CN109867636A - A kind of compound and its synthetic method of anti-CVA16 type hand-foot-and-mouth disease - Google Patents

Abstract

" a kind of compound and its synthetic method of anti-CVA16 type hand-foot-and-mouth disease " of the invention, belong to technical field of medicine synthesis, for the chemical formula of the compound as shown in I, Antiviral breeding, which is shown, has good anti-CVA16 type virus activity, can be used as the candidate medicine of anti-hand-foot-and-mouth-disease virus.

Description

A kind of compound and its synthetic method of anti-CVA16 type hand-foot-and-mouth disease

Technical field

The present invention relates to medicine synthesis techniques, specifically, be related to a kind of anti-CVA16 type hand-foot-and-mouth disease compound and its Synthetic method agent.

Technical background

Hand-foot-and-mouth disease (HFMD) is global sexually transmitted disease, is especially widely current in the Asian-Pacific area.In recent years, which is me The highest Class C infectious disease of state's morbidity and mortality falls ill patient based on children.From 1981, in Shanghai, discovery should in China Disease, Beijing, Hebei etc. more than ten of province (city) per having been reported that every year later, and report of infectious disease data is shown in recent years, China's hand-foot-and-mouth disease In sprawling ascendant trend.The prevention and control and treatment of the hand-foot-and-mouth disease public health problem important as one, pay close attention to by people.

Hand-foot-and-mouth disease is the infectious disease being caused by enterovirus, and the enterovirus for causing hand-foot-and-mouth disease has more than 20 kinds (types), It is wherein most commonly seen with coxsackie virus A 16-type (CVA 16) and enterovirns type 71 (EV 71).The common fever of clinical manifestation, Oral cavity and brothers position fash and bleb etc., children with serious disease can cause the mortality such as myocarditis, pulmonary edema, aseptic meningoencephalitis Complication, individual children with serious disease progression of the disease are fast, lead to death.Lack definite effective antiviral drugs at present, it is clinical main Based on symptomatic treatment, mitigates patient symptom, prevent the generation and development of severe complication.

Currently, first 71 vaccine of EV has reached phase III clinical test in China, which feels clinical EV 71 The protective rate of the hand-foot-and-mouth disease of dye is up to 90%, but this vaccine is obvious to the nothing such as other pathogens such as CVA 16 for causing hand-foot-and-mouth disease Protecting effect.It is popular more at home and abroad as the first preponderant genotype for being found pathogen CVA 16 relevant to hand-foot-and-mouth disease Year, but society can not show a candle to EV 71 to its attention rate, and it is also insufficient to the research of its aetology.

The capsid protein of 16 virus of CVA is symmetrical 12 spherical face stereochemical structures, diameter about 30nm.Nucleocapsid is by list Positive chain RNA and protein composition, no protrusion and coating.Genome is made of about 7410 nucleotide.Viral genome is by 5 ' Noncoding region (UTRs), the area P1, P2 and P3 and 3 ' noncoding regions (UTRs) composition.5 ' UTRs include a virion protein (VPg1), related with the synthesis of viral RNA and assembly, 3 ' UTRs have the function of enhanced virus infection ability.Viral genome The open reading frame of albumen, preceding albumen can pass through the hydrolysis of protease before only one poly being made of 2193 amino acid Effect, is cut into tri- kinds of precursor proteins of P1, P2 and P3.P1 can continue to degrade, and ultimately form tetra- kinds of structure eggs of VP1-VP4 White, wherein three kinds are located at viral case surface, i.e. VP1, VP2 and VP3, the overwhelming majority in antigenic determinant is included in it In, and VP4 is embedded on the inside of virus and is connected with viral RNA.Identification of these surface antigen determinants in virus to host It plays a significant role in invasion.P2 and P3 encodes 7 non-structural proteins of 2A, 2B, 2C, 3A, 3B, 3C and 3D, and the region is to virus Duplication and posttranslational modification play an important role, and also play an important role during viral effectively infection host cell.

