LV10503B - Method for producing of ll-f-28249 23-(c1-c6-alkyloxime) - Google Patents

Method for producing of ll-f-28249 23-(c1-c6-alkyloxime) Download PDF

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Publication number
LV10503B
LV10503B LVP-93-697A LV930697A LV10503B LV 10503 B LV10503 B LV 10503B LV 930697 A LV930697 A LV 930697A LV 10503 B LV10503 B LV 10503B
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Prior art keywords
mmojih
dimethylsulfoxide
nitrobenzoyl
okco
npn
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LVP-93-697A
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English (en)
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LV10503A (lv
Inventor
Maulding Donald Roy Dr
Kumar Anil
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American Cyanamid Co
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Publication of LV10503A publication Critical patent/LV10503A/lv
Publication of LV10503B publication Critical patent/LV10503B/lv

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D493/00Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/22Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains four or more hetero rings
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07HSUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/01Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing oxygen

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
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  • Biotechnology (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Fats And Perfumes (AREA)
  • Steroid Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Pyridine Compounds (AREA)
  • Photoreceptors In Electrophotography (AREA)
  • Liquid Crystal Substances (AREA)
  • Cosmetics (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Lubricants (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Saccharide Compounds (AREA)

Description

LV 10503 CI10C0B nOJIREHMH 23-(Cj-C6 AJ1KMJI0KCMM0B) - Li- F 28249
OnHcaHHe
HacTOHmee Η3θ6ρβτβΗΗβ othocmtch k ycoBepmeHCTBOBaHHOMy cno-co(5y nojiy^eHHH coeflHHeHHfi 23-(Cj-C0 anKMJiOKCHMOB)-//~F 28249. 0ČO3HatieHHe LL -F 28249 HCnojib3yiOT rjir onncaHHfl pH,ū,a οοθαμηθηκη , npOflyi],HpyeMHX φΘρΜΘΗΤ3ΤΗΒΗΗΜ 6yJIb0H0M nOJĶBHfla BHfla Streptomyces cyaneogrisens,flenOHHpOBaHHOro B KOJIJieKLJHH NRRL noj; ηομθρομ 15773.
Uejibio flaHHoro Η3θ6ρβτβΗΗΗ HBJineTCH co3,n,aHHe cnocoča nojiy^e-hhh coeflHHeHHfi 23-(Cj-Cg aJiKHJioKCHM)-//- F 28249, h dojiee koh-κρβτΗο - 23 - (μθτμοκοημ) -LL - F 28249 (MOKCn,n,eKTHHa) CHJīb- HOAeficTByioinero θη,π,θκτοφϊ,π,ηογο areHTa. JļaHHoe H3o6peTeHHe othochtch k cnoco(5y ποπ^θηηη οοθαηηθηημ 23 - (Cj-Cg ajimnoKCHM) - LL - F 28249, BKHKwaromeMy 3aiiļHTy rHflpoKCHJībHOH rpynnbi b nojioHceHHH 5 coeflHHeHHK LL - F 28249 π - HHTpo6eH30HJixj!opHja,OM c o6pa30BaHHeM cooTBeTCTByiomero coe,n,H- 2 ηθηιίη 5-0-(n-HMTpo6eH3OHJi) - L L - F 28249; OKKCJieHHe yKa3aH-ΗΟΓΟ COe^HHeHMH C 06pa3OBaHHeM np0H3B0flH0r0 5-0-(n-HHTpo6eH-30mji ) - 23-okco - L. L_- F 28249 b KpucTajuiimecKOM coctohhhh; peaKUļHfo yKa3aHHoro npon3BOflCTBa c Cj-Cg ajiKOKcmiaMHHOM hjim ero cojibio c 0(5pa30BaHneM HHTepMeflHaTa 23-(Cj-Cg ajiKMJioKCHM) -5-0-(n-HHTpo6eH30MJi) - L L- F 28249 b KpHCTajuiH^ecKOM coc-tohhm; ΐΛ οηητμθ 3ainHTH c yKa3aHHoro HHTepMeflHaTa b npncyTCT-bhh ocHOBaHHH c 0(5pa30BaHneM iļeJieBoro coeflHHeHUH 23-(Cj-Cg aji-khjiokchm) - L L - F 28249. Bo3mokho οηητηθ satņuTH c KpHCTajum-HecKHx npoH3Bo,n,Hbix 5-0-( n-HHTpo6eH30HJi) - 23-okco L L - F 28249 Β npHCyTCTBHH OCHOBaHHH C 00pa30BaHHeM COOTBeTCTByK)ip[X COeAHHe- ηιλΡι 23-okco - L IrF 28249, h peaKijHH yKa3aHHbix οοθαμηθηηΚ c Cļ-Cg ajiKOKCHJiaMHHOM hjih ero cojibio c o6pa30BaHHeM qeJieBoro coe-Αηηθηηη 23-(Cj-Cg ajiKHJioKCHM) - LL - F 28249. M3BecTeH cnoco(5 nojiy^eHMH coeflHHeHHH 23-(Cj-Cg ajiKHJiOKCHMOB) - LL - F 28249 CM.naTeHT UļB 2192630.0Π 1988 r., hx ncnoJib30BaHHe b Ka^ecTBe npOTHBOrejrbMHHTHHX , HHCeKTHLļHflHbIX, Πρ0ΤΗΒ0ΗβΜ3Τ0^ΗΗΧ, ΙφΟΤΗΒΟ-3KTonapa3HTapHbix κ aKapHmmHbix areHTOB onHcaHbi b naTeHTe CU1A # 4916154. .JļaHHoe n30(5peTeHHe othochtch k ynpomeHHOMy 3a c^eT 6ojiee npOCTOft O^MCTKH M BblfleJieHHH npOMe*yTOqHOro ΟΟΘ,Π,ΗΗΘΗΗΗ, cnoco- 6y nojiy^eHHH 23-(Cj-Cg ajiKOKCHMHbnc) προΜ3Βθ,ηΗΗΧ coe^HHeHHii L L - F 28249. CoejļHHeHHfl LL - F 28249 n3o6pa«aiOTCH Humecjie-jnyiomeH oČiņeM cTpyκTypHοVi $opMyjioft: LV 10503
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Κ0ΜΠ0Η6ΗΤ RI % R3 R, L L- F 28249 CH(CH3)2 H ch3 CHg LL - F 28249 ch3 H ch3 CHg L L - F 28249 C ch3 ch3 ch3 ch3 L L- F 28249 CH(CH3)2 H H CHg LL- F 28249 CHgCHg H ch3 CHg LL- F 28249 CM(CH3)2 H CHg CHgCHg L L- F 28249 CH(CH3)2 H ch2ch3 CHg LL- F 28249 CH(CH3)2 ch3 CHg CHg ļanee, npeflJiaraeTCH cnocoCi nojiyweHHH coeflHHeHHft 23-(Cj-Cg ajiKHJiOKCHM) - L L - F 28249, b κοτοροΜ c KpHCTajunwecKHX npo-H3B0flHHX 5-0-( n-HHTpo(5eH30HJi) - 23-okco- L L - F 28249 b πρκ-cjttctbhh ocHOBaHHH CHHMaiOT 3amttTy, noji^aa cooTBeTCTBjrmpīe coe-Αηηθηηη 23-okco - L L - F 28249, h npHBOflflT peaKiļHio yKa3aHHHx 4 coejļmemPi c Cj-Cg ajiKOKcmamHou hjih ero cojibm c πολ^θηηθμ qejieBoro οοθαμηθηηη 23-(Cj-Cg ajiKHJiOKCHM) LL - F 28249.
ΠρΗ HCn0JIb30B&HHH B Ka^ieCTBe ΜΟΧΟβΗΟΓΟ COeflHHeHHH L L - F 28249 m cojiHHOKHCJioro MeTOKCHJiaMHHa b Ka^ecTBe Cj-Cg aJIKOKCHJiaMHHa 3aflBJIHeMhlfi CnOCO(5 MO)KHO npOHJIJIIOCTpMpOBaTb HH*e-cjiefl^Too^efi flHarpaMMoft I, b κοτοροΑ ΠΗΒ o(5o3HayaeT $yHKu;HOHa^bHyio rpynny - Π-ΗΗΤρθ6θΗ30Μ.Π. LV 10503
I
I
ΟΡΝΒ 6 3amwTa γηαροκοηλβηομ rpynnu b noJiomeHHH 5 οοθαηηθηηη L L - F 28249oC ocymecTBJiHeTCn peaKijHeM Me«Ay L L - F 28249 H n-HHTpo6eH30HJIXJIOpHAOM B npHCyTCTBHH OpraHM^eCKOTO paCTBOpM-τβΛΗ , TaKoro KaK, HanpHMep, TOJiyoji, xjiopHCTbift μθτμλθη, 3THJiaiļe-TaT, aiļeTOHHTpuJi h hm noAOČHbie, npeflno^TMTeJibHO b npHcyTCTBHH TOjryoJia, h opraHH^ecKoro ocHosaHHH, Tanoro KaK, HanpHMep, nnpn-AHH, TpK3THJiaMMH, N - MeTHJinHppOJIHAOH , H HM ΠΟΑ00ΗΗβ, ΠρθΑΠΟ^-THTeJIbHO Β npMCyTCTBHH TpH3THJiaMHHa.
