ethyl (1R,2R)-2-hydroxycyclohexane-1-carboxylate

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

Procedure: To ethyl (1R,2R)-2-hydroxycyclohexane-1-carboxylate (166) (1.7 g, 10 mmol) and BF3.EtO2 (280 mg, 250 μL, 2 mmol) in toluene (10 mL) was added dropwise a solution of 3,4-dimethoxyphenethoxy trichloroacetimidate (16) (3.26 g, 10 mmol) in toluene (15 mL). The resultant solution was stirred at ambient temperature for 2 hrs. The reaction mixture was then quenched with water (10 mL), the organic layer was collected, dried over anhydrous MgSO4 and concentrated in vacuo to give 3.71 g (quant. yield) of ethyl (1R,2R)-2-(3,4-dimethoxyphenethoxy)cyclohexane-1-carboxylic acid (167) which was used without further purification in the next step. The reaction mixture was then quenched with water (10 mL) the organic layer was collected dried over anhydrous MgSO4 concentrated in vacuo

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

Procedure: To ethyl (1R,2R)-2-hydroxycyclohexane-1-carboxylate (166) (1.7 g, 10 mmol) and BF3.EtO2 (280 mg, 250 μL, 2 mmol) in toluene (10 mL) was added dropwise a solution of 3,4-dimethoxyphenethoxy trichloroacetimidate (16) (3.26 g, 10 mmol) in toluene (15 mL). The resultant solution was stirred at ambient temperature for 2 hrs. The reaction mixture was then quenched with water (10 mL), the organic layer was collected, dried over anhydrous MgSO4 and concentrated in vacuo to give 3.71 g (quant. yield) of ethyl (1R,2R)-2-(3,4-dimethoxyphenethoxy)cyclohexane-1-carboxylic acid (167) which was used without further purification in the next step. The reaction mixture was then quenched with water (10 mL) the organic layer was collected dried over anhydrous MgSO4 concentrated in vacuo

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

Procedure: Ethyl cyclohexanone-2-carboxylate (85.0 g, 0.5 mole) was dissolved in ethanol (200 ml) and the solution cooled to 0° C. Sodium borohydride (13.2 g, 0.35 mole) suspended in ethanol (80 ml) was added in small portions whilst the temperature was maintained at below 0° C. After stirring for 2 hours at 0° C. the reaction mixture was made faintly acid by the addition of 50% sulphuric acid and filtered. The filtrate was concentrated in vacuo, taken up in ether and washed with sodium bicarbonate solution. The organic phase was dried over magnesium sulphate and evaporated in vacuo. The residue was chromatographed on silica-gel, eluting initially with 3:1 hexane/ethyl acetate followed by 2:1 hexane/ethyl acetate to give 21.5 g of cis- and 10.0 g of trans-ethyl 2-hydroxycyclohexanecarboxylate. was added in small portions whilst the temperature was maintained at below 0° C filtered The filtrate was concentrated in vacuo washed with sodium bicarbonate solution The organic phase was dried over magnesium sulphate evaporated in vacuo The residue was chromatographed on silica-gel eluting initially with 3:1 hexane/ethyl acetate

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

Procedure: Ethyl cyclohexanone-2-carboxylate (85.0 g, 0.5 mole) was dissolved in ethanol (200 ml) and the solution cooled to 0° C. Sodium borohydride (13.2 g, 0.35 mole) suspended in ethanol (80 ml) was added in small portions whilst the temperature was maintained at below 0° C. After stirring for 2 hours at 0° C. the reaction mixture was made faintly acid by the addition of 50% sulphuric acid and filtered. The filtrate was concentrated in vacuo, taken up in ether and washed with sodium bicarbonate solution. The organic phase was dried over magnesium sulphate and evaporated in vacuo. The residue was chromatographed on silica-gel, eluting initially with 3:1 hexane/ethyl acetate followed by 2:1 hexane/ethyl acetate to give 21.5 g of cis- and 10.0 g of trans-ethyl 2-hydroxycyclohexanecarboxylate. was added in small portions whilst the temperature was maintained at below 0° C filtered The filtrate was concentrated in vacuo washed with sodium bicarbonate solution The organic phase was dried over magnesium sulphate evaporated in vacuo The residue was chromatographed on silica-gel eluting initially with 3:1 hexane/ethyl acetate

