WO2021203572A1 - 一种 1,2- 二 (4- 吡啶基 ) 乙烷 - 阿昔莫司共晶 - Google Patents

一种 1,2- 二 (4- 吡啶基 ) 乙烷 - 阿昔莫司共晶 Download PDF

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WO2021203572A1
WO2021203572A1 PCT/CN2020/101518 CN2020101518W WO2021203572A1 WO 2021203572 A1 WO2021203572 A1 WO 2021203572A1 CN 2020101518 W CN2020101518 W CN 2020101518W WO 2021203572 A1 WO2021203572 A1 WO 2021203572A1
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ethane
pyridyl
bis
acilimus
crystal
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PCT/CN2020/101518
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French (fr)
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翟立海
夏祥来
马超
余军厚
刘忠
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山东新时代药业有限公司
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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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • 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

Definitions

  • the invention belongs to the technical field of organic drug co-crystals, and particularly relates to a 1,2-bis(4-pyridyl)ethane-acilimus co-crystal.
  • Drug co-crystal is based on the principle of supramolecular chemistry, that is, molecular recognition and supramolecular self-assembly through mutual cooperation between molecules.
  • the active pharmaceutical ingredient (API) and a suitable cocrystal former (CCF) self-assemble through hydrogen bonds, or non-covalent bonds with saturation and directionality (such as van der Waals forces of aromatic hydrocarbons or benzene rings, ⁇ - ⁇ conjugation and halogen bond) assembled to form a new type of structure, that is, drug co-crystal. It is based on hydrogen bonds. It does not need to form new covalent bonds or destroy existing covalent bonds.
  • Acipimox is a niacin derivative. It is a broad-spectrum long-acting lipid-lowering drug used in various primary and secondary hyperlipidemias. It mainly acts on adipose tissue and inhibits the release of free fatty acids from adipose tissue. , Reduce the synthesis of plasma low-density lipoprotein and very low-density lipoprotein, thereby reducing the level of plasma low-density lipoprotein and very low-density lipoprotein, and increase the plasma HDL level by inhibiting liver lipase activity.
  • Acipimox is manufactured by Farmitalia, Italy Carlo Erba was researched and developed, and it was listed in Italy in 1985. After that, with its high safety and remarkable efficacy, it has been listed in Germany, Chile, Switzerland, Hong Kong and other countries and regions.
  • Drug co-crystals will affect the physical and chemical properties of the drug, directly affect the dissolution and absorption efficiency of the drug under physiological pH 7.4 conditions, and then affect the drug's bioavailability and clinical efficacy.
  • the advantages of co-crystal can be used well, which plays a very important role in understanding and mastering the spatial arrangement and physical and chemical properties of drug effective molecules.
  • the present invention provides a 1,2-bis(4-pyridyl)ethane-acilimus co-crystal.
  • acipimox is chemically named 5-methylpyrazine-2-carboxylic acid-4-oxide, which is a white or off-white crystalline powder.
  • CAS number: 51037-30-0 the molecular formula is C 6 H 6 N 2 O 3 , and its structural formula is shown in a.
  • the co-crystal former selected in the invention is 1,2-bis(4-pyridyl)ethane ,
  • the molecular formula is C 12 H 12 N 2 , and its structural formula is shown in b.
  • the first aspect of the present invention provides a 1,2-bis(4-pyridyl)ethane-acilimus co-crystal.
  • the molar ratio of acipimox to 1,2-bis(4-pyridyl)ethane is 2:1.
  • the 1,2-bis(4-pyridyl)ethane-acilimus co-crystal using Cu-K ⁇ radiation, the X-ray diffraction spectrum expressed in 2 ⁇ is 9.88 ⁇ 0.2°, 13.92 ⁇ 0.2° , 24.56 ⁇ 0.2°, 26.12 ⁇ 0.2°, 26.86 ⁇ 0.2° have characteristic peaks.
  • the 1,2-bis(4-pyridyl)ethane-acilimus co-crystal uses Cu-K ⁇ radiation, and the X-ray diffraction spectrum expressed in 2 ⁇ is 9.88 ⁇ 0.2°, 13.92 ⁇ 0.2°, 15.38 ⁇ 0.2°, 15.70 ⁇ 0.2°, 24.56 ⁇ 0.2°, 26.12 ⁇ 0.2°, 26.86 ⁇ 0.2°, 29.59 ⁇ 0.2°, 36.90 ⁇ 0.2° have characteristic peaks.
  • the 1,2-bis(4-pyridyl)ethane-acilimus co-crystal uses Cu-K ⁇ radiation, and its characteristic peaks conform to the X-ray powder diffraction pattern shown in FIG. 1.
