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CAS No. : | 88912-27-0 | MDL No. : | MFCD03094685 |
Formula : | C6H4ClNO2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | MYAZXWFEMDJTFE-UHFFFAOYSA-N |
M.W : | 157.55 | Pubchem ID : | 2735816 |
Synonyms : |
|
Num. heavy atoms : | 10 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.0 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 36.21 |
TPSA : | 50.19 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.54 cm/s |
Log Po/w (iLOGP) : | 0.94 |
Log Po/w (XLOGP3) : | 1.01 |
Log Po/w (WLOGP) : | 1.43 |
Log Po/w (MLOGP) : | -0.51 |
Log Po/w (SILICOS-IT) : | 1.39 |
Consensus Log Po/w : | 0.85 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.56 |
Log S (ESOL) : | -1.83 |
Solubility : | 2.32 mg/ml ; 0.0148 mol/l |
Class : | Very soluble |
Log S (Ali) : | -1.65 |
Solubility : | 3.5 mg/ml ; 0.0222 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -2.0 |
Solubility : | 1.57 mg/ml ; 0.00998 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.24 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P280-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302 | Packing Group: | N/A |
GHS Pictogram: |
* 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 |
---|---|---|
56% | Stage #1: With potassium carbonate In dimethyl sulfoxide for 0.5 h; Stage #2: at 20℃; for 2 h; |
Potassium carbonate (36.3 g, 263 mmol) was added to 3-chloroisonicotinic acid (10.35 g, 65.7 mmol) in DMSO (50 mL). After 30 min, MeI (8.22 mL, 131 mmol) was added. The mixture was stirred at room temperature for 2 h, quenched with saturated NH4Cl (300 mL) and water (200 mL), and extracted with EtOAc (3x200 mL). The combined extracts were washed with brine (2x50 mL), dried (MgSO4) and concentrated. Silica gel chromatography, eluting with 10-30percent ethyl acetate in hexanes, gave methyl 3-chloroisonicotinate as a colorless liquid (6.275 g, 56percent yield). MS (ES+) m/z: 172 (M+H); LC retention time: 2.45 min (analytical |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
12% | With hydrogenchloride; n-butyllithium; carbon dioxide; diisopropylamine; lithium diisopropyl amide In tetrahydrofuran | A. 3-Chloro-N-(4-chlorophenyl)pyridine-4-carboxamide. A solution of 3-chloropyridine (1.00 mL, 10.5 mmol) in THF at -78° C. was treated dropwise with a solution of lithium diisopropylamide in THF [freshly prepared by addition of butyllithium (7.21 mL, 11.5 mmol) to diisopropylamine (11.5 mmol)]. After 0.25 h, the mixture was treated with carbon dioxide(g) and slowly warmed to ambient temperature. The mixture was concentrated, partitioned between EtOAc and water, and the aqueous layer was washed with EtOAc (2*). The pH of the aqueous layer was adjusted (~3) by addition of 1 N HCl and then washed with EtOAc (3*). The combined extracts were dried with magnesium sulfate and concentrated. The residue was recrystallized from EtOAc yielding 200 mg (12percent) of 3-chloroisonicotinic acid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | Potassium carbonate (36.3 g, 263 mmol) was added to 3-chloroisonicotinic acid (10.35 g, 65.7 mmol) in DMSO (50 mL). After 30 min, MeI (8.22 mL, 131 mmol) was added. The mixture was stirred at room temperature for 2 h, quenched with saturated NH4Cl (300 mL) and water (200 mL), and extracted with EtOAc (3x200 mL). The combined extracts were washed with brine (2x50 mL), dried (MgSO4) and concentrated. Silica gel chromatography, eluting with 10-30% ethyl acetate in hexanes, gave methyl 3-chloroisonicotinate as a colorless liquid (6.275 g, 56% yield). MS (ES+) m/z: 172 (M+H); LC retention time: 2.45 min (analytical |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With copper; | Method HAn appropriate aromatic o-halocarboxylic acid is suspended in f°r/-butanol or another suitable solvent with approximately 1.5 equivalents of an appropriate beta-diketone. To this mixture is added approximately 0.25 equivalents of copper, copper (I) bromide or copper (I) iodide. The suspension is then treated with approximately 1.6 equivalents of potassium fert-butoxide or sodium ethoxide, sealed in a pressure-resistant vessel and heated in a microwave reactor with stirring at around 180C for approximately 1 hour. Alternatively, a solvent with a sufficiently high boiling point (such as izetaiV-dimethylacetamide) may be used and the mixture is heated at reflux in an open vessel until the substrate has been substantially converted. The resulting mixture is diluted with water, neutralised with aqueous NH4Cl and extracted with a suitable organic solvent. The organic extracts are dried and concentrated and the residue may be purified by flash chromatography. The lactone intermediate is then hydrolysed by treatment with dilute aqueous hydroxide solution using acetonitrile as a co-solvent.3-r2-(4-Chlorophenyl)-2-oxoethyl]-isonicotinic acid3-[2-(4-Chlorophenyl)-2-oxoethyl]-isonicotinic acid (above) was prepared by Method H using <strong>[88912-27-0]3-chloro-isonicotinic acid</strong> and l,3-bis-(4-chlorophenyl)-propane-l,3-dione. <n="52"/>1H NMR (300 MHz, d6-DMSO) delta 4.74 (s, 2H), 7.62 (d, 2H, J 8.7Hz), 7.72 (d, IH, J 5.0Hz), 8.06 (d, 2H, J8.7Hz), 8.51 (s, IH), 8.57 (d, lH, J5.0Hz).ESI-MS m/z calculated [M+H]+: 276.0; found: 276.1 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
130 mg (38%) | In pyridine; dichloromethane; | A solution of the acid (200 mg) in methylene chloride (6 mL) and dimethyl formamide (0.01 mL) was treated with oxalyl chloride (0.22 mL, 2.55 mmol). After 0.25 h, the mixture was concentrated, the residue dissolved in methylene chloride (6 mL) and then added dropwise to a solution of 4-chloroaniline (323 mg, 2.55 mmol) in pyridine (4 mL). After 1 h, the mixture was concentrated, the residue partitioned between EtOAc and water, the organic layer was washed with 1 N NaOH, brine, and dried with sodium sulfate; then concentrated. The residue was purified by column chromatography (SiO2, 2:3 EtOAc:hexanes) yielding 130 mg (38%) of the title compound. 1NMR; IS-MS, m/e 265 (m-1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
200 mg (12%) | With hydrogenchloride; n-butyllithium; carbon dioxide; diisopropylamine; lithium diisopropyl amide; In tetrahydrofuran; | A. 3-Chloro-N-(4-chlorophenyl)pyridine-4-carboxamide. A solution of 3-chloropyridine (1.00 mL, 10.5 mmol) in THF at -78 C. was treated dropwise with a solution of lithium diisopropylamide in THF [freshly prepared by addition of butyllithium (7.21 mL, 11.5 mmol) to diisopropylamine (11.5 mmol)]. After 0.25 h, the mixture was treated with carbon dioxide(g) and slowly warmed to ambient temperature. The mixture was concentrated, partitioned between EtOAc and water, and the aqueous layer was washed with EtOAc (2*). The pH of the aqueous layer was adjusted (~3) by addition of 1 N HCl and then washed with EtOAc (3*). The combined extracts were dried with magnesium sulfate and concentrated. The residue was recrystallized from EtOAc yielding 200 mg (12%) of 3-chloroisonicotinic acid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1-(3-Chloro-4-pyridyl)-5(4H)-tetrazolinone (1.8 g) was obtained by the same process as was used in the Example 2 with the exception that <strong>[88912-27-0]3-chloroisonicotinic acid</strong> (4.7 g) was used instead of 2-chloroisonicotinic acid. m.p. 176-178.5 C. (decomposition). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With thionyl chloride; at 20℃; for 20h; | Preparation of 3-methyl-isonicotinoyl chloride; To <strong>[88912-27-0]3-chloroisonicotinic acid</strong> (413 mg, 2.62 mmol) was added thionyl chloride (5mL,68.5 mmol). The reaction mixture was stirred at room temperature for about 20 hours. The solution was concentrated under reduced pressure and the residue was dried under high vacuum for 1 hour to give 3-chloro-isonicotinoyl chloride. | |
With thionyl chloride; for 3h;Reflux;Product distribution / selectivity; | Reference Production Example 57 A mixture of 0.88 g of <strong>[88912-27-0]3-chloroisonicotinic acid</strong>, 5 ml of thionyl chloride and 20 mg of DMF was heated to reflux for three hours. After the reaction mixture was cooled to room temperature, it was concentrated under reduced pressure to give <strong>[88912-27-0]3-chloroisonicotinic acid</strong> chloride. The resultant <strong>[88912-27-0]3-chloroisonicotinic acid</strong> chloride and 4 ml of DMF was added dropwise to a mixture of 1.0 g of 3-amino-2-hydroxy-5-trifluoromethylpyridine, 1.14 g of triethylamine and 8 ml of DMF while ice-cooling. The reaction mixture was stirred at room temperature for one hour, and then stirred while heating at 50C for 30 minutes. The reaction mixture was cooled to room temperature, and then water was added to the reaction mixture, followed by extraction with ethyl acetate twice. The combined organic layers were washed with water and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.87 g of 3-chloro-N-[2-hydroxy-5-(trifluoromethyl)pyridin-3-yl]isonicotinamide. [Show Image] 1H-NMR (CDCl3) delta: 12.59 (br s, 1H), 9.18 (br s, 1H), 8.85-8.83 (m, 1H), s, (s, 1H), 8.69 (d, J=4.9 Hz, 1H), 7.69 (d, J=4.9 Hz, 1H), 7.55-7.53 (m, 1H) | |
With thionyl chloride; for 3.5h;Reflux; | Reference Production Example 41A mixture of 0.69 g of <strong>[88912-27-0]3-chloroisonicotinic acid</strong>, 5 ml of thionyl chloride and 30 mg of DMF was heated to reflux for 3.5 hours. The reaction mixture was cooled to room temperature, and then the reaction mixture was concentrated under reduced pressure to give <strong>[88912-27-0]3-chloroisonicotinic acid</strong> chloride. A mixture of the resultant <strong>[88912-27-0]3-chloroisonicotinic acid</strong> chloride and 4 ml of DMF was added dropwise to a mixture of 0.85 g of 2-amino-5-fluoro-4-trifluoromethylphenol, 0.88 g of triethylamine and 4 ml of DMF while ice-cooling. Thereafter, the reaction mixture was stirred at room temperature for one hour and at 50 C. for one hour. The reaction mixture was cooled to room temperature, and then water was added, followed by extraction with ethyl acetate twice. The combined organic layers wee washed with water and a saturated sodium chloride solution, then dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resultant solid was washed with diethyl ether to give 0.77 g of 3-chloro-N-[4-fluoro-2-hydroxy-5-(trifluoromethyl)phenyl]-isonicotinamide.1H-NMR (DMSO-d6) delta: 10.20 (br s, 1H), 8.75 (s, 1H), 8.64 (d, J=4.8 Hz, 1H), 8.23 (d, J=8.5 Hz, 1H), 7.62 (d, J=4.8 Hz, 1H), 6.91-6.85 (m, 1H) |
With thionyl chloride; In N,N-dimethyl-formamide; for 3.5h;Reflux; | Reference Production Example 41A mixture of 0.69 g of <strong>[88912-27-0]3-chloroisonicotinic acid</strong>, 5 ml of thionyl chloride and 30 mg of DMF was heated to reflux for 3.5 hours. The reaction mixture was cooled to room temperature, and then the reaction mixture was concentrated under reduced pressure to give <strong>[88912-27-0]3-chloroisonicotinic acid</strong> chloride. A mixture of the resultant <strong>[88912-27-0]3-chloroisonicotinic acid</strong> chloride and 4 ml of DMF was added dropwise to a mixture of 0.85 g of 2-amino-5-fluoro-4- trifluoromethylphenol, 0.88 g of triethylamine and 4 ml of DMF while ice-cooling.Thereafter, the reaction mixture was stirred at room temperature for one hour and at 50C for one hour. The reaction mixture was cooled to room temperature, and then water was added, followed by extraction with ethyl acetate twice. The combined organic layers wee washed with water and a saturated sodium chloride solution, then dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resultant solid was washed with diethyl ether to give 0.77 g of 3-chloro-N-[4-fluoro-2-hydroxy-5-(trifluoromethyl)phenyl]- isonicotinamide.1H-NMR (DMSO-d6) delta: 10.20 (br s, 1H), 8.75 (s, 1H), 8.64 (d, J=4.8 Hz, 1H), 8.23 (d, J=8.5 Hz, 1H), 7.62 (d, J=4.8 Hz, 1H), 6.91-6.85 (m, 1H) | |
