Umberger utilized the formation of a dye from isonicotinoylhydrazide (INAH) with Δ4-3-ketosteroid and benzylideneacetone for colorimetric determination of INAH. In order to elucidate the structure of this dye and mechanism of its formation, ultraviolet absorption spectra of hydrazones of INAH were examined and it was clarified that this dye is a salt-forming coloration caused by addition of a proton to the pyridine portion of INAH hydrazone.
It had been surmised that the coloration of isonicotinoylhydrazones of aromatic carbonyl compounds is due to the change in contribution of amide resonance structure, from ultraviolet absorption spectra of such compounds. In the present series of work, infrared spectra of furfurylidene isonicotinoylhydrazones and their hydrochlorides were measured and the assignment of their characteristic absorption bands was determined. From their carbonyl bands, contribution of resonance structures was discussed and previous presumption was found to be appropriate.
The isonicotinoylhydrazones of aromatic carbonyl compounds possessing electron-releasing group, such as dimethylamino and amino, in the para-position, form salts by the addition of a proton to the nitrogen in azomethine group and their ultraviolet absorption maximum shifts to a longer wave-length region than that of the hydrazones. This suggests changes in their resonance structure by salt formation and its mechanism was clarified through infrared spectral analysis.
Mutual solubility of pyridine base-water-salt system was determined. Pyridine bases used were pyridine and 2-picoline, and salts tested were potassium and sodium carbonate, sodium and ammonium sulfate, and potassium and sodium chloride. It was thereby found that aliphatic primary amines and pyridine bases had following characteristics in common: (a) Conjugation curves drawn in molar fraction units became approximately linear within a certain limited concentration range; (b) dehydration of amines became easier with increasing number of methylene groups in the homologs; and (c) linear parts of the conjugation curves of amine homologs to one kind of a salt are approximately parallel. It was clarified that there is a definite order in the dehydrative ability of the salts and dehydrative effect of ions was found to be K+>Na+, and CO32-≅SO42->OH->Cl-. It was also found that anions had greater effect on dehydrative action than cations.
The gases that interfere in the Dumas method will be oxygen, carbon monoxide, and nitrogen oxides, and this is the reason why reduced copper is used to eliminate oxygen and reduce nitrogen oxides to nitrogen. Complete reduction of nitrogen oxides by reduced copper requires a temperature of 500-600° and at temperatures above 600°, dissociation of carbon dioxide to carbon monoxide and oxygen will occur. It was found that the use of Raney nickel in dry state will effect removal of oxygen and complete reduction of nitrogen oxides, without affecting dissociation of carbon dioxide. This was applied to the micro-Dumas method and satisfactory analytical result was obtained without the reduced copper furnace.
Starting from ethyl 3-aminopropionate, ethyl 3-(N-cyanomethyl-N-ethoxycarbonylamino) propionate (II) was prepared, which was converted to ethyl 2-cyano-3-oxo-1-pyrrolidinecarboxylate (III) by Dieckmann condensation. (III) was then subjected to Knoevenagel condensation with ethyl cyanoacetate, followed by catalytic hydrogenation and alkaline hydrolysis to afford 2-carboxy-3-pyrrolidinemalonic acid (IX) and 2-carboxy-3-pyrrolidineacetic acid (X). (IX) and (X), both of which were difficult to crystalize due to their hygroscopic property, were identified as the corresponding N-ethoxycarbonyl methyl ester derivatives, (XII) and (XI), respectively.
As a starting material required for the synthesis of 2-carboxy-3-pyrrolidineacetic acid, ethyl 4-cyanocrotonate (VI) was prepared by heating ethyl 4-chlorocrotonate (V) or ethyl 4-bromocrotonate (VIII) with copper cyanide. (VI) was also obtained by hydrolysis followed by decarboxylation of diethyl 2-cyanoethylmalonate (X), bromination to ethyl 2-bromo-4-cyanobutyrate (XIII), and final dehydrobromination.
Addition of diethyl malonate to ethyl 4-cyanocrotonate (VI), in the presence of sodium ethoxide, afforded diethyl (1-ethoxycarbonylmethyl-2-cyanoethyl) malonate (XXIV) which was submitted to high-pressure reduction to form ethyl 2-oxo-3-ethoxycarbonyl-4-piperidineacetate (XXV). The 3-position in (XXV) was chlorinated with sulfuryl chloride and subsequent treatment with hot barium hydroxide gave 2-carboxy-3-pyrrolidineacetic acid (XXVIII), which was identified as methyl 1-ethoxycarbonyl-2-methoxycarbonyl-3-pyrrolidineacetate (XXIX).
