CN112851692B - Oxazolo [5,4-d ] pyrido [1,2-a ] pyrimidone derivative and application thereof - Google Patents

Oxazolo [5,4-d ] pyrido [1,2-a ] pyrimidone derivative and application thereof Download PDF

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CN112851692B
CN112851692B CN202110091670.9A CN202110091670A CN112851692B CN 112851692 B CN112851692 B CN 112851692B CN 202110091670 A CN202110091670 A CN 202110091670A CN 112851692 B CN112851692 B CN 112851692B
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阿吉艾克拜尔·艾萨
曾艳
聂礼飞
胡尔西地·博扎罗夫
赵江瑜
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Xinjiang Technical Institute of Physics and Chemistry of CAS
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Abstract

The invention relates to an oxazolo [5,4-d]Pyrido [1,2-a]Pyrimidinone derivativesUsing ethyl cyanoacetate as raw material, under the action of sodium nitrite and phosphoric acid producing hydroxylamine compound (A), using sodium hydrosulfite to make reduction to obtain 2-amino ethyl cyanoacetate (B), under the condition of alkali making them respectively react with different substituted acyl chloride to produce different substituted 5-amino-4-formic ester oxazole compound (D1-D48) under the action of trifluoroacetic acid, then under the action of phosphorus oxychloride making it react with valerolactam to obtain oxazolo [5,4-d]Pyrido [1,2-a]Pyrimidinone 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: 11 compounds have inhibitory activity on Hela cervical carcinoma cells; 8 compounds have inhibitory activity on MCF-7 breast cancer cells; 5 compounds have inhibitory activity against A549 lung cancer cells. Wherein E32, E33, E45, E46 and E47 have inhibitory activity on three tumor cells; e29 and E42 have inhibitory activity on Hela cervical cancer cells and MCF-7 breast cancer cells.

Description

Oxazolo [5,4-d ] pyrido [1,2-a ] pyrimidone derivative and application thereof
Technical Field
The invention relates to an oxazolo [5,4-d ] pyrido [1,2-a ] pyrimidone derivative and application thereof, wherein the compounds are shown by cell activity screening results as follows: 11 compounds have inhibitory activity on Hela cervical carcinoma cells; 8 compounds have inhibitory activity on MCF-7 breast cancer cells; 5 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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[2] Phyllanthus urinaria, attempts to address the development situation of anticancer drugs [ J ]. strait pharmacology, 1995,3(7):63-64.
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[4]2Bai,Z.S.；Wang,D.X.Heterocyclic Compounds Genetic Engineering and Pesticides in21 Century.Pesticides 1998,37(6),2-6.
[5]Feng,K.S.；Chen,R.Y.；et al.Synthesis and Structure of3,4-Dipheny-3-diazaphos-pholidin-2-thione-4-oxides Sulfides.Chem.J.Chin,Univ.1993,14(9),1244-1249.
[6]Zhang,C X.；Zhan,Z.B.；et al Synthesis of Cyclic Glycerophospho-lipid Conjugates of Adenosine.Chem.J.Chin.Univ.199,19(6),913-916.
[7]Zhou,J；et al.Synthesis and Herbicidal Activity of l-Aryl-2-phenyl-3-methyl-3-isopropyl-1,4,2-diazaphosp-holidin-5-one-2-oxides.Chem,J.Chin,Univ,1999,20(7),1058-1062.
[8]Zhang,H.Z,Zhao,Z.L,Zhou,C.H.Recent advance in oxazolebased medicinal chemistry,[J].Eur J Med Chem，2018,144:444-492.
[9]Zhang,H.Z，Gan,L.L,Wang,H.et al.New progress in azole compounds as antimicrobial agents,[J].Mini-Rev Med Chem,2017,17(2)：122-166.
[10]Mayer,J.C.P.；Sauer,A.C.；Iglesias,B.A.；et al.Ferrocenylethenyl substituted 1,3,4-oxadiaz-olyl-1,2,4-oxadiazoles:Synthesis,characterization and DNA-binding assays[J].J Organomet Chem,2017,841:1-11.
[11]Revuelta,J,Machetti,F,Cicchi,S.Modern Heterocyclic Chemistry.Berlin:Wiley,2011.
[12]Hanusek,J.Study of formation and transformation of some five-and six-membered heterocyclic compounds containing nitrogen and sulfur.Chem Listy,2008,102(9):801-810.
[13]Abele,E.；Abele,R.；Lukevics,E.Chemistry of Heterocyclic Compounds.New York:Springer,2007.
[14] The synthesis research progress of five-membered heterocyclic compound, chemical technology and development, 2008,37(3):22-35.
[15]Kashyap,S.J.；Garg,V.K.；Sharma,P.K.；Kumar,N.；Dudhe,R.；Gupta,J.K.Thiazoles:Having diverse biological activities.Med Chem Res,2012,DOI10.1007/s00044-011-9685-2.
[16]Galm,U.；Wang,L.；Huang,S.X.；Unsin,C.；Comparative analysis of the biosynthetic gene clusters and pathways for three structurally related antitumor antibiotics:Bleomycin,tallysomycin,and zorbamycin.J Nat Prod,2011,74(3):526-536.
[17]Moghadam,M.S.；Maleki,S.；Darabpour,E.；Motamedi,H.；Antibacterial activity of eight Iranian plant extracts against methicillin and cefixime restistant staphylococcous aureus strains.Asian Pac J Trop Med,2010,3(4):262-265.
[18]Teoh,D.；Ayeni,T.A.；Rubatt,J.M.；Adams,D.J.；Grace,L.；Dasatinib has synergistic activity with paclitaxel and carboplatin in ovarian cancer cells.Gynecol Oncol,2011,121(1):187-192.
[19] Zhao Na, Zhang Xichen, Niuzonide clinical application research progress, Chinese journal of etiology and biology, 2010,5(2):146-152.
[20]Ah,Y.C.；Choi,J.K.；Choi,Y.K.；Ki,H.M.；Bae,J.H.；A novel transdermal patch incorporating meloxicam:In vitro and in vivo characterization.Int J Pharm,2010,385(2):12-19.
On the basis of comprehensive analysis of relevant patents and documents at home and abroad, the invention carries out total synthesis on oxazolo [5,4-d ] pyrido [1,2-a ] pyrimidone compounds, carries out systematic modification and modification, introduces phenyl, aliphatic group and heterocyclic ring containing different substituents into oxazolo [5,4-d ] pyrido [1,2-a ] pyrimidone compound molecules so as to improve the drug-forming property of the oxazolo [5,4-d ] pyrido [1,2-a ] pyrimidone compounds, researches the inhibitory activity of the compounds on Hela cervical carcinoma cells, MCF-7 breast cancer cells and A549 lung cancer cells, and finds candidate drugs with significant curative effect and definite target anti-tumor activity. The activity screening result shows that: 11 compounds have inhibitory activity on Hela cervical carcinoma cells; 8 compounds have inhibitory activity on MCF-7 breast cancer cells; 5 compounds have inhibitory activity against A549 lung cancer cells.
Disclosure of Invention
The invention aims to provide an oxazolo [5,4-D ] pyrido [1,2-a ] pyrimidone derivative and application thereof, wherein ethyl cyanoacetate is used as an initial raw material, a hydroxylamine compound (A) is generated under the action of sodium nitrite and phosphoric acid, sodium hydrosulfite is used for reduction to obtain 2-amino ethyl cyanoacetate (B), the 2-amino ethyl cyanoacetate (B) is respectively reacted with acyl chlorides with different substitutions under the alkali condition, oxazole compounds (D1-D48) with different substitutions are generated through cyclization under the action of trifluoroacetic acid, and then the oxazole compounds (E1-E48) are generated through cyclization with valerolactam under the action of phosphorus oxychloride. 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: 11 compounds have inhibitory activity on Hela cervical carcinoma cells; 8 compounds have inhibitory activity on MCF-7 breast cancer cells; 5 compounds have inhibitory activity against A549 lung cancer cells. Wherein E32, E33, E45, E46 and E47 have inhibitory activity on three tumor cells; e29 and E42 have inhibitory activity on Hela cervical cancer cells and MCF-7 breast cancer cells.
