CN111517971A - Antifungal compound, synthesis method and application thereof - Google Patents

Abstract

The invention belongs to the technical field of drug synthesis, and relates to an antifungal compound, in particular to an antifungal compound, a synthesis method and an application thereof, wherein the antifungal compound is amino acid carbon ester or pharmaceutically acceptable salt thereof, and the amino acid carbon ester has the following structural formula:

wherein R is₁Is one of C5-C17 alkyl or C5-C17 alkenyl; the R is₂Is an amino acid side chain group; also provides a synthetic method of the antifungal compound and application in the antifungal field.

Description

A kind of antifungal compound, synthetic method and application thereof

technical field

The invention belongs to the technical field of drug synthesis, relates to an antifungal compound, in particular to an antifungal compound, a synthesis method and an application thereof.

Background technique

Fungal infection is one of the main clinical infectious diseases, which can be divided into superficial mycosis and invasive mycosis. Among them, the incidence and mortality of invasive fungal diseases have been increasing year by year in recent decades. Especially in some special patient populations, such as organ transplant patients, critically ill patients in ICU, and immunocompromised patients with blood diseases, the morbidity rate is as high as 29%, and the fatality rate is as high as 49%.

At present, there are not many types of drugs that can be used in clinical treatment of fungal infections, mainly polyenes, pyrroles, echinocandins and 5-fluorocytosine (5-FC). Polyenes are the earliest antifungal drugs used in clinic, mainly amphotericin B and its analogs, which inhibit fungal growth by acting on the unique sterol binding on the fungal cell membrane, impairing the permeability of the fungal cell membrane. The advantages of this class of drugs are broad antifungal spectrum and strong activity, while the disadvantage is high toxicity, such as hepatotoxicity, nephrotoxicity and infusion-related toxicity. Pyrroles include imidazoles and triazoles, which affect the stability of the cell membrane by acting on ergosterol on the fungal cell membrane, causing the fungal cell to rupture and die. The main representative drugs of imidazoles are ketoconazole, clotrimazole, miconazole, etc., which are suitable for the treatment of superficial fungal infections. The main representative drugs of triazoles are fluconazole, voriconazole, itraconazole, etc., which can be used for the treatment of deep fungal infections. These drugs have certain effects on liver and kidney function and have some other adverse reactions. The mechanism of action of 5-fluorocytosine is to interfere with the nucleic acid and protein synthesis of fungal cells, and it is prone to fungal drug resistance, so it is generally not used alone. Echinocandins are relatively new potent antifungal drugs, which destroy the fungal cell wall by the non-competitive inhibitor 1,3-β-D-glucan synthase and cause the fungus to dissolve and die. Effect. Its representative drugs are caspofungin, micafungin and so on.

In recent decades, the research and development of antifungal drugs has progressed slowly. The newer echinocandins, caspofungin, were discovered in 1970 and began to be clinically applied in 2000. In the past 20 years, no new antifungal drugs have been developed and combined. successfully applied. Due to the lack of available types and quantities of clinical antifungal drugs, the situation of fungal resistance has become more and more serious, and even "super fungi" have repeatedly appeared to be the last line of defense against caspofungin, micafungin and other antifungal drugs. The emergence of drug resistance is a serious threat to the life and health of patients. Therefore, finding more and better new antifungal drugs as soon as possible to effectively overcome the problem of fungal resistance is an important task that scientific and technological workers urgently need to solve.

SUMMARY OF THE INVENTION

In view of the problems in the prior art, the present invention provides an antifungal compound with good antifungal effect, which can be used to prepare an antifungal agent.

For realizing the above technical purpose, the technical scheme of the present invention is:

An antifungal compound, the antifungal compound is an amino acid carbon ester or a pharmaceutically acceptable salt thereof.

Described amino acid carbon ester has following structural formula:

Wherein, R ¹ is one of a C5-C17 alkane group or a C5-C17 alkene group; the R ² is an amino acid side chain group.

Further, the R ₁ is one of a straight chain alkane group with a total carbon number of C5-C17 or a side chain alkane group with a total carbon number of C5-C17.

Further, the R ₁ is one of a straight-chain olefin group with a total carbon number of C5-C17 or a side chain olefin group with a total carbon number of C5-C17.

