МСОС Лекции с поиском и закладками
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nenTHAHblM cMHTe3
npeAcTasneHHe cxeM CHHTe3a
Ha AOM:
CocraB&Hb cxeMy C&i1HTe3a U,erpope/1&i1KCa C &i1CnO/lb3083H&i1eM MBHA-CMO/lbl (Boe - crparer&i1R}
H-D-Nal-D-(pCl)Phe-D-Pal-Ser-Tyr-D-Cit-Leu-Arg-Pro-D-Nal--NH2
H-D•(pCl)Phe-OH |
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H-0-Pal-OH |
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1.repWKOBi-14 A.A. Ci-iHTe3 nenT AOB. PeareHTbl i-1 MeTOAbl, 1987, 264 c
2.Peptide Chemistry and Drug Design. Ben M. Dunn (Ed.), 2015
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CMHTe3bl Ha OCHOBe 60A3
AMKap60HHnbHblX COeAHHeHMM
CrpoeHMe H o6w_aft xapaKTepMCTHKa peaKU.MOHHO cnoco6HOCTM 1,3-AMKap60HMnbHblX coeAMHeHMM
II "' |
X= Ac (EAA); |
X=C02Et (DEM); |
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EtO X |
X=CN (ECA) |
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BblCOKaR KHCJIOTHOCTb a-CH-cBR3H (pKa =10-15) l-1 cnoco6HOCTb reHep111poeaTb n0A Ae CTBl-1eM OCHOBaHl-1 (EtONa, NaH) pe30HaHCH0 CTa61A/W13l-1pOBaHHbl aHl-10H,
RB/lRtOL141A'1CR Clll/lbHblM C-Nu - K/lt04eBble oco6eHHOCTIA 1,3-A11tKap60H11t/lbHblX COeAIAHeHIA |
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EtONa |
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EtO |
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'""')(;x |
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EtO |
EtO x |
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SN2 or AdN |
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EtOH |
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C-Nu |
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-KeTOKap60HOBble KHC/IOTbl nOABepralOTCSI AeKap60KCM/1MpoeaHMIO
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NaO |
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H'r |
EtO1n .x |
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NaO x |
H ► H !yx - o,► |
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H20 |
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x
1. DMSO(wet)/NaOl(LiCl)/T (Kpan4o)
2. TsOH/Kc111no.n/1S0°c |
MeTOAbl npRMoro |
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3. DMAP/PhMe/ |
AeKap6o3T0Kc1,un1poeaH R |
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MeTOAbl nony\.feHMff l,3-AMKap6oHMnbHblX coeAMHeHMM
1. CMHTe3 npoM3BOAHblX ManoHoeoH KHCJlOTbl (DEM, ECA)
NaO
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Cl
NaCN
----•►
Me2CO Nao
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rN
MeOH |
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N MeOH |
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HCI/T |
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EtO |
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HCI/T. |
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0O
EtO Et
2. CHHTe3 -KeTOKHCJlOT (EAA) no peat<L\HH KnstM3eHa
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R e..__OE |
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Et0H |
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OEt -EtOH |
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RJ.+ |
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R II |
EtONa |
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l O |
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1/ |
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3. nepeKpeCTHaR peaKL\MR KnRH3eHa |
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OEt |
R-{Me |
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EtONa |
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RJ.____,JlOEt |
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R=CF3 |
' t•Bu, Ph |
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00
RJyJloEt
R
24. AL\M/U1poeaHHe DEM H 1,3-AHKap60HM/1bt4hlX coeAMHeHHH
XMMM ecKMe ceoi:1cTea l,3-AHKap6oHMnbHblX coeAMHeHHM
1. AAKHllHpoeaHHe 1,3-AHKap60HHl1bHblX cOeAHHeHHH |
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(reHepMpoeaHMe aHM0H0B npoeoART AeMCTBMeM ocHoeaHMM B: EtONa, NaH .-11n1 PTC) |
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1.1. AnKMllMpoeaHMe EAA a11KM/lra11oreHMAaMM1,1 |
3n0KCMAaMM B CMHTe3e KeT0H0B |
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3cf>Mp08 |
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fl |
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EtBr |
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NaOH/H 0 |
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EtON: |
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OEt |
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H+/ t:,. |
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OEt |
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(·CO-2 |
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-AcONa |
NaOH |
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"J |
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OEt |
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KOHl.l.) |
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uuJl |
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OB |
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.0 (±) |
-EtONa |
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. -: Na |
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HNEt2 |
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H /NH |
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Hf!r/t:,. |
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NEt2 |
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Br |
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NiRa |
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-CO2 |
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NH2 |
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Cl |
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NEt2 |
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Cl |
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3 J |
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DMF/t:,. |
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XnopoxviHI |
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XMMM ecKMe ceoHcTea 1,3-AMKap6oHMnbHblX coeAMHeHMM
1.2. AnK111n111poeaHMe DEM anKMnranoreHMAaMM nporeKaer aHanorMl.fHO
NaCI/DMSO <xo
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OEt |
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2. A4111.n111poeaHMe 1,3-AHt<ap6oHM.nbHblX COeAMHeHHH
2.1. A41i1n111poeaHMe EAA AaeT TpMKap60HMnbHble COeAHHeHMff
I)
fl |
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0 0 |
O |
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1. EtONa |
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OEt 2.BzCI |
Ph OEt |
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XHMH ecKHe ceoi1crsa 1,3-AHKap6oHHnbHblX coeAHHeHHM
2.2. A4Mm11poeaHMe MarHMeBblX coneM DEM wMpOKO 1o1cnonb3Yt0T e CMHTe3e |
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AHKap60HHJ1bHbl)( coep.HHeHHM H MeTHJlKeTOHOB |
