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CAS No. : | 38496-18-3 |
Formula : | C6H3Cl2NO2 |
M.W : | 192.00 |
SMILES Code : | O=C(O)C1=C(Cl)N=C(Cl)C=C1 |
MDL No. : | MFCD00075583 |
InChI Key : | AJPKQSSFYHPYMH-UHFFFAOYSA-N |
Pubchem ID : | 854047 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | at 129℃; for 4 h; | Step a 2-chloro-6-oxo-1 ,6-dιhydropyrιdιne-3-carboxylιc acιd; ° A 500-mL round-bottom flask was charged with 2,6-dιchloronιcotιnιc acid (25 0 g 130 mmol), NaOH solution (325 ml_, 2N) and the solution was refluxed at 1290C for 4 hours The reaction mixture was cooled to room temperature and acidified with a 6N aq HCI solution The resulting precipitate was filtered and dried under reduced pressure yielding to the desired product (19 87g, 88percent) |
4 g | Stage #1: at 120℃; for 4 h; Inert atmosphere Stage #2: With hydrogenchloride In water at 20℃; |
2,6-Dichloronicotinic acid (6 g) was placed in a 250 mL round bottom flask, and sodium hydroxide solution (80 mL) was added.The mixture was heated to 120 ° C for 4 hours. After the reaction was completed, it was cooled to room temperature, acidified with 6N hydrochloric acid, and the solid was precipitated, filtered, and dried to give the title compound (4 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96.4% | With potassium tert-butylate; | Example 40 Synthesis of (S)-N-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)-6-methoxy-2-phenylnicotinamide Compound 86a. To a solution of 2,6-dichloronicotinic acid (2.0 g, 10.41 mmol, 1.0 equiv) in MeOH (50 mL) was added compound potassium tert-butoxide (4.7 g, 41.66 mmol, 4.0 equiv), and resulting reaction mixture was heated at 70 C. for 3 h. Product formation was confirmed by LCMS and TLC. After the completion of reaction, the reaction mixture was concentrated and diluted with water (50 ml). Aqueous layer extracted with ethyl acetate (30 mL*3). Combined organic extracts were washed with brine (50 mL), dried over anhydrous Na2SO4 and concentrated. The crude product obtained was purified by flash chromatography (5% MeOH in DCM as an eluent) to obtain 2-chloro-6-methoxynicotinic acid (1.8 g, 96.4%) as white solid LCMS 188 [M+H]+ 1H NMR 1H NMR (400 MHz, DMSO-d6) delta 13.33 (br. s., 1H), 8.06-8.24 (m, 1H), 6.92 (d, J=8.77 Hz, 1H), 3.91 (s, 3H). |
86% | With potassium tert-butylate; for 48h;Reflux; | 2,6-Dichloronicotinic acid (10 g, 52.1 mmol, 1.0 eq) was dissolved in methanol (460 mL) and potassium t-butoxide was added.(23.37 g, 208.3 mmol, 4.0 eq), heated to reflux for 48 hours.The reaction was completely detected by LC-MS. The mixture was evaporated to room temperature, and concentrated under reduced pressure.A large amount of white solid precipitated, suction filtration,The filter cake is washed with water (300mL×3),Drying to a white solid product (8.5 g, yield: 86% |
84% | 2-Chloro-6-methoxypyridine-3-carboxylic acid [00213] A mixture of 2,6-dichloropyndme-3-carboxyhc acid (6 5 g, 33mmol), potassium tert- butoxide (11 4 g, 0 10 mol), and anhydrous methanol (30OmL) was heated to reflux for 4 days and cooled to room temperature After evaporation of the solvent, the residue was diluted with water and acidified with 35% aqueous hydrochloric acid The resulting solid was collected by filtration, washed with water, and dried to give 4 8 g (84%) of 2-chloro-6-methoxypyridine-3-carboxyhc acid as a white solid[00214] 1H NMR (DMSO-(Z5, 400MHz) delta 13 33 (brs, 1H, OH, exchangeable with D2O), 8 19 (d, J=8 5Hz, 1H), 6 92 (d, J=8 5Hz, 1H), 3 92 (s, 3H) |
