Mechanism of Alkaline Hydrolysis of Diazepam

Diazepam (1) is a frequently prescribed hypnotic/anxiolytic drug in worldwide use. Compound 1 is hydrolyzed in alkaline medium to form 2-methylamino-5-chlorobenzophenone imine (2) and 2-methylamino-5-chlorobenzophenone (3) ; the ratio of 2:3 increases with increasing NaOH concentration (J. Pharm. Sci. 85, 745–748, 1996). The mechanism in the conversion of 1 to 2 and 3 via various intermediates is the subject of this report. Results of hydrolysis kinetics and structural identification of some intermediate products indicated an initial hydroxide attack at the C2-carbonyl carbon of 1 , resulting in the formation of a dioxide ( 7 , 7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2,2-dioxide). Compound 7 was characterized by proton NMR spectroscopy and via its monomethyl ether ( 8 , 7-chloro-1,3-dihydro-2-hydroxy-2-methoxy-l-methyl-5-pheny]-2H-1,4-benzodiazepine). The seven-member diazepine ring of 7 opened at the N1-C2 bond to form a glycinate [ 5 , 2-methylamino-5-chloro-α-(phenylhenzylidene)glycinate]. Compound 7 (and/or 5 ) underwent an additional hydroxide attack at the C5-N4 imine bond to form a tetrahedral intermediate, which decomposed to form 2 and 3 .     

A Short and Efficient Synthesis of Novel N-(2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-2-carboxamides

Summary.  Several novel N-(2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-2-carboxamides were prepared by acyl coupling of 2-aminobenzophenones with α-(benzotriazol-1-yl)-N-acylglycines followed by displacement of the benzotriazole ring with ammonia and cyclization of the resulting monoacyl aminals. In addition to high yields and shorter reaction sequences due to avoiding deprotection and acylation of the protected 3-amino-1,4-benzodiazepin-2-one intermediates, the present approach did not involve the use of toxic and odoriferous materials as is the case with other methods. Received September 20, 2000. Accepted (revised) November 29, 2000     

2-R-5-Ar(Het)-5,6-dihydro-7H-[1,2,4]triazolo[5,1-b][1,3]thiazin-7-ones

A novel method for synthesis of 2-R-5-Ar(Het)-5,6-dihydro-7H-[1,2,4]triazolo[5,1-b][1,3]thiazin-7-ones by condensation of 3-R-4,5-dihydro-1H-1,2,4-triazole-5-thiones with 3-aryl(heteryl)-2-propenoyl chlorides is proposed.     

Aminolysis of 2-Aryl-5-R-5,6-dihydro-7H-[1,2,4]triazolo[5,1-<Emphasis Type="Italic">b</Emphasis>]1,3]thiazin-7-ones

We have established that the products of aminolysis of 2-aryl-5-R-5,6-dihydro-7H-[1,2,4]triazolo-[5,1-b][1,3]thiazin-7-ones in boiling ethanol are 3-R-3-(5-aryl-4H-1,2,4-triazol-3-ylsulfanyl)-propanamides, and at 180°C–210°C (depending on the structure of the substituent R): 3-phenyl-4,5-dihydro-1H-1,2,4-triazoline-5-thione and 3-arylacrylamides or 3-(3-aryl-5-thioxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)propanamides. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 10, pp. 1587–1592, October, 2005.     

Synthesis and transformations of 2-(5-amino-(mercapto)-1,3,4-thiadiazolylthio)-7-methyl-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidines

The reactions of 2-amino-5-mercapto-(or 2,5-dimercapto)-1,3,4-thiadiazoles with 2-bromo-7-methyl-5-oxo-5H-1, 3,4-thiadiazolo[3, 2-a]pyrimidine to give the corresponding sulfides have been studied. The possibility of S-alkylation and addition of quinone at the free mercapto group in the 1,3,4-thiadiazole ring has been shown. The reactions at the amino group with benzoyl chloride and chloroformates have been investigated. The conditions of cyciodehydration at the amino group with ethyl acetoacetate and bromination of the pyrimidine fragment of 7-methyl-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine have been found.Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 11, pp. 1954–1957, November, 1993     

New approach to the synthesis of 4-amino-2-pyridone and 1-phenyl-1,6-naphthyridinone derivatives based on substituted 3-and 5-formyl-2-pyridones

The reactions of 3-cyano-3(5)-formyl-2-oxo-4-(phenylamino)-1,2-dihydropyridines with CH acids were studied. The previously unknown fused 2-pyridone derivatives containing the 4-aminopyridine fragment were synthesized by the Knoevenagel reaction. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 8, pp. 1416-1420, August, 2006.     

