| 62.6% |
Stage #1: (3-chloro-2-pyridyl)hydrazine With sodium ethanolate In ethanol for 0.5h; Reflux;
Stage #2: Diethyl maleate In ethanol for 0.5h; Reflux; |
|
| 59% |
With sodium In ethanol for 1h; Reflux; |
2.2 (2) Synthesis of ethyl 5-oxo-2-(3-chloropyridin-2-yl)pyrazoline-3-carboxylate VII
To a 250 ml single-necked round bottom flask was added 100 ml absolute ethanol,Add 1.77 grams of 55 millimoles of metallic sodium,The temperature rose slightly,After stirring for 10 minutes, a uniform clear solution was formed;A mixture of 7.1 g of 50 mmol of 3-chloro-2-hydrazinopyridine VI was added to form a yellow suspension,Heated to reflux,To the reflux was added dropwise 11.2 g of 65 mmol of diethyl maleate,Drop finished,Continue to return for 1 hour;After the TLC monitoring reaction was complete,Cooled to 40 degrees Celsius,Add 3.5 ml of glacial acetic acid;The reaction mixture was concentrated to near dryness,The crude product was recrystallized from ethanol to give 7.9 g of yellow solid VII,Yield 59% |
| 59% |
With ethanol; sodium for 1h; Reflux; |
2.2 (2) Ethyl 5-oxo-2- (3-chloropyridin-2-yl) pyrazoline-3-carboxylateSynthesis of VII:
To a 250 ml single-necked round bottom flask was added 100 ml of absolute ethanol,Add 1.77 grams or 55 millimoles of sodium metal in portions and the temperature rises slightly,After stirring for 10 minutes to form a uniform transparent solution;7.1 g (50 mmol) of 3-chloro-2-hydrazinopyridine VI was added to form a yellow suspension, which was heated to reflux.11.2 g or 65 mmol of diethyl maleate were added dropwise under reflux,Di completed, continue to reflow 1 hour; TLC monitoring reaction was completed, cooled to 40 degrees Celsius,3.5 ml glacial acetic acid was added; the reaction mixture was concentrated to near dryness,The crude product was recrystallized from ethanol to give 7.9 g of yellow solid VII in 59% yield; |
| 57.2% |
With sodium In ethanol at 40 - 45℃; for 5h; |
3.4 (4) Synthesis of ethyl 2-(3-chloro-2-pyridyl)-5-carbonylpyrazolon-3-carboxylate
Chopped sodium lumps (24 g, 1.04 mol) were added to absolute ethanol (920 g) in portions and warmed to reflux naturally. After the sodium was completely dissolved, the solution was cooled to below 40° C., and 3-chloro-2-pyridinylhydrazine (120 g, 0.836 mol) was added at a time. Diethyl maleate (210 g, 1.22 mol) was added dropwise over 1 h while the temperature was maintained at 40-45° C. The reaction was continued for 4 h while the temperature was maintained at 40-45° C. Then, the reaction solution was cooled to room temperature, and poured into glacial acetic acid in cold water batchwise with stirring. Ethanol (650-700 mL) was distilled off under reduced pressure, and then the solution was cooled to room temperature, stood, and filtered. The filter cake was washed with ethanol (65 mL×2), collected, and dried to obtain a finished product (120 g). The filtrate and washings were combined, and concentrated under reduced pressure to remove almost all ethanol and obtain a large amount of a dark green solution with black solid. The solution was extracted with chloroform (200 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness. Toluene (50 mL) was added, and heated to obtain a uniform solution. The solution was cooled to room temperature, frozen in a refrigerator overnight, filtered, washed with toluene (15 mL), and dried to obtain a dark green solid (9 g, total yield 57.2%). |
| 55% |
Stage #1: (3-chloro-2-pyridyl)hydrazine; Diethyl maleate With sodium ethanolate In ethanol for 0.333333h; Heating / reflux;
Stage #2: With acetic acid at 65℃; |
1.A EXAMPLE 1;
PREPARATION OF 1- (3-CHLORO-2-PYRIDINYL)-N-R2, 4-DICHLORO-6-R (METHYLAMINO) CARBONYLLPHEN
3- (METHYLSULFONYL) OXYL-LH-PYRAZOLE-5-CARBOXAMIDE; Step A: Preparation of Ethyl 1-(3-CHLORO-2-PYRIDINYL)-3-PYRAZOLIDINONE-5-CARBOXYLATE
