HUE031895T2 - Új indolizin-származékok, eljárás elõállításukra és ilyen vegyületeket tartalmazó, rákos megbetegedések kezelésére alkalmas gyógyászati készítmények - Google Patents
Új indolizin-származékok, eljárás elõállításukra és ilyen vegyületeket tartalmazó, rákos megbetegedések kezelésére alkalmas gyógyászati készítmények Download PDFInfo
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- HUE031895T2 HUE031895T2 HUE13704189A HUE13704189A HUE031895T2 HU E031895 T2 HUE031895 T2 HU E031895T2 HU E13704189 A HUE13704189 A HU E13704189A HU E13704189 A HUE13704189 A HU E13704189A HU E031895 T2 HUE031895 T2 HU E031895T2
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/472—Non-condensed isoquinolines, e.g. papaverine
- A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/475—Quinolines; Isoquinolines having an indole ring, e.g. yohimbine, reserpine, strychnine, vinblastine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
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- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
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- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
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- A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
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- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
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Description
NSW INDOL121NK COMPOUNDS,
A PROCESS FOR THEIR PREPARATION
AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM 1 Hi psvAOis' res.sk:· to s-eu irtdoskko cainponssk to a process for tk=r psv p&nsdon ssnb to ' ai\ v .\C v>' "s "! vív s V 5 U e O') '·>«η,Ν ot p:evk u\'jtso' ·.<. '' -nd h.:s. u ' V4sh,k>fe p;'*tns..i «k e'.->''nss... tes-stS' in 4 í J ' »Vp>Ov v v '<Sk. « g\
Apbpidsis, Or psognsnssssed cell degf|p)y § plj^síwlisgíestt iwosse^ss ÍíIiísF Is &S' orotísT^OíO dovoloptsont and t's dns?'; exe ot tsssor iK'mC'Xko.ss
Xvj. ' «. i'p> V O'S'S OSS:' U 'to pk (. 'T 0 3. 'Λ >.: h ." SS \kov>' ' ' 0 5« V' P\ x hősnőm is; ion süsd aSso bsoeisetnicai piser ooicses such as Use activation of easpases x-i:x.h usfce damage to hey structural conspooerris of the ced. so isuixahstg its; disassvod>iy and death. Regulation sd'the pnscsBs of u compk"·, -t ' 'V'\v <« 'Μηλιόπ »» t ytt >s. > of s,w .d tnukc h sdststsiksg pathways vG,-y. x ..d, Nature Res oo dancer. Λ>Τ·. 4, 047-050¾
Desegsbrnkm vt apoptosis is involved in certain pashobgies. increased apoptosis is s&ssseisSeti with reumdegenerative disease* ->ach ,ο* Parkinson» disease. AUsheisoerN disease and sschaends.· Itdhvprsaly; ddkiK in the implementation of apop?os*s play a signitkasa roie in jfii deydtepmeot of canoery aiidjdtejr ehem<'n.'sis}ona.\ in auto-iramuRe diseases, inilammatory diseases and y§M ibbpdoos. Ascssdhsgly, ghsenee of apoptosis i;. ooe of the phenotypic- signature* of cancer (HanahmvD. et o/., Ceil 208Ö, HM). $7-70).
Tits anii-apoptotk proteins oi the Bd-2 itumiy are associated with numerous pailtoiogiess. Hse ittypfvemepp of proteins of the Bel-!·; trmoi) is desseríbed »« numerates type* of caoeef, stsefs i*s colorectssi estpoer, 1¾¾¾ c «xer. sm-dt seU Unto ranee*, oon-smalhevh kssg eas\e:\ Hadder e-mser, ovariao cancer, prosp» gitftitpi ckonie SoapU-tid Ictskacntia. kÜkokss· lymphoma. sitydomn. pmsiase cancer, ek. OvefeKprvssion oi she ssmi-.spopsoik proteins ofíha Bd-2 famrív is involved in lumorigenesis. so resistance So chemoihetnpy sod k tt>e shmes-d nroaoosir. of paucRts-afleeted by cancer ilteso Is, therefore, nytit^afpd&tft^:fm «ompo.um&· thru inbdnt she ants-opo}dotic activity ofibe proteins of f^".lk..i«2 hnroly. J bo Sv' Λ' .d de\r»kv \d>v«^»\dMtoia>e cotnpotetds &s BcI4 )ah*kt«»N <r*n» Most:. <.;beoiyLek< if-t-'di o- .ysn-yyt esut i?o?-G"\ O' .-..íj ϊ on so t'CsiSg s>c\' do Όίο.·'Όθ:Κ vt'sisc S'u cs-s MHCoisvsss Po5c fv^->j^R.'pk»tK ps'opetistss snaking it possible \:o ssse thens in pot hoi odes invoivmg a defcc» is; aprsplosis, ssscis ns, for exantpik in-.the treatme»} at" coiscxs' sitsd of nnmstfkf Add iso-o-insnsooe discssses. I t ? r C V Ot * 0*0 f«V V \( y'S Ο'-'Χ 4«K i« '"U <* ^'"^h
m
Wmmii ·:# X isiid Y teprewrt a varfxm atom o« a usixugen atoms it É&ü :.ɧ$S 1%%$" &pf. OO'sYtSOvOUSiy ΚφΟ'Ο'ΐύ ÍWÍ! i.arhonst SO s'OS Oi tWO oibuSUn 8ioS>«k·:, * ;the-lfei*ró^:©í;tte;.^m«.p
pspesssis anofiknadiysu^^stut^- or aosnaronsane ring con-posed of 5, b or 7 mg mcmbent which may eoninió, in addition to dsc nitrogen ropfosented % Xhsrbu: Y, :fw>ttvowt»'::3-h«S«r#^ews· stdsoisd iodepmRmiy thorn o\yg««,:. being nodes skx;d that the mtsojsen «» ψίδ,Υο» may ix? sobs! luoed hy a group söprése non a a hydrogen siutts* o hocor or b-andxni. tkWYhdkyi group or « gronp -tXOs-O-Atk wherein Yik Is a lln» or branched iCY-€YAi|:yS gnuig, •:f,.. ii * and; la kdegepdosniy #: doe drspiher seprésén*m: %4dmpana&s« nr s ifea*; w iraoehed spr tYjalkyl gsoup, orR. ->nd R> Idrm with dsn oinogoo atom carrying s'ing ivii.'vnhm. which may eonudn, In addifton to tin: nttrngsn::shnnrs anntsrnr SsetetonRtnn selected tkom oxygen, t>tdphs;t. SO; and NR wbxresn otanehi^dfsr \ 'K\ h »·* it Os » s\»\ g ns ' o p a smear ns yt,s ,,,ί^,ινίΛΥίίηη.Χί . r, s proof !\θΗ> \»xwSun Vi, ,, laxams brairdxal i* ? dhdYi group, ♦ R; 'ipjownts -s k:x,o <m branched ογ Cshdkvi .group, « IV'R sdkeígI group, a. >,v;^Ikytwi
gnsnp, λ soehnsskr I runup, a kec,o' o-'hrandred St Yt :O«N'h,! Y '>4}R> 'ϊ:' ηγ! Y>tSS nr a hetomaryl group, ·♦ Ri seprősem*. ,m aryi group, a hetetxtaryJ group, ,t eyek'-ikyi group os <t &W 445 tts^neu o-* t.Ygstkyi group, ;#ϊ R; represents a hydrogen atom or a haingeo atom. * RS::%x é lassogeo8ksOs5:e adás? ar soasssbeb i« >t il'w i «rx>up a bssesss:· ordrasss. s^a t<\ Ov sado\x .'soup x K'd«t>\> m. áraoehed (C: 'Qipolx fsafealkvl gto.ap.iOr a sriikrttojocthoxY grosso os she $s.ibxSstsscs3Sa ö* s>oe <rf IPo pár;; fRJsb.k (R^Rb* or íRJ-W; fam ««gate obsh she carbon «κβμ* casrryi«8 &«*» a t»«fe ®®mi 5 3 ·«» ' nmm N xns * m» no t<ss K * in * hS' ' ^oor- v eít-c- iksos :0ψ§8ΐ% ssipfsor and »imppb ii Mstl.^M#&töóá tMp:|fte: rsm-bisd Iá ^ sdastftáted ·% "a-spaug ,r«ps«se»tisjf &:%áy%§h aionk á WilarRt? bíassebcd (bV-hobáRvi 03 o gtmsp -CsOí-O-AÍfe ssÉernifí á!k ts.dhnear or branched. (C,-C^}3lky1 m»»tp is <*l«l Í>C*!'B untkmood ifs:á ossa or more^«arisso gíoms öl tbe ring dobok! |í|r#oib«fos-éss>?% be dvut&i#l? ít:bsssm: essdorkooíi thts!: •f lljjpkfcp oö-bsiktsy! ρ?«»ρ„ * 'dMemtss'y!'' meat»» say snuno- or bj-cyeUc gtosps cotsxpossd of from 5 to U> tsog meR^r8' ΡΛνί88 οί least one aro!SS8t;e snoseiy ássd eontsisáss Imm 1 so J bcssrb stonss setecfcsi frosts oxs-gcss, stMpsiur orssi oitsogess. * ::c;y»U>sdyP rsscísas. assy mosso- or iikpit «on-sironiistk· osrixscycbsc .group coníabsrog frocss 4 to Itt rlts»:»:sstte%
beis-g poskbk- fos she kkyi. ísryb heiuYOSssvk cyciossskyl sod beserycydosslky! groups so defm«tí so be sssbiastssted b\ boos s -o ' osoups. selected Rom hssesr os hr a e Used tCrkbdisíkys. (Ó>-ο;.ρρ>ο>, linear or SOOsched *CV' -knkev, st. s-t pákysdk, hydroxy. οχο (or .Voxsde evhete .spfsropnau-Λ. nőm. cyao#*./-··· rOOR", MR Tik hsstusr or Sosnched (C.-Cdsposyboloolkyl sttflsioromethosy, i"s\VCd;skyls«ipho:o; t«' tssiogess. it besssg uottarsfood shos R* sssxl R' isukjxsHlatstly os' osso another repres^»st oyoons^a sstosss or s iiseisr or htaox isosl (CrCo>»^> I ^
Jtthetopp®ssáll« lor tlísíik! TssoioSy of sfso: gross g dsflssesf sserstske sosyí: so bS/Siffíssfsúsfésf :hy sfe jp-s>tsp Sííiííüteíl lirissjnt Irrsmr i>r bmts^hsil biKym.;ΐ ir^liáÓtlfsMfRíd'tfsók' •Rí* asá thsessms· sioitsdiOssss os Rse gtosxgs R’ sssd R" ssse-sSsooed hcressxhotors\ so siiidr {.iiSitsUHssoors sssti d;sss>íro<ssssssss«ís, ássd to ad-iUsosi ossits sises'eof xvsds a phssrssxateusssraiiy atoesissabie tsessf or hitre, :.itaos|§ Steffen itdotei s«;ry :¾ ssxOostsJootk vvisisooi isaplying m$ iinsMsO, sapift tód, acetic ssási triRti>>{xi3<.etso 0¾ tók .sekk p>rtsvie add máteás«iBftlbswálákeaátóí·gháárk..ádd fsxtrsas'si. vsc-d, tanaricjáeid :#ld.:clfiá sse sás aseorlds: ssotsfi οκοίfe otsitk soeds;:íss«ss!|ild>dfo: seidi;: tsoosphotse :»0 Mm
Atssotsp the phattoaeeubctsUy acceptable hasé* there assy isi- njcsstiosseá. o-dhíMt :pbt3fy|s% ::sst| límtiátsos, -sdsiiex iK'hovík- o-oínnÍsíOi bx-.avícs^jc, tsíeSSoioisbsc. tét.t\ SacaeC ess. rise group:
íírtv3.üí;^eo;HÍ> nspreseafc m*x of U* foífoxvmg group* 5^t ^8'tetí#yáire>É|#?íns opiumaih subomued by a hydsmyx rodoikiRS;» L.?,at4-fí5trihydu>pym5Íi>i K>-«ipy?<5;asfi£t, £p%t\ i .VM&ydropy*roM ij.·-ufpyraaarteOf = dVradiosybu?, 3x·dbivdso 1/ΜχπχΡορ, s -c\\ s ,4 josados. 2 4-d1h\drrt-d/'p>sYís:;dí;í\
op5fou,Mi\ vob-JíUJH't h\ ah'vd»o\' o \« κ; ι'''λν'', ^""U '·ν!·'ί>,Ί\κηΛ κΊο <4 .ü'v^i'V is: thtí psYíVrred <\s:5spo:.:Pus ofthc irvradö;. R: ami Tí.- cads rem'ixcm-i. lsí; aiky s proap oppomdíy aubsítólgá. bv ο mefbovv. t»r R: ami R: fono orb ibr mirage sím'· rarrymp íhou} a rxlaixxdmbkyi sdreird Isss íha following groups: (norpholmc ophonaUy whastitfcd by c-m? or more l5n«f»t or bwoebM* oxsdrsmorphobui?, thRonorpholioc l.l-díö.\id* s.-i-ONasfepaR, 3-m«5hox>p>rrolkl»ne. .k.kcbífenigymaisíaKSi N X i i\ ’ NK O. sisdtu. «V pi > U >' > P '<i ' « „ . 5hc »«,' Ή f s V U0 s 'V ! ! *d ·> a Pms&r \» r* .o-dKd »1 . x »5*d $,50-05. x ‘'Vsm ,' kranstei J 0 x }ys*aiOt&$« ,-gMV vS! ·*··· üsethyKoíphony) gK-up.
Rsvofu ^ R ,ad \ r <.h x<(\ * >όι >v'» »^»' x d R- R Rom R\. rd u or di'- x boa *U05s&::. . osm fog 5 hero a ),3*<i50>xd,3ne group so which ous ofihe carbon atoms is- cpMoaasiy deu!era!ed»-a i»4*dK»a»» group, a M*dioxejx*R groups or Rs> R;. ;asd K^eadi r^resenf* a-.hydmgaa doro as5«S;%repro8eRís *·&**$$%· a rodhyl, a mdhosy, apdblpcy, a iHlluoromdhyiora iriflisoroinratti»^ | ,RiiroW'-s-55>droN^p^ b- ΐ'χ pd.t.od - ,ϋΟ'-X ' sR fl, ru'!KV'S'.r a iWp Xx\-,<ul "0*0 r '""' - Í0005t\ Ssddtm, I —' 'i- dd5dy,dn^.ffoolfor. 3 4-üihyds'ft'2//d.4-heaA»Ni52.ioo> mdaixe, l/Rrodisroky pvnrmdmo, rydobmyboadvd, CYCkspropyisieíhvi, */-kpyrarote. pyridine, pyr5d&d«fe>,ilios« guaspY ορ»ο.!.·»,>ν having Orsii or siKa-e sahYtkaoBf.;; sdcckai Roro bsiogeib brsear or brassdied (Cr* ;· } ··»'?« ^:"·· b.K-.r or bvata'bed d';rC\;kiikösy: :1¾¾ próírviYxi covopixmds of ihe (nvoattoP -s: 0 i-ítodbctó^: • S'bi"\do^vpx·'^; 5 ;ov^'n) x-0-»)«wVlhoP K'Ou.W * di hoqubx){my1}-:a{boo>iiddíbav.od50kO?-5o'>)'^^««>-p5>^7'8'-te}mhydíft"J''Mídí>l!8:}ne r&ibis^as^sifr, - .P{5-<fdo«^2-Uí3·¾·^^^··ίnoípho«J^l8íe4M^5>'?^Λyáf<^·2ιí//)·íisoöts«»5''?íyb'{ortx>ayίs·p<<ií»y!>.
Af'-íJ-iivíítoXjphoaylJ-.V-f i-sikethyMír-sR^i-S-yh-ő.bd.S-íotrshydrív j-bxMirüPs cxstöx-íooor, -< ^4b sisv^^ix >s<. f) \ s I ou-íbd j fkai so vi Y-x Γ-' - J dKtex n;»' <» Κϊ' <> ' ; ^ M'SOIV X ,d' ' i .15 Ί ' h" S\i '1' M - ' '' ,X3 '' 5 ' ie-xaisvdxs-; -sadoisrioe asrdxxasibdo.
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' U < ívJ M V ( 'íXíSV s\' d 5V, ,v|<í-oxk> 6 *í ''< kJ rís^rfíkfthíivimeibviKM-dshyihv-.k;í/)'<S!\:ulni>i^>d>:&dx.íixy||- I,í -licixavJiO'cwKV'yl^SA?»^ ksy;xhvdr<,- $ -ixífthíifse carbt^nuís. - '' - >v x!^so-4~!u.íV;- -(4-r>;>->fph4kx\ Vxcth> i kU 45S--x4k> k S /A4- \ρ,*ηκ>·'.ϋχ ϊκ<ϋ1χ·<ί<·- í|p«cs,\Ϊ :-N-M-h>J^»'ypho«n)>-\-íi-sm‘h\!-: -dihxür-' U* wdos·'' O- -- f* 'S u-h.íby.tu» carhossRiuk. .V-^4-hydr<í\yf5h?!tyí)- V--í) -sxeíbyi · i /AísísJokS-yU-í- ?ö-k(3:kh3-'(4'iíKírnExd45ySmd%y||-3i4r >4ihydr4-.5( 1 //Η&ο^ΐϊίηοΗϊχ^^-ίΓίχίπ^Ι^'ί^'-ίχ'ΐίίϊϊ^ίοχίϊΙ-δϊνΓρ-.ΐ-ϊϊκΙίϊΙίί.ίίκϊ csíh^saiskie, * ' 1 - > ,i ' Λ^\·; x ,4 'n?hut. v> *n v í x 'N J «) i \i X»» í.n k »»lx« v \i
Mi Mkvj\xphuxU> \ -1 íxeSüv ' ' 44".dt>'-í,x -vnío. ^.'-1 (txi'ltíiüti xix->x3inu:Hy " ,N ,s <h xro ' U(^v ' a .v.'rohokH mxil.vh 1 v»s\ '«v '«» IjcastavílpHSByfeí A44vhydroxyph<3>yr>-íV-4Jhenyk;i.4-djhyd?o-1 fí-pym>l<s\2 i Mi i J4}«x4.í.lr.i>^-carb<:íxiimíik'> - -M3-n«woph«»syik V-f4-hydro\>phsay)j-.Ήδ-i|(3^>3*{ηκ>φΐ5»Η«·»4·>kn^jylt \ 4- jc^rbími?» > -1,3 .be«acsdi«xo1'5-yl)-*5A 3.8-5eirshydK:Kidoikinc·· í - xasbojsarí-uSix shelf ο-οοοίοίοοο: sok! dhokaesoswna». áhs! applet swlss Ροίροί with a iPwoouwaSksPy kSeopphk ssiikl os· |km hhv ss-venoos: íYfópss álsü so s possss Tó? gpMPSlOii öf sospxasods W iwsshlsss;!), whish peeps ip :phtíp«t##é4% thai: .¾. yis§4 $£ pppsa! she Oopiphod of fpSlPia (’Of
I: s ·; wkfSYp % 1½ .¾ <«>d if; spp sleipsd: faf Pppla (1), whl0h-epp|3fpu.sá|; at (§ py&{fe<$ed| (ο ο Hpek S'ePÜpo ΐβ SOI espöoosοϊ· orgsoée psdsuso p the pessspe i>f ο |pi)sp Rí«'| khssjpki > &t$ pf ss phospo he api of lip spopoípii pf IspíPp f i 11):
:;m> wlpssPa Pe gsoops K; V gRá:í;tet»r«.-RS deősssd & Ipsisois (!), U) ofeóoss the soiopoosP »i: hsnwPs OV·:
J1V 5 whose h? tpiP. pís X. Ypsíi Méíta¢*^'#fi««íl^ferfRfWpl8.P)r th« aldehyde hisotiat? --ef which ca»i|>ööcíi:of fs»iMíIh CW! V oxidised St Sior eitSsssRytie siesd So idM did eompeussd of f'ermtis ( Vf:
m if» Y ss«f Bet are ys dsdodd Sor fS>:mssi|a (ff which coaspoeod tf Sormola S V) R thee eedisRed So pepdddeooplioss wiSSs rdidopoOsSil of Shi^hfe (¥!'}:
Wl) tehetem Rs R>. arsdR* am:«s-.dsi«8dferSl^wsia1:l),
So yield the competed of formeis. CVS!};
m\i wherein 8*fű. Rv> Κψ R, h\\ R\X. V sík! H<p art· as defined for formulatli, fo,, estei function ol ohieh eunij'ousid ot formula iVH) 's fy.f.-..-h red to melo me . .οίνον-όκ acid. or the ifMt'poki’%v.>'Kv -v:, nfo..' ' ' H νθ"..*<ο! ·ηϊ<' ! t , vc'toteu sv! n ^ ehk sde oi tlx eftiCispomUng mfoydrkk betöm befog coopted ndt; as- amine NHR,R, cvhorein K« and R< have the same tPeMfor» as for formula'll;, «* yield foe compouad <>*' formula (I)» «hieh compound of formula (is suae he peeided t-ccoo-has; to a conventional seuxaedioo iechmeme. which ts aooVeftcsd: il »*v <«e e no o s vtuh , tfo) iiuu 5 s 'esed 'Λ' κ Λ ot hív λ» Ateth \ 05. doo Jis sagmated mío 0·- isovc-'s s-o orvang ;o j c>.nceoti<mai se?'a! arson H'Chmguc·. it being understood that, ar nus fone considered appropriate in the ccinrse of tin; afoVvefoescinbeei process, íxeteío groups (hydroxy, ammo. ,} of the reagents or mtersriöeh&tej, orsytlhpfos may be protected and them tk pco\' PM ies-'Kinp to the impose neo>s oi s> 'tin s especially, who» one of (he groups fo or R* ed die amine RHKjR; 0 substituted by a hydroxy fonciism, dia latte? may foe· ghhjecteet befoeehmsd to a protection reactifos prior to coupling wth-őts «itifooxyllc aeiá fprötpd ffpíh ther pmpound of formtsia tVÍI), or cvilh a corrospotsding add derivative thersofo fosrescdticsg protected eomsMund of too mim ti) subsequently tmdoigoes e depsotecmoii icaoxots and ts then optrensiiv ecmeerfod t«fo 00« of ti;· adilhmn sah? *nh a plummseuncalK urceptabfo ucul or base the compounds of formulae tin. till). <VT> and the amine NHR>R> are either tomnocblly cmfohfofo or m\ he e-huooesi hy the person sfoUed in ihe set esit-g conventions! chemical reactions; rleserbxfo m ms titcrattirfe:-.
Rhsirtixicokxrc at study or toe compound? of the indention has sík-o η foot tiny hose 0-0 .oieptoe-c pieperxes ihe ahihiy to reactivate the apepio-k poseess in caneeroos ceils ip r>| nsapo tiieitoxortn· interest tn ihe !K Ovi v+e 1 C !S t oil U i JUi O' d:sv 'vs, \10iC e"|Vvti'h the vornp" nds v'sv u in 0 he i>ow’ ssh oe isvitti 1 «>ί«η\ d >. in-0 raiio-tes-istani cancm. tthd to onihgoaot ha«tn(ipa*hies and stnah-ceh sung cancer. ?\tr:osirt the cancer ireaiosgsits eovisageti there may be mentioned, cvirlioi.it in-piyiog. atsy íííOíMÍPo, eaticers of the tkfo's orm fi-yret s d c.s , , ^ s pm rt?<r 0 is c k 11 iVs.i S nos ot the oea^kagiis and ffodp lyfophohiastie teukamias.. fölbctdar lymphooias ««abgimm hacmnpth%
Oi\vO!<'i· v'v 0,0' vniCv C' snii.'vtU'ig is. > sVn'riO.'S iü S< i I P Cv'i'C s fÜí'ü#b.iW SiHiS·jR) phaonacesiticat coiSi|foSilm«s comprising at ^ρρό;|η4 :»f· formtikt (I) so comhimtisoti tenth otte at oxus' sfo nmnv'\di''>vRs «'v.'pt it'i. c\c«p\nt s.
Aipoog tins pharititiceotietd eomjxeoticfoe serc'oimo tt> the invesmon mrstt may he nnsnooocd ntore er-pecs.oty those .that are stiimbie for otah parenK-sah nasal. p*r- or irans-enumonuc reual. f^rünguai. cscxdut c.-r íMfdmtoa admloísírstioig espssslliv íáioá or dragees, sabtmgual ssbkdik sachea ]>api%; o^pöks, gksssstm Isseipis, and deoMd^ '0«? dosap yaiíes aeeoídőpis Ülsssx. aggood weíild rssfthc {«map íhe íbcrapöiig-iftátelea,: er sí sp ossooiaW toaomís?^ esd mngpi:%«m I4.;1m«rfi. OSSöf m»SK::3d^dniSS«í03S;
Fynhenoorg, the present myeíhmo reisies also to die assoossdks of a cumpouad el tbnmda (0 wkh &». stilesmcsr sgest selected kom gasstosk: sg®kg mkosc poisons, so-aomtsbolkev pokeasssse inhibitor?, ikmaso ssksbliörs sód Mibodies. ami aks topharatMesiivsi sospsshkms cmprisiss"úm i$pg~vf sH.ywisti«5) •md too omí o; tik ¢5¾ mofksa. «ί kukkere?.. \ k« v-em the kcaiok-m a y.sa'ct. lie compssods sí tkt ia^siíssímsg afe fos medlsáígHisilibs wISvíÉjkskerSp ;|p#e^
Ids f^ííöwli^#r^^tíö»&^í:lt«^]pfes IÍI»ai8íhs ístyésslbs fesids #t ÍJ mii íí ssfiospie Mid
Stee.&' Wemj f~2~pip?ri4fitgC6rbe)iylfc mid. Γο a Mkiíiftíi a’ 4s g of a fscdjtíic mixiure <;t ,k|ape.ndi!k:earlxs:tyl:e a< iá <ö.,> 10 moiosí m 3Sii mi. «1 tormsc U 0«. t5' >C \ v’\*Jl^N !N< i* ' j"‘ SÍ a iu'I. lA i ~ Tk^'O SÍ M > s v. í j .msbksd terííí'-ííáO.sííí overnight Uk k\KSek ' dxtors is then coek-d so Ö<-( . hytkok red Sy Sí* .sdokkve os aö ok. f>t water arsd stirred fyr hah as hvisr ál s'C before being txekSkrokevi to dev-seis. ide nd se oHamed *s. sohets kiii h iSÓdí ikk óiosbihimsl sódí ihass: isoseestatsd .Mds^tsssss 11«' sild gadMl; is sbssissb sy &* Itstsi ot álhsoi íkriher f «ilheaiissg: lse Ibs állováig: s4p> didso \m-y SsomVvK kth'k) η o (m. sH OH} Sv U' Ui .ddeh>a) 4.9~'a. aj. IH>i a N .«U a k >l a -í a.'O ym. Ί Í I‘' ^ o? v»,.' .M .? i i« »} l Γ>ρ> KkiK) 3Rí v: -OH' daCKí-3000 cm 5 acni, v: '< =·=0 I ?03 cm'* bmad band ΦΜΐβ* -?A ?<8~tetr«hy4r»~ ΜηΦ»8ζΐη*<'α¥$$$ρ($ί$· 'hs a ss-ikiiioj! sí Kí g <h\.(ir!x;xj Uc acisisblsksed m Sios A <b3.6· mmol) ks 65 ohi oí dís-Síisjsothsss yssre s?e sddú'd is sscu;3$íí«t I >.4 g oiíoi’.d vhíörido (76.4 ínaxdk I i .5 mL ·>ί -oesvv! 2-cldofOMfy1si6 \s í.>.5 ssssoi} 3«d them dror-*Kc\ 17.8 mi.«í A; •V.íV->ktelhyhmjisJs Π2? 2 The sMvmm misíüm is then reiíuxed for 1.5 hose's, h is tik-a Os'okghl lo skihsest Síoopioaíors. sód dk::;í .5 ősi. js'íkcisyi .>chktf»acryla$e i4S.'> mioo!.;. íM' v> vv\k *> » s v \ S l <‘t s. 1' x s » s Ovid...., ..k .vh...........,o™vO sd 0 s 'se k Η >«> ív.-h *.«>!· í^íxíís^: w, ^übssqiít'íitiy dde-eo with tssethyiene eh kaidé, washed ϊ>« voecevnon with a ι N HU : <s. W< k \ 0*.' \<«! < ! {> d ‘ 1' J \> «Vi*. \ιΟ \ > V Η K Si'.'''ét pH V i) .i<> .fcYi, she- iotgu-sv piláfé r* thets dned over MgXO», filtered, co-seenUated so ötytus* aad putti»v»j by vttr<on8t<3gsj^|h>: 1 Ni! «. d nj s <. *1 V.P it > ' Vttkpfvss .« ΐ h . ted's the ' ' »0 ' ' '8 ::íiülí:j (400 MB* CSX.k 300;:K5: #J6k.4i:p;: 2H. :^WMfd5«didteNs| Η 3H H, 311 roeshyi eip| 'Ή HI i! PU! 'll V* C Ok t mIv! 0 ! i\ k> 3 > vS s < S' S> fv'
Hb v:'<'™<) i{>42 cm'* «»κ·ί 5¾¾) U MefM S-ib-J&myl / Jkfc'n ν»<ί*»γ»/ U'fí-1 6 dm-
To ss so ιοί km oi <>.4 g of the roster obtained m keg B US.? mos*) so 12 oo. o« ^V-dmiethyhi'ieiaistkse shore are .srkkd so mseer «most Γ* ^ a? s- Í" >!)» \ t-be \«itk"o\ '-c,i UsUehUr s''' ' ssvtis'fi .md " r o« emtaUosa sseeute « ·I ,4 ormot;. .so,; sh« wised-'; - tkon -.«so-sU o«-h:rso go a da ?0 «süttök·». ;.3 o cd paiisrhors; eatakst PíiCIgi-BhíS;; il 8 sronoh <«rs she» added. she react hut -íüKUire k «.ttbserpsSfsdy heated at Ui)”t. k«r rme kosr Before 13d t.d <4 H-f* are .aided soereto Heating :-5 mointttűird at that saroe tsmiper-sbue «veitngkt fhe mixture is allowed te rehtrn u< őrsi c » L. síp. s s-e s i e, sv s h « -> '· 3<Λ \s id'tí.-.*ik
Uded (2 y |x-r g <4' pfOiisKí) Siiki dsg svisok' is stimrd ai si?sbi>>si K'-sips'ratiiís.' i;>í o-w gyár ássd thstss ídu'ísxl i hv orgsiak pha?? ss then w&ghcst with 'aster. ..ified over maut«?3iuttt >sdpk;Be asset <í>iis.gístnsU:5 t·' ds^neks Itw s.b; te gí\>ii'i.i -a ws'USfkd >k i's.}stY>t an ask.a gi' xhvptajse ^a's'i krasik-'-O Tks isik pssV>ts': >k ysbis.isss'-s us thedon» öf fetidili ‘H-NMRt δ: «40β ΜΗ* dmso-dO; 333 44): 3),63 (s. \H, H altkhydt;): ? 3-7.15 (2y 214. Ii atowatic): 6.45 1*
;H k'iS'idík.K' irk'lse-rsr"' A H> s\ ii'fc'S'i\ie«e«!í.'!\' s 'Ό v> Ht tu«t"v «^stor < >l! l" B kiBrívd'auivJs'iíeissek « 0-tu) 'it tetess.dtostdelv uc', i 8* ssn B s '^sseat.'SvMi'!' .ss 11<; v '-€"43 Γ645 «.".is” es-i·.':·, v: >í>s.) ifi Bt ciu'5
Stei* í>: 6~(l-ai?ik/iXfCMhm?>ih$>&JJ~Í^kytfm^miÍs!tiütty^h$~&&>w&^e!«-$-<ritt’&ifX?ifce£Í{Í Thcrs; »«: ptopami a. sói taton eotttausiog 3.3? g-of thescotrs|xtattd obtained .*0·>&$ρ· C f ttt,3 «ttoois in R-3 ott- >>i-a«8'ooe and 8!8 mT#8 24 tnm# which sohniott is placed at Q%\ Titer» ate added, dropstise. 0.3 mL df&n agaeoss wldt'ibn oohisirthtg st nistt«uv of 3.3 g oi"Na<'i^ d tdi'.o? n»sstoi.t .end 3 0 g of- sóbsefjaenity- stlfTedsiat ttatSkt?# .fgtnpsMtre. tdr 7 k0dik.: ritedidpdiftdi : otixtuiv tk thea cöscersSíateíi in <N'der t<s remove the stkiette. Use soitd tta«n sdnatoed is fdteted. washed wnh wati v v f-eo drted tn v«o«o .t 4o O w.mtx v i \ t tk p o>i \ k v'st > ό > htv \ s«s > .·»! J e>4ieh k reed soBse.gsesidg ^«hoot tvs«sp «OrsBed ieithes
Hl-NMR: «' s B'-t MHe. dfrssu-di\ 300'K > i2 i0 ins. i Η, H «.«trboxv in -sprig ?.-kk«.08 t.B. ?H t i aKauatk). d.etsdk th. U tcittshydfotadoli^ne): 6.18 td, 2H. H methyiettedioxy); 3-70 {* 3Π. meksyi *4erg 3,35 <t. ,2il l^Í^d^ÍiSo^#il^:C^lH!ktfahyd?otndoiteifsehlitö.líis. 4Π, \i tetrahydrnintioir/tns:3 11¾ 5: ϊΐ «OH; -SÖ(tóf2!^ÖÖ ssp' ' add ΐ v: PdFi I $ίϋ*Ί:δ:$& asn'! PsieM'abkb V: b@b04' 1 §8$ ·:«??&'' Ö!S$SÍ|&ÍSJ1 i 4'Ms?esie~^| | sls3;á«s^feléll*isf í|fe® I hS: pímsdufe: ss i^:;«> íl® ipsesss öt fepamibsn 1* "episelng 88«s* ih iiifeg C by -'^J'dsIss'sssíssjbssiíÍslíSssIwsissf 'Tbaüss ,|§. ssbbbnsd s s«|ss«nlsdi:% cl^sssisii^pspisyi ;É|l|5g|a|Íö|iJ; 4'€lsÍ«f8-^í|lí||8iSíbö5sy8srfem>1)“S,^?J^gn<s5l5yíír^3''mdöH*is53íl|l?«®*^:®^ lik ps^íiS-ífers:is: ssi&í.llss grtííisss oí i%:pmi!isn I, ntpsacuíg ihe 8*feí%>?5Jö<-4p^ílfeK2-öáj^^^‘^'^s’^^^P^:' »4 inlkp F by 2^f«8Ki»y|^hte?feeR2al5fc'lpl®«:. .fkpjsfaúea 4: 4-'F!eor^#|I^iiaetéili&s>'««^oayi>'$»6«?<8'-leSr»h^tO<34n«ÍáillKl}<yi|^^^'^^: 1'1'isí |n»eei«ny ib;«s i^öÜS pmnss <sfIsíipeiböss: 1, íbplaebsg if*e 8$«sl i« i Step C hy. ·
Pmamssfen............|fe; ^|1~|p^j;fs0sygarfiS5íyl>-5>ft>'?!8'^?faifeyílís>-3~lssí«íl»iSiylíIi3?^^^f^^"fe^ Í3^SííSÍSslÍíi:s«|jfÍí?^^«SríS«sS^í1«:^^ÍHtí
Tfife pasecikse is as in iW pnxesa oi' Ptepr»n«n j, a-plaüng ifi? m%ừ Sicp i. s>> 8'troaK-.'.4-J:h>8nj'.?^'K-'bt«s«dbsc{»i»«-'?-vartaldeíÍyáf...