With the development of drug research new method and new technology, more and more protein three-dimensional structures are confirmed, and are generated More and more drug targets, a large amount of target proteins have been chosen as potential therapeutic targets and have been studied.Molecular docking side Method is widely used to drug research and design, and this main Applied Computer Techniques of method divide to simulate smaller ligand with big Recombination reaction between sub- receptor, to realize area of computer aided drug virtual screening.Virtual screening based on molecular docking technology Method can largely save the research cost of drug and be effectively shortened drug development cycle.Molecular docking technology be according to Receptor structure carries out the important method of drug design, is the important means of innovation research and development drug.

Summary of the invention

In order to solve the problems in the existing technology, the purpose of the present invention is according to small molecule compound and drug targets Between molecular docking operation, a kind of medicament of anti-CVA16 type hand-foot-and-mouth disease of the new high-efficiency with accurate molecular target is provided.

Technical scheme is as follows:

A kind of I compound represented of formula,

The derivative of compound shown in above-mentioned formula I, chemical formula are as follows:

Wherein, R is methyl, ethyl, carboxymethyl, nitre Base, methoxyl group, formoxyl, acetyl group, formamido, acetylamino or phenyl.

The purposes prepared in drug of compound or derivatives thereof shown in Formulas I, the drug refers to treats for hand-foot-and-mouth disease Or the drug of prevention, the drug is using compound or derivatives thereof shown in Formulas I as active pharmaceutical ingredient.

The purposes prepared in drug of compound or derivatives thereof shown in Formulas I, the drug refer to the medicine for anti-CVA16 type Object, the drug is using compound or derivatives thereof shown in Formulas I as the active constituent of anti-CVA16 type virus.

It further include that pharmaceutically acceptable auxiliary material is added in compound of formula I in above-mentioned pharmaceutical applications.

The synthetic method of compound shown in formula I, which is characterized in that synthetic route is as follows:

Preferably, synthesis step is as follows:

Step 1.

1 septichen of compound, succinic anhydride and pyridine are added in round-bottomed flask, is with 4-dimethylaminopyridine Catalyst is heated to 85-95 DEG C of reaction 4-6h；After reaction, after solvent is removed in vacuum distillation, methylene chloride and methanol are used Mixed liquor as mobile phase carry out pillar layer separation, obtain compound 2；

Step 2.

Above compound 2, diethylene glycol monomethyl ether, catalyst dicyclohexylcarbodiimide and two are added in round-bottomed flask Chloromethanes is heated to flowing back, and reacts 10-14h；After solvent is removed in vacuum distillation after reaction, with methylene chloride and methanol Mixed liquor carries out pillar layer separation as mobile phase, obtains compound 4.

Step 3.

Compound 4 and DMF are added into round-bottomed flask, thionyl chloride is added dropwise under the conditions of nitrogen protection, reacts at room temperature After 2-4h, it is added 2- amino -5- nitrothiazole, after the reaction was continued 4-6h, after vacuum distillation removal solvent, with methylene chloride and first The mixed liquor of alcohol carries out pillar layer separation as mobile phase, obtains light yellow solid Compound I.

Preferably, above-mentioned synthetic method are as follows:

1 septichen 1.38g of compound, succinic anhydride 1.46g, pyridine are added in step 1.50ml round-bottomed flask 15ml, catalyst 4-dimethylaminopyridine 2.47g are heated to 90 DEG C of reaction 5h；After reaction, solvent is removed in vacuum distillation Afterwards, use the methylene chloride of volume ratio 2:1: methyl alcohol mixed liquor obtains compound 2 as mobile phase pillar layer separation；

2.38g compound 2,1.4g diethylene glycol monomethyl ether, 2.47g catalyst is added in step 2. in 50ml round-bottomed flask Dicyclohexylcarbodiimide and 5ml methylene chloride, are heated to flowing back, and react 12h；Solvent is removed in vacuum distillation after reaction Afterwards, use the methylene chloride of volume ratio 3:1 later: methyl alcohol mixed liquor obtains compound 4 as mobile phase pillar layer separation；

