Picolinic acid → 2-Ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-4-methyl-6-(3-oxo-morpholin-4-yl)-pyridine-3-carboxylic acid amide

HRID 1753890Notes

Reaction equation

HRID 1753890 reaction equation
Cl[C:2]1[N:7]=[C:6]([S:8][CH2:9][CH3:10])[C:5]([C:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)=[O:12])=[C:4]([CH3:22])[CH:3]=1.[Na+].[I-].ClC([SiH3])(Cl)Cl.C([O-])([O-])=O.[Cs+].[Cs+].N1C=CC=CC=1C(O)=O.[NH:45]1[CH2:50][CH2:49][O:48][CH2:47][C:46]1=[O:51]>C(#N)CC.[Cu]I>[CH2:9]([S:8][C:6]1[C:5]([C:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)=[O:12])=[C:4]([CH3:22])[CH:3]=[C:2]([N:45]2[CH2:50][CH2:49][O:48][CH2:47][C:46]2=[O:51])[N:7]=1)[CH3:10]

Participants

9

Reactant 6

HCID 1018Picolinic acidHCID 5238Sodium IodideHCID 10796Cesium carbonateHCID 669533-MorpholinoneHCID 71317501CID 71317501HCID 866643146-chloro-2-ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-4-methyl-pyridine-3-carboxylic acid amide

Product 1

HCID 672872292-Ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-4-methyl-6-(3-oxo-morpholin-4-yl)-pyridine-3-carboxylic acid amideYield 5.1%

Reagents, catalysts & solvents 2

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 7854PropionitrileSolvent

Conditions

Temperature
110 °C

Procedure

A solution of 1.0 g (2.95 mmol) 6-chloro-2-ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-4-methyl-pyridine-3-carboxylic acid amide (synthesis is described in section b) of example 2) in propionitrile (20 ml) was treated with 1.33 g (8.87 mmol) NaI and 1.0 ml (8.28 mmol) trichloromethylsilane. Subsequently the solution was heated at 110° C. for 16 h. The mixture was then partitioned between a 2M aq. NaOH sol and EtOAc. The organic layer was separated, washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was dissolved in dioxane (10 ml) and 2.26 g (7.0 mmol) Cs2CO3 and 114 mg (0.92 mmol) picolinic acid were added. This mixture was degassed for 30 min followed by the addition of 88 mg (0.46 mmol) CuI and 470 mg (4.65 mmol) 3-morpholinone. The reaction solution was then heated to 100° C. for 16 h and subsequently concentrated in vacuo. The residue was dissolved in water and was extracted with EtOAc. The organic layer was washed with water and brine, dried over Na2SO4 and concentrated in vacuo. Purification of the residue by CC (hexane/EtOAc 7:3) provided 60 mg (0.15 mmol, 5%) 2-Ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-4-methyl-6-(3-oxo-morpholin-4-yl)-pyridine-3-carboxylic acid amide (example 312). [M+H]+404.1.

Workup

  1. customThe mixture was then partitioned between a 2M aq. NaOH sol and EtOAc
  2. customThe organic layer was separated
  3. washwashed with brine
  4. dry with materialdried over Na2SO4
  5. concentrationconcentrated in vacuo
  6. dissolutionThe residue was dissolved in dioxane (10 ml)
  7. customThis mixture was degassed for 30 min
  8. temperatureThe reaction solution was then heated to 100° C. for 16 h
  9. concentrationsubsequently concentrated in vacuo
  10. dissolutionThe residue was dissolved in water
  11. extractionwas extracted with EtOAc
  12. washThe organic layer was washed with water and brine
  13. dry with materialdried over Na2SO4
  14. concentrationconcentrated in vacuo
  15. customPurification of the residue by CC (hexane/EtOAc 7:3)

Sources & evidence

ORD record
ord-f35465ba036547bfba952171b6145e12
Source dataset
uspto-grants-2015_10
Patent number
US09168259B2

Reaction notes

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