1) Synthetic process for 3-nitro-4-acetamidobenzenesulfonyl chloride (VIII) was examined and it was found that the o-nitrophenylurethan method is better than ethyl o-nitrophenyloxamate method described in literature. Nitration of p-acetamido-benzenesulfonyl chloride results in poor yield of (VIII) if the period of nitration is extended and 4-amino-3, 5-dinitrobenzenesulfonyl chloride is formed if the reaction mixture is left over night. 2) N-Substituted 3-nitro-4-acetamidobenzenesulfonamides (Table I) were prepared by application of 16 kinds of primary amines and 10 kinds of secondary amines to (VIII). These sulfonamides were derived to N-substituted 2-methyl-5(or6)-benzimidazoles (Table II) by application of reductive cyclization with sodium dithionite, described previously.
Reaction of 3, 4-dimethyl-5-aminoisoxazole with 2-haloacyl halide afforded 3, 4-dimethyl-5-(2-haloacylamido)isoxazole and its reaction with dimethylamine, diethylamine, piperidine, and morpholine gave the corresponding amine compounds. Reaction of 3, 4-dimethyl-5-aminoisoxazole with p-nitrobenzoyl chloride 3, 4-dimethyl-5-(4-nitrobenzamido)isoxazole, which was catalytically reduced at ordinary pressure to 3, 4-dimethyl-5-(4-aminobenzamido)isoxazole, and its reaction with 2-haloacyl halide afforded haloacyl compounds. Condensation of these compounds with various amines gave the corresponding amine compounds. Toxicity and analgesic activity of these new compounds were examined.
Reaction of metallic sodium and 2-alkoxyethyl bromide on acetonitrile afforded 2-(2-alkoxyethyl)-3-iminobutyronitrile which was condensed with hydroxylamine hydrochloride to prepare 3-methyl-4-(2-alkoxyethyl)-5-aminoisoxazole. Its reaction with 2-haloacyl halide to form the haloacyl compound and condensation with dimethylamine, diethylamine, and morpholine afforded the corresponding amino derivatives. Application of p-nitrobenzoyl chloride to 3-methyl-4-(2-alkoxyethyl)-5-aminoisoxazole afforded 3-methyl-4-(2-alkoxyethyl)-5-(4-nitrobenzamido)isoxazole which was submitted to catalytic reduction at ordinary pressure to prepare 3-methyl-4-(2-alkoxyethyl)-5-(4-nitrobenzamido)isoxazole. Toxicity and analgesic action of these new compounds were examined.
Univalent copper chelates of 4, 4′-disubstituted 2, 2′-biquinolines (I to X) were extracted with isoamyl alcohol and their spectrophotometric constants were measured. The ultraviolet absorption maxima of these compounds were as follows: mμ(ε): (II: -CONHEt) 565 (3, 100), (III: -CONH-iso-Pr) 566 (7, 100), (VI: -CONMe2) 560 (6, 130), (VII: -CONEt2) 561 (6, 260), (VIII: -CON (iso-Pr)2) 556 (2, 810), (IX: -CONBu2) 561 (5, 150), and (X: -CONMePh) 567 (7, 370). (I), (IV), and (V) were sparingly soluble and spectral measurement could not be made. Of these compounds, (X) showed absorption maximum in the longest wave-length region with the highest absorbance. Examinations were made on the determination of copper, using sodium hydroxide solution of 2, 2′-bicinchoninic acid. The ratio of the acid to copper was 2:1 and the solution colored violet in aqueous solution of a univalent copper, the absorption maximum of this violet solution being at 565mμ (ε 8, 000), and limit of detection, 0, 02 γ/cc. The solution followed the Beer's law when concentration of copper was below 20γ/cc., the color being stable at pH 3-13 and a temperature below 65°. There was no change in absorbance even after two days under these conditions. This coloration is not interfered by the presence of alkali metals, alkaline earth metals, NH4+, Cl-, NO3-, SO42-, AcO-, and H2PO4-. Some interference is observed in the presence of metals which form sparingly soluble hydroxides, CO32-, and BO2-, but their effect can be removed by dilution.
