WO2022011727A1 - 一种瑞德西韦有关物质及其制备方法和应用 - Google Patents

一种瑞德西韦有关物质及其制备方法和应用 Download PDF

Info

Publication number
WO2022011727A1
WO2022011727A1 PCT/CN2020/102963 CN2020102963W WO2022011727A1 WO 2022011727 A1 WO2022011727 A1 WO 2022011727A1 CN 2020102963 W CN2020102963 W CN 2020102963W WO 2022011727 A1 WO2022011727 A1 WO 2022011727A1
Authority
WO
WIPO (PCT)
Prior art keywords
remdesivir
preparation
acid
solution
formula
Prior art date
Application number
PCT/CN2020/102963
Other languages
English (en)
French (fr)
Inventor
付明伟
李令超
肖雅
顾问
马燕
葛敏
Original Assignee
南京正济医药研究有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 南京正济医药研究有限公司 filed Critical 南京正济医药研究有限公司
Publication of WO2022011727A1 publication Critical patent/WO2022011727A1/zh

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
    • 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
    • G01N30/26—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
    • 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
    • G01N30/86—Signal analysis
    • G01N30/8675—Evaluation, i.e. decoding of the signal into analytical information
    • G01N30/8679—Target compound analysis, i.e. whereby a limited number of peaks is analysed
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the invention relates to a pharmaceutical impurity and a preparation method and application thereof, in particular to a Remdesivir related substance and a preparation method and application thereof.
  • Remdesivir a nucleoside analog with antiviral activity, is currently undergoing clinical studies for the treatment of the novel coronavirus (COVID-19) in many countries around the world.
  • the structural formula of Remdesivir is as follows:
  • the purpose of the present invention is to study the synthesis process of Remdesivir, and to provide a related substance produced during the synthesis of Remdesivir. Another object of the present invention is to disclose the preparation method of the related substance. Another object of the present invention is to point out the application of the related substance in the raw drug of Remdesivir and its preparation impurity reference substance.
  • step 1 I-A and I-B are condensed in the presence of a solvent and under Lewis acid catalysis and basic conditions to obtain I-C;
  • step 2 Formula I-C is depropylidated in an acidic environment The protecting group affords compound I.
  • the solvent described in step 1 is selected from one or both of N-methylpyrrolidone, acetonitrile, tetrahydrofuran, 1,4-dioxane and 2-methyltetrahydrofuran;
  • the Lewis acid in step 1 is selected from aluminum trichloride, ferric chloride, titanium tetrachloride, magnesium chloride, and tin tetrachloride; preferably aluminum trichloride, magnesium chloride, and more preferably magnesium chloride.
  • the base described in step 1 is selected from one or both of N,N-diisopropylethylamine, triethylamine, pyridine, and substituted pyridine; preferably N,N-diisopropylethylamine, triethylamine .
  • the acid added in the acidic environment in step 2 is selected from one or both of sulfuric acid, hydrochloric acid, phosphoric acid, formic acid, trifluoromethanesulfonic acid, trifluoroacetic acid, p-toluenesulfonic acid, and methanesulfonic acid;
  • the solvent is selected from N- One or both of methylpyrrolidone, isopropyl acetate and 2-methyltetrahydrofuran.
  • the high-performance liquid chromatography method for separating and measuring Remdesivir and this Remdesivir-related substance comprises the following steps:
  • Detection inject the prepared remdesivir solution into the liquid chromatograph, record the chromatogram and analyze it.
  • the present invention studies the related substances that may be produced during the synthesis of Remdesivir, and the impurities prepared by the above method are used as the impurity reference substance in the quality study of Remdesivir raw materials.
  • the present invention also provides a liquid chromatographic analysis method for the separation and determination of Remdesivir and its related substances (Formula I), which can quickly detect whether the API contains related substances (Formula I), which is for qualitative and quantitative detection of Remdesivir raw materials. It provides a new selection method for the drug, which is of great significance to the quality control and research of the Remdesivir API technology.
  • Mobile phase 0.1% phosphoric acid aqueous mobile phase A, acetonitrile as mobile phase B, linear gradient elution as follows:
  • Remdesivir weigh an appropriate amount of Remdesivir, put it in a measuring bottle, dissolve and dilute it with acetonitrile to a solution of 0.5 mg/mL as the test solution.
  • Formula I positioning solution, system adaptability solution, and Remdesivir test solution 10 ⁇ L each, were injected into the high-performance liquid chromatograph respectively, and the chromatogram was recorded. The results show that this method can achieve good separation of related substances (formula I) and remdesivir, remdesivir peaks at 8.1min, and related substances (formula I) peaks at 16.1min.
  • the test results of the test solution showed that the Remdesivir API prepared by Nanjing Zhengji Pharmaceutical Research Co., Ltd. did not contain related substances (Formula I).

