The picoline, lutidine, and collidine fractions from the coal tar bases were quantitatively determined by the ultraviolet absorption spectra and qualitatively estimated by the infrared absorption spectra. Determination of a mixture (β-picoline fraction) of β- and γ-picolines and 2, 6-lutidine, and a mixture (2, 4-lutidine fraction) of 2, 4-, 2, 5-, and 2, 3-lutidines gave satisfactory results but that of a mixture (sym-collidine fraction) of 2, 4, 6- and 2, 3, 5-collidine and 3, 5-lutidine was somewhat inaccurate.
Hydrolysis of the pale yellow crystals (I), m.p. 140°, C16H18O2N2, obtained at the time of the pyrolysis of kainic acid, afforded a monocarboxylic acid of a pyrrole compound as colorless needles, m.p. 175° (decomp.), C8H11O2N. This substance agrees with one (m.p. 175° (decomp.)) of the two α-monocarboxylic acids obtained by the Grignard reaction of 3-isopropylpyrrole formed by the soda-lime dry-distillation of kainic acid. It also agrees with 2-carboxy-4-isopropylpyrrole (II), m.p. 180° (decomp.), C8H11O2N, obtained by the decarboxylation, under various conditions, of 2-carboxy-3-ethoxycarbonyl-4-isopropylpyrrole (III). It has now been clarified that (II) is obtained during the alkali fusion of kainic and dihydrokainic acids, and that (I) is the pyrrocol compound of (II), i.e. 4, 4′-diisopropylpyrrocol. At the same time, 2, 3-dicarboxy-4-isopropylpyrrole, m.p. 200° (decomp.), and 3-carboxy-4-isopropylpyrrole, m.p. 121° (decomp.), were derived from (III), showing that the crystals of m.p. 132° (decomp.), obtained as the α-carboxylic acid of 3-isopropylpyrrole, is 2-carboxy-3-isopropylpyrrole.
Heating of β-aminoethanol as a hydrochloride or hydrobromide for 1.5-3.5hours at 240-250° results in the formation of piperazine in 44-51% yield of the theoretical amount and a small amount of β, β′-diaminodiethyl ether (2-5% of the theoretical yield) is formed as a by-product. Heating of β-methylaminoethanol hydrochloride under the same conditions affords N-methylpiperazine (yield, 26%), N, N′-dimethylpiperazine (yield, 5%), and N, N′-dimethylethylenediamine (yield, 12%). The same reaction of β-dimethylaminoethanol gives only N, N′-dimethylpiperazine (yield, 26%). In the case of β-aminoethanol and mono-, di-, or trialkylamine hydrochloride gives, according to reaction conditions, N-alkyl- or N-dialkylethylenediamine and N-alkylpiperazine. In the case of β-aminoethanol and aromatic amines, only N-arylethyl enediamine is formed and N-arylpiperazine is not obtained. Catalytic vapor phase reactions of the above substances were not successful.
Water-soluble vitamin E derivative was obtained by the reaction of α-tocopheryl dichlorophosphate and polyethylene glycol. The reaction product was purified through alumina chromatography and from the phosphorus content, ultraviolet and infrared absorption, average molecular weight, and the hydrolyzates, the product was assumed to be a mixed phosphate of α-tocopherol and polyethyleneglycol.
ACTH, obtained from bovine anterior pituitary by the oxycellulose method, was examined by paper electrophoresis and this revealed that it was composed of at least two components. The amino acid component contained, besides the usual amino acids, an unknown substance which colors with Amidoschwarz 10B. As the terminal group phenylalanine, threonine, tyrosine, and the foregoing unknown substance were observed.
The ACTH obtained from bovine anterior pituitary was purified by column chromatography using oxycellulose. By elution with hydrochloric or acetic acid, the effluent was divided into 3-4 fractions. The initial effluent lacked the ACTHaction and colored violet with Amidoschwarz 10B. The next effluent had the strongest hormone activity and is an ACTH-active peptide.