Application of ethyl benzoylacetate to o- and m-anisidine, and o- and m-phenetidine gave o- and 2-benzoyl-m-acetanisidide, and o- and 2-benzoyl-m-acetophenetidide, which, together with the corresponding para compound obtained earlier, was cyclized by the action of polyphosphoric acid into 4-phenyl-6-methoxy-, -7-methoxy-8-methoxy, -6-ethoxy, -7-ethoxy-, and -8-ethoxy-carbostyrils. These carbostyrils were heated with phosphoryl bromide to form 2-bromo-4-phenyl-6-, -7-, and -8-methoxyquinolines, and 2-bromo-4-phenyl-6-, -7-, and -8-ethoxyquinolines, which were dimerized to prepare 4, 4′-diphenyl-6, 6′-dimethoxy-, -7, 7′-dimethoxy-, -8, 8′-dimethoxy-, -6, 6′-diethoxy-, -7, 7′-diethoxy-, and -8, 8′-diethoxy-2, 2′-biquinolines. 4, 4′-Dimethyl-8, 8′-dimethoxy-2, 2′-biquinoline was treated with hydrobromic acid to form 4, 4′-dimethyl-2, 2′-biquinoline-8, 8′-diol and its reaction with the 7, 7′-diol derivative, with application of benzoyl chloride, afforded 4, 4′-dimethyl-8, 8′- and -7, 7′-bisbenzoyloxy-2, 2′-biquinoline. 4, 4′-Dimethyl-8, 8′-bisacetoxy-2, 2′-biquinoline was obtained by treatment with acetic anhydride.
Application of ethyl 3-oxovalerate to aniline, and o-, m-, and p-toluidines afforded 2-propionyl-o-, m-, and p-acetotoluidides which were cyclized by treatment with sulfuric acid to form 4-ethyl-, 4-ethyl-8-methyl-, -7-methyl-, and -6-methyl-carbostyrils. These carbostyrils were heated with phosphoryl bromide to prepare 2-bromo-4-ethyl-, 2-bromo-4-ethyl-8-methyl-, -7-methy-, and -6-methylquinolines and dimerized to form 4, 4′-diethyl-, 4, 4′-diethyl-8, 8′-dimethyl-, -7, 7′-dimethyl-, and -6, 6′-dimethyl-2, 2′-biquinolines. Cyclization of 4′-phenylacetoacetanilide and o-acetoacetophenetidide, prepared from 4-aminobiphenyl and o-phenetidine with ethyl acetoacetate, were cyclized to 4-methyl-6-phenyl- and 4-methyl-8-ethoxy-carbostyrils which were brominated to 2-bromo-4-methyl-6-phenyl- and 2-bromo-4-methyl-8-ethoxy-quinolines and dimerized to 4, 4′-dimethyl-6, 6′-diphenyl- and 4, 4′-dimethyl-8, 8′-diethoxy-2, 2′-biquinolines. 2, 2′-Biquinoline 1, 1′-dioxide was also prepared.
Recently, it was found that cyanogen chloride is formed by the oxidation of β-hydroxyamino acid with a mixture of Chloramine-T and periodate. Therefore serine and threonine were decomposed by the mixed oxidizer and oxidation products were identified by preparing derivatives and quantitative analysis. From the data obtained, it was concluded that serine and threonine are decomposed by the mixed oxidizer according to the following equation: RCH(OH)CH(NH2)COOH IO4-→Chloramine-T RCHO+ClCN+CO2
Condensation of acetoacetanilides with 2-ethoxyethyl bromide yielded 2-(2-ethoxyethyl) acetoacetanilides (I, IV, V, VI, VII, and VIIa), from which, without purification, 3-(2-ethoxyethyl)-4-methylcarbostyrils (II, VIII, IX, X, and XI) were obtained by the Knorr quinoline synthesis. Cyclization from (VIIa) to (XIIa) failed. Infrared spectrum of (II) showed a strong amide-carbonyl band at 1650 cm-1. Heating of the foregoing carbostyrils with polyphosphoric acid furnished 4-methyl-2, 3-dihydrofuro[2, 3-b]quinolines (III, XII, XIII, XIV, and XV). These compounds had sharp and strong infrared absorption bands in the range of 1630-1635cm-1 (cf. Table I). It may therefore be interpreted that these bands are due to the C=N stretching in quinoline ring and not the C=C stretching in furan ring, as stated by Briggs and Colebrook. (III) strongly contracts guinea-pig uterus (1:200, 000).