52% | With potassium tert-butylate; at 60℃; for 1h; | [752] Step A: 2-chloro-6-methoxy-nicotinic acid [753] Potassium botoxide (483 mg, 4.31 mmol) and MeOH (8 mL) were added to 2,6-dichloro-nicotinicacid (207 mg, 1.07 mmol), and the mixture was stirred usingmicrowave at 60 for 1 hour.After the termination of the reaction, the reactant was filtered, and 1N HClwas added thereto at 0 to adjust the pH to 3. Thesolid was dried by N2 gas to obtain the title compound (106 mg,52%).[754] 1H-NMR (DMSO-d6) delta 8.17(1H, d), 6.92(1H, d),3.92(3H, s) |
3.15 g | With potassium tert-butylate; for 10h;Reflux; | To a solution (250 mL) of 2,6-dichloronicotinic acid (5.00 g) in methanol was added potassium tert-butoxide (8.77 g), and the mixture was heated under reflux for 10 hr. The solvent in the reaction mixture was evaporated under reduced pressure, and the residue was suspended in water and neutralized with 1N HCl. The precipitate was collected by filtration to give the title compound (3.15 g) as a white solid. (1368) MS (ESI+): [M+H]+ 188.0. |
With potassium tert-butylate; at 65℃; for 96h; | Into a 250-mL round-bottom flask, was placed 2,6-dichloropyridine-3-carboxylic acid (5.0 g, 26.04 mmol), methanol (30 mL) and (tert-butoxy)potassium (5.86 g, 52.22 mmol). The resulting solution was stirred for 4 days at 65 C in an oil bath. The resulting mixture was concentrated under vacuum. The residue was dissolved in 30 mL of water and the pH value of the solution adjusted to 3-4 with HC1. The resulting precipitate was collected by filtration resulting in 4.6 g (94%) of 2-chloro-6- methoxypyridine-3-carboxylic acid as a white crude solid. | |
Example 11; [0163] (a) I-Chloro--methoxynicotinic acid. A mixture of 2,6- dichloronicotinic acid (50 g, 0.26 mol) and potassium tert-butoxide (87.7 g, 0.783 mol) in MeOH (2300 mL) was heated at reflux for 48 hours. After evaporation of the solvent, the residue was diluted with H2O and acidified with concentrated HCl. The solid precipitate was filtered, washed with water, and dried in vacuo to give the title compound as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | Dissolve 2,6-dichloronicotinic acid (1000 mg, 5.21 mmol) in anhydrous tetrahydrofuran (5 niL). Cool to 0 0C. Add borane-tetrahydrofuran complex (7.82 mL5 7.82 mmol, 1.0 M in tetrahydrofuran) slowly. Stir the mixture at room temperature overnight. Add water (1 niL) and potassium carbonate, stir for 2 hours, filter and concentrate to give a residue. Chromatograph the residue on silica gel eluting with 10:90 to 20:80 ethyl acetate:hexanes to give (2,6-dichloropyridin-3-yl)-methanol (876 mg, 94%). 1H NMR (400 MHz5 MeOH-d4) delta 7.96 (d, IH, J = 8.0 Hz), 7.45 (d, IH, J = 8.0 Hz), 4.64 (s, 2H). | |
80% | With sodium tetrahydroborate; boron trifluoride diethyl etherate; In tetrahydrofuran; at 0 - 20℃; for 10.0h; | To a solution of 2,6-dichloronicotinic acid (1 g, 5.2 mmol) in THF (10 mL) was added NaBH4 (591 mg, 15.6 mmol) at 0C. The mixture was stirred for 30 min and then BF3.OEt2 (2.2g, 15.6 mmol) was added drop wise at 0C. After addition was complete, the mixture was stirred at room temperature for 10 hr, until the reaction was completed. The reaction mixture was quenched by the addition of saturated NH4C1 solution (50 mL) and extracted with ethyl acetate (3x30 mL). The combined organic layers were washed with brine (30 mL), dried over Na2S04 and concentrated to give the desired product as a white solid which was used in next step without further purification. (820 mg, Yield 80%). |