Knoevenagel condensation of ethyl 4-cyanocrotonate (VI) and acetone, with β-alanine as a catalyst, afforded ethyl 4-cyano-5-methyl-trans-2, 4-hexadienoate (XXX). Its allied compound, ethyl 4-cyano-5-methyl-cis-2-hexenoate (XLI) was prepared from isopropylidenecyanoacetic acid.
Addition of diethyl malonate to ethyl 4-cyano-5-methyl-cis-2-hexanoate (XLI) and ethyl 4-cyano-5-methyl-trans-2, 4-hexadienoate (XXX), in the presence of sodium ethoxide, respectively afforded diethyl (1-ethoxycarbonylmethyl-2-cyano-3-methylbutyl)-malonate (XLIV-i) and diethyl (1-ethoxycarbonylmethyl-2-cyano-3-methyl-2-butenyl)-malonate (XLVI). High-pressure reduction of these compounds were found to form diethyl 2-oxo-5-isopropyl-4-piperidinemalonate (XLV) from (XLIV-i) and ethyl 2-oxo-3-ethoxycarbonyl-5-isopropyl-4-piperidineacetate (XLVIII) from (XLVI). L-α-Dihydroal-lokainic acid was prepared from (XLVIII).
Knoevenagel condensation of ethyl 4-cyanocrotonate (VI) and ethoxyacetone (LVI) with β-alanine as a catalyst, afforded ethyl 4-cyano-5-methyl-6-ethoxy-trans-2, 4-hexadienoate (LVII). Addition of diethyl malonate to (LVII) in the presence of sodium ethoxide gave diethyl (1-ethoxycarbonylmethyl-2-cyano-3-methyl-4-ethoxy-2-butenyl) malonate (LX), which was submitted to high-pressure reduction to form ethyl 2-oxo-3-ethoxycarbonyl-5-(1-methyl-2-ethoxyethyl)-4-piperidineacetate (LXIII). Chlorination of (LXIII) followed by treatment with barium hydroxide formed the pyrrolidine compound (LXV), and substitution of its 1-methyl-2-ethoxyethyl group with isopropenyl finally afforded L-α-allokainic acid.
Effect of strontium-, calcium-, and barium nitrate, magnesium sulfate, and other salts on the conductance of monosodium salts of ethyl 6-hydroxycomenate, comenic acid, monoethyl meconate, and 6-hydroxycomenic acid was examined and ease of the formation of hardly dissociating compound from these monosodium salts and metal ions was compared. The reaction mechanism was assumed to be 2 RONa+M(NO3)2⇔2 NaNO3+RO-M-OR. Comparison of the value of E=A+B-D/A+B-C×100, where A, B, C, and D respectively denote conductance in aqueous solution containing 2 RONa, M(NO3)2, 2 NaNO3, and the first two, showed a great difference between Sr2+ and Ca2+ only in the case of ethyl 6-hydroxycomenate and it was found that the hardly dissociating compounds formed easily in the order of strontium, magnesium, barium, and calcium ions.
Ethyl comenate, obtained in a simple manner from the residue left after extraction of morphine from opium, showed stable color reaction with Fe3+ and this coloration was followed by spectrophotometry, from which the use of ethyl comenate as analytical reagent for Fe3+ was examined. The fact that this coloration is due to chelate formation was confirmed by potentiometric titration using a glass electrode pH meter. It was found through the Job method that the composition of the chelate in dil. sulfuric acid solution is Fe3+/R=1/2, while that in Walpole's buffer of pH 5.0 is 1/3. Dissociation constant in this buffer was 5.3×10-12 by the molar ratio method and excess of the reagent prevented dissociation. The colored solution was no change in its absorbancy at 420mμ for 4-68 hours after coloration, indicating this color to be stable.
Crystalline components, m.p. 176° (decomp.) (I), m.p. 76° (II), m.p. 205° (III), and m.p. 204° (decomp.) (IV), were isolated from the stalk of Trachelospermum asiaticum NAKAI var. intermedium NAKAI (I) was considered to be a new glycoside and named tracheloside. Its molecular formula agrees with C36H50O18, containing four methoxyls and having glucose as its sugar portion. (II) was found to be acetamide, C2H5ON, (III) inositol dimethyl ether, C8H16O6, and (VI) a flavone glycoside of (C10H14O6)n.
