CN111574435B - 4,4' -dipyridyl methylpyrazine derivative eutectic crystal - Google Patents
4,4' -dipyridyl methylpyrazine derivative eutectic crystal Download PDFInfo
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- CN111574435B CN111574435B CN201910122788.6A CN201910122788A CN111574435B CN 111574435 B CN111574435 B CN 111574435B CN 201910122788 A CN201910122788 A CN 201910122788A CN 111574435 B CN111574435 B CN 111574435B
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- -1 4,4' -dipyridyl methylpyrazine derivative Chemical class 0.000 title claims abstract description 55
- 239000013078 crystal Substances 0.000 title claims description 45
- MWVTWFVJZLCBMC-UHFFFAOYSA-N 4,4'-bipyridine Chemical group C1=NC=CC(C=2C=CN=CC=2)=C1 MWVTWFVJZLCBMC-UHFFFAOYSA-N 0.000 claims abstract description 22
- CAWHJQAVHZEVTJ-UHFFFAOYSA-N methylpyrazine Chemical class CC1=CN=CC=N1 CAWHJQAVHZEVTJ-UHFFFAOYSA-N 0.000 claims abstract description 21
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/06—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
- C07D213/22—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom containing two or more pyridine rings directly linked together, e.g. bipyridyl
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D241/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
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- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
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- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyridine Compounds (AREA)
Abstract
The invention belongs to the technical field of medicines, and particularly provides a 4,4' -dipyridyl methylpyrazine derivative eutectic, a preparation method thereof and application thereof in preparation of a blood fat reducing medicine. The 4,4 '-bipyridyl methylpyrazine derivative eutectic prepared by the invention is formed by combining a methylpyrazine derivative and 4,4' -bipyridyl according to a molar ratio of 2: characteristic peaks are at 9.5 +/-0.2 degrees, 16.5 +/-0.2 degrees, 25.1 +/-0.2 degrees and 27.1 +/-0.2 degrees. The 4,4' -dipyridyl methylpyrazine derivative eutectic prepared by the invention is high in product purity and good in stability after being placed in a solid state, and animal experiments prove that the eutectic has good drug effect. The invention has simple preparation process and better industrial application prospect.
Description
Technical Field
The invention belongs to the technical field of organic drug co-crystals, and particularly relates to a 4,4' -dipyridyl methylpyrazine derivative co-crystal.
Background
Pharmaceutical co-crystals are based on the supramolecular chemistry, i.e. molecular recognition and supramolecular self-assembly by intermolecular interactions. The pharmaceutical active ingredient (API) is self-assembled with a suitable co-crystal former (CCF) through hydrogen bonds, or non-covalent bonds with saturation and directionality (such as Van der Waals force of aromatic hydrocarbon or benzene ring, pi-pi conjugation and halogen bonds), to form a novel structure, namely, the pharmaceutical co-crystal. The method is based on hydrogen bonds, does not need to form new covalent bonds or destroy existing covalent bonds, can modify the physicochemical properties of the medicament while retaining the pharmacological action of the medicament, such as improving the stability of the medicament, reducing the hygroscopicity of the medicament, improving the solubility, improving the bioavailability and the like, and provides a wide development prospect for the application of pharmaceutical co-crystals in the aspect of pharmaceutical industry. In recent years, pharmaceutical co-crystal research has received increasing attention. At the present stage, the research on pharmaceutical co-crystals in foreign countries is gradually increased and deepened; and domestic research on the method is relatively less. For the imitation drugs, the research on the pharmaceutical co-crystal can also break the patent protection of the original research pharmaceutical company on the pharmaceutical crystal form, and is beneficial to the market of the imitation drugs. Therefore, obtaining more novel, practical and creative pharmaceutical co-crystals is of great practical significance, especially for some water-insoluble drugs.
Acipimox is a nicotinic acid derivative, is a broad-spectrum long-acting lipid regulating drug, is used for various primary and secondary hyperlipidemias, mainly acts on adipose tissues, reduces the synthesis of plasma low-density lipoprotein and very low-density lipoprotein by inhibiting the release of free fatty acid from the adipose tissues, thereby reducing the levels of the plasma low-density lipoprotein and the very low-density lipoprotein in the plasma and simultaneously increasing the level of plasma HDL by inhibiting the activity of liver lipase. Acipimox was developed by Farmitalia caro Erba company of italy and marketed in italy in 1985, and then, by virtue of its high safety and remarkable therapeutic effect, it was marketed successively in germany, chile, switzerland and many other countries and regions.
