A method for removing aripiprazole BQB impurities
By adding DCP hydrochloride, 7-CBQ and alkali to the reaction solvent, combined with slurry crystallization technology, the problem of complex and costly removal of BQB impurities in the existing technology was solved, and high-purity aripiprazole was prepared.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- ZHEJIANG HUAHAI PHARMACEUTICAL CO LTD
- Filing Date
- 2021-11-30
- Publication Date
- 2026-05-26
AI Technical Summary
Existing technologies for removing BQB impurities from aripiprazole have issues such as affecting 7-CBQ yield or increasing costs, failing to effectively remove impurities, and being complex to operate.
Aripiprazole was obtained by reacting DCP hydrochloride, 7-CBQ and alkali in a reaction solvent, followed by cooling and adding water to slurry and crystallize, and then filtering. The specific steps included selecting appropriate temperature, solvent ratio and slurrying time.
The preparation of high-purity aripiprazole with BQB impurity content below 0.15% was achieved. The operation is simple and cost-effective, and the product quality is improved.
Smart Images
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Abstract
Description
Technical Field
[0001] This invention relates to the field of chemical synthesis technology, and specifically to a method for removing aripiprazole BQB impurities. Background Technology
[0002] Aripiprazole is a novel atypical antipsychotic drug used to treat various acute and chronic schizophrenia and schizoaffective disorder. Its structural formula is shown below:
[0003]
[0004] BQB impurity is a key impurity in aripiprazole, and its structural formula is shown in Formula I:
[0005]
[0006] Its main origin is from the synthesis of aripiprazole intermediate 7-CBQ:
[0007]
[0008] To date, there are two main methods for removing BQB impurities from aripiprazole:
[0009] 1) Removing BQB impurities by alumina adsorption in the 7-CBQ preparation step will affect the yield of 7-CBQ; 2) Reducing the amount of BQB impurities by increasing the amount of 1,4-bromochlorobutane in the 7-CBQ preparation step will increase the cost due to the increased amount of 1,4-bromochlorobutane. Summary of the Invention
[0010] This invention provides a method for removing aripiprazole BQB impurities, comprising the following steps:
[0011] The reaction of DCP hydrochloride, 7-CBQ (containing impurity BQB) and base in a reaction solvent is heated to a predetermined temperature. After the reaction is completed, the temperature is lowered to a predetermined temperature, and water is added at the predetermined temperature to slurry and crystallize. Filtration can effectively remove impurity BQB and obtain high-quality aripiprazole.
[0012]
[0013] Preferably, the predetermined temperature is 50℃~90℃, and more preferably 80℃~90℃.
[0014] Preferably, the reaction solvent is selected from N,N-dimethylformamide or N,N-dimethylacetamide, and more preferably N,N-dimethylformamide.
[0015] Preferably, the alkali is selected from potassium carbonate, and the molar ratio of the alkali to 7-CBQ is 1.08. Preferably, the molar ratio of 7-CBQ to DCP hydrochloride is 0.92.
[0016] Preferably, the weight ratio of 7-CBQ to the reaction solvent is 1:10.
[0017] Preferably, the mass ratio of the reaction solvent to water is 1:(1-4), and more preferably 1:3.
[0018] Preferably, the pulping and crystallization time is 1-10 hours, and more preferably 3-5 hours.
[0019] The reaction product prepared by this invention can be filtered to obtain high-purity aripiprazole with a purity greater than 99% and a BQB impurity content of less than 0.15%. The method provided by this invention for removing BQB impurities from aripiprazole is simple to operate and has high quality. Detailed Implementation
[0020] The present invention will be further described in detail below through specific embodiments. All raw materials used in the embodiments are commercially available.
[0021] Example 1
[0022] In a 3000 ml reaction flask, DCP hydrochloride (69 g, 0.26 mol), 7-CBQ (60 g, 0.24 mol) (containing 1% BQB), 600 g DMF, and potassium carbonate (36 g, 0.26 mol) were added sequentially. The mixture was heated to 95 ± 3 °C and stirred for 3 ± 0.5 hours. The mixture was then cooled to a predetermined temperature, and 1800 mL of water was added dropwise over one hour at the predetermined temperature to form a slurry. Crystallization was maintained at the predetermined temperature for 3 hours. The slurry was filtered, dried, and sent for testing.
