Tetrahydrofuran → (2S,4R)-1-(3-Benzothiazol-2-yl-5-chloro-2-oxo-2,3-dihydro-1H-indol-3-yl)-4-hydroxy-pyrrolidine-2-carboxylic acid dimethylamide

HRID 2040421Notes

Reaction equation

HRID 2040421 reaction equation
Cl.[CH3:2][N:3]([CH3:12])[C:4]([C@@H:6]1[CH2:10][C@@H:9]([OH:11])[CH2:8][NH:7]1)=[O:5].[S:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[C:14]1[C:22]1(Cl)[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([Cl:31])[CH:29]=2)[NH:24][C:23]1=[O:32].C1COCC1.CCN(C(C)C)C(C)C>ClCCl.O>[CH3:2][N:3]([CH3:12])[C:4]([C@@H:6]1[CH2:10][C@@H:9]([OH:11])[CH2:8][N:7]1[C:22]1([C:14]2[S:13][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[N:15]=2)[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([Cl:31])[CH:29]=2)[NH:24][C:23]1=[O:32])=[O:5]

Participants

7

Reactant 4

HCID 8028TetrahydrofuranHCID 81531DiisopropylethylamineHCID 23535508(2S,4R)-4-hydroxy-N,N-dimethylpyrrolidine-2-carboxamide hydrochlorideHCID 575177513-Benzothiazol-2-yl-3,5-dichloro-1,3-dihydroindol-2-one

Product 1

HCID 67043934(2S,4R)-1-(3-Benzothiazol-2-yl-5-chloro-2-oxo-2,3-dihydro-1H-indol-3-yl)-4-hydroxy-pyrrolidine-2-carboxylic acid dimethylamide

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6344DichloromethaneSolvent

Procedure

(2S,4R)-4-hydroxy-pyrrolidine-2-carboxylic acid dimethylamide hydrochloride (0.78 g, 4.0 mmol) was added to a solution of the intermediate from Step B in a mixture of dichloromethane (9 ml), THF (2 ml) and DIPEA (2 ml). The reaction mixture was stirred at room temperature for 48 h. After addition of water, the mixture was extracted four times with ethyl acetate. The combined organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The less polar diastereomer, as judged by thin-layer-chromatography using 5% MeOH in dichloromethane, precipitated on concentration and was filtered off. Purification by chromatography (silica gel, 5% MeOH in dichloromethane) resulted in 0.28 g of the less polar diastereomer. Purification by chromatography (silica gel, 5% MeOH in dichloromethane) of the mother liquor resulted in 0.36 g of the more polar diastereomer.

Workup

  1. extractionthe mixture was extracted four times with ethyl acetate
  2. dry with materialThe combined organic layer was dried over magnesium sulfate
  3. filtrationfiltered
  4. concentrationconcentrated under reduced pressure
  5. customprecipitated on concentration
  6. filtrationwas filtered off
  7. customPurification by chromatography (silica gel, 5% MeOH in dichloromethane)
  8. customresulted in 0.28 g of the less polar diastereomer
  9. customPurification by chromatography (silica gel, 5% MeOH in dichloromethane) of the mother liquor
  10. customresulted in 0.36 g of the more polar diastereomer

Sources & evidence

ORD record
ord-6f9fe7c143ac4b2d8fa9241d8ecc440d
Source dataset
uspto-grants-2013_11
Patent number
US08580842B2

Reaction notes

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