Freeze-drying preparation method of tigoraz pyroglutamate

Abstract

The invention discloses a freeze-drying preparation method of tegorasone pyroglutamate, which adopts a freeze-drying method to prepare a tegorasone pyroglutamate compound, solves the problems that the solvent residue is difficult to remove and the clarity is unqualified in the process of preparing the tegorasone pyroglutamate by a solvent method, improves the product yield and purity, and has the advantage of environmental protection. The method is suitable for commercial production.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to a freeze-drying preparation method of ticoraxan pyroglutamate. Background Technology

[0002] Tigorasen is used for the prevention and treatment of diseases mediated by acid pump antagonistic activity, including (but not limited to) gastrointestinal diseases such as gastroesophageal diseases, gastroesophageal reflux disease, peptic ulcers, gastric ulcers, duodenal ulcers, NSAID-induced ulcers, gastritis, Helicobacter pylori infection, dyspepsia, functional dyspepsia, Zollinger-Ellison syndrome, non-erosive reflux disease (NERD), visceral radicular pain, purosis, nausea, esophagitis, dysphagia, drooling, airway disorders, or asthma.

[0003] Because tigora has very low water solubility, it is difficult to directly formulate it into injectable preparations. However, preparing it as a salt compound can improve its water solubility. The method disclosed in patent CN109769392B involves reacting tigora with L-pyroglutamic acid to form tigora pyroglutamate salt. This salt compound exhibits good stability and is readily soluble in water, making it a superior salt compound.

[0004] The chemical name of tigorafenib pyroglutamate is (S)-4-[(5,7-difluorobenzodihydropyran-4-yl)oxy]-N,N,2-trimethyl-1H-benzo[d]imidazolium-6-carboxamide pyroglutamate, and its structural formula is as follows:

[0005]

[0006] The preparation method mentioned in the existing original salt-type patent CN109769392B is as follows:

[0007] A benzimidazole derivative (100 g) and approximately 1.05 eq. L-pyroglutamic acid (34.98 g) were completely dissolved in 10 volumes of methanol at 25 °C. The resulting reaction solution was then concentrated under reduced pressure at 50 °C with stirring until a large amount of solid precipitate formed. A co-solvent of acetone and ethyl acetate was added to the concentrate at a ratio of 1:4 (5 volumes) at 25 °C, and the resulting solution was vigorously stirred for 30 minutes. The solution was filtered under reduced pressure, washed with 1 volume of ethyl acetate, and dried under vacuum at 40 °C for 16 hours to obtain a white, powdery, amorphous compound.

[0008] However, the following shortcomings still exist:

[0009] (1) The product obtained by the method of concentration and precipitation with acetone and ethyl acetate has a clarity greater than that of turbidity liquid No. 1. Even if it is filtered in the formulation process, it may still lead to the finished product being unqualified after reconstitution.

[0010] (2) The concentration process leading to the precipitation of a large amount of solids is not controllable in the factory production process. If too much methanol remains, it will have a significant impact on the product yield and properties.

[0011] (3) The crystallization process of adding antisolvent is subject to the limitations of production equipment due to the vigorous stirring process, which poses a high risk.

[0012] Therefore, choosing a suitable preparation method is of great significance for the preparation of ticoraxan pyroglutamate. Summary of the Invention

[0013] The purpose of this invention is to provide a freeze-drying preparation method for ticoraxan pyroglutamate, which solves the problems of difficult removal of solvent residue and unqualified product clarity in the solvent method for preparing ticoraxan pyroglutamate, while improving product yield and reducing material costs.

[0014] During the research process, we were pleasantly surprised to find that tigorafenib pyroglutamate is easily soluble in water, thus meeting the prerequisites for freeze-drying and making it more suitable for commercial production.

[0015] This invention provides a freeze-drying preparation method for ticoraxin pyroglutamate, wherein the preparation method uses freeze-drying to obtain ticoraxin pyroglutamate.

[0016] Preferably, the preparation method involves dissolving ticoraxan in a reaction solvent, adding L-pyroglutamic acid, and after the reaction is completed, removing the solvent, dissolving in water, filtering, and freeze-drying to obtain ticoraxan pyroglutamic acid salt.

