Sodium Carbonate → 5-Ethoxycarbonylmethyl-3-(4-fluoro-2-methanesulfonyl-phenyl)-2-methyl-2,5-dihydro-[1,2,4]oxadiazole-5-carboxylic acid ethyl ester

HRID 1822705Notes

Reaction equation

HRID 1822705 reaction equation
[F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([S:10]([CH3:13])(=[O:12])=[O:11])[CH:3]=1.Cl.[CH3:15][NH:16][OH:17].C(=O)([O-])[O-].[Na+].[Na+].[C:24]([C:31]([O:33][CH2:34][CH3:35])=[O:32])#[C:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>O.C(O)C>[CH2:34]([O:33][C:31]([C:24]1([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[O:17][N:16]([CH3:15])[C:6]([C:5]2[CH:8]=[CH:9][C:2]([F:1])=[CH:3][C:4]=2[S:10]([CH3:13])(=[O:12])=[O:11])=[N:7]1)=[O:32])[CH3:35]

Participants

6

Reactant 4

HCID 10340Sodium CarbonateHCID 69803Diethyl acetylenedicarboxylateHCID 77906N-methylhydroxylamine hydrochlorideHCID 167539464-Fluoro-2-(methylsulfonyl)benzonitrile

Product 1

HCID 696379205-Ethoxycarbonylmethyl-3-(4-fluoro-2-methanesulfonyl-phenyl)-2-methyl-2,5-dihydro-[1,2,4]oxadiazole-5-carboxylic acid ethyl esterYield 64%

Reagents, catalysts & solvents 1

HCID 19096565Water ethanolSolvent

Conditions

Temperature
80 °C

Procedure

To a stirred suspension of 4-fluoro-2-(methylsulfonyl)benzonitrile (prepared according to the procedure described in Anthonyl, N. J. et al PCT Appl. WO 02/30931, 2002) (2.2 g, 11 mmol) and N-methylhydroxylamine hydrochloride (1.66 g, 20 mmol) in 1:1 water/ethanol (40 mL) was added sodium carbonate (1.06 g, 10 mmol) in small portions and the resulting mixture stirred at 80° C. for 3 h. The reaction mixture was concentrated and the residue was re-dissolved into 1:1 water :ethanol (50 mL). To this solution was added diethyl acetylene-dicarboxylate (1.92 mL, 12 mmol) and the resulting mixture stirred for 30 min at room temperature. The reaction mixture was then taken-up into ethyl acetate (150 mL), washed successively with water and brine (50 mL each), dried (MgSO4), filtered and concentrated to give yellow oil. The crude product was purified on silica gel column (3:7 to 2:3 ethyl acetate/hexanes) to afford the title product as a white solid (2.9122 g, 64% yield). 1HNMR (500 MHz, CDCl3) δ: 7.89 (1H, dd, J=8.09, 2.59 Hz), 7.62 (1H, dd, J=8.39, 5.04 Hz), 7.40 (1H, td, J=8.24, 2.44 Hz), 4.35–4.26 (2H, m), 4.19–4.13 (2H, m), 3.40 (3H, s), 3.38 (1H, d, J=16.17 Hz), 3.15 (1H, d, J=16.17 Hz), 3.02 (3H, s), 1.36–1.30 (3H, m), 1.27–1.23 (3H, m). HRMS (ESI) calcd for C17H22FN2O7S (M+H): 417.1132; found: 417.1116.

Workup

  1. customprepared
  2. concentrationThe reaction mixture was concentrated
  3. dissolutionthe residue was re-dissolved into 1:1 water
  4. stirringthe resulting mixture stirred for 30 min at room temperature
  5. washtaken-up into ethyl acetate (150 mL), washed successively with water and brine (50 mL each)
  6. dry with materialdried (MgSO4)
  7. filtrationfiltered
  8. concentrationconcentrated
  9. customto give yellow oil
  10. customThe crude product was purified on silica gel column (3:7 to 2:3 ethyl acetate/hexanes)

Sources & evidence

ORD record
ord-b70d071374f547f7aaa360e3a57c5e80
Source dataset
uspto-grants-2006_05
Patent number
US07037908B2

Reaction notes

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