Reaction of ammonia water and a diketene in sodium hydroxide solution in the cold affords 3-acetyl-6-methyl-2, 4-pyridinedione (II) besides acetoacetamide (I). This reaction was carried out under the same condition with various aliphatic amines, and Nsubstituted pyridinone-type compounds (V) were obtained from the reaction with methylamine, ethylamine, propylamine, ethanolamine, and benzylamine, but structurally isomeric pyrone-type compounds (VI) were obtained from the reaction with isopropylamine, tert-butylamine, and cyclohexylamine. Formation of the latter was considered to be due to the steric effect of the amines used.

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Syntheses of 1-spiroalkano-, 1-spiroheteroalkano-, and 1, 1-disubstituted 1, 2, 3, 4-tetrahydroisoquinolines are described. 3-(2-Aminoethyl)phenol as a starting material was synthesized as follows. Demethylation of m-methoxyphenylacetonitrile, which was obtained by benzyne reaction of o-chloroanisole with acetonitrile, with pyridine hydrochloride gave m-hydroxyphenylacetonitrile, whose ethanolic solution saturated with ammonia was hydrogenated in the presence of Raney nickel and gave the expected 3-(2-aminoethyl)phenol. On the other hand, one cycloalkanone, cyclohexanone, three heterocyclic ketones, 1-methyl-4-piperidone, 1-benzyl-4-piperidone, and 2, 3, 5, 6-tetrahydro-1, 4-thiapyrone, and four noncyclic ketones, acetone, ethyl methyl ketone, benzaldehyde, and acetophenone, were used as one of the starting materials, followed by usual phenolic cyclization, to afford eight kinds of the corresponding new tetrahydroisoquinolines.

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Examinations were made on the chelate titration of 3, 4, 5, 6-tetrachloro-3', 4', 5', 6'-tetrahydroxyfluoran methyl ester (Cl-gall-CH₃) using rare earth elements (La, Ce, Pr, Sm, Nd, Y, Gd), and absorption photometric determination of rare earth elements using cetylpyridinium bromide and Cl-gall-CH₃. It was thereby found that rare earth elements can be determined by absorption spectrophotometry, in the amount approximately 0-4 μg/ml, by using Cl-gall-CH₃-rare earth element complex (2 : 1 molar coordinate) with the metal reagent of La, Ce, and Y, at pH 7.1, using absorptions at 655 mμ (Ce), 660 mμ (Gd), and 670 mμ (La, Pr, Sm, Nd, Y).

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Treatment 3, 5-dimethoxyphenylacetonitrile(II) with (CH₃)₂NCHO and POCl₃ under the usual conditions of the Vilsmeier reaction gave 3-chloro-6, 8-dimethoxyisoquinoline(IV). Although IV had already been synthesized from II by the Gattermann reaction, ⁴⁾its formation from II by the Vilsmeier reaction has not been described. Under the conditions of the Vilsmeier reaction only modified by using H₂NCHO in place of (CH₃)₂NCHO, 2-(3, 5-dimethoxyphenyl)-5-(4-methoxyphenyl)-3-oxopentanonitrile (V) gave 4-isoquinolinecarbonitriles(VI and VII). The formation of VII may proceed through the elimination of the acyl group, since 4-methoxydihydrocinnamamide (VIII) was isolated from the reaction mixture. Several other α-acyl-3, 5-dimethoxyphenylacetonitriles (IXa, b, c, and d) were used to generalize this direct isoquinoline synthesis, and the corresponding 4-isoquinolinecarbonitriles(Xa, b, c, and d) were obtained without any acyl group elimination. In the case of IXa and IXd, enamines(XIa and XId) were also isolated as by-products.

