methyl 1-(hydroxymethyl)cyclopentane-1-carboxylate

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

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

Procedure: To a solution of cyclopentane-1,1-dicarboxylic acid methyl ester (1.00 g, 5.81 mmol) and triethylamine (808 uL, 5.81 mmol) in THF (15 mL) is added isobutyl chloroformate (750 uL, 5.81 mmol) at 0° C. The mixture is stirred at 0° C. for 20 minutes. The mixture is filtrated, and the filtrate is added to a suspension of NaBH4 (242 mg) in THF (15 mL) at 0° C. The mixture is stirred at 0° C. for 3 hours and at room temperature for 12 hours. To the mixture, H2O is added and the mixture is extracted with EtOAc. The organic layer is dried over MgSO4, and concentrated under reduced pressure. The obtained residue is purified by silica gel column chromatography to give 1-hydroxymethyl-cyclopentanecarboxylic acid methyl ester (433 mg, 47%); TLC (hexane/EtOAc, 1:1) Rf 0.43. The mixture is filtrated the filtrate is added to a suspension of NaBH4 (242 mg) in THF (15 mL) at 0° C The mixture is stirred at 0° C. for 3 hours and at room temperature for 12 hours To the mixture, H2O is added the mixture is extracted with EtOAc The organic layer is dried over MgSO4 concentrated under reduced pressure The obtained residue is purified by silica gel column chromatography

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

Procedure: To a solution of cyclopentane-1,1-dicarboxylic acid methyl ester (1.00 g, 5.81 mmol) and triethylamine (808 uL, 5.81 mmol) in THF (15 mL) is added isobutyl chloroformate (750 uL, 5.81 mmol) at 0° C. The mixture is stirred at 0° C. for 20 minutes. The mixture is filtrated, and the filtrate is added to a suspension of NaBH4 (242 mg) in THF (15 mL) at 0° C. The mixture is stirred at 0° C. for 3 hours and at room temperature for 12 hours. To the mixture, H2O is added and the mixture is extracted with EtOAc. The organic layer is dried over MgSO4, and concentrated under reduced pressure. The obtained residue is purified by silica gel column chromatography to give 1-hydroxymethyl-cyclopentanecarboxylic acid methyl ester (433 mg, 47%); TLC (hexane/EtOAc, 1:1) Rf 0.43. The mixture is filtrated the filtrate is added to a suspension of NaBH4 (242 mg) in THF (15 mL) at 0° C The mixture is stirred at 0° C. for 3 hours and at room temperature for 12 hours To the mixture, H2O is added the mixture is extracted with EtOAc The organic layer is dried over MgSO4 concentrated under reduced pressure The obtained residue is purified by silica gel column chromatography

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

Procedure: To a solution of cyclopentane-1,1-dicarboxylic acid methyl ester (1.00 g, 5.81 mmol) and triethylamine (808 uL, 5.81 mmol) in THF (15 mL) is added isobutyl chloroformate (750 uL, 5.81 mmol) at 0° C. The mixture is stirred at 0° C. for 20 minutes. The mixture is filtrated, and the filtrate is added to a suspension of NaBH4 (242 mg) in THF (15 mL) at 0° C. The mixture is stirred at 0° C. for 3 hours and at room temperature for 12 hours. To the mixture, H2O is added and the mixture is extracted with EtOAc. The organic layer is dried over MgSO4, and concentrated under reduced pressure. The obtained residue is purified by silica gel column chromatography to give 1-hydroxymethyl-cyclopentanecarboxylic acid methyl ester (433 mg, 47%); TLC (hexane/EtOAc, 1:1) Rf 0.43. The mixture is filtrated the filtrate is added to a suspension of NaBH4 (242 mg) in THF (15 mL) at 0° C The mixture is stirred at 0° C. for 3 hours and at room temperature for 12 hours To the mixture, H2O is added the mixture is extracted with EtOAc The organic layer is dried over MgSO4 concentrated under reduced pressure The obtained residue is purified by silica gel column chromatography

