Preparation method of ixazomib citrate raw material medicine
Ixazomib citrate in crystalline form 2 was prepared by a gradient cooling crystallization method, which solved the problem of excessive solvent residue and enabled the industrial production of ixazomib citrate raw material with high yield and pharmaceutical quality.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- 深圳万乐药业有限公司
- Filing Date
- 2025-12-17
- Publication Date
- 2026-04-21
AI Technical Summary
In the existing technology, ixazomib citrate products have the problem of excessive solvent residue, which makes it difficult to meet the pharmaceutical quality requirements, and the existing preparation methods are not suitable for industrial production.
Ixazomib citrate crude product was used as the starting material. It was dissolved in tetrahydrofuran and concentrated under reduced pressure. Then, it was crystallized by gradient cooling using ethyl acetate, acetone or a mixed solvent of tetrahydrofuran and ethyl acetate to obtain crystalline form 2 of ixazomib citrate.
This method enables the preparation of 2-crystal form ixazomib citrate with low solvent residue, high yield, and meeting pharmaceutical quality requirements, making it suitable for industrial production.
Smart Images
Figure FT_1 
Figure FT_2 
Figure FT_3
Abstract
Description
Technical Field
[0001] This invention belongs to the field of pharmaceutical chemistry technology, specifically relating to a method for preparing ixazomib citrate raw material suitable for industrial production. Background Technology
[0002] Ixazomib citrate is the first oral second-generation proteasome inhibitor developed by Takeda Pharmaceutical Company of Japan. After oral administration, ixazomib citrate is rapidly broken down into ixazomib in the body to exert its effect. Compared with the first-generation proteasome inhibitor bortezomib, ixazomib has a shorter dissociation half-life with the 20S proteasome and a dissociation rate about 6 times faster than bortezomib. The longer-lasting binding leads to drug retention in circulation, affecting its antitumor activity. Mouse studies have demonstrated that ixazomib controls tumors better than bortezomib and is also effective against bortezomib-resistant myeloma cells. The chemical name of ixazomib citrate is: 2-[(1R)-1-[[2-[(2,5-dichlorobenzoyl)amino]acetyl]amino]-3-methylbutyl]-5-oxo-1,3,2-dioxoboronyl-4,4-diacetic acid, and its structural formula is as follows (Formula I):
[0003] Formula I
[0004] The original patent CN10349720A discloses the preparation of ixazomib citrate capsules using ixazomib citrate crystallized in form 2, and also discloses the preparation method of ixazomib citrate crystallized in form 2, the reaction formula of which is as follows:
[0005] This method uses Formula II, i.e., ixazomib free boric acid, as the starting material, which is dissolved in ethyl acetate with citric acid. Heating and reacting the solutions crystallizes to obtain form 2 crystalline ixazomib citrate, with a yield exceeding 90%. However, repeated experiments revealed that the resulting product contained a significant amount of residual ethyl acetate solvent, failing to meet the safety requirements for pharmaceutical preparation. The patent also discloses the preparation of other crystalline forms of ixazomib citrate besides form 2 crystals, using the reaction of ixazomib free boric acid with citric acid, but with differences in the solvents and preparation processes.
[0006] For ixazomib citrate product in form 2 with solvent residue, as well as other different crystal forms of ixazomib citrate that do not meet pharmaceutical requirements, from the perspective of suitability for industrial production, in order to avoid product waste, it is necessary to study further purification and preparation methods to obtain ixazomib citrate raw material in crystal form 2 that meets the requirements for pharmaceutical preparation and whose solvent residue does not exceed the standard. Summary of the Invention
[0007] This invention provides a method for preparing ixazomib citrate in crystalline form 2. The method uses crude ixazomib citrate as the starting material, has a simple process operation, low solvent residue, high yield, and is suitable for industrial production.
