Fodor, Gábor

Kiss, József

English

Fodor Gábor

Kiss József

University of Szeged

26 Wenig Erfolg hatten die, die direkte Herstellung der Verbin-dung bezweckenden Versuche. Im Wasser erwärmt, reagierte ein stöchiometrisches Gemisch von PbJ, + 2CaO + PbO nur sehr träge-Nach gewisser Zeit erstarrt das Gemisch. Ebenso führte zu keinen. Resultaten dlas Kochen von den folgenden- Gemischen: 3PbS04 + 2KJ f 4CaO, bzw. 3Pb012 + 2KJ + 4CaO Zusammenfassung. Zur Bestimmung des Cyangehaltes der PbS04 haltigen geröste-ten Erzen wurde die Liebig-Deniges Metbode gewählt. Bei der Zu-gabe von H.NOH zu den Ca(OH)2 haltigen Filtrat entsteht mit K J ein hellgelber kristalliger Niederschlag mit der Zusammensetzung:. Pb3Ca2J204. 7H20. Dieser entsteht wahrscheinlich aus dem in der Lösung befindlichen CaPb02 nach der Gleichung: 3CaPb02 + 2KJ + xH,0 = = PbJ2(CaPb02)2. 7H20 + Ca(OH)2 + 2KOH + (x — 9)H20 .In A'lkalipltimbit Lösung entsteht mit KJ kein Niederschlag. Institute of Organic Chemistry of the University of Szeged. Director: Prof. G FODOR-. The Synthesis of dl-erythro-3,4-dihydroxyphenyl-serin (nor-adrenaline carboxylic acid) G . FODOB a n d J . KISB Received Aug. 1949 Rosenmund and! Dornsaft, (1) prepared d'l-3,4-dihydroxyphenyl>--serin-ethylester by ¡addition of protocatechualdehyde audi glycocoll-ethylester and subsequently hydrolised it to 3,4-dihydroxyphenyl--serin. Later Dalgliesh and Mann (2) improving this route facilated the preparation of the compound. Lately the biological interest centering on 3,4-dihydroxyphenyl. 2-amino ethanol has increased through Blaschko's recent investiga--rions (3) proving that in the human organism the adrenaline synthesis-proceeds through nor-adrenaline. In pathologic cases as observed by Tullar (4) — whose observations were also supported by Ho'lton (5) and Goldenberg (6) — e.g. in the case of adren'al tumors, the equilibrium of nor-adrenaline and adrenaline has practically com-pletely shifted in the direction of the formation of nor-adlrenaline. Consequently the next chain-link to investigate is the elucidation, of the formation of nor-adrenaline. Blaschko assumed that nor-adrenaline forms through decarb-oxylation of dl-3,4-dihydroxyphenyl-.serin. To control this sugges-tion Blaschko, Holton and Stanley (7) performed different enzy-matic decarboxylation experiments with kidtncy and adrenal gland extracts of guinea-pigs, they could, however, not observe carbon1 27" dioxide formation. Although, it is true that they succeeded in the presence of Streptococcus faeoalis R, in decarboxylating 3,4-dihydr-oxyphenyl-serin into dl-nor-adrenaline, however, the occurence of this conversion can of course not he directly applied to the humaiv organism. On the base of these experiments the formation, of nor-adrenaline from the so called nor-adrerialine-carboxylic-acid was. discarded. On the base of our most recent investigations (8) concerning, diastereoisomeric amino alcohol chemistry we were of the opinion* that the synthesis of Daigliesh and Rosenmund (1) had to lead to the respective diastereoisomeric amino-hydroxycarboxylie-aeid agre-eing in spatial structure to that of the pseudo-ephedrine one. Thus-knowing the extremely specific functioning- of ferments the suppo-sition arose> as to whether it wouldl be possible that the enzymes of the adrenal gland and the kidneys are only capable of decomposing one of the racemates of 3,4-dihydro'xy-phenyl-serin and exert, no effect on the other one. To decide this question we had first to-prepare the as yet not synthesized diaistereoisomer of 3,4-dihyd-roxyphenyl-seriii possessing an identical