Alkyl N-methylfuroxanylcarbamates. Synthesis and structure. II

From 3-methyl-4-furoxancarboxylic acid hydrazide and 4-methyl-3-furoxancarboxylic acid hydrazide the corresponding azides have been synthesized. 3-Methyi-4-furoxancarboxylic acid azide normally underwent the Curtius reaction to give the expected carbamic acid derivative. The degradation of 4-methyl-3-furoxancarboxylic acid azide led to the N-(4-methylfuroxan-3-yl)-carbamic acid derivative at low temperatures and to N-(3-methylfuroxan-4-yl)carbamic acid derivative at higher temperatures.     

Synthesis and Reactions of (6-Methyl-2-methylsulfanyl-4-oxo-3,4-dihydro-3-pyrimidinyl)acetyl Azide

Nitrosation of (6-methyl-2-methylsulfanyl-4-oxo-3,4-dihydro-3-pyrimidinyl)acetic acid hydrazide using sodium nitrite in acid medium gave the corresponding azide. Reaction of the latter with alcohols or phenols gave carbamates and with amines gave carbamides.     

Synthesis and metal binding behavior of hydroxamic acid resins from poly(ethyl acrylate) crosslinked with divinylbenzene and hydrophilic crosslinking agent

Porous poly(hydroxamic acid) chelating resin was prepared by the reaction with poly(ethyl acrylate) crosslinked with divinylbenzene and hydrophilic crosslinking agent, and hydroxylamine. The hydrophilic crosslinking agents and diluent used in this article were ethylene glycol dimethacrylate or butanediol dimethacrylate, and 2,2,4-trimethyl pentane, respectively. The characterization of this type chelating resin was carried out by IR spectroscopy, density measurement, and scanning electron microscopy. Various metal binding properties such as extraction, kinetics, and selectivity were investigated with atomic absorption spectrometer and inductively coupled plasma spectrometer. Poly(hydroxamic acid) resins crosslinked with mixed crosslinking agents showed better metal extraction properties and faster adsorption rate than those crosslinked with divinylbenzene alone. And alkali treatment enhances the binding rate for metal ions because of the formation of other chelating ligands or micropores. © 1995 John Wiley & Sons, Inc.     

The synthesis of poly(acrylic acid hydrazide) and poly(methylacrylic acid hydrazide) and their reaction products with ribonucleoside dialdehydes

Atactic and syndiotactic poly(acrylic acid hydrazide) and atactic, syndiotactic and isotactic poly(methylacrylic acid hydrazide) have been reacted with the di-aldehydes derived from adenosine, guanosine, inosine, cytidine and uridine to give polymers each containing a single type of base residue. Not all of the hydrazide residues of the polymeric hydrazides reacted; guanosine dialdehyde gave the most reaction and inosine dialdehyde the least. Isotactic poly(methylacrylic acid hydrazide) was much less reactive than the other polymeric hydrazides. The adenine-containing and the cytosine-containing polymers with atactic backbones had a low solubility in water whereas those with syndiotactic backbones had a relatively high solubility. For a given polymeric hydrazide backbone the adenine-containing polymers were always the least soluble in water. Most of the ribonucleoside dialdehyde-containing polymers, with the exception of those containing uridine dialdehyde, had only a low solubility in salt solution (0.3M sodium chloride, 0.03M trisodium citrate). No evidence could be obtained for any interaction of these polymers with polynucleotides.     

Reversed-phase liquid chromatographic determination of isoniazide in human urine as a test of the genetically predetermined type of biotransformation by acetylation

A new method of determination of genetically predetermined type of biotransformation by acetylation rate using reversed-phase liquid chromatography (RP-HPLC) was described. The method is based on determination of isonicotinic hydrazide (INH) which is excreted with the patient's urine during 24 h period after oral administration of 0.4 g of the drug. INH is used as pharmacogenetic marker. Precolumn derivatization of 4-chloro-5,7-dinitrobenzofurazan is used at RP-HPLC determination of INH and a new drug phosphabenzide (diphenylphosphinylacetic hydrazide, DPPAH) with specrtophotometric detection in urine. The limit of INH detection was 0.27 mug ml(-1) and the one of DPPAH was 0.82 mug ml(-1). As a result of pharmacokinetic investigation it was discovered that bimodal distribution by acetylation rate for DPPAH is less apparent than in the case of INH. It is shown, that immunomodulator xymedone (N-(beta-oxyethyl)-4,6-dimethyldihydropirimidon-2) is the acetylation inductor of xenobiotics.     

