p-Toluenesulfonic acid → 5,7-Difluoro-2-(6-(4-isopropylpiperazin-1-yl)pyridin-2-yl)quinazolin-4(3H)-one

HRID 922385Notes

Reaction equation

HRID 922385 reaction equation
[NH2:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([F:12])[C:3]=1[C:4]([NH2:6])=[O:5].COC1C=C(OC)C=C2C=1C(=O)N[C:19]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([N:33]3[CH2:38][CH2:37][N:36]([CH2:39][CH2:40]S(C)(=O)=O)[CH2:35][CH2:34]3)[N:28]=1)=N2.[C:46]1(C)C=CC(S(O)(=O)=O)=CC=1.OS([O-])=O.[Na+]>CC(N(C)C)=O>[F:12][C:7]1[CH:8]=[C:9]([F:11])[CH:10]=[C:2]2[C:3]=1[C:4](=[O:5])[NH:6][C:19]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([N:33]3[CH2:34][CH2:35][N:36]([CH:39]([CH3:40])[CH3:46])[CH2:37][CH2:38]3)[N:28]=1)=[N:1]2

Participants

6

Reactant 4

HCID 6101p-Toluenesulfonic acidHCID 23665763Sodium BisulfiteHCID 594419592-Amino-4,6-difluorobenzamideHCID 1362488345,7-dimethoxy-2-(6-(4-(2-(methylsulfonyl)ethyl)piperazin-1-yl)pyridin-2-yl)quinazolin-4(3H)-one

Product 1

HCID 1364081515,7-Difluoro-2-(6-(4-isopropylpiperazin-1-yl)pyridin-2-yl)quinazolin-4(3H)-oneYield 20.5%

Reagents, catalysts & solvents 1

HCID 31374DimethylacetamideSolvent

Conditions

Temperature
110 °C

Procedure

A mixture of 2-amino-4,6-difluorobenzamide (7, 330 mg, 1.70 mmol), 6-(4-isopropylpiperazin-1-yl)picolinaldehyde (8, Scheme 6, 330 mg, 1.42 mmol), p-toluenesulfonic acid (590 mg, 3.12 mmol), NaHSO3 (370 mg, 3.55 mmol) and DMA (15 mL) was heated for 24 h at 110° C. under nitrogen. The mixture was partitioned between water (25 mL) and CH2Cl2 (25 mL) and shaken vigorously. The layers were separated and the organic phase was dried over sodium sulfate and filtered. The solvent was removed under reduced pressure and the residue was purified by silica gel chromatography eluting with 0-5% MeOH in CH2Cl2 to provide the title compound (112 mg, 20%): 1H NMR (500 MHz, CDCl3) δ 10.59 (s, 1H), 7.85 (d, J=7.3 Hz, 1H), 7.67 (dd, J=7.3, 8.5 Hz, 1H), 7.30-7.26 (m, 1H), 6.93-6.89 (m, 1H), 6.86 (d, J=8.5 Hz, 1H), 3.69-3.60 (m, 4H), 2.82-2.73 (m, 1H), 2.71-2.66 (m, 4H), 1.12 (s, 3H), 1.11 (s, 3H).

Workup

  1. customThe mixture was partitioned between water (25 mL) and CH2Cl2 (25 mL)
  2. customThe layers were separated
  3. dry with materialthe organic phase was dried over sodium sulfate
  4. filtrationfiltered
  5. customThe solvent was removed under reduced pressure
  6. customthe residue was purified by silica gel chromatography
  7. washeluting with 0-5% MeOH in CH2Cl2

Sources & evidence

ORD record
ord-cf6bd48bf021461ea63679dea5cd3ba4
Source dataset
uspto-grants-2016_03
Patent number
US09278940B2

Reaction notes

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