Large-Scale Cyclopropanation of Butyl Acrylate with Difluorocarbene and Classical Resolution of a Key Fluorinated Building Block
- Adam E. Goetz*Adam E. Goetz*Email: [email protected]Chemical Research and Development, Pfizer Worldwide Research and Development, Groton Laboratories, Eastern Point Road, Groton, Connecticut 06340, United StatesMore by Adam E. Goetz
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- Husein BecirovicHusein BecirovicAnalytical Research and Development, Pfizer Worldwide Research and Development, Groton Laboratories, Eastern Point Road, Groton, Connecticut 06340, United StatesMore by Husein Becirovic
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- Florian BlasbergFlorian BlasbergAMRI, Euticals GmbH, Industriepark Höchst D569, 65926 Frankfurt am Main, GermanyMore by Florian Blasberg
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- Bo ChenBo ChenPorton R&D Center, No. 1299 Ziyue Rd, Zizhu Science Park, Minhang District, Shanghai, ChinaMore by Bo Chen
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- Hugh J. ClarkeHugh J. ClarkeAnalytical Research and Development, Pfizer Worldwide Research and Development, Groton Laboratories, Eastern Point Road, Groton, Connecticut 06340, United StatesMore by Hugh J. Clarke
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- Matteo Colombo
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- Pedro DaddarioPedro DaddarioAnalytical Research and Development, Pfizer Worldwide Research and Development, Groton Laboratories, Eastern Point Road, Groton, Connecticut 06340, United StatesMore by Pedro Daddario
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- David B. DamonDavid B. DamonChemical Research and Development, Pfizer Worldwide Research and Development, Groton Laboratories, Eastern Point Road, Groton, Connecticut 06340, United StatesMore by David B. Damon
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- Christelle DepretzChristelle DepretzAMRI, Euticals S.A.S., Zone Industrielle de Laville, 47240 Bon-Encontre, FranceMore by Christelle Depretz
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- Yves R. DumondYves R. DumondAMRI, Euticals S.A.S., Zone Industrielle de Laville, 47240 Bon-Encontre, FranceMore by Yves R. Dumond
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- Maria D. Grilli
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- Lu HanLu HanChemical Research and Development, Pfizer Worldwide Research and Development, Groton Laboratories, Eastern Point Road, Groton, Connecticut 06340, United StatesMore by Lu Han
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- Tim L. HouckTim L. HouckChemical Research and Development, Pfizer Worldwide Research and Development, Groton Laboratories, Eastern Point Road, Groton, Connecticut 06340, United StatesMore by Tim L. Houck
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- Amber M. JohnsonAmber M. JohnsonChemical Research and Development, Pfizer Worldwide Research and Development, Groton Laboratories, Eastern Point Road, Groton, Connecticut 06340, United StatesMore by Amber M. Johnson
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- Kris N. JonesKris N. JonesChemical Research and Development, Pfizer Worldwide Research and Development, Groton Laboratories, Eastern Point Road, Groton, Connecticut 06340, United StatesMore by Kris N. Jones
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- Jörg JungJörg JungAMRI, Euticals GmbH, Industriepark Höchst D569, 65926 Frankfurt am Main, GermanyMore by Jörg Jung
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- Michel Leeman
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- Fangfang LiuFangfang LiuAnalytical Research and Development, Pfizer Worldwide Research and Development, Groton Laboratories, Eastern Point Road, Groton, Connecticut 06340, United StatesMore by Fangfang Liu
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- Cuong V. LuCuong V. LuChemical Research and Development, Pfizer Worldwide Research and Development, Groton Laboratories, Eastern Point Road, Groton, Connecticut 06340, United StatesMore by Cuong V. Lu
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- Emilio J. MangualEmilio J. MangualAnalytical Research and Development, Pfizer Worldwide Research and Development, Groton Laboratories, Eastern Point Road, Groton, Connecticut 06340, United StatesMore by Emilio J. Mangual
