Carbon Tetrachloride → (R)-N,N-dimethyl-2-(4-(1-(pyridin-2-ylmethyl)-1H-indazol-5-ylamino)quinazolin-5-yloxy)propanamide

HRID 1162204Notes

Reaction equation

HRID 1162204 reaction equation
[CH3:1][N:2]([CH3:19])[C:3](=[O:18])[C@H:4]([O:6][C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[C:9](=O)[NH:10][CH:11]=[N:12]2)[CH3:5].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)Cl.[N:44]1[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=1[CH2:50][N:51]1[C:59]2[C:54](=[CH:55][C:56]([NH2:60])=[CH:57][CH:58]=2)[CH:53]=[N:52]1>ClCCCl.C(#N)C>[CH3:1][N:2]([CH3:19])[C:3](=[O:18])[C@H:4]([O:6][C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[C:9]([NH:60][C:56]1[CH:55]=[C:54]3[C:59](=[CH:58][CH:57]=1)[N:51]([CH2:50][C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][N:44]=1)[N:52]=[CH:53]3)=[N:10][CH:11]=[N:12]2)[CH3:5]

Participants

7

Reactant 4

HCID 5943Carbon TetrachlorideHCID 11776TriphenylphosphineHCID 219523661-(Pyridin-2-ylmethyl)-1H-indazol-5-amineHCID 136346624(2R)-N,N-dimethyl-2-[(4-oxo-3,4-dihydroquinazolin-5-yl)oxy]propanamide

Product 1

HCID 16116961(R)-N,N-dimethyl-2-(4-(1-(pyridin-2-ylmethyl)-1H-indazol-5-ylamino)quinazolin-5-yloxy)propanamideYield 43%

Reagents, catalysts & solvents 2

HCID 111,2-DichloroethaneSolventHCID 6342AcetonitrileSolvent

Conditions

Temperature
45 °C

Procedure

A mixture of (2R)—N,N-dimethyl-2-[(4-oxo-3,4-dihydroquinazolin-5-yl)oxy]propanamide (783 mg, 3 mmol), triphenylphosphine (2.35 g, 9 mmol) and carbon tetrachloride (8.62 ml, 90 mmol) in 1,2-dichloroethane (20 ml) was stirred at 45° C. for 2 hours. The mixture was cooled and the solvents were evaporated under vacuum. 1-(Pyridin-2-ylmethyl)-1H-indazol-5-amine (706 mg, 3.15 mmol) and acetonitrile (15 ml) were added. The mixture was stirred at 75° C. for 1 hour. After cooling, the solvents were evaporated under vacuum. The residue was diluted in DCM and extracted with 2N hydrochloric acid. The aqueous layer was neutralised by addition of 6N aqueous ammonia and extracted with DCM. The DCM layer was dried over magnesium sulfate and the solvents were evaporated under vacuum. The residue was purified twice by chromatography on silica gel (first eluant: 3% 6N methanolic ammonia in DCM; second eluant: 3% methanol in DCM) to give the title compound as a white foam (600 mg, 43%); NMR Spectrum (CDCl3) 1.72 (d, 3H), 3.06 (s, 3H), 3.14 (s, 3H), 5.43 (q, 1H), 5.75 (s, 2H), 6.81 (m, 2H), 7.17 (m, 1H), 7.41 (d, 1H), 7.48 (d, 1H), 7.62-7.53 (m, 2H), 7.81 (dd, 1H), 8.10 (s, 1H), 8.44 (d, 1H), 8.58 (d, 1H), 8.62 (s, 1H); Mass spectrum 468.

Workup

  1. temperatureThe mixture was cooled
  2. customthe solvents were evaporated under vacuum
  3. stirringThe mixture was stirred at 75° C. for 1 hour
  4. temperatureAfter cooling
  5. customthe solvents were evaporated under vacuum
  6. additionThe residue was diluted in DCM
  7. extractionextracted with 2N hydrochloric acid
  8. additionThe aqueous layer was neutralised by addition of 6N aqueous ammonia
  9. extractionextracted with DCM
  10. dry with materialThe DCM layer was dried over magnesium sulfate
  11. customthe solvents were evaporated under vacuum
  12. customThe residue was purified twice by chromatography on silica gel (first eluant: 3% 6N methanolic ammonia in DCM; second eluant: 3% methanol in DCM)

Sources & evidence

ORD record
ord-e8cf2e4eb11347a7b9db52df51d1b152
Source dataset
uspto-grants-2010_10
Patent number
US07820683B2

Reaction notes

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