Methyl-(2S,3S)-1-{[(3-chloro-4-cyano-2-methylphenyl)amino]-carbonyl}-3-(tert-butyl-dimethylsilanyloxy)-pyrrolidine-2-carboxylate → (2R,3S)-N-(3-Chloro-4-cyano-2-methylphenyl)3-(tert-butyldimethylsilanyloxy)-2-(hydroxymethyl)pyrrolidine-1-carboxamide

HRID 501600Notes

Reaction equation

HRID 501600 reaction equation
C[O:2][C:3]([C@@H:5]1[C@@H:9]([O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])[CH2:8][CH2:7][N:6]1[C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[C:23]([Cl:29])[C:22]=1[CH3:30])=[O:19])=O.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[Cl:29][C:23]1[C:22]([CH3:30])=[C:21]([NH:20][C:18]([N:6]2[CH2:7][CH2:8][C@H:9]([O:10][Si:11]([C:14]([CH3:15])([CH3:16])[CH3:17])([CH3:12])[CH3:13])[C@H:5]2[CH2:3][OH:2])=[O:19])[CH:26]=[CH:25][C:24]=1[C:27]#[N:28]

Participants

4

Reactant 2

HCID 11719388Methyl-(2S,3S)-1-{[(3-chloro-4-cyano-2-methylphenyl)amino]-carbonyl}-3-(tert-butyl-dimethylsilanyloxy)-pyrrolidine-2-carboxylateHCID 21226445Aluminium lithium hydride

Product 1

HCID 11568035(2R,3S)-N-(3-Chloro-4-cyano-2-methylphenyl)3-(tert-butyldimethylsilanyloxy)-2-(hydroxymethyl)pyrrolidine-1-carboxamideYield 78%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
0 °C

Procedure

To a solution of compound 55B (300 mg, 0.66 mmol) in anhydrous THF (6.7 mL) at −25° C. was added 1 N LAH in THF (1.34 mL, 1.34 mmol) over a period of 10 min. The solution was then warmed to 0° C. and stirred for 2.0 h before quenching with H2O (0.05 mL), 15% NaOH (0.05 mL) and H2O (0.16 mL). After warming to rt, the mixture was extracted with EtOAc (2×40 mL). The combined organic phases were washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The resultant off-white solid was chromatographed (silica gel; EtOAc/hexane gradient) to yield the title compound (217.2 mg, 78%) as a white solid, mp 174-176° C. HPLC: 3.23 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=7.11 min (96.1%); Conditions: AD (4.6×250 mm); Eluted with 20% isopropanol in heptane for 30 min at 1 mL/min. MS (ES) m/z 424 [M+H]+.

Workup

  1. custombefore quenching with H2O (0.05 mL), 15% NaOH (0.05 mL) and H2O (0.16 mL)
  2. temperatureAfter warming to rt
  3. extractionthe mixture was extracted with EtOAc (2×40 mL)
  4. washThe combined organic phases were washed with brine
  5. dry with materialdried (Na2SO4)
  6. filtrationfiltered
  7. concentrationconcentrated under reduced pressure
  8. customThe resultant off-white solid was chromatographed (silica gel; EtOAc/hexane gradient)

Sources & evidence

ORD record
ord-12fc87a6f6c248eda8cf07ea7414bce0
Source dataset
uspto-grants-2010_08
Patent number
US07772267B2

Reaction notes

Loading…