WO2022206010A1 - Procédé de préparation simple d'isoxazolines - Google Patents

Procédé de préparation simple d'isoxazolines Download PDF

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Publication number
WO2022206010A1
WO2022206010A1 PCT/CN2021/136208 CN2021136208W WO2022206010A1 WO 2022206010 A1 WO2022206010 A1 WO 2022206010A1 CN 2021136208 W CN2021136208 W CN 2021136208W WO 2022206010 A1 WO2022206010 A1 WO 2022206010A1
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WO
WIPO (PCT)
Prior art keywords
isoxazoline
nmr
mhz
cdcl
olefin
Prior art date
Application number
PCT/CN2021/136208
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English (en)
Chinese (zh)
Inventor
万小兵
马亮
成雄略
江港钟
陶苏艳
李星星
杨金炜
Original Assignee
苏州大学
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Filing date
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Application filed by 苏州大学 filed Critical 苏州大学
Publication of WO2022206010A1 publication Critical patent/WO2022206010A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/04—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
    • C07J1/0003—Androstane derivatives
    • C07J1/0018—Androstane derivatives substituted in position 17 beta, not substituted in position 17 alfa
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J7/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms
    • C07J7/0005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21
    • C07J7/001—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group
    • C07J7/0015—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group not substituted in position 17 alfa
    • C07J7/002—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group not substituted in position 17 alfa not substituted in position 16