Tiif i'iiicafiisv is as in isse prou-sss nf fepsrnissns |, iefsladng ifié inbrmno- i ,3-t>sts:«sdi(sxofe-:ncssrbsidehyde a&eri sí: Ssep <' by 2'bro«»4*m«tosyl^aiW«h^áSí
Fr^paí^8í>n ^Í %rf ls|Mgitesy£s8jsl5ö»yÍ|pI^^j^®ír8|iyáí ^3"lís<inifeli}yilspl Í^^itesíanáfelsfe {fbpsriasyic «éli
The pusccditse is as in íisc process oí ibepsssnioss. I. repladisg She i)-brors>oi>3d;sn«txiii>x<5fe-5 sarbniisshyde amd sí: Si«p C by? ísbmsííO'S^'iihysis'os^^;'^nxödlnxift^'#-esíMiiebyiev
Pben«^ilaa §; 4^ÍÍ}ns^4iM«s^fesymrbnnyM^Jiilelrslíyir84~ini«liafa^l|b«iánfe«IÍ
Tb« inaceihrsls m m she process of fhepaseithís 1, sep|M:;í«g; Ttsé b-in»íní> i dsd>ca}«mHoxolö~3-earb«i<fehyde issed hi: §i«f> C by 2d5KaHiMvHh<>xyb<3zalddsyde.
Frens««lljins fi iplíyeKSei^^iy^elböxyenrbnnYlFSíbd^ielí^Síyiro^-iííinfMbyíl-íjl-benimiiisbie-^'enbbnxylie «di áÉ^Li' l'n a soluison of 10 g «I :<,4xHbydsnssybC!}.íaSíkbs:de φΐ? mmoi) m 110 ml. <>f xsisydfoiss £>MP there are bíliai ni sanassssicas 114 g ssfeaesstssís eafhonau t ^-t" mm<»il ami 23 mi. of dktemermed sssstfiykíib «binm!« ws*, i«e reaeiKm smxtare »v μκ'-,ν k » "t > * d y >Ήκ krih «* o\ n' x \(k if me mvdubk; oods·»5 «χ« eekk, dse χ'όιΗο, bhrAk' ; vsbvxpiemh S'\rheK\<v (". ad Pi so> of (Op χ\ m t-vaisr end dmo extraued «-ids cl by I aceiase ('(·ο orgsttx· phases &re (hex combated, washed adds a satiated UCt solsdbkfarsd dish dmi pvet MgStV After coftesfrxrsbtvs ίο dry««s% tbs reYtdpv *f pm'ftM b^ cdirosetdography oyer pitied ggtfpetroieiim ether/AcC® gradim?). Ί he ode product iyobtsiigedlP \bf fonp ff ksiiif t40<'\iHAd».^d6, ksd'M M HakWitdes f x no Hi H asomasx} ÍR; v C Ό sddehvde: (67(( cm 5
Mens B; tb~8?mub'2.2~Mimfem>~$J~bgiw^kiXitk'~$<ixsrfc&k'h}>iiii
To s wtkiHon of I.0 get the eompou»d abt&iaed m Step Λ (65,7 mmol) So 100 ml- ofmebxsrsoS footed k> OX’ (here are added dropwise 3.7 ml, of a solution of híöbixsr (5 1 mobr e»pxv&kmts<} is H> mi., of mdtbsod|. The whole, is. aebsepaeotiy siifröd si ambssm tesípésslkke ovetmgh; Oso reperip» mistsxe is eMceriiXsssed to
OMikv v>< fti}» Vii' \ii'> >'X * e f tn> > ,1 \χΐ'>\ ,i s ‘ 0 > ,.d tx* tixr orted d(40(1¾¾ diiisfKtdfIW:K): 104 is. 1HJ!shkhydey 7.4(s, JN,Hematic},7.05b, Hi H aroxsaoe)
Hi- t; t' oMebfde: (h'O cm !; f C afonmtk(bit cm ' [Step (> 2,^Diiíetnerí9~^'^i~íms^tffiyí'íst,h(/>s}'ib.^>>'f>^--(eiF&hyiirt>~S~hi^úií^t fy//'id-6e«;odmoo.4'-5~
sm'iMixytii: aeM (he p>"tedui« a- ,!f m do props >d Jes<.rlk>: as Siep5 0 m.d H os '·ϊο;-\γ:Ρκό i, xp .xsng die η-ροχοο- ,x h<m.r.obx!xobdx:snxddehyd<! ov.si iri Step C hy 6-bromoO.ihdideuseno-1 ,MxesAxhoxole-5x:ar!Xik>ehvik·. IQ'epiSTpiiOd.....10: 3-| f(Methotvearhos:> 1 )-5,6,” .8-titsahy drO'i'isukdkhit 1(-4-((nOuoromvíbyifheaxftic '('ha psocedme Ή as itv die protocol desx'xhed ie Fsxparad'so (, repiariag ;ise é-hiwsisio-i.í-hekíBxbo^öle-^-«athsldehyite osed ip Si«p C by ^rbrOino^-'Cttiftuuromcihjdibenxaidehyde··.
Praosraikks Η; 2'θ(,(6^3|·Η>χ>^χίί4ίθ!ϊ,ΐ1,Ρ5,(>>·Α8-1ο(ΠίΡνίίί·ο-3'ίο4ο(Ηΐχγ1(-·4·<;«πΟ«οη>ίοοί1ο)χν4χ*»ϊοκ'' sK'id ( he psoeasiae is as ist the protocol described (h Preparálso?( Idfepiaemg six· O^Rfiki-i,3-boiupéloxíde·'?-cstbsddehydo esed io Step C by 2-bx)íoo-4'Cío(lsX5rottieíhoxy)heo;sdde(tv\li.'.
Ilödfíitd.ib.df Ili 2'{l>(bíeibxiste»fbt>xt O-S.edib-UdfaSrydr«'ddifitidHisn'ii(íe«fok siesd
'fhé |ϋίρ?6'ρ4ΐ(ί^5ΐΙ' dlil^.^é· j^rpíbíid.r 4dldHb®ái: iOdSIipitoílbO i> replacx'L ’ x o hvrisen,.''hen.»xko\.»>'e N tv't S!d Ο V i St^p '\ ') > ' . 'Ό ^l'fd δ·I MM&'íl!0vv««lHíSíy^"S-5!SílöH;-s^yi|'·i^^íesxoUtosyk'-S-csffeosyi^ sH<§ ^ΙΐίΈ,;?.· i"ír#^ATH«%(í»^2"áígííííi®'«(/^í8S! &t amide Λ'' · 'w * ' * . ^· >ν*?
To .> Mid.,' ϊ-'-Γ" of ' 0 5 O'b, Of ρΥΠχίΟΧ X \5tí iOOVS' Μ ΐ ''ÍJ OU 'X θΦθ ΐ .Χχ! ί <. ifiísX Ο*. XÍ\W 0¾ ;\xS»'N,'s ' Yj^ g (20ο ηοηοΓ? of lo'oofofuxxii. ne?<i. fhs vH:s>k; k subxtoiisoíiv ybnyx: ;o ao;b;ens kn?>p<;'«nise ονΐ5**5^5*' N5\íípi ' (0 oh Sií.0 n x o OiX K'Í S Vi '%>" U' *Üí\S Vi U \^ ''<> Λ Slib
Mwsíud o tU fi' !0 oí pxu' \ 'ívfa í'm J ah S>í i <'lb' xní>p ’H-NMRj δ <4UÖ Mik. dmso-dfx 360'K> CU$ -bf 2H, H iiswr-iitio ρ\π·.ΙΙη£ΪΚ 8 ? (i ! Η, Η it. Hl H annunfiíb. ' 65 (a 1:H, H OkCOOHf !R; v: C =--0: i?32 yob; -OH &UU: .kOÖcnf5 Λ)\;|ί §; Hh'íhyi f-iítdadkineeuthaxyim<.· 1 <:. ii jjijNpcnsimi of 6.55 g oí the pyridiniurn uAx obtained oí Skip á (3U «>tn«0 b; 3.40 ml, of soloobP ^!ΙΪ5ίί aíx: ;i.kívO in j.iKoöSs.ioo 50.7 mS.. oí ük'íKí .χί'\ ints· ξϊορ "Snob;, 4 .? ox of ni ό χΟονηκ ; -b οοηοί) <*«-'
Pu'O <i pt"U(Ui fb ό x Ss: MslV xf SO χ-ϊX '<-:' Í dC UiK'-O - xsíkk\pí-.íOH\ b.'SkV .5 'i.ox' hx UiOUXb Akis X ' Οχ x X 0< !< XÍ 1 >.' N ί X 0 < '· .. f 0 6 ! !\n 00 ΐ Í.Í X s'nU ' 0 SO Of'· X 'k ! <· j JtXJi-U '< then iSoiixsod by nos is kon do; os; ydies gd Hu-ptsf^AcOÍ.'t gob dint; iMfHd in be form At' as b-l ery.-iUdHsea *&ϊη e;>ki !li-.N>m: b ('06 \S!i.-\ sSroso-b'x 'd<>xf S.Od, IB. it kxNieukXX tUH uS< HI Si oddf/usd. ; Μ-·- US, U üí^Sx-i'seb ' S'5 un. ?H, H -mSoSiexx'S *> ¢^-, Íf4 U ΟΗίηϊχ^ηχ'ΐ s 7M. HA. i -'N s* '$'- -C{0)CH-CHt> IH % \ xtNu 6“s'bo v i .o .Rk ' 'fon;
Xiú'LlJ *-/?-* ih'dh'ixvi ííj'Axíío/í- >-iítí/í»/f*/»i’f/'i.c*-A.'H<;íííí«ív«*ía'^íw*»3U0.,//e avid i hí-- ρηχ;\ί;θχ' ín o', ίο t?K' ptoSocol dor-yajlnxi its Step.; C .uxi f> of iTnponníxJ!; S ,
Prefi»r»ll»8 14ς 4>-<! f}l»r»'2«{ f-isssfhosyTSS'konyit-A-'inOsiiiKisyiipsen^oSe Sbííi "> >v ; I'j K'nht η i d vv'd'» e ) 'Ks\\< < v x> s Mi\s ' » s Oa^swrti. >h ) ' »0 ! ÍN n !' '"..s! \ o'íJt vb Ko> J, S x> ' l Ο Ν' <4 <k«N «*$<>' >NpN ‘ í 50 U í!s
Sbxp.sív'S'it'í b. iNplnsíig Sín t'-bsoíOo-S '-SxíXixyoM'k'-^-.nH-aíOtshyOe o-eo o; x;ep '' b; ’ Nofsa» í ibi<.un>bn»ziOdehyik:
Fn-oomjoi? |k 7-1 ;--t6tnHnísyi'ooS>;;íiySffi-íi;o;nií>oiívif.A3'-sbSíyiko--1,4-lí»ft'ia«N»»l»c^:8rí>«xylic aeki
kfesbyi t -indíjHeítteesfbnxyiáífö *5 idsoxed sceovdsng í<> U«e gíOessí. descíihe-J Síi Sinps-Á aná B S3. Th<- Hite pSTxliicí is. í^S;3Sft«íl;:acee?Hiíi|.xto :be; pystoexl::iSsseHbsxi is; SSepy Cl s»á Pxofí ' » «'° - on ο I U vU"· * ',k,' x n ' c, y x ' t mi '' ' ' .d'O- ^ViV'ViiXt \'Ό , '!, 4de'3Xk
MethvS ktmkiHitHxecstboxvUo x iouxxf οα'χφ.ίχ; 3x she mv*-- Jrxrsix'd m Ssejx Λ .x;d B ot Preparation U. me ttife product x tabswjtKolk obtsinxi ix-xsdi^ 3-' ps«k.xd A'xxhxi m Svsx 0 asd'.D efi Preparation I. replacing the <S-brem»-IJ-t'enxMmxolev.^.c^idehyde nsed In Step 0 by Mjsvnno^-jReshosykcnzaldehyde.
EiWli!»__üt V|2^^8utex)ícerl^RylH^ia<>th^p.r^«yn· I ,3^4detr»M*»Rri?**tot W- a |py raatfct -4' y i| Ί im o kxvea t boxy lie sc kl ;Vf££.-i-' i-ii;ri~8m->i $ methyl é^mnv^iJ^ipemzitii'diciwhüAyime h> ΐ Oution o$'pe)i5.dht''X'|>3kx\ x .Os mi nt atn'.dtxsx et\rat<s'\ sttete are .td-k 3 ϊχ x.-ceRsxx;. 44 . χ s eihxi-d''' !Í!Sí"^K''V fK'pf^xk-CAfS:· tdmmde x'4x a mx ' «5 jvw'-ii smd - m3. <4 txx ' 0 !.k„' srsRsm ·. The xhOe it: xsmx x «mbieus seiiaxa-iime for3. hossx. Thorn x «Ρχχχίχφ added & mlsture of 53 s sk 3-<v.\~-mt\l : meihxl \ d-pspe.wsxdsímívx'J ste < ! A3 a mo*', .m3 3 8 mi of 3xt3h\ ianusv y i P) «remi* sokit-ms ss >;3 ssd. oi'CHjOj. The xvhoie issiirsxsi oxesntgks at amhunxi tetstpetatufe. Πκ: reaction snielure -μ hydtaiyssd íwsthxan i-N 4κμ«\\' '"k xk*ην» md s>x\kR\! w»d> $43,*'3 Iht ‘M^nn phaxs a*o stdneqaertJiy cosnbined und 3hcn » n>iteá uiUj 4 snturused skptiisssx NaHCOs sdkitips ind tJNen o-sth <3 isattííoíed ttígteous Hot. i unitit3033 untd nemről. Alter drying over MgSO*, filtration· stxd ^^?enrrat?nn ko ό\ xxx.. the prxhxi j$ koistVd by rhro.'JiatogrsptsY over xkeu gd tpOtokmm ether Telíbs gonbetn 0-3<3'vO, 1 he title praduei x oftaksed as she idrnt of an oil 1H; e t O' iA74-i745ét# mit KCrih^fiXi :r-l 3ϊΜ· ϊ »<t 333 «Μ<·Ν&)\ 5o"!253 (»Ι453| LS'tep S: Γο a ;.ols;ik>n <k'28 y <4' the eonspoutid oiÉaióeif isi is«p A {103 5t33ts(3Í 'in á i 5 ádohd 4 8 .' i>f 3 a.)}i ft}"' íüííí-íU in xhisisott so ii'i'i )5s| o{ 33.3 f sík- vOvio jn .»iiiX'0 >>t <''v:iS'!"!)' tem^asinc 3x<s 4 hoots Tha inaction mishite it subw^sentlf. tmmmmM m-é$mm oats dhvl su'tak- fh·' i3sk 3>e«i;sc3 is syhfsitet m the ibrssv tif a.sb'M ssKá lsosmf ^fek^ ^t sfe Μ1ό®Ι?ί||; eyhHptkssxi0ti|i. '0 (StMío'ot, 4' s-do. AO ki 30 s'. 3. psínoaraci. 45-3g s>x 0 fn.v-.t/s k i ',ftSvtN5· rii|'".ír:i,''.h'!;í); 30 :'- 3 \ í. 3lts).
If|í y:; C’”'Oí 1:03:04430 fSkf;! 4.hp..Cv ?~f0gt*Bittyí fcfiwtHyl Γο a stestóaskia of 20 κ oí'll-e sotnyoiiSie okamed ia Sin- 8 Π03 ussmdes) la $00 »U <M dk:hsorGet"'!!'u; Üs ^ >11 Λ* ! Í ΙΗ!^Λ\·'! '4 £ ot l>S'v' ί. iYiXk ι!2*ϊ OK » !> 'U '**. oU'M ' Oil *>νχ'χ'8Α'i! aiaad i ;:Si5u thi'i; 3¾ i'ííL of hdetkykiSibax' <'24? torooíss). Πχ'- 'wSSvde ss ^ííííxx; x> se fiús ssm' 2 hivass. Ad>·' y.x·' ^ H ^»f(l Í' US (X ' I V K * i ^ 'ÜK' ki Ί s sV^ '''iá <5Ü>3fc-4 ••K«CI w>iubo« umtl neural. Aikr Uryiflg <wcr M[§Sí>.<. itiimtíon md uMwctrtratíon Ki dsyisess, Utó ?íMk jw „ \ í-sAVÍ' vl'om ΟΊν' ' Af' íc< s;s· Hu A ν' xiídkin > * ')> : x biti solid. IH-NMRi δ (4(50 MHz; U«n<3KÍ(i; lOiPKt: 6:fMs,43 í'm, 28. 3i pytrok); -4.75-3.75 isss, óH, H pspexffiihídíh > ?3 {s, 3H,! i COÖClBy 1.48 (\ OH, H %& !lk v: 0--Oi«Kij«aaftíd esiesl: ΠΪ2 <;ssV!;<>0 (^Nassíisk IMxssí ' j^ZW&ext^Srxaeifwgtlte m0
The procedure ss as in the protocol described is Sseps C &«d 0 of korpás ai ios< !. fíNiOsnHdiii M: 6*|?»<M*(&<»iV«*rtM>»YlVl*3^ií«vdm-l/l*övrtoJi*i«'-5*vl|'*U*be»atói&x»fe*S?: wrtw'wwS'wwww'Ny'y' :·: .·*· ·>.· <· .....> * ·· :w · < ·>;..·. · · > c&rlK>syíic add T he:pí-occdui'ű is ss in Ide psxSocd dessiihsd; sö ikeparsdiofi k roplaeitig the 2-p7>eridhiiesteixisyd« 3chi osed ül Sic··' A by fiedite
Prefttireiiüii 1¾ 4»Chl»f&>3i»i?“(mgtfaOi;yc»rbfti»yl5-23"<IUii.v<lm-l#/“jE>yrfaH3áa-&-yl|bg«zo5e-'sgM: 11té;|>mCsdei'e :iS;&s dí she prwuxrid described ja PtspsM'iöR K Kjp}aetng.áje'2:*fjpöá't««a«toxylk: ikiá ίδ»0 Ϊ» Siép A -Ily ;psidmö, vxhik die 6-Ηη>οκ>-1,34je«/0álox-öfe~5-<.arfesWdtydft sissd Isi StepAxis replaced by 2* hxxxo· i-xhkoolxxroddehyde.
UnsOd^tidd 20; 4s-Oijdrtkiei|t|psgtlio^yearb*>ftyl|f3,d •dsfeydiíisliihi^is-rojftPslixJjl >í}Iks«x<>k add %o procedtjnr is sis io it reposing I?" morphol isípesrbox y I it; seid. while the ddormod ;3'henK<>di»xti«eu<íe'baidehy<;e esed üt Step C Is replaced by h.-hiviiisii'd •ehküidieiushit'hyde i^feOk^iidd .....2Jr <St*|ÍHfV1d!i»y5 **r5m«ylV.M'djhy dm· l//-p>m»!e$J'Vj{ Mjos&sJnA-Yij. 1,3-
Ik- üíxid 1οό> js-§« e« r bn sy be sc is!
The pusCedlir* is SStlti: IhS:SSfökSSöl desesifeöd:3ii:fskpídai:íísi::k íe||ÍiKldg S^dpeiidütósístsbösylié Sid:iÍ :%3χ :i«öípi!diüieeiii-hti\y lk &üd.
Pi'dddá^Üod 22; 4'Chkirtí-2«|!(dK:t'is«!iv<'SifjKi«yl)-(i,7}8t§->tiO'sbydn>^2iiyri'«k8ÍI,2'ss»id«*p!8e3" yÍ{5Kíd®ök isid ! hi, pXKs'iSU'-' m if;' r>s4s\Oi licw ' -Vsi in i'fSjNii'J' = 1 tsi'R it. .Sfiparibi si eNuvin 4s "t 1 ", ,' •.v&eoftnecatlxwyHc acid. sebiie she <Vbn>inO'-!.í-btín:-^.:dii:>^i.;k:'5'«ikH!hkh\ds: used ή< Yep C is replaced by 2-1¾ ΐ ϊϊϊϊϊ Íörííbíí s^áiáMfelí^ í Jíí s 13; 6*i í-{M«ih«\>i>8í'b»8>1í“bs7sB>,í'i<‘ti'Yís>'ííi'<>"3?í'|)J i *2-8{a*eplft"d~3d|' 1,3* hesísád kaó$$*$*m rh& yylk aekf hite procedure is as itt >he protocol described irt Pteparatioti 1. rephsesug l·:· pipa'idiseesi-bocyne «dn Pv ,:· a/epaoecnrhoxyltc acid. ^ # >C'N Ιΐ> f"s>s3 ώ| 3^1¾¾ ^SÍm> ®cyí - s‘ ϊ> «> IJ-' í ö iSi£i Ιΐ^ίί ίί<ϊ« S ^ isjí I) |j«:íiiSf#ÍCr =^¾ S’te& .4:- \$gth?i /-fi- ihf$8t<f&iiiyi)~ fH~pyervh<-2~mrb{}\yie& f:\ & caspenae-si tb b ' g t341.7 smrsoi) ot Maii (80¾) In 4bi> ml.. of irfshvOrotis s ill- &i b'C the te cps adoed 2ba.iUsi.l5 tntnoi) of tnethyi [//-rsyrroie-Marho'S) íate fsee i&rtnh$ii>a*t 30tí.b. 64, Rí?)- 1be whose ]§ i iNss1 f a' i' i\ Híj. n as i ' t os ú e l> i 'tr a »tH' a s < dec 1 \ttet tbc -* 8 í u4" the rcacüáii mixture ;s hasted ,it reilua for 12 boars. ibe predpttato oipsioed ;s tittered osí ano then wasttea :w&h THh she filtrate n. s-ubseouendt concentrated to utyness Tbc <ot«poaod is ihett kolated hy chioiíinioginptiv '»vvr síiíca nel {C'.í.iotie's.tftc udeJ acetate spUsherst; 0 to ,S2U) yo ibe kinti o> &t> sül. míenH*H&lyxti? %C :’.;>// %N :M:Bf i.. i.i / \ *: í/ít U- íf 4f. / -·' 3.·>.:' di.ád .//'*. .· r f i>?.c:S·:/ 5.56 Ϊ.29 5(>
Ití yr -C-CI::: 1/00 i.'-cs !: y; 1238 esrr .Sh't* U: .Mcibyí 5>- '\H- A solatia off i ilöj/mtmd) of tlissii^ftiiiyíledvlériyst/íye bbtóieb itt 8hef Adó btmg$i to Tlm^sdáy^ftefsfei&.^ldfc· of k «rádkra & uA# mmir defi :51 ;:ίί$ΐφ and s-t 30 _ sti t\n*Y$y t hXt -fontot) ό <t>0 nn of it'snc's' 1 be wbok s.- ts*'l o^d ttv .dtnas- tbc ie-ntk-n i^ixtot® Is síáiseítoersde coticestráist! h>:#ys$e*s. WM íhóihlaö by cfeir^blpl^l^i· ·;·^ί á:fa:pli|k^^eaa^M%i:aedt«te gnidietü á to 10¾):« isse fevrtn of an nit. 0 (400 MHsí; COK 1.-; 30tsi?K): n.bbtd, ilL H pp?t>b>i; >.83 (d, iff» H. 8pfdle|( 4dÓ (f 2(1. f ffj tBdoit/MwV .Uö;s 3H. XlcV. 2.8b it, 21L fH> wdoliaane); 12=5 (nt, 3H- <.'H» i/idobaine); 1.80 (ηκ 2H. Ol; lísdbbpite) : ÍR; yy-C'ydi K>05 esc 5 ,:$tep (: 4~i 'ttiiir(f~2'f3-(nietit*ixrMrőtmyl}'$t(í. «s.«/ y ie ips'öcedtiro is ;es ni ihe protocol desctil^d to Steps C -esc P of RspurtiO^t-L: SS: S'SMOSs«m'»5dHmyS>'ddCkB'SOsxdmS?'oSsKSoSia:S?«ckySj d-meihyS&esxöSe sdd h. ' ej *, >v sx «SS t r v'>* k ν!ιϊίΛ seosOívob v ;«s.«d in Step C by I-toiao^^m^byJto^ldehyífe.
Preeamkss 2b; 1 M~p\ r r«ie||í|>#i| ί.ί$Ν$Ρ?Ν*$* vlj késsék a e sd I ^ |Κι \Λ v \ ' v vul»\vb 1 ‘ * * 0' s'í *> > ’fi' 1 < ' \ i^ >i! ' 2- movphoSsnec&rk^yk &aó. while she b-konn>- I J-VnaodsexoSn- S-e&rtaldghyde used m kqs 0 k sqsbced » *« s λ í *Ho «vt/}'(khik‘
Pm>ar»$Sa8 2?: ^Fleer^^ir^msthoxy^arboayO'S’^^ihyilr^’H^^lreltfMNasatett^l»?^ iödfctlfcSaj-^ytjbetiseökaelíl
Sj^^Ai Methyi8'<4'tii‘i\e"8-iKü<pirefá$fóct'(itie~7-eerí>o,s$ie(c 'Kví p«'k i 3 íh V t 8 Í P il[iM ¢0 d h\> Ss { S *\tt\l' sis d<Vx * s>d >)S Sl 'd x PíN as esnie 3«>i ve esi os dseSs •.ppvmS <see 1 kev,«e a.\!S'd > .xsd'<,4 ss';r>>í\.í'!.vi' f>>? ísvsk < íratok- «.ed ik > «ίϊ. ! s< \ « «'d'is· S \ u 5 !>xíx 01 lvs \x 3Í> 1' \ v so >' O* po s s'tO'SMX . *dtok£> síp «> ^Ss\S -veíáí'í The "S^sísk' phaNv *s sSíb>i\:tseidSs' wadsed ss·* vucce&skw ebb ;s í N NuOB ^olsstkm water, dsess w hb « saturated NH.,03 keSud-an ss*$SiS is neutral pH w reas'Ued, Ss w s«Sx Cxpwsaíy sked «ver MMbhsídm ssslpssese. S'sheíed sb?l: te Őse oss s& akssssed h psídl^á? by OasSd rhí’omnsogí&phy thepíankikssy S cscesste gnsdsesst ). 1 Ser sssSe product s\ okaesed in Sks Skse of sas ed. ΉΛΜ8 MlOoMSO d'Oso-cS*- W K> SÍM' Hí, v'fO\ ' d 0 ' v«e, S}S Ms, e«>3> i* i ' pe Ki, 4SS cshyicnedksxy * HS «hphatk pipes kiáss·; .<.'?(; ss, .)H, Nko. >,4-2 4 (2m, Síi, SS aliphatic piperidine); 23- 1 f,' \»n. dlt, II alspbado *«p««he«V i 3-5,3 üss, 2SS, SS &hph»ísypspersdme) M?p Mid 5 x 2v ' et SÍK' \ ' epe-ovi «Oas xe«i ss' "S<v \ *>.’ ' *"S'''" «sx ds -> \κ·Λ ss' !w» r »* < \a v \ so ..Psor <xi S .'·? s\ss os'sbS Svs'sH s^-ídssen tS>'s>ps>ss?·. üsd ;k ^holejsv.Hsnvcl »u ankuvnl ten»{H.f sS«:» fo» v»'\ S«><' Issei'?· •sfo 'sssS'vt spsoistb asLSxsS s '5 ;;sS v't Skt Sít s. <sí)d sbv r ;>ίορ«;!ον; í exs».:' s '-s 's uh s-sk sí' s ns ;>? S< ií'-e Isse pppassSs.' pSsssse sss árasa <sv M\N * Ili 'séd d s.vvs^íSSfaS’rss s d s.s ss n t s ps»> s is *!» vi s'ssí'SS': id's psswdpT. ‘HrsNMKt d (4ÚÖ y i L·, dssS^o-slís. tOsHk t S ^ <- S 2 <0», S H< Ölik b S - t d v2- 'SS, Cl iO' S't'lN'k '1*
SSSv'Seers 4 SS S S‘χ=ϊ!,-'Ss, osSsskisedsew í t2 S'y2ses Πϊ, M ,p *,oíc p»|\ ' * 'd^ksx Sh, SS ^ p α ( p j sisasnes: ' s (ss 4x Sí di'HPspS' Ss >-SI4: s OSS j''<20~2i>k>s'ie s -C u t xsi ' Odedrdes S " - :í ^ t u-!
Step Ci í'k ο " ' ο > ' '» ' η vr* ο ».s ο 'SsoP ' Μ ο| <. o'<\ * adsfed hi sitoeessiost .¥} S rol, (.Bg 4 romolj of íriethylamtoe a»d then, by spskdu, I3.S g (63.6 romol? of poru-iohieoesoíplsmyl <. Időddé aud >3.? ud, (ί>Β.4 :^ϊm<>sí of tnethyí eídoroaerylaie. The whole Is stirred at 3033 íbr id hours. Hit* reaedon ?χό store is< sobsegeeus l\ fdte*ed ow* eVue I be file ue s? suhso-gtieotK washed wstb 8 saturated N&iiOb srdotiess aosl them with a saturated Niidbi soiutioo. The orgastic phase is shied over MgSO*,. filtered taxi eosieeatrated ks dryness. The öli so obsaiued ss ptisihed by bash t 'ÍO . " pl V OXf \ éti", x UU'ili'i 4 iiiv ptOdM i-ob'sti'f'd f i'C»U>'0 χ > v fH-MhlR? b «dOO Mil/; dnuu>-ut\ teo k> f. "0 {d. Hi. pw'iTeT o,,|o wl, ül prtrolet, do* g. .: T ti *' ''a»v oiXM'ut > |\» -Ti v.i \ vivus 1 0 tv >r methyl); 3.15 (s, 211« ü I: 0> ij. ,?.H, H ulipls&be ps|\f;dtüe) IRr ' t <4 testőrt <.0?
Step Ik Metftyi ^^{$^jkwrih~2~pmpyiph<.>»y(hS\é'-dfh)^.t^^^ÍmiiJ~dkntttem'-2s?<üniMiztee/~l·'-ii'iifbt>xytete Ί lie procedure is as ui the possess <3' step C of Preparation í. sepiasmg 6'bi'öioo4ya'beogpd50>k4feb' carbiddehyde by dd^i'ObiO-d-íiuaiiiben.pkksiydí. mm·........E: 4-mm- 2-fi y(lbenzmv műé >is * <s\« χμϊ N p Xs Ο?ΧΧΉ>0 Í »'* 'f > *
IkhMsahhmMi dTHtioeo^líMbS'hydrosy'íHsHdbuxyearfHjdyl^.J-dÍliydrO'díf'pyrrtiifetd-·^- yl|hpsxd»seld
Step A: M&h}i(4K^-tfteri~&í*t?i(diMeth??}siÍyif{txyhí',P**)8mte
Ibe poueeiioo of the alcohol function of oreihyl <4*Η'Μ*Φ'' ^pwiinate by a /e^buiyldmiethylxilYf group Is tam-ied Oist according to ilt&protocol dexerihedm slocutnon* 201.,-.04034.4.
Top Vtako'f idAH 4 tfteit btíteh^ílmykfO*ί&i}fktpl·l·β»^M?M Ψ*^™**** 13 ? ;; 02 g *mmi> of expound of Step A arc dosolved m 100 mL of awaonift tie. There ere: added thereto 13.2 g (79J mm»l> <4 (4-nitrophcuyl) fonnate apd ?y mi. W$ mwol) of dhsopropylethybrnioe. 1% whole is stirred at ambtent ’onperratre for 6 boors. The rMötibb mhlxux is cvuporakd ίο dryoexs eoti htleti up ia et's , , \ > pi. s, ;s <<: .;.i s v.soxd . r -u( ,o-k>o onh r i \ but H i soloiioo ouh o,>Hi.
sob shen with a ^teresed ΝΗ,Π soiuo»r ut-di oeohxd it b subsegoooily dried over iroigoeriuni sulphide, !H,J ! ^ V. 4 1 hV sn v Ο O s to V. Hitsl'w ^.OMMOv ij.'s Oio U‘X d\h:oroa;eth.ox ,ί-ιοοοΐΟο-ο.’ 'O'" ':"3r ioo'tih’ oiodos 1 ;s obtas seo to o-e torn- oi ,o' oo Η \ ν'ίί^ 'η ír <λ ' !‘>w > * ' ^ u n'?5r>,? Λνν,( Μ',ιί ΠιίΛ'ι»! 0.\Ι « S < I "VJ '·>' '1 'ϊροίν' 1 "iii, 2H proime), 0.8 <s. 9H, Si*Bu); 0.0? is. OH, Si*fe>)· |R; γ <' <.> **w ! 749 vffiU o t^mvlc I059 cm ' !Mp Ct ÍÁtkhtm
The compound of Stop B >29.2 g; <M.I tmnol) is dissolved »« 450 ml. of diomme. Λ .sóinkon ed JOhmm hűhóink' M 2 g ion mmoi> m xstu B*n sm s !\ -ukkJ S0.·..' ohoio ín -nmed <sí ^mmení teinpentuix mr 7 hour... fhv read ints mixture is evaporated io dryness sík! used ss sued for Őse lotkwmg s»«p.
