Preparation method of nitroso ceritinib as genotoxic impurity of ceritinib
Through the low-temperature nitration reaction method, a three-step process is used to generate nitroso seritinib during the preparation of seritinib, which solves the problem of difficulty in effectively preparing and controlling nitroso genotoxic impurities in the prior art, and realizes an efficient and low-cost preparation process and high-purity products.
Patent Information
- Application Number
- CN202411838022.5
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-12-13
- Publication Date
- 2025-04-29
AI Technical Summary
The prior art is difficult to effectively prepare and control nitrosogenotoxic impurities, which affects the preparation process of ceritinib.
The low-temperature nitration reaction method was adopted, and a three-step process was carried out: first synthesize the intermediate, then carry out a deprotection group reaction, and finally react with sodium nitrite under low temperature and acid conditions to prepare nitrosogratinib.
The efficient preparation of nitrosogratinib was achieved, the occurrence of side reactions was controlled, and qualified impurity control products were obtained, with high product purity and low cost.
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Abstract
Description
Technical Field
[0001] The invention relates to a preparation method of nitroso-ceritinib, and belongs to the field of drug synthesis. Background Art
[0002] Ceritinib, chemically named 5-chloro-N4-[(2-isopropylsulfonyl)phenyl]-N2-[2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl]-2,4-pyrimidinediamine, is a second-generation anaplastic lymphoma kinase (ALK) receptor inhibitor developed by Novartis, Switzerland. It is clinically used as a first-line drug for the treatment of metastatic non-small cell lung cancer that is positive for anaplastic lymphoma kinase mutation or cannot tolerate crizotinib. It was approved for marketing by DA in 2014 and approved for marketing in China in 2018. Its structure is shown below:
[0003] Chen Li et al. published four potential genotoxic impurities with warning structures in Chinese Modern Applied Pharmacy, Vol. 38, No. 24, December 2021. The specific structures are as follows:
[0004] Among them, compound 2 and compound 13 contain aniline warning structures, and compound 6 and compound 7 contain nitrobenzene warning structures.
[0005] According to the ICH M7 guidelines, in order to further study the nitroso-genotoxic impurities that may be produced during the preparation or storage of ceritinib, it is necessary to explore the preparation process of this impurity. Summary of the invention
[0006] The invention discloses a method for preparing nitroso-ceritinib. By adopting a low-temperature nitration reaction, the occurrence of other side reactions is effectively controlled, and a qualified impurity reference substance is prepared.
[0007] The above technical objectives of the present invention are achieved through the following technical solutions: A method for preparing nitroso-ceritinib comprises the following steps: 2,5-dichloro-N-[2-(isopropylsulfonyl)phenyl]pyrimidin-4-amine (starting material 1) and tert-butyl 4-(4-amino-5-isopropoxy-2-methylphenyl)-1-piperidinecarboxylate (starting material 2) are used as starting materials, and heated under reflux at an appropriate feed ratio (molar ratio), reaction solvent and catalyst until the reaction is complete, and cooled and crystallized to obtain an intermediate: tert-butyl 4-[4-[[5-chloro-4-[[2(isopropylsulfonyl)phenyl]amino]pyrimidin-2-yl]amino]-5-isopropoxy-2-methylphenyl]-1-piperidinecarboxylate.
[0008] (2) treating the intermediate with an appropriate strong acid to remove the protecting group to obtain ceritinib; (3) Finally, ceritinib is reacted with sodium nitrite in a suitable organic solvent under low temperature and acidic conditions to obtain nitroso-ceritinib.
[0009] By adopting the above technical scheme, nitroso-ceritinib is prepared through a simple three-step process, the preparation method is simple, and the raw materials are easily available.
[0010] The reaction process is:
[0011] The specific implementation scheme is as follows: the appropriate feed ratio (molar ratio) described in the first step reaction is: starting material 1: starting material 2 = 1:1~1:1.5; preferably: 1:1.2; the suitable solvent is: methanol, ethanol or isopropanol; the amount of solvent is: organic solvent: starting material (1+2) = 4-6 times (volume / mass); the catalyst is: triethylamine or di(isopropyl)amine; the amount of catalyst is: catalyst: starting material 1 = 0.1:1~0.5:1 (molar ratio); the cooling crystallization temperature is: 0-5°C, and the crystallization time is: 0.5-2 hours; The appropriate strong acid described in the second step reaction is trifluoroacetic acid; the dosage is: trifluoroacetic acid: intermediate = 5:1 (V / M); The suitable organic solvent described in the third step reaction is: dichloromethane, chloroform or 1,2-dichloroethane; the amount of solvent used is: organic solvent: starting material (1+2) = 5-10 times (volume / mass); the acidic condition is: concentrated hydrochloric acid; the pH value is adjusted to: 1~2; the low temperature is: 0~10°C, preferably: 0°C.
[0012] In summary, the present invention has the following beneficial effects: The reaction route of the present invention has fewer steps, mild reaction conditions, does not involve reactions under harsh conditions, and does not involve high-pressure dangerous processes; at the same time, the conversion rate of each step is high, and the quality is stable and reliable; in addition, the raw materials of the present invention are inexpensive and the cost is low; finally, due to mild synthesis conditions, few by-products are produced, and the purity of the obtained product is high, which meets the requirements of quality research.
[0013] Attached photos Attached Figure 1 :HPLC chromatogram of Nitrosoceritinib DETAILED DESCRIPTION
[0014] The present invention is further described below. The following examples are only used to more clearly illustrate the technical solution of the present invention, and are not intended to limit the protection scope of the present invention.
