1,2-Cyclopropanedicarboxylicacid,monoethylester,(1R,2R)-(9CI)

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

实验步骤: To a mixture of 3,4-diaminobenzonitrile (326 mg, 2.45 mmol), trans-2-(ethoxycarbonyl)cyclopropanecarboxylic acid (323 mg, 2.04 mmol), and triethylamine (1.44 mL, 10.2 mmol) in DMF (10 mL) was added HBTU (1.01 g, 2.66 mmol). After stirring at room temperature for 3 h, the mixture was poured into water, and the aqueous phase was extracted with EtOAc twice. The combined organic layer was dried over sodium sulfate and concentrated in vacuo. To the residue was added acetic acid (10 mL), and the mixture was stirred at 90° C. for 12 h. After cooling to room temperature, the solvent was removed in vacuo. The residue was poured into saturated sodium bicarbonate aqueous solution, and the aqueous layer was extracted with EtOAc twice. The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate to give 210 mg (40%) of the title compound as a white amorphous: the aqueous phase was extracted with EtOAc twice The combined organic layer was dried over sodium sulfate concentrated in vacuo To the residue was added acetic acid (10 mL) the mixture was stirred at 90° C. for 12 h After cooling to room temperature the solvent was removed in vacuo The residue was poured into saturated sodium bicarbonate aqueous solution the aqueous layer was extracted with EtOAc twice The combined organic layers were dried over sodium sulfate concentrated in vacuo The residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate

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

实验步骤: The same operation as in Example (93a) was performed using tert-butyl 5-amino-1,3-dihydro-2H-inden-2-carboxylate (described in Andronati, S. A.; Krys'ko, A. A.; Chugunov, B. M.; Kabanova, T. A.; Artemenko, A. G.; Russ. J. Org. Chem.; 42; 8; 2006; 1174-1182, 0.19 g, 0.77 mmol), trans-2-(ethoxycarbonyl)cyclopropanecarboxylic acid (described in Wessjohann, Ludger A.; Fulhorst, Michael; Zakharova, Svetlana; Pol. J. Chem.; 80; 4; 2006; 673-678, 182 mg, 1.15 mmol), WSC hydrochloride (0.29 g, 1.5 mmol), DMAP (10 mg) and dichloromethane (20 mL). Purification by silica gel column chromatography (elution solvent: hexane/ethyl acetate=4/1, 2/1, 1/1, 1/2) gave 0.24 g of the title compound as a colorless solid (81%). Purification by silica gel column chromatography (elution solvent: hexane/ethyl acetate=4/1, 2/1, 1/1, 1/2)

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

实验步骤: tert-Butyl 5-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-1,3-dihydro-2H-isoindole-2-carboxylate (described in Example (92a), 0.17 g, 0.42 mmol) was dissolved in dichloromethane (3 mL) and methanol (1 mL). A 4 N hydrochloric acid/ethyl acetate solution (15 ml, 60 mmol) was added, followed by stirring for 20 minutes. The solvent was evaporated under reduced pressure. The resulting residue was dissolved in dichloromethane (5 mL) and DMA (5 mL). trans-2-(Ethoxycarbonyl)cyclopropanecarboxylic acid (described in Wessjohann, Ludger A.; Fulhorst, Michael; Zakharova, Svetlana, Pol. J. Chem., 80, 4, 2006, 673-678, 87 mg, 0.55 mmol), WSC (191 mg, 1 mmol) and DMAP (10 mg) were added, and the mixture was stirred at room temperature for one hour. The reaction solution was concentrated, diluted with ethyl acetate, washed with water and brine, and dried over anhydrous magnesium sulfate. Following concentration under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: chloroform/methanol=95/5, 90/10) to obtain 117 mg of the title compound as a light brown solid (65%). The solvent was evaporated under reduced pressure The resulting residue was dissolved in dichloromethane (5 mL) the mixture was stirred at room temperature for one hour The reaction solution was concentrated diluted with ethyl acetate washed with water and brine dried over anhydrous magnesium sulfate concentration under reduced pressure the residue was purified by silica gel column chromatography (elution solvent: chloroform/methanol=95/5, 90/10)

