CN108794469A - A kind of new technique for synthesizing of azole compounds and the purposes of antitumor action - Google Patents

Abstract

The invention discloses a new synthesis process of pyrrole compound and its anti-tumor application, and specifically relates to the compound 1-benzenesulfonyl-4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine, A new synthesis process of hydrates and their salts and the application of anti-tumor effect. This synthesis process uses 1H-pyrrolo[2,3-b]pyridine as the starting material, and prepares 1-benzene Sulfonyl-4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine, hydrates and salts thereof provide a new process with simple operation and high yield, the preparation method is simple to operate, and the reaction The condition is mild, and the compound has remarkable antitumor activity and little toxicity to normal cells, which is favorable for its wide promotion in the field of antitumor.

Description

A new synthesis process of pyrrole compound and its anti-tumor effect application

technical field

The invention relates to the field of pyrrole compounds, in particular to a new synthesis process of pyrrole compounds and the application of anti-tumor effect.

technical background

In medicine, cancer refers to malignant tumors originating from epithelial tissue, which is the most common type of malignant tumors. Correspondingly, malignant tumors originating in mesenchymal tissue are collectively referred to as sarcomas. There are a few malignant tumors not named according to the above principles, such as Wilms tumor, malignant teratoma, etc. Generally speaking, "cancer" generally refers to all malignant tumors.

Over the years, although the scientific community has made great progress in the research on the mechanism of cancer formation and development, effective treatments for cancer are still relatively lacking so far. At present, almost all antineoplastic drugs in the domestic and foreign markets generally have the disadvantages of slow onset of action, large side effects, and easy drug resistance, so their clinical use is limited to a certain extent. Finding new anti-cancer targets and developing highly effective and low-toxic anti-cancer drugs targeting these new targets are currently important scientific tasks.

Contents of the invention

One of the objects of the present invention is to provide a new synthetic process for pyrrole compounds, hydrates and salts thereof. The new synthetic process has mild reaction conditions, short reaction time, low requirements for equipment, and low degree of side reactions. The yield is higher.

The second object of the present invention is to provide a kind of application of pyrrole compound, hydrate and its salt in antitumor effect, specifically compound 1-benzenesulfonyl-4-chloro-5-nitro-1H-pyrrolo[2 , 3-b] pyridine, hydrates and salts thereof in anti-tumor purposes, 1-benzenesulfonyl-4-chloro-5-nitro-1H-pyrrolo [2,3-b] pyridine, hydrates and Its salt can effectively inhibit HepG2 (human liver cancer) cells, TE1 (human esophagus cancer) cells, MCF7 (human breast cancer) cells, and lung cancer cells.

Aiming at the problems mentioned in the background technology, the technical scheme adopted by the present invention is: a new process for the synthesis of pyrrole compounds, specifically 1-benzenesulfonyl-4-chloro-5-nitro-1H-pyrrolo[2, A new process for the synthesis of 3-b]pyridine, hydrates and their salts. The structural formula of 1-benzenesulfonyl-4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine is:

The structural formula of 1-benzenesulfonyl-4-chloro-5-nitro-1H-pyrrolo[2,3-b]hydrate and its salts is:

X represents any organic acid and inorganic acid that can form salts acceptable to this compound, and hydrates in any proportion.

The synthetic method of 1-benzenesulfonyl-4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine, hydrate and salt thereof comprises the following steps:

The new synthesis process of pyrrole compound 1-benzenesulfonyl-4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine, its salt or its hydrate is as follows:

Synthesis of GXY2010-1:

Synthesis of GXY2010-2:

Synthesis of GXY2010-3:

Synthesis of GXY2010-4:

Said a is, mix the raw material 7-azaindole with dimethyl ether (DME), stir to dissolve, add m-chloroperoxybenzoic acid in batches under 0-10°C ice-salt bath, and control the temperature at 10-20°C , reaction 1 ~ 3h.

