CN112724157A

CN112724157A - Dihydrooxazolo [5,4-d ] pyrrolo [1,2-a ] pyrimidin-9 (5H) -one derivatives and use thereof

Info

Publication number: CN112724157A
Application number: CN202110091653.5A
Authority: CN
Inventors: 阿吉艾克拜尔·艾萨; 曾艳; 聂礼飞; 胡尔西地·博扎罗夫; 赵江瑜
Original assignee: Xinjiang Technical Institute of Physics and Chemistry of CAS
Current assignee: Xinjiang Technical Institute of Physics and Chemistry of CAS
Priority date: 2021-01-23
Filing date: 2021-01-23
Publication date: 2021-04-30
Anticipated expiration: 2041-01-23
Also published as: CN112724157B

Abstract

The invention relates to dihydro-oxazolo [5,4-d]Pyrrolo [1,2-a]Pyrimidine-9 (5)H) The ketone derivative is prepared with ethyl cyanoacetate as initial material and through the reaction of sodium nitrite and phosphoric acid to produce hydroxylamine compound (A), reduction of sodium hydrosulfite to produce ethyl 2-aminocyanoacetate (B), reaction with acyl chloride in alkali condition to produce oxazole compound D1-D48 of 5-amino-4-formic ether in trifluoroacetic acid, and reaction with pyrrolidone in phosphorus oxychloride to produce dihydro oxazolo [5,4-d]Pyrrolo [1,2-a]Pyrimidine-9 (5)H) Ketones E1-E48. The 48g compounds are examined to inhibit the activity of Hela cervical carcinoma cells, MCF-7 breast cancer cells and A549 lung cancer cells, and the results show that: compounds E5, E10, E13, E16, E18, E19, E24, E42 and E43 have inhibitory activity on Hela cervical cancer cellsSex; compounds E22, E24, E47 and E48 have inhibitory activity against MCF-7 breast cancer cells; compounds E18 and E20 had inhibitory activity against a549 lung cancer cells.

Description

Dihydrooxazolo [5,4-d ] pyrrolo [1,2-a ] pyrimidin-9 (5H) -one derivatives and use thereof

Technical Field

The invention relates to dihydro-oxazolo [5,4-d ] pyrrolo [1,2-a ] pyrimidine-9 (5H) -ketone derivatives and application thereof, wherein cell activity screening results of the compounds show that: 9 compounds have inhibitory activity on Hela cervical carcinoma cells; 4 compounds have inhibitory activity against MCF-7 breast cancer cells; 2 compounds have inhibitory activity against a549 lung cancer cells.

Background

According to the statistical data of the world health organization, about 1000 million people suffer from cancer and about 700 million people die of cancer worldwide each year, the number of people suffering from cancer in China is about 120 ten thousand every year, and the number of people dying from cancer in each year is more than 90 ten thousand, so that the cancer-killing composition becomes the second killer of people who are second only to cardiovascular diseases. Although chemically synthesized anticancer drugs also have toxic side effects on normal cells of the human body in many cases. However, there are few reports on finding anticancer active ingredients with low toxicity and high therapeutic effect from natural animals and plants, so that chemically synthesized anticancer drugs are still one of the hot spots of research of domestic and foreign scientists in recent years.

Heterocyclic compounds are a class of compounds with good biological activity and occupy a very important position in medicinal chemistry. Because nitrogen elements are deeply related to life, most of nitrogen-containing heterocyclic compounds have the characteristics of high efficiency, low toxicity and good environmental compatibility, are irreplaceable biological medicines and become the mainstream of medicine research and development. Thus, many drug molecules are designed and screened using nitrogen-containing heterocycles as precursors.

Oxazoles containing nitrogen and oxygen atoms have many unique properties and biological activities. To date, oxazole-based drugs have been used clinically, such as linezolid, oxacillin, sulfisoxazole, raltegravir, furazolidone, toloxanone, and the like. Oxazole compounds are receiving increasing attention as bioisosteres of thiazoles, imidazoles, benzimidazoles, triazoles and tetrazoles, and it is expected that novel oxazoles having broad spectrum, high efficacy, low toxicity and excellent pharmacokinetic properties will be found.

The thiazole ring is an important five-membered aromatic heterocycle, contains nitrogen and sulfur heteroatoms, has abundant electrons, is easy to form hydrogen bonds, is coordinated with metal ions, has static electricity, hydrophobic interaction and other non-covalent bond interactions, has a plurality of special properties, has wide potential applications in a plurality of fields, draws great attention of a plurality of workers, and related research works including the synthesis method thereof are increased day by day. Especially, with the success of a series of thiazole compounds in clinical and agricultural production, the development of thiazole compounds has become one of the hot areas of research in recent years. In the medical field, thiazole compounds can be combined with targets such as various enzymes and receptors in organisms so as to show various biological activities, almost covers the whole medical field, and a plurality of thiazole compounds are used clinically, such as antibiotic drug cefixime, anticancer drug dasatinib, antiparasitic drug nitazoxanide, anti-inflammatory drug meloxicam and the like which are first-line drugs of clinical preference;

therefore, from the biological activities of the oxazole pyrimidine derivatives and thiazole pyrimidine derivatives, the searching and exploring of the synthesis methods of the compounds have great theoretical and application values for searching lead compounds such as new medicines.

Reference documents:

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On the basis of comprehensive analysis of relevant patents and documents at home and abroad, the invention fully synthesizes dihydro-oxazolo [5,4-d ] pyrrolo [1,2-a ] pyrimidine-9 (5H) -ketone compounds, carries out systematic modification and modification, introduces phenyl, aliphatic group and heterocyclic ring containing different substituents into dihydro-oxazolo [5,4-d ] pyrrolo [1,2-a ] pyrimidine-9 (5H) -ketone compound molecules so as to improve the drug success rate, researches the inhibitory activity of the compounds on Hela cervical carcinoma cells, MCF-7 breast cancer cells and A549 lung cancer cells, and discovers candidate drugs with obvious curative effect and definite antitumor activity. The activity screening result shows that: 9 compounds have inhibitory activity on Hela cervical carcinoma cells; 4 compounds have inhibitory activity against MCF-7 breast cancer cells; 2 compounds have inhibitory activity against a549 lung cancer cells.

Disclosure of Invention

The invention aims to provide a dihydro-oxazolo [5,4-d ] pyrrolo [1,2-a ] pyrimidine-9 (5H) -ketone derivative and application thereof. The compound takes ethyl cyanoacetate as an initial raw material, hydroxylamine compounds (A) are generated under the action of sodium nitrite and phosphoric acid, then sodium hydrosulfite is reduced to obtain 2-amino ethyl cyanoacetate (B), the 2-amino ethyl cyanoacetate reacts with different substituted acyl chlorides under the alkali condition, oxazole compounds (D1-D48) with different substituted 5-amino-4-formic ester are generated through cyclization under the action of trifluoroacetic acid, and then the oxazole compounds react with pyrrolidone under the action of phosphorus oxychloride to form dihydro-oxazolo [5,4-D ] pyrrolo [1,2-a ] pyrimidine-9 (5H) -ketone compounds (E1-E48). The 48 compounds are examined on the inhibitory activity of Hela cervical carcinoma cells, MCF-7 breast cancer cells and A549 lung cancer cells, and the results show that: compounds E5, E10, E13, E16, E18, E19, E24, E42, E43 have inhibitory activity on Hela cervical cancer cells; the compounds E22, E24, E47 and E48 have inhibitory activity on MCF-7 breast cancer cells; the compounds E18 and E20 have inhibitory activity on A549 lung cancer cells.

The invention relates to a dihydro-oxazolo [5,4-d ] pyrrolo [1,2-a ] pyrimidone derivative, which has a structural formula as follows:

wherein:

compound E1 is 2-methyl-6, 7-dihydrooxazolo [5,4-d ] pyrrolo [1,2-a ] pyrimidin-9 (5H) -one;

compound E2 is 2-ethyl-6, 7-dihydrooxazolo [5,4-d ] pyrrolo [1,2-a ] pyrimidin-9 (5H) -one;

compound E3 is 2-propyl-6, 7-dihydrooxazolo [5,4-d ] pyrrolo [1,2-a ] pyrimidin-9 (5H) -one;

compound E4 is 2-butyl-6, 7-dihydrooxazolo [5,4-d ] pyrrolo [1,2-a ] pyrimidin-9 (5H) -one;

compound E5 is 2-dodecyl-6, 7-dihydrooxazolo [5,4-d ] pyrrolo [1,2-a ] pyrimidin-9 (5H) -one;

compound E6 is 2- (2-propenyl) -6, 7-dihydrooxazolo [5,4-d ] pyrrolo [1,2-a ] pyrimidin-9 (5H) -one;

compound E7 is 2-tert-butyl-6, 7-dihydrooxazolo [5,4-d ] pyrrolo [1,2-a ] pyrimidin-9 (5H) -one;

compound E8 is 2-adamantyl-6, 7-dihydrooxazolo [5,4-d ] pyrrolo [1,2-a ] pyrimidin-9 (5H) -one;

compound E9 is 2-benzyl-6, 7-dihydrooxazolo [5,4-d ] pyrrolo [1,2-a ] pyrimidin-9 (5H) -one;

compound E10 is 2-phenethyl-6, 7-dihydrooxazolo [5,4-d ] pyrrolo [1,2-a ] pyrimidin-9 (5H) -one;

compound E11 is 2-cyclopropyl-6, 7-dihydrooxazolo [5,4-d ] pyrrolo [1,2-a ] pyrimidin-9 (5H) -one;

compound E12 is 2-cyclobutyl-6, 7-dihydrooxazolo [5,4-d ] pyrrolo [1,2-a ] pyrimidin-9 (5H) -one;

compound E13 is 2-cyclopentyl-6, 7-dihydrooxazolo [5,4-d ] pyrrolo [1,2-a ] pyrimidin-9 (5H) -one;

compound E14 is 2-cyclohexyl-6, 7-dihydrooxazolo [5,4-d ] pyrrolo [1,2-a ] pyrimidin-9 (5H) -one;

compound E15 is 2- (furan-2-yl) -6, 7-dihydrooxazolo [5,4-d ] pyrrolo [1,2-a ] pyrimidin-9 (5H) -one;

compound E16 is 2- (thiophen-2-yl) -6, 7-dihydrooxazolo [5,4-d ] pyrrolo [1,2-a ] pyrimidin-9 (5H) -one;

compound E17 is 2- (tetrahydro-2H-pyran-4-yl) -6, 7-dihydrooxazolo [5,4-d ] pyrrolo [1,2-a ] pyrimidin-9 (5H) -one;

compound E18 is 2- (naphthalen-1-yl) -6, 7-dihydrooxazolo [5,4-d ] pyrrolo [1,2-a ] pyrimidin-9 (5H) -one;

compound E19 is 2- (naphthalen-2-yl) -6, 7-dihydrooxazolo [5,4-d ] pyrrolo [1,2-a ] pyrimidin-9 (5H) -one;

compound E20 is 2- (1,1' -biphenyl-4-yl) -6, 7-dihydrooxazolo [5,4-d ] pyrrolo [1,2-a ] pyrimidin-9 (5H) -one;

compound E21 is 2-phenyl-6, 7-dihydrooxazolo [5,4-d ] pyrrolo [1,2-a ] pyrimidin-9 (5H) -one;

compound E22 is 2- (2-methylphenyl) -6, 7-dihydrooxazolo [5,4-d ] pyrrolo [1,2-a ] pyrimidin-9 (5H) -one;

compound E23 is 2- (3-methylphenyl) -6, 7-dihydrooxazolo [5,4-d ] pyrrolo [1,2-a ] pyrimidin-9 (5H) -one;

compound E24 is 2- (4-methylphenyl) -6, 7-dihydrooxazolo [5,4-d ] pyrrolo [1,2-a ] pyrimidin-9 (5H) -one;

compound E25 is 2- (2-chlorophenyl) -6, 7-dihydrooxazolo [5,4-d ] pyrrolo [1,2-a ] pyrimidin-9 (5H) -one;

compound E26 is 2- (3-chlorophenyl) -6, 7-dihydrooxazolo [5,4-d ] pyrrolo [1,2-a ] pyrimidin-9 (5H) -one;

compound E27 is 2- (4-chlorophenyl) -6, 7-dihydrooxazolo [5,4-d ] pyrrolo [1,2-a ] pyrimidin-9 (5H) -one;

compound E28 is 2- (2-bromophenyl) -6, 7-dihydrooxazolo [5,4-d ] pyrrolo [1,2-a ] pyrimidin-9 (5H) -one;

compound E29 is 2- (3-bromophenyl) -6, 7-dihydrooxazolo [5,4-d ] pyrrolo [1,2-a ] pyrimidin-9 (5H) -one;

compound E30 is 2- (4-bromophenyl) -6, 7-dihydrooxazolo [5,4-d ] pyrrolo [1,2-a ] pyrimidin-9 (5H) -one;

compound E31 is 2- (3, 5-xylyl) -6, 7-dihydrooxazolo [5,4-d ] pyrrolo [1,2-a ] pyrimidin-9 (5H) -one;

compound E32 is 2- (3, 4-dichlorophenyl) -6, 7-dihydrooxazolo [5,4-d ] pyrrolo [1,2-a ] pyrimidin-9 (5H) -one;

