Methanol → HCID 131727323, compound

HRID 1727999Notes

Reaction equation

HRID 1727999 reaction equation
[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]=[N:10][C:11]([O:13][Si](C)(C)C)=[CH2:12].C(OC([N:25]1[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([Cl:34])[CH:32]=2)/[C:27](=[CH:35]/[C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=2)/[C:26]1=[O:43])=O)(C)(C)C.CO>C1(C)C=CC=CC=1>[Cl:34][C:31]1[CH:32]=[C:33]2[NH:25][C:26](=[O:43])[C:27]3([CH:35]([C:36]4[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=4)[CH2:13][C:11](=[O:12])[NH:10][CH:9]3[C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])[C:28]2=[CH:29][CH:30]=1

Participants

5

Reactant 3

HCID 887MethanolHCID 66640668Z-6-chloro-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl esterHCID 70262088HCID 70262088, compound

Product 1

HCID 131727323HCID 131727323, compoundYield 63.9%

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent

Conditions

Temperature
140 °C

Procedure

To a solution of 1-(2,4-difluorophenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene prepared in example 41a (2.4 g, 9.40 mmol) in toluene (30 mL) was added E/Z-6-chloro-3-(3-chlorobenzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester prepared in Example 24a (0.3 g, 0.77 mmol). The reaction mixture was stirred under nitrogen in a sealed tube at 140° C. for 0.5 h. After the solution was cooled to room temperature, methanol (10 mL) was added. The reaction mixture was filtered through a short pad of celite gel and washed with ethyl acetate. The filtrate was concentrated. The residue was dissolved in dichloromethane (20 mL) and trifluoroactic acid (15 mL) was added. After the reaction mixture was stirred at room temperature for 1 h, the mixture was concentrated. The residue was partitioned between saturated NaHCO3 solution and ethyl acetate. The aqueous layer was extracted with ethyl acetate. The combined organic layer was dried over Na2SO4 and concentrated. The residue was purified by chromatography (EtOAc:hexanes=2:1) to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(2,4-difluorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as an off-white solid (Yield 0.23 g, 63.9%).

Workup

  1. temperatureAfter the solution was cooled to room temperature
  2. filtrationThe reaction mixture was filtered through a short pad of celite gel
  3. washwashed with ethyl acetate
  4. concentrationThe filtrate was concentrated
  5. dissolutionThe residue was dissolved in dichloromethane (20 mL)
  6. additiontrifluoroactic acid (15 mL) was added
  7. stirringAfter the reaction mixture was stirred at room temperature for 1 h
  8. concentrationthe mixture was concentrated
  9. customThe residue was partitioned between saturated NaHCO3 solution and ethyl acetate
  10. extractionThe aqueous layer was extracted with ethyl acetate
  11. dry with materialThe combined organic layer was dried over Na2SO4
  12. concentrationconcentrated
  13. customThe residue was purified by chromatography (EtOAc:hexanes=2:1)

Sources & evidence

ORD record
ord-099c11fcb58c4fa893a29e696bee7ae5
Source dataset
uspto-grants-2009_02
Patent number
US07495007B2

Reaction notes

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