Imidazole → Methyl-(2S,3S)-1-{[(3-chloro-4-cyano-2-methylphenyl)amino]-carbonyl}-3-(tert-butyl-dimethylsilanyloxy)-pyrrolidine-2-carboxylate

HRID 751114Notes

Reaction equation

HRID 751114 reaction equation
[CH3:1][O:2][C:3]([C@@H:5]1[C@@H:9]([OH:10])[CH2:8][CH2:7][N:6]1[C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[C:16]([Cl:22])[C:15]=1[CH3:23])=[O:12])=[O:4].N1C=CN=C1.[Si:29](Cl)([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30].CO>CN(C=O)C>[CH3:1][O:2][C:3]([C@@H:5]1[C@@H:9]([O:10][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])[CH2:8][CH2:7][N:6]1[C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[C:16]([Cl:22])[C:15]=1[CH3:23])=[O:12])=[O:4]

Participants

6

Reactant 4

HCID 795ImidazoleHCID 887MethanolHCID 28928tert-Butyldimethylsilyl chlorideHCID 59754269(2S,3S)-1-(3-Chloro-4-cyano-2-methylphenylcarbamoyl)-3-hydroxy-pyrrolidine-2-carboxylic acid methyl ester

Product 1

HCID 11719388Methyl-(2S,3S)-1-{[(3-chloro-4-cyano-2-methylphenyl)amino]-carbonyl}-3-(tert-butyl-dimethylsilanyloxy)-pyrrolidine-2-carboxylateYield 107.3%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
0 °C

Procedure

A cooled (0° C.) solution of compound 55A (510.1 mg, 1.51 mmol) and imidazole (516 mg, 7.58 mmol) in dry DMF (2.6 mL) was treated with 97% tert-butyldimethylsilyl chloride (572 mg, 3.68 mmol), stirred at 0° C. for 5 min then at rt for 24 h. Methanol (3.5 mL) was added and the solution stirred at rt for another 24 h. The mixture was partitioned between 10% citric acid (5.3 mL) and EtOAc (3×50 mL). The combined organic phases were washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The resulting syrup was chromatographed (silica gel; EtOAc/hexane gradient) to yield the title compound (732.3 mg, 100%) as a white solid, mp 123-125° C. HPLC: 3.38 min (retention time) (Conditions: YMC S-5 C-18 (4.6×50 mm), eluting with 0-100% B, 4 min gradient. (A=90% H2O—10% CH3CN—0.1% TFA and B=10% H2O—90% CH3CN—0.1% TFA); Flow rate at 4 mL/min. UV detection at 220 nm. Chiral HPLC: retention time=9.30 min (98.6%); Conditions: AD (4.6×250 mm); Eluted with 20% isopropanol in heptane for 30 min at 1 mL/min. MS (ES) m/z 452 [M+H]+.

Workup

  1. waitat rt for 24 h
  2. stirringthe solution stirred at rt for another 24 h
  3. customThe mixture was partitioned between 10% citric acid (5.3 mL) and EtOAc (3×50 mL)
  4. washThe combined organic phases were washed with brine
  5. dry with materialdried (Na2SO4)
  6. filtrationfiltered
  7. concentrationconcentrated under reduced pressure
  8. customThe resulting syrup was chromatographed (silica gel; EtOAc/hexane gradient)

Sources & evidence

ORD record
ord-d47c0c2c285d412a8ed0a2e70fc4c86a
Source dataset
uspto-grants-2008_07
Patent number
US07405234B2

Reaction notes

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