Document Z434aQ3jZMMopy8e70p6j9YDd

lap 7 1381 Synthesis and Characterization of N-Ethylrose-Y4c Docenbor 11, 1980 Concucted at: During: Synthesis Conducted bys CaonmdmeRrickiearlLCabhoermaitcoarlisesD,iviIsnci.on SStu. Paul, Minnesota 55144 april 197 to July, 1979 rz. Bene Specific Activity and Radiochemical - J.D. Johnson and 5.0. Gibson Purity Determination by: Report bys Qube 3/6/5/ S3e.0n.ior3 fbchenical PhamaDcaotleogist Riker Loratories, Tne Fees Gos YA R.e5s.earBechhr,Sphec.iDa.itst Date Commercial Chemicals Division CShpaercaicftiecrAizcattiivointySaencdtiRonadiochemical Reviewed by: A d 3/188! MRRai.nkE.aegreOrbL,earb,obrraPuthgo.rDM.ieetsa,bolInicsD.mate ~ 03457 2 Sumaary Tchtehansoynlth(eNs-iEsthoyfl FaOS1E0-.10C,),1otL-4o5f452,-N-isethdyelspcerrifbleudcr(ocoacrtbaenneestuolfsaunlifduor atan is labeled). The specific activity was determined to be 0.483 + 0.020,4Ci/my. hadioclionical purity dotormination showed tho N-Ethyl Ff0os2r-1'mCetabotloisbem asttudlieeass.t 98% pure. The N-Ethyl FOSE was found suitable Introduction AN-TstehryilesFOoSfE=e'y"gCe.rimeTnotsfahcaislibteaeten tshteasretedextpeoriimnevnetsst,igactaerbtohne-1m4etlaabboelliesdm of Ni-lEltuhsytlraFtOeSdEinwaFsigsuyrnetheIsiiszeddesacnrdibcehda.racterized. The synthetic pathway 003458 > A. Synthesis of N-it I. practicution voofsucpM, er(cLr-s4n54e5).(step 1. 1STho2er5t2ef3nr5a5ecthisaosne-able,eenteptrioivnitciuosnayofsoscernuideen:ce1draiinbigesmnfriomecohllorrnn H Mmtestion of cp, or sp (step 2). Re CIeontEteoxtacn anraa'xaeSde eGr2y56i05n7ga0a1tu1ttbhers:ee.h-Aann:emcaykSbeisedahosaeknrseavmeobdsti-hobyeoStteotmeoainmieesdssioocCehlmaoTsaknnevettaarsnoaaadsdeSeedd EEGSeEohascHahtrEeiv.oendRamatotietxdtuChteFoeieunursaiysleocvshsaeiesidnactdrcoeaosdtftauiFkhtreoTGmovorernescemFioiicuetrrhl1is5mpsbpneheoresreaewrtnoacCs?Bo.enyoSrynpoioebrraeoszen TEgShiaoerteiveNansascsupwrhCesaresedewaattaseosschaeTGaygitamehcsdeusatikmheean.Sd0isto(iCnotocnftoi2oro.fn30).ns3u5iiMchseaenrtii"es SamchbeeosthrSneaaspisens sacs Te1SEEE matrer acta CBf0rooamr0sase0..27e55ammTeeD).apEewrroau)peoernnoacdshcdeoesoadlinicsanaamglp,tpothnthahesefemraeiwnsneiushatieeae swspashadeeonSewesivFiehmeineBlaeremnoee2(oaa1msemsi,C11, Cater untii che Bi of tha wash sotetiom ves 4.5 toon our k wCFaoaxtteer0r.2w3asahheeesrsatwteerrveeciunoeeneddeopdf.r6e7sTa7hues5 fl((uvahercoIecsheBpmaeiwrc)a.aleewCaoatsnreehnmesmautnedraot s7i0nC III. bSesectirem sof Nepthy)hperflusrocctanessitensmige vith pinyiens