3-Methoxyaniline → 5-((4-aminopiperidin-1-yl)methyl)-N-(3-methoxyphenyl) quinazolin-4-amine

HRID 900317Notes

Reaction equation

HRID 900317 reaction equation
[Br-].Cl[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[CH2:13][N+:14]([CH2:19][CH3:20])([CH2:17][CH3:18])CC)[N:6]=[CH:5][N:4]=1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][CH:29]=1)[NH2:26].CC(O[C:35]([NH:37]C1CCNCC1)=O)(C)C>CC#N>[NH2:37][CH:35]1[CH2:18][CH2:17][N:14]([CH2:13][C:11]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:12]=2[C:3]([NH:26][C:25]2[CH:27]=[CH:28][CH:29]=[C:23]([O:22][CH3:21])[CH:24]=2)=[N:4][CH:5]=[N:6]3)[CH2:19][CH2:20]1

Participants

5

Reactant 3

HCID 108243-MethoxyanilineHCID 7238334-(N-Boc-amino)piperidineHCID 86607964N-((4-chloroquinazolin-5-yl)methyl)-N,N-diethylethanaminium bromide

Product 1

HCID 118475975-((4-aminopiperidin-1-yl)methyl)-N-(3-methoxyphenyl) quinazolin-4-amineYield 17.3%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Conditions

Temperature
55 °C

Procedure

A mixture of 14A (80 mg, 0.223 mmol) and 3-methoxyaniline (18.6 mg, 0.151 mmol) in CH3CN (1.5 ml) was heated at 55° C. for 2 h. After cooling to room temperature, 4-N-Boc-aminopiperidine (300 mg, 1.5 mmol) was added and the mixture was heated at 60° C. overnight. The reaction mixture was concentrated in vacuo and the residue was purified by prep HPLC. The desired fraction was concentrated and the resulting residue was dissolved in a mixture of TFA/DCM (1 ml/1 ml) and stirred at room temperature for 1 h, then concentrated. The residue was purified by SCX column, followed by silica gel flash column (DCM/MeOH/NH4OH=90/10/1) to give 14B (9.5 mg, 17%). The compound has an analytical HPLC retention time=1.288 min (Chromolith SpeedROD column 4.6×50 mm, 10-90% aqueous methanol containing 0.1% TFA over 4 minutes, 4 mL/min, monitoring at 254 nm) and a LC/MS M++H=364+.

Workup

  1. temperatureAfter cooling to room temperature
  2. temperaturethe mixture was heated at 60° C. overnight
  3. concentrationThe reaction mixture was concentrated in vacuo
  4. customthe residue was purified by prep HPLC
  5. concentrationThe desired fraction was concentrated
  6. dissolutionthe resulting residue was dissolved in a mixture of TFA/DCM (1 ml/1 ml)
  7. concentrationconcentrated
  8. customThe residue was purified by SCX column

Sources & evidence

ORD record
ord-33e3c35bc3b9474491a8b649f696d068
Source dataset
uspto-grants-2008_04
Patent number
US07358256B2

Reaction notes

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