Reaction Steps
A stirred solution of 4-(2-(morpholin-4-yl)ethoxy)phenylamine (11) (4.00 g, 18.0 mmol) in water (38 mL) and concentrated HCl (12 mL) was treated dropwise at 0° C. with a solution of NaNO2 (1.36 g, 19.8 mmol) in water (3.8 mL) and the resulting mixture was stirred for 30 min at 0° C. (solution A). Ethyl 2-methylacetoacetate (2.75 mL, 18.9 mmol) was added dropwise to a suspension of NaOAc (15.3 g) in EtOH (29 mL) at 0° C. After stirring for 30 min at this temperature, ice (18 g) was added (solution B). Then, solution A was added to solution B by a transfer cannula at 0° C., the mixture was allowed to warm to room temperature and was stirred for a further 2.5 h. After that, the reaction mixture was basified by slow addition of a saturated aqueous solution of Na2CO3 at 0° C. and extracted with CH2Cl2 (3×200 mL). The combined organic layers were washed with water (300 mL), dried (MgSO4), and the solvent was removed in vacuo. The residue was then dissolved in absolute EtOH (15 mL), treated with a freshly prepared saturated solution of HCl in absolute EtOH (15 mL) and heated at reflux for 40 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, 20:1) of the residue after evaporation of the mother liquor provided 12 (4.07 g, 71% overall yield) as a yellow solid. 1H NMR (300 MHz, CDCl3): δ 1.41 (t, J=7.1 Hz, 3 H, OCH2CH3), 2.61 (mc, 4 H, 3″-H2, 5″-H2), 2.84 (t, J=5.7 Hz, 2 H, 2′-H2), 3.76 (mc, 4 H, 2″-H2, 6″-H2), 4.15 (t, J=5.7 Hz, 2 H, 1′-H2), 4.40 (q, J=7.1 Hz, 2 H, OCH2CH3), 6.99 (dd, J=9.0, 2.4 Hz, 1 H, 6-H), 7.08 (d, J=2.4 Hz, 1 H, 4-H), 7.13 (d, J=1.3 Hz, 1 H, 3-H), 7.30 (d, J=9.0 Hz, 1 H, 7-H), 9.13 (sbr, 1 H, NH) ppm; 13C NMR (50.3 MHz, CDCl3): δ=14.4 (OCH2CH3), 54.1 (C-3″, C-5″), 57.7 (C-2′), 60.9 (OCH2CH3) 66.2 (C-1′), 66.9 (C-2″, C-6″), 103.7 (C-4), 108.1 (C-3), 112.7 (C-7), 117.3 (C-6), 127.7, 127.9 (C-2, C-3a), 132.3 (C-7a), 153.7 (C-5), 162.0 (C═O) ppm; MS (70 eV, EI): m/z (%)=318 (14) [M]+, 100 (100) [CH2N(CH2)4O]+; C17H22N2O4 (318.37): calcd. C, 64.13; H, 6.97; found C, 63.85; H, 7.12.