The pharmaceutical co-crystal can affect the physicochemical properties of the medicine, directly affect the dissolution and absorption efficiency of the medicine under the condition of physiological pH 7.4, and further affect the bioavailability, clinical curative effect and the like of the medicine. By means of drug co-crystallization, the advantages of co-crystallization can be well applied, which has very important effect on understanding and mastering the space arrangement and physicochemical properties of effective molecules of drugs.
At present, a lot of reports about acipimox exist, but reports about preparation, physicochemical properties, pharmacology and other properties of the acipimox are mainly about, reports about a crystal eutectic structure of the acipimox are less, patents US2005239803A1, CN 103508963A and the like all report about a preparation method of the acipimox, and patent CN86103304A obtains an acipimox precipitate with a crystal property, which is acipimox hydrate, and the yield is lower. In the previous reports, the reports of the acipimox eutectic crystal are less, and the characterization parameters of the acipimox eutectic crystal are not mentioned.
Disclosure of Invention
In view of the defects of the prior art, the invention provides a 4,4' -dipyridyl methyl pyrazine derivative eutectic.
The methylpyrazine derivative is acipimox, and the 4,4 '-dipyridyl methylpyrazine derivative eutectic is 4,4' -dipyridyl acipimox eutectic.
The acipimox serving as the medicinal component of the invention has the chemical name of 5-methylpyrazine-2-carboxylic acid-4-oxide, and is white or off-white crystalline powder. CAS number: 51037-30-0 molecular formula C 6 H 6 N 2 O 3 The structural formula is shown as a, and is selected in the inventionThe selected eutectic formation is 4,4' -bipyridine with molecular formula C 10 H 8 N 2 The structural formula is shown as b.
In a first aspect of the present invention, a co-crystal of a 4,4' -bipyridylmethylpyrazine derivative is provided. In the co-crystal, the molar ratio of the methylpyrazine derivative to the 4,4' -bipyridine is 2.
The 4,4' -dipyridyl methylpyrazine derivative eutectic uses Cu-Ka radiation, and an X-ray diffraction spectrogram expressed by 2 theta has characteristic peaks at 9.5 +/-0.2 degrees, 16.5 +/-0.2 degrees, 25.1 +/-0.2 degrees and 27.1 +/-0.2 degrees.
Preferably, the 4,4' -bipyridyl methylpyrazine derivative eutectic has characteristic peaks in an X-ray diffraction spectrum expressed by 2 theta at 9.5 +/-0.2 degrees, 10.3 +/-0.2 degrees, 13.9 +/-0.2 degrees, 16.5 +/-0.2 degrees, 19.2 +/-0.2 degrees, 20.0 +/-0.2 degrees, 25.1 +/-0.2 degrees and 27.1 +/-0.2 degrees by using Cu-Kalpha radiation.
Preferably, the 4,4' -bipyridyl methyl pyrazine derivative eutectic is irradiated by Cu-Ka, and the characteristic peak of the eutectic accords with an X-ray powder diffraction pattern shown in figure 1.
Preferably, the 4,4' -dipyridyl methyl pyrazine derivative eutectic has an endothermic peak in a Differential Scanning Calorimetry (DSC) curve, which is 185.73 ℃.
Preferably, the 4,4' -dipyridyl methyl pyrazine derivative eutectic has the following crystallographic parameters: triclinic system, space group of
The unit cell parameters are:
α =73.0010 (10) °, β =88.4890 (10) °, γ =63.454 (2) °, unit cell volume->
The second aspect of the invention provides a preparation method of a 4,4' -bipyridyl methylpyrazine derivative eutectic, which comprises the following specific preparation steps: adding the methylpyrazine derivative and 4,4 '-bipyridine into an organic solvent A, heating for dissolving, after the solution is clarified, carrying out reflux reaction, cooling for crystallization, filtering and drying to obtain the 4,4' -bipyridine methylpyrazine derivative eutectic.