compound E33 is 2- (3, 5-dichlorophenyl) -6, 7-dihydrooxazolo [5,4-d ] pyrrolo [1,2-a ] pyrimidin-9 (5H) -one;

compound E34 is 2- (2, 6-dichlorophenyl) -6, 7-dihydrooxazolo [5,4-d ] pyrrolo [1,2-a ] pyrimidin-9 (5H) -one;

compound E35 is 2- (2-fluorophenyl) -6, 7-dihydrooxazolo [5,4-d ] pyrrolo [1,2-a ] pyrimidin-9 (5H) -one;

compound E36 is 2- (3-fluorophenyl) -6, 7-dihydrooxazolo [5,4-d ] pyrrolo [1,2-a ] pyrimidin-9 (5H) -one;

compound E37 is 2- (4-fluorophenyl) -6, 7-dihydrooxazolo [5,4-d ] pyrrolo [1,2-a ] pyrimidin-9 (5H) -one;

compound E38 is 2- (3, 5-difluorophenyl) -6, 7-dihydrooxazolo [5,4-d ] pyrrolo [1,2-a ] pyrimidin-9 (5H) -one;

compound E39 is 2- (3, 4-difluorophenyl) -6, 7-dihydrooxazolo [5,4-d ] pyrrolo [1,2-a ] pyrimidin-9 (5H) -one;

compound E40 is 2- (2, 6-difluorophenyl) -6, 7-dihydrooxazolo [5,4-d ] pyrrolo [1,2-a ] pyrimidin-9 (5H) -one;

compound E41 is 2- (2- (trifluoromethyl) phenyl) -6, 7-dihydrooxazolo [5,4-d ] pyrrolo [1,2-a ] pyrimidin-9 (5H) -one;

compound E42 is 2- (3- (trifluoromethyl) phenyl) -6, 7-dihydrooxazolo [5,4-d ] pyrrolo [1,2-a ] pyrimidin-9 (5H) -one;

compound E43 is 2- (4- (trifluoromethyl) phenyl) -6, 7-dihydrooxazolo [5,4-d ] pyrrolo [1,2-a ] pyrimidin-9 (5H) -one;

compound E44 is 2- (3, 5-bis (trifluoromethyl) phenyl) -6, 7-dihydrooxazolo [5,4-d ] pyrrolo [1,2-a ] pyrimidin-9 (5H) -one;

compound E45 is 2- (2- (trifluoromethoxy) phenyl) -6, 7-dihydrooxazolo [5,4-d ] pyrrolo [1,2-a ] pyrimidin-9 (5H) -one;

compound E46 is 2- (3- (trifluoromethoxy) phenyl) -6, 7-dihydrooxazolo [5,4-d ] pyrrolo [1,2-a ] pyrimidin-9 (5H) -one;

compound E47 is 2- (4- (trifluoromethoxy) phenyl) -6, 7-dihydrooxazolo [5,4-d ] pyrrolo [1,2-a ] pyrimidin-9 (5H) -one;

compound E48 is 2- (4- (tert-butyl) phenyl) -6, 7-dihydrooxazolo [5,4-d ] pyrrolo [1,2-a ] pyrimidin-9 (5H) -one.

The applications of E5, E10, E13, E16, E18, E19, E24, E42 and E43 in the dihydro-oxazolo [5,4-d ] pyrrolo [1,2-a ] pyrimidine-9 (5H) -ketone compounds in the preparation of medicines for treating Hela cervical cancer.

The applications of E22, E24, E47 and E48 in dihydro-oxazolo [5,4-d ] pyrrolo [1,2-a ] pyrimidine-9 (5H) -ketone compounds in preparing medicines for treating MCF-7 breast cancer are provided.

The applications of E18 and E20 in the dihydro oxazolo [5,4-d ] pyrrolo [1,2-a ] pyrimidine-9 (5H) -ketone compound in preparing medicaments for treating A549 lung cancer.

The structure of the dihydro-oxazolo [5,4-d ] pyrrolo [1,2-a ] pyrimidine-9 (5H) -ketone derivative is shown as a general formula (I):

the invention relates to a dihydro-oxazolo [5,4-d ] pyrrolo [1,2-a ] pyrimidine-9 (5H) -ketone derivative and application thereof, wherein the preparation method of the dihydro-oxazolo [5,4-d ] pyrrolo [1,2-a ] pyrimidine-9 (5H) -ketone derivative comprises the following steps:

preparation of Compound A

Under the condition of-10 ℃, 57.3g of sodium nitrite, 0.83mol of sodium nitrite and 100g of ethyl cyanoacetate, 0.83mol of ethyl cyanoacetate are dissolved in 700ml of pure water, then 36.6ml of 85 percent concentrated phosphoric acid and 0.055mol of 85 percent are slowly dripped, the dripping time lasts for 3 hours, then the temperature is increased to 45 ℃, the stirring is carried out for 1 hour, then 74ml of concentrated hydrochloric acid and 0.88mol of concentrated hydrochloric acid are added, the stirring is continued overnight under the condition of 0 ℃, a large amount of white solid is separated out, and the white compound A is obtained by filtering without purification and is used for the next reaction.

Preparation of Compound B

Dissolving 43g of the white compound A obtained in the previous step in 0.3mol of pure water 500ml at room temperature, slowly dropwise adding 350ml of saturated sodium bicarbonate solution under stirring, then adding 156g of sodium hydrosulfite and 0.9mol, heating to 35 ℃, reacting for 1 hour, then reacting for 3 hours at room temperature, extracting for 3 times by using 500ml of dichloromethane, combining organic phases, drying and concentrating, and performing gradient elution by using forward silica gel column chromatography, wherein an eluent is petroleum ether and ethyl acetate in a volume ratio of 2:1 to obtain a compound B.

Preparation of Compounds C1-C48

Dissolving the obtained compound B1.28g and 10mmol in 50mL of anhydrous dichloromethane, adding 12mmol of different substituted formyl chlorides under the ice bath condition, then slowly dropwise adding 1.25g and 12mmol of triethylamine, reacting at room temperature until all raw materials disappear, filtering the reaction liquid, concentrating, and performing gradient elution by adopting forward silica gel column chromatography, wherein an eluent is petroleum ether and ethyl acetate in a volume ratio of 10:1 to respectively obtain the compounds C1-C48.

Preparation of Compounds D1-D48

Dissolving the obtained compound C1-C4810 mmol in anhydrous dichloromethane, slowly dropwise adding 10mL trifluoroacetic acid, reacting at room temperature until the raw materials disappear, filtering the reaction solution, concentrating, and performing gradient elution by adopting forward silica gel column chromatography, wherein the eluent is petroleum ether and ethyl acetate with the volume ratio of 2:1 to respectively obtain the compounds D1-D48.

Preparation of Compounds E1-E48

Dissolving the obtained compound D1-D4810 mmol in 20mL anhydrous dioxane, adding cyclohexanamide 15mmol, slowly dropwise adding phosphorus oxychloride 2.5mmol, refluxing to react until the raw materials disappear, filtering the reaction solution, concentrating, performing gradient elution by forward silica gel column chromatography, wherein the eluent is pure ethyl acetate, and obtaining the compounds E1-E48 respectively.

The dihydro-oxazolo [5,4-d ] pyrrolo [1,2-a ] pyrimidine-9 (5H) -ketone derivative is prepared by taking ethyl cyanoacetate as a starting material, synthesizing different substituted oxazole derivatives through multiple steps in sequence, and reacting with pyrrolidone under the action of phosphorus oxychloride to obtain the dihydro-oxazolo [5,4-d ] pyrrolo [1,2-a ] pyrimidone derivative, wherein the synthetic route is as follows:

Detailed Description

The present invention is further illustrated by the following examples, but is not limited thereto;

reagent: all reagents were commercially available analytical grade;

example 1

Preparation of compound a:

under the condition of the temperature of minus 10 ℃, 57.3ml of sodium nitrite, 0.83mol of sodium nitrite and 100g of ethyl cyanoacetate and 0.83mol of sodium nitrite are dissolved in 700ml of pure water, then 36.6ml of 85 percent concentrated phosphoric acid and 0.055mol of 85 percent are slowly dripped, after the dripping time lasts for 3 hours, the temperature is raised to 45 ℃ and stirred for 1 hour, then 74ml of concentrated hydrochloric acid and 0.88mol of concentrated hydrochloric acid are added, the mixture is continuously stirred overnight at the temperature of 0 ℃, a large amount of white solid is separated out and filtered, and a white compound A which is ethyl 2-cyano-2-hydroxyiminoacetate is obtained and is used for the next reaction without purification;

preparation of compound B:

under the condition of room temperature, dissolving obtained white compound A which is 43g of 2-cyano-2-hydroxyiminoethyl acetate in 0.3mol in 500ml of pure water, slowly dropwise adding 350ml of saturated sodium bicarbonate solution under stirring, then adding 156g of sodium hydrosulfite and 0.9mol, heating to 35 ℃, reacting for 1 hour, then reacting for 3 hours at room temperature, extracting for 3 times by using 500ml of dichloromethane, combining organic phases, drying and concentrating, performing gradient elution by adopting forward silica gel column chromatography, wherein an eluant is petroleum ether and ethyl acetate in a volume ratio of 2:1, and obtaining compound B which is 2-amino-2-cyanoethyl acetate, and the compound B is used for the next reaction without purification;

preparation of Compounds C1-C48:

dissolving 1.28g of obtained compound B2-amino-2-cyanoethyl acetate in 10mmol of anhydrous dichloromethane 50mL, adding 12mmol of formyl chloride substituted differently under the ice bath condition, slowly dropwise adding 1.25g of triethylamine and 12mmol of triethylamine, reacting at room temperature until all raw materials disappear, filtering the reaction solution, concentrating, performing gradient elution by adopting forward silica gel column chromatography, and respectively obtaining compounds C1-C48 by using an eluant of petroleum ether and ethyl acetate in a volume ratio of 10:1, wherein the eluant is used for the next reaction without purification;

compound C1 is N- (1-cyano-2-ethylperoxyethyl) acetamide;

compound C2 is N- (1-cyano-2-ethylperoxyethyl) propionamide;

compound C3 is N- (1-cyano-2-ethylperoxyethyl) butanamide;

compound C4 is N- (1-cyano-2-ethylperoxyethyl) pentanamide;

compound C5 is N- (1-cyano-2-ethylperoxyethyl) tridecamide;

compound C6 is N- (1-cyano-2-ethylperoxyethyl) methacrylamide;

compound C7 is N- (1-cyano-2-ethylperoxyethyl) adamantane-1-carboxamide;

compound C8 is N- (1-cyano-2-ethylperoxyethyl) neopentenamide;

compound C9 is N- (1-cyano-2-ethylperoxyethyl) -2-phenylacetamide;

compound C10 is N- (1-cyano-2-ethylperoxyethyl) -2-phenylacrylamide;

compound C11 is N- (1-cyano-2-ethylperoxyethyl) cyclopropylamide;

compound C12 is N- (1-cyano-2-ethylperoxyethyl) cyclobutanamide;

compound C13 is N- (1-cyano-2-ethylperoxyethyl) cyclopentamide;

compound C14 is N- (1-cyano-2-ethylperoxyethyl) cyclohexanamide;

compound C15 is N- (1-cyano-2-ethylperoxyethyl) furan-2-carboxamide;

compound C16 is N- (1-cyano-2-ethylperoxyethyl) thiophene-2-carboxamide;

compound C17 is N- (1-cyano-2-ethylperoxyethyl) tetrahydrofuran-4-carboxamide;

compound C18 is N- (1-cyano-2-ethylperoxyethyl) -1-naphthamide;

compound C19 is N- (1-cyano-2-ethylperoxyethyl) -2-naphthamide;

compound C20 is N- (1-cyano-2-ethylperoxyethyl) -biphenyl-4-carboxamide;

compound C21 is N- (1-cyano-2-ethylperoxyethyl) benzamide;

compound C22 is N- (1-cyano-2-ethylperoxyethyl) -2-methylbenzamide;

compound C23 is N- (1-cyano-2-ethylperoxyethyl) -3-methylbenzamide;

compound C24 is N- (1-cyano-2-ethylperoxyethyl) -4-methylbenzamide;

compound C25 is N- (1-cyano-2-ethylperoxyethyl) -2-chlorobenzamide;

compound C26 is N- (1-cyano-2-ethylperoxyethyl) -3-chlorobenzamide;

compound C27 is N- (1-cyano-2-ethylperoxyethyl) -4-chlorobenzamide;

compound C28 is N- (1-cyano-2-ethylperoxyethyl) -2-bromobenzamide;

compound C29 is N- (1-cyano-2-ethylperoxyethyl) -3-bromobenzamide;

compound C30 is N- (1-cyano-2-ethylperoxyethyl) -4-bromobenzamide;

compound C31 is N- (1-cyano-2-ethylperoxyethyl) -3, 5-dimethylbenzamide;

compound C32 is N- (1-cyano-2-ethylperoxyethyl) -3, 4-dichlorobenzamide;

compound C33 is N- (1-cyano-2-ethylperoxyethyl) -3, 5-dichlorobenzamide;

compound C34 is N- (1-cyano-2-ethylperoxyethyl) -2, 6-dichlorobenzamide;

compound C35 is N- (1-cyano-2-ethylperoxyethyl) -2-fluorobenzamide;

compound C36 is N- (1-cyano-2-ethylperoxyethyl) -3-fluorobenzamide;

compound C37 is N- (1-cyano-2-ethylperoxyethyl) -4-fluorobenzamide;

compound C38 is N- (1-cyano-2-ethylperoxyethyl) -3, 5-difluorobenzamide;

compound C39 is N- (1-cyano-2-ethylperoxyethyl) -3, 4-difluorobenzamide;

compound C40 is N- (1-cyano-2-ethylperoxyethyl) -2, 6-difluorobenzamide;

compound C41 is N- (1-cyano-2-ethylperoxyethyl) -2-trifluoromethylbenzamide;

compound C42 is N- (1-cyano-2-ethylperoxyethyl) -3-trifluoromethylbenzamide;

compound C43 is N- (1-cyano-2-ethylperoxyethyl) -4-trifluoromethylbenzamide;

compound C44 is N- (1-cyano-2-ethylperoxyethyl) -3, 5-bistrifluoromethylbenzamide;

compound C45 is N- (1-cyano-2-ethylperoxyethyl) -2-trifluoromethoxy benzamide;

compound C46 is N- (1-cyano-2-ethylperoxyethyl) -3-trifluoromethoxy benzamide;

compound C47 is N- (1-cyano-2-ethylperoxyethyl) -4-trifluoromethoxy benzamide;

compound C48 is N- (1-cyano-2-ethylperoxyethyl) -4-tert-butylbenzamide.

