* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
With triethylamine In tetrahydrofuran at -78 - 30℃; for 3.16667 h;
Step 1-Synthesis of 1-(3-hydroxyazetidin-1-yl)ethan-1-one To a solution of azetidin-3-ol (3.0 g, 27.40 mmol) and triethylamine (8.33 g, 82.48 mmol) in tetrahydrofuran (150 mL) was added acetyl chloride (2.15 g, 27.39 mmol) dropwise with stirring at -78° C. over 10 min. The resulting solution was stirred for 3 h at 20-30° C. The solid material was removed by filtration. The filtrate was concentrated under vacuum and purified on a silica gel column (methanol/ethyl acetate (1/10)) to afford 500 mg (14percent) of 1-(3-hydroxyazetidin-1-yl)ethan-1-one as yellow oil. 1H NMR (400 MHz, DMSO) delta 3.60 (t, J=4.8 Hz, 2H), 2.83 (t, J=4.8 Hz, 2H), 2.21 (s, 3H).
Reference:
[1] Patent: US2012/214762, 2012, A1, . Location in patent: Page/Page column 169
[2] Patent: US5130309, 1992, A,
2
[ 143329-27-5 ]
[ 118972-96-6 ]
Reference:
[1] Journal of Organic Chemistry, 1996, vol. 61, # 16, p. 5453 - 5455
[2] Tetrahedron Letters, 1998, vol. 39, # 31, p. 5481 - 5484
(1) In 10 mL of methylene chloride was dissolved 1.00 g of <strong>[118972-96-6]1-(3-hydroxy-1-azetidinyl)-1-ethanone</strong>, and 1.19 mL of 3,4-dihydro-2H-pyran and 0.08 g of p-toluenesulfonic acid monohydrate were added to the solution, after which the resulting mixture was stirred overnight at room temperature. To the reaction mixture was added 10 mL of water and the pH was adjusted to 8 with a saturated aqueous sodium hydrogencarbonate solution, after which the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by a column chromatography (eluent; chloroform~chloroform : methanol = 25 : 1) to obtain 1.79 g of 1-[3-(tetrahydro-2H-pyran-2-yloxy)-1-azetidinyl]-1-ethanone as a yellow oil. IR(neat)cm-1: 2945,2875,1654,1458,1138,1036,971 NMR(CDCl3)delta values: 1.5-1.9(6H,m), 1.87(3H,s) 3.4-3.6(1H,m), 3.8-4.4(5H,m), 4.5-4.7(2H,m)
With 1,8-diazabicyclo[5.4.0]undec-7-ene; In dichloromethane; at 0 - 20℃; for 1.0h;
(1) In 50 mL of methylene chloride was dissolved 10.0 g of <strong>[118972-96-6]1-(3-hydroxy-1-azetidinyl)-1-ethanone</strong>, and 31.2 mL of 1,8-diazabicyclo[5,4,0]undec-7-ene and 29.1 g of trityl chloride were added thereto under ice-cooling, after which the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into 100 mL of ice water and the organic layer was separated. The organic layer was washed with diluted hydrochloric acid, water and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then distilled under reduced pressure to remove the solvent. Diisopropyl ether was added to the residue and the crystals precipitated were collected by filtration to obtain 21.7 g of 1-[3-(trityloxy)-1-azetidinyl]-1-ethanone as light-yellow crystals. IR(KBr)cm-1: 1646,1450,1124,750,711 NMR(CDCl3)delta values: 1.74(3H,s), 3.6-3.8(4H,m), 4.4-4.5(1H.m), 7.2-7.5(15H,m)
With triethylamine; In tetrahydrofuran; at -78 - 30℃; for 3.16667h;
Step 1-Synthesis of 1-(3-hydroxyazetidin-1-yl)ethan-1-one To a solution of azetidin-3-ol (3.0 g, 27.40 mmol) and triethylamine (8.33 g, 82.48 mmol) in tetrahydrofuran (150 mL) was added acetyl chloride (2.15 g, 27.39 mmol) dropwise with stirring at -78 C. over 10 min. The resulting solution was stirred for 3 h at 20-30 C. The solid material was removed by filtration. The filtrate was concentrated under vacuum and purified on a silica gel column (methanol/ethyl acetate (1/10)) to afford 500 mg (14%) of 1-(3-hydroxyazetidin-1-yl)ethan-1-one as yellow oil. 1H NMR (400 MHz, DMSO) delta 3.60 (t, J=4.8 Hz, 2H), 2.83 (t, J=4.8 Hz, 2H), 2.21 (s, 3H).
