Cesium carbonate → racemic (2'S,3S,4'R)-1'-(aminocarbonyl-methyl)-6-chloro-2'-(3-chlorophenyl)-4'-(5-fluoro-2-methyl-phenyl)spiro[3H-indole-3,3'-piperidine]-2,6'(1H)-dione

HRID 1728083노트

반응식

HRID 1728083 반응식
[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:32])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=4[CH3:23])[CH2:14][C:13](=[O:24])[NH:12][CH:11]3[C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=3)[C:5]2=[CH:4][CH:3]=1.COC([Si](C)(C)C)C.Br[CH2:42][C:43]([NH2:45])=[O:44].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.FC(F)(F)C(O)=O.ClCCl>[NH2:45][C:43]([CH2:42][N:12]1[C:13](=[O:24])[CH2:14][CH:15]([C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[CH3:23])[C:10]2([C:5]3[C:6](=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[NH:8][C:9]2=[O:32])[CH:11]1[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=1)=[O:44]

참가 물질

7

반응물 3

HCID 10796Cesium carbonateHCID 696322-BromoacetamideHCID 775809006-Chloro-2'-(3-chlorophenyl)-4'-(5-fluoro-2-methyl-phenyl)-2,3-dihydro-2,6'-dioxo spiro[indole-3,3'-piperidine] 1-methoxyethyl trimethylsilane

생성물 1

HCID 76568085racemic (2'S,3S,4'R)-1'-(aminocarbonyl-methyl)-6-chloro-2'-(3-chlorophenyl)-4'-(5-fluoro-2-methyl-phenyl)spiro[3H-indole-3,3'-piperidine]-2,6'(1H)-dione수율 19%

시약·촉매·용매 3

HCID 6228Dimethylformamide용매HCID 6344Dichloromethane용매HCID 6422Trifluoroacetic acid용매

실험 절차

In a manner similar to the method described in example 146d and 146e racemic (2′S,3S,4′R)-6-chloro-2′-(3-chlorophenyl)-4′-(5-fluoro-2-methyl-phenyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane (50 mg g, 0.08 mmol) was reacted with 2-bromo-acetamide (35 mg, 0.25 mmol) and cesium carbonate (163 mg, 0.50 mmol) in DMF (2 ml). The resulting residue was dissolved in a mixture solution of trifluoroacetic acid (5 mL) and dichloromethane (5 mL). The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was concentrated. The residue was redissolved in methanol (10 mL). To the resulting solution was added N,N′-diisopropylethylamine and the crude was refluxed for 1 h. The reaction mixture was concentrated and the residue was partitioned between ethyl acetate and HCl aqueous solution (1N). The organic layer was separated, dried over MgSO4 and concentrated. The residue was triturated purified by Prep-HPLC to give racemic (2′S,3S,4′R)-1′-(aminocarbonyl-methyl)-6-chloro-2′-(3-chlorophenyl)-4′-(5-fluoro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (8 mg).

후처리

  1. concentrationThe reaction mixture was concentrated
  2. dissolutionThe residue was redissolved in methanol (10 mL)
  3. additionTo the resulting solution was added N,N′-diisopropylethylamine
  4. temperaturethe crude was refluxed for 1 h
  5. concentrationThe reaction mixture was concentrated
  6. customthe residue was partitioned between ethyl acetate and HCl aqueous solution (1N)
  7. customThe organic layer was separated
  8. dry with materialdried over MgSO4
  9. concentrationconcentrated
  10. customThe residue was triturated
  11. custompurified by Prep-HPLC

출처 및 근거

ORD 기록
ord-8cf1b2705e204fcfb86fbcce12660f62
출처 데이터셋
uspto-grants-2009_02
특허 번호
US07495007B2

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