Example 2

Preparation of Compounds D1-D48:

dissolving C1-C4810 mmol of the compound of example 1 in anhydrous dichloromethane, slowly dropwise adding 10mL of trifluoroacetic acid, reacting at room temperature until all raw materials disappear, concentrating the reaction solution, performing forward silica gel column chromatography gradient elution, and respectively obtaining compounds D1-D48, wherein the eluent is petroleum ether and ethyl acetate with the volume ratio of 2: 1;

compound D1 is 2-methyl-5-amino-4-carboxylic acid ethyl ester oxazole, yield: 84% of light yellow solid;

¹H NMR(400MHz,CDCl₃)δ5.31(s,2H),4.33(q,J＝7.2Hz,2H),2.34(s,3H),1.37(t,J＝7.1Hz,3H)；

compound D2 is 2-ethyl-5-amino-4-carboxylic acid ethyl ester oxazole, yield: 80% of a light yellow solid,

¹H NMR(400MHz,CDCl₃)δ5.58(s,2H),4.25(q,J＝7.1Hz,2H),2.58(q,J＝7.6Hz,2H),1.28(t,J＝7.1Hz,3H),1.20(t,J＝7.6Hz,3H)；

compound D3 is 2-propyl-5-amino-4-carboxylic acid ethyl ester oxazole, yield: 76%, a light yellow solid,¹H NMR(400MHz,CDCl₃)δ5.31(s,2H),4.31(q,J＝7.1Hz,2H),2.60(q,J＝7.5Hz,2H),1.71(t,J＝7.5Hz,2H),1.35(t,J＝7.1Hz,3H),0.95(t,J＝7.4Hz,3H).

compound D4 is 2-butyl-5-amino-4-carboxylic acid ethyl ester oxazole, yield: 86% light yellow solid;

¹H NMR(400MHz,CDCl₃)δ5.39(s,2H),4.29(q,J＝7.1Hz,2H),2.68(q,J＝7.5Hz,2H),1.64(t,J＝7.6Hz,2H),1.42–1.25(m,5H),0.88(t,J＝7.6Hz,3H)；

compound D5 was 2-dodecyl-5-amino-4-carboxylic acid ethyl ester oxazole, yield: 81% of a light yellow solid;

¹H NMR(400MHz,CDCl₃)δ5.33(s,2H),4.31(q,J＝7.1Hz,2H),2.59(q,J＝7.6Hz,2H),1.67(t,J＝7.7Hz,2H),1.34(t,J＝7.1Hz,3H),1.30–1.12(m,18H),0.85(t,J＝6.8Hz,3H)；

compound D6 is 2- (2-propenyl) -5-amino-4-carboxylic acid ethyl ester oxazole, yield: 78%, light yellow solid;

¹H NMR(400MHz,CDCl₃)δ5.69(s,1H),5.51(s,2H),5.27(s,1H),4.35(q,J＝7.1Hz,2H),2.10(d,J＝0.6Hz,3H),1.36(t,J＝7.1Hz,3H)；

compound D7 is 2-tert-butyl-5-amino-4-carboxylic acid ethyl ester oxazole, yield: 71% of a light yellow solid;

¹H NMR(400MHz,CDCl₃)δ5.34(s,2H),4.32(q,J＝7.1Hz,2H),1.35(t,J＝7.1Hz,3H),1.32(s,9H)；

compound D8 is 2-adamantyl-5-amino-4-carboxylic acid ethyl ester oxazole, yield: 79% of light yellow solid;

¹H NMR(400MHz,CDCl₃)δ5.30(s,2H),4.32(q,J＝7.1Hz,2H),2.06-2.01(m,3H),1.98-1.92(m 6H),1.81–1.65(m,6H),1.35(t,J＝7.1Hz,3H)；

compound D9 is 2-benzyl-5-amino-4-carboxylic acid ethyl ester oxazole, yield: 82% light yellow solid;

¹H NMR(400MHz,CDCl₃)δ7.30-7.20(m 5H),5.39(s,2H),4.30(q,J＝7.1Hz,2H),3.94(s,2H),1.34(t,J＝7.6Hz,3H)；

compound D10 is 2-phenethyl-5-amino-4-carboxylic acid ethyl ester oxazole, yield: 86% light yellow solid;

¹H NMR(400MHz,CDCl₃)δ7.30-7.26(m,2H),7.22-7.17(m,3H),5.30(s,2H),4.29(q,J＝7.1Hz,2H),3.04-2.99(m,2H),2.97–2.87(m,2H),1.36(t,J＝7.1Hz,3H)；

compound D11 is 2-cyclopropyl-5-amino-4-carboxylic acid ethyl ester oxazole, yield: 81% of a light yellow solid;

¹H NMR(400MHz,CDCl₃)δ5.30(s,2H),4.30(q,J＝7.1Hz,2H),1.90(tt,J＝8.4,5.2Hz,1H),1.34(t,J＝7.1Hz,3H),1.04–0.81(m,4H)；

compound D12 is 2-cyclobutyl-5-amino-4-carboxylic acid ethyl ester oxazole, yield: 71% of a light yellow solid;

¹H NMR(400MHz,CDCl₃)δ5.51(s,2H),4.28(q,J＝7.1Hz,2H),3.44(p,J＝8.7Hz,1H),2.37-2.30(m,2H),2.29–2.15(m,2H),2.07–1.76(m,2H),1.31(t,J＝7.1Hz,3H)；

compound D13 is 2-cyclopentyl-5-amino-4-carboxylic acid ethyl ester oxazole, yield: 74% light yellow solid;

¹H NMR(400MHz,CDCl₃)δ5.33(s,2H),4.31(q,J＝7.1Hz,2H),3.06(p,J＝8.2Hz,1H),2.03-1.94(m,2H),1.87–1.68(m,4H),1.64–1.55(m,2H),1.34(t,J＝7.1Hz,3H)；

compound D14 is 2-cyclohexyl-5-amino-4-carboxylic acid ethyl ester oxazole, yield: 77% of light yellow solid;

¹H NMR(400MHz,CDCl₃)δ5.32(s,2H),4.31(q,J＝7.1Hz,2H),2.63(tt,J＝11.7,3.5Hz,1H),1.98(dd,J＝13.3,1.9Hz,2H),1.82–1.45(m,4H),1.34(t,J＝7.1Hz,3H),1.32–1.20(m,2H)；

compound D15 is 2- (furan-2-yl) -5-amino-4-carboxylic acid ethyl ester oxazole, yield: 83% of light yellow solid;

¹H NMR(400MHz,CDCl₃)δ7.47(d,J＝1.4Hz,1H),6.90(dd,J＝3.5,0.8Hz,1H),6.52–6.41(m,1H),5.60(s,2H),4.35(q,J＝7.1Hz,2H),1.37(t,J＝7.1Hz,3H)；

compound D16 is 2- (thiophen-2-yl) -5-amino-4-carboxylic acid ethyl ester oxazole, yield: 87% of light yellow solid;

¹H NMR(400MHz,CDCl₃)δ7.31(d,J＝1.4Hz,1H),6.64(dd,J＝3.5,0.8Hz,1H),6.31–6.25(m,1H),5.67(s,2H),4.28(q,J＝7.1Hz,2H),1.35(t,J＝7.1Hz,3H)；

compound D17 is 2- (tetrahydro-2H-pyran-4-yl) -5-amino-4-carboxylic acid ethyl ester oxazole, yield: 85% of light yellow solid;

¹H NMR(400MHz,CDCl₃)δ5.41(s,2H),4.31(q,J＝7.1Hz,2H),3.98(dt,J＝11.6,3.4Hz,2H),3.51–3.37(m,2H),2.99–2.81(m,1H),1.93–1.74(m,3H),1.34(t,J＝7.1Hz,3H)；

compound D18 is 2- (naphthalen-1-yl) -5-amino-4-carboxylic acid ethyl ester oxazole, yield: 78%, light yellow solid;

¹H NMR(400MHz,DMSO)δ8.27(d,J＝0.7Hz,1H),8.04–7.86(m,3H),7.56-7.51(m,3H),5.73(s,2H),4.20(q,J＝7.1Hz,2H),1.26(t,J＝7.1Hz,3H)；

compound D19 is 2- (naphthalen-2-yl) -5-amino-4-carboxylic acid ethyl ester oxazole, yield: 74% light yellow solid;

¹H NMR(400MHz,DMSO)δ8.27(d,J＝0.7Hz,1H),8.04–7.84(m,3H),7.56-7.52(m,3H),5.73(s,2H),4.20(q,J＝7.1Hz,2H),1.26(t,J＝7.1Hz,3H)；

compound D20 is 2- (1,1' -biphenyl-4-yl) -5-amino-4-carboxylic acid ethyl ester oxazole, yield: 81% of a light yellow solid;

¹H NMR(400MHz,DMSO)δ7.83(d,J＝8.5Hz,2H),7.77(d,J＝8.6Hz,2H),7.69(d,J＝7.3Hz,2H),7.48(m,2H),7.45(t,J＝7.6Hz,2H),7.36(t,J＝7.3Hz,1H),4.19(q,J＝7.1Hz,2H),1.25(t,J＝7.1Hz,3H)；

compound D21 is 2-phenyl-5-amino-4-carboxylic acid ethyl ester oxazole, yield: 83% of light yellow solid;

¹H NMR(400MHz,CDCl₃)δ7.98–7.84(m,2H),7.48–7.32(m,3H),5.56(s,2H),4.38(q,J＝7.1Hz,2H),1.39(t,J＝7.1Hz,3H)；

compound D22 is 2- (2-methylphenyl) -5-amino-4-carboxylic acid ethyl ester oxazole, yield: 74% light yellow solid;

¹H NMR(400MHz,CDCl₃)δ7.82(d,J＝7.7Hz,1H),7.36–7.11(m,3H),5.55(s,2H),4.37(q,J＝7.2Hz,2H),2.63(s,3H),1.39(t,J＝7.1Hz,3H)；

compound D23 is 2- (3-methylphenyl) -5-amino-4-carboxylic acid ethyl ester oxazole, yield: 72% light yellow solid;

¹H NMR(400MHz,CDCl₃)δ7.79(s,1H),7.70(d,J＝7.8Hz,1H),7.28(t,J＝7.7Hz,1H),7.19(d,J＝7.9Hz,1H),5.52(s,2H),4.39(q,J＝7.1Hz,2H),2.36(s,3H),1.40(t,J＝7.1Hz,3H)；

compound D24 is 2- (4-methylphenyl) -5-amino-4-carboxylic acid ethyl ester oxazole, yield: 83% of light yellow solid;

¹H NMR(400MHz,DMSO)δ7.64(d,J＝8.2Hz,2H),7.35(s,2H),7.26(d,J＝8.0Hz,2H),4.17(q,J＝7.1Hz,2H),2.31(s,3H),1.24(t,J＝7.1Hz,3H)；

compound D25 is 2- (2-chlorophenyl) -5-amino-4-carboxylic acid ethyl ester oxazole, yield: 87% of light yellow solid;

¹H NMR(400MHz,CDCl₃)δ7.94–7.83(m,1H),7.57–7.37(m,2H),7.37–7.21(m,1H),5.66(s,2H),4.36(q,J＝7.1Hz,2H),1.37(t,J＝5.5Hz,5H)；

compound D26 is 2- (3-chlorophenyl) -5-amino-4-carboxylic acid ethyl ester oxazole, yield: 70% of light yellow solid;

¹H NMR(400MHz,DMSO)δ7.68(t,J＝3.4Hz,2H),7.50(s,2H),7.48(d,J＝7.0Hz,2H),4.18(q,J＝7.1Hz,2H),1.23(t,J＝7.1Hz,3H)；

compound D27 is 2- (4-chlorophenyl) -5-amino-4-carboxylic acid ethyl ester oxazole, yield: 72% light yellow solid;

