CN109369546B - Methylpyrazine derivative theophylline hemihydrate - Google Patents
Methylpyrazine derivative theophylline hemihydrate Download PDFInfo
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- CN109369546B CN109369546B CN201811644150.0A CN201811644150A CN109369546B CN 109369546 B CN109369546 B CN 109369546B CN 201811644150 A CN201811644150 A CN 201811644150A CN 109369546 B CN109369546 B CN 109369546B
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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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- 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
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
- C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
- C07D473/06—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3
- C07D473/08—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3 with methyl radicals in positions 1 and 3, e.g. theophylline
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- 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
Abstract
The invention belongs to the technical field of medicines, and particularly provides a methylpyrazine derivative theophylline hemihydrate, a preparation method thereof and application thereof in preparation of a blood fat reducing medicine. The methylpyrazine derivative theophylline hemihydrate prepared by the invention uses Cu-Kalpha radiation, and an X-ray diffraction spectrum expressed by 2 theta is as follows: characteristic peaks are at 8.0 +/-0.2 degrees, 9.2 +/-0.2 degrees, 14.5 +/-0.2 degrees and 26.9 +/-0.2 degrees. The methylpyrazine derivative theophylline hemihydrate prepared by the method has high stability, basically unchanged placing purity in a dissolved state and a solid state, higher bioavailability and better industrial application prospect, and the solubility of the methylpyrazine derivative theophylline hemihydrate in different media is 2.5 times that of the conventional crystal forms.
Description
Technical Field
The invention belongs to the technical field of organic pharmaceutical co-crystals, and particularly relates to a methylpyrazine derivative theophylline hemihydrate.
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 physical and chemical 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 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, 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 caro Erba company of italy, marketed in italy in 1985, and then, by virtue of its high safety and remarkable therapeutic effect, it was marketed successively in many countries and regions of germany, chile, switzerland, hong kong, china, etc.
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 pH7.4, 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 eutectic structure of a crystal form of the acipimox are less, patents US2005239803A1, CN 103508963A and the like report preparation methods of the acipimox, and patent CN86103304-2 obtains an acipimox precipitate with a crystal character, which is hydrated acipimox, and has low yield. 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 deficiencies of the prior art, one aspect of the present application provides a methylpyrazine derivative theophylline hemihydrate.
The methylpyrazine derivative theophylline hemihydrate referred to herein is acipimox theophylline hemihydrate and the methylpyrazine derivative is acipimox.
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 C6H6N2O3The structural formula is shown as a, the selected eutectic forming substance is theophylline, and the molecular formula is C7H8N4O2The structural formula is shown as b.
According to a first aspect of the present invention, there is provided a crystalline form of the methylpyrazine derivative theophylline hemihydrate. In the crystal, a methylpyrazine derivative: theophylline: the molar ratio of water is 1: 1: 0.5.
according to the methylpyrazine derivative theophylline hemihydrate crystal form, Cu-Kalpha radiation is used, and an X-ray diffraction spectrogram expressed by 2 theta has characteristic peaks at 8.0 +/-0.2 degrees, 9.2 +/-0.2 degrees, 14.5 +/-0.2 degrees and 26.9 +/-0.2 degrees.
Preferably, the methylpyrazine derivative theophylline hemihydrate crystal form has characteristic peaks at 8.0 +/-0.2 degrees, 9.2 +/-0.2 degrees, 14.5 +/-0.2 degrees, 20.4 +/-0.2 degrees, 25.8 +/-0.2 degrees, 26.9 +/-0.2 degrees, 29.2 +/-0.2 degrees and 32.3 +/-0.2 degrees by using Cu-Kalpha radiation and an X-ray diffraction spectrum expressed by 2 theta.
Preferably, the methylpyrazine derivative theophylline hemihydrate crystal form is characterized in that a characteristic peak of the crystal form conforms to an X-ray powder diffraction pattern shown in figure 1 by using Cu-Ka radiation.
Preferably, the methylpyrazine derivative theophylline hemihydrate crystal form has two endothermic peaks in a Differential Scanning Calorimetry (DSC) curve, wherein the two endothermic peaks are 76.92 ℃ and 220.99 ℃.
