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WO2023108601A1 - Procédé de synthèse de loxoprofène et de ses analogues - Google Patents

Procédé de synthèse de loxoprofène et de ses analogues Download PDF

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Publication number
WO2023108601A1
WO2023108601A1 PCT/CN2021/139085 CN2021139085W WO2023108601A1 WO 2023108601 A1 WO2023108601 A1 WO 2023108601A1 CN 2021139085 W CN2021139085 W CN 2021139085W WO 2023108601 A1 WO2023108601 A1 WO 2023108601A1
Authority
WO
WIPO (PCT)
Prior art keywords
loxoprofen
acid
add
synthetic method
compound
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/CN2021/139085
Other languages
English (en)
Chinese (zh)
Inventor
梅义将
李洁平
李永刚
于帅
胡剀
王长发
汪路峰
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.)
Zhejiang Jiuzhou Pharmaceutical Co Ltd
Original Assignee
Zhejiang Jiuzhou Pharmaceutical 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 Zhejiang Jiuzhou Pharmaceutical Co Ltd filed Critical Zhejiang Jiuzhou Pharmaceutical Co Ltd
Publication of WO2023108601A1 publication Critical patent/WO2023108601A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C253/00—Preparation of carboxylic acid nitriles
    • C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
    • C07C255/32—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring
    • C07C255/40—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by doubly-bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/317—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by splitting-off hydrogen or functional groups; by hydrogenolysis of functional groups
    • C07C67/32—Decarboxylation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
    • C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
    • C07C69/738—Esters of keto-carboxylic acids or aldehydo-carboxylic acids

Definitions

  • the invention relates to the field of drug synthesis, in particular to a method for synthesizing loxoprofen and its analogues.
  • Loxoprofen (2-[4-(2-oxopentylmethyl)phenylpropionic acid) is a non-steroidal anti-inflammatory and analgesic drug, which has significant analgesic, anti-inflammatory and antipyretic effects, especially analgesic effects Very strong.
  • the finished drug is formed of its sodium salt, that is, loxoprofen sodium, which is a prodrug and is converted into an active metabolite in the body after being absorbed by the digestive tract.
  • the active metabolite exerts analgesic effects by inhibiting the synthesis of prostaglandins , anti-inflammatory and antipyretic effects.
  • the mixed acid is not effectively recovered, resulting in a large amount of waste of acid water and environmental pollution. Even if it is recovered, resources need to be invested and the treatment cost will be increased.
  • the invention provides a method for synthesizing loxoprofen and its analogs, which avoids the use of a large amount of acid solution.
  • the present invention adopts following technical scheme:
  • reaction formula A kind of synthetic method of loxoprofen and analog thereof, reaction formula is as follows:
  • Compound I reacts under the catalysis of catalyst to generate compound II.
  • the catalyst is an inorganic metal salt of halogen such as fluorine, chlorine, bromine, iodine, organic ammonium salt, organic phosphine salt (tetramethylphosphine bromide, tetraphenylphosphine bromide, etc.), organic One or more mixtures of amines (including alkylamines and nitrogen-containing heterocycles), hydrochlorides, hydrobromides, and hydroiodides of organic phosphines.
  • halogen such as fluorine, chlorine, bromine, iodine, organic ammonium salt, organic phosphine salt (tetramethylphosphine bromide, tetraphenylphosphine bromide, etc.), organic One or more mixtures of amines (including alkylamines and nitrogen-containing heterocycles), hydrochlorides, hydrobromides, and hydroiodides of organic phosphines.
  • the reaction temperature is 100-200°C.
  • the reaction is carried out without a solvent or in a solvent with a boiling point exceeding 100°C.
  • the reaction temperature of the reaction in the invention usually needs to reach 100°C, so a solvent-free reaction or a solvent with a boiling point exceeding 100°C is selected.
  • the reaction substrate is in a liquid state at high temperature and can act as a solvent. Dipolar solvents, oxygen-containing solvents, and a small amount of water can effectively increase the solubility of the catalyst and accelerate the reaction. In non-polar solvents such as toluene, the solubility of the catalyst decreases and the reaction speed is relatively slow.
  • the solvent with a boiling point exceeding 100°C is DMF (N,N-dimethylformamide), DMAC (N,N-dimethylacetamide), NMP (N-methylpyrrolidone) , DMSO (dimethyl sulfoxide), toluene, xylene, chlorobenzene, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, etc. or one or more.
  • organic amines including alkylamines and nitrogen-containing heterocyclic rings
  • organic phosphine sodium oxalate, sodium acetate, sodium propionate, sodium butyrate, disodium malonate, malic acid in the reaction system
  • basic compounds such as metal salts of organic acids such as sodium and sodium citrate, or metal salts of phenolic compounds such as phenol and p-nitrophenol
  • the catalyst can also be recovered and applied mechanically.
  • adding a small amount of water in the reaction system is beneficial for the reaction to proceed.
  • the present invention has the following advantages:
  • the present invention avoids the use of large quantities of acid solutions.
  • the invention can be carried out under the condition of no solvent, and is more green and environment-friendly.
  • the catalyst used in the method of the invention can be recycled and used mechanically, and the recovery rate of the catalyst reaches 98%, which greatly reduces the emission of three wastes and environmental pollution.

