Toluene → (2S)-2-[4-[4-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-fluorophenyl]-3-chlorophenyl]propanoic acid

HRID 1930186Notes

Reaction equation

HRID 1930186 reaction equation
[C:1]([C:4]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([C:22](=[CH2:26])[C:23]([OH:25])=[O:24])=[CH:18][C:17]=3[Cl:27])=[C:12]([F:28])[CH:11]=2)[C:7]([CH3:29])=[N:6][C:5]=1[CH3:30])(=[O:3])[NH2:2].C1(C)C=CC=CC=1>CO.[B-](F)(F)(F)F.C1CC=CCCC=C1.C1CC=CCCC=C1.[Rh].CC1C(P([C@H]([C]2[C](P(C(C)(C)C)C(C)(C)C)[CH][CH][CH]2)C)C2C(C)=CC=CC=2)=CC=CC=1.[CH]1[CH][CH][CH][CH]1.[Fe]>[C:1]([C:4]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([C@H:22]([CH3:26])[C:23]([OH:25])=[O:24])=[CH:18][C:17]=3[Cl:27])=[C:12]([F:28])[CH:11]=2)[C:7]([CH3:29])=[N:6][C:5]=1[CH3:30])(=[O:3])[NH2:2]

Participants

6

Reactant 2

HCID 1140TolueneHCID 596276332-[4-[4-(6-Carbamoyl-3,5-dimethylpyrazin-2-yl)-2-fluorophenyl]-3-chlorophenyl]prop-2-enoic acid2×

Product 1

HCID 49846226(2S)-2-[4-[4-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-fluorophenyl]-3-chlorophenyl]propanoic acid

Reagents, catalysts & solvents 3

HCID 5702662Rhodium(1+), bis((1,2,5,6-eta)-1,5-cyclooctadiene)-, tetrafluoroborate(1-) (1:1)CatalystHCID 16218718(1S)-1-[Bis(tert-butyl)phosphino]-2-[(1S)-1-[bis(2-methylphenyl)phosphino]ethyl]ferroceneCatalystHCID 887MethanolSolvent

Conditions

Temperature
45 °C

Procedure

2-[4-[4-(6-Carbamoyl-3,5-dimethylpyrazin-2-yl)-2-fluorophenyl]-3-chlorophenyl]prop-2-enoic acid (Intermediate 31-10; 142 g, 283.44 mmol), bis(1,5-cyclooctadiene)rhodium(I) tetrafluoroborate (1.381 g, 3.40 mmol), (R)-1-[(Sp)-2-(di-tert-butylphosphino)ferrocenyl]ethylbis(2-methylphenyl)phosphine (2.102 g, 3.68 mmol) in degassed methanol (2.5 L) and degassed toluene (836 mL) were stirred under an atmosphere of hydrogen at 5 bar and 45° C. for 4 hours. Chiral HPLC analysis (chiralpak AD 5 μm, 250 mm×4.6 mm column, eluted with 60% isohexane/40% ethanol/0.2% acetic acid, retention time for required enantiomer 14.5 minutes) indicated the ratio of desired to undesired enantiomer was 87:13. The solvent was removed in vacuo. The crude product was dissolved in 5% methanol/dichloromethane and then chromatographed on silica (5 Kg of Merck lichro prep silica 15-25 μm, 200 mm diameter column), eluting with a solvent mixture of 5% methanol/dichloromethane. Pure fractions were evaporated to dryness to afford the mixture of the enantiomers, chiral prep HPLC chromatography (5 Kg of chiralpak AD 20 μm, 200 mm diameter column, eluted with 70% isohexane/30% ethanol/0.2% acetic acid, retention time for required enantiomer 17 minutes) then gave (2S)-2-[4-[4-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-fluorophenyl]-3-chlorophenyl]propanoic acid (58 g, 40%, 99% ee) as a white solid.

Workup

  1. washChiral HPLC analysis (chiralpak AD 5 μm, 250 mm×4.6 mm column, eluted with 60% isohexane/40% ethanol/0.2% acetic acid, retention time for required enantiomer 14.5 minutes)
  2. customThe solvent was removed in vacuo
  3. dissolutionThe crude product was dissolved in 5% methanol/dichloromethane
  4. customchromatographed on silica (5 Kg of Merck lichro prep silica 15-25 μm, 200 mm diameter column)
  5. washeluting with a solvent mixture of 5% methanol/dichloromethane
  6. customPure fractions were evaporated to dryness
  7. customto afford
  8. additionthe mixture of the enantiomers, chiral prep HPLC chromatography (5 Kg of chiralpak AD 20 μm, 200 mm diameter column
  9. washeluted with 70% isohexane/30% ethanol/0.2% acetic acid, retention time for required enantiomer 17 minutes) then gave (2S)-2-[4-[4-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-fluorophenyl]-3-chlorophenyl]propanoic acid (58 g, 40%, 99% ee) as a white solid

Sources & evidence

ORD record
ord-d7e85fd2781d42e39d2137fc0b652fa3
Source dataset
uspto-grants-2012_05
Patent number
US08188092B2

Reaction notes

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