4-(Phenylacetyl) allophanic acid esters were prepared by the reaction of phenylacetyl isocyanates and carbamates, or of 2-phenylacetamides and ethyl isocyanatoformate. Anti-convulsant action of these products was examined.
1) 4-Thiocyanato-1-naphthylamine (I), 5-thiocyanato-8-aminoquinoline (II), 5-amino-6-chloroquinoline (IV), 4-nitronaphthylamine (V), and 5-thiocyanato-6-chloro-8-aminoquinoline (III) were each diazotized and reacted with potassium thiocyanate and copper thiocyanate to prepare 1, 4-bis (thiocyanato) naphthalene (VII), 5, 8-bis (thiocyanato) quinoline (IX), 5-thiocyanato-6-chloroquinoline (VI), 1-nitro-4-thiocyanatonaphthalene (VIII), and 5, 8-bis(thiocyanato)-6-chloroquinoline (X). Nitration of 8-acetamidoquinoline with sulfuric and nitric acid mixture afforded 5-nitro-8-acetamidoquinoline (XI), whose structure was ascertained by the formation of 5-nitroquinoline from XI by its hydrolysis, diazotization, and deamination. Application of potassium chlorate to XI and 5-nitro-8-aminoquinoline (XII) in hydrochloric acid solution afforded 5-nitro-7-chloro-8-aminoquinoline (XIII) from XII but XI was recovered unchanged. Diazotization of XII and XIII, followed by treatment with potassium thiocyanate and copper thiocyanate afforded 5-nitro-8-thiocyanate and copper thiocyanate afforded 5-nitro-8-thiocyanatoquinoline (XIV) and 5-nitro-7-chloro-8-thiocyanatoquinoline (XV), respectively. Anti-candida effect of these compounds was carried out. 2) p-Thiocyanatoaniline and 3-chloro-4-thiocyanatoaniline were diazotized and reaction with phenol, or with o- or m-chlorophenol in neutral or weakly alkaline solution to prepare the compounds XVIII to XXI. Anti-candida effect of these compounds was also tested.
Twenty-three kinds of 7-(2-hydroxy-3-alkylaminopropyl)theophylline (III to XXXV) were prepared by the reaction of amines with 7-(2, 3-epoxypropyl)theophylline (I) or 7-(2-hydroxy-3-chloropropyl)theophylline, prepared from theophylline sodium and epichlorohydrin, and from theophylline and 1-dialkylamino-2, 3-epoxypropane, and also 13 kinds of their acyl derivatives (XXVI to XXXVIII). Similarly, 10 kinds of 1-(2-hydroxy-3-alkylaminopropyl)theobromine (XL to XLIX) and two kinds of 1-(2-benzoyloxy-3-alkylaminopropyl)theobromine (L and LI) were prepared from theobromine. Among these compounds synthesized, 7-(2-benzyloxy-3-diisobutylaminopropyl)theophylline was found to be an excellent coronary artery dilator.
As a preliminary experiment for the syntheses of compound (I) and its dihydro derivative, synthesis of ethyl 1-methyl-4-oxo-trans-decahydro-3-quinolinecarboxylate (II) was investigated. Two methods, the Dieckmann condensation of ethyl trans-2-(N-methyl-2-ethoxycarbonylethylamino)cyclohexanecarboxylate (IVb) or its cis isomer (VII) and the Mannich reaction of ethyl (1-cyclohexenylcarbonyl)acetate (X) with methylamine and formaldehyde solution were found to yield compound (II) in a satisfactory yield.
1-Acetoxy-3-methoxy-6(1H)-pyridazinone (II) and 1, 3-dimethoxy-6(1H)-pyridazinone (IV) are formed by the reaction of 3, 6-dimethoxypyridazine 1-oxide (I) and acetic anhydride, but IV can also be obtained by merely heating I. Reaction of 4-methyl-3, 6-dimethoxypyridazine 1-oxide (V) and acetic anhydride results in the formation of a compound in which the acetoxyl group had undergone rearrangement to the side chain, dehydroxylated compound (VIII), and 1-hydroxy-6(1H)-pyridazinone (IX). In the case of 3-methoxy-4-methyl-6-chloropyridazine 1-oxide, the same reaction also afforded a 4-chloromethyl compound (XV). The structure of the products formed by rearrangement to the side chain was determined by oxidation of the side chain with potassium dichromate and sulfuric acid to a carboxylic acid.