Methyi t28}-2~ftim'ktítytí&m^j>0sfy'fyKV}-'-2J-4fk?érir· t 7^ré&^$fá® lo » solatkm of 22.4 g iW 2 romot t <0 the lithium «.arboxylate obtained in Step 14 in 940 soL »i dicbinroethaRe there őrs sd-.Sed m smcceNsino .:? ml. f 172 mmol) of t8 g (96 tm&ol) of/tmxMüioetKtstjIphooü.' «hint ide and 9.7 ml, 194.2 mmol) ot?ité^l-^kH8fl£r£$Ée.--lfc^feacii<iBt s? i«Mtcd at xOus for 18 horn.· sód then e.-okd and diluted in ethyl ácsMs. tóé·orgpsbn pttossS ts oaxlted n-ith omvr and thsa with bt me, before hetog drtvd over Mg$0$ AÉfef emt\v>e n Ό NviiNpí u M\'vípr c < pm. í\í<k'x. n hepisncíetnys us^-íate). 10« mk :;pst$dSP||s pOppnéd: ifi. iilte idesb bí W$tfk lH-NM8'. 61400 MH/;<!«*«·<&; 500:'Κ.ί 6.7 td, Uh B pyrrole); 6.4 <4 IH, H pyrrole); 10 tm, HÍ SiOCHd; 4.2-3.?$ íAÖx, 2H. 211 dibydsopyrmiióm); 2.3ki 8 íABx,. 2H. Ut dihydropirrolsrme); i.?0 K Ml CU{Cllj>; 0.9 t n. OH.. %Uh Ö.HKAB*, bil SIMe*)
Ikt v o.o-0 t estes'»: 170! cm i SiOb: i249 cm *; Si-O: i fílUMÖ cnVh $i-C ht>-7?7cm': Ι$ψ. M: Metkyi p^&iizfm~?^wbaxytate Tík' pn^edore is as. so she pte*cvs» cd Step C »f: Frepratkm I. repiaring. 6·brv>ií>o· 1 <) 'huííeoá^ol^ls···· 6<iHkddb5i>'dií by; 3^bmni0»44pnöí'nbsníiddébyáei "Stm. /; 2«f{2Ml-2-$m~Buiyi(dkn»ih}Wfy(fr.xyh t >(rN*mlh 'fhttmíbmztie tíci/l I:iip..pidcedis5:e is as in i;0b |>rm;ess ol'físp P <>í Orepanidon k
OrenxíXiBcio 29; 4-fhiorO"2-.|!2S)-2-hydrosy'7-(ftíethoxyrsrlKí5syl}'-2.3'<Hhyílrn.'l/i|>yrroll?Jí)'-S-yíjfeéöasíie arid 77ts-:pss>eöd;0rs :is ss la ifié fsr-íássessis·:·^:^' I^^Tgprítmtkírí: .th«; · -jtr«í:i^jíl · <4 step A by rt^iylidS^rhyOfps.y^íistólitnOn·. frwpftrfrrtwk 30: 4<Fteor»^-|7-iky<líoicy-Hiií«(be\vf*rboe>íí'S>6,7,8-íeír«riydrtóeíi«ÍferÍB-5-yMbe*i*«lc sscfcl }!;<· prcvedntv :s- m m she f'iwu,:, as'hYpiSmsmts scpctcing '*'< 2-hmm. <4-1 m - -;abm;.mtm'>de tsed f! S(<?« D 6v 6-brmnO' I.:I - be fScíodHíjí ol - 5 -e a- hald ekyde. £mmEMlSa^6''i8't^fe0H>x>aírböB>i;^>i'mk)|L:^8lpyí'a:«iY-^>ll>i>34M:«ívdl«)iOl^S.A'ín'b<nyS:h>Mi<l S'frít Λ: Wtfriípxiwtofít^ftfáyM i xWfeuteíf fe a ;.okt;íors of iO g (6.1? nsmh s of meihyi pyraytnO-ySöeesate so 267 ml. <>t tmlsvdmsís action® ¢4 ml mmol' there ars· added *n sucst^On V* s oi'hdmmt homol |-'w '' nmi-dl 27 i g ot wütsusn bkmhmah? !.:?;> t mmol) tmd shess 6.4 ml· s>( chíorsjscetsddehyste (Sü‘1 sóiul tors as water) ¢72.6 nsmelesd· The whole is ttibjeonemh basted at redos oumsighl The steel ton mixture ss subsequent iv concentrated-to devises-s ssid thot> t*iK<sn up is* eth>l restate. 1he organic phase is washed with a saturated sodium <ntpmfe -solution,.<IHM; os or magnvstxm. \ui|'hat' ' msed ^tro d\n o'kcn 'ateé to dryness, i'hea- ss -obt&med m oil» schich ss p..i i i.. j ;--. v <v a "o, f v -du.a ! t 1 sKI -mse v „ .. 1 ‘ > Mhr okuoration. tise rssie pmd- ct '<·. nH-savd i's tm vms m a «md ΠΝΜΗ*,·ί4ίι Vi u·,. , tp's K , t i si '·< *e> 6 m* -do, its, h pyt-wasrm}?, *-6 tOs, 2h< Is *'w-' "v "-m'S'oh' ' v!* '1 Ί,.κίν ' ^ m s*OH ^ IH v < tsuomts siet-Orr) <"6>νη
Step B: é~í^~{!^tetkiKiíystif,h{fepí}pyFmífffÍf2~s}pym^tt~^pU-'it^-i>sítiii(H^t»i«~S-cetéiKK^Si'fiii^ S' s'SC 3a u ϊ >l-< i dü < \ smp-< 0 -! \> 1 * Γ epim s^< ! EölSTMilMLáli ^dBsw^'S-IHmfcthuxyearhonyihJ'iadodaSnytlbi'aaofc *c{^
Methyl idndtdiaitsecarboxshne 1' lonne-t steosdirsg h- She pmce-m deses shed ssj Steps; Λ iuid H ot· Preparation-I i The stile product ss. jisifccquefttly oh-slned aeeoccfesg m >toe protocol oercssbed m Steps 6 8t?d 0 ot I SClO.ttloB I. >0«>Ι-Κ »j> I', ' s' tK "Κ'ΟΛΝ >OvN'-s X Uhtkk'hMÍO Sissfii iss hop L by .053^00)0--4^ iHSi\y-hef;.'.sl't.'h\ de
Frs-panssssm Γχ t^,l-i4-hl)rplmis«>kssetbyl)-i,0,M-tetrafeydr<ds^MÍU«lm®: fk-'tsrp i s iSbS^i-S'tHiitphűíitti'h ofh<»í7i-d.7-<í/ftyf/ffl-'2í///)-4ríí^«í«tfíáto Is ,s mh0ís3ts ,4 7 e esi Vl-74ihu3?rh3y\)usshs'Ss>n-s.7.\-i-H'ts'<shNdss3-'--S'<s>sptssseSissev\4SÍ3e'\xík siesd SÍ6 ísssssélMts 160 SS3.I, oi dlchieíosr.ethsssse tisem &tc misfed i.> ml- <*l rssospis^llsst (17 6 romot) msd then 0 mi., of ν,Λ \-trsHh>hssvmse síd 5nmni\ 1 ΐ e ef l-etiss 1-7-4' •dlsS3eiÍ5vi«>siS!s«pt<.-s'vSw<ei\3dslesede ti 11") 04f2 msssíssí süsd 7.6 g οΓ hydro*ybeoaw£rk»aote íHOBí ; (ÍVl. tnssmi), Ihe reaoliots srsixtssve l· süti eb sí ssmhett temperatstre:trvemight attd is thets psnisod oiste a sohatnu ^ftatptpuniutn ehiovKls^ «std-«xtrac-tsíd vvitts etrtys 8:t:s3íate. The organk phase Isssidsetisiestsly ds'ied over sisagpssttsss stssphase arid then ilitered stsd evepc-rtsted lo idfytsestt. life erode· pedoet m- bpstsded ip Wm mssifled1: % :dhráisí:#d|il|>líy -over 1¾¾ :gei díelömíiöfsdíiádí, 'ií-N^ÍH: 5 ¢,-100 Msi/, dnto-do. ír <'M «' X sso Mi tfcm'j,!}. " i ' íux ÜUífomfsSiíO, 3 J-S.ís (tss: Hk 2H hen<t>l IH dihydroixoiptHSt.dine); 4.75-4.8 ¢.20. ÓH ddsydmisoíparolhte); {m, Sri ns-xrphtxhtsc). '.;5- 4,4 sydo. ail 0;s'r<di-'i^'-ííJi>i-,í0no' |R; v. H/ -0: |#J4;J65t> cm'!
SdT.^' duosp'/ ? «V, í-^-fífíífji'WiVív/ífKü'í^r/» K-t-díhj d>o f Íi)~ístiift4m>ititic coí Το a Αίοηοη χ - r of she otodaes obssdneo ο Step \ ·:! - '> Otnoft to 4 "o ssxl μ ί'Ί?«0>\ν1»οι\ο«ΐι d es, are added U ml of BH;Mc;> ;>'.' 0 mmoTtai ynptent tcnípe^Hse χ-hok? he-dt ο tor 4 hoof- at SO t Η t;' allowed to return us anshietsS suepeoasi.ov. and then there are added '? nxt <14 mmol) of fdlAIoA. The teámon nntomet\ atstse htutod at 8ü'V ío- ? h>nn- I ne tettnhvvitoíuron o nnhx-etpseísth evaporated ui;' n-d there are then added ssksxvlv ?ste; honol and thee 5.6 tnL of SN hydrochloric sxesd CX7.H tnmel). The roxxtsHc is sthred at ambient tempemtnte overnight and then ¢¢5 SOX' tor one hour. There is vtshn.xpn:ndy added a xss orated MssHCOj solution to ihe macison mixture at 4vO nud; a pH of 0 ss reached, and then ex;rácsion with vth\ soei.t;:-' o eau-ed oos the organic phase k *.obt<tN|tsemh dried ore; magne-nom e’dphase ami then f noed u d c- xpn'Oto I v< .."vato-. ihe n;h ρ*adoos s- opined ns the nonx -o on od ΐ II \\$H ^Ml 4". ;t s 10 > o x o i -. \ * b ' 4 tot -Τ'! ϊο^νοοΤ fdh im. 1R 2H henry!); 4.7v-4.4v -d. .01 dthydutisoguinolim:). 4 58 set. HI dihydsxsisoqohisxlliseh 5.50 (m„ 4H morpholine): 3.0.:-4.54 phi Ml :lth>droiso<.pdnohrto); 5. 6:-5 i:h ; in tse.solved peak, Sii, dli morpholine. Hi s>o>t|5htiim»k 2.15 (dd, 114 morphol»»?)
Hi. s Oli rSioent ; - ' C ¢5 ·η44 ct;t \ \ Ό'-ti-t'- 1114 cof!; \: -I'il-Ai >'51' oO" urs'!
StmC; (SSj - *· i c- a voiotiess; os 4.4 « ot the eosopothxd of Step B 118.4 romol! ist 6'f :roL »1' ethanol there is added 09S0 g of nnlHdltao ddtedroxidt? tio^- hv tna-d al aiohse-n icmperotstrt. Ihe t^ Ktax- -otsOne s\ ptaoed ts u-, s a |ve of hydo>itett at 4 Isooo;. it is sobvetpsefstly poxved steer a .Whaá-roan filter, sotd thesx the: palladium Is rinsed second tisoov Idté .ithrah· »\ es8faM«ue4;4«' dtps»,;:'iM' ttife^odusPis: : obtained itt the form of an oil,
H \tr1R , t t x. * *0' tit \ ‘1 h t t tw , s S ίο; ·\> ΟΓ H sestatodsos-asaíoo^oat. U 4H ιηοφΟοίϋιοϊ, c i58 tt;;. SH tott'attt.dott-v.'nstoc4int'S, ..'68 <dd, iH ;«sr;rhxdots.vohtstoctisne); a 5-4-3 (unresolved sessk. hit', iH tefrohydroisotitdrsoliste, 611 osorphoitne, HI NH) IH s \-t -'ddros X 't'-ft-l - itsácn- x 'til· St "‘-HAso*
FrOisar^tlidh; i|3í4iV3'-(4-Mttrphniioxlnsethyí>-?s.2r3sd-Sei:s'ah5:drölso<|olKSOÍlne <i, V S is i 'ν' \v v*Xi« ' v '< X !\ v M- t\' ^ >\' K »'0!»\l I ‘ ' «tububo ' c., P »sc«*m$K'v x J\"xaK"' Varbwil·» "' ' 'MemdxMl - ' '<X.O\gSSSXObU£XvidxO.\xbX <«·«'*·
Pn'ps>r»dott 3‘: blS>3A|3'MeihyM 'pifmmi»¥l>8H'*hytH ,1*M-tBtra&ydrisIsQiiajiKditxst
IV pfviXXksiV sx X\ ;{X tbc ρτ<\\'ΧΧ yf PieptV.n-i'O n'pXx X;C Fx iJsOípHobtaí !>m\1 S!X SSCX \ K btSXUisXS 'pippaxiixe.
Fcfemjratkxt4\M\m^3l>4'Ox^?xx^ft'4'ylnHkb>3kLaJ><b^kxtb;ydrtilt.^tbjttbbK- IV p'>xi\btsc i> «S' its c;:<- piCii'v, VS SVvXiXOO S xep'xsdox She iiXesAxbhxe s)vb SO XSCp 'X b\ i«4- iXX&SSSpiKi. ^^!Miradt>aS<ikiS>.K^{ia^K^M^Hv1at«r8ltftix»yni«^feYlM4^4^ty&>liydrftisft<iMia&ii»g 1 he |;nx:-xii.»c h a·: »« t?»« i>f*;:css <»s'Prepámmá S\ replacing ?be mftíphohti* ««d hx Step Λ by n/?Kk ctscth>SiHi>iphi>{«5e.
TteJM^jM3^<^>'^<H'^>3-M«l$>y$m$)rp5toHrt>dÍme$hyl^$Á3^^tía$iydi-ois<Mpb$e$b>e TV procixiutt· sx s«. i« the proem tsf it^psra&p: P, reptemg tb« tusxiphpipp ρ«1 I» Step Λ by (35)-3-mcih> íísxsxfphöiksc
Fs-gt>jtyskb>jt.xb í-VVkA?jbK%\MKkS'm»xt't!tyiBtorpMiixxilmwbyl|-?,2Λ4-Setrahxdrote}«bxs>b»« •ThetttwewuMtv·*»*«$·«« td^snw v N P * , » \i 1 » * >\\} o *c avd f v*p s b' 's 'n * ibnKxhv I m<x rp h sxhtxs. Ό Oiw<tbjti^v>'l,k\i'teti^Uxdro~3 ro'pxíxíiolhox S jouSiussssrohxe The procsdtstx? is &s «« she pr«em os' IVparatbax I*, repkídíxg she mmpbotine ir*gd «s Step Λ hycM^, Amkthy Vssihv ££SBI!MkMLS!* ^^"^^{J-.Metboxxetbyllpipecas'trs-l -xSjx»sSb\db kSJcbSr'SnilsythxVo^iakioHne • be pty v< }X ' l s i o J.XV K't vptsiit ! \i *b xx S! b S'C i! Sep \ '\ i-s>- xseshoxyeiby! spi per»?.* nc, .*«&&!!»>,2J.4'tttr»h>drrtl8oqtilft«M8»3">Nt<'tbxijpipero/it»-Soshí 5 Sse pít5Ppi|tííp *3 bk :te ;dXo :|>rpp^jj: pf Sh; tpplppbss^: tbg ísxpípbíxikss. üssed: lb Step: A by: Jx is)eibyfpi|xs:nt:ebx-2.fx.rse. OSSHSÜSüJiZí 2"^x'tb«\j Nv methyl· S-{(A.WS ,2-d»4*tet» shx V'obtxpbiscSbxPy'X. baxetSp IsetSi.-iSsissssbse lisp P Oe \!vC í\ S' Í a » ill t \s ,XÍ P '1 n'l (' Λν« «' be X «I V Xu' * Si \ XciSXsWi· · A-: toe! by kthanmnaxe. the r !OxíXÍí«x is λ- so the -A ^í'ívo^s.w Γ. opi&tag íík- fsn>rghvimy sss^d hí Ν^ρΛ 5?) A-^h\i,;n mvíhoxyethaííaiymie. L!b i-VS* MH í^Uíh'kHSt'íh«'>npi{H'S&/ío f-%l|nitt^\|}-UJ^-Mi*l»íUroilsoq8Í8«ím«: $k >k s »1^ ! th* ,'!>uw oi won t S''í'^c»p^ sv morphoh**e U.W is Síppá Isy 1-
Sj'sKtíh)· boiphOííV i ?ph>í!;:Í.S:K·.
Pmí&rathffl N1- rinfhírtí'OiSiíí Upí}>OÍ<i**« * vJ|«u«th$ü t.íxxV4dejrah>dr«H««^>inöHii»'
Jk proeeourr n ί Χί£ρ;<χχ > ns ;s "ív,' na I . su'dnt'f"' 'h' ίκ *f4>í*í* íxxd sn v>v \ V iO 'J ΡίΡΟ«η·ίίΟ·η jA\ í3x^ T'S !J' t f:0\id ('? h <-'0 O' S fíhrt S < O Hír ih}dívisO<pí!tiOÍ«ae
The pmce<i»se SS. as É: :É| prygeye őf P^pymmín 1¾ repíaeo-y she innsyhoiirip esed h Ssep A fey Shk'ihOS'phObíSP 1 „ 1 nkdsSdO.
Preoaratloa 16’: tixVV^ Ji3-Metho\spytíoh«b8't-st)methyi|-l}2^x4«teirahydroKo<|«i«olüife fhe po^uJura K a-· so the pro»x'h» ot Preparation V. fq>hs<ing fh<·. «norphoiine sisgd:m SíepA by 3^ me? has ypym<! idisíe. llttEEllliMtlZ-- <^V)-3*!í3^dSí8uorot>jrrotkim«l»jl>mMhyl|-l,2>3,'t-tfir8Íí>'drHíí,e<|Hi»«5}He‘
The procedure hs as is the process oJ fteptratio» t; 3&p?a$ij?% she mí»ph«|.%íf $S|d |« Ssep;A ;!w dííluoíopyrrplMIstfs IZB-MmtlEÜl.1.: «'-Sx9)-3~lí3~Metfeoicya^tidíö~?xAví>tnethyli''S<2^^-letr»hydíOlsoqi!f5«otíae
The procedure § -4$ Aü the process -0 PtefxUUí-x\t i\ replying th* mon«S>oS-o" ms*. » »* Mxjpín 7 íHethoxywüeiídíne..
Pmatnts k>Sí Mb (ASVjyjíS'FSHyroasíetíáío-t-slímpíííySj-fdtyM-'Setraiiydrokoípíhuítitte
The procedure ^ as m the pr«*eo» »f )’reparation !'. sephusúg she ssorphotssse mad in Step A by J- :llhdAs3!®!<ííhe.
Pmta ratios 1”: 4'f|/eít-B«tyítdh^éthyt)s:dj1|«syhA^pheí»yls«íÍ!He ío <r solution af 5.;. § of d*»oii«K»phetsi>} ib4;7 mmoí) hí 2Ö0 mi, cd acetoniinse them sra-added at ansiMettt.· tenspiraSare e ? g yí níSHÍ^.-'nk' ;A7 ί,Α ΒΊ;η<>ί': 8«Ί H t g v<: tc>< hHíU{ehh>ft*>»t!»t)eth\|»f{atíe !?'-' t»t snn'-nS' t he whyte stirred si ?(PC for 4 hoars. Thea she rcscíiors síysnre ?\ p-nared oííío y«ter esni estraited wish M ' a Xf 5 X J' V S ! X t X í i Ϊ W IX ÍJ' \ n ti 1 1 ’hxíí { Sx í. i ! Xx \ ! >'x ' Ϊ j 5{>< ^ ^ viuct so oiRa ax! » \o N* * ^ '' <b * * * 9' '·'"·» 'll/W <νΊ ^ \ί«ν·4.^.ν- ulvx dvht>vw<ottba«»' k'MxoO. íh·' mié i-Rvídtí 5» uK·»!^·' *.* dv Mn* "t * fv'Met !Η\'ΜΚ:^μΐΜ»!ΛνΝ>Λ. W ΙΟ 'ίί*ΜΐΐΜΓ. "r o, Ml V o ** «c -Ή ‘ {'u5 íd :?H műim: 6.n id, iÍHpbeaa* κ fc.?::o, Hl 0 «5 (χ 911 Ö.J5 {a, 611 dsmahyi) 18·. X'· >NH: :a03 cs«'!;''Ar: 1 W csn*
Ux ,,i5V!H^ NMIUk vTekk- k. mm i\ ««kpu^k'»·.*· dj»- .m-'ihm op -S!i ·(ί>1 befcto*f>i pk-up VwO'lílkO «*«, "fOJl £k tik m\\v '’Csík-aííxd'<> '' UtvkíU >,'<9k í'\ í! t >\ 5 V 0i> -.' ~! * ;y 27-50. Chmbs M D. «*<>/.. Grpmx: liters. 3005. 7. 3965-300%). The readk* of piotcctioa of íhe hydroxy fwíkOoo ut -üí i*únnnp\*nni scribed in Pu'pstr&uon I* eas 1¾ afpliM to vmvm^mámy· ,ΗΙ,Λ S {* k sv '.IT >. v Ok v. x< >. o >· s οIV **CH Í**e> áré««ilüblSí commercially. Alwowthwiy ftc s.««mdao *a*ines havs% u leusí m* hydroxy subatböem·· :hssv m:-. *®númk&á d&eedy s« & p«4e<u-d fane. i.« stanmg from repots «*<** hydroxy fcaetiatt*}M&ec»-.d K k'*» o x o* ov * vau, vjps .t*· s'K »d K^' >» * * prefexrsd. ,\W'V h. .« i.sM R ' 1*«.* -I vm)Í íiKv ton íu udto* vntK* sí V <ompmsodsöfth« mvemdos ihere my he πκβώχ*<1 4-4-i-tiMddmi%hakoh Ί.(4ahk»ro^üjm>}ph«^: :«ptero4*;: oxsMiaadxkOpheod, I· f4-Rrsnik'rooje?hoxy)kís6ójo|phsooh 4-|Wwdmx?amlm<yjphe»ml, (á-|(kmRdsyM I A6hKk>;.6'-y Oomn'K'jpheto. I; modmaol. 4 ·(.:. T-dlhyds-v1 //Imííd-ö-yiamism ípheaoí. M'l I -meíhyl-2 J- v'hxiW iH adó ,1'v v 4 I * κ '' w '*» Nh ' ''memoirsvSau«W*, y].»mmo]cxvb-hexanoi, ι ( »κ«*ό * k .doo .oíoj "Π.ηϋϊο|. ,'Ί ^{•Rl-oíöRyi^i.X’: dihyíko· Jlí· i .a - hefkvo\a.íio-" vl)a»i»io]ph«fru'!. 4 -I < dwíhx Isodkoskohík'iphsool. 40 2,j-dihydro-1 ti- md«n-5-s j<s«sRk;)pli««<d. 4-1; I -oxohyl I /-/-«via -xsí -5-. ikoosnolphöEioh. 4-j4 \ •-»^th>-J-r.2'“dlhy<ko'spte*'· , N v . ÍJ i,> I s !>m í<'ph^.ol ' I 0 '4 kit' > ' ! s < i-::-y:)«s«!i.oipik'a<>l.
444-m<-fho\v I imi'laoRV^R.v.UxRiMoV^-o.'l. ·Ι 11 ^moÜ>\Katj>h.vj' k sm^^d«»öjpReHö-U > í»i<.'ftw ki !BUh\í H« !. siói s \tV>M0«'ph-rj»i * K' s.'hk. t w-a,ioh--\ η»ν«ί.>|, htooí, I-íé :-<'thyh2J-dhiVilKf- í í.í'ii><ii>h·? .ySyiooni/lphaiK.h, 4-((; · Ϊ;.ορ5·ορν!-:3..>ο6ΐ5γόίν-1 //-iixlos-5-ylhiíVMioipheí;í>l 4-yhoiyt-· ísivs!«Opt>coi>h >-(/ l-iruíiliyl'l//-ií5di>i-?->l)<tmsno]-l-propassol, H'i l-nselhys-1/-/-ímlo5-.S-ylki50fki|-1 ·· IkfSanoi. 4-(i i-tkt(xo-4-methylphtíny l)a»«m<>)pheftol 4-f(3'<h{ofO'4.j«<flhyipÍj««yh»inm»|ph«i0ö4/;: #/|pv flskxoph.'kvh.5»5lí)OÍplíUH'l. -hSyl'kXh;) 5-:/Η·>Íío;oí2.3-/4ps!!d«o5->r!;oo;ís>i!phe?soh O-IU-íhsoroftk'tjytV-ía»a*oo|phcTR>l. 4-f(2'íkii>E<>i>he«syi}0«ds5O|pheíií>l 4-fi}-íhakopheny I>amhu>]phenof, 4-|í2.4-difluot^te^;: íiiouKí|p6c?i;->l. 'k|(:k4'diik:orophvO>4);Ri>i)X(|p6ö«ísi: 3-(í<S'H>drox>-pbe»yl)í*mmo]fc<f8?S)«i4Hl5? -Mi '--«oi4hosypikí!yv'i}aoiÓKsÍph>:n<>l, 4-|f.k5'dií1iK!{«pbeííyb>Msdm>)pii.;8<}l. -i-[(l-}?K'lhylphenyl);i«»i«í|phí.'5;iíl 4-(<4 hxdH'N'Rhonvn.»n>'fk‘ib«.«í»8Hötkx 4 (.',> Jdofophoik!i,ioo)V'b'he«ol, S-(p\.«ü>4üs-2-> ιοϊϊ^ϊοοír-lx-«ot, 4 (Ee,yclóiki5yln>iíi:h>díi3íÍohií>Íph«i»<jl. S.f/d'bydRíxypbeny.OamsiKsibanxoottriki 4^-1(11osfotbykI /•/•^yra*oi4c y S)í«el Isy > Ϊ ü ϊ ·6 no} ;>Ih: i uh t 5-((c>C:op>^pyb«dli>hiM!dnt>|ph«ni}4i -4-((( lonethys-l /-/'pyr«:íoi«5-y OmeíbyH" amitufípiteokl, 4obut4?yo- {-y{í«n>«í>)pf*eaoL .4-(p57Wdb4*Hő^‘0<l)^90dl»4l|pyi lám-I?-ylatnmojpb^wi 4* Cpyrldaaisí-S^yismhioiphenoi, -lop\ Hmldínyf^amlmJ^b^ooi. i-CpyiidítóyyiismPf^phssíoL O-Hío-íSiilaoro- 44O'iíMOí<>-4-n;gíhox>phai>08;«íí^]pHgsöL 2 a giwro lato 5 no >j a r : svod * o - 4 - ui. r^'hím > íH|a-íjf5ftuorm mefhyhph$fiyl|smii«)} pbciKd.. fix h>.Síov;< iWtmoiO of íhe αο^4ι>> xnmov Swxv* ,d;,o< l«W« <fd ^mJ\wd k\ « wodde vJOCU« , W 0 0 <v ν&Μ&ΜΜ·* Μ «Μ ν' >C * u"> ',ίι^’ Λ 's^ S\fi > H\ pS'ííí ídmg pSic;·..;! pu-fXWS.
Ixsmsklí <V-.(4--H>^rox>y 5h>u>-1K1<· (6-fí(áS>^í-í míírpfeoiiítvIm^hylH^üMíi'dm-^ SI/)- í&<K|íib>«bís^Ij««rbí>öy!|''1í3'-lKíiísodíös<d'S'j}|'A'''phesy1'5s6s7>§'U’:U'^bj;dí'<í''!'Sft<i«^i£íSí! gkffedMOiMo
hydros íiíofláe iVfe&A: MM tmtmikmil Μ7Ι·5Λ 7.Memknfm· ÍAnd&lkimmrk&xykm
To a sokbioo oí 2 g of.íhe oTPrcpanMior* \ in 20 m| <sí dlekiofosöeliatié ste ars ^ieá « ííírshiíVi! ÚOT-pOraÍ!«<' > S so; of ,V..V.'Vo;-;cSh>oisy!f-c (ó.Oo m;Oí>h, 3.53 e of the compound of ^partition V íiosioO; ««ti th«« 0;00 g: <}f hydf«5sy»t;o;0>0s&X0W. OPd 5,24 g,-uf l^hykHí-diruethyív a«5)»npm{w)κιφ^κκι^ (,I.\I.H:S.> oíxOO onnois· kies iea«x«>.8 -tó- *ufc$SOuöMU> stirred &% ássbífenf tewjftessíw nveontgisi. séd js iíwr pontod onm am mMitiiti chsursde .(p5oOí>s> árut extracme \nixi othyl tócsák; fhe organic pisaw k s«b^»5s«Hy tinód over magnesium «dphate and then BI|sa^f'»á.eva^s:atíá:*ö díyoevi. ! he crude pwnkwí so ok: u»\o ;v ojcss 'tnífkxí h* ; 5uv»3^5>>gí.,iO(\ eves: t»;5m« gél (heptane*AcÜLl gro-jmm''' 5 íic üde p-v-ocS ;, ->5't, ';\d;' V 0«; ' of an η·» lH NVk ν'! \n dow* »< t # o' -*k ' on 5 t 0 >< < 0' u \ 1 \ ‘'Htv' g.g\ 6n. 3H, H aromatic g 4.35-0,56-6.06 On, 5 5 5. Í5 ietMhjdroindoif.one). 0 5'-6.5 5 tm. 214, 54 ovetiwkamdioxy): 5.06-4.§4 ftn. 5 55, H dih>dfXOitxpd«oi-ik'}. 4,20-4 5? in's, 354. 5 5 -.‘3=5;y-:3^¾¾s:;;.isrs;>;;ísc4f 3.65-3 0-3.55 (m. 3H, y «p esten; ;3J41 (m. 2H. H mirahydrnlndwinoe}; 5.555-3.5 ttn, 4f5, \i otorpholine); 5.33-5.05 <m. 454, >55 ííihydtxsís^uinoÍme. 2H 5:s5is5if|f630&jfS£ljie); 1.08-2,36 (so, 455, B motyMmeh 1 4-5 0 «><', 4H U kit Win3».« tdwinotd
Mr v; >CO 5095 cm'1 ester; v: >t>0 5038 cm‘; asuide; v: 'fN-O-C' 52 54-15 70-0 5 58 cm s; >(.05-4)· T12- Cíí> ' jTte/i B< lii'hiiwt 3~f6*jOS)*J*{mtttphtiiinimmkyfl· 3,4'&Β)?<ίη).Μ$ε&ψί®βΜβ&··2^^η$^$*ϊ· b<'H>Jt<·\o ’.O-r f.ni'iyiO-. ~kkst7ifmm> jriwKylew
To a soiaOois of 4 6 s of Ose '.xi-?s;x;«i><i ofhiep .0 (8.36 ?»sno!.} is; '4 s?d ;>f diocsao sOt'ic ή .adöed a ;K>suuon of Hdiinsn h>dt<o>sdc (0?5.«sg, 50.5 sOinoB 5 5«' wli<*|<- i;; giaced «s a 540 W micro-wave ovea ;d HSOT.. ior a P<-sηV o5 , 5Ή w,« fsoe miMuio ? sohscg«Cjn5s ',ΌόϊοΟ t«d d»n»1 i'n Msi -nw-NSiraM o JrkV at
Tlf'C to a hot {sabjisei io s5-c piesvocox-t PsO<.< !II·NMR: d <460 MHk dmso-d6; 3:664:): 653-335 p.ooesiOlved peak.. 6R; H snomain); 6-3: (:c Ui, 11 moonas-?. 6 6>- ?\ ΊΙ|Ϊ ondo Ιοοοοη-χ;. 5 4 0-^-4 ui\!x -'had ?o ?\. M* v'd!xd;o'x<.\o!nonrr" M-R tohpsajlved peak, 3H mirtd$drt>mdeli»m«, 3H marpiiGlmsB; 3.5-5:1 .(unrysolypsi tHkh. 4H* -2.H semmydrikndotmine, 2H morpheme); 1.5-3.4 frmfXíSdlved-peak»
Ik; v .65-0 Í 567 broad an 5 acem-e; v: 1336 ess'5 $m* €: Ν' asfhmümkhr Tí; ts soidfim? nf 5.6 § ol the eonipoond oíSrep B (4.75 mond) in 43 ml. of diebiopmsoíhnrse there ar* a<M«d, stepwise. 1.3 mi. of osáiyl iditondo: ai ö%', Jbe fesetion mixture κ wtmi a&p&ient temperatute fúr i f boors, and fed. m*m*p»mvá se*£mi$m$$ wdh dichlormnethane.. ? he pröduot so. ohtmaed h suspended in 3? ml. or dichtorroimiham: ami is Ilién addoilio a sotebe of 2.1 g of the eonsgoimd obtamed in Prepánkon I'··· p::J mmol) is? 10 ml.· of dieídoromeiífane in the presence of 6.6 ml., of pyridine (7.1 mmoB The whole ή; siimM·, «t ambient teroperspne overnight. The reaction modoré is «or-eemntted ami porifkd by «wat6$&*.§#:{dilite»i#!^'61#ik8«ol gradient! Ike title prodod is obhdoed i« i: form of a fonni. :7<-6;61R;. 6 tSdOMlte; sfowo-dtr 5TTK « 6 0.7.3 :9H aromatic): 6J6 <3H aromatic >: 6.75-6.37 v>H momso. 6 6,6; ¢51 i snonmne). 66 1;5H nxfioieoedsov, >. 5.(:5-45/-441 dthy-Oowoonmoin-C! 4.53-4 15 ¢511 dihydrnlnimimolme); 3.4-1-χ 3 (41 i morpholine). 3.62-3 52 62 H cosihydrolndoiimne): 4.0- 5.6 (41 (.. 2H tótra-: ls\v-rf'mdx< - one. 0( dihulftnxoousnohti''? ,' ν·ν «oM tamt-hodne); 1,61-1 53 mil !vimhydrn;nd<:ba;n«>; 0.63 (Qii iro-bofyB; 0. i 7 (61 i dimeibyi) 15i:v.'( if p'-i.RU-sj 3 v. :-6-0-6-: >5'5? <m 1 e.16'4 vm"! 61-6'· 6Ηκ?η ! 4 ll--\r Son cm ! m0i0iÍmm^Hmrhei^íph^eftz/idimfflSf^^kmyí~5A?,»~mN(hyér^í~f^ÍiiJmc^<ixmni4ií Éyikmi&tmkk
To s solo?ion of' 1.6 g or the compound obtained in Skp (5 (2 3 noenl) so 4 ml.· of melisaoo] there 1« added 0.64:* s> (il -. oiorti - of poi.teom hydros ide -.hxxoked so 8 ml of methanol The whole w stirred at eminent ίοη-ρηηη,ο Ό 0 aon-dcs Tin ix\v,nn : mono. -χ -joh^oco'' m «red n dtehk -<ίι .dw<e ,4 -0-¾.¾)1 X, xr x!! \ η η i ? - Vn'i.. ^ x> vü.' >x On xxSn *>x'\ 5 χθ! n 0 ( i -..,- uo',: pH ix o-u'm 1 Ihe 00 írni' ohose xei-eo n"Oh 4:.e-f o\'er m.une nm' η"ρ1?,η<, filtered and «vapor;?!e;f The erode product sor:biain«d ?x po?:6vd ->; ciika gel Kllohlofomethaoe tnethanul gradieatj The xy- s t s of'xygoeodx d< 0 %t xi *« v ?r 6 s x o·. 4 i ”* n> ' 4 - ' h? ' χ n x ' <N~ 1? are adxied (1k- whote ix ;<iiifx-d for Orso 1k->« and ovo x\..ipo;'and k- d'\o«:<; if-ydro-'li-'orsdx'.« x-4 tirn -i ·χ dsx^oked <! a xroier act η<η>ί! ;P «uxímk ootil Cx?n-pletek ifn oKixí rod dv"- f. ¢:-,.66 χ«6 mmm0 %C ' W %Cf Üateuk)k><t 69.14 ,$.& ?,S 4*?Φ Fúrná 6-t$5 6 46 ? J/ 4.44 m0mm mmmM· * IIP M ** "> h M«it*y Míübíüíí: % H ^ <* Λ M4 íayjp&oHsnS&ntfe^ikM”· íithy<ír«>-3(Ϊ>kIs«>í|í*í*>»ϊΪj«j 1 jcsy!><*ϊ>^í| M ktwíMtdíuvol ^ % 1} * δΛ.ίΜ£ί*Λ&'ι&ν i-is^ksiicuse· esrlsosaöiísis· hydi eclítorkk 1 he pfi>:'?í.^src ío ví; (sí ihv' ot Í ASííjípií ;, replacing kv<.i>!ap<Mnd «5 t’res^í^on \" used se NeeC Py ^^O'fW'fr'hxíty k<hs^i'Shy!)sí:lyí|ösy| - lphc«> I shmikse.