[0008] The present invention provides a method for preparing ixazomib citrate raw material in crystalline form 2, characterized by comprising the following steps: Step 1): Dissolve crude ixazomib citrate in tetrahydrofuran until clear; Step 2): Concentrate to dryness under reduced pressure, dissolve in a crystallization solvent by heating, and crystallize using a gradient cooling method. The crystallization solvent is one or more of ethyl acetate, acetone, and tetrahydrofuran. Step 3): After filtration or centrifugation and drying, ixazomib citrate in crystalline form 2 is obtained.
[0009] Further optimization involves using a weight-to-volume ratio of crude ixazomib citrate to tetrahydrofuran in step 1) of 1:15~30, with a dissolution temperature of 20~50℃.
[0010] The crystallization solvent in step 2) is preferably acetone, or a mixture of tetrahydrofuran and ethyl acetate.
[0011] In step 2), when the crystallization solvent is acetone, the gradient crystallization method is as follows: in the first stage, the crystallization is carried out by stirring at 35-55°C for 2-4 hours; in the second stage, the crystallization is carried out by stirring at 5-35°C for 1-3 hours; and in the third stage, the crystallization is carried out by stirring at -10-5°C for 1-3 hours. The preferred gradient crystallization method is as follows: in the first stage, the crystallization is carried out by stirring at 50±5°C for 2 hours; in the second stage, the crystallization is carried out by stirring at 20±10°C for 1 hour; and in the third stage, the crystallization is carried out by stirring at 0±5°C for 1 hour.
[0012] In step 2), when the crystallization solvent is a tetrahydrofuran / ethyl acetate mixed solvent, the gradient crystallization method is as follows: the first stage is crystallization at 60-75℃ for 3-5 hours, the second stage is crystallization at 45-66℃ for 2-6 hours, and the third stage is crystallization at 10-30℃ for 1-3 hours; the preferred gradient crystallization method is crystallization at 72±3℃ for 3 hours, the second stage is crystallization at 63±3℃ for 5 hours, and the third stage is crystallization at 25±5℃ for 1 hour. The cooling rate from the first stage to the second stage is 3 to 9℃ / 30min, preferably 6℃ / 30min; the cooling rate from the second stage to the third stage is 2.5 to 10℃ / 30min, preferably 7.5℃ / 30min.
[0013] This invention uses crude ixazomib citrate as the starting material. After dissolving in tetrahydrofuran and evaporating under reduced pressure, an amorphous crude product is obtained. Then, using a specific gradient crystallization method with a crystallization solvent, ixazomib citrate raw material with crystal form 2 as described in the original patent CN103497210 is prepared. This method is simple to operate, achieves a yield of over 90%, and the solvent residue meets quality requirements. It is a suitable method for industrial production of further preparing crude ixazomib citrate into crystalline form 2 of ixazomib citrate raw material that meets pharmaceutical requirements.
[0014] The present invention will be further described below with reference to specific embodiments and accompanying drawings. Attached Figure Description
[0015] Figure 1 DSC chromatogram of ixazomib citrate prepared in Example 1
[0016] Figure 2 Crystal form 2 Ixazomib citrate DSC diagram
[0017] Figure 3 X-ray powder diffraction pattern of icazomib citrate in crystal form 2
[0018] Figure 4 Comparative Example 1 Product DSC Chart
[0019] Figure 5 Comparative Example 5 Product DSC Chart
[0020] Figure 6 X-ray powder diffraction pattern of the product in Comparative Example 5 Detailed Implementation
[0021] Example 1: Preparation of crude ixazomib citrate
[0022] In this embodiment, the crude ixazomib citrate was prepared according to the method of the original patent CN10349720A.
[0023] 10g of ixazomib free boric acid was added to a reaction flask, followed by 160ml of ethyl acetate. The mixture was stirred to dissolve and heated to 74℃. 6.4g of citric acid was added, and the mixture was stirred to induce crystallization for 2 hours. The mixture was then cooled to room temperature and allowed to continue crystallization for 1 hour. The mixture was filtered, and the filter cake was washed with 100ml of ethyl acetate and dried under vacuum at 45℃ to obtain 9.6g of the product, with a yield of 96%. The product was analyzed by differential scanning calorimetry (DSC) (see attached image). Figure 1 The resulting product was a mixed crystal, and a mixture of crystal forms 1 and 2 disclosed in the original patent; the product was tested by gas chromatography and found to contain 0.84% (limit 0.5%) of the residual solvent ethyl acetate, which did not meet the pharmaceutical quality standards.
