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A kind of asymmetric synthesis method of heteroatom substituted pyrrolidine derivatives

A synthesis method and technology of pyrrolidine, applied in the field of asymmetric synthesis of pyrrolidine derivatives, can solve the problems that pyrrolidine derivatives have not been reported.

Inactive Publication Date: 2022-01-21
CHONGQING UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0016] Although the construction method of the pyrrolidine skeleton has been relatively mature, the construction of N-containing N-containing polychiral centers through the [3+2] cycloaddition reaction of isocyanoacetate compounds and heteroatom-substituted unsaturated double bonds , O, S and other heteroatom-substituted pyrrolidine derivatives have not been reported yet.

Method used

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  • A kind of asymmetric synthesis method of heteroatom substituted pyrrolidine derivatives
  • A kind of asymmetric synthesis method of heteroatom substituted pyrrolidine derivatives
  • A kind of asymmetric synthesis method of heteroatom substituted pyrrolidine derivatives

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] Preparation of Compound 1-1

[0036]

[0037] step:

[0038]

[0039] Accurately weigh Ligand 1 (6.1 mg, 0.01 mmol) and silver acetate (0.83 mg, 0.005 mmol) into a 10 mL reaction tube equipped with a stirrer, add 2 mL of dichloromethane and stir at -30°C for 5 minutes. Then isocyanoacetate 1a (11.88 mg, 0.12 mmol) and starting material 1 (20.8 mg, 0.1 mmol) were added, and reacted at -30° C., monitored by TLC until the reaction of starting material 1 was complete. Install a 3cm long silica gel column, quickly filter the reaction solution, rinse with ethyl acetate, spin the filtrate dry, add 1mL methanol to dissolve, add sodium cyanoborohydride (12.6mg, 0.2mmol) and acetic acid (12mg, 0.2mmol) in sequence ) stirred at room temperature for 0.5 hour until the reaction was complete. The reaction solution was directly concentrated, and separated and purified by column chromatography to obtain 24.7 mg of product 1-1 with a yield of 80%.

[0040] Colorless oil, R f =...

Embodiment 2

[0043] Preparation of compound 2-1

[0044]

[0045] step:

[0046]

[0047] Ligand 2 (12.3mg, 0.02mmol) and silver carbonate (2.7mg, 0.01mmol) were accurately weighed and placed in a 10mL reaction tube equipped with a stirring bar, 1.5mL of tetrahydrofuran was added and stirred at -20°C for 5 minutes. Then isocyanoacetate 1a (11.88mg, 0.12mmol) and starting material 2 (16.0mg, 0.1mmol) were added and reacted at -20°C, monitored by TLC until the reaction of starting material 2 was complete. Install a 3cm long silica gel column, quickly filter the reaction solution, rinse with ethyl acetate, spin the filtrate dry, add 1mL methanol to dissolve, add sodium cyanoborohydride (12.6mg, 0.2mmol) and acetic acid (12mg, 0.2mmol) in sequence ) stirred at room temperature for 0.5 hour until the reaction was complete. The reaction solution was directly concentrated, and separated and purified by column chromatography to obtain 22.9 mg of product 2-1 with a yield of 88%.

[0048] C...

Embodiment 3

[0051] Preparation of compound 3-1

[0052]

[0053] step:

[0054]

[0055] Accurately weigh ligand 3 (17.4mg, 0.03mmol) and silver trifluoromethanesulfonate (3.8mg, 0.015mmol) into a 10mL reaction test tube equipped with a stirring bar, add 1mL of toluene and stir at 0°C for 5 minutes . Then isocyanoacetate 1a (11.88 mg, 0.12 mmol) and starting material 3 (17.4 mg, 0.1 mmol) were added and reacted at 0° C., monitored by TLC until the reaction of starting material 3 was complete. Install a 3cm long silica gel column, quickly filter the reaction solution, rinse with ethyl acetate, spin the filtrate dry, add 1mL methanol to dissolve, add sodium cyanoborohydride (12.6mg, 0.2mmol) and acetic acid (12mg, 0.2mmol) in sequence ) stirred at room temperature for 0.5 hour until the reaction was complete. Concentrate the reaction solution directly, separate and purify by column chromatography, and obtain 22.0 mg of product 3-1 with a yield of 80%.

[0056] Colorless oil, R f ...

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Abstract

Pyrrolidine derivatives are an important class of alkaloids with high application value. The present invention relates to an asymmetric synthesis method of pyrrolidine derivatives, which is to carry out 1,3-dipolar cycloaddition reaction between isocyanoacetate compounds and α,β-unsaturated double bonds, and the reaction can be rapidly and efficiently Construction of heteroatom-substituted pyrrolidine derivatives containing multiple chiral centers with high atom economy. The substrate used in the invention is easy to prepare, low in price, mild in reaction conditions, simple in operation, and can obtain the target compound with high yield and high enantioselectivity without anhydrous and oxygen-free operation, and the substrate has a wide application range.

Description

technical field [0001] The invention belongs to the field of organic synthesis methodology and relates to an asymmetric synthesis method of heteroatom-substituted pyrrolidine derivatives containing quaternary carbon centers. Background technique [0002] Pyrrolidine is a very important class of natural alkaloids, which are ubiquitous in active pharmaceutical molecules and widely used in total synthesis. In recent years, pyrrolidine derivatives have attracted extensive attention in many fields such as organic synthesis, medicinal chemistry, and chemical biology. The development of efficient synthesis methods for chiral pyrrolidine derivatives is not only conducive to the development of disciplines, but also to the development of new drugs and pharmaceuticals. Career development is also important. [0003] Chiral pyrrolidine is considered to be a "superior framework" and widely exists in many natural products, organic catalysts and synthetic materials with biological activity...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D207/16C07D403/04C07F7/18
CPCC07D207/16C07D403/04C07F7/1892
Inventor 邵攀霖王志鹏胡平贺耘
Owner CHONGQING UNIV