Chloroform → Carvacrol

To a suspension of 2-chloro-4-methyl-5,6,7,8-tetrahydro-1,6-naphthyridine hydrochloride (4.03 g, 18.39 mmol) in DCM (100 mL), 2 M aq Na2CO3 (100 mL) was added. After stirring for 30 min, the mixture was diluted with brine (200 mL). The products were extracted twice with DCM. The combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. A suspension of the residue (3.25 g), 5-isopropyl-2-methylphenyl trifluoromethanesulfonate (11.42 g, 40.5 mmol), Pd2(dba)3.CHCl3 adduct (0.762 g, 0.736 mmol), rac-BINAP (0.945 g, 1.471 mmol) and Cs2CO3 (17.98 g, 55.2 mmol) in toluene (17 mL) and t-butanol (3 mL) was allowed to stir at 90° C. for 23 h under argon. The reaction was cooled to rt, and diluted with EtOAc and brine. The products were extracted three times with EtOAc. The combined organic layer was dried over Na2SO4, and filtered. The filtrate was added to 60 g of silica gel and then concentrated. The residue was washed with EtOAc on a funnel, and then the filtrate was concentrated. The residue was purified by flash column chromatography on 330 g of silica gel (with 25 g pre-column; eluent: heptane/EtOAc=100:0 to 80:20) to give the desired product along with 18 mol % of Carvacrol (2.97 g). The mixture was purified by flash column chromatography on 55 g of NH-modified silica gel (with 20 g of aminopropyl-modified silca gel as pre-column; eluent: heptane/EtOAc=100:0 to 90:10) to give 2-chloro-6-(5-isopropyl-2-methylphenyl)-4-methyl-5,6,7,8-tetrahydro-1,6-naphthyridine (2.50 g) as a yellow oil: 1H NMR (400 MHz, CDCl3) δ ppm 7.16 (d, J=7.83 Hz, 1 H), 6.99-7.00 (m, 2 H), 6.92-6.95 (m, 1 H), 3.98 (s, 2 H), 3.28 (t, J=5.81 Hz, 2 H), 3.12 (br t, J=5.68 Hz, 2 H), 2.84-2.94 (m, 1 H), 2.29 (s, 3 H), 2.20 (s, 3 H), 1.26 (d, J=6.82 Hz, 6 H); MS (ESI+) m/z 315.34 (M+H)+.

1. additionwas added
2. extractionThe products were extracted twice with DCM
3. washThe combined organic layer was washed with brine
4. dry with materialdried over Na2SO4
5. filtrationfiltered
6. concentrationconcentrated
7. stirringto stir at 90° C. for 23 h under argon
8. extractionThe products were extracted three times with EtOAc
9. dry with materialThe combined organic layer was dried over Na2SO4
10. filtrationfiltered
11. additionThe filtrate was added to 60 g of silica gel
12. concentrationconcentrated
13. washThe residue was washed with EtOAc on a funnel
14. concentrationthe filtrate was concentrated
15. customThe residue was purified by flash column chromatography on 330 g of silica gel (with 25 g pre-column; eluent: heptane/EtOAc=100:0 to 80:20)

ORD-Eintrag

ord-f7329ee3768d4150af7b8f7c735706e9

Quelldatensatz

uspto-grants-2014_09

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US08846656B2