Tuduranine (IVa) was isolated from the root tuber of Stephania rotunda LOUREIRO and was identified. Stepharine (II) was heated with 3N sulfuric acid and tuduranine was obtained by the dienone-phenol rearrangement which proved that the absolute configuration of tuduranine is represented by the formula IVa.

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The NMR spectrum of domoic acid (in CF₃COOH) indicates signals for a methyl at 1.43 p.p.m. (d;J=6.6 c.p.s.) and at 1.94 p.p.m. (a broad singlet), and no signal for an ethyl group. The methyl signal at 1.94 p.p.m. shows a long-range I-I coupling due to spin decoupling. The NMR spectrum of trimethyl domoate (in CDCl₃) shows a doublet methyl (J=7.0 c.p.s.) at 1.29 p.p.m., a methyl signal which indicates an allylic coupling at 1.79 p.p.m., and an olefinic proton signal corresponding to 3H at 5.5∼6.6 p.p.m. From its first-order analysis, the configuration of the 1, 3-hexadienyl side chain was determined as trans : trans : S-trans. The infrared spectra of both domoic acid and trimethyl domoate show absorption due to the trans-double bond. The NMR spectrum of tetrahydrodomoic acid (in CF₃COOH) shows signals for a methyl bonded to a secondary carbon at 1.12 p.p.m. (d;J=6.0 c.p.s.) and at 1.22 p.p.m. (d;J=6.6 c.p.s.). It was concluded from these observations that the structure of domoic acid would be more appropriately represented as L_s-arabo-2-carboxy-4-(1-methyl-5-carboxy-trans : trans : S-trans-1, 3-hexadienyl)-3-pyrrolidineacetic acid (VIII) rather than the previously proposed L_s-arabo-2-carboxy-4-(1-methyl-2-carboxy-1, 3-hexadieny1)-3-pyrrolidineacetic acid (I).

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The water-soluble fraction of the Chinese drug, "Bezoar Orientale" was deproteinized with trichloroacetic acid, the glacial acetic acid solution of its fraction was extracted with ether, and the ether extract was decolorized with animal charcoal. The ether extract was purified by ethanol and a crude peptide-like substance was obtained. The aqueous solution of this substance showed pH 5. The thin-layer chromatogram of the substance gave two Ninhydrinpositive spots which had absorption maximum at around 280 mμ. This substance showed a marked contraction of digestive smooth muscles and this activity is selectively inhibited by atropine. The substance effects transitory fall of blood pressure in rabbits and this effect is also inhibited by atropine. In other words, this substance has an acetylcholine-like pharmacological activity.

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Three kinds of phenolic biscoclaurine-type bases are obtained from the embryo (lien tze hsin) of lotus (Nelumbo nucifera GAERTN.), liensinine (I), isoliensinine (II), and neferine (III). By utilizing their O-trideuteromethylation and the deuterium-exchange reaction of the aromatic proton, the signals for the methoxyl group and the aromatic proton in the NMR spectrum of O, O-dimethylliensinine (IV) were assigned as shown in Chart 1.

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Treatment of 5-(o-aminophenylthio)-4-chloro-3(2H)-pyridazinone (I) with hydrochloric acid results in rearrangement-cyclization to produce 10H-benzo[b]pyridazino[4, 5-e]-(1, 4)-thiazine-4(3H)-one (II), but 5-(o-aminophenylthio)-4-chloro-2-methyl-3(2H)-pyridazinone (IV) does not undergo rearrangement by treatment with hydrochloric acid. Treatment of IV with potassium carbonate in dimethylformamide results in direct cyclization to produce 2-methyl-10H-benzo[b]pyridazino[4, 5-e]-(1, 4)-thiazin-1(2H)-one (V). Derivatives of II substituted in 3-position with various groups were synthesized.

