4-Methylmorpholine → 5-Chloro-2-(4-fluoro-phenoxy)-N-[4-(1-hydroxy-1-methyl-ethyl)-benzyl]-nicotinamide

HRID 1297593Notes

Reaction equation

HRID 1297593 reaction equation
[Cl:1][C:2]1[CH:3]=[N:4][C:5]([O:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.CN1CCOCC1.ClC(OCC(C)C)=O.[OH:34][C:35]([C:38]1[CH:45]=[CH:44][C:41]([CH2:42][NH2:43])=[CH:40][CH:39]=1)([CH3:37])[CH3:36]>ClCCl.O>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([O:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[C:6]([CH:10]=1)[C:7]([NH:43][CH2:42][C:41]1[CH:44]=[CH:45][C:38]([C:35]([OH:34])([CH3:36])[CH3:37])=[CH:39][CH:40]=1)=[O:9]

Participants

7

Reactant 4

HCID 79724-MethylmorpholineHCID 62365Isobutyl chloroformateHCID 101542112-[4-(aminomethyl)phenyl]propan-2-olHCID 178328455-Chloro-2-(4-fluorophenoxy)nicotinic acid

Product 1

HCID 589151875-Chloro-2-(4-fluoro-phenoxy)-N-[4-(1-hydroxy-1-methyl-ethyl)-benzyl]-nicotinamideYield 75.8%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6344DichloromethaneSolvent

Procedure

5-Chloro-2-(4-fluoro-phenoxy)-nicotinic acid (1.37 g) was dissolved in anhydrous dichloromethane (15 mL). 4-Methylmorpholine (0.80 mL) was added and the solution cooled in a dry ice/acetone bath. Isobutyl chloroformate (0.85 mL) was added and the solution stirred for 15 minutes. 4-(1-Hydroxy-1-methyl-ethyl)-benzyl amine (0.946 g) was added and the solution warmed to ambient temperature overnight. The solution was then poured into a separatory funnel and water (15 mL) was added. The solution was shaken, and the organics were removed. The remaining aqueous portion was extracted with dichloromethane (6×20 mL). The combined organics were dried over magnesium sulfate, filtered and concentrated to dryness in vacuo to yield the crude product (2.65 g). Purification of the crude material by silica gel chromatography (ethyl acetate:hexanes 1:3) yielded pure title compound (1.61 g).

Workup

  1. temperaturethe solution cooled in a dry ice/acetone bath
  2. additionThe solution was then poured into a separatory funnel
  3. stirringThe solution was shaken
  4. customthe organics were removed
  5. extractionThe remaining aqueous portion was extracted with dichloromethane (6×20 mL)
  6. dry with materialThe combined organics were dried over magnesium sulfate
  7. filtrationfiltered
  8. concentrationconcentrated to dryness in vacuo
  9. customto yield the crude product (2.65 g)
  10. customPurification of the crude material by silica gel chromatography (ethyl acetate:hexanes 1:3)

Sources & evidence

ORD record
ord-7845f9e65ce84993968ef16b775a4342
Source dataset
uspto-grants-2007_07
Patent number
US07250518B2

Reaction notes

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