HeoKHAaHHO dbiJio HaMfleHo, ^το OKHCJieHne οοθαμηθηηη 5-0-(n-HHTpo6eH30HJi) LL- F 28249 jļaeT KpncTajiJiH*iecKnft npoflyKT - coot-BeTCTByiomee coeAHHeHHe 5-0-( n-HHTpodeH30HJi) - 23-okco -LL- F 28249. KpHCTajiJiH^ecKoe coctohhh6 HHTepMeAnaTa πο3βοληθτ ocjniļecTBJiHTb ero npoCTyio h 3$$eKTHBHyio oyncTKy nyTeM nepeKpnc-TajurH3aij;nH hx noAXOAflmero opraHHuecKoro pacTBopHTeAH h ycTpaHHTb cjiojKHyio, A^HTeJibHyio npoiļeAypy o^hctkh c noMonļbio τβκμχ μθτοαοβ,
KaK KOJiOHcmHaH xpoMaTorpa$nn. Οκηολθηηθ οοθαπηθηhh 5-0-(π-ΗΗτρο-6eH30HJi) - L L - F 28249 ycnemHo ocyiqecTBJiHeTCH c ncnojib30BaHneM OKHCJIHIOmeft CHCTeMH, BbldpaHHO^ H3 rpymiH, ΟΟΟΤΟΗΐηβίί H3 ΠΗρΗΑΗΗΑΗ-xpoMaTa η yKcycHoro aHrnApHAa; nnpnflHHflHxpoMaTa h AHMeTHJi$opMa-MHAa; TpeT-(5yTOKCHajnoMHHHH h opTo6eH3oxnHOHa; πητηοκηοη $oc$opa h A™eTHJicyjib$oKCHAa; AHU,HKJioreKCHJiKap0oAHHMHAa h AHMeTHJicyjib$o-KCHAa; AByoKHCH MapraHLļa; h yKcycHoro aHmjļpiijļS. h AHMeTHJicyjib$o-KCHAa. IIpeAno^THTejibHofi OKMCJiaromen οηοτθμοΜ κάε οκηολθηηη οοθαηηθ-ΗΗΜ 5-0-( Π-ΗΗΤρθ6θΗ30ΗΑ) - LL - F 28249 HBJIfleTCfl AayOKHCb Map-ramja b npncyTCTBnn pacTBopHTeJin, TaKoro KaK, HanpHMep, xjiopHC-thh μθτηλθη, aqeTOHHTpHJi, 3THJiaqeTaT hjih hm ποαο6ηηθ, πρθΑποπ-THTeJībHO - B npHCyTCTBHH 3THJiaij[eTaTa. Βοαθθ npeAno^THTeJibHOH οκκοΑπιοηβΗ cHCTeMoii AJia οκηο-τιθηηη οοβΑΗΗβΗΗίί 5-0-(n-HHTpo6eH3OHJi) - L L - F 28249 ηβληθτοη yKcyc-HHft aHPHApHA H AMMeTHJICyJlb$OKCHA B npHCyTCTBHH nHpHAHHa H KHC— jiotu, TaKOH KaK, HanpHMep, yKcycHaH KHCJiOTa, TpH$TopyKcycHaH KHCJioTa, AHXJiopyKcycHaH KHCJiOTa, MOHOXJiopyKcycHafl KHCJiOTa h hm ποαο6ηηθ, npeAno^THTeJibHO - MOHOxjiopyKcycHafl KHCJioTa. HeojKHAaH-ho 6hjio HaftAeHO, mto Hcnojib30BaHHe yKcycHoro aHTHApHAa η αημθτηλ-cyjib$oKCHAa b npHcyTCTBHH nnpHAHHa h khcjioth CHJībHO yBejrHnHBaeT ββτχοα npoH3BOAHbix 5-0-(n-HHTpo(5eH30Hjr)-23-okco L L - F 28249 no LV 10503
CpaBHeHMK) C HCn0Jlb30BaHHeM TOJIbKO yKCyCHOrO aHrHflpMfla H £ΗΜΘ-TMJicyjrb$oKCHfla. HanpuMep, ecm οκηοπθηηθ yKcycHbTM aHrHApHAOM H AHMeTHJICyJIb$OKCHAOM ΠρΟΒΟβΗΤ B npHCyTCTBHH nHpMflMHa H MOHO-xjiopyKcycHOii khcjiotm, to βηχο^ 5-0-(n-HHTpo6eH30HJi)-23-OKCo-LL - F 28249 cC cocTaBJineT 76%; ecjin to xe οκηοιεθηηθ ripoBO-£HT B OTCyTCTBHe nupHAHHa H MOHOXJIOpyKCyCHOii KHCJIOTbl, BbTX0fl cocTaBJineT 2-4%.
KpHCTajiJiH^ecKoe npoH3BOAHoe 5-0-(n-HHTpo(5eH3OHJi)-23-OKCo-L L - F 28249 mojkho ο^ηοτητβ nepeKpncTaJuiH3aij;KeM H3 ποαχοαη-qero pacTBOpHTejifl (npeAnoHTHTeJifeHO h3 H-nponaHOJia) nepefl chh-τηθμ 3amHTH (yAajieHHeM n-HHTpo<5eH30HJibHoft rpynnbi) hjih peaKiļHefi C COJIHHOKHCJIblM Cj-Cg aJIKOKCHJiaMHHOM. ripeflno^THTejibHO προΒο,π,Ητ peaKiļnio pacTBopa HeomimeHHoro npo-AyKTa peaKu;HH 5-0-( n-HHTpo(5eH30HJi)-23-OKCo- LL- F 28249 b op-raroraecKOM pacTBopHTeJie, TaKOM, KaK TOJiyoji, c βο,π,ηημ pacTBopoM coJiHHOKHCJioro Cj-Cg ajīKOKCHJiaMHHa h ai^eTaTa HaTpHH πρκ nepeMe-DIHBaHHH flO ΤΘΧ ΠΟρ, ĪIOKa ΗΘ 3aBepfflHTCfl 06pa30BaHHe OKCHMa. Πο— jiyyeHHHft TaKHM o6pa30M HHTepMeflHaT 23-(Cj-Cg ajimnoKCKM )-5-0-(n—HHTpodeH30HJi) - 28249 BUfleJinioT h o*iHmaioT nepeKpHCTajuiH3au;HeH H3 ποΑΧΟΑΗΐηθΓο pacTBopHTeJiH, npeflnoxiTHTejibHO H3 H-(5yTaH0Jia.
B nepeKpncTajuin30BaHH0M οοθαηηθηηη 23-(Cj-Cg ajimnoKCHM) -5-0-(n-HHTpo6eH30HJi)- LL - F 28249 CHHMaiDT 3amHTHyro rpynny peaKiļneft c rHApooKHCbK) HaTpHH npn 0°C-25°C, nojiytian ijejieBofi npo,nyKT - 23-(Cj-Cg ajimnoKcnM)- L L - F 28249. Οηητηθ 3aiiļHTH ocymecTBJiHK)T peaKqnefi Me*fly pacTBopoM οοθ,π,ηηθηηη 23-(Cj-Cg aji-khjiokchm) - 5-0-( n-HHTpo6eH30HJi)- L L - F 28249 b opraHHViecKOM pacTBopHTeJie, TaKOM KaK TOJiyoji, AHOKca, H-6yTaH0Ji η τ.π., πρββ-nO^THTeJIbHO B AMOKCaHe, C BOflHHM paCTBOpOM ΓΗ,ΠρΟΟΚΗΟΗ HaTpHH npn 0°C-25°C h BbmeJieHHeM noJiy^eHHoro οοββΗΗβΗΗΗ 23-(Cj-Cg an-khjiokchm)- L L - F 28249 H3 opraHH^ecKoii $a3bi c ηοποηβ30βηηηθμ 0(5bBJHbIX ΜΘΤΟΑΗΚ, ΤΗΚΗΧ KaK KOHlļeHTpnpOBaHHe Η (JlHJIbTpOBaHH0 HJIH yAajieHHe pacTBopHTeJin.
