HCID 15168500, compound → HCID 15168499, compound

To a suspension of 5,7-dichloro-4-hydroxyimino-2-methoxycarbonyl-1,2,3,4-tetrahydroquinoline (8.0 g, 27.7 mmol) in glacial acetic acid (240 ml) was added zinc dust (12.0 g, 18 mmol) and the resulting mixture was heated at 60°-65° C., under an atmosphere of nitrogen, with stirring for 4 hours. The reaction mixture was allowed to cool, then filtered and the filtrate was evaporated in vacuo. The residue was redissolved in ethyl acetate (400 ml), washed with saturated sodium bicarbonate solution (2×200 ml) and saturated brine solution (1×200 ml) then dried (MgSO4), filtered and concentrated under vacuum to give a brown foam (6.60 g). To a solution of this foam in dichloromethane (350 ml) was added di-tertiary-butyl-dicarbonate (12.0 g, 55 mmol) and the mixture was stirred at room temperature for 65 hours under an atmosphere of nitrogen. To the reaction mixture was added N,N-dimethylethylenediamine (6.6 ml, 60 mmol) and stirring was continued for a further 2 hours. The reaction mixture was washed successively with 0.5M citric acid solution (2×200 ml) and brine (1×200 ml), dried (MgSO4), filtered and the solvent was removed under vacuum to give an oily solid (5.8 g). This was purified by flash chromatography using 20% ethyl acetate in petroleum ether (bp 60°-80° C.) as eluent to give a mixture of cis and trans isomers. Trituration of this mixture with diethyl ether gave a solid which was collected by filtration and was recrystallised from hot ethyl acetate/petroleum ether (bp 60°-80° C.) to give, as colourless needles, the less polar Trans-4-tertiarybutyloxycarbonylamino-5,7-dichloro-2-methoxycarbonyl-1,2,3,4-tetrahydroquinoline (1.33 g, m.p. 210°-211° C.). Purification of the mother liquors by normal phase Lobar chromatography using 15% ethyl acetate in petroleum ether (bp 60°-80° C.) followed by recrystallisation from hot ethyl acetate/petroleum ether (bp 60°-80° C.) gave the more polar cis-4-tertiary-butyloxycarbonylamino-5,7-dichloro-2-methoxycarbonyl-1,2,3,4-tetrahydroquinoline (0.43 g, m.p. 172°-173° C.). Data for trans: δ (360 MHz, CDCl3) 1.66 (1H, ddd, J= 13.1, 12.7 and 3.6 Hz, CHACHBHCCHD), 1.48 (9H, s, C(CH3)3), 2.61 (1H, dm, J=13.1 Hz, CHACHBHCCHD), 4.00 (1H, dd, J=12.7 and 3.0 Hz, CHACHBHCCHD), 4.52 (1H, m, CHACHBHCCHD), 4.84 (1H, br, s, NH), 4.98 (1H, br, s, NH), 6.53 (1H, d, J=2.0 Hz, 6-H or 8-H), 6.72 (1H, d, J=2.0 Hz, 6-H or 8-H); m/e (CI+) 375 (M+1); Found: C, 51.34; H, 5.43; N, 7.46; C16H20Cl2N2O4 requires C, 51.21; H, 5.37; N, 7.47%. Data for cis δ (360 MHz, CDCl3) 1.43 (9H, s, C(CH3)3, 2.05 (1H, m, CHACHBHCCHD), 2.88 (1H, dm, J=14.2 Hz, CHACHBHCCHD), 4.08 (1H, m, CHACHBHCCHD), 4.34 (1H, m, CHACHBHCCHD), 4.58 (1H, br, s, NH), 4.90 (1H, br, s, NH), 6.56 (1H, d, J=2.0 Hz, 6-H or 8-H), 6.75 (1H, d, J=2.0 Hz, 6-H or 8-H); m/e 374 (M+), 198 (100%, M-NHCO2, tBu, CO2CH3 and H); Found: C, 51.37; H, 5.40; N, 7.55; C16H20Cl2N2O4 requires C, 51.21; H, 5.37; N, 7.47%.

1. customThis was purified by flash chromatography
2. customto give
3. additiona mixture of cis and trans isomers
4. filtrationwas collected by filtration
5. customwas recrystallised from hot ethyl acetate/petroleum ether (bp 60°-80° C.)
6. customto give, as colourless needles
7. customPurification of the mother liquors by normal phase Lobar chromatography
8. customfollowed by recrystallisation from hot ethyl acetate/petroleum ether (bp 60°-80° C.)

ORD record

ord-5fce9345bc0d4a67a3e2cab78ea716d5

Source dataset

uspto-grants-1993_07

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US05231102