顺式-2-(4-氟苄基氨基)环戊烷甲酸乙酯

反应条件: temp:23.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Sodium triacetoxyborohydride (62.1 g, 293 mmol) was suspended in a 1:1 mixture of glacial acetic acid and acetonitrile (200 mL) at 0° C. The crude 2-(4-fluoro-benzylamino)-cyclopent-1-enecarboxylic acid ethyl ester was added via cannula over 15 min and the resulting orange/brown suspension was allowed to warm to 23° C. over 19 h. A 4.0 M aqueous hydrochloric acid solution (60 mL) was then carefully added and the mixture was stirred at 23° C. for 20 min. The mixture was transferred to a large Erlenmeyer flask containing a stir bar and was cooled to 0° C. Aqueous sodium hydroxide (98 g dissolved in 350 mL; approx. 8.0 M) was then added over 20 min with gentle stirring and continued external cooling (large exotherm noted; melted ice was replenished). After the exotherm subsided, the mixture was transferred to a separatory funnel and the phases were separated. The aqueous phase was extracted with ethyl acetate (1×300 mL) and the combined organic layers were washed with half-saturated aqueous sodium bicarbonate solution (1×200 mL), dried over sodium sulfate, filtered and were concentrated in vacuo. Purification of the residue by flash chromatography (Teledyne Isco RediSep Column; 15-40% ethyl acetate in hexanes) afforded the desired product, cis-2-(4-fluoro-benzylamino)-cyclopentanecarboxylic acid ethyl ester (19.9 g, 77% over two steps), as a pale yellow oil. 1H NMR (CDCl3) δ: 1.27 (3H, t, J=7.0), 1.55-1.71 (2H, m), 1.81-1.91 (4H, m), 1.98-2.06 (1H, m), 2.90-2.96 (1H, m), 3.26-3.31 (1H, m), 3.73 (1H, d, J=13.1), 3.77 (1H, d, J=13.2), 4.15 (2H, q, J=7.3), 6.94-7.00 (2H, m), 7.24-7.28 (2H, m). 13C NMR (CDCl3) δ: 14.8, 22.7, 27.9, 32.2, 48.0, 51.9, 60.5, 61.7, 115.2 (d, J=21.5), 129.6 (d, J=8.4), 136.5 (d, J=3.1), 161.9 (d, J=243.8), 174.7. Anal. calculated for C15H20FNO2: C, 67.90; H, 7.60; N, 5.28. found: C, 67.92; H, 7.88; N, 5.55. Continued elution of the silica gel column with increasing amounts of ethyl acetate (up to 100% of eluent concentration) afforded trans-2-(4-fluoro-benzylamino)-cyclopentanecarboxylic acid ethyl ester (3.2 g, 12%) as a dark orange oil. 1H NMR (CDCl3) δ: 1.26 (3H, t, J=7.0), 1.40-1.49 (1H, m), 1.67-1.77 (2H, m), 1.82-1.91 (1H, m), 1.97-2.05 (2H, m), 2.58 (1H, q, J=7.9), 3.31 (1H, q, J=7.3), 3.72 (1H, d, J=13.2), 3.77 (1H, d, J=12.5), 4.14 (2H, q, J=7.0), 6.96-7.01 (2H, m), 7.24-7.29 (2H, m). The mixture was transferred to a large Erlenmeyer flask containing a stir bar was cooled to 0° C with gentle stirring continued external cooling (large exotherm noted; melted ice was replenished) the mixture was transferred to a separatory funnel the phases were separated The aqueous phase was extracted with ethyl acetate (1×300 mL) the combined organic layers were washed with half-saturated aqueous sodium bicarbonate solution (1×200 mL) dried over sodium sulfate filtered were concentrated in vacuo Purification of the residue by flash chromatography (Teledyne Isco RediSep Column; 15-40% ethyl acetate in hexanes)