With thionyl chloride; In N,N-dimethyl-formamide; for 3h;Reflux; | Reference Production Example 57A mixture of 0.88 g of <strong>[88912-27-0]3-chloroisonicotinic acid</strong>, 5 ml of thionyl chloride and 20 mg of DMF was heated to reflux for three hours. After the reaction mixture was cooled to room temperature, it was concentrated under reduced pressure to give <strong>[88912-27-0]3-chloroisonicotinic acid</strong> chloride. The resultant <strong>[88912-27-0]3-chloroisonicotinic acid</strong> chloride and 4 ml of DMF was added dropwise to a mixture of 1.0 g of 3-amino-2-hydroxy-5-trifluoromethylpyridine, 1.14 g of triethylamine and 8 ml of DMF while ice-cooling. The reaction mixture was stirred at room temperature for one hour, and then stirred while heating at 50C for 30 minutes. The reaction mixture was cooled to room temperature, and then water was added to the reaction mixture, followed by extraction with ethyl acetate twice. The combined organic layers were washed with water and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.87 g of 3-chloro-N-[2-hydroxy-5- (trifluoromethyl)pyridin-3-yl]isonicotinamide.1H-NMR (CDC13) delta: 12.59 (br s, 1H), 9.18 (br s, 1H), 8.85-8.83 (m, 1H), 8.77 (s, 1H), 8.69 (d, J=4.9 Hz, 1H), 7.69 (d, J=4.9 Hz, 1H), 7.55-7.53 (m, 1H) | |
With thionyl chloride; In N,N-dimethyl-formamide; for 3.5h;Reflux;Product distribution / selectivity; | A mixture of 0.69 g of <strong>[88912-27-0]3-chloroisonicotinic acid</strong>, 5 ml of thionyl chloride and 30 mg of DMF was heated to reflux for 3.5 hours. The reaction mixture was cooled to room temperature, and then the reaction mixture was concentrated under reduced pressure to give <strong>[88912-27-0]3-chloroisonicotinic acid</strong> chloride. A mixture of the resultant <strong>[88912-27-0]3-chloroisonicotinic acid</strong> chloride and 4 ml of DMF was added dropwise to a mixture of 0.85 g of 2-amino-5-fluoro-4- trifluoromethylphenol, 0.88 g of triethylamine and 4 ml of DMF while ice-cooling.Thereafter, the reaction mixture was stirred at room temperature for one hour and at 50C for one hour. The reaction mixture was cooled to room temperature, and then water was added, followed by extraction with ethyl acetate twice. The combined organic layers wee washed with water and a saturated sodium chloride solution, then dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resultant solid was washed with diethyl ether to give 0.77 g of 3-chloro-N-[4-fluoro-2-hydroxy-5-(trifluoromethyl)phenyl]- isonicotinamide.-NMR (DMSO-d6) delta: 10.20 (br s, 1H), 8.75 (s, 1H), 8.64 (d, J=4.8 Hz, 1H), 8.23 (d, J=8.5 Hz, 1H), 7.62 (d, J=4.8 Hz, 1H), 6.91-6.85 (m, 1H) | |
With thionyl chloride; In N,N-dimethyl-formamide; for 3 - 3.5h;Reflux; | A mixture of 0.69 g of <strong>[88912-27-0]3-chloroisonicotinic acid</strong>, 5 ml of thionyl chloride and 30 mg of DMF was heated to reflux for 3.5 hours. The reaction mixture was cooled to room temperature, and then the reaction mixture was concentrated under reduced pressure to give <strong>[88912-27-0]3-chloroisonicotinic acid</strong> chloride. A mixture of the resultant <strong>[88912-27-0]3-chloroisonicotinic acid</strong> chloride and 4 ml of DMF was added dropwise to a mixture of 0.85 g of 2-amino-5-fluoro-4- trifluoromethylphenol, 0.88 g of triethylamine and 4 ml of DMF while ice-cooling.Thereafter, the reaction mixture was stirred at room temperature for one hour and at 50C for one hour. The reaction mixture was cooled to room temperature, and then water was added, followed by extraction with ethyl acetate twice. The combined organic layers wee washed with water and a saturated sodium chloride solution, then dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resultant solid was washed with diethyl ether to give 0.77 g of 3-chloro-N-[4-fluoro-2-hydroxy-5-(trifluoromethyl)phenyl]- isonicotinamide. 1 H-NMR (DMSO-d6) delta: 10.20 (br s, IH), 8.75 (s, IH), 8.64 (d, J=4.8 Hz, IH), 8.23 (d, J=8.5 Hz, IH), 7.62 (d, J=4.8 Hz, IH), 6.91-6.85 (m, IH) | |
With thionyl chloride; for 3.5h;Reflux;Product distribution / selectivity; | Reference Production Example 41A mixture of 0.69 g of <strong>[88912-27-0]3-chloroisonicotinic acid</strong>, 5 ml of thionyl chloride and 30 mg of DMF was heated to reflux for 3.5 hours. The reaction mixture was cooled to room temperature, and then the reaction mixture was concentrated under reduced pressure to give <strong>[88912-27-0]3-chloroisonicotinic acid</strong> chloride. A mixture of the resultant <strong>[88912-27-0]3-chloroisonicotinic acid</strong> chloride and 4 ml of DMF was added dropwise to a mixture of 0.85 g of 2-amino-5-fluoro-4- trifluoromethylphenol, 0.88 g of triethylamine and 4 ml of DMF while ice-cooling.Thereafter, the reaction mixture was stirred at room temperature for one hour and at 50C for one hour. The reaction mixture was cooled to room temperature, and then water was added, followed by extraction with ethyl acetate twice. The combined organic layers wee washed with water and a saturated sodium chloride solution, then dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resultant solid was washed with diethyl ether to give 0.77 g of 3-chloro-N-[4-fluoro-2-hydroxy-5-(trifluoromethyl)phenyl]- isonicotinamide.-NMR (DMSO-d6) delta: 10.20 (br s, 1H), 8.75 (s, 1H), 8.64 (d, J=4.8 Hz, 1H), 8.23 (d, J=8.5 Hz, 1H), 7.62 (d, J=4.8 Hz, 1H), 6.91-6.85 (m, 1H) | |
With thionyl chloride; In N,N-dimethyl-formamide; for 3.5h;Reflux;Product distribution / selectivity; | Reference Production Example 41A mixture of 0.69 g of <strong>[88912-27-0]3-chloroisonicotinic acid</strong>, 5 ml of thionyl chloride and 30 mg of DMF was heated to reflux for 3.5 hours. The reaction mixture was cooled to room temperature, and then the reaction mixture was concentrated under reduced pressure to give <strong>[88912-27-0]3-chloroisonicotinic acid</strong> chloride. | |
With thionyl chloride; at 20℃; for 20h; | Preparation of 3-chloro-isonicotinoyl chloride; To <strong>[88912-27-0]3-chloroisonicotinic acid</strong> (413 mg, 2.62 mmol) was added thionyl chloride (5 mL, 68.5 mmol). The reaction mixture was stirred at RT for about 20 h. The solution was concentrated under reduced pressure and the residue was dried under high vacuum for 1 h to give 3-chloro- isonicotinoyl chloride. | |
136 mg | With oxalyl dichloride; In dichloromethane; N,N-dimethyl-formamide; at 20℃; for 3h;Inert atmosphere; | To a so[ution of 121 mg (0.77 mmo[) 3-ch[oroisonicotinic acid and 349 pL (9.77 mmo[) oxa[y[ ch[oride in 4 mL dry dich[oromethane, a few drops of DMF were added under an argon atmosphere. After stirring for 3 hours at room temperature the reaction mixture was concentrated in vacuo to give 136 mg of the tit[e compound as a so[id materia[ which was used without further purification. |
With thionyl chloride; N,N-dimethyl-formamide; at 80℃; for 3h; | General procedure: To a solution of 3m-o (5mmol) and catalyzed DMF (3-4 drops) in anhydrous thionyl chloride (20mL) was stirred at 80C for about 3 hours. After cooling to room temperature, the solution was removed under vacuum, the residue was directly used in the next step, without further purified. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97.4% | step 1-To a solution of 140 (1 mmol) in DCM (10 ml) was added EDC-HCl (1.1 mmol), HOBt (1.1 mmol), NMP (2.5 mmol). The resulting mixture was stirred at RT for 5 min, then 116 (1 mmol) was added and the reaction was stirred for 5 h. The mixture was quenched with a solution of 2% NaOH (10 mL) and extracted with DCM (3*10 mL). The combined organic extracts was washed with brine (15 mL), dried (Na2SO4), filtered, and evaporated to afford 659 mg (97.4%) of 142 a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 2.1; N-(3-chloroisonicotinoyl)-0-{2-[6-(tnethylamino)pyridin-2-yllethvU-L-tyrosineTo a solution of 3-chloro-4-pyridine carboxylic acid (58 mg, 0.37 mmol) in DMF (1 ml) was added POCl3 (80 mul, 0.86 mmol). The mixture was stirred at room temperature for 1 hour. A suspension of methyl O-{2-[6-(methylamino)pyridin-2-yl]ethyl}-L-tyrosinate dihydrochloride (NMR strength 90%) (110 mg, 0.25 mmol) and N-methylmorpholine (135 mul, 1.23 mmol) in methylene chloride (1 ml) was added. The reaction mixture was stirred at room temperature for 1 hour and evaporated to dryness. The residue was redisolved in MeOH (0.5 ml). Then LiOH (103 mg, 2.46 mmol) and water (0.5 ml) were added and the mixture was stirred for 24 hours. A filtration was directly followed by purification by Cl 8 reverse phase chromatography (basic conditions) to afford example 2.1 as a solid (30 mg, 26%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | To a mixture of <strong>[88912-27-0]3-chloroisonicotinic acid</strong> (0.89 g, 5.48 mmol) in acetonitrile (10 ml_) was added lambda/-[3-(dimethylamino)propyl]-/V-ethylcarbodiimide hydrochloride (1.05 g, 5.50 mmol) <n="47"/>and 1H-1 ,2,3-benzotriazol-1-ol (0.84 g, 5.50 mmol) and it was stirred at room temperature for 30 min. A solution of Intermediate 1 (1.30 g, 5.30 mmol) and triethyl amine (0.78 ml_, 5.6 mmol) in acetonitrile (10 ml_) was added during 15 min and the resulting mixture was stirred at room temperature for 1 hour. Water (40 ml_) was added and the precipitate was filtered, rinsed with water and dried to yield the title compound as a yellowish solid (1.37 g, 68%).LRMS (m/z): 375 (M+1)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With diphenyl phosphoryl azide; triethylamine; at 100℃; for 5.5h; | Example 6: Preparation of N'- (4- { [5-bromo-2- (3-chloro- pyridin -2-yl) -2H-pyrazole-3-carbonyl] -amino}-5-chloro- pyridine-3- carbonyl) -hydrazinecarboxylic acid methyl ester (6); Step 1: Preparation of (3-chloro-pyridin-4-yl) -carbamic acid fcert-butyl ester; 3-Chloro-isonicotinic acid (3.0 g) was dissolved in tert- butanol (80 rtiL) , diphenyl phosphoryl azide (5.24 g) and triethylamine (2.7 mL) were added and the reaction mixture was stirred at 1000C for 5.5 h. After cooling to room temperature, the reaction mixture was concentrated in vacuum and the residue was dissolved in ethyl acetate and water. The layers were separated and the aqueous layer was 2x extracted with ethyl acetate, the combined organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuum. The residue was purified by column chromatography (silica 60, hexane/ethyl acetate 3:1, Rf =0.30) to afford 2.74 g of the title compound of the formulaas a white solid. 1H-NMR (CDCl3, TMS) delta (ppm) : 1.55 (9H, s) , 7.18 (IH, br s) , 8.15 (IH, d, J = 6 Hz), 8.36 (IH, d, J = 6 Hz), 8.46 (IH, s) . |
Yield | Reaction Conditions | Operation in experiment |
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81% | 3-isobutoxyisonicotinic acid[00200] Sodium metal (7.3 g, 0.32 mol) was added in small portions to 2-methyl-l-propanol (145 mL, 0.63 mol) at 80 0C over 30 min period, and the reaction mixture was stirred for an additional 3 h at 80 0C. Subsequently, a solution of commerially available <strong>[88912-27-0]3-chloroisonicotinic acid</strong> (1Og, 63 mmol) in 5 mL of DMSO was added to the reaction mixture at 80 0C. The resulting slurry was heated to 120 0C for an additional 16h, then cooled down to room temperature, concentrated down to half volume under the reduced pressure, and filtered. The filtrate was concentrated down to half volume under the reduced pressure, and filterred again. The combined solids were mixed with 10 mL of MeOH and 1 mL of water and acidified with concentrated HCl at 0 0C to pH = 7. The resulting precipitate was filterred out and dried under <n="56"/>vacuum, resulting in 10 g ( 81%) of 3-isobutoxyisonicotinic acid. 1H-NMR (400MHz, beta- DMSO): delta 8.47 (s, IH), 8.23 (d, IH), 7.46 (d, IH), 3.91 (d, 2H), 2.04 (m, IH), 0.94 (d, 6H). MS (EI) for C10 H13NO3: 196 (MH+). | |