Syntheses based on 3,4-dimethyl-2-thioxothiazoline-5-carboxylic acid hydrazide and azide

Treatment of 3,4-dimethyl-2-thioxothiazoline-5-carboxylic acid hydrazide with NH₄SCN and PhCONCS gave the corresponding thiosemicarbazides, arylsulfochlorides yielded the arylsulfonylhydrazides, and diazotization conditions gave the corresponding azide. The interactions of the latter with different nucleophiles have been studied and a series of novel carbamic acid, urea, and semicarbazide derivatives containing a thiazoline fragment have been prepared. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 430–436, March, 2006.     

Azides of N-substituted aziridine-2-carboxylic acids. Reaction with methyl esters of amino acids

The corresponding azide was obtained by nitrosation of 1-benzylaziridine-2-carboxylic acid hydrazide. Reaction of the azide with methyl esters of amino acids gave N-(1-benzyl-2-aziridinylcarbonyl)-substituted methyl esters of amino acids.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 10, pp. 1350–1352, October, 1980.     

Synthesis and reactions of 3-carbethoxy and 3-aroyl-3,4-dihydro-1h-2,3-benzoxazin-1-ones

A series of 3-substituted 3,4-dihydro-1H-2,3-benzoxazin-1-ones (IV) (Scheme I) was prepared by reaction of 2-bromomethylbenzoyl chlorides (II) with N-hydroxyethylcarbamate (III) or with benzohydroxamic acids. Acid hydrolysis of 3-carbethoxy (IVa) and 3-benzoyl derivatives (IVb) afforded a mixture of 2-(hydroxyaminomethyl)benzoic acid (V) and 2,3-dihydro-2-hydroxy-1H-1-isoindolinone (VII). Compound IVa reacted with ethanol, amines or hydrazine to yield the ethyl ester X, amides XIV (Scheme II) and the hydrazide XII of 2-(N-carbethoxy-N-hydroxy-aminomethyl)benzoic acid. Diazotization of the hydrazide XII afforded the unstable azide XIII which did not undergo the Curtius reaction but gave the benzoxazinone IVa by loss of hydrazoic acid.     

Study on the murexide reaction. V

Although the reaction of caffeine with hydrogen peroxide/hydrochloric acid or nitric acid and then with ammonia has been known to give a purple coloration (Murexide reaction), the use of hydrazine instead of ammonia is found to provide no purple coloration. The reaction of caffeine with hydrogen peroxide/hydrochloric acid and then with hydrazine hydrate afforded a yellow reaction mixture, from which 4-methyl-6-(N-methylcarbamoyl)-3,5-dioxo-2,3,4,5-tetrahydrotriazine 9 , oxalyl hydrazide 10 and hydroxylamine hydrochloride were isolated. The reaction of caffeine with nitric acid and then with hydrazine hydrate furnished a yellow reaction mixture, from which 8-amino-1,3,7-trimethyl-2,6-dioxo-1H,3H,7H-xanthine 11, 9 and hydroxylamine nitrate were isolated. Compound 9 was clarified to be produced from 3-hydroxy-4,6-dimethyloxazolo[4,5-d]pyrimidine-2,5,7(3H,4H,6H)-trione 3 and 1,3-dimethylalloxan 7 by the ring transformation with hydrazine.     

