An aminothiazole oxime amide compound, a preparation method and application thereof

Abstract

The application discloses an aminothiazole oxime amide compound in the field of organic chemistry, as shown in the general formula III: wherein R is hydrogen, methyl, methoxy, nitro, fluorine, chlorine or bromine; R1 is alkyl containing 1-6 carbons. Some target objects of the aminothiazole oxime amide compound prepared in the application have significant antibacterial activity, especially the activity on methicillin-resistant Staphylococcus aureus (MRSA) and fluoroquinolone-resistant Escherichia coli (FREC).

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of organic chemistry, and particularly relates to an aminothiazole oxime amide compound and a preparation method and application thereof. BACKGROUND

[0002] Nowadays, the extensive use and abuse of antibacterial drugs have led to drug resistance of bacteria, and even "super bacteria", which has brought severe challenges to clinical treatment. The development of new antibacterial drugs is far behind the emergence of drug-resistant bacteria, such as methicillin-resistant Staphylococcus aureus (MRSA), fluoroquinolone-resistant Escherichia coli (FREC), etc., which are very difficult to treat in clinical treatment. Therefore, it is urgent to develop new antibacterial drugs to cope with the problem of drug-resistant bacteria. SUMMARY

[0003] The present application aims to provide an aminothiazole oxime amide compound with antibacterial effect.

[0004] The aminothiazole oxime amide compound in the present application is shown in the general formula III:

[0005] ;

[0006] wherein, R is hydrogen, methyl, methoxy, nitro, fluorine, chlorine or bromine; R1 is an alkyl group containing 1-6 carbons.

[0007] A preparation method of an aminothiazole oxime amide compound, and the synthetic route is shown as follows:

[0008] ;

[0009] Preparation of compound I: at 5-15℃, diphenyl disulfide, 1,2-dichloroethane are sequentially added into a reaction container, stirred for 20-30 min, then ammonia thioacid is added, stirred for 30-40 min, 0.5 g of triethylamine is added, stirred for 40-60 min, 2.3 g of triethyl phosphite is added, stirred for 3-5 h, filtered under reduced pressure, washed and dried to obtain a light yellow powder, which is compound I; wherein the addition amount ratio of diphenyl disulfide, 1,2-dichloroethane, ammonia thioacid, triethylamine and triethyl phosphite is 45 g: 100-300 mL: 15-20 g: 5-8 g: 20-30 g;

[0010] Preparation of compound II: benzaldehyde or substituted benzaldehyde, ammonium acetate, phosphonite are weighed into a reaction vessel, stirred at room temperature for 10-20 min, then aluminum triflate is added, stirred at 80-110℃ for 30-40 min, finished, add distilled water, then acidified with HCl solution to pH 1, first extracted with cyclohexane, then extracted with ethyl acetate, alkalized with NaOH solution to pH 7-8, finally, extracted with ethyl acetate until the product is completely extracted, combine the extract, concentrated under reduced pressure, to obtain compound II; wherein the addition amount ratio of benzaldehyde or substituted benzaldehyde, ammonium acetate, phosphonite, aluminum triflate and distilled water is 24 mmol: 18-20 mmol: 18-20 mmol: 0.1-0.2 mmol: 100-200 mL;

[0011] Preparation of compound III: compound I is added to a mixture of compound II, tetrahydrofuran and triethylamine under stirring at a reaction temperature of 20-40℃, followed by TLC tracking, finished, filtered under reduced pressure, washed with THF, dried, to obtain white solid compound III, i.e. amino thiazole oxime amide compound; wherein the addition amount ratio of compound I, compound II, tetrahydrofuran and triethylamine is 5-7 mmol: 5 mmol: 15-30 mL: 2-4 mL.

[0012] Al(OTf)3 is aluminum triflate.

