反-2-己烯酸

反应条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A flask equipped with an overhead stirred, thermometer and addition funnel was placed under a nitrogen atmosphere then charged with (E)-hex-2-enoic acid (89.8 g, 787 mmol), EDCI (158.3 g, 826 mmol), HOBt (112.0 g, 826 mmol) and IPAc (890 mL) then cooled to 0±5° C. The addition funnel was charged with NMM (99.1 mL, 1.6 mol) which was then added to the reaction mixture maintaining the temperature at 0±5° C. The mixture was stirred for 30 minutes then cyclopropylamine (60.0 mL, 866 mmol) was added and the reaction allowed to warm to 25±5° C. over 16 hours. The reaction mixture was washed by adding hydrochloric acid (500 mL, 1.0 N) and the mixture stirred vigorously for 30 minutes then allowed to sit for 30 minutes; the layers were separated and the washing procedure repeated. Sodium hydroxide (500 mL, 1.0 N) was added and then the mixture stirred vigorously for 30 minutes then allowed to sit for 30 minutes; the layers were separated and base wash procedure repeated. Water (500 mL) was added and then the mixture stirred vigorously for 30 minutes then allowed to sit for 30 minutes; the layers were separated and the wash procedure repeated. The combined organic phases were concentrated under reduced pressure to ⅓ original volume then IPAc (600 mL) was added; this was repeated two times when a white precipate formed. The slurry was then concentrated under atmospheric pressure to ⅔ original volume then cooled to 50±5° C. N-heptane (890 mL) was slowly added while the reaction was cooled to −5±5° C. and held at this temperature for 4 hours. The solid was filtered, washed with cold n-heptane (2×250 mL) and dried to provide the title amide (82.4 g, 68%) as a fine white solid. A flask equipped with an overhead thermometer and addition funnel was then added to the reaction mixture maintaining the temperature at 0±5° C The mixture was stirred for 30 minutes to warm to 25±5° C. over 16 hours The reaction mixture was washed by adding hydrochloric acid (500 mL, 1.0 N) the mixture stirred vigorously for 30 minutes the layers were separated Sodium hydroxide (500 mL, 1.0 N) was added the mixture stirred vigorously for 30 minutes to sit for 30 minutes the layers were separated base wash procedure Water (500 mL) was added the mixture stirred vigorously for 30 minutes to sit for 30 minutes the layers were separated The combined organic phases were concentrated under reduced pressure IPAc (600 mL) was added formed The slurry was then concentrated under atmospheric pressure then cooled to 50±5° C N-heptane (890 mL) was slowly added while the reaction was cooled to −5±5° C. held at this temperature for 4 hours The solid was filtered washed with cold n-heptane (2×250 mL) dried

反应条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A flask equipped with an overhead stirrer, thermometer and addition funnel was placed under a nitrogen atmosphere then charged with trans-2-hexenoic acid (69.8 g, 611 mmol), water (420 mL) and acetone (420 mL). Sodium bicarbonate (NaHCO3, 224 g, 2.66 mol) was then added portion-wise keeping the reaction temperature at 25±5° C. Once all of the sodium bicarbonate had been added, a solution of OXONE® (454 g, 738 mmol) in 4×10−4 M ethylenediaminetetraacetic acid disodium salt dehydrate (Na2EDTA; 1.32 L) was charged to the addition funnel and added over 90 minutes keeping the reaction temperature at 25±5° C. and the pH between 9.5 and 7.5. The reaction mixture was then allowed to stir for 16 h, after which time no (E)-hex-2-enoic acid was observed by HPLC analysis. The mixture was cooled to 0±5° C., acidified to pH 2 with 6 N HCl (515 mL, 2.8 mol) and extracted with ethyl acetate (EtOAc; 3×250 mL). The combined organic phases were dried over sodium sulfate (Na2SO4), filtered then concentrated under reduced pressure to provide the title compound (60.4 g, 76%) as a yellow oil. A flask equipped with an overhead stirrer thermometer and addition funnel at 25±5° C added over 90 minutes at 25±5° C. extracted with ethyl acetate (EtOAc; 3×250 mL) The combined organic phases were dried over sodium sulfate (Na2SO4) filtered then concentrated under reduced pressure