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Determination of sodium cyclamate was studied by the polarographic method. Sodium cyclamate was decomposed by heating with AcOH and NaNO₂, and sulfuric ions liberated from sodium cyclamate were completely precipitated as PbSO₄ in 50% EtOH solution by the addition of excess of Pb(AcO)₂. The precipitate of PbSO₄ was filtered and surplus Pb ions were measured by polarography in the electrolytic solution of 45% EtOH with 0.04N NH₄CNS and 0.01N HCl as a supporting electrolyte, and Triton X-100 as a maximum suppressor. The amount of sodium cyclamate was inversely proportional to the wave height of Pb ions and, therefore, sodium cyclamate of 0.2∼9 mg./ml., particularly even 2.5 μg., could be easily determined indirectly. This method was not interfered by glucose, lactose, sucrose, starch, saccharin sodium, or dulcin. Consequently, this method is thought to be a very convenient and accurate way for the determination of sodium cyclamate, especially in artificial sweetening preparations.

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The sedimentation rate determination is often used for the measurement of particle size distribution in a suspension, and various apparatus for measurement, such as sedimentation balance, have been devised. In the present series of work, measurement of particle distribution was examined by the use of integrating sphere turbidimeter. First, relationship between specific scattering intensity and particle radius was examined by using periodical change of specific turbidity and particle size distribution function (f) obtained from sedimentation balance. When the particle radius is sufficiently small and the particles are monodispersed, colorless and spherical, the specific scattering intensity should be proportional to the cube of the particle radius, R. In a polydispersed system, this relationship does not hold and the intensity becomes constant, irrespective of R. In other words, turbidity of the silica suspension used in the present series of experiments is not related to the particle radius and is dependent only on concentration. Cumulative weight percentage, w (%), was then calculated from the periodical change of τ/τ₀ obtained from the integrating sphere turbidimeter, and logarithmic normal distribution equation was found to be established. Measurement with the granular balance requires higher sample concentration and a long time is required for measurement. From the result of the present series of experiments, particle distribution obtained from the integrating sphere turbidimeter seems to be more appropriate.

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The stability of thiamine in the presence of sulpyrin in buffered aqueous solutions was examined over a pH range of 3.5 to 6.0. The apparent first-order rate constants at various pH and various sulpyrin concentrations were determined. The influence of ionic strength and acetate ion concentration was also investigated. By the addition of sulpyrin decomposition product, 4-methylaminoantipyrine, bis(4-methylaminoantipyrinyl)methane, aminopyrine, or formaldehyde sodium bisulfite, the hydrolysis of thiamine in the presence of sulpyrin appears to be catalyzed by bisulfite ion formed as a result of hydrolytic cleavage of sulpyrin. Decomposition of thiamine with sulpyrin yielded a substance (VIII) of m.p. 183∼184°, which was found to be N-methyl-N-[(2-methyl-4-amino-5-pyrimidyl)methyl]-4-aminoantipyrine from its ultraviolet and infrared spectra, color reaction, and elementary analysis. Further, 4-methyl-5-thiazoleethanol and 2-methyl-4-amino-5-pyrimidinemethanol were identified as the decomposition products of thiamine.

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Action mechanism of the leukocytosis-promoting activity of Saliva Parotin-A was examined by using intact and X-irradiated rabbits. This activity of Saliva Parotin-A is chiefly carried on by granulocytes, and effects weak decreasing action on lymphocytes and monocytes. The serum from rabbits 2 and 6 hours after the administration of Saliva Parotin-A has a strong leukocytosis-promoting activity originating from granulocytes. Since the immunochemical measurement revealed that this reaction is not due to the originally administered Saliva Parotin-A, it is considered that a leukocytosis-promoting factor is produced secondarily in vivo by the administration of Saliva Parotin-A, and this factor appears in the serum. This factor was observed similarly in both X-irradiated and intact rabbits.

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Comparative examinations were made on the action mechanism of leukocytosis promoting activity of Parotin isolated from the bovine parotid gland and S-Parotin isolated from the bovine submaxillary gland. The leukocytosis promoting activity of Parotin and S-Parotin is chiefly carried on by granulocytes, and effects decrease of lymphocytes and monocytes. Since this activity originating from granulocytes is observed in the rabbit serum 2 hours after the administration of Parotin or S-Parotin, it is considered that a leukocytosis promoting factor is produced in vivo after such administration, as in the case of Saliva Parotin A.

