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

HRID 712525Notes

Reaction equation

HRID 712525 reaction equation
[N:1]1[N:2]=[CH:3][N:4]2[CH2:9][CH2:8][NH:7][CH2:6][C:5]=12.[Br:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][C:24]([O:33][CH3:34])=[C:25]([O:28][CH2:29][CH2:30][CH2:31]Cl)[CH:26]=3)[N:21]=[CH:20][N:19]=2)=[C:13]([F:35])[CH:12]=1.C(Cl)Cl>CN(C=O)C>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][C:24]([O:33][CH3:34])=[C:25]([O:28][CH2:29][CH2:30][CH2:31][N:7]4[CH2:8][CH2:9][N:4]5[CH:3]=[N:2][N:1]=[C:5]5[CH2:6]4)[CH:26]=3)[N:21]=[CH:20][N:19]=2)=[C:13]([F:35])[CH:12]=1

Participants

5

Reactant 3

HCID 6344DichloromethaneHCID 179987185H,6H,7H,8H-(1,2,4)triazolo(4,3-a)pyrazineHCID 86729473HCID 86729473, compound

Product 1

HCID 86729523N-(4-bromo-2-fluorophenyl)-6-(3-(5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)propoxy)-7-methoxyquinazolin-4-amineYield 18.6%

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 (0.15 g) in DMF (8 mL) was added Ag2CO3 (1.00 g) and a solution of N-(4-bromo-2-fluorophenyl)-6-(3-chloropropoxy)-7-methoxy quinazolin-4-amine (0.40 g) in DMF (2 mL) at room temperature under stirring. The mixture was stirred at 80° C. for 36 h under N2 and cooled to room temperature. To this, CH2Cl2 (100 mL) was added. The mixture was washed with brine (100 mL×3), 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 product (89 mg, 18.50%), HPLC: 91.13%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 528.1 (M+1); 1H NMR (400 MHz, CDCl3) δ: 2.03-2.10 (m, 2H), 2.68 (t, J=13.20 Hz, 2H), 3.03 (t, J=10.80 Hz, 2H), 3.75 (s, 2H), 3.89 (s, 3H), 4.03 (t, J=10.80 Hz, 2H), 4.08 (t, J=12.40 Hz, 2H), 7.03 (m, 1H), 7.24 (s, 1H), 7.32 (m, 1H), 7.38 (s, 1H), 7.81-7.84 (m, 2H), 8.46 (s, 1H), 8.70 (s, 1H) ppm.

Workup

  1. temperaturecooled to room temperature
  2. washThe mixture was washed with brine (100 mL×3)
  3. dry with materialdried 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-cd4792bdb77245079c1b70e7eb955140
Source dataset
uspto-grants-2015_11
Patent number
US09181277B2

Reaction notes

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