HUE031370T2 - Eljárás 3,4-dimetoxibiciklo[4.2.0]okta-l,3,5-trién-7-karbonitril elõállítására, ennek alkalmazása ivabradine szintézisében, továbbá ennek gyógyszerészetileg elfogadható savval alkotott addíciós sója - Google Patents

Description

Mim iOD K)R. SYNTÍifdfsiNG 3.4-D! MB ΓΗΟΧΥB!CY('L<)í4.2.0j()C1M-1,3/ 1 lUDNSi-'Z-CARBONCmií J' AND USB TÖR SYNTH!'RISING ! VABRADINK AND TI ÍR ADDED SAL.1S THEREOF Wil Η Λ HMRMACWUCALLY

ACCEPTABLE ACID

The present invention relates to a proeess for the synthesis of i|4 JJlJoNp" I s3D-C!jpéR^öa^sal!rfte of lómitilá (If: \Ji l] © s'--" VOM« ·/

N and to the application thereof in the synthesis of tvahradtne and addition salts thereof with a |datitiacetmeaHy acceptable acttf

The compound ol lommla (I) obtained by the process of the invention A useful m the synthesis of i vabradine of formula t Πρ OMe

rlTl . W ......v /-™\ }.......°m Y il W s......../ ....... 0 or 4iS^Ö;]iöciU“ i. ^ aminolpropy i} -7*8-dimetltn<i y-! 3,4 J tetrahydrO"2//“3“hett/ay.epi O“2*0«es· of audita >e .mU:··. í heron vdth a phnrcoaeoutieaHy m.ccptable acid. and ol hydra tea thereof.

Kahntdhte ami addition suits thereof with a pharmaceutically ueceptabie odd. and mote especially the hydrochloride thereof Itnve sery valuable pharmacologies! anti therapeutic properties, especiall> hradyeardic properties. which {coder those corn pounds useful Itt the treatment or prevention t>f various elinica) conditions at myoea;rdisl pf bspnla, stich as angina peetoiiSj snyncardtal hithrcíttsn and apöefátgá rhythrn disordépv as w#i ha Ift wo« pathologies invotohig fhytko 4hmá%m>. especially supraventricular rhythm disosdess, und in heun failure Ί he preparation arai therapeutic use of ivabradine and addition salts thereof with a pharmaceutically aeeeptehls aekli. hud inore especinUy the hydrochloride- thereof, have been described in huropean patent bP 0 534 859.

That patent dcsenbes the preparation of ivabradine starting front 04 dtmftht»xyhiCYC}o|4.2.0)οο^·τ I ^-tnenew-earbonkrile of formula (I):

(1} which Iseoovertod into the compound o! formula till);

(HO which is resol ved to yield dmcdOspoand of ibiiMda (IV):

(tv) which is reacted with the compound of formula (V):

(V) to yield the eomposntd offtaiostla (Víg

(VI) she eatulym: hydrogenation of nhh:h yields: ivabrauine. which is thets converted ima hr hydrochloride, in- view öf MiéJíKiusfrial value of svubrudhu? and salts thereof it was imperative to find an effective process allma-ing the compound of formula «!} to be obtained m a good yield.

Application WO dÖl lilSI 62S desedhes the preparation of Che éaPipbttád of ihnmda (f) by intrarmdeetslar cyelisation of l-í2«bromO“4}5“dhnetho'sr^heoy:|:)* pmpm:te~.tiityi!e try tits presetted of bthita-n diefh|bamide or liihhnn diisopropykmMe.

The present invention relates to a process fór tie sjmthestl of' the eothpoahd of tonnida t.1}:

(!) eharecterised in that the compound of formula (VII);

tVh) is sobjeeted to the -action of l^is0Cyanontethylsulph«nyl}-4“TuethyibensseM·

