Phenylglycine derivative as well as synthesis method and application thereof

Abstract

The invention provides a phenylglycine derivative as well as a synthesis method and application thereof, and belongs to the field of preparation of phenylglycine derivatives. The 2-morpholine-2-phenylacetic acid derivative is obtained by taking a phenylboronic acid derivative as a substrate and carrying out Petasis'one-pot method 'reaction on the phenylboronic acid derivative, glyoxylic acid and morpholine in a solvent. The method has the advantages of high yield, high selectivity, mild conditions and environmental protection. The invention provides a new way for industrial production of phenylglycine, and provides a new way for developing phenylglycine and new functional materials thereof.

Description

Technical Field

[0001] The invention belongs to the field of preparation of phenylglycine derivatives, and specifically relates to a phenylglycine derivative and a synthesis method and application thereof. Background Art

[0002] In recent years, phenylglycine drugs have been widely used. Phenylglycine has extremely important application value in the construction of organic molecules and natural products with biological activity, and is widely used in pharmaceutical intermediates. Phenylglycine and its derivatives are important intermediates for the preparation of β-lactam antibiotics, and are commonly used in the preparation of drugs such as ampicillin, ceftriaxone, cefaclor, ceftriaxone, oxypiperazine penicillin, and cefoperazone. It is also an important intermediate for the synthesis of polypeptide hormones and various pesticides, and is widely used in the fields of medicinal chemistry and organic synthesis. Due to its wide range of uses, the synthesized pharmaceutical products can be injected or taken orally, so it has broad prospects in the pharmaceutical market. [1] Among them, chlorophenylglycine derivatives are not only used in the preparation of antibacterial drugs, antithrombotic drugs and pesticides, but also in the synthesis of penicillin derivatives and cephalosporin derivatives. [2] Therefore, researching and developing the synthesis method of environmentally friendly green phenylglycine products is of great significance to the development of my country's antibiotic industry and pesticides.

[0003] Traditional methods for preparing phenylglycine mainly include the Bucher-Bergs method, 2-halophenylacetic acid amination method, asymmetric synthesis method, and enzyme-catalyzed stereoselective synthesis method. However, these methods have certain defects in terms of product purity, yield, selectivity, etc. [1] .

[0004] [1]Xu Yarong. Research on the synthesis process of phenylglycine and p-chlorophenylglycine[D]. Nanjing University of Technology, 2005.

[0005] [2] Li Huachong, Su Xiaoyan, Yang Dacheng. Synthesis of L-aminophenylglycine derivatives and their anti-diabetic activity [C] / / Chinese Chemical Society, National Natural Science Foundation of China. Innovation in organic synthesis - a new driving force for industrialization - Abstracts of the Third National Symposium on Organic Synthesis Chemistry and Processes of the Chinese Chemical Society. College of Chemistry and Chemical Engineering, Southwest University, 2010: 2. Summary of the invention

[0006] The present invention is made to solve the above problems, and aims to provide a phenylglycine derivative and a synthesis method and application thereof.

[0007] The present invention provides a phenylglycine derivative having the following characteristics: in, include

[0008] The present invention also provides a method for synthesizing phenylglycine derivatives, which has the following characteristics: based on the Petasis reaction, the method is used to synthesize the aforementioned phenylglycine derivatives, and comprises the following steps: S10, dissolving glyoxylic acid in a solvent to obtain a first mixture; S20, dissolving morpholine in the first mixture to react to obtain a second mixture; S30, dissolving a phenylboronic acid derivative in the second mixture to react to obtain a third mixture; S40, extracting, separating and purifying the third mixture to obtain the phenylglycine derivatives.

[0009] The method for synthesizing phenylglycine derivatives provided by the present invention may also have the following characteristics: wherein the solvent includes any one or more of dichloromethane, acetonitrile, ethylene glycol, 1,2-dichloroethane, methanol, isopropanol, ethanol, chloroform, DMSO or chloroform.

[0010] The method for synthesizing phenylglycine derivatives provided by the present invention may also have the following characteristics: wherein the molar ratio of glyoxylic acid, morpholine, phenylboronic acid derivatives and solvent feed amounts is (1.0-1.2):(1.0-1.2):(1.0-1.2):(39.0-39.6).