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Sythesis of mescaline (V) was examined and high-pressure reduction of IV afforded the compound in a good yield. V was formylated by the usual method and the product (X) was cyclized to 3, 4-dihydro6, 7, 8-trimethoxy-isoquinoline (XI). In order to effect selective demethylation, XI was heated with aluminum trichloride or tribromide in carbon disulfide, or heated for a few hours in conc. hydrochloric acid, by which the phenolic base (XII) was obtained. Reduction of the methiodide (XIII) or XII gave a product which agreed neither with an authentic sample of anhalidine nor with 1, 2, 3, 4-tetrahydro-7, 8-dimethoxy-2-methyl-6-isoquinolinol, and it was considered that the demethylation occurred from the methoxyl in 7-position. Therefore, 4-benzyloxy-3, 5-dimethoxyphenethylamine (XXVII) was synthesized from XXI via XXVI, and debenzylation of XXIX obtained by cyclization of the formylated product (XXVIII) of XXVII finally afforded the objective XII. This compound was found to be identical with the product (XII) obtained by selective demethylation of XI with hydrochloric acid. Reduction of XVIII with lithium aluminum hydride gave anhalamine (XIX) directly, without passing through XVIIIa.

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As a new method for synthesis of carbocyanine dyes, ketal-type intermediate (IV) was synthesized and its reaction with various active methylene compounds was examined. Reaction of 3-ethyl-2-acylmethylenebenzothiazoline (or benzoselenazoline)(II) with triethyloxonium fluoroborate gave III which was reacted with sodium alkoxide to obtain the ketal (IV) of II. IV underwent very facile reaction with active methylene compounds and afforded the objective carbocyanine dyes. This has shown that IV is a very useful compound as an intermediate in the syntheses of carbocyanine dyes. Many kinds of cyanine and merocyanine dyes were synthesized by the reaction of IV with various reactive methyl and methylene compounds.

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The MSH-like substance in the urine of patients with retinopigmentosis, differing from that in normal persons, has no melanocyte-expanding effect, nor other physiological actions. In order to examine their difference physicochemically, adipokinetic activity of these substances were compared. While that from the normal person had the same activity as MSH, that from the patients lacked this tendency. Effects of the MSH-like substances on the free fatty acid in plasma was analyzed by gas chromatography and the substance from the urine of patients showed considerable difference from that of normal persons, such as in increasing the amount of lauric acid. Examination of a difference between these substances in chemical structure showed that the substance from the patients' urine lacked methionine in the structural amino acids, which is present in that from normal persons. It was proved through the experiment on recovery of effect by cysteine reduction and by identification of methionine sulfoxide by paper chromatography that in the structure of the MSH-like substance from patients' urine, methionine portion is in the form of methionine sulfoxide.

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Air oxidation of 2, 3-bis(2-furyl)-5, 6-dihydropyrazine (I) and 2, 3-bis(2-furyl)-5-methyl-5, 6-dihydropyrazine (II) in ethanol, with application of potassium cyanide, afforded 5, 6-bis-(2-furyl)-2-pyrazinamide (III) from I and 5, 6-bis(2-furyl)-3-methyl-2-pyrazinamide (IV) from II, both in a good yield. Hydrolysis of III and IV, followed by esterification and nitration respectively gave ethyl 5, 6-bis(5-nitro-2-furyl)-2-pyrazinoate(XIII) and ethyl 5, 6-bis(5-nitro-2-furyl)-3-methyl-2-pyrazinoate (XIV), which were respectively hydrolyzed to the corresponding carboxylic acids (XV and XVI). On the other hand, air oxidation of I and II in alkaline solution gave the corresponding pyrazines which were respectively nitrated to 2, 3-bis(5-nitro-2-furyl)pyrazine (VII) and 2, 3-bis(5-nitro-2-furyl)-5-methylpyrazine (VIII). A total of 11 kinds of amine derivatives were prepared from XIII, XIV, XV, and XVI. Antibacterial activity of these compounds was examined and several of them showed antibacterial activity approximately equal to that of 3-(5-nitro-2-furyl)acylamide.