反应条件: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A solution of cis-2-(4-fluoro-benzylamino)-cyclopentanecarboxylic acid ethyl ester (prepared as described in Example 11, 154 mg, 0.580 mmol), (7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,4]thiazin-3-yl)-acetic acid (175 mg, 0.527 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (117 mg, 0.609 mmol) in anhydrous N,N-dimethylformamide (6 mL) was treated with N-methylmorpholine (123 mg, 134 μL, 1.22 mmol). The reaction was stirred for 1 h at 25° C., diluted with 1.0 M aqueous hydrochloric acid solution (20 mL), and extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was taken up in ethanol (6 mL) and treated with a 60% oil dispersion of sodium hydride (93 mg, 3.87 mmol). The reaction was heated at 70° C. for 1 h, allowed to cool to 25° C., and quenched with 1.0 M aqueous hydrochloric acid solution (50 mL). The resulting mixture was extracted with ethyl acetate (3×50 mL), and the combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude oil was purified by prep-HPLC [Column: Thomson C18 ODSA, 5 micron, 50×21.2 mm ID; 45-70% acetonitrile in water; 30 mL/min flow rate for 4 min run] to afford the desired product, cis-N-{3-[1-(4-fluoro-benzyl)-4-hydroxy-2-oxo-2,4a,5,6,7,7a-hexahydro-1H-[1]pyrindin-3-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,4]thiazin-7-yl}-methanesulfonamide (60 mg, 0.112 mmol, 21%), as a light yellow solid. 1H NMR (400 MHz, CDCl3) 1H NMR (400 MHz, Acetone-d6) δ: 1.34-1.47 (m, 1H), 1.50-1.91 (m, 4H), 2.32-2.42 (m, 1H), 2.96-3.03 (m, 1H), 3.11 (s, 3H), 3.83-3.94 (m, 1H), 4.54-4.67 (m, 1H), 4.97-5.07 (m, 1H), 5.37-5.78 (m, 2H), 7.07-7.14 (m, 2H), 7.36-7.54 (m, 3H), 7.66-7.71 (m, 1H), 7.81-7.83 (m, 1H), 8.95 (bs, 1H). LC-MS calcd for C24H24FN3O6S2 533.6, found 534.3 [M+H+]. extracted with ethyl acetate (3×50 mL) The combined organic layers were dried over magnesium sulfate filtered concentrated in vacuo The reaction was heated at 70° C. for 1 h to cool to 25° C. quenched with 1.0 M aqueous hydrochloric acid solution (50 mL) The resulting mixture was extracted with ethyl acetate (3×50 mL) the combined organic layers were dried over magnesium sulfate filtered concentrated in vacuo The crude oil was purified by prep-HPLC [Column: Thomson C18 ODSA, 5 micron, 50×21.2 mm ID; 45-70% acetonitrile in water; 30 mL/min flow rate for 4 min run]

反应条件: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a stirred solution of cis-2-(4-fluoro-benzylamino)-cyclopentanecarboxylic acid ethyl ester (prepared as described in Example 11, 1.33 g, 5 mmol) and (7-iodo-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (2.20 g, 6.0 mmol) in anhydrous N,N-dimethylformamide (15 mL) under a nitrogen atmosphere, a 1.0 M solution of N,N′-dicyclohexylcarbodiimide solution in dichloromethane (6.5 mL, 6.5 mmol) was slowly added. After stirring for 1.5 h at 25° C., the mixture was diluted with ethyl acetate, washed with water and saturated aqueous brine solution, dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo to afford the amide intermediate, which was used directly in the next step without further purification. washed with water and saturated aqueous brine solution dried over magnesium sulfate filtered The filtrate was concentrated in vacuo