Landscapes

  • Chemical & Material Sciences (AREA)
  • Biochemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Immunology (AREA)
  • Analytical Chemistry (AREA)
  • General Physics & Mathematics (AREA)
  • Physics & Mathematics (AREA)
  • Pathology (AREA)
  • Organic Chemistry (AREA)
  • Molecular Biology (AREA)
  • Engineering & Computer Science (AREA)
  • Library & Information Science (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

一种瑞德西韦有关物质及其制备方法和应用，该有关物质可作为一种瑞德西韦杂质对照品，用于高效液相色谱方法分离测定瑞德西韦与式(Ⅰ)化合物。该制备方法反应条件温和，后处理简单，可以规模化制备出纯度符合要求的式(Ⅰ)化合物，以作为瑞德西韦质量研究的杂质对照品。

Description

一种瑞德西韦有关物质及其制备方法和应用 技术领域
本发明涉及一种药物杂质及其制备方法和应用，具体为一种瑞德西韦有关物质及其制备方法和应用。
背景技术
自2019年12月以来，全球各地发现多起由新型冠状病毒(COVID-19)引起的病毒性肺炎病例，给世界各国人民的生产生活带来了极其巨大的影响。瑞德西韦(Remdesivir)是一种核苷类似物，具有抗病毒活性，目前正在世界多个国家进行对新型冠状病毒(COVID-19)治疗的临床研究。瑞德西韦的结构式如下所示：
Figure PCTCN2020102963-appb-000001
原料药及制剂的质量控制一直是药物研发过程中的重点和难点，而对杂质的研究又是质量控制中的重中之重。瑞德西韦合成过程中的起始原料、中间体、反应副产物、降解杂质等均可能成为残留在终产物(瑞德西韦)中的杂质，从而影响药品质量。目前对瑞德西韦有关物质的研究以及质控分析方法的研究鲜有报道。
发明内容
发明目的：本发明的目的在于研究瑞德西韦合成工艺，提供了一种瑞德西韦合成过程中产生的有关物质。本发明的另一个目的在于公开该有关物质的制备方法。本发明还有一个目的在于指出该有关物质在瑞德西韦原料药及其制剂杂质对照品中的应用。
技术方案：本发明所述的瑞德西韦有关物质，包含式(Ⅰ)所示的化合物：
Figure PCTCN2020102963-appb-000002
所述的瑞德西韦有关物质的制备方法，合成路线如下：
Figure PCTCN2020102963-appb-000003
所述的制备方法，步骤1：Ⅰ-A与Ⅰ-B在溶剂存在下及路易斯酸催化和碱性条件下缩合反应得到Ⅰ-C；步骤2：式Ⅰ-C在酸性环境下脱丙叉保护基得到化合物Ⅰ。
步骤1中所述溶剂选自N-甲基吡咯烷酮、乙腈、四氢呋喃、1，4-二氧六环、2-甲基四氢呋喃中的一种或者两种；
步骤1中所述路易斯酸选自三氯化铝、三氯化铁、四氯化钛、氯化镁、四氯化锡；优选三氯化铝、氯化镁，更优选氯化镁。
步骤1中所述碱选自N,N-二异丙基乙胺、三乙胺、吡啶、取代吡啶中的一种或者两种；优选N,N-二异丙基乙胺、三乙胺。
步骤2中酸性环境所加入的酸选自硫酸、盐酸、磷酸、甲酸、三氟甲磺酸、三氟乙酸、对甲苯磺酸、甲磺酸中的一种或者两种；溶剂选自N-甲基吡咯烷酮、醋酸异丙酯、2-甲基四氢呋喃中的一种或者两种。
所述的瑞德西韦有关物质在瑞德西韦原料药及其制剂杂质对照品中的应用。
所述的应用，分离测定瑞德西韦与该瑞德西韦有关物质的高效液相色谱方法包含以下步骤：
