Ni-Catalyzed C–H Functionalization in the Formation of a Complex Heterocycle: Synthesis of the Potent JAK2 Inhibitor BMS-911543

Fitzgerald, Monica A.; Soltani, Omid; Wei, Carolyn S.; Skliar, Dimitri; Zheng, Bin; Li, Jun; Albrecht, Jacob; Schmidt, Michael A.; Mahoney, Michelle; Fox, Richard J.; Tran, Kristy; Zhu, Kun; Eastgate, Martin D.

doi:10.1021/acs.joc.5b00572

Cited by 33 publications

(39 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…17 In the discovery phase, the compound was prepared in a laborious 19 linear step sequence involving stepwise functionalization of 2,6-dichloropyridine. 17 In the discovery phase, the compound was prepared in a laborious 19 linear step sequence involving stepwise functionalization of 2,6-dichloropyridine.…”

Section: Heterocycle Formation Using C-h Functionalizationmentioning

confidence: 99%

Modern advances in heterocyclic chemistry in drug discovery

et al. 2016

View full text Add to dashboard Cite

New advances in synthetic methodologies that allow rapid access to a wide variety of functionalized heterocyclic compounds are of critical importance to the medicinal chemist as it provides the ability to expand the available drug-like chemical space and drive more efficient delivery of drug discovery programs. Furthermore, the development of robust synthetic routes that can readily generate bulk quantities of a desired compound help to accelerate the drug development process. While established synthetic methodologies are commonly utilized during the course of a drug discovery program, the development of innovative heterocyclic syntheses that allow for different bond forming strategies are having a significant impact in the pharmaceutical industry. This review will focus on recent applications of new methodologies in C-H activation, photoredox chemistry, borrowing hydrogen catalysis, multicomponent reactions, regio- and stereoselective syntheses, as well as other new, innovative general syntheses for the formation and functionalization of heterocycles that have helped drive project delivery. Additionally, the importance and value of collaborations between industry and academia in shaping the development of innovative synthetic approaches to functionalized heterocycles that are of greatest interest to the pharmaceutical industry will be highlighted.

show abstract

Section: Heterocycle Formation Using C-h Functionalizationmentioning

confidence: 99%

Modern advances in heterocyclic chemistry in drug discovery

et al. 2016

View full text Add to dashboard Cite

show abstract

“…While the above route allowed the formation of the desired pyrazoles, we required a more flexible synthetic sequence to allow a more efficient exploration of the 4‐position, whilst avoiding regioselectivity issues. To this end, 1,3‐dimethylpyrazol‐3‐ol hydrochloride ( 11 ), prepared from but‐2‐ynoic acid as previously described, [10] was arylated with 2‐chloro‐5‐fluoropyrimidine to afford 12 (Scheme 2). A three‐step sequence of iodination, palladium‐catalysed coupling with pinacol borane and subsequent oxidative cleavage provided the key 4‐hydroxypyrazole intermediate 15 .…”

Section: Resultsmentioning

confidence: 99%

“…2‐(1,5‐Dimethylpyrazol‐3‐yl)oxy‐5‐fluoropyrimidine (12) . A mixture of 1,5‐dimethylpyrazol‐3‐ol hydrochloride [10] (5.00 g, 33.6 mmol), 2‐chloro‐5‐fluoropyrimidine (4.46 g, 33.6 mmol), Cs 2 CO 3 (38.4 g, 118 mmol) and CuI (490 mg, 6.73 mmol) in acetonitrile (70 ml) was heated at 80 °C for 2 h. The mixture was cooled to rt, filtered through Celite with EtOAc washing then concentrated. The crude product was purified by chromatography (silica gel, 0–100 % EtOAc in heptane gradient) to afford the title compound 12 (4.80 g, 69 %) as an orange solid.…”

Section: Methodsmentioning

confidence: 99%

“…When the desired pyrazole is substituted with an haloalkyl group in the 5‐position (i. e. R 2 =CF 3 ), alkylhydrazines can be reacted with acetylenic esters [8] and 3‐amino, 3‐methoxy and 3‐haloacrylates [9] to give preferentially the 3‐hydroxypyrazole regioisomer. A completely regioselective method for the approach of 1,5‐dimethyl‐3‐hydroxypyrazole has been reported by amide coupling of 2‐butynoic acid with N ‐Boc‐ N ‐methylhydrazine, followed by acid‐promoted deprotection and cyclisation [10] …”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Flexible Synthesis and Herbicidal Activity of Fully Substituted 3‐Hydroxypyrazoles

Judge

Chacktas

et al. 2021

Eur J Org Chem

View full text Add to dashboard Cite

The synthesis and herbicidal efficacy of a novel library of fully substituted 3‐hydroxypyrazoles is reported. An efficient, divergent approach to introduce phenyl, phenoxy, phenylsulfanyl, anilino and benzyl substituents in the 4‐position of the pyrazole, alongside a flexible synthesis of N1‐alkyl analogues is described via final step diversification of key intermediates. Herbicidal screening of the prepared compounds against key weed species identified the lead compound 2‐[4‐(2,4‐difluorophenoxy)‐1,5‐dimethyl‐pyrazol‐3‐yl]oxy‐5‐fluoropyrimidine, which was prepared on a multi‐gram scale using an optimised synthetic route.

show abstract

“…This concerns the initial actions to extend the techniques of annulation of the derivatives of nicotinamide, which ended up suffering low reaction rate. Alternatively, as evidenced by the process in scheme 3, a nickel-catalyzed C-H functionalization can be a crucial phase in a small, convergent scale-up means to the BMS-911543, which is a strong inhibitor of the Janus kinase 2 (JAK2) [11]. The Hoffman-Löffler-Freytag (HLF) reaction, which is one of the effective techniques of the C-H functionalization, the authors employed this technique during the production of diazatricyclodecane agonists of the G-protein receptor 119 (GPCR119) [12].…”

Section: Scheme1: Synthesis Of Oxindoles Using Palladium Catalysed C-mentioning

confidence: 99%

Untitled

Sapra¹,

Patel²,

Meshram³

2020

J. Med. Chem. Sci.

View full text Add to dashboard Cite

Novel developments in the synthetic techniques that facilitate rapid access to various functionalized heterocyclic compounds are essential in medicinal chemistry. They enable an expansion of the available drug-associated chemical space and enhance the efficiency of drug delivery. In addition, the creation of more robust synthetic techniques that can increase the drug yield can enhance the drug production rate. While researchers and manufacturers utilize established synthetic techniques during a program aimed at drug discovery, the innovation of heterocyclic synthesis processes that permit varied bond formation strategies is influencing the pharmaceutical industry in the most significant way. This review focuses on the utilization of some novel methods of activation of the C-H bonds, hydrogen borrowing catalysis, photoredox chemistry, regio-and stereoselective synthesis, and multi component reactions for the functionalization and creation of heterocycles that aided in driving project delivery.

show abstract

Ni-Catalyzed C–H Functionalization in the Formation of a Complex Heterocycle: Synthesis of the Potent JAK2 Inhibitor BMS-911543

Cited by 33 publications

References 50 publications

Modern advances in heterocyclic chemistry in drug discovery

Modern advances in heterocyclic chemistry in drug discovery

Flexible Synthesis and Herbicidal Activity of Fully Substituted 3‐Hydroxypyrazoles

Untitled

Contact Info

Product

Resources

About