ethyl 2-(hydroxymethyl)cyclopropane-1-carboxylate

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

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

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 1-(biphenyl-4-ylmethyl)-4,6-difluoro-5-iodo-2-(methylsulfonyl)-1H-benzimidazole (Intermediate 5, 0.500 g, 0.954 mmol) and 2-hydroxymethyl-cyclopropanecarboxylic acid ethyl ester (Intermediate 10, 0.550 g, 3.81 mmol) in 3.2 mL of DMF was added DBU (0.575 mL, 3.81 mmol) dropwise via syringe. The reaction was heated at 80° C. for 2 h, and then diluted with EtOAc and H2O. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The resulting crude residue was purified on silica gel (eluted 2-15% then 15-20% EtOAc/hexanes: gradient elution) to furnish the desired product. LCMS: calculated for C27H23F2IN2O3 588.38, observed m/e 588.9 (M+H)+ (Rt 2.51/4 min). The layers were separated the aqueous layer was extracted with EtOAc The combined organic layers were washed with brine dried over Na2SO4 filtered concentrated The resulting crude residue was purified on silica gel ( eluted 2-15% 15-20% EtOAc/hexanes: gradient elution)

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

Procedure: Ethyl 2-formyl-1-cyclopropanecarboxylate (2 ml, 15.11 mmol) was dissolved in methanol (35 ml) and cooled to 0° C. under N2. Sodium borohydride (1.2 g, 31.7 mmol) was added in portions and resulting solution stirred at 0° C. for 2 h. The solution was then diluted by the dropwise addition of water, followed by the addition of EtOAc (100 mL). The aqueous layer was separated and extracted with EtOAc (2×50 mL). The combined organic layers were washed with brine, dried over sodium sulphate and concentrated in vacuo to give the title compound. TLC: 20% EtOAc/hexanes, high Rf: 0.35, low Rf: 0.3. resulting solution The aqueous layer was separated extracted with EtOAc (2×50 mL) The combined organic layers were washed with brine dried over sodium sulphate concentrated in vacuo

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

Procedure: To a solution of ethyl 2-formylcyclopropanecarboxylate (2.00 g, 13.68 mmol) in absolute ethanol (55.0 mL) at room temperature and under an anhydrous atmosphere was added sodium borohydride (0.776 g, 20.53 mmol) in one portion. The reaction mixture was stirred at room temperature for 5 h then quenched with an aqueous pH 7 phosphate buffer solution (100 mL) and the ethanol was removed under reduced pressure. The aqueous layer was mixed with methylene chloride (100 mL), decanted, then extracted with methylene chloride (2×100 mL). The combined organic extracts were then successively washed with an aqueous pH 7 phosphate buffer solution (70 mL) and brine (70 mL), dried over MgSO4, filtered, and concentrated to give ethyl 2-(hydroxymethyl)cyclopropanecarboxylate (C-5) as a light yellow oil (1.334 g, 68% yield), which was used for the next step without additional purification. MS (M+1): m/e 145. then quenched with an aqueous pH 7 phosphate buffer solution (100 mL) the ethanol was removed under reduced pressure The aqueous layer was mixed with methylene chloride (100 mL) decanted extracted with methylene chloride (2×100 mL) The combined organic extracts were then successively washed with an aqueous pH 7 phosphate buffer solution (70 mL) and brine (70 mL) dried over MgSO4 filtered concentrated

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

Procedure: To a solution of ethyl 2-formylcyclopropanecarboxylate (2.00 g, 13.68 mmol) in absolute ethanol (55.0 mL) at room temperature and under an anhydrous atmosphere was added sodium borohydride (0.776 g, 20.53 mmol) in one portion. The reaction mixture was stirred at room temperature for 5 h then quenched with an aqueous pH 7 phosphate buffer solution (100 mL) and the ethanol was removed under reduced pressure. The aqueous layer was mixed with methylene chloride (100 mL), decanted, then extracted with methylene chloride (2×100 mL). The combined organic extracts were then successively washed with an aqueous pH 7 phosphate buffer solution (70 mL) and brine (70 mL), dried over MgSO4, filtered, and concentrated to give ethyl 2-(hydroxymethyl)cyclopropanecarboxylate (C-5) as a light yellow oil (1.334 g, 68% yield), which was used for the next step without additional purification. MS (M+1): m/e 145. then quenched with an aqueous pH 7 phosphate buffer solution (100 mL) the ethanol was removed under reduced pressure The aqueous layer was mixed with methylene chloride (100 mL) decanted extracted with methylene chloride (2×100 mL) The combined organic extracts were then successively washed with an aqueous pH 7 phosphate buffer solution (70 mL) and brine (70 mL) dried over MgSO4 filtered concentrated