PreferablyThe crystal form of the methylpyrazine derivative theophylline hemihydrate comprises the following crystallographic parameters: monoclinic system, space group is C2/C; the unit cell parameters are:
α is 90.00 °, β is 105.926(2 °), γ is 90.00 °, unit cell volume
The second aspect of the application provides a preparation method of a methylpyrazine derivative theophylline hemihydrate crystal form, which comprises the following specific preparation steps: adding the methylpyrazine derivative and theophylline into a mixed solution of an organic solvent and water, heating for dissolving, stirring for reaction, cooling for crystallization, filtering and drying to obtain the methylpyrazine derivative theophylline hemihydrate.
The organic solvent is selected from one or more of acetonitrile, acetone, tetrahydrofuran, methanol, ethanol, isopropanol and tert-butanol.
Further preferably, the organic solvent is selected from one or more of acetonitrile, acetone and tetrahydrofuran.
The molar ratio of the methylpyrazine derivative to the theophylline is 1: 1.5-2.5.
Preferably, the molar ratio of the methylpyrazine derivative to the theophylline is 1: 1.8-2.2.
The mass-volume ratio of the methylpyrazine derivative to the organic solvent in the system is 3-9: 1, wherein the mass is in mg and the volume is in ml.
Preferably, the mass-volume ratio of the methylpyrazine derivative to the organic solvent is 5-7: 1, wherein the mass is in mg and the volume is in ml.
The mass-volume ratio of the methylpyrazine derivatives to water in the system is 10-55: 1, wherein the mass is mg, and the volume is ml.
Preferably, the mass-to-volume ratio of the methylpyrazine derivative to the water is 25-50: 1, wherein the mass is mg and the volume is ml.
The temperature of the dissolution heating is 45-75 ℃.
The cooling crystallization temperature is 0-15 ℃.
The crystallization time is 40-62 hours.
The following details the preparation of the crystalline form of the invention:
adding the methylpyrazine derivative and theophylline into a mixed solution of an organic solvent and purified water, heating to 45-75 ℃ for dissolving, stirring for reacting for 8-14 hours, cooling to 0-15 ℃ for crystallizing for 40-62 hours, filtering, washing a filter cake, and drying to obtain the methylpyrazine derivative theophylline hemihydrate.
The solvent for washing the filter cake is selected from one of acetonitrile, methanol, ethanol and ethyl acetate.
Preferably, the temperature for cooling and crystallizing is 5-10 ℃.
The drying temperature is 50-70 ℃, and the drying time is 8-12 hours.
In a third aspect of the present application, there is provided a pharmaceutical composition comprising the crystals of the methylpyrazine derivative theophylline hemihydrate described herein, and further comprising 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.
In a fourth aspect of the present application, there is provided a use of crystals of a methylpyrazine derivative theophylline hemihydrate as an active ingredient for the manufacture of a medicament for the treatment of hypolipidemic disorders.
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 calculated by a ShelXT program in olex2 software, the ShelXL program is adopted to correct the structure parameters and judge the atom species by a least square method, the positions of all hydrogen atoms are obtained by a geometric calculation method and a difference Fourier method, the goodness of fit (GooF value) is 1.057 and is close to 1.0, and the weight scheme is proper and the structure is accurate.
The crystallographic data obtained by testing and analyzing the crystals of the methylpyrazine derivative theophylline compound prepared by the invention are shown in a table 1, wherein the crystallographic parameters are as follows: monoclinic system, space group is C2/C; the unit cell parameters are:
α is 90.00 °, β is 105.926(2 °), γ is 90.00 °, unit cell volume
The molecular formula is: [ C ]6H6N2O3·C7H8N4O2·0.5H2O]The molecular weight is: 343.31. the ORTEP diagram of the methylpyrazine derivative theophylline hemihydrate crystal of the present invention shows that the methylpyrazine derivative and theophylline are linked together by intramolecular hydrogen bonds, wherein the carboxyl group H3 of the methylpyrazine derivative forms a hydrogen bond with N3 on the theophylline, and O5 on the theophylline forms an intramolecular hydrogen bond with H6A of a water molecule, which is located on the symmetry axis and is common to two eutectic units, so that 0.5 molecule of water exists in the crystal, as shown in fig. 3. The hydrogen bond diagram of the methylpyrazine derivative theophylline hemihydrate of the invention is shown in the attached figure 2.
TABLE 1 Methylpyrazine derivative theophylline hemihydrate crystalline form principal crystallographic data
The X-ray powder diffraction test instrument and the test conditions of the invention are as follows: 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 40 mA; a diverging slot 1/4; an anti-scatter slit 1; 0.04rad of cable pull slit; step length: 0.5 s; scanning range: 3 to 50 degrees.