81% | Sodium metal (7.3 g, 0.32 mol) was added in small portions to 2-methyl-l- propanol (145 mL, 0.63 mol) at 80 0C over 30 min period, and the reaction mixture was stirred for an additional 3 h at 80 0C. Subsequently, a solution of 3- chloroisonicotinic acid (1Og, 63 mmol) in 5 mL of DMSO was added to the reaction mixture at 80 0C. The resulting slurry was heated to 120 0C for an additional 16h, then cooled down to room temperature, concentrated down to half volume under the reduced pressure, and filterred. The filtrate was concentrated down to half volume under the reduced pressure, and filterred again. The combined solids were mixed with 10 mL of MeOH and 1 mL of water and acidified with concentrated HCl at 0 0C to pH = 7. The resulting precipitate was filterred out and dried under vacuum, resulting in 10 g ( 81%) of 3-isobutoxyisonicotinic acid. 1H-NMR (400MHz, d6- <n="266"/>DMSO): 8.47 (s, IH), 8.23 (d, IH), 7.46 (d, IH), 3.91 (d, 2H), 2.04 (m, IH), 0.94 (d, 6H). MS (EI) for Ci0 Hi3NO3: 196 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
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With thionyl chloride; In toluene; at 20 - 100℃; for 3h; | To a suspension of <strong>[88912-27-0]3-chloroisonicotinic acid</strong> (750 mg, 4.76 mmol, 1.0 eq) in 25 mL of toluene was added thionyl chloride (3.0 mL, 41.6 mmol, 8.7 eq) at room temperature. The reaction mixture was stirred at 100 C for 3 hours. The mixture was concentrated under reduced pressure, dissolved in 25 mL of toluene and concentrated again to give crude 3- chloroisonicotinoyl chloride hydrochloride salt, which was used in the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
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58% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃; for 20h; | Example 1-964-(3-Chloro-4-pyridinyl)-7V-(3-methylphenyl)-l,3-thiazol-2-amine (174). [0380] 3-Chloro-7V-methyl-7V-(methyloxy)-4-pyridinecarboxamide (171). Et3N(7.1 mL, 50.8 mmol) was added to a stirred suspension of 3-chloro-4- pyridinecarboxylic acid (2.0 g, 12.7 mmol), EDCI (2.68 g, 14 mmol), HOBT (1.9 g, 14.0 mmol) and MeNHOMe-HCl (1.86 g, 19.0 mmol) in dry DCM (50 mL), and the mixture was stirred at 20 0C for 20 h. The resulting solution was diluted with DCM (110 mL) and washed with water (2 x 50 mL), washed with brine (50 mL), dried and the solvent evaporated. The residue was purified by column chromatography, eluting with 50% EtO Ac/pet, ether, to give amide 171 (1.46 g, 58%) as a white solid: mp (EtO Ac/pet, ether) 54-56 0C; 1H NMR (CDCl3) delta 8.65 (s, 1 H, H-2), 8.55 (d, J= 4.8 Hz, 1 H, H-6), 7.25 (d, J= 4.8 Hz, 1 H, H-5), 3.49 (s, 3 H, OCH3), 3.39 (s, 3 H, NCH3); MS m/z 201.4/203.4 (MH+, 100%). |
Yield | Reaction Conditions | Operation in experiment |
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With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 0.5h; | Example 174: 3-Chloro-Lambda/-(1-{r4-(methyloxy)-2-(trifluoromethyl)phenyllmethyl}- 1H-pyrazol-3-yl)-4-pyridinecarboxamide; To a solution of S-chloro^-pyridinecarboxylic acid (103 mg, 0.654 mmol, Aldrich) in Lambda/,Lambda/-dimethylformamide (0.5 ml) was added HATU (250 mg, 0.657 mmol), DIPEA (0.27 ml, 1.55 mmol) and then 1-[4-(methyloxy)-2-(trifluoromethyl)phenyl]methyl}- 1/-/-pyrazol-3-amine (for a preparation see Intermediate 52)(135 mg, 0.498 mmol). The resulting brown solution was stirred at ambient temperature for 30 min. The reaction mixture was diluted with methanol (1 ml) and purified by MDAP on an Xbridge column using Acetonitrile-Water with an ammonium carbonate modifier (Method E). The solvent was evaporated in vacuo to give the title compound as an orange foam (160 mg); LCMS (System 4) MH+ = 411 , tRET = 2.69 min. Similarly prepared were |
Yield | Reaction Conditions | Operation in experiment |
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A solution of S-chloroisonicotinic acid (0.075 g, 0.48 mmol), lambda/-[(dimethylamino)(3H- [1 l2,3]triazolo[4l5-b]pyridin-3-yloxy)methylene]-lambda/-methylmethanaminium hexafluorophosphate (0.178 g, 0.47 mmol) and lambda/-ethyl-lambda/-isopropylpropan-2-amine (0.15 ml_, 0.86 mmol) in DMF (1mL) was stirred 15 minutes. Finally, 3"-fluoro-3,2':3',4"- terpyridine-5',6'-diamine (Intermediate 1 , 0.11 g, 0.39 mmol) in DMF (2.9 mL) was added and the mixture was stirred at room temperature 3.5 hours. The crude mixture was extracted between ethyl acetate and water. The organic layer was washed with water and brine, dried (MgSO4) and evaporated. The residue (0.195 g) was used in the next step without further purification.ESI/MS m/e: 421 ([M+H]+, C2iH14CIFN6O). |
Yield | Reaction Conditions | Operation in experiment |
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19% | (Example 33) 4-(2-(N'-(3-Chloropyridine-4-carbonyl)hydrazino)-1-(3-ethoxy-4-isopropoxyphenyl)-2-oxoethylamino)benzamidine trifluoroacetate [Show Image] A mixture of <strong>[88912-27-0]3-chloro-4-pyridinecarboxylic acid</strong> (5.0 mg, 0.0317 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (6.1 mg, 0.0318 mmol), 1-hydroxybenzotriazole monohydrate (4.9 mg, 0.0320 mmol) and N,N-dimethylformamide (0.6 ml) was stirred at 0C for 1 hour. To the reaction mixture was added 4-(((3-ethoxy-4-isopropoxyphenyl)hydrazinocarbonylmethyl)amino)benzamidine dihydrochloride (15 mg, 0.0327 mmol) prepared in Example 4b, followed by stirring overnight at room temperature. The reaction mixture was purified by reversed-phase high performance liquid chromatography to give the title compound as a pale yellow solid (3.91 mg, yield: 19%). 1H-NMR (400 MHz, CD3OD) delta: 1.30 (d, J = 6.0 Hz, 6H), 1.40 (t, J = 7.2 Hz, 3H), 4.10 (q, J = 7.2 Hz, 2H), 4.53 (sept, J = 6.0 Hz, 1H), 5.14 (s, 1H), 6.88 (d, J = 8.8 Hz, 2H), 6.96 (d, J = 8.4 Hz, 1H), 7.09 (dd, J = 8.4, 2.0 Hz, 1H), 7.21 (d, J = 2.0 Hz, 1H), 7.58 (dd, J = 4.8, 0.8 Hz, 1H), 7.64 (d, J = 8.8 Hz, 2H), 8.57 (d, J = 4.8 Hz, 1H), 8.68 (d, J = 0.8 Hz, 1H); Mass spectrum (ESI) m/z: 525 (M+H)+ |
Yield | Reaction Conditions | Operation in experiment |
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32% | (Example 18) 4-(2-(N'-(3-Chloropyridine-4-carbonyl)hydrazino)-1-(2-fluoro-4,5-dimethoxyphenyl)-2-oxoethylamino)benzamidine trifluoroacetate [Show Image] A mixture of <strong>[88912-27-0]3-chloroisonicotinic acid</strong> (5.2 mg, 0.0330 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (6.1 mg, 0.0318 mmol), 1-hydroxybenzotriazole monohydrate (4.9 mg, 0.0320 mmol) and N,N-dimethylformamide (1 ml) was stirred at 0C for 1 hour. To the reaction mixture was added 4-(((2-fluoro-4,5-dimethoxyphenyl)hydrazinocarbonylmethyl)amino)benzamidine dihydrochloride (14 mg, 0.0322 mmol) prepared in Example 14d, followed by stirring overnight at room temperature. The reaction mixture was purified by reversed-phase high performance liquid chromatography to give the title compound as a yellow solid (6.24 mg, yield: 32%). 1H-NMR (400 MHz, CD3OD) delta: 3.825 (s, 3H), 3.831 (s, 3H), 5.47 (s, 1H), 6.86 (d, J = 11.6 Hz, 1H), 6.89 (d, J = 8.8 Hz, 2H), 7.21 (d, J = 6.8 Hz, 1H), 7.59 (d, J = 5.2 Hz, 1H), 7.65 (d, J = 8.8 Hz, 2H), 8.58 (d, J = 5.2 Hz, 1H), 8.69 (s, 1H); Mass spectrum (ESI) m/z: 501 (M+H)+ |
Yield | Reaction Conditions | Operation in experiment |
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13% | (Example 61) 2-(4-(1-(4-Carbamimidoylphenylamino)-2-(N'-(3-chloropyridine-4-carbonyl)hydrazino)-2-oxoethyl)-2-ethoxyphenoxy)-N,N-dimethylacetamide trifluoroacetate [Show Image] 3-Chloroisonicotinic acid (6 mg, 0.038 mmol) was dissolved in N,N-dimethylformamide (0.28 ml) and cooled to 0C. To the reaction mixture were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (4 mg, 0.0209 mmol) and 1-hydroxybenzotriazole monohydrate (5 mg, 0.0326 mmol), followed by stirring for 1 hour and addition of a solution of 2-(4-((4-carbamimidoylphenylamino)hydrazinocarbonylmethyl)-2-ethoxyphenoxy)-N,N-dimethylacetamide dihydrochloride (10 mg, 0.015 mmol) prepared in Example 58b in N,N-dimethylformamide (0.1 ml). The reaction mixture was stirred overnight at room temperature and then directly purified by reversed-phase high performance liquid chromatography to give the title compound as a colorless solid (1.80 mg, yield: 13%). 1H-NMR (400 MHz, CD3OD) delta: 1.41 (t, J = 6.8 Hz, 3H), 2.96 (s, 3H), 3.11 (s, 3H), 4.12 (q, J = 7.6 Hz, 2H), 4.80 (s, 2H), 5.15 (s, 1H), 6.87 (d, J = 8.8 Hz, 2H), 6.93 (d, J = 8.4 Hz, 1H), 7.08 (dd, J = 2.0, 8.4 Hz, 1H), 7.23 (d, J = 2.0 Hz, 1H), 7.58 (d, J = 4.8 Hz, 1H), 7.63 (d, J = 8.8 Hz, 2H), 8.57 (d, J = 5.2 Hz, 1H), 8.68 (s, 1H); Mass spectrum (ESI) m/z: 568 (M+H)+ |
Yield | Reaction Conditions | Operation in experiment |
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15% | (64c) 4-(2-(N'-(3-Chloropyridine-4-carbonyl)hydrazino)-1-(5-ethoxy-2-fluoro-4-isopropoxyphenyl)-2-oxoethylamino)benzamidine trifluoroacetate [Show Image] A mixture of <strong>[88912-27-0]3-chloroisonicotinic acid</strong> (5.0 mg, 0.0314 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (6.6 mg, 0.0346 mmol), 1-hydroxybenzotriazole monohydrate (5.3 mg, 0.0346 mmol) and N,N-dimethylformamide (0.8 ml) was stirred at 0C for 30 minutes. To the reaction mixture was added 4-(((5-ethoxy-2-fluoro-4-isopropoxyphenyl)hydrazinocarbonylmethyl)amino)benzamidine dihydrochloride (15 mg, 0.0314 mmol) prepared in Example 64b, followed by stirring overnight at room temperature. The reaction mixture was purified by reversed-phase high performance liquid chromatography to give the title compound (2.55 mg, yield: 15%). 1H-NMR (400 MHz, CD3OD) delta: 1.21 (d, J = 6.4 Hz, 6H), 1.35 (t, J = 6.8 Hz, 3H), 4.01-4.08 (m, 2H), 4.57 (sept, J = 6.4 Hz, 1H), 5.46 (s, 1H), 6.84 (d, J = 11.6 Hz, 1H), 6.87-6.90 (m, 2H), 7.20 (d, J = 7.2 Hz, 1H), 7.59 (d, J = 5.2 Hz, 1H), 7.64-7.67 (m, 2H), 8.58 (d, J = 5.2 Hz, 1H), 8.69 (s, 1H); Mass spectrum (ESI) m/z: 543 (M+H)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28% | (Example 78) 4-(2-(N'-(3-Chloropyridine-4-carbonyl)hydrazino)-1-(3-ethoxy-4-(2-methoxyethoxy)phenyl)-2-oxoethylamino)benzamidine trifluoroacetate [Show Image] A mixture of <strong>[88912-27-0]3-chloroisonicotinic acid</strong> (5.2 mg, 0.0330 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (6.1 mg, 0.0318 mmol), 1-hydroxybenzotriazole monohydrate (4.9 mg, 0.0320 mmol) and N,N-dimethylformamide (0.6 ml) was stirred at 0C for 1 hour. To the reaction mixture was added 4-(((3-ethoxy-4-(2-methoxyethoxy)phenyl)hydrazinocarbonylmethyl)amino)benzamidine dihydrochloride (15 mg, 0.0316 mmol) prepared in Example 73b, followed by stirring overnight at room temperature. The reaction mixture was purified by reversed-phase high performance liquid chromatography to give the title compound as a colorless solid (5.70 mg, yield: 28%). 1H-NMR (400 MHz, CD3OD) delta: 1.39 (t, J = 6.8 Hz, 3H), 3.42 (s, 3H), 3.72-3.75 (m, 2H), 4.07-4.15 (m, 4H), 5.15 (s, 1H), 6.87 (d, J = 8.8 Hz, 2H), 6.99 (d, J = 8.4 Hz, 1H), 7.11 (dd, J = 8.4, 2.0 Hz, 1H), 7.21 (d, J = 2.0 Hz, 1H), 7.58 (d, J = 4.8 Hz, 1H), 7.64 (d, J = 8.8 Hz, 2H), 8.58 (d, J = 4.8 Hz, 1H), 8.68 (s, 1H); Mass spectrum (ESI) m/z: 541 (M+H)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
