МСОС Лекции с поиском и закладками
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nenTMAHblM CMHTe3
2.4. MeTOA aKTMBMp0B3HHblX 3<t,Mp0B
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noll |
eH"1e --- |
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HO-N |
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R |
----1(_ |
X=3A |
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Ho{)No2 |
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HO-N |
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AKT"18"1pOB8HHbllil |
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HO-X |
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OH |
DCC |
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b |
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34>1,1p |
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HO-NP |
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HO-PFP |
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HO-Su |
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HO-Bt |
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/ '-.,;" l OH---------- |
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/l('NH 0 |
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5_ .,,.,. Jl |
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HO u |
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Pip |
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NHFmoc |
DCC/DMSO/RT |
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NHFmoc |
DMSO |
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FmocHN |
0 |
DMSO |
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FmocMet- •OH |
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Fmoc-Met-OSu |
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•tBu |
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90% |
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Fmoc-Met-Pro-O+Bu |
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Fmoc-Phe-O FP |
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1. Pip/DMSO |
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90% |
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__.,_ H-Met-Pro-O-t-Bu --- |
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Phe-Met-Pro-O+Bu -------11 |
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Fmoc- |
2. Fmoc-Ala-03t |
► Fmoc-Ala-Phe-Met•Pro•O+Bu |
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AoctoMHctea |
DMSO |
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DMSO |
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-CTa6M/1bHOCTb, BblXOA >90%, BblCOKa CKOPOCTb peaKLJ.1,1"1, OTC'{TCTBllle
pau_eMll13aU,"1"1, AOCTYOHOCTb peareHTOB HeAOCTaTt<M
-CT0"1MOCTb
■At<T"1BMpoeaHHble 3<f>Mpb1 WMpOKO MC00/1b3YK>TAJlR CMHTe3a aMMAOB 11 nenTMAOB
nenTMAHblM cMHTe3
2.5. KOHAeHCMpytow.Me peareHTbl
V-N |
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V-N N |
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o=N\ N- |
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peareHT KacTpo |
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N 0-N)Q |
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,,N \ @ |
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/NMe |
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b<.t) |
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0X |
b-{ |
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4-NMe2 |
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PFs 00 |
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2 |
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PFs |
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-N |
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BOP |
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NMe2 |
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PyBOP |
0 |
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HBTU (X=PFs) /N |
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Benzotriazol- l- |
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TBTU (X=BF,i) |
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yloxy1r1s(dlme111yIamIno)phosp |
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honium hexaffoorophosphate |
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MexaHM3M aKTHBa4HH Kap60KCHnbHOM rpynnbl |
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BtO |
aW/-. NMe2 |
8 |
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H |
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O |
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O |
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-NMe2PF6 |
0 ..,.,---- |
0 |
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_/J |
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o _;N, |
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D A |
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R\ |
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► RJ |
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_/ NMe2 |
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R .Jr |
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B |
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@ NM82 |
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l |
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')f |
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R-{ |
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OH |
DMF/RT \· |
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► \ |
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Jli |
R |
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Jli |
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1 |
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-HOBl |
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0 |
O-P.-NMe2-HMPA |
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Bl |
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N |
-R |
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0: |
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-OBl |
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AOCTOHHCTBa |
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PF |
6 |
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,/ |
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NMe:> |
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" |
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-He B3al-1MOAe111crayK>T c N-KoMnoHeHroi:1 (He rpe6yK>r npeABapl-1TellbHOi:1 aKTl-1Bau,vn1); TFA He aKTl-1Bl-1pyeTCA (MO>t<HO l-1CnO/lb30BaTb TFA*AK); BblXOA >95%; B03MO>f<HOCTb l-1CnO/lb30BaH"1A «M"1H"'1MaJlbHOIII 3al.11i"1Tbl»; BblCOKa.R Ct<OpOCTb peat<u,1,,11-1; OTCyTCTB"'1e pa4eM1-13aU.l-1"'1
HeAOCTaTKH
-(T0"'1MOCTb
t<OHAeHCHPYtOU,\Me peareHTbl Wl-tPOKO "1C110/tb3VI-OT AJlSI CIIIHTe3a aMll1A08 H nenTHAOB
Boc-Phe-OH H-Tyr-OBn► Boc-Phe-Tyr-OBn |
TFA► |
TFA· H-Phe-Tyr-OBn |
Boe-Ser-OH |
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Boc-Ser-Phe-Tyr-OBn |
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Py |
OP/E |
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IA/ |
O |
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PyBOP/EOI |
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/C |
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BDMSO |
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OMSO |
A |
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950,0 |
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95 /c |
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nenTHAHblM CHHTe3
2.6. TeepAo<l>a3HblM MeTOA CMHTe3a (SPS-synthesis)
Crparen14ecKaR MOA"1Q>"1KaU,"1R c1i1Hre3a nenT"1AOB B pacraope npoBeAeHa a 1963 r. P.
