Simple method for preparing ellipticine or substituted ellipticine

A technology for ellipticine and a preparation process, which is applied in the production of bulk chemicals, organic chemistry, etc., can solve the problems of low total yield, harsh reaction conditions, and difficulty in obtaining raw materials, and achieves simple and convenient process operation and high total yield. Effect

Active Publication Date: 2020-05-05
INST OF MATERIA MEDICA AN INST OF THE CHINESE ACAD OF MEDICAL SCI
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  • Abstract
  • Description
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  • Application Information

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Problems solved by technology

[0008] Literature (Backvall JE, Plobeck NA. New synthesis of the 6H-pyrido[4,3-b]carbazoles ellipticine and olivacine via cycloloaddition of 2-phenylsulfonyl 1,3-dienes to indoles[J]. J O

Method used

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  • Simple method for preparing ellipticine or substituted ellipticine
  • Simple method for preparing ellipticine or substituted ellipticine
  • Simple method for preparing ellipticine or substituted ellipticine

Examples

Experimental program
Comparison scheme
Effect test

Example Embodiment

[0039] Example 1 Preparation of ellipticine

[0040] Preparation of Intermediate 2

[0041] Add 11.7g (0.1mol) of indole and 11.4g (0.1mol) of 2,5-hexanedione in a round bottom flask, mix and stir to dissolve, add 0.03 equivalent of montmorillonite powder preloaded with p-toluenesulfonic acid, React in a microwave reactor for 10 minutes. The reaction solution was cooled to room temperature, diluted with ethyl acetate, filtered off the montmorillonite catalyst, the solid was washed with ethyl acetate, the organic phase was washed with saturated sodium carbonate solution, purified water, saturated sodium chloride solution, and dried with anhydrous sodium sulfate overnight. Concentrated to obtain 17.5 g of white solid with a yield of 90.0%. m.p.92-93℃. 1 H NMR(500MHz, CDCl 3 )δ8.16(d,J=7.8Hz,1H),7.45-7.36(m,2H),7.23(s,1H),7.11(d,J=7.2Hz,1H),6.92(d,J=7.2 Hz, 1H), 2.83 (s, 3H), 2.48 (s, 3H) ( figure 1 ).

[0042] Preparation of Intermediate 3

[0043] 13.5 g (0.1 mol) of N-methyl-N-ph...

Example Embodiment

[0050] Example 2 Preparation of 9-methoxy ellipticine

[0051]

[0052] Preparation of Intermediate 8

[0053] In a round bottom flask, add 14.7g (0.1mol) 5-methoxyindole and 13.5g (0.1mol) 2,5-hexanedione, mix and stir to dissolve, and add 0.03 equivalent of the monoxide preloaded with p-toluenesulfonic acid. The stone-free powder was reacted for 10 minutes in a microwave reactor. The reaction solution was cooled to room temperature, diluted with ethyl acetate, filtered off the montmorillonite catalyst, the solid was washed with ethyl acetate, the organic phase was washed with saturated sodium carbonate solution, purified water, saturated sodium chloride solution, and dried with anhydrous sodium sulfate overnight. After concentration, 19.7 g of 8 was obtained as a white solid, the yield was 87.6%, and the melting point was 135-137°C.

[0054] Preparation of Intermediate 9

[0055] 3.85g (28.5mmol) of N-methyl-N-phenylformamide was added to the three-neck flask, 4.62g (29.5mmol) of...

Example Embodiment

[0061] Example 3 Ellipticine Chromatographic Analysis Method

[0062] The purity of ellipticine was determined by HPLC method, with ODS-3C18 chromatographic column, the particle size of the filler is 5μm, the specification is 250×4.6mm, the mobile phase is water (0.01%TFA)-methanol (0.01%TFA) for gradient elution (5%-95% methanol), flow rate 1.8ml / min, column temperature is 45℃, detection wavelength is 299nm, elution time is 60min, the purity of ellipticine is 95.75% ( Figure 7 And the table below).

[0063] peak# keep time area height Peak start Peak end area% 127.52798513754593827.14730.45395.74627 243.187126005910342.90143.6161.456051 344.15254325260043.61644.5870.627764 445.2411730471299545.00348.321.999545 546.28314746118446.05946.5810.170368

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Abstract

The invention relates to a synthesis process for preparing ellipticine. Ellipticine is obtained through six steps of reaction and three steps of crystallization separation, the target product total yield is high, column chromatography separation is not needed for an intermediate product and the target product, and the method is particularly suitable for large-scale preparation.

Description

technical field [0001] The invention relates to a preparation process of ellipticine. The biggest feature of the process is that the products in each step do not need to be separated by column chromatography, the total yield is high and the process is simplified, and it is especially suitable for large-scale preparation. Background technique [0002] Ellipticine (also known as elliptic ellipticine) naturally exists in the leaves of Ochrosia elliptica Labill., the bark and leaves of O. balansae, Mohs rose tree ( O.moorei) and other plants, can be obtained by chemical synthesis. It belongs to cytotoxic alkaloids, has anti-tumor effect, and can inhibit the activity of topoisomerase IIα (Topo IIα). French scientists have shown that ellipticine derivatives can effectively inhibit the spread of tumors, and at the same time, they have strong anti-metastasis activity and produce relatively small side effects. This research result will open up a new way for cancer treatment. [000...

Claims

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Application Information

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IPC IPC(8): C07D471/04
CPCC07D471/04Y02P20/55
Inventor 潘显道林菁菁沈珑瑛杜国华
Owner INST OF MATERIA MEDICA AN INST OF THE CHINESE ACAD OF MEDICAL SCI
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