Hydrolysis of tracheloside resulted in its decomposition into trachelogenin and a sugar portion which was confirmed as a glucosazone. Determination by the Bertrand method showed that two moles of glucose is bonded to the genin. Tracheloside possesses four methoxyls and the presence of γ-lactone and a benzene ring was suggested by its infrared spectral measurement. Alkali treatment of tracheloside afforded trachelonic acid. Trachelogenin possesses a phenol and γ-lactone, forms trachelogenic acid with alkali, and methyltrachelogenic acid again undergoes lactonization by the action of mineral acid to form methyltrachelogenin. These facts showed that trachelogenin possesses a benzene ring as the parent structure, contains phenol, four methoxyls, and a γ-lactone. It follows, therefore that tracheloside is a glucoside formed by bonding of two moles of glucose to its phenol group.
Permanganate oxidation of trachelogenin afforded methyl 3-methoxy-4-hydroxyphenylacetate and a structurally unknown acid substance of m.p. 163°. From this and the formation of 3-methoxy-4-hydroxybenzoic acid and 3, 4-dimethoxyphenylacetic acid by permanganate oxidation of acetyltrachelogenin, it was found that trachelogenin possesses 3, 4-dimethoxy- and 3-methoxy-4-hydroxyphenyl ring as the parent structure, separated by one γ-lactone ring, one secondary alcoholic group, and one methoxyl, and is a kind of lignan-type substance.
The intermediate in the synthesis of 4-isopropenylproline, ethyl 2-oxo-(1-methyl-2-ethoxyethyl) nipecotinate (Ib), was saponified to form its potassium salt (IIb) which was brominated and decarboxylated to form bromopiperidone compound (IVb). Dehydro-bromination of (IVb), followed by acetylation afforded N-acetyldihydropyridone compound (VIb), which was submitted to Michael condensation with diethyl malonate to form (X), saponified to form the semi-ester (XI), and decarboxylated to (XII). 3-Monobromopiperidone compound (XIV) was obtained by the application of bromine to (XII) in the presence of red phosphorus, and treatment of (XIV) with barium hydroxide gave a pyrrolidine compound (XV) with the side chains at 3- and 4-positions in trans configuration. In order to obtain (XV) with the side chains at 2- and 3-positions in trans configuration, retro-kainic conversion of (XV) was carried out and (XVI) of α-allo system was obtained. The ethoxyl group at 4-position in (XVI) was saponified with 48% hydrobromic acid to alcohol compound (XIX) and its N-ethoxycarbonyl compound (XX) was treated with phosphorus tribromide. Distillation of the product gave the isopropenyl compound (XXI) whose saponification finally afforded DL-α-allokainic acid (XXII). The l-ephedrine salt obtained by optical resolution of (XXII) was found to be identical with the l-ephedrine salt of L-α-allokainic acid, one of the effective principles of Digenea. Optical resolution of (XXII) with the use of d-ephedrine afforded the antipode, D-α-allokainic acid.
Heating of diethyl 1, 2-diethoxycarbonyl-4-(1-methyl-2-ethoxyethyl)-3-pyrrolidine-malonate (I) with hydrobromic acid results in the formation of a lactone (V) of m. p. 283° (decomp), besides α-allokainic acid (IX) and α-isokainic acid (X). This lactone is also obtained on the same treatment of 2-carboxy-4-(1-methyl-2-ethoxyethyl)-3-pyrrolidineacetic acid (VI′), which differs from (I) in the steric configuration of the side chain at 4-position of the pyrrolidine ring, with hydrobromic acid. Infrared spectra of (V) and its various derivatives exhibit absorptions at 5.64-5.69μ and this fact indicates that (V) is the γ-lactone of α-allokainic acid.
It has been found that L-α-kainic acid (III), L-α-allokainic acid (VI), L-α-isokainic acid (V), L-α-kainic acid δ-lactone (VII), and L-α-allokainic acid δ-lactone (VIII) all transit to the most stable α-allokainic acid γ-lactone (IV), m.p. 284° (decomp.), on heating with hydrobromic acid for a long period of time. These reaction routes were clarified and considerations were made on its reaction mechanism based on the new observation that δ-lactone changes into γ-lactone by the action of acid. The same treatment of D-β-kainic acid (X) or its derivative (XI) with hydrobromic acid was found to form (IV) with retro-kainic inversion while heating of (III) with hydrochloric or sulfuric acid failed to form (IV). Heating of (VII) with hydrochloric acid, however, was found to cause transition of a part of it to (V).
