Chloroiodomethane → tert-Butyl 1-[(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}-phenyl)(cyclopropyloxy)methyl]cyclopropanecarboxylate

HRID 1475681Notes

Reaction equation

HRID 1475681 reaction equation
Cl[CH2:2]I.[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([O:22][CH:23]=[CH2:24])[C:12]2([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:14][CH2:13]2)=[CH:7][C:6]=1[NH:25][C:26](=[O:41])[C@H:27]([C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=1)[C@@H:28]([CH3:33])[C:29]([F:32])([F:31])[F:30]>[Zn].[Cu].C(OCC)C>[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([O:22][CH:23]2[CH2:2][CH2:24]2)[C:12]2([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:14][CH2:13]2)=[CH:7][C:6]=1[NH:25][C:26](=[O:41])[C@H:27]([C:34]1[CH:35]=[CH:36][C:37]([Cl:40])=[CH:38][CH:39]=1)[C@@H:28]([CH3:33])[C:29]([F:32])([F:31])[F:30]

Participants

5

Reactant 2

HCID 11644ChloroiodomethaneHCID 67957882tert-Butyl 1-[(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}-phenyl)(vinyloxy)methyl]cyclopropanecarboxylate

Product 1

HCID 68006794tert-Butyl 1-[(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}-phenyl)(cyclopropyloxy)methyl]cyclopropanecarboxylate

Reagents, catalysts & solvents 2

HCID 10290809Zinc copper coupleCatalystHCID 3283Diethyl EtherSolvent2×

Procedure

68 mg (0.52 mmol) of zinc/copper pair were taken up in 5 ml of abs. diethyl ether, and 41 μl (0.56 mmol) of chloroiodomethane were added at room temperature. A solution of 200 mg (0.35 mmol) of tert-butyl 1-[(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]-amino}phenyl)(vinyloxy)methyl]cyclopropanecarboxylate (as diastereomer mixture) in 10 ml of abs. diethyl ether was then added dropwise to the reaction mixture. The reaction solution was then heated to reflux and stirred overnight. After cooling, the solution was filtered through kieselguhr and the kieselguhr was washed repeatedly with diethyl ether. The filtrate obtained was washed with saturated aqueous sodium bicarbonate solution and with water, dried over magnesium sulphate and concentrated to dryness under reduced pressure. The residue was purified by preparative RP-HPLC (mobile phase methanol/water 80:20, isocratic). This gave 54 mg (27% of theory) of the target compound.

Workup

  1. temperatureThe reaction solution was then heated
  2. temperatureto reflux
  3. temperatureAfter cooling
  4. filtrationthe solution was filtered through kieselguhr
  5. washthe kieselguhr was washed repeatedly with diethyl ether
  6. customThe filtrate obtained
  7. washwas washed with saturated aqueous sodium bicarbonate solution and with water
  8. dry with materialdried over magnesium sulphate
  9. concentrationconcentrated to dryness under reduced pressure
  10. customThe residue was purified by preparative RP-HPLC (mobile phase methanol/water 80:20, isocratic)

Sources & evidence

ORD record
ord-2e22014f074d4350a843118b10ba7b9a
Source dataset
uspto-grants-2015_04
Patent number
US09018258B2

Reaction notes

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