Ethyl Acetate → Ethyl (S)-3-(6-aminopyridin-3-yl)-2-{1-[5-(5-chlorothiophen-2-yl)isoxazol-3-ylmethyl]-1H-imidazol-4-yl}propionate

HRID 1666981Notes

Reaction equation

HRID 1666981 reaction equation
[H-].[Na+].[NH2:3][C:4]1[N:9]=[CH:8][C:7]([CH2:10][CH:11]([C:15]2[N:16]=[CH:17][NH:18][CH:19]=2)[C:12]([OH:14])=[O:13])=[CH:6][CH:5]=1.CS(O[CH2:25][C:26]1[CH:30]=[C:29]([C:31]2[S:32][C:33]([Cl:36])=[CH:34][CH:35]=2)[O:28][N:27]=1)(=O)=O.[C:37](OCC)(=O)[CH3:38]>CN(C=O)C>[NH2:3][C:4]1[N:9]=[CH:8][C:7]([CH2:10][C@@H:11]([C:15]2[N:16]=[CH:17][N:18]([CH2:25][C:26]3[CH:30]=[C:29]([C:31]4[S:32][C:33]([Cl:36])=[CH:34][CH:35]=4)[O:28][N:27]=3)[CH:19]=2)[C:12]([O:14][CH2:37][CH3:38])=[O:13])=[CH:6][CH:5]=1

Participants

6

Reactant 4

HCID 8857Ethyl AcetateHCID 24758Sodium hydrideHCID 865958785-(5-Chlorothiophen-2-yl)isoxazol-3-ylmethyl methanesulfonateHCID 178507560HCID 178507560, compound

Product 1

HCID 67444646Ethyl (S)-3-(6-aminopyridin-3-yl)-2-{1-[5-(5-chlorothiophen-2-yl)isoxazol-3-ylmethyl]-1H-imidazol-4-yl}propionate

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

Under argon, 0.485 g (60% in mineral oil, 19.21 mmol) of sodium hydride was added to a solution of 5.0 g (19.21 mmol) of 3-(6-aminopyridin-3-yl)-2-(1H-imidazol-4-yl)propionic acid in 200 ml of absolute DMF. The mixture was stirred for 30 min at RT, 5.643 g (19.21 mmol) of 5-(5-chlorothiophen-2-yl)isoxazol-3-ylmethyl methanesulfonate were then added and the mixture was stirred at RT for another 3 h. The reaction mixture was concentrated under reduced pressure, and the residue obtained was chromatographed on silica gel using CH2Cl2/MeOH/water/acetic acid 90:10:1:1. This gave two product-containing fractions which were purified by preparative HPLC. The fractions of value were combined and freeze-dried. The residue obtained was dissolved in ethyl acetate, washed with saturated NaHCO3 solution, dried over Na2SO4, filtered and concentrated. The material obtained in this manner (3.7 g) was separated into its enantiomers by chiral HPLC (column Chiralpak AD-H/55, 250×4.6 mm, flow rate 1 ml/min, mobile phase heptane:isopropanol:methanol 3:1:1+0.1% TFA). 0.1 g (218 μmol) of the product obtained was dissolved in 5 ml of water/acetic acid (1:1) and freeze-dried (0.108 g, 95%).

Workup

  1. stirringthe mixture was stirred at RT for another 3 h
  2. concentrationThe reaction mixture was concentrated under reduced pressure
  3. customthe residue obtained
  4. customwas chromatographed on silica gel
  5. customThis gave two product-containing fractions which
  6. customwere purified by preparative HPLC
  7. customfreeze-dried
  8. customThe residue obtained
  9. washwashed with saturated NaHCO3 solution
  10. dry with materialdried over Na2SO4
  11. filtrationfiltered
  12. concentrationconcentrated
  13. customThe material obtained in this manner (3.7 g)
  14. customwas separated into its enantiomers by chiral HPLC (column Chiralpak AD-H/55, 250×4.6 mm, flow rate 1 ml/min, mobile phase heptane:isopropanol:methanol 3:1:1+0.1% TFA)

Sources & evidence

ORD record
ord-d671829e323c4c58b389b91ff0ab8fd9
Source dataset
uspto-grants-2011_10
Patent number
US08044208B2

Reaction notes

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