The method of Grewe and others for synthesis of 10-hydroxydecahydroisoquinoline requires several steps for formation of the skeletal structure and is poor in yield, while that of Mannich and others for 4-substituted derivative is limited to formation of N-benzyl compound and cannot be used for synthesis of N-methyl derivatives which are pharmacologically valuable. Studies were carried out in order to prepare 4-substituted derivatives of 2-methyl-10-hydroxydecahydroisoquinoline, known as an analgesic, and a new process illustrated in Chart 1 was found. This new synthetic method is a combination of the Mannich reaction and the subsequent aldol condensation-type cyclization. The procedure is very simple and the product is obtained in good yield. 2-Methyl-4-anisoyl-10-hydroxydecahydroisoquinoline was first prepared by this method and the two kinds of isomer produced during this reaction were separated by the difference in their solubility in chloroform. Examinations were then made on the properties of each isomer, their isomerization, and the relationship between reaction conditions and formation ratio of isomers.
In order to elucidate the steric and plane structure of (IVα) and its isomer (IVβ) prepared by the new method of synthesis developed by the present writers, derivatives of each were prepared. For the confirmation of angular OH, dehydration and chlorination were examined and the formation of dehydrated and monochlorinated products was proved. In these reactions, a marked difference was observed in the reaction velocity between (IVα) and (IVβ) and this was assumed to be due to the difference in their steric configuration. Dehydration of (IVα) and (IVβ) afforded the same product (V) and the same monochloro compound (VI) was obtained by chlorination. It is considered that these facts offer valuable means in elucidating correlationship of the two isomers and these points will be discussed in a later report.
Acetylation of the angular OH in (IVα) and (IVβ) was attempted and respective monoacetylated compounds (VIIα and VIIβ) were produced. It was found that, similar to the dehydration and chlorination reactions reported in the preceding paper, the α-type reacted more easily than β-type in this reaction. Catalytic reduction of (IVα) and (IVβ) resulted in absorption of 1 mole of hydrogen in each case to afford (IXα) and (IXβ). The same difference between the two isomers was also found in this case, β-type requiring ca. 5 times longer than α-type in absorption of 1 mole of hydrogen. The difference in the reactivity of hydroxyl and carbonyl between α- and β-types is considered to be due to their steric configuration. It was found through the present series of experiments that (IVα) and (IVβ) possessed one hydroxyl and one carbonyl groups in each molecule and that the isomerization does not occur by their acetylation and reduction.
Chemical properties were examined in the homogeneous product of gonadotropic hormone obtained from the placenta and that obtained from the urine of pregnant women, and it was found that the two substances were qualitatively identical in the constituent amino acids, sugars, amino sugar, and C- and N-terminal amino acids, although there was a slight difference in each amount. On the other hand, molecular weight of the substance obtained from the placenta was about twice that of the substance obtained from the urine. It was assumed from the foregoing facts that the gonadotropic hormone is present as a dimer in the placenta and this is dissociated during excretion into the urine.
Synthesis of dl-isolaureline (1, 2-methylenedioxy-9-methoxyaporphine) (I) by Pschorr's cyclization reaction has already been carried out independently by Marion and Faltis, but no report has been made regarding side reaction in this procedure. This point was followed in the present series of experiments and reëxamination was made on Pschorr's phenanthrene cyclization reaction of the amine (VIII). The synthesis was carried out in accordance with the procedure described in the past literature and shown in Chart 1, and the result same as that described was obtained. However, this cyclization reaction of the amine (VIII), besides giving the main product of aporphine (I) in approximately the same yield as that obtained by past workers, was accompanied by the formation of a small amount of two kinds of substances, hydrohydrastinine (IX) and 5-methoxyindiazole (X), whose formation was not mentioned in the said literature. It was thereby confirmed that this cyclization reaction is also accompanied by a side reaction by which a part of the reactant was severed into two upper and lower fragments, exactly the same as in the Pschorr reaction during synthesis of 1, 2, 9-trimethoxyaporphine (II) experienced by the present authors.
