Studies On The Synthesis And Biological Activity Of Spirodihydropyrimidine Derivatives

Dihydropyrimidine is a class of heterocyclic compounds containing two nitrogen atoms,the derivatives of which have a wide range of pharmacological and biological activities,such as anti-cancer,anti-inflammatory,anti-hypertensive,antibacterial and herbicidal activities.Spirothiophene is a kind of spiro-heterocyclic compounds containing sulfur atoms,and its derivatives also have antibacterial,antifungal and antitumor biological activities.Based on the principle of bioactivity superposition,a series of novel spiro-dihydropyrimidine derivatives were designed and synthesized by combining the mother nucleus of dihydropyrimidine with spirothiophene skeleton,and structural confirmation of the synthesized target product ethyl 5-aryl-4'-hydroxy-7-methyl-3-oxo-2'-aryl-3,4',5,5'-tetrahydro-2'H-spiro[thiazolo[3,2-a]pyrimidine-2,3'-thiophene]-6-carboxylate by modern characterization methods such as IR,¹H NMR,¹³C NMR and HRMS,at the same time,the antitumor activity of ethyl 5-aryl-4'-hydroxy-7-methyl-3-oxo-2'-aryl-3,4',5,5'-tetrahydro-2'H-spiro[thiazolo[3,2-a]pyrim idine-2,3'-thiophene]-6-carboxylate compounds were also preliminarily studied.The research results of this paper are as follows:The synthesis of the target compounds are divided into four steps.In the first step,under the catalysis of sulfamic acid,a three-component one-pot Biginelli condensation reaction was carried out by substituting benzaldehyde,thiourea and ethyl acetoacetate to synthesize 13 intermediates ethyl 2-mercapto-4-methyl-6-aryl-1,6-dihydropyrimidine-5-carboxylate 1;In the second step,the intermediate 1 and the ethyl bromoacetate are cyclized in an alkaline environment of pyridine to synthesize13 intermediates ethyl 7-methyl-3-oxo-5-aryl-3,5-dihydro-2H-thiazolo[3,2-a]pyrimi-dine-6-carboxylate 2;Thirdly,under the catalysis of piperidine,16 intermediates ethyl2-arylmethylidene-7-methyl-3-oxo-5-aryl-3,5-dihydro-2H-thiazolo[3,2-a]pyrimidine-6-carboxylate 3 were synthesized by aldol condensation reaction between inter-mediate 2 and substituted benzaldehyde;Fourth,under the catalysis of triethylamine,the intermediate 3 was reacted with 2,5-dihydroxy-1,4-dithianes to synthesize 16novel target products ethyl 5-aryl-4'-hydroxy-7-methyl-3-oxo-2'-aryl-3,4',5,5'-tetra-hydro-2'H-spiro[thiazolo[3,2-a]pyrimidine-2,3'-thiophene]-6-carboxylate 4.At the same time,the synthesis conditions of target product 4 were optimized,finally,the possible reaction mechanism of intermediate 3 with 2,5-dihydroxy-1,4-dithianes to synthesize target product 4 was speculated.The antitumor activity of 15 target products ethyl 5-aryl-4'-hydroxy-7-methyl-3-oxo-2'-aryl-3,4',5,5'-tetrahydro-2'H-spiro[thiazolo[3,2-a]pyrimidine-2,3'-thiophene]-6-car-boxylate synthesized was tested,it was found that some of the target compounds had good inhibitory activity on human gastric cancer cells?MGC-803?and human prostatic cancer cells?PC-3?.