tert-butyl 3-oxa-7,9-diazabicyclo[3.3.1]nonane-7-carboxylate

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Commercially available tert-Butyl 3-oxa-7,9-diazabicyclo[3.3.1]nonane-7-carboxylate (300 mg, 1.3 mmol) and 4-methyl-5-[(2R)-oxiran-2-yl]-2-benzofuran-1(3H)-one (INTERMEDIATE 2) (380 mg, 2.0 mmol) were dissolved in ethanol (10 ml) and heated in a microwave reactor at 140° C. for 1 hour. The reaction was concentrated and purified by MPLC on ISCO RediSep® purification column and eluted with 50%-100% ethyl acetate/hexane to provide tert-butyl 9-[(2R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]-3-oxa-7,9-diazabicyclo[3.3.1]nonane-7-carboxylate. The reaction was concentrated purified by MPLC on ISCO RediSep® purification column eluted with 50%-100% ethyl acetate/hexane

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of tert-butyl 3-oxa-7,9-diazabicyclo[3.3.1]nonane-7-carboxylate (0.500 g, 2.2 mmol) in dichloromethane (5 ml) was added triethylamine (0.443 g, 4.4 mmol) at room temperature. The mixture was stirred at room temperature for a few mins, and then benzyl chloroformate (0.751 g, 4.4 mmol) was added to the reaction mixture. The resulting mixture was stirred at room temperature overnight. The mixture was partitioned between dichloromethane and water. The organic phase was dried, and concentrated. The residue was purified by silica gel chromatography to give 9-benzyl 7-tert-butyl 3-oxa-7,9-diazabicyclo[3.3.1]nonane-7,9-dicarboxylate 133b (0.637 g, 80.0%). MS: calc'd (MH+) 363, measured (MH+) 363. The resulting mixture was stirred at room temperature overnight The mixture was partitioned between dichloromethane and water The organic phase was dried concentrated The residue was purified by silica gel chromatography

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Compound 53b was prepared in analogy to intermediate AC in Example 15, starting from 3-oxa-7,9-diaza-bicyclo[3.3.1]nonane-7-carboxylic acid tert-butyl ester and methyl (4R)-4-(2-bromo-4-fluoro-phenyl)-6-(bromomethyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate 53a, while 53a was prepared in analogy to compound C in Example 1.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of 3-oxa-7,9-diaza-bicyclo[3.3.1]nonane-7-carboxylic acid tert-butyl ester (171 mg, 0.75 mmol) and DIPEA (0.45 mL, 2.5 mmol) in CH2Cl2 (10 mL) was added (R)-6-bromomethyl-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester (222 mg, 0.5 mmol). The mixture was stirred at room temperature for 16 hours. The mixture was concentrated in vacuo. The residue was purified by flash column chromatography to afford 9-[(R)-6-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-3-oxa-7,9-diaza-bicyclo[3.3.1]nonane-7-carboxylic acid tert-butyl ester as yellow oil (0.28 g, 94%). MS: calc'd (MH+) 592, measured (MH+) 592. The mixture was concentrated in vacuo The residue was purified by flash column chromatography

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 3-oxa-7,9-diaza-bicyclo[3.3.1]nonane-7-carboxylic acid tert-butyl ester (716 mg, 3.14 mmol, WuXy AppTech) and 9-fluorenylmethoxycarbonyl-N-hydroxysuccinimide (1058 mg, 3.14 mmol) was prepared in anhydrous THF (11 mL) and stirred at RT for 2.5 hours. The reaction mixture was concentrated under vacuum to give a yellow oil. After purification by flash chromatography (silica, heptane/EtOAc), the title compound was obtained as a white foam (1.36 g, 93%). 1H NMR (300 MHz, CDCl3) δ 7.77 (d, J=7.5 Hz, 2H), 7.55 (d, J=7.3 Hz, 2H), 7.45-7.37 (m, 2H), 7.36-7.28 (m, 2H), 4.65-4.57 (m, 2H), 4.35-3.49 (m, 9H), 3.17-2.78 (m, 2H), 1.46 (s, 9H). HPLC (max plot) 96.5%; Rt 5.07 min. UPLC/MS: (MS+) 451.4 ([M+H]+). The reaction mixture was concentrated under vacuum to give a yellow oil After purification by flash chromatography (silica, heptane/EtOAc)