CN115611879A - Oxazole derivative and synthetic method thereof - Google Patents

Oxazole derivative and synthetic method thereof Download PDF

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CN115611879A
CN115611879A CN202211383966.9A CN202211383966A CN115611879A CN 115611879 A CN115611879 A CN 115611879A CN 202211383966 A CN202211383966 A CN 202211383966A CN 115611879 A CN115611879 A CN 115611879A
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phenylalanine
oxazole
copper
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唐剑
陆丰杰
张馨怡
于子辰
张国栋
杨志宇
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Qufu Normal University
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    • C—CHEMISTRY; METALLURGY
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    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
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    • A01N43/74—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms five-membered rings with one nitrogen atom and either one oxygen atom or one sulfur atom in positions 1,3
    • A01N43/76—1,3-Oxazoles; Hydrogenated 1,3-oxazoles
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Abstract

The invention belongs to the technical field of compound preparation, and particularly provides an oxazole derivative and a synthesis method thereof. The method for synthesizing the oxazole derivative comprises the following steps: dissolving copper salt, oxidant and phenylalanine in solvent to form mixed solution, reacting the mixed solution under heating condition, and separating out reaction product after reaction. The synthetic method disclosed by the invention is simple to operate, efficient in reaction and higher in atom economy.

Description

Oxazole derivative and synthetic method thereof
Technical Field
The invention relates to an oxazole derivative and a synthetic method thereof, belonging to the technical field of compound preparation.
Background
The information in this background section is disclosed to enhance understanding of the general background of the invention and is not necessarily to be construed as an admission or any form of suggestion that this information forms part of the prior art already known to a person of ordinary skill in the art.
Oxazole compounds widely exist in natural products, and the compounds show excellent biological activity, such as antibiosis, antivirus, antiphlogosis and the like. The synthesis of the compound mostly depends on the participation of acyclic precursors or multiple components, however, the synthesis and application of the polysubstituted oxazoles and oxazolines are limited by harsh reaction conditions, lower atom economy and complex starting materials.
In recent years, transition metal catalysis has shown great advantages in the synthesis of oxazole and oxazoline derivatives, and researchers have made great progress in the construction of such core frameworks by applying transition metal catalysis. Oxazole synthesis is achieved, for example, using palladium catalyzed oxidative cyclization. Another technique achieves oxazole synthesis by cyclization of oximes and diazo esters via rhodium catalysis. The other technology realizes the cyclization of imine by cobalt-catalyzed free radical nitrogen Heck reaction and selectively realizes the synthesis of oxazole and oxazoline. However, the present inventors have found that the above-mentioned method is based on the use of a complicated reaction substrate and an expensive catalyst in the synthesis of oxazoles and oxazolines catalyzed by transition metals, and has a certain disadvantage in terms of atom economy and the like.
Disclosure of Invention
The invention provides an oxazole derivative and a synthesis method thereof. In addition, the synthetic method disclosed by the invention is simple to operate, efficient in reaction and high in atom economy.
In order to achieve the purpose, the invention is realized by the following technical scheme:
an oxazole derivative having the structure shown below:
Figure 45696DEST_PATH_IMAGE001
the R is 1 Selected from H, F, cl, br, tBu, CN, ph, me, NO 2 、CF 3 Any one of OH group;
or said R is 2 Selected from H, F, cl, br, tBu, CN, ph, me, NO 2 、CF 3 Any one of the groups;
or said R is 3 Any one of Me and Bn groups.
A method for synthesizing the oxazole derivative by catalyzing phenylalanine derivative with copper comprises the following specific synthetic route:
Figure 556312DEST_PATH_IMAGE002
on the basis of the method for synthesizing the oxazoline derivative by catalyzing the phenylalanine derivative by copper, the method comprises the following steps:
1) Dissolving copper salt, an oxidant and a phenylalanine derivative in a solvent to form a mixed solution;
2) Reacting the mixed solution formed in the step 1) under the heating condition;
3) The reaction product is isolated after the reaction is complete.
On the basis of the method for synthesizing the oxazole derivative by catalyzing phenylalanine derivative with copper, the solvent is any one of dichlorohydrocarbon, acetone, methanol, acetonitrile and dimethyl sulfoxide; preferably, the solvent is dichlorohydrocarbon.
