Lithium borohydride → (2S,4R)-N-(3-Chloro-4-cyano-2-methylphenyl)-4-(tert-butyldimethylsilanyloxy)-2-(hydroxymethyl)pyrrolidine-1-carboxamide

HRID 751118Notes

Reaction equation

HRID 751118 reaction equation
[Cl:1][C:2]1[C:3]([CH3:30])=[C:4]([NH:10][C:11]([N:13]2[CH2:17][C@H:16]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[CH2:15][C@H:14]2[C:26](OC)=[O:27])=[O:12])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[Li+].[BH4-]>C1COCC1>[Cl:1][C:2]1[C:3]([CH3:30])=[C:4]([NH:10][C:11]([N:13]2[CH2:17][C@H:16]([O:18][Si:19]([C:22]([CH3:23])([CH3:24])[CH3:25])([CH3:20])[CH3:21])[CH2:15][C@H:14]2[CH2:26][OH:27])=[O:12])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]

Participants

4

Reactant 2

HCID 4148881Lithium borohydrideHCID 59754277Methyl (2S,4R)-1-{[(3-chloro-4-cyano-2-methylphenyl)amino]-carbonyl}-4-(tert-butyldimethylsilanyloxy)pyrrolidine-2-carboxylate

Product 1

HCID 59754308(2S,4R)-N-(3-Chloro-4-cyano-2-methylphenyl)-4-(tert-butyldimethylsilanyloxy)-2-(hydroxymethyl)pyrrolidine-1-carboxamideYield 93%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
0 °C

Procedure

To a solution of compound 56C (145 mg, 0.32 mmol) in anhydrous THF (3.0 mL) at 0° C. was added dropwise a solution of 2 M LiBH4 in THF (0.24 ml, 0.48 mmol) as described by Terry Rosen et. al. J. Med. Chem. 31 (8), 1598-1611 (1988). The solution was stirred at 0° C. for 2.5 h, quenched with 1.0 M K2CO3 (1.0 mL) and extracted with EtOAc (2×25 mL). The combined organic phases were washed with 1 M K2CO3, brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was chromatographed (silica gel; EtOAc/hexane gradient) to yield the title compound (125.4 mg, 93%) as a white solid, mp 169-171° C. HPLC: 3.31 min (retention time) (Conditions: YMC S-5 C-18 (4.6×250 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=7.01 min (99.96%); 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. customquenched with 1.0 M K2CO3 (1.0 mL)
  2. extractionextracted with EtOAc (2×25 mL)
  3. washThe combined organic phases were washed with 1 M K2CO3, brine
  4. dry with materialdried (Na2SO4)
  5. filtrationfiltered
  6. concentrationconcentrated under reduced pressure
  7. customThe residue was chromatographed (silica gel; EtOAc/hexane gradient)

Sources & evidence

ORD record
ord-dbac762189e94a458d6157b07920cbc5
Source dataset
uspto-grants-2008_07
Patent number
US07405234B2

Reaction notes

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