1,1,3,3-Tetramethylguanidine → Methyl 2-(4-(6-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)pyridin-2-yl)piperazin-1-yl)acetate

HRID 1519418Notes

Reaction equation

HRID 1519418 reaction equation
Cl.Cl.[N:3]1([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.CN(C)C(N(C)C)=N.F[C:23]1[N:28]=[C:27]([C:29]2[NH:38][C:37](=[O:39])[C:36]3[C:31](=[CH:32][C:33]([O:42][CH3:43])=[CH:34][C:35]=3[O:40][CH3:41])[N:30]=2)[CH:26]=[CH:25][CH:24]=1>CS(C)=O.C(OCC)(=O)C>[CH3:41][O:40][C:35]1[CH:34]=[C:33]([O:42][CH3:43])[CH:32]=[C:31]2[C:36]=1[C:37](=[O:39])[NH:38][C:29]([C:27]1[N:28]=[C:23]([N:6]3[CH2:7][CH2:8][N:3]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH2:4][CH2:5]3)[CH:24]=[CH:25][CH:26]=1)=[N:30]2

Participants

6

Reactant 3

HCID 664601,1,3,3-TetramethylguanidineHCID 53398818Methyl 2-(piperazin-1-yl)acetate dihydrochlorideHCID 1364081482-(6-fluoropyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one

Product 1

HCID 136248835Methyl 2-(4-(6-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)pyridin-2-yl)piperazin-1-yl)acetateYield 61.1%

Reagents, catalysts & solvents 2

HCID 679Dimethyl SulfoxideSolventHCID 8857Ethyl AcetateSolvent

Procedure

To a stirred suspension of methyl 2-(piperazin-1-yl)acetate dihydrochloride (0.67 g, 2.92 mmol) in dry DMSO (1.5 mL) was added 1,1,3,3-tetramethylguanidine (0.15 g, 1.07 mmol). The resulting mixture was stirred at rt for 10 min. Then 2-(6-fluoropyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.40 g, 1.33 mmol) was added as a solid. The reaction was heated at 90° C. for 4.5 h. After that time the reaction was cooled to rt and diluted with ethyl acetate (30 mL). The organic phase was washed with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The product was purified by flash column chromatography (silica gel, 98:2 dichloromethane/methanol) followed by trituration with diethyl ether to give methyl 2-(4-(6-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)pyridin-2-yl)piperazin-1-yl)acetate (0.357 g, 61%) as a light yellow solid: mp 176-177° C.; 1H NMR (400 MHz, CDCl3) δ 10.30 (br s, 1H), 7.86 (d, J=7.03 Hz, 1H), 7.63-7.71 (m, 1H), 6.80-6.86 (m, 2H), 6.48 (d, J=2.34 Hz, 1H), 3.99 (s, 3H), 3.94 (s, 3H), 3.77 (s, 3H), 3.67-3.73 (m, 4H), 3.34 (s, 2H), 2.73-2.79 (m, 4H); ESI MS m/z 440 [M+H]+.

Workup

  1. temperatureThe reaction was heated at 90° C. for 4.5 h
  2. temperatureAfter that time the reaction was cooled to rt
  3. washThe organic phase was washed with water and brine
  4. dry with materialdried over sodium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated under reduced pressure
  7. customThe product was purified by flash column chromatography (silica gel, 98:2 dichloromethane/methanol)

Sources & evidence

ORD record
ord-17d0d15147644b2dbeaa75c3fea881b4
Source dataset
uspto-grants-2015_07
Patent number
US09073878B2

Reaction notes

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