Ethyl Acetate → [(R)-1-(2-chloro-5-nitro-pyrimidin-4-yl)-pyrrolidin-2-yl]-acetic acid methyl ester

HRID 2111440Notes

Reaction equation

HRID 2111440 reaction equation
Cl.[CH3:2][O:3][C:4](=[O:11])[CH2:5][C@H:6]1[CH2:10][CH2:9][CH2:8][NH:7]1.[Cl:12][C:13]1[N:18]=[C:17](Cl)[C:16]([N+:20]([O-:22])=[O:21])=[CH:15][N:14]=1.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>C(Cl)(Cl)Cl>[CH3:2][O:3][C:4](=[O:11])[CH2:5][C@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:15]1[C:16]([N+:20]([O-:22])=[O:21])=[CH:17][N:18]=[C:13]([Cl:12])[N:14]=1

Participants

6

Reactant 4

HCID 8857Ethyl AcetateHCID 516892Sodium BicarbonateHCID 5212662,4-Dichloro-5-nitropyrimidineHCID 68738055methyl 2-((2R)-pyrrolidin-2-yl)acetate hydrochloride

Product 1

HCID 86623422[(R)-1-(2-chloro-5-nitro-pyrimidin-4-yl)-pyrrolidin-2-yl]-acetic acid methyl esterYield 91.5%

Reagents, catalysts & solvents 1

HCID 6212ChloroformSolvent

Procedure

To a solution of 2.0 g (0.012 mole) of D-beta-homoproline hydrochloride in 20 mL of methanol was added slowly 1.8 mL (0.024 mole) of thionyl chloride at 0 degrees. The mixture was stirred overnight, then concentrated under reduced pressure. The solid was slurried in ether, and collected by filtration to give 2.2 g of (2R)-pyrrolidin-2-yl-acetic acid methyl ester hydrochloride as a white solid. A solution of 2.2 g (0.012 mole) of (2R)-pyrrolidin-2-yl-acetic acid methyl ester hydrochloride in 3 mL of chloroform was added over 5 minutes to a cooled (0 degrees) mixture of 2.34 g (0.012 mole) of 2,4-dichloro-5-nitro-pyrimidine, 5.1 g (0.060 mole) of sodium bicarbonate and 25 mL of ethyl acetate. The cooling bath was removed and the mixture stirred for 17 hours at room temperature. Activated charcoal was added and after stirring briefly, the mixture was filtered through a pad of Celite, washing the filter pad with ethyl acetate. The filtrate was concentrated under reduced pressure. Purification of the residue by silica gel chromatography, eluting with hexanes-ethyl acetate (100:0-70:30) gave 3.3 g of [(R)-1-(2-chloro-5-nitro-pyrimidin-4-yl)-pyrrolidin-2-yl]-acetic acid methyl ester (IV-102) as a yellow thick oil.

Workup

  1. temperaturea cooled
  2. customThe cooling bath was removed
  3. additionActivated charcoal was added
  4. stirringafter stirring briefly
  5. filtrationthe mixture was filtered through a pad of Celite
  6. washwashing the filter pad with ethyl acetate
  7. concentrationThe filtrate was concentrated under reduced pressure
  8. customPurification of the residue by silica gel chromatography
  9. washeluting with hexanes-ethyl acetate (100:0-70:30)

Sources & evidence

ORD record
ord-6d5a635c61954abca14bf9efb3d4614c
Source dataset
uspto-grants-2009_04
Patent number
US07517873B2

Reaction notes

Loading…