WO2023104063A1 - 一种碘佛醇水解物的制备方法 - Google Patents

一种碘佛醇水解物的制备方法 Download PDF

Info

Publication number
WO2023104063A1
WO2023104063A1 PCT/CN2022/137106 CN2022137106W WO2023104063A1 WO 2023104063 A1 WO2023104063 A1 WO 2023104063A1 CN 2022137106 W CN2022137106 W CN 2022137106W WO 2023104063 A1 WO2023104063 A1 WO 2023104063A1
Authority
WO
WIPO (PCT)
Prior art keywords
ioversol
hydrolyzate
preparation
iodide
add
Prior art date
Application number
PCT/CN2022/137106
Other languages
English (en)
French (fr)
Inventor
饶经纬
沈艳阳
岳永力
顾建军
鲁飞
林立
张建
Original Assignee
安庆朗坤药业有限公司
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 安庆朗坤药业有限公司 filed Critical 安庆朗坤药业有限公司
Publication of WO2023104063A1 publication Critical patent/WO2023104063A1/zh
Priority to ZA2023/07893A priority Critical patent/ZA202307893B/en

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/14—Preparation of carboxylic acid amides by formation of carboxamide groups together with reactions not involving the carboxamide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups

Definitions

  • the invention belongs to the field of medicinal chemistry, and in particular relates to a preparation method of a pharmaceutical intermediate ioversol hydrolyzate.
  • ioversol is 5-(N-2-hydroxyethyl) hydroxyacetamide-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-1 , 3-phthalamide, is a non-ionic X-ray contrast agent, its preparation is ioversol injection, the dosage is relatively large, and the requirements on the limit of impurities are strict.
  • Patents US4396598, WO2008/104853, etc. all prepare ioversol by iodide, and the prepared ioversol has many impurities, and it is difficult to meet large-scale industrial production by preparative chromatographic purification.
  • Patent WO93/16981 reported that iodide and ethoxyacetyl chloride were catalyzed by N,N-lutidine to prepare acetylated intermediates, and then further substituted and hydrolyzed to prepare ioversol.
  • the present invention provides a method for preparing high-purity ioversol hydrolyzate (CAS: 77868-40-7), which uses iodide (I) and acetoxyacetyl chloride (acetoxyacetylchloride, AAcCl, II) as raw materials , carry out acetoacetylation reaction in the environment of adding acid-binding agent to obtain intermediate (III); then carry out hydrolysis reaction to obtain ioversol hydrolyzate (IV).
  • iodide (I) and acetoxyacetyl chloride acetoxyacetylchloride, AAcCl, II
  • the ioversol hydrolyzate prepared by the method has a yield of more than 90% and a purity of more than 99.5%, which meets the needs of industrial production of ioversol; at the same time, the method has fewer steps, is safe to operate, and is environmentally friendly, and the raw materials used are all commercially available products , suitable for large-scale industrial production.
  • a preparation method of ioversol hydrolyzate, its concrete steps are as follows:
  • the solvent includes at least one of N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, and dimethylsulfoxide;
  • the acid-binding agent includes at least one of triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, and pyridine, preferably using triethylamine;
  • step 2) At a temperature of 0-50°C, add an alkaline solution dropwise to the reactant in step 1), adjust the pH of the reactant solution to 12-14, stir, and perform a hydrolysis reaction for 0.5h-2h; then add concentrated hydrochloric acid (37% by mass ), adjust the pH of the solution to 4-7 (pH is preferably 5-7), a large amount of solids are precipitated in the reaction solution, after solid-liquid separation (preferably suction filtration), take the solid (filter residue) 60-80 ° C blast drying or After vacuum drying, the obtained white solid is the target product ioversol hydrolyzate (IV).
  • the molar ratio of ethoxyacetyl chloride (II) and iodide (I) is 5.2-6.6: 1.
  • the mass ratio of solvent to iodide (I) is 1-5:1.
  • the reaction in the ethoxyacetylation reaction involved in step 1) of the present application, if no acid-binding agent is added, the reaction will be difficult to complete completely. After hydrolysis, there will be more raw material iodide remaining, and the product purification loss will be relatively large. Yet under the situation that acid-binding agent proportioning is more, reaction has a small amount of target product ioversol hydrolyzate to generate. Therefore, the molar ratio of the added acid-binding agent to iodide (I) is preferably 3.0-4.2:1.
  • the concentration of the alkaline solution added in step 2) is 10%-35%; the alkaline solution is preferably sodium hydroxide solution, lithium hydroxide solution, At least one of potassium hydroxide solution.
  • the preparation method provided by the examples of the present application has the following beneficial effects:
  • the preparation method provided by this application uses the commercially available product iodide (I) as a raw material, and the preparation of this raw material does not need to go through the stage of preparing acid chlorides, which is easy to prepare and has less environmental pollution.
  • the preparation method provided by the examples of the present application is simpler than the existing preparation method using iodide as a raw material, and the reaction steps are shorter than the reaction steps disclosed in patent US 4396598 and WO2008/104853.
  • Patent US4396598 requires three-step reactions
  • Patent WO2008/104853 requires three or four steps of reaction
  • the reaction route of this application only needs two steps of reaction to prepare the target product ioversol hydrolyzate, the steps are simplified, and it is more suitable for large-scale industrial production.
  • the preparation method provided by the examples of the present application has a high yield of the target product ioversol hydrolyzate with a similar preparation route and a high purity. High, more suitable for industrial applications.
  • the preparation reaction of the route provided by this application is completed by a one-pot reaction.
  • the obtained ethoxyacetylated product (III) does not need to be separated and purified, and the product ioversol hydrolyzate (IV) has fewer impurities and higher purity.
  • Fig. 1 is the high performance liquid phase chromatogram of ioversol hydrolyzate prepared in embodiment 1.
  • the white solid obtained by liquid chromatography detection (GL Sciences, 9L3704-02, C18 4.6*250,5um; phosphoric acid aqueous solution (pH3.0)-acetonitrile 90:10 is the mobile phase; detection wavelength: 240nm; flow rate: 1.0ml /min; column temperature 35° C.; area normalization method, the same below), which proves that it is ioversol hydrolyzate, and the purity obtained in this embodiment is 53.72%.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