[0013] The amino thiazole oxime amide compound is used for preparing an anti-staphylococcus aureus and / or prophylactic staphylococcus aureus drug. S. aureus The amino thiazole oxime amide compound is used for preparing an anti-staphylococcus aureus and / or prophylactic staphylococcus aureus drug.

[0014] The amino thiazole oxime amide compound is used for preparing an anti-staphylococcus aureus and / or prophylactic staphylococcus aureus drug. E. coli The amino thiazole oxime amide compound is used for preparing an anti-staphylococcus aureus and / or prophylactic staphylococcus aureus drug.

[0015] The amino thiazole oxime amide compound is used for preparing an anti-staphylococcus aureus and / or prophylactic staphylococcus aureus drug.

[0016] The amino thiazole oxime amide compound is used for preparing an anti-staphylococcus aureus and / or prophylactic staphylococcus aureus drug.

[0017] The active amino thiazole oxime amide compound of the present application can be used in combination with clinical antibacterial drugs or with antibacterial active ingredients. DETAILED DESCRIPTION

[0018] The following is further described in detail through specific embodiments:

[0019] The application will be further described in connection with the following examples, but the application is not limited to the following examples. It is predictable that those skilled in the art can make various changes in the implementation in the light of the prior art.

[0020] The preparation of the compound of general formula III (amino thiazole oxime amide compound) is as follows:

[0021]

[0022] Note: Al(OTf)3 is aluminum triflate.

[0023] Example 1

[0024] Preparation of compound IIIa

[0025] First, 4.5 g of benzothiazole disulfide, 20 mL of 1,2-dichloroethane were sequentially added to a three-necked flask at 5-10 ℃, stirred for 30 min, 2 g of amino thiazole oxime acid was added, stirred for 30 min, 0.5 g of triethylamine was added, stirred for 40 min, 2.3 g of triethyl phosphite was added, stirred for 5 h, filtered under reduced pressure, washed and dried to obtain a light yellow powder, i.e. compound I.

[0026] Then, 2.4 mmol of benzaldehyde, 2 mmol of ammonium acetate, and 2 mmol of dimethyl phosphite were sequentially weighed in a reaction bottle, stirred at room temperature for 10 min, then 0.01 mmol of aluminum triflate [Al(OTf)3] was added, stirred at 80 ℃ for 40 min, then 15 mL of distilled water was added; then, acidified with 1 mol / L HCl to pH 1, first extracted with cyclohexane, then extracted with ethyl acetate, and alkalized with 1 mol / L NaOH to pH 7-8; finally, extracted with ethyl acetate until the product was completely extracted, the combined extract was concentrated under reduced pressure to obtain compound IIa.

[0027] Finally, 0.5 mmol of compound IIa, 20 mL of tetrahydrofuran (THF) and 0.2 mL of triethylamine (Et3N) were taken in a 50 mL reaction bottle, 0.2103 g (0.6 mmol) of compound I was added to the reaction bottle under stirring, and the reaction was carried out at 20 ℃, TLC tracking was carried out, after completion, filtered under reduced pressure, washed with THF and dried to obtain a white solid, i.e. compound IIIa.

[0028] Example 2

[0029] Preparation of compound IIIe

[0030] First, 4.5 g of bis-benzothiazyl disulfide, 20 mL of 1,2-dichloroethane were sequentially added into a three-necked flask at 10-15 °C, stirred for 20 min, 2 g of aminothioacid was added, stirred for 30 min, 0.5 g of triethylamine was added, stirred for 40 min, 2.3 g of triethyl phosphite was added, stirred for 3 h, filtered under reduced pressure, washed, and dried to obtain a light yellow powder, i.e. compound I.

[0031] Then, 2.4 mmol of o-fluorobenzaldehyde, 2 mmol of ammonium acetate, and 2 mmol of diethyl phosphite were sequentially weighed into a reaction bottle, stirred at room temperature for 10 min, 0.01 mmol of aluminum triflate [Al(OTf)3] was then added, stirred at 100 °C for 30 min, and then 15 mL of distilled water was added; then, acidified with 1 mol / L HCl to pH 1, extracted with cyclohexane first, and then extracted with ethyl acetate, and then alkalized with 1 mol / L NaOH to pH 7-8; finally, extracted with ethyl acetate until the product was completely extracted, combined the extract, and concentrated under reduced pressure to obtain compound IIe.

