CN111518040B - Methylpyrazine derivative-piperazine eutectic - Google Patents
Methylpyrazine derivative-piperazine eutectic Download PDFInfo
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- CN111518040B CN111518040B CN201910105398.8A CN201910105398A CN111518040B CN 111518040 B CN111518040 B CN 111518040B CN 201910105398 A CN201910105398 A CN 201910105398A CN 111518040 B CN111518040 B CN 111518040B
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- piperazine
- methylpyrazine derivative
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- methylpyrazine
- derivative
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- CAWHJQAVHZEVTJ-UHFFFAOYSA-N methylpyrazine Chemical class CC1=CN=CC=N1 CAWHJQAVHZEVTJ-UHFFFAOYSA-N 0.000 title claims abstract description 134
- 230000005496 eutectics Effects 0.000 title claims abstract description 54
- 238000002360 preparation method Methods 0.000 claims abstract description 10
- 230000005855 radiation Effects 0.000 claims abstract description 5
- 238000002441 X-ray diffraction Methods 0.000 claims abstract description 4
- 239000003524 antilipemic agent Substances 0.000 claims abstract 2
- 239000013078 crystal Substances 0.000 claims description 42
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 39
- DJQOOSBJCLSSEY-UHFFFAOYSA-N Acipimox Chemical group CC1=CN=C(C(O)=O)C=[N+]1[O-] DJQOOSBJCLSSEY-UHFFFAOYSA-N 0.000 claims description 31
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- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
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- AQQXBVGYEITTEZ-UHFFFAOYSA-N C(O)CN.C(=O)(O)C1=NC=C([N+](=C1)[O-])C.CO Chemical compound C(O)CN.C(=O)(O)C1=NC=C([N+](=C1)[O-])C.CO AQQXBVGYEITTEZ-UHFFFAOYSA-N 0.000 description 1
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- HWGBHCRJGXAGEU-UHFFFAOYSA-N Methylthiouracil Chemical compound CC1=CC(=O)NC(=S)N1 HWGBHCRJGXAGEU-UHFFFAOYSA-N 0.000 description 1
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- LELTZNKIJPKMAU-UHFFFAOYSA-N ethyl 5-methyl-4-oxidopyrazin-4-ium-2-carboxylate Chemical compound CCOC(=O)C1=C[N+]([O-])=C(C)C=N1 LELTZNKIJPKMAU-UHFFFAOYSA-N 0.000 description 1
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- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 1
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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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4965—Non-condensed pyrazines
-
- 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
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
- C07D295/027—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring
-
- 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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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Obesity (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Hematology (AREA)
- Diabetes (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the technical field of medicines, and particularly provides a methylpyrazine derivative-piperazine cocrystal, a preparation method thereof and application thereof in preparation of a hypolipidemic drug. The methylpyrazine derivative-piperazine eutectic prepared by the invention uses Cu-Ka radiation, and an X-ray diffraction spectrogram expressed by 2 theta is as follows: characteristic peaks are at 8.8 +/-0.2 degrees, 13.0 +/-0.2 degrees, 14.7 +/-0.2 degrees, 25.2 +/-0.2 degrees, 27.2 +/-0.2 degrees and 28.9 +/-0.2 degrees. After the methylpyrazine derivative-piperazine eutectic prepared by the invention is placed in a solid state, the product purity is high, the stability is good, and the bioavailability is high as verified by animal experiments. The invention has simple preparation process and better industrial application prospect.
Description
Technical Field
The invention belongs to the technical field of organic pharmaceutical co-crystals, and particularly relates to a methylpyrazine derivative-piperazine co-crystal.
Background
Pharmaceutical co-crystals are based on the supramolecular chemistry principle, 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 counterfeit medicine, 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 favorable for bringing the counterfeit medicine to the market. Therefore, it is of great practical significance to obtain more novel, practical and inventive pharmaceutical co-crystals, especially 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 Carlo Erba, italy and marketed in 1985 in italy, and then, by virtue of its high safety and remarkable therapeutic effect, it was marketed in several countries and regions in germany, chile, switzerland, etc., in succession.
