Preparation and properties of the S-benzylthiuronium salts of fourteen barbituric acid derivatives are described

I. Guštak-Mašek

K. Jemrić

V. Hahn

Z. Kochansky

English

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CR 0 AT IC A CHEM I CA ACT A 28 (1956) 119 CCA-19 547.854.5 S-Benzylthiuronium Salts of Some Barhituric Acid Derivatives* V. Hahn, Z. Kochansky, I. Gustak-Masek and K. Jemric Laboratory of Organic Chemistry, Technicai Facuity, University Zagreb, Croatia, Yugosiavia Reseived Mayi 31, 1956 Preparation and properties of the S-benzylthiuronium salts of fourteen barbituric acid derivatives are described: -The :prreparation of S-ibenJzylthiiuronium salts (»SBT salts«) of oT'ganic acids for identification pumposes ha:s been st11ggested first by Chamtbers and Soherer1 and, more ·recenhly, by Dmrlea:vy2, VeLbel a!Illd Lrnelund3, Chambers and Watts4 and other authors5• Smee then, SBT isailts of a 1allige 1nu1mber of Ollig'1mic acids, -especially of swlfonic and cairlboixyl:i:c acids, have been reported . In the course of synthetic work-carried out duri,Illg the last yearn in at11r laboratory, SBT 1salts of o:riganic acids of different types ha1v.e lbeen prrepaired6. The purpose of this :paper is -to describe the ;preparation and proiperties of the SBT salts of some 5-«Ilonosuibs tituted, one 1,5- and several 5,5-disUJbsti:tuted hall"bitiuric acids. The well crystailli1zed SBT 1salts I-XIV 'Usted in talble 1 hai\"e ibeen obta!ined in the ruSIU!aJ way from the cnrresiponding 1:>odium salts with S'"'benizylthLuronium chl:orrLde as rerugent5• Whereas the SBT salts of 5-monoalikyl-(arralikyl- or acryl-) barbitrurric acids showed to ·be relati•vely staibie cO!IDp:ound:s-, the SBT salts of 5,5-dislUlbstituted ba1rbituric acids · iprocved to .be much less staible. Durr:ing recry-s talliizatiorn fr:om diluted ethanol they were pa:rtly o'r completely hydrolysed with liilberation of l.benizyl m ercaptan an:d, therefore, ;purifiication of t hese salts had to 1be l imited to at moist one orysitaHi1zati:on**. Bar.bitu:ric ,acid, contrarily to 2-thiiobarbi:turic acid {see taible 1, XII) :flailled ·to giive .a stai.ble SBT salt, whether one o r two equivalents of a.J!kalli aind of ·the :reagent were added. All but three of 'the !Prepan~d salts (V, VI and XII) showed charraderistic and sharp melting points which were diistriibuteid over a w!ide rrange of rtempemtures. The l'esrults obtained in thii:s wo11k l ead to ·the condusiK)f!L that .barbituri.c acLd .der:ivatives forrm weH crrystallii.zed SBT isalts which, however, are of limited v.aliue for identificat1ion pruriposes ibeca1use of the lo·W staibility of the salts obtaim.ed f'l'lom ·the pharmaco1ogica1ly important 5,5-disuibetituted harbitUTates. * A part of this paper has been presented at the Meeting of Yugoslav Chemists and the First Croatian Congress of Pure and Applied Chemistry, Zagreb, October 195·2. ** It was observed that after three crystallizations Of some of the prepared salts. (e . g. IX) :the free