2-Hydroxyisobutyric acid → 2-hydroxy-1-(4-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)piperidin-1-yl)-2-methylpropan-1-one

HRID 1498292Notes

Reaction equation

HRID 1498292 reaction equation
FC(F)(F)C(O)=O.[CH:8]([N:11]1[C:15]([C:16]2[N:25]=[C:24]3[N:18]([CH2:19][CH2:20][O:21][C:22]4[CH:29]=[C:28]([CH:30]5[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]5)[CH:27]=[CH:26][C:23]=43)[CH:17]=2)=[N:14][CH:13]=[N:12]1)([CH3:10])[CH3:9].[OH:36][C:37]([CH3:42])([CH3:41])[C:38](O)=[O:39].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.C(=O)(O)[O-].[Na+]>>[OH:36][C:37]([CH3:42])([CH3:41])[C:38]([N:33]1[CH2:34][CH2:35][CH:30]([C:28]2[CH:27]=[CH:26][C:23]3[C:24]4[N:18]([CH:17]=[C:16]([C:15]5[N:11]([CH:8]([CH3:10])[CH3:9])[N:12]=[CH:13][N:14]=5)[N:25]=4)[CH2:19][CH2:20][O:21][C:22]=3[CH:29]=2)[CH2:31][CH2:32]1)=[O:39]

Participants

7

Reactant 6

HCID 116712-Hydroxyisobutyric acidHCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimideHCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 516892Sodium BicarbonateHCID 670507222-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-8-piperidin-4-yl-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene trifluoroacetic acid salt

Product 1

HCID 582044852-hydroxy-1-(4-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)piperidin-1-yl)-2-methylpropan-1-oneYield 43%

Procedure

A solution of 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-8-piperidin-4-yl-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene trifluoroacetic acid salt (350 mg, 0.71 mmol), 2-hydroxyisobutyric acid (111 mg, 1.07 mmol), EDCI (327 mg, 1.7 mmol, HOBt (230 mg, 1.7 mmol) and DIPEA (0.36 mL, 2.13 mmol) was stirred at RT for 5 h before the addition of saturated aqueous sodium bicarbonate. The resultant mixture was extracted with DCM (2×30 mL), the combined extracts washed with brine then dried (MgSO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0 to 5% MeOH in DCM) then freeze dried to give 227 as a white solid (141 mg, 43%). 1H NMR δ (ppm) (DMSO-d): 8.31 (1 H, d, J=8.29 Hz), 7.82 (1 H, s), 7.78 (1 H, s), 7.03 (1 H, d, J=8.38 Hz), 6.90 (1 H, s), 5.85-5.77 (1 H, m), 4.69 (2 H, d, J=13.25 Hz), 4.48 (4 H, t, J=7.99 Hz), 2.91-2.74 (4 H, m), 1.85 (2 H, d, J=13.04 Hz), 1.63-1.49 (2 H, m), 1.49 (6 H, d, J=6.64 Hz), 1.37 (6 H, s). LCMS: RT=3.92 min, M+H+=465

Workup

  1. extractionThe resultant mixture was extracted with DCM (2×30 mL)
  2. washthe combined extracts washed with brine
  3. dry with materialthen dried (MgSO4)
  4. filtrationfiltered
  5. concentrationconcentrated in vacuo
  6. customthen freeze dried

Sources & evidence

ORD record
ord-f8c07053ef6e4f748ed67da730dc08a8
Source dataset
uspto-grants-2015_12
Patent number
US09198918B2

Reaction notes

Loading…