PnhIleanakdtecoreb,danSaphnroec"-dactdiraipoztpdeieedodnr2aav0ddi0itehfmucametiehSvdrLoeenecapi-nundlefacaoktneimedoen.pnindseehor.euisnss,d6-1ssb.eoo7btet3mccimomemedtSeoproaomsamekbse,waenirw2hsihch TDRChietexihthyuiairnerecni.lsurs(eei3yt5vc:ha6oasln5o)b(le3vs.ta(5es1d0maB15di,0e)nSTvSoatGso3bwt0oehee7edfsfvteohacpnvtideeocnShhs0e0SShFsireoerrceimhnoaertmroeiceehneetaptreaensoebi.n STSo5efa0sm7tmehvty.nalacpnuecTurhhmt.elaumnoiTrdxhoteouFsrriteanenvasealris,addcotfmohoeelntemmahdiaidTnieoe.]za4ea3n0escw,ass0tohBsmeoeweevtesesedSthcahceihvTSepeoncerbiseoinniaeolrSeeesatermm Snhyious possered sosiun sathonate. C8 53, eehprane Shomeiamerie v(i1g7h.r0omuls) raencdtieotnhylceonmeurigeldycoa8l t(h3e3.a0iemlb)urewewreesamddoetderrapTiadLlyh.c.A 2 fe raw ratertar, Quality Control Manual called for 96.0% min. C03459 ACafsterTesttheedinFiirtsitalteox3o0thCermFiocr r1e:a0cthitonandhadthesnubsthiededC,inptehemivmiinxeture oCvVfaaatsceturho,necimb2ei6rdxint7eu5troCe(.8tw0harCsGereaardtnaeid.inseaetslhd)tectmhoaienxld1t1ut5(rh7eeC2.fvr1oae3rss)iad5uvcaahhslresd.wvaatcseTuurhscemcvemadsisisxgitesvuieerirleliyeosvpiettdohby yT ielTd tawe o frac5tionRs: TFR #1,Gi5l7.3angi,yebi.sp.s,had;ed14P2a-14414anadndMF5Rt#o2, coronaCrsg25dtg0n (soe xefozence 2). TThaestenomna-tdsirsitaill,labTlhe mIaLtearndial42 (w5i.s0e5)tavmabsineadlsscnadrdseodloaesdrtaodisoiavcetive SNCo-omEkatitniPoOfnSr,Eo?m t(LhS-et1e5op05r,3a)lCairnsbue6mn4p-.l19dgannldaybiweeallsedd.SNssEiALantPeeOdnSEgt.rheamEsoalmtpolreinwgasdos B. Specific Activity Determination of N-Ethyl rose-Y4c. TSuhciteisons)tawnedraerdpsroelpuatrieodnshyofweNl-aBhtihnyglIF1o7sa4-71cmEg, (111-453495.55s.een3,Synatnhdesis T0a7re25a.i0S8usmtgedintoto10hraekswi10thm1metchlaanseslAavnodltuhmeetfrliacskslaswkeerSe.misTheed vbyoluses SiSTiienxiivqneutr1oi0ttiisln13agtaianboaydnhtoaScniodxut.hno5tei0sCnga1lciovibAnarLttiaaaqit.uneeidtnmsgTioco5rf0tohpSebiasipceheSt1otisfoqourltosuhsTMtesiwovenifrareloBsmiurecseaoeccntdhtlaytPoiRniAianRntlAgoiTqYu10ot41 ` mTsoaoaillnuytieincogsn,vioaf1lmsthlrweeoerf:ewsapttraeenprdiararendddswo1li5utthalio2no.s5f Amaqilulaoosfwolsceeoftmhpwaaenrrciehsoanandddoefd7..i5hcTaehbseporrfiem=MIaSrSyE. vCCeoilmTomrnaoitrnieginsot.nsoefiMnattiihv1eslepastrieoconifsi1soo0lnvbeionftasn.tdheal5ml0ioo1wrs1opaciloipmqspucaeurtciet.sso.nfrOoMfme.esoaubcreheMlsioeifrtuytt:iuon ailov oc(oMr2nk5l5e.dbe1fstoorteos"teuftaehnieeygewrbeaartseeerdcnotuadnmtpMeeqdsuetatuusoro.eltainnLodasa&alvtleocw5eemrdingVuoolt.ee)qsuielaFichbheravstiaetm.phlienastvheers PCmEaeEctLkoahiroodncMyodewlas3d3e8t5erLmiiqnueidd