Lewis Acid-Catalyzed Synthesis of 4-Aminopyrimidines: A Scalable Industrial Process

Létinois, Ulla; Schütz, Jan; Härter, Ralph; Stoll, Rinke; Huffschmidt, Florian; Bonrath, Werner; Karge, Reinhard

doi:10.1021/op300190s

Cited by 16 publications

(14 citation statements)

References 16 publications

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“…29 Furthermore, the ketones made available in this way would be suitable prochiral candidates for reductions to provide useful intermediates for the chiral synthetic pool and/or enzymatic studies. 30,31…”

Section: Resultsmentioning

confidence: 99%

Unusual Nucleophilic Addition of Grignard Reagents in the Synthesis of 4-Amino-pyrimidines

et al. 2018

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Pyrimidines have always received considerable attention because of their importance in synthesis and elucidation of biochemical roles, in particular that of vitamin B1. Herein, we describe a reaction pathway in a Grignard reagent-based synthesis of substituted pyrimidines. A general synthesis of α-keto-2-methyl-4-amino pyrimidines and their C6-substituted analogues from 4-amino-5-cyano-2-methylpyrimidine is reported. The presence of the nitrile substituent in the starting material also results in an unusual reaction pathway leading to C6-substituted 1,2-dihydropyrimidines. Grignard reagents that give normal pyrimidine products under standard reaction conditions can be switched to give dihydropyrimidines by holding the reaction at 0 °C before quenching.

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Section: Resultsmentioning

confidence: 99%

Unusual Nucleophilic Addition of Grignard Reagents in the Synthesis of 4-Amino-pyrimidines

et al. 2018

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“…Aminophilic Lewis acids were found to be more effective as catalysts. Iron chloride (FeCl 2 ) enhanced the yield of the final product to 60% [ 54 ].…”

Section: Synthetic Strategies Of Pyrimidinesmentioning

confidence: 99%

“…Also, the amidine hydrochloride and ZnCl 2 stoichiometry affects the stirrability of the mixture. A mixture of 1.4 equiv of amidine hydrochloride with 0.15 equiv of ZnCl 2 had non-stirrability issues, while 1.1 equiv of amidine hydrochloride with 0.2 equiv of ZnCl 2 solved the stirring problem in isopropanol and toluene solvent [ 54 ].…”

Section: Synthetic Strategies Of Pyrimidinesmentioning

confidence: 99%

Synthetic Strategies of Pyrimidine-Based Scaffolds as Aurora Kinase and Polo-like Kinase Inhibitors

et al. 2021

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The past few decades have witnessed significant progress in anticancer drug discovery. Small molecules containing heterocyclic moieties have attracted considerable interest for designing new antitumor agents. Of these, the pyrimidine ring system is found in multitude of drug structures, and being the building unit of DNA and RNA makes it an attractive scaffold for the design and development of anticancer drugs. Currently, 22 pyrimidine-containing entities are approved for clinical use as anticancer drugs by the FDA. An exhaustive literature search indicates several publications and more than 59 patents from the year 2009 onwards on pyrimidine derivatives exhibiting potent antiproliferative activity. These pyrimidine derivatives exert their activity via diverse mechanisms, one of them being inhibition of protein kinases. Aurora kinase (AURK) and polo-like kinase (PLK) are protein kinases involved in the regulation of the cell cycle. Within the numerous pyrimidine-based small molecules developed as anticancer agents, this review focuses on the pyrimidine fused heterocyclic compounds modulating the AURK and PLK proteins in different phases of clinical trials as anticancer agents. This article aims to provide a comprehensive overview of synthetic strategies for the preparation of pyrimidine derivatives and their associated biological activity on AURK/PLK. It will also present an overview of the synthesis of the heterocyclic-2-aminopyrimidine, 4-aminopyrimidine and 2,4-diaminopyrimidine scaffolds, and one of the pharmacophores in AURK/PLK inhibitors is described systematically.

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“…Létinois and co-workers reported the ring-opening reaction of unsubstituted isoxazole (1) in the presence of NaOMe (lower than 2 °C) to obtain product 3 in a high yield (Scheme 3). 10 This 3-H deprotonation induced ring opening is a common feature of 1,2-azoles. As a unique feature of isoxazole, lithiation at the 5-position of isoxazoles also leads to ring opening.…”

Section: Scheme 2 Difficulties In Introducing Functional Groups To Ismentioning

confidence: 96%

Step-by-Step Multifunctionalization of Isoxazoles Based On SEAr Reactions and C–H Direct Arylations

2017

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Functionalized isoxazoles are important as pharmaceuticals and agrochemicals. Generally, electrophilic aromatic substitution or generation of carbanions/electrophilic trapping approach is used to introduce functional groups into unsubstituted heteroaromatics. However, these approaches have not been simple to apply to unsubstituted isoxazoles due to their poor nucleophilicity and instability under basic conditions. Recently several approaches have been reported to overcome these problems. This review summarizes the functionalization of isoxazoles, including SEAr reactions and C–H direct arylations, towards the step-by-step multifunctionalization of isoxazoles.1 Introduction2 SEAr Reaction of Isoxazoles3 Preparation of Isoxazolyl Anions and Their Use for the Synthesis of Functionalized Isoxazoles4 Other C–C and C–N Bond Formations of Isoxazoles5 Transition-Metal-Catalyzed C–H Direct Functionalization of Isoxazoles6 Step-by-Step Multifunctionalization of Isoxazoles7 Summary and Outlook

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Lewis Acid-Catalyzed Synthesis of 4-Aminopyrimidines: A Scalable Industrial Process

Cited by 16 publications

References 16 publications

Unusual Nucleophilic Addition of Grignard Reagents in the Synthesis of 4-Amino-pyrimidines

Unusual Nucleophilic Addition of Grignard Reagents in the Synthesis of 4-Amino-pyrimidines

Synthetic Strategies of Pyrimidine-Based Scaffolds as Aurora Kinase and Polo-like Kinase Inhibitors

Step-by-Step Multifunctionalization of Isoxazoles Based On SEAr Reactions and C–H Direct Arylations

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