Diisopropylethylamine → (2S,3S)-1-(3-Chloro-4-cyano-2-methylphenylcarbamoyl)-3-hydroxy-pyrrolidine-2-carboxylic acid methyl ester

HRID 501598Notes

Reaction equation

HRID 501598 reaction equation
Cl.[CH3:2][O:3][C:4]([C@@H:6]1[C@@H:10]([OH:11])[CH2:9][CH2:8][NH:7]1)=[O:5].CCN(C(C)C)C(C)C.[Cl:21][C:22]1[C:29]([CH3:30])=[C:28]([N:31]=[C:32]=[O:33])[CH:27]=[CH:26][C:23]=1[C:24]#[N:25]>C(Cl)Cl>[CH3:2][O:3][C:4]([C@@H:6]1[C@@H:10]([OH:11])[CH2:9][CH2:8][N:7]1[C:32]([NH:31][C:28]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[C:22]([Cl:21])[C:29]=1[CH3:30])=[O:33])=[O:5]

Participants

5

Reactant 3

HCID 81531DiisopropylethylamineHCID 167318492-Chloro-4-isocyanato-3-methylbenzonitrileHCID 66605223methyl (2S,3S)-3-hydroxypyrrolidine-2-carboxylate hydrochloride

Product 1

HCID 59754269(2S,3S)-1-(3-Chloro-4-cyano-2-methylphenylcarbamoyl)-3-hydroxy-pyrrolidine-2-carboxylic acid methyl esterYield 75.3%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Conditions

Temperature
0 °C

Procedure

A solution of ester 1A (500 mg, 2.75 mmol) in dry CH2Cl2 (10 mL) was cooled to 0° C., treated with Hunig's base (0.53 mL, 3.04 mmol) and stirred at 0° C. for 30 min. The solution was treated with isocyanate 23E (505 mg, 2.62 mmol), and the resulting suspension was stirred at rt for 3 h. The insoluble solids were filtered off and the filtrate was partitioned between aqueous NH4Cl (6.0 mL) and CH2Cl2 (3×60 mL). The combined organic phases were washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue and insoluble solids were combined and chromatographed (silica gel; EtOAc/hexane gradient) to yield the title compound (177.2 mg, 75.3%) as a white solid, mp 189-191° C. HPLC: 1.72 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=22.2 min (100%); Conditions: AD (4.6×250 mm); Eluted with 20% isopropanol in heptane for 30 min at 1 mL/min. MS (ES) m/z 338 [M+H]+.

Workup

  1. stirringthe resulting suspension was stirred at rt for 3 h
  2. filtrationThe insoluble solids were filtered off
  3. customthe filtrate was partitioned between aqueous NH4Cl (6.0 mL) and CH2Cl2 (3×60 mL)
  4. washThe combined organic phases were washed with brine
  5. dry with materialdried (Na2SO4)
  6. filtrationfiltered
  7. concentrationconcentrated under reduced pressure
  8. customchromatographed (silica gel; EtOAc/hexane gradient)

Sources & evidence

ORD record
ord-81edad070b234164a897053e76b701fb
Source dataset
uspto-grants-2010_08
Patent number
US07772267B2

Reaction notes

Loading…