Sulfone Displacement Approach for Large-Scale Synthesis of 4-Chloro-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine,Organic Process Research & Development

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Sulfone Displacement Approach for Large-Scale Synthesis of 4-Chloro-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine
Organic Process Research & Development ( IF 3.1 ) Pub Date : 2021-12-30 , DOI: 10.1021/acs.oprd.1c00314
Chaomin Li ₁ , Fredrik Haeffner ₂ , Shujun Wang ₃ , Cuicui Yuan ₄ , Deju Shang ₄ , Xianglin Shi ₂ , Bin Ma ₅ , Brian T. Hopkins ₅ , Erin M. O’Brien ₁

Affiliation

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.

中文翻译：

大规模合成 4-氯-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine 的砜置换方法

描述了 4-氯-N- (1-甲基-1 H-吡唑-4-基)嘧啶-2-胺 ( 1 ) 的路线评估、工艺开发和大规模生产。改进的路线包括两个线性化学步骤：将 4-氯-2-(甲硫基)嘧啶 ( 11 ) 氧化为 4-氯-2-(甲基磺酰基)嘧啶 ( 7 ) 和用N- (1- ) 置换磺酰基在碱性条件下甲基-1 H-吡唑-4-基)甲酰胺( 10 )随后原位水解N-甲酰基中间体以提供化合物1。N- (1-甲基-1 H-吡唑-4-基)甲酰胺 (10 )很容易由1-甲基-1H-吡唑-4-胺( 4 )通过与甲酸反应制备。该路线允许大规模生产4-氯-N- (1-甲基-1 H-吡唑-4-基)嘧啶-2-胺( 1 )。进行密度泛函理论 (DFT) 计算以更好地了解观察到的反应性和选择性。

更新日期：2022-01-21

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