flpsMlC:! !« tie presence of a base in e» oi'gp«c solvent or a mixture of otgeale solvents ts> yield the dontpohoh of tbnpola (IT h'K* íifuoüm üi S-shmc>\mom<dhylsulphonylM-meihyihen2ene preferably used to '.i.iií) Olit tUe COnVíUSíOn <U 11ti; Compound Ot ÍOrmiíia (VII) tO ΙΟ-ΎΠ tbc COmpOUdd öf feldúl» (!) is from 2 to 5 equivalents. .•"sn'ifiig the oases ihat may he used to carry out the conversion of the compound· oS lortmaa t v (I? to torm the compound ol formula i I h there tnay be menthonod,. without implying any limitation, organic hoses of the aikoxlde type such a$ potassium }ert~ rmio.xide, sodium ror/dxuoxule, potassium e?hoxkk\ sodium «dhoxidc, potassium; methnxide and sodium met hősidé. ihe ease preiemoly nscct to varr} on; me conversion of the compound of lormuia |Vt() to form the compound of formula (Π is potassium me^btdoxlde.. /Among toe organic solvents that may he used to carry ont the conversion of the compound of lomtula (Vli) to form the compound of formula (I), there may he ttiérniooed, without implying any limitation,, alcohols such as methanol, ethanol· tsopropuooh /«TMxuiannl, ietraimlrofuran, ethylene glycol and dimethyl suiphoxide. s he organic solvent used to cans out the conversion of the compound of formula (YU i to toon the conspunnd of formula (I) may also he composed >:d a mixture of two solvents from among the afore-mentioned organic solvents. ihe solvent preferably used to carry out the conversion of the compound of formula (VII) to torm the compound ©1 tormula-fl)',¾. of {pífftihydtdíhían and methanol !he conversion oi the compound oi iurtMla (¥11) hr. .form the compound of formula il) is preferably carried run at a temperature from -20CC m 5Q°C. ihe present invention relates also in a process tor the synthesis of the compound ol tormum (I) starting from she compound oi formula (VHk characterised in that said compound oi iormula (Yll) is prepared starting from the corn pound ol formula fVUI );

.(VEi) which is mm&amp;MM-ÍMé a (I5C):

(£X) whemtp. E ffipvgssnls a (dXWhOatkyi grpip.

In the presence óin 1Jo!hdke>syeihene, therein she aikoxy groups have írom I to 4 carbon atoms, and un organt «metallic compound in an organic solvent, which is converted into the eomfxmmJ of lonMda (ΥΙΓρ

(vtn by a hydrolysis rgaeboig which is convened into the product of formula (1):

it) in aceprdáiiee with the process described hereinbefore.

The I .i-dialkoxyetheoe preferably used to carry out the conversion oi the compound ot formula (VIlh to toon ;hu compound of fonnuia (JX) is I,I-diethoxyethene.

The Mwurst psid;to -páöry: bhitte eottvefston of the eomfxrottif of fóomttó; (Vili.) fo forth tllcs eofhpetmd dí SsSsÉ (IX) lé: fern ()J tó 5 eputvakmis.

Among the organometulliv compounds that may he used to cam out the conversion of the compound of formula i Vffi) to form the compound of formula fIXh there may he tnemioned, without implying any hmhatmn, mbutyituhlum, v-butyfhthhnn. r-bulyliifhium, plumy Ihthium ínul is*^r&amp;pylndtgnésium.eMndde*

The organoruetallh: compound preferably used to carry nut the conversion of the compound of formula (Vilit to form (he compound of formula (IX t is β~ Imiyiíúhmm,

The amount of mhutyliithiuro preferably used to carry out the conversion or the compound of formula (VIII) to fonts the compound of formula (DO is front i to 3 epiuvuiems.

Among the organic solehnts that may be used to carry out the conversion of the contpound of formula tVfllj to. form the compound of formula (LX), there may be mentioned, without impfyprg atry limitation, toluene^ fhtinhydrufemrn dlcltiommethápe: ártó chlprebeuaeM,

The srdveni preferably used to cany out the conversion ot the eompuostd of fpmtuia (Vili t to form the compound of fonottja t IX ) is toluene. "The conversion of the compound of formula fVilit to form the compound of funnuiu (IX) is preferably carried out at a temperature from "2CPC to IMPC2 1'he hydrolysis reaction performed on the compound of formula (IX) tu form the compound of tormuUs tVlit may be carried or it in an organoatuseous acidic medium composed of a mistun.·: * of an organic solvent such as teirnhydrofnran, ethyl acetate, toluene or diehloromefham* and » m abí<! suchás hydmbhlcrlb sddöN le 12H) io excess.

Tbc íbllám«;g Examples iJtusUute the invention,

The melting points were measured using a capillary melting point apparatus of the Buchi B-545 Melling point type, •fho· $4MMI specter aré:r«®0ft$eá sna 8Ar apparatus m 400 MB* for Ok? prolan spectra and at 100 ΜΗ* lor the carbon .spectra.

The chemical shifts ti>) arc expressed in rcrrr.cs oh ppm maenad standard: I MS).