A preparation method of an antifungal compound, that is, the preparation method of the amino acid carbon ester, takes amino acid and carbon alcohol as raw materials, and is obtained by refluxing reaction, and the specific steps are as follows:

Step 1, amino acid is dissolved in toluene to form amino acid toluene liquid, and the concentration of described amino acid in toluene is 0.5mol/L;

In step 2, carbon alcohol and p-toluenesulfonic acid are added to the amino acid toluene liquid for reflux reaction, and water is azeotropically separated to obtain amino acid carbon ester. The molar amounts of amino acids are the same, and the reflux reaction adopts a slow heating method to raise the temperature to the reflux temperature.

In the step 2, thin-layer chromatography is used to monitor the reaction.

Further, the purification step of described amino acid carbon ester is as follows:

In step a, the reaction mixture after azeotropic separation of water is concentrated in vacuo, and the residue is obtained by filtration;

Step b, using ethyl acetate to extract the residue, then sequentially using sodium carbonate aqueous solution and brine washing, and using sodium sulfate to dry the organic layer, vacuum concentration to obtain a crude product, the mass concentration of sodium carbonate in the sodium carbonate aqueous solution is 5%;

In step c, the crude product is chromatographed on silica gel to obtain the product, MeOH:DCM=1:50-1:5 in the silica gel.

An application of an antifungal compound as an antifungal agent, that is, an application of an amino acid carbon ester or a pharmaceutically acceptable salt thereof as an antifungal agent.

An application of an antifungal compound, the application of the antifungal compound in the preparation of an antifungal drug, that is, the application of an amino acid carbon ester or a pharmaceutically acceptable salt thereof in the preparation of an antifungal drug.

An antifungal composition, comprising an antifungal compound as an active ingredient, and one or more pharmaceutically acceptable adjuvants, specifically an amino acid carbon ester or a pharmaceutically acceptable salt thereof as an active ingredient, and a combination of a one or more pharmaceutically acceptable excipients.

As can be seen from the above description, the present invention has the following advantages:

1. The antifungal compound of the present invention has a good antifungal effect and can be used to prepare an antifungal agent.

2. The present invention adopts the mode of slow heating to cooperate with the reflux reaction, effectively controls the progress of the reaction, has good reaction efficiency and reaction stability, and effectively reduces side reactions.

3. The present invention uses thin-layer chromatography to track the progress of the reaction, which can effectively control the progress of the reaction and effectively ensure the high efficiency of the reaction.

Description of drawings

Fig. 1 is the infrared spectrogram of the leucine dodecyl ester in the embodiment of the present invention 1;

Fig. 2 is the mass spectrogram of the leucine dodecyl ester in the embodiment of the present invention 1;

Fig. 3 is the nuclear magnetic spectrogram of the leucine dodecyl ester in the embodiment of the present invention 1;

Fig. 4 is the nuclear magnetic spectrogram of the leucine octadecyl ester in the embodiment of the present invention 2;

Fig. 5 is the nuclear magnetic spectrum of leucine octadecyl ester in Example 3 of the present invention.

Detailed ways

1 to 3, a specific embodiment of the present invention is described in detail, but does not make any limitation to the claims of the present invention.

Leucine:

Example 1

An antifungal compound, the antifungal compound is leucine dodecyl ester, and the structural formula of the leucine dodecyl ester is as follows:

The preparation method of described leucine dodecyl ester is as follows:

Dodecanol (16.8 g, 0.1 mol) and p-toluenesulfonic acid (20.9 g, 0.1 mol) were added to a solution of DL-leucine (13.1 g, 0.1 mol) in toluene (200 mL), and the temperature was slowly raised to reflux temperature , water was azeotropically separated, and the reaction was monitored by thin-layer chromatography. The reaction mixture was concentrated in vacuo and the resulting residue was extracted with ethyl acetate (200 ml), washed with 5% aqueous _Na2CO3 ( ₃ x 50 ml), then brine solution. _The organic layer was dried over _Na2SO4 , concentrated in vacuo to give the crude product, and chromatographed on silica gel (MeOH:DCM=1:50) to give leucine dodecyl ester (10 g, 33%) as a yellow oil.

Fig. 1 is the infrared spectrum of leucine dodecyl ester, Fig. 2 is the mass spectrogram of leucine dodecyl ester, Fig. 3 is the nuclear magnetic spectrum of leucine dodecyl ester, after the graph 1 to Figure 3 can verify that the product is leucine dodecyl ester.