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 CN86103304-2 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 methylpyrazine derivative-piperazine eutectic.
The methylpyrazine derivative is acipimox, and the methylpyrazine derivative-piperazine eutectic is acipimox-piperazine eutectic.
The acipimox as the medicine component of the present invention has the chemical name of 5-methylpyrazine-2-carboxylic acid-4-oxide and is white or white-like crystalline powder. CAS number: 51037-30-0, molecular formula is C 6 H 6 N 2 O 3 The structural formula is shown as a, the inventionThe selected eutectic former is piperazine with a molecular formula of C 4 H 10 N 2 The structural formula is shown as b.
In a first aspect of the invention, a methylpyrazine derivative-piperazine eutectic is provided. In the co-crystal, the molar ratio of the methylpyrazine derivative to the piperazine is 1.
According to the methylpyrazine derivative-piperazine eutectic, cu-Ka radiation is used, and an X-ray diffraction spectrogram expressed by 2 theta has characteristic peaks at 8.8 +/-0.2 degrees, 13.0 +/-0.2 degrees, 14.7 +/-0.2 degrees, 25.2 +/-0.2 degrees, 27.2 +/-0.2 degrees and 28.9 +/-0.2 degrees.
Preferably, the methylpyrazine derivative-piperazine eutectic has characteristic peaks at 8.8 +/-0.2 °,13.0 +/-0.2 °,14.7 +/-0.2 °,15.5 +/-0.2 °,17.5 +/-0.2 °,19.6 +/-0.2 °,20.7 +/-0.2 °,25.2 +/-0.2 °,27.2 +/-0.2 ° and 28.9 +/-0.2 ° in an X-ray diffraction spectrum expressed by 2 theta by using Cu-Kalpha radiation.
Preferably, the methylpyrazine derivative-piperazine 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 methylpyrazine derivative-piperazine eutectic has an endothermic peak in a Differential Scanning Calorimetry (DSC) curve, and is 290.12 ℃.
Preferably, the methylpyrazine derivative-piperazine eutectic has the crystallographic parameters: triclinic system, space group is P-1; the unit cell parameters are:
α =104.129 (4) °, β =98.807 (3) °, γ =90.498 (4) °, unit cell volume
The second aspect of the invention provides a preparation method of a methylpyrazine derivative-piperazine eutectic, which comprises the following specific preparation steps: adding the methylpyrazine derivative and piperazine into an organic solvent A, heating for dissolving, cooling for crystallization after the solution is clarified, filtering and drying to obtain the methylpyrazine derivative-piperazine eutectic.
The organic solvent A is selected from one or more of methanol, ethanol, acetonitrile, acetone, tetrahydrofuran and isopropanol.
Further preferably, the organic solvent a is selected from one or two of methanol and acetone.
The molar ratio of the methylpyrazine derivative to piperazine is 0.8-1.2.
Preferably, the molar ratio of the methylpyrazine derivative to piperazine is 0.95 to 1.05.
The mass-volume ratio of piperazine to the organic solvent A in the system is 3-7, wherein the mass is mg, and the volume is ml.
The temperature for dissolving and heating is 55-75 ℃.
The temperature for cooling and crystallizing is 10-30 ℃.
Preferably, the temperature for cooling and crystallization is 15-25 ℃.
The crystallization time is 25 to 30 hours.
Further preferably, the preparation method comprises the following steps:
dissolving the methylpyrazine derivative and piperazine in an organic solvent A, heating and dissolving at 55-75 ℃, stirring, refluxing, reacting for 7-12 hours, cooling to 10-30 ℃, crystallizing for 25-30 hours, filtering, washing a filter cake, and drying to obtain the methylpyrazine derivative-piperazine eutectic.
The solvent for washing the filter cake is selected from one of ethanol and acetone.
The drying temperature is 50-65 ℃, and the drying time is 6-10 hours.
In a third aspect of the invention, a pharmaceutical composition is provided, which comprises the methylpyrazine derivative-piperazine eutectic and other pharmaceutically acceptable auxiliary components.
