Synthesis and biological properties of 3-methyl-10-propargyl-5,8-dideazafolic acid

The synthesis of N³-methyl-10-propargyl-5,8-dideazafolic acid ( 1b ) is described. Ring closure of methyl-5-methylanthranilate with chloroformamidine hydrochloride gave a high yield of pure 2-amino-4-hydroxy-6-methylquinazoline treatment of which with iodomethane/sodium hydroxide provided the corresponding 3-methylquinazoline (6) which was converted to its 2-pivaloylamino derivative. This synthetic approach, next involving functionalisation of the 6-methyl group, was not further pursued because of difficulty encountered in removing the pivaloyl group. Methyl 5-methylanthranilate was treated with p-toluenesulfonyl chloride and the product then N-methylated. The tosyl group was cleaved with hydrogen bromide/phenol and the resulting methylamine ring-closed with chloroformamidine hydrochloride to provide 2-amino-1,4-dihydro-1,6-dimethyl-4-oxoquinazoline ( 11 ). The 2-pivaloylamino derivative of 11 was prone to hydrolytic deamination when attempts were made to remove the pivaloyl group and further elaboration of this heterocycle, with the intention of obtaining N¹-methyl-10-propargyl-5,8-dideazafolic acid was, too, not attempted. Di-t-butyl N-(4-propargylamino)benzoyl)-L-glutamate was therefore prepared and coupled with 2-amino-6-bromomethyl-4-hydroxyquinazoline hydrobromide. The resulting antifolate diester was N-monomethylated. Removal of the t-butyl groups with trifluoracetic acid afforded the target compound 1b and its structure was proved by degradation to the quinazoline 6 . Its IC₅₀ for L1210 thymidylate synthase (TS) was 26 μM; the control value for 10-propargyl-5,8-dideazafolic acid ( 1a ) was 0.02 μM. Thus the substitution of the lactam hydrogen in 1a by a methyl group reduced the TS inhibition by 1300-fold. Compound 1b was poorly cytotoxic to L1210 cells in culture (ID₅₀ > 100 μM). An unperturbed lactam group in this class of antifolate is important for binding to TS.     

5-三氟甲基-2-茚酮的合成及表征

三氟甲基化合物和茚酮化合物具有许多独特的理化性质和生物活性,在农药、医药、染料和功能材料领域应用广泛。以对三氟甲基苯甲醛为原料,经Knoevenagel缩合、分子内Friedel-Crafts酰化、环氧化物不对称开环等步骤,经9步反应以总收率22%得目标化合物5-三氟甲基-2-茚酮,其结构经1H NMR、13C NMR、DEPT、HR-ESI-MS和元素分析表征。     

Synthesis and structural determination of 5H-benzocyclohepten-5,8-imines

Treatment of 4-hydroxy-N-methylisoquinolinium iodide with triethylamine in tetrahydrofuran or acetonitrile forms 2-methyl-4-oxidoisoquinolinium ( 2 ) in situ. Once formed, 2 can be trapped with dipolarophiles possessing varying degrees of activation to form the 5H-benzocyclohepten-5,8-imine ring system. Various 2-D nmr experiments were used in the identification of the stereochemical and regiochemical assignments for the ring system.     

Synthesis and preliminary biological evaluation of 5-fluoro-5,8-dideazaisoaminopterin

The new folate antagonist, 5-fluoro-5,8-dideazaisoaminopterin was synthesized in four steps beginning with 2,4-diamino-5-fluoroquinazoline. It was found to be a potent inhibitor of human dihydrofolate reductase. Against L1210 leukemia in mice, 5-fluoro-5,8-dideazaisoaminopterin was equiactive with methotrexate at approximately one half of the total dose employed.     

Synthesis and antitumor activity of 5-trifluoromethyl-2,4- dihydropyrazol-3-one nucleosides

2,4-Dihydropyrazole glucosides 3a-3c were prepared and tested for their antitumor activity. The structures of these compounds were established by (1)H and (13)C-NMR spectroscopy. Glucoside 3b shows an in vitro IC(50) value of 16.4 muM against proliferation of the human promyelotic leukemia (HL60) cell line.     

