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The BI-3802 was designed by Boehringer Ingelheim and could be obtained free of charge through the Boehringer Ingelheim open innovation portal opnMe.com, associated with its negative control.
Synonyms: AKOS BBS-00004231
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CAS No. : | 2942-59-8 |
Formula : | C6H4ClNO2 |
M.W : | 157.55 |
SMILES Code : | C1=C(C(=NC=C1)Cl)C(O)=O |
Synonyms : |
AKOS BBS-00004231
|
MDL No. : | MFCD00006236 |
InChI Key : | IBRSSZOHCGUTHI-UHFFFAOYSA-N |
Pubchem ID : | 76258 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H332-H335 |
Precautionary Statements: | P261-P280-P305+P351+P338 |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97.1% | With perfluorosulfonic acid resin; In water; at 65 - 70℃; for 2.5h;Industrial scale; | 300 L of water was added to a 1000 L reactor, 131.9 kg (837.5 mol) of 2-chloronicotinic acid and 140 kg of <strong>[54396-44-0]2-methyl-3-trifluoromethylaniline</strong> (800 mol) were added separately, stirred, 1.4kg perfluorosulfonated resin was added, the temperature was raised to 65 °C -70 °C, and reacted for 2.5h.Filtered, the filtrate was adjusted to pH 4.5 with a 60percent sulfuric acid solution, stirred for 15-20min, filtered , filter cake was washed with 30kg of water, filter cake was dried to obtain 230.1 kg of flunixin, the yield was 97.1percent, and the purity was 99.9percent, purity was tested according to the method of USP38, the same below. |
83% | With potassium hydroxide; toluene-4-sulfonic acid; In water; | iv.) A mixture of <strong>[54396-44-0]2-methyl-3-trifluoromethylaniline</strong> (368 g, 2.1 moles) and 2-chloronicotinic acid (158.0 g, 1.0 mole) in 400 ml of water is heated at 100° C. for 24 hours together with p-toluenesulfonic acid (15.0 g) monohydrate as the acid catalyst. Potassium hydroxide (ca. 145 g) in water (255 ml) is added and the pH is maintained above 11. After diluting the reaction mixture to 1.2 liters with water, the mixture is cooled to 50° C., adjusted to pH 11, treated with 7 g of a decolorizing charcoal and 15 g of a filter aid, and clarified by filtration. The flitrate is diluted with 750 ml of water and the pH is adjusted to 5.0 with concentrated sulfuric acid. Agitation of the suspension for 10 minutes and filtration gives crude, precipitated 2-[[2-methyl-3-(trifluoromethyl)phenyl]amino]-3-pyridinecarboxylic acid (flunixin) (83percent yield). The compound can be further purified by crystallization in methanol and washing with water. |
With toluene-4-sulfonic acid; copper(II) oxide; sodium hydroxide; In 1,2-dimethoxyethane; water; at 45℃; for 0.6h; | (1) 2-chloronicotinic acid and <strong>[54396-44-0]2-methyl-3-trifluoromethylaniline</strong> are stirred and added to an aqueous sodium hydroxide solution, 2-chloronicotinic acid and 2-methyl-3-trifluoromethyl The molar ratio of aniline is 3:1; the molar ratio of 2-chloronicotinic acid to sodium hydroxide used to prepare aqueous sodium hydroxide solution is 1:2; ethylene glycol and chain polyethylene glycol dialkyl are added. The ether and the catalyst A, the chain polyethylene glycol dialkyl ether is used in an amount of 3percent of the mass of 2-chloronicotinic acid; the catalyst A is