WO2023124236A1 - 用于合成帕罗韦德的中间产物及制备方法 - Google Patents
用于合成帕罗韦德的中间产物及制备方法 Download PDFInfo
- Publication number
- WO2023124236A1 WO2023124236A1 PCT/CN2022/118602 CN2022118602W WO2023124236A1 WO 2023124236 A1 WO2023124236 A1 WO 2023124236A1 CN 2022118602 W CN2022118602 W CN 2022118602W WO 2023124236 A1 WO2023124236 A1 WO 2023124236A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- compound
- preparation
- synthesizing
- paxlovid
- reaction
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/56—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having carbon atoms of carboxamide groups bound to carbon atoms of carboxyl groups, e.g. oxamides
-
- 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
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/52—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring condensed with a ring other than six-membered
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
-
- 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 the preparation of antiviral drugs, in particular to an intermediate product and a preparation method for synthesizing Parovade.
- Paxlovid is used to treat mild to moderate new coronary pneumonia, and the applicable population is high-risk patients over 12 years old and weighing more than 40 kg.
- Paxlovid is a combination preparation consisting of 300mg (two 150mg tablets) of nirmatrelvir and one tablet of 100mg ritonavir, Paxlovid reduces the risk of hospitalization or death by 89% (starting treatment within 3 days after symptom onset) and 88% (5 days after symptom onset).
- nirmatrelvir is a novel master protease (Mpro, also known as 3CL protease) inhibitor from Pfizer Laboratories, specifically designed to block the activity of SARS-CoV-2 Mpro, the enzyme that Required for coronavirus replication.
- Mpro master protease
- Low-dose ritonavir helps slow down the metabolism or breakdown of nirmatrelvir, allowing it to remain active in the body for a longer period of time at higher concentrations to help fight the virus.
- Parovade (PF-07321332) uses a large number of condensing agents, which has different degrees of racemization risk, and even introduces a variety of metabolic impurities, and the post-treatment is relatively complicated.
- the purpose of the present invention is to solve the deficiencies of the prior art, design key intermediate compounds in the synthetic route, simplify the synthetic route, reduce the risk of racemization, and simplify the post-reaction treatment steps.
- a kind of preparation method of above-mentioned compound that is used for synthesizing Parovade, described compound preparation route is as follows:
- a preparation method for synthesizing the intermediate product of Parovade the intermediate product is synthesized by the above-mentioned compound, and the second compound is obtained by reacting the compound with SM-1, and the second compound is reacted with thionyl chloride
- the preparation route is as follows:
- a method for synthesizing Parovade using the above-mentioned intermediate product is as follows:
- the advantages of the present invention are as follows: the carboxylic acid is directly made into an acid chloride, a key intermediate is made, the risk of racemization is reduced, the post-treatment operation is simplified, and the yield is increased.
- reaction solution was evaporated to dryness under reduced pressure until no liquid dripped out. Evaporate to dryness to obtain 1.05 kg of yellow oily compound, which is directly used in the next step.
- SM-1 (0.78kg, 4.07mol) was dissolved in dichloromethane (DCM, 15.6L), and N,N-diisopropylethylamine (DIPEA, 1.58kg, 12.21mol) was added under nitrogen protection.
- DIPEA N,N-diisopropylethylamine
- the temperature of the reaction solution was lowered to 0°C, compound 2 (the second compound, 1.05kg, 4.27mol) was dissolved in DCM (2.1L), slowly dropped into the reaction solution, and the temperature in the reaction system was controlled below 5°C. After the dropwise addition was completed, it was stirred at 0° C. for 30 min, and the reaction progress was monitored by high performance liquid chromatography (HPLC).
- HPLC high performance liquid chromatography
- reaction solution was poured into 1N hydrochloric acid solution (14 L), stirred evenly, and allowed to stand until the reaction solution was separated into layers, and the organic phase was separated.
- the organic phase was washed with saturated sodium chloride solution (10 L), dried by adding anhydrous sodium sulfate, and the organic phase was separated and evaporated to dryness.
- reaction solution was evaporated to dryness under reduced pressure until no liquid dripped out. Evaporate to dryness to obtain 1.25 kg of yellow oil compound, which is directly used in the next step.
- SM-2 (0.72kg, 3.43mol) was dissolved in DCM (25L), and DIPEA (1.27kg, 9.81mol) was added under nitrogen protection. Adjust the temperature of the reaction system to 0°C, dissolve compound 4 (1.25kg, 3.27mol) in DCM (2.5L), slowly drop into the reaction solution, and control the internal temperature of the reaction system below 5°C. After the dropwise addition, the mixture was stirred at 0° C. for 30 min, and the reaction progress was monitored by high performance liquid chromatography (HPLC).
