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

HRID 2381356Notes

Reaction equation

HRID 2381356 reaction equation
[CH:1]1([CH2:6][O:7][C:8]2[CH:13]=[N:12][NH:11][C:10](=[O:14])[CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH3:17][O:18][C:19](=[O:28])[CH:20](Br)[CH2:21][CH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1>O1CCCC1>[CH3:17][O:18][C:19](=[O:28])[CH:20]([N:11]1[C:10](=[O:14])[CH:9]=[C:8]([O:7][CH2:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[CH:13]=[N:12]1)[CH2:21][CH:22]1[CH2:23][CH2:24][CH2:25][CH2:26]1

Participants

5

Reactant 3

HCID 24758Sodium hydrideHCID 57919172Methyl 2-bromo-3-cyclopentylpropanoate2×HCID 668751985-(cyclopentylmethoxy)pyridazin-3(2H)-one

Product 1

HCID 668748313-cyclopentyl-2-(4-cyclopentylmethoxy-6-oxo-6H-pyridazin-1-yl)-propionic acid methyl esterYield 80.7%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
0 °C

Procedure

A solution of 5-cyclopentylmethoxy-2H-pyridazin-3-one (494.8 mg, 2.54 mmol) in tetrahydrofuran (12 mL, 0.21 M) cooled to 0° C. was treated with a 60% suspension of sodium hydride in mineral oil (0.12 g, 3.0 mmol). The reaction stirred at 0° C. for 5 min and then at 25° C. for an additional 30 min. After this time, the reaction was treated with 2-bromo-3-cyclopentyl-propionic acid methyl ester (Intermediate 10, 0.67 g, 2.84 mmol). The reaction was then warmed to 50° C., where it stirred overnight. The reaction sat 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 organic layers were washed with a saturated aqueous sodium chloride solution (1×75 mL), dried over magnesium sulfate, filtered, rinsed and concentrated in vacuo. Silica gel column chromatography (AnaLogix 40 g, 10-30% ethyl acetate/hexanes) afforded 3-cyclopentyl-2-(4-cyclopentylmethoxy-6-oxo-6H-pyridazin-1-yl)-propionic acid methyl ester (713.9 mg, 80%) as a clear light yellow oil; ES+-HRMS m/e calcd for C19H28N2O4 [M+H+] 349.2122, found 349.2120. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.18 (m, 2H), 1.23-1.82 (m, 15H), 1.87-1.98 (m, 1H), 2.05-2.23 (m, 1H), 2.23-2.37 (m, 1H), 3.61 (s, 3H), 3.91 (d, J=7.0 Hz, 2H), 5.39 (dd, J=10.9, 4.3 Hz, 1H), 6.31 (d, J=2.8 Hz, 1H), 7.83 (d, J=2.8 Hz, 1H).

Workup

  1. waitat 25° C. for an additional 30 min
  2. temperatureThe reaction was then warmed to 50° C.
  3. stirringwhere it stirred overnight
  4. waitThe reaction sat at 25° C. for 2 d
  5. customAfter this time, the reaction was partitioned between water (75 mL) and methylene chloride (3×75 mL)
  6. washThe combined organic layers were washed with a saturated aqueous sodium chloride solution (1×75 mL)
  7. dry with materialdried over magnesium sulfate
  8. filtrationfiltered
  9. washrinsed
  10. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-8111da500945459782f14297a3062c59
Source dataset
uspto-grants-2012_09
Patent number
US08258134B2

Reaction notes

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