1-Methylpiperazine → 9-Fluoro-2-(2-isopropyl-5-methyl-1,2,4-triazol-3-yl)-10-[1-(4-methylpiperazin-1-yl)ethyl]-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine

HRID 1530727Notes

Reaction equation

HRID 1530727 reaction equation
Br[CH:2]([C:4]1[C:5]([F:27])=[CH:6][C:7]2[O:16][CH2:15][CH2:14][N:13]3[C:9](=[N:10][C:11]([C:17]4[N:18]([CH:23]([CH3:25])[CH3:24])[N:19]=[C:20]([CH3:22])[N:21]=4)=[CH:12]3)[C:8]=2[CH:26]=1)[CH3:3].[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.CCN(C(C)C)C(C)C>O1CCOCC1>[F:27][C:5]1[C:4]([CH:2]([N:32]2[CH2:33][CH2:34][N:29]([CH3:28])[CH2:30][CH2:31]2)[CH3:3])=[CH:26][C:8]2[C:9]3[N:13]([CH:12]=[C:11]([C:17]4[N:18]([CH:23]([CH3:25])[CH3:24])[N:19]=[C:20]([CH3:22])[N:21]=4)[N:10]=3)[CH2:14][CH2:15][O:16][C:7]=2[CH:6]=1

Participants

5

Reactant 3

HCID 531671-MethylpiperazineHCID 81531DiisopropylethylamineHCID 683131309-(1-bromoethyl)-8-fluoro-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene

Product 1

HCID 683131259-Fluoro-2-(2-isopropyl-5-methyl-1,2,4-triazol-3-yl)-10-[1-(4-methylpiperazin-1-yl)ethyl]-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepineYield 63.3%

Reagents, catalysts & solvents 1

HCID 312751,4-DioxaneSolvent

Procedure

A solution of 9-(1-bromoethyl)-8-fluoro-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene from Example 374 (99 mg, 0.23 mmol), N-methylpiperazine (28 μL, 0.25 mmol) and DIPEA (60 μL, 0.35 mmol) in dioxane (1 mL) was stirred at RT for 72 h. The reaction mixture was concentrated in vacuo and the residue was purified by column chromatography (Si-PPC, gradient 0-8% 2 M NH3/MeOH in DCM) to give 66 mg of a pale yellow oil. The compound was further purified by reverse phase column chromatography (C18, gradient 2-50% MeOH in 1% TFA/H2O) and then loaded in MeOH onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the product eluted with 2 M NH3 in MeOH. The basic fraction was concentrated in vacuo to afford 373 (47 mg, 40% over 2 steps) as a white solid. LCMS (Method K): RT 2.70 min [M+H]+ 454.2. 1H NMR (CD3OD, 400 MHz): δ 8.54 (1H, d, J=8.6 Hz), 7.68 (1H, s), 6.76 (1H, d, J=11.0 Hz), 5.83 (1H, sept., J=6.7 Hz), 4.49 (4H, br s), 3.84 (1H, q, J=6.8 Hz), 2.47 (8H, br s), 2.33 (3H, s), 2.22 (3H, s), 1.53 (3H, d, J=6.7 Hz), 1.52 (3H, d, J=6.7 Hz), 1.40 (3H, d, J=6.8 Hz)

Workup

  1. concentrationThe reaction mixture was concentrated in vacuo
  2. customthe residue was purified by column chromatography (Si-PPC, gradient 0-8% 2 M NH3/MeOH in DCM)

Sources & evidence

ORD record
ord-24fadd5d87224038a85f25147b4d4acb
Source dataset
uspto-grants-2015_07
Patent number
US09090628B2

Reaction notes

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