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Mg(OEtb |
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DEM |
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Cl |
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TsOH ... OEt |
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Hm,t |
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C5H4Mei/ll |
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[ EtO OEtl |
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(MeTOA PaTKe) |
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MgOEt |
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gCl2/2NEt3 |
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WO DEM .. |
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,.../\ |
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1, NaOH(eq.) |
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2Buli |
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P"1M8HTAA"1H |
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3. A4M11MpoaaHMe AM3Hr.tOHa EM npHMeHsuoT AnR CMHTe3a AMKap60HH lbHb1x coep.1o1HeHHM
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1P |
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DEM |
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.,_ |
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0. O |
C |
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2. |
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2L_+ |
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0 H+/ A |
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EtO |
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OH THF/-78 |
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EtO |
O1 |
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OEt |
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·C |
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u• |
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O2 |
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XMMH ecKHe ceo'1cTBa 1,3-AHKap6oHHnbHblX coeAMHeHMM
3. KOHP,eHCaU.HR C Kap60HH/lbHblMH COeAHHeHHRMH (KHeeeHarenR)
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3.1. CHHTe3 aKpHIIOBblX KHC/IOT H3 Ma/lOHOBOM KHCJlOTbl |
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R |
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Ho |
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OH• |
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HO |
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OH |
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Cop6HHoeas:i K•Ta |
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Py/ |
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Py/6. |
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oH
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RJ bH |
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- o
(aKpHnOBble,
KOpH Hble KHC.nOTbl)
3.2. KOHAeHca4HR c 1,3-AHKap60HH/lbHblX COeAHHeHHH H rpaHc<l>opMaL\HR
MeTHIIHAeHOBblX npOH3BOAHblX
DEM
EtO
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H► |
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(o |
q"j |
Pd/C |
0 |
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Et0 |
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OEt |
..... ,1 |
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_H_2_►►. EtO OEt |
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Pip•AcOH/ |
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AK4enTop |
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Ph |
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l!::' |
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M111xaa11Sl |
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1. cN a |
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2.H |
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H20 |
O .,.........., |
_jl |
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OEt H / |
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Ph |
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HO |
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tJ. |
►► .. |
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----t |
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NaCl► |
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Ph |
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0MSO/T |
OEt |
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Me |
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yN 0 |
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MeNH |
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AcOH/ |
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<t>eHcyK4111M111A Ph
XMMM\feCKMe CBOMCTBa 1,3-AMKap6oHM/lbHblX COeAMHeHMM
npMMeHeHMe KOHAeHca4MM KHeBeHaren.R B CMHTe3e··M··K CnOT
N
'D
ECA------1►
Plp•AcOH/.6.
o
N yoe1
0
1.NaCN
2.H+ ►
3.3. KOHAeHca4MM KHeBeHaren.R c npMCOeAMHeHMeM 1,3-AMKap60HMnbHblX coeAMHeHMH no MMxa3n10
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eto oet |
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OEt |
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OEM |
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NHEt2/6 |
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6+,,___.-- |
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XMMM eCKMe CBOMCTBa 1,3-AHKap60HMnbHblX COeAMHeHHM
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1/2 |
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EtO |
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Ph |
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EAA |
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NHEt2/a |
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o |
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----► |
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NH3 |
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o AcOH/a |
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OEt 1.NaOH(co .) OmO_Ac20►► |
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0 |
-2Ac0Na |
OH |
Ph |
OH |
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-2Et0H |
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H
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1.Br |
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/Na0H |
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H2N 0 |
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Ph |
OH |
Ph |
Ph |
¢eHl-16yT |
3.4. npoAYKTbl KOHAeHca4111111 KHeeeHarenR EAA 3a1.4acryto scrynatoT TaHAeMHb1e npespaU4eHHR (Kap6o111 reTepo4111Kn1113a4M111)
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OH |
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[1/oE• |
MEI |
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EAA |
H )l!!,. |
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OEt |
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Pip"'AcOH/ |
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- 20 |
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EtO
8