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Details are given on previously reported rearrangement of alkyl N, N-dimethylthionocarbamates holding a neighboring anchimeric group at β-position of alkyl group to the corresponding N, N-dimethylthiolcarbamates.²⁾ Several 2-dialkylaminoalkyl N, N-di-methylthionocarbamates were thermally treated. When the dimethylamino group and the thionocarbamate group of these compounds were in the antiparallel coplanarity, they underwent rearrangement to the corresponding N, N-dimethylthiolcarbamates, while the compounds with both groups situated in the cis relationship did not undergo this rearrangement. A pair of position isomers, DL-1-dimethylamino-2-propyl N, N-dimethylthionocarbamate (XVII) and DL-2-dimethyl-amino-1-propyl N, N-dimethylthionocarbamate (XVIII), gave the same rearrangement product, DL-2-dimethylamino-1-propyl N, N-dimethylthiolcarbamate (XX). These findings are correspond to those reported earlier on dialkylaminoalkyl S-methyl xanthates.^{4a, b)} This analogy between xanthates and thionocarbamates further supports the reaction mechanism^4b) postulated previously for this kind of rearrangement.

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Digestion of boiled rice by various amylases was tested in vitro at pH 6.0 and 4.7, and at 37°. The results showed that the digestion was best related to the starch liquefying activity of the amylases among the three expressions of the amylase activity, i. e., saccharifying, dextrinizing, and liquefying. A. oryzae amylase was weak in the dextrinzing activity on amylopectin itself, and was weaker on that in starch, because it had more affinity to amylose than to amylopectin so that it was the weakest of all in the starch liquefying activity. A. oryzae amylase was adsorbed markedly on boiled rice at pH 4.7 and 37°, and it remained active as a saccharifying amylase losing its original liquefying character. Salivary amylase was weak in the dextrinizing activity on amylopectin itself, but it was strong in the starch liquefying activity because of its marked affinity to amylopectin in starch. B. subtilis amylase was strong in the starch liquefying activity as well as in the dextrinizing activity on amylopectin itself, and was characterized by its high reaction rate in early stage of amylopectin decomposition. The above dextrinizing activity of amylase on amylopectin itself was discussed on the . basis of its dextrinizing activity on amylose itself, and the starch liquefying activity and the dextrinizing activity on amylopectin in starch were discussed on the basis of its starch dextrinizing activity.

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Examinations were made on the reactivity of alicyclic ether compounds and nitriles in the presence of Lewis acid. Various kinds of oxazoline and oxazines were synthesized in one step from epoxides, oxetanes, or corresponding glycols, and the raaction mechanism involved in this synthesis was discussed. The compound obtained from tetrahydrofuran was not the corresponding oxazepine but N -acylpyrrolidine.

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In order to examine antibacterial and antifungal activity, a number of sulfur-containing pyridazinone derivatives were synthesized. Among the compounds tested, some of the mercapto, alkylthio, alkylsulfonyl, alkylsulfinyl, and thiocyanato derivatives revealed strong antibacterial or antifungal activities in vitvo.

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Oxidation of 1-phenoxy-or 1-(2-substituted)phenoxy-3-diethylamino-2-propanols(I) to the corresponding ketones with various reagents was examined. 1) Oxidation of I with hydrogen peroxide or periodic acid resulted in recovery of the starting material. 2) Mild oxidation of I with acidic potassium permanganate afforded a fair amount of amino-ketones, together with cleaved products, phenoxyacetic acid, diethylamine, and carbon dioxide. At the same time, a small amount of bis(1-phenoxy-3-diethylaminopropyl) ether was obtained as the abnormal oxidation product. The presence of a nitro group in the ortho position accelerated the cleavage reaction and o-nitrophenol was isoated in the oxidation of 1-(o-nitrophenoxy)-3-diethylamino-2-propanol. 3) Oxidation with chromium trioxide or potassium dichromate gave result similar to that of permanganate oxidation. 4) Amino-ketones were obtained in a satisfactory yield, without being accompanied by cleavage reaction, by the use of aluminum or potassium tert-butoxide. 5) The amino-ketones were cleaved into phenoxyacetic acid and diethylmethylamine by treatment with alkali hydroxide solution.