configuration to ephedrine. The fact of their also being a'great difference between the physiolo-gical effect of ephedrine and pseudo-ephedrine in favour of the-former seemed to support our suggestion. Our synthesis proceeded in the manner usually leading to-amtino alcohols the configuration of which agree with that, of ephed-rine. Just for this reason we chose as key intermediate (III) «-isonitroso-3,4-dihydroxy-benzoyl-aceta,te. We synthesised ethyl 3,4-dihydroxybenzoylaoetate from pyro-catechol (I) and ethyl hydrogen malonate using boron, trifluoride: (S). We succeeded in obtaining with isobutylnitrite (II) in absolute ether the suitable oximino' ketone (III) which separated as an amor-phous powder. As the purifying of the substance caused dtifficulties-we had to employ direct catalytical hydrogenation e. g. in the pre-sence of Pd'-charcoai in alcoholic hydrogenchloride, after taking up 8 moles of hydrogen we obtained the 3,4-dihydroxyphenyl-serin--ethylester hydrochloride; the m. p. of which differs from that of• the nor-adrenaline-carboxylic aeid-ethylester .hydrochloride prepared' by Rosenmund and Daigliesh, its analytical data, however, agree with the calculated valines. The obtained ethylester (IV) was hyd-roilysed according; to Rosenmundl and Daigliesh using dilute sodium, hydroxide in a hydrogen atmosphere: The m. p. of the obtained product and its nitrogen content indicated that during the alkaline saponification the serin deriva-tive was decarboxylated and! nor-adrenaline (V) formed. The strong blood pressure increasing effect of the product supports this view.. Subsequently we carried out the hydrolysis in dilute hydrochloric acid at 50° in a, Hj2 current. The analytical data of the nor-adre-naline-carboxy]ic-acid-hy d r o ehlo ri de (VI) obtained in this way agreed with the calculated values. At our request decarboxylation experi-ments were carried out with the diastereoisomers of both nor-adre-naline-oarboxylic-acids at the Pharmacological Institute and ' the-Neurological Clinic of the University of Szeged. According to the experiments, on the action of decarboxylase ferment prepared from. 1 28 the ki'dlney of the guinea-pig, the isomer of pseudo-ephedrine con-figuration does not decarboxylate at all, the recently prepared "somer nor-adrenaline carboxylic-acid on the other hand, partly undergoes decarboxylation. The further investigation of the bioche-mical' side of the question extends over the frame of this paper and necessitates very thorough studies on ferments. The results of these further examinations will be reported elsewhere. Authors are indebtedl to Jenő Domonkos and Tibor Stiirzer assistants at the University of Szeged, who aided us in performing the biological tests. < HO. ¡HO Summary. We synthesised according to the principle of Hairtung's amino-alcohol synthesis the hitherto unknown racemate of nor-adrenaline--carboxylic-acid (its configuration agrees with that, of ephedrine). We experienced that on treaiting it with alkali it decarboxylated easily. Fermentatively —: e, g. in the presence of guinea pig kidney extract — it also decarboxylates partly thus strongly diverging from the behaviour of the racemate of the isomeric pseudo-ephedrine series. Further enzymatic decarboxylation experiments are in progress. -O / \ 11 _ / v \ H O - C -H O -H O _ iHO-CH, -COOC 2 H 5 o - . C - C - C O O C o H 5 II NOH III: OH I -CH — CH,—NH» V. - A - C H . - C O O C . H . OH • I - C H - C H - C O O C „ H 5 I NHo.HCi . IV. I HCI OH I - C H - C H - C O O H I NH® • HCI -VI. NaOH Experimental. ( Ethyl-3, 4-dihydroxy-benzoylacetate. 