- HPLC high performance liquid chromatography
- reaction solution was poured into 1N hydrochloric acid solution (12 L), stirred evenly, left to stand until the reaction solution was separated, and the organic phase was separated.
- the organic phase was washed with saturated sodium chloride solution (10 L), dried by adding anhydrous sodium sulfate, and the organic phase was separated and evaporated to dryness.
- reaction solution was poured into 1N ammonium chloride solution (12 L), stirred evenly, and allowed to stand until the reaction solution was separated into layers, and the organic phase was separated.
- the organic phase was washed with saturated sodium chloride solution (10 L), dried by adding anhydrous sodium sulfate, and the organic phase was separated and evaporated to dryness.
- the whole synthesis steps can be simplified; the carboxyl group can be converted into acid chloride by thionyl chloride, which can reduce the risk of racemization, simplify the post-treatment operation, and increase the yield.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明涉及抗病毒药物的制备,具体涉及用于合成帕罗韦德的中间产物及制备方法,两种用于合成帕罗韦德(PF-07321332)的中间产物,结构分别为制备两种中间产物的合成方法均是将羧酸在二氯亚砜的作用下变为酰氯,得到制备过程中的关键中间产物,降低消旋风险,简化合成步骤及后处理步骤,提高产率。
Description
本发明涉及抗病毒药物的制备,具体涉及用于合成帕罗韦德的中间产物及制备方法。
据美国食品和药物管理局(FDA)当地时间12月22日消息,辉瑞公司的口服新冠药“Paxlovid”当天成为了美国首个获批的口服抗新冠病毒药物。报道称,“Paxlovid”用于治疗轻中度新冠肺炎,适用人群为12岁以上、体重40公斤以上的高危患者。Paxlovid是一种复方制剂,由300mg(2片150mg)nirmatrelvir和一片100mg利托那韦组成,Paxlovid将住院或死亡风险降低89%(症状出现后3天内启动治疗)和88%(症状出现后5天内启动治疗)。Paxlovid活性药物成分中,nirmatrelvir是一种源于辉瑞实验室的新型主蛋白酶(Mpro,也被称为3CL蛋白酶)抑制剂,专门设计用于阻断SARS-CoV-2Mpro的活性,这种酶是冠状病毒复制所需要的。低剂量利托那韦有助于减缓nirmatrelvir的代谢或分解,使其在较高浓度下在体内保持较长时间的活性,以帮助对抗病毒。
现有的帕罗韦德(PF-07321332)的合成方法,使用大量缩合剂存在不同程度的消旋风险,甚至引入多种代谢杂质,后处理相对复杂。
发明内容
本发明的目的在于解决现有技术的不足,设计出合成路线中关键的中间体化合物,简化合成路线,降低消旋风险,简化反应后处理步骤。
一种上述用于合成帕罗韦德的化合物的制备方法,所述化合物制备路线如下:
一种用于合成帕罗韦德中间产物的制备方法,所述中间产物由上述的化合物合成,由化合物与SM-1反应后制得第二化合物,第二化合物再通过与二氯亚砜反应制备中间产物,制备路线如下:
一种由上述方法直接制得的中间产物,所述中间产物分子结构如下:
一种应用上述中间产物合成帕罗韦德的方法,合成方法具体如下:
与现有技术相比,本发明的优点如下:将羧酸直接做成酰氯,做出关键的中间体,降低消旋风险,简化后处理操作,提高收率。
以下结合实施例对于本发明做进一步说明,此处所描述的具体实施例仅仅用以解释本发明,并不用于限定本发明的保护范围。
步骤1
反应方程式:
原料使用一览表:
Materials | MW(g/mol) | Weight(kg) | Moles(mol) | eq. |
化合物1 | 227.18 | 1.00 | 4.40 | 1.0 |
SOCl2 | 118.97 | 1.05 | 8.80 | 2.0 |
DCM | \ | 10.0L | \ | 10Vol |
实验操作:
反应釜中,氮气保护下加入化合物1(1.00kg,4.4mol),二氯甲烷(DCM,10.0L)。反应液降温至-5-0℃,缓慢滴加二氯亚砜(SOCl2,1.00kg,8.8mol),控制反应体系内温度低于10℃。滴加完毕后,将体系温度调至20-25℃,搅拌4-5h。通过高效液相色谱(HPLC)监控反应进度。
待反应完全后,将反应液减压蒸干至无液体滴出。蒸干得到的黄色油状物化合物1.05kg,直接用于下一步。
步骤2
反应方程式:
原料使用一览表:
Materials | MW(g/mol) | Weight(kg) | Moles(mol) | Eq. |
化合物2 | 245.63 | 1.05 | 4.27 | 1.05 |
SM-1 | 191.66 | 0.78 | 4.07 | 1.0 |
DIPEA | 129.24 | 1.58 | 12.21 | 3.0 |
DCM | \ | 15.6L | \ | 20vol |
实验操作:
将SM-1(0.78kg,4.07mol)溶于二氯甲烷(DCM,15.6L)中,氮气保护下加入N,N-二异丙基乙胺(DIPEA,1.58kg,12.21mol)。反应液降温至0℃,化合物2(第二化合物,1.05kg,4.27mol)溶于DCM(2.1L)中,缓慢滴入反应液,控制反应体系内温度低于5℃。滴加完毕后于0℃下搅拌30min,通过高效液相色谱(HPLC) 监控反应进程。
待反应完全后,将反应液倒入1N盐酸溶液(14L)中,搅拌均匀,静置待反应液分层,分离出有机相。有机相用饱和氯化钠溶液(10L)洗涤后,加入无水硫酸钠干燥,分离出有机相,蒸干。
用乙酸乙酯,正庚烷搅拌结晶得白色固体化合物3(1.29kg,两步yield:80%)。
步骤3
反应方程式:
原料使用一览表:
Materials | MW(g/mol) | Weight(kg) | Moles(mol) | Eq. |
化合物3 | 364.36 | 1.19 | 3.26 | 1.0 |
SOCl2 | 118.97 | 0.78 | 6.52 | 2.0 |
DCM | \ | 10.0L | \ | 10Vol |
实验操作:
反应釜中,氮气保护下加入化合物3(第三化合物,1.19kg,3.26mol),DCM(10.0L)。反应液降温至-5-0℃,滴加SOCl2(0.78kg,6.52mol),控制反应体系内温度低于10℃。滴加完毕,将体系温度调至20-25℃,搅拌4-5h,通过高效液相色谱(HPLC)监控反应进程。
反应完毕后,反应液减压蒸干至无液体滴出。蒸干得黄色油状物化合物1.25kg,直接用于下一步。
步骤4
反应方程式:
原料使用一览表:
Materials | MW(g/mol) | Weight(kg) | Moles(mol) | Eq. |
化合物4 | 382.13 | 1.25 | 3.27 | 1.00 |
SM-2 | 207.66 | 0.72 | 3.43 | 1.05 |
DIPEA | 129.24 | 1.27 | 9.81 | 3.00 |
DCM | \ | 25L | \ | 20vol |
实验操作:
将SM-2(0.72kg,3.43mol)溶于DCM(25L)中,氮气保护下加入DIPEA(1.27kg,9.81mol)。调节反应体系温度降至0℃,化合物4(1.25kg,3.27mol)溶于DCM(2.5L),缓慢滴入反应液,控制反应体系内温低于5℃。滴加完毕后于0℃下搅拌30min,通过高效液相色谱(HPLC)监控反应进程。
待反应完全后,将反应液倒入1N盐酸溶液(12L)中,搅拌均匀,静置待反应液分层,分离出有机相。有机相用饱和氯化钠溶液(10L)洗涤后,加入无水硫酸钠干燥,分离出有机相,蒸干。
用乙酸乙酯,正庚烷搅拌结晶得白色固体化合物5(1.46kg,两步yield:86%)。
步骤5
反应方程式
原料使用一览表:
Materials | MW(g/mol) | Weight(kg) | Moles(mol) | Eq. |
化合物5 | 517.54 | 1.45 | 2.8 | 1.00 |
TFAA | 210.03 | 1.76 | 8.4 | 3.0 |
Et3N | 101.19 | 1.70 | 16.8 | 6.00 |
DCM | \ | 29L | \ | 20vol |
实验操作:
将化合物(51.45kg,2.8mol)溶于DCM(29L)中,氮气保护,加入三乙胺(Et3N,1.70kg,16.8mol)。反应液降温至-10-0℃,三氟醋酸酐(TFAA,1.76kg,8.4mol)缓慢滴入反应液中,控制反应体系内温低于5℃。滴加完毕后于0℃下搅拌30min,通过高效液相色谱(HPLC)监控反应进程。
待反应完全后,将反应液倒入1N氯化铵溶液(12L)中,搅拌均匀,静置待反应液分层,分离出有机相。有机相用饱和氯化钠溶液(10L)洗涤后,加入无水硫酸钠干燥,分离出有机相,蒸干。
用乙酸乙酯,正庚烷搅拌结晶得白色固体化合物6(1.18kg,yield:84%)。
通过设计出关键的中间产物化合物2,化合物4,可以简化整个合成步骤;通过二氯亚砜将羧基变成酰氯,可以降低消旋风险,简化后处理操作,提高产率。
Claims (5)
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202111667768.0 | 2021-12-31 | ||
CN202111667768.0A CN114213275B (zh) | 2021-12-31 | 2021-12-31 | 用于合成帕罗韦德的中间产物及制备方法 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2023124236A1 true WO2023124236A1 (zh) | 2023-07-06 |
Family
ID=80707698
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/CN2022/118602 WO2023124236A1 (zh) | 2021-12-31 | 2022-09-14 | 用于合成帕罗韦德的中间产物及制备方法 |
Country Status (2)
Country | Link |
---|---|
CN (1) | CN114213275B (zh) |