Application of tosyl or benzoyl chloride to quinoline 1-oxide, in the presence of pyridine, chiefly affords 1-(4- or 2-quinolyl)pyridinium salt and its decomposition with aniline gives the corresponding 4- or 2-aminoquinoline. Exchange reaction with aniline hydrochloride, on the other hand, affords anilinoquinoline, which is suitable for following this reaction. Similar reactions progress smoothly in quinoline 1-oxide homologs and isoquinoline 2-oxide. Some considerations were made on the mechanims of this reaction.
Reaction of pyridine 1-oxides and tosyl chloride, in the presence of pyridine, results in quaternization reaction. In the case of pyridine 1-oxide, 1-(2- and 4-pyridyl)-pyridinium salts are formed but, in the case of 2- and 4-picoline 1-oxides, the active methyl group enters into the reaction to form 1-[(2- or 4-pyridyl)methyl] pyridinium salts, accompanied by ring-substituted by-products. In the case of 2, 6-lutidine 1-oxide, the substitution occurs only in the 4-position and the active methyl group remains inert to the reaction. Exchange reaction of 1-[(2- or 4-pyridyl)-methyl]pyridinium salts with aniline hydrochloride results in rearrangement to form 2- or 4-(p-aminobenzyl)pyridine.
Reaction of 1-[(2- and 4-pyridyl)methyl]pyridinium chloride and 1-[(6-methyl-2-pyridyl)methyl]pyridinium chloride with aniline hydrochloride was examined. The reaction at 140-150° resulted in formation of the corresponding anilino compounds and temperature above 200° afforded the rearrangement product of the former, p-aminobenzyl compound, while intermediate temperature gave a mixture of these two compounds. Rearrangement reaction of these 2- and 4-anilinomethylpyridine to 2- or 4-(p-aminobenzyl)pyridine was examined and it was found to be the result of an intermolecular reaction, differing in mechanism from that of Hofmann-Martius rearrangement reaction.
Synthesis of 2, 4-dimethoxy-6-aminopyrimidine (I) by the direct amination of 2, 4-dimethoxy-6-chloropyrimidine (III) is considered to be difficult. Examinations were made to derive 2, 4-dimethoxy-6-hydrazinopyrimidine (IV), obtained from (III), to (I) was examined and it was found that (I) can be obtained easily and in a good yield by refluxing (IV) in alcohol, in the presence of Raney nickel W-5 or by catalytic hydrogenation in the presence of Raney nickel catalyst, at a high pressure. This reaction was found to be effected in the case of various other derivatives of (IV), such as ethylidene, benzylidene, 2-acetyl- and 2-benzoylhydrazino compounds, and afforded (I). The same reaction was carried out on other hydrazinopyrimidines, such as 2, 4-dimethoxy-6-(1-methylhydrazino)-, 2-hydrazino-, and 2, 4-dimethyl-6-hydrazinopyrimidines, and the corresponding methylamino or amino compounds were obtained.
Dornow and others synthesized 2-aminonicotinic acid derivatives by the condensation of β-diketone and amidine or imino ethers. Pyridine cyclization by the condensation of β-diketones with non-symmetrical structure and malonamideamidine or ethyl 3-amino-3-ethoxyacrylate was examined and a new derivative of 2-aminonicotinic acid derivatives, which may serve as intermediate for synthesis of pyridoxine, were obtained. The compounds synthesized were ethyl 2-amino-4-ethoxymethyl-6-methylnicotinate, diethyl 2-amino-6-methyl-3, 4-pyridinedicarboxylate, and ethyl 2-amino-4-carbamoyl-6-methylnicotinate, and their structures were determined.
Blood level after administration of salicylic acid derivatives, such as salicylic acid, acetylsalicylic acid, p-aminosalicylic acid, gentisic acid, and salicylamide, in a rabbit was found to decrease according to the first-order reaction formula and constants for excretion velocity and half-life period of each compound were calculated. Bonding of plasma protein from rabbits and humans with salicylic acid derivatives was measured by ultrafiltration method and it was found that the order of this binding ratio and the order of excretion velocity were in parallel. Binding with bovine albumin was found to be the same as in human and rabbit plasma.
