methyl 4-(3-hydroxypropyl)benzoate

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

Procedure: A solution of 4-(3-hydroxy-propyl)-benzoic acid methyl ester (11.98 g) and 1,1′-carbonyldiimidazole (9.0 g, 55.50 mmol) in CH3CN (200 mL) was stirred at room temperature for 1.5 h. Allyl bromide (20 mL) was added and the reaction mixture was heated under reflux for 20 h. The reaction mixture was cooled to room temperature and saturated aqueous NaHCO3was added. The aqueous solution was washed with EtOAc (3×) and the organic solutions were combined, dried (MgSO4), filtered and concentrated. Purification by medium pressure chromatography (9:1 hexanes:EtOAc) provided the title compound of Preparation 4. the reaction mixture was heated under reflux for 20 h saturated aqueous NaHCO3was added The aqueous solution was washed with EtOAc (3×) dried (MgSO4) filtered concentrated Purification by medium pressure chromatography (9:1 hexanes:EtOAc) provided

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

Procedure: A solution of 4-(3-hydroxy-prop-1-ynyl)-benzoic acid methyl ester (12.65 g) in EtOAc (75 mL) and MeOH (75 mL) was hydrogenated at 50 psi on a Parr shaker in the presence of 10% palladium on carbon (2 g) for 24 h. The catalyst was removed by filtration through Celite® and the filtrate was concentrated. The reaction was repeated by adding 10% palladium on carbon (2 g) and hydrogenating on a Parr shaker for 24 h. After filtering through Celite®, the solution was concentrated in vacuo to provide 4-(3-hydroxy-propyl)-benzoic acid methyl ester (11.98 g). The catalyst was removed by filtration through Celite® the filtrate was concentrated by adding 10% palladium on carbon (2 g) After filtering through Celite® the solution was concentrated in vacuo

Conditions: temp:-15.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-(3-Hydroxy-propyl)-benzoic acid methyl ester (1.27 g, 6.5 mmol) and triethylamine (1 ml, 7.1 mmol) are dissolved in dichloromethane (30 ml), cooled to −15° C., methanesulfonylchloride (510 μl, 6.5 mmol) is added and stirred at room temperature for 4 h. The reaction mixture is diluted with dichloromethane, washed with potassiumhydrogensulfoate solution and potassiumcarbonate solution, the organic phase is dried over Na2SO4 and concentrated in vacuo. LC (method F): tR=1.88 min; Mass spectrum (ESP): m/z=295 [M+Na]+. washed with potassiumhydrogensulfoate solution and potassiumcarbonate solution the organic phase is dried over Na2SO4 concentrated in vacuo

Conditions: temp:-15.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-(3-Hydroxy-propyl)-benzoic acid methyl ester (1.27 g, 6.5 mmol) and triethylamine (1 ml, 7.1 mmol) are dissolved in dichloromethane (30 ml), cooled to −15° C., methanesulfonylchloride (510 μl, 6.5 mmol) is added and stirred at room temperature for 4 h. The reaction mixture is diluted with dichloromethane, washed with potassiumhydrogensulfoate solution and potassiumcarbonate solution, the organic phase is dried over Na2SO4 and concentrated in vacuo. LC (method F): tR=1.88 min; Mass spectrum (ESP): m/z=295 [M+Na]+. washed with potassiumhydrogensulfoate solution and potassiumcarbonate solution the organic phase is dried over Na2SO4 concentrated in vacuo

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

Procedure: 4-(2-Carboxy-ethyl)-benzoic acid methyl ester (5 g, 24 mmol) is dissolved in THF (50 ml), N,N-carbonyldiimidazole (4.25 g, 26.2 mmol) is added and stirred for 1 h at room temperature. Then sodium borohydride (1.9 g, 50 mmol) and water (10 ml) are added to the reaction mixture and stirred for additional 1 h. 1M HCl is added dropwise to the reaction mixture, extracted with ethyl acetate, the organic phase is dried and concentrated in vacuo. The residue is chromatographed on silica gel (dichloromethane/methanol) to afford the title compound. LC (method F): tR=1.83 min; Mass spectrum (ESI+): m/z=195 [M+H]+. stirred for additional 1 h extracted with ethyl acetate the organic phase is dried concentrated in vacuo The residue is chromatographed on silica gel (dichloromethane/methanol)

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

Procedure: A solution of 4-(3-hydroxy-propyl)-benzoic acid methyl ester (11.98 g) and 1,1′-carbonyldiimidazole (9.0 g, 55.50 mmol) in CH3CN (200 mL) was stirred at room temperature for 1.5 h. Allyl bromide (20 mL) was added and the reaction mixture was heated under reflux for 20 h. The reaction mixture was cooled to room temperature and saturated aqueous NaHCO3 was added. The aqueous solution was washed with EtOAc (3×) and the organic solutions were combined, dried (MgSO4), filtered and concentrated. Purification by medium pressure chromatography (9:1 hexanes:EtOAc) provided the title compound of Preparation 4. the reaction mixture was heated under reflux for 20 h The aqueous solution was washed with EtOAc (3×) dried (MgSO4) filtered concentrated Purification by medium pressure chromatography (9:1 hexanes:EtOAc) provided

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

Procedure: A solution of 4-(3-hydroxy-prop-1-ynyl)-benzoic acid methyl ester (12.65 g) in EtOAc (75 mL) and MeOH (75 mL) was hydrogenated at 50 psi on a Parr shaker in the presence of 10% palladium on carbon (2 g) for 24 h. The catalyst was removed by filtration through Celite® and the filtrate was concentrated. The reaction was repeated by adding 10% palladium on carbon (2 g) and hydrogenating on a Parr shaker for 24 h. After filtering through Celite®, the solution was concentrated in vacuo to provide 4-(3-hydroxy-propyl)-benzoic acid methyl ester (11.98 g). The catalyst was removed by filtration through Celite® the filtrate was concentrated by adding 10% palladium on carbon (2 g) After filtering through Celite® the solution was concentrated in vacuo

