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Oxacyclononadiene derivative, and pharmaceutical composition, preparation method and application thereof

An oxygen heterocycle, nonadiene technology, applied in the directions of drug combination, pharmaceutical formula, organic chemical method, etc., can solve the problems of limited industrial production, complex production process, low product yield, etc., achieve good anti-tumor effect, broad The effect of market application prospects

Pending Publication Date: 2020-02-28
CHENGDU ORGANIC CHEM CO LTD CHINESE ACAD OF SCI +1
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] At present, some progress has been made in the research on the synthesis of related structural analogs of oxacyclic nonadiene in the prior art. However, the production process of related compounds of oxacyclic nonadiene in the prior art is complicated, and the product yield is low. greatly limited its industrial production

Method used

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  • Oxacyclononadiene derivative, and pharmaceutical composition, preparation method and application thereof
  • Oxacyclononadiene derivative, and pharmaceutical composition, preparation method and application thereof
  • Oxacyclononadiene derivative, and pharmaceutical composition, preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0068] Compound: (3E,7Z)-5,5-Dicyano-4,8-diphenyl-2,5,6,9-tetrahydrooxacyclononadiene-3-ethyl acetate

[0069]

[0070] Preparation:

[0071] S1, preparation of dicyanodiene 5:

[0072] Step 1: Put benzaldehyde 1 (1.0eq) into a 250mL round-bottomed flask, add distilled water (100mL) as a solvent, put in a clean stirring bar, then add malononitrile (1.2eq), and react at room temperature for 12h . After the reaction was detected by TLC, a large amount of solids were precipitated, filtered, the filter cake was washed with petroleum ether, and the white solid product benzylidene malononitrile 3 was dried;

[0073] Step 2: Weigh benzylidene malononitrile 3 (1.0eq), catalyst PPh 3 (0.2eq) was added to a 250mL round-bottomed flask with a stirring magnet, and a reaction device with a constant pressure dropping funnel was assembled. Under the protection of argon, accurately measure 25mL of toluene into the round-bottomed flask with a syringe, and then accurately measure Ethyl pr...

Embodiment 2

[0088] Compound: (3E,7Z)-4-(3-chlorophenyl)-5,5-dicyano-8-phenyl-2,5,6,9-tetrahydrooxacyclononadiene-3- ethyl acetate

[0089]

[0090] Preparation:

[0091] The difference with the preparation method of embodiment 1 is:

[0092] (1) In step S3, the reaction catalyst is palladium tetrakistrifurylphosphine; the reaction temperature is 15°C; the molar ratio of palladium tetrafurylphosphine, dicyanodiene 5 and the alkenyl cyclic carbonate 11 satisfies: 0.04:0.8:1.2; The reaction time is 20h; The reaction solvent is dichloromethane;

[0093] (2) Compound 1 is 3-chlorobenzaldehyde, compound 4 is ethyl propiolate, and compound 6 is acetophenone; the product is a light yellow solid with a yield of 69%;

[0094] 1 H NMR (600MHz, CDCl 3 )δ (ppm): 7.54 (d, J = 7.8Hz, 2H), 7.41–7.36 (m, 4H), 7.33 (t, J = 8.4Hz, 1H), 7.20 (s, 1H), 7.10 (d, J=7.2Hz, 1H), 6.24(t, J=9.0Hz, 1H), 4.61(s, 2H), 4.56(d, J=4.8Hz, 2H), 3.91(q, J=6.0Hz, 2H) ,3.62(d,J=11.4Hz,2H),0.87(t,J=7.2Hz,3H).

[0095...

Embodiment 3

[0097] Compound: (3E,7Z)-4-(3-bromophenyl)-5,5-dicyano-8-phenyl-2,5,6,9-tetrahydrooxacyclononadiene-3- ethyl acetate

[0098]

[0099] Preparation:

[0100] The difference with the preparation method of embodiment 1 is:

[0101] (1) In step S3, the reaction catalyst is tetrakistributylphosphine palladium; the reaction temperature is 22°C; the molar ratio of tetrakistributylphosphine palladium, dicyanodiene 5 and the alkenyl cyclic carbonate 11 satisfies : 0.06:1.5:2.2; the reaction time is 30h;

[0102](2) Compound 1 is 3-bromobenzaldehyde, compound 4 is ethyl propiolate, and compound 6 is acetophenone;

[0103] The product is a yellow semi-solid with a yield of 53%;

[0104] 1 H NMR (600MHz, CDCl 3 )δ(ppm):7.59–7.51(m,3H),7.44–7.36(m,3H),7.36–7.32(m,1H),7.28(d,J=8.4Hz,1H),7.15(d,J =7.8Hz, 1H), 6.23(t, J=9.0Hz, 1H), 4.60(s, 2H), 4.56(d, J=4.2Hz, 2H), 3.91(q, J=7.2Hz, 2H), 3.62(dd,J=9.0,5.4Hz,2H),0.87(t,J=7.2Hz,3H).

[0105] 13 C NMR (150MHz, CDCl 3 )δ (ppm): 167....

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Abstract

The invention provides an oxacyclononadiene derivative, a stereochemical isomer thereof, a solvate thereof or a pharmaceutically acceptable salt thereof. The oxacyclononadiene derivative can achieve arelatively good anti-tumor effect. The invention also provides a preparation method of the oxacyclononadiene derivative. The preparation method comprises the following steps: adding a palladium catalyst into a reactor, then dissolving dicyanodiene and alkenyl cyclic carbonate into a solvent, adding the formed solution into the reactor under the protection of argon, carrying out a reaction for 20-30 hours at a temperature of 15-22 DEG C, and performing concentrating and purifying to obtain the oxacyclononadiene derivative. The preparation method is simple in process, high in yield and convenient for industrial popularization and application. In addition, the invention also provides a pharmaceutical composition with the oxacyclononadiene derivative as an active ingredient and application ofoxacyclononadiene in preparation of antitumor drugs.

Description

technical field [0001] The present invention relates to the field of medicine and chemical industry, in particular, to an oxacyclononadiene derivative, its pharmaceutical composition, its preparation method and application. Background technique [0002] The oxacyclic nonadiene skeleton widely exists in natural products and synthetic drugs. Relevant studies have shown that compounds containing this skeleton have a variety of important biological and pharmaceutical activities. The modification of substituents and the derivation of structural analogues of such compounds The evaluation of chemical properties and further biological activity has become a research hotspot. [0003] At present, some progress has been made in the research on the synthesis of related structural analogs of oxacyclic nonadiene in the prior art. However, the production process of related compounds of oxacyclic nonadiene in the prior art is complicated, and the product yield is low. Greatly limit its ind...

Claims

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Application Information

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IPC IPC(8): C07D313/00C07D409/04A61P35/00A61K31/335A61K31/381
CPCC07D313/00C07D409/04A61P35/00C07B2200/13
Inventor 王启卫张翔成大智张雪玲李俊龙黄晴菲李青竹戴青松何鑫磊
Owner CHENGDU ORGANIC CHEM CO LTD CHINESE ACAD OF SCI
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