Synthesis of 4-amino-5-(4,6-diphenyl-2-pyrimidinyl)-3,4-dihydro-2H-1,2,4-triazole-3-thione and its reactions with C-electrophiles

4-Amino-5-(4,6-diphenyl-2-pyrimidinyl)-3,4-dihydro-2H-1,2,4-trazole-3-thione is formed from the reaction of 4,6-diphenylpyrimidinecarboxylic acid or its ethyl ester with thiocarbonyl hydrazide. Alkylation of the product leads to S-alkyl derivaties or 6-substituted 3-(4,6-diphenyl-2-pyriimidinyl)-7H-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazine. Acetylation of 4-amino-5-(4,6-diphenyl-2-pyrimidinyl)-3,4-dihydro-2H-1,2,4-triazole-3-thione gave under different conditions monoacetyl-, diacetyl, and triacetyl derivatives at the amino group and the N₍₂₎ atom, whereas benzoylation gave a benzoyl group at the amino group and 3-(4,6-diphenyl-2-pyrimidinyl)-6-phenyl-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazole. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, 1088–1094, July, 2007.     

Synthesis and Crystal Structure of Trans-4-[(5-(2,4-Dichlorophenoxy)-3-methyl-1-phenyl-1H-pyrazol-4-yl)methyleneamino]-1,5-dimethyl-2-phenyl-1,2-dihydropyrazol-3-one

The title compound trans-4-[(5-(2,4-dichlorophenoxy)-3-methyl-1-phenyl-1H-pyra-zol-4-yl)methyleneamino]-1,5-dimethyl-2-phenyl-1,2-dihydropyrazol-3-one 3 (C28H23Cl2N5O2, Mr = 532.41) has been synthesized and its crystal structure was determined by single-crystal X-ray diffraction analysis. It crystallizes in triclinic, space group P1 with a = 8.9438(4), b = 11.6065(5), c = 14.2215(6) , α = 112.566(1), β = 92.324(2), γ = 102.91(1)o, V = 1315.65(10) 3, Z = 2, Dc = 1.344 g/cm3, μ(MoKα) = 0.282 mm-1, λ = 0.71073 , F(000) = 552, the final R = 0.0587 and wR = 0.1578 for 5071 observed reflections (I > 2σ(I)). X-ray analysis reveals that the product is a thermodynamically stable trans isomer. Intra-and intermolecular C(12)-H(12)···O(1) and C(28)-H(28)···O(1)#1 hydrogen bonds were observed in the title compound.     

Unusual reaction of 5-benzoyl-3-ethoxycarbonyl-6-methylthio-1-r-1,2-dihydropyridin-2-ones with nitrogen-containing 1,4-dinucleophiles

The reaction of 5-benzoyl-3-ethoxycarbonyl-6-methylthio-1-R-1,2-dihydropyridin-2-ones with the nitrogen-containing 1,4-dinucleophiles o-phenylenediamine, o-aminothiophenol, and ethylenediamine, proceeds as a recyclization, the products of which are derivatives of 5-(1H-benzimidazol-2-yl)-2H-2-pyranone, 5-(benzothiazol-2-yl)-2H-2-pyranone, and 5-(4,5-dihydro-1H-imidazol-2-yl)-2H-2-pyra-none respectively. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 1089–1095, July, 2008.     

Synthesis, spectroscopic and DFT investigation of dimethyl-2-(5-acetyl-2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-yl)-3-(triphenylphosphinylidene)succinate

Dimethyl-2-(5-acetyl-2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-yl)-3-(triphenylphosphinylidene)succinate has been synthesized and characterized by elemental analysis, FT-IR and ¹H, ¹³C and ³¹P NMR. The vibrational wavenumbers, gauge including atomic orbital (GIAO) ¹H and ¹³C chemical shift values of title compound in the ground state have been computed with density functional theory method (DFT) and the B3LYP functional. The basis sets used are 6-311G(d,p) and 6-31G(d). The harmonic vibrational wavenumbers have been computed and the scaled values have been compared with the experimental FT-IR spectra. The complete assignments have been performed on basis of the total energy distribution (TED) of the vibrational modes, calculated with scaled quantum mechanics (SQM) method. Most of the computed wavenumbers are found to be in good agreement with the observed spectrum.     

