RS53562B1 - Tripeptidi, inhibitori hepatitisa c - Google Patents

Tripeptidi, inhibitori hepatitisa c

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Publication number
RS53562B1
RS53562B1 YU20090459A YUP9401A RS53562B1 RS 53562 B1 RS53562 B1 RS 53562B1 YU 20090459 A YU20090459 A YU 20090459A YU P9401 A YUP9401 A YU P9401A RS 53562 B1 RS53562 B1 RS 53562B1
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Serbia
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mmol
mixture
amino
alkyl
group
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YU20090459A
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English (en)
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Bruno Simoneau
Murray D. Bailey
Montse Llinas-Brunet
Dale Cameron
Anne-Marie Faucher
Dominik M. Wernic
Nathalie Goudreau
Marc-André Poupart
Jean Rancourt
Youla S. Tsantrizos
Teddy Halmos
Elise Ghiro
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Boehringer Ingelheim (Canada) Ltd.
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Publication of RS53562B1 publication Critical patent/RS53562B1/sr

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Abstract

Postupak odvajanja enantiomerae smeše metil estra 1-amino-2-vinilciklopropil karboksilne kiseline, ili njegove N-zaštićene smeše, obuhvata korake tretiranja navedene smeše sa esterazom kako bi se dobio željeni enantiomer metil estra 1 -amino-2-vinilciklopropiI karboksilne kiseline ili njegov N-zaštitni oblik.Prijava sadrži još 7 patentih zahteva.

Description

OBLASTPRONALASKA
Ovaj se pronalazak odnosi na postupak odvajanja enentiomerne smeše derivata 1-aminociklopropil karboksilne kiseline kao što je definisano u zahtevima.
Jimenez at al opisuje u Tetrahedron Pismima 35/32: 5945-5948 (1994), sterokontrolisani sintetički put do enantiočistoće derivata 1-aminociklopropan-l-Karboksilne kiseline.
Fliche at al opisuje u Svnthetic Communications 24 (20): 2873-2876 (1994), sintezu (1R,2S) i (1S,2S) dehidrokoronaminskih kiselina sukcesivno korišćenjem dve esteraze sa različitim regioselektivitetima i konvencionalnom hernijom.
Yee et al opisuje u J Org. Chem 57: 3525-3527 (1992) postupak za enzimsko odvajanje estara a-supstituisane karboksilne kiseline.
Spero i Kapadia opisuju u J Org Chem 61: 7398-7401 (1996), enentioselektivnu sintezu derivata a,a-disusptituisane amino kiseline preko enzimskog odvajanja.
Sledeći tripeptidi su inhibitori NS3 proteaze hepatitis C virusa.
u kojoj B jeste H, C-6 ili Cioaril, C7.16aralkil; Het ili (niži aIkil)-Het, svaka od njih eventualno supstituisana sa Ci_6alkilom; C1-6alkoksi; C1-6alkanoil; hidroksi; hidroksialkil; halogeno; halogenoalkil; nitro; cijano;, cijanoalkil; amino grupa eventualno supstituisana sa Ci? alkilom; amido; ili (niži alkil)amid; ili, B jeste acil derivat formule R4-C(0)-; karboksil formule Rt-O-C(O)-; amid formule R4-N(R5)-C(0)-; tioamid formule R4-N(R5)-C(S)-; ili sulfonil formule RrSOigde R4 jeste grupa, (i) Ci.10alkil opciono supstituisana sa grupom karboksil, Ci_6alkanoil, hidroksi, C1.6alkoksi, amino grupom opciono mono- ili di-supstituisanom sa grupom C1.6alkil, amido ili (niži alkil)amid; (ii) C3.7cikloalkil, C3.7cikloalkoksi, ili C4.10alkilcikloalkil, sve opciono supstituisane sa grupom hidroksi, karboksil, (C1-6alkoksi)karbonil, amino opciono mono- ili di-supstituisanom sa grupom C]_6alkil, amido, ili (niži alkil)amid; (iii) amino opciono mono- ili di-supstituisana sa C1-6alkilom; amido; ili (niži alkil)amid; (iv) C6ili Cioaril ili C7_i6aralkil, sve opciono supstituisane sa grupom C1.6alkil, hidroksi, amido, (niži alkil)amid, ili amino grupa opciono mono- ili di-supstituisana sa Ci_6alkilom; ili (v) Het ili (niži alkil)-Het, obe opciono supstituisane sa grupom C1.6alkil, hidroksi, amido, (niži alkil)amid, ili amino grupa opciono mono- ili di-supstituisana sa Ci-6alkilom;
RsjeH ili Ct.6 alkil;
uz uslov, da kada R4 jeste amid ili tioamid, R4nije (ii) cikloalkoksi grupa; a Y jeste H ili C1-6alkil grupa;
R<3>jeste grupa Ci-s alkil, C3-7cikloalkil, ili C4.10alkilcikloalkil, sve eventualno supstituisane sa grupom hidroksi, Ci_6alkoksi, Ci-6tioalkil, amido, (niži alkil)amido, C6ili Cioaril, ili C7-16aralkil;
R2jeste CH2-R20, NH -R20, O -R20ili S -R20, gde R2ojeste zasićena ili nezasićena C3.7cikloalkil ili C4.10(alkilcikloalkil) grupa, od kojih su sve opciono mono-, di- ili tri-supstituisane sa R21,
ili, R20jeste C6ili Cio aril ili C7.14aralkil grupa, sve opciono mono-, di- ili tri-supstituisane sa R21,
ili, R20 jeste Het ili (niži alkil)-Het, obe opciono mono-, di- ili tri- supstituisane sa R2i,
gde svaka R21jeste nezavisno, grupa C1-6alkil; C]_6alkoksi; niži tioalkil; sulfonil;
N02; OH; SH; halogeno; halogenoalkil; amino grupa eventualno mono- ili di-supstituisana sa grupom Ci-6alkil, Cćili Cioaril, C7.14aralkil, Het ili (niži alkil)-Het;
amido grupa eventualno mono-supstituisana sa grupom C)_6alkil,C(,ili Cioaril, C7-14aralkil, Het ili (niži alkil)-Het;
karboksil; karboksi(niži alkil);Ceili Cioaril, C7-14aralkil ili Het, a pomenute aril, aralkil ili Het grupe su opciono supstituisane sa R22;
gde R22 jeste grupa C]_6alkil; C3.7cikloalkil; Ci_6alkoksi; amino opciono mono- ili di-supstituisana sa Ci_6alkilom; sulfonil; (niži alkil)sulfonil; N02;
OH; SH; halogeno; halogenoalkil; karboksil; amid; (niži alkil)amid; ili Het eventualno supstituisan sa Ci-6alkilom,
R<1>jeste H, grupa Ci-6alkil, C3-7cikloalkil, C2-6alkenil, ili C2_6alkinil, sve eventualno supstituisane sa halogenom;
ili njihova farmaceutski prihvatljiva so ili estar.
Definicije
Kako su ovde upotrebljene, sledeće definicije, ukoliko nije drugo rečeno, označavaju: Oznaka "Pl, P2 i P3", kako je ovde upotrebljena, odnosi se na položaj ostataka amino kiseline polazeći od kraja završnog C atoma peptidnih analoga pa pružajući se ka završnom N atomu [tj. Pl odnosi se na položaj 1 od završnog C atoma, P2: drugi položaj od završnog C atoma, itd.) (vidi Berger A & Schechter 1., Transactions of the Royal Societv London series(1970), B257. 249 - 264].