Preferably, the organic solvent A is selected from one or more of acetonitrile, acetone, tetrahydrofuran, methanol, ethanol and isopropanol.
Preferably, the organic solvent A is selected from one or two of acetonitrile, acetone and tetrahydrofuran.
Preferably, the molar ratio of the methylpyrazine derivative to the 4,4' -bipyridine is 1.8 to 2.2.
Preferably, the molar ratio of the methylpyrazine derivative to the 4,4' -bipyridine is 1.95 to 2.05.
Preferably, the mass-to-volume ratio of the 4,4' -bipyridine to the organic solvent A in the system is 3-6, wherein the mass is mg and the volume is ml.
Preferably, the temperature for the dissolution heating is 45-75 ℃.
Preferably, the temperature for cooling and crystallizing is 0-15 ℃.
Preferably, the temperature for cooling and crystallization is 5-10 ℃.
Preferably, the crystallization time is 40 to 62 hours.
Further preferably, the preparation method comprises the following steps:
dissolving the methylpyrazine derivative and 4,4 '-bipyridyl in an organic solvent A, heating and dissolving at 45-75 ℃, stirring, refluxing and reacting for 7-12 hours, cooling to 0-15 ℃, crystallizing for 40-62 hours, filtering, washing a filter cake, and drying to obtain the 4,4' -bipyridyl methylpyrazine derivative eutectic.
Preferably, the solvent for washing the filter cake is selected from one of acetone, acetonitrile and tetrahydrofuran.
Preferably, the drying temperature is 50-70 ℃, and the drying time is 8-12 hours.
The third aspect of the invention provides the application of the 4,4' -dipyridyl methyl pyrazine derivative eutectic serving as an active ingredient in preparing a medicament for treating hypolipidemia.
Confirmation of the Crystal Structure
X-ray crystal data were collected on a jtaab Synergy model instrument, japan, testing temperature 293 (2) K, irradiating with CuKa, collecting data in an omega scan fashion and Lp correction. The crystal structure is obtained by calculation through a Shell XT program in olex2 software, the Shell XL program is adopted to correct structure parameters and judge atom species through a least square method, all hydrogen atom positions are obtained by using a geometric calculation method and a difference Fourier method, the goodness of fit (GooF value) is 1.056 and is close to 1.0, and the weight scheme is suitable and the structure is accurate.
The crystallographic data obtained by testing and analyzing the crystals of the methylpyrazine derivative prepared by the invention are (Table 1), wherein the crystallographic parameters are as follows: triclinic system, space group of
The unit cell parameters are:
α =73.0010 (10) °, β =88.4890 (10) °, γ =63.454 (2) °, unit cell volume
The molecular formula is: [ C ] 12 H 12 N 4 O 6 ·C 10 H 8 N 2 ]The molecular weight is: 464.44. the ORTEP diagram of the 4,4 '-bipyridyl methylpyrazine derivative eutectic crystal of the invention shows that the methylpyrazine derivative and the 4,4' -bipyridine are connected together through intramolecular hydrogen bonds, wherein the carboxyl H3 of the methylpyrazine derivative forms a hydrogen bond with the N3 on the 4,4 '-bipyridine, and the H6 on the carboxyl of the other methylpyrazine derivative molecule forms a partial bond with the N4 on the 4,4' -bipyridineIntramolecular hydrogen bonds, as shown in FIG. 3. The stacking diagram of the 4,4' -dipyridyl methylpyrazine derivative of the invention is shown in figure 2.
TABLE 14,4' -Bipyridylmethyl pyrazine derivatives Co-crystals Primary crystallography data
X-ray powder diffraction test instrument and test conditions: x-ray powder diffractometer PANalytical E; cu-K alpha; a sample stage: a flat plate; the incident light path is BBHD; diffraction light path: PLXCEL; voltage 45kv and current 40mA; 1/4 of divergent slit; an anti-scatter slit 1; 0.04rad of cable pull slit; step length: 0.5s; scanning range: 3 to 50 degrees.
According to the above crystallographic data, the characteristic peak of the corresponding X-ray powder diffraction pattern (Cu-Ka) is detailed in figure 1 and table 2.