[0017] The reaction route is as follows:

[0018]

[0019] Preferably, the reaction solvent is one or two of methanol, anhydrous ethanol, or dichloromethane.

[0020] Preferably, the molar ratio of ticoraxan to L-pyroglutamic acid is 1:1.0 to 1.1; more preferably, the molar ratio of ticoraxan to L-pyroglutamic acid is 1:1.01 to 1.05.

[0021] Preferably, the reaction temperature of tigorasine with L-pyroglutamic acid is 10–35°C, more preferably 15–25°C.

[0022] Preferably, the solvent removal is performed by vacuum distillation at a temperature of 30–55°C, more preferably 40–45°C.

[0023] Preferably, the volume ratio of water dissolved to ticoraxan weight is 8-20:1 mL / g, more preferably 10:1 mL / g.

[0024] Preferably, the water used for dissolving is at a temperature of 0–25°C, more preferably 0–10°C.

[0025] Preferably, the freeze-drying conditions are as follows:

[0026] 1) The pre-freezing temperature is -50 to -30℃;

[0027] 2) The temperature for the first stage of sublimation drying is -30℃ to -10℃; the temperature for the second stage of sublimation drying is -10℃ to 0℃; the temperature for the third stage of sublimation drying is -5℃ to 5℃.

[0028] 3) The temperature of the first stage of the analytical drying process is 0-25℃; the temperature of the second stage of analytical drying is 25-50℃.

[0029] The present invention achieves the following beneficial technical effects:

[0030] (1) The present invention uses freeze-drying to prepare ticoraxin pyroglutamate, which solves the problem that the solvent residue is not easy to remove and the clarity is not up to standard in the process of preparing ticoraxin pyroglutamate by solvent method, and improves the product yield and purity.

[0031] (2) In the post-processing of this invention, the use of organic solvents is reduced, further reducing the risk of environmental pollution and making it more suitable for commercial production. Detailed Implementation

[0032] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, specific embodiments of the present invention will be described in detail below to facilitate further understanding of the present invention. Unless otherwise specified, all experimental methods used in the following embodiments are conventional methods. Unless otherwise specified, all materials and reagents used in the following embodiments are commercially available.

[0033] Example 1: Preparation of ticoraxan pyroglutamate

[0034] Add 1.5L of methanol to a 3L glass reaction flask, then add 150g of ticoraxan while stirring, and stir until mostly dissolved. Add 55g of L-pyroglutamic acid, and stir until mostly dissolved. React at 10–35°C for 16 hours.

[0035] After the reaction is complete, maintain the temperature at 30–55°C and concentrate the reaction solution under reduced pressure. Continue concentrating under reduced pressure until no liquid flows out, then stop the concentration. Simultaneously, pre-cool 2L of purified water (to 0–5°C) for later use.

[0036] After vacuum concentration, the temperature was lowered to 0–5°C. 3L of pre-cooled purified water (pre-cooled to 0–5°C) was added, maintaining the system temperature at 0–15°C throughout the addition process. After addition, the solution was stirred until dissolved. The solution was filtered through a 0.22μm membrane (the freeze dryer was pre-cooled to 0–5°C during filtration for later use). After filtration, the filtration system was washed with 0.3L of pre-cooled purified water. The filtrate and washings were combined and freeze-dried. The freeze-drying curve is shown below:

[0037]

[0038] After freeze-drying, the product was discharged. 190.46 g of deticoraxate pyroglutamate was obtained, yielding 95.2% and purity 99.675%.

[0039] Example 2: Preparation of ticoraxan pyroglutamate

[0040] Add 9L of methanol to a 30L glass reactor, then add 900g of ticoraxan while stirring, and stir until basically dissolved. Add 300g of L-pyroglutamic acid, and stir until basically dissolved. React at 10–35°C for 16 hours.

[0041] After the reaction is complete, maintain the temperature at 30–55°C and concentrate the reaction solution under reduced pressure. Concentrate under reduced pressure until no liquid flows out, then stop the concentration. Simultaneously, pre-cool 11L of purified water (to 0–5°C) for later use.