According to the crystallography data, the characteristic peaks in the corresponding X-ray powder diffraction pattern (Cu-Ka) are detailed in attached figure 1 and table 2.
Table 2 PXRD peaks for the methylpyrazine derivative theophylline hemihydrate crystalline form
All samples prepared in the examples have the same crystallographic parameters and X-ray powder diffraction patterns.
The TGA/DSC thermal analysis tester and the test conditions in the invention are as follows: TGA/DSC thermogram METTLER TOLEDO TGA/DSC3 +; dynamic temperature section: 30-300 ℃; heating rate: 10 ℃/min; segment gas N2(ii) a Gas flow rate: 50 mL/min; crucible: an aluminum crucible of 40. mu.l.
The TGA/DSC test result of the methylpyrazine derivative crystal prepared by the method is shown in figure 4, and the DSC test result has two endothermic peaks corresponding to the temperatures of 76.92 ℃ and 220.99 ℃. According to TGA detection results, two weight loss steps exist, calculation shows that the aximin eutectic is hemihydrate, and DSC/TGA detection results show that the crystal form prepared by the method is a methylpyrazine derivative theophylline hemihydrate crystal form.
Compared with the currently reported crystal form of the methylpyrazine derivative, the crystal form of the methylpyrazine derivative theophylline hemihydrate prepared by the method has the following advantages:
(1) the stability is high. The methylpyrazine derivative theophylline hemihydrate has high stability in both solid state and dissolved state. When the solid-state catalyst is in a solution state, the content of the impurity 5-methylpyrazine-2-carboxylic acid is less than 0.15 percent and the content of the total impurities is less than 0.25 percent along with the prolonging of the dissolving time. When the crystal is in a solid state, the HPLC purity is still higher than 99.2 percent and higher than that of the existing crystal form through illumination, high temperature and high humidity tests.
(2) The solubility is good. The solubility of the methylpyrazine derivative theophylline hemihydrate is about 2.5 times of that of the existing crystal form, and the solubilities of the methylpyrazine derivative theophylline hemihydrate in different media are all higher than that of the existing crystal form.
(3) Has high bioavailability. The methylpyrazine derivative theophylline hemihydrate can effectively reduce the concentration of cholesterol, triglyceride and low-density lipoprotein in the serum of a fatty liver rat.
Drawings
FIG. 1: PXRD pattern of the methylpyrazine derivative theophylline hemihydrate crystalline form.
FIG. 2: hydrogen bond diagram of the crystal form of the methylpyrazine derivative theophylline hemihydrate.
FIG. 3: ORTEP diagram of the methylpyrazine derivative theophylline hemihydrate crystalline form.
FIG. 4: TGA/DSC of the crystalline form of the methylpyrazine derivative theophylline hemihydrate.
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 (0.4mmol) of methylpyrazine derivative and 144.0mg (0.8mmol) of theophylline into 12ml of mixed solvent (10ml of acetonitrile +2ml of purified water), heating to 60 ℃, stirring for reaction for 10 hours, slowly cooling to 5-10 ℃, standing at controlled temperature for crystallization for 48 hours, filtering, leaching filter cake with acetonitrile, vacuum drying at 50 ℃ for 10 hours to obtain the methylpyrazine derivative theophylline hemihydrate with the yield of 96.45%, the purity of 99.95%, and the impurity I: 0.03 percent.
Example 2:
adding 61.6mg (0.4mmol) of methylpyrazine derivatives and 129.6mg (0.72mmol) of theophylline into 15ml of mixed solvent (12.5ml of acetone and 2.5ml of purified water), heating to 50 ℃, stirring for reaction for 12 hours, slowly cooling to 0-5 ℃, standing at controlled temperature for crystallization for 40 hours, filtering, leaching filter cakes with ethanol, and vacuum drying at 60 ℃ for 8 hours to obtain the methylpyrazine derivative theophylline hemihydrate, wherein the yield is 95.21%, the purity is 99.92%, and the impurity I: 0.04 percent.
