BENZYL 3-HYDROXYAZETIDINE-1-CARBOXYLATE

To a solution of azetidin-3-ol hydrochloride 7 (25 g, 0.23 mol) in water (150 mL) and THF (300 mL) was added K[0802] A mixture of azetidin-3-ol hydrochloride (12 g, 109.53 mmol, 1.00 equiv), tetrahydrofuran (150 mL), water (70 mL), and potassium carbonate (30 g, 217.07 mmol, 2.00 equiv) was stirred for 30 mm at room temperature. This was followed by the addition of benzyl chloroformate (22 g, 128.96 mmol, 1.20 equiv) dropwise with stirring at 0°C in 30 mm. The resulting solution was stirred overnight at room temperature. The solids were filtered out and the solution was extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by a silica gel colunm eluting with ethyl acetate/petroleum ether (1:2) to afford the title compound (20 g, 87percent) as light yellow oil. LCMS [M+H] 208; ‘HNMR (400 MHz, DMSO-d6) 7.39 - 7.30 (m, 5H), 5.70 - 5.69 (d, J = 5.2 Hz, 1H), 5.03 (s, 2H), 4.44 - 4.42 (m, 1H), 4.10 (m, 2H), 3.69 (m, 2H).To a stirred solution of intermediate A (10.00 g, 91 mmol, ) in HExample 50 To a solution of azetidin-3-ol hydrochloride in tetrahydrofuran (90 mL) and water (10 mL) was added triethylamine (15 mL, 0.106 mol) followed by slow addition of benzyl chloroformate (8.0 mL, 0.056 mol) at room temperature. The reaction mixture was stirred at room termperature for 16 hours then partitioned with water and ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by flash chromatography (SiOTo a solution of azetidin-3-ol hydrochloride in tetrahydrofuran (90 mL) and water (10 mL) was added triethylamine (15 mL, 0.106 mol) followed by slow addition of benzyl chloroformate (8.0 mL, 0.056 mol) at room temperature. The reaction mixture was stirred at room termperature for 16 hours then partitioned with water and ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by flash chromatography (SiOTo a solution of azetidin-3-ol hydrochloride in tetrahydrofuran (90 mL) and water (10 mL) was added triethylamine (15 mL, 0.106 mol) followed by slow addition of benzyl chloroformate (8.0 mL, 0.056 mol) at room temperature. The reaction mixture was stirred at room termperature for 16 hours then partitioned with water and ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by flash chromatography (SiOA solution of azetidin-3-ol (14.7 g) dissolved in THF (170 mL) and water (85 mL) was treated with potassium carbonate (37.1 g) under nitrogen. The mixture was stirred at RT for 30 minutes before cooling to 0 °C and adding benzyl carbonochloridate (20.0 mL) dropwise over 30 minutes at 0 °C. The resulting mixture was stirred at 20 °C for 60 hours. The reaction mixture was diluted with water (150 mL), and extracted with ethyl acetate (200 mL). The organic was dried over magnesium sulfate, filtered and evaporated to afford crude product as a colourless oil. The crude product was purified by flash silica chromatography, elution 50percent ethyl acetate in isohexane to 100percent ethyl acetate. Pure fractions were evaporated to dryness to afford the sub-title product (19.40 g, 69.8 percent) as a colorless oil. 1H NMR (500 MHz, CDCLA solution of azetidin-3-ol (14.7 g) dissolved in THF (170 mL) and water (85 mL) was treated with potassium carbonate (37.1 g) under nitrogen. The mixture was stirred at RT for 30 minutes before cooling to 0 °C and adding benzyl carbonochloridate (20.0 mL) dropwise over 30 minutes at 0 °C. The resulting mixture was stirred at 20 °C for 60 hours. The reaction mixture was diluted with water (150 mL), and extracted with ethyl acetate (200 mL). The organic was dried over magnesium sulfate, filtered and evaporated to afford crude product as a colourless oil. The crude product was purified by flash silica chromatography, elution 50percent ethyl acetate in isohexane to 100percent ethyl acetate. Pure fractions were evaporated to dryness to afford