A new phenolic tertiary base was isolated from Formosan Stephania japonica MIERS (Japanese name “Hasunohakazura”). It was isolated as a benzene adduct of m. p. 171-173° and was named stepholine. Its empirical formula is represented as C32H26O2(OH)2(OCH3)2(NCH3)2. Its methylation with diazomethane gives isotetradrine (VII), C32H26(OCH3)4(NCH3)2, one of the known non-phenolic bi coclaurine-type bases. Cleavage reaction of O, O-diethylstepholine (IX), obtained by ethylation of stepholine with diazoethane, with metallic sodium in liquid ammonia afforded D-(-)-N-methyl-O, O-diethylisococlaurine (XIII) as a non-phenolic base and L-(+)-N-methylcoclaurine (XI) as the phenolic base. Permanganate oxidation of O, O-diethylstepholine gave 4-ethoxy-3, 4′-oxydibenzoic acid (X). These experimental evidences indicate that the structure of stepholine should be represented as V.
An attempt was made to synthesize zeolite-like crystals hydrothermally and to study its physicochemical properties. The hydrothermal reaction was effected by the use of silica sol or sodiumm metasilicate for silicon source, sodium aluminate solution or aluminum hydroxide sol for aluminum source, and sodium hydroxide solution for alkali metal source. To study the crystallization products, optical microscope, X-ray powder diffraction method, infrared absorption spectra, and refractive index measurement were used. It was concluded that crystallization can be effected by a method different from that known in the literature, by using the mixture of solutions instead of dry gel as the starting material, or by using sodium metasilicate solution or aluminum hydroxide sol, and at the temperature lower than 100°.
Examinations were made on the coloration of various phenols by 3-methyl-2-benzothiazoline hydrazone-ammonium cerium sulfate. Majority of phenols undergo coloration by this method, irrespective of the kind and position of the substituent present but the presence of a negative group in the para-position tended to cause greater difficulty in coloration. Compounds whose absorption maximum lies above 500mμ and which color red to reddish violet are only catechol and hydroquinone among the polyphenols, and the coloration of resorcinol derivatives is orange to yellowish orange, the absorption maxima lying below 500mμ. The higher sensitivity of this method can be obtained by reacting a phenol and 3-methyl-2-benzothiazolinone hydrazone with ammonium cerium sulfate, in sulfuric acidity, and immediate basification with triethanolamine. In this case, absorption maximum was found to shift to a longer wave-length region. Coloration of para-substituted phenols is easier by the present method than by the existing coloration reactions. Colorimetric determination of phenols by the present method gave a satisfactory result, with accuracy of σ=1.48% (n=6).
Starch was oxidized with nitric acid under various conditions and the amount of glucuronic acid residue (I), non-uronyl carboxyl group (II), and carbonyl groups (III) of free aldehyde and ketone groups was determined in the oxidized starch. I was determined by the continuous furfural extraction method, II was calculated from the difference of total acid radical by alkali titration and that based on the amount of I, and III was calculated from the amount of hydrogen consumed in sodium borohydride reduction. Free aldehyde group was determined by sodium chlorate oxidation. It was thereby revealed that nitric acid oxidation of starch effects oxidation of secondary alcohol as well as primary alcohol, the maximum of glucuronic acid residue in oxidized starch being ca. 50%. Low-temperature oxidation with high concentration of nitric acid is marked by formation of carbonyl group and high-temperature oxidation with low concentration of nitric acid, non-uronyl carboxyl group.