一种碘佛醇水解物的制备方法，该方法以工业化的碘化物为原料，经过与乙酰氧基乙酰氯进行乙酰氧基乙酰化反应、水解后调酸得到碘佛醇水解物。该方法在水溶液中进行析晶，安全环保，所得目标产物的收率在90％以上，纯度在99.5％以上，适合作为碘佛醇工业化生产的原料使用。

Description

一种碘佛醇水解物的制备方法 技术领域
本发明属于药物化学领域，具体涉及一种医药中间体碘佛醇水解物的制备方法。
背景技术
碘佛醇化学名称为5-(N-2-羟乙基)羟乙酞胺基-N,N’-双(2，3-二羟丙基)-2，4，6-三碘-1，3-苯二甲酰胺，是一种非离子型X-射线造影剂，其制剂为碘佛醇注射液，用量较大，对杂质限度要求严格。专利US4396598、WO2008/104853等均通过碘化物来制备碘佛醇，制备的碘佛醇杂质较多，通过制备色谱纯化，难以满足大规模工业化生产。
由于碘化物易于制备，价格低廉，通过碘化物制备高纯度碘佛醇中间体碘佛醇水解物对制备高纯度产品碘佛醇有重要意义。专利WO93/16981报道了碘化物和乙氧乙酰氯在N,N-二甲基吡啶催化下，制备乙酰化中间体，然后进一步取代后水解反应制备碘佛醇，然而乙氧乙酰氯和碘化物在N,N-二甲基吡啶催化下，反应难以完全进行，水解物中有较多的碘化物原料剩余，不宜用于大规模工业生产。
文献“5-(N-2-羟乙基)羟乙酰氨基-N,N'-双(2,3-二羟丙基)-2,4,6-三碘-1,3-苯二甲酰胺的合成”(“邹霈等，有机化学，25(10)，1244-1247；2005”)报道了一种通过碘化物和乙氧乙酰氯制备碘佛醇水解物的一种方法，该方法制备碘佛醇水解物纯度较低，需要乙二醇单甲醚和正丁醇混合溶剂多次精制才能达到99％以上，且收率较低，且制备步骤繁琐，同样不宜工业应用。
发明内容
针对上述问题，本发明提供一种高纯度碘佛醇水解物(CAS:77868-40-7)制备方法，该方法以碘化物(I)和乙氧乙酰氯(acetoxyacetylchloride,AAcCl,II)为原料，在添加缚酸剂环境中进行乙酰乙酰化反应，获得中间体(III)；然后进行水解反应，得到碘佛醇水解物(IV)。该方法制备的碘佛醇水解物收率达90％以上，纯度达99.5％以上，满足碘佛醇工业化生产需求；同时该方法步骤较少，操作安全，绿色环保，所用原料均为市售产品，适合大规模工业化生产。
具体来说，本申请是通过如下技术方案实现的：
一种碘佛醇水解物的制备方法，其具体步骤如下：
1)将碘化物
Figure PCTCN2022137106-appb-000001
和乙氧乙酰氯
Figure PCTCN2022137106-appb-000002
在溶剂中混合均匀，降温至0-5℃，滴加缚酸剂，滴加完成后，0-40℃保温搅拌24h，进行乙氧乙酰化反应，获得乙氧乙酰化产物(III)；
所述溶剂包括N,N-二甲基甲酰胺，N,N-二甲基乙酰酰胺，N-甲基吡咯烷酮，二甲亚砜中的至少一种；
所述缚酸剂包括三乙胺，N,N-二异丙基乙胺，N-甲基吗啉，吡啶中的至少一种，优选的使用三乙胺；
