Sodium Bicarbonate → 4-{4-[1-(3-fluoro-benzyl)-1H-indazol-5-ylamino]-pyrrolo[2,1-f][1,2,4]triazin-5-ylmethoxy}-piperidine-1-carboxylic acid tert-butyl ester

HRID 1072091Notes

Reaction equation

HRID 1072091 reaction equation
Br[CH2:2][C:3]1[CH:4]=[CH:5][N:6]2[C:11]=1[C:10](Cl)=[N:9][CH:8]=[N:7]2.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([OH:26])[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].C([O-])(O)=O.[Na+].[F:32][C:33]1[CH:34]=[C:35]([CH:47]=[CH:48][CH:49]=1)[CH2:36][N:37]1[C:45]2[C:40](=[CH:41][C:42]([NH2:46])=[CH:43][CH:44]=2)[CH:39]=[N:38]1>CC#N.C(Cl)Cl>[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([O:26][CH2:2][C:3]2[CH:4]=[CH:5][N:6]3[C:11]=2[C:10]([NH:46][C:42]2[CH:41]=[C:40]4[C:45](=[CH:44][CH:43]=2)[N:37]([CH2:36][C:35]2[CH:47]=[CH:48][CH:49]=[C:33]([F:32])[CH:34]=2)[N:38]=[CH:39]4)=[N:9][CH:8]=[N:7]3)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]

Participants

7

Reactant 4

HCID 516892Sodium Bicarbonate2×HCID 643502Tert-butyl 4-hydroxypiperidine-1-carboxylateHCID 71470731-(3-Fluorobenzyl)-1H-indazol-5-amineHCID 218743865-(Bromomethyl)-4-chloropyrrolo[2,1-f][1,2,4]triazine

Product 1

HCID 674103854-{4-[1-(3-fluoro-benzyl)-1H-indazol-5-ylamino]-pyrrolo[2,1-f][1,2,4]triazin-5-ylmethoxy}-piperidine-1-carboxylic acid tert-butyl esterYield 36.7%

Reagents, catalysts & solvents 2

HCID 6342AcetonitrileSolventHCID 6344DichloromethaneSolvent

Procedure

A suspension of 5-bromomethyl-4-chloro-pyrrolo[2,1-f][1,2,4]triazine (61 mg, 0.25 mmole), 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (500 mg, 10 equiv) and NaHCO3 (42 mg, 2 equiv) in dry CH3CN (0.5 mL) under N2 was left stirring at RT for 3 days. 1-(3-Fluoro-benzyl)-1H-indazol-5-ylamine (54 mg, 0.9 equiv) and additional NaHCO3 (42 mg, 2 equiv) were added and the reaction was left stirring overnight. The reaction was diluted with DCM, washed with water, and dried (Na2SO4). Removal of the solvent followed by radial chromatography (2 mm silica gel plate, gradient elution with DCM containing 0 to 3% MeOH) afforded 4-{4-[1-(3-fluoro-benzyl)-1H-indazol-5-ylamino]-pyrrolo[2,1-f][1,2,4]triazin-5-ylmethoxy}-piperidine-1-carboxylic acid tert-butyl ester as a foam (47 mg, 33%). This was treated with a mixture of DCM (1.5 mL) and TFA (1 mL) for 40 min and then the solvents were removed. The residue was taken up in DCM, washed with sat. aq. NaHCO3 solution, and dried (Na2SO4). Removal of the solvent followed by radial chromatography (2 mm silica gel plate, gradient elution with DCM containing 0 to 5% MeOH) afforded the pure amine (11 mg, 29%) as an oil. 1H NMR (CDCl3) δ 1.1-1.3 (m, 2H), 1.7-1.9 (m, 4H), 2.5-2.6 (m, 2H), 3.0-3.1 (m, 2H), 3.44 (d, 2H, J=7 Hz), 4.85 (s, 2H), 5.59 (s, 2H), 6.55 (d, 1H, J=2 Hz), 6.8-7.0 (m, 3H), 7.2-7.5 (m, 4H), 7.97 (s, 1H), 8.05 (s, 1H), 8.20 (d, 1H, J=2 Hz), 9.70 (s, 1H); MS: 486 (M+H)+; HPLC Ret Time: 1.35 min (YMC S7 C18, 3.0×50 mm, 2 min gradient, 5 mL/min.

Workup

  1. waitwas left
  2. waitthe reaction was left
  3. stirringstirring overnight
  4. washwashed with water
  5. dry with materialdried (Na2SO4)
  6. customRemoval of the solvent
  7. washfollowed by radial chromatography (2 mm silica gel plate, gradient elution with DCM containing 0 to 3% MeOH)

Sources & evidence

ORD record
ord-e4b439c5d44245e2b560475035bfbcb1
Source dataset
uspto-grants-2005_06
Patent number
US06908916B2

Reaction notes

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