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muM MM MM ·ΜΜ 9.03 MM immmmmn Μι M #*& ép||I: £xa«spk4; AH3*ESö«}tts-?-8jeihyIpíí«»j'M'Af'f4-hyün>!typhe«ylKkf<i-}í{M>'i"C4-íts«fpfe(ííifiyl>‘ msthylKM-d^ydrO'^ Ϊ //} kmialsoíiajíícertíosj lj' i ,3- h*'íU*4kA0Í- 3 •y!|'5d<'\hS«'Srishydríí-Ϊ -imfeSkto oadmamkle feyíkaehiftvkk üv ρΛιν,Μκν i\ a\ s^v'gOx o SviT'k •'kt. íi? vKti \u\ ' kv(\Svinis s -s S p( d-llf'e'-f'buishvkfneihyksshikv^. I -Λ^.Μ^-οο -í AeíhUehel·'·. Iaa.·;:··, m<ns (KSh-fr
Fmpsricai SormoUs: C^H,iFhist\: ιΜ'ΗΓ vak»* wv '·*' V4* jMí-ΗΓ meS'ieoT 'Mi.Ji'Si)
MetetM? pomst;;«}' ί 4ί.ϊ.'Τ' (c ····· 2.5 sng/sssL, MeOH) kMülgkJ:. íV-(4-Hj<Ír<»sy|sheat3rlj-J-fí'H{M>^-í4-í«»rphioiliiyÍm*tfeylKK4'<l4hv<lrft«J<tlí>~ lodöíliis» esThosssokh; kyheoebipfife
The pr< >ce<kri? is «; k she process pf f-.Rampk h rephsdssg the somjpokd <>? Prepasassoo í ” sssed so $ter> C hv %C %H -%N: %CÍ~ CüíCidxltd hlülT 5.49 (x?4 4.26
Pffumi ái.íH 4 sfS 4.24
Esasp&k h: A',.V'fe{sH-l“iíyíSj'}>'typ&í?s>yl)*3*|ih'}í(3i1Í>'í*{4'8!Lor^hoH«yM»eílíyl>-3,4-áitejár<vv2(i/#j- köhiíÍRo!ísíyÍ)eaiS'h*oyikk3-heois^sííS0^5“jlh?/í,T3'-í«írol\v<!rí^í^»döH¥hí{»«{5rfesíMftsMh hydrochloride
The pss>s«dorehs as k she process of Psyparatkssf 1" xssod hs Step C by * vHhd'f» S Λ \S SO V <f , Íí PO \ \ s * x ! ' | '<Λ v I v)'\ )' > n„ W&tmiiM tiánmattetytim IW;:· Wt f® \MCir C:.4a;iaí#4 '$$$$ 4-48 24S4 4-64 Το;;/?;# 6 ?. /; 4-4P' Of 4.24 ,ilWÍ<Vl'/*í'<* S' ' v “ ^ ' 1 > ''! \!ν(ΐ' s lotampk ?ι. W*f4^t(ydr<Mymet$^^feei^ti<»AMivW^yMtf^Mk^$*yih<H^i&3&’síM4* ihTí5íphohs5yis^o4h>ih^'^^{^>hfís-'2<LifhhfH|sshK5lfísylk8^ö«yíÍ'T3~lK;s!iiíosfí<f¥oh^'y?h'S?h,?,8'- Íeh^hyirtklslaíiiíslkhse ««rfeoxíajRfeie hyhroKhhsrlílo
The emcukre H síi Bxasnpk·. ! s íppiikbig ih<? cmnposUKl of i^epaíshteíí i” m®á-Mík®p C by \ ! -5 ^:Iitkvbmvlk- iVm i|o\'-; n*t\hs i > k m iM mtlv-i- T-mhoi-' nor no
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Hnmhyiim-l^?Kkhh«fKM:iuTííxawidebH(lmh'»ehhirids)
Hs" is as in ih<? *f Rxampt* *, repl&ong hie coj«po^s0'0l:^f^«fe». S .-1 J.m\- k>, Sv^ii'-c-'hv k-ikMo-uir^mk ^ snJok^msms l iemeritmmm$M§mí %C %H HM %a
Ckckutm m n |p 8M mo
Feu>;J Mi# j# Soil 7k>
Rmtiimy pmr>:r: iii.) F' -' --- kk)* (o 3,5 ínpnnk Ms-OHi
Iksumsk T- A«|'HH><lr»xyií>h«8jÍ|'-V-(k«í^ifevk2l4*áiHjtfrö^liÉMeá6|=#it><i^#‘|Í^3^pte{4» m<trph«Ísííyl»ieilíyi)".k-i-<hfii5ídrtí'2{tl#)“li^ííÍRnUftj’íí«,8rhíí(íyJ|“-l*3 - l>eK^d;^5ss>ii-^ t«?tr^N>'drc»>MfttlöSs£*«<· osrbftsamiík hysirosym kk
Fhv prsx-eiUsre is. as in tis* pror of Example k repfcK-ing ihe compound et'Pr&parsaísnoJ” uml «sSispC by \-i k ΐ\' líij;'. !í- 'SnoShs k-ih ' ΐ''<Λ k?k ' - i!' t -;noH<) s -- iülk*! :!>í>)í iítSv.
Higk-resm'm'tm .-««.« íB'/si,-!' nyárim! íktünsta: C.;Jk-kkkr rM«-Hf c-isicískted: Ί6(\$Μ$ ÍM* Η!'' m«;sarsii okkohö1 kssmamk it: íV^d-fH f&r«xy}phe«y 1}*N«ifs?l- i iek'shj'hm- i -isídoikhse öarímssmkk irydrockknkk; s (,á vo ro she c! t B .x ;».**.*$ »<*>' <oo»fvu«\i of sk«$s*í»SiíHS P «sed m ssspCísy n vs $ifv,"r4Mstj ÍphCísji'-i-nítM'^.ií-üxM·'' -αν-ακ- fMmmisimicrmsmiyais; s(hson fa? ).) HCsf:
'Mg;'· ?#7 MM MIT <\ 'iikuMed Ű$M W0i $. ?i 4.β$
Mami éS.M 5.55 <y.^ 5.53
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BmISIIIíJÍI ^ιί^- {5 í'í> p í> v 0 ísíí> r jí ί>ϊϊ» y í s® seí ii s-4~:«lllííyíS rt>« .2^¾ J #0 hytlwxihksrkte f ' o cdo £ ss ' v ' v<> <".s >*.·'. : v s . p k !fv vt> j< ,(»* >. 5 > í » > !:*<l m S«p Λ by t«? COí'ís.Mli?^ 'ifkKp.ir.:: OtS 5'. /: iem mfai micrammfysh:
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Bmsm??*; 12: V.-0--m<4hsl· Ι7/·Β84οΒ5-·> (5-5-(4-| f {3>S>.M 4- mf>rpk<5á>vfsíH3kvr)v3í4'4ih>drft'.kkf,¥y^!KpilaíkSi?yffí'aí1íi'>BySkk3-h{'ti?{i{lfí)S»Í-'5>5l'-SA?,k-· tat rs h y d γ»- i - i st<| okx 5 sav íwrkoxsmkisi liydrsídíförkk· 3 ise :|í?ísí;eiki?e is as sii flse:k?s>«gss öf:BssíkpIé 1¾ stf^íseifig íhe cöíripíítiíiitt of ^íssissí^íísííí 1 ‘ íaseá m S?^:é; ky ·:·:^' í:ii-<|i^;í;í-{fcíí;í Í^ÍCíis mef;f :?5y I íSí j>f SS^í'Hv;^ >S'-öj:sí i ίΐ:«·; ííiph^rt-minitttfi man f£§i·*);
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The psocadme is, as; in ί!κ· ρ«κ«&; of example L replacihg <m the one hand the uxnpooad ofiNypsmhds: T n;>.xl in Step Λ by the compound <st ihepaxatkm 3\ and on die other hand the cotnpcmnd of f*r«paratiöu l·’4 i a >"kps *' ' -* hn'\ 'ii íV'm I ovs'pfc.:·' N -meti' i < na<J^-<nak ·$}β$0$8( mk'fm η afysi«? %(' %ii W3Í: %C1 %Ct i.'ifleuiiVriJ rift 43 ,'i. v’j 9..39 $.34 $.34 t -rnühí íi6 Jé .$;?$ 9,S3 3. / / 7.6?
Rxlnhirc pú*>.'>. ηιΛ n öo.I'o mg ml , MeOHt
Vt4'B>JÍro\vphe«>l)-\V(íntkdhyI-l&'-i»d<d-í->IV3-{6dt{3&'ydbt t^-avxa/epstí^* > hnethx *Τ3 4 ddmh n- '$ I ?|)*tvdt|n»miitn í RarlntnyS j»íkh-he««mliox<d"í^'i}-^íh?tlhtetrahydro~1* hidoíhnne esrhosumide hydrochloride
The prosedntv is as «t the process of Example I, replaeisíg öó 5¾¾ «ne kasd íhe somponnd sf i^psrstioo 1' -xs -ed m Si«p 4. b> the compound of Ptxíjxitxn íoj* 4\ and ön the other hand the compound of fTepamioa I" used in Step C by .V-í 4- {{hTPhöiy l(dmiethyi }x%]|p^pheRyi^l*^%d*í/fc'ÍRdálÍ«atOÍIt«> 6aml$sm
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Cak-uhsed 69.33 3.94 "&M &M: 43$
pdóíd 69 J 4 3 56 S.52 4.4" 4. U
Example IS; AH4dÍydröxyph«iyO“^dknHnin'h tMd«dnt-5- vi)--3-dhd«vWí-3-'||<3^)-d· asethylrfiorph«lt«y!{r5itíltyl|-3,4-dilíydr»>~2:(l/#>)-míqM»Kdi«y§)earíxo5vy4|-dí3dtÉtsí;o<hosnl~S-"j'l|-5,6j?^S' tel ndtyd rö-1-ssKhdiai ne ca rhoxsm ide hydrochloride
The procedure is as In the process of fixatnple I, replacing on the one hand the compound'd? Preparation 1' used >n Step A by the stoinponod of Preparation S', and on the other Κβ8&&&«οηφΘ(ΗΗ£ oi Ersparattoft I" used in Step C by #-44 -; f nvr-hnty Kdinrethylysdy IJoxyjphenyD- 5
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Ssssmmisi lé; A^(4«Hydrosyphí??sy5>^<I*»«<tfe*4. ||íiS>>3*. «»««btj-imt^ri>i*«?!!«> Ií«*<?*^r«2í!HyquitKdht>t}<»rS>utti IP I ^fe«»3s«H?»o.· t^mtbydi'íí“Í'Í8d?>U:5ms «srSb^íísmiík5 hyér««.l5kírWs
The pi'>i's<kíEt· ü as hs the process of Evarttpíe 1, replacing on the «η- h·>ϊϊ^.ϊ Eh;; compound of i-Tetiarafhri Γ .'Λίΐ -ο Μορ Λ k t-v i'o atvaad ot ;' .-ρα· .short íí , a.id on thi othiΐ hood she cuouvitud ot preparation Γ o-ad m K'\ p 0 hv s v-t--: Bo''- bMUtpí{imt^tVíKí|‘rt5 !phcn>h t •iirethvMhkadoS-Mtron»'
Kiemmtot mkrmwfysis: %i: %tt %N %Ci <'<(ia<U*J 6932 SM X.m -/ 55
hbimd 0M 33$ $.44 XfS
Eumuth. Π: 3*(6»{t{MHMI(d5i$S)--ddMHtnfcthylHaerpfcoSUiyl|reeifivSl'3e4“d&hytSro-2íU#)' ss<s*3«ki<4m>Ik's* tam>!\ 5 .3-heiiiodiosohS-i Π- 5’-{4-hydro\i phenj B-VtBI-1 í/'íníh>f-$>yi>*: S/í/TJ-teEríshyih'o-h-lfííhhüksuí e8H)«s.ij!skk' hydmehSorldt-
The ptocedure is as it- She i?coee-.s <4 Sssmpk- l, repsacing on the o^c hand vhc const-miad of Preparation P oicd a) Step *. h> the ei-ntpouod - -s' íVparatkin k <o-d on ko ether hat'd die voinposnut tdkkepsraiisiis I" VM1 !,i Step ( h\ *! {, I (h tuv tniihiiV* >t ov. ;P>\' "· · fi'kkl iff <no<4 o <n> ή
EkmmtiU wf*srm*afyssi$i %c %u %n mt
Ciiioftotsfii 6939 (>$)$ $.4a kylf
Fi-nnd 69.2$ 5 52 5.45 #p E^tgglgXf; 3-t6-Br«8so~'2-'ií<M>3-4^«í<irp&«il»ylm«dtylh3í4^ithydrO”2({í#>'tsí>gt}t?5adP>{p i ite protuSttre is &s in the pfheessof Ikaatpse I, rég?;u:ksg on the one hand the cinnpomtef of Preparation t U;eo ül aav A k the i-ant'oret-i ot kipattanón .5 and vn the othet hattd the .omponod -s'soqwetkn k iR.ed in Step € hy Λ'-pt. t μΐ:ί; .l-atyhdhneihvnahySkixy; phenyty i -methyl· Í 2/dndoh S-smine.
Wigh-wstifaffott mttss >'£Sh):
Baa-sack fúrnia Is. t kuo'ShNe >.5 jM-Hj laicidtned [St 1st a-ii isared knk 5'UhBrosstű2'k<^XM4-mrp&oli8v3»isth>SKM-dih*dt»'iO m b^nUsMmvl) «sHioiivilfíhííSííl-iV^^líyílr^^^ííyD^fl-msthyl-tl^^Hh í(if^.1#í-ia*|«S-5-v|^j^s«ir8Ííj-ár<i-?~. 'i»döUíís* car hmrss tóidé hydrsKltiorkii; iK ' >K\'it, s ís ' \'piu \S ί,Λι e oUsea ! v >s\ S* x '{\ v j.'Hi v rsstkm f iped *o -Skip A by she compound of i^spsraisar* fi, &s*d <>« Ute other hand she compound of Preparation Γ «.ted in Skip C by i|íeeí'4>osy!fdimesh;'4}dS4}o>:>i|)hefi>4>-V-moshyb-5-iiKbSii';a!nk>e fiíghi-rewlatim msi$ {FSl··}: lümpsrieai fontad»: :fMHt| eokikaSed: &ϊ0.2£Π .IM-s-Hj' mea.sored: hoO.fMi
Essjssanle 3tk 3»|S'CMoro'2-}f{;&>;H4-ms>rph«Unylmeth>í}«'3,4*dMiydrö*2í*//)ds&$öhaölift$!Í):? earfcos*Mlp?ienyt}-A^4-hjdroi>jUí«öyIHV..phe»yt4S1d>?^t*i!rahydrö-ld8döJi;íd»eearlm8amy« hydroeltioríde fhe proredttre U ae in Use prosx·^ o* fvample i,rcpkicmg she compound orpíopai^tok!\8^iP:'St«p.á by she eomponssd onvepamuon3.
Elemwf&i mii wmatyxiv « 'W: lír f.'.í/eiíhifeíf bk.M' :.0$\ ||S: 4ÉÍ jmm &fM Ml Μ'?
Rfttemy pm*ft; f«) ^ ·= > $\'"'! k' ·" A mg·nd., MíOI I s bilSMUlt 11: 5-'{S'rbló«>2»|C<M'K^C4~o^oí'ptio5íssytmoíhv|)-3,4''dshyd5vsí--2nf/)'issns|íJisíoílíi\:1>esrh!>i}^|-> pbsi*íyl^A;42,3-dMsyánt·· y/^ssskiS'S-yiVAH 4d5)drnsy phony IksS/sfíed-HOreSiVíSro-S-ksíloHabse ^Phbss aside IdgUyslreehtorUM) she procedure is as is* Use process of Example i, «pacing on Use one Uasxl bus compound of Preparation i: :^d η* Step A by she expound * Preparation 3. and os* the other fssmd she compound of Pseparatioa P :u$ed in Step é b\ λ-<4·![ί. >í-hesiystet*^-esnyOssK t|ovy5pf*e«>i
Higft'fmiimiiW nms (i-Si*): U τ*ρΦa\si ínsssusUs C5,JS j M ; Hf cak ssiated: 742.31 t>0 |';V1 isk un-usured: 'M2.3 S2.0
Bxatsmk 21:. 3-{5»0*fc*v« J ffHsnrpt ioollpyl)·' carbony ijphany §}- •bA'B-hydt ns>ypb?8j U'^KJ-mifeyh tiiMstdob 5-\v .gS-íéSrsíhydrty t earhoxasnitfe hydro* hkinda ?fhe ^nx'vds.ü'í' Η λ·ν in the procass of Bnampk i> svphtcing on the on*' hand Ü-e compnisííd oí tht pánidon t used in Step A by she unnc-hüíd ot Ft * swot fost 3, and on six ntner n-tüo the contp>.ntins n; Psep.ifssoon i used m Step C by 5Ppt-{[írít -holy hditnuhyijstíyTJonv}phenyft- t ·tnedjys - t >’/-tnd<-\ · ν·»ηχίχ·. ${£ %H %N '$M?
Ctíicuhued oé'IM 3 V 8:M 494
Fmmd fiZ*4 U6 8 64 5.2Ϊ 8<mmy pmvtsr in.) :-y' * 55 r (c -"/ ots/od.. ívíeOí í)
Bsant*ak* 25; ^jS.f’bimti-2'Sf^Vih5~j4»mi}>bnila^ ImethviK^^'dihydt^^tMy-ixdraítydrn- I -i»dí»Msí»tf corbo tot aside bh{byílrn<-blftrlde) !hn pívv-vdinn is n.\ in dx poxi's* of i'voopk· L Hp'h<.;ng <.>n tix one band the vOftspohttd οΐ PíigMnütotí i ttsed in Step A by she cithtpoond of pfeperanon 3. and oft tlx; other wmű the ootnpbhoo ni Pfspápttfosy b as«d in Stsíp O by A'g'4'if.n;>nxbifi:yiiö}ínoihyi};;iiSyi|i)xy}|>ÍHdtyi.bi'Pté?ti>d-5-inslojing3>»ni;- EMnmmf mMfmmiysin ne %h %v %n %cr € mrnímd 6tJ8 sM fis e sj #·;!> fonml Pl /.? ;5.# -V. .*« ló .77 W4 ftturi t; i#> s · hoo'iv 6 nxMOt MoUH' ESiMM3!h2ii.5''^''l<dtrom-24(|3A>M;4-'OforphídhtylmethyiK^4xiihydm.x2(il/>· isÍdhiholbtiyl)<&rb«»yí|pb««yi}-'A}44'-itydrosypfee8>'lpA!4i>f«eihybi/#ap5<|<iP$vyi}-'SA'?3'-í*<^^yt^'»’^“ Ιιϋ@ίΙϋϋ^ <$r!m*myeltyárftebM4$' tbc procedure is sts in the process of Lixampth i, replacing oh the ont* Stand she corepooret of She nanus iort S stox4* o'- Meg -\ b> the i-Oittpnond ol PMMfntvo 4, and "n tűi, otbet hatni the i ο'ορ>Όθ>ί of Bsepus ttxsa I stsbd ipStepC hy A"^4' i i'íi.íí-^tfytídtíneí^iyOijny'Mö^vIP^fertvl)-1 I tsjtftil ö-itíitiOe. Ψ$ξ: %h ni ':Μβ' ÜúiúóShiéé 69.80 .5 88 ). 04 ''$&$ Fúrni: ms? S.82 FM "'lii? ö*·” -í' s^gii, m«oh) V-^isgj«j.35y 3*|S»Fi{»}tí}»2-{(í3>S}-3-(4->í8«iE|íbioil«yí8íeíííy1í-3>4~<ílhjfdri}'l(I//^'&o<f«iiioíÍa3f|>* exrhxxv11§du'xyi| Vi4 h\ *ltfss.\pb!, ml}'V-pix m b6r»· i-nniuHafee es$f box&sskfsí ||?<ÍrÓsli|jsrye f be procedure se <iá sn ih«· prxxx-sí v* t xsosspiv L X'phscing sh*» eosxp»n:Sxi of kívp'SXsísixx í nv-d üs xsep Λ by ^he €ö8-sp0í.is«^ oí Prep&ralfon h
Wkmtuai mktmttiifysL·: %e m %n %a rmmum 6«n $.*- ?.r m
Fomd 69.70 SJ2 ?.’'? 4-& .i:^mgk26í ^IS^feter^»|{^yb-3^4-mer»iioÍtevlm»th.vl^3«4»ilil^í^»Mtl^i§«^.»l9ölÍ»^ ^8rW»s^5|phtf«vl|'V«<4-ís>OítKvpfíí‘n^4» 5 ><i s«s4fnl 6'^í*íftohiu kér8bybf!>'1 '-mdölksssí; esríHí^smíds· b ukodtSoHík she pío.xdare o sxs. in Un- psixe·.: oíbx^xpk 'i, sepíadng on dií- one ixuxl she coTTípossod y fkípsranon S m-d hx Sí·'!.! ,·.\ n> Uíí ^!nn;;<‘Hi!!!! '·! Γκρ jxS\«x * ,ísx; nn tlx oíhx-f fxsd she ‘.vmp-xxS'í of í¥es>e etsosx Γ' vd '?> '-ke x In ^ » i\ bf'\ < hsk í'sí γ* χ\Γί <\ι'ν ' '4X „Xivíko-6 íXíhsokísasxxx·. Í.ó>miri>oű mk'mamifyih; fthe<»y for 1.5 HC!) %C 4«// %N %0
Caksflaited 66.0? 6 0S 8.49 0.46
Fmmd 66.80 5 55 dj> E*amgk 27; ü-f$>Cftf<ire«2-{t(3.V)''3»?4-f»orpfe«»lf»yi«s«hylí~i»4«dfhyám“2(í/fHsoQö<SföÖ#W?^^· pfeeosff}'iVvf4'hjyro!ty|>h«»yl|'AH4-mo*hyf-3>4*^<feyd«V“2W~Í>4'“fee»*03i«xi»'-?-“yl^5A’?>8^:p8íJ^|^i»|.». sndoflKkse earfeosasnkk hjdrgehioráte fix p»<vxihíu" n a s six pt^ sí1 '\<ínpi' í »ep,o. ι'^>ί *' >>í\ hx d Oxo »\> tOs'Xl >t sheen anon svM'Stp x “V ' <.o sxn s d < M'cpy* x x < «sx > x'Sh'.s xs sí \\í „ iti>' >'! epohs^e i ί!ί "'Ηϊ'' s. K ϊ ιηί'Φ\ΐ \4 ddp.d?v ^<ws.*v:4sr>- anshse. : jgtmmktí |heöíf: :|hr ί, flIOÍf «:: ?«/ 4<w ;»*
CMaMuM 44 5J $.M f,&? MÉM
Fmmé 445$·* Oö M4? MÉM ^(S'C'htet ^{{QSbi 44*mwph^$m*ihylyXMálk^mMÍHywv«múlinyimé&fpfc. #«»vlKV'{^köfeihvIamlno^h^syli-^í'íMsyiIrsiXflíK^yi^SA?,^lefeé&píxM mdstiüise tmhwsmM* hydríKOdorkk * 5 4Γν"„\\4..',; s ί,” 'ík ruKí, - <4 I Ννί«φϊ·ν' K fcrLifítsg«'« iK' "*>v fusKi 0x >..^vponm3 ns sln'w* «*<'5 É üst;! in ‘>sep .4 by she compound of Prcpara-km <, and os? the βΐίκχ hsad Öté cö^öpöand «fl’repiimUsft i;i ayedm §igp£!dsy Λί=^^íhy ^ í;ü iy ? joxy ΐ fdie?syi)--^fA>4-<!ígisl^|·· 154‘%8*eni«^i»mtr*8.
MiMmfM for Κ4|4€% m: mm ?#r %a iMmMM· MM Wá Ift difi:
főnné 44 'Ί ÁM ,jf.jp MM famafe 1$: 3»ÍS»Chleyt>-2«Hr^.dl^4.«i»^éifevÍ^daivlK^4»dih^im>S< ρΐΗ'?5ν|;-Λ4ΐ^ iSidsd? o- lU'máúú-^-’Λϊ S >,4-Imií í i \y|>l«-asd VkO,7,8-ts-Sm4v d í ;>-i >;o:kdki««í i'.mhaxaskids fsydvochlorkk
Hu- pnnCiídsak k as ;s< dtC p;<SiX5.S *>< Γ *£ίϊ.:ϊϊ^1φ 1 < SXydaemk s>ü íhc Oí'í- hSfiá Ok eníkíVs-nd ίίΠ'ΥΟϊΧϊΓ-η'Κ^ \\ asad 0; Skp Λ b\ dn; Ckkispaand of drep'Snsdon ?\ and úti -he uihet hand Osc coínpoanO of Onparasson |«. siíkx; ;n Sícp C hy A:-i4-f liars-í;)ísyi(diioe0;s4sdiy;)o> -> sphejA s)"5~iadanass>lno
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Mmmé 444? X4Í :?:?/ 4.2! hkmKSjjk'AVk J jíd-soethxM ppx$sut mjOioeibs íf-eM ddntbx MII* Ho^8ínöSÍ8>!K*^>»>«>'Mii^t»yi}''^'í-Í5jüfmíphvnyi^\*tí-«í6íiíyMiM«tioÍ'5-víV$A',.S*mr»hy)Jt«-í* Imltílame isrbos&íftkk'· txs(h v <| rtxp b>ri ée .1 llvj $»xHCit v v *> m \ x 0\n v'í UiX\ iv\'li(.'!'j; v'n >)ív. ον,. Κ'Κ tfw ..λ"|>olsö#::0fíf«^ís^í§Jtáí·! í'íkí 1' sxa;i so Ship A by ttx- x-'»|mxise i.x«ipxxsixk hí' Ptepivaítotí:· .5 ;sod s"; s«-i >x; the oihtx haswt the coinpoisüd id PrspsiSi-hh í" esőd χ· Skip € b> Af-<4- |{^kbat*Hd«8^hyU4dy&}<^>i phboyf)'I'tnethyMáfc ::::XK>: 'i-iSÍÍijüii
High~rtss#luUoi> »® ihSHi; b.mpsritxd íerstmtá'. í |M^M|y edculeied ?«>? 3W |Μ.·*·Η]ν sms&iüred:. ?h/;34?b kjjyi»aig 31: gÉ^^ÍT^ISdM^á./^iaof ph<4ái#jí»«tliyÍI4^4k<ÍÍbvdr»»3f 1/jh·· ladMíxlsó esf^asstfsídfe hvdrp^fhtldó
The prove-lare is <ss itt the pnx ess óf ixatopk ?, repkchsp the compound oí f!rsp;snuh>n ! ytte-d in Step Λ by the coiiipiMsüd of fhvparatsft» s
Iligh-xx ohítkai m>:s« {t'Sl·^·}; i.-mpirsciti ionxs.da: iVIb.Ai k'>, ^ t Ϊ' *. íLt i \ i v t<
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Uk ooved hv I'· sti iht' ps.vess <> t vjutpk t x'oWxto oo Sx' <χχ h<sod tK -. oop ·-' ex Γ χχχχίχχί \ ,,-xxt x -> ,p 4 i<\ ti\ \<x vu«>d ef fxxvxhiix· ' 4*»t the "tbes hat** the compand ^ Γίορ haste® Γ , ^x Χχ p * h\ \- \ \ < > I 1 'p t' o ties ! ' i ooíhvbtíMitotíks-aHttRe,
Efemetiftti micnamniyuv: X® %H %N 7*<v Í iVoxavk-iferf 69.&% 6 0$ H, 4 f 4. ··$ /h ··:'·.%./ &9.2J hi-fi 4- / b {δβ<|»ΐ09ΐΐ»^Ι)ε&*·ίκ>»)Ί}ρ^8νΐν^0'«ί€Λ^Μ^Ι»00^Ι>«§,^»*Ι«»η»^ί»».Ι^«ίίι«Ι^««: earböx&msA- hydrochloride "The piocvdtue j% av is; the process of f:xmpk l. (vptmmg sas she m« tod thetíöíöpousisS of fb'epamk>t3 I :med m Step A by fhv cotopound <A Preparátum 6... aad.ass tbe other h;sssd she conspoaKd of £fcepa?aiőtt· Γ* »V ' v C ' '1 Ii\v U)\ »0'θ!Κ¥ίρθ«5»'l> * SíiiSiV *i 'iJ> ^ ' ' 5 £
Mémmml piíammaHM
Mfi MM %N %Ci WMiiiilüM MM- ?US Mi Ml
Ibmil MM >.M MM 4JP 'ΜιϋάΜψβ#^?' io)*, ' * i ' s'-hiüil WOJVs I^áSJUtkilí V(4-H>«h<m phi SiVíkki^j(OSV3-(4-í»erpbolíoy tele J hy IKh4--dsb vdro~t( í Hl jsí«|ííiöí>liayl)csrböftyM-'-3~íiihy(írft· M'hi8iiXodk>>hS“é*yfhA“ph«syÍ~S5&>7 jAeís^hydro^dsstksíMse ϊ artonantlde hydfsahiai-kk;
Thbílsh^élí^ ls áSdh fsa procsss· bf;Issstsffe: % rspfedsíg íheibsaiperf^í^efafatljí» t osed fellep A % fed epipitó!«#:íítípsíylöa M
Etetwtmi ftik-nnimshtiv m: mm mm ml r
Ifefedfeftífe 0M SM: MM" 4.66
Found 69J9 :|p. Mm Ml
Koie&ay ptwor: <«) 5/ * * 3-1.5" (e 8 iagAnfe Md SS; >
KxtatapledSt A^(4-Hy<lftn:}fpti«evIkí'V^l.«8«<h>l-'í/l'milol-«S-yíh3'^*H<^Vh3“(^*8*«*'Pfe^y^*^i|liÍI 3<4-diIsvdm*2fl#í>»}s«q«l»oHsijTH'«rb0»yl|»S3“áMíj'dr»»l>4»bb0X«>ál<>>Í8^*yl}-S>6,7,8í'tgi#«fey'ámiÍ*:: mdsrtfehse esrbosissKkfe :Th« fssdeedmi sshíss: fer.Éss |Ms«»:.of;&ss«pfe 1 *;.^tó»gm;|ÍNe.m& hasd tie eetapoetiás»f l^pmliössN'i: esesí 5ss Step A by she toseps'uad a? íbűpssraü»:* ?% ássd ο?: She «she* hasal tbc coinpouod ol'IAepsSsStoss * S^* <. s s ^ ! h i '' 't \ s vSh\»X \i\iw 1 p 5v.8\i! ^ s > s e»us«< A sH-sna: .soaferssood shssr the product so obtained « aot subjected to a step cd sah tonoabon La fe^píds§fi£dfefefesrsíisi bydrcspofeífobdfe Eíemmtstf wfcroemfysb; ihkmim&t.· 71 s? 6.09 9.űo
Found -MlFf 1.7Ú 1. 65
RnUFoty /WMW,' i'«] ti'1”·"· + 58.25 (e. - 7 mg/m;.. MeOH)
Example 36: i-|íkEthosy-'2*{íf3SKM,4-}a6rpho!3aySsH£t&> lk3»4-dHiydfö-2í i M}~ boq«»a&N«i> ifcaritKS»y !|ph< n> 1}-.%'-] 4' hydros> f >heay !>-.V-í i -met S*> s - í íí~ h'Ht>>k*-¥! n$d> JdMt í rah?. íko- l- iaftolíxiae csHxre&iakfc hydrochlafMe·· 'T^--|>w«daí«::^:''a®Aiít’íe pmeesss^iissiaple Ί. eeidiwsipg. «rite-we haod .tht-eömpstmá nf: Ikepsksdn :|;: ássd ín S4^A%:---%e-.eöm|^8ad;iÍ#-#f«|»mífe8 §* ásd.;*sa16« sihe? hand íds seaípmd rf0?«|S8F8tte;{ * \V. t n-Si^pt K\ % v5d; Sínyli 'ítt\í.'5í:vOidyl)síN%*p5Stíi>h' 5 TS3t>* \ 5 Sí üKSnkkuVí'he .Bím^MíMémamiysisiy %C MM:·. 'MíV %Cs
Cidadaíed .7.0. S3·' 6.30 ·Μ?·$ 4.43 Ά 7? 33^ 3M· 333
Esassmk; 3”; Λη 4-llvd;«ey plíeay !)~!V.4 i -«asthyl-l £6 ÍRá«S"S'y)}-&> f22kdideíderiO'6d{fd>5>'3d4“ mf3rphoH8y!miíí!sy}y-^4'<li&ydi<»“2{i/#)-i^q»i»öll»yí)<?8FÍHí«>1Hyi.|}«ft«ittiio*ol-5~yii-5,6,7$' í * i sah y d rs-1 d Hd;> h #: s se e&riboxsmide hydi'oehktí ide ^fe«'p}^«ákí»%«Cfe:'íib.p{«c<-Ns sf Example k rsfdaemg m ás fötssiihand ífe:«öm|^U8Íöf:P«pFaftésj:!i:: síssii ím Step·. A fey ites-eöíkpöand · of' ^epif^to·:^ s«d::<«B ide öifeeí hand the compound sf ..Pfep&tsikat: í* axsd th Step V hy .v -(4·«{te^butyiklij'sieOíylMjllllp^yl^h^y^^iöeűtj 6 s/í-stklokS «kme>. £%k-oo iokííhm mm.% i£Si <·}: hmptnsai Ssmnda: C.sji:jN .OJ7.
