Acetoxyacetyl chloride → HCID 11213353, compound

HRID 857952Notes

Reaction equation

HRID 857952 reaction equation
C(O)C.Cl.Cl.[Cl:6][C:7]1[C:8]([F:33])=[C:9]([CH:30]=[CH:31][CH:32]=1)[NH:10][C:11]1[C:20]2[C:15](=[CH:16][C:17]([O:28][CH3:29])=[C:18]([O:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[CH:19]=2)[N:14]=[CH:13][N:12]=1.C([O:37][CH2:38][C:39](Cl)=[O:40])(=O)C>CN(C)C1C=CN=CC=1.C(#N)C>[Cl:6][C:7]1[C:8]([F:33])=[C:9]([CH:30]=[CH:31][CH:32]=1)[NH:10][C:11]1[C:20]2[C:15](=[CH:16][C:17]([O:28][CH3:29])=[C:18]([O:21][CH:22]3[CH2:27][CH2:26][N:25]([C:38](=[O:37])[CH2:39][OH:40])[CH2:24][CH2:23]3)[CH:19]=2)[N:14]=[CH:13][N:12]=1

Participants

5

Reactant 2

HCID 26297Acetoxyacetyl chlorideHCID 694369224-(3-Chloro-2-fluoroanilino)-7-methoxy-6-(piperidin-4-yloxy)-quinazoline dihydrochloride ethanol

Product 1

HCID 11213353HCID 11213353, compoundYield 83.9%

Reagents, catalysts & solvents 2

HCID 142844-(Dimethylamino)pyridineCatalystHCID 6342AcetonitrileSolvent2×

Procedure

4-(3-Chloro-2-fluoroanilino)-7-methoxy-6-(piperidin-4-yloxy)-quinazoline dihydrochloride ethanol solvate (91.8 g), 4-(dimethylamino)pyridine (73.3 g) and acetonitrile (330 ml) were stirred at 20° C. to 25° C., under nitrogen. Acetoxyacetyl chloride (28 ml) was added maintaining the temperature at less than 30° C., followed by an acetonitrile line wash (37 ml). The reaction mixture was stirred at ambient for 60 minutes before water (250 ml) and 47% w/w sodium hydroxide solution (77.2 ml) were added followed by a water line wash (25 ml), keeping the temperature at less than 30° C. The reaction mixture was stirred at ambient for 120 minutes before the lower aqueous layer was separated. Water (735 ml) was added to the organic layer and mixture stirred at ambient until a solid crystallised. The solid was filtered, washed with a 50% aqueous acetonitrile (2×90 ml), and then dried in a vacuum oven between 50° C. and 55° C. to give the title product (65.8 g; 83.9% yield); melting point 195.5–196.5° C.; NMR Spectrum: (DMSO d6) 1.64–1.83 (m, 2H); 1.98–2.14 (m 2H); 3.28–3.48 (m, 1H); (m, 2H); 3.57–3.67 (m, 1H); 3.81–3.92 (m, 1H); 4.00 (s 3H); 4.14 (s, 2H); 4.81 (m 1H); 7.27 (s 1H); 7.36 (t 1H); 7.54–7.64 (m 2H); 8.00 (s 1H); 8.66 (s 1H); Mass Spectrum: (M+H)30 460.9.

Workup

  1. temperaturemaintaining the temperature at less than 30° C.
  2. washwash (37 ml)
  3. additionwere added
  4. washwash (25 ml)
  5. customat less than 30° C
  6. stirringThe reaction mixture was stirred at ambient for 120 minutes before the lower aqueous layer
  7. customwas separated
  8. additionWater (735 ml) was added to the organic layer and mixture
  9. stirringstirred at ambient until a solid
  10. customcrystallised
  11. filtrationThe solid was filtered
  12. washwashed with a 50% aqueous acetonitrile (2×90 ml)
  13. customdried in a vacuum oven between 50° C. and 55° C.

Sources & evidence

ORD record
ord-06c7ddd4241b457fa7eeb1031eda8e69
Source dataset
uspto-grants-2006_12
Patent number
US07148230B2

Reaction notes

Loading…