Thionyl Chloride → 2-(2-adamantyl)-N-(2-isopropyl-4-oxoquinazolin-3(4H)-yl)acetamide

HRID 1853395Notes

Reaction equation

HRID 1853395 reaction equation
S(Cl)(Cl)=O.[CH:5]12[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][CH:7]([CH2:8]3)[CH:6]1[CH2:15][C:16](O)=[O:17])[CH2:12]2.[NH2:19][N:20]1[C:29](=[O:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]=[C:21]1[CH:31]([CH3:33])[CH3:32].C(N(C(C)C)CC)(C)C>>[CH:5]12[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][CH:7]([CH2:8]3)[CH:6]1[CH2:15][C:16]([NH:19][N:20]1[C:29](=[O:30])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]=[C:21]1[CH:31]([CH3:33])[CH3:32])=[O:17])[CH2:12]2

Participants

5

Reactant 4

HCID 24386Thionyl ChlorideHCID 81531DiisopropylethylamineHCID 8709902-(Adamantan-2-yl)acetic acidHCID 51882113-Amino-2-isopropyl-4(3H)-quinazolinone

Product 1

HCID 498723312-(2-adamantyl)-N-(2-isopropyl-4-oxoquinazolin-3(4H)-yl)acetamideYield 22%

Conditions

Temperature
80 °C

Procedure

Thionyl chloride (1.72 mL, 23.5 mmol) was added to adamant-2-yl acetic acid (241 mg, 1.24 mmol, prepared as described in J. Med. Chem, (2007), 50(1), 149-164) in a 25 mL round-bottom flask with stir bar. The resulting solution was heated at 80° C. for 1 hour, and then concentrated under vacuum. The residue was taken up in CH2Cl2 (3 mL) and concentrated under vacuum. This process was repeated twice more to ensure removal of excess thionyl chloride. The residue was taken up in fresh CH2Cl2 (2 mL) and 3-amino-2-isopropyl-4(3H)-quinazolinone (252 mg, 1.24 mmol) was added. The mixture was stirred at 20-25° C. After 18 hours, diisopropylethylamine (0.40 mL) was added and the solution was stirred for 1 hour longer, and then concentrated under vacuum. The residue was purified by flash chromatography (silica gel, eluted with hexanes-EtOAc, 90:10-70:30). Unreacted quinazolinone (80 mg, 31% recovered) eluted first, followed closely by a second fraction from which crystals precipitated on standing at room temperature for 1 hour. The crystals were collected by filtration and dried at 50° C. under vacuum to provide the title compound (102 mg, 22% yield). 1H NMR (300 MHz, CDCl3) δ ppm 1.32 (2 d, J=6.7 Hz, 6H), 1.58-1.96 (m, 14H), 2.41 (br. t, J=7.3 Hz, 1H), 2.64 (d, J=7.5 Hz, 2H), 3.16 (hept, J=6.7 Hz, 1H), 7.43 (td, J=7.3, 1.2 Hz, 1H), 7.68 (s, 1H), 7.69 (d, J=8.7 Hz, 1H), 7.75 (t, J=7.5 Hz, 1H), 8.21 ppm (d, J=7.5 Hz, 1H); MS (DCI) m/z 380 (M+H)+; Elemental Analysis calculated for C23H29N3O2.0.3H2O: C, 71.77; H, 7.75; N, 10.92. Found: C, 71.70; H, 7.68; N, 10.76.

Workup

  1. concentrationconcentrated under vacuum
  2. concentrationconcentrated under vacuum
  3. customremoval of excess thionyl chloride
  4. stirringThe mixture was stirred at 20-25° C
  5. stirringthe solution was stirred for 1 hour longer
  6. concentrationconcentrated under vacuum
  7. customThe residue was purified by flash chromatography (silica gel, eluted with hexanes-EtOAc, 90:10-70:30)
  8. washUnreacted quinazolinone (80 mg, 31% recovered) eluted first
  9. customprecipitated
  10. waiton standing at room temperature for 1 hour
  11. filtrationThe crystals were collected by filtration
  12. customdried at 50° C. under vacuum

Sources & evidence

ORD record
ord-64c4a1600ee44b8a9870330d681c9826
Source dataset
uspto-grants-2015_02
Patent number
US08962639B2

Reaction notes

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