Water → 2-(5-Cyclopropylmethoxy-2-fluoro-4-nitro-phenyl)-4-methyl-pentanoic acid cyclopropylmethyl ester

HRID 385322Notes

Reaction equation

HRID 385322 reaction equation
[Li][CH2:2][CH2:3][CH2:4][CH3:5].C([O:8][C:9](=[O:26])[CH:10]([C:15]1[CH:20]=[C:19](F)[C:18]([N+:22]([O-:24])=[O:23])=[CH:17][C:16]=1[F:25])[CH2:11][CH:12]([CH3:14])[CH3:13])C.O.[CH:28]1([CH2:31][OH:32])[CH2:30][CH2:29]1>>[CH:4]1([CH2:5][O:8][C:9](=[O:26])[CH:10]([C:15]2[CH:20]=[C:19]([O:32][CH2:31][CH:28]3[CH2:30][CH2:29]3)[C:18]([N+:22]([O-:24])=[O:23])=[CH:17][C:16]=2[F:25])[CH2:11][CH:12]([CH3:13])[CH3:14])[CH2:2][CH2:3]1

Participants

5

Reactant 4

HCID 962WaterHCID 75644Cyclopropanemethanol2×HCID 579956072-(2,5-Difluoro-4-nitro-phenyl)-4-methyl-pentanoic acid ethyl esterHCID 178418339Butyllithium

Product 1

HCID 687350142-(5-Cyclopropylmethoxy-2-fluoro-4-nitro-phenyl)-4-methyl-pentanoic acid cyclopropylmethyl esterYield 81%

Conditions

Temperature
25 °C

Procedure

Cyclopropylmethanol (10.0 g, 138.8 mmol) was treated with n-BuLi (2.5M in hexane 7.4 g, 46 mL, 115.6 mmol) at −15° C. under nitrogen, and the reaction mixture was stirred 1 h at 25° C. To the mixture was added 2-(2,5-difluoro-4-nitro-phenyl)-4-methyl-pentanoic acid ethyl ester (29 g, 96 mmol) in Cyclopropylmethanol (30 mL) dropwise at 25° C. and the reaction mixture stirred for an additional 16 h. Water (100 mL) was added and the reaction mixture was extracted with EtOAc (3×100 mL). The combined organic phases washed with water (3×100 mL), brine (100 mL) and dried (MgSO4). Evaporation of the solvent under reduced pressure gave a brown oil which was purified by column chromatography over silica gel (Heptane-EtOAc gradient) to give 29.5 g, (81%) of 2-(5-cyclopropylmethoxy-2-fluoro-4-nitro-phenyl)-4-methyl-pentanoic acid cyclopropylmethyl ester as a yellow oil. 1H NMR (300 MHz, CDCl3/TMS): δ 7.60 (d, J=9.0 Hz, 1H), 7.15 (d, J=5.7 Hz, 1H), 4.07 (t, J=7.7 Hz, 1H), 4.00-3.80 (m, 4H), 2.01-1.92 (m, 1H), 1.68-1.60 (m, 1H), 1.52-1.43 (m, 1H), 1.34-1.20 (m, 1H), 1.19-1.00 (m, 1H), 0.94 (d, J=6.3 Hz, 6H), 0.65 (d, J=7.7 Hz, 2H), 0.54 (d, J=7.7 Hz, 2H), 0.39 (d, J=4.4 Hz, 2H), 0.25 (d, J=4.4 Hz, 2H); 13C NMR (75 MHz, CDCl3/TMS): δ 172.6, 152.7 (d, 1JCF=243.4 Hz), 148.8, 138.1, 133.3 (d, 2JCF=15.7 Hz), 115.8, 112.6 (d, 2JCF=29.5 Hz), 75.1, 70.0, 42.1, 41.7, 26.1, 22.5, 22.2, 10.0, 9.8, 3.4.

Workup

  1. stirringthe reaction mixture stirred for an additional 16 h
  2. extractionthe reaction mixture was extracted with EtOAc (3×100 mL)
  3. washThe combined organic phases washed with water (3×100 mL), brine (100 mL)
  4. dry with materialdried (MgSO4)
  5. customEvaporation of the solvent under reduced pressure
  6. customgave a brown oil which
  7. customwas purified by column chromatography over silica gel (Heptane-EtOAc gradient)

Sources & evidence

ORD record
ord-91a560bf0334476a90d1181281752de9
Source dataset
uspto-grants-2013_02
Patent number
US08367863B2

Reaction notes

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