o-Phenylenediamine reacts rapidly and quantitatively with phthalaldehyde in sulfuric acid-ethanol soultion to form strongly fluorescent 11H-isoinodolo [2, 1-α] benzimidazole (I). By using the excited wave length of 320 mμ and fluorescence wave length of around 350 mμ of I, a fluorometric determination of o-phenylenediamine in a concentration of 1×10-12 to 6×10-9 moles in 1 ml of a sample solution has been proposed. Reaction of m- and p-phenylenediamine with phthalaldehyde respectively give 2, 2'-(1, 3-phenylene)-di-1-isoindolinone (II) and 2, 2'-(1, 4-phenylene)-di-1-isoindolinone (III). Formation of II and III is much slower than that of I, their fluorescence intensity is weaker, and the wave lengths of their fluorescence differ markedly from that of I. By using such a difference in the optical properties of I, II, and III, the present method of determination made it possible to selectively determine o-phenylenediamine in the presence of m- and p-phenylenediamines.
On heating α-acyl-3, 4-dimethoxyphenylacetonitriles (I) with H2NCHO and POCl3, pyrimidines (III) were obtained, but isoquinolines could not isolated : the α-formyl derivative (Ia) gave 4-amino-5-(3, 4-dimethoxyphenyl) pyrimidine (IIIa), the α-acetyl derivative (Ib) gave 4-amino-5-(3, 4-dimethoxyphenyl)-6-methylpyrimidine (IIIb), and the α-benzoyl derivative (Ic) gave 4-amino-5-(3, 4-dimethoxyphenyl)-6-phenylpyrimidine (IIIc). 3, 4-Dimethoxyphenylacetonitrile (II) gave IIIa under the same reaction conditions.
All the starting materials use in the previous work on were benzylcarbonyl compounds with a cyano group in the α-position. The CN function was favorably involved in this reaction to lead to a pyrimidine. Experiments with compounds without a CN group were undertaken in the hope that they may furnish the desired isoquinolines. Heating of 3, 4-methylenedioxyphenylacetone (Ia) or 3, 4-dimethoxyphenylacetone (Ib) with formamide and phosphoryl chloride gave the corresponding isoquinolines (II) as expected. However, homopiperonal (III) gave a naphthalene derivative (IV), benzoin (Va) or piperoin (Vb) afforded an oxazole derivative (VI), anisoin (Vc) formed an imidazole derivative (VII), and desoxybenzoin (VIII) was led to 4, 5-diphenylpyrimidine (IX) under similar reaction conditions.
A method has been established for the judgement of hemp (Cannabis sativa L.) by the use of infrared absorption spectrum. In this method, ether is added to hemp or hemp resin and the mixture is shaken in a water bath at the boiling point of ether. The extract solution is filtered, the filtrate is concentrated, and a part of the concentrated extract is spotted on a KBr disc with a capillary to form a thin membrane. This membrane is submitted to infrared spectral measurement. Hemp and hemp resin show absorptions in common wave-numbers, though of different intensity, and it was possible to discriminate hemp from other plants or similar substances from the presence or absence of characteristic absorptions and the concerted pattern formed from these absorptions. Characteristic absorptions appear at 1700-1740, 1620, 1560-1580, 1510-1515, 1460-1465, 1425-1430, 1380-1385, 1255-1280, 1120-1135, 1050-1080, 825-860, and 720-735 cm-1. Tobacco plant, Moraceae family plants, and other allied substances often mixed in hemp do not show much absorptions under the present extraction conditions, or show different absorption pattern, and can clearly be distinguished from those of hemp. This method showed a good accuracy in many of the substances to be evaluated and the result agreed well with that of the existing method. The present method is simple as a method for rapid and micro-amount determination, has a good accuracy, and does not require standard substance as in thin-layer and gas chromatography. Above all, there is no less of the sample (evidential substance) that the method will be quite suited for use in forensic chemistry.
5-Amino-3, 4-dimethylisoxazole (I) was treated with nitrous acid in a large excess of concentrated hydrochloric acid, followed by gradual warming, and afforded 3-chloro-2-methyl-butenamide-2 (Xb). In the case of equimolar hydrochloric acid, a dimeric product (III) was obtained. In another way, the dimeric compound (III) was prepared from ethyl α-methylacetoacetate (V) and hydroxylamine hydrochloride. Reaction of 3-amino-5-methylisoxazole (XII) in acetone or methyl ethyl ketone with excess hydrochloric acid and ethyl nitrite gave the only corresponding hydrazone (XV or XVI), which result from the coupling of the diazotised XII with acetone or methyl ethyl ketone, respectively. Under these conditions the expected halogenated isoxazole was not obtained from these methyl-aminoisoxazoles.
