0

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

实验步骤: To a stirred solution of methyl (1R,2S)-2-aminocyclopentanecarboxylate (240 mg, 1.68 mmol) in methanol (10 mL) under a nitrogen atmosphere, 3-methyl-benzaldehyde (202 mg, 1.68 mmol) was added. The mixture was stirred for 10 min, and then acetic acid (0.4 mL) was added followed by sodium cyanoborohydride (265 mg, 4.2 mmol). The resulting mixture was stirred at 25° C. for 16 h, and then poured into a mixture of saturated aqueous sodium bicarbonate solution (50 mL) and ethyl acetate (100 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous brine solution, dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo to afford the desired product, methyl (1R,2S)-2-[(3-methylbenzyl)amino]cyclopentanecarboxylate (330 mg, 1.34 mmol, 80%), as a clear oil. 1H NMR (400 MHz, CDCl3) δ: 1.62 (1H, m), 1.71 (1H, m), 1.91 (3H, m), 2.05 (1H, m), 2.37 (3H, s), 2.99 (1H, m), 3.34 (1H, m), 3.72 (3H, s), 3.77 (1H, d, J=12.8 Hz), 3.82 (1H, d, J=12.8 Hz), 7.24-7.07 (4H, m). The resulting mixture was stirred at 25° C. for 16 h The layers were separated the aqueous layer was extracted with ethyl acetate The combined organic layers were washed with saturated aqueous brine solution dried over magnesium sulfate filtered The filtrate was concentrated in vacuo

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

实验步骤: To a stirred solution of methyl (1R,2S)-2-aminocyclopentanecarboxylate (240 mg, 1.68 mmol) in methanol (10 mL) under a nitrogen atmosphere, 3-methyl-benzaldehyde (202 mg, 1.68 mmol) was added. The mixture was stirred for 10 min, and then acetic acid (0.4 mL) was added followed by sodium cyanoborohydride (265 mg, 4.2 mmol). The resulting mixture was stirred at 25° C. for 16 h, and then poured into a mixture of saturated aqueous sodium bicarbonate solution (50 mL) and ethyl acetate (100 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous brine solution, dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo to afford the desired product, methyl (1R,2S)-2-[(3-methylbenzyl)amino]cyclopentanecarboxylate (330 mg, 1.34 mmol, 80%), as a clear oil. 1H NMR (400 MHz, CDCl3) δ: 1.62 (1H, m), 1.71 (1H, m), 1.91 (3H, m), 2.05 (1H, m), 2.37 (3H, s), 2.99 (1H, m), 3.34 (1H, m), 3.72 (3H, s), 3.77 (1H, d, J=12.8 Hz), 3.82 (1H, d, J=12.8 Hz), 7.24-7.07 (4H, m). The resulting mixture was stirred at 25° C. for 16 h The layers were separated the aqueous layer was extracted with ethyl acetate The combined organic layers were washed with saturated aqueous brine solution dried over magnesium sulfate filtered The filtrate was concentrated in vacuo

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

实验步骤: To a stirred solution of methyl (1R,2S)-2-aminocyclopentanecarboxylate (310 mg, 2.17 mmol) in methanol (10 mL) under a nitrogen atmosphere, 4-fluoro-3-methyl-benzaldehyde (0.27 mL, 2.17 mmol) was added. The mixture was stirred for 10 min, and then acetic acid (0.4 mL) was added followed by sodium cyanoborohydride (340 mg, 5.42 mmol). The resulting mixture was stirred at 25° C. for 16 h, and then poured into a mixture of saturated aqueous sodium bicarbonate solution (50 mL) and ethyl acetate (100 mL). Two layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous brine solution, dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo to afford the desired product, methyl (1R,2S)-2-[(4-fluoro-3-methylbenzyl)amino]cyclopentanecarboxylate (460 mg, 1.73 mmol, 80%), as a clear oil. 1H NMR (400 MHz, CDCl3) δ: 1.68 (2H, m), 1.89 (3H, m), 2.04 (1H, m), 2.28 (3H, d, J=2.0 Hz), 2.97 (1H, m), 3.31 (1H, m), 3.71 (3H, s), 3.72 (2H, m), 6.93 (1H, t, J=8.4 Hz), 7.07 (1H, m), 7.11 (1H, m). The resulting mixture was stirred at 25° C. for 16 h Two layers were separated the aqueous layer was extracted with ethyl acetate The combined organic layers were washed with saturated aqueous brine solution dried over magnesium sulfate filtered The filtrate was concentrated in vacuo

