α-Kainic acid, its vinyl homolog and α-allokainic acid were synthesized from the ester of methyl ketone compound of α-kainic acid and α-allokainic acid (2R:3R:4S (or 4R)-3-carboxymethyl-4-acetyl-2-pyrrolidinecarboxylic acid) by the Wittig reaction using alkylidenetriphenylphosphorane. The Wittig reagents of triphenylphosphoranes and phosphonate carbanions possessing an ester group and an alkyl chain in their α-position were prepared and reacted with the ketone compound. The latter reagent showed a stronger reactivity and increased further the reactivity by replacement of its carbonyl ester group with a nitrile.
These observations were utilized in the syntheses of domoic acid homologs (XVIII) and 4-methyl-5-carbamoyl-4-nonenoic acid (XXV).
The α-methyl ketone compound reacted with alkylidenetriphenylphosphoranes without inversion but with phosphonate carbanions containing a carboxylic ester group as yielding the α-allo compound with isomerization.

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In a previous work, kainic acid and its derivatives were synthesized from 3-carboxymethyl-4-acetyl-2-pyrrolidinecarboxylic acid (the methyl ketone compound of kainic acid). In order to complete the total synthesis of these compounds, an attempt to synthesize the methyl ketone compound was made. Oxidative cleavage of cis-2-benzoyl-4-methyl-tetrahydro-4H-cyclopenta [c] pyrrol-5 (6H)-one (III) with potassium permanganate afforded trans-4-acetyl-3-pyrrolidineacetic acid (VI) (the 2-decarboxy-methyl ketone compound).
So, in order to synthesize the methyl ketone compound of kainic acid, a compound possessing a carboxyl group in 1-position of III was prepared. The route shown in Chart 1 failed to give the cyclized pyrrolidine compound, cis-3a, 4, 7, 7a-tetrahydro-1-isoindolinecarboxylic acid (XV), but XV was obtained by the route starting with XII and via the cyanohydrin compound (XVII).

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Previous paper reported the synthesis of 2-decarboxymethyl-ketone compound from 2-methylcyclopentanone derivative by its oxidative cleavage but this procedure is too long and tedious to synthesize the methyl-ketone compound of kainic acid. Therefore, a new synthetic method was tried by the addition of 3-hydroxyglutamic acid to the methyl vinyl ketone and cyclization to the pyrrolidine ring by the intramolecular Michael condensation of its product. As indicated in Chart 1, favourable cyclization reaction did not proceed with the diamide (XIII) of 3-hydroxyglutamic acid but the cyclization product, (2R:3R:4R) 2-carboxy-4-acetyl-3-pyrrolidineacetic acid (L-α-allokainic acid methyl-ketone compound) (α-allo-I), was obtained by the method shown in chart 2. Consequently, a new method for total syntheses of α-allokainic acid and its derivatives was completed.

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In the mass spectra of opium alkaloids, parent peak (M⁺ ion peak) often becomes a base peak. Quantitative determination of opium alkaloids by mass spectrograph can be made by comparison of the parent peak of individual alkaloids with that of the reference standard of definite quantity added, and by calculation of the amount from preliminarily prepared calibration curve. The parent peak varies with ionization voltage. At a low ionization voltage, other fragment peaks do not appear and M⁺ ion peak can be detected clearly but this M⁺ ion peak itself is small. When the ionization voltage is elevated, M⁺ ion peak becomes higher but many other fragment peaks appear at the same time and overlapping of the peaks occur.
In the present series of works, examinations were made on the relationship between the intensity of M⁺ ion peak and ionization voltage. It was concluded that ionization voltage of 10-80eV is appropriate when comparing the height of M⁺ ion peak but for calculation of overlapping of fragment peaks from reference standard, ionization voltage of 70eV, usually used for measurement of mass spectrum, seems to be the most appropriate.

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Use of mass spectrograph for the analysis of organic compounds contained in various pharmaceutical preparations has not been attempted. Previous report of this series showed that it is possible to determine the amount of various alkaloids present in opium preparations by comparison of M⁺ and fragment peaks in their mass spectrum, and calculating from their mass number. In the present of work, determination of codeine and dihydrocodeine was carried out. Since the M⁺ peak of codeine and dihydrocodeine is not interfered by the peaks of other opium alkaloids present, and it is rare that both codeine and dihydrocodeine are present in the same preparation. Consequently, dihydrocodeine can be used as a reference substance for codeine, and vice versa. Mass spectral analysis of codeine or dihydrocodeine, added with a definite quantity of the corresponding reference substance, is carried out and plotting of the ratio of their M⁺ peak gives a linear relationship. This line is used as the calibration curve from which the amount of codeine and dihydrocodeine in various opium preparations can be easily determined.
Examinations were also made on the ratio of M⁺ peak height at various ionization voltage and on decrease of M⁺ peak with time.

