Methanamine, N-methoxy-, hydrochloride (1:1) → 5-(2-chloro-phenyl)-3-(tetrahydro-pyran-2-yloxymethyl)-isoxazole-4-carboxylic acid methoxy-N-methyl-amide

HRID 349261Notes

Reaction equation

HRID 349261 reaction equation
C([Mg]Cl)(C)C.C(O[C:9]([C:11]1[C:12]([CH2:23][O:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)=[N:13][O:14][C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[Cl:22])=[O:10])C.Cl.[CH3:32][NH:33][O:34][CH3:35]>C1COCC1>[CH3:35][O:34][N:33]([CH3:32])[C:9]([C:11]1[C:12]([CH2:23][O:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)=[N:13][O:14][C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[Cl:22])=[O:10]

Participants

5

Reactant 3

HCID 81138Methanamine, N-methoxy-, hydrochloride (1:1)HCID 691236215-(2-Chloro-phenyl)-3-(tetrahydro-pyran-2-yloxymethyl)-isoxazole-4-carboxylic acid ethyl esterHCID 178418918HCID 178418918, compound

Product 1

HCID 866012155-(2-chloro-phenyl)-3-(tetrahydro-pyran-2-yloxymethyl)-isoxazole-4-carboxylic acid methoxy-N-methyl-amideYield 52%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

Add 2M iso-propylmagnesium chloride (717 mL, 1.4 mol) to a −10° C. solution of 5-(2-chloro-phenyl)-3-(tetrahydro-pyran-2-yloxymethyl)-isoxazole-4-carboxylic acid ethyl ester (175 g, 478 mmol) and N,O-dimethylhydroxylamine hydrochloride (56 g, 574 mmol) in THF (2 L). Stir the reaction for 45 min. and then slowly quench with a 1:1 mixture of sat. NH4Cl and water (750 mL). Extract the mixture with EtOAc (3×500 mL). Wash the organic phase with brine (1000 mL), dry over Na2SO4, filter, and concentrate under reduced pressure. Purification by flash chromatography (silica gel, 7:3 hexanes/EtOAc) gives the title compound (27 g, 52%). MS (m/e): 381 (M+H)+; m.p.=51–56° C.; 1H NMR (300 MHz, CDCl3) δ7.32–7.60 (m, 4H), 5.00 (d, J=14 Hz, 1H), 4.78–4.81 (m, 1H), 4.73 (d, J=14 Hz, 1H), 3.85–3.98 (m, 1H), 3.52–3.61 (m, 1H), 3.40 (s, 3H), 3.10–3.29 (m, 3H), 1.50–1.82 (m, 6H); HPLC >99%; TLC Rf=0.41 (1:1 Hexanes/EtOAc).

Workup

  1. customthe reaction for 45 min.
  2. customslowly quench with a 1:1 mixture of sat. NH4Cl and water (750 mL)
  3. extractionExtract the mixture with EtOAc (3×500 mL)
  4. washWash the organic phase with brine (1000 mL)
  5. dry with materialdry over Na2SO4
  6. filtrationfilter
  7. concentrationconcentrate under reduced pressure
  8. customPurification by flash chromatography (silica gel, 7:3 hexanes/EtOAc)

Sources & evidence

ORD record
ord-1b42bbf7faa847fba63004f56f48a505
Source dataset
uspto-grants-2007_02
Patent number
US07179804B2

Reaction notes

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