a.设置色谱条件：以十八烷基硅烷键合硅胶为色谱柱填充剂，以0.1％磷酸水溶液为流动相A，以乙腈为流动相B，进行梯度洗脱；
b.配制溶液：采用甲醇溶解瑞德西韦原料药，配制成浓度为0.1～0.5mg/mL的瑞德西韦溶液；
c.检测：取配制的瑞德西韦溶液注入液相色谱仪，记录色谱图并进行分析。
所述的应用，梯度洗脱程序如下：
Figure PCTCN2020102963-appb-000004
有益效果：本发明对瑞德西韦合成过程中可能产生的有关物质进行了研究，通过上述方法制备出的杂质，用以作为瑞德西韦原料药质量研究中的杂质对照品。本发明还提供了分离测定瑞德西韦与其有关物质(式Ⅰ)的液相色谱分析方法，可以快速检测出原料药中是否含有关物质(式Ⅰ)，为定性定量检测瑞德西韦原料药提供新的选择方法，对瑞德西韦原料药工艺的质量控制及研究具有重要的意义。
具体实施方式
瑞德西韦原料药以及相关中间体均由南京正济医药研究有限公司自制。
实施例
Figure PCTCN2020102963-appb-000005
在反应瓶中加入10.0g化合物Ⅰ-A，再加入34.0g化合物Ⅰ-B，120g乙腈，7.2g氯化镁。然后控制内温50℃下，滴加9.8g N,N-二异丙基乙胺。反应3小时后，加入200g水和200g乙酸乙酯，分层。有机层依次用10％柠檬酸溶液、10％碳酸钠溶液、饱和氯化钠水溶液洗涤，减压浓缩除去溶剂，结晶得到21.6g化合物Ⅰ-C。
Figure PCTCN2020102963-appb-000006
在反应瓶中加入20.0g化合物Ⅰ-C，再加入60g三氟乙酸，然后控制内温20-30℃下，反应1-3小时.加入200g水和200g醋酸异丙酯，分层。有机层依次用饱和碳酸氢钾溶液、饱和氯化钠水溶液洗涤，减压浓缩除去溶剂，结晶得到10.2g化合物Ⅰ。HPLC纯度：98.0％；1H NMR(400MHz,MeOD)δ8.06(s,1H),7.29(qd,J＝8.5,4.1Hz,6H),7.23–7.10(m,4H),7.08(d,J＝4.7Hz,1H),6.97(d,J＝4.6Hz,1H),4.72(d,J＝5.3Hz,1H),4.44–4.32(m,2H),4.32–4.19(m,2H),4.14–4.08(m,1H),4.02(dd,J＝10.9,5.8Hz,1H),3.98–3.90(m,3H),3.87(dd,J＝10.9,5.6Hz,2H),1.45(dd,J＝12.5,6.2Hz,1H),1.41–1.18(m,17H),0.89–0.75(m,12H).ESI(+)M/Z:914.36，ESI(-)M/Z:912.35.
分析方法
仪器：Agilent 1100/1260高效液相色谱仪
色谱柱：YMC-Pack ODS-A(250×4.6mm,5μm)
流动相：0.1％磷酸水溶液流动相A，以乙腈为流动相B，按下表进行线性梯度洗脱：
Figure PCTCN2020102963-appb-000007
检测波长：238nm
流速：1mL/min
柱温：30℃
进样量：10μL
取上述制备的有关物质(式Ⅰ)，精密称定，加入甲醇溶解并稀释制成每1mL约含0.25mg的溶液作为定位溶液。
称取瑞德西韦适量，加入式(Ⅰ)定位溶液，制成每1mL约含瑞德西韦0.5mg，分 别含式(Ⅰ)约2.5μg的溶液，作为系统适应性溶液。
称取瑞德西韦适量，置于量瓶中，用乙腈溶解并稀释成0.5mg/mL的溶液作为供试品溶液。
测定：式Ⅰ定位溶液、系统适应性溶液、瑞德西韦供试品溶液各10μL分别注入高效液相色谱仪，记录色谱图。结果表明该方法可以实现有关物质(式Ⅰ)和瑞德西韦的良好分离，瑞德西韦出峰在8.1min，有关物质(式Ⅰ)在16.1min出峰。供试品溶液测定结果表明南京正济医药研究有限公司制备的瑞德西韦原料药中不含有关物质(式Ⅰ)。

