.3,4 - Dihydro-isoquinoline -1 - Synthesis Of Ketone Derivatives

A novel method for the synthesis of 3,4-dihydro-1(2H)-isoquinolinones from isovanillin was reported.Isovanillin was oxidized into 3-hydroxy-4-Methoxybenzoate(2) with Ag₂O and(2) was esterificated to produce(3).Then the compound(3) and allyl bromide together was refluxed in acetone under the presence of K₂CO₃ to give allyl ether(4).The compound(4) was taken play Claisen rearrangement reaction in N,N-dimethylaniline to produce mainly the ortho-position product (5).Then(5) was oxidized with OsO₄/NaIO₄ to give aldehyde(6),The compound(6) was a key intermediate for the synthesis of target compounds.The addition-elimination reaction of(6) with primary amines gave Schiff-base intermediate,then it was reduced with NaBH(OAc)₃ to produce second amines,the later was converted to target compounds by intermolecular amidation of ester.In this novel method,target compounds were synthesized via eight steps.Actually,the three steps imine-forming,reductive and intermolecular amidation,were completed in one-pot at room temperature.This synthetic method was mild,simple in operation,higher yield in overall.Nine target compounds(1a～1i) were synthesized by this novel method.Because when R' is aryl group, the three steps were not completed in one-pot at room temperature.So other three compounds(1j～1l) were synthesized by another method.All of these compounds(1a～1l) have never reported so far and were confirmed by ¹H NMR,¹³C NMR,MS,elemental analysis.A pilot evaluation on their anti-tumor activities in vitro was given and the results indicated that compounds(1g～1i) have inhibition on ECV-304/Human Umbilical Vein Endothelial Cell Line.Which have a potential anti-tumor activity,the value of further research and development.The anti-tumor activity of other compounds will be further investigated.This paper is consisted of three parts as follows:In the first part,the researching progress in the derivatives of isoquinolinones was described. There are mainly involving two aspects:The section one is researching progress in synthetic methods.For example,Dieckman condensation,Bischler-Napieralski cyclization,the rearrangement method,Pd-catalysted method et al.But the above methods have many disadvantages such as the expensive starting materials and reagents,the harsh conditions,the lower total yield and not suit the enlargement.The section two is researching progress in the pharmacological effects of isoquinolinones such as disinfection,antitissue form,Antihypertensive,Anti-diabetes,Diuretic and anti-spasm,inflammation et al.In the second part,twelve target compounds were synthesized by this novel route.2-benzyl-5-hydroxy-6-methoxy-3,4-dihydroisoquinolin-1(2H)-one(1a),2-ethyl-5-hydroxy-6-methoxy-3,4-dih ydroisoquinolin-1(2H)-one(1b),(R)-5-hydroxy-6-methoxy-2-(1-phenylethyl)-3,4-dihydroisoquinoli n-1(2H)-one(1c),ethyl 2-(5-hydroxy-6-methoxy-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl) acetate(1 d),2-hexadecyl-5-hydroxy-6-methoxy-3,4-dihydroisoquinolin-1(2H)-one(1e),ethyl2-(5-hydroxy-6 -methoxy-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)-3-phenylpropanoate(1f),2-(2-(diethylamino) eth yl)-5-hydroxy-6-methoxy-3,4-dihydroisoquinolin-1(2H)-one(1g),5-hydroxy-6-methoxy-2-(2-morph olinoethyl)-3,4-dihydroisoquinolin-1(2H)-one(1h),5-hydroxy-6-methoxy-2-(2-(piperidin-1-yl)ethy 1)-3,4-dihydroisoquinolin-1(2H)-one(1i),5-hydroxy-6-methoxy-2-p-tolyl-3,4-dihydroisoquinolin-1-(2H)-one(1j), 2-(3-chloro-4-fluorophenyl)-5-hydroxy-6-methoxy-3,4-dihydroisoquinolin-1(2H)-one (1k),5-hydroxy-6-methoxy-2-phenyl-3,4-dihydroisoquinolin-1(2H)-One(1l).All of these target com pounds were never reported so far and were confirmed by ¹H NMR,¹³C NMR,MS,elemental analys is.Five intermediates were synthesized according to the references.3-hydroxy-4-methoxybenzoic ac id(2),methyl 3-hydroxy-4-methoxybenzoate(3),methyl 3-(allyloxy)-4-methoxybenzoate(4),methyl 2-allyl-3-hydroxy-4-methoxybenzoate(5),methyl 3-hydroxy-4-methoxy-2-(2-oxoethyl) benzoate (6).Three of these were never reported so far and were confirmed by IR,¹H NMR.In the last part,a pilot evaluation on their anti-tumor activities in vitro of compounds(1g～1i) was investigated by MTT method.The IC₅₀ of these compounds were:(1g),33.74μM;(1h),32.78μM;(1i),41.03μM.This results indicate that compounds(1g～1i) have inhibition onECV-304/Hu man Umbilical Vein Endothelial Cell Line which have a potential anti-tumor activity,the value of further research and development.The anti-tumor activity of other compounds will be further investiga ted.