Water → 4-(4-{3-[5-(2-fluoro-1-fluoromethyl-1-methyl-ethyl)-2-p-tolyl-2H-pyrazol-3-yl]-ureido}-isoquinolin-1-yloxy)-piperidine-1-carboxylic acid tert-butyl ester

HRID 729621Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 729621
ClC(Cl)(Cl)CO[C:5](=[O:25])[NH:6][C:7]1[N:8]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)[N:9]=[C:10]([C:12]([CH2:16][F:17])([CH3:15])[CH2:13][F:14])[CH:11]=1.CCN(C(C)C)C(C)C.[C:37]([O:41][C:42]([N:44]1[CH2:49][CH2:48][CH:47]([O:50][C:51]2[C:60]3[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=3)[C:54]([NH2:61])=[CH:53][N:52]=2)[CH2:46][CH2:45]1)=[O:43])([CH3:40])([CH3:39])[CH3:38].O>CS(C)=O>[C:37]([O:41][C:42]([N:44]1[CH2:45][CH2:46][CH:47]([O:50][C:51]2[C:60]3[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=3)[C:54]([NH:61][C:5]([NH:6][C:7]3[N:8]([C:18]4[CH:19]=[CH:20][C:21]([CH3:24])=[CH:22][CH:23]=4)[N:9]=[C:10]([C:12]([CH2:16][F:17])([CH3:15])[CH2:13][F:14])[CH:11]=3)=[O:25])=[CH:53][N:52]=2)[CH2:48][CH2:49]1)=[O:43])([CH3:40])([CH3:38])[CH3:39]

Komponenten

6

Edukt 4

HCID 962WaterHCID 81531DiisopropylethylamineHCID 578328234-(4-Amino-isoquinolin-1-yloxy)-piperidine-1-carboxylic acid tert-butyl esterHCID 68538054[5-(2-fluoro-1-fluoromethyl-1-methyl-ethyl)-2-p-tolyl-2H-pyrazol-3-yl]-carbamic acid 2,2,2-trichloro-ethyl ester

Produkt 1

HCID 690593934-(4-{3-[5-(2-fluoro-1-fluoromethyl-1-methyl-ethyl)-2-p-tolyl-2H-pyrazol-3-yl]-ureido}-isoquinolin-1-yloxy)-piperidine-1-carboxylic acid tert-butyl ester

Reagenzien, Katalysatoren, Lösungsmittel 1

HCID 679Dimethyl SulfoxideLösungsmittel

Reaktionsbedingungen

Temperatur
85 °C

Versuchsvorschrift

Add [5-(2-fluoro-1-fluoromethyl-1-methyl-ethyl)-2-p-tolyl-2H-pyrazol-3-yl]-carbamic acid 2,2,2-trichloro-ethyl ester (Preparation 27, 2.7 mmol, 1.2 g) and DIPEA (2.9 mmol, 0.5 mL) to a solution of 4-(4-amino-isoquinolin-1-yloxy)-piperidine-1-carboxylic acid tert-butyl ester (Preparation 22, 2.9 mmol, 1.0 g) in 4 mL of DMSO and stir at 85° C. overnight. Cool down, add water and extract with dichloromethane. Combine the organic layers and wash with saturated aq. sodium chloride. Dry over sodium sulfate, filter, and concentrate under reduced pressure to give a residue. Subject residue to silica gel chromatography eluting with hexanes/ethyl acetate in gradient (from 15 to 70%) to yield 4-(4-{3-[5-(2-fluoro-1-fluoromethyl-1-methyl-ethyl)-2-p-tolyl-2H-pyrazol-3-yl]-ureido}-isoquinolin-1-yloxy)-piperidine-1-carboxylic acid tert-butyl ester. LCMS ES+ (m/z) 635 [M+H].

Aufarbeitung

  1. temperatureCool down,
  2. extractionextract with dichloromethane
  3. washwash with saturated aq. sodium chloride
  4. dry with materialDry over sodium sulfate
  5. filtrationfilter
  6. concentrationconcentrate under reduced pressure
  7. customto give a residue
  8. washSubject residue to silica gel chromatography eluting with hexanes/ethyl acetate in gradient (from 15 to 70%)

Quellen und Nachweise

ORD-Eintrag
ord-59e9d4eb2ee742469451bf382e9aace8
Quelldatensatz
uspto-grants-2009_09
Patentnummer
US07582638B2

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