TABLE 24 PXRD peaks of Co-crystals of 4,4' -bipyridylmethylpyrazine derivatives
All samples prepared in the examples have the same crystallographic parameters and X-ray powder diffraction patterns.
The eutectic TGA/DSC test result of the 4,4' -bipyridyl methyl pyrazine derivative prepared by the method is shown in figure 4, and the DSC test result has an endothermic peak with the corresponding temperature of 185.73 ℃. According to the TGA detection result, a weight loss step exists, and the DSC/TGA detection result shows that the 4,4' -bipyridyl methyl pyrazine derivative eutectic prepared by the invention does not contain other solvents.
Compared with the currently reported crystal form of the methylpyrazine derivative, the 4,4' -dipyridyl methylpyrazine derivative eutectic prepared by the method has the following advantages:
(1) The stability is high. After the 4,4 '-bipyridine methylpyrazine derivative eutectic is subjected to a light test and placed in a high-temperature and high-humidity environment, the HPLC purity is still higher than 99.55%, and the solid state stability of the 4,4' -bipyridine methylpyrazine derivative eutectic is good compared with the existing methylpyrazine derivative crystal form.
(2) The drug effect is good. The 4,4' -dipyridyl methylpyrazine derivative eutectic can effectively reduce the concentration of cholesterol, triglyceride and low-density lipoprotein in the serum of a fatty liver rat.
Drawings
FIG. 1: an X-ray powder diffraction pattern of the 4,4' -bipyridine methylpyrazine derivative eutectic.
FIG. 2: a stacking diagram of the eutectic of the 4,4' -bipyridyl methyl pyrazine derivative.
FIG. 3: ORTEP diagram of 4,4' -bipyridyl methylpyrazine derivative cocrystals.
FIG. 4: a Differential Scanning Calorimetry (DSC) chart of the eutectic crystal of the 4,4' -dipyridyl methyl pyrazine derivative.
Detailed Description
The advantageous effects of the present invention will now be further described by the following examples, which are for illustrative purposes only and do not limit the scope of the present invention, and it is within the scope of the present invention to include changes and modifications apparent to those of ordinary skill in the art in light of the present invention, impurity I being 5-methylpyrazine-2-carboxylic acid, and the methylpyrazine derivative being acipimox.
Example 1:
adding 61.6mg of acipimox and 31.2mg of 4,4 '-bipyridyl into 8ml of acetonitrile, heating to 75 ℃, stirring for dissolving, carrying out reflux reaction for 10 hours, slowly cooling to 5-10 ℃, standing at controlled temperature for crystallization for 48 hours, filtering, washing a filter cake with acetonitrile, and carrying out vacuum drying at 50 ℃ for 12 hours to obtain 4,4' -bipyridyl acipimox eutectic, wherein the yield is 95.33%, the purity is 99.96%, and the impurity I:0.03 percent.
Example 2:
adding 61.6mg of acipimox and 32.0mg of 4,4 '-bipyridyl into 10ml of acetone, heating to 45 ℃, stirring for dissolving, carrying out reflux reaction for 12 hours, slowly cooling to 0-5 ℃, standing at controlled temperature for crystallization for 40 hours, filtering, washing a filter cake with acetone, and carrying out vacuum drying at 70 ℃ for 8 hours to obtain 4,4' -bipyridyl acipimox eutectic, wherein the yield is 94.56%, the purity is 99.94%, and the impurity I:0.04 percent.
Example 3:
adding 61.6mg of acipimox and 30.5mg of 4,4 '-bipyridyl into 5ml of tetrahydrofuran, heating to 60 ℃, stirring for dissolving, carrying out reflux reaction for 7 hours, slowly cooling to 10-15 ℃, standing at controlled temperature for crystallization for 62 hours, filtering, washing a filter cake with acetonitrile, and carrying out vacuum drying at 60 ℃ for 10 hours to obtain the 4,4' -bipyridyl acipimox eutectic, wherein the yield is 93.85%, the purity is 99.92%, and the impurity I:0.06 percent.