acid was obtained in pure form. 120 V. HAHN, Z. ,KOCHANSKY, I. GUSTAK-MASEK AND K. JEMRIC No. I II III IV v VI VII VIII IX x XI XII XIII XIV TABLE 1 S-Benzylthiuronium Salts of Barbituric Rs Acid Derivatives Ri , /co .N , C C = X R2 / "- CO . NH / Barbituric acid R1 5-Methyl- CHs 5-Ethyl- C2Hs 5-n-Propyl- CHsCH2CH2 5-Phenyl- C5Hs 5-Benzyl- C5HsCH2 5-(2' -Furfuryl)- C4HsO. CH2 1-Met!J.yl-5-ethyl- C2Hs 5,5-Diethyl- (VERON AL) C2Hs 5,5-Diallyl- (DIAL) CH2 = CHCH2 5-Etllyl-5-phenyl-(LUMINAL) C2H5 5-(1'-methylpropyl).- CHsCH2~H 5-(2'-bromoallyl) CHs (PERNOCTON) 2-Thio- H 5-Ethyl-2-thio- C2Hs 5-Ethyl-5-(l'methyl)-butyl)-2-thio-(PENTOTHAL) C2Hs * Monohydrate ;• Semihydrate HN ' C . S . CH2 . C5H5 H2N / R2 Rs H H H H H H H H H H H H H CHs C2H; H CH2= CHCH2 H C5H5 H CH2 = CBrCH2 H H H H H H CHsCH2CH2C:H CHs EXPERIMENTAL Ix / 0 0 0 0 0 0 0 0 0 0 0 s s s M. P. 168-1690 *' 178-1790 182- 1830 240-2410 > 3200 (d.) > 3200 (d.) 159-1600 82-830. 89-900 **' · 134-1350 100-1010 . > 3200 (d.) 156---1570 *' 111-1120> The melting points (m. p .) are uncorrected. They were determined in capillary tubes, up to rnoo in a Thiele apparatus, above rnoo in a copper block. The analytical samples were dried in vacuo under phosphorus :pentoxyde for 2 hours. The barbituric acids used in this work have all ibeen described in the litera-ture. While the 5-mono- and 1,5-disubstituted acids as well as 2-thioba rbituriic have been prepared by known methods, samples of the pure commercial 5·,5-disubstituted barbiturates were available. Preparation of the S-benzylthiuronium salts (»SBT salts«) The barbituric acid (0.002-0.003 mole) w as dissolved or suspended in 4-5 ml. of warm water and mixed with the equivalent quantity of a 15°/o aqueous solution o.f sodium hydroxyde. In some cases •the sodium salt of the barbituric acid served as starting material. To the clear solution of the sodium salt 1-2 drops of N hydro-chloric acid and then the calculated amount of S-benzylthiuronium chloride, dissloved in 3-5 ml. of water, were added. From the cooled mixture the SBT salt separated in form of crystals or as an oil which solidified quickly on cooling and scratching with a glass rod. Purification of the crude products, obtained in most cases in a quantitative yield, was carried out by recrystallization (usually from a mixture of equal parts of ethanol and water), taking in account the limited stability of the SBT salts of 5,5-disubstituted barbituric acids, pointed out in the first part of this p aper. SBT salt of 5-methylbarbituric acid (I) By the above described procedure the m o no h yd r a t e of I was obtained in a n almost quantitative yield. Colorless prismatic crystals from aqueous ethanol (1 : 1) , m . p. 168--1690. The analytical ·sample was dried at room temperature. BARBITURIC ACID DERIVATIVES Anal. 22.874 mg subst.: 40.1 mg. C02, 10.9 mg. H 20 3.207 mg. subst.: 0.468 ml. N2 (210, 759 mm) C1aH160aN4S.H20 (326.37) calc'd: C 47.84; H 5.56; N 17.170/o found : C 47.84; H 5.33; N 16.920/o 121 When dried