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With triethylamine In dichloromethane at 0 - 20℃; for 16h;
2.B.1 Preparation of intermediate 8005
Step 1 : A solution of intermediate 8005A (prepared analogously to the procedure in J. Org. Chem., 74, 2009, 2250, herein incorporated by reference) (350 mg, 1 .71 mmol) in DCM (10 ml_) is treated with Et3N (380 μΙ_, 2.73 mmol, 1 .6 eq) and cooled to 0°C. Methanesulfonyl chloride (198 μΙ_, 2.56 mmol, 1 .5 eq) is added and the reaction mixture is stirred at RT for 16 h. The reaction mixture is treated with a saturated aqueous sodium bicarbonate solution (10 ml_) and diluted with DCM. The phases are separated and the aqueous layer is extracted with DCM (3 x 10 ml_). The combined organic layers are dried over MgS04, filtered over a small plug of silica gel and concentrated to afford intermediate 8005B which is used without further purification.
With triethylamine In dichloromethane at 0 - 20℃;
1 Synthesis of compound 4062 Step 1
Step 1 : A solution of 3-fluoro-3-hydroxymethyl-azetidine-1 -carboxylic acid tert-butyl ester (prepared analogously to the procedure in J. Org. Chem., 74, 2009, 2250, herein incorporated by reference ) (350 mg, 1 .71 mmol) in DCM (10 ml.) is treated with triethylamine (380 μΙ_, 2.73 mmol, 1 .60 eq) and cooled to 0°C. Methanesulfonyl chloride (198 uL, 2.56 mmol, 1 .50 eq) is added and the reaction mixture is warmed to RT and stirred for 16 h at RT. At 0°C, triethylamine (200 μΙ_) and methanesulfonyl chloride (200 μΙ_) are added and the reaction mixture is stirred for 1 h at RT. The reaction mixture is treated with an aqueous sodium bicarbonate solution and diluted with DCM. The phases are separated and the aqueous layer is extracted with DCM (3x). The combined organic layers are dried over MgS04, filtered over a small plug of silica gel and concentrated to provide intermediate 4062A, which is used without further purification.
4-((1-(tert-butoxycarbonyl)-3-fluoroazetidin-3-yl)methoxy)-5-chloro-2-fluorobenzoic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium <i>tert</i>-butylate In dimethyl sulfoxide at 14 - 20℃; for 0.583333h;
66.1 Step 1: Preparation of 4- ( (1- (tert-butoxycarbonyl) -3-fluoroazetidin-3-yl) methoxy) -5-chloro-2-fluorobenzoic acid
To a solution of tert-butyl 3-fluoro-3- (hydroxymethyl) azetidine-1-carboxylate (0.161 g, 0.784 mmol) and 5-chloro-2, 4-difluoro-benzoic acid (151 mg, 0.784 mmol) in dimethyl sulfoxide (4.00 mL/mmol, 44.1 mmol, 99.8 mass) at 14 (bath) was added potassium tert-butoxide (194 mg, 1.73 mmol) . The mixture was stirred at that temp for 5 min then at rt for 30 min. Diluted with EtOAc, the contents were washed with 1: 4 mixture of 0.3M HCl and 0.3M NaH2PO4(3x) and brine, and dried (Na2SO4) . After filtration and concentration, the white solid crude (327 mg) was used as-is.
methyl 3-hydroxy-5-(5-methyl-1,3-thiazol-2-yl)benzoate[ No CAS ]
tert-butyl 3-fluoro-3-[3-(methoxycarbonyl)-5-(5-methyl-1,3-thiazol-2-yl)phenoxy]methyl}azetidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
41%
With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 0 - 20℃; for 110h;
4CL tert-butyl 3-fluoro-3-[3-(methoxycarbonyl)-5-(5-methyl-1,3-thiazol-2-yl)phenoxy]methyl}azetidine-1-carboxylate
To a stirred 0 °C solution of Intermediate 3 (300 mg, 1.201 mmol), tert-butyl 3- fluoro-3-(hydroxymethyl)azetidine-1 -carboxylate (321 mg, 1 .56 mmol) and triphenylphosphine (1 .26 g, 4.81 mmol) in anhydrous THF (3 mL) was added DIAD (472 pL, 2.41 mmol) dropwise. After 10 mins the reaction mixture was warmed toRT and stirred for 16 h. Additional DIAD (200 pL, 1.02 mmol) was added and the reaction stirred at RT for 24 h. Additional DIAD (200 pL, 1 .02 mmol) was added and the reaction stirred at RT for 70 h. The reaction mixture was concentrated at reduced pressure and purified by Biotage IsoleraTM chromatography (eluting with 0 - 100% gradient EtOAc in heptane on a pre-packed KP-Si02 column) to give 1.43 g(41% yield) of the title compound as colourless oil. The material was used without further purification.LC-MS (Method A) Rt =1 .37 mm, MS (ESIpos): m/z = 437 (M+H)+.
