Tetrahydrofuran → (1R,2S)-2-(1H-indazol-6-yl)-5'-methylspiro[cyclopropane-1,3'-indolin]-2'-one

HRID 447501Notes

Reaction equation

HRID 447501 reaction equation
C([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH3:17])=[CH:14][CH:15]=2)[C@:10]2([CH2:19][C@H:18]2[C:20]2[CH:28]=[C:27]3[C:23]([CH:24]=[N:25][N:26]3CC3C=CC=CC=3)=[CH:22][CH:21]=2)[C:9]1=[O:36])C1C=CC=CC=1.C1COCC1.CC([O-])(C)C.[K+]>CS(C)=O>[NH:26]1[C:27]2[C:23](=[CH:22][CH:21]=[C:20]([C@H:18]3[C@@:10]4([C:11]5[C:16](=[CH:15][CH:14]=[C:13]([CH3:17])[CH:12]=5)[NH:8][C:9]4=[O:36])[CH2:19]3)[CH:28]=2)[CH:24]=[N:25]1

Participants

5

Reactant 3

HCID 8028TetrahydrofuranHCID 23665647Potassium tert-butoxideHCID 67446303(1R,2S)-1'-benzyl-2-(1-benzyl-1H-indazol-6-yl)-5'-methylspiro[cyclopropane-1,3'-indolin]-2'-one2×

Product 1

HCID 58486155(1R,2S)-2-(1H-indazol-6-yl)-5'-methylspiro[cyclopropane-1,3'-indolin]-2'-one

Reagents, catalysts & solvents 1

HCID 679Dimethyl SulfoxideSolvent

Conditions

Temperature
0 °C

Procedure

To a 100 mL flask charged with (1R,2S)-1′-benzyl-2-(1-benzyl-1H-indazol-6-yl)-5′-methylspiro[cyclopropane-1,3′-indolin]-2′-one (469 mg, 1 mmol) was added dry THF (2 mL) and the resulting mixture was stirred at 0° C. before KOtBu (1 M in THF, 18 mL, 18 mmol) was added over 2 min. After addition, the resulting mixture was stirred for 15 min at 0° C. and DMSO (1.85 mL) was added. Oxygen was bubbled through for 1 h and reaction turned from homogeneous to heterogeneous. LC-MS showed good conversion at 50 min. It was quenched with sat. NH4Cl. The above reaction was repeated on a larger scale using (1R,2S)-1′-benzyl-2-(1-benzyl-1H-indazol-6-yl)-5′-methylspiro[cyclopropane-1,3′-indolin]-2′-one (1.41 g, 3 mmol). After quenching with saturated NH4Cl, two reactions were combined, diluted with H2O and extracted with EtOAc (100 mL×2). Purification by Biotage Isolera (10-95% EtOAc in hexane) gave the title compound as a light solid (680 mg, 53%). 1H NMR (400 MHz, CD3OD) δ 8.02 (s, 1H), 7.67 (d, J=8.4 Hz, 1H), 7.46 (s, 1H), 6.94 (d, J=8.4 Hz, 1H), 6.85 (d, J=8.0 Hz, 1H), 6.81 (d, J=7.6 Hz, 1H), 5.78 (s, 1H), 3.32 (t, overlapping with MeOH residue), 2.20-2.12 (m, 2H), 1.87 (s, 3H); MS ESI 290.1 [M+H]+, calcd for [C18H15N3O+H]+ 290.1.

Workup

  1. additionwas added over 2 min
  2. additionAfter addition
  3. customOxygen was bubbled through for 1 h and reaction
  4. customat 50 min
  5. customIt was quenched with sat. NH4Cl
  6. customThe above reaction
  7. customAfter quenching with saturated NH4Cl, two reactions
  8. additiondiluted with H2O
  9. extractionextracted with EtOAc (100 mL×2)
  10. customPurification by Biotage Isolera (10-95% EtOAc in hexane)

Sources & evidence

ORD record
ord-0b010621bd39466eb7f299f425796d79
Source dataset
uspto-grants-2013_07
Patent number
US08481525B2

Reaction notes

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