WO2009109989A1 - Nouveau procédé de préparation d'éthers de dihydroartémisinine - Google Patents

Nouveau procédé de préparation d'éthers de dihydroartémisinine Download PDF

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Publication number
WO2009109989A1
WO2009109989A1 PCT/IN2009/000050 IN2009000050W WO2009109989A1 WO 2009109989 A1 WO2009109989 A1 WO 2009109989A1 IN 2009000050 W IN2009000050 W IN 2009000050W WO 2009109989 A1 WO2009109989 A1 WO 2009109989A1
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WO
WIPO (PCT)
Prior art keywords
dihydroartemisinin
chloride
ethers
product
pro
Prior art date
Application number
PCT/IN2009/000050
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English (en)
Inventor
Chintamani Prabhakar Bapat
Sushil Joginderpal Dheer
Somnath Kisan Dhamale
Original Assignee
Calyx Chemicals And Pharmaceuticals 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 Calyx Chemicals And Pharmaceuticals Ltd. filed Critical Calyx Chemicals And Pharmaceuticals Ltd.
Publication of WO2009109989A1 publication Critical patent/WO2009109989A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/22—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains four or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
    • A61P33/06—Antimalarials

Definitions

  • the present invention relates to a novel process for the preparation of ethers of dihydroartemisinin, commonly known as artemether, the methyl ether derivative and arteether, the ethyl ether derivative.
  • the present invention more particularly relates to a novel process for the preparation of artemether and arteether containing more than 99% of ⁇ isomer.
  • Artemisinin is a new class of compounds found to be effective in the treatment of uncomplicated/severe complicated/cerebral malaria. This class of compounds is found to be effective against multi-drug resistant strains. Artemisinin is derived from Artimisia annua. Derivatives of artemisinin are used either singly or in combination with other antimalarial drugs in the treatment of severe malaria and are effective against both chloroquine-resistant and sensitive strains of Plasmodium falciparum. Artesunate, arteether, artemether and dihydroartemisinin are among the preferred derivatives. Above mentioned compounds are safe, and do not have side effects.
  • Dihydroartemisinin is obtained from artemisinin by sodium borohydride reduction.
  • Arteether, artemether and other ethers of dihydroartemisinin are generally prepared from dihydroartemisinin. Both ⁇ - and ⁇ - isomers of the ethers are formed during the synthesis.
  • Arteether is sold as a mixture of ⁇ / ⁇ which is known as Rapither AB and as ⁇ -arteether known as Artemotil. Artemotil is injectable formulation of ⁇ -arteether in sesame oil and Betamotil is injectable formulation of ⁇ -arteether in Araeze oil. In 2006, ⁇ -arteether formulation, Artemotil was pre-qualified by WHO for the treatment of malaria.
  • Artemether is sold as ⁇ -artemether.
  • Ethers of dihydroartemisinin are prepared from dihydroartemisinin by reacting it with an alkylating agent in the presence of a strong acid as catalyst in a suitable solvent.
  • IN 191588 discloses a one pot process for the preparation of artemether wherein artemisinin is reduced to dihydroartemisinin by sodium borohydride which is converted to ether in the presence of a cation exchange resin wherein the ratio of dihydroartemisinin to the cation exchange resin is l:3.
  • the product is obtained as mixture of ⁇ / ⁇ artemether which is separated by column chromatography to obtain pure ⁇ - and ⁇ - isomers.
  • IN 173947 discloses a process for the preparation of arteether wherein etherification of dihydroartemisinin is carried out using ethanol in dry benzene with boron trifluoride etherate as catalyst which produces a 70:30 diastereoisomeric mixture of arteether which is then fractionally crystallized to provide both the enantiomers.
  • Indian patent application 00542/DEL/2003 describes a process for the preparation of arteether by reacting dihydroartemisinin with dry. EtOH in toluene at 50-60° for 15 min. using anhydrous AICI 3 as catalyst. The product is obtained as a mixture of ⁇ - and ⁇ - isomers in the ratio of 29.6:71.8.
  • Indian patent application 00432/MUM/2007 describes a process for the preparation of artemether by reacting dihydroartemisinin with MeOH in toluene using Me 3 SiCl to give a mixture of ⁇ - and ⁇ -artemether.
  • a Chinese patent CNl 106012 describes a process which uses strong acids such as trifluoromethanesulfonic acid, perchloric acid in a mixture of aprotic solvent and alcohol.