32% | (Example 55) 4-(1-(4-(2-Dimethylaminoethoxy)-3-ethoxyphenyl)-2-oxo-2-(N'-(3-chloropyridine-4-carbonyl)hydrazino)ethylamino)benzamidine trifluoroacetate [Show Image] 3-Chloroisonicotinic acid (4 mg, 0.025 mmol) was dissolved in N,N-dimethylformamide (0.25 ml) and cooled to 0C. To the reaction mixture were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (4 mg, 0.0209 mmol) and 1-hydroxybenzotriazole monohydrate (5 mg, 0.0326 mmol), followed by stirring for 1 hour and addition of a solution of 4-(((4-(2-dimethylaminoethoxy)-3-ethoxyphenyl)hydrazinocarbonylmethyl)amino)benzamidine bistrifluoroacetate (10 mg, 0.0155 mmol) prepared in Example 52b in N,N-dimethylformamide (0.1 ml). The reaction mixture was stirred overnight at room temperature and then directly purified by reversed-phase high performance liquid chromatography to give the title compound as a colorless solid (3.22 mg, yield: 32%). 1H-NMR (400 MHz, CD3OD) delta: 1.43 (t, J = 6.8 Hz, 3H), 3.03 (s, 6H), 3.58 (t, J = 5.2 Hz, 2H), 4.18 (q, J = 6.8 Hz, 2H), 4.3 (t, J = 4.4 Hz, 2H), 5.19 (s, 1H), 6.88 (d, J = 8.8 Hz, 2H), 7.08 (d, J = 8.0 Hz, 1H), 7.16 (dd, J = 2.0, 8.4 Hz, 1H), 7.32 (d, J = 2.0 Hz, 1H), 7.58 (dd, J = 0.4, 4.4 Hz, 1H), 7.65 (d, J = 9.2 Hz, 2H), 8.56 (d, 4.8 Hz, 1H), 8.68 (s, 1H); Mass spectrum (ESI) m/z: 554 (M+H)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; at 60℃; for 4h; | Reference Production Example 13 To a mixture of 1.77 g of <strong>[454-81-9]2-amino-4-(trifluoromethyl)phenol</strong>, 1.58 g of 3-chloroisonicotinic acid and 15 ml of pyridine, 2.70 g of WSC was added and stirred while heating at 60C for four hours. The reaction mixture was cooled to room temperature, and then concentrated under reduced pressure. Water was added to the residue, followed by extraction with ethyl acetate twice. The combined organic layers were washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was washed with a mixture solvent of tert-butyl methyl ether and hexane to give 1.80 g of 3-chloro-N-[2-hydroxy-5-(trifluoromethyl)phenyl]isonicotinamide. [Show Image] 1H-NMR (DMSO-d6) delta: 10.89 (br s, 1H), 10.19 (br s, 1H), 8.75 (s, 1H), 8.64 (d, J=4.9 Hz, 1H), 8.32 (d, J=2.0 Hz, 1H), 7.63 (d, J=4.9 Hz, 1H), 7.40 (dd, J=8.5, 2.1 Hz, 1H), 7.08 (d, J=8.5 Hz, 1H) | |
With pyridine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; at 60℃; for 4h; | Reference Production Example 13 To a mixture of 1.77 g of <strong>[454-81-9]2-amino-4-(trifluoromethyl)phenol</strong>, 1.58 g of 3-chloroisonicotinic acid and 15 ml of pyridine, 2.70 g of WSC was added and stirred while heating at 60 C. for four hours. The reaction mixture was cooled to room temperature, and then concentrated under reduced pressure. Water was added to the residue, followed by extraction with ethyl acetate twice. The combined organic layers were washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was washed with a mixture solvent of tert-butyl methyl ether and hexane to give 1.80 g of 3-chloro-N-[2-hydroxy-5-(trifluoromethyl)phenyl]isonicotinamide.1H-NMR (DMSO-d6) 5: 10.89 (br s, 1H), 10.19 (br s, 1H), 8.75 (s, 1H), 8.64 (d, J=4.9 Hz, 1H), 8.32 (d, J=2.0 Hz, 1H), 7.63 (d, J=4.9 Hz, 1H), 7.40 (dd, J=8.5, 2.1 Hz, 1H), 7.08 (d, J=8.5 Hz, 1H) | |
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In pyridine; at 60℃; for 4h; | Reference Production Example 13To a mixture of 1.77 g of <strong>[454-81-9]2-amino-4-(trifluoromethyl)phenol</strong>, 1.58 g of 3- chloroisonicotinic acid and 15 ml of pyridine, 2.70 g of WSC was added and stirred while heating at 60C for four hours. The reaction mixture was cooled to room temperature, and then concentrated under reduced pressure. Water was added to the residue, followed by extraction with ethyl acetate twice. The combined organic layers were washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was washed with a mixture solvent of tert-butyl methyl ether and hexane to give 1.80 g of 3-chloro-N-[2-hydroxy-5- (trifluoromethyl)phenyl]isomcotinamide.1H-NMR (DMSO-de) delta: 10.89 (br s, IH), 10.19 (br s, IH), 8.75 (s, IH), 8.64 (d, J=4.9 Hz, IH), 8.32 (d, J=2.0 Hz, IH), 7.63 (d, J=4.9 Hz, IH), 7.40 (dd, J=8.5, 2.1 Hz, IH), 7.08 (d, J=8.5 Hz, IH) |
With pyridine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; at 60℃; for 4h; | To a mixture of 1.77 g of <strong>[454-81-9]2-amino-4-(trifluoromethyl)phenol</strong>, 1.58 g of 3- chloroisonicotinic acid and 15 ml of pyridine, 2.70 g of WSC was added and stirred while heating at 60C for four hours. The reaction mixture was cooled to room temperature, and then concentrated under reduced pressure. Water was added to the residue, followed by extraction with ethyl acetate twice. The combined organic layers were washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was washed with a mixture solvent of tert-butyl methyl ether and hexane to give 1.80 g of 3-chloro-N-[2-hydroxy-5- (trifluoromethyl)phenyl]isonicotinamide.-NMR (DMSO-d6) delta: 10.89 (br s, IH), 10.19 (br s, IH), 8.75 (s, IH), 8.64 (d, J=4.9 Hz, IH), 8.32 (d, J=2.0 Hz, IH), 7.63 (d, J=4.9 Hz, IH), 7.40 (dd, J=8.5, 2.1 Hz, IH), 7.08 (d, J=8.5 Hz, IH) | |
With pyridine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; at 60℃; for 4h; | To a mixture of 1.77 g of <strong>[454-81-9]2-amino-4-(trifluoromethyl)phenol</strong>, 1.58 g of 3- chloroisonicotinic acid and 15 ml of pyridine, 2.70 g of WSC was added and stirred while heating at 60C for four hours. The reaction mixture was cooled to room temperature, and then concentrated under reduced pressure. Water was added to the residue, followed by extraction with ethyl acetate twice. The combined organic layers were washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was washed with a mixture solvent of tert-butyl methyl ether and hexane to give 1.80 g of 3-chloro-N-[2-hydroxy-5- (trifluoromethyl)phenyl]isonicotinamide.1 H-NMR (DMSO-d6) delta: 10.89 (br s, IH), 10.19 (br s, IH), 8.75 (s, IH), 8.64 (d, J=4.9 Hz, IH), 8.32 (d, J=2.0 Hz, IH), 7.63 (d, J=4.9 Hz, IH), 7.40 (dd, J=8.5, 2.1 Hz, IH), 7.08 (d, J=8.5 Hz, IH) | |
With pyridine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; at 60℃; for 4h; | Reference Production Example 13To a mixture of 1.77 g of <strong>[454-81-9]2-amino-4-(trifluoromethyl)phenol</strong>, 1.58 g of 3- chloroisonicotinic acid and 15 ml of pyridine, 2.70 g of WSC was added and stirred while heating at 60C for four hours. The reaction mixture was cooled to room temperature, and then concentrated under reduced pressure. Water was added to the residue, followed by extraction with ethyl acetate twice. The combined organic layers were washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was washed with a mixture solvent of tert-butyl methyl ether and hexane to give 1.80 g of 3-chloro-N-[2-hydroxy-5- (trifluoromethyl)phenyl]isonicotinamide.1H-NMR (DMSO-de) delta: 10.89 (br s, IH), 10.19 (br s, IH), 8.75 (s, IH), 8.64 (d, J=4.9 Hz, IH), 8.32 (d, J=2.0 Hz, IH), 7.63 (d, J=4.9 Hz, IH), 7.40 (dd, J=8.5, 2.1 Hz, IH), 7.08 (d, J=8.5 Hz, IH) | |
With pyridine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; at 60℃; for 4h; | Reference Production Example 13To a mixture of 1.77 g of <strong>[454-81-9]2-amino-4-(trifluoromethyl)phenol</strong>, 1.58 g of 3- chloroisonicotinic acid and 15 ml of pyridine, 2.70 g of WSC was added and stirred while heating at 60C for four hours. The reaction mixture was cooled to room temperature, and then concentrated under reduced pressure. Water was added to the residue, followed by extraction with ethyl acetate twice. The combined organic layers were washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was washed with a mixture solvent of tert-butyl methyl ether and hexane to give 1.80 g of 3-chloro-N-[2-hydroxy-5- (trifluoromethyl)phenyl]isonicotinamide.1 H-NMR (DMSO-d6) delta: 10.89 (br s, IH), 10.19 (br s, IH), 8.75 (s, IH), 8.64 (d, J=4.9 Hz, IH), 8.32 (d, J=2.0 Hz, IH), 7.63 (d, 5=4.9 Hz, IH), 7.40 (dd, J=8.5, 2.1 Hz, IH), 7.08 (d, J=8.5 Hz, IH) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; at 80℃; for 3h; | Reference Production Example 31 A mixture of 0.60 g of 2-amino-4-(trifluoromethylthio)phenol, 0.45 g of <strong>[88912-27-0]3-chloroisonicotinic acid</strong>, 0.71 g of WSC and 6 ml of pyridine was stirred while heating at 80C for three hours. The reaction mixture was cooled to room temperature, and then water was added to the reaction mixture, followed by extraction with ethyl acetate three times. The combined organic layers were washed with water and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.63 g of 3-chloro-N-[2-hydroxy-5-(trifluoromethylthio)phenyl]isonicotinamide. [Show Image] 1H-NMR (DMSO-d6) delta: 10.89 (br s, 1H), 10.14 (br s, 1H), 8.74 (s, 1H), 8.63 (d, J=4.8 Hz, 1H), 8.31 (d, J=2.2 Hz, 1H), 7.63 (d, J=4.8 Hz, 1H), 7.39 (dd, J=8.5, 2.2 Hz, 1H), 7.03 (d, J=8.5 Hz, 1H) | |
With pyridine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; at 80℃; for 3h; | Reference Production Example 31A mixture of 0.60 g of 2-amino-4-(trifluoromethylthio)phenol, 0.45 g of <strong>[88912-27-0]3-chloroisonicotinic acid</strong>, 0.71 g of WSC and 6 ml of pyridine was stirred while heating at 80 C. for three hours. The reaction mixture was cooled to room temperature, and then water was added to the reaction mixture, followed by extraction with ethyl acetate three times. The combined organic layers were washed with water and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.63 g of 3-chloro-N-[2-hydroxy-5-(trifluoromethylthio)phenyl]isonicotinamide.1H-NMR (DMSO-d6) delta: 10.89 (br s, 1H), 10.14 (br s, 1H), 8.74 (s, 1H), 8.63 (d, J=4.8 Hz, 1H), 8.31 (d, J=2.2 Hz, 1H), 7.63 (d, J=4.8 Hz, 1H), 7.39 (dd, J=8.5, 2.2 Hz, 1H), 7.03 (d, J=8.5 Hz, 1H) | |
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In pyridine; at 80℃; for 3h; | Reference Production Example 31A mixture of 0.60 g of 2-amino-4-(trifluoromethylthio)phenol, 0.45 g of 3- chloroisonicotinic acid, 0.71 g of WSC and 6 ml of pyridine was stirred while heating at 80C for three hours. The reaction mixture was cooled to room temperature, and then water was added to the reaction mixture, followed by extraction with ethyl acetate three times. The combined organic layers were washed with water and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.63 g of 3 -chloro-N- [2-hydroxy-5 -(trifluoromethylthio)pheny 1] isonicotinamide.1H-NMR (DMSO-de) delta: 10.89 (br s, IH), 10.14 (br s, IH), 8.74 (s, IH), 8.63 (d, J=4.8 Hz, IH), 8.31 (d, J=2.2 Hz, IH), 7.63 (d, J=4.8 Hz, IH), 7.39 (dd, J=8.5, 2.2 Hz, IH), 7.03 (d, J=8.5 Hz, IH) |
With pyridine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; at 80℃; for 3h; | A mixture of 0.60 g of 2-amino-4-(trifluoromethylthio)phenol, 0.45 g of 3- chloroisonicotinic acid, 0.71 g of WSC and 6 ml of pyridine was stirred while heating at 80C for three hours. The reaction mixture was cooled to room temperature, and then water was added to the reaction mixture, followed by extraction with ethyl acetate three times. The combined organic layers were washed with water and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.63 g of 3-chloro-N-[2-hydroxy-5-(trifluoromethylthio)phenyl]isonicotinamide.1 H-NMR (DMSO-d6) delta: 10.89 (br s, IH), 10.14 (br s, IH), 8.74 (s, IH), 8.63 (d, J=4.8 Hz, IH), 8.31 (d, J=2.2 Hz, IH), 7.63 (d, J=4.8 Hz, IH), 7.39 (dd, J=8.5, 2.2 Hz, IH), 7.03 (d, J=8.5 Hz, IH) | |
With pyridine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; at 80℃; for 3h; | A mixture of 0.60 g of 2-amino-4-(trifluoromethylthio)phenol, 0.45 g of 3- chloroisonicotinic acid, 0.71 g of WSC and 6 ml of pyridine was stirred while heating at 80C for three hours. The reaction mixture was cooled to room temperature, and then water was added to the reaction mixture, followed by extraction with ethyl acetate three times. The combined organic layers were washed with water and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.63 g of 3 -chloro-N- [2-hydroxy-5 -(trifluoromethylthio)phenyl] isonicotinamide .1H-NMR (DMSO-de) delta: 10.89 (br s, IH), 10.14 (br s, IH), 8.74 (s, IH), 8.63 (d, J=4.8 Hz, IH), 8.31 (d, J=2.2 Hz, IH), 7.63 (d, J=4.8 Hz, IH), 7.39 (dd, J=8.5, 2.2 Hz, IH), 7.03 (d, J=8.5 Hz, IH) | |