2)0-50℃温度，向步骤1)反应物中滴加碱性溶液，调节反应物溶液pH至12-14，搅拌，进行水解反应0.5h-2h；再加入浓盐酸(质量百分比37％)，调节溶液pH至4-7(pH优选的5-7)，反应液中有大量固体析出，进行固液分离(优选抽滤)后，取固体(滤渣)60-80℃鼓风干燥或真空干燥,获得的白色固体即为目标产物碘佛醇水解物(IV)。
本申请方法涉及的反应方程式如下:
Figure PCTCN2022137106-appb-000003
优选的，本申请所提供的碘佛醇水解物制备方法中，步骤1)进行乙氧乙酰化反应时，乙氧乙酰氯(II)和碘化物(I)的摩尔配比为5.2-6.6：1。
优选的，本申请所提供的碘佛醇水解物制备方法中，步骤1)乙氧乙酰化反应时，溶剂与碘化物(I)质量比为1-5：1。
本申请步骤1)涉及的乙氧乙酰化反应中，如果不加入缚酸剂，反应难以彻底完成，水解后有较多原料碘化物剩余，产品纯化损失较大。然而在缚酸剂配比 较多的情况下，反应有少量目标产物碘佛醇水解物生成。因此所加入的缚酸剂和碘化物(I)摩尔比例优选为3.0-4.2：1。
优选的，本申请所提供的碘佛醇水解物制备方法中，步骤2)所加入的碱性溶液浓度为10％-35％；所述碱性溶液优选氢氧化钠溶液、氢氧化锂溶液、氢氧化钾溶液中的至少一种。
与现有的碘佛醇水解物制备方法相比，本申请实施例所提供的制备方法具有以下有益效果：
1、本申请提供的制备方法以市售产品碘化物(I)为原料，该原料制备不需要经过制备酰氯阶段，易于制备，对环境污染较少。
2、本申请实施例提供的制备方法较以碘化物为原料的现有制备方法更为简便，较专利US 4396598和WO2008/104853所公开的反应步骤反应步骤更短，专利US4396598需要三步反应，专利WO2008/104853需经过三步或四步反应，而本申请反应路线仅需两步反应即可制备目标产物碘佛醇水解物，步骤简化，更加适合大规模工业生产。
3、本申请实施例提供的制备方法较相似制备路线的专利WO93/16981和文献Youji huaxue,25(10)，1244-1247；2005相比，所得目标产物碘佛醇水解物收率高，纯度高，更适合工业化的应用。
4、本申请提供的路线制备反应通过一锅法反应来完成，所获得的乙氧乙酰化产物(III)不需分离纯化，产品碘佛醇水解物(IV)杂质较少，纯度较高。
附图说明
图1为实施例1中制备获得的碘佛醇水解物的高效液相色谱图。
具体实施方式
除非特别说明，以下实施例使用得原料和试剂均为市售。
实施例1
100ml反应瓶中加入N,N-二甲基乙酰胺(DMAC)10.6g，搅拌，加入碘化物7.1g(0.01mol)，三乙胺6.7g(0.066)，降温至0-5℃，滴加入乙氧乙酰氯8.2g(0.06mol)，加毕，升温至35℃，保温搅拌24h，滴加入23g33％的氢氧化钠溶液，搅拌1h，浓盐酸调节溶液pH6-7，有大量固体析出，抽滤，取滤饼(过率获得的固体)加入少许10％甲醇/纯化水(质量百分比)清洗，然后将清洗后 的滤饼置于70℃鼓风干燥8h后，得白色固体6.5g，即为碘佛醇水解物，收率为85.2％(收率为摩尔收率，下同)。
