Vesonaka biphenyl impurity and preparation method thereof
The synthesis of Veneclabiphenyl impurities via Grignard exchange reaction at low temperatures solves the problems of complex synthesis and high cost in existing technologies, achieving high yields and reliable supply of standards, thus supporting drug development.
Patent Information
- Application Number
- CN202511959753.X
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-12-24
- Publication Date
- 2026-03-06
AI Technical Summary
The existing methods for synthesizing Veneclabiphenyl impurities are complex and costly, and cannot effectively provide reliable standards, thus affecting the drug development process.
Vineclabiphenyl impurities were synthesized under low-temperature, oxygen-free conditions using a Grignard exchange reaction. An intermediate state was formed by reacting compound (II) with isopropyl magnesium chloride, followed by reaction with compound (III). Solvents such as tetrahydrofuran were used, and the reaction temperature was controlled between -20 and 10 °C for 0.5 to 4 h to obtain compound (I).
The directed synthesis of Vineclabiphenyl impurities was achieved under mild reaction conditions, with simple operation, high yield, and reliable standards, thus reducing research and development costs.
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Figure CN121609631A_ABST
Abstract
Description
Technical Field
[0001] This invention belongs to the field of chemical drug analysis and drug synthesis technology, specifically relating to a veneclabiphenyl impurity and its preparation method. Background Technology
[0002] Venetoclax (CAS Registry No.: 1257044-40-8), chemically named 2-((1H-pyrrolo[2,3-B]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide), with the following structural formula: .
[0003] Venecella is a first-in-class synthetic peptide developed by AbbVie and belongs to the class of selective BCL-2 inhibitors (BCL-2 protein is an important regulatory component of apoptosis and is widely present and highly expressed in tumor cells). Venecella is currently the only approved apoptosis drug developed based on the mechanism of apoptosis that has been approved for marketing worldwide.
[0004] On December 2, 2020, Veneclav received approval from the China National Medical Products Administration (NMPA) for sale by AbbVie under the brand name Vico®. Global sales of Veneclav have steadily increased, reaching RMB 14 billion in 2022. In China, the price of a 0.1g tablet of Veneclav ranges from RMB 117.5 to 4860. Based on the RMB 14 billion in sales in 2022, the estimated global usage of Veneclav raw material in 2022 was approximately 300–11900 kg, with an estimated annual global demand exceeding 1000 kg.
[0005] Although there are numerous reports on Veneclare patents, information regarding related impurities is rarely mentioned. Impurity research is a crucial step in drug development, and establishing quality standards requires a certain amount of reference materials. Therefore, developing methods for synthesizing impurities is an important task in drug development.
[0006] Veneclabiphenyl impurity is a specific process impurity in Veneclabi intermediates. There are currently no literature reports on the synthesis method of this impurity. In the current research and development process, it can only be extracted from a very large amount of crude intermediate. However, the extraction process of this impurity is complex and extremely costly. Summary of the Invention
[0007] To address the problems in the prior art, the present invention aims to provide a veneclabiphenyl impurity and its preparation method, thereby obtaining the veneclabiphenyl impurity through directed synthesis, providing a reliable standard for drug development, and effectively reducing research and development costs.
[0008] To achieve the above objectives and technical effects, the technical solution adopted by this invention is as follows: A vernacle biphenyl impurity has the structure of formula (I): .
[0009] This invention also discloses a method for preparing veneclabiphenyl impurities, comprising the following steps: 1) The compound of formula (II) is added to a solvent and subjected to Grignard exchange with isopropyl magnesium chloride under low temperature and oxygen-free conditions to form an intermediate state; 2) The intermediate reacts with compound (III) to give compound (I): .
[0010] Furthermore, the solvent is one or a combination of several of tetrahydrofuran, 2-methyltetrahydrofuran, toluene, diethylene glycol dimethyl ether, and diethyl ether.
[0011] Furthermore, the molar ratio of the compound of formula (II), isopropyl magnesium chloride, and the compound of formula (III) is 1:1 to 2:2 to 4.
[0012] Furthermore, in step 1), the reaction temperature is -20 to 10°C, preferably -5 to 5°C, and the reaction time is 0.5 to 2 hours.
[0013] Furthermore, in step 2), the reaction temperature is -20 to 10°C, preferably -5 to 5°C, and the reaction time is 2 to 4 hours.
[0014] Compared with the prior art, the beneficial effects of the present invention are as follows: This invention proposes for the first time a Veneclabiphenyl impurity and its preparation method. The Veneclabiphenyl impurity is obtained through directed synthesis under mild reaction conditions, is easy to operate, and has a high yield. This not only enriches and improves the impurity spectrum of Veneclabiphenyl and provides reliable standards for drug development, but also has significant implications for the comprehensive control of Veneclabiphenyl quality and effectively reduces research and development costs. Attached Figure Description
[0015] Figure 1 This is a reaction route diagram of the present invention; Figure 2 The HPLC chromatogram of the white solid in Example 1 of the present invention; Figure 3The MS spectrum of the white solid in Example 1 of the present invention; Figure 4 The white solid of Example 1 of the present invention 13 CNMR spectrum; Figure 5 The white solid of Example 1 of the present invention 1 HNMR spectrum. Detailed Implementation
[0016] The present invention will now be described in detail so that its advantages and features can be more easily understood by those skilled in the art, thereby providing a clearer and more explicit definition of the scope of protection of the present invention.
