Benzylidene-d-sorbitol undergoes gelation when dissolved in various solvents with warming and the solution allowed to cool. The state of gelation is the same as in the case of high-molecular gel-forming substances like gelatin but the viscosity of this solution differs from that of gelatin solution, not showing polymer-like properties but those agreeing with Einstein's viscosity formula. From such a fact, the state of gelation of benzylidene-d-sorbitol solution is similar to polymer-like gel-forming substances like gelatin but does not behave like a polymer from the point of viscosity. The solution before gelation has viscosity no different from that of ordinary solutions but an abnormal viscosity occurs at around the gelation point, and this is assumed to be due to a change in the structure inside the solution during gelation. From such a change in viscosity, relationship between the gelation phenomenon of a solution and coagulation of a gelation agent was examined by measuring dielectric constant of the solution. Increase of dielectric constant decreases with increasing concentration at around the gelation point and this suggested that there is a connection between polarity of benzylidene-d-sorbitol and gelation.

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Following the synthesis of 2-carbamoylcyclohexane-1, 3-dione reported in the preceding paper, the cyclohexane-1, 3-dione derivatives possessing the carbamoyl group in 4- or 5-position were prepared and their properties were examined.

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Addition of 1-1.5 moles of thiourea to alcoholic solution of 1 mole of methyl- or ethyl-mercuric bromide and refuxing of this mixture was found to result in formation of methyl- or ethyl-mercurithiourea hydrobromide. This reaction is the same as that of alkyl halide and thiourea but in the case of higher alkylmcrcuric halide and thiourea, decompoyition takes place and the reaction does not occur, S-Methyl- or S-ethyl-mercurithiourea hydrobromide easily forms methyl- or ethyl-mercurithiol by the action of sodium hydroxide. These mercurials have powerful antibacterial and antifungal activity and, therefore, pharmacological action of S-methylmercurithiourea hydrobromide was examined, including acute toxicity (LD₅₀), actions on the respiration and blood pressure in rabbit, on excised heart of a toad, on excised intestine of a rabbit, and on aural blood vessel of a rabbit.

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In order to clarify the relationship between chemical structure and analgesic action, the structure of morphine was simplified and 1, 2-diphenylethylamine derivatives were taken up. These derivatives have already been studied by Dodds, et al. who found no such activities. Primary amines, N-methylated, N, N-dimethylated, and optically active compounds of these derivatives were newly synthesized, and their toxicity and analgesic action were examined by the Haffner and D'Amour-Smith methods. Of these nine kinds of amine derivative, all racemic compounds had weak action and tertiary amines showed slight analgesic action. All dextrorotatory compounds had no activity, while levorotatory compounds showed the activity, the action being the strongest in the N, N-dimethylated compound.

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Various kinds of alkyl halide were reacted with dl-N-methyl-1, 2-diphenylethylamine or its levorotatory isomer and N-alkyl-N-methyl-1, 2-diphenylethylamine derivatives and their levorotatory isomers were synthesized. The toxicity and analgesic action of these derivatives were examined. Analgesic action as examined by the Haffner method was negative in all racemic compounds alone and a slight action was observed in the p-aminophenylethyl derivative (XII) examined by the Haffner method added with morphine. Levorotaroy derivatives, (III), (V), (IX), and (XI), showed analgesic activity, the action being the strongest in the p-aminophenethyl derivative (XI). This action, however, was somewhat weaker than that of l-N, N-dimethyl-1, 2-diphenyl-ethylamine.

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N, N-Dimethyl-1, 2-diphenylethylamine derivatives possessing various kinds of substituent in the 4-position of the benzene ring at 2-position of ethylamine, and their toxicity and analgesic action (Haffner method) were examined. The substituent present was nitro, amino, methoxyl, hydroxyl, or chlorine. The synthesis followed the Leuckart, Grignard, or Hofmann reaction. Single administration by the Haffner method showed that the hydroxyl derivative (II) had a slight action and all other derivatives were negative. In the case of the Haffner method added with threshold amount of morphine, (II) showed a slight action but all other derivatives were weak. It was thereby found that these derivatives with any of the substituents had lower activity than N, N-dimethyl-1, 2-diphenylethylamine, with about the same degree of toxicity.