Skraćenice za oc-amino kiseline korišćene u ovoj prijavi prikazane su u tabeli A.
Izraz "halogeno", kako je ovde korišćen označava halogeni supstituent odabran između bromo, hloro, fluoro ili jodo naziva.
Izraz "Ci-6alkil" ili "(niži)alkiP', kako je ovde korišćen, bilo sam ili u kombinaciji sa drugim supstituentom, označava aciklične alkil supstituente, sa pravim ili razgranatim nizom koji sadrže od 1 do šest atoma, a obuhvataju na primer, metil, etil, propil, butil,terc.-butil, heksil,1-metiletil, 1-metilpropil, 2-metilpropil, 1,1-dimetiletil.
Izraz "C3.7cikloalkil" , kako je ovde korišćen, bilo sam ili u kombinaciji sa drugim supstituentima, označava cikloalkil supstituent koji sadrži od tri do sedam atoma ugljenika, a uključuje ciklopropil, ciklobutil, ciklopentil, cikloheksil i cikloheptil grupe.
Ovaj izraz takođe obuhvata "spiro"-cikličnu grupu, kao spiro-ciklopropil ili spiro-ciklobutil:
Izraz "nezasićeni cikloalkil" obuhvata, na primer, cikloheksenil:
Izraz "C4.10(alkilcikloalkil)", kako je ovde korišćen, označava cikloalkil radikal koji sadrži od tri do sedam atoma ugljenika, povezanih u alkil radikal, a vezani radikali sadrže do deset atoma ugljenika: na primer, ciklopropilmetil, ciklopentiletil, cikloheksilmetil, cikloheksiletil ili cikloheptiletil.
Izraz "C2-10alkenil", kako je ovde korišćen, bilo sam ili u kombinaciji sa drugim radikalom, označava alkil radikal kao što je gore definisano, koji sadrži od 2 do 10 atoma ugljenika, a sadrži još i bar jednu duplu vezu. Na primer, alkenil uključuje alil i vinil.
Izraz "C|.6alkanoil", kako je ovde korišćen, bilo sam ili u kombinaciji sa drugim radikalom, označava prave ili razgranate 1-oksoalkil radikale koji sadrže jedan do šest atoma ugljenika i obuhvata formil, acetil, 1-oksopropil (propionil), 2-metil-l-oksopropil, 1-oksoheksil i slično.
Izraz "Ci.6alkoksi", kako je ovde korišćen, bilo sam ili u kombinaciji sa drugim radikalom, označava radikal -0(Ci_6alkil), gde alkil kao što je gore definisano sadrži do 6 atoma ugljenika. Alkoksi obuhvata metoksi, etoksi, propoksi, 1-metiletoksi, butoksi i 1,1-dimetiletoksi. Poslednji radikal je obično poznat kao/erc.-butoksi.
Izraz "C3.7cikloalkoksi", kako je ovde korišćen, bilo sam ili u kombinaciji sa drugim radikalom, označava C3.7cikloalkil grupu vezanu za atom kiseonika, kao što je na primer:
Izraz "Cćili Cioaril", kako je ovde korišćen, bilo sam ili u kombinaciji sa drugim radikalom, označava ili aromatsku monocikličnu grupu koja sadrži 6 atoma ugljenika ili aromatsku bicikličnu grupu koja sadrži 10 atoma ugljenika. Na primer, aril uključuje fenil, 1-naftil ili 2-naftil.
Izraz "C7-16aralkil ", kako je ovde korišćen, bilo sam ili u kombinaciji sa drugim radikalom, označavaCeili Cioaril, kao što je gore definisano, vezan za alkil grupu, gde alkil definisan kao gore sadrži od 1 do 6 atoma ugljenika. C7.16aralkil obuhvata na primer, benzil, butilfenil i 1-naftilmetil.
Izraz "amino aralkil", kako je ovde korišćen, bilo sam ili u kombinaciji sa drugim radikalom, označava amino grupu supstituisanu sa C7.16aralkil grupom, kao na primer, amino aralkil:
Izraz "(niži alkil)amid", kako je ovde korišćen, bilo sam ili u kombinaciji sa drugim radikalom, označava amid, mono-supstituisan sa C|.6alkilom, kao što je:
Izraz "karboksi(niži)alkil", kako je ovde korišćen, bilo sam ili u kombinaciji sa drugim radikalom, označava karboksil grupu (COOH) vezanu preko (niži)alkil grupe, kao što je gore definisano a obuhvata na primer buternu kiselinu.
Izraz "heterocikl" ili "Het", kako je ovde korišćen, bilo sam ili u kombinaciji sa drugim radikalom, označava monovalentan radikal dobijen uklanjanjem vodonika iz peto-, {esto- ili sedmo-članog zasićenog ili nezasićenog (uključujući aromat) heterocikla koji sadrži od jedan do četiri hetero-atoma odabranih od azota, kiseonika i sumpora. Dalje, "Het", kako je ovde korišćeno, označava heterociklično jedinjenje kao što je definisano gore, "stopljeno" u jedan ili vi{e drugih prstenova, bili oni hetero-prstenovi ili drugi prstenovi. Primeri pogodnih heterocikla obuhvataju: pirolidin, tetrahidrofuran, tiazolidin, pirol, tiofen, diazepin, lH-imidazol, izoksazol, tiazol, tetrazol, piperidin, 1,4-dioksan, 4-morfolin, piridin, pirimidin, tiazolo[4,5-b]piridin, hinolin ili indol, ili slede}e heterocikle:
Izraz "(niži alkil)-Het", kako je ovde korišćen, označava heterocikličan radikal kao što je gore definisano vezan preko prave ili razgranate alkil grupe, pri čemu alkil, definisan kao gore, sadrži do 1 do 6 atoma ugljenika. Primeri (niži alkil)-Het obuhvataju:
Izraz "farmaceutski prihvatljiv estar", kako je ovde korišćen, bilo sam ili u kombinaciji sa drugi supstituentom, označava estre jedinjenja formule I, u kojoj su karboksilne funkcije molekula, a prvenstveno karboksi zavšetak. zamenjeni alkoksikarbonil funkcijom:
u kojoj je deo R, estra, odabran od alkila (npr. metil, etil,n-propil,/-butil,«-butil); alkoksialkila (npr. metoksimetil); alkoksiacila (npr. acetoksimetil); aralkila (npr. benzil; ariloksialkila (npr. fenoksimetil); arila (npr. fenil), eventualno supstituisan sa halogenom, Cmalkil ili Ci? alkoksi grupom. Drugi pogodni prolek estri mogu se naći u Design ofprodrugs, Bundgaard, H. Ed. Elsevier (1985), uključenim ovim kao referenca. Takvi farmaceutski ptihvatljivi estri obično hidrolizujuin vivokada se injektuju u sisara i transformišu se u oblik kiseline jedinjenja formule I.
Sto se tiče gore opisanih estara, ukoliko nije drukčije specificirano, svaki prisutan alkil deo prvenstveno sadrži 1 do 16 atoma ugljenika, naročito 1 do 6 atoma ugljenika. Svaki aril deo u takvim estrima prvenstveno sadrži fenil grupu.