WO (1) | WO2023124236A1 (zh) |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN114213275B (zh) * | 2021-12-31 | 2023-08-04 | 戊言医药科技(上海)有限公司 | 用于合成帕罗韦德的中间产物及制备方法 |
WO2023200364A1 (ru) * | 2022-04-15 | 2023-10-19 | Общество С Ограниченной Ответственностью "Промомед Рус" | Способы получения (1r,2s,5s)-n-[(1s)-1-циано-2-[(3s)-2-оксопирролидин-3-ил]этил]-3-[(2s)-3,3-диметил-2-[(2,2,2-трифторацетил)амино]бутаноил]-6,6-диметил-3-азабицикло[3.1.0]гексан-2-карбоксамида |
CN114989045B (zh) * | 2022-06-14 | 2023-09-08 | 斯坦德药典标准物质研发(湖北)有限公司 | 合成奈玛特韦的中间体及其制法以及合成奈玛特韦的方法 |
WO2024003737A1 (en) * | 2022-06-30 | 2024-01-04 | Pfizer Inc. | Process and intermediates useful for preparing nirmatrelvir |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2021226546A1 (en) * | 2020-05-08 | 2021-11-11 | The Board Of Trustees Of The Leland Stanford Junior University | Protease inhibitors for treatment or prevention of coronavirus disease |
WO2021250648A1 (en) * | 2020-09-03 | 2021-12-16 | Pfizer Inc. | Nitrile-containing antiviral compounds |
CN114031543A (zh) * | 2021-12-21 | 2022-02-11 | 上海朴颐化学科技有限公司 | 一种帕罗韦德中间体的制备方法 |
CN114213275A (zh) * | 2021-12-31 | 2022-03-22 | 戊言医药科技(上海)有限公司 | 用于合成帕罗韦德的中间产物及制备方法 |
CN114591299A (zh) * | 2021-12-24 | 2022-06-07 | 雅本化学股份有限公司 | 一种帕罗韦德中间体及其制备和应用 |
-
2021
- 2021-12-31 CN CN202111667768.0A patent/CN114213275B/zh active Active
-
2022
- 2022-09-14 WO PCT/CN2022/118602 patent/WO2023124236A1/zh unknown
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2021226546A1 (en) * | 2020-05-08 | 2021-11-11 | The Board Of Trustees Of The Leland Stanford Junior University | Protease inhibitors for treatment or prevention of coronavirus disease |
WO2021250648A1 (en) * | 2020-09-03 | 2021-12-16 | Pfizer Inc. | Nitrile-containing antiviral compounds |
CN114031543A (zh) * | 2021-12-21 | 2022-02-11 | 上海朴颐化学科技有限公司 | 一种帕罗韦德中间体的制备方法 |
CN114591299A (zh) * | 2021-12-24 | 2022-06-07 | 雅本化学股份有限公司 | 一种帕罗韦德中间体及其制备和应用 |
CN114213275A (zh) * | 2021-12-31 | 2022-03-22 | 戊言医药科技(上海)有限公司 | 用于合成帕罗韦德的中间产物及制备方法 |
Non-Patent Citations (3)
Title |
---|
DAFYDD, R. OWEN ET AL.: "An Oral SARS-CoV-2 Mpro Inhibitor Clinical Candidate for the Treatment of COVID-19", SCIENCE, vol. 374, no. 6575, 2 November 2021 (2021-11-02), XP093017184, ISSN: 0036-8075, DOI: 10.1126/science.abl4784 * |
DUAN, CHUANQI ET AL.: "Review of Synthetic Route of Oral Small-Molecule Anti-COVID-19 Drugs Monupivir and Parovade", CHINESE JOURNAL OF PHARMACEUTICALS, vol. 52, no. 12, 10 December 2021 (2021-12-10), XP009547271, ISSN: 1001-8255 * |