In order to follow the behavior of main metabolites of þ-aminosalicylic acid, separatiory determination of PAS, acetyl-PAS, and þ-aminosalicyluric acid (PASU) was carried out, with considerations on PASU which had not been treated quantita-tively. Unchanged PAS and acetyl-PAS in the urine was found to be changed into MAP by heat decomposition but not to PASU. Application of diazotized þ-nitro-aniline to the decomposition solution in alkalinity resulted in extraction of colored substance of MAP by isopentyl acetate but not due to PASU. This was utilized for separatory determination of MAP and PASU, and examination was made on the combi-nation of this procedure with the usual method for separatory determination of PAS and acetyl-PAS. Separatory determination was carried on these substances excreted into urine after administration of PAS.
Examinations were made on the relationship between urinary excretion, metabolites, and urine pH after administration of salicylic acid derivatives (salicylic acid, gentisic acid, p-aminosalicylic acid, and salicylamide) in man. In the case of acid urine, excretion of unchanged salicylic acid and PAS was small and markedly increased in the case of alkaline urine. Amount of gentisic acid increased only slightly and that of salicylamide remained entirely unchanged. This is thought to be because the non-dissociated form is more easily re-absorbed than the dissociated form through the urinary duct and is less absorbed, the smaller the distribution coefficients between organic solvents. The difference in the rate of change in the body between acid and alkaline urine was smaller, the greater the excretion velocity. It was found that excretion of p-aminosalicyluric acid was not changed greatly the reaction of the urine but the amount of N-acetyl-PAS was greater when the urine was acid and smaller when alkaline. There was not difference in the amount of glucuronide and sulfate excreted in the case of salicylamide.
A new furoquinoline base of Flindersia maculosa LINDL., maculine (I), was synthesized by the following route (cf. Chart 1). Condensation of 3, 4-methylenedioxyaniline (II) and diethyl (2-benzyloxyethyl) malonate (III) afforded 3-(2-benzyloxyethyl)-4-hydroxy-6, 7-methylenedioxycarbostyril (IV), which was methylated with diazomethane to the 4-methoxy compound (VI). This was cyclized by the action of polyphosphoric acid to 4-methoxy-6, 7-methylenedioxy-2, 3-dihydrofuro[2, 3-b]quinoline (VII) and its dehydrogenation with N-bromosuccinimide to form (I). Following this process for synthesis of (I), 3-(2-benzyloxyethyl)-4-hydroxy-6, 7-dimethoxycarbostyril (XIV), its 4-methoxy compound (XVI), and 4, 6, 7-trimethoxy-2, 3-dihydrofuro[2, 3-b]quinoline (XVII) were synthesized by dehydrogenation of (XVII) was extremely difficult.
Optical resolution of dl-7-methylcoclaurine (II) was effected with di-p-toluoyl-d- and -l-tartaric acid in acetone. The optically active compounds thereby obtained melted at 151-152° (oxalate, m.p. 228-230°) and had extremely low optical rotation, which was confirmed by optical dispersion, as indicated in Tables I and II. N-Methylation of the d- and l-compounds respectively afforded d- and l-armepavine (V).
In order to clearify various factors that have effect on granulation process, some examinations were made with a granule model and the results were already reported. The effect of these various factors was confirmed in the present series of experiments, using granules of calcium p-aminosalicylate prepared with a rotary wet granulator. It was found that the chief factors affecting granule strength and apparent density of granules were the following. The binders used were divided into two kinds, as shown in Table II; one of a binder solution formed by dissolving a solid adhesive agent in water and another of binder liquid, a pure liquid not containing a solid adhesive agent. Both were termed a binder. The binder used in this experiment was such that it did not cause flocculation of the powder. 1) The granule strength is affected by the particle size, apparent density, and true density of the powder, amount of binder for compounding, surface tension of the binder, and adhesive force of the agent. 2) Apparent density of the granules is affected by the particle size, apparent density, and true density of the powder, and amount and surface tension of the binder.
