Preparation method and control of abelsilil impurity A
By designing a reasonable synthesis route and adding recrystallization purification operations, the difficulties in the preparation and control of Abecili impurity A in the prior art were solved, and the controllability of high-purity impurity A preparation and drug quality were achieved.
Patent Information
- Application Number
- CN202411989406.7
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-12-31
- Publication Date
- 2025-05-02
- Estimated Expiration
- Not applicable · inactive patent
AI Technical Summary
There is a lack of effective methods in the prior art to prepare and control Abecili impurity A, affecting the purity and safety of the drug.
A method for preparing abecili impurity A is provided. Through a reasonably designed synthesis route and good selective reaction sites, the preparation of impurity A is achieved, and the impurity A is effectively removed by adding recrystallization purification operations during the intermediate 02 post-treatment process.
The high purity preparation of Abecili impurity A was achieved, with the purity of the target product reaching more than 95%, which improved the effectiveness and safety of the drug, reduced production costs, and simplified the subsequent treatment process.
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Figure CN119912431A_ABST
Abstract
Description
Technical Field
[0001] The present invention relates to the technical field of chemical synthesis, and in particular to a preparation method of abemaciclib impurity A and control thereof. Background Art
[0002] Abemaciclib, with the English name Abemaciclib, CAS number [1231929-97-7], chemical name N-[5-[(4-ethyl-1-piperazine)methyl]-2-pyridinyl]-5-fluoro-4-[4-fluoro-2-methyl-1-isopropyl-1H-benzimidazol-6-yl]-2-pyrimidinamine, has a structural formula as shown in Formula I: .
[0003] Abemaciclib is an oral cyclin-dependent kinase CDK4 / 6 inhibitor developed by Eli Lilly and Company. Its main indication is hormone receptor-positive (HR+) and HER2-negative (HER2-) breast cancer.
[0004] With the progress of the times and the improvement of scientific and technological levels, people have a more comprehensive understanding of the importance of scientific evaluation of the quality, safety and efficacy of drugs before they are put on the market. Among them, the control of impurities contained in drugs is closely related to the quality of drugs. Therefore, in the research, production, storage and clinical application of drugs, the purity of drugs must be maintained and the impurities of drugs must be reduced, so as to ensure the effectiveness and safety of drugs. The impurity inspection of drugs is a very important link in controlling the purity of drugs and improving the quality of drugs. However, there is no report on the research on the preparation method of impurity A of abemaciclib. Summary of the invention
[0005] Purpose of the invention: In view of the problems existing in the prior art, the present invention provides a method for preparing impurity A of abemaciclib and its control. The present invention has a reasonable design route, good reaction site selectivity, and can obtain impurity A with higher purity.
[0006] Technical solution: The present invention provides a method for preparing abemaciclib impurity A, and the synthesis route is as follows: .
[0007] Furthermore, the specific steps are as follows: S1. Compound I and a nucleophilic reagent undergo aromatic ring nucleophilic substitution reaction in an organic reagent, and the organic phase is washed, dried, filtered, and concentrated under reduced pressure to obtain compound II: ; S2. Compound II, compound III, palladium catalyst, base and organic solvent are mixed and heated to reflux under nitrogen protection to cause Suzuki coupling reaction. The organic phase is concentrated under reduced pressure to remove most of the solvent, and the filter cake is washed with tetrahydrofuran to obtain compound IV: ; S3. Compound IV is subjected to a demethylation reaction to obtain compound V: ; S4. Compound V reacts with a chlorinating agent, and unreacted chlorinating agent is removed by distillation under reduced pressure, and separated and purified to obtain abemaciclib impurity A: .
[0008] Furthermore, in S1, the nucleophilic reagent is a compound with an -OR group such as sodium methoxide, sodium ethoxide, or a mixed reagent of an alcohol solvent R-OH and a base; the molar ratio of the compound I to the nucleophilic reagent is 1:3; the specific conditions of the aromatic ring nucleophilic substitution reaction are: the reaction temperature is 50°C and the reaction time is 3 hours.
[0009] Further, in S2, the palladium catalyst is bistriphenylphosphine palladium dichloride, tetrakis(triphenylphosphine)palladium, palladium acetate, palladium chloride or [1,3-bis(2,6-diisopropylphenyl)imidazolylidene](3-chloropyridyl)palladium dichloride; In S2, the base is potassium carbonate, sodium carbonate, cesium carbonate or potassium phosphate; In S2, the organic solvent is tetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether, dimethyl sulfoxide, N,N-dimethylformamide or 2-methyltetrahydrofuran.
