1-Hydroxybenzotriazole → (2S)-N1-((1S,2R)-1-benzyl-3-(cyclopentyloxy)[(4-methoxyphenyl)sulfonyl]amino-2-hydroxypropyl)-2-[(2-quinolinylcarbonyl)amino]butanediamide

A mixture of N1-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-N1-(cyclopentyloxy)-4-methoxy-1-benzenesulfonamide (Step 1, Example 48), (73 mg, 0.168), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (34 mg, 0.18 mmol), N-hydroxybenzotriazole (24 mg, 0.18 mmol), and (2S)-4-amino-4-oxo-2-[(2-quinolinylcarbonyl) amino]butanoic acid hydrochloride (57 mg, 0.18 mmol, Eur. Pat. Appl. EP 432694) was combined under an Argon atmosphere at ambient temperature in anhydrous dLmethylformamide (2 mL). After addition of N,N-diisopropylethylamine (896 μL, 0.513 mmol), the mixture was stirred for 16 hours. The reaction solvent was removed in vacuo and the residue was dissolved in ethyl acetate. The solution was transferred to a separatory funnel and washed twice with 1N sodium hydrogen sulfate. The combined aqueous layers were extracted with ethyl acetate. The combined organic layers were washed with 5% aqueous potassium carbonate and brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. The residue was purified on a preparative TLC plate (20×20 cm, 1000 μM) eluting with 97:3 chloroform : methanol. The product band was removed, eluted with 3:1 methylene chloride methanol, filtered, and evaporated in vacuo. The residue was triturated with hexane and diethyl ether. The slurry was evaporated in vacuo to a residue and dried under high vacuum to provide (2S)-N1-((1S,2R)-1-benzyl-3-(cyclopentyloxy)[(4-methoxyphenyl)sulfonyl]amino-2-hydroxypropyl)-2-[(2-quinolinylcarbonyl)amino]butanediamide (49 mg, 41%) as a white solid. HL-NMR (chloroform-D3): 1.52 (m, 4H), 1.75 (m, 4H), 2.82 (m, 5H), 3.10 (m, 1H), 3.82 (b, 1H), 3.84 (s, 3H), 3.91 m, 1H), 4.29 (m, 1H), 4.78 (m, 1H), 4.95 (m, 1H), 5.76 (b, 1H), 6.22 (b, 1H), 7.00 (m, 5H), 7.12 (d, 2H), 7.22 (d, 1H), 7.60 (m, 1H). 7.75 (m, 3H), 7.83 (d, IH), 8.14 (m, 2H), 8.25 (d, 1H), 9.15 (d, 1H). MS(ESI): 704(M+H).

1. customwas combined under an Argon atmosphere at ambient temperature in anhydrous dLmethylformamide (2 mL)
2. customThe reaction solvent was removed in vacuo
3. dissolutionthe residue was dissolved in ethyl acetate
4. customThe solution was transferred to a separatory funnel
5. washwashed twice with 1N sodium hydrogen sulfate
6. extractionThe combined aqueous layers were extracted with ethyl acetate
7. washThe combined organic layers were washed with 5% aqueous potassium carbonate and brine
8. dry with materialdried over anhydrous magnesium sulfate
9. filtrationfiltered
10. customevaporated in vacuo
11. customThe residue was purified on a preparative TLC plate (20×20 cm, 1000 μM)
12. washeluting with 97:3 chloroform
13. customThe product band was removed
14. washeluted with 3:1 methylene chloride methanol
15. filtrationfiltered
16. customevaporated in vacuo
17. customThe residue was triturated with hexane and diethyl ether
18. customThe slurry was evaporated in vacuo to a residue
19. customdried under high vacuum

ORD-Eintrag

ord-9ac89237158049e18e230777ce2800d3

Quelldatensatz

uspto-grants-2003_09

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US06613743B2