p-toluenesulfonic acid and copper oxide, the pair The molar ratio of toluenesulfonic acid to copper oxide is 3:1; the temperature is controlled at 45 ° C, after 0.6 hours of reaction, the pH of the solution is adjusted, stirred and allowed to stand for stratification, stirred, filtered, and the filter cake is washed and dried to obtain flunixin.; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In dimethyl sulfoxide; ethyl acetate; | Preparation 6 Sodium 2-[(1-methyl-3-pyrrolidinyl)oxy]-3-pyridinecarboxylate To a stirred suspension of 6.4 g (0.13 mole) of 50percent sodium hydride (mineral oil) in 50 ml of dimethylsulfoxide was added dropwise 6.4 g (0.063 mole) of <strong>[13220-33-2]1-methyl-3-pyrrolidinol</strong>. During addition, the temperature rose from 25° C. to 31° C. After 10 minutes, a solution of 10 g (0.063 mole) of 2-chloronicotinic acid in 50 ml of dimethylsulfoxide was added dropwise causing the temperature to rise. When the temperature reached 55° C., it was maintained there by the intermittent use of an ice bath until addition was complete. The mixture was then heated to 55°-60° C. for 1.5 hr., cooled and filtered. The filter cake was suspended in 100 ml of ethyl acetate and filtered. The solid was recrystallized from ethyl acetatemethanol. Yield of product was 5 g., dec. 240° C. The NMR analysis showed that the compound contained 1/3 mole of sodium acetate as impurity. Analysis: Calculated for C11 H13 N2 O3 Na.1/3C2 H3 O2 Na: C, 51.62; H, 5.20; N, 10.32. Found: C, 51.81; H, 5.15; N, 10.39. | |
In dimethyl sulfoxide; ethyl acetate; | PREPARATION 6 Sodium-2-[(1-methyl-3-pyrrolidinyl)oxy]-3-pyridinecarboxylate To a stirred suspension of 6.4 g (0.13 mole) of 50percent sodium hydride (mineral oil) in 50 ml of dimethylsulfoxide was added dropwise 6.4 g (0.063 mole) of <strong>[13220-33-2]1-methyl-3-pyrrolidinol</strong>. During addition, the temperature rose from 25° C. to 31° C. After 10 minutes, a solution of 10 g (0.063 mole) of 2-chloronicotinic acid in 50 ml of dimethylsulfoxide was added dropwise causing the temperature to rise. When the temperature reached 55° C., it was maintained there by the intermittent use of an ice bath until addition was complete. The mixture was then heated to 55°-60° C. for 1.5 hr., cooled and filtered. The filter cake was suspended in 100 ml of ethyl acetate and filtered. The solid was recrystallized from ethyl acetatemethanol. Yield of product was 5 g., dec. 240° C. The NMR analysis showed that the compound contained 1/3 mole of sodium acetate as impurity. Analysis: Calculated for C11 H13 N2 O3 Na.1/3C2 H3 O2 Na: C, 51.62; H, 5.20; N, 10.32. Found: C, 51.81; H, 5.15; N, 10.39. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Method B. (i) In a 100 mL three-neck round-bottom flask was charged 2-chloronicotinic acid 1 (0.3151 g, 2.0 mmol), HOBt (0.4054 g, 3.0 mmol), and EDAC (0.5751 g, 3.0 mmol) were dissolved in CH 2 Cl 2 (10 mL). After stirring for 10 min, 4-(2-aminoethyl)-1-boc-piperazine (0.4586 mL, 2.0 mmol) was added followed by Et 3 N (0.5733 mL, 4.0 mmol) and the reaction mixture stirred at room temperature for 16 h. After completion of the reaction, the solution was washed with water (30 mL), and the product was extracted with CH 2 Cl 2 (3 X 20 mL). The combined organic phases were washed with brine, and dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The concentrated crude oil tert-butyl 4-(2-(2-chloronicotinamido)ethyl)piperazine-1-carboxylate intermediate was obtained (0.63 g, 1.71 mmol, 86%). The product was used in the next step without further purification. Step (ii) In a 100 mL three neck round bottom flask equipped with a stirring bar and reflux condenser, tert-butyl 4-(2-(2 chloronicotinamido)ethyl)piperazine-1-carboxylate (0.630 g, 1.71 mmol) and 9-ethyl-9H-carbazol-3-amine (0.0361 g, 1.72 mmol) were dissolved in 5 mL of DMSO. To the solution, CuI (0.0651 g, 0.3 mmol) and Cs 2 CO 3 (1.11 g, 3.42 mmol) were added and heated at 90 C for 24 hr. After the reaction was complete (analyzed by TLC), the mixture was allowed to reach room temperature. The mixture was washed with water (30 mL), and extracted with CH 2 Cl 2 (3 X 30 mL). The combined organic phases were washed with brine and dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The crude oil was purified via column chromatography over silica gel and the product 4b was obtained as a white solid (0.08g, 0.15 mmol, 9%). TLC analysis in CH 2 Cl 2 -MeOH (9:1), R f =0.44. 1 H NMR (400 MHz, CDCl 3 ) delta 1.26 (4H, t, J = 7.1 Hz), 1.42 (3H, t, J = 7.3 Hz), 1.46 (9H, s), 1.65 (3H, s), 2.04 (2H, s), 2.48 (3H, t, J = 4.6 Hz), 2.65 (2H, t, J = 5.9 Hz), 3.47 (4H, t, J = 5.3 Hz), 3.56 (2H, q, J = 5.6 Hz), 4.11 (1H, q, J = 7.1 Hz), 4.34 (2H, q, J = 7.6 Hz) 6.64(1H, q, J = 4.8 Hz), 7.19 (1H, t, J = 6.3 Hz), 7.26 (1H, s,), 7.35 (1H, d, J = 4.3 Hz), 7.39 (1H, d, J = 3.8 Hz), 7.43 (1H, t, J = 7.6 Hz), 7.65 (1H, d, J = 1.8 Hz), 7.67 (1H, t, J = 2.3 Hz), 7.69 (1H, d, J = 2.0 Hz), 8.08 (1H, d, 7.6 Hz), 8.31 (1H, d, J = 1.5 Hz), 8.32 (1H, d, J = 1.8 Hz), 8.33 (1H, d, J = 2.0 Hz), 10.40 (1H, s); 13 C NMR (100 MHz, CDCl 3 ) delta 13.8, 37.5, 42.2, 44.8, 45.5, 66.6, 108.3, 112.8, 115.3, 118.3, 120.5, 120.7, 122.8, 123.2, 125.4, 131.6, 132.8, 136.5, 132.0, 140.3, 147.6, 167.8. GC-MS m/z (rel%): [M] 542 (0.01), [M-C 17 H 19 N 3 O] 281 (67.5), [M-C 12 H 23 N 3 O 3 ] 257 (2.6), [M-C 11 H 17 N 3 O] 207 (100). | ||
(i) In a 100 mL three-neck round-bottom flask was charged 8 2-chloronicotinic acid 9 1 (0.3151 g, 2.0 mmol), 10 HOBt (0.4054 g, 3.0 mmol), and 11 EDAC (0.5751 g, 3.0 mmol) were dissolved in 16 CH2Cl2 (10 mL). After stirring for 10 min, 40 4-(2-aminoethyl)-1-boc-piperazine (0.4586 mL, 2.0 mmol) was added followed by 14 Et3N (0.5733 mL, 4.0 mmol) and the reaction mixture stirred at room temperature for 16 h. After completion of the reaction, the solution was washed with water (30 mL), and the product was extracted with CH2Cl2 (3×20 mL). The combined organic phases were washed with brine, and dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The concentrated crude oil tert-butyl 4-(2-(2-chloronicotinamido)ethyl)piperazine-1-carboxylate intermediate was obtained (0.63 g, 1.71 mmol, 86percent). The product was used in the next step without further purification. |
Tags: 2-Chloronicotinic acid | AKOS BBS-00004231 | Pyridines | Chlorides | Carboxylic Acids | Organic Building Blocks | Heterocyclic Building Blocks | 2942-59-8
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