The invention relates to an oxazolo [5,4-d ] pyrido [1,2-a ] pyrimidone derivative, which has the following structure:
Figure BDA0002912820420000041
Figure BDA0002912820420000051
wherein:
compound E1 is 2-methyl-5, 6,7, 8-tetrahydro-10H-oxazolo [5,4-d ] pyrido [1,2-a ] pyrimidin-10-one;
compound E2 is 2-ethyl-5, 6,7, 8-tetrahydro-10H-oxazolo [5,4-d ] pyrido [1,2-a ] pyrimidin-10-one;
compound E3 is 2-propyl-5, 6,7, 8-tetrahydro-10H-oxazolo [5,4-d ] pyrido [1,2-a ] pyrimidin-10-one;
compound E4 is 2-butyl-5, 6,7, 8-tetrahydro-10H-oxazolo [5,4-d ] pyrido [1,2-a ] pyrimidin-10-one;
compound E5 is 2-dodecyl-5, 6,7, 8-tetrahydro-10H-oxazolo [5,4-d ] pyrido [1,2-a ] pyrimidin-10-one;
compound E6 is 2- (2-propenyl) -5,6,7, 8-tetrahydro-10H-oxazolo [5,4-d ] pyrido [1,2-a ] pyrimidin-10-one;
compound E7 is 2-tert-butyl-5, 6,7, 8-tetrahydro-10H-oxazolo [5,4-d ] pyrido [1,2-a ] pyrimidin-10-one;
compound E8 is 2-adamantyl-5, 6,7, 8-tetrahydro-10H-oxazolo [5,4-d ] pyrido [1,2-a ] pyrimidin-10-one;
compound E9 is 2-benzyl-5, 6,7, 8-tetrahydro-10H-oxazolo [5,4-d ] pyrido [1,2-a ] pyrimidin-10-one;
compound E10 is 2-phenethyl-5, 6,7, 8-tetrahydro-10H-oxazolo [5,4-d ] pyrido [1,2-a ] pyrimidin-10-one;
compound E11 is 2-cyclopropyl-5, 6,7, 8-tetrahydro-10H-oxazolo [5,4-d ] pyrido [1,2-a ] pyrimidin-10-one;
compound E12 is 2-cyclobutyl-5, 6,7, 8-tetrahydro-10H-oxazolo [5,4-d ] pyrido [1,2-a ] pyrimidin-10-one;
compound E13 is 2-cyclopentyl-5, 6,7, 8-tetrahydro-10H-oxazolo [5,4-d ] pyrido [1,2-a ] pyrimidin-10-one;
compound E14 is 2-cyclohexyl-5, 6,7, 8-tetrahydro-10H-oxazolo [5,4-d ] pyrido [1,2-a ] pyrimidin-10-one;
compound E15 is 2- (furan-2-yl) -5,6,7, 8-tetrahydro-10H-oxazolo [5,4-d ] pyrido [1,2-a ] pyrimidin-10-one;
compound E16 is 2- (thiophen-2-yl) -5,6,7, 8-tetrahydro-10H-oxazolo [5,4-d ] pyrido [1,2-a ] pyrimidin-10-one;
compound E17 is 2- (tetrahydro-2H-pyran-4-yl) -5,6,7, 8-tetrahydro-10H-oxazolo [5,4-d ] pyrido [1,2-a ] pyrimidin-10-one;
compound E18 is 2- (naphthalen-1-yl) -5,6,7, 8-tetrahydro-10H-oxazolo [5,4-d ] pyrido [1,2-a ] pyrimidin-10-one;
compound E19 is 2- (naphthalen-2-yl) -5,6,7, 8-tetrahydro-10H-oxazolo [5,4-d ] pyrido [1,2-a ] pyrimidin-10-one;
compound E20 is 2- (1,1' -biphenyl-4-yl) -5,6,7, 8-tetrahydro-10H-oxazolo [5,4-d ] pyrido [1,2-a ] pyrimidin-10-one;
compound E21 is 2-phenyl-5, 6,7, 8-tetrahydro-10H-oxazolo [5,4-d ] pyrido [1,2-a ] pyrimidin-10-one;
compound E22 is 2- (2-methylphenyl) -5,6,7, 8-tetrahydro-10H-oxazolo [5,4-d ] pyrido [1,2-a ] pyrimidin-10-one;
compound E23 is 2- (3-methylphenyl) -5,6,7, 8-tetrahydro-10H-oxazolo [5,4-d ] pyrido [1,2-a ] pyrimidin-10-one;
compound E24 is 2- (4-methylphenyl) -5,6,7, 8-tetrahydro-10H-oxazolo [5,4-d ] pyrido [1,2-a ] pyrimidin-10-one;
compound E25 is 2- (2-chlorophenyl) -5,6,7, 8-tetrahydro-10H-oxazolo [5,4-d ] pyrido [1,2-a ] pyrimidin-10-one;
compound E26 is 2- (3-chlorophenyl) -5,6,7, 8-tetrahydro-10H-oxazolo [5,4-d ] pyrido [1,2-a ] pyrimidin-10-one;
compound E27 is 2- (4-chlorophenyl) -5,6,7, 8-tetrahydro-10H-oxazolo [5,4-d ] pyrido [1,2-a ] pyrimidin-10-one;
compound E28 is 2- (2-bromophenyl) -5,6,7, 8-tetrahydro-10H-oxazolo [5,4-d ] pyrido [1,2-a ] pyrimidin-10-one
Compound E29 is 2- (3-bromophenyl) -5,6,7, 8-tetrahydro-10H-oxazolo [5,4-d ] pyrido [1,2-a ] pyrimidin-10-one
Compound E30 is 2- (4-bromophenyl) -5,6,7, 8-tetrahydro-10H-oxazolo [5,4-d ] pyrido [1,2-a ] pyrimidin-10-one;
compound E31 is 2- (3, 5-xylyl) -5,6,7, 8-tetrahydro-10H-oxazolo [5,4-d ] pyrido [1,2-a ] pyrimidin-10-one;
compound E32 is 2- (3, 4-dichlorophenyl) -5,6,7, 8-tetrahydro-10H-oxazolo [5,4-d ] pyrido [1,2-a ] pyrimidin-10-one;
compound E33 is 2- (3, 5-dichlorophenyl) -5,6,7, 8-tetrahydro-10H-oxazolo [5,4-d ] pyrido [1,2-a ] pyrimidin-10-one;
compound E34 is 2- (2, 6-dichlorophenyl) -5,6,7, 8-tetrahydro-10H-oxazolo [5,4-d ] pyrido [1,2-a ] pyrimidin-10-one;
compound E35 is 2- (2-fluorophenyl) -5,6,7, 8-tetrahydro-10H-oxazolo [5,4-d ] pyrido [1,2-a ] pyrimidin-10-one;
compound E36 is 2- (3-fluorophenyl) -5,6,7, 8-tetrahydro-10H-oxazolo [5,4-d ] pyrido [1,2-a ] pyrimidin-10-one;
compound E37 is 2- (4-fluorophenyl) -5,6,7, 8-tetrahydro-10H-oxazolo [5,4-d ] pyrido [1,2-a ] pyrimidin-10-one;
compound E38 is 2- (3, 5-difluorophenyl) -5,6,7, 8-tetrahydro-10H-oxazolo [5,4-d ] pyrido [1,2-a ] pyrimidin-10-one;
compound E39 is 2- (3, 4-difluorophenyl) -5,6,7, 8-tetrahydro-10H-oxazolo [5,4-d ] pyrido [1,2-a ] pyrimidin-10-one;
compound E40 is 2- (2, 6-difluorophenyl) -5,6,7, 8-tetrahydro-10H-oxazolo [5,4-d ] pyrido [1,2-a ] pyrimidin-10-one;
compound E41 is 2- (2- (trifluoromethyl) phenyl) -5,6,7, 8-tetrahydro-10H-oxazolo [5,4-d ] pyrido [1,2-a ] pyrimidin-10-one;
compound E42 is 2- (3- (trifluoromethyl) phenyl) -5,6,7, 8-tetrahydro-10H-oxazolo [5,4-d ] pyrido [1,2-a ] pyrimidin-10-one;
compound E43 is 2- (4- (trifluoromethyl) phenyl) -5,6,7, 8-tetrahydro-10H-oxazolo [5,4-d ] pyrido [1,2-a ] pyrimidin-10-one;
compound E44 is 2- (3, 5-bis (trifluoromethyl) phenyl) -5,6,7, 8-tetrahydro-10H-oxazolo [5,4-d ] pyrido [1,2-a ] pyrimidin-10-one;
compound E45 is 2- (2- (trifluoromethoxy) phenyl) -5,6,7, 8-tetrahydro-10H-oxazolo [5,4-d ] pyrido [1,2-a ] pyrimidin-10-one;
compound E46 is 2- (3- (trifluoromethoxy) phenyl) -5,6,7, 8-tetrahydro-10H-oxazolo [5,4-d ] pyrido [1,2-a ] pyrimidin-10-one;
compound E47 is 2- (4- (trifluoromethoxy) phenyl) -5,6,7, 8-tetrahydro-10H-oxazolo [5,4-d ] pyrido [1,2-a ] pyrimidin-10-one;
compound E48 is 2- (4- (tert-butyl) phenyl) -5,6,7, 8-tetrahydro-10H-oxazolo [5,4-d ] pyrido [1,2-a ] pyrimidin-10-one.
The applications of E18, E20, E29, E32, E33, E38, E39, E42, E45, E46 and E47 in the oxazolo [5,4-d ] pyrido [1,2-a ] pyrimidinone compounds in the preparation of medicines for treating Hela cervical carcinoma are provided.
The oxazolo [5,4-d ] pyrido [1,2-a ] pyrimidone compound has the application of E29, E32, E33, E42, E45, E46, E47 and E48 in preparing medicines for treating MCF-7 breast cancer.
The oxazolo [5,4-d ] pyrido [1,2-a ] pyrimidone compounds have the application of E32, E33, E45, E46 and E47 in preparing medicaments for treating A549 lung cancer.
The oxazolo [5,4-d ] pyrido [1,2-a ] pyrimidone compounds are E32, E33, E45, E46 and E47 in preparation of drugs for treating Hela cervical cancer, MCF-7 breast cancer and A549 lung cancer.
The applications of E29 and E42 in the oxazolo [5,4-d ] pyrido [1,2-a ] pyrimidone compound in the preparation of medicaments for treating Hela cervical cancer and MCF-7 breast cancer.
