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 729621Notes

Reaction equation

HRID 729621 reaction equation
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]

Participants

6

Reactant 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

Product 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

Reagents, catalysts & solvents 1

HCID 679Dimethyl SulfoxideSolvent

Conditions

Temperature
85 °C

Procedure

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].

Workup

  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%)

Sources & evidence

ORD record
ord-59e9d4eb2ee742469451bf382e9aace8
Source dataset
uspto-grants-2009_09
Patent number
US07582638B2

Reaction notes

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