5-Chloropyrazolo[1,5-a]pyrimidine

Description

5-Chloropyrazolo[1,5-a]pyrimidine is formed by replacing the hydrogen atom at position 5 of the pyrazolo[1,5-a]pyrimidine compound structure with a chlorine atom. It can serve as a pharmaceutical intermediate for synthesising other bioactive compounds. Pyrazolo[1,5-a]pyrimidine derivatives function as ATP-competitive and allosteric inhibitors of protein kinases, with those targeting the epidermal growth factor receptor (EGFR) demonstrating potential in the treatment of non-small cell lung cancer (NSCLC).

Uses

5-Chloropyrazolo[1,5-a]pyrimidine was used in the preparation of β-substituted biarylphenylalanine amides as selective amino amide dipeptidyl peptidase IV inhibitors for treatment of type 2 diabetes.

Synthesis

General procedure for the synthesis of 5-chloropyrazolo[1,5-a]pyrimidin-5-ol from pyrazolo[1,5-a]pyrimidin-5-ol: Pyrazolo[1,5-a]pyrimidin-5-ol (17.0 g, 126 mmol) was dissolved in phosphorus triclosan (100 mL) and heated to reflux for 3 hours. Upon completion of the reaction, the reaction was cooled to room temperature and the reaction mixture was concentrated under reduced pressure to remove excess phosphorous trichloride. Dichloromethane (100 mL) was added to the residue to dissolve it, followed by careful washing of the organic phase with saturated aqueous sodium bicarbonate solution (100 mL x 3) to neutralize acidic impurities. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by short silica gel column chromatography, using 50% ethyl acetate in hexane solution as eluent, the target fraction was collected and concentrated under reduced pressure to give 5-chloropyrazolo[1,5-a]pyrimidine (13.1 g, 68% yield).

References

[1] Patent: WO2011/29027, 2011, A1. Location in patent: Page/Page column 42
[2] Patent: US2016/168156, 2016, A1. Location in patent: Paragraph 0350; 0354; 0355
[3] Patent: WO2013/12915, 2013, A1. Location in patent: Paragraph 00681
[4] Patent: WO2014/151147, 2014, A1. Location in patent: Paragraph 00641
[5] Patent: US9295673, 2016, B2. Location in patent: Page/Page column 351