Methanol → 2-((cyclopropylamino)(4-fluorophenyl)methyl)-N-(5-methyl-1H-pyrazol-3-yl)quinazolin-4-amine

HRID 1801962Notes

Reaction equation

HRID 1801962 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[N:19]=[C:18]([NH:20][C:21]3[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=3)[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)=O)=[CH:4][CH:3]=1.[CH:27]1([NH2:30])[CH2:29][CH2:28]1.[BH4-].[Na+].CO>CC(O)C>[CH:27]1([NH:30][CH:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[C:10]2[N:19]=[C:18]([NH:20][C:21]3[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=3)[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)[CH2:29][CH2:28]1

Participants

6

Reactant 4

HCID 887Methanol2×HCID 69828Cyclopropylamine2×HCID 4311764Sodium borohydride2×HCID 46892243(4-fluorophenyl)(4-(5-methyl-1H-pyrazol-3-ylamino)quinazolin-2-yl)methanone

Product 1

HCID 468935212-((cyclopropylamino)(4-fluorophenyl)methyl)-N-(5-methyl-1H-pyrazol-3-yl)quinazolin-4-amineYield 9%

Reagents, catalysts & solvents 1

HCID 3776IsopropanolSolvent2×

Conditions

Temperature
140 °C

Procedure

To (4-fluorophenyl)(4-(5-methyl-1H-pyrazol-3-ylamino)quinazolin-2-yl)methanone from Example 3 (100 mg, 0.28 mmol) in 2-propanol (3 mL) were added cyclopropylamine (0.1 mL) and 3A (8-12 mesh) molecular sieves, and the mixture was heated at 140° C. in a Biotage microwave reactor. Additional cyclopropylamine (0.15 mL) was added and the mixture in a sealed vial was heated conventionally at 90° C. for 4 d. Then a suspension of sodium borohydride (140 mg) in 2-propanol was added dropwise and the mixture was stirred at rt for 1 h. Then MeOH (0.1 mL), sodium borohydride (100 mg), and more MeOH (2 mL) were added, and the mixture was filtered and the filtrate was concentrated. To the residue were added THF (5 mL), MeOH (2 mL) and sodium borohydride (100 mg) and the mixture was stirred for 1 h at rt. AcOH (0.4 mL) was then added and the mixture was concentrated. DMSO (3 mL) was added and the mixture was purified by preparative HPLC (Varian diphenyl reverse phase column, eluting with a gradient of solvent B=0.05% HOAc/MeOH and solvent A=0.05% HOAc/H2O) followed by further purification by preparative HPLC (Phenomonex C-18 reverse phase column, eluting with a gradient of solvent B=0.05% HOAc/MeOH and solvent A=0.05% HOAc/H2O) to afford 2-((cyclopropylamino)(4-fluorophenyl)methyl)-N-(5-methyl-1H-pyrazol-3-yl)quinazolin-4-amine (5.5 mg, 9%). 1H NMR (300 MHz, DMSO-d6) δ 0.34 (m, 4 H) 1.24 (m, 1H) 2.03 (m, 1H) 2.26 (s, 3H) 4.91 (s, 1H) 6.41 (m, 1H) 7.11 (t, 2H) 7.4-7.6 (m, 3H) 7.76 (m, 2H) 8.56 (d, 1H) 10.38 (bs, 1H) 12.15 (bs, 1H); LC-MS (ESI) m/z 389 (M+H)+.

Workup

  1. temperaturethe mixture in a sealed vial was heated conventionally at 90° C. for 4 d
  2. additionwas added dropwise
  3. filtrationthe mixture was filtered
  4. concentrationthe filtrate was concentrated
  5. additionTo the residue were added THF (5 mL), MeOH (2 mL) and sodium borohydride (100 mg)
  6. stirringthe mixture was stirred for 1 h at rt
  7. additionAcOH (0.4 mL) was then added
  8. concentrationthe mixture was concentrated
  9. additionDMSO (3 mL) was added
  10. customthe mixture was purified by preparative HPLC (Varian diphenyl reverse phase column
  11. washeluting with a gradient of solvent B=0.05% HOAc/MeOH and solvent A=0.05% HOAc/H2O)
  12. customfollowed by further purification by preparative HPLC (Phenomonex C-18 reverse phase column
  13. washeluting with a gradient of solvent B=0.05% HOAc/MeOH and solvent A=0.05% HOAc/H2O)

Sources & evidence

ORD record
ord-0ecf945325aa4fb7836d00d9e6a3f967
Source dataset
uspto-grants-2013_01
Patent number
US08349851B2

Reaction notes

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