[H-].[Na+].[OH:3][CH2:4][CH2:5][N:6]1[C:10](=[O:11])[C:9]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:8]2[C:7]1=[O:16].Cl[CH2:18][C:19](=[O:25])[CH2:20][C:21]([O:23][CH3:24])=[O:22].[Cl-].[NH4+].Cl>CN(C)C=O>[CH3:24][O:23][C:21](=[O:22])[CH2:20][C:19](=[O:25])[CH2:18][O:3][CH2:4][CH2:5][N:6]1[C:10](=[O:11])[C:9]2[C:8](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]1=[O:16]To a stirred suspension of sodium hydride (60% dispersion in mineral oil, 6.28 g, 157 mmol) in N,N-dimethylformamide (150 mL) under nitrogen at 0° C. was added portion wise N-(2-hydroxyethyl)phthalimide (2, 20 g, 105 mmol). The reaction mixture was then allowed to warm to ambient temperature with stirring for 30 minutes. To a stirred suspension in a separate flask of sodium hydride (60% dispersion in mineral oil, 6.28 g, 157 mmol) in N,N-dimethylformamide (150 mL) under nitrogen at 0° C. was added portion wise methyl 4-chloroacetoacetate (1, 12.1 ml, 105 mmol). The reaction mixture was then allowed to warm to ambient temperature with stirring for 30 minutes. The two reaction mixtures were then combined portion wise and stirred at ambient temperature under nitrogen for 6 hours. After cooling to 0° C., a further portion of sodium hydride (2.0 g, 50.0 mmol) was added. The mixture was stirred for 10 minutes at 0° C., then a further portion of methyl 4-chloroacetoacetate (3.0 ml, 26.0 mmol) was added. The reaction mixture was then stirred at ambient temperature for 18 hours, then poured onto a mixture of ice and saturated ammonium chloride, and then neutralized with aqueous HCl (10 N). The precipitate which formed was filtered off and re-crystallized from ethyl acetate to give a first crop of 3 as a yellow solid. The combined filtrates were extracted with ethyl acetate (3×300 mL). The combined organic layers were washed with saturated brine (2×300 mL) and water (300 mL), dried over MgSO4 and concentrated under reduced pressure to leave a residue which was purified by column chromatography over silica gel (50 g pre-packed Isolute® column) using ethyl acetate/hexane (1:1) as eluent to give a second crop of 3 as a yellow solid, which was combined with the first crop to give methyl 4-((2′-hydroxyethyl)phthalimide)acetoacetate (3) (10.8 g, 34% yield, 95% pure by LCMS and 1H NMR), 1H NMR (400 MHz; CDCl3): δ 8.13 (m, 2H); 7.69 (m, 2H); 4.53 (s, 2H); 3.80 (m, 2H); 3.70 (m, 2H); 3.67 (s, 3H); 3.41 (s, 2H).
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