| 86% |
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General procedure: To a 50 mL flask containing tert-butyl 2-[(R)-5-bromo-2,3-dihydro-1H-inden-1-yl]-2,7-diazaspiro[3.5]nonane-7-carboxylate 3 (4.0 g, 9.49 mmol) were added bis(triphenylphosphine)palladium(II) chloride (0.17 g, 0.24 mmol), potassium acetate (3.73 g, 37.97 mmol), and bis(pinacolato)diboron (2.65 g, 10.44 mmol) followed by degassing via vacuum then backfilling with nitrogen five times. De-oxygenated (N2 stream for 30 min) toluene (40 mL) was added to the mixture and the reaction was heated at 100 C for 1.5 h. The reaction was monitored for completion by HPLC. Upon formation of the boronic ester intermediate, the reaction was cooled to 40 C and charged with a degassed solution of 4 M sodium hydroxide (11.87 mL, 47.46 mmol) followed by the addition of <strong>[3435-25-4]4-chloro-6-methylpyrimidine</strong> 5g (1.53 g, 11.87 mmol). The resulting mixture was then heated to 90 C for 5 h under nitrogen. The reaction was cooled to room temperature and charged with water (25 mL). After stirring for 20 min, the mixture was filtered to remove black solids. The organic layer was extracted to an aqueous solution containing HCl (40 mL). The organic layer was removed and the resulting solution was treated with (4 g) ISOLUTE Ultra Pure Si-Thiol silica gel for 1.5 h and filtered. The pH of the aqueous solution was then adjusted with 4 N NaOH to pH 7.8 and extracted to toluene (40 mL). The toluene layer was concentrated to approximately 15 mL under reduced pressure at 45 C and heptane (75 mL) was added slowly with stirring at 20 C for 1 h. The product was then filtered and dried under vacuum at 45 C for 8 h to afford 6g (3.56 g, 86%) as a white solid. 1H NMR (500 MHz, Cd3Od): 9.00 (s, 1 H), 8.03 (s, 1 H), 7.98 (d, J = 5.0 Hz, 1 H), 7.86 (s, 1 H), 7.49 (d, J = 10.0 Hz, 1 H), 4.074.04 (m, 1 H), 3.36 (s, 4 H), 3.323.29 (m, 2 H), 3.26 (d, J = 5.0 Hz, 2 H), 3.163.10 (m, 1 H), 2.932.87 (m, 1 H), 2,57 (s, 3 H), 2.292.23 (m, 1 H), 1.961.90 (m, 1 H), 1.721.67 (m, 4 H), 1.45 (s, 9 H); 13C NMR (125 MHz, Cd3Od): 167.9, 164.4, 157.9, 155.3, 146.2, 145.7, 136.4, 125.6, 125.0, 123.7, 116.9, 79.8, 71.6, 62.3, 48.0, 35.6, 33.9, 30.1, 29.3, 27.5, 22.7; HRMS (CI): m/z 435.2753 (Calculated 435.2755 for C26H34N4O2 + H) |
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With sodium hydroxide;bis-triphenylphosphine-palladium(II) chloride; In toluene; at 90℃; for 5h;Inert atmosphere; |
Preparation of 2-[(R)-5-(6-Methylpyrimidin-4-yl)-indan-1-yl]-2,7-diazaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester (3-1n To a 50 mL flask charged with (R)-tert-butyl 2-(5-bromo-2,3-dihydro-1H-inden-1-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (3-1a, 4.0 g, 9.49 mmol) was added bis(triphenylphosphine)palladium(II) chloride (0.17 g, 0.24 mmol), potassium acetate (3.73 g, 37.97 mmol), bis(pinacolato)diboron (2.65 g, 10.44 mmol) followed by degassing via vacuum then backfilling with nitrogen 5 times. De-oxygenated (nitrogen stream for 30 minutes prior to addition) toluene (40 mL) was added to the mixture and the reaction was heated at 100 C. for 1.5 hours. The reaction was monitored for completion by HPLC. Upon formation of the boronic ester intermediate, the reaction was cooled to 40 C. and charged with a degassed solution of 4 M sodium hydroxide (11.87 mL, 47.46 mmol) followed by addition of <strong>[3435-25-4]4-chloro-6-methylpyrimidine</strong> (1.53 g, 11.87 mmol). The resulting mixture was then heated to 90 C. for 5 hours under nitrogen. The reaction was cooled to room temperature and charged with water (25 mL). After stirring for 20 minutes, the mixture was filtered to remove black solids. The organic layer was extracted to an aqueous solution containing 1.5 equiv of HCl (40 mL). The organic layer was removed and the resulting solution was treated with (4 g) ISOLUTE Ultra Pure Si-Thiol silica gel for 1.5 hours and filtered. The aqueous solution was adjusted to pH 7.8 with 4N NaOH and extracted with toluene (40 mL). The toluene layer was concentrated to approximately 15 mL under vacuum at 45 C. and heptane (75 mL) was added slowly and the mixture was stirred at 20 C. for 1 hour. The product was filtered and dried under vacuum at 45 C. for 8 hours to afford the title compound (3-1f) as a white solid (3.56 g, 86%). MS (ES+) 435.5 (M+H)+. 1H NMR (CDCl3) delta 1.46 (s, 9H), 1.70-1.74 (m, 4H), 1.90-2.01 (m, 1H), 2.13-2.26 (m, 1H), 2.59 (s, 3H), 2.84-2.93 (m, 1H), 3.04-3.21 (m, 5H), 3.30-3.38 (m, 4H), 3.95-4.02 (m, 1H), 7.40 (d, 1H), 7.56 (s, 1H), 7.87 (d, 1H), 7.95 (s, 1H), 9.12 (s, 1H). |
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