  • the 1,2-bis(4-pyridyl)ethane-acilimus co-crystal has an endothermic peak in the differential scanning calorimetry curve DSC, which is 184.43°C.
  • the second aspect of the present invention provides a method for preparing 1,2-bis(4-pyridyl)ethane-acilimus co-crystal.
  • the specific preparation steps include: combining acipimox and 1,2-bis( Add 4-pyridyl)ethane to organic solvent A, heat to dissolve, after the solution is clarified, control the temperature to reflux, react, cool down and crystallize, filter and dry to obtain 1,2-bis(4-pyridyl)ethane-Axi Moss eutectic.
  • the organic solvent A is selected from one or two of methanol, acetonitrile, acetone, ethyl acetate, tetrahydrofuran, ethanol, and isopropanol.
  • the organic solvent A is selected from one or two of methanol, ethanol, and ethyl acetate.
  • the molar ratio of the acipimox to 1,2-bis(4-pyridyl)ethane is 1:0.4 to 0.6.
  • the molar ratio of acipimox to 1,2-bis(4-pyridyl)ethane is 1:0.5.
  • the mass-volume ratio of 1,2-bis(4-pyridyl)ethane and the organic solvent A in the system is 4-6:1, wherein the mass is in mg and the volume is in ml.
  • the cooling crystallization temperature is 0-10°C.
  • the cooling crystallization temperature is 5-10°C.
  • the crystallization time is 30-50 hours.
  • the preparation method includes the following steps:
  • the solvent for washing the filter cake is selected from one of methanol, ethanol, and ethyl acetate.
  • the drying temperature is 55-75°C, and the drying time is 8-10 hours.
  • the third aspect of the present invention provides a use of 1,2-bis(4-pyridyl)ethane-acilimus co-crystal as an active ingredient in preparing a therapeutic hypolipidemic drug.
  • X-ray crystallographic data on a Rigaku model instrument collects XtaLAB Synergy, test temperature 293 (2) K,, to ⁇ scanning using CuK a radiation collected data and corrects L p.
  • the crystal structure was calculated using the ShelXT program in the olex2 software, and the ShelXL program was used to modify the structural parameters through the least square method and to distinguish the atom types.
  • the geometric calculation method and the difference Fourier method were used to obtain the positions of all hydrogen atoms.
  • the goodness of fit ( GooF value) 1.123, which is close to 1.0, indicating that the weighting scheme is appropriate and the structure is accurate.
  • the molecular formula is: C 24 H 24 N 6 O 6 , and the molecular weight is: 492.49.
  • the ORTEP diagram of the 1,2-bis(4-pyridyl)ethane-acipimox co-crystal of the present invention shows that acipimox and 1,2-bis(4-pyridyl)ethane pass intramolecularly Hydrogen bonds are connected together, in which the carboxyl group H4 of acipimox forms a hydrogen bond with the N4 on the 1,2-bis(4-pyridyl)ethane, and the carboxyl group of the other acipimox molecule forms a hydrogen bond with H3 and 1,2-di
  • the N3 on the (4-pyridyl)ethane forms an intramolecular hydrogen bond, as shown in Figure 3.
  • the stacking diagram of 1,2-bis(4-pyridyl)ethane-acilimus of the present invention is shown in FIG. 2.
  • X-ray powder diffraction test instrument and test conditions X-ray powder diffractometer: PANalyticalE; Cu-K ⁇ ; sample stage: flat plate; incident light path: BBHD; diffraction light path: PLXCEL; voltage 45kv, current 40mA; divergence slit: 1/4; Anti-scatter slit: 1; Solar slit: 0.04rad; Step length: 0.5s; Scan range: 3 ⁇ 50°.
  • the TGA/DSC test result of the 1,2-bis(4-pyridyl)ethane-acilimus co-crystal prepared by the method of the present invention is shown in Figure 4.
  • the DSC test result has an endothermic peak, and the corresponding temperature is 184.43°C.
  • the TGA detection result it can be seen that there is a weightlessness step, and the combined DSC/TGA detection result shows that the 1,2-bis(4-pyridyl)ethane-acilimus co-crystal prepared by the present invention does not contain other solvents.
  • the 1,2-bis(4-pyridyl)ethane-acilimus co-crystal prepared by the method of the present invention has the following advantages over the currently reported acipimox crystal form:
  • HPLC purity of 1,2-bis(4-pyridyl)ethane-acilimus co-crystal is still higher than 99.70% after exposure to light test and high temperature and high humidity environment, and its solid state stability is good .
