WO2023201802A1 - Procédé de synthèse d'ensitrelvir - Google Patents

Procédé de synthèse d'ensitrelvir Download PDF

Info

Publication number
WO2023201802A1
WO2023201802A1 PCT/CN2022/093012 CN2022093012W WO2023201802A1 WO 2023201802 A1 WO2023201802 A1 WO 2023201802A1 CN 2022093012 W CN2022093012 W CN 2022093012W WO 2023201802 A1 WO2023201802 A1 WO 2023201802A1
Authority
WO
WIPO (PCT)
Prior art keywords
reaction
ensetvir
potassium
synthesis method
sodium
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/CN2022/093012
Other languages
English (en)
Chinese (zh)
Inventor
王鹏
陈正树
田湘寅
刘国杰
钱刚
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Hangzhou Guorui Bio Technology Co Ltd
Original Assignee
Hangzhou Guorui Bio Technology Co Ltd
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 Hangzhou Guorui Bio Technology Co Ltd filed Critical Hangzhou Guorui Bio Technology Co Ltd
Publication of WO2023201802A1 publication Critical patent/WO2023201802A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • 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
    • C07D403/14—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 three or more hetero rings

Definitions

  • the present invention relates to the technical field of compound synthesis, and specifically relates to a method for synthesizing ensetivir.
  • Ensitrelvir is a small molecule drug jointly developed by Japan's Shionogi Company and Hokkaido University to target the new coronavirus. This is a 3CL protease inhibitor, mainly used to inhibit the activity of the new coronavirus and various mutant strains, thereby achieving the purpose of treating the new coronavirus. Unlike Pfizer Paxlovid (PF-07321332), ensetvir can get rid of dependence on P450 enzyme inhibitors (such as ritonavir) and achieve single-drug treatment of COVID-19 without worrying about other drugs that need to be taken at the same time due to P450 enzyme inhibitory effects. and produce pharmacological reactions.
  • P450 enzyme inhibitors such as ritonavir
  • the present invention aims to provide a synthesis method of ensetvir small molecule drug with simplified synthesis steps, low raw material prices, high yield, and suitable for industrial production.
  • the present invention provides a synthesis method of ensetvir, and the synthesis method is:
  • the hydrolysis reaction from SM to C-1 described in the above synthesis method is carried out in an alkaline or acidic environment;
  • the base is selected from one or more of sodium hydroxide, potassium hydroxide, and lithium hydroxide;
  • the acid is one or more of hydrochloric acid, sulfuric acid, phosphoric acid, formic acid, and acetic acid; preferably it is one of sodium hydroxide or sulfuric acid.
  • the reaction from C-1 to C-2 needs to be carried out under conditions containing a reaction reagent, and the reaction reagent is selected from diethyl azodicarboxylate or diisopropyl azodicarboxylate.
  • the reaction reagent is diisopropyl azodicarboxylate.
  • the reaction of intermediates C-2 to C-3 described in the above synthesis method is the reaction of intermediate C-2 and 2,4,5-trifluorobenzyl bromide under the action of a base;
  • the base is selected from potassium carbonate , one or more of sodium carbonate, cesium carbonate, potassium phosphate, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide, triethylamine and pyridine; preferably potassium carbonate or Sodium methoxide.
  • product C-4 which is the reaction of intermediate C-3 and 6-chloro-2-methyl-2H-indazole-5-amine under the action of alkali; so Described base is selected from potassium carbonate, sodium carbonate, potassium phosphate, potassium tert-butoxide, sodium tert-butoxide, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, lithium bistrimethylsilylamide, bistrimethylsilylamide One or more of sodium bistrimethylsilylamide and potassium bistrimethylsilylamide; preferably lithium bistrimethylsilylamide or potassium carbonate.
  • a synthesis method of ensetvir specifically includes the following steps:
  • the heating reaction described in step (1) is carried out under alkaline or acidic conditions, and the alkali is one or more of sodium hydroxide, potassium hydroxide and lithium hydroxide; preferably sodium hydroxide;
  • the acid is one or more of hydrochloric acid, sulfuric acid, phosphoric acid, formic acid and acetic acid; preferably sulfuric acid.
  • the reaction reagent described in step (2) is diethyl azodicarboxylate or diisopropyl azodicarboxylate.
  • reaction reagent described in step (2) is diisopropyl azodicarboxylate.
  • the solvent 1 described in step (2) is one or more of tetrahydrofuran, diethyl ether, ethyl acetate, acetonitrile, N,N-dimethylformamide, dichloromethane and toluene.
  • the crystallization solvent described in step (2) and step (3) is one or more of methyl tert-butyl ether, diethyl ether, ethyl acetate, n-heptane, petroleum ether, acetonitrile, dichloromethane and toluene.
  • the crystallization solvent described in step (2) and step (3) is one or more of ethyl acetate, methyl tert-butyl ether and toluene.
  • the alkali described in step (3) is potassium carbonate, sodium carbonate, cesium carbonate, potassium phosphate, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide, triethylamine and pyridine one or more.
  • the base described in step (3) is potassium carbonate or/and sodium methoxide.
  • the base described in step (4) includes potassium carbonate, sodium carbonate, potassium phosphate, potassium tert-butoxide, sodium tert-butoxide, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, and lithium bistrimethylsilylamide. , one or more of sodium bistrimethylsilylamide and potassium bistrimethylsilylamide.
  • the base described in step (4) is lithium bistrimethylsilylamide or/and potassium carbonate.
  • reaction of intermediate C-1 with (1-methyl-1H-1,2,4-triazol-3-yl)methanol selectively reacts with the nitrogen at position 6 to avoid the use in the original research route. It is a cumbersome step to protect the nitrogen at position 2 or 4 with tert-butyl group and then remove the protecting group.