[0042] After vacuum concentration, the temperature was lowered to 0–5°C, and 7.2 L of purified water was added, maintaining the system temperature at 10–25°C throughout the addition process. After addition, the solution was stirred until dissolved. The solution was filtered through a 0.22 μm filter (the freeze dryer was pre-cooled to 0–5°C during filtration for later use). After filtration, the filtration system was washed with 1.8 L of pre-cooled purified water. The filtrate and washings were combined and freeze-dried. The freeze-drying curve is shown below:

[0043]

[0044] After freeze-drying, the product was discharged. 1126.60g of deticoraxate was obtained, with a yield of 93.8% and a purity of 99.736%.

[0045] Example 3: Preparation of ticoraxan pyroglutamate

[0046] Add 1L of dichloromethane to a 2L glass reaction flask, then add 100g of ticoraxan while stirring, and stir until basically dissolved. Add 33.66g of L-pyroglutamic acid, and stir until basically dissolved. React at 15-25°C for 16 hours with stirring.

[0047] After the reaction is complete, maintain the temperature at 35–45°C and concentrate the reaction solution under reduced pressure. Concentrate under reduced pressure until no liquid flows out, then stop the concentration. Simultaneously, pre-cool 2L of purified water (to 0–5°C) for later use.

[0048] After concentration under reduced pressure, the temperature was lowered to 0–5°C. 1 L of pre-cooled purified water (pre-cooled to 0–5°C) was added, maintaining the system temperature at 0–10°C throughout the addition process. After addition, the solution was stirred until dissolved. The solution was filtered through a 0.22 μm membrane (the lyophilizer was pre-cooled to 0–5°C during filtration for later use). After filtration, the filtration system was washed with 0.2 L of pre-cooled purified water. The filtrate and washings were combined and lyophilized. The lyophilization curve is shown below:

[0049]

[0050] After freeze-drying, the product was discharged. 126.60 g of deticoraxate pyroglutamate was obtained, yielding 95.0% and purity 99.936%.

[0051] Example 4: Preparation of ticoraxan pyroglutamate

[0052] Add 9L of methanol to a 30L glass reactor, then add 900g of ticoraxan while stirring, and stir until basically dissolved. Add 314.96g of L-pyroglutamic acid, and stir until basically dissolved. React at 15-25℃ for 16 hours.

[0053] After the reaction is complete, maintain the temperature at 40–45°C and concentrate the reaction solution under reduced pressure. Continue concentrating under reduced pressure until no liquid flows out, then stop the concentration. Simultaneously, pre-cool 10L of purified water (to 0–5°C) for later use.

[0054] After vacuum concentration, the temperature was lowered to 0–5°C. 9 L of pre-cooled purified water (pre-cooled to 0–5°C) was added, maintaining the system temperature at 0–10°C throughout the addition process. After addition, the solution was stirred until dissolved. The solution was filtered through a 0.22 μm filter (the freeze dryer was pre-cooled to 0–5°C during filtration for later use). After filtration, the filtration system was washed with 1.8 L of pre-cooled purified water. The filtrate and washings were combined and freeze-dried. The freeze-drying curve is shown below:

[0055]

[0056] After freeze-drying, the product was discharged. 1152.00 g of deticoraxate was obtained, yielding 96.0% and purity 99.938%.

[0057] Example 5: Preparation of ticoraxan pyroglutamate

[0058] Add 9L of anhydrous ethanol to a 30L glass reactor, then add 900g of ticoraxan while stirring, and stir until basically dissolved. Add 314.96g of L-pyroglutamic acid, and stir until basically dissolved (no obvious insoluble particles). React at 15-25℃ for 16 hours with stirring.

[0059] After the reaction is complete, maintain the temperature at 40–45°C and concentrate the reaction solution under reduced pressure. Concentrate under reduced pressure until no liquid flows out, then stop the concentration. Simultaneously, pre-cool 11L of purified water (to 0–5°C) for later use.