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Use of m-cresol improved the reproducibility of data and lowering of blank value from any other method for the determination of ammonia through indophenol formation. The present method demonstrated a straight linearity between the concentration of ammonium sulfate, from 0 to 30 μg/ml, and the absorbance. Apparent molar extinction coefficient on the basis of N atom and coefficient of variance at 20 μg/ml ammonium sulfate were 2.48 x 10⁴ and 1.60%, respectively. Absorbance of blank solution was satisfactorily as low as 0.012±0.003. Reagents used remained stable only for three days. New imformations concerning reaction mechanism were also obtained. First, the absorbance was dependent not only on the order or the interval of the addition of hypochlorite and m-cresol but also concurrently on the concentration of the former (Fig. 2). Secondly, the decrease in the concentration of monochloramine, which had formed at the early stage of the reaction, resulted in lowering of absorbance that declined exponentially as a function of addition interval of the two reagents.

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Using tablet surface, adhesive forces between the same or different kinds of pharmaceutical powder were measured by the centrifugal method. Materials used were salicylic acid, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium citrate, and polished iron plate. In this measurement, and adhesive force between the same kind of particles was discussed only with salicylic acid and sodium hydrogencarbonate, and for forces between the different kinds of particles or between the particle and the plate, with all four powders and the iron plate. It was found that the contact time before the measurement had a considerable influence on the result. In the case of different kinds of particles, especially when they react with each other, the adhesive forces depend on which kind of particles is tabletted. Namely when the scattered material and tabletted material were exchanged, the results were different after a long contact time (90 min), but it was not so different after a short contact time (20 min). The theories proposed by Iinoya, Rumpf and Newitt were applied to the discussion about the tendency of the results.

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Reaction of 1.0 molar equivalent of 5, 5-diphenylhydrantoin (I) with 1.0 molar equivalent of phenylsulfonyl chloride (II) in the presence of sodium hydroxide or triethylamine results in the formation of 3-phenylsulfonyl-5, 5-diphenylhydrantoin (III), while the use of 2.0 molar equivalent of II gives 1, 3-diphenylsulfonyl-5, 5-diphenylhydantoin (IV). When pyridine is used as the base, only III is obtained from either 1.0 or 2.0 molar equivalent of II. Heating of III with equimolar amount of sodium hydride in benzene results in rearrangement to from 1-phenylsulfonyl-5, 5-diphenylhydantoin (IV). Structure of III, IV, and VI was their from proved infrared, nuclear magnetic resonance spectra, and from their chemical reactions.

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Examinations were made on the decomposition reaction of 3-phenylsulfonyl-(I), 1-phenylsulfonyl-(II), and 1, 3-bis(phenylsulfonyl)-5, 5-diphenylhydantoin (III) with sodium hydroxide, hydrochloric acid, or amines. It was found that I, II, and III differed in stability and direction of decomposition. I was comparatively easily decomposed, especially when treated with sodium hydroxide, and underwent cleavage at 1-2 and 3-4 positions even at room temperature, while heating with dilute hydrochloric acid effected liberation of phenylsulfonyl group and cleavage between 3 and 4 positions. Heating with amines resulted in cleavage of 3-4 position. II was very stable but underwent cleavage at 2-3 position when heated with conc. sodium hydroxide over a long period. The phenylsulfonyl group in 3-position of III was very easily liberated, forming II when heated with dil. sodium hydroxide, hydrochloric acid, or amines.

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It is necessary, in order to diminish the differences in weight distribution of tablets, to control compression punch and die to make its size uniform. It is also important to have the material of good fluidity, with sufficiently small size in comparison with the compression punch size, and having uniform granularity, to adopt filling mechanisms suited to the physical properties of the material to be compressed, and to compress with strong, highefficiency tableting machine of good precision, It is natural, though not experimentally proved, that care should be taken to correlate the compressing mechanism with compounding formula so as not to cause friction, sticking, chipping, and capping which are the greatest cause in producing weight variation of tablets. After setting up the procedure with above precautions, it is still necessary to control the actual work by seeing that the hopper is always filled to more than one-half of its capacity with the material to be compressed, with the effective use of control limit from the x^^- chart, or by automatic control with automatic weight control device. The tablets produced immediately after start of the work and those immediately before the end of the work should be removed, or inspected carefully. It is important to know the limit of tableting speed from the relationship between the physical properties of the material to be compressed and capacity of the tableting machine, and to make tableting speed as fast as possible.

