88157-42-0

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1,1-Cyclopropane dicarboxylic acid-1-methyl ester (4 g, 27.8 mmol) was mixed with DIPEA (6 ml, 34.4 mmol) in THF (50 ml) and stirred at a 0° C. for 10 min. To the reaction was slowly added ethyl chloroformate (2.7 ml, 28.1 mmol). The reaction was stirred for 1.5 hours and allowed to warm to ambient temperature. The reaction was then re-cooled to 0° C. and NaBH4 (1.6 g, 42.3 mmol) was slowly added, followed by the addition of methanol (3 ml, 74.2 mmol). The reaction was allowed to warm to ambient temperature over 2 h. Then the reaction was diluted with EtOAc and water. The aqueous layer was separated and extracted with EtOAc three times. The combined organic layers were washed with water, then brine, dried over (MgSO4), filtered, and concentrated to afford the title compound. 1H NMR (500 MHz, CDCl3): δ 3.70 (s, 3H), 3.60 (s, 2H), 1.25 (m, 2H), 0.85 (m, 2H). The reaction was stirred for 1.5 hours to warm to ambient temperature The reaction was then re-cooled to 0° C. to warm to ambient temperature over 2 h The aqueous layer was separated extracted with EtOAc three times The combined organic layers were washed with water brine, dried over (MgSO4) filtered concentrated

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The compound (9.0 g) obtained in Referential Example 161 and triethylamine (9.7 ml) were dissolved in tetrahydrofuran (180 ml), and the solution was cooled to −10° C., to which isobutyl chloroformate (9.1 ml) was added dropwise, and the resultant mixture was stirred for 1 hour. On the other hand, sodium borohydride (7.1 g) was dissolved in tetrahydrofuran (100 ml)-water (25 ml) and cooled with ice. While removing insoluble matter by filtration, the solution prepared previously was added dropwise, and the resultant mixture was stirred at the same temperature for 1 hour. The reaction mixture was poured into a cooled 10% aqueous solution of citric acid to conduct extraction with ethyl acetate. After the extract was washed with saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The resultant residue was purified by column chromatography on silica gel (ethyl acetate:hexane=1:9-2:1) to obtain the title compound (4.25 g). was added dropwise cooled with ice While removing insoluble matter by filtration the solution prepared previously was added dropwise extraction with ethyl acetate After the extract was washed with saturated aqueous solution of sodium chloride dried over anhydrous sodium sulfate the solvent was distilled off under reduced pressure The resultant residue was purified by column chromatography on silica gel (ethyl acetate:hexane=1:9-2:1)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of LDA (115 mmol) in THF (300 mL), at −78° C., a solution of 1-hydroxymethyl-cyclopropanecarboxylic acid methyl ester (5 g, 28.4 mmol) in CH3CN (5.91 mL, 115 mmol) is added. The reaction is allowed to reach rt. At this point it is quenched with 1N HCl (200 mL) and extracted with EtOAc (200 mL×3). It is then dried and evaporated to give 3-(1-hydroxymethyl-cyclopropyl)-3-oxo-propionitrile. 1H NMR (400 MHz, DMSO-d6) δ ppm 4.26 (s, 2H) 4.03 (s, 1H) 3.58 (br. s., 2H) 1.15-1.16 (m, 2H) 0.92-0.95 (m, 2H). to reach rt At this point it is quenched with 1N HCl (200 mL) extracted with EtOAc (200 mL×3) It is then dried evaporated

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of cyclopropane-1,1-dicarboxylic acid methyl ester (9 g, 62.4 mmol) in THF (180 mL), is cooled to 0° C. and triethylamine (9.7 mL, 69.6 mmol) and 3-methyl-butyryl chloride (9.1 mL, 9.6 mmol) are added and the reaction stirred for 1 h. In a separate flask, sodium borohydride (7.1 g, 188 mmol) is dissolved in THF (100 mL)/H2O (25 mL) and cooled to 0° C. The mixed anhydride is filtered through a sintered funnel to remove salts from previous reaction and added to the flask containing sodium borohydride and the reaction stirred for 1 h at 0° C. 1 N HCl is added and the product is extracted with EtOAc and then with CCl3H/iPrOH. It is then purified via FCC eluting with Heptane/EtOAc (100:0 to 20:80) to give 1-hydroxymethyl-cyclopropanecarboxylic acid methyl ester. 1H NMR (400 MHz, DMSO-d6) δ ppm 4.61 (t, J=5.81 Hz, 1H) 3.59 (s, 3H) 3.55 (d, J=6.06 Hz, 2H) 1.01 (d, J=3.03 Hz, 2H) 1.01 (d, J=10.36 Hz, 1H) 0.87 (d, J=3.03 Hz, 1H) 0.85-0.88 (m, 1H). The mixed anhydride is filtered through a sintered funnel to remove salts from previous reaction added to the flask the reaction stirred for 1 h at 0° C the product is extracted with EtOAc It is then purified via FCC eluting with Heptane/EtOAc (100:0 to 20:80)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: By using 4-bromophenol (1.33 g) and methyl 1-(hydroxymethyl)cyclopropane carboxylate (663 mg), the procedure was carried out in the same manner as in Reference example 2-1) to obtain methyl 1-[(4-bromophenoxy)methyl]cyclopropane carboxylate (1.03 g).

