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WO2019214482A1 - 一种苯基氨基丙酸钠衍生物、其制备方法和应用 - Google Patents

一种苯基氨基丙酸钠衍生物、其制备方法和应用 Download PDF

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Publication number
WO2019214482A1
WO2019214482A1 PCT/CN2019/084921 CN2019084921W WO2019214482A1 WO 2019214482 A1 WO2019214482 A1 WO 2019214482A1 CN 2019084921 W CN2019084921 W CN 2019084921W WO 2019214482 A1 WO2019214482 A1 WO 2019214482A1
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Prior art keywords
compound
formula
preparation
sodium
derivative
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PCT/CN2019/084921
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English (en)
French (fr)
Inventor
鲁先平
李志斌
王祥辉
高伟君
邓兴玉
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深圳微芯生物科技股份有限公司
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Priority to CA3099503A priority Critical patent/CA3099503A1/en
Priority to JP2020562699A priority patent/JP7047136B2/ja
Priority to MX2020011763A priority patent/MX2020011763A/es
Priority to KR1020207034580A priority patent/KR102512807B1/ko
Priority to RU2020139828A priority patent/RU2759745C1/ru
Priority to BR112020022543-6A priority patent/BR112020022543A2/pt
Priority to US17/053,364 priority patent/US11981638B2/en
Priority to AU2019267849A priority patent/AU2019267849B2/en
Priority to EP19800412.9A priority patent/EP3792249A4/en
Publication of WO2019214482A1 publication Critical patent/WO2019214482A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/80—[b, c]- or [b, d]-condensed
    • C07D209/82—Carbazoles; Hydrogenated carbazoles
    • C07D209/86—Carbazoles; Hydrogenated carbazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the ring system
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N1/00—Sampling; Preparing specimens for investigation
    • G01N1/28—Preparing specimens for investigation including physical details of (bio-)chemical methods covered elsewhere, e.g. G01N33/50, C12Q
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G01N30/04—Preparation or injection of sample to be analysed
    • G01N30/06—Preparation
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G01N30/26—Conditioning of the fluid carrier; Flow patterns
    • G01N30/28—Control of physical parameters of the fluid carrier
    • G01N30/34—Control of physical parameters of the fluid carrier of fluid composition, e.g. gradient
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N1/00—Sampling; Preparing specimens for investigation
    • G01N1/28—Preparing specimens for investigation including physical details of (bio-)chemical methods covered elsewhere, e.g. G01N33/50, C12Q
    • G01N2001/2893—Preparing calibration standards
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G01N2030/022—Column chromatography characterised by the kind of separation mechanism
    • G01N2030/027—Liquid chromatography
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G01N30/04—Preparation or injection of sample to be analysed
    • G01N2030/042—Standards
    • G01N2030/047—Standards external
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G01N30/04—Preparation or injection of sample to be analysed
    • G01N30/06—Preparation
    • G01N2030/062—Preparation extracting sample from raw material
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G01N30/88—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86
    • G01N2030/8809—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86 analysis specially adapted for the sample
    • G01N2030/884—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86 analysis specially adapted for the sample organic compounds

Definitions

  • the invention belongs to the field of chemical pharmacy, in particular to a sodium phenylaminopropionate derivative, and to a preparation method of the sodium phenylaminopropionate derivative and a medicament thereof for use as siglistatin or a derivative thereof
  • the use of quality control of a drug substance or preparation; in particular, the sodium phenylaminopropionate derivative can be used as an impurity or related substance in a drug substance or preparation of siglitastat or a salt thereof (for example, a sodium salt) Check the reference or standard.
  • Sigliflozin has the ability to selectively activate PPAR- ⁇ , PPAR- ⁇ and PPAR- ⁇ and can be used to treat diseases associated with metabolic syndrome such as diabetes, hypertension, obesity, insulin resistance, and high triglyceride blood. Symptoms, high blood sugar, high cholesterol, atherosclerosis, coronary heart disease, etc.
  • sigtastatin sodium having a purity of more than 99% can be obtained, and the process is stable and controllable, and is suitable for industrial production.
  • HPLC HPLC analysis
  • column C 18 column, Shim-pack VP-ODS 5 ⁇ m 250 L ⁇ 4.6; mobile phase: methanol-water-tetrahydrofuran-acetic acid 40:30:30:0.5
  • the detection wavelength: 236 nm; flow rate: 1.5 mL/min indicates that there is always an unknown structural impurity at a relative retention value of about 2.4, and the impurity fluctuates within a certain range as the relative proportion of the raw material 1 and the raw material 2 changes.
  • the impurity content is about 0.18% (area normalization method); when the ratio of the raw material 1 to the raw material 2 is 1:1.5, the impurity content is about 0.06%. (area normalization method). Since the existence and structure of the impurity have not been disclosed and reported in the prior art, the pharmacological and toxicological properties are also unknown, and thus pose a risk to the safe drug. At the same time, since the impurity structure is unknown, and the prior art does not disclose any impurity information and separation method of siglitastat, it is extremely difficult to separate and identify the impurity.
