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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.

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An efficient and scalable synthesis of the immunomodulating drug fingolimod hydrochloride has been developed with the aziridine regioselective ring-opening reaction as a key step. This manuscript describes design, detailed synthetic route scouting, and optimization study of the aziridine ring-opening reaction. As a starting material for the polar part of the fingolimod molecule, cheap, common, and widely commercially available tris­(hydroxymethyl)­aminomethane was used. n-Octyl group was introduced into the molecule either via Kumada or Negishi cross-couplings, or alternatively by Sonogashira cross-coupling followed by hydrogenation. The final step consists of a one-pot acidic deprotection both of the acetonide and Boc group, providing thus highly pure fingolimod hydrochloride from the crude reaction mixture directly. The described process is highly effective, is industrially applicable, and has been successfully applied to 500 g scales of the target product.