Antianexiety activity of pyridine derivatives synthesized from 2-chloro-6-hydrazino-isonicotinic acid hydrazide

A series of oxadiazole pyridine derivatives were synthesized by using 2-chloro-6-hydrazinoisonicotinic acid hydrazide as starting material. Treatment of the hydrazide with carbon disulfide to afford the oxadiazole derivative, which was treated with 5-methyl-2-furancarbaldehyde, formic acid, acetic acid/acetic anhydride, or phthalic anhydride to yield the corresponding pyridinodiazoles and on imide. Condensation of the hydrazide with p-fluorobenzaldehyde in ethanol or acetic acid in the presence of sodium acetate afforded hydrazone and oxadiazole derivatives, which were acetylated and cyclized with acetic anhydride to N-acetyloxadiazole derivatives. The hydrazone was treated with acetic acid in the presence of sodium acetate, or bromine water/sodium acetate to give on oxadiazole, while it was cyclized with chloroacetyl chloride in the presence of TEA to oxoazetidinaminoisonicotinamide. Finally, condensation of the hydrazide with acid anhydrides in refluxing glacial acetic acid afforded the corresponding bisimide derivatives. The pharmacological screening showed that many of these obtained compounds have good antianexiety activity comparable to diazepam^® as positive control.     

Synthesis and application of chalcones to the preparation of heterocyclic structures

Condensation of methyl N-(4-acetylphenyl)carbamate with aromatic aldehydes in basic and acid environment, and also with hetarylaldehydes in the presence of bases afforded chalcones with the carbamate function. Under the conditions of basic catalysis a nucleophilic substitution was observed of a methoxy group in the carbamate moiety of the chalcone for an ethoxy group. The reactions of the obtained chalcones with hydrazine hydrate, isonicotinic acid hydrazide, guanidine and hydroxylamine hydrochlorides, thiourea, and selenium dioxide furnished the corresponding derivatives of pyrazole, oxazole, pyrimidine, and selenadiazole.     

Hydrazide as a Carboxyl Protecting Group deprotection by acidolysis

Elimination of the hydrazide group was studied with the model compounds N-benzoyl-glycine hydrazide and N-benzoyl-L -phenylalanine hydrazide, using phosphorus oxychloride, hydrogen bromide or hydrogen chloride in acetic acid, or 60% perchloric acid. It was found that treatment of N-benzoyl-L -phenylalanine hydrazide with perchloric acid gave N-benzoyl-L -phenylalanine in 100% yield and without racemisation.     

Immobilization of protein on ferromagnetic Dacron

Ferromagnetic Dacron (polyethyleneterephthalate) is proposed as a matrix to immobilize proteins covalently. Dacron in powder was magnetized by reacting ferrous (Fe+2) and ferric (Fe+3) ions with its hydrazide form at pH 8.3. Ferromagnetic hydrazide Dacron was converted to ferromagnetic azide Dacron and amyloglucosidase (E.C. 3.2.1.3) was covalently bound through the latter group. The catalytic property of the enzyme was preserved (8% of the specific activity estimated for the soluble enzyme) and all the magnetic amyloglucosidase Dacron derivative was recovered by using a magnetic field. No activity was detected in the supernatant.     

Energetic 2,2‐Dimethyltriazanium Salts: A New Family of Nitrogen‐Rich Hydrazine Derivatives

Amination of 1,1‐dimethylhydrazine with NH₂Cl or hydroxylamine‐O‐sulfonic acid yields 2,2‐dimethyltriazanium (DMTZ) chloride ( 3 ) and sulphate ( 4 ), respectively. The DMTZ cation was paired with the nitrogen‐rich anions 5‐aminotetrazolate ( 5 ), 5‐nitrotetrazolate ( 6 ), 5,5′‐azobistetrazolate ( 7 ), and azide ( 8 ), yielding a new family of energetic salts. The synthesis was carried out by metathesis reactions of salts 3 or 4 and a suitable silver or barium salt. To minimize the risks involved when using heavy metal salts, we used electrodialysis for the synthesis of azide 8 , which avoids the use of highly sensitive species. The DMTZ derivatives were characterized by IR and multinuclear NMR spectroscopy, elemental analysis, and X‐ray diffraction. Thermal stabilities were measured using DSC analysis and their sensitivities towards classical stimuli were determined using standard tests. Lastly, the relationship between hydrogen bonding in the solid state and sensitivity is discussed.     