1. Antifungal susceptibility test

The antifungal detection of the leucine dodecyl ester in this example was carried out by means of a half-dilution experiment, and caspofungin was used as a control, and the caspofungin was a commercially available drug.

The detection concentrations are as follows:

drug name Detection concentration (μg/mL) This embodiment 100,50,25,12.5,6.25,3.125,1.56,0.78,0.39,0.195 Caspofungin 100,50,25,12.5,6.25,3.125,1.56,0.78,0.39,0.195

The experimental strains were Aspergillus fumigatus, sporozoite, Cryptococcus, and Rhizopus; positive control bacteria: subsmoothing, Kerou.

in:

The product of this example (MIC): the lowest drug concentration that inhibits the fungal growth rate by 100% compared with the positive control well.

Caspofungin (MIC/MEC): the lowest drug concentration that inhibited bacterial growth by 50% compared to the positive control wells. The growth of filamentous bacteria was restricted compared to the positive control wells, and the lowest drug concentration for colony shrinkage was the minimum effective concentration (MEC).

From the above data, it can be clearly concluded that the antifungal effect of leucine dodecyl ester in some fungi is significantly better than that of caspofungin, therefore, leucine dodecyl ester has good antifungal effect. Bacteriostatic effect.

In this embodiment, the leucine dodecyl ester formed by amino acid and dodecanol has amphoteric lipid formed by combining with amide bond. This structure is the main component of cell membrane and an important component of signal molecule. It is involved in a variety of cellular processes and plays an important role, such as endocytosis, cell signal transduction, cellular heat stress response and apoptosis, etc. It also plays an important role in the pathogenesis of fungal cells, with good Antifungal effect.

Example 2

A kind of antifungal compound, described antifungal compound is leucine octadecyl ester, and the preparation method of described leucine octadecyl ester is as follows:

Add octadecanol (0.1 mol) and p-toluenesulfonic acid (0.1 mol) to a solution of leucine (0.1 mol) in toluene (200 mL), slowly warm up to reflux temperature, azeotropically separate water, and use thin layer chromatography The reactants were monitored. The reaction mixture was concentrated in vacuo and the resulting residue was extracted with ethyl acetate (200 ml), washed with 5% aqueous _Na2CO3 ( ₃ x 50 ml), then brine solution. _The organic layer was dried over _Na2SO4 , concentrated in vacuo to give the crude product, and chromatographed on silica gel (MeOH:DCM=1:5) to give leucine octadecyl ester (39%).

Fig. 4 is the nuclear magnetic spectrum of leucine octadecyl ester, which can be easily analyzed by Fig. 4, and the product is leucine octadecyl ester.

The antifungal test of leucine octadecyl was carried out by using the same experiment as the antifungal detection in Example 1, and the results showed that leucine octadecyl ester has a good effect on antifungal and its drug resistance.

Example 3

An antifungal compound, the antifungal compound is leucine hexaalkyl ester, and the preparation method of described leucine hexaalkyl ester is as follows:

Hexanol (0.1 mol) and p-toluenesulfonic acid (0.1 mol) were added to a solution of leucine (0.1 mol) in toluene (200 mL), the temperature was slowly raised to reflux temperature, and water was azeotropically separated. The reactants were monitored. The reaction mixture was concentrated in vacuo and the resulting residue was extracted with ethyl acetate (200 ml), washed with 5% aqueous _Na2CO3 ( ₃ x 50 ml), then brine solution. _The organic layer was dried over _Na2SO4 , concentrated in vacuo to give crude product, and chromatographed on silica gel (MeOH:DCM=1:20) to give leucine hexaalkyl ester (36%).

Fig. 5 is the nuclear magnetic spectrum of leucine hexaalkyl ester, which can be easily analyzed by Fig. 5, and the product is leucine hexaalkyl ester.

The antifungal test of leucine hexaalkyl ester was carried out using the same experiment as the antifungal detection in Example 1, and the results showed that leucine hexaalkyl ester had good antifungal effect.