the sub-title product (19.40 g, 69.8 percent) as a colorless oil. EXAMPLE 112 Example 196 Example 148 General procedure: With no precautions to exclude air or moisture, the ElectraSyn vial (5 ml) with a stir bar was charged with carboxylic acid (0.2 mmol, 1.0 equiv.), alcohol (0.6 mmol, 3.0 equiv.), 2, 4, 6-collidine (0.6 mmol, 3.0 equiv.), nBu4NPF6 (0.3 mmol, 1.5 equiv.), 3 A molecular sieves (150 mg), AgPF6 (0.3 mmol, 1.5 equiv.) and CH2Cl2 (3.0 ml). The ElectraSyn vial cap equipped with anode (graphite) and cathode (graphite) were inserted into the mixture. After pre-stirring for 15 min, the reaction mixture was electrolysed at a constant current of 10 mA for 3 h. The ElectraSyn vial cap was removed, and electrodes were rinsed with Et2O (2 ml), which was combined with the crude mixture. Then, the crude mixture was further diluted with Et2O (30 ml). The resulting mixture was washed with 2 M HCl (20 ml) and NaHCO3 (aq.) (20 ml), dried over Na2SO4 and concentrated in vacuo. The crude material was purified by preparative thin-layer chromatography to furnish the desired product. Full experimental details and characterization of new compounds can be found in the Supplementary Information.General procedure: With no precautions to exclude air or moisture, the ElectraSyn vial (5 ml) with a stir bar was charged with carboxylic acid (0.2 mmol, 1.0 equiv.), alcohol (0.6 mmol, 3.0 equiv.), 2, 4, 6-collidine (0.6 mmol, 3.0 equiv.), nBu4NPF6 (0.3 mmol, 1.5 equiv.), 3 A molecular sieves (150 mg), AgPF6 (0.3 mmol, 1.5 equiv.) and CH2Cl2 (3.0 ml). The ElectraSyn vial cap equipped with anode (graphite) and cathode (graphite) were inserted into the mixture. After pre-stirring for 15 min, the reaction mixture was electrolysed at a constant current of 10 mA for 3 h. The ElectraSyn vial cap was removed, and electrodes were rinsed with Et2O (2 ml), which was combined with the crude mixture. Then, the crude mixture was further diluted with Et2O (30 ml). The resulting mixture was washed with 2 M HCl (20 ml) and NaHCO3 (aq.) (20 ml), dried over Na2SO4 and concentrated in vacuo. The crude material was purified by preparative thin-layer chromatography to furnish the desired product. Full experimental details and characterization of new compounds can be found in the Supplementary Information.potassium carbonate (2.1 g, 15 mmol), and N-(benzyloxycarbonyloxy)succinimide (1.4 g, 5.6 mmol) were treated with dioxane (8.0 mL) and water (8.0 mL). The mixture was stirred at room temperature overnight, and then partitioned between ethyl acetate and 0.5 M aqueous hydrochloric acid. The aqueous phase was extracted with ethyl acetate. The combined organic extracts were washed with sat. aq. sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated to a residue under reduced atmosphere. The residue was purified by silica flash chromatography to afford tBuOK (340 mg, 3.04 mmol) was added to a solution of benzyl 3- hydroxyazetidine-l -carboxylate (500 mg, 2.42 mmol) in DMSO (10 mL). The reaction was stirred for 30 min and 4-(6-chloro-4-iodopyridin-2-yl)morpholine (650 mg, 2.0 mmol) was added. The reaction was stirred overnight at rt under N2. The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (50 mL x3). The combined organics were washed with brine (50 mLx2), dried over sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=20: l) to give benzyl 3-(2-chloro-6-morpholinopyridin-4-yloxy)azetidine-l- carboxylate (280 mg, 35% yield). The compound was confirmed with LC-MS only: 403.93 (M+H)+, C2oH22ClN304.Into a 100-mL round-bottom flask, was placed

Molecular Weight:207.23
XLogP3:0.8
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:3
Exact Mass:207.08954328
Monoisotopic Mass:207.08954328
Topological Polar Surface Area:49.8
Heavy Atom Count:15
Complexity:220
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes