Diisopropylethylamine → 8-bromo-7-fluoro-3-methyl-2-((1-methylcyclopropyl)amino)quinazolin-4(3H)-one

HRID 1056420Notes

Reaction equation

HRID 1056420 reaction equation
[Br:1][C:2]1[C:3]([F:15])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9](Cl)[N:8]([CH3:13])[C:7]2=[O:14].Cl.[CH3:17][C:18]1([NH2:21])[CH2:20][CH2:19]1.C(N(C(C)C)C(C)C)C>CS(C)=O.CCOC(C)=O>[Br:1][C:2]1[C:3]([F:15])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:21][C:18]1([CH3:17])[CH2:20][CH2:19]1)[N:8]([CH3:13])[C:7]2=[O:14]

Participants

6

Reactant 3

HCID 81531DiisopropylethylamineHCID 12953687(1-Methylcyclopropyl)amine hydrochlorideHCID 897818838-Bromo-2-chloro-7-fluoro-3-methyl-quinazolin-4-one

Product 1

HCID 897822548-bromo-7-fluoro-3-methyl-2-((1-methylcyclopropyl)amino)quinazolin-4(3H)-oneYield 43.8%

Reagents, catalysts & solvents 2

HCID 679Dimethyl SulfoxideSolventHCID 8857Ethyl AcetateSolvent

Procedure

A brown solution of 8-bromo-2-chloro-7-fluoro-3-methylquinazolin-4(3H)-one (720, 180 mg, 0.617 mmol), 1-methylcyclopropanamine hydrochloride (Small Molecules, Inc., 133 mg, 1.235 mmol), and N-ethyl-N-isopropylpropan-2-amine (237 μL, 1.358 mmol) in DMSO (6.2 mL) was stirred at 80° C. for 1 h when product was observed via LCMS. The reaction mixture was diluted with EtOAc (100 mL), added to a separatory funnel, and washed with saturated aqueous NaHCO3 (2×75 mL); the organic layer was separated, dried over Na2SO4, and concentrated. The crude product was adsorbed onto silica and was purified via automated flash chromatography (silica gel) with 0-100% EtOAc in hexanes to give 8-bromo-7-fluoro-3-methyl-2-((1-methylcyclopropyl)amino)quinazolin-4(3H)-one (510a, 88 mg, 0.270 mmol, 43% yield) as a brown oil. 1H NMR (400 MHz, CDCl3) δ ppm 0.80-0.87 (m, 2H) 0.87-0.93 (m, 2H) 1.61 (s, 3H) 3.42 (s, 3H) 5.12 (br. s., 1H) 6.92 (t, J=8.51 Hz, 1H) 8.06 (dd, J=8.80, 6.06 Hz, 1H). 19F NMR (376 MHz, CDCl3) δ ppm −96.48 (s, 1F). MS (ESI, pos. ion) m/z: 326.0/328.0 (M+1).

Workup

  1. additionadded to a separatory funnel
  2. washwashed with saturated aqueous NaHCO3 (2×75 mL)
  3. customthe organic layer was separated
  4. dry with materialdried over Na2SO4
  5. concentrationconcentrated
  6. customwas purified

Sources & evidence

ORD record
ord-9aa93d69ec6348e0954989555aab9304
Source dataset
uspto-grants-2016_07
Patent number
US09394297B2

Reaction notes

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