Apjok, József

Czombos, József

Felföldi, K.

Kárpáti, E.

Molnár, Árpád

Notheisz, Ferenc

English

Felföldi K.

Molnár Árpád

Apjok József

Czombos József

Notheisz Ferenc

Kárpáti E.

University of Szeged

CHEMISTRY OF 1.3-BIFUNCTIONAL COMPOUNDS, XXVII* PREPARATION OF 4-N-SUBSTITUTED PIPERAZINYL-1-PROPYL ESTERS By K. FELFÖLDI, Á. MOLNÁR, J. APJOK, J. CZOMBOS, F. NOTHEISZ Department of Organic Chemistry, Attila József University, 6720 Szeged, Hungary and E. KÁRPÁTI Chemical Works of Gedeon Richter Ltd., 1475 Budapest, P.O.B. 27, Hungary (Received 12th May, 1982) As a continuation of the synthesis and pharmacological examination of different aminoal-kyl esters [1—6], esters containing the piperazine skeleton have been prepared by various methods. Some of them display coronary dilating and cardiac arrhythmia-inhibitory effects. We earlier reported the synthesis and pharmacological properties of various ami-noalkyl esters. In a number of cases, appreciable local anaesthetic [1], bronchial spasmolytic [3], coronary dilating [4, 5] and arrhythmia-inhibitory [6] effects were found. Numerous of the various piperazinyl-1-alkyl esters exhibit considerable phar-Table I Pharmacologycal data of some esters Compound Elevation of the fibrillation threshold (%) 2 mg/kg 1 mg/kg 0.5 mg/kg 58 — 21.5 13.2 54 — 22.4 — 91 — 30.3 14.2 38 — 27.6 18.9 35 31.1 — — 118 — 36.4 — Chinidin 34.5 20.6 — * Part XXVI: M. Bartók, Á. Molnár, G. Bozóki—Bartók: Acta Chim. Hung. in press. 226 K. FELFÖLDI and HIS COWORKERS (B u se u. X 0<N I I o U <N — r*-1 o a H o d m o o 0 1 o I c I 0 1 X o X <J I X o 0 ü - ö n X o o Z 8 НЭСО. H 3 C O - < X J ) - C H 2 -Н 3 С 0 ' — — — ' — 0 . 7 8 — С [14] 9 @ > - < с н 2 ) 2 - 1 7 0 — 1 7 2 3 — — — 5 9 С — 10 ( С Н 2 ) 2 -осн3 — — 6 2 — 6 3 0 . 8 9 6 5 с — 11 < 0 } - ( с н 2 > 3 - 1 8 8 — 1 9 0 1 1 . 5 3 2 3 — — 7 5 с — 12 < ¡ 5 ) — ' 0 - ( C H J ) 2 -1 8 5 — 1 8 8 0 . 5 — 3 6 — 3 7 — . 6 3 с — 13 ^ Q ^ — с н ° - с н - с н 2 - 1 6 5 — 1 7 0 1 1 . 5 5 4 0 — 0 . 6 5 5 7 с — .14 ( Ç H ^ N - ( С Н 2 ) 3 — " — — . — 0 . 3 7 — с — 1 5 с2н5оос— 1 4 8 — 1 5 0 2 1 . 4 8 4 0 — 0 . 8 8 6 5 А , [ 1 5 ] 16 / С Н 3 - ( O V - N H - C - C H , -\ / д сн3 ; — — — 1 3 7 — 1 3 9 0 . 4 2 7 3 А — 3 >< о и I—» •я о t > г о о S ч О ы ы -J 228 K. FELFOLDI and HIS COWORKERS Table III . ^ a ^-(CH2)3-OH  R N o As R M.p. (°C) R F Yield % Ref. 1 7 H 73—74 0.9 77 [16] 1 8 P -CH3 CH3 144—148" — 68 — 1 9 CH3 158—160" 65 — 2 0 CH3 CH3 H 58—59 52 — 2 1 % OCH3 H 92—93 0 . 6 7 77 [17] 2 2 OCH3 H 94—95 — 68 — 2 3 H 87—89 — 75 [8] 2 4 C H 3 0 - ( S ) - CH3 69—71 — 48 — 2 5 H 99—100 — 52 .[18] 2 6 p -CI H 84—85 0.87 82 • Method A b Boiling point at 1 ram Hg. CHEMISTRY OF 1,3-BIFUNCTIONAL COMPOUNDS, XXVII. 229 Table III No Ar R M.p. C O R f Yield % Ref. 2 7 H 1 0 9 — 1 1 0 0 . 