Example 4

An antifungal compound, the antifungal compound is an isostearyl leucine ester, and the preparation method of the isostearyl leucine ester is as follows:

Isostearyl alcohol (0.1 mol) and p-toluenesulfonic acid (0.1 mol) were added to a solution of leucine (0.1 mol) in toluene (200 mL), the temperature was slowly raised to reflux temperature, water was azeotropically separated, and a thin layer The reaction was monitored by chromatography. The reaction mixture was concentrated in vacuo and the resulting residue was extracted with ethyl acetate (200 ml), washed with 5% aqueous _Na2CO3 ( ₃ x 50 ml), then brine solution. _The organic layer was dried over _Na2SO4 , concentrated in vacuo to give the crude product, and chromatographed on silica gel (MeOH:DCM=1:10) to give the isomeric octadecylleucine ester (36%).

The antifungal test of the isomerized octadecylleucine ester was carried out by the same experiment as the antifungal detection in Example 1. The results showed that the isomerized octadecylleucine ester was both effective in antifungal and its drug resistance. Has a nice effect.

Example 5

An antifungal compound, the antifungal compound is 3-methylpentyl leucine ester, and the preparation method of the 3-methyl pentyl leucine ester is as follows:

3-Methyl-1-pentanol (0.1 mol) and p-toluenesulfonic acid (0.1 mol) were added to a solution of leucine (0.1 mol) in toluene (200 mL), the temperature was slowly raised to reflux temperature, and water was azeotropically separated , the reaction was monitored by thin layer chromatography. The reaction mixture was concentrated in vacuo and the resulting residue was extracted with ethyl acetate (200 ml), washed with 5% aqueous _Na2CO3 ( ₃ x 50 ml), then brine solution. _The organic layer was dried over _Na2SO4 , concentrated in vacuo to give the crude product, and chromatographed on silica gel (MeOH:DCM=1:10) to give 3-methylpentylleucine ester (37%).

The antifungal test of 3-methylpentyl leucine ester was carried out using the same experiment as the antifungal test in Example 1. The results show that: 3-methylpentyl leucine ester has good antifungal properties. Effect.

Example 6

An antifungal compound, the antifungal compound is 3-methyl-4-n-decyl leucine ester, and the preparation method of the 3-methyl pentyl leucine ester is as follows:

3-Methyl-4-n-decanol (0.1 mol) and p-toluenesulfonic acid (0.1 mol) were added to a solution of leucine (0.1 mol) in toluene (200 mL), the temperature was slowly raised to reflux temperature, and water was azeotroped Separate and monitor the reaction by thin layer chromatography. The reaction mixture was concentrated in vacuo and the resulting residue was extracted with ethyl acetate (200 ml), washed with 5% aqueous _Na2CO3 ( ₃ x 50 ml), then brine solution. _The organic layer was dried over _Na2SO4 , concentrated in vacuo to give the crude product, and chromatographed on silica gel (MeOH:DCM=1:10) to give 3-methyl-4-n-decylleucine ester (37%).

The antifungal test of 3-methyl-4-n-decylleucine ester was carried out using the same experiment as the antifungal test in Example 1, and the results showed that: 3-methyl-4-n-decylleucine Esters have good antifungal effects.

Example 7

An antifungal compound, the antifungal compound is 9-octadecene-1-leucine ester, and the preparation method of the 9-octadecene-1-amino acid ester is as follows:

9-octadecen-1-ol (0.1mol) and p-toluenesulfonic acid (0.1mol) were added to a solution of leucine (0.1mol) in toluene (200mL), the temperature was slowly raised to reflux temperature, and water was azeotropically separated , the reaction was monitored by thin layer chromatography. The reaction mixture was concentrated in vacuo and the resulting residue was extracted with ethyl acetate (200 ml), washed with 5% aqueous _Na2CO3 ( ₃ x 50 ml), then brine solution. _The organic layer was dried over _Na2SO4 , concentrated in vacuo to give the crude product, and chromatographed on silica gel (MeOH:DCM=1:5) to give 9-octadecene-1-leucine ester (35%).

The antifungal test of 9-octadecene-1-leucine ester was carried out using the same experiment as the antifungal test in Example 1, and the results showed that: 9-octadecene-1-leucine ester was equally effective in antifungal aspect. Has a nice effect.

