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

HRID 1874731Notes

Reaction equation

HRID 1874731 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 A/B (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 A/B (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-0154d8d43d4f4ff7a0d2ec4661c56ae4
Source dataset
uspto-grants-2012_11
Patent number
US08304446B2

Reaction notes

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