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

HRID 1056395Notes

Reaction equation

HRID 1056395 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([NH2:22])[CH2:21][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:22][C:18]1([CH3:17])[CH2:21][CH2:20][CH2:19]1)[N:8]([CH3:13])[C:7]2=[O:14]

Participants

6

Reactant 3

HCID 81531DiisopropylethylamineHCID 183324491-Methylcyclobutan-1-amine hydrochlorideHCID 897818838-Bromo-2-chloro-7-fluoro-3-methyl-quinazolin-4-one

Product 1

HCID 897820938-bromo-7-fluoro-3-methyl-2-((1-methylcyclobutyl)amino)-quinazolin-4(3H)-oneYield 43%

Reagents, catalysts & solvents 2

HCID 679Dimethyl SulfoxideSolventHCID 8857Ethyl AcetateSolvent

Procedure

A solution of 8-bromo-2-chloro-7-fluoro-3-methylquinazolin-4(3H)-one (720, 239 mg, 0.820 mmol), 1-methylcyclobutanamine hydrochloride (Oakwood Products, Inc., West Columbia, S.C., 199 mg, 1.640 mmol), and N-ethyl-N-isopropylpropan-2-amine (314 μL, 1.804 mmol) in DMSO (8.2 mL) was stirred at 80° C. for 1 h. The reaction mixture was diluted with EtOAc (100 mL), added to a separatory funnel, and washed with saturated aqueous NaHCO3 (3×100 mL); the organic layer was separated, dried over Na2SO4, and concentrated. The crude product was loaded onto the column and was purified via automated flash chromatography (silica gel) with 0-40% EtOAc in hexanes to give 8-bromo-7-fluoro-3-methyl-2-((1-methylcyclobutyl)amino)quinazolin-4(3H)-one (502a, 0.120 g, 0.353 mmol, 43% yield) as a brown amorphous solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.74 (s, 3H) 1.89-2.00 (m, 2H) 2.26-2.36 (m, 2H) 2.38-2.49 (m, 2H) 3.46 (s, 3H) 4.72 (br. s., 1H) 6.90 (t, J=8.51 Hz, 1H) 8.06 (dd, J=8.80, 6.06 Hz, 1H). 19F NMR (377 MHz, CDCl3) δ ppm −96.60 (s, 1F). MS (ESI, pos. ion) m/z: 340.0/341.9 (M+1).

Workup

  1. additionadded to a separatory funnel
  2. washwashed with saturated aqueous NaHCO3 (3×100 mL)
  3. customthe organic layer was separated
  4. dry with materialdried over Na2SO4
  5. concentrationconcentrated
  6. customwas purified

Sources & evidence

ORD record
ord-9491a701601f4b6eb501c1e3d8fd4639
Source dataset
uspto-grants-2016_07
Patent number
US09394297B2

Reaction notes

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