Example 3:
adding 61.6mg (0.4mmol) of methylpyrazine derivatives and 158.4mg (0.88mmol) of theophylline into 10ml of mixed solvent (8.8ml of tetrahydrofuran +1.2ml of purified water), heating to 70 ℃, stirring for reaction for 8 hours, slowly cooling to 10-15 ℃, standing at controlled temperature for crystallization for 60 hours, filtering, leaching filter cakes with ethyl acetate, and vacuum drying at 55 ℃ for 12 hours to obtain the methylpyrazine derivative theophylline hemihydrate, wherein the yield is 94.36%, the purity is 99.90%, and the impurity I: 0.06 percent.
Example 4:
adding 61.6mg (0.4mmol) of methylpyrazine derivatives and 108.0mg (0.6mmol) of theophylline into 13ml of mixed solvent (6.8ml of ethanol and 6.2ml of purified water), heating to 45 ℃, stirring for reaction for 14 hours, slowly cooling to-5-0 ℃, standing at controlled temperature for crystallization for 35 hours, filtering, leaching filter cakes with acetonitrile, and drying in vacuum at 45 ℃ for 15 hours to obtain the methylpyrazine derivative theophylline hemihydrate, wherein the yield is 93.15%, the purity is 99.87%, and the impurity I: 0.07 percent.
Example 5:
adding 61.6mg (0.4mmol) of methylpyrazine derivative and 154.1mg (1.0mmol) of theophylline into 21.6ml of mixed solvent (20.5ml of acetonitrile and 1.1ml of purified water), heating to 75 ℃, stirring for reaction for 8 hours, slowly cooling to 15-20 ℃, standing at controlled temperature for crystallization for 60 hours, filtering, leaching a filter cake with methanol, and drying in vacuum at 70 ℃ for 6 hours to obtain the methylpyrazine derivative theophylline hemihydrate, wherein the yield is 92.61%, the purity is 99.85%, and the impurity I: 0.09 percent.
Example 6:
adding 61.6mg (0.4mmol) of methylpyrazine derivative and 86.5mg (0.48mmol) of theophylline into 32ml of mixed solvent (31ml of isopropanol and 1ml of purified water), heating to 40 ℃, stirring for reaction for 16 hours, slowly cooling to-10 to-5 ℃, standing at controlled temperature for crystallization for 50 hours, filtering, leaching a filter cake with ethanol, and drying in vacuum at 50 ℃ for 10 hours to obtain the methylpyrazine derivative theophylline hemihydrate with yield of 92.26%, purity of 99.83%, and impurity I: 0.11 percent.
Example 7:
adding 61.6mg (0.4mmol) of methylpyrazine derivative and 216.2mg (1.2mmol) of theophylline into 13ml of mixed solvent (5.0ml of acetonitrile +8ml of purified water), heating to 80 ℃, stirring for reaction for 6 hours, slowly cooling to 5-10 ℃, standing at controlled temperature for crystallization for 48 hours, filtering, and drying in vacuum at 45 ℃ for 10 hours to obtain the methylpyrazine derivative theophylline hemihydrate with the yield of 92.13%, 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 ℃, heating for reaction for 1h, and slowly adding 5.5kg of water and 164.9g of sodium tungstate (Na)2WO4·2H2O), 623.0g of hydrogen peroxide with the mass concentration of 30 percent, continuously heating and stirring for 8h, cooling and crystallizing for 4h under the ice bath condition, filtering the solid, drying for 12h at 100 ℃ and preparing 595g of acipimox product. The product yield in this reaction was 77.3%; HPLC purity 96.2%, impurity I: 2.8 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 for crystallization for 7h after dropwise adding, performing suction filtration, washing a filter cake with acetone, and drying (0.01MPa, 80 ℃) to obtain the off-white acipimox with a yield of 88.6%. HPLC purity: 98.3%, 5-methylpyrazine-2-carboxylic acid (impurity I): 0.5 percent.
Comparative example 3:
330mg (1mmol) of Na2WO4·2H2O 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 (400g/L) (44mmol) peroxygenAdding hydrogen hydride into the solution, diluting with dilute H2SO4The pH was adjusted to 1.5 and 5.52g (40mmol) 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%. HPLC purity: 95.1%, impurity I: 2.3 percent.
Comparative example 4:
250mg (0.75mg) of Na was added2WO4·2H2O 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 (400g/L) (38mmol) hydrogen peroxide were added to the solution, diluted H2SO4The pH was adjusted to 2.0 and then 3.76g of 98% (30mmol) 2-carboxy-5-methylpyrazine were 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 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. This 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)2O-11.35 percent; calculated value of monohydrate product H2O-11.3%), yield 63%. HPLC purity: 94.2%, impurity I: 3.4 percent.