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- Jade D. NelsonJade D. NelsonChemical Research and Development, Pfizer Worldwide Research and Development, Groton Laboratories, Eastern Point Road, Groton, Connecticut 06340, United StatesMore by Jade D. Nelson
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- Angela L. A. Puchlopek-DermenciAngela L. A. Puchlopek-DermenciChemical Research and Development, Pfizer Worldwide Research and Development, Groton Laboratories, Eastern Point Road, Groton, Connecticut 06340, United StatesMore by Angela L. A. Puchlopek-Dermenci
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- Sally Gut RuggeriSally Gut RuggeriChemical Research and Development, Pfizer Worldwide Research and Development, Groton Laboratories, Eastern Point Road, Groton, Connecticut 06340, United StatesMore by Sally Gut Ruggeri
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- Paul A. SimondsPaul A. SimondsChemical Research and Development, Pfizer Worldwide Research and Development, Groton Laboratories, Eastern Point Road, Groton, Connecticut 06340, United StatesMore by Paul A. Simonds
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- Barbara SitterBarbara SitterChemical Research and Development, Pfizer Worldwide Research and Development, Groton Laboratories, Eastern Point Road, Groton, Connecticut 06340, United StatesMore by Barbara Sitter
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- Daniel E. VirtueDaniel E. VirtueAnalytical Research and Development, Pfizer Worldwide Research and Development, Groton Laboratories, Eastern Point Road, Groton, Connecticut 06340, United StatesMore by Daniel E. Virtue
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- Shuguang WangShuguang WangPorton R&D Center, No. 1299 Ziyue Rd, Zizhu Science Park, Minhang District, Shanghai, ChinaMore by Shuguang Wang
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- Lixin YuLixin YuPorton R&D Center, No. 1299 Ziyue Rd, Zizhu Science Park, Minhang District, Shanghai, ChinaMore by Lixin Yu
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- Tao YuTao YuPorton R&D Center, No. 1299 Ziyue Rd, Zizhu Science Park, Minhang District, Shanghai, ChinaMore by Tao Yu
Abstract
To address challenges in the preparation of a key building block containing a difluorocyclopropane moiety, we have developed a new protocol for difluorocarbene generation that relies on a Krapcho-type dealkylation of ethyl bromodifluoroacetate (EBDFA), an inexpensive and readily available fluorinated feedstock. Application of DoE and kinetic modeling was used to understand key reaction parameters and identify an optimal process. We report two variants of this procedure that offer different processing advantages and that have both been scaled successfully multiple times to deliver hundreds of kilograms of the resulting difluorocyclopropane. To access a single enantiomer of the target compound, we have also developed a classical resolution strategy and recycling protocol for the undesired enantiomer to replace previous chromatographic methods for separation.
Cited By
This article is cited by 4 publications.
- Toshiyuki Itoh, Shuichi Hayase, Toshiki Nokami. Synthesis of Selectively gem ‐Difluorinated Molecules; Chiral gem ‐Difluorocyclopropanes via Chemo‐Enzymatic Reaction and gem ‐Difluorinated Compounds via Radical Reaction. The Chemical Record 2023, 61 https://doi.org/10.1002/tcr.202300028
- Thomas Louis‐Goff, Huu Vinh Trinh, Eileen Chen, Arnold L. Rheingold, Jakub Hyvl. Synthesis of Chiral Hypervalent Trifluoromethyl Organobismuth Complexes and Enantioselective Olefin Difluorocarbenation Screenings. ChemPlusChem 2023, 88 (2) https://doi.org/10.1002/cplu.202200450
- Oleksandr O. Grygorenko, Kostiantyn P. Melnykov, Serhii Holovach, Oleksandr Demchuk. Fluorinated Cycloalkyl Building Blocks for Drug Discovery. ChemMedChem 2022, 17 (21) https://doi.org/10.1002/cmdc.202200365
- Jindian Duan, Pui Ying Choy, Kin Boon Gan, Fuk Yee Kwong. N -Difluoromethylation of N -pyridyl-substituted anilines with ethyl bromodifluoroacetate. Organic & Biomolecular Chemistry 2022, 20 (9) , 1883-1887. https://doi.org/10.1039/D2OB00119E