Four kinds of the known N, N-diethyl-2-(6-allyl-2-R-phenoxy) ethylamines [R: methoxy (A), methoxycarbonyl (B), propionyl (C), and phenyliminomethyl (D)] show excellent uterus contracting action, while N-2-chloroethyl-N-ethyl-2-(2-benzylphenoxy) ethylamine (E) and N, N-diethyl-2-(2-benzyl-6-chlorophenoxy) ethylamine (F) possess strong antiadrenaline action. Various kinds of N, N-dialkyl-2-(o-allylaryloxy) ethylamines (XV to XXXII) were synthesized in order to examine the variation in physiological activity on the introduction of allyl, chlorine, nitro, or amino radical, relation between allyl and chlorine, and increase of molecular weight and changes is aromaticity, based on the foregoing facts.
The treatment of sodium S-ethylmercuri-thiosalicylate with essential oil of garlic (Allium sativum), resulted in the formation of bis (ethylmercuric) sulfide and diphenyl disulfide-2, 2-dicarboxylic acid. Bis (ethylmercuric) sulfide proved to have a strong antibacterial activity against some kinds of pathogenic fungi (Trichophyton, Microsporon, and Candida) and some kinds of bacteria.
Bis (alkylmercuric) sulfides (methyl-, ethyl-, propyl-, isopropyl-, butyl-, amyl-, isoamyl-, hexyl- and cyclohexyl-), bis (arylmercuric) sulfides (p-ethoxyphenyl- and o-methoxyphenyl- and bis (aralkylmercuric) sulfide (benzyl-) were synthesized. And antibacterial activities of these sulfides were examined comparatively against Staphylococcus aureus FDA 209 P, Escherichia coli CS-1, E. coli K-12, Salmonella typhi 2 V, Shigella flexneri 3 a 102349, Candida albicans U-1, Trichophyton asteroides and Tri. interdigitale. It was found that bis (arylmercuric) sulfides are unstable and have not so effective activities generally.
1) 1-(2-Furyl)-1-methoxy-2-nitroethane (II) was prepared in a good yield By condensation of furfural with nitromethane, in the presence of a small amount of sodium methoxide. 2) The amount of 1-(2-furyl)-2-nitroethylene (I) to (II) in the condensation mixture was calculated from the elaborated chart of the refractive index of the above two components. 3) After reducing (II) with zinc dust in 5% acetic solution, the amino componud was acetylated with acetic anhydride. Nitration of the N-acetylated compound (IV) with a mixture of acetic anhydride and conc. nitric acid was accomplished. 4) 2-Amino-3-(2-furyl)-3-methoxypropanol (IX) was prepared in a stepwise manner from (II) by hydroxymethylation and reduction. N-[1-Acetoxymethyl-2-(2-furyl)-2-methoxyethyl]-dichloroacetamide (XI) was synthesized from (IX) by acylation of the amino group with dichloroacetic acid and then of hydroxyl group with acetic anhydride in the presence of a small amount of pyridine. Nitration of the above two acylated compounds failed to give the desired crystalline product.
1) Condensation of 5-nitrofurfural with glycine ethyl ester, at various temperatures and in different solvents (benzene, ether, ethyl acetate, chloroform, and chlorobenzene), only gave erythro-3-(5-nitro-2-furyl)-DL-serine ethyl ester. 2) In contrast to the above result, it was found that the reaction gives only threo-3-(5-nitro-2-furyl)-DL-serine ethyl ester by using a benzene solution containing a catalytic amount of piperidinium acetate, although the yield was poor. 3) Attempting to make better the yield, fourteen kinds of piperidinium salt were used trying this reaction. Among these catalysts, piperidinium 3-(5-nitro-2-furyl)-acrylate gave threo-3-(5-nitro-2-furyl)-DL-serine ethyl ester hydrochloride in the best yield. In order to estimate the amount of this ester hydrochloride formed, the two melting point curves shown in Fig. 3 and 4, were plotted. Fig. 3 was made by the melting point determination of various mixtures of pure N-benzoyl-erythro- and pure N-benzoyl-threo-3-(5-nitro-2-furyl)-DL-serine ethyl ester, and Fig. 4 by the determination of variously benzoylated mixtures derived from a mixture of pure erythro- and threo-3-(5-nitro-2-furyl)-DL-serine ethyl ester hydrochloride by direct benzoylation. In this work, the determination of the yield was conditionally accomplished by using Fig. 4. 4) No depression of the melting point occured on fusion of O, N-dibenzoyl compound of the above-mentioned threo-3-(5-nitro-2-furyl)-DL-serine ethyl ester hydrochloride with the O, N-dibenzoylated product obtained from N-benzoyl-erythro-3-(5-nitro-2-furyl)-DL-serine ethyl ester through inversion with thionyl chloride. 5) The infrared spectra of N-benzoyl-erythro- and N-benzoyl-threo-3-(5-nitro-2-furyl)-DL-serine ethyl ester did not show the regularity like that of ephedrine and chloramphenicol. Similar observations were made with ethyl esters of N-benzoyl-3-phenylserine and N-benzoyl-3-(p-nitrophenyl) serine.
