Water → HCID 53465112, compound

HRID 404842Notes

Reaction equation

HRID 404842 reaction equation
[CH2:1]([C:8]1[S:12][C:11]([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[F:20])=[N:10][C:9]=1[C@H:21]([N:26]([CH2:32][C@H:33]1[C@@H:37]([F:38])[CH2:36][N:35](C(OCC2C=CC=CC=2)=O)[CH2:34]1)[C:27](=[O:31])[C@@H:28]([OH:30])[CH3:29])[C:22]([CH3:25])([CH3:24])[CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O>C(O)C.C(#N)C.[Pd]>[CH2:1]([C:8]1[S:12][C:11]([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[F:20])=[N:10][C:9]=1[C@H:21]([N:26]([CH2:32][C@H:33]1[C@@H:37]([F:38])[CH2:36][NH:35][CH2:34]1)[C:27](=[O:31])[C@@H:28]([OH:30])[CH3:29])[C:22]([CH3:25])([CH3:23])[CH3:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1

Participants

6

Reactant 2

HCID 962WaterHCID 89771883HCID 89771883, compound

Product 1

HCID 53465112HCID 53465112, compoundYield 75%

Reagents, catalysts & solvents 3

HCID 23938PalladiumCatalystHCID 702EthanolSolventHCID 6342AcetonitrileSolvent

Procedure

To a solution of (3R,4R)-benzyl 3-(((S)-N-((R)-1-(5-benzyl-2-(2,5-difluorophenyl)thiazol-4-yl)-2,2-dimethylpropyl)-2-hydroxypropanamido)methyl)-4-fluoropyrrolidine-1-carboxylate (108 mg, 0.159 mmol) in degassed ethanol (3 mL, 0.05 M solution) was added Pd/C (17.2 mg) under anhydrous N2 atmosphere. After flushed with hydrogen gas, the reaction mixture equipped with a hydrogen gas balloon was stirred at room temperature for 30 min. The reaction mixture was filtered through Celite® pad that was washed with methanol and EtOAc. The volatile organic filtrate was removed in vacuo to give the crude amine, 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 product obtained was then dissolved in acetonitrile and water (1:1 ratio) and lyophilized for 48 h. The white powdery (S)-N-((R)-1-(5-benzyl-2-(2,5-difluorophenyl)thiazol-4-yl)-2,2-dimethylpropyl)-N-(((3S,4R)-4-fluoropyrrolidin-3-yl)methyl)-2-hydroxypropanamide was obtained in 75% yield (66 mg, over 2 steps) as the free amine. 1H NMR (CD3Cl, 400 MHz): δ 7.87 (1H, m), 7.33-7.27 (4H, m), 7.22-7.14 (2H, m), 7.08 (1H, m), 6.08 (1H, s), 4.71-4.62 (1H, m), 4.60-4.40 (1H, m), 4.23 (2H, s), 3.95 (1H, m), 3.63 (2H, m), 3.01-2.86 (1H, m), 2.70-2.46 (2H, m), 2.14-2.06 (2H, m), 1.45 (3H, m), 1.03 (9H, s). LC/MS (uplc): MH+ 546.4, 1.00 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 methanol and EtOAc
  5. customThe volatile organic filtrate was removed in vacuo
  6. customto give the crude amine, 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. customThe product obtained

Sources & evidence

ORD record
ord-14b802562e974c3899dfb6abed16678b
Source dataset
uspto-grants-2014_06
Patent number
US08748626B2

Reaction notes

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