[0024] Example 2 Preparation of ixazomib citrate in crystalline form 2
[0025] 1.5 g of crude ixazomib citrate prepared by the method in Example 1 was added to a reaction flask, along with 30 ml of tetrahydrofuran. The mixture was stirred and dissolved at room temperature, concentrated to dryness under reduced pressure at 35°C, and then 15 ml of acetone was added. The mixture was stirred and crystallized at 50°C for 2 hours, allowed to cool naturally to room temperature, and then stirred and crystallized again for 1.5 hours. Finally, the mixture was cooled to 0°C in a low-temperature constant-temperature reaction bath and stirred and crystallized for 1 hour. The mixture was filtered, the filter cake was washed with acetone at 0°C, and then dried under vacuum at 50°C to obtain 1.35 g of the product, with a yield of 90%. The product was analyzed by DSC and X-ray powder diffraction, and compared with the original patent, it was determined to be crystalline form 2. The spectra are attached. Figure 2 and attached Figure 3 The gas chromatography analysis of the product revealed the following residual solvent results: acetone residue was 0.22% (limit 0.5%), and tetrahydrofuran residue was 0.003% (limit 0.072%), which meets pharmaceutical quality standards.
[0026] Example 3 Preparation of ixazomib citrate in crystalline form 2
[0027] 10.0 g of crude ixazomib citrate prepared by the method of Example 1 was added to a reaction flask, along with 230 ml of tetrahydrofuran. The mixture was stirred and dissolved at room temperature, then concentrated to dryness under reduced pressure at 35°C. 40 ml of tetrahydrofuran and 100 ml of ethyl acetate were added, and the mixture was stirred and dissolved. Crystallization was carried out at 71°C for 3 hours, then cooled to 60°C at a rate of 6°C / 30 minutes. Crystallization was carried out at 60°C for 5 hours, then cooled to room temperature at a rate of 7.5°C / 30 minutes. Crystallization was carried out at room temperature for 1 hour. The mixture was filtered, and the filter cake was washed with ethyl acetate and dried under vacuum at 50°C to obtain 9.71 g of the product, with a yield of 97.1%. The product was analyzed by DSC and X-ray powder diffraction, and the crystal form was determined to be crystalline form 2. The detection pattern is consistent with... Figure 2 , Figure 3 The results were largely consistent. Gas chromatography analysis of the product revealed the following residual solvents: ethyl acetate 0.11% (limit 0.5%) and tetrahydrofuran 0.008% (limit 0.072%), meeting pharmaceutical quality standards. Crystallization was carried out for 3 hours, then cooled to 60°C at a rate of 6°C / 30 minutes, and crystallized at 60°C for 5 hours. Crystallization was then carried out at room temperature at a rate of 7.5°C / 30 minutes for 1 hour. The product was filtered, the filter cake was washed with ethyl acetate, and vacuum dried at 50°C to obtain 9.71g of product, with a yield of 97.1%. DSC and X-ray powder diffraction analysis showed the product to be crystal form 2, and the detection chromatograms were consistent with... Figure 2 , Figure 3The results are largely consistent. Gas chromatography analysis of the product revealed the following residual solvent levels: ethyl acetate 0.11% (limit 0.5%) and tetrahydrofuran 0.008% (limit 0.072%), meeting pharmaceutical quality standards.