  • one of the objects of the present invention is to disclose the above-mentioned unknown structural compound present in a drug such as siglitastat or sigrita sodium salt prepared by a prior art process.
  • the impurity is 3-(4-(2-(9H-carbazol-9-yl)ethoxy)phenyl)-2-((2-(4-(4-(2-) Sodium formate 2-((2-(4-fluorobenzoyl)phenyl)amino)ethyl)phenoxy)benzoyl)phenyl)amino)propionate, the structure of which is represented by formula (I) :
  • the production of the above compound of formula (I) is not limited to the above-described reaction route for the preparation of sicilita sodium, which may likewise be present in the synthesis product of siglitastat.
  • reaction solvent and the base used in the above reaction scheme are all illustrative and not limiting, and those skilled in the art can make appropriate transformations and adjustments.
  • compound (a) is subjected to a condensation reaction with compound (b) to give compound (c).
  • the reaction may be carried out using cesium carbonate as a catalyst, preferably N,N-dimethylformamide as a solvent, the reaction temperature may be 80 to 120 ° C, and the reaction time may be 20 to 30 hours.
  • cesium carbonate as a catalyst
  • the reaction temperature may be 80 to 120 ° C
  • the reaction time may be 20 to 30 hours.
  • the crude product obtained was used in the next step without further purification.
  • Compound (c) is acidified to give compound (d).
  • the acidification is preferably carried out with hydrochloric acid.
  • the reaction is preferably carried out using ethyl acetate and water as a solvent, the reaction temperature may be room temperature, and the reaction time may be 4 to 5 hours.
  • the crude product obtained was used in the next step without further purification.
  • Compound (d) is hydrolyzed in the presence of lithium hydroxide to give compound (e).
  • the reaction is preferably carried out using tetrahydrofuran and water as a solvent, the reaction temperature may be room temperature, and the reaction time may be from 12 to 16 hours.
  • the crude product obtained was used in the next step without further purification.
  • Acidification of compound (e) gives compound (f).
  • the acidification is preferably carried out with hydrochloric acid.
  • the reaction is preferably carried out using ethyl acetate and water as a solvent, the reaction temperature may be room temperature, and the reaction time may be 4 to 5 hours.
  • the crude product obtained is separated by a semi-preparative liquid chromatography column (column: YMC-Pack ODS-AQ 5 ⁇ m 250 L ⁇ 20; mobile phase: methanol-water-tetrahydrofuran-glacial acetic acid 48:22: 30:0.5; detection wavelength: 236 nm; flow rate: 8 ml/min), a compound (f) having a purity of more than 97% was obtained.
  • Compound (f) is neutralized with sodium hydroxide to give a compound of formula (I).
  • the reaction can be carried out using methanol as a solvent, the reaction temperature can be room temperature, and the reaction time can be 20 to 40 minutes.
  • the invention also provides the use of a compound of formula (I) for the quality control of a drug substance or formulation of siglitastat or a derivative thereof.
  • the invention provides the use of a compound of formula (I) as a reference or standard for the examination of impurities or related substances in a drug of siglitastat or sigridastat.
  • the present invention provides quality control of a drug substance or preparation of siglita or a derivative thereof Process for the use of a compound of formula (I) according to the invention as a control or standard for impurities or related Substance inspection.
  • the present invention provides a method for detecting the content of impurities or related substances in a drug of siglita or a derivative thereof, which comprises using a compound of the formula (I)
  • the above detection method is preferably an HPLC method.
  • the conditions of the HPLC method are as follows:
  • the above HPLC detection method of the invention has the advantages that the measurement result is accurate and reliable, the specificity is strong, the utility is strong, the above impurities can be effectively detected, and the impurity is well separated from siglita or its salt.
  • Impurity research is an important part of drug research and development, which runs through the development of drugs and directly affects the quality and safety of drugs.
  • To provide quality control for the quality studies of siglitastat or its derivatives to improve the quality standards of siglitastat or its derivatives, and compositions containing sicilitastat or its derivatives, including pharmaceutical preparations.
  • the present invention studies, synthesizes and identifies the process impurities.
  • the siglitastat derivative includes not only the siglita free acid but also a salt thereof such as an inorganic salt such as a sodium salt, and a hydrate thereof.
  • impurities and “relative retention values”: Any substance that affects the purity of a drug is referred to as an impurity.
  • an impurity refers to a chemical substance other than the active drug substance introduced or produced during production and storage. It is well known to those skilled in the art that secondary methods, by-products, and additional reagents (collectively referred to as “impurities”) can be identified using spectroscopic methods and by other physical methods, such that impurities and peak positions in the chromatogram (or spots on a thin layer chromatography plate) ) (Strobel, HA; Heineman, WR, Chemical Instrumentation: Asystematic Approach, 3rd. (Wiley & Sons: New York 1989)).