[0011] The method for synthesizing phenylglycine derivatives provided by the present invention may also have the following characteristics: wherein, in step S10, the dissolution method is mixing and stirring at 38°C to 42°C for 2 minutes; and in step S20, the dissolution method is mixing and stirring at 38°C to 42°C for 2 minutes.

[0012] The method for synthesizing phenylglycine derivatives provided by the present invention may also have the following characteristics: wherein, in step S30, the phenylboronic acid derivatives include

[0013] The method for synthesizing phenylglycine derivatives provided by the present invention may also have the following characteristics: wherein, in step S30, the dissolution method is mixing and stirring at 38° C. to 42° C. for 2 minutes, and the reaction condition is stirring and reacting for 16 hours.

[0014] The method for synthesizing phenylglycine derivatives provided by the present invention may also have the following characteristics: wherein, in step S30, the third mixture is monitored by TLC method until the reaction of glyoxylic acid, morpholine and phenylboronic acid derivatives in the third mixture is terminated.

[0015] The method for synthesizing phenylglycine derivatives provided by the present invention may also have the following characteristics: wherein, in step S40, the solvent used for extraction is ethyl acetate, and the separation and purification method is column chromatography.

[0016] The invention also provides an application of a phenylglycine derivative in a pharmaceutical intermediate.

[0017] Functions and Effects of the Invention

[0018] The present invention relates to a phenylglycine derivative and a synthesis method and application thereof. Phenylboronic acid derivatives are used as substrates, and a one-pot petasis reaction is carried out with glyoxylic acid and morpholine in a solvent to obtain 2-morpholine-2-phenylacetic acid derivatives. The derivatives exhibit good high yield, high selectivity, mild conditions and are green and environmentally friendly.

[0019] The invention provides a new way for the industrial production of phenylglycine and a new approach for the development of phenylglycine and new functional materials thereof. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Figure 1 1 is a synthetic route diagram of the phenylglycine derivatives of the embodiments of the present invention;

[0021] Figure 2 is a flowchart of a method for synthesizing a phenylglycine derivative according to an embodiment of the present invention;

[0022] Figure 3 is the H NMR spectrum of 2-morpholine-2-(4-fluoro-2-methylphenyl)acetic acid synthesized in the examples of the present invention;

[0023] Figure 4 It is the NMR carbon spectrum of 2-morpholine-2-phenylacetic acid synthesized in the embodiment of the present invention. DETAILED DESCRIPTION

[0024] In order to make the technical means, creative features, objectives and effects of the present invention easy to understand, the following examples and drawings specifically describe a phenylglycine derivative of the present invention and its synthesis method and application.

[0025] <Example>

[0026] Figure 1 1 is a synthetic route diagram of the phenylglycine derivatives of the embodiments of the present invention; Figure 2 It is a flowchart of the synthesis method of the phenylglycine derivative according to the embodiment of the present invention.

[0027] like Figure 1 and 2As shown, this embodiment provides a phenylglycine derivative and a synthesis method thereof, and the synthesis method of the phenylglycine derivative comprises the following steps:

[0028] S10, adding glyoxylic acid to dichloromethane at 40° C. and stirring for 2 min to dissolve the mixture to obtain a first mixture.

[0029] S20, adding morpholine to the first mixture at 40° C., stirring for 2 minutes to dissolve morpholine, and obtaining a second mixture.

[0030] S30, adding phenylboronic acid derivatives to the second mixture at 40°C, stirring for 2 minutes to dissolve, and then stirring for 16 hours to obtain a third mixture. The molar ratio of the actual amount of each substance added in steps S10 to S30 is phenylboronic acid derivatives: glyoxylic acid: morpholine: dichloromethane = 1:1.2:1.2:(39.0-39.6).

[0031] In this step, the third mixture is monitored by TLC method until the reaction of glyoxylic acid, morpholine and phenylboronic acid derivatives in the third mixture is terminated.

[0032] Among them, phenylboronic acid derivatives include

[0033] S40, extracting and collecting the organic phase of the third mixture with ethyl acetate to obtain an organic phase of a 2-morpholine-2-phenylacetic acid derivative, and then separating and purifying it by column chromatography to obtain a 2-morpholine-2-phenylacetic acid derivative, namely, a phenylglycine derivative.