通过液相色谱检测获得的白色固体，(GL Sciences,9L3704-02,C18 4.6*250,5um；磷酸水溶液(pH3.0)-乙腈90：10为流动相；检测波长：240nm；流速：1.0ml/min；柱温35℃；面积归一法，下同)，证明其为碘佛醇水解物，本实施例获得的纯度为53.72％。
实施例2
100ml反应瓶中加入N,N-二甲基乙酰胺(DMAC)10.6g，搅拌，加入7.1g(0.01mol)碘化物，三乙胺4.1g(0.04mol)，降温至0-5℃，滴加入乙氧乙酰氯7.5g(0.055mol)，加毕，升温至35℃，保温搅拌24h，滴加入23g33％的氢氧化钠溶液，搅拌1h，浓盐酸调节溶液pH6-7，有大量固体析出，抽滤，取少许10％甲醇/纯化水(质量百分比)洗涤抽滤获得的滤饼，70℃鼓风干燥8h后的白色固体7.2，即为碘佛醇水解物，收率为94.3％,纯度为99.81％。
实施例3
100ml反应瓶中加入N,N-二甲基甲酰胺(DMF)10.6g，搅拌，加入7.1g(0.01mol)碘化物，三乙胺4.1g(0.04mol)，降温至0-5℃，滴加入乙氧乙酰氯7.5g(0.055mol)，加毕，升温至35℃，保温搅拌24h，滴加入23g33％的氢氧化钠溶液，搅拌1h，浓盐酸调节溶液pH6-7，有大量固体析出，抽滤，少许10％甲醇/纯化水(质量百分比)洗涤抽滤获得的滤饼，70℃鼓风干燥8h后的白色固体7.0，即为碘佛醇水解物，收率为91.7％,纯度为99.78％。
实施例4
100ml反应瓶中加入N,N-二甲基乙酰胺(DMAC)10.6g，搅拌，加入7.1g(0.01mol)碘化物，三乙胺4.1g(0.04mol)，降温至0-5℃，滴加入乙氧乙酰氯8.2g(0.06mol)，加毕，升温至25℃，保温搅拌24h，滴加入23g33％的氢氧化钠溶液，搅拌1h，浓盐酸调节溶液pH5-6，有大量固体析出，抽滤，少许10％甲醇/纯化水(质量百分比)洗涤滤饼，70℃鼓风干燥10h后的白色固体7.1g，即为碘佛醇水解物，收率为93.0％,纯度为99.84％。
实施例5
100ml反应瓶中加入N,N-二甲基乙酰胺(DMAC)10.6g，搅拌，加入7.1g (0.01mol)碘化物，吡啶3.3g(0.042mol)，降温至0-5℃，滴加入乙氧乙酰氯8.2g(0.06mol)，加毕，升温至25℃，保温搅拌24h，滴加入30g25％的氢氧化钠溶液，搅拌1h，浓盐酸调节溶液pH5-6，有大量固体析出，抽滤，少许10％甲醇/纯化水(质量百分比)洗涤滤饼，70℃鼓风干燥10h后的白色固体6.9g，即为碘佛醇水解物，收率为90.4％,纯度为99.62％。
实施例6
100mL反应瓶中加入N,N-二甲基乙酰胺(DMAC)10.6kg，搅拌，加入7.05kg(10mol)碘化物，三乙胺4.05kg(40mol)，降温至0-5℃，滴加入乙氧乙酰氯7.5kg(5.5mol)，加毕，升温至35℃，保温搅拌24h，滴加入23kg33％的氢氧化钠溶液，加毕，搅拌2h，浓盐酸调节溶液pH6-7，有大量固体析出，抽滤，少许10％甲醇/纯化水(质量百分比)洗涤滤饼，70℃鼓风干燥24h后的白色固体7.15kg，即为碘佛醇水解物，收率为93.7％,纯度为99.86％。