Example 4:
adding 61.6mg of acipimox and 34.7mg of 4,4 '-bipyridine into 8ml of methanol, heating to 60 ℃, stirring for dissolving, carrying out reflux reaction for 10 hours, slowly cooling to-5-0 ℃, standing at a controlled temperature for crystallization for 35 hours, filtering, washing a filter cake with acetone, and carrying out vacuum drying at 50 ℃ for 10 hours to obtain the 4,4' -bipyridine acipimox eutectic, wherein the yield is 89.90%, the purity is 99.90%, and the impurity I:0.08 percent.
Example 5:
adding 61.6mg of acipimox and 28.4mg of 4,4 '-bipyridyl into 4ml of ethanol, heating to 77 ℃, stirring for dissolving, carrying out reflux reaction for 8 hours, slowly cooling to 15-20 ℃, standing at a controlled temperature for crystallization for 65 hours, filtering, washing a filter cake with acetonitrile, and carrying out vacuum drying at 70 ℃ for 10 hours to obtain the 4,4' -bipyridyl acipimox eutectic, wherein the yield is 92.42%, the purity is 99.90%, and the impurity I:0.09 percent.
Example 6:
adding 61.6mg of acipimox and 25.0mg of 4,4 '-bipyridyl into 12ml of isopropanol, heating to 80 ℃, stirring for dissolving, carrying out reflux reaction for 10 hours, slowly cooling to 5-10 ℃, standing at controlled temperature for crystallization for 48 hours, filtering, washing a filter cake with tetrahydrofuran, and carrying out vacuum drying at 50 ℃ for 10 hours to obtain 4,4' -bipyridyl acipimox eutectic, wherein the yield is 90.60%, the purity is 99.88%, and the impurity I:0.11 percent.
Example 7:
adding 61.6mg of acipimox and 36.7mg of 4,4 '-bipyridyl into 10ml of mixed solvent (5 ml of acetonitrile and 5ml of ethanol), heating to 55 ℃, stirring for dissolving, carrying out reflux reaction for 12 hours, slowly cooling to-5-0 ℃, standing for crystallization for 30 hours at controlled temperature, filtering, washing a filter cake with ethanol, and carrying out vacuum drying at 50 ℃ for 10 hours to obtain 4,4' -bipyridyl acipimox eutectic crystal, wherein the yield is 85.0%, the purity is 99.85%, and the impurity I:0.12 percent.
Comparative example 1:
adding 2730ml of 98% concentrated sulfuric acid into a 10L glass reaction kettle, adding 910.0g of 5-methylpyrazine-2, 3-dicarboxylic acid under stirring, heating to 60 deg.C, reacting for 1h, and slowly adding 5.5kg of water and 164.9g of sodium tungstate (Na) 2 WO 4 ·2H 2 O), 623.0g of hydrogen peroxide with the mass concentration of 30 percent, continuously heating and stirring for 8 hours, cooling and crystallizing for 4 hours under the ice bath condition, filtering the solid, and drying for 12 hours at the temperature of 100 ℃ to prepare 595g of the product acipimox. The product yield in this reaction was 77.30%; HPLC purity 96.20%, impurity I:2.80 percent.
Comparative example 2:
adding 200ml of water into 100g of the acipimox crude product, heating to 100 ℃, stirring to dissolve, adding 3.0g of activated carbon, continuing to keep the temperature and stirring for 20 minutes, and performing suction filtration; cooling the filtrate to 60 ℃ at a speed of 10 ℃/h, then dropwise adding 220g of acetone into the filtrate, cooling to 5 ℃ at a speed of 10 ℃/h after the dropwise adding is finished, crystallizing for 7h, performing suction filtration, washing a filter cake with acetone, and drying (0.01MPa, 80 ℃) to obtain the off-white acipimox with a yield of 88.60%. HPLC purity: 98.30%, 5-methylpyrazine-2-carboxylic acid (impurity I): 0.50 percent.
Comparative example 3:
330mg (1 mmol) of Na 2 WO 4 ·2H 2 O was placed in a 50ml flask, dissolved in 16ml of water and fitted with mechanical stirring, reflux cooler and thermometer. 3.75ml of 40% w/v (400 g/L) (44 mmol) hydrogen peroxide were added to the solution, diluted H 2 SO 4 The pH was adjusted to 1.5 and 5.52g (40 mmol) of 2-carboxy-5-methylpyrazine were then added.