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

实验步骤: To a stirred solution of methyl (1R,2S)-2-aminocyclopentanecarboxylate (310 mg, 2.17 mmol) in methanol (10 mL) under a nitrogen atmosphere, 4-fluoro-3-methyl-benzaldehyde (0.27 mL, 2.17 mmol) was added. The mixture was stirred for 10 min, and then acetic acid (0.4 mL) was added followed by sodium cyanoborohydride (340 mg, 5.42 mmol). The resulting mixture was stirred at 25° C. for 16 h, and then poured into a mixture of saturated aqueous sodium bicarbonate solution (50 mL) and ethyl acetate (100 mL). Two layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous brine solution, dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo to afford the desired product, methyl (1R,2S)-2-[(4-fluoro-3-methylbenzyl)amino]cyclopentanecarboxylate (460 mg, 1.73 mmol, 80%), as a clear oil. 1H NMR (400 MHz, CDCl3) δ: 1.68 (2H, m), 1.89 (3H, m), 2.04 (1H, m), 2.28 (3H, d, J=2.0 Hz), 2.97 (1H, m), 3.31 (1H, m), 3.71 (3H, s), 3.72 (2H, m), 6.93 (1H, t, J=8.4 Hz), 7.07 (1H, m), 7.11 (1H, m). The resulting mixture was stirred at 25° C. for 16 h Two layers were separated the aqueous layer was extracted with ethyl acetate The combined organic layers were washed with 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 methyl (1R,2S)-2-{[(benzyloxy)carbonyl]amino}cyclopentanecarboxylate (6.5 g, 23.5 mmol) in ethyl acetate (200 mL), 5% Palladium on carbon (1.3 g, 20% w/w) was added. The flask was degassed and backfilled with hydrogen gas via balloon. The mixture was stirred at 25° C. for 1.5 h, passed through a plug of Celite and rinsed with ethyl acetate. The filtrate was concentrated in vacuo to afford the desired product, methyl (1R,2S)-2-aminocyclopentanecarboxylate (4.30 g, 30.05 mmol, quantitative), as a clear oil. 1H NMR (400 MHz, CDCl3) δ: 1.57 (2H, m), 1.90 (3H, m), 2.05 (1H, m), 2.81 (1H, m), 3.61 (1H, m), 3.72 (3H, s). The flask was degassed rinsed with ethyl acetate The filtrate was concentrated in vacuo

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

实验步骤: To a solution of (1R,2S)-2-aminocyclopentanecarboxylic acid (0.15 g, 0.9 mmol) in methanol (5 mL) was added 4N HCl in dioxane (1 mL) and the reaction mixture was stirred at reflux overnight. The reaction mixture was concentrated in vacuo to afford an oil which was used directly for the next step. at reflux overnight The reaction mixture was concentrated in vacuo to afford an oil which

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

实验步骤: To a solution of (1R,2S)-2-aminocyclopentanecarboxylic acid (0.15 g, 0.9 mmol) in methanol (5 mL) was added 4N HCl in dioxane (1 mL) and the reaction mixture was stirred at reflux overnight. The reaction mixture was concentrated in vacuo to afford an oil which was used directly for the next step. at reflux overnight The reaction mixture was concentrated in vacuo to afford an oil which

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

实验步骤: (1R,2S)-2-(2-((R)-3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxamido)cyclopentane-1-carboxylic acid was prepared from (R)-2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxylic acid and methyl (1R,2S)-2-aminocyclopentane-1-carboxylate using Amidation Method 1 (HATU) and Ester Hydrolysis Method 1 (LiOH). 1H NMR (400 MHz, DMSO-d6) δ 11.9 (s, 1H), 8.68 (s, 2H), 8.08 (d, 1H), 7.02 (d, 1H), 6.89 (m, 3H), 4.51 (m, 1H), 4.28 (m, 2H), 3.95 (m, 3H), 3.75 (m, 2H), 2.90 (m, 1H), 1.89 (m, 8H), 1.51 (m, 2H), 1.23 (t, 3H). MS (ES+) 455.3 (M+H).

