(2E,4E)-hexa-2,4-dienoic acid

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 47% (w/w) sodium hydroxide (5.5 g) is added to slurry of sorbic acid (5.6 g, 0.05 mol) in water (100 mL) at 70° C. to give a clear slightly alkaline solution. A solution of zinc chloride (3.4 g, 0.025 mol) in water (50 mL) is added and a precipitate is formed immediately. The mixture is stirred at 70° C. for further 2.5 hours. The precipitate is then filtered and dried to yield 5.5 g (76%) zinc sorbate as a fine white powder. IR absorption bands: 1521 and 1418 cm−1. to give a clear slightly alkaline solution a precipitate is formed immediately The precipitate is then filtered dried

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

Procedure: To the stirred acetone solution of metoprolol base (19.3 mol), acetone (30 l) and sorbic acid (2.12 kg, 18.9 mol) were added at room temperature. The mixture was heated to reflux and the hot solution was filtered. The filtrate was allowed to cool slowly to 0° C. The crystals were centrifugated off, washed with cold acetone (10 l) and dried for three days in vacuo at room temperature to yield 5.95 kg of crystalline (S)-metoprolol. (81% from (4)). The mixture was heated to reflux the hot solution was filtered washed with cold acetone (10 l) dried for three days in vacuo at room temperature

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

Procedure: To the stirred acetone solution of metoprolol base (19.3 mol), acetone (30 l) and sorbic acid (2.12 kg, 18.9 mol) were added at room temperature. The mixture was heated to reflux and the hot solution was filtered. The filtrate was allowed to cool slowly to 0° C. The crystals were centrifugated off, washed with cold acetone (10 l) and dried for three days in vacuo at room temperature to yield 5.95 kg of crystalline (S)-metoprolol. (81% from (4)). The mixture was heated to reflux the hot solution was filtered washed with cold acetone (10 l) dried for three days in vacuo at room temperature

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

Procedure: Preparation of example 90 from the title compound of Example 7 (hydrochloride) (41 mg, 0.131 mmol), (2E,4E)-hexa-2,4-dienoic acid (18 mg, 0.157 mmol), triethylamine (0.055 mL, 0.393 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (60 mg, 0.157 mmol) in CH2Cl2 (0.4 mL) and N,N-dimethylformamide (0.4 mL) was carried out analogously to Example 11. Silica gel chromatography (eluted with 2:1 hexane:acetone), also in an analogous manner, after a final trituration with methanol afforded the title compound (8 mg, 0.022 mmol) as a yellow powder in 16% yield. Silica gel chromatography (eluted with 2:1 hexane:acetone)

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

Procedure: Japanese Unexamined Patent Application Publication No. 54-163516 discloses a process for producing a sorbic acid. In this process, a polyester obtained from ketene and crotonaldehyde is decomposed with hydrochloric acid in the presence of, for example, a urea compound, the resulting decomposition reaction mixture is filtrated and rinsed to yield a crude sorbic acid, followed by addition of an aqueous sodium hydroxide solution to the crude sorbic acid to thereby yield an aqueous sodium sorbate solution, the aqueous sodium sorbate solution is treated with activated carbon, is neutralized and is cooled to thereby crystallize sorbic acid. is filtrated rinsed to yield a crude sorbic acid

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

Procedure: To 31 mg of sorbic acid in 1 ml of tetrahydrofuran are added 40 μl of isobutyl chloroformate followed by 45 μl of N-methylmorpholine whilst cooling with an ice bath. The white suspension is stirred for one minute, then a solution of 100 mg of 6-amino-4-[(3-bromophenyl)amino]-7-[3-(1-methylpiperidin-4-yl)propyloxy]quinazoline in 1.5 ml of pyridine is added. The ice bath is removed and the reaction mixture is stirred overnight. For working up, it is poured onto 20 ml of ice water, stirred for 30 minutes and adjusted to pH 9-10 with a few drops of 2 N sodium hydroxide solution. The aqueous phase is extracted with methylene chloride, the combined organic phases are dried over sodium sulfate and concentrated by evaporation. The resin-like crude product is purified by chromatography over an aluminium oxide column (activity III) with methylene chloride/methanol (99.5:0.5). Yield: 62 mg (52% of theory); Rf value: 0.29 (aluminium oxide, activity III; methylene chloride/methanol=98:2); mass spectrum (EI): m/z=563, 565 [M]+. whilst cooling with an ice bath The ice bath is removed the reaction mixture is stirred overnight it is poured onto 20 ml of ice water stirred for 30 minutes The aqueous phase is extracted with methylene chloride the combined organic phases are dried over sodium sulfate concentrated by evaporation The resin-like crude product is purified by chromatography over an aluminium oxide column (activity III) with methylene chloride/methanol (99.5:0.5)

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

Procedure: Preparation of example 90 from the title compound of Example 7 (hydrochloride) (41 mg, 0.131 mmol), (2E,4E)-hexa-2,4-dienoic acid (18 mg, 0.157 mmol), triethylamine (0.055 mL, 0.393 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (60 mg, 0.157 mmol) in CH2Cl2 (0.4 mL) and N,N-dimethylformamide (0.4 mL) was carried out analogously to Example 11. Silica gel chromatography (eluted with 2:1 hexane:acetone), also in an analogous manner, after a final trituration with methanol afforded the title compound (8 mg, 0.022 mmol) as a yellow powder in 16% yield. Silica gel chromatography (eluted with 2:1 hexane:acetone)