[0010] Furthermore, in S2, the molar ratios of compound II, compound III, palladium catalyst, base and organic solvent are 1:1:0.02:3:20 respectively.
[0011] Furthermore, in S3, the demethylation reagent used in the demethylation reaction is trimethylchlorosilane, pyridine hydrochloride, boron tribromide, hydroiodic acid or hydrobromic acid in acetic acid.
[0012] Furthermore, in S4, the chlorination agent is phosphorus oxychloride, phosphorus pentachloride or oxalyl chloride.
[0013] Preferably, in S4, a chlorination reagent is directly used as a solvent (10v); the specific conditions of the reaction are: a reaction temperature of 100°C and a reaction time of 6 hours.
[0014] The present invention also provides a method for controlling impurity A of Abemaciclib: in the process of preparing Abemaciclib, a recrystallization purification operation is added in the post-treatment process of intermediate 02, which can effectively remove impurity A of Abemaciclib and avoid continued derivatization in each step during the subsequent reaction process; wherein, the specific steps of the recrystallization purification operation are as follows: Take the crude intermediate 02, add tetrahydrofuran, heat up with stirring, add methanol dropwise and keep warm, then slowly cool to room temperature, filter, and rinse with methanol.
[0015] Furthermore, liquid chromatography is used to detect the purity of the intermediate 02 after recrystallization purification operation using the abemaciclib impurity A prepared by any of the above methods.
[0016] Beneficial effects: Compared with the prior art, the present invention has the following specific beneficial effects: The design route of the present invention is reasonable, impurity A can be obtained and the purity of impurity A is high, and the purity of the target product is as high as more than 95%. In the process of preparing abemaciclib, due to the competition of its reactive active sites, a certain amount of impurity A is generated, which can be further derived into the key impurity I of abemaciclib API. The derived API impurity I needs to be recrystallized many times during the post-treatment process, and it is difficult to remove it, and the yield is greatly reduced. In order to ensure the controllable quality and drug safety of API and control the production cost, when preparing the intermediate, the content of the intermediate impurity A should be strictly controlled. Therefore, the preparation of the intermediate impurity A provides a basis for studying its physicochemical properties and removal methods, and provides convenience for the impurity analysis and research of abemaciclib raw materials and preparations thereof, further improving the production and drug safety of abemaciclib, suitable for the needs of our lives, meeting market demand, improving the activity of the drug, and reducing toxic side effects. BRIEF DESCRIPTION OF THE DRAWINGS
[0017] Figure 1 The mass spectrum of the impurity A of the intermediate of Abemaciclib obtained in the present invention; Figure 2 is a hydrogen nuclear magnetic resonance spectrum of the impurity A of the abemaciclib intermediate obtained in the present invention; Figure 3 This is a purity detection diagram of the impurity A of the abemaciclib intermediate obtained in the present invention; Figure 4 This is the HPLC detection spectrum of the refined intermediate 02; Figure 5 This is the HPLC detection spectrum of the crude product of Abemaciclib prepared by the original process. DETAILED DESCRIPTION
[0018] The present invention is described in detail below in conjunction with the embodiments.
[0019] Implementation 1: This embodiment provides a method for preparing abemaciclib impurity A: 6-(4-chloro-5-fluoropyrimidin-2-yl)-4-fluoro-1-isopropyl-2-methyl-1H-benzimidazole, and the synthesis route is as follows: .
[0020] The specific steps are as follows: Step 1:
[0021] Take 5 g of the above compound Ⅰ (2,4-dichloro-5-fluoropyrimidine) and add it to 50 ml of methanol. Add 4.88 g of sodium methoxide and stir at 50 ° C for 3 hours. After the reaction is completed by TLC monitoring, add 20 ml of water and 100 ml of ethyl acetate to the reaction solution, stir for 10 min, and separate the liquids; the organic phase is then washed with 20 ml of water and 20 ml of sodium chloride aqueous solution in turn, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 4.89 g of white solid compound Ⅱ, which is directly used for the next step reaction.
[0022] Step 2:
[0023] Take 2.5g of the above compound II, 4.8g of compound III, 0.3g of PdCl2(PPh3)2, 6.4g of potassium carbonate, 50ml of tetrahydrofuran and 250ml of water and add them into a three-necked flask in sequence. Heat the reaction solution under reflux for 4h under nitrogen protection. After the reaction is completed by TLC monitoring, separate the liquids, and concentrate the organic phase under reduced pressure to a small amount of tetrahydrofuran remaining, and stop concentrating. Cool the reaction solution to 10-20℃, stir for 30min, and filter. Wash the filter cake with a small amount of tetrahydrofuran and dry it to obtain 4.1g of compound IV.