  • Indian patent application 00013/DEL2007 describes a process for the preparation of artemether by reacting dihydroartemisinin with trimethylorthoforrnate in presence of p- toluenesulfonic acid as acid catalyst.
  • ⁇ - isomer of ethers of dihydroartemisinin can be obtained in a high yield and purity by reacting dihydroartemisinin with an alcohol and acid chloride as a pro-acid catalyst in the presence of a co-solvent such as trialkylorthoformate.
  • the amount of pro-acid catalyst required to carry out reaction of the present invention is very small as compared to the catalysts used in the prior art.
  • a novel process for the preparation of ethers of dihydroartemisinin containing more than 99% of ⁇ isomer from dihydroartemisinin comprising the steps of: a) Reacting dihydroartemisinin with an alcohol in presence of a pro-acid catalyst and in the presence of a co-solvent at 0 - 45°C.
  • the present invention provides a novel process for the preparation of ethers of dihydroartemisinin, more particularly artemether and arteether
  • the present invention particularly relates to a novel process for the preparation of artemether or arteether containing more than 99% of ⁇ isomer from dihydroartemisinin which comprises: a) reacting dihydroartemisinin with an ⁇ alcohol and hydrolysable organic halides as a pro-acid catalyst in the presence of a co-solvent at 0 - 45°C b) diluting the reaction mixture with an aqueous solution of mild bases such as sodium bicarbonate, sodium acetate or triethanolamine c) cooling the reaction mass to 0°C-5°C and stirring to obtain the solid product d) filtering the solid to obtain the ethers of dihydroartemisinin e) recrystallizing the product from suitable solvent mixture such as alcohol and water to obtain ethers of dihydroartemisinin containing more than 99% of ⁇ isomer
  • the product ( ⁇ - isomer) obtained after a simple work up is a crystalline solid with >99% purity.
  • dihydroartemisinin is reacted with an alcohol and acid halide as a pro-acid catalyst in the presence of a co-solvent to obtain artemether or arteether containing more than 99% of ⁇ isomer.
  • the pro-acid catalyst is selected from aliphatic acid halide, aromatic acid halide, and inorganic acid halide or sulfonyl chloride.
  • aliphatic acid halide is selected form acetyl chloride, acetyl bromide, pivaloyl chloride, oxalyl chloride, more preferably acetyl chloride.
  • aromatic acid halide is selected form benzoyl chloride or reactive halo compounds such as benzotrichloride
  • inorganic acid chloride is selected from sulfur or phosphorus oxy chloride and trimethyl silylchloride, more preferably thionyl chloride.
  • sulfonyl chloride is selected from methane sulfonylchloride, bezene sulfonylchloride or p-toluene sulfonyl chloride.
  • the ratio of dihydroartemisinin to pro-acid catalyst is from 1:0.01 to 0.1 preferably 1: 0.02 to 0.05, more preferably 1: 0.03.
  • the co-solvent is selected from trialkylorthoformate, tiralkylorthoaceate, liquids having acetal or ketal functional groups such as 2,2-dimethoxypropane, or enol ethers such as 2-methoxypropene, preferably trialkyl orthoformates.
  • the ratio of dihydroartemisinin to the co- solvent is 1: 0.1 to 1:6 preferably 1: 2 to 1:4.
  • the ratio of dihydroartemisinin to the alcohol is 1:3 to 1:12, preferably 1:6.
  • reaction is carried out between O 0 C- 45 0 C, preferably between 5°C-30°C, more preferably between 10 0 C-15°C.
  • Another aspect of the present invention is to provide a process for the preparation of artemether and arteether by using an acid chloride as a pro-acid catalyst in very small amount (mole percent 0.03 to 0.06 with respect to dihydroartemisinine).
  • Inventors of the present invention found out that the desired product is obtained using very less quantity of pro-acid catalyst as compared to the other acid catalysts that are used in the prior art. It makes the process of the present invention cost effective and environmentally friendly.
  • US 6346631 discloses the use of dihydroartemisinin and solid acid catalyst in the ratio of 1 to 2:1.
  • IN191588 describes the use of dihydroartemisinin and cation exchange resin in the ratio of 1:3.
  • the ratio of dihydroartemisinin to pro-acid catalyst used in the present invention is 1:0.03 to 1:0.06
  • the product is isolated by easy work up procedure wherein the reaction mass after treating with a mild aqueous base cooled to O 0 C- 5°C and the precipitated product is filtered which is then recrystallised from a mixture of alcohol and water to get the ethers of dihydroartemisinin containing more than 99% pure ⁇ - isomer.
  • Dihydroartemisinin used in the examples was prepared by methods known in the literature.
  • the beta isomer was confirmed by NMR and showed characteristic proton signal for ClO-H.

