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With palladium 10% on activated carbon; hydrogen In ethanol; ethyl acetate at 20℃; for 3.75h;
23.2 Step Two. fe/ -Butyl (4-aminopyridin-2-yl)carbamate (A3).
Step Two. fe/ -Butyl (4-aminopyridin-2-yl)carbamate (A3). A suspension of compound A2 (560 mg, 2.34 mmol) and 10% palladium on carbon (50% wet, 150 mg) in ethanol (10 mL) and ethyl acetate (25 mL) was stirred under 1 atmosphere of hydrogen at ambient temperature for 3.75 h. After this time, the reaction mixture was filtered through a short pad of diatomaceous earth and the filtrate was concentrated under reduced pressure to afford compound A3 (460 mg, 94%) as a white solid: 1H NMR (500 MHz, DMSO- 6) δ 9.15 (br s, 1H), 7.66 (d, J = 5.5 Hz, 1H), 7.01 (d, J = 2.0 Hz, 1H), 6.14 (dd, J = 6.0, 2.5 Hz, 1H), 5.96 (br s, 2H), 1.45 (s, 9H).
With palladium on activated charcoal; hydrogen In methanol at 20℃; for 1h;
66.1 Step 1: Synthesis of Tert-butyl N-(4-aminopyridin-2-yl)carbamate
To a mixture of tert-butyl N-(4-nitropyridin-2-yl)carbamate (2.7 g, 11.29 mmol, 1.0 equiv)in MeOH (20 ml) was added Pd/C (200 mg).The resulting mixture was stirred for 1 h at room temperature under hydrogen atmosphere.The resulting mixture was filtered, the filter cake was washed with MeOH (3x20 mL). The filtrate was concentrated under reduced pressure.The crude product was used in the next step directly without further purification.
In dimethyl sulfoxide at 0 - 20℃; for 1h; Inert atmosphere;
23.3 Steps Three and Four. fe/t-Butyl (4-(6-hydroxy-2,4-dioxo- l,2,3,4- tetrahvdropyrimidine-5-carboxamido)pyridin-2-yl)carbamate (A6).
Steps Three and Four. fe/t-Butyl (4-(6-hydroxy-2,4-dioxo- l,2,3,4- tetrahvdropyrimidine-5-carboxamido)pyridin-2-yl)carbamate (A6). To a stirred solution of compound A3 (460 mg, 2.19 mmol) in anhydrous DMSO (4 mL), at 0-5 °C and under a nitrogen atmosphere, was added Ι, Γ-carbonyldiimidazole (391 mg, 2.40 mmol). The reaction mixture was then stirred at ambient temperature for 1 h to provide a solution of compound A4 in DMSO which was used directly in the subsequent step.
tert-butyl (4-aminopyridin-2-yl)carbamate[ No CAS ]
tert-butyl (4-((7-chloroisoquinolin-1-yl)amino)pyridin-2-yl)carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 140℃;Inert atmosphere;
A mixture of the appropriate chloride (Vila) or (VIIb) (ex: 5-chloro-N-(2-chloropyridin-4-yl)isoquinolin-1 -amine) (1 eq), the appropriate amine NH2-PG1(ex: tert-butyl carbamate)(1.5 eq), Pd2(dba)3 (0.1 eq), XantPhos (0.2 eq) and cesium carbonate (2 eq) in dioxane (5.3 mL/mmol) (pre- degasified) was heated at 140C for 2-5h under nitrogen atmosphere. The mixture was filtered through a celite pad and concentrated under reduced pressure. Alternatively, extractionwith ethyl acetate, washing with brine and drying with sodium sulphate was also performed. The residue was purified by flash column chromatography (dichloromethane/methanol or hexanes/ethyl acetate) to obtain the desired product (Villa) or (VII Ib) (ex: tert-Butyl (4-((5-chloroisoquinolin-1 - yl)am ino)pyridin-2-yl)carbamate). HPLC-MS (method A): Rt= 2.30 mm, [M+H] mlz 371 373. Yield: next step without purification.