Landscapes

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

Abstract

L'invention concerne un procédé de synthèse de loxoprofène et d'analogues de celui-ci tel que représenté dans la formule de réaction suivante, le composé (I) subissant une réaction sous la catalyse d'un catalyseur pour générer le composé (II). Le procédé évite l'utilisation d'une grande quantité d'une solution acide et peut être mis en oeuvre dans des conditions sans solvant, et par conséquent le procédé est plus respectueux de l'environnement. Le catalyseur utilisé peut être recyclé et réutilisé, le taux de récupération du catalyseur atteint 98 %, et l'évacuation des trois déchets et la pollution environnementale sont considérablement réduites.
PCT/CN2021/139085 2021-12-13 2021-12-17 Procédé de synthèse de loxoprofène et de ses analogues Ceased WO2023108601A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202111513343.4A CN114276243A (zh) 2021-12-13 2021-12-13 一种洛索洛芬及其类似物的合成方法
CN202111513343.4 2021-12-13

Publications (1)

Publication Number Publication Date
WO2023108601A1 true WO2023108601A1 (fr) 2023-06-22

Family

ID=80872007

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2021/139085 Ceased WO2023108601A1 (fr) 2021-12-13 2021-12-17 Procédé de synthèse de loxoprofène et de ses analogues

Country Status (2)

Country Link
CN (1) CN114276243A (fr)
WO (1) WO2023108601A1 (fr)

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997024308A1 (fr) * 1995-12-29 1997-07-10 Nippon Zeon Co., Ltd. Procede de preparation de composes carbonyle
CN101412670A (zh) * 2007-10-19 2009-04-22 浙江普洛医药科技有限公司 洛索洛芬钠的合成方法
CN104326903A (zh) * 2014-10-14 2015-02-04 合肥远志医药科技开发有限公司 一种高纯度洛索洛芬钠二水合物的工业化生产方法
WO2015075981A1 (fr) * 2013-11-22 2015-05-28 株式会社クレハ Procédé de préparation d'un composé carbonylé
CN104684881A (zh) * 2012-11-27 2015-06-03 株式会社吴羽 羰基化合物的制备方法
CN104710309A (zh) * 2015-02-05 2015-06-17 浙江普洛医药科技有限公司 洛索洛芬钠及其中间体的合成方法
CN108440274A (zh) * 2018-03-06 2018-08-24 大桐制药（中国）有限责任公司 一种高纯度非甾体消炎药洛索洛芬钠的合成方法

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2001081066A (ja) * 1999-09-10 2001-03-27 Nippon Petrochem Co Ltd 置換スチレン誘導体
US8846743B2 (en) * 2010-08-13 2014-09-30 Abbott Laboratories Aminoindane derivatives, pharmaceutical compositions containing them, and their use in therapy
CN103449946B (zh) * 2013-09-04 2015-01-14 黄山学院 一种ɑ-单氯代酮类化合物的制备方法
CN104591989B (zh) * 2015-01-05 2017-08-29 上海华谊（集团）公司 5‑[(4‑氯苯基)甲基]‑2,2‑二甲基环戊酮的制备方法
CN108083967A (zh) * 2017-12-27 2018-05-29 安徽金善化工科技有限公司 一种甲苯的蒸馏回收方法

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997024308A1 (fr) * 1995-12-29 1997-07-10 Nippon Zeon Co., Ltd. Procede de preparation de composes carbonyle
CN101412670A (zh) * 2007-10-19 2009-04-22 浙江普洛医药科技有限公司 洛索洛芬钠的合成方法
CN104684881A (zh) * 2012-11-27 2015-06-03 株式会社吴羽 羰基化合物的制备方法
WO2015075981A1 (fr) * 2013-11-22 2015-05-28 株式会社クレハ Procédé de préparation d'un composé carbonylé
CN104326903A (zh) * 2014-10-14 2015-02-04 合肥远志医药科技开发有限公司 一种高纯度洛索洛芬钠二水合物的工业化生产方法
CN104710309A (zh) * 2015-02-05 2015-06-17 浙江普洛医药科技有限公司 洛索洛芬钠及其中间体的合成方法
CN108440274A (zh) * 2018-03-06 2018-08-24 大桐制药（中国）有限责任公司 一种高纯度非甾体消炎药洛索洛芬钠的合成方法

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