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Following previous reports on mixing of different particles, ^{1, 3)} mixing of salicylic acid and sodium hydrogencarbonate was examined, using a V-type mixer. Mixing ratio was varied from 1 : 10 to 1 : 1000, and under constant mixing time, the relationship between the coefficient of variation as a mixing index and mixing ratio, and sample weight was examined. In the case of adhesive active ingredient such as salicylic acid, its charging point and the size of diluent were found to have a marked effect on the mixing rate. Such phenomenon was thought to be due to the difference in the adhesive force between the same or different kinds of particle, or between the particle and the wall of the mixer. Results of the measurement of adhesive force by the centrifugal method⁴⁾ were employed to explain this cause. The equilibrium mixed states were compared with that of Stange's equation on the combination in each size range of two components.

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3, 4, 5, 6-Tetrabenzoyl-aldehydo-D-glucose (V) was isolated as white crystals on heating the dioxan solution of 1-deoxy-1, 1-di(p-toluidino)-3, 4, 5, 6-tetrabenzoyl-aldehydo-D-glucose (VI) and oxalic acid in nitrogen stream, and 1-deoxy-1-(p-toluidino)-3, 4, 5, 6-tetrabenzoyl-keto-D-fructose (VII) reported by Micheel was not obtained. The results obtained here are in favor of the report of Weygand and of Isbell that Amadori rearrangement took route A as shown in Chart 1 and enaminol was an intermediate. N-(p-Tolyl)-D-glucosylamine-[1-¹⁴C] and N-(p-tolyl)-D-glucosylamine-[2-¹⁴ C] were cleaved oxidatively in contact with p-toluidine and N, N'-di(p-tolyl)formamidine salt of D-arabonic acid (III), N, N'-di(p-tolyl)formamidine (IIIf), 1-(p-tolyl)-2, 6-dimethylbenzimidazole (VIII), and p-tolylarabonamide (IX) were isolated. The results of ¹⁴ C incorporation into these decomposed products indicated that (1) the cleavage of C₁-C₂ bond of glucose gave formamidine and arabonic acid which were formed from C₁ or C₂-C₆ fragment, respectively. (2) Benzimidazole was not formed from formamidine, but from C₁-C₂ fragment formed as a result of C₂-C₃ bond cleavage.

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A new colorimetric determination of thiamine was proposed. The optimum conditions for this determination were examined by a Technicon Autoanalyzer. The procedure is as follows : A sample solution of 9.0 ml of containing 100-500 μg of thiamine is transfered to a 50 ml volumetric flask and the solution is cooled in ice water. To this solution, 20 ml of an aqueous solution containing 0.25% bromine and 6.5% pyridine, 4 ml of 0.5_N Na₂S₂O₃, and 15 ml of 1_N NaOH are added with shaking, and the mixture is diluted to 50 ml with water. The absorbance of the developed color is measured at 445 mμ against the reagent blank. The present method can be applied to the determination of thiamine in mixed preparations.

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By the use of a crosslinked sodium polyacrylate, with a mean polymerization degree of 4850 between two adjacent crosslinks, as a sample, in the system containing various inorganic and organic salts, hydrochloric acid, and sodium hydroxide, examination was made on the effect of the concentration of the salt added, C_s, on the degree of equilibrium swelling, Q_v, of these salts. In the system of univalent-univalent inorganic salts, there was no difference in Q_v according to the kind of cations present but a slight difference in Q_v was seen according to the kind of anions present at around 0.1 N of C_s. This difference appeared markedly in the organic salt system, and the values of Q_v decreased in the order of sodium carbazol-chrome sulfonate>sodium acetate≒sodium benzoate>dl-methylephedrine hydrochloride>ephedrine hydrochloride>pyridoxine hydrochloride. In the system of bivalent-univalent salts, decrease of Q_v was marked and its values were not affected by C_s. In the univalent-univalent salt system, relationship between Q_v⁵/₃ and C_s²/₃ was linear, which was found not to agree with the swelling theory of Vermaas and Hermans.