反应条件: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of (7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in Example 1j, 0.140 g, 0.241 mmol) and cis-2-(4-fluoro-benzylamino)-cyclopentanecarboxylic acid ethyl ester (0.064 g, 0.241 mmol) in N,N-dimethylformamide (10 mL) was added a 2.0 M solution of N,N′-dicyclohexylcarbodiimide in N,N-dimethylformamide (121 μL, 0.241 mmol) and the reaction mixture was stirred at 25° C. for 16 h. The solvent was removed in vacuo and the residue was purified by flash column chromatography (Teledyne Isco RediSep Flash Column 4 g; 0-10% methanol in dichloromethane) to afford the desired product, cis-2-{(4-fluoro-benzyl)-[2-(7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetyl]-amino}-cyclopentanecarboxylic acid ethyl ester (0.04 g, 0.0689 mmol, 28.6%). LC-MS (ESI) calcd for C25H29FN4O7S2 580.15, found 581.2 [M+H+]. The solvent was removed in vacuo the residue was purified by flash column chromatography (Teledyne Isco RediSep Flash Column 4 g; 0-10% methanol in dichloromethane)

反应条件: temp:23.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Sodium triacetoxyborohydride (62.1 g, 293 mmol) was suspended in a 1:1 mixture of glacial acetic acid and actonitrile (200 mL) at 0° C. The crude 2-(4-fluoro-benzylamino)-cyclopent-1-enecarboxylic acid ethyl ester was added via cannula over 15 min and the resulting orange/brown suspension was allowed to warm to 23° C. over 19 h. A 4.0 M aqueous hydrochloric acid solution (60 mL) was then carefully added and the mixture was stirred at 23° C. for 20 min. The mixture was transferred to a large Erlenmeyer flask containing a stirbar and was cooled to 0° C. Aqueous sodium hydroxide (98 g dissolved in 350 mL; approx. 8.0 M) was then added over 20 min with gentle stirring and continued external cooling (large exotherm noted; melted ice was replenished). After the exotherm subsided, the mixture was transferred to a separatory funnel and the phases were separated. The aqueous phase was extracted with ethyl acetate (1×300 mL) and the combined organic layers were washed with half-saturated aqueous sodium bicarbonate solution (1×200 mL), dried over sodium sulfate, filtered and were concentrated in vacuo. Purification of the residue by flash chromatography (Teledyne Isco RediSep Column; 15-40% ethyl acetate in hexanes) afforded the desired product, cis-2-(4-fluoro-benzylamino)-cyclopentanecarboxylic acid ethyl ester (19.9 g, 77% over two steps), as a pale yellow oil. 1H NMR (CDCl3) δ: 1.27 (3H, t, J=7.0), 1.55-1.71 (2H, m), 1.81-1.91 (4H, m), 1.98-2.06 (1H, m), 2.90-2.96 (1H, m), 3.26-3.31 (1H, m), 3.73 (1H, d, J=13.1), 3.77 (1H, d, J=13.2), 4.15 (2H, q, J=7.3), 6.94-7.00 (2H, m), 7.24-7.28 (2H, m). 13C NMR (CDCl3) δ: 14.8, 22.7, 27.9, 32.2, 48.0, 51.9, 60.5, 61.7, 115.2 (d, J=21.5), 129.6 (d, J=8.4), 136.5 (d, J=3.1), 161.9 (d, J=243.8), 174.7. Anal. calcd for C15H20FNO2: C, 67.90; H, 7.60; N, 5.28; Found: C, 67.92; H, 7.88; N, 5.55. Continued elution of the silica gel column with increasing amounts of ethyl acetate (up to 100% of eluent concentration) afforded trans-2-(4-fluoro-benzylamino)-cyclopentanecarboxylic acid ethyl ester (3.2 g, 12%) as a dark orange oil. 1H NMR (CDCl3) δ: 1.26 (3H, t, J=7.0), 1.40-1.49 (1H, m), 1.67-1.77 (2H, m), 1.82-1.91 (1H, m), 1.97-2.05 (2H, m), 2.58 (1H, q, J=7.9), 3.31 (1H, q, J=7.3), 3.72 (1H, d, J=13.2), 3.77 (1H, d, J=12.5), 4.14 (2H, q, J=7.0), 6.96-7.01 (2H, m), 7.24-7.29 (2H, m). The mixture was transferred to a large Erlenmeyer flask containing a stirbar was cooled to 0° C with gentle stirring continued external cooling (large exotherm noted; melted ice was replenished) the mixture was transferred to a separatory funnel the phases were separated The aqueous phase was extracted with ethyl acetate (1×300 mL) the combined organic layers were washed with half-saturated aqueous sodium bicarbonate solution (1×200 mL) dried over sodium sulfate filtered were concentrated in vacuo Purification of the residue by flash chromatography (Teledyne Isco RediSep Column; 15-40% ethyl acetate in hexanes)

