Trimethylsilyl triflate → (S)-1-{(S)-2-[(S)-2-(2-Cyano-2-methyl-but-3-enoylamino)-3-methyl-butyrylamino]-propionyl}-hexahydro-pyridazine-3-carboxylic acid 2,2,2-trichloro-ethyl ester

A stirred solution of (S)-1-[(S)-2-((S)-2-tert-butoxycarbonylamino-3-methyl-butyrylamino)-propionyl]-hexahydro-pyridazine-3-carboxylic acid 2,2,2-trichloro-ethyl ester (692 mg, 1.3 mmol) in dry dichlormethane (39 mL) was cooled to 0° C. under nitrogen and then trimethylsilyl trifluoromethanesulfonate (578 mg, 471 μL, 2.6 mmol) was added. The reaction was stirred for 1 h and then quenched with saturated sodium bicarbonate solution. The organic layer was separated and washed with further saturated sodium bicarbonate solution (2×), dried over anhydrous sodium sulfate, filtered and evaporated. To the residue was added 4 Å molecular sieves (powdered, 1.3 g) and a solution of the crude 2-cyano-2-methyl-but-3-enoic acid (2 mmol) in dry acetonitrile (39 mL) followed by 1-hydroxybenzotriazole (containing 20% H2O) (307 mg, 1.82 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (349 mg, 1.82 mmol). The mixture was stirred for 3.5 h, filtered through Celite, washing with extra dichloromethane and the filtrate washed with saturated ammonium chloride solution, water then saturated brine, 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 1:3 to afford the title compound (356 mg, 51%) as a white solid as a mixture of diastereoisomers. 1H NMR (300 MHz, CDCl3) δ 0.90-0.97 (m, 3H), 0.99 (d, J=6.9 Hz, 3H), 1.33 (app t, J=7.1 Hz, 3H), 1.54-1.61 (m, 1H), 1.70-1.79 (m, 1H), 1.71 (s, 1.5H), 1.72 (s, 1.5H), 1.89-2.00 (m, 1H), 2.09-2.25 (m, 2H), 2.91-3.02 (m, 1H), 3.65-3.76 (m, 1H), 3.84 (d, J=11.2 Hz, 1H), 4.22-4.36 2H), 4.72 (d, J=12.1 Hz, 1H), 4.97 (dd, J=12.1 Hz, 2.5 Hz, 1H), 5.31-5.38 (m, 1H), 5.44 (t, J=9.8 Hz, 1H), 5.70 (dd, J=17.2, 10.3 Hz, 1H), 5.87-6.02 (m, 1H), 6.53-6.60 (m, 1H), 6.73-6.87 (m, 1H). LCMS (m/z) 538.0, 540.0, 542.0 [M+H], Tr=2.68 min.

1. customquenched with saturated sodium bicarbonate solution
2. customThe organic layer was separated
3. washwashed with further saturated sodium bicarbonate solution (2×)
4. dry with materialdried over anhydrous sodium sulfate
5. filtrationfiltered
6. customevaporated
7. additionTo the residue was added 4 Å molecular sieves (powdered, 1.3 g)
8. stirringThe mixture was stirred for 3.5 h
9. filtrationfiltered through Celite
10. washwashing with extra dichloromethane
11. washthe filtrate washed with saturated ammonium chloride solution, water
12. dry with materialsaturated brine, dried over anhydrous sodium sulfate
13. filtrationfiltered
14. customevaporated
15. customThe residue was purified by silica gel chromatography

ORD record

ord-99fc0ce975e2435da99f24d0a1e6e763

Source dataset

uspto-grants-2015_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09145441B2