Ethyl 2-methylacetoacetate → HCID 11623861, compound

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.

1. extractionextracted with CH2Cl2 (3×200 mL)
2. washThe combined organic layers were washed with water (300 mL)
3. dry with materialdried (MgSO4)
4. customthe solvent was removed in vacuo
5. dissolutionThe residue was then dissolved in absolute EtOH (15 mL)
6. additiontreated with a freshly prepared saturated solution of HCl in absolute EtOH (15 mL)
7. temperatureheated
8. temperatureat reflux for 40 min
9. temperatureAfter cooling to room temperature the solvent
10. customwas removed under reduced pressure
11. customthe residue was partitioned between water (50 mL) and CH2Cl2 (100 mL)
12. extractionextracted with CH2Cl2 (3×100 mL)
13. washThe combined organic layers were washed with brine (200 mL)
14. dry with materialdried (MgSO4)
15. concentrationconcentrated in vacuo
16. customPurification
17. customby crystallization from iPr2O and column chromatography (CH2Cl2/MeOH, 20:1) of the residue
18. customafter evaporation of the mother liquor

ORD record

ord-8aacbf15411148979e1faf23cee7004b

Source dataset

uspto-grants-2015_01

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08940784B2