WO2021063347A1 - 化合物及其制备方法和用途 - Google Patents

化合物及其制备方法和用途 Download PDF

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WO2021063347A1
WO2021063347A1 PCT/CN2020/118775 CN2020118775W WO2021063347A1 WO 2021063347 A1 WO2021063347 A1 WO 2021063347A1 CN 2020118775 W CN2020118775 W CN 2020118775W WO 2021063347 A1 WO2021063347 A1 WO 2021063347A1
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solution
add
reaction
dichloromethane
compound
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PCT/CN2020/118775
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周凤梅
谭文娟
唐倩倩
王进荣
张睿
余飞
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山东绿叶制药有限公司
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Priority to JP2022518720A priority Critical patent/JP2022550299A/ja
Priority to EP20872689.3A priority patent/EP4039678A4/en
Priority to CN202080065958.2A priority patent/CN114423746A/zh
Priority to US17/763,636 priority patent/US20220340539A1/en
Publication of WO2021063347A1 publication Critical patent/WO2021063347A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
    • C07D333/20—Radicals substituted by singly bound hetero atoms other than halogen by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/08—Hydrogen atoms or radicals containing only hydrogen and carbon atoms
    • C07D333/10—Thiophene
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/017—Esters of hydroxy compounds having the esterified hydroxy group bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/02—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen
    • C07C69/22—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen having three or more carbon atoms in the acid moiety
    • C07C69/24—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen having three or more carbon atoms in the acid moiety esterified with monohydroxylic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline

Definitions

  • Parkinson’s disease is a common degenerative disease of the nervous system in middle-aged and elderly people.
  • Dopamine receptor agonists are an important class of drugs for the treatment of Parkinson’s disease.
  • Dopamine receptor agonists currently in clinical use include dopamine agonist drugs such as rotigo Ting, pramipexole, ropinirole, pergolide, cabergoline, etc.
  • Rotigotine behenate which has been disclosed in WO2018014277, is a twenty-two carbon saturated long-chain ester of rotigotine, which has the effect of maintaining long effective blood concentration, high bioavailability, and long-term stable release.
  • the patent application discloses that the saturated or unsaturated esters of rotigotine long-chain esters with more or less than 22 carbons do not have the above-mentioned good effects. Its structure is shown below, and is used for early secondary Parkinson's disease And adjuvant treatment of advanced Parkinson's disease.
  • Impurities in drugs refer to substances that have no therapeutic effect or affect the stability and efficacy of the drug, and are even harmful to human health.
  • the adverse reactions caused by the drug in clinical use are sometimes closely related to the impurities in the drug. Therefore, a standardized study of impurities will directly affect the quality and safety of marketed drugs.
  • the purpose of the present invention is to provide new compounds and their preparation methods and uses.
  • Compound I is an S configuration compound.
  • Compound I can be prepared by the following method, weighing (S)-6-(2-(thiophen-2-yl)ethylamino)-5,6,7,8-tetralin-1-ol hydrobromide , Triethylamine, dichloromethane, and stir at room temperature; add di-tert-butyl dicarbonate and stir overnight at room temperature.
  • Compound II is an S configuration compound.
  • Compound II can be prepared by the following method: Weigh (S)-6-(propylamino)-5,6,7,8-tetralin-1-ol hydrobromide, triethylamine, dichloromethane, Stir at room temperature; add di-tert-butyl dicarbonate dropwise, stir for 4h, distill off the solvent under reduced pressure, and column chromatography to obtain Intermediate I; Weigh Intermediate I, behenic acid, DMAP, EDCI, and toluene, stir evenly, and react Complete; add NH 4 Cl solution and stir, add diatomaceous earth for suction filtration, let stand overnight, wash once with NH 4 Cl solution, add water and stir, stand still to remove the water phase; evaporate the organic phase solvent and perform column chromatography to obtain the middle Body II; Weigh Intermediate II, dissolve in dichloromethane, add N-methylmorpholine, stir evenly, then add TMSI, stir at room temperature for reaction; distill off the organic solvent under reduced pressure, add petroleum ether, stir, filter with suction
  • the NH 4 Cl solution added in the above method is a 20% NH 4 Cl solution.
  • Compound III can be prepared by the following method: adding 5-hydroxy-1-tetralone, imidazole, and TBS-Cl to DMF to form a light-brown yellow solution, and the reaction is complete; pour the reaction solution into water to separate out solids, and filter After rinsing the filter cake with water, dissolve it in dichloromethane, rinse with water, add petroleum ether after drying, and pass through a silica gel pad to obtain 5-(tert-butyldimethylsiloxy)-3,4-di Hydronaphthalene-1(2H)-ketone was dissolved in tetrahydrofuran, methanol was added, sodium borohydride was added in batches, the reaction was complete; the reaction solution was concentrated, the organic solvent was removed, and the product was extracted with ethyl acetate to obtain a pale yellow oil.
  • dichloromethane Dissolve it in dichloromethane, add 5-(tert-butyldimethylsilyloxy)-1,2,3,4-tetrahydronaphthalene-1-ol in dichloromethane solution and triethylamine
  • dichloromethane control the temperature, add methyl yellow acyl chloride-600mL dichloromethane dropwise, concentrate the reaction solution, add water to disperse, extract with tert-butyl methyl ether, dry and concentrate, and silica gel column chromatography to obtain tert-butyl- (7,8-Dihydronaphthalene-1-yloxy)dimethylsilane; add it to methanol, add cesium fluoride, and react under nitrogen protection. The reaction is complete.
  • the reaction solution is concentrated, evaporated to dryness and extracted with DCM
  • the compound III is 7,8-dihydronaphthalene-1-yl behenate.
  • the dichloromethane solution of 5-(tert-butyldimethylsilyloxy)-1,2,3,4-tetrahydronaphthalene-1-ol and triethylamine are added to the dichloromethane In, the temperature control is less than 20°C.
  • Any compound of compound I-III can be used as a reference substance for qualitative or quantitative determination of impurities in rotigotine behenate or its preparations. Specifically, it can be determined by high performance liquid chromatography: dissolve any compound of compound I-III in a solution to prepare a reference solution, and dissolve rotigotine behenate or its preparation in a solution to prepare a test product The solution is analyzed by liquid chromatography to obtain the liquid chromatograms of the reference solution and the test solution.
  • DMAP 4-dimethylaminopyridine
  • EDCI 1-ethyl-3 (3-dimethylpropylamine) carbodiimide
  • TMSI trimethyl iodosilane
  • TBS-Cl Tert-butyldimethylchlorosilane
  • DMF N,N-dimethylformamide
  • DCM dichloromethane
  • PE petroleum ether
  • TLC thin layer chromatography
  • HPLC high performance liquid chromatography
  • UPLC ultra high performance Liquid chromatography.
