Diisopropylethylamine → Tert-butyl 3-[({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl) (methyl)amino]-3-[(methylamino)carbonyl]azetidine-1-carboxylate

HRID 1867771Notes

Reaction equation

HRID 1867771 reaction equation
C(N(C(C)C)CC)(C)C.[CH3:10][NH:11][C:12]1([C:23]([NH:25][CH3:26])=[O:24])[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13]1.[Cl:27][C:28]1[C:29]([F:49])=[C:30]([NH:34][C:35]2[C:44]3[C:39](=[CH:40][C:41]([O:47][CH3:48])=[C:42]([CH2:45]Cl)[CH:43]=3)[N:38]=[CH:37][N:36]=2)[CH:31]=[CH:32][CH:33]=1>CN(C=O)C>[Cl:27][C:28]1[C:29]([F:49])=[C:30]([NH:34][C:35]2[C:44]3[C:39](=[CH:40][C:41]([O:47][CH3:48])=[C:42]([CH2:45][N:11]([CH3:10])[C:12]4([C:23]([NH:25][CH3:26])=[O:24])[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:13]4)[CH:43]=3)[N:38]=[CH:37][N:36]=2)[CH:31]=[CH:32][CH:33]=1

Participants

5

Reactant 3

HCID 81531DiisopropylethylamineHCID 57979822HCID 57979822, compoundHCID 69050792Tert-butyl 3-(methylamino)-3-[(methylamino)carbonyl]azetidine-1-carboxylate

Product 1

HCID 69047412Tert-butyl 3-[({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl) (methyl)amino]-3-[(methylamino)carbonyl]azetidine-1-carboxylateYield 41%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent2×

Conditions

Temperature
85 °C

Procedure

Diisopropylethylamine (0.55 ml, 3.10 mmol) was added to a solution of tert-butyl 3-(methylamino)-3-[(methylamino)carbonyl]azetidine-1-carboxylate (301 mg, 1.24 mmol) in DMF (0.5 ml). After 5 minutes of stirring, the reaction mixture became homogeneous and was warmed up to 85° C. N-(3-chloro-2-fluorophenyl)-6-(chloromethyl)-7-methoxyquinazolin-4-amine (400 mg, 1.03 mmol) was added portionwise over 2 hours. The reaction mixture was cooled to room temperature, diluted with DMF (2 ml) and purified by preparative HPLC (standard basic condition) to afford tert-butyl 3-[({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)(methyl)amino]-3[(methylamino)carbonyl]azetidine-1-carboxylate (235 mg, 41%) as a white solid. 1H NMR Spectrum: (CDCl3) 1.45 (s, 9H), 2.34 (s, 3H), 2.90 (d, 3H), 3.78 (brs, 2H), 4.01 (s, 3H), 4.10 (d, 2H), 4.25 (brs, 2H), 6.84 (brs, 1H), 7.17 (m, 2H), 7.29 (s, 1H), 7.60 (brs, 1H), 7.78 (brs, 1H), 8.53 (brs, 1H), 8.75 (s, 1H); Mass Spectrum: (M+H)+ 559.

Workup

  1. temperatureThe reaction mixture was cooled to room temperature
  2. custompurified by preparative HPLC (standard basic condition)

Sources & evidence

ORD record
ord-04363565021b4965a7745c0155e3b338
Source dataset
uspto-grants-2009_12
Patent number
US07632840B2

Reaction notes

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