With pyridine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; at 80℃; for 3h; | Reference Production Example 31A mixture of 0.60 g of 2-amino-4-(trifluoromethylthio)phenol, 0.45 g of 3- chloroisonicotinic acid, 0.71 g of WSC and 6 ml of pyridine was stirred while heating at 80C for three hours. The reaction mixture was cooled to room temperature, and then water was added to the reaction mixture, followed by extraction with ethyl acetate three times. The combined organic layers were washed with water and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.63 g of 3 -chloro-N- [2-hydroxy-5 -(trifluoromethylthio)pheny 1] isonicotinamide.1H-NMR (DMSO-d6) delta: 10.89 (br s, IH), 10.14 (br s, IH), 8.74 (s, IH), 8.63 (d, J=4.8 Hz, IH), 8.31 (d, J=2.2 Hz, IH), 7.63 (d, J=4.8 Hz, IH), 7.39 (dd, J=8.5, 2.2 Hz, IH), 7.03 (d, J=8.5 Hz, IH) | |
With pyridine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; at 80℃; for 3h; | Reference Production Example 31A mixture of 0.60 g of 2-amino-4-(trifluoromethylthio)phenol, 0.45 g of 3- chloroisonicotinic acid, 0.71 g of WSC and 6 ml of pyridine was stirred while heating at 80C for three hours. The reaction mixture was cooled to room temperature, and then water was added to the reaction mixture, followed by extraction with ethyl acetate three times. The combined organic layers were washed with water and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.63 g of 3 -chloro-N- [2-hydroxy-5 -(trifluoromethy lthio)phenyl] isonicotinamide.1 H-NMR (DMSO-de) delta: 10.89 (br s, IH), 10.14 (br s, IH), 8.74 (s, IH), 8.63 (d, J=4.8 Hz, IH), 8.31 (d, J=2.2 Hz, IH), 7.63 (d, J=4.8 Hz, IH), 7.39 (dd, J=8.5, 2.2 Hz, IH), 7.03 (d, J=8.5 Hz, IH) |
Yield | Reaction Conditions | Operation in experiment |
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With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 2h; | Reference Production Example 48 A mixture of 0.3 g of 2-amino-4-trifluoromethoxy phenol, 0.29 g of <strong>[88912-27-0]3-chloroisonicotinic acid</strong>, 1.04 g of (benzotriazole-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (hereinafter, referred to as a BOP reagent), 0.24 g of triethylamine and 5 ml of DMF was stirred at room temperature for two hours. Water was added to the reaction mixture, precipitated solid was collected by filtration. The resultant solid was dissolved in ethyl acetate. Then, the organic layer was washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.43 g of 3-chloro-N-[2-hydroxy-5-(trifluoromethoxy)phenyl]isonicotinamide. [Show Image] 1H-NMR (DMSO-d6) delta: 10.37 (br s, 1H), 10.15 (br s, 1H), 8.75-8.73 (m, 1H), 8.64-8.61 (m, 1H), 8.04-8.01 (m, 1H), 7.63-7.60 (m, 1H), 7.07-7.02 (m, 1H), 6.98-6.94 (m, 1H) | |
With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 2h; | Reference Production Example 48A mixture of 0.35 g of 2-amino-4-trifluoromethoxy phenol, 0.29 g of <strong>[88912-27-0]3-chloroisonicotinic acid</strong>, 1.04 g of (benzotriazole-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (hereinafter, referred to as a BOP reagent), 0.24 g of triethylamine and 5 ml of DMF was stirred at room temperature for two hours. Water was added to the reaction mixture, precipitated solid was collected by filtration. The resultant solid was dissolved in ethyl acetate. Then, the organic layer was washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.43 g of 3-chloro-N-[2-hydroxy-5-(trifluoromethoxy)phenyl]isonicotinamide.1H-NMR (DMSO-d6) delta: 10.37 (br s, 1H), 10.15 (br s, 1H), 8.75-8.73 (m, 1H), 8.64-8.61 (m, 1H), 8.04-8.01 (m, 1H), 7.63-7.60 (m, 1H), 7.07-7.02 (m, 1H), 6.98-6.94 (m, 1H) | |
With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 2h; | Reference Production Example 48A mixture of 0.35 g of 2-amino-4-trifluoromethoxy phenol, 0.29 g of 3- chloroisonicotinic acid, 1.04 g of (benzotriazole-l-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (hereinafter, referred to as a BOP reagent), 0.24 g of triethylamine and 5 ml of DMF was stirred at room temperature for two hours. Water was added to the reaction mixture, precipitated solid was collected by filtration. The resultant solid was dissolved in ethyl acetate. Then, the organic layer was washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.The residue was subjected to silica gel column chromatography to give 0.43 g of 3-chloro- N-[2-hydroxy-5-(trifluoromethoxy)phenyl]isonicotinamide.1H-NMR (DMSO-d6) delta: 10.37 (br s, 1H), 10.15 (br s, 1H), 8.75-8.73 (m, 1H), 8.64-8.61 (m, 1H), 8.04-8.01 (m, 1H), 7.63-7.60 (m, 1H), 7.07-7.02 (m, 1H), 6.98-6.94 (m, 1H) |
With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 2h; | A mixture of 0.35 g of 2-amino-4-trifluoromethoxy phenol, 0.29 g of 3- chloroisonicotinic acid, 1.04 g of (benzotriazole-l-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (hereinafter, referred to as a BOP reagent), 0.24 g of triethylamine and 5 ml of DMF was stirred at room temperature for two hours. Water was added to the reaction mixture, precipitated solid was collected by filtration. The resultant solid was dissolved in ethyl acetate. Then, the organic layer was washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.The residue was subjected to silica gel column chromatography to give 0.43 g of 3-chloro- N-[2-hydroxy-5-(trifluoromethoxy)phenyl]isonicotinamide.-NMR (DMSO-d6) delta: 10.37 (br s, 1H), 10.15 (br s, 1H), 8.75-8.73 (m, 1H), 8.64-8.61 (m, 1H), 8.04-8.01 (m, 1H), 7.63-7.60 (m, 1H), 7.07-7.02 (m, 1H), 6.98-6.94 (m, 1H) | |
With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 2h; | A mixture of 0.35 g of 2-amino-4-trifluoromethoxy phenol, 0.29 g of 3- chloroisonicotinic acid, 1.04 g of (benzotriazole-l-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (hereinafter, referred to as a BOP reagent), 0.24 g of triethylamine and 5 ml of DMF was stirred at room temperature for two hours. Water was added to the reaction mixture, precipitated solid was collected by filtration. The resultant solid was dissolved in ethyl acetate. Then, the organic layer was washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.43 g of 3-chloro- N-[2-hydroxy-5-(trifluoromethoxy)phenyl]isonicotinamide.-NMR (DMSO-d6) delta: 10.37 (br s, 1H), 10.15 (br s, 1H), 8.75-8.73 (m, 1H), 8.64-8.61 (m, 1H), 8.04-8.01 (m, 1H), 7.63-7.60 (m, 1H), 7.07-7.02 (m, 1H), 6.98-6.94 (m, 1H) | |
With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 2h; | Reference Production Example 48A mixture of 0.35 g of 2-amino-4-trifluoromethoxy phenol, 0.29 g of 3- chloroisonicotinic acid, 1.04 g of (benzotriazole-l-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (hereinafter, referred to as a BOP reagent), 0.24 g of triethylamine and 5 ml of DMF was stirred at room temperature for two hours. Water was added to the reaction mixture, precipitated solid was collected by filtration. The resultant solid was dissolved in ethyl acetate. Then, the organic layer was washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.43 g of 3-chloro- N-[2-hydroxy-5-(trifluoromethoxy)phenyl]isonicotinamide.-NMR (DMSO-d6) delta: 10.37 (br s, 1H), 10.15 (br s, 1H), 8.75-8.73 (m, 1H), 8.64-8.61 (m, 1H), 8.04-8.01 (m, 1H), 7.63-7.60 (m, 1H), 7.07-7.02 (m, 1H), 6.98-6.94 (m, 1H) | |
With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 2h; | Reference Production Example 48A mixture of 0.35 g of 2-amino-4-trifluoromethoxy phenol, 0.29 g of 3- chloroisonicotinic acid, 1.04 g of (benzotriazole-l-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (hereinafter, referred to as a BOP reagent), 0.24 g of triethylamine and 5 ml of DMF was stirred at room temperature for two hours. Water was added to the reaction mixture, precipitated solid was collected by filtration. The resultant solid was dissolved in ethyl acetate. Then, the organic layer was washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.43 g of 3-chloro- N-[2-hydroxy-5-(trifluoromethoxy)phenyl]isonicotinamide.1H-NMR (DMSO-d6) delta: 10.37 (br s, 1H), 10.15 (br s, 1H), 8.75-8.73 (m, 1H), 8.64-8.61 (m, 1H), 8.04-8.01 (m, 1H), 7.63-7.60 (m, 1H), 7.07-7.02 (m, 1H), 6.98-6.94 (m, 1H) |
Yield | Reaction Conditions | Operation in experiment |
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Reference Production Example 26 To a mixture of 0.58 g of WSC and 5 ml of pyridine 5ml, 0.48 g of <strong>[88912-27-0]3-chloroisonicotinic acid</strong> was added. The reaction mixture was stirred at room temperature for 25 minutes. To the reaction mixture, 0.75 g of 2-amino-4-(heptafluoroisopropyl)phenol was added and was stirred while heating at 60C for three hours. The reaction mixture was cooled to room temperature, the 0.24 g of <strong>[88912-27-0]3-chloroisonicotinic acid</strong> and 0.29 g of WSC was added and stirred while heating at 60C for 1.5 hours and then at 80C for 1.3 hours. The mixture reaction was cooled to room temperature, and then concentrated under reduced pressure. Then, water was added to the residue, followed by extraction with ethyl acetate twice. The combined organic layers were washed with a saturated sodium chloride solution, was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.90 g of 3-chloro-N-[2-hydroxy-5-(heptafluoroisopropyl)phenyl]isonicotinamide. [Show Image] 1H-NMR (DMSO-d6) delta: 10.19 (br s, 1H), 8.75 (s, 1H), 8.63 (d, J=4.9 Hz, 1H), 8.36 (d, J=1.9 Hz, 1H), 7.65 (d, J=4.9 Hz, 1H), 7.32 (dd, J=8.8, 2.0 Hz, 1H), 7.12 (d, J=8.8 Hz, 1H) | ||
Reference Production Example 26To a mixture of 0.58 g of WSC and 5 ml of pyridine 5m1, 0.48 g of <strong>[88912-27-0]3-chloroisonicotinic acid</strong> was added. The reaction mixture was stirred at room temperature for 25 minutes. To the reaction mixture, 0.75 g of 2-amino-4-(heptafluoroisopropyl)phenol was added and was stirred while heating at 60 C. for three hours. The reaction mixture was cooled to room temperature, the 0.24 g of <strong>[88912-27-0]3-chloroisonicotinic acid</strong> and 0.29 g of WSC was added and stirred while heating at 60 C. for 1.5 hours and then at 80 C. for 1.3 hours. The mixture reaction was cooled to room temperature, and then concentrated under reduced pressure. Then, water was added to the residue, followed by extraction with ethyl acetate twice. The combined organic layers were washed with a saturated sodium chloride solution, was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.90 g of 3-chloro-N-[2-hydroxy-5-(heptafluoroisopropyl)phenyl]isonicotinamide.(DMSO-d6) delta: 10.19 (br s, 1H), 8.75 (s, 1H), 8.63 (d, J=4.9 Hz, 1H), 8.36 (d, J=1.9 Hz, 1H), 7.65 (d, J=4.9 Hz, 1H), 7.32 (dd, J=8.8, 2.0 Hz, 1H), 7.12 (d, J=8.8 Hz, 1H) | ||
Reference Production Example 26To a mixture of 0.58 g of WSC and 5 ml of pyridine 5ml, 0.48 g of 3- chloroisonicotinic acid was added. The reaction mixture was stirred at room temperature for 25 minutes. To the reaction mixture, 0.75 g of 2-amino-4-(heptafluoroisopropyl)phenol was added and was stirred while heating at 60C for three hours. The reaction mixture was cooled to room temperature, the 0.24 g of <strong>[88912-27-0]3-chloroisonicotinic acid</strong> and 0.29 g of WSC was added and stirred while heating at 60C for 1.5 hours and then at 80C for 1.3 hours. The mixture reaction was cooled to room temperature, and then concentrated under reduced pressure. Then, water was added to the residue, followed by extraction with ethyl acetate twice. The combined organic layers were washed with a saturated sodium chloride solution, was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.90 g of 3-chloro-N-[2- hydroxy-5-(heptafluoroisopropyl)phenyl]isonicotinamide.1H-NMR (DMSO-d6) delta: 10.19 (br s, IH), 8.75 (s, IH), 8.63 (d, J=4.9 Hz, IH), 8.36 (d, J=1.9 Hz, IH), 7.65 (d, J=4.9 Hz, IH), 7.32 (dd, J=8.8, 2.0 Hz, IH), 7.12 (d, J=8.8 Hz, IH) |