  • impurities can be identified by their position in the chromatogram.
  • the position in the chromatogram is usually calculated in minutes between the time the sample is injected onto the column and the time when a particular component is passed through the detector. time". This time period varies daily based on the conditions of the instrument used and many other factors.
  • relative retention times or relative retention values
  • the relative retention of impurities is the ratio of their retention time divided by the retention time of a reference marker (eg, a control or reference standard).
  • the standard can also be used to measure the amount of another compound in the mixture.
  • the standards are added directly to the mixture, which is referred to as the "internal standard". Standards can be used as internal standards when the standard mixture is not intentionally added to the standard, but a technique known as "standard addition” is used to make the unknown mixture contain a detectable amount of reference standard.
  • Siglitastat sodium prepared according to the method of Chinese patent application 201410856282.5 and 201610855107.3, purity >99%.
  • Methyl 2-[(2-(4-fluorobenzoyl)phenyl)amino]-3-(4-hydroxyphenyl)propanoate (Compound (b)): produced by Beijing Lewei Taike Pharmaceutical Technology Co., Ltd. Purity >96%.
  • Proton nuclear magnetic resonance Instrument: Varian INOVA 500; solvent: DMSO-d 6 .
  • High-resolution mass spectrometry Instrument: VG ZAB-HS color-mass spectrometer; detection method: fast atom bombardment ionization (FAB).
  • Instrument VG ZAB-HS color-mass spectrometer; detection method: fast atom bombardment ionization (FAB).
  • sigridastat sodium prepared according to the methods of Chinese Patent Application Nos. 201410856282.5 and 201610855107.3 were separated by a semi-preparative liquid chromatography column (column: YMC-Pack ODS-AQ 5 ⁇ m 250 L ⁇ 20; mobile phase: methanol-water- Tetrahydrofuran-glacial acetic acid 48:22:30:0.5; detection wavelength: 236 nm; flow rate: 8 ml/min), the effluent was collected for 30 to 42 minutes, and neutralized to pH 7 with a 1 mol/L aqueous sodium hydrogencarbonate solution.
  • Example 2 A compound of formula (I) is used as a reference for the determination of impurities in the drug of siglitastat sodium
  • Instrument UltiMate 3000; column: C 18 column, Shim-pack VP-ODS 5 ⁇ m 250 L ⁇ 4.6; detector: VWD-3100, mobile phase: methanol-water-tetrahydrofuran-acetic acid 40:30:30:0.5; detection wavelength: 236 nm; flow rate: 1.5 mL/min.
  • the compound of formula (I) was confirmed to be an impurity having a relative retention value of about 2.4 in the sample of siglitastat sodium.
  • Example 3 A compound of formula (I) is used as a standard for the determination of impurities in a drug of siglitastat sodium
  • Instrument UltiMate 3000; column: C 18 column, Shim-pack VP-ODS 5 ⁇ m 250 L ⁇ 4.6; detector: VWD-3100, mobile phase: methanol-water-tetrahydrofuran-acetic acid 40:30:30:0.5; detection wavelength: 236 nm; flow rate: 1.5 mL/min.
  • siclistatin sodium sample was accurately weighed, placed in a 100 ml volumetric flask, dissolved in a solvent methanol-water-tetrahydrofuran (40:30:30) and diluted to the mark, and shaken to obtain a test solution.
  • Another compound of formula (I) is about 10mg, accurately weighed, placed in a 100ml volumetric flask, dissolved in solvent methanol-water-tetrahydrofuran (40:30:30) and diluted to the mark, shaken, and accurately transferred 1mL Place in a 1000 ml volumetric flask, dissolve in the solvent methanol-water-tetrahydrofuran (40:30:30) and dilute to the mark, shake well, as a reference solution. 20 ⁇ l of each of the above two solutions was accurately aspirated and injected into a liquid chromatograph to record a chromatogram. The content of the compound of formula (I) in the siglitastat sodium sample was calculated by the external standard method by the peak area.
  • Siglitastat sodium sample Compound (I) content (%) 20160817 batch 0.07 20160909 batch 0.08 20160923 batch 0.08 .

