Critical relative humidity (CRH) of the mixture with three component system among which any reaction does not take place, can be calculated from the equation (4).
As to CRH of the mixture with two component system which produce double salt, either the equation (5) or (6) will be formed experimentally, not only in Fig. 2 but also in Fig. 3 and at least one CRH out of the two can be calculated from these equations.

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The relationship between the absorption amount of moisture, W, and relative humidity, H, of both water-soluble mixture and crystalline solid was shown by linearity, at the beginning of moistening, and it was found that equation (1) was roughly established experimentally. Therefore, critical relative humidity (CRH), calculated by the pre-equlibrium method, was found to be an approximate value to the humidity when the hygroscopic velocity becomes zero. A selection of relative humidity, H, and time, t, in order to obtain CRH with high accuracy, was examined.
K of equation (1) is a constant stipulated only by the kind and temperature of the component in the mixture but it was found to be influenced slightly by the composition and inhomogenuity of the mixture. If the component of the mixture is biassed to one side, or if it is extremely inhomogeneous, the accuracy of CRH become poor.

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4-(4-Dimethylaminostyryl) quinoline 1-oxide (I) and 4-styrylquinoline 1-oxide (II) were synthesized and their reactions with various acylating agents were examined. The reaction with I developed intense color in all the cases and expected products were not obtained. In the case of II with phosphorus trichloride, phosphorul chloride, benzoyl chloride-potassium cyanide and benzoyl chloride-potassium hydroxide, the similar reactions to that of quinoline 1-oxide proceeded and no effect of 4-styryl group was noted. The reaction of II with tosyl chloride gave 3-tosyloxy-derivative in good yield. With acetic anhydride II gave 3-acetyloxy-derivative and a diacetate of 1-(4-quinolyl)-2-phenylethane-1, 2-diol. In both these cases the effect of 4-styryl group was encountered.

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Application of acetyl chloride to 4-nitroquinaldine 1-oxide results in consecutive formation of 4-nitroquinaldine 1-oxide (II), 4-chloroquinaldaldehyde 1-oxide oxime acetate (III) and or 4-chloroquinaldaldehyde 1-oxide (IV), and 4-chloroquinaldonitrile 1-oxide (V). Reaction of quinaldine 1-oxide, acetyl chloride, and silver nitrite takes exactly the same course. Structure of the products obtained by this reaction was clarified.

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Reaction of excess acetyl chloride on 4-nitro-2-picoline 1-oxide (I) with cooling results in the formation of 4-chloro-2-picoline 1-oxide (II) in 68% yield, together with formation of 4-chloropicolinaldehyde 1-oxide oxime (V) in 12% yield. If this reaction is carried out on a water bath, yield of II decreases to 4.2% with concurrent formation of 57% of 4-chloropicolinonitrile 1-oxide III and 6.3% of 4-chloropicolinic acid (IV).
When equimolar mixture of I and acetyl chloride in chloroform is allowed to stand at room temperature, 17% of II is obtained besides 42% recovery of I. If this reaction is carried out by warming on a water bath, 20-33% of II, 7-9% of III, 17% of 4-nitropicolinaldehyde 1-oxide oxime (VI), and 7.8% of 4-nitropicolinonitrile 1-oxide (VII) are obtained. This latter reaction is considered to be due to the nitrosation reaction of acetyl nitrite, formed by the reaction of I and acetyl chloride at the time of formation of II, on the active methyl group in α-position.

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As one of the series studies of the syntheses of water soluble papaverine analogs, amongst six derivatives possessing two hydroxyl groups in the phenyl ring at 1-position of isoquinoline ring, 2, 4-, 2, 5-, 3, 4- and 3, 5-dihydroxy compounds were already synthesized. In the present study 2, 3- and 2, 6-dihydro and 2-hydroxy-6-methoxy derivatives were synthesized. 2, 3-Dihydroxy derivative was synthesized from methyl 2, 3-dihydroxybenzoate via the dibenzyl ether carboxylic acid chloride. The latter was condensed with α-methyl-β-methoxy-3, 4-methylenedioxy-β-phenethylamine into the amide which was subjected to a ring closure reaction with phosphorus oxychloride to isoquinoline derivative and then debenzylated. 2-Hydroxy-6-methoxy derivative was obtained from 2′, 6′-dihydroxyacetophenone via 2-benzyloxy-6-methoxy compound, carboxylic acid chloride which was condensed with amine to acid amide and applied to ring closure reaction with phosphorus oxychloride and then debenzylated. 2, 6-Dihydroxy derivative was synthesized by demethylation of isoquinoline derivative obtained from 2, 6-dimethoxybenzoic acid. The amide which is an intermediate of 2, 6-dihydroxy derivative exists in two forms, m. p. 214-215° and m. p. 130.5-132.5°.