3.40g compound 4 and 15ml DMF are added into 50ml round-bottomed flask for step 3., are added dropwise under the conditions of nitrogen protection After reacting 3h at room temperature, 1.56g 2- amino -5- nitrothiazole is added in thionyl chloride, after the reaction was continued 5h, vacuum distillation removal After solvent, use the methylene chloride of volume ratio 2:1: methyl alcohol mixed liquor obtains light yellow solid as mobile phase pillar layer separation Compound I.

The synthetic method of the derivative of compound of formula I, compound 1 in step 1Wherein R be methyl, Ethyl, carboxymethyl, nitro, methoxyl group, formoxyl, acetyl group, formamido, acetylamino or phenyl.

The present invention is that target is designed and screened using molecular docking technology with coxsackie virus A 16-type (CVA 16) A kind of pair of coxsackie virus A 16-type (CVA 16) has the small molecule compound medicament of good inhibitory effect, and antiviral drug effect is real Test the result shows that, the small molecule compound to 16 type virus of CVA have excellent antiviral activity.The present invention further provides The synthetic method of the small molecule agent.

The ingredient dose shown in the above-mentioned methods is interpreted as ratio, in an actual embodiment, according to preparation process Different scales, equimultiple increases various raw materials to carry out synthesis technology.

Specific embodiment

The preferred embodiment of the present invention is described in detail below in conjunction with embodiment.It will be appreciated that following real Providing merely to play the purpose of explanation for example is applied, is not used to limit the scope of the present invention.The skill of this field Art personnel without departing from the spirit and purpose of the present invention, can carry out various modifications and replace to the present invention.

Experimental method used in following embodiments is conventional method unless otherwise specified.

The materials, reagents and the like used in the following examples is commercially available unless otherwise specified.

The route of synthesis and condition of compound shown in 1. formula of embodiment (I)

Synthetic route is as follows:

Step 1.

1 septichen of compound (1.38g, 10mmol) is added in 50ml round-bottomed flask, succinic anhydride (1.2g, 12mmol), pyridine 15ml, catalyst DMAP (4-dimethylaminopyridine, 1.46g, 12mmol) are to be heated to 90 DEG C of reaction 5h.

After reaction, vacuum distillation uses methylene chloride after removing solvent: methanol (volume ratio 2:1) is as mobile phase column Chromatographic isolation obtains compound 2.

Step 2.

Compound 2 (2.38g, 10mmol) is added in 50ml round-bottomed flask, compound 3 (Cas#111-77-3, diethylene glycol Monomethyl ether, 1.4g, 12mmol), catalyst DCC (dicyclohexylcarbodiimide, 2.47g, 12mmol) and methylene chloride (5ml). It is heated to flowing back, reacts 12h.After solvent is removed in vacuum distillation after reaction, later with methylene chloride: methanol (volume ratio 3: 1) it is used as mobile phase pillar layer separation, obtains compound 4.

Step 3.

Compound 4 (3.40g, 10mmol) and DMF (15ml) are added into 50ml round-bottomed flask, under the conditions of nitrogen protection Thionyl chloride is added dropwise, after reacting 3h at room temperature, addition compound 5 (cas#121-66-4,2- amino -5- nitrothiazole 1.56g, 12mmol), after the reaction was continued 5h, after vacuum distillation removal solvent, use methylene chloride: methanol (volume ratio 2:1) is as mobile phase Pillar layer separation obtains light yellow solid object.

