Hydrochloric Acid → 2-Ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-6-[(3S)-3-(hydroxymethyl)-morpholin-4-yl]-4-methyl-pyridine-3-carboxylic acid amide

HRID 1753886Notes

Reaction equation

HRID 1753886 reaction equation
[NH:1]1[CH2:6][CH2:5][O:4][CH2:3][C@@H:2]1[CH2:7][OH:8].C[Si](C)(C)N[Si](C)(C)C.C[Si](C)(C)Cl.Cl[C:24]1[N:29]=[C:28]([S:30][CH2:31][CH3:32])[C:27]([C:33]([NH:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([F:43])[CH:38]=2)=[O:34])=[C:26]([CH3:44])[CH:25]=1.CCN(C(C)C)C(C)C.Cl.C([O-])(O)=O.[Na+]>C1COCC1.CN1C(=O)CCC1>[CH2:31]([S:30][C:28]1[C:27]([C:33]([NH:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([F:43])[CH:38]=2)=[O:34])=[C:26]([CH3:44])[CH:25]=[C:24]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][C@@H:2]2[CH2:7][OH:8])[N:29]=1)[CH3:32]

Participants

10

Reactant 7

HCID 313Hydrochloric AcidHCID 6397Chlorotrimethylsilane2×HCID 13838HexamethyldisilazaneHCID 81531DiisopropylethylamineHCID 516892Sodium BicarbonateHCID 1514268(S)-3-HydroxymethylmorpholineHCID 866643146-chloro-2-ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-4-methyl-pyridine-3-carboxylic acid amide

Product 1

HCID 569625252-Ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-6-[(3S)-3-(hydroxymethyl)-morpholin-4-yl]-4-methyl-pyridine-3-carboxylic acid amideYield 13.1%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolventHCID 13387N-methyl-2-pyrrolidoneSolvent

Procedure

To a cooled (ice-bath) solution of 450 mg (1.32 mmol) (S)-morpholin-3-yl-methanol in THF (5 ml) were added at 0° C. 570 μl (2.78 mmol) 1,1,1,3,3,3 hexamethyldisilazane and 33 μl (0.26 mmol) trimethylchlorosilane. The mixture was then stirred at RT for 1 h. Then another 33 μl (0.26 mmol) trimethylchlorosilane was added and stirring was continued at RT for 1 h followed by concentration in vacuo. The residue, 450 mg (1.3 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) and 903 μl (5.3 mmol) DIPEA were suspended in NMP (1.5 ml). Then the reaction mixture was heated at 180° C. for 32 h and stirred at RT for 72 h. Subsequently a 1M hydrochlorid acid was added and the mixture was stirred at RT for 15 min. After neutralization with a sat. aq. NaHCO3 sol. EtOAc was added and the layers were separated. The organic layer was washed with water and brine, dried over MgSO4 and concentrated in vacuo. Purification of the residue by CC (cyclohexane/EtOAc 1:1) provided mg (0.17 mmol, 13%) 2-Ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-6-[(3S)-3-(hydroxymethyl)-morpholin-4-yl]-4-methyl-pyridine-3-carboxylic acid amide (example 263). [M+H]+420.2

Workup

  1. additionwere added at 0° C
  2. stirringstirring
  3. waitwas continued at RT for 1 h
  4. concentrationfollowed by concentration in vacuo
  5. temperatureThen the reaction mixture was heated at 180° C. for 32 h
  6. stirringstirred at RT for 72 h
  7. stirringthe mixture was stirred at RT for 15 min
  8. customthe layers were separated
  9. washThe organic layer was washed with water and brine
  10. dry with materialdried over MgSO4
  11. concentrationconcentrated in vacuo
  12. customPurification of the residue by CC (cyclohexane/EtOAc 1:1)

Sources & evidence

ORD record
ord-a65a86f848de48b3bc734497f8640522
Source dataset
uspto-grants-2015_10
Patent number
US09168259B2

Reaction notes

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