Claims (7)

  1. 一种碘佛醇水解物的制备方法，其特征在于，具体步骤如下：
    1)将碘化物
    Figure PCTCN2022137106-appb-100001
    和乙氧乙酰氯在溶剂中混合均匀，0-5℃滴加缚酸剂；滴加完成后，0-40℃进行乙氧乙酰化反应，获得乙氧乙酰化产物；
    所述溶剂包括N,N-二甲基甲酰胺、N,N-二甲基乙酰酰胺、N-甲基吡咯烷酮、二甲亚砜中的至少一种；
    所述缚酸剂包括三乙胺、N,N-二异丙基乙胺、N-甲基吗啉、吡啶中的至少一种；
    2)0-50℃，向步骤1)乙氧乙酰化产物中滴加碱性溶液，调节溶液pH至12-14，水解反应0.5h-2h；再加入浓盐酸调节溶液pH至4-7，反应液析出固体，固液分离后，取固体干燥，即为碘佛醇水解物。
  2. 根据权利要求1所述碘佛醇水解物的制备方法，其特征在于，步骤1)中乙氧乙酰氯与碘化物的摩尔比为5.2-6.6：1。
  3. 根据权利要求1所述碘佛醇水解物的制备方法，其特征在于，步骤1)中溶剂与碘化物的质量比为1-5：1。
  4. 根据权利要求1所述碘佛醇水解物的制备方法，其特征在于，步骤1)中缚酸剂和碘化物的摩尔比为3.0-4.2：1。
  5. 根据权利要求1所述碘佛醇水解物的制备方法，其特征在于，步骤2)中所使用的碱性溶液为氢氧化钠溶液、氢氧化钾溶液、氢氧化锂溶液中的一种。
  6. 根据权利要求1所述碘佛醇水解物的制备方法，其特征在于，步骤2)中所使用的碱性溶液的质量浓度为10％-35％。
  7. 根据权利要求1所述碘佛醇水解物的制备方法，其特征在于，步骤2)中所述干燥是指60-80℃鼓风干燥或真空干燥。
PCT/CN2022/137106 2022-01-17 2022-12-07 一种碘佛醇水解物的制备方法 WO2023104063A1 (zh)

Priority Applications (1)

Application Number Priority Date Filing Date Title
ZA2023/07893A ZA202307893B (en) 2022-01-17 2023-08-14 Preparation method for ioversol hydrolysate

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202210049754.0A CN114409566B (zh) 2022-01-17 2022-01-17 一种碘佛醇水解物的制备方法
CN202210049754.0 2022-01-17

Publications (1)

Publication Number Publication Date
WO2023104063A1 true WO2023104063A1 (zh) 2023-06-15

Family

ID=81272913

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2022/137106 WO2023104063A1 (zh) 2022-01-17 2022-12-07 一种碘佛醇水解物的制备方法

Country Status (3)