[0060] After vacuum concentration, the temperature was lowered to 0–5°C. 9 L of pre-cooled purified water (pre-cooled to 0–5°C) was added, maintaining the system temperature at 0–10°C throughout the addition process. After addition, the solution was stirred until dissolved. The solution was filtered through a 0.22 μm filter (the freeze dryer was pre-cooled to 0–5°C during filtration for later use). After filtration, the filtration system was washed with 1.8 L of pre-cooled purified water. The filtrate and washings were combined and freeze-dried. The freeze-drying curve is shown below:

[0061]

[0062] After freeze-drying, the product was discharged. 1157.00 g of deticoraxate was obtained, yielding 96.4% and purity 99.927%.

[0063] The embodiments described above are some, but not all, embodiments of the present invention. The detailed description of the embodiments of the present invention is not intended to limit the scope of protection claimed by the present invention, but merely to illustrate selected embodiments of the present invention. All other embodiments obtained by those skilled in the art based on the embodiments of the present invention without inventive effort are within the scope of protection of the present invention.

[0064] Experimental Example 1: Study on the Clarity of Solution

[0065] The tigorafenib pyroglutamate-type compounds prepared according to the embodiments of the present invention were compared with the sample prepared by patent CN109769392B in terms of solution clarity. The results are shown in Table 1.

[0066] Table 1: Study on solution clarity

[0067] Experimental Example 2: Solvent Residue Study

[0068] The tigorafenib pyroglutamate-type compounds prepared according to the embodiments of the present invention were compared with the samples prepared by patent CN109769392B in a solvent residue study. The results are shown in Table 2.

[0069] Table 2: Solvent Residue Study

[0070]

Claims

1. A freeze-drying preparation method of ticoraxan pyroglutamate, characterized in that, The preparation method described above uses freeze-drying to obtain ticoraxan pyroglutamate.

2. The method for preparing ticoraxate pyroglutamate by freeze-drying as described in claim 1, characterized in that, The preparation method involves dissolving ticoraxan in a reaction solvent, adding L-pyroglutamic acid, and after the reaction is complete, removing the solvent, dissolving in water, filtering, and lyophilizing to obtain ticoraxan pyroglutamic acid salt.

3. The method for preparing tigorafenibrate pyroglutamate by freeze-drying as described in claim 2, characterized in that, The reaction solvent is one or two of methanol, anhydrous ethanol, or dichloromethane.

4. The method for preparing ticoraxate pyroglutamate by freeze-drying as described in claim 2, characterized in that, The molar ratio of tegoprase to L-pyroglutamic acid is 1:1.0 to 1.

1.

5. The method for preparing ticoraxate pyroglutamate by freeze-drying as described in claim 4, characterized in that, The molar ratio of tegoprase to L-pyroglutamic acid is 1:1.01 to 1.

05.

6. The method for preparing ticoraxate pyroglutamate by freeze-drying as described in claim 2, characterized in that, The reaction temperature of ticoraxan with L-pyroglutamic acid is 10–35°C, preferably 15–25°C.

7. The method for preparing ticoraxate pyroglutamate by freeze-drying as described in claim 2, characterized in that, The solvent removal is performed by vacuum distillation at a temperature of 30–55°C, preferably 40–45°C.

8. The method for preparing ticoraxate pyroglutamate by freeze-drying as described in claim 2, characterized in that, The volume ratio of water dissolved to ticoraxan weight is 8-20:1 mL / g, preferably 10:1 mL / g.

9. The method for preparing ticoraxate pyroglutamate by freeze-drying as described in claim 2, characterized in that, The temperature for dissolving in water is 0–25°C, preferably 0–10°C.

10. The method for preparing ticoraxate pyroglutamate by freeze-drying as described in claim 2, characterized in that, The freeze-drying conditions are as follows: 1) The pre-freezing temperature is -50 to -30℃; 2) The temperature for the first stage of sublimation drying is -30℃ to -10℃; the temperature for the second stage of sublimation drying is -10℃ to 0℃; the temperature for the third stage of sublimation drying is -5℃ to 5℃. 3) The temperature of the first stage of the analytical drying process is 0-25℃; the temperature of the second stage of analytical drying is 25-50℃.

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