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Biochemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Analytical Chemistry (AREA)
  • Physics & Mathematics (AREA)
  • General Health & Medical Sciences (AREA)
  • General Physics & Mathematics (AREA)
  • Immunology (AREA)
  • Pathology (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Indole Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

公开了苯基氨基丙酸钠衍生物、其制备方法和应用。具体来说，公开了3-(4-(2-(9H-咔唑-9-基)乙氧基)苯基)-2-((2-(4-(4-(2-甲酸钠-2-((2-(4-氟苯甲酰基)苯基)氨基)乙基)苯氧基)苯甲酰基)苯基)氨基)丙酸钠，其制备方法及其用于西格列他或其衍生物的原料药或制剂的质量控制的用途。特别地，该化合物可以用作西格列他或其钠盐药物中杂质/有关物质检查的对照品或标准品。

Description

一种苯基氨基丙酸钠衍生物、其制备方法和应用
本申请要求于2018年5月9日提交到中国专利局的发明名称为“一种苯基氨基丙酸钠衍生物、其制备方法和应用”的中国专利申请201810437901.5的优先权，其内容通过引用以整体并入本文。
技术领域
本发明属于化学制药领域，具体涉及一种苯基氨基丙酸钠衍生物，本发明还涉及所述苯基氨基丙酸钠衍生物的制备方法以及其用作西格列他或其衍生物药物中的原料药或制剂的质量控制的用途；特别地，所述苯基氨基丙酸钠衍生物可以用作西格列他或其盐(例如钠盐)的原料药或制剂中杂质或有关物质检查的对照品或标准品。
背景技术
2-(2-(4-氟苯甲酰基)苯基氨基)-3-(4-(2-(9H-咔唑-9-基)乙氧基)苯基)丙酸，通用名为西格列他，是一种对于代谢性疾病具有治疗和预防活性的苯丙氨酸类化合物，其化学结构式如下：
Figure PCTCN2019084921-appb-000001
在中国专利申请CN03126974.5和美国专利申请US7,268,157中均记载了该化合物的药理活性。西格列他具有选择性激活PPAR-α、PPAR-γ和PPAR-δ的能力，可以用于治疗与代谢综合症相关的疾病，如糖尿病、高血压、肥胖、胰岛素抵抗、高甘油三酯血症、高血糖、高胆固醇、动脉粥样硬化、冠心病等。
在现有技术中，中国专利申请201610855107.3和中国专利申请201410856282.5中公开了西格列他及其钠盐的合成方法。
在中国专利申请201610855107.3中公开了西格列他的一种可工业化的制备方法，其合成路线如下：
Figure PCTCN2019084921-appb-000002
该方法适合工业化生产，所得目标化合物纯度高。然而，由于西格列他的稳定性较差，在药物制造、贮存和运输过程中易分解，严重影响了该药物的安全性和有效性，因此，需将其制成稳定性更好的钠盐，即西格列他钠。在中国专利申请201410856282.5中公开了西格列他钠的制备方法，所述方法如下：
Figure PCTCN2019084921-appb-000003
按照上述现有技术中的制备方法，可以制得纯度大于99％的西格列他钠，且工艺稳定可控，适合工业化生产。然而，本发明人通过大量研究意外地发现，HPLC分析(色谱柱：C 18柱，Shim-pack VP-ODS 5μm 250L×4.6；流动相：甲醇-水-四氢呋喃-醋酸40：30：30：0.5；检测波长：236nm；流速：1.5mL/min)表明，在相对保留值约2.4处始终有一未知结构杂质，该杂质随原料1和原料2的用量相对比例变化在一定范围内波动。当原料1与原料2的比例为1:1时，该杂质含量约为0.18％(面积归一化法)；当原料1与原料2的比例为1:1.5时，该杂质含量约为0.06％(面积归一化法)。由于现有技术中一直未公开和报道该杂质的存在及其结构，其药理毒理性质也是未知的，因此给安全用药带来风险。同时，由于该杂质结构未知，且现有技术也未公开报道西格列他钠的任何杂质信 息及分离方法，这给该杂质的分离和鉴定带来极大困难。
一方面，为了保证患者的用药安全，需要确认该未知杂质的结构；另一方面，需要研究该杂质化合物的制备方法，获得其对照品或参比标准品，用于西格列他或西格列他钠等药物的质量控制，尤其是用作有关物质/杂质检查的对照品或参比标准品。
发明内容
基于现有技术中的上述需要，本发明的目的之一在于公开现有技术工艺制得的西格列他或西格列他钠盐等药物中存在的上述未知结构化合物。
本发明人研究发现，该杂质为3-(4-(2-(9H-咔唑-9-基)乙氧基)苯基)-2-((2-(4-(4-(2-甲酸钠-2-((2-(4-氟苯甲酰基)苯基)氨基)乙基)苯氧基)苯甲酰基)苯基)氨基)丙酸钠，其结构如式(I)所示：
