WO2009049493A1 - Préparation de séseline et de ses dérivés - Google Patents

Préparation de séseline et de ses dérivés Download PDF

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Publication number
WO2009049493A1
WO2009049493A1 PCT/CN2008/001708 CN2008001708W WO2009049493A1 WO 2009049493 A1 WO2009049493 A1 WO 2009049493A1 CN 2008001708 W CN2008001708 W CN 2008001708W WO 2009049493 A1 WO2009049493 A1 WO 2009049493A1
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WO
WIPO (PCT)
Prior art keywords
reaction
compound
solvent
temperature
hours
Prior art date
Application number
PCT/CN2008/001708
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English (en)
Chinese (zh)
Inventor
Lan Xie
Huanfang Guo
Original Assignee
Institute Of Pharmacology And Toxicology Academy Of Military Medical Sciences P.L.A. China
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
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Application filed by Institute Of Pharmacology And Toxicology Academy Of Military Medical Sciences P.L.A. China filed Critical Institute Of Pharmacology And Toxicology Academy Of Military Medical Sciences P.L.A. China
Publication of WO2009049493A1 publication Critical patent/WO2009049493A1/fr

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    • 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
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/04—Ortho-condensed systems

Definitions

  • the present invention relates to a process for the synthesis and preparation of Seseli and its derivatives. Background technique
  • Artemisinin (1) and its derivatives are widely found in the roots of the genus Rutaceae, the fruit of the umbelliferous plant, the fruit of the genus Artemisia argyi, and the bark of the pepper. Only 20 species of P. sylvestris have been isolated. Things. Artemisinin and its analogs isolated from natural products exhibit a variety of biological activities, such as praeruptorin, which has the effect of lowering blood pressure and relaxing coronary vessels, and its mechanism of action is calcium ion antagonism. According to the available literature, its biological activity is manifested as follows: Antifungal effects (Bandara BMR, et al., Phytochem., 1991, 29: 297; Norma CC0.
  • Suksdorfin (2) was found to have significant anti-HIV activity in the screening of numerous plant natural products for anti-HIV activity, and its EC 5 . for 1.3 ⁇ (Lee, TT, et al., Bioorg. & Med. Chem., 1994 2: 1051). Then, through the structural modification of Suksdorfin, the chiral molecule (3, R, 4' R)-3, 4' - dicomphanoyl- (+) -cis-khel with the dihydroartemisinin skeleton structure (3) was discovered. Lactone (DCK) and its analogs (4) have considerable anti-HIV activity (Xie L., J. Med. Chem., 1999, 42: 2662).
  • DCK: R, , H Since artemisinin and its analogues have many biological activities and can serve as important intermediate compounds, many years have been studied on their synthesis methods [ Raghao S. Mali Et al., Tetrahedeon Lett., 1995, 36: 7109; Demetrios N. Nicolaides et al., Eur. J. Med. Chem., 2004, 39: 323; J. Hlubucke et al., Aust. J. Chem., 1971, 24: 2347; Mohammad R. Saidi et al., J. Chem. Reseach(s), 1998, 800-801; Raghao S. Mali et al., J. Chem. Soc., Perkin Trans.
  • the present invention provides a novel synthetic route and method and a preparation process suitable for mass synthesis of artemisinin having a horny pyranocoumarin tricyclic skeleton structure and a derivative thereof, which can be applied to artemisinin Mass production and industrial production of analogs.
  • the invention relates to a method of synthesizing the following formula artemisinin and its derivatives: among them,
  • RR 2 , R 3 and R 4 are each independently selected from H, OH, halogen, c "c 4 fluorenyl, dC 4 alkoxy, (C “C 4 ) -X, CN, NH 2 ;
  • X is F, CI, Br, CN, N0 2 , NH 2 or OH,
  • the compound (E) obtained in the step (4) is reduced by NaBH 4 to obtain a 4,-hydroxycaryosin compound;
  • reaction yield of each step is above 80%, and the total yield of the last five steps is ⁇ 60%, which is obviously higher than the two-step preparation method (38%) reported in the literature and patents;
  • the intermediates of each step can be purified by recrystallization, avoiding time-consuming column stratification, simplifying the purification method, and being suitable for industrial production.
  • the synthetic route of the present invention is a step The process is long, but each step is simple in operation, controllable in conditions, short in reaction time, low in cost, single in product, and high in total yield. Among them, the products of steps 1, 3 and 4 need not be separated and purified, and the next reaction can be directly carried out. The linear isomer can be removed by recrystallization from Step 2 or Step 3 to ensure that the subsequent reaction gives the desired single product.
  • the synthetic route and method are superior to the various methods reported in the literature, and are suitable for mass production and industrial production, and have practical value and broad application prospects. detailed description:
  • Example 1 Preparation of 3,4-dimercapto-7-acetoxycoumarin (C1) 9.5 g (50 mmol) 3,4-dimercapto-7-hydroxycoumarin (B1), 20 HCl acetic anhydride, heated to reflux for 90 minutes, cooled to about 50, poured into 150 g of ice water with vigorous stirring, continue to stir vigorously, precipitate a pale yellow solid, suction filtration, wash to neutral. The obtained solid was recrystallized from about 500 mL of ethanol to give pale yellow needle crystals 11. lg, yield 95.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)