Mepp1i1q>li1J1AOM, KOTOpbl npeAJ10>Kl/tJl npOBOAl!tTb Cl/tHTe3 Ha nOJ1"1MepHblX HOC&i1Te/1flX. "1CXOAHa.A C-KOHL\e8a.A AK C8R3bl8aerc.A K08aJ1eHTHO C Hepacreop&i1MblM no/1&-1MepoM 1,1 ace noCJ1eAOBaTe/1bHble CTaA"1"1 C"1HTe3a nenT&i1AHOl1 Uien&-1 npOBOARTCR Ha 3TOM HOC11tTeJ1e. np11t 3TO ornaAaer He06XOAl!tMOCTb BbtAe/leHl,1.A Ha K3>+<AOi1 CT3A"11-1 C1,1HTe3a no/ly4eHHblXnenTltlAOB, TaK KaK OHl,1 OCTalOTCR CBR3aHbl C HOCll1TeneM, 4TO 003B0/lReT npocro npOMblBKO HOC1,1TeJ1R vAallRTb no6o4Hbte npOAYKTbl -et,1Hre3a 1,1 Henpopear11tpoaaewl-1e 1,1cxoAHbte seUJ,ecrea.
- - ...
--------- npoTO'-lHble peaKTOpbl ,qm1 SPS
nenTHAHblH CMHTe3
2.6. TeepAo<l>a3HblH MeTOA CMHTe3a (SPS-synthesis)
Crparer1114ect<aR MOAIIIQ>11tt<a1..1i111R c111Hre3a nenTli1A0B B pacrsope npoBeAeHa s 1963 r. P. |
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Mepp1114>11111AOM, Koro-...."'---------------------------------- |
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CX0AHoR C-K0Hu,eaa |
npMHL,\Mn SPS-CMHTe3a |
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noc/leA0BaTe/lbHble |
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ornaAaer Heo6xOAIIIM |
MWIrradiation |
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K |
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Kat< 0H"1 0CTal-OTCR CBR |
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vAa,rnrb no6o4Hble n |
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FIIIOO<lffllflO lcld |
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C1.tona Mepp111cj)L1J1Aa
AocroMHCTBa
- BbtX0A >99%; ynpow.eHbl npo1..1ieAYPbt cv1ttre3a 111 0411tCTK111, B03M0>+<H0CTb asr0Mar1113au.111111
C"'1HTe3a; BblCOKaR CKOpOcrb;
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HeAocran<M |
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O6pa3osaH1i1e no6o4HblX «missense» nenT"1A0B, TPYAH0CTb K0HTpo11R nporeKaH1i1R peaKt-4"1 ; |
nenTHAHblM CMHTe3
2.6. TeepAo<J,a3HblM MeTOA CHHTe3a (SPS-synthesis)
BbtC0KaR 3<f>q>eKT"18HOCTb SPSS n0380/llA/IIA 1968 r. P. Meppv!q>l-1/lAY Cll1HTe3111posaTb p1-160HyK11ea3y (124 AK, 370 CTaA"1H, BblX0A 7%).
Boc- - ___.....,.. Boc-Gly-0 |
_Q |
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TFA |
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-@ ------41 |
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---I-- |
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Gly OH |
c,--@ |
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H Gly-o |
Boc-Phe-OSu |
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1.TFA |
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Cs2CO;y'OMF |
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DMF |
► Boc-Phe-Gly-o--@ |
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BnO |
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2. NaHC03 |
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99% |
2. NaHCOl |
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Bn9 |
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-@ HF/PhOMe |
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__... H-Phe•Gfy-0 |
--@ |
Boe Asp-OH |
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H-Asp-Phe-Gly-OH |
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... |
Boc-Asp-Phe-Gly o |
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PyBOP/EDIN |
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99 |
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DMF |
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CTpaTerMA c1o1Hre3a nOJ11o1nenTMAOB SPSS
1.AaroMaT1t14eCK&-1M SPS-c1-1Hre3aropoM no11y1..1atoT 6110K"1 no 15-20AK (c K0HU.eBblMl-1 He pau,eM&-13YtoW."1M"1CR AK (Gly, Pro}
2.Q41,1w.at0T nolly'-leHHble nenn1,D,bl B3>KX
3.Cw1-1sator 61101<1,1a noJll,menn1AHYto u,enb «spyYHyto» (a3"1AHblM MeT0A0M 1-1m1 PyBOP).