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

Procedure: To a solution of cyclopentane-1,1-dicarboxylic acid methyl ester (1.00 g, 5.81 mmol) and triethylamine (808 uL, 5.81 mmol) in THF (15 mL) is added isobutyl chloroformate (750 uL, 5.81 mmol) at 0° C. The mixture is stirred at 0° C. for 20 minutes. The mixture is filtrated, and the filtrate is added to a suspension of NaBH4 (242 mg) in THF (15 ml) at 0° C. The mixture is stirred at 0° C. for 3 hours and at room temperature for 12 hours. To the mixture, H2O is added and the mixture is extracted with AcOEt. The organic layer is dried over MgSO4, and concentrated under reduced pressure. The obtained residue is purified by silica gel column chromatography to give 1-hydroxymethyl-cyclopentanecarboxylic acid methyl ester (433 mg, 47%); TLC (hexane/AcOEt, 1:1) Rf 0.43, 1H NMR (400 MHz, chloroform-d) δ ppm 1.61-1.77 (m, 6H), 1.93-2.00 (m, 2H), 2.53 (m, 1H), 3.57 (d, 2H), 3.72 (s, 3H). The mixture is filtrated the filtrate is added to a suspension of NaBH4 (242 mg) in THF (15 ml) at 0° C The mixture is stirred at 0° C. for 3 hours and at room temperature for 12 hours To the mixture, H2O is added the mixture is extracted with AcOEt The organic layer is dried over MgSO4 concentrated under reduced pressure The obtained residue is purified by silica gel column chromatography

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

Procedure: To a solution of cyclopentane-1,1-dicarboxylic acid methyl ester (1.00 g, 5.81 mmol) and triethylamine (808 uL, 5.81 mmol) in THF (15 mL) is added isobutyl chloroformate (750 uL, 5.81 mmol) at 0° C. The mixture is stirred at 0° C. for 20 minutes. The mixture is filtrated, and the filtrate is added to a suspension of NaBH4 (242 mg) in THF (15 ml) at 0° C. The mixture is stirred at 0° C. for 3 hours and at room temperature for 12 hours. To the mixture, H2O is added and the mixture is extracted with AcOEt. The organic layer is dried over MgSO4, and concentrated under reduced pressure. The obtained residue is purified by silica gel column chromatography to give 1-hydroxymethyl-cyclopentanecarboxylic acid methyl ester (433 mg, 47%); TLC (hexane/AcOEt, 1:1) Rf 0.43, 1H NMR (400 MHz, chloroform-d) δ ppm 1.61-1.77 (m, 6H), 1.93-2.00 (m, 2H), 2.53 (m, 1H), 3.57 (d, 2H), 3.72 (s, 3H). The mixture is filtrated the filtrate is added to a suspension of NaBH4 (242 mg) in THF (15 ml) at 0° C The mixture is stirred at 0° C. for 3 hours and at room temperature for 12 hours To the mixture, H2O is added the mixture is extracted with AcOEt The organic layer is dried over MgSO4 concentrated under reduced pressure The obtained residue is purified by silica gel column chromatography

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

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

Procedure: The title compound was prepared according to the procedure described in Step 2 of EXAMPLE 7 using tert-butyl 4-{[(4-hydroxy-1,2-benzisoxazol-3-yl)oxy]methyl}piperidine-1-carboxylate (EXAMPLE 17, step 2) and methyl 1-(hydroxymethyl)cyclopentanecarboxylate (EXAMPLE 51, Step 1) instead of 4-(benzyloxy)-1,2-benzisoxazol-3-ol and tert-butyl 4-(2-hydroxyethyl)piperidine-1-carboxylate.

