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Stage #1: at 0 - 20℃; for 3.66667 h; Stage #2: at 0℃;
B. Preparation of tert-butyl 3-acetylazetidine-1-carboxylate (C56). A solution of C55 (27.1 g, 0.111 mol) in THF (200 mL) was added drop-wise to a 1.4M solution of methylmagnesium bromide in a mixture of THF and toluene (25:75) (99.0 mL, 0.139 mol) over 40 mins, while the reaction temp was kept at about 0° C. After completion of the addition, the mixture was stirred at 10-15° C. for 2 hours, followed by 1 h at room temp. The reaction mixture was cooled to 0° C. and quenched with a 10percent aqueous citric acid solution (150 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (2*300 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (2*250 mL), and dried over sodium sulfate. Filtration and removal of solvent gave a residue, which was purified by silica gel chromatography (Eluant: chloroform) to afford C56. Yield: 20.6 g, 0.10 mol, 93percent. 1H NMR (400 MHz, CDCl3): δ 4.04-4.02 (m, 4H), 3.43-3.35 (m, 1H), 2.16 (s, 3H), 1.42 (s, 9H).
93.4%
Stage #1: at 0 - 20℃; for 3.66667 h; Stage #2: With water; citric acid In tetrahydrofuran; toluene at 0℃;
Preparation 85 tert-Butyl 3-acetylazetidine-1 -carboxylate; A solution of tert-butyl 3-(methoxy(methyl)carbamoyl)azetidine-1-carboxylate (Preparation 84, 27.1 g, 0.111 mol) in tetrahydrofuran (20OmL) was added dropwise to a 1.4 M solution of methylmagnesium bromide in a 25:75 mixture of tetrahydrofuran and toluene (99.0 mL, 0.139 mol, 1.25 eq) over 40 minutes. The reaction temperature was kept at ~0°C. After the addition, the mixture was stirred at 10-150C for 2 hours and then at room temperature for 1 hour. The mixture was cooled to 00C and 10percent aqueous citric acid (15OmL) was added. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (60OmL). The organic layers were combined, washed with brine (50OmL) and dried using anhydrous sodium sulfate to give a residue which was purified by chromatography on silica gel, eluting with chloroform, to afford the title compound (20.6 g, 93.4percent).1H NMR (400 MHz, CDCI3): δ = 4.04-4.02 (m, 4H), 3.43-3.35 (m, 1 H), 2.16 (s, 3H), 1.42 (s, 9H) ppm.
77%
at 0 - 20℃; for 17 h;
Methylmagnesium bromide (3M solution in THF, 10.4 mL, 31.3 mmol) was added dropwise to a cooled (0° C.) solution of tert-butyl 3-(methoxy(methyl)carbamoyl)azetidine-1-carboxylate (87a, 5.1 g, 20.88 mmol) in anhydrous THF (100 mL). Stirring was continued at 0° C. for one hour, then at room temperature for 16 hours. The mixture was cooled to 0° C. and quenched with sat. aq. NaHCO3 (35 mL), then extracted with ethyl acetate (3×40 mL). The combined organic extracts were washed with brine (3×40 mL), dried over sodium sulfate, filtered, concentrated, and purified by silica gel chromatography (eluting with petroleum ether/ethyl acetate from 10:1 to 3:1) to give tert-butyl 3-acetylazetidine-1-carboxylate (87b, (3.20 g, 77percent yield) as light yellow oil. 1H NMR (400 MHz, CDCl3) δ 4.05 (d, J=7.6 Hz, 4H), 3.41 (quint, J=7.6 Hz, 1H), 2.18 (s, 3H), 1.43 (s, 9H).