22 g (0.2 mole) pyrocatechol is' dissolved in. 53 g (0.4 mole) ethyl-hydro-gen-malonate subsequently boron i fluoride gas is introduced into the system. The temperature of the reaction mixture is kept, between 35—40°. The pyrocaitechol dissolves in 12—15 minutes. Under cooling with iced water the boronfluoride is introduced until the increase in weight reaches 28 g. Subsequ-ently. it is heated on a hot steam bath for 40 mintthes and then poured under stirring into 56 g of sodium acétat'e which, has been diluted with 200 ml water. A fine red oily suspension is obtained. It is extracted with 2 x 8 0 ml of n-butanol and *ihe butanol solution is wáshed with a 5 % NaHC0 3 solution till the formation •of C0 2 can be observed. Instead of butanol 250 ml ether can be used for the 29 extraction. The butanol or ether solution is dried on fused Na 2S0 4 . After distilla-tion in vacuo of the solvent the residue was. submitted to molecular distillation. At 0.01 mm a viscous pale yellow oil distillating between 110—120° is obtained. Analysis.-Calculated for CnH^O-, : OC,,Hr„ 20.1. Found: OC2Hr„ 22.8%. Ethyl-a-oximino-3t4-tdihydroxy-benzoylacetate. 25 g of the preceeding ester is dissolved in 100 ml. dry-ether and then 18 g 20% abs. ethereal hydrogen-chloride is added. Subsequently w t add under stir-ring dropwise during an hour at a temptrature of about 0°, 11 g of freshly dis-tilled n-butylnitrite in 35 ml of abs. ether. The dark red reaction mixture is kepit overnight in the refrigerator and ithe solvent removed at 30°. It yields a dark red. viscous oil, which was submitted to catalytical hidrogenation. Nor-Adrenaline-carboxylicracid-iethylester. The oil', 29.3. g, obtained by the evaporation of the above mentioned ethereal •solution is dissolved in 120 ml abs. ethanol, and subsequently hydrogenated over Pd-charcoal in the usual manner in the presence of 40 ml of 4 N abs. ethanolic hydrogen chloride. During 12 hours it absorbed 7.7 1 of hydrogen. The a l -coholic solution is filtered off from the catalyst it has a pale yellow colour and is evaporated alt 50° in vacuo. It yields a viscous oil which is still, twice dissolved in abs. ethanol (80 ml) and then evaporated again. The residue, a thick oil was rubbed with 120 ml of abs. ether. It solidifies into a pale drab crystalline powder. The ether is decanted a few times and then quickly filtered and dried in a desiccator over phosphorus-pentixede. It yields a pale drab powder resembling ,,corbasil" hydrochloride (10) M. p. 112—120 (decomposition). Analysis. Calculated for C n H l a 0 5 N C l : CI, 1 2 . 7 7 V . Found C l / 1J.2o/o-N , 5.00 „ N . 4 .5 „ OC 2 H 6 , 1 6 . 2 1 » OC2H5, 20.7 ^ Alkaline hydrolysis of ethyl nor-adrenaline- carboxylate. 2.8 g of the nor-adrenaline carboxylic acid ethylester described above is introduced into a flask (150 ml) for hydrolysis and shaken for an hour in a cur -rent of hydrogen with 60 ml' NaOH. The yellowish-red coloured aqueous, solution is neutralised with 51 ml NJHCI and again shaken in a current of hydrogen. The solution does not decolorise. It is then decolorised with 0.1 g 14% Pd, charcoal in a hydrogen atmosphere. It had still taken up 105 ml hydrogen gas. It was f i l -tered. The solution is as clear as water. At 20° the water is removed and a pale drab amorphous powder is obtained, which is again evaporated with 60 ml abs. ethanol. Subsequently it is still twice dissolved in abs. ethanol the undissolved NaCl is filtered off it is evaporated and finally dried over P2Os in vacum des-sicator. Yield pale drab hygroscopic powder. Analysis, calculated for CsH110 :LN -N, 8.3 Foud: N. 8.7%. The result of the analysis indicates that the substance has undergone decarboxylation under saponification with sodium hydroxide and nor-adrenaline has formed. The same fact is supported by ithe strong blood pressure; accelerating effect it exerts on the experimentally decapitated cat. The other diastereoisomeric ethylester (threo) obtained by similar saponificaton with alkali causes hardly any rise in blood pressure. ( Acid hydrolysis of noradrenaline carboxylic acid ethylester. 