Naročito, estri mogu biti Ci_i6alkil estar, neki nesupstituisani benzil estar ili benzil estar supstituisan sa bar jednom halogenom, C1.6alkil, C,^alkoksi, nitro ili trifiuormetil grupom.
Izraz "farmaceutski prihvatljiva so", kako je ovde korišćen, obuhvata one izvedene od farmaceutski prihvatljivih baza. Primeri pogodnih baza obuhvataju holin, etanolamin i etilendiamin. Na<+>, K<+>i Ca++ soli takođe dolaze u obzir kao predmet pronalaska (vidi takođe Pharmaceutical salts, Birge, S.M. et al., J. Pharm. Sci., (1977), 66, 1 -19).
Pl je ciklopropil prsten u kome ugljenik 1 imaRkonfiguraciju,
a R1 je etil, vinil, ciklopropil, 1 ili 2-bromoetil ili 1 ili 2-bromovinil.
Jedinjenja prema ovom pronalasku sintetizuju se prema opštem postupku kao što je prikazano na shemi I (gde CPG jeste karboksilna zaštitna grupa a APG je amino zaštitna grupa):
Sinteza 4 moguća izomera 2- supstituisane t- aminociklopropil- karboksilne kiseline
Sinteza je izvedena prema shemi VI.
a) Ukratko, đi-protektovan malonat Via i 1,2-dihalogenoalkan VIb ili ciklični sulfat Vic (sintetizovano prema K. Burgess i Chun-Yen KE (Svnthesis, (1996), 1463 - 1467),
reagovali su pod baznim uslovima dajući diestar Vid.
b) Regioselektivnom hidrolizom manje zaklonjenog estra dobijena je kiselina Vle.
c) Ta kiselina Vic je podvrgnuta pregrupisavanju po Curtius-u dajući racemsku smešu
derivata l-aminociklopropil-karboksilne kiseline Vlf sa R<1>usynpoložaju u odnosu na
karboksilnu grupu. Specifičan način izvođenja te sinteze prikazanje u primeru 9.
d, e) Alternativno, selektivno stvaranje estra od kiselline Vle, sa pogodnim halogenidom (P CI) ili alkoholom (P OH), daje diestar VIg u kome je P estar kompatibilan sa selektivnom hidrolizom P estra. Hidroliza P estra daje kiselinu VIh.
f) PregrupisavanjeVIh,po Curtius-u, daje racemsku smešu derivata 1-aminociklopropil-karboksilne kiseline Vli sa R<l>grupom uantipoložaju u odnosu na
karboksilnu grupu. Specifičan način izvođenja te sinteze prikazanje u primeru 14.
Alternativna sinteza za pripremanje derivata Vllf (kada R<1>jeste vinil, a nalazi se usynpoložaju prema karboksil grupi) opisana je u narednom tekstu.
Tretman komercijalno dostupnih, ili koji se lako mogu pripremiti, imina Vila sa 1,4-dihalogenobutenomVllbu prisustvu baze, posle hidrolize dobijenog imina VIIc, dajeVlldsa alil supstituentom usynpoložaju u odnosu na karboksilnu grupu. Specifični načini izvođenja tog postupka prikazani su u primeru 15 i 19.
Razdvajanje svih gornjih enantiomernih smeša ugljenika 1 (Vle i Vlld) može da se izvede putem:
enzimskog razdvajanja (primeri 13, 17 i 20) sa esterazom.
Sledeće odvajanje, utvrđivanje apsolutne stereohemije se može izvesti kao što je prikazano u Primeru 11.
Enantiomersko odvajanje i stereohemijsko određivanje se može izvesti na isti način kao i za enantiomerske smeše na ugljeniku 1 gde je supstituent na C2antiu odnosu na karboksilnu grupu (VII).
PRIMERI
Primeri koji se ne odnose na postupak koji je definisan u zahtevima su samo za svrhu reference.
Ovaj pronalazak je ilustrovan podrobnije sledećim primerima kojima se pronalazak ne ograničava.
Temperature su date u stepenima po Celzijusu. Procentni rastvori daju odnos mase prema zapremini, a odnosi rastvora izra'avaju odnos zapremine prema zapremini, ukoliko nije drukčije dato. Spektri nuklearne magnetne rezonance (NMR) snimani su na spektrometru Bruker 400 MHz; hemijska pomeranja (8) data su u delovima na 1 milion. Fleš hromatografija je rađena na silikagelu (Si02) prema postupku Still fleš hromatografske tehnike (W.C. Still at al., J. Org. Chem., (1978), 43 2923).
Skraćenice upotrebljene u primerima obuhvataju: Bn: benzil; Boe:lerc-butiloksi-karbonil {Me3COC(0)}; BSA: goveđi serumski albumin; CHAPS: 3-[(3-holamido-propil)-dimetilamonio]-l-propansulfonat; DBU: l,8-diazabiciklo[5.4.0]undek-7-en; CH2CI2= DCM: metilenhlorid; DEAD: dietilazodikarboksilat; DIAD: diizopropil-azodikarboksilat; DIEA: diizopropiletilamin; DIPEA: dizipropiletilamin; DMAP: dimetilaminopiridin; DCC: 1,3-dicikloheksilkarbodiimid; DME: 1,2-dimetiloksietan; DMF: dimetilformamid; DMSO: dimetilsulfoksid; DTT: ditiotreitol ili treo-1,4--dimerkapto-2,3-butandiol; DPPA: difenilfosforil azid; EDTA: etilendiamin-tetrasirćetna kiselina; Et: etil; EtOH: etanol; EtOAc: etilacetat; Et20: dietiletar; HATU: [0-7-azabenzotriazol-l-il)-l,l,3,3-tetrametiluronijum heksafluorofosfat]; HPLC: tečna hromatografija pod visokim pritiskom; MS: masena spektrometrija (MALD1-TOF: Matrix Assisted Laser Disorption Ionization-Time od Flight, FAB: bombardovanje brzim atomima); LAH: litijum-aluminjum-hidrid; Me: metil; MeOH: metanol; MES: (2-{N-morfolino}etan-sulfonska kiselina); NaHMDS: natrijum bis(trimetilsilil)-amid; NMM: N-metilmorfolin; NMP: N-metilpirolidin; Pr: propil: Suce: 3-karboksipropanoil; PNA: 4-nitrofenilamino ili p-nitroanilid; TBAF: tetra-n--butilamonijum-fluorid; TBTU: 2(lH-benzotriazol-l-il)-l,l,3,3-tetrametiluronijum tetrafluoroborat; TCEP: tris(2-karboksietil)fosfin hidrohlorid; TFA: trifluoro-sirćetna kiselina; THF: tetrahidrofuran; TIS: triizopropilsilan; TLC: tankoslojna hromatografija; TMSE: trimetilsililetil; Tris/HCl: tris(hidroksimetil)aminometan hidrohlorid.