  • Figure 1 X-ray powder diffraction pattern of 1,2-bis(4-pyridyl)ethane-acilimus co-crystal.
  • Figure 2 Stacking diagram of 1,2-bis(4-pyridyl)ethane-acilimus co-crystal.
  • Figure 3 ORTEP diagram of 1,2-bis(4-pyridyl)ethane-acilimus co-crystal.
  • FIG. 4 Differential scanning calorimetry (DSC) graph of 1,2-bis(4-pyridyl)ethane-acilimus co-crystal.
  • impurity I is 5-methylpyrazine-2-carboxylic acid.
  • the reaction was carried out in a 500mL.x.4-necked flask equipped with a mechanical stirrer, a water condenser (with a gas inlet) and a thermocouple.
  • Sodium trimethylsilanate (3.71g) and THF (90g) were added to the reactor, then 5-methylpyrazinecarboxylic acid-4-oxide ethyl ester (6.00g) were added, and the mixture was stirred at room temperature for 4 After hours, the solid was collected by filtration and rinsed with THF (3x45g). Vacuum drying (25 inches of mercury, 65°C), to obtain 5.38 g (yield: 92.50%) of sodium salt as an off-white solid, HPLC purity: 96.80%, impurity I: 2.41%.
  • the specific stability test method is carried out with reference to the guidance method for stability inspection in the fourth part of the Chinese Pharmacopoeia 2015 edition.
  • the purity test is tested by HPLC method.
  • the specific test results are shown in the following table.

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Abstract

提供1,2-二(4-吡啶基)乙烷-阿昔莫司共晶及其制备方法。该1,2-二(4-吡啶基)乙烷-阿昔莫司共晶是由阿昔莫司与1,2-二(4-吡啶基)乙烷按照摩尔比2:1结合而成，且使用Cu‑Kα辐射，以2θ表示的X射线衍射谱图在：9.88±0.2°，9.1±0.2°，13.92±0.2°，24.56±0.2°，26.12±0.2°，26.86±0.2°处有特征峰。该共晶产品纯度高、稳定性高，制备工艺简单。

Description

一种1,2-二(4-吡啶基)乙烷-阿昔莫司共晶 技术领域
本发明属于有机药物共晶技术领域，特别涉及一种1,2-二(4-吡啶基)乙烷-阿昔莫司共晶。
 背景技术
药物共晶是基于超分子化学原理，即通过分子间的相互协同作用进行的分子识别和超分子自组装。药物活性成分（API）与合适的共晶形成物（cocrystal former,CCF）通过氢键自组装，或者带有饱和性和方向性的非共价键（如芳烃或苯环的范德华力，π-π共轭作用和卤键）组装形成的一种新型结构，即药物共晶。它以氢键为基础，既不需要形成新的共价键，又不需要破坏已有的共价键，在保留药物本身的药理作用的同时，又能修饰药物的理化性质，如提高药物的稳定性、降低其引湿性、提高溶解性、提高生物利用度等，为药物共晶在制药工业方面的应用提供了广阔的发展前景。近几年来，药物共晶研究越来越受到人们的关注。现阶段，国外对药物共晶的研究开始逐渐增多并深入；而国内对其研究还相对较少。对于仿制药来说，药物共晶的研究也可以打破原研药公司对药物晶型的专利保护，利于将仿制药推向市场。因此，获得更多具有新颖、实用和创造性的药物共晶具有重要的现实意义，特别是一些水不溶性药物。