[0023] Table 1
[0024]
[0025]
[0026] As can be seen from the data in the table above, the removal effect of BQB impurities is best when the predetermined temperature is 80℃-90℃.
[0027] Example 2
[0028] In a 3000 ml reaction flask, DCP hydrochloride (69 g, 0.26 mol), 7-CBQ (60 g, 0.24 mol) (containing 1% BQB), 600 g of reaction solvent, and potassium carbonate (36 g, 0.26 mol) were added sequentially. The mixture was heated to 95 ± 3 °C and stirred for 3 ± 0.5 hours. The temperature was then lowered to 80 ± 3 °C, and 1800 mL of water was added dropwise over 1 hour at 80 ± 3 °C to form a slurry. Crystallization was carried out at 80 ± 3 °C for 3 hours. The slurry was filtered, dried, and sent for testing.
[0029] Table 2
[0030] solvent Aripiprazole HPLC (purity) BQB (content) N,N-Dimethylformamide 99.33％ 0.12 N,N-Dimethylacetamide 99.38％ 0.13 N-Methylpyrrolidone 99.17％ 0.46
[0031] As can be seen from the table above, the removal effect of BQB impurities is best when the reaction solvent is N,N-dimethylformamide.
[0032] Example 3
[0033] In a 3000 ml reaction flask, DCP hydrochloride (69 g, 0.26 mol), 7-CBQ (60 g, 0.24 mol) (containing 1% BQB), and DMF (600 g) and potassium carbonate (36 g, 0.26 mol) were added sequentially. The mixture was heated to 95 ± 3 °C and stirred for 3 ± 0.5 hours. The temperature was then lowered to 80 ± 3 °C, and a predetermined amount of water was added dropwise over 1 hour at 80 ± 3 °C to form a slurry. Crystallization was carried out at 80 ± 3 °C for 3 hours. The mixture was filtered, and the dried filter cake was sent for testing.
[0034] Table 3
[0035]
[0036]
[0037] As can be seen from the table above, the optimal reaction solvent-to-water mass ratio is 1:2.5-3.5.
[0038] Example 4
[0039] In a 3000 ml reaction flask, DCP hydrochloride (69 g, 0.26 mol), 7-CBQ (60 g, 0.24 mol) (containing 1% BQB), 600 g DMF, and potassium carbonate (36 g, 0.26 mol) were added sequentially. The mixture was heated to 95 ± 3 °C and stirred for 3 ± 0.5 hours. The temperature was then lowered to 80 ± 3 °C, and 1800 mL of water was added dropwise over 1 hour at 80 ± 3 °C to form a slurry. The mixture was then kept at 80 ± 3 °C for a predetermined time to allow crystallization. After filtration, the filter cake was dried and sent for testing.
[0040] Table 4
[0041] Time (hours) Aripiprazole HPLC (purity) BQB (content) Yield % 1 99.42％ 0.06 81.07 2 99.37％ 0.08 88.29 3 99.35％ 0.11 91.10 4 99.37％ 0.15 90.79 5 99.35％ 0.14 91.02 6 99.19％ 0.19 91.23 7 99.05％ 0.21 90.06 8 98.93％ 0.27 92.37 9 98.88％ 0.28 91.18 10 98.75％ 0.27 91.16
[0042] As can be seen from the table above, considering both purity and yield, the optimal pulping and crystallization time is 3-5 hours.
[0043] Example 5
[0044] In a 3000 mL reaction flask, DCP hydrochloride (69 g, 0.26 mol), 7-CBQ (60 g, 0.24 mol) (containing 1% BQB), 600 g DMF, and potassium carbonate (36 g, 0.26 mol) were added sequentially. The mixture was heated to 95 ± 3 °C and stirred for 3 ± 0.5 hours. The temperature was then lowered to 80 ± 3 °C, and 1800 mL of water was added dropwise over 1 hour at 80 ± 3 °C to form a slurry. Crystallization was then carried out at 80 ± 3 °C for 3 hours, followed by filtration. The filter cake was dried to obtain 96.57 g of aripiprazole as a white solid, with a yield of 91.10%, HPLC purity of 99.35%, and BQB content of 0.13%.
