ChemicalBook CAS DataBase List Niraparib

Niraparib synthesis

8synthesis methods

Product Name:Niraparib
CAS Number:1038915-60-4
Molecular formula:C19H20N4O
Molecular Weight:320.39

Niraparib, also known as MK4827, is an orally active, potent and selective poly(ADP-Ribose) polymerase (PARP) inhibitor that radiosensitizes human lung and breast cancer cells. Niraparib inhibits PARP1/PARP2 with IC50 of 3.8 nM/2.1 nM respectively. Niraparib is currently in Phase 3 clinical trials for ovarian cancer and BRCA+ breast cancer. Synthetic Description Reference: Jones, Philip; Ontoria Ontoria, Jesus Maria; Scarpelli, Rita; Schultz-Fademrecht, Carsten. Preparation of piperidinylphenylindazolylcarboxamide for use as poly(ADP-ribose)polymerase inhibitors. WO 2008084261. (Assignee Istituto Di Ricerche Di Biologia Molecolare P. Angeletti SpA, Italy) Synthetic Description Reference: Foley, Jennifer R.; Wilson, Robert Darrin. Preparation of pharmaceutically acceptable salts of (3S)-3-[4-[7-(aminocarbonyl)-2H-indazol-2-yl]phenyl]piperidines as inhibitors of poly(ADP-ribose)polymerase (PARP). WO 2009087381. (Assignee Merck Sharp & Dohme Ltd., UK; Merck & Co., Inc.) Synthetic Description Reference: Liang, Chengyuan; Jia, Minyi; Tian, Danni; Sun, Han; Ding, Shunjun; Tian, Lei. Method for synthesizing PARP inhibitor Niraparib. CN 106496187. (Assignee Shaanxi University of Science & Technology, Peop. Rep. China) Synthetic Description Reference: Liang, Chengyuan; Jia, Minyi; Tian, Danni. Process for the preparation of Niraparib. CN 106467513. (Assignee Shaanxi University of Science & Technology, Peop. Rep. China) Synthetic Description Reference: Wu, Xueping; Chen, Yao. Method for synthesizing niraparib. CN 108084157. (Assignee Anqing CHICO Pharmaceutical Co., Ltd., Peop. Rep. China) Synthetic Description Reference: Tang, Yonghong; Liang, Chengyuan; Chang, Minghui; Qi, Huafeng; Qian, Bo. Synthetic method of oral anticancer drug Niraparib. CN 106831708. (Assignee Xi'an Taikomed Pharmaceutical Technology Co., Ltd., Peop. Rep. China) Synthetic Description Reference: Wang, Xuegen; He, Lingyun; Yu, Yang; Wei, Chao. A method for preparing niraparib. CN 106749181. (Assignee Nanjing Aide Kaiteng Biomedical Co., Ltd., Peop. Rep. China) Synthetic Description Reference: Liang, Chengyuan; Jia, Minyi; Tian, Danni; Sun, Han. Synthetic method of anticancer drug niraparib. CN 106632244. (Assignee Shaanxi University of Science & Technology, Peop. Rep. China) Synthetic Description Reference: Chen, Linghao. Process for the preparation of anticancer drug 2-[4-((3S)-3-piperidyl)phenyl]-2H-indazol-7-methanamide. CN 106432188. (Assignee Qingdao Chenda Biotechnology Co., Ltd., Peop. Rep. China) Synthetic Description Reference: Wang, Chuanxiu. Chiral separation method of 2-[4-(-3-piperidyl)phenyl]-2H-indazol-7-methanamide. CN 106432187. (Assignee Qingdao Yuntian Biotechnology Co., Ltd., Peop. Rep. China)

Synthetic Routes

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Reference: Jones, Philip; Ontoria Ontoria, Jesus Maria; Scarpelli, Rita; Schultz-Fademrecht, Carsten. Preparation of piperidinylphenylindazolylcarboxamide for use as poly(ADP-ribose)polymerase inhibitors. WO 2008084261. (Assignee Istituto Di Ricerche Di Biologia Molecolare P. Angeletti SpA, Italy)

1038915-73-9 Synthesis

1038915-73-9
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1038915-60-4
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Yield:1038915-60-4 75.9%

Reaction Conditions:

with sodium hydroxide in 2-methyltetrahydrofuran at 20; for 0.5 h;

Steps:

1 Preparation of niraparib freebase (Form I)
To a mixture of 50.0 g (97.9 mmol) Niraparib tosylate monohydrate in 2-MeTHF (1L) was added 1% NaOH solution (500 mL) at room temperature. After the mixture was stirred for 30 minutes, the aqueous layer was separated and extracted with 2-MeTHF (0.5L, twice). The combined organic layer was washed with water (1L). The solution was concentrated under partial vacuum slowly below 30 °C until about 20 ml of suspension was left. The mixture was stirred for 30 minutes at room temperature and the solids were collected by filtration, to give 23.8 g (75.9%) of off-white crystalline solids (m.p. 189 °C). [M+H]⁺ at m/z 321, with the expected isotope pattern. Purity was found to be approximately 99.9% by HPLC. (0424) [000244] NMR (500.12 MHz, DMSO-de) d 9.27 (s, 1H), 8.59 (dd, 1H, J=l.8, 4.7 Hz), 8.07 (dd, 1H, J= 1.1, 7.0 Hz), 8.04 (d, 2H, J=8.7 Hz), 8.02 (dd, 1H, J=l.l, 8.1 Hz), 7.90 (br. s, 1H), 7.46 (d, 2H, J=8.5 Hz), 7.27 (dd, 1H, J=7.2, 8.3 Hz), 3.00 (br. d, 1H, J=l2.l Hz), 2.94 (br. d, 1H, J=l2.l Hz), 2.70 (m, 1H), 2.51 (m, 2H), 1.91, (d, 1H, J=l3.0 Hz), 1.68 (m, 1H), 1.61 (m, 1H), 1.49 (m, 1H). (0425) [000245] ¹³C NMR (125.77 MHz, DMSO-de) d 166.1, 146.5, 146.4, 138.0, 130.1, 128.7 (2C), 125.8, 123.9, 123.8, 122.3, 121.9, 121.1 (2C), 54.0, 46.4, 43.6, 32.3 and 27.0

References:

TESARO, INC.;STEWART, Alistair, James;WANG, Yi;WU, George;YIN, Jianguo WO2020/72796, 2020, A1 Location in patent:Paragraph 000242-000245

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