In connection with earlier work on muscarine from this laboratory the following compounds have been synthesized: from DL-tropinic acid dimethyl ester (I) 1-methyl-2-hydroxymethyl-5-(2 \u27-hydroxyethylpyrrolidine (II) and 1,1-dimethyl-2-hydroxymethyl-5-(2\u27-hydroxyethyl)pyrrolidinium iodide (III) were prepared; from 1,2,6-trimethyl-4-hydroxypiperidine and methyl iodide 1,1,2,6-tetramethyl-4-hydroxypiperidinium iodide (IV) was prepared; catalytic
hydrogention of 1-methyl-3-hydroxypyridone-(4) gave 1-methyl-3,4-dihydroxypiperidine, from which, by reacting with methyl iodide, 1,1-dimethyl-3,4-dihydroxypiperidinium iodide (V) was obtained

J. Jančulev

N. Bregant

S. Ghyczy

English

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AR HIV Z A KEM I JU 27 (1955) 189 Synthesis of Some Quaternary Bases Related to Tropine. Studies in the Muscarine Series. V* N. Bregant, J. JancuLev•• and s. Ghyczy C hemical I n stitute, Faculty of Science, Univer sity of Zagreb, Strossmayerov trg 14, Zagreb, Croatia, Yugo slavia R eceived Nove mber 25, 1955 In connection with earlier work on muscarine from this labo-ratory' the following compounds have been synthesized : from DL-tropinic acid dimethyl ester (I) 1-methyl-2-hydroxymethyl-5-(2'-hydroxyethylpyrrolidine (II) and l,l-dimethyl-2-hydroxymethyl-5-(2'-hydroxyethyl)IPYIT'Olidintum ~odide (III) were pr®ared; from 1,2,6-trimethyl-4-hydroxypi,peridine and methyl iodide 1,1,2,6-:tetra-methyl-4-hydroxypiperidinium iodide (IV) was prepared; catalytic hydrogention of 1-methyl-3-hydroxy;pyridone-(4) gave 1-methyl-3,4-dihydroxypiperidine, from which, by reacting with methyl iodide, l,1-dimethyl-3,4-dihydroxypiperidinium iodide (V) was obtained. In the second communication of this series1 the new formula for muscarine, C9H2002N+, p:riopooed by Eugster and Waser2 was discussed, and in connection with the completely saturated nature of the compound it was stated that the muscaii:iine molecule must contain a ring; it was also pointed out, with the welJ-known muscacrine: atropine antagoni:sm ·in mind3, that this new formula for muscarrine had the same carbon and hydrogen collltent as methylated tro-pine, and that fission of 0111e Ting in the tro.pine molecule, and addition of one molecule of water should lead to a compound of the same empirical formula as muscarine. It is also known that koipine ritself shows an antagonistic action against muscarine on :frog hearts4 • We considered, therefore, to be of interest tJo synthesize some q uat.ernary bases related to the tropine skeleton, conta.Lning pyi"ro.hldine or piiperidine nuclei. DL-Tropinic acid, obtained by vigourous oxidation of tropine5 was con-verted to DL-tropinic acid dimethyl ester (1)6 and rreduced with lithium alu-minum hydride to 1-methy 1-2-hydiroxymethyl-5-(2' -hydroxyethy l)pyrrroil.idine (II) . The di'Ol II was then converted, using methyl iodide, to the quaternary saJt III. The qua:ternary saHs IV and V were prepared foom the corresponding pyrone derri.vatives. Reaction of 2,6-dim ethylpyrone and meconic acid with m ethyl ami:ne8• 10, and sUJbsequent catalytic hydrogenation gave 1,2,6-'trimethyl-4-hydroxypiperridine7 and 1-methyil-3,4-dihy droxypiperidine, respecti:vely. These piperidine deri·vatives were converted to IV and V. * Communication No. 48 from the Chemical Institute, Paper IV, Chemistry & Industry 1956, 23. ** Present address: Chemical Institute, University of Skopje. 