Water → tert-butyl (+/-)-4-(4-(5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxamido)-1-methyl-1H-pyrazol-5-yl)-2-methylpiperazine-1-carboxylate

HRID 1915841Notes

Reaction equation

HRID 1915841 reaction equation
[NH2:1][C:2]1[CH:3]=[N:4][N:5]([CH3:21])[C:6]=1[N:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:9]([CH3:20])[CH2:8]1.[C:22]([O:26][C:27]([NH:29][C:30]1[S:34][C:33]([C:35]2[C:40]([F:41])=[CH:39][CH:38]=[CH:37][C:36]=2[F:42])=[N:32][C:31]=1[C:43](O)=[O:44])=[O:28])([CH3:25])([CH3:24])[CH3:23].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.O>CN(C=O)C>[C:22]([O:26][C:27]([NH:29][C:30]1[S:34][C:33]([C:35]2[C:40]([F:41])=[CH:39][CH:38]=[CH:37][C:36]=2[F:42])=[N:32][C:31]=1[C:43]([NH:1][C:2]1[CH:3]=[N:4][N:5]([CH3:21])[C:6]=1[N:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:14])[CH:9]([CH3:20])[CH2:8]1)=[O:44])=[O:28])([CH3:25])([CH3:23])[CH3:24]

Participants

6

Reactant 4

HCID 962WaterHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 674381985-((Tert-butoxycarbonyl)amino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acidHCID 86680057tert-butyl (+/-)-4-(4-amino-1-methyl-1H-pyrazol-5-yl)-2-methylpiperazine-1-carboxylate

Product 1

HCID 86680059tert-butyl (+/-)-4-(4-(5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxamido)-1-methyl-1H-pyrazol-5-yl)-2-methylpiperazine-1-carboxylateYield 52%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
25 °C

Procedure

To a solution of tert-butyl (±)-4-(4-amino-1-methyl-1H-pyrazol-5-yl)-2-methylpiperazine-1-carboxylate (400 mg, 2.05 mmol), 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid (630 mg, 2.46 mmol), HATU (0.83 g, 8.19 mmol) in DMF (15 mL) was added TEA (1.5 mL). The reaction mixture was stirred at 25° C. for 20 hours and poured into water (100 mL). The mixture was extracted with EtOAc (50 mL×2). The combined organic layers was washed with water (50 mL×2) and brine (30 mL×2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography using DCM/MeOH (1:1) as eluting solvents to afford tert-butyl (±)-4-(4-(5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxamido)-1-methyl-1H-pyrazol-5-yl)-2-methylpiperazine-1-carboxylate (280 mg, 52%) as white solid. 1H NMR (500 MHz, CDCl3) δ (ppm): 10.32 (s, 1H), 8.70 (s, 1H), 7.80 (s, 1H), 7.38-7.35 (m, 1H), 7.06-7.03 (m, 2H), 4.34 (s, 1H), 3.94-3.97 (m, 1H), 3.81 (s, 3H), 3.67-3.40 (m, 1H), 3.20-3.25 (m, 2H), 3.04-3.06 (m, 1H), 2.88-2.90 (m, 1H), 1.55 (s, 9H), 1.47 (s, 9H), 1.34-1.36 (d, J=6.4 Hz, 3H); MS (ESI) m/z=434 (M+H+).

Workup

  1. extractionThe mixture was extracted with EtOAc (50 mL×2)
  2. washThe combined organic layers was washed with water (50 mL×2) and brine (30 mL×2)
  3. dry with materialdried over Na2SO4
  4. filtrationfiltered
  5. concentrationconcentrated under reduced pressure
  6. customto give a residue
  7. customThe residue was purified by silica gel chromatography
  8. washas eluting solvents

Sources & evidence

ORD record
ord-f45a585a64494c19b6c99765c9a4ad32
Source dataset
uspto-grants-2013_12
Patent number
US08614206B2

Reaction notes

Loading…