Application of alkanethiol to methyl β-D-glucofuranosiduronolactone (I) and acetylation of the resulting D-glucuronolactone dialkyl dithioacetal (II) afforded 2, 4, 5-tri-O-acetyl-D-glucuronolactone dialkyl dithioacetal (III). Treatment of (II) and (III) with ammonia and acetylation of its product, D-glucuronamide dialkyl dithioacetal (IV) gave 2, 3, 4, 5-tetra-O-acetyl-D-glucuronamide dialkyl dithioacetal (V). (IV) and (V) were also obtained directly from D-glucuronamide. Partial dethiolation of (IV) afforded alkyl 1-thio-α-D-glucofuranosiduronamide (VII) whose acylation gave alkyl thic-2, 3, 5-tri-O-acetyl-α-D-glucofuranosiduronamide (VIII). This cyclized structure was confirmed by periodate oxidation, Weerman test, and from infrared spectrum. By the reaction of methyl 1-bromo-1-deoxy-2, 3, 4-tri-O-acetyl-α-D-glucopyranuronate (XII) and 1-bromo-1-deoxy-2, 3, 4-tri-O-acetyl-α-D-glucopyranuronamide (IX) with sodium ethylmercaptide, ethyl 1-thio-β-D-glucopyranosiduronamide (XI) was prepared.
Sodium (alkyl-1-thio-α-D-glucofuranosid) uronate (III) was prepared from sodium D-glucuronate dialkyldithioacetal (II) and its structure was determined by derivation of (III) to its methyl ester (V) by methanolic hydrochloric acid, its amidation to alkyl 1-thio-α-D-glucopyranosiduronamide (VI), and its acetylation with acetic anhydride and pyridine to alkyl 1-thio-2, 3, 4-tri-O-acetyl-α-D-glucopyranosiduronamide (VII). Examinations were made on these ring shifts.
Infrared absorption spectra of 11 kinds of glucofuranuonic acid were measured and characteristic absorption bands for discrimination from glucopyranuronic acid derivatives and difference in the spectra between α- and β-anomers have been described. In these acetylated compounds, characteristic absorption bands specific for furanose compounds appear at around 1105cm-1 and a comparatively strong band appears at around 950cm-1 in β-anomers. The absorption bands at around 1075 and 900cm-1 in these derivatives are considered to be due to the skeletal antisymmetric and symmetric stretching vibrations of the ether bond in the furanose ring, same as in the case of the pyranose compounds.
1-Alkoxyphthalazine forms only one kind of N-oxide, 1-alkoxyphthalazine 3-oxide, by the action of monoperphthalic acid in ether or hydrogen peroxide in acetic acid (Table III). Phthalazine itself also forms only one kind of N-oxide, phthalazine 2-oxide, by the same treatment. 1, 4-Dialkoxyphthalazine is inert to treatment with monoperphthalic acid in ether and only a part of the alkoxyl group undergoes hydrolysis by the action of hydrogen peroxide in acetic acid to form 4-alkoxy-1(2H)-phthalazinone, the majority of the starting material being recovered. It may be concluded that the alkoxyl groups in 1- and 4-positions of the phthalazine ring cause steric hindrance of nitrogen in 2- and 3-positions at the time of N-oxidation.
The structure of the product obtained by the reaction of N, N′-(3, 5-cyclohexadiene-1, 2-diylidene)bisbenzamide and phenol was examined and the product was proved to be N-hydroxyphenyl-N, N′-(o-phenylene)bisbenzamide. The structure of the product obtained by the reaction of N, N′-(3, 5-cyclohexadiene-1, 2-diylidene)bisbenzamide and diethyl malonate was found to be diethyl (3, 4-bisbenzamidophenyl)malonate. The determination of these structures was made through derivation of the products to 2-phenylbenzimidazole derivatives.
Manske isolated four kinds of alkaloids, protopine, adlumidine, l-corypalmine, and structurally unknown substance, C19H19O5N, from Corydalis incisa. Extraction of the same plant, collected in Hyogo and Kyoto Prefectures afforded seven kinds of alkaloids as tertiary bases and two these were identified as sanguinarine and protopine. The others are still of unknown structure, C21H21O5N of m.p. 216-217°, C21H21O5N of m.p. 235-236°, C22H23O6N of m.p. 240°, C21H19O5N of m.p. 209°, and C21H21O4N2 forming a methiodide of m.p. 163°.