Figure PCTCN2019084921-appb-000004
不受任何理论的限制，在大量的检测和研究后，本发明人猜测，上述式(I)化合物可能是由于下列副反应所产生的：
Figure PCTCN2019084921-appb-000005
Figure PCTCN2019084921-appb-000006
事实上，上述式(I)化合物的产生并不局限于上述制备西格列他钠的反应途径，其同样可存在于西格列他的合成产物中。
在另一方面，本发明的目的是提供一种制备上述式(I)化合物的方法，所述方法的一个示例性合成路线如下所示：
Figure PCTCN2019084921-appb-000007
需要指出的是，上述反应路线中所用的反应溶剂和碱均是示例性的而不是限定性的，本领域技术人员可以进行适当的变换和调整。
在示例性的实施方案中，使化合物(a)与化合物(b)进行缩合反应得到 化合物(c)。该反应可以以碳酸铯为催化剂，优选以N,N-二甲基甲酰胺为溶剂，反应温度可以为80～120℃，反应时间可为20～30小时。所得粗产品可未经进一步纯化，直接用于下一步反应。
将化合物(c)酸化得到化合物(d)。所述酸化优选用盐酸进行。该反应优选以乙酸乙酯和水为溶剂，反应温度可以为室温，反应时间可为4～5小时。所得粗产品可以未经进一步纯化，直接用于下一步反应。
将化合物(d)在氢氧化锂存在下进行水解得到化合物(e)。该反应优选以四氢呋喃和水为溶剂，反应温度可以为室温，反应时间可为12～16小时。所得粗产品可以未经进一步纯化，直接用于下一步反应。
将化合物(e)酸化得到合物(f)。所述酸化优选用盐酸进行。该反应优选以乙酸乙酯和水为溶剂，反应温度可以为室温，反应时间可为4～5小时。在一个示例性的实施方案中，所得粗产品用半制备液相色谱柱分离(色谱柱：YMC-Pack ODS-AQ 5μm 250L×20；流动相：甲醇-水-四氢呋喃-冰醋酸48:22:30:0.5；检测波长：236nm；流速：8ml/min)，得到纯度大于97％的化合物(f)。
将化合物(f)用氢氧化钠中和得到式(I)化合物。该反应可以以甲醇为溶剂，反应温度可为室温，反应时间可为20～40min。
——在另一方面，本发明还提供了式(I)化合物用于西格列他或其衍生物的原料药或制剂的质量控制的用途。特别地，本发明提供了式(I)化合物作为西格列他或西格列他钠药物中杂质或有关物质检查的对照品或标准品的用途。
相应地，本发明提供了一种西格列他或其衍生物的原料药或制剂的质量控 制方法，包括使用本发明的式(I)化合物作为对照品或标准品用于杂质或有关 物质检查。
此外，本发明还提供了一种检测西格列他或其衍生物药物中杂质或有关物质的含量的方法，所述方法包括采用式(I)化合物
Figure PCTCN2019084921-appb-000008
作为对照品或标准品。
优选地，上述检测方法优选HPLC方法。
在本发明的一个示例性实施方案中，所述HPLC法的条件如下：
色谱柱：C 18柱，Shim-pack VP-ODS 5μm 250L×4.6；
流动相：甲醇-水-四氢呋喃-醋酸40：30：30：0.5；
检测波长：236nm；流速：1.5mL/min)。
以式(I)化合物作对照品，在西格列他钠样品溶液中加入适量式(I)化合物，记录色谱图，确认式(I)化合物就是相对保留值约2.4的杂质。分别记录西格列他钠样品溶液和式(I)化合物标准品溶液的色谱图，采用外标法计算西格列他钠药物中式(I)化合物的含量。
本发明的上述HPLC检测方法的优点是测定结果准确可靠，专属性强，实用性强，可以有效检出上述杂质，且所述杂质与西格列他或其盐之间达到良好分离。
杂质研究是药品研发的重要内容，贯穿于药品研发的始终，直接影响到药物的质量和安全性。为了给西格列他或其衍生物的质量研究提供有关物质对照品，提高西格列他或其衍生物、以及含有西格列他或其衍生物的组合物(包括药物制剂)的质量标准，为安全用药提供重要的指导，本发明研究、合成并鉴定了所述工艺杂质。
具体实施方式
下面结合实施例进一步阐明本发明的内容，但本发明的保护范围并不仅仅局限于这些实施例。本发明所述的百分比除特别注明外，均为重量百分比。说明书中所描述的数值范围，如计量单位或百分比，均是为了提供明白无误的书 面参考。本领域熟练技术人员在实践本专利时，基于本发明的教导和原则，使用在此范围之外或有别于单个数值的温度、浓度、数量等，仍然可以得到预期的结果。
术语与定义：
“衍生物”：在本发明中，西格列他衍生物不仅包括西格列他游离酸，还包括其盐，例如无机盐，例如钠盐，以及其水合物。
