Darunavir

Common name: Darunavir, UIC-94017, TMC-114

Trademarks: Prezista (Tibotec)

Molecular Formula: C₂₇H₃₇N₃O₇S

CAS Registry Number: 206361-99-1

CAS Name: N-[3-[N-(4-Aminophenylsulfonyl)-N-isobutylamino]-1(S)-benzyl-2(R)-hydroxypropyl]carbamic acid (3R,3aS,6aR)-perhydrofuro[2,3-b]furan-3-yl ester

Molecular Weight: 547.6693

Activity: AIDS Medicines, Anti-HIV Agents, ANTIINFECTIVE THERAPY, HIV Protease Inhibitors

Darunavir synthesis: WO1999067254A2

Synthesis of Darunvair can be divided into two parts.

Part 1: Synthesis of bis-tetrahydrofuranyl alcohol (Many routes are available in the literature, will report as much as possible)

Scheme 1 (Tetrahedron Lett 1995, 36(4), 505-508)

Scheme 2 (Org Proc Res Dev 2007, 11, 972-980)

Scheme 3 (Paterno-Buchi photochemical route; WO2003024974A2)

Part 2: Epoxide synthesis

Scheme 1 (Synthesis 2001, 15, 2203-2229)

Scheme 2 (J Med Chem 1993, 36(16), 2300-2310)

Finally, Darunavir

A diastereomer of Darunavir is synthesized starting with D-phenyl alanine: Indian J Chem (Sec B) 2012, 51B, 849-854 (also see US20060148865A1, for the intermediate and also for a new potential HIV inhibitor)

References:

1. Ghosh, A. K.; et. al. Potent HIV protease inhibitors incorporating high-affinity P2-ligands and (R)-(hydroxyethylamino)sulfonamide isostere. Bioorg Med Chem Lett 1998, 8, 687.
2. Ghosh, A. K.; et. al. Multi-drug resistant retroviral protease inhibitors and associated methods. WO1999067254A2
3. Ghosh, A. K.; et. al. Synthesis and optical resolution of high affinity P2-ligands for HIV-1 protease inhibitors Tetrahedron Lett 1995, 36(4), 505-508.
4. Yu, R. H.; et. al. Research and Development of an Efficient Synthesis of Hexahydrofuro[2,3-b]furan-3-ol Moiety-A Key Component of the HIV Protease Inhibitor Candidates. Org Proc Res Dev 2007, 11, 972-980.
5. Ghosh, A. K.; et. al. Syntheses of FDA Approved HIV Protease Inhibitors. Synthesis 2001, 15, 2203-2229.
6. Davis, R. D.; et. al. Process for preparing protease inhibitor intermediates. WO2003024974A2
7. Ghosh, A. K.; et. al. Potent HIV protease inhibitors: the development of tetrahydrofuranylglycines as novel P2-ligands and pyrazine amides as P3-ligands. J Med Chem 1993, 36(16), 2300-2310.

For more drugs and their synthesis: Synayurajan database