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Prepared as above from 150.0 mg (0.35 mmol) of the pyridyl ketone, 308.2 mg (0.70 mmol) of (4-carboxy-butyl)triphenylphosphonium bromide, and 1.4 mL (1.4 mmol) of 1.0 M t-BuOK in 1.5 mL of THF at 0° C. for :1.5 hr. Flash chromatography followed by preparative HPLC with MeOH-AcOH-CH2Cl2 (3.5:1.5:95) furnished 107.9 mg 60.2%) of (E)-hexenoic acid and 35.4 mg (19.8%) of (Z)-hexenoic acid (E/Z=3:1). The title (E)-isomer was characterized as follows: mp 86-90° C.; 1H NMR (CDCl3) δ8.55 (br s, 1H), 8.45 (d, J=4.7 Hz, 1H), 8.25 (s, 1H), 8.04 (d, J=8.1 Hz, 2H), 7.47 (d, J=8.0 Hz, 1H), 7.29 (d, J=8.2 Hz, 2H), 7.21 (m, 1H), 7.12 (distorted t, J=~5.1 Hz, 1H), 6.19 (t, J=7.5 Hz, 1H), 3.44 (dt, J=7.0, 6.7, Hz, 2H), 2.34 (t J=7.1 Hz, 2H), 2.25 (dt, J=7.4, 7.3 Hz, 2H), 1.68-0.82 (m, 19H); FDMS 516 (M+1). Anal. (C31H37N3O4) C, H, N.

反应条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A solution of N,N-dicyclohexylcarbodiimide (0.18 g, 0.8 mmol) in dichloromethane (10 cm3) is added to a solution of (E)-hex-2-enoic acid (0.07 g, 0.7 mmol), 1-[4-(trans-5-hydroxydioxan-2-yl) phenyl]-4-pentylbicyclo[2.2.2]octane (0.25 g, 0.7 mmol), 4-(dimethylamino) pyridine (0.04 g) in dichloromethane (20 cm3), cooled in an ice bath (0° C.) under an atmosphere of nitrogen. The reaction mixture is stirred overnight, filtered to remove precipitated material and the filtrate was evaporated down under reduced pressure. The crude product is purified by column chromatography on silica gel using a 9:1 petroleum ether (40-60° C.)/ethyl acetate mixture as eluent, followed by recrystallisation from ethanol to yield the desired ester. filtered to remove precipitated material the filtrate was evaporated down under reduced pressure The crude product is purified by column chromatography on silica gel using a 9:1 petroleum ether (40-60° C.)/ethyl acetate mixture as eluent followed by recrystallisation from ethanol

反应条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A solution of N,N-dicyclohexylcarbodiimide (0.22 g, 1.1 mmol) in dichloromethane (10 cm3) is added to a solution of (E)-hex-2-enoic acid (0.10 g, 0.9 mmol), 1-[4-(5-hydroxypyrimidin-2-yl) phenyl]-4-pentylbicyclo[2.2.2]octane (0.25 g, 0.9 mmol), 4-(dimethylamino)pyridine (0.04 g) in dichloromethane (20 cm3), cooled in an ice bath (0° C.) under an atmosphere of nitrogen. The reaction mixture is stirred overnight, filtered to remove precipitated material and the filtrate is evaporated down under reduced pressure. The crude product is purified by column chromatography on silica gel using a 9:1 petroleum ether (40-60° C.)/ethyl acetate mixture as eluent, followed by recrystallisation from ethanol to yield the desired ester (0.15 g, 45%). filtered to remove precipitated material the filtrate is evaporated down under reduced pressure The crude product is purified by column chromatography on silica gel using a 9:1 petroleum ether (40-60° C.)/ethyl acetate mixture as eluent followed by recrystallisation from ethanol

