阅读说明：本技术 一种吡非尼酮光降解杂质及其制备方法 (Pirfenidone photodegradation impurities and preparation method thereof ) 是由 施路 许加龙 胡丰锦 于 2020-12-09 设计创作，主要内容包括：本发明公开了一种吡非尼酮光降解杂质6-甲基-2苯基-2-氮杂双环[2.2.0]己-5-烯-3-酮及其制备方法。步骤简单,反应条件温和,产物收率高且纯度较高。本发明为吡非尼酮原料药及相关制剂的降解杂质检测提供了新的对照品,更有利于工艺研究和质量控制,进而控制吡非尼酮的产品质量,具有重大的意义和实用价值。(The invention discloses a pirfenidone photodegradation impurity 6-methyl-2 phenyl-2-azabicyclo [2.2.0] hex-5-en-3-one and a preparation method thereof. Simple steps, mild reaction conditions, high product yield and high purity. The invention provides a new reference substance for detecting the degradation impurities of the pirfenidone bulk drug and related preparations, is more beneficial to process research and quality control, further controls the product quality of pirfenidone, and has great significance and practical value.)

1. A compound of formula I:

2. compound I according to claim 1, characterized in that it is a photodegradable impurity of pirfenidone.

3. The method for synthesizing the compound I according to claim 1, wherein the synthesizing step comprises:

(1) dissolving pirfenidone and a photosensitive catalyst in a solvent by taking pirfenidone as a starting material and uniformly mixing;

(2) carrying out photocatalytic reaction on the mixture obtained in the step (1) under the irradiation of a light source;

(3) and (3) separating and purifying the reaction liquid obtained in the step (2) to obtain a target product.

4. The method according to claim 3, wherein the solvent is one or more selected from the group consisting of water, ethanol, methanol and tetrahydrofuran.

5. The method according to claim 3, wherein the photosensitive catalyst is selected from one or more of benzophenone, 4-bis (dimethoxy) thiobenzophenone, thioxanthone, and titanium dioxide.

6. The preparation method according to claim 3, wherein the purification method in the step (3) comprises concentrating the reaction solution, performing silica gel column chromatography, and then refluxing and pulping with ethyl acetate to obtain the target compound.

7. The preparation method of the compound of claim 6, wherein the mobile phase of the silica gel column chromatography is a mixed solution of ethyl acetate and petroleum ether, and the volume ratio of the ethyl acetate to the petroleum ether is (5-2): 1.

8. The method of claim 3, wherein the molar ratio of pirfenidone to photocatalyst is 2-5:1, preferably 3: 1.

9. The method according to claim 3, wherein the reaction temperature in the step (2) is 10 to 40 ℃, preferably 15 to 25 ℃.

10. The method as claimed in claim 3, wherein the light source is UV light having a wavelength of 300-380 nm.

Technical Field

The invention relates to the technical field of medicines, and particularly relates to a pirfenidone photodegradation impurity and a preparation method thereof.

Background

Pirfenidone (PFD) is 5-methyl-1-phenyl-2- (1H) -pyridone, white or light yellow powder, molecular formula is C12H11NO, and molecular weight is 185.22. Pirfenidone is a novel pyridone compound with a broad-spectrum anti-fibrosis effect, can prevent and reverse fibrosis and scar formation, and is a first choice drug for treating pulmonary fibrosis. It is a potent cytokine inhibitor that can inhibit the biological activity of fibroblasts by participating in the regulation of certain factors, resulting in a decrease in cell proliferation and matrix collagen synthesis. The following are the major targets for PFD: transforming growth factor-beta (TGF-. beta.l), Platelet Derived Growth Factor (PDGF), tumor necrosis factor-alpha (TNF-. alpha.), Connective Tissue Growth Factor (CTGF), and other inflammatory factors, and the like.