[0032] Finally, 0.5 mmol of compound IIe, 20 mL of tetrahydrofuran (THF), and 0.2 mL of triethylamine (Et3N) were taken into a 50 mL reaction bottle, 0.2103 g (0.6 mmol) of compound I was added to the reaction bottle under stirring, and the reaction was carried out at 30 °C, and TLC tracking was performed, after completion, filtered under reduced pressure, washed with THF, and dried to obtain a white solid, i.e. compound IIIe.

[0033] Example 3

[0034] Preparation of compound IIIe

[0035] First, 4.5 g of bis-benzothiazyl disulfide, 20 mL of 1,2-dichloroethane were sequentially added into a three-necked flask at 10-15 °C, stirred for 20 min, 2 g of aminothioacid was added, stirred for 30 min, 0.5 g of triethylamine was added, stirred for 40 min, 2.3 g of triethyl phosphite was added, stirred for 3 h, filtered under reduced pressure, washed, and dried to obtain a light yellow powder, i.e. compound I.

[0036] Then, 2.4 mmol of p-fluorobenzaldehyde, 2 mmol of ammonium acetate and 2 mmol of diethyl phosphite were weighed into a reaction bottle in turn, stirred at room temperature for 10 min, 0.01 mmol of aluminum triflate [Al(OTf)3] was added, stirred at 95 ℃ for 30 min, and then 20 mL of distilled water was added. Then, 1 mol / L HCl was used to acidify to pH 1, first extracted with cyclohexane, then extracted with ethyl acetate, and 1 mol / L NaOH was used to alkalify to pH 7-8. Finally, ethyl acetate was used for extraction until the product was completely extracted, the extract was combined, and concentrated under reduced pressure to obtain compound II f.

[0037] Finally, 0.5 mmol of compound II f, 20 mL of tetrahydrofuran (THF) and 0.2 mL of triethylamine (Et3N) were taken into a 50 mL reaction bottle, 0.2103 g (0.6 mmol) of compound I was added to the reaction bottle under stirring, and the reaction was carried out at 25 ℃. TLC tracking was performed, and after completion, the product was filtered under reduced pressure, washed with THF, and dried to obtain a white solid, which was compound III f.

[0038] Example 4

[0039] Preparation of compound III i

[0040] First, 4.5 g of dithiobisbenzothiazole, 20 mL of 1,2-dichloroethane were added to a three-necked flask at 10-15 ℃, stirred for 20 min, 2 g of aminothioacid was added, stirred for 30 min, 0.5 g of triethylamine was added, stirred for 40 min, 2.3 g of triethyl phosphite was added, stirred for 4 h, filtered under reduced pressure, washed and dried to obtain a light yellow powder, which was compound I.

[0041] Then, 2.4 mmol of p-fluorobenzaldehyde, 2 mmol of ammonium acetate and 2 mmol of diisopropyl phosphite were weighed into a reaction bottle in turn, stirred at room temperature for 15 min, 0.01 mmol of aluminum triflate [Al(OTf)3] was added, stirred at 90 ℃ for 35 min, and then 20 mL of distilled water was added. Then, 1 mol / L HCl was used to acidify to pH 1, first extracted with cyclohexane, then extracted with ethyl acetate, and 1 mol / L NaOH was used to alkalify to pH 7-8. Finally, ethyl acetate was used for extraction until the product was completely extracted, the extract was combined, and concentrated under reduced pressure to obtain compound II i.