反应条件: temp:23.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Sodium triacetoxyborohydride (62.1 g, 293 mmol) was suspended in a 1:1 mixture of glacial acetic acid and actonitrile (200 mL) at 0° C. The crude 2-(4-fluoro-benzylamino)-cyclopent-1-enecarboxylic acid ethyl ester was added via cannula over 15 min and the resulting orange/brown suspension was allowed to warm to 23° C. over 19 h. A 4.0 M aqueous hydrochloric acid solution (60 mL) was then carefully added and the mixture was stirred at 23° C. for 20 min. The mixture was transferred to a large Erlenmeyer flask containing a stirbar and was cooled to 0° C. Aqueous sodium hydroxide (98 g dissolved in 350 mL; approx. 8.0 M) was then added over 20 min with gentle stirring and continued external cooling (large exotherm noted; melted ice was replenished). After the exotherm subsided, the mixture was transferred to a separatory funnel and the phases were separated. The aqueous phase was extracted with ethyl acetate (1×300 mL) and the combined organic layers were washed with half-saturated aqueous sodium bicarbonate solution (1×200 mL), dried over sodium sulfate, filtered and were concentrated in vacuo. Purification of the residue by flash chromatography (Teledyne Isco RediSep Column; 15-40% ethyl acetate in hexanes) afforded the desired product, cis-2-(4-fluoro-benzylamino)-cyclopentanecarboxylic acid ethyl ester (19.9 g, 77% over two steps), as a pale yellow oil. 1H NMR (CDCl3) δ: 1.27 (3H, t, J=7.0), 1.55-1.71 (2H, m), 1.81-1.91 (4H, m), 1.98-2.06 (1H, m), 2.90-2.96 (1H, m), 3.26-3.31 (1H, m), 3.73 (1H, d, J=13.1), 3.77 (1H, d, J=13.2), 4.15 (2H, q, J=7.3), 6.94-7.00 (2H, m), 7.24-7.28 (2H, m). 13C NMR (CDCl3) δ: 14.8, 22.7, 27.9, 32.2, 48.0, 51.9, 60.5, 61.7, 115.2 (d, J=21.5), 129.6 (d, J=8.4), 136.5 (d, J=3.1), 161.9 (d, J=243.8), 174.7. Anal. calcd for C15H20FNO2: C, 67.90; H, 7.60; N, 5.28; Found: C, 67.92; H, 7.88; N, 5.55. Continued elution of the silica gel column with increasing amounts of ethyl acetate (up to 100% of eluent concentration) afforded trans-2-(4-fluoro-benzylamino)-cyclopentanecarboxylic acid ethyl ester (3.2 g, 12%) as a dark orange oil. 1H NMR (CDCl3) δ: 1.26 (3H, t, J=7.0), 1.40-1.49 (1H, m), 1.67-1.77 (2H, m), 1.82-1.91 (1H, m), 1.97-2.05 (2H, m), 2.58 (1H, q, J=7.9), 3.31 (1H, q, J=7.3), 3.72 (1H, d, J=13.2), 3.77 (1H, d, J=12.5), 4.14 (2H, q, J=7.0), 6.96-7.01 (2H, m), 7.24-7.29 (2H, m). The mixture was transferred to a large Erlenmeyer flask containing a stirbar was cooled to 0° C with gentle stirring continued external cooling (large exotherm noted; melted ice was replenished) the mixture was transferred to a separatory funnel the phases were separated The aqueous phase was extracted with ethyl acetate (1×300 mL) the combined organic layers were washed with half-saturated aqueous sodium bicarbonate solution (1×200 mL) dried over sodium sulfate filtered were concentrated in vacuo Purification of the residue by flash chromatography (Teledyne Isco RediSep Column; 15-40% ethyl acetate in hexanes)