Pirfenidone was developed by Marnac, usa, and japanese salt wild drug was acquired in japan, korea, and taiwan, 1997, 4. In 4 months 2002, InterMune corporation gained global development rights for this compound in addition to the above three markets. In 10 months 2008, the product was first approved in Japan by the pharmaceutical application of salt Yew under the trade name Pirespa (Specification: 200 mg). Currently, pirfenidone has become the first drug approved for the treatment of Idiopathic Pulmonary Fibrosis (IPF) in multiple countries. Pirfenidone marketed by FDA and EuropeThe specification of the tablet and the capsule are 267mg, and at present, 200mg pirfenidone tablets produced by Beijing Kaiyin science and technology GmbH are sold on the market at home.

Under the condition of carrying out a pirfenidone stability study, the inventor detects that pirfenidone is degraded into a compound shown in the following structure under the condition of illumination:

the existence of this compound has not been reported in the literature. The degradation impurities of the medicine directly influence the stability of the medicine and the research of related preparations, so the method has great significance for the research of the pirfenidone photodegradation impurities.

Disclosure of Invention

The invention aims to provide a pirfenidone photodegradation impurity and a preparation method thereof, the method has simple steps and mild reaction conditions, and the pirfenidone photodegradation impurity can be efficiently and excellently obtained.

The specific technical scheme is as follows:

a compound of formula I:

this compound I is a photodegradable impurity of pirfenidone.

The synthesis steps comprise:

(1) dissolving pirfenidone and a photosensitive catalyst in a solvent by taking pirfenidone as a starting material and uniformly mixing;

(2) carrying out photocatalytic reaction on the mixture obtained in the step (1) under the irradiation of a light source;

(3) and (3) separating and purifying the reaction liquid obtained in the step (2) to obtain a target product.

Preferably, the solvent is one or more of water, ethanol, methanol and tetrahydrofuran; ethanol is preferred. Because pirfenidone is most soluble in ethanol.

Preferably, the photosensitive catalyst is selected from one or more of benzophenone, 4-bis (dimethoxy) thiobenzophenone, thioxanthone and titanium dioxide. Benzophenone is preferred. Because the rate of the benzophenone for catalyzing the photodegradation of the pirfenidone is higher, and the interference of other impurities is smaller.

Preferably, the purification method in the step (3) comprises concentrating the reaction solution, performing silica gel column chromatography, and then refluxing and pulping with ethyl acetate to obtain the target compound. The mobile phase of the silica gel column chromatography is a mixed solution of ethyl acetate and petroleum ether, and the volume ratio of the ethyl acetate to the petroleum ether is (5-2): 1.

And the reaction solution concentration step is to filter the reaction solution after the reaction is finished, evaporate most of the solvent from the filtrate, add ethyl acetate/water for extraction, wash the obtained organic phase with saturated sodium chloride solution, dry the organic phase with anhydrous sodium sulfate, and concentrate the organic phase to obtain a crude product of the target product.

Preferably, the molar ratio of pirfenidone to the photoactive catalyst is 2-5:1, preferably 3: 1.

Preferably, the reaction temperature in step (2) is 10 to 40 ℃, preferably 15 to 25 ℃. The reaction rate decreases with decreasing temperature and the other impurities increase with increasing temperature.

Preferably, the light source is UV light with the wavelength of 300-380nm, such as a medium-pressure mercury lamp with the input power of 500-3000 w.

Compared with the prior art, the invention has the following beneficial technical effects:

the invention discloses a pirfenidone photodegradation impurity 6-methyl-2 phenyl-2-azabicyclo [2.2.0] hex-5-en-3-one and a preparation method thereof. Simple steps, mild reaction conditions, high product yield and high purity. The invention provides a new reference substance for detecting the degradation impurities of the pirfenidone bulk drug and related preparations, is more beneficial to process research and quality control, further controls the product quality of pirfenidone, and has great significance and practical value.

Drawings

FIG. 1 is a liquid phase diagram of the compound of formula 1 prepared in example 1.

FIG. 2 is an MS spectrum of the compound of formula 1 prepared in example 1.

FIG. 3 is a hydrogen spectrum of the compound of formula 1 prepared in example 1.

FIG. 4 is a carbon spectrum diagram of the compound of formula 1 prepared in example 1.

Detailed Description

The present invention will be described in further detail with reference to the following examples. It should not be understood that the scope of the above-described subject matter of the present invention is limited to the following examples.