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Several kinds of ketones (C₆H₅-CH₂-CO-R) were submitted to the Leuckart reaction to form various amine derivatives and these amines were reacted with formaldehyde solution to prepare their N, N-dimethylated derivatives. Toxicity and analgesic action (Haffner method) of the various amine derivatives so obtained were examined. These derivatives generally had weaker action than N, N-dimethyl-1, 2-diphenylethylamine, and only p-chloro (XIII) and p-tolyl (VI) derivatives had somewhat comparable activity, although their toxicity was stronger. Optical resolution of (VI) was carried out in order to effect increase in activity. The levorotatory compound had weaker toxicity and stronger analgesic effect than the racemic compound but the activity was somewhat weaker than that of l-N, N-dimethyl-1, 2-diphenylethylamine.

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Erythro and threo types of N, N-dimethyl-1, 2-diphenyl-2-hydroxyethylamine and their optical isomers were prepared, and their toxicity and analgesic action (Haffner method) were compared with those of 1, 2-diphenyl-2-hydroxyethylamine derivatives. The physiological activity was extremely weak in all the derivatives and there seemed to be no difference between the erythro and threo forms, or between primary and tertiary amines. The physiological activity was somewhat stronger in levorotatory than dextrorotatory compounds.

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1, 2-Diphenyl-3-dimethylamino-2-butanol (IV), its optically active compounds (V and VI), and its propionyl derivatives (VII, VIII, and IX) were prepared by the Grignard reaction and their toxicity and analgesic action were compared with those of the alkanolamine derivatives of (I), (II), and (III). None of these derivatives had any analgesic activity, as examined by the Haffner and D'Amour-Smith methods. When examined by the Haffner method added with threshold amount of morphine, (I), (II), and (III) showed some activity, and the derivatives (IV) to (IX) showed weak activity, contrary to expectations.

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Heating of the methiodide of dl-laudanosine (III), the non-phenolic base of coclaurine type, and the methiodide of O, O-dimethylcorytuberine (IV), the non-phenolic base of aporphine type, with ethanolamine by the Hünig's method for 30 minutes in an oil bath of 160-170° results in the formation of a tertiary base, dl-laudanosine (III) or O, O-dimethylcorytuberine (IV). It was found that the heating of the dimethiodides of isotetrandrine (V), cycleanine (VI), and insularine (VII) for 30 minutes at 170-175° (oil bath temp.) respectively affords the corresponding tertiary bases, isotetrandrine (V), cycleanine (VI), and insularine (VII). The yield of these reactions is very good. The reaction of the dimethiodide of isotetrandrine (V), when carried out by heating at 160-170° for 10 or 30 minutes, gave colorless cubic crystals of m. p. 239-240° (decomp.), corresponding to its monomethiodide.

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It was revealed in the preceding paper that the structure of sophoradiol consisted of a β-amyrin skeleton possessing two hydroxyls, one of which is in 3-position and the other in 15, 19, or 22-position. In the present series of experiments, examinations were made on the possibility of the one hydroxyl present in 22-position and on steric structure of this substance, and it was assumed that sophoradiol would be represented as olean-12-ene-3β(e), 22β(a)-diol.

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In order to examine the effect of inorganic salt addition on the gas-liquid equilibrium of diethylamine-water system, flash distillation at atmospheric pressure was carried out on the diethylamine-water-sodium chloride, diethylamine-water-potassium chloride, and diethylamine-water-sodium sulfate systems, and equilibrium diagram of each system was prepared. Mutual solubility between diethylamine and water saturated with inorganic salt was measured and liquid-liquid equilibrium diagram of each system was prepared. Effect of various salts on the gas-liquid equilibrium of diethylamine-water system was compared from these results and sodium chloride was found to have the greatest effect, followed by potassium chloride and sodium sulfate, in that order.

