ChemicalBook CAS DataBase List Darunavir ethanolate

Darunavir ethanolate synthesis

5synthesis methods

Product Name:Darunavir ethanolate
CAS Number:635728-49-3
Molecular formula:C29H43N3O8S
Molecular Weight:593.74

64-17-5

(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl 4-nitrophenyl carbonate

192725-55-6

4-AMINO-N-[(2R,3S)-3-AMINO-2-HYDROXY-4-PHENYLBUTYL]-N-ISOBUTYLBENZENE-1-SULFONAMIDE

169280-56-2

635728-49-3

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%.

tert-Butyl [(1S,2R)-1-benzyl-2-hydroxy-3-[isobutyl[(4-nitrophenyl)sulfonyl]amino]propyl]carbamate

191226-98-9
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635728-49-3
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Yield:-

Steps:

Multi-step reaction with 3 steps
1.1: hydrogen; triethanolamine / palladium 10% on activated carbon / methanol / 2 h / 40 - 45 °C
2.1: hydrogenchloride; water / 2 h / Reflux
3.1: 1-methyl-pyrrolidin-2-one / 10 h / -4 - 30 °C
3.2: 1 h / 45 - 50 °C

References:

US2012/251826,2012,A1