Cseh István

Földeák Sándor

Matkovics Béla

Pórszász János

Tegyei Zsuzsa

English

University of Szeged

SYNTHESIS OF SUBSTANCES EFFECTING ON C.N.S. VI Synthesis and Previous Pharmacological Examinations of ketoxime Isomer—Pairs By B. MATKOVICS, S FÖLDEÁK and Miss ZS. TEGYEI Institute of Organic Chemistry, József Attila University, Szeged I. CSEH Institute of General and Physical Chemistry, József Attila University, Szeged J. PÓRSZÁSZ Institute of Physiology, Medical University, Szeged f Received June IS, 1963) During our earlier synthetic examinations efforts have been made to separate some syn- and anti-isomers of piperidine-ketoximes. This paper presents the separation of ketoxime-isomers and their informing pharmacological investigations. Generally in the literature, of the aldoxime and ketoxime isomers is described either alone the more stabile or the mixture of the syn- and anti-oximes. V A R G H A , Oes K A Y [1,2] treated the production and separation of the various furyl-ketoxime-pairs and the determination of their configuration. The general and the above mentioned authors' experience is in most of the cases the m. p. of anti-isomer is higher that is the most stabile form and the syn-isomer can be produced from the anti-isomer with dry etheric-HCl or with HCl-gas. These authors could demonstrate differences also in the UV-spectrum of the ketoxime-isomer-pairs [1]. Several y-aminoketones were prepared to the synthesis of p-alkyl-aryl-propene-derivatives [3] and so in many cases there was a possibility to prepare the oxime isomer pairs. F O U L H O U X [ 4 ] observed that the monoizonitroso-acetone possesses strong antinicotine activity [4]. So in the case of some amino-ketones oxime-isomer pairs were prepared in order to be able to examine the eventual difference observ-able between their pharmacological activity and to connect it with the chemical structure. Our further aim is to prepare to investigate the complex-forming properties of oxime isomers and to reveal its UV-spectrum further to synthetize their various derivatives such as acetate and tosylate, etc. 1 4 4 B. MATKOVICS. S. FÖLDEÁK, ZS. TEGYEI, I. CSEH A N D J. PORSZASZ The ketoximes where prepared in alkalic conditions when taking into considera-tion the mechanism suggested by I N G O L D [5]. N H 2 . O H + O H ( - ) = N H ( - ) . O H + H 2 0 O R . C . C H 2 . C H 2 . N . R , R 2 + N H 2 . o ( _ ) tl R . C . ( C H 2 ) 2 . N . R , R 2 , _ } 0 N H . O H I + H 2 o R . C . ( C H 2 ) 2 . N . R 1 R 2 + O H ( _ ) H O N H . O H - h 2 O R . C . (CH 2 ^ 2 . N . R t R 2 -f OH ( " ' II NOH I and 11 isomer pairs are existing: N . O H II R . C . ( C H 2 ) 2 . N . R 1 R 2 H O . N I = R-anti-ketoxime R. C. (CH2)2 . N. R j R 2 II - R-syn-ketoxime "When I and II subjected to BECKMANN-rearrangement and hydrolysis the fol-lowing derivatives can be expected in 1: R - N H 2 + H 0 2 C - ( C H 2 ) 2 - N - R 1 R 2 whereas in II: H 2 N-(CH 2 ) 2 -N-R t R 2 + H 0 2 C - R as it is generally known in BECKMANN-rearrangement always the group in the anti-position is shifted. Carrying out S C H M I D T reaction the following two products ( A , B ) were obtained in the case of l-piperidino-3-phenyl-propanone-3 examined [6] and produced also by us C 6 H 5 . C . N H . ( C H 2 ) 2 . N C 5 H 1 0 A., O C 6 H 5 . N H . C . ( C H 2 ) 2 . N C 5 H 1 0 II o B „ SYNTHESIS OF SUBSTANCES EFFECTING ON C .N .S . VII 145 Having hydrolised the substances A, B we obtained the designated products. The structure of syn- and anti-oxime isomers can, be studied with F O L D I ' S complex forming method [7]. We could demonstrate a difference in pharmacological activity between the two l-piperidino-3-phenyl-propanone-3-oxim-isomers, inasmuch as the anti-isomer of a higher m. p. showed in a smaller dose a higher antinicotinic activity than the syn-pair. Experimental: l-piperidino-3-phenyl-propanon-3-( I). Substance 1 was obtained from piperidine-HCl, paraformaldehyde and acetophe-none with Mannich-condensation. [8]. l-piperidino-3-phenyt-propanone-oxime-3-HCI (11, III). It was produced with different methods and in spite of different circumstances always obtained, the presumable R-anti-oxime with the higher m. p. (II). Two typical examples: 20% hydroxilamine-HCl excess later NH2OH-HCl is added to the 100 mL ethanol solution of 15,3 g I. and.refluxed in water bath for 3 hours. Then filter i t hot and evaporate the alcohol at atmospherical pressure and dry with benzene ethanol azeotrop. Dissolving the substance in abs. acetone 12 g of crystalline sub-stance is obtained. M. p.: 8 9 - 9 0 °C. The substance is extremely hygroscopic. It can be well solved in benzene, methanol, ethanol and butanol; while in acetone very poorly, if cold it is not solving