tert-butyl 3-fluoro-3-((tosyloxy)methyl)azetidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With triethylamine In dichloromethane at 0 - 20℃;
A tert-butyl 3-fluoro-3-((tosyloxy)methyl)azetidine-l-carboxylate
p-Toluenesulfonylchloride (1.02 g, 5.32 mmol) was added to a stirred solution of tert-butyl 3 -fluoro-3 -(hydroxymethyl)azetidine-1-carboxylate (993 mg, 4.84 mmol) and triethylamine (742 jiL, 5.32 mmol) in DCM (20 mL) at 0 °C. The reaction mixture was allowed to warm to rt, then additional triethylamine (337 jiL, 2.66 mmol) was added. After stirring overnight, the reaction mixture was concentrated in vacuo, and the resulting residue was purified by columnchromatography on silica gel (0-60% EtOAc in hexanes as eluent) to give the title compound. LC-MS [M
3-(((4-bromo-2-chloro-5-fluorobenzyl)oxy)methyl)-3-fluoroazetidine-1-carboxylic acid tert-butyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
48%
Stage #1: 3-fluoro-3-hydroxymethylazetidine-1-carboxylic acid tert-butyl ester With sodium hydride In N,N-dimethyl-formamide at 0℃; for 0.25h;
Stage #2: 1-bromo-4-(bromomethyl)-5-chloro-2-fluorobenzene In N,N-dimethyl-formamide at 0℃; for 0.5h;
25.3 3-((4-Bromo-2-chloro-5-fluorobenzyl)oxy)methyl)-3-fluoroazetidine-1-carboxylic acid tert-butyl ester
Dissolving 3-fluoro-3-(hydroxymethyl)azetidin-1-carboxylic acid tert-butyl ester 25c (8.9 g, 43.4 mmol) at 0 °CSodium hydride (3.47 g, 86.8 mmol) was slowly added to 70 mL of N,N-dimethylformamide and stirred at 0 ° C for 15 min. Will be 1-Bromo-4-(bromomethyl)-5-chloro-2-fluorobenzene 1c (13.0 g, 43.4 mmol) was dissolved in 60 mL of N,N-dimethylformamide at 0 ° CThe mixture was slowly added dropwise to the above reaction solution, and reacted at 0 ° C for 0.5 hour. The reaction solution was quenched by adding 40 mL of water to ethyl acetate.(100mL × 3) extraction, the organic phase was combined, washed with saturated sodium chloride solution (100mL), the aqueous layer was separated, the organic phase was anhydrous sulfurThe sodium salt was dried, filtered, and concentrated under reduced pressure.((4-Bromo-2-chloro-5-fluorobenzyl)oxy)methyl)-3-fluoroazetidine-1-carboxylic acid tert-butyl ester 25d (8.9g, light yellow oilShape), yield: 48%. MS m/z (ESI): 369.7 [M-55]
With borane-THF In tetrahydrofuran at 0 - 20℃; for 4h;
25.2 3-fluoro-3-(hydroxymethyl)azetidin-1-carboxylic acid tert-butyl ester
1-(tert-Butoxycarbonyl)-3-fluoroazetidin-3-carboxylic acid 25b (10.0 g, 4.6 mmol) was dissolved in 100 mL of fourA solution of borane tetrahydrofuran (100 mL, 1 M/THF) was added dropwise to the mixture, and the mixture was reacted at room temperature for 4 hours. 0 ° C downThe reaction solution was slowly added with 20 mL of methanol to quench the reaction. Concentrate under reduced pressure and add 200 mL of saturated sodium bicarbonate solution to the residue.Extracted with ethyl acetate (200 mL×3), and the organic phases were combined and washed with saturated sodium chloride solution (150 mL×2).Drying with sodium sulfate, filtration, and concentrated under reduced pressure to give 3-fluoro-3-(hydroxymethyl)azetidine-1-carboxylic acid tert-butyl ester 25c(8.9 g, pale yellow oil), yield: 92%.
