Methyl Acrylate → 4-QuinazolineAcetic Acid 8-Fluoro-1,2,3,4-Tetrahydro-3-[2-Methoxy-5-(TrifluoroMethyl)Phenyl]-2-Oxo-Methyl ester

HRID 2410225Notes

Reaction equation

HRID 2410225 reaction equation
Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:14]=1[O:23][CH3:24])=[O:11].C(N(CC)CC)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[C:54]([O:58][CH3:59])(=[O:57])[CH:55]=[CH2:56]>C(#N)C(C)C.CC#N.CC#N.Cl[Pd]Cl.O>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]2[C:3]=1[NH:9][C:10](=[O:11])[N:12]([C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:14]=1[O:23][CH3:24])[CH:56]2[CH2:55][C:54]([O:58][CH3:59])=[O:57]

Participants

8

Reactant 4

HCID 7294Methyl AcrylateHCID 8471TriethylamineHCID 80271Tri-o-tolylphosphineHCID 578575301-(2-Bromo-6-fluorophenyl)-3-(2-methoxy-5-(trifluoromethyl)phenyl)urea

Product 1

HCID 120019934-QuinazolineAcetic Acid 8-Fluoro-1,2,3,4-Tetrahydro-3-[2-Methoxy-5-(TrifluoroMethyl)Phenyl]-2-Oxo-Methyl esterYield 75%

Reagents, catalysts & solvents 3

HCID 6093782Bis(acetonitrile)dichloropalladiumCatalystHCID 962WaterSolventHCID 6559IsobutyronitrileSolvent

Conditions

Temperature
95 °C

Procedure

N-(2-Bromo-6-fluorophenyl)-N′-[2-methoxy-5-(trifluoromethyl)phenyl]urea (2.5 kg) is suspended in isobutyronitrile under a nitrogen atmosphere (9 l), then triethylamine (1.31 kg), bis(acetonitrile)dichloropalladium (64.9 g), tris(o-tolyl)phosphine (149 g) and methyl acrylate (1.59 kg) are added in this sequence. The resulting suspension is stirred at 90-100° C. for 22 h, then cooled to room temperature. Water (9 l) is added and the mixture is stirred at room temperature for 1 h, then the solid is filtered off with suction and washed with water/methanol (1:1, 2.5 l) and acetonitrile (850 ml). The residue is dried overnight at 45° C. in the VDO to constant mass (21 h) using entraining nitrogen. A total of 1.90 kg of methyl {8-fluoro-3-[2-methoxy-5-(trifluoromethyl)phenyl]-2-oxo-1,2,3,4-tetrahydroquinazolin-4-yl}acetate are obtained as a solid, corresponding to 74.9% of theory.

Workup

  1. temperaturecooled to room temperature
  2. stirringthe mixture is stirred at room temperature for 1 h
  3. filtrationthe solid is filtered off with suction
  4. washwashed with water/methanol (1:1, 2.5 l) and acetonitrile (850 ml)
  5. customThe residue is dried overnight at 45° C. in the VDO to constant mass (21 h)

Sources & evidence

ORD record
ord-a33175c58f254c1ea13836a2bd76cb17
Source dataset
uspto-grants-2014_08
Patent number
US08816075B2

Reaction notes

Loading…