The following abbreviations base been used to describe tire peaks, single! (sg do chi oi Big doublet of doublets {dd)t triplet (A. gcadroplot (qk mnlhpler hoc

Iiy;i!ÍJ&amp;Ercsja?msís ntdpl m.p.: melting point I'l l I d teoahydrolurac

TmMIC; I -tisocyanomeThylstdpkm v 1)-4nenethy Ibeos&amp;ne.

Preparation A: 1.2 1M!>roroo- To áimeihoxyhenaane 16,16 g of l.^;HlteMhpj?jfb'etósénb -(11 7 mtnoi) are shoex! atiHC; In CCdly (126 mL), 1X2 enL of dlhróndM (2.2 eq; XST4 irnneld 41J 3 §) disaoIvMln €.04:05 mL) am added dropwise (50 min! whilst monmning she temperature {Ο-Μ'ΤΜ [fit an outiéi which hubbies into a solution of Na.><.'0} in order to neutralise dtc hydrobrnmh, acid which forms], A iter stirring tor 2 bouts at tr:C, the reaction mixture is then poured onto a mÍKüue of water Hct·; am) the organic phase is washed with aqueous .10% NaHSO* solution and then os id aqueous 10% N’aOH solution. .Alter evaporation and drying, 13.42 g of a white solid corresponding to the title product are obtained.

Vidd ··· 07*« sn,p: 92-ETC illlMS ICIXdl: d ===7,06 ts: 211): 3.56 (s: 614), 1'X N'MIi iCDChj: d - 140; 115.9: 114.7; 56.2. jErtpa ration B; I i 1 -Oietteyetfef»#·

The equipment set-up Is as fbllavss; a 5(MpI flask provided with a dlstllfetlep set (column -20 cm; iondeftSét -20 cm, distillation tliartadroefer), 2itg of 2-hrotno/U~ dieihoxyethane (1(0.25 mmol) arc quickly added (I minute) n> potassium ten'' hutuKide (102 mmek 11.,4 g) cooled in uu ice hath Very dense white smoke is lormed, When the reaction ts complete (5-10 nunutes). the reaction mixture is heated to l2tM30;X' fhot-pinte reading), and the ten-htdamd generated during the reaction is distilled otY at atmospheric pressure When ait she lert-heUmol has bee a distilled off, a water-jet pomp is connected to the distillation set. !« this way, the. expected product is distilled otT hi. vtmm in a law seconds, &amp;.§: g of a eolourtess liquid containing traoes of terMniinnol are obtained,

Iliid-72% Ί{.NMji ((.ΤΧ,Ίρ; h - 3.7H iq; 4Ηκ .103 is; 2H); 1/25 U; 6Hs.

Example It 7/}s.|>pq|u>^y''3,d'-diraethoxybicyidtqdX,ipsaia -13,5--krieue 2.5S g of 13'dihromo'd,5-dimeihoxybenzene (S.o2 nunol; 2 eq) and 500 tug of 1,1-dicthnxyethene (431 rnmnl; I eo|) in 25 mh of toluene are stirred at 0"(.: under argon. 3.5 ml, of «-butyllithium 02.5M in hexane, 8.62 mmol; 2 eq) ate added dropwise at (f"C. When the addition is complete, the reaction mixture is stirred tor 22 hours at ambient temperature. The reaction mixture is then hydrolysed and extracted 3 times with ethyl acetate. The organic phases ere dried and evaporated, and the crude product Is pari/ted by column ehromaiogntphy over silica gel (eluant', heptane'ethyl acetate 70/10/ There are obtained 333 mg of a yellow oil which crystallises at ambient tMopcrotum,

Yield -31% 111 NME (COOO: § - 6.86 (s; 111), 6.72 (s; ill); 334 (s; #1); 3.72 at; 4H); 3.30 (s; 211): 1.25 (t; fdl). ÍMÉ. 2; 3,4-Dí s»eü»>xybicydo[4.2.0 joeis-1 337τ1*η·-7-οη£ (1.7¾ % flJI menői) b stirred síi a mixture of ITHvwafcr (6.Ί) at. ambtent temperature, SIS mg of un aqucouo 1 IN 1 Ül sokason (1 Λ eg. 7.7 mrnoij are then added. The reaction mixture is stirred sor 2 honra ambient temperature. Water is added to SacHIran too extractions with ethyl acetate (2--3¾) *nf.l The organic phases are dried roe?· MgSO.s and then subjected to drying- l itere are obtained KOI g rd the title product irt the form of a pey: powder, jl.NMR íCPCu): 7.07 is; 7:1 it6.82 (s: 1H); 3.00 3H>; 3.87 (s; 5! 1). nC NMR. (CDCIV 185.8. 155.* 151.4; 146.2: 08 7; 105.6; 102.1 56 4; 56.1; 51 0.

