Acetonitrile → (2S)-4,4-difluoro-1-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-9-yl)pyrrolidine-2-carboxamide

HRID 1498459Notes

Reaction equation

HRID 1498459 reaction equation
[CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21](O)[N:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].Cl.[F:25][C:26]1([F:34])[CH2:30][NH:29][C@H:28]([C:31]([NH2:33])=[O:32])[CH2:27]1.CCN(C(C)C)C(C)C.C(#N)C>O>[F:25][C:26]1([F:34])[CH2:30][N:29]([C:21]2[N:20]=[CH:19][C:16]3[C:17]4[N:11]([CH:10]=[C:9]([C:8]5[N:4]([CH:1]([CH3:2])[CH3:3])[N:5]=[CH:6][N:7]=5)[N:18]=4)[CH2:12][CH2:13][O:14][C:15]=3[CH:22]=2)[C@H:28]([C:31]([NH2:33])=[O:32])[CH2:27]1

Participants

6

Reactant 4

HCID 6342AcetonitrileHCID 81531DiisopropylethylamineHCID 451589094,4-Difluoro-L-prolinamide hydrochlorideHCID 1360309132-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-ol

Product 1

HCID 58204366(2S)-4,4-difluoro-1-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-9-yl)pyrrolidine-2-carboxamideYield 11%

Reagents, catalysts & solvents 1

HCID 962WaterSolvent

Procedure

Following the procedures of Example 339, 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-ol from Example 93 and 4,4-difluoro-L-prolinamide hydrochloride with added DIPEA (2.2 eq.) were reacted and the crude product subjected to RPHPLC (C18 column, gradient 5 to 95% acetonitrile in water+0.1% HCO2H) then recrystallisation from IMS to give 381 as a white solid (24 mg, 11%). LCMS: RT=3.21 min, [M+H]+=445. 1H NMR 400 MHz (DMSO-d6) δ: 9.11 (1 H, s), 7.90 (1 H, d, J=0.64 Hz), 7.87 (1 H, s), 7.53 (1 H, br), 7.14 (1 H, br), 6.08 (1 H, s), 5.99-5.91 (1 H, m), 4.61 (1 H, dd, J=9.53, 4.24 Hz), 4.58-4.49 (4 H, m), 4.00-3.98 (2 H, m), 2.91-2.90 (1 H, m), 2.45 (1 H, dd, J=13.51, 4.18 Hz), 1.49 (6 H, dd, J=6.59, 3.35 Hz)

Workup

  1. customwere reacted
  2. customrecrystallisation from IMS

Sources & evidence

ORD record
ord-9f89840a949442d28662b1c43b6a0014
Source dataset
uspto-grants-2015_12
Patent number
US09198918B2

Reaction notes

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