[0034] The structural formula of the phenylglycine derivative synthesized in this embodiment includes

[0035]

[0036] Figure 3 is the H NMR spectrum of 2-morpholine-2-(4-fluoro-2-methylphenyl)acetic acid synthesized in the examples of the present invention; Figure 4 It is the NMR carbon spectrum of 2-morpholine-2-phenylacetic acid synthesized in the embodiment of the present invention.

[0037] like Figures 3-4 As shown, this example successfully synthesized 2-morpholine-2-(4-fluoro-2-methylphenyl)acetic acid and 2-morpholine-2-phenylacetic acid, i.e., phenylglycine derivatives. (The nuclear magnetic resonance spectra of the remaining phenylglycine derivatives in this example will not be repeated)

[0038] The reaction activities of the above 12 phenylglycine derivatives synthesized in this embodiment are 83%, 74%, 68%, 60%, 72%, 66%, 58%, 91%, 70%, 75%, 71% and 69%, respectively.

[0039] Among them, during the preparation process, phenylboronic acid containing a strong electron-donating methoxy group has better reaction activity, and o-dimethylphenylboronic acid has the highest reaction activity.

[0040] This embodiment also provides an application of a phenylglycine derivative in a pharmaceutical intermediate.

[0041] Among them, the phenylglycine derivatives in this embodiment are used for the synthesis of β-lactam antibiotics, and the chlorophenylglycine derivatives are used for the preparation of antibacterial drugs, antithrombotic drugs and pesticides, and are also used for the synthesis of penicillin derivatives and cephalosporin derivatives.

[0042] Those skilled in the art should understand that the present invention is not limited to the above embodiments, and the above embodiments and descriptions are only for explaining the principles of the present invention. Without departing from the spirit and scope of the present invention, the present invention may have various changes and improvements, and these changes and improvements fall within the scope of the present invention to be protected. The scope of protection of the present invention is defined by the attached claims and their equivalents.

Claims

1. A phenylglycine derivative, characterized in that: The phenylglycine derivative is in, include 2. A method for synthesizing a phenylglycine derivative, characterized in that: Based on the petasis reaction, the method for synthesizing the phenylglycine derivative according to claim 1 comprises the following steps: S10, dissolving glyoxylic acid in a solvent to obtain a first mixture; S20, dissolving morpholine in the first mixture to react to obtain a second mixture; S30, dissolving the phenylboronic acid derivative in the second mixture to react to obtain a third mixture; S40, extracting, separating and purifying the third mixture to obtain the phenylglycine derivative.

3. The method for synthesizing a phenylglycine derivative according to claim 2, characterized in that: in, The solvent includes any one or more of dichloromethane, acetonitrile, ethylene glycol, 1,2-dichloroethane, methanol, isopropanol, ethanol, chloroform, DMSO or chloroform.

4. The method for synthesizing a phenylglycine derivative according to claim 2, characterized in that: in, The molar ratio of glyoxylic acid, morpholine, phenylboronic acid derivatives and the solvent is (1.0-1.2):(1.0-1.2):(1.0-1.2):(39.0-39.6).

5. The method for synthesizing a phenylglycine derivative according to claim 2, characterized in that: in, In step S10, the dissolution method is to mix and stir at 38°C to 42°C for 2 minutes. In step S20, the dissolution method is to mix and stir at 38°C to 42°C for 2 minutes.

6. The method for synthesizing a phenylglycine derivative according to claim 2, characterized in that: in, In step S30, the phenylboronic acid derivatives include 7. The method for synthesizing a phenylglycine derivative according to claim 2, characterized in that: in, In step S30, the dissolution method is to mix and stir at 38°C to 42°C for 2 minutes, and the reaction condition is to stir and react for 16 hours.

8. The method for synthesizing a phenylglycine derivative according to claim 2, characterized in that: in, In step S30, the third mixture is monitored by TLC method until the reaction of glyoxylic acid, morpholine and phenylboronic acid derivatives in the third mixture is terminated.

9. The method for synthesizing a phenylglycine derivative according to claim 2, characterized in that: in, In step S40, the solvent used for extraction is ethyl acetate. The separation and purification method is column chromatography.

10. Use of the phenylglycine derivative according to claim 1 in pharmaceutical intermediates.

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