PRIMER 9
A) Sinteza sme{e( 1R, 2R)/( 1S, 2R)1 -amino-2-etilcikIopropiI-karboksiIne kiseline
a) U suspenziju benziltrietilaminijum-hlorida (21,0 g, 92,19 mmol) u 50% vodenom rastvoru NaOH (92,4 g u 185 ml H2O), jedno za drugim, dodati sud\- terc-butil-malonat (20,0 g, 92,47 mmol) i 1,2-dibrombutan (30,0 g, 138,93 mmol). Reakciona smeša je snažno mešana rokom noći na sobnoj temperaturi, pa je dodata smeša leda i vode. Sirovi proizvod je ekstrahovan sa CH2CI2(3x), pa jedno za drugim, opran je vodom (3x) i rastvorom soli. Organski sloj je osušen (MgS04), profiitriran pa koncentrovan. Ostatak je prečišćen fleš hromatografljom (7 cm, 2 do 4% Et20 u heksanu), dajući žljeni derivat ciklopropana 9c (19,1 g, 70,7 mmol, prinos 76%). *H NMR (CDC13) 5 1,78 - 1,70 (m, IH), 1,47 (s, 9H), 1,46 (s, 9H), 1,44 - 1,39 (m, IH), 1,26 - 1,64 (m, 3H), 1,02 (t, 3H, J = 7,6 Hz). b) U suspenziju kalijum-ferc -butoksida (6,71 g, 59,79 mmol, 4,4 ekv.) u suvom etru (100 ml), na 0 °C dodata je H20 (270 jal, 15,00 mmol, 1,1 ekv.). Posle 5 min, u suspenziju je dodat diestar 9c (3,675 g, 13,59 mmol) u etru (10 ml). Reakciona smeša je tokom noći mešana na sobnoj temperaturi, zatim je izlivena u smešu leda i vode pa je oprana etrom (3x). Vodeni sloj je zakiseljen sa 10% aq. rastvorom limunske kiseline, na 0 °C pa je ekstrahovan sa AcOEt (3x). Sjedinjeni organski slojevi su, jedno za drugim, oprani vodom (2x) i vodenim rastvorom soli. Posle uobičajenog tretmana (Na2S04, filtriranje, koncentrovanje), željena kiselina 9d je izolovana kao bledožuto ulje (1,86 g, 8,68 mmol, prinos 64%).<1>H NMR (CDCI3) 8 2,09 - 2,01 (m, IH), 1,98 (dd, J = 3,8, 9,2 Hz, IH), 1,81 - 1,70 (m, IH), 1,66 (dd, J = 3,0, J = 8,2 Hz, IH), 1,63 - 1,56 (m, IH), 1,51 (s, 9H), 1,0 (t, J = 7,3 Hz, 3H). c) U kiselinu 9d (2,017 g, 9,414 mmol) u suvom benzenu (32 ml), jedno za drugim, su dodati Et3N (1,50 ml, 10,76 mmol, 1,14 ekv.) i DPPA (2,20 ml, 10,21 mmol, 1,08 ekv.).
Reakciona smeša je refluksovana 3,5 h pa je dodat 2-trimetilsililetanol (2,70 ml, 18,84 mmol, 2,0 ekv.). Refluks je održavan tokom noći, zatim je reakciona smeša razblažena sa Et20 pa je jedno za drugim, prana sa 10% vod. rastvorom limunske kiseline, vodom, zasićenim vodenim rastvorom NaHC03, vodom (2x) i vodenim rastvorom soli. Posle uobičajenog tretmana (MgS04, filtriranje, koncentrovanje) ostatak je prečišćen fleš hromatografijom (5 cm, 10% AcOEt - heksan) dajući željeni karbamat 9e (2,60 g, 7,88 mmol, prinos 84%) kao bledo'uto ulje. MS (FAB) 330 (MH<+>); 'H NMR (CDC13) 8 5,1 (bs, IH), 4,18-4,13 (m, 2H), 1,68 - 1,38 (m, 4H) 1,45 (s, 9H), 1,24 - 1,18 (m, IH), 1,00 - 0,96 (m, 5H), 0,03 (s, 9H).
d) U karbamat 9e (258 mg, 0,783 mmol) dodat je 1,0M rastvor TBAF u THF (940 u.1, 0,94 mmol, 1,2 ekv.). Posle 4,5 h dodata je dodatna količina 1,0M rastvora
TBAF (626 u.1, 0,63 mmol, 0,8 ekv.). Reakciona smeša je mešan tokom noći na sobnoj temperaturi, refluksovano je 30 min, pa je razblaženo sa AcOEt. Rastvor je, jedno za drugim, opran vodom (2x) i rastvorom soli. Posle uobičajenog tretmana (MgS04, filtriranje i koncentrovanje) izolovan je željeni amin 9f (84 mg, 0,453 mmol, prinos 58%), kao bledožuta tečnost. 'H NMR (CDC13) 8 1,96 (bs, 2H), 1,60 - 1,40 (m, 2H), 1,47 (s, 9H), 1,31 - 1,20 (m, IH), 1,14 (dd, J = 4,1, 7,3 Hz, IH), 1,02 (dd, J = 4,1, 9,2 Hz, IH), 0,94 (t, J = 7,3 Hz, 3H).
PRIMER 10
Hemijsko razdvajanjet- butil-( lR, 2R)/( 1S, 2R)l-amino-2-etilcikIopropiI-karboksilata (iz primera 9):
Jedinjenje 9e, iz primera 9 (8,50 g, 25,86 mmol) tretirano je sa IM TBAF/THF (26 ml), uz refluks 45 min. Ohla|ena reakciona smeša je razblažena sa EtOAc, oprana sa vodom (3x) i rastvorom soli (lx), zatim osušena (MgS04), profiltrirana i uparena dajući slobodni amin, kao svetložuto ulje. Slobodni amin je rastvoren u anhidrovanom CH2CI2(120 ml), pa su, jedno za drugim, dodati NMM (8,5 ml, 77,57 mmol), jedinjenje 4 (primer 4) (10,08 g, 27,15 mmol) i HATU (11,79 g, 31,03 mmol). Reakciona smeša je tokom noći mešana na sobnoj temperaturi, pa je dalja obrada izvedena kao što je prethodno opisano. Sirova dijastereomerna smeša je razdvojena pomoću fleš hromatografije (eluent - heksan : Et20; 25 : 75), dajući dipeptid10a(manje polaran eluirani deo) kao belu penu (4,42 g; 64 teor.%) i10b(polarniji eluirani deo) kao penu boje slonovače (4,5 g, 57 teor.%). U tom trenutku su oba izomera bila razdvojena ali apsolutna stereohemijska struktura još nije bila poznata.
PRIMER11
Određivanje apsolutne stereohemijske strukture jedinjenja 10a i 10b, putem korelacije sa poznatim t-butil (lR-amino-2R-etikikIopropil-karboksilatom
Prof. A. Charette, sa Univerziteta u Montrealu, dobio je jedinjenje11asa apsolutnom stereohemijskom strukturom kao što je prikazano, koja je određena pomoću rendgenske kristalografije (J. Am. Chem. Soc, 1995, 117, 12721). Jedinjenje 11a (13,2 mg, 0,046 mmol) rastvoreno je u IM HCl/EtOAc (240 u.1) pa je mešano približno 48 sati. Smeša je uparena do suva dajući jedinjenje 11b, kao svetložutu pastu, pa je ono kuplovano sa jedinjenjem 4 (18 mg, 0,049 mmol) kao što je opisano u primeru 10, upotrebom NMM (20,3 ul, 0,185 mmol) i HATU (21,1 mg, 0,056 mmol) u CH2C12. Sirovi materijal je prečišćen fleš hromatografijom (eluent - heksan : Et20; 50 : 50) dajući dipeptid 11c, kao ulje (7,7 mg; 31%). Upoređivanjem pomoću TLC, HPLC i NMR, nađeno je da je dipeptid 11c identičan sa manje polarnim jedinjenjem 10a, dobijenim u primeru 10, identifikujući tako apsolutnu stereohemijsku strukturu jedinjenja10akao( 1R, 2R).
