Trimethylsilyl triflate → (S)-1-{(S)-2-[(S)-2-((E)-(R)-2-Cyclopropylmethyl-pent-3-enoylamino)-3-methyl-butyrylamino]-propionyl}-hexahydro-pyridazine-3-carboxylic acid (R)-1-(7-vinyl-quinolin-2-yl)-ethyl ester

Temperature

0 °C

A cooled (0° C.) solution of (S)-1-[(S)-2-((S)-2-tert-butoxycarbonylamino-3-methyl-butyrylamino)-propionyl]-hexahydro-pyridazine-3-carboxylic acid (R)-1-(7-vinyl-quinolin-2-yl)-ethyl ester (340 mg, 0.585 mmol) in anhydrous dichloromethane (20 mL) under nitrogen was treated with trimethylsilyl-trifluoromethanesulfonate (212 μL, 1.17 mmol). After stirring for 1.5 h at 0° C., the reaction was quenched with saturated sodium bicarbonate solution and stirred for 20 minutes. The organic layer was separated and washed with saturated sodium bicarbonate solution. The organics were dried over anhydrous sodium sulfate, filtered and evaporated. To the residue in anhydrous acetonitrile (15 mL) was added 4 Å molecular sieves (1 g) followed by a solution of (E)-(R)-2-cyclopropylmethyl-pent-3-enoic acid (108 mg, 0.702 mmol) in anhydrous acetonitrile (5 mL). N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (157 mg, 0.819 mmol) and 1-hydroxybenzotriazole (119 mg, 0.702 mmol) were then added and the resulting mixture stirred for 69 h. The reaction mixture was filtered through Celite with dichloromethane and the filtrate was washed with saturated aqueous ammonium chloride solution, water then brine. The organics were dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography using a gradient of iso-hexanes/ethyl acetate 1:1 to 0:1 to afford the title compound (142 mg, 39%) as a white solid. 1H NMR (300 MHz, CDCl3) δ 0.03-0.12 (m, 2H), 0.37-0.45 (m, 2H), 0.63-0.71 (m, 1H), 0.87-0.94 6H), 1.30 (d, J=6.9 Hz, 3H), 1.45-1.66 (m, 2H), 1.71-1.74 (m, 6H), 1.92-1.95 (m, 1H), 2.02-2.09 (m, 1H), 2.12-2.20 (m, 1H), 2.75-2.87 (m, 1H), 2.93 (q, J=7.3 Hz, 1H), 3.58-3.68 (m, 1H), 3.81-3.91 (m, 1H), 4.27 (dd, J=8.5, 6.1 Hz, 1H), 4.45 (br d J=12.5 Hz, 1H), 5.28 (app pentet, J=6.9 Hz, 1H), 5.44 (br d J=10.9 Hz, 1H), 5.48-5.65 (m, 2H), 5.98 (d, J=17.6 Hz, 1H), 6.13 (q, J=6.7 Hz, 1H), 6.19-6.24 (m, 1H), 6.65 (br d, J=7.6 Hz, 1H), 6.93 (dd, J=17.5, 10.8 Hz, 1H), 7.41 (d, J=8.5 Hz, 1H), 7.69 (dd, J=8.5, 1.3 Hz, 1H), 7.79 (d, J=8.5 Hz, 1H), 8.04 (s, 1H), 8.18 (d, J=8.5 Hz, 1H). LCMS (m/z) 618.3 [M+H], Tr=3.07 min.

1. customthe reaction was quenched with saturated sodium bicarbonate solution
2. stirringstirred for 20 minutes
3. customThe organic layer was separated
4. washwashed with saturated sodium bicarbonate solution
5. dry with materialThe organics were dried over anhydrous sodium sulfate
6. filtrationfiltered
7. customevaporated
8. additionTo the residue in anhydrous acetonitrile (15 mL) was added 4 Å molecular sieves (1 g)
9. stirringthe resulting mixture stirred for 69 h
10. filtrationThe reaction mixture was filtered through Celite with dichloromethane
11. washthe filtrate was washed with saturated aqueous ammonium chloride solution, water
12. dry with materialThe organics were dried over anhydrous sodium sulfate
13. filtrationfiltered
14. customevaporated
15. customThe residue was purified by silica gel chromatography

ORD record

ord-2518427ec8734ceeb3268b30030b8f4a

Source dataset

uspto-grants-2015_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09145441B2