TaKHM odpa30M, npHHiļHnnajībHoe οτηη^ηθ HacTOHDļero H3o6peTe-hhh 3aoiowaeTCH b cjieflyroiqeM: a) Hcnojib30BaHHe ηοβοη π-ΗΗτροόβΗ-30HJIbH0ft rpynribl flJIH nOJiytieHHH KpHCTaJIHH^eCKOrO Πρ0Η3Β0ΑΗ0Γ0 5-(n-HHTpo6eH30HJi) - 23-KeTOHa hjih 5-(π-ηητρο6θη30ηλ) - 23- 8
MeTOKcrnvia, Ka^biM H3 κοτορΗχ MOsceT 6biTb nepeKpHCTajum30BaH, h b) OKHCJieHHe 5-3aMemeHHoro npon3BO,n,Horo LL - F 28249od yK-CyCHbIM aHrHflpHflOM, j]MC0, ΠΗρΗ,Π,ΗΗΟΜ h kmcjiotoK c 0Čpa30BaHHeM 5-3aMemeHHoro 23-KeTOHa; n-HHTpo(5eH30HJibHafi rpynna ηβληθτοη ηθ TOJibKO xopoineft 3amHTH0fi rpynnoM, ho TaK»e no3BOJifleT npoBec-th npocTyio o^HCTKy npoMemyT01tiHbix coeflHHeHHfi KpHCTajuiH3aL(HeM, a Ηθ ,Π,ΟρΟΓΟΟΤΟΒΙΙ^ΪΟ OqHCTKy KOJlOHO^HOf! XpOMaTOrpa$Hei;t. H0BH3Ha OKHCJieHHH yKcycHbiM aHrHApH^OM - JļMCO 3aKJiioyaeTCH b τβχ cneiļH-<|)H*ieCKHX yCJIOBHHX peaKIļHH, KOTOpbie ΗβοβΧΟ,Π,ΗΜΗ B AaHHOM CJiyyae flJIH ΤΟΓΟ, UTO(5bI np0H30DIJI0 OKHCJieHHe. SKCnepHMeHTaJIbHHe yCJIOBHH, npHBO^HMHe paHee b ΧΗΜΗ^βοκοΑ JiHTepaType ajih yKcycHoro anrHflpH-,ņa - JJŅiCO, He ^aioT npoflyKTa. ΥHHKaJIbHOCTb 5-(n-HHTp0ČeH30HJI) Πρ0Η3Β0,Π,Η0Γ0 o(5HapymHBaeT-CH ΠρΗ paCCMOTpeHHH pa60TbI Sutherland H AP· (na- τθητ GULA 4900753; BpnTaHCKHH naTeHT N° 2192630, M.KJI.C07 β 493/22, ony6jiHKOBaH b 1988 r.). B npHMepe I (a) OKHCJieHHe 5-ΚΘΤΟ- ΠΡ0Η3Β0ΑΗ0Γ0 ,H,HXpOMaTOM HaTpHH IipHBOflHT K 5,23-ΑΗΚΘΤΟ-$aKTopy A - npoMe«yTOtJHOMy coeflHHeHHio, oxapaKTepH30BaHHOMy b ΒΗ,ηβ cmojih. ]ββχ.β nocjie ohhctkh cmojih kojioho^ihom xpoMaTorpa$Heii iļejieBofi npo,nyKT BbmejieH b ΒΠββ πθηη. KpoMe τογο, Heo0xo,n,HMOCTb xpoMaTorpa$H^ecKofi o^hctkh hcho noKa3aHa TaKHte κ nocjie,n,yK)mero COeflHHeHHH B 3T0H riOCJieflOBaTeJībHOCTH - 5-KeTO-23-MeTOKCHHMHHO-$aKTopa A, nojiy^eHHoro ΜβτοκρΗΗΜΗΗκροΒΒΗΗβΜ 5,23-AHKeTO-$aKTO-pa A (npHMep I (b)).
HecMOTpfl Ha npHMeHeHHe xpoMaTorpa$HtiecKOH o^hctkh npoMesy-TOtiHoe 5-KeTO-23-MeTOKCHHMHHonpoH3BOAHoe BbmeJieHO b βη,π,θ TBep-floft πθηη. itpyrne npHMepH npoK3BO,n,Hbix $aKTopa A, Tpe<5yiomHx owhct-kk xpoMaTorpa$HpoBaHHeM, πρηβο,ιι,ητοη b naTeHTe BeJiHKO(5pHTaHHH 2I76I82 b npHMepax 2-4, 6, 8, II, 14, 18, 21, 22, 28, 30, 40, 41, 44, 45-52, 56, 57, 60, 69, 70, 76, 88, 103, 105, 109, III, 112 η 123-127. To, uto 5-(π-ΗΗτρο<5βΗ3θΗϋ)-23-κβτοΗ hjih 5-(n-HHTpo6eH30HJi)-23-MeTOKCHM, a ηθ 5, 23-αηκθτο- η 5-κβτο-23 (E)-MeT0KCHM0np0H3B0AH0e MOryT ČHTb Ο^ΗίςβΗΗ npOCTOH KpKCTajIJIHaaiļHeii c noJiy^eHneM mhcthx KpHCTajuiHyecKHx npo,nyKTOB, HBJineTCH īiojio&h-TejibHHM npeHMymecTBOM 3aHBJieHHoro cnocoča nepeA ciioco6om naTeH-Ta BeJiHKOČpHTaHHH N» 2192630. 0—aiļHJinpoBaHHe n-HHTpočeH30HJixjio-Phaom cymecTBeHHO OTJiHdaeTCfl ot npHMepa, β κοτοροΜ π-ΗΗτρο6βΗ- LV 10503 30HHyiC> KKCJIOTy HCnOJIb3yK)T BMeCTe C ΤρΗφβΗΗΛφΟΟφΗΗΟΜ- flH3THJia30-flHKapdoKcmiaTOM. B ΕβροπθΜοκομ naTeHTe 307224 O-ajiKHJiHpoBaHHe 5-TpeT-6yTHJiflHMeTH^CHJiHJioKCM- φaκτopa A π-ημτρο6θη30κηομ khcjio-TOH Η ΤρΗφθΗΗΛφΟΟφΗΗΟΜ npOHCXOflHT C OČpameHHeM KOHφHΓypa^HH 23-rnflpoKCHJia, hto He ημθθτ MecTa b cjiynae ncnojib30BaHHH b Ka-^ecTBe aiļHJiHpyiomero cpeflCTBa n-HHTpodeH30HJixjiopHAa. Ba>KHbiH bh-boa npn 3tom saKjno^aeTCH b tom, hto npoMemyTO<iHoe οοθαηηθηηθ ημθθτ n-HHTpo6eH3oaTHyw rpynny b 23-πολοκθηηΚ c očpanjeHHOH koh-$HrypaqHefi η προ^κτ oxapaKTepH30BaH b βη,π,θ πθηη Aa*e nocjie Abomhoh xpoMaτoΓpaφH¾ecκofi ohhctkh. HanpoTHB 5-(n-HHTpo6eH30HJi)-23-ΚΘΤΟΗ H 5-(n-HHTp0(5eH30HJl)- 23-ΜΘΤΟΚΟΗΜ, OTHOCflmHeCH K Hac-τοπιςθΗ 3anBKe, ηθ ημθιοτ očpameHHOfi κΟΗφΗrypaqHη b πολοτκθηηη, co-AepjKaujeM π-ηητρο6θη30ηλ, h o(5a hbjihkjtch κρκcTaji jihheckhmh npoAyK-TaMH. Μηογηθ μ3βθοτηηθ OKHCJiHTejiH AawT HeyAOBJieTBopHTeJibHHe py-3yjibTaTBi πρκ οκηολθηηη 5-3aMemeHHoro F- 28249 aJIbφa. flame πρκ-BeAeHHan Ta<5jiHqa II noKa3HBaeT, hto HecKOJibKO OKHCJiHTeJieft, H3-ΒΘΟΤΗΗΧ CnOCOČHOCTbK) C ΧΟρΟΠΙΗΜΗ ΒΒΙΧ0Α9-ΜΜ npeBpaiņaTb ΒΤΟρΗΗΗΗΘ ΟΠΗρΤΗ B ΚΘΤΟΗΗ, ΗΘ ΠρΗΓΟΑΗΗ A^H Α^ΗΗΟίτ ΟΗΟΤΘΜΗ. ΧθΤΗ OKHCJIHTe-JIH Ha OCHOBe XpOMa AO ΗΘΚΟΤΟροΚ ΟΤΘΠΘΗΗ ycnemHO OKHCJlflIOT 23-ΓΗΑ-poKCHJi, τθμ ηθ μθηθθ , OAHaKO, nacTO KOMnjiecoo6pa30BaHHe