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In tetrahydrofuran (26 mL) was dissolved 5-bromo-4-methylpyridin-2-ol (1.3 g), methyl 1-(hydroxymethyl)cyclopropanecarboxylate (1.08 g) and triphenylphosphine (2.72 g), and 40% diethyl azodicarboxylate-toluene solution (4.72 mL) was added dropwise to the solution at 0° C. The mixture was stirred at 70° C. for 4 hours. The reaction mixture was cooled to room temperature, water and ethyl acetate were added to the mixture, and the organic layer was washed with a saturated brine and dried over anhydrous sodium sulfate. After concentrating the mixture under reduced pressure, the obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=99:1 to 99:5) to obtain methyl 1-{[(5-bromo-4-methylpyridin-2-yl)oxy]-methyl}cyclopropanecarboxylate (2.08 g). was added dropwise to the solution at 0° C The reaction mixture was cooled to room temperature the organic layer was washed with a saturated brine dried over anhydrous sodium sulfate After concentrating the mixture under reduced pressure the obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=99:1 to 99:5)

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In tetrahydrofuran (26 mL) was dissolved 5-bromo-4-methylpyridin-2-ol (1.3 g), methyl 1-(hydroxymethyl)cyclopropanecarboxylate (1.08 g) and triphenylphosphine (2.72 g), and 40% diethyl azodicarboxylate-toluene solution (4.72 mL) was added dropwise to the solution at 0° C. The mixture was stirred at 70° C. for 4 hours. The reaction mixture was cooled to room temperature, water and ethyl acetate were added to the mixture, and the organic layer was washed with a saturated brine and dried over anhydrous sodium sulfate. After concentrating the mixture under reduced pressure, the obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=99:1 to 99:5) to obtain methyl 1-{[(5-bromo-4-methylpyridin-2-yl)oxy]-methyl}cyclopropanecarboxylate (2.08 g). was added dropwise to the solution at 0° C The reaction mixture was cooled to room temperature the organic layer was washed with a saturated brine dried over anhydrous sodium sulfate After concentrating the mixture under reduced pressure the obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=99:1 to 99:5)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of LDA (115 mmol) in THF (300 mL), at −78° C., a solution of 1-hydroxymethyl-cyclopropanecarboxylic acid methyl ester (5 g, 28.4 mmol) in CH3CN (5.91 mL, 115 mmol) is added. The reaction is allowed to reach rt. At this point it is quenched with 1N HCl (200 mL) and extracted with EtOAc (200 mL×3). It is then dried and evaporated to give 3-(1-hydroxymethyl-cyclopropyl)-3-oxo-propionitrile. 1H NMR (400 MHz, DMSO-d6) δ ppm 4.26 (s, 2 H) 4.03 (s, 1 H) 3.58 (br. s., 2 H) 1.15-1.16 (m, 2 H) 0.92-0.95 (m, 2 H). to reach rt At this point it is quenched with 1N HCl (200 mL) extracted with EtOAc (200 mL×3) It is then dried evaporated

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of cyclopropane-1,1-dicarboxylic acid methyl ester (9 g, 62.4 mmol) in THF (180 mL), is cooled to 0° C. and triethylamine (9.7 mL, 69.6 mmol) and 3-methyl-butyryl chloride (9.1 mL, 9.6 mmol) are added and the reaction stirred for 1 h. In a separate flask, sodium borohydride (7.1 g, 188 mmol) is dissolved in THF (100 mL)/H2O (25 mL) and cooled to 0° C. The mixed anhydride is filtered through a sintered funnel to remove salts from previous reaction and added to the flask containing sodium borohydride and the reaction stirred for 1 h at 0° C. 1N HCl is added and the product is extracted with EtOAc and then with CCl3H/iPrOH. It is then purified via FCC eluting with Heptane/EtOAc (100:0 to 20:80) to give 1-hydroxymethyl-cyclopropanecarboxylic acid methyl ester. 1H NMR (400 MHz, DMSO-d6) δ ppm 4.61 (t, J=5.81 Hz, 1 H) 3.59 (s, 3 H) 3.55 (d, J=6.06 Hz, 2 H) 1.01 (d, J=3.03 Hz, 2 H) 1.01 (d, J=10.36 Hz, 1 H) 0.87 (d, J=3.03 Hz, 1 H) 0.85-0.88 (m, 1 H). The mixed anhydride is filtered through a sintered funnel to remove salts from previous reaction added to the flask the reaction stirred for 1 h at 0° C the product is extracted with EtOAc It is then purified via FCC eluting with Heptane/EtOAc (100:0 to 20:80)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of LDA (115 mmol) in THF (300 mL), at −78° C., a solution of 1-hydroxymethyl-cyclopropanecarboxylic acid methyl ester (5 g, 28.4 mmol) in CH3CN (5.91 mL, 115 mmol) is added. The reaction is allowed to reach rt. At this point it is quenched with 1N HCl (200 mL) and extracted with EtOAc (200 mL×3). It is then dried and evaporated to give 3-(1-hydroxymethyl-cyclopropyl)-3-oxo-propionitrile. 1H NMR (400 MHz, DMSO-d6) δ ppm 4.26 (s, 2 H) 4.03 (s, 1 H) 3.58 (br. s., 2 H) 1.15-1.16 (m, 2 H) 0.92-0.95 (m, 2 H). to reach rt At this point it is quenched with 1N HCl (200 mL) extracted with EtOAc (200 mL×3) It is then dried evaporated