PRIMER 12
Pripremanje( 1R, 2R)/( 1S, 2R)-l-Boc-amino-2-etilciklopropil-karboksiInekiseline (12a):
Karbamat 9e iz primera 9 (2,6 g, 7,88 mmol) mešan je 40 min u TFA, na 0 °C. Smeša je zatim koncentrovana pa razblažena sa THF (10 ml). Dodat je vodeni rastvor NaOH (700 mg, 17,5 mmol u 8,8 ml H20) pa zatim rastvor (Boc)20 (2,06 g, 9,44 mmol, 1,2 ekv.) u THF (13 ml). Reakciona smeša je mešana tokom noći na sobnoj temperaturi (pH je održavan na 8 dodavanjem 10% vodenog rastvora NaOH, kada je bilo potrebno), onda je razblaženo sa H20, oprano sa Et20 (3x) pa je na 0 °C zakiseljeno sa 10% aq. rastvorom limunske kiseline. Vodeni rastvor je ekstrahovan sa EtOAc (3x) pa je, jedno za drugim, pran sa H20 (2x) i vodenim rastvorom soli. Posle uobičajenog tretmana (MgSC»4, filtriranja i koncentrovanja), izolovana je željena amino kiselina zaštićena sa Boe (12a) (788 mg, 3,44 mmol, prinos 44%). 'H NMR (CDC13) 5 5,18 (bs, IH), 1,64 - 1,58 (m, 2H), 1,55 - 1,42 (m, 2H), 1,45 (s, 9H), 1,32 - 1,25 (m, IH), 0,99 (t, 3H, J = 7,3 Hz).
Pripremanje metilestra( 1R, 2R)/( 1S,2J?>l-Boc-amino-2-etilcikIopropil-
karboksilne kiseline (12b):
Boe derivat12a(0,30 g, 1,31 mmol) rastvoren je u Et20 (10 ml) pa je tretiran sa sveže pripremljenim diazometanom u Et20, na 0 °C, sve dok je bilo žute boje od neznatnog viška diazometana. Posle mešanja 20 min na sobnoj temperaturi, rakciona smeša je uparena do suva dajući12bkao bistro bezbojno ulje (0,32 g, 100%).<*>H NMR (CDCI3) 5 5,1 (bs, IH), 3,71 (s,3H), 1,62- 1,57 (m, 2H), 1,55 (s, 9H), 1,53 - 1,43 (m, IH), 1,28 - 1,21 (m, 2H), 0,95 (t, J = 7,3 Hz, 3H).
PRIMER 13
Enzimsko razdvajanje metil( 1R, 2R)/( 1S, 2R)Boc-l-amino-2-etiIciklopropiI-
karboksilata:
a) Enantiomerna smeša metilestra( 1S, 2R)/( 1R, 2R)l-Boc-amino-2-etilkarboksil-ne kiseline iz primera 10 (0,31 g, 1,27 mmol) rastvorena je u acetonu (3 ml) pa je onda
uz brzo mešanje razblaženo vodom (7 ml). Sa 0,05M vodenim rastvorom NaOH
podešeno je pH rastvora na 7,5 pre nego što je dodata Alcalase<®>[2,4L ekstrakt od Novo Nordisk Industrials] (300 mg). Za vreme inkubacije pH je stabilizo-vano pomoću NaOH a pH-metar je priključen da prati dodavanje rastvora NaOH. Posle 40 h smeša je razblažena sa EtOAc i H2O (sa 5 ml zas. NaHC03) pa su faze razdvojene. Vodena faza je zakiseljena sa 10% vodenim rastvorom HC1 pa je ekstrahovana sa EtOAc, osušeno je (MgS04), profiltrirano i koncentrovano, dajući kiselinu 13a (48,5 mg). Apsolutna stereohemijska struktura određena je upotrebom korelacije opisane u primerima 10 i 11.
b) Tretmanom alikvota kiseline 13a sa diazometanom u Et20, radi dobijanja metil estra, a zatim HPLC analizom uz upotrebu hiralne kolone [Chiracel<®>OD-H, 2,5%
izopropanol/heksan, izokratna], dobijenje odnos 51 : 1 (S,R) izomera.
PRIMER 14
Sinteza( 1R, 2S)/( JS, 2S)l-amino-2-etiIciklopropil-karboksilne kiseline:
Polazeći od kiseline 9d opisane u primeru 9:
c) U 9d (1,023 g, 4,77 mmol) u CH3CN (25 ml), jedno za drugim su dodati DBU (860 ul, 5,75 mmol, 1,2 ekv.) i alilbromid (620 ul, 7,16 mmol, 1,5 ekv.). Reakciona smeša je
mešana 4 h na sobnoj temperaturi pa je koncentrovana. Ostatak je razblažen sa Et20 pa je, jedno za drugim, prano sa 10% aq. rastvorom limunske kiseline (2x), H20, zasićenim vodenim rastvorom NaHC03, H20 (2x) i rastvorom soli. Posle uobičajenog tretmana (MgS04, filtracija i koncentrovanje) izolovan je željeni estar14a(1,106 g, 3,35 mmol, prinos 91%), kao bezbojno ulje. MS (FAB) 255 (MH<+>); 'H NMR (CDC13) 5 5,96 - 5,86 (m, IH), 5,37 - 5,22 (m, 2H), 4,70 - 4,65 (m, IH), 4,57 - 4,52 (m, IH), 1,87 - 1,79 (m, IH), 1,47 (s, 9H), 1,45 - 1,40 (m, IH), 1,33 - 1,24 (m, 3H), 1,03 (t, J = 7,3 Hz, 3H).
d) U estar14a(1,106 g, 4,349 mmol) u suvom CH2C12(5 ml), na sobnoj temperaturi je dodat TFA (5 ml). Reakciona smeša je mešana 1,5 h pa je koncentrovana dajući 14b
(854 mg, 4,308 mmol, prinos 99%). MS (FAB) 199 (MH<+>); 'H NMR (CDC13) 5 5,99 -
5,79 (m, IH), 5,40 - 5,30 (m, 2H), 4,71 - 4,62 (m, 2H), 2,22 - 2,00 (m, 2H), 1,95 - 1,88 (m, IH), 1,84 - 1,57 (m, 2H), 0,98 (t, J = 7,3 Hz, 3H). e) U kiselinu14b(853 mg, 4,30 mmol) u suvom benzenu (14,8 ml), jedno za drugim, dodati su Et3N (684 jul, 4,91 mmol, 1,14 ekv.) i DPPA (992 ul, 4,60 mmol, 1,07 ekv.).