  • the compound has a purity of at least 80%, preferably a purity of at least 90%, more preferably a purity of at least 95%, and most preferably a purity of at least 99%.
  • the present invention also provides a rotigotine behenate or its preparation.
  • the rotigotine behenate or its preparation contains less than 0.5% of any compound of compound I-III by weight.
  • Figure 2-1 is the UPLC of (S)-6-(2-(2-thienyl)ethyl)amino)-5,6,7,8-tetrahydronaphthalene-1-yl behenate reference substance Chromatogram.
  • Figure 2-2 shows the compound of rotigotine behenate and (S)-6-(2-(2-thienyl)ethyl)amino)-5,6,7,8-tetrahydronaphthalene-1- UPLC chromatogram of the peak time comparison of the test product of behenyl behenate.
  • Figure 3 is a high-resolution mass spectrum of (S)-6-(propylamino)-5,6,7,8-tetrahydronaphthalene-1-yl behenate.
  • Figure 4-1 is the UPLC chromatogram of (S)-6-(propylamino)-5,6,7,8-tetrahydronaphthalene-1-yl behenate reference substance.
  • Figure 5 is a high-resolution mass spectrum of 7,8-dihydronaphthalene-1-yl behenate.
  • Figure 6-1 is the UPLC chromatogram of 7,8-dihydronaphthalene-1-yl behenate reference substance.
  • Figure 6-2 is the UPLC chromatogram of the peak time comparison between the rotigotine behenate compound (peak No. 2) and 7,8-dihydronaphthalene-1-yl behenate (peak No. 1).
  • octadecyl-bonded silica gel as the filler, column (XBridge BEH C18 2.1*100mm, 1.7 ⁇ m, Waters); use a pH9.0 20mmol/L ammonium acetate solution (take 1.54g of ammonium acetate and dilute with water to 1000ml , Adjust the pH value of ammonia to 9.0) as mobile phase A, acetonitrile as mobile phase B, isopropanol as mobile phase C, gradient elution according to the following table; column temperature 45°C; flow rate: 0.32ml/min, detection wavelength 235nm, the number of theoretical plates based on rotigotine behenate should not be less than 5000. Take 3 ⁇ l each of the reference solution or the test solution and inject it into the ultra-high performance liquid chromatograph.
  • Figure 2-1 is a separate injection of (S)-6-(2-(2-thienyl)ethyl)amino)-5,6,7,8-tetrahydronaphthalene-1-yl behenate
  • the UPLC chromatogram, attached figure 2-2 shows the injection of rotigotine behenate and the addition of (S)-6-(2-(2-thienyl)ethyl)amino)-5,6,7,
  • the UPLC chromatogram of 8-tetrahydronaphthalene-1-yl behenate compared with peak time.
  • Figure 7 shows the comparison of (S)-6-(2-(2-thiophene) in the rotigotine behenate product.
  • Test Example 2 (S)-6-(2-(2-Thienyl)ethyl)amino)-5,6,7,8-tetrahydronaphthalene-1-yl behenate is used in the determination of rotigotine Application of microsphere preparation as reference substance in impurity content
  • octadecyl-bonded silica gel as the filler, column (XBridge BEH C18 2.1*100mm, 1.7 ⁇ m, Waters); use a pH9.0 20mmol/L ammonium acetate solution (take 1.54g of ammonium acetate and dilute with water to 1000ml , Adjust the pH value of ammonia to 9.0) as mobile phase A, acetonitrile as mobile phase B, isopropanol as mobile phase C, gradient elution according to the following table; column temperature 45°C; flow rate: 0.32ml/min, detection wavelength 235nm, the number of theoretical plates based on rotigotine behenate should not be less than 5000. Take 3 ⁇ l each of the reference solution or the test solution and inject it into the ultra-high performance liquid chromatograph.
  • Test Example 3 (S)-6-(propylamino)-5,6,7,8-tetrahydronaphthalene-1-yl behenate was used as a control in determining the impurity content of rotigotine behenate compound Product application
  • octadecyl-bonded silica gel as the filler, column (XBridge BEH C18 2.1*100mm, 1.7 ⁇ m, Waters); use a pH9.0 20mmol/L ammonium acetate solution (take 1.54g of ammonium acetate and dilute with water to 1000ml , Adjust the pH value of ammonia to 9.0) as mobile phase A, acetonitrile as mobile phase B, isopropanol as mobile phase C, gradient elution according to the following table; column temperature 45°C; flow rate: 0.32ml/min detection, measurement wavelength For 220nm, the number of theoretical plates based on rotigotine behenate should not be less than 5000. Take 3 ⁇ l each of the reference solution or the test solution and inject it into the ultra-high performance liquid chromatograph.
  • Figure 4-1 is the UPLC chromatogram of (S)-6-(propylamino)-5,6,7,8-tetrahydronaphthalene-1-yl behenate injected separately, Figure 4-2 It is the comparison between the injection of rotigotine behenate and the addition of (S)-6-(propylamino)-5,6,7,8-tetrahydronaphthalene-1-yl behenate UPLC
  • the chromatogram, Figure 8 is a comparison of (S)-6-(propylamino)-5,6,7,8-tetrahydronaphthalene-1-yl behenate (1 No.
  • octadecyl-bonded silica gel as the filler, column (XBridge BEH C18 2.1*100mm, 1.7 ⁇ m, Waters); use a pH9.0 20mmol/L ammonium acetate solution (take 1.54g of ammonium acetate and dilute with water to 1000ml , Adjust the pH value of ammonia to 9.0) as mobile phase A, acetonitrile as mobile phase B, isopropanol as mobile phase C, perform gradient elution according to the following table, column temperature 45°C, flow rate: 0.32ml/min, measure wavelength For 220nm, the number of theoretical plates based on rotigotine behenate should not be less than 5000. Take 3 ⁇ l each of the reference solution or the test solution and inject it into the ultra-high performance liquid chromatograph.
  • the temperature of the ice water was controlled at 0°C, sodium borohydride was added in batches, and a total of 27 g sodium borohydride (maximum temperature 22°C) was added after 1 h, and the reaction was complete.
  • the reaction solution was concentrated, and the organic solvent was removed. After the organic solvent was removed, the product was extracted with 2*400 mL of ethyl acetate, dried and evaporated to dryness to obtain 327 g of light yellow oil, which was calculated based on 170 g of product and dissolved in dichloromethane.
  • the NMR spectrum is assigned in Table 3, and the high-resolution mass spectrum is shown in Figure 5.
  • Figure 6-1 is the UPLC chromatogram of the 7,8-dihydronaphthalene-1-yl behenate reference substance injected alone
  • Figure 6-2 is the injection of rotigotine behenate and 7 , 8-dihydronaphthalene-1-yl behenate, the UPLC chromatogram of the peak time.