Stage #1: 1-ethoxy-3-(2,4,5-trifluorophenyl)propane-1,3-diol; orthoformic acid triethyl ester With acetic anhydride at 100℃; for 2h; Inert atmosphere;
Stage #2: tert-butyl N-(4-aminopyridin-2-yl)carbamate In dimethyl sulfoxide at 20℃; for 2h; Inert atmosphere;
Stage #3: With potassium carbonate In dimethyl sulfoxide Inert atmosphere;
66.2 Step 2: Synthesis of Ethyl 1-{2-[(tert-butoxycarbonyl)amino]pyridin-4-yl}-6,7-difluoro-4- oxoquinoline-3-carboxylate
To a mixture of 1-ethoxy-3-(2,4,5-trifluorophenyl)propane-1,3-diol (85.0 g, 0.34 mol, 1.0 equiv) and triethyl orthoformate (2.71 g, 18.279 mmol, 1.5 equiv) was added Ac2O (3.73 g, 36.56 mmol, 3.0 equiv). The resulting mixture was stirred for 2 h at 100 °C under nitrogen atmosphere. The resulting mixture was concentrated under vacuum.To the above mixture was added tert-butyl N-(4- aminopyridin-2-yl)carbamate (3.82 g, 18.28 mmol, 1.5 equiv) in DMSO (10 ml).The resulting mixture was stirred for 2 h at room temperature under nitrogen atmosphere. To the above mixture was added K2CO3(228.6 g, 1.66 mol, 5.0 equiv). The resulting mixture was stirred overnight. The reaction was quenched with water at room temperature. The precipitated solids were collected by filtration and washed with water. The residue was purified by silica gel column chromatography, eluted with Petroleum ether / EtOAc (5:1) to afford ethyl 1-{2-[(tert-butoxycarbonyl)amino]pyridin-4-yl}- 6,7-difluoro-4-oxoquinoline-3-carboxylate(1.32 g, 24.32%) as a yellow solid. LCMS (ESI) [M+H]+: 446.1.
Stage #1: ethyl 3-(5-chloro-2,4-difluorophenyl)-3-oxopropanoate; orthoformic acid triethyl ester With acetic anhydride at 100℃; for 2h;
Stage #2: tert-butyl N-(4-aminopyridin-2-yl)carbamate In dimethyl sulfoxide at 25℃; for 2h;
Stage #3: With potassium carbonate In dimethyl sulfoxide at 100℃; for 1h;
65.1 Step 1: Synthesis of Ethyl 1-{2-[(tert-butoxycarbonyl)amino]pyridin-4-yl}-6-chloro-7-fluoro-4- oxoquinoline-3-carboxylate
To a mixture of ethyl 3-(5-chloro-2,4-difluorophenyl)-3-oxopropanoate (1.0 g, 3.81 mmol, 1.0 equiv) in acetic anhydride (1.2 g, 11.42 mmol, 3.0 equiv) was added triethyl orthoformate (0.9 g, 5.71 mmol, 1.5 equiv). The resulting mixture was stirred at 100 °C for 2 h. The resulting mixture was concentrated under vacuum. To the resulting mixture in DMSO (70 mL) was added tert-butyl N-(4- aminopyridin-2-yl)carbamate (0.8 g, 3.81 mmol, 1.0 equiv). The resulting mixture was stirred at 25 °C for 2 h. To the resulting mixture was added K2CO3 (1.1 g, 7.61 mmol, 2.0 equiv). The resulting mixture was stirred at 100 °C for 1 h. The reaction was quenched by the addition of 80 mL water. The precipitated solids were collected by filtration. This resulted in ethyl 1-{2-[(tert- butoxycarbonyl)amino]pyridin-4-yl}-6-chloro-7-fluoro-4-oxoquinoline-3-carboxylate (1.8 g, crude) as a yellow solid. LCMS (ESI) [M+H]+: 462.1.
Multi-step reaction with 3 steps
1.1: acetic anhydride / 2 h / 100 °C
1.2: 2 h / 25 °C
1.3: 1 h / 100 °C
2.1: hydrogen bromide / 1.5 h / 100 °C
3.1: triethylamine / dimethyl sulfoxide / 2 h / 100 °C / Inert atmosphere
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