Abstract

L'invention concerne un procédé de préparation de séseline et de ses dérivés. La séseline est synthétisée à partir de résorcine substituée par réaction de Pechmann, acétylation, réarrangement de Fries, cyclisation, réduction et déshydratation, séquentiellement.
PCT/CN2008/001708 2007-10-12 2008-10-09 Préparation de séseline et de ses dérivés WO2009049493A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CNA2007101639597A CN101407522A (zh) 2007-10-12 2007-10-12 邪蒿素及其衍生物的制备方法
CN200710163959.7 2007-10-12

Publications (1)

Publication Number Publication Date
WO2009049493A1 true WO2009049493A1 (fr) 2009-04-23

Family

ID=40566988

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2008/001708 WO2009049493A1 (fr) 2007-10-12 2008-10-09 Préparation de séseline et de ses dérivés

Country Status (2)

Country Link
CN (1) CN101407522A (fr)
WO (1) WO2009049493A1 (fr)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107094782A (zh) * 2017-05-26 2017-08-29 江苏省中国科学院植物研究所 邪蒿素作为农业杀菌剂的用途
CN109303776B (zh) * 2018-09-30 2020-12-18 江苏省中国科学院植物研究所 邪蒿素在制备治疗炎症性疾病药物中的应用
CN112062773B (zh) * 2019-06-11 2021-11-26 中国科学院大连化学物理研究所 一种酸催化4-羟基香豆素与异戊二烯环化反应的方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5637589A (en) * 1993-10-29 1997-06-10 University Of North Carolina At Chapel Hill Suksdorfin, analogs, compositions thereof, and methods for making and using thereof
US5892060A (en) * 1994-08-03 1999-04-06 Sarawak Medichem Pharmaceuticals, Inc. Method for the preparation of (+)-calanolide a and analogues thereof
CN1636997A (zh) * 2003-11-13 2005-07-13 中国人民解放军军事医学科学院毒物药物研究所 取代的三环香豆素类化合物、其制备及抗hiv的应用

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5637589A (en) * 1993-10-29 1997-06-10 University Of North Carolina At Chapel Hill Suksdorfin, analogs, compositions thereof, and methods for making and using thereof
US5892060A (en) * 1994-08-03 1999-04-06 Sarawak Medichem Pharmaceuticals, Inc. Method for the preparation of (+)-calanolide a and analogues thereof
CN1636997A (zh) * 2003-11-13 2005-07-13 中国人民解放军军事医学科学院毒物药物研究所 取代的三环香豆素类化合物、其制备及抗hiv的应用

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Publication number Publication date
CN101407522A (zh) 2009-04-15

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