The oxazolo [5,4-d ] pyrido [1,2-a ] pyrimidone derivative has a structure shown in a general formula (I):
Figure BDA0002912820420000081
the invention relates to an oxazolo [5,4-d ] pyrido [1,2-a ] pyrimidone derivative and application thereof, wherein the preparation method of the oxazolo [5,4-d ] pyrido [1,2-a ] pyrimidone derivative comprises the following steps:
preparation of compound a:
under the condition of the temperature of minus 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 raised to 45 ℃, the stirring is carried out for 1 hour, then 74ml of concentrated hydrochloric acid and 0.88mol of concentrated phosphoric 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 and concentrating the reaction solution, and performing gradient elution by adopting forward silica gel column chromatography, wherein an eluent is petroleum ether and ethyl acetate with the volume ratio of 10:1 to respectively obtain a compound 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 completely, filtering the reaction solution, concentrating, performing gradient elution by adopting forward silica gel column chromatography, and respectively obtaining compounds D1-D48 by using petroleum ether and ethyl acetate with the volume ratio of 2:1 as eluent;
preparation of Compounds E1-E48:
dissolving the obtained compound D1-D4810 mmol in 20mL anhydrous dioxane, adding valerolactam 15mmol, slowly dropwise adding phosphorus oxychloride 2.5mmol, refluxing to react until all raw materials disappear, filtering the reaction solution, concentrating, and performing forward silica gel column chromatography gradient elution to obtain a compound E1-E48 respectively, wherein the eluent is petroleum ether and ethyl acetate in a volume ratio of 1: 2.
The invention relates to an oxazolo [5,4-d ] pyrido [1,2-a ] pyrimidone derivative, which is prepared by taking ethyl cyanoacetate as a starting material, synthesizing different substituted oxazole derivatives in four steps in sequence, and then reacting the oxazole derivatives with valerolactam under the action of phosphorus oxychloride, wherein the synthetic route is as follows:
Figure BDA0002912820420000091
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, 36.6ml of 85 percent concentrated phosphoric acid and 0.055mol 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, 74ml of concentrated hydrochloric acid and 0.88mol of sodium nitrite are added, the stirring is continuously carried out overnight at the temperature of 0 ℃, a large amount of white solid is separated out, and the white compound A is filtered to obtain 2-cyano-2-hydroxyiminoacetate which is used for the next reaction without purification;
preparation of compound B:
under the condition of room temperature, dissolving 43g of obtained white compound A, namely 2-cyano-2-hydroxyiminoethyl acetate, 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, reacting for 3 hours at room temperature, extracting for 3 times by using 500ml of dichloromethane, combining organic phases, drying, concentrating, performing gradient elution by adopting forward silica gel column chromatography, and using petroleum ether and ethyl acetate with the volume ratio of 2:1 as eluent to obtain 2-amino-2-cyanoethyl acetate as the compound B, wherein 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 different substituted formyl chlorides 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, and performing gradient elution by adopting forward silica gel column chromatography, wherein an eluant is petroleum ether and ethyl acetate in a volume ratio of 10:1 to respectively obtain compounds C1-C48 which are 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 the compound 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 the compound C1-C4810 mmol obtained in example 1 in anhydrous dichloromethane, slowly dropwise adding 10mL trifluoroacetic acid, reacting at room temperature until the raw materials disappear completely, concentrating the reaction solution, and performing gradient elution by adopting forward silica gel column chromatography, wherein an eluent is petroleum ether and ethyl acetate with the volume ratio of 1:1, and the compounds D1-D48 are respectively obtained;
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 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% of 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% 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%, a pale 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 0.15g and 15mmol of valerolactam, then slowly adding 0.38g and 2.5mmol of phosphorus oxychloride dropwise, refluxing to react until all raw materials disappear, extracting by dichloromethane, drying by anhydrous sodium sulfate, concentrating under reduced pressure, performing gradient elution by forward silica gel column chromatography, and using petroleum ether and ethyl acetate in a volume ratio of 1:2 as eluent to obtain compound E1, namely 2-methyl-5, 6,7, 8-tetrahydro-10H-oxazolo [5,4-D ] pyrido [1,2-a ] pyrimidine-10-one, wherein the yield is as follows: 76%, light yellow solid, melting point: 89-91 ℃;
1H NMR(400MHz,CDCl3)δ4.09(t,J＝6.1Hz,2H),3.00(t,J＝6.7Hz,2H),2.57(s,3H),2.03–1.91(m,6H).13C NMR(100MHz,CDCl3)δ162.62,160.05,158.34,157.01,118.81,42.89,32.11,21.97,19.10,14.57.HRMS(ESI)calcd for C10H11N3O2[M-H]+205.0927,found 205.0851。
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 0.15g and 15mmol of valerolactam, then slowly adding 0.38g and 2.5mmol of phosphorus oxychloride dropwise, refluxing to react until all raw materials disappear, extracting by dichloromethane, drying by anhydrous sodium sulfate, concentrating under reduced pressure, performing gradient elution by forward silica gel column chromatography, and using petroleum ether and ethyl acetate in a volume ratio of 1:2 as eluent to obtain compound E2, namely 2-ethyl-5, 6,7, 8-tetrahydro-10H-oxazolo [5,4-D ] pyrido [1,2-a ] pyrimidine-10-one, wherein the yield is as follows: 80%, light yellow solid, melting point: 94-96 ℃;
1H NMR(400MHz,CDCl3)δ4.10(t,J＝6.1Hz,2H),3.00(t,J＝6.7Hz,2H),2.89(q,J＝7.6Hz,2H),2.13–1.87(m,4H),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 0.15g and 15mmol of valerolactam, then slowly adding 0.38g and 2.5mmol of phosphorus oxychloride dropwise, refluxing to react until all raw materials disappear, extracting by dichloromethane, drying by anhydrous sodium sulfate, concentrating under reduced pressure, performing gradient elution by forward silica gel column chromatography, and using petroleum ether and ethyl acetate in a volume ratio of 1:2 as eluent to obtain a compound E3, namely 2-propyl-5, 6,7, 8-tetrahydro-10H-oxazolo [5,4-D ] pyrido [1,2-a ] pyrimidine-10-one, wherein the yield is as follows: 83%, light yellow solid, melting point: 112 ℃ and 114 ℃;
1H NMR(400MHz,CDCl3)δ4.11(t,J＝6.1Hz,2H),3.01(t,J＝6.6Hz,2H),2.85(t,J＝7.4Hz,2H),2.02–1.92(m,4H),1.87(q,J＝7.4Hz,2H),1.02(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 0.15g and 15mmol of valerolactam, then slowly adding 0.38g and 2.5mmol of phosphorus oxychloride dropwise, refluxing to react until all raw materials disappear, extracting by dichloromethane, drying by anhydrous sodium sulfate, concentrating under reduced pressure, performing gradient elution by forward silica gel column chromatography, and using petroleum ether and ethyl acetate in a volume ratio of 1:2 as eluent to obtain compound E4, namely 2-butyl-5, 6,7, 8-tetrahydro-10H-oxazolo [5,4-D ] pyrido [1,2-a ] pyrimidine-10-one, wherein the yield is as follows: 82%, light yellow solid, melting point: 131 ℃ and 133 ℃;