8 5 75. [8] 2 8 CI H 8 6 — 8 8 0 . 7 6 8 2 — 2 9 p -CF3 H 1 5 8 — 1 6 0 " 0 . 8 5 • 6 8 — 3 0 H 8 0 — 8 1 0 . 8 6 75 — macological effects, e.g. central nervous system [7], sedative and hypotensive [8] and tranquillant [9] effects. Some of the new compounds we have prepared display good anti-arrhythmic action in anaesthetized cats [10] in comparison with that of quinidine used as reference substance (Table I). Experimental The esters were prepared from the corresponding piperazinylpropanols and acid chlorides in acetone or benzene; by the addition of HC1 dissolved in ethanol, the dihydrochloride salts were then precipitated and subsequently purified by recrystalli-zation from aqueous ethanol (Table IV). Besides the data resulting from microanaly-tical elemental analysis (C, H and CI ), thin-layer chromatography was used to check the purity. Of the starting materials, N-carbethoxypiperazine, N-benzylpiperazine, iV-butyl-piperazine and the iV-arylpiperazines were products of Aldrich. 3-Chloropropanol, p-fluorobenzyl chloride, 3-phenylpropyl bromide, 3-chlorocrotyl chloride, 2-phenyl-éthyl bromide and 3-phenylallyl bromide were products of Fluka. l-Methoxy-3--chloromethylcyclohexane (b.p. : 95—100 °C/2 mm Hg;nf,°: 1.4682), 3, 4, 5-trimeth-oxybenzyl chloride, 2-(2-methoxyphenyl)-ethyl chloride (b.p. : 74—76 °C/7 mm Hg ; ng»: 1.5345) and 2-phenoxyethyl chloride (b.p.: 68—70 °C/6 mm Hg; nf,0: 1.5342) were prepared with SOCl2 from the alcohols, synthetized by LiAlH4 reduction of the esters of the corresponding carboxylic acids (Fluka products), and were purified by distillation. 3-Heptamethyleniminopropyl chloride was prepared as in [2]. Some of the carboxylic acid chlorides were Fluka products; the others were prepared from the corresponding carboxylic acids with SOCl2 or oxalyl chloride and were purified by distillation. / Table IУ / \ R — ' y _ / N — î ^ - O - Ç - X . R No RI RS X Formula Derivative M.p. (°C) 31 i-CjH7— H p-OCH3 CIGHJOCLJNJOJ 2 HCl 228—229 32 " n - C t H , - H р ъ OCH3 CIEH32Cl2NAOA 2 HCl • 215—217 33 n - C 4 H g - H CIEH2„Cl2FN202 2 HCl 224—226 34 N - C 4 H , - H C25H34CI2N3O3 2 HCl 188—190 35 N-CTH¿- H C2,H38J2N2O3 2 CHJL 193—195 36 CHj=CH-CH2- H è C nH 2 0Cl 2N 2O 2 , 2 HCl 189—191 CHEMISTRY OF 1,3-BIFUNCTIONAL COMPOUNDS, XXVII. 231 2 HCl 189—190 2 HCl 209—210 2 HCl 185—187 2 HCl 189—191 2 HCl 186—188 2 HCl 196—199 2 HCl 158—159 es О z G s и О Z 0 о es œ и О Z и-0 а и О Z « 0 Я J О Z G о я -в> и Ö" Z G 9 « Я J О Z G я" «4 и (SU ^ ^ о Ф и_ Ж M 1 CI X О X О г> <-> о 1 х I о (qT ( s u v о Я ж Я S ас я я 1 гч 1 X 0 1 X о, 11 ÍN X . о i Г*4 X <_) 1 X о X о 0 1 X о I  U - Ö п> X о 'гм X. О го I о i cg X О j à го X О 1 ÍN X о é Ín X О è г-m к г> от о -ч- •Ч1 N t го •ч-Table IУ N