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

Procedure: A solution of 4-(3-hydroxy-propyl)-benzoic acid methyl ester (11.98 g) and 1,1′-carbonyldiimidazole (9.0 g, 55.50 mmol) in CH3CN (200 mL) was stirred at room temperature for 1.5 h. Allyl bromide (20 mL) was added and the reaction mixture was heated under reflux for 20 h. The reaction mixture was cooled to room temperature and saturated aqueous NaHCO3was added. The aqueous solution was washed with EtOAc (3×) and the organic solutions were combined, dried (MgSO4), filtered and concentrated. Purification by medium pressure chromatography (9:1 hexanes:EtOAc) provided the title compound of Preparation 4. the reaction mixture was heated under reflux for 20 h saturated aqueous NaHCO3was added The aqueous solution was washed with EtOAc (3×) dried (MgSO4) filtered concentrated Purification by medium pressure chromatography (9:1 hexanes:EtOAc) provided

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

Procedure: A solution of 4-(3-hydroxy-prop-1-ynyl)-benzoic acid methyl ester (12.65 g) in EtOAc (75 mL) and MeOH (75 mL) was hydrogenated at 50 psi on a Parr shaker in the presence of 10% palladium on carbon (2 g) for 24 h. The catalyst was removed by filtration through Celite® and the filtrate was concentrated. The reaction was repeated by adding 10% palladium on carbon (2 g) and hydrogenating on a Parr shaker for 24 h. After filtering through Celite®, the solution was concentrated in vacuo to provide 4-(3-hydroxy-propyl)-benzoic acid methyl ester (11.98 g). The catalyst was removed by filtration through Celite® the filtrate was concentrated by adding 10% palladium on carbon (2 g) After filtering through Celite® the solution was concentrated in vacuo

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

Procedure: A solution of 4-(3-hydroxy-prop-1-ynyl)-benzoic acid methyl ester (12.65 g) in EtOAc (75 mL) and MeOH (75 mL) was hydrogenated at 50 psi on a Parr shaker in the presence of 10% palladium on carbon (2 g) for 24 h. The catalyst was removed by filtration through Celite® and the filtrate was concentrated. The reaction was repeated by adding 10% palladium on carbon (2 g) and hydrogenating on a Parr shaker for 24 h. After filtering through Celite®, the solution was concentrated in vacuo to provide 4-(3-hydroxy-propyl)-benzoic acid methyl ester (11.98 g). The catalyst was removed by filtration through Celite® the filtrate was concentrated by adding 10% palladium on carbon (2 g) After filtering through Celite® the solution was concentrated in vacuo

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

Procedure: Preparation of methyl-(4-cyano-4-ethoxycarbonylbutyl)benzoate ##STR21## To a 250 mL flame dried round bottom flask were charged 10.0 g (51.5 mmol) of methyl 4-(-hydroxypropyl)benzoate and 5.48 mL (51.5 mmol) of ethyl cyanoacetate dissolved in 40 mL of anhydrous tetrahydrofuran (THF). To this solution was then added dropwise to a solution of 20.2 g (77 mmol) of triphenylphosphine and 12.1 mL (77 mmol) of diethyl azodicarboxylate dissolved in 60 mL of anhydrous THF. After the addition, the reaction was stirred at ambient temperature for 1.5 hours. The volatiles were removed in vacuo and the crude oil was dissolved in 300 mL of EtOAc, washed with brine, dried over Na2SO4, and removed in vacuo. This crude oil was then purified on silica gel using a Waters Prep LC 2000 eluting with a gradient of 1:1 MeCl2 /Hex to 100% MeCl2 to give 6.0 g (40%) of methyl 4-(4-cyano-4-ethoxycarbonylbutyl)benzoate as a pale yellow oil. flame dried round bottom flask After the addition The volatiles were removed in vacuo the crude oil was dissolved in 300 mL of EtOAc washed with brine dried over Na2SO4 removed in vacuo This crude oil was then purified on silica gel using a Waters Prep LC 2000 eluting with a gradient of 1:1 MeCl2 /Hex to 100% MeCl2

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

Procedure: Preparation of methyl-(4-cyano-4-ethoxycarbonylbutyl)benzoate ##STR21## To a 250 mL flame dried round bottom flask were charged 10.0 g (51.5 mmol) of methyl 4-(-hydroxypropyl)benzoate and 5.48 mL (51.5 mmol) of ethyl cyanoacetate dissolved in 40 mL of anhydrous tetrahydrofuran (THF). To this solution was then added dropwise to a solution of 20.2 g (77 mmol) of triphenylphosphine and 12.1 mL (77 mmol) of diethyl azodicarboxylate dissolved in 60 mL of anhydrous THF. After the addition, the reaction was stirred at ambient temperature for 1.5 hours. The volatiles were removed in vacuo and the crude oil was dissolved in 300 mL of EtOAc, washed with brine, dried over Na2SO4, and removed in vacuo. This crude oil was then purified on silica gel using a Waters Prep LC 2000 eluting with a gradient of 1:1 MeCl2 /Hex to 100% MeCl2 to give 6.0 g (40%) of methyl 4-(4-cyano-4-ethoxycarbonylbutyl)benzoate as a pale yellow oil. flame dried round bottom flask After the addition The volatiles were removed in vacuo the crude oil was dissolved in 300 mL of EtOAc washed with brine dried over Na2SO4 removed in vacuo This crude oil was then purified on silica gel using a Waters Prep LC 2000 eluting with a gradient of 1:1 MeCl2 /Hex to 100% MeCl2