The suspension of water produced by the reaction was heated to 70 ℃ with stirring and maintained at this temperature for 2.5 hours. Thus a gradually solubilised suspension is obtained. Finally, a part of the product was found to precipitate. The mixture was allowed to stand at room temperature overnight to cause precipitation of the reaction product in a crystal form. This product was filtered, washed with ice water and dried on a bisque-fired plate to give 4.68g, corresponding to 4.54g, of partially hydrated (2.83%) 2-carboxy-5-methylpyrazine-4-oxide as an anhydrous product. The yield was 73.01%. HPLC purity: 95.10%, impurity I:2.30 percent.
Comparative example 4:
250mg (0.75 mg) of Na was added 2 WO 4 ·2H 2 O was placed in a 50ml flask, dissolved in 13ml of water and fitted with mechanical stirring, reflux cooler and thermometer. 3.23ml of 40% w/v (400 g/L) (38 mmol) hydrogen peroxide was added to the solution, diluted H 2 SO 4 The pH was adjusted to 2.0 and then 3.76g 98% (30 mmol) of 2-carboxy-5-methylpyrazine was added.
The suspension of water produced in the reaction was heated to 80 ℃ with stirring and maintained at this temperature for 2 hours. After 45min, a completely solubilized suspension was obtained. Finally, the solution was allowed to stand at room temperature overnight to cause precipitation of the reaction product in a crystal form. The product was filtered, washed with ice water and dried on a bisque-fired plate to obtain 3.02g of monohydrate of 2-carboxy-5-methylpyrazine-4-oxide (Experimental value H) 2 O-11.35 percent; calculated value of monohydrate product H 2 O-11.3%), yield 63.02%. HPLC purity: 94.21%, impurity I:3.40 percent.
Comparative example 5:
2-carboxy-5-methylpyrazine 4-oxide (2.5 g) was added to a mixed solution of methanol (60 ml) and ethanolamine (1.1 ml). The mixture was heated at reflux for 20 minutes, then cooled and filtered to give after crystallization from methanol 2-carboxy-5-methylpyrazine 4-oxide ethanolamine salt (2.1 g), mp.177 ° -180 ℃, yield: 60.17%, HPLC purity: 96.81%, impurity I:2.10 percent.
Comparative example 6:
the reaction was carried out in a 500ml.x.4 neck flask equipped with a mechanical stirrer, water condenser (with gas inlet) and thermocouple under nitrogen. Sodium trimethylsilanolate (3.71 g) and THF (90 g) were added to the reactor, followed by ethyl 5-methylpyrazinecarboxylate-4-oxide (6.00 g), the mixture was stirred at room temperature for 4 hours, and the solid was collected by filtration and rinsed with THF (3X 45 g). Drying in vacuo (25 inches of mercury, 65 ℃) afforded 5.38g (yield: 92.50%) of the sodium salt as an off-white solid, HPLC purity: 96.80%, impurity I:2.41 percent.
Stability test
Temperature, humidity and light test
The specific stability test method refers to a guidance method related to stability investigation in the fourth part of the Chinese pharmacopoeia 2015 edition, the purity detection is performed by an HPLC method, and specific test results are shown in the following table.
Table 3 stability test results of crystal forms of methylpyrazine derivatives under light, high temperature and high humidity conditions
Tests prove that all the 4,4' -dipyridyl methylpyrazine derivative eutectic prepared by the invention can achieve similar stability effect. The purity and the appearance of the 4,4 '-bipyridyl methylpyrazine derivative eutectic prepared by the invention are not obviously changed under the conditions of illumination, high temperature and high humidity, the purity of the crystals of the comparative examples 1 to 6 is greatly reduced under the same experimental conditions, the impurity content of the crystals is obviously increased, namely, the crystals are deteriorated, and the 4,4' -bipyridyl methylpyrazine derivative eutectic prepared by the invention has better chemical stability compared with the existing crystals.
Experiment of treatment effect of 4,4' -dipyridyl methylpyrazine derivative eutectic on fatty liver rat
(1) Material
(1) Medicine
I. Acipimox capsules (le zhi apple), production lot number: and Z210A.
II. 4,4' -dipyridyl methyl pyrazine derivative eutectic capsule.
Preparation of co-crystal capsules of 4,4' -bipyridyl methylpyrazine derivative was prepared according to the prescription of Lezhi apple.