3-取代硫基-5-(1-羟基苯基)-4H-1,2,4-三唑类化合物的合成及抑菌活性

依据邻羟基二苯醚及三唑类化合物的抗菌特性及生物活性叠加原理, 将邻羟苯基和1,2,4-三唑分子片断有机结合, 设计合成了12个新型3-取代硫基-5-(1-羟基苯基)-4H-1,2,4-三唑类化合物. 首先, 水杨酸甲酯与水合肼反应生成水杨酰肼, 水杨酰肼再与硫氰酸铵和盐酸反应, 生成5-(1-羟基苯基)-4H-1,2,4-三唑-3-硫酮(3), 最后在碱性条件下化合物3与取代苯乙酮、氯苄和碘甲烷发生烷基化反应生成目标化合物, 化合物结构经 1H NMR及IR等表征确认. 抑菌测试结果表明, 当化合物质量分数为0.01%时, 目标化合物对白色念珠菌和大肠杆菌的抑菌率高达90%, 具有强抑菌活性; 对金黄色葡萄球菌的抑菌率高达80%, 具有一定的抑菌活性.     

Interaction of 2-bromo-7-methyl-5-oxo-5H-1,3,4-thiadiazolo[3,2-α]pyrimidine with methylene-active compounds and acid hydrolysis of its products

Reactions of 2-bromo-7-methyl-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine with sodium derivatives of pentane-2,4-dione, malonodinitrile, Meldrum acid, acetoacetic, cyanoacetic and malonic esters have been shown to give the respective substituted derivatives. Azinyl-ylidene tautomerism has been found to be characteristic of these compounds, the latter existing mainly in the ylidene form. The acid hydrolysis of pentane-2, 5-dione and cyanoacetic and malonic esters derivatives has been investigated.Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 11, pp. 1957–1961, November, 1993     

Reactions of cyclic 1,3-dicarbonyl compounds with 1,2(1,4)-dihydro-1-methyl-2(4)-methylene-N-heterocycles. A new access to 6,12-methano-dibenz[d,g]-[1,3]oxazocinones

Summary The enamine-type methylene-N-heterocycles1–5 react with cyclic 2-ethoxymethylene-1,3-dicarbonyl compounds6 to give 2-[2-(hetarylidene)ethylidene]-1,3-dicarbonyl compounds7–14. The result of the reactions between 1,2-dihydro-1-methyl-2-methylene-quinoline (1a) and cyclic 1,3-dicarbonyl compounds depends on the nature of the dihydro intermediatesA/B. Dehydrogenation of keton intermediatesA results in 2-(1,2-dimethyl-4(1H)-quinolylidene)-1,3-dicarbonyl compounds17–21. Enol intermediatesB with 6-membered dicarbonyl ring form 6,12-methano-dibenz-[d,g][1,3]oxazocinones22–25.¹H NMR spectra and X-ray structure analysis prove the structure of23.

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Reaktionen cyclischer 1,3-Dicarbonylverbindungen mit 1,2(1,4)-Dihydro-1-methyl-2(4)-methylen-N-heterocyclen. Ein neuer Zugang zu 6,12-Methano- dibenz[d,g][1,3]oxazocinonen

Zusammenfassung Aufgrund ihres Enamincharakters reagieren die Methylen-N-heterocyclen1–5 mit cyclischen 2-Ethoxymethylen-1,3-dicarbonylverbindungen6 zu den 2-[2-(Hetaryliden)ethyliden]-1,3-dicarbonylverbindungen7–14. Das Ergebnis der Reaktionen zwischen 1,2-Dihydro-1-methyl-2-methylen-chinolin (1a) und cyclischen 1,3-Dicarbonylverbindungen hängt von der Natur der zwischenzeitlich entstehenden DihydroverbindungenA/B ab. Die Intermediat-KetoneA gehen durch Dehydrierung während der Reaktion in die 2-(1,2-Dimethyl-4(1H)chinolyliden)-1,3-dicarbonylverbindungen17–21 über. Die Intermediat-EnoleB mit sechsgliedrigem Dicarbonylring bilden in intramolekularer Reaktion die 6,12-Methano-dibenz[d,g][1,3]oxazocinone22–25, deren Struktur am Beispiel der Verbindung23 durch¹H-NMR sowie durch Röntgenkristallstrukturanalyse bewiesen wird.

     

2,6-二甲基-3-苯基-4a-对甲苯基-7-苯甲酰基-4a,5,6,12-四氢-1H,7H-1,3-噁嗪并[3,2-d][1,5]-苯并二氮杂-1-酮的合成及晶体结构

通过2-甲基-4-对甲苯基-1-苯甲酰基-2，3-二氢-1H－1，5-苯并二氮杂与由不对称1-苯基-2-偶氮-1，3-丁二酮热解产生的a-羰基烯酮的[2＋4]环加成反应制备了标题化合物（C34H30N2O3，Mr=514．62），用X射线衍射测定了其单晶结构。晶体属单斜晶系，空间群为P21／n，a=11．560（1），b=19．058（3），c=13．207（2）A，β=106.82（1）°，V=2785.2（7）A3，Z=4，Dc=1．230g．cm-3，MoKa（λ=0.71073A），μ=0．064mm-1，F（000）=1088，2278个可观测衍子射点，R=0．046，Rw=0．049。分子骨架为由苯环、具有类扭船式构象的七元二氮杂环和略微扭曲的唑酮环构成的三环体系。     