4.YAaflRtoT cra61-111bHbte PG 1,1 oy111w.ator
no111-1nenntA
nenTMAHblM CMHTe3
2.6. TeepAo<J>a3HblH MeTOA CHHTe3a (SPS-synthesis)
BbtCOKaR 3q>q>eKTli18HOCTb SPSS no3801H1/ll-1 1968 r. P. Meppt,,1q>t;1J1AY Cli1HTe3li1POBaTb p&.-160HyK11ea3y (124 AK, 370 CTaAl-1t:i, BblXOA 7%).
Cl-@ |
1 TFA |
.., |
H Gly |
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Boc-Gly-OH --- Boc-Gly-0 |
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Cs2C03/0MF |
BnO |
2. |
NaHC03 |
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_,. H-Phe-Gly-0---@ |
Boe Asp-OH |
Bn? |
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.,. Boc-Asp-Phe-Gly• |
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99% |
PyBOP/EDIA/ |
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DMF |
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CrparerMR CMHTe3a no11MnenTMAOB SPSS
1.ABTOMan14eCKl-1M SPS-Cli1HTe3aropoM noJ1y4at0r 6J10K1-1 no 15-20AK (c KOH1.1iesb1Mi.1 He pa'-'ieMl-13YK)LLI_l-1Ml-1CR AK (Gly, Pro)
2.Q41,1w_aK)T no11y4eHHble nenTl-1Abl 83>-t<X
3.Cw1-1aat0r 6110Kli1 a no11&.-1nenr1-1AHYt0 1.1ienb «BPY"myt0» (a3l-1AHblM MeTOAOM l-11u.1 PyBOP).
4.YAaflRK)T CTa6&.-111bHb1e PG 1,1 041,1w_aK)T
n0J11-1nenr1,1A
AeToMaTM eCKMM MW/SPS-cMHTeJaTop
1 |
1 |
2 |
DoprottctiOfl In |
W4$hlngir, |
COllpllngin |
minute |
minute |
minute$ |
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nenTHAHblH CHHTe3
1.
2.6. TeepAo<l>a3HblM MeTOA CMHTe3a. MarpM4b1 (resins) AJIH SPSS |
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CMona |
MeppHq>HnAa |
npMMeHeHHe |
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Pacw.enneHMe c |
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v1MM06v111v13au,1,1R t<"1C/IOT, cpeHOllOB,cn1,1pTOB, |
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TpaHc4>opMa4 eM |
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aM"1HOB, nenTVIAOB (Boc-CTparerviR) |
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(Ps) |
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PactJ.4en11eHMe |
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RJ"oJ |
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HF/PhOMe; TfOH/PhOMe; NaOH; H |
P |
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I UBH,\_ |
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NH '/ |
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'J |
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if |
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MeOH |
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'rTHF |
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◄ ~Bn-CI ► |
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H"13Kaf! u,eHa, BblCOKaR 3arpy3Ka (2 MM01lb*r)/ |
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_/OH |
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_f' |
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HeAOCTaTKM |
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R-{ |
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R-( |
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>t<eCTKVle YC/IOBVIR CHRTv!R |
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NH2 |
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OMe |
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2. TpMTH/lbHaR CM0/1a
-Tr-Cl
◄
X= M. eO......; H;•Cl
.L YCTOvi"IIIIBOCTb
'K KIIICflOTaM
npMMeHeHMe |
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111MM06vtllvt3aU,HR Kv!CllOT, <f>eH0/108, |
HMM06M/1"133LJ."1R |
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en1-1pros, aM1i1HOa, v1Mv1Aa30.110a, |
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nenTHAOB (Fmoc-crparernR) |
R |
0 |
(or Im. |
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Pacw.enneHMe |
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TFA (5%)/DCM |
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Hamine) |
R_jJ |
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,O.oc,JI 'itTE |
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Cl |
DIEA/DCM |
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MRrt<Vle YCllOBll1R CHRTll1R |
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HE!AOCT3TKH |
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H |
R-0- 0p |
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Hecra6vt/lbHOCTb t< KlitC/IOTHblM |
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PYffHF |
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peareHTaM |
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nenTHAHblM CHHTe3
2.6. TeepAO<l>a3HblM MeTOA CMHTe3a. MaTpMU,bl (resins)AJIR SPSS
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3. CM011a BaHra |
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npHMeHeHMe |
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111MM06"1/H13aU,li1 t<li1C/10T (OH-resin/COi), <f,eH0/108, cn1i1pT0B, aM"1H0B |
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(Br-resin), c1i1Hre3 nenT"1A0B (Fmoc-crparer1i1s:1), |
Hy1<neon1AOB |
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Pac1.4en11eHHe |
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TFA /DCM; CAN; HifPd/C |
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p.oc,, , |
'l, |
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MflrK111e ycnOBll1fl CHRTll1fl, yCTOi14111BOCTb K Nu |
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HeAOCTaTKt1 |
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Hecra61i1.11bHOCTb K l<li1C/10THblM peareHTaM |
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4. MBHA-cM011a |
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npHMeHeHHe |
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CLitHTe3 aM"1A0B, aM"1A0B-nenT"1A0B |
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◄ |
-Bzh-NH2 ... |
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Pacw.enneHMP |
