Carbon Tetrachloride → 4-[(R)-1-(3,5-Dichloro-4-fluoro-phenyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[1,2-a]imidazol-3-ylmethyl]-benzonitrile

HRID 1040518Notes

Reaction equation

HRID 1040518 reaction equation
[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C@:10]([NH:24][C:25]([NH:27][CH2:28][CH:29](OC)OC)=O)([CH3:23])[C:11]([NH:13][C:14]2[CH:19]=[C:18]([Cl:20])[C:17]([F:21])=[C:16]([Cl:22])[CH:15]=2)=[O:12])=[CH:5][CH:4]=1)#[N:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCN(CC)CC.C(Cl)(Cl)(Cl)Cl.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.CCCCCCC.C(OC(C)C)(=O)C>CC#N>[Cl:22][C:16]1[CH:15]=[C:14]([N:13]2[C:11](=[O:12])[C@:10]([CH2:9][C:6]3[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)([CH3:23])[N:24]3[CH:29]=[CH:28][N:27]=[C:25]23)[CH:19]=[C:18]([Cl:20])[C:17]=1[F:21]

Participants

8

Reactant 6

HCID 5943Carbon TetrachlorideHCID 8471TriethylamineHCID 11776TriphenylphosphineHCID 521998p-Toluenesulfonic acid monohydrateHCID 18406121n-Heptane isopropyl acetateHCID 67389254(R)-3-(4-Cyano-phenyl)-N-(3,5-dichloro-4-fluoro-phenyl)-2-[3-(2,2-dimethoxy-ethyl)-ureido]-2-methyl-propionamide

Product 1

HCID 584311004-[(R)-1-(3,5-Dichloro-4-fluoro-phenyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[1,2-a]imidazol-3-ylmethyl]-benzonitrileYield 91.8%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Conditions

Temperature
0 °C

Procedure

To a room temperature suspension of (R)-3-(4-cyano-phenyl)-N-(3,5-dichloro-4-fluoro-phenyl)-2-[3-(2,2-dimethoxy-ethyl)-ureido]-2-methyl-propionamide (62.6 g, 125.9 mmol), PPh3 (51.98 g, 198.17 mmol), and Et3N (29.35 mL, 210.6 mmol) in MeCN (250 mL) was added CCl4 (20.3 mL, 210.6 mmol) in one portion. The reaction was stirred for 2 h and then cooled to 0° C. To this solution was added p-toluenesulfonic acid monohydrate (37.7 g, 198.2 mmol) and the reaction was heated at 70° C. for 2 h. The volatiles were evaporated in vacuo, and the residue was diluted with isopropyl acetate (i-PrOAc) (500 mL) and water (500 mL). The water layer was removed and the organic layer was washed with aqueous Na2CO3 (5 wt %, 500 mL) and then aqueous NaCl (3 wt %, 500 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo to give an oily solid. A mixture of Heptane/i-PrOAc (150 mL, 80:20 heptane:i-PrOAc) was added causing precipitation of a solid. The resulting slurry was stirred overnight and then filtered. The filtrate was evaporated in vacuo to give a brown oil. The oil was re-processed using the same conditions 3 more times. The remaining brown oil from the filtrate was then purified by flash chromatography on silica gel (20-50% EtOAc/hexanes) to give 48.0 g of the title compounds as a white solid, m/z 415.7 [M+H]+.

Workup

  1. temperaturethe reaction was heated at 70° C. for 2 h
  2. customThe volatiles were evaporated in vacuo
  3. additionthe residue was diluted with isopropyl acetate (i-PrOAc) (500 mL) and water (500 mL)
  4. customThe water layer was removed
  5. washthe organic layer was washed with aqueous Na2CO3 (5 wt %, 500 mL)
  6. dry with materialThe organic layer was dried over Na2SO4
  7. concentrationconcentrated in vacuo
  8. customto give an oily solid
  9. additionwas added
  10. customprecipitation of a solid
  11. stirringThe resulting slurry was stirred overnight
  12. filtrationfiltered
  13. customThe filtrate was evaporated in vacuo
  14. customto give a brown oil
  15. customThe remaining brown oil from the filtrate was then purified by flash chromatography on silica gel (20-50% EtOAc/hexanes)

Sources & evidence

ORD record
ord-6d9bdf6dd68c41d99f901d658db16d4b
Source dataset
uspto-grants-2013_10
Patent number
US08552205B2

Reaction notes

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