Reaction #61101

Reaction equation

(2S,3S)-2-{(R)-2-amino-2-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-acetylamino}-3-phenyl-N-(4-propionyl-thiazol-2-yl)-butyramide

diphosgene

diisopropylethylamine

→

(2S,3S)-2-{4-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-2,5-dioxo-imidazolidin-1-yl}-3-phenyl-N-(4-propionyl-thiazol-2-yl)-butyramide

Solvents

tetrahydrofuran

tetrahydrofuran

Conditions

Workup

1. 1
   Otherpartitioned between ethyl acetate and water
2. 2
   OtherThe organic layer was separated
3. 3
   Dryingdried over sodium sulfate
4. 4
   Filtrationfiltered
5. 5
   Concentrationconcentrated in vacuo
6. 6
   OtherThe residue was purified by chromatography over silica gel gradient
7. 7
   Washeluted with 0-100% ethyl acetate in hexanes
8. 8
   Otherthe isolated material further purified by preparative thin layer chromatography
9. 9
   Washeluted with ethyl acetate
10. 10
    OtherPrecipitation of the isolated product from dichloromethane with an excess of hexanes

Procedure

Crude (2S,3S)-2-{(R)-2-amino-2-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-acetylamino}-3-phenyl-N-(4-propionyl-thiazol-2-yl)-butyramide (≈0.19 mmol) was dissolved in tetrahydrofuran (10 mL) that contained diisopropylethylamine (160 μL, 122 mg, 0.94 mmol) and was transferred via cannula to a solution of diphosgene (16 μL, 26 mg, 0.13 mmol) in tetrahydrofuran (15 mL) at 0° C. The reaction mixture was stirred for 20 minutes and then partitioned between ethyl acetate and water. The organic layer was separated and dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography over silica gel gradient eluted with 0-100% ethyl acetate in hexanes and the isolated material further purified by preparative thin layer chromatography using silica gel eluted with ethyl acetate. Precipitation of the isolated product from dichloromethane with an excess of hexanes gave (2S,3S)-2-{4-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-2,5-dioxo-imidazolidin-1-yl}-3-phenyl-N-(4-propionyl-thiazol-2-yl)-butyramide as an off white solid (32 mg, 29%).

Source