Triphenylphosphine → 5-Cyclopropyl-N-methyl-2-(5-methylpyridin-2-yl)-6-{(methylsulfonyl)[2-(oxetan-3-yl)ethyl]amino}-2H-indazole-3-carboxamide

HRID 2202573Notes

Reaction equation

HRID 2202573 reaction equation
[CH:1]1([C:4]2[C:12]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[CH:11][C:10]3[C:6](=[C:7]([C:25]([NH:27][CH3:28])=[O:26])[N:8]([C:18]4[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=4)[N:9]=3)[CH:5]=2)[CH2:3][CH2:2]1.[O:29]1[CH2:32][CH:31]([CH2:33][CH2:34]O)[CH2:30]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.CCOC(C)=O>[CH:1]1([C:4]2[C:12]([N:13]([S:14]([CH3:17])(=[O:15])=[O:16])[CH2:34][CH2:33][CH:31]3[CH2:32][O:29][CH2:30]3)=[CH:11][C:10]3[C:6](=[C:7]([C:25]([NH:27][CH3:28])=[O:26])[N:8]([C:18]4[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=4)[N:9]=3)[CH:5]=2)[CH2:2][CH2:3]1

Participants

7

Reactant 4

HCID 11776Triphenylphosphine2×HCID 5363146Diisopropyl azodicarboxylate2×HCID 108443452-(Oxetan-3-yl)ethan-1-olHCID 717669535-Cyclopropyl-N-methyl-2-(5-methylpyridin-2-yl)-6-[(methylsulfonyl)amino]-2H-indazole-3-carboxamide

Product 1

HCID 717666615-Cyclopropyl-N-methyl-2-(5-methylpyridin-2-yl)-6-{(methylsulfonyl)[2-(oxetan-3-yl)ethyl]amino}-2H-indazole-3-carboxamideYield 59%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Procedure

To a stirred suspension of Compound 1 (11 mg, 0.03 mmol) and 2-(oxetan-3-yl)ethanol (5.6 mg, 0.06 mmol) in THF (200 μL) was added triphenylphosphine (11 mg, 0.04 mmol) followed by DIAD (8 μL, 0.04 mmol). The suspension dissolved slowly upon stirring. Analysis of the reaction mixture after 2.5 h by LCMS showed the presence of starting material and so further aliquots of triphenylphosphine (5.0 mg, 0.05 mmol) and DIAD (8 μL, 0.04 mmol) were added. After stirring for 2 h, the reaction was diluted with EtOAc (10 mL), the organics washed with water (10 mL), brine (10 mL) and dried (MgSO4). The organics were concentrated in vacuo and the residue purified by automated column chromatography on silica gel (Biotage SP4, 4 g Grace Resolve cartridge) eluting with acetic acid: DCM (10% v/v, 10 CV) to remove the triphenylphosphine oxide followed by MeOH: DCM (gradient elution, 0% to 20%, 20 CV) to give Compound (4) (7.8 mg, 59%). ESI-MS m/z calculated for [M+H]+: 484.2; found: 484.2. 1H NMR (400 MHz, CDCl3) δ 8.47 (brs, 1H), 8.36 (s, 1H), 7.83-7.76 (m, 2H), 7.72 (s, 1H), 7.60 (s, 1H), 4.84-4.71 (m, 2H), 4.34 (q, J=6.0 Hz, 2H), 3.74-3.56 (m, 2H), 3.10-2.99 (m, 7H), 2.47 (s, 3H), 2.30 (ddd, J=13.6, 8.3, 5.4 Hz, 1H), 2.07-1.95 (m, 2H), 1.09-0.94 (m, 3H), 0.65-0.56 (m, 1H).

Workup

  1. dissolutionThe suspension dissolved slowly
  2. stirringAfter stirring for 2 h
  3. washthe organics washed with water (10 mL), brine (10 mL)
  4. dry with materialdried (MgSO4)
  5. concentrationThe organics were concentrated in vacuo
  6. customthe residue purified by automated column chromatography on silica gel (Biotage SP4, 4 g Grace Resolve cartridge)
  7. washeluting with acetic acid
  8. customDCM (10% v/v, 10 CV) to remove the triphenylphosphine oxide

Sources & evidence

ORD record
ord-3fd5f8e9b7b545e5b8cbf1769af8e821
Source dataset
uspto-grants-2016_06
Patent number
US09365554B2

Reaction notes

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