Product inspection method:

Instrument: the instrument designation Model Bruker 400Hz that nuclear-magnetism detection uses, the instrument designation Model of Mass Spectrometer Method Agilent6520；

Testing result data:

MS:m/z=468.01 [M+H]⁺

¹HNMR (CDCl3, δ ppm): 8.69 (1H, s), 7.85 (1H, dd), 7.7 (1H, td), 7.47 (1H, td), 7.32 (1H,dd),4.20(2H,m),3.82-3.74(4H,m),3.394(3H,s),3.85(2H,m),2.42(4H,m)

Testing result shows that light yellow solid object be chemical formula is C₁₉H₂₁O₉N₃Compound shown in the Formulas I of S.

The derivative of compound shown in 2. formula of embodiment (I)

The derivative of compound I

Wherein, R is methyl, ethyl, carboxymethyl, nitre Base, methoxyl group, formoxyl, acetyl group, formamido, acetylamino or phenyl etc..

Synthetic route is the same as embodiment 1.

Step 1.

Compound 1 (1.38g, 10mmol) is added in 50ml round-bottomed flask, succinic anhydride (1.2g, 12mmol), pyridine 15ml, catalyst DMAP (4-dimethylaminopyridine, 1.46g, 12mmol) are to be heated to 90 DEG C of reaction 5h.

After reaction, vacuum distillation uses methylene chloride after removing solvent: methanol (volume ratio 2:1) is as mobile phase column Chromatographic isolation obtains compound 2.

Compound 1 isWherein R be methyl, ethyl, carboxymethyl, nitro, methoxyl group, formoxyl, acetyl group, Formamido, acetylamino or phenyl.

Step 2.

Compound 2 (2.38g, 10mmol) is added in 50ml round-bottomed flask, compound 3 (Cas#111-77-3, diethylene glycol Monomethyl ether, 1.4g, 12mmol), catalyst DCC (dicyclohexylcarbodiimide, 2.47g, 12mmol) and methylene chloride (5ml). It is heated to flowing back, reacts 12h.After solvent is removed in vacuum distillation after reaction, later with methylene chloride: methanol (volume ratio 3: 1) it is used as mobile phase pillar layer separation, obtains compound 4.

Step 3.

Compound 3 (3.40g, 10mmol) and DMF (15ml) are added into 50ml round-bottomed flask, under the conditions of nitrogen protection Thionyl chloride is added dropwise, after reacting 3h at room temperature, is added compound 5 (1.56g, 12mmol), after the reaction was continued 5h, vacuum distillation is gone After solvent, use methylene chloride: methanol (volume ratio 2:1) obtains light yellow solid Compound as mobile phase pillar layer separation I。

With embodiment 1, testing result is shown detection method, and light yellow solid is compound I.

The antiviral activity of 1 formula of experimental example (I) compound detects.

For the Anti-viral activity in vitro for detecting test compound, CVA 16 is isolated from brothers mouthful clinical samples, is used Plaque assay carries out the artificial cumulative evidence of extracorporeal antivirus effect to test compound.

By 1 × 10⁶(the pernicious embryo's rhabdomyoma cell of people, Cat NO.:CL-0193, tissue come the RD cell in a/hole Source: muscle, rhabdomyosarcoma) 6 orifice plates are inoculated in, it is after being incubated overnight, virus liquid to be measured is thin by 10 times of dilution proportion infection RD Born of the same parents, each dilution repeat 3 holes, supernatant is removed after 37 DEG C of infection 1h, are added and contain 1.2% methylcellulose, 2% serum Semisolid culturemedium (DMEM high sugar (article No.: PM150210)+10%FBS (article No.: 164210-500)+1%P/S (article No.: PB180120)), incubator culture 5-6 days to virus plaques are placed in be formed.

Fixed through paraformaldehyde, the rinsing of violet staining, clear water, dry after make plaque counting, calculate virus titer.

The RD cell of 6 orifice plates is inoculated in the virus liquid to be measured infection of MOI=0.001/0.01, after infection, addition contains 5 The semisolid culturemedium of μm ol/L chemical compounds I, is placed in 37 DEG C of incubator cultures, and carry out plaque counting.Contain solvent to be added The semisolid culturemedium of DMSO is control, investigates influence of the test compound I to virus titer.

