WO2020233288A1 - 托拉塞米钠一水合物、其晶型及组合物 - Google Patents

托拉塞米钠一水合物、其晶型及组合物 Download PDF

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WO2020233288A1
WO2020233288A1 PCT/CN2020/084801 CN2020084801W WO2020233288A1 WO 2020233288 A1 WO2020233288 A1 WO 2020233288A1 CN 2020084801 W CN2020084801 W CN 2020084801W WO 2020233288 A1 WO2020233288 A1 WO 2020233288A1
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torsemide
sodium
sodium monohydrate
acetone
compound
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French (fr)
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魏农农
郑永勇
金华
周峰
黄美花
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上海勋和医药科技有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/02—Nasal agents, e.g. decongestants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/10—Antioedematous agents; Diuretics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—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 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
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
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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

Definitions

  • the present invention relates to the technical field of biomedicine, in particular to torsemide sodium monohydrate, its crystal form and composition.
  • torasemide is 1-[4-(3-methylphenyl)aminopyridin-3-yl]sulfonyl-3-isopropylurea. It is a new generation of high-efficiency loop diuretic with pKa value 6.44, almost insoluble in water, slightly soluble in 0.1mol/L sodium hydroxide solution. More than 20 years of clinical application has proved that torsemide has a wide range of indications, rapid, strong and long-lasting diuretic effects, and is a class of high-efficiency diuretics worth promoting in clinical practice.
  • torasemide is marketed as injections, tablets, and capsules. In the preparation process of injections, it is hoped that the crude drug has high water solubility. Torasemide is very slightly soluble in water (European Journal of Pharmaceutics and Biopharmaceutics 53(2002)75-86).
  • sodium hydroxide and a large amount of excipients need to be added to aid dissolution.
  • the excipients used include: Polyethylene glycol 400, tromethamine, sodium hydroxide, hydrochloric acid.
  • Patent US4861786A discloses a preparation scheme for torasemide injection.
  • torasemide raw material is dissolved in sodium hydroxide or potassium hydroxide, and prepared by adding auxiliary materials such as polyethylene glycol 400 and tromethamine Torasemide injection.
  • the torsemide raw material used in the patent is in free form and has poor solubility.
  • the addition of sodium hydroxide aqueous solution and organic excipients to aid the dissolution process has the risk of exothermic degradation.
  • torsemide lithium salt is an important intermediate in the process and is used to purify free torsemide.
  • the structure of the torasemide lithium salt was identified by single crystal, XRD, DSC, and IR, and it was patented as an important intermediate.
  • the medicinal use of the torasemide lithium salt was not mentioned.
  • the torsemide lithium salt has serious hygroscopicity, and its feasibility as an API is poor.
  • Patent AT505929A1 discloses torsemide calcium salt and its medicinal use, and the structure has been identified by single crystal, XRD, DSC, and IR. Calcium salt as an alkali salt is often used to improve the solubility of drugs with limited effect, and the solubility of torsemide calcium salt is significantly lower than that of torsemide sodium salt of the present application.
  • the purpose of the present invention is to provide a torsemide sodium monohydrate, characterized in that the structure is shown in the following formula 1:
  • the second objective of the present invention is to provide the crystalline form of torsemide sodium monohydrate.
  • the X-ray powder diffraction spectrum has 2 ⁇ values of 4.7, 5.4, 6.9, 10.1, 11.7, 12.6, 15.6, 16.7, 17.9, 18.8, 19.4 , 20.7, 21.4, 22.3, 23.2 have characteristic peaks.
  • the X-ray powder diffraction pattern of the above-mentioned torsemide sodium monohydrate crystal form is basically as shown in FIG. 1.
  • the differential scanning calorimetry (DSC) curve of torsemide sodium monohydrate provided by the present invention has an endothermic peak at 70°C.
  • the DSC spectrum is shown in Figure 2.
  • the torsemide sodium monohydrate provided by the invention has a water content of 4.62% as measured by a Karl Fischer moisture meter, which contains approximately one molecule of water.
  • the torsemide sodium monohydrate provided by the present invention has a sodium content of 5.91% as measured by ICP-OES, which contains approximately one molecule of sodium.
  • the X single crystal diffraction pattern of the above single crystal is shown in FIG. 3.
  • the third aspect of the present invention is to provide the use of torsemide sodium monohydrate in the preparation of diuretics; or to provide torsemide sodium monohydrate in the preparation and treatment of heart failure, renal failure, liver cirrhosis, ascites, renal edema, Use in drugs for cerebral edema, pulmonary edema, diabetes insipidus, hypertension, thrombosis, angina pectoris, asthma, glaucoma, intraocular pressure reduction, acute or chronic bronchitis, ischemia or concussion.
  • the fourth aspect of the present invention is to provide the use of torsemide sodium monohydrate in the preparation of diuretics; or provide the use of torsemide sodium monohydrate in the preparation of drugs for the treatment of heart failure, edema diseases or hypertension .
  • the fifth aspect of the present invention is to provide a pharmaceutical composition, which comprises a therapeutic amount of torasemide sodium monohydrate and other pharmaceutically acceptable excipients.
  • the sixth aspect of the present invention is to provide a pharmaceutical composition comprising a therapeutic amount of torsemide sodium monohydrate and other pharmaceutically acceptable excipients.
  • the seventh aspect of the present invention is to provide a method for preparing torsemide sodium monohydrate, including the following steps
  • the molar ratio of compound 3 and compound 2 in the step (1) is 1.1:1 to 1:1.
  • the alkali in the step (1) is sodium hydroxide, sodium bicarbonate or sodium carbonate.
  • the molar ratio of base to compound 2 in the step (1) is 1.1:1 to 1:1.
  • the volume ratio of acetone/H 2 O in the recrystallization process of step (2) is 100:1-10:1; further, the volume of acetone/H 2 O in the step (1) recrystallization process The ratio is 100:1 to 50:1.
  • the beneficial effects of the present invention are that the provided torsemide sodium monohydrate has the characteristics of high solubility, difficulty in attracting moisture, high stability, convenient preparation and preparation, etc., and is easy to be industrialized and used for medical purposes.
  • Figure 1 is an X-ray powder diffraction pattern of torsemide sodium monohydrate
  • Figure 2 is a graph of X-ray powder diffraction data of torsemide sodium monohydrate
  • Figure 3 is a DSC chart of torsemide sodium monohydrate
  • Figure 4 shows the spatial structure of torsemide sodium monohydrate single crystal
  • Figure 5 is a spatial structure diagram of torsemide sodium monomethanolate single crystal.
  • Preparation composition 11.15g torsemide sodium monohydrate, 2000mL water for injection.
  • step (1) The solution A in step (1) is sterilized and filtered with two 0.22 ⁇ m polyethersulfone filter elements to obtain intermediate product B;
  • Preparation composition 11.15g torsemide sodium monohydrate, 2000mL water for injection.
  • the preparation process is as follows:
  • step (2) The solution B in step (2) is sterilized and filtered with two 0.22 ⁇ m polyethersulfone filter elements to obtain solution C, filled and half-pressed to obtain intermediate product D;
  • the intermediate D is subjected to a freeze-drying treatment under the conditions of a temperature of -40°C to -50°C and a pressure of 10Pa-22Pa, and the freeze-drying treatment adopts the following procedure to heat up:
  • Press stopper take out the box, and tie the lid to get torsemide sodium lyophilized powder injection.

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Abstract

本发明涉及生物医药技术领域，具体涉及托拉塞米钠一水合物、其晶型及组合物。本发明的有益效果在于提供的托拉塞米钠一水合物具有溶解度高、不易引湿、稳定性高、制备制剂方便等特点，易于产业化放大并用于医药用途。

Description

托拉塞米钠一水合物、其晶型及组合物 技术领域
本发明涉及生物医药技术领域，具体涉及托拉塞米钠一水合物、其晶型及组合物。
背景技术
托拉塞米化学名为1-[4-(3-甲基苯基)氨基吡啶-3-基]磺酰-3-异丙基脲，是新一代高效髓袢利尿剂，其pKa值为6.44，在水中几乎不溶，略溶于0.1mol/L的氢氧化钠溶液。20多年临床应用证实，托拉塞米适应症广，利尿作用迅速、强大且持久，是临床上值得推广的一类高效利尿剂。
目前托拉塞米上市剂型有注射剂、片剂、胶囊剂。在注射剂的制备过程中，希望原料药具有较高的水溶性。托拉塞米在水中极微溶解(European Journal of Pharmaceutics and Biopharmaceutics 53(2002)75-86)，在制备托拉塞米注射剂型时，需加入氢氧化钠及大量辅料助溶，所用辅料包括：聚乙二醇400、氨丁三醇、氢氧化钠、盐酸。上述辅料的加入带来了诸多不利：1)氢氧化钠水溶液溶解托拉塞米过程中放热明显，易产生制剂降解杂质；2)聚乙二醇400、氨丁三醇等有机助溶剂的加入，对注射剂用药安全性带来隐患。人们总是期望减少配方的成分数以便减少病人可能产生的副反应。
因此开发更高水溶性、更利于制剂制备的托拉塞米原料药成为一大挑战。
专利US4861786A公开了托拉塞米注射剂的制备方案，在该专利中托拉塞米原料药溶解在氢氧化钠或氢氧化钾中，通过添加辅料聚乙二醇400、氨丁三醇等辅料制备托拉塞米注射剂。该专利中所用托拉塞米原料药为游离形式，溶解性较差，通过添加氢氧化钠水溶液、有机辅料助溶，过程中有放热降解风险。
WO2003097603A1在制备高纯度托拉塞米原料药过程中，托拉塞米锂盐为该工艺重要中间体，用来纯化游离态托拉塞米。该托拉塞米锂盐经单晶、XRD、DSC、IR鉴定了结构，并作为重要中间体进行了专利保护，未提及该托拉塞米锂盐药用用途。且在本申请研究中发现，托拉塞米锂盐引湿性严重，作为原料药可行性差。
专利AT505929A1公开了托拉塞米钙盐及其药用用途，并经单晶、XRD、DSC、IR鉴定了结构。钙盐作为碱盐用于改善药物溶解度往往效果有限，托拉塞米钙盐与本申请托拉塞米钠盐溶解性相比有明显差距。
综上，目前尚无文献报道一种可行的能够改善托拉塞米注射用药方法，在增加溶解性的同时避免相关副作用。
发明内容
本发明的目的在于提供一种托拉塞米钠一水合物，其特征在于，结构如下式1所示：
Figure PCTCN2020084801-appb-000001
本发明的第二目的在于提供托拉塞米钠一水合物的晶型，X射线粉末衍射光谱在2θ值为4.7、5.4、6.9、10.1、11.7、12.6、15.6、16.7、17.9、18.8、19.4、20.7、21.4、22.3、23.2处 具有特征峰。
具体的，上述托拉塞米钠一水合物的晶型，X射线粉末衍射图基本上如图1所示。
本发明提供的托拉塞米钠一水合物其差示扫描量热(DSC)曲线在70℃处有吸热峰。DSC图谱见图2。
本发明提供的托拉塞米钠一水合物经卡尔费休水分仪测得水分含量4.62％，约含一分子水。
本发明提供的托拉塞米钠一水合物经ICP-OES测得钠含量为5.91％，约含一分子钠。
上述单晶的X单晶衍射图谱如图3所示。
本发明的第三方面在于提供托拉塞米钠一水合物在制备利尿剂中的用途；或提供托拉塞米钠一水合物在制备治疗心力衰竭、肾衰、肝硬化腹水、肾水肿、脑水肿、肺水肿、尿崩症、高血压、血栓、心绞痛、哮喘、青光眼、眼内压降低、急性或慢性支气管炎、局部缺血或脑震荡药物中的用途。
本发明的第四方面在于提供托拉塞米钠一水合物在制备利尿剂中的用途；或提供托拉塞米钠一水合物在制备治疗心衰、水肿性疾病或高血压药物中的用途。
本发明的第五方面在于提供一种药物组合物，其包括治疗量的托拉塞米钠一水合物，以及其他药学上可接受的辅料。
本发明的第六方面在于提供一种药物组合物，其包括治疗量的托拉塞米钠一水合物，以及其他药学上可接受的辅料。
本发明的第七方面在于提供一种托拉塞米钠一水合物的制备方法，包括以下步骤
(1)式2化合物与式3化合物在丙酮、碱存在下反应得到托拉塞米钠；
(2)托拉塞米钠再经丙酮/水体系重结晶，生成式1托拉塞米钠一水合物，反应式如下所示：
Figure PCTCN2020084801-appb-000002
优选的，所述步骤(1)中化合物3和2的摩尔比为1.1:1～1:1。
优选的，所述步骤(1)中所述碱为氢氧化钠、碳酸氢钠或碳酸钠。
优选的，所述步骤(1)中碱和化合物2的摩尔比为1.1:1～1:1。
优选的，所述步骤(2)重结晶过程中丙酮/H 2O的体积比为100:1～10:1；进一步的，所述步骤(1)重结晶过程中丙酮/H 2O的体积比为100:1～50:1。
本发明的有益效果在于提供的托拉塞米钠一水合物具有溶解度高、不易引湿、稳定性高、制备制剂方便等特点，易于产业化放大并用于医药用途。
附图说明
图1为托拉塞米钠一水合物的X射线粉末衍射图；
图2为托拉塞米钠一水合物的X射线粉末衍射数据图；
图3为托拉塞米钠一水合物的DSC图；
图4为托拉塞米钠一水合物单晶的空间结构图；
图5为托拉塞米钠一甲醇合物单晶的空间结构图。
具体实施方式
以下结合实施例对本发明作进一步作具体描述，但不局限于此。
实施例1托拉塞米钠一水合物的制备
500mL反应瓶中加入丙酮(300mL)、化合物2(30.0g，0.114mol，1eq)，冰浴搅拌下在分批加入氢氧化钠(5.02g，0.125mol，1.1eq)，保持内温5-10℃。加完后，保持内温5-10℃滴加化合物3(10.68g，0.125mol，1.1eq)。升温至内15-20℃反应2h，反应液先变澄清，随着反应进行有白色固体析出，过滤。所得滤饼加入丙酮(50mL)/H 2O(1mL)体系，加热至内温55-60℃，加入药用活性炭2g，搅拌30min，趁热过滤。母液冷至内温20-25℃重结晶，过滤，干燥得托拉塞米钠一水合物(40.9g，收率92.4％)，HPLC纯度99.95％。MS:348[M-Na+1], 1H NMR(400MHz，D 2O)δ:8.51(s,1H),7.98-7.99(d,J＝4.0Hz,1H),7.23-7.26(m,1H),6.99-7.04(m,3H),6.89-6.90(m,1H),3.55-3.57(m,1H),2.23(s,3H),0.94(s,3H),0.93(s,3H)。元素分析：C,49.52％；H,5.41％；N,14.38％(实测)；C，49.48％；H,5.45％；N,14.42％(理论)。水分：4.62％，钠含量：5.91％。分子结构经单晶衍射确定为托拉塞米钠一水合物，见附图4。
实施例2托拉塞米钠一水合物的制备
500mL反应瓶中加入丙酮(300mL)、化合物2(30.0g，0.114mol，1eq)，冰浴搅拌下在分批加入氢氧化钠(4.78g，0.12mol，1.05eq)，保持内温5-10℃。加完后，保持内温5-10℃滴加化合物3(10.2g，0.12mol，1.05eq)。升温至内15-20℃反应2h，反应液先变澄清，随着反应进行有白色固体析出，过滤。所得滤饼加入丙酮(50mL)/H 2O(0.5mL)体系，加热至内温55-60℃，加入药用活性炭2g，搅拌30min，趁热过滤。母液冷至内温20-25℃重结晶，过滤，干燥得托拉塞米钠一水合物(41.8g，收率94.5％)，HPLC纯度99.93％。水分：4.64％，钠含量：5.89％。
实施例3托拉塞米钠一水合物的制备
500mL反应瓶中加入丙酮(300mL)、化合物2(30.0g，0.114mol，1eq)，冰浴搅拌下在分批加入碳酸氢钠(10.53g，0.125mol，1.1eq)，保持内温5-10℃。加完后，保持内温5-10℃滴加化合物3(10.68g，0.125mol，1.1eq)。升温至内15-20℃反应2h，反应液先变澄清，随着反应进行有白色固体析出，过滤。所得滤饼加入丙酮(50mL)/H 2O(1mL)体系，加热至内温55-60℃，加入药用活性炭2g，搅拌30min，趁热过滤。母液冷至内温20-25℃重结晶，过滤，干燥得托拉塞米钠一水合物(40.5g，收率91.5％)，HPLC纯度99.97％。水分：4.61％，钠含量：5.92％。
实施例4托拉塞米钠一水合物的制备
500mL反应瓶中加入丙酮(300mL)、化合物2(30.0g，0.114mol，1eq)，冰浴搅拌下在分批加入碳酸钠(12.08g，0.125mol，1eq)，保持内温5-10℃。加完后，保持内温5-10℃滴加化合物3(9.7g，0.125mol，1eq)。升温至内15-20℃反应2h，反应液先变澄清，随着反应进行有白色固体析出，过滤。所得滤饼加入丙酮(50mL)/H 2O(0.67mL)体系，加热至内温55-60℃，加入药用活性炭2g，搅拌30min，趁热过滤。母液冷至内温20-25℃重结晶，过滤，干燥得托拉塞米钠一水合物(41.2g，收率93.1％)，HPLC纯度99.98％。水分：4.65％，钠含量：5.90％。
实施例5托拉塞米钠注射液的制备
制剂组成：托拉塞米钠一水合物11.15g，注射用水2000mL。
制备方法：
(1)量取注射用水2000mL，加入托拉塞米11.15g，搅拌均匀，经板框过滤器进行预过滤，得溶液A；
(2)将步骤(1)中溶液A用两道0.22μm聚醚砜滤芯进行除菌过滤，得中间产品B；
(3)中间体B经灌装、熔封、包装，既得产品。
实施例6托拉塞米钠冻干粉针制备
制剂组成：托拉塞米钠一水合物11.15g，注射用水2000mL。
制备过程如下：
(1)取70％选定体积注射用水，加入选定重量的托拉塞米钠一水合物，搅拌至完成溶解，得溶液A；
(2)取30％选定体积注射用水，加入至上述溶液A中，搅拌下调节pH值8.5至9.5，经板框过滤器进行预过滤，得溶液B；
(3)将步骤(2)中溶液B用两道0.22μm聚醚砜滤芯进行除菌过滤，得溶液C，灌装，半压塞，得中间产品D；
(4)将所述中间体D在温度为-40℃～-50℃，压力为10Pa～22Pa的条件下进行冷冻干燥处理，所述冷冻干燥处理采用如下程序进行升温：
(a)设置温度为-45℃～-30℃，进行预冻2.0h；
(b)升温至温度为-30℃～-20℃，进行升华4.0h；
(c)升温至温度为-20℃～-10℃，进行升华1.5h；
(d)升温至温度为-10℃～0℃，进行升华1.0h；
(e)升温至温度为0℃～15℃，进行升华1.5h；
(f)升温至温度为15℃～25℃，进行保温2.0h；
压塞、出箱、扎盖，即得托拉塞米钠冻干粉针。
比较例1托拉塞米钠一甲醇合物的制备
500mL反应瓶中加入丙酮(300mL)、化合物2(30.0g，0.114mol，1eq)，冰浴搅拌下在分批加入氢氧化钠(5.02g，0.125mol，1.1eq)，保持内温5-10℃。加完后，保持内温5-10℃滴加化合物3(10.68g，0.125mol，1.1eq)。升温至内15-20℃反应2h，反应液先变澄清，随着反应进行有白色固体析出，过滤。所得滤饼加入甲醇(50mL)/H 2O(1mL)体系，加热至内温55-60℃，加入药用活性炭2g，搅拌30min，趁热过滤。母液冷至内温20-25℃重结晶，过滤，干燥得托拉塞米钠一甲醇合物(40.7g，收率88.7％)，HPLC纯度99.89％。水分：0.02％，甲醇含量：8.02％(GC测试)，钠含量：5.70％。分子结构经单晶衍射确定为托拉塞米钠一甲醇合物，见附图5。
比较例2托拉塞米钠一乙醇合物的制备
500mL反应瓶中加入丙酮(300mL)、化合物2(30.0g，0.114mol，1eq)，冰浴搅拌下在分批加入氢氧化钠(5.02g，0.125mol，1.1eq)，保持内温5-10℃。加完后，保持内温5-10℃滴加化合物3(10.68g，0.125mol，1.1eq)。升温至内15-20℃反应2h，反应液先变澄清，随着反应进行有白色固体析出，过滤。所得滤饼加入乙醇(50mL)/H 2O(1mL)体系，加热至内温55-60℃，加入药用活性炭2g，搅拌30min，趁热过滤。母液冷至内温20-25℃重结晶，过滤，干燥得托拉塞米钠一乙醇合物(41.0g，收率86.4％)，HPLC纯度99.88％。水分：0.05％，乙醇含量：11.06％(GC测试)，钠含量：5.48％。
比较例3托拉塞米锂水合物的制备
参照文献WO2003097603第36页实施例5，进行如下操作：
4-(3-甲基苯基)氨基吡啶-3-磺酰胺(7.5g，26.0mmol)，氢氧化锂一水合物(11.4g，27.2mmol)和水(32g)加入反应瓶中。25-35℃搅拌下，该混合物完全溶解，该混合液以甲苯萃取3次(3x9g)。
异丙基氨基甲酸苯酯(6.3g，35.0mmol)的丙酮(10.8g)溶液加入上述混合物中。该反应液65-75℃下搅拌反应18h，在降温至45℃反应0.5h。过滤生成的固体，热丙酮(3x10g)冲洗滤饼3次，50-60℃真空干燥至恒重，得白色固体托拉塞米锂盐水合物5.0g，HPLC纯度99.85％。。
比较例4托拉塞米钙水合物的制备
参照文献AT505929说明书第9页，进行如下操作：
500mL烧瓶(500ml)中，将Ca(OH) 2(2.55g,34.4mmol)加入2-丙醇(80mL)和水(20mL) 混合体系中，加热至回流。将托拉塞米(10g,28.7mmol)加入上述Ca(OH) 2悬浮液中并剧烈搅拌5分钟。过滤浑浊的溶液，取滤液。剧烈搅拌下将200mL水滴加到仍然热的澄清滤液中，并在30分钟内冷却至室温。搅拌下，在冰浴中将其冷却至内温10℃，过滤，鼓风干燥(40℃)24小时。得到8.3g托拉塞米钙盐水合物，为细晶白色盐，HPLC纯度99.80％。。
对托拉塞米、托拉塞米钠水合物、醇合物、托拉塞米锂、托拉塞米钙进行了详细的溶解性、引湿性、稳定性比较，结果如下：
表1、不同形式托拉塞米水溶性比较
Figure PCTCN2020084801-appb-000003
溶解度实验结果表明，托拉塞米钠一水合物溶解性优于托拉塞米其它形式。
表2、不同托拉塞米盐型引湿性比较(按照中国药典2015版9103药物引湿性试验指导原则进行)
Figure PCTCN2020084801-appb-000004
引湿性实验结果表明，托拉塞米钠一水合物引湿性优于托拉塞米其它盐及钠盐其它溶剂合物形式。
表3、不同托拉塞米盐型稳定性比较(HPLC有关物质)
Figure PCTCN2020084801-appb-000005
Figure PCTCN2020084801-appb-000006
稳定性实验结果表明，托拉塞米钠一水合物在高温、高湿、光照条件下均表现出良好的稳定性，其稳定性优于托拉塞米其它形式。
本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。

Claims (13)

  1. 一种托拉塞米钠一水合物，其特征在于，结构如下式1所示：
    Figure PCTCN2020084801-appb-100001
  2. 一种托拉塞米钠一水合物的晶型，其特征在于，所述晶型的X射线粉末衍射光谱在2θ值为4.7、5.4、6.9、10.1、11.7、12.6、15.6、16.7、17.9、18.8、19.4、20.7、21.4、22.3、23.2处具有特征峰。
  3. 如权利要求2所述的托拉塞米钠一水合物的晶型，其特征在于，上述晶型的X射线粉末衍射图基本上如图1所示。
  4. 如权利要求1所述的托拉塞米钠一水合物在制备利尿剂中的用途。
  5. 如权利要求2或3所述的托拉塞米钠一水合物在制备利尿剂中的用途。
  6. 一种药物组合物，其包括治疗量的托拉塞米钠一水合物，以及其他药学上可接受的辅料。
  7. 一种药物组合物，其包括治疗量的如权利要求2或3所述的托拉塞米钠一水合物，以及其他药学上可接受的辅料。
  8. 一种制备如权利要求2或3所述的托拉塞米钠一水合物的方法，其特征在于包括以下步骤：
    (1)式2化合物与式3化合物在丙酮、碱存在下反应得到托拉塞米钠；
    (2)托拉塞米钠再经丙酮/水体系重结晶，生成式1托拉塞米钠一水合物，反应式如下所示：
    Figure PCTCN2020084801-appb-100002
  9. 如权利要求8所述的托拉塞米钠一水合物的方法，其特征在于，所述步骤(1)中化合物3和2的摩尔比为1.1:1～1:1。
  10. 如权利要求8所述的托拉塞米钠一水合物的方法，其特征在于，所述步骤(1)中碱和化合物2的摩尔比为1.1:1～1:1。
  11. 如权利要求8～10任一项所述的托拉塞米钠一水合物的方法，其特征在于，所述步骤(2)重结晶过程丙酮/水体系中丙酮/H2O的体积比为100:1～10:1。
  12. 如权利要求11所述的托拉塞米钠一水合物的方法，其特征在于，所述步骤(2)重结晶过程丙酮/水体系中丙酮/H2O的体积比为100:1～50:1。
  13. 如权利要求8所述的托拉塞米钠一水合物的方法，其特征在于，所述步骤(1)中的碱为氢氧化钠、碳酸氢钠和/或碳酸钠。
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