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

Procedure: Preparation of example 90 from the title compound of Example 7 (hydrochloride) (41 mg, 0.131 mmol), (2E,4E)-hexa-2,4-dienoic acid (18 mg, 0.157 mmol), triethylamine (0.055 mL, 0.393 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (60 mg, 0.157 mmol) in CH2Cl2 (0.4 mL) and N,N-dimethylformamide (0.4 mL) was carried out analogously to Example 11. Silica gel chromatography (eluted with 2:1 hexane:acetone), also in an analogous manner, after a final trituration with methanol afforded the title compound (8 mg, 0.022 mmol) as a yellow powder in 16% yield. Silica gel chromatography (eluted with 2:1 hexane:acetone)

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

Procedure: In a 1000 ml four-neck flask, equipped with thermometer, intense cooler, submerged tube for phosgene and KPG agitator, 100 g (0.88 mol) of all-E-sorbic acid and 600 g of ethyl acetate are charged. To the resultant suspension are added 101.2 g (1 mol) of triethylamine, whereupon a clear yellow solution forms. The batch was then cooled using a cooling bath to 0-5° C. Then, in the course of 4 hours at 0-5° C., 50.7 g (0.51 mol) of phosgene were introduced, wherein the deposition of the triethylamine hydrochloride is immediately observed. After completion of phosgene metering, the batch was stirred overnight at RT. After examination for freedom from phosgene, the batch was filtered and the suction filter residue was washed with 200 ml of ethyl acetate. The resultant brownish-yellow filtrate was concentrated on a rotary evaporator in a vacuum. The resultant brown oil (90.7 g) was placed under nitrogen into a clear glass bottle and rapidly solidified at room temperature. A GC analysis gave a content of 85.9 weight % of all-E-sorbic anhydride; 9.13 weight % unreacted sorbic acid and 0.31% sorbyl chloride. In 1H-NMR, a content of 94.5 weight % anhydride and 2.9 weight % of triethylamine was observed. Isomerization was not observed. Based on the GC content, a yield of 85.6% of theory was determined, based on sorbic acid used. In a 1000 ml four-neck flask, equipped with thermometer, intense cooler are charged The batch was then cooled to 0-5° C After examination for freedom from phosgene, the batch was filtered the suction filter residue was washed with 200 ml of ethyl acetate The resultant brownish-yellow filtrate was concentrated on a rotary evaporator in a vacuum rapidly solidified at room temperature

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

Procedure: In a 1000 ml four-neck flask, equipped with thermometer, intense cooler, submerged tube for phosgene and KPG agitator, 100 g (0.88 mol) of all-E-sorbic acid and 600 g of ethyl acetate are charged. To the resultant suspension are added 101.2 g (1 mol) of triethylamine, whereupon a clear yellow solution forms. The batch was then cooled using a cooling bath to 0-5° C. Then, in the course of 4 hours at 0-5° C., 50.7 g (0.51 mol) of phosgene were introduced, wherein the deposition of the triethylamine hydrochloride is immediately observed. After completion of phosgene metering, the batch was stirred overnight at RT. After examination for freedom from phosgene, the batch was filtered and the suction filter residue was washed with 200 ml of ethyl acetate. The resultant brownish-yellow filtrate was concentrated on a rotary evaporator in a vacuum. The resultant brown oil (90.7 g) was placed under nitrogen into a clear glass bottle and rapidly solidified at room temperature. A GC analysis gave a content of 85.9 weight % of all-E-sorbic anhydride; 9.13 weight % unreacted sorbic acid and 0.31% sorbyl chloride. In 1H-NMR, a content of 94.5 weight % anhydride and 2.9 weight % of triethylamine was observed. Isomerization was not observed. Based on the GC content, a yield of 85.6% of theory was determined, based on sorbic acid used. In a 1000 ml four-neck flask, equipped with thermometer, intense cooler are charged The batch was then cooled to 0-5° C After examination for freedom from phosgene, the batch was filtered the suction filter residue was washed with 200 ml of ethyl acetate The resultant brownish-yellow filtrate was concentrated on a rotary evaporator in a vacuum rapidly solidified at room temperature

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 47% (w/w) sodium hydroxide (5.5 g) is added to slurry of sorbic acid (5.6 g, 0.05 mol) in water (100 mL) at 70° C. to give a clear slightly alkaline solution. A solution of zinc chloride (3.4 g, 0.025 mol) in water (50 mL) is added and a precipitate is formed immediately. The mixture is stirred at 70° C. for further 2.5 hours. The precipitate is then filtered and dried to yield 5.5 g (76%) zinc sorbate as a fine white powder. IR absorption bands: 1521 and 1418 cm−1. to give a clear slightly alkaline solution a precipitate is formed immediately The precipitate is then filtered dried

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

Procedure: 22.6 g of promethazine HCl, 25.0 g of polyvinylpyrrolidone K 90 prepared as in Example 8, 5.0 g of citric acid, 2.0 g of sorbic acid and 60.0 g of sucrose were dissolved in 975.0 g of demineralized water at 50° C., and the solution was cooled to room temperature and dispensed into 50 ml amber glass bottles.