Potassium Carbonate → N-((4S)-2-amino-7'-methoxyspiro[1,3-oxazole-4,9'-xanthen]-2'-yl)-5-chloro-2-pyridinecarboxamide

A 5 mL smith synthesizer vial was charged with (R)-2′-bromo-7′-methoxy-5H-spiro[oxazole-4,9′-xanthen]-2-amine (1.248 g, 3.46 mmol), sodium azide (0.684 g, 10.52 mmol), L-ascorbic acid sodium salt (0.057 g, 0.288 mmol), copper(I) iodide (0.131 g, 0.688 mmol), and (1R,2R)—N1,N2-dimethylcyclohexane-1,2-diamine (0.116 mL, 0.736 mmol) in EtOH (6.0 mL), water (2.6 mL) and the reaction was heated to 100° C. in the microwave for 35 minutes. The reaction vial was cooled to RT and concentrated on the rotary evaporator and the resulting residue was taken up in ethyl acetate (125 mL), water (50 mL) the organic layer was separated. The organic layer was dried over sodium sulfate and concentrated to yield the crude product which was purified by silica gel flash column chromatography (using a 40 G ISCO silica gel cartridge), and eluted using hexanes/ethyl acetate gradient. The fractions were combined and concentrated to yield (S)-2′-azido-7′-methoxy-5H-spiro[oxazole-4,9′-xanthen]-2-amine as a yellowish solid. MS (ESI pos. ion) m/z: 324 (M+1). Step 2: A solution of (S)-2′-azido-7′-methoxy-5H-spiro[oxazole-4,9′-xanthen]-2-amine (1.162 g, 3.59 mmol) in dichloromethane (25 mL) was treated with pyridine (0.775 mL, 9.50 mmol) followed by trifluoroaceticacid anhydride (0.9 mL, 6.43 mmol) at RT. The reaction was allowed to stir for 2 hours during which formation of desired product was detected (M+H˜420) along with traces of unreacted starting material. The reaction was allowed to stir for another 6 hours and diluted with DCM (75 mL), water (20 mL), and separated the organic layer. The organic layer was dried over anhydrous sodium sulfate, and concentrated to yield (S)—N-(2′-azido-7′-methoxy-5H-spiro[oxazole-4,9′-xanthene]-2-yl)-2,2,2-trifluoroacetamide as a yellowish solid. MS (ESI pos. ion) m/z: 420 (M+1). Step 3: A solution of (S)—N-(2′-azido-7′-methoxy-5H-spiro[oxazole-4,9′-xanthene]-2-yl)-2,2,2-trifluoroacetamide (0.410 g, 0.978 mmol) in ethanol (12 mL) and THF (8 mL) was stirred with palladium hydroxide, 20 wt % pd (dry basis) on carbon, wet, degussa type e101 ne/w (0.136 g, 0.978 mmol) under hydrogen at atmospheric pressure and RT for 2 hours. The catalyst was removed by filtration over a celite-pad, washed with EtOH (15 mL). The combined filtrates were concentrated to yield the crude product (104584-37-2). The product (S)—N-(2′-amino-7′-methoxy-5H-spiro[oxazole-4,9′-xanthene]-2-yl)-2,2,2-trifluoroacetamide was obtained as an off-white solid. MS (ESI pos. ion) m/z: 394 (M+1). Step 4: A 25 mL RBF containing a solution of (S)—N-(2′-amino-7′-methoxy-5H-spiro[oxazole-4,9′-xanthene]-2-yl)-2,2,2-trifluoroacetamide (0.058 g, 0.147 mmol), 5-chloropyridine-2-carboxylic acid (0.030 g, 0.190 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.045 g, 0.235 mmol) in DCM (4 mL) and DMF (0.25 mL) was treated with 1-hydroxy-1H-benzotriazole (0.014 g, 0.104 mmol) and stirred for 1.5 hrs at RT. The reaction was diluted with DCM (50 mL) and water (15 mL). The DCM layer was separated, dried over anhydrous sodium sulfate, and concentrated to dryness to yield (S)-5-chloro-N-(2′-methoxy-2-(2,2,2-trifluoroacetamido)-5H-spiro[oxazole-4,9′-xanthene]-7′-yl)picolinamide as a brownish solid. MS (ESI pos. ion) m/z: 533 (M+1). Step 5: A solution of (S)-5-chloro-N-(2′-methoxy-2-(2,2,2-trifluoroacetamido)-5H-spiro[oxazole-4,9′-xanthene]-7′-yl)picolinamide (0.054 g, 0.101 mmol) in methanol (3.5 mL) was treated with potassium carbonate anhydrous (0.045 g, 0.326 mmol) and stirred at RT for 30 minutes. The catalyst was removed by filtration and the filtrate was concentrated to yield the crude product as a yellowish gummy solid. The crude product was purified by preparative HPLC [gradient 10-90% MeCN (0.1% TFA)/H2O (0.1% TFA)] to give pure product which was dissolved in methanol (5 mL) and neutralized by passing the solution through a Polymer Lab-HCO3 macroporous resin cartridge, and the filtrate was concentrated to give N-((4S)-2-amino-7′-methoxyspiro[1,3-oxazole-4,9′-xanthen]-2′-yl)-5-chloro-2-pyridinecarboxamide as an off-white solid. MS (ESI pos. ion) m/z: 437 (M+1).