Dissolution Properties of 2-(Dinitromethylene)-5-methyl-1,3-diazacyclopentane in Dimethyl Sulfoxide and N-Methyl Pyrrolidone

The molar enthalpies of dissolution for 2-(dinitromethylene)-5-methyl-1,3-diazacyclopentane(DNMDZ) in dimethyl sulfoxide(DMSO) and N-methyl pyrrolidone(NMP) were measured using an RD496-2000 Calvet microcalorimeter at 298.15 K under atmospheric pressure. Empirical formulae for the calculation of the molar enthalpies of dissolution(Δ_dissH) were obtained from the experimental data of the dissolution processes of DNMDZ in DMSO or NMP. The relationships between the rate constant(k) and the molality(b) and between the reaction order(n) and the molality(b) were determined. The corresponding kinetic equations describing the two dissolution processes were dα/dt=10^-2.16(1-α)^1.01 for the dissolution of DNMDZ in DMSO, and dα/dt=10^-2.02(1-α)^0.85 for the dissolution of DNMDZ in NMP, respectively.     

Reaction ofN-(3,3,3-trifluoro-2-trifluoromethylprop-1-enyl)dimethylamine with MgSO4·7H2O. Synthesis of 4,4-difluoro-5-trifluoromethyl-2-(2,2,2-trifluoro-1-trifluoromethylethyl)-4H-1,3-dioxine andcis/trans-3-dimethylamino-2-trifluoromethacryloyl fluoride

4,4-Difluoro-5-trifluoromethyl-2-(2,2,2-trifluoro-1-trifluoromethylethyl)-4H-1,3-dioxine andcis/trans-3-dimethylamino-2-trifluoromethacryloyl fluoride were obtained by reaction ofN-(3,3,3-trifluoro-2-trifluoromethylprop-1-enyl)dimethylamine with MgSO₄·7H₂O. Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 5, pp. 1069–1071, May, 1997.     

Estrogenic Activity of Mycoestrogen (3β,5α,22E)-Ergost-22-en-3-ol via Estrogen Receptor α-Dependent Signaling Pathways in MCF-7 Cells

Armillariella tabescens (Scop.) Sing., a mushroom of the family Tricholomataceae, has been used in traditional oriental medicine to treat cholecystitis, improve bile secretion, and regulate bile-duct pressure. The present study evaluated the estrogen-like effects of A. tabescens using a cell-proliferation assay in an estrogen-receptor-positive breast cancer cell line (MCF-7). We found that the methanol extract of A. tabescens fruiting bodies promoted cell proliferation in MCF-7 cells. Using bioassay-guided fractionation of the methanol extract and chemical investigation, we isolated and identified four steroids and four fatty acids from the active fraction. All eight compounds were evaluated by E-screen assay for their estrogen-like effects in MCF-7 cells. Among the tested isolates, only (3β,5α,22E)-ergost-22-en-3-ol promoted cell proliferation in MCF-7 cells; this effect was mitigated by the ER antagonist, ICI 182,780. The mechanism underlying the estrogen-like effect of (3β,5α,22E)-ergost-22-en-3-ol was evaluated using Western blot analysis to detect the expression of extracellular signal-regulated kinase (ERK), phosphatidylinositol 3-kinase (PI3K), Akt, and estrogen receptor α (ERα). We found that (3β,5α,22E)-ergost-22-en-3-ol induced an increase in phosphorylation of ERK, PI3K, Akt, and ERα. Together, these experimental results suggest that (3β,5α,22E)-ergost-22-en-3-ol is responsible for the estrogen-like effects of A. tabescens and may potentially aid control of estrogenic activity in menopause.     

Preparation, characterization and thiol-thione tautomeric studies of 2-thiono-4-methyl-5-(2,2,2-trifluoro-1-trifluoromethylethyl)-1,3-thiazoline

The synthesis of a new trifluoromethyl 2-mercapto-1,3-thiadiazole derivative from 5,5,5-trifluoro-4-(trifluoromethyl)-3-penten-2-one, its structural study in the solid state and in the liquid phase and the thiol-thione tautomeric equilibrium study of the title compound are reported. The crystalline structure shows short intermolecular FF contacts. Theoretical calculations using HF and DFT methods were performed. Vibrational spectra were calculated for both tautomers and compared with experimental data. The experimental and theoretical results can be interpreted in terms of the existence of a thione tautomer in the solid and in solution.