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

Procedure: To a solution of methyl 1-formylcyclopentanecarboxylate (954 mg, 6.11 mmol, Synthesis 1997, 32-34) in ethanol (10 mL) was added sodium tetrahydroborate (104 mg, 2.75 mmol) at ambient temperature. After being stirred for 30 min, the mixture was concentrated in vacuo to give an oil. The residual oil was dissolved with ethyl acetate, and the solution was washed with brine. The extract was dried over magnesium sulfate and concentrated in vacuo to afford 806 mg (83%) of the title compound as a colorless oil. The crude product was used in the next step without further purification. the mixture was concentrated in vacuo to give an oil the solution was washed with brine The extract was dried over magnesium sulfate concentrated in vacuo

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

Procedure: To a solution of methyl 1-formylcyclopentanecarboxylate (954 mg, 6.11 mmol, Synthesis 1997, 32-34) in ethanol (10 mL) was added sodium tetrahydroborate (104 mg, 2.75 mmol) at ambient temperature. After being stirred for 30 min, the mixture was concentrated in vacuo to give an oil. The residual oil was dissolved with ethyl acetate, and the solution was washed with brine. The extract was dried over magnesium sulfate and concentrated in vacuo to afford 806 mg (83%) of the title compound as a colorless oil. The crude product was used in the next step without further purification. the mixture was concentrated in vacuo to give an oil the solution was washed with brine The extract was dried over magnesium sulfate concentrated in vacuo

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

Procedure: To a solution of cyclopentane-1,1-dicarboxylic acid methyl ester (1.00 g, 5.81 mmol) and triethylamine (808 uL, 5.81 mmol) in THF (15 mL) is added isobutyl chloroformate (750 uL, 5.81 mmol) at 0° C. The mixture is stirred at 0° C. for 20 minutes. The mixture is filtrated, and the filtrate is added to a suspension of NaBH4 (242 mg) in THF (15 ml) at 0° C. The mixture is stirred at 0° C. for 3 hours and at room temperature for 12 hours. To the mixture, H2O is added and the mixture is extracted with AcOEt. The organic layer is dried over MgSO4, and concentrated under reduced pressure. The obtained residue is purified by silica gel column chromatography to give 1-hydroxymethyl-cyclopentanecarboxylic acid methyl ester (433 mg, 47%); TLC (hexane/AcOEt, 1:1) Rf 0.43, 1H NMR (400 MHz, chloroform-d) 8 ppm 1.61-1.77 (m, 6H), 1.93-2.00 (m, 2H), 2.53 (m, 1H), 3.57 (d, 2H), 3.72 (s, 3H). The mixture is filtrated the filtrate is added to a suspension of NaBH4 (242 mg) in THF (15 ml) at 0° C The mixture is stirred at 0° C. for 3 hours and at room temperature for 12 hours To the mixture, H2O is added the mixture is extracted with AcOEt The organic layer is dried over MgSO4 concentrated under reduced pressure The obtained residue is purified by silica gel column chromatography

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

Procedure: To a solution of cyclopentane-1,1-dicarboxylic acid methyl ester (1.00 g, 5.81 mmol) and triethylamine (808 uL, 5.81 mmol) in THF (15 mL) is added isobutyl chloroformate (750 uL, 5.81 mmol) at 0° C. The mixture is stirred at 0° C. for 20 minutes. The mixture is filtrated, and the filtrate is added to a suspension of NaBH4 (242 mg) in THF (15 ml) at 0° C. The mixture is stirred at 0° C. for 3 hours and at room temperature for 12 hours. To the mixture, H2O is added and the mixture is extracted with AcOEt. The organic layer is dried over MgSO4, and concentrated under reduced pressure. The obtained residue is purified by silica gel column chromatography to give 1-hydroxymethyl-cyclopentanecarboxylic acid methyl ester (433 mg, 47%); TLC (hexane/AcOEt, 1:1) Rf 0.43, 1H NMR (400 MHz, chloroform-d) δ ppm 1.61-1.77 (m, 6H), 1.93-2.00 (m, 2H), 2.53 (m, 1H), 3.57 (d, 2H), 3.72 (s, 3H). The mixture is filtrated the filtrate is added to a suspension of NaBH4 (242 mg) in THF (15 ml) at 0° C The mixture is stirred at 0° C. for 3 hours and at room temperature for 12 hours To the mixture, H2O is added the mixture is extracted with AcOEt The organic layer is dried over MgSO4 concentrated under reduced pressure The obtained residue is purified by silica gel column chromatography