o RI Rs X Formula Derivative M.p. CC) 4 4 H CH3O CH3O C23H3.,CI2N2O4 2 HCl 219—221 4 5 H C29H32CI2N2O3 2 HCl 204—206 4 6 H P -OCH3 C22H29CI2FN2O3 2 HCl 220—221 4 7 H XL C21H20CI3FN2O2 2 HCl 229—231 4 8 C H 3 0 . C H 3 ° \ Q ) " " C H 2 ~ C H 3 O ^ H C31H38C12N2OO 2 HCl 196—198 4 9 H C29H34CI2N2O3 2 HCl 193—194 CHEMISTRY OF 1,3-BIFUNCTIONAL COMPOUNDS, XXVU. 233 2 HCl 182—183 2 HCl 192—193 2 HCl 176—178 2 HCl 187—189 2 HCl 181—182 2 НС1.Н20 205—206 HCl 145—148 О « Z ö n Я <0 о US О M Z ö A sc . о « О Z Ö « » Я о n и te О N • Z ö" » « Я uS и О* Z M и n я о и Л О « Z о . Ö •в « а «0 и О 01 Z ö 9) Я и А . . 9 . 1 9 . X О X о п о О ж n 1 Cl X о X о ci О CJ é о Y о m 1 ci X О X О Cl <_> X о <g> è к К я я я я я гм _ гм Г 1 о В ! 1 Г» ÍN X О ( О ) 1 Г) -ÍN X О é 1 сч '"Rt X О т о è 1 ÍM X • о т о (Q) 1 ín ÍN X О é у i о о о и> X M о е m «п (Ч V) <•> V) t VI •л in VO V) 8 Table IУ No R. RI X Formula Derivative M.p. CC) 57 C2H5OOC— H ( ß h -0CH3 C18H27CIN2O5 HCl 162—164 58 C2H5OOC— H C24H20C1N2OS HCl 144—145 s 59 C2H5OOC- H C25H31JN2O6 CH3I decomp. 60 ^ O ) — C H = C H - C H 2 - H P -OCH3 CMH3BCI2N2O3. 2 HCl 179—181 61 CH°CH-CH 2 - H P -OCH3 C24H32CI2N2O3 2 HCl 200—201 62 CH~CH-CH2- H CH30 C H 3 O - ( © ) -CH30 C20H30CI2N2O5 2 HCl 215—217 CHEMISTRY OF 1,3-BIFUNCTIONAL COMPOUNDS, XXVII. 235 Table IУ No Ri Rs X Formula Derivative M.p. (°C) 69 H C2oH26Cl2FN2Oa 2 HCl 196—198 70 H p-CF3 C21Har,ClaF3NaOa 2 HCl 178—180 71 H ( O L ^ I O ) C27H3„C12N203 2 HCl 152—153 72 / H © J ® 2̂8 H31JN2O3 CH31 169—170 73 H cy C,BHS4ClANAO, 2 HCL 166—167 74 CH3 CH3 C22H29CI2FN2O2 2 HCl 188—190 75 CH3 CH3 NCH3 C23H32CI2N2OA 2 HCl 166—168 CHEMISTRY OF 1,3-BIFUNCTION AL COMPOUNDS, XXVII. 237 2 HCl 139—140 2 HCl 167—168 2 HCl 148—149 2 HCl 168—170 2 HCl 211—212 2 HCl ,; 205 2 HCl 209—210 iâ О el Z . G «a «9 •Д и M • 0 M Z «9 ' и e» SC M M и n О N ' % G - И SC m M и « О w Z я G « M я • M и а . О О) Z : G . « . sc-, «. и я О Z " Pu "• • M G -п. ' SC . о : ; . п О ; 0 л • ас . в S и А . 0 Т о m 1 п 1 О X О ("> О X о & ( ß > о ф ; о п X о ^ ^ о ю) — / о ; « В О й sc и я SC и Я X О S X ' д : Ю Г , ' • ^ ^ ^ о Ф Хч • $ о го X $ О го X го X " Ф Х " И го % О го X Ж -О • VO H R- 00 О\ T- О OE -: N 1 00 I Table IУ No R» Ri X ' Formula Derivative M.p. CC) 83 & CH3 H a ' ' / CJOHJJCINJOJ 1 HCl 210^-211 84 OCH3 H CaiHjjCljFNjOs 2 HCl ' 181 85 <oV-0CH3 H CH30 . . C H 3 Ö C,4H,«C1,N,0, \ 2 HCl 167 86 0CH3 H C28H,aClNa04 * HCl 193—195 87 OCHJ H CieH2( jC l2Nj04 2 HCl 165—166 88 0CH3 H QiHisCI jNjOj 2 HCl 167—168 CHEMISTRY OF 1,3-BIFUNCTION AL COMPOUNDS, XXVII. 