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Components of commercial pyrabital preparations were determined by gas chromatography. The stationary phase used was 1.5% and 20% SE-30 (Chromosorb-W, 60-80 mesh), and determination of pyrabital and acetophenetidine was carried out by the conditions given in Fig. 1. Bromvalerylurea was determined by programmed-temperature gas chromatography, and caffeine was determined after removal of the co-existing acetophenetidine by extraction. Determination was made by the absolute calibration method and by internal standard method. Standard deviation was within 2.62%.

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Ease or difficulty of sugar coating procedure cannot be measured easily by a physical method. Factors affecting this procedure would be the shape of the tablets to be sugar-coated, and nature of liquids, powders, and tablets to be sugar-coated. It would be of advantage to know the shape or form of tablets which would make the sugar-coating process easier. For these reasons, considerations were made on the form or shape of tablets to be coated, making other factors constant, and an empirical formula was derived from status analysis for tablet form that would express the ease or difficulty of the procedure. Examinations were also made on the compatibility of this empirical formula. It was thereby learned that if the tablets to be sugar-coated had a shape that would make the coefficient for the ease or difficulty of sugar-coating procedure constant, sugar-coating can be carried out with the same degree of ease or difficulty, irrespective of the size of the tablets.

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In order to clarify the counter-ionic effect of arabic acid salts (X-AA) in the complex coacervation of arabic acid salt-gelatine system, coacervation intensity (θ) was measured as the function of mixing ratio of X-AA, using various kinds of X-AA system in which the counter-ions were varied (Li, Na, K, Rb, Cs, Be, Mg, Ca, Sr, Ba, Cu (I), Cu (II), Ag, Zn, Cd, Mn, Ni, and Co salts), at a definite polymer concentration (0.8%) and constant temperature (40°). The θ vs. mixing ratio curve exhibited the maximum (θ_max) when X-AA was mixed in equivalent amount. This maximum intensity increased with increasing radius of the counter-ion (Fig. 9). In the X-AA system having Ia ions (Li, Na, K, Rb, Cs) and/or IIa ions (Mg, Ca, Sr, Ba) as the counter-ions, relationship between ionic charge (Ze) and ionic radius (r) of an ion and intensity maximum was expressed by the formula θ_max=a⋅Ze/r²+b, where a and b are constants. This relation wat not satisfied in other X-AA systems. Induction of coacervation was found to be on a much wider scale in X-AA system having b group ions than those with a group ions as the counterion.

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The effect of γ-ray from cobalt-60 on thiamine hydrochloride powder drug, mixed with calcium carbonate and dibasic calcium phosphate, was about the same as when the powder was warmed and accelerated the decomposition of thiamine hydrochloride. This effect of acceleration was in proportion to the dilution of the powder and irradiation dose of the γ-ray. By calculating the specific inactivation dose from the residual rate curve obtained from the powder of low concentration, decomposition rate of thiamine hydrochloride in powders of high concentration by optional dose of γ-ray can be predicted to a certain degree. Effect of sodium chloride added as a stabilizer to the powder of thiamine hydrochloride, mixed with dibasic calcium phosphate, appears in the same ratio in γ-ray irradiation or warmimg.
These results seem to indicate the possibility that γ-ray can be used effectively for stability test of powdered drugs.

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Effect of γ-ray from cobalt-60 on methyl linolate mixed with lactose is the same as its warming in the presence of air and accelerates oxidative decomposition of methyl linolate. This effect is proportional to the dilution of the powder and dose of irradiation. By calculating the specific inactivation dose from the residual rate curve obtained from the powders of low concentration, decomposition rate of the linolate in powders of high concentration by optional dose of γ-ray can probably be predicted.
As was stated in the preceding paper, these results indicate that γ-ray can be used effectively for stability test even in the case of powdered drugs of lipoid nature.

