[Synthesis]
GENERAL METHOD: To a solution of THF/MeOH/H2O (55:50:100 mL) of compound 23 (26.0 g, 0.103 mol) was added LiOH-H2O (17.3 g, 0.411 mol, 4 eq.). The mixture was stirred for 1 h and concentrated. DCM was added and the organic layer was washed sequentially with 1N HCl, saturated NaHCO3 solution and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was washed with PE to give compound 51 (16.2 g, 80% yield). To a mixture of compound 51 (14.2 g, 67 mmol) and silica gel (14.2 g) in DCM (268 mL) was added PCC (21.6 g, 0.1005 mol, 1.5 equiv). The mixture was stirred for 2 hours and then filtered and the filtrate was concentrated. The residue was purified by silica gel column chromatography to afford the target product 52 (11.8 g, 84.2%) as a solid. To a DMSO (75 mL) solution of compound 52 was added a one-time addition of a DMSO (75 mL) solution of PhOPCH2OMe chloride (29.4 g, 3.6 eq.) and t-BuOK (9 g, 3.4 eq.). The mixture was stirred at room temperature for 1 hour, then a one-time addition of a DMSO (50 mL) solution of compound 52 (5 g, 1 eq.) was added at 0 °C and stirring was continued overnight. The reaction solution was poured into water, extracted with EA, the organic phase was washed with brine, dried over anhydrous Na2SO4, filtered and evaporated. The residue was purified by silica gel column chromatography to give compound 53 (4.1 g, 72% yield) as a yellow solid.TLC (silica gel plate, PE/EA=10:1): Rf=0.45.To a solution of compound 53 (2 g, 8.37 mmol) in THF (42 mL) was added 6N HCl (14 mL) at room temperature, and the reaction was refluxed for 1 hour. After cooling, it was poured into water and extracted with EA, the organic phase was washed sequentially with water and brine, dried over anhydrous Na2SO4 and evaporated to give the crude product 54 (2.54 g) as an oil.TLC (silica gel plate, PE/EA=10:1): Rf=0.2. To a solution of compound 54 (2.54 g) in methanol (20 mL) was added batchwise NaBH4 (319 mg. 1 eq.), which was added over 10 min. After stirring for 1 hr water (50 mL) was added and stirring was continued for 10 min. Extracted with EA, the organic phase was washed with water, dried over Na2SO4 and evaporated to give the crude product 55 (2.41 g) as an oil.TLC (silica gel plate, PE/EA=3:1): Rf=0.3. To a solution of compound 55 (2.41 g) and Et3N (1.2 g, 1.1 eq.) in DCM (35 mL) was added dropwise at 0 °C acetyl chloride ( 0.84 g, 1 equiv). The reaction was stirred at 0 °C and water (50 mL) was added. Extracted with EA, the organic phase was washed with brine, dried over anhydrous Na2SO4 and evaporated. The residue was purified by silica gel column chromatography (PE/EA=10:1) to afford compound 56 (2.2 g, 98% overall yield in three steps).1H NMR (300 MHz, CDCl3): δ 7.57 (d, 1H), 7.48 (d, 1H), 7.37 (t, 1H), 4.32 (t, 2H), 3.15 (t, 2H), 2.03 (s , 1H) ppm. to a mixture of compound 56 (1 g), pin2B2 (1.04 g, 1.1 eq.) and KOAc (0.73 g, 2 eq.) of 1,4-dioxane (20 mL) was added Pd(dppf)Cl2 (100 mg, 5 mol%) and refluxed for 2 hr under N2 protection. After cooling to room temperature it was poured into water (50 mL) and extracted with EA. The organic phase was washed sequentially with water and brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography (PE/EA=10:1) to give compound 57 (0.9 g) as a colorless oil.TLC (silica gel plate, PE/EA=3:1): Rf=0.7. NaOH (0.254 g, 2 eq.) was added in a single addition to a solution of MeOH (20 mL) of compound 57 (1 g) at 0 °C. MeOH was removed by rotary evaporation after stirring at room temperature for 1 h. The residue was mixed with 6N HCl (1.1 mL). After stirring overnight it was quenched with 1N NaOH (10 mL) and washed with EA. The aqueous phase was acidified to pH 1-2 with 1N HCl and extracted with EA. The organic layers were combined, washed with brine, dried over Na2SO4 and evaporated to give compound 58 (540 mg, 51% yield) as a white solid.1H NMR (300 MHz, DMSO-d6): δ 8.84 (s, 1H), 7.67 (d, 1H), 7.54 (m, 2H), 4.07 (t, 2H), 2.94 (t, 2H). MS: m/z=174 (M+1, ESI+). To a solution of HCOOH/water (5.4:0.54 mL) of compound 58 (540 mg, 3.12 mmol) was added Raney Ni. The solution was stirred at 100 °C for 1 h then cooled to room temperature, quenched with water and extracted with EA. The organic phase was washed sequentially with water and brine, dried over Na2SO4 and concentrated. Purification of the residue by silica gel column chromatography (PE/EA=3:1) afforded compound 59 (460 mg, 85%) as a white solid.1H NMR (300 MHz, DMSO-d6): δ 10.69 (s, 1H), 9.01 (s, 1H), 7.74 (q, 1H), 7.54 (m, 2H), 4.09 (t, 2H). 2.96 (t, 1H) ppm. ms: m/z = 177 (M+1, ESI+). NaH (60%, 68 mg, 3 eq.) was added to a solution of Ph3PCH2COOCH2CH3 bromide in THF (6 mL). After stirring for 1 h at room temperature under N2 protection, a THF (2 mL) solution of compound 59 (100 mg, 1 eq.) was added in a single addition at 0 °C. After stirring overnight it was quenched with water (10 mL) and 1N HCl (10 mL) and extracted with EA. The organic phase was washed with brine, dried over Na2SO4 and concentrated. Purification of the residue by silica gel column chromatography (PE/EA=10:1-3:1) afforded compound 60 (140 mg, 98% yield) as a white solid.1H NMR (300 MHz, DMSO-d6): δ 8.73 (s, 1H), 8.70 (d, 1H), 7.70 (d, 1H), 7.42 (t, 1H), 7.26 (d. 1H), 6.45 (d, 1H), 4.30 (q, 2H), 4.03 (t, 2H), 2.89 (t, 2H). |