Trifluoroacetic acid → 6-{[2-(Azetidin-3-yl)ethyl](methylsulfonyl)amino}-2-(4-chlorophenyl)-5-cyclopropyl-N-methyl-2H-indazole-3-carboxamide

HRID 63542Notes

Reaction equation

HRID 63542 reaction equation
[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([C:17](=[O:20])[NH:18][CH3:19])=[C:15]3[C:10]([CH:11]=[C:12]([N:24]([S:38]([CH3:41])(=[O:40])=[O:39])[CH2:25][CH2:26][CH:27]4[CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28]4)[C:13]([CH:21]4[CH2:23][CH2:22]4)=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:29]1[CH2:30][CH:27]([CH2:26][CH2:25][N:24]([S:38]([CH3:41])(=[O:40])=[O:39])[C:12]2[C:13]([CH:21]3[CH2:22][CH2:23]3)=[CH:14][C:15]3[C:10]([CH:11]=2)=[N:9][N:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[C:16]=3[C:17]([NH:18][CH3:19])=[O:20])[CH2:28]1

Participants

4

Reactant 2

HCID 6422Trifluoroacetic acidHCID 71768611tert-butyl 3-(2-{[2-(4-chlorophenyl)-5-cyclopropyl-3-(methylcarbamoyl)-2H-indazol-6-yl] (methylsulfonyl)amino}ethyl)azetidine-1-carboxylate

Product 1

HCID 717690346-{[2-(Azetidin-3-yl)ethyl](methylsulfonyl)amino}-2-(4-chlorophenyl)-5-cyclopropyl-N-methyl-2H-indazole-3-carboxamideYield 43.8%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a solution of tert-butyl 3-(2-{[2-(4-chlorophenyl)-5-cyclopropyl-3-(methylcarbamoyl)-2H-indazol-6-yl](methylsulfonyl)amino}ethyl)azetidine-1-carboxylate (prepared by reacting 2-(4-chlorophenyl)-5-cyclopropyl-N-methyl-6-[(methylsulfonyl)amino]-2H-indazole-3-carboxamide with tert-butyl 3-(2-hydroxyethyl)azetidine-1-carboxylate), (25 mg, 0.04 mmol) in DCM (3 mL) was added TFA (1 mL) and the reaction stirred at ambient temperature. After 1 h, the reaction was concentrated in vacuo and the residue partitioned between EtOAc (25 mL) and aq. saturated sodium bicarbonate (15 mL). The organic layer was separated and the aqueous layer extracted with EtOAc (3×15 mL). The combined organics were washed with brine (15 mL), dried (MgSO4), concentrated in vacuo and purified by preparative HPLC eluting with acetonitrile:0.1% formic acid in water to afford Compound (6) (8.8 mg, 42%). ESI-MS m/z calculated for [M+H]+: 502.2. found: 502.1 1H NMR (400 MHz, CD3CN) δ 8.40 (s, 1H), 7.83 (s, 1H), 7.64-7.54 (m, 4H), 7.39 (s, 1H), 7.37 (br d, J=3.9 Hz, 1H), 3.94-3.81 (m, 2H), 3.76-3.59 (m, 2H), 3.59-3.50 (m, 2H), 3.09 (d, J=10.3 Hz, 3H), 2.97-2.86 (m, 4H), 2.43-2.33 (m, 1H), 1.95-1.86 (m, 2H), 1.14-1.00 (m, 3H), 0.71-0.59 (m, 1H).

Workup

  1. concentrationthe reaction was concentrated in vacuo
  2. customthe residue partitioned between EtOAc (25 mL) and aq. saturated sodium bicarbonate (15 mL)
  3. customThe organic layer was separated
  4. extractionthe aqueous layer extracted with EtOAc (3×15 mL)
  5. washThe combined organics were washed with brine (15 mL)
  6. dry with materialdried (MgSO4)
  7. concentrationconcentrated in vacuo
  8. custompurified by preparative HPLC
  9. washeluting with acetonitrile

Sources & evidence

ORD record
ord-364eebdd2e194dc1998f3654dfc40d9c
Source dataset
uspto-grants-2016_09
Patent number
US09447080B2

Reaction notes

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