  • Figure 9 shows the comparison of 7,8-dihydronaphthalene-1-yl dihydronaphthalene in the rotigotine behenate product.
  • UPLC chromatogram of lauric acid ester peak No. 3
  • rotigotine behenate sustained-release microspheres (approximately equivalent to 10mg of rotigotine behenate), accurately weigh it, and place it in a 10ml measuring flask, add 10ml of tetrahydrofuran to dissolve it, and use it as the test solution ; Accurately weigh an appropriate amount of 7,8-dihydronaphthalene-1-yl behenate, and dilute quantitatively with tetrahydrofuran to make a solution of about 0.005mg per 1ml as a reference solution.
  • octadecyl-bonded silica gel as the filler, column (XBridge BEH C18 2.1*100mm, 1.7 ⁇ m, Waters); use a pH9.0 20mmol/L ammonium acetate solution (take 1.54g of ammonium acetate and dilute with water to 1000ml , Adjust the pH value of ammonia to 9.0) as mobile phase A, acetonitrile as mobile phase B, isopropanol as mobile phase C, gradient elution according to the following table; column temperature 45°C; flow rate: 0.32ml/min, detection wavelength 235nm, the number of theoretical plates based on rotigotine behenate should not be less than 5000. Take 3 ⁇ l each of the reference solution and the test solution and inject them into the ultra-high performance liquid chromatograph.
  • the weight percentage of 7,8-dihydronaphthalene-1-yl behenate in the three batches of rotigotine behenate microspheres is less than 0.5%.

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Abstract

提供罗替戈汀山嵛酸酯杂质新化合物，和含有重量百分比少于0.5％所述杂质化合物的罗替戈汀山嵛酸酯或其制剂，以及所述杂质化合物在罗替戈汀山嵛酸酯或其制剂的杂质检测中作为对照品的应用。

Description

化合物及其制备方法和用途 技术领域
本发明属于医药领域，具体涉及新的化合物及其制备方法和其应用。
背景技术
帕金森症是一种常见的中老年神经系统变性疾病，多巴胺受体激动剂为治疗帕金森症的一类重要药物，目前临床使用的多巴胺受体激动剂有多巴胺激动剂类药物如罗替戈汀、普拉克索、罗匹尼罗、培高利特、卡麦角林等。
罗替戈汀山嵛酸酯，在WO2018014277中已公开，是罗替戈汀二十二个碳饱和长链酯，具备有效血药浓度维持时间长、生物利用度高和长效稳定释放的效果，专利申请披露罗替戈汀长链酯多于或少于二十二个碳的饱和或不饱和酯均不具备上述良好效果，其结构如下所示，用于早期继发性帕金森氏病和晚期帕金森氏病的辅助治疗。
Figure PCTCN2020118775-appb-000001
药物的杂质是指药物中存在的无治疗作用或影响药物稳定性和疗效，甚至对人体健康有害的物质。杂质的来源，主要有两个：一是由生产过程中引入，包括未反应的起始原料、起始原料中包含的杂质的化学衍生物、合成副产物以及降解产物；二是在贮藏过程中受外界条件的影响，引起药物理化性质发生变化而产生。药品在临床使用中产生的不良反应除了与药品本身的药理活性有关外，有时与药品中存在的杂质也有很大关系。所以规范地进行杂质的研究，将直接关系到上市药品的质量及安全性。
通过了解杂质的化学结构和合成途径，以及通过鉴别影响终产物中杂质含量的参数，能够极大增强对药用活性物质的杂质的管理。对药用活性物质的杂质监控要求建立质量标准，确立合适的分离与检测条件，使杂质能得到很好控制；在质量标准中，目前普遍采用的杂质检测方法主要为液相色谱法等。
发明内容
本发明的目的在于提供新的化合物及其制备方法和用途。
本发明提供的具体化合物如下：
化合物Ⅰ，化学名称：(S)-6-(2-(2-噻吩基)乙基)氨基)-5,6,7,8-四氢萘-1-基二十二酸酯，具有式Ⅰ结构式：
Figure PCTCN2020118775-appb-000002
化合物Ⅰ是S构型化合物。
化合物Ⅰ可以采用以下方法制备，称量(S)-6-(2-(噻吩-2-基)乙胺基)-5，6，7，8-四氢萘-1-醇氢溴酸盐、三乙胺、二氯甲烷，室温搅拌；加二碳酸二叔丁基酯室温搅拌过夜，反应完全将溶剂减压蒸除，硅胶搅拌样品，柱层析得中间体Ⅰ；称取中间体Ⅰ、山嵛酸、DMAP、EDCI，加入甲苯，搅拌均匀，反应完全，加入NH 4Cl溶液搅拌，加硅藻土抽滤，静置过夜，NH 4Cl溶液洗涤一次，有机相加水搅拌，静置，去除水相；蒸除有机相溶剂后进行柱层析，得中间体Ⅱ；称取中间体Ⅱ，二氯甲烷溶解，加入N-甲基吗啉搅拌均匀后加入TMSI，室温搅拌反应完全；将有机溶剂减压蒸除，加入石油醚搅拌，抽滤，母液浓缩蒸干，加入二氯甲烷，水洗涤两遍；有机相浓缩蒸干，干燥得(S)-6-(2-(2-噻吩基)乙基)氨基)-5,6,7,8-四氢萘-1-基二十二酸酯。