[0015] Example: (1) Synthesis of tert-butyl 4-[4-[[5-chloro-4-[[2(isopropylsulfonyl)phenyl]amino]pyrimidin-2-yl]amino]-5-isopropoxy-2-methylphenyl]-1-piperidinecarboxylate (intermediate): 40 ml of ethanol, 2,5-dichloro-N-[2-(isopropylsulfonyl)phenyl]pyrimidine-4-amine (3.46 g, 0.01 mol), 4-(4-amino-5-isopropoxy-2-methylphenyl)-1-piperidinecarboxylic acid tert-butyl ester (3.11 g, 8.9 mmol), and triethylamine (0.3 g, 3 mmol) were added to a 100 ml flask in sequence, heated to reflux, stirred and reacted for 16 to 20 hours, and the reaction end point was detected by TLC (developing solvent: ethyl acetate: n-hexane = 1:9). After the reaction was completed, it was slowly cooled to 0°C for crystallization for 2 hours, and the solid was precipitated, filtered, and rinsed with a little ethanol to obtain a crude product. The crude product was recrystallized by adding 50 ml of ethanol to obtain 3.2 g of the intermediate, with a yield of 48.6%.
[0016] (2) Synthesis of Ceritinib 3.2 g (5 mmol) of the intermediate was added to a 250 ml three-necked flask, dissolved in 20 ml of dichloromethane, cooled to 0-5 ° C, 15 ml of trifluoroacetic acid was added dropwise, and the reaction was kept warm for about 1 hour. The reaction end point was detected by TLC (developing solvent: dichloromethane: methanol = 20:1), the pH value was adjusted to 9-10 with 50% sodium hydroxide solution, and 50 ml of ethyl acetate was added for extraction, washed with water, dried over anhydrous magnesium sulfate, filtered, and distilled under reduced pressure to obtain 2.1 g of Ceritinib, with a yield of 77.8%.
[0017] (3) Synthesis of Nitrosoceritinib Dissolve 2.1g (3.8mmol) of Ceritinib in 120ml of dichloromethane, cool with ice water to 0-5℃, add 0.79g (11.4mmol) of sodium nitrite, add concentrated hydrochloric acid dropwise to adjust the pH value to 1-2, keep warm for reaction, detect the reaction end point by TLC (developing solvent: dichloromethane: methanol = 20:1), add 180ml of ice water and stir, let stand, separate the organic layer, extract the aqueous layer with dichloromethane (100ml×2), combine the organic layers, wash with water, dry over anhydrous magnesium sulfate, filter, and dry under reduced pressure to obtain the target compound. The purity is shown in the attached Figure 1 .
Claims
1. A method for preparing nitroso-ceritinib containing genotoxic impurity of ceritinib, characterized in that: The following steps are involved: (1) Using 2,5-dichloro-N-[2-(isopropylsulfonyl)phenyl]pyrimidin-4-amine (starting material 1) and tert-butyl 4-(4-amino-5-isopropoxy-2-methylphenyl)-1-piperidinecarboxylate (starting material 2) as starting materials, heating under reflux at an appropriate feed ratio (molar ratio), reaction solvent and catalyst until the reaction is complete, cooling and crystallizing to obtain an intermediate: tert-butyl 4-[4-[[5-chloro-4-[[2(isopropylsulfonyl)phenyl]amino]pyrimidin-2-yl]amino]-5-isopropoxy-2-methylphenyl]-1-piperidinecarboxylate; (2) treating the intermediate with an appropriate strong acid to remove the protecting group to obtain ceritinib; (3) Finally, ceritinib is reacted with sodium nitrite in a suitable organic solvent under low temperature and acidic conditions to obtain nitroso-ceritinib.
2. The process is as follows:
3. The method for preparing nitroso-ceritinib according to claim 1, characterized in that: The appropriate feed ratio (molar ratio) in step (1) is: starting material 1: starting material 2 = 1:1 to 1:1.
5.
4. The method for preparing nitroso-ceritinib according to claim 1, characterized in that: The suitable solvent described in step (1) is: methanol, ethanol or isopropanol; the amount of the solvent is: organic solvent: starting material (1+2) = 4-6 times (volume / mass).
5. The method for preparing nitroso-ceritinib according to claim 1, characterized in that: The catalyst described in step (1) is triethylamine or di(isopropyl)amine; the amount of the catalyst used is catalyst: starting material 1 = 0.1:1~0.5:1 (molar ratio).
6. The method for preparing nitroso-ceritinib according to claim 1, characterized in that: The cooling crystallization temperature in step (1) is 0-5°C, and the crystallization time is 0.5-2 hours.
7. The method for preparing nitroso-ceritinib according to claim 1, characterized in that: The appropriate strong acid described in step (2) is trifluoroacetic acid; the dosage is: trifluoroacetic acid: intermediate = 5:1 (V / M).
8. The method for preparing nitroso-ceritinib according to claim 1, characterized in that: The suitable organic solvent described in step (3) is: dichloromethane, chloroform or 1,2-dichloroethane; the amount of solvent used is: organic solvent: starting material (1+2) = 5-10 times (volume / mass).
9. The method for preparing nitroso-ceritinib according to claim 1, characterized in that: The acidic condition described in step (3) is: concentrated hydrochloric acid; the pH value is adjusted to: 1~2.
10. The method for preparing nitroso-ceritinib according to claim 1, characterized in that: The low temperature described in step (3) is: 0~10℃.