Sodium hydride → 2-[4-(2-cyano-phenoxy)-6-oxo-6H-pyridazin-1-yl]-3-cyclopentyl-propionic acid methyl ester

HRID 2381352Notes

Reaction equation

HRID 2381352 reaction equation
[O:1]=[C:2]1[NH:7][N:6]=[CH:5][C:4]([O:8][C:9]2[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=2[C:11]#[N:12])=[CH:3]1.[H-].[Na+].[CH3:19][O:20][C:21](=[O:30])[CH:22](Br)[CH2:23][CH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1>O1CCCC1>[CH3:19][O:20][C:21](=[O:30])[CH:22]([N:7]1[C:2](=[O:1])[CH:3]=[C:4]([O:8][C:9]2[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=2[C:11]#[N:12])[CH:5]=[N:6]1)[CH2:23][CH:24]1[CH2:25][CH2:26][CH2:27][CH2:28]1

Participants

5

Reactant 3

HCID 24758Sodium hydrideHCID 57919172Methyl 2-bromo-3-cyclopentylpropanoate2×HCID 579191842-(6-Oxo-1,6-dihydro-pyridazin-4-yloxy)-benzonitrile

Product 1

HCID 579192452-[4-(2-cyano-phenoxy)-6-oxo-6H-pyridazin-1-yl]-3-cyclopentyl-propionic acid methyl esterYield 63.6%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
-10 °C

Procedure

A solution of 2-(6-oxo-1,6-dihydro-pyridazin-4-yloxy)-benzonitrile (13.4 g, 62.9 mmol) in tetrahydrofuran (300 mL) cooled to −10° C. under nitrogen was treated with a 60% suspension of sodium hydride in mineral oil (3.5 g, 88.1 mmol). The reaction was stirred at −10° C. for 10 min and then warmed to 25° C. where it stirred for an additional 40 min. After this time, the reaction was treated with 2-bromo-3-cyclopentylpropionic acid methyl ester (Intermediate 10, 17.7 g, 75.5 mmol). The reaction was warmed to 50° C. for 18 h. After this time, the reaction was partitioned between water and methylene chloride. The aqueous layer was back extracted with methylene chloride. The combined organics were washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, rinsed and concentrated in vacuo. Silica gel column chromatography afforded 2-[4-(2-cyano-phenoxy)-6-oxo-6H-pyridazin-1-yl]-3-cyclopentyl-propionic acid methyl ester (14.7 g, 63%) as a pale yellow solid; ESI-MS 368 [M+H+]; HPLC: >92% (purity). 1H-NMR (300 MHz, CDCl3) δ 7.91 (s, 1H), 7.69-7.79 (m, 2H), 7.41-7.46 (m, 1H), 7.28-7.31 (m, 1H), 5.97 (s, 1H), 5.52-5.57 (m, 1H), 3.73 (s, 3H), 2.28-2.37 (m, 1H), 2.04-2.15 (m, 1H), 1.48-1.81 (m, 7H), 1.11-1.28 (m, 2H).

Workup

  1. temperaturewarmed to 25° C. where it
  2. stirringstirred for an additional 40 min
  3. temperatureThe reaction was warmed to 50° C. for 18 h
  4. customAfter this time, the reaction was partitioned between water and methylene chloride
  5. extractionThe aqueous layer was back extracted with methylene chloride
  6. washThe combined organics were washed with a saturated aqueous sodium chloride solution
  7. dry with materialdried over sodium sulfate
  8. filtrationfiltered
  9. washrinsed
  10. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-12540bed6060458a9c7eff30fbbf95be
Source dataset
uspto-grants-2012_09
Patent number
US08258134B2

Reaction notes

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