methyl cyclobutanecarboxylate

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

Procedure: 1-(4-Bromobutyl)cyclobutane carboxylic acid methyl ester was prepared from 1,4-dibromobutane and cyclobutane carboxylic acid methyl ester using the general procedure described in example 168.

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

Procedure: A solution of diisopropylamine (1.05 mL, 7.5 mmol) in THF (5 mL) was colled to −10° C. and a solution of n-butyl lithium (2.9 mL, 7.25 mmol) in hexanes was added dropwise while maintaining the temperature below 0° C. After addition, the solution was stirred for 30 min at 0° C. The solution was cooled to −70° C. and a solution of methyl cyclobutane carboxylate (0.57 g, 5 mmol) in THF (2 mL) was added dropwise maintaining the internal temperature between −60 to −70° C. After addition, the reaction mixture was stirred for 30 min at −50 to −60° C. Then, a solution of 4-(1-methyltetrazol-5-yl)benzyl chloride (0.94 g, 4.5 mmol) in THF (5 mL) was added dropwise and the reaction mixture was stirred for 1 h at −60 to −70° C. Then, it was allowed to warm to room temperature and stirred overnight at which point TLC analysis indicated the absence of 4-(1-methyltetrazol-5-yl)benzyl chloride (Note: the product and 4-(1-methyltetrazol-5-yl)benzyl chloride has the same Rf value, however they were differentiated by spraying with PMA). The mixture was poured into a mixture of water (70 mL) and ethyl acetate (70 mL). An emulsion formed and was filtered through celite. The resulting two layers were separated and the aqueous layer was extracted with ethyl acetate (2×50 mL). The combined extracts were washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the solution was concentrated under vacuum and the residue was purified by silica gel chromatography eluting with 1:2 ethyl acetate:hexane to give methyl 1-[[4-(1-methyltetrazol-5-yl)phenyl]methyl]cyclobutane carboxylate (0.42 g, 32%) as a syrup. HR MS: obs. mass, 301.1668. Calcd mass, 301.1664. was colled to −10° C. while maintaining the temperature below 0° C After addition The solution was cooled to −70° C. maintaining the internal temperature between −60 to −70° C After addition the reaction mixture was stirred for 30 min at −50 to −60° C the reaction mixture was stirred for 1 h at −60 to −70° C to warm to room temperature stirred overnight at which point TLC analysis An emulsion formed was filtered through celite The resulting two layers were separated the aqueous layer was extracted with ethyl acetate (2×50 mL) The combined extracts were washed with saturated brine dried over anhydrous magnesium sulfate After filtration the solution was concentrated under vacuum the residue was purified by silica gel chromatography eluting with 1:2 ethyl acetate

Conditions: temp:-20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 27 gm of isopropylcyclohexylamine in 200 ml of dry tetrahydrofuran (THF) was cooled to -20° C. under argon and treated with 115 ml of 1.6 M n-butyl lithium in hexane. The solution was stirred for about 30 min. at -20° C. and then cooled to -70° C. A solution of 14 grams of methyl cyclobutane carboxylate in 100 ml of THF was added dropwise over a one hour period. After the addition was complete, the solution was allowed to warm to near 0° C. and 33 grams of methyl iodide was added rapidly. The reaction mixture was allowed to warm to room temperature and then was poured into a mixture of ether and 1N HCl. The organic layer was separated and combined with a subsequent ethyl acetate extraction of the aqueous layer. The combined organic extracts were washed with dilute sodium sulfite solution, twice with water and dried over sodium sulfate. The solvent was removed by distillation at atmospheric pressure, and the residue was distilled under reduced pressure to give 11.4 grams of methyl 1-methylcyclobutane carboxylate. cooled to -70° C After the addition to warm to near 0° C. to warm to room temperature The organic layer was separated combined with a subsequent ethyl acetate extraction of the aqueous layer The combined organic extracts were washed with dilute sodium sulfite solution, twice with water dried over sodium sulfate The solvent was removed by distillation at atmospheric pressure the residue was distilled under reduced pressure