Claims (10)

  1. 一种瑞德西韦有关物质，其特征在于，包含式(Ⅰ)所示的化合物：
    Figure PCTCN2020102963-appb-100001
  2. 如权利要求1所述的瑞德西韦有关物质的制备方法，其特征在于，包含如下合成路线：
    Figure PCTCN2020102963-appb-100002
  3. 根据权利要求2所述的制备方法，其特征在于，步骤1：Ⅰ-A与Ⅰ-B在溶剂存在下及路易斯酸催化和碱性条件下缩合反应得到Ⅰ-C；步骤2：式Ⅰ-C在酸性环境下脱丙叉保护基得到化合物Ⅰ。
  4. 根据权利要求3所述的制备方法，其特征在于，步骤1中所述溶剂选自N-甲基吡咯烷酮、乙腈、四氢呋喃、1，4-二氧六环、2-甲基四氢呋喃中的一种或者两种；
  5. 根据权利要求3所述的制备方法，其特征在于，步骤1中所述路易斯酸选自三氯化铝、三氯化铁、四氯化钛、氯化镁、四氯化锡。
  6. 根据权利要求3所述的制备方法，其特征在于，步骤1中所述碱选自N,N-二异 丙基乙胺、三乙胺、吡啶、取代吡啶中的一种或者两种。
  7. 根据权利要求3所述的制备方法，其特征在于，步骤2中酸性环境所加入的酸选自硫酸、盐酸、磷酸、甲酸、三氟甲磺酸、三氟乙酸、对甲苯磺酸、甲磺酸中的一种或者两种；溶剂选自N-甲基吡咯烷酮、醋酸异丙酯、2-甲基四氢呋喃中的一种或者两种。
  8. 如权利要求1所述的瑞德西韦有关物质在瑞德西韦原料药及其制剂杂质对照品中的应用。
  9. 根据权利要求8所述的应用，其特征在于，分离测定瑞德西韦与权利要求1所述瑞德西韦有关物质的高效液相色谱方法包含以下步骤：
    a.设置色谱条件：以十八烷基硅烷键合硅胶为色谱柱填充剂，以0.1％磷酸水溶液为流动相A，以乙腈为流动相B，进行梯度洗脱；
    b.配制溶液：采用甲醇溶解瑞德西韦原料药，配制成浓度为0.1～0.5mg/mL的瑞德西韦溶液；
    c.检测：取配制的瑞德西韦溶液注入液相色谱仪，记录色谱图并进行分析。
  10. 根据权利要求9所述的应用，其特征在于，所述梯度洗脱程序如下：
    Figure PCTCN2020102963-appb-100003
PCT/CN2020/102963 2020-07-17 2020-07-20 一种瑞德西韦有关物质及其制备方法和应用 WO2022011727A1 (zh)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202010690131.2 2020-07-17
CN202010690131.2A CN111961079A (zh) 2020-07-17 2020-07-17 一种瑞德西韦有关物质及其制备方法和应用

Publications (1)

Publication Number Publication Date
WO2022011727A1 true WO2022011727A1 (zh) 2022-01-20

Family

ID=73360700

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2020/102963 WO2022011727A1 (zh) 2020-07-17 2020-07-20 一种瑞德西韦有关物质及其制备方法和应用

Country Status (2)

Country Link
CN (1) CN111961079A (zh)
WO (1) WO2022011727A1 (zh)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115561367A (zh) * 2022-11-09 2023-01-03 山东海雅医药科技有限公司 痛风药物有关物质的高效液相色谱检测方法

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112730659B (zh) * 2020-12-21 2022-05-27 江苏正济药业股份有限公司 一种瑞德西韦中间体有关物质的检测方法
CN112920203A (zh) * 2021-01-26 2021-06-08 浙江永太科技股份有限公司 一种瑞德西韦有关物质及其制备方法
CN113092624A (zh) * 2021-04-07 2021-07-09 河南泰丰生物科技有限公司 瑞德西韦有关物质及含量测定方法
CN113831377A (zh) * 2021-09-30 2021-12-24 江苏正济药业股份有限公司 一种Molnupiravir有关物质及其制备方法和应用