Definitions

  • the invention relates to a method for preparing isoxazoline, belonging to the technical field of organic synthesis.
  • Isoxazolines are the core skeletons that widely exist in natural products, drug molecules, bioactive molecules, pesticides and functional materials. In addition, it has also been used as a ligand for transition metal catalysis. Chemists have developed a series of methods for the preparation of isoxazolines, but they all have obvious shortcomings, such as: requiring a large excess of oxidant or dehydrating agent; expensive raw materials or complicated preparation; harsh reaction conditions; expensive and harmful transition metals, etc. .
  • the purpose of the present invention is to provide a method for preparing isoxazoline, which has the advantages of abundant raw material sources, wide universality of reaction substrates, simple operation, mild reaction conditions and the like.
  • the technical scheme adopted in the present invention is: a simple preparation method of isoxazoline, using aldehyde, p-toluenesulfonyl hydrazide, alkene and nitrite as reaction substrates, in the presence of alkali and copper catalyst. Under the following conditions, the isoxazoline is obtained by reaction in an organic solvent.
  • the product that the present invention obtains is isoxazoline, and its chemical structural formula is: .
  • the general formula of the chemical structure of the aldehyde is: ;
  • the general chemical structure of the alkene is: ;
  • the general formula of chemical structure of described nitrite is: .
  • R 1 is selected from aryl, substituted aryl, heteroaryl, naphthyl or alkenyl, such as aryl or substituted aryl:
  • R 2 and R 3 are independently selected from hydrogen, alkyl, fluorine, chlorine, bromine, carboxylic acid, amide, thioether, amino, alkoxy, trifluoromethyl, nitro, cyano, ester, hydroxyl or sulfone group;
  • R 4 , R 5 are independently selected from hydrogen, alkyl, aryl, ester, ether, amide, carbonyl, silicon, hydroxyl, acetal, cyano, halogen, alkynyl, carboxyl, phosphoric acid Ester group;
  • R 6 is selected from tert-butyl, n-butyl, isobutyl, isopropyl.
  • the copper catalyst is cupric chloride, cuprous chloride, cuprous bromide or cuprous iodide; preferably, the copper catalyst is cupric chloride.
  • the amount of the copper catalyst is 5-20% of the mole of the olefin; the preferred amount of the copper catalyst is 10% of the mole of the olefin.
  • the invention also discloses a method for preparing isoxazoline without metal catalyst. After mixing benzaldehyde compound and p-toluenesulfonyl hydrazide in methanol solvent, olefin, nitrite, organic solvent and alkali are added to react to obtain Isoxazoline; wherein, the general formula of the chemical structure of the benzaldehyde compound is as follows: .
  • R 1 is selected from hydrogen, alkyl, fluorine, chlorine, bromine, carboxylic acid, amide, thioether, amino, alkoxy, trifluoromethyl, nitro, cyano, ester, hydroxyl or sulfone ;
  • R 2 is selected from alkyl, aryl, ester, carbonyl, ether, amide, silicon, hydroxyl, benzal compound, cyano, halogen, alkynyl, carboxyl or phosphate group;
  • R 6 is selected from tertiary Butyl, n-butyl, isobutyl or isopropyl.
  • R 1 is selected from hydrogen, alkyl, fluorine, chlorine, bromine;
  • R 2 is selected from aryl, ester group, such as phenyl, -COOEt, substituted phenyl.
  • the benzaldehyde compound and p-toluenesulfonyl hydrazide are stirred in an alcohol solvent at 60° C. for 30 minutes, the methanol solvent is removed, and olefin, nitrite, organic solvent and alkali are added to react to obtain isoxazole. morpholino.
  • the reaction temperature of the reaction is 25-80°C; the reaction time is 12-24 hours; the preferred reaction temperature is 65°C; and the reaction time is 24 hours.
  • the reaction is carried out in the presence of a base, and the bases used are TMEDA, DABCO, and sodium carbonate; and the organic solvent is ethyl acetate, tetrahydrofuran, acetonitrile, acetone, chloroform, N , N -dimethylmethane amide.
  • the base is preferably an organic amine, such as TMEDA, and the organic solvent is tetrahydrofuran.
  • the amount of the aldehyde compound is 1 to 1.5 times the mole of the olefin; the amount of p-toluenesulfonyl hydrazide is 1 to 1.5 times the mole of the olefin, and the amount of nitrite is 3 to 5 times the mole of the olefin;
  • the dosage is 1 to 1.8 times the mole weight of olefin; preferably, the dosage of the aldehyde compound is 1.3 times the mole weight of olefin; the dosage of p-toluenesulfonyl hydrazide is 1.4 times the mole weight of olefin, and the dosage of nitrite is the mole weight of olefin 4 times the amount of the base, and the amount of the base is 1.5 times the molar amount of the olefin.
  • the reaction of the present invention is carried out in air. After the reaction, it was quenched with saturated sodium chloride solution, extracted with ethyl acetate, the solvent was removed by rotary evaporator, adsorbed on silica gel, and finally the product was obtained by column chromatography with a mixed solvent of ethyl acetate and petroleum ether. Isoxazoline.
  • the preparation method of the present invention is shown as follows: The invention also discloses the isoxazoline prepared according to the above method.
  • the present invention has the following advantages compared with the prior art: the present invention uses CuCl 2 as a catalyst to realize the multi-component reaction of aldehyde, p-toluenesulfonyl hydrazide, olefin and tert-butyl nitrite to prepare Isoxazoline is more economical in reaction, more widely applicable to substrates, easy to obtain raw materials, and easier to functionalize later, compared with the prior art, which is difficult to prepare raw materials, large amount of raw materials and harsh conditions.
  • the method disclosed by the invention has mild reaction conditions, cheap catalyst and less dosage, good gram-scale reaction, convenient post-processing, and is beneficial to the application in drug molecule synthesis and large-scale industrialization.
  • the reactants, additives, bases, catalysts and other raw materials used in the invention are cheap and easy to obtain, the reaction composition is reasonable, no ligand is required, and the reaction steps are few, and the functionalized isoxazoline can be obtained by only one step of reaction, which is in line with green chemistry and medicine. Chemistry requirements and directions.
  • the present invention discloses a catalyst-free method for preparing isoxazoline, which avoids the use of transition metals and is favorable for further use in the synthesis of drug molecules and biologically active molecules.
  • the aldehyde, olefin, p-toluenesulfonyl hydrazide, alkali, nitrite, catalyst and solvent of the present invention are all marketable commodities and can be purchased directly.
  • the specific operation method and test method of the experiment are conventional methods in the field, and the reaction is carried out in a conventional environment.
  • test tube was sealed with parafilm, stirred at 65 °C for 24 h, quenched with saturated sodium chloride solution, extracted with ethyl acetate, removed the solvent by rotary evaporator, adsorbed on silica gel, and finally used ethyl acetate and petroleum
  • the product isoxazoline 3aa can be obtained by column chromatography with the mixed solvent of ether .
  • Example 2 On the basis of Example 1, the reaction conditions were changed by a single factor: the THF (2.0 mL) added for the second time was replaced with acetone (2.0 mL), and the yield was 84%.
  • Tetramethylethylenediamine TMEDA was replaced with N,N-dimethylethanolamine DABCO (0.75 mmol), yield: 68%.
  • Tetramethylethylenediamine TMEDA was replaced by sodium carbonate (0.75 mmol), yield: 16%.
  • Tetramethylethylenediamine TMEDA was replaced with potassium carbonate (0.75 mmol) in ⁇ 1% yield.
  • Tetramethylethylenediamine TMEDA was replaced with sodium hydroxide (0.75 mmol) in ⁇ 1% yield.
  • Example 3 On the basis of Example 1, omitting the copper catalyst: in the air, to a test tube with a magnetic stirrer, add p-bromobenzaldehyde (0.65 mmol), p-toluenesulfonylhydrazide (0.7 mmol) and MeOH (1 mL), the mixture was stirred at 60 °C for 30 min. After the solvent was removed in vacuo, ethyl acrylate (0.5 mmol), TMEDA (0.75 mmol), TBN (2.0 mmol) and THF (2.0 mL) were added sequentially.
  • test tube was sealed with parafilm, stirred at 65 °C for 24 h, quenched with saturated sodium chloride solution, extracted with ethyl acetate, removed the solvent by rotary evaporator, adsorbed on silica gel, and finally used ethyl acetate and petroleum
  • the product isoxazoline 3aa can be obtained by column chromatography with the mixed solvent of ether . Yield: 61%.
  • R 1 is phenyl.
  • benzaldehyde (0.65 mmol), p-toluenesulfonylhydrazide (0.7 mmol) and MeOH (1 mL) were added, and the mixture was stirred at 60 °C for 30 min. After the solvent MeOH was removed in vacuo, CuCl2 (0.05 mmol), THF (2.0 mL), ethyl acrylate (0.5 mmol), TMEDA (0.75 mmol), TBN (2.0 mmol) and THF (2.0 mL) were sequentially added.
  • test tube was sealed with parafilm and stirred at 65 °C for 24 h. Quenched with saturated sodium chloride solution, extracted with ethyl acetate, removed the solvent with a rotary evaporator, adsorbed on silica gel, and finally performed column chromatography with a mixed solvent of ethyl acetate and petroleum ether to obtain the product isoxazoline 4 .
  • Embodiment 6 On the basis of Embodiment 4, compound 1 and compound 2 are replaced, and the rest remain unchanged to obtain the following product.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

