Potassium Carbonate → 5-Cyclopropyl-N-methyl-2-(4-methylphenyl)-6-{(methylsulfonyl)[2-(oxetan-3-yl)ethyl]amino}-2H-indazole-3-carboxamide

HRID 63537Notes

Reaction equation

HRID 63537 reaction equation
CS(O[CH2:6][CH2:7][CH:8]1[CH2:11][O:10][CH2:9]1)(=O)=O.O1CC(CCO)C1.CS(Cl)(=O)=O.CCN(C(C)C)C(C)C.[CH:33]1([C:36]2[C:44]([NH:45][S:46]([CH3:49])(=[O:48])=[O:47])=[CH:43][C:42]3[C:38](=[C:39]([C:57]([NH:59][CH3:60])=[O:58])[N:40]([C:50]4[CH:55]=[CH:54][C:53]([CH3:56])=[CH:52][CH:51]=4)[N:41]=3)[CH:37]=2)[CH2:35][CH2:34]1.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl.C(#N)C.CCOC(C)=O>[CH:33]1([C:36]2[C:44]([N:45]([S:46]([CH3:49])(=[O:48])=[O:47])[CH2:6][CH2:7][CH:8]3[CH2:9][O:10][CH2:11]3)=[CH:43][C:42]3[C:38](=[C:39]([C:57]([NH:59][CH3:60])=[O:58])[N:40]([C:50]4[CH:55]=[CH:54][C:53]([CH3:56])=[CH:52][CH:51]=4)[N:41]=3)[CH:37]=2)[CH2:34][CH2:35]1

Participants

10

Reactant 6

HCID 11430Potassium CarbonateHCID 31297Methanesulfonyl chlorideHCID 81531DiisopropylethylamineHCID 108443452-(Oxetan-3-yl)ethan-1-olHCID 86698999HCID 86698999, compound2×HCID 86699000HCID 86699000, compound

Product 1

HCID 717482695-Cyclopropyl-N-methyl-2-(4-methylphenyl)-6-{(methylsulfonyl)[2-(oxetan-3-yl)ethyl]amino}-2H-indazole-3-carboxamideYield 14%

Reagents, catalysts & solvents 3

HCID 6342AcetonitrileSolventHCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolvent

Procedure

To a stirred solution of 2-(oxetan-3-yl)ethyl methanesulfonate (11 mg, 0.06 mmol, prepared by treating 2-(oxetan-3-yl)ethanol with methanesulfonyl chloride in DCM in the presence of DIPEA) was added 5-cyclopropyl-6-(methanesulfonamido)-N-methyl-2-(p-tolyl)indazole-3-carboxamide (24 mg, 0.06 mmol) followed by potassium carbonate (68 mg, 0.49 mmol). The resultant suspension was heated at 60° C. for 18 h whereupon another portion of (oxetan-3-yl)ethyl methanesulfonate (81 mg, 0.45 mmol) in ACN (2 mL) was added and heating/stirring continued. After 24 h, the reaction mixture was diluted with EtOAc (15 mL) and the organics washed with water (20 mL). The aqueous layer was back-extracted into EtOAc (15 mL) and the combined organics were then washed with brine (10 mL), dried (MgSO4) and the volatiles removed in vacuo. The residue was purified by preparative HPLC eluting with ACN:0.1% formic acid in water (gradient elution, 5% to 30% to 40% to 100%) to give Compound (3) (4 mg, 14%). ESI-MS m/z calculated for [M+H]+: 483.2 found: 483.1. 1H NMR (400 MHz, CD3CN) δ 7.78 (s, 1H), 7.58 (s, 1H), 7.51 (d, J=8.2 Hz, 2H), 7.40 (d, J=7.94 Hz, 2H), 5.63 (brs, 1H), 4.86-4.78 (m, 2H), 4.40-4.33 (m, 2H), 3.70 (t, J=7.94 Hz, 2H), 3.18-3.05 (m, 4H), 2.98 (d, J=5.0 Hz, 3H), 2.51 (s, 3H), 2.47-2.38 (m, 1H), 2.17-1.97 (m, 2H), 1.19-1.03 (m, 3H), 0.72-0.63 (m, 1H).

Workup

  1. additionwas added
  2. washthe organics washed with water (20 mL)
  3. extractionThe aqueous layer was back-extracted into EtOAc (15 mL)
  4. washthe combined organics were then washed with brine (10 mL)
  5. dry with materialdried (MgSO4)
  6. customthe volatiles removed in vacuo
  7. customThe residue was purified by preparative HPLC
  8. washeluting with ACN

Sources & evidence

ORD record
ord-8227a37ccf354b5a9a6fff2ccde362d3
Source dataset
uspto-grants-2016_09
Patent number
US09447080B2

Reaction notes

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