Comparative example 5:
2-carboxy-5-methylpyrazine 4-oxide (2.5g) was added to a mixed solution of methanol (60ml) 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 (2.1g), mp.177 ° -180 ℃, yield: 60.17%, HPLC purity: 96.8%, impurity I: 2.1 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 (3.71g) and THF (90g) were added to the reactor, followed by ethyl 5-methylpyrazinecarboxylate-4-oxide (6.00g), the mixture was stirred at room temperature for 4 hours, and the solid was collected by filtration and rinsed with THF (3X45 g). Drying in vacuo (25 inches of mercury, 65 ℃) afforded 5.38g (yield: 92.5%) of the sodium salt as an off-white solid, HPLC purity: 96.8%, impurity I: 2.4 percent.
Stability test
1. Stability test of methylpyrazine derivative theophylline hemihydrate in solution state
Samples of the methylpyrazine derivatives prepared in examples 1 to 7 and comparative examples 1 to 6 were dissolved in water, the methylpyrazine derivative solution was placed in an environment at 25 ℃, the stability of the crystal form of the methylpyrazine derivatives in the solution state was examined, samples were taken every two hours to test the content of impurities therein, and the test results are shown in table 3.
Table 3 stability test results of crystal forms of methylpyrazine derivatives in solution state
Tests show that all the methylpyrazine derivative theophylline hemihydrate prepared by the scheme of the invention can achieve similar stability effect. It is known from table 3 that the existing crystal form of methylpyrazine derivative has high contents of impurity I (5-methylpyrazine-2-carboxylic acid) and total impurities, and the contents of impurity I and total impurities increase with the increase of the dissolution time. Tests show that the purity of the sample, the content of the impurity I and the total impurity content of the methylpyrazine derivative theophylline hemihydrate prepared by the method are not obviously changed; in contrast, in the crystal forms of comparative examples 1 to 6, the content of the impurity I and the content of the total impurities are continuously increased under the same conditions, so that the methylpyrazine derivative theophylline hemihydrate prepared by the invention has better stability in a solution state compared with the existing crystal forms of the methylpyrazine derivative.
2. Temperature, humidity and light test
The specific stability test method is carried out according to the guidance method of stability investigation in the fourth part of the Chinese pharmacopoeia 2015 edition, the purity is detected by an HPLC method, and the specific test results are shown in Table 4.
Table 4 stability test results of crystal forms of methylpyrazine derivatives under light, high temperature and high humidity conditions
Experiments show that all the methylpyrazine derivative theophylline hemihydrate prepared by the scheme of the invention can achieve similar stability effect. As can be seen from table 4, the purity and the appearance of the methylpyrazine derivative theophylline hemihydrate prepared by the invention are not changed obviously under the conditions of illumination, high temperature and high humidity, while the purity of the crystal forms of comparative examples 1 to 6 is greatly reduced under the same experimental conditions, and the impurity content of the crystal forms is obviously increased, namely, the crystal forms are deteriorated, so that the methylpyrazine derivative theophylline hemihydrate prepared by the invention has better chemical stability compared with the existing crystal forms.
2. Solubility test
The specific solubility test is referred to the chinese pharmacopoeia 2015. The crystal excesses of the methylpyrazine derivatives of examples 1 to 7 and comparative example were precisely weighed, respectively placed in vials, respectively added with water, 0.1mol/L hydrochloric acid, and a phosphate buffer solution with ph of 7.4 to prepare a saturated solution of the methylpyrazine derivatives, shaken up to dissolve, filtered, and subjected to ultraviolet-visible spectrophotometry (general rule 0401) to measure absorbance at a wavelength of 270nm to calculate the solubility thereof.
Table 5 solubility of the methylpyrazine derivative crystalline forms in different media
Experiments show that all the methylpyrazine derivative theophylline hemihydrate prepared by the scheme of the invention can achieve similar solubility effect. As can be seen from table 5, the solubility of the methylpyrazine derivative theophylline hemihydrate prepared by the scheme of the present invention in solutions with different pH values is higher than that of the crystal forms of comparative examples 1 to 6, and the crystal form of the methylpyrazine derivative prepared by the present invention has higher solubility compared with the existing crystal forms.