The sugar portion of the new glycolipide obtained from oyster was examined and its structure was assumed to be D-glucopyranose 4↔1 D-glucopyranose 4↔1 L-fucopyranose, a trisaccharide composed of 2 moles of D-glucose and 1 mole of L-fucose.
As a preliminary to following biological change of mesoxalic acid, possessing glycopenic action, microdetection and microdetermination of mesoxalic acid were examined. For the microdetection, paper partition chromatography was employed. Mesoxalic acid was derived to its p-nitrophenylhydrazone, submitted to paper chromatography, the isolated spot was cut out, eluted, and the solution basified with sodium hydroxide was submitted to colorimetry. Tartronic acid formed by the reduction of mesoxalic acid was found to form molybdenum blue with phosphomolybdic acid solution and this was utilized for colorimetry.
1) Electric conductivity of a solution of diphenylhydantoin sodium, while heating above the saturation temperature and cooling below saturation temperature, was measured. The specific electric conductivity-temperature curve suddenly breaks at a point where the crystals completely dissolve or where crystals begin to precipitate out. The electric conductivity curve shows a hysteresis loop at the time of rise or fall of the temperature. 2) When the solution of diphenylhydantoin sodium is cooled to supersaturation below the saturation temperature, the logK-1/T curves are represented by two straight lines crossing each other at the saturation temperature, and the slope of the straight line on the supercooled solution side is usually greater than that of the solution line. 3) The foregoing results have shown that it is possible to know the solubility of diphenylhydantoin sodium by the measurement of the electric conductivity of its solution.
3, 4-Diethoxydiphenyl ether-6, 4′-dicarboxylic acid (XVIII), m.p. 245-247°, and its dimethyl ester (XIX), m.p. 106-108°, were synthesized in order to compare with substances corresponding to the diethoxydiphenyl ether-dicarboxylic acid, m.p. 265-267°, obtained by the oxidation of magnolamine tetraethyl ether, and its dimethyl ester, m.p. 112-113°. The melting points of the synthetic products were found to be similar to but lower than those of the products obtained by the oxidation of the natural substance. In order to obtain the corresponding diethoxy compound (XVIII) from 3, 4-dimethoxydiphenyl ether-6, 4′-dicarboxylic acid (II) by the demethylation of the latter with hydrobromic acid followed by ethylation, an attempt was made on the demethylation with hydrobromic acid and acetic acid by which 3, 4-dihydroxydiphenyl ether-4′-carboxylic acid (VI), in which the carboxyl group in the 6-position of (II) had liberated as carbon dioxide, was obtained, instead of the objective 3, 4-dihydroxydiphenyl ether-6, 4′-dicarboxylic acid (III).
2, 3-Diethoxydiphenyl ether-5, 4′-dicarboxylic acid (VIII), m.p. 229-230°, and its dimethyl ester (VII), m.p. 72-73°, were prepared. The starting material for such synthesis, 3, 4-dimethoxy-6-bromobenzoic acid (III) or the corresponding diethoxy compound, when treated with hydrogen bromide and glacial acetic acid, undergoes dealkylation to form 3, 4-dihydroxy-6-bromobenzoic acid, as well as the transition of the bromine from 6- to 5-position and to form 3, 4-dihydroxy-5-bromobenzoic acid (IV).
A paper chromatographic technique whereby the compounds of the tetracycline series separated from each other or from vitamin B12 was devised by impregnating various kinds of filter paper with Theorell buffer of varying pH and developing with the upper layer of a freshly prepared mixture of butanol, acetic acid, and water (4:1:5). In order to obtain a definite Rf values, the filter paper chosen must show no fluorescence, no absorption, and small adsorption. The Theorell buffer is adjusted to pH 3.5-6.2 and in order to impregnate a definite amount of the solution in the filter paper, the value of (aS-aW)/aW was fixed at 3.0-4.0. The objective was attained by developing with the above solvent mixture by the the one-dimensional ascending method.
