Trifluoroacetic acid → (S)-1-[(S)-2-tert-Butoxycarbonylamino-3-(3-methyl-oxetan-3-ylmethoxy)-propionyl]-hexahydro-pyridazine-3-carboxylic acid 2,2,2-trichloro-ethyl ester

To (S)-tetrahydro-pyridazine-1,2,3-tricarboxylic acid 1,2-di-tert-butyl ester 3-(2,2,2-trichloro-ethyl)ester (1.76 g, 3.81 mmol) in anhydrous dichloromethane (12 mL) at room temperature and under an atmosphere of nitrogen was added trifluoroacetic acid (12 mL, 152 mmol). The solution was warmed to room temperature and stirred for 16 h. The reaction was concentrated in vacuo and the residue co-evaporated from toluene (3×). The resulting residue was dissolved in anhydrous acetonitrile (5 mL) and added to a solution of (S)-2-tert-butoxycarbonylamino-3-(3-methyl-oxetan-3-ylmethoxy)-propionic acid (1.1 mg, 3.81 mmol), N,N-diisopropylethylamine (2.7 mL, 15.2 mmol) and 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate methanaminium (1.40 g, 3.81 mmol) in anhydrous acetonitrile (20 mL) that had been previously stirred at 0° C. for 20 minutes. The reaction was warmed to room temperature and stirred for 16 h. The reaction was cooled to 0° C. diluted with ethyl acetate and quenched with 1 M hydrochloric acid. The organic layer was separated and washed with a saturated aqueous solution of sodium bicarbonate (2×) and brine (1×). The organic layer was then dried through a hydrophobic frit and concentrated in vacuo. The residue was purified by silica gel chromatography using iso-hexanes/ethyl acetate 1:1 to give the title compound (1.2 g, 59%) as a clear viscous oil. 1H NMR (300 MHz, CDCl3) δ 1.27 (s, 3H), 1.46 (s, 9H), 1.63-2.18 (m, 5H), 3.13-3.27 (m, 1H), 3.45-3.60 (m, 3H), 3.73-3.87 (m, 2H), 4.05-4.17 (m, 1H), 4.38 (d, J=5.6 Hz, 2H), 4.57 (dd, J=7.8, 5.6 Hz, 2H), 4.79 (d, J=11.8 Hz, 1H), 4.91 (d, J=11.8 Hz, 1H), 5.33-5.60 (m, 2H). LCMS (m/z) 532.3 [M+H], Tr=2.75 min.

1. concentrationThe reaction was concentrated in vacuo
2. dissolutionThe resulting residue was dissolved in anhydrous acetonitrile (5 mL)
3. stirringhad been previously stirred at 0° C. for 20 minutes
4. temperatureThe reaction was warmed to room temperature
5. stirringstirred for 16 h
6. temperatureThe reaction was cooled to 0° C.
7. customquenched with 1 M hydrochloric acid
8. customThe organic layer was separated
9. washwashed with a saturated aqueous solution of sodium bicarbonate (2×) and brine (1×)
10. customThe organic layer was then dried through a hydrophobic frit
11. concentrationconcentrated in vacuo
12. customThe residue was purified by silica gel chromatography

ORD 기록

ord-1323fd6f241f4fe9bc6d02931d7b2c7f

출처 데이터셋

uspto-grants-2015_09

DOI

10.6084/m9.figshare.5104873.v1

특허 번호

US09145441B2