Hydrochloric Acid → (R)-cyanomethyl 3-(methyldisulfanyl)-2-(pent-4-enamido)propanoate

Trifluoroacetic acid (1.76 ml, 22.8 mmol) and triisopropylsilane (0.934 ml, 4.56 mmol) were added to a solution of (R)-2-(pent-4-enamido)-3-(tritylthio)propanoic acid (Compound 2h) (1.01 g, 2.28 mmol) in dichloromethane (10 ml), and the mixture was stirred at room temperature for 10 minutes. The reaction mixture was then concentrated under reduced pressure. A solution of S-methyl methanesulfonothioate (1.44 g, 11.4 mmol) in ethanol (5 ml) was added dropwise to a solution of the resulting residue and sodium carbonate (1.21 g, 11.4 mmol) in water (5 ml) at 0° C., and the mixture was then stirred at room temperature for 30 minutes. The reaction mixture was then adjusted to pH 2 by adding concentrated hydrochloric acid thereto at 0° C. The mixture was extracted by dilution with ethyl acetate. The resulting organic extract was washed with brine, dried over magnesium sulfate and then concentrated under reduced pressure. 2-Bromoacetonitrile (0.438 ml, 6.29 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.440 ml, 2.52 mmol) were added to a solution of the resulting residue in DMF (1 ml), and the mixture was stirred at room temperature for 10 minutes. A saturated aqueous ammonium chloride solution (3 ml) was added to the reaction mixture, after which the mixture was extracted with ethyl acetate and the organic layer was washed with water. The organic extract was then dried over magnesium sulfate. Following concentration under reduced pressure, the resulting residue was purified by reverse-phase silica gel column chromatography (10 mM aqueous ammonium acetate solution/methanol=70/30→0/100) to afford (R)-cyanomethyl 3-(methyldisulfanyl)-2-(pent-4-enamido)propanoate (Compound 21-D) (291 mg, 48%).

1. concentrationThe reaction mixture was then concentrated under reduced pressure
2. stirringthe mixture was then stirred at room temperature for 30 minutes
3. customat 0° C
4. extractionThe mixture was extracted by dilution with ethyl acetate
5. extractionThe resulting organic extract
6. washwas washed with brine
7. dry with materialdried over magnesium sulfate
8. concentrationconcentrated under reduced pressure
9. stirringthe mixture was stirred at room temperature for 10 minutes
10. extractionafter which the mixture was extracted with ethyl acetate
11. washthe organic layer was washed with water
12. extractionThe organic extract
13. dry with materialwas then dried over magnesium sulfate
14. concentrationconcentration under reduced pressure
15. customthe resulting residue was purified by reverse-phase silica gel column chromatography (10 mM aqueous ammonium acetate solution/methanol=70/30→0/100)

ORD record

ord-14290af50b0b470a859fc6a25cd11a26

Source dataset

uspto-grants-2016_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09409952B2