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Air oxidation of furfural in alkaline solution at 40° in the presence of Ag₂O-CuO catalyst was studied, employing a batch reactor and a multi-stage contactor of gas-liquid counter-flow type. In the initial step, the rate of reaction was 0 th order and in the successive one it was proportional to the concentration of furfural and the catalyst, and the amount of by-products was negligible. As the stripping of furfural from the reaction mixture was observed, some stages for absorption of gaseous furfural into liquid were provided above the feed stage for furfural. It was noted that gas-liquid equilibrium did not fit Henry's law under the operating conditions. Assuming the fictious equilibrium lines for absorption and desorption, mass balance equations for each stage were obtained. The curves calculated by adopting the Runge-Kutta method, and the values under steady state by trial and error method agreed well with experimental data. Within the operating condition (0<x<6.5×10^-4[-], 0.6<G_M<1.3 [g.-mole/min.]), the over-all volumetric coefficient of mass-transfer K_xa was 3∼12[g.-mole/L.min.Δx].

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A new monoterpene glucoside, daphylloside, has been isolated from domestic Daphniphyllum macropodum MIQ. together with asperuloside. Structure of the former was clarified on the basis of spectroscopic and chemical evidences.

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Examinations were made on the conditions for crystallization of sodium aluminosilicate. At the temperature of 80°, with A-type zeolite, rate of crystallization was faster, the higher the concentration of the starting mixture, and crystallization was effected in 30 minutes with a concentration of 0.5 mole/L. Degree of crystallization was found to be unaffected by the concentration of the starting mixture. On the other hand, with the X-type zeolite, rate of crystallization was faster with higher concentration of the starting mixture but the degree of crystallization decrease with concentrations above 0.25 mole/L. A concentration of about 0.2 mole/L. was therefore found to give zeolite with the best degree of crystallization. Evaluation of the degree of crystallization by X-ray powder diffraction showed that there is a good correlation in the crystallization degree between that obtained from the height of the diffraction peak and that obtained from the peak area.

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Infrared spectra of 34 aminochloropyrimidine derivatives were measured. The NH₂ stretching and deformation frequencies of pyrimidine derivatives were proved to be those of the primary amino group. The skeletal vibration frequencies appeared in the region of 1600∼1520 cm^-1. Discussion were also made on the characteristic deformation frequencies of CH in the pyrimidine ring.

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In order to examine their analgesic activity, 1-(2-dialkylaminoacyl)-3-(2-indanyl)ureas (VII to XXI) were synthesized and they were found to have activity comparable to or less than that of aminopyrine.

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By utilizing the almost quantitative formation of 2-thietanevaleramide from α-lipoamide and potassium cyanide, examinations were made on the determination of α-lipoamide in pharmaceutical preparations by gas chromatography and a new method of determination, with high specificity, was established. A good result was obtained by determination of α-lipoamide in commercial preparations by the use of the present method.

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Changes of terephthalic acid concentration in blood plasma were studied in the rabbit, and the half-life of terephthalic acid in plasma was determined in the rabbit and the rat. Terephthalic acid, when intraperitoneally injected, was rapidly absorbed in plasma and then excreted from plasma into the urine through the kidney. Terephthalic acid concentration in plasma reached a maximum level within 1 hour after the injection and decreased gradually, and any detectable amount was not found after 24 hours. Half-life of terephthalic acid in plasma is about 1.8 hours. (Fig. 1). Terephthalic acid suspension was orally administered in doses of 200 and 100 mg./kg. each. Terephthalic acid concentration in plasma reached a maximum level within 8 to 10 hours, and decreased slowly. In this case terephthalic acid concentration in plasma was very low, which was only 11.7 μg./ml. at the 8th hour after the administration of 200 mg./kg. Half-life of terephthalic acid in plasma after its oral administration is 27 hours. (Fig. 1). These results indicate that tereththalic acid concentration in plasma after its oral administration is more influenced by its absorption through the digestive tract than by its excretion thruogh the kidney. Urine excretion ratios in the rabbit were 67% by oral administration and 93% by intraperitoneal injection. In the rat, half-life of terephthalic acid in plasma is about 1.0 hour in the case of intraperitoneal injeation and about 3.4 hours. after oral administration. Both the rates of urinary excretion and absorption through the gastrointestinal tract of terephthalic acid in the rat are faster than those in the rabbit.

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Some of the alithatic acylamino acids show notable surface activitv or antibacterial activity. Direct Schotten-Baumann reaction of amino acids afforded N-lauryl-L-threonine (80% yield), O, N-dilauryl-L-tyrosine (50%), and N, N-dilauryl-L-lysine (53%). N-Stearyl-L-glutamic acid was obtained by the application of stearyl chloride to diethyl L-glutamate in dimethylformamide, in the presence of pyridine. In this way, about 50 kinds of aliphatic acylamino acids were obtained from various amino acids, and C_<8∼22> saturated acids and some unsaturated acids.

