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Synthetic process of 3-chloro-octahydro-2(1h)-quinolinone

A synthesis process, quinolinone technology, applied in the direction of organic chemistry, can solve problems such as poor selectivity, low conversion rate, and difficulty in achieving small test results

Active Publication Date: 2018-04-17
大连鼎燕医药化工有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] 2. Since the series of side reactions in the above-mentioned hydrogenation reduction reaction process are difficult to control, the lower reaction conversion rate has to be controlled
[0010] 3. Due to the double impact of poor selectivity and low conversion rate, it is difficult to improve the quality of the product, which has obvious negative effects on subsequent reactions.
[0011] 4. Since the above-mentioned reaction process control needs to take into account both selectivity and conversion rate, there are many factors affected, and it is difficult to achieve the results of the small test in the process of process amplification, which makes the process difficult to stabilize, resulting in high production costs.

Method used

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  • Synthetic process of 3-chloro-octahydro-2(1h)-quinolinone

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] Add 3,3-dichloro-octahydro-2(1H)-quinolinone 100g, 2kg of chloroform, 1kg of ethanol, 700g of 10% sulfuric acid in a 5L round bottom reaction flask equipped with a stirrer and a thermometer, Slowly add 60g of zinc powder under the condition of stirring at 20-25°C for about 3 hours, continue to stir for 1 hour and then stand for stratification. After the obtained organic layer is concentrated, add an equal proportion of ethanol / isopropyl ether to the residue of the kettle Mixed solvent 300ml, the precipitated solid product 3-chloro-octahydro-2(1H)-quinolinone was filtered, washed and dried to obtain off-white solid 3-chloro-octahydro-2(1H)-quinoline Ketones 75.3g, 1 H-NMR (CDCl 3 ), δ: 1.00~2.78(m, 12H), δ: 2.83~2.92(t, 1H), δ: 4.35(s, 1H).

[0028] Through gas chromatography analysis, its area-normalized content was 97.7%, and the yield was 87.1%.

Embodiment 2

[0030] Add 3,3-dichloro-octahydro-2(1H)-quinolinone 100g, 2kg of chloroform, 1kg of ethanol, 500g of 10% sulfuric acid in a 5L round bottom reaction flask equipped with a stirrer and a thermometer, Slowly add 60g of zinc powder under the condition of stirring at 20-25°C for about 3 hours, continue to stir for 1 hour and then stand for stratification. After evaporating the solvent, add an equal proportion of ethanol / isopropyl ether mixed solvent to the obtained organic layer. 300ml, the precipitated solid product was filtered, washed and dried to obtain 80.2g of off-white solid 3-chloro-octahydro-2(1H)-quinolinone, 1 H-NMR (CDCl 3 ), δ: 1.00~2.78(m, 12H), δ: 2.83~2.92(t, 1H), δ: 4.35(s, 1H). After gas chromatography analysis, the area normalized content was 85.8%, and the yield was 81.4%.

Embodiment 3

[0032] Add 100 g of 3,3-dichloro-octahydro-2(1H)-quinolinone, 2 kg of dichloromethane, 1 kg of methanol, and 10% sulfuric acid into a 5 L round-bottomed reaction flask equipped with a stirrer and a thermometer. 500g, add 55g of zinc powder slowly and gradually in about 3 hours at 20-28°C under stirring conditions, continue to stir for 1h and then stand for stratification. After evaporating the solvent, add an equal proportion of ethanol / isopropyl ether to the obtained organic layer Mixed solvent 300ml, the precipitated solid product was filtered, washed, and dried to obtain 76.1 g of off-white solid 3-chloro-octahydro-2(1H)-quinolinone, 1 H-NMR (CDCl 3 ), δ: 1.00~2.78(m, 12H), δ: 2.83~2.92(t, 1H), δ: 4.35(s, 1H). Through gas chromatography analysis, the area normalized content was 70.2%, and the yield was 63.2%.

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Abstract

The invention discloses a synthesis technology of 3-chloro-octahydro-2(1H)-quinolinone. In a solvent, the 3-chloro-octahydro-2(1H)-quinolinone is used as a raw material, zinc powder and sulfuric acid are used as a reducing agent, a reaction is performed at the temperature of 0-50 DEG C for 2-6 h, a water phase is separated out, an organic phase is concentrated, a recrystallization solvent is added for stirring, and filtering and drying are performed to obtain the 3-chloro-octahydro-2(1H)-quinolinone. The synthesis technology is significantly characterized in that activation energies required by two chlorine atom reduction reactions are much different, and the reactions can be easily controlled in the single-chlorine reduction stage just by strictly controlling the reaction temperature and selecting the proper mixing solvent and the proportions thereof. Due to the fact that a series of side reactions are inhibited, the influence on the reaction time is small, and the high conversion rate is easily ensured. Due to the fact that few influence factors of the technology exist, the control conditions are mold, the technology is easily magnified, large-scale production is achieved, and guarantees on the multiple aspects of cost, quality and the like are provided for transolapril commercialized marketing.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a synthesis process of 3-chloro-octahydro-2(1H)-quinolinone. Background technique [0002] 3-Chloro-octahydro-2(1H)-quinolinone is an important intermediate of a new drug for hypertension—Trandolapril (Trandolapril), and it is the most critical factor affecting the preparation cost of Trandolapril. Puli's core steps. So far, two documents published abroad are 3-chloro-octahydro-2(1H)-quinolinone prepared from 3,3-dichloro-octahydro-2(1H)-quinolinone, these two documents Using the same process route: [0003] [0004] The method disclosed in US4933361 is: 15.9g of 3,3-dichloro-octahydro-2(1H)-quinolinone is dissolved in ethanol solution, 10ml of triethylamine is added, the catalyst is Raney nickel, at 20~25℃ After the reaction, concentrate the reaction solution, extract the residue twice with ethyl acetate and water, dry the organic phase with anhydrous sodium sulfate, fil...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D215/227
CPCC07D215/227
Inventor 南海军王洋蔡鲁伯张绥英吕永智崔立财薛丽红
Owner 大连鼎燕医药化工有限公司
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