上述方法中加入NH 4Cl溶液为20％NH 4Cl溶液。
上述方法中所述称取中间体Ⅰ、山嵛酸、DMAP、EDCI、甲苯，搅拌反应是在40℃完成。
上述方法中所述添加二碳酸二叔丁基酯为缓慢滴加。
化合物Ⅱ，化学名称：(S)-6-(丙胺基)-5,6,7,8-四氢萘-1-基二十二酸酯，具有式II结构式：
Figure PCTCN2020118775-appb-000003
化合物II是S构型化合物。
化合物II可以采用以下方法制备：称取(S)-6-(丙基氨基)-5，6，7，8-四氢萘-1-醇氢溴酸 盐、三乙胺、二氯甲烷，室温搅拌；滴加二碳酸二叔丁基酯，搅拌4h，溶剂减压蒸除，柱层析得中间体Ⅰ；称取中间体Ⅰ、山嵛酸、DMAP、EDCI、甲苯，搅拌均匀，反应完全；加入NH 4Cl溶液搅拌，加硅藻土抽滤，静置过夜，NH 4Cl溶液洗涤一次，加水搅拌，静置，去除水相；蒸除有机相溶剂后进行柱层析，得中间体II；称取中间体II，二氯甲烷溶解，加入N-甲基吗啉，搅拌均匀，后加入TMSI，室温搅拌反应；将有机溶剂减压蒸除，加入石油醚搅拌，抽滤，滤饼丢弃；母液浓缩蒸干，加入二氯甲烷，水洗涤二氯甲烷相两遍；有机相浓缩蒸干,干燥得(S)-6-(丙胺基)-5,6,7,8-四氢萘-1-基二十二酸酯。
上述方法中加入NH 4Cl溶液为20％NH 4Cl溶液。
上述方法中所述称取中间体I、山嵛酸、DMAP、EDCI、甲苯，搅拌反应是在40℃完成。
上述方法中所述添加二碳酸二叔丁基酯为缓慢滴加。
化合物III，化学名称：化合物7，8-双氢萘-1-基二十二酸酯，具有式III结构式：
Figure PCTCN2020118775-appb-000004
化合物III可以采用以下方法制备：将5-羟基-1-四氢萘酮、咪唑、TBS-Cl加入到DMF中，形成浅棕黄色溶液，反应完全；将反应液倒入水中，析出固体，过滤，滤饼用水淋洗后，溶于二氯甲烷中，用水淋洗，干燥后加入石油醚，过硅胶垫，得5-(叔丁基二甲基甲硅烷氧基)-3，4-二氢萘-1(2H)-酮，将其溶于四氢呋喃中，加入甲醇，分批加入硼氢化钠，反应完全；浓缩反应液，除去有机溶剂，用乙酸乙酯萃取产品得到浅黄色油状物，将其溶于二氯甲烷中，将5-(叔丁基二甲基甲硅烷氧基)-1，2，3，4-四氢萘-1-醇的二氯甲烷溶液、三乙胺加入到二氯甲烷中，控温，滴加甲基黄酰氯——600mL二氯甲烷，浓缩反应液，加入水分散，用叔丁基甲醚萃取，干燥后浓缩，硅胶柱层析，得到叔丁基-(7，8-二氢萘-1-基氧基)二甲基硅烷；将其加入到甲醇中，加入氟化铯，氮气保护下反应，反应完全，浓缩反应液，蒸干后用DCM萃取产品，再蒸干DCM，加入碱性氧化铝搅拌样品，过碱性氧化铝柱子(PE：DCM＝5：1)得7,8-双氢萘酚，将其加入到二氯甲烷中，加入三乙胺，加二十二酰氯的二氯甲烷溶液,反应完全，向反应液中加入水，搅拌，过滤。得化合物III即7，8-双氢萘-1-基二十二酸酯。
上述方法中所述氮气保护下反应是加热到60℃反应。
上述方法中所述将5-(叔丁基二甲基甲硅烷氧基)-1，2，3，4-四氢萘-1-醇的二氯甲烷溶液、三乙胺加入到二氯甲烷中，控温小于20℃。
化合物I-III任一化合物可以作为罗替戈汀山嵛酸酯或其制剂的杂质定性或定量测定的对照品。具体可以采用高效液相色谱法进行测定：将化合物I-III任一化合物溶解在溶液中制备为对照品溶液，将罗替戈汀山嵛酸酯或其制剂溶解在溶液中制备为供试品溶液，采用液相色谱法分析，获得对照品溶液、供试品溶液的液相色谱图，对比对照品溶液、供试品溶液的液相色谱图中的出峰时间，确定供试品溶液含有化合物I-III任一化合物，对比对照品溶液及供试品溶液的液相色谱图中化合物I-III任一化合物的峰面积，按外标法测定出罗替戈汀山嵛酸酯或其制剂中化合物I-III任一化合物的重量百分比。
所述缩写对应的中文名称，DMAP：4-二甲氨基吡啶；EDCI：1-乙基-3(3-二甲基丙胺)碳二亚胺；TMSI：三甲基碘硅烷；TBS-Cl：叔丁基二甲基氯硅烷；DMF：N,N-二甲基甲酰胺；DCM：二氯甲烷；PE：石油醚；TLC：薄层色谱；HPLC：高效液相色谱法；UPLC:超高效液相色谱法。
本发明的化合物I-III任一化合物用HPLC或UPLC测定时，该化合物纯度为至少80％，优选纯度为至少90％，更优选纯度为至少95％，最优选纯度为至少99％。
本发明同时提供一种罗替戈汀山嵛酸酯或其制剂，所述罗替戈汀山嵛酸酯或其制剂中含有重量百分比少于0.5％化合物I-III任一化合物。
附图说明
图1是(S)-6-(2-(2-噻吩基)乙基)氨基)-5,6,7,8-四氢萘-1-基二十二酸酯的高分辨质谱图。
图2-1是(S)-6-(2-(2-噻吩基)乙基)氨基)-5,6,7,8-四氢萘-1-基二十二酸酯对照品的UPLC色谱图。
图2-2是罗替戈汀山嵛酸酯化合物与(S)-6-(2-(2-噻吩基)乙基)氨基)-5,6,7,8-四氢萘-1-基二十二酸酯的供试品的对比出峰时间UPLC色谱图。
图3是(S)-6-(丙胺基)-5,6,7,8-四氢萘-1-基二十二酸酯的高分辨质谱图。
图4-1是(S)-6-(丙胺基)-5,6,7,8-四氢萘-1-基二十二酸酯对照品的UPLC色谱图。
图4-2是罗替戈汀山嵛酸酯化合物(2号峰)与(S)-6-(丙胺基)-5,6,7,8-四氢萘-1-基二十二酸酯(1号峰)的对比出峰时间UPLC色谱图。
图5是7，8-双氢萘-1-基二十二酸酯的高分辨质谱图。
图6-1是7，8-双氢萘-1-基二十二酸酯对照品的UPLC色谱图。
图6-2是罗替戈汀山嵛酸酯化合物(2号峰)与7，8-双氢萘-1-基二十二酸酯(1号峰)的对比出峰时间UPLC色谱图。
图7罗替戈汀山嵛酸酯中检测(S)-6-(2-(2-噻吩基)乙基)氨基)-5,6,7,8-四氢萘-1-基二十二酸酯(3号峰)UPLC色谱图
图8罗替戈汀山嵛酸酯中检测(S)-6-(丙胺基)-5,6,7,8-四氢萘-1-基二十二酸酯(1号峰)UPLC色谱图
图9罗替戈汀山嵛酸酯中检测7，8-双氢萘-1-基二十二酸酯(3号峰)UPLC色谱图
具体实施方式
以下通过实施例和试验例来进一步说明本发明，但不以任何方式限制本发明。
实施例1(S)-6-(2-(2-噻吩基)乙基)氨基)-5,6,7,8-四氢萘-1-基二十二酸酯的制备
500ml单口瓶中，加入(S)-6-(2-(噻吩-2-基)乙胺基)-5，6，7，8-四氢萘-1-醇氢溴酸盐20.98g，三乙胺14.98g，二氯甲烷210ml，室温搅拌；
缓慢滴加二碳酸二叔丁基酯15.51g，滴毕室温搅拌过夜17h，TLC检测，原料反应完全；
将溶剂减压蒸除，硅胶拌样，柱层析得10.66g中间体I.
