3-Bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid

At -78 deg.] C solution of 2- (3-bromo -1H- pyrazol-1-yl) -3-chloro - pyridine (3.04 g, 11.8mmol) solution in the absence of THF (25mL) to maintain the temperature below the rate of -71 dropwise LDA solution (6mL, 2M). Stirring the mixture at -78 deg.] C for 15 minutes and then with carbon dioxide bubbled through 10 minutes, allowed to warm to -57 deg.] C, the reaction mixture was allowed to warm to -20 deg.] C, and quenched with water. The reaction mixture was concentrated, then dissolved in water (100ml) and ether (80mL), followed by addition of aqueous NaOH (1N, 2mL). The aqueous extract was washed with ether, and acidified with aqueous HCl (2N). The precipitated solids were filtered, washed with water and dried to give 2 g of the title compound as a tan solid, yield: 59percent.Step D: Preparation of 3-Bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acidStep D: Preparation of 3-Bromo- 1 -(3-chloro-2-py- ridinyl)-1 H-pyrazole-5-carboxylic acidTo a solution of the pyrazole product from Step C (30.4 g, 118 mmol) in dry tetrahydroffiran (250 mE) at .-76° C. was added dropwise a solution of lithium diisopropylamide (118 mmol) in tetrahydrofuran at such a rate as to maintain the temperature below .-7 1° C. The reaction mixture was stirred for 15 minutes at .-76° C., and carbon dioxide was then bubbled through for 10 minutes, causing warming to .—57° C. The reaction mixture was warmed to 20° C. and quenchedwith watet The reaction mixture was concentrated and then taken up in water (1 E) and ether (500 mE), and then aqueous sodium hydroxide solution (1 N, 20 mE) was added. The aqueous extracts were washed with ether and acidified with hydrochloric acid. The precipitated solids were filtered, washed with water and dried to afford the title product as a tan solid (27.7 g). (Product from another run following similar procedure melted at 200-201° C.)‘H NMR (DMSO-d5) ö 7.25 (s, 1H), 7.68 (dd, 1H), 8.24 (d, 1H), 8.56 (d, 1H).32 g of ethyl 3-bromo-1- (3-chloropyridin-2-yl) -1H-pyrazole-5-carboxylate was added to the reaction flask, Sodium hydroxide 5.5g, Methanol (110 ml) and water (100 ml)Stirring reaction at room temperature 5.5h, Methanol was distilled off under reduced pressure, The organic layer was extracted with ether, The aqueous phase was acidified with concentrated hydrochloric acid to pH = 2, There is a fixed precipitation, filter, Dried to give 1- (3-chloropyridin-2-yl) -3-bromo-1H-pyrazole-5-carboxylic acid.A [300-ML] four-necked flask equipped with a mechanical stirrer, thermometer, and nitrogen inlet was charged with ethyl [3-BROMO-1-(3-CHLORO-2-PYRIDINYL)-LH-PYRAZOLE-] 5-carboxylate (i. e. the product of Step C) (98.5percent pure, 25.0 g, 0.0756 mol), methanol (75 mL), water (50 mL), and sodium hydroxide pellets (3.30 g, 0.0825 mol). Upon adding the sodium hydroxide the mixture self-heated from 29 to [34 °C] and the starting material began to dissolve. After being stirred for 90 minutes under ambient conditions, all of the starting material had dissolved. The resulting dark orange solution was concentrated to about 90 [ML] on a rotary evaporator. The concentrated reaction mixture was then diluted with water (160 mL). The aqueous solution was extracted with ether (100 mL). Then the aqueous layer was transferred to a [500-ML] Erlenmeyer flask equipped with a magnetic stirrer. The solution was treated dropwise with concentrated hydrochloric acid (8.50 g, 0.0839 mol) over a period of about 10 minutes. The product was isolated via filtration, reslurried with water (2 x 40 mL), cover washed once with water (25 mL), and then air-dried on the filter for 2 hours. The product consisted of a crystalline, tan powder (20.9 g, [91percent] yield). The only appreciable impurities observed by [1H] NMR were about 0.8percent of an unknown and 0.7percent ether. [H] NMR (DMSO-d6) 8 7.25 (s, 1H), 13.95 (br s, 1H), 8.56 (d, 1H), 8.25 (d, 1H), 7.68 (dd, 1H).Step C: Preparation of 3-Bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid (alternatively named 1-(3-chloro-2-pyridinyl)-3-bromopyrazole-5-carboxylic acid)Step C: Preparation of 3-Bromo. 