Diisopropylethylamine → 3-bromo-N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-5-[ethyl(oxan-4-yl)amino]-2-fluoro-6-methylbenzamide

HRID 1530298Notes

Reaction equation

HRID 1530298 reaction equation
[Br:1][C:2]1[C:3]([F:21])=[C:4]([C:8]([CH3:20])=[C:9]([N:11]([CH2:18][CH3:19])[CH:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:10]=1)[C:5]([OH:7])=O.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[NH2:64][CH2:65][C:66]1[C:67](=[O:74])[NH:68][C:69]([CH3:73])=[CH:70][C:71]=1[CH3:72]>CN(C)C=O.CCOC(C)=O>[Br:1][C:2]1[C:3]([F:21])=[C:4]([C:8]([CH3:20])=[C:9]([N:11]([CH2:18][CH3:19])[CH:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:10]=1)[C:5]([NH:64][CH2:65][C:66]1[C:67](=[O:74])[NH:68][C:69]([CH3:73])=[CH:70][C:71]=1[CH3:72])=[O:7]

Participants

7

Reactant 4

HCID 81531DiisopropylethylamineHCID 2724699PyBOPHCID 70638443-(Aminomethyl)-4,6-dimethyl-1,2-dihydropyridin-2-oneHCID 866726643-Bromo-5-[ethyl(oxan-4-yl)amino]-2-fluoro-6-methylbenzoic acid

Product 1

HCID 866726653-bromo-N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-5-[ethyl(oxan-4-yl)amino]-2-fluoro-6-methylbenzamideYield 41%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Procedure

To a solution of 3-bromo-5-[ethyl(oxan-4-yl)amino]-2-fluoro-6-methylbenzoic acid (200 mg, 0.56 mmol) in N,N-Dimethylformamide (2 ml) at room temperature and under nitrogen was added PyBOP (346.72 mg, 0.67 mmol) followed by N-ethyl-N-(propan-2-yl)propan-2-amine (145 μl, 0.83 mmol) and 3-(aminomethyl)-4,6-dimethyl-1,2-dihydropyridin-2-one (89%, 104 mg, 0.61 mmol). After stirring for 1 hour at room temperature no starting material was observed by LCMS. EtOAc (20 ml) was added to the reaction mixture and this was then washed with deionized water (5 ml) followed by saturated NaHCO3 (aq) (3×5 ml). The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was then purified by FCC (5 g silica, Isolute cartridge, gradient of eluents; 100% DCM to 97:3 DCM:MeOH) to give 112 mg (41%) of 3-bromo-N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-5-[ethyl(oxan-4-yl)amino]-2-fluoro-6-methylbenzamide as a pale yellow solid. LC-MS 97%, 1.85 min (3 minute LC-MS method), m/z=494.0/496.0, 1H NMR (500 MHz, Chloroform-d) δ ppm 11.66 (s, 1H), 7.23 (d, J=6.5 Hz, 1H), 5.95 (s, 1H), 4.65-4.43 (m, 2H), 3.93 (d, J=11.0 Hz, 2H), 3.38-3.22 (m, 2H), 2.97 (q, J=7.0 Hz, 2H), 2.91-2.79 (m, 1H), 2.37 (s, 3H), 2.24-2.11 (m, 6H), 1.72-1.53 (m, 4H), 0.83 (t, J=7.0 Hz, 3H).

Workup

  1. washthis was then washed with deionized water (5 ml)
  2. dry with materialThe organic phase was dried over MgSO4
  3. filtrationfiltered
  4. concentrationconcentrated under reduced pressure
  5. customThe residue was then purified by FCC (5 g silica, Isolute cartridge, gradient of eluents; 100% DCM to 97:3 DCM:MeOH)

Sources & evidence

ORD record
ord-5db0cfa3f72e4e40bc87206ab834ea3d
Source dataset
uspto-grants-2015_07
Patent number
US09090562B2

Reaction notes

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