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Various derivatives were prepared from 2-pyridineacetonitrile (III). Benzylation of III gave 1-benzyl-2-pyridineacetonitrile (IV) and 1, 1-dibenzyl-2-pyridineacetonitrile (V) which transited to their corresponding acid amides (VI and IX) by hydrolysis. Esterification of IV gave the ester (VII) of 1-benzyl-2-pyridineacetic acid. Reaction of VII with N, N-diethylethylenediamine gave the corresponding amide (VIII). The Curtius reaction of the methyl ester (VII a) of VII afforded 1-benzylimidazo [1, 5-a] pyridin-3 (2H)-one (XII) instead of the anticipated amine. Reaction of IV with 2-chloroethyldimethylamine gave 1-benzyl-(2-dimethylaminoethyl)-2-pyridineacetonitrile (XIII) whose Grignard reaction furnished the corresponding ketone compound (XV).

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Dehydroepiandrosterone, progesterone, desoxycorticosterone, and testosterone were converted to the following products by incubation with Gibberella saubinetti (MONT.) SACC. Dehydroepiandrosterone gave 3β, 7α-dihydroxyandrost-5-en-17-one, 3β-hydroxyandrost-5-ene-7, 17-dione, 3β, 17β-dihydoxyandrost-5-en-7-one, androst-5-ene-3β, 7α, 17β-triol, and 3β, 7α, ?-trihydroxyandrost-5-en-17-one. Progesterone gave 15α-hydroxyprogesterone and 6β, 15α-dihydroxyprogesterone (?). Desoxycorticosterone afforded 15α-hydroxydesoxycorticosterone, and testosterone gave 15α-hydroxytestosterone.

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14α, 15α-Epoxy- and 14β, 15β-epoxy-β-anhydrodigitoxigenin were synthesized. Fission of the former epoxide with sulfuric acid yielded 15α-hydroxydigitoxigenin. Some observations on the oxidative cleavage of these epoxides and their derivatives are presented.

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A new base was isolated from Formosan Cassytha filiformis L. (Japanese name “Sunazuru, ” Chinese name “wu-ken-ts'ao”) (Lauraceae) and was named cassyfiline. This base occurs as light orangeish brown, microgranules of m.p. 217° (decomp.), [α]_D¹⁵-89.6° (CHCl₃), and its composition corresponds to C₁₉H₁₉O₅N. Its solution in organic solvents exhibit a strong green fluorescence. The ultraviolet spectrum of cassyfiline has absorption maxima at 284.5 and 305mμ, suggesting an aporphine-type base. Its NMR spectrum (CDCl₃) indicated a phenolic secondary base possessing two benzene protons, one methylenedioxy group, and two methoxyl groups.
O, N-Dimethylcassyfiline (III) occurs as colorless columnar crystals of m.p. 139-140°, [α]_D²⁴+42.6° (CHCl₃), C₂₁H₂₃O₅N, which was identified with ocoteine, m.p. 137-138°, by mixed melting point and comparison of infrared spectra (CHCl₃) (Fig. 3) and NMR spectra (CDCl₃) (Fig. 2).
Determination of the position of the hydroxyl group followed the method used by Barton and his co-workers for that in apo crotonosine. N-Methyldeuterocassyfiline (V) was prepared from N-methylcassyfiline (IV), and NMR spectra of these two were compared. From the disappearance of the peak at 3.20τ, hydrogen in 8-position was found to have been deuterated, which proved the presence of a hydroxyl in 9-position. From these results, the structure of cassyfiline was clarified as 1, 2-methylenedioxy-3, 10-dimethoxy-9-hydroxy-N-noraporphine (I).

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Ornithine, citrulline, arginine, γ-aminobutyric acid, glutamic acid, aspartic acid, and leucine were isolated and identified from the rhizome of Arisaema ringens SCHOTT. Serine, glycine, alanine, tyrosine, valine, and phenylalanine were identified further by two-dimensional paper chromatography.
β-Aminobutyric acid was isolated as crystals and identified as a new natural amino acid from the pinellia tuber. The tuber also yielded γ-aminobutyric acid, glutamic acid, aspartic acid, and arginine, which were isolated, and the presence of ornithine, citrulline, lysine, serine, glycine, alanine, tyrosine, valine, and leucine were identified by paper chromatography.

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In order to synthesize 1, 2, 3, 4, 6-pentahydro-5H-2, 6-methanobenzo [d] [1, 3] diazocine (I), a compound related to 1-azabenzomorphane, 2-substituted 4-quinolineacetic acid derivatives were synthesized for use as its starting material. Diethyl 3-oxoglutarate was prepared from citric acid, reaction of the glutarate with aniline furnished the dianilide which was cyclized and esterified to ethyl 2-oxo-1, 2-dihydroquinoline-4-acetate (II). II was derived to the chloro compound (III) and then through the acetamide (VII) tothe objective amino acid (VIII) by treatment with 48% hydrobromic acid. The compound (VIII) was identified as its ester (IX) and acetylated compound (XI). Reduction of IX was not effected.