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N-p-Tolyl-D-glucosylamine (GPT). and N-p-anisyl-D-glucosylamine. (GPA) were cleaved autoxidatively in ethanol solution containing p-toluidine and p-anisidine, respectively, and N, N'-diarylformamidine salt of D-arabonic acid (III), N-aryl-D-arabonamide (IV), N, N'-diaryloxalamide (V), and 1-aryl-2-aryliminomethylbenzimidazoloe (VI) were isolated. These N-aryl-D-glucosylamines reacted with benzylamine and cyclohexylamine, and IV and V were formed, but not III and VI. The results obtained here indicate that oxalic acid is easily formed by C-chain cleavage of sugars. GPT[1-¹⁴C], GPT[2-¹⁴C], N-cyclohexyl-D-glucosylamine[1-¹⁴C] and N-cyclohexyl-D-glucosylamine[2-¹⁴C] were cleaved in contact with p-toluidine or cyclohexylamine, and oxalamides (V) were isolated. The results of ¹⁴C incorporation into these decomposed products indicate that C-1 and C-2 of glucose were containted in oxalic acid and N-aryl-D-glucosylamine in which RNH₂ bonded was decomposed by free amine R₁NH₂, and three types of oxalamide [chemical formula] were isolated. These results indicate that there are two routes for the formation of oxalic acid ; one is the cleavage of C₂-C₃ bond in glucose, and the other, the cleavage of C₁-C₂ bond and polymerization of C₁ fragment.

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The interaction between some thiamine derivatives and styrene-maleic anhydride copolymer(SMA) was studied. Ultraviolet absorption measurements on the mixed solutions of O, S-bis(ethoxycarbonyl)thiamine, thiamine tetrahydrofurfuryldisulfide, and pyrimidine derivatives with SMA indicate the presence of donor-acceptor type binding between acid anhydride group in the SMA and pyrimidine group in the thiamine derivatives. The interaction of the following six thiamine derivatives of thiol type with SMA was also examined through a distribution method at 25° and 37° : O, S-bis(benzoyl)thiamine disulfide, O, S-bis(ethoxycarbonyl)thiamine, S-ethoxycarbonylthiamine, S-butoxycarbonylthiamine, O-benzoylthiamine, and thiamine tetrahydrofurfuryldisulfide. It was found that these derivatives show a strong affinity to SMA, and that the binding process is a Langmuir-type relationship. The temperature dependence of the binding showed a decrease in binding constant with increase in the temperature from 25° to 37°. The maximum amount of each derivative bound to SMA was found to be 0.2 to 0.3 mmole/g, regardless of the temperature, and each value for O, S-disubstituted derivatives was smaller than that for S-monosubstituted derivatives. Each amount thus obtained also indicated that one thiamine derivative molecule was bound by about 10 monomeric units of the copolymer chain. The significance of these results was discussed in relation to a possible binding mechanism.

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Data are presented for the interaction of β-cyclodextrin with 11 pharmaceuticals in aqueous solution. By means of the solubility method of analysis, definite interactions were found to occur with all the compounds tested. Larger molecules showed a lower degree of interaction with β-cyclodextrin, indicating the importance of molecular size and structure for optimum reactivity, but quinine ethylcarbonate, having a comparativery large molecule, formed a relatively stable complex with β-cyclodextrin. This fact shows that the interactions involve not only inclusion formation but also other attractive forces. The amount of these pharmaceuticals in equilibrium with their respective solid phase increased progressively with β-cyclodextrin concentration. A concentration of 1.5 g of β-cyclodextrin per 100 ml of water increased the solubility of most compounds tested (except one) by 20-150%. A 14.4-fold increase in the solubility of quinine ethylcarbonate was observed in a system containing 1.5% β-cyclodextrin. Hydrolysis of procaine, atropine, and acetylsalicylic acid in aqueous solution was retarded in the presence of β-cyclodextrin.