N-cyclopropyl-2-(difluoromethoxy)-4-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-6-methoxybenzamide[ No CAS ]
tert-butyl 3-[[3-[4-(cyclopropylcarbamoyl)-3-(difluoromethoxy)-5-methoxyphenyl]imidazo[1,2-a]pyridin-7-yl]oxymethyl]-3-fluoroazetidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Stage #1: 3-fluoro-3-hydroxymethylazetidine-1-carboxylic acid tert-butyl ester With sodium hydride In N,N-dimethyl-formamide; mineral oil for 0.166667h;
Stage #2: N-cyclopropyl-2-(difluoromethoxy)-4-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-6-methoxybenzamide In N,N-dimethyl-formamide; mineral oil at 20℃; for 20h;
2.81 2.81. Cpd 187
To a solution oftert-butyl 3-fluoro-3-(hydroxymethyl)azetidine-l-carboxylate (CAS 1126650-66- 5; 157 mg, 0.77 mmol, 5 eq.) in DMF (1 mL) at RT is added NaH (60% dispersion in mineral oil, 31 mg, 0.77 mmol, 5 eq.) and the mixture is stirred for 10 min. Then Int 1 (60 mg, 0.15 mmol, 1 eq.) is added and the reaction mixture is stirred at RT for 20 h. The reaction is quenched with water and a precipitate forms. The solid is filtered, dried and purified by preparative HPLC to give Cpd 187.
tert-butyl 7-(3-amino-8-((tert-butoxycarbonyl)amino)-7-fluoroisoquinolin-6-yl)-8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-carboxylate[ No CAS ]
tert-butyl 7-[8-(tert-butoxycarbonylamino)-3-[(1-tert-butoxycarbonyl-3-fluoroazetidin-3-yl)methoxycarbonylamino]-7-fluoro-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
35.4%
With N-ethyl-N,N-diisopropylamine In dichloromethane at 0℃; for 2h;
194.1 Step 1: tert-Butyl 7-[8-(tert-butoxycarbonylamino)-3-[(1-tert-butoxycarbonyl-3-fluoro-azetidin-3-yl)methoxycarbonylamino]-7-fluoro-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate
To a solution of tert-butyl 7-[3-amino-8-(tert-butoxycarbonylamino)-7-fluoro-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate (150 mg, 0.29 mmol), tert-butyl 3-fluoro-3-(hydroxymethyl)azetidine-1-carboxylate (116 mg, 0.57 mmol) and DIEA (108 mg, 0.84 mmol) in dichloromethane (15 mL) was added triphosgene (120 mg, 0.40 mmol) at 0° C. The reaction was stirred for 2 hours at 0° C. The reaction mixture was concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with methanol/dichloromethane (15%) to afford tert-butyl 7-[8-(tert-butoxycarbonylamino)-3-[(1-tert-butoxycarbonyl-3-fluoro-azetidin-3-yl)methoxycarbonylamino]-7-fluoro-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate (85 mg, 0.101 mmol, 35.4% yield) as a yellow solid. LCMS (ESI) [M+H]+=757.0.
tert-butyl 3-fluoro-3-formylazetidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
97%
With Dess-Martin periodane In dichloromethane at 20℃; for 2h;
289; 296 Intermediate 39: N-(azetidin-3-ylmethyl)cyclopropanamine dihydrochloride
A suspension of tert-butyl 3-fluoro-3-(hydroxymethyl)azetidine-1-carboxylate (500 mg, 2.44 mmol) and Dess-Martin periodinane (1.24 g, 2.92 mmol) in dichloromethane (15 mL) was stirred at room temperature for 2 hours. The reaction mixture was diluted with an aqueous sodium thiosulfate (10% w/v) and sat. aqueous sodium hydrogen carbonate and stirred for 20 minutes. The mixture was passed through a phase separator and the organics concentrated under reduced pressure yielding a colourless oil, which was taken on without further purification (480 mg; 97% yield).