On the basis of the method for synthesizing the oxazole derivative by catalyzing phenylalanine derivative with copper, the molar ratio of copper salt, oxidant and phenylalanine derivative is copper salt: oxidizing agent: phenylalanine =1:10:10 to 1:100:200.
on the basis of the method for synthesizing the oxazole derivative by catalyzing the phenylalanine derivative by copper, the copper salt is any one of copper acetate, copper trifluoroacetate, copper chloride and cuprous bromide.
On the basis of the method for synthesizing the oxazole derivative by catalyzing phenylalanine derivative with copper, the oxidant is silver salt or/and sodium acetate, preferably any one of silver acetate, silver carbonate, silver chloride and silver phosphate.
On the basis of the method for synthesizing the oxazole derivative by catalyzing phenylalanine derivative with copper, the phenylalanine derivative is PA-Phe-OMe, PA-4-F-Phe-OMe, 6-OH-PA-Phe-OMe and 4-NO 2 -PA-Phe-OMe.
On the basis of the method for synthesizing the oxazole derivative by catalyzing phenylalanine derivative with copper, the heating conditions are as follows: the rotary evaporator is used for carrying out reduced pressure concentration under the conditions that the rotating speed is 112rps, the water bath temperature is 50 ℃, and the vacuum degree of a water pump is 0.1 MPa.
On the basis of the method for synthesizing the oxazole derivative by catalyzing phenylalanine derivatives by copper, a method for separating reaction products is as follows: after the reaction is finished, the product is separated by column chromatography, and the final product, namely the oxazoline derivative is obtained by gradient elution with petroleum ether-ethyl acetate as eluent.
The invention has the advantages that:
(1) According to the invention, cheap transition metal copper is used as a catalyst, and phenylalanine is used as a reaction raw material, so that the selective synthesis of oxazole or oxazoline is efficiently realized. Meanwhile, different groups are introduced into the compound to successfully realize the tri-substituted oxazole or oxazoline compound.
(2) The invention utilizes the phenylalanine derivative as a reaction substrate, and has the advantages of simple operation, high reaction efficiency and higher atom economy. On the other hand, when 6-hydroxypyridine-2-carboxylic acid is used as a protecting group, the preparation of the oxazoline derivative can be selectively and efficiently achieved because: when 6-OH-pyridine-2-formic acid is taken as a protective group, N-H in pyridine and oxygen of amido bond can form hydrogen bond; the formation of hydrogen bonds promotes the divalent copper to be further oxidized into a trivalent copper intermediate, and then, the oxazole derivative is directly generated after oxidation reduction; when pyridine is connected with other substituent groups, the reaction intermediate undergoes reductive dehydrogenation to favor the generation of double bonds, and is more favorable for the generation of oxazole derivatives.
Drawings
The accompanying drawings, which are incorporated in and constitute a part of this specification, are included to provide a further understanding of the invention, and are included to illustrate an exemplary embodiment of the invention and not to limit the invention. Embodiments of the invention are described in detail below with reference to the attached drawing figures, wherein:
FIG. 1 is a nuclear magnetic resonance spectrum of an oxazole compound synthesized in the first example of the present invention.
FIG. 2 is a nuclear magnetic resonance spectrum of an oxazole compound synthesized in the second example of the present invention.
FIG. 3 is a nuclear magnetic resonance spectrum of an oxazoline compound synthesized in the third example of the present invention.
FIG. 4 is a nuclear magnetic resonance spectrum of an oxazoline compound synthesized in the fourth example of the present invention.
Detailed Description
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out according to conventional conditions or according to conditions recommended by the manufacturers.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The reagents or starting materials used in the present invention can be purchased from conventional sources, and unless otherwise specified, the reagents or starting materials used in the present invention can be used in a conventional manner in the art or in accordance with the product specification. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred methods and materials described in this invention are exemplary only. The invention will now be further described with reference to the drawings and detailed description of the specification.
