Reaction #61096

Reaction equation

1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride

(R)-tert-butoxycarbonylamino-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-acetic acid

1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride

(R)-tert-Butoxycarbonylamino-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-acetic acid

(R)-tert-butoxycarbonylamino-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-acetic acid

(2S,3S)-2-amino-3-phenyl-N-(4-propionyl-thiazol-2-yl)-butyramide

(2S,3S)-2-[(R)-4-(4-Methoxy-phenyl)-2,5-dioxo-imidazolidin-1-yl]-3-phenyl-N-(4-propionyl-thiazol-2-yl)-butyramide

→

{(R)-[(1S,2S)-2-Phenyl-1-(4-propionyl-thiazol-2-ylcarbamoyl)-propylcarbamoyl]-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methyl}-carbamic acid tert-butyl ester

Solvents

tetrahydrofuran

Conditions

Workup

1. 1
   workup.ADDITIONwas added to the reaction mixture
2. 2
   Otherwas partitioned between ethyl acetate and brine
3. 3
   Extractionthe organic extract
4. 4
   Dryingwas dried over sodium sulfate
5. 5
   Concentrationconcentrated in vacuo
6. 6
   Otherthe resulting residue purified by chromatography over silica gel
7. 7
   Washeluted first with ethyl acetate
8. 8
   Washgradient eluted with dichloromethane containing from 0 to 10% methanol

Procedure

(R)-tert-Butoxycarbonylamino-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-acetic acid (740 mg, ≈1.96 mmol) was dissolved in tetrahydrofuran (30 mL) and (2S,3S)-2-amino-3-phenyl-N-(4-propionyl-thiazol-2-yl)-butyramide (250 mg, 0.78 mmol) (prepared as described in example 4) was added followed by 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (180 mg, 0.94 mmol) at 0° C. The reaction mixture was allowed to slowly warm to room temperature. After stirring for 3.5 hours additional (R)-tert-butoxycarbonylamino-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-acetic acid (320 mg, ≈0.85 mmol) was added to the reaction mixture. After stirring for an additional 1.5 hours an additional aliquot of (R)-tert-butoxycarbonylamino-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-acetic acid (300 mg, ≈0.82 mmol) was added to the reaction mixture along with additional 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (90 mg, 4.72 mmol). After stirring at room temperature for an additional 1 hour the mixture was partitioned between ethyl acetate and brine, the organic extract was dried over sodium sulfate, concentrated in vacuo and the resulting residue purified by chromatography over silica gel eluted first with ethyl acetate and then gradient eluted with dichloromethane containing from 0 to 10% methanol. {(R)-[(1S,2S)-2-Phenyl-1-(4-propionyl-thiazol-2-ylcarbamoyl)-propylcarbamoyl]-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methyl}-carbamic acid tert-butyl ester was obtained as a white solid (120 mg, 24%).

Source