Landscapes

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

Abstract

La présente invention relève en particulier du domaine technique de la synthèse de composés. Est divulgué un procédé de synthèse d'ensitrelvir. Le procédé de synthèse comprend les étapes suivantes consistant à : réaliser une réaction sur du chlorure cyanurique (SM) comme matériau de départ pour obtenir un intermédiaire C-1 ; faire réagir l'intermédiaire C-1 avec du (1-méthyl-1H-1,2,4-triazol-3-yl)méthanol pour obtenir un intermédiaire C-2 ; réaliser une réaction sur l'intermédiaire C-2 pour obtenir un intermédiaire C-3 ; puis réaliser une réaction sur l'intermédiaire C-3 pour obtenir un produit C-4, à savoir l'ensitrelvir. Le procédé de synthèse décrit dans la présente invention simplifie les étapes de synthèse, réduit le coût des matériaux de départ, et présente un rendement élevé, étant ainsi approprié pour une production industrielle.
PCT/CN2022/093012 2022-04-20 2022-05-16 Procédé de synthèse d'ensitrelvir Ceased WO2023201802A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202210418682.2 2022-04-20
CN202210418682.2A CN114805314B (zh) 2022-04-20 2022-04-20 一种恩赛特韦的合成方法

Publications (1)

Publication Number Publication Date
WO2023201802A1 true WO2023201802A1 (fr) 2023-10-26

Family

ID=82504841

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2022/093012 Ceased WO2023201802A1 (fr) 2022-04-20 2022-05-16 Procédé de synthèse d'ensitrelvir

Country Status (2)

Country Link
CN (1) CN114805314B (fr)
WO (1) WO2023201802A1 (fr)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023193818A1 (fr) * 2022-04-08 2023-10-12 湖北九康通生物医药有限公司 Procédé de synthèse d'un composé triazine polysubstitué
CN115109041B (zh) * 2022-06-07 2024-03-19 杭州科巢生物科技有限公司 一种3cl蛋白抑制剂恩赛特韦的合成方法及其中间体
CN115819407A (zh) * 2022-12-13 2023-03-21 浙江乐普药业股份有限公司 一种Ensitrelvir类似物及其制备方法和抗新冠用途
CN116514786A (zh) * 2023-06-26 2023-08-01 北京科翔中升医药科技有限公司 一种氘代吲唑三嗪类化合物的制备方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113773300A (zh) * 2021-09-27 2021-12-10 成都施贝康生物医药科技有限公司 磺酰胺类化合物、其制备方法及用途
WO2022138988A1 (fr) * 2021-04-14 2022-06-30 塩野義製薬株式会社 Dérivé de triazine ayant un effet inhibiteur sur la propagation de virus, et composition pharmaceutique le contenant