“杂质”与“相对保留值”：任何影响药物纯度的物质均称为杂质，一般而言，杂质是指在生产和储存过程中引进或产生的活性药物物质以外的其他化学物质。本领域技术人员公知，可以利用光谱方法和通过其它物理方法识别次要产物、副产物和附加试剂(总称为“杂质”)，于是杂质与色谱中的峰位置(或薄层色谱板上的斑点)有关(Strobel，H.A.；Heineman，W.R.，Chemical Instrumentation：Asystematic Approach，3rd.(Wiley&Sons：New York1989))。此后，杂质可以通过其在所述色谱中的位置被识别出来，色谱中的位置通常用样品注射到柱上和特定的组分经检测器流出之间的时间以分钟计算，被称为“保留时间”。这一时间段基于使用仪器的条件和许多其它因素每天变化。为减轻这样变化对杂质准确鉴别的影响，专业人员使用“相对保留时间”(或相对保留值)来鉴别杂质。杂质的相对保留值是其保留时间除以参考标记物(例如对照品或参比标准品)的保留时间的比值。
“对照品”与“标准品”：制药领域的研发人员都知道，相当纯态的化合物可用作“标准品”或“对照品”。对照品一般系指用于鉴别、检查、含量测定和校正检定仪器性能的标准物质，而标准品系通常指用于生物检定、抗生素或生物药品中含量或效价测定的标准物质。本发明中对二者不做严格区分。标准品可用于定性分析，也用于定量测定未知混合物中待检测化合物的含量。在采用相同技术分析已知浓度的标准品的溶液以及未知混合物时，标准品是“外标物”。化合物在混合物中的含量可以通过比较检测器响应值大小来测定。同样也可参见美国专利6,333,198，其内容在此引作参考。如果补偿检测器对两个化合物的敏感度差异的“响应因子”已经预先确定，则标准品也可以用于测量混合物中另一化合物的含量。为此，将标准物直接加到混合物中，其被称为“内标物”。在不特意加入标准品而是利用称作“标准品加入”的技术使未知混合物包含可检测量的参比标准品时，则标准品可用作内标物。
起始原料和试验仪器：
西格列他钠：按照中国专利申请201410856282.5和201610855107.3的方法制备，纯度>99％。
2-[(2-(4-氟苯甲酰基)苯基)氨基]-3-(4-羟基苯基)丙酸甲酯(化合物(b))：北京乐威泰克医药科技有限公司生产，纯度>96％。
高效液相色谱：仪器：UltiMate3000；色谱柱：C 18柱，Shim-pack VP-ODS 5μm 250L×4.6；检测器：VWD-3100。
半制备液相色谱：仪器：UltiMate3000；色谱柱：YMC-Pack ODS-AQ 5μm 250L×20；检测器：VWD-3100。
质子核磁共振：仪器：Varian INOVA 500；溶剂：DMSO-d 6。
高分辨质谱：仪器：VG ZAB-HS色质联用仪；检测方法：快原子轰击电离(FAB)。
实施例1：式(I)化合物的分离、制备与鉴定
Figure PCTCN2019084921-appb-000009
1.分离
将0.5g西格列他钠(按照中国专利申请201410856282.5和201610855107.3的方法制备)用半制备液相色谱柱分离(色谱柱：YMC-Pack ODS-AQ 5μm 250L×20；流动相：甲醇-水-四氢呋喃-冰醋酸48:22:30:0.5；检测波长：236nm；流速：8ml/min)，收集30～42min的流出液，用1mol/L的碳酸氢钠水溶液中和至pH 7。重复上述分离操作40次，合并每次中和后的液体，真空浓缩除去有机溶剂，用1mol/L稀盐酸中和至pH 5～6，过滤，水洗，收集固体，室温真空干燥24h得5mg化合物(f)，纯度(HPLC)97.8％，LC-MS(m/z)933(M+1)。
在反应瓶中依次加入5mg(0.0054mmol)化合物(f)和1mL甲醇，搅拌溶 解。将0.43mg(0.011mmol)氢氧化钠溶于0.5mL甲醇，滴加到上述溶液中，室温搅拌30min。将反应液滴加到15mL无水乙醚中，过滤，于60℃真空干燥8h得5mg式(I)化合物，纯度(HPLC)98.4％。
结构鉴定：
HRMS(M ++1)(C 58H 45N 3O 8FN 2)计算值(％)：976.2986；实测值(％)：976.2992。
1H NMR(DMSO-d 6)δ2.87(dd,1H,CH 2之一)，3.02(dd,1H,CH 2之一)，3.05(dd,1H,CH 2之一)，3.22(dd,1H,CH 2之一)，3.91(m,1H,CH)，4.06(m,1H,CH)，4.24(t,2H,CH 2)，4.71(t,2H,CH 2)，6.40(m,2H,Ar-H)，6.58(d,2H,Ar-H)，6.65(d,1H,Ar-H)，6.69(d,1H,Ar-H)，6.90(d,4H,Ar-H)，7.00(d,2H,Ar-H)，7.17(t,2H,Ar-H)，7.27(m,8H,Ar-H)，7.42(m,2H,Ar-H)，7.47(m,2H,Ar-H)，7.57(m,2H,Ar-H)，7.62(d,2H,Ar-H)，8.11(d,2H,Ar-H)，8.60(d,1H,NH)，8.81(dd,1H,NH)。
2.制备
在反应瓶中依次加入400mL N,N-二甲基甲酰胺、23.76g(40mmol)2-(2-(4-氟苯甲酰基)苯基氨基)-3-(4-(2-(9H-咔唑-9-基)乙氧基)苯基)丙酸钠(即化合物(a))、19.65g(50mmol)2-[(2-(4-氟苯甲酰基)苯基)氨基]-3-(4-羟基苯基)丙酸甲酯(即化合物(b))和16.25g(50mmol)碳酸铯，于120℃反应25h，过滤，将滤液加入4000mL饱和氯化钠溶液中，过滤，水洗，收集固体，将所得固体真空干燥得化合物(c)粗产品，纯度(HPLC)12.2％，LC-MS(m/z)969(M+1)。所得产品未经进一步纯化，直接用于下一步反应。