Plaque assay is the results show that compared with DMSO solvent control group, in the presence of test compound I, plaque Forming number significantly reduces, and shows test compound to a certain extent and can inhibit the duplication of CVA16 virus, has antiviral work Property.

The viral suppression of 2. formula of experimental example (I) compound measures.

The cell maintenance medium containing 2% serum is used (DMEM culture solution preparation method: to be added to the tire inactivated 16 suspension of CVA Cow's serum is separately added into penicillin and streptomysin to final concentration of 100 μ g/mL, glutamine to dense eventually to final concentration of 2% Degree is 2mmol/L) the various concentration gradient dilution from 10-1 to 10-10, it is titrated respectively in the adherent RD for covering with 96 orifice plate single layers On cell, continue to cultivate in 37 DEG C 5% of CO2 incubator with new cell maintenance medium.

After 96 orifice plate cells of virus infection are incubated for 48h in the incubator, cytopathic effect is estimated under microscope (CPE), there is the titration of virus concentration and lesion hole count of cytopathy in observation, calculates virus liquid according to Reed-Muench formula Cell culture 50 3nfective dose (TCID₅₀), when subsequent experimental, uses virus concentration for 100TCID₅₀。

The cell inoculation of logarithmic growth phase is in 96 orifice plates, in 37 DEG C 5% of CO₂After culture grows up to single layer in incubator, Culture solution is discarded, PBS is washed twice, and the 100TCID of bulk testing compound is added₅₀100 μ l of viral suspension, 37 DEG C 5% CO₂After being incubated for 1.5h in incubator, infection liquid is discarded, PBS is washed three times, is separately added into containing 20 μ g/mL and 10 μ g/mL test The DMEM cell maintenance medium of compound continues to cultivate.

After 48h, when cytopathic effect about 90% occur in virus control wells, the lesion of microscopic visual measurement medicine group cell is imitated It answers.

Whole experiment process sets without any processing for cell controls group, and being added without trial drug is virus control Group.

Cell CPE judgment criteria: cell-free lesion is denoted as-, 25% or less cytopathy is denoted as+, 25-50% cytopathy It is denoted as ++, 50-75% cytopathy is denoted as +++, 75% or more cytopathy is denoted as ++++.

The tissue culture plate supernatant removal that cytopathy effect observation is finished, PBS is washed twice, with MTT colorimetric method meter Calculate viral suppression:

After measured, the TCID of strain CVA 16 is tested₅₀It is 10^-5.9, the virus concentration that when test uses is 100TCID₅₀.It presses Virus liquid is diluted according to above-mentioned dilution gradient, after infection cell, CPE occur in 48h virus control group cell is ++++when, microscope Drug-treated is estimated for the inhibiting effect of virus, it is 58% that mtt assay, which measures viral suppression,.

The measurement of the derivative of formula (I) compound is shown, similar result is obtained.

CC50, EC50 and SI of 3 formula of experimental example (I) compound are measured.

CC50, that is, median toxic concentration has guided the drug concentration of 50% poisoning of drug of cell.Test compound DMSO (diformazan Base sulfoxide) it is configured to the mother liquor of 10mg/mL, respective concentration is diluted to cell maintenance medium when experiment.It will have been grown in 96 orifice plates Culture solution is removed at the RD cell of single layer, is replaced respectively with the cell maintenance medium containing various concentration dilution drug.Each concentration 3 A repetition, concurrently setting normal cell is control group.37 DEG C 5% of CO₂48h is cultivated in incubator.It is observed under inverted microscope Cytotoxicity situation after various concentration drug-treated, and with MTT colorimetric method for determining cell survival rate.The Probit of SPSS software The Return Law calculates drug CC50.