[0045] Example 7
[0046] In a 3000 mL reaction flask, DCP hydrochloride (69 g, 0.26 mol), 7-CBQ (60 g, 0.24 mol) (containing 1% BQB), 600 g DMF, and potassium carbonate (36 g, 0.26 mol) were added sequentially. The mixture was heated to 95 ± 3 °C and stirred for 3 ± 0.5 hours. The temperature was then lowered to 80 ± 3 °C, and 900 mL of water was added dropwise over 1 hour at 80 ± 3 °C to form a slurry. Crystallization was then carried out at 80 ± 3 °C for 3 hours, followed by filtration. The filter cake was dried to obtain 54.35 g of aripiprazole as a white solid, with a yield of 51.27%, HPLC purity of 99.58%, and BQB content of 0.08%.
[0047] Example 8
[0048] In a 3000 mL reaction flask, DCP hydrochloride (69 g, 0.26 mol), 7-CBQ (60 g, 0.24 mol) (containing 1% BQB), 600 g DMF, and potassium carbonate (36 g, 0.26 mol) were added sequentially. The mixture was heated to 95 ± 3 °C and stirred for 3 ± 0.5 hours. The temperature was then lowered to 80 ± 3 °C, and 1800 mL of water was added dropwise over 1 hour at 80 ± 3 °C to form a slurry. Crystallization was then carried out at 80 ± 3 °C for 1 hour, followed by filtration. The filter cake was dried to obtain 85.93 g of aripiprazole as a white solid, with a yield of 81.07%, HPLC purity of 99.42%, and BQB content of 0.06%.
[0049] Comparative Example 1
[0050] In a 3000 mL reaction flask, DCP hydrochloride (69 g, 0.26 mol), 7-CBQ (60 g, 0.24 mol) (containing 1% BQB), 600 g NMP, and potassium carbonate (36 g, 0.26 mol) were added sequentially. The mixture was heated to 95 ± 3 °C and stirred for 3 ± 0.5 hours. The temperature was then lowered to 80 ± 3 °C, and 1800 mL of water was added dropwise over 1 hour at 80 ± 3 °C. Crystallization was maintained at 80 ± 3 °C for 3 hours, followed by filtration. The filter cake was dried to obtain 94.02 g of aripiprazole as a white solid, with a yield of 88.70%, HPLC purity of 99.17%, and BQB content of 0.46%.
Claims
1. A method for removing aripiprazole BQB impurities, characterized in that... Includes the following steps: DCP hydrochloride, 7-CBQ containing impurity BQB, and a base are reacted in a reaction solvent at a higher temperature. After the reaction is completed, the temperature is lowered to a predetermined temperature, and water is added at the predetermined temperature to slurry and crystallize. The mixture is then filtered to remove impurity BQB and obtain aripiprazole. The predetermined temperature is 80℃~90℃; The reaction solvent is selected from N,N-dimethylformamide or N,N-dimethylacetamide; The mass ratio of the reaction solvent to water is 1:2.5~3.5; The pulping and crystallization time is 1-5 hours.
2. The method for removing aripiprazole BQB impurities according to claim 1, characterized in that... The reaction solvent is N,N-dimethylformamide.
3. The method for removing aripiprazole BQB impurities according to claim 1, characterized in that... The alkali is selected from potassium carbonate, the molar ratio of the alkali to 7-CBQ is 1.08, and the molar ratio of 7-CBQ to DCP hydrochloride is 0.
92.
4. The method for removing aripiprazole BQB impurities according to claim 1, characterized in that... The weight ratio of 7-CBQ to the reaction solvent is 1:
10.
5. The method for removing aripiprazole BQB impurities according to claim 1, characterized in that... The mass ratio of the reaction solvent to water is 1:
3.
6. The method for removing aripiprazole BQB impurities according to claim 1, characterized in that... The pulping and crystallization time is 3-5 hours.