It has been found that the heating of chlorotetracycline or tetracycline in dilute hydrochloric acid resulted in the facile formation of the corresponding anhydrotetracycline compounds. These substances had already been prepared by Waller and others and by Conover and others from the tetracycline compounds under drastic conditions such as by treatment with hydrogen iodide or with methanolic hydrochloric acid and their structures have already been elucidated. However, since no report has been made on their biological actions, this point was examined. 1) Antibacterial spectrum: Both showed approximately the same antibacterial action against the gram-positive and gram-negative bacteria. Antibacterial action against avian type tubercle bacilli was apparent but extremely small against human type bacilli. 2) Relationship between pH and antibacterial spectrum: High antibacterial power was shown in an acid medium. 3) Resistance of antibiotic-producing Actinomyces against these substances: Actinomyces which produce chlorotetracycline, oxytetracycline, chloramphenicol, dextromycin, actinomycin, and streptothricin do not show any resistance to the present substances. These results suggest that the aromatization of the C-ring in the molecules of the tetracycline series compounds does not result in the loss of the antibacterial action and that such action mechanism is different from that of chlorotetracycline or oxytetracyline.
Heating of triethanolamine hydrochloride at 200° for three hours afforded β-4-morpholinoethanol in 50% yield but the difference in the reaction temperature and duration results in the formation of morpholine, 1, 2-dimorpholinoethane, 2, 2′-dimorpholinediethyl ether, and piperazine. Heating of triethanolamine with the hydrochloride of mono-, di-, or trialkylamine at 250° invariably affords N-alkylpiperazine in approximately 30% yield, with about 15% of morpholine as a by-product. Vapor phase reaction of ethylene glycol and ammonia, with silica-alumina catalyst, failed to form piperazine and morpholine, and only a small amount of α- and γ-picoline were detected.
1, 4-Diazabicyclo [2, 2, 2] octane (triethylenediamine) was prepared by catalytic vapor phase reaction with silica-alumina coprecipitate as the catalyst. The reaction temperature was 275-350°, either at ordinary or reduced pressure. The yield was 4% from monoethanolamine, 6% from diethanolamine, 21% from N-(β-hydroxyethyl)-piperazine, and 32% from N, N′-di (β-hydroxyethyl) piperazine. In this reaction, the formation of piperazine was totally nil or if formed, only in a minute amount.
By coupling 1 mole of diazonium salt of aniline, o-toluidine, or p-nitroaniline to 1 mole of resorcinol monomethyl ether, compounds in which the coupling occured in the para-position of the hydroxyl and the ortho-position of the methoxyl were obtained as the chief reaction products. The use of 2 moles of the diazonium salts afforded bisazoresorcinol monomethyl ether, m.p. 176° (acetate, m.p. 167°), in the case of aniline, and of m.p. 170° (acetate, m.p. 141°) in the case of o-toluidine. The position of the azo group in these compounds must be 4, 6-position since the application of 1 mole of the diazonium salt to 4-azoresoicinol 1-methyl ether and 4-azoresorcinol 3-methyl ether always gives identical compound. When two moles of diazonium salt is coupled to resorcinol, the product is either 2, 4- or 4, 6- bisazoresorcinol according to whether the medium is mild or caustic alkali. In the case of resorcinol monomethyl ether, there was no difference in the site of coupling of the azo group with the change in the medium.
By the application of α-haloacyl halides to 5-aminocamphor or d-borneol, 3-α-haloacylaminocamphors and d-bornyl α-haloacylates were prepared. Condensation of these haloacyl derivatives with dimethyl- or diethylamine afforded the coresponding 3-α-dialkylaminoacylaminocamphors and d-bornyl α-dialkylaminoacylates. By the application of β-diethylaminoethyl chloride to 3-aminocamphor, 3-β-diethyaminoethylaminocamphor was prepared and by the condensation of β-diethylaminoethyl and β-dimethylaminoethyl chlorides to the sodium salt of d-borneol, the corresponding β-dialkylaminoethyl d-bornyl ethers were obtained.