In each of the following examples, the reaction equation is as follows:
Figure 70470DEST_PATH_IMAGE003
example one
A method for synthesizing an oxazole derivative by catalyzing a phenylalanine derivative with copper comprises the following steps:
(1) PA-Phe-OMe (0.5 mmol), 1, 2-dichloroethane (5.0 ml), copper acetate (0.1 mmol), silver carbonate (1.0 mmol) and sodium acetate (1.0 mmol) were added to a 35ml pressure resistant tube and heated in an oil bath at 120 ℃ for 12 hours;
(2) After the reaction is finished, carrying out reduced pressure concentration on the reaction mixture by using a rotary evaporator under the conditions that the rotating speed is 112rps, the water bath temperature is 50 ℃ and the vacuum degree of a water pump is 0.1 MPa;
(3) The product was then separated by silica gel column chromatography with petroleum ether (b.p. 60-90 ℃ C.) ethyl acetate as eluent in a gradient elution to give the oxazole compound of formula A in a yield of 76%.
The oxazole compound constructed in this example was subjected to nuclear magnetic resonance detection, and the detection result was:
Figure 59155DEST_PATH_IMAGE004
wherein δ represents the chemical shift of a hydrogen atom, 1 H， 2 H， 3 h is the number of hydrogen atoms in the compound.
FIG. 1 shows the oxazole compound (1HNMR, 500M, solvent CDCl) prepared in this example 3 I.e., chloroform) nuclear magnetic resonance spectrum.
Figure 342369DEST_PATH_IMAGE005
As can be seen, in the embodiment, the construction of the tri-substituted oxazole derivative is efficiently realized by taking copper acetate as a catalyst and pyridine-2-formic acid as a protecting group.
Example two
A method for synthesizing an oxazole derivative by catalyzing a phenylalanine derivative with copper comprises the following steps:
(1) Adding PA-4-F-Phe-OMe (0.5 mmol), 1, 2-dichloroethane (5.0 ml), copper acetate (0.1 mmol), silver carbonate (1.0 mmol) and sodium acetate (1.0 mmol) into a 35ml pressure resistant tube, and heating in an oil bath at 120 ℃ for reaction for 15h;
(2) After the reaction is finished, carrying out reduced pressure concentration on the reaction mixture by using a rotary evaporator under the conditions that the rotating speed is 112rps, the water bath temperature is 50 ℃ and the vacuum degree of a water pump is 0.1 MPa;
(3) And separating the product by silica gel column chromatography, and performing gradient elution by using petroleum ether-ethyl acetate as eluent, wherein the boiling point b.p of the petroleum ether is 60-90 ℃, so as to obtain the oxazole compound shown in the formula B with the yield of 73%.
The oxazole compound constructed in this example was subjected to nuclear magnetic resonance detection, and the detection result was:
Figure 758306DEST_PATH_IMAGE007
wherein δ represents the chemical shift of a hydrogen atom, 1 H， 2 H， 3 h is the number of hydrogen atoms in the compound.
FIG. 2 shows the oxazole compound (1HNMR, 500M, solvent CDCl) prepared in this example 3 I.e. chloroform) nuclear magnetic resonance spectrum.
Figure 494181DEST_PATH_IMAGE008
It can be seen that in the present example, the construction of the tri-substituted oxazole derivative is efficiently realized by using copper acetate as a catalyst and pyridine-2-carboxylic acid as a protecting group.
EXAMPLE III
A method for synthesizing oxazoline derivatives from phenylalanine derivatives under the catalysis of copper comprises the following steps:
(1) Adding 6-OH-PA-Phe-OMe 0.5 mmol), 1, 2-dichloroethane (5.0 ml), copper acetate (0.1 mmol), silver carbonate (1.0 mmol) and sodium acetate (1.0 mmol) into a pressure resistant tube of 15 ml, and heating in an oil bath at 120 ℃ for reaction for 15h;
(2) After the reaction is finished, carrying out reduced pressure concentration on the reaction mixture by using a rotary evaporator under the conditions that the rotating speed is 112rps, the water bath temperature is 50 ℃ and the vacuum degree of a water pump is 0.1 MPa;
(3) The product was then isolated by silica gel column chromatography with petroleum ether (b.p. 60-90 ℃ C.) ethyl acetate as eluent in a gradient elution to give the oxazoline compound of formula A in a yield of 75%.
