Dichloromethane → N-(3-chloro-4-fluorophenyl)-6-(3-(5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)propoxy)-7-methoxyquinazolin-4-amine

HRID 712385Notes

Reaction equation

HRID 712385 reaction equation
[N:1]1[N:2]=[CH:3][N:4]2[CH2:9][CH2:8][NH:7][CH2:6][C:5]=12.[Cl:10][C:11]1[CH:12]=[C:13]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([O:34][CH3:35])=[C:26]([O:29][CH2:30][CH2:31][CH2:32]Cl)[CH:27]=3)[N:22]=[CH:21][N:20]=2)[CH:14]=[CH:15][C:16]=1[F:17].C(Cl)Cl>CN(C=O)C>[Cl:10][C:11]1[CH:12]=[C:13]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([O:34][CH3:35])=[C:26]([O:29][CH2:30][CH2:31][CH2:32][N:7]4[CH2:8][CH2:9][N:4]5[CH:3]=[N:2][N:1]=[C:5]5[CH2:6]4)[CH:27]=3)[N:22]=[CH:21][N:20]=2)[CH:14]=[CH:15][C:16]=1[F:17]

Participants

5

Reactant 3

HCID 6344DichloromethaneHCID 179987185H,6H,7H,8H-(1,2,4)triazolo(4,3-a)pyrazineHCID 50742265N-(3-Chloro-4-fluorophenyl)-6-(3-chloropropoxy)-7-methoxyquinazolin-4-amine

Product 1

HCID 71572111N-(3-chloro-4-fluorophenyl)-6-(3-(5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)propoxy)-7-methoxyquinazolin-4-amineYield 31.2%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent2×

Conditions

Temperature
80 °C

Procedure

To a solution of 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine (0.18 g) in DMF (8 mL) was added Ag2CO3 (1.12 g, 5 eq). The mixture was then added into a solution of N-(3-chloro-4-fluorophenyl)-6-(3-chloropropoxy)-7-methoxyquinazolin-4-amine (0.21 g) in DMF (2 mL) at rt under stirring. The reaction mixture was heated at 80° C. for 36 h under N2, and cooled to room temperature. To the reaction mixture was added CH2Cl2 (100 mL), and the reaction mixture was washed with brine (100 mL×3). The organic layer was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was chromatographed with a silica gel column (eluting agent: 20:1 (v/v) CH2Cl2/CH3OH) to give the title compound (80.00 mg, 17.62%), HPLC: 88.57%. The title compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 484.2 (M+1); and 1H NMR (400 MHz, CDCl3) δ: 22.02-2.08 (m, 2H), 2.75 (t, J=13.20 Hz, 2H), 2.89 (t, J=10.80 Hz, 2H), 3.73 (s, 2H), 3.94 (s, 3H), 4.01 (t, J=10.80 Hz, 2H), 4.12 (t, J=12.40 Hz, 2H), 7.10 (m, 1H), 7.24 (s, 1H), 7.27 (t, J=6.00 Hz, 1H), 7.43 (s, 1H), 7.54-7.58 (m, 1H), 7.82-7.84 (m, 1H), 8.05 (s, 1H), 8.44 (s, 1H), 8.64 (s, 1H) ppm.

Workup

  1. temperaturecooled to room temperature
  2. washthe reaction mixture was washed with brine (100 mL×3)
  3. dry with materialThe organic layer was dried over anhydrous Na2SO4
  4. filtrationfiltered
  5. concentrationThe filtrate was concentrated in vacuo
  6. customthe residue was chromatographed with a silica gel column (eluting agent: 20:1 (v/v) CH2Cl2/CH3OH)

Sources & evidence

ORD record
ord-058b51b98b5e48c094f201b0fdb56ca8
Source dataset
uspto-grants-2015_11
Patent number
US09181277B2

Reaction notes

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