Structure of 777899-57-7
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CAS No. : | 777899-57-7 |
Formula : | C7H5ClN2O4 |
M.W : | 216.58 |
SMILES Code : | O=C(OC)C1=C([N+]([O-])=O)C=NC(Cl)=C1 |
MDL No. : | MFCD19105213 |
InChI Key : | SBGNWCJYDUUYTN-UHFFFAOYSA-N |
Pubchem ID : | 45480451 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In methanol; chloroform; | To a stirred solution of the above acid (5.3 g, 26.17 mmol) in methanol (50 ml) was added chloroform (200 ml). 2M TMS-diazomethane solution in hexanes was added to the solution dropwise until the color of the solution remained yellow (apprx. 20 ml). The residual TMS-diazomethane was quenched by addition of acetic acid, and the solvent was removed under reduced pressure. The oily residue was subjected to silica gel chromatography eluted with 50-70percent ethyl acetate in hexanes to provide methyl 2-chloro-5-nitroisonicotinate. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | Oxalyl chloride (12.7 g, 100 mmol) was added to a suspension of <strong>[907545-47-5]2-chloro-5-nitroisonicotinic acid</strong> (16 g, 80 mmol) in dichloromethane (150 mL) at 0 C. After the addition was completed, the mixture was stirred at room temperature for 3 h. Methanol (100 mL) was added, the reaction mixture was stirred at room temperature for another 4 h and then concentrated. The crude product was dissolved in dichloromethane (200 mL), the mixture was washed with sodium bicarbonate solution (100 mL*2), dried over anhydrous sodium sulfate and concentrated to obtain methyl 2-chloro-5-nitroisonicotinate (17.2 g, yield: 98%). | |
A solution of 2-chloro-4-methyl-5-nitropyridine (5.13 g, 29.73 mmol) in concentrated sulfuric acid (42 mL) was cooled to 0 C., and chromium trioxide (9.81 g, 98.1 mmol) was added. The mixture was stirred at 0 C. for 1 hour and then warmed to room temperature, with an oil bubbler attached, for overnight stirring. The reaction mixture was poured onto ice (300 ml) and diluted with water (150 ml). The mixture was warmed to room temperature, and the solid was filtered and then dried under vacuum to yield <strong>[907545-47-5]2-chloro-5-nitroisonicotinic acid</strong>. To a stirred solution of the above material (5.3 g, 26.17 mmol) in methanol (50 ml) was added chloroform (200 ml). TMS-diazomethane as a solution in hexane (2M) was added dropwise until the color of the reaction mixture remained yellow (20 mL). The residual TMS-diazomethane was quenched by addition of acetic acid, and the solvent was removed under reduced pressure. The oily residue was subjected to silica gel chromatography eluted with 50-70% ethyl acetate in hexane to provide methyl 2-chloro-5-nitroisonicotinate. A solution of the above material (5.66 g, 26.13 mmol), methyl 4'-(aminomethyl)-3,3'-difluorobiphenyl-2-carboxylate (7.971 g, 28.75 mmol, prepared according to procedures described in WO 03/066577), and triethylamine (3.97 g, 39.20 mmol) in methanol (100 ml) was stirred at room temperature overnight. The solution was then heated at 60 C. for 4 hours and cooled to ambient temperature for continued stirring over the weekend. Solvent was removed, and the residue was subjected to silica gel chromatography eluted with 25-50% ethyl acetate in hexane to provide methyl 2-([3,3'-difluoro-2'-(methoxycarbonyl)biphenyl-4-yl]methyl}amino)-5-nitroisonicotinate as a yellow solid. A solution of the above material (9.3 g, 20.33 mmol) in methanol (330 ml) was purged with nitrogen, and 10% Pd/C catalyst (1 g) was added. The reaction vessel was again purged with nitrogen and then with hydrogen from a balloon. After 23 hours of stirring under hydrogen, nitrogen was bubbled through the solution for 10 minutes prior to filtration through a celite pad. The filtrate was concentrated under reduced pressure to provide methyl 5-amino-2-([3,3'-difluoro-2'-(methoxycarbonyl)biphenyl-4-yl]methyl}amino)isonicotinate. Into a solution of the above material (8.45 g, 19.77 mmol) in THF (440 ml) at 0 C. were added hypophosphorous acid (50% solution in water, 110 ml) and sodium nitrite (2.73 g, 39.54 mmol). After 10 minutes of stirring, a catalytic amount of copper (I) oxide was added every 30 minutes for 7.5 hours. The reaction mixture was partitioned between ethyl acetate and water, and the aqueous layer was extracted with additional ethyl acetate. The combined organic layers were washed with saturated sodium bicarbonate and brine, then dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel chromatography eluted with 20-40% ethyl acetate in hexane to provide methyl 2-([3,3'-difluoro-2'-(methoxycarbonyl)biphenyl-4-yl]methyl}amino)isonicotinate. To a stirred solution of the above material (3.96 g, 9.60 mmol) in methanol (85 ml) was added 1N NaOH (11.5 ml), and the solution was heated at 40 C. for 3.5 hours. Solvent was removed under reduced pressure prior to dilution with water. The aqueous solution was washed with diethyl ether twice, and the residual diethyl ether in the aqueous solution was removed under reduced pressure. The aqueous solution was neutralized by addition of 1N HCl (11.5 ml), and the resulting thick suspension was heated (70 C.) and then slowly cooled to ambient temperature before being cooled to 0 C. for 30 minutes. The solid was filtered and dried under vacuum, providing the title compound as a white solid. LRMS (ES, M+H+): 399. 