As the quaternary bases of Corydalis incisa, corysamine (a new base) and coptisine, were isolated and identified. Corysamine is a protoberberine-type base, the molecular composition corresponding to C20H16O4NI (iodide), C20H16O3NCl⋅3 1/2H2O (chloride), and C20H19O4N (tetrahydro compound). These molecular compositions correspond to that of worenine, but the melting point of the reduction product differs from that of tetrahydroworenine and the two substances must be different.
It was found that the use of cuprous chloride in the Grignard reaction of α, β-acetylenic acid resulted in the 1, 4-addition reaction. Several reactions were carried out with compounds having methyl, butyl, or phenyl as R and R′ in the above formulae and it was found that interchange of R and R′ resulted in the formation of the same 3, 3-disubstituted acrylic acid, i.e.a stable trans compound. From this fact, this 1, 4-addition reaction was assumed to proceed through the formation of an intermediate (A).
Following the preceding work on the action of hydrogen peroxide on α-cyano-ketones, a total of 20 kinds of α-cyano esters and α-cyanamides were synthesized and their reactivity with hydrogen peroxide in dilute alkali hydroxide solution was examined. The compounds synthesized included six kinds of ethyl arylcyanoacetates (I), six kinds of 2-aryl-2-cyanoacetamides (II), four kinds of ethyl 2-cyano-3-aryl-propionates (III), and four kinds of 2-cyano-3-arylpropionamides (IV), which are structurally related to α-cyanoketones. (I) and (II), which are similar to α-cyano-ketones in that they dissolve rapidly in the dilute alkali hydroxide solution, also formed the corresponding arylcarboxylic acids in 60-95% yield by decomposition with hydrogen peroxide and the manner of their decomposition was found to be the same as that of α-cyanoketones. On the other hand, (III) and (IV) are sparingly soluble in the alkaline reaction solution and their decomposition seemed to proceed in a different manner from that of α-cyanoketones. With one exception of (III), which formed arylacetic acid derivatives, all formed only a few per cent of aryl-carboxylic acid. The mechanism of this decomposition reaction by hydrogen peroxide was examined from the foregoing experimental evidences. It was thereby assumed that the compounds of (I) and (II) types, in which the effect of aryl and cyano groups work additively to form enolic C=C bond between the α-carbon and CO, undergo oxidative cleavage at this portion to form arylcarboxylic acid, while in the compounds of (III) and (IV) types, in which aryl and cyano groups do not work additively and there is no formation of the enolic bond, a double bond character between the methylene and α-carbon conjugated to the aryl group is increased to a certain extent and oxidative decomposition of this bond results in the formation of arylcarboxylic acid. The present series of experiments have given some evidences on the effect of cyano and aryl groups on enolization of a carbonyl in esters and amides with small carbonyl activity.
Menisperine was newly isolated, besides the bases found and reported to date, from the trunk bark of Phellodendron amurense RUPR. (Japanese name “Kihada”). Examination of bases in the root bark resulted in isolation of berberine, jatrorrhizine, phellodendrine. and candicine. Berberine was also isolated from the wood and berberine and jatrorrhizine from the fruit, including the seeds.
Examinations were made on the alkaloids of Liriodendron tulipifera L. (Japanese name “Yurinoki”) and liriodenine (oxoushinsunine) (II) was isolated and identified. Its mother liquor was submitted to multibuffered paper chromatography and multibuffer extraction, and two kinds of aporphine-type tertiary bases were isolated; B-Base hydroiodide, m. p. 237-239° (decomp.), C22H25O5N⋅HI=C17H11 (OCH3)3 (CH2O-O-)-(N-CH3)⋅HI, and C-base, m. p. 208-210° (decomp.), [α] D-236.3° (CHCl3), C19H19O4N=C16H10(OCH3) (CH2O-O-) (OH) (N-CH3).
The alkaloid, dehydroevodiamine, m. p. 189-190°, obtained from the leaves of Evodia rutaecarpa HOOKER FIL. ET THOMSON, was assined the structure of an anhydronium base by the following reasons. 1) Crystals have a beautiful red color which is common to anhydronium bases. 2) Basicity is stronger than evodiamine and bathochromic shift in spectrum is observed in dilute alkali solution. 3) There is no absorption of indole NH in its infrared spectrum. 4) Application of methyl iodide results in formation of an indole N-methyl derivative and this was derived to 13-methylrutaecarpine and 13-methylevodiamine.