HCID 86658515, compound → HCID 53482759, compound

HRID 1037494Notes

Reaction equation

HRID 1037494 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[N:13]=[C:12]([C@H:14]([N:19]([CH2:27][C@H:28]2[C@@H:32]([F:33])[CH2:31][N:30](C(OCC3C=CC=CC=3)=O)[CH2:29]2)[C:20]([C@@H:22]2[CH2:26][CH2:25][CH2:24][O:23]2)=[O:21])[C:15]([CH3:18])([CH3:17])[CH3:16])[N:11]([CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[C:47]([F:51])[CH:46]=2)[N:10]=1>CCOC(C)=O.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[N:13]=[C:12]([C@H:14]([N:19]([CH2:27][C@H:28]2[C@@H:32]([F:33])[CH2:31][NH:30][CH2:29]2)[C:20]([C@@H:22]2[CH2:26][CH2:25][CH2:24][O:23]2)=[O:21])[C:15]([CH3:16])([CH3:18])[CH3:17])[N:11]([CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[C:47]([F:51])[CH:46]=2)[N:10]=1

Participants

4

Reactant 1

HCID 86658515HCID 86658515, compound

Product 1

HCID 53482759HCID 53482759, compoundYield 10.4%

Reagents, catalysts & solvents 2

HCID 23938PalladiumCatalystHCID 8857Ethyl AcetateSolvent

Procedure

To a solution of (3R,4R)-benzyl 3-(((S)—N—((R)-1-(3-(2,5-difluorophenyl)-1-(3-fluorobenzyl)-1H-1,2,4-triazol-5-yl)-2,2-dimethylpropyl)tetrahydrofuran-2-carboxamido)methyl)-4-fluoropyrrolidine-1-carboxylate (580 mg, 0.82 mmol) in degassed EtOAc (80 mL, 0.1 M solution) was added Pd/C (873 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 overnight. 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 (S)—N—((R)-1-(3-(2,5-difluorophenyl)-1-(3-fluorobenzyl)-1H-1,2,4-triazol-5-yl)-2,2-dimethylpropyl)-N-(((3S,4R)-4-fluoropyrrolidin-3-yl)methyl)tetrahydrofuran-2-carboxamide was obtained in 10.4% yield (48.9 mg) as a free amine. 1H NMR (CD3Cl, 400 MHz): 7.82 (1H, m), 7.34-7.25 (3H, m), 7.22 (1H, m), 7.15 (1H, m), 7.07 (1H, m), 6.98 (1H, m), 6.10 (1H, s), 5.44 (2H, m), 4.86 (2H, m), 4.19 (1H, m), 3.96 (1H, m), 3.86 (2H, m), 3.05 (1H, m), 3.05 (1H, m), 2.37-1.70 (2H, m), 1.35-1.02 (5H, m), 0.99 (9H, s). LC/MS (uplc): MH+ 574.4, 0.98 min.

Workup

  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

Sources & evidence

ORD record
ord-5122d4b0e4ec4a24af123ec24d6007e9
Source dataset
uspto-grants-2013_10
Patent number
US08546434B2

Reaction notes

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