To a mixture of 0.58 g of WSC and 5 ml of pyridine 5ml, 0.48 g of 3- chloroisonicotinic acid was added. The reaction mixture was stirred at room temperature for 25 minutes. To the reaction mixture, 0.75 g of 2-amino-4-(heptafluoroisopropyl)phenol was added and was stirred while heating at 60C for three hours. The reaction mixture was cooled to room temperature, the 0.24 g of <strong>[88912-27-0]3-chloroisonicotinic acid</strong> and 0.29 g of WSC was added and stirred while heating at 60C for 1.5 hours and then at 80C for 1.3 hours. The mixture reaction was cooled to room temperature, and then concentrated under reduced pressure. Then, water was added to the residue, followed by extraction with ethyl acetate twice. The combined organic layers were washed with a saturated sodium chloride solution, was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.90 g of 3-chloro-N-[2- hydroxy-5 -(heptafluoroisopropyl)phenyl] isonicotinamide.1H-NMR (DMSO-d6) delta: 10.19 (br s, 1H), 8.75 (s, 1H), 8.63 (d, J=4.9 Hz, 1H), 8.36 (d, J=1.9 Hz, 1H), 7.65 (d, J=4.9 Hz, 1H), 7.32 (dd, J-8.8, 2.0 Hz, 1H), 7.12 (d, J=8.8 Hz, 1H) | ||
To a mixture of 0.58 g of WSC and 5 ml of pyridine 5ml, 0.48 g of 3- chloroisonicotinic acid was added. The reaction mixture was stirred at room temperature for 25 minutes. To the reaction mixture, 0.75 g of 2-amino-4-(heptafluoroisopropyl)phenol was added and was stirred while heating at 60C for three hours. The reaction mixture was cooled to room temperature, the 0.24 g of <strong>[88912-27-0]3-chloroisonicotinic acid</strong> and 0.29 g of WSC was added and stirred while heating at 60C for 1.5 hours and then at 80C for 1.3 hours. The mixture reaction was cooled to room temperature, and then concentrated under reduced pressure. Then, water was added to the residue, followed by extraction with ethyl acetate twice. The combined organic layers were washed with a saturated sodium chloride solution, was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.90 g of 3-chloro-N-[2- hydroxy-5-(heptafluoroisopropyl)phenyl]isonicotinamide.-NMR (DMSO-de) delta: 10.19 (br s, 1H), 8.75 (s, 1H), 8.63 (d, J=4.9 Hz, 1H), 8.36 (d, J=1.9 Hz, 1H), 7.65 (d, J=4.9 Hz, 1H), 7.32 (dd, J=8.8, 2.0 Hz, 1H), 7.12 (d, J=8.8 Hz, 1H) | ||
Reference Production Example 26To a mixture of 0.58 g of WSC and 5 ml of pyridine 5ml, 0.48 g of 3- chloroisonicotinic acid was added. The reaction mixture was stirred at room temperature for 25 minutes. To the reaction mixture, 0.75 g of 2-amino-4-(heptafluoroisopropyl)phenol was added and was stirred while heating at 60C for three hours. The reaction mixture was cooled to room temperature, the 0.24 g of <strong>[88912-27-0]3-chloroisonicotinic acid</strong> and 0.29 g of WSC was added and stirred while heating at 60C for 1.5 hours and then at 80C for 1.3 hours. The mixture reaction was cooled to room temperature, and then concentrated under reduced pressure. Then, water was added to the residue, followed by extraction with ethyl acetate twice. The combined organic layers were washed with a saturated sodium chloride solution, was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.90 g of 3-chloro-N-[2- hydroxy-5-(heptafluoroisopropyl)phenyl]isonicotinamide.1H-NMR (DMSO-d6) delta: 10.19 (br s, 1H), 8.75 (s, 1H), 8.63 (d, J=4.9 Hz, 1H), 8.36 (d, J=1.9 Hz, 1H), 7.65 (d, J=4.9 Hz, 1H), 7.32 (dd, J=8.8, 2.0 Hz, 1H), 7.12 (d, J=8.8 Hz, 1H) | ||
Reference Production Example 26To a mixture of 0.58 g of WSC and 5 ml of pyridine 5ml, 0.48 g of 3- chloroisonicotinic acid was added. The reaction mixture was stirred at room temperature for 25 minutes. To the reaction mixture, 0.75 g of 2-amino-4-(heptafluoroisopropyl)phenol was added and was stirred while heating at 60C for three hours. The reaction mixture was cooled to room temperature, the 0.24 g of <strong>[88912-27-0]3-chloroisonicotinic acid</strong> and 0.29 g of WSC was added and stirred while heating at 60C for 1.5 hours and then at 80C for 1.3 hours. The mixture reaction was cooled to room temperature, and then concentrated under reduced pressure. Then, water was added to the residue, followed by extraction with ethyl acetate twice. The combined organic layers were washed with a saturated sodium chloride solution, was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.90 g of 3-chloro-N-[2- hydroxy-5-(heptafluoroisopropyl)phenyl]isonicotinamide.1 H-NMR (DMSO-ck) delta: 10.19 (br s, IH), 8.75 (s, IH), 8.63 (d, J=4.9 Hz, IH), 8.36 (d, J=1.9 Hz, IH), 7.65 (d, J=4.9 Hz, IH), 7.32 (dd, J=8.8, 2.0 Hz, IH), 7.12 (d, J=8.8 Hz, IH) |
Yield | Reaction Conditions | Operation in experiment |
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With pyridine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; at 80℃; for 3h; | Reference Production Example 33 A mixture of 0.60 g of 2-amino-4-chloro-5-trifluoromethylphenol, 0.43 g of <strong>[88912-27-0]3-chloroisonicotinic acid</strong>, 0.67 g of WSC and 5 ml of pyridine was stirred while heating at 80C for three hours. The reaction mixture was cooled to room temperature, and then water was added, followed by extraction with ethyl acetate three times. The combined organic layers were washed with water and a saturated sodium chloride solution, dried anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.67 g of 3-chloro-N-[5-chloro-2-hydroxy-4-trifluoromethylphenyl]isonicotinamide. [Show Image] 1H-NMR (DMSO-d6) delta: 8.75 (s, 1H), 8.64 (d, J=4.8 Hz, 1H), 8.36 (s, 1H), 7.62 (d, J=4.8 Hz, 1H), 7.28 (s, 1H) | |
With pyridine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; at 80℃; for 3h; | Reference Production Example 33A mixture of 0.60 g of 2-amino-4-chloro-5-trifluoromethylphenol, 0.43 g of <strong>[88912-27-0]3-chloroisonicotinic acid</strong>, 0.67 g of WSC and 5 ml of pyridine was stirred while heating at 80 C. for three hours. The reaction mixture was cooled to room temperature, and then water was added, followed by extraction with ethyl acetate three times. The combined organic layers were washed with water and a saturated sodium chloride solution, dried anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.67 g of 3-chloro-N-[5-chloro-2-hydroxy-4-trifluoromethylphenyl]isonicotinamide.1H-NMR (DMSO-d6) delta: 8.75 (s, 1H), 8.64 (d, J=4.8 Hz, 1H), 8.36 (s, 1H), 7.62 (d, J=4.8 Hz, 1H), 7.28 (s, 1H) | |
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In pyridine; at 80℃; for 3h; | Reference Production Example 33A mixture of 0.60 g of 2-amino-4-chloro-5-trifluoromethylphenol, 0.43 g of 3- chloroisonicotinic acid, 0.67 g of WSC and 5 ml of pyridine was stirred while heating at 80C for three hours. The reaction mixture was cooled to room temperature, and then water was added, followed by extraction with ethyl acetate three times. The combined organic layers were washed with water and a saturated sodium chloride solution, dried anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.67 g of 3-chloro-N-[5-chloro-2- hydroxy-4-trifluoromethylphenyl]isonicotinamide.1H-NMR (DMSO-d6) delta: 8.75 (s, 1H), 8.64 (d, J=4.8 Hz, 1H), 8.36 (s, 1H), 7.62 (d, J=4.8 Hz, 1H), 7.28 (s, 1H) |
With pyridine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; at 80℃; for 3h; | A mixture of 0.60 g of 2-amino-4-chloro-5-trifiuoromethylphenol, 0.43 g of 3- chloroisonicotinic acid, 0.67 g of WSC and 5 ml of pyridine was stirred while heating at 80C for three hours. The reaction mixture was cooled to room temperature, and then water was added, followed by extraction with ethyl acetate three times. The combined organic layers were washed with water and a saturated sodium chloride solution, dried anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.67 g of 3-chloro-N-[5-chloro-2- hydroxy-4-trifluoromethylphenyl] isonicotinamide.-NMR (DMSO-d6) delta: 8.75 (s, IH), 8.64 (d, J=4.8 Hz, IH), 8.36 (s, IH), 7.62 (d, J=4.8 Hz, IH), 7.28 (s, IH) | |
With pyridine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; at 80℃; for 3h; | A mixture of 0.60 g of 2-amino-4-chloro-5-trifluoromethylphenol, 0.43 g of 3- chloroisonicotinic acid, 0.67 g of WSC and 5 ml of pyridine was stirred while heating at 80C for three hours. The reaction mixture was cooled to room temperature, and then water was added, followed by extraction with ethyl acetate three times. The combined organic layers were washed with water and a saturated sodium chloride solution, dried anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.67 g of 3-chloro-N-[5-chloro-2- hydroxy-4-trifluoromethylphenyl]isonicotinamide.1 H-NMR (DMSO-d6) delta: 8.75 (s, IH), 8.64 (d, J=4.8 Hz, IH), 8.36 (s, IH), 7.62 (d, J=4.8 Hz, IH), 7.28 (s, IH) | |
With pyridine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; at 80℃; for 3h; | Reference Production Example 33A mixture of 0.60 g of 2-amino-4-chloro-5-trifluoromethylphenol, 0.43 g of 3- chloroisonicotinic acid, 0.67 g of WSC and 5 ml of pyridine was stirred while heating at 80C for three hours. The reaction mixture was cooled to room temperature, and then water was added, followed by extraction with ethyl acetate three times. The combined organic layers were washed with water and a saturated sodium chloride solution, dried anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.67 g of 3-chloro-N-[5-chloro-2- hydroxy-4-trifluoromethylphenyl]isonicotinamide.1H-NMR (DMSO-d6) delta: 8.75 (s, 1H), 8.64 (d, J=4.8 Hz, 1H), 8.36 (s, 1H), 7.62 (d, J=4.8 Hz, 1H), 7.28 (s, 1H) | |
With pyridine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; at 80℃; for 3h; | Reference Production Example 33A mixture of 0.60 g of 2-amino-4-chloro-5-trifluoromethylphenol, 0.43 g of 3- chloroisonicotinic acid, 0.67 g of WSC and 5 ml of pyridine was stirred while heating at 80C for three hours. The reaction mixture was cooled to room temperature, and then water was added, followed by extraction with ethyl acetate three times. The combined organic layers were washed with water and a saturated sodium chloride solution, dried anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.67 g of 3-chloro-N-[5-chloro-2- hydroxy-4-trifluoromethylphenyl]isonicotinamide. 1H-NMR (DMSO-di) delta: 8.75 (s, IH), 8.64 (d, J=4.8 Hz, IH), 8.36 (s, IH), 7.62 (d, J=4.8 Hz, IH), 7.28 (s, IH) |
Yield | Reaction Conditions | Operation in experiment |
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With pyridine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; at 80℃; for 3h; | Reference Production Example 36 A mixture of 0.50 g of 2-amino-5-chloro-4-trifluoromethylphenol, 0.36 g of <strong>[88912-27-0]3-chloroisonicotinic acid</strong>, 0.56 g of WSC and 5 ml of pyridine was stirred while heating at 80C for three hours. The reaction mixture was cooled to room temperature, and then water was added, followed by extraction with ethyl acetate three times. The combined organic layers were washed with water and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.46 g of 3-chloro-N-[4-chloro-2-hydroxy-5-trifluoromethylphenyl]isonicotinamide. [Show Image] 1H-NMR (DMSO-d6) delta: 10.32 (br s, 1H), 8.75 (s, 1H), 8.64 (d, J=4.8 Hz, 1H), 8.43 (s, 1H), 7.63 (d, J=4. Hz, 1H), 7.13 (s, 1H) | |
With pyridine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; at 80℃; for 3h; | Reference Production Example 36 A mixture of 0.50 g of 2-amino-5-chloro-4-trifluoromethylphenol, 0.36 g of <strong>[88912-27-0]3-chloroisonicotinic acid</strong>, 0.56 g of WSC and 5 ml of pyridine was stirred while heating at 80 C. for three hours. The reaction mixture was cooled to room temperature, and then water was added, followed by extraction with ethyl acetate three times. The combined organic layers were washed with water and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.46 g of 3-chloro-N-[4-chloro-2-hydroxy-5-trifluoromethylphenyl]isonicotinamide.1H-NMR (DMSO-d6) delta: 10.32 (br s, 1H), 8.75 (s, 1H), 8.64 (d, J=4.8 Hz, 1H), 8.43 (s, 1H), 7.63 (d, J=4.8 Hz, 1H), 7.13 (s, 1H) | |