1) Application of benzoyl, p-chlorobenzoyl, or m-bromobenzoyl chloride to 1-ethyl-, 1-phenyl-, and 1-p-chlorophenyl-2-dimethylaminomethylcyclohexanol, afforded the corresponding benzoates. Treatment of 1-ethyl- and 1-phenyl-2-dimethylamino-methylcyclohexanol with thionyl chloride afforded 1-chloro derivatives. 2) Grignard reagents were prepared from o-chlorobromobenzene, p-methyl-m-chloroiodobenzene, p-chloroiodobenzene, m-dibromobenzene, and p-dibromobenzene, these were respectively reacted with 2-dimethylaminomethylcyclohexanone, and the corresponding 1-halophenyl-2-dimethylaminomethylcyclohexanols were prepared. 3) m-Nitrobenzoate obtained by the condensation of 1-ethyl-2-dimethylamino-methylcyclohexanol and m-nitrobenzoyl chloride was reduced to the amino derivative and condensed with ethyl chlorocarbonate to obtain m-ethoxycarbonylamino derivative.
Determination of trans-π-oxocamphor was established by reacting trans-π-oxocamphorwith 2, 4-dinitrophenylhydrazine, removing the hydrazone thereby formed, and measuring the amount of 2, 4-dinitrophenylhydazine before and after the reaction by azotometry.
1) Determination of aldehydes was successfully established by reacting aldehydes with an excess of the Nessler reagent and determining the excess amount of Nessler reagent by azotometry. 2) Aromatic hydroxyaldehydes cannot be determined by this method.
Application of alkyl iodide to 3-(2-methyl-4-amino-5-pyrimidylmethyl)-3a-methyltetrahydrofuro [2, 3-d] thiazoline-2-thione (III) and 4-hydroxy-4-methyl-5 β-hydroxyethylthiazolidine-2-thione, and its acyl derivative (IV) affords, according to the amount of the alkyl iodide used and reaction conditions, mono or dihydriodide of thiochromine (II). It was shown in the present series of experiments that (II) is formed from (III) and (IV), respectively through the intermediates (V) and (VI).
N-Benzyl-4-methyl-4-hydroxy-5-benzylidenethiazolidine-2-thione (IV), obtained by the condensation of benzylamine, carbon disulfide, and α-bromobenzalacetone, formed N-benzyl-4-methylene-5-benzylidenethiazolidine-2-thione (V) by hydration and undergoes addition reaction with maleic acid to give a malefic acid adduct (VI). On the other hand, 4-benzyl-4-methyl-5-vinylthiazoline-2-thione (VIII) and 3-(2-methyl-4-amino-5-pyrimidylmethyl)-4-methyl-5-vinylthiazoline 2-thione (VIII′) do not form such an adduct. N-Benzyl-4-hydroxy-4-methyl-5-benzylidenethiazolidine-2-thione (IX) gives a benzoyl ester (X).
1) Potency determination of synthetic curare-active substances was successfully made by the preparation of a blood-perfusion sample of rat diaphragm. Comparison of this method with the existing head-drop and Claude-Bernard methods was made with 8 kinds of polymethylene-bis (3-methyl-6, 7-methylenedioxy-Py-tetrahydroiso quinoline) methiodide and somewhat parallel results were obtained. 2) Of the samples used, the decamethonium compound showed the strongest activity and the relationship between the number of the methylene group and the curare-like action was approximately equal to the rules heretofore reported. 3) There was found no significant relationship between the curare-like action and toxicity. 4) The action of this decamethonium compound is antagonized by neostigmine.