HOHOB MeTajiJiHtiecKoro xpoMa c κοηθηηημ npoAyKTOM MemaeT ero οηηοτκθ m b pe3yjibTaTe πρΗΒΟΑΗΤ κ οηη*θηηιο βηχοαοβ η ηηοτοτη. iķixpoMaT HaTpuH η cepHafl KHCJiOTa, onHCaHHbie α-πη οκηολθηηη 23-rHApoKCHJia 5-κeτo-φaκτopa A b EBponeficKOM naTeHTe # 307222, BpHA JiH πρπθΜ-jihmh ajih aHanorHMHoro npeBpameHHH 5-0-ajiKHJiHpoBaHHoro npoH3BOA-ηογο. B npeAJioateHHOM cnocoče noKa3aHO, hto 0-3aMemeHHe b 5-nojio-κθηηη AeJiaeT TaKoe npoH3BOAHoe yfl3BHMHM κ a6^ctbhki khcjiot. Jļjin-TejibHoe αθΑοτβηθ κηολοτη Ha 5-0-3aMemeHHoe npou3B0AHoe πρηβοαητ κ apoMaTH3aiļHH HHsmero inecTHHJieHHoro iņiKJia b pe3yjibTaTe AernApa-TaqHH c ynacTHeM 7-rHApoKCHJia η 1,2-3JiHMHHHpoBaHHH npH yHaeTHM 5- n-HHTpo6eH3oaTHoii rpynnu. yCJIOBHH OKHCJieHHH B npHCyTCTBHM yKCyCHOrO aHrHApHAa - JĪMCO, ΠρΗΒΘΑβΗΗΗΘ B HaCTOHmeM Η30(5ρθΤΘΗΗΗ, TaKJKe HBJIHKJTCH yHHKaJIbHbIMH. Xopomo H3BecTHaH aKcnepHMeHTajībHan cncTeMa yKcycHbii! aHrnApHA -JļMCO (cm. J.D. Mbright u L. Goldman, J. Am. Chem. Soc., 89, 2416 (1967) ) AaeT μθηθθ Z% 23-KeTOHa H3 5 ΙΟ -(n-HMTpodeH30HJi)- F - 28249 ajībi^a. Μ3ο6ρθτθηηθ nJiJiiocTpHpyeTCH npHMepaMH:
ΠΡΜΜΕΡ I
Πολυ^θηηθ 5-0-(n-HHTpo(5eH3OHJi) - L L- F 28249 OC
IlepeMeiiiHBaeMbifi pacTBop LL- F 28249 (X (6,36 r, 10,4 mmo-JIh) B XJIOpHCTOM ΜΘΤΗΛΘΗΘ OČpaČaTHBaiOT ΠΗρΗ,Π,ΗΗΟΜ (1,98 Γ, 25,0 MMOJIH) H n-HHTpo6eH30HJIXJIOpHAOM (2,45 r, 13,2 mmojih) ΓφΗ 20°-25°C. Hepee 4 ^aca p6aKiļHOHHyio CMecb npH 20°-25°C o6pa6aTHBaioT
HaCtnqeHHbIM paCTBOpOM 6MKap60HaTa HaTpHH H XJIOpHCTfeIM ΜΘΤΗΛΘΗΟΜ h nepeMeuiHBaioT ,π,ο ποληογο pacTBopeHHH. Φa3L·I pa3,n,ejiHK>T, opraHH-uecKyio $a3y npoMHBaioT nocjieflOBaTejibHO HacumeHHbiM pacTBopoM 6h-Ka6oHaTa HaTpHH, 5%-Hoii cojihhoK khcjiotom h HacbniļeHHHM pacTBopoM xjiopMCToro HaTpHH, h KomjeHTpHpyioT b BaKyyMe, nojiy*iaH ijejieBoe ΟΟΘ,ϋ,ΗΗβΗΗΘ B BHfle ΤΒΘρ,Π,ΟΜ ΠΘΗΗ B KOJIHtieCTBe 7,9 Γ (ΚΟΛΗ^βΟΤΒΘΗ-hhm ΒΗχο,η); H,iļeHTH$HiļHpyiOT khakocthoM xpoMaTorpa$Hei;i, MHMP-aHa-J1H30M K MaCC-CneKTpOCKOnH^eCKHM aHajIH30M. ΠΡΗΜΕΡ 2
IlojiyxieHHe 5-0-(n-HHTpo6eH3OHJi) - L L- F 28249oc riepeMeiiiHBaeMHH pacTBop LL - 28249cC (6,13 r, 10,0 mmo-jieii) b TOJiyojie očpačaTHBaioT TpH3THJiaMHH0M (2,53 r, 25 MMOJieM), oxjiajKflaioT jļo I5°C, otfpadaTHBaioT ηθοκοηβκημη πορρΗΗΜΗ π-Ηπτρο-6eH30HJixjiopH,n,a (2,60 r, 14 MOJieft) npn TeMnepaType ot 15° So 22°C, h nepeMeuiHBaioT B Tenemie 6 nācos npn 20°-24°C. PeaKLļHOH-Hyio CMecb očpatfaTbiBaiOT βο,π,ομ, nepeMeniHBaioT b τθ^θηηθ 10 MHHyT, h $HJibTpyioT. $HJibTpaT οτ,π,θηηιοτ , opraHH^ecKyio $a3y npoMHBaioT nocjieflOBaTeJibHO HactnqeHHb!M pacTBopoM 0HKap6oHaTa HaTpHH, 3 co-JIHHOtt KHCJIOTOM Η ΒΟ,Π,Οίί, H KOHIļeHTpHpyiOT B BaKyyMe, I10Jiy^aH ije-JieBoft npo,nyKT b βη^θ τβθρ,π,ομ πθηη b KOJiHnecTBe 7,55 r. LV 10503 ΠΡΙ4ΜΕΡ 3
Ilojiy^eHHe 5-0-( π-ΗΗτρο<5θΗ3οιυι)-23-οκοο LL - F 28249c* C HCn0JIb30Ba.HHeM nnpHflMHflHXpOMaTa H flMMeTH^|)OpMaMHfla riepeMeiiiMBaeMHH pacTBop 5-0-(n-HHTpo6eH30HJi) LL - P 28249<X (3,12 r, 4,10 mmojīh) b £HMeTHJi$opMaMHfle o6pa6aTtiBaroT nupn^MH-flHxpoMaTOM (18,8 r, 50 MMOJieft), BSHTbiM b BHfle OflHofi nopiļMH, ne-peMeinHBaioT ripu 20°-25°C b τβ^βΗΗβ 6 tiacoB κ BbuiHBaioT b BOAy. PeaKiļMOHHyio CMecb nepeMemuBaioT β τθ^θηηθ 15 MHHyT h $HJibTpyioT. 0T$MJibTpoBaHHbift oca^oK npoMUBaioT BOAOft, cyinaT Ha B03,nyxe h ne-Ρθηοοητ b 9THJiaLļeTaT. nojiyyeHHyio CMecb κηπητητ c oČpaTHHM xojio-AHJIbHHKOM Β Τθ^βΗΗΘ 15 MHHyT, O<5pa(5aTbrBai0T ^HaTOMHTOM H $HJIb-TpyioT. ^HJībTpaT κ0Hiļ6HTpnpyK)T b BaKyyMe c očpasoBaHueM Kpacno-KopHtiHeBoro TBep^oro BemecTBa, κοτοροβ nepeKpncTajuiH30BbiBaroT H3 H-nponaHOJia, nojiytiaH qeJieBoft προ,π^κτ b βηαθ KpHCTajuioB 6e-jioro iļBeTa β KOJinnecTBe 3,33 r (βηχοα - 52$ b pacneTe Ha LL - F 28249o< ); τβΜΠ.Γυι.2Ι7-22Ι°0, HAeHTJKfmļHpoBaH HflMP-aHajin30M h Macc-cneKTpocKonH^ecKHM aHajiH30M. ΠΡΜΜΕΡ 4 IIoJiļnieHHe 5-0-(n-HWTpo<5eH3OKJi)-23-oKCo- L L - F 28249c* C HCn0JIb30BaHHeM nHpH,IļHH1ĪI,HXpOMaTa H yKCyCHOTO aHrHflpHAa