反应条件: temp:23.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Sodium triacetoxyborohydride (62.1 g, 293 mmol) was suspended in a 1:1 mixture of glacial acetic acid and acetonitrile (200 mL) at 0° C. The crude 2-(4-fluoro-benzylamino)-cyclopent-1-enecarboxylic acid ethyl ester was added via cannula over 15 min and the resulting orange/brown suspension was allowed to warm to 23° C. over 19 h. A 4.0 M aqueous hydrochloric acid solution (60 mL) was then carefully added and the mixture was stirred at 23° C. for 20 min. The mixture was transferred to a large Erlenmeyer flask containing a stir bar and was cooled to 0° C. Aqueous sodium hydroxide (98 g dissolved in 350 mL; approx. 8.0 M) was then added over 20 min with gentle stirring and continued external cooling (large exotherm noted; melted ice was replenished). After the exotherm subsided, the mixture was transferred to a separatory funnel and the phases were separated. The aqueous phase was extracted with ethyl acetate (1×300 mL) and the combined organic layers were washed with half-saturated aqueous sodium bicarbonate solution (1×200 mL), dried over sodium sulfate, filtered and were concentrated in vacuo. Purification of the residue by flash chromatography (Teledyne Isco RediSep Column; 15-40% ethyl acetate in hexanes) afforded the desired product, cis-2-(4-fluoro-benzylamino)-cyclopentanecarboxylic acid ethyl ester (19.9 g, 77% over two steps), as a pale yellow oil. 1H NMR (CDCl3) δ: 1.27 (3H, t, J=7.0), 1.55-1.71 (2H, m), 1.81-1.91 (4H, m), 1.98-2.06 (1H, m), 2.90-2.96 (1H, m), 3.26-3.31 (1H, m), 3.73 (1H, d, J=13.1), 3.77 (1H, d, J=13.2), 4.15 (2H, q, J=7.3), 6.94-7.00 (2H, m), 7.24-7.28 (2H, m). 13C NMR (CDCl3) δ: 14.8, 22.7, 27.9, 32.2, 48.0, 51.9, 60.5, 61.7, 115.2 (d, J=21.5), 129.6 (d, J=8.4), 136.5 (d, J=3.1), 161.9 (d, J=243.8), 174.7. Anal. calculated for C15H20FNO2: C, 67.90; H, 7.60; N, 5.28. found: C, 67.92; H, 7.88; N, 5.55. Continued elution of the silica gel column with increasing amounts of ethyl acetate (up to 100% of eluent concentration) afforded trans-2-(4-fluoro-benzylamino)-cyclopentanecarboxylic acid ethyl ester (3.2 g, 12%) as a dark orange oil. 1H NMR (CDCl3) δ: 1.26 (3H, t, J=7.0), 1.40-1.49 (1H, m), 1.67-1.77 (2H, m), 1.82-1.91 (1H, m), 1.97-2.05 (2H, m), 2.58 (1H, q, J=7.9), 3.31 (1H, q, J=7.3), 3.72 (1H, d, J=13.2), 3.77 (1H, d, J=12.5), 4.14 (2H, q, J=7.0), 6.96-7.01 (2H, m), 7.24-7.29 (2H, m). The mixture was transferred to a large Erlenmeyer flask containing a stir bar was cooled to 0° C with gentle stirring continued external cooling (large exotherm noted; melted ice was replenished) the mixture was transferred to a separatory funnel the phases were separated The aqueous phase was extracted with ethyl acetate (1×300 mL) the combined organic layers were washed with half-saturated aqueous sodium bicarbonate solution (1×200 mL) dried over sodium sulfate filtered were concentrated in vacuo Purification of the residue by flash chromatography (Teledyne Isco RediSep Column; 15-40% ethyl acetate in hexanes)