Said b is, after the reaction is completed, add n-heptane to the reaction liquid under stirring, and suction filter after stirring for half an hour. The filter cake is washed once with DME:n-heptane=1:1 solution, and the solid is naturally dried to obtain earthy gray Solid (Y:89%).

Said c is, add the intermediate GXY2010-1 and phosphorus oxychloride to the reaction vessel, and stir it to form a reddish-brown mixed liquid. After heating up to 40-60°C, stir for 1 hour, continue heating to 90°C, and wait until the temperature of the mixed liquid is stable. , stirring and reacting for 10-15 hours; after the reaction, cool down to room temperature, distill phosphorus oxychloride off under reduced pressure, add acetonitrile to the remaining liquid to dilute, slowly add water to quench phosphorus oxychloride, adjust the pH to 9, and the precipitated soil The yellow solid was filtered by suction, washed with water and dried.

Said d is, sequentially add intermediate GXY2010-2, dichloromethane (DCM), 4-dimethylaminopyridine (DMAP) and triethylamine (Et3N) into the reaction flask, add PhSO ₂ Cl in batches, and the temperature rises High, the temperature of the water bath is lowered to control the feeding temperature below 35°C, and the addition is completed in 60 minutes. After the addition is completed, continue to stir at room temperature for 20 hours and the reaction ends.

The above e is post-treatment, dilute hydrochloric acid to adjust the pH to 2-5, DCM phase, washing with lye, washing with water, taking the organic phase to dry, and evaporating to dryness under reduced pressure to obtain the crude product.

The f is, add intermediate GXY2010-3, DCM and TBAN to the reaction flask, stir until the solid is completely dissolved, add trifluoroacetic anhydride (TFAA) and trimellitic anhydride (TMA) in batches, and control the addition temperature at - Below 10～-20℃, add in 20 minutes, after adding, stir at 0℃～20℃ for 24h.

The h is post-processing, filtering, the filter cake is washed with acetonitrile, and the filter cake is the product; the filtrate is spin-dried and filtered. Dry to obtain light yellow this product altogether, light yellow this product compound is 1-benzenesulfonyl-4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine, nuclear magnetic data is 1H-NMR (300MHz , CDCl3, ppm) δ: 9.005(s, 1H), 8.244(m, 2H), 7.965(d, J=3.9Hz, 1H), 7.696(m, 1H), 7.584(m, 2H), 6.886(d , J=3.9Hz, 1H).

A new synthesis process of pyrrole compound and its anti-tumor application, specifically 1-benzenesulfonyl-4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine, hydrate and its salt Novel application in antitumor, 1-benzenesulfonyl-4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine, its salt or its hydrate can effectively inhibit HepG2 (human liver cancer) cells, TE1 (human esophageal cancer) cells, MCF7 (human breast cancer) cells, lung cancer cells, 1-phenylsulfonyl-4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine, hydrated The compounds and their salts have a more significant killing effect on the above cancer cells, and can be used to make medicines for treating malignant tumors such as human liver cancer, breast cancer, esophageal cancer, and lung cancer.

As a preference, the method for preparing capsule preparations with 1-benzenesulfonyl-4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine, hydrates and salts thereof is as follows:

Take 420-450 parts of soybean oil, 25-30 parts of beeswax, and 5.5-6.0 parts of span-80, mix well, heat to 70-72°C to completely melt the beeswax, stir and cool to 35°C, add 45-48 parts of traditional Chinese medicine extract for super Micropowder, 0.03～0.05 parts of 1-benzenesulfonyl-4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine or its hydrate or its salt, stir evenly, vacuumize to remove air bubbles, and set aside ; Take gelatin, glycerin, and water and add them to a water-bath type plastic tank according to the ratio of 0.4-0.5:0.6-0.8:1, stir and melt, keep warm for 2 hours, vacuumize to eliminate air bubbles, pass through a 100-160 mesh screen, and place in a 50- Insulate the plastic bucket at 60°C, and let it stand for 2 hours; use a soft capsule press machine at 24-25°C and a relative humidity of 45-50%, fill in the above materials, and press out soft capsules; at 25-26°C, relative humidity Dry at 10-15% environment for 24 hours to obtain the capsule preparation; the capsule preparation is reasonable in prescription and feasible in technology, and the content is taupe viscous colloid with slight gas and bitter taste. Rapid, good stability, easy to take and other advantages, the effective ingredients of soft capsules Chinese herbal preparations and 1-benzenesulfonyl-4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine, its salt or The dissolution rate of its hydrate is high, which is conducive to the rapid absorption of the body, so as to play its role in killing cancer cells.

Compared with the prior art, the present invention has the advantages of:

1) A new synthesis process of pyrrole compounds, hydrates and their salts. The new synthesis process has mild reaction conditions, short reaction time, low requirements on equipment, low degree of side reactions, and high product yield;

2) A pyrrole compound, hydrate and its salt can effectively inhibit HepG2 (human liver cancer) cells, TE1 (human esophagus cancer) cells, MCF7 (human breast cancer) cells, lung cancer cells, 1-benzenesulfonyl-4-chloro -5-nitro-1H-pyrrolo[2,3-b]pyridine, its salt or its hydrate has a relatively significant killing effect on the above cancer cells, and can be produced for the treatment of human liver cancer, breast cancer, esophageal cancer , lung cancer and other malignant tumor drugs.

Detailed ways

Below by embodiment the scheme of the present invention is further described:

Example 1:

The synthetic method of 1-benzenesulfonyl-4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine, hydrate and salt thereof comprises the following steps:

In the above synthesis steps, the a is as follows: mix the raw material 7-azaindole with dimethyl ether (DME), stir to dissolve, add m-chloroperoxybenzoic acid in batches under 1°C ice-salt bath, control the temperature at 15 ℃, reaction 2h;

Said b is, after the reaction is completed, add n-heptane to the reaction liquid under stirring, and suction filter after stirring for half an hour. The filter cake is washed once with DME:n-heptane=1:1 solution, and the solid is naturally dried to obtain earthy gray Solid (Y:89%);

Said c is, add intermediate GXY2010-1 and phosphorus oxychloride to the reaction vessel, and stir it to form a reddish-brown mixed solution. After heating up to 45°C, stir for 1 hour, and continue heating to 90°C. When the temperature of the mixed solution is stable, stir React for 12 hours; after the reaction is completed, cool down to room temperature, distill off the phosphorus oxychloride under reduced pressure, add acetonitrile to the remaining liquid to dilute, slowly add water dropwise to quench the phosphorus oxychloride, adjust the pH to 9, and filter the precipitated khaki solid with suction , washed with water and dried;

Said d is, sequentially add intermediate GXY2010-2, dichloromethane (DCM), 4-dimethylaminopyridine (DMAP) and triethylamine (Et3N) into the reaction flask, add PhSO ₂ Cl in batches, and the temperature rises High, the temperature of the water bath is lowered to control the feeding temperature below 35°C, and the addition is completed in 60 minutes. After the addition is completed, continue to stir at room temperature for 20 hours and the reaction ends;

The above e is post-treatment, dilute hydrochloric acid to adjust the pH to 2.5, DCM phase, washing with lye, washing with water, taking the organic phase to dry, and evaporating to dryness under reduced pressure to obtain the crude product;

