Ammonium Chloride → (5-Cyano-2-nitro-phenyl)-(5-morpholin-4-ylmethyl-pyridin-2-yl)-acetic acid ethyl ester

HRID 423147Notes

Reaction equation

HRID 423147 reaction equation
[CH2:1]([O:3][C:4](=[O:19])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:8][N:7]=1)[CH3:2].F[C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=1[N+:29]([O-:31])=[O:30])[C:24]#[N:25].CC(C)([O-])C.[Li+].[Cl-].[NH4+]>C1(C)C=CC=CC=1.O1CCCC1>[CH2:1]([O:3][C:4](=[O:19])[CH:5]([C:21]1[CH:22]=[C:23]([C:24]#[N:25])[CH:26]=[CH:27][C:28]=1[N+:29]([O-:31])=[O:30])[C:6]1[CH:11]=[CH:10][C:9]([CH2:12][N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:8][N:7]=1)[CH3:2]

Participants

7

Reactant 4

HCID 25517Ammonium ChlorideHCID 27833993-Fluoro-4-nitrobenzonitrileHCID 236647642-Propanol, 2-methyl-, lithium salt (1:1)HCID 44248634Ethyl 2-[5-(morpholin-4-ylmethyl)pyridin-2-yl]acetate

Product 1

HCID 66674207(5-Cyano-2-nitro-phenyl)-(5-morpholin-4-ylmethyl-pyridin-2-yl)-acetic acid ethyl ester

Reagents, catalysts & solvents 2

HCID 1140TolueneSolventHCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-20 °C

Procedure

To a solution of (5-Morpholin-4-ylmethyl-pyridin-2-yl)-acetic acid ethyl ester (51.03 g, 74.5% w/w %, 143.8 mmol; Example 5) in toluene (204.1 ml) was added a solution of 3-fluoro-4-nitrobenzonitrile (24.5 g, 151 mmol) in tetrahydrofuran (357 ml) and the solution was degassed three times with nitrogen and then cooled to −20° C. Lithium tert-butoxide solution in tetrahydrofuran (137. ml, 20 w/w %, 302 mmol) was added dropwise over 1 hr. After stirring for an additional 1 hr 20 min the reaction mixture was then added to a cold aqueous solution of ammonium chloride (188 ml, 4.58M, 6862.7 mmol) at 0° C. The biphasic mixture was warmed to 30° C. and Celite® (76.5 g) added, then filtered. The filter cake was washed twice with toluene (153 ml) then the combined filtrate was separated and the organic layer washed twice with water (153 ml). The organic layer was concentrated by distillation to give (5-Cyano-2-nitro-phenyl)-(5-morpholin-4-ylmethyl-pyridin-2-yl)-acetic acid ethyl ester as a toluene solution (196 ml) (titration, HClO4, assay 80.47 w/w %). The crude product mixture is directly used in the next step.

Workup

  1. customthe solution was degassed three times with nitrogen
  2. temperatureThe biphasic mixture was warmed to 30° C.
  3. additionCelite® (76.5 g) added
  4. filtrationfiltered
  5. washThe filter cake was washed twice with toluene (153 ml)
  6. customthe combined filtrate was separated
  7. washthe organic layer washed twice with water (153 ml)
  8. concentrationThe organic layer was concentrated by distillation

Sources & evidence

ORD record
ord-64e891ea3dc64d47a406b41b7485951e
Source dataset
uspto-grants-2012_01
Patent number
US08101750B2

Reaction notes

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