Exploration of a Nitromethane-Carbonylation Strategy during Route Design of an Atropisomeric KRAS G12C Inhibitor
Route design and proof of concept synthesis was conducted on a synthetically challenging atropisomeric KRAS inhibitor to support clinical API manufacture. Improvements to the synthesis of a chiral piperazine fragment gave reduced step count and streamlined protecting group strategy via the formation...
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| Veröffentlicht in: | Journal of organic chemistry 2022-02, Vol.87 (4), p.2075-2086 |
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| container_end_page | 2086 |
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| container_issue | 4 |
| container_start_page | 2075 |
| container_title | Journal of organic chemistry |
| container_volume | 87 |
| creator | Douglas, James J Tatton, Matthew R de Bruin, Daniël Buttar, David Cook, Calum Dai, Kuangchu Ferrer, Catalina Leslie, Kevin Morrison, James Munday, Rachel Ronson, Thomas O Zhao, Hucheng |
| description | Route design and proof of concept synthesis was conducted on a synthetically challenging atropisomeric KRAS
inhibitor to support clinical API manufacture. Improvements to the synthesis of a chiral piperazine fragment gave reduced step count and streamlined protecting group strategy via the formation and methanol ring opening of an
-carboxy-anhydride (NCA). The complex atropisomeric nitroquinoline was accessed via an early stage salt-resolution followed by a formal two-part nitromethane-carbonylation, avoiding a high temperature Gould-Jacobs cyclization that previously led to atropisomer racemization. The substrate scope of the formal nitromethane-carbonylation strategy was further explored for a range of
-substituted bromo/iodo unprotected anilines. |
| doi_str_mv | 10.1021/acs.joc.1c01736 |
| format | Article |
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-carboxy-anhydride (NCA). The complex atropisomeric nitroquinoline was accessed via an early stage salt-resolution followed by a formal two-part nitromethane-carbonylation, avoiding a high temperature Gould-Jacobs cyclization that previously led to atropisomer racemization. The substrate scope of the formal nitromethane-carbonylation strategy was further explored for a range of
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-carboxy-anhydride (NCA). The complex atropisomeric nitroquinoline was accessed via an early stage salt-resolution followed by a formal two-part nitromethane-carbonylation, avoiding a high temperature Gould-Jacobs cyclization that previously led to atropisomer racemization. The substrate scope of the formal nitromethane-carbonylation strategy was further explored for a range of
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-carboxy-anhydride (NCA). The complex atropisomeric nitroquinoline was accessed via an early stage salt-resolution followed by a formal two-part nitromethane-carbonylation, avoiding a high temperature Gould-Jacobs cyclization that previously led to atropisomer racemization. The substrate scope of the formal nitromethane-carbonylation strategy was further explored for a range of
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| fulltext | fulltext |
| identifier | ISSN: 0022-3263 |
| ispartof | Journal of organic chemistry, 2022-02, Vol.87 (4), p.2075-2086 |
| issn | 0022-3263 1520-6904 |
| language | eng |
| recordid | cdi_crossref_primary_10_1021_acs_joc_1c01736 |
| source | MEDLINE; American Chemical Society Journals |
| subjects | Methane - analogs & derivatives Nitroparaffins Proto-Oncogene Proteins p21(ras) |
| title | Exploration of a Nitromethane-Carbonylation Strategy during Route Design of an Atropisomeric KRAS G12C Inhibitor |
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