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In pyridine; at 80℃; for 3h; | Reference Production Example 36A mixture of 0.50 g of 2-amino-5-chloro-4-trifluoromethylphenol, 0.36 g of 3- chloroisonicotinic acid, 0.56 g of WSC and 5 ml of pyridine was stirred while heating at 80C for three hours. The reaction mixture was cooled to room temperature, and then water was added, followed by extraction with ethyl acetate three times. The combined organic layers were washed with water and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.46 g of 3-chloro-N-[4-chloro-2- hydroxy-5-trifluoromethylphenyl]isonicotinamide.1 H-NMR (DMSO-de) delta: 10.32 (br s, IH), 8.75 (s, IH), 8.64 (d, J=4.8 Hz, IH), 8.43 (s, 7.63 (d, J=4.8 Hz, IH), 7.13 (s, IH) |
With pyridine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; at 80℃; for 3h; | A mixture of 0.50 g of 2-amino-5-chloro-4-trifluoromethylphenol, 0.36 g of 3- chloroisonicotinic acid, 0.56 g of WSC and 5 ml of pyridine was stirred while heating at 80C for three hours. The reaction mixture was cooled to room temperature, and then water was added, followed by extraction with ethyl acetate three times. The combined organic layers were washed with water and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.46 g of 3-chloro-N-[4-chloro-2- hydroxy-5-trifluoromethylphenyl]isonicotinamide.1 H-NMR (DMSO-d6) 6: 10.32 (br s, IH), 8.75 (s, IH), 8.64 (d, J=4.8 Hz, IH), 8.43 (s, 7.63 (d, J=4.8 Hz, IH), 7.13 (s, IH) | |
With pyridine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; at 80℃; for 3h; | A mixture of 0.50 g of 2-amino-5-chloro-4-trifluoromethylphenol, 0.36 g of 3- chloroisonicotinic acid, 0.56 g of WSC and 5 ml of pyridine was stirred while heating at 80C for three hours. The reaction mixture was cooled to room temperature, and then water was added, followed by extraction with ethyl acetate three times. The combined organic layers were washed with water and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.46 g of 3-chloro-N-[4-chloro-2- hydroxy-5-trifluoromethylphenyl]isonicotinamide.-NMR (DMSO-d6) delta: 10.32 (br s, 1H), 8.75 (s, 1H), 8.64 (d, J=4.8 Hz, 1H), 8.43 (s, 1H), 7.63 (d, J=4.8 Hz, 1H), 7.13 (s, 1H) | |
With pyridine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; at 80℃; for 3h; | Reference Production Example 36A mixture of 0.50 g of 2-amino-5-chloro-4-trifluoromethylphenol, 0.36 g of 3- chloroisonicotinic acid, 0.56 g of WSC and 5 ml of pyridine was stirred while heating at 80C for three hours. The reaction mixture was cooled to room temperature, and then water was added, followed by extraction with ethyl acetate three times. The combined organic layers were washed with water and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.46 g of 3-chloro-N-[4-chloro-2- hydroxy-5-trifluoromethylphenyl]isonicotinamide.-NMR (DMSO-d6) delta: 10.32 (br s, 1H), 8.75 (s, 1H), 8.64 (d, J=4.8 Hz, 1H), 8.43 (s, 1H), 7.63 (d, J=4.8 Hz, 1H), 7.13 (s, 1H) | |
With pyridine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; at 80℃; for 3h; | Reference Production Example 36A mixture of 0.50 g of 2-amino-5-chloro-4-trifluoromethylphenol, 0.36 g of 3- chloroisonicotinic acid, 0.56 g of WSC and 5 ml of pyridine was stirred while heating at 80C for three hours. The reaction mixture was cooled to room temperature, and then water was added, followed by extraction with ethyl acetate three times. The combined organic layers were washed with water and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.46 g of 3-chloro-N-[4-chloro-2- hydroxy-5-trifluoromethylphenyl]isonicotinamide. 1H-NMR (DMSO-d6) delta: 10.32 (br s, lH), 8.75 (s, 1H), 8.64 (d, J=4.8 Hz, 1H), 8.43 (s, 1H), 7.63 (d, J=4.8 Hz, 1H), 7.13 (s, 1H) |
Yield | Reaction Conditions | Operation in experiment |
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With pyridine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; at 80℃; for 3h; | Reference Production Example 37 A mixture of 0.68 g of 6-amino-1,1,3,3-tetrafluoro-5-hydroxy-1,3-dihydroisobenzofuran, 0.48 g of <strong>[88912-27-0]3-chloroisonicotinic acid</strong>, 0.76 g of WSC and 7 ml of pyridine was stirred while heating at 80C for three hours. The reaction mixture was cooled to room temperature, and then water was added, followed by extraction with ethyl acetate three times. The combined organic layers were washed with water and a saturated sodium chloride solution, then dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.68 g of 3-chloro-N-(1,1,3,3-tetrafluoro-6-hydroxy-1,3-dihydroisobenzafuran-5-yl)isonicotinamide. [Show Image] 1H-NMR (DMSO-d6) delta: 10.47 (br s, 1H), 8.76 (s, 1H), 8.65 (d, J=4.6 Hz, 1H), 8.55 (s, 1H), 7.64 (d, J=4.8 Hz, 1H), 7.27 (s, 1H) | |
With pyridine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; at 80℃; for 3h; | Reference Production Example 37A mixture of 0.68 g of 6-amino-1,1,3,3-tetrafluoro-5-hydroxy-1,3-dihydroisobenzofuran, 0.48 g of <strong>[88912-27-0]3-chloroisonicotinic acid</strong>, 0.76 g of WSC and 7 ml of pyridine was stirred while heating at 80 C. for three hours. The reaction mixture was cooled to room temperature, and then water was added, followed by extraction with ethyl acetate three times. The combined organic layers were washed with water and a saturated sodium chloride solution, then dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.68 g of 3-chloro-N-(1,1,3,3-tetrafluoro-6-hydroxy-1,3-dihydroisobenzofuran-5-yl)isonicotinamide.1H-NMR (DMSO-d6) delta: 10.47 (br s, 1H), 8.76 (s, 1H), 8.65 (d, J=4.6 Hz, 1H), 8.55 (s, 1H), 7.64 (d, J=4.8 Hz, 1H), 7.27 (s, 1H) | |
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In pyridine; at 80℃; for 3h; | Reference Production Example 37A mixture of 0.68 g of 6-amino-l,l,3,3-tetrafluoro-5-hydroxy-l,3- dihydroisobenzofuran, 0.48 g of <strong>[88912-27-0]3-chloroisonicotinic acid</strong>, 0.76 g of WSC and 7 ml of pyridine was stirred while heating at 80C for three hours. The reaction mixture was cooled to room temperature, and then water was added, followed by extraction with ethyl acetate three times. The combined organic layers were washed with water and a saturated sodium chloride solution, then dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.68 g of 3-chloro-N-(l,l,3,3-tetrafluoro-6-hydroxy-l,3-dihydroisobenzofuran-5- yl)isonicotinamide. -NMR (DMSO-d6) delta: 10.47 (br s, 1H), 8.76 (s, 1H), 8.65 (d, J=4.6 Hz, 1H), 8.55 (s, 7.64 (d, J=4.8 Hz, 1H), 7.27 (s, 1H) |
With pyridine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; at 80℃; for 3h; | Amixture of 0.68 g of 6-amino-l,l,3,3-tetrafluoro-5-hydroxy-l,3- dihydroisobenzofuran, 0.48 g of <strong>[88912-27-0]3-chloroisonicotinic acid</strong>, 0.76 g of WSC and 7 ml of pyridine was stirred while heating at 80C for three hours. The reaction mixture was cooled to room temperature, and then water was added, followed by extraction with ethyl acetate three times. The combined organic layers were washed with water and a saturated sodium chloride solution, then dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.68 g of 3-chloro-N-(l,l,3,3-tetrafluoro-6-hydroxy-l,3-dihydroisobenzofuran-5- yl)isonicotinamide.1H-NMR (DMSO-d6) delta: 10.47 (br s, IH), 8.76 (s, IH), 8.65 (d, J=4.6 Hz, IH), 8.55 (s, 7.64 (d, J=4.8 Hz, IH), 7.27 (s, IH) | |
With pyridine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; at 80℃; for 3h; | A mixture of 0.68 g of 6-amino-l,l,3,3-tetrafluoro-5-hydroxy-l,3- dihydroisobenzofuran, 0.48 g of <strong>[88912-27-0]3-chloroisonicotinic acid</strong>, 0.76 g of WSC and 7 ml of pyridine was stirred while heating at 80C for three hours. The reaction mixture was cooled to room temperature, and then water was added, followed by extraction with ethyl acetate three times. The combined organic layers were washed with water and a saturated sodium chloride solution, then dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.68 g of 3-chloro-N-(l,l,3,3-tetrafluoro-6-hydroxy-l,3-dihydroisobenzofuran-5- yl)isonicotinamide.-NMR (DMSO-d6) delta: 10.47 (br s, 1H), 8.76 (s, 1H), 8.65 (d, J=4.6 Hz, 1H), 8.55 (s, 1H), 7.64 (d, J=4.8 Hz, 1H), 7.27 (s, 1H) | |
With pyridine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; at 80℃; for 3h; | Reference Production Example 37A mixture of 0.68 g of 6-amino-l,l,3,3-tetrafluoro-5-hydroxy-l,3- dihydroisobenzofuran, 0.48 g of 3 -chloroisonicotinic acid, 0.76 g of WSC and 7 ml of pyridine was stirred while heating at 80C for three hours. The reaction mixture was cooled to room temperature, and then water was added, followed by extraction with ethyl acetate three times. The combined organic layers were washed with water and a saturated sodium chloride solution, then dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.68 g of 3 -chloro-N-( 1 , 1 ,3 ,3 -tetrafluoro-6-hydroxy- 1 ,3 -dihydroisobenzofuran-5- yl)isonicotinamide.1 H-NMR (DMSO-d6) delta: 10.47 (br s, IH), 8.76 (s, IH), 8.65 (d, J=4.6 Hz, IH), 8.55 (s, IH), 7.64 (d, J=4.8 Hz, 1 H), 7.27 (s, 1 H) | |
With pyridine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; at 80℃; for 3h; | Reference Production Example 37A mixture of 0.68 g of 6-amino-l,l,3,3-tetrafluoro-5-hydroxy-l,3- dihydroisobenzofuran, 0.48 g of <strong>[88912-27-0]3-chloroisonicotinic acid</strong>, 0.76 g of WSC and 7 ml of pyridine was stirred while heating at 80C for three hours. The reaction mixture was cooled to room temperature, and then water was added, followed by extraction with ethyl acetate three times. The combined organic layers were washed with water and a saturated sodium chloride solution, then dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.68 g of 3-chloro-N-(l ,1 ,3,3-tetrafluoro-6-hydroxy-l ,3-dihydroisobenzofuran-5- yl)isonicotinamide.-NMR (DMSO-d6) delta: 10.47 (br s, 1H), 8.76 (s, 1H), 8.65 (d, J=4.6 Hz, 1H), 8.55 (s, 1H), 7.64 (d, J=4.8 Hz, 1H), 7.27 (s, 1H) |
Yield | Reaction Conditions | Operation in experiment |
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Reference Production Example 24 To a mixture of 0.44 g of WSC and 4 ml of pyridine, 0.36 g of <strong>[88912-27-0]3-chloroisonicotinic acid</strong> was added. The reaction mixture was stirred at room temperature for 15 minutes. To the reaction mixture, 0.45 g of 2-amino-4-(pentafluoroethyl)phenol was added and stirred while heating at 60C for two hours. The reaction mixture was cooled to room temperature, and then concentrated under reduced pressure. Water was added to the residue, followed by extraction with ethyl acetate twice. The combined organic layers were washed with water and a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.25 g of 3-chloro-N-[2-hydraxy-5-(pentafluoroethyl)phenyl]isonicotinamide. [Show Image] 1H-NMR (DMSO-d6) delta: 10.99 (br s, 1H), 10.20 (br s, 1H), 8.75 (s, 1H), 8.64 (d, J=4.9 Hz, 1H), 8.31 (d, J=2.2 Hz, 1H), 7.64 (d, J=4.6 Hz, 1H), 7.36 (dd, J=8.6, 2.1 Hz, 1H), 7.11 (d, J=8.6 Hz, 1H) | ||
Reference Production Example 24To a mixture of 0.44 g of WSC and 4 ml of pyridine, 0.36 g of <strong>[88912-27-0]3-chloroisonicotinic acid</strong> was added. The reaction mixture was stirred at room temperature for 15 minutes. To the reaction mixture, 0.45 g of 2-amino-4-(pentafluoroethyl)phenol was added and stirred while heating at 60 C. for two hours. The reaction mixture was cooled to room temperature, and then concentrated under reduced pressure. Water was added to the residue, followed by extraction with ethyl acetate twice. The combined organic layers were washed with water and a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.25 g of 3-chloro-N-[2-hydroxy-5-(pentafluoroethyl)phenyl]isonicotinamide.1H-NMR (DMSO-d6) delta: 10.99 (br s, 1H), 10.20 (br s, 1H), 8.75 (s, 1H), 8.64 (d, J=4.9 Hz, 1H), 8.31 (d, J=2.2 Hz, 1H), 7.64 (d, J=4.6 Hz, 1H), 7.36 (dd, J=8.6, 2.1 Hz, 1H), 7.11 (d, J=8.6 Hz, 1H) | ||