A 2-L four-necked flask equipped with a mechanical stilTer, thermometer, addition funnel, reflux condenser, and nitrogen inlet was charged with absolute ethanol (250 mL) and an ethanolic solution of SODIUM ETHOXIDE (21%, 190 mL, 0.504 mol). The mixture was heated to reflux at about 83 C. It was then treated with 3-CHLORO-2-HYDRAZINOPYRIDINE (68.0 g, 0.474 mol). The mixture was re-heated to reflux over a period of 5 minutes. The yellow slurry was then treated dropwise with diethyl maleate (88.0 mL, 0.544 mol) over a period of 5 minutes. The reflux rate increased markedly during the addition. By the end of the addition all of the starting material had dissolved. The resulting orange-red solution was held at reflux for 10 minutes. After being cooled to 65 C, the reaction mixture was treated with glacial acetic acid (50.0 ML, 0.873 mol). A precipitate formed. The mixture was diluted with water (650 mL), causing the precipitate to dissolve. The orange solution was cooled in an ice bath. Product began to precipitate at 28 C. The slurry was held at about 2 C for 2 hours. The product was isolated via filtration, washed with aqueous ethanol (40%, 3 x 50 mL), then air-dried on the filter for about 1 hour. The title product compound was obtained as a highly crystalline, light orange powder (70.3 g, 55% yield). No significant impurities were observed by 1H NMR. 1H NMR (DMSO-d6) 8 1.22 (t, 3H), 2.35 (d, LH), 2.91 (dd, LH), 4.20 (q, 2H), 4.84 (d, LH), 7.20 (dd, LH), 7.92 (d, LH), 8.27 (d, LH), 10.18 (s, LH). |
| 50% |
With sodium ethanolate; acetic acid In ethanol Reflux; |
|
| 49% |
Stage #1: (3-chloro-2-pyridyl)hydrazine With sodium ethanolate In ethanol for 0.166667h; Reflux;
Stage #2: Diethyl maleate In ethanol for 0.5h; Reflux; |
|
| 49% |
Stage #1: (3-chloro-2-pyridyl)hydrazine With ethanol; sodium for 0.166667h; Reflux;
Stage #2: Diethyl maleate Reflux; |
|
| 49% |
Stage #1: (3-chloro-2-pyridyl)hydrazine With ethanol; sodium for 0.166667h; Reflux;
Stage #2: Diethyl maleate In ethanol for 0.5h; Reflux; |
|
| 46% |
Stage #1: (3-chloro-2-pyridyl)hydrazine; Diethyl maleate With sodium In ethanol for 0.5h; Reflux;
Stage #2: With acetic acid at 40℃; |
|
| 45% |
With bis-triphenylphosphine-palladium(II) chloride; sodium ethanolate; sodium In ethanol at 24 - 32℃; for 12h; |
1 EXAMPLE 1:
725 ml of absolute ethanol (1.4 litres/mole) was charged into the reactor followed by addition of sodium pieces (14.15 gms; 1.21 gm atom/mole), under stirring till complete dissolution to obtain solution containing sodium ethoxide. 3-chloro-2-hydrazinopyridine (73 gms; 0.5 mole) was added to the solution containing sodium ethoxide, followed by the addition of Pd(PPh3)2Cl2 catalyst (0.107gm; 0.0003 mole/mole) under stirring at 24°C to obtain reaction mixture. Diethyl maleate (106 gms; 1.21 mole/mole) was added slowly to the reaction mixture over a period of 3 hours keeping reaction temperature between 30-32 °C to obtain a reaction mass. The reaction mass was equilibrated at 30-32°C and monitored by HPLC. The reaction mass was maintained at 32 °C for 9 hours showed 57% product formation and worked up to obtain ethyl 2-(3-chloropyridin-2-yl)-5-oxo-pyrazolidine-3-carboxylate. The yield of 2-(3-chloropyridin-2-yl)-5-oxo-pyrazolidine-3-carboxylate was 45% and purity was 96%. |
|
Stage #1: (3-chloro-2-pyridyl)hydrazine With sodium ethanolate In ethanol for 0.0833333h; Reflux;
Stage #2: Diethyl maleate In ethanol for 0.166667h; Reflux;
Stage #3: With acetic acid In ethanol at 65℃; |
1.1