PacTBop 5-0-(n-HHTpodeH30HJi) LL - F 28249c* (0,38 r, 0,5 mmojīh) b xjiophctom MeTHJieHe ,n,o(5aBJiflK)T κ CBemenpHroTOBJieHHoft CMecH nHpHl]ļHH1iļHxpoMaTa (0,19 r, 0,5 mmojib) h yKcycHoro aHrHApn-fla (0,3 r, 3,0 mmojīh) πρκ ηητθηοηβηομ nepeMeniHBaHMH. PeaKiļHOH-Hyio CMecb nepeMeiiiHBaioT ripu κομηητηοη TeMnepaType β τθ^θηηθ 15 MHHyT, ΚΜΠΗΤΗΤ C OČpaTHbIM XOJIOflMJIbHHKOM Β ΤΘ^ΘΗΗΘ 6-8 HaCOB, oxjiasAaiOT ,π,ο κομηητηομ TeMnepaTypH m o(5pa6aTbiBaioT bo£OM. riocjie μητθηοηβηογο nepeMeniHBaHHH $a3bi pa3£eJinioT h opraHHciecKyio $a3y npOMHBaiOT HaCblIIļeHHblM paCTBOpOM 6HKap60HaTa HaTpHH Η ΚΟΗ£ΘΗΤρΜ-pyiOT b BaKyyMe, nojiy^an οοτητοκ . 3τοτ οοτητοκ πβρβκοοΗτ b 3thji-aneTaT η xpoMaTorpa$HpyioT, Hcnojib3yfl CHJiHKareJib h 3THJiai^eTaT b Ka^iecTBe oJiioeHTa, nojiyHan 6jie£Hoe «eJiTo-cepoe BemecTBO. 3to 12 τβθραοθ BemecTBO nepeMemuBaioT co CMecbio 3THJiaqeTaT : reKcaH (odteMH. οτηοπιθημθ 55:45), $MJibTpyioT, h φϊυΐΒτρβτ κοΗΐίβΗτρκργιοτ b BaKyyMe, nojijrvan qeJieBoe οοθαμηθηηθ μ b βμαθ ČJieAHO-meJiToro τβθραογο Be^ecTBa b KOJitreecTBe 0,26 r, κοτοροθ HAeHTH$HqnpyioT H^flMP - h ΚΧΒβ - aHajin3aMM. ĪIPMMEP 5 ilojiy^eHne 5-0-(n-HHTpodeH3OKJi)-23-OKCO- LL- F 28249c< C HCn0JIb30BaHMeM TpeT-6yTOKCMaJIIOMMHHH H 0pT0-6eH30XHH0Ha nepeMemnBaeMyio CMecb 5-0-(π-ηητρο6θη3Οκα) LL - F 28249^ (0,38 r, 0,50 mmojih) , TpeT-6yT0KCHajiKMHHHH (0,184 r, 0,75 mmojih) h 0pT00eH30XHH0Ha (0,216 r, 2,0 mmojih) b TOJiyojie κηπητητ c O^paTHblM XOJIOAHJIbHMKOM B ΤΘ^ΘΗΗΘ 2 ^aCOB, OXAaKAaiOT AO KOMHaTHOM TeMnepaTypbi, o<5pa6aTHBaioT TOJiyo;ioM κ pa30aBJieHH0ft cepHoii khcjio-TOM (16%), nepeMeniHBaiOT 5 MHHyT H (|)HJIbTpyK)T. ΦΗΛΒΤρΑΤ OTAeJIflIOT h npoMHBaioT opraHM<JecKyKi $a3y βοαομ h KOHqeHTpnpyioT b BaKyyMe, nojiytiaH CTeKJiOBHAHbiK TBepAHfi ocTaTOK. OcTaTOK nepeHOCHT b othji-aqeTaT h (f)ObTpyiOT nepe3 HeMTpajibHyio oKHCb aAioMMHHfl. ΦοπτρΗτ KOHqeHTpnpyiOT b BaKyyMe, nojijn-iaH ueJieBOM npoAyKT b βηαθ TBepAO-ro 6θαογο BeujecTBa β KOJiimecTBe 0,324 r (βηχοα 71%, corjiacHO AaHHbiM )KXB^-aHajiH3a. ΠΡΜΜΕΡ 6 noAytjeHMe 5-0-(n-HHTpo6eH3onJi)-23-oKco- LL- F 28249/)( C HCn0JIb30BaHHeM ΠΗΤΜΟΚΜΟΜ $OC$Opa H AHMeTMJICyJIb$OKCHAa
PacTBop 5-0-(n-HHTpo6eH30MA) — LL - F 28249<X(0,38 r, 0,50 mmojih) k A^MeTMJicyjib$OKCHAa (0,75 r, 9,6 MMOAefi) b xjiopmctom M6THJieHe o6pa6aTbmaiOT nopoiHKOo0pa3HOMnHTKOKncbio $oc$opa (0,107 r, 0,75 mmojih), B3HT0H b bmag OAHOft nopilu, nepeMeinMBaioT npn 20°-25°C b Te^eHMe 19 ^acoB, odpačaraBaioT α°6αβαηθμημ no KanjiHM τρκ-OTHJiaMHHOM (0,30 r, 3,0 mmojih), nepeMeniHBaiOT β τθ^θηηθ 30 MHHyT, 3aTeM o6pa6aTbiBaioT xjiopHCTbiM MeTMJieHOM κ boaoM m nepeMeniHBaiOT β τθ^θηηθ 5 MHHyT. (&a3bi pa3AeAHiOT, h opraHireecKyD $a3y npoMH- LV 10503
BaiOT pa3(5aBJieHHOfi COJIHHOfi KMCJIOTOft (7%) M KOHIļeHTpHpyiOT B Ba-KyyMe, nojiy^aH iļejreBOtf npo,nyKT b ΒΗ,ιι,β 6ejioro τβθρ,π,ογο BemecTBa b KOJiimeCTBe 0,28 r (ĪiMCTOTa 47%, no flaHHbiM )KXB(iI,-aHajiH3a). ΠΡΜΜΕΡ 7
IlojiytieHMe 5-0-(π-ΗΗτρο6βΗ3θκ;ι)-23-οκοο- L L·- F 28249 <x c Hcnojib30BaHneM flByoKHCH MapraHiļa κ χπορηοτογο MeTHJieHa b KatiecTBe pacτbopnτ e jih
PacTBop 5-0-(n-HHTpo6eH30HJi)- L L- F 28249(0,19 r, 0,25 MMOJIh) B XJIOpHCTOM ΜΘΤΗ-ΠβΗΘ 06pa6aTHBaiOT ABJTOKHCbK) Map-raHiļa (8,0 r, 92 mmojih), nepeMeniH BaiOT npn 20°-25°C b τθ^θηηθ 2 nacoB, o(5pa6aTHBaK)T 3aTeM xjiophcthm μθτηπθηομ, πβρβΜΘίπκBaiOT b TetieHne 5 μηηυτ m $HJibTpyioT. ®mibTpaT κοΗΐ^βΗτρηργιοτ b BaKy-yMe, nojijrtian iļejieBoe οοθ,π,ηηθηηθ b βη,π,θ tfenoro TBepfloro BemecT-Ba b KOJin^ecTBe 0,08 r, miCTOTa 51% no ftaHHbiM MB.lļ-aHajiHsa. ΠΡΗΜΕΡ 8 ĪIojiytīeHHe 5-0-(π-ημτρο6θη3οηπ)-23-οκοο- LL- F 28249<x c Hcnojib30BaHHeM ,n,ByoKHCn MapraHiļa n aiļeTOHHTpnjia b
Ka^eCTBe pacTBopHTeJin
PacTBop 5-0-(n-HHTpo(SeH30M^)- LL- F 28249oč (0,19 r, 0,25 mmojih) b aijeTOHHTpHJie o^paCiaTbiBaioT flByoKncbio MapraHiļa (8,0 r, 92 mmojih), nepeMemHBaioT b Tenei-me 3 tiacoB npn κομηητ-HOft TeMnepaType, 3aTeM otSpaCaraBanT aiļeTOHHTpmiOM, nepeMeniHBa-K)T b τθ^θηηθ 5 MHHyT h $HJibTpyiOT. 0T$njibTpoBaHHbifi oca^oK cyc-neH,n,HpyK)T B XJIOpWCTOM ΜβΤΗΛβΗβ H $HJIbTpyK)T. AljeTOHHTpHJIbHHft H ΜΘΤΜΠΘΗΧΠΟρΗ,Π,ΗΗίί $HJIbTpaTbI COBMeUļaiOT, npOMHBaiOT BOflOft Η ΚΟΗΙ1ΘΗ-TpnpyioT b BaxyyMe, nojiyyan iļejieBoe οοθ,π,ηηθημθ b βμ^θ dejioro τβθρ,π,ογο BeiņecTBa b KOJinnecTBe 0,14 r, tiHCTOTa 69%, no ,n,aHHbiM SiXBfl-aHajiH3a. 14 ΠΡΜΜΕΡ 9 ĪIojiyweHne 5-0-(n-HHTpo6eH3OHJi)-23-OKCo- L L - F 26249c< c Mcnojib30BaHHeM ,n,ByoKncn Mapramja h 3THJiaijeTaTa b Ka-
