4-(N-Boc-amino)piperidine → tert-butyl 1-((4-(1-(3-fluorobenzyl)-1H-indazol-5-ylamino)quinazolin-5-yl)methyl)piperidin-4-ylcarbamate

HRID 900325Notes

Reaction equation

HRID 900325 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.[F:21][C:22]1[CH:23]=[C:24]([CH:36]=[CH:37][CH:38]=1)[CH2:25][N:26]1[C:34]2[C:29](=[CH:30][C:31]([NH2:35])=[CH:32][CH:33]=2)[CH:28]=[N:27]1.N1CC[CH:42]([NH:45][C:46](=[O:52])[O:47][C:48]([CH3:51])([CH3:50])[CH3:49])CC1>CC#N>[F:21][C:22]1[CH:23]=[C:24]([CH:36]=[CH:37][CH:38]=1)[CH2:25][N:26]1[C:34]2[C:29](=[CH:30][C:31]([NH:35][C:3]3[C:12]4[C:7](=[CH:8][CH:9]=[CH:10][C:11]=4[CH2:13][N:14]4[CH2:17][CH2:18][CH:42]([NH:45][C:46](=[O:52])[O:47][C:48]([CH3:51])([CH3:50])[CH3:49])[CH2:20][CH2:19]4)[N:6]=[CH:5][N:4]=3)=[CH:32][CH:33]=2)[CH:28]=[N:27]1

Participants

5

Reactant 3

HCID 7238334-(N-Boc-amino)piperidineHCID 71470731-(3-Fluorobenzyl)-1H-indazol-5-amineHCID 86607964N-((4-chloroquinazolin-5-yl)methyl)-N,N-diethylethanaminium bromide

Product 1

HCID 58711715tert-butyl 1-((4-(1-(3-fluorobenzyl)-1H-indazol-5-ylamino)quinazolin-5-yl)methyl)piperidin-4-ylcarbamateYield 27%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent2×

Conditions

Temperature
55 °C

Procedure

A mixture of 14A (120 mg, 0.34 mmol) and 1-(3-fluorobenzyl)-1H-indazole-5-amine (81.0 mg, 0.34 mmol; prepared as described in US 2003/0186983 A1) in CH3CN (1.2 ml) was heated at 55° C. for 45 min. After cooling to rt, tert-butyl piperidin-4-ylcarbamate (672 mg, 3.34 mmol) was added and the mixture was heated at 60° C. for 16 h. After cooling to rt. this mixture was then diluted with CH3CN (2.4 mL), and heated at 70° C. for 4 h and at 80° C. for 4 d. The reaction mixture was concentrated in vacuo and the residue was purified by prep HPLC to give 21A (52 mg, 27%). It has an analytical HPLC retention time=2.86 min (Chromolith SpeedROD column 4.6×50 mm, 10-90% aqueous methanol containing 0.2% H3PO4 over 4 minutes, 4 mL/min, monitoring at 220 nm) and a LC/MS M++H=582+.

Workup

  1. temperatureAfter cooling to rt
  2. temperaturethe mixture was heated at 60° C. for 16 h
  3. temperatureAfter cooling to rt
  4. temperatureheated at 70° C. for 4 h and at 80° C. for 4 d
  5. concentrationThe reaction mixture was concentrated in vacuo
  6. customthe residue was purified by prep HPLC

Sources & evidence

ORD record
ord-0e0c643015744560bfe7bd797111adcf
Source dataset
uspto-grants-2008_04
Patent number
US07358256B2

Reaction notes

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