Benzylamine → [3-Amino-3-(3-benzyl-7-chloro-4-oxo-3,4-dihydro-quinazolin-2-yl)-propyl]-carbamic acid tert-butyl ester

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Reaction Conditions

Reaction Steps

Formula 106 where R1, R2, R4, R6, R7, R8 and R9 are H; R3 is Chloro; and R5 is Benzyl: To a solution of Formula 101, 4-tert-butoxycarbonylamino-2-(9H-fluoren-9-ylmethoxycarbonylamino)-butyric acid (1.00 g, 2.27 mmol) in 20 mL of anhydrous THF was added anhydrous N-methylmorpholine (274 μL, 2.50 mmol). After the mixture was stirred in an ice-bath for 1 minute, isobutyl chloroformate (324 μL, 2.50 mmol) was added dropwise over 15 minutes at 0° C. The mixture was stirred in the ice-bath for 1 hour, after which 4-chloro-anthranilic acid (389 mg, 2.27 mmol) in 2 mL of THF was added, affording the corresponding compound of Formula 103, 2-[4-tert-butyxycarbonylamino-2-(9H-fluoren-9-ylmethoxy-carbonylamino)-butyrylamino]-4-chloro-benzoic acid, following 2 hours of additional stirring at 0° C. To the stirring compound of Formula 103, anhydrous N-methylmorpholine (274 μL, 2.50 mmol) was added and the mixture stirred overnight while slowly warming to room temperature. The mixture was then cooled to 0° C. and treated with anhydrous N-methylmorpholine (274 μL, 2.50 mmol) and isobutyl chloroformate (324 μL, 2.50 mmol). This was followed by addition of benzylamine (992 μL, 3.92 mmol) in four equal portions at room temperature. Once the starting material was consumed, the solvents were evaporated and the residue partitioned between DCM and saturated sodium bicarbonate. The organic layer was dried over sodium sulfate and the solvent was evaporated, affording a mixture of the corresponding compounds of Formula 104 and Formula 105, [1-(2-benzylcarbamoyl-5-chloro-phenyl-carbamoyl)-3-tert-butoxycarbonylamino-propyl]-carbamic acid 9H-fluoren-9-ylmethyl ester and [1-(3-benzyl-7-chloro-4-oxo-c,4–3,4-dihydro-quinazolin-2-yl)-3-tert-butoxycarbonyl-amino-propyl]-carbamic acid 9H-fluoren-9-ylmethyl ester, respectively (about 6:1 by LCMS) which was dried under vacuum and then treated with lithium hydroxide monohydrate (95 mg, 2.27 mmol) in 60 mL of 1,4-dioxane/ethylene glycol (2/1) under reflux for 5 hours. The reaction solution was poured into 200 mL of water and the product extracted with DCM. After drying the organic layers over sodium sulfate, the solvent was evaporated and the crude product purified by flash silica gel chromatography (stepwise gradient 1:4, 1:2, 1:1, 2:1, 4:1 with ethyl acetate:hexanes as eluent) to give the corresponding product of Formula 106, [3-amino-3-(3-benzyl-7-chloro-4-oxo-3,4-dihydro-quinazolin-2-yl)-propyl]-carbamic acid tert-butyl ester (700 mg, 70%).

Provenance & Evidence