Diiodomethane → HCID 23582473, compound

HRID 1874232Notes

Reaction equation

HRID 1874232 reaction equation
[F:1][C:2]1[CH:42]=[CH:41][C:5]([C:6]([NH:8][C@:9]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[C:33]([O:38][CH:39]=[CH2:40])[CH:32]=2)([C:17]2[CH:22]=[C:21]([O:23][C:24]([F:29])([F:28])[CH:25]([F:27])[F:26])[CH:20]=[C:19]([F:30])[CH:18]=2)[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])=[CH:4][C:3]=1[C:43]([F:46])([F:45])[F:44].[Zn](CC)[CH2:48]C.C(I)I>C1(C)C=CC=CC=1>[CH:39]1([O:38][C:33]2[CH:32]=[C:31]([C@@:9]([NH:8][C:6](=[O:7])[C:5]3[CH:41]=[CH:42][C:2]([F:1])=[C:3]([C:43]([F:46])([F:45])[F:44])[CH:4]=3)([C:17]3[CH:22]=[C:21]([O:23][C:24]([F:28])([F:29])[CH:25]([F:26])[F:27])[CH:20]=[C:19]([F:30])[CH:18]=3)[CH2:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:36]=[CH:35][C:34]=2[F:37])[CH2:48][CH2:40]1

Participants

5

Reactant 3

HCID 6346DiiodomethaneHCID 59458689HCID 59458689, compoundHCID 178418750HCID 178418750, compound

Product 1

HCID 23582473HCID 23582473, compoundYield 52%

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent

Conditions

Temperature
120 °C

Procedure

To a solution of (R)-4-fluoro-N-(1-(4-fluoro-3-(vinyloxy)phenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-3-(trifluoromethyl)benzamide (66 mg, 0.10 mmol) in 0.5 ml toluene was added Et2Zn (1 N, 0.2 ml, 0.2 mmol), followed by CH2I2 (16 ml, 0.2 mmol). The reaction mixture was stirred at 120° C. for 3 h. The reaction mixture was quenched by addition of 1 N HCl and the aqueous layer was extracted with CH2Cl2. The organic layer was washed with sat. NaHCO3 and concentrated under reduced pressure. The resulting residue was purified by ISCO silica gel column using 0 to 50% to EtOAc in hexane as eluting solvents and Prep HPLC (phenomenex AXIA Luna 75×30 mm, 5u column eluting with 10-90% ACN/H2O over 10 minutes containing 0.1% TFA; 40 mL/min, monitoring at 220 nm) to afford (R)—N-(1-(3-cyclopropoxy-4-fluorophenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-4-fluoro-3-(trifluoromethyl)benzamide (Example 305) as white lyophillate (36 mg, 52% yield). LCMS: RT=4.268 min [M+H] 672.3 (4 min Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220 nm. NMR: 400 MHz 1H (CDCl3) ppm 0.45-0.73 (m, 4 H), 3.51-3.59 (m, 1H), 3.76 (d, J=13.18 Hz, 1H), 4.22 (d, J=12.74 Hz, 1H), 6.13-6.44 (m, 1H), 6.66-6.76 (m, 3H), 6.97-7.08 (m, 3H), 7.10-7.23 (m, 5H), 7.42-7.50 (m, 1H), 7.95-8.03 (m, 2H).

Workup

  1. customThe reaction mixture was quenched by addition of 1 N HCl
  2. extractionthe aqueous layer was extracted with CH2Cl2
  3. washThe organic layer was washed with sat. NaHCO3
  4. concentrationconcentrated under reduced pressure
  5. customThe resulting residue was purified by ISCO silica gel column
  6. washas eluting
  7. washsolvents and Prep HPLC (phenomenex AXIA Luna 75×30 mm, 5u column eluting with 10-90% ACN/H2O over 10 minutes containing 0.1% TFA; 40 mL/min, monitoring at 220 nm)

Sources & evidence

ORD record
ord-b36a07d863314efdad4c5b4557e8e3a5
Source dataset
uspto-grants-2012_11
Patent number
US08304403B2

Reaction notes

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