[0042] Finally, 0.5 mmol of compound IIi, 20 mL of tetrahydrofuran (THF) and 0.2 mL of triethylamine (Et3N) were taken in a 50 mL reaction bottle, 0.2103 g (0.6 mmol) of compound I was added to the reaction bottle under stirring, and the reaction was carried out at 20 ℃, TLC tracking was performed, after completion, filtration was performed under reduced pressure, THF washing was performed, and drying was performed, to obtain a white solid, which was compound IIIi.

[0043] Example 5

[0044] Preparation of compound IIIk

[0045] Firstly, 4.5 g of benzothiazyl disulfide, 20 mL of 1,2-dichloroethane were sequentially added to a three-necked flask at 5-10 ℃, stirring was performed for 30 min, 2 g of aminothioacid was added, stirring was performed for 40 min, 0.5 g of triethylamine was added, stirring reaction was performed for 60 min, 2.3 g of triethyl phosphite was added, stirring reaction was performed for 5 h, filtration was performed under reduced pressure, washing was performed, and drying was performed, to obtain a light yellow powder, which was compound I.

[0046] Then, 2.4 mmol of o-fluorobenzaldehyde, 2 mmol of ammonium acetate and 2 mmol of dibutyl phosphite were sequentially weighed in a reaction bottle, stirring reaction was performed at room temperature for 10 min, 0.01 mmol of aluminum triflate [Al(OTf)3] was further added, stirring reaction was performed at 110 ℃ for 30 min, after completion, 20 mL of distilled water was added, then, acidification was performed with 1 mol / L HCl until the pH was 1, extraction was performed with cyclohexane first, and then extraction was performed with ethyl acetate, and alkalization was performed with 1 mol / L NaOH until the pH was 7-8, finally, extraction was performed with ethyl acetate until the extraction of the product was complete, the extraction liquid was combined, and concentration was performed under reduced pressure, to obtain compound IIk.

[0047] Finally, 0.5 mmol of compound IIk, 20 mL of tetrahydrofuran (THF) and 0.2 mL of triethylamine (Et3N) were taken in a 50 mL reaction bottle, 0.2103 g (0.6 mmol) of compound I was added to the reaction bottle under stirring, and the reaction was carried out at 40 ℃, TLC tracking was performed, after completion, filtration was performed under reduced pressure, THF washing was performed, and drying was performed, to obtain a white solid, which was compound IIIk.

[0048] The related data of some compounds III are as follows:

[0049]

[0050] The antibacterial activity test of the present application: oxacillin was used as a control drug, and the microdilution method was used to determine the antibacterial activity of the compound of general formula III on Staphylococcus aureus (ATCC 29213) and Escherichia coli (ATCC 25922). S. aureus), Escherichia coli ( E. coli The minimum inhibitory concentrations (MICs) of methicillin-resistant Staphylococcus aureus (MRSA) and fluoroquinolone-resistant Escherichia coli (FREC) are shown in Table 1.

[0051] Table 1

[0052]

[0053] The experimental results above clearly demonstrate that the compounds of general formula III protected by this invention possess potential antibacterial activity. For example, compounds IIIf and IIIi are effective against Staphylococcus aureus (…). S. aureus The inhibitory effect of compounds IIIe and IIIh on Escherichia coli (E. coli) was similar to that of the control drug oxacillin. E. coli The inhibitory effect of compounds IIIf and IIIi on Escherichia coli ( ) was consistent with that of the control drug oxacillin. E. coli Compounds IIIb, IIIc, IIId, IIIe, IIIf, IIIg, IIIh, and IIIi showed superior inhibitory activity against methicillin-resistant Staphylococcus aureus (MRSA) compared to oxacillin. Compounds IIIe and IIIh exhibited comparable inhibitory activity against fluoroquinolone-resistant Escherichia coli (FREC) to oxacillin, while compounds IIIf and IIIi showed superior inhibitory activity against FREC compared to oxacillin. The significant antibacterial activity of these derivatives suggests their potential application against Staphylococcus aureus (MRSA). S. aureus ), Escherichia coli ( E. coli It is used to treat diseases caused by methicillin-resistant Staphylococcus aureus (MRSA) and fluoroquinolone-resistant Escherichia coli (FREC). It can also be used in combination with other antibacterial active substances.