Example 8

An antifungal compound, the antifungal compound is 3-hexene-1-leucine ester, and the preparation method of the 3-hexene-1-leucine ester is as follows:

3-Hexen-1-ol (0.1 mol) and p-toluenesulfonic acid (0.1 mol) were added to a solution of leucine (0.1 mol) in toluene (200 mL), the temperature was slowly raised to reflux temperature, and water was azeotropically separated, The reaction was monitored by thin layer chromatography. The reaction mixture was concentrated in vacuo and the resulting residue was extracted with ethyl acetate (200 ml), washed with 5% aqueous _Na2CO3 ( ₃ x 50 ml), then brine solution. _The organic layer was dried over _Na2SO4 , concentrated in vacuo to give the crude product, and chromatographed on silica gel (MeOH:DCM=1:10) to give 3-hexene-1-leucine ester (38%).

The antifungal test of 3-hexene-1-leucine ester was carried out using the same experiment as the antifungal test in Example 1. The results showed that: 3-hexene-1-leucine ester had good antifungal properties. Effect.

Example 9

An antifungal compound, the antifungal compound is 11-hexadecene-1-leucine ester, and the preparation method of the 11-hexadecene-1-leucine ester is as follows:

11-hexadecenol (0.1 mol) and p-toluenesulfonic acid (0.1 mol) were added to a solution of leucine (0.1 mol) in toluene (200 mL), the temperature was slowly raised to reflux temperature, and water was azeotropically separated, using The reaction was monitored by thin layer chromatography. The reaction mixture was concentrated in vacuo and the resulting residue was extracted with ethyl acetate (200 ml), washed with 5% aqueous _Na2CO3 ( ₃ x 50 ml), then brine solution. _The organic layer was dried over _Na2SO4 , concentrated in vacuo to give the crude product, and chromatographed on silica gel (MeOH:DCM=1:40) to give 11-hexadecene-1-leucine ester (34%).

The antifungal test of 11-hexadecene-1-leucine ester was carried out using the same experiment as the antifungal test in Example 1. All aspects have good effects.

Example 10

A kind of antifungal compound, described antifungal compound is 6-methyl-3-heptene-2-leucine ester, the preparation method of described 6-methyl-3-heptene-2-leucine ester as follows:

6-Methyl-3-hepten-2-ol (0.1 mol) and p-toluenesulfonic acid (0.1 mol) were added to a solution of glutamic acid (0.1 mol) in toluene (200 mL), and the temperature was slowly raised to reflux temperature, The water was azeotropically separated and the reaction monitored by thin layer chromatography. The reaction mixture was concentrated in vacuo and the resulting residue was extracted with ethyl acetate (200 ml), washed with 5% aqueous _Na2CO3 ( ₃ x 50 ml), then brine solution. _The organic layer was dried over _Na2SO4 , concentrated in vacuo to give crude product, chromatographed on silica gel (MeOH:DCM=1:10) to give 6-methyl-3-heptene-2-leucine ester (37%) .

The antifungal test of 6-methyl-3-heptene-2-leucine ester was carried out using the same experiment as the antifungal test in Example 1, and the results showed that: 6-methyl-3-heptene-2-leucine Amino esters have good antifungal effects.

Other amino acids:

Example 11

An antifungal compound, the antifungal compound is valine dodecyl ester, and the preparation method of described valine dodecyl ester is as follows:

Dodecanol (0.1 mol) and p-toluenesulfonic acid (0.1 mol) were added to a solution of valine (0.1 mol) in toluene (200 mL), the temperature was slowly raised to reflux temperature, water was azeotropically separated, and thin-layer chromatography was used. The reactants were monitored. The reaction mixture was concentrated in vacuo and the resulting residue was extracted with ethyl acetate (200 ml), washed with 5% aqueous _Na2CO3 ( ₃ x 50 ml), then brine solution. _The organic layer was dried over _Na2SO4 , concentrated in vacuo to give the crude product, and chromatographed on silica gel (MeOH:DCM=1:5) to give valine dodecyl ester (38%).

The antifungal test of valine dodecyl ester was carried out using the same experiment as the antifungal detection in Example 1, and the results showed that: valine dodecyl ester has good antifungal effect.

