Chinese Journal of Magnetic Resonance >
Discovery and Structural Characterization of Impurities in the Synthesis of Darolutamide Intermediate
Received date: 2023-08-25
Online published: 2023-10-18
Darolutamide is an important drug for the treatment of prostate cancer. When studying its synthesis process, three impurities A, B, and C were discovered and purified in the first step of Suzuki coupling and the second step of hydrolysis deprotection reactions. Impurities A and B came from the first-step reaction, and impurity C came from the second-step reaction. The structures of impurities A and B were further determined through high-resolution mass spectrometry (HRMS), 1H nuclear magnetic resonance (NMR), and 13C NMR methods. It was discovered that impurities A and B were the deborated pinacol ester product of compound 2 and the double coupling product of compound 1, respectively. The accurate structures of compound 3 and impurity C were determined using HRMS, 1H NMR, 13C NMR, 1H-1H COSY (correlation spectroscopy), 1H-13C HSQC (heteronuclear singular quantum correlation), 1H-13C HMBC (heteronuclear multiple bond correlation) and 1H-1H NOESY (nuclear overhauser effect spectroscopy). The formation mechanisms and avoidance methods of these impurities were also discussed.
Key words： darolutamide intermediate; NMR; drug impurities
Huifang MA , Yue TONG , Rongfan WANG , Jianwei XIE . Discovery and Structural Characterization of Impurities in the Synthesis of Darolutamide Intermediate[J]. Chinese Journal of Magnetic Resonance, 2024 , 41(1) : 56 -66 . DOI: 10.11938/cjmr20233078
| [1] | FERLAY J, COLOMBET M, SOERJOMATARAM I, et al. Estimating the global cancer incidence and mortality in 2018: GLOBOCAN sources and methods[J]. Int J Cancer, 2019, 144(8): 1941-53. |
| [2] | DAS R, GREGORY P A, FERNANDES R C, et al. MicroRNA-194 promotes prostate cancer metastasis by inhibiting SOCS2[J]. Cancer Res, 2017, 77(4): 1021 -1034. |
| [3] | FIZAZI K, SMITH M R, TOMBAL B. Clinical development of darolutamide: a novel androgen receptor antagonist for the treatment of prostate cancer[J]. Clin Genitourin Cancer, 2018, 16(5): 332-40. |
| [4] | MOILANEN A-M, RIIKONEN R, OKSALA R, et al. Discovery of ODM-201, a new-generation androgen receptor inhibitor targeting resistance mechanisms to androgen signaling-directed prostate cancer therapies[J]. Sci Rep, 2015, 5: 12007. |
| [5] | CHEN B C. New drug for the treatment of prostate cancer-darolutamide[J]. Herb Med, 2020, 39(3): 422-427. |
| [5] | 陈本川. 治疗前列腺癌新药—达洛鲁胺(darolutamide)[J]. 医药导报, 2020, 39(3): 422-427. |
| [6] | FAN Z Z, SU L L, HU W, et al. Graphical synthetic routes to darolutamide[J]. Chin J Med Chem, 2022, 32(8): 652-656. |
| [6] | 范昭泽, 苏立林, 胡伟, 等. 达罗他胺合成路线图解[J]. 中国药物化学杂志, 2022, 32(8): 652-656. |
| [7] | GERD W, OLLI T, HARRI S, et al. Androgen receptor modulating compounds: WO2011051540A1[P]. 2010-10-27. |
| [8] | OLLI T, GERD W, HARRI S, et al. Androgen receptor modulating carboxamides: WO2012143599A1[P]. 2012-10-26. |
| [9] | YU J, ZHOU P, HU M, et al. Discovery and biological evaluation of darolutamide derivatives as inhibitors and down-regulators of wild-type AR and the mutants[J]. Eur J Med Chem, 2019, 182: 111608. |
| [10] | HORST F. Basic one-and two-dimensional NMR spectroscopy (5th Ed.)[M]. New York, 2010. |
| [11] | ZHAI C G, WANG P C, SHAN Y B, et al. Structure characterization and analgesic activity of novel pyrazolo[3,4-d]pyrimidin-4-one Derivatives[J]. Chinese J Magn Reson, 2023, 40(1): 1-9. |
| [11] | 翟重钢, 汪鹏程, 单玉宝, 等. 新型吡唑并[3,4-d]嘧啶-4-酮类衍生物的结构表征和镇痛活性[J]. 波谱学杂志, 2023, 40(1): 1-9. |
| [12] | WANG Z H, HU X, WANG T, et al. NMR spectroscopic studies on C-2 monosubstituted norbornene derivatives[J]. Chinese J Magn Reson, 2021, 38(3): 323-335. |
| [12] | 王子豪, 徐赫, 汪涛, 等. 外型和内型C-2位单取代降冰片烯衍生物的核磁共振波谱研究[J]. 波谱学杂志, 2021, 38(3): 323-335. |
/
| 〈 |
|
〉 |