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Preparation method of n-phenyl lactam and its intermediate

A technology of phenyllactam and aniline, which is applied in the field of medicine and can solve problems such as unfavorable industrial production, lower yield, and difficult separation of by-products and target compounds.

Active Publication Date: 2015-09-09
ZHEJIANG YONGNING PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The applicant found in the research that when triethylamine is used as the base, the amino group on the aniline is very easy to react with 2 equivalents of acid chloride, resulting in an increase in by-products in the reaction and a reduction in the yield
On the other hand, the produced by-products are extremely difficult to separate from the target compound, resulting in complicated post-treatment process, which is not conducive to the realization of industrial production

Method used

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  • Preparation method of n-phenyl lactam and its intermediate
  • Preparation method of n-phenyl lactam and its intermediate
  • Preparation method of n-phenyl lactam and its intermediate

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Experimental program
Comparison scheme
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Embodiment 1

[0064]

[0065] Add 100kg of p-nitroaniline (1 equivalent) represented by formula (II-1), 86kg of pyridine (1.5 equivalent), and 2500L of dichloromethane into a 5000L reactor. Under the protection of nitrogen, lower the temperature to -10~0°C, add 112.2 kg (1 equivalent) of 5-chlorovaleryl chloride represented by the formula (III) dropwise, and control the temperature to <20°C. After the dropwise addition was completed, the temperature was raised to 20-30°C and stirred for 1 hour, 800 L of purified water was added, and after stirring for 10 minutes, dichloromethane was distilled off under reduced pressure, centrifuged, and dried to obtain 184.6 kg of the compound represented by formula (IV-1), Yield 99%, HPLC purity 99.8%.

[0066] figure 1 It shows the HPLC chromatogram of the compound shown in (IV-1) prepared by this method. After the reaction, it is not processed and immediately sampled and detected. The position of retention time 17 is the compound shown in (IV-1). As ...

Embodiment 2

[0068] Add 50g of formula (II-1) p-nitroaniline, 55g of triethylamine (1.5 equivalents), and 750ml of dichloromethane into the reaction flask. Under the protection of nitrogen, lower the temperature to -10~0°C, add 68g of 5-chlorovaleryl chloride represented by formula (III) dropwise, and control the temperature to <10°C. After completion of the dropwise addition, raise the temperature to 20-30°C and stir for 24 hours, add 300ml of purified water, stir for 5 minutes, separate the organic layer, wash with 200ml of purified water, 200ml of saturated brine in turn, dry over anhydrous sodium sulfate, and remove the disulfide under reduced pressure. Chloromethane was obtained as a crude product, and the purity was 60.6% by HPLC detection. Further, 47.4 g of the compound of formula (IV-1) was obtained by recrystallization from methanol, with a yield of 51% and an HPLC purity of 99.1%.

[0069] figure 2 It shows the HPLC spectrum of the compound shown in IV-1 prepared by adding tr...

Embodiment 3

[0071]

[0072] Add 100kg of p-nitroaniline (1 equivalent) represented by formula (II-1), 86kg of pyridine (1.5 equivalent), and 2500L of dichloromethane into a 5000L reactor. Under the protection of nitrogen, lower the temperature to -10~0°C, add 112.2 kg (1 equivalent) of 5-chlorovaleryl chloride represented by the formula (III) dropwise, and control the temperature to <20°C. After the dropwise addition was completed, the temperature was raised to 20-30°C and stirred for 1 hour, 800 L of purified water was added, and after stirring for 10 minutes, dichloromethane was distilled off under reduced pressure, centrifuged, and dried to obtain 184.6 kg of the compound represented by formula (IV-1), Yield 99%, HPLC purity 99.8%.

[0073] Add 184.6kg of compound (IV-1), 2000L of dichloromethane, 1000L of purified water, and 81kg of potassium hydroxide into a 5000L reactor, and conduct a reflux reaction for 24 hours. Separate the water layer and wash with 1000L of 5% hydrochloric a...

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Abstract

The invention relates to the field of medicine, and in particular relates to a preparation method of N-phenyl lactam and an intermediate thereof. The preparation method of a compound (N-phenyl lactam) shown in the formula (I) comprises the two steps of: amidating phenylamine shown in the formula (II) and 5-halogenated valeryl chloride shown in the formula (III) and then cyclizing. During research process, applicants discover that pyridine is used in an acylation reaction stage of the preparation method, so that production of by-product is reduced effectively, and the problem of low yield in lactam synthetic process is overcome. When the dose in the preparation method is selected to be the dose of pyridine, the reaction almost generates no impurity difficult to treat, the reaction is more complete, yield is higher, and sequentially, post-treatment process becomes simple, so that the preparation method is suitable for industrialized production. In research, the applicants further unexpectedly discover that due to application of pyridine in acylation process, dose of the 5-halogenated valeryl chloride is lowered greatly, complete reaction can be guaranteed without over dose, and reaction cost is reduced.

Description

technical field [0001] The invention relates to the field of medicine, in particular to a preparation method of N-phenyllactam and its intermediate. Background technique [0002] 4,5-dihydro-pyrazolo[3,4-c]pyridin-2-one compounds are a class of factor Xa inhibitors, the representative drug apixaban was developed by Bristol-Myers Squibb Approved for thromboprophylaxis in patients who have had hip or knee replacement surgery. Its structural formula is as follows: [0003] [0004] In the synthesis process of this series of compounds, the N-phenyl lactam shown in the following formula (I) is an important intermediate. [0005] [0006] where X is an electron-withdrawing group. In the compound of formula (I) shown, X is a monosubstitution at any position of the benzene ring. [0007] Patent WO2010030983 discloses a method for preparing the compound N-(4-iodo-phenyl)lactam by using iodoaniline and 5-bromovaleryl chloride as raw materials through amidation-cyclization in...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D211/76C07C233/15C07C231/02
CPCC07C231/02C07D211/76C07C233/15
Inventor 叶凤起陆修伟刘涛马苏旺
Owner ZHEJIANG YONGNING PHARMA