[0017] The following provides a brief overview of one or more aspects to offer a basic understanding of them. This overview is not an exhaustive summary of all conceived aspects, nor is it intended to identify key or decisive elements of all aspects, nor to define the scope of any or all aspects. Its sole purpose is to present some concepts of one or more aspects in a simplified form to prepare for the more detailed descriptions that follow.
[0018] like Figure 1-5 As shown, this invention discloses a Veneclabiphenyl impurity having the structure of formula (I): .
[0019] This invention also discloses a method for preparing veneclabiphenyl impurities, comprising the following steps: 1) The compound of formula (II) is added to a solvent and subjected to Grignard exchange with isopropyl magnesium chloride under low temperature and oxygen-free conditions to form an intermediate state. The reaction temperature is -20 to 10°C, preferably -5 to 5°C, and the reaction time is 0.5 to 2 h. The solvent is one or a combination of tetrahydrofuran, 2-methyltetrahydrofuran, toluene, diethylene glycol dimethyl ether, and diethyl ether. 2) The intermediate reacts with the compound of formula (III) to obtain the compound of formula (I). The reaction temperature is -20 to 10°C, preferably -5 to 5°C, and the reaction time is 2 to 4 hours. .
[0020] The molar ratio of compound (II), isopropyl magnesium chloride, and compound (III) is 1:1 to 2:2 to 4.
[0021] Example 1 100 ml of tetrahydrofuran and compound (II) (10.0 g, 0.041 mmol, 1.0 eq) were added to a three-necked reaction flask. The mixture was stirred until dissolved, purged with nitrogen, and cooled to 5 °C. Isopropyl magnesium chloride solution (31.2 ml, 0.062 mmol, 1.5 eq) was slowly added dropwise, and the reaction was carried out at 5 °C for 30 min. Compound (III) (17.56 g, 0.082 mmol, 2.0 eq) was then slowly added dropwise, and the reaction was carried out at 5 °C for 2 h. After the reaction was complete, the mixture was cooled, and the reaction was quenched with a mixed solution of 20% citric acid and saturated sodium chloride. The mixture separated into layers, and the organic phase was collected and concentrated to obtain crude compound (I). The crude compound (I) was subjected to ethyl acetate:n-heptane column chromatography to obtain 2.99 g of compound (I) with a purity of 99.3% and a yield of 23.7%.
[0022] Final substance analysis: The HPLC chromatogram of the white solid is as follows: Figure 2 As shown, it can be seen that the compound of formula (I) has a high purity, exceeding 99%.
[0023] MS spectrum of white solid as follows Figure 3 As shown, the white solid 13 CNMR spectra as follows Figure 4 As shown, the white solid 1 HNMR spectra as follows Figure 5 As shown, the chemical structure of the impurity is correct, which is indirectly proven from the molecular weight, the number and distribution of carbon atoms, and the number and chemical shift of hydrogen atoms. The synthesized substance is the Veneclabiphenyl impurity.
[0024] Example 2 Add 200 ml of tetrahydrofuran and compound (II) (20.0 g, 0.082 mmol, 1.0 eq) to a three-necked reaction flask. Stir until dissolved, purge with nitrogen, and cool to -5°C. Slowly add isopropyl magnesium chloride solution (83.2 ml, 0.165 mmol, 2.0 eq) at -5°C and react for 1 h. Slowly add compound (III) (52.68 g, 0.246 mmol, 3.0 eq) at -5°C and stir for 3 h. After the reaction is complete, cool and quench the reaction with a mixed solution of 20% citric acid and saturated sodium chloride. Separate the layers, collect the organic phase, concentrate, and obtain crude compound (I). Crude compound (I) is then subjected to ethyl acetate:n-heptane column chromatography to obtain 6.21 g of compound (I) with a purity of 98.1% and a yield of 24.6%.
[0025] The rest is the same as in Example 1.
[0026] Any parts or structures not specifically described in this invention can be made using existing technologies or products, and will not be elaborated upon here.
[0027] The above description is merely an embodiment of the present invention and does not limit the patent scope of the present invention. Any equivalent structural or procedural transformations made based on the content of the present invention specification, or direct or indirect applications in other related technical fields, are similarly included within the patent protection scope of the present invention.
Claims
1. A venetoclax biphenyl impurity characterized by, A structure of formula (I): 。 2. A process for the preparation of a venetoclax biphenyl impurity, characterized in that, Comprising the following steps: 1) A compound of formula (II) is added to a solvent, and is subjected to Grignard exchange with isopropyl magnesium chloride under low-temperature and anaerobic conditions to form an intermediate state; 2) The intermediate state is reacted with a compound of formula (III) to obtain a compound of formula (I): 。 3. A process for the preparation of a venetoclax biphenyl impurity according to claim 2, characterized in that, The solvent is one or a combination of several of tetrahydrofuran, 2-methyltetrahydrofuran, toluene, diethylene glycol dimethyl ether, and diethyl ether.
4. The method for preparing a vernacle biphenyl impurity according to claim 2, characterized in that, The molar ratio of the compound of formula (II), isopropyl magnesium chloride, and the compound of formula (III) is 1:1-2:2-4.
5. The method of preparing a venetoclax biphenyl impurity according to claim 2, wherein, In step 1), the reaction temperature is -20-10°C, and the reaction time is 0.5-2h.
6. The method of preparing a venetoclax biphenyl impurity according to claim 2, wherein, In step 2), the reaction temperature is -20-10°C, and the reaction time is 2-4h.