(2) Reagent: total Cholesterol (TC), triacylglycerol (TG), low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), alanine Aminotransferase (ALT), aspartate Aminotransferase (AST), alkaline phosphatase (ALP), and a blood glucose kit. Liver tissue superoxide dismutase (SOD) and Malondialdehyde (MDA) kits.
(3) The instrument comprises the following steps: an ADVIA 2400 type full-automatic biochemical analyzer, an Axioskop-plus type optical microscope, a tissue embedding machine, a full-automatic tissue dehydrator, a paraffin slicer, a pathological image analysis system and the like.
(2) Animal(s) production
Male Wistar rats, after being acclimatized for 1 week, were randomly divided into a normal control group, a model group, a lescheng apple group and a 4,4' -bipyridylmethylpyrazine derivative cocrystal group, each group containing 5 animals. Each group of rats was given free water intake, basal diet for normal control group, and high fat diet (containing 88.8% basal diet, 10% lard, 1% cholesterol, 0.2% methyl thiouracil) for the remaining 3 groups, and were fed continuously for 5 weeks. From the end of the 6 th week of the experiment, rats in each group are fed as before, and the normal control group and the model group are subjected to intragastric gavage by 1mL of physiological saline; the melezein group is administrated with Acipimox capsule of 0.06 g/(kg d) and is administrated with 1mL, the 4,4 '-dipyridyl methyl pyrazine derivative eutectic group is administrated with 4,4' -dipyridyl methyl pyrazine derivative eutectic capsule of 0.09 g/(kg d), and the content of the Acipimox administrated by each rat is ensured to be equal. The rats in 4 groups are subjected to continuous gavage for 4 weeks, killed 24h after the last gavage, blood is taken, and livers are sampled and corresponding indexes are detected.
(3) Detection of
The mental status of rats was observed, triglyceride (TG), cholesterol (TC), low-density lipoprotein (LDL-C), high-density lipoprotein cholesterol (HDL-C) levels in serum were measured, and the change in liver tissue sections of different groups was observed.
(4) Results
Mental status of rats: the early-stage food consumption of the rats fed with the high-fat feed is larger than that of the normal control group, the body mass is increased quickly, the later-stage food consumption is reduced, and the activity is reduced. The food intake and the activity of rats in the apple group and the 4,4' -bipyridine methylpyrazine derivative eutectic group are obviously superior to those of the control group. The mass of the 4,4' -dipyridyl methyl pyrazine derivative eutectic rat is obviously lighter than that of the model group.
Liver tissue slice changes: after the rats are sacrificed, liver tissues are taken for visual observation, and the liver tissues of the normal control group are normal in color and dark red, and the section of the liver tissues is not greasy; the rats in the model group have the defects of fat liver, yellow surface and greasy section. The liver tissues of the le-known apple group and the 4,4' -bipyridine methylpyrazine derivative eutectic group are slightly larger, most of the liver tissues are dark red in color and are close to normal expression. Under a light microscope, the liver tissue structure of the normal control group rat is complete and clear, the hepatic lobule structure is normal, the central vein is large and thin-walled, the liver tissue is arranged into hepatic cords, the hepatic cords are radially distributed around the central vein, and the cells are polygonal. The model group shows severe fatty liver-like change, diffuse steatosis and vacuolation-like change, the denatured liver tissue is extremely swollen and round, the volume is obviously larger than that of the normal liver tissue, the cell nucleus is extruded to one side by lipid drops, and similarly to fat cells, the liver sinus is compressed and narrowed or even disappears, and the liver cord arrangement is disordered. The apple group and the 4,4' -bipyridine methylpyrazine derivative eutectic group only have trace inflammatory cell infiltration and necrosis focus, and are close to normal performance.
Group serum lipid comparison: compared with the model group, the levels of TG, TC and LDL-C in the leprosy apple group and the 4,4' -bipyridyl methylpyrazine derivative eutectic group are obviously reduced. The results are shown in Table 4.
TABLE 4 comparison of serum lipids for each group
Note: (1) p <0.05 compared to model group.
The research result shows that the 4,4' -bipyridine methylpyrazine derivative cocrystal group can reduce the TC, TG and LDL-C levels of the serum of a fatty liver rat and eliminate partial lipid accumulation in liver cells; the pathological histological change is obviously improved under the microscope, the liver tissues of the rats in the eutectic group of the 4,4 '-bipyridine methylpyrazine derivatives have only a small amount of lipid drops accumulated and slight steatosis, the shapes of the liver cells tend to normal cell expression, and the eutectic of the 4,4' -bipyridine methylpyrazine derivatives has better treatment effect on the fatty liver rats.
Claims (7)
1. The 4,4 '-bipyridine methylpyrazine derivative eutectic is characterized by being formed by combining a methylpyrazine derivative and 4,4' -bipyridine according to a molar ratio of 2; the methylpyrazine derivative is acipimox; using Cu-K alpha radiation, the characteristic peaks follow the X-ray powder diffraction pattern as shown in fig. 1.
2.4, 4' -bipyridylmethylpyrazine derivative co-crystal according to claim 1, characterized in that it has an endothermic peak at 185.73 ℃ in a Differential Scanning Calorimetry (DSC) curve.
3. A co-crystal of 4,4' -bipyridylmethylpyrazine derivative according to any of claims 1 to 2, characterized in that it has crystallographic parameters such as: triclinic system, space group of
The unit cell parameters are:
α =73.0010 (10) °, β =88.4890 (10) °, γ =63.454 (2) °, unit cell volume
4. A method for preparing a co-crystal of a 4,4' -bipyridylmethylpyrazine derivative according to any one of claims 1 to 2, characterized by comprising the following specific steps: adding the methylpyrazine derivative and 4,4 '-bipyridine into an organic solvent A, heating for dissolving, after the solution is clarified, carrying out reflux reaction, cooling for crystallization, filtering and drying to obtain a 4,4' -bipyridine methylpyrazine derivative eutectic; the organic solvent A is selected from one or more of acetonitrile, acetone, tetrahydrofuran, methanol, ethanol and isopropanol; the methylpyrazine derivative is acipimox.
5. The method for preparing a co-crystal of 4,4 '-bipyridylmethylpyrazine derivative according to claim 4, wherein the molar ratio of the methylpyrazine derivative to the 4,4' -bipyridine is 1.8 to 2.2.
6. The method for preparing a co-crystal of 4,4 '-bipyridylmethylpyrazine derivative according to claim 5, wherein the molar ratio of the methylpyrazine derivative to the 4,4' -bipyridine is 1.95 to 2.05.
7. Use of a co-crystal of a 4,4' -bipyridylmethylpyrazine derivative according to any one of claims 1 to 2 for the preparation of a hypolipidemic agent.
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| CN106699718A (en) * | 2016-12-28 | 2017-05-24 | 佳木斯大学 | Myricetin 4, 4'-dipyridyl ethanol eutectic crystal and preparation method thereof |
| CN107311915A (en) * | 2017-06-28 | 2017-11-03 | 云南警官学院 | A kind of salicylic acid organic pharmaceutical co-crystal and preparation method thereof |
| CN108191734A (en) * | 2018-02-06 | 2018-06-22 | 云南农业大学 | A kind of indole -5-carboxylic acid's organic pharmaceutical co-crystal and preparation method thereof |
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| US7153965B2 (en) * | 2004-05-18 | 2006-12-26 | Isp Investments Inc. | Pharmaceutically acceptable inorganic and organic salts of 5-methylpyrazine-2-carboxylic acid-4-oxide |
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| CN106699718A (en) * | 2016-12-28 | 2017-05-24 | 佳木斯大学 | Myricetin 4, 4'-dipyridyl ethanol eutectic crystal and preparation method thereof |
| CN107311915A (en) * | 2017-06-28 | 2017-11-03 | 云南警官学院 | A kind of salicylic acid organic pharmaceutical co-crystal and preparation method thereof |
| CN108191734A (en) * | 2018-02-06 | 2018-06-22 | 云南农业大学 | A kind of indole -5-carboxylic acid's organic pharmaceutical co-crystal and preparation method thereof |
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