The f is, add intermediate GXY2010-3, DCM and TBAN to the reaction flask, stir until the solid is completely dissolved, add trifluoroacetic anhydride (TFAA) and trimellitic anhydride (TMA) in batches, and control the addition temperature at - Add at 15°C for 20 minutes. After adding, stir at 1°C for 24h; in this step f, add trimellitic anhydride (TMA) in batches. The nitrogen atom forms a hydrogen bond, thereby increasing the steric hindrance of the nitrogen atom, making the active nitroso group far away from the carbon atom on the nitrogen atom's ortho position, and then replacing the hydrogen on the nitrogen atom's meta carbon atom greatly increased, which can greatly reduce the formation of by-products and increase the yield and output of the product GXY2010-4; on the other hand, under the coexistence of trifluoroacetic anhydride and trimellitic anhydride, the positive reaction of the f reaction system The speed is greatly increased, while the speed of the reverse reaction is reduced, which helps the reactants to generate the final product GXY2010-4, makes the reaction complete quickly, and increases the yield and output of the final product.

The h is post-processing, filtering, the filter cake is washed with acetonitrile, and the filter cake is the product; the filtrate is spin-dried and filtered. Dry to obtain light yellow this product altogether, light yellow this product compound is 1-benzenesulfonyl-4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine, nuclear magnetic data is 1H-NMR (300MHz , CDCl3, ppm) δ: 9.005(s, 1H), 8.244(m, 2H), 7.965(d, J=3.9Hz, 1H), 7.696(m, 1H), 7.584(m, 2H), 6.886(d , J=3.9Hz, 1H).

Example 2:

The in vitro MTT method was used to measure the killing effect of the compound on tumor cells: the tumor cell density was about 15,000, and the tumor cells were inoculated in a 96-well plate, that is, 3,000 cells were inoculated in each well. After the cells adhered to the wall, the drug was administered, and the structure In the in vitro MTT experiment, it significantly killed human breast cancer cells, liver cancer cells, esophageal cancer cells, etc.

As shown in Table 1, after administration of different concentrations of the compound 1-benzenesulfonyl-4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine, human breast cancer cells, The relative survival rates of liver cancer cells, human esophageal cancer cells, and human lung cancer cells were significantly decreased, and the lethality of cancer cells was positively correlated with the dose, indicating that the compound 1-benzenesulfonyl-4-chloro-5-nitro -1H-pyrrolo[2,3-b]pyridine has a more significant killing effect on human breast cancer cells, liver cancer cells, human esophageal cancer cells, and human lung cancer cells, and can be produced for the treatment of human liver cancer, breast cancer, esophagus Drugs for malignant tumors such as cancer and lung cancer.

Table 1. Relative survival of relevant cancer cells after drug administration

Example 3:

Prepare capsule preparations with 1-benzenesulfonyl-4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine, hydrates and salts thereof:

Preparation of soft capsules: Take 420 parts of soybean oil, 28 parts of beeswax, and 5.5 parts of span-80, mix well, heat to 70°C to completely melt the beeswax, stir and cool to 35°C, add 45 parts of traditional Chinese medicine extract superfine powder, 0.03 parts of 1- Benzenesulfonyl-4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine, hydrate and its salts, stir evenly, vacuumize to remove air bubbles, set aside; take gelatin, glycerin, water according to 0.4 : Add the ratio of 0.6:1 into the water-bath type plastic tank, stir and melt, keep warm for 2 hours, vacuumize to eliminate air bubbles, pass through a 100-mesh screen, put it in a plastic bucket at 60°C for heat preservation, and let it stand for 2 hours; at 25°C and relative humidity of Use a soft capsule press machine in an environment of 45%, fill in the above materials, and press out soft capsules; dry at 25°C and a relative humidity of 15% for 24 hours to obtain capsule preparations; It is taupe viscous colloid with slight gas and bitter taste. This dosage form has the advantages of high bioavailability, less toxic and side effects, rapid absorption, good stability, and easy to take. The effective ingredients of soft capsules are Chinese herbal preparations and 1-benzenesulfonyl- 4-Chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine, its salt or its hydrate has a high dissolution rate, which is conducive to the rapid absorption of the body, thereby exerting its role in killing cancer cells .