反应条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A solution of N,N-dicyclohexylcarbodiimide (0.22 g, 1.1 mmol) in dichloromethane (10 cm3) is added to a solution of (E)-hex-2-enoic acid (0.10 g, 0.9 mmol), 1-[4-(trans-4-hydroxycyclohexyl) phenyl]-4-pentylbicyclo[2.2.2]octane (0.32 g, 0.9 mmol), 4-(dimethylamino) pyridine (0.04 g) in dichloromethane (20 cm3), cooled in an ice bath (0° C.) under an atmosphere of nitrogen. The reaction mixture is stirred overnight, filtered to remove precipitated material and the filtrate is evaporated down under reduced pressure. The crude product is purified by column chromatography on silica gel using a 9:1 petroleum ether (40-60° C.)/ethyl acetate mixture as eluent, followed by recrystallization from ethanol to yield the desired ester (0.26 g, 64%). filtered to remove precipitated material the filtrate is evaporated down under reduced pressure The crude product is purified by column chromatography on silica gel using a 9:1 petroleum ether (40-60° C.)/ethyl acetate mixture as eluent followed by recrystallization from ethanol

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution (100 mL) of (2E)-hex-2-enoic acid (5.0 g) in tetrahydrofuran were added dropwise under ice-cooling oxalyl chloride (3.76 mL) and N,N-dimethylformamide (1 mL). The mixture was stirred at the same temperature for 30 min, methanol (10 mL) was gradually added to the reaction mixture, and the mixture was stirred at room temperature for 2 hr. The solvent was evaporated under reduced pressure, and the residue was treated with 6% aqueous sodium hydrogencarbonate solution, and extracted with diethyl ether. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure (50 Torr, water bath 10° C.) to give the title compound as a colorless oil (yield 5.67 g, about 100%). the mixture was stirred at room temperature for 2 hr The solvent was evaporated under reduced pressure the residue was treated with 6% aqueous sodium hydrogencarbonate solution extracted with diethyl ether The extract was washed with saturated brine dried over anhydrous sodium sulfate concentrated under reduced pressure (50 Torr, water bath 10° C.)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution (100 mL) of (2E)-hex-2-enoic acid (5.0 g) in tetrahydrofuran were added dropwise under ice-cooling oxalyl chloride (3.76 mL) and N,N-dimethylformamide (1 mL). The mixture was stirred at the same temperature for 30 min, methanol (10 mL) was gradually added to the reaction mixture, and the mixture was stirred at room temperature for 2 hr. The solvent was evaporated under reduced pressure, and the residue was treated with 6% aqueous sodium hydrogencarbonate solution, and extracted with diethyl ether. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure (50 Torr, water bath 10° C.) to give the title compound as a colorless oil (yield 5.67 g, about 100%). the mixture was stirred at room temperature for 2 hr The solvent was evaporated under reduced pressure the residue was treated with 6% aqueous sodium hydrogencarbonate solution extracted with diethyl ether The extract was washed with saturated brine dried over anhydrous sodium sulfate concentrated under reduced pressure (50 Torr, water bath 10° C.)

反应条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A flask equipped with an overhead stirred, thermometer and addition funnel was placed under a nitrogen atmosphere then charged with (E)-hex-2-enoic acid (89.8 g, 787 mmol), EDCI (158.3 g, 826 mmol), HOBt (112.0 g, 826 mmol) and IPAc (890 mL) then cooled to 0±5° C. The addition funnel was charged with NMM (99.1 mL, 1.6 mol) which was then added to the reaction mixture maintaining the temperature at 0±5° C. The mixture was stirred for 30 minutes then cyclopropylamine (60.0 mL, 866 mmol) was added and the reaction allowed to warm to 25±5° C. over 16 hours. The reaction mixture was washed by adding hydrochloric acid (500 mL, 1.0 N) and the mixture stirred vigorously for 30 minutes then allowed to sit for 30 minutes; the layers were separated and the washing procedure repeated. Sodium hydroxide (500 mL, 1.0 N) was added and then the mixture stirred vigorously for 30 minutes then allowed to sit for 30 minutes; the layers were separated and base wash procedure repeated. Water (500 mL) was added and then the mixture stirred vigorously for 30 minutes then allowed to sit for 30 minutes; the layers were separated and the wash procedure repeated. The combined organic phases were concentrated under reduced pressure to ⅓ original volume then IPAc (600 mL) was added; this was repeated two times when a white precipitate formed. The slimy was then concentrated under atmospheric pressure to ⅔ original volume then cooled to 50±5° C. N-heptane (890 mL) was slowly added while the reaction was cooled to −5±5° C. and held at this temperature for 4 hours. The solid was filtered, washed with cold n-heptane (2×250 mL) and dried to provide compound 37 as a fine white solid. 1H NMR (500 MHz, d6-DMSO) 7.89 (s, 1H), 6.58 (dt, J=15.2, 7.0 Hz, 1H), 5.80 (dt, J=15.2, 1.3 Hz, 1H), 2.70-2.65 (m, 1H), 2.12-2.06 (m, 2H), 1.44-1.37 (m, 2H), 0.88 (t, J=7.3 Hz, 3H), 0.64-0.60 (m, 2H), 0.42-0.38 (m, 2H). A flask equipped with an overhead thermometer and addition funnel was then added to the reaction mixture maintaining the temperature at 0±5° C The mixture was stirred for 30 minutes to warm to 25±5° C. over 16 hours The reaction mixture was washed by adding hydrochloric acid (500 mL, 1.0 N) the mixture stirred vigorously for 30 minutes the layers were separated Sodium hydroxide (500 mL, 1.0 N) was added the mixture stirred vigorously for 30 minutes to sit for 30 minutes the layers were separated base wash procedure Water (500 mL) was added the mixture stirred vigorously for 30 minutes to sit for 30 minutes the layers were separated The combined organic phases were concentrated under reduced pressure IPAc (600 mL) was added formed The slimy was then concentrated under atmospheric pressure then cooled to 50±5° C N-heptane (890 mL) was slowly added while the reaction was cooled to −5±5° C. held at this temperature for 4 hours The solid was filtered washed with cold n-heptane (2×250 mL) dried