在反应瓶中依次加入400mL乙酸乙酯和上述化合物(c)，搅拌30min，加入230mL水，滴加150mL 3mol/L稀盐酸，搅拌4h，分离有机相，真空浓缩得化合物(d)粗产品，所得产品未经进一步纯化，直接用于下一步反应。
将上述化合物(d)溶于350mL四氢呋喃，加入48mL 12mol/L氢氧化锂水溶液，室温搅拌反应14h，分离有机相，真空浓缩得化合物(e)粗产品，所得产品未经进一步纯化，直接用于下一步反应。
在反应瓶中依次加入480mL乙酸乙酯和上述化合物(e)，搅拌30min，加入230mL水，滴加150mL 3mol/L稀盐酸，搅拌4h，分离有机相，真空浓缩得化合物(f)粗产品，纯度(HPLC)18.9％，LC-MS(m/z)933(M+1)。
将0.5g化合物(d)的粗产品用半制备液相色谱柱分离(色谱柱：YMC-Pack ODS-AQ 5μm 250L×20；流动相：甲醇-水-四氢呋喃-冰醋酸48:22:30:0.5；检测波长：236nm；流速：8ml/min)，收集30～42min的流出液，用1mol/L的碳酸氢钠水溶液中和至pH 7。重复上述分离操作5次，合并每次中和后的液体，真空浓缩除去有机溶剂，用1mol/L稀盐酸中和至pH 5～6，过滤，水洗，收集固体，室温真空干燥24h得230mg化合物(f)，纯度(HPLC)98.0％，LC-MS(m/z)933(M+1)。
在反应瓶中依次加入230mg(0.247mmol)化合物(f)和5mL甲醇，搅拌溶解。将19.76mg(0.494mmol)氢氧化钠溶于1mL甲醇，滴加到上述溶液中，室温搅拌30min。将反应液滴加到45mL无水乙醚中，过滤，于60℃真空干燥8h得236mg式(I)化合物，纯度(HPLC)98.6％。
经结构鉴定表明，所制备的化合物与上述分离得到的化合物的HRMS和 1HNMR均相符。
实施例2：式(I)化合物用作西格列他钠药物中杂质含量测定的对照品
一、测试条件
仪器：UltiMate3000；色谱柱：C 18柱，Shim-pack VP-ODS 5μm 250L×4.6；检测器：VWD-3100，流动相：甲醇-水-四氢呋喃-醋酸40：30：30：0.5；检测波长：236nm；流速：1.5mL/min。
二、测试方法
(1)取西格列他钠样品约10mg，精密称定，置于100ml容量瓶中，用溶剂甲醇-水-四氢呋喃(40：30：30)溶解并稀释至刻度，摇匀，作为供试品溶液A，精密吸取20μl，注入液相色谱仪，记录色谱图。
(2)取式(I)化合物约10mg，精密称定，置于100ml容量瓶中，用溶剂 甲醇-水-四氢呋喃(40：30：30)溶解并稀释至刻度，摇匀，精密移取1mL置于100ml容量瓶中，用溶剂甲醇-水-四氢呋喃(40：30：30)溶解并稀释至刻度，摇匀，作为供试品溶液B，精密吸取20μl，注入液相色谱仪，记录色谱图。
(3)分别移取0.5mL供试液A和0.5mL供试液B，摇匀，作为供试品溶液C，精密吸取20μl，注入液相色谱仪，记录色谱图。
三、测试结果
在供试品溶液A的色谱图中，西格列他钠的出峰时间为15.1min，同时，在35.8min处有一杂质峰，相对面积为0.05％。
在供试品溶液B的色谱图中，式(I)化合物的出峰时间35.8min。
在供试品溶液C的色谱图中，西格列他钠的出峰时间为15.1min，同时，在35.8min处有一杂质峰，相对面积为0.7％。
结论：式(I)化合物被确认是西格列他钠样品中相对保留值约2.4的杂质。
实施例3：式(I)化合物用作西格列他钠药物中杂质含量测定的标准品
一、测试条件
仪器：UltiMate3000；色谱柱：C 18柱，Shim-pack VP-ODS 5μm 250L×4.6；检测器：VWD-3100，流动相：甲醇-水-四氢呋喃-醋酸40：30：30：0.5；检测波长：236nm；流速：1.5mL/min。
二、测试方法
取西格列他钠样品约10mg，精密称定，置于100ml容量瓶中，用溶剂甲醇-水-四氢呋喃(40：30：30)溶解并稀释至刻度，摇匀，作为供试品溶液。另取式(I)化合物标准品约10mg，精密称定，置于100ml容量瓶中，用溶剂甲醇-水-四氢呋喃(40：30：30)溶解并稀释至刻度，摇匀，精密移取1mL置于1000ml容量瓶中，用溶剂甲醇-水-四氢呋喃(40：30：30)溶解并稀释至刻度，摇匀，作为对照品溶液。分别精密吸取上述两种溶液各20μl，注入液相色谱仪，记录色谱图。按外标法以峰面积计算西格列他钠样品中式(I)化合物的含量。
三、测试结果
共测定了三批西格列他钠样品，测定结果见表1。
表1西格列他钠样品中式(I)化合物的含量
西格列他钠样品 式(I)化合物含量(％)
20160817批 0.07
20160909批 0.08
20160923批 0.08
。

Claims (11)

  1. 式(I)化合物：
