Darunavir ethanolate

Uses

Darunavir Ethanolate (Prezista) is an HIV protease inhibitor. Derivative of Darunavir (D193500), a second generation HIV-1-protease inhibitor; structurally similar to amprenavir. Antiviral. It is a COVID19-related research product.

Uses

Darunavir Ethanolate(Prezista) is an inhibitor of HIV protease. [1] Darunavir was designed to form robust interactions with the protease enzyme from many strains of HIV, including strains from treatment-experienced patients with multiple resistance mutati

Biological Activity

darunavir ethanolate is a nonpeptidic hiv protease inhibitor approved for the treatment of hiv infection[1].transepithelial transport of darunavir in caco-2 cell monolayers is 2-fold greater in the basal-to-apical direction compared to that in the opposite direction. in l-mdr1 cell, darunavir (121 mm) inhibits p-glycoprotein-mediated efflux of calcein-acetoxymethyl ester[1].darunavir is effective against wild-type and pi-resistant hiv, and has a low oral bioavailability (37%). when used in combination with ritonavir, bioavailability can be increased to 82%[2].[1]. fujimoto h, higuchi m, watanabe h, et al. p-glycoprotein mediates efflux transport of darunavir in human intestinal caco-2 and abcb1 gene-transfected renal llc-pk1 cell lines. biological & pharmaceutical bulletin, 2009, 32(9): 1588-1593.[2]. bhalekar mr, et al. in-vivo bioavailability and lymphatic uptake evaluation of lipid nanoparticulates of darunavir. drug deliv, 2016, 23(7): 2581-2586.

Synthesis

GENERAL STEPS: A solution of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl (4-nitrophenyl) carbonate (75.4 g) was prepared by dissolving it in N-methyl-2-pyrrolidone (300 mL). This solution was slowly added to a pre-cooled solution of 4-amino-N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-N-isobutylbenzenesulfonamide (100 g) in N-methyl-2-pyrrolidinone (200 mL) at -4 to 0 °C, maintaining the temperature at 2±2 °C for 2 hours. Subsequently, the temperature of the reaction mixture was slowly increased to 25-30 °C and kept at this temperature for 8 hours. The reaction process was monitored by TLC. Upon completion of the reaction, ethyl acetate (1000 mL) and purified water (500 mL) were added to the reaction mixture and layered. The organic layer was washed sequentially with sodium carbonate solution (2 x 500 mL) and sodium chloride solution. After concentrating the organic layer, ethanol (300 mL) was added and heated to 45-50 °C and kept for 1 h. Then it was filtered and washed with ethanol. The wet compound was added to a mixture of ethyl acetate-ethanol (7:93, 600mL), heated to reflux, activated carbon added and filtered. The filtrate was cooled to 0-5 °C, the separated solid was filtered and washed with ethanol. Finally, the wet compound was dried at 45 °C to give 124.3 g of the target product, i.e., the ethanol salt of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl ((2S,3R)-4-(4-amino-N-isobutylbenzenesulfonamido)-3-hydroxy-1-phenylbutan-2-yl)carbamate, which had an HPLC area purity of 99.79%. The area of difuranyl impurity determined by HPLC was 0.08%, and the yield was 82.5%.

in vivo

IC 50

HIV-1

References

[1] Patent: US2012/251826, 2012, A1. Location in patent: Page/Page column 10