With acetic acid In 1,4-dioxane; water at 100 - 110℃; for 0.5 h; Microwave irradiation
Step 3: 3-Acetyl-azetidine-l-carboxylic acid tert- butyl esterA solution of 3-(2,2-dimethyl-4,6-dioxo-[l,3]dioxane-5-carbonyl)-azetidine-l- carboxylic acid terf-butyl ester (1.0 g, 3.05 mmol) in a mixture of actic acid (0.5 mL), water 0.25 mL and dioxane (3 mL) was stirred under microwaves at 100°C for 30 minutes. After concentration to dryness, the residue was coeveoparted with dichloromethane (2 x 100 mL). The title product was obtained as a colorless gum (600 mg, 100percent).LCMS (ESI-APCI) m/z 308.2 (M + H)+
70%
With acetic acid In 1,4-dioxane; water at 150℃; for 0.5 h; Microwave irradiation
To a stirring solution of compound 1 (2.8 g, 8.6 mmol) in dry dioxane (20 mL) was added AcOH (1.5 mL) and H20 (0.75 mL), then stirred at 150 °C for 30 mm with microwave heating.Quenched with water, extracted with EtOAc, concentrated under reduced pressure to obtain cmde product, which was purified by combiflash (methanol:DCM = 1:20) to give compound 2 (1.2 g, 70percent). LC-MS: m/z = 100.0 [M+H-Boc]
2) Synthesis of N-t.butoxycarbonyl-3-acetyl-azetidine 110 mg (0.45 mmol) of N-t.butoxycarbonyl-3-(methoxy-methyl-carbamoyl)-azetidine is solubilized in 2 ml of ether under argon. This solution is cooled down to 0 C. using an ice bath and 1 ml of a 1.6 M solution of methyllythium in ether is added dropwise. The reaction medium is stirred for 2 hours at this temperature then treated with a 1 M aqueous solution of hydrochloric acid. The aqueous and ether phases are decanted and separated. This operation is repeated 3 times then the ethereal phases are collected and dried over MgSO4, then after filtration the ether is evaporated under reduced pressure. 40 mg of a colourless oil is recovered. TLC: Rf=0.35 (silica gel, eluent: heptane/ethyl acetate 50:50 1H-NMR (CDCl3): δ 1.44 (s, 9H,); 2.2 (s, 3H, -CO-C); 3.45 (m, 1H,); 3.67 (s, 3H, -O-C); 4.07 (m, 4H, and)
Step 2: tert-butyl 3-acetylazetidine-l-carboxylateTo a 100 ml round bottom flask was added tert-butyl 3-[methoxy(methyl)amino]carbonyl}azetidine-l-carboxylate (2.6 g, 10.6 mmol) and 20 ml tetrahydrofuran. The resulting solution was cooled to 0C and methylmagnesium chloride tetrahydrofuran solution (4.3 ml, 3M, 12.8 mmol) was added by a syringe. The reaction mixture was stirred at 0 C for 1 hour. It was diluted with 100 ml ether, and the resulting mixture was washed twice with 100 ml saturated ammonium chloride solution. The organics were dried over sodium sulfate, filtered and concentrated. The crude product was used for the next step without further purification.1H-NMR (CDCl3): 64.05 (m, 4H), 3.43 (m, IH), 2.20 (s, 3H), 1.45 (s, 9H).
B. Preparation of tert-butyl 3-acetylazetidine-1-carboxylate (C56). A solution of C55 (27.1 g, 0.111 mol) in THF (200 mL) was added drop-wise to a 1.4M solution of methylmagnesium bromide in a mixture of THF and toluene (25:75) (99.0 mL, 0.139 mol) over 40 mins, while the reaction temp was kept at about 0 C. After completion of the addition, the mixture was stirred at 10-15 C. for 2 hours, followed by 1 h at room temp. The reaction mixture was cooled to 0 C. and quenched with a 10% aqueous citric acid solution (150 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (2*300 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (2*250 mL), and dried over sodium sulfate. Filtration and removal of solvent gave a residue, which was purified by silica gel chromatography (Eluant: chloroform) to afford C56. Yield: 20.6 g, 0.10 mol, 93%. 1H NMR (400 MHz, CDCl3): δ 4.04-4.02 (m, 4H), 3.43-3.35 (m, 1H), 2.16 (s, 3H), 1.42 (s, 9H).