    Figure PCTCN2019084921-appb-100001
  2. 权利要求1所述的式(I)化合物的制备方法，包括使式(f)化合物与氢氧化钠反应：
    Figure PCTCN2019084921-appb-100002
  3. 如权利要求2所述的式(I)化合物的制备方法，其中式(f)化合物是由式(e)化合物酸化得到：
    Figure PCTCN2019084921-appb-100003
  4. 如权利要求3所述的式(I)化合物的制备方法，其中式(e)化合物由式(d)化合物与氢氧化锂反应得到：
    Figure PCTCN2019084921-appb-100004
  5. 如权利要求4所述的式(I)化合物的制备方法，其中式(d)化合物由式(c)化合物酸化得到：
    Figure PCTCN2019084921-appb-100005
  6. 如权利要求5所述的式(I)化合物的制备方法，其中式(c)化合物由式(a)化合物与式(b)化合物反应得到：
    Figure PCTCN2019084921-appb-100006
  7. 权利要求1所述的式(I)化合物用于西格列他或其衍生物的原料药或制剂的质量控制的用途。
  8. 权利要求7所述的用途，其中所述式(I)化合物用作西格列他或其衍生物药物中杂质或有关物质检查的对照品或标准品。
  9. 一种检测西格列他或其衍生物药物中杂质或有关物质的含量的方法，所述方法包括采用式(I)化合物
    Figure PCTCN2019084921-appb-100007
    作为对照品或标准品。
  10. 权利要求9所述的检测方法，所述方法为HPLC法，其中式(I)化合物作为外标使用，测定条件为：色谱柱：C 18柱；流动相：甲醇-水-四氢呋喃-醋酸40：30：30：0.5；检测波长：236nm。
  11. 西格列他或其衍生物合成工艺中控制质量的方法，包括采用式(I)化合物
    Figure PCTCN2019084921-appb-100008
    用于杂质或有关物质的含量检测或控制。
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RU2020139828A RU2759745C1 (ru) 2018-05-09 2019-04-29 Производное фениламинопропионата натрия, способ его получения и его применение
BR112020022543-6A BR112020022543A2 (pt) 2018-05-09 2019-04-29 derivado de fenil amino propionato de sódio, método de preparação para o mesmo e aplicação do mesmo
US17/053,364 US11981638B2 (en) 2018-05-09 2019-04-29 Phenyl amino sodium propionate derivative, preparation method therefor and application thereof
AU2019267849A AU2019267849B2 (en) 2018-05-09 2019-04-29 Phenyl amino sodium propionate derivative, preparation method therefor and application thereof
EP19800412.9A EP3792249A4 (en) 2018-05-09 2019-04-29 PHENYLAMINODIUM PROPIONATE DERIVATIVE, METHOD OF PRODUCTION THEREOF AND USE THEREOF

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JP2021523897A (ja) 2021-09-09
JP7047136B2 (ja) 2022-04-04
US11981638B2 (en) 2024-05-14
AU2019267849A1 (en) 2020-11-26
KR20210003254A (ko) 2021-01-11
TW201946899A (zh) 2019-12-16
MX2020011763A (es) 2021-02-15
KR102512807B1 (ko) 2023-03-23
BR112020022543A2 (pt) 2021-02-02
EP3792249A1 (en) 2021-03-17
CN110467560A (zh) 2019-11-19
RU2759745C1 (ru) 2021-11-17
EP3792249A4 (en) 2022-01-19

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