The oxazoline compound constructed in the embodiment is subjected to nuclear magnetic resonance detection, and the detection result is as follows:
Figure 20977DEST_PATH_IMAGE010
wherein δ represents the chemical shift of a hydrogen atom, 1 H， 2 H， 3 h is the number of hydrogen atoms in the compound.
FIG. 3 is an oxazoline compound (1HNMR, 500M, solvent CDCl) prepared in this example 3 I.e. chloroform) nuclear magnetic resonance spectrogram.
Figure 158698DEST_PATH_IMAGE011
It can be seen that in this example, the construction of the tri-substituted oxazoline derivative is efficiently achieved by using copper acetate as a catalyst and 6-hydroxy-pyridine-2-carboxylic acid as a protecting group.
Example four
A method for synthesizing oxazoline derivatives from phenylalanine derivatives under the catalysis of copper comprises the following steps:
(1) Reacting 4-NO 2 PA-Phe-OMe (0.5 mmol), 1, 2-dichloroethane (5.0 ml), copper acetate (0.1 mmol), silver carbonate (1.0 mmol), sodium acetate (1.0 mmol) were added to a 35ml pressure tube and heated in an oil bath at 120 ℃ for 12 hours;
(2) After the reaction is finished, carrying out reduced pressure concentration on the reaction mixture by using a rotary evaporator under the conditions that the rotating speed is 112rps, the water bath temperature is 50 ℃ and the vacuum degree of a water pump is 0.1 MPa;
(3) The product was then isolated by silica gel column chromatography with petroleum ether (b.p. 60-90 ℃ C.) ethyl acetate as eluent in a gradient elution to give the oxazoline compound of formula A in a yield of 70%.
The oxazoline compound constructed in the embodiment is subjected to nuclear magnetic resonance detection, and the detection result is as follows:
Figure 745537DEST_PATH_IMAGE013
wherein δ represents the chemical shift of a hydrogen atom, 1 H， 2 H， 3 h is the number of hydrogen atoms in the compound.
FIG. 4 shows the oxazoline compounds (1HNMR, 500M, solvent CDC) prepared in this example l3 Chloroform) nuclear magnetic resonance spectrum.
Figure 968708DEST_PATH_IMAGE014
It can be seen that in this example, the construction of the tri-substituted oxazole derivative is efficiently realized by using copper acetate as a catalyst and 6-hydroxy-pyridine-2-carboxylic acid as a protecting group.
EXAMPLE five
A method for synthesizing an oxazole derivative by catalyzing a phenylalanine derivative with copper comprises the following steps:
(1) PA-Phe-OMe (0.5 mmol), 1, 2-dichloroethane (5.0 ml), cuprous chloride (0.1 mmol) and silver acetate (0.5 mmol) were added into a 35ml pressure resistant tube and heated in an oil bath at 150 ℃ for 12 hours;
(2) After the reaction is finished, carrying out reduced pressure concentration on the reaction mixture by using a rotary evaporator under the conditions that the rotating speed is 120rps, the water bath temperature is 45 ℃ and the vacuum degree of a water pump is 0.1 MPa;
(3) Then separating the product by silica gel column chromatography, and performing gradient elution by using petroleum ether (b.p. 60-90 ℃) and ethyl acetate as eluent to obtain the tri-substituted oxazole compound with the yield of 65%.
Example six
A method for synthesizing an oxazole derivative by catalyzing a phenylalanine derivative with copper comprises the following steps:
(1) PA-Phe-OMe (10 mmol), 1, 2-dichloroethane (5.0 ml), cuprous bromide (0.1 mmol) and silver chloride (5.0 mmol) were added to a 35ml pressure-resistant tube and heated in an oil bath at 60 ℃ for 24 hours;
(2) After the reaction is finished, carrying out reduced pressure concentration on the reaction mixture by using a rotary evaporator under the conditions that the rotating speed is 120rps, the water bath temperature is 45 ℃ and the vacuum degree of a water pump is 0.1 MPa;
(3) The product was then separated by column chromatography on silica gel with petroleum ether (b.p. 60-90 ℃ C.) ethyl acetate as eluent to give the oxazole compound in 58% yield.
EXAMPLE seven
A method for synthesizing oxazoline derivatives from phenylalanine derivatives under the catalysis of copper comprises the following steps:
(1) PA-Phe-OMe (5 mmol), 1, 2-dichloroethane (5.0 ml), copper trifluoroacetate (0.1 mmol) and silver phosphate (2.5 mmol) were added to a 35ml pressure resistant tube and heated in an oil bath at 90 ℃ for reaction for 18 hours;
(2) After the reaction is finished, carrying out reduced pressure concentration on the reaction mixture by using a rotary evaporator under the conditions that the rotating speed is 120rps, the water bath temperature is 45 ℃ and the vacuum degree of a water pump is 0.1 MPa;
(3) The product was then separated by silica gel column chromatography with petroleum ether (b.p. 60-90 ℃ C.) ethyl acetate as eluent in a gradient elution to give the oxazole compound of formula A in 67% yield.
The antibacterial activity of the oxazoline derivative synthesized by catalyzing the phenylalanine derivative by copper is determined as follows:
1) Preparation of culture solution
RPMI1640 culture solution: weighing RPMI1164010.5 g, sodium carbonate 1.0g, MOPS34 weighing 3g, adding 500ml of triple distilled water for dissolving, adjusting pH to 7.0 with 1M sodium hydroxide at 25 ℃, fixing volume to 1000ml, sterilizing, and storing in a refrigerator at 4 ℃.
2) Preparation of YEPD culture solution
Weighing 5g of yeast extract, 10g of peptone and 10g of glucose by using a balance, adding 500ml of triple distilled water for dissolving, then adding 50ml of chloramphenicol aqueous solution with the concentration of 2mg/ml into the solution, finally using triple distilled water for fixing the volume to 1000ml, sterilizing at high temperature, and storing in a refrigerator at 4 ℃.
3) Preparation of Sambo glucose agar Medium (SDA)
5g of peptone, 20g of glucose and 9g of agar were dissolved in 500ml of triple distilled water, and then 30ml of a chloramphenicol aqueous solution having a concentration of 2mg/ml was added to adjust the pH of the solution to 7.0 to a constant volume of 1000ml, and the solution was stored after autoclaving.
4) Preparation of bacterial liquid
Selecting bacillus subtilis, escherichia coli, pseudomonas fluorescens and staphylococcus aureus from an SDA culture medium stored at 4 ℃, inoculating the bacillus subtilis, escherichia coli, pseudomonas fluorescens and staphylococcus aureus to 1mL of YEPD culture solution, incubating and activating for 16h at 35 ℃ to enable the fungi to be in the later period of exponential growth phase, taking the bacillus to 1mL of YEPD culture solution, continuing activating according to the method, counting by using a blood cell counting plate after 16h, and adjusting the concentration of the bacteria to 1 × 103-5 × 103cfu/mL by using RPMI1164 culture solution.
5) Preparation of medicinal liquid
The oxazole derivatives prepared in the first to fourth examples were each dissolved in DMSO to prepare a 1mg/mL solution, stored at-20 ℃ and, before the experiment, the solution was thawed in a 35 ℃ incubator and diluted four-fold to prepare a concentration gradient to prepare final test concentrations of 50, 12.5, 3.125, 0.781, 0.195 and 0.049. Mu.g/mL.
6) MIC value determination
The OD value was measured at 570nm with a microplate reader, and the inhibition ratio was calculated according to the following formula:
inhibition rate = [1- (test sample OD value-blank OD value)/(negative control OD value-blank OD value) ] × 100
The minimum concentration with the inhibition rate of not less than 50% is taken as the MIC50 (minimum inhibition concentration) of the tested sample, and when the MIC value of the medicine exceeds the measuring concentration range, the statistics is carried out according to the following method: MIC value is more than 50 mug/mL when the highest concentration is 50 mug/mL; MIC value is lower than the lowest concentration or below the lowest concentration, and is calculated to be less than or equal to 0.0049 mu g/mL without distinction. All the above experiments were performed in parallel 3 times and the mean value was taken as the final MIC of the compound. The in vitro antibacterial activity of target compounds on bacillus subtilis (B. Subtilis), staphylococcus aureus (S. Aureus), escherichia coli (E. Coli) and pseudomonas fluorescens (P. Fluorescens) is adopted in the work by adopting an MIC method. The antibacterial activity of the obtained oxazoline derivatives is shown in Table 1.
