tert-butyl 3-(hydroxymethyl)azetidine-1-carboxylate

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Diisopropyl ethyl amine (124.28 g, 0.961 mol) was added dropwise to stirred solution of compound tert-butyl 3-(hydroxymethyl)azetidine-1-carboxylate (150 g, 0.80 mol) in dichloromethane (500 mL) at 0° C. Dimethyl phosphinyl chloride (90 g, 0.80 mol) in dichloromethane (300 mL) was added to above reaction mixture over a period of 90 min at same temperature. Then, the reaction mixture was warmed to room temperature and continued stirring for 2 h. After completion of the reaction, the mixture was diluted with water (300 mL). The layers were separated. The organic layer was washed with brine (300 ml), dried over sodium sulfate and concentrated. The resultant concentrated product was purified via column chromatography on silica gel using chloroform/methanol (95/5) to afford tert-butyl 3-{[(dimethylphosphoryl)oxy]methyl}azetidine-1-carboxylate (146.8 g, 68.3%) as brown liquid. After completion of the reaction The layers were separated The organic layer was washed with brine (300 ml) dried over sodium sulfate concentrated The resultant concentrated product was purified via column chromatography on silica gel

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a stirred solution of 3-hydroxymethyl-azetidine-1-carboxylic acid tert-butyl ester (1.5 mmol, 281 mg) in THF (4.0 mL) at 0° C., NaH (60% dispersion in mineral oil, 1.5 mmol, 60 mg) was added and stirring continued for 10 min at room temperature, then 4-(4-benzyloxy-phenyl)-3-butyl-6-chloro-pyridazine (Example 1, 1.0 mmol, 352 mg) was added. The resulting mixture was stirred at 50° C. for 1 hour, poured into water, and extracted with ethyl acetate. The organic layers were combined and concentrated under reduced pressure. The product was purified by column chromatography using 50% ethyl acetate in hexanes to give 3-[5-(4-benzyloxy-phenyl)-6-butyl-pyridazin-3-yloxymethyl]-azetidine-1-carboxylic acid tert-butyl ester, which was dissolved in dichloromethane (1.0 mL), added 4.0 M HCl in dioxane (1.0 mL) and stirred at room temperature for 1 hour. Solvents were evaporated to give 6-(azetidin-3-ylmethoxy)-4-(4-benzyloxy-phenyl)-3-butyl-pyridazine dihydrochloride. The resulting mixture was stirred at 50° C. for 1 hour extracted with ethyl acetate concentrated under reduced pressure The product was purified by column chromatography

反応条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Oxalyl chloride (2.1 mL; 24.0 mmol) was dissolved in methylene chloride (30 mL) and cooled to -78° C. Dimethyl sulfoxide (2.3 mL; 32.0 mmol) was added. A solution of 3-hydroxymethylazetidine-1-carboxylic acid tert-butyl ester (3.0 g; 16.0 mmol) in methylene chloride (20 mL) was added dropwise to the reaction mixture. Triethyl amine (11.1 mL; 80.1 mmol) was added and the reaction mixture was heated to room temperature. Methylene chloride (200 mL) and hydrochloric acid (200 mL; 1 N) was added. The aqueous phase was extracted with methylene chloride (100 mL). The combined organic phases were washed with saturated sodium hydrogen carbonate (100 mL), dried (magnesium sulfate) and evaporated in vacuo. The residue was chromatographed on silica (3×30 cm) using ethyl acetate/heptane (4:1) as eluent to afford 1.11 g of 3-formylazetidine-1-carboxylic acid tert-butylester. the reaction mixture was heated to room temperature The aqueous phase was extracted with methylene chloride (100 mL) The combined organic phases were washed with saturated sodium hydrogen carbonate (100 mL) dried (magnesium sulfate) evaporated in vacuo The residue was chromatographed on silica (3×30 cm)

反応条件: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of tert-butyl 3-(hydroxymethyl)azetidine-1-carboxylate (200 mg, 1.07 mmol), 4-bromophenol (222 mg, 1.28 mmol), triphenylphosphine (368 mg, 1.40 mmol) and DIAD (259 mg, 1.28 mmol) in anhydrous THF (5 mL) was heated to 110° C. under nitrogen for 5 hours. The reaction mixture was concentrate in vacuo to give a brown residue, which was purified by flash chromatography (petroleum ether/ethyl acetate 20:1 to 5:1) to give tert-butyl 3-[(4-bromophenoxy)methyl]azetidine-1-carboxylate (310 mg, 84%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.38 (d, 2H), 6.78 (d, 2H), 4.06 (m, 4H), 3.79 (m, 2H), 2.96 (m, 1H), 1.45 (s, 9H). The reaction mixture was concentrate in vacuo to give a brown residue, which was purified by flash chromatography (petroleum ether/ethyl acetate 20:1 to 5:1)

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid (3.00 g, 14.9 mmol) in tetrahydrofuran (15 mL) was added N-methylmorpholine (1.80 mL, 16.4 mmol) and isobutyl chloroformate (2.13 mL, 16.4 mmol) at 0° C. The mixture was stirred for 20 min. The resulting precipitate was filtered off and the filter cake was washed with tetrahydrofuran (1 mL). The filtrate was cooled to 0° C. and a solution of sodium borohydride (0.846 g, 22.4 mmol) in water (2 mL) was added. The resulting mixture was stirred for 1 h. and quenched with sodium bicarbonate aqueous solution. The mixture was extracted with ethyl acetate (55 mL). The organic layer was washed with brine (30 mL) and dried over sodium sulfate. The resulting solution was concentrated in vacuo. The crude product (2.79 g) was used for the next step without purification. The resulting precipitate was filtered off the filter cake was washed with tetrahydrofuran (1 mL) The resulting mixture was stirred for 1 h. quenched with sodium bicarbonate aqueous solution The mixture was extracted with ethyl acetate (55 mL) The organic layer was washed with brine (30 mL) dried over sodium sulfate The resulting solution was concentrated in vacuo The crude product (2.79 g) was used for the next step without purification

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid (3.00 g, 14.9 mmol) in tetrahydrofuran (15 mL) was added N-methylmorpholine (1.80 mL, 16.4 mmol) and isobutyl chloroformate (2.13 mL, 16.4 mmol) at 0° C. The mixture was stirred for 20 min. The resulting precipitate was filtered off and the filter cake was washed with tetrahydrofuran (1 mL). The filtrate was cooled to 0° C. and a solution of sodium borohydride (0.846 g, 22.4 mmol) in water (2 mL) was added. The resulting mixture was stirred for 1 h. and quenched with sodium bicarbonate aqueous solution. The mixture was extracted with ethyl acetate (55 mL). The organic layer was washed with brine (30 mL) and dried over sodium sulfate. The resulting solution was concentrated in vacuo. The crude product (2.79 g) was used for the next step without purification. The resulting precipitate was filtered off the filter cake was washed with tetrahydrofuran (1 mL) The resulting mixture was stirred for 1 h. quenched with sodium bicarbonate aqueous solution The mixture was extracted with ethyl acetate (55 mL) The organic layer was washed with brine (30 mL) dried over sodium sulfate The resulting solution was concentrated in vacuo The crude product (2.79 g) was used for the next step without purification