Methyl iodide → 4-[5-(3,5-Dichloro-phenyl)-4-methyl-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoic acid methyl ester

HRID 69400Notes

Reaction equation

HRID 69400 reaction equation
[CH:1](NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15](=[O:40])[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH2:26][C:25]([C:31]3[CH:36]=[C:35]([Cl:37])[CH:34]=[C:33]([Cl:38])[CH:32]=3)([C:27]([F:30])([F:29])[F:28])[O:24][N:23]=2)=[CH:18][C:17]=1[CH3:39].CI>O1CCCC1>[CH3:13][O:14][C:15](=[O:40])[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:26]([CH3:1])[C:25]([C:31]3[CH:32]=[C:33]([Cl:38])[CH:34]=[C:35]([Cl:37])[CH:36]=3)([C:27]([F:30])([F:28])[F:29])[O:24][N:23]=2)=[CH:18][C:17]=1[CH3:39]

Participants

6

Reactant 4

HCID 6328Methyl iodide2×HCID 7912DiisopropylamineHCID 59563501Methyl 4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzoateHCID 178418339Butyllithium

Product 1

HCID 669865514-[5-(3,5-Dichloro-phenyl)-4-methyl-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoic acid methyl ester

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
0 °C

Procedure

To a solution of N,N-diisopropylamine (0.24 ml) in dry tetrahydrofuran (8 ml) stirred under argon at 0° C., was added n-butyl lithium (“n-BuLi”) (2.5 M in hexane) (0.74 ml). The solution was stirred at 0° C. for 30 minutes then was cooled to −85° C. To this solution was added a solution of 4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoic acid methyl ester (made as described in EP 1,731,512) (500 mg) in dry tetrahydrofuran (3 ml). The reaction mixture was stirred at −85° C. until deprotonation was completed as monitored by thin layer chromatography. Then, to this solution was added methyl iodide (0.14 ml) and the reaction mixture was stirred at −85° C. for 1 hour. More methyl iodide (0.08 ml) was added and the reaction mixture was stirred at −85° C. for a further 30 minutes. Then the reaction was quenched by addition of aqueous ammonium chloride (saturated) at −85° C. The mixture allowed to warm to ambient temperature and was then extracted with dichloromethane. The combined organic extracts were dried over magnesium sulfate and concentrated. The residue was purified by chromatography on silica gel (eluent: heptane/ethyl acetate 85:15) to give 4-[5-(3,5-dichloro-phenyl)-4-methyl-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoic acid methyl ester (290 mg) as a white foam. 1H-NMR (CDCl3, 400 MHz): 7.98-7.92 (m, 1H), 7.58-7.38 (m, 5H) 4.22-4.05 (m, 1H), 3.90 (s, 3H), 3.89 (s, 3H), 2.63 (s, 3H), 2.60 (s, 3H), 1.58-1.56 (m, 3H), 0.94-0.92 (m, 3H) ppm.

Workup

  1. temperaturethen was cooled to −85° C
  2. stirringThe reaction mixture was stirred at −85° C. until deprotonation
  3. stirringthe reaction mixture was stirred at −85° C. for 1 hour
  4. stirringthe reaction mixture was stirred at −85° C. for a further 30 minutes
  5. customThen the reaction was quenched by addition of aqueous ammonium chloride (saturated) at −85° C
  6. temperatureto warm to ambient temperature
  7. extractionwas then extracted with dichloromethane
  8. dry with materialThe combined organic extracts were dried over magnesium sulfate
  9. concentrationconcentrated
  10. customThe residue was purified by chromatography on silica gel (eluent: heptane/ethyl acetate 85:15)

Sources & evidence

ORD record
ord-67bebb1123ab41178aacbebf91baaa63
Source dataset
uspto-grants-2014_09
Patent number
US08822502B2

Reaction notes

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