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Simple preparation method of 5,6-dihydropyridine-2 (1H)-one derivative

A technology of dihydropyridine and derivatives, applied in the field of medicinal chemistry, can solve the problems of large amount of waste water, no practical application value and high price

Active Publication Date: 2020-05-19
XINFA PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] The iodide raw material 1-(4-iodophenyl)-2-piperidone and 1-(4-iodophenyl)-3,3-dichloropiperidine- The price of 2-ketone is high, and there are many reaction steps, cumbersome operation, and high cost; the selectivity of phosphorus pentachloride dichloride reaction in the synthesis route 1 is low, and the amount of phosphorus-containing wastewater is large, which has no practical application value; the synthesis route 2 uses 1-(piperidin-2-one-1-yl)-4-(5,6-dihydro-3-(morpholin-4-yl)pyridin-2(1H)-one-1-yl)benzene ( I2) as a key intermediate, although the yield is high compared to synthetic route 1, the raw material price used in its preparation method is high, and the reaction with piperidin-2-ketone needs cuprous bromide-triphenylphosphine catalyst, and the reaction required High temperature, low total yield, high cost and large amount of waste water

Method used

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  • Simple preparation method of 5,6-dihydropyridine-2 (1H)-one derivative
  • Simple preparation method of 5,6-dihydropyridine-2 (1H)-one derivative
  • Simple preparation method of 5,6-dihydropyridine-2 (1H)-one derivative

Examples

Experimental program
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Effect test

Embodiment 1

[0082] Example 1: Preparation of N,N'-bis(5-hydroxyl-n-valeryl)-p-phenylenediamine (Ⅲ)

[0083] In a 1000 ml four-necked flask connected with a stirrer, a thermometer and a condenser tube, add 350 grams of toluene, 30 grams of N,N-dimethylformamide, 54.0 grams (0.5 moles) of p-phenylenediamine (II), 120 Gram (1.2 moles) of δ-valerolactone, heating, stirring reaction at 105-110°C for 4 hours, cooling to 20-25°C, filtering, washing the filter cake with 30 g of toluene, drying to obtain 141.7 g of N,N'-di (5-Hydroxyn-pentanoyl)-p-phenylenediamine (Ⅲ), the yield is 92.0%, and the liquid phase purity is 99.6%.

Embodiment 2

[0084] Example 2: Preparation of N,N'-bis(5-hydroxy-n-valeryl)-p-phenylenediamine (Ⅲ)

[0085] To a 500 ml four-neck flask connected with a stirrer, a thermometer, and a condenser tube, add 250 g of N,N-dimethylformamide, 54.0 g (0.5 mole) of p-phenylenediamine (II), 120 g (1.2 mole ) δ-valerolactone, heated, stirred at 115-120°C for 4 hours, cooled to 50-70°C, recovered N,N-dimethylformamide by distillation under reduced pressure, and recrystallized the residue with 400 grams of 75% methanol , filtered, washed the filter cake with 30 g of water, and dried to obtain 143.6 g of N,N'-di(5-hydroxy-n-pentanoyl)-p-phenylenediamine (Ⅲ), with a yield of 93.2% and a liquid phase purity of 99.8%.

Embodiment 3

[0086] Embodiment 3: Preparation of 1,4-bis(piperidin-2-one-1-yl)benzene (Ⅴ)

[0087] In the 500 milliliter four-neck flask that is connected with agitator, thermometer, reflux condenser and connected with 30wt% sodium hydroxide aqueous solution absorption device, add 150 grams of 1,2-ethylene dichloride, 30.8 grams (0.1 moles) implement Example 2 Method Gained N,N'-bis(5-hydroxyl n-pentanoyl) p-phenylenediamine (Ⅲ), heating, and keeping the internal temperature between 30-40°C, add dropwise 35.7 grams (0.3 moles) of chlorinated chlorinated The solution of sulfone and 60 g of 1,2-dichloroethane was added dropwise in 2 hours, and thereafter, the reaction was stirred at 55-60° C. for 3 hours. Cool to 30°C, change to a vacuum distillation device, and recover 1,2-dichloroethane and excess thionyl chloride by vacuum distillation (for the next batch reaction after analyzing the content), after the distillation is completed, cool to 20- At 25°C, the obtained residue N,N'-bis(5-chlor...

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Abstract

The invention provides a simple and convenient preparation method of a 5,6-dihydropyridine-2(1H)-one derivative. The preparation method comprises the following steps: amidating p-phenylenediamine as araw material and delta-valerolactone, and reacting and condensing the hydroxyl of the obtained amidation product and a halogenating reagent 1 or sulfonyl chloride to obtain 1,4-bis(piperidine-2-keto-1-yl)benzene; carrying out carbonyl ortho-halogenation and elimination to obtain 1-(piperidine-2-keto-1-yl)-4-(5,6-dihydropyridine-2(1H)-keto-1-yl)benzene, and carrying out addition and elimination with a halogenating reagent 3 or carrying out elimination substitution in the presence of morpholine to obtain the 5,6-dihydropyridine-2(1H)-one derivative (I). The preparation method has the advantagesof cheap and easily available raw materials, short steps and low cost; the process operation is simple, reaction conditions are easy to realize, the wastewater yield is low, and safety and greennessare realized; and the reaction selectivity of each step is high, the product yield and purity are high, and industrial production is facilitated.

Description

technical field [0001] The present invention relates to a convenient preparation method of 5,6-dihydropyridine-2(1H)-one derivatives, specifically 1-(piperidin-2-one-1-yl)-4-(5,6- A preparation method of dihydro-3-R substituent pyridin-2(1H)-one-1-yl)benzene belongs to the technical field of medicinal chemistry. Background technique [0002] Apixaban (Apixaban), chemical name l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1-yl)phenyl]-4 ,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide is a novel direct factor Xa inhibitor jointly developed by Bristol-Myers Squibb and Pfizer , was approved by the European Union and the US FDA in March 2011 and December 2012, respectively. The trade name is Eliquis, which is used to prevent venous thromboembolism (VTE) and atrial fibrillation in adult patients undergoing hip or knee replacement. Wherein 1-(piperidin-2-one-1-yl)-4-(5,6-dihydro-3-chloro Pyridin-2(1H)-one-1-yl)benzene (I1) and 1-(piperidin-2-one-1-yl)-4-(5,6-dihydro-...

Claims

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Application Information

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IPC IPC(8): C07D211/86
CPCC07D211/86
Inventor 刘月盛戚聿新于启欣潘秉辰李森
Owner XINFA PHARMA
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