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Dehydrogenation of 2, 3-dimethyl-5, 6-dihydropyrazine (I) and trans-2, 3-dimethyl-piperazine (II) was effected by catalytic vapor-phase reaction and 2, 3-dimethylpyrazine (III) was obtained in a good yield. The catalysts used were copper chromite, cadmium phosphate, ferric oxide, and titanium oxide, and Japanese acid clay and silica-alumina were used as the carrier. In the case of (I), possessing a double bond inside the molecule, dehydrogenation was comparatively easy and (III) was obtained in 40-60% yield with any of the catalysts at 350-400°. The best result was obtained on using ferric oxide-acid clay catalyst, dehydrogenation occurring already at the reaction temperature of 300°, and a good yield of 74.3% was obtained. In the case of (II), not possessing a double bond inside the molecule, dehydrogenation was somewhat more sluggish than in the case of (I), and the yield was 32-46% when using copper chromite- and cadmium phosphate-acid clay catalysts, the yield being still lower with ferric oxide and titanium oxide catalyst.

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The reaction of 2-propynyl bromide with phenol or 2-naphthol in acetone, in the presence of potassium carbonate, results in the formation of phenyl or 2-naphthyl 2-propynyl ether. Claisen rearrangement reaction of these ethers was carried out. Reaction of phenol and phenylpropioloyl chloride in dehyd. benzene, in the presence of magnesium, afforded phenyl phenylpropiolate which, on being warmed with aluminium chloride in tetrachloroethane at 40° for 1.5 hours, converted to flavone. The reaction of p-hydroxybenzaldehyde and phenylethynylmagnesium bromide gave 2-phenyl-3-(4-hydroxyphenyl)-1-propyn-3-ol and its oxidation with manganese dioxide afforded 1-phenyl-3-(4-hydroxyphenyl)-1-propyn-3-one.

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1-Phenyl-3-(2-hydroxyphenyl)-, 1-(4-methoxyphenyl)-3-(2-hydroxyphenyl)-, and 1-(4-methoxyphenyl)-3-(2-hydroxy-4-methoxyphenyl)-1-propyn-3-ol were prepared and their oxidation with manganese dioxide gave the corresponding ketones, 1-propyn-3-ones. Application of polyphosphoric acid to these acetylenic ketones in glacial acetic acid afforded the corresponding flavones, i.e. flavone, 4′-methoxyflavone, and 7, 4′-dimethoxyflavone. Application of sodium hydroxide to the warm ethanolic solution of the acetylenic ketones resulted in the formation of corresponding benzylidene-coumaranone compounds, i.e. 2-benzylidene-, 2-(4-methoxybenzylidene)-, and 2-(4-methoxybenzylidene)-6-methoxycoumaran-3-ones.

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Grignard reaction of 16-oxoestradiol 3-methyl ether (Ia) with methylmagnesium iodide gave 16α-methyl-3-methoxy-1, 3, 5(10)-estratriene-16β, 17β-diol (IIa), which formed 16, 17-acetonide (IIIa) by the action of acetone and hydrogen chloride. Hydrolysis of (IIIa) with hydrochloric acid in dioxane reverted it to (IIa). Similarly, 16-oxoestradiol diacetate (Ic) afforded the glycol (IIc) and its 16, 17-acetonide (IIIc), and 3β, 17β-diacetoxy-5-androsten-16-one (IV) formed the glycol (V) and its 16, 17-acetonide (VI).

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Acetylation of 16α-methoxy-3-methoxy-1, 3, 5(10)-estratriene-16β, 17β-diol (I) by the usual method gave the 17-acetate (II) which was dehydrated with phosphoryl chloride and pyridine to 16-methylene-17β-acetoxy compound (III). Hydrolysis of (III) with alkali in methanol afforded 16-methylene-17β-hydroxy compound (IV), whose hydrogenation over platinum oxide gave 16β-methyl-3-methoxy-1, 3, 5(10)-estratrien-17β-ol (V). Treatment of (I) with acetic anhydride and acetic acid yielded the 16, 17-diacetate (VI).

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Optically active 2-dimethylaminoethyl 2, 3-diphenylpropionate hydrochloride was prepared and its pharmacological action was examined. It was found that analgesic action was the strongest in the levorotatory compound, while hypothermic action and potentiation with methylhexabital was the strongest in the dextrorotatory compound, which suggests that there is a difference between isomers in the central action, but no difference was recognized in the peripheral action. There was also no difference between the isomers in toxicity.