1H NMR(400MHz,CDCl3)δ4.09(t,J＝6.1Hz,2H),3.00(t,J＝6.7Hz,2H),2.85(t,J＝7.5Hz,2H),2.04–1.89(m,4H),1.81(p,J＝7.5Hz,2H),1.45-1.35(m,2H),0.93(t,J＝7.3Hz,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 0.15g and 15mmol of valerolactam, then slowly adding 0.38g and 2.5mmol of phosphorus oxychloride dropwise, refluxing to react until all raw materials disappear, extracting by dichloromethane, drying by anhydrous sodium sulfate, concentrating under reduced pressure, performing gradient elution by forward silica gel column chromatography, and using petroleum ether and ethyl acetate in a volume ratio of 1:2 as eluent to obtain a compound E5, namely 2-dodecyl-5, 6,7, 8-tetrahydro-10H-oxazolo [5,4-D ] pyrido [1,2-a ] pyrimidin-10-one, wherein the yield is as follows: 79%, light yellow solid, melting point: 89-91 ℃;
1H NMR(400MHz,CDCl3)δ4.06(t,J＝6.1Hz,2H),2.98(t,J＝6.6Hz,2H),2.82(t,J＝7.5Hz,2H),2.04–1.87(m,4H),1.80(p,J＝7.5Hz,2H),1.42–1.16(m,18H),0.84(t,J＝6.8Hz,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 0.15g and 15mmol of valerolactam, 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 petroleum ether and ethyl acetate in a volume ratio of 1:2 to obtain a compound E6, namely 2- (2-propenyl) -5,6,7, 8-tetrahydro-10H-oxazolo [5,4-D ] pyrido [1,2-a ] pyrimidin-10-one, and the yield is as follows: 71%, light yellow solid, melting point: 120-122 ℃;
1H NMR(400MHz,CDCl3)δ6.13(m,1H),5.55(s,1H),4.10(t,J＝6.0Hz,2H),3.02(t,J＝6.6Hz,2H),2.21(s,3H),2.11–1.90(m,4H)。
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 0.15g and 15mmol of valerolactam, then slowly adding 0.38g and 2.5mmol of phosphorus oxychloride dropwise, refluxing to react until all raw materials disappear, extracting by dichloromethane, drying by anhydrous sodium sulfate, concentrating under reduced pressure, performing gradient elution by forward silica gel column chromatography, and using petroleum ether and ethyl acetate in a volume ratio of 1:2 as eluent to obtain a compound E7, namely 2-tert-butyl-355, 6,7, 8-tetrahydro-10H-oxazolo [5,4-D ] pyrido [1,2-a ] pyrimidin-10-one, wherein the yield is as follows: 75%, light yellow solid, melting point: 104-106 ℃;
1H NMR(400MHz,CDCl3)δ4.09(t,J＝6.1Hz,2H),3.01(t,J＝6.7Hz,2H),2.00-1.90(m,4H),1.43(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 0.15g and 15mmol of valerolactam, then slowly adding 0.38g and 2.5mmol of phosphorus oxychloride dropwise, refluxing to react until all raw materials disappear, extracting by dichloromethane, drying by anhydrous sodium sulfate, concentrating under reduced pressure, and performing gradient elution by forward silica gel column chromatography, wherein an eluent is petroleum ether and ethyl acetate in a volume ratio of 1:2 to obtain a compound E8, namely 2- ((3r,5r,7r) adamantyl-1-yl) -5,6,7, 8-tetrahydro-10H-oxazolo [5,4-D ] pyrido [1,2-a ] pyrimidin-10-one, wherein the yield is as follows: 77%, light yellow solid, melting point: 121-123 ℃;
1H NMR(400MHz,CDCl3)δ4.09(t,J＝6.1Hz,2H),3.00(t,J＝6.6Hz,2H),2.09(s,9H),2.00-1.91(m,4H),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 0.15g and 15mmol of valerolactam, then slowly adding 0.38g and 2.5mmol of phosphorus oxychloride dropwise, refluxing to react until all raw materials disappear, extracting by dichloromethane, drying by anhydrous sodium sulfate, concentrating under reduced pressure, performing gradient elution by forward silica gel column chromatography, and using petroleum ether and ethyl acetate in a volume ratio of 1:2 as eluent to obtain compound E9, namely 2-benzyl-5, 6,7, 8-tetrahydro-10H-oxazolo [5,4-D ] pyrido [1,2-a ] pyrimidine-10-one, wherein the yield is as follows: 86%, light yellow solid, melting point: 189-191 deg.C;
1H NMR(400MHz,CDCl3)δ7.51–7.19(m,5H),4.19(s,2H),4.09(t,J＝6.1Hz,2H),2.99(t,J＝6.7Hz,2H),2.02-1.89(m,4H)。
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 0.15g and 15mmol of valerolactam, then slowly adding 0.38g and 2.5mmol of phosphorus oxychloride dropwise, refluxing to react until all raw materials disappear, extracting by dichloromethane, drying by anhydrous sodium sulfate, concentrating under reduced pressure, performing gradient elution by forward silica gel column chromatography, and using petroleum ether and ethyl acetate in a volume ratio of 1:2 as eluent to obtain a compound E10, namely 2-phenethyl-355, 6,7, 8-tetrahydro-10H-oxazolo [5,4-D ] pyrido [1,2-a ] pyrimidin-10-one, wherein the yield is as follows: 83%, light yellow solid, melting point: 171 ℃ and 173 ℃;
1H NMR(400MHz,CDCl3)δ8.65–6.82(m,5H),4.10(t,J＝6.1Hz,2H),3.18(s,4H),3.01(t,J＝6.7Hz,2H),2.03-1.90(m,4H)。
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 0.15g and 15mmol of valerolactam, then slowly adding 0.38g and 2.5mmol of phosphorus oxychloride dropwise, refluxing to react until all raw materials disappear, extracting by using dichloromethane, drying by using anhydrous sodium sulfate, concentrating under reduced pressure, performing gradient elution by using forward silica gel column chromatography, and using petroleum ether and ethyl acetate in a volume ratio of 1:2 as eluent to obtain a compound E11, namely 2-cyclopropyl-355, 6,7, 8-tetrahydro-10H-oxazolo [5,4-D ] pyrido [1,2-a ] pyrimidin-10-one, wherein the yield is as follows: 78%, light yellow solid, melting point: 103-105 ℃;
1H NMR(400MHz,CDCl3)δ4.39(t,J＝6.1Hz,2H),3.05(t,J＝6.7Hz,2H),2.12(tt,J＝8.4,4.9Hz,1H),1.95–1.68(m,6H),1.24-1.20(m,2H),1.15–1.07(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 0.15g and 15mmol of valerolactam, then slowly adding 0.38g and 2.5mmol of phosphorus oxychloride dropwise, refluxing to react until all raw materials disappear, extracting by dichloromethane, drying by anhydrous sodium sulfate, concentrating under reduced pressure, performing gradient elution by forward silica gel column chromatography, and using petroleum ether and ethyl acetate in a volume ratio of 1:2 as eluent to obtain a compound E12, namely 2-cyclobutyl-355, 6,7, 8-tetrahydro-10H-oxazolo [5,4-D ] pyrido [1,2-a ] pyrimidin-10-one, wherein the yield is as follows: 74%, light yellow solid, melting point: 117 ℃ and 119 ℃;
1H NMR(400MHz,CDCl3)δ4.10(t,J＝6.1Hz,2H),3.71(p,J＝8.5Hz,1H),3.01(t,J＝6.6Hz,2H),2.57-2.47(m,2H),2.45–2.36(m,2H),2.17–1.87(m,6H)。
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 0.15g and 15mmol of valerolactam, then slowly adding 0.38g and 2.5mmol of phosphorus oxychloride dropwise, refluxing to react until all raw materials disappear, extracting by using dichloromethane, drying by using anhydrous sodium sulfate, concentrating under reduced pressure, performing gradient elution by using forward silica gel column chromatography, and using petroleum ether and ethyl acetate in a volume ratio of 1:2 as eluent to obtain a compound E13, namely 2-cyclopentyl-355, 6,7, 8-tetrahydro-10H-oxazolo [5,4-D ] pyrido [1,2-a ] pyrimidin-10-one, wherein the yield is as follows: 86%, light yellow solid, melting point: 137-139 ℃;
1H NMR(400MHz,CDCl3)δ4.08(t,J＝6.1Hz,2H),3.29(p,J＝8.0Hz,1H),2.99(t,J＝6.7Hz,2H),2.15–2.04(m,2H),2.03–1.88(m,6H),1.87–1.73(m,2H),1.72-1.68(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 0.15g and 15mmol of valerolactam, then slowly adding 0.38g and 2.5mmol of phosphorus oxychloride dropwise, refluxing to react until all raw materials disappear, extracting by dichloromethane, drying by anhydrous sodium sulfate, concentrating under reduced pressure, performing gradient elution by forward silica gel column chromatography, and using petroleum ether and ethyl acetate in a volume ratio of 1:2 as eluent to obtain compound E14, namely 2-cyclohexyl-5, 6,7, 8-tetrahydro-10H-oxazolo [5,4-D ] pyrido [1,2-a ] pyrimidine-10-one, wherein the yield is as follows: 87%, light yellow solid, melting point: 161-163 ℃;
