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Azepine argireline or pharmaceutically acceptable salt thereof and preparation method and application thereof

A nitrogen-heterocyclic and pharmaceutical technology, applied in the field of azacyclohexyl peptide or its pharmaceutically acceptable salt and its preparation, can solve the problems that the compound has no significant stereoselectivity, cannot be applied to industrial production, and the yield is not high

Active Publication Date: 2010-02-17
SHANGHAI TECHWELL BIOPHARMACEUTICALS CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] In the prior art, the method for synthesizing caspofungin often requires more reaction steps, and the synthesized compound has no significant stereoselectivity or low yield, and cannot be applied to industrial production

Method used

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  • Azepine argireline or pharmaceutically acceptable salt thereof and preparation method and application thereof
  • Azepine argireline or pharmaceutically acceptable salt thereof and preparation method and application thereof
  • Azepine argireline or pharmaceutically acceptable salt thereof and preparation method and application thereof

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preparation example Construction

[0044] The present invention provides a kind of preparation method of the compound shown in formula 4, described method comprises the following steps:

[0045] In the first step, the compound of formula 2 is mixed with a strong leaving group, and reacted to obtain the compound shown in formula 3;

[0046] In the second step, the compound of formula 3 and ethylenediamine are mixed and reacted to obtain the compound shown in formula 4.

[0047] Further, the obtained compound of formula 4 can be mixed with a reducing agent to react to obtain the compound shown in formula 1.

[0048]

[0049] The starting compound of formula 2 in the preparation method provided by the present invention can be prepared by methods well known in the art, such as but not limited to, described in US Patent No. 5,021,341 published on June 4, 1991: in the rich Zalerionarboricola ATCC 20868 was grown in a nutrient medium with mannitol as the main carbon source.

[0050] The strong leaving group in th...

Embodiment 1

[0082] Compound of formula 2 prepares compound of formula 7

[0083]

[0084] Under nitrogen protection, compound 2 (100g, 94.0mmol, dehydrated), phenylboronic acid (22.9g, 188mmol) and thiophenol (29.0ml, 282mmol) were added to 3L acetonitrile, the suspension was cooled to -15°C, and added Trifluoromethanesulfonic acid (24.9ml, 282mmol) was maintained at -15°C for 2.5h, and the reaction was completed. An aqueous solution of sodium acetate (333ml, 282mol) was added to produce a large amount of precipitate. The suspension was heated to 17°C, stirred for 2 hours, then cooled to 0°C, filtered, and washed with 1:9 (v / v) water / acetonitrile Post-drying gave compound 7 (93.4 g, 93.4%).

[0085] MS(ESI)1157.6(M+H + ), 1179.6 (M+Na + );

[0086] 1H NMR (500MHz, CD3OD) δ7.56-7.55 (om, 2H), 7.28-7.22 (om, 3H), 7.13 (m, 2H), 6.76-6.74 (m, 2H), 5.58 (d, 1H), 5.05(d, 1H), 4.94(d, 1H), 4.57(dd, 1H), 4.42-4.26(om, 9H), 3.88(om, 3H), 3.70(om, 2H), 2.76(dd, 1H) , 2.45(dd, 1H), 2.40(om,...

Embodiment 2

[0089] Compound of formula 2 prepares compound of formula 8

[0090]

[0091] Under nitrogen protection, compound 2 (10.0g, 9.4mmol), phenylboronic acid (2.3g, 18.8mmol) and p-methylthiophenol (3.56g, 28.6mmol) were added to 3L acetonitrile, and the suspension Cool to -15°C, add trifluoromethanesulfonic acid (2.49ml, 28.2mmol), maintain -15°C for 2.5h, and the reaction ends. An aqueous solution of sodium acetate (33.3ml, 28.2mol) was added to produce a large amount of precipitation. The suspension was warmed up to 17°C, stirred for 2 hours, then cooled to 0°C, filtered, and washed with 1:9 (v / v) water / After washing with acetonitrile, it was dried to obtain compound 5 (9.0 g, 90%).

[0092]Under the protection of nitrogen, compound 5 (9.0g, 7.7mmol) was dissolved in 36ml of methanol, cooled to -10°C, and ethylenediamine (36ml, 537.8mmol) was slowly added dropwise, and the dropping temperature was controlled not to exceed 2°C. , reacted at 30° C., reacted overnight, added ...

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Abstract

The invention discloses azepine argireline or pharmaceutically acceptable salt thereof and a preparation method and application thereof. The structure of the azepine argireline is shown in formula 4.

Description

technical field [0001] The present invention relates to the field of organic compounds, in particular to an azepine peptide or a pharmaceutically acceptable salt thereof, a preparation method and application thereof. Background technique [0002] In 1974, it was discovered that echinocandin compounds had good antibacterial activity. Since then, the pharmacological activity of many semi-synthetic echinocandins has been studied. Until 2001, caspofungin was officially approved by the U.S. FDA to go on the market, and people's research on antifungal drugs has made a breakthrough. Caspofungin is a drug with a unique action site, broad spectrum and low toxicity, and its structure is shown in formula 1: [0003] [0004] In the prior art, the method for synthesizing caspofungin often requires more reaction steps, and the synthesized compound has no significant stereoselectivity or low yield, and cannot be applied to industrial production. In U.S. Patent No. 5,378,804, caspofu...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K7/56C07K1/06A61K38/12A61P31/10
Inventor 许天惠方涛卓忠浩郑云满季晓铭
Owner SHANGHAI TECHWELL BIOPHARMACEUTICALS CO LTD
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