反应条件: temp:-50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Add isobutylchloroformate (0.41 mL, 3.16 mmol) and N-methylmorpholine (0.35 mL, 3.16 mmol) to a solution of (+/−)-trans-cyclopropane-1,2-dicarboxylic acid monoethyl ester (0.50 g, 3.161 mmol) in tetrahydrofuran (21 mL) at −50° C. Stir for 5 minutes and then filter into a slurry of sodium borohydride (0.084 g, 2.21 mmol) in tetrahydrofuran (9 mL) and cool to −50° C. Warm to room temperature over night and then add 9 mL of water. Remove tetrahydrofuran under reduced pressure and extract aqueous layer with diethyl ether (3×20 mL). Wash combined organic layers with saturated aqueous sodium chloride and dry over magnesium sulfate. Concentrate under reduced pressure and subject residue to silica gel chromatography eluting with 25-65% ethyl acetate in hexanes to provide the desired compound (0.224 g, 49.1%). Warm to room temperature over night Remove tetrahydrofuran under reduced pressure and extract aqueous layer with diethyl ether (3×20 mL) Wash dry over magnesium sulfate Concentrate under reduced pressure eluting with 25-65% ethyl acetate in hexanes

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

实验步骤: Add a solution of 0.709 g (17.72 mmol) sodium hydroxide in 7.38 mL ethanol to a solution of (+/−)-trans-cyclopropane-1,2-dicarboxylic acid diethyl ester (3.00 g, 16.11 mmol) in 36.9 mL acetone. Stir at room temperature for 24 hours. Pour reaction mixture into 100 mL water and extract with ethyl acetate (1×70 mL). Acidify the aqueous layer with 5N HCl and concentrate under reduced pressure. Add ethyl acetate and filter the resulting slurry. Concentrate the filtrate under reduced pressure to provide the desired compound (2.26 g, 88.7%). Pour extract with ethyl acetate (1×70 mL) concentrate under reduced pressure Add ethyl acetate and filter the resulting slurry Concentrate the filtrate under reduced pressure

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

实验步骤: Add 1-hydroxybenzotriazole (HOBT) (1.46 g, 10.8118 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (2.07 g, 10.8118 mmol) to a solution of crude trans-cyclopropane-1,2-dicarboxylic acid monoethyl ester (1.71 g, 10.8118 mmol) in N,N-dimethylformamide (11 mL). Stir for 30 minutes. Add triethylamine (2.26 mL, 16.2177 mmol) and methylpropylamine (1.11 mL, 10.8118 mmol) and stir for 16 hours. Quench with 10% aqueous potassium carbonate (10 mL) and extract with ethyl acetate (3×50 mL). Combine the organic extracts, wash with 0.1 N aqueous citric acid (30 mL) and 1 N lithium chloride, dry (magnesium sulfate), concentrate and crystallize with xylenes to give the desired compound (1.02 g, 50%). Quench with 10% aqueous potassium carbonate (10 mL) extract with ethyl acetate (3×50 mL) Combine the organic extracts, wash with 0.1 N aqueous citric acid (30 mL) and 1 N lithium chloride dry (magnesium sulfate) concentrate crystallize with xylenes

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

实验步骤: The same operation as in Example (93a) was performed using tert-butyl 5-amino-1,3-dihydro-2H-inden-2-carboxylate (described in Andronati, S. A.; Krys'ko, A. A.; Chugunov, B. M.; Kabanova, T. A.; Artemenko, A. G.; Russ. J. Org. Chem.; 42; 8; 2006; 1174-1182, 0.19 g, 0.77 mmol), trans-2-(ethoxycarbonyl)cyclopropanecarboxylic acid (described in Wessjohann, Ludger A.; Fulhorst, Michael; Zakharova, Svetlana; Pol. J. Chem.; 80; 4; 2006; 673-678, 182 mg, 1.15 mmol), WSC hydrochloride (0.29 g, 1.5 mmol), DMAP (10 mg) and dichloromethane (20 mL). Purification by silica gel column chromatography (elution solvent: hexane/ethyl acetate=4/1, 2/1, 1/1, 1/2) gave 0.24 g of the title compound as a colorless solid (81%). Purification by silica gel column chromatography (elution solvent: hexane/ethyl acetate=4/1, 2/1, 1/1, 1/2)