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HF/PhOMe; MsOH/PhOMe |
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'°1MM06H/1H3a HSI/Pacw.enneHHe |
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2 |
0 |
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R H |
► |
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.. |
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R' |
0 |
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PyBOP |
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---- |
:I►-- |
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HF/PhOMe |
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/EDIA/OMF |
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NH2 |
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◊F
Br HO |
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O;, |
O |
NOz |
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0p---1 |
DIEAIDCM |
0----' |
-0#- |
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cMona BaHra |
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R K,C
NH |
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,IDMF/p\_ |
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o /
HN-R, -0---NO'
1 |
Na2S,04'DMF•H20 |
2 |
R,_// IOMF/T |
------► |
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NH |
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UEt |
3 TFAIDCM
H
r |
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1 |
/ |
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R.. |
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r;:\__,,_ |
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Bo1 cHN |
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,..H2ByBOPI |
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1 |
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DIENDMF |
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MBHA•cMona |
-----11 |
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2.TFA |
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1 |
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r-<R |
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_.. {v-NH 1-i'N B ':_ R |
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2 |
O |
R |
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roo |
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R |
1 |
Br |
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, |
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---:-.. |
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Br |
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BHfTHF |
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N |
2 |
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/---,,,. '/ |
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Jlir |
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ByBOPI |
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H |
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,.H |
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NH |
;_. |
H |
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DIEA/DMF |
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HN |
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R.1 |
Pip/f |
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1. Pd(OAc)fCul cG |
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f |
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R |
1 |
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1 |
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SrCN |
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&,Jr-{,_N |
Cs2C03/DMF/T |
-.;;:: |
N |
-< |
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' |
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DCM► |
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'\( |
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2 |
2. HF/PhOMe |
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B8,K |
U ) |
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NH |
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R2 |
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nenTHAHblM cMHTe3 npeAcraeneHMe cxeM CMHTe3a
np111secn1 cxeMy C"1HTe3a MeTHOH"'1/13HKe<pa11111Ha C "1Cn0/1b30BaH"1eM CMO/lbl
Mepp1114>1-111Aa (Boe - cTpaTernR)
H |
-Tyr---- |
Gly---- |
Gly--- |
Phe- ---- |
Met-O |
H |
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, |
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Boe- |
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Boe |
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Boe OSu H |
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Boe |
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Boe- --OSu H |
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Boe- |
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Bn |
--OH H |
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Boc- |
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8""" |
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Boe- |
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H
H-
Boe-
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H ) Boc20
H c1---
cMona |
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Me <J)Mruta |
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® 1cs |
co |
3 |
2 |
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Boe-
-OH H-
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-0-©)TFA |
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0-0)DCC/HOBIIDMF |
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)TFA |
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TFA |
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07.!:/ |
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0 p |
) |
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)TFA |
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o-@ )
o-@ DCC/HOBt/DMF
OH