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An Improved Synthesis of Elvitegravir
Author(s) -
Rádl Stanislav,
Stach Jan,
Píša Ondřej,
Cinibulk Josef,
Havlíček Jaroslav,
Zajícová Markéta,
Pekárek Tomáš
Publication year - 2016
Publication title -
journal of heterocyclic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.321
H-Index - 59
eISSN - 1943-5193
pISSN - 0022-152X
DOI - 10.1002/jhet.2477
Subject(s) - elvitegravir , chemistry , lithium diisopropylamide , yield (engineering) , combinatorial chemistry , trimethylsilyl , medicinal chemistry , organic chemistry , stereochemistry , deprotonation , human immunodeficiency virus (hiv) , ion , materials science , family medicine , antiretroviral therapy , metallurgy , viral load , medicine
An improved process for the active pharmaceutical ingredient of a new HIV integrase inhibitor elvitegravir ( 1 ) has been developed. It starts from commercially available 2,4‐dimethoxyacetophenone, which is selectively halogenated into the position 5. The 5‐halo acetophenones are condensed with dialkyl carbonates to give the corresponding benzoylacetates. Their treatment with N , N ‐dimethylformamide dimethyl acetal followed by ( S )‐valinol then provided the corresponding intermediate benzoyl acrylates. Cyclization to the required 1,4‐dihydroquinolin‐4‐oxo derivatives by aromatic nucleophilic substitution of the 2‐methoxy group was achieved by treatment with N , O ‐bis(trimethylsilyl)‐acetamide, which also protected the OH group as the trimethylsilyl derivative. Finally, the Negishi coupling with 2‐fluoro‐3‐chlorobenzylzinc bromide and the following hydrolysis provided elvitegravir ( 1 ). The preferred variant, the seven‐step procedure starting from 2,4‐dimethoxyacetophenone, provides elvitegravir in 29.3% yield.