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

HRID 712383Notes

Reaction equation

HRID 712383 reaction equation
[CH2:1]([C:3]1[N:7]2[CH2:8][CH2:9][NH:10][CH2:11][C:6]2=[N:5][N:4]=1)[CH3:2].[Cl:12][C:13]1[CH:14]=[C:15]([NH:20][C:21]2[C:30]3[C:25](=[CH:26][C:27]([O:36][CH3:37])=[C:28]([O:31][CH2:32][CH2:33][CH2:34]Cl)[CH:29]=3)[N:24]=[CH:23][N:22]=2)[CH:16]=[CH:17][C:18]=1[F:19].C(Cl)Cl>CN(C=O)C>[Cl:12][C:13]1[CH:14]=[C:15]([NH:20][C:21]2[C:30]3[C:25](=[CH:26][C:27]([O:36][CH3:37])=[C:28]([O:31][CH2:32][CH2:33][CH2:34][N:10]4[CH2:9][CH2:8][N:7]5[C:3]([CH2:1][CH3:2])=[N:4][N:5]=[C:6]5[CH2:11]4)[CH:29]=3)[N:24]=[CH:23][N:22]=2)[CH:16]=[CH:17][C:18]=1[F:19]

Participants

5

Reactant 3

HCID 6344DichloromethaneHCID 450883133-ethyl-5H,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 71572222N-(3-chloro-4-fluorophenyl)-6-(3-(3-ethyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl) propoxy)-7-methoxyquinazolin-4-amineYield 23.2%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent2×

Conditions

Temperature
80 °C

Procedure

To a solution of 3-ethyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine (0.12 g) in DMF (5 mL) was added Ag2CO3 (0.73 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) with stirring. The reaction mixture was heated at 80° C. for 40 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 phase 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 (63.00 mg, 15.56%), HPLC: 90.54%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 512.1 (M+1); 1H NMR (400 MHz, CDCl3) δ: 1.29 (t, J=12.80 Hz, 3H), 2.61-2.69 (m, 2H), 2.70 (t, J=13.60 Hz, 2H), 2.86 (t, J=11.20 Hz, 3H), 3.49 (s, 2H), 3.65 (s, 2H), 3.81 (t, J=13.60 Hz, 2H), 3.91 (s, 1H), 4.08 (t, J=12.40 Hz, 2H), 7.09 (m, 1H), 7.23-7.27 (m, 1H), 7.55-7.59 (m, 2H), 7.76-7.78 (m, 1H), 8.64 (s, 1H), 8.76 (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 phase 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-8ab0603bd4164f788e31583a0577338b
Source dataset
uspto-grants-2015_11
Patent number
US09181277B2

Reaction notes

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