EC50, that is, medium effective concentration refers to 50% drug concentration for effectively inhibiting virus.Refer to cytopathy in embodiment 2 Number observation of steps are almost the same, and drug concentration is set as multiple and different concentration gradients.CPE lesion occur to virus control group is ++++ When, the cytopathy situation of microscopically observation various concentration drug-treated group, the respective HIV suppression of MTT colorimetric method for determining Rate.The Probit Return Law of SPSS software calculates drug EC50.

SI, that is, drug therapeutic index=CC50/EC50.SI value is bigger, illustrates that antiviral potentiality are bigger.

The result is as follows:

16 activity of cytotoxicity and anti-CVA of table invention formula (I)

The measurement of the derivative of formula (I) compound is shown, similar result is obtained.

Small molecule agent compound of the invention has passed through specific real as the application of anti-16 type viral agent of CVA Example is described, those skilled in the art can use for reference the content of present invention, and the links such as appropriate feed change, process conditions are realized Corresponding other purposes, correlation change all without departing from the contents of the present invention, this be to those skilled in the art it is aobvious and It is clear to.Therefore, these modifications for being done without departing from theon the basis of the spirit of the present invention improve, and belong to that the present invention claims guarantors The range of shield.

Claims (10)

1. a kind of I compound represented of formula,

2. the derivative of compound described in claim 1, chemical formula are as follows:

Wherein, R is methyl, ethyl, carboxymethyl, nitro, methoxy Base, formoxyl, acetyl group, formamido, acetylamino or phenyl.

3. the purposes prepared in drug of compound or derivatives thereof shown in Formulas I, the drug refer to for hand-foot-and-mouth disease treatment or The drug of prevention, the drug using derivative shown in compound shown in Formulas I described in claim 1 or claim 2 as Active pharmaceutical ingredient.

4. the purposes prepared in drug of compound or derivatives thereof shown in Formulas I, the drug refers to the medicine for anti-CVA16 type Object, the drug is using derivative shown in compound shown in Formulas I described in claim 1 or claim 2 as anti-CVA16 type The active constituent of virus.

5. pharmaceutical applications according to claim 3 or 4, the drug further includes pharmaceutically acceptable auxiliary material.

6. the synthetic method of compound shown in formula I described in claim 1, which is characterized in that use synthesis road as shown below Line:

7. synthetic method according to claim 6, including following synthesis step:

Step 1.

1 septichen of compound, succinic anhydride and pyridine are added in round-bottomed flask, is catalysis with 4-dimethylaminopyridine Agent is heated to 85-95 DEG C of reaction 4-6h；After reaction, after solvent is removed in vacuum distillation, the mixed of methylene chloride and methanol is used Liquid is closed as mobile phase and carries out pillar layer separation, obtains compound 2；

Step 2.

Above compound 2, diethylene glycol monomethyl ether, catalyst dicyclohexylcarbodiimide and dichloromethane are added in round-bottomed flask Alkane is heated to flowing back, and reacts 10-14h；After solvent is removed in vacuum distillation after reaction, with the mixing of methylene chloride and methanol Liquid carries out pillar layer separation as mobile phase, obtains compound 4；

Step 3.

Compound 4 and DMF are added into round-bottomed flask, thionyl chloride is added dropwise under the conditions of nitrogen protection, reacts 2-4h at room temperature Afterwards, 2- amino -5- nitrothiazole is added, after the reaction was continued 4-6h, after vacuum distillation removal solvent, with methylene chloride and methanol Mixed liquor carries out pillar layer separation as mobile phase, obtains light yellow solid Compound I.

