1-(3-Fluorobenzyl)-1H-indazol-5-amine → (3R,4R)-1-((4-(1-(3-fluorobenzyl)-1H-indazol-5-ylamino)quinazolin-5-yl)methyl)-4-azidopiperidin-3-ol

HRID 900323Notes

Reaction equation

HRID 900323 reaction equation
[Br-].Cl[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[CH2:13][N+](CC)(CC)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.[N:39]([C@@H:42]1[CH2:47][CH2:46][NH:45][CH2:44][C@H:43]1[OH:48])=[N+:40]=[N-:41]>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:45]4[CH2:46][CH2:47][C@@H:42]([N:39]=[N+:40]=[N-:41])[C@H:43]([OH:48])[CH2:44]4)[N:6]=[CH:5][N:4]=3)=[CH:32][CH:33]=2)[CH:28]=[N:27]1

Participants

5

Reactant 3

HCID 71470731-(3-Fluorobenzyl)-1H-indazol-5-amineHCID 58649721(3R,4R)-4-azidopiperidin-3-olHCID 86607964N-((4-chloroquinazolin-5-yl)methyl)-N,N-diethylethanaminium bromide

Product 1

HCID 58711712(3R,4R)-1-((4-(1-(3-fluorobenzyl)-1H-indazol-5-ylamino)quinazolin-5-yl)methyl)-4-azidopiperidin-3-olYield 45%

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 cooled to rt, (3R,4R)-4-azidopiperidin-3-ol (475 mg, 3.34 mmol; prepared as described in U.S. patent application Ser. No. 10146 PSP) was added and the mixture was heated at 60° C. for 16 h. This mixture was diluted with CH3CN (2.4 mL), and then 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 19A (78 mg, 45%). It has an analytical HPLC retention time=2.43 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=524+.

Workup

  1. temperatureAfter cooled to rt
  2. customprepared
  3. addition10146 PSP) was added
  4. temperaturethe mixture was heated at 60° C. for 16 h
  5. temperatureheated at 70° C. for 4 h and at 80° C. for 4 d
  6. concentrationThe reaction mixture was concentrated in vacuo
  7. customthe residue was purified by prep HPLC

Sources & evidence

ORD record
ord-22caf0361bc743709528d7a92502b449
Source dataset
uspto-grants-2008_04
Patent number
US07358256B2

Reaction notes

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