阿昔莫司为烟酸衍生物，是一种广谱长效调血脂药，用于各种原发性和继发性高脂血症，主要作用于脂肪组织，通过抑制脂肪组织释放游离脂肪酸，减少血浆低密度脂蛋白及极低密度脂蛋白的合成，从而降低血浆中血浆低密度脂蛋白及极低密度脂蛋白的水平，同时通过抑制肝脂肪酶活性而增高血浆HDL水平。阿昔莫司由意大利Farmitalia Carlo Erba公司研制开发，于1985年在意大利上市，而后，凭借其较高的安全性及显著的疗效，相继在德国、智利、瑞士、中国香港等多个国家和地区上市。
药物共晶会影响药物的理化性质，直接影响药物在生理pH7.4条件下的溶出及吸收效率，进而影响药物的生物利用度，临床疗效等。通过药物共晶的方式，可以很好的应用共晶优势，这对于理解和掌握药物有效分子的空间排布以及理化性质具有非常重要的作用。
 技术问题
目前关于阿昔莫司的相关报道较多，但是主要是关于其制备、制剂、理化性质及药理等性质的报道，关于其晶体共晶结构的报道较少，专利US2005239803A1、CN 103508963 A等均报道了阿昔莫司的制备方法，专利CN86103304-2得到晶体性状的阿昔莫司沉淀物，为阿昔莫司水合物，产率较低。在之前的报道中，对于阿昔莫司晶体共晶报道较少，阿昔莫司共晶晶体学表征参数未有提及。
 技术解决方案
鉴于现有技术的不足，本发明提供了一种1,2-二(4-吡啶基)乙烷-阿昔莫司共晶。
阿昔莫司作为本发明的药物成分，化学名为5-甲基吡嗪-2-羧酸-4-氧化物，为白色或类白色结晶性粉末。CAS号：51037-30-0，分子式为C 6H 6N 2O 3，其结构式如a所示，发明中所选择的共晶形成物为1,2-二(4-吡啶基)乙烷，分子式为C 12H 12N 2，其结构式如 b 所示。
Figure 158657dest_path_image001
。
本发明的第一方面，提供了1,2-二(4-吡啶基)乙烷-阿昔莫司共晶。所述共晶体中，阿昔莫司与1,2-二(4-吡啶基)乙烷的摩尔比为2:1。
所述的1,2-二(4-吡啶基)乙烷-阿昔莫司共晶，使用Cu-K α辐射，以2θ表示的X射线衍射谱图在9.88±0.2°，13.92±0.2°，24.56±0.2°，26.12±0.2°，26.86±0.2°有特征峰。
优选地，所述的1,2-二(4-吡啶基)乙烷-阿昔莫司共晶，使用Cu-K α辐射，以2θ表示的X射线衍射谱图在9.88±0.2°，13.92±0.2°，15.38±0.2°，15.70±0.2°，24.56±0.2°，26.12±0.2°，26.86±0.2°，29.59±0.2°，36.90±0.2°有特征峰。
优选地，所述的1,2-二(4-吡啶基)乙烷-阿昔莫司共晶，使用Cu-K α辐射，其特征峰符合如图1所示的X射线粉末衍射图谱。
优选地，所述的1,2-二(4-吡啶基)乙烷-阿昔莫司共晶，其在差示扫描量热曲线DSC中存在吸热峰，为184.43℃。
优选地，所述的1,2-二(4-吡啶基)乙烷-阿昔莫司共晶，其晶体学参数是：其晶体学参数是：单斜晶系，空间群为 P2 1/c ；晶胞参数为： a=7.41451(9)Å， b=24.5306(3)Å， c=12.60172(14)Å， a=90°， b= 99.3338(11)°， g=90°，晶胞体积 V=2261.69(5)Å 3。
本发明的第二方面提供一种1,2-二(4-吡啶基)乙烷-阿昔莫司共晶的制备方法，具体制备步骤包括：将阿昔莫司和1,2-二(4-吡啶基)乙烷加入有机溶剂A中，加热溶解，溶液澄清后，控制温度至回流，反应，降温析晶，过滤干燥得1,2-二(4-吡啶基)乙烷-阿昔莫司共晶。
所述的有机溶剂A选自甲醇、乙腈、丙酮、乙酸乙酯、四氢呋喃、乙醇、异丙醇的一种或两种。
优选地，所述有机溶剂A选自甲醇、乙醇、乙酸乙酯的一种或两种。
所述阿昔莫司与1,2-二(4-吡啶基)乙烷的摩尔比为1：0.4~0.6。
优选地，阿昔莫司与1,2-二(4-吡啶基)乙烷的摩尔比为1：0.5。
所述体系中1,2-二(4-吡啶基)乙烷和有机溶剂A的质量体积比为4～6：1，其中质量以mg计，体积以ml计。
所述的降温析晶温度为0~10℃。
优选地，降温析晶温度为5~10℃。
所述的析晶时间为30~50小时。
进一步优选地，所述制备方法包括以下步骤：
将阿昔莫司和1,2-二(4-吡啶基)乙烷溶于有机溶剂A中，50~80℃加热溶解，搅拌回流反应7-10小时，降温至0~10℃析晶30~50小时，过滤，洗涤滤饼，干燥得1,2-二(4-吡啶基)乙烷-阿昔莫司共晶。
所述洗涤滤饼的溶剂选自甲醇、乙醇、乙酸乙酯中的一种。
所述干燥温度为55~75℃，干燥时间为8~10小时。