MecTBe pacTBopuTeJiH
PacTBop 5-0-(n-HHTpo6eH3OMJi)- LL- F 26249o( (1,0 r, 1,3 mmojih) b 3mnaqeTaTe očpadaTHBaioT flByoKHCbio MapraHu;a (20,0 r, 230 MMOJiefi), nepeMemHBaioT ripu 20°-25°C b Te^eHHe 3 yaCOB H $H^bTpyiOT. 0T$HJIbTpOBaHHHfl OC^IļOK npOMHBaiOT 3TMJiaiļe-TaTOM. $HJibTpaTH co6nparoT βμθοτθ, o(5pa(5aTHBaioT ,n,ByoKncbK) Map-ramja (8,0 r, 92 mmojih), nepeMemHBaioT ripu 20°-25°C b τθ^θηηθ 3 tiaCOB K $HJIbTpyi0T. 0τφΗ Jlb TpOBaHHbIM OCcl^OK npOMblBaiOT 3THJI-ai^eTaTOM; $mibTpaTbi cočupaioT ΒΜβοτβ n KOHiļeHTpnpyioT b BaKyyMe, nojiynaH iļejieBoii npoflyKT β βμ,π,θ dejioro TBep^oro BeiņecTBa b kojih-necTBe 0,6 r (miCTOTa 70% no flaHHHM HXB,Il1~aHajiH3a). TBepAbifi npo-flyKT nepeKpHCTajiJiH30BHBaioT H3 H-nponaHOJia, noJiy^aH čejine κρηο-Tajuiti c TeMnepaTypon njlaBJieHKH 2I8-222°C. ΠΡΜΜΕΡ 10 nojiy^eHne 5-0-(π-ΗΜτρο6θΗ3θΐυι)-23-οκοο- LL- F 28249<X C HCnOJIb30BaHIieM flHHHKJIOreKCHJIKapdojļHHMHfla H flHMeTHJI- cyjib$OKCHAa
PacTBop 5-0-(n-HHTpo6eH30HJi)- L L - F 28249<* (0,33 r, 0,50 mmojih) b 6eH30Jie o6pa0aTHBaiOT nocjieflOBaTejibHO ,π,ΗΜΘτιυι-cyjib$OKCH^OM (0,78 r, 10 MMOJieft), πηρη,π,ηηομ (0,04 r, 0,5 mmojih), TpM$TopyKcycHOfi KHCJioTOft (0,03 r, 0,25 mmojih) h AniļHKJio-reKCHJiKapeoAHHMHflOM (0,31 r, 1,5 mmojih), nepeMemHBaioT npn 20°-25°C b TeneHne 21 naca, 3aTeM očpačaTbiBaioT 6eH30JiOM h (ļ)MJIbTpyK)T. 0T$HJIbTpOBaHHHM ΟΟΘ,Π,ΟΚ npOMblBaiOT 6eH30JIOM. Co6paH-Hue βμθοτθ $HJibTpaTH προκΗΒ3ΐοτ βο,π,ΟΗ η KOHiļeHTpHpyioT β BaKyy-μθ, nojiynan iļejieeoe οοθ,β,ηηθηηθ β βη,π,θ τβθρη,ογο BemecTBa οβθτ-jioro opaHmeBO-KopunHeBoro iļBeTa β KOJinnecTBe 0,34 r, ββγχο,π, 75% no flaHHHM IXB,Iļ-aHajiH3a. LV 10503
ΠΡΙ4ΜΕΡ II riojiytieHHe 5-0-(n-HHTpo(5eH3OHJī)-23-OKCO- L L - F 26249<K c McnoJib30BaHneM yKcycKoro aHrHApnAa h flHMeTMJicyjib(So-KCHfla B npHCyTCTBMH nHpHflMHTpH$TOpaiļeTaTa CMecb 5-0-(n-HHTpo6eH3OMJi)~ L L - F 28249<X (0,38r, 0,5 mmojih) , (n,nMeTHJīcyjib$OKCH(n,a (0,78 r, 10 MMOJiefi) h πκρΗ,π,ΗΗτρΗ-$TopaiļeTaTa (0,97 r, 0,5 mmojih) b orajiaijeTaTe oČpatfaTHBaiOT flodaBJineMHM no KanjiHM yKcycHbiM ηηγη,ιι,ρηαομ (0,26 r, 2,5 mmojih), nepeMenmBaiOT b TeneHne 24 qacoB npn 20°-25°C h odpadaraBaiOT 3THJiau,eTaT0M h βοαοΚ. $a3bi pa3,n,ejiHīOT: opraHHnecKyio $a3y npoMbi-BaioT BOflon n KOHiļeHTpnpyiOT b BanyyMe, nojiynan οοτητοκ b βη,π,θ βη3κογο Macjia. OcTaTOK nepeHOCHT b xjiopHCTbift mothjioh h KOHiļeH-TpnpyiOT b BaKyyMe, nojiywaH iļeJieBOfi npoflyKT b βη,ιι,θ sejiToro TBep-floro BemecTBa b KOJinnecTBe 0,36 r; Η^βΗΤΗφκΐίΗροBaH ΗΧΒ,Ε,-aHajin- 30M. ΠΡΜΜΕΡ 12 ĪIojiyneHne 5-0-(n-HHTpo(5eH3OHJi)-23-OKCO- LL- F 28249<X c Hcnojib30BaHneM yKcycHoro aHrnApHAa m AHMeTHJicyjib(f)o-.KCHfla B npHCyTCTBHH nupH^HHa H AHXJIOpyKCyCHOft KHCJIOTbl CMecb 5-0-(n-HHTpo6eH3OHJi)- LL- Γ 28249c< (7,26 r, 10 MMOJiei!) h nHpnflHHa (31,6 r, 400 MMOJieii) o6pa6aTHBaiOT ρμ-Memncyjib(ļ)0Kcnfl0M (15,6 r, 200 MMOjieii) h rn)nxjiopyKcycHOH khc-jioth (1,29 r, 10 MMOJieii), oxjianyi;aH3T flo 2°-3°C, o<5pa6aTbiBafOT AodaBJineMbiM no KanjiHM yKcycHHM aHrHApnflOM (5,1 r, 50 MMOJiefi) npn 3°-7°C h oČpatfaTbiBaiOT xjiopkcthm M8THJieH0M n boaoh. PeaK-u;noHHyio CMecb nepeMeniHBaioT npn TeMnepaType OKpywaiomen cpeflbi b TeneHne 15-30 MMHyT, v. pa3A,eJiHK)T $a3bi. OpraHnneCKyio $a3y npOMH-BaioT xojioahom pa30aBJieHHoft cojiHHoft kmcjiotok (5%), η 5%-ηημ pac-TBopoM xjiopMCToro HaTpHH v. KOHiļ6HTpMpyioT b BaKyyMe, nojiy^afl iļe-jieBOM npoflyKT b βηαθ τβθρ,π,ομ πθηβι aceJiToro i^BeTa b KOJin^ecTBe 7,47 r, nHCTOTa 73% no ^aimiM JKXB,iļ-aHajin3a. Mcnojib3yH no cyme-CTBy tot iKe cnocotf, ηο μθηηη ncnojib3yeMbifi KucjioTHbii! peareHT, nojiynaioT cjieAyiomne βηχοα,η npoflyKTa, πρμβθ,π,θηηηθ b TaČJiniļe I.