¹H NMR(400MHz,DMSO)δ7.73(d,J＝8.6Hz,2H),7.50(d,J＝8.6Hz,2H),7.45(s,2H),4.18(q,J＝7.1Hz,2H),1.23(t,J＝7.1Hz,3H)；

compound D28 is 2- (2-bromophenyl) -5-amino-4-carboxylic acid ethyl ester oxazole, yield: 76% of a light yellow solid;

¹H NMR(400MHz,CDCl₃)δ7.83(d,J＝7.5Hz,1H),7.68(dd,J＝7.8,1.7Hz,1H),7.49–7.28(m,2H),5.91(s,2H),4.28(q,J＝7.3Hz,2H),1.29(t,J＝7.1Hz,3H)；

compound D29 is 2- (3-bromophenyl) -5-amino-4-carboxylic acid ethyl ester oxazole, yield: 81% of a light yellow solid;

¹H NMR(400MHz,CDCl₃)δ7.97(t,J＝1.7Hz,1H),7.71(dd,J＝18.1,8.3Hz,2H),7.35(t,J＝7.9Hz,1H),5.58(s,2H),4.39(q,J＝7.3Hz,2H),1.39(t,J＝7.1Hz,3H)；

compound D30 is 2- (4-bromophenyl) -5-amino-4-carboxylic acid ethyl ester oxazole, yield: 83% of light yellow solid;

¹H NMR(400MHz,DMSO)δ7.66(s,2H),7.64(s,2H),7.49(s,2H),4.18(q,J＝7.1Hz,2H),1.24(t,J＝7.1Hz,3H)；

compound D31 is 2- (3, 5-xylyl) -5-amino-4-carboxylic acid ethyl ester oxazole, yield: 79% of light yellow solid;

¹H NMR(400MHz,CDCl₃)δ7.55(s,2H),7.00(s,1H),5.63(s,2H),4.38(q,J＝7.1Hz,2H),2.35(s,6H),1.38(t,J＝7.1Hz,3H)；

compound D32 was 2- (3, 4-dichlorophenyl) -5-amino-4-carboxylic acid ethyl ester oxazole, yield: 77% of light yellow solid;

¹H NMR(400MHz,DMSO)δ7.84(d,J＝1.8Hz,1H),7.72(d,J＝8.5Hz,1H),7.68(dd,J＝8.5,1.9Hz,1H),7.56(s,2H),4.19(q,J＝7.1Hz,2H),1.24(t,J＝7.1Hz,3H)；

compound D33 was 2- (3, 5-dichlorophenyl) -5-amino-4-carboxylic acid ethyl ester oxazole, yield: 76% of a light yellow solid;

¹H NMR(400MHz,DMSO)δ7.64(s,1H),7.63(s,2H),7.58(s,2H),4.19(q,J＝7.1Hz,2H),1.24(t,J＝7.1Hz,3H)；

compound D34 was 2- (2, 6-dichlorophenyl) -5-amino-4-carboxylic acid ethyl ester oxazole, yield: 82 percent, light yellow solid,¹H NMR(400MHz,DMSO)δ7.34(s,1H),7.30(s,2H),7.21(s,2H),4.36(q,J＝7.1Hz,2H),1.35(t,J＝7.1Hz,3H).

compound D35 is 2- (2-fluorophenyl) -5-amino-4-carboxylic acid ethyl ester oxazole, yield: 85% of light yellow solid;

¹H NMR(400MHz,CDCl₃)δ7.96(td,J＝7.7,1.7Hz,1H),7.48–7.27(m,1H),7.16(ddd,J＝19.5,9.4,4.7Hz,2H),5.62(s,2H),4.38(q,J＝7.2Hz,2H),1.39(t,J＝7.1Hz,3H)；

compound D36 is 2- (3-fluorophenyl) -5-amino-4-carboxylic acid ethyl ester oxazole, yield: 79% of light yellow solid;

¹H NMR(400MHz,DMSO)δ7.58(d,J＝7.9Hz,1H),7.48(s,2H),7.54–7.42(m,2H),7.25(td,J＝8.2,2.0Hz,1H),4.18(q,J＝7.1Hz,2H),1.24(t,J＝7.1Hz,3H)；

compound D37 is 2- (4-fluorophenyl) -5-amino-4-carboxylic acid ethyl ester oxazole, yield: 76% of a light yellow solid;

¹H NMR(400MHz,DMSO)δ7.81–7.75(m,2H),7.44(s,2H),7.30(t,J＝8.9Hz,2H),4.18(q,J＝7.1Hz,2H),1.24(t,J＝7.1Hz,3H)；

compound D38 was 2- (3, 5-difluorophenyl) -5-amino-4-carboxylic acid ethyl ester oxazole, yield: 82% light yellow solid;

¹H NMR(400MHz,DMSO)δ7.56(s,2H),7.34(s,1H),7.32(s,2H),4.19(q,J＝7.1Hz,2H),1.24(t,J＝7.1Hz,3H)；

compound D39 was 2- (3, 4-difluorophenyl) -5-amino-4-carboxylic acid ethyl ester oxazole, yield: 81% of a light yellow solid;

¹H NMR(400MHz,CDCl₃)δ7.96(d,J＝7.6Hz,1H),7.71(d,J＝7.8Hz,1H),7.51(s,1H),5.73(s,2H),4.33(q,J＝7.1Hz,2H),1.35(t,J＝7.1Hz,3H)；

compound D40 was 2- (2, 6-difluorophenyl) -5-amino-4-carboxylic acid ethyl ester oxazole, yield: 87% of light yellow solid;

¹H NMR(400MHz,CDCl₃)δ8.03(d,J＝2.0Hz,1H),7.75(dd,J＝8.4,2.0Hz,1H),7.47(d,J＝8.5Hz,1H),5.57(s,2H),4.39(q,J＝7.1Hz,2H),1.40(t,J＝7.1Hz,3H)；

compound D41 is 2- (2- (trifluoromethyl) phenyl) -5-amino-4-carboxylic acid ethyl ester oxazole, yield: 78%, light yellow solid;

¹H NMR(400MHz,CDCl₃)δ8.18(s,1H),8.09(d,J＝8.1Hz,1H),7.62(d,J＝7.8Hz,1H),7.52(t,J＝7.8Hz,1H),5.63(s,2H),4.39(q,J＝7.1Hz,2H),1.40(t,J＝7.1Hz,3H)；

compound D42 is 2- (3- (trifluoromethyl) phenyl) -5-amino-4-carboxylic acid ethyl ester oxazole, yield: 75% of light yellow solid;

¹H NMR(400MHz,CDCl₃)δ8.18(s,1H),8.10(d,J＝7.8Hz,1H),7.62(d,J＝7.8Hz,1H),7.52(t,J＝7.8Hz,1H),5.63(s,2H),4.39(q,J＝7.1Hz,2H),1.40(t,J＝7.1Hz,4H)；

compound D43 is 2- (4- (trifluoromethyl) phenyl) -5-amino-4-carboxylic acid ethyl ester oxazole, yield: 88% of light yellow solid;

¹H NMR(400MHz,CDCl₃)δ8.03(d,J＝8.1Hz,2H),7.65(d,J＝8.2Hz,2H),5.61(s,2H),4.40(q,J＝7.1Hz,2H),1.40(t,J＝7.1Hz,3H)；

compound D44 is 2- (3, 5-bis (trifluoromethyl) phenyl) -5-amino-4-carboxylic acid ethyl ester oxazole, yield: 81% of a light yellow solid;

¹H NMR(400MHz,CDCl₃)δ8.36(s,2H),7.85(s,1H),5.70(s,2H),4.41(q,J＝7.1Hz,2H),1.41(t,J＝7.1Hz,3H)；

compound D45 is 2- (2- (trifluoromethoxy) phenyl) -5-amino-4-carboxylic acid ethyl ester oxazole, yield: 79% of light yellow solid;

¹H NMR(400MHz,CDCl₃)δ8.08(dd,J＝7.9,1.7Hz,1H),7.44–7.37(m,1H),7.32(ddd,J＝9.7,5.1,1.3Hz,2H),5.60(s,2H),4.37(q,J＝7.1Hz,2H),1.38(t,J＝7.1Hz,3H)；

compound D46 is 2- (3- (trifluoromethoxy) phenyl) -5-amino-4-carboxylic acid ethyl ester oxazole, yield: 86% light yellow solid;

¹H NMR(400MHz,CDCl₃)δ7.87(d,J＝7.9Hz,1H),7.77(s,1H),7.43(t,J＝8.0Hz,1H),7.22(d,J＝0.8Hz,1H),5.58(s,2H),4.39(q,J＝7.1Hz,2H),1.40(t,J＝7.1Hz,3H)；

compound D47 is 2- (4- (trifluoromethoxy) phenyl) -5-amino-4-carboxylic acid ethyl ester oxazole, yield: 80% of light yellow solid;

¹H NMR(400MHz,DMSO)δ7.85(d,J＝8.8Hz,2H),7.48(s,1H),7.45(d,J＝8.5Hz,2H),4.18(q,J＝7.1Hz,2H),1.24(t,J＝7.1Hz,3H)；

compound D48 is 2- (4- (tert-butyl) phenyl) -5-amino-4-carboxylic acid ethyl ester oxazole, yield: 73% as a pale yellow solid;

¹H NMR(400MHz,CDCl₃)δ7.85(d,J＝8.6Hz,2H),7.41(d,J＝8.6Hz,2H),5.53(s,2H),4.38(q,J＝7.1Hz,2H),1.39(t,J＝7.1Hz,3H),1.31(s,9H)；

example 3

Preparation of compound E1:

dissolving 0.17g and 10mmol of compound D1 obtained in example 2, namely 2-methyl-5-amino-4-ethyl formate oxazole, in 20mL of anhydrous dioxane, adding 0.13g and 15mmol of pyrrolidone, then slowly adding 0.38g and 2.5mmol of phosphorus oxychloride dropwise, refluxing until all raw materials disappear, extracting with dichloromethane, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and performing gradient elution by forward silica gel column chromatography, wherein an eluent is pure ethyl acetate to obtain a compound E1, namely 2-methyl-6, 7-dihydrooxazolo [5,4-D ] pyrrolo [1,2-a ] pyrimidin-9 (5H) -one, and the yield is as follows: 73% of light yellow solid, mp 120-;

¹H NMR(400MHz,CDCl₃)δ4.24(t,J＝8.0Hz,2H),3.20(t,J＝8.0Hz,2H),2.58(s,3H),2.34(m,6H)。

example 4

Preparation of compound E2:

dissolving 0.18g and 10mmol of compound D2 obtained in example 2, namely 2-ethyl-5-amino-4-ethyl formate oxazole, in 20mL of anhydrous dioxane, adding 0.13g and 15mmol of pyrrolidone, then slowly adding 0.38g and 2.5mmol of phosphorus oxychloride dropwise, refluxing until all raw materials disappear, extracting with dichloromethane, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and performing gradient elution by forward silica gel column chromatography, wherein an eluent is ethyl acetate to obtain a compound E2, namely 2-ethyl-6, 7-dihydrooxazolo [5,4-D ] pyrrolo [1,2-a ] pyrimidin-9 (5H) -one, wherein the yield is as follows: 76% of light yellow solid, m p 128-;

¹H NMR(400MHz,CDCl₃)δ4.23(t,J＝8.1Hz,2H),3.19(t,J＝8.0Hz,2H),2.88(q,J＝7.6Hz,2H),2.37-2.29(m,2H),1.39(t,J＝7.6Hz,3H)。

example 5

Preparation of compound E3:

dissolving 0.20g and 10mmol of compound D3 obtained in example 2, namely 2-propyl-5-amino-4-ethyl formate oxazole, in 20mL of anhydrous dioxane, adding 0.13g and 15mmol of pyrrolidone, then slowly adding 0.38g and 2.5mmol of phosphorus oxychloride dropwise, refluxing until all raw materials disappear, extracting with dichloromethane, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and performing gradient elution by forward silica gel column chromatography, wherein an eluent is ethyl acetate to obtain compound E3, namely 2-propyl-6, 7-dihydrooxazolo [5,4-D ] pyrrolo [1,2-a ] pyrimidin-9 (5H) -one, wherein the yield is as follows: 80% of light yellow solid, m p 151-;

1H NMR(400MHz,CDCl3)δ4.25(t,J＝8.1Hz,2H),3.20(t,J＝8.0Hz,2H),2.84(t,J＝7.4Hz,2H),2.34(p,J＝7.8Hz,2H),1.91-1.82(m,2H),1.01(t,J＝7.4Hz,3H).

example 6

Preparation of compound E4:

dissolving 0.21g and 10mmol of compound D4 obtained in example 2, namely 2-butyl-5-amino-4-ethyl formate oxazole, in 20mL of anhydrous dioxane, adding 0.13g and 15mmol of pyrrolidone, then slowly adding 0.38g and 2.5mmol of phosphorus oxychloride dropwise, refluxing until all raw materials disappear, extracting with dichloromethane, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and performing gradient elution by forward silica gel column chromatography, wherein an eluent is ethyl acetate to obtain compound E4, namely 2-butyl-6, 7-dihydrooxazolo [5,4-D ] pyrrolo [1,2-a ] pyrimidin-9 (5H) -one, wherein the yield is as follows: 81% of light yellow solid, m p 167-;