239 2 HCl Мб—in HCl 178—179 2 HCl 180—181 2 HCl 161—163 2 HCl 171—173 2 HCl 171—173 2 HCl 162—163 2 HCl 172—174 6 z и о я и О Z Ö . в « Я и О Z е* ö СО Я ; . и О . о . Z со Ö я ; о » О Z (0 ÖH Ö • 91 Я о . О Z Ö ' о я" 9» и О «1 z ö; et Я' и-С9 О N Z Ö о IM Я О х " Ч У Ч И О JL о ( о Г ( Q U -• О х Ч ^ / Ч И о 6 ф Я я Я •'Я Я Я Я' » Я и Ю З ' х о Ю Г X v " о ¿ U о ф о п X • и ф 0 í-i 1 о ф -о /п X о ф 0 п 1 О ф о п X О 0\ se о ON о\ Г ) Os л -ч-0\ V) о\ VO о\ Table IУ No R i R, X .. . Formula Derivative M.p. (°C) 97 CH3 C23H32CI2N203 2 HCl. 1 6 8 — 1 6 9 98 CHS 0 C H 3 CjaWjjCljNjOj 2 HCl 1 5 1 — 1 5 2 99 H C20H24G2N2O2 HCl 1 7 9 — 1 8 0 1 0 0 # H CH3 C21H- 20 CI 2N 20 2 HCl 1 9 3 — 1 9 4 1 0 1 H CI C20H23O3N2O2 HCl 1 9 3 — 1 9 4 102 p-CI H • C20H2iCl3FN2Oj.. 2 HCl 187—188 1 0 3 CI H 0 C H 3 Q i ^ s C l s N j O s HCL.HjO 1 7 2 — 1 7 3 CHEMISTRY OF 1,3-BIFUNCTIONAL COMPOUNDS, XXVII. 241 Table IУ N o R i R f X Formula Derivative M.p. C O 113 < -CF3 H p-OCH3 C22H27a2F3N803 2 HCl 159—161 114 P-CF3 H CjgH^CIjFjNaOa 2 HCl 124—126 115 CF3 H (X CmH^C^FaNjOa 2 HCl 167—168 116 H CigHjsCIjNjOa 2 HCl 197—199 117 # H ClflH24Cl2FN3Oa 2 HCl 188—190 118 # H C H 3 0 ' CH30—yOy— CH30 CaaHjjCljNjOs 2 HCl 199—201 119 # H C26H20CI2N3O3 2 HCl 168—171 CHEMISTRY OF 1,3-BIFUNCTION AL COMPOUNDS, XXVII. 243 The piperazinylpropyl alcohols (Tables II—III) were prepared in one or other of the following three methods (Methods A, B and C). In three cases (5, 8 and 14) the resulting aminoalcohol was not purified, because of the small amount of material; instead, the crude reaction product was reacted with the acid chloride. The thin-layer chromatographic examinations were performed on a Kieselgel (Merck) layer 0:5 mm in thickness; the running mixture was 5% NH4OH — ethanol, and the developer was the Draggendorf reagent. Method A A mixture of 0.15 mole N-substituted-piperazine, 15.5 g (0.16 mole) 3-chloro-propanol and 20 g anhydrous, well-powdered K2C03 was boiled for 20—25 hr with stirring in 120 ml ethanol. 100 ml ether was added to the cooled reaction mixture, the precipitated inorganic salt was filtered off, the filtrate was evaporated to dryness, and the residue was distilled or recrystallized from a benzene — petroleum ether mixture. Method B A mixture of 32 g (0.2 mole) Ar-carbethoxypiperazine, 0.22 mole halogen com-pound and 25 g anhydrous K2C03 was boiled for 30 hr with stirring in 150 ml etha-nol. The inorganic salt was filtered off the cooled reaction mixture, the filtrate was evaporated to dryness, and the residue was boiled with 60 ml conc. HC1 for 24 hr [19]; after renewed evaporation to dryness, the residue was triturated in ethanol, and the mixture was filtered. The crystalline 7V-substituted-piperazine dihydrochloride was dissolved in water, and concentrated NaOH solution was added to liberate the free base, which was extracted with ether. The solution in ether was dried and evap-orated to dryness, and the resulting crude substituted