反应条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A flask equipped with an overhead stirred, thermometer and addition funnel was placed under a nitrogen atmosphere then charged with (E)-hex-2-enoic acid (89.8 g, 787 mmol), EDCI (158.3 g, 826 mmol), HOBt (112.0 g, 826 mmol) and IPAc (890 mL) then cooled to 0±5° C. The addition funnel was charged with NMM (99.1 mL, 1.6 mol) which was then added to the reaction mixture maintaining the temperature at 0±5° C. The mixture was stirred for 30 minutes then cyclopropylamine (60.0 mL, 866 mmol) was added and the reaction allowed to warm to 25±5° C. over 16 hours. The reaction mixture was washed by adding hydrochloric acid (500 mL, 1.0 N) and the mixture stirred vigorously for 30 minutes then allowed to sit for 30 minutes; the layers were separated and the washing procedure repeated. Sodium hydroxide (500 mL, 1.0 N) was added and then the mixture stirred vigorously for 30 minutes then allowed to sit for 30 minutes; the layers were separated and base wash procedure repeated. Water (500 mL) was added and then the mixture stirred vigorously for 30 minutes then allowed to sit for 30 minutes; the layers were separated and the wash procedure repeated. The combined organic phases were concentrated under reduced pressure to ⅓ original volume then IPAc (600 mL) was added; this was repeated two times when a white precipate formed. The slurry was then concentrated under atmospheric pressure to ⅔ original volume then cooled to 50±5° C. N-heptane (890 mL) was slowly added while the reaction was cooled to −5±5° C. and held at this temperature for 4 hours. The solid was filtered, washed with cold n-heptane (2×250 mL) and dried to provide the title amide (82.4 g, 68%) as a fine white solid. A flask equipped with an overhead thermometer and addition funnel was then added to the reaction mixture maintaining the temperature at 0±5° C The mixture was stirred for 30 minutes to warm to 25±5° C. over 16 hours The reaction mixture was washed by adding hydrochloric acid (500 mL, 1.0 N) the mixture stirred vigorously for 30 minutes the layers were separated Sodium hydroxide (500 mL, 1.0 N) was added the mixture stirred vigorously for 30 minutes to sit for 30 minutes the layers were separated base wash procedure Water (500 mL) was added the mixture stirred vigorously for 30 minutes to sit for 30 minutes the layers were separated The combined organic phases were concentrated under reduced pressure IPAc (600 mL) was added formed The slurry was then concentrated under atmospheric pressure then cooled to 50±5° C N-heptane (890 mL) was slowly added while the reaction was cooled to −5±5° C. held at this temperature for 4 hours The solid was filtered washed with cold n-heptane (2×250 mL) dried