1H NMR(400MHz,CDCl3)δ4.07(t,J＝6.1Hz,2H),2.98(t,J＝6.7Hz,2H),2.86(tt,J＝11.3,3.7Hz,1H),2.11-2.07(m,2H),2.03–1.86(m,4H),1.83-1.78(m,2H),1.73–1.57(m,3H),1.47–1.14(m,4H)。
example 17
Preparation of compound E15:
dissolving 0.22g and 10mmol of compound D15 obtained in example 2, namely 2- (furan-2-yl) -5-amino-4-ethyl formate oxazole, in 20mL of anhydrous dioxane, adding 0.15g and 15mmol of valerolactam, 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 petroleum ether and ethyl acetate in a volume ratio of 1:2 to obtain compound E15, namely 2- (furan-2-yl) -5,6,7, 8-tetrahydro-10H-oxazolo [5,4-D ] pyrido [1,2-a ] pyrimidin-10-one, and the yield is as follows: 76%, light yellow solid, melting point: 148 ℃ and 150 ℃;
1H NMR(400MHz,CDCl3)δ7.63(dd,J＝1.8,0.8Hz,1H),7.23(dd,J＝3.5,0.8Hz,1H),6.58(dd,J＝3.5,1.8Hz,1H),4.12(t,J＝6.1Hz,2H),3.04(t,J＝6.7Hz,2H),2.08–1.90(m,4H)。
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 0.15g and 15mmol of valerolactam, then slowly adding 0.38g and 2.5mmol of phosphorus oxychloride dropwise, refluxing until all raw materials disappear, extracting by using dichloromethane, drying by using anhydrous sodium sulfate, concentrating under reduced pressure, and carrying out forward silica gel column chromatography gradient elution by using a petroleum ether-ethyl acetate eluent in a volume ratio of 1:2 to obtain a compound E16, namely 2- (thiophene-2-yl) -5,6,7, 8-tetrahydro-10H-oxazolo [5,4-D ] pyrido [1,2-a ] pyrimidine-10-one, wherein the yield is as follows: 75%, light yellow solid, melting point: 156 ℃ and 158 ℃;
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),4.14(t,J＝6.1Hz,2H),3.05(t,J＝6.7Hz,2H),2.16–1.88(m,4H)。
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-ethyl formate oxazole, in 20mL of anhydrous dioxane, adding 0.15g and 15mmol of valerolactam, then slowly adding 0.38g and 2.5mmol of phosphorus oxychloride dropwise, refluxing to react until all raw materials disappear, extracting by using dichloromethane, drying by using anhydrous sodium sulfate, concentrating under reduced pressure, performing forward silica gel column chromatography gradient elution, wherein an eluant is petroleum ether and ethyl acetate with the volume ratio of 1:2 to obtain a compound E17, namely 2- (tetrahydro-2H-pyran-4-yl) -5,6,7, 8-tetrahydro-10H-oxazolo [5,4-D ] pyrido [1,2-a ] pyrimidin-10-one, yield: 65%, light yellow solid, melting point: 145-147 ℃;
1H NMR(400MHz,CDCl3)δ4.10(t,J＝6.1Hz,2H),4.03(dt,J＝11.6,3.6Hz,2H),3.54(td,J＝11.6,3.3Hz,2H),3.15(tt,J＝9.9,4.7Hz,1H),3.01(t,J＝6.6Hz,2H),2.11–1.88(m,8H)。
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 0.15g and 15mmol of valerolactam, then slowly adding 0.38g and 2.5mmol of phosphorus oxychloride dropwise, refluxing until all raw materials disappear, extracting by dichloromethane, drying by anhydrous sodium sulfate, concentrating under reduced pressure, and carrying out forward silica gel column chromatography gradient elution by using a petroleum ether-ethyl acetate eluent in a volume ratio of 1:2 to obtain a compound E18, namely 2- (naphthalene-1-yl) -5,6,7, 8-tetrahydro-10H-oxazolo [5,4-D ] pyrido [1,2-a ] pyrimidine-10-one, wherein the yield is as follows: 78%, light yellow solid, melting point: 239-241 ℃;
1H NMR(400MHz,CDCl3)δ8.71(s,1H),8.27(dd,J＝8.6,1.7Hz,1H),7.97-7.94(m,2H),7.91–7.85(m,1H),7.62–7.47(m,2H),4.16(t,J＝6.1Hz,2H),3.08(t,J＝6.6Hz,2H),2.11–1.90(m,4H)。
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 0.15g and 15mmol of valerolactam, then slowly adding 0.38g and 2.5mmol of phosphorus oxychloride dropwise, refluxing until all raw materials disappear, extracting by dichloromethane, drying by anhydrous sodium sulfate, concentrating under reduced pressure, and carrying out forward silica gel column chromatography gradient elution by using a petroleum ether-ethyl acetate eluent in a volume ratio of 1:2 to obtain a compound E19, namely 2- (naphthalene-2-yl) -5,6,7, 8-tetrahydro-10H-oxazolo [5,4-D ] pyrido [1,2-a ] pyrimidine-10-one, wherein the yield is as follows: 83%, light yellow solid, melting point: 209-211 ℃;
1H NMR(400MHz,CDCl3)δ8.71(s,1H),8.27(dd,J＝8.6,1.7Hz,1H),7.95(d,J＝8.6Hz,2H),7.91–7.85(m,1H),7.68–7.51(m,2H),4.17(t,J＝6.0Hz,2H),3.09(t,J＝6.6Hz,2H),2.15–1.91(m,4H)。
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 0.15g and 15mmol of valerolactam, then slowly dropwise adding 0.38g and 2.5mmol of phosphorus oxychloride, refluxing to react until all raw materials disappear, extracting by using dichloromethane, drying by using anhydrous sodium sulfate, concentrating under reduced pressure, performing gradient elution by using forward silica gel column chromatography, and obtaining a compound E20, namely 2- (1,1' -biphenyl-4-yl) -5,6,7, 8-tetrahydro-10H-oxazolo [5,4-D ] pyrido [1,2-a ] pyrimidin-10-one, wherein the eluent is petroleum ether and ethyl acetate in a volume ratio of 1:2, yield: 84%, light yellow solid, melting point: 183-185 ℃ C;
1H NMR(400MHz,CDCl3)δ8.26(d,J＝8.6Hz,2H),7.80–7.70(m,2H),7.69–7.62(m,2H),7.53–7.43(m,2H),7.43–7.36(m,1H),4.16(t,J＝6.1Hz,2H),3.07(t,J＝6.6Hz,2H),2.27–1.84(m,4H)。
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 0.15g and 15mmol of valerolactam, then slowly adding 0.38g and 2.5mmol of phosphorus oxychloride dropwise, refluxing to react until all raw materials disappear, extracting by dichloromethane, drying by anhydrous sodium sulfate, concentrating under reduced pressure, performing gradient elution by forward silica gel column chromatography, and using petroleum ether and ethyl acetate in a volume ratio of 1:2 as eluent to obtain compound E21, namely 2-phenyl-5, 6,7, 8-tetrahydro-10H-oxazolo [5,4-D ] pyrido [1,2-a ] pyrimidine-10-one, wherein the yield is as follows: 91%, light yellow solid, melting point: 210 ℃ and 212 ℃;
1H NMR(400MHz,CDCl3)δ8.20(dd,J＝7.5,2.0Hz,2H),7.61–7.41(m,3H),4.15(t,J＝6.1Hz,2H),3.06(t,J＝6.6Hz,2H),2.27–1.87(m,4H)。
example 24
Preparation of compound E22:
dissolving compound D22 obtained in example 2, which is 2- (2-methylphenyl) -5-amino-4-ethyl formate oxazole 0.25g and 10mmo, in 20mL of anhydrous dioxane, adding valerolactone (0.15g and 15mmo), slowly adding dropwise oxychloride (0.38g and 2.5mmo), refluxing to react until all the 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 petroleum ether and ethyl acetate at a volume ratio of 1:2 to obtain compound E22, which is 2- (2-methylphenyl) -5,6,7, 8-tetrahydro-10H-oxazolo [5,4-D ] pyrido [1,2-a ] pyrimidin-10-one, in a yield: 82%, light yellow solid, melting point: 177-179 ℃ C;
1H NMR(400MHz,CDCl3)δ8.29–8.05(m,1H),7.46–7.34(m,1H),7.34–7.27(m,2H),4.13(t,J＝6.1Hz,2H),3.05(t,J＝6.6Hz,2H),2.77(s,3H),2.05-1.92(m,4H)。
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 0.15g and 15mmol of valerolactam, 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 petroleum ether and ethyl acetate in a volume ratio of 1:2 to obtain a compound E23, namely 2- (3-methylphenyl) -5,6,7, 8-tetrahydro-10H-oxazolo [5,4-D ] pyrido [1,2-a ] pyrimidin-10-one, and the yield is as follows: 85%, light yellow solid, melting point: 191-193 ℃;
1H NMR(400MHz,CDCl3)δ8.04(s,1H),7.97(d,J＝7.6Hz,1H),7.37(t,J＝7.6Hz,1H),7.31(d,J＝7.5Hz,1H),4.13(t,J＝6.1Hz,2H),3.05(t,J＝6.6Hz,2H),2.41(s,2H),2.18–1.90(m,4H)。
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 0.15g and 15mmol of valerolactam, 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 petroleum ether and ethyl acetate in a volume ratio of 1:2 to obtain a compound E24, namely 2- (4-methylphenyl) -5,6,7, 8-tetrahydro-10H-oxazolo [5,4-D ] pyrido [1,2-a ] pyrimidin-10-one, and the yield is as follows: 87%, light yellow solid, melting point: 264 ℃ and 266 ℃;