称取中间体I 14.0g，山嵛酸14.05g，DMAP 5.45g，EDCI 9.35g，210ml甲苯加入1000ml单口瓶内，搅拌均匀，40℃反应3h，TLC检测反应完全；
加入210ml 20％的NH 4Cl溶液搅拌0.5h，加硅藻土抽滤，静置过夜，有机相用190ml 20％的NH 4Cl溶液洗涤一次，有机相加水搅拌0.5h，静置1h，除去水相；
蒸除有机相溶剂，柱层析，得中间体225.4g。
500ml三口瓶中加入中间体218.8g，二氯甲烷190ml溶解，N-甲基吗啉21.8g，搅拌均匀，后加入TMSI 21.6g，室温搅拌反应2h，TLC检测，反应完全；
将有机溶剂减压蒸除(60℃,0.5h)，加入200ml石油醚搅拌15min,抽滤，滤饼丢弃；
母液浓缩蒸干，加入二氯甲烷150ml,水150ml洗涤二氯甲烷两遍；
有机相浓缩蒸干，40℃鼓风干燥2h得(S)-6-(2-(2-噻吩基)乙基)氨基)-5,6,7,8-四氢萘-1-基二十二酸酯14.1g。
核磁共振图谱归属见表1，高分辨质谱图见附图1。
表1(S)-6-(2-(2-噻吩基)乙基)氨基)-5,6,7,8-四氢萘-1-基二十二酸酯核磁共振图谱归属
NO 1H NMR 13C NMR NO 1H NMR 13C NMR
1 / 148.92 1” / 172.06
2 6.936 119.29 2” 2.598 36.70
3 7.117 126.98 3” 1.424 25.09
4 6.965 123.58 4” 1.283 28.94
5 3.017,2.953 34.229 5” 1.283 29.21
6 2.735 52.75 6” 1.283 29.67
7 1.555,1.770 29.71 7” 1.283 29.67
8 2.565,2.614 22.38 8” 1.283 29.67
9 / 128.63 9” 1.283 29.67
10 / 137.38 10” 1.283 29.67
1’ 3.057 48.36 11” 1.283 29.67
2’ 3.038 30.70 12” 1.283 29.67
3’ / 142.54 13” 1.283 29.67
4’ 6.936 126.34 14” 1.283 29.67
5’ 6.834 126.84 15” 1.283 29.67
6’ 7.153 125.03 16” 1.283 29.67
      17” 1.283 29.67
      18” 1.283 29.67
      19” 1.283 29.27
      20” 1.283 31.94
      21” 1.424 22.70
      22” 0.891 14.13
核磁共振结构编号如下
Figure PCTCN2020118775-appb-000005
试验例1(S)-6-(2-(2-噻吩基)乙基)氨基)-5,6,7,8-四氢萘-1-基二十二酸酯在测定罗替戈汀山嵛酸酯化合物杂质含量中作为对照品的应用
样品准备：
称取罗替戈汀山嵛酸酯适量，加四氢呋喃溶解制成每1ml中约含1mg的溶液，为供试品 溶液；精密称取(S)-6-(2-(2-噻吩基)乙基)氨基)-5,6,7,8-四氢萘-1-基二十二酸酯适量，用四氢呋喃溶解并定量稀释制成每1ml中约0.008mg的溶液，作为对照品溶液。
色谱条件：
用十八烷基键合硅胶为填充剂，色谱柱(XBridge BEH C18 2.1*100mm，1.7μm，Waters)；以pH9.0的20mmol/L乙酸铵溶液(取乙酸铵1.54g，用水稀释至1000ml,氨水调pH值至9.0)为流动相A，乙腈为流动相B，异丙醇为流动相C，按下表进行梯度洗脱；柱温45℃；流速：0.32ml/min，检测波长为235nm，理论板数以罗替戈汀山嵛酸酯计应不得低于5000。取对照品溶液或供试品溶液各3μl，注入超高效液相色谱仪。
流动相洗脱梯度
时间(min) A(％) B(％) C(％)
0 80 20 0
10 15 45 40
26 10 40 50
32 10 40 50
32.2 0 40 60
42 0 40 60
43 80 20 0
48 80 20 0
附图2-1是单独进样(S)-6-(2-(2-噻吩基)乙基)氨基)-5,6,7,8-四氢萘-1-基二十二酸酯的UPLC色谱图,附图2-2是进样罗替戈汀山嵛酸酯与添加(S)-6-(2-(2-噻吩基)乙基)氨基)-5,6,7,8-四氢萘-1-基二十二酸酯的对比出峰时间UPLC色谱图，图7是对罗替戈汀山嵛酸酯产品中(S)-6-(2-(2-噻吩基)乙基)氨基)-5,6,7,8-四氢萘-1-基二十二酸酯(3号峰)检测的UPLC色谱图，按外标法计算，3批罗替戈汀山嵛酸酯化合物中(S)-6-(2-(2-噻吩基)乙基)氨基)-5,6,7,8-四氢萘-1-基二十二酸酯的含量均为0.5％以下。
试验例2(S)-6-(2-(2-噻吩基)乙基)氨基)-5,6,7,8-四氢萘-1-基二十二酸酯在测定罗替戈汀微球制剂杂质含量中作为对照品的应用
取罗替戈汀山嵛酸酯缓释微球适量(约相当于罗替戈汀山嵛酸酯10mg)，精密称定，加四氢呋喃溶解制成每1ml中约含1mg的溶液，为供试品溶液；精密称取(S)-6-(2-(2-噻 吩基)乙基)氨基)-5,6,7,8-四氢萘-1-基二十二酸酯适量，用四氢呋喃溶解并定量稀释制成每1ml中约0.008mg的溶液，作为对照品溶液。
色谱条件：
用十八烷基键合硅胶为填充剂，色谱柱(XBridge BEH C18 2.1*100mm，1.7μm，Waters)；以pH9.0的20mmol/L乙酸铵溶液(取乙酸铵1.54g，用水稀释至1000ml,氨水调pH值至9.0)为流动相A，乙腈为流动相B，异丙醇为流动相C，按下表进行梯度洗脱；柱温45℃；流速：0.32ml/min，检测波长为235nm，理论板数以罗替戈汀山嵛酸酯计应不得低于5000。取对照品溶液或供试品溶液各3μl，注入超高效液相色谱仪。