Est divulgué dans la présente invention un procédé de préparation simple d'isoxazolines, comprenant : l'utilisation d'aldéhyde, d'hydrazide de p-toluènesulfonyle, d'oléfine et de nitrite de tert-butyle comme substrat, à l'aide de chlorure de cuivre en tant que catalyseur, à l'aide de tétraméthyléthylènediamine (TMEDA) en tant qu'alcali, et la synthèse efficace d'une série de composés d'isoxazoline à l'aide d'un procédé monotope en deux étapes. Les avantages sont les suivants : le catalyseur est bon marché, la réaction est économique, l'universalité du substrat est plus large, les matières premières sont faciles à obtenir, la fonctionnalisation ultérieure de l'étage est plus commode, les conditions de réaction sont douces, et la réaction de l'échelle du gramme est bonne ; et en particulier, dans la présente invention, un produit peut être obtenu à un rendement modéré en l'absence de catalyseur, le post-traitement est simple et pratique, et il est avantageux pour une application dans la synthèse de molécules de médicament et l'industrialisation à grande échelle, satisfaisant ainsi les exigences et les directions de la chimie verte contemporaine et de la chimie pharmaceutique.
PCT/CN2021/136208 2021-03-29 2021-12-07 Procédé de préparation simple d'isoxazolines WO2022206010A1 (fr)

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CN202110333839.7 2021-03-29
CN202110333839.7A CN113149924B (zh) 2021-03-29 2021-03-29 一种异噁唑啉的简单制备方法

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CN113149924B (zh) * 2021-03-29 2023-11-03 苏州大学 一种异噁唑啉的简单制备方法
CN113698359B (zh) * 2021-08-27 2023-04-07 安徽中医药大学 一种基于三组分反应合成3，5-二取代异恶唑类化合物的方法

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