1 -(3-chloro-2-py- ridinyl)- 1H-pyrazole-5-carboxylic acid (alternatively named 1 -(3-chloro-2-pyridinyl)-3-bromopyrazole-5-carboxylic acid)A 300-mL four-necked flask equipped with a mechanical stirrer, thermometer, and nitrogen inlet was charged with ethyl 3-bromo-l -(3-chloro-2-pyridinyl)- 1H-pyrazole-5-car-boxylate (i.e. the product of Step B) (98.5percent pure, 25.0 g, 0.0756 mol), methanol (75 mL), water (50 mL), and sodium hydroxide pellets (3.30 g, 0.0825 mol). Upon adding the sodium hydroxide the mixture self-heated from 29 to 34° C. and the starting material began to dissolve. After being stirredfor 90 minutes under ambient conditions, all of the starting material had dissolved. The resulting dark orange solution was concentrated to about 90 mL on a rotary evaporatot The concentrated reaction mixture was then diluted with water (160 mE). The aqueous solution was extracted with ether (100 mE). Then the aqueous layer was transferred to a 500-mE Erlenmeyer flask equipped with a magnetic stirrer. The solution was treated dropwise with concentrated hydrochloric acid (8.50 g, 0.0839 mol) over a period of about 10 minutes. The product was isolated via filtration, reslurried with water (2x40 mE), cover washed once with water (25 mE), and then air-dried on the filter for 2 hours. The product consisted of a crystalline, tan powder (20.9 g, 91percent yield). The only appreciable impurities observed by ‘H NMR were about 0.8percent of an unknown and 0.7percent ethet‘H NMR (DMSO-d5) ö 7.25 (s, 1H), 13.95 (br s, 1H), 8.56 (d, 1H), 8.25 (d, 1H), 7.68 (dd, 1H).To a 50 ml single-necked round bottom flask was added 3.0 mmol of 3-halo-1- (3-chloropyridin-2-yl) -1H-pyrazole-5-carboxylic acid ethyl ester IX, 10 ml of methanol, 0.2 grams of 5.0 millimoles of sodium hydroxide, Stirred at room temperature for 8 hours, After the TLC monitoring reaction was complete, Concentrate to remove most of the solvent, Add 20 ml of ice water, The aqueous solution was washed once with ethyl acetate, 2 moles / liter dilute hydrochloric acid to pH = 4, There is a white solid, filter, Filter cake washed, Vacuum drying, To give a pale yellow solid 3-halo-1- (3-chloro-pyridin-2-yl) lH-pyrazole-5-carboxylic acid II0.63g, Yield 70percent;The 3-halo-1- (3-chloropyridin-2-yl) -1H-pyrazole-5-carboxylic acid II is selected from the group consisting of 3-chloro-1- (3-chloro-pyridin-2-yl)-1H-pyrazole-5-carboxylic acid, 3-bromo-1- (3-chloropyridin-2-yl) -1H-pyrazole-5-carboxylic acidS4. 1 eq of 5-bromo-1H-3-pyrazolecarboxylic acid (4) and 1.2 eq of 2, 3-dichloropyridine were dissolved in an appropriate amount of ethanol solution, 3eq potassium carbonate solid was added, Heated to reflux reaction 18h;After cooling to room temperature and washing with ethyl acetate three times, adding 1 M hydrochloric acid solution to the aqueous layer to make the pH of the reaction solution acidic, extracting with EtOAc three times, drying the organic layer over anhydrous sodium sulfate;After drying, it was concentrated by filtration to obtain the intermediate 1- (3-chloro-2-pyridyl) -3-bromo-1H-5-pyrazolecarboxylic acid (5) with a yield of 75percent.1 eq of 5-bromo-1H-3-pyrazolecarboxylic acid (23) and 1.2 eq of 2, 3-dichloropyridine (8) were dissolved in an appropriate amount of ethanol solution, 3 eq of potassium carbonate solid was added, and the reaction was refluxed for 18 h.After that, it was cooled to room temperature, and the mixture was washed three times with ethyl acetate.After drying and filtration, it was concentrated to give 1-(3-chloro-2-pyridyl)-3-bromo-1H-5-pyrazolecarboxylic acid (3-OH).The yield was 73.7percent.

Molecular Weight:302.51
XLogP3:2.7
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:2
Exact Mass:300.92537
Monoisotopic Mass:300.92537
Topological Polar Surface Area:68
Heavy Atom Count:16
Complexity:282
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes