Sulfoxonium, trimethyl-, iodide (1:1) → 2-(4-Chlorophenyl)-5-cyclopropyl-N-methyl-6-{(methylsulfonyl)[3-(oxetan-2-yl)propyl]amino}-2H-indazole-3-carboxamide

HRID 63540Notes

Reaction equation

HRID 63540 reaction equation
[CH3:1]C(C)([O-])C.[K+].[I-].C[S+](C)(C)=O.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:28]([C:29]([NH:31][CH3:32])=[O:30])=[C:27]3[C:22]([CH:23]=[C:24]([N:36]([S:43]([CH3:46])(=[O:45])=[O:44])[CH2:37][CH2:38][CH2:39][CH:40]4[CH2:42][O:41]4)[C:25]([CH:33]4[CH2:35][CH2:34]4)=[CH:26]3)=[N:21]2)=[CH:16][CH:15]=1>C(O)(C)(C)C>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:28]([C:29]([NH:31][CH3:32])=[O:30])=[C:27]3[C:22]([CH:23]=[C:24]([N:36]([S:43]([CH3:46])(=[O:45])=[O:44])[CH2:37][CH2:38][CH2:39][CH:40]4[CH2:42][CH2:1][O:41]4)[C:25]([CH:33]4[CH2:34][CH2:35]4)=[CH:26]3)=[N:21]2)=[CH:16][CH:15]=1

Participants

5

Reactant 3

HCID 74498Sulfoxonium, trimethyl-, iodide (1:1)HCID 23665647Potassium tert-butoxideHCID 866990022-(4-chlorophenyl)-5-cyclopropyl-N-methyl-6-{(methylsulfonyl)[3-(oxiran-2-yl)propyl]amino}-2H-indazole-3-carboxamide

Product 1

HCID 717686122-(4-Chlorophenyl)-5-cyclopropyl-N-methyl-6-{(methylsulfonyl)[3-(oxetan-2-yl)propyl]amino}-2H-indazole-3-carboxamideYield 16%

Reagents, catalysts & solvents 1

HCID 6386tert-ButanolSolvent2×

Conditions

Temperature
50 °C

Procedure

An oven-dried flask was charged with a mixture of potassium tert-butoxide (426 mg, 3.8 mmol) and trimethylsulfoxonium iodide (860 mg, 3.9 mmol) in anhydrous tert-butanol (7.5 mL) under argon. The reaction mixture was stirred vigorously at 50° C. for 5 h under argon then added to a stirred solution of crude (ii) (191 mg) in anhydrous tert-butanol (2.5 mL) in a single portion. The reaction was stirred at 50° C. overnight under argon, cooled to RT and concentrated in vacuo. The residue was then partitioned between water (50 mL) and EtOAc (50 mL) and the organics separated. The aqueous layer was extracted aq with EtOAc (2×50 mL) and the combined organic layers dried (MgSO4) and concentrated in vacuo. The residue was dissolved in DMSO (2.5 mL) and the mixture centrifuged. The supernatant solution was collected and subjected to preparative HPLC (0.1% formic acid in acetonitrile: 0.1% formic acid in water, gradient elution 0% to 45% to 60% to 100%) to give Compound (4) (31 mg, 16% over 2 steps). 1H NMR (400 MHz, CD3CN) δ 7.80 (s, 1H), 7.60-7.50 (m, 4H), 7.35 (s, 1H), 6.98 (br s, 1H), 4.75-4.64 (m, 1H), 4.55-4.46 (m, 1H), 4.39-4.31 (m, 1H), 3.78-3.69 (m, 2H), 3.07 (s, 3H), 2.89 (d, J=4.8 Hz, 3H), 2.64-2.53 (m, 1H), 2.42-2.32 (m, 1H), 2.31-2.19 (m, 1H), 1.81-1.49 (m, 3H), 1.09-0.97 (m, 3H), 0.67-0.58 (m, 1H). ESI-MS m/z calculated for [M+H]+: 517.2. found: 517.0; m/z calculated for [M+Na]+: 539.2. found: 539.1.

Workup

  1. stirringThe reaction was stirred at 50° C. overnight under argon
  2. temperaturecooled to RT
  3. concentrationconcentrated in vacuo
  4. customThe residue was then partitioned between water (50 mL) and EtOAc (50 mL)
  5. extractionThe aqueous layer was extracted aq with EtOAc (2×50 mL)
  6. dry with materialthe combined organic layers dried (MgSO4)
  7. concentrationconcentrated in vacuo
  8. dissolutionThe residue was dissolved in DMSO (2.5 mL)
  9. customThe supernatant solution was collected
  10. washsubjected to preparative HPLC (0.1% formic acid in acetonitrile: 0.1% formic acid in water, gradient elution 0% to 45% to 60% to 100%)

Sources & evidence

ORD record
ord-5d729e4a8bd14896a660e10360e1f980
Source dataset
uspto-grants-2016_09
Patent number
US09447080B2

Reaction notes

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