Example 12

An antifungal compound, the antifungal compound is 6-heptene-3-glutamate, and the preparation method of the 6-heptene-3-glutamate is as follows:

6-hepten-3-ol (0.1 mol) and p-toluenesulfonic acid (0.1 mol) were added to a solution of glutamic acid (0.1 mol) in toluene (200 mL), the temperature was slowly raised to reflux temperature, and water was azeotropically separated, The reaction was monitored by thin layer chromatography. The reaction mixture was concentrated in vacuo and the resulting residue was extracted with ethyl acetate (200 ml), washed with 5% aqueous _Na2CO3 ( ₃ x 50 ml), then brine solution. _The organic layer was dried over _Na2SO4 , concentrated in vacuo to give the crude product, and chromatographed on silica gel (MeOH:DCM=1:10) to give 6-heptene-3-glutamate (38%).

The antifungal test of 6-heptene-3-glutamate was carried out using the same experiment as the antifungal test in Example 1. The results showed that 6-heptene-3-glutamate had good antifungal properties. Effect.

Example 13

A kind of antifungal compound, described antifungal compound is pentyl threonine ester, and the preparation method of described pentyl threonine ester is as follows:

N-amyl alcohol (0.1 mol) and p-toluenesulfonic acid (0.1 mol) were added to a solution of threonine (0.1 mol) in toluene (200 mL), the temperature was slowly raised to reflux temperature, water was azeotropically separated, and thin-layer chromatography was used. The reactants were monitored. The reaction mixture was concentrated in vacuo and the resulting residue was extracted with ethyl acetate (200 ml), washed with 5% aqueous _Na2CO3 ( ₃ x 50 ml), then brine solution. _The organic layer was dried over _Na2SO4 , concentrated in vacuo to give the crude product, and chromatographed on silica gel (MeOH:DCM=1:10) to give pentyl threonine ester (37%).

The antifungal test of pentyl threonine ester was carried out using the same experiment as the antifungal detection in Example 1, and the results showed that: pentyl threonine ester has good antifungal effect.

Example 14

An antifungal compound, the antifungal compound is 3-hexadecylserine, and the preparation method of the 3-hexadecylserine is as follows:

3-hexadecanol (0.1 mol) and p-toluenesulfonic acid (0.1 mol) were added to a solution of serine (0.1 mol) in toluene (200 mL), the temperature was slowly raised to reflux temperature, water was azeotropically separated, and thin layer chromatography was performed. The reactants were monitored by the method. The reaction mixture was concentrated in vacuo and the resulting residue was extracted with ethyl acetate (200 ml), washed with 5% aqueous _Na2CO3 ( ₃ x 50 ml), then brine solution. _The organic layer was dried over _Na2SO4 , concentrated in vacuo to give the crude product, and chromatographed on silica gel (MeOH:DCM=1:40) to give 3-hexadecylserine (38%).

The antifungal test of 3-hexadecylserine was carried out using the same experiment as the antifungal detection in Example 1, and the results showed that 3-hexadecylserine had good antifungal effects.

Example 15

An antifungal compound, the antifungal compound is 4-pentene-1-arginine ester, and the preparation method of the 4-pentene-1-arginine ester is as follows:

4-Penten-1-ol (0.1 mol) and p-toluenesulfonic acid (0.1 mol) were added to a solution of arginine (0.1 mol) in toluene (200 mL), the temperature was slowly raised to reflux temperature, and water was azeotropically separated, The reaction was monitored by thin layer chromatography. The reaction mixture was concentrated in vacuo and the resulting residue was extracted with ethyl acetate (200 ml), washed with 5% aqueous _Na2CO3 ( ₃ x 50 ml), then brine solution. _The organic layer was dried over _Na2SO4 , concentrated in vacuo to give crude product, and chromatographed on silica gel (MeOH:DCM=1:40) to give 4-pentene-1-arginine ester (34%).

The antifungal test of 4-pentene-1-arginine ester was carried out using the same experiment as the antifungal test in Example 1. The results showed that: 4-pentene-1-arginine ester has good antifungal properties. Effect.

Example 16

An antifungal compound, the antifungal compound is 2,6-dimethylheptene-5-serine ester, and the preparation method of the 2,6-dimethylheptene-5-serine ester is as follows:

2,6-Dimethyl-5-heptenol (0.1 mol) and p-toluenesulfonic acid (0.1 mol) were added to a solution of threonine (0.1 mol) in toluene (200 mL), the temperature was slowly raised to reflux temperature, water The azeotropic separation was carried out and the reaction was monitored by thin layer chromatography. The reaction mixture was concentrated in vacuo and the resulting residue was extracted with ethyl acetate (200 ml), washed with 5% aqueous _Na2CO3 ( ₃ x 50 ml), then brine solution. _The organic layer was dried over _Na2SO4 , concentrated in vacuo to give the crude product, and chromatographed on silica gel (MeOH:DCM=1:15) to give 2,6-dimethylheptene-5-serine ester (39%).