The analytical values of the glycoside A agree with that of a mixture of kaempferol monorhamnoside and 3, 5, 7, 4′-tetrahydroxyflavanone monorhamnoside but the separation of these two substances by various solvents proved difficult. Methylation of glycoside A with diazomethane under mild conditions and hydrolysis of the product afforded 3, 5-dihydroxy-7, 4′-dimethoxyflavone (III) as yellow needles, m.p. 179-180° and 3, 5-dihydroxy-7, 4′-dimethoxyflavanone (IV) as colorless needles, m.p. 189-190°. when a large excess of diazomethane was applied, hydrolysis of the product afforded 3-hydroxy-5, 7, 4′-trimethoxyflavone (V) as pale yellow needles, m.p. 145-146°, and 3-hydroxy-5, 7, 4′-trimethoxyflavanone (VI) as amorphous substance of m.p. 60° (indistinct). Therefore, the glycoside A is assumed to be a mixed cystals of kaempferol 3-L-rhamnoside (VII) and 3, 5, 7, 4′-tetrahydroxyflavanone 3-L-rhamnoside (VIII). (VIII) can be isolated by adsorption of (VII) on carbon from 70% ethanolic solution of the glycoside A. The hydrolysis of glycoside B (IX), C21H22O10, afforded L-rhamnose and rac.-3, 5, 7, 4′-terahydroxyflavanone, m.p. 231-232°. Application of an excess of diazomethane followed by hydrolysis results in the formation of 3-hydroxy-5, 7, 4′-trimethoxyflavanone as an amorphous substance of m.p. 60° (indistinct). Therefore, (IX), as (VIII), is assumed to be 3, 5, 7, 4′-tetrahydroxyflavanone 3-L-rhamnoside. Both (VIII) and (IX) give reactions common to flavonoids and their ultraviolet absorption spectra suggest them to be flavanonol compounds (Fig. 1) They are probably stereoisomers. Both are new substances and were named engelitin (VIII) and isoengelitin (IX).
α-Aceto-γ-butyrolactone reacts easily with aniline in ethanol to form phenylimino-acetobutyrolactone. When this is heated with phosphoryl chloride in a sealed tube, the lactone ring is cleaved to chloroethyl and carboxyl, the latter undergoes dehydration in the ortho-position of aniline to form 4-oxoquinoline. This is immediately enolized and chlorinated to form 3-chloroethyl-4-chloroquinaldine (II), which is derived to 3-vinylquinaldine (IV) and 3-ethylquinaldine (V).
Condensation characteristics of acetobutyrolactone were examined with 16 kinds of aromatic amines and it was found that p-nitroaniline alone failed to undergo condensation. Use of aniline analogs possessing methyl, methoxyl, hyroxyl, or halogen substituents afford phenylimino-acetobutyrolactone and makes it possible to prepare 3-chloroethyl-4-chloroquinaldines with such substituents in 5-, 6-, 7-, or 8-positions.
Mutual solubility of pyridine-water-sodium hydroxide system was measured at 0, 30, 60, and 90°, and their equilibrium diagrams and conjugation curves were obtained. Mutual solubility of pyridine and water is markedly affected by temperature and the presence of caustic alkali. At a definite temperature, the mutual solubility decreases with an increase in the concentration of sodium hydroxide, while the concentration of pyridine in equilibrium with a definite concentration of sodium hydroxide solution increases with the increase of temperature.
Vapor pressure of the triethylene glycol-water system in temperature ranges of 30-70° was determined and empirical formula was proposed from the vapor pressure curve and logp-1/T curve. The water activity and vapor density were calculated from the vapor pressure of the aqueous solution and using aqueous triethylene glycol solution, it was made possible to seek conditions required to maintain the atmospheric moisture at a definite rate from a graph. The vapor pressure of triethylene glycol was determined in the temperature range of 15-30° with a pendulum tensimeter and the following empirical formula was obtained. logp=8.9933-3534.0/T
Tate's entrainer method was utilized to determine moisture in polyethylene glycols and carbowax compounds. As the entrainer, benzene, toluene, and xylene were examined and it was found that benzene and toluene would be suitable because they entrain up to 99.7% moisture while xylene entrains only about 90%. The time required until the maximum entrainment of moisture was over 150minutes with toluene and over 240minutes with benzene.
It was shown that N1-acyl-4-acetylaminonaphthalenesulfonamide-1 could be prepared by the Schotten-Baumann reaction of 4-acetylaminonaphthalenesulfonamide-1 in alkali hydroxide solution with acylation agent, such as acid anhydride or acyl chloride.