[Mdi-if eskadaiad: 766.3573 [Μ Η!]* meaaníed: 766.3533
Raums-y fí?hv>\ κΠ * ^ 1 ~ > 6 MeOH' esebösaittiiéiliydröeysseide: AA/A^ííísbíöíobíf-&·/*'''V* ,í ,;4
Thpposedoyp ss m-tóshe pp@e«s& «('Bsnospk:!.y.;;!E^1íPÜs§:^hSf6í>ppw<; of Prepára? tó« fepsodtóirsp :&K$p íom?»?K)r< 1» she prmtóWíáfsÉÉmáli : ísjíilísps «Η tódífeí i&s cost tód: »ísis0(%5tó tho loifews 8% S-?«p;ÍS:· .VPy H. ^~{4-Hyiifax}'ithiífíyí}^S~f2,^~diih'sierht~Ú~Í({ tS'}'3~(4~tth*tphi*tfnylmethy#~3.4*tíi%$ér$>2fí4fh hxqiuni4fflyi)i'M}xm}4j-LJ~ht'mix$h>x>4~5\\if~8>~phe&}-mrbifxemMií·: ki'dr&ikkidife ":Ü®·:pÁ» ö&mtótóiftóltóp-¾% d&söi:ybsI sü dkb2 tói: of lk tóteroai: hydf-ogps ehlorltó: m. sBtóál The wbofetó siípd: Itó m»:kmt; astóltós*« vapmy :::tó:'ililyiltócifetós «0 Sítósilel :i; slsssölyed !p;a waser.'-Keíonitrife «sűrűre sanh i.*>mpbis*l>· tó^oivetó nssd >s %C mM %.V Sig|: «ti5 CííIííkIPísí? 68.93. 3.8ű oTd 4í3Á 4,35.
FiWi'ui 6K4< .149 ?5:" 4.6) 4,54" £%ímmk. í9t JVH4-IÍ>^r<>jyphc»ylV'.V-{í-M»tíííyí-*/i-í«diHWÍ-5“y0-3-{7-l«MV3-(*-moíTphtóÍ»3rite»«tl»y0‘ ΐί.4'*ΙΗ^ϋί»-5«ί#/Μ&<Κ|Μ»8ΐ>Ιΐ8>Ίν»ΓΪ>08ν1|'2ν3-ϋίΙ)>·<}?»»Ι.>4>Ι»κ»5Κ>0Ι«ί««·^5Γΐ!^6,?,β*Ι«Ιι«^4ΓΛ'ί-·
Suiioltói»* eiPtesa tóidé lipl roefc lurid* tik :pss«tósrg ffe m m #&paöís»s &fMkmfk h, s^ptóotóg: oa The:ops^tai: tóé mspmmi -si' Itóps-tótóss 1 ;n Ssep A by ihe <on;pö«S or Prepámtól ?, and on the other hand she compound of Psepamtóo Γ ?ned ifi Step € by :V-(T f^^tóny]ubín«íbyí)yib1|on y} phessyi}- i -meshy I-! //.«tóastó-S-amtóe.
FfmmmilmkrmmlysM %C MH ?*€/ »tóöM no7b 5 hí fiUr 4.35
Fmmi ö?.$2 >25 9.4? TiS ..ito>ff»»w., <<«> Ay U.62{c 8 mg/ns!., McOHl ::m«m^fe.^»mi4>Hydraxv»fceav^¥4táiatófcvfe:ÍJa>4'fe^i<ydr<>^tó8<»Íla»l)-3>i7-l{{M>J><4-> mösrpM»^ia«tóyU*J<4vdtóydr^ai im-tó>ptómtós> p'ösrhonvS j--2 3-dshydro-1^N?a^dtótói»%% áiyd ro> l -sottólktóe ess rfbxa bydst>fibkrtó«
Tte:p?®e«te:k:pytó^ :íb«::pneogS& öí
ami tó $tep A %; rise cosnpoartó or: Pfepsotóon ?, sad o« the otiser hasd íbe noppöaml: Φ Pfepstóors: P
Mi'd id Step Q by VO-\| A '* d>s$U udm«dh\r*s»k sjv\\}phe«>11 l*«*cth\ t \ ' '.>HoH>thNd»v 6 qttmoiimniine.
Khmimuti micmimitfysW %C MW %N mm w:r
Cak'diiteJ 66. SI 6J-6 KOS SJS 8JS
Fvimd 66. S3 SMS 6. 04 6.4? 6 IS
liSMÍ&fe díj d\{4-J4\dri>\>j>lH'^vi>- V(-l-mtst3^bd,-4dshxdrsí2//-Í,<4-bí'S5iy<.í\íf,íh'! ^3)3-)7-13fd-VhdN4-ssíorphuditíUtfií-tlst SKM-difndm- '(1 MMiquhtuHnylkar bmn 1)-L.3 dshtds<.s- Ld-heisaodMUso-dHtSV S^T^ictrabydn^:! hydrotdddriöe Ϊ Hií pioeuduse n. isi' üi tbc ps-ve^s ''f F\<nop3e d sep^oiíip un the őrse hand the cosstpmstid ->t Pa-ptt-sinns s used 1st Step A by the eonuntund of P-vparstsott 7. end on she other -hand the eompotstto of Prepáitiot> l?> -.-ed u Step 0 bx h ,l »S -- Mse etK '-si' ο\\)ον*χ- - i-s'seth-i ' n-hhxdsn ''' ' 4Kn owst-ammo.
Hiigh-mwiutkm mms (SiSi·!;
Eti|?iHcaI fdrthidd: C::Hr)Ni<Ov ÍM-eHV «siashtted; 796 >730 fM-s-H]’ mtssmired: 796J6H7
Ex&mrdg 42s 3*{$»€?hiur«-2“}l<d£KV(4-Hs<»rjth»!sHylmelh>3)"J,4-d'dtydfti-&ii/>· t^oqMStioURxiU'itHHsaxIsphi'nxH'k ii-hydtinvphessyi) V() «Mb^t }H us dead J* tii S6,7,8-tots'áhyd*:o-l>mdislhf me eat hoxatntde hydroehh>nde 3 i;' pso-tdm*' ss a in the yente,e; os' L'vt’sijde : , sepia- ;ug —s tin one is,-,nd Use eosopeessd ut Preparation 3 sssei'i in Step Λ by the compound tsf Preparahyrs 7. esni on isse other bund the composmd of Preparation i” uss.d ;ss Step € bt V.{.+. {iítrí--b«íyUdjmedsyi)sstyi jo-ty Iphent is- i-ssteihsi- S/j,-is^d&;-toi-5--uiViStie:
ElmfmtMmMtffifioh «%; ;|S€ %H SÍN %(7 bd. ",? $:$$ 10.6 \ S. up 4 4¾ /-'ijttnt §6.oJ i.Of, i. tj 7 eh
Example 43: l -J5~Chlw<e b-llfMVd-set-jstni'pittstissyksteíhyU'díd-físhydrP-l-fld^ Κοΐ|«ίΐϊθ!ί«> hestrhony Ssphrsxy ssj dsxm phemD-.M l-nsethv 3^ih>dt«-i#dudo3-S>-v tetnshysiso-d -SíKki!í2siK· eső btsassroide htdtoe bin tide 1 fii' piocerhre η ro át tise proves:; of ooso-pss L tspköep oo the <w hasid she coropoorcj of ÍVep-ar»ts< >*1 § Ood at Step s h\ tK- i.0.'0pt'00o ot Pfv;'so.OOn „·<, sop oo to. oik s Osed do, oOtpoooJ os' favporao.sa ; issedtlaSiefs Γ Hy A?.<4'ífífr^h«{>dfdimí{hyniH>'i]ox>-}plKi«^! -asedsyi- I/-/dedol-S-toae. ;p||í Wi UN $ÍGl 'w Ws I?# -$M $-97
UmmN 78.29 iJí 8,76 994 l:s&mp&44; 3-a-Fjjioro-2-f;';M>'M^P»triiJP^ftP»^P^HhvlKV4'dihuitoki-r^oieoot0ool;o>rKotroooy1l· :gíÉehiyl|»^4*hydr«ayphíífiyí^-i^!'i:^ía*^>'*-<í^e(^aw^y^SA?^ÍMetr«hy(lr8^l-':ÍRil«lhíitte· csrboxa mkle hydmeftferíde :%»':pw«ÉM h &s inihh pí-öpsss ef tomplé 1, »f#í«p»aitoi issed in Step Λ by She eoospo-oid of PrepiosOioo 4, sód sas ibe odor hsad ;Pe voropotKid oí Preptsraíim; P issed -n Step C hy ,SP4dTíe«-halyltdioseihyltdsypoxs ipiooyP- 1 -loediyl-1 fpauleooks-aasios ff" :to %ii 8m Műt űáímúmi dill? 3.TP 4tóf: kd? foss/iív MM· |$/ 7MM 2.24
IkMpaaiS.-it; ^ 4 bb>*o : ,^ΜΊ M* ss«opkkss ltot shelf M dkv.lso kJfA i^iMfcfthíiyMtíarfeötiylh pheiieSf \p4- he dóm pinán IV S (1* mohk kf dih^b^sHemjeydopi'opsine- O’-íaáöil^S'^'ijhS.Sj.TtS»· ieleolivílfο -1 ootolodoe e&rbóXioa ide
The procedure is as ío 1 he process ofEastiSsple 1, teikickg oo She one hátid the compound of f reparission...... ősei! it) Step A by the earapeiasd of Piepsi&ike) ?, and on the other hetid die coiapmntsf of fh\sp«r«!ton iK esed ίο Step (' hy -V-{4- U&v/-bnty Itdsmelhyi pals Ijoxy) phassyiM Ϊ knethyh 1 \2klshydrosp; rojeyeksp?opano-IJ oadi>lJP:ktoto.
Ek'mmfá! mknxmái}\u>i:;
%C %H %N Cüknímuí 72. !S 6 .IS > so fosaid "/.ff é ró íö osrKnn lebeny ^ X- íj'hydso!o<pSon-nΓ·· \ Λ nk-hns U# onhd>$«yíy khJJ tySusimSs'n· ΕνηηΙ«Ε*®« es rli»x e mid* h v<| r»v h íöHíI s;
The procedure is ss in tbc process oh Exsmph; h replacing <>» »5« osj* hand the >x;n:ns>s$nsh. &f Vvsspm&imn il ond Γ íist. ο in 'ik-n A h5· Un· s\ sssves-ve vof^pnosu?^ ni ihk-r'U'isiinsn * nini 4\ <.m she othes·' t'sSSíi áss iipfilmihd. QÍ ^spáíllib 1” US|d si C. ;b>í: ilüíí^íi^ Ϊííy|]<iK^>'^hi£5íS^>HÍ;Íi^mstí^ ί·/ί*:: ksdki-S'íiínink |igf p# fP: fi|iá%í^· |í#: pJ# f· - >.·;;. í n.e. i$ 3.4.5 Λ ->4 8o*iWti, !>*». , > <o ^ θ)ξ , Met í romaié d*; kk^livh.o'. jdvnviV ^ <« t»iíl»jt Sh'-v-nkd x- > I Vd~ s 2 * [íyA5VA~í4-s«ospisolmy kssíet hyi>~ JJkhh>drk-2(líifM$ö<|4km>dinl>n5kikk!yf|-5H$?.diwk\km'dí*Hidkk^li-£4n?Jkí£trahy4rö~i4rHfeyöSie eartmamid* hydrochloride *-* 'Hvydxf^ "v *s i'vvp vC^ ^ \o íí c i <l>« f \'ií il. t Ja. ' tu* 'm '<Hss;d xh PreparalsöH i iíXvd ín Step A by the compound of Prepttmikut KK suns on she odú'*· hasd sSse compound .·»$;1%«ρδ^ίΙ«8:: \n n v>'p i Sr\ S ·. y |^v ' Jidu'x s*nsiv |ήχ η V i v s-i *-sí * " ,5 kne. Μ^ΜΦίίβί mkroimniyvh: $ÍC & MN : Mgf
ΦΜΜχΟ MM" IP $$$ 4..ÍD mmi: MM' IP MM·" 4|f
Ilx.SISMkáÉí. ^-<4*nvdinxy í»{iC»>i)-V-(1'iS)«rSh}h í/f~fndi}l'5“>ii',k| 2-j((ASV3 S 4 són r phkisssyhn * s h>S}· J.4-<sdudt«í«-(lí#} Kotpnmdmvik\artu>nvi)-M*nfluiiío«»«4feím í Jk'nJ!-kS>,'J retrsimlro· § ni.'SJmíie oa rbn x n so id* hydros: h ksrsskí ihO iMv'COihSfS !X is )0 íik >' í \'·ημί· * ix*’M( ϋ,;οΛΠ. ' ví í !\ .' s\VSi o 'f H«oas-ahöBí:X'· issed in Step A by the compound of Prepaomon i L ami ο» sin: οίΐη.τ hand she 'kíüSkOisne: Pk^jgfaSSXSS l”· nsesi m Sigp C by .S^pkCl^-'hotyisdimethyl ísiiyI|os:y|>hvnvt>' t-methyl·! //'•mdoi-S-awintt. gietamtaf mfei-ttmtafysh: %c MB MM κο %ct tótó&tótó >·11 1.¾ 1? ·ί. 22 /.tó
Found '6Χ7Β- ,1 s/k ki:i /..1? 4.;M
ItóMÉtó&tótó mór gjhiíüiSíítvÍBíe'tííjO'^'i'í'^^í^tP'il^íí· -mttMimv ^síi^ss y is- Y-(V«Mrírswfcx \*iJ~úifcyáro~Ul· l»üoí-$.ylV :5A^tór8&y€P8síl«É8^|l*ÍRe€*rl)0S8TO^ 1:1¾ tyw&sém. k as: á* íbrfjsaew sxbtóitópk 11 F^jliiij|;-.öfs- itó. tóixIÉ&Sife»:. <sÉi#!8SÉ#í?l§|s^|iI^ J, vmálfa Si®|í íl by Ilié osxaspasid of HepsraMon 1, and on tho othi·» ham! thv onmfvntó λ*· Pupation 1” áSiísli sn Sisp C fey |l fkysp atósrstood thai iho pmduct so oHstóptósd : k* a stop df:iÉsi?l&s;8^:iöö· aí 5tó:plbósóa bf'díitótól i %ábsgesidy!ödds;. áltató^ ΜίεΜβηφΜ*: MG %H $m
(btóstótó IGtó &fí $M
fmm MMG mi MM
Emmák Mi MM4tóyd»tóitóivb-tój i -m^bykilfekdi8^I*Mlk^pj^iaig«!!$jia»$»l tó rtóydrsi-14tukdtó«* «8 rtósstóde hyd rtótótóh 1¾¾ pmestduts ás m m tó? oraesss tó tóatis/tó h. r*ntó'«)*j on ftó osr; hand tó: compound of ftóparsttUP * ias®á4» :-Stef -Á-% ító^tóltó % and oo ftó tóiét tótó tó: cumpound oí kapásaktól* s.iisxS Iss Stop C by ^^^s--l|i>rí'bísiylibbnv:tby}>S)!yi!íssy|ρh^y!>-^·m¾bs;yG1íGis!ΐbi^o^ítótóm?. MNummulrnkmum^m ne %hr %N mm; (Mmmrn m'mh sm mx4ú ·<·?/ tóístó W7 5.W 10.2* Í tó
Esssmttó Ms tóftóf4μηrnd m^hy1pbKfiyl)'' V><dí|ydfs>sspbe8>í>'3'-!2,2-<!MiHitS‘í‘ks'!l'HGl.S)'-3-'{4' inoq4tólSiy!8tófeyltó,4 xbb y ühs-2^1//}-iSí>í^iii}tósiyl)taf1)«nyM-l ,.l'ls«-í}xtóÍ<>so!-5~yM'-5,<sG^8- ic-i rss byd m-1 4nds jfeiso oartós a s« «te hysírocbtó-kle
The pnx:>;xlara k as In itó fírosass tóf.sainpk \. röpkékig on er&m limá she mmpmmá af PiXpa?aooa ; ssxtó wt Stop Λ by she compound <4 ttópsrtó-xi Ί and s>ti ítótóblh ható she compound of f/repsitsdtós \ ’ svbsa tópx Hs \ (k-kó:rH>ssrs <d«nv'ih4*vk! λ'-', sotsasiyb-tótóoso i s\a tóotóse 7ff'' 7/.// 5¾¾ ΐ&Ιίλί
Caii.'ithtfed fi Rfi-7 .ISP 7. / 7 ./. 5·? FúUfid fi".#<£ sip® 7. f J..Í ./ ,'//
Example 51* 3-i5>Chíore'2'K(5.V>-5-j<Uim«<fe>Uunmo)nuíj»yi|-3*4-«lihyár«rl{ü/i-íso<|tdííoHísySK'8r^o«y31pfes:8yi}^H4>lsyár(ysy|>lsesyÍ)^H^fiHíthyÍ-l?í-í^öól->y^V5j6j'í#-ís^rs5ísys^'ö'í;·· indoiiídne esrhoxnsnkie hydrochloride f'he r<iYK,sYissrv ss ,$λ síi she ρηχν·** OS I x orspic \ svphsesop oo she one hand she es'Sssp>>ssnds üf hsepasatssssss s und " uu\l m Ακγ \ k\ \h' sCs/Ksssu- <\>mp<.'sukk yt p{cs\nut«»n\ < ásd $\ ásd o« bse other hand 1½. ί,Ί v<n>v M M, \>, .n s s,k 3' siey < \ 7 > 1 '!,*" s ssishdsnss'h' ;x sh'CsXMphesexk MoeíOsM h ií'sdol-S-ansbsC.
High-reMiími-ns ono» tl'Si-);
Esopkssos thorn· Uc C.sdhEY.INíO·· CM Mí| emulated: 712.3054 | Μ · Π Γ measured: 7 s 7.3 ÍRÉ' p&mgriΜ) ^^^ίίΙΙΐΐΡί:fe ' 6 rog/snE, RkOBs I'.xij3s;>k 53t 3»|S-€h Íoro~24((d5>d-<d~OK>rph«lmyimeíÍsy1Mckdlhydr<:>' 2¾ I Íi)~ isftq«ínoiisjÍkss b<>síy|||>h<i)yi|-.V^4'hydr<>xypheKyi)”AEjs|-mtkho!íy iHiHflöos'öskí'HsykiJkefsySI'-^v&.'E^ ses sah} <ir<s-'t dsdolkkse c&r&osnműte hydrochloride
The procedure- ss as so she process of hscaoxpíe 1, replacing on she one ted the compound of Preparation I u&vd in Step A by she compound of Preparation X and on site other ted the compound of Preparation. V Usu' so ishs-' e hx h pi *|ti'si ssii!\iMjsoeihv IkshSk-xs !sOví-v' I siRihi'ss ' (n-thiisn ns sethsIssiiskne.
Ek(0ifmtmkT^mfy%m
Me ME Ieív MM
MeMMM eew eee MM err ::1¾¾¾¾ () i í Ei 4\<k> iE/ER j ~v.: E somok- 54: J - f S-C biero-2* |Cf3y^-{4-moi^%dii%Í^iÍs^y^^<lilt¥dro^ I M}~ iwg»wuHHylk*rboRylfpb«o}U-^4-hvdrosyph«»yl)oVMvim«th$‘lsylphH«>IM~ tkklnoromuiiyOpikoxytl-S^JoeirsshYsfrO'idHdnikkiv ensbousmkie hydrochloride
The «hire is as in she pro<o?e οΠίλ«ίϊφ!ο i. ivpbkjng ->n Ük· <..-ne bard -.he eon;ps>uííd o) köspar-ítjön i 5 V * } Vi. \ x ' ! i. 'U P\ K i <1 V vi* 5 ^ ^ P ^ '
Used in Step ír: by ' U -. di v * Η' plk d Mb ' Γ -*'v ' i;:ni)uopnneb;y Daphne. Ι1»β»#ί!Β« fy «« %C » %M AA Í4f
iiMil »W <09 45b .$?$ 4M &tm#.r 62. io 4'M 44? M$- &β' l\ni«n4 44 5'(5 k hb'Mv5-psAN i-e-i t-rsen alKdmyknelhylT-S^-dshyíIrö-Sí ?8> npr i<ibn\ilcaiSs 5 ^3-ftuwti 4 hvls- ^pSi£U>il· V(i Riuksl I/Í jpüw!*5? >1) *s6 *“ 8 ««•irah\aríí'$>ÍRii'»hí»»< earbovirnnk hjdun bins Me
The procedure h as in the process sd'E* ample L replacing »itM«tgplgsd ike comjxxm<i <d Prefw&tiOft 1 »N M- S ry \ N úi -,m\ i 4 4<|\«u O' l aki o'> \ otlkt Yi 5 d e νθ·>'ίθΛ * o Vr{\j« ' >v Yu M s v ' : 1 \ 'kdn'kYn rkihOovM 4 tAk-rophe k A 5 medyd '-«oíoí s μλι £4>'.n.{<?jíV?l mkrwmlysls: %c fi# I®' . a.?,loir? 65..¾ 5.4V fii 4# /•W?d 65.41 44: 6.54 454 fcsönglebk V(4~BrJfostpheosík V(|-nteílnMíí-mdoi ssh** |2 IdbVM *.4 ouuphehasuMthM*· 3,4-iSifesdro-íí l//)-kws|wifK>!s8yS^arlHín5Ítphtmylj-l~mdötiíÍHe eaAKisundd*- bsdrm'hUjfhls hhe í'T'i'v'eJyii, er n 5 e pu-ce?s ot' I s,.* nplc 1, e<.ph ci% o> ύ '' k Iksed sh> f\<-poundt'seyarYon 5 esed ró Step A b> Me voeipound öl iAeysraboo i", and oe Ae <-45S:ví bend the compound of ihvpakbhn'· ϊ used in Step Ο by Λ·4.4'Ρρη44ο;>1ό:ίίηκ6ρ4Ηΐ!ν?]<ί\νeosgyy]:.: .rp^dívi·.\//óndííkAnmíoe. ί^ί νΛ· ’ _-^Λν. yX; V -- . ,νν m: 551? ;44 %a
CaictdaieJ "1.5? 5,5? 9Ji 4JÍ
Fmmd 2174 5 2S W *M £Mdit>kJ,!,. b-ídAAiirosjpbecish 5?t-methrl-tk undd 5-^1)-3-14-13(4.4-3--1(4síiéibvbb |>i|xsira?:iRyl)R5eUsyi|-5,4-díbydnV'S(Í#)'4s«í|abKíisnykí<'55rb6)r)dl-'13''bfc'8aud5«^öl'-b'y£'ki««lrdl*ll<í earbossRiide hi«<hydroehlbr1#s) !' 5i' !! t' 5 !v\-'ss .if I ' onfh l '''f' v.C*"R 0 i tK > iR Ϊ Ü"1 ' U vOft'i? \SO(k. M' d< V R\kKO\ i .88$ Γ A'%:4ÍK »sp§f^'iv«v'iS6Wgéi^4i' ol 13 ^1.:..¾ MMMb tlfö::Mhyr 3¾¾¾ Ihf- ea&sj^sunái?#1M$p8t^i§8£ i?-««I ® StsjyM fej·:!··IM* n^kd-S-andoo mc !>-h' ma %cr MM ."49 9.94 ,tJ$
Fmmif fiA 69 S 35 ?% Aki Λμβλμϊ f<"w; .«) * i K. 2' sy t> hr> nd . MeOltt
Issmáfe Ml A^{44iy<lr8^5|ílse«y5,í- ^*|'fkp'C3á:>344-'S««rpfeöÍhi>bisíí:íÍ554h3,4'-«1ih3rd5<:>''2{1/l}·-^^.8s»bíln^Sk»rW8y5}s:S^l^xMkníyi'f^íH^'d^^bMaáftHaíaé carfeos&mtde hydr&cfctorály
Tbí prornktsy is ns t« she prosíoo; of í-xMoph; I «ρΜ,-Μο. on iho 08c hand the compound <>f ixspsoiUK'n í mü-é'm Siep Λ by $.h« eonoxROKi oíMeparsidn 13. ÉÍmmM'mtermmfy$i$?- '%£' %h mű mmt
mkihml M.M Ilii 3..II: 4M
Fkmtti $M't SM Mi) 4M'
Rtmwv ro*ef° x>\i s ' MM x 0 < y «Η MM>M IMiSidif.Jfl ^li4<-flyds<íxy|sl:!««yj)..Ai.f|.BM:dyvÍ'iÍ33dmi«bl^ylK^'Id-|ÍMMM14»55«:ír|>ded»ylmi1Iíy|y -3,4-álliy«lro· itH#Í|ls*3í|»lbelsis^)<
NydroídUorkk'
Uh- p .vodm1 is ss in íhc puííP.s uí kxaioois i, ropUüxng 0« iho oiu- hand the compound of Prepsrndon ] xn-cd ns s-sop A hy the· cxsnspoxi.od of Prepnrniioít i 3. and 00 iho other hsnd *he coíopos-nd 0?Γ Píxporsdoo \!! xsscd in 3k-.p C hy Add·' \ [fo?t-boiyi(dio'!»tivv5isdyiMx>1 ídiSSsviVl ooeksyi- s ií-Mfoi-S-amiííS
MmenMmfarw**fymt m: mm mm *íf fA/so/opM iíil' dill:: MiM' é:$$' 'fp.mti M,Mi ''i.S:' MiT $<M:·
MiRsR.iry (·%):< '::: > s U:.J": íc " 3 iOj.v«d.; Mikid I) MMatösMí -dlilá^^l^^^el^ílbfbea^P^M^^^I^II'l-ieáolbsí^ esílMsssmM«^sis^NlörMe
Use procuduse »s a\ hí the i«'»m ' Ό F'o.5H'\' L lep*'*'*$ on ko o»«r hand she νοηφοβη&αΐ;í&«psf»omi: ;-u ! in Seep Λ h\ the* mnp><iwd of Pt< pofonon P. ~set un the oshu h^nd the e.Ompound oh^epamiíst ti” esed hí Step t: by Λ'·{4-f||i:!í4-4th|pP:hí5«isv!};4Syijoxj I!>h<tny?>·' I -cshyi~ 1 H-hiddKS^tihst
FkmmFfi mkmmmsyú^ %(' %a m m? idí&st/íiíed 6U.66 6.4? 8.64 4.38
Found 69.8! 8 !3 8.64 4.38
ExamTskél; A^4-IIytií^íÍVjthe«vh-A>{KmethyhgJ-tlhÍVíÍeB>ll^t;síhí|-S~x1VS^(h^Hh^>'3'(4-ntWpNMnytoeíht^'.M-'áiltydrA'lO^FHöqMSStuHnyiksr^nyihlJ· Steuxudioek-i-tdH -sndtdkhse esrlKtsssmide hysiroehhirhfe
Ilié procedure H as hí tbc procs.ss »f fixat-ipSe L replaesstg un the <n\e hasúi She compound td Preparanewt 5 nved in Step Λ bt site osxnfxntnd of Prepare»: son S.'\ ásd őst the other hasd the eempthht! p> dkephhStspst J* esed St e ot s x * v > > *\i's (v Í5\ i N \i(\ ' v se > (>y v ^ i'A \*« n< ih'gk-m&ffíüfifw (mm íFSí 8; b'stípsrse'aí So »\o s 0, ]S,»Nd\ jM ss ,.< verted 'tO Ok' fM- HJ' siseasured; H232%4 £yo«apki hl; íV-ld-dlydt'oeypheísylhjFd I^F<sjtrepyhOf~tsd<d--S-yi)-4"|h"l^d41~3d4--stserphulis'tylsaeShyS)'' kydrisehkstide
The prefcedur® h ss in she process of Exantpte 1» tepsaeing otHhe este iw)á she ponspoopd $t Prepaí&swst S issed os Sssep Λ s>y She utíispotsrid td hrepsíiroue i ;ΐ, and on the üthet hand the compound os hepm-stse-s · ' issed ssí Step t >st S-í'S-Ssi-í't-hess'uhsneiht isdsSh'Ss ipfie'S'Js-S-iMtp'os^s l· - now.oto-'e hJemmutím'íftwafy’th: o 'es*>\ e- '1 «Ό·.. 44Í4 in.// födi FSC-i
Cp^d/híídd d;,s i/.|f 5 /> 50' ttdP /· -0(.((8 64.6(> 5 36 8.49 e;,í:d mörpk>knylsTi<;AsylV34^^<k'ft<íí lkVmK|iskKAi5>y?ksrfe««y?|v.k3,^}jii^.0<j^SlXj>^<i..v||^^i.Kj{^^!;K; csrboxomkie hydrochtorkk 1|sf |5f®e«4«re l| os In the process ni' hAampie I, replacing on the on« hassd the cotopoond of krepsastiot! i used in Step & by tha-otwnjxamd «1' ktepansnon XX iwul on the other hsM the oststgotttid o# Psopamtos I" ttsed ?st Step € by A-(d-{fíeíóhatykökneltiyl'5si1y:i|osy}phe:syí)- i ^hyk5rind<dmtmPo& &trmenmlmícrmmih'$k;; ttheon tor 5 > Hck ?íC uh uh !m::i i 'aíctdiihU 60:5? Xé: 0' Λ / 16$ FúuíhÍ 68, .11 .1JJ X.-M 5.63 löí«g^j4t íVvp4»MMmsyphssyikA^kls*prttft>kJ^V».kkytlr<>'í//'-kt<kíl'S'-yl}'3-{b-|{(35Sr)-A^4-ssns'plinlisiylnteilsylkJr^-dihydr^Vip^yósopnktoihtylk'srkonyk-l^'dnsoeinknxíd'S'ylkl.-iítdeyeloe esrbösostshie hydroehksside i lse ptoevtho'e ss &s its the process of Kxantpk· h repisetnp on $wim..hmA $&« waptnfflrf;ai:iy^ | óvd its Step Λ b\ the eompwaad of Ptepsttoios* 13> and on the ölte:'taá.í!Ü«í«08í^aft4 <# k%«p»b€sfp.:: IP osed s« Stes< C hy N't-M jfm-hitiykdmselhyi)«MyijMy)^ny|^'kiso^«pyM4kd^ífe8mfe«., &émmmímkmaoai}'!ií%: 1*ϊΐ«·<χ*> ier i.3 M£t) %C %ii %N %(5
SWanoíVd 65. 6$ ·$::Μ·. S.S& 5. SS /;οόηίΙ lliili J.Sp A. S</ 5 iú fekampte bSt ..k($Xhiors>Ak{t'{iAyA-f(4-ioethyhS“ptper8skiyl}«stkhylj<M'ddiydt'0"2(y/p kní|uisoktsyi>ent in ott Ijρlsenv I(- S'-f4St>drwvy phetss fn 3okntelhs k| lA-kstkOS yI}· I dtsthtStstne esrbosoíftsde hss{hydro«h!o?ide) ^.lf:p^®áüre.-ts a« ihsdpipfbö^k^'^kmpilM.» seplecihttyOtt the one hand the cosnpottrKk οΠΑη^Μοοόη® i and 5' utsad so Step Λ by the respective ossmpuumis of krenanstissos 14 ostiitS^ andsns the oth«f hand the compound. <tt krepamOers i” acted in Step C by h'-{4-|fó'íy-i>otyittiiotetbyissisyttoyylpheosipinssethylvl/k indok S-amiste.
