L-Hydroxyproline → HCID 66558671, compound

HRID 1530529Notes

Reaction equation

HRID 1530529 reaction equation
Br[C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[N:10]([CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1)[CH:9]=[C:8]([C:14]1[N:15]([CH:19]([CH3:21])[CH3:20])[N:16]=[CH:17][N:18]=1)[N:7]=3.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH2:32]1[C@@H:36]([C:37](O)=O)[NH:35][CH2:34][C@@H:33]1O>CS(C)=O.[Cu]I>[CH:19]([N:15]1[C:14]([C:8]2[N:7]=[C:6]3[C:5]4[CH:22]=[CH:23][C:2]([N:35]5[CH2:34][CH2:33][CH2:32][C@@H:36]5[CH2:37][N:35]5[CH2:36][CH2:32][CH2:33][CH2:34]5)=[CH:3][C:4]=4[O:13][CH2:12][CH2:11][N:10]3[CH:9]=2)=[N:18][CH:17]=[N:16]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]azulene2×

Product 1

HCID 66558671HCID 66558671, compoundYield 34%

Reagents, catalysts & solvents 2

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

Conditions

Temperature
100 °C

Procedure

A mixture of 8-bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene, also named as 9-bromo-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine 95 (200 mg, 0.27 mmol), (R)-pyrrolidynlmethylpyrrolidine (412 mg, 1.33 mmol), K3PO4 (228 mg, 0.53 mmol), CuI (20 mg, 0.05 mmol) and L-4-transhydroxyproline (14 mg, 0.11 mmol) in DMSO (1 mL) was heated at 100° C. for 18 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 purified by column chromatography (Si-PCC, gradient 0-10% MeOH in DCM then C18, gradient 5-45% MeOH in H2O). The resulting residue 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 freeze-dried from MeCN/H2O to afford 144 (41 mg, 34%) as a white solid. LCMS: RT 4.78 min [M+H]+ 448.4. 1H NMR (DMSO, 400 MHz): δ 8.19 (1H, d, J=8.92 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), 5.96-5.93 (1H, m), 4.47-4.36 (4H, m), 3.89-3.81 (1H, m), 3.40-3.38 (1H, m), 3.14-3.04 (1H, m), 2.64-2.57 (2H, m), 2.50-2.34 (4H, m), 1.98-1.96 (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. customThe resulting residue was purified by column chromatography (Si-PCC, gradient 0-10% MeOH in DCM
  4. washwas washed with MeOH
  5. washthe product eluted with 2M NH3/MeOH
  6. dry with materialThe resulting residue was freeze-dried from MeCN/H2O

Sources & evidence

ORD record
ord-fbc5df869f1c4047923c315e872bddbe
Source dataset
uspto-grants-2015_07
Patent number
US09090628B2

Reaction notes

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