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Two-step synthesis of shihunine is described. The first step of the synthesis was Claisen condensation of dimethyl phthalate with 1-methyl-2-pyrrolidinone, affording 3-(1-methyl-2-oxo-3-pyrrolidinylidene) phthalide (II). Then the ketonic fission of II gave shihunine, which was identical with the natural alkaloid in all respects.

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Aqueous extract of Heterochordaria abietina (RUPR.) SETCH. ET GARDN. (Chordariaceae) was found to contain lamine (trimethyl-(5-amino-5-carboxypentyl) ammonium), yuaine (tetrahydro-1, 4-thiazine-3-carboxylic acid 1-oxide), cystathionine, alanine, arginine, asparagine, aspartic acid, glutamic acid, lysine, proline, tyrosine, 2-aminoethanol, and choline. Presence of cystine, glycine, glutamine, isoleucine, leucine, phenylalanine, serine, threonine, and valine was also detected.

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A method for the separation of L-pipecolic acid (2-piperidinecarboxylic acid) was examined and by a simple method employing its separation and purification as a picrate from the neutral amino acid fraction this acid was isolated and identified ascrystals of ginger. Asparagine was also isolated and identified as crystals. Two-dimensional paper chromatography of the amino acid fraction proved the presence of glutamic acid, aspartic acid, serine, glycine, threonine, alanine, glutamine, arginine, γ-aminobutyric acid, valine, and phenylalanine.

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Saure carried out a reaction of aqueous pyridine with cyanuric chloride to produce 6-(2 (or 4)-pyridyl)-1, 3, 5-triazine-2, 4-diol (II) and 1-[4-hydroxy-6-(2 (or 4)-pyridyl)-1, 3, 5-triazin-2-yl] pyridinium chloride (III) at room temperature and 100°, separately. However, by various chemical and physical methods, their structures were proved to be 1-(4, 6-dihydroxy-1, 3, 5-triazine-2-yl) pyridinium hydroxide, inner salt (X) and 1, 1′-(6-hydroxy-1, 3, 5-triazine-2, 4-diyl) dipyridinium chloride hydroxide, inner salt (XI), respectively. The whole route of the examinations is indicated in Chart 2.

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Cleavage reaction of methylenedioxy group in 1-benzyl-2-methyl-6, 7-methylenedioxy-1, 2, 3, 4-tetrahydroisoquinoline (V) with metallic sodium in liquid ammonia had been carried out by Sasaki and others who assumed that the product (as picrate of m.p. 172-174°) is a 7-hydroxy compound (VI, R=H). This reaction was examined in detail and the products obtained were found to be the 6-hydroxy compound (VII, R=H. Picrate, m.p. 179-181°) and 7-hydroxy compound (VI, R=H), m.p. 166-168°, indicating that the reaction progresses in two direction. The 7-hydroxy compound (VI) was identified by comparison of the infrared (CHCl₃) and NMR spectra of its O-methyl ether (VI, R=CH₃) with 1-benzyl-2-methyl-7-methoxy-1, 2, 3, 4-tetrahydroisoquinoline (XV) (picrate, m.p. 159-161°) synthesized by the route shown in Chart 1.

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Friedelin and epifriedelanol were isolated from the bark of Pirus serotina REHDER.

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Chemical shift of -O-CH₂-O- of 12 kinds of compounds derived from piperonal in NMR was compared with the characteristic absorption of methylenedioxy group in infrared spectrum and maximum absorption wave-length of the B band in the ultraviolet spectrum, and there seemed to be a correlation among these three factors.

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Chemical shift of methoxyl group in NMR, symmetric stretching vibration of C-O-C in infrared spectrum, and maximum absorption wave-length of the B band in ultraviolet spectrum were listed for a large number of ortho-, meta-, or para-substituted anisole derivatives, and presence of correlation among these three factors was suggested.

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Antifungal activities of decanohydroxamic acid in vitro and in vivo, and its antibacterial activity in vitro were examined, and it was found that this acid had almost no antibacterial activity. Antifungal activity was practically nil in a concentration below 7.5γ/ml., but growth inhibition was effected in approximately one half of the tested strains in 10γ/ml. concentration. At 100γ/ml., the acid showed growth inhibition on all the fungi tested except Monosporium apiospermum 213. There was no effect of pH in in vitro culture. Both 1% ointment and 1% tincture of decanohydroxamic acid had some effect in preventing the infection of Trichophyton interdigitale.

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