Hydrochloric Acid → HCID 59459253, compound

HRID 1874252Notes

Reaction equation

HRID 1874252 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]([NH:26][C:27]([NH:29][CH2:30][C:31]([F:34])([F:33])[F:32])=[O:28])([C:12]2[CH:17]=[C:16]([O:18][C:19]([F:24])([F:23])[CH:20]([F:22])[F:21])[CH:15]=[C:14]([F:25])[CH:13]=2)[CH2:9][CH:10]=[CH2:11])=[CH:4][C:3]=1[C:35]([F:38])([F:37])[F:36].[CH2:39]([Zn]CC)C.ICI.Cl>C1(C)C=CC=CC=1>[CH:10]1([CH2:9][C@@:8]([NH:26][C:27]([NH:29][CH2:30][C:31]([F:32])([F:33])[F:34])=[O:28])([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C:35]([F:38])([F:36])[F:37])[CH:4]=2)[C:12]2[CH:17]=[C:16]([O:18][C:19]([F:23])([F:24])[CH:20]([F:22])[F:21])[CH:15]=[C:14]([F:25])[CH:13]=2)[CH2:39][CH2:11]1

Participants

6

Reactant 4

HCID 313Hydrochloric AcidHCID 6346DiiodomethaneHCID 59458490HCID 59458490, compoundHCID 178418750HCID 178418750, compound

Product 1

HCID 59459253HCID 59459253, compoundYield 32%

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent

Conditions

Temperature
110 °C

Procedure

At 0° C. under argon, to a solution of (R)-1-(1-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)but-3-enyl)-3-(2,2,2-trifluoroethyl)urea (40 mg, 0.070 mmol), prepared as described in Procedure 6 and 10, in dry toluene (1 mL) was added diethyl Zinc (1.0 M in hexane, 1.2 mL, 1.2 mmol), followed by dropwise addition of diiodomethane (0.2 mL). The reaction mixture was gradually warmed to 110° C., and heated at 110° C. for 1 h. After cooling, 1 N HCl was added and the reaction mixture was stirred at room temperature for 5 min. The reaction mixture was extracted with EtOAc and the organic layer was washed with H2O, sat. NaHCO3, sat. NaCl, dried over Na2SO4, filtered and concentrated. The residue was purified by Prep HPLC (phenomenex AXIA Luna 75×30 mm, 5 u column eluting with 50-100% MeOH in H2O with 0.1% TFA, 40 mL/min, monitoring at 220 nm) to give (R)-1-(2-cyclopropyl-1-(4-fluoro-3-(trifluoromethyl)-phenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)ethyl)-3-(2,2,2-trifluoroethyl)urea (Example 317) as white solid (13 mg, yield 32%). LCMS: RT=3.26 min [M+H] 583.2 (Phenomenex Luna C18 column, 4.6×50 mm eluting with 50-90% MeOH/H2O over 4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220 nm). 1H NMR (400 MHz, CDCl3) δ ppm 7.55 (d, J=6.6 Hz, 1H), 7.46 (m, 1H), 7.12 (t, J=9.3 Hz, 1H), 6.94-6.85 (m, 3H), 5.84 (tt, J=52.8, 2.8 Hz, 1H), 5.61 (br, s, 1H), 4.78 (br, t, J=6.1 Hz, 1H), 3.69 (m, 2H), 2.31 (m, 2H), 0.36 (m, 3H), 0.00 (m, 2H).

Workup

  1. temperatureheated at 110° C. for 1 h
  2. temperatureAfter cooling
  3. extractionThe reaction mixture was extracted with EtOAc
  4. washthe organic layer was washed with H2O, sat. NaHCO3, sat. NaCl
  5. dry with materialdried over Na2SO4
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customThe residue was purified by Prep HPLC (phenomenex AXIA Luna 75×30 mm, 5 u column eluting with 50-100% MeOH in H2O with 0.1% TFA, 40 mL/min, monitoring at 220 nm)

Sources & evidence

ORD record
ord-f96a073d02eb48868bb50e21b1f3c47d
Source dataset
uspto-grants-2012_11
Patent number
US08304403B2

Reaction notes

Loading…