1H NMR(400MHz,CDCl3)δ8.07(d,J＝8.2Hz,2H),7.29(d,J＝8.0Hz,2H),4.13(t,J＝6.1Hz,2H),3.05(t,J＝6.7Hz,2H),2.41(s,3H),2.24–1.85(m,4H)。
example 27
Preparation of compound E25:
dissolving 0.27g and 10mmol of compound D25 obtained in example 2, namely 2- (2-chlorophenyl) -5-amino-4-ethyl formate oxazole, in 20mL of anhydrous dioxane, adding 0.15g and 15mmol of valerolactam, 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 petroleum ether and ethyl acetate in a volume ratio of 1:2 to obtain a compound E25, namely 2- (2-chlorophenyl) -5,6,7, 8-tetrahydro-10H-oxazolo [5,4-D ] pyrido [1,2-a ] pyrimidin-10-one, and the yield is as follows: 78%, light yellow solid, melting point: 218 ℃ and 220 ℃;
1H NMR(400MHz,CDCl3)δ8.17(dd,J＝7.5,1.9Hz,1H),7.53(dd,J＝7.8,1.2Hz,1H),7.43(td,J＝7.5,1.9Hz,1H),7.39(td,J＝7.5,1.5Hz,1H),4.15(t,J＝6.1Hz,2H),3.07(t,J＝6.7Hz,2H),2.38–1.70(m,4H)。
example 28
Preparation of compound E26:
dissolving 0.27g and 10mmol of compound D26 obtained in example 2, namely 2- (3-chlorophenyl) -5-amino-4-ethyl formate oxazole, in 20mL of anhydrous dioxane, adding 0.15g and 15mmol of valerolactam, 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 petroleum ether and ethyl acetate in a volume ratio of 1:2 to obtain a compound E26, namely 2- (3-chlorophenyl) -5,6,7, 8-tetrahydro-10H-oxazolo [5,4-D ] pyrido [1,2-a ] pyrimidin-10-one, and the yield is as follows: 83%, light yellow solid, melting point: 208-210 ℃;
1H NMR(400MHz,CDCl3)δ8.20(s,1H),8.07(d,J＝7.5Hz,1H),7.45(dt,J＝15.6,8.0Hz,2H),4.15(t,J＝6.0Hz,2H),3.07(t,J＝6.6Hz,2H),2.08-1.94(m,4H)。
example 29
Preparation of compound E27:
dissolving 0.27g and 10mmol of compound D27 obtained in example 2, namely 2- (4-chlorophenyl) -5-amino-4-ethyl formate oxazole, in 20mL of anhydrous dioxane, adding 0.15g and 15mmol of valerolactam, 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 petroleum ether and ethyl acetate in a volume ratio of 1:2 to obtain a compound E27, namely 2- (4-chlorophenyl) -5,6,7, 8-tetrahydro-10H-oxazolo [5,4-D ] pyrido [1,2-a ] pyrimidin-10-one, and the yield is as follows: 81%, light yellow solid, melting point: 251 and 253 ℃;
1H NMR(400MHz,CDCl3)δ8.11(d,J＝8.8Hz,2H),7.47(d,J＝8.5Hz,2H),4.14(t,J＝6.1Hz,2H),3.05(t,J＝6.6Hz,2H),2.08-1.93(m,4H)。
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 0.15g and 15mmol of valerolactam, 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 petroleum ether and ethyl acetate in a volume ratio of 1:2 to obtain a compound E28, namely 2- (2-bromophenyl) -5,6,7, 8-tetrahydro-10H-oxazolo [5,4-D ] pyrido [1,2-a ] pyrimidin-10-one, and the yield is as follows: 79%, light yellow solid, melting point: 198-191 deg.C;
1H NMR(400MHz,CDCl3)δ8.08(dd,J＝7.8,1.8Hz,1H),7.72(dd,J＝8.0,1.2Hz,1H),7.42(td,J＝7.6,1.2Hz,1H),7.33(td,J＝7.8,1.8Hz,1H),4.13(t,J＝6.1Hz,2H),3.05(t,J＝6.7Hz,2H),2.63–1.83(m,4H)。
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 0.15g and 15mmol of valerolactam, 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 petroleum ether and ethyl acetate in a volume ratio of 1:2 to obtain a compound E29, namely 2- (3-bromophenyl) -5,6,7, 8-tetrahydro-10H-oxazolo [5,4-D ] pyrido [1,2-a ] pyrimidin-10-one, and the yield is as follows: 74%, light yellow solid, melting point: 230 ℃ to 232 ℃;
1H NMR(400MHz,CDCl3)δ8.32(t,J＝1.8Hz,1H),8.07(d,J＝7.9Hz,1H),7.62(dd,J＝8.0,1.9Hz,1H),7.35(t,J＝7.9Hz,1H),4.12(t,J＝6.1Hz,2H),3.04(t,J＝6.6Hz,2H),2.11–1.82(m,4H)。
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 0.15g and 15mmol of valerolactam, 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 petroleum ether and ethyl acetate in a volume ratio of 1:2 to obtain a compound E30, namely 2- (4-bromophenyl) -5,6,7, 8-tetrahydro-10H-oxazolo [5,4-D ] pyrido [1,2-a ] pyrimidin-10-one, and the yield is as follows: 80%, light yellow solid, melting point: 233-235 ℃;
1H NMR(400MHz,CDCl3)δ8.05(d,J＝8.4Hz,2H),7.64(d,J＝8.4Hz,2H),4.15(t,J＝6.1Hz,2H),3.06(t,J＝6.6Hz,2H),2.28–1.81(m,4H)。
example 33
Preparation of compound E31:
dissolving 0.26g and 10mmol of compound D31 obtained in example 2, namely 2- (3, 5-xylyl) -5-amino-4-ethyl formate oxazole in 20mL of anhydrous dioxane, adding 0.15g and 15mmol of valerolactam, then slowly adding 0.38g and 2.5mmol of phosphorus oxychloride dropwise, refluxing until all raw materials disappear, extracting by dichloromethane, drying by anhydrous sodium sulfate, concentrating under reduced pressure, and performing forward silica gel column chromatography gradient elution, wherein an eluent is petroleum ether and ethyl acetate in a volume ratio of 1:2 to obtain a compound E31, namely 2- (3, 5-dimethylphenyl) -5,6,7, 8-tetrahydro-10H-oxazolo [5,4-D ] pyrido [1,2-a ] pyrimidine-10-one, and the yield is as follows: 82%, light yellow solid, melting point: 190 ℃ and 192 ℃;
1H NMR(400MHz,CDCl3)δ7.83(s,2H),7.15(s,1H),4.14(t,J＝6.1Hz,2H),3.06(t,J＝6.7Hz,2H),2.38(s,6H),2.22–1.85(m,4H)。
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 0.15g and 15mmol of valerolactam, then slowly adding 0.38g and 2.5mmol of phosphorus oxychloride dropwise, refluxing to react until all raw materials disappear, extracting by dichloromethane, drying by anhydrous sodium sulfate, concentrating under reduced pressure, and performing forward silica gel column chromatography gradient elution, wherein an eluent is petroleum ether and ethyl acetate in a volume ratio of 1:2 to obtain compound E32, namely 2- (3, 4-dichlorophenyl) -5,6,7, 8-tetrahydro-10H-oxazolo [5,4-D ] pyrido [1,2-a ] pyrimidine-10-one, and the yield is as follows: 80%, light yellow solid, melting point: 196 ℃ and 198 ℃;
1H NMR(400MHz,CDCl3)δ8.28(d,J＝2.0Hz,1H),7.99(dd,J＝8.4,2.0Hz,1H),7.57(d,J＝8.4Hz,1H),4.14(t,J＝6.1Hz,2H),3.06(t,J＝6.6Hz,2H),2.07-1.94(m,4H)。
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 0.15g and 15mmol of valerolactam, then slowly adding 0.38g and 2.5mmol of phosphorus oxychloride dropwise, refluxing to react until all raw materials disappear, extracting by dichloromethane, drying by anhydrous sodium sulfate, concentrating under reduced pressure, and performing forward silica gel column chromatography gradient elution, wherein an eluent is petroleum ether and ethyl acetate in a volume ratio of 1:2 to obtain compound E33, namely 2- (3, 5-dichlorophenyl) -5,6,7, 8-tetrahydro-10H-oxazolo [5,4-D ] pyrido [1,2-a ] pyrimidine-10-one, and the yield is as follows: 75%, light yellow solid, melting point: 277-279 ℃ C;
1H NMR(400MHz,CDCl3)δ7.45–7.38(m,3H),4.14(t,J＝6.1Hz,2H),3.07(t,J＝6.7Hz,2H),2.10–1.89(m,4H)。
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 0.15g and 15mmol of valerolactam, then slowly adding 0.38g and 2.5mmol of phosphorus oxychloride dropwise, refluxing to react until all raw materials disappear, extracting by dichloromethane, drying by anhydrous sodium sulfate, concentrating under reduced pressure, and performing forward silica gel column chromatography gradient elution, wherein an eluent is petroleum ether and ethyl acetate in a volume ratio of 1:2 to obtain compound E34, namely 2- (2, 6-dichlorophenyl) -5,6,7, 8-tetrahydro-10H-oxazolo [5,4-D ] pyrido [1,2-a ] pyrimidine-10-one, and the yield is as follows: 78%, light yellow solid, melting point: 183-185 ℃ C;
1H NMR(400MHz,CDCl3)δ8.08(d,J＝1.9Hz,2H),7.49(t,J＝1.9Hz,1H),4.15(t,J＝6.1Hz,2H),3.07(t,J＝6.7Hz,2H),2.42–1.86(m,4H)。
example 37
Preparation of compound E35:
dissolving 0.25g and 10mmol of compound D35 obtained in example 2, namely 2- (2-fluorophenyl) -5-amino-4-ethyl formate oxazole, in 20mL of anhydrous dioxane, adding 0.15g and 15mmol of valerolactam, 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 petroleum ether and ethyl acetate in a volume ratio of 1:2 to obtain a compound E35, namely 2- (2-fluorophenyl) -5,6,7, 8-tetrahydro-10H-oxazolo [5,4-D ] pyrido [1,2-a ] pyrimidin-10-one, and the yield is as follows: 74%, light yellow solid, melting point: 177-179 ℃ C;