Conditions: temp:-20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 27 gm of isopropylcyclohexylamine in 200 ml of dry tetrahydrofuran (THF) was cooled to -20° C. under argon and treated with 115 ml of 1.6 M n-butyl lithium in hexane. The solution was stirred for about 30 min. at -20° C. and then cooled to -70° C. A solution of 14 grams of methyl cyclobutane carboxylate in 100 ml of THF was added dropwise over a one hour period. After the addition was complete, the solution was allowed to warm to near 0° C. and 33 grams of methyl iodide was added rapidly. The reaction mixture was allowed to warm to room temperature and then was poured into a mixture of ether and 1N HCl. The organic layer was separated and combined with a subsequent ethyl acetate extraction of the aqueous layer. The combined organic extracts were washed with dilute sodium sulfite solution, twice with water and dried over sodium sulfate. The solvent was removed by distillation at atmospheric pressure, and the residue was distilled under reduced pressure to give 11.4 grams of methyl 1-methylcyclobutane carboxylate. cooled to -70° C After the addition to warm to near 0° C. to warm to room temperature The organic layer was separated combined with a subsequent ethyl acetate extraction of the aqueous layer The combined organic extracts were washed with dilute sodium sulfite solution, twice with water dried over sodium sulfate The solvent was removed by distillation at atmospheric pressure the residue was distilled under reduced pressure

Conditions: temp:-20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 27 gm of isopropylcyclohexylamine in 200 ml of dry tetrahydrofuran (THF) was cooled to -20° C. under argon and treated with 115 ml of 1.6M n-butyl lithium in hexane. The solution was stirred for about 30 min. at -20° C. and then cooled to -70° C. A solution of 14 grams of methyl cyclobutane carboxylate in 100 ml of THF was added dropwise over a one hour period. After the addition was complete, the solution was allowed to warm to near 0° C. and 33 grams of methyl iodide was added rapidly. The reaction mixture was allowed to warm to room temperature and then was poured into a mixture of ether and 1N HCl. The organic layer was separated and combined with a subsequent ethyl acetate extraction of the aqueous layer. The combined organic extracts were washed with dilute sodium sulfite solution, twice with water and dried over sodium sulfate. The solvent was removed by distillation at atmospheric pressure, and the residue was distilled under reduced pressure to give 11.4 grams of methyl 1-methylcyclobutane carboxylate. cooled to -70° C After the addition to warm to near 0° C. to warm to room temperature The organic layer was separated combined with a subsequent ethyl acetate extraction of the aqueous layer The combined organic extracts were washed with dilute sodium sulfite solution, twice with water dried over sodium sulfate The solvent was removed by distillation at atmospheric pressure the residue was distilled under reduced pressure

Conditions: temp:-20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 27 gm of isopropylcyclohexylamine in 200 ml of dry tetrahydrofuran (THF) was cooled to -20° C. under argon and treated with 115 ml of 1.6M n-butyl lithium in hexane. The solution was stirred for about 30 min. at -20° C. and then cooled to -70° C. A solution of 14 grams of methyl cyclobutane carboxylate in 100 ml of THF was added dropwise over a one hour period. After the addition was complete, the solution was allowed to warm to near 0° C. and 33 grams of methyl iodide was added rapidly. The reaction mixture was allowed to warm to room temperature and then was poured into a mixture of ether and 1N HCl. The organic layer was separated and combined with a subsequent ethyl acetate extraction of the aqueous layer. The combined organic extracts were washed with dilute sodium sulfite solution, twice with water and dried over sodium sulfate. The solvent was removed by distillation at atmospheric pressure, and the residue was distilled under reduced pressure to give 11.4 grams of methyl 1-methylcyclobutane carboxylate. cooled to -70° C After the addition to warm to near 0° C. to warm to room temperature The organic layer was separated combined with a subsequent ethyl acetate extraction of the aqueous layer The combined organic extracts were washed with dilute sodium sulfite solution, twice with water dried over sodium sulfate The solvent was removed by distillation at atmospheric pressure the residue was distilled under reduced pressure

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

Procedure: 1-(4-Bromobutyl)cyclobutane carboxylic acid methyl ester was prepared from 1,4-dibromobutane and cyclobutane carboxylic acid methyl ester using the general procedure described in example 168.

