Development of Scalable Syntheses of Selective PI3K inhibitors

Huang, Qinhua; Richardson, Paul; Sach, Neal W.; Zhu, JinJiang; Liu, Kevin K.‐C.; Smith, Graham; Bowles, Daniel M.

doi:10.1021/op100286g

Cited by 45 publications

(21 citation statements)

References 13 publications

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“…According to the experimental results, the stronger electronic withdrawing groups in unsymmetrical 1,3-dicarbonyl compounds were exclusively removed. 13 Hence, this novel procedure is more efficient and environmentally friendly than the conventional methods. Also, among the afforded adducts, 1f was regarded as the key intermediate of ZPI3K inhibitors.…”

Section: Tetrasubstituted Thiophene Synthesismentioning

confidence: 99%

Highly mild approach towards synthesis of tetrasubstituted thiophenes by an organic salt afforded by cyclic thioureas and ketene dithioacetals

et al. 2015

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An organic salt generated by cyclic thioureas and 2-di(methylsulfanyl)methylene malononitrile in reaction with primary and secondary a-haloketones leads to tetrasubstituted thiophenes without using additional base or catalyst at room temperature. The S-methylisothiourea moiety of this salt as an organocatalyst performs a hybrid function of thiourea and imidazole to activate electrophiles via H-bonding and trigger cyclization via Lewis basicity character, respectively. Interestingly, a green solvent (in two step mode), short reaction time, easy purification, high yield and selectivity accompany this protocol. The structures of the intermediate and afforded adducts are fully characterized by analytical investigations and X-ray crystallography.

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Section: Tetrasubstituted Thiophene Synthesismentioning

confidence: 99%

Highly mild approach towards synthesis of tetrasubstituted thiophenes by an organic salt afforded by cyclic thioureas and ketene dithioacetals

et al. 2015

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“…The facile, practical and efficient one-pot reaction of acyl amidine 109 with hydrazine hydrate reliably provided potent PI3K inhibitor 110 with a special structure of thiophene triazole, but the reaction mechanism was not mentioned (Scheme 44) [163]. Another synthesis was the conversion of amides with N,N-dimethylformamide dimethyl acetal (DMF-DMA) at 100 °C to the corresponding ylideneamide, followed by the reaction with hydrazine to form desired triazole derivative 110.…”

Section: Cyclizations Of Hydrazinesmentioning

confidence: 99%

Current Developments in the Syntheses of 1,2,4-Triazole Compounds

Zhang¹,

Damu²,

Cai³

et al. 2014

COC

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Heterocyclic 1,2,4-triazole derivatives possess unusually spacious potentiality as medicinal agents, agricultural chemicals, functional materials, ionic liquids, supramolecular catalysts as well as artificial enzymes and receptors for supramolecular recognition and biomimetic catalysis, and their various researches and developments have been being a quite rapidly developing and active highlight topic with an infinite space. Numerous efforts have been directed toward various types of possible applications of 1,2,4-triazole-based compounds and a lot of important progress has been made, especially their preparations have attracted increasing attention. This review systematically summarized the recent advances in the syntheses of 1,2,4-triazole derivatives, including: (1) Cyclizations to form triazole ring; (2) Transformations of heterocyclic compounds to construct triazole ring; (3) Substitutions on 1,2,4-triazole ring; (4) Structural modifications in side chains of 1,2,4-triazole ring. It was hoped that this review would be helpful for the design and development of highly efficient preparation of 1,2,4-triazole derivatives with various sorts and varieties of extensively potential applications in medicine, agriculture, chemistry, materials, supramolecular sciences and so on.

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“…70 The critical part of these syntheses involved finding Suzuki coupling conditions that would convert the sterically hindered tetra substituted thiophene ( 228 ) into a biaryl benzene thiophene ( 229 ). Pd(P(tBu) 3 ) 2 and CsF proved to be the optimal catalyst/base combination for this cross coupling.…”

Section: Azolesmentioning

confidence: 99%

Recent syntheses of PI3K/Akt/mTOR signaling pathway inhibitors

Welker

Kulik

2013

Bioorganic & Medicinal Chemistry

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This review focuses on the syntheses of PI3K/Akt/mTOR inhibitors that have been reported outside of the patent literature in the last 5 years but is largely centered on synthetic work reported in 2011 and 2012. While focused on syntheses of inhibitors, some information on in vitro and in vivo testing of compounds is also included. Many of these reported compounds are reversible, competitive adenosine triphosphate (ATP) binding inhibitors, so given the structural similarities of many of these compounds to the adenine core, this review presents recent work on inhibitors based on where the synthetic chemistry was started, i.e. inhibitor syntheses which started with purines/pyrimidines are followed by inhibitor syntheses which began with pyridines, pyrazines, azoles, and triazines then moves to inhibitors which bear no structural resemblance to adenine: liphagal, wortmannin and quercetin analogs. The review then finishes with a short section on recent syntheses of phosphotidyl inositol (PI) analogs since competitive PI binding inhibitors represent an alternative to the competitive ATP binding inhibitors which have received the most attention.

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Development of Scalable Syntheses of Selective PI3K inhibitors

Cited by 45 publications

References 13 publications

Highly mild approach towards synthesis of tetrasubstituted thiophenes by an organic salt afforded by cyclic thioureas and ketene dithioacetals

Highly mild approach towards synthesis of tetrasubstituted thiophenes by an organic salt afforded by cyclic thioureas and ketene dithioacetals

Current Developments in the Syntheses of 1,2,4-Triazole Compounds

Recent syntheses of PI3K/Akt/mTOR signaling pathway inhibitors

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