Triethylamine → N-[(3-{[3-{[(5-Chloro-2-thienyl)sulfonyl]amino}-4-(1-hydroxyethyl)-1H-indazol-1-yl]methyl}phenyl)methyl]-2-hydroxy-2-methylpropanamide

HRID 1808642Notes

Reaction equation

HRID 1808642 reaction equation
C(N(CC)CC)C.[NH2:8][CH2:9][C:10]1[CH:11]=[C:12]([CH2:16][N:17]2[C:25]3[C:20](=[C:21]([CH:26]([OH:28])[CH3:27])[CH:22]=[CH:23][CH:24]=3)[C:19]([NH:29][S:30]([C:33]3[S:34][C:35]([Cl:38])=[CH:36][CH:37]=3)(=[O:32])=[O:31])=[N:18]2)[CH:13]=[CH:14][CH:15]=1.C([O:42][C:43]([CH3:48])([CH3:47])[C:44](Cl)=[O:45])(=O)C.C(=O)([O-])[O-].[K+].[K+]>ClCCl.CS(C)=O.CO>[Cl:38][C:35]1[S:34][C:33]([S:30]([NH:29][C:19]2[C:20]3[C:25](=[CH:24][CH:23]=[CH:22][C:21]=3[CH:26]([OH:28])[CH3:27])[N:17]([CH2:16][C:12]3[CH:11]=[C:10]([CH2:9][NH:8][C:44](=[O:45])[C:43]([OH:42])([CH3:48])[CH3:47])[CH:15]=[CH:14][CH:13]=3)[N:18]=2)(=[O:32])=[O:31])=[CH:37][CH:36]=1

Participants

8

Reactant 4

HCID 8471TriethylamineHCID 11430Potassium CarbonateHCID 1234962-Acetoxyisobutyroyl chlorideHCID 59456025N-[1-{[3-(Aminomethyl)phenyl]methyl}-4-(1-hydroxyethyl)-1H-indazol-3-yl]-5-chloro-2-thiophenesulfonamide

Product 1

HCID 59455995N-[(3-{[3-{[(5-Chloro-2-thienyl)sulfonyl]amino}-4-(1-hydroxyethyl)-1H-indazol-1-yl]methyl}phenyl)methyl]-2-hydroxy-2-methylpropanamideYield 37%

Reagents, catalysts & solvents 3

HCID 679Dimethyl SulfoxideSolventHCID 887MethanolSolventHCID 6344DichloromethaneSolvent

Procedure

Triethylamine (0.021 mL, 0.151 mmol) was added to N-[1-{[3-(aminomethyl)phenyl]methyl}-4-(1-hydroxyethyl)-1H-indazol-3-yl]-5-chloro-2-thiophenesulfonamide (for a preparation see Intermediate 77) (24 mg, 0.050 mmol) in dichloromethane (1 mL). 2-Chloro-1,1-dimethyl-2-oxoethyl acetate (7.92 μL, 0.055 mmol) was added and the reaction mixture was stirred at room temp for 2 h. The reaction mixture was concentrated on the blowdown unit, potassium carbonate (69.5 mg, 0.503 mmol) and methanol (2 mL) was added and the mixture was stirred at room temp for 1 h. The mixture was concentrated, acidified with 2N HCl and extracted with EtOAc (2×15 mL). The combined organic layers were dried by passing through a hydrophobic frit and concentrated to afford the crude product. The residue was dissolved in DMSO (1 mL) and purified by Mass Directed AutoPrep on Sunfire C18 column using Acetonitrile Water with a Formic acid modifier (Method A). The solvent was removed under a stream of nitrogen in the Radleys blowdown apparatus to give the title compound (10.5 mg, 37%). LCMS (System A) RT=0.99 min, ES+ve m/z 563/565 (M+H)+.

Workup

  1. additionwas added
  2. stirringthe mixture was stirred at room temp for 1 h
  3. concentrationThe mixture was concentrated
  4. extractionextracted with EtOAc (2×15 mL)
  5. customThe combined organic layers were dried
  6. concentrationconcentrated
  7. customto afford the crude product
  8. custompurified by Mass Directed AutoPrep on Sunfire C18 column
  9. customThe solvent was removed under a stream of nitrogen in the Radleys blowdown apparatus

Sources & evidence

ORD record
ord-30150ac9a9eb42d3a8cd3641435495a7
Source dataset
uspto-grants-2013_01
Patent number
US08357716B2

Reaction notes

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