lo I—I OKHCJieHne 5-0-(n-HMTpo6eH3OHJi)- L L- F 28249c< b 5-0-(π-ΗΜτρο6θΗ3θκ.π)-23-οκοο L L - F 28249 o< c Mcnojib30BaHneM yKcycHoro aHrM,n,pnIii,a c ,nHMeTMJicyjib<ī)OKCHfla b
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cd E-< ct LO LO o p; O ·—' LO CO co o X ^ CO 1 i 1 te x «fl --- o o co ω K 0Q co co X o >3 δ o X w o 2 — LO co >3 >3 CD JT CO t—1 a o Py — o CQ PS >3 X Oy x o to Ov E- lO LO LO ίο co 1 E-· >& o CO CO co co X o I I 1 1 o II a Η o o o o co Eh Osi co co co 5d et X s II I 1 ft 1 o Eh w Ο Λ >=l 1=: x p; w >3 CQ Pļ o co X 2 s o e« e~* ω o o E-ι cd Eh>& E-< Ο E-· Pi co CO <D S 0 X cd cd x o a x 2 Λ 2 i=; e Pu Py EH o o 5& 4S1 o p; • #» cd o Ei x O w t? O • · « s tļ m o o o o δ w o X ·* #S ψ> X ^—- S co I—* 1—ļ h-i o ω >3 δ • x o X X w JS sr ω >3 o N -—- Λ o & l=3 cd o X s O cd p; <D o i=C Eh « w w X Ό O o >s >, >3 >3 o X Pv p? ΘΙ ΘΙ ei ΘΙ o X II 2 c o Eh E-< E-» E-* o X x 2 W a tQ X H-l II p; cd >3 Sd • *·> X X cd <D x x Pļ t=l i=t s o O >o S L—( t—t 1—t L—t co t=; s cd Pt> o o eh x • r s X e cd s E-· CQ o e p; δ o iS l=C o ω Eh 3 X x ω >3 s & « § o X >3 S io CO co co o K E-< a O X cd >& E S X X ω >s cd o a « 2 >3 ω E-< o E-< Eh X K X ω Ct »-*3 II re 5 x ft- o cd I o O « n m P! « p; θι o x s o o o o o o X EH a co E* >& -ό* s c w <D Λ t=L • «» co 2 tJ cd 2 ω 5 & II E- o X tx 3 K pļ K X >3 o cd J3 t=3 s K ω a O Eh S 3 LO cO £> co C I—I i—i 1—) 1—1 h—f cd Ό O LV 10503 18 ΠΡΜΜΕΡ 13 riojiytieHHe 5-0-(n-HHTpočeH30HJi)-23-OKco- L L - F 28249<X c ncnojib30BaHH6M yKcycHoro aHrHAP^Aa m ji,HMeTHJīcyjib$o-KCH,n,a b npncyTCTBHn nnpn,n,MHa h MOHOxjiopyKcycHOii kmcjiotlī Ομθοβ 5-0-(n-HMTpo6eH3onji) LL - F 26249i* (1,52 r, 2,0 mmojih) h nupMAHHa (3,16 r, 40 MMOJiefi) b TOJiyojie odpačaTbraaioT rn,HMeTMJICyJIb$OKCMiniOM (3,12 Γ, 40 MMOJiefi) H MOHOXJIOpyKCyCHOK kmcjiotoM (0,19 r, 2,0 mmojih), oxjiajKflajoT AP 2°-3°C, odpačaTbi-BaroT ^,o6aBJiHeMbiM no KanjiHM yKcycHbiM aHrnflpHflOM (0,82 r, 8,0 mmojih) npn 3°-5°C, nepeMeniHBaioT npn 2°-3°C b Teneroie 7 qacoB h flajiee oČpadaTbreaioT TOJiyojiOM h Βο,π,οίί. Ilocjie nepeMemHBaHHH peaKijHOHHofi CMecn npn I5°-20°C β Tenerae 10 MnnyT $a3bi pas^e-jihkdt . OpraHHnecKyio <f»3y npoMHBaioT nocjie,n,OBaTeJibHO xojio,n,HOft 2,4 N cojihhoK KucjioTOft h boaoM npn I5-20°C h KOHLļeHTpnpyiOT b BaKyyMe, nojiynaH LjeJieBoft npojļyKT β βη,π,θ τβθραοΑ πθηη aceJiToro ijBeTa b KOJinnecTBe 1,4 r, nncTOTa 71% no flaHHbiM JKKBJI-aHajiHsa. ΠΡΜΜΕΡ 14
Oi^eHKa oKHCJieHHH 5-0-(n-HHTpo(5eH3OHJi)- LL- F 28249oC c o6pa30BaHneM 5-0-(n-HHTpo6eH3OHJi)-23-OKCo- L L- F 28249 C< C HCn0JIb30BaHHeM pa3JIH^HbIX OKHCHHTeJiefi
Bbuia npoBefleHa ou;eHKa pa3JinnHbix ομοτθμ, OKncjiHiomHx 5-0-(n—HHTpo6eH30HJi)- LL- F 28249o< b 5-0-(n-HHTpo(5eH3OMJi)-23-okco- LL- F 28249 <Λ . PeareHTbi, ycjiOBHH προΒβΑΘΗΜΗ peaK-iļHH n npoijeHT nojiyneHHoro 5-0-(n-HHTpo(5eH3onji)-23-OKCo- L L- F 28249<X onpefleJieHHoro lXBjļ-aHajiH30M, πρκΒθΑβΗΗ b Ta6jmiļe II. LV 10503 σ> \—i
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ω ι 2 cd X cū 3 o LO o o o o CD LO CD 1—1 X S E LO o r> O t=5 pa x o to o LO co o co 1—1 o ν' o C\i o a ω I—I cO I—I H-i 1—1 V S p >=5 ir 1 s O o X Osi X 1 s 32 1— t=C o o 2 Λ LO o s a CD 2 (=5 co 1 1 o 1 >jcd 3 X t=5 ω • ν' X E 1=5 a X E X PvE CQ CD cd E ν' o O ω o s s s o 5 S s O 1 E* Ό S o o εΟΘΈ^ Cto t=i e a KE 1 X J3 t=5 c. KH S Λ CD X S Λ S >& Osi cd o O O c CO s PvR 2 *5 Pv^ Pv S E o -<» PvX s s s oj 32 cd S X X S X s Pvčd Osi cd s a a o PQ CQ O 03 C2 01=210 32 O n E-I X 32 CQ E2 X o o E 3 σ> O t—1 c\i co LO cO E I—k 1—1 1—1 1—1 \—i l-H i—1 O LV 10503 ΠΡΜΜΕΡ 15 ΠοΛγ^θΗΗΘ 5-0- ( Π-ΗΗΤρ00ΘΗ30ΚΛ ) -23- (MeTMJIOKCHM) L L - F 28249<*
PacTBop 5-0-(n-HHTpo6eH30MJī)-23-OKCo- LL- F 28249o< , (10,67 r, 14,0 MMOJieiO b H-6yTaHOJie o6pa6aTHBaiOT pacTBopOM COJIHHDKHCJIOrO MeTOKCHJiaMMHa (2,34 Γ, 28,1 MMOJIA ) M 6e3B0R-ηογο aueTOHa HaTpMfl (2,30 r, 28,1 mmojia) b βο,π,θ npn 20-22°C, nepeMemuBaroT b TetieHHe 2 nacoe ripu 20°-22°C μ φιυΐΒτργιοτ. Οτ-$HJibTpoBaHHHft oca^oK cymaT Ha B03,nyxe m nepeKpKCTajijiH30BHBaK)T H3 H-6yTaHOJia (ropfl^ee $HJibTpoBaHHe), nojiyHafl nejieBoe coeAMHe-ηηθ b BH^e 6eciļBeTHoro τβθρλογο BenjecTBa b KOJinnecTBe 3,6 r, miCTOTa 91% no flaHHbiM 2CXB^3,. ΠΡΜΜΕΡ 16 Ποα^θηηθ 5-0- (n-HHTpo(5eH30HJi) -23- ( μθτηλοκοημ ) LL- Γ 28249o<
PacTBop 5-0-(n-HHTpo6eH3OKJi)-23-OKCo- L L- F 28249o{ (1,5 r, 2,0 mmojih) b TOJiyojie očpatfaTHBaiOT pacTBopOM cojiahokhc-Jioro MeTOKCHJiaMMHa (0,25 r, 3,0 mmojia) η (5θ3Βοαηογο aijeTaTa HaTpHA (0,25 r, 3,0 mmojia) β βο,π,θ h nepeMemHBaioT npn 20°-25°C b τθ^θηηθ 10 *iacoB. ToJiyojibHyio $a3y οτλθααιοτ, npoMHBaioT bo^oh h KOHpeHTpHpyiOT b BaKyyMe, nojiy^afl TBepAHfi οοτατοκ. 3tot ocTa-tok nepeKpHCTajiAH30BbiBaiOT H3 H-6yTaHOJia, nojrjniafl iļejieBOH npo-flyKT, 0,65 r, HAeHTH$HLļHpoBaH IXB^-aHajiH30M. ΠΡΜΜΕΡ 17 nojijmeHHe 23-(MeTHJiOKCHM)- L L- F 28249(/,.