93.4%
Preparation 85 tert-Butyl 3-acetylazetidine-1 -carboxylate; A solution of <strong>[820971-67-3]tert-butyl 3-(methoxy(methyl)carbamoyl)azetidine-1-carboxylate</strong> (Preparation 84, 27.1 g, 0.111 mol) in tetrahydrofuran (20OmL) was added dropwise to a 1.4 M solution of methylmagnesium bromide in a 25:75 mixture of tetrahydrofuran and toluene (99.0 mL, 0.139 mol, 1.25 eq) over 40 minutes. The reaction temperature was kept at ~0C. After the addition, the mixture was stirred at 10-150C for 2 hours and then at room temperature for 1 hour. The mixture was cooled to 00C and 10% aqueous citric acid (15OmL) was added. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (60OmL). The organic layers were combined, washed with brine (50OmL) and dried using anhydrous sodium sulfate to give a residue which was purified by chromatography on silica gel, eluting with chloroform, to afford the title compound (20.6 g, 93.4%).1H NMR (400 MHz, CDCI3): δ = 4.04-4.02 (m, 4H), 3.43-3.35 (m, 1 H), 2.16 (s, 3H), 1.42 (s, 9H) ppm.
77%
In tetrahydrofuran; at 0 - 20℃; for 17h;
Methylmagnesium bromide (3M solution in THF, 10.4 mL, 31.3 mmol) was added dropwise to a cooled (0 C.) solution of <strong>[820971-67-3]tert-butyl 3-(methoxy(methyl)carbamoyl)azetidine-1-carboxylate</strong> (87a, 5.1 g, 20.88 mmol) in anhydrous THF (100 mL). Stirring was continued at 0 C. for one hour, then at room temperature for 16 hours. The mixture was cooled to 0 C. and quenched with sat. aq. NaHCO3 (35 mL), then extracted with ethyl acetate (3×40 mL). The combined organic extracts were washed with brine (3×40 mL), dried over sodium sulfate, filtered, concentrated, and purified by silica gel chromatography (eluting with petroleum ether/ethyl acetate from 10:1 to 3:1) to give tert-butyl 3-acetylazetidine-1-carboxylate (87b, (3.20 g, 77% yield) as light yellow oil. 1H NMR (400 MHz, CDCl3) δ 4.05 (d, J=7.6 Hz, 4H), 3.41 (quint, J=7.6 Hz, 1H), 2.18 (s, 3H), 1.43 (s, 9H).
In tetrahydrofuran; at 0 - 20℃; for 2h;
[0301] To a solution of <strong>[820971-67-3]tert-butyl 3-(methoxy(methyl)carbamoyl)azetidine-1-carboxylate</strong> (7.0 g,28.7 mmol) in THF (150 mL) was added CH3MgBr (43 mL, 43 mmol) at 0 C, then slowlywarmed to R T for about 2 hr. 10% aqueous of citric acid (30 mL) was added to the mixture, andextracted with EA (50 mL x 3), the combined organic phases were washed with brine (20 mL),dried over N a2S04, filtered, concentrated and purified by column chromatography on silica gel(200-300 mesh, PE/EA = 211), to give the crude product (4.0 g, 70%) as a colorless oil. MS(ESI) m/e [M-55t 144.0.
In tetrahydrofuran; at 0 - 20℃; for 2h;
At 0C,To a solution of tert-butyl 3-(methoxy(methyl)carbamomidonyl)azetidine-1-carboxylate (7.0 g, 28.7 mmol) in THF (150 mL),Add CH3MgBr (43 mL, 43 mmol),It is then slowly warmed to room temperature over about 2 hours.To the mixture was added 10% aqueous citric acid solution (30 mL) and extracted with EA (50 mL x 3). The combined organic phases were washed with saturated brine (20 mL), dried over Na2SO4, filtered, concentrated, and applied on a silica gel column (200-300). Head, PE/EA = 2/1) purification,The crude product was obtained as a colorless oil (4.0 g, 70%).
In tetrahydrofuran; diethyl ether; at -20℃; for 2.25h;
(1) To a solution of tert-butyl 3-[methoxy(methyl)carbamoyl]azetidine-1-carboxylate (120 mg) obtained from methoxy(methyl)amine by the method described in Example 005-(1) or a method equivalent thereto in THF (2.5 mL) was added a 3 mol/L solution of methyl magnesium bromide in diethyl ether (250 μL) at -20 C., and the mixture was stirred at the same temperature for 135 minutes. To the reaction solution was added an aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate, and concentrated. The residue was subjected to silica gel column chromatography (eluent: ethyl acetate/n-hexane) to obtain crude tert-butyl 3-acetylazetidine-1-carboxylate.
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