流动相洗脱梯度
时间(min) A(％) B(％) C(％)
0 80 20 0
10 15 45 40
26 10 40 50
32 10 40 50
32.2 0 40 60
42 0 40 60
43 80 20 0
48 80 20 0
按外标法计算，3批罗替戈汀山嵛酸酯微球中(S)-6-(2-(2-噻吩基)乙基)氨基)-5,6,7,8-四氢萘-1-基二十二酸酯的重量百分比均为0.5％以下。
实施例2(S)-6-(丙胺基)-5,6,7,8-四氢萘-1-基二十二酸酯的制备
称取(S)-6-(丙基氨基)-5，6，7，8-四氢萘-1-醇氢溴酸盐26.4g，三乙胺21.46g，二氯甲烷260ml，室温搅拌；缓慢滴加26.16g二碳酸二叔丁基酯，滴毕室温搅拌4h，TLC检测，原料反应完全；将溶剂减压蒸除，柱层析得24.1g中间体I。
称取中间体I 24.1g，山嵛酸29.56g，DMAP 11.47g，EDCI 19.66g，350ml甲苯，搅拌均匀，40℃反应3h，TLC检测反应完全；360ml 20％的NH 4Cl溶液搅拌0.5h，加硅藻土抽滤，静置过夜，有机相用360ml 20％的NH 4Cl溶液洗涤一次，有机相加水搅拌0.5h，静置；蒸除有机相溶剂，柱层析，得中间体248.0g。
称取中间体212.56g，二氯甲烷130ml溶解,N-甲基吗啉16.18g，搅拌均匀，后加入TMSI16.0g，室温搅拌反应2h，TLC检测，反应完全；将有机溶剂减压蒸除(60℃，0.5h)，加入150ml石油醚搅拌15min，抽滤，滤饼丢弃；母液浓缩蒸干，加入二氯甲烷150ml,水150ml洗涤二氯甲烷两遍；有机相浓缩蒸干，40℃鼓风干燥2h得7.3g(S)-6-(丙胺基)-5,6,7,8-四氢萘-1-基二十二酸酯。
核磁共振图谱归属见表2，高分辨质谱图见附图3。
表2(S)-6-(丙胺基)-5,6,7,8-四氢萘-1-基二十二酸酯核磁共振图谱归属
NO 1H NMR NO 1H NMR
1 / 1” /
2 6.832 2” 2.552
3 7.117 3” 1.560
4 6.973 4” 1.252
5 3.050,2.604 5” 1.252
6 2.903 6” 1.252
7 1.782,1.522 7” 1.252
8 2.916,2.535 8” 1.252
9 / 9” 1.252
10 / 10” 1.252
1’ 2.668 11” 1.252
2’ 1.423 12” 1.252
3’ 0.950 13” 1.252
    14” 1.252
    15” 1.252
    16” 1.252
    17” 1.252
    18” 1.252
    19” 1.252
    20” 1.252
    21” 1.423
    22” 0.887
核磁共振结构编号如下
Figure PCTCN2020118775-appb-000006
试验例3(S)-6-(丙胺基)-5,6,7,8-四氢萘-1-基二十二酸酯在测定罗替戈汀山嵛酸酯化合物杂质含量中作为对照品的应用
样品准备：
称取罗替戈汀山嵛酸酯适量，加四氢呋喃溶解制成每1ml中约含1mg的溶液，为供试品溶液；精密称取(S)-6-(丙胺基)-5,6,7,8-四氢萘-1-基二十二酸酯适量，用四氢呋喃溶解并定量稀释制成每1ml中约0.005mg的溶液，作为对照品溶液。
色谱条件：
用十八烷基键合硅胶为填充剂，色谱柱(XBridge BEH C18 2.1*100mm，1.7μm，Waters)；以pH9.0的20mmol/L乙酸铵溶液(取乙酸铵1.54g，用水稀释至1000ml,氨水调pH值至9.0)为流动相A，乙腈为流动相B，异丙醇为流动相C，按下表进行梯度洗脱；柱温45℃；流速：0.32ml/min检，测波长为220nm，理论板数以罗替戈汀山嵛酸酯计应不得低于5000。取对照品溶液或供试品溶液各3μl，注入超高效液相色谱仪。
流动相梯度
时间(min) A(％) B(％) C(％)
0 80 20 0
10 15 45 40
26 10 40 50
32 10 40 50
32.2 0 40 60
42 0 40 60
43 80 20 0
48 80 20 0
附图4-1是单独进样(S)-6-(丙胺基)-5,6,7,8-四氢萘-1-基二十二酸酯的UPLC色谱图,附图4-2是进样罗替戈汀山嵛酸酯与添加(S)-6-(丙胺基)-5,6,7,8-四氢萘-1-基二十二酸酯的对比出峰时间UPLC色谱图，图8是对罗替戈汀山嵛酸酯产品中(S)-6-(丙胺基)-5,6,7,8-四氢萘-1-基二十二酸酯(1号峰)检测的UPLC色谱图，按外标法计算，3批罗替戈汀山嵛酸酯化合物中(S)-6-(丙胺基)-5,6,7,8-四氢萘-1-基二十二酸酯的含量均为0.5％以下。
试验例4(S)-6-(丙胺基)-5,6,7,8-四氢萘-1-基二十二酸酯在测定罗替戈汀山嵛酸酯微球制剂杂质含量中作为对照品的应用
样品准备：
取罗替戈汀山嵛酸酯缓释微球适量(约相当于罗替戈汀山嵛酸酯10mg)，精密称定，置10ml量瓶中，加四氢呋喃10ml使溶解，作为供试品溶液；精密称取(S)-6-(丙胺基)-5,6,7,8-四氢萘-1-基二十二酸酯适量，用四氢呋喃定量稀释制成每1ml中约0.005mg的溶液，作为对照品溶液。
色谱条件：
用十八烷基键合硅胶为填充剂，色谱柱(XBridge BEH C18 2.1*100mm，1.7μm，Waters)；以pH9.0的20mmol/L乙酸铵溶液(取乙酸铵1.54g，用水稀释至1000ml,氨水调pH值至9.0)为流动相A，乙腈为流动相B，异丙醇为流动相C，按下表进行梯度洗脱，柱温45℃，流速：0.32ml/min检，测波长为220nm，理论板数以罗替戈汀山嵛酸酯计应不得低于5000。取对照品溶液或供试品溶液各3μl，注入超高效液相色谱仪。
流动相洗脱梯度
