3-BROMO-5-CHLOROPYRAZOLO[1,5-A]PYRIMIDINE

Description

3-Bromo-5-chloropyrazolo[1,5-a]pyrimidine is a versatile heterocyclic structural unit used in pharmaceuticals and agrochemicals. It is a key intermediate in the synthesis of kinase inhibitors, antiviral agents, and crop protection active substances. Its bromine and chlorine substituents can be further selectively functionalized.

Uses

3-Bromo-5-chloropyrazolo[1,5-A]pyrimidine shows much similarity to 4H-Pyrazolo[1,5-a]pyrimidin-7-one which is a moiety present in a variety of chemical anti-inflammatory and antischistosomal drugs.

Synthesis

The general procedure for the synthesis of 3-bromo-5-chloropyrazolo[1,5-A]pyrimidines from 5-chloropyrazolo[1,5-a]pyrimidines is as follows: intermediate Example A Preparation of 3-bromo-5-chloro-pyrazolo[1,5-a]pyrimidine [Intermediate A]. To a stirred mixture of 5-chloro-pyrazolo[1,5-a]pyrimidine solution (46.4 g, 0.3 mol) in glacial acetic acid (700 mL), bromine (42 mL, 0.81 mol) was added dropwise at room temperature. After the dropwise addition was completed, the reaction mixture was continued to be stirred for 1 hour. The precipitate was collected by filtration, washed sequentially with glacial acetic acid and ether, and then dried. The filtrate was retained. The residue was suspended in water (500 mL) and the mixture was neutralized to neutral with concentrated ammonia. The crude product was filtered, washed sequentially with water, isopropanol and hexane and dried to give 3-bromo-5-chloro-pyrazolo[1,5-a]pyrimidine [Intermediate A] (34.6 g, 49% yield). The retained filtrate was diluted with ice water and neutralized with concentrated ammonia, and the resulting crude product was filtered, washed sequentially with isopropanol and hexane, and dried to give additional 3-bromo-5-chloro-pyrazolo[1,5-a]pyrimidine [Intermediate A] (23.6 g, 33% yield). The product was characterized by 1H-NMR (400 MHz, d6-DMSO): δ= 9.18 (2H, d), 8.41 (1H, s), 7.19 (2H, d) ppm.

References

[1] Patent: WO2007/147647, 2007, A1. Location in patent: Page/Page column 60
[2] Patent: WO2011/29027, 2011, A1. Location in patent: Page/Page column 43
[3] Patent: WO2013/134228, 2013, A1. Location in patent: Page/Page column 25
[4] Patent: WO2015/142714, 2015, A1. Location in patent: Page/Page column 12
[5] Patent: EP2960234, 2015, A1. Location in patent: Paragraph 0554