MommOslmfymmiHym: (theory: ksr 1 íl£di %C %ίϊ %H UCf ll'iih'uh.iiiU 00. Sri 5.-/4 10.05/ 3.09
Ff.amH 00. i is SI. JÓ P. SO ". 70 I xanfoh; Mi j'iM hh>w 2-fiyM'yf 5-.4 ddudi'í-ihl/íi 4\ο<|«5ϊ?ο§$ϊ?5;Ι)«$ fheov llptse-ayl} 4Y-$ 4~h\ú rosy· pfe»> i}-AAf i -iSfd&yi-^jd'dfhydtix· | lAiödpff·*pjffe> |sr3<s1íK5«* fonisoxfsfsskk' MsChytlt’tK&i&rikie} Ütő ;> o^odnu S- ο~ u Oh i scpUf'p 'fi 0 ' η x Mfds'x f,.""oov V ojss, jt » > U'C<Í m Si-n- -X Oy dto ο<»η§νηοό >'Γ í^vparftftftft 14, ami m íík <'d >o haod fho νοοψΉχο! of l’iCfvoaih'o Γ $mú iO Step C bv \ÍMC Mff M/f %&
fGléifipM *4 4s? f;j.? -fofG / ·? f P ^OÍiM; 6t> 4.: -11.·: / f,$$ MtM. :·' l’ö^ 4.5 m&sssf, \1eOH) fGMillkJil: > IS-Ch kmi''2'(f33Ak'M4-«K!rphoiínsfmeik’8Mo^$hy4í'n-2(fl4S' i^i5Sfi<iffo>lK8í1>ö«J!l|p^ö>1hA^4'!s><tmif>phos>>3}-A4l»sn«thyí'-íl^tsáol^43^!'5MoSi*ii8« asrhos aís 14c hyd rOfihko· 4:1 0 1 f··:· pfocvikü-e ;·> as is tha pox:exx ot Example K ?apiac?fi£ on she of-e hand tbo <:-MOfx;uüd of Piopandioo 1 i»MOl So "stop .4 b\ ths coo>j>oaod οΠ’'κ|\;γοΙϊο?$ N, arid on iha other hand -the eontpoend of ίΑορκίΧΟοη Γ' uxod in Siop € by .V-ob ^/v^^^|(^joxcthyl)sdyljoxy|0f^|}r|-!fM^I-Ui-indo3*-§.'t^feie!i;
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Example of: ,H5-< hlo&X' 2-|ΑΑ.ν}.3^4“ϊοηΓρ'4ί4ΐο\^οί?ΐΙί>i3'i'4-ddiy4fo IfSEh· fo.>i)ióoo1ii>y4|carfKfoy liphsöy4f-'A'l4''flooíoyfivs-oy fo/Vd 3-nief§i>d~li/-ioekiOkyÍ)“í4«dolf3oe oorhox omuls· hy dro<. bkaíde ffsp: :pfocd|Mfíí ?S affii ,!|f pír0Ö4í;íá:¢5fi;£sií4imp3* i > tepfiififl ff iff c-f fbepiwaoon f i'SsO f' Άο X ' ^ \ ' r ex íjo oí Yeo ' ! ' ! !" >. r i ^ ^ ! v ηΉ \ \< <p a d >K * '.oo^i f fsad ih Step''-fey> f bánig «sHlerOixx; liter ':ídfö Í.3 » iiinihtd to a step of foroxaiosi of sho hvdroxhK^ixfe m: %h %m mer i.3kuimek bo 5i 5.// ><· M 4.49
Fomu! 68 44 /.7/ 9.Ű9 4.28 «sof|>feoSKí5:le)Pthyl>-3,4-difeydí-ft-2iUÍ>'»'»^»»8wHR>lkí>Fbft8yt!>1*3-d5fsydro»l»'í'b^R«»áíí>jiíín-^'>0-^. Oxlotbíisfí carkosssmMo hydrtK&forkle
The i-fiMredeie is as hi ihe pt<x:c>.s. of bssomple I, s-spfadsig <·« she otsehssx) the eoiShmtiid öTí^pgmíiori I: used ifi Skp A hv she compound of fhepdmtiofs IS, and on the snfcer hasti Ite ^«pohn/l'-öfltt^síiíaltm: P; /ise<? is Sifip 0 by Af~(4- ifífí^b;siyl(fh5nethy:Khyí]<.ixy; pheovib i -meShs-l·- i //.3,-bten'ahydix^s'b quinohíssoöra? WMP^e*0#0#· 4mm (ESH):
Finpifiail fm-smskx C^B.: .·Ν/>·> ΙΜΤΟΓ eakolaled: 734).3605 (M -Fif fs'ieasfAS'efi: 700.3S$: gssmote "U b o Ihduoxphcnxl) Vti mdlui Ui sotkO V xl) 3 Γ O.Hf ) ¢4 ntmphoooUsseSinO id'dibsdiXi'-Ti i //)~χΛί]i>ΐU'iiiSivbeerhs.say40)d-d km)nv 5, t hrniOvIío^Mi fc-xi}-í 'hxkkwmes «srimxasskk· hydsx'dilorkk: ! \ p \>\ . ' 'Ϊ íss . , \i''í«\ ,i !' \!Ui, Ο i'i.ív) i! V. *.0'"}VW \4 t. ) p^ep&fviU.'ií used se Ssep by ;he comps': use; ol kHspaaik-.n- i>, aed ess she ote' hsad she eosap-mmi <:>í IbfiissrsXkm s : ased O'. Stq>O by :7-/4-;sísXí-eifsyhdsssiyí/sdsydyjjoxysehessysi- s-ü .'th\S-d//- ossoKvosomo %f ///1 :>p: ?/<T %/7 kakukk 69.66 5/3 A A·/ 4.3* 438 /·y:-íV'ív/ fíO.si.) /öó' :>. 5b b·/ 9:4 i kmomk- '?$: n * MMtovxphcavh 0 }S »u'<feo\>-2 ki TV) *>,4 mmpfioibnisfSíthxlKM-dstere tyftl· kbipinnlootes kírnyljpisi-tíxl} b >1-sas ih/M/f oss/oí S OH dsxkkkks* caHk-vsamk hxdoteha üde
The .OOXXxhsi'O SS 3S -Ts ids,' sXsssX'SS ef t'x.esp-d S, ‘'Opbuissg íj), ,,sS!' h.ssxs X s ^sl Of'íCifik oí IVí p-XaiiOis I sided sfi Sivp A by ide vísnspousíd of Ptepasxs'dxi ;d, ;s.ad oa six οϊΐν» deed ids: eosxssOoad a: f/e/ar-saen S" issed so Stop t by A1-//.jp-yifvtmiyfídisxeíiols^uyifoxylpbeny0-1-ístotbsl·l/Phk)tsS>Sykitibe, "J%k ~rtxoiMknt m»<κ {£37+/; s' χ. ο Ví\ ivw-H'j" mmúmé: 7ΜΜΜ ssellsHsd; &SlS$ib3ll ΓeΓ^b«tyl^|}4«hvtí«)χ^Π-as^hy^·íí^¾!8»^‘S“yl)»»INm>}<»ι¾%||^{#;p|^s3N[¾í m»rj>h»Hnylmt«hylH,4^}hydrö*l(l/<>>®«Hj«i8oiií8yj|p!rk«n3rl|“U5"b««t»(»!i(bsisiíS*y||^^í dshydr«pwöisf! Jksjpyrsidskí' I( ií/pcssfiMmlirtií *U. 'MVl* ) 'S » <i \fo\0' WVpU <-J<v4í.!f^ >i. iW '!"(j !k 4ft'\\t!|>\ Ot P x Pcí x'H a) i used in Siep Λ by dtc expound of Preparation Π. and ott íhe oüw hand the eoropoaod oí PrapasaHoa Γ u-kd .n S.ís'i' s K Λ-s4-ΐ! ft-fb;u\4,d; s skihu f - ί ΐ y i|o\\ J p he n vi s - i s no h> l· i //-!miw Λ · xsmme. ^ m-mg > x k*Ox' !\it i!\ (.ι'λΙ'.ιι,! *o '4 i 4 ! \ svi^ mkv ki xí síé·'· ot s^i k>n(H κ>γ< sn dk p x. eme <" >'íhck<" hv'iiü^cn chfmkk. %C MM »
'CMítuhrMÉ 69.43 6. <>·:; 9:M :pí'Hmd. 69 41 X 44 X 69
Exsmok·___2á» ¥*ft b«*>i ^-||4-hy<Í!fífsy^1'ínsíby|--l3-dÜ5ydr<kÍf/“mds^',3'yl)ssllÍ88|csrfes>nyí|r:#'|^·' 3-b4-íSKiS-|iböífn>\Íí«svHi>lK3>4'<iíisydr«''J-('1 f/bkiK|«ls?olb4yb^aTtoíy!|·'í 3' dtby dn>pym>kd U3~sj|>yraíí»e-2f I ffH íübosyisk· l'be procedure is m die process ot 5 xnrnpíe L 'mpMcing őrs the mss hand the expound of Prepák·.!Ion 1 used m Step A by she eonipöU! , v o> 'dot* de j r\nd Uk xO< pont <* ot p.opa x‘su'< i“ v í í ki \ f k ** f-v‘k ' 1 Sd *'U{ x jxHSfpk· * ) n >'í<k sí o *< 'ijv s \,s"y r <£''41 >' , 'rpi^' ft-'Mivd ιΊ> \i^x ka *0 í. step χ"'Ά f >tí»'.xt*f "i >< t'\ ;< eseeoí \kk‘k bydt&ge® ohiáüáe*
Mkmrnt^mkrmmtyxkr
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MiMsmií MM 9 M 9.69
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He· |^íse«dam::!s::ss k tte fmcsss of iksoigte I, replaelog on th* 08¾ haniJhs costifwtd of Prepáik*: I: osM I»·Si«|> A by tint cosopoosui of fbcjutatioo I ?, a«<f on the ottwc hasul {Ik cotapotnid ot Preparál ss»s i" p*ip) Si'S s 0 < Ή |t 'i I'H pip iHd's e v-! r f'l 1,1 ''H *k !' K*'\ osáííMooJ teat ϊ{-5.ΐ po>sh;es -¾ obobosb a. 00; .osbjeuod O' -i step <0 sob forrhasufi: so she presence of s these,d feíifíígöo chlonde as deses shed as Step U ot fAerople s she eoshpotete so obtains! ss deppxeeiesi so she presOSioe 'if 10 exphsaieshs of titthss>f<ctce*»c acid m sitehlosrofisathafie 110 ttsí .-fitnudi al atnfclvht tcsoiteystfife .overnight 5hess, the prodtM S' >uhsespsehd\ totaled by <osuent*«t«ng the tcauton 8«'««*· todsfssm It s§ Insslly sisbjsséteíl so a step salt Ihsmasfhts iss tbs; p rose sox? of ethereal íipfögeh ddorüle. lbs T9f!€ff flíT ill if#?; ?S£'f i OPsoAfteif $$&$ ? U. PS '<:&$$ fifh'-hí 64.48 $!$$ M0$ W4 K&a snple ?5s AMd^iYsfrtesybke&ylVAM Í , methyls!J>'dihyiPb''|:^-kdi>f-f>-yf>-b-f6-\{{&fy&-(4r ssss>s'phölbssiss!eSiS>1pd,4'sÍiÍi>ais'i>'3{f/fasei><ps}ssoHhyh«srh<íhy{pS,^'he8s^mftexs!Í'S--ylh-1>23ef'' te í mim? m py r roh>| I fim | pyr.m:hte--8-e« dm s ssslde frlsCliysism'hlssmk'sy
The OTOiX'sksmTs as iss {.he pssxress of flxashpie I, replaetstf <«s sho ost« hsttei the eom{5ousul of fbeparatíéfi. ! sssed os Step A by the cmwpmmá of Preparation I?, aod on she othor hatul the ctehpeossd of heparsfiloh Γ sseo is’ biop C h> ,Vp4-spoP-hsiS>Hsfioiosh^hiK!::o\yfphs;osh'h!s-sPhy;-;;-hoPhiioiisa)o, it Kong understood ship tlte poksseihő obtesssM k pot ahshteeted to a step of salt formákon m she presaoev of etheeeil hydrogen eh1o^e»ik::I«^-i^i:::tb's:ll^: tTrf BmwpIc L The compound $0 obtained » d«prnte<1«l sss Éb pstehhoe of I0 eqambehts of trisltehmctess ecu! iss dichiornsnethatve < if tsL-iniiid*) at atebiesn tetstpeteteise OYomsghif: Thess,: the pfosisses Is sohsepisssosly: faolak-d h\ utncesnnfimg she reaetkm snixtere h* dsyooss. ft ss i«slly st^|egjleé*ö a. step of salt thsass mloss isshite; pteseoest of gthaypl hyofoghh: sihtensle. M immfiMmkrmmfyshi 'őse: Ψ&Η isfv '':'····' t'fá/iiS'ífö'iííií P S. Ρ :f pi. it ·? ip f'tl >.<'. ?·'·· fóuHif Ó/.05 5 i.> £$! ?l.?l Éxhhtfite ?&; rsstsyphsay ΙρΛΗff"bss;ksl-'S"yl>''S"{§» |(I AS>3<{(4, metbyI-1 -
The: pro;:e<;ase Is as, so the psoees.5. of fvhopte L taplstckg $>fi the os;e bssnU tbc ooniptusnsH ol l>repa«-afto8i.:.|; ásd V ps.íívl i?i bsep Λ by the tespsctlssi vompoafids dftltepsiiiflphs Usfsid ,t\ ossd s>h she s>ther hsos;! the 'IWI'U' lf "iá ! * 5is\ s \ (Ni* ' *' -. i N \Us !p v'i i 1 > »idol>5>*jelne.
Higk-retetiutimt mtta f&$hp Γϊϊφκίί.·!^ i«fí?MJÍ3· CsJ-l^bi^X .}M/B] ‘ csii.'iiisíiíd.' 7<?3 -,361185 |Μ·:·Η|' s-HumsRíil XdJS/d SISIBBIlZZs. pyrr«ll3»8e^?<« rb*« a mitte hiss/ byd rsdsbí'kk) S lse ptoc«»kirc is as m ilss pmcexa ««' Ikampit h replacing, on.the. »ee:fetttd-the «·08^>0?»^:8|.:Ι^8ρ»«ϋ'«;:| ao*I 5 uv'íí sí Step \ <λ tfu »*·>** ci \»x coiisi\Há\X ,>5 Preparations 1*2 as*<i 5 \ stiíi ön sbe dbes' hcssnl/Iss νΡϋϋ>·>ϋχ/5 í'i »»{>««» S is' Mo>' /' hs Xt 4 is/s'.'X'SssyXíiír.XsVX'· üv^s ίρΧ'ϋ',Ρ ' '*y«h\? *//- .Skswy f;>í I 9 HCI| :¾¾ %H. %N %CÍ 5:/¾ Ml? 5:/.¾ jygy# '&&$$: $.$$ HM& /.<15 $isaiai8.t£.*?.§· 6' ^'C/li!si5-«y/4((5.y|- ;i.-(4 /ssi/>s'|shi>lssiiv'ti5ii<;lbj-1;i-'Js4' íHb>ái'ís' 2(1 Ny ísoqtífíJöliöyllcörhonyljphvflylI-’S (4-bWrm*pheayO-iY'phsoy 1-3,4dihsilnsdMpyn'sjiátM'' / I (1 ,4|©*<m öe-S-ea rhmam l<le hy<| rods bárkié í'v s<.\<.d s \ is < s. S\ss i( íi| vs s-vi-i sdlk s > Sii V Oi !' tj t Ss.s Viy \ :ihe s'<ü?ipoun.í <>{ l>rvpijrist}<-:-i X? /// /:.// /:: .V //.:.:'
/ .ü/<-'«/«ís»/ 66.57 4.-.4 S'· / .S? X,M F<ífm</ isii,?..? >;?/ /55 /..>' fc/d óikig; 7/2; ls»^»fe8lj»yfH:8H^»yl)pb«í»yl^/Vd2>dlb^ám-|/W»aöb§«yl)^4.hydr«xyp:b«»yl>-3^JM*^® pyrri>lfi|2íl-c||l>4|<sx5S®m«'*S'<:«í'bsüXjii}í>i(k's bis{ hydmcb ksr bis) ΙΊκ* prsefidsitfi: is SS É -ise pmccv, T RsafBpk I, reptesíig cömpösiid e# dispfSilor í osed is; k;ep Λ P >*-*< ‘ifi \ nd >* \\ p ot <"!« \í i\T' h. οχΚ> <κ«χ <h ·.<. s ,"ííi'i<U\}»','U'' i esed in SispC by id<4-|^<w^usy;C(Ilmsíh^ndyMAsy!ph^iys}-5dfidD!kaíiSBxe.
Js^ifisídí mtem&mksM %c mi mn mm
Camimm am mm mm? «μ found ój.á-t 5 T SJ9 MM: c){ Mjössaifts-S^arboxarnkki
The pössdxisí Is í}s iss die fröseas «$' Example i, tspimkng.:m ide:«sne band ibsmmitpmítöí é$ ffs^amtáati íísfiiliii Siisjs 'A 1¾ íte fimspöissíil <>í PiepasaPn 21, arsáiöBili«áfám-Isasáthv«r&spasfcíőR m used m Sifip C by T44fif|íSxe4>mykdims%i)»d\iJsxy}pesyt}-3^^ íf Nih§: 'ö«á«?ádt#lNlflÍid gmdiiet sö ökaitsfid is aut usbjveied fó a sisp df salt fomxsikm is ife paessrswe «1 «fersal hydksgp sdltódfi. ,hkm&i>aí mkr^tiftafyv S% 'iiT ·$$Μ> mm
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The p*oc«d«re H ss ϊη ihe process of i-sa-npk í ?ep!;Kmg >v ide ítse ihssíd iisis: ssmpöuiíd iT fkpa«kiöd i iymi-M Ship A ily $d^Mmp^df0dl%|i^d^Í^'.2^ianái::3B dxe other hasd ΐ: siNX'ii ifi StosC h\ S-s,4'||,', (< l'iiish'Ss x^ilnibíMV'W HsvT- I mehoT* edektvoTUbS· ,·Ιίϋ^Ι|ί'Λ(»»»φ<ίΙ MM μη Mm MM"
Cah'MueM 6?. 20 $M :g;7P 4MÍ.
Foimd őé.ó? 5 Ti y ío , Easmitje 82» 6-IS'€hiftrK-3'j^3'V)-3-r4~t»&yohoHav8ift;e{feylh3'4>0íh>Ur^^í?/^ Jso<|ttíftott8yí)e8í1mií$í|pbe8y|}-/V^d'?!«í>ny4-we{hvl|>fce»yiKM44t>dix»svphe«yly3}4'dihydr»-i/f' pymsto jlM ΐ s4 jet ssehse-S-e»rh«entn $do hydíochtekk'! TV pmtedefr I» ös is* she process of Example I, repkedott os* the ooe VsnP tbc < ooxponod of SVepunsssoo tsséd hs Step A by she eomimuhd of-Preparation 20, nnd on the other h:«sd the compound of Pscpartumn 5'» used''^cni ^ u ο *y3 ' xlev pHo 5 mv)«v xsetht ne %€ mi §w wéí sav Cémiümí MJA -5jf: WiW &;|f: 4; 5#
Jmstkí V> 41) III y /d 4 40 kt in* > x p ^ o? vn s V íh ,, e\„ S Wdií ksoounk 82h ^{S'CMersr-^'KC&rí^HmmrpholfnyimelhyihNM'tltfcYdro'SICJf/)* iMH|«i»öliöylíe#rlK«»3rl!phe«jl}'/V<><4“b>ílr<>sy0««ylHV*<í!i»>«tbjr<Híf*<i»áöi'4i>*yíH>>?3»^t«í)f»fcyörö» 5//· pyrr ukíf 1,2··u1iesKfsínt-:- t-enrbnxssmkfe' hydrocMorkié 3 !'í pxxed su r ,so n the process re f \ampk í, vcpVciep on the one As sd tin- compound of Preparation ΐ uo-xt Ιο Step A ι>ν the compound of {‘reparation 22, and on she other hand the compound os' Prepanploo f’ used:Ip Step € by AP« p[Orytony!(diouXh>lA!t>l!oxy}phenvl)· t-fkhdiylf
Ernpxtc*! formula: ÍM >tir xdouM* o VE 'M ‘ jKHH]' measured. V-tLS'S* E^hmPlé84iiV“f4-lrlydfpyypheóylh-A^(1^mefhy|*l#-Puloh^-.vlh3"jA'k{S-y>-3A4"mnrphfth»yImethylp
Sj^llhytifp^fí/^^AiPmtdmykcsdKíoyipkJ'beoíodktsof'Syylh'A^^^'teUohvdt'O'S^'pyrroioll^S'· 7he procedure x ;*s in the process of Exon-píe !, replacing no the one hand she somponssd of Preparation 1 vj-rtxi In Step A V. the cotopound of Preparation 2.5, and os* sK·. othss h-sad she eontpoond of Preparas jot» Γ' used in Step C b> A-PH(orr-hist> if dmtethylysdy i|o\>}phtssypH -medsy 1 · I//-isnkd-Hm-mc.
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High~fg$0h<4i<jíf ffiif'ft (J:'Sh}: h-upingíí! thrmuke C^WftiOhiSC|S: IM = t i: císlessOOed: ?50.295í M k ü\,sOva "ν> fisamoie §d; V-Bun ΟΛΟ e hy 0» »>-<.> pbenj h- MMudd') dR-t-nun gihobty imoth'i IHM-dshydn~*( IMb ísotpihtohftyrH'srhftiíySbbd-lx"öáotlloXíO'^'U)'>S4'í4?í8"ti'troh^íifs>'i"i5s<.kíHí%?íí ^nrhsíxsnthk hydroehbmb 1¾¾ procedure s* as in Ok:·.process o! Example \, replacing the οοοϊρηιηκί of :hrepamtks» I" used m éhep C by "n b»'i'i t ‘{ív'*/ OuOlídmKiVJ'fc.dtilow ?.k-dsn>'
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Fémé MM 6.3i) Z ~4 ;®I Ιδθ^»{κοίί«5»Ι><ϊ«;ρ|>ί>0^ί|<|»3»^ηκ00ί<ί8:ο^§“ϊί^''5ί6Λ^“<*ίϊϊ'«ϊ»>^Γ»Ί-Ϊ0^οΜ*ί»^ϊ)ίΗ*<Ιί^Ι|·>ί-Ι>«*&»»»»ϊββ kykrodaíorkle Í»V >. Ín s s tk n*\nn Ο λΙΊμ v, ^ " ík ,!' '[\. \UÜK>»«0 X' "'VpOkv us A'/v-dsbuiykrnis^, íi beiag »«<£ersk»sd th u Skp 13 is ihco ÜihocíÍ -~m a s&p of foutóksss vk she hydrochloride IHgíi'fesiiímii<ií mim t£St* f i svpo'kai íOí'.uii&· *\ KkV \ |M-Hf calculated: 6'5.3859 f M Hl' ifissf kib|; 66$ Jfö> iÖEilfeS vk|54;'blm,is-'í kkW)-n-í4-í?íin'|>h«Bísyím«thylK1<4''dlíí>^í'«-^l//)' isoqoinolkiyllcarbooy^fcioyiK^M^'hydrosypM^yO'^HI mdöíkm<? e;«'b*ssns>kl<· hy6mi:hksrUk; ! Ik* procedure is as m i?«e ptoce». of i.Kampu i. replacing m ífec eft#;^^::':lii&'"Cő}öpeand":tíf Plppais&lon* í: used io Ssep Λ b\ ík compound k l*rcp&ration 3, and no ösc <#su bsak eampetmá ®f^mparáSö».P v n v'í k- \ |/x#·/ :u\J ! <*}»% sik^i-s*. r o»>\,Vi*metfeyl·íW-'inook^^^OiO». nmeim*; %c %H «fV ki 7 ~MC$
CúhMih-ti 06 66 6 26 9.26 9 3? 4.6F
Ftmnd 06 61 6.6? 9.36 9}? Mf
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The proeedure Is as m -he process of Kxaasple L repia«.|»g on the óra* hSfKI^ eonapotsnd ol i^VEdsíV?.' · ased «ΐ ’Step A by (be cert-pouaad of Prcpaí&aáon 3,· saxl oaa tíae otbci (Mftd üao eonapeuod of Eaepv.dlf'fd · iV.b«iStOpv b\ S-pi'fl·' <> b«ayUd*fOCíKjP> iKi|0\\.íph< Jsla s v«b'0' ^''m5fs\'5fobo«.
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The procedure is ;as sta abc process ot Example I. «.-piecing on üic one hmn.1 ahe eomp-ouod οΓ fb-epar&iapaa l osed ős bier \ he abc cumpfxmd <d (Vepmsaak-n '->. ,md on rhe "te·" hamd ffce co-aaaxmnU of VivjViitemk I used i'Ncpf. \-YÍ-!;x"'-t»íi;'vKdinacahU« K ]\Λ\ ,;Ί αa i'« 'Kos, -f : x :'t 'o ;m
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;ílö|bííkjtóíf bő //'v :;|íl:|' ||.:|P i&Mi::. '&&· :ff;:|7 y I j e so- ho a > 11 p k e t r y í k 2 · by<lfo-^y - V-44-hy(Ifs>«y phessylh V phetó I ,\3'ílibyíim^llA-py3'e<(li:eií>e'd?v e « y bc< sas m kk- h> «Irescbbí riúi: <Í#/fVfb!v'sí<í#/íí/íí;fb>.5-dí'kf/kj//oífeboífv^pAx<ífyík?íi“íAAyi,fye>-,íM-f\vwb«Ajíi?-7-íwbiiA^;Mbí
Use po'xxJ s*s. t·- ;\ xü thepkxoo o* *>íep « οΠ Ό>»*ρΙο s, ss-pbvme thv eom}<oai»d οΠνρ&ο»ί*ί«ί I P'< bso eompíKííis' of Preparation 28; yifm/'b&ttyi}phmtfhi~ft0m0*2J*ílfhytfm~ltt<w>tmfízfm'7»m?fobxgiete to 3 solus lots of the compound <>*· Step A ti g; 134 mmoh m. ?Hf tS sstLs litere ?» stskJeb a I hl («tTabutylasnpKmtgip tlaomk· sohstsori O ? est: 1.7 sssrisoly fhe read tots mtxtsrte ís sd»t?.§á lóri hours »1 tsmbxmi temperáimé, ássd illett the Ή U·' 3 evisrOtaseb oltásul seplstíed by eibyi acetate I be misuse phase sx uashed «ids usaer and sbea wsth brltx?, be Ibse besng dried «oet b!gSO<f filtered and coeeetkrated to drynes's. The erode ptoduet ohubeed (870 mg) is uses! as such as the iolhsovmg step, II'NMR; 5 t SOO Μ He; drassxbh; aOiHfO 7 5 7-0,0 ssss, 711. H aroirsatk); h.SS-O.a* tm. sib hi atosxaix dskybrojomdúdnes; S3-SJ lm. IH, afeohoit: >.7b'4.o ovs, st-t, H tertiary ietrahydrehoqttititshnei; > tt-4.2. s«$< SH. 5| ssbpkits^ ;eoab>Alois,\{enoh!sO\ s 9¾-s*H Ht <bh ' " li'tsb b t‘Met 'U Ί5 ' ο κ ο ν ϊ ·> χ -¾ \ ' ; \ Mi ' ϋ osfh' χ i ' 'U I xfhdxox tf'Mx xxiO \Π 50 χΝ ‘ο \» ^ si'O t>> Ο* χ! * ο Ο I ί fi ι χ ' “xiOU'i» iStep C: Methyl {3R}-?-{S-Jhie^t^~^(.(S"i~y.?~^aotphoHn‘4''plPitihy!hJt4'éfiiydtt3H&^iiiii&íift-'2{tiih· ylÍMi?bi)ttx;}phex0· 2··ΐρηψ*2··€!^ l-\i0xs}~2J--dÍhrdr&·' ‘ Γο 0 x'lisJíxO'x >Γ 05fh >' p vi ?+ 05 ΐΟ ' 0\ϊ>\'\ > ' hx J*'χ 0 8 ’"Μ Ο x'Ai'dfOO Π 55 ' xS''-*d ÍO i) í' tik Sx t
Jví 05 X i 0 <v i lo s 'Jf *X < í Ο η "Ίϋ! 50 hi SO ttíi i l vi' Ot X Oxi *'Mi J> J fx'5 i ' ΐίί'",:ϊ'.:·Ν xii Ϊϊ’ν hl 0 xs Mi'""., ,gk 'f!\ xukkd (' Ír· };H í 1 x''! -Ofivh x'S xiiM iOSOl ló, d'iYOJSx i h jtoactiosí mkinu· U Sxií'rsvd for 5 hours <k niohiesn seiopeiooirh and then iododvs-xí ohh is ssiumied argseont sodhns bk"!iÍH:rtíife mMaooo and ostrírcoos ölik dkyoroioe-dsrsc The organic phsx.e k dried over MgSú.:. sok ΛΪ sop <.0 CxiXsuoi'd so ji\rev.. } be »\' \o xídkofsod k psohk-d h> dUh <.!0"Putoeis«'kx ph o? >s dís-S'ö'íooHi5i,-o·' xi>tKOx«o.«')i síxshiooh ío ^esd she ndo product ín xoiid íorrsf. Ίΐ Wik P 0 fi * xif'Mt Jo i 5 * * 8 1.0 vi í »Oii\ > í ' i!« iíx
dsbyössípyrroliPisídfi -S;S is·»: t||s 11 aMyl); $.$Φ$ί CdX: :üMl. fci 8|)p)í PIPiíT Τηρ ill, H »e ϊ ι. sv no x <* s 1 ϊ' h xf! nn. * fű" 'xtf' o x > i >\it 1 h 8V' fío J 5, ihiiiplKOf'. dd'xdi'oíomsiiííif^ix-i d-d s i (so. x lixf IKhdiyi-xX ' '' :; 5 (ro h í, * >Kk 5 ' hS-i 5 fío, iM , morphohne*. ' i ms, 4H ir-nphoio-o nod H cdiphoiso dihyO?opuT<dtdmeX 2 o- i .7 soy PH, ínorphoÜsís: soil OI;>N) pytr#iki#m TkmrMmmkii!
The poicedoie is. os in dse piXicesses of Sfeps B «síd C onhsiiípifi I · ϊ( ϊ H)-ylfcifré8t®>$pliettyl) - S-ky^tixxy- N-phettyi-2J~áiítp!fm· íii-ρχ rmíMm·· '? eartmmmkk
Them ss fhen carrsod oos s maeitwi os'deproteciíon vf ki-ι slhi group in ih. oíiísíííKí, ni lh--dioxoih>;· pviiiTsidsOv'-ii -i,0f ]/i, \-:ih/'/;-Sfií>f!i.' (oi'xO csiíx,:j oníxitdivi feasNturaííi oo >sirokísiuίοο^ονí- phosphiíie.ipiidsdii'fn 2iKh' 1 í ρ 3Í h>> #ÉAÉ
iícr ' x'<. Nf O díx < »1 Px*'· \ % x'\x x M 0'' íliix’lo i íxi 'iOf\.{'P* >'( vN Mx >ifi i \ íf n X tsűv?<mfíLhh>>h;
:pC MM IIP1 PCX .C&vtaHCit MM III 4m MM :'|||: ^
Wg^rstoistiw fmm (ESH.k f-írspiiKvíí formula: Γ^ΓΗ-ν,ΝλΟ? jSÍ + Mj Λϋαίϋηί,'ϋ. :-¾'? ΓΜ *I!; í'V'-ísíUcíí' ^87.¾¾¾¾
Zsarnok' 103; JíüS-€htorO'H{f3A>3*im«rptn*Mo·4·> hssíh?l>-3^-á»»3^r«ls«»|Ui.tt<ais-2(líf>: >ΐ|cϊϊr!χΐ?ΐ>ΐ11^1¾¾εϊ> ÍV <\'(Ήη drovjphemi}- V 0 na *fej í £ -p> γϊο!ο|“ϊ^"&ΙΡ>* ielrslívd r ouukdk ísí«-'I '-mtmarnkk
The p'c<.i-.x-sIu;í: a on in she proutso of FistanpUí l. rc-püciog ο» &<' »»» oo^poíkSsM'l’ípprtlon *
s μ) n \top v k\ v «.ovpv v í>* P'^pií ««>«-' ' * fid -ο» kiskáftef öa»4 *be compouml. »f I ^ i \ j v X \ st | ! ' Ki»' K «0 n fK'l> t * v v “ ^ ,x » ' °'v ' ///if3~ί'ΐ'ϊ···;/««,->tí #?ÍÍM f/-.'Λ7 I ii>r!Ki\ií ionnck C ννΠ]15Λ ! \ ,V M K<M! ,Λ V8*
Ekoiuok104: % {*Hv<i«*H»lie«%h '7 dlltyároKo^alííOtíö'Sí iíí^-yljcarbonyll pk'üYli-AM l-mí-ifivl- ? #í-s8á*xol»5-j.ií-S,6,7,S* tetrah*tir*>í¥>*1 *>fí?iíív- í~ií»ríKisaroíd« :sy-ir*i:líkirfde 1 ti·' 5'KK*dn c- 5x ,ο 11 ík' P\\a- x ''vonok i, rtrp a mg oa tfi« om haoó ifco'eom&MMd of Prepar&tím i. m.cd in &eo a ly> thö compound of Prepörsíiost ?i. «.üti m kis odisflisud iks compound of l/óspioadon !“ < u Mc t \ »4 J * i' t\ v η'!' i ti n’?.·iyjaetbvl·ihm\d&zis>b>?&m\m.