The antifungal test of 2,6-dimethylheptene-5-serine ester was carried out in the same experiment as the antifungal test in Example 1, and the results showed that: 2,6-dimethylheptene-5-serine ester was in It has a good effect on antifungal.

Example 17

A kind of antifungal compound, described antifungal compound is undecylenyl alanine ester, and the preparation method of described undecylenyl alanine ester is as follows:

Undecenol (0.1 mol) and p-toluenesulfonic acid (0.1 mol) were added to a solution of alanine (0.1 mol) in toluene (200 mL), the temperature was slowly raised to reflux temperature, water was azeotropically separated, and a thin layer of The reaction was monitored by chromatography. The reaction mixture was concentrated in vacuo and the resulting residue was extracted with ethyl acetate (200 ml), washed with 5% aqueous _Na2CO3 ( ₃ x 50 ml), then brine solution. _The organic layer was dried over _Na2SO4 , concentrated in vacuo to give the crude product, and chromatographed on silica gel (MeOH:DCM=1:10) to give undecenylalanine ester (37%).

The antifungal test of undecylenyl alanine ester was carried out using the same experiment as the antifungal detection in Example 1, and the results showed that: undecylenyl alanine ester all had good antifungal effects.

It can be understood that the above specific description of the present invention is only used to illustrate the present invention and is not limited to the technical solutions described in the embodiments of the present invention. Those of ordinary skill in the art should understand that the present invention can still be modified or equivalently replaced to achieve the same technical effect; as long as it meets the needs of use, it is within the protection scope of the present invention.

Claims (7)

1. An antifungal compound characterized by: the antifungal compound is an amino acid carbon ester or a pharmaceutically acceptable salt thereof.

2. The antifungal compound of claim 1, wherein: the amino acid carbon ester has the following structural formula:

wherein R is₁Is one of C5-C17 alkyl or C5-C17 alkenyl; the R is₂Is an amino acid side chain group.

3. A process for the preparation of an antifungal compound, characterized in that: taking amino acid and carbon alcohol as raw materials, and carrying out reflux reaction to obtain amino acid carbon ester; the preparation method comprises the following specific steps:

step 1, dissolving amino acid in toluene to form amino acid toluene liquid, wherein the concentration of the amino acid in the toluene is 0.5 mol/L;

step 2, adding carbon alcohol and p-toluenesulfonic acid into amino acid toluene liquid for reflux reaction, and performing water azeotropic separation to obtain amino acid carbon ester, wherein the addition amount of the carbon alcohol is consistent with the molar amount of the amino acid, the addition amount of the p-toluenesulfonic acid is consistent with the molar amount of the amino acid, and the reflux reaction is performed by raising the temperature to the reflux temperature in a slow temperature raising manner; the reaction was monitored by thin layer chromatography.

4. A process for the preparation of antifungal compounds as claimed in claim 3, characterized in that: the purification steps of the amino acid carbon ester are as follows:

step a, concentrating a reaction mixture subjected to water azeotropic separation in vacuum, and filtering to obtain a residue;

step b, extracting residues by using ethyl acetate, washing by using a sodium carbonate aqueous solution and saline water in sequence, drying an organic layer by using sodium sulfate, and concentrating in vacuum to obtain a crude product, wherein the mass concentration of sodium carbonate in the sodium carbonate aqueous solution is 5%;

step c, the crude product was chromatographed on silica gel with MeOH in silica gel: DCM ═ 1:50 to 1:5 to give the product.

5. Use of an antifungal compound according to any one of claims 2 to 4 as an antifungal agent, i.e. as an antifungal agent, an amino acid carbon ester or a pharmaceutically acceptable salt thereof.

6. Use of an antifungal compound according to any one of claims 2 to 4 in the preparation of an antifungal medicament, i.e., the use of a carbon ester of an amino acid or a pharmaceutically acceptable salt thereof in the preparation of an antifungal medicament.

7. Use of an antifungal compound according to any one of claims 2 to 4, an antifungal composition comprising as active ingredient an antifungal compound together with one or more pharmaceutically acceptable excipients.

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