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We have synthesized a series of papaverine analogs possessing thiophene nucleus in 1-position and investigated their pharmacological properties. In this report, as papaverine analogs four derivatives of 6, 7-methylenedioxy-3, 4-dihydroisoquinoline (II) and four derivatives of 1, 2, 3, 4-tetrahydroisoquinoline (III) corresponding to n=0-3 were synthesized. They were prepared by the cyclization of acid amide with phosphorus oxychloride in toluene and the tetrahydro-derivatives were prepared by reduction of methiodides with sodium borohydride. The free bases of these derivatives (n=1) which possess one reactive methylene group were oxidized to keto compounds. The same oxidation to form keto derivatives was also observed in the cases of their picrates and hydrochlorides.

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As a part of synthesis of actinomycine-like polypeptides, attempt was made to synthesize polypeptides by substitution of the 1-phenazinecarboxylic acid, the parent skeleton of these antibiotics, with phenoxazine, and dipeptides and tripeptides of several kinds of amino acid were prepared. N-(1-Phenazinylcarbonyl)glycine and its ethyl ester, N-(1-phenazinylcarbonyl)-DL-alanine, -DL-valine, -DL-leucine, -DL-norvahne, -DL-norleucine, and -DL-phenylalanine were obtained by the Schotten-Baumann reaction. By the azide method using N-(1-phenazinylcarbonyl)glycine ethyl ester, N-[N-(1-phenazinylcarbonyl)glycyl]-DL-alanine methyl ester and methyl N-[N-(1-phenazinylcarbonyl)glycyl]-DL-2-aminobutyrate were obtained. As a hydroxyamino acid derivative, N-[N-(1-phenazinylcarbonyl)glycyl]-DL-serine methyl ester was obtained by the use of N, N′-dicyclohexylcarbodiimide.

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Membrane permeation was tested with bovine eye-lens capsule at 18, 25, and 37°, and the values of permeability constant (P) of the membrane and apparent membrane constant (f*) or (P/D) were calculated. The value of f* showed a maximum at 25° and the rate of decrease of f* showed a minimum value at 25°. It seemed, therefore, that the optimal temperature for permeation through this capsule is between 25° and 37°, and that this temperature probably agrees with the temperature of the anterior capsule in the living body. This temperature was measured with an electric thermistor-type thermometer and it was found to be 33.9° in bovines of 3-4 years of age.
The values of the diffusion constant (D) and degree of association (n) of Phenoxazone compounds, and of P and f* were measured at 30° and 33.9°, and the value of f* showed a maximum at 33.9° in all the dyes tested.
When membrane permeation was carried out using sodium chloride or when permeation of sodium chloride was measured after pretreatment with a dye, the relationship between permeation time and the logarithm of membrane constant was linear. Calculation of the rate of decrease of membrane constant at each temperature from the slope of this straight line showed that the rate was the smallest at 33.9°.
These experimental resultss have shown that membrane permeation of phenoxazone compounds through the bovine eye-lens capsule is the most facile at the biological temperature of the anterior capsule and that the clogging of membrane pores with sodium chloride hardly occurred at this temperature.

