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

HRID 1519422Notes

Reaction equation

HRID 1519422 reaction equation
Cl.Cl.[N:3]1([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.F[C:16]1[N:21]=[C:20]([C:22]2[NH:31][C:30](=[O:32])[C:29]3[C:24](=[CH:25][C:26]([O:35][CH3:36])=[CH:27][C:28]=3[O:33][CH3:34])[N:23]=2)[CH:19]=[CH:18][CH:17]=1.CN(C)C(N(C)C)=N>CS(C)=O.O>[CH3:34][O:33][C:28]1[CH:27]=[C:26]([O:35][CH3:36])[CH:25]=[C:24]2[C:29]=1[C:30](=[O:32])[NH:31][C:22]([C:20]1[N:21]=[C:16]([N:6]3[CH2:7][CH2:8][N:3]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH2:4][CH2:5]3)[CH:17]=[CH:18][CH:19]=1)=[N:23]2

Participants

6

Reactant 3

HCID 664601,1,3,3-TetramethylguanidineHCID 45792123Methyl 3-(piperazin-1-yl)propanoate dihydrochlorideHCID 1364081482-(6-fluoropyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one

Product 1

HCID 136408150Methyl 3-(4-(6-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)pyridin-2-yl)piperazin-1-yl)propanoateYield 66.5%

Reagents, catalysts & solvents 2

HCID 679Dimethyl SulfoxideSolventHCID 962WaterSolvent

Conditions

Temperature
85 °C

Procedure

To a stirred suspension of methyl 3-(piperazin-1-yl)propanoate dihydrochloride (0.358 g, 1.46 mmol) and 2-(6-fluoropyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.220 g, 0.73 mmol) in dry DMSO (1.5 mL) was added 1,1,3,3-tetramethylguanidine (0.336 g, 2.92 mmol). The resulting mixture was heated at 85° C. for 5 h. After that time the reaction was cooled to rt, diluted with water (20 mL) and extracted with ethyl acetate (3×25 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, 99:1 dichloromethane/methanol to 97:3 dichloromethane/methanol) to give methyl 3-(4-(6-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)pyridin-2-yl)piperazin-1-yl)propanoate (0.220 g, 66%) as an off-white solid: 1H NMR (400 MHz, CDCl3) δ 10.31 (s, 1H), 7.85 (d, J=7.42 Hz, 1H), 7.62-7.70 (m, 1H), 6.79-6.85 (m, 2H), 6.48 (d, J=2.34 Hz, 1H), 3.99 (s, 3H), 3.94 (s, 3H), 3.72 (s, 3H), 3.59-3.67 (m, 4H), 2.75-2.83 (m, 2H), 2.54-2.66 (m, 6H); ESI MS m/z 454 [M+H]+.

Workup

  1. temperatureAfter that time the reaction was cooled to rt
  2. extractionextracted with ethyl acetate (3×25 mL)
  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, 99:1 dichloromethane/methanol to 97:3 dichloromethane/methanol)

Sources & evidence

ORD record
ord-1f925e844d8d48bf85d1357e7cac6f80
Source dataset
uspto-grants-2015_07
Patent number
US09073878B2

Reaction notes

Loading…