[0028] Example 4 Preparation of ixazomib citrate in crystalline form 2
[0029] 10.0 g of crude ixazomib citrate prepared by the method in Example 1 was added to a reaction flask, along with 300 ml of tetrahydrofuran. The mixture was stirred and dissolved at room temperature, then concentrated to dryness under reduced pressure at 35°C. 50 ml of tetrahydrofuran and 100 ml of ethyl acetate were added, and the mixture was stirred and dissolved. Crystallization was carried out at 69°C for 4 hours, then cooled to 60°C at a rate of 7.8°C / 30 minutes, and crystallized at 60°C for 6 hours. Crystallization was then carried out at room temperature at a rate of 8.5°C / 30 minutes for 1 hour, filtered, and the filter cake was washed with ethyl acetate and dried under vacuum at 50°C to obtain 9.33 g of the product, with a yield of 93.3%. The product was analyzed by DSC and X-ray powder diffraction, and the crystal form was identified as crystalline form 2. The detection chromatogram was consistent with... Figure 2 , Figure 3 The results are largely consistent. Gas chromatography analysis of the product revealed the following residual solvent levels: ethyl acetate 0.12% (limit 0.5%) and tetrahydrofuran 0.010% (limit 0.072%), meeting pharmaceutical quality standards.
[0030] Comparative Example 1
[0031] 2.0 g of crude ixazomib citrate prepared by the method in Example 1 was added to a reaction flask, 20 ml of ethanol was added, and the mixture was heated to 70 °C to dissolve. 10 ml of n-hexane was added, and the mixture was allowed to crystallize at room temperature for 1 hour, then at 0 °C for 2.5 hours. The mixture was filtered, the filter cake was washed with n-hexane, and dried to obtain 1.72 g of the product, with a yield of 86%. The product was analyzed by differential scanning calorimetry (DSC) (see Appendix). Figure 4 The diagrams of crystal form 2 and crystalline form 2 are attached. Figure 2 The results were inconsistent. The product obtained was a mixture of the crystal form of the product in Example 1 and the ethanol solvate of ixazomib citrate. In other words, the crystal form of the product obtained by using ethanol and n-hexane as crystallization solvents did not meet the requirements.
[0032] Comparative Example 2
[0033] 2.0 g of crude ixazomib citrate prepared by the method in Example 1 was added to a reaction flask, along with 40 ml of tetrahydrofuran. The mixture was heated to 60 °C to dissolve, cooled to room temperature until no crystals precipitated, and concentrated under reduced pressure to half its volume. 30 ml of n-heptane was added, and the mixture was stirred at room temperature for 4 hours to induce crystallization. The mixture was filtered, the filter cake was washed with n-heptane, and dried to obtain 1.84 g of the product, with a yield of 92%. The product was analyzed by DSC chromatogram and... Figure 1 Consistent crystal structure, meaning the product is a mixed crystal, indicates that the crystal form of the product obtained by using tetrahydrofuran and n-heptane as crystallization solvents does not meet the requirements.
[0034] Comparative Example 3
[0035] 5.0 g of crude ixazomib citrate prepared by the method in Example 1 was added to a reaction flask, along with 115 ml of tetrahydrofuran. The mixture was stirred and dissolved at room temperature, concentrated to dryness under reduced pressure at 35°C, and then 100 ml of acetone was added. Crystallization was carried out at room temperature for 1.5 hours. The mixture was filtered, the filter cake was washed with acetone, and dried under vacuum at 45°C to obtain 1.53 g of the product, with a yield of 61.2%. The product was analyzed by DSC, and the chromatogram was consistent with the attached... Figure 1 Consistent crystal structure, meaning the resulting product is a mixed crystal. Compared to Example 2, the crystallization temperature in this example was maintained at room temperature throughout, and no gradient crystallization method was adopted, resulting in a product with a crystal form that did not meet the requirements.