IB&amp;" 146:>C

Example 3; 3eí"ölnmUHfxybicyehíj4.L0fuct8--Md5-dmne--7~e8riíO»itríí<? Λ solution of I'osVHC (03>K g. 4.08 mmol, 2.3 eq) ht THE (3 ml.) is poured, over 20 iMadiéN idio á sedation of potasaltaBdeN'-beloxide (1,22 g; Ki# romol; 6 eqj in 11 if (7.5 mil stirred at tl'C under nitrogen. Then 2 00 n.L os'ntethastol are added t<> the mixture and stirring is maintained lor 30 minutes at (f'C, In parallel 3,4-- (1132 gí 2.17 hirnoi ! égi lithium bromide (0.19 g, 2.17 rnmoi, 1 eq? and TMF (2.5 mi.,} are loaded into a second three-necked flask, .after coo lag to (r"C under nitrogen. Ore solution of TosMlC arai potassium rwr-butoxide is transferred to the reaction mixture. .After returning to ambient temperature, the solution Is heated to TOY.' arid stirred for 16 hours at that temperature The mixture is then hydrolysed wuh a solution rd I IN 11C1 (0 ? ml , 7,73 mmol* in water (2 ml.). Alter eutporatmg off She (T1F under reduced pressure, the product is extracted with 5 mi. td'dichloromeihane. The organic phase is washed twice with 2X5 no. of water before being dried, 'the crude product is purified by coiu cun chromatography mer si boa gel using the binary mixture gestpe 75/25 to obtain the title product in tire form of a c rca no colon red powder.

Yield548-¾ tCDCEr 06 (si 11!κ i>.6K |s; IN); 4,i4 írn: Ili); λ 83 (s; 6H); 3.59-3.41 (m; 214}. ÍtelMÍ (C3DCk|: 151,4: 1¾¾ ! 44.2: 129.9; 119,9: 106.1; 56.2; 35.5; 2241

Exatnpk- 4: díOHnuthtrxY-'Orm'tkyiideych^OdlIncinO.'kOrk’ítOstmkto Based őrs IIIs 0 5.34 352 &amp;&amp;D.J.' 3,d43in5en5oxybicyelol4,2.ü]octa-l .3.>"trien-?"«minc hydrochloride 3 I 2 mi <>5a malar soha ion oí horune completed with ΠΙΕ ara added dropOw\ and whslsi sürdmj M imbieht témperahimno a Mliiilon of 26 g of d^dlóiothöxvfetoyete" [4.3.0joí.ta~1.3.Ü-nneííO-'earhiíndrde ht 250 ml. of Ilii· and led in contact for T2 hoars, 20(s mL óf étkmöl. arothm «ddetl am$ -storing Is carried nut for I ho:»·. 100 mi, ot 5.5N t ΚΊ hí ether a-re added drop-wise. 2?.? g of the expected product are obtained.

Vidd -= 90% md>: - 20X1'

Step 2: Ethyl (3 0''dlviXdh:0\yb!r:yolo|4,.?..01oepv-E>a5--tnen'?--yl}vndaamnte 1.5 ml., oi ethyl ehloroformate arc perused into a suspension of 3.4 g ot'she compound obtained is: Step 1 at 4,5 ml. of tricthytarthue and 50 nth. of dldiknomcdtauc, The whole is stirred overnight at ambient temperature anti then washed with water and IN hydrochloric acid. Drying is carried out and the solvent is evaporated off to dryness, 5.2 g of ass oil corresponding us the expected product are obtained.

Vidd - K0% 5w|l3; 3.4 - f dlmeth* wy-d-methylhu.· ytiof 4.2.0 jocta -1.5.5 -trien-d-astd ae 3.2 g of the compound obtained itt Step 2 dissolved in 30 snl, of Til!' are added to a Ipspenstop of 0.9 g of EiAiEid 1ft 20 ml, of T14F. This whole is ryfhrsdd: lor :1 boot lit hdPdtds add litert hydrolysed using thh mt df water: abddlJ ml, δΟΙΜ sodtism hydroxide solution amf finally, 2J ml,· of water. The mineral salts are .then ÍHiéred off and rinsed. with Tilly and then the filtrateobtained Is evaporated to dryness, 2,3: g of the expected: eornpound are obtained,