¹H NMR(400MHz,CDCl₃)δ4.23(t,J＝8.0Hz,2H),3.19(t,J＝8.0Hz,2H),2.85(t,J＝7.5Hz,2H),2.37-2.29(m,2H),1.81(p,J＝7.5Hz,2H),1.45-1.36(m,2H),0.93(t,J＝7.4Hz,3H)。

example 7

Preparation of compound E5:

dissolving 0.32g and 10mmol of compound D5 obtained in example 2, namely 2-dodecyl-5-amino-4-ethyl formate oxazole, in 20mL of anhydrous dioxane, adding 0.13g and 15mmol of pyrrolidone, then slowly adding 0.38g and 2.5mmol of phosphorus oxychloride dropwise, refluxing until all raw materials disappear, extracting with dichloromethane, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and performing gradient elution by forward silica gel column chromatography, wherein an eluent is ethyl acetate to obtain a compound E5, namely 2-dodecyl-6, 7-dihydrooxazolo [5,4-D ] pyrrolo [1,2-a ] pyrimidin-9 (5H) -one, wherein the yield is as follows: 78% of light yellow solid, m p 104-;

¹H NMR(400MHz,CDCl₃)δ4.24(t,J＝8.0Hz,2H),3.20(t,J＝8.0Hz,2H),2.85(t,J＝7.6Hz,2H),2.38-2.30(m,2H),1.83(p,J＝7.6Hz,2H),1.48–1.17(m,18H),0.87(t,J＝6.9Hz,3H)。

example 8

Preparation of compound E6:

dissolving 0.19g and 10mmol of compound D6 obtained in example 2, namely 2- (2-propenyl) -5-amino-4-ethyl formate oxazole, in 20mL of anhydrous dioxane, adding 0.13g and 15mmol of pyrrolidone, then slowly adding 0.38g and 2.5mmol of phosphorus oxychloride dropwise, refluxing until all raw materials disappear, extracting with dichloromethane, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and performing gradient elution by forward silica gel column chromatography, wherein an eluent is ethyl acetate to obtain a compound E6, namely 2- (2-propenyl) -6, 7-dihydrooxazolo [5,4-D ] pyrrolo [1,2-a ] pyrimidin-9 (5H) -one, and the yield is as follows: 80% of light yellow solid, m p 159-161 ℃;

¹H NMR(400MHz,CDCl₃)δ6.13(s,1H),5.55(s,1H),4.37–4.21(m,2H),3.22(t,J＝8.0Hz,2H),2.35(p,J＝7.9Hz,2H),2.21(s,3H)。

example 9

Preparation of compound E7:

dissolving 0.21g and 10mmol of compound D7 obtained in example 2, namely 2-tert-butyl-5-amino-4-ethyl formate oxazole, in 20mL of anhydrous dioxane, adding 0.13g and 15mmol of pyrrolidone, then slowly adding 0.38g and 2.5mmol of phosphorus oxychloride dropwise, refluxing until all raw materials disappear, extracting with dichloromethane, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and performing gradient elution by forward silica gel column chromatography, wherein an eluent is ethyl acetate, to obtain a compound E7, namely 2-tert-butyl-6, 7-dihydrooxazolo [5,4-D ] pyrrolo [1,2-a ] pyrimidin-9 (5H) -one, wherein the yield is as follows: 75% of light yellow solid, m p 139-;

¹H NMR(400MHz,CDCl₃)δ4.25(t,J＝8.0Hz,2H),3.20(t,J＝8.0Hz,2H),2.38-2.30(m,2H),1.44(s,9H)。

example 10

Preparation of compound E8:

dissolving 0.29g and 10mmol of compound D8 obtained in example 2, namely 2-adamantyl-5-amino-4-ethyl formate oxazole, in 20mL of anhydrous dioxane, adding 0.13g and 15mmol of pyrrolidone, then slowly adding 0.38g and 2.5mmol of phosphorus oxychloride dropwise, refluxing until all raw materials disappear, extracting with dichloromethane, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and eluting with a forward silica gel column chromatography gradient, wherein the eluent is ethyl acetate to obtain compound E8, namely 2- ((3r,5r,7r) adamantyl-1-yl) -6, 7-dihydrooxazolo [5,4-D ] pyrrolo [1,2-a ] pyrimidin-9 (5H) -one, wherein the yield is as follows: 62% of light yellow solid, m p 153-;

¹H NMR(400MHz,CDCl₃)δ4.24(t,J＝8.0Hz,2H),3.19(t,J＝8.0Hz,2H),2.37-2.29(m,2H),2.09(s,9H),1.77(s,6H)。

example 11

Preparation of compound E9:

dissolving 0.25g and 10mmol of compound D9 obtained in example 2, namely 2-benzyl-5-amino-4-ethyl formate oxazole, in 20mL of anhydrous dioxane, adding 0.13g and 15mmol of pyrrolidone, then slowly adding 0.38g and 2.5mmol of phosphorus oxychloride dropwise, refluxing until all raw materials disappear, extracting with dichloromethane, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and performing gradient elution by forward silica gel column chromatography, wherein an eluent is ethyl acetate to obtain a compound E9, namely 2-benzyl-6, 7-dihydrooxazolo [5,4-D ] pyrrolo [1,2-a ] pyrimidin-9 (5H) -one, wherein the yield is as follows: 81% of light yellow solid, m p 219-;

¹H NMR(400MHz,CDCl₃)δ9.12–6.80(m,5H),4.23(t,J＝8.0Hz,2H),4.19(s,2H),3.18(t,J＝8.0Hz,2H),2.37-2.29(m,2H)。

example 12

Preparation of compound E10:

dissolving 0.26g and 10mmol of compound D10 obtained in example 2, namely 2-phenethyl-5-amino-4-ethyl formate oxazole, in 20mL of anhydrous dioxane, adding 0.13g and 15mmol of pyrrolidone, then slowly adding 0.38g and 2.5mmol of phosphorus oxychloride dropwise, refluxing until all raw materials disappear, extracting with dichloromethane, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and performing gradient elution by forward silica gel column chromatography, wherein an eluent is ethyl acetate to obtain a compound E10, namely 2-phenethyl-6, 7-dihydrooxazolo [5,4-D ] pyrrolo [1,2-a ] pyrimidin-9 (5H) -one, wherein the yield is as follows: 73 percent of light yellow solid, m p 207-209 ℃;

¹H NMR(400MHz,CDCl₃)δ7.86–6.52(m,5H),4.25(t,J＝8.0Hz,2H),3.22(t,J＝8.0Hz,2H),3.19(s,4H),2.38-2.31(m,2H)。

example 13

Preparation of compound E11:

dissolving 0.20g and 10mmol of compound D11 obtained in example 2, namely 2-cyclopropyl-5-amino-4-ethyl formate oxazole, in 20mL of anhydrous dioxane, adding 0.13g and 15mmol of pyrrolidone, then slowly adding 0.38g and 2.5mmol of phosphorus oxychloride dropwise, refluxing to react until all raw materials disappear, extracting with dichloromethane, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and performing gradient elution by forward silica gel column chromatography, wherein an eluent is ethyl acetate to obtain a compound E11, namely 2-cyclopropyl-6, 7-dihydrooxazolo [5,4-D ] pyrrolo [1,2-a ] pyrimidin-9 (5H) -one, and the yield is as follows: 74% of light yellow solid, m p 125-;

¹H NMR(400MHz,CDCl₃)δ4.22(t,J＝8.0Hz,2H),3.18(t,J＝8.0Hz,2H),2.36-2.29(m,2H),2.12(tt,J＝8.4,4.9Hz,1H),1.28-1.21(m,2H),1.16–1.09(m,2H)。

example 14

Preparation of compound E12:

dissolving 0.21g and 10mmol of compound D12 obtained in example 2, namely 2-cyclobutyl-5-amino-4-ethyl formate oxazole, in 20mL of anhydrous dioxane, adding 0.13g and 15mmol of pyrrolidone, then slowly adding 0.38g and 2.5mmol of phosphorus oxychloride dropwise, refluxing until all raw materials disappear, extracting with dichloromethane, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and performing gradient elution by forward silica gel column chromatography, wherein an eluent is ethyl acetate to obtain a compound E12, namely 2-cyclobutyl-6, 7-dihydrooxazolo [5,4-D ] pyrrolo [1,2-a ] pyrimidin-9 (5H) -one, wherein the yield is as follows: 76% of light yellow solid, m p 134-;

¹H NMR(400MHz,CDCl₃)δ4.25(t,J＝8.0Hz,2H),3.71(p,J＝8.5Hz,1H),3.20(t,J＝8.0Hz,2H),2.57-2.48(m,2H),2.46–2.29(m,4H),2.20–1.96(m,2H)。

example 15

Preparation of compound E13:

dissolving 0.22g and 10mmol of compound D13 obtained in example 2, namely 2-cyclopentyl-5-amino-4-ethyl formate oxazole, in 20mL of anhydrous dioxane, adding 0.13g and 15mmol of pyrrolidone, then slowly adding 0.38g and 2.5mmol of phosphorus oxychloride dropwise, refluxing until all raw materials disappear, extracting with dichloromethane, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and performing gradient elution by forward silica gel column chromatography, wherein an eluent is ethyl acetate to obtain a compound E13, namely 2-cyclopentyl-6, 7-dihydrooxazolo [5,4-D ] pyrrolo [1,2-a ] pyrimidin-9 (5H) -one, and the yield is as follows: 79% of light yellow solid, m p 162-164 ℃;

¹H NMR(400MHz,CDCl₃)δ4.31–4.19(t,J＝8.0Hz,2H),3.31(p,J＝8.1Hz,1H),3.20(t,J＝8.0Hz,2H),2.38-2.30(m,2H),2.16–2.07(m,2H),2.06-1.98(m,2H),1.91–1.76(m,2H),1.74–1.64(m,2H)。

example 16

Preparation of compound E14:

dissolving 0.24g and 10mmol of compound D14 obtained in example 2, namely 2-cyclohexyl-5-amino-4-ethyl formate oxazole, in 20mL of anhydrous dioxane, adding 0.13g and 15mmol of pyrrolidone, then slowly adding 0.38g and 2.5mmol of phosphorus oxychloride dropwise, refluxing until all raw materials disappear, extracting with dichloromethane, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and performing gradient elution by forward silica gel column chromatography, wherein an eluent is ethyl acetate to obtain a compound E14, namely 2-cyclohexyl-6, 7-dihydrooxazolo [5,4-D ] pyrrolo [1,2-a ] pyrimidin-9 (5H) -one, wherein the yield is as follows: 87% of light yellow solid, m p 192-194 ℃;

¹H NMR(400MHz,CDCl₃)δ4.24(t,J＝8.0Hz,2H),3.20(t,J＝8.0Hz,2H),2.89(tt,J＝11.3,3.7Hz,1H),2.47–2.28(m,2H),2.19–2.06(m,2H),1.87-1.81(m 2H),1.75–1.55(m,4H),1.49–1.21(m,4H)。

example 17

Preparation of compound E15:

dissolving 0.22g and 10mmol of compound D15 obtained in example 2, which is 2- (furan-2-yl) -5-amino-4-ethyl formate oxazole, in 20mL of anhydrous dioxane, adding 0.13g and 15mmol of pyrrolidone, then slowly adding 0.38g and 2.5mmol of phosphorus oxychloride dropwise, refluxing until all the raw materials disappear, extracting with dichloromethane, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and eluting with a forward silica gel column chromatography gradient, wherein the eluent is ethyl acetate, to obtain compound E15, which is 2- (furan-2-yl) -6, 7-dihydrooxazolo [5,4-D ] pyrrolo [1,2-a ] pyrimidin-9 (5H) -one, in yield: 76% of light yellow solid, m p 179-180 ℃;

¹H NMR(400MHz,CDCl₃)δ7.64(dd,J＝1.6,0.6Hz,1H),7.24(dd,J＝3.5,0.8Hz,1H),6.59(dd,J＝3.5,1.7Hz,1H),4.28(t,J＝8.0Hz,2H),3.25(t,J＝8.0Hz,2H),2.41-2.33(m,2H)。

example 18

Preparation of compound E16:

dissolving 0.24g and 10mmol of compound D16 obtained in example 2, namely 2- (thiophene-2-yl) -5-amino-4-ethyl formate oxazole, in 20mL of anhydrous dioxane, adding 0.13g and 15mmol of pyrrolidone, then slowly adding 0.38g and 2.5mmol of phosphorus oxychloride dropwise, refluxing until all raw materials disappear, extracting with dichloromethane, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and performing forward silica gel column chromatography gradient elution, wherein an eluent is ethyl acetate, so as to obtain compound E16, namely 2- (thiophene-2-yl) -6, 7-dihydrooxazolo [5,4-D ] pyrrolo [1,2-a ] pyrimidin-9 (5H) -one, and the yield is as follows: 79% of light yellow solid, m p 185-;

¹H NMR(400MHz,CDCl₃)δ7.85(dd,J＝3.7,1.2Hz,1H),7.53(dd,J＝5.0,1.2Hz,1H),7.16(dd,J＝5.0,3.8Hz,1H),4.29(t,J＝8.0Hz,2H),3.25(t,J＝8.0Hz,2H),2.41-2.34(m,2H)。

example 19

Preparation of compound E17:

dissolving 0.24g and 10mmol of compound D17 obtained in example 2, namely 2- (tetrahydro-2H-pyran-4-yl) -5-amino-4-carboxylic acid ethyl ester oxazole, in 20mL of anhydrous dioxane, adding 0.13g and 15mmol of pyrrolidone, then slowly adding 0.38g and 2.5mmol of phosphorus oxychloride dropwise, refluxing until all raw materials disappear, extracting with dichloromethane, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and performing forward silica gel column chromatography gradient elution by using ethyl acetate as an eluent to obtain a compound E17, namely 2- (tetrahydro-2H-pyran-4-yl) -6, 7-dihydrooxazolo [5,4-D ] pyrrolo [1,2-a ] pyrimidine-9 (5H) -one, wherein the yield is as follows: 68% of light yellow solid, m p 181-;

