Enabling Synthesis of ABBV-2222, A CFTR Corrector for the Treatment of Cystic Fibrosis

Greszler, Stephen N.; Shelat, Bhadra; Voight, Eric A.

doi:10.1021/acs.orglett.9b02099

Cited by 16 publications

(9 citation statements)

References 11 publications

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“…In 2019, Greszler illustrated that diethyl bromodifluoromethyl-phosphonate is a suitable difluorocarbene reagent to access ABBV-2222, a CFTR corrector for the treatment of cystic fibrosis (Scheme 64). 207 Despite the exothermic nature of the difluorocarbene reaction, ABBV-2222 was prepared on 130 g scale.…”

Section: Industrial State Of Playmentioning

confidence: 99%

Late-stage difluoromethylation: concepts, developments and perspective

et al. 2021

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Section: Industrial State Of Playmentioning

confidence: 99%

Late-stage difluoromethylation: concepts, developments and perspective

et al. 2021

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“…and late-stage difluoromethylation. 4,8,[232][233][234][235][236] This is possible owing to the high reactivity of difluorocarbene towards heteroatom nucleophiles and soft carbon nucleophiles and the low cost of difluorocarbene sources such as HCF2Cl. Pharmaceuticals and agrochemicals synthesized using this electrophilic difluoromethylation method include the aforementioned anti-pulmonary disease drug Roflumilast FIG.…”

Section: [H2] Pharmaceutical and Agrochemical Productionmentioning

confidence: 99%

Contemporary synthetic strategies in organofluorine chemistry

Britton

Gouverneur

Lin

et al. 2021

Nat Rev Methods Primers

202

115

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At this stage, I've edited the manuscript for brevity and clarity. Queries are meant to draw your attention to edits, inconsistencies or issues that are unclear. If we just ask you to confirm edits are correct, a simple yes/ok between the brackets will do [Au:OK? Is this what you meant? Edits OK? yes]. If questions are asked, please rephrase/update the manuscript text when addressing queries, so that the message is conveyed to the reader (please do not just type your answer to our query unless it is unclear).As the reviewers noted, the manuscript is in very good shape and most comments and edits are fairly minor. However, there is an outstanding issue that must be addressed before we go forward. Figures 7 and 8 are currently referred to in the text in an alternating fashion (e.g. Figure 7A, 8A, 7B, 8B). This is against our style and might make that part of the manuscript difficult to follow for the reader owing to the need to refer to multiple figures at a time while reading the text. To clarify this issue, I recommend restructuring these figures. To do this, can you provide new chemdraw/PDFs with amended figures, including the following amendments: a. Merge Figures 7A and 8A to create a new 'Figure 7' that shows the methods of introducing CF2H at sp3-carbons. b. Merge figures 7B and 8B to make a new figure 8 that shows the main protocols of introducing CF2H at heteroaromatic carbons. 7C could be shown in it's own small figure (Figure 9) or could be added as panel B in the new figure 8. c. Amend the figure legends accordingly Apologies for another figure change but this is essential to keep the figure callouts in style and I think it will make the figures much easier for the reader to follow. I've asked the art editor to delay redrawing these particular figures until we receive these updated chemdraws/PDFs. If there are any issues with this change, please do let me know as soon as possible and we can discuss further.

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“…The large-scale synthesis (>130 g) of the most successful hit was later published by Greszler et al (Scheme 11) [6]. In 2019, another expansion of the substrate scope for the synthesis of substituted flavanones was done by Liu et al…”

Section: Catalytic Systems Based On Pyridineoxazolines Ligandsmentioning

confidence: 99%

“…Scheme 11: Multigram-scale synthesis of ABBV-2222 [6]. Mechanistic studies of this catalytic system were also made by Stoltz's group.…”

Section: Catalytic Systems Based On Pyridineoxazolines Ligandsmentioning

confidence: 99%

“…The asymmetric 1,4-addition of arylboronic acids to conjugated cyclic enones and chromones is a very important reaction nowadays. For illustration, the addition products are very promising in medicinal chemistry research [1][2][3][4][5][6][7] and in natural products total syntheses [8][9][10][11][12][13][14][15][16]. Chiral complexes of Rh [17][18][19][20][21][22][23][24] and Pd usually catalyse the reaction, however, palladium holds a special place in this area.…”

Section: Introductionmentioning

confidence: 99%

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Recent advances in palladium-catalysed asymmetric 1,4–additions of arylboronic acids to conjugated enones and chromones

Bartáček¹,

Svoboda²,

Kocúrik³

et al. 2021

Beilstein J. Org. Chem.

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The transition metal (palladium)-catalysed asymmetric 1,4-addition of arylboronic acids to conjugated enones belong to the most important and emerging strategies for the construction of C–C bonds in an asymmetric fashion. This review covers known catalytic systems used for this transformation. For clarity, we are using the type of ligand as a sorting criterion. Finally, we attempted to create a flowchart facilitating the selection of a suitable ligand for a given combination of enone and arylboronic acid.

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Enabling Synthesis of ABBV-2222, A CFTR Corrector for the Treatment of Cystic Fibrosis

Cited by 16 publications

References 11 publications

Late-stage difluoromethylation: concepts, developments and perspective

Late-stage difluoromethylation: concepts, developments and perspective

Contemporary synthetic strategies in organofluorine chemistry

Recent advances in palladium-catalysed asymmetric 1,4–additions of arylboronic acids to conjugated enones and chromones

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