With triethylamine; In tetrahydrofuran;
PREPARATION 8 1-Acetyl-3-azetidinol Acetyl chloride (923.1 g, 296 mmol) was added slowly to a stirring slurry of azetidin-3-ol (18.0 g, 246 mmol) and triethylamine (37.3 g, 369 mmol) in tetrahydrofuran (500 mL) maintained at -78 C. The reaction was allowed to warm slowly to ambient temperature over 2 h. The reaction mixture was filtered to remove some solid material and the solid was washed with tetrahydrofuran (~200 mL). The filtrate was concentrated in vacuo. The residue was diluted with hexane and concentrated (repeated twice) to give 23.2 g (82%) of a white solid. A small sample (0.5 g) was recrystallized from ethyl acetate and hexane to give 0.48 g of white solid, mp 57-60 C. Analysis: Calculated for C5 H9 NO2: C, 52.16; H, 7.88; N, 12.17. Found: C, 52.01; H, 7.94; N, 12.17.
With potassium tert-butylate; In N,N-dimethyl-formamide; at 20℃;Inert atmosphere; Sealed vial;
Step 2-Synthesis of 1-(3-[[1-(2-aminopyrimidin-4-yl)-6-bromo-1H-1,3-benzodiazol-2-yl]oxy]azetidin-1-yl)ethan-1-one A mixture of 4-[6-bromo-2-(trichloromethyl)-1H-1,3-benzodiazol-1-yl]pyrimidin-2-amine (500 mg, 1.23 mmol), <strong>[118972-96-6]1-(3-hydroxyazetidin-1-yl)ethan-1-one</strong> (1 g, 8.69 mmol) and potassium t-butoxide (500 mg, 5.21 mmol) in N,N-dimethylformamide (5 mL) kept under nitrogen in a 30-mL sealed tube was stirred overnight at room temperature. The reaction mixture was filtered through a frit filter and the filtrate was purified on a C18 column (acetonitrile/water, 5:95-80:20) to yield 160 mg (29%) of 1-(3-[[1-(2-aminopyrimidin-4-yl)-6-bromo-1H-1,3-benzodiazol-2-yl]oxy]azetidin-1-yl)ethan-1-one as a yellow solid. LC-MS: m/z=+403 (M+H)+.
tert-butyl 7-(3-amino-8-chloro-7-fluoro-6-isoquinolyl)-8-methyl-3,4-dihydro-2H-1,5-naphthyridine-1-carboxylate[ No CAS ]
[ 118972-96-6 ]
tert-butyl 7-[3-[(1-acetylazetidin-3-yl)oxycarbonylamino]-8-chloro-7-fluoro-6-isoquinolyl]-8-methyl-3,4-dihydro-2H-1,5-naphthyridine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
53.1%
Step 1: tert-Butyl 7-[3-[(1-acetylazetidin-3-yl)oxycarbonylamino]-8-chloro-7-fluoro-6-isoquinolyl]-8-methyl-3,4-dihydro-2H-1,5-naphthyridine-1-carboxylate A solution of tert-butyl 7-(3-amino-8-chloro-7-fluoro-6-isoquinolyl)-8-methyl-3,4-dihydro-2H-1,5-naphthyridine-1-carboxylate (200 mg, 0.45 mmol), <strong>[118972-96-6]1-(3-hydroxyazetidin-1-yl)ethanone</strong> (80 mg, 0.69 mmol) and DIEA (180 mg, 1.40 mmol) in dichloromethane (15 mL) was stirred at 0 C. for 5 min. Then a solution of triphosgene (60 mg, 0.20 mmol) in dichloromethane (1 mL) was added dropwise to the reaction solution at 0 C. The reaction was stirred at room temperature for 1 hour. The resulting solution was extracted with dichloromethane (200 mL). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with methanol/dichloromethane (7%) to afford tert-butyl 7-[3-[(1-acetylazetidin-3-yl)oxycarbonylamino]-8-chloro-7-fluoro-6-isoquinolyl]-8-methyl-3,4-dihydro-2H-1,5-naphthyridine-1-carboxylate (200 mg, 0.2397 mmol, 53.1% yield) as a yellow solid. LCMS (ESI) [M+H]+=584.0.