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

Procedure: To a solution of ethyl 2-formylcyclopropanecarboxylate in methanol (0.7 M) was added at −0° C. sodium borohydride portionwise. The resulting reaction mixture was stirred at 0° C. for 30 min and then at RT for 1.5 h. The reaction was quenched with sat. aq. NH4Cl and then extracted with ether. The combined organic extracts were washed with water and brine, dried over MgSO4, and filtered. Concentrated of the filtrate in vacuo afforded the title compound as a colorless oil. The resulting reaction mixture at RT for 1.5 h The reaction was quenched with sat. aq. NH4Cl extracted with ether The combined organic extracts were washed with water and brine dried over MgSO4 filtered Concentrated of the filtrate in vacuo

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 1-(biphenyl-4-ylmethyl)-4,6-difluoro-5-iodo-2-(methylsulfonyl)-1H-benzimidazole (Intermediate 5, 0.500 g, 0.954 mmol) and 2-hydroxymethyl-cyclopropanecarboxylic acid ethyl ester (Intermediate 10, 0.550 g, 3.81 mmol) in 3.2 mL of DMF was added DBU (0.575 mL, 3.81 mmol) dropwise via syringe. The reaction was heated at 80° C. for 2 h, and then diluted with EtOAc and H2O. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The resulting crude residue was purified on silica gel (eluted 2-15% then 15-20% EtOAc/hexanes: gradient elution) to furnish the desired product. LCMS: calculated for C27H23F2IN2O3 588.38, observed m/e 588.9 (M+H)+ (Rt 2.51/4 min). The layers were separated the aqueous layer was extracted with EtOAc The combined organic layers were washed with brine dried over Na2SO4 filtered concentrated The resulting crude residue was purified on silica gel ( eluted 2-15% 15-20% EtOAc/hexanes: gradient elution)

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 1-(biphenyl-4-ylmethyl)-4,6-difluoro-5-iodo-2-(methylsulfonyl)-1H-benzimidazole (Intermediate 5, 0.500 g, 0.954 mmol) and 2-hydroxymethyl-cyclopropanecarboxylic acid ethyl ester (Intermediate 10, 0.550 g, 3.81 mmol) in 3.2 mL of DMF was added DBU (0.575 mL, 3.81 mmol) dropwise via syringe. The reaction was heated at 80° C. for 2 h, and then diluted with EtOAc and H2O. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The resulting crude residue was purified on silica gel (eluted 2-15% then 15-20% EtOAc/hexanes: gradient elution) to furnish the desired product. LCMS: calculated for C27H23F2IN2O3 588.38, observed m/e 588.9 (M+H)+ (Rt 2.51/4 min). The layers were separated the aqueous layer was extracted with EtOAc The combined organic layers were washed with brine dried over Na2SO4 filtered concentrated The resulting crude residue was purified on silica gel ( eluted 2-15% 15-20% EtOAc/hexanes: gradient elution)

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

Procedure: Ethyl 2-formyl-1-cyclopropanecarboxylate (2 ml, 15.11 mmol) was dissolved in methanol (35 ml) and cooled to 0° C. under N2. Sodium borohydride (1.2 g, 31.7 mmol) was added in portions and resulting solution stirred at 0° C. for 2 h. The solution was then diluted by the dropwise addition of water, followed by the addition of EtOAc (100 mL). The aqueous layer was separated and extracted with EtOAc (2×50 mL). The combined organic layers were washed with brine, dried over sodium sulphate and concentrated in vacuo to give the title compound. TLC: 20% EtOAc/hexanes, high Rf: 0.35, low Rf: 0.3. resulting solution The aqueous layer was separated extracted with EtOAc (2×50 mL) The combined organic layers were washed with brine dried over sodium sulphate concentrated in vacuo

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

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