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Method for synthesizing polyarylation substituted oxazolidine

An oxazolidine and polyaryl technology, which is applied in the field of pharmaceutical synthesis and chemical industry, can solve the problems of insufficient product structure diversity, narrow substrate reaction applicability, poor substrate adaptability and other problems, and achieves rich and diverse reaction product structures, Broad reactivity and substrate applicability, high selectivity effect

Inactive Publication Date: 2012-07-04
EAST CHINA NORMAL UNIV
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Problems solved by technology

The traditional one-step chemical synthesis method for the efficient preparation of polyaryl-substituted oxazolidines is synthesized by 3+2 cyclization reactions: 3+2 cycloaddition reactions of carbonyl ylides and imines, or azomethine ylides and The 3+2 cycloaddition reaction of aldehydes is prepared, but there are few related literature reports so far, and the reaction applicability of the substrate is very narrow, only limited to the reaction of some raw materials and substrates, or only limited to the 3+ in the molecule 2 reaction, the 3+2 reaction between molecules is difficult to occur
(Tetrahedron: Asymmetry 2009, 20, 723-725 J.Org.Chem.1999, 64, 4079-4088; J.Org.Chem.1987, 52, 235-244; Org.Lett.2001, 3, 3741-3744 ; J.Am.Chem.Soc.2003,125,4692-4693), these factors make the method for one-step efficient preparation of polyaryl substituted oxazolidines have great limitations: low selectivity, poor substrate adaptability Extensive, cumbersome operation, insufficient diversity of product structure, etc.
However, there are relatively large limitations in its reaction substrates: diazo compounds are limited to ethyl diazoacetate (there are no other reports of diazo compounds with different activities such as phenyl diazoacetate methyl esters), and imines are limited to Imines generated from benzylamine and aromatic aldehydes (imines generated from aniline and benzaldehyde do not undergo the above 3+2 cycloaddition reaction)

Method used

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  • Method for synthesizing polyarylation substituted oxazolidine
  • Method for synthesizing polyarylation substituted oxazolidine
  • Method for synthesizing polyarylation substituted oxazolidine

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Experimental program
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Embodiment 1

[0035]N-benzylidene phenyl imine (0.25mmol), benzaldehyde (0.25mmol), Molecular sieve (0.1g), Lewis acid (Yb(OTf) 3 , 0.025mmol) and Rh 2 (OAc) 4 (0.005mmol) The reaction system consisting of co-catalysts was protected by nitrogen, then dichloromethane (1.0ml) was added, and then cooled to -20°C, and 1.0mL of dichloromethane was mixed with p-methoxyphenyldiazoacetic acid methyl The ester solution (0.275 mmol) was added dropwise to the reaction system within 1 hour using an auto-sampling pump. At the end of the injection, stir at -20°C for 0.5 hours, then add saturated NaHCO dropwise to the reaction system 3 Aqueous solution (0.1 ml) was used to quench the reaction. The solvent was removed by rotary evaporation under reduced pressure to obtain a crude product. The crude product was subjected to column chromatography (ethyl acetate:petroleum ether=1:50~1:30) to obtain pure polyaryl-substituted oxazolidine products. Yield 69%, diastereoselectivity greater than 70:30.

Embodiment 2

[0037] N-benzylidene phenyl imine (0.25mmol), benzaldehyde (0.25mmol), Molecular sieve (0.1g), Lewis acid (Yb(OTf) 3 , 0.025mmol) and Rh 2 (OAc) 4 (0.005mmol) reaction system nitrogen protection of co-catalyst composition, add toluene (1.0ml) again, then cool to-20 ℃, under stirring condition, p-methoxyphenyl diazoacetic acid methyl ester (0.275mmol) of 1.0mL toluene ) solution was added dropwise to the reaction system within 1 hour with an autosampler pump. At the end of the injection, stir at -20°C for 0.5 hours, then add saturated NaHCO dropwise to the reaction system 3 Aqueous solution (0.1 ml) was used to quench the reaction. The solvent was removed by rotary evaporation under reduced pressure to obtain a crude product. The crude product was subjected to column chromatography (ethyl acetate:petroleum ether=1:50~1:30) to obtain pure polyaryl-substituted oxazolidine products. Yield 63%, diastereoselectivity greater than 70:30.

Embodiment 3

[0039] N-benzylidene phenyl imine (0.25mmol), benzaldehyde (0.25mmol), Molecular sieve (0.1g), Lewis acid (Yb(OTf) 3 , 0.025mmol) and Rh 2 (OAc) 4 (0.005mmol) The reaction system composed of co-catalyst is protected by nitrogen, then p-xylene (1.0ml) is added, then cooled to -20°C, and 1.0mL of p-xylene in p-methoxyphenyldiazoacetic acid methyl The ester (0.275 mmol) solution was added dropwise to the reaction system within 1 hour using an auto-sampling pump. At the end of the injection, stir at -20°C for 0.5 hours, then add saturated NaHCO dropwise to the reaction system 3 Aqueous solution (0.1 ml) was used to quench the reaction. The solvent was removed by rotary evaporation under reduced pressure to obtain a crude product. The crude product was subjected to column chromatography (ethyl acetate:petroleum ether=1:50~1:30) to obtain pure polyaryl-substituted oxazolidine products. Yield 57%, diastereoselectivity greater than 70:30.

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Abstract

The invention relates to a method for synthesizing polyarylation substituted oxazolidine. The method comprises the following steps: taking three components of diazol compound, aldehyde and imine as raw materials, taking Lewis acid and carboxylic rhodium as catalysts, taking an organic solvent as a solvent, taking a molecular sieve as a water-absorbing agent, after one-step reaction, removing the solvent and obtaining coarse products; and carrying out column chromatography on the coarse products by using solution with the volume ratio of ethyl acetate and petroleum ether of being 1:50-1:30, and obtaining a polyarylation substituted oxazolidine product with high diastereomeric selectivity. The mole ratio of the diazol compound, the aldehyde, the imine, the Lewis acid and the carboxylic rhodium is 1.1:1:1:0.1:0.02; and the put material amount of the molecular sieve is 2-5g / mmol of diazol compound. The method has the advantages of high atom economy, high selectivity and high yield and hassimple and safe operation. The polyarylation substituted oxazolidine with high diastereomeric selectivity obtained by the method is an important chemical and medical intermediate and is widely applied in the medical and industrial fields.

Description

technical field [0001] The invention relates to a method for synthesizing polyaryl-substituted oxazolidines. It belongs to the technical field of pharmaceutical synthesis and chemical engineering. Background technique [0002] Polyaryl substituted oxazolidines are an important intermediate skeleton structure for the construction of natural products, and their hydrolyzed products are α-hydroxy-β-amino acid derivatives, which are used in the side chain of anticancer drug paclitaxel (Taxol), peptidase inhibitor A This kind of skeleton structure is found in the structures of Amastatin and Bestatin; it can also be used to synthesize many other antitumor drugs, antibiotics, and antifungal drugs. The traditional one-step chemical synthesis method for the efficient preparation of polyaryl-substituted oxazolidines is synthesized by 3+2 cyclization reactions: 3+2 cycloaddition reactions of carbonyl ylides and imines, or azomethine ylides and The 3+2 cycloaddition reaction of aldehyd...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D263/04
Inventor 胡文浩徐新芳郭新邱林周静杨琍苹
Owner EAST CHINA NORMAL UNIV
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