Acetic Acid → N-({3-[(3-{[(5-Chloro-2-thienyl)sulfonyl]amino}-4-fluoro-1H-indazol-1-yl)methyl]phenyl}methyl)acetamide

HRID 1892966Notes

Reaction equation

HRID 1892966 reaction equation
CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:25]([OH:28])(=O)[CH3:26].C(N(CC)C(C)C)(C)C.[NH2:38][CH2:39][C:40]1[CH:41]=[C:42]([CH2:46][N:47]2[C:55]3[C:50](=[C:51]([F:56])[CH:52]=[CH:53][CH:54]=3)[C:49]([NH:57][S:58]([C:61]3[S:62][C:63]([Cl:66])=[CH:64][CH:65]=3)(=[O:60])=[O:59])=[N:48]2)[CH:43]=[CH:44][CH:45]=1>CN(C)C=O.CO.CS(C)=O>[Cl:66][C:63]1[S:62][C:61]([S:58]([NH:57][C:49]2[C:50]3[C:55](=[CH:54][CH:53]=[CH:52][C:51]=3[F:56])[N:47]([CH2:46][C:42]3[CH:41]=[C:40]([CH2:39][NH:38][C:25](=[O:28])[CH3:26])[CH:45]=[CH:44][CH:43]=3)[N:48]=2)(=[O:60])=[O:59])=[CH:65][CH:64]=1

Participants

7

Reactant 4

HCID 176Acetic AcidHCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 58054591N-(1-{[3-(Aminomethyl)phenyl]methyl}-4-fluoro-1H-indazol-3-yl)-5-chloro-2-thiophenesulfonamide

Product 1

HCID 58054387N-({3-[(3-{[(5-Chloro-2-thienyl)sulfonyl]amino}-4-fluoro-1H-indazol-1-yl)methyl]phenyl}methyl)acetamideYield 6%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolvent2×HCID 22036561Dimethyl sulfoxide methanolSolvent

Procedure

To a solution of HATU (122 mg, 0.198 mmol) in anhydrous N,N-dimethylformamide (3 mL) was added at room temperature acetic acid (10.29 mL, 0.180 mmol) followed by N,N-diisopropylethylamine (0.094 mL, 0.539 mmol) and finally a solution of N-(1-{[3-(aminomethyl)phenyl]methyl}-4-fluoro-1H-indazol-3-yl)-5-chloro-2-thiophenesulfonamide (for a preparation see Intermediate 39) (81 mg, 0.18 mmol) in anhydrous N,N-dimethylformamide (2 mL). The reaction mixture was stirred at room temperature for 30 min, and then partitioned between saturated aqueous sodium hydrogen carbonate solution and ethyl acetate. The organic layer was separated, washed with brine-water (1:1), passed through a hydrophobic frit and evaporated in-vacuo to yield a colourless oil. The residue was dissolved in MeOH-DMSO (1 mL) and purified by Mass Directed AutoPreparative HPLC MDAP (Sunfire C18 column 150 mm×30 mm i.d. 5 μm packing diameter at ambient temperature) eluting with solvents NB (A: 0.1% v/v solution of formic acid in water, B: 0.1% v/v solution of formic acid in acetonitrile) over 25 min. The appropriate fraction was evaporated in-vacuo to yield a colourless oil (5.9 mg, 6%). LCMS (System B): RT=2.53 min, ES+ve m/z 493/495 (M+H)+.

Workup

  1. custompartitioned between saturated aqueous sodium hydrogen carbonate solution and ethyl acetate
  2. customThe organic layer was separated
  3. washwashed with brine-water (1:1)
  4. customevaporated in-vacuo
  5. customto yield a colourless oil
  6. custompurified by Mass Directed AutoPreparative HPLC MDAP (Sunfire C18 column 150 mm×30 mm i.d
  7. customat ambient temperature
  8. washeluting with solvents NB (A: 0.1% v/v solution of formic acid in water, B
  9. wait0.1% v/v solution of formic acid in acetonitrile) over 25 min
  10. customThe appropriate fraction was evaporated in-vacuo

Sources & evidence

ORD record
ord-acba8c7e180e4ca7b5164b2fd4098c23
Source dataset
uspto-grants-2013_08
Patent number
US08507543B2

Reaction notes

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