Water → HCID 56848547, compound

HRID 1424446Notes

Reaction equation

HRID 1424446 reaction equation
Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[O:14])[N:3]=1.[CH3:22][C:23]1[NH:27][N:26]=[C:25]([NH2:28])[CH:24]=1.CCN(C(C)C)C(C)C.O>CN(C=O)C>[F:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:28][C:25]3[CH:24]=[C:23]([CH3:22])[NH:27][N:26]=3)=[N:3][C:4]([C:13]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[O:14])=[N:5]2)=[CH:10][CH:9]=1

Participants

6

Reactant 4

HCID 962WaterHCID 81531DiisopropylethylamineHCID 931461H-Pyrazol-3-amine, 5-methyl-HCID 86649052HCID 86649052, compound

Product 1

HCID 56848547HCID 56848547, compoundYield 45%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

To a solution of ethyl 4-chloro-7-fluoroquinazoline-2-carboxylate (122 mg, 0.479 mmol) in 5 mL THF at −40° C. was added 1M 4-fluorophenylmagnesium bromide/THF (0.58 mL, 0.58 mmol) and the mixture was stirred at −40° C. for 2 h. Saturated aq NH4Cl was added and the mixture was concentrated under reduced pressure. The residue was partitioned between H2O (100 mL) and DCM (50 mL). The separated aqueous phase was extracted with DCM (2×50 mL) and the combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure to afford a solid (130 mg) containing (4-chloro-7-fluoroquinazolin-2-yl)(4-fluorophenyl)methanone. A solution of the solid (130 mg, ca. 0.43 mmol) and KI (78 mg, 0.47 mmol) in DMF (6 mL) was stirred at rt for 30 min, and then 5-methyl-1H-pyrazol-3-amine (88 mg, 0.88 mmol) and DIEA (96 uL, 0.56 mmol) were added. The mixture was stirred at rt for 24 h, and then water was added. The precipitated solid was collected by filtration washing with water. The solid was purified by preparative reverse-phase HPLC eluting with 10-80% ACN/H2O containing 0.05% HOAC to afford (7-fluoro-4-(5-methyl-1H-pyrazol-3-ylamino)quinazolin-2-yl)(4-fluorophenyl)methanone as a solid (96 mg, 45%). 1H NMR (300 MHz, DMSO-d6) δ ppm 2.18 (s, 3H), 6.48 (s, 1H), 7.39 (m, 2H), 7.63 (m, 2H), 8.13 (m, 2H), 8.84 (m, 1H), 10.80 (s, 1H), 12.08 (br s, 1H).

Workup

  1. filtrationThe precipitated solid was collected by filtration
  2. washwashing with water
  3. customThe solid was purified by preparative reverse-phase HPLC
  4. washeluting with 10-80% ACN/H2O containing 0.05% HOAC

Sources & evidence

ORD record
ord-2bfbc9787a4d4f1cbab9314e10ba9f83
Source dataset
uspto-grants-2015_01
Patent number
US08927711B2

Reaction notes

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