Sodium hydride → (1R*,2S*)-2-(3-((E)-2-(pyridin-3-yl)vinyl)-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indolin]-2'-one

HRID 2383651Notes

Reaction equation

HRID 2383651 reaction equation
[I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[N:9]1[CH:14]=[CH:13][CH:12]=[C:11](/[CH:15]=[CH:16]/[C:17]2[C:25]3[C:20](=[CH:21][C:22](/[CH:26]=[C:27]4/[C:28](=[O:36])[NH:29][C:30]5[C:35]/4=[CH:34][CH:33]=[CH:32][CH:31]=5)=[CH:23][CH:24]=3)[NH:19][N:18]=2)[CH:10]=1.[NH4+].[Cl-]>CN(C=O)C>[N:9]1[CH:14]=[CH:13][CH:12]=[C:11](/[CH:15]=[CH:16]/[C:17]2[C:25]3[C:20](=[CH:21][C:22]([C@H:26]4[C@@:27]5([C:35]6[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=6)[NH:29][C:28]5=[O:36])[CH2:2]4)=[CH:23][CH:24]=3)[NH:19][N:18]=2)[CH:10]=1

Participants

6

Reactant 4

HCID 24758Sodium hydride2×HCID 25517Ammonium ChlorideHCID 74498Sulfoxonium, trimethyl-, iodide (1:1)2×HCID 178517051HCID 178517051, compound

Product 1

HCID 58486164(1R*,2S*)-2-(3-((E)-2-(pyridin-3-yl)vinyl)-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indolin]-2'-oneYield 34.4%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent2×

Procedure

To a mixture of trimethylsulfoxonium iodide (176 mg, 0.8 mmol) and 60% NaH (96 mg, 2.4 mmol) in a RBF was added DMF (5 mL). The resulting mixture was stirred for 2 min at rt then cooled to 0° C. A solution of (E)-3-((3-((E)-2-(pyridin-3-yl)vinyl)-1H-indazol-6-yl)methylene)indolin-2-one (122 mg, 0.33 mmol)) in DMF (20 mL) was added via a pipet. After addition, the resulting mixture was heated at 55° C. (oil temp.) for 2 h and cooled to rt. Additional trimethylsulfoxonium iodide (176 mg, 0.8 mmol) and 60% NaH (96 mg, 2.4 mmol) were added and the resulting mixture was stirred O/N at rt and poured onto ice (80 mL). It was acidified with sat. NH4Cl and extracted with EtOAc (40 mL×3). The combined extracts were dried (Na2SO4) and concentrated to give a light brown liquid. This residue was purified by flash chromatography (eluent: CH2Cl2 to CH2Cl2/MeOH/Et3N=200:10:1) to give the crude title compound as a light yellow solid which was triturated with MeOH (5 mL) and suction filtered to give the title compound as a yellow solid (43 mg, 34%). 1H NMR (400 MHz, DMSO-d6) δ 13.21 (s, 1H), 10.64 (s, 1H), 8.86 (s, 1H), 8.45 (d, J=3.2 Hz, 1H), 8.15 (d, J=8.0 Hz, 1H), 8.09 (d, J=8.4 Hz, 1H), 7.65 (d, J=16.8 Hz, 1H), 7.49 (d, J=16.8 Hz, 1H, partially overlapping with the peak at 7.47 ppm), 7.47 (s, 1H, partially overlapping with the peak at 7.49 ppm), 7.40 (dd, J=8.0 Hz, J=4.8 Hz, 1H), 7.03 (d, J=8.4 Hz, 1H), 6.99 (d, J=7.2 Hz, 1H), 6.86 (d, J=7.6 Hz, 1H), 6.53 (t, J=7.4 Hz, 1H), 6.01 (d, J=7.6 Hz, 1H), 3.21 (t, J=8.4 Hz, 1H), 2.32 (dd, J=7.6 Hz, J=4.8 Hz, 1H), 2.00 (dd, J=9.0 Hz, J=4.8 Hz, 1H); MS ESI 379.1 [M+H]+, calcd for [C24H18N4O+H]+ 379.1.

Workup

  1. temperaturethen cooled to 0° C
  2. additionAfter addition
  3. temperaturethe resulting mixture was heated at 55° C. (oil temp.) for 2 h
  4. temperaturecooled to rt
  5. stirringthe resulting mixture was stirred O/N at rt
  6. additionpoured onto ice (80 mL)
  7. extractionextracted with EtOAc (40 mL×3)
  8. dry with materialThe combined extracts were dried (Na2SO4)
  9. concentrationconcentrated
  10. customto give a light brown liquid
  11. customThis residue was purified by flash chromatography (eluent: CH2Cl2 to CH2Cl2/MeOH/Et3N=200:10:1)
  12. customto give the crude title compound as a light yellow solid which
  13. customwas triturated with MeOH (5 mL) and suction
  14. filtrationfiltered

Sources & evidence

ORD record
ord-65104c33dc2c4dbc8337b05a47ae6239
Source dataset
uspto-grants-2012_09
Patent number
US08263596B2

Reaction notes

Loading…