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It had been observed earlier that conversion of the ethoxycarbonyl group into acetyl in ethyl 6, 7-dimethoxy-1-methyl-3, 4-dihydro- and -1.2, 3, 4-tetrahydroisoquinoline-3-carboxylate was accompanied by dehydrogenation to form 3-acetyl-6, 7-dimethoxy-1-methylisoquinoline. In the present series of work, condensation of ethyl 6, 7-dimethoxy-3, 4-dihydro-(III) and-1, 2, 3, 4-tetrahydroisoquinoline-1-carboxylate (VI) with ethyl acetate and ketonic decomposition of its product was found to be also accompanied by dehydrogenation, as in the foregoing reaction, forming 1-acetyl-6, 7-dimethoxyisoquinoline (V). In order to prove the structure of V, III was submitted to dehydrogenation reaction and the compound VIII obtained as its product was submitted to the same reaction as above. The product thereby obtained was found to be identical with V obtained as above.

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One of the important starting materials for biscoclaurine-type alkaloids, dl-3'-bromo-7, 4'-O, O-dibenzyl-N-methylcoclaurine (III) was synthesized through its amide (VIII), 3, 4-dihydroisoquinoline (IX), and the methiodide (X). Optical resolution of III using di- p-toluoyl-d-tartaric acid gave the levorotatory III. The dextrorotatory III was obtained from the free base recovered from the mother liquor by treatment with l-tartaric acid.

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After benzylation of methyl 3.5-dihydroxy-4-methoxybenzoate (III), the product was submitted to the McFadyen-Stevens reaction and derived to the amine (IX) in several steps. Condensation of IX with 4-methoxyphenacetyl chloride by the Schotten -Baumann reaction gave the amide (X) which was cyclized to XI by the usual Bischler-Napieralski reaction and debenzylated to the obtain objective 3, 4-dihydro-7-methoxy-1-(4-methoxybenzyl)-6, 8-isoquinolinediol (II). Application of 1 mole of diazomethane to 1 mole of II resulted in the formation of a phenolic base (XIII) in which the hydroxyl in 8-position had been methylated, besides the compound (XII) with all the hydroxyl groups in II methylated. XIII was proved by deriving it to XIV. However, the objective 8-hydroxy derivative with the 6-hydroxy methylated was not obtained so that it was impossible to derive the product to the objective I through its methiodide.

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As the starting material for the synthesis of cepharanthine, 1-(p-benzyloxybenzyl)-8-bromo-2-methyl-6, 7-methylenedioxy-1, 2, 3, 4-tetrahydroisoquinoline (X) was successfully prepared. The amide (VII) was submitted to the usual Bischler-Napieralski reaction to obtain the 3, 4-dihydroisoquinoline (VIII) which was derived to its methiodide (IX), and its reduction with sodium borohydride afforded X. It was found that X is also obtained when the hydrochloride of VIII was reduced with sodium borohydride and its product submitted to the Eschweiler-Clarke reaction with formaldehyde and sodium borohydride. At the same time, it was also found that when IX was left in the air, the methylene in the 1-benzyl group was oxidized. There may be two directions in the cyclization of the amide (VII) but there was ample evidence that the cyclization occurred in the position ortho to the bromine atom since debromination of X with lithium aluminium hydride gave a substance which was in complete agreement with 1-(p-benzyloxybenzyl)-6, 7-methylenedioxy-1, 2, 3, 4-tetrahydroisoquinoline synthesized by another route.

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An air-bath melting point apparatus for micro-quantity of a sample (Fig. 1) was designed with a little modified furnace which had been reported in a previous paper. The sample is placed between two pieces of glass plate (10×75 mm.), and introduced into the furnace in such a way as to place the sample on the mercury bulb of a thermometer. The sample holder is protected from a hot stream of air by a piece of glass plate of 10 mm. width, which is set on the holder at a distance of about 3 mm. The sample is heated intermittently by turning the dial of a bimetal regulator with the proper heater. Table I proved that the rise in temperature of 1° per more than 5 seconds might give a practical constant value in the neighborhood of the melting point.

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