¹H NMR(400MHz,CDCl₃)δ4.24(t,J＝8.0Hz,2H),4.02(dt,J＝11.7,3.6Hz,2H),3.54(td,J＝11.6,3.1Hz,2H),3.20(t,J＝8.0Hz,2H),3.14(tt,J＝10.0,4.7Hz,1H),2.38-2.30(m,2H),2.12–1.97(m,4H)。

example 20

Preparation of compound E18:

dissolving 0.28g and 10mmol of compound D18 obtained in example 2, namely 2- (naphthalene-1-yl) -5-amino-4-ethyl formate oxazole, in 20mL of anhydrous dioxane, adding 0.13g and 15mmol of pyrrolidone, then slowly adding 0.38g and 2.5mmol of phosphorus oxychloride dropwise, refluxing until all raw materials disappear, extracting with dichloromethane, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and performing forward silica gel column chromatography gradient elution, wherein an eluent is ethyl acetate, so as to obtain compound E18, namely 2- (naphthalene-1-yl) -6, 7-dihydrooxazolo [5,4-D ] pyrrolo [1,2-a ] pyrimidin-9 (5H) -one, and the yield is as follows: 74% of light yellow solid, m p 261-;

¹H NMR(400MHz,CDCl₃)δ8.71(s,1H),8.27(dd,J＝8.6,1.7Hz,1H),8.03–7.93(m,2H),7.93–7.85(m,1H),7.71–7.50(m,2H),4.31(t,J＝8.0Hz,2H),3.28(t,J＝8.0Hz,2H),2.58–2.27(m,2H)。

example 21

Preparation of compound E19:

dissolving 0.28g and 10mmol of compound D19 obtained in example 2, namely 2- (naphthalene-2-yl) -5-amino-4-ethyl formate oxazole, in 20mL of anhydrous dioxane, adding 0.13g and 15mmol of pyrrolidone, then slowly adding 0.38g and 2.5mmol of phosphorus oxychloride dropwise, refluxing until all raw materials disappear, extracting with dichloromethane, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and performing forward silica gel column chromatography gradient elution, wherein an eluent is ethyl acetate, so as to obtain compound E19, namely 2- (naphthalene-2-yl) -6, 7-dihydrooxazolo [5,4-D ] pyrrolo [1,2-a ] pyrimidin-9 (5H) -one, and the yield is as follows: 82% of light yellow solid, m p 243-245 ℃;

¹H NMR(400MHz,CDCl₃)δ8.72(s,1H),8.27(dd,J＝8.7,1.7Hz,1H),7.96(d,J＝8.3Hz,2H),7.92–7.86(m,1H),7.66–7.50(m,2H),4.32(t,J＝8.0Hz,2H),3.28(t,J＝8.0Hz,2H),2.43-2.36(m,2H)。

example 22

Preparation of compound E20:

dissolving 0.31g and 10mmol of compound D20 obtained in example 2, namely 2- (1,1 '-biphenyl-4-yl) -5-amino-4-ethyl formate oxazole, in 20mL of anhydrous dioxane, adding 0.13g and 15mmol of pyrrolidone, then slowly adding 0.38g and 2.5mmol of phosphorus oxychloride dropwise, refluxing until all raw materials disappear, extracting with dichloromethane, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and performing forward silica gel column chromatography gradient elution by using ethyl acetate as an eluent to obtain a compound E20, namely 2- (1,1' -biphenyl-4-yl) -6, 7-dihydrooxazolo [5,4-D ] pyrrolo [1,2-a ] pyrimidin-9 (5H) -one, wherein the yield is as follows: 79% of light yellow solid, m p 219-;

¹H NMR(400MHz,CDCl₃)δ8.26(d,J＝8.5Hz,2H),7.76–7.71(m,2H),7.67–7.63(m,2H),7.50–7.45(m,2H),7.43–7.37(m,1H),4.30(t,J＝8.0Hz,2H),3.26(t,J＝8.0Hz,2H),2.42-2.34(m,2H)。

example 23

Preparation of compound E21:

dissolving 0.23g and 10mmol of compound D21 obtained in example 2, namely 2-phenyl-5-amino-4-ethyl formate oxazole, in 20mL of anhydrous dioxane, adding 0.13g and 15mmol of pyrrolidone, then slowly adding 0.38g and 2.5mmol of phosphorus oxychloride dropwise, refluxing until all raw materials disappear, extracting with dichloromethane, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and performing gradient elution by forward silica gel column chromatography, wherein an eluent is ethyl acetate to obtain a compound E21, namely 2-phenyl-6, 7-dihydrooxazolo [5,4-D ] pyrrolo [1,2-a ] pyrimidin-9 (5H) -one, wherein the yield is as follows: 77% of light yellow solid, m p 286-288 ℃;

¹H NMR(400MHz,CDCl₃)δ8.20(dd,J＝7.6,2.0Hz,2H).,7.70–7.40(m,3H),4.30(J＝8.1Hz,2H),3.26(t,J＝8.0Hz,2H),2.38(p,J＝7.8Hz,2H)。

example 24

Preparation of compound E22:

dissolving 0.25g and 10mmol of compound D22, which is 2- (2-methylphenyl) -5-amino-4-ethyl formate oxazole, in 20mL of anhydrous dioxane, adding 0.13g and 15mmol of pyrrolidone, slowly adding 0.38g and 2.5mmol of phosphorus oxychloride dropwise, refluxing until all the raw materials disappear, extracting with dichloromethane, drying over anhydrous sodium sulfate, concentrating under reduced pressure, and eluting with a forward silica gel column chromatography gradient, wherein the eluent is ethyl acetate, to obtain compound E22, which is 2- (2-methylphenyl) -6, 7-dihydrooxazolo [5,4-D ] pyrrolo [1,2-a ] pyrimidin-9 (5H) -one, in yield: 72% light yellow solid, m p 226-;

¹H NMR(400MHz,CDCl₃)δ8.14-8.12(m,1H),7.42-7.38(m,1H),7.34-7.30(m,2H),4.29(t,J＝8.1Hz,2H),3.26(t,J＝8.0Hz,2H),2.78(s,2H),2.42-2.34(m,2H)。

example 25

Preparation of compound E23:

dissolving 0.25g and 10mmol of compound D23 obtained in example 2, namely 2- (3-methylphenyl) -5-amino-4-ethyl formate oxazole, in 20mL of anhydrous dioxane, adding 0.13g and 15mmol of pyrrolidone, then slowly adding 0.38g and 2.5mmol of phosphorus oxychloride dropwise, refluxing until all raw materials disappear, extracting with dichloromethane, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and eluting with a forward silica gel column chromatography gradient, wherein an eluent is ethyl acetate to obtain a compound E23, namely 2- (3-methylphenyl) -6, 7-dihydrooxazolo [5,4-D ] pyrrolo [1,2-a ] pyrimidin-9 (5H) -one, and the yield is as follows: 79% of light yellow solid, m p 231-233 ℃;

¹H NMR(400MHz,CDCl₃)δ8.03(s,1H),7.96(d,J＝7.6Hz,1H),7.37(t,J＝7.6Hz,1H),7.32(d,J＝7.6Hz,1H),4.28(t,J＝8.1Hz,2H),3.24(t,J＝8.0Hz,2H),2.42(s,3H),2.39–2.29(m,2H)。

example 26

Preparation of compound E24:

dissolving 0.25g and 10mmol of compound D24 obtained in example 2, namely 2- (4-methylphenyl) -5-amino-4-ethyl formate oxazole, in 20mL of anhydrous dioxane, adding 0.13g and 15mmol of pyrrolidone, then slowly adding 0.38g and 2.5mmol of phosphorus oxychloride dropwise, refluxing until all raw materials disappear, extracting with dichloromethane, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and eluting with a forward silica gel column chromatography gradient, wherein an eluent is ethyl acetate to obtain a compound E24, namely 2- (4-methylphenyl) -6, 7-dihydrooxazolo [5,4-D ] pyrrolo [1,2-a ] pyrimidin-9 (5H) -one, and the yield is as follows: 82% of light yellow solid, m p 270-272 ℃;

¹H NMR(400MHz,CDCl₃)δ8.07(d,J＝8.3Hz,2H),7.30(d,J＝8.0Hz,2H),4.28(t,J＝8.1Hz,2H),3.24(t,J＝8.0Hz,2H),2.42(s,3H),2.42–2.28(m,2H)。

example 27

Preparation of compound E25:

dissolving 0.27g and 10mmol of compound D25 obtained in example 2, which is 2- (2-chlorophenyl) -5-amino-4-carboxylic acid ethyl ester oxazole, in 20mL of anhydrous dioxane, adding 0.13g and 15mmol of pyrrolidone, then slowly adding 0.38g and 2.5mmol of phosphorus oxychloride dropwise, refluxing until all the raw materials disappear, extracting with dichloromethane, drying over anhydrous sodium sulfate, concentrating under reduced pressure, eluting with a forward silica gel column chromatography gradient, and eluting with ethyl acetate to obtain compound E25, which is 2- (2-chlorophenyl) -6, 7-dihydrooxazolo [5,4-D ] pyrrolo [1,2-a ] pyrimidin-9 (5H) -one, in yield: 75% of light yellow solid, m p 228-;

¹H NMR(400MHz,CDCl₃)δ8.15(dd,J＝7.7,1.9Hz,1H),7.53(dd,J＝7.8,1.5Hz,1H),7.43(td,J＝7.7,1.9Hz,1H),7.39(td,J＝7.5,1.5Hz,1H),4.29(t,J＝8.1Hz,2H),3.26(t,J＝8.0Hz,2H),2.42-2.34(m,2H)。

example 28

Preparation of compound E26:

dissolving 0.27g and 10mmol of compound D26 obtained in example 2, which is 2- (3-chlorophenyl) -5-amino-4-carboxylic acid ethyl ester oxazole, in 20mL of anhydrous dioxane, adding 0.13g and 15mmol of pyrrolidone, then slowly adding 0.38g and 2.5mmol of phosphorus oxychloride dropwise, refluxing until all the raw materials disappear, extracting with dichloromethane, drying over anhydrous sodium sulfate, concentrating under reduced pressure, eluting with a forward silica gel column chromatography gradient, and eluting with ethyl acetate to obtain compound E26, which is 2- (3-chlorophenyl) -6, 7-dihydrooxazolo [5,4-D ] pyrrolo [1,2-a ] pyrimidin-9 (5H) -one, in yield: 73% of light yellow solid, m p 216-;

¹H NMR(400MHz,CDCl₃)δ8.18(s,1H),8.05(d,J＝7.6Hz,1H 1H),7.45(dt,J＝15.6,8.1Hz,2H),4.29(t,J＝8.1Hz,2H),3.26(t,J＝8.0Hz,2H),2.42-2.34(m,2H)。

example 29

Preparation of compound E27:

dissolving 0.27g and 10mmol of compound D27 obtained in example 2, which is 2- (4-chlorophenyl) -5-amino-4-carboxylic acid ethyl ester oxazole, in 20mL of anhydrous dioxane, adding 0.13g and 15mmol of pyrrolidone, then slowly adding 0.38g and 2.5mmol of phosphorus oxychloride dropwise, refluxing until all the raw materials disappear, extracting with dichloromethane, drying over anhydrous sodium sulfate, concentrating under reduced pressure, eluting with a forward silica gel column chromatography gradient, and eluting with ethyl acetate to obtain compound E27, which is 2- (4-chlorophenyl) -6, 7-dihydrooxazolo [5,4-D ] pyrrolo [1,2-a ] pyrimidin-9 (5H) -one, in yield: 79% of light yellow solid, m p 293-;

¹H NMR(400MHz,CDCl₃)δ8.11(d,J＝8.7Hz,2H),7.47(d,J＝8.7Hz,2H),4.29(t,J＝8.1Hz,2H),3.26(t,J＝8.0Hz,2H),2.42-2.34(m,2H)。

example 30

Preparation of compound E28:

dissolving 0.31g and 10mmol of compound D28 obtained in example 2, namely 2- (2-bromophenyl) -5-amino-4-ethyl formate oxazole, in 20mL of anhydrous dioxane, adding 0.13g and 15mmol of pyrrolidone, then slowly adding 0.38g and 2.5mmol of phosphorus oxychloride dropwise, refluxing until all raw materials disappear, extracting with dichloromethane, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and eluting with a forward silica gel column chromatography gradient, wherein an eluent is ethyl acetate to obtain a compound E28, namely 2- (2-bromophenyl) -6, 7-dihydrooxazolo [5,4-D ] pyrrolo [1,2-a ] pyrimidin-9 (5H) -one, and the yield is as follows: 76% of light yellow solid, m p 206-;