Reakciona smeša je 4,5 h refluksovana pa je onda dodat 2-trimetilsililetanol (1,23 ml, 8,58 mmol, 2,0 ekv.). Refiuks je održavan tokom noći, a onda je reakciona smeša razblažena sa Et20, pa je, jedno za drugim, prana sa 10% vodenim rastvorom limunske kiseline, vodom, zasićenim vodenim rastvorom NaHC03, vodom (2x) i rastvorom soli. Posle uobičajenog tretmana (MgSC»4, filtriranje, koncentrovanje), ostatak je prečišćen fleš hromatografijom (5 cm, 10 do 15% AcOEt - heksan) dajući karbamat14c(1,212 g, 3,866 mmol, prinos 90%), kao bledožuto ulje. MS (FAB) 314 (MFT); 'H NMR (CDC13) 8 5,93 - 5,84 (m, IH), 5,32 - 5,20 (m, 2H), 5,05 (bs, IH), 4,60 - 4,56 (m, 2H), 4,20 - 4,11 (m, 2H), 1,71 - 1,60 (m, 3H), 1,39 - 1,22 (m, IH), 1,03 (t, J = 7,6 Hz, 3H), 0,96 - 0,86 (m, 1H), 0,04 (s, 9H). f) U karbamat14c(267 mg, 0,810 mmol) dodat je 1,0M rastvor TBAF u THF (1,62 ml, 1,62 mmol, 2,0 ekv.). Reakciona sme{a je me{ana tokom noći na sobnoj temperaturi, refluksovana je 30 min pa je onda razblažena sa AcOEt. Rastvor je, jedno za drugim, pran vodom (2x) i rastvorom soli. Posle uobičajenog tretmana (MgS04, filtriranje, koncentrovanje), izolovan je željeni amin14d(122 mg, 0,721 mmol, prinos 89%), kao bledožuta tečnost.<!>H NMR (CDC13) 8 5,94 - 5,86 (m, IH), 5,31 - 5,22 (m, 2H), 4,58 (d, J = 5,7 Hz, 2H), 1,75 (bs, 2H), 1,61 - 1,53 (m, 2H), 1,51 - 1,42 (m, 2H), 1,00 (t, J = 7,3 Hz, 3H), 0,70-0,62 (m, IH).
PRIMER 15
Sintezaetil-( lR, 2S)/( 1S, 2S)-l-amino-2-vinilciklopropil-karboksilata:
a) U rastvor kalijum-terc -butoksida (4,62 g, 41,17 mmol, 1,1 ekv.) u THF (180 ml), na
-78 °C je dodat komercijalno dostupni imin 15a (10,0 g, 34,41 mmol) u THF
(45 ml). Reakciona smeša je zagrejana do 0 °C pa je na toj temperaturi mešana 40 min. Smeša je onda opet rashlađena do -78 °C da bi se dodao 1,4-dibromobuten 15b (8,0 g, 37,40 mmol), mešana je 1 h na 0 °C, pa je ponovo rashlađena na -78 °C radi dodavanja kalijum-terc -butoksida (4,62 g, 41,17 mmol, 1,1 ekv.). Na kraju je
reakciona smeša mešana još jedan sat na 0 °C, pa je posle koncentrovanja dobijeno jedinjenje 15c.
b, c, d) U Et20 (265 ml) uneto je jedinjenje 15c pa je tretirano sa IM aq. rastvorom HC1 (106 ml). Posle 3,5 h na sobnoj temperaturi, slojevi su razdvojeni i vodeni sloj je opran sa Et20 (2x) pa je zaalkalisan sa zasićenim aq. rastvorom NaHC03. Željeni amin je ekstrahovan sa Et20 (3x) a sjedinjeni organski ekstrakti su oprani sa rastvorom soli. Posle uobičajenog tretmana (MgS04, filtriranje i koncentrovanje) ostatak je tretiran sa 4M rastvorom HC1 u dioksanu (187 ml, 748 mmol). Posle koncentrovanja, hidrohloridna so15dje izolovana kao braon čvrsta supstanca (2,467 g, 12,87 mmol, prinos 34%). 'H NMR (CDC13) 5 9,17 (bs, 3H), 5,75 - 5,66 (m, IH), 5,39 (d, J = 17,2 Hz, IH), 5,21 (d, J = 10,2 Hz, IH), 4,35 - 4,21 (m, 2H), 2,77 - 2,70 (m, IH), 2,05 (dd, J = 6,4,10,2 Hz, IH), 1,75 (dd, J = 6,4, 8,3 Hz IH), 1,33 (t, J = 7,0 Hz, 3H).
PRIMER 16
Pripremanjeetilestra( 1R, 2S)/( 1S, 2S)-1-Boc -amino-2-vinilciklopropil-karboksilne kiseline:
Hidrohloridna so15d(1,0 g, 5,2 mmol) i (Boc)20 (1,2 g, 5,7 mmol) ratsvoreni su u THF (30 ml) i tretirani sa DMAP (0,13 g, 1,04 mmol, 0,2 ekv.) i diizopropiletilami-nom (2,8 ml, 15,6 mmol). Reakciona smeša je mešana 24 h pre nego što je razblažena sa EtOAc (40 ml) pa je, jedno za drugim, prana sa zasićenim NaHC03(aq.), 5% vodenim rastvorom HC1 i zasićenim rastvorom soli. Organska faza je osušena (MgS04), profiltrirana i koncentrovana dajući16a(0,29 g, 23%), posle prečišćavanja fleš hromatografijom (15% EtOAc/heksan).<]>H NMR (CDC13) 5 5,80 - 5,72 (m, IH), 5,29 - 5,25 (dd, J = 17,2, 17,2 Hz, IH), 5,24 - 5,1 (bs, IH), 5,10 (dd, J = 9,2 9,2 Hz, IH), 4,22 - 4,13 (m, 2H), 2,15 - 2,04 (m, IH), 1,85 - 1,73 (bs, IH), 1,55 - 1,5 (m, IH), 1,49 (s, 9H), 1,26 (t, J = 7,3 Hz, 3H).
PRIMER 17
Enzimsko razdvajanje etil( 1R, 2S)/( 1S, 2S)l-amino-2-vinilciklopropiI-karboksilata:
a) Racemski derivat 17a (0,29 g, 1,14 mmol) rastvoren je u acetonu (5 ml) i raz-blažen sa H20 (10 ml). Sa 0,2M vodenim rastvorom NaOH podešeno je pH na 7,2 pre
nego što je dodata Alcalase<®>(300 mg). Da bi se za vreme inkubacije pH održavalo konstantnim, dodavan je rastvor NaOH pomoću titracionog ure|aja dirigovanog pH-metrom, tokom 9 dana sve dok teorijska količina baze nije bila dodata. Zatim je vršena ekstrakcija kiselinom/bazom, kao što je opisano u primeru 13, pa su izolovani nehidrolizovan estra (0,15 g, 100%) i hidrolizovan materijal (0,139 g, 95%). Analiza nehidrolizovanog estra pomoću HPLC, upotrebom hiralne kolone, utvrđen je odnos 43 : 1 željenog jedinjenja 17c, što je pripisano( R, S)stereohemijskoj strukturi, na osnovu hemijske korelacije kao što je opisano u primerima 10 i 11.
Uslovi za HPLC analizu: Chiralcel<®>OD-H (4,6 mm x 25 cm), izokratni uslovi uz upotrebu mobilne faze sa 2,5% izopropanol/heksana.
