Chiral five-membered bicyclic guanidine compound, preparation method and application thereof

A technology of compound and bicyclic guanidine, which is applied in the field of chiral five-membered bicyclic guanidine compound and its preparation, can solve the problems of catalyst application limitation, low reaction yield, and inability to carry out the reaction, and achieve good asymmetric reaction catalytic performance, good The effect of applying the foreground

Active Publication Date: 2012-10-10
RAFFLES PHAMRMATECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Although the compound 1 can catalyze multiple reactions, its catalyzed reaction substrates have certain limitations
Usually, for a certain class of substrates that can be reacted, only fine-tuning of its structure can be performed. Too much modification will lead to low reaction yield or even inability to carry out the reaction.
Th...

Method used

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  • Chiral five-membered bicyclic guanidine compound, preparation method and application thereof
  • Chiral five-membered bicyclic guanidine compound, preparation method and application thereof
  • Chiral five-membered bicyclic guanidine compound, preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] Example 1 Preparation of chiral five-membered bicyclic guanidine compound of formula (I)

[0037] (1) In a flask, add benzene (5.0 ml) and trifluoromethanesulfonic acid (20.0 ml), add Amino alcohol 3 (1.0 g), stirred for 3 to 6 hours. The reaction solution was poured into about 100 g of ice, stirred thoroughly, neutralized with sodium hydroxide solution, and extracted with chloroform. The organic phase was washed successively with water and saturated brine, and finally dried over magnesium sulfate, filtered, and the solvent was removed under reduced pressure to obtain Amino alcohol 4 The crude product (1.29 g, 96% yield). The crude product can be directly used in the next reaction.

[0038] (2) Add in the flask Amino alcohol 4 (1 g), triethylamine (2.1 ml) and dry acetonitrile (11 ml), stirred and cooled to 0~5°C in an ice bath. Add p-toluenesulfonyl chloride (0.8 g), stir in an ice bath for half an hour, naturally warm to room temperature, and stir for another...

Embodiment 2

[0044] Embodiment 2 catalytic experiment

[0045] Below, we provide examples of the application of the compound of formula (I) to catalyze the Michael addition reaction of 2-cyclopentenone and dimethyl malonate.

[0046] 2-Cyclopentenone (0.025 mmol) and dimethyl malonate (0.03 mmol, 1.2 eq) were dissolved in toluene (0.1 ml), and stirred at room temperature. The compound catalyst (1.1 mg, 0.0025 mmol, 0.01 equivalent) described in formula (I) was dissolved in 0.01 ml of toluene, added to the reactant, stirred, and the progress of the reaction was monitored by thin layer chromatography. After stirring at room temperature for 6 days, the reaction was stopped and the product was separated by column 12 . (2.94 mg, 55% yield).

[0047]

[0048] to detect Product (S)-(-)-12 The chiral purity of the product can be transformed into Acetal (S)-13 Afterwards, the chiral purity was analyzed by chiral column chromatography. The conditions are: CHIRALCEL OD-H (4.6 mm i.d. x 2...

Embodiment 3

[0051] Embodiment 3 catalytic performance comparative experiment

[0052] The Michael addition reaction between nitrostyrene and dimethyl malonate is widely used in the synthesis of chiral molecules.

[0053] Unlike the cyclic substrate of 2-cyclopentenone in Example 2, a nitrostyrene is actually a linear substrate. However, due to Compound 1 The catalytic performance or catalytic conditions are limited, and have not yet been used Compound 1 Report on the successful catalyzed Michael addition of nitrostyrene to dimethyl malonate. We have carried out the following experiments with the compound of formula (I) as catalyst:

[0054] Nitrostyrene (0.025 mmol) and dimethyl malonate (0.03 mmol, 1.2 equiv) were dissolved in toluene (0.1 ml), and stirred at room temperature. The compound catalyst (1.1 mg, 0.0025 mmol, 0.01 equivalent) described in formula (I) was dissolved in 0.01 ml of toluene, added to the reactant, stirred, and the progress of the reaction was monitored by t...

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Abstract

The invention discloses a chiral five-membered bicyclic guanidine compound, a preparation method and an application thereof. The chiral five-membered bicyclic guanidine compound is shown as Formula (I). The preparation method can be obtained by referring to existing synthetic routes of the chiral five-membered bicyclic guanidine compound and performing proper changes. The two side chains of the chiral five-membered bicyclic guanidine compound are diphenylmethyl, so that a larger chiral space is formed. Moreover, phenyl may form Pi-Pi overlap with a substrate containing conjugated groups so as to improve the effects of chiral induction. Therefore, more substrates as catalysts can be applied to the compound of Formula (I), and the chiral five-membered bicyclic guanidine compound of the invention is better than the existing chiral five-membered bicyclic guanidine compound as for catalytic performance.

Description

technical field [0001] The invention relates to the field of compound synthesis, in particular to a chiral five-membered bicyclic guanidine compound and a preparation method and application thereof. Background technique [0002] Guanidine is a strong organic base, and it has been reported that guanidine compounds can catalyze a series of base-catalyzed asymmetric reactions (see literature Ishikawa, T.; Isobe, T. Chem. Eur. J. 2002, 8, 553~557 ), such as epoxidation reactions, addition reactions, silylation reactions of secondary alcohols, and Strecker reactions of Schiff bases, etc. In 2008, Tan's research group developed a chiral five-membered bicyclic guanidine compound 1, which has been proven to be an effective catalyst for small organic molecules, which can catalyze Michael addition, Mannich, protonation and other reactions ( See literature Advanced Synthesis and Catalysis, 2007, 349, 2454~2458; Chem. Eur. J. 2011, 17, 3571~3574; Chem. Eur. J. 2010, 16, 779~782; Angew....

Claims

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Application Information

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IPC IPC(8): C07D487/04C07B53/00B01J31/02
CPCB01J31/0251C07B53/00C07D487/04B01J31/02B01J2231/32
Inventor 徐俊烨叶伟平
Owner RAFFLES PHAMRMATECH CO LTD
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