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1,4-Sulfur bridged polycyclic compound containing dihydrobenzofuran structure, its preparation method and use

A polycyclic compound, dihydrobenzene technology, applied in organic chemistry methods, organic chemistry, drug combination and other directions, to achieve the effects of easy availability of raw materials and catalysts, mild reaction conditions, and good stereoselectivity

Active Publication Date: 2022-03-25
CHENGDU UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, through literature research, we found that asymmetric reactions involving nitroheteroaromatic compounds are mainly used to construct chiral polycyclic ring compounds and chiral polycyclic spiro compounds, while there are few reports on the construction of bridged polycyclic compounds. few

Method used

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  • 1,4-Sulfur bridged polycyclic compound containing dihydrobenzofuran structure, its preparation method and use
  • 1,4-Sulfur bridged polycyclic compound containing dihydrobenzofuran structure, its preparation method and use
  • 1,4-Sulfur bridged polycyclic compound containing dihydrobenzofuran structure, its preparation method and use

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] Embodiment 1: synthetic compound I-aa

[0039]

[0040] Add 2-nitrobenzofuran Ⅱ-a 0.2mmol, 5H-thiazolone Ⅲ-a 0.26mmol, 5A molecular sieve 100mg and chiral catalyst A / B / C / D into a dry reaction test tube, then add 2.0 mL of solvent was reacted at room temperature under the protection of argon. After the reaction was complete, the crude product was separated and purified by column chromatography to obtain compound I-aa. The different reaction conditions are shown in Table 2. The specific reaction process is as follows:

[0041]

[0042] Table 2 Different reaction conditions

[0043] serial number catalyst x solvent time (h) Molecular sieve Ar Yield (%) dr ee(%) 1 A 20 CHCl 3

20 none none 40 >20:1 73 2 B 20 CHCl 3

20 none none 41 >20:1 61 3 C 20 CHCl 3

10 none none 39 >20:1 64 4 D 20 CHCl 3

24 none none 33 >20:1 85 5 D 20 CH 2 Cl 2

24 none none ...

Embodiment 2

[0050] Embodiment 2: synthetic compound I-ba

[0051]

[0052] Add 2-nitrobenzofuran II-b 0.2mmol, 5H-thiazolone III-a 0.26mmol, 5A molecular sieve 100mg and chiral catalyst D 0.02mmol in a dry reaction test tube, then add 2.0mL dichloromethane , reacted at room temperature under the protection of argon; after the reaction was complete, the crude product was separated and purified by column chromatography to obtain compound I-ba.

[0053] Pale yellow solid; 87% yield; >20:1dr, 94%ee; m.p.178.5-179.5℃, [α] D 25 =-425.5(c 1.0, CH 2 Cl 2 ).

[0054] Wherein, the mensuration of ee value adopts HPLC method: Chiralpak IC chromatographic column; Mobile phase 95 / 5hexane / EtOH; Flow velocity: 1.0mL / min; Detection wavelength λ=220nm; major =21.78min,t minor = 12.01 min.

[0055] Structure Identification: 1 H NMR (400MHz, DMSO-d 6 )δ10.23(s,1H),7.59–7.53(m,2H),7.51–7.45(m,3H),7.37(dd,J=8.1,2.4Hz,1H),7.26–7.18(m,2H) ,4.83(s,1H),1.61(s,3H). 13 C NMR (101MHz, DMSO-d 6 )δ176.5,...

Embodiment 3

[0056] Embodiment 3: synthetic compound I-ca

[0057]

[0058] Add 2-nitrobenzofuran II-c 0.2mmol, 5H-thiazolone III-a 0.26mmol, 5A molecular sieve 100mg and chiral catalyst D 0.02mmol in a dry reaction test tube, then add 2.0mL dichloromethane , reacted at room temperature under the protection of argon; after the reaction was complete, the crude product was separated and purified by column chromatography to obtain compound I-ca.

[0059] Pale yellow solid; 95% yield; >20:1dr, 90%ee; m.p.138.2-139.1℃, [α] D 25 =-538.6(c 1.0, CH 2 Cl 2 ).

[0060] Wherein, the mensuration of ee value adopts HPLC method: Chiralpak IC chromatographic column; Mobile phase 90 / 10hexane / EtOH; Flow velocity: 1.0mL / min; Detection wavelength λ=220nm; major =23.51min,t minor = 14.52 min.

[0061] Structure Identification: 1 H NMR (400MHz, DMSO-d 6 )δ10.28(s,1H),7.58(dd,J=6.8,3.0Hz,2H),7.55–7.47(m,3H),7.43–7.29(m,2H),7.21–7.11(m,1H) ,4.94(s,1H),1.61(s,3H). 13 C NMR (101MHz, DMSO-d 6 )δ176.4...

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Abstract

The invention discloses a class of 1,4-sulfur-bridged polycyclic compounds containing a dihydrobenzofuran structure, which belongs to the field of organic synthesis, and has a structure as shown in formula (I); it also discloses a preparation method of 2 ‑Nitrobenzofuran (II) and 5 H ‑Thiazolone (Ⅲ) is dissolved in an organic solvent, then molecular sieves and chiral catalyst are added, and the reaction is stirred at room temperature under the protection of argon. After the reaction is completed, the 1,4‑sulfur containing dihydrobenzofuran structure is separated and purified Bridged polycyclic compound; the polycyclic compound provided by the present invention has a substructure of dihydrobenzofuran and 1,4-thiopiperidinone; the use of this type of compound in the preparation of antitumor drugs is also disclosed, It has very good potential value in antitumor drug research; and the preparation method of the invention has the advantages of novelty, simplicity, simple operation, mild reaction conditions, high yield, high stereoselectivity and the like.

Description

technical field [0001] The invention relates to the field of organic synthesis, in particular to a 1,4-sulfur-bridged polycyclic compound containing a dihydrobenzofuran structure, its preparation method and application. Background technique [0002] Bridged polycyclic compounds widely exist in natural products and drug molecules, have a wide range of biological activities, and are important sources for the development of new drugs. Morphine, as a very important clinically important potent analgesic, is a bridged polycyclic drug with a dihydrobenzofuran structure. In view of the important biological activity of benzofuran structure and the extensive pharmacological properties of bridged polycyclic compounds, the synthesis of bridged polycyclic compounds containing dihydrobenzofuran structure is of great scientific significance. At the same time, from the perspective of drug design, combining two or more pharmacological functional groups into one molecule may produce unexpect...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D513/18A61P35/00A61P35/02
CPCC07D513/18A61P35/00A61P35/02C07B2200/07C07B2200/13A61K31/429
Inventor 赵建强周顺袁伟成游勇王振华
Owner CHENGDU UNIV