Preferably, the pharmaceutical composition of the present invention is prepared as follows: the compounds of the present invention are combined with pharmaceutically acceptable solid or liquid carriers and optionally with pharmaceutically acceptable adjuvants and excipients using standard and conventional techniques to prepare useful dosage forms.
Preferably, the other components include other active ingredients, excipients, fillers, etc. that may be used in combination.
Preferably, the pharmaceutical composition is a spray, a tablet, a capsule, a powder injection, a liquid injection and the like.
The fourth aspect of the invention provides application of the methylpyrazine derivative-piperazine eutectic as an active ingredient in preparation of 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. Analyzing the structure by a direct method, finding out all non-hydrogen atoms by a difference Fourier method, obtaining all hydrogen atoms on carbon and nitrogen by theoretical hydrogenation, and refining the structure by a least square method.
The crystallographic data obtained by testing and analyzing the crystals of the methylpyrazine derivative prepared by the invention are shown in table 1, and the crystallographic parameters are as follows: triclinic system, space group is P-1; the unit cell parameters are:
α =104.129 (4) °, β =98.807 (3) °, γ =90.498 (4) °, unit cell volume
The molecular formula is: c 16 H 22 N 6 O 6 The molecular weight is: 394.39. the ORTEP diagram of the methylpyrazine derivative-piperazine eutectic of the invention shows that the methylpyrazine derivative and piperazine are connected together through intramolecular hydrogen bonds, wherein the carboxyl O of the methylpyrazine derivative 2 With H on piperazine 3 Hydrogen bonds are formed as shown in figure 3. The hydrogen bond diagram of the methylpyrazine derivative-piperazine eutectic is shown in the attached figure 2.
TABLE 1 Methylpyrazine derivative-piperazine Co-crystals Primary crystallography data
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 2 PXRD peaks of methylpyrazine derivative-piperazine cocrystal
All samples prepared in the examples have the same crystallographic parameters and X-ray powder diffraction patterns.
The Differential Scanning Calorimetry (DSC) result of the methylpyrazine derivative-piperazine eutectic prepared by the method is shown in figure 4, wherein only one endothermic peak in the Differential Scanning Calorimetry (DSC) is 290.12 ℃, and the endothermic peak is the melting point of the methylpyrazine derivative organic drug eutectic; thermogravimetric analysis (TGA) only has one weight loss step, which shows that the methylpyrazine derivative organic drug eutectic does not have a solvent and has a stable structure. The methylpyrazine derivative-piperazine eutectic has a DSC/TGA spectrum shown in figure 4.
Compared with the currently reported crystal form of the methylpyrazine derivative, the methylpyrazine derivative-piperazine eutectic prepared by the method disclosed by the invention has the following advantages:
(1) The stability is high. After the methylpyrazine derivative-piperazine eutectic is subjected to a light test and placed in a high-temperature and high-humidity environment, the HPLC purity is still higher than 99.4%, and the solid state stability of the methylpyrazine derivative-piperazine eutectic is good compared with the existing methylpyrazine derivative crystal form.
(2) Has high bioavailability. The methylpyrazine derivative-piperazine 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 methylpyrazine derivative-piperazine eutectic.
FIG. 2: hydrogen bond diagram of methylpyrazine derivative-piperazine eutectic.
FIG. 3: ORTEP map of methylpyrazine derivative-piperazine co-crystals.
FIG. 4: differential Scanning Calorimetry (DSC) profile of methylpyrazine derivative-piperazine co-crystals.
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 68.9mg of acipimox and 38.5mg of piperazine into 8ml of methanol, heating to 60 ℃, stirring for dissolving, carrying out reflux reaction for 10 hours, slowly cooling to 15-20 ℃, standing at a controlled temperature for crystallization for 26 hours, filtering, and carrying out vacuum drying at 50 ℃ for 8 hours for acipimox-piperazine eutectic crystal, wherein the yield is 95.88%, the purity is 99.94%, and the impurity I:0.04 percent.