ZHAO YAO, FANG CHAO, ZHANG QI, ZHANG RUXUE, ZHAO XIANGBO, DUAN YINKAI, WANG HAOFENG, ZHU YAN, FENG LU, ZHAO JINYI, SHAO MAOLIN, YA: "Crystal structure of SARS-CoV-2 main protease in complex with protease inhibitor PF-07321332", PROTEIN & CELL, SPRINGER ASIA, BEIJING, CN, vol. 13, no. 9, 1 September 2022 (2022-09-01), Beijing, CN , pages 689 - 693, XP093074503, ISSN: 1674-800X, DOI: 10.1007/s13238-021-00883-2 * |
Also Published As
Publication number | Publication date |
---|---|
CN114213275B (zh) | 2023-08-04 |
CN114213275A (zh) | 2022-03-22 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
WO2023124236A1 (zh) | 用于合成帕罗韦德的中间产物及制备方法 | |
JP4016081B2 (ja) | ベンゼン環に置換基があるo−カルバモイル−フェニルアラニノールとその薬剤学的に有用な塩及びその製造方法 | |
EP0415850A1 (fr) | Sels de métaux bivalents de l'acide N, N-di(carboxyméthyl)amino-2 cyano-3 carboxyméthyl-4 carboxy-5 thiophène,leur procédé de préparation et les compositions pharmaceutiques les renfermant | |
JPS59163400A (ja) | ウルソデソキシコ−ル酸硫酸エステルのナトリウム塩 | |
CN111848365A (zh) | 一种大麻二酚的合成方法 | |
US4330472A (en) | Meta-sulfonamido-benzamide derivatives | |
CN114437043B (zh) | 一种抗新冠药物Nirmatrelvir的制备方法 | |
US3812109A (en) | Substituted indenyl glucoronide esters | |
CN110498829B (zh) | 雷公藤内酯醇衍生物及其制备方法和其药物组合物与用途 | |
CA1097684A (fr) | PROCEDE DE PREPARATION D'ACIDES.gamma.ARYL .gamma.OXO ISOVALERIQUES | |
FI82045B (fi) | Foerfarande foer framstaellning av den terapeutiskt anvaendbara polymorf i-formen av monoetanolaminosaltet av n-(2-pyridyl)-2-metyl-4-hydroxi-2h-1,2-bensotiazin-3-karboamid-1,1 dioxid. | |
EP0656364B1 (fr) | Nouveaux dérivés de l'érythromycine, leur procédé de préparation et leur application comme médicaments | |
US4301167A (en) | 2-Amino thiazoline derivatives | |
US4559360A (en) | Cysteine derivatives, a process for their preparation, and pharmaceutical compositions which contain them | |
CN115448826B (zh) | 一种天然冰片代谢物的分离与鉴定 | |
CA1099290A (fr) | Procede de preparation du 7-amino 6,7 dihydro (5h) benzocycloheptene | |
CN116891450A (zh) | 一种艾拉莫德的合成方法 | |
Harwood et al. | THE SYNTHESIS OF LAURIC ACID AND DODECYLAMINE CONTAINING CARBON FOURTEEN1 | |
JPH11503755A (ja) | 塩酸ラニチジンフォーム1の製造方法 | |
JPS60231634A (ja) | ビフエニルオキシアミノアルカン類および医薬 | |
CN110128498B (zh) | 一种薯蓣皂苷元衍生物及其药物组合物与其制备和应用 | |
TW201837046A (zh) | 伊克薩姆畢(Ixazomib)檸檬酸中間體之製造方法以及使用其製造之伊克薩姆畢檸檬酸 | |
CN104974154A (zh) | 毛钩藤碱类似物及其在制备抗高血压药物中的用途 | |
IL29838A (en) | Diethyl alpha-(2-dibenzofuranyl)-malonate | |
FR2509298A1 (fr) | Nouveaux derives de cystine et leurs sels utiles comme medicaments et procede de leur preparation |
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: 22913505 Country of ref document: EP Kind code of ref document: A1 |