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 1072091ノート

反応式

HRID 1072091 の反応式
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]

参加物

7

反応物 4

HCID 516892Sodium Bicarbonate2 回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

生成物 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 ester収率 36.7%

試薬・触媒・溶媒 2

HCID 6342Acetonitrile溶媒HCID 6344Dichloromethane溶媒

実験手順

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.

後処理

  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)

出典と根拠

ORDレコード
ord-e4b439c5d44245e2b560475035bfbcb1
出典データセット
uspto-grants-2005_06
特許番号
US06908916B2

反応ノート

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