piperazine was reacted with 3-chloropropanol as in Method A. Method C JV-(3-Hydroxypropyl)-piperazine was prepared as in [11]. From this the amino-alcohols were obtained by Method A with the use of the corresponding halogen compound; the aminoalcohols were purified by distillation or by recrystallization. Acknowledgements The authors express their thanks to Katalin Nagy and to Gizella Koródi for their assistance in the syntheses. 244 К. FELFÖLDI and HIS COWORKERS: CHEMISTRY OF 1,3-BIFUNCTIONAL COMPOUNDS. XXVII. References [1] Felföldi, К., Á. Molnár, M. Bartók: Acta Chim. (Budapest) 90, 75 (1976). [2] Felföldi, K., Á. Molnár,-M. Bartók: Acta Chim. (Budapest) 91, 333 (1976). [3] Felföldi, К., M. Laszlaoik, M. Bartók, E. Kárpáti: Acta Phys. et Chem. Szeged 26, 163 (1980). [4] Felföldi, К., M. Laszlaoik, M. Bartók;E. Kárpáti: Acta Phys. et Chem. Szeged 26, 171 (1980). [5] Felföldi, K., Á. Molnár, M. Bartók, R. A. Karakhanov: Acta Phys. et Chem. Szeged 26, 177 (1980). [6] Notheisz, F„ K. Felföldi, M. Bartók, E. Kárpáti: Acta Phys. et Chem. Szeged 26, 185 (1980). [7] Ratouis, R., G. Combes: Bull. Soc. Chim. Fr. 1959, 576. [8] Hayao, S., R. N. Schut, W. G. Strycker: J. Med. Chem. 6, 133 (1963). [9] Morreu, ff. G.: Belg. pat. 557,030 (1958), C. A. 53, 16170b (1953). [10] Szekeres, L., J. Papp: British J. Pharmacol. 17, 167 (1964). [11] McElvain, S. M., W. Bannister: J. Am. Chem. Soc. 76, 1126 (1954). [12] Hromatka, O., J. Grass, F. Sauter: Monatsh. 87, 701 (1956). [13] Sherlock, M. ff.: U.S. Pat. 2,899,431 (1959); C. A. 54, 587h (1959). [14] Morreu, ff. G.: Belg. Pat. 560,330 (1958); C. A. 53, 16168Í (1958). [15] Barrett, P. A., A. G. Caldwell, L. P. Walls: J. Chem. Soc. 1961, 2404. [16] Brit. Pat. 889,223 (1962); C. A. 57, 13777h (1962). * [17] Parcell, R. F.: U. S. Pat. 2,922,788 (1960); C. A. 54, 9966g (1960). [18] Parcell. R. F.: U. S. Pat. 2,833,770 (1958); C. A. 52, 15601a (1958). [19] Stewart, ff. W., R. J. Turner: J. Org. Chem. 13, 134 (1948). . ХИМИЯ 1,3-БИФУ НКЦИОН АЛЬНЫХ СОЕДИНЕНИЙ, XXVII СИНТЕЗ СЛОЖНЫХ ЭФИРОВ 4-Ы-ЗАМЕЩЕННЫХ ПИПЕР АЗИНИ Л-1 -П РОП АНО Л ОВ К. Фелфельди, А. Молпар, Й. Апйок, Й. Цомбош, Ф. Нотейс и Э. Карпати В продолжение исследований в области синтеза и изучения фармакологического действия сложных эфиров разных аминоспиртов [1—6], синтезированы разными методами сложные эфиры, имеющие пиперазиновое кольцо. Некоторые соединения обладают венечным вазодил-ятаторным и антиаритмическим действием. 

Chemistry of 1,3-bifunctional compounds 27. : Preparation of 4-n-substituted piperazinyl-1 esters

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Chemistry of 1,3-bifunctional compounds 27. : Preparation of 4-n-substituted piperazinyl-1 esters

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