Trifluoroacetic acid → (3s)-n-[(3-{[3-{[(5-Chloro-2-thienyl)sulfonyl]amino}-5-fluoro-4-(methyloxy)-1h-indazol-1-yl]methyl}phenyl)methyl]-3-morpholinecarboxamide

HRID 1892976Notes

Reaction equation

HRID 1892976 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])[C:15]([F:19])=[CH:16][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](O)=[O:46])=O)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[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:19])[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:46])[CH:8]=[CH:7][CH:6]=3)[N:11]=2)(=[O:25])=[O:24])=[CH:30][CH:29]=1

Participants

7

Reactant 5

HCID 6422Trifluoroacetic acidHCID 81531DiisopropylethylamineHCID 1512537(3S)-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 59455989N-[1-{[3-(Aminomethyl)phenyl]methyl}-5-fluoro-4-(methyloxy)-1H-indazol-3-yl]-5-chloro-2-thiophenesulfonamide

Product 1

HCID 59456083(3s)-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 1

HCID 6344DichloromethaneSolvent

Procedure

N-[1-{[3-(Aminomethyl)phenyl]methyl}-5-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 DCM (1 mL), (3S)-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 stirred 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. 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 required product (as TFA salts). 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 as a colourless glassy solid (71 mg, 57%). LCMS (System A) RT=0.82 min, ES+ve m/z 594/596 (M+H)+.

Workup

  1. stirringstirred over the weekend
  2. waitleft
  3. stirringto stir for 1 h and 50 min
  4. concentrationwas concentrated under a stream of nitrogen
  5. dissolutionThe sample was dissolved in 1:1 MeOH-DMSO (1 mL)
  6. custompurified by Mass Directed AutoPrep on Sunfire C18 column
  7. customThe solvent was evaporated in vacuo

Sources & evidence

ORD record
ord-f1a89514adce42c6866e62cab9885e95
Source dataset
uspto-grants-2013_08
Patent number
US08507543B2

Reaction notes

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