Diisopropylethylamine → (R)-tert-butyl 2-bromo-4-(1-cyclopropyl-5-(4-(2,2,2-trifluoroacetamido)azepan-1-yl)-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate

HRID 1915798Notes

Reaction equation

HRID 1915798 reaction equation
[CH:1]1([N:4]2[C:8]([N:9]3[CH2:15][CH2:14][CH2:13][C@@H:12]([NH:16][C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])[CH2:11][CH2:10]3)=[C:7]([N+:23]([O-])=O)[CH:6]=[N:5]2)[CH2:3][CH2:2]1.C([O-])=O.[NH4+].[Br:30][C:31]1[S:32][C:33]([NH:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])=[C:34]([C:36](O)=[O:37])[N:35]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CO.[Pd].O>[Br:30][C:31]1[S:32][C:33]([NH:39][C:40](=[O:41])[O:42][C:43]([CH3:45])([CH3:44])[CH3:46])=[C:34]([C:36](=[O:37])[NH:23][C:7]2[CH:6]=[N:5][N:4]([CH:1]3[CH2:3][CH2:2]3)[C:8]=2[N:9]2[CH2:15][CH2:14][CH2:13][C@@H:12]([NH:16][C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])[CH2:11][CH2:10]2)[N:35]=1

Participants

9

Reactant 5

HCID 81531DiisopropylethylamineHCID 2723923Ammonium formateHCID 2724699PyBOPHCID 581821562-Bromo-5-((tert-butoxycarbonyl)amino)thiazole-4-carboxylic acidHCID 86658415(R)-N-(1-(1-cyclopropyl-4-nitro-1H-pyrazol-5-yl)azepan-4-yl)-2,2,2-trifluoroacetamide

Product 1

HCID 86680007(R)-tert-butyl 2-bromo-4-(1-cyclopropyl-5-(4-(2,2,2-trifluoroacetamido)azepan-1-yl)-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate

Reagents, catalysts & solvents 3

HCID 23938PalladiumCatalystHCID 887MethanolSolventHCID 962WaterSolvent

Conditions

Temperature
80 °C

Procedure

To a solution of (R)—N-(1-(1-cyclopropyl-4-nitro-1H-pyrazol-5-yl)azepan-4-yl)-2,2,2-trifluoroacetamide (0.725 g, 2.00 mmol) in MeOH (20 mL) was added 10% palladium on carbon (0.75 g, 7.07 mmol) and ammonium formate (0.507 g, 8.03 mmol). The mixture was heated at 80° C. for 3 hr. The mixture was filtered through Celite® and the filtrate concentrated under reduced pressure. The residue was re-dissolved in DCM (20 mL) and 2-bromo-5-(tert-butoxycarbonylamino)thiazole-4-carboxylic acid (0.74 g, 2.29 mmol), PyBOP (1.57 g, 3.01 mmol) and DIPEA (1 mL, 5.6 mmol) were added. The reaction mixture was stirred at room temperature for 18 hr. Water (20 mL) was added and stirring continued for 10 min. The layers were separated and the aqueous extracted with DCM (2×20 mL). The combined organic layers were passed through a phase separation cartridge and the solvent removed under reduced pressure. The residue was purified by silica gel column chromatography (0-100% EtOAc/isohexane) to afford (R)-tert-butyl 2-bromo-4-(1-cyclopropyl-5-(4-(2,2,2-trifluoroacetamido)azepan-1-yl)-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate as a pale brown solid (0.98 g, 77% over two steps). 1H NMR (400 MHz, CDCl3) δ 10.26 (s, 1H), 8.43 (s, 1H), 7.71 (s, 1H), 6.47 (d, J=8.3 Hz, 1H), 4.25-4.15 (m, 1H), 3.47-3.35 (m, 3H), 3.29-3.13 (m, 2H), 2.46-1.57 (m, 6H), 1.52 (s, 9H), 1.23-1.17 (m, 2H), 1.12-0.96 (m, 2H).

Workup

  1. filtrationThe mixture was filtered through Celite®
  2. concentrationthe filtrate concentrated under reduced pressure
  3. dissolutionThe residue was re-dissolved in DCM (20 mL)
  4. stirringstirring
  5. waitcontinued for 10 min
  6. customThe layers were separated
  7. extractionthe aqueous extracted with DCM (2×20 mL)
  8. customThe combined organic layers were passed through a phase separation cartridge
  9. customthe solvent removed under reduced pressure
  10. customThe residue was purified by silica gel column chromatography (0-100% EtOAc/isohexane)

Sources & evidence

ORD record
ord-ec0583235b1a46e086f86065ffa6b77a
Source dataset
uspto-grants-2013_12
Patent number
US08614206B2

Reaction notes

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