Background and overview[1]
2-Piperazinemethanol dihydrochloride is a pharmaceutical intermediate that can be used to prepare PARP inhibitors. The ribozyme poly(ADP-ribose)polymerase-1 (PARP-1) is a member of the PARP enzyme family. This growing family of enzymes consists of PARP (eg, PARP-1, PARP-2, PARP-3, and Vault-PARP). PARP plays a role in the repair of DNA strand breaks, so its inhibition is an established method of cancer treatment. PARP inhibition can be particularly beneficial when combined with DNA damaging treatments, such as with ionizing radiation or following treatment with DNA damaging agents such as methylating agents, topoisomerase I inhibitors and other chemotherapeutic agents such as cisplatin and bleomycin. Effective.
Apply[1]
2-Piperazinemethanol dihydrochloride can be used to prepare 6-[3-(hydroxymethyl)-4-[3-(4-oxo-3H-quinazoline-2-) with the following structure yl)propionyl]piperazin-1-yl]pyridine-3-carbonitrile, this compound is a PARP inhibitor.
The method is as follows:
To a stirred solution of 2-piperazinemethanol dihydrochloride (100 mg, 0.53 mmol) in DMSO (3 mL) at room temperature, 6-chloropyridine-3-carbonitrile (88 mg, 0.63 mmol), K2CO3 (146mg, 1.062mmol) and Cu(MeCN)4P antioxidant F6 (3.9mg, 0.01mmol). The reaction mixture was heated at 140 °C for 12 h (TLC indicated complete consumption of starting material), quenched with water (10 mL) and extracted with EtOAc (3x 10 mL). The combined organic extracts were dried over Na2SO4, concentrated under reduced pressure to give a crude residue, which was purified by column chromatography (100-200 silica gel, 5g, 5% MeOH-DCM) to provide 6-[ as a white solid 3-(hydroxymethyl)piperazin-1-yl]pyridine-3-carbonitrile hydrochloride (50 mg, 32%). LCMS:m/z:219[M+H]+.
To 6-[3-(hydroxymethyl)piperazin-1-yl]pyridine-3-carbonitrile hydrochloride (120 mg, 0.55 mmol) and 3-(4-oxo-3H- To a stirred solution of quinazolin-2-yl)propionic acid (120 mg, 0.55 mmol) in dry DMF (2 mL) was added EDC·HCl (157 mg, 0.825 mmol), HOBt (113 mg, 0.825 mmol) and DIPEA (0.2 mL , 1.1 mmol) and stirred for 16 h (TLC indicated that the starting material was completely consumed). The reaction mixture was quenched with cold water (20 mL) and extracted with EtOAc (3x 10 mL). The combined organic extracts were dried over Na2SO4, concentrated under reduced pressure to give a residue, which was purified by preparative HPLC to give 6-[3-(hydroxymethyl)-4-[3-( 4-Oxo-3H-quinazolin-2-yl)propionyl]piperazin-1-yl]pyridine-3-carbonitrile (26 mg, 11%).
References
[1] [Invented in China] CN201780082024.8 Poly-ADP ribose polymerase (PARP) inhibitor