[0054] The above description is only a preferred embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any equivalent substitutions or modifications made by those skilled in the art within the scope of the technology disclosed in the present invention, based on the technical solution and inventive concept of the present invention, should be covered within the scope of protection of the present invention.

Claims

1. An aminothiazole oxime amide compound, characterized by: As shown in general formula III: ； Wherein, R is hydrogen, methyl, methoxy, nitro, fluorine, chlorine or bromine; R1 is alkyl containing 1-6 carbons; the specific amino thiazole oxime amide compound is IIIc, IIId, IIIe, IIIf, IIIh or IIIi; The structural formula of the amino thiazole oxime amide compound IIId is as follows: ； The structural formula of the amino thiazole oxime amide compound IIId is as follows: ； The structural formula of the amino thiazole oxime amide compound IIIe is as follows: ； The structural formula of the amino thiazole oxime amide compound IIIf is as follows: ； The structural formula of the amino thiazole oxime amide compound IIIh is as follows: ； The structural formula of the amino thiazole oxime amide compound IIIi is as follows: 。 2. The method for preparing an aminothiazole oxime amide compound according to claim 1, characterized in that: The synthetic route is as follows: ； Preparation of compound I: at 5-15℃, add benzothiazole disulfide, 1,2-dichloroethane into the reaction container in turn, stir for 20-30 min, add amino thioacid, stir for 30-40 min, add 0.5 g triethylamine, stir for 40-60 min, add 2.3 g triethyl phosphite, stir for 3-5 h, filter under reduced pressure, wash and dry to obtain light yellow powder, which is compound I; wherein the addition amount ratio of benzothiazole disulfide, 1,2-dichloroethane, amino thioacid, triethylamine and triethyl phosphite is 45 g: 100-300 mL: 15-20 g: 5-8 g: 20-30 g; Preparation of compound II: weigh benzaldehyde or substituted benzaldehyde, ammonium acetate and phosphonite in the reaction container in turn, stir for 10-20 min at room temperature, then add aluminum triflate, stir for 30-40 min at 80-110℃, complete, add distilled water, then acidify with HCl solution to pH 1, first extract with cyclohexane, then extract with ethyl acetate, alkalinize with NaOH solution to pH 7-8, finally, extract with ethyl acetate until the product is completely extracted, combine the extract, concentrate under reduced pressure to obtain compound II; wherein the addition amount ratio of benzaldehyde or substituted benzaldehyde, ammonium acetate, phosphonite, aluminum triflate and distilled water is 24 mmol: 18-20 mmol: 18-20 mmol: 0.1-0.2 mmol: 100-200 mL; Preparation of compound III: at a reaction temperature of 20-40℃, add compound I to the mixture of compound II, tetrahydrofuran and triethylamine under stirring, track by TLC, complete, filter under reduced pressure, wash with THF and dry to obtain white solid compound III, which is an amino thiazole oxime amide compound; wherein the addition amount ratio of compound I, compound II, tetrahydrofuran and triethylamine is 5-7 mmol: 5 mmol: 15-30 mL: 2-4 mL.

3. The use of the amino thiazole oxime amide compound of claim 1 in the preparation of a drug for resisting and / or preventing Staphylococcus aureus.

4. The use of the amino thiazole oxime amide compound of claim 1 in the preparation of a drug for resisting and / or preventing Escherichia coli.

5. Use of the aminothiazole oxime amide compound according to claim 1 in the preparation of a medicament for resisting and / or preventing methicillin-resistant Staphylococcus aureus.

6. Use of the aminothiazole oxime amide compound according to claim 1 in the preparation of a medicament for resisting and / or preventing fluoroquinolone-resistant Escherichia coli.

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