at 1000 for 3 hours the anhydrous s a 1 t melting at 173-1740· was obtained. ' ·-Anal. 18.430 mg. subst.: 34.0 mg. C02, 8.6 mg. H 20 2.575 mg. subst.: 0.419 ml N2 (230, 744 mm) C1aH160sN4S (308.35) calc'd: C 50.63; H 5.23; N 18.170/o found: C 50.34; H 5.22; N 18.370/o SBT salt of 5-ethylbarbituric acid (II) Almost colorless prisms from aqueous ethanol, m. p. 178-1790, yield 750/o. The analytical sample was dried at 1000. Anal. 19.498 mg .. subst.; 37.5 mg. C02, 9.4 mg. H 20 3.325 mg. subst.: 0.5,15 ml. N2 (270, 751 mm) C14H1s03N4S (322.38) calc'd: C 52.16; H 5.63; N 17.380/o . found: C 52.48; H 5.40; N 17.410/o' SBT salt of 5-n-propylbarbituric acid (III) Colorless prisms from aqueous ethanol, m. p . 182-1830, yield 880/o. The analytical! sample was dried at room temperature. Anal. 23.921 mg. subst.: 46.8 mg. C02, 12.3 mg. H20 3.508 mg. subst.: 0.508 ml. N2 (200, 755 mm) C1sH2o03N4S (336.40) calc'd : C 53.55; H 5.99; N 16.660/o found: C 53.39; H 5.75,; N 16.760/o SBT salt of 5-phenylbarbituric acid (IV) Colorless shiny prisms from water, m. p. 240-2410, yield 700/o. The analytical sample was dried at 1000. Anal. 20.296 mg. subst.: 43.5 mg. C02, 9.2 mg. H20 3.9,22 mg. subst.: 0.5,32 ml. N2 (260, 752 mm) C1sH1s03N4S (3'70.42) calc'd: C 58.36,; H 4.90 ; N 15.130/o found: C 58.49; H 5.07; N 15.320/o SBT salt 'of 5-benzylbarbituric acid (V) Colorless needles from aqueous ethanol which darken at about 2000 and d·ecom-·pose without melting up to 3.200; yield 910/o. The analytical sample was dried at 1000. Anal. 18.381 mg. subst.: 39.8 mg. C02, 8.6 mg. H20 2.542 mg. subst.: 0.318 ml. N2 (220, 75,2 mm) C19H2oOsN4S (384.44) cak'd : C 59.36; H 5.25; N 14.580/o found: C 59.09; H 5.24; N 14.320/o SBT salt of 5-(2'-furfuryl)-barbituric acid (VI) Almost colorless prisms from aqueous ethanol which darken at about 1800 and decompose without melting up to 3200; yield almost quantitative. The analytical sample w as dried at 1000. Anal. 21.894 mg. subst.: 43.4 mg. C02, 9.2 mg. H 20 2.696 mg. subst.: 0.348 ml. N2 (200, 763 mm) C17H1 80 4N4S (374.41) calc'd: C 54.54; H 4.85; N 14.960/o found: C 54.11; H 4.70; N 15.100/o l22 V. HAHN, Z. KOCHANSK Y, I. GUSTAK-MASEK AND K. JEMRIC SBT salt of 1-methyl-5-ethylbarbituric acid (VII) Colorless ·crystals from abs. ethanol + ether melting a t 159- 1600, yield 910/o . . Analy t . sampl.e dried at 1000. Anal. 4.022 mg. subst.: 0.576 ml. N2 (190, 750 mm) C1sH200aN4S (336.4-0) cak'd: N 16.660/o found: N 16'. 520/o SBT salt of 5,5-diethylbarbituric acid (Veronal) (VIII) The crude product, m . p. 79--800, which was obtained in an almost quantitative y ield, showed to be the m o n o h y d r a t e of VIII. After one crystallization from aqueous ethanol it was obtained in form of colorless crystals melting at 82-830. The analytical sample w as dried at room temperature. Anal. 23.890 mg. subst.: 46.0 mg. C02, 13·.7 mg.H 20 3.019 mg. subst.: 0.402 ml.N2 (230, 758 mm) C16H2203N4S.H 20 (368.45) calc'd: C 52.15 ; H 6.57; N 15.210/o found : C 52.54 ; H 6.42 ; N 15.320/o We were not albe to obtain the anhydrous salt because heating of the mono-h ydrate above the melting point (either at ordinary pressure or 'in vacua) caused de-composition. SBT salt of 5,5-diallylbarbituric acid (Dial) (IX) The crude product, obtained in almost quan t ita tive yield, melted unsharply a t 81-850. After crystallization from aqueous ethanol it was obta ined in form of c olorless c rystals, m . p. 89-900. On the b asis of the obtained an alyt ical d a t a it was identified as the s em i h yd r a t e of IX. The analytical s ample was dried at room temperature. Anal. 19.203 mg. subst. : 39.6 mg. C02, 10.0 m g. H 20 3.749 m g. subst. : 0.498 ml. N2 (250, 744 mm) C18Hb O::lN4S.l/2H 20 (383.46) calc 'd : C 56.38; H 6.05; N 14.610/o found : C 56.28; H 5.83; N 14.890/o The beh avior of t he sem ih yd rate on heat in g was th e sam e as of th e mono-h ydr.ate of VIII an d no anhydrous IX could be obtained. SBT salt of 5-ethyl-5-phenylbarbituric acid (Luminal) (X) Colorless prisms from aqueous ethanol, m . p . 134-1350, yield a lmost quantita-tive. Analyt. sample dried at r oom temper atur e. A nal. 23.605 mg. subst.: 51.8 mg. C02 11.4 mg. H 20 2.618 mg. s ubst.: 0.312 ml. N2 (210, 767 mm) C20H220 3N4S (398.47) calc'd : C 60.28; H 5.57; N 14.060/o found : C 59.89 ; H 5.40 ; N 13.960/o SBT salt of 5-(l'methylpropyl)-5-(2'-bromoallyl)-barbi turic acid (Pernocton) (XI) The crude product obtained in an almost quantita tive yield , m. p. 96-970, crystallized from aqueou s ethan ol in form of colorless crystals melting at 100- 101°-The analy tical s ample was dried at 600. Anal. 22.581 mg. subst.: 40.2 mg. C0 2, 10.6 mg. H 20 2.167 mg. subst. : 0.221 m l. N2 (190, 752 mm) C19H250 aN4SBr (469.40) calc'd : C 48.61 ; H 5.37; N 11.940/o found: C 48.58 ; H 5.25; N 11.800/o BARBITURIC ACID DERIVATIVES 123 S BT salt of 2-thiobarbituric acid (XII) Almost colo rless prisms from aqueous ethanol which d arken at about 2100 .and decompose without melting up to 3200; y ield 80---900/o. The analytical sample was dried at 1000. Anal. 21.299 mg. sub st . : 36.3 mg. C02, 8.2 mg. · H 20 2.606 mg. subst.: 0.418 ml. N2 (27°, 753 mm) C12H1402N4S2 (310.38) cals:;'d : ~ 46.43; H 4.55; N 18.050/o fourid: C 46.51; H 4.31 ; N 18.080/o SBT salt of 5-ethyl-2-thiobarbituric acid (XIII) The mono hydrate, obtained in an almost quantitative yield, melted after r ecrystallization from aqueous ethanol at 156-1570. The analytical sample was <!ried at room temperature. Anal. 18.048 mg. subst.: 31.0 mg. C02, 9.2 mg. H 20 2.225 mg. subst . : 0.310 ml. N2 (24-0, 748 mm) C14H1s0 2N4S 2.H 20 (356.46) calc'd : C 47.17 ; H 5.66; N 15.720/o found: C 46.87 ; H 5.70; N 15.760/o When a sample of the monohydra te was dried in vacuo at 1000 for 3 hours, -the anhydrous salt, m . p. 180--1810, was obtained. Anal. 21.834 m g. subst.: 39.6 mg. C02, 10.2 mg. H 20 3.697 mg. subst. : 0.512 ml. N 2 (180, 771 mm) C14H1s0 2N4S2 {338.44) icalc'd : C 49.68 ; H 5.36; N 16.