本发明的第三方面提供一种1,2-二(4-吡啶基)乙烷-阿昔莫司共晶作为活性成分制备治疗降血脂药中的用途。
晶体结构的确认
X射线晶体数据在日本理学XtaLAB Synergy 型号仪器上收集，测试温度293(2) K，用CuK a辐射，以ω扫描方式收集数据并进行 Lp校正。晶体结构用olex2软件中的ShelXT程序计算得到，并采用ShelXL程序通过最小二乘法修正结构参数和判别原子种类，使用几何计算法和差值Fourier法获得全部氢原子位置，拟合优度( GooF值)1.123，接近于1.0，表明权重方案合适、结构准确。
测试及解析本发明制备的1,2-二(4-吡啶基)乙烷-阿昔莫司共晶所得晶体学数据是(表1)：其晶体学参数是：单斜晶系，空间群为 P2 1/c ；晶胞参数为： a =7.41451(9)Å， b=24.5306(3)Å， c=12.60172(14)Å， a=90°， b=99.3338(11)°， g=90°，晶胞体积 V=2261.69(5)Å 3。分子式是：C 24H 24N 6O 6，分子量是：492.49。本发明的1,2-二(4-吡啶基)乙烷-阿昔莫司共晶晶体的 ORTEP图表明，阿昔莫司和1,2-二(4-吡啶基)乙烷通过分子内氢键连接在一起，其中阿昔莫司羧基H4与1,2-二(4-吡啶基)乙烷上的N4形成氢键，另一个阿昔莫司分子羧基上H3与1,2-二(4-吡啶基)乙烷上的N3形成分子内氢键，如附图3所示。本发明的1,2-二(4-吡啶基)乙烷-阿昔莫司的堆积图，如附图2所示。
Figure 819314dest_path_image002
Figure 726090dest_path_image003
。
X-射线粉末衍射测试仪器及测试条件：X-射线粉末衍射仪:PANalyticalE；Cu-K α；样品台：平板；入射光路:BBHD；衍射光路：PLXCEL；电压45kv，电流40mA；发散狭缝:1/4；防散射狭缝:1；索拉狭缝:0.04rad；步长：0.5s；扫描范围：3～50°。
依据上述晶体学数据，其对应的X射线粉末衍射图（Cu-K α）中特征峰详见附图1及表2。
Figure 349970dest_path_image004
Figure 767745dest_path_image005
。
实施例中所制备的所有样品都具有相同的晶体学参数及X射线粉末衍射谱图。
 有益效果
本发明所述方法制备的1,2-二(4-吡啶基)乙烷-阿昔莫司共晶TGA/DSC测试结果如图4所示，DSC检测结果有一个吸热峰，对应温度为184.43°C。根据TGA检测结果可以看出存在一个失重台阶，结合DSC/TGA检测结果表明，本发明制备的1,2-二(4-吡啶基)乙烷-阿昔莫司共晶不含其它溶剂。
本发明所述方法制备的1,2-二(4-吡啶基)乙烷-阿昔莫司共晶相对于目前报道的阿昔莫司晶型具有以下优势：
稳定性高，1,2-二(4-吡啶基)乙烷-阿昔莫司共晶经过光照试验和高温、高湿环境放置后，HPLC纯度仍然高于99.70%，其固体状态稳定性好。
 附图说明
图1：1,2-二(4-吡啶基)乙烷-阿昔莫司共晶的X射线粉末衍射图谱。
图2：1,2-二(4-吡啶基)乙烷-阿昔莫司共晶的堆积图。
图3：1,2-二(4-吡啶基)乙烷-阿昔莫司共晶的 ORTEP图。
图4：1,2-二(4-吡啶基)乙烷-阿昔莫司共晶的差示扫描量热曲线(DSC)图。
 本发明的实施方式
现通过以下实施例来进一步描述本发明的有益效果，实施例仅用于例证的目的，不限制本发明的范围，同时本领域普通技术人员根据本发明所做的显而易见的改变和修饰也包含在本发明范围之内，杂质I为5-甲基吡嗪-2-羧酸。
实施例 1
将154.12mg阿昔莫司，92.12mg1,2-二(4-吡啶基)乙烷加入到20ml的甲醇中，搅拌溶解，控温65℃，回流反应8h，反应完毕，缓慢降温至5~10℃后，静置析晶40h，析晶结束，过滤，甲醇洗涤滤饼，50℃下真空干燥12h，得1,2-二(4-吡啶基)乙烷阿昔莫司共晶，收率98.33%，纯度99.95%。
实施例 2
将154.12mg阿昔莫司，73.70mg1,2-二(4-吡啶基)乙烷加入到15ml乙醇中，搅拌溶解，控温至回流，反应10h，反应完毕，缓慢降温至0~5℃后，静置析晶40h，析晶结束，过滤，乙醇洗涤滤饼，55℃下真空干燥8h，得1,2-二(4-吡啶基)乙烷阿昔莫司共晶，收率96.56%，纯度99.94%。
实施例 3
将154.12mg阿昔莫司，110.54mg1,2-二(4-吡啶基)乙烷加入到25ml乙酸乙酯中，搅拌溶解，控温至回流，反应7h，反应完毕，缓慢降温至10~15℃后，静置析晶48h，过滤，甲醇洗涤滤饼，60℃下真空干燥10h，得1,2-二(4-吡啶基)乙烷阿昔莫司共晶，收率96.88%，纯度99.90%。
实施例 4
将154.12mg阿昔莫司，64.48mg1,2-二(4-吡啶基)乙烷加入到10ml的丙酮中，搅拌溶解，控温至回流，反应8h，反应完毕，缓慢降温至-5~0℃后，静置析晶35h，过滤，用乙酸乙酯洗涤滤饼，50℃下真空干燥10h得1,2-二(4-吡啶基)乙烷阿昔莫司共晶，收率94.51%，纯度99.82%。
实施例 5
将154.12 mg阿昔莫司，119.76mg1,2-二(4-吡啶基)乙烷加入到35ml的乙腈中，搅拌溶解，控温至回流，反应7h，反应完毕，缓慢降温至5~10℃后，静置析晶30h，过滤，用甲醇洗涤滤饼，50℃下真空干燥12h，得1,2-二(4-吡啶基)乙烷阿昔莫司共晶，收率94.33%，纯度99.84%。
实施例 6
将154.12 mg阿昔莫司，92.12mg1,2-二(4-吡啶基)乙烷加入到20ml混合溶剂（10ml甲醇+10ml乙醇）中，控温至回流，反应8h，反应完毕，缓慢降温至5~10℃后，控温静置析晶40h，过滤，用甲醇洗涤滤饼，50℃下真空干燥10h，得1,2-二(4-吡啶基)乙烷阿昔莫司共晶，收率97.12%，纯度99.90%。
对比实施例 1 ：
在10L玻璃反应釜中加入2730ml质量浓度为98% 的浓硫酸，搅拌条件下加入910.0g 的5-甲基吡嗪-2,3-二羧酸，加热至60℃，加热反应1h，然后缓慢加入5.5kg 水、164.9g 钨酸钠（Na 2WO 4·2H 2O），623.0g质量浓度为30%的双氧水，继续加热搅拌8h,冰浴条件下冷却析晶4h，抽滤固体，100℃下干燥12h，制备出产品阿昔莫司595g。该反应中产品收率77.30%；HPLC 纯度96.20%，杂质I：2.80%。
对比实施例 2 ：
向100g阿昔莫司粗品中加入200ml水，加热至100℃，搅拌溶解后加入3.0g活性炭继续保温搅拌20分钟，抽滤；将滤液以10℃/h降温至60℃，然后向其中滴加220g丙酮，滴毕，以10℃/h降温至5℃析晶7h，抽滤，用丙酮洗涤滤饼，烘干(0.01MPa，80℃)即得类白色的阿昔莫司，收率为88.60％。HPLC纯度：98.30％，5-甲基吡嗪-2-羧酸（杂质I）：0.50％。
对比实施例 3 ：
将330mg（1mmol）的Na 2WO 4 ·2H 2O置于50ml烧瓶中，以16ml水溶解并配以机械搅拌、回流冷却器及温度计。将3.75ml 40%重量/体积（400g/L）(44mmol)的过氧化氢加入于溶液中，用稀H 2SO 4调至pH值为1.5，然后加入5.52g（40mmol）的2-羧基-5-甲基吡嗪。
反应产生的水的悬浮物在搅拌下加热至70℃并维持在这温度2.5小时。因而得到逐渐增溶的悬浮物。最后发现有部分产物沉淀。将混合物在室温下静置过夜，而产生晶体形状的反应产物的沉淀。这产物经过滤及用冰水洗涤，再置于素烧板上干燥便可获得部分是水合式（2.83%）的2-羧基-5-甲基吡嗪-4-氧化物4.68g，相当于4.54g的无水产物。产率为73.01%。HPLC纯度：95.10%，杂质I：2.30%。
对比实施例 4 ：
将250mg（0.75mg）的Na 2WO 4 ·2H 2O置于50ml烧瓶中，以13ml水溶解并配以机械搅拌、回流冷却器及温度计。将3.23ml40%重量/体积（400g/L）(38mmol)的过氧化氢加入于溶液中，用稀H 2SO 4调至pH值为2.0，然后加入3.76g 98%（30mmol）的2-羧基-5-甲基吡嗪。
反应产生的水的悬浮物在搅拌下加热至80℃并维持在这温度2小时。而45min后即可获得完全增溶的悬浮物。最后，溶液在室温下静置过夜而产生晶体形状的反应产物的沉淀。这产物经过滤及用冰水洗涤，再置于素烧板上干燥获得3.02g 2-羧基-5-甲基吡嗪-4-氧化物的一水合物（实验值H 2O-11.35%;一水合物产物的计算值H 2O-11.3%），产率为63.02%。HPLC纯度：94.21%，杂质I：3.40%。
对比实施例 5 ：
将2-羧基-5-甲基吡嗪4-氧化物（2.5g）加入到甲醇（60ml）和乙醇胺（1.1ml）的混合溶液中。混合物加热回流20分钟，然后冷却并过滤，从甲醇结晶后得到2-羧基-5-甲基吡嗪4-氧化物乙醇胺盐（2.1g）,mp.177°-180℃，收率：60.17%，HPLC纯度：96.81%，杂质I：2.10%。
对比实施例 6 ：
氮气保护下，在配有机械搅拌器、水冷凝器（带有气体入口）和热电偶的500mL.x.4颈瓶中进行反应。向反应器中加入三甲基硅醇钠（3.71g）和THF（90g），然后加入5-甲基吡嗪羧酸-4-氧化物乙酯（6.00g），将混合物在室温下搅拌4小时，过滤收集固体并用THF（3x45g）冲洗。真空干燥（25英寸汞柱，65℃），得到5.38g（收率：92.50％）钠盐，为灰白色固体，HPLC纯度：96.80%，杂质I：2.41%。
 工业实用性
稳定性试验
温湿度及光照试验
具体的稳定性试验方法参照中国药典2015版第四部有关稳定性考察的指导方法进行，纯度检测用HPLC法进行检测，具体的试验结果见下表。
Figure 84457dest_path_image006
Figure 478529dest_path_image007
Figure 155367dest_path_image008
经试验，本发明制备得到所有的1,2-二(4-吡啶基)乙烷甲基-阿昔莫司共晶均可达相近的稳定性效果。本发明制备得到的1,2-二(4-吡啶基)乙烷-阿昔莫司共晶在光照、高温及高湿的条件下其纯度、外观均未发生比较明显的变化，而对比例1至对比例6晶型在相同的实验条件下其纯度大幅降低，其杂质含量都有较明显的升高，即出现了变质的情况，可见本发明制备的1,2-二(4-吡啶基)乙烷-阿昔莫司共晶相比于现有的晶型具有较好的化学稳定性。

Claims (10)

1,2-二(4-吡啶基)乙烷-阿昔莫司共晶，其特征在于，是由阿昔莫司与1,2-二(4-吡啶基)乙烷按照摩尔比2：1结合而成。
如权利要求1所述的1,2-二(4-吡啶基)乙烷-阿昔莫司共晶，其特征在于，使用Cu-K α辐射，以2θ表示的X射线衍射谱图在9.88±0.2°，13.92±0.2°，24.56±0.2°，26.12±0.2°，26.86±0.2°处有特征峰。
如权利要求2所述的1,2-二(4-吡啶基)乙烷-阿昔莫司共晶，其特征在于，使用Cu-K α辐射，以2θ表示的X射线衍射谱图在在9.88±0.2°，13.92±0.2°，15.38±0.2°，15.70±0.2°，24.56±0.2°，26.12±0.2°，26.86±0.2°，29.59±0.2°，36.90±0.2°有特征峰。
如权利要求3所述的1,2-二(4-吡啶基)乙烷-阿昔莫司共晶，其特征在于，使用Cu-K α辐射，其特征峰符合如图1所示的X射线粉末衍射图谱。
如权利要求1所述的1,2-二(4-吡啶基)乙烷-阿昔莫司共晶，其特征在于，其在差示扫描量热曲线DSC中存在一个吸热峰，为184.43℃。
如权利要求1-5任一项所述的1,2-二(4-吡啶基)乙烷-阿昔莫司共晶，其特征在于，其晶体学参数是：单斜晶系，空间群为P21/c；晶胞参数为： a=7.41451(9)Å， b=24.5306(3)Å， c=12.60172(14)Å， a=90°， b=99.3338(11)°， g=90°，晶胞体积 V=2261.69(5)Å 3。
如权利要求1所述的1,2-二(4-吡啶基)乙烷-阿昔莫司共晶的制备方法，其特征在于，具体制备步骤包括：将阿昔莫司和1,2-二(4-吡啶基)乙烷加入有机溶剂A中，搅拌溶解，控温反应，回流，反应完毕，降温析晶，过滤干燥，得1,2-二(4-吡啶基)乙烷甲基吡嗪衍生物共晶。
如权利要求7所述的1,2-二(4-吡啶基)乙烷-阿昔莫司共晶的制备方法，其特征在于，甲基吡嗪衍生物与1,2-二(4-吡啶基)乙烷的摩尔比为1：0.4~0.6。
如权利要求7所述的1,2-二(4-吡啶基)乙烷-阿昔莫司共晶的制备方法，其特征在于，有机溶剂A选自甲醇、乙腈、丙酮、乙酸乙酯、四氢呋喃、乙醇、异丙醇的一种或两种。
权利要求1-5中任一项所述的1,2-二(4-吡啶基)乙烷-阿昔莫司共晶在制备用于降血脂药中的用途。
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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1361967A (en) * 1972-04-28 1974-07-30 Erba Carlo Spa Pyrazine 4-oxide derivatives and process for their preparation
US20050261312A1 (en) * 2004-05-18 2005-11-24 Isp Investments Inc. Pharmaceutically acceptable inorganic and organic salts of 5-methylpyrazine-2-carboxylic acid-4-oxide
US20150051280A1 (en) * 2012-04-11 2015-02-19 Politecnico Di Milano Co-Crystals of 3-Iodopropynyl Butylcarbamate
CN109369546A (zh) * 2018-12-30 2019-02-22 山东新时代药业有限公司 一种甲基吡嗪衍生物茶碱半水合物