Bioavailability experiment: experiment of treatment effect of methylpyrazine derivative theophylline hemihydrate on fatty liver rat
(1) Material
Medicine
I. Acipimox capsules (le zhi apple), production lot number: Z210A.
II. Methylpyrazine derivative theophylline hemihydrate
Reagent II: 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: 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 lesch apple group and a methylpyrazine derivative theophylline hemihydrate group, with 5 animals per 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 apple group and the methylpyrazine derivative theophylline hemihydrate group were administered 0.06/(kg. d) of methylpyrazine derivative with 1mL of intragastric lavage. 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 theophylline hemihydrate group are obviously superior to those of the control group. The constitution of the methylpyrazine derivative theophylline hemihydrate group rats is obviously lighter than that of the control 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 apple group and the methylpyrazine derivative theophylline hemihydrate 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 le-know apple group and the methylpyrazine derivative theophylline hemihydrate group are obviously reduced. The results are shown in Table 6.
TABLE 6 comparison of serum lipids for each group
The research result shows that the methylpyrazine derivative theophylline hemihydrate can reduce the serum TC, TG and LDL-C levels of fatty liver rats and eliminate partial lipid accumulation in liver cells; the pathological histological change is obviously improved under the microscope, liver tissues of rats with the methylpyrazine derivative theophylline hemihydrate group only have a small amount of lipid drops accumulated, the liver cell morphology tends to normal cell expression, and the methylpyrazine derivative theophylline hemihydrate group has a good treatment effect on fatty liver rats.
Claims (8)
1. The methylpyrazine derivative theophylline hemihydrate is characterized in that the methylpyrazine derivative is prepared from: theophylline: water is added according to a molar ratio of 1: 1: 0.5 bond formation using Cu-Ka radiation, X-ray diffraction pattern expressed in 2 θ in: 8.0 +/-0.2oThe theophylline hemihydrate of the methylpyrazine derivative is acipimox theophylline hemihydrate, the methylpyrazine derivative is acipimox, the structural formula of the acipimox serving as a pharmaceutical ingredient is shown as a, and the structural formula of the theophylline serving as a eutectic formation is shown as b:
。
2. the methylpyrazine derivative theophylline hemihydrate of claim 1, wherein an X-ray diffraction pattern expressed in terms of 2 Θ using Cu-ka radiation has characteristic peaks at 8.0 ± 0.2 °, 9.2 ± 0.2 °, 14.5 ± 0.2 °, 20.4 ± 0.2 °, 25.8 ± 0.2 °, 26.9 ± 0.2 °, 29.2 ± 0.2 °, 32.3 ± 0.2 °.
3. Methylpyrazine derivative theophylline hemihydrate according to claim 2, characterized in that, using Cu-ka radiation, its characteristic peaks follow the X-ray powder diffraction pattern as shown in figure 1.
4. The methylpyrazine derivative theophylline hemihydrate of claim 1, wherein the differential scanning calorimetry curve is as shown in figure 4.
5. A methylpyrazine derivative theophylline hemihydrate according to any one of claims 1 to 4 having the crystallographic parameters: monoclinic system, space group is C2/C; the unit cell parameters are: a = 24.1927(4) a, b = 4.97050(10) a, c = 25.9664(4) a, a =90.00 °, b =105.926(2) ° g =90.00 °, unit cell volume V =3002.61(10) a3。
6. A process for the preparation of the methylpyrazine derivative theophylline hemihydrate as claimed in any one of claims 1 to 4, comprising the specific steps of: adding a methylpyrazine derivative and theophylline into a mixed solution of an organic solvent and water, heating for dissolving, stirring for reaction, cooling for crystallization, filtering and drying to obtain the methylpyrazine derivative theophylline hemihydrate, wherein the molar ratio of the methylpyrazine derivative to the theophylline is 1: 1.5-2.5, the dissolving and heating temperature is 45-75 ℃, the cooling and crystallization temperature is 0-15 ℃, and the crystallization time is 40-62 hours.
7. The process for producing a methylpyrazine derivative theophylline hemihydrate according to claim 6, wherein the organic solvent is one or more selected from acetonitrile, acetone, tetrahydrofuran, methanol, ethanol, isopropanol and tert-butanol.
8. The method according to claim 7, wherein the organic solvent is one or more selected from acetonitrile, acetone and tetrahydrofuran.
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| Cocrystallization with flufenamic acid: comparison of physicochemical properties of two pharmaceutical cocrystals;Srinivasulu Aitipamula et al.;《CrystEngComm》;20131203;第16卷(第26期);第5793-5801页 * |
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