¹H NMR(400MHz,CDCl₃)δ8.08(dd,J＝7.8,1.7Hz,1H),7.72(dd,J＝8.0,1.1Hz,1H),7.43(td,J＝7.6,1.0Hz,1H),7.34(td,J＝7.7,1.7Hz,1H),4.28(t,J＝8.1Hz,2H),3.25(t,J＝8.0Hz,2H),2.41-2.33(m,2H)。

example 31

Preparation of compound E29:

dissolving 0.31g and 10mmol of compound D29 obtained in example 2, namely 2- (3-bromophenyl) -5-amino-4-ethyl formate oxazole, in 20mL of anhydrous dioxane, adding 0.13g and 15mmol of pyrrolidone, then slowly adding 0.38g and 2.5mmol of phosphorus oxychloride dropwise, refluxing until all raw materials disappear, extracting with dichloromethane, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and eluting with a forward silica gel column chromatography gradient, wherein an eluent is ethyl acetate to obtain a compound E29, namely 2- (3-bromophenyl) -6, 7-dihydrooxazolo [5,4-D ] pyrrolo [1,2-a ] pyrimidin-9 (5H) -one, and the yield is as follows: 80% of light yellow solid, m p 242-246 ℃;

¹H NMR(400MHz,CDCl₃)δ8.31(t,J＝1.7Hz,1H),8.07(d,J＝7.8Hz,1H),7.61(dd,J＝8.0,1.9,1H),7.35(t,J＝7.9Hz,1H),4.27(t,J＝8.0Hz,2H),3.24(t,J＝8.0Hz,2H),2.41-2.33(m,2H)。

example 32

Preparation of compound E30:

dissolving 0.31g and 10mmol of compound D30 obtained in example 2, namely 2- (4-bromophenyl) -5-amino-4-ethyl formate oxazole, in 20mL of anhydrous dioxane, adding 0.13g and 15mmol of pyrrolidone, then slowly adding 0.38g and 2.5mmol of phosphorus oxychloride dropwise, refluxing until all raw materials disappear, extracting with dichloromethane, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and eluting with a forward silica gel column chromatography gradient, wherein an eluent is ethyl acetate to obtain a compound E30, namely 2- (4-bromophenyl) -6, 7-dihydrooxazolo [5,4-D ] pyrrolo [1,2-a ] pyrimidin-9 (5H) -one, and the yield is as follows: 83% of light yellow solid, m p 294-296 ℃;

¹H NMR(400MHz,CDCl₃)δ8.04(d,J＝8.4Hz,2H),7.63(d,J＝8.4Hz,2H),4.29(t,J＝8.0Hz,2H),3.25(t,J＝8.0Hz,2H),2.42-2.34(m,2H)。

example 33

Preparation of compound E31:

dissolving 0.26g and 10mmol of compound D31 obtained in example 2, which is 2- (3, 5-xylyl) -5-amino-4-ethyl formate oxazole, in 20mL of anhydrous dioxane, adding 0.13g and 15mmol of pyrrolidone, then slowly adding 0.38g and 2.5mmol of phosphorus oxychloride dropwise, refluxing until all raw materials disappear, extracting with dichloromethane, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and performing gradient elution by forward silica gel column chromatography, wherein the eluent is ethyl acetate, to obtain compound E31, which is 2- (3, 5-xylyl) -6, 7-dihydrooxazolo [5,4-D ] pyrrolo [1,2-a ] pyrimidin-9 (5H) -one, in yield: 68% of light yellow solid, m p 260-;

¹H NMR(400MHz,CDCl₃)δ7.80(s,2H),7.12(s,1H),4.26(t,J＝8.1Hz,2H),3.22(t,J＝8.0Hz,2H),2.36(s,6H),2.39–2.27(m,2H)。

example 34

Preparation of compound E32:

dissolving 0.3g and 10mmol of compound D32 obtained in example 2, namely 2- (3, 4-dichlorophenyl) -5-amino-4-ethyl formate oxazole, in 20mL of anhydrous dioxane, adding 0.13g and 15mmol of pyrrolidone, then slowly adding 0.38g and 2.5mmol of phosphorus oxychloride dropwise, refluxing until all raw materials disappear, extracting with dichloromethane, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and performing forward silica gel column chromatography gradient elution, wherein an eluent is ethyl acetate, so as to obtain compound E32, namely 2- (3, 4-dichlorophenyl) -6, 7-dihydrooxazolo [5,4-D ] pyrrolo [1,2-a ] pyrimidine-9 (5H) -one, and the yield is as follows: 73% of light yellow solid, m p 253-;

¹H NMR(400MHz,CDCl₃)δ8.27(d,J＝2.0Hz,1H),7.99(dd,J＝8.4,2.0Hz,1H),7.57(d,J＝8.4Hz,1H),4.29(t,J＝8.1Hz,2H),3.26(t,J＝8.0Hz,2H),2.67–2.17(m,2H)。

example 35

Preparation of compound E33:

dissolving 0.3g and 10mmol of compound D33 obtained in example 2, namely 2- (3, 5-dichlorophenyl) -5-amino-4-ethyl formate oxazole, in 20mL of anhydrous dioxane, adding 0.13g and 15mmol of pyrrolidone, then slowly adding 0.38g and 2.5mmol of phosphorus oxychloride dropwise, refluxing until all raw materials disappear, extracting with dichloromethane, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and performing forward silica gel column chromatography gradient elution, wherein an eluent is ethyl acetate, so as to obtain compound E33, namely 2- (3, 5-dichlorophenyl) -6, 7-dihydrooxazolo [5,4-D ] pyrrolo [1,2-a ] pyrimidine-9 (5H) -one, wherein the yield is as follows: 86% of light yellow solid, m p 353-355 ℃;

¹H NMR(400MHz,CDCl₃)δ7.45–7.39(m,3H),4.28(t,J＝8.1Hz,2H),3.26(t,J＝8.0Hz,2H),2.42-2.33(m,2H)。

example 36

Preparation of compound E34:

dissolving 0.3g and 10mmol of compound D34 obtained in example 2, namely 2- (2, 6-dichlorophenyl) -5-amino-4-ethyl formate oxazole, in 20mL of anhydrous dioxane, adding 0.13g and 15mmol of pyrrolidone, then slowly adding 0.38g and 2.5mmol of phosphorus oxychloride dropwise, refluxing until all raw materials disappear, extracting with dichloromethane, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and performing forward silica gel column chromatography gradient elution, wherein an eluent is ethyl acetate, so as to obtain compound E34, namely 2- (2, 6-dichlorophenyl) -6, 7-dihydrooxazolo [5,4-D ] pyrrolo [1,2-a ] pyrimidine-9 (5H) -one, wherein the yield is as follows: 80% of light yellow solid, m p 208-210 ℃;

¹H NMR(400MHz,CDCl₃)δ8.08(d,J＝1.8Hz,2H),7.49(t,J＝1.8Hz,1H),4.30(t,J＝7.3Hz,2H),3.27(t,J＝8.0Hz,2H),2.43-2.35(m,2H)。

example 37

Preparation of compound E35:

dissolving 0.25g and 10mmol of compound D35 obtained in example 2, which is 2- (2-fluorophenyl) -5-amino-4-carboxylic acid ethyl ester oxazole, in 20mL of anhydrous dioxane, adding 0.13g and 15mmol of pyrrolidone, then slowly adding 0.38g and 2.5mmol of phosphorus oxychloride dropwise, refluxing until all the raw materials disappear, extracting with dichloromethane, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and eluting with a forward silica gel column chromatography gradient, wherein the eluent is ethyl acetate, to obtain compound E35, which is 2- (2-fluorophenyl) -6, 7-dihydrooxazolo [5,4-D ] pyrrolo [1,2-a ] pyrimidin-9 (5H) -one, with the yield: 70% of light yellow solid, m p 270-272 ℃;

¹H NMR(400MHz,CDCl₃)δ8.21(td,J＝7.6,1.8Hz,1H),7.62–7.45(m,1H),7.32–7.15(m,2H),4.30(t,J＝8.0Hz,2H),3.26(t,J＝8.0Hz,2H),2.42-2.36(m,2H)。

example 38

Preparation of compound E36:

dissolving 0.25g and 10mmol of compound D36 obtained in example 2, which is 2- (3-fluorophenyl) -5-amino-4-carboxylic acid ethyl ester oxazole, in 20mL of anhydrous dioxane, adding 0.13g and 15mmol of pyrrolidone, then slowly adding 0.38g and 2.5mmol of phosphorus oxychloride dropwise, refluxing until all the raw materials disappear, extracting with dichloromethane, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and eluting with a forward silica gel column chromatography gradient, wherein the eluent is ethyl acetate, to obtain compound E36, which is 2- (3-fluorophenyl) -6, 7-dihydrooxazolo [5,4-D ] pyrrolo [1,2-a ] pyrimidin-9 (5H) -one, with the yield: 75% of light yellow solid, m p 196-198 ℃;

¹H NMR(400MHz,CDCl₃)δ7.95(d,J＝7.8,1H),7.85(dt,J＝9.4,2.5,Hz,1H),7.46(td,J＝8.1,5.6Hz,1H),7.20(td,J＝8.4,2.6,Hz,1H),4.28(t,J＝8.0Hz,2H),3.25(t,J＝8.0Hz,2H),2.42-2.34(m,2H)。

example 39

Preparation of compound E37:

dissolving 0.25g and 10mmol of compound D37 obtained in example 2, which is 2- (4-fluorophenyl) -5-amino-4-carboxylic acid ethyl ester oxazole, in 20mL of anhydrous dioxane, adding 0.13g and 15mmol of pyrrolidone, then slowly adding 0.38g and 2.5mmol of phosphorus oxychloride dropwise, refluxing until all the raw materials disappear, extracting with dichloromethane, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and eluting with a forward silica gel column chromatography gradient, wherein the eluent is ethyl acetate, to obtain compound E37, which is 2- (4-fluorophenyl) -6, 7-dihydrooxazolo [5,4-D ] pyrrolo [1,2-a ] pyrimidin-9 (5H) -one, with the yield: 77% of light yellow solid, m p 245-247 ℃;

¹H NMR(400MHz,CDCl₃)δ8.18(dd,J＝8.6,5.3Hz,2H),7.18(t,J＝8.5Hz,2H),4.29(t,J＝8.0Hz,2H),3.25(t,J＝8.0Hz,2H),2.42-2.34(m,2H)。

example 40

Preparation of compound E38:

dissolving 0.27g and 10mmol of compound D38 obtained in example 2, which is 2- (3, 5-difluorophenyl) -5-amino-4-carboxylic acid ethyl ester oxazole, in 20mL of anhydrous dioxane, adding 0.13g and 15mmol of pyrrolidone, then slowly adding 0.38g and 2.5mmol of phosphorus oxychloride dropwise, refluxing until all the raw materials disappear, extracting with dichloromethane, drying over anhydrous sodium sulfate, concentrating under reduced pressure, eluting with a forward silica gel column chromatography gradient, and eluting with ethyl acetate to obtain compound E38, which is 2- (3, 5-difluorophenyl) -6, 7-dihydrooxazolo [5,4-D ] pyrrolo [1,2-a ] pyrimidin-9 (5H) -one, in yield: 71% of light yellow solid, m p 243-245 ℃;

¹H NMR(400MHz,CDCl₃)δ7.69(d,J＝7.3,2H),6.96(tt,J＝8.6,2.2Hz,1H),4.29(t,J＝6.4Hz,2H),3.26(t,J＝7.7Hz,2H),2.47–2.28(m,2H)。

EXAMPLE 41

Preparation of compound E39:

dissolving 0.27g and 10mmol of compound D39 obtained in example 2, namely 2- (3, 4-difluorophenyl) -5-amino-4-ethyl formate oxazole in 20mL of anhydrous dioxane, adding 0.13g and 15mmol of pyrrolidone, then slowly adding 0.38g and 2.5mmol of phosphorus oxychloride dropwise, refluxing until all raw materials disappear, extracting with dichloromethane, drying with anhydrous sodium sulfate, concentrating under reduced pressure, eluting by a forward silica gel column chromatography gradient, and eluting with ethyl acetate to obtain compound E39, namely 2- (3, 4-difluorophenyl) -6, 7-dihydrooxazolo [5,4-D ] pyrrolo [1,2-a ] pyrimidin-9 (5H) -one, wherein the yield is as follows: 74% of light yellow solid, m p 236-;

¹H NMR(400MHz,CDCl₃)δ8.01(ddd,J＝10.6,7.5,2.1Hz,1H),7.95(ddd,J＝7.9,3.7,1.8Hz,1H),7.40–7.28(m,1H),4.30(t,J＝8.0Hz,2H),3.26(t,J＝8.0Hz,2H),2.43-2.35(m,2H)。

example 42

Preparation of compound E40:

dissolving 0.27g and 10mmol of compound D40 obtained in example 2, which is 2- (2, 6-difluorophenyl) -5-amino-4-carboxylic acid ethyl ester oxazole, in 20mL of anhydrous dioxane, adding 0.13g and 15mmol of pyrrolidone, then slowly adding 0.38g and 2.5mmol of phosphorus oxychloride dropwise, refluxing until all the raw materials disappear, extracting with dichloromethane, drying over anhydrous sodium sulfate, concentrating under reduced pressure, eluting with a forward silica gel column chromatography gradient, and eluting with ethyl acetate to obtain compound E40, which is 2- (2, 6-difluorophenyl) -6, 7-dihydrooxazolo [5,4-D ] pyrrolo [1,2-a ] pyrimidin-9 (5H) -one, in a yield: 81% of light yellow solid, m p 221-223 ℃;

