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

HRID 63541Notes

Reaction equation

HRID 63541 reaction equation
ClC1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([C:17]([NH:19][CH3:20])=[O:18])=[C:15]3[C:10]([CH:11]=[C:12]([N:24]([S:30]([CH3:33])(=[O:32])=[O:31])[CH2:25][CH2:26]CC=C)[C:13]([CH:21]4[CH2:23][CH2:22]4)=[CH:14]3)=[N:9]2)=CC=1.[O:34]1[CH2:37][CH:36](CCO)[CH2:35]1.[C:41]1(P(C2C=CC=CC=2)C2C=CC=CC=2)[CH:46]=CC=C[CH:42]=1.CC(OC(/[N:66]=N/C(OC(C)C)=O)=O)C>C1COCC1.CCOC(C)=O>[CH:21]1([C:13]2[C:12]([N:24]([S:30]([CH3:33])(=[O:32])=[O:31])[CH2:25][CH2:26][CH:36]3[CH2:35][O:34][CH2:37]3)=[CH:11][C:10]3[C:15](=[C:16]([C:17]([NH:19][CH3:20])=[O:18])[N:8]([C:5]4[CH:6]=[CH:7][C:41]([CH3:46])=[CH:42][N:66]=4)[N:9]=3)[CH:14]=2)[CH2:23][CH2:22]1

Participants

7

Reactant 4

HCID 11776Triphenylphosphine2×HCID 5363146Diisopropyl azodicarboxylate2×HCID 108443452-(Oxetan-3-yl)ethan-1-olHCID 866990012-(4-Chlorophenyl)-5-cyclopropyl-N-methyl-6-[(methylsulfonyl)(pent-4-en-1-yl)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 5-cyclopropyl-N-methyl-2-(5-methylpyridin-2-yl)-6-[(methylsulfonyl)amino]-2H-indazole-3-carboxamide (i) (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. LCMS analysis of the reaction after 2.5 hr showed the presence of starting material and 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 (5) (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. customLCMS analysis of the reaction after 2.5 hr
  3. additionwere added
  4. stirringAfter stirring for 2 h
  5. washthe organics washed with water (10 mL), brine (10 mL)
  6. dry with materialdried (MgSO4)
  7. concentrationThe organics were concentrated in vacuo
  8. customthe residue purified by automated column chromatography on silica gel (Biotage SP4, 4 g Grace Resolve cartridge)
  9. washeluting with acetic acid
  10. customDCM (10% v/v, 10 CV) to remove the triphenylphosphine oxide

Sources & evidence

ORD record
ord-6383373a85ef46b2ac94a48bb421955e
Source dataset
uspto-grants-2016_09
Patent number
US09447080B2

Reaction notes

Loading…