New Synthetic Route to Tucatinib

Lingfeng Yin; Yongjun Mao; Yaowei Liu; Lehao Bu; Long Zhang; Wenxin Chen

doi:10.1055/s-0037-1610706

New Synthetic Route to Tucatinib

Synthesis ◽

10.1055/s-0037-1610706 ◽

2019 ◽

Vol 51 (13) ◽

pp. 2660-2664

Author(s):

Lingfeng Yin ◽

Yongjun Mao ◽

Yaowei Liu ◽

Lehao Bu ◽

Long Zhang ◽

...

Keyword(s):

Synthetic Route ◽

Hplc Purification ◽

Mild Conditions ◽

Purification Methods

A new and improved synthetic route to tucatinib is described that involves three key intermediates. The first of these, 4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylaniline, was prepared on a 100 g scale in 33% yield over five steps and 99% purity. Next, N 4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)quinazoline-4,6-diamine was isolated in 67% yield over three steps and >99% purity. Then, 4,4-dimethyl-2-(methylthio)-4,5-dihydrooxazole trifluoromethanesulfonate was prepared under mild conditions in 67% yield over two steps. Finally, tucatinib was obtained in 17% yield over nine steps and in >99% purity (HPLC). Purification methods used to isolate the product and the intermediates involved in the route are also reported.

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Copper-Catalyzed Synthesis of Axially Chiral Biaryls with Diaryliodonium Salts as Arylation Reagents

Molecules ◽

10.3390/molecules26113223 ◽

2021 ◽

Vol 26 (11) ◽

pp. 3223

Author(s):

Ji-Wei Zhang ◽

Shao-Hua Xiang ◽

Shaoyu Li ◽

Bin Tan

Keyword(s):

Amino Alcohols ◽

Sigmatropic Rearrangement ◽

Synthetic Route ◽

Mild Conditions ◽

Good Substrate ◽

Diaryliodonium Salts ◽

Axially Chiral

NOBIN and BINAM derivatives harboring biaryl frameworks are recognized as a class of important atropisomers with versatile applications. Here, we present an efficient synthetic route to access such compounds through copper-catalyzed domino arylation of N-arylhydroxylamines or N-arylhydrazines with diaryliodonium salts and [3,3]-sigmatropic rearrangement. This reaction features mild conditions, good substrate compatibility, and excellent efficiency. The practicality of this protocol was further extended by the synthesis of biaryl amino alcohols.

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Consecutive Multicomponent Reactions: Synthesis of 3-Acyl-4-alkynyl-Substituted 1,3-Thiazolidines

Synthesis ◽

10.1055/s-0036-1591873 ◽

2018 ◽

Vol 50 (05) ◽

pp. 1123-1132 ◽

Cited By ~ 2

Author(s):

Jürgen Martens ◽

Torben Schlüter ◽

Nils Frerichs ◽

Marc Schmidtmann

Keyword(s):

Functional Groups ◽

Multicomponent Reactions ◽

Terminal Alkynes ◽

Synthetic Route ◽

Acyl Chlorides ◽

Mild Conditions ◽

Three Component Reaction

This work describes the synthesis of compounds containing thiazolidine and propargylamidic motifs. Their preparation follows a synthetic route containing two multicomponent reactions. First, the Asinger four-component reaction is used to prepare 3-thiazolines and 3-oxazolines. Secondly, these heterocyclic imines are converted into propargylamides by a copper-catalyzed three-component reaction using acyl chlorides and terminal alkynes. The synthetic route is characterized by mild conditions and many functional groups are tolerated. The formation of an unexpected α-alkynoxyamide is also presented.

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Organic Photoredox Catalysis for Pschorr Reaction: A Metal-Free and Mild Approach to 6H-Benzo[c]chromenes

Synlett ◽

10.1055/s-0037-1610279 ◽

2018 ◽

Vol 29 (17) ◽

pp. 2311-2315 ◽

Cited By ~ 5

Author(s):

Gaofeng Feng ◽

Jing-Yao He ◽

Qi-Fan Bai ◽

Chengan Jin

Keyword(s):

Diazonium Salts ◽

Eosin Y ◽

Photoredox Catalysis ◽

Synthetic Route ◽

Metal Free ◽

Mild Conditions ◽

Pschorr Reaction

An expedient organic photoredox Pschorr reaction has been developed that opens up a synthetic route to 6H-benzo[c]chromenes. The process can be performed under mild conditions by using eosin Y as a photoredox catalyst and acetonitrile as the solvent. The diazonium salts can be either preformed or generated in situ from the corresponding amines with t-BuONO. The process is amenable to gram-sale synthesis of 6H-benzo[c]chromenes, which can be further transformed into both 6H-benzo[c]chromen-6-ones through oxidation or to 6H-benzo[c]chromen-6-amine through sp3 C–H bond amination. The protocol provides an attractive route for the synthesis of a library of 6H-benzo[c]chromes.

