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Alternatively, instead of the hydrazone linkage describe above, the compounds may have an amide linkage (see Scheme I below). The synthesis consists of 3 steps. First, to a stirred solution of 4-(2-hydroxyethyl)morpholine (B) (2.8 g, 21.3 mmol) in anhydrous THF (45 mL) at 0 0C, sodium hydride, 60percent dispersion in mineral oil, (0.9 g, 22.5 mmol) is added in three portions under nitrogen purge. Ice-bath was removed and a mixture is stirred at room temperature for 20-30 minutes. The mixture is cooled to 0 0C and added drop-wise (using syringe or dropping funnel) under nitrogen purge to a solution of methyl 2,4-dichloropyrirnidine carboxylate (A) (4.03 g, 19.4 mmol) in anhydrous THF (35 mL) at 0 0C. The resultant solution is stirred for 30 minutes at 0 0C, followed by 30 minutes at room temperature. It is then quenched carefully with ice-water (115mL) and diluted with ethyl acetate (115 mL). Organic layer is separated, water layer extracted once with ethyl acetate, combined ethyl acetate extracts are washed with brine and dried over anhydrous sodium sulfate. Concentration, followed by column chromatography with gradient eluation (hexane : ethyl acetate, 1:1; hexane : ethyl acetate,l:2; ethyl acetate; dichloromethane-acetone-methanol, 3:1:01) affords 3 fractions: first (0.56 g, 9.5percent ) - mostly isomer C, second (1.28 g, 21.8percent)- a mixture of C and D, and byproduct (E), third (0.7 g, 11.9percent) - mostly isomer (D). EPO <DP n="99"/>In the second step, a solution of compound C (0.6 g, 2 mmol), 5-amino-2,3- dimethylindole (F) (0.32 g, 2 mmol) and DIPEA (0.28 g, 2.2 mmol)in dioxane is heated at reflux for two hours. Ethyl acetate and water are added to the concentrated reaction mixture, water layer extracted with ethyl acetate, combined ethyl acetate extracts washed with brine and dried over anhydrous sodium sulfate. Product G (0.64 g, 75percent) is isolated by column chromatography with gradient eluation (ethyl acetate; dichloromethane- acetone-methanol, 3:1:01).In the same manner compound D is converted into product H.Compounds H is then converted into their corresponding amides (I) using appropriate amines following general procedure for amide formation.To a stirred mixture of ester (1 mmol) and amine (1.05 mmol) in toluene (3.2 mL)., 2 M solution of trimethylaluminum in toluene (1.6 eq) is added drop-wise under nitrogen purge. The reaction mixture is stirred until gas evolution halted, and then mixture is micro waved at 120 0C for 5-7 minutes (Emrys Optimizer). To the reaction mixture were added IN NaOH solution and dichloromethane, organic layer separated, washed with water, brine and dried over anhydrous sodium sulfate. Flash column chromatography purification affords about 65-75percent of a desired amide (I). |
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