Diisopropylcarbodiimide → 3-cyclopentyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-[6-oxo-4-(2-trifluoromethyl-phenoxy)-6H-pyridazin-1-yl]-propionamide

HRID 2381418Notes

Reaction equation

HRID 2381418 reaction equation
[CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([F:28])([F:27])[F:26])[CH:13]=[N:12]2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N=C=NC(C)C)(C)C.ON1C2C=CC=CC=2N=N1.[NH2:48][C:49]1[CH:53]=[CH:52][N:51]([CH2:54][C:55]([CH3:58])([OH:57])[CH3:56])[N:50]=1>C(Cl)Cl>[CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([F:26])([F:28])[F:27])[CH:13]=[N:12]2)[C:8]([NH:48][C:49]2[CH:53]=[CH:52][N:51]([CH2:54][C:55]([OH:57])([CH3:56])[CH3:58])[N:50]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1

Participants

6

Reactant 4

HCID 12734DiisopropylcarbodiimideHCID 757711-HydroxybenzotriazoleHCID 579191393-cyclopentyl-2-[6-oxo-4-(2-trifluoromethyl-phenoxy)-6H-pyridazin-1-yl]-propionic acid2×HCID 593449381-(3-amino-1H-pyrazol-1-yl)-2-methylpropan-2-ol2×

Product 1

HCID 444635023-cyclopentyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-[6-oxo-4-(2-trifluoromethyl-phenoxy)-6H-pyridazin-1-yl]-propionamideYield 54.1%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent3×

Conditions

Temperature
25 °C

Procedure

A solution of 3-cyclopentyl-2-[6-oxo-4-(2-trifluoromethyl-phenoxy)-6H-pyridazin-1-yl]-propionic acid (Intermediate 21, 200.4 mg, 0.50 mmol) in methylene chloride (5.0 mL, 0.10 M) at 25° C. was treated with N,N′-diisopropylcarbodiimide (80 μL, 0.51 mmol) and 1-hydroxybenzotriazole (70.3 mg, 0.52 mmol). The solution was stirred at 25° C. for 45 min. After this time, the reaction was added to a solution of 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (Intermediate 1, 95.3 mg, 0.61 mmol) in methylene chloride (2.0 mL) at 25° C. The reaction was stirred at 25° C. overnight. After this time, the reaction was diluted with methylene chloride (50 mL) and was washed with a 1N aqueous hydrochloric acid solution (2×50 mL), a saturated aqueous sodium bicarbonate solution (2×50 mL), water (1×50 mL) and a saturated aqueous sodium chloride solution (1×50 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. Silica gel column chromatography (AnaLogix, 40 g, 1-4% methanol/methylene chloride) followed by silica gel column chromatography (AnaLogix 40 g, 1-3% methanol/methylene chloride) afforded 3-cyclopentyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-[6-oxo-4-(2-trifluoromethyl-phenoxy)-6H-pyridazin-1-yl]-propionamide (144.2 mg, 53%) as a white solid; ES+-HRMS m/e calcd for C26H30N5O4F3 [M+H+] 534.2323, found 534.2321. 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.05 (s, 3H), 1.06 (s, 3H), 1.07 (m, 1H), 1.27-1.77 (m, 8H), 1.92 (m, 1H), 2.25 (m, 1H), 3.89 (s, 2H), 4.67 (s, 1H), 5.47 (dd, J=4.4, J=10.8 Hz, 1H), 5.91 (d, J=2.8 Hz, 1H), 6.40 (d, J=2.2 Hz, 1H), 7.52 (d, J=2.2 Hz, 1H), 7.53-7.63 (m, 2H), 7.83 (t, J=7.8 Hz, 1H), 7.90 (d, J=7.2 Hz, 1H), 8.18 (d, J=2.8 Hz, 1H), 10.84 (s, 1H).

Workup

  1. stirringThe reaction was stirred at 25° C. overnight
  2. washwas washed with a 1N aqueous hydrochloric acid solution (2×50 mL)
  3. dry with materiala saturated aqueous sodium bicarbonate solution (2×50 mL), water (1×50 mL) and a saturated aqueous sodium chloride solution (1×50 mL), dried over magnesium sulfate
  4. filtrationfiltered
  5. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-5be1270db8dc49429e5888859e31ad6b
Source dataset
uspto-grants-2012_09
Patent number
US08258134B2

Reaction notes

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