Example 2:
adding 65.5mg of acipimox and 38.5mg of piperazine into 5.5ml of ethanol, heating to 70 ℃, stirring for dissolving, carrying out reflux reaction for 11 hours, slowly cooling to 20-25 ℃, standing at a controlled temperature for crystallization for 28 hours, filtering, and carrying out vacuum drying at 45 ℃ for 8 hours for acipimox-piperazine eutectic crystal, wherein the yield is 95.68%, the purity is 99.92%, and the impurity I:0.05 percent.
Example 3:
adding 72.3mg of acipimox and 38.5mg of piperazine into 13ml of acetone, heating to 55 ℃, stirring for dissolving, carrying out reflux reaction for 12 hours, slowly cooling to 10-15 ℃, standing at a controlled temperature for crystallization for 30 hours, filtering, and carrying out vacuum drying at 50 ℃ for 8 hours for acipimox-piperazine eutectic crystal, wherein the yield is 94.81%, the purity is 99.90%, and the impurity I:0.07 percent.
Example 4:
adding 82.7mg of acipimox and 38.5mg of piperazine into 8ml of mixed solvent (3 ml of methanol and 5ml of acetone), heating to 60 ℃, stirring for dissolving, carrying out reflux reaction for 8 hours, slowly cooling to 5-10 ℃, standing at a controlled temperature for crystallization for 48 hours, filtering, and carrying out vacuum drying at 50 ℃ for 8 hours to obtain an acipimox-piperazine eutectic crystal, wherein the yield is 93.58%, the purity is 99.88%, and the impurity I:0.09 percent.
Example 5:
adding 55.1mg of acipimox and 38.5mg of piperazine into 4ml of mixed solvent (1.0 ml of acetonitrile and 3.0ml of methanol), heating to 75 ℃, stirring for dissolving, carrying out reflux reaction for 7 hours, slowly cooling to 25-30 ℃, standing at a controlled temperature for crystallization for 42 hours, filtering, and carrying out vacuum drying at 50 ℃ for 8 hours to obtain an acipimox-piperazine eutectic crystal with the yield of 93.35%, the purity of 99.86%, and the impurity I:0.10 percent.
Example 6:
adding 48.2mg of acipimox and 38.5mg of piperazine into 15ml of tetrahydrofuran, heating to 50 ℃, stirring for dissolving, carrying out reflux reaction for 15 hours, slowly cooling to 5-10 ℃, standing at a controlled temperature for crystallization for 32 hours, filtering, and carrying out vacuum drying at 50 ℃ for 8 hours for acipimox-piperazine eutectic crystal, wherein the yield is 92.05%, the purity is 99.83%, and the impurity I:0.11 percent.
Example 7:
adding 96.5mg of acipimox and 38.5mg of piperazine into 10ml of isopropanol, heating to 80 ℃, stirring for dissolving, carrying out reflux reaction for 6 hours, slowly cooling to 0-5 ℃, standing for crystallization for 10 hours at controlled temperature, filtering, and carrying out vacuum drying at 50 ℃ for 8 hours to obtain an acipimox-piperazine eutectic crystal with the yield of 91.82%, the purity of 99.80%, 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 dropwise adding, 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, some 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. And after 45min, the product is obtainedA fully solubilized suspension can be 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 methylpyrazine derivative-piperazine eutectic prepared by the method can achieve similar stability effect. The purity and the appearance of the methylpyrazine derivative-piperazine eutectic prepared by the invention are not obviously changed under the conditions of illumination, high temperature and high humidity, the purity of the crystal forms of comparative examples 1 to 6 is greatly reduced under the same experimental conditions, the impurity content of the crystal forms is obviously increased, and the crystal forms are deteriorated.