TABLE 1 antibacterial Activity (MIC, mg/mL) of oxazoline derivatives
Compound (I) Bacillus subtilis (B.subtilis) Staphylococcus aureus (S.aureus) Pseudomonas fluorescens (P. Fluorescens) Escherichia coli (E.coli)
Example one 7.16 10.37 12 8.55
Example two 8.20 10.11 10.45 6.33
EXAMPLE III 6.20 12.45 8.30 5.33
Example four 10.59 12.58 5.26 6.52
Kanamycin B 0.35 1.58 3.15 3.16
Penicillin G 1.62 1.69 6.52 5.98
As can be seen from the above table, the first to fourth examples all have in vitro antibacterial activity against bacillus subtilis (b.subtilis), staphylococcus aureus (s.aureus), escherichia coli (e.coli), pseudomonas fluorescens (p.fluorescens), and the derivatives of the first, second and third examples all have a good antibacterial effect against escherichia coli (e.coli); the derivative of the fourth embodiment has a good inhibition effect on pseudomonas fluorescens (p.
Although the present invention has been described in detail with reference to the foregoing embodiments, it will be apparent to those skilled in the art that changes may be made in the embodiments and/or equivalents thereof without departing from the spirit and scope of the invention. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims (10)

1. An oxazole derivative characterized by having a structure shown below:
Figure 809410DEST_PATH_IMAGE001
said R is 1 Selected from H, F, cl, br, tBu, CN, ph, me, NO 2 、CF 3 Any one of the above groups;
or said R is 2 Selected from H, F, cl, br, tBu, CN, ph, me, NO 2 、CF 3 Any one of the groups;
or the said R 3 Any one of Me and Bn groups.
2. A method for synthesizing an oxazole derivative as defined in claim 1 by copper-catalyzed phenylalanine derivative, wherein the method comprises the steps of: the specific synthetic reaction formula is as follows:
Figure 501423DEST_PATH_IMAGE002
。
3. the method of claim 2, comprising the steps of:
1) Dissolving copper salt, an oxidant and a phenylalanine derivative in a solvent to form a mixed solution;
2) Reacting the mixed solution formed in the step 1) under the heating condition;
3) The reaction product is isolated after the reaction is complete.
4. The method of claim 3, wherein: the solvent is any one of dichlorohydrocarbon, acetone, methanol, acetonitrile and dimethyl sulfoxide; preferably, the solvent is dichlorohydrocarbon.
5. The method of claim 3, wherein: the mol ratio of the copper salt to the oxidant to the phenylalanine derivative is copper salt: oxidizing agent: phenylalanine =1:10:10 to 1:100:200.
6. the method of claim 3, wherein: the cupric salt is any one of cupric acetate, cupric trifluoroacetate, cupric chloride and cuprous bromide.
7. The method of claim 3, wherein: the oxidant is silver salt or/and sodium acetate, preferably any one of silver acetate, silver carbonate, silver chloride and silver phosphate.
8. The method of claim 3, wherein: the phenylalanine derivatives are PA-Phe-OMe, PA-4-F-Phe-OMe, 6-OH-PA-Phe-OMe, and 4-NO 2 -PA-Phe-OMe.
9. The method of claim 3, wherein: the heating conditions were as follows: the rotary evaporator is used for carrying out reduced pressure concentration under the conditions that the rotating speed is 112rps, the water bath temperature is 50 ℃, and the vacuum degree of a water pump is 0.1 MPa.
10. The method of claim 3, wherein: the method for separating out the reaction product is as follows: after the reaction is finished, separating the product by column chromatography, and performing gradient elution by using petroleum ether-ethyl acetate as eluent to obtain the final product, namely the oxazole derivative.
CN202211383966.9A 2022-11-07 2022-11-07 Oxazole derivative and synthetic method thereof Pending CN115611879A (en)

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