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 1892974Notes

Reaction equation

HRID 1892974 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.C(OCC)(=O)C.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

10

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 5

HCID 887MethanolSolventHCID 1049PyridineSolventHCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolventHCID 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 concetrated 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. washwashed three times with water (50 mL)
  8. dry with materialThe organic layer was dried over anhydrous magnesium sulfate
  9. custombefore being evaporated in vacuo
  10. customto leave a yellow residue
  11. custompurified by Mass Directed AutoPrep on Sunfire C18 column
  12. customThe solvent was evaporated in vacuo

Sources & evidence

ORD record
ord-8a1296e619f842d38bdae45ca2ac4bcd
Source dataset
uspto-grants-2013_08
Patent number
US08507543B2

Reaction notes

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