The preparation method of the superfine powder of traditional Chinese medicine extract is as follows: take scorpion stalks, Ganoderma lucidum, bezoar, and ochre, mix them according to the ratio of mass ratio 100:2:5:6, crush them, pass through a 60-mesh sieve, add 8 times of water and boil them slowly 3h, take the solid matter and add 6 times of water to decoct for 3h, combine the liquid, concentrate at low temperature until the relative density is above 1.2 to get the Chinese medicine extract, and then get the Chinese medicine extract superfine powder after ultrafine grinding; ultrafinely pulverize the Chinese medicine extract After the preparation of soft capsules, not only the dissolution rate of the active ingredients is increased, but also the fluidity of the particles is improved. The filling capacity of the capsules is stable and the production efficiency is high. Lower labor intensity and lower production costs.

Every 500 parts of glycerin contains 2.8 parts of methyl oleate, every 1000 parts of water contains 1.7 parts of glyceraldehyde, and the mass ratio of L-(-)-glyceraldehyde to D-(-)-glyceraldehyde in glyceraldehyde is 83 : 17; α chain, β chain and γ chain in gelatin can be quickly cross-linked under the catalysis of glyceraldehyde, which can form covalent cross-links between longer gelatin segments, thereby effectively increasing the viscosity and freezing point of gelatin and jelly strength, improve the stability of capsules, and prolong the shelf life of capsules; the cross-linked gelatin is a collagen group, which will be quickly denatured by gastric acid after entering the body, and gelatin is decomposed into peptone by pepsin, and further decomposed into small peptides, Amino acids are absorbed and utilized by the body; on the other hand, part of methyl oleate can be hydrolyzed to generate oleic acid, which can seize and react with oxidants in the system, thereby reducing the 1-benzenesulfonyl-4-chloro- Oxidation probability of 5-nitro-1H-pyrrolo[2,3-b]pyridine, hydrates and their salts, preserving their biological functions against cancer cells; special ratio of L-(-)- in glyceraldehyde Glyceraldehyde and D-(-)-glyceraldehyde can have a synergistic effect, which can effectively mediate the interaction between hydroxypropyl cellulose and gelatin, fill the "gap" between the two, and strengthen the capsule gel coat. The mechanical strength and density not only protect the contents of the capsules from oxidative degradation, but also greatly prolong the shelf life of the capsules without affecting the dissolution rate of the contents after the capsules enter the body, comprehensively improving the quality of the capsules from all aspects.

Conventional operations in the operation steps of the present invention are well known to those skilled in the art and will not be repeated here.

The embodiments described above have described the technical solutions of the present invention in detail. It should be understood that the above descriptions are only specific embodiments of the present invention, and are not intended to limit the present invention. All done within the principle scope of the present invention Any modification, supplement or substitution in a similar manner shall be included within the protection scope of the present invention.

Claims (10)