190 . N. BREGANT, J. JANCULEV AND S. GHYCZY CH2--CH-C02CHa I I I CH3-~ T02CH3 CH2--CH-CH2 I CH2--CH-CH20H I I I (CH3)2N+ J -I I CH2--CH-CH2CH20H III CH2--CH-CH20H I I I CHa-N I I CH2--CH-CH2CH20H II CHa-CH--CH2 I I J - +N(CHalz CHOH I I CHa-CH--CH2 IV CH2----CHOH I I J - +N(CHalz CHOH I I CH2 CH2 v Results of the detemnination of muscarinic activities of comrporUnds III, IV a:nd V will ·be pu!blished elsewhere. EXPERIMENT AL ' · All m.elting points are . uncorrected. DL~Tropinic acid dimethyl ester The · ester was prepared froin tropine according to Merlinga and Willstatter6. Red'l.lCUon of DL-tropinic acid dimethyl ester I:n.to, .a four-necked reaction flask fitted with reflux condenser, thermometer, c1r9_ppingfunnel and c,alcium cP,loride tube, and containing absolute ether (20 ml.) tind finely Powdered lithium ·. a l:Uminum hydride (1 ·g.), a solution of DL-tropiriic acid dimethyl ester (I, 1.5 g., 0.007 mole) in ether (20 ml.) was added dropwise during orie hJH,ll.', undeT ccantinuous srtiirriri,g. The addition of the ester wais ca,rried out gradually, the temperature of the reaction mixture remaining about 30-320. After standing at room temperature for 6 hours, wet ether and water (20 ml.) were added to the reaction mixture. The aqueous layer together with the precipitate was extracted witP, : .ether in a liquid/liquid extractor during 24 hours. The combined ethereal extracts were dried (Na2S04) and evaporated to dryness. 1-Methyl-2-hydroxymethyl-5-(2'-hydroxyethyl)-pyrrolidine remained as a yellow hygroscopic oil, yield 0.7 g. (630/o). For analysis the substance was distilled over powdered sodium hydroxide. The ~mre product was obtained as a colourless oil, b. p. 85-950/0.0025 mm. Anal. 8.47 mg. subst.: 18.69 mg. C02, 8.05 mg. H20 CsH11N02 (159.22) calc'd: C 60.34; H 10.760/o found: C 60 .22; H 10.640/o 1,1-Dimethyi-2-hydroxymethyl-5-(2' -hydroxyethyl)-pyrrolidinium iodide (III) The quaternary salt was prepared from a solution of 1-methyl-2-hydroxymethyl-5-(2'-hydroxyethyl)-pyrrolidine (II, 100 mg.) in acetone (5 ml.), and methyl. iodide (0.5 ml.). The crude 1,l-dimethyl-2-hydroxymethyl-5-(2'-hydroxyethyl)-pyrrolidinium iodide separated as a viscous yellow oil which after removal of acetone in vacuo could be recrystallized from ethanol-ether (5 :1). Colourless prisms, m. p. 103-1040. Anal. 10.43 mg. subst.: 13.83 mg. C02, 6.40 mg. H20 C9H20IN02 (301.18) calc'd.: C 35.89; H 6.69% found: C 36.19; H 6.870/o SOME QUATERNARY BASES RELATED TO TROPINE 191 1,2 ,6-Trimeth y l pyridone-( 4) The compound was prepared from 2,6-dimethylpyrone and methyl amine according to Campbell, Ackerman and Campbells. 1,2,6-Trimethyl-4-hydroxypiperidine 1,2,6-Trimethyl-4-hydroxypiperidine was first prepared by hydrogenation over platinum black of 1,2,6-trimethylpyridone-(4) in glacial acetic acid7. We prepared this compound by reduction of 1,2,6-trimethylpyridone-(4) (lQ g.) with sodium (3.8 g.) and ethanol (300 ml.) under the conditions of Bouveault-Blanc reduction. From the reaction mixture 1,2,6-trimethyl-4-hydroxypiperidine was isolated in the usual man-nerD, yield 7.0 g. (670/o) of pale yellow oil, b . p . 100-1100/12 mm. (B. p. 215-2200 at atmospheric ipressure7). 1,1,2,6-Tetramethyl-4-hydroxypiperidinium iodide (IV) Methyl iodide (3 ml.) was added to a .solution of 1,2,6-trimethyl-4-hidroxy-piperidine. (1.1 g.) in acetone (20 ml.). After standing for a few hours the separated quaternary salt was collected, yield 1.7 g. (77°/o) of 1,1,2,6-tetramethyl-4-hydroxy-piperidinium iodide. After repeated recrystallization from absolute ethanol, white prisms of the pure compound showed m. p. 2820 . . Ana[. 9.40 mg. subst.: 13.07 mg. C02, 5.89 mg. H20 C9H20INO (285.18) calc'd: C 37.90; H 7.060/o found: C 37.95; H 7.010/o 1-Methyl-3-hydroxypyridone-( 4) The compound was obtained from methyl amine and meconic a.cid according to Wibaut and Kleipoo110. 