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

Procedure: To ethyl (1R,2R)-2-hydroxycyclohexane-1-carboxylate (166) (1.7 g, 10 mmol) and BF3.EtO2 (280 mg, 250 μL, 2 mmol) in toluene (10 mL) was added dropwise a solution of 3,4-dimethoxyphenethoxy trichloroacetimidate (16) (3.26 g, 10 mmol) in toluene (15 mL). The resultant solution was stirred at ambient temperature for 2 hrs. The reaction mixture was then quenched with water (10 mL), the organic layer was collected, dried over anhydrous MgSO4 and concentrated in vacuo to give 3.71 g (quant. yield) of ethyl (1R,2R)-2-(3,4-dimethoxyphenethoxy)cyclohexane-1-carboxylic acid (167) which was used without further purification in the next step. The reaction mixture was then quenched with water (10 mL) the organic layer was collected dried over anhydrous MgSO4 concentrated in vacuo

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

Procedure: To ethyl (1R,2R)-2-hydroxycyclohexane-1-carboxylate (166) (1.7 g, 10 mmol) and BF3.EtO2 (280 mg, 250 μL, 2 mmol) in toluene (10 mL) was added dropwise a solution of 3,4-dimethoxyphenethoxy trichloroacetimidate (16) (3.26 g, 10 mmol) in toluene (15 mL). The resultant solution was stirred at ambient temperature for 2 hrs. The reaction mixture was then quenched with water (10 mL), the organic layer was collected, dried over anhydrous MgSO4 and concentrated in vacuo to give 3.71 g (quant. yield) of ethyl (1R,2R)-2-(3,4-dimethoxyphenethoxy)cyclohexane-1-carboxylic acid (167) which was used without further purification in the next step. The reaction mixture was then quenched with water (10 mL) the organic layer was collected dried over anhydrous MgSO4 concentrated in vacuo

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

Procedure: To a one-liter four-necked flask were added 102.5 g (595 mmol) of ethyl (R,R)-2-hydroxycyclohexanecarboxylate and 400 mL of 2-propanol and stirring was started. Hydrazine monohydrate (44.7 g; 893 mmol) was dropped thereinto at 13° C. taking 30 minutes. After the dropping, the mixture was stirred at 80° C. for 9.5 hours. Followed by, heating was stopped and the mixture was cooled to room temperature to precipitate the crystals. The crystals were filtered and washed with a small amount of 2-propanol. The resulting crystals were dried to give 30.10 g of the title compound. The yield was 32%. After the dropping, the mixture was stirred at 80° C. for 9.5 hours Followed by, heating to precipitate the crystals The crystals were filtered washed with a small amount of 2-propanol The resulting crystals were dried

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

Procedure: To ethyl (1R,2R)-2-hydroxycyclohexane-1-carboxylate (166) (1.7 g, 10 mmol) and BF3.EtO2 (280 mg, 250 μL, 2 mmol) in toluene (10 mL) was added dropwise a solution of 3,4-dimethoxyphenethoxy trichloroacetimidate (16) (3.26 g, 10 mmol) in toluene (15 mL). The resultant solution was stirred at ambient temperature for 2 hrs. The reaction mixture was then quenched with water (10 mL), the organic layer was collected, dried over anhydrous MgSO4 and concentrated in vacuo to give 3.71 g (quant. yield) of ethyl (1R,2R)-2-(3,4-dimethoxyphenethoxy)cyclohexane-1-carboxylic acid (167) which was used without further purification in the next step. The reaction mixture was then quenched with water (10 mL) the organic layer was collected dried over anhydrous MgSO4 concentrated in vacuo

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

Procedure: Ethyl cyclohexanone-2-carboxylate (85.0 g, 0.5 mole) was dissolved in ethanol (200 ml) and the solution cooled to 0° C. Sodium borohydride (13.2 g, 0.35 mole) suspended in ethanol (80 ml) was added in small portions whilst the temperature was maintained at below 0° C. After stirring for 2 hours at 0° C. the reaction mixture was made faintly acid by the addition of 50% sulphuric acid and filtered. The filtrate was concentrated in vacuo, taken up in ether and washed with sodium bicarbonate solution. The organic phase was dried over magnesium sulphate and evaporated in vacuo. The residue was chromatographed on silica-gel, eluting initially with 3:1 hexane/ethyl acetate followed by 2:1 hexane/ethyl acetate to give 21.5 g of cis- and 10.0 g of trans-ethyl 2-hydroxycyclohexanecarboxylate. was added in small portions whilst the temperature was maintained at below 0° C filtered The filtrate was concentrated in vacuo washed with sodium bicarbonate solution The organic phase was dried over magnesium sulphate evaporated in vacuo The residue was chromatographed on silica-gel eluting initially with 3:1 hexane/ethyl acetate