开发一种通过原子转移的合成路线到Vonoprazan 通过激进循环的合成路线
Ken-Ichi Ojima1, Ryoya Imaizumi1, Tatsuya Komori1
1API Process Research I Department, API Business Unit, R&D Division, Towa Pharmaceutical Co., Ltd., Amagasaki Research Incubation Center 3F, 7-1-3, Doi-cho, Amagasaki, Hyogo 660-0083, Japan.
The Journal of organic chemistry
|February 26, 2025
概括
使用原子转移激素循环 (ATRC) 的新型合成路径有效地产生vonoprazan. 这种方法简化了关键醇环的合成,并允许在没有中间隔离的情况下进行大规模生产.
科学领域:
- 有机化学 有机化学
- 药用化学 医学化学
- 合成化学 合成化学
背景情况:
- 诺普拉桑是一种与具有竞争力的酸阻塞剂,用于治疗与酸有关的胃肠道疾病.
- 现有的合成路径到vonoprazan可能是复杂的,涉及多个步骤与中间隔离.
研究的目的:
- 开发一种新的,高效的合成路径,使诺普拉桑.
- 为了利用原子转移激素循环 (ATRC) 构建核心醇结构.
- 为了实现可扩展和精简的合成vonoprazan.
主要方法:
- 原子转移激进循环化 (ATRC) 用于醇环的形成.
- 同时的芳香化和N-甲基化循环 imine.
- 在pyrrole 1位置上的硫化.
- 没有中间隔离的单合成.
主要成果:
- 通过ATRC成功合成了诺普拉桑的关键的1,3,5-三位替代型醇环.
- 实现了同时的芳香化和引入N-甲基胺部分.
- 通过醇硫化完成了合成.
- 在一个一个的过程中证明了vonoprazan (0.7公斤) 的可扩展合成.
结论:
- 描述的基于ATRC的策略为诺普拉桑合成提供了一种高效和精简的方法.
- 这条新的路线避免了中间的隔离,为大规模生产提供了优势.
- 该方法适用于诺普拉桑的工业合成.
相关概念视频
Radical Chain-Growth Polymerization: Overview
2.3K
Chain-growth or addition polymerization is successive addition reactions of monomers with a polymer chain. In radical chain-growth polymerization, the reaction proceeds via a free-radical intermediate. The free radical is formed from radical initiators, which spontaneously generate free radicals by homolytic fission. Organic peroxides (such as dibenzoyl peroxide, as shown in Figure 1) or azo compounds are popular radical initiators. A low concentration ratio of radical initiator to monomer is...
2.3K
Cyclohexenones via Michael Addition and Aldol Condensation: The Robinson Annulation
2.1K
Robinson annulation is a base-catalyzed reaction for the synthesis of 2-cyclohexenone derivatives from 1,3-dicarbonyl donors (such as cyclic diketones, β-ketoesters, or β-diketones) and α,β-unsaturated carbonyl acceptors. Named after Sir Robert Robinson, who discovered it, this reaction yields a six-membered ring with three new C–C bonds (two σ bonds and one π bond).
2.1K
Radical Reactivity: Intramolecular vs Intermolecular
1.7K
Radical reactions can occur either intermolecularly or intramolecularly. In an intermolecular radical reaction, a nucleophilic radical adds to an electrophilic alkene or vice versa. In such reactions, the radical and generally the alkene, which is also called the radical trap, are two different molecules. Additionally, for such intermolecular reactions to occur, the radical trap must be active, present in an excess concentration, and the radical starting material must have a weak...
1.7K
Radical Formation: Overview
2.0K
A bond can be broken either by heterolytic bond cleavage to form ions or homolytic bond cleavage to yield radicals. A fishhook arrow is used to represent the motion of a single electron in homolytic bond cleavage. There are two main sources from which radicals can be formed:
Radicals from spin-paired molecules:
Radicals can be obtained from spin-paired molecules either by homolysis or electron transfer. While two radicals are formed in the former, an electron is added in the...
Radicals from spin-paired molecules:
Radicals can be obtained from spin-paired molecules either by homolysis or electron transfer. While two radicals are formed in the former, an electron is added in the...
2.0K
Radical Formation: Elimination
1.6K
Another method of radical formation is the elimination process. It is the opposite of the addition route and is driven by the instability of the radical. For example, as depicted in Figure 1, dibenzoyl peroxide yields a pair of unstable radicals upon homolysis. Given its instability, this radical spontaneously undergoes elimination via a C–C bond cleavage to form a relatively more stable phenyl radical. The mechanism involves cleavage of the bond between the α and β positions...
1.6K
Preparation of 1° Amines: Hofmann and Curtius Rearrangement Mechanism
3.4K
The Hofmann and Curtius rearrangement reactions can be applied to synthesize primary amines from carboxylic acid derivatives such as amides and acyl azides. In the Hofmann rearrangement, a primary amide undergoes deprotonation in the presence of a base, followed by halogenation to generate an N-haloamide. A second proton abstraction produces a stabilized anionic species, which rearranges to an isocyanate intermediate via an alkyl group migration from the carbonyl carbon to the neighboring...
3.4K


![Solid-phase Synthesis of [4.4] Spirocyclic Oximes](/_next/image?url=https%3A%2F%2Fcloudfront.jove.com%2FCDNSource%2Fteasers%2F58508.jpg&w=3840&q=50)