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107073005A (zh) * 2014-10-29 2017-08-18 吉利德科学公司 治疗丝状病毒科病毒感染的方法

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES2909419T3 (es) * 2015-09-16 2022-05-06 Gilead Sciences Inc Métodos para el tratamiento de infecciones por coronaviridae

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107073005A (zh) * 2014-10-29 2017-08-18 吉利德科学公司 治疗丝状病毒科病毒感染的方法

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
"Protective Groups in Organic Synthesis", 31 October 2004, EAST CHINA UNIVERSITY OF SCIENCE AND TECHNOLOGY, CN, ISBN: 7-5628-1607-7, article GREENE, T. W.; WUTS, P. G. M.: "The Protection of Organophosphate Groups", pages: 692, XP009533822 *
BARAI HASI RANI, LEE HAI WHANG: "Kinetics and mechanism of the anilinolysis of aryl phenyl isothiocyanophosphates in acetonitrile", BEILSTEIN JOURNAL OF ORGANIC CHEMISTRY, vol. 9, no. 9, 26 March 2013 (2013-03-26), pages 615 - 620, XP055887985, DOI: 10.3762/bjoc.9.68 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115561367A (zh) * 2022-11-09 2023-01-03 山东海雅医药科技有限公司 痛风药物有关物质的高效液相色谱检测方法
CN115561367B (zh) * 2022-11-09 2023-06-30 山东海雅医药科技有限公司 痛风药物有关物质的高效液相色谱检测方法

Also Published As

Publication number Publication date
CN111961079A (zh) 2020-11-20

Similar Documents

Publication Publication Date Title
WO2022011727A1 (zh) 一种瑞德西韦有关物质及其制备方法和应用
Harbeson et al. Stereospecific synthesis of peptidyl. alpha.-keto amides as inhibitors of calpain
MXPA06005660A (es) Impureza de micofenolato mofetil.
EP1879852A1 (en) Pregabalin free of lactam and a process for preparation thereof
CN106938998A (zh) 卡格列净有关物质的合成方法
CN112110897B (zh) 一种氘代克里唑蒂尼及其衍生物的制备方法
CN108169399B (zh) 去甲氨噻肟酸乙酯粗品中杂质的分离方法
CN112321642A (zh) 一种瑞德西韦有关物质及其制备方法和用途
Hashizume et al. Dimerization of tryptophan derivatives in trifluoroacetic acid.
Gu et al. Synthesis of β-phenyl-δ, ε-unsaturated amino acids and stereoselective introduction of side chain groups into [4, 3, 0]-bicyclic β-turn dipeptides
CN112358504A (zh) 一种瑞德西韦有关物质及其制备方法和用途
CN112694421A (zh) 帕拉米韦有关物质的制备方法和应用
CN104945468A (zh) Mmaf手性异构体的制备方法及其应用
WO2022017317A1 (zh) 一种规模化合成河豚毒素的方法
CN108912018B (zh) 一种用于合成舒必利的关键中间体中杂质化合物的制备方法及其用途
CN109096273A (zh) 美洛西林钠杂质c、d和f的分离制备方法
CN114341155A (zh) 一种肽酰胺类化合物及其中间体的制备方法
ZA200109554B (en) 1-trifluoromethyl-4-hydroxy-7-piperidinyl-aminomethyl-chroman derivatives.
US8877947B2 (en) Process for preparation of substantially pure fosamprenavir calcium and its intermediates
Marzoni et al. A convenient, large scale synthesis of N-Cbz-(S-phenyl)-L-cysteine
JP2629375B2 (ja) アミノ基が保護されたドーパ又はドーパ誘導体の製造法
Szókán et al. Chromatographic studies on the racemization of thiopeptides
Uematsu et al. 5-Hydroxymethyltubercidin. Synthesis, biological activity, and role in pyrrolopyrimidine biosynthesis
Chen et al. Total Synthesis of C-8 Hydroxyl Substituted Lomefloxacin as the Photolysis Impurity
CN108727234B (zh) 多肽类化合物及其在制备组织蛋白酶d抑制剂中的用途

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 20945510

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 20945510

Country of ref document: EP

Kind code of ref document: A1