1H NMR(400MHz,CDCl3)δ8.22(td,J＝7.5Hz,1.6Hz,1H),7.53-7.47(m,1H),7.36–7.16(m,2H),4.15(t,J＝6.1Hz,2H),3.07(t,J＝6.6Hz,2H),2.07-1.94(m,4H)。
example 38
Preparation of compound E36:
dissolving 0.25g and 10mmol of compound D36 obtained in example 2, namely 2- (3-fluorophenyl) -5-amino-4-ethyl formate oxazole, in 20mL of anhydrous dioxane, adding 0.15g and 15mmol of valerolactam, 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 petroleum ether and ethyl acetate in a volume ratio of 1:2 to obtain a compound E36, namely 2- (3-fluorophenyl) -5,6,7, 8-tetrahydro-10H-oxazolo [5,4-D ] pyrido [1,2-a ] pyrimidin-10-one, and the yield is as follows: 78%, light yellow solid, melting point: 145-147 ℃;
1H NMR(400MHz,CDCl3)δ7.99(d,J＝7.8Hz,1H),7.89(dt,J＝9.2,2.0Hz,1H),7.48(td,J＝8.1,5.6Hz,1H),7.22(td,J＝8.3,2.5Hz,1H),4.15(t,J＝6.1Hz,2H),3.07(t,J＝6.6Hz,2H),2.06-1.96(m,4H)。
example 39
Preparation of compound E37:
dissolving 0.25g and 10mmol of compound D37 obtained in example 2, namely 2- (4-fluorophenyl) -5-amino-4-ethyl formate oxazole, in 20mL of anhydrous dioxane, adding 0.15g and 15mmol of valerolactam, 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 petroleum ether and ethyl acetate in a volume ratio of 1:2 to obtain a compound E37, namely 2- (4-fluorophenyl) -5,6,7, 8-tetrahydro-10H-oxazolo [5,4-D ] pyrido [1,2-a ] pyrimidin-10-one, and the yield is as follows: 84%, light yellow solid, melting point: 236-238 ℃;
1H NMR(400MHz,CDCl3)δ8.18(dd,J＝8.7,5.3Hz,2H),7.18(t,J＝8.6Hz,2H),4.14(t,J＝6.1Hz,2H),3.06(t,J＝6.6Hz,2H),2.15–1.88(m,4H)。
example 40
Preparation of compound E38:
dissolving 0.27g and 10mmol of compound D38 obtained in example 2, namely 2- (3, 5-difluorophenyl) -5-amino-4-ethyl formate oxazole, in 20mL of anhydrous dioxane, adding 0.15g and 15mmol of valerolactam, then slowly adding 0.38g and 2.5mmol of phosphorus oxychloride dropwise, refluxing until all raw materials disappear, extracting by dichloromethane, drying by anhydrous sodium sulfate, concentrating under reduced pressure, and eluting by a forward silica gel column chromatography gradient, wherein an eluent is petroleum ether and ethyl acetate in a volume ratio of 1:2 to obtain compound E38, namely 2- (3, 5-difluorophenyl) -5,6,7, 8-tetrahydro-10H-oxazolo [5,4-D ] pyrido [1,2-a ] pyrimidin-10-one, and the yield is as follows: 71%, light yellow solid, melting point: 165-167 ℃;
1H NMR(400MHz,CDCl3)δ7.72(d,J＝5.8Hz,2H),6.96(tt,J＝8.6,2.5Hz,1H),4.15(t,J＝6.0Hz,2H),3.07(t,J＝6.6Hz,2H),2.06-1.96(m,4H)。
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 0.15g and 15mmol of valerolactam, then slowly adding 0.38g and 2.5mmol of phosphorus oxychloride dropwise, refluxing until all raw materials disappear, extracting by dichloromethane, drying by anhydrous sodium sulfate, concentrating under reduced pressure, and eluting by a forward silica gel column chromatography gradient, wherein an eluent is petroleum ether and ethyl acetate in a volume ratio of 1:2 to obtain compound E39, namely 2- (3, 4-difluorophenyl) -5,6,7, 8-tetrahydro-10H-oxazolo [5,4-D ] pyrido [1,2-a ] pyrimidin-10-one, and the yield is as follows: 73%, light yellow solid, melting point: 188-190 ℃;
1H NMR(400MHz,CDCl3)δ8.01(ddd,J＝10.4,7.5,2.1Hz,1H),7.95(ddd,J＝8.7,4.0,1.8Hz,1H),7.36–7.28(m,1H),4.14(t,J＝6.1Hz,2H),3.06(t,J＝6.6Hz,2H),2.07-1.94(m,4H)。
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 0.15g and 15mmol of valerolactam, 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 petroleum ether and ethyl acetate in a volume ratio of 1:2 to obtain compound E40, which is 2- (2, 6-difluorophenyl) -5,6,7, 8-tetrahydro-10H-oxazolo [5,4-D ] pyrido [1,2-a ] pyrimidin-10-one, in a yield: 85%, light yellow solid, melting point: 201-203 ℃;
1H NMR(400MHz,CDCl3)δ7.48(tt,J＝8.5,6.1Hz,1H),7.05(t,J＝8.4Hz,1H),4.13(t,J＝6.1Hz,2H),3.06(t,J＝6.6Hz,2H),1.94-2.05(m,4H)。
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 0.15g and 15mmol of valerolactam, then slowly adding 0.38g and 2.5mmol of phosphorus oxychloride dropwise, refluxing until all raw materials disappear, extracting by dichloromethane, drying by anhydrous sodium sulfate, concentrating under reduced pressure, and carrying out forward silica gel column chromatography gradient elution by using an eluent, namely petroleum ether and ethyl acetate in a volume ratio of 1:2 to obtain compound E41, namely 2- (2- (trifluoromethyl) phenyl) -5,6,7, 8-tetrahydro-10H-oxazolo [5,4-D ] pyrido [1,2-a ] pyrimidin-10-one, wherein the yield is as follows: 79%, light yellow solid, melting point: 151 ℃ and 153 ℃;
1H NMR(400MHz,CDCl3)δ8.19(d,J＝7.1Hz,1H),7.93–7.78(m,1H),7.75–7.58(m,2H),4.15(t,J＝6.1Hz,2H),3.08(t,J＝6.7Hz,2H),2.33–1.84(m,4H)。
example 44
Preparation of compound E42:
0.3g, 10mmol of compound D42 from example 2 as 2- (3- (trifluoromethyl) phenyl) -5-amino-4-carboxylic acid ethyl ester oxazole was dissolved in 20mL of anhydrous dioxane and 0.15g, 15mmol of valerolactam was added, then slowly dropwise adding 0.38g and 2.5mmol of phosphorus oxychloride, carrying out reflux reaction until all raw materials disappear, extracting by using dichloromethane, drying by using anhydrous sodium sulfate, concentrating under reduced pressure, carrying out gradient elution by using forward silica gel column chromatography, wherein an eluant is petroleum ether with a volume ratio of 1: 2: ethyl acetate to give compound E42 as 2- (3- (trifluoromethoxy) phenyl) -5,6,7, 8-tetrahydro-10H-oxazolo [5,4-d ] pyrido [1,2-a ] pyrimidin-10-one in yield: 82%, light yellow solid, melting point: 209-211 ℃;
1H NMR(400MHz,CDCl3)δ8.49(s,1H),8.36(d,J＝7.9Hz,1H),7.77(d,J＝7.8Hz,1H),7.64(t,J＝7.8Hz,1H),4.16(t,J＝6.1Hz,2H),3.08(t,J＝6.7Hz,2H),2.28–1.79(m,4H)。
example 45
Preparation of compound E43:
0.3g, 10mmol of compound D43 from example 2 as 2- (4- (trifluoromethyl) phenyl) -5-amino-4-carboxylic acid ethyl ester oxazole was dissolved in 20mL of anhydrous dioxane and 0.15g, 15mmol of valerolactam was added, then slowly dropwise adding 0.38g and 2.5mmol of phosphorus oxychloride, carrying out reflux reaction until all raw materials disappear, extracting by using dichloromethane, drying by using anhydrous sodium sulfate, concentrating under reduced pressure, carrying out gradient elution by using forward silica gel column chromatography, wherein an eluant is petroleum ether with a volume ratio of 1: 2: ethyl acetate to give compound E43 as 2- (4- (trifluoromethoxy) phenyl) -5,6,7, 8-tetrahydro-10H-oxazolo [5,4-d ] pyrido [1,2-a ] pyrimidin-10-one in yield: 86%, light yellow solid, melting point: 253 ℃ and 255 ℃;
1H NMR(400MHz,CDCl3)δ8.28(d,J＝8.2Hz,2H),7.75(d,J＝8.3Hz,2H),4.14(t,J＝6.1Hz,2H),3.06(t,J＝6.6Hz,2H),2.22–1.86(m,4H)。
example 46
Preparation of compound E44:
dissolving 0.37g and 10mmol of compound D44 obtained in example 2, namely 2- (3, 5-bis (trifluoromethyl) phenyl) -5-amino-4-ethyl formate oxazole in 20mL of anhydrous dioxane, adding 0.15g and 15mmol of valerolactam, then slowly adding 0.38g and 2.5mmol of phosphorus oxychloride dropwise, refluxing to react until all raw materials disappear, extracting by using dichloromethane, drying by using anhydrous sodium sulfate, concentrating under reduced pressure, performing gradient elution by using forward silica gel column chromatography, and obtaining a compound E44, namely 2- (3, 5-bis (trifluoromethyl) phenyl) -5,6,7, 8-tetrahydro-10H-oxazolo [5,4-D ] pyrido [1,2-a ] pyrimidin-10-one, wherein the eluent is petroleum ether and ethyl acetate in a volume ratio of 1:2, yield: 69%, light yellow solid, melting point: 219-221 ℃;