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

实验步骤: (1R,2S)-2-(6-((R)-3-(2-ethoxyphenoxy)piperidin-1-yl)-5-fluoronicotinamido)cyclopentane-1-carboxylic acid was prepared from (R)-6-(3-(2-ethoxyphenoxy)piperidin-1-yl)-5-fluoronicotinic acid and methyl (1R,2S)-2-aminocyclopentane-1-carboxylate using Amidation Method 2 (EDCl) and Ester Hydrolysis Method 1 (LiOH). 1H NMR (400 MHz, DMSO-d6) δ 11.3 (s, 1H), 8.35 (s, 1H), 7.59 (dd, 1H), 7.03 (d, 1H), 6.91 (m, 3H), 4.38 (m, 1H), 4.05 (dd, 1H), 3.93 (m, 3H), 3.69 (m, 1H), 3.50 (m, 2H), 2.33 (m, 1H), 1.98 (m, 4H), 1.79 (m, 1H), 1.60 (m, 3H), 1.45 (m, 2H), 1.25 (t, 3H). MS (ES+) 472.0 (M+H).

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

实验步骤: (1R,2S)-2-(2-((R)-3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxamido)cyclopentane-1-carboxylic acid was prepared from (R)-2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxylic acid and methyl (1R,2S)-2-aminocyclopentane-1-carboxylate using Amidation Method 1 (HATU) and Ester Hydrolysis Method 1 (LiOH). 1H NMR (400 MHz, DMSO-d6) δ 11.9 (s, 1H), 8.68 (s, 2H), 8.08 (d, 1H), 7.02 (d, 1H), 6.89 (m, 3H), 4.51 (m, 1H), 4.28 (m, 2H), 3.95 (m, 3H), 3.75 (m, 2H), 2.90 (m, 1H), 1.89 (m, 8H), 1.51 (m, 2H), 1.23 (t, 3H). MS (ES+) 455.3 (M+H).

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

实验步骤: (1R,2S)-2-(6-((R)-3-(2-ethoxyphenoxy)piperidin-1-yl)-5-fluoronicotinamido)cyclopentane-1-carboxylic acid was prepared from (R)-6-(3-(2-ethoxyphenoxy)piperidin-1-yl)-5-fluoronicotinic acid and methyl (1R,2S)-2-aminocyclopentane-1-carboxylate using Amidation Method 2 (EDCl) and Ester Hydrolysis Method 1 (LiOH). 1H NMR (400 MHz, DMSO-d6) δ 11.3 (s, 1H), 8.35 (s, 1H), 7.59 (dd, 1H), 7.03 (d, 1H), 6.91 (m, 3H), 4.38 (m, 1H), 4.05 (dd, 1H), 3.93 (m, 3H), 3.69 (m, 1H), 3.50 (m, 2H), 2.33 (m, 1H), 1.98 (m, 4H), 1.79 (m, 1H), 1.60 (m, 3H), 1.45 (m, 2H), 1.25 (t, 3H). MS (ES+) 472.0 (M+H).

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

实验步骤: To a stirred solution of methyl (1R,2S)-2-aminocyclopentanecarboxylate (240 mg, 1.68 mmol) in methanol (10 mL) under a nitrogen atmosphere, 3-methyl-benzaldehyde (202 mg, 1.68 mmol) was added. The mixture was stirred for 10 min, and then acetic acid (0.4 mL) was added followed by sodium cyanoborohydride (265 mg, 4.2 mmol). The resulting mixture was stirred at 25° C. for 16 h, and then poured into a mixture of saturated aqueous sodium bicarbonate solution (50 mL) and ethyl acetate (100 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous brine solution, dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo to afford the desired product, methyl (1R,2S)-2-[(3-methylbenzyl)amino]cyclopentanecarboxylate (330 mg, 1.34 mmol, 80%), as a clear oil. 1H NMR (400 MHz, CDCl3) δ: 1.62 (1H, m), 1.71 (1H, m), 1.91 (3H, m), 2.05 (1H, m), 2.37 (3H, s), 2.99 (1H, m), 3.34 (1H, m), 3.72 (3H, s), 3.77 (1H, d, J=12.8 Hz), 3.82 (1H, d, J=12.8 Hz), 7.24-7.07 (4H, m). The resulting mixture was stirred at 25° C. for 16 h The layers were separated the aqueous layer was extracted with ethyl acetate The combined organic layers were washed with saturated aqueous brine solution dried over magnesium sulfate filtered The filtrate was concentrated in vacuo