Malonic Acid → 2-(3-Hydroxy-5-iodo-2-oxo-2,3-dihydro-1H-indol-3-yl)-N,N-dimethyl-acetamide

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Reaction Conditions

Reaction Steps

A 2 L flask with mechanical stirrer is charged with 5-iodo-isatin (78.1 g, 0.286 mol), malonic acid (35.7 g, 0.343 mol), and pyridine (90.4 g, 1.144 mol). The mixture is heated to 80° C. When most of the isatine has dissolved, ethyl acetate (100 mL) is added to prevent blocking of the stirrer by the precipitating pyridinium (3-hydroxy-5-iodo-2-oxo-2,3-dihydro-1H-indol-3-yl)-acetate. After 1 hour, precipitation of the latter salt starts, and when the mixture has been kept stirring for another 2 hours, a suspension of the salt in an orange solution has formed. To this is added triethyl amine (43.3 g, 0.429 mol), and the salt dissolves to give a dark solution. Then a solution of dimethyl carbamoyl chloride (40 g, 0.372 mol) in ethyl acetate (50 mL) is added dropwise during 20 minutes. A solid starts to precipitate, and the mixture is stirred for another 2 hours at 80° C. Then 4 N HCl is added (350 mL), and stirring is continued for 30 additional minutes in order to hydrolyze any excess carbamoyl chloride. The mixture is then filtered, and the filter cake is washed with 50% ethanol and the with water. After drying 72.6 g (70.5%) of a grayish powder of the title compound, mp.=246° C. 1H-NMR (DMSO-D6, 300 MHz) δ 2.62, 2.91 (2 s, 3 each, N(CH3)2); 2.91, 3.25 (AB, 2H, |2J|=16.4 Hz, CH2); 5.97 (br s, 1H, OH); 6.59 (d, 1H, 3J=7.9 Hz, H-7); 7.46 (dd, 1H, 4J=1.5 Hz, H-6); 7.54 (d, 1H, H-4); 10.15 (br s, 1H, NH). 13C-NMR (DMSO-D6, 75 MHz) δ 35.08, 37.48 (N(CH3)2); 40.86 (CH2); 73.76 (C-3); 84.29 (C-5); 112.49 (C-7); 132.44 (C-4); 136.06 (C-9); 137.72 (C-6); 143.66 (C-8); 168.93 CONMe2); 178.47 (C-2).

Provenance & Evidence