Trifluoroacetic acid → HCID 59456014, compound

HRID 1808630Notes

Reaction equation

HRID 1808630 reaction equation
Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH2:10][N:11]2[C:19]3[C:14](=[C:15]([O:20][CH3:21])[CH:16]=[CH:17][CH:18]=3)[C:13]([NH:22][S:23]([C:26]3[S:27][C:28]([Cl:31])=[CH:29][CH:30]=3)(=[O:25])=[O:24])=[N:12]2)[CH:7]=[CH:8][CH:9]=1.C([NH:39][C:40]([CH3:45])([C:42](O)=[O:43])[CH3:41])(OC(C)(C)C)=O.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.C(O)(C(F)(F)F)=O>CN(C=O)C.CO.CS(C)=O>[Cl:31][C:28]1[S:27][C:26]([S:23]([NH:22][C:13]2[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH3:21])[N:11]([CH2:10][C:6]3[CH:5]=[C:4]([CH2:3][NH:2][C:42](=[O:43])[C:40]([CH3:45])([CH3:41])[NH2:39])[CH:9]=[CH:8][CH:7]=3)[N:12]=2)(=[O:25])=[O:24])=[CH:30][CH:29]=1

Participants

8

Reactant 5

HCID 6422Trifluoroacetic acid3×HCID 81531DiisopropylethylamineHCID 2733845N-((1,1-dimethylethoxy)carbonyl)-2-methyl-alanineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 66632476N-[1-{[3-(Aminomethyl)phenyl]methyl}-4-(methyloxy)-1H-indazol-3-yl]-5-chloro-2-thiophenesulfonamide hydrochloride

Product 1

HCID 59456014HCID 59456014, compoundYield 42%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 22036561Dimethyl sulfoxide methanolSolvent

Procedure

A mixture of N-[1′-{[3-(aminomethyl)phenyl]methyl}-4-(methyloxy)-1H-indazol-3-yl]-5-chloro-2-thiophenesulfonamide hydrochloride (for a preparation see intermediate 4) (529 mg, 1.06 mmol), N—BOC-alpha-methylalanine (Sigma) (248 mg, 1.22 mmol), HATU (503 mg, 1.32 mmol) was stirred in DMF (2 mL) and DIPEA (0.75 mL, 4.4 mmol) until the mixture dissolved and then stood overnight at room temperature. The mixture was then treated with TFA (1.5 mL, 19.5 mmol) at room temperature and after 45 min more TFA (1.5 mL, 19.5 mmol) added. After 1.5 h more TFA (1 mL) was added and the mixture was stirred for 18 h. The mixture was concentrated under reduced pressure and the residue was loaded in methanol and purified by SPE on ion exchange cartridge (SCX-2) 50 g eluting with MeOH, followed by 10% aqueous ammonia in MeOH. The appropriate ammoniacal fractions were combined and evaporated in vacuo to give the crude product. The sample was dissolved in 1:1 MeOH-DMSO 8 mL and purified by Mass Directed AutoPrep on Xbridge column using Acetonitrile Water with an ammonium carbonate modifier (Method C) collecting the peak with RT˜6.0 min. The solvent was evaporated in vacuo to give the title compound (242 mg, 42%): LCMS (System C) RT=2.01 min, ES+ve m/z 548/550 (M+H)+; NMR δ (CD3OD) 7.26-7.13 (4H, m), 7.10 (1H, br d, J 7 Hz), 7.05 (1H, br s), 6.92 (1H, d, J 8 Hz), 6.86 (1H, d, J 4 Hz), 6.40 (1H, d, J 8 Hz), 5.45 (2H, s), 4.31 (2H, s), 3.77 (3H, s), 1.31 (6H, s).

Workup

  1. additionadded
  2. concentrationThe mixture was concentrated under reduced pressure
  3. custompurified by SPE on ion exchange cartridge (SCX-2) 50 g
  4. washeluting with MeOH
  5. customevaporated in vacuo
  6. customto give the crude product
  7. custompurified by Mass Directed AutoPrep on Xbridge column
  8. customcollecting the peak with RT˜6.0 min
  9. customThe solvent was evaporated in vacuo

Sources & evidence

ORD record
ord-3bb1bfb748fe4ab9bbee9b1ecc2cc929
Source dataset
uspto-grants-2013_01
Patent number
US08357716B2

Reaction notes

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