1H NMR(400MHz,CDCl3)δ8.65(s,2H),8.00(s,1H),4.16(t,J＝6.1Hz,2H),3.09(t,J＝6.7Hz,2H),2.09-1.96(m,4H)。
example 47
Preparation of compound E45:
compound D45 obtained in example 2, which is 2- (2- (trifluoromethoxy) phenyl) -5-amino-4-carboxylic acid ethyl ester oxazole 0.32g, 10mmol, was dissolved in 20mL of anhydrous dioxane, and valerolactam 0.15g, 15mmol, then slowly dropwise adding 0.38g and 2.5mmol of phosphorus oxychloride, carrying out reflux reaction until all raw materials disappear, extracting by using dichloromethane, drying by using anhydrous sodium sulfate, concentrating under reduced pressure, carrying out gradient elution by using forward silica gel column chromatography, wherein an eluant is petroleum ether with a volume ratio of 1: 2: ethyl acetate to give compound E45 as 2- (2- (trifluoromethoxy) phenyl) -5,6,7, 8-tetrahydro-10H-oxazolo [5,4-d ] pyrido [1,2-a ] pyrimidin-10-one in yield: 75%, light yellow solid, melting point: 182 ℃ and 184 ℃;
1H NMR(400MHz,CDCl3)δ8.32(dd,J＝7.9,1.7Hz,1H),7.56(td,J＝7.9,1.7Hz,1H),7.50–7.38(m,2H),4.15(t,J＝6.1Hz,2H),3.08(t,J＝6.7Hz,2H),2.63–1.83(m,4H)。
example 48
Preparation of compound E46:
compound D46 obtained in example 2, which is 2- (3- (trifluoromethoxy) phenyl) -5-amino-4-carboxylic acid ethyl ester oxazole 0.32g, 10mmol, was dissolved in 20mL of anhydrous dioxane, and valerolactam 0.15g, 15mmol, then slowly dropwise adding 0.38g and 2.5mmol of phosphorus oxychloride, carrying out reflux reaction until all raw materials disappear, extracting by using dichloromethane, drying by using anhydrous sodium sulfate, concentrating under reduced pressure, carrying out gradient elution by using forward silica gel column chromatography, wherein an eluant is petroleum ether with a volume ratio of 1: 2: ethyl acetate to give compound E46 as 2- (3- (trifluoromethoxy) phenyl) -5,6,7, 8-tetrahydro-10H-oxazolo [5,4-d ] pyrido [1,2-a ] pyrimidin-10-one in yield: 88%, light yellow solid, melting point: 185 ℃ and 157 ℃;
1H NMR(400MHz,CDCl3)δ8.13(d,J＝7.9Hz,1H),8.06(s,1H),7.54(t,J＝8.0Hz,1H),7.37(dd,J＝8.9,1.6Hz,1H),4.15(t,J＝6.1Hz,2H),3.08(t,J＝6.6Hz,2H),2.08-1.96(m,4H)。
example 49
Preparation of compound E47:
compound D47 obtained in example 2, which is 2- (4- (trifluoromethoxy) phenyl) -5-amino-4-carboxylic acid ethyl ester oxazole 0.32g, 10mmol, was dissolved in 20mL of anhydrous dioxane, and valerolactam 0.15g, 15mmol, then slowly dropwise adding 0.38g and 2.5mmol of phosphorus oxychloride, carrying out reflux reaction until all raw materials disappear, extracting by using dichloromethane, drying by using anhydrous sodium sulfate, concentrating under reduced pressure, carrying out gradient elution by using forward silica gel column chromatography, wherein an eluant is petroleum ether with a volume ratio of 1: 2: ethyl acetate to give compound E47 as 2- (4- (trifluoromethoxy) phenyl) -5,6,7, 8-tetrahydro-10H-oxazolo [5,4-d ] pyrido [1,2-a ] pyrimidin-10-one in yield: 87%, light yellow solid, melting point: 181-183 ℃;
1H NMR(400MHz,CDCl3)δ8.22(d,J＝8.8Hz,2H),7.33(d,J＝8.4Hz,2H),4.14(t,J＝6.1Hz,2H),3.06(t,J＝6.6Hz,2H),2.06-1.94(m,4H)。
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-carboxylic acid ethyl ester oxazole, in 20mL of anhydrous dioxane, adding 0.15g and 15mmol of valerolactam, 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 by using a forward silica gel column chromatography gradient, wherein the eluent is petroleum ether, namely ethyl acetate is 1:2, to obtain a compound E48, namely 2- (4- (tert-butyl) phenyl) -5,6,7, 8-tetrahydro-10H-oxazolo [5,4-D ] pyrido [1,2-a ] pyrimidin-10-one, and the yield is as follows: 84%, light yellow solid, melting point: 226-228 ℃;
1H NMR(400MHz,CDCl3)δ8.12(d,J＝8.4Hz,2H),7.51(d,J＝8.4Hz,2H),4.14(t,J＝6.1Hz,2H),3.05(t,J＝6.6Hz,2H),2.14–1.89(m,4H),1.35(s,9H)。
example 51
The screening of the anti-tumor activity of the oxazolo [5,4-d ] pyrido [1,2-a ] pyrimidone 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
Figure BDA0002912820420000301
Figure BDA0002912820420000311
As can be seen from the table: the results of 48 compounds in the oxazolo [5,4-d ] pyrido [1,2-a ] pyrimidone derivatives in the invention on the inhibition of Hela human cervical carcinoma cells, MCF-7 breast cancer cells and A549 lung cancer cells show that: compounds E18, E20, E29, E32, E33, E38, E39, E42, E45, E46, E47 have inhibitory activity on Hela cervical cancer cells; compounds E29, E32, E33, E42, E45, E46, E47, E48 have inhibitory activity against MCF-7 breast cancer cells; the compounds E32, E33, E45, E46 and E47 have inhibitory activity on A549 lung cancer cells, and the compounds E32, E33, E45, E46 and E47 have inhibitory activity on Hela cervical carcinoma, MCF-7 breast cancer and A549 lung cancer; the compounds E29 and E42 have inhibitory activity on Hela cervical cancer and MCF-7 breast cancer.

Claims (6)

1. An oxazolo [5,4-d ] pyrido [1,2-a ] pyrimidone derivative is characterized in that the derivative has the structure:
Figure FDA0003506459790000011
wherein:
compound E18 is 2- (naphthalen-1-yl) -5,6,7, 8-tetrahydro-10H-oxazolo [5,4-d ] pyrido [1,2-a ] pyrimidin-10-one;
compound E20 is 2- (1,1' -biphenyl-4-yl) -5,6,7, 8-tetrahydro-10H-oxazolo [5,4-d ] pyrido [1,2-a ] pyrimidin-10-one;
compound E29 is 2- (3-bromophenyl) -5,6,7, 8-tetrahydro-10H-oxazolo [5,4-d ] pyrido [1,2-a ] pyrimidin-10-one
Compound E32 is 2- (3, 4-dichlorophenyl) -5,6,7, 8-tetrahydro-10H-oxazolo [5,4-d ] pyrido [1,2-a ] pyrimidin-10-one;
compound E33 is 2- (3, 5-dichlorophenyl) -5,6,7, 8-tetrahydro-10H-oxazolo [5,4-d ] pyrido [1,2-a ] pyrimidin-10-one;
compound E38 is 2- (3, 5-difluorophenyl) -5,6,7, 8-tetrahydro-10H-oxazolo [5,4-d ] pyrido [1,2-a ] pyrimidin-10-one;
compound E39 is 2- (3, 4-difluorophenyl) -5,6,7, 8-tetrahydro-10H-oxazolo [5,4-d ] pyrido [1,2-a ] pyrimidin-10-one;
compound E42 is 2- (3- (trifluoromethyl) phenyl) -5,6,7, 8-tetrahydro-10H-oxazolo [5,4-d ] pyrido [1,2-a ] pyrimidin-10-one;
compound E45 is 2- (2- (trifluoromethoxy) phenyl) -5,6,7, 8-tetrahydro-10H-oxazolo [5,4-d ] pyrido [1,2-a ] pyrimidin-10-one;
compound E46 is 2- (3- (trifluoromethoxy) phenyl) -5,6,7, 8-tetrahydro-10H-oxazolo [5,4-d ] pyrido [1,2-a ] pyrimidin-10-one;
compound E47 is 2- (4- (trifluoromethoxy) phenyl) -5,6,7, 8-tetrahydro-10H-oxazolo [5,4-d ] pyrido [1,2-a ] pyrimidin-10-one;
compound E48 is 2- (4- (tert-butyl) phenyl) -5,6,7, 8-tetrahydro-10H-oxazolo [5,4-d ] pyrido [1,2-a ] pyrimidin-10-one.
2. Use of E18, E20, E29, E32, E33, E38, E39, E42, E45, E46 and E47 in the oxazolo [5,4-d ] pyrido [1,2-a ] pyrimidinone compounds according to claim 1 in the preparation of a medicament for treating Hela cervical cancer.
3. Use of E29, E32, E33, E42, E45, E46, E47, and E48 in the oxazolo [5,4-d ] pyrido [1,2-a ] pyrimidinone compound according to claim 1 in the preparation of a medicament for treating MCF-7 breast cancer.
4. Use of E32, E33, E45, E46 and E47 in the oxazolo [5,4-d ] pyrido [1,2-a ] pyrimidone compound of claim 1 in preparation of a medicament for treating A549 lung cancer.
5. Use of E32, E33, E45, E46 and E47 in the oxazolo [5,4-d ] pyrido [1,2-a ] pyrimidone compound of claim 1 in the preparation of medicaments for treating Hela cervical cancer, MCF-7 breast cancer and A549 lung cancer.
6. Use of E29 and E42 in the oxazolo [5,4-d ] pyrido [1,2-a ] pyrimidone compound as claimed in claim 1 in preparation of medicaments for treating Hela cervical cancer and MCF-7 breast cancer.
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