反应条件: temp:23.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Sodium triacetoxyborohydride (62.1 g, 293 mmol) was suspended in a 1:1 mixture of glacial acetic acid and acetonitrile (200 mL) at 0° C. The crude 2-(4-fluoro-benzylamino)-cyclopent-1-enecarboxylic acid ethyl ester was added via cannula over 15 min and the resulting orange/brown suspension was allowed to warm to 23° C. over 19 h. A 4.0 M aqueous hydrochloric acid solution (60 mL) was then carefully added and the mixture was stirred at 23° C. for 20 min. The mixture was transferred to a large Erlenmeyer flask containing a stir bar and was cooled to 0° C. Aqueous sodium hydroxide (98 g dissolved in 350 mL; approx. 8.0 M) was then added over 20 min with gentle stirring and continued external cooling (large exotherm noted; melted ice was replenished). After the exotherm subsided, the mixture was transferred to a separatory funnel and the phases were separated. The aqueous phase was extracted with ethyl acetate (1×300 mL) and the combined organic layers were washed with half-saturated aqueous sodium bicarbonate solution (1×200 mL), dried over sodium sulfate, filtered and were concentrated in vacuo. Purification of the residue by flash chromatography (Teledyne Isco RediSep Column; 15-40% ethyl acetate in hexanes) afforded the desired product, cis-2-(4-fluoro-benzylamino)-cyclopentanecarboxylic acid ethyl ester (19.9 g, 77% over two steps), as a pale yellow oil. 1H NMR (CDCl3) δ: 1.27 (3H, t, J=7.0), 1.55-1.71 (2H, m), 1.81-1.91 (4H, m), 1.98-2.06 (1H, m), 2.90-2.96 (1H, m), 3.26-3.31 (1H, m), 3.73 (1H, d, J=13.1), 3.77 (1H, d, J=13.2), 4.15 (2H, q, J=7.3), 6.94-7.00 (2H, m), 7.24-7.28 (2H, m). 13C NMR (CDCl3) δ: 14.8, 22.7, 27.9, 32.2, 48.0, 51.9, 60.5, 61.7, 115.2 (d, J=21.5), 129.6 (d, J=8.4), 136.5 (d, J=3.1), 161.9 (d, J=243.8), 174.7. Anal. calculated for C15H20FNO2: C, 67.90; H, 7.60; N, 5.28. found: C, 67.92; H, 7.88; N, 5.55. Continued elution of the silica gel column with increasing amounts of ethyl acetate (up to 100% of eluent concentration) afforded trans-2-(4-fluoro-benzylamino)-cyclopentanecarboxylic acid ethyl ester (3.2 g, 12%) as a dark orange oil. 1H NMR (CDCl3) δ: 1.26 (3H, t, J=7.0), 1.40-1.49 (1H, m), 1.67-1.77 (2H, m), 1.82-1.91 (1H, m), 1.97-2.05 (2H, m), 2.58 (1H, q, J=7.9), 3.31 (1H, q, J=7.3), 3.72 (1H, d, J=13.2), 3.77 (1H, d, J=12.5), 4.14 (2H, q, J=7.0), 6.96-7.01 (2H, m), 7.24-7.29 (2H, m). The mixture was transferred to a large Erlenmeyer flask containing a stir bar was cooled to 0° C with gentle stirring continued external cooling (large exotherm noted; melted ice was replenished) the mixture was transferred to a separatory funnel the phases were separated The aqueous phase was extracted with ethyl acetate (1×300 mL) the combined organic layers were washed with half-saturated aqueous sodium bicarbonate solution (1×200 mL) dried over sodium sulfate filtered were concentrated in vacuo Purification of the residue by flash chromatography (Teledyne Isco RediSep Column; 15-40% ethyl acetate in hexanes)

反应条件: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A solution of cis-2-(4-fluoro-benzylamino)-cyclopentanecarboxylic acid ethyl ester (prepared as described in Example 11, 154 mg, 0.580 mmol), (7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,4]thiazin-3-yl)-acetic acid (175 mg, 0.527 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (117 mg, 0.609 mmol) in anhydrous N,N-dimethylformamide (6 mL) was treated with N-methylmorpholine (123 mg, 134 μL, 1.22 mmol). The reaction was stirred for 1 h at 25° C., diluted with 1.0 M aqueous hydrochloric acid solution (20 mL), and extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was