¹H NMR(400MHz,CDCl₃)δ7.48(tt,J＝8.4,6.1Hz,1H),7.06(t,J＝8.5Hz,2H),4.28(t,J＝8.1Hz,2H),3.26(t,J＝8.0Hz,2H),2.44-2.35(m,2H)。

example 43

Preparation of compound E41:

dissolving 0.3g and 10mmol of compound D41 obtained in example 2, namely 2- (2- (trifluoromethyl) phenyl) -5-amino-4-ethyl formate oxazole, in 20mL of anhydrous dioxane, adding 0.13g and 15mmol of pyrrolidone, then slowly adding 0.38g and 2.5mmol of phosphorus oxychloride dropwise, refluxing until all raw materials disappear, extracting with dichloromethane, drying with anhydrous sodium sulfate, concentrating under reduced pressure, eluting with a forward silica gel column chromatography gradient, and obtaining a compound E41, namely 2- (2- (trifluoromethyl) phenyl) -6, 7-dihydrooxazolo [5,4-D ] pyrrolo [1,2-a ] pyrimidin-9 (5H) -one, wherein the eluent is ethyl acetate: 65% of light yellow solid, m p 169-171 ℃;

¹H NMR(400MHz,CDCl₃)δ8.19(d,J＝7.1Hz,1H),7.88–7.79(m,1H),7.75–7.61(m,2H),4.15(t,J＝6.1Hz,2H),3.08(t,J＝6.7Hz,2H),2.22–1.90(m,2H)。

example 44

Preparation of compound E42:

dissolving 0.3g and 10mmol of compound D42 obtained in example 2, namely 2- (3- (trifluoromethyl) phenyl) -5-amino-4-ethyl formate oxazole, in 20mL of anhydrous dioxane, adding 0.13g and 15mmol of pyrrolidone, then slowly adding 0.38g and 2.5mmol of phosphorus oxychloride dropwise, refluxing until all raw materials disappear, extracting with dichloromethane, drying with anhydrous sodium sulfate, concentrating under reduced pressure, eluting with a forward silica gel column chromatography gradient, and obtaining a compound E42, namely 2- (3- (trifluoromethyl) phenyl) -6, 7-dihydrooxazolo [5,4-D ] pyrrolo [1,2-a ] pyrimidin-9 (5H) -one, wherein the eluent is ethyl acetate: 69% of light yellow solid, m p 211-213 ℃;

¹H NMR(400MHz,CDCl₃)δ8.48(s,1H),8.36(d,J＝7.9Hz,1H),7.77(d,J＝7.8Hz,1H),7.64(t,J＝7.8Hz,1H),4.31(t,J＝8.0Hz,2H),3.27(t,J＝8.0Hz,2H),2.43-2.36(m,2H)。

example 45

Preparation of compound E43:

dissolving 0.3g and 10mmol of compound D43 obtained in example 2, namely 2- (4- (trifluoromethyl) phenyl) -5-amino-4-ethyl formate oxazole, in 20mL of anhydrous dioxane, adding 0.13g and 15mmol of pyrrolidone, then slowly adding 0.38g and 2.5mmol of phosphorus oxychloride dropwise, refluxing until all raw materials disappear, extracting with dichloromethane, drying with anhydrous sodium sulfate, concentrating under reduced pressure, eluting with a forward silica gel column chromatography gradient, and obtaining a compound E43, namely 2- (4- (trifluoromethyl) phenyl) -6, 7-dihydrooxazolo [5,4-D ] pyrrolo [1,2-a ] pyrimidin-9 (5H) -one, wherein the eluent is ethyl acetate: 74% of light yellow solid, m p 264-266 ℃;

¹H NMR(400MHz,CDCl₃)δ8.30(d,J＝8.6Hz,2H),7.76(d,J＝8.5Hz,2H),4.30(t,J＝8.0Hz,2H),3.27(t,J＝8.0Hz,2H),2.43-2.36(m,2H)。

example 46

Preparation of compound E44:

dissolving 0.37g and 10mmol of compound D44 obtained in example 2, which is 2- (3, 5-bis (trifluoromethyl) phenyl) -5-amino-4-carboxylic acid ethyl ester oxazole, in 20mL of anhydrous dioxane, adding 0.13g and 15mmol of pyrrolidone, then slowly adding 0.38g and 2.5mmol of phosphorus oxychloride dropwise, refluxing until all the raw materials disappear, extracting with dichloromethane, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and eluting with forward silica gel column chromatography gradient, wherein the eluent is ethyl acetate, to obtain compound E44, which is 2- (3, 5-bis (trifluoromethyl) phenyl) -6, 7-dihydrooxazolo [5,4-D ] pyrrolo [1,2-a ] pyrimidin-9 (5H) -one, in the following yield: 61% of light yellow solid, m p 236-238 ℃;

¹H NMR(400MHz,CDCl₃)δ8.64(s,2H),7.99(s,1H),4.31(t,J＝8.0Hz,2H),3.29(t,J＝8.0Hz,2H),2.44-2.37(m,2H)。

example 47

Preparation of compound E45:

dissolving 0.32g and 10mmol of compound D45 obtained in example 2, namely 2- (2- (trifluoromethoxy) phenyl) -5-amino-4-ethyl formate oxazole, in 20mL of anhydrous dioxane, adding 0.13g and 15mmol of pyrrolidone, then slowly adding 0.38g and 2.5mmol of phosphorus oxychloride dropwise, refluxing until all raw materials disappear, extracting with dichloromethane, drying with anhydrous sodium sulfate, concentrating under reduced pressure, eluting with a forward silica gel column chromatography gradient, and obtaining a compound E45, namely 2- (2- (trifluoromethoxy) phenyl) -6, 7-dihydrooxazolo [5,4-D ] pyrrolo [1,2-a ] pyrimidin-9 (5H) -one, wherein the eluent is ethyl acetate: 75% of light yellow solid, m p 187-189 ℃;

¹H NMR(400MHz,CDCl₃)δ8.32(dd,J＝7.9,1.4Hz,1H),7.56(td,J＝8.2,1.7Hz,1H),7.48-7.39(q,J＝7.9Hz,2H),4.29(t,J＝8.1Hz,2H),3.27(t,J＝8.0Hz,2H),2.42-2.34(m,2H)。

example 48

Preparation of compound E46:

dissolving 0.32g and 10mmol of compound D46 obtained in example 2, namely 2- (3- (trifluoromethoxy) phenyl) -5-amino-4-ethyl formate oxazole, in 20mL of anhydrous dioxane, adding 0.13g and 15mmol of pyrrolidone, then slowly adding 0.38g and 2.5mmol of phosphorus oxychloride dropwise, refluxing until all raw materials disappear, extracting with dichloromethane, drying with anhydrous sodium sulfate, concentrating under reduced pressure, eluting with a forward silica gel column chromatography gradient, and obtaining a compound E46, namely 2- (3- (trifluoromethoxy) phenyl) -6, 7-dihydrooxazolo [5,4-D ] pyrrolo [1,2-a ] pyrimidin-9 (5H) -one, wherein the eluent is ethyl acetate: 78% of light yellow solid, m p 196-198 ℃;

¹H NMR(400MHz,CDCl₃)δ8.12(d,J＝8.0Hz,1H),8.05(s,1H),7.54(t,J＝8.0Hz,1H),7.37(dd,J＝8.9,1.6Hz,1H),4.30(t,J＝8.0Hz,2H),3.27(t,J＝8.0Hz,2H),2.43-2.35(m,2H)

example 49

Preparation of compound E47:

dissolving 0.32g and 10mmol of compound D47 obtained in example 2, namely 2- (4- (trifluoromethoxy) phenyl) -5-amino-4-ethyl formate oxazole, in 20mL of anhydrous dioxane, adding 0.13g and 15mmol of pyrrolidone, then slowly adding 0.38g and 2.5mmol of phosphorus oxychloride dropwise, refluxing until all raw materials disappear, extracting with dichloromethane, drying with anhydrous sodium sulfate, concentrating under reduced pressure, eluting with a forward silica gel column chromatography gradient, and obtaining a compound E47, namely 2- (4- (trifluoromethoxy) phenyl) -6, 7-dihydrooxazolo [5,4-D ] pyrrolo [1,2-a ] pyrimidin-9 (5H) -one, wherein the eluent is ethyl acetate: 83% of light yellow solid, m p 258-;

¹H NMR(400MHz,CDCl₃)δ8.23(d,J＝8.9Hz,2H),7.34(d,J＝8.9Hz,2H),4.30(t,J＝8.0Hz,2H),3.26(t,J＝8.0Hz,2H),2.43-2.36(m,2H)。

example 50

Preparation of compound E48:

dissolving 0.29g and 10mmol of compound D48 obtained in example 2, namely 2- (4- (tert-butyl) phenyl) -5-amino-4-ethyl formate oxazole, in 20mL of anhydrous dioxane, adding 0.13g and 15mmol of pyrrolidone, then slowly adding 0.38g and 2.5mmol of phosphorus oxychloride dropwise, refluxing until all raw materials disappear, extracting with dichloromethane, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and eluting with a forward silica gel column chromatography gradient, wherein an eluent is ethyl acetate, so that compound E48, namely 2- (4- (tert-butyl) phenyl) -6, 7-dihydrooxazolo [5,4-D ] pyrrolo [1,2-a ] pyrimidin-9 (5H) -one, is obtained, wherein the yield is as follows: 86% of light yellow solid, m p 263-265 ℃;

¹H NMR(400MHz,CDCl₃)δ8.11(d,J＝8.7Hz,2H),7.51(d,J＝8.7Hz,2H),4.28(t,J＝8.1Hz,2H),3.24(t,J＝8.0Hz,2H),2.65–2.24(m,2H),1.34(s,9H)。

example 51

The screening of the anti-tumor activity of the dihydro-oxazolo [5,4-d ] pyrrolo [1,2-a ] pyrimidine-9 (5H) -ketone comprises the following steps:

cell survival rate by thiazole blue method:

the experimental process comprises the following steps:

sucking the cells growing in the logarithmic growth phase, removing the culture medium, washing once with phosphate buffer solution, digesting with pancreatin, adding the culture medium, stopping, gently blowing, counting, inoculating in a 96-well plate (100 mu l/well) at a corresponding cell density, culturing overnight, adding compounds (20 mu l/well), setting a concentration gradient for each compound, setting 3 wells for each concentration, culturing for 48 hours in an incubator at 37 ℃, removing the old culture medium, adding 100 mu l of thiazole blue, continuing to culture for 2 hours, incubating at 37 ℃ for 2 hours, and measuring the light absorption value (OD) at 570nm by using an MB microplate reader;

calculating the formula:

percent cell viability ═ 100% of (compound OD-blank OD/control OD-blank OD);

cytostatic rate ═ 1 ═ cell viability ═ 1- (compound OD-blank OD/control OD-blank OD)]X 100%, fitting with graphpad to obtain IC₅₀；

Sample treatment: dissolving a sample by using thionyl chloride, storing at low temperature, and controlling the concentration of the thionyl chloride in a final system within a range not influencing the detection activity;

data processing and results description: the activity of the sample is tested by initially selecting a single concentration condition, such as 50 μ M monomeric compound concentration and 50 μ g/μ L extract, and the inhibition rate% is more than 50%, and further testing the dose dependence of the activity, i.e. IC₅₀Values, obtained by nonlinear fitting of sample concentrations to sample activities, were calculated as Graphpad Prism 4, and in general, each sample was set with duplicate wells (n.gtoreq.3) in the test, and are expressed in the results as Standard Deviation (SD) in Table 1:

TABLE 1 results of antitumor biological Activity of derivatives of E1-E48

As can be seen from the table: the results of 48 compounds in the dihydro-oxazolo [5,4-d ] pyrrolo [1,2-a ] pyrimidine-9 (5H) -ketone derivatives in the invention on the inhibition effect of Hela human cervical carcinoma cells, MCF-7 breast cancer cells and A549 lung cancer cells show that: compounds E5, E10, E13, E16, E18, E19, E24, E42 and E43 have inhibitory activity on Hela cervical cancer cells; compounds E22, E24, E47 and E48 have inhibitory activity against MCF-7 breast cancer cells; compounds E18 and E20 had inhibitory activity against a549 lung cancer cells.

Claims

1. A dihydro-oxazolo [5,4-d ] pyrrolo [1,2-a ] pyrimidin-9 (5H) -one derivative is characterized in that the structural formula of the derivative is as follows:

wherein:

2. Use of E5, E10, E13, E16, E18, E19, E24, E42, E43 in dihydro-oxazolo [5,4-d ] pyrrolo [1,2-a ] pyrimidin-9 (5H) -one compounds according to claim 1 in the preparation of a medicament for the treatment of Hela cervical cancer.

3. Use of E22, E24, E47 and E48 in dihydro-oxazolo [5,4-d ] pyrrolo [1,2-a ] pyrimidin-9 (5H) -one compounds according to claim 1 in preparation of medicaments for treating MCF-7 breast cancer.

4. Use of E18, E20 in dihydro-oxazolo [5,4-d ] pyrrolo [1,2-a ] pyrimidin-9 (5H) -one compounds according to claim 1 in the preparation of a medicament for the treatment of a549 lung cancer.