A new method is described by which the determination of methoxyl and ethoxyl groups and the distinction of their kind are carried out simultaneously. In this method, the alkyl iodide formed by hydrolysis of a sample with hydriodic acid is introduced into a combustion tube and burned with platinum contact in air stream. Iodine and carbon dioxide are formed quantitatively, the former is absorbed by a silver gauze, the latter by a carbon dioxide absorption tube, and weighed. From the molar ratio between the carbon dioxide and iodine, the kind of alkoxyl groups is distinguished. From the weight of iodine, content of the alkoxyl groups is determined.
The effect of the addition of sodium hydroxide on the vapor-liquid equilibrium of diethylamine-water system was examined. Addition of sodium hydroxide to the diethylamine-water system results in the increase of partial pressure of diethylamine in the vapor phase and decrease of partial pressure of water. It was found that addition of sodium hydroxide increases the difference in the volatility of diethylamine and water, and increases distillation effect, this effect being greater, the greater the concentration of sodium hydroxide. The temperature-composition curves, x-y equilibrium diagram, and relative volatility curves were indicated.
Zygadenine, the original alkamine of the hypotensive principle of domestic Veratrum plants, was derived to its acetonide and esters of zygadenine at 3-position, such as veratroylzygadenine, were prepared. Esters at 16- and 15, 16-positions were prepared by the use of these esters of zygadenine at 3-position.
N-Furfurylidenne-amines (Table I), N-(5-methylfurfurylidene)-amines (Table II), and N-(5-nitrofurfurylidene)-amines (Table III) were prepared respectively from furfural, 5-methylfurfural, and 5-nitrofurfural. Condensation of furfural and 5-methylfurfural with the amine was more difficult than with 5-nitrofurfural. N-(5-Nitrofurfurylidene)-amines so obtained did not show the deep purple coloration with aniline hydrochloride. Application of aliphatic primary amines as hydrochloride to N-(furfurylidene)-alkyl-amines (E′) failed to cause any reaction, but application of 2 moles of aromatic amine hydrochlorides to 1 mole of the furan compound resulted in facile reaction to form the Stenhouse dye (B) in quantitative yield. On the other hand, application of 1 mole of the amine or 1 mole each of aromatic amine and its hydrochloride to 1 mole of the furan compound resulted in separation of the aliphatic amine constituting the furan compound as its hydrochloride. N-Furfurylidene-alkylamine did not react with aromatic amine itself.
5-Halofurfural formed orange crystalline substance by reaction with aniline and the structure of this product has been assumed as 2-bis (phenylarnino) methyl-5-halo-furan (A). Reëxamination of this reaction indicated that the halogen in this product is ionic and reacts quite easily with silver nitrate and alkali. The present workers therefore deny the formula (A) and propose the structure of N-(5-anilinofurfurylidene)-aniline hydrochloride (B). Treatment of (B) with alkali gives dehydrohalogenated substance as yellow crystals, m. p. 147°(decomp.), and its base would be represented by formula (C). Application of hydrochloric or hydrobromic acid to (C) results in instantaneous conversion of the yellow crystals to orange (B), while application of hydriodic acid results in the formation of the hydriodide of (B), which is considered to be formed from 5-iodofurfural and aniline. The foregoing facts were further confirmed by application of various aromatic primary amines other than aniline to 5-chloro- and 5-bromo-furfural. Application of phenylhydrazine to the (C)-type compounds listed in Table IV afforded the 5-arylaminofurfural phenylhydrazones shown in Table V. Treatment of (C) with sulfanilic acid afforded N-(5-anilinofurfurylidene) sulfanilic acids. It is considered that this kind of substitution reaction gives evidence to the structure of (B) and (C).
Determination of total ecgonine, formed by hydrolysis of crude cocaine with acid, was carried out. The ecgonine formed was adsorbed on strongly acid ion exchange resin (Amberlite IR-120), eluted with ammoniacal ethanol, and the ecgonine obtained was submitted to non-aqueous titration with perchloric acid solution in glacial acetic acid. Determination of cocaine by non-aqueous titration was carried out by adsorption of cocaine from ethanolic solution of crude cocaine on weakly acid ion exchange resin (Amberlite IRC-50), thereby separating cocaine alone from ecgonine and benzoylecgonine, eluted by ammoniacal ethanol, and titrated by the same method.