[0024] Step 3:
[0025] Add 1.0 g of the above compound IV, 10 ml of acetonitrile, and 1.42 g of sodium iodide to the reaction flask and stir. Add 1.0 g of TMSCl to the reaction solution, and after the addition, heat the reaction solution to 85°C and react for 4 hours. After the reaction is completed by TLC monitoring, add 30 ml of water, 30 ml of ethyl acetate and 10 ml of methyl tert-butyl ether to the reaction solution, filter, rinse the filter cake with 5 ml of water, and drain to obtain 0.73 g of compound V.
[0026] Step 4:
[0027] Add POCl3 20ml, compound V 2.0g to the reaction flask, heat the reaction solution to 100℃, and react for 5h. After the reaction is completed by TLC monitoring, remove phosphorus oxychloride by vacuum distillation. Add 30ml of dichloromethane to the system, stir to dissolve, add 30.0ml of water to the reaction solution, stir for 15min, and separate the liquids. Vacuum distill the organic phase until a small amount of dichloromethane remains, add 40ml of n-heptane to the reaction flask, continue to vacuum distill until a small amount of n-heptane remains, and stop distillation. Control the temperature at 20-30℃ and stir for 2h, filter, and dry to obtain 1.42g of compound A.
[0028] MS (m / z): 321.74 [M+H]+; 1HNMR (400MHz, DMSO-d6) δppm = 8.59 (t, J = 8Hz, 1H), 8.34 (s, 1H), 8.00 (dd, J = 4Hz, 1H), 4.71-4.78 (m, 1H), 2.69 (s, 3H), 1.71 (doublet, 6H). See for details Figure 1-2 .
[0029] Implementation 2: This embodiment is substantially the same as Embodiment 1, except that in Step 2 of this embodiment, the catalyst PdCl2(PPh3)2 is replaced by Pd(PPh3)4.
[0030] Apart from this, this embodiment is completely the same as Embodiment 1 and will not be described in detail here.
[0031] Implementation 3: This embodiment is substantially the same as Embodiment 1, except that the demethylation reagent TMSCl in step 3 of this embodiment is replaced by boron tribromide: The specific operation of step 3 is as follows: add 1.0g of the above-mentioned compound IV and 10ml of dichloromethane to the reaction bottle, stir and cool to -20°C. Add a dichloromethane solution (1mol / L) of BBr3 (2.5g) to the reaction solution, and after the addition, control the temperature of the reaction solution to below 0°C for 8h. After the reaction is completed by TLC monitoring, add 30ml of water to the reaction solution, add 30ml of dichloromethane to extract twice, wash the organic phase with 30ml of saturated brine, stand and separate, and concentrate the organic phase under reduced pressure to obtain compound V.
[0032] Apart from this, this embodiment is completely the same as Embodiment 1 and will not be described in detail here.
[0033] Implementation 4: This embodiment provides a method for controlling abemaciclib impurity A in the production process of abemaciclib, which is as follows: The original process for preparing crude abemaciclib is as follows:
[0034] Due to competition for active reaction sites, a certain amount of impurity A is generated in the preparation process, which can be further derived into the key impurity I of the abemaciclib API. The derived API impurity I needs to undergo multiple recrystallizations during post-processing, which makes it very difficult to remove and greatly reduces the yield.
[0035] Derivatization route of impurity I:
[0036] In this embodiment, when preparing the crude product of Abemaciclib in the original process, a recrystallization purification step is added during the post-treatment of the intermediate 02, which can effectively remove the impurity A and avoid the continued derivation into the impurity I in each step during the subsequent reaction process. The specific operation is as follows: Take 10 g of crude intermediate 02, add 10 ml of tetrahydrofuran, heat and stir for 0.5 hours, add 50 ml of methanol dropwise, keep warm for 1 hour after the addition is complete, slowly cool to room temperature, filter, and rinse with 10 ml of methanol to obtain the refined intermediate 02.
[0037] The refined intermediate 02 was tested by HPLC, and the spectrum is shown in Figure 4 The intermediate 02 can control the formation of abemaciclib impurity A through one-step recrystallization. The abemaciclib impurity A is not detected in the refined intermediate 02, the purity reaches more than 99%, and the yield is 95%.
