Acetic Acid → 2-((R)-9-((S)-1-(4-chlorophenyl)ethyl)-6-fluoro-8-(methylsulfonyl)-2,3,4,9-tetrahydro-1H-carbazol-1-yl)acetic acid

HRID 1744882

反応式

HRID 1744882 の反応式
C([O:3][C:4](=[O:33])[CH2:5][C@@H:6]1[C:18]2[N:17]([C@H:19]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)[CH3:20])[C:16]3[C:11](=[CH:12][C:13]([F:32])=[CH:14][C:15]=3[S:28]([CH3:31])(=[O:30])=[O:29])[C:10]=2[CH2:9][CH2:8][CH2:7]1)C.C(OC(=O)C[C@H]1C2N([C@H](C3C=CC(Cl)=CC=3)C)C3C(=CC(F)=CC=3S(C)(=O)=O)C=2CCC1)C.[Li+].[OH-].CC(O)=O>C1COCC1.CO>[Cl:27][C:24]1[CH:23]=[CH:22][C:21]([C@@H:19]([N:17]2[C:18]3[C@@H:6]([CH2:5][C:4]([OH:33])=[O:3])[CH2:7][CH2:8][CH2:9][C:10]=3[C:11]3[C:16]2=[C:15]([S:28]([CH3:31])(=[O:29])=[O:30])[CH:14]=[C:13]([F:32])[CH:12]=3)[CH3:20])=[CH:26][CH:25]=1

参加物

6

反応物 4

HCID 176Acetic AcidHCID 3939Lithium HydroxideHCID 66967751ethyl[(1R)-9-[(1S)-1-(4-chlorophenyl)ethyl]-6-fluoro-8-(methylsulfonyl)-2,3,4,9-tetrahydro-1H-carbazol-1-yl]acetate2 回HCID 86615644ethyl[(1S)-9-[(1S)-1-(4-chlorophenyl)ethyl]-6-fluoro-8-(methylsulfonyl)-2,3,4,9-tetrahydro-1H-carbazol-1-yl]acetate

生成物 1

HCID 112597972-((R)-9-((S)-1-(4-chlorophenyl)ethyl)-6-fluoro-8-(methylsulfonyl)-2,3,4,9-tetrahydro-1H-carbazol-1-yl)acetic acid

試薬・触媒・溶媒 1

HCID 21899815MeOH tetrahydrofuran溶媒

反応条件

温度
0 °C

実験手順

The diastereomeric mixture of ethyl[(1R)-9-[(1S)-1-(4-chlorophenyl)ethyl]-6-fluoro-8-(methylsulfonyl)-2,3,4,9-tetrahydro-1H-carbazol-1-yl]acetate and ethyl[(1S)-9-[(1S)-1-(4-chlorophenyl)-ethyl]-6-fluoro-8-(methylsulfonyl)-2,3,4,9-tetrahydro-1H-carbazol-1-yl]acetate (1 eq) was dissolved in a 3.5/1 mixture of THF/MeOH (0.25M) and cooled at 0° C. Aqueous LiOH 1N (1 eq) was slowly added and the mixture was stirred at 0° C. for 12 h or until almost complete hydrolysis of ethyl[(1R)-9-[(1S)-1-(4-chlorophenyl)ethyl]-6-fluoro-8-(methylsulfonyl)-2,3,4,9-tetrahydro-1H-carbazol-1-yl]acetate, the other diastereomer was only slightly hydrolyzed under these conditions. AcOH was added and the solvent was removed by evaporation. The residue was taken up in EtOAc/H2O and the organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. Ethyl[(1S)-9-[(1S)-1-(4-chlorophenyl)ethyl]-6-fluoro-8-(methylsulfonyl)-2,3,4,9-tetrahydro-1H-carbazol-1-yl]acetate and [(1R)-9-[(1S)-1-(4-chloro-phenyl)ethyl]-6-fluoro-8-(methylsulfonyl)-2,3,4,9-tetrahydro-1H-carbazol-1-yl]acetic acid were separated by flash chromatography eluting with 40% EtOAc in hexanes containing 1% AcOH to give the desired [(1R)-9-[(1S)-1-(4-chlorophenyl)ethyl]-6-fluoro-8-(methylsulfonyl)-2,3,4,9-tetrahydro-1H-carbazol-1-yl]acetic acid with de>90% which was swished in 30% EtOAc in hexane to give the desired compound as a white solid with de>95%.

後処理

  1. customthe solvent was removed by evaporation
  2. washthe organic layer was washed with brine
  3. dry with materialdried over Na2SO4
  4. filtrationfiltered
  5. concentrationconcentrated
  6. customEthyl[(1S)-9-[(1S)-1-(4-chlorophenyl)ethyl]-6-fluoro-8-(methylsulfonyl)-2,3,4,9-tetrahydro-1H-carbazol-1-yl]acetate and [(1R)-9-[(1S)-1-(4-chloro-phenyl)ethyl]-6-fluoro-8-(methylsulfonyl)-2,3,4,9-tetrahydro-1H-carbazol-1-yl]acetic acid were separated by flash chromatography
  7. washeluting with 40% EtOAc in hexanes containing 1% AcOH

出典と根拠

ORDレコード
ord-def5d5a3037f4963810bd4a0edbba765
出典データセット
uspto-grants-2006_03
特許番号
US07019022B2

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