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 1072091노트

반응식

HRID 1072091 반응식
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]

참가 물질

7

반응물 4

HCID 516892Sodium Bicarbonate2회HCID 643502Tert-butyl 4-hydroxypiperidine-1-carboxylateHCID 71470731-(3-Fluorobenzyl)-1H-indazol-5-amineHCID 218743865-(Bromomethyl)-4-chloropyrrolo[2,1-f][1,2,4]triazine

생성물 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 ester수율 36.7%

시약·촉매·용매 2

HCID 6342Acetonitrile용매HCID 6344Dichloromethane용매

실험 절차

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.

후처리

  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)

출처 및 근거

ORD 기록
ord-e4b439c5d44245e2b560475035bfbcb1
출처 데이터셋
uspto-grants-2005_06
특허 번호
US06908916B2

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