PacTBop 5-0-(n-HHTpo6eH30HJi)-23-(MeTMJIOKCHM) LL- F 28249o<. (1,58 r, 2,0 mmojia) b AMOKcaHe odpačaTbmaiOT ^ofiaBJifle- 22 ΜΗΜ ΠΟ KanJIHM 4%-HHM paCTBOpOM ΓΗ^ρΟΟΚΗΟΜ HaTpHH (3,0 Γ, 3,0 MMOJieii NaOH) npH 8-I2°C, nepeMeuiHBaioT b τθηθηηθ 3 nacoB πρκ 8-I2°C, o6pa6aTbiBaioT TOJiyojiOM η boaom, m nepeMemHBaroT b τθπθ-Hwe 5 MHHyT npn TeMnepaType OKpy?KaiomeM cpeflbi. $a3bi pa3flejiHK)T, h opraHHMeCKyio $a3y npoMHBaiOT 10%-hhm xjiophcthm HaTpneM h koh-u;eHTpnpyiOT b BaKyyMe, nojiywan nejieBoe οοθαηηθηκθ b bHfle TBepflon πθηη čejioro iļBeTa b KOJinnecTBe 1,15 r, nncTOTa 89%, no αθηηημ }KXB/ļ-aHajīH3a. ΠΡΜΜΕΡ 18 nojiyneHne 23-okco LL- F 28249o^ Ομθοβ 5-0-(n-HHTpo6eH3onit)-23-OKCo- LL- F 28249oc (1,52 r, 2,0 mmojih) η 4%-hoh ΓΗ^ροοκηοΜ HaTpnn (3,3 r, 3,3 mmojih NaOH) b flHOKcaHe nepeMemuBaiOT npn 23°C b τθπθηηθ 2 nacoB, odpadaTHBaiOT TOJiyo;iOM η boaoh h BCTpHXHBaiOT. $a3bi pa3jļeJiHK)T, h opraHnnecKyio $a3y npoMHBaiOT βο,π,ομ η κοΗη,βΗτρη-pyiOT b BaKyyMe, nojiynafl iļeJieBoe οοθ,π,ηηθηηθ β^ βη,π,θ τβθραοΜ ΠΘΗΗ B KOJIH^eCTBe 0,90 Γ, HAeHTH$HnHpOBaHO HHMP. ΠΡΜΜΕΡ 19
IIojryneHne 23-(μθτηλοκομμ)- LL- F 28249cL CMecb 23-okco- L L- F 28249c* (0,90 r, 1,5 mmojih), cojih- ηοκηοιιογο MeTOKCHJiaMHHa (0,42 r, 5,0 mmojih), 6θ3βοαηογο aiļeTaTa HaTpnn (0,41 r, 5,0 MMOJien), yKcycHOft khcjioth h AHOKcaHa nepeMe-uiHBaiOT npn 20°-25°C b τθηθηηθ 22 nacoB, o<5pa6aTHBaiOT TOJiyojiOM h BOflon h nepeMeniHBaiOT b τθηθηηθ 5 MHHyr. 3>a3H pa3,n,eJiHK)T, h opra-HnnecKyro $a3y npoMHBaiOT boaoh m KOHi^eHTpnpyioT b BaKyyMe, nojiynan iļejieeoe οοθαηηθηηθ b βη,π,θ TBepnoft πθηη b KOJinneCTBe 0,84 r, hhc-TOTa 71%, no flaHHHM ®XB1H1-aHajiH3a. LV 10503 23
ΦΟΡΜΜ M30EPETEHMH 1. Cnocod nojiyxieHHH 23-(Cj-Cg ajiKHJiOKCHMOB)- LL - F 28249, ο τ ji in a ioh h ii c a τθμ, *ιτο 3amnmai0T rHflpoKcmibHyio rpyn-ny b nojiOHteHHH 5 coeflHHeHHH LL - F 28249 n-HHTpo6eH30HJixjiopn-flOM, nojiyweHHoe οοθ,π,ηηθηηθ 5-0-(n-HHTpo<5eH3OHJi)- LL - F 28249 okhcjīhiot , nojiytian npoH3BOflHoe 5-0-(n-HHTpo6eH3omi)-23-OKCo- L L- F 28249 b KpMCTajuiiraecKOM coctohhhh, nocjie ^ero ocymecT-BJIHIOT B JIIOdOM ΠΟρΗβΚΘ peaKIļHIO C Cj-Cg ajīKOKCHJiaMHHOM HJIH ero cojibio, noJiy^eHHoro npoMe«yToyHoro b npHcyTCTBnn ocHOBaHMH h CHHTHe 3amHTH. 2. Cn0C06 ΠΟΠ.Ι, OTJIHtiaiOIDļHMCH ΤΘΜ, ^TO OKMC-JieHHe npOBOflHT HCFI0JIb3yH OKUCJIAKU^/TO CHCT8My, BbI(5paHHyiO H3 rpyn-πη, cocTOHmeM M3: yKcycHoro aHrHflpwfla m ftMMeTHJicyjib$OKCH,n,a; ABy-okmch MapraHUļa; nHpM,n,nHAHxpoMaTa n yKcycHoro aHTH^pH^a; τρβτ-6yT0KCHaJIK)MMHHfl H 0pT0-6eH30XHH0Ha; ΠΗΤΗΟΚΗΟΗ $oc$opa 1Λ βΗΜΘΤΗΛ-cyjib$OKCH,n;a; ^HiļMKJioreKCHJiKapdoflHHMHfla h flHMeTHJicyjrb<|)OKCima. 3. CnocoO non.2, OTJiH^aronļHMCH τθμ, ^το b Ka-yecTBe OKHCJīnmiefi οηοτθμη Hcnojib3yroT yKcycHbift aHrH^pH,!!, η αημθ-THJICyJIb$OKCHfū1, H OKHCJieHHe ΠρΟΒΟ^ΗΤ B npHCyTCTBHH nnpn1iļHHa H KHCJIOTH. 4. Cnocoč no n.2, OTJin^aiomiiHCH τθμ, ητο b Ka-iiecTBe OKHCJiHromeii οηοτθμη Hcnojib3yiOT ,n,ByoKMCb MapraHua, h okhc-jieHne npoBOflHT b npHcyTCTBHn 3THJiaijeTaTa. 5. Cnocoč non.2, OTotiaioiiļiiilCH τθμ, ^to b Ka-^iecTBe OKHCJiHiomeH οκοτθμη Hcnojib3yiOT nnpHflHHflnxpoMaT m yKcycHbin aH rumpim. 24 6. CnocoČ no n.I, oTJiHtiaiomHiiCfl τθμ, wto npon3-βο,π,ηοθ 5-0-(n-HMTpo6eH3OHJi)-23-oKCO- L L - F 28249Φ otnnuaroT c nOMOIIJbK) nepeKpMCTaJIJIH3ai4HH H3 ΠΟ,Π,ΧΟ,Π,ΗΐηθΓΟ paCTBOpHTeJIH. 7. Cnocoč ΠΟ Π.Ι, OTJĪHtiaiOmHfiCH ΤΘΜ, WTO npOMe-ΤΚγΤΟ^ΗΒΙΗ ηρΟΑΥΚΤ peaKDļHM C Cj-Cg aJlKOKCHJiaMHHOM HJIM ΘΓΟ COJIbK) o^nmaioT nepeKpncTajuin3aiļHeii H3 noflxoflHmero pacTBopuTejiH. LV 10503 25 ΡΕΦΕΡΑΤ
OnHCHBaeTCH cnocod nojiyyeHM coe^HHeHMfi 23-(Cj-Cg ajiKKJi-okcmm)- LL - F 28249 πγτβΜ οκμολθηηη KpncTajumtiecKHX coeflH-hghhh 5-0-n-HHTpo(5eH3OHJi L L - F 28249.

Claims (7)

  1. LV 10503 Izgudrojuma formula 1. Paņēmiens savienojuma LL-F-20249 23-(0,*8ΐΙ<ΙΙοΙ<8ϊηηυ) iegūšanai, kas atšķiras ar to, ka aizsargā savienojuma LL-F-28249 5-hidroksilgrupu ar p-nitrobenzoilhloridu, iegūstot 5-0-(p-nitrobenzoil)-LL-F-28249, kuru oksidē, iegūstot kristālisku 5-0-(p-nitrobenzoil)-23-okso-LL-F-28249, un tālāk jebkurā secībā to apstrādā ar C^lkoksiamīnu vai tā sāli un noņem aizsarggrupu.
  2. 2. Paņēmiens pēc 1. punkta, kas atšķiras ar to, ka oksidēšanu veic ar oksidējošo sistēmu no rindas: etiķskābes anhidrīds un dimetilsulfoksids; mangāna dioksīds; piridīna hromāts un acetanhidrids; terc-butoksialumlnijs un orto-benzohinons; fosfora pentoksīds un dimetilsulfoksids; dicikloheksilkarbodiimīds un dimetilsