WO2023168650A1 - 一种美氟尼酮晶型的制备方法 - Google Patents

一种美氟尼酮晶型的制备方法 Download PDF

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WO2023168650A1
WO2023168650A1 PCT/CN2022/080109 CN2022080109W WO2023168650A1 WO 2023168650 A1 WO2023168650 A1 WO 2023168650A1 CN 2022080109 W CN2022080109 W CN 2022080109W WO 2023168650 A1 WO2023168650 A1 WO 2023168650A1
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ethanol
preparation
crystal form
methyl
piperazinyl
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PCT/CN2022/080109
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English (en)
French (fr)
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王兴旺
林寨伟
郑琴香
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广州南新制药有限公司
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Priority to PCT/CN2022/080109 priority Critical patent/WO2023168650A1/zh
Publication of WO2023168650A1 publication Critical patent/WO2023168650A1/zh

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    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
    • 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
    • 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
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/64—One oxygen atom attached in position 2 or 6

Definitions

  • the present invention relates to the field of medicine, and in particular to a preparation method of meflunidone crystals.
  • Fibrosis can occur in various organs of the human body.
  • the main pathological changes are the increase of fibrous connective tissue and the decrease of parenchymal cells in organ tissues. Continued progression can cause organ structural damage and functional decline, or even failure, seriously threatening human health and life.
  • Tissue fibrosis plays an important role in the occurrence and development of diseases in major organs of the human body.
  • extensive research has been conducted on the mechanisms, diagnostic methods, and prevention and treatment measures of organ or tissue fibrosis.
  • Meflunidone (1-(4-(3-(4-methyl-1-piperazinyl)propyl)amino)benzyl-5-trifluoromethyl-2(1H)-pyridone hydrochloride , ZHC-116) is a new type of anti-renal fibrosis molecule, which showed significant inhibitory effect in the inhibition experiment of NIH3T3 fibroblasts.
  • the activity of ZHC-116 is about 300 times higher than that of pirfenidone.
  • 1 ZHC-116 can significantly inhibit the expression of FN and CTGF in mouse glomerular mesangial cells (MES) induced by high glucose; 2 ZHC-116 can significantly inhibit the expression of mouse glomerular mesangial cells induced by TGF- ⁇ 1 (MES) ⁇ -SMA expression increases E-cadherin expression.
  • Meflunidone can be used as a candidate compound to develop anti-renal fibrosis and diabetic nephropathy. From the perspective of developing pharmaceutical preparations and their industrial production, it is very necessary to prepare stable crystal forms.
  • the object of the present invention is to provide a method for preparing melfronidone crystal form, which is carried out according to the following steps: adding 1-(4-(3-(4-methyl-1-piperazinyl)propyl)amino)benzyl Dissolve methyl-5-trifluoromethyl-2(1H)-pyridone hydrochloride in absolute ethanol. After dissolution, add dropwise an ethanol solution of concentrated hydrochloric acid with a volume concentration of 16.7%. After the addition, stir for 1.5 hours and filter with suction. , wash the filter cake with ethanol, and dry the filter cake under vacuum at 60°C for 6 hours to obtain a white solid product.
  • the temperature of the 95% ethanol is 0-5°C.
  • the differential thermal analysis spectrum (DSC) of the crystal form prepared by the preparation method of the present invention has an absorption peak at 200.7°C.
  • the invention has beneficial technical effects: the meflunidone A crystal form provided by the invention has low hygroscopicity, and its preparation method has simple process, high yield and good product quality.
  • the sources of raw materials and excipients are commercially available pharmaceutical raw materials or excipients.
  • concentration or dosage of the solvent during the preparation process is well known in the art.
  • the measurement method is specified in the Pharmacopoeia of the People's Republic of China or a method well known in the art.
  • Dissolve ZHC-116 hydrochloride (7.5g) in 95% ethanol at 0°C. After dissolution, add dropwise the ethanol solution of concentrated hydrochloric acid (concentrated hydrochloric acid 5mL + ethanol 25mL). After adding, stir for 1.5h, filter with suction, and wash with ethanol. The filter cake was vacuum dried at 60°C for 6 hours to obtain 4.8 g of a white solid product.
  • the differential thermal analysis spectrum (DSC) has an absorption peak at 200.7°C.
  • Dissolve ZHC-116 hydrochloride (15g) in 95% ethanol at 5°C. After dissolution, add dropwise the ethanol solution of concentrated hydrochloric acid (5mL of concentrated hydrochloric acid + 25mL of ethanol). After the addition, stir for 2 hours, filter with suction, and wash the filter cake with ethanol. , the filter cake was vacuum dried at 65°C for 8 hours to obtain 10g of white solid product.
  • the differential thermal analysis spectrum (DSC) has an absorption peak at 200.7°C.
  • each melfronidone crystal form prepared in the above two examples was placed in an open container at room temperature. After one week, a sample was taken to test the moisture content. The moisture content increased from 5.5% to 6.7%.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Urology & Nephrology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

涉及一种美氟尼酮晶型的制备方法。与现有技术相比，所述制得的美氟尼酮晶型具有较低的吸湿性，其制备方法过程简单、收率高、产品质量好。

Description

一种美氟尼酮晶型的制备方法 技术领域
本发明涉及医药领域，特别地涉及美氟尼酮晶的制备方法。
背景技术
纤维化(fibrosis)可发生于人体多种器官，主要病理改变为器官组织内纤维结缔组织增多，实质细胞减少，持续进展可致器官结构破坏和功能减退，乃至衰竭，严重威胁人类健康和生命。组织纤维化在人体各主要器官疾病的发生和发展过程中均起着重要作用。目前对器官或组织纤维化的发生机制、诊断方法和防治措施已进行广泛的研究。
美氟尼酮(1-(4-(3-(4-甲基-1-哌嗪基)丙基)氨基)苄基-5-三氟甲基-2(1H)-吡啶酮盐酸盐，ZHC-116)是一种新型的抗肾纤维化分子，其在NIH3T3成纤维细胞的抑制实验中显示明显抑制作用ZHC-116的活性，比吡啡尼酮高约300倍。机制研究表明：①ZHC-116能够显著抑制高糖诱导的小鼠肾小球系膜细胞(MES)FN、CTGF的表达；②ZHC-116能够显著抑制TGF-β1诱导的小鼠肾小球系膜细胞(MES)α-SMA的表达，增加E-钙粘蛋白的表达。美氟尼酮可以作为开发抗肾纤维化及糖尿病肾病的候选化合物。从开发药物制剂及其工业化生产的角度出发，制备稳定的晶型是十分必要的。
美氟尼酮的结构式如下式：
Figure PCTCN2022080109-appb-000001
发明内容
本发明的目的在于提供一种美氟尼酮晶型的制备方法，按以下步骤进行：将1-(4-(3-(4-甲基-1-哌嗪基)丙基)氨基)苄基-5-三氟甲基-2(1H)-吡啶酮盐酸盐溶于无水乙醇，溶解后滴加体积浓度为16.7％的浓盐酸的乙醇溶液，加完后搅拌1.5h，抽滤，用乙醇洗涤滤饼，滤饼在60℃真空干燥6h得到白色固体产物。
在一个优选的技术方案中，溶解1-(4-(3-(4-甲基-1-哌嗪基)丙基)氨基)苄基-5-三氟甲基-2(1H)-吡啶酮盐酸盐的乙醇为95％乙醇。
在一个优选的技术方案中，所述95％乙醇的温度为0-5℃。
本发明的制备方法制得的晶型的差热分析图谱(DSC)在200.7℃有吸收峰。
本发明具有有益的技术效果：本发明提供的美氟尼酮A晶型具有较低的吸湿性，其制备方法过程简单、收率高、产品质量好。
具体实施方式
本发明结合下述具体实施例，对本发明进行进一步完整、清楚的说明，以便于本领域技术人员理解本发明的内容，但是应当理解，下述实施例仅用于解释说明，而不以任何方式限制本发明的范围。基于本发明的实施例，本领域技术人员可以对本发明进行适当的修饰和改进，但这都属于本发明保护的范围之内。
如果没有特别说明，原料和辅料来源均为市售药用原料或辅料级别，制备过程中溶剂的浓度或用量为本领域熟知的，测定方法为中华人民共和国药典规定的或本领域熟知的方法。
实施例1
将ZHC-116盐酸盐(7.5g)溶于0℃的95％乙醇，溶解后滴加浓盐酸的乙醇溶液(浓盐酸5mL+乙醇25mL)，加完后搅拌1.5h，抽滤，用乙醇洗涤滤饼，滤饼在60℃真空干燥6h得到白色固体产物4.8g。差热分析图谱(DSC)在200.7℃有吸收峰。
实施例2
将ZHC-116盐酸盐(15g)溶于5℃的95％乙醇，溶解后滴加浓盐酸的乙醇溶液(浓盐酸5mL+乙醇25mL)，加完后搅拌2h，抽滤，用乙醇洗涤滤饼，滤饼在65℃真空干燥8h得到白色固体产物10g。差热分析图谱(DSC)在200.7℃有吸收峰。
实施例3
从上述两个实施例制得的美氟尼酮晶型各取1g放置于室温敞口容器中，一个星期后取样测试水份，水份含量从5.5％增加到6.7％。

Claims (3)

1-(4-(3-(4-甲基-1-哌嗪基)丙基)氨基)苄基-5-三氟甲基-2(1H)-吡啶酮盐酸盐的晶型A的制备方法，其特征在于按照如下步骤制备：
将1-(4-(3-(4-甲基-1-哌嗪基)丙基)氨基)苄基-5-三氟甲基-2(1H)-吡啶酮盐酸盐溶于乙醇，溶解后滴加体积浓度为16.7％的浓盐酸的乙醇溶液，加完后搅拌1.5h，抽滤，用乙醇洗涤滤饼，滤饼在60℃真空干燥6h得到白色固体产物。
根据权利要求1所述的制备方法，其特征在于：溶解1-(4-(3-(4-甲基-1-哌嗪基)丙基)氨基)苄基-5-三氟甲基-2(1H)-吡啶酮盐酸盐的乙醇为95％乙醇。
根据权利要求2所述的制备方法，其特征在于：所述95％乙醇的温度为0-5℃。
PCT/CN2022/080109 2022-03-10 2022-03-10 一种美氟尼酮晶型的制备方法 WO2023168650A1 (zh)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010135976A1 (zh) * 2009-05-25 2010-12-02 中南大学 1-（取代苄基）-5-三氟甲基-2-（1h）吡啶酮化合物及其盐，其制备方法及其用途
CN106466318A (zh) * 2015-08-21 2017-03-01 中南大学 1-杂环取代苄基吡啶酮类化合物在制备治疗糖尿病肾病药物中的应用
CN107652228A (zh) * 2016-10-28 2018-02-02 广州南新制药有限公司 抗肾纤维化药物1‑（取代苄基）‑5‑三氟甲基‑2(1h)‑吡啶酮盐酸盐的合成方法
CN107663167A (zh) * 2016-10-19 2018-02-06 广州南新制药有限公司 1‑（取代苄基）‑5‑三氟甲基‑2(1h)‑吡啶酮盐酸盐的晶型及制备方法

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010135976A1 (zh) * 2009-05-25 2010-12-02 中南大学 1-（取代苄基）-5-三氟甲基-2-（1h）吡啶酮化合物及其盐，其制备方法及其用途
CN106466318A (zh) * 2015-08-21 2017-03-01 中南大学 1-杂环取代苄基吡啶酮类化合物在制备治疗糖尿病肾病药物中的应用
CN107663167A (zh) * 2016-10-19 2018-02-06 广州南新制药有限公司 1‑（取代苄基）‑5‑三氟甲基‑2(1h)‑吡啶酮盐酸盐的晶型及制备方法
CN107652228A (zh) * 2016-10-28 2018-02-02 广州南新制药有限公司 抗肾纤维化药物1‑（取代苄基）‑5‑三氟甲基‑2(1h)‑吡啶酮盐酸盐的合成方法

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