The crude 3-(2-methyl-4-amino-5-pyrimidylmethyl)-4-hydroxy-4-methyl-5-β-chloroethylthiazolidine-2-thione (III), obtained by the treatment of γ-aceto-γ-chloropropyl chloride (I) and 2-methyl-4-amino-5-aminomethylpyrimidine (II) with carbon disulfide, in the presence of ammonia, was separated and purified as the hydrochloride sparingly soluble in water and the treatment of (III) with alkali also afforded it in a pure state. The properties of this compound were examined.
The known synthetic methods for 1-chlorophthalazine and quinazoline were examined and none of them were found satisfactory. Good results were obtained by the following modified process. 1) Naphthalene was oxidized with potassium permanganate to phthalonic acid, its ketocarboxylic acid solution was reacted with hydrazine to 1-phthalazone-4-carboxylic acid, and its decarboxylation afforded 1-phthalazone in a good yield. Its chlorination by the usual method gave 1-chlorophthalazine in a good yield. 2) o-Nitrotoluene was oxidized with freshly formed mercury oxide to o-nitrobenzaldehyde in a good yield, derived to o-nitrobenzaldiformamide, and its reduction with iron and hydrochloric acid afforded quinazoline in a good yield. Reduction with zine and acetic acid by the known method afforded only a minute amount of quinazoline besides indazole.
Transetherification reactions of benzodiazine and benzothiazole derivaties were carried out with ethanol and isopropanol. It was found that such transetherification is possible in quinazoline, cinnoline, phthalazine, and benzothiazole derivatives. Such transetherification does not occur in quinoline and isoquinoline rings, and quinoxazaline underwent transetherification in a degree intermediate of the foregoing two kinds of substances.
1) Detection of m-dinitrophenyl compounds by acetone and sodium hydroxide, and color reaction of reducive organic compounds by o-dinitrobenzene were examined. 2) Detection of phenyl radical, indirectly, by nitration of phenyl compounds and coloration of the polynitrophenyl compounds thereby formed with acetone and sodium hydroxide or glucose and sodium hydroxide, were examined.
By the application of α-chloropropionyl chloride, α-bromopropionic anhydride, or 4-halopropionic acid (or its ester) to 4-aminoantipyrine, 4-halopropionylamino derivatives were prepared. Condensation of mono- or dimethylamine to these derivatives afforded 4-α-mono (or di) methylaminopropionylaminoantipyrines. Reaction of 4-aminoantipyrine with hydrochloride or esters of α-dimethylaminopropionic acid under the presence of phosphorus pentoxide also afforded the 4-α-dimethylaminopropionylaminoantipyrine. By the application of α-halopropionyl halides or α-bromopropionic anhydride to 4-methylaminoantipyrine, 4-methyl-4-α-halopropionyl derivatives were prepared and these were condensed with mono- and dimethylamine to afford 4-methyl-4-α-mono (and di) methylpropionylaminoantipyrines.
2-Methoxy (or ethoxy)-6-nitrobenzamide was derived to 2-methoxy (or ethoxy)-6-nitrobenzoic acid by the application of sodium nitrite and sulfuric acid. Reaction of 2-methoxy-6-aminobenzoic acid and nitroacetaldoxime, in hydrochloric acid solution, afforded 2-methoxy-6-(β-nitroethylidene) aminobenzoic acid, whose cyclization gave 3-nitro-4-hydroxy-5-methoxyquinoline. Decomposition of 2-cyanoquinolines in acetone, by the Radziszewsky method, afforded the corresponding acid amides in a good yield.
Methanol extract of the terrestrial portion of Dicranopteris dichotoma Bernh. was treated by the usual method and quercitrin (quercetin 3-rhamnoside) was obtained from the precipitate formed from methanol by lead acetate, and afzelin (kaempferol 3-rhamnoside) from its mother liquor. Both were identified by hydrolysis, determination of the position of the sugars, and physical properties.
By heating an aqueous solution of sodium nonanoylhydrazinomethanesulfonate, dinonanoylhydrazine, m.p. 151.5°, was obtained. In general, sodium acylhydrazinomethanesulfonate, RCONHNHCH2SO3Na (R=alkyl), undergoes decomposition when heated in aqueous solution and forms diacylhydrazine.