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Exploration of new reaction tools for late-stage functionalization of complex chemicals

Canadian Journal of Chemistry ◽

10.1139/cjc-2018-0357 ◽

2019 ◽

Vol 97 (2) ◽

pp. 67-85 ◽

Cited By ~ 4

Author(s):

Alejandra Dominguez-Huerta ◽

Xi-Jie Dai ◽

Feng Zhou ◽

Pierre Querard ◽

Zihang Qiu ◽

...

Keyword(s):

Environmental Impact ◽

Late Stage ◽

Chemical Transformations ◽

Synthetic Route ◽

Atom Economy ◽

Complex Molecules ◽

Mild Conditions ◽

The Past ◽

Renewable Feedstocks ◽

Selective Chemical

Chemistry has always had as a target the conversion of molecules into valuable materials. Nevertheless, the aim of past synthesis has primarily focused on achieving a given transformation, regardless of the environmental impact of the synthetic route. Given the current global situation, the demand for sustainable alternatives has substantially increased. Our group focuses on developing selective chemical transformations that benefit from mild conditions, improved atom economy, and that can make use of renewable feedstocks as starting materials. This account summarizes our work over the past two decades specifically regarding the selective removal, conversion, and addition of functional groups that can, later on, be applied at a late stage for the modification of complex molecules.

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Designing Rh(I)-Half-Sandwich Catalysts for Alkyne [2+2+2] Cycloadditions

Synlett ◽

10.1055/s-0040-1707284 ◽

2020 ◽

Author(s):

Laura Orian ◽

F. Matthias Bickelhaupt

Keyword(s):

Rational Design ◽

Computational Studies ◽

Synthetic Route ◽

Mechanistic Studies ◽

Mild Conditions ◽

Aromatic Ligand ◽

Polycyclic Aromatic ◽

Metal Catalyzed ◽

Cyclopentadienyl Anion ◽

Half Sandwich

AbstractMetal-mediated [2+2+2] cycloadditions of unsaturated molecules to cyclic and polycyclic organic compounds are a versatile synthetic route affording good yields and selectivity under mild conditions. In the last two decades, in silico investigations have unveiled important details about the mechanism and the energetics of the whole catalytic cycle. Particularly, a number of computational studies address the topic of half-sandwich catalysts which, due to their structural fluxionality, have been widely employed, since the 1980s. In these organometallic species, the metal is coordinated to an aromatic ring, typically the ubiquitous cyclopentadienyl anion, C5H5 –(Cp) or to the Cp moiety of a larger polycyclic aromatic ligand (Cp′). During the catalytic process, the metal continuously ‘slips’ on the ring, changing its hapticity. This phenomenon of metal slippage and its implications for the catalyst’s performance are discussed in this work, referring to the most important computational mechanistic studies reported in literature for Rh(I) half-metallocenes, with the purpose of providing hints for a rational design of this class of compounds.1 Introduction2 Mechanism of Metal-Catalyzed Acetylene [2+2+2] Cycloaddition to Benzene and the Problem of the Indenyl Effect2.1 Acetylene-Acetonitrile [2+2+2] Co-cycloaddition to 2-Methylpyridine: Evidence of the Indenyl Effect2.2 Heteroaromatic Catalysts and the Evidence of a Reverse Indenyl Effect2.3 Booth’s Mechanistic Hypothesis and the Evidence of the Indenyl Effect3 Structure–Reactivity Correlation: The Slippage-Span Model4 Conclusions and Perspectives

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Copper/Silver Cocatalyzed Regioselective C5–H Functionalization of 8-Aminoquinoline Amides with 1,3-Dicarbonyl Compounds

Synthesis ◽

10.1055/s-0039-1690806 ◽

2020 ◽

Vol 52 (07) ◽

pp. 1007-1014 ◽

Cited By ~ 1

Author(s):

Fuxu Zhan ◽

Wei Zhang ◽

Huaiqing Zhao

Keyword(s):

Coupling Reaction ◽

Catalytic Transformation ◽

Synthetic Route ◽

Dicarbonyl Compounds ◽

Mild Conditions ◽

Dehydrogenative Coupling

A copper/silver co-catalyzed cross-dehydrogenative coupling reaction is developed to achieve exclusively remote C5–H coupling of 8-aminoquinoline amides with the methylenic sp3 C–H bond of 1,3-dicarbonyl compounds. This protocol provides a highly regioselective synthetic route for the functionalization of 8-aminoquinoline amides at C5 under mild conditions. Preliminary experiments reveal that radicals may be involved in this catalytic transformation.

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