8. synthetic method according to claim 7, the synthesis step is as follows:

The step 1 are as follows: 1 septichen 1.38g of compound, succinic anhydride 1.46g, pyridine are added in 50ml round-bottomed flask 15ml, catalyst 4-dimethylaminopyridine 2.47g are heated to 90 DEG C of reaction 5h；After reaction, solvent is removed in vacuum distillation Afterwards, use the methylene chloride of volume ratio 2:1: methyl alcohol mixed liquor obtains compound 2 as mobile phase pillar layer separation；

The step 2 are as follows: 2.38g compound 2,1.4g diethylene glycol monomethyl ether, 2.47g catalysis are added in 50ml round-bottomed flask Agent dicyclohexylcarbodiimide and 5ml methylene chloride, are heated to flowing back, and react 12h；Solvent is removed in vacuum distillation after reaction Afterwards, use the methylene chloride of volume ratio 3:1 later: methyl alcohol mixed liquor obtains compound 4 as mobile phase pillar layer separation；

The step 3 are as follows: 3.40g compound 4 and 15ml DMF are added into 50ml round-bottomed flask, is dripped under the conditions of nitrogen protection Add thionyl chloride, after reacting 3h at room temperature, be added 1.56g 2- amino -5- nitrothiazole, after the reaction was continued 5h, vacuum distillation is gone After solvent, use the methylene chloride of volume ratio 2:1: methyl alcohol mixed liquor obtains light yellow solid as mobile phase pillar layer separation Body compound I.

9. the synthetic method of the derivative of compound shown in formula I as claimed in claim 2, including following synthesis step:

Compound 1, succinic anhydride and pyridine is added in step 1. in round-bottomed flask, using 4-dimethylaminopyridine as catalyst, adds Heat is to 85-95 DEG C of reaction 4-6h；After reaction, after solvent is removed in vacuum distillation, the mixed liquor of methylene chloride and methanol is used Pillar layer separation is carried out as mobile phase, obtains compound 2；

Above compound 2, diethylene glycol monomethyl ether, catalyst dicyclohexylcarbodiimide are added in step 2. round-bottomed flask, and Methylene chloride is heated to flowing back, and reacts 10-14h；After solvent is removed in vacuum distillation after reaction, with methylene chloride and methanol Mixed liquor as mobile phase carry out pillar layer separation, obtain compound 4；

Compound 4 and DMF are added into round-bottomed flask for step 3., thionyl chloride are added dropwise under the conditions of nitrogen protection, at room temperature instead After answering 2-4h, be added 2- amino -5- nitrothiazole, after the reaction was continued 4-6h, after vacuum distillation removal solvent, with methylene chloride and The mixed liquor of methanol carries out pillar layer separation as mobile phase, obtains light yellow solid Compound I；

The compound 1 isFor wherein R is methyl, ethyl, carboxymethyl, nitro, methoxyl group, formoxyl, acetyl Base, formamido, acetylamino or phenyl.

10. synthetic method according to claim 9, the synthesis step is as follows:

The step 1 are as follows: 10mmol compound 1, succinic anhydride 1.46g, pyridine 15ml, catalyst are added in 50ml round-bottomed flask 4-dimethylaminopyridine 2.47g is heated to 90 DEG C of reaction 5h；After reaction, after solvent is removed in vacuum distillation, volume ratio is used The methylene chloride of 2:1: methyl alcohol mixed liquor obtains compound 2 as mobile phase pillar layer separation；

The step 2 are as follows: 2.38g compound 2,1.4g diethylene glycol monomethyl ether, 2.47g catalysis are added in 50ml round-bottomed flask Agent dicyclohexylcarbodiimide and 5ml methylene chloride, are heated to flowing back, and react 12h；Solvent is removed in vacuum distillation after reaction Afterwards, use the methylene chloride of volume ratio 3:1 later: methyl alcohol mixed liquor obtains compound 4 as mobile phase pillar layer separation；

The step 3 are as follows: 3.40g compound 4 and 15ml DMF are added into 50ml round-bottomed flask, is dripped under the conditions of nitrogen protection Add thionyl chloride, after reacting 3h at room temperature, be added 1.56g 2- amino -5- nitrothiazole, after the reaction was continued 5h, vacuum distillation is gone After solvent, use the methylene chloride of volume ratio 2:1: methyl alcohol mixed liquor obtains light yellow solid as mobile phase pillar layer separation Body compound I.