Diisopropylethylamine → 6-chloro-4'-(3-chlorophenyl)-2'-(5-fluoro-2-methylphenyl)-1'-(3-morpholin-4-yl-propyl)spiro[3H-indole-3,3'-piperidine]-2,6'(1H)-dione

HRID 1728015Notes

Reaction equation

HRID 1728015 reaction equation
[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:36])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[N:12]([CH2:24][CH2:25][CH2:26]Cl)[CH:11]3[C:28]3[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=3[CH3:35])[C:5]2=[CH:4][CH:3]=1.[CH3:37][O:38][CH:39]([Si](C)(C)C)[CH3:40].C[CH2:46][N:47](C(C)C)C(C)C>N1CCOCC1>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:36])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[N:12]([CH2:24][CH2:25][CH2:26][N:47]4[CH2:40][CH2:39][O:38][CH2:37][CH2:46]4)[CH:11]3[C:28]3[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=3[CH3:35])[C:5]2=[CH:4][CH:3]=1

Participants

4

Reactant 2

HCID 81531DiisopropylethylamineHCID 775807906-Chloro-4'-(3-chlorophenyl)-1'-(3-chloro-propyl)-2'-(5-fluoro-2-methylphenyl)-2,3-dihydro-2,6'-dioxo spiro[indole-3,3'-piperidine] 1-methoxyethyl trimethylsilane

Product 1

HCID 1317273286-chloro-4'-(3-chlorophenyl)-2'-(5-fluoro-2-methylphenyl)-1'-(3-morpholin-4-yl-propyl)spiro[3H-indole-3,3'-piperidine]-2,6'(1H)-dioneYield 37.9%

Reagents, catalysts & solvents 1

HCID 8083MorpholineSolvent

Conditions

Temperature
120 °C

Procedure

The mixture of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methylphenyl)-2,3-dihydro-1′-(3-chloro-propyl)-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane (0.24 g, 0.36 mmol) prepared in example 60a and morpholine (10 mL) was heated at 120° C. for 1 h. The mixture was concentrated to dryness. The resulting residue was added dichloromethane (20 mL) and then trifluoroacetic acid (20 mL). The reaction mixture was stirred at room temperature for 4 h. The reaction mixture was concentrated and the residue was partitioned between ethyl acetate and saturated NaHCO3 solution. The organic layer was separated and concentrated. The residue was redissolved in methanol (10 mL). To the resulting solution was added N,N′-diisopropylethylamine (2 mL, 11.0 mmol) and the crude was heated at 100° C. for 1 h. The reaction mixture was concentrated and the residue was purified by chromatography (MeOH:EtOAc=1:9) to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methylphenyl)-1′-(3-morpholin-4-yl-propyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield 0.08 g, 37.9%).

Workup

  1. concentrationThe mixture was concentrated to dryness
  2. additionThe resulting residue was added dichloromethane (20 mL)
  3. concentrationThe reaction mixture was concentrated
  4. customthe residue was partitioned between ethyl acetate and saturated NaHCO3 solution
  5. customThe organic layer was separated
  6. concentrationconcentrated
  7. dissolutionThe residue was redissolved in methanol (10 mL)
  8. temperaturethe crude was heated at 100° C. for 1 h
  9. concentrationThe reaction mixture was concentrated
  10. customthe residue was purified by chromatography (MeOH:EtOAc=1:9)

Sources & evidence

ORD record
ord-478fa437f22e441ab4b0793265cdd27e
Source dataset
uspto-grants-2009_02
Patent number
US07495007B2

Reaction notes

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