Pyridine → (-)-4,5-difluoro-2-(S)-methyl-1-[(S)-N-p-toluenesulfonylprolyl]-2,3-dihydroindole

HRID 2081564Notes

Reaction equation

HRID 2081564 reaction equation
[F:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH:5]([CH3:12])[NH:6]2.N1C=CC=CC=1.[C:19]1([CH3:36])[CH:24]=[CH:23][C:22]([S:25]([N:28]2[CH2:35][CH2:34][CH2:33][C@H:29]2[C:30](O)=[O:31])(=[O:27])=[O:26])=[CH:21][CH:20]=1.S(Cl)(Cl)=O>C(Cl)Cl>[F:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][C@H:5]([CH3:12])[N:6]2[C:30](=[O:31])[C@@H:29]1[CH2:33][CH2:34][CH2:35][N:28]1[S:25]([C:22]1[CH:23]=[CH:24][C:19]([CH3:36])=[CH:20][CH:21]=1)(=[O:27])=[O:26]

Participants

6

Reactant 4

HCID 1049PyridineHCID 24386Thionyl ChlorideHCID 691957(2S)-1-(4-methylbenzenesulfonyl)pyrrolidine-2-carboxylic acidHCID 13146144(+)-2-methyl-4,5-difluoro-2,3-dihydro-1H-indole

Product 1

HCID 54347967(-)-4,5-difluoro-2-(S)-methyl-1-[(S)-N-p-toluenesulfonylprolyl]-2,3-dihydroindole

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

(±)-4,5-difluoro-2-methyl-2,3-dihydroindole, 47.4 g, was dissolved in 470 ml of methylene chloride, to which was added 45 ml of pyridine under ice-cooling. To the resultant mixture was added dropwise under ice-cooling 300 ml of a methylene chloride a solution of the acid chloride prepared from 98.8 g of (S)-N-p-toluenesulfonyl proline and 80 ml of thionyl chloride. After the dropwise addition, the reaction was conducted for 1.5 hours at room temperature. The reaction mixture was washed with 750 ml of 10% hydrochloric acid, with a saturated aqueous solution of sodium hydrogencarbonate, and with a saturated aqueous solution of sodium chloride, in this order, and dried over anhydrous magnesium sulfate. Methylene chloride was evaporated off, the residue was washed with ether, with benzene and with ethanol, in this order. All of the washings were combined and concentrated, and the residue was subjected to column chromatography on 3 kg of silica gel with elution with benzene-ethyl acetate (30:1-15:1), to give a main product and a by-product. The main product was recrystallized from isopropanol-benzene, to give 51.8 g of (-)-4,5-difluoro-2-(S)-methyl-1-[(S)-N-p-tol uenesulfonylprolyl]-2,3-dihydroindole (Compound (a)) having the following physical characteristics.

Workup

  1. temperaturecooling
  2. additionAfter the dropwise addition
  3. washThe reaction mixture was washed with 750 ml of 10% hydrochloric acid, with a saturated aqueous solution of sodium hydrogencarbonate
  4. dry with materialwith a saturated aqueous solution of sodium chloride, in this order, and dried over anhydrous magnesium sulfate
  5. customMethylene chloride was evaporated off
  6. washthe residue was washed with ether, with benzene and with ethanol, in this order
  7. concentrationconcentrated
  8. washthe residue was subjected to column chromatography on 3 kg of silica gel with elution with benzene-ethyl acetate (30:1-15:1)
  9. customto give a main product
  10. customThe main product was recrystallized from isopropanol-benzene

Sources & evidence

ORD record
ord-25e1f42095a74143ab701ef49d466b04
Source dataset
uspto-grants-1993_02
Patent number
US05185337

Reaction notes

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