1-Methyl-3,4-dihydroxypiperidine 1-Methyl-3-hydroxypyridone-(4) (10 g. ,' o.8 mole) in ethanol (70 ml.) was hydro-' genated in the presence of Raney-nickel catalyst (obtafned from 10 g~ of nickel-aJ,uminum alloy, nickel content 400/o prepared according to Paul a.rid Hilly11) at 160° and 1'10 atm. pressure during 3 hours. The catalyst was removed by decanting off the reaction mixture through a filter. The filtrate was evaporated to dryness and extracted with acetone. The crude 1-methyl-3,4-dihydrdx ypiperidine was obtained by evaporation of the solvent. Yield 6.5 g. (630/o). The analytical sample was obtained by distillation of the crude compound at 90-1000/0.03 mm.; a colourless oil was obtained. Anal. 10.03 mg. subst.: 20.06 mg. C02, 8.98 mg. H20 C6H 13N02 (131.17) calc'd.: C 54.94; H 9.990/o found: C 54.57; H 10.0·2°/o 1,1 -Dimethyl-3,'1-dihydroxypiperidinium iodide (V) To a solution of the crude l-methyl-3,4.:dihydroxypiperidine (2 g.) in acetone (30 ml.), methyl iodide (5 ml.) was added. After standing at room temperature for 24 hours, 1,1-dimethyl-3,4-dihydroxypiperidinium iodide separated from the reaction mixture in theoretical yield, m. p. 2540. After repeated recrystallization from absolute ethanol, colourless prisms of the pure compound, m. p. 2600 wer.e obtained. Anal. 8.95 mg. subst.: 10.21 mg. C02, 4.78 mg. H20 C1H10IN02 (273.13) calc'd.: C 30.78; H 5.900/o found: C 31.11; H 5.970/o Acknowledgments. One of us (J. J.) wishes to thank the University of Skopje for a fellowship during the winter ·semester 1954/55. The authors wish to thank Dr. R. Seiwerth, Research Institute, »Pliva« Pharma -ceutical and Chemical Works, Zagreb, for facilities in carrying out catalytic hydro-genations in his laboratory. Thank are also due to Professor K. Balenovic for his interest in this work, and to Mrs. Z. Stefanac for the microanalyses. 192 N. BREGANT, J. JANC:ULEV AND S. GHYCZY REFERENCES 1. K. B a 1 en o v i c, N. B reg ant and T . Ga 1 i j an, Arhiv k em . 26 (1954) 233. 2. C. H. E u g s t er and P. G. W aser, Ex perientia 10 (1954) 298. 3. Prevost and Monnier, Gaz. med. de Paris (1874) 243 . 4. R . Go t t 1 i e b, Arch. ex p. Path. Pharmakol. 37 (1896) 218. 5. G. Me r 1 in g, Ann. 216 (1882) 348. 6. R. W i 11 s tat t e r, Ber. 28 (1895) 3271. 7. B . Emmert, Chem· Z entr. 1916, II. 116: DRP 292871 . 8. K. N. C a mpbell, J . F. Ackerma n and B . K. Campbe l l, J . Org. Chem. 15 (1950) 337. 9. B . Emmert and W. Do rn, B er. 48 (1915) 687. 10. J . P. W i b a u t and R. J. C. K 1 e i pool, Ree. trav. chim. 66 (1947) 24. 11. R. Pa u 1 and G . Hi 11 y, Bu ll . Soc. Chim. F rance (5) 3 (1936) 2330. IZVOD Sinteza nekih kvaternih baza srodnih tropinu. Istrazivanja o muskarinu. V N . Bregant, J. Jancuiev and S. Ghyczy U vezi s dosadanjim radovima o muSik:arinu1, s intetizirani su ovi spojevi: iz dimetilnog estera DL-tropinske kiseline (I) priredeni su 1-metil-2-oksimetil-5-(2'-oksi-etil)pirolidin (II) i 1,1-dimetil-2-oksimetil-5-(2'-oksietil)pirolidinium jodid (III); iz 1,2,6-trimetil-4-oksipiperidina i metiljodida prireden je 1,1,2,6-tetrametil:-4-oksipiperi-dini:um jodid (IV); katalitickim hidriranjem 1-metil-3-oksipiridona-(4) dobiven je 1-metil-3,4-dioksipiperidin, iz kojega je, reagiranjem s metiljodidom, dobiven 1,1-dimetil-3,4-dioksipiperidinium jodid (V). Rezultati bioloskog ispitivanja tih spojeva u pogledu muskarinskoga djelovanj a bit ce objavljeni na drugome mjestu. PRIRODOSLOVNO-MATEMATICKI F AKULTET KEMIJSKI INSTITUT ZAGREB I INSTITUT »RUDER BOSKOVIC« BIOKEMIJSKI ODJEL ZAGREB Primljeno 25. novembra 1955. 

Synthesis of Some Quaternary Bases Related to Tropine. Studies in the Muscarine Series. V

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