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Preparation method of five-membered bicyclic guanidine compounds

A compound and bicyclic guanidine technology, which is applied in the field of preparation of five-membered bicyclic guanidine compounds, can solve the problems of chirality, long reaction time, danger, etc., and achieve the effects of simple process operation and favorable production scale.

Active Publication Date: 2014-03-26
SHENZHEN HUAXIAN PHARMA TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This route has a certain degree of innovation in the synthesis of chiral five-membered bicyclic guanidines. The disadvantage is that this route uses a strong reducing agent in multiple steps, and also uses Pd / H 2 Deprotection, there is a greater risk in operation
This method seems to synthesize five-membered bicyclic guanidine compounds in one step. However, the method requires high temperature and long reaction time; in addition, this method can only synthesize five-membered bicyclic guanidine compounds with simple structure, which has chirality and structure for synthesis. Relatively complex five-membered bicyclic guanidine compounds appear powerless

Method used

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  • Preparation method of five-membered bicyclic guanidine compounds
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  • Preparation method of five-membered bicyclic guanidine compounds

Examples

Experimental program
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Embodiment 1

[0039] Preparation of S, S-dibenzyl five-membered bicyclic guanidine 1a

[0040]

[0041] Step 1: Preparation of Compound 4a

[0042] Add 2a (60g, 0.40mol) and ethyl acetate (480mL) into a 1000mL three-neck flask, stir at room temperature for 5min, and add Boc2O (96g, 0.44mol) dropwise. After the dropwise addition, react at room temperature for 1 h, and then add TEA (52.6 g, 0.52 mol) dropwise. After the dropwise addition was completed, MsCl (50.5 g, 0.44 mol) was slowly added dropwise. After the dropwise addition was completed, react at room temperature for 15 minutes, add 300ml of water to quench the reaction, concentrate under reduced pressure to remove ethyl acetate, filter, wash the filter cake with water (50mlx3), and dry in vacuo to obtain 124.2g of white solid 4a with a yield of 95%. 1HNMR (400 MHz, CDCl 3 ): δ 1.40 (s,9H), 2.69-2.95 (m,2H), 3.01 (s,3H ),4.05-4.13 ( m,2H), 4.20-4.29 (m ,1H), 4.73(brs,1H ) , 7.18-7.38 (m ,5H).

[0043]

[0044] Step 2: Preparat...

Embodiment 2

[0059] Preparation of S, S-bis-tert-butyl five-membered bicyclic guanidine 1b

[0060]

[0061] Step 1: Preparation of Compound 4b

[0062] Add 2b (46.9g, 0.40mol) and ethyl acetate (470mL) into a 1000mL three-necked flask, stir at room temperature for 5min, and add Boc2O (96g, 0.44mol) dropwise. After the dropwise addition, react at room temperature for 1 h, and then add TEA (52.6 g, 0.52 mol) dropwise. After the dropwise addition was completed, MsCl (50.5 g, 0.44 mol) was slowly added dropwise. After the dropwise addition was completed, react at room temperature for 15 minutes, add 300ml of water to quench the reaction, separate the organic layer, and extract the aqueous layer with ethyl acetate (80mLx2). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 111.1 g of white solid 4b, with a yield of 94%. 1HNMR (300 MHz, CDCl 3 ) : δ 0.98 (s, 9H), 1.45 (s, 9H), 3.04 (s, 3H), 3.73 (m, 1H), 4.30 (dd, 2H), ...

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Abstract

The invention relates to the field of organic synthesis, and particularly relates to a preparation method of five-membered bicyclic guanidine compounds. The preparation method of five-membered bicyclic guanidine compounds comprises the following steps: performing amino protection and hydroxy protection on alkamine; performing substitution reaction with imine anions; de-protecting the obtained product with hydrazine hydrate, thus obtaining primary amine; on the other hand, under alkaline conditions, forming the alkamine subjected to amino protection and hydroxy protection into a three-membered cyclamine compound; performing coupling reaction on the primary amine and the three-membered cyclamine compound; and finally, performing ring-closing reaction on the coupling product to obtain the five-membered bicyclic guanidine compounds. Compared with the prior art, raw materials for preparation of the five-membered bicyclic guanidine compounds and intermediate compounds are cheap and accessible; and the technological operation is simple, does not need column chromatography separation and is beneficial to scale-up production, thereby providing a convenient way for preparation of chiral and achiral five-membered bicyclic guanidine compounds.

Description

technical field [0001] The invention relates to the field of organic synthesis, in particular to a preparation method of five-membered bicyclic guanidine compounds. Background technique [0002] Five-membered bicyclic guanidine compounds are widely used in organic synthesis and polymer additives due to their strong basicity; in recent years, chiral five-membered bicyclic guanidine compounds have been used in catalyzing asymmetric organic synthesis, such as in asymmetric Michael reaction, asymmetric Henry reaction , asymmetric Strecker reaction, asymmetric TMS cyanation, asymmetric azidation, showing excellent catalytic effect. [0003] However, the synthesis conditions of five-membered bicyclic guanidine compounds, especially chiral five-membered bicyclic guanidine compounds, are still relatively harsh, which greatly limits the research and application of five-membered bicyclic guanidine compounds. [0004] In 1989, E.J. Corey ( Tertahedron Lett. (1989), 30(39), 527-5230) ...

Claims

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Application Information

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IPC IPC(8): C07D487/04
CPCC07D487/04
Inventor 叶伟平徐俊烨黄志宁吴鸿翔肖诗华谢香兰陈飞
Owner SHENZHEN HUAXIAN PHARMA TECH CO LTD
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