4-Aminobenzoic Acid → HCID 52109435, compound

HRID 406855Notes

Reaction equation

HRID 406855 reaction equation
Cl[C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[NH2:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=1>CN(C)C=O.C(OCC)(=O)C.C(O)CCC>[O:16]1[CH2:17][CH2:18][N:13]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=[C:2]([NH:19][C:20]3[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=3)[N:11]=2)[CH2:14][CH2:15]1

Participants

7

Reactant 3

HCID 9784-Aminobenzoic AcidHCID 8083MorpholineHCID 2528862,4-Dichloroquinazoline

Product 1

HCID 52109435HCID 52109435, compoundYield 100%

Reagents, catalysts & solvents 3

HCID 2631-ButanolSolvent2×HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Procedure

A mixture of 2,4-dichloroquinazoline (200 mg, 1.00 mmol) and morpholine (131 mg, 1.50 mmol) in dimethylformamide (1 mL) was stirred at rt for 5 min. The reaction mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate and 5% aqueous lithium chloride and dried over sodium sulfate. The solvent was removed on a rotary evaporator to give a white solid. A mixture of this material and 4-aminobenzoic acid (119 mg, 0.868 mmol) in n-butanol (2.5 mL) was heated to 135° C. until the butanol was boiled off. The solid residue was collected and washed with water to give 4-(4-morpholinoquinazoline-2-ylamino)benzoic acid (303 mg, 100%) an off-white solid that was used without further purification. This material was combined with 2,6-dimethylaniline (210 mg, 1.73 mmol), Hunig's base (300 μL, 1.72 mmol) and HATU (329 mg, 0.865 mmol) in DMF (5 mL), and the mixture was heated to 65° C. overnight. The reaction was cooled to rt, diluted with ethyl acetate and extracted with water. The organic layer was washed with saturated sodium bicarbonate and concentrated on a rotary evaporator. The resulting residue was purified by preparative reverse phase HPLC to give N-(2,6-dimethylphenyl)-4-[(4-morpholin-4-ylquinazolin-2-yl)amino]benzamide (120 mg, 26%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 10.50 (bs, 1H), 9.70 (bs, 1H), 8.05-8.01 (m, 3H), 7.83-7.79 (m, 3H), 7.63 (d, 1H), 7.40 (t, 1H), 7.13 (s, 3H), 3.97 (bs, 4H), 3.84-3.82 (m, 4H), 2.19 (s, 6H). MS (EI) for C27H27N5O2: 454.0 (MH+).

Workup

  1. washwashed with saturated sodium bicarbonate and 5% aqueous lithium chloride
  2. dry with materialdried over sodium sulfate
  3. customThe solvent was removed on a rotary evaporator
  4. customto give a white solid
  5. customThe solid residue was collected
  6. washwashed with water

Sources & evidence

ORD record
ord-a52b738afec043d392dcef084a9c918a
Source dataset
uspto-grants-2014_06
Patent number
US08754092B2

Reaction notes

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