taken up in ethanol (6 mL) and treated with a 60% oil dispersion of sodium hydride (93 mg, 3.87 mmol). The reaction was heated at 70° C. for 1 h, allowed to cool to 25° C., and quenched with 1.0 M aqueous hydrochloric acid solution (50 mL). The resulting mixture was extracted with ethyl acetate (3×50 mL), and the combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude oil was purified by prep-HPLC [Column: Thomson C18 ODSA, 5 micron, 50×21.2 mm ID; 45-70% acetonitrile in water; 30 mL/min flow rate for 4 min run] to afford the desired product, cis-N-{3-[1-(4-fluoro-benzyl)-4-hydroxy-2-oxo-2,4a,5,6,7,7a-hexahydro-1H-[1]pyrindin-3-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,4]thiazin-7-yl}-methanesulfonamide (60 mg, 0.112 mmol, 21%), as a light yellow solid. 1H NMR (400 MHz, CDCl3) 1H NMR (400 MHz, Acetone-d6) δ: 1.34-1.47 (m, 1H), 1.50-1.91 (m, 4H), 2.32-2.42 (m, 1H), 2.96-3.03 (m, 1H), 3.11 (s, 3H), 3.83-3.94 (m, 1H), 4.54-4.67 (m, 1H), 4.97-5.07 (m, 1H), 5.37-5.78 (m, 2H), 7.07-7.14 (m, 2H), 7.36-7.54 (m, 3H), 7.66-7.71 (m, 1H), 7.81-7.83 (m, 1H), 8.95 (bs, 1H). LC-MS calcd for C24H24FN3O6S2 533.6, found 534.3 [M+H+]. extracted with ethyl acetate (3×50 mL) The combined organic layers were dried over magnesium sulfate filtered concentrated in vacuo The reaction was heated at 70° C. for 1 h to cool to 25° C. quenched with 1.0 M aqueous hydrochloric acid solution (50 mL) The resulting mixture was extracted with ethyl acetate (3×50 mL) the combined organic layers were dried over magnesium sulfate filtered concentrated in vacuo The crude oil was purified by prep-HPLC [Column: Thomson C18 ODSA, 5 micron, 50×21.2 mm ID; 45-70% acetonitrile in water; 30 mL/min flow rate for 4 min run]

反应条件: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a stirred solution of cis-2-(4-fluoro-benzylamino)-cyclopentanecarboxylic acid ethyl ester (prepared as described in Example 11, 1.33 g, 5 mmol) and (7-iodo-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (2.20 g, 6.0 mmol) in anhydrous N,N-dimethylformamide (15 mL) under a nitrogen atmosphere, a 1.0 M solution of N,N′-dicyclohexylcarbodiimide solution in dichloromethane (6.5 mL, 6.5 mmol) was slowly added. After stirring for 1.5 h at 25° C., the mixture was diluted with ethyl acetate, washed with water and saturated aqueous brine solution, dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo to afford the amide intermediate, which was used directly in the next step without further purification. washed with water and saturated aqueous brine solution dried over magnesium sulfate filtered The filtrate was concentrated in vacuo

反应条件: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of (7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in Example 1j, 0.140 g, 0.241 mmol) and cis-2-(4-fluoro-benzylamino)-cyclopentanecarboxylic acid ethyl ester (0.064 g, 0.241 mmol) in N,N-dimethylformamide (10 mL) was added a 2.0 M solution of N,N′-dicyclohexylcarbodiimide in N,N-dimethylformamide (121 μL, 0.241 mmol) and the reaction mixture was stirred at 25° C. for 16 h. The solvent was removed in vacuo and the residue was purified by flash column chromatography (Teledyne Isco RediSep Flash Column 4 g; 0-10% methanol in dichloromethane) to afford the desired product, cis-2-{(4-fluoro-benzyl)-[2-(7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetyl]-amino}-cyclopentanecarboxylic acid ethyl ester (0.04 g, 0.0689 mmol, 28.6%). LC-MS (ESI) calcd for C25H29FN4O7S2 580.15, found 581.2 [M+H+]. The solvent was removed in vacuo the residue was purified by flash column chromatography (Teledyne Isco RediSep Flash Column 4 g; 0-10% methanol in dichloromethane)

