Triethylamine → 5-(2-Chloro-phenyl)-3-(tetrahydro-pyran-2-yloxymethyl)-isoxazole-4-carboxylic acid ethyl ester

HRID 349260

Reaction equation

HRID 349260 reaction equation
[N+:1]([CH2:4][CH2:5][O:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][O:8]1)([O-:3])=O.[CH2:13]([O:15][C:16](=[O:26])[C:17]#[C:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[Cl:25])[CH3:14].C1(N=C=O)C=CC(N=C=O)=CC=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:13]([O:15][C:16]([C:17]1[C:4]([CH2:5][O:6][CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][O:8]2)=[N:1][O:3][C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[Cl:25])=[O:26])[CH3:14]

Participants

6

Reactant 4

HCID 8471TriethylamineHCID 610091,4-DiisocyanatobenzeneHCID 641308Ethyl 3-(2-chlorophenyl)prop-2-ynoateHCID 37486562-(2-Nitroethoxy)tetrahydropyran

Product 1

HCID 691236215-(2-Chloro-phenyl)-3-(tetrahydro-pyran-2-yloxymethyl)-isoxazole-4-carboxylic acid ethyl esterYield 94.2%

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent2×

Conditions

Temperature
70 °C

Procedure

Add 2-(2-nitroethoxy)tetrahydropyran (41 mL, 270 mmol) dropwise in toluene (100 mL) to a solution of (2-chloro-phenyl)-propynoic acid ethyl ester (28.3 g, 135 mmol), 1,4-phenylene diisocyanate (67 g, 420 mmol) and triethylamine (15 mL) in toluene (900 mL). Stir at reflux for 10 h. While still warm (˜70° C.), filter the reaction mixture through Celite®, washing the solids with EtOAc. Wash the filtrate with 1N HCl (500 mL) and brine (500 mL). Dry the organics over Na2SO4, filter and concentrate under reduced pressure. Purification by flash chromatography (silica gel, 85:15 Hexanes/EtOAc) gives the title compound (46.5 g, 94%). MS (m/e): 282 (M−C5H8O+H+); 1H NMR (300 MHz, CDCl3) δ 7.35–7.55 (m, 4H), 5.09 (d, J=13 Hz, 1), 4.85–4.91 (m, 2H), 4.15–4.22 (m, 2H), 3.91–4.01 (m, 1H), 3.52–3.61 (m, 1H), 1.49–1.92 (m, 6H), 1.12 (t, J=7 Hz, 3H); TLC Rf=0.53 (7:3 Hexanes/EtOAc).

Workup

  1. temperatureat reflux for 10 h
  2. filtrationfilter the reaction mixture through Celite®
  3. washwashing the solids with EtOAc
  4. washWash the filtrate with 1N HCl (500 mL) and brine (500 mL)
  5. dry with materialDry the organics over Na2SO4
  6. filtrationfilter
  7. concentrationconcentrate under reduced pressure
  8. customPurification by flash chromatography (silica gel, 85:15 Hexanes/EtOAc)

Sources & evidence

ORD record
ord-341fc749cbda49a795d8b7d91d739698
Source dataset
uspto-grants-2007_02
Patent number
US07179804B2

Linked notes

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