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Reaction of 2-ethoxymethyl-3-ethoxy-3-methoxypropionitrile (I), 2-methoxymethylene-3-ethoxypropionitrile (II), or 2-ethoxymethoxymethylacrylonitrile and o-nitrophenylhydrazine gives 1-(o-nitrophenyl)-3-pyrazoline-4-carbonitrile (VI), whose catalytic reduction over 2.5% palladium-carbon gives 1-(o-aminophenyl) compound (VII) and its diazotization affords 1H-benzo[e]pyrazolo[1, 2-a][1, 2, 3, 4]tetrazine-2-carbonitrile (VIII). On the other hand, treatment of VI with 35% palladium-carbon gives 1-(o-nitrophenyl)-4-pyrazolecarbonitrile (IX) and its catalytic reduction over 2.5% palladium-carbon results in amination to X whose diazotization gives 1-phenyl-4-pyrazolecarbonitrile (XI). By a similar reaction, ethyl 2-ethoxymethyl-3-ethoxy-3-methoxypropionate (IV) and ethyl 2-methoxymethylene-3-ethoxypropionate give ethyl 1-(o-nitrophenyl)-3-pyrazoline-4-carboxylate (XV), whose treatment with 35% palladium carbon affords the pyrazole compound (XVI). Catalytic reduction of XVI and diazotization give ethyl 1-phenyl-4-pyrazolecarboxylate (XVIII). Reaction of I, II, III, IV, and V with 2, 4-dinitrophenylhydrazine results in the formation of corresponding 1-(2, 4-dinitrophenyl)-3-pyrazoline-4-carbonitrile and ethyl 1-(2, 4-dinitrophenyl)-3-pyrazoline-4-carboxylate.

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An antitumor substance, Lampterol (C₁₅H₂₀O₄) has been isolated from a japanese poisonous mushroom Lampteromyces japonicus (KAWAM.) SING., in an overall yield of 2×10^-3% from the raw mushroom. The procedure is described in Chart 1. The activity of lampterol as measured against Ehrlich ascitic tumor in mice is 120γ/kg., and the toxicity as measured by intraperitoneal injection into normal mice is 5mg./kg. Lampterol gave a diacetate. Lampterol is isomerized to isolampterol when passed through an alumina column; isolampterol gave a triacetate.

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Cross-test between morphine, codeine, and some other drugs on antitussive and analgesic action was investigated.
(1) Antitussive action: The coughing dogs and coughing guinea pigs were used as test animals (Fig. 1). Tolerance to morphine, morphine N-oxide, codeine, and promethazine was observed. Tolerance to morphine appeared more rapidly than to codeine. Although the structure of morphine was changed into its N-oxide, days required to establish tolerance was almost the same for the two. Cross-tolerance was clearly observed between morphine and morphine N-oxide, and codeine, but such a relationship between the addicting drugs and non-addicting drugs was not found in the present experiments (Table I).
(2) Analgesic action: Morphine (100mg./kg.) or codeine (140mg./kg.) was given to guinea pigs subcutaneously. Pressure pain on the toe of the forefoot of guinea pigs was used as the test method. When small doses of morphine (8mg./kg.) or of codeine (140mg./kg.) were used to recognize the analgesic effect, induction of tolerances to drugs was observed easily and cross-tolerance between morphine and codeine was found (Fig. 2, 3, and 4).
(3) Effect for body weight: First morphine 100mg./kg. was injected to guinea pigs subcutaneously once a day for 7 days and next the same dose of morphine was given twice a day for 9 days. After this treatment, administration of drugs was suddenly stopped and a rapid decrease of body weight due to physical dependence was observed in these animals. After codeine (100mg./kg.) was given subcutaneously for 9 days to animals which were administered with morphine (100mg./kg.) for 7 days and administration of drug was suddenly stopped, no decrease of body weight was observed, suggesting compensative relationship between morphine and codeine (Fig. 6). Effect of morphine for body weight was observed more clearly on adult animals than on young animals (Fig. 5 and 6).

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Fourteen nitrofuran derivatives were comparatively examined for the ratio of their degradation rate in rat liver homogenates to their corresponding antibacterial activities. Results are shown in Table I and Fig. 1. This ratio probably indicates whether a sample should be used as a chemotherapeutic (when the ratio is more than 2) or as a preservative (when less than 1). Discussions were given about this relationship.

