Trifluoroacetic acid → Trifluoroacetic acid

HRID 1892977Notes

Reaction equation

HRID 1892977 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)[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.CC(OC([N:39]1[CH2:44][CH2:43][O:42][CH2:41][C@@H:40]1[C:45]([OH:47])=O)=O)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.[F:65][P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[F:81][C:82]([F:87])([F:86])[C:83]([OH:85])=[O:84]>ClCCl.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][CH:16]=[C:15]([F:65])[C:14]=3[O:20][CH3:21])[N:10]([CH2:9][C:5]3[CH:4]=[C:3]([CH2:2][NH:1][C:45]([C@H:40]4[CH2:41][O:42][CH2:43][CH2:44][NH:39]4)=[O:47])[CH:8]=[CH:7][CH:6]=3)[N:11]=2)(=[O:25])=[O:24])=[CH:30][CH:29]=1.[C:83]([OH:85])([C:82]([F:87])([F:86])[F:81])=[O:84]

Participants

9

Reactant 5

HCID 6422Trifluoroacetic acidHCID 81531DiisopropylethylamineHCID 1512538(3R)-4-(tert-Butoxycarbonyl)morpholine-3-carboxylic acidHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 66664251N-[1-{[3-(Aminomethyl)phenyl]methyl}-6-fluoro-4-(methyloxy)-1H-indazol-3-yl]-5-chloro-2-thiophenesulfonamide

Product 2

HCID 6422Trifluoroacetic acidHCID 59456045(3r)-n-[(3-{[3-{[(5-Chloro-2-thienyl)sulfonyl]amino}-5-fluoro-4-(methyloxy)-1h-indazol-1-yl]methyl}phenyl)methyl]-3-morpholinecarboxamide

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 22036561Dimethyl sulfoxide methanolSolvent

Procedure

N-[1-{[3-(Aminomethyl)phenyl]methyl}-6-fluoro-4-(methyloxy)-1H-indazol-3-yl]-5-chloro-2-thiophenesulfonamide (for a preparation see Intermediate 61) (100 mg, 0.208 mmol) was suspended in dichloromethane (1 mL), (3R)-4-{[(1,1-dimethylethyl)oxy]carbonyl}-3-morpholinecarboxylic acid (52.9 mg, 0.229 mmol) and HATU (87 mg, 0.229 mmol) were added to the reaction mixture and stirred for 5 min. DIPEA (0.109 mL, 0.624 mmol) was added to the reaction mixture and it was left to stir over the weekend. LCMS showed the coupling had gone to completion. Trifluoroacetic acid (0.25 mL, 3.24 mmol) was added to the reaction and left to stir for 1 h and 50 min. LCMS showed the reaction had gone to completion so the mixture was concentrated under a stream of nitrogen to afford a brown residue. The residue 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 required product as an off white residue (as TFA salt). The residue was dissolved in methanol and loaded onto a methanol pre-conditioned SCX-2 ion-exchange cartridge (10 g). The cartridge was washed well with methanol, followed by 2M ammonia in methanol. Evaporation of the solvent from the ammoniacal fractions gave the title compound (76 mg, 61% yield). LCMS (System A) RT=0.83 min, ES+ve m/z 594/596 (M+H)+.

Workup

  1. waitwas left
  2. stirringto stir over the weekend
  3. waitleft
  4. stirringto stir for 1 h and 50 min
  5. concentrationwas concentrated under a stream of nitrogen
  6. customto afford a brown residue
  7. custompurified by Mass Directed AutoPrep on Sunfire C18 column
  8. customThe solvent was evaporated in vacuo

Sources & evidence

ORD record
ord-5b49205a547746e4820a202f7147fbbb
Source dataset
uspto-grants-2013_08
Patent number
US08507543B2

Reaction notes

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