&60/o found : C 49.49; H 5.23; N 16.480/o ,SBT salt of 5-ethyl-5-(l'methylbutyl)-2-thio-barbituric acid (Pentothal) (XIV) Almost colorless crystals from aqueous ethanol, m . p . 111- 1120, yield 600/o. 'The .an alytical sample was dried a t .500. Anal. 20.895 m g. subst .: 42.8 m g. C02, 12.6 m g. H 20 3.189 m g. s ubst.: 0.3·74 ml. N2 (210, 767 mm) ~19li2s02N.i;S 2 (408.57) ica lc 'd : C 55.85; H 6.91; N 13.710/o found : C 55.90; H 6.75; N 13.740/o A cknow ledgment. We are indebted to t he F und fo r Scientific Resear ch of t he University of Zagreb for fin ancial assistance during 1954, an d to Professor D . :Bar koviC, F aculty of P h armacy, University Zagreb, fo r th e gen erou s gift of pure _samples of some comm er cial barbiturates. REFERENCES 1. R. F . C h a m be r s and· R . C. Schere r , I nd. Eng. Chem. 16 (1924) 1272; cit. from Chem. Z entr. 1925. I. 844. ·2. J . J. D on 1 ea v y, J. Am. Chem. Soc. 58 (1936) 1004. :3. S. Ve i be l and H . Li 11e1 u n d, Bull. soc. chim. France [5] 5 (1938) i153; cit. from Chem. Z entr. 1939. I . 2411. 4. E. C h am b er s and G . W. W a t t s, J. Org. Chem. 6 (1941) 376 . . 5. Compare also: a) F. W i 1 d, Characterisation of Organic Compounds, Cam bridge Univ. Press (1947) pp. 148, 159. b) R. L. Shriner and R. C. Fuson, The Systematic Identification of Organic Compounds 3rd. Ed. Wiley Ed. New York (1948) p. 215. c) Houben - Wey 1 Methoden der organischen Chemie 4th Ed. Vol. II. G. Thieme Ed. Stuttgart (1953) p . 492. <6 . V. Hahn, z. Kochan sky, T. G h y c z y, K. J em r i c and T. G ju r i c, Report presented at the Meeting of Yugoslav Chemists and the First Croatian Con gress of Pure and Applied Chemistry, Zagreb, October 1952. 124 V. HAHN, Z . KOCHANSKY, I. GUSTAK-MASEK AND K. JEMRIC IZVOD S-Benziltiuronijeve soli nekih dei:ivata barbiturne kiseline V. Hahn, Z. Kochansky, I. Gustak-Masek i K. Jemric Pripravljene SU lijepo kristalizirane S-benziltiuronijeve soli {»SBT soli«) cetr-naest razlicitih derivata barbiturne kiseline (I-XIV), prikazane u tabeli 1. Dok su, se SBT soli 5-moriosupstituiranih barbiturnih kiselina pokazale relativno stabilnim. spojevima, SBT soli dobivene iz 5,5-disupstituiranih barbiturata mnogo su manje· stabilne, pa se vec nakon nekoliko prekristaliz.acija iz razredenog etanola hidroliticki cijepaju uz stvaranje benzilmerkaptana i ishodne kiseline. Kako je iz tabele 1 vidljivo, pripravljene SBT soli pokazuju karakteristicna talista, koja lefo u sirokom temperaturnom intervalu. Izuzetak su soli V, VI i XII, koje se kod ea. 200° C mijenjaju uz rpotamnjenje, .ali se ne rastale do 3.200. Na osnovu dobivenih rezultata moze se zakljuciti da derivati barbiturne kiseline daju lijepo kristalizfrane SBT son, koje medutim nisu podeshe za svrhe identifikacije zbog ogranicene stabilnosti SBT soli farmakoloski va:lnih 5,5-disupsti-tuir.anih ba.rbiturata. ZA VOD ZA ORGANSKU KEMIJU TEHNICKOG FAKULTETA ZAGREB Primljeno ·31. maja 1956-

S-Benzylthiuronium Salts of Some Barhituric Acid Derivatives*

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