There are two kinds of chief products by thorough catalytic oxidation of benzyl maltoside (I) and they were confirmed to be benzyl 4-O-(α-D-glucopyranosiduronyl)-D-glucoside (II) and benzyl glucuronoside (III). II was isolated as the crystalline methyl ester hexaacetate (IV) by the acetylation of a mixture of oxidation products. All the protective groups in III were liberated and purified by cellulose adsorption to glucuronic acid (VIII). The structure of II was determined from the analyses of IV, of 4-O-(α-D-glucopyranosiduronyl)-D-glucose prepared from VI, and of two kinds of methylated sugar obtained by methylation of VI followed by acid hydrolysis. VIII was confirmed by its derivation to crystalline glucuronolactone (XI). Contrary to expectations, presence of benzyl 4-O-(α-D-glucopyranosiduronyl)-D-glucuronoside (XII) was not detected in the oxidation product. Further catalytic oxidation of II merely gave III, with recovery of II and formation of XII was not detected. Oxidation of II, therefore, seems to cause severance of the α (1, 4) linkage. Various properties of the new compound (VI), especially the result of its acid hydrolysis, are discussed.
The reaction of 1 mole of maltose and 3.6 moles of trityl chloride in pyridine followed by acetylation afforded 6′-tritylheptaacetylmaltose (IV), m. p. 162-163°, and 6, 6′-ditritylhexaacetylmaltose (V), m. p. 215-217°. Deacetylation of IV and V respectively afforded 6′-tritylmaltose (VI), m. p. 137-139°, and 6, 6′-ditritylmaltose (VII), m. p. 149-152°. The structure of these compounds was determined from their analytical values, their infrared spectra, and confirmation of methylglucoses obtained by methylation of VI and VII, followed by acid hydrolysis. The ditritylmaltose, m. p. 137-139°, and ditritylhexaacetylmaltose, m. p. 116-119°, reported by Josephson are not a unity and were proved by the present work to be a mixture, respectively, of VI and VII, and of IV and V. The use of a large excess of trityl chloride in tritylation of I results in by-product formation of VI and VII alone is not obtained, indicating that the two primary alcohols in I behave differently. Detritylation of IV and V respectively gave heptaacetylmaltose (XI) and hexaacetylmaltose (XII). It was found that Helferich's method cannot be used in the case of V since this method results in the by-product formation of acetobromo compound.
Oxidation of the primary alcohol group (-CH2OH) in sugar acetates to carboxylic acid group (-COOH) had been effected by potassium permanganate method reported by Stacey but this was found to be not applicable to disaccharides like heptaacetyimaltose (I) and hexaacetylmaltose (II) because the reaction rate is extremely small and the yield is low. Oxidation agents to be used in such cases were examined and the concurrent use of chromium trioxide and potassium permanganate was found to be a good method. Application of 2/3 mole of chromium trioxide to 1 mole of primary alcohol in I and II under limited conditions and subsequent oxidation with potassium permanganate afforded heptaacetyl-4-O-(α-D-glucopyranosiduronyl)-D-glucose (III) and hexaacetyl-4-O-(α-D-glucopyranosiduronyl)-D-glucuronic acid (IV), which were deacetylated respectively to 4-O-(α-D-glucopyranosiduronyl)-D-glucose (VII) and 4-O-(α-D-glucopyranosiduronyl)-D-glucuronic acid (VIII). The reaction rate of this oxidation is very large and the yield is very high but the condition of chromium trioxide oxidation is very limited and the sugar is decomposed outside this condition, Various properties of the new compound (VIII), especially the result of its acid hydrolysis, are discussed.
Direct oxidation of glucose polymers like starch with oxidation agents of nitrogen dioxide system does not afford glucuronic acid polymers. Therefore, amylase (I) was tritylated to tritylamylose (II), its acetylation to acetyltritylamylose (III), and detritylation of III gave (poly 2, 3-acetyl) amylose (IV). Oxidation of IV with chromium trioxide and potassium permanganate by the method previously reported afforded the objective α (1, 4) polysaccharides (VIII) of glucuronic acid. Oxidation of IV under various conditions or repeated oxidation of IV resulted in termination of the reaction invariably when one-half the amount of primary alcohol group in IV had been oxidized to the carboxylic acid group. Various properties of VIII were examined and it was found that glucuronic acid residues were distributed randomly, resulting in the concurrent presence of glucose and glucuronic acid polymer structures in the molecule. Intrinsic viscosity was found to be obtained by measuring its viscosity in the glycocoll buffer solution (pH 9). The various properties of VIII were found to be different from those of oxidized starch obtained by oxidation with nitric acid.