EkmxXii í^h'r^iijiiih'sh: |ácf 'fix MN MCf Üsihwkiia-J :|| I:Í: I® ^ /í?.:$t; /..5?/
Found MfJH M3 Hl S3 IW 2ίtjísny pe i;>'-i|(Ί!Ή£'«κíhoxuíhyEplpr&ím-f \tjssarsptbsM·
Ihf procedsirs ss os Mil?# pppM p Example ΐ,; s-epfssΐs?g the.coíj>p<h?h4 of If 2g#pis>p Γ ase<? ks Slop A by ipíPéppsmpí öf FyopMfp ff M&?tt^f&i:8ih'?i>aft{ti}'$&Í· ne mi $im lmmimd: fsx 77 ő.U 8 5i
Found é&.SV éjé SKi··
Wmmak Hife: <ISVJH^Flu asriKsxsmkle hysiruclslksiroite by íhs c^mpooío} os' SbepswsíK'n 29
WmtemáPmfem*mfy<tiii}!· mi mi mn mm
Cdculssed 1¾¾ :X22; 2X5'· 2. XX
'f'bíííJí’i Ó<Í fő ,X / I /. /'λ? ‘Svy-V h$ám*$fktnyih#-< l-BuetkyM ν*|·5,6Λ&· ;é«sö^íi^á:iN3öte!idiíiÍfel hyámhíorijle
IhpsmeeslW 12% sn she process of iisawp; 5, sopki bs>> <*» ü*^ o;;e hand sh*? compoosás p Frspnsiiosss { onsf F %ed sss Stcr A hs she s%piv%o coisspstspi os í-*t»|«»mti«ívs 3 .sód ff <«»«J % th* othes hsad sSse SJOSS'SpSPS^ ΟΓ Ps'íSpSí'fUSOís i" oHS'd !í> SU'p b ;'>' Λ’·ί·4··{>?Ví'í'-biSÍVS{dh'ií%y ί íO:y*joxy|p|)0Oy|s>! ·ίϊ?%Ρ^·!~!//' iadoMinaune :|£&í%?í?M tó;rf?ífíf«/yspi PC1; :X// Xi# KVF KV! pffeoXpo# XXJC Xs'íib ΧαΧΧ; Kp? -m*
Fosuk! ΧΧΙ,Χ ,ΙΧΧ /X /5 :ÖX 2-55 kk^k-iTdrabyEkötssdefemed -<^rlxns$mük bvdTöf bbírkk
Th-í p:'Öv<:íksní SS iSS ifi 'liS pFOCSíS öi ΪΪX;1 ) . rSpí&CS!:}.1 \;S SÍR' RÜS hi:>í'.Í SliV CUSVipOUUbs öf i'i'í'pSSi'iStiOiSS ! f s ‘ \S 4 i) sps|' \ Ss ths ' í f v\ "li 'S '* ' H"v<3 ivi' < - i'd ' í il '! tÍK 0 iK hűi u i'í císsspssuiiil <jf Fs'SpSi'RSkSíSí S' uss-ed its blííp C> 3vd4^{í^.fk>uty]{:dias&th^íhftkr'Í|ííX3í.|pbíinyíjS'!»o>®tbyb >»’ ssu.b! ;; sunisss.
WMmmM %C %H %N ?i€f Céimimm (3 }# :»' $M 447 μ mm sm tw mm
ExasmOg MdE AM441>droxvphrm>Í>-H0"nEl$V3-|(4-Oiddomorpho0n»4»>1)methylhk4> diÍsvdf«iiisíK|»íi«>Sbi%2{1Mh¥Sii'íR'boRvS}-b:4-'bifH«idkf5fi)b'b^yiEA;i>b^R>ybbíS;bbPftteihydfxb8<.I<.díi:bif--'b·
Sbrkoxaftíkk K v k i < i R \ Ni' ak ' <« *<oks' otí\ \ I i"'SO ti 5 í' RR'fs' s added bi |Χϊ«'κ;ϋ\ í»rííí-chÍÍ>toisírbíí!iz«>k' add (0.24? to& 5 4 mmed). The whofe H sobseqssesuty birred af amhkrm temperaiore eviYibpisí. lbs sescssos· ;>b ss«s'é k subsesisa'asly versCvidrfiSvd to dsyrisss, aod dssb Φί: »„s*xS«e s- ;'«!!'!<"' ('\ ifTf-sf i'íuv !i-!vb vb \ *t »pb·. < i>r-ofh'3 os3o;''i'S!e R üSf jiííIoorv*? \ o* fc* í here ssotatlsi&Lggterconcwsfas^lfeM&progg#ki the torsaof a solid.
Biemonfoí i)(h'titSHs^?sL·; M(l EH BN>
< k/r;í/»f/<?i| ·ΜΜ EM
Found 2th 17 5.5 >5 7 60 idigh~fie$&i(tti0ti Mm'S (.07*}i Empirics? (Worn hr CsdE.'^O-.
iMl'SJlbislébkísd; 7213,132 |M*Hj‘ assured: 727.1 ISO
Example Ilik 3b5-C?Sf(oro--2-3j(MKVii^skvk2^?ieíhosvéthylMÍsiSI(kb(kyll-3(4-dibkd^kÖkd:^bid" 2( t/?)'Vl|esr(í«syí jpheoy tk(V-(d-bydr<}xypks«yt^iVk I · {ikki7k:(723sdSkS»|!)-S^7^« lekdh^dí^délMiM-í earbömmiiks berkeklóiddá T!)ö liS: s« íh« prdcéss:sií 1,.njpkisibM PS ills ont: SusskI ibc íoííss-össíkS:: ölí^ppaíítilöpis:;:|| sí«í| 1‘ pspi in Sí«;> Λ by sh··: ísspssiivs íompoiss-k s'sí Pi'spnrsliíSks η üsni 5?', sík! n« ihs dÉdr lipáiÉP 5.-nsnpn\sHÍ η; Ρ^Γ^ίϋ-'ϋ 5" övíI In Sí τ k I"- ? ; i-kk. >Μ>η?>ή J' nJi^l^WI )>'.> if N |h<3M's νίηηικ *e %u Μ* %a mmáieé 0*4? *12 skv. -U9 fotmd 6*.44 S <"# 4 24
Emunak; Ili; d^Chbro-2HS<3AKH^&rP^*^'í*,asíkyHsM'^í^ár8Í»><58l8ölí8'S{lf*y* yl|usrbn?iyi;plKinyl>-;V44~nn;ifnpikni}Pn.^M4-'hydr«xvplHi«yip-Stfn?J-t«ís-nl5v<lri)l»dftlkmS'l'· vn s'bos sm ide Is ycl rot Pld siti c ' v. ,, s \ n í '{ W * y * l s{' xS" ' S x xSxl V itt«Knsft« M tócPá*-a»«Yö Í
y^,« Ín Step Λ by she <.xwp»and <··! Pssps-snisen .’ ,s;sd on Uu othes hand she eo^psmd 8f:i%ps®ilmF íjsxP i's Stí'p X K-t-sj. ' hw*shvi«>\sf,xPs,sK >s*l 'v « í-t)ts-'Svj'no'\i««riding
High~rm>i?ű4H íES!*): I nS|>sns;sl tóműik: C.í:i* - A IN^O*. íM^Hjf eaküi^ed: 71^22 :\Ηίϊ nv^ursd "^ £MMíl&JillkWS-Pyd}i>xyphe8yl)^(Íi8Mhdxy^||P5>"3-Cs>t<íS'ph<>$ís$'4-ylm*ll$5f$>-d<4'· d5lky<^ídsösp}ktöM&'2{l//>yl|<'íssdKiíwlH^he8yl}-íV-phsií>dAf^??S*tets'shydmíSíífe>lkiís&'l-eiisrb0SShslde kydrwbtendd i \ j< (\u\'.K is is 'he íSvit.'ss el s \j!'. pk' i 'sy v 1 i Sí. iht. v w>pv'n*iO x»t S'sxp.s nísen < - xsd itt lstö> Λ by IM ééísspouisd yfSYeparaüor* §-;
EktmtiOii mk:tiWrO:ify^ii: ml i|¥ :|1|:' Isip ddÍMMfd· f: '·v ?i#2· faund ~<U? .S.rv ” y; 2d:? l-lSiMfeJ-li? 7'dly<lföxy-kiddi¥íi«>syplsífisj'IVn-'(ftdH^>sk0í!!<íS'pfeöliis--d''yhsSí:tlíyl>--3t4-tlíhydm!Sö>s^íks<>ISjSv2(|/íby!|0íSelKis>yf^'íí3diesíí\<ss:iHiiis>k^'<yS^Av|>b«»ykS>?jpk8~íetí'shy{lí'<ssrsdoU*hsS'd · c» rfeöxa misi e by d rocb b>rkf «* fe«íw/í*i.vo#-5>r0<r.4^dsiiydf(>^l^tft)i}J~(iii>^ttmie~SJ’^idú^ef^mfb(i^k^ \ be pmecdum * tss m ibe *'f ?o«p a o* 1 xample I- txplacl&g tha %|&® compound uffLxp&rtituvít 30. .yLtg 4L~ M&W J'fg- ffÍ.iSl· i->{tMrphulf*t~4~sfttN!tÍtylh-.iJ-d!h$ · 4Λ ?~e w-áA i mhtwyto» ': r< $ of tlx uttnpewd or *^ορ a «4 d-* no-wR s s ' m . t m'TJIF ..itss-omd so tltsip^smxxsll? ísfi Killíllík péff dpfpf · I$'§öUSti.:, 1 (Up:t$%> of wsM sod ISO ^ΙΙ::Θΐ«ίΙ^Ϊ:·«δ&ίί&έβ:::8β·δ:.8<Ιίΐ04 SsLtho T^Skksj dsiHhfd·: I4ks‘d are st|isí5s|sklglf hd<|§^· 4 § of ffó|4pfL (4.7 iftssssi) isi |xto:déL4hsao sktit s btssse pM is o-.aehed she xowposmd Is osuotued with etlpl acetate, as»0 the organic ptaae isidrisd mwM^O^ bkbted ípá *ί$* 'Φ& fiOsstes: Its tÉkliktf 1« the tom of so m i, >. j oo v* \ ** * j< ' s «Π Ό , i ki H <« «iUu s OkO tsn.
Hs. It ai'öíoiítki, 0 04-5.0? ts«, Hi Π ruomeiic ieSttntydsoO'dkHsnes: 6. Γ? Hl, 2H, t.H> tnaiOviessethoxy); ' o,J S 8ft·4 '» pu, HI. Η χχν\Λ ;íí'shs.0roi;''xoofí"osx'!. 4 40 4 .:'04 .:4 pm HL H aüpisatn.
lOO'Shy όκ-ΧΟφΗηοΟοί'L 4 22·.' 45 (m. -IH, H aliphatic ietíúhssfosssdnhrmeh 2 59-3.49 (so. 41L II ahphaifc ' « *> x ' ' x < * ' > ' „ k\m .Jt , >„i t 'nOsOsXK <ο\5 s k m, 1H<H .sSphüiL' tetr4sh\druintioiia:intf4 2 S§-1 «4 (:n, SH. H tdiphasie morpholine »· OH)
Sie/t C: Metkyi U> s οΆο.'Ό ot Iff p os 0Ό 'OsopoíO'o ka.'uxd x! v.^' R vi.k íoososi is' Ht ml >»' oRxtmooS thíTC ofo added o' portiosH '58 mg {14 ?5 mmoM s>·'s**!mm K»rohyti«de. Tik tvsteboo toksoré .^^ttedviö^pcSpi-st ssnbkot tssí-ocrauoo, 50 siti. of SM llt.l sss sfcbscvpwoliy sokkxToaö the meth&psl is Ovsptmtteh off Τ0<' oqososss phsiMt Is ssstnequcnuy nootralbed oith Mai ICO artd tte exomisd wlfb sdfp|^ppsef.l»peí sO* sitgasík' ph.i\e is xst.in'd is mscckOMíííí with HjO> dncd s.ivst MssísL)^: fOtesed ássd (oMoefhog®^ Ls dsyness i oo J s v. o Is'. t s' ' so' 'Uí' s s..sv λο ')ío tht t.fstistiisiioss entiscH * s
iS5;C pí-sdoít is vík Si'X'i !« ι'ϊΟ hi.! i OS .! cX'hO !li"NMIL h (SOOMílz; tlss)so*tf0» 300*K); ? 2i-0 0? ísts, 4H. I s tsttsssssiSsc tetrabydAitstöqosnolioc); T 05 (Soffh H arassostics: 0 80 k, Hl, H aftsrss&su·}; 0 H-'dJ/d.o'5 sm, HI, II atostsassc t^rcsltydmsHáolulmH; 0.10 f0< 414 CH;· íssoihyieoodfoxy); 5.0's s»o, HL H tcslhsry tótmhjdmL'oqasJtolósií); 4.§?-4.2l Oo, 211, II tettaikifeoissirth:ííhi«)L O^Ö-ltOfl :|s:oy 31¾ fi sliiphsffc ktrsshyíkolstdoíkisioi? iolMtlS ifid.: 414 B foítkí| fetiOíhydtoiiiiiftisriíSi'.!: I0'! > 5S 0, Ή, Me); 'A')-.4.52 (t^, 4R H ahpfeatfo sooí-pholöxO; 2 % < 2.43 ists, *14.. H öliplostiv lelTahydttsiMsquwolsai.'»: 2 55- 2.0 int. OH, |S * Uptake í-soyphoits® 4 f.'ffO. 2.4-1 5 (tSL #4 B sh|5tí;stfc: íort;#!yshxsffióiS:hshis):
Ipr OfÍ J2:IÓ mf%(sshO'}:: 11^0 oto''; >C";0:|s«shílo}:s 1024 «Sif5: C-C-Otl ;>uxooO-ary alixthtsfL fOod «trf Κκ ííWis'U' < 1 'ÍNH^M ^ '! uí ,0 '1 o> v lH‘ u'.J ‘í'' v ' *,»ΚΗ\ί : r Γ ka \' sn>noh <0 the sumpois.>d oS'Mss'íM n Síi-'!' Utó s-us^vo,' is 'ϊο\4 0- b onu :ps a; 0'i\ síid this's a xoksfiosi «f 790 μί, HU annoí) of ally; btoncntte m Hí rsst. oil HF is tsddcsl sk*wH f<n*r a p^OXi s>f U sísís-ísRU í K' sWss'Oo s Sssnt'K? s„ StsíSsXÍ M OSss' ΟΧΓ ,;s <>0 issd íhs'Ss Soí 5* K'sSrt sft 'VOOs, sí temperature; The solution is li^'dtoh'Síd with a saturated· &ί)μο<>:Η j Siöiiiíios's: Iheeotnpoond s*. extracted wrih eshvl acetate; the organic phase: k űried öve* MgSf )* filtered &h<l conccattsteo te dryness, 1¾¾. ·οϋ· so obtained it: purified to ftash c&makrgraphy (eyvlohexsioefethyi acetate gradient) lire title produu it obtained in she fönn of :s solid. ^IfMÍS; § (Sikf MHx; tidio-sjfj; 300'!K); ? 2-6.9 <>6, 4! I, H 7.2-6 8 (m, 2H H 'rS<o!V\isk \ 0 ,t S< \! >5 s', 5 H.. H >5S>MSiiS! 5S ROOsh éi OSSsslofs -ΧΟΉ, U § 0 S'2H, s Hi S0<,its\ !<?SK\ise*\\ K t if (ίίχ. ΙΗ»tsHvH; 5.35-5. KM'nr» 2H.ai)y|>; ;υΜ 4 75 (nt, flf,. ílí&fdfetry·^íeí?'afiydi'0ít<i^píh<5|íSe.h4..í5'.í.9fto; 211, <Ή· ssísvi); ptn, IB» H H ahphatie morpholine); ^,9*3.4- ífíi. Isi. 52 í ishnhstie tetrahydroüxioilxtoft t 2ii «liph&He tetrahydroiso^iitKdinc); 3.8*3.6 s>. 3H, Me); 2.55-5 ;* ton tdi U díph isse morphohnc * OH;; )J>; 5 Hn. FII. 4H ;ihph,s;ie tenahuiroindotj/isR 2H ,dipiutíe SetRdwdroi.tOípotVEdise)
Step £; !S-{4-fite^Biityii(imtefhy^%Ífyti&xyÍpke0t^3-(^(ÍiS^$^MtpMé0m^^m^fhp0^é~
The proeednre H as ifi the fsttscesses of Steps B sad C of Example I
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Cakvkaetl 64 9$ 3 4< UM d.M
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Esafttók 139; 3^5*Chloro«^»IH3^»<3k«»orohQll)HHMtlB>glhvt)T3«4->dlhvdrblsO€j«fe&te^Í:1.^>::· hvidtóPhíoHdé 11k' ptoccdt«v ss m the pr«es\ vt b\a»rplc L tepi^'iop »v tt» >mh bkod the «apsomEof Ereparafesdl. used Is Step A by the compound of Preparation 3. ami ost the oiiss; hand the etmspoomifof Pt^arsi&m 1" used it) Step C by Ayf4-1[AoU-bm\ 1(0ImeUys iHoystnxy|ohenyIjpyhdutxgxiosiits.
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Found 6?. íd 3. 3 7 9. /1 yl{®»®lKtf*5Íííik$í>yi^AM44iydr<«ey|díeíiyiyAt-íjE»yrldsxfft,*3*y&HM^$“i$i*,8ii7deQÍí»dy|l$k»ii?*:!í"< íisífeössm b$® b y<l«K- kfarkk; Γί'.Ο píUCí. J:i! 1' !\ is 1ΪΪ 'Í!Í píXkVw , í I ' osííj'V ; ,<pHoi pi. s'í; ih,' SüK bSfiv! Ov sX'íiifÁUná !>l PsTJMriiti^ií s vd ) v!( \ h^ ^Λ pOv >! ip* < ikJ on *5 <.0u h 4 oiXiv «' nf ' »P ooí \ ^ ^ ·>ν ' P * ' * \ P\ i ' ·>\ 5 ' ' 1 /*'4'«-í'í'Vií&y/iiN ftuitA il'$ir j;
Htöpirfcái toésitda: tC^HjXlN^ b 1Μ-ΗΓ c;d< uLsiccL ΗΗΟΠΗ f ki » üj‘ measured: "Ö3.3”83 £-ssam>k; 141; 3^5-€klara-^*H3&>^ro»rftbo0m4-vSm*thYl)^^<8ttydftdgs>u8f»»Um3ilii> yl|c»rkQnyl||>ls«m1y'A7í4v|}ydF^ypkí{?¥Í)"^^pyHí8k?í»vS'>yí)<-^és?>S-?»íísk>*írí>laá»k?Ms<-»y t$rfe»xaii* ide ti y<lr«^|ÍPrkl« l'he procedure is ss m (be process. yi* &x ample (. replacing &a-tiporni (issa (he caoijpbmu oi sbpjsaratiös 1 iKií isi Sís'i> A by (h® <οκ?ρο«ϊϊίΙ af íkepaíarnm 1, &»<1 «>» íbs ötbe; haad (he caiupmmd öi Piep&i&ikx* i “ vMÍ.is 'v \ - 'ja'*-! bulbil-modi'.ΑμΚΠο'Λ:pkcu\ mnim»ba ' >ar ac 0mnmM mkrmmijmh; %C %H ?<>.v ~:M't:
Cafatimed' 68J2 JJ$> i i. #$ MM
Found 68J)S X 32 //£? Üíí
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High-re'OfkiFoo *mm ίί'Χί ϊ ΐ;
Empirical kWsula: (7<^Βΐ;.ΟΝ<.0, Ϊ S5 H| í-;ticu5öK-d '03 3 »n*i |'M-fií)' measure-ib 702.-285¾ 113 * Λ- í Síkííis-i'í^U1 («tíötpNdu t xínK'tnihM dthvtltmv »t»n «Sin ' lift íyrah%dms«d«iiskse-t i'sí't'^ss^y? hyár*vhhn uh' Πιβ procedure ív av in thv process t>f Example L tepfcn Ing '>55 sh« one hand «he <^®$ms)á:-i$#íe$ps.$kí«.$$ SíS^sf ííi: tisp & %#. 3. and esi ibis yfeibstSid ths eoo^snaá nf iFsepararisn' ·Ρ «Ό «> 'íU"1'*. K \ x'5"|í!' , Hív ,onrt«*\ \ χ\ί'«\» $ρίνί<ν|ί·.ι^*\Ι»ήΒν«" 4 '!'Íííösvsiíiiteí. ί«%Λ-?;'ν*&ίη< 'í WíritOk ií Si*h
Entpincaí fö?:mí.i|sj Ο.^Η^ΟΙΡίΗ,:?)* ίΜ·:·ΗΓ cain.dated; 76/,27^
[M+Hf fí'fciiS'isreíi: ?&7.?8úM fearnnk 1<S4; 3-<5“CíílorO“3“-{K3iSfí-3“<s«o*'pKí>Íí»->4-s!lo:ieíh>'I>-v3>4~^4h3t<SroÍs<>ííöÍíSí>Hö'3<l##>“ yílcsrbtssylílíhé'SVÍKV-íihvür^plíe^SíAMiíynáSíí^l'Vh'S^^^írafeydföíRdtílteiiíse-l'CsrbttSiSíakk hk(hydr<H'hkír iíkí
Hu» procedure ss ^ m the .'toc^A- os’ Sample L tapiactng re «he <whtmdsthereompHtnd er ikepttítAn I osvd >0 Ste-p A b\ íhc compound of íkepsr&tkm 3, and on she other hpd 'the compound Γ* J >\ ku Ο K \ i;u {; >M«!^5«0'5<íeíhvikikíkiv> vphoi'iS'íi'í^iKhs^'ksiiOine, Í${í*h - resifhnhw ro«ra ($£SH}? ibtpirkaí tomvalfe €4 .Η*£ΙΝ*0$:> j\Vt íii f eytpMe#|'?02.?8'l2 |Μ· ΙΗΓ nicasisrcd. ?0.7 ?.Í4?. I^ehrbósssdde h ydiwhtkrid# :Th«: |)®ee#i« process; of Example t. replacing on the -:>ísv hand Ebe compound of'^reparatain αψ$ in·. Söfp A hf the íOnspound of Preparation k ami on the ötbe? hanti tbc c<u«|SO!Usufi öf krepsisysdöít: 1-used in Síq>C by íV-C^dle^butyKttiítsethyjHtiyMnsyiphenytJ^yiunfv^'TstethosyanHiue. fiigít-tüSúliiiioit trnfv {EM-i·}: íöngoseal Rsnusdn CYtk-Cil íijO* IM+Hf arictibwd 74 d 2«8 tSSiiiin-ed ?4M 2§?8 caHíoxamkle hj«lr<*dkí«f tde·
Pk, N , , s „ <u -s , iji\ rí' *' ^ '',h'' * HViK *' l'X!'' '5 N ·-' ! n^p xx S.:he ’ίχΐϊ^ροί·!'!·! -:>í krq>8rad:>« : · \ 5%C Mi -'^ :A"' géMimd $#m &05 '?*#$' [g^"· Fúuifti ű8'S4 .1 ?> 5 i'?$$ ^'Síi
Ks&taaie 147; 3.(¾. {|{3£kHf I„I ca í'Ikíss «5 ki e k> «I roe híe d<k-
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Kiemsntui mierntmefysh? %C %!! 9iA’ :M ίβ- :MM :;14S: 4-í>4 446 f'&mui 6>. :?? 1 /j ?.i-t J-# 4-$® llÜMMllálí AMS-Hydraxypyrlblííik^-yiHKikyCMIi^k'ssorpisollS^A'í^^^y^··'^4· dihYdrmsxKpdoyim-lf 1 ií}~}4\i sfkopdM^dapuodkí'íökí?») IVA*plt$tr k5>6, >k-kOr»hvdroóxdokdóí'd·' earhosaaside i H il« os'os&'sfa k
í \ í”í\0<k is , o. u soo'A U oxd t sNfiíí-'psva's'on.'v^pk k x p* o ke, ik xooifioo. .¾ k P^p-oksoo 5 '' iivó i(! Sí-.'r d P\ 5"tiu'-'\O-k'\x)'''“pi{<'iSyipxiOi:«id!P-d-05Oif!C ^ρΜ:Ν»&ΙΜΜΧΜχΗΜίάί»~2Α>η~*-ίά.ΜαςΜ-(ΜΜ>Η*βΗΒ·4ΜΜ&Μ)~3>Μ®}'*ΜίΜφ(1*(>$^1***- V\,' 'pnrJdV^xAí- x 0 ' ^ ltMui <íd?" x'lí'Cíí ' M ^ lOnck^H ,Ά"χ " o\'" 0 kíduo; > xJd'Ni ! ;-e χχ,;ϊ">γ χη^ί-οχ ' st íhm noxl-o - k-O-Oo-'n oíoe'kkooí xl J v* * 1<i} ^'' hcHif.s ;o;d k; theo üké red over o WhiOtsars fkcí, eooe-ooOoooi in vn·. «:.< xok ponoxd kv rov.soo-ro-yxi ο hí '!*vn*j\!píi* «.ci'iríMk· *n the r*- -"u-x uí iutw^vcstm λί^ Πκ. >Ví,?d ptvds ,.; «s ö!5Sííí<\,' í« *he twm »>í o. íídluöbs^eísís gált tíigh-moltitiM *m< (ESf*·# Fíí-spirícal iormaia; CuH^NJO* [Μ·*·ΗΓ cafcwlated: 7 Π.3012 I M‘-H j' measured: 7i s JOSd
Example 14$: .%'-{44lyár«x>'phí-iíyl>J^6"|k'3.V>'3-|0-m^kí.'X¥p>'S'r«^kHíí-l“jl}mí-sfsyij-;M· dlk>áryiyys|«kíoüsS"2(^^>y!|^rhííí*y^*í^4^&?^íiósÖki^p)WV^pfe««ykS^7^''kírskyíimí»#öl^Nfe'?í'' esir tx>iss iáidé h> őrm'h Stmde * s U ,1>k' l 'qj'Mf'.'Vv ΜΊΓΟ OOtí'llAhi'l . ^ m M. ' \ t' sí C > *' OUi'UÍ ÍU i'iipo 8**0?; )o, micfpmafyiSs: %c %h W m3
Ciüi'iiiah’d 89. .;;· .>. 9(> ZM 4.64 foumi 434 ?3£ 4 $4
EttarapSe ISfe 3-<5-€hkm»»2-1{QS^AH$* y ijc&rbetny I iphea yi I -earbos&mide hydraefekride
The procedure H as. m the r-rpess »f L^antpie :l, diVd# one hand the compound of Prepkssis# ? used in Step ·\ b> the u>mp<&0d ef ^separates» 3. add'ón the>:>íhe?· hand the compound of :¾ 'fi Step t ''·. 8 (v:^j|:.,-f;.bunkvsisoesh>n^ii'Mss\x>pk:ovSissii:i!«o|'2 oictho\\beí«o*i!tnle,
High «>i4m(f)>t #tí<m íO-sá"
Empirical tonnák C «HcCINs<?*: ΓΜ+ΗΓ taíonlated. 756J«1M ί'Μ ί-ΗΓ measured: #50,2917
Eatamaie ISI: .^l^'Hydtö^yphesslslF^CS^i^hesy'l-lltMVS^líöFijldMs^'pkéthytl^í^ ietpshysl ró ü ndoiklBe-í -&a r ísös st nddá ky disphte ide 11«E m 5« dte ptoeeu of íxvwnpte K rcplaeiov' anikfmz haíssi ths; mt«po»od oí Í7s«p«iön i
<,vk J‘ Mv v \ 's < O'» \Ki K »> tV" ti Skit í> i>ic v V >· i'< HIk t'Ot'Otik >t f . S'ÜV «<! m H'^p c Ον ΛΜ4-^#^θΟ«(ν8(α6θί?%1ί3»1>1!οκ>·|ρ^ο^Ι)· 0-!O«%f0i/-^!S^sf4 -ssnioo. *»«** (K$t*):
Implikál iVrmoi» C»H*iN*,©v [M; HV csúkífiíoo' >0] ΛΜ6 f M i H) rnogtonxi: 70; M4o
Bsamok i$li l^«0|5lOí-O-4-|fCM\HH^orpEí>loi'4'yím«ífí5ff}-'3^”<Sihyiíí'OBOí|sík!o!iS''2fl#í)>· yljcaffeoRyf}pboo^i>>,V-('t*í*yáfosypfe«R)l>-iV~|3»flrlfliiöroí»ethyOpí»esyi|-SA'?>8'tWf«H>ár«í«doH*Í80' Í^f*Í«*^plÍfe:l>3fd«se:hlorfd«··
tlis procedure h «a in m$m&m #&ρ#ί is mpisoioien she ooe-%mMk sompouiid t^ttqpNMÉtoS oaeti \n Step A by the compound of PmpsoÉ»'% aod os Ihs W ívcá o' Siof C bt Λ-t t-^v».'-í>öt>U»host.'tHvii?'Kilox>ipheojiV' 4isiWro«tcih> isiimé
Higk~rsí<&ii-iűi?íi m&si föi-i-j;
Bmpü jeni foromla: C*}H*,CSFfKl€ií*
|>1:·ΗΓ cakalstsd: 700.2600 iM ;-H] ;;kOva;tn.f 700.27! S
EssohOo 1S3; 3-(íf-|({lA>l-i0K3'-<i*^«^f'*>|)yrr<Ilii.íso.-t-yího«-'th):ip4>4-0i0v<ÍroEí>í|OÍ»i>IIO'2(i.i/y vl]«8r0t>n%íl-444K:nío4ioaoP5-yíoA<-ó4'hv(irü%vpín;s?y14A-ísh«nyi-5i;7J-Ít'í'ralíV{ÍreiSíÍBÍi:í0'ttk4 -cs rbfts o ns ide· fej?d reeh lóridé <k£\ v í ts Í> t. ss t s t " m' V> k k > t 't Ϊ ni if . ;x kit i." i tvdíiS s ;hs compound of Preparsooti 57' mk:nnwiiiym;
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Fmmií Wi8f ·Μ6&' 4JI. EMtoytfe ISI; .A-Cl'HydríísyphovíyiEA-Ci'íOí-Hsyi· i^pyt^yoi ylos«thyiKEd'díhydmisoooiso55o-7^ 5 ffpy i ] «s rf>« st- í f4E4"d4t > dr»' i ,4-6*?« í od so %. ϊο '6~y 5)-5,4,7.^4-i^írsijydnPoíkdigisís-l'íOifhftssiiOitií' hydiwhíorido
Tbc ís;iM:<>ds.i:X: is so ifi Ihs piocoi.s <s( f.xsispic t.. repkedő; M: Ide 00« hand iAbAbmpoopd sSf FífpMsóltf 0O.J !0 Wp «X 0) SÍR' COPiOnod of piíCs«;«"0 \ 000 - ;' " -0 OCR i S' ·>;'! b'O '.Οον-ΛΟ- ! Oi ^00-0,.0 O- i“ »-$vd isi Síep C hy #-(4- ílií.vi-lyiaiyi^íliníe-í^VÍí^s^'il^^y?f*he-«y'i>·'i'íOvííxyl-ia-íoi—Í'«fsíííí«;. 2(IÍf>->4^e8rb»8j4^23^1(!sy<(m--(#-besí<«^*>xsíx-'é--y(>--:\X(|(yr5í«kH!ií-^--yl)--S4k?;S-íe^'8lsj!iJrö5*íd<>lklRí:'
The poeídore is<s<· ns she proems of f.x&mpk. I. κ-pücinp »>« (ír- o-r- hand the compoond ol frspsrsskín l used i« Stop A by she compound of iböpsf&tion 7 -osd »o ok- oda-i hősid the compound of s'seporunoo s" os-.i !'í stop ¢. M \.<i h "m\S#s msiniVtMh \xχ-Φοϊ"*>{.'' ' ríooVvUv c LMmgde i5ó; V-(4'Hj'ár<íXj'piícmiK-M^'I|í3iS>O'i0'ín»*h«i'x>se«tkHH’“Í'X?pttvlh^M'sM* sii^íIrííissjqMlaolln-SítííVj'ÍKsíf ίχί^Η-ί'^^ίΛΗΗηχ^Ι^'νΟΛ^ίΐ^ί'^’ϊ,Η'ί^δΙϊ^ίθίΒ^ίίίχίδί.'' I-carboss midé
The procedure A so; in me process of οχ&ηψΑ í, ríp;acsna do compound o? Preparation Γ need in btep Λ by: dimcompoundofPo-píiOíOOR iá'.
