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Bionic synthesis and preparation method of (+/-)-isomacahydantoin B

A biomimetic synthesis, thiourea technology, applied in the direction of organic chemistry, can solve the problems of limited biological activity research, structural identification errors, lack and other problems, and achieve the effect of simple and efficient method.

Inactive Publication Date: 2017-12-15
YUNNAN MINZU UNIV
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Problems solved by technology

However, the structure of (±)-macahydantoin B identified by Qiu et al. has the problem of structural identification errors, and the structure is identified as (±)-isomacahydantoin B, an analog of (±)-macahydantoin A, because (±)-isomacahydantoin B has a novel However, due to the lack of samples of (±)-isomacahydantoin B, its further biological activity research is limited. In order to prepare enough compounds to carry out in-depth research on pharmacological activity and its mechanism of action, this paper The invention carried out biomimetic synthesis research on (±)-isomacahydantoin B, and realized the simple and efficient biomimetic synthesis and gram-level preparation process of this compound for the first time, thus solving the resource problem

Method used

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  • Bionic synthesis and preparation method of (+/-)-isomacahydantoin B
  • Bionic synthesis and preparation method of (+/-)-isomacahydantoin B
  • Bionic synthesis and preparation method of (+/-)-isomacahydantoin B

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preparation example Construction

[0032] The preparation method of (±)-isomacathiourea B uses Boc-piperidin-3-one as the starting material for the reaction, and then performs nucleophilic reaction with trimethylsilylcyanide (TMSCN) catalyzed by zinc iodide Substitution reaction to obtain Boc-2-cyano-3-hydroxypiperidine (first step reaction A), and then hydrolysis by concentrated hydrochloric acid to obtain 3-hydroxy-piperidine-3-carboxylate hydrochloride (second step reaction B ), and finally (±)-isomacathiourea B was obtained by Edman reaction with 3-methoxybenzyl isothiocyanate (third step reaction C). The yield of this three-step reaction route is as high as 60~70%, and it can achieve gram-level preparation. The specific route is:

[0033]

[0034] (A) Preparation of Boc-2-cyano-3-hydroxypiperidine: Boc-piperidin-3-one (0.199~19.9 g, 1.0~100.0mmol) was dissolved in 5~500 mL of anhydrous dichloromethane solution , under nitrogen protection, fully stirred and dissolved, added zinc iodide (0.318~31.8 g, 1.0~...

Embodiment 1

[0039]

[0040] Boc-piperidin-3-one (0.398 g, 2.0 mmol) was dissolved in 10 mL of anhydrous dichloromethane solution, under nitrogen protection, after fully stirring and dissolving, zinc iodide (0.636 g, 2.0 mmol ) and trimethylsilylcyanide (0.396g, 3.0 mmol), stirred at room temperature for 6 hours. The reaction solution was filtered with a suction filter bottle, and after zinc iodide was filtered out, it was evaporated to dryness with a rotary evaporator under reduced pressure. After vacuum filtration, it was dried in a vacuum oven for 12 hours to obtain Boc-2-cyano-3-hydroxypiperone A sample of pyridine (0.566 g, about 80% pure) yielded about 90%. The obtained Boc-2-cyano-3-hydroxypiperidine (0.258 g, 2.0 mmol) was dissolved in 15 mL of concentrated hydrochloric acid solution, and refluxed at 85°C for 12 hours. The reaction solution was evaporated to dryness under reduced pressure with a rotary evaporator, filtered under reduced pressure and dried in a vacuum oven for 1...

Embodiment 2

[0042]

[0043] Boc-piperidin-3-one (1.990 g, 10.0 mmol) was dissolved in 50 mL of anhydrous dichloromethane solution, under nitrogen protection, after fully stirring and dissolving, zinc iodide (3.180 g, 10.0 mmol ) and trimethylsilylcyanide (1.980 g, 15.0 mmol), stirred at room temperature for 6 hours. The reaction solution was filtered with a suction filter bottle, and after zinc iodide was filtered out, it was evaporated to dryness with a rotary evaporator under reduced pressure, and after vacuum filtration, it was dried in a vacuum oven for 6 hours to obtain Boc-2-cyano-3-hydroxypiperol A sample of pyridine (2.830 g, about 80% pure) yielded about 90%. The obtained Boc-2-cyano-3-hydroxypiperidine (1.290 g, 10.0 mmol) was dissolved in 45 mL of concentrated hydrochloric acid solution, and refluxed at 85 degrees Celsius for 12 hours. The reaction solution was evaporated to dryness with a rotary evaporator, filtered under reduced pressure and dried in a vacuum oven for 12 ...

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Abstract

The invention discloses a bionic synthesis and preparation method of (+ / -)-isomacahydantoin B. The (+ / -)-isomacahydantoin B is a derivative of a natural alkaloid (+ / -)-macahydantoin A found in a medicinal plant maca, uses biogenic precursors benzyl isothiocyanate and 3-hydroxyl-piperidine-3-carboxylic acid as raw materials and is an artificially synthesized natural product-like compound obtained through biomimetic synthesis based on a 'one-pot method'. The (+ / -)-isomacahydantoin B is structurally characterized by consisting of a 1,3-diazabicyclo[3.3.1]nonane parent nucleus and a 3-hydroxybenzyl substituted group, and a chemical structure is shown in the description. The bionic synthesis and preparation method uses Boc-piperidine-3-ketone as a starting material for reaction, nucleophilic substitution reaction is performed between the starting material and zinc iodide catalyzed trimethylsilyl cyanide (TMSCN) to obtain Boc-2-cyano-3-hydroxyl piperidine, and then 3-hydroxyl-piperidine-3 carboxylic acid hydrochloride is obtained through hydrolysis with concentrated hydrochloric acid; the (+ / -)-isomacahydantoin B is obtained through Edman reaction with 3-methoxyl benzyl isothiocyanate. The synthesis method is simple and efficient, and gram-level preparation of the compound can be achieved.

Description

technical field [0001] The invention belongs to the technical field of compound synthesis, and in particular relates to a biomimetic synthesis preparation method of (±)-isomacathiourea B. Background technique [0002] Maca (Latin name Lepidium meyenii Walp), a 1-2-year-old herbaceous medicinal plant of the genus Brassicaceae, native to the Andes in South America (3500-4500 altitude above sea level), is a commonly used medicinal plant and edible material in the local area, known as "Peruvian ginseng". . It was introduced in my country in early 1990, among which Lijiang and Shangri-La in Yunnan are the main planting areas. At the same time, it is also widely planted in Huize, Zhaotong, Yuxi and other areas in Yunnan. Qiu et al. have studied the chemical composition and biological activity of the plant and found that the The plant contains a novel sulfur-containing alkaloid (±)-macahydantoins A and B with a 1,3-diazabicyclo[3.3.1]nonane skeleton, suggesting that this component...

Claims

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Application Information

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IPC IPC(8): C07D471/08
CPCC07D471/08
Inventor 叶艳青陈彦君周敏耿慧春张芮绮胡秋芬
Owner YUNNAN MINZU UNIV
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