Yiek) === 92%

Example 3; {7S>~3«4-Di»*M&amp;ö«f*:^t»íéi&amp;^IMís^eI»|4i2ve|#ct»<í'!:^lí§*fri^^«t«.l»«:

Based on HP 0 534 859

The amine obtained te Example: 4 Is reacted wltlx an epelmdlar ampupl of fd! camphomulphonie acid in ethanol. .After evaporating off the solvent in vacuo, the salt Is seer¥SCafIbsed itrat from ethyl aectate and than fiam: acetonitrile orbit the mrget enanliorner is obtained with an optical purity of rnore than 99% feveloaied .fey ΉΡΙ.Γ on a Chunked' Of> column's. E sample hr 3"f3'-|{|{?S)~fM~Blmethox\bkyd»|4,2dl)9€ia*‘13,S“ifk»-7'yl}~ m ei hv S } {met hyt gt m ina \ propyl boxy- 1,3-d i hy drok11 "3 - Is e ncaeep i n ~2 - ope

Based on O' is 514 05V A solution of the ids eamphorsulphonate salt obtained in Example 5 in ethyl acetate is brought to haste pH using sodium hydroxide and then the organic phase is separated oil. washed, dried out Nu-jSO.; and evaporated. A mixture composed of 5.6 g of potassium eetfeooate. 2.2· g of the above amine in 10Ö ntk of acetone and 4 g of bensavepinA'-one is then refluxed for IB hours.

The solvent is evaporated otV m vacuo, and the residue is taken up in ethyl acetate ami then extraeted with YN hydoKhlone acid

The aqueous phase separated oiT hr feonght to basic pH using sodium hydroxide and is then exiraetyd with ethyl acetate. Alter washing until neutral and drying over MgVO.;, evaporation hi vacuo is carried out to obtain 4.5 g ofAo oik which is purified on a silica eehtmb using a ihtxfofi of d!o|t|ofometica;c'mekumol f 90/111} ax' eloaM.

Yiekl::: 64% txxnmple ?; 3~f 3-j f |{7S)*3$4»Dii»e*hexy I I|«* 8H,0tyÍ|{methyi|ams«o)pröpyi}~?J8-dimeih«xy4vM3Aeíyabyíírö-2ll“3·' benr.&amp;iiepbi ^"«nc Eased on b.h 0 514 8$<> 5 g of die compound obtained in Example t> in 50 ml. of glacial acetic acid are hydrogenated in a Parr apparatus under a hydrogntr pressure of C9 bar at ambient temper;ante for 14 hours in the presence of 1 g of 101« palladium hydroxide. The catalyst is Eltéred off. the solvent is evaporated off and then the dry residue is taken up in voiku and. ethyl aeeiate. I he ingunk phase is dried ote.i anhydrous magnesium sulphate, concentration hi vacuo is eurrted out and then die residue is purified on a silica column using a mixture of nldrlorumethanedneihanol Ehv'5) as eluant, After recrystaHisation iVom ethyl acetate, 2 goftbo expected compound ate obtained.

Ire hi -ho it

ntjy ' iOi HU'V

Claims (6)

1. 8M>séskm igheygysttok

   1Iliiké (I) képMk vegyiket

   ÍÖ οΙΜΗίί&amp;ϊΡΡ:*. avval jeik-ssaeavo, hogy ( VH) képiéi;-! vegyelek;;

   (VS) alávstsüsfe fíksMlC): kstssikskk egy Mtí$ jélépléídbétv «gy s-am-es ddé&amp;seeben, így kap|«k a:(S) képletS: vsgyülélet:
2. 2. Az i. Igéeypoísí «.arioh ekáíás. sxxsí jelieseeeve, hegy a (VH) képlelk vegye let (!) képlete vegygletls '!$$£<$ áfc^íiás&amp;rd· 1)¾½¾¾