Rats were fed on a rice diet containing 0.06% of 4-dimethylaminoazobenzene (DAB) and their urine was examined by two-dimensional paper chromatography. In normal rats, free amino acids in the urine were approximately seven kinds, glycine being the most abundant, and including alanine, glutamic acid, cystine, arginine, histidine, and leucine. In the urine of DAB-administered rats, kind and amount of amino acids increased with increasing dosage of DAB given. The amount of tyrosine and kynu-renine tended to increase markedly. Quantitative determination was made on the total nitrogen, free tyrosine, and free kynurenine in the 24-hour urine of one rat per week during 16 weeks after the start of administration of DAB, corresponding to the period for formation of liver tumor. There was no great variation in the amount of total nitrogen in the urine during this period but the amount of free tyrosine and free kynurenine was found to increase markedly parallel with the preceding formation of a tumor.
A glycoside, isolated from the fresh root of Polygonum cuspidatum SIEB. et ZUCC. and named polydatin, was newly examined. Its molecular formula corresponded to C20H22O8⋅3H2O and its constants were m. p. 225-226°, [α]D27 -74.9° (c=1.709, EtOH). Its hydrolysis afforded a phenol, C14H12O3, and glucose. The aglycone formed an acetate (C20H18O6), methylate (methoxide) (C17H18O3), benzoate (C35H24O6), and a dihydro derivative (C14H14O3). The ultraviolet spectra of these derivatives resembled those of stilbene derivatives. Oxidative decomposition of the methylated glycoside afforded anisic acid and the same treatment of the methylated aglycone gave anisic acid and 3, 5-dimethoxybenzoic acid. These experimental evidences indicate that the aglycone is resveratrol and the glycoside was identified as 3, 4′, 5-trihydroxystilbene-3-β-mono-D-glucoside (piceid). An anthraquinone and resveratrol were isolated from the ether-soluble portion and the latter was identified through paper partition chromatography and mixed melting point determination.
Hasubanonine, m.p. 116°, C21H27O5N=C16H12O(OCH3)4⋅NCH3, one of the alkaloids of Stephania japonica MIERS (family Menispermaceae. Japanese name “Hasunohakazura”), forms acetylhasubanol, C19H18O5, by the Hofmann degradation followed by acetolysis, and hydrolysis of the acetylhasubanol gives hasubanol, C17H16O4, which is positive to the Gibbs reagent and forms methylhasubanol, C18H18O4, on methylation. Methyl-hasubanol was confirmed as 3, 4, 6, 8-tetramethoxyphenanthrene (III) by synthesis. Since hasubanol is positive to the Gibbs reagent, Satomi assumed it to be 3, 4, 6-trimethoxy-8-hydroxyphenanthrene. In the present series of work, hasubanol was derived to ethylhasubanol, which was proved to be 3, 4, 8-trimethoxy-6-ethoxyphenanthrene (VI) by its synthesis. It follows, therefore, that hasubanol is not II but is 3, 4, 8-trimethoxy-6-phenanthrenol (VII).
Basic components in the root and terrestrial portion of Formosan Stephania japonica MIERS (family Menispermaceae. Japanese name “Hasunohakazura”) were systematically isolated. Metaphanine (IX), epistephanine (I), protostephanine (V), and stephanine (IV) were isolated as the non-phenolic tertiary bases, and hypoepistephanine (II) and bases tentatively designated as A, B, and C were isolated as the phenolic tertiary bases (cf. Table I). Hasubanonine (VII), contained in the Japanese Stephania japonica, was not isolated or detected in the Formosan plant.
Colorimetric determination of thebaine was examined by the use of its coloration with 3-methyl-2-benzothiazolinone hydrazone. Treatment of thebaine with dilute hydrochloric acid, reaction with 3-methyl-2-benzothiazolinone hydrazone with ammonium cerium sulfate in acidity, and basification with triethanolamine produces a reddish violet color which has an absorption maximum at 550mμ. Determination of thebaine by this method was found to be possible with good sensitivity. Presence of codeine, narcotine, and papaverine, in an amount twice that of thebaine, does not interfere in this coloration. Morphine does not interfere in this reaction as long as its amount is one-half that of thebaine but causes positive error above that amount. When morphine is present, its effect can be eliminated by using a sample solution containing it as the control without treatment with hydrochloric acid. Accuracy of determination by this method is σ=1.01% (n=6).