Water → 1,1-dimethylethyl 4-{[(3-(1,1-dimethylethyl)-6-fluoro-1-methyl-9-(methyloxy)-5-{3-methyl-4-[(phenylmethyl)oxy]phenyl}-3H-pyrazolo[3,4-c]isoquinolin-8-yl)oxy]methyl}piperidine-1-carboxylate

HRID 253287Notes

Reaction equation

HRID 253287 reaction equation
[CH3:1][C:2]([N:5]1[C:9]2[N:10]=[C:11]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[C:24]([CH3:36])[CH:23]=3)[C:12]3[C:13]([F:21])=[CH:14][C:15]([OH:20])=[C:16]([O:18][CH3:19])[C:17]=3[C:8]=2[C:7]([CH3:37])=[N:6]1)([CH3:4])[CH3:3].C(=O)([O-])[O-].[Cs+].[Cs+].CS(O[CH2:49][CH:50]1[CH2:55][CH2:54][N:53]([C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])[CH2:52][CH2:51]1)(=O)=O.O>CN(C=O)C>[CH3:4][C:2]([N:5]1[C:9]2[N:10]=[C:11]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)=[C:24]([CH3:36])[CH:23]=3)[C:12]3[C:13]([F:21])=[CH:14][C:15]([O:20][CH2:49][CH:50]4[CH2:55][CH2:54][N:53]([C:56]([O:58][C:59]([CH3:60])([CH3:62])[CH3:61])=[O:57])[CH2:52][CH2:51]4)=[C:16]([O:18][CH3:19])[C:17]=3[C:8]=2[C:7]([CH3:37])=[N:6]1)([CH3:1])[CH3:3]

Participants

6

Reactant 4

HCID 962WaterHCID 10796Cesium carbonateHCID 2765838Tert-butyl 4-(methylsulfonyloxymethyl)piperidine-1-carboxylateHCID 178493877HCID 178493877, compound

Product 1

HCID 668913001,1-dimethylethyl 4-{[(3-(1,1-dimethylethyl)-6-fluoro-1-methyl-9-(methyloxy)-5-{3-methyl-4-[(phenylmethyl)oxy]phenyl}-3H-pyrazolo[3,4-c]isoquinolin-8-yl)oxy]methyl}piperidine-1-carboxylateYield 73.8%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
90 °C

Procedure

To a solution of 3-(1,1-dimethylethyl)-6-fluoro-1-methyl-9-(methyloxy)-5-{3-methyl-4-[(phenylmethyl)oxy]phenyl}-3H-pyrazolo[3,4-c]isoquinolin-8-ol (207 mg, 0.42 mmol) in DMF (2 mL) was added cesium carbonate (274 mg, 0.84 mmol) and tert-butyl 4-{[(methylsulfonyl)oxy]methyl}piperidine-1-carboxylate (135 mg, 0.46 mmol). The mixture was heated to 90° C. and stirred for 1.5 h. After cooling to rt, water was added and the resulting aqueous mixture was extracted twice with ethyl acetate. The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by flash chromatography (gradient: 25% ethyl acetate in hexanes to 30% ethyl acetate in hexanes) to provide 1,1-dimethylethyl 4-{[(3-(1,1-dimethylethyl)-6-fluoro-1-methyl-9-(methyloxy)-5-{3-methyl-4-[(phenylmethyl)oxy]phenyl}-3H-pyrazolo[3,4-c]isoquinolin-8-yl)oxy]methyl}piperidine-1-carboxylate (214 mg, 0.31 mmol, 73% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3): δ 7.51-7.34 (m, 7H), 6.98 (d, 1H), 6.83 (d, 1H), 5.16 (s, 2H), 4.22 (br m, 2H), 3.98 (d, 2H), 3.91 (s, 3H), 2.89 (s, 3H), 2.80 (br m, 2H), 2.37 (s, 3H), 2.12 (m, 1H), 1.93-1.88 (m, 2H), 1.85 (s, 9H), 1.48 (s, 9H), 1.39-1.35 (m, 2H); MS (I) for C41H49FN4O5: 697 (MH+).

Workup

  1. temperatureAfter cooling to rt
  2. extractionthe resulting aqueous mixture was extracted twice with ethyl acetate
  3. dry with materialThe combined organic extracts were dried over magnesium sulfate
  4. filtrationfiltered
  5. concentrationconcentrated in vacuo
  6. customThe crude residue was purified by flash chromatography (gradient: 25% ethyl acetate in hexanes to 30% ethyl acetate in hexanes)

Sources & evidence

ORD record
ord-6a833e237d9e4d599bc682b567efaa46
Source dataset
uspto-grants-2011_01
Patent number
US07872014B2

Reaction notes

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