PRIMER 18
Razdvajanje( 1R, 2S)/( 1S, 2S)l-amino-2-vinilciklopropil-karboksilata putem kristalizacije sa dibenzoil-D-vinskoni kiselinom
U rastvor sirovog racemata(\ S, 2Si\ R,25) etil l-amino-2-vinilciklopropil-karboksilata [dobijen od etilestra N-(difenilmetilen)glicina (25,0 g, 93,5 mol) kao što je opisano u primeru 15] u EtOAc (800 ml) dodata je dibenzoil-D-vinska kiselina (33,5 g, 93,5 mol). Smeša je zagrevana do refluksa, ostavljena 15 min na sobnoj temperaturi a zatim ohlađena na 0 °C. Posle 30 min dobijena je bela čvrsta supstanca. Čvrsta faza je odvojena filtriranjem, oprana je sa EtOAc (100 ml) pa je osušeno na vazduhu. Čvrsta faza je suspendovana u acetonu (70 ml), sonifikovana, pa profiltrirana (3x), a zatim je dvaput prekristalisana iz vrelog acetona (deo A). Matični lugovi su koncentrovani pa je ostatak prekri stali san triput iz vrelog acetona (deo B). Oba dela amorfne čvrste supstance, soli dibenzoil-D-vinske kiseline su sjedinjena (5,53 g) i suspendovana u smeši Et20 (250 ml) i zasićenog rastvora NaHC03(150 ml). Organski sloj je opran sa rastvorom soli, osušen (MgSCU) i profiltriran. Filtrat je razblažen sa IM HCl/Et20 (100 ml) pa je koncentrovan pod smanjenim pritiskom. Uljasti ostatak je otparen sa CCU, dajući hidrohlorid etil-l-(7?>amino-2-f^-vinil-cikIopropan-karboksilata (940 mg, prinos 11%), kao belu čvrstu higroskopnu supstancu: [a]<25>D= +39,5° (c = 1,14 MeOH); [a]<25>365= +88,5° (c = 1,14 MeOH); 'H NMR (DMSO-d6) S 9,07 (bs, 2H), 5,64 (ddd, J = 17,2, 10,4, 8,7 Hz, IH), 5,36 (dd, J = 17,2, 1,6 Hz, IH), 5,19 (dd, J = 10,4, 1,6 Hz, IH), 4,24 - 4,16 (m, 2H), 2,51 - 2,45 (m, pikove ometa DMSO, IH), 1,84 (dd, J = 10,0, 6,0 Hz, IH), 1,64 (dd, J = 8,3, 6,0 Hz, IH), 1,23 (t, J = 7,1 Hz, 3H); MS (ESI) m/z 156 (MH)<+>; pomoću HPLC analize (CHIRALPAK AS<®>kolona, heks. :/'-PrOH) utvrđeno je daje enantiomerna čistoća Boe derivata 91% ee.
PRIMER 19
Pripremanje hidrohlorida metilestra( 1R, 2S)/( 1S,2£)-l-amino-2-vinilciklopropan-
- karboksilne kiseline (191)
Pripremanje imina19b
Hidrohlorid etilestra glicina 19a (1519,2 g, 10,88 mol, 1,0 ekv.) suspendovan je uterc -butilmetil etru (8 lit.). Dodati su benzaldehid (1155 g, 10,88 mol, 1 ekv.) i anhi-drovani natrijum-sulfat (773 g, 5,44 mol, 0,5 ekv.) pa je smeša ohlađena na 5 °C u kupatilu led-voda. U toku 15 min dokapan je trietilamin (2275 ml, 16,32 mol, 1,5 ekv.), (upotrebljeno 0,5 lit.terc-butilmetil etra za ispiranje) pa je smeša mešana 40 h na sobnoj temperaturi. Reakcija je prekinuta dodavanjem ledene vode (5 lit.) pa je organski sloj odvojen. Vodena faza je ekstrahovana sa terc-butilmetil etrom (1 lit.), sjedinjene organske faze su oprane smešom zasićenog rastvora NaHC03(400 ml), vode (1,6 lit.) a zatim rastvorom soli. Rastvor je osušen preko MgS04, koncentrovan pod smanjenim pritiskom a dobijeno žuto ulje je sušeno do konstantne mase, pod vakuumom. Imin19bje dobijen kao gusto žuto ulje koje očvršćava na -20 °C (2001 g, prinos 96%): 'H NMR (CDCI3, 400 MHz) 8 8,30 (s, IH), 7,79 (m, 2H), 7,48 - 7,39 (m, 3H), 4,40 (d, J = 1,3 Hz, 2H), 4,24 (q, J - 7 Hz, 2H), 1,31 (t, J = 7 Hz, 3H).
Pripremanje hidrohlorida etilestra racemske N-Boc-( 1R, 2S)/( 1S,25>l-amino-vin-ilciklopropan-karboksilne kiseline 19e: U suvom toluenu (60 ml) suspendovan je litijum-terc -butoksid (4,203 g, 52,5 mmol, 2,1 ekv.). U suvom toluenu (30 ml) rastvoreni su imin 19b (5,020 g, 26,3 mmol, 1,05 ekv.) i dibromid 19c (5,348 g, 25 mmol, 1 ekv.), pa je taj rastvor dokapa-van 30 min u rastvor LiOtBu, uz mešanje na sobnoj temperaturi. Posle završetka, tamno crvena smeša je mešana još 10 min pa je reakcija prekinuta dodavanjem vode (50 ml) iterc-butilmetil etra (TBME, 50 ml). Vodena faza je odvojena pa je po drugi put ekstrahovana sa TBME (50 ml). Organske faze su sjedinjene, dodata je IM HC1 (60 ml) pa je smeša mešana 2 h na sobnoj temperaturi. Organska faza je odvojena i ekstrahovana sa vodom (40 ml). Vodene faze su sjedinjene, zasićene solju (35 g) pa je dodat TBME (50 ml). Smeša je uz mešanje zaalkalisana do pH 13 - 14, pažjivim dodavanjem 10M NaOH. Organski sloj je odvojen a vodena faza je ekstrahovana sa TBME (2 x 50 ml). Organski ekstrakti koji su sadržavali slobodan amin19dsu sjedinjeni pa je dodatd\- terc-butildikarbonat (5,46 g, 25 mmol, 1 ekv.). Posle mešanja tokom noći na sobnoj temperaturi, TLC je pokazala nešto neproreagovalog slobodnog amina. Dodato je jošdi- terc-butildikarbonata (1,09 g, 5 mmol, 0,2 ekv.) pa je smeša refluksovana 2 h, kada je TLC analizom utvrđena potpuna konverzija19du karbamat 19e. Rastvor je ohlađen na sobnu temperaturu, osušen preko MgS04i koncentrovan pod smanjenim pritiskom. Ostatak je prečišćen fleš hromatografijom upotrebom kao eluenta 10% pa 20% EtOAc/heksana. Prečišćeni 19e je dobijen kao bistrožuto ulje koje polako očvršćava pod vakuumom (4,014 g, prinos 63%).
'H NMR (CDC13, 400 MHz) 5 5,77 (ddd, J = 17, 10, 9 Hz, 1 H), 5,28 (dd, J = 17, 1,5 Hz, IH), 5,18 (bs, IH), 5,11 (dd, J = 10, 1,5 Hz, IH), 4,24 - 4,09 (m, 2H), 2,13 (q, J = 8,5 Hz, IH), 1,79 (bm, IH); 1,46 (m, IH), 1,45 (s, 9H), 1,26 (t, J = 7 Hz, 3H).