   2. Az ? s&amp;gy 2 igéeypoot sísnok kijárás, assail jelkueesve, hogy a (¥ü> képleté veg>ttl«í (!> képkiö vegyükaté íttítéaS ákhakkkska h&amp;sx’kd; bash; baburo-im'buiatieléí, násrksot'i'íe'e-btbeoolét, káHun'í-crsanolás, eáttkeo-íí&amp;sxoiik kklkao-metsaokk ésaittriuevmelSLoelás kbxtt; van ki válásai va 4. Λ 2. igéoypo-e sserhsü ekóhh, ássál Jdiemexve, hogy a (VH) képlett) vagyaiét fi) képlett! ypgyáMkí töstéoö síalakMwPa hasxahk báxis káHtort-fm'· buts&amp;nol&amp;t.
3. 5. Az 1-4. sgéovpotooh béreielylke sseo/ttl eljárási »ex*8 Jeiieises.viy hogy a (VH) képkiü vegyiket (I) képklp vegysletté iöriéttS étetékllsskkt tuísgohl) ssetves pklóaéét' leéttseek etaooL iMgröpasök íprée^atssipi, teisshttkbttgihy otHép'fHkhi és dkobiihkiíttl ibsM vagy &amp;jp. oldásttetek kiMtí kettő keveréke kögltt vett kMfsssttya. 6. Λ?. 5. igénypont s&amp;ínsei eiktrá-e aesal jellemeevo, hogy &amp; (VH) képlett) vegyiket ()} képlete vegyökih; terttínö öialakiiá-dn) has evéé ss-ove;; okiósi&amp;'r tae;kobmí\;r«o és metaool keveréke
4. 7. Ax 1-6. Igéoypovook hájo-ehlke ?áattí$U eijásas. sasai jelieosee.ve, bogy a (VII) képkiü vegylllpt (.1) képk'O's vgavó letté Ktnéeó asekiklttlttki -20'(. - .Hré. hbsoé-sóhieieii vpgee.seL k. Aa s. jgéoypoei saetstttl eljárás, ami jéilettteséé, hogy á (Vll| képMS vegyttlPkt (Vili) képkttl veg>b leiből kbódulva allitluk elő.

   (Vitt) ísOíCisv· éttuakOttok t!X) képkia vegvpkíse

   ρκ) ábéí Xjetpikése (ΟΜ,ΑΜίΜοροη. I.!'dssikoxfctés'K amelyben ex ibsosresopossak 1--4 sséoskíníesak, és -így sxerves 1¾ süvegeibe · )etekll!étas egy sxerVes sldisxéébkh.. amdy I \X} képiek! veg> ök'td sxenes.-v;ges ssvss káKégbéPÍVll) klplsbl vegyíSlghl

   bíésöllgállök. % és I- Ig-ééypöst ss|tö$ eyiris, ggKbt jejlkdisye, hegy g (Vlij) képletS vegybkt (IXj képisák t^s$h&amp;Ít:tP-vtíyfcoxt«í«ft ax XáMiekíXioiie. 5 0 A V igénypons szerinti eljárás, arad jdkieíexvf, hogy « IS'Ül) képiek! :Y§gy&amp;M 0X$. ké^loti. vlgybieeé íéirtérso átaiskitásáre hasxíiáiii J-dietoxidln «i«fmyiségft 0-S-S ekvivalens. Η. Λ 8“íí> igcnyponiok bármely ike szene: s eljárás, sexei jsik'oíose, hogy a i VIHj hépleUs vegyibe! í l X; képiek! Y«ey«krHe röHéno ,Pakd·; kásán* immák szerves fénvvegék:· «'bsitiUítmm* a~bk?iiHtiym, AlshIIIitiubg féhj 1.1 Misé) Is IMkiöpIlmlgnéxIom^hlwsd kopp! vm kiváissstvs.
5. 12, Λ II. igénypont szerinti eljárás, axxsl jellemmé, hogy a íVill) képiéi! Vhgybtéi fiX) képiéül vegyöleíté történd áMakhásání használtsserves Íésnyegyltlíb «áosííllltiitm, Ϊ5.Λ 12. sgényponí szerint! dját&amp;k a*x*S |e!le«urxve, hogy a (VUh képlete wgvblei (IX) képiek! vegyök'tíé történd átalakítisáro hasasait «-hötíllfttu*» mennyisége K> ekvivalens. M A ihB. Igloygpsrkík: bármelyike széniül epráe, *m! jellemezve, hogy a iYIO) képiek; vegyibe; (IX) képjétb VégyhlsM !Ss#nb étrbákMsáza. hásxkájl: szerves oldószer löktől. tetnihidroiorárt, dfcklörroetán és blbrhéüsöi késmii vm kiváláséivá., !5. Λ M. ígés-ypoor szerinti eysrás. azzal jdlmexve, kegy a fVUS) képiek! vegyibe!; (I) képiéül yegySiéitl iöriéph áiá1ábl|ásim hgszrkpt szerves plálsxlr iplhof, Iá- Ah i--.1.-5 < sgékypöhipk bánkélyika szén bt! é páráé, gézéi jébekiéévét hegy g (kbllj kégiétk vegyiket ( IX) kép leik végálbeké iöriéitl álalákítákk
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