反应详情

To a stirred solution of 4-((1-methylpiperidin-4-yl)methoxy)phenylamine (25) (2.00 g, 9.08 mmol) in water (19 mL) and concentrated HCl (6 mL) was added dropwise a solution of NaNO2 (689 mg, 9.99 mmol) in water (2 mL) at 0° C., and stirring was continued for 50 min at 0° C. (solution A). Ethyl 2-methylacetoacetate (1.39 mL, 9.53 mmol) was added dropwise to a stirred suspension of NaOAc (7.8 g) in EtOH (15 mL) at 0° C. and stirring was continued for 30 min at this temperature; then ice (9 g) was added (solution B). Solution A was added to solution B by a transfer cannula at 0° C. and the mixture was allowed to warm to room temperature. After 2.5 h the reaction mixture was basified by slow addition of a saturated aqueous solution of Na2CO3 at 0° C. and extracted with CH2Cl2 (3×100 mL). The combined organic layers were washed with water (200 mL), dried (MgSO4), and the solvent was removed in vacuo. The residue was then dissolved in absolute EtOH (10 mL), treated with a freshly prepared saturated solution of HCl in absolute EtOH (10 mL) and heated at reflux for 50 min. After cooling to room temperature the solvent was removed under reduced pressure and the residue was partitioned between water (50 mL) and CH2Cl2 (100 mL). The aqueous layer was basified using a saturated aqueous solution of Na2CO3 and extracted with CH2Cl2 (3×100 mL). The combined organic layers were washed with brine (200 mL), dried (MgSO4), and concentrated in vacuo. Purification by crystallization from iPr2O and column chromatography (CH2Cl2/MeOH, 30:1, 2% NEt3) of the residue obtained after evaporation of the mother liquor provided 26 (2.06 g, 72% overall yield) as a yellow solid. 1H NMR (300 MHz, CDCl3): δ=1.36-1.54 (m, 5 H, OCH2CH3, 3′-Hax, 5′-Hax), 1.73-2.06 (m, 5 H, 2-Hax, 3′-Heq, 4′-H, 5′-Heq, 6′-Hax), 2.30 (s, 3 H, NMe), 2.87-2.97 (m, 2 H, 2′-Heq, 6′-Heq), 3.83 (d, J=6.2 Hz, 2 H, ArOCH2), 4.40 (q, J=7.2 Hz, 2H, OCH2CH3), 6.98 (dd, J=8.9, 2.4 Hz, 1 H, 6-H), 7.05 (d, J=2.0 Hz, 1 H, 3-H), 7.12 (mc, 1 H, 4-H), 7.30 (d, J=8.9 Hz, 1 H, 7-H), 9.11 (sbr, 1 H, NH) ppm. —13C NMR (50.3 MHz, CDCl3): δ=14.4 (OCH2CH3), 29.2 (C-3′, C-5), 35.3 (C-4′), 46.4 (NMe), 55.5 (C-2′, C-6′), 60.9 (OCH2CH3), 73.2 (ArOCH2), 103.4 (C-4), 108.1 (C-3), 112.7 (C-7), 117.2 (C-6), 127.8 (C-2, C-3a), 132.2 (C-7a), 154.1 (C-5), 162.0 (C═O) ppm. −MS (70 eV, EI): m/z (%)=316 (6) [M]+, 112 (100) [C7H14N]+. —C18H24N2O3 (316.39): calcd. C, 68.33; H, 7.65; found C, 68.03; H, 7.84.

1. stirringstirring
2. waitwas continued for 30 min at this temperature
3. extractionextracted with CH2Cl2 (3×100 mL)
4. washThe combined organic layers were washed with water (200 mL)
5. dry with materialdried (MgSO4)
6. customthe solvent was removed in vacuo
7. dissolutionThe residue was then dissolved in absolute EtOH (10 mL)
8. additiontreated with a freshly prepared saturated solution of HCl in absolute EtOH (10 mL)
9. temperatureheated
10. temperatureat reflux for 50 min
11. temperatureAfter cooling to room temperature the solvent
12. customwas removed under reduced pressure
13. customthe residue was partitioned between water (50 mL) and CH2Cl2 (100 mL)
14. extractionextracted with CH2Cl2 (3×100 mL)
15. washThe combined organic layers were washed with brine (200 mL)
16. dry with materialdried (MgSO4)
17. concentrationconcentrated in vacuo
18. customPurification
19. customby crystallization from iPr2O and column chromatography (CH2Cl2/MeOH, 30:1, 2% NEt3) of the residue
20. customobtained
21. customafter evaporation of the mother liquor