Hydrochloric Acid → N-[(3-{[3-{[(5-Chloro-2-thienyl)sulfonyl]amino}-6-fluoro-4-(methyloxy)-1H-indazol-1-yl]methyl}phenyl)methyl]-2-hydroxy-2-methylpropanamide

HRID 1808633Notes

Reaction equation

HRID 1808633 reaction equation
[NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([CH2:9][N:10]2[C:18]3[C:13](=[C:14]([O:20][CH3:21])[CH:15]=[C:16]([F:19])[CH:17]=3)[C:12]([NH:22][S:23]([C:26]3[S:27][C:28]([Cl:31])=[CH:29][CH:30]=3)(=[O:25])=[O:24])=[N:11]2)[CH:6]=[CH:7][CH:8]=1.C([O:35][C:36]([CH3:41])([CH3:40])[C:37](Cl)=[O:38])(=O)C.C(=O)([O-])[O-].[K+].[K+].Cl>ClCCl.N1C=CC=CC=1.CO.CO.CS(C)=O>[Cl:31][C:28]1[S:27][C:26]([S:23]([NH:22][C:12]2[C:13]3[C:18](=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[O:20][CH3:21])[N:10]([CH2:9][C:5]3[CH:4]=[C:3]([CH2:2][NH:1][C:37](=[O:38])[C:36]([OH:35])([CH3:41])[CH3:40])[CH:8]=[CH:7][CH:6]=3)[N:11]=2)(=[O:25])=[O:24])=[CH:30][CH:29]=1

Participants

9

Reactant 4

HCID 313Hydrochloric AcidHCID 11430Potassium CarbonateHCID 1234962-Acetoxyisobutyroyl chloride3×HCID 66664251N-[1-{[3-(Aminomethyl)phenyl]methyl}-6-fluoro-4-(methyloxy)-1H-indazol-3-yl]-5-chloro-2-thiophenesulfonamide

Product 1

HCID 59456058N-[(3-{[3-{[(5-Chloro-2-thienyl)sulfonyl]amino}-6-fluoro-4-(methyloxy)-1H-indazol-1-yl]methyl}phenyl)methyl]-2-hydroxy-2-methylpropanamideYield 51%

Reagents, catalysts & solvents 4

HCID 887MethanolSolventHCID 1049PyridineSolventHCID 6344DichloromethaneSolventHCID 22036561Dimethyl sulfoxide methanolSolvent

Conditions

Temperature
40 °C

Procedure

N-[1-{[3-(Aminomethyl)phenyl]methyl}-6-fluoro-4-(methyloxy)-1H-indazol-3-yl]-5-chloro-2-thiophenesulfonamide (for a preparation see Intermediate 54) (100 mg, 0.208 mmol) (intermediate) was dissolved in dichloromethane (0.5 mL) and pyridine (0.5 mL), and then treated with 2-chloro-1,1-dimethyl-2-oxoethyl acetate (0.031 mL, 0.218 mmol). The mixture was stirred for 2 h. LCMS showed starting material remaining so more 2-chloro-1,1-dimethyl-2-oxoethyl acetate (0.021 mL, 0.146 mmol) was added to the reaction mixture and stirred for 1.5 hr. LCMS showed starting material remaining so a further portion of 2-chloro-1,1-dimethyl-2-oxoethyl acetate (0.015 mL, 0.104 mmol) was added to the reaction and stirred for 1.25 h. The reaction mixture was concentrated under a stream of nitrogen to leave a yellow residue, which was dissolved in methanol (1 mL) and potassium carbonate (86 mg, 0.624 mmol) was added to the solution. The reaction mixture was heated to 40° C. for 1 hand then neutralised with 2M HCl and concentrated in vacuo. The residue was dissolved in ethyl acetate (50 mL), washed three times with water (50 mL) and once with brine (50 mL). The organic layer was dried over anhydrous magnesium sulfate before being evaporated in vacuo to leave a yellow residue. The sample was dissolved in 1:1 MeOH-DMSO (1 mL) and purified by Mass Directed AutoPrep on Sunfire C18 column using Acetonitrile Water with a TFA modifier (Method B). The solvent was evaporated in vacuo to give the title compound (60 mg, 51%). LCMS (System A) RT=1.04 min, ES+ve m/z 481/483 (M+H)+.

Workup

  1. additionwas added to the reaction mixture
  2. stirringstirred for 1.5 hr
  3. additionwas added to the reaction
  4. stirringstirred for 1.25 h
  5. concentrationThe reaction mixture was concentrated under a stream of nitrogen
  6. customto leave a yellow residue, which
  7. concentrationconcentrated in vacuo
  8. dissolutionThe residue was dissolved in ethyl acetate (50 mL)
  9. washwashed three times with water (50 mL)
  10. dry with materialThe organic layer was dried over anhydrous magnesium sulfate
  11. custombefore being evaporated in vacuo
  12. customto leave a yellow residue
  13. custompurified by Mass Directed AutoPrep on Sunfire C18 column
  14. customThe solvent was evaporated in vacuo

Sources & evidence

ORD record
ord-2b8aff17bf8a42dc8dd153a6c3cc738d
Source dataset
uspto-grants-2013_01
Patent number
US08357716B2

Reaction notes

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