1. A pyrrole compound, characterized in that: the pyrrole compound is 1-benzenesulfonyl-4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine, hydrates and salts thereof, The structural formula of the 1-benzenesulfonyl-4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine is: The structural formula of the hydrate of 1-benzenesulfonyl-4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine or its salt is: 2. A new process for the synthesis of pyrrole compounds, characterized in that: the pyrrole compounds are 1-benzenesulfonyl-4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine, hydrate And its salt, its synthetic new technique comprises the following steps: 3. The new synthetic process of a kind of pyrrole compound according to claim 2, characterized in that: said X represents any organic acid and inorganic acid acceptable for salt formation, and hydrates in any proportion. 4. the synthetic new process of a kind of pyrrole compound according to claim 2, is characterized in that: Said a is, mix the raw material 7-azaindole and dimethyl ether, stir and dissolve, add m-chloroperoxybenzoic acid in batches under 0-10°C ice-salt bath, control the temperature at 10-20°C, and react 1 ~3h; Said b is, after the reaction is completed, add n-heptane to the reaction solution under stirring, suction filter after stirring for half an hour, wash the filter cake once with DME:n-heptane=1:1 solution, and dry the solid naturally to obtain earthy gray solid; Said c is, add the intermediate GXY2010-1 and phosphorus oxychloride to the reaction vessel, and stir it to form a reddish-brown mixed liquid. After heating up to 40-60°C, stir for 1 hour, continue heating to 90°C, and wait until the temperature of the mixed liquid is stable. , stirring and reacting for 10-15 hours; after the reaction, cool down to room temperature, distill phosphorus oxychloride off under reduced pressure, add acetonitrile to the remaining liquid to dilute, slowly add water to quench phosphorus oxychloride, adjust the pH to 9, and the precipitated soil The yellow solid was filtered by suction, washed with water and dried; Said d is, sequentially add intermediate GXY2010-2, dichloromethane, 4-dimethylaminopyridine and triethylamine into the reaction flask, add PhSO ₂ Cl in batches, raise the temperature, and cool the temperature in a water bath to control the feeding temperature at 35 Below ℃, 60min to complete the addition, after the completion of the addition, continue to stir at room temperature for 20h and then the reaction ends; The above e is post-treatment, dilute hydrochloric acid to adjust the pH to 2-5, DCM phase, washing with lye, washing with water, taking the organic phase to dry, and evaporating to dryness under reduced pressure to obtain the crude product; The f is, add intermediate GXY2010-3, DCM and TBAN to the reaction flask, stir until the solid is completely dissolved, add trifluoroacetic anhydride and trimellitic anhydride in batches, and control the feeding temperature below -10～-20°C , 20min to complete the addition, after the completion of the addition, stir at 0°C to 20°C for 24h; The h is post-processing, filtering, washing the filter cake with acetonitrile, and the filter cake is the product; the filtrate is spin-dried and filtered, and dried to obtain a light yellow product. The compound of the light yellow product is 1-benzenesulfonyl-4-chloro- 5-nitro-1H-pyrrolo[2,3-b]pyridine. 5. A use of pyrrole compound for antitumor effect, said pyrrole compound is 1-benzenesulfonyl-4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine, hydrate and salt thereof , characterized in that: the new use of the 1-benzenesulfonyl-4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine, hydrates and salts thereof in antitumor. 6. The use of a pyrrole compound for anti-tumor effect according to claim 5, characterized in that: the use of the pyrrole compound in inhibiting HepG2 human liver cancer cells. 7. The use of a pyrrole compound for anti-tumor effect according to claim 5, characterized in that: the use of the pyrrole compound in inhibiting TE1 human esophageal cancer cells. 8. The use of a pyrrole compound for anti-tumor effect according to claim 5, characterized in that: the use of the pyrrole compound in inhibiting MCF7 human breast cancer cells. 9. The use of a pyrrole compound for anti-tumor effect according to claim 5, characterized in that: the use of the pyrrole compound in inhibiting lung cancer cells. 10. The use of a kind of pyrrole compound with antitumor effect according to claim 5, characterized in that: the method for preparing the capsule preparation of the pyrrole compound is as follows: take 420-450 parts of soybean oil, 25-30 parts of beeswax, 5.5-30 parts of beeswax, Mix 6.0 parts of span-80, heat to melt the beeswax completely, add 45~48 parts of traditional Chinese medicine extract superfine powder, 0.03~0.05 parts of 1-benzenesulfonyl-4-chloro-5-nitro-1H-pyrrole after stirring and cooling And[2,3-b]pyridine or its hydrate or its salt, stir evenly, vacuumize to eliminate air bubbles, and set aside; take gelatin, glycerin and water into the glue tank, stir and melt, keep warm, vacuumize to eliminate air bubbles, After sieving, heat preservation and stand still; fill the above-mentioned materials into a soft capsule pressing machine, and press to produce soft capsules; after drying, the capsule preparation is obtained.