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Various kinds of benzoylurea derivative were synthesized and their antagonistic acitivity against pentetrazol and electric shock was examined. (I) was found to have the strongest action and, therefore, its analgesic, anticonvulsive, and hypothermic actions, potentiation against hypnotics, and its acute toxicity were examined in comparison with (II) and (III). It was suggested from these results that (I) had either the effect intermediate of (II) and (III), or had the properties of both these compounds. An effect comparable to (II) as an antiepileptics may be expected and a decrease in untoward side-effects can be made, since the toxicity of (I) is weaker than that of (II).

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4-Nitroquinoline 1-oxide has not only strong antibacterial and antif ungal activity but also strong mutagenic and carcinogenic activity. It also shows distinct anticancer activity and is of interest from physiological point. The compound, however, is sparingly soluble in water and has a strong toxicity, which are of inconvenience in its application. In an attempt to prepare some derivatives of 6-nitroquinoline 1-oxide by introduction of a hydrophilic group, derivatives with 6-carboxyl, 6-sulfonyl, 2-pyridinomethyl, 2-hydroxymethyl, and 2-(2-carboxyethyl) group were synthesized.

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Intradermal diffusion of dyes by testicular hyaluronidase is considered to be due to hydrolysis of hyaluronic acid by enzymic action, resulting in the lowering of viscosity and increase in permeability. The hyaluronidase prepared from bovine testicle by ammonium sulfate purification was fractionated by zone electrophoresis with starch and spreading activity of each fraction was examined. It was thereby found that the fractions without any enzymic activity also had spreading activity. Aqueous solution of hyaluronidase, after having lost its enzymic activity by heat denaturation also showed some spreading activity.

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Oxidation of 2, 3-dimethylpyrazine with potassium permanganate afforded 3-methylpyrazine-2-carboxylic acid but not pyrazine-2, 3-dicarboxylic acid. Further permanganate oxidation of 3-methylpyrazine-2-carboxylic acid afforded the 2, 3-dicarboxylic acid, though in an extremely poor yield. 3-Methylpyrazine-2-carboxylic acid was also obtained by electrolytic oxidation in the presence of potassium permanganate. Copper, nickel and lead were used as the electrode. There was no great increase in the yield in spite of changes in electrolytic conditions such as the kind of electrode used, current density, reaction of the solution, and temperature.

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Chlorination of 2, 7-dimethyldibenzo-p-dioxin (II) with dry chlorine gas in dehyd. benzene, with irradiation of ultraviolet rays, afforded a dichloro compound (III) as colorless needles of m. p. 231°. The dichloro compound (III) was entirely identical with the dichloro compound obtained from the dinitro compound (IV) formed by nitration of (II) with fuming nitric acid in glacial acetic acid, via the diamino compound. It was thereby evidenced that the dichloro compound obtained by the chlorination reaction is not a chloromethyl compound but a ring-substituted dichloro compound.
In order to prove the positions of chlorine and nitro substituted in the ring, the dinitro compound of (II) was derived to the dimethoxyl compound by the route shown in Chart 1. On the other hand, 1-methyl-2-methoxy-4-hydroxy-5-bromobenzene (XVII) was prepared from o-toluidine and the Ullmann reaction of the potassium salt of (XVII) afforded 2, 7-dimethyl-3, 8-dimethoxydibenzo-p-dioxin (VII). These two dimethoxyl compounds were in complete agreement and, consequently, the position on the ring which suffers substitution during chlorination or nitration of 2, 7-dimethyldibenzo-p-dioxin (II) is at 3 and 8.

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Cleavage reaction with metallic sodium in liquid ammonia was carried out on benzyl phenyl ether (III), p-benzyloxyanisole (IV), p-methoxybenzyl phenyl ether (V), depsidan (II), and didepsidan (VI), and examinations were made on the direction of cleavage in the benzyl ether-type bond and ether-type oxygen bond constituting the diphenyl ether, and products of cleavage. Experimental results are listed in Table I.