反应条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A flask equipped with an overhead stirred, thermometer and addition funnel was placed under a nitrogen atmosphere then charged with (E)-hex-2-enoic acid (89.8 g, 787 mmol), EDCI (158.3 g, 826 mmol), HOBt (112.0 g, 826 mmol) and IPAc (890 mL) then cooled to 0±5° C. The addition funnel was charged with NMM (99.1 mL, 1.6 mol) which was then added to the reaction mixture maintaining the temperature at 0±5° C. The mixture was stirred for 30 minutes then cyclopropylamine (60.0 mL, 866 mmol) was added and the reaction allowed to warm to 25±5° C. over 16 hours. The reaction mixture was washed by adding hydrochloric acid (500 mL, 1.0 N) and the mixture stirred vigorously for 30 minutes then allowed to sit for 30 minutes; the layers were separated and the washing procedure repeated. Sodium hydroxide (500 mL, 1.0 N) was added and then the mixture stirred vigorously for 30 minutes then allowed to sit for 30 minutes; the layers were separated and base wash procedure repeated. Water (500 mL) was added and then the mixture stirred vigorously for 30 minutes then allowed to sit for 30 minutes; the layers were separated and the wash procedure repeated. The combined organic phases were concentrated under reduced pressure to ⅓ original volume then IPAc (600 mL) was added; this was repeated two times when a white precipate formed. The slurry was then concentrated under atmospheric pressure to ⅔ original volume then cooled to 50±5° C. N-heptane (890 mL) was slowly added while the reaction was cooled to −5±5° C. and held at this temperature for 4 hours. The solid was filtered, washed with cold n-heptane (2×250 mL) and dried to provide the title amide (82.4 g, 68%) as a fine white solid. A flask equipped with an overhead thermometer and addition funnel was then added to the reaction mixture maintaining the temperature at 0±5° C The mixture was stirred for 30 minutes to warm to 25±5° C. over 16 hours The reaction mixture was washed by adding hydrochloric acid (500 mL, 1.0 N) the mixture stirred vigorously for 30 minutes the layers were separated Sodium hydroxide (500 mL, 1.0 N) was added the mixture stirred vigorously for 30 minutes to sit for 30 minutes the layers were separated base wash procedure Water (500 mL) was added the mixture stirred vigorously for 30 minutes to sit for 30 minutes the layers were separated The combined organic phases were concentrated under reduced pressure IPAc (600 mL) was added formed The slurry was then concentrated under atmospheric pressure then cooled to 50±5° C N-heptane (890 mL) was slowly added while the reaction was cooled to −5±5° C. held at this temperature for 4 hours The solid was filtered washed with cold n-heptane (2×250 mL) dried

反应条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A flask equipped with an overhead stirrer, thermometer and addition funnel was placed under a nitrogen atmosphere then charged with trans-2-hexenoic acid (69.8 g, 611 mmol), water (420 mL) and acetone (420 mL). Sodium bicarbonate (NaHCO3, 224 g, 2.66 mol) was then added portion-wise keeping the reaction temperature at 25±5° C. Once all of the sodium bicarbonate had been added, a solution of OXONE® (454 g, 738 mmol) in 4×10−4 M ethylenediaminetetraacetic acid disodium salt dehydrate (Na2EDTA; 1.32 L) was charged to the addition funnel and added over 90 minutes keeping the reaction temperature at 25±5° C. and the pH between 9.5 and 7.5. The reaction mixture was then allowed to stir for 16 h, after which time no (E)-hex-2-enoic acid was observed by HPLC analysis. The mixture was cooled to 0±5° C., acidified to pH 2 with 6 N HCl (515 mL, 2.8 mol) and extracted with ethyl acetate (EtOAc; 3×250 mL). The combined organic phases were dried over sodium sulfate (Na2SO4), filtered then concentrated under reduced pressure to provide the title compound (60.4 g, 76%) as a yellow oil. A flask equipped with an overhead stirrer thermometer and addition funnel at 25±5° C added over 90 minutes at 25±5° C. extracted with ethyl acetate (EtOAc; 3×250 mL) The combined organic phases were dried over sodium sulfate (Na2SO4) filtered then concentrated under reduced pressure