1H NMR (CD3OD, 400 MHz) delta 8.04 (d, J=5.6 Hz, 1H), 7.55 (m, 1H), 7.44 (t, J=8 Hz, 1H), 7.23 (m, 3H), 7.10 (m, 3H), 4.65 (s, 2H), 3.66 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate; In N,N-dimethyl-formamide; at 20℃;Inert atmosphere; Cooling with ice; | Intermediate 26A: Methyl 2-chloro-5-nitroisonicotinateTo a solution of <strong>[907545-47-5]2-chloro-5-nitroisonicotinic acid</strong> (Intermediate 25A) (0.64 g, 3.17 mmol) in DMF (15 mL) under nitrogen was added sodium carbonate (1.0 g, 9.51 mmol). Reaction cooled in an ice bath and methyliodide (1 .35 g, 9.51 mmol) was added dropwise. After complete addition, reaction allowed to warm to room temperature and stirred overnight under nitrogen. The reaction mixture was filtered and concentrated. The resultant crude material was purified by a 20g silica column eluting with 40percent ethylacetate in hexane to afford methyl 2-chloro-5-nitroisonicotinate (0.62 g, 2.86 mmol). | |
In N,N-dimethyl-formamide; at 0 - 15℃; for 15h; | To a solution of <strong>[907545-47-5]2-chloro-5-nitroisonicotinic acid</strong> (20.2g, 100 mmol) in DMF (500 mL) was added dropwise iodomethane (10 mL, 160 mmol) at 0 . After addition, the mixture was gradually warmed to 15 and stirred for 15 h. The reaction was quenched with saturated aqueous NH4Cl (200 mL) and extracted with EtOAc (300 mL *3) . The combined organic phase was washed with 10aqueous LiCl (50 mL*2) , dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by chromatography (silica gel: 200-300 mesh, petroleum ether/EtOAc 50/1to 10/1, v/v) to give the product as a solid.1HNMR(400 MHz, CDCl3) delta 9.04 (s, 1H) , 7.59 (s, 1H) , 3.97 (s, 3H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Potassium hydroxide (90 g) was dissolved in diethyl ether (300 ml) and water (30 ml), and N-methyl-N-nitrosourea (30.9 g, 300 mmol) was slowly added thereto. After stirring at 0° C. for 20 minutes, the organic layer (ether solution) was separated. 2-Chloro-5-nitroisonicotinic acid (20.2 g, 100 mmol) was dissolved in ethyl acetate (100 ml), and the mixture was cooled to 0° C. Then, the above-described ether solution was added to this mixture, followed by stirring for 1 hour. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=6:1 to 2:1). The obtained compound (10.8 g, 50.0 mmol) was dissolved in methanol (100 ml), and sodium methoxide (8.10 g, 150 mmol) was added thereto, followed by stirring at 65° C. for 4 hours. After cooling to room temperature, the reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=8:1 to 4:1). The obtained compound (8.0 g, 37 mmol) was dissolved in methanol (100 ml), and iron (10.6 g, 175 mmol) and a saturated aqueous ammonium chloride solution (50 ml) were added thereto, followed by stirring at 65° C. for 2 hours. After cooling to room temperature, the pH was adjusted to 7 or higher by adding a saturated aqueous sodium hydrogen carbonate solution. Then, ethyl acetate (100 ml×3) was added, and the organic layer was washed with water and saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. After the solvent was removed under reduced pressure, the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=4:1 to 1:1) to obtain the title compound (5.8 g, 58percent over three steps). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | In diethyl ether; ethyl acetate; at 0℃; for 1h; | (Step 2) Methyl 2-chloro-5-nitro-pyridine-4-carboxylate (0170) (0171) 2-Chloro-5-nitro-pyridine-4-carboxylic acid (20.2 g, 100 mmol) was dissolved in ethyl acetate (100 ml), the resulting solution was cooled to 0° C., then a diazomethane/diethyl ether solution was added thereto, and the resulting mixture was stirred at 0° C. for 1 hour. The reaction liquid was concentrated, then the obtained residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=6:1 to 2:1) to obtain the title compound (20.0 g, 92percent). |
Tags: 777899-57-7 synthesis path| 777899-57-7 SDS| 777899-57-7 COA| 777899-57-7 purity| 777899-57-7 application| 777899-57-7 NMR| 777899-57-7 COA| 777899-57-7 structure
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