L-Hydroxyproline → HCID 66558505, compound

HRID 1530513Notes

Reaction equation

HRID 1530513 reaction equation
Br[C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[CH:16][N:15]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O[C@H:33]1[CH2:37][NH:36][C@H:35]([C:38](O)=O)[CH2:34]1>CS(C)=O.[Cu]I>[CH:19]([N:18]1[C:14]([C:12]2[N:13]=[C:6]3[C:5]4[CH:22]=[CH:23][C:2]([N:36]5[CH2:37][CH2:33][CH2:34][C@H:35]5[CH2:38][N:36]5[CH2:37][CH2:33][CH2:34][CH2:35]5)=[CH:3][C:4]=4[O:10][CH2:9][CH2:8][N:7]3[CH:11]=2)=[N:15][CH:16]=[N:17]1)([CH3:21])[CH3:20]

Participants

6

Reactant 3

HCID 5810L-HydroxyprolineHCID 62657Potassium Phosphate, TribasicHCID 582043138-bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene

Product 1

HCID 66558505HCID 66558505, compoundYield 89.4%

Reagents, catalysts & solvents 2

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 679Dimethyl SulfoxideSolvent

Conditions

Temperature
90 °C

Procedure

A mixture of 9-bromo-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine 95 from Example 95 (100 mg, 0.27 mmol), (S)-pyrrolidinylmethylpyrrolidine (206 mg, 1.34 mmol), K3PO4 (114 mg, 0.53 mmol), trans-4-hydroxyproline (14 mg, 0.11 mmol) and CuI (10 mg, 0.05 mmol) in DMSO (0.5 mL) was heated at 90° C. for 23 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH. The resulting residue was dissolved in DCM and washed with 10% citric acid, dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient 0-6% MeOH in DCM) then Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH. The resulting residue was freeze-dried from MeCN/H2O to afford 133 (22 mg, 19%) as a white solid. LCMS: RT 2.81 min [M+H]+ 448.4. 1H NMR (DMSO, 400 MHz): δ 8.19 (1H, d, J=8.93 Hz), 7.88 (1H, d, J=0.63 Hz), 7.77 (1H, s), 6.45 (1H, dd, J=9.00, 2.43 Hz), 6.13 (1H, d, J=2.38 Hz), 5.93-5.92 (1H, m), 4.48-4.36 (4H, m), 3.89-3.81 (1H, m), 3.42-3.35 (1H, m), 3.15-3.05 (1H, m), 2.64-2.57 (2H, m), 2.43-2.40 (4H, m), 2.00-1.98 (4H, m), 1.74-1.66 (4H, m), 1.47 (6H, d, J=6.61 Hz)

Workup

  1. washwas washed with MeOH
  2. washthe product eluted with 2M NH3/MeOH
  3. dissolutionThe resulting residue was dissolved in DCM
  4. washwashed with 10% citric acid
  5. dry with materialdried (Na2SO4)
  6. concentrationconcentrated in vacuo
  7. customThe resulting residue was purified by column chromatography (Si-PCC, gradient 0-6% MeOH in DCM)
  8. washIsolute® SCX-2 cartridge which was washed with MeOH
  9. washthe product eluted with 2M NH3/MeOH
  10. dry with materialThe resulting residue was freeze-dried from MeCN/H2O

Sources & evidence

ORD record
ord-de32830fdc52490ab67fb4532ebe247e
Source dataset
uspto-grants-2015_07
Patent number
US09090628B2

Reaction notes

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