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

HRID 1728081Notes

Reaction equation

HRID 1728081 reaction equation
[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:40])[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])[N:12]([CH2:25][C:26]([O:28]C(C)(C)C)=[O:27])[CH:11]3[C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[CH:34]=3)[C:5]2=[CH:4][CH:3]=1.COC([Si](C)(C)C)C.FC(F)(F)C(O)=O.CCN(C(C)C)C(C)C>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:40])[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])[N:12]([CH2:25][C:26]([OH:28])=[O:27])[CH:11]3[C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[CH:34]=3)[C:5]2=[CH:4][CH:3]=1

Participants

5

Reactant 3

HCID 6422Trifluoroacetic acidHCID 81531DiisopropylethylamineHCID 77581377racemic (2'S,3S,4'R)-6-chloro-2'-(3-chlorophenyl)-4'-(5-fluoro-2-methyl-phenyl)-2,3-dihydro-1'-[(tert-butoxycarbonyl)methyl]-2,6'-dioxo spiro[indole-3,3'-piperidine] 1-methoxyethyl trimethylsilane

Product 1

HCID 76568188racemic (2'S,3S,4'R)-6-chloro-2'-(3-chlorophenyl)-4'-(5-fluoro-2-methyl-phenyl)-1'-hydroxycarbonylmethyl-spiro[3H-indole-3,3'-piperidine]-2,6'(1H)-dioneYield 70.1%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a solution of racemic (2′S,3S,4′R)-6-chloro-2′-(3-chlorophenyl)-4′-(5-fluoro-2-methyl-phenyl)-2,3-dihydro-1′-[(tert-butoxycarbonyl)methyl]-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane (0.85 g, 1.19 mmol) prepared in example 146d in dichloromethane (10 mL) was added trifluoroacetic acid (20 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 (1.57 mL, 8.70 mmol) 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 with ethyl acetate and hexane to give racemic (2′S,3S,4′R)-6-chloro-2′-(3-chlorophenyl)-4′-(5-fluoro-2-methyl-phenyl)-1′-hydroxycarbonylmethyl-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a yellow solid (Yield 440 mg, 70%).

Workup

  1. concentrationThe reaction mixture was concentrated
  2. dissolutionThe residue was redissolved in methanol (10 mL)
  3. temperaturethe crude was refluxed for 1 h
  4. concentrationThe reaction mixture was concentrated
  5. customthe residue was partitioned between ethyl acetate and HCl aqueous solution (1N)
  6. customThe organic layer was separated
  7. dry with materialdried over MgSO4
  8. concentrationconcentrated
  9. customThe residue was triturated with ethyl acetate and hexane

Sources & evidence

ORD record
ord-b12c56497ee24f4eb3a2512decd2d70e
Source dataset
uspto-grants-2009_02
Patent number
US07495007B2

Reaction notes

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