%C %H %N
Calculated ΨΜ& #11 ?.X8
Fmm 7.A i2 SS} ".9$
Higé- íoso/íí?f 5« mám (£Si*)i lovsidró;f tosmukt: C.; Ji-kd \,
|Ml·· ki' cuietúated: 714 J Π7 ffify oB EBá8X«feil^f34^ilf3#^ifJ~fj0osÍ^g^^íá~yxigíjKéiMy-^i4'<Hhy(lmist>n»saohavay/l>'yiknjti?x^yil· Í3'b*8Xí>ílbx<d'-S-yi>#'(4'-iiydmsyph«»yi>Af--phe8ybS^o®'íx^*'8ÍfVdrxMndhH^«^ÍoefeSBsm|kx hydroefs&Híde Ί1| procedure iü ío: fp the primes* of Lxatopie !, replacing the compound öf:lhBpBf4lKíR 1* mxb in Step A by the to ropom# <>tVpr«|>arabes:! b'.
Example IM; Bd'B-'BI«o«>7-d(AVyBoíiHfrpbotbo4y4siMPhyfB(l-'d!tixdsoKsKpiíPohis-iiA#> ydx^eboíxylIphesixdHA-i'i-hjdyoyxfhcnxy X ^í-meíh'd-l H pyioesd 4-o'o Ε*η\Η'(Μι shnboliKksIams.·· i'-íiij'hoxsmkSí hydroedko ide Πο psoeesknv is m m d>e of S \ftvs^«k k sophíesEin os? the o*ie ϊη> -Ϊ hse en,<s?pos!ee of IS aTmosim, i used in Step A by die eenipotmd ot Prepare too -T and on the other bund bn- compound of Preparation V' used in Step é by Λ -(Ή |κ·>t•buiyUoitneiHyi>.'>Ι>Ι|ο·<> i phenyl)' S'-otebts ^biP-pyri^oM-sfpipC: lMabitl§it^dS--Pluoe«--S-|Hdsi>-d-<yoorpiKbm^-yto5«tbyip3i4--dbty<trobmpnn»bo-2{iAp yb\usrbo»yi||>tuo5yn~s^eol4iytbmsypbe«yp-:^l-oo*biybi/^pv^^M-yib»dobxbavb-eei'b»s«usMe hvitiXR'blorklfe the p<>\ed?sK is ,s\ ?; <p.' moem < o? i vunpie k sxpiasonp on me one nxnd the eo-u^iμ»Ι «,* Γ sp..s**"ou used its Step A by the otHupoorid of Preparation 32, aod on the other hand the ixunpound eb Preparation Γ u;n\t hi Step C by Λ-pbf|ípí-/-bu?yifchmethyl)ssí>tjoxyíphenyS}- i~meShyb! í/vpyptóeb-d--itn)ine. le$18liil§hl,lSl^S-Chh.i$'ei"2--{l(x3.$>;H"nte!rphnUit'‘ti$meihyhi-3,<lxlihydi-ohf.o)$isol8$iv2!'|^>s yt jesr&ooyl) phenyl)''A'~(4-it>'drosypbeotdpAíA I °u«íhyM H-pyraxoM-yipstdotsstme·' f''C&rhoxAmlsfo hydrochloride
Ihe proeC'iute is us sj, the promos ot t xumpk i, u-pioe mp ott she one hatni the svntpoond sd sSepatsneo s isised hi Step A by the compound of Preparation R, and os? the <jth«t hanti ti?« compound of Preparation ; R tise t ?t? Step i to 3 ; t pfe>obetiHdsnte;hmAiKt|o^s ipneo>'t-bo?esh;, i Rí.^os/R •.kasiooe.
EiPáIIMA.Sdö,LiMjXC:^l*-^JJ!íi^!k bKáMaJhAUiJsüJMiiob jiíMLIaü^^
The noeyeseonee pomriaatton tents ven.' carried out on ttilcropistex RS-t oebs; The Bet-2 pom-in. a- a fsna! icomentrfttRm of 2.3dxfbs M. is mixed nibs ?? thmrexxns fxtpsíde seksmesiCeh?-\ ks AT í ‘3'\BsN \ \?)3 s x, >?i mvOí.eninu r o btA ? '3' t) , px'í od? sse* tso,*.', l ?M, NsCi rSO OíM. i O'XX-oT) ü t?.V-,,. p}t " i), so the presence or in the «Rimre ssf incs-eussug cosies-nirtdiosss of ,s'v ..eissp, so?!. , Λrtc- -s\s t' ins" hv ,' ' uotx the 'tuo'cv,* nee pots, season sne,"i.,x'd t'he ivMih'i ,sis' ss<.pic>-".'d ?! u\ <?t?e s?>neentratt!'n R entnpon ·ύ shat inhibits iloorcsydnee pRafj.?*»tets by SOR? ,s?sd <s?v pressed hs iatsts, i feejoxv. t'hs re-usts sho'n d?*s? the compounds· of she jsocnt?ou nth-hit intense ·?ο?3 hesoeen the tkt-f protein and the fluorescent peptide despbised heresssbefoix?: s H<; CYK^oxk.sH osdko wers c. arasd Μ «rs -He RS4;I § Pshsoos-n isoonir iPso
Tip sslls sR'íí dlstrkmiod öposwsfpilM&S ask ííspossd lívIke isist coöí|5íst«Hls fét 48 kouíx !8sősit vkásilky I* #áí ípípíiioíif 8y s sölöHstyínc ppspffp ^Mö¾iti|í»í<^Te¾MΛ»n *fea? to>, Üf- $42), i& 1¾¾¾¾ sopypSPikst ofoop|i£«md ihat mksikts ««11 vkhíHiy SÖ%} st$).8t£ pppptod Ili 1akis 1 MÍo>o l%s ikfikis alom diai: the cosnpouads oíihe iavemion .arc oytohnse.
EXAMPLE O
The «ί ise £«5|58íí8Ís *í ths mwnoon les ;®'ív»!<5 osspas-a 7 ss evahiaiek m » xenografí model iif ÍLS4;11 ieukaeróa-cells. ; i s ii)7 RÍ4;11 .cdlís:«'#aSy sök-íastaíssöösijf fou^dta^unmappcctted mirt (SCID afc&m). 2? io 70 days átevlka gmlt^71® ssiimsls srs megisd-ondívwith ihp ^gíi^y? compound*. Sixteen homs akar treatment, th& ' <*mi l>vcd, asdldiresspase 2 .«tfivivv is messed in >t-c turnout h-&aU'S. 9%ί$*ιβ^ικβιΐ& mmmmumi' kccmkű- öuí' by · wayingi th® apptwaíwöf-a- •Dl VT.Xs.iS ;87;islivf 7^8segís$ ll Is asfsmssed h ikmftsm'-Mfím nmímtíim;.ímUir 8»£'ki|^í5'iki:n|2i 0:is rikis becses dm two «aspa<* ucth-ittev. ki? sadvby iba i^ykÉife:'Í^5Íli::ji>V''«Í!ie Itedlie miásn.
?*M* 2 and^wkWifei-'s^^ais 'ét tíw iwstMxm W ^étslísg a?sofy?«ís iA%tl via® 5» M *tto
mypy; a;OaiiLífajlaáiteíÍgiilffiLy&^^ 1>ís» abiihy ol the· íí?íRíK>ts«dv of bse inveatm» ίο aetsvate cas$»ase > \u β>3ΐ·ϋ«ο<1 m a w:os>g?';·^! model of d$4;U fsukéba «!!* :¾ i o': RB4:! I cells áré. .gliftéd SUl>-eHtssi«00s!>' Mbs :ámyHisö»5jppresS|dTi;|0 days: ιίκ aalmuK ars treated vsaik ^i*h «he various uuofvumls Altar treatment. the tumour masses. i-ιίΚί ijfsed. ass<J ihe cleaved isanated} form of usspo-íe 3 H i.unobikd m the tumour iy&en·:. T**? tfi^bW < ‘ <%' » S'»» «. * Ον Í s s \ s' X* "χΜ. N v XU> ! W'd'd ft lk\ I'lo'k'il'S t\ ' Ch. ' C<. "'sail·, ".. ^ C Ϊ CO *0 ' ot ·. C.-OX ' !5 5, S n»'-.'s\<.d ! the 5"' > «1 &o activation 5x£?Or·: íkhibsgsMdíli£ so the ratio Klswm the quantity of cleaved caspare * in the treated mice divided by the; quantity s>f cleaved ccspsse s so the control truce. lti£ result» obuoi>ed s:e presumed s- ksbk' c and .heo ihat ;V compound's s'? th< mx-noon s. spabla..of tedoCUig apOptOibs in KS M 1 íUnívStu O'- 555 fft 'ΌΌ
Table 3; Caspase (Μ^&Μξ^<ώΛΜί^&ΑΜ^^ΜΑΜΜΒΜΪΐΜΜΜΜύΜΚ^ΛΜΜΜ
The aotMsiKiour activity ot the tompot» »H o?*the inveotiett is evaluated hí a model as RS4-.it: kiik,\ot>.t sX-ih í x iO'’ RS4:i: ΐ«Η» are piaffed .-Silt-euiatteaysiY imo ümnunostif-pf cssed iuics fSOiD aif-tln). 2S to .10 visya aikr Site graft, a ϊκ-η ihetasnout tuass has teatheti ahova ; SO mm\ she stilee au- freak;! orally ο-ΐΟ; the v&sfO® <a p ι\λ uv OvU > vg ' > d s Ka Ki "í < ' 0 ' ι\ι í' e\ -.s αο οό S a i'' 'oaurfmk >"Oeh v \ϊ 1 lie o' \ϊ -tfiss n uesvs„\> 'vp<U$ K t ,k si > t s' iscaistuit
The compotmd.· at the investtk»;; have aak-iimKasr activtites, by Use «Mai xvsk% hi the RS-4.i l leulisesOa model «acme iemphobiasito kvhacmiih okh A7<C k|«aiifkath>o parameifcr of ibe activity of a produef. VUif''h 's A OO Í ,:, OiO Í 0-0 ΐ,ΧΧ'ϋί ,o|i{«b' of fhv U<\:kd giYOO ΑΟ'ϊΟίΟ VOÍ ΟΪΌ Ό ihc VsOUOííClI (.U-'tOoi group) ranging from AS to -46% rofaied to utntour regivüsioa. 1 he ms«it$-o&tawed: Üwrotbw s<bow ihat the ,>-mpoundv of Ac mw-obves rr, capaNo of mdoutsC .-ngft'ficaoi unnom r:gtvss»oa Ovaiog the nvMSukot period. i X^MPU F Ohmtoaerkkeai cumposttstm fakktv f -.-ο IA < i < ίο r a- vv oi" < s ,οοροκ<ν w o uf }V ) f xs «pk\ f κ t*o - *, ^^/ϊϊΐΚϊί St&r«h -ΐί; y'- iyy·' ^ y <:y . y: i ,. i e ΤΛ J - -. y - < i.y> y^.-., . S> j-jy ? ,.iS>.=:S->:e5g^AS^i=y i -ΐ.-ΕΗ -.Ϊ ^ - -Ι'ΐίϊ - ΐ ΐ> .-:>'^:j:> . > s.: 20 g 'Ifsfssi stareli ,Α-οχ-χν::· <,·,. ..-.--.:..,..--,0-¾ '-Mi 8 kíiiajC-ÍSSSíe: S;:: ^ . ::¾.¾. ί: ;;ί.ψ>.... ey:íyy > -;<:;· -:-:Η>ΐΐ::: - - , -,τ y .^.-: ί -.< -.-- ί:ί.--V ^ -.' y ;j:. - ^ c lyg-iO·· f":'; - - i-i; --: - '-'.-·ΐ·ί>.'·' : ΐ>-ΐ'ΐ^--ξί;'ί·ί-i ViS:H=i:' t.: g t^iagfiéskim MCSOíko., y-kiA-kiOé'·:.·.--Ο ---,--:----A:-,·:·.,· ^-ΟΑ- : .:χ,>· ..·.:.,. -.-ν·.ν;·:- -1;::: -.:--- Ο -;·-1 - -‘ - i-'.-Oy-- Ο- g ;:.^|t.i*«: \.y i l· yy :-|i ::: y: i. >y::-.--- ϊ:λ^:.;:·.·:-.- y, :.ί. -.- ί.;- i -: .--..-...:00 ί - - :, - ^, -:-:;>>>:-·: - - - Ο -·:·-:- -:- -- -0-::; - -01- --Οίΐΐ--1 g i UJi-'O pít-pV iodhiiOVe . . ...... ............................ ... ......... .* g
Claims (4)
- SaápasW jgéswpoxítek 1. f f > vegyük?# •SkŐfik^í Φ X és V jdemshc szaksa vagy skkogenikoin. a«ías s eaegkkiessek ángy ^ysdegH#; sfem «ék kend wjémtomoi vágj *c«6 aumgepíon-nx ♦ aképlet» csopoR Hes mokíkníaréa^ aden cselben lídyeöeskcík aramás·-va^y nem-aromás* 5,.6 vagy ? gyürüasgbá! áko gyűrű, aimly i,?. X vagy Y álra! ideinek smrogenatoiV; mdielí l - 3, eogdi, !.<·» os isii-· o -'kcvde^m > <. ti > ind (ίΛ ívk* üetcrado' a it<h , us « n > * >.vk ». v> i h ^ Mxúisss mtmgéuaiom helyei*a,:ftve.fchsa hkkpgéasipng eggeass ^l^alkilyyapky?;: gsgy· Mjj^Éfc ssopml É# ssöpaslbél .a^gsüla^öH üsgp*ldg:ghpl kg: ;Ms:o:y|Pg :eallftéö; csoportján Alk jelennie egyenessvsgy elSgaaű láncú k-'pC^dkikasopes;, # lg ^ysná^:'fiiggie%}jsí:||i^fi^sjaföp vagy agppg a: Aagy ellgagő ligse a u’.yc^'salkjkvopoit. V;így Rs é::. ;<·> 4 képedid ax/d « »ku;gdvaS:oymmü, amelyhs*: vV > y w jnhíu ον· ‘k t.« i's ^ti ki s S<\ v \Rk.almo div pícoU> hderaatnmot tarea!m.»*hat, ,iiöiag:«táfebÍ!mírR;:|aíe8®esshidragéndonp cg) «nos vagy dágavö láncú iC j^jalkUoscfOrt.iCpCJalkitsgulfoístc'iíípon, egyenes- vág) siágap láncú '*' ^Vv'you'S'lik'^n^' l,0'v«\ík v'ttti^\cjvx Ms·, c»s ^ ' w, k,^ \ ,!- ay í'«i kaa'M (krt\v\bk'kN^f''N?t, Φ k, jtík'otsse egyenes vagy ekpp ;am:-s Cí,\ C^kúkkesöpon. (C2 A'Jf>lkes*nesoporí. íCrí.'6>ja!kWj!k'Mípo{t( cikloaíhlcsopmk egyenes ssgy dcn>a?0 láncú l<VC5íi*c&k>slkfl·-A . a 'ctó;S· ik'fVípon jí ik'X'pO' ϊ \ igy VkX'ankvnpan, Í1I§2IP®2A MRdG ψ· Η;ϊ selsmes* anícxu|>orr: aeiv:roasucv<.g>i>n; vss:a>siso«sopmi vagy ygcíss '==·».; -<·" ·> ; C ?> >a Ϊ k í ♦ Rí; jelsnífcHc lisiSrogiUiOMo w.gy haiögéísatom. φ :R|, h!ilf?>gtHaK;r:\ höRgrérudook ügyvue* vagy da.gaao IsUxO {€ rC5palkiir:s>iXsro ígvsv* vagy eí&ga&ó Ííuxó tC.R^kiksHkaopan hkK>xóes<xxvü egyeney \ s , i í. > j v w ^ i ^íí^a. k ^•''ps s i v Mf a-o ^ vX'vMsOt x »!·.' a ^ X\ ' *, '* v;*gy íR^R;í} párok valamelyikének i?uhs2Űttt»nsei 5 · ? gyűríiísgOdS álló .gyűrűi kyp<x-lxímek ásókká! * sáéfUU-.xxük'Kak iuvalyskhe? kaMoKíditak, ':> ov a gyűrű oxsgso.. kra v> ruOügéx kikul kiválasztott 1 - 3 Oetcfuaíötixst iarkSm«/hk; ·χ:χ·χ a nsíukistossík houy n ktXskksx. ioifogduaiooi Ιχχννόοίχίνο k'űei hamv ' k> ! M Í5X R v Vk sMX V ^ R^O \K'a^t«v\'«'tU>Síii cvopsxOxx axígvsSssuaoO csoporttal, ahol a/, «tolj ára asulitast csuponOau Alk jcaaOssSvgy^v;: sagy vl-<'ga > iXUí.1, i >» «,> vs ·ν» tm ι λ i ' ük > l l>o ^ 4 k>> űíuXílöloHáirgyii-arug.y vagy több s.i'őoaű'snja dsütet&k ívűül.. sk.xai: S: ShögköiíRSiRiOógy ~:%jiíy jétefeífeRiksftp^i smSiteporR^ . vűeii'!X!a.nl” jelentése b-ármeSy aiyxa: S>· ü) gyúniiSiílvi alia musttá vagy blelRRíSös vsopsdí ss^ly l«pllRsfe eay ar0t0űk:it&s2£i Ok és oxigén, kéu tv niíKigeu ko/öl klvahts.no?? i x 3 iMPiytsO>m?x titn&tessg, - "clbfcatkr jekiOóxe Oármely; 4 10 gylkosagbói álló motto- vagy bk skktsovo^xíHorm karbocikb>sos csu por?, ishói a:s;k^^^^vá^bMÍii=^lSÍ^,-^-ít?> s&teSiil «fttt msihm: 0® lyaOssÓfeii ggyeíiüs ^gy:é]%aM:Íiác6':CC':jyC%^ki|ii; vg|y saafea iC:-Ci:}aik<«i} {€,.QRaíkil-ÍK hídn*8, oxo (vagy adót? esetben Aniskt roo®, smm^ «€$R\ MW? rgyuovs vagy elágazó iámat ?C s-fV.jpoiihategénalkfi, fr»nuom«toxi, <C,-Cfc)«SMIs*uSfuBtS és balogét? al- kssOa BSigyorílxIk sxaaválairusi i > «?abif?Ou»fe'»u<s«í ixuveiiv^óauok lehumak. ga«r R gx R ''«g^^Ík.Í^#e»8i.fe5^#mb>ovv8gy «gy«í»e« ^«gy iasKu ii rd.^jíukiksppp, Sfíókó kóf|0tf3fidi5Í5OÍlST^n vagy dage* i^-ú bi^KÍK KW ^ habgúo «Ikoga vvupoóhvO kvlyetívrow Sebet, aomvlku RR# ^ ^jüjpis* »ió pi;rk;k korábbat «-üg&ifcn jslgmésóvul % ím í Λ t , , u,l(.,i|k't . 4 *' - mx"Í' ' ' 11 OÍÓS sói. \ , * ' > í í X : 1 ? V ) kí'jf í'ÜU'^k a '0 :ss"X\'OR .ΐ lOwKi . X ; v-puOek VitiBí- <->' .CXB J<0lí <ídOi'> i.-CiK i sSx k»1'OMk\ujX«}StvR ikKotk's'\.R v.'.x i<arahKki>iníkdi:d5v indcdiii.ny. I ..-Mai -ugrafcidropif'mkd $«2*αIfMra*.»*,· 44*ífcjMdf<*-pim)U>t I ^t||>«8^a>^(. koivnNavuac-PU'dwka. ' I dküku- RR pa-uM\i ,ls UkKV'n a,lak e-^dvn Vgv h>-iio\ ^->γ<}·η.ρ ho-^•'«vakn 2,5 JPv.ko '!> wo^h/ü^k .sykH.'nd'üiiü W pnu-doii * oja-cpin vxg\ ρ*ϊ j ->3o| l 1 c^pnu.Bn λ V í <gv *<.jv*8 ;"'cfí-!í! (!' képkén vvgcékn akoi R; vS R m-aak-gyfke a-.?"1? v-uhen cc-rtKK-m'vopfttttal hdycikn-ksR aikdccop<>rtot jeienk vagy Rj ks R> s köve?.keg6 asöpuniíi; kkakl saegVidsSííR>U h^tínKÍkk>alkiksoport«i képeik auval 5¾ nKw^éMaimBsI^aK^to'^is^öíSáask adoikesdkss égy vagy R4h g|g«i5:Sa vagy éliggsa i&ncá (C rC%3a&>kwpontd hgiyaisvRsM::mofi»!kg itlomöifsteU* t. \í -> Kí!-"ip a. si>r í id p T fi n t v\a rtk»1 ^ nor'k ^ >í‘f avpp’i'i' i;^yí|5iR^^'n-t-stó::^íöi#^li^#:^jwt hd^itesuvecva» «jpeamavagy üMgmb lh^é:í^^ptk'ilm^tt^· i-gye-oss vagy dágaaé kgani 5.C, R.^Í-pííkhalí'RWíaÍkiksoiKtrtfaí vagy (su'aikaükoaík'svipOi'UsL
- 4, Az L igenyponí .,-<'!aki Hi képkén vvy>kké, ahol H.;, iJs R^ miadegyííce hidKsgénaiünsca jvR'ni és ; R;.,R,) vokkal & aédnaíounskka;, amelyekbe a kacsolódnak. a.í cgvik valnalomjén adót? esessen dansc-rait ka- dk'XoRnv.' 'pooot. 5 5'0<ο\<5ηη·η.ί,νο vasa. k-kvK'OpáiVSUiWt.'t .kk-ai, vagy R,, R. és Ikpaknlvg^nkp Jin-ko-gv vK'iVs {fkai x> R·., Hano··^ i'.dngío-nnat v&g\ *!\;>i , on-k-M , víoxí-, fnHí»«H>«OÍ '••kJ K-af"*Í R Λ a 1. igényposk cser ind (ki képkén vagyak;, akié R $ jekttóc é-hirfk-vPikBksupon kdkxv-a· hsiiíiixifKíSik'.sops>{í vagy 5-ktdrojdpá knsdsacvopod.
- 6. Az k ig«5Wpi>íií saes'tsiíí: sí) fcépkéó vagyüké, »!xR R·* jídeoíése fsaik, kidsxk, kaioissv ·, Μ>-ν?· bids síkmssiío>5 'kd kki!ikav2k- kka>íttaivasai!i- , indán-, i H- mámA. ?// pl:fmk>|'2.3-k|piriilin-< pirikdikny idkkibíiíiinvatik. eiklopcopíSroanh 5/·/-pús*ss>k. pkkísn- vagy píndasántsopori, és sisak adsRí esaSfesn hakijíé?'·-mm vagy vgyenigs vagy vi%a/á km.ú {Cs-Íaglalkík. iiasKv· Is gpenes vagy eilgavi lánca (.< v^>aikosii:si>fxM8lfeRa8söpö!SM! íBéivlIasiS»R agy vagy iökk sapfesHÍiHCScsíi kckeUéSik'tikk. v. Aa. 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- 27. A bbI. igénypont ϊ-λίβϊβϊ gy-Agyassai! kéviskmériy hóiyagrök, agyrnL mdldk, niéimsk. bvvmsa·;; lyfttgbpib feiídívdi kükB'sksál s.v iák, 5%!§ife-SiÉ^ máfrálg Jyí&phöMa&it: feM? véfüségefe, iiksS* gy Röfe- aj^yÉ^kgRiRbíiki ssglgsöiaáRj rós&akáb'S&íö ysRbgisgsegelg:: fes^dkYekkls^kaieli #8íb líissgjtds: ükk-A. pii>v.-íuiei«l A íBwjgBN deAA AeekHen.- x Ab alkalmazás» 2b. Az i R>. Igény pmaok bárotelyilce cterino ?ij képiéül vegyül*! vagy egy gybgvbszabiaa vRogidhsil víw&í vagy báe-vsíii a S kdeit «diikibs vöie hóixagdk. agytstk, nieUrák. méh fák. \ rönikuv isnighokl Sekssvéí üsé· gíL kdosekkíHa dk, nvcikivbdk, míijták, iyingkinblasxi íehétvérüivégek, tüv?.öv nyiroksaOviíí-AiganaSok, iBi-ki-Kisi-ák, mss^BiMnik vévbekigvbgvk, evn»?vdö4^*natnk, apt::il§8e3^'-^^tókg|í«^^a-í' rák é& kkseftev üí-kkák k*«e!eái5r* vals> aöialHiaaásra, 2kk A < I - Jk íg*ByiXB;k>k hártndvik* v/sssaís <i) képien? vegyikéi gen?)í?>síss«3 ágcíkeL nni*Sai«n niek\k aeii ait5al\ikiA, m*iea*Otfi iSihiNtnuvís., kín$& t^5Íltós^::A«Is«i· süikiöi alkískki .köHibínádöla. ÍR. ÜyégyávaMs ké^itmé«>, smvly a Igén*p*pMő^Í^«5^ni^í-&gl«|s'«ígé;b^s gvívgvdvait!»?' likaytdkeKt <ι*^«Λη?\^^ίΙ ks'snRííiviOiAae ti \ a en\ po ü sí!'* a'. MvBbBi \ B> · Anv B\Bvh„ky>,\ ->:k kB-k k e5í >,aki dk. iki azii·»:??. Í2. Az I -21. igéo><m>ni«k bám^eíyik* s^^tN|1t:k^ftt:S?*0*Ő.fe!.sii^Eí^épl^|.;:kínob!r>ái ?d>a>v#tes ij'a'vlaiegedévBk kaiadéseíe vain alk&ü«a/asr«
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| FR1200193A FR2986002B1 (fr) | 2012-01-24 | 2012-01-24 | Nouveaux derives d'indolizine, leur procede de preparation et les compositions pharmaceutiques qui les contiennent |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| FR2986002B1 (fr) | 2012-01-24 | 2014-02-21 | Servier Lab | Nouveaux derives d'indolizine, leur procede de preparation et les compositions pharmaceutiques qui les contiennent |
| FR3008979B1 (fr) * | 2013-07-23 | 2015-07-24 | Servier Lab | Nouveaux derives phosphates, leur procede de preparation et les compositions pharmaceutiques qui les contiennent |
| FR3008976A1 (fr) * | 2013-07-23 | 2015-01-30 | Servier Lab | "nouveaux derives d'indolizine, leur procede de preparation et les compositions pharmaceutiques qui les contiennent" |
| FR3008977A1 (fr) * | 2013-07-23 | 2015-01-30 | Servier Lab | Nouveaux derives d'isoindoline ou d'isoquinoline, leur procede de preparation et les compositions pharmaceutiques qui les contiennent |
| FR3008975A1 (fr) * | 2013-07-23 | 2015-01-30 | Servier Lab | Nouveaux derives de pyrrole, leur procede de preparation et les compositions pharmaceutiques qui les contiennent |
| FR3008978A1 (fr) * | 2013-07-23 | 2015-01-30 | Servier Lab | "nouveaux derives d'indole et de pyrrole, leur procede de preparation et les compositions pharmaceutiques qui les contiennent" |
| FR3015483B1 (fr) * | 2013-12-23 | 2016-01-01 | Servier Lab | Nouveaux derives de thienopyrimidine, leur procede de preparation et les compositions pharmaceutiques qui les contiennent |
| US20150320755A1 (en) | 2014-04-16 | 2015-11-12 | Infinity Pharmaceuticals, Inc. | Combination therapies |
| WO2016190847A1 (en) * | 2015-05-26 | 2016-12-01 | Calitor Sciences, Llc | Substituted heteroaryl compounds and methods of use |
| FR3037956B1 (fr) * | 2015-06-23 | 2017-08-04 | Servier Lab | Nouveaux derives d'acide amine, leur procede de preparation et les compositions pharmaceutiques qui les contiennent |
| FR3037958B1 (fr) | 2015-06-23 | 2019-01-25 | Les Laboratoires Servier | Nouveaux derives d'hydroxy-acide, leur procede de preparation et les compositions pharmaceutiques qui les contiennent |
| FR3037959B1 (fr) | 2015-06-23 | 2017-08-04 | Servier Lab | Nouveaux derives bicycliques, leur procede de preparation et les compositions pharmaceutiques qui les contiennent |
| WO2017013271A1 (en) * | 2015-07-23 | 2017-01-26 | Les Laboratoires Servier | Combination of an inhibitor of phosphatidylinositol 3-kinase delta and a bcl-2 inhibitor, uses and pharmaceutical compositions thereof |
| UY37316A (es) | 2016-07-07 | 2018-01-31 | Servier Lab | Dispersión sólida farmacéutica de un inhibidor de bcl-2, composiciones farmacéuticas de ésta, y usos para el tratamiento de cáncer |
| UY37342A (es) | 2016-07-22 | 2018-01-31 | Servier Lab | Combinación de un inhibidor de bcl-2 y un inhibidor de mcl1, usos y composiciones farmacéuticas de éstos |
| WO2018158225A1 (en) | 2017-02-28 | 2018-09-07 | Les Laboratoires Servier | Combination of a bcl-2 inhibitor and a mdm2 inhibitor, uses and pharmaceutical compositions thereof |
| WO2019008126A1 (en) | 2017-07-06 | 2019-01-10 | Les Laboratoires Servier | NOVEL CRYSTALLINE FORM OF BCL-2 INHIBITOR, PROCESS FOR PREPARATION THEREOF, AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME |
| AU2018305614B2 (en) | 2017-07-27 | 2022-05-12 | Jiangsu Hengrui Medicine Co., Ltd. | Piperazine heteroaryl derivative, preparation method therefor and use of same in medicine |
| FR3072679B1 (fr) * | 2017-10-25 | 2020-10-30 | Servier Lab | Nouveaux derives macrocycliques, leur procede de preparation et les compositions pharmaceutiques qui les contiennent |
| WO2019134970A1 (en) | 2018-01-05 | 2019-07-11 | Les Laboratoires Servier | Novel salts of a bcl-2 inhibitor,related crystalline forms,method for preparing the same and pharmaceutical compositions containing the same |
| MX2020008569A (es) * | 2018-02-16 | 2020-09-21 | Abbvie Inc | Inhibidores selectivos de bcl-2 en combinacion con un anticuerpo anti-pd-1 o anti-pd-l1 para el tratamiento de tipos de cancer. |
| FI3969000T3 (fi) | 2019-05-14 | 2023-11-20 | Servier Lab | Bcl-2-inhibiittoreita käytettäväksi bcl-2-välitteisen gly101val-mutaation sisältävän syövän hoitamisessa |
| CA3138058A1 (en) | 2019-05-20 | 2020-11-26 | Matthew T. Burger | Mcl-1 inhibitor antibody-drug conjugates and methods of use |
| JP2023553808A (ja) | 2020-11-24 | 2023-12-26 | ノバルティス アーゲー | Ｍｃｌ－１阻害剤抗体－薬物コンジュゲートおよび使用方法 |
| AU2022218128A1 (en) | 2021-02-02 | 2023-08-17 | Les Laboratoires Servier | Selective bcl-xl protac compounds and methods of use |
| KR20230157419A (ko) * | 2021-03-12 | 2023-11-16 | 에일 테라퓨틱스 인코포레이티드 | Bcl-2 저해제로서의 테트라하이드로인돌리진-1-카복스아마이드를 갖는 화합물 |
| WO2023225320A1 (en) | 2022-05-20 | 2023-11-23 | Novartis Ag | Epha2 bcl-xl inhibitor antibody-drug conjugates and methods of use thereof |
| WO2023225359A1 (en) | 2022-05-20 | 2023-11-23 | Novartis Ag | Antibody-drug conjugates of antineoplastic compounds and methods of use thereof |
| WO2023225336A1 (en) | 2022-05-20 | 2023-11-23 | Novartis Ag | Met bcl-xl inhibitor antibody-drug conjugates and methods of use thereof |
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| US5932590A (en) * | 1996-12-05 | 1999-08-03 | Merck & Co., Inc. | Inhibitors of farnesyl-protein transferase |
| MXPA04002243A (es) * | 2001-09-19 | 2004-06-29 | Aventis Pharma Sa | Compuestos quimicos. |
| AU2003234464B2 (en) * | 2002-05-03 | 2009-06-04 | Exelixis, Inc. | Protein kinase modulators and methods of use |
| US20050070570A1 (en) | 2003-06-18 | 2005-03-31 | 4Sc Ag | Novel potassium channels modulators |
| CA2577752A1 (en) * | 2004-08-20 | 2006-03-02 | The Regents Of The University Of Michigan | Small molecule inhibitors of anti-apoptotic bcl-2 family members and the uses thereof |
| MX2009011211A (es) * | 2007-04-16 | 2009-10-30 | Abbott Lab | Indoles sustituidos en la posicion 7 inhibidores de mci-1. |
| CA2707445A1 (en) | 2007-11-30 | 2009-06-11 | Biota Scientific Management Pty Ltd | Tetrahydro-isoquinoline ppat inhibitors as antibacterial agents |
| JP2011506932A (ja) | 2007-12-07 | 2011-03-03 | リンデ アクチエンゲゼルシヤフト | 水素燃料補給システムを監視する方法 |
| JP5496915B2 (ja) | 2008-02-13 | 2014-05-21 | シージーアイ ファーマシューティカルズ，インコーポレーテッド | ６−アリール−イミダゾ［１，２−ａ］ピラジン誘導体、その製造方法、及びその使用方法 |
| WO2012040242A1 (en) | 2010-09-22 | 2012-03-29 | Intermune, Inc. | Substituted proline inhibitors of hepatitis c virus replication |
| JP2014521595A (ja) * | 2011-05-25 | 2014-08-28 | ブリストル−マイヤーズ スクイブ カンパニー | 抗アポトーシスＢｃｌ阻害剤として有用な置換スルホンアミド |
| FR2986002B1 (fr) | 2012-01-24 | 2014-02-21 | Servier Lab | Nouveaux derives d'indolizine, leur procede de preparation et les compositions pharmaceutiques qui les contiennent |
| FR3008976A1 (fr) | 2013-07-23 | 2015-01-30 | Servier Lab | "nouveaux derives d'indolizine, leur procede de preparation et les compositions pharmaceutiques qui les contiennent" |
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