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Previous papers of this series reported on the new method of optical resolution of amino acids. This new method is a culture of a soil bacteria in a synthetic medium containing a benzoyl derivative of DL-amino acid as the carbon source and ammonia as the nitrogen source, and L-amino acid and benzoyl-D-amino acid are obtained in a good yield. Lysine, methionine, phenylalanine, leucine, threonine, glutamic acid, aspartic acid, p-methoxyphenylalanine, and 3, 4-methylenedioxyphenylalanine have been resolved into optical isomers by this new method. In the present series of work, three kinds of soil samples from different localities were examined to find a bacteria capable of effecting optical resolution of lysine and three strains, KT-301, KT-305, and KT-307, were easily isolated. It was thereby considered that bacteria that effects optical resolution is distributed widely and could easily be isolated from the soil at any time.

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Digestive enzyme preparations like pancreatin and diastase are generally sensitive to gastric juice and their major portion is destroyed on contact with gastric juice. In order to obtain acid-stable digestive enzyme, which would fully exhibit its digestive power in gastric juice, approximately 170 strains of Aspcrgillus sp. were isolated from natural source, submitted to wheat bran culture, and potency assay was carried out on their culture extract. One of the strain isolated, belonging to Aspergillus oryzae morphologically, had stronger proteinolytic activity at pH 3-6 than Aspergillus niger and was named Aspergillus oryzae TPR-18.

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Digestive power of the acid-stable digestive enzyme, prepared from the newly isolated strain, Aspergillus oryzae TPR-18, was tested by various methods such as (i) pH-activity curves of protease and amylase, (ii) activity in simulated gastric juice and model stomach, (iii) velocity of protease action, and (iv) determination of proteolytic action using the assay method of J. P. VI. Results of these determinations showed that the new enzyme, named Vernase, had stronger protease and amylase actions in acid and neutral reactions than the existing digestive enzyme preparations.

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m-Dinitrobenzene derivatives possessing electronegative groups in symmetric position, such as nitro, cyano, sulfonic acid and its derivatives, and carboxylic acid and its derivatives, or electropositive groups, such as methoxyl, hydroxyl, or amino groups, were prepared and their coloration to alkali in acetone, the socalled Janovsky color reaction, was examined. The degree of coloration and stability of the color formed were found to parallel the degree of negativity, while compounds containing electronegative groups (hydroxyl, amino) did not give this color reaction.

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Condensation of potassium 3, 5-dinitrobenzenesulfonate and methyl ketones, i.e. acetone and acetophenone, in the presence of alkali afforded purplish black crystalline powder. This product showed absorption spectrum similar to that of a product obtained by condensation of potassium 3, 5-dinitrobenzenesulfonate and active methylene compounds, like cardiotonic glycoside, and was considered to have been formed by a similar type of reaction. These condensates undergo gradual decomposition when allowed to stand in a solution and are decomposed into each component in acid solution. The condensate colors bright reddish purple to alkali in the presence of hydrogen peroxide. The condensate forms S-benzylthiuronium salt with potassium sulfonate. The salt from the acetone condensate, m.p. 120°, and the salt from the acetophenone condensate, m.p. 222° (decomp.).

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Condensation of acetoacetic ester and benzoylacetic ester with methyl 2- or 4-chloro-3, 5-dinitrobenzenesulfonate is impossible, while that with phenyl 2- or 4-chloro-3, 5-dinitrobenzenesulfonate gave condensation products. Ketonic decomposition of these compounds afforded phenyl dinitrobenzenesulfonate of acetonyl or phenacyl, but their saponification to the objective free sulfonic acid was not effected. Considering these results and the sulfonic esters capable of undergoing ketonic decomposition and saponification at the same time, the ester of 2-ethoxyethanol was used and a good result was obtained. 2-Ethoxyethanol ester of 2- or 4-chloro-3, 5-dinitrobenzene-sulfonic acid was prepared and its condensation with acetoacetic ester and benzoyl-acetic ester was carried out. The products thereby obtained underwent smooth ketonic condensation and saponification at the same time, and the free acids and their potassium salts, i.e. 2- or 4-acetonyl- and 2- or 4-phenacyl-3, 5-dinitrobenzenesulfonic acids were obtained. S-Benzylthiuronium salts of these compounds were prepared. The S-benzylthiuronium salts reported in Part III of this series^*1 were found to be identical with the salts of 2-acetonyl or 2-phenacyl compounds. These facts show that 3, 5-dinitrobenzenesulfonic acid undergoes condensation with acetone and acetophenone, in the presence of alkali, condensation taking place at position 2 to the sulfonic acid, and (XXV) is formed.

