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

HRID 1930186노트

반응식

HRID 1930186 반응식
[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]

참가 물질

6

반응물 2

HCID 1140TolueneHCID 596276332-[4-[4-(6-Carbamoyl-3,5-dimethylpyrazin-2-yl)-2-fluorophenyl]-3-chlorophenyl]prop-2-enoic acid2회

생성물 1

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

시약·촉매·용매 3

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

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온도
45 °C

실험 절차

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.

후처리

  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

출처 및 근거

ORD 기록
ord-d7e85fd2781d42e39d2137fc0b652fa3
출처 데이터셋
uspto-grants-2012_05
특허 번호
US08188092B2

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