Chemistry of amino acid thionoester derivatives. An unexpected change in the reaction course between heterocyclic-2-carboxylic acid hydrazides and N-substituted thionoglycinates. Preferential formation of 4-amino-1,2,4-triazole adducts over 1,3,4-oxadiazole products

The reaction between benzoic acid hydrazides and ethyl N-carbobenzyloxythionoglycinate produces the expected 2-aminomethyl-1,3,4-oxadiazoles in good yield. Heterocyclic carboxylic acid hydrazides give similar products when the hydrazide moiety is located at either the three or four position (relative to the heteroatom) in the ring. However, when heterocyclic-2-carboxylic acid hydrazides are utilized, oxadiazole formation is dramatically reduced. Instead, the intermediate imidates are usually isolated as the major products of the reaction from one equivalent of these hydrazides. These imidate products are accompanied by significant amounts of 4-amino-1,2,4-triazole derivatives which arise from incorporation of two equivalents of the hydrazide. The structure of these unexpected 4-aminotriazole products was confirmed by nmr and mass spectral data as well as an X-ray analysis. In the presence of a stoichiometric amount of these hydrazides, the 4-aminotriazoles become the major products of the reaction. This phenomenon was found to be general for 2-thienyl, 2-furoic, picolinic, and pyrazinoic acid hydrazides. The intermediate imidates for each of these systems were isolated, characterized and found to have a remarkable thermal stability. Conversion of these imidates to the corresponding 1,3,4-oxadiazoles could only be accomplished in hot acetic anhydride. A mechanistic rationale is presented which suggests that some stabilization of the intermediate imidate must occur in these examples which allows an intermolecular process to compete so effectively with an intramolecular cyclization. Since the cyclization to oxadiazole is presumed to be acid catalyzed, this stabilization is proposed to occur specifically by the formation of a hydrogen bond between the ring heteroatom and the proton-ated imino nitrogen present in the imidate prior to cyclization. The formation of such a hydrogen bond removes the carboxylate oxygen from its opportune position for cyclization, while the protonated imino nitrogen can still activate the imidate for subsequent reaction with a second equivalent of hydrazide. In all cases where this heteroatom is capable of hydrogen bond formation, 4-aminotriazoles predominate. The relative amount of 4-aminotriazole product is directly correlatable with the donor capability of the ring hetero-atom. This proposed model was tested by examining a system where steric congestion would be expected to prevent hydrogen bond formation. Indeed, when N-methyl-2-pyrrole carboxylic acid hydrazide was utilized in the reaction, the corresponding 1,3,4-oxadiazole was formed as expected in high yield. Conversely, an acyclic aliphatic hydrazide specifically bearing a beta heteroatom (N-carbobenzyloxyglycine hydrazide) produced the expected 4-aminotriazole adduct in high yield. This therefore appears to be a general phenomenon which provides a useful synthetic entry to several new unsymmetrically substituted 4-amino-1,2,4-triazole derivatives.     

Synthesis and antimicrobial activity of some derivatives of (7-hydroxy-2-oxo-2H-chromen-4-yl)-acetic acid hydrazide

(7-Hydroxy-2-oxo-2H-chromen-4-yl)-acetic acid hydrazide (2) was prepared from (7-hydroxy-2-oxo-2H-chromen-4-yl)-acetic acid ethyl ester (1) and 100% hydrazine hydrate. Compound 2, is the key intermediate for the synthesis of several series of new compounds such as Schiff's bases 3a-l, formic acid N'-[2-(7-hydroxy-2-oxo-2H- chromen-4-yl)acetyl] hydrazide (4), acetic acid N'-[2-(7-hydroxy-2-oxo-2H-chromen-4- yl)-acetyl] hydrazide (5), (7-hydroxy-2-oxo-2H-chromen-4-yl)-acetic acid N'-[2-(4- hydroxy-2-oxo-2H-chromen-3-yl)-2-oxoethyl] hydrazide (6), 4-phenyl-1-(7-hydroxy-2- oxo-2H-chromen- 4-acetyl) thiosemicarbazide (7), ethyl 3-{2-[2-(7-hydroxy-2-oxo-2H- chromen-4-yl)-acetyl]hydrazono}butanoate (8), (7-hydroxy-2-oxo-2H-chromen-4-yl)- acetic acid N'-[(4-trifluoromethylphenylimino)methyl] hydrazide (9) and (7-hydroxy-2- oxo-2H-chromen-4-yl)acetic acid N'-[(2,3,4-trifluorophenylimino)-methyl] hydrazide (10). Cyclo- condensation of compound 2 with pentane-2,4-dione gave 4-[2-(3,5- dimethyl-1H-pyrazol-1-yl)-2-oxoethyl]-7-hydroxy-2H-chromen-2-one (11), while with carbon disulfide it afforded 7-hydroxy-4-[(5-mercapto-1,3,4-oxadiazol-2-yl)methyl]-2H- chromen-2-one (12) and with potassium isothiocyanate it gave 7-hydroxy-4-[(5- mercapto-4H-1,2,4-triazol-3-yl)methyl]-2H-chromen-2-one (14). Compound 7 was cyclized to afford 2-(7-hydroxy-2-oxo-2H-chromen-4-yl)-N -(4-oxo-2-phenylimino- thiazolidin-3-yl) acetamide (15).     