3 g of the preceeding ester hydrochloride is dissolved in 50 ml N. HCL,. and heated at 50° for an hour in a current of hydrogen. Subsequently the so lu -3 0 tion is purfied with charcoal it has a red colour, then i-l is hydrogenated in the usual manner with 0.1 g Pd-charcoal. It absorbed 65 ml hydrogen. The catalyst is filtered off ond the colourless solution is freed from the ^solvent at 30°, a ¿raish-drab solid foam is obtained, which is dried over phosphorus-pentoxide -and solid sodium hydroxide in a vacuum desiccator. Analysis. Calculated'for CoHnOsRHCl : N. 5.6%. Found: N. 5.00% : For the investigation relating 'io the blood pressure enhancing effect a .1/1000 solution was used. The decarboxylation experiments were accomplished in a 1/100 molar solution under the conditions laid down by Blaschko and co,-wor-kers. The aqueous nor-adrenaline-carboxylic-ajcid solution was fixed with a phos-phate buffer at pH 7.5. The decarboxylase ferment was extracted with water from the kidney of a guinea-pig. In the case of the threo-derivatives obtained by sapo-nification we did noit experience C 0 2 formation^ whereas the .substance obtained iby saponification of acidified erythro series /evolved on the average (0.4 m) 32.5 min C02 . References. 1. Rosenmund, K. W. and Dornsaft, H. Ber. dtsch. chem. Ges. 52. (1919) 1734. 2. Dalgliesh, C. and Mann, F. G. J. Chem. Soc. (1947) 658. 3. Blashko, H., J. Physiol., 101. (1942) 337. • N 4. Tullar, Science 109, 536 <1949). 5. Holton, P. Nature, London 163. (1949) 534. / 6. Goldenberg, M„ et al Science 109, (1949) 534. 7. Blashko, Hv Holton, R.r Stanley, S„ British Journ. Pharm, and Chemo'ther. ^1948) 3. 8. Fodor; Bruckner, Kiss and Ohegyi, Journ,. Org. Chem. 14. (1949) 337; Fodor and Kiss, Nature, London,, 163. (1949) 287. 9. One of us (J. Kiss) carried out the preparation of many polyhydroxy-ssry, alkyl ketones with boronfluoride as catalyst; these resul'is are still unpublished. 10. Bruckner and Fodor, Ber. dtsch. Chem. Ges. 76. (1943) 466. "fnstitule of General and Physical Ch?mis!ry of the University of Szeged (Hungary) Director: Prof A. Kiss Examination of layer inhibiting the corrosion of Aluminium on the base of the differential-effect Preliminary Report BY G Y . BACSKAI AND K . KOVACS The interpretation of the protecting power of natural and ar-tificial coating layers covering the metal surface may be attempted on the base of the general theory of corrosion. On corrosion of metal anodfe plaices are formed, which are iu conducting correlation on the surface, on the action of the local current inducted by the polyelektrode^systeme evolved in this man-ner, the ground metal goes into solution. The local current is deter-mined by the general! equation of the polyelektrode-corrosion ^theory: • • """ . E — E p ' lL - f ( W i + w 2 + . . . + wn) 0 ) 

The Synthesis of dl-erythro-3,4-dihydroxyphenyl-serin (nor-adrenaline carboxylic acid)

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The Synthesis of dl-erythro-3,4-dihydroxyphenyl-serin (nor-adrenaline carboxylic acid)

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