Pharmacological activities of three optical isomers of 1, 2-diphenyl-1-pyrrolidinoethane hydrochloride were examined. A) Differences in pharmacological activities of the isomers were as follows : (1) Antitussive effect : The 50% antitussive doses of the d-, dl-and l-isomers, evaluated by the "coughing dog and cat" methods, were 2.84, 1.92, and 1.18 mg/kg (i.v.), respectively, in unanesthetized dogs ; 3.30, 2.02 and 1.36 mg/kg (i.v.), respectively, in lightly pentobarbitalized cats. In dogs, all of the isomers tested were more potent than codeine ; the l-isomer, the most potent one, was 3.18 times, and even the least potent d-isomer was 1.25 times as effective as codeine. (2) All of the three isomers were more potent than codeine in the potentiating action on hexobarbital anesthesia in mice. The l-isomer was the most potent in this action, followed by the dl- and d-isomers. (3) In the hypothermic action on rat body temperature, the dl- and l-isomers were weaker than the d-isomer, and the l-isomer was the weakest. (4) The d-isomer produced a significant inhibitory effect on transportation of intestinal contents in mice. On the other hand, the dl- and l-isomers had no effect. (5) All the three isomers were more potent than procaine in both surface and infiltration anesthesia in guinea pigs. The l-isomer was the most potent in this action, followed by the dl- and d-isomers. The potency of the isomers ranged from 1.6 to 2.8 times that of procaine. B) The three isomers showed similar qualitative as well as quantitative effects in the following items : (1) Toxic symptoms and LD50 in mice. (2) No analgesic action in mice. (3) Effects on respiration and blood pressure in urethanized rabbits. (4) Antagonistic effect on acetylcholine-, BaCl2-, and histamine-induced spasms of the isolated guinea pig ileum. C) Pharmacological characteristics of d-isomer as an antitussive were as follows : The safety margin of antitussive effect by intravenous administration in the dog was roughly estimated as 8.8-10.6, which is a smaller value than that of codeine. The antitussive effect of the compound was not antagonized by Nalorphine. However, tolerance developed rapidly by repeated daily administrations. No withdrawal symptoms were observed by an abrupt withdrawal of the compound or Nalorphine substitution.
The reaction of 5-amino-4-ethoxycarbonyl-3-methylisoxazole (II), synthesized by ring closure of ethyl α-cyanoacetoacetate (I) with hydroxylamine, with nitrous acid in large excess of hydrochloric acid, hydrobromic acid, or hydrofluoric acid afforded the corresponding chloro-, bromo-, or fluoro-isoxazole (III, VI, and VII) in about 40% yield. This method was applied further to methyl o-aminobenzoate (XX) and o-nitroaniline (XXII) which are not fluorinated by the normal Schiemann reaction and the corresponding fluorinated compounds (XXI, XXIII) were obtained in 10-15% yield. The halogen in 5-haloisoxazoles was substituted with nucleophilic reagents, such as ammonia, morpholine, etc. These halogens are activated by the presence of adjacent carbonyl group (Chart 2 and 3). It was therefore, conclude that this procedure is suitable for fluorination of compounds whose intermediate diazoniumfluoroborate is soluble in water, and of aminoazole derivatives.
The absorption, distribution, excretion, and metabolism of 14-hydroxydihydro-6β-thebainol 4-methyl ether (oxymethebanol) (I), a new strong antitussive derivative of morphine, in rats and mice were examined by radiochemical and autoradiographic methods. A peak blood level was reached within one hour after its subcutaneous administration and nearly 60 and 80% of the dose were excreted in urine during the first 6 and 12 hours, respectively. Dihydrocodeine, used for comparison, showed somewhat lower urinary excretion and relatively higher fecal excretion. Whole-body autoradiography in mice using oxymethebanol [1-3H] showed that in addition to the urinary route, which mainly contributes to the excretion, excretion into stomach and bile is also involved, in particular, at the early and later stages, respectively. At 24 hours after the administration a slight radioactivity remained only in bile and intestinal contents, showing no other organ or tissue to retain the radioactivity. Brain uptake of oxymethebanol was found to be very small except pituitary, while dihydrocodeine showed an appreciable penetration into the brain. Tissue concentrations of oxymethebanol in rats reached a maximum at around one hour after its subcutaneous administration, the concentration increasing in the following order ; kidney>liver>stomach wall>lung>diaphragm>cardiac muscle>blood>brain. Dihydrocodeine was characteristic in higher concentrations in brain and stomach wall. Most of the radioactivity in urine after subcutaneous and oral administration of oxymethebanol was due to unchanged oxymethebanol and its bound form, possibly glucuronic acid conjugate, with small amounts of 3-O-demethylated (IV), N-demethylated (V), and 3-O, N-demethylated (VII) compounds. Among rat tissue homogenates, only liver showed an activity for demethylating oxymethebanol.
