Synthesis of some novel 2,6‐disubstituted pyridazin‐3‐ones as TMC120 analogues

Different analogues of TMC120 derived from pyridazin‐3(2H)‐one rings were synthesized by coupling of 3,6‐dichloropyridazine with arylacetonitriles, phenols and/or aniline derivative followed by hydrolysis and alkylation with different benzyl bromide derivatives.     

Base‐promoted rearrangements of ester groups in 3a,7a‐dihydroindole‐2,3,3a,4‐tetraester

Tetramethyl 3a,7a‐dihydro‐1‐methyl‐1H‐indole‐2,3,3a,4‐tetracarboxylate which is an 1:2 adduct of 1‐methylpyrrole and dimethyl acetylenedicarboxylate underwent isomerization catalyzed by sodium methoxide to form a 5,7a‐dihydro‐1‐methyl‐1H‐indole‐2,3,4,5‐tetracarboxylate, its 5,6‐dihydro isomer, and a ring opening product which is an azonine derivative. Fully aromatized esters such as 1‐methylindole‐2,3,4‐triester, 1‐methylindole‐2,3,4,5‐tetraester and 1‐methyl‐2,3,4,6‐tetraester were also isolated. An indole compound which could be formed by conjugative addition of the methoxide ion was also isolated.     

The Kinetic Modeling of Strong Diffusion‐Limited Reaction with Cyclization for Three Isomers – Diallyl Ortho‐, Iso‐ and Tere‐Phthalate in a Bulk

Free radical polymerization kinetic in a bulk for three diallyl phthalate isomers – diallyl orthophthalate, diallyl isophthalate and diallyl terephthalate was investigated in a temperature range from 50 to 70 °C initiated with dicyclohexan peroxydicarbonate as initiator at three different initiator concentrations. Conversion points were measured using Fourier Transform Raman measurements. A new kinetic model for polymerization of three diallyl phthalate isomers was developed. It demands the inclusion of only two new kinetic parameters k_DegC and k_pc which were obtained as a ratio k_DegC/k_pc from an additional set of experiments conducted. Computed conversions from the proposed kinetic model show good agreement with the conversion and molecular weight measured data for all three investigated diallyl phthalate isomers.

     

Synthesis of 1,3‐thiazole and 1,2,4‐oxadiazole substituted spiro[3H‐indole‐3,2′‐thiazolidine]‐2,4′(1H)‐diones

Some new derivatives of spiro[3H‐indole‐3,2′‐thiazolidine]‐2,4′(1H)‐dione with the heterocyclic ring such as substituted thiazole and 1,2,4‐oxadiazole attached to the indolinone ring via CH₂ linkage has been synthesized in moderate yields. The synthesis have been carried out by making use of the reactivity of the NH group of the indolinone moiety present in spiro[3H‐indole‐3,2′‐thiazolidine]‐2,4′(1H)‐dione.     

Synthesis of 3‐(2‐hydroxy‐1‐phenylethyl)‐ and 3‐(2‐hydroxy‐2‐phenylethyl)adenine,DNA adducts derived from styrene

3‐(2‐Hydroxy‐2‐phenylethyl)‐ and 3‐(2‐hydroxy‐1‐phenylethyl)adenine, DNA adducts derived from styrene, along with their 9‐substituted analogues were prepared by alkylation of 8‐bromoadenine with corresponding allyl‐protected bromohydrins followed by a new deallylation procedure using tetrakis(triphenylphosphine)palladium catalyzed reductive cleavage by poly(methylhydrosiloxane) in the presence of p‐toluenesulphonic acid. This novel procedure proved to be useful for purine derivatives, which were resistant to other deallylation protocols. Structure of positional isomers was assigned using 2D NMR experiments HMBC and HMQC.     

An efficient and modified biginelli one‐pot synthesis of new isoxazole substitted 3,4‐dihydropyrimidin‐2(1H)‐ones and thiones catalyzed by VCl3

An efficient and modified Biginelli one‐pot synthesis of new‐isoxazole substituted 3,4‐dihydropyrimidin‐2(1H)‐ones and thiones from aromatic aldehydes, ketoamide and urea/thiourea in acetonitrile using VCl₃ as the catalyst is described.     

1,3‐Dipolar cycloadditions: Investigation of cycloadditions of c‐aryl‐n‐(4‐chlorophenyl) nitrones to n‐cinnamoyl piperidines

Investigation of cycloadditions of C‐aryl‐N‐(4‐chlorophenyl)nitrones to N‐cinnamoyl piperidines was carried out. Two diastereoisomeric and one regioisomeric cycloadducts, and in some cases ring‐opened compounds were characterized by spectroscopic and X‐ray data. Molecular modelling was carried out for conformational studies.     