SocrinctaiclhlatsiaomnplSepebyc.trtohmeetienrc.ornaTlhesccaonudnatridng TThoex caavcehravgieadl.dataThveerdeatreeadvuecedshotowndipnm Taanbdlethe1. KCTir/eagovvearsaiclalscvuelraetgeed specific activity based on the 36 replicates (12 from each weighing) wFTLarCCsiiia//ma0mgrg.y4bb8waa3ettiww0sae.hoe0i2nnn0gA1s0uqCuvi3Ae/1smeega.1wndiatTnh5h0idenN1mT113e:3a3al8nvieqoirufCaeitt/ewrmiegtwohevirfneeoruwen4li-dl1t0hf;mioenrtane0n:.ad7c0ht:ThoeoefDetmehenean 2 2Ri-kNe-rBthTyslotpoeprefluNourmobeorcta46n8e.sulfonamido ethanol. < RATE Weighings wYeerceantaicycommepelnishceadliobnrataedS-pblyacoem MHeettrtolteornyH.64 electronic balance Conny | Hs Heropimetor Lab Taducris, Berkeley, ca. 03450 MyooduifsinegdianTod81nuci2e5a.r2,3soPs70t,on,1.M0a1ss3. Dimethyl FOPOP and 3.8 1 toluene.  L Jadio vdomdical l truao rriittyycMMaah llyyssie issoom ffNN--i ikttiiyc yllr1on ossuul --21cc 4: Mhiuiaver Chromatography Systems and Carbon-14 Analysis oPTlfhaetteahsnianml-ylrsaeiyserrooufstyisrntaeedlmiysocduhesevimenilgcoaplSeGdpFuri2ni50ty10miwcaxrsonc12a"prrreti-hesidcno-orluaetydewUrintihtpalanavktsag?rsi?e.ty wwfieidrteetesdaelgwlmioetwnhetdsg.ltoashsdeev1eisldcsopraapn1i5dngclmiwnaaesnddawwciectrohempslsaictsruharepadetdiwoilntahptaedarsatcl,ulsytopimnl-amt0a.ed5se cm 0sg-ee5imnpctlimaltlewaidtatinhod.nsvThihaaerlpssecncreoadnptesadtianisininllgeiscsa2.5sgetmlelelsoefgsmpmeaentttuhslaanwoeglrr.eo.ucnTodolltetohceetxemadectithnlaynol, c7o-5olmeld minute oi(nfcpmMt)IheSwSedrwaeraks.caodrdTrehedec.tesdaTmhpfeolressbawamecprklsgesrocwuoenurdneteumdsiianxgneddabtshyueistchaoabuklnietnsgbpiaesnnrdk pT(hlueastuceaalrblbeyoinnt-gw1o4as0sc.ao5ynetcdea)n.tseogfmTheeenatcschpmsscewrgeamrpeeendtnofwtraoscmoebrxrepelrcoetwsesdtehdefoaorsreipgfeifrnicceionentnctyoh.fe total carbon-14 ca the plate: TumEmofocnpsaeoqnmepnlta_ts*\. 100= carbon--141ccoonttentin segsemgemenntt.. sTShheoegwmipennegtrcnetuhnmetbercraa.dribooanTc-ht1ii4svpictroyonvtipeednaetkdsofacoetrahrciehns-plsoaenygdemirenngtrawtdaoisoscpehplraoortmatatetedodgvrecaronsmupsonents in the matcrial applied to the plate. II. Colum Chromatography system Ii(nsedecahlnmoerxotCfooslreunc.mtiownaAsoC-npIeaIcIak)ledawaltsioqua2op1tplcioaefdwNi-ttEohthtayhleslucFrOozSlyEu-mLo.ifCstTiheleiscticcsaovalucumitaio?n ywcoahrsleoreoelfvuoatrpenod-rmasetutechdcaenstoosli,vdreyalnynedsws2i,0t0hrme2lc0o0nosmftlmietotufhtaecndhollio.nrof2o0Tr0hma,WLth2or0fe0e1ml:f1roacfcthil1mo:me1sesfTyhoesrtnPe-lmmaetatsehsaPnlo(alNto.eanN6do,.s7t,5r.eaankded8)onwetrhereedesveeplaorpaetdein5 txhe20sacmaeplsaotlevse.nt - III. SoR Solluuta tiiondUUssei eddffoo orr c Radih ochee micaml ppuiriittyc yAAna naallyyl sis p\Pliramecbciieonrlgu46t28i6)o.n16inuntsgoedo2ft1oN0-.sE0ttraheylalkcFltaOhsSesE-tAIh'iCvno-ll(uaRmyieektrerripclIasotfteloasspkew,asIandpvjreunestptoairrnyegd by FtFhiiifgsteyysloWullmuteoifon0thwi1as0s.s0aopBlpLultwiiieotdnhwtaomsetthhaeapnpolslii,leidacintcod emaicxhinpglabtye.hanOdnebymlimosefrting. acid colum. IV. Results and Discussion gTSeaipvnoacrbetl)it,sheheudnclhbaeybmeilcseyandltNhi-edEsetinhstyilatnyFdOoSgfEastwhaecshNrn-ooBmttahtycolog-rcaPhpOrhSoyEm-a2(t4soCegeriSasepchwteeidioln A, this with the C0461 Asnpaaltrecch,tn7e5, BlBueleleHfeonntDer,iveP,ennNseywlavrakn,iaD.elaware. nCoimspialn,y,acItnci.v,ateWdillsiialmiscpiocrta,ciPden1n0s0y/l1v2a0nimae.sh, Clarkson Chemical "6 N-Bthyl Fose-'%c. The results of the thin-layer radiochemical purity analysis are shown in Table 1 and Pigures 1-5. Small amounts of impurity (<2%)were present either at the origin or just wbeerfeoreseptaheratNe-dEthbyyl tFheOScEo-l-u`mCn;pea9k9.i2n% Plates of the No. 1-5. The radioactivity impurities recovered w0a.s1% ewliutthedmweithtahnoclh.loroPfloartme, No0..76% with is a r1g:1giocchhlroormoaftoorgnr-ammetohfanothleand cofhlothreofotrotmalfrraactdiioona.ctivTihteyN-rEetchoyvlereFOdSEf-r~ omCthpeeakplactoen.tainTheuds,99.th3i%s analysis total in tihnedicfartaecstiaonra[d9i9.o2c4h]emi=ca9l8.p5u)r.ityThoef 98.5% (99.3% of the presence of small afmroaucnttisonsofbyimPpluartietsieNso.is7daenmdons8.traNtoedatftoermptthewaosthmeardetwtoocoilduemnntify Nt-hEestehylmiFnOoSrE-iggu"Criitsieast. leOavsetra9l81l., tThheisraidsiocihnemaigcraelempeunrtiwtiythoffhe GiLsCsauniatlaybsliesfo(rsemoetSaebcotliiosnmA,stutdhiiess.report). The N-Ethyl FOSE-1'C Acknowledgement oTfhethaeuthcoarrsbong-r1a4teflualbleyledacckenlolwlderdagienitnhgesgaasndchNr-oEmtahtyolgrFaOpShEi-g1`aCnadloynseis gbyratMre.fulTloyddaMcakntohwilseedngeoftCheommaesrsciistaalncCeheomifcaJloshnDiC.visHiaonns.en aTnhde authors LlaarbreyleGd. CgHge1a7d%%rS;iO!cFk. during the electrochemical fluorination of ; 05482 oe References 1. J(oRhenpsorotn) NJDovaendmbeBrehr3, FE1:979.Synthesis and Characterization ofre-95-c 2. analytical Report Number 14557. 03482 8 Table 1 Specific Activity Determination of N-Ethyl FosE-1%c solution I 17.47 19/20.0 m1 uCi/mg 00..44883524 0.4811 0.4822 0.4827 0.4790 0.0.54090385 0.5080 00..44299578 0.4100 0.%776%0.0287 Solution IT 37.55 m3/10.0 m1 wei/mg 0.5048 0.4986 0.5000 0.4533 0.4749 0.4635 00..44896543 0.4900 0.4843 0.4920 0.4773 0.785020. 