Sodium hydride → (1R*,2S*)-5'-Methoxy-2-(3-(6-morpholinopyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)-methyl)-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indolin]-2'-one

HRID 2383645Notes

Reaction equation

HRID 2383645 reaction equation
[H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[CH3:9][O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15](=[O:20])/[C:14]/2=[CH:21]/[C:22]1[CH:30]=[C:29]2[C:25]([C:26]([C:39]3[CH:40]=[N:41][C:42]([N:45]4[CH2:50][CH2:49][O:48][CH2:47][CH2:46]4)=[CH:43][CH:44]=3)=[N:27][N:28]2[CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])=[CH:24][CH:23]=1>CN(C=O)C>[CH3:9][O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15](=[O:20])[C@:14]12[CH2:4][C@H:21]1[C:22]1[CH:30]=[C:29]2[C:25]([C:26]([C:39]3[CH:40]=[N:41][C:42]([N:45]4[CH2:46][CH2:47][O:48][CH2:49][CH2:50]4)=[CH:43][CH:44]=3)=[N:27][N:28]2[CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:36])[CH3:37])=[CH:24][CH:23]=1

Participants

5

Reactant 3

HCID 24758Sodium hydrideHCID 74498Sulfoxonium, trimethyl-, iodide (1:1)HCID 66734145(E)-5-Methoxy-3-((3-(6-morpholinopyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-6-yl)methylene) indolin-2-one

Product 1

HCID 67955021(1R*,2S*)-5'-Methoxy-2-(3-(6-morpholinopyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)-methyl)-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indolin]-2'-oneYield 44%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent2×

Procedure

To a solution of NaH (84 mg, 2.1 mmol) in DMF (5 mL) at 0° C. was added trimethylsulfoxonium iodide (154 mg, 0.70 mmol). The resulting mixture was stirred at rt for 30 min followed by the addition of (E)-5-Methoxy-3-((3-(6-morpholinopyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-6-yl)methylene)indolin-2-one in DMF (2 mL). The reaction mixture was then heated to 55° C. for 3 h. The reaction was cooled to 0° C. and quenched with saturated NH4Cl. The mixture was extracted with EtOAc and the combined organic extracts were washed with brine, dried over MgSO4 and concentrated to give yellow viscous oil. The crude product was purified by silica gel chromatography (95:5 CH2Cl2/MeOH) to yield a bright yellow powder, which was triturated with EtOAc to give the title compound as a pale yellow powder (93 mg, 44%). 1H NMR (400 MHz, CD3OD) δ 10.45 (br. s, 1H), 8.71 (s, 1H), 8.10 (d, J=8.5 Hz, 1H), 7.93 (d, J=7.2 Hz, 1H), 7.84 (s, 1H), 7.08 (d, J=7.2 Hz, 1H), 6.98 (d, J=7.2 Hz, 1H), 6.73 (d, J=5.4 Hz, 1H), 6.56 (d, J=6.0 Hz, 1H), 5.86-5.75 (m, 3H), 3.71 (br s, 4H), 3.52 (br s, 4H), 3.40-3.16 (m, 6H), 2.42 (br. s, 1H), 2.00 (br. s, 1H), 0.79 (br s, 2H), −0.13 (s, 9H); MS ESI 598.4 [M+H]+, calcd for [C33H39N5O4Si+H]+ 598.28.

Workup

  1. temperatureThe reaction mixture was then heated to 55° C. for 3 h
  2. temperatureThe reaction was cooled to 0° C.
  3. customquenched with saturated NH4Cl
  4. extractionThe mixture was extracted with EtOAc
  5. washthe combined organic extracts were washed with brine
  6. dry with materialdried over MgSO4
  7. concentrationconcentrated
  8. customto give yellow viscous oil
  9. customThe crude product was purified by silica gel chromatography (95:5 CH2Cl2/MeOH)
  10. customto yield a bright yellow powder, which
  11. customwas triturated with EtOAc

Sources & evidence

ORD record
ord-df8e5135e6f54266ada7218bc81154c3
Source dataset
uspto-grants-2012_09
Patent number
US08263596B2

Reaction notes

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