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6-Keto group of 14-hydroxydihydrothebainone and its 4-methyl ether (V) was reduced with sodium borohydride, lithium aluminum hydride and by Ponndorf and Bouveault-Blanc procedure. The production ratios of the resulting isomers of alcohols (III and IV, VI and VIII) were investigated. The results obtained above were compared with those of the reduction of 4, 5-ether derivative (I) (Table I and Fig. 1). The orientation of 6-hydroxyl groups of newly prepared isomers (III, IV, VI and VII) were elucidated on the basis of the results of their ethoxycarbonylation (Fig. 2) and Oppenauer oxidation.

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Ponndorf and Bouveault-Blanc reductions of 6-keto group of dihydrothebainone (VI) and its 4-methyl ether were carried out. The production ratio of the resulting 6-OH-isomers was compared with those of 6-OH-isomers obtained by the same reduction of dihydrocodeinone (III) possessing 4, 5-ether ring. On Ponndorf reduction, also in 14-H-series the orientation of 6-hydroxy group of the main product i.e. alcohol was opposite with respect to the presence or absence of 4, 5-ether ring. These results are identical with those of 14-OH-series.

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Hydrogenation of 1-benzyl-2-oxo-5-isopropyl-Δ^{4, α}-piperidine acetic acid (IV) with platinum oxide in methanol gave cis- and trans-1-benzyl-2-oxo-5-isopropyl-4-piperidine acetic acid (Xa and Xb). Xa was also obtained by hydrolysis and decarboxylation of diethyl trans-1-benzyl-2-oxo-5-isopropyl-4-piperidinemalonate (XIII), which was prepared by the Michael condensation of diethyl malonate and 1-benzyl-5-isopropyl-5, 6-dihydro-2(1H)-pyridone (XII) obtained from IV by hydrogenation with sodium borohydride and subsequent dehydration in the usual manner.
IV was prepared by acylation of I with half ester of malonyl chloride into ethyl 2-[(N-ethoxycarbonylacetylbenzylamino)methyl]isovalerate (II) and subsequent cyclization by the Dieckmann condensation, followed by hydrolysis and decarboxylation.

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A new quantitative method of atropine by fluorophotometric determination has been deviced. A sample which contains 1-100μg. of atropine is evaporated to dryness, and to this 0.5cc. of nitric acid is added. It is also evaporated to dryness on a water-bath, similarly to the treatment in the Vitali reaction. The residue is dissolved in 1cc. of water, basified by 10% sodium hydroxide, and it is reduced by zinc-grains. After the reduction for half an hour, the reduced product is diluted to the definite volume with a ethanol-water mixture (1:1) and the intensity of the fluorescence is measured. Simultaneously the standard and blank are treated similarly followed by the calculation of atropine contents in the sample. As to the filters for the measurement, Matsuda UV-D₂ is used for the excited light sorce, AKA-FL-B₁, for the selection of fluorescence and AKA-UV-O₁, for shattering the excited fluorescence. The light sorces for the excitation is the Toshiba super high-voltage merculy lamp. In this measurement, the fluorescence of atropine is stable, and the intensity shows the Iinearlity in 1-100μg. The presumable standard error for the recurrent line is considered to be σ=0.1048 (=0.3μg. Atropine).

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In order to synthesize 4-styrylquinoline derivatives possessing the substituent at 2-position of quinoline ring, condensation of 2-substituted lepidine and Benzaldehyde or p-dimethylaminobenzaldehyde were examined. Zinc chloride, acetic anhydride and potassium alcoholate were employed as the condensing agents. This method was mostly not befitting for the syntheses of 2-substituted 4-styrylquinoline derivatives since the substitution at 2-position affected greatly the activity of methyl group at 4-position.

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A convenient apparatus for precise determination of melting point was devised, using the m. p. tube of J, P. VII. (m. p. tube for visual thermal analysis adopted by Reinboldt) Through the left side arm, a thin glass tube is inserted into the bath liquid. The cork stopper supports two thermometers, one of which serves for temperature correction, and a glass tube which is connected to a water aspirator by polyvinylchloride tubing. A m. p. capillary is set through the right arm and by gentle suction, air bubbles come from the left one and stirr the liquid completely. Thus the temperature of the bath becomes uniform throughout. By this simple apparatus, rapid and accurate determination of melting point (<±0.2°) can be easily made and the danger of inhaling harmful vapor from the bath liquid is completely avoided. This is also very useful for the thermal analysis of two-component system of organic compounds. Some data of comparison between this apparatus and the original J. P. VII type were shown.

