Tertiary leucine derived chiral amine compound as well as preparation method and application thereof

A tertiary leucine and compound technology, which is applied in the field of preparation of chiral amine compounds, can solve the problems of poor diastereoselectivity, poor universality of reactions, limited few reactions, etc., and achieves high-efficiency catalytic performance and good controllability Effect

Active Publication Date: 2013-10-23
EAST CHINA UNIV OF SCI & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] Although catalysts derived from natural amino acids such as proline, phenylalanine, phenylglycine, and tryptophan have a wide range of sources and are cheap and easy to obtain, these catalysts have more or less shortcomings, for example, poor reaction universality, Often limited to a few reactions; or the enantioselectivity of the reaction is better, but the diastereoselectivity is poor, etc.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

preparation Embodiment 1

[0047] The preparation of a chiral amine compound derived from tert-leucine comprises the following steps:

[0048] (1) Dissolve 0.68g (8.0 mmol) of piperidine in 40 mL of anhydrous acetonitrile, and add 2.27 g (8.0 mmol) of ( S )-N-p-nitrobenzenesulfonyl-1-tert-butyl-cycloethyleneimine in 40ml of acetonitrile solution, stirred at 20°C for 36 hours, TLC detected that the reaction was complete; the mixture was concentrated under reduced pressure, and the residue was chromatographed on a silica gel column (petroleum ether and ethyl acetate, their volume ratio = 3:1) to obtain 2.80 g of a white solid, with a yield of 95%.

[0049] (2) Dissolve 1.85 g (5.0 mmol) of the white solid obtained in step (1) in 30 mL of DMF, add potassium carbonate (2.07 g, 15.0 mmol concentration), thioglycolic acid (0.92 g, 10.0 mmol), and mix 50 Stirring at ℃ for 12 hours, TLC detected that the reaction was complete; the mixture was added with 100 mL of ethyl acetate, washed three times with 5M sodiu...

preparation Embodiment 2

[0055] The difference between Preparation Example 2 and Preparation Example 1 is that the amine used in step (1) is N-Ts protected 1,2-diphenylethylenediamine, the temperature used is 100°C, and the amine used in step (2) The temperature is 80°C, other preparations and conditions are the same as in Example 1, the final product is a white solid chiral primary amine product, and the product configuration is R , R , S ; 1 for hydrogen, R 2 It is 1,2-diphenylethylamine protected by N-Ts, and its structural formula is as follows:

[0056] .

[0057] Melting point 120-121°C; 1 H NMR (400 MHz, CDCl 3 ): d 7.41-7.39 (m, 2H), 7.16-7.15 (m, 3H), 7.06-7.03 (m, 5H), 6.96-6.94 (m, 4H), 4.33 (d, J = 8.0 Hz, 1H), 3.64 (d, J = 8.8 Hz, 1H), 2.66 (dd, J = 11.0, 2.5 Hz, 1H), 2.52 (d, J = 12.3 Hz, 4H), 2.35 (s, 3H), 2.28 (dd, J = 12.3, 2.8 Hz, 3H), 0.94 (9H, s). 13 C NMR (100 MHz, CDCl 3 ): d 142.7, 139.6, 138.4, 137.3, 129.1, 128.3, 127.9, 127.6, 127.5, 127.4, 127.2, 127.1, 6...

preparation Embodiment 3

[0059] The difference between Preparation Example 3 and Preparation Example 1 is that the amine used in step (1) is cyclohexylamino alcohol, the temperature used is 20°C, the temperature used in step (2) is 20°C, and other preparation steps and conditions are the same Preparation Example 1. The final product is a colorless oily chiral primary amine product, and the product configuration is R , R , S ; 1 for hydrogen, R 2 For o-hydroxycyclohexane, its structural formula is as follows:

[0060] .

[0061] 1 H NMR (400MHz, CDCl 3 ): δ 3.40 (m, 1H), 2.82 (dd, J = 2.4, 8.8 Hz, 1H), 2.40 (dd, J = 2.4, 8.4 Hz, 1H), 2.35 (td, J = 3.6, 10.4 Hz, 1H), 2.16 (t, J = 11.2 Hz, 1H), 1.85 (d, J = 12.0 Hz, 2H), 1.67-1.71 (m, 2H), 1.55-1.59 (m, 1H), 1.08-1.24 (m, 4H), 0.85 (s, 9H). 13 C NMR (100MHz, CDCl 3 ): δ60.4, 57.0, 48.5, 33.9, 33.6, 33.5, 26.2, 26.2, 25.1, 25.0. HRMS (ESI): Theory (M+H) + C 12 h 27 N 2 O 215.2123, yielding m / z 215.2125.

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Abstract

The invention discloses a tertiary leucine derived chiral amine compound as well as a preparation method and application thereof. The chiral amine compound contains a tert-butyl group, a primary amine, a secondary amine or a tertiary amine functional group and has the structural formula as shown in the specification; and chiral amine and salts thereof are prepared through simple preparation steps by taking common tert-leucine as the raw material to form the chiral amine compound. The chiral amine and the salts thereof can be used for the asymmetrical Michael additive reaction between alpha, beta-unsaturated ketone and a nucleophilic reagent such as nitrocarbol, malonic ester, substituted oxazolone and the like and the asymmetrical cascade reaction between the alpha, beta-unsaturated ketone and fifth-position unsaturated rhodanine, between fifth-position unsaturated hydantoin and the alpha, beta-unsaturated ketone; and the tertiary leucine derived chiral amine compound has very high catalytic activity and stereoselectivity as well as the highest diastereoselectivity of 30/1 and the highest enantioselectivity of 99%, and is wide in oligomer range.

Description

technical field [0001] The invention relates to a novel chiral amine compound derived from tertiary leucine, and relates to a preparation method and a new application of the chiral amine compound. Background technique [0002] Organic small molecule catalysts with simple synthesis methods, high catalytic efficiency, and large-scale realization of asymmetric catalytic capabilities are the goals that organic chemistry researchers have always pursued, and the application of organic catalysts to drug molecules, bioactive molecules, or structural units of natural products It is an important content in the field of organic catalysis research. [0003] In the past ten years, the main content of the success of organocatalysis research lies in the discovery and confirmation of general models for catalyst activation of substrates. The general activation model describes the type of reaction, and can participate in various types of chemical reactions with stable high enantioselectivity...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D295/13C07C311/08C07C303/40C07C215/44C07C213/00C07C211/35C07C211/09C07C209/50C07C49/657C07C45/72B01J31/02C07B53/00C07B37/02C07C205/45C07C201/12C07C69/738C07C67/347C07D263/40C07D277/60
CPCY02P20/55
Inventor 叶金星黄慧才顾晓栋于峰吴文彬胡淏翔
Owner EAST CHINA UNIV OF SCI & TECH
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