时间(min) A(％) B(％) C(％)
0 80 20 0
10 15 45 40
26 10 40 50
32 10 40 50
32.2 0 40 60
42 0 40 60
43 80 20 0
48 80 20 0
按外标法计算，3批罗替戈汀山嵛酸酯微球中(S)-6-(丙胺基)-5,6,7,8-四氢萘-1-基二十二酸酯的重量百分比均为0.5％以下。
实施例3 7，8-双氢萘-1-基二十二酸酯的制备
将93g 5-羟基-1-四氢萘酮、103g咪唑、106gTBS-Cl加入到500mL DMF中，形成浅棕黄色溶液，20min后反应液中析出白色固体，继续反应1h后TLC检测，反应完全。将反应液倒入3L水中，析出大量白色固体，搅拌10min后，过滤，滤饼用水淋洗后，溶于500mL二氯甲烷中，用水淋洗，干燥后加入石油醚，过100g硅胶垫(PE：DCM＝2：1)，得5-(叔丁基二甲基甲硅烷氧基)-3，4-二氢萘-1(2H)-酮，将其185g溶于800mL四氢呋喃中，形成浅黄色溶液，加入800mL甲醇。冰水控温0℃，分批加入硼氢化钠，1h后共计加入27g硼氢化钠(最高温度22℃)反应完全。浓缩反应液，除去有机溶剂。待有机溶剂除去后，用2*400mL乙酸乙酯，萃取产品，干燥并蒸干，得到327g浅黄色油状物，按其中含有170g产品计算，溶于二氯甲烷中。
将1330g 5-(叔丁基二甲基甲硅烷氧基)-1，2，3，4-四氢萘-1-醇的二氯甲烷溶液(按150g原料计算)、225g三乙胺加入到1.3L二氯甲烷中，控温小于20℃，滴加117.8g甲基黄酰氯——600mL二氯甲烷。滴毕，10min后TLC检测，原料有剩余；补加110g甲基黄酰氯之后，浓缩反应液，加入500mL水分散，用2*1L叔丁基甲醚萃取，干燥后浓缩，硅胶柱层析，得到45g叔丁基-(7，8-二氢萘-1-基氧基)二甲基硅烷；将40g叔丁基-(7，8-二氢萘-1-基氧基)二甲基硅烷加入到500mL甲醇中，加入22.7g氟化铯，氮气保护下加热到60℃反应，形成白色浊液；1h后TLC检测，反应完全，浓缩反应液，蒸干后用DCM萃取产品，再蒸干DCM，加入55g碱性氧化铝搅拌样品,过40g碱性氧化铝柱子(PE：DCM＝5：1)，得8.3g 7,8-双氢萘酚。
8.3g 7,8-双氢萘酚加入到150mL二氯甲烷中，加入8g三乙胺，滴加二十二酰氯的二氯甲烷溶液(约含二十二酰氯19g)，反应完全，向反应液中加入100mL水，搅拌一段时间后有大量固体，过滤；得10.3g类白色固体，即7，8-双氢萘-1-基二十二酸酯。
核磁共振图谱归属见表3，高分辨质谱图见附图5。
表3 7，8-双氢萘-1-基二十二酸酯核磁共振图谱归属
NO 1H NMR 13C NMR NO 1H NMR 13C NMR
1 / 147.89 7’ 1.297 29.72
2 6.860 120.74 8’ 1.297 29.72
3 7.152 126.77 9’ 1.297 29.72
4 6.913 127.06 10’ 1.297 29.72
5 6.476 123.73 11’ 1.297 29.72
6 6.049 127.42 12’ 1.297 29.72
7 2.292 22.71 13’ 1.297 29.72
8 2.647 20.62 14’ 1.297 29.72
9 / 135.68 15’ 1.297 29.72
10 / 128.95 16’ 1.297 29.72
1’ / 172.02 17’ 1.297 29.72
2’ 2.569 34.26 18’ 1.297 29.72
3’ 1.769 25.10 19’ 1.297 29.38
4’ 1.347 29.21 20’ 1.297 31.94
5’ 1.323 29.27 21’ 1.392 22.36
6’ 1.308 29.72 22’ 0.891 14.13
核磁共振结构编号如下
Figure PCTCN2020118775-appb-000007
试验例5 7，8-双氢萘-1-基二十二酸酯在测定罗替戈汀山嵛酸酯化合物杂质含量中作为对照品的应用
样品准备：
称取罗替戈汀山嵛酸酯适量，加四氢呋喃溶解制成每1ml中约含1mg的溶液，为供试品溶液；精密称取7，8-双氢萘-1-基二十二酸酯适量，用四氢呋喃溶解并定量稀释制成每1ml中约0.005mg的溶液，作为对照品溶液。
色谱条件：
用十八烷基键合硅胶为填充剂，色谱柱(XBridge BEH C18 2.1*100mm，1.7μm，Waters)； 以pH9.0的20mmol/L乙酸铵溶液(取乙酸铵1.54g，用水稀释至1000ml,氨水调pH值至9.0)为流动相A，乙腈为流动相B，异丙醇为流动相C，按下表进行梯度洗脱；柱温45℃；流速：0.32ml/min，检测波长为235nm，理论板数以罗替戈汀山嵛酸酯计应不得低于5000。取对照品溶液及供试品溶液各3μl，注入超高效液相色谱仪。
流动相洗脱梯度
时间(min) A(％) B(％) C(％)
0 80 20 0
10 15 45 40
26 10 40 50
32 10 40 50
32.2 0 40 60
42 0 40 60
43 80 20 0
48 80 20 0
附图6-1是单独进样7，8-双氢萘-1-基二十二酸酯对照品的UPLC色谱图,附图6-2是进样罗替戈汀山嵛酸酯与7，8-双氢萘-1-基二十二酸酯的对比出峰时间UPLC色谱图，图9是对罗替戈汀山嵛酸酯产品中7，8-双氢萘-1-基二十二酸酯(3号峰)检测的UPLC色谱图，按外标法计算，3批罗替戈汀山嵛酸酯化合物中7，8-双氢萘-1-基二十二酸酯的含量均为0.5％以下。
试验例6 7，8-双氢萘-1-基二十二酸酯在测定罗替戈汀山嵛酸酯微球制剂杂质含量中作为对照品的应用
样品准备：
取罗替戈汀山嵛酸酯缓释微球适量(约相当于罗替戈汀山嵛酸酯10mg)，精密称定，置10ml量瓶中，加四氢呋喃10ml使溶解，作为供试品溶液；精密称取7，8-双氢萘-1-基二十二酸酯适量，用四氢呋喃定量稀释制成每1ml中约0.005mg的溶液，作为对照品溶液。
