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A kind of preparation method of 5,6-dihydropyridin-2(1h)-one derivative

A technology of dihydropyridine and derivatives, applied in the field of medicinal chemistry, can solve the problems of low total yield, cumbersome operation, and large amount of phosphorus-containing wastewater, and achieve high product purity and yield, simple process operation, and cheap and easy raw materials The effect

Active Publication Date: 2021-05-14
XINFA PHARMA
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0013] 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 dichlorination reaction in synthetic route 1 is low, the amount of phosphorus-containing wastewater is large, the total yield is low, and it has no practical application value ; Synthetic route 2 utilizes 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 higher than that of synthetic route 1, the raw material price used in its preparation method is high, and the reaction with piperidin-2-one needs cuprous bromide-triphenylphosphine Catalyst, high temperature required for reaction, low total yield, high cost, large amount of waste water

Method used

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  • A kind of preparation method of 5,6-dihydropyridin-2(1h)-one derivative
  • A kind of preparation method of 5,6-dihydropyridin-2(1h)-one derivative
  • A kind of preparation method of 5,6-dihydropyridin-2(1h)-one derivative

Examples

Experimental program
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Effect test

Embodiment 1

[0098] Example 1: Preparation of N-(5-hydroxyl-n-pentanoyl)-N'-acetyl p-phenylenediamine (Ⅲ)

[0099] In a 1000 ml four-neck flask connected with a stirrer, a thermometer, and a condenser tube, add 350 grams of toluene, 30 grams of N,N-dimethylformamide, 75.0 grams (0.5 moles) of para-acetamidoaniline (II), 70.0 Gram (0.7 moles) δ-valerolactone, heating, 110-115 ℃ of stirring reaction 4 hours, cooling to 20-25 ℃, filtering, 30 gram of toluene washing filter cakes, drying, obtains 115.8 gram of N-(5-hydroxyl N-pentanoyl)-N'-acetyl-p-phenylenediamine (Ⅲ), the yield is 92.6%, and the liquid phase purity is 99.5%.

Embodiment 2

[0100] Example 2: Preparation of N-(5-hydroxy-n-pentanoyl)-N'-acetyl p-phenylenediamine (Ⅲ)

[0101] To a 500 ml four-necked flask connected with a stirrer, a thermometer, and a condenser tube, add 250 g of N,N-dimethylformamide, 75.0 g (0.5 mole) of p-acetamidoaniline (II), 70.0 g (0.7 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 , filter, 30 grams of water wash the filter cake, dry to obtain 118.6 grams of N-(5-hydroxyl n-valeryl)-N'-acetyl p-phenylenediamine (Ⅲ), the yield is 94.9%, and the liquid phase purity is 99.9% %.

Embodiment 3

[0102] Example 3: Preparation of 4-(piperidin-2-one-1-yl)-N-acetylaniline (Ⅴ)

[0103] 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, 25.0 grams (0.1 moles) implement N-(5-hydroxyl n-pentanoyl)-N'-acetyl p-phenylenediamine (Ⅲ) obtained by the method of example 2 is heated, and kept between 40-50°C of internal temperature, to which 23.8 grams (0.2 mol) of thionyl chloride and 50 g of 1,2-dichloroethane, the solution 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 resulting residue N-(5-chloro-n-valeryl)-N...

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Abstract

The invention provides a preparation method of 5,6-dihydropyridine-2(1H)-one derivatives, specifically 1-(piperidin-2-one-1-yl)-4-(5,6-di The preparation method of hydrogen-3-R substituent pyridine-2(1H)-one-1-yl)benzene, the R substituent is chlorine or morpholin-4-yl. The present invention uses p-acetamidoaniline as a raw material, undergoes amidation with δ-valerolactone, halogenates with a halogenating agent or sulfonylates with sulfonyl chloride, condenses, deacetylates, and then reacts with 2,2-dichloro-δ - Amidation of valerolactone, halogenation with halogenating reagents or sulfonylation with sulfonyl chloride, followed by condensation elimination or condensation elimination substitution in the presence of morpholine to prepare the target product. The raw materials used in the preparation method of the invention are cheap and easy to obtain, and the cost is low; the process is simple and easy to operate, the reaction conditions are easy to realize, the amount of waste water generated is small, and it is safe and green; the reaction selectivity of each step is high, the product yield and purity are high, and it is beneficial to industrial production.

Description

technical field [0001] The present invention relates to a preparation method of 5,6-dihydropyridine-2(1H)-one derivatives, specifically 1-(piperidin-2-one-1-yl)-4-(5,6-di The preparation method of hydrogen-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. Among them, 1-(piperidin-2-one-1-yl)-4-(5,6-dihydro-3-chloro Pyridine-2(1H)-one-1-yl)benzene(I1) and 1-(piperidin-2-one-1-yl)-4-(5,6-dihydro-3-...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D401/10
CPCC07D401/10
Inventor 戚聿新刘月盛钱余峰唐兆宁
Owner XINFA PHARMA
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