97%
With Dess-Martin periodane In dichloromethane at 20℃; for 2h;
289; 296 Intermediate 39: N-(azetidin-3-ylmethyl)cyclopropanamine dihydrochloride
A suspension of tert-butyl 3-fluoro-3-(hydroxymethyl)azetidine-1-carboxylate (500 mg, 2.44 mmol) and Dess-Martin periodinane (1.24 g, 2.92 mmol) in dichloromethane (15 mL) was stirred at room temperature for 2 hours. The reaction mixture was diluted with an aqueous sodium thiosulfate (10% w/v) and sat. aqueous sodium hydrogen carbonate and stirred for 20 minutes. The mixture was passed through a phase separator and the organics concentrated under reduced pressure yielding a colourless oil, which was taken on without further purification (480 mg; 97% yield).
tert-butyl 3-fluoro-3-(methoxymethyl)azetidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
98.4%
Stage #1: tert-butyl 3-fluoro-3-(hydroxymethyl)azetidine-1-carboxylate With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 0.166667h;
Stage #2: iodomethane In tetrahydrofuran; mineral oil at 0 - 20℃; for 0.75h;
145.1 Step 1: tert-butyl 3-fluoro-3-(methoxymethyl)azetidine-1-carboxylate.
To a solution of Tert-butyl 3-fluoro-3-(hydroxymethyl)azetidine-1-carboxylate (600 mg, 2.92 mmol) in tetrahydrofuran (14.6 mL) at 0°C was added sodium hydride (60% in mineral oil, 175 mg, 4.39 mmol) and stirred at ambient temperature for 10 minutes. Iodomethane (364 L, 5.85 mmol) was added and stirred at ambient temperature for 45 minutes. The solution was partitioned between saturated NaHCO3 and DCM and the organic layer was washed with brine, dried over Na2SO4, filtered, concentrated, then purified by silica gel chromatography (5-75% EtOAc/hex) to give tert-butyl 3-fluoro-3-(methoxymethyl)azetidine-1-carboxylate (631 mg, 98.4 % yield).
98.4%
Stage #1: tert-butyl 3-fluoro-3-(hydroxymethyl)azetidine-1-carboxylate With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 0.166667h;
Stage #2: iodomethane In tetrahydrofuran; mineral oil at 0 - 20℃; for 0.75h;
145.1 Step 1: tert-butyl 3-fluoro-3-(methoxymethyl)azetidine-1-carboxylate.
To a solution of Tert-butyl 3-fluoro-3-(hydroxymethyl)azetidine-1-carboxylate (600 mg, 2.92 mmol) in tetrahydrofuran (14.6 mL) at 0°C was added sodium hydride (60% in mineral oil, 175 mg, 4.39 mmol) and stirred at ambient temperature for 10 minutes. Iodomethane (364 L, 5.85 mmol) was added and stirred at ambient temperature for 45 minutes. The solution was partitioned between saturated NaHCO3 and DCM and the organic layer was washed with brine, dried over Na2SO4, filtered, concentrated, then purified by silica gel chromatography (5-75% EtOAc/hex) to give tert-butyl 3-fluoro-3-(methoxymethyl)azetidine-1-carboxylate (631 mg, 98.4 % yield).
98.4%
Stage #1: tert-butyl 3-fluoro-3-(hydroxymethyl)azetidine-1-carboxylate With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 0.166667h;
Stage #2: iodomethane In tetrahydrofuran; mineral oil at 0 - 20℃; for 0.75h;
145.1 Step 1: tert-butyl 3-fluoro-3-(methoxymethyl)azetidine-1-carboxylate.
To a solution of Tert-butyl 3-fluoro-3-(hydroxymethyl)azetidine-1-carboxylate (600 mg, 2.92 mmol) in tetrahydrofuran (14.6 mL) at 0°C was added sodium hydride (60% in mineral oil, 175 mg, 4.39 mmol) and stirred at ambient temperature for 10 minutes. Iodomethane (364 L, 5.85 mmol) was added and stirred at ambient temperature for 45 minutes. The solution was partitioned between saturated NaHCO3 and DCM and the organic layer was washed with brine, dried over Na2SO4, filtered, concentrated, then purified by silica gel chromatography (5-75% EtOAc/hex) to give tert-butyl 3-fluoro-3-(methoxymethyl)azetidine-1-carboxylate (631 mg, 98.4 % yield).
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