Synthesis of 2,6-dichloropyridin-3-yl)methanolTo a solution of the compound 2,6-dichloronicotinic acid (0.5g, 2.6mmol) in tetrahydrofuran (10ml) at 00C was added sodium borohydride (0.29g, 7.8mmol) portion wise and stirred the reaction mixture at room temperature for 30 minutes. The resulting reaction mixture was again cooled to 0C followed by the addition of etheral solution of boron trifmoride (1.1 ml, 7.8 mmole) dropwise and stirred the mixture at room temperature for overnight. The reaction mixture was quenched with aqueous sodium hydroxide (IN) and the solvent was evaporated under reduced pressure to furnish the title compound. The residue thus obtained was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to furnish the title compound. Yield: 0.44g. |
In tetrahydrofuran; methanol; | PREPARATION EXAMPLE 23-1 Lithium aluminum hydride (1.78 g) was suspended in dry tetrahydrofuran (10 ml), and 2,6-dichloronicotinic acid was added under ice-cooling at an inside temperature of not more than 10 C. The mixture was stirred under ice-cooling for 1 hr and 28% aqueous amonia was added dropwise to the reaction mixture until foams disappeared. Methanol was added and the mixture was stirred at room temperature for 3 hr, and filtered through celite. The mother liquor was concentrated and the residue was applied to flash silica gel column chromatography (silica gel, 200 ml) and eluted with chloroform:ethyl acetate=8:1 to give 2,6-dichloro-3-hydroxymethylpyridine as colorless crystals (2.89 g). 1H-NMR (CDCl3): 2.11 (1H, t, J=7 Hz), 4.77 (2H, d, J=7 Hz), 7.32 (1H, d, J=8 Hz), 7.87 (1H, d, J=8 Hz). MASS (ESI): m/z 176 (M-1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium tert-butylate; In methanol; at 80℃; for 24h;Inert atmosphere; | Synthesis of 2-chloro-6-methoxynicotinic acid (2) (0685) To a suspension of 2,6-dichloronicotinic acid (1, 20.0 g, 105.2 mmol) in methanol (250 mL) under nitrogen, potassium tert-butoxide (35.0 g, 316.0 mol) was added at room temperature. The reaction mixture was allowed to stir at 80 C. for 24 h. After completion, solvent was removed under reduced pressure and crude was treated with 6 M hydrogen chloride. Precipitated solid was filtered and dried under vacuum to afford 2-chloro-6-methoxynicotinic acid (2) as white solid. Yield: 20.0 g, crude; MS (ESI) m/z 188.06[M+1]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With methanol; at 70℃; for 5h; | Step A: 2,6-Dichloronicotinic acid (30g, 156.3 mmol) was dissolved in methanol (300 mL) at room temperature. Sodium ethoxide (5.4 M in MeOH, 781.3 mmol, 145 mL) was added slowly at the same temperature. The reaction mixture was stirred at 70 C for 5 hours and cooled to room temperature. The precipitated solid from reaction mixture was filtered off and the mother liquor was concentrated under vacuum. All solid collected was dissolved in water (300 mL) and the solution was acidified with 6N HC1 solution to pH 6 at 0 C. The aqueous layer was extracted with ethyl acetate five times. The combined organic layers were dried over MgS04. The organic layer was filtered off and concentrated to give a 1 : 1 mixture of 6-chloro-2- methoxynicotinic acid and 2-chloro-6-methoxynicotinic acid (20.22g, 69%). MS m/z 188 [M+H]+. |
Tags: 2,6-Dichloronicotinic acid | Pyridines | Chlorides | Carboxylic Acids | Organic Building Blocks | Heterocyclic Building Blocks | 38496-18-3
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