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

HRID 2381493Notes

Reaction equation

HRID 2381493 reaction equation
[CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[CH:14][CH:13]=[N:12]2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[B-](F)(F)(F)F.CN(C(ON1C(=O)CCC1=O)=[N+](C)C)C.C(N(CC)C(C)C)(C)C.[NH2:47][C:48]1[CH:52]=[CH:51][N:50]([CH2:53][C:54]([CH3:57])([OH:56])[CH3:55])[N:49]=1>C(Cl)Cl>[CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[CH:14][CH:13]=[N:12]2)[C:8]([NH:47][C:48]2[CH:52]=[CH:51][N:50]([CH2:53][C:54]([OH:56])([CH3:55])[CH3:57])[N:49]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1

Participants

6

Reactant 4

HCID 81531DiisopropylethylamineHCID 98575222-(2,5-Dioxopyrrolidin-1-yl)-1,1,3,3-tetramethylisouronium tetrafluoroborateHCID 593449381-(3-amino-1H-pyrazol-1-yl)-2-methylpropan-2-ol2×HCID 668753533-cyclopentyl-2-(6-oxo-6H-pyridazin-1-yl)-propionic acid

Product 1

HCID 579191103-cyclopentyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-(6-oxo-6H-pyridazin-1-yl)-propionamideYield 7.6%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Conditions

Temperature
25 °C

Procedure

A solution of 3-cyclopentyl-2-(6-oxo-6H-pyridazin-1-yl)-propionic acid (183 mg, 0.77 mmol) in methylene chloride (4.30 mL, 0.18M) at 25° C. was treated with N,N,N′,N′-tetramethyl-O—(N-succinimidyl)uronium tetrafluoroborate (0.28 g, 0.92 mmol) and N,N-diisopropylethylamine (0.40 mL, 2.32 mmol). The resulting solution was stirred at 25° C. for 2 h. After this time, the reaction was treated with 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (Intermediate 1, 156 mg, 1.0 mmol). The resulting solution was stirred at 25° C. for 2 d. After this time, the reaction was partitioned between water (75 mL) and methylene chloride (3×75 mL). The combined organics were dried over sodium sulfate, filtered and concentrated in vacuo. Silica gel column chromatography (ISCO, 40 g, 1-2% methanol/methylene chloride) afforded 3-cyclopentyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-(6-oxo-6H-pyridazin-1-yl)-propionamide as an off-white solid (21.9 mg, 7.6%); ES+-HRMS m/e calcd for C19H27N5O3 [M+H+] 374.2187 found 374.2187. 1H-NMR (300 MHz, DMSO-d6) δ ppm 0.99-1.72 (m, 9H), 1.05 (s, 3H), 1.06 (s, 3H), 1.92 (m, 1H, CH), 2.28 (m, 1H), 3.89 (s, 2H), 4.67 (s, 1H), 5.52 (dd, J=4.2, J=10.6 Hz, 1H), 6.39 (d, J=2.3 Hz, 1H), 6.94 (dd, Jo=9.4 Hz, Jm=1.5 Hz, 1H), 7.42 (dd, Jo=9.4, Jo=3.8 Hz, 1H), 7.52 (d, J=2.3 Hz, 1H), 8.00 (dd, Jo=3.8 Hz, Jm=1.5 Hz, 1H), 10.79 (s, 1H).

Workup

  1. stirringThe resulting solution was stirred at 25° C. for 2 d
  2. customAfter this time, the reaction was partitioned between water (75 mL) and methylene chloride (3×75 mL)
  3. dry with materialThe combined organics were dried over sodium sulfate
  4. filtrationfiltered
  5. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-714f80b1e44b40e098dea12f3a7213f6
Source dataset
uspto-grants-2012_09
Patent number
US08258134B2

Reaction notes

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