Colorimetric determination of Chlorpheniramine maleate (I) and Tripelennamine hydrochloride (II) in mixed anti-cold pharmaceutical preparations was examined, and a selective assay method was established. It is based on the formation of water-insoluble and organic solvent-soluble combaltothiocyanate complexes from aqueous solution of I and II. Each of these complexes is found to have the formula (Base·H)2 [Co (NCS)4]. The molar extinction coefficients (ε) of the complexes in CHCl3 at 620 mμ (λmax) are 1600 for Chloropheniramine maleate and 1620 for Tripelennamine hydrochloride. Assay method is as follows : To 2.0 ml of sample solution (I or II, 0.2-2 mg/ml) is added 10.0 ml of cobalt thiocyanate solution, prepared by dissolving 27.2 g of potassium thiocyanate, 20.4 g of cobalt nitrate, 13.6g of sodium acetate, and 10 ml of 1N hydrochloric acid in water to make 100 ml. After extracting the resulting complex with 10.0 ml of benzene, the extract solution is dried over anhydrous sodium sulfate, and absorbance is determined at 625 mμ. Standard solution is prepared in the same way.
Some hydroxyindoloquinoxaline derivatives were prepared to obtain their metal complexes. Both 1-methoxy- and 4-methoxyindoloquinoxalines (I and II) are formed when isatin (III) is condensed with 2, 3-diaminoanisole in glacial acetic acid, but it was found that only I is formed by condensation of III with 2-amino-3-methylaminoanisole, and only II with 2-methylamino-3-aminoanisole. 7-Hydroxy and 10-hydroxy derivatives were obtained by the condensation of III derivatives with o-phenylenediamine.
Trialkyltin chlorides were reacted with magnesium in tetrahydrofuran to obtain hexaalkylditins in a good yield (hexaethylditin, 86.0% ; hexabutylditin, 70.3%). The reaction of hexaethylditin with aroyl chlorides (R·C6H4COCl : R=H ; o-, m-, or p-CH3 ; o-, m-, or p-Cl ; p-OCH3 ; p-NO2) was examined. In the case of R=H, CH3, or Cl, the corresponding cis- and trans-α, α'-bis (aroyloxy) stilbenes (Ia-g, IIa-g) were obtained in 20-64% yield. The configuration of these stilbenes was determined by comparing UV or IR spectrum of each analogue. In the case of R=OCH3 or NO2, however, only the corresponding aroic anhydride was unexpectedly obtained.
25-O-Acetylcimigenoside (I), mp 234-235°, C37H58O10, is obtained from the subterranean portion of Cimicifuga acerina and 25-O-methylcimigenoside (IV), mp 268-270°, C36H58O9, from that of C. acerina and C. japonica. Enzymic hydrolysis of I gave 25-O-acetylcimigenol (II) while its acid hydrolysis gave cimigenol (VII) and xylose. Acetylation of I, followed by chromium trioxide oxidation and acid hydrolysis gave cimigen-15-one (III). From these evidences and from the measurement of NMR spectrum and ORD, formula I was given to 25-O-acetylcimigenoside. IV formed 25-O-methylcimigenol (V), either by refluxing with 50% acetic acid or by enzymic hydrolysis. Acetylation of IV followed by chromium trioxide oxidation and consecutive alkaline and acid hydrolyses gave 25-O-methylcimigen-15-one (VI). Formula IV was given to 25-O-methylcimigenoside from the above experimental results and measurement of NMR spectrum and ORD.
Cimicifugenol, C30H48O, occurs as colorless needles, mp 112-113°, [α]15D+21.4°, and is obtained in a free form and as an ester from the subterranean portion of Cimicifuga acerina, C. simplex, and C. japonica. From its chemical reactions and physicochemical properties, its structure was determined as represented by formula I. I forms an acetate (IV) of mp 118-119°, C32H50O2. Its hydrogenation in ethanol-ethyl acetate over platinum dioxide or palladium carbon results in the formation of a dihydro compound (V), mp 116.5-117.5°, C32H52O2. Treatment of V with tert-butyl chromate gives an α, β-unsaturated ketone (VI), mp 185-186°, C32H50O3, whose treatment with lithium in ammonia gives a ketoacetate (VII), mp 179-180°, C32H48O3. The Huang-Minlon reduction of VII produces a cycloartanol (III). On the other hand, hydrogenation of I over palladium-carbon in acetic acid-acetic anhydride results in the formation of a tetrahydro compound (X), mp 128-129°, C30H52O, whose treatment with phosphorus pentachloride gives a dehydrated rearrangement product (XII).