Amino acid derivatives,part 2: Synthesis,antiviral, and antitumor activity of simple protected amino acids functionalized at N‐terminus with naphthalene side chain

Coupling of various acylated amino acid derivatives with (naphthalen‐2‐lyloxy)acetic acid ( 3 ) in the presence of 1‐hydroxy‐benzoteriazole (HOBt) and DCC afforded the new amides 6–12 . Alternatively, the latter compounds were prepared from reaction of the corresponding hydrazide 5 , via the azide‐coupling method, with the acylated amino acid derivatives. Treatment of 6, 10–12 with N₂H₄ċH₂O afforded the hydrazides 13–16 , respectively, as key intermediates for the synthesis of peptide derivatives. Reaction of 12 , as a acceptor, with the glycosyl‐trichloroimidate 18 , as donors in the presence of TMSOTf gave the new glycoside 19 . The new compounds were evaluated for their anti‐HIV‐1, antibovine viral diarrhea virus (BVDV), and antitumor activity. © 2005 Wiley Periodicals, Inc. Heteroatom Chem 16:148–222, 2005; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/hc.20082     

Two directions of the reaction of 3,4-dihydroxy-6-oxoalka-2,4-dienoic acid esters with anthranilic acid hydrazide

Methyl 3,4-dihydroxy-6-oxoalka-2,4-dienoates reacted with anthranilic acid hydrazide to give methyl [5-alkyl-1-(2-aminobenzamido)-2-hydroxy-3-oxo-2,3-dihydro-1H-pyrrol-2-yl]acetates. The reaction of anthranilic acid hydrazide with ethyl 3,4-dihydroxy-6-oxohepta-2,4-dienoate afforded ethyl (2Z)-(3a-hydroxy-2-methyl-10-oxo-3,3a,5,10-tetrahydro-4H-pyrazolo[5,1-c][1,4]benzodiazepin-4-ylidene)acetate as solvate with one methanol molecule. The structure of the isolated compounds was determined on the basis of IR and NMR spectra and X-ray diffraction data.     

Synthesis of cyclic oligomers from histidine-derived building blocks using dynamic combinatorial chemistry

Histidine-derived hydrazide acetal monomers (3-dimethoxymethylbenzoyl)-L-histidine methyl ester 1 and (3-dimethoxymethylbenzoyl)-tau-benzyl-L-histidine methyl ester 2 were prepared from a histidine methyl ester and a tau-benzyl-histidine methyl ester by N-acylation with 3-(dimethoxymethyl)benzoic acid (3) followed by hydrazinolysis. Acid-promoted hydrolysis of each acetal hydrazide initially produced a library of cyclic oligomers that eventually converted to a cyclic dimer. The cyclic dimers 12 and 22 were spectroscopically characterized and found to direct their imidazole-bearing sidechains outward (exo). No evidence for templating the cyclic oligomers was observed using various metal ions and anionic substrates. The average of pKa1 and pKa2 of dimer 12 was determined by potentiometric titration to be 6.6. Dimer 12 was found to catalyze the hydrolysis of p-nitrophenylacetate 10 times faster than 4-methyl imidazole.     

A colorimetric method for the estimation of glutamic acid in protein hydrolyzates

On heating with hydroxylamine and on subsequent treatment with ferric chloride, pyrrolidonecarboxylic acid gives a colour reaction. This reaction can be used for the quantitative estimation of glutamic acid in protein hydrolyzates since this acid is almost completely converted into pyrrohdonecarboxylic acid at 125° and pH 3–4.