HRID1930186

反应详情

EQUATION

反应方程式

REACTANTS

反应物

HCID1140

Toluene

C7H8

结构：C=C(C(=O)O)c1ccc(-c2ccc(-c3nc(C(N)=O)c(C)nc3C)cc2F)c(Cl)c1

HCID59627633

未命名化合物

2 次

PRODUCTS

生成物

结构：Cc1nc(C)c(-c2ccc(-c3ccc([C@H](C)C(=O)O)cc3Cl)c(F)c2)nc1C(N)=O

HCID49846226

未命名化合物

AUXILIARIES

试剂、催化剂与溶剂

$结构：C1=C\CC/C=C\CC/1.C1=C\CC/C=C\CC/1.F[B-](F)(F)F.[Rh]$

催化剂HCID5702662

未命名化合物

结构：Cc1ccccc1P(c1ccccc1C)[C@@H](C)[C]1[CH][CH][CH][C]1P(C(C)(C)C)C(C)(C)C.[CH]1[CH][CH][CH][CH]1.[Fe]

催化剂HCID16218718

未命名化合物

溶剂HCID887

Methanol

CH4O

CONDITIONS

反应条件

温度: 45 °C

PROCEDURE

实验过程

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

后处理

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)
customThe solvent was removed in vacuo
dissolutionThe crude product was dissolved in 5% methanol/dichloromethane
customchromatographed on silica (5 Kg of Merck lichro prep silica 15-25 μm, 200 mm diameter column)
washeluting with a solvent mixture of 5% methanol/dichloromethane
customPure fractions were evaporated to dryness
customto afford
additionthe mixture of the enantiomers, chiral prep HPLC chromatography (5 Kg of chiralpak AD 20 μm, 200 mm diameter column
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

来源与证据

来源类型: Open Reaction Database
ORD 记录: ord-d7e85fd2781d42e39d2137fc0b652fa3
来源数据集: uspto-grants-2012_05
DOI: 10.6084/m9.figshare.5104873.v1
专利: US08188092B2
来源说明: uspto-grants-2012_05

反应 SMILES

[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]