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In order to synthesize cycleanine (I) which is one of the biscoclaurine type bases, an intermediate 1-(4-hydroxybenzyl)-2-methyl-8-bromo-6, 7-dimethoxy-1, 2, 3, 4-tetra-hydroisoquinoline (dl-8-bromoarmepavine) (III) was prepared. An attempted Ullmann reaction of III failed to give I but two products, dl-armepavine (XIII), and dl-N, O, O-trimethylcoclaurine (dl-O-methylarmepavine) (XIV) were isolated from the reaction mixture. The former was formed by the dehalogenation while the latter by dehalogenation and O-methylation of III.

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As reported by Tomita, et al. the usual Ullmann reaction of potassium salt of 8-bromocorypalline (I) did not give dibenzo-p-dioxin derivative (IV) but afforded corypalline (II) and O-methylcorypalline (III). In this report, author carried out Ullmann reaction of I with potassium carbonate and copper powder in pyridine and examined the resulting products. In this case, besides II another non-phenolic base whose analytical values corresponded with IV was obtained and product III could not be detected. Since this product whose analytical values were consistent with IV showed negative dibenzo-p-dioxin reaction it would be V.

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Further detailed examinations were made on isosinomenine, m. p. 210-212°, reported as one of the alkaloids contained in Sinomenium acutum REND. et WILS. Its molecular formula was found to be C₂₀H₂₅O₄N and it had an ethoxyl group. This substance must have a structure of 3-methoxy-4-hydroxy-6-oxo-7-ethoxy-N-methyl-Δ⁵-morphinan (I) or 3-methoxy-4-hydroxy-6-ethoxy-7-oxo-N-methyl-Δ⁵-morphinan (II), and the name isosinomenine should be abolished.

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Chemical components of two Japanese ferns were studied. From the leaves of Sphenomeris chusana, vitexin (a flavonoid compound), syringic acid, protocatechualdehyde, and protocatechuic acid were isolated and identified. From the leaves of Cyathea Fauriei, vitexin was isolated and identified. This is the first occurrence of vitexin in ferns.

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The leaves of Ligularia tussilaginea MAKINO have been used from olden times as a home remedy for suppurating eruptions, same as Houttuynia cordata THUNB. The crude drug of Ligularia tussilaginea was submitted to low-pressure steam distillation and a substance with an odor of this plant was isolated, which was later identified as 2-hexanal. 2-Hexanal was effective against Staphylococcus pyogenes in 1:5000 dilution and against Trichophyton asteroides in 1:10000 dilution.

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Stability constants of iron (III) sulfate and chloride complexes (FeSO₄⁺, FeCl²⁺) at 20° were calculated by the analyses of absorption spectra of the mixed solutions of iron (III) perchlorate, perchloric acid, and sulfuric acid or sodium chloride. For this measurement, mixed solutions are prepared with constant ionic strength, constant total iron concentration, constant hydrogen ion concentration, and varying concentrations of sulfate or chloride ion. Dissociation constant of sulfuric acid (k₂) is deduced by the same operation.
Stability constants K_FeSO4⁺ and k₂ are shown in Table I, and K_FeCl²⁺ are 11.7, 6.5, and 5.2 under the ionic strength of 0.05, 0.20, and 1.0, respectively. These results are in good agreement with the value obtained by Kumai, and by Rabinowitch and Stockmyer.

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From the Aralia elata root bark mixed crystals of stigmasterol and β-sitosterol were obtained besides oleanolic acid. Also, from the Melia azedrach var. Japonica, Vitex cannabifolia, and Pinellia ternata a sterol whose physical constants were consistent with β-sitosterol was obtained. But gas chromatographic results showed the sterol to exist as mixed crystals of β-sitosterol, stigmasterol and another component probably campesterol. It follows from the above results, therefore, that pure β-sitosterol is difficult to isolate from the natural sources.

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Ethoxycarbonylation of morphine alkaloids takes place rapidly at the equatorial hydroxyl in 6-position and this was found to be a useful means for determining its configuration, especially in the presence of a hydroxyl in 14-position.

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