Triethylamine → [(6R)-6,8-dihydro-5H-imidazo[2,1-c][1,4]oxazin-6-yl]methyl 2-(indan-2-ylamino)-5,7-dihydropyrrolo[3,4-d]pyrimidine-6-carboxylate

Participants

Reaction Conditions

Reaction Steps

Add 1,1′-carbonyldiimidazole (0.477 g; 1.1 equiv; 2.94 mmoles) to a solution of [(6R)-6,8-dihydro-5H-imidazo[2,1-c][1,4]oxazin-6-yl]methanol (0.412 g; 1.0 equiv; 2.67 mmoles) in 1,2-dichloroethane (15 mL) and tetrahydrofuran (5 mL). Heat the solution to 50° C. for 30 minutes, then add N-(2,3-dihydro-1h-inden-2-yl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-amine dihydrochloride hydrate (1.01 g; 1.1 equiv; 2.94 mmoles) followed by triethylamine (1.30 mL; 3.5 equiv; 9.35 mmoles). Stir the resulting solution for 3 hours at 50° C. Pour the mixture into 50% saturated sodium bicarbonate and dichloromethane (50 mL each). Separate the layers and further extract the aqueous layer with dichloromethane (2×50 mL). Dry the combined organic extracts over magnesium sulfate, filter, and concentrate to give a red oil. Purify the crude product by column chromatography (1 to 8% methanol in chloroform) to afford the desired [(6R)-6,8-dihydro-5H-imidazo[2,1-c][1,4]oxazin-6-yl]methyl 2-(indan-2-ylamino)-5,7-dihydropyrrolo[3,4-d]pyrimidine-6-carboxylate (1.12 g; 97%). Determine enantiomeric excess by chiral HPLC analysis (0.46×15 cm Chiralpak™ AS-H column, 100% methanol elution). Isolated product elutes at 13 minutes whereas the enantiomer elutes at 9.1 minutes, demonstrating the product to be 98.3% ee. MS (m/z): 433(M+1).

Provenance & Evidence