Chiral nitrogen-containing heterocyclic compound, and synthesis method and application thereof

A nitrogen heterocyclic compound and compound technology, applied in the fields of chiral nitrogen-containing heterocyclic compound, synthesis and application

Inactive Publication Date: 2011-08-17
SHANGHAI INST OF ORGANIC CHEM CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In addition, the method of constructing chiral center by desymmetry through aza-Michael reaction has not been reported yet.

Method used

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  • Chiral nitrogen-containing heterocyclic compound, and synthesis method and application thereof
  • Chiral nitrogen-containing heterocyclic compound, and synthesis method and application thereof
  • Chiral nitrogen-containing heterocyclic compound, and synthesis method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0018] Embodiment 1: the preparation of chiral phosphoric acid

[0019] Under the protection of argon at room temperature, dissolve the derivative of BINOL (0.5mmol) in 1mL of dry pyridine in a dry reaction tube, and slowly drop (1.0mmol) of phosphine oxychloride under the condition of rapid stirring Added to the system, stirred at room temperature for 3 hours. 1 mL of water was slowly added dropwise to the system, and stirred at room temperature for 30 minutes. Dichloromethane was added to dissolve, washed with 1N aqueous hydrochloric acid (3×10 mL), the organic layer was dried over anhydrous sodium sulfate, the solvent was spun off under reduced pressure, and the residue was separated by column chromatography to obtain the product.

[0020] (S)-3,3'-[3,5-bis(trifluoromethyl)phenyl]2-1,1'-binaphthol phosphate (1a)

[0021] (S)-3,3′-[3,5-Bis(trifluoromethyl)phenyl]2-1,1′-binaphthyl phosphate(1a)

[0022]

[0023] White solid, 89% yield. 1 H NMR (400MHz, CDCl 3 )δ8.01(s...

Embodiment 2

[0024] Embodiment 2: the preparation of chiral thiourea

[0025] Under the protection of argon at room temperature, 9-amino cinchonine (2.93g, 10mmol) was dissolved in dry tetrahydrofuran (30mL) in a dry reaction tube, and 3,5-bistrifluoromethylbenzene isothiocyanate was added at room temperature A solution of the acid ester (2.70 g, 10 mmol) in tetrahydrofuran (10 mL). After reacting overnight, the solvent was spinned off under pressure, and the residue was separated by column chromatography (EtOAc / MeOH / =300 / 5) to obtain the catalyst thiourea.

[0026] 1-(3,5-bistrifluoromethylphenyl)3-(R)-4-quinoline-(2R,4S,5R)-5-vinyl-2-quininemethylthiourea (2a) 1-(3,5-bis(trifluoromethyl)phenyl)-3-((R)-quinolin-4-yl((2R,4S,5R)-5-vinylquinuclidin-2-yl)methyl)thiourea(2a)

[0027]

[0028] White solid, 80% yield. 1 H NMR (300MHz, CD 3 OD) δ0.77-0.85(m, 2H), 1.12-1.20(m, 1H), 1.43-1.51(m, 3H), 2.25-2.28(m, 1H), 2.89-2.99(m, 3H), 3.11 -3.24(m, 3H), 5.08-5.14(m, 2H), 5.80-5.92(m, 1H), ...

Embodiment 3

[0029] Example 3: Intramolecular Aza-Michael Reaction Catalyzed by Chiral Thiourea

[0030]

[0031] Method A: Under argon protection, add cyclohexadienone derivative (0.3 mmol), chiral thiourea catalyst 2a (8.5 mg, 5 mol%) and dichloromethane (3 mL) in a dry reaction tube. React at room temperature until the starting material disappears (TLC detection). The solvent was spun off under reduced pressure, and the residue was separated by plate chromatography to obtain the product.

[0032] Method B: Under argon protection, add cyclohexadienone derivative (0.3mmol), chiral thiourea catalyst 2a (33.8mg, 20mol%), and dichloromethane (0.6mL) in a dry reaction tube . The reaction was heated to reflux until the starting material disappeared (TLC detection). The solvent was spun off under reduced pressure, and the residue was separated by plate chromatography to obtain the product.

[0033]

[0034] (3aS,7aS)-3a-Hydroxy-1-p-methylbenzenesulfonyl-3,3a,7,7a-tetrahydro-1H-indol-6...

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Abstract

The invention relates to a chiral nitrogen-containing heterocyclic compound, and a synthesis method and application thereof. The nitrogen-containing heterocyclic compound can be a chiral pyrrolidine compound, chiral piperidine compound or chiral morpholine compound which is synthesized by carrying out intramolecular aza Michael reaction on chiral phosphoric acid or chiral thiocarbamide-catalyzed cyclohexadiene ketone derivatives in a high-efficiency high-enanatioselectivity mode. The nitrogen-containing heterocyclic compound can be used for preparing alkaloid (-)-Mesembrine. The method has the advantage of mild reaction conditions and is simple to operate. In addition, no metallic salt compound is added in the reaction, thereby being beneficial to production and treatment of potential bioactive compounds. The reaction yield is high (generally 73-97%), and the enanatioselectivity is high (generally 89-99%).

Description

technical field [0001] The invention relates to a chiral nitrogen-containing heterocyclic compound, specifically a chiral pyrrolidine compound, a chiral piperidine compound or a chiral morpholine compound, which is a cyclohexane compound catalyzed by chiral phosphoric acid or chiral thiourea. Dienone derivatives undergo intramolecular aza-Michael reaction to synthesize chiral pyrrolidine compounds, piperidine compounds and morpholine compounds with high efficiency and high enantioselectivity, among which chiral pyrrolidine compounds can be used to prepare alkaloids (-) -Mesembrine. Background technique [0002] In recent years, organic small molecule catalysis has attracted widespread attention from academia and industry all over the world due to its advantages of easy synthesis, convenient structure modification, and no heavy metal residue [(a) Seayad, J.; List, B.Org .Biomol.Chem.2005,3,719-724.(b) Dalko, P.I.; Moisan, L.Angew.Chem.Int.Ed.2004,43,5138-5175.], wherein chir...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/32C07D209/40C07D209/12C07D265/36B01J31/02B01J31/18
CPCY02P20/55
Inventor 游书力顾庆赵卓安
Owner SHANGHAI INST OF ORGANIC CHEM CHINESE ACAD OF SCI
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