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103153968B (zh) * 2010-08-10 2016-02-03 盐野义制药株式会社 三唑衍生物及含有其的具有镇痛作用的药物组合物
CN114853741B (zh) * 2022-05-07 2023-08-04 苏州立新制药有限公司 一种新冠病毒主蛋白酶抑制剂的制备方法

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022138988A1 (fr) * 2021-04-14 2022-06-30 塩野義製薬株式会社 Dérivé de triazine ayant un effet inhibiteur sur la propagation de virus, et composition pharmaceutique le contenant
CN113773300A (zh) * 2021-09-27 2021-12-10 成都施贝康生物医药科技有限公司 磺酰胺类化合物、其制备方法及用途

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
UNOH YUTO, UEHARA SHOTA, NAKAHARA KENJI, NOBORI HARUAKI, YAMATSU YUKIKO, YAMAMOTO SHIHO, MARUYAMA YUKI, TAODA YOSHIYUKI, KASAMATSU: "Discovery of S-217622, a Non-Covalent Oral SARS-CoV-2 3CL Protease Inhibitor Clinical Candidate for Treating COVID-19", BIORXIV, 26 January 2022 (2022-01-26), XP093086254, DOI: 10.1101/2022.01.26.477782 *

Also Published As

Publication number Publication date
CN114805314B (zh) 2023-12-15
CN114805314A (zh) 2022-07-29

Similar Documents

Publication Publication Date Title
WO2023201802A1 (fr) Procédé de synthèse d'ensitrelvir
CN107365275B (zh) 高纯度的赛乐西帕
CN106146379A (zh) 一种奥拉西坦的合成方法
CN105399736A (zh) 一种依匹哌唑新的制备方法
WO2017096996A1 (fr) Procédé de préparation de cobimetinib
CN102206178B (zh) 制备艾瑞昔布的方法
WO2019127903A1 (fr) Procédé simple de préparation d'avibactam
CN115521337A (zh) 一种瑞德西韦中间体的合成方法
MXPA04008109A (es) Metodo para preparar cloruro de bencisoxasol metano sulfonilo y su amidacion para formar zonisamida.
CN108129513A (zh) 一种合成布格替尼中间体的方法
CN108373468B (zh) 一种n-2-吡啶-5-嘧啶甲胺的制备方法
KR102674919B1 (ko) 3-브로모-5-(2-에틸이미다조[1,2-a]피리딘-3-카르보닐)-2-하이드록시벤조니트릴의 합성
CN115286491B (zh) 一种2-[2-(6-溴己氧基)乙氧基甲基]-1,3-二氯苯的制备方法
CN110878097A (zh) 菲格替尼的制备方法
CN115784992A (zh) 一种吡唑巯甲基化衍生物的制备方法及其应用
CN103880859B (zh) （3aS,6aR）-1,3-二苄基四氢-4H-噻吩并[3,4-d]咪唑-2,4-（1H）-二酮的制备方法
CN109476591B (zh) 6-芳基氨基吡啶酮甲酰胺mek抑制剂化合物的中间体的制备方法
CN111499622B (zh) 一种治疗胆管癌的药物的制备方法
CN103012256B (zh) 罗氟司特的合成方法
CN116535326A (zh) 一种普瑞巴林杂质的制备方法
CN114560862A (zh) 一种吡咯并[1,2-a]喹喔啉-4(5h)-酮及其衍生物的合成方法
JPH03261778A (ja) 新規ベンゾフラン誘導体、尿酸排泄剤及びその製法
CN101293854B (zh) 培美曲塞的新中间体及制备方法与应用
WO2020125581A1 (fr) Dérivés d'amide et procédé de préparation d'intermédiaires de ceux-ci
CN110590771A (zh) 一种[1,5-a]-吡啶并咪唑-1-腈及其化学合成方法

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: 22938036

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: 22938036

Country of ref document: EP

Kind code of ref document: A1