven and vacuum dried at 40-50°C for 10 h to obtain 5.39 g of tigolasan pyroglutamic acid with a molar yield of 80.9%.

[0022] Example 2

[0023] 275 mL of ethanol was added to the reaction bottle, and 5.0 g of tigolasan was added. After stirring until the solid was completely dissolved, 2.0 g of L-pyroglutamic acid was added, and the mixture was stirred at room temperature for 1-2 h. Activated carbon was added and stirred for decolorization for 30 minutes. The mixture was filtered with a membrane, and the filtrate was collected to obtain a reaction solution. The reaction solution was added to the material hopper of the spray dryer, and the spray pressure was set to 0.2 MPa and the spray temperature was set to 60°C for spray drying. The spray-dried material was transferred to a vacuum drying oven and vacuum-dried at 40-50°C for 10 h to obtain 5.86 g of tigolasan pyroglutamic acid with a molar yield of 87.9%.

[0024] Example 3

[0025] 425 mL of methanol was added to the reaction bottle, and 5.0 g of tigolasan was added. After stirring until the solid was completely dissolved, 1.7 g of L-pyroglutamic acid was added, and the mixture was stirred at room temperature for 1-2 h. Activated carbon was added and stirred for decolorization for 30 minutes. The mixture was filtered with a membrane, and the filtrate was collected to obtain a reaction solution. The reaction solution was added to the material hopper of the spray dryer, and the spray pressure was set to 0.2 MPa and the spray temperature was set to 30°C for spray drying. The spray-dried material was transferred to a vacuum drying oven and vacuum dried at 40-50°C for 10 h to obtain 5.55 g of tigolasan pyroglutamic acid with a molar yield of 83.2%.

[0026] Example 4

[0027] 400 mL of ethanol was added to the reaction bottle, and 5.0 g of tigolasan was added. After stirring until the solid was completely dissolved, 1.7 g of L-pyroglutamic acid was added, and the mixture was stirred at room temperature for 1-2 h. Activated carbon was added and stirred for decolorization for 30 minutes. The mixture was filtered with a membrane, and the filtrate was collected to obtain a reaction solution. The reaction solution was added to the material hopper of the spray dryer, and the spray pressure was set to 0.2 MPa and the spray temperature was set to 30°C for spray drying. The spray-dried material was transferred to a vacuum drying oven and vacuum dried at 40-50°C for 12 h to obtain 5.73 g of tigolasan pyroglutamic acid with a molar yield of 85.9%.

[0028] Example 5

[0029] 100 mL of isopropanol was added to the reaction bottle, and 5.0 g of tigolasan was added. After stirring until the solid was completely dissolved, 1.7 g of L-pyroglutamic acid was added, and the mixture was stirred at room temperature for 1-2 h. Activated carbon was added and stirred for decolorization for 30 minutes. The mixture was filtered with a membrane, and the filtrate was collected to obtain a reaction solution. The reaction solution was added to the material hopper of the spray dryer, and the spray pressure was set to 0.2 MPa and the spray temperature was set to 30°C for spray drying. The spray-dried material was transferred to a vacuum drying oven and vacuum dried at 40-50°C for 12 h to obtain 5.21 g of tigolasan pyroglutamic acid with a molar yield of 78.2%.

[0030] Comparative Example 1

[0031] 5.0 g of tegrasin and 1.7 g of pyroglutamic acid were dissolved in methanol at room temperature, concentrated at 50°C until a large amount of solid was produced, and 400 ml of a mixed solution of acetone and ethyl acetate (acetone:ethyl acetate=1:4) was added.

[0032] The mixture was stirred and slurried, filtered, washed with 100 ml of ethyl acetate, and dried under vacuum at 45° C. for 12 h to prepare 5.67 g of teigolan pyroglutamate with a molar yield of 85.0%.

[0033] 1. Residual Solvent Data

[0034] Experimental method: The products prepared in Comparative Example 1 and Examples 1-5 of the present invention were respectively tested for residual solvents, and the residual solvent determination method of Method 0861, Part 4, General Rules of the 2020 Edition of the Chinese Pharmacopoeia was referred to. The test results are shown in Table 1.