色谱条件：
用十八烷基键合硅胶为填充剂，色谱柱(XBridge BEH C18 2.1*100mm，1.7μm，Waters)；以pH9.0的20mmol/L乙酸铵溶液(取乙酸铵1.54g，用水稀释至1000ml,氨水调pH值至9.0)为流动相A，乙腈为流动相B，异丙醇为流动相C，按下表进行梯度洗脱；柱温45℃；流速：0.32ml/min，检测波长为235nm，理论板数以罗替戈汀山嵛酸酯计应不得低于5000。取对照品溶液及供试品溶液各3μl，注入超高效液相色谱仪。
流动相洗脱梯度
时间(min) A(％) B(％) C(％)
0 80 20 0
10 15 45 40
26 10 40 50
32 10 40 50
32.2 0 40 60
42 0 40 60
43 80 20 0
48 80 20 0
按外标法计算，3批罗替戈汀山嵛酸酯微球中7，8-双氢萘-1-基二十二酸酯的重量百分比均为0.5％以下。

Claims (10)

  1. 一种具有式Ⅰ结构式的化合物：
    Figure PCTCN2020118775-appb-100001
  2. 一种具有式II结构式的化合物：
    Figure PCTCN2020118775-appb-100002
  3. 一种具有式III结构式的化合物：
    Figure PCTCN2020118775-appb-100003
  4. 权利要求1所述化合物Ⅰ的制备方法，其特征在于所述方法步骤如下：称取(S)-6-(2-(噻吩-2-基)乙胺基)-5，6，7，8-四氢萘-1-醇氢溴酸盐、三乙胺、二氯甲烷，室温搅拌；加二碳酸二叔丁基酯，反应完全，溶剂减压蒸除，得中间体I；称取中间体I、山嵛酸、DMAP、EDCI、甲苯，搅拌均匀；反应完全，加NH 4Cl溶液搅拌，抽滤，静置过夜，NH 4Cl溶液洗涤一次，加水搅拌，静置，去除水相；蒸除有机相溶剂，柱层析，得中间体II；称取中间体II，二氯甲烷溶解,加入N-甲基吗啉，搅拌均匀，后加入TMSI,室温搅拌反应；反应完全将有机溶剂减压蒸除,加入石油醚搅拌,抽滤，母液浓缩蒸干,加入二氯甲烷，水洗涤；有机相浓缩蒸干，干燥得化合物I；优选所述加入NH 4Cl溶液为20％NH 4Cl溶液；优选所述称取中间体I、山嵛酸、DMAP、EDCI、甲苯，搅拌反应是在40℃完成；优选所述添加二碳酸二叔丁基酯为缓慢滴加。
  5. 权利要求2所述化合物II的制备方法，其特征在于所述方法步骤如下：称取(S)-6-(丙基氨基)-5，6，7，8-四氢萘-1-醇氢溴酸盐、三乙胺、二氯甲烷，室温搅拌；加二碳酸二叔 丁基酯，反应完全，溶剂减压蒸除，得中间体I；称取中间体I、山嵛酸、DMAP、EDCI、甲苯，搅拌均匀；反应完全，加NH 4Cl溶液搅拌，抽滤，静置过夜，NH 4Cl溶液洗涤一次，加水搅拌，静置，去除水相，蒸除有机相溶剂，柱层析，得中间体II；称取中间体II，二氯甲烷溶解,加入N-甲基吗啉，搅拌均匀，后加入TMSI,室温搅拌反应；反应完全将有机溶剂减压蒸除,加入石油醚搅拌,抽滤,母液浓缩蒸干,加入二氯甲烷，水洗涤；有机相浓缩蒸干，干燥得化合物II；优选所述方法加人的NH 4Cl溶液为20％NH 4Cl溶液；优选所述方法中称取中间体I、山嵛酸、DMAP、EDCI、甲苯，搅拌反应是在40℃完成；优选所述添加二碳酸二叔丁基酯为缓慢滴加。
  6. 权利要求3所述化合物III的制备方法，其特征在于所述方法步骤如下：将5-羟基-1-四氢萘酮、咪唑、TBS-Cl加入到DMF中，形成浅棕黄色溶液，反应完全；将反应液倒入水中，析出固体，过滤，滤饼用水淋洗后，溶于二氯甲烷中，用水淋洗，干燥后加入石油醚，过硅胶垫，得5-(叔丁基二甲基甲硅烷氧基)-3，4-二氢萘-1(2H)-酮，将其溶于四氢呋喃中，加入甲醇，分批加入硼氢化钠，反应完全；浓缩反应液，除去有机溶剂，用乙酸乙酯萃取产品得到浅黄色油状物，将其溶于二氯甲烷中，将5-(叔丁基二甲基甲硅烷氧基)-1，2，3，4-四氢萘-1-醇的二氯甲烷溶液、三乙胺加入到二氯甲烷中，控温，滴加甲基黄酰氯—二氯甲烷，浓缩反应液，加入水分散，用叔丁基甲醚萃取，干燥后浓缩，硅胶柱层析，得到叔丁基-(7，8-二氢萘-1-基氧基)二甲基硅烷；将其加入到甲醇中，加入氟化铯，氮气保护下反应，反应完全，浓缩反应液，蒸干后用DCM萃取产品，再蒸干DCM，加入碱性氧化铝搅拌样品，过碱性氧化铝柱子(PE：DCM＝5：1)得7,8-双氢萘酚，将其加入到二氯甲烷中，加入三乙胺，加二十二酰氯的二氯甲烷溶液，反应完全，向反应液中加入水，搅拌，过滤，得化合物III；优选所述氮气保护下反应是加热到60℃反应；优选所述将5-(叔丁基二甲基甲硅烷氧基)-1，2，3，4-四氢萘-1-醇的二氯甲烷溶液、三乙胺加入到二氯甲烷中，控温小于20℃。
  7. 权利要求1-3任一所述化合物在罗替戈汀山嵛酸酯或其制剂的杂质检测中作为对照品的应用。
  8. 一种用于测定罗替戈汀山嵛酸酯或其制剂杂质含量的方法，采用液相色谱法分析，其特征在于权利要1-3任一所述的化合物作为对照品。
  9. 权利要求8所述的方法，其特征在于将权利要求1-3任一所述化合物溶解在溶液中制备为对照品溶液，将罗替戈汀山嵛酸酯或其制剂溶解在溶液中制备为供试品溶液，采用液相色谱法分析，获得对照品溶液、供试品溶液的液相色谱图，对比对照品溶液、供试品溶液的液相色谱图中的出峰时间，确定供试品溶液含有权利要求1-3任一所述的化合物，按外 标法测定出罗替戈汀山嵛酸酯或其制剂中权利要求1-3任一所述化合物的重量百分比。
  10. 一种罗替戈汀山嵛酸酯或其制剂，其特征在于所述罗替戈汀山嵛酸酯或其制剂中含有重量百分比少于0.5％权利要求1-3任一所述化合物。
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