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

HRID 1519438Notes

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

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

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

Sources & evidence

ORD record: ord-144c9b06f24e4f39a99259d5446f8d46
Source dataset: uspto-grants-2015_07
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US09073878B2

Reaction notes

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