反应条件: temp:23.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Sodium triacetoxyborohydride (62.1 g, 293 mmol) was suspended in a 1:1 mixture of glacial acetic acid and actonitrile (200 mL) at 0° C. The crude 2-(4-fluoro-benzylamino)-cyclopent-1-enecarboxylic acid ethyl ester was added via cannula over 15 min and the resulting orange/brown suspension was allowed to warm to 23° C. over 19 h. A 4.0 M aqueous hydrochloric acid solution (60 mL) was then carefully added and the mixture was stirred at 23° C. for 20 min. The mixture was transferred to a large Erlenmeyer flask containing a stirbar and was cooled to 0° C. Aqueous sodium hydroxide (98 g dissolved in 350 mL; approx. 8.0 M) was then added over 20 min with gentle stirring and continued external cooling (large exotherm noted; melted ice was replenished). After the exotherm subsided, the mixture was transferred to a separatory funnel and the phases were separated. The aqueous phase was extracted with ethyl acetate (1×300 mL) and the combined organic layers were washed with half-saturated aqueous sodium bicarbonate solution (1×200 mL), dried over sodium sulfate, filtered and were concentrated in vacuo. Purification of the residue by flash chromatography (Teledyne Isco RediSep Column; 15-40% ethyl acetate in hexanes) afforded the desired product, cis-2-(4-fluoro-benzylamino)-cyclopentanecarboxylic acid ethyl ester (19.9 g, 77% over two steps), as a pale yellow oil. 1H NMR (CDCl3) δ: 1.27 (3H, t, J=7.0), 1.55-1.71 (2H, m), 1.81-1.91 (4H, m), 1.98-2.06 (1H, m), 2.90-2.96 (1H, m), 3.26-3.31 (1H, m), 3.73 (1H, d, J=13.1), 3.77 (1H, d, J=13.2), 4.15 (2H, q, J=7.3), 6.94-7.00 (2H, m), 7.24-7.28 (2H, m). 13C NMR (CDCl3) δ: 14.8, 22.7, 27.9, 32.2, 48.0, 51.9, 60.5, 61.7, 115.2 (d, J=21.5), 129.6 (d, J=8.4), 136.5 (d, J=3.1), 161.9 (d, J=243.8), 174.7. Anal. calcd for C15H20FNO2: C, 67.90; H, 7.60; N, 5.28; Found: C, 67.92; H, 7.88; N, 5.55. Continued elution of the silica gel column with increasing amounts of ethyl acetate (up to 100% of eluent concentration) afforded trans-2-(4-fluoro-benzylamino)-cyclopentanecarboxylic acid ethyl ester (3.2 g, 12%) as a dark orange oil. 1H NMR (CDCl3) δ: 1.26 (3H, t, J=7.0), 1.40-1.49 (1H, m), 1.67-1.77 (2H, m), 1.82-1.91 (1H, m), 1.97-2.05 (2H, m), 2.58 (1H, q, J=7.9), 3.31 (1H, q, J=7.3), 3.72 (1H, d, J=13.2), 3.77 (1H, d, J=12.5), 4.14 (2H, q, J=7.0), 6.96-7.01 (2H, m), 7.24-7.29 (2H, m). The mixture was transferred to a large Erlenmeyer flask containing a stirbar was cooled to 0° C with gentle stirring continued external cooling (large exotherm noted; melted ice was replenished) the mixture was transferred to a separatory funnel the phases were separated The aqueous phase was extracted with ethyl acetate (1×300 mL) the combined organic layers were washed with half-saturated aqueous sodium bicarbonate solution (1×200 mL) dried over sodium sulfate filtered were concentrated in vacuo Purification of the residue by flash chromatography (Teledyne Isco RediSep Column; 15-40% ethyl acetate in hexanes)