[0036] Comparative Example 4
[0037] 2.0 g of crude ixazomib citrate prepared by the method in Example 1 was added to a reaction flask, along with 46 ml of tetrahydrofuran. The mixture was dissolved by stirring at room temperature, concentrated to dryness under reduced pressure at 35°C, and then 50 ml of acetone was added. Crystallization was carried out at 50°C with stirring for 1 hour, followed by crystallization at 0°C for another hour. The mixture was filtered, the filter cake was washed with acetone, and dried under vacuum at 45°C to obtain 1.23 g of the product, with a yield of 61.5%. The product was analyzed by DSC and X-ray powder diffraction, and the crystal form was identified as crystalline form 2. The detection chromatogram was consistent with... Figure 2 , Figure 3 The results are largely consistent. Gas chromatography analysis of residual solvents showed that acetone residue was 0.55% (limit 0.5%) and tetrahydrofuran residue was 0.13% (limit 0.072%). Both acetone and tetrahydrofuran residues did not meet pharmaceutical quality standards, indicating that changing the gradient crystallization method affected the product's solvent residue compared to Example 2.
[0038] Comparative Example 5
[0039] 2.0 g of crude ixazomib citrate prepared by the method in Example 1 was added to a reaction flask, along with 46 ml of tetrahydrofuran. The mixture was stirred and dissolved at room temperature, concentrated to dryness under reduced pressure at 35°C, and then 2 ml of tetrahydrofuran was added. The mixture was stirred and dissolved, and then 50 ml of ethyl acetate was added. Crystallization was carried out at 50°C for 1 hour, followed by crystallization at room temperature for 2 hours. The mixture was filtered, and the filter cake was washed with ethyl acetate and dried under vacuum at 50°C to obtain 1.50 g of the product, with a yield of 75%. The product was analyzed by DSC and X-ray powder diffraction, and the crystal form was consistent with the crystalline form 1 disclosed in the original patent (see attached chromatogram). Figure 5 and Figure 6 Compared with Examples 3 and 4, the crystallization solvent was the same, but the crystallization temperature and time were different, and the resulting crystal form did not meet the product requirements.
[0040] Comparative Example 6
[0041] 2.0 g of crude ixazomib citrate prepared by the method in Example 1 was added to a reaction flask, along with 46 ml of tetrahydrofuran. The mixture was stirred and dissolved at room temperature, concentrated to dryness under reduced pressure at 35°C, and then 8 ml of tetrahydrofuran and 20 ml of ethyl acetate were added. The mixture was stirred and dissolved, crystallized at 70°C for 1 hour, at 60°C for 2 hours, and at room temperature for 1 hour. The crystals were filtered, the filter cake was washed with ethyl acetate, and dried under vacuum at 50°C to obtain 1.76 g of the product, with a yield of 88%. The product was analyzed by DSC and X-ray powder diffraction, and the crystal form was identified as crystalline form 2. The detection chromatogram was consistent with... Figure 2 , Figure 3 The results are largely consistent. Gas chromatography analysis revealed the following residual solvent levels: ethyl acetate 0.31% (limit 0.5%) and tetrahydrofuran 0.11% (limit 0.072%). The tetrahydrofuran residue does not meet pharmaceutical quality standards. Compared to Examples 2 and 3, the gradient crystallization method used in this example differs, indicating that the gradient crystallization method leads to unacceptable residual solvent levels in the product.
[0042] Comparative Example 7
[0043] 2.0 g of crude ixazomib citrate prepared by the method in Example 1 was added to a reaction flask, along with 46 ml of tetrahydrofuran. The mixture was stirred and dissolved at room temperature, then concentrated to dryness under reduced pressure at 35°C. 8 ml of tetrahydrofuran and 20 ml of ethyl acetate were added, and the mixture was stirred and dissolved. Crystallization was carried out at 74°C for 1.5 hours. The temperature was then lowered to 60°C at a rate of 12°C / 30 minutes, and crystallization continued at 60°C for 2 hours. The mixture was then cooled to room temperature at a rate of 15°C / 30 minutes, and crystallization continued at room temperature for 1 hour. The mixture was filtered, and the filter cake was washed with ethyl acetate and dried under vacuum at 50°C to obtain 1.90 g of the product, with a yield of 95%. The product was analyzed by DSC and X-ray powder diffraction, and the crystal form was identified as crystalline form 2. The detection chromatogram was consistent with... Figure 2 , Figure 3 The results were largely consistent. Gas chromatography analysis revealed the following residual solvent levels: ethyl acetate 0.23% (limit 0.5%) and tetrahydrofuran 0.09% (limit 0.072%). The tetrahydrofuran residue did not meet pharmaceutical quality standards. Compared to Examples 2 and 3, the cooling rate differed in this example, indicating that the cooling rate affects the residual solvent when tetrahydrofuran and ethyl acetate are used as crystallization solvents.