In order to find furan derivatives possessing antitubercular and antifungal activity, N-alkyl-2-furamides were prepared. Compounds of this series with alkyl groups of C13H27 to C15H31 indicated strong antibacterial activity against H37Rv strain of tubercle bacilli. These compounds generally showed strong growth-inhibitory activity against Trichophyton and Microsporum, but were not effective against Candida, Saccharomyces, and Aspergillus.
N-Alkylated 5-chloro-2-furamides (I) and 5-nitro-2-furamides (II) were prepared as antifungal agents. None of the compounds of (I) series showed strong antitubercular activity but some of (II) compounds with alkyl group of C6H13 and C7H15 showed growth inhibition against H37Rv strain of tubercle bacilli in 1γ/cc. concentration. Some of the compounds of (I) and (II) series were effective against Trichophyton and Microsporum but none showed growth inhibition against Candida, Saccharomyces, or Aspergillus.
During the preparation of 5-alkylated and 5, N-dialkylated 2-furamides, introduction of alkyl group into α-position of the ring was effected by acylation of the furan ring and reduction of carbonyl by the Wolff-Kishner reduction. None of the compounds prepared had strong antitubercular action but 5-alkylated compounds showed strong antifungal activity against Trichophyton, Microsporum and Aspergillus spp.
In order to fortify the antimicrobial activity of 2-methoxymethyl-5-nitrofuran (I), which is known as the antifungal agent, the methoxyl group was substituted with alkoxyl group. The 2-alkoxymethyl compounds so formed showed antifungal activity against Trichophyton and Microsporum spp., and the compounds with alkyl group of C3H7 to C8H17 also showed strong antibacterial activity against H37Rv strain of tubercle bacilli.
As the alkylated derivatives of 5-nitrofuran and its allied compounds, 5-nitro-2-furaldehyde 4-alkylsemicarbazone and 4-alkylthiosemicarbazones were prepared. None of these compounds showed antitubercular activity but some of the compounds had growth-inhibitory action against Trichophyton and Microsporum spp. at low concentration. None of the compounds were effective against Candida and Saccharomyces.
1-(5-Nitro-2-furfurylideneamino)-5-alkylhydantoin, an alkylated derivative of nitrofurantoin known as the urethral antiseptic, was prepared. Of these compounds, the isobutyl derivative showed growth inhibition against H37Rv strain of tubercle bacilli in 3γ/cc. concentration. These compounds in general had strong antifungal activity against Trichophyton and Microsporum spp.
Ultraviolet spectra of the aqueous solution of compounds related to meconic acid showed varying stability and some labile substances were found. In order to find relationship between structure and stability of ultraviolet spectrum, and its reason, variation in molar extinction of over 20 kinds of compounds related to meconic acid was measured in aqueous, 0.05N hydrochloric acid, and 0.05N sodium hydroxide solutions after leaving for 24 hours. The ultraviolet spectrum in the aqueous solution was extremely labile in a compound with hydroxyl in the 5-position which is considered to take the keto form easily. However, even this compound became stable in 0.05N hydrochloric acid solution in which the γ-pyrone ring would hardly undergo ring opening. The compound was completely stabilized when derived to the enol form by chelating with a metal. The compounds with stable ultraviolet spectrum in aqueous solution became labile in 0.05N sodium hydroxide solution when their γ-pyrone ring was opened. It was thereby found that the compounds not only underwent ring cleavage in 0.05N sodium hydroxide solution but also underwent decomposition after ring cleavage to a β-diketone compound. From such facts, the reason why compounds whose hydroxyl in 5-position easily takes the keto form alone show extremely labile ultraviolet spectrum in aqueous solution was explained as shown in Chart 1. Decomposition rate of these compounds in 0.05N sodium hydroxide solution was measured from the ultraviolet spectrum measured after leaving in 0.05N sodium hydroxide solution for 24 hours and the solution acidified with hydrochloric acid to effect cyclization. By this means, effect of 5-OH, 5-OCH3, and 2-COOH on the stability of γ-pyrone ring in meconic acid derivatives was examined. In this case, γ-pyrone ring becomes more easily liable to alkaline attack as the symmetry around ketone group in 4-position of γ-pyrone ring is destroyed.