[0038] The crude product of Abemaciclib was prepared according to the original process, and the crude product of Abemaciclib was tested by HPLC. The spectrum is shown in Figure 5 ; HPLC test results are shown in Table 1:
[0039] The crude product of Abemaciclib was recrystallized (DCM: MeOH = 3V: 20V). During the recrystallization process, the impurity content and the finished product recovery rate were tested. The specific results are shown in Table 2:
[0040] In this embodiment, by adding a recrystallization purification step to the intermediate 02, the generation of abemaciclib impurity A can be controlled, thereby avoiding subsequent multiple recrystallization work and avoiding the problem of decreased yield.
[0041] We added a process to remove impurity A in the intermediate 02 step and continued to make API from the intermediate 02 without removing impurity A. We compared the process conditions, quality and yield of the two batches of API. The results are shown in Table 3:
[0042] The above embodiments are only for illustrating the technical concept and features of the present invention, and their purpose is to enable people familiar with the technology to understand the content of the present invention and implement it accordingly, and they cannot be used to limit the protection scope of the present invention. Any equivalent transformation or modification made according to the spirit of the present invention should be included in the protection scope of the present invention.
Claims
1. A method for preparing abemaciclib impurity A, characterized in that: The synthetic route is as follows: 。 2. The method for preparing abemaciclib impurity A according to claim 1, characterized in that: The specific steps are as follows: S1. Compound I and a nucleophilic reagent undergo aromatic ring nucleophilic substitution reaction in an organic reagent, and the organic phase is washed, dried, filtered, and concentrated under reduced pressure to obtain compound II; S2. Compound II, compound III, a palladium catalyst, a base and an organic solvent are mixed and heated to reflux under nitrogen protection to cause a Suzuki coupling reaction. The organic phase is concentrated under reduced pressure to remove most of the solvent, and the filter cake is washed with tetrahydrofuran to obtain compound IV; S3. Compound Ⅳ is subjected to a demethylation reaction to obtain compound Ⅴ; S4. Compound V is reacted with a chlorinating agent, unreacted chlorinating agent is removed by distillation under reduced pressure, and then separated and purified to obtain abemaciclib impurity A.
3. The method for preparing abemaciclib impurity A according to claim 2, characterized in that: In S1, the nucleophilic reagent is a compound with an -OR group such as sodium methoxide, sodium ethoxide, or a mixed reagent of an alcohol solvent R-OH and a base; the molar ratio of the compound I to the nucleophilic reagent is 1:1-1:5; the specific conditions of the aromatic ring nucleophilic substitution reaction are: the reaction temperature is 30-70°C, and the reaction time is 2-5 hours.
4. The method for preparing abemaciclib impurity A according to claim 2, characterized in that: In S2, the palladium catalyst is bistriphenylphosphine palladium dichloride, tetrakis(triphenylphosphine)palladium, palladium acetate, palladium chloride or [1,3-bis(2,6-diisopropylphenyl)imidazolylidene](3-chloropyridyl)palladium dichloride; In S2, the base is potassium carbonate, sodium carbonate, cesium carbonate or potassium phosphate; In S2, the organic solvent is tetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether, dimethyl sulfoxide, N,N-dimethylformamide or 2-methyltetrahydrofuran.
5. The method for preparing abemaciclib impurity A according to claim 2, characterized in that: In S2, the molar ratio of compound II, compound III, palladium catalyst, base and organic solvent is 1:1:0.02:3:
20.
6. The method for preparing abemaciclib impurity A according to claim 2, characterized in that: In S3, the demethylation reagent used in the demethylation reaction is trimethylchlorosilane, pyridine hydrochloride, boron tribromide, hydroiodic acid or hydrobromic acid in acetic acid.
7. The method for preparing abemaciclib impurity A according to claim 2, characterized in that: In S4, the chlorination agent is phosphorus oxychloride, phosphorus pentachloride or oxalyl chloride.
8. The method for preparing abemaciclib impurity A according to claim 2, characterized in that: In S4, the specific conditions of the reaction are: reaction temperature is 80-110° C., and reaction time is 4-8 hours.
9. A method for controlling impurity A of abemaciclib, characterized in that: In the process of preparing abemaciclib, adding a recrystallization purification operation in the post-treatment process of intermediate 02 can effectively remove the impurity A of abemaciclib and avoid continued derivatization in each step during the subsequent reaction process; wherein, the specific steps of the recrystallization purification operation are as follows: Take the crude intermediate 02, add tetrahydrofuran, heat up with stirring, add methanol dropwise and keep warm, then slowly cool to room temperature, filter, and rinse with methanol.
10. The method for controlling abemaciclib impurity A according to claim 9, characterized in that: Liquid chromatography is used to detect the purity of the intermediate 02 after recrystallization purification using the abemaciclib impurity A prepared by the method of any one of claims 1 to 8.