Reference Production Example 24To a mixture of 0.44 g of WSC and 4 ml of pyridine, 0.36 g of 3- chloroisonicotinic acid was added. The reaction mixture was stirred at room temperature for 15 minutes. To the reaction mixture, 0.45 g of 2-amino-4-(pentafluoroethyl)phenol was added and stirred while heating at 60C for two hours. The reaction mixture was cooled to room temperature, and then concentrated under reduced pressure. Water was added to the residue, followed by extraction with ethyl acetate twice. The combined organic layers were washed with water and a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.25 g of 3-chloro-N-[2-hydroxy-5- (pentafluoroethyl)phenyl]isonicotinamide.-NMR (DMSO-d6) delta: 10.99 (br s, IH), 10.20 (br s, IH), 8.75 (s, IH), 8.64 (d, J=4.9 Hz, IH), 8.31 (d, J=2.2 Hz, IH), 7.64 (d, J=4.6 Hz, IH), 7.36 (dd, J=8.6, 2.1 Hz, IH), 7.11 (d, J=8.6 Hz, IH) |
To a mixture of 0.44 g of WSC and 4 ml of pyridine, 0.36 g of 3- chloroisonicotinic acid was added. The reaction mixture was stirred at room temperature for 15 minutes. To the reaction mixture, 0.45 g of 2-amino-4-(pentafluoroethyl)phenol was added and stirred while heating at 60C for two hours. The reaction mixture was cooled to room temperature, and then concentrated under reduced pressure. Water was added to the residue, followed by extraction with ethyl acetate twice. The combined organic layers were washed with water and a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.25 g of 3-chloro-N-[2-hydroxy-5- (pentafluoroethyl)phenyl]isonicotinamide.-NMR (DMSO-de) delta: 10.99 (br s, 1H), 10.20 (br s, 1H), 8.75 (s, 1H), 8.64 (d, J=4.9 Hz, 1H), 8.31 (d, J=2.2 Hz, 1H), 7.64 (d, J=4.6 Hz, 1H), 7.36 (dd, J=8.6, 2.1 Hz, 1H), 7.11 (d, J=8.6 Hz, 1H) | ||
To a mixture of 0.44 g of WSC and 4 ml of pyridine, 0.36 g of 3- chloroisonicotinic acid was added. The reaction mixture was stirred at room temperature for 15 minutes. To the reaction mixture, 0.45 g of 2-amino-4-(pentafluoroethyl)phenol was added and stirred while heating at 60C for two hours. The reaction mixture was cooled to room temperature, and then concentrated under reduced pressure. Water was added to the residue, followed by extraction with ethyl acetate twice. The combined organic layers were washed with water and a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.25 g of 3-chloro-N-[2-hydroxy-5- (pentafluoroethyl)phenyl]isonicotinamide.-NMR (DMSO-d6) delta: 10.99 (br s, 1H), 10.20 (br s, 1H), 8.75 (s, 1H), 8.64 (d, J=4.9 Hz, 1H), 8.31 (d, J=2.2 Hz, 1H), 7.64 (d, J=4.6 Hz, 1H), 7.36 (dd, J=8.6, 2.1 Hz, 1H), 7.11 (d, J=8.6 Hz, 1H) | ||
Reference Production Example 24To a mixture of 0.44 g of WSC and 4 ml of pyridine, 0.36 g of 3- chloroisonicotinic acid was added. The reaction mixture was stirred at room temperature for 15 minutes. To the reaction mixture, 0.45 g of 2-amino-4-(pentafluoroethyl)phenol was added and stirred while heating at 60C for two hours. The reaction mixture was cooled to room temperature, and then concentrated under reduced pressure. Water was added to the residue, followed by extraction with ethyl acetate twice. The combined organic layers were washed with water and a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.25 g of 3-chloro-N-[2-hydroxy-5- (pentafluoroethyl)phenyl]isonicotinamide. 1H-NMR (DMSO-de) delta: 10.99 (br s, 1H), 10.20 (br s, 1H), 8.75 (s, 1H), 8.64 (d, J=4.9 Hz, 1H), 8.31 (d, J=2.2 Hz, 1H), 7.64 (d, J=4.6 Hz, 1H), 7.36 (dd, J=8.6, 2.1 Hz, 1H), 7.11 (d, J=8.6 Hz, 1H) | ||
Reference Production Example 24To a mixture of 0.44 g of WSC and 4 ml of pyridine, 0.36 g of 3- chloroisonicotinic acid was added. The reaction mixture was stirred at room temperature for 15 minutes. To the reaction mixture, 0.45 g of 2-amino-4-(pentafluoroethyl)phenol was added and stirred while heating at 60C for two hours. The reaction mixture was cooled to room temperature, and then concentrated under reduced pressure. Water was added to the residue, followed by extraction with ethyl acetate twice. The combined organic layers were washed with water and a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.25 g of 3-chloro-N-[2-hydroxy-5- (pentafluoroethyl)phenyl]isonicotinamide.1H-NMR (DMSO-d6) delta: 10.99 (br s, 1H), 10.20 (br s, 1H), 8.75 (s, 1H), 8.64 (d, J=4.9 Hz, 1H), 8.31 (d, J=2.2 Hz, 1H), 7.64 (d, J=4.6 Hz, 1H), 7.36 (dd, J=8.6, 2.1 Hz, 1H), 7.11 (d, J=8.6 Hz, 1H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; at 60℃; for 1.3h; | Reference Production Example 3A mixture of 1.69 g of 4-trifluoromethoxyaniline, 1.50 g of 3-chloroisonicotic acid, 2.37 g of WSC and 10 ml of pyridine was stirred at 60C for 1.3 hours. The reaction mixture was cooled down to room temperature. The reaction mixture was poured into water. This mixture was extracted with ethyl acetate twice. The combined organic layers were washed with water and saturated saline, dried over magnesium sulfate, then, concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, to obtain 2.87 g of 3-chloro-N- [ ( 4- trifluoromethoxy) phenyl] isonicotinamide .1 H-N R (CDC13) delta: 8.71 (s, 1H) , 8.63 (d, J=5.1 Hz, 1H) , 8.14 (br s, 1H) , 7.68 (d, J=8.8 Hz, 2H) , 7.65 (d, J=5.1 Hz, 1H) , 7.26 (d, J=8.8 Hz, 2H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; at 60℃; for 1h; | Reference Production Example 2A mixture of 1.53 g of 4-trifluoromethylaniline, 1.50 g of 3-chloroisonicotic acid, 2.37 g of l-ethyl-3- ( 3- dimethylaminopropyl) carbodiimide hydrochloride (hereinafter, referred to as WSC) and 10 ml of pyridine was stirred at 60C for 1 hour. The reaction mixture was cooled down to room temperature. To the reaction mixture, water was poured, and the resultant mixture was extracted with ethyl acetate twice. The combined organic layers were washed with water and saturated saline, dried over magnesium sulfate, then, concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, to obtain 1.59 g of 3-chloro-N- [ (4- trifluoromethyl ) phenyl] isonicotinamide . ^-NMR (CDCI3) delta: 8.73 (s, 1H) , 8.66 (d, J=4.9 Hz, 1H) , 8.20 (br s, 1H) , 7.78 (d, J=8.3 Hz, 2H) , 7.70-7.64 (m, 3H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68.3% | General procedure: A mixture of 11 (100 mg, 0.24 mmol), an acid (0.72 mmol), EDCI (125 mg, 0.78 mmol), HOBt (88 mg, 0.78 mmol), TEA (0.167 mL, 1.2 mmol) and DMF (4 mL) was stirred at ambient temperature under N2 protection for 24 h, the reaction was monitored by TLC (CH2Cl2:MeOH = 5:1), upon the completion of the coupling reaction, MeOH (5 mL), and K2CO3 (199 mg, 1.44 mmol) were added to the mixture and stirred at ambient temperature overnight. The mixture was then filtered through celite. The filtrate was concentrated to remove DMF and methanol. The residue was partitioned between CH2Cl2 (50 mL) and H2O (50 mL). The organic layer was separated and washed with H2O (50 mL x 3), dried over anhydrous MgSO4, concentrated under reduced pressure. The residue was then purified by column chromatography (Silica Gel 15 g), eluented with CH2Cl2 (150 mL), CH2Cl2/MeOH (80:1, 160 mL), CH2Cl2/MeOH (60:1, 180 mL), CH2Cl2/MeOH (40:1, 160 mL),CH2Cl2/MeOH (20:1, 160 mL), CH2Cl2/MeOH (10:1, 200 mL) successively to afford the corresponding target compound as free base. Upon confirmation by 1H NMR and 13C NMR, the free base was then transformed into hydrochloride salt by soluting in MeOH (0.1 mL), adding HCl methanol solution (1.25 M, 0.3 mL) and stirred at ambient temperature for 30 min. Diethyl ether (10 mL) was then added and the precipitate formed was collected by filtration, dried in vacuum to give the target compound as hydrochloride salt. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
THF (25 mL), 2-{4-bromo-3-[(3-chloro-5-cyanophenyl)oxy]-2- fluorophenyl}acetohydrazide (700 mg, 1.76 mmol), <strong>[88912-27-0]3-chloro-4-pyridinecarboxylic acid</strong> (276 mg, 1.76 mmol), HATU (669 mg, 1.76 mmol,) and DIPEA (0.610 mL, 3.52 mmol) were combined and stirred at rt for 45 min. Burgess Reagent (2.06 g, 8.80 mmol) was added and the reaction stirred overnight. The reaction mixture was diluted with ethyl acetate and washed with water. The solvent was removed and the crude material was purified via silica gel chromatography to give 430 mg of the title compound. 1H NMR (DMSO-d6) delta 8.85 (s, 1 H), 8.68 (d, 1 H), 7.89 (d, 1 H), 7.71 - 7.82 (m, 1 H), 7.64 (dd, 1 H), 7.27 - 7.54 (m, 3 H), 4.49 (s, 2 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sulfuric acid;Reflux; | A solution of 3-chloroisonicotinic acid (18.6 mmol) in 120 mL EtOH and 3 mL cone. H2S04 was heated to reflux overnight. The mixture was concentrated in vacuo, redissolved in aq. NaHC03 solution and extracted with EtOAc (2x). The combined organic layers were dried over MgS04 and concentrated in vacuo to give the desired product as yellow oil; LC-MS (A): tR = 0.63 min; [M+H]+: 186.08. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45.2 mg | With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In acetonitrile; at 20 - 200℃;Microwave irradiation; | Example Ia4 l-(3-Chloro-pyridin-4-yl)-4-methyl-[l,2,4]triazolo[4,3-a]quinoxaline. A mixture of <strong>[88912-27-0]3-chloroisonicotinic acid</strong> (49 mg), Ila (49 mg), and N-(3-dimethylaminopropyl)-iV- ethylcarbodiimide hydrochloride (59 mg) in acetonitrile (2 mL) was stirred at ambient temperature overnight. The mixture was then heated at 200 C for 0.5h under MW conditions. Water (15 mL) was added and the mixture was partially evaporated to about half the original volume. A red precipitate formed, and this was collected by filtration, washed with water and dried to yield example Ia4 (45.2 mg) as a brick-red solid. LC/MS (method 350): RT(PDA)=0.49 min; PDA / ELS-purities 94.4% / 100%; mass observed 296.3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 18h; | A mixture of amine 4 (1eq.), carboxylic acid (1.2 eq.), diisopropylethylamine (DIEA) (1.5 eq.), and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimidehydrogen chloride (EDC·HCl) (1.2 eq.) in dichloromethane was stirred at room temperature for18 h. The reaction mixture was diluted with dichloromethane and washed withwater and brine. The organic layer was dried over MgSO4 andconcentrated. The crude product was purified by normal phase column chromatography(SP1, Biotage) to yield compound 5. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 0 - 90℃; for 12h;Inert atmosphere; | General procedure: A mixture of compound 5 (0.13 mmol), the appropriate acid (0.17 mmol), HOBt (0.17 mmol), and EDCI (0.19 mmol) in dry DMF was cooled to 0 C under nitrogen atmosphere. To the reaction mixture, triethylamine (0.16 mmol) was added at 0 C. The mixture was then stirred at 90 C for 12 h. The reaction mixture was cooled and then partitioned between water and ethyl acetate and the organic layer was separated. The aqueous layer was then extracted with ethyl acetate and the combined organic extracts were washed with brine and dried over anhydrous Na2SO4. After evaporation of the organic solvent, the residue was purified by column chromatography to afford the corresponding compounds 1a-l. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sulfuric acid; In ethanol; | A.2.4.1 Synthesis of 3-chloroisonicotinic acid ethyl ester A solution of 3-chloroisonicotinic acid (18.6 mmol) in 120 mL EtOH and 3 mL conc. H2SO4 was heated to reflux overnight. The mixture was concentrated in vacuo, redissolved in aq. NaHCO3 solution and extracted with EtOAc (2*). The combined organic layers were dried over MgSO4 and concentrated in vacuo to give the desired product as yellow oil; LC-MS (A): tR=0.63 min; [M+H]+: 186.08. |
Tags: 88912-27-0 synthesis path| 88912-27-0 SDS| 88912-27-0 COA| 88912-27-0 purity| 88912-27-0 application| 88912-27-0 NMR| 88912-27-0 COA| 88912-27-0 structure
[ 1060810-03-8 ]
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