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

Procedure: A solution of diisopropylamine (1.05 mL, 7.5 mmol) in THF (5 mL) was colled to −10° C. and a solution of n-butyl lithium (2.9 mL, 7.25 mmol) in hexanes was added dropwise while maintaining the temperature below 0° C. After addition, the solution was stirred for 30 min at 0° C. The solution was cooled to −70° C. and a solution of methyl cyclobutane carboxylate (0.57 g, 5 mmol) in THF (2 mL) was added dropwise maintaining the internal temperature between −60 to −70° C. After addition, the reaction mixture was stirred for 30 min at −50 to −60° C. Then, a solution of 4-(1-methyltetrazol-5-yl)benzyl chloride (0.94 g, 4.5 mmol) in THF (5 mL) was added dropwise and the reaction mixture was stirred for 1 h at −60 to −70° C. Then, it was allowed to warm to room temperature and stirred overnight at which point TLC analysis indicated the absence of 4-(1-methyltetrazol-5-yl)benzyl chloride (Note: the product and 4-(1-methyltetrazol-5-yl)benzyl chloride has the same Rf value, however they were differentiated by spraying with PMA). The mixture was poured into a mixture of water (70 mL) and ethyl acetate (70 mL). An emulsion formed and was filtered through celite. The resulting two layers were separated and the aqueous layer was extracted with ethyl acetate (2×50 mL). The combined extracts were washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the solution was concentrated under vacuum and the residue was purified by silica gel chromatography eluting with 1:2 ethyl acetate:hexane to give methyl 1-[[4-(1-methyltetrazol-5-yl)phenyl]methyl]cyclobutane carboxylate (0.42 g, 32%) as a syrup. HR MS: obs. mass, 301.1668. Calcd mass, 301.1664. was colled to −10° C. while maintaining the temperature below 0° C After addition The solution was cooled to −70° C. maintaining the internal temperature between −60 to −70° C After addition the reaction mixture was stirred for 30 min at −50 to −60° C the reaction mixture was stirred for 1 h at −60 to −70° C to warm to room temperature stirred overnight at which point TLC analysis An emulsion formed was filtered through celite The resulting two layers were separated the aqueous layer was extracted with ethyl acetate (2×50 mL) The combined extracts were washed with saturated brine dried over anhydrous magnesium sulfate After filtration the solution was concentrated under vacuum the residue was purified by silica gel chromatography eluting with 1:2 ethyl acetate

Conditions: temp:-20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 27 gm of isopropylcyclohexylamine in 200 ml of dry tetrahydrofuran (THF) was cooled to -20° C. under argon and treated with 115 ml of 1.6 M n-butyl lithium in hexane. The solution was stirred for about 30 min. at -20° C. and then cooled to -70° C. A solution of 14 grams of methyl cyclobutane carboxylate in 100 ml of THF was added dropwise over a one hour period. After the addition was complete, the solution was allowed to warm to near 0° C. and 33 grams of methyl iodide was added rapidly. The reaction mixture was allowed to warm to room temperature and then was poured into a mixture of ether and 1N HCl. The organic layer was separated and combined with a subsequent ethyl acetate extraction of the aqueous layer. The combined organic extracts were washed with dilute sodium sulfite solution, twice with water and dried over sodium sulfate. The solvent was removed by distillation at atmospheric pressure, and the residue was distilled under reduced pressure to give 11.4 grams of methyl 1-methylcyclobutane carboxylate. cooled to -70° C After the addition to warm to near 0° C. to warm to room temperature The organic layer was separated combined with a subsequent ethyl acetate extraction of the aqueous layer The combined organic extracts were washed with dilute sodium sulfite solution, twice with water dried over sodium sulfate The solvent was removed by distillation at atmospheric pressure the residue was distilled under reduced pressure

Conditions: temp:-20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 27 gm of isopropylcyclohexylamine in 200 ml of dry tetrahydrofuran (THF) was cooled to -20° C. under argon and treated with 115 ml of 1.6M n-butyl lithium in hexane. The solution was stirred for about 30 min. at -20° C. and then cooled to -70° C. A solution of 14 grams of methyl cyclobutane carboxylate in 100 ml of THF was added dropwise over a one hour period. After the addition was complete, the solution was allowed to warm to near 0° C. and 33 grams of methyl iodide was added rapidly. The reaction mixture was allowed to warm to room temperature and then was poured into a mixture of ether and 1N HCl. The organic layer was separated and combined with a subsequent ethyl acetate extraction of the aqueous layer. The combined organic extracts were washed with dilute sodium sulfite solution, twice with water and dried over sodium sulfate. The solvent was removed by distillation at atmospheric pressure, and the residue was distilled under reduced pressure to give 11.4 grams of methyl 1-methylcyclobutane carboxylate. cooled to -70° C After the addition to warm to near 0° C. to warm to room temperature The organic layer was separated combined with a subsequent ethyl acetate extraction of the aqueous layer The combined organic extracts were washed with dilute sodium sulfite solution, twice with water dried over sodium sulfate The solvent was removed by distillation at atmospheric pressure the residue was distilled under reduced pressure

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

Procedure: 1-(4-Bromobutyl)cyclobutane carboxylic acid methyl ester was prepared from 1,4-dibromobutane and cyclobutane carboxylic acid methyl ester using the general procedure described in example 168.

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

Procedure: 1-(4-Bromobutyl)cyclobutane carboxylic acid methyl ester was prepared from 1,4-dibromobutane and cyclobutane carboxylic acid methyl ester using the general procedure described in example 168.