Claims
1. A method for preparing ixazomib citrate raw material in crystalline form 2, characterized in that, The operation includes the following steps: Step 1): Dissolve crude ixazomib citrate in tetrahydrofuran until clear; Step 2): Concentrate to dryness under reduced pressure, dissolve in a crystallization solvent by heating, and crystallize using a gradient cooling method. The crystallization solvent is one or more of ethyl acetate, acetone, and tetrahydrofuran. Step 3): After filtration or centrifugation and drying, ixazomib citrate in crystalline form 2 is obtained.
2. The preparation method according to claim 1, characterized in that, In step 1), the weight-to-volume ratio of crude ixazomib citrate to tetrahydrofuran is 1:15~30.
3. The preparation method according to claim 1, characterized in that, In step 1), the temperature for dissolving crude ixazomib citrate in tetrahydrofuran is 20-50°C.
4. The preparation method according to claim 1, characterized in that, The crystallization solvent mentioned in step 2) is acetone or a mixture of tetrahydrofuran and ethyl acetate.
5. The preparation method according to claim 1, characterized in that, In step 2), when the crystallization solvent is acetone, the gradient crystallization method is as follows: in the first stage, the crystallization is carried out by stirring at 35-55℃ for 2-4 hours; in the second stage, the crystallization is carried out by stirring at 5-35℃ for 1-3 hours; and in the third stage, the crystallization is carried out by stirring at -10-5℃ for 1-3 hours.
6. The preparation method according to claim 5, characterized in that, When the crystallization solvent in step 2) is acetone, the gradient crystallization method is as follows: in the first stage, the crystallization is carried out by stirring at 50±5℃ for 2 hours; in the second stage, the crystallization is carried out by stirring at 20±10℃ for 1 hour; and in the third stage, the crystallization is carried out by stirring at 0±5℃ for 1 hour.
7. The preparation method according to claim 1, characterized in that, When using the tetrahydrofuran / ethyl acetate mixed solvent as the crystallization solvent in step 2), the gradient crystallization method is as follows: in the first stage, the crystallization is carried out by stirring at 60-75℃ for 3-5 hours; in the second stage, the crystallization is carried out by stirring at 45-66℃ for 2-6 hours; and in the third stage, the crystallization is carried out by stirring at 10-30℃ for 1-3 hours.
8. The preparation method according to claim 7, characterized in that, When using the tetrahydrofuran / ethyl acetate mixed solvent as the crystallization solvent in step 2), the gradient crystallization method is as follows: in the first stage, the crystallization is carried out by stirring at 72±3℃ for 3 hours; in the second stage, the crystallization is carried out by stirring at 63±3℃ for 5 hours; and in the third stage, the crystallization is carried out by stirring at 25±5℃ for 1 hour.
9. The preparation method according to claim 7 or 8, characterized in that, When using the tetrahydrofuran / ethyl acetate mixed solvent as the crystallization solvent in step 2), the cooling rate during gradient crystallization is 3-9℃ / 30min from the first stage to the second stage, and 2.5-10℃ / 30min from the second stage to the third stage.
10. In the preparation method according to claim 7 or 8, when the crystallization solvent in step 2) is a tetrahydrofuran / ethyl acetate mixed solvent, the cooling rate during gradient crystallization is 6℃ / 30min from the first stage to the second stage, and 7.5℃ / 30min from the second stage to the third stage.