The preparation of 6-methyl-2-phenyl-2-azabicyclo [2.2.0] hex-5-en-3-one is carried out by the following technical route:

wherein the used raw material drug pirfenidone (5-methyl-1-phenyl-2- (1H) -pyridone) is synthesized by the prior art.

Main instruments used in the following examples

A photoreactor: beijing Zhongji Boteng technologies, Inc.;

the HPLC detection conditions were as follows:

example 1: preparation of 6-methyl-2-phenyl-2-azabicyclo [2.2.0] hex-5-en-3-one

Adding 5-methyl-1-phenyl-2- (1H) -pyridone (5g, 0.027mol) into 500mL of ethanol for cleaning, adding 14.7g of benzophenone, mixing uniformly, placing into a photoreactor, starting a 500W medium-pressure mercury lamp, controlling the temperature to be 15-25 ℃, stirring for reaction for 36-40H, stopping the reaction when the liquid phase monitoring conversion rate is more than 80%, filtering the reaction solution, removing most of the solvent by rotary evaporation at 40 ℃ of the filtrate, adding ethyl acetate/water for extraction, washing the organic phase with saturated saline, drying with anhydrous sodium sulfate, separating and purifying the concentrated crude product by silica gel column chromatography (using ethyl acetate/petroleum ether (5-2): 1(V/V as a mobile phase), refluxing and pulping by using ethyl acetate after decompression and desolventization, drying and blasting the solid at 50 ℃ to obtain 6-methyl-2 phenyl-2-azabicyclo [2.2.0] hex-5-ene- 3-Ketone 1.3g in total, HPLC purity 98%.

Example 2: preparation of 6-methyl-2-phenyl-2-azabicyclo [2.2.0] hex-5-en-3-one

Adding 5-methyl-1-phenyl-2- (1H) -pyridone (5g, 0.027mol) into 800mL tetrahydrofuran for dissolving, adding 14.7g benzophenone, mixing uniformly, placing into a photoreactor, starting a 500W medium-pressure mercury lamp, controlling the temperature to 15-25 ℃, stirring for reaction for 36-40H, stopping the reaction when the liquid phase monitoring conversion rate is more than 80%, filtering the reaction solution, removing most of the solvent by rotary evaporation at 40 ℃, then adding ethyl acetate/water for extraction, washing the organic phase with saturated common salt, drying with anhydrous sodium sulfate, separating and purifying the concentrated crude product by silica gel column chromatography (using ethyl acetate/petroleum ether (5-2): 1(V/V as a mobile phase), refluxing and pulping with ethyl acetate after reduced pressure desolventization, drying and blasting the solid at 50 ℃ to obtain 6-methyl-2 phenyl-2-azabicyclo [2.2.0] hex-5-ene- 3-Ketone 1.3g in total, HPLC purity 96%.

Example 3: preparation of 6-methyl-2-phenyl-2-azabicyclo [2.2.0] hex-5-en-3-one

Adding 5-methyl-1-phenyl-2- (1H) -pyridone (5g, 0.027mol) into 500mL of ethanol, adding 20.6g of 2-isopropyl thioxanthone, uniformly mixing, placing into a photoreactor, starting a 500W medium-pressure mercury lamp, stirring and reacting for 36-40H at the temperature of 15-25 ℃, stopping the reaction when the liquid phase monitoring conversion rate is more than 80%, filtering the reaction solution, performing rotary evaporation on the filtrate at 40 ℃ to remove most of the solvent, then adding ethyl acetate/water for extraction, washing the organic phase with saturated sodium chloride, drying with anhydrous sodium sulfate, separating and purifying the concentrated crude product through silica gel column chromatography (using ethyl acetate/petroleum ether (5-2): 1(V/V as a mobile phase), performing reflux beating with ethyl acetate after reduced pressure desolvation, and drying the solid at 50 ℃ by air blasting to obtain 6-methyl-2-phenyl-2-azabicyclo [2.2.0] hexane-5 -en-3-one 1.3g in total, 95% HPLC purity.