in ether and ethylate all, heated it slowly solves in latter two cases. Recrystallized from ethanol, acetone (1:2) mixture an other product is separated its m. p. 177 °C. This is likely the R-anti-modification (II). Solving substance 11 in dry MeOH streaming it HCl-gas with cooling (9) quantitatively a substance of lower rri. p. is produced. M. p.: 128-130 °C. Presumably this will be an other isomer (R-syn modification) 111. The analysis of both substances is in good agreement with the oxime-hydrochlorides (Tabl. 1). (The physico-chemical and analytical data of the substances are shown in Table f.) The oxime is prepared with an other method with N H 2 O H - H Q and NaHC0 3 in aqueous MeOH: 5 g substance 1 is solved in 50 ml of MeOH and adding the solution of 2,2 g N a H C 0 3 in 15 ml of distilled water and 1,8 g of NH2OH-HCl. Refluxed it in water bath for 2 hours and after distilled the solvent. The residue is. suspended in water and extract it with ether. Drying (Na 2S0 4 sicc.), filtering and evaporating, small white crystalls are obtained. M. p.: 107—109 °C, presumably it is a mixture of two isomers, which during the recrystallization becomes the stable isomer (II). After streaming dry HC1 gas through its solution can be turned substance III, too. B. MATK0V1CS. S. F Ö L D E Á K , ZS . TEGYE1, I . CSEH • A N D J . P Ó R S Z Á S Z >--I < Z < U o 00 o' Tf oC tM — — vo rN O o O m T U o o o r̂ l d d c E I a E <N u I o a P co-piperidino-acetophenone (IV) (10). Substance IV was obtained by condensing tw-bromo-aceto-phenone and piperidine. <o-piperidino-acetophenone-oxime (V, VI) (11). Oxime V was prepared from HCi of substance IV. M. p.: 118-120 °C. Solving oxime V in abs. MeOH and bubbling dry HCl-gas through the solution the HCI salt of the other oxime-isomer is ob-tained (VI). M. p.: 190 °C. The m.p. of oxime-VI 135 — 137 °C (11), which can be obtai-ned by fractionated crystallization of isomer V from MeOH. l-N-piperidino-3-butanone (VII) (12). It was prepared from pipe-ridine-HCl, paraformaldehyde and acetone. u o o u u o o o o o o o z z z z z z - - 9- a-I I I X X X Ő 0 Ü Ü u u Ö Ö C Ö Ö Ö X X X I * I X Q, X • o m i » cn J * •o c 'C = u re a a. O a m o O r̂ i c a T> c o c o « a a a o — a «5. . c a o D. o •0 0) 13 1) •CP 'C a £ a g _L c u D. X •3.8 _1 c c o c rt 3 •O Ó e Z ? 8 . 2 a . --i * Z o _1 r-l <4 l-N-piperidino-3-butanon-oxime (VIII). 10 g of ketone (Vll) is solved in 35 ml of abs. EtOH and 4,5 g of NH2OH-HCl and 5,47 g dry NaOAc is added to it. Refluxed in water bath for 5 hours. The hot solution is filtered. Evapo-rated it white precipitate occurs m .p . : 165-170 °C. Recrystalli-zed from MeOH m.p . : 150— 152 °C. (Table 1.) We wish to express our thanks to Gedeon Richter Phar-SYNTHESIS OF SUBSTANCES EFFECTING O N C . N . S . VII 1 4 7 maceutical Works, Budapest, for the substances, for the analyses to our Analytical Laboratory, and to Miss L. N A G Y , chemist and to J . F Ü L Ö P , laboratory technician, for their valuable assistance. И З У Ч Е Н И Е ДЕЙСТВИЯ М Е Ж Д У ФИЗИОЛОГИЧЕСКИМИ И Х И М И Ч Е С К И М И СРОЕНИЯМИ ВЕЩЕСТВ, Д Е Й С Т В У Ю Щ И Х НА Ц Е Н Т Р А Л Ь Н Ы Й Н Е Р В Н Ы Й МОЗГ. VI Синтез измерных пар кетоксина и их фартакологическое рассмотрение Б. Маткович, Ш. Фельдеак, Ж• Тедеи, И. Чех, Й. Порсас. У ж е раньше удалось приготовить изомерную пару многих пиперидин-кетоксима. П у б л и к а ц и я занимается изготовлением изомеров кетоксима и их предворительными фармакологическими рассмотренияамн. References [11 Vargha L., Gy. Ocskav: MTA Kémiai Tud. Oszt. Közleményei, 10, 355 (1958). [2] Ocskav, Gy., L. Vargha: Tetrahedron, 2, 140 (1958). [3] Földeák, S., M. Matkovics, I. Dobó. J. Pórszász: Acta Phys. et Chem. Szeged (in press). [4] Foulhoiix, P.: Comp. rend., 152, 1116 (1958). [5] Ingold C. K.: Structure and Mechanism of Organic Chemistrv (G. Bell and Sons Ltd., London, 1957). [6] Schmid>, H. J., A. Hunger, K. Hoffmann: Helv. Chirn. Acta, 39, 607 (1956). [7] Földi, Z.: Acta Chim. Hung. 10, 1 (1957). [8] Mannich C., D. Lanvnering: Ber., 55, 3510 (1922). [9] Vo<;el A. / . : Practical Organic Chemistry (Longmans, Green and Co., London, 1954). [10] Rabe, P., W. Schneider: Ber., 41, 872 (1908). [11] Cromwell, N. H., H. Hoeksema: J. Amer. Chem. Soc., 66, 870 (1944). [12] Wilds, A. L., R.C. Weill,: J. Org. Chem., 17, 1149 (1952). 

Synthesis of substances effecting on C.N.S. VI. : Synthesis and previous pharmacological examinations of ketoxime isomer - pairs

http://acta.bibl.u-szeged.hu/23634/1/phys_chem_009_fasc_003_004_143-147.pdf

Synthesis of substances effecting on C.N.S. VI. : Synthesis and previous pharmacological examinations of ketoxime isomer - pairs

Abstract

Similar works

Full text

Available Versions

University of Szeged