Pripremanje jedinjenja 19f, navedenog u naslovu, putem reesterifikacije estra 19e: Etilestar 19e (10,807 g, 42,35 mmol) rastvoren je u suvom metanol (50 ml) pa je dodat rastvor natrijum-metoksida u MeOH (25% mas./mas., 9,7 ml, 42 mmol, 1 ekv.). Smeša je zagrevana 2 h na 50 °C, u kom trenutku je TLC analizom utvrđena potpuna reesterifikacija (19e Rf0,38, 19f Rf0,34, u 20% EtOAc/heksan). Reakciona smeša je ohlađena na sobnu temperaturu i zakiseljen do pH 4 korišćenjem 4M HC1 u dioksanu. Istaloženi NaCl je uklonjen filtriranjem (upotrebljenterc-butilmetil etar za ispiranje) pa su isparljivi sastojci uklonjeni pod smanjenim pritiskom. Na ostatak je dodatterc -butilmetil etar (100 ml) pa su čvrste supstance uklonjene filtriranjem. Uparavanjem filtrata pod smanjenim pritiskom i sušenjem pod vakuumom dobijen je čist metilestar19f (10,11g, prinos 99%).
'H NMR (CDCI3, 400 MHz) 6 5,75 (ddd, J = 17, 10, 9 Hz, IH), 5,28 (dd, J = 17, 1 Hz, IH), 5,18 (bs, IH), 5,11 (ddd, J = 10, 1,5, 0,5 Hz, IH), 3,71 (s, 3H), 2,14 (q, J = 9 Hz, IH), 1,79 (bm, IH), 1,50 (bm, IH), 1,46 (s, 9H).
PRIMER 20
Enzimsko razdvajanje hidrohlorida metilestra( 1R,25>-I-amino-2-vinilciklo-propan-karboksilne kiseline
Pripremanje metilestra N-Boc-(7/?, 2S)-l-amino-2-vinilpropan-karboksilne kiseline, 20a: Racemski estar19f(0,200 g, 0,83 mmol) rastvoren je u acetonu (3 ml) pa je dodata voda (7 ml). Dodat je 0,05M NaOH (1 kap) da se pH rastvora dovede na~8 pa je onda dodata Alcalase® 2,4L (Novo Nordisk Biochem, 0,3 g u 1 ml vode). Smeša je energično mešana na sobnoj temperaturi, održavanjem pH rastvora na 8, upotrebom automatskog titratora. Na početku 4. i 5. dana mešanja, pri pH 8, unet je dodatni enzimski rastvor (2 x 0,3 g). Posle ukupno 5 dana, upotrebljeno je ukupno 8,3 ml 0,05M NaOH. Reakciona smeša je razblažena sa EtOAc i vodom pa je organska faza odvojena. Posle pranja sa rastvorom soli, organski ekstrakt je osušen (MgSO-0i koncentrovan pod vakuumom. Jedinjenje 20a (0,059 g, prinos 30%) dobijeno je kao bistro ulje:<*>H NMR je identičan onom od jedinjenja 19f. HPLC (Chiralcel OD-H, 4,6 x 250 mm, izokratno 1% EtOH u heksanu, protok 0,8 ml/min): (1R, 2S)-2 Rf19,3 min (97%); (1S, 2R)-2 Rf17,0 min (3%).
Pripremanje hidrohlorida metilestra( 1R,2S>l-amino-2-vinilciklopropan-karboksilne kiseline, 20b: Jedinjenje 20a (39,96 g, 165,7 mmol) rastvoreno je u dioksanu (25 ml) pa je rastvor dokapan uz mešanje u 4M HC1 u dioksanu (Aldrich, 250 ml). Posle 45 min, TLC analiza je pokazala da je izvršeno potpuno deprotektovanje. Isparljivi sastojci su uklonjeni pod smanjenim pritiskom, a ostatak je dvaput uparavan sa MeOH (2 x 100 ml). Etar (300 ml) i MeOH (10 ml) dodati su u braon, uljasti ostatak pa je smeša mešana tokom noći na sobnoj temperaturi, dajući polučvrst precipitat. Unet je dodatni MeOH (15 ml) a mešanje je nastavljeno još 6 h, kada je žućkasta čvrsta supstanca sakupljena filtriranjem. Proizvod je opran sa 5% MeOH u etru (50 ml) i sa etrom (2 x 50 ml), osušen jein vacuo,dajući jedinjenje 20b, kao žućkastu čvrstu supstancu (22,60 g, prinos 76%). Filtrati (uklju~uju}i te~nosti od pranja), upareni su u vakuumu dajući dodatno 20b kao braon ulje (7,82 g, prinos 26%). Obe frakcije su bile dovoljno čiste za upotrebu u sintezi inhibitora proteaze HCV-a: [ct]D<25>= +38,2° (c = 1,0 MeOH).
'H NMR (400 MHz, DMSO-ds) 5 9,15 (bs, 3H), 5,65 (ddd, J = 17, 10, 9 Hz, IH), 5,36 (dd, J = 17, 1,5 Hz, IH), 5,19 (dd, J = 10, 1,5 Hz, IH), 3,74 (s, 3H), 2,50 (q, preklapa se sa signalom DMSO, J = 9 Hz, IH), 1,86 (dd, J = 10, 6 Hz, IH), 1,64 (dd, J = 8, 6 Hz,
IH).

Claims (8)

1. Postupak odvajanja enantiomerne smeše metil estra l-amino-2-vinilcikIopropil karboksilne kiseline, ili njegove N-zaštićene smeše, obuhvata korake tretiranja navedene smeše sa esterazom kako bi se dobio željeni enantiomer metil estra 1-amino-2-vinilciklopropil karboksilne kiseline ili njegov N-zaštitni oblik.
2. Postupak prema zahtevu l, gde navedena esteraza je Alcalase®.
3. Postupak odvajanja enantiomerne smeše metil( 1R, 2R)/( 1S, 2S)Boc-l-amino-2-etilciklopropil karboksilata koji ima formulu: obuhvata tretiranje smeše sa Alcalase® kako bi se dobili proizvodi formula:
4. Postupak prema zahtevu 3 gde je smeša tretirana sa Alcalase® pod uslovima u kojima je pH kontrolisana.
5. Postupak odvajanja enantiomerne smeše etil (1R,2S)/(1S,2R) Boc-l-amino-2-vinilciklopropil karboksilata koji ima formulu: obuhvata tretiranje smeše sa Alcalase® kako bi se dobili porizvodi formula:
6. Postupak prema zahtevu 5 gde je smeša tretirana sa Alcalase® pod uslovima u kojima je pH kontrolisana.
7. Postupak odvajanja enantiomerne smeše metil( 1R, 2S)/( 1S, 2R)Boe-1-amino-2-vinilciklopropil karboksilata koji ima formulu: obuhvata tretiranje smeše sa Alcalase® kako bi se dobio proizvod formule:
8.Postupak prema zahtevu 7 gde je smeša tretirana sa Alcalase® pod uslovima u kojima je pH kontrolisana.
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