Synthesis of alicyclic N‐substituted 1,3‐amino alcohols via 1,3‐oxazines

Alicyclic N‐substituted 1,3‐amino alcohols 13‐18 were prepared in a facile way in a one‐pot procedure from 1,3‐oxazines 5‐8 in the presence of a ketone 9‐12 . The complex reaction involves palladium‐catalyzed reduction, debenzylation and/or transimination and further reduction.     

Biginelli‐like three component reaction: Synthesis of some new ethyl 6‐ethoxycarbonylmethyl‐4‐aryl‐2‐oxo‐1,2,3,4‐tetrahydropyrimidine‐5‐carboxylate derivatives

In the context of our high‐throughput organic synthesis program, we have studied the reactivity of special β‐keto esters toward the Biginelli reaction. We have found that a diethyl‐3‐oxoglutarate reacts with one molecule of urea and one molecule of aldehyde under solvent‐free conditions to give a new family of 3,4‐dihydropyrimidin‐2(1H)‐ones in good yields.     

Synthesis of a novel class of 3‐(2′‐benzothiazolyl)‐2,3‐dihydroquinazolin‐4(1H)‐ones under solvent‐free and catalyst‐free conditions

A solvent‐ and catalyst‐free one‐pot three‐component condensation reaction approach was developed for the synthesis of a new class of 3‐(2′‐benzothiazolyl)‐2,3‐dihydroquinazolin‐4(1H)‐ones in relatively good yields.     

Synthesis of novel 3,5,7‐triaryl‐5,6‐dihydro‐4h‐1,2,5‐triazepines

Several hitherto unknown 3,5,7‐triaryl‐5,6‐dihydro‐4H‐1,2,5‐triazepines have been synthesised by cyclocondensation of N,N‐bis(phenacyl)anilines with hydrazine hydrate in ethanol or ethyleneglycol under reflux condition. Increased yields were obtained in the presence of p‐toluenesulfonic acid compared to the uncatalysed reaction.     

Synthesis and structure elucidation of 3,4‐dihydroxy‐2‐quinolin‐2‐ylpyrido[3,2,1‐jk]carbazol‐6‐ones

3,4‐Dihydroxy‐2‐quinolin‐2‐ylpyrido[3,2,1‐jk]carbazol‐6‐ones 6 were obtained by cyclocondensation of carbazole 1 with malonates 2 in the presence of quinoline. The assignment of the structures of 6 was performed by NMR experiments such as 1D ¹H, ¹³C and DEPT, as well as 2D COSY, HSQC, HMBC and 1,1‐ADEQUATE spectra.     

Synthesis and antimalarial activity of 7‐benzylamino‐1‐isoquinolinamines

Computer modelling suggests that 7‐benzylamino‐1‐isoquinolinamines should mediate antimalarial effects by a mechanism distinct from that employed by existing antimalarial drugs. A series of these compounds was prepared in seven synthetic steps, via reductive amination of 1,7‐isoquinolinediamine. In vitro efficacy testing of the novel compounds against Plasmodium falciparum revealed them to be potent antimalarial agents.     

Solvent‐free synthesis of 5‐methyl‐7‐aryl‐4,7‐dihydrotetrazolo[1,5‐a]pyrimidine‐6‐carboxylic esters catalyzed by sulfamic acid

The solvent‐free synthesis of 5‐methyl‐7‐aryl‐4,7‐dihydrotetrazolo[1,5‐a]pyrimidine‐6‐carboxylic esters was performed and effectively catalyzed by sulfamic acid. Compared with conventional methods, this protocol features mild reaction conditions and high yields. Furthermore, it is solvent‐free and thus eco‐friendly.     

Synthesis and antitumor activities of 2‐(substituted)phenyl‐1,2,4‐triazolo[1,5‐a]pyridines

Twenty‐three 2‐(substituted)phenyl‐1,2,4‐triazolo[1,5‐a]pyridines have been synthesized by cycloadditison reaction between N‐amino methylpyridinium mesitylenesulfonates and substituted benzonitriles under the presence of potassium hydroxide at room temperature. The structures of all products were confirmed by ¹H NMR, MS and elemental analyses. The antitumor activities of these compounds were evaluated against human ovary cancer cell line (HO‐8910) in vitro by MTT method. The preliminary results showed that compound 1e (IC₅₀ 28μM) and compound 1w (IC₅₀ 31μM) exhibited stronger antitumor activities than cisplatin (IC₅₀ 35μM) in vitro. Hence, 1e and 1w have potential antitumor activities and are worth further investigation.