Sulfone Displacement Approach for Large-Scale Synthesis of 4‑Chloro‑N‑(1-methyl‑1H‑pyrazol-4-yl)pyrimidin-2-amine

Route evaluation, process development, and large-scale manufacturing of 4-chloro-N-(1-methyl-1H-pyrazol-4-yl)­pyrimidin-2-amine (1) are described. The improved route consists of two linear chemical steps: oxidation of 4-chloro-2-(methylthio)­pyrimidine (11) to 4-chloro-2-(methylsulfonyl)­pyrimidine...

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Published inOrganic process research & development Vol. 26; no. 1; pp. 137 - 143
Main Authors Li, Chaomin, Haeffner, Fredrik, Wang, Shujun, Yuan, Cuicui, Shang, Deju, Shi, Xianglin, Ma, Bin, Hopkins, Brian T, O’Brien, Erin M
Format Journal Article
LanguageEnglish
Published WASHINGTON American Chemical Society 21.01.2022
Amer Chemical Soc
Subjects
Chemistry
Chemistry, Applied
Chemistry, Organic
Physical Sciences
Science & Technology
DFT calculation
chloropyrimidine
aminopyrazole
SNAr reaction
sulfone displacement
formamide
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Summary:Route evaluation, process development, and large-scale manufacturing of 4-chloro-N-(1-methyl-1H-pyrazol-4-yl)­pyrimidin-2-amine (1) are described. The improved route consists of two linear chemical steps: oxidation of 4-chloro-2-(methylthio)­pyrimidine (11) to 4-chloro-2-(methylsulfonyl)­pyrimidine (7) and displacement of the sulfonyl with N-(1-methyl-1H-pyrazol-4-yl)­formamide (10) under basic conditions followed by in situ hydrolysis of the N-formyl intermediate to deliver compound 1. N-(1-Methyl-1H-pyrazol-4-yl)­formamide (10) was readily prepared from 1-methyl-1H-pyrazol-4-amine (4) via reaction with formic acid. The route allows for large-scale production of 4-chloro-N-(1-methyl-1H-pyrazol-4-yl)­pyrimidin-2-amine (1). Density functional theory (DFT) calculations were carried out to better understand the observed reactivity and selectivity.
ISSN:1083-6160
1520-586X
DOI:10.1021/acs.oprd.1c00314