Example 1; Preparation of 3-bromo-N-(2-methyl-4-chloro-6-(methylcarbamoyl)phenyl)-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxamide (Compound 13 in Table 1); (1) Synthesis of ethyl 1-(3-chloro-2-pyridinyl)-3-oxopyrazolidine-5-carboxylate; To a 1000 mL flask, anhydrous ethanol (300 mL), sodium ethoxide (16.97 g, 0.249 mol) and 3-chloro-2-hydrazinylpyridine (30.47 g, 98%, 0.21 mol) were added. The reaction mixture was heated to reflux for 5 minutes. Diethyl maleate (36.0 g, 0.31 mol) was added dropwise and heated to reflux for 10 minutes. After being cooled to 65° C., the reaction mixture was neutralized with glacial acetic acid (45.36 g, 0.42 mol) and then diluted with 300 mL water. The reaction mixture was cooled down to room temperature, solid is separated to be filtered, washed with 40% aqueous solution of ethanol (3×50 mL) and dried to give ethyl 1-(3-chloro-2-pyridinyl)-3-oxopyrazolidine-5-carboxylate (31.03 g) as an orange solid in 52% yield. HPLC area normalization method content is 94% (Analytical condition: chromatographic column: ZORBAX Eclipse XDB-C8 4.6×150 mm 5 μm, mobile phase:the ratio of acetonitrile to water is 70:30).1H NMR (300 MHz, DMSO): 8.289-8.269 (q, 1H), 7.956-7.190 (q, 1H), 7.231-7.190 (q, 1H), 4.862-4.816 (q, 1H), 4.236-4.165 (q, 2H), 2.967-2.879 (q, 1H), 2.396-2.336 (q, 1H), 1.250-1.202 (t, 3H). |
|
With sodium ethanolate In ethanol Reflux; |
|
|
With sodium ethanolate In ethanol at 45℃; for 5h; |
1-(6-chloropyrazin-2-yl)-3-pyrazolidone-5-carboxylic acid ethyl ester (4a).
General procedure: Sodium (0.70 g, 30.44 mmol) was dissolved in 50 mL of anhydrous ethanol, and 2-chloro-6-hydrazinylpyrazine (2a) (4.00 g, 27.67 mmol) was added. The reaction solution was heated to 60 °C until the mixture was totally dissolved. Keep the temperature of the reaction below 40 °C, and diethyl maleate (4.77 g, 27.67 mmol) was added dropwise. The reaction was heated to 45 °C and cooled to room temperature after 5 h. The reaction was quenched with glacial acetic acid (1.83 g, 30.44 mol) and stirred for 1 h. The resulting solution was evaporated in vacuo, dissolved in 50 mL of water, extracted with CH2Cl2 (3×50 mL). The extracts was washed with brine, dried with anhydrous MgSO4 and evaporated to give the crude product, which was further purified with recrystallization (diehyl ether) as a yellow solid, 4.25 g. |
|
With sodium ethanolate In ethanol Reflux; |
|
|
Stage #1: (3-chloro-2-pyridyl)hydrazine With sodium ethanolate In ethanol Reflux;
Stage #2: Diethyl maleate In ethanol Reflux; |
1.b b. Preparation of 2-(3-chloro-2-pyridyl)-5-oxo-3-pyrazolidinecarboxylic acid ethyl ester
With thermometer , Add sodium ethoxide and absolute ethanol into the reflux condenser and mechanically stirred three-necked flask, Then add 3-chloro-2-hydrazinopyridine, Stir for 20-25min, Slowly add diethyl maleate dropwise, Heat to reflux, reflux for 3-4h, After the reaction, the temperature is reduced to room temperature, Add acetic acid to adjust PH=6-7, When water is added dropwise, a solid will precipitate out. Stir and crystallize at 0-5°C for 1-2h. Suction filter, get 2-(3-chloro-2-pyridyl)-5-oxo-3-pyrazolidinecarboxylic acid ethyl ester; |
|
With sodium ethanolate In ethanol at 60℃; |
1-3 Example one
Put 2,3-dichloropyridine in a 500ml reaction flask, then put in hydrazine hydrate, reflux at 100°C for 10 hours, then cool to 10°C and centrifuge to obtain 3-chloro-2-pyridyl wet product, which is dried in a drying box. Put the ethanol into ethanol, raise the temperature to 20°C, pour in the maleic acid diethyl ester and sodium ethoxide at 60°C, cool down to 10°C, and centrifuge to obtain 2-(3-chloro-2-pyridyl)-5-oxo-3-pyrazolidine. 2-(3-Chloro-2-pyridyl)-5-oxo-3-pyrazolidine is reacted with tribromophosphorus bromide in acetonitrile to produce 3-bromo-1-(3-chloro-2-pyridyl) )-4,5-Dihydro-1H-pyrazole-5-carboxylic acid ethyl ester wet product. |
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