Bioavailability experiment: experiment of treatment effect of methylpyrazine derivative-piperazine eutectic on fatty liver rat
(1) Material
(1) Medicine
I. Acipimox capsules (le zhi apple), production lot number: and Z210A.
II. Methylpyrazine derivative-piperazine co-crystal.
(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 model 2400 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 Lezhi apple group and a methylpyrazine derivative-piperazine cocrystal group, and 5 rats were administered to each group. 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 amphetamine group and the methylpyrazine derivative-piperazine eutectic group were administered with 0.06/(kg. D) of methylpyrazine derivative for intragastric administration of 1mL. 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 appetite and the activity of rats in the le Zhi apple group and the methylpyrazine derivative-piperazine eutectic group are obviously superior to those of the control group. The weight of the rat body of the methylpyrazine derivative-piperazine eutectic group is obviously lighter than that of the control group.
Liver tissue section 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 Zhi Ping group and the methylpyrazine derivative-piperazine eutectic group are slightly larger, most of the liver tissues are dark red, and the color is close to normal.
Group serum lipid comparison: compared with the model group, the levels of TG, TC and LDL-C in the leprosy apple group and the methylpyrazine derivative-piperazine eutectic group are obviously reduced. The results are shown in Table 4.
TABLE 4 comparison of serum lipids for each group
The research result shows that the methylpyrazine derivative-piperazine 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 tissue of a rat in the methylpyrazine derivative-piperazine eutectic group has only a small amount of fat drops accumulated and slight steatosis, the liver cell morphology tends to normal cell expression, and the methylpyrazine derivative-piperazine eutectic has a good treatment effect on the fatty liver rat.
Claims (9)
1. A methylpyrazine derivative-piperazine eutectic is characterized in that Cu-Kalpha radiation is used, and an X-ray diffraction spectrogram expressed by 2 theta has characteristic peaks at 8.8 +/-0.2 degrees, 13.0 +/-0.2 degrees, 14.7 +/-0.2 degrees, 15.5 +/-0.2 degrees, 17.5 +/-0.2 degrees, 19.6 +/-0.2 degrees, 20.7 +/-0.2 degrees, 25.2 +/-0.2 degrees, 27.2 +/-0.2 degrees and 28.9 +/-0.2 degrees; in the co-crystal, the molar ratio of the methylpyrazine derivative to the piperazine is 1; the methylpyrazine derivative is acipimox.
2. The methylpyrazine derivative-piperazine co-crystal according to claim 1, wherein Cu-ka radiation is used, and the characteristic peaks thereof correspond to the X-ray powder diffraction pattern shown in fig. 1.
3. The methylpyrazine derivative-piperazine cocrystal according to claim 1, wherein an endothermic peak at 290.12 ℃ is present in a Differential Scanning Calorimetry (DSC).
4. Methylpyrazine derivative-piperazine cocrystals according to any one of claims 1 to 3, characterized in that the crystallographic parameters are: triclinic system, space group is P-1; the unit cell parameters are:
α =104.129 (4) °, β =98.807 (3) °, γ =90.498 (4) °, unit cell volume
5. A method for preparing a methylpyrazine derivative-piperazine cocrystal according to any one of claims 1 to 3, comprising the following specific steps: adding the methylpyrazine derivative and piperazine into an organic solvent A, heating for dissolving, cooling for crystallization after the solution is clarified, filtering and drying to obtain a methylpyrazine derivative-piperazine eutectic; the organic solvent A is selected from one or more of methanol, ethanol, acetonitrile, acetone, tetrahydrofuran and isopropanol; the methylpyrazine derivative is acipimox.
6. The method for producing a methylpyrazine derivative-piperazine cocrystal according to claim 5, wherein a molar ratio of the methylpyrazine derivative to piperazine is 0.8 to 1.2.
7. The method for producing a methylpyrazine derivative-piperazine cocrystal according to claim 6, wherein a molar ratio of the methylpyrazine derivative to piperazine is 0.95 to 1.05.
8. A pharmaceutical composition comprising the methylpyrazine derivative-piperazine co-crystal according to any one of claims 1 to 3, and further comprising a pharmaceutically acceptable adjuvant component.
9. Use of a methylpyrazine derivative-piperazine cocrystal according to any one of claims 1 to 3 for the preparation of a hypolipidemic agent.
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