(3R,4R)-benzyl 3-(((2S,6R)-N-((R)-1-(1-benzyl-3-(2,5-difluorophenyl)-1H-1,2,4-triazol-5-yl)-2,2-dimethylpropyl)-2,6-dimethylmorpholine-4-carboxamido)methyl)-4-fluoropyrrolidine-1-carboxylate → (2S,6R)-N-((R)-1-(1-benzyl-3-(2,5-difluorophenyl)-1H-1,2,4-triazol-5-yl)-2,2-dimethylpropyl)-N-(((3S,4R)-4-fluoropyrrolidin-3-yl)methyl)-2,6-dimethylmorpholine-4-carboxamide

To a solution of (3R,4R)-benzyl 3-(((2S,6R)—N—((R)-1-(1-benzyl-3-(2,5-difluorophenyl)-1H-1,2,4-triazol-5-yl)-2,2-dimethylpropyl)-2,6-dimethylmorpholine-4-carboxamido)methyl)-4-fluoropyrrolidine-1-carboxylate (91 mg, 0.124 mmol) in degassed ethanol (12 mL, 0.1 M solution) was added Pd/C (2.64 mg, 10 wt %) under anhydrous N2 atmosphere. After flushed with hydrogen gas, the reaction mixture equipped with a hydrogen gas balloon was stirred at room temperature for 45 min. The reaction mixture was filtered through Celite® pad that was washed with EtOAc. The volatile organic filtrate was removed in vacuo to give the crude product, which was purified by preparative reverse phase HPLC. The combined fractions of the product were neutralized with saturated NaHCO3 solution, which was then extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The dried product was then dissolved in acetonitrile and water (1:1 ratio) and lyophilized for 48 h. The white powdery (2S,6R)—N—((R)-1-(1-benzyl-3-(2,5-difluorophenyl)-1H-1,2,4-triazol-5-yl)-2,2-dimethylpropyl)-N-(((3S,4R)-4-fluoropyrrolidin-3-yl)methyl)-2,6-dimethylmorpholine-4-carboxamide was obtained in 94% yield (70 mg) as a free amine 1H NMR (CD3Cl, 300 MHz): δ 7.83 (1H, m), 7.52 (2H, m), 7.34-7.27 (3H, m), 7.08 (1H, m), 7.04 (1H, m), 5.94 (2H, m), 5.41 (1H, s), 3.92-3.62 (3H, m), 3.60-3.45 (3H, m), 3.17-2.58 (3H, m), 2.57-2.37 (1H, m), 2.35-2.04 (2H, m), 1.85 (2H, m), 1.20 (6H, s), 0.9 (1H, m), 0.8 (9H, s). LC/MS (uplc): MH+ 599.5, 1.06 min.

1. customAfter flushed with hydrogen gas
2. customthe reaction mixture equipped with a hydrogen gas balloon
3. filtrationThe reaction mixture was filtered through Celite® pad that
4. washwas washed with EtOAc
5. customThe volatile organic filtrate was removed in vacuo
6. customto give the crude product, which
7. customwas purified by preparative reverse phase HPLC
8. extractionwas then extracted with EtOAc
9. dry with materialThe organic layer was dried over anhydrous sodium sulfate
10. filtrationfiltered
11. concentrationconcentrated in vacuo
12. dissolutionThe dried product was then dissolved in acetonitrile
13. waitwater (1:1 ratio) and lyophilized for 48 h

ORDレコード

ord-9822c80915944f7fb2f553f9b57f9c64

出典データセット

uspto-grants-2013_10

DOI

10.6084/m9.figshare.5104873.v1

特許番号

US08546434B2