0154 Solution IIT 25.08 mg/10.0 m1 uei/mg 0.4828 0.4848 0.4853 0.4749 0.4709 0.4853 00..54096555 0.4946 0.4833 0.4916 0.4939 0.3875%0.0096 ' Aquasol WCi/mg 0.4854 0.4832 00..44891315 00..55000808 0.4986 0.5048 0.5000 0.4864 0.4953 00..44892080 0.4848 00..54086553 0.4955 0.4946 0-493120. 6087 rss uei/mg 0.4822 0.4827 00..44729907 0.4958 0.4100 0.4533 0.4749 0.4635 0.4843 0.4920 0.4773 0.4749 0.4708 0.4853 0.4833 0.4916 0.4939 G.473520.0225 0m Ci/mg 0.4854 0.4832 00..44881212 0.4827 0.4790 0.4986 0.5048 0.5000 0.4533 0.4749 0.4635 0.4828 0.4848 0.4853 0.4749 0.4709 0.4853 0.481820.0123 50 m1 uci/mg 0.4935 0.5008 00..45209870 0.4958 0.4100 0.4864 0.4953 0.4900 0.4843 0.4920 0.4773 0.5065 0.4955 0.4946 0.4833 0.4916 0.4939 5.484920.0251. Overall average = 0.48340.0195 See text (Section B) for description of sample preparation. 03484 -o- List of Tables and Figures Table 1: Specific Activity Determination of N-Ethyl FosE->`c. NB 51807 p. 41, 43. Table 2: TNBhin5-1l80a7yerp.Ch1r4,o1m5a.tography Systems for N-EthylFosE- c. Figure 1: NSBynt5h0e9t4i2c pP.at3h8w-a4y2.for Synthesis of N-Ethyl Fose- ic. Figure 2: TPlhaitne-laNoy.er1.RaNdBio5c1h8r0o7mapt.og1r4a.m of N-Ethyl Fose->%c, Figure 3: PTlhaitne-laNoy.er2RaNdBioc51h8r0o7mapt.og1r4a.m of N-Bthyl Fos-`c, Figure 4: TPhliante-laNoy.er3RaNdBio5c1h8r0o7mapt.og1r4a.m of N-Bthyl Fose-ldc, Figure 5: TPlhaitne-laNoy.er4RaNdBio5c1h8r0o7mapt.ogr15a.m of N-Ethyl FosE-1%c, Figure 6: Thin-layer Radiochromatogram Plate No. 5 NB 51807 p. 15. of N-Ethyl FosE-l%c, ' Figure 7: TNh-iEnt-hlyalyeFOrSER-a1g'jCo,chPrloamtaetoNgor.am6ofNCBhl5o18r0o7fopr.m C16o,l1u7.m Eraction Figure 8: FTrhaicnt-iloanyerofRNa-dEitohcyhlroFmOaStEo-g'g'gCm,ofPla1tiel NCoh.lor7ofNoBrm5-1H8e0t7hanol . 16,17. Figure 9: Thin-layer of N-Ethyl FRaOdSiEo-g'hCr,omPaltaotgeraNmo.of8MeNthBan5o1l80C7 opl.um16,F1r7a.ction (03485 -1o- Table 2 Thin-Layer Chromatography Systems for N-Ethyl FOSE-14c r--_i--es Yo. Sysosttvoenns? E2rmvy rote ----- ee 1 110000 accheltoornoe.forn 0.67 2 110000 mcehtlhoarnooflorm 071 2 acetic acia 3 11000 wbauttearnol 0.73 10 acetic acta 4 15500 mcehtlhoarnooflorn 0.80 5 ammonium hydroxideS , 5 10350 mcehtlhoarnoofl,orn 0.70 S ammonium hydroxide? --- 2 mSioxltvuernetswwasereadpdreedpatroedthveolcuhmreo:matvooglruampeh;y atan1k0.0 ml aliquot of solvent 2 &, 4s of major (98%) peak on the thin-layer chromatography plate. Acetic acid and ammonium hydroxide were concentrated. 