CN109400540A (zh) * 2018-12-30 2019-03-01 山东新时代药业有限公司 一种烟酰胺甲基吡嗪衍生物共晶a
CN109438371A (zh) * 2018-12-30 2019-03-08 山东新时代药业有限公司 一种甲基吡嗪衍生物精氨酸水合物
CN109503475A (zh) * 2018-12-30 2019-03-22 山东新时代药业有限公司 一种异烟酰胺甲基吡嗪衍生物共晶i

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1361967A (en) * 1972-04-28 1974-07-30 Erba Carlo Spa Pyrazine 4-oxide derivatives and process for their preparation
US20050261312A1 (en) * 2004-05-18 2005-11-24 Isp Investments Inc. Pharmaceutically acceptable inorganic and organic salts of 5-methylpyrazine-2-carboxylic acid-4-oxide
US20150051280A1 (en) * 2012-04-11 2015-02-19 Politecnico Di Milano Co-Crystals of 3-Iodopropynyl Butylcarbamate
CN109369546A (zh) * 2018-12-30 2019-02-22 山东新时代药业有限公司 一种甲基吡嗪衍生物茶碱半水合物
CN109400540A (zh) * 2018-12-30 2019-03-01 山东新时代药业有限公司 一种烟酰胺甲基吡嗪衍生物共晶a
CN109438371A (zh) * 2018-12-30 2019-03-08 山东新时代药业有限公司 一种甲基吡嗪衍生物精氨酸水合物
CN109503475A (zh) * 2018-12-30 2019-03-22 山东新时代药业有限公司 一种异烟酰胺甲基吡嗪衍生物共晶i

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
GUO LIHONG, XIA XIANGLAI;ZHAI LIHAI;ZHANG GUIMIN: "Preparation, Characterization and Properties of Acipimox-isonicotinamide Co-crystal", CHINESE JOURNAL OF PHARMACEUTICALS, SHANGHAI YIYAO GONGYE YANJIUYUAN,SHANGHAI INSTITUTE OF PHARMACEUTICAL INDUSTRY, CN, vol. 50, no. 4, 25 April 2019 (2019-04-25), CN, XP055855680, ISSN: 1001-8255, DOI: 10.16522/j.cnki.cjph.2019.04.011 *
JI BAO-MING, DENG DONG-SHENG, MA NING, MIAO SHAO-BIN, LIU PENG, LI XIAN-FEI: "Multiple Hydrogen Bonds in the Self-assembly of Binaphthol with N-Containing Compounds", CHEMICAL JOURNAL OF CHINESE UNIVERSITIES, JILIN DAXUE, BEIJING, CN, vol. 32, no. 9, 10 September 2011 (2011-09-10), CN, pages 2114 - 2122, XP055855684, ISSN: 0251-0790 *
JIANG CHENGJUN, CHENG GUILIN: "Progress in Co-Crystallization as A Separation Technology", CHEMICAL INDUSTRY AND ENGINEERING PROGRESS, vol. 39, no. 1, 5 January 2020 (2020-01-05), pages 311 - 319, XP055855681, ISSN: 1000-6613, DOI: 10.16085/j.issn.1000-6613.2019-0620 *

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