Seven isoamyl esters and four diethylaminoethyl esters were synthesized, and their atropine-like and papaverine-like antispasmodic activities were estimated. Isoamyl acetate lacks acetylcholine (ACh)-like action and has some atropine-like and papaveri ne-like anti-ACh actions. These facts shows the indispensability of a cationic center for ACh-like action. The indexes of Ferguson's thermodynamic activity on atropine-like and papaverine-like actions were calculated from the solubility of esters and free bases in water. The isoamyl esters and weak bases such as papaverine have the indexes of a same magnitude and can be interpreted that they act through some physicochemical property of their molecules. The indexes of diethylaminoethyl esters on papaverine-like action were somewhat smaller than the above two groups and ionic state would also be supposed to contribute to papaverine-like action to some extent.
Ring cleavage of 1, 8-epoxide ring of cineole was attempted with hydrochloric, phosphoric, or acetic acid at pH 1, 2, and 3, respectively. The degree of this cleavage was about the same as that in the case of sulfuric acid and it was found that the cleavage was dependent on pH at lower concentrations, and that the degree of cleavage decreased in samples of lower concentrations, variation curve becoming very gradual. Application of sodium hydrogen sulfite to this cineole resulted in the formation of terpine hydrate and α-terpineol, indicating that sodium hydrogen sulfite works as an acid in this case. Behavior of the epoxide ring on cleavage of carbon ring was examined by cleavage of dimethyl cineolate by the application of sulfuric acid to its solution in methanol. The cleavage was effected as in the case of cineole which changed into an acid corresponding to α-terpineol. Formation of addition products by the application of various reagents to dimethyl cineolate was attempted and adducts of composition similar to those of cineole were obtained. However, it required a longer time for the formation of adducts by dimethyl cineolate and melting points of the products formed were lower.
A new substance, considered to be a glycoside, was isolated from the needles of Hokkaido pine, Picea Glehnii MASTERS, and was named piceid, C20H22O8⋅H2O, m.p. 225-226° [α]D27:-75.7° (c=5.21, EtOH). Presence of three phenolic hydroxyls and one double bond in the aglycone structure was clarified.
The two kinds of new glycoside, paeonoside and paeonolide, obtained from peony bark, were found to be β-glycosides and their hydrolysis was found to be different from that reported by Peron who stated that the extract solution of glycoside of peony bark was not affected either by emulsin or invertin. Examination of this point revealed that Peron's result must have been due to the presence of thymol added to the extract solution for antiseptic purpose. This showed that thymol had the power to inhibit hydrolysis of glycosides and that fact was confirmed by experiments with 8 kinds of glycoside, including paeonoside. It was also revealed that phenols other than thymol had the same inhibitive action on hydrolysis of glycosides, by testing 11 kinds of phenols.
The aqueous solution of paeonoside and paeonolide, the two new glycosides from peony bark, was found to undergo hydrolysis by irradiation of ultraviolet rays and that this phenomenon was general in phenolic glycosides. Action of ultraviolet rays on phenolic glycosides was found to be as follows. 1) Ultraviolet absorption spectra of phenolic and acetylphenolic glycosides were similar to those of their aglycones, with the absorption maxima weaker than those of the aglycones. In a pair of α- and β-glycosides, α-type had absorption maxima of stronger intensity than the β-type. 2) Hydrolysis was affected by the wave length of ultraviolet rays, the shorter the wave length, the stronger was the hydrolytic action. 3) Aqueous solution of lower pH was more liable to be hydrolyzed by ultraviolet rays. 4) Aqueous solution of glycosides in 0.6% concentration was hydrolyzed to 30-90% during 24 hours. 5) In a pair of α- and β-glycosides, α-type was generally more easily hydrolyzed than the β-type. Glycosides with reactive side chain in the aglycone portion were also more easily hydrolyzed.
Synthesis of thianaphthenopyridines had heretofore been effected by the final formation of pyridine ring, starting from thianaphthene derivatives, ring closure by either Bischler-Napieralski or Pomeranz-Fritsch reaction, followed by dehydration, or treatment of the adduct of haloethylthianaphthenes with hexamethylenetetramine which was formed by Delépine reaction, with hydrochloric acid in ethanol. In the present series of work, this synthesis was attempted, starting from phenylthiopyridines and forming the thiophene ring in the last stage by Pschorr reaction by which thianaphtheno [3, 2-c] pyridines and 3-chlorothianaphtheno [2, 3-b] pyridine were successfully obtained.