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3β-Hydroxyandrost-5-en-16-one (VIIIa) and its 5α-dihydro derivative (VIIIb) were synthesized from 17-oxosteroids (Ia and Ib) by the six-step sequence involving 16-formyl intermediates. The final products were obtained by direct recrystallization in 60% overall yield, when the sequences were carried out without any purification of all the intermediates.

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To clarify the effect of exogenous ubiquinone on the respiration of FM3A cells, the amount of O₂ consumption was determined by the Warburg manometer. On the other hand, properties of the cells in respiration were investigated from the point of Crabtree effect and electron-transport system in mitochondria. The results were as follows : Thirty min and 8 hr after addition of ubiquinone, the activity of respiration in the medium, from which L-phenylalanine and L-tyrosine were excluded, was not recovered, but apparent recovery of respiratory activity was observed 42-47 hr after the addition of ubiquinone. Endogenous respiration of FM3A cells was inhibited by the addition of 20 or 30 mM D-glucose, that is, Crabtree effect was observed. The FM3A cells can utilize succinate and NAD-linked substrate, glutamate, as the respiratory substrate, and the control of respiration was released by 2, 4-dinitrophenol (100 or 25 μM). The respiration in FM3A cells with succinate was almost completely inhibited by Antimycin-A (1 μg/ml) and 10^-4M KCN. Respiratory control ratio was raised by repeated respiration with 200 μM ADP, but increase in ratio did not run parallel with ADP to O/P ratio. This was different from the results in HeLa cells.

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Modified synthesis of 2-amino-1, 1-diphenyl-1-butene (IIIg), one of the hypertensive agents, was examined and an increase in its yield was observed either by dehydration of ethyl 2-ethyl-3-hydroxy-3, 3-diphenylpropionate (II), synthesis of 2-ethyl-3, 3-diphenylacrylamide (IIId), or reduction of IIId with lithium aluminum hydride. The Grignard reaction of the aminoketone (XI), obtained by the Mannich reaction of X, with phenylmagnesium bromide afforded the aminopropanol (XII), whose dehydration with an acetic acid solution of hydrogen chloride afforded 2-aminomethyl-1, 1-diphenyl-1-butenes (XIIIa-e).

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A number of 2-nitrophenylpyridazinone derivatives were prepared for the purpose of screening their antibacterial and antifungal activity. Some of them revealed stronger antitubercular or antifungal activities in vitro than those of 2-phenylpyridazinone derivatives.

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Seven kinds of vinyl ketones and two kinds of γ-diketones were synthesized by reacting two kinds of methyl ketones and five kinds of aldehydes in acetic acid, with addition of a small amount of sulfuric acid, at 40° for 2-7 days or by refluxing in acetic anhydride for 2-3 hours. From the reaction of these synthesized vinyl ketones (three kinds) and γ-diketones (two kinds) with carbonyl reagents, six kinds of derivatives, including 3, 5-bis(5-nitro-2-furyl)pyridazine (XVIa), were synthesized.

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Ethynylation of 2-furyl (para-substituted phenyl) ketones (Ia-d), 2-(5-nitrofuryl) (para-substituted phenyl) ketones (IIIa, b), p, p'-disubstituted benzophenones (Va, b and VIIa-c), and 2-thienyl phenyl ketone (IXa) with lithium acetylide or lithium acetylideethylenediamine afforded the corresponding ethynylcarbinol (IIa-d, IVa, b, VIa, b, VIIIa-c, and Xa) in 30-84% yield. Isolation of the corresponding ethynylcarbinols (IVc and IVd) was not successful in the case of 2-(5-nitrofuryl) p-chlorophenyl ketone (IIIc) and 2-(5-nitrofuryl) p-bromophenyl ketone (IIId).

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