Cesium carbonate → 4-amino-8-((5-chloro-3-(2-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)pyrido[2,3-d]pyrimidin-5(8H)-one

HRID 2074513Notes

Reaction equation

HRID 2074513 reaction equation
[NH2:1][C:2]1[C:3]2[C:11](=[O:12])[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].[Cl:19][C:20]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:21]=1[C:22](=[O:40])[N:23]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[O:38][CH3:39])[C:24]([CH2:30]Cl)=[N:25]2>CN(C=O)C>[NH2:1][C:2]1[C:3]2[C:11](=[O:12])[CH:10]=[CH:9][N:8]([CH2:30][C:24]3[N:23]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=4[O:38][CH3:39])[C:22](=[O:40])[C:21]4[C:26](=[CH:27][CH:28]=[CH:29][C:20]=4[Cl:19])[N:25]=3)[C:4]=2[N:5]=[CH:6][N:7]=1

Participants

5

Reactant 3

HCID 10796Cesium carbonateHCID 57067884-aminopyrido[2,3-d]pyrimidin-5(8H)-oneHCID 223165905-Chloro-2-chloromethyl-3-(2-methoxyphenyl)-3H-quinazolin-4-one

Product 1

HCID 575561664-amino-8-((5-chloro-3-(2-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)pyrido[2,3-d]pyrimidin-5(8H)-oneYield 60.1%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
100 °C

Procedure

To a mixture of 4-aminopyrido[2,3-d]pyrimidin-5(8H)-one (0.1 g, 0.616 mmol), Cs2CO3 (0.3013 g, 0.925 mmol, 1.5 eq), and KI (0.0102 g, 0.0616 mmol, 0.1 eq) in DMF (2 mL) was added 5-chloro-2-(chloromethyl)-3-(2-methoxyphenyl)quinazolin-4(3H)-one (0.2273 g, 0.678 mmol, 1.1 eq) and the mixture was stirred at 100° C. for 1 h. The mixture was concentrated under reduced pressure. The crude product was purified by column chromatography on a 40 g of Redi-Sep™ column using 0 to 100% gradient of :MeOH:NH4OH (89:9:1) in CH2Cl2 over 14 min as eluent to provide 4-amino-8-((5-chloro-3-(2-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)pyrido[2,3-d]pyrimidin-5(8H)-one as yellow solid (0.1707 g, 60%). The yellow solid was triturated with MeOH and filtered to provide 4-amino-8-((5-chloro-3-(2-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)pyrido[2,3-d]pyrimidin-5(8H)-one [PI3Kδ IC50=13 nM] as yellow solid. 1H NMR (DMSO-d6) δ ppm 9.53 (1 H, d, J=4.7 Hz), 8.20 (1 H, s), 8.14 (1H, d, J=4.7 Hz), 7.88 (1 H, d, J=7.8 Hz), 7.65-7.72 (1 H, m), 7.49-7.59 (3 H, m), 7.37 (1 H, dd, J=8.2, 1.2 Hz), 7.31 (1 H, dd, J=8.6, 1.2 Hz), 7.15-7.21 (1 H, m), 6.20 (1 H, d, J=8.2 Hz), 4.91-5.13 (2 H, m), 3.85 (3 H, s). Mass Spectrum (ESI) m/e=461.0 (M+1).

Workup

  1. concentrationThe mixture was concentrated under reduced pressure
  2. customThe crude product was purified by column chromatography on a 40 g of Redi-Sep™ column
  3. customover 14 min

Sources & evidence

ORD record
ord-8d981c6c36914a089749ed0e09ff427d
Source dataset
uspto-grants-2011_04
Patent number
US07919498B2

Reaction notes

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