Fatty acid monoesters of ascorbic acid (I) reduce selenious acid quantitatively to reddish elemental selenium. By using this reaction, a new method for determination of I was established. This quantitative method has a higher sensitivity and a better accuracy than any other known method. The oxidation products of I, and the usual substances contained in ordinary vitamin preparations such as vehicles, antioxidants, preservatives and all the other vitamines do not interfer with the determination. However, strong reducing agents must be absent because they show the same reaction. These interferences can be removed by extraction of (I) with chloroform. Minimum of (I) determinable by this method is 2.0 mg/ml.
Thirty kinds of azine series compounds and 29 kinds of p-bromosalicyloylhydrazine derivatives were synthesized and their antibacterial activity was tested against human tubercle bacilli, H37Rv strain. None of the azine series compounds proved to be effective when tested in the Kirchner medium added with 10% serum, using the sensitive strain and a strain resistant to three agents (>50 μg/ml of PAS, >50 μg/ml of INH, and>300μg/ml of streptomycin). Among the p-bromosalicyloylhydrazine derivatives tested in Tween-albumin medium, using a sensitive strain, p-bromosalicyloylhydrazones of 2-hydroxybenzaldehyde, 2-pyridinecarboxaldehyde, 2-hydroxy-1-naphthaldehyde, 8-hydroxy-5-quinolinecarboxaldehyde, and 8-hydroxy-2-quinolinecarboxaldehyde all inhibited bacillary growth at 12.5 μg/ml, indicating that the substitution of the amino group in p-aminosalicyloylhydrazine with bromine resulted in marked decrease of the antibacterial activity and that the presence of an amino group in the 4-position of PAS is a requisite for its antibacterial activity.
Ether cleavage reaction of (±)-O-methylstepharotine (XIVa) by metallic sodium in liquid ammonia results in the demethylation of the methoxyl at 9-position of the tetrahydroprotoberberine skeleton to form (±)-9-hydroxy-2, 3, 10, 11-tetramethoxy-5, 6, 13, 13a-tetrahydro-8H-dibenzo [a, g] quinolizine (XXVII). Proof of the structure of the phenolic base (XXVII) was given by a Pictet-Spengler type dibenzoquinolizine synthesis which gave rise to both (XXVII) and (±)-stepharotine (XXVIII).
Fatty acid monoesters of ascorbic acid (I) in chloroform solution reduce selenious acid at room temperature and release selenium which appears as a stable brick-red colored colloidal solution. Because of the sensitivity of the reaction it is possible to identify very small quantities of I. The simplicity of the procedure permits rapid analysis, suitable for routine control. The method is highly specific for the identification of I in the presence of free ascorbic acid, its dehydro derivatives (III) and all the other substances normally found in pharmaceutical preparations. The limit of sensitivity of the method is 40 μg/ml.
The alkaloidal components of the leaves of Cocculus laurifolius DC. (Menispermaceae ; Japanese name, "Kohshu Uyaku") were examined. From the phenolic base fraction, L-reticuline (VIII) of known structure was isolated. As the non-phenolic alkaloid, a new alkaloid was isolated and was named erythroculine (IX). The known alkaloids, laurifoline (V) and magnoflorine (VI), were also isolated from the water-soluble quaternary base fraction.
A new general method for synthesis of 5-aryl-2-methyl-1, 3, 4-thiadiazoles by the reaction of ethyl dithioacetate and acylhydrazine in boiling ethanol was attempted and it was unexpectedly found that 1, 3, 4-oxadiazole is sometimes formed. Under a comparatively mild reaction condition or by a proper selection of reaction medium, a few thioacetylacylhydrazines, and 2-methyl-, 2, 5-dimethyl-, 2-methyl-5-(3-pyridyl)-, and 2-methyl-5-(4-pyridyl)-1, 3, 4-thiadiazoles were found to be formed.
Composition of the fruits of Melia azedarach L. var. japonica MAKINO was examined and three kinds of triterpenoid were isolated. These were tentatively designated as compd. A (I), mp 220-223°, compd. B (II), mp 202-206° and compd. A acetate (III), mp 184-186°, respectively. Two kinds of diacetates derived from compd. B were found to be identical with two acetates of turraeanthin. Compd. A and compd. A acetate were presumed to be epimers at C21 of melianone and melianone acetate, respectively.