Triethylamine → HCID 118157551, compound

To a mixture of No. 5317776, 1-tert-butyl (S)-2-{(E)-(S)-1-[(S)-2-(4-but-2-ynyloxy-phenyl)-1-methoxycarbonyl-ethylcarbamoyl]-10-oxo-heptadec-2-enyl}-2-hydroxy-succinate (863 mg, 1.21 mmol), ammonium chloride (324 mg, 6.06 mmol), and DMF (40 mL) were added HOBt (735 mg, 5.44 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1,043 mg, 5.44 mmol), and N,N-diisopropylethylamine (1.57 mL, 9.11 mmol), and the mixture was stirred at room temperature for 1 day. After confirming the consumption of the starting materials by LCMS, ethyl acetate was added. The mixture was washed with water and a saturated brine, and dried over anhydrous sodium sulfate. The filtrate was then concentrated under reduced pressure. The resulting residue was purified with SP1 (SiO2 cartridge, 5% methanol/dichloromethane, Rf=0.3) to obtain No. 5463635, tert-butyl (E)-(2S,3S)-3-[(S)-2-(4-but-2-ynyloxy-phenyl)-1-methoxycarbonyl-ethylcarbamoyl]-2-carbamoylmethyl-2-hydroxy-12-oxo-nonadec-4-enoate (672 mg, 78%, ESI (LC/MS positive mode) m/z 713 (M+H); Rt 2.97 min.). A mixture of No. 5463635 and THF (30 mL) was cooled to 0° C., and trifluoroacetic acid anhydride (145 μL, 1.04 mmol) and triethylamine (263 μL, 1.89 mmol) were added. After stirring for 3 hours, the consumption of the starting materials was confirmed by LCMS. Ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated brine, and then dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure to obtain No. 6801972, tert-butyl (E)-(2S,3S)-3-[(S)-2-(4-but-2-ynyloxy-phenyl)-1-methoxycarbonyl-ethylcarbamoyl]-2-carbamoylmethyl-2-hydroxy-12-oxo-nonadec-4-enoate (600 mg, 91%, ESI (LC/MS positive mode) m/z 695 (M+H); Rt 3.28 min.). To No. 6801972 (520 mg, 0.748 mmol) was added formic acid (15 mL) and the mixture was stirred at room temperature. After confirming the consumption of the starting materials by LCMS, formic acid was distilled off under reduced pressure. The resulting residue was purified by preparative HPLC. The obtained fraction was freeze-dried to obtain the title compound (160 mg, 33% yield, white solid).

1. additionTo a mixture of No
2. customthe consumption of the starting materials by LCMS, ethyl acetate
3. additionwas added
4. washThe mixture was washed with water
5. dry with materiala saturated brine, and dried over anhydrous sodium sulfate
6. concentrationThe filtrate was then concentrated under reduced pressure
7. customThe resulting residue was purified with SP1 (SiO2 cartridge, 5% methanol/dichloromethane, Rf=0.3)
8. customto obtain No
9. additionA mixture of No
10. stirringAfter stirring for 3 hours
11. customthe consumption of the starting materials
12. additionEthyl acetate and water were added
13. extractionthe mixture was extracted with ethyl acetate
14. washThe organic layer was washed with water
15. dry with materiala saturated brine, and then dried over anhydrous sodium sulfate
16. concentrationThe filtrate was concentrated under reduced pressure
17. customto obtain No
18. stirringthe mixture was stirred at room temperature
19. customthe consumption of the starting materials by LCMS, formic acid
20. distillationwas distilled off under reduced pressure
21. customThe resulting residue was purified by preparative HPLC
22. customThe obtained fraction was freeze-dried

ORD record

ord-7408a7c9349a4c90b0fa28b610a8077c

Source dataset

uspto-grants-2016_02

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09266853B2