Landscapes

  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un procédé de préparation d'éthers de dihydroartémisinine contenant plus de 99 % d'isomère ß de dihydroartémisinine, qui comprend la réaction de dihydroartémisinine avec un alcool et des halogénures organiques hydrolysables en tant que catalyseur pro-acide en présence d'un co-solvant à 0 - 45 °C, la dilution du mélange réactionnel avec une solution aqueuse de bases douces comme le bicarbonate de sodium, l'acétate de sodium ou la triéthanolamine, le refroidissement de la masse réactionnelle à 0 - 5 °C et son agitation pour obtenir le produit solide, la filtration du solide pour obtenir les éthers de dihydroartémisinine, la recristallisation du produit dans un mélange de solvants approprié tel qu'un mélange d'alcool et d'eau afin d'obtenir des éthers de dihydroartémisinine contenant plus de 99 % d'isomère ß.
PCT/IN2009/000050 2008-01-21 2009-01-21 Nouveau procédé de préparation d'éthers de dihydroartémisinine WO2009109989A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN140MU2008 2008-01-21
IN140/MUM/2008 2008-01-21

Publications (1)

Publication Number Publication Date
WO2009109989A1 true WO2009109989A1 (fr) 2009-09-11

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102351875A (zh) * 2011-09-14 2012-02-15 浙江医药股份有限公司新昌制药厂 一种蒿甲醚生产过程中所产生的母液的回收利用方法
WO2012042536A2 (fr) * 2010-09-27 2012-04-05 Sequent Scientific Limited Procédé de préparation de dérivés éther de la dihydroartémisinine
CN103113385A (zh) * 2013-01-24 2013-05-22 张家港威胜生物医药有限公司 以双氢青蒿素为原料制备青蒿素10位醚类衍生物的简单大生产工艺
CN112358488A (zh) * 2020-11-05 2021-02-12 张家港威胜生物医药有限公司 一种β-蒿甲醚的制备方法

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1106012A (zh) * 1994-01-28 1995-08-02 中信技术公司 制备双氢青蒿素醚类衍生物的改进方法

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1106012A (zh) * 1994-01-28 1995-08-02 中信技术公司 制备双氢青蒿素醚类衍生物的改进方法

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
"PROCESSES FOR PREPARING ETHER DERIVATIVES OF DIHYDRO-ARTEMESININ", IP.COM JOURNAL, IP.COM INC., WEST HENRIETTA, NY, US, 12 September 2007 (2007-09-12), XP013122033, ISSN: 1533-0001 *
BOEHM, MATTHIAS ET AL: "An Improved Manufacturing Process for the Antimalaria Drug Coartem. Part I", ORGANIC PROCESS RESEARCH & DEVELOPMENT , 11(3), 336-340 CODEN: OPRDFK; ISSN: 1083-6160, 2007, XP002539923 *
DATABASE WPI Week 199730, Derwent World Patents Index; AN 1997-320740, XP002539924 *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012042536A2 (fr) * 2010-09-27 2012-04-05 Sequent Scientific Limited Procédé de préparation de dérivés éther de la dihydroartémisinine
WO2012042536A3 (fr) * 2010-09-27 2012-05-31 Sequent Scientific Limited Procédé de préparation de dérivés éther de la dihydroartémisinine
CN102351875A (zh) * 2011-09-14 2012-02-15 浙江医药股份有限公司新昌制药厂 一种蒿甲醚生产过程中所产生的母液的回收利用方法
CN102351875B (zh) * 2011-09-14 2014-07-02 浙江医药股份有限公司新昌制药厂 一种蒿甲醚生产过程中所产生的母液的回收利用方法
CN103113385A (zh) * 2013-01-24 2013-05-22 张家港威胜生物医药有限公司 以双氢青蒿素为原料制备青蒿素10位醚类衍生物的简单大生产工艺
CN112358488A (zh) * 2020-11-05 2021-02-12 张家港威胜生物医药有限公司 一种β-蒿甲醚的制备方法

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