Route of decomposition of ethyl comanate (III), chelidonic acid (IV), ethyl O-methylcomenate (VII′), methyl 5, 6-dimethoxycomanate (IX), and dimethyl O-methyl meconate (XI) as a 0.05 m. M solution in 0.05N sodium hydroxide solution at ordinary temperature was clarified through periodical change of their ultraviolet spectra in 0.05N sodium hydroxide solution, their ultraviolet spectrum after leaving them in 0.05N sodium hydroxide solution for a definite length of time and acidification with hydrochloric acid, ultraviolet spectra of several β-diketone compounds in 0.05N sodium hydroxide solution, polarogram of these compounds in 0.1N sodium hydroxide, and coloration reaction of β-diketones to UO2-, Ti3+, and Fe3+. It was thereby found that, after ring cleave, (III) underwent decomposition to acetone through the enolate of formylacetone (XXXII), (IV) to acetone through the enolate of oxalylacetone, (VII′) to methoxyacetone through the enolate of ethyl 1-ethoxyoxalyl-3-methoxyacetone (XXIX), (IX) to methoxyacetone through the enolate of methyl 2-methoxyacetoacetate (XXVII), and (XI) to methoxyacetone through the enolate of methyl 1-methoxyoxalyl-3-methoxyacetone (XXX).
By the catalytic vapor-phase reaction with cadmium phosphate-acid clay as the catalyst, formation of picoline and aniline from cyclohexanone and ammonia was observed. Similarly, 2, 3-lutidine and o-toluidine were formed from methylcyclohexanone and ammonia, 2, 6-lutidine and m-toluidine from 3-methylcyclohexanone and ammonia, and 2, 4, 6-collidine and 3, 5-xylidine from 3, 5-dimethylcyclohexanone and ammonia. In the reaction of 4-methylcyclohexanone and ammonia, formation of pyridine base was not recognized and only p-toluidine was identified. 2-Picoline and aniline were obtained from the reaction of ammonia and 2-cyclohexenone, considered to be the intermediate of this reaction, and 2, 4, 6-collidine and 3, 5-xylidine from 3, 5-dimethyl-2-cyclohexenone and ammonia.
In order to make systematic examination of solubilizing action of acid amides, the strength of solubilizing action and relationship in the concentration of solubilizing agent and solubilizate were examined with 17 kinds of compounds possessing hydroxyl, amino, or carbonyl as the solubilizate, and five kinds of amide, urea, acetamide, cyanoacetamide, nicotinamide, and isonicotinamide, as the solubilizing agent. The order of this strength was: isonicotinamide ≅ nicotinamide>>cyanoacetamide>>acetamide≅urea. It was found that the volubility of the solubilizate increased in proportion to the concentration of solubilizing agent, as indicated in Figs. 1 and 2.
Acid amides are generally used as a solubilizing agent but their solubilization mechanism is still almost unknown. In order to clarify such mechanism of urea, acetamide, cyanoacetamide, nicotinamide, and isonicotinamide, whose solubilizing action was reported previously, refractive index of their aqueous solution was measured by the method of Arshid and Giles, to examine interaction, if any, between the acid amide and the solubilizate. It was thereby found that these acid amides and the solubilizate, such as phenol, benzyl alcohol, and p-toluidine, formed a complex of 1:1 molar ratio and that these amides are complex-forming solubilizing agent.
Formation of a complex between the solubilizate and a solubilizing agent, the acid amides, in aqueous or alcoholic solution was further confirmed by measurement of partition coefficient, and a relationship between increased solubility of a solubilizate by the use of a solubilizing agent and formation of a complex was examined with salicylamide and nicotinamide. Measurement of partition coefficient of nicotinamide and salicylamide between benzene and water showed that nicotinamide is present only in the water phase and does not transfer to the benzene phase, while the coefficient of salicylamide to benzene/water=1.265 at 25°C. Apparent partition coefficients in a solution containing both nicotinamide and salicylamide showed that the amount of salicylamide is constant in benzene phase while its amount in water phase was found to increase in proportion to the amount of nicotinamide. Since it is known that salicylamide and nicotinamide form a complex in solution, this increase can be attributed to the formation of a complex and calculation of equilibrium constant of the equilibrium system of complex formation from partition coefficient gave a constant value, satisfying the equilibrium system and agreeing with the law of partition.