03486 ue Figure) Synthetic Pathway for Synthois of n-Ethy) rose-10dc? Step 1 step 2 C2HsCHC50SOF Bnr [E. NC c,F, "cr ,S0,F Fractional 718 7272 giceiacion cP "CF, S0,F Ts98.15~022 cpp.lerysoe + acum, --S.s cop.torson'<82,S \H seep 3 cpl.cr,s0, 7 C,CHa,s s i 1) i NaOCHs . . 887,1s tpFany ? C,H,5 ' BR 2) ccacHon cucuon N-Ethyl rose-Yc "Denotes position of carbon-14 label. 25-Eehyl POSE 1s 2-N-ethylpereluorooctfaonneansiudlo ethanol. 03487 0 60 : F5R Ta s &a 20. "12igure 2 TN-hEitnh-yllayeFOrSER-a1g'jCo,chrPolamtaetogNor.an1of sirr Uniplate,:. 116000 SchhIlOoFrOoKform Total CPM on Plate = 88,572 x 12 3 4 5 6 7 8 Distance from Origin (cu) 1 11 12 13 37 Co348g  - 3 fant nin-1ayes r sage jochri omsto, gean of 1%imonpaeemss `otal CPM on Plate = 82,187 8 2 w . CI: 13 v7 I 3 BE LE wR ptosancefnom origin C0489 2 oo 8 so 8 a & 30 uvigurae Thin-layer Radjochromatogram of N-Ethyl FOSE-''C, Plate No. 3 SGF Uniplate: 100 butanol 10 water 10 acetic acid Total CPM on Plate = 89,696 20. 10 1 2 3 4 5 e 7 8 9 fo 11 12 135 13 1s Distance from Origin =) C3470 0 "0 5 Ly iw ase pigue s MEint-lsayerrosraagjhoes, hproamtaetovgasraa4of sce niplate: 155003 mmchtolhnoarinoooflnormhydroxide Total CPM on Plate = 91,164 ~ 30 a 20 p I Ty 4i x 112 3 14 I Distance f)rom origin Cosa 20 0 3& 85 2a & Fw 20. 10 te PFiigguurree66 TN-hEitnh-yllayeFOrSER-a1g'jCo,chPrloamtaetoNgor.an5of SGF Uniplate: 100 chloroform 35S maemtohnainuonl hydroxide Total CPM on Plate = 90,961 12 3 4 5S 6 7 8 9 120 1m 12 13 14 15 Distance from Origin =) C0472 0 oo 0. 2 : sw & 30 & 2 a piqure 7 TNhBitnh-yllayeProsR.agjLoicc, hFrloamcaatoNgoz.anof Chlorofors column fraction Ser niplate: 10305 cmehtlhoarnooflora 5 ammonium hydroxide Total CoH on Plate = 372,20 . ! 10 o 1 2 3 4 56 7 8 9 10 1 12 13 14 15 Distance f@rom origin 03473 " i : z 3 3& i 3 20 ce Flare 8 hHFeaittnhelananoyele.rCoRraadmiocFrharcocmiaotnogeetanBoofr11t1 CsoheircteigcoTrmr SF Update: 103505 mScmeheltoohnratonafemorhmydroxide Total . cau on Plate = 2,594 , 10 0 CE TE TT Tra Distance tfryom origin C0347 0 0 o 2s 58 ER Ss & 30 20 Figures TFrhaicnt-iloanyeorfRNa-dEitohcyhlzoFmOaStEo-g1t'gCm, ofPlMateethNaon.ol8Column sa Uniplate: 10350 mcehtlhoarnooflorm 5 ammonium hydroxide Total CPM on Plate = 354 10 o 1 2 3 45 6 7 8 5 20 1 1213 nis Distance from Origin (an 03475 Distribution List nT. case 28-2 5.7. Chang 2102 6.3. Conard 282 HE. Freier 201-28 L.1. Harrison 2182 3.0. Lazerte 236-1 L.3. Magill 223-65 R.A. Nelson 281 R.E. Ober R.A. Prokop AL. Rosenthal Fa. wel P. Venkateswariu HA. Vogel 218-2 : 236-38 230-3 220-22 236-2 236-3 Drug Metabolism Central File Tech Communications 28-2 200-2 03476