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Condensation of 3, 5-dinitrobenzoic acid and methyl ketones, such as acetone and acetophenone, was carried out in the presence of alkali and a condensate was obtained as blackish purple crystalline powder. Acidification of these condensates effected decomposition into each component, while oxidation with hydrogen peroxide in acetic acid solution afforded a substance which colors reddish violet to alkali. These were considered to be compounds formed by introduction of acetonyl or phenacyl group into the ring. Condensation of 2- or 4-acetonyl- and 2- or 4-phenacyl compounds with ethyl 2- or 4-chloro-3, 5-dinitrobenzoate and ethyl acetoacetate and ethyl benzoyl-acetate was carried out. Ketonic decomposition of the condensates so obtained effected concurrent saponification, and 3-methyl- and 3-phenyl-5, 7-dinitroisocoumarin, m. p. 104° and m. p. 211°, and 4-acetonyl- and 4-phenacyl-3, 5-dinitrobenzoic acid, m. p. 196° and m. p. 202°, were obtained. The oxidation products of the blackish purple condensates were identical with 3-methyl- and 3-phenyl-5, 7-dinitroisocoumarin, and this fact proved that the condensation took place at the position 2 to the carboxyl group.
The condensation of 2- or 4-chloro-3, 5-dinitrobenzoic acid and acetone, and acidification of the condensate so obtained afforded 3-methyl-5, 7-dinitro-8-chloroisocoumarin as the chief component and a small amount of 3-methyl-6, 7-dinitro-6-chloroisocoumarin from the 2-chloro derivative. It was concluded that in this case also, as in the case of the foregoing 3, 5-dinitrobenzoic acid, the condensation took place at the position 2 to the carboxyl group.

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Separatory determination of scopolamine, homatropine, and atropine was attempted by ion-exchange chromatography using weakly acid cation exchange resin. A buffer solution prepared from boric acid, lithium chloride, and lithium hydroxide was added to the R-H form of the weakly acid exchanger to render it to the form of R-Li+R-H. Separation was the best when the swelling ratio of the exchanger became ca. 1.17 by addition of the buffer to the exchanger. The use of 0.2M lithium chloride as the elutriant effects quantitative elution of scopolamine. Subsequent elution with 1M potassium chloride or sodium acetate results in desorption of atropine, thereby separating these two substances. Homatropine and atropine can also be separated by the same method. When the ratio of R-Li/R-H becomes greater or smaller than the above value, separation becomes difficult. This separation becomes impossible when R-Na+R-H or R-NH₄+R-H form is used in place of R-Li+R-H form, even if their ratio is varied. It was considered that strongly acid cation exchange resin is not suitable for the present purpose.

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Earlier, Ito classified capillary images of various substances into four fundamental types, A, B, C, and D. Capillary images of soluble salts of metals were prepared. Each ion produced by dissociation of the salt were separated, cations as B-type and anions as A-type. Further, B-type metal cations were divided into two kinds by the type of the front of absorption bands. The normal B-type was those with dented front to which belonged bivalent ions such as Mg, Ca, Sr, Ba, Mn, Co, Ni, Zn, and Cu⁺ and Ag⁺. The hetero B-type was those with onvex front and included Cu²⁺, Al³⁺, and Fe³⁺. The normal B-type agrees well with Ito's formula and determination of the concentration can be made from the height, h, to the absorption band but the hetero B-type does not agree by the appearance of a secondary striped structure. For determination, it is more convenient to use a modification of Ito's formula, logh=p-1/plog[M]_σ-logk₀.

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