Hydrochloric Acid → tert-butyl ((1S,2R,3R,5S)-5-(3-aminopyridin-4-yl)-3-methyl-2-(2-oxopyridin-1(2H)-yl)cyclohexyl)carbamate

温度

70 °C

To a solution of (1R,2R,4R,6S)-2-(tert-butoxycarbonylamino)-4-(3-(tert-butoxycarbonylamino)pyridin-4-yl)-6-methylcyclohexyl methanesulfonate (1.0 equiv.) Cs2CO3 (3.0 equiv.) in DMF (0.15 M) was added pyridin-2-ol (1.0 equiv). The mixture was stirred at 70° C. for 5 hrs. The reaction was worked up with EtOAc and Brine. The organic layer was concentrated and was treated with 4N HCl (30.0 equiv.) in Dioxane for 2 hrs at which time the volatiles were removed in vacuo. The redisue was dissolved in THF (0.15 M) and tert-butyl 2,5-dioxopyrrolidin-1-yl carbonate (1.5 equiv.) was added, followed by DIEA (3.0 equiv.). After stirring at rt for 3 hrs, the reaction was quenched with sat. NaHCO3 and extracted with EtOAc. The organic layer was washed with Brine, dried over Na2SO4 and concentrated. The crude was purified by prep HPLC to yield two major peaks. The fractions of the first product peak was combined and neutralized with sat. NaHCO3 and extracted with EtOAc. The organic layer was washed with Brine, dried over Na2SO4 and concentrated. Purification was completed via SFC (20% (MeOH with 10% DEA), 100 mL/min, AD column) to yield tert-butyl ((1R,2S,3S,5R)-5-(3-aminopyridin-4-yl)-3-methyl-2-(2-oxopyridin-1(2H)-yl)cyclohexyl)carbamate (8% yield, 99% ee) and tert-butyl ((1S,2R,3R,5S)-5-(3-aminopyridin-4-yl)-3-methyl-2-(2-oxopyridin-1(2H)-yl)cyclohexyl)carbamate (9% yield, 99% ee). LC/MS (m/z)=399.2 (MH+), Rt=0.60 min. 1H NMR (400 MHz, <dmso>) δ ppm 0.72 (s, 3 H), 1.30 (s, 9 H), 1.63-1.81 (m, 2 H), 1.89-2.00 (m, 2 H), 2.02-2.18 (m, 2 H), 3.04-3.13 (m, 1 H), 4.03-4.12 (m, 1 H), 4.91-5.02 (m, 1 H), 5.04-5.13 (m, 2 H), 6.17-6.26 (m, 1 H), 6.31-6.41 (m, 1 H), 6.98-7.07 (m, 1 H), 7.32-7.41 (m, 2 H), 7.68-7.74 (m, 1H), 7.74-7.82 (m, 1 H), 7.85-7.90 (m, 1 H). The fractions of the second product peak was combined and neutralized with sat. NaHCO3 and extracted with EtOAc. The organic layer was washed with Brine, dried over Na2SO4 and concentrated. Purification was completed via SFC (20% (MeOH with 10% DEA), 100 mL/min, AD column) to yield tert-butyl ((1R,2S,3S,5R)-5-(3-aminopyridin-4-yl)-3-methyl-2-(pyridin-2-yloxy)cyclohexyl)carbamate (14% yield, 99% ee) and tert-butyl ((1S,2R,3R,5S)-5-(3-aminopyridin-4-yl)-3-methyl-2-(pyridin-2-yloxy)cyclohexyl)carbamate (15% yield, 99% ee). LC/MS (m/z)=399.2 (MH+), Rt=0.65 min. 1H NMR (400 MHz, <cdcl3>) δ ppm 0.95 (d, J=6.65 Hz, 3 H), 1.35-1.78 (m, 12 H), 1.97-2.08 (m, 2 H), 2.76 (t, J=11.93 Hz, 1 H), 3.72 (br. s., 2 H), 3.88 (d, J=4.70 Hz, 1 H), 5.43 (d, J=7.43 Hz, 1 H), 5.59 (br. s., 1H), 6.79-6.94 (m, 2H), 7.08 (d, J=5.09 Hz, 1 H), 7.56-7.65 (m, 1 H), 7.98-8.17 (m, 3 H).

1. concentrationThe organic layer was concentrated
2. customwere removed in vacuo
3. dissolutionThe redisue was dissolved in THF (0.15 M)
4. stirringAfter stirring at rt for 3 hrs
5. customthe reaction was quenched with sat. NaHCO3
6. extractionextracted with EtOAc
7. washThe organic layer was washed with Brine
8. dry with materialdried over Na2SO4
9. concentrationconcentrated
10. customThe crude was purified by prep HPLC
11. customto yield two major peaks
12. extractionextracted with EtOAc
13. washThe organic layer was washed with Brine
14. dry with materialdried over Na2SO4
15. concentrationconcentrated
16. customPurification

ORDレコード

ord-b38ea8c692ad4ca69fbf56f4b5c10a45

出典データセット

uspto-grants-2015_11

DOI

10.6084/m9.figshare.5104873.v1

特許番号

US09173883B2