Synthesis of 5-Phenyl-7-trifluoromethyl-2,3-dihydroimidazo[1,2-a]pyridines

Syntheses are reported for a series of 2-alkylamino-6-phenyl-4-trifluoromethylpyridines. The reaction of 3-cyano-2-(hydroxyalkylamino)-6-phenyl-4-trifluoromethylpyridines with thionyl chloride gave the corresponding 2-(chloroalkylamino)pyridines, 8-cyano-5-phenyl-7-trifluoromethyl-2,3-dihydro-imidazo[1,2-a]pyridines, and 9-cyano-6-phenyl-8-trifluoromethyl-2,3,4-trihydropyrido[1,2-a]-pyrimidines. X-ray diffraction structural analysis was used to study 8-cyano-5-phenyl-7-trifluoromethyl-2,3-dihydroimidazo[1,2-a]pyridine.     

Synthesis of isomerically pure 3-(5-trifluoromethyl-1,2,3-triazol-4-yl)cinnamic acid derivatives via the reaction of 4-aryl-6-trifluoromethyl-2-pyrones with sodium azide

Treatment of 4-aryl-6-trifluoromethyl-2-pyrones with sodium azide in DMSO afforded the corresponding (Z)-3-(5-trifluoromethyl-1,2,3-triazol-4-yl)cinnamic acids in good yields. Similarly, 4-aryl-3-carbethoxy-6-trifluoromethyl-2-pyrones smoothly reacted with sodium azide in acetonitrile to produce (E)-2-ethoxycarbonyl-3-(5-trifluoromethyl-1,2,3-triazol-4-yl)cinnamic acids in high yields, whereas their reactions in ethanol, accompanied by a configurational change, gave the thermodynamically more stable (Z)-2-ethoxycarbonyl-3-(5-trifluoromethyl-1,2,3-triazol-4-yl)cinnamic acids.     

Synthesis and antibacterial activity of some 5-hydroxy-5-trifluoromethyl-4,5-dihydropyrazol-1-thiocarboxamides, 3-trifluoromethylpyrazol-1-thiocarboxamides and 4-aryl-2-(5(3)-trifluoromethyl-1-pyrazolyl)thiazoles

5-Hydroxy-5-trifluoromethyl-4,5-dihydropyrazol-1-thiocarboxamides 3 and 3-trifluoromethylpyrazol-1-thiocarboxamides 4, regioselectively obtained by the condensation of trifluoromethyl-β-diketones with thiosemicarbazide under neutral and acidic conditions, on further reaction with phenacyl bromides 5 afforded 4-aryl-(5-trifluoromethyl-pyrazol-1-yl)thiazoles 6 and 4-aryl-(3-trifluoromethyl-pyrazol-1-yl)thiazoles 7, respectively. Five 4,5-dihydropyrazoles (3a–e) and two pyrazolylthiazoles (6a and 6c) were tested against one Gram-positive and one Gram-negative bacteria to assess their in vitro antibacterial activity. Compounds 3a, 3b and 3e showed moderate antibacterial activity against Gram-positive bacterium, Bacillus pumilus.     

Unexpected synthesis of perhydro-1,4:5,8-bismethano-9,10-nitrilo(trifluoromethyl)metheno-9-trifluoromethyl-10-fluoroanthracene

Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. 9, pp. 2185–2186, September, 1990.     

Vibrational spectra of structures of 5-trifluoromethyl- and 1-methyl-5-nitrotetrazole

The frequencies and forms of the normal vibrations of 5-trifluoromethyl- and 1- methyl-5-nitrotetrazole and the potential energy constants were calculated, and the effect of electron-acceptor substituents on the electronic structure of the tetrazole ring was investigated. The position of the hydrogen atom for 5-trifluoromethyltetrazole was established by the methods of vibrational spectroscopy.The frequencies in the experimental spectra were assigned to the principal types of normal vibrations.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 843–847, June, 1977.     

A New Synthesis of Quinoline-5,8-Quinone

Sensitised photo-oxidations of 8-hydroxy quinoline (l)or5-hydroxy quinoline (2) gives quinoline-5,8-quinone (3) in 64-70% yield.     

A Simple Efficient Synthesis of 5,8-Isoquinolinedione

5,8-Isoquinolinedione was synthesized from 5-hydroxyisoquinoline by nitrosation at C-8, reduction of the nitroso group and oxidation of the resultant 5-hydroxy-8-aminoisoquinoline.     

Synthesis of 2-trifluoromethyl-4,6-diphenyl-1,3,5-triazine

Conclusions Methods have been developed for the preparation of the simplest fluorine-containing phenyltriazine, viz., 2-trifluororaethyl-4,6-diphenyl-1,3,5-triazine, in virtually quantitative yield.Translated from Izvestiva Akademii Nauk SSSR, Seriya Khimieheskaya, No. 4, pp. 919–920, April, 1986.