Hydrochloric Acid → (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

(S)-1-[(S)-2-((S)-2-tert-Butoxycarbonylamino-3-methyl-butyrylamino)-propionyl]-hexahydro-pyridazine-3-carboxylic acid methyl ester (562 mg, 1.36 mmol) was suspended in tetrahydrofuran (14 mL) then lithium hydroxide monohydrate (63 mg, 1.49 mmol) and water (3 mL) were added. The mixture was rapidly stirred for 30 minutes and then hydrochloric acid (2 M, 0.68 mL) was added. The mixture was evaporated and the residue was then suspended in anhydrous dichloromethane (13.5 mL) with 4 Å molecular sieves (powdered, 2 g). To the stirred mixture, under nitrogen, was added (R)-1-(7-vinyl-quinolin-2-yl)-ethanol (271 mg, 1.36 mmol) in anhydrous dichloromethane (13.5 mL), followed by N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (366 mg, 1.90 mmol) and 4-dimethylaminopyridine (166 mg, 1.36 mmol) and the resulting mixture was stirred for 16 h. A further portion of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (131 mg, 0.68 mmol) and 4-dimethylaminopyridine (83 mg, 0.68 mmol) were then added and the reaction mixture stirred for a further 5 h. The mixture was filtered through Celite and the filtrate washed with saturated aqueous ammonium chloride solution, followed by water and then brine. The organics were dried over anhydrous sodium sulfate, filtered and the filtrate evaporated. The residue was purified by silica gel chromatography using a gradient of iso-hexanes/ethyl acetate 1:3 to 1:1 to afford the title compound (366 mg, 46%) as a white foam. 1H NMR (300 MHz, CDCl3) δ 0.86-1.00 (m, 6H), 1.33 (d, J=6.7 Hz, 3H), 1.46 (s, 9H), 1.52-1.61 (m, 1H), 1.74 (d, J=6.7 Hz, 3H), 1.84-2.27 (m, 4H), 2.74-2.88 (m, 1H), 3.58-3.69 (m, 1H), 3.74-3.87 (m, 1H), 3.91-4.02 (m, 1H), 4.41-4.51 (m, 1H), 5.06-5.16 (m, 1H), 5.29 (app pentet, J=6.9 Hz, 1H), 5.44 (d, J=10.9 Hz, 1H), 5.97 (d, J=17.6 Hz, 1H), 6.13 (q, J=6.7 Hz, 1H), 6.73 (d, J=7.1 Hz, 1H), 6.94 (dd, J=17.8, 10.7 Hz, 1H), 7.41 (d, J=8.5 Hz, 1H), 7.69 (dd, J=8.5, 1.3 Hz, 1H), 7.79 (d, J=8.7 Hz, 1H), 8.03 (s, 1H), 8.18 (d, J=8.5 Hz, 1H). LCMS (m/z) 582.2 [M+H], Tr=2.58 min.

1. customThe mixture was evaporated
2. stirringthe resulting mixture was stirred for 16 h
3. stirringthe reaction mixture stirred for a further 5 h
4. filtrationThe mixture was filtered through Celite
5. washthe filtrate washed with saturated aqueous ammonium chloride solution
6. dry with materialThe organics were dried over anhydrous sodium sulfate
7. filtrationfiltered
8. customthe filtrate evaporated
9. customThe residue was purified by silica gel chromatography

ORD record

ord-e6b9bc0d8f834d39badce3f085fb5d24

Source dataset

uspto-grants-2015_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09145441B2