It had been clarified that the solubilizing action of acid amides and the increased solubility of a solubilizate are due to complex formation. In order to analyze the complex formation reaction of acid amides and solubilizate as aid to the study of solubilizing agents, thermodynamic constants of interaction between a solubilizate and several of the solubilizing agents, such as nicotinamide and salicylamide, which had strong activity, were examined. In order to obtain such thermodynamic constants, it was necessary to know equilibrium constants at different temperatures and constants were measured at 10°, 25°, and 35°. It was found that the energy of complex formation was 1, 500-5, 000cal./mole, indicating that the reaction is exothermic. Free energy difference showed that such reaction took place easily.
Methanol extract of the dried leaves of Taxodium distichum afforded avicularin, quercetin, sequoyitol, and a new flavonoid glycoside, m.p. 261-263°(decomp.), [α]D15: -178.1°(c=1.37, EtOH⋅pyridine=9:1), C21H20O11⋅1/2H2O. The new glycoside was named distichin and its structure was assumed to be isorhamnetin L-arabinoside.
5-Halofurfurylideneamines (I to IV) were obtained as colorless crystals by the reaction of 5-halofurfural and aliphatic primary amines (diphenylmethylamine, benzylamine, and cyclohexylamine). Examination of the action of these amines to these furfurylidene compounds showed that the reaction does not take place in the case of aliphatic amines and their hydrochlorides, and aniline does not react with the compounds (I), (II), and (III). Aniline did react with (IV) by which amine exchange reaction occured to form N-(5-halofurfurylidene)-aniline. In the case of aniline hydrochloride or aniline and aniline hydrochloride, N-(5-anilinofurfurylidene)-aniline hydrochloride (A) was formed in a good yield. 5-Chlorofurfural azine (V) did not react with aniline or benzylamine. Application of hydroxylamine hydrochloride to (I) afforded 5-chlorofurfural oxime.
Absorption coefficient of the color produced from santonin and lumisantonin with sodium methoxide was obtained and the content of santonin in Artemisia kurramensis QUAZ. was determined by the application of concurrent determination of the two components.
In studying the analytical method for organic oxygen, examination was made of various methods now being performed and the Unterzaucher method was considered to be the most suitable. Some variations in the method were carried out and it was found that good results would be obtained by the use of pyrogallol and reduced copper for purification of nitrogen gas and by maintaining the temperature of carbon-contact furnace at 1, 120°.
Reëxamination of the Unterzaucher method as a new determination for organic oxygen was carried out by the use of a platinum-carbon, prepared by the authors' own method, and with the temperature of the carbon-contact furnace lowered to 950°. Analyses of substances consisting of carbon, hydrogen, nitrogen, and oxygen, as well as those containing halogen or sulfur gave good results. The decreased size of the apparatus and simplification of the procedure made it possible to determine oxygen directly and just as easily as the analyses of other elements, in equal accuracy.
Separatory determination of mixed hormones in tablets was attempted with tablets containing ethynylestradiol and ethysterone or methyltestosterone. It is possible to determine the content of ethysterone and methyltestosterone from the ultraviolet absorption spectrum at 241mμ, without the effect of ethynylestradiol. The content of ethynylestradiol can be determined by column chromatography through alumina, removing ethysterone or methyltestosterone by elution of the column with 2% ethanolic benzene, eluting out ethynylestradiol with 30% ethanolic benzene, evaporating this eluted solution, and coloring the residue by the hydroquinone method.
Formation of a molecular compound between berberine hydrochloride and sulfa drugs was examined by thermal analysis using sulfanilamide, free homosulfaniiamide, sulfathiazole, sulfaguanidine, sulfadiazine, sulfamerazine, and sulfisoxazole. It was found that berberine hydrochloride formed molecular compound in 1:1 molar ratio with sulfanilamide and sulfaguanidine. The fact was further confirmed from elemental analysis and infrared absorption spectrum.