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

实验步骤: tert-Butyl 5-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-1,3-dihydro-2H-isoindole-2-carboxylate (described in Example (92a), 0.17 g, 0.42 mmol) was dissolved in dichloromethane (3 mL) and methanol (1 mL). A 4 N hydrochloric acid/ethyl acetate solution (15 ml, 60 mmol) was added, followed by stirring for 20 minutes. The solvent was evaporated under reduced pressure. The resulting residue was dissolved in dichloromethane (5 mL) and DMA (5 mL). trans-2-(Ethoxycarbonyl)cyclopropanecarboxylic acid (described in Wessjohann, Ludger A.; Fulhorst, Michael; Zakharova, Svetlana, Pol. J. Chem., 80, 4, 2006, 673-678, 87 mg, 0.55 mmol), WSC (191 mg, 1 mmol) and DMAP (10 mg) were added, and the mixture was stirred at room temperature for one hour. The reaction solution was concentrated, diluted with ethyl acetate, washed with water and brine, and dried over anhydrous magnesium sulfate. Following concentration under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: chloroform/methanol=95/5, 90/10) to obtain 117 mg of the title compound as a light brown solid (65%). The solvent was evaporated under reduced pressure The resulting residue was dissolved in dichloromethane (5 mL) the mixture was stirred at room temperature for one hour The reaction solution was concentrated diluted with ethyl acetate washed with water and brine dried over anhydrous magnesium sulfate concentration under reduced pressure the residue was purified by silica gel column chromatography (elution solvent: chloroform/methanol=95/5, 90/10)

反应条件: temp:-50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Add isobutylchloroformate (0.41 mL, 3.16 mmol) and N-methylmorpholine (0.35 mL, 3.16 mmol) to a solution of (+/−)-trans-cyclopropane-1,2-dicarboxylic acid monoethyl ester (0.50 g, 3.161 mmol) in tetrahydrofuran (21 mL) at −50° C. Stir for 5 minutes and then filter into a slurry of sodium borohydride (0.084 g, 2.21 mmol) in tetrahydrofuran (9 mL) and cool to −50° C. Warm to room temperature over night and then add 9 mL of water. Remove tetrahydrofuran under reduced pressure and extract aqueous layer with diethyl ether (3×20 mL). Wash combined organic layers with saturated aqueous sodium chloride and dry over magnesium sulfate. Concentrate under reduced pressure and subject residue to silica gel chromatography eluting with 25-65% ethyl acetate in hexanes to provide the desired compound (0.224 g, 49.1%). Warm to room temperature over night Remove tetrahydrofuran under reduced pressure and extract aqueous layer with diethyl ether (3×20 mL) Wash dry over magnesium sulfate Concentrate under reduced pressure eluting with 25-65% ethyl acetate in hexanes

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

实验步骤: Add a solution of 0.709 g (17.72 mmol) sodium hydroxide in 7.38 mL ethanol to a solution of (+/−)-trans-cyclopropane-1,2-dicarboxylic acid diethyl ester (3.00 g, 16.11 mmol) in 36.9 mL acetone. Stir at room temperature for 24 hours. Pour reaction mixture into 100 mL water and extract with ethyl acetate (1×70 mL). Acidify the aqueous layer with 5N HCl and concentrate under reduced pressure. Add ethyl acetate and filter the resulting slurry. Concentrate the filtrate under reduced pressure to provide the desired compound (2.26 g, 88.7%). Pour extract with ethyl acetate (1×70 mL) concentrate under reduced pressure Add ethyl acetate and filter the resulting slurry Concentrate the filtrate under reduced pressure

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

实验步骤: Add 1-hydroxybenzotriazole (HOBT) (1.46 g, 10.8118 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (2.07 g, 10.8118 mmol) to a solution of crude trans-cyclopropane-1,2-dicarboxylic acid monoethyl ester (1.71 g, 10.8118 mmol) in N,N-dimethylformamide (11 mL). Stir for 30 minutes. Add triethylamine (2.26 mL, 16.2177 mmol) and methylpropylamine (1.11 mL, 10.8118 mmol) and stir for 16 hours. Quench with 10% aqueous potassium carbonate (10 mL) and extract with ethyl acetate (3×50 mL). Combine the organic extracts, wash with 0.1 N aqueous citric acid (30 mL) and 1 N lithium chloride, dry (magnesium sulfate), concentrate and crystallize with xylenes to give the desired compound (1.02 g, 50%). Quench with 10% aqueous potassium carbonate (10 mL) extract with ethyl acetate (3×50 mL) Combine the organic extracts, wash with 0.1 N aqueous citric acid (30 mL) and 1 N lithium chloride dry (magnesium sulfate) concentrate crystallize with xylenes

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

实验步骤: To a solution of diethyl trans-1,2-cyclopropanedicarboxylate (110 mg, 0.59 mmol) in ethanol (3 mL) is added aqueous 1M NaOH (0.65 mL, 0.65 mmol) and the mixture is stirred at room temperature for 48 hours. To this mixture is added 0.65 mL of aqueous 1M HCl and the solvent is removed under reduced pressure to afford the title compound. the solvent is removed under reduced pressure