Country Link
CN (1) CN114409566B (zh)
WO (1) WO2023104063A1 (zh)
ZA (1) ZA202307893B (zh)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114409566B (zh) * 2022-01-17 2022-11-22 安庆朗坤药业有限公司 一种碘佛醇水解物的制备方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993016981A1 (en) * 1992-02-28 1993-09-02 Mallinckrodt Medical, Inc. Synthesis of ioversol using a minimal excess of acetoxyacetylchloride
CN109134289A (zh) * 2017-06-16 2019-01-04 成都西岭源药业有限公司 一种高效率的造影剂合成方法及其应用
WO2022002953A1 (en) * 2020-06-29 2022-01-06 Ge Healthcare As Process for the preparation of iopamidol
CN114409566A (zh) * 2022-01-17 2022-04-29 安庆朗坤药业有限公司 一种碘佛醇水解物的制备方法

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110028418A (zh) * 2019-03-26 2019-07-19 大道隆达（北京）医药科技发展有限公司 一种碘佛醇的制备方法

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993016981A1 (en) * 1992-02-28 1993-09-02 Mallinckrodt Medical, Inc. Synthesis of ioversol using a minimal excess of acetoxyacetylchloride
CN109134289A (zh) * 2017-06-16 2019-01-04 成都西岭源药业有限公司 一种高效率的造影剂合成方法及其应用
WO2022002953A1 (en) * 2020-06-29 2022-01-06 Ge Healthcare As Process for the preparation of iopamidol
CN114409566A (zh) * 2022-01-17 2022-04-29 安庆朗坤药业有限公司 一种碘佛醇水解物的制备方法

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
ZOU PEI, LIU YA-LING, LUO SHI-NENG, XIE MIN-HAO, SHEN YONG, -JIA: "Synthesis of N,N’-Bis（2,3-dihydroxypropyl）-5-[N-（2-hydroxyethyl）-hydroxy-acetamido]-2,4,6-triiodoisophthalamide", CHINESE JOURNAL OF ORGANIC CHEMISTRY, SCIENCE PRESS, BEIJING., CN, vol. 25, no. 10, 1 January 2005 (2005-01-01), CN , pages 1244 - 1247, XP093072603, ISSN: 0253-2786 *

Also Published As

Publication number Publication date
ZA202307893B (en) 2024-04-24
CN114409566B (zh) 2022-11-22
CN114409566A (zh) 2022-04-29

Similar Documents

Publication Publication Date Title
WO2020147861A1 (zh) 一种β-三氟甲基酰胺类化合物的电化学制备方法
CN104177272B (zh) 一种溴芬酸钠的制备方法
JP4892915B2 (ja) エパルレスタット製造法
WO2023104063A1 (zh) 一种碘佛醇水解物的制备方法
CN109384664B (zh) 一种艾乐替尼中间体的制备方法
CN106146330B (zh) 一种制备艾曲波帕中间体的方法
CN108383718A (zh) 一种2，4，5-三氟苯乙酸的制备方法
CN108586399A (zh) 一种非罗考昔的合成方法
CN106117168B (zh) 一种呋塞米的制备方法
CN107445858A (zh) 三碘化造影剂的生产
CN102267934B (zh) 一种6-甲氧羰基吲哚酮的制备方法
CN103012176A (zh) 一种长链烷基四羧基阴离子表面活性剂的制备方法
CN104447509B (zh) 一种盐酸替罗非班的制备工艺
CN108997209A (zh) 一种瑞戈非尼的制备方法
CN109897075B (zh) 一种三氯蔗糖-6-乙酸酯的绿色合成方法
CN101575301B (zh) 一种2-氨基-5-氯苯甲酰胺的制备方法
CN113874351B (zh) 一种氟苯尼考的合成方法
WO2016155596A1 (zh) 一种3-卤代-d-丙氨酸甲酯或其酸式盐的合成方法
CN104557604B (zh) 5‑乙酰基水杨酰胺的合成方法
CN110878064A (zh) 一种非布司他的某个特定杂质的高收率合成方法
WO2019179286A2 (zh) 一种苯氧乙酸酯的制备方法
CN110642804A (zh) 一种非布司他的某个特定杂质的制备方法
CN109761914A (zh) 一种制备5-三氟甲基尿嘧啶的方法
CN103755706A (zh) 一种合成叶酸的环保制备方法
JPH01258649A (ja) ２，４−ジクロロ−３−アルキル−６−ニトロフェノールの製造方法

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: 22903485

Country of ref document: EP

Kind code of ref document: A1