[0035] Table 1: Comparison of residual solvent data

[0036]

[0037] As can be seen from Table 1, the product obtained by the present invention has fewer types of residual solvents, and the residual solvent content is much lower than the total residual solvent content of Comparative Example 1.

[0038] 2. Dissolution Test

[0039] Experimental method: 100 mg of the products prepared in Comparative Example 1 and Examples 1-5 of the present invention were added into 10 mL of water to dissolve, and the dissolution time was investigated. The results are shown in Table 2.

[0040] Table 2: Comparison of dissolution time

[0041] Experimental comparison Dissolution time Comparative Example 1 (Solvent Method) 25S Example 1 4S Example 2 5S Example 3 5S Example 4 6S Example 5 4S

[0042] As shown in Table 2, the product prepared by the method of the present invention dissolves quickly and is suitable for injection.

[0043] 3. Clarity test

[0044] Experimental method: After the products prepared in comparative example 1 and embodiments 1-5 of the present invention were dissolved in water respectively, an aqueous solution with a concentration of 10 mg / mL was prepared and placed at room temperature to examine the clarity. The results are shown in Table 3.

[0045] Table 3: Comparison of clarity tests

[0046]

[0047] The results in Table 3 show that the product prepared by the method of the present invention remains clear after being placed at room temperature for 24 hours. Therefore, the stability of the product obtained by the present invention is better than that of the product obtained by the solvent method in Comparative Example 1.

[0048] 4. Stability test

[0049] Experimental method: The pyroglutamic acid teigolan prepared in Comparative Example 1 and Examples 1-5 of the present invention were respectively packed into low-density polyethylene bags and stored in a stable chamber at 50° C. and 75% RH for 1 month. The impurity content was checked by HPLC analysis and calculated by the area normalization method. The results are shown in Table 4.

[0050] Table 4: Comparison of stability test data

[0051]

[0052] As shown in Table 4, after the product prepared by the present invention was placed for one month, the increase in the maximum single impurity and total impurity content was lower than that in Comparative Example 1, indicating that the product prepared by the present invention has better stability.

[0053] The embodiments described above are part of the embodiments of the present invention, rather than all of the embodiments. The detailed description of the embodiments of the present invention is not intended to limit the scope of the present invention, but merely represents selected embodiments of the present invention. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

Claims

1. A method for preparing tegolanthrin pyroglutamate, characterized in that: The method described is prepared by spray drying.

2. The method according to claim 1, characterized in that The method is to prepare tigolasan and L-pyroglutamic acid through a spray drying method.

3. The method according to claim 1, characterized in that The method comprises the following steps: 1) dissolving tigolasan in an alcohol solvent, adding L-pyroglutamic acid, and stirring until dissolved; 2) decolorizing with activated carbon, filtering with a membrane, and collecting the filtrate; 3) spray drying the filtrate in step 2) and transferring it into a vacuum drying oven to prepare tegolanthrin pyroglutamate.

4. The method according to claim 3, characterized in that The alcohol solvent in step 1) is at least one of methanol, ethanol or isopropanol.

5. The method according to claim 3, characterized in that: The mass volume ratio of tegrassen to alcohol solvent in step 1) is 1:20-85 g / mL.

6. The method according to claim 5, characterized in that The mass volume ratio of tegrassen to alcohol solvent in step 1) is 1:55-80 g / mL.

7. The method according to claim 3, characterized in that The spray drying temperature in step 3) is 10-60°C.

8. The method according to claim 7, characterized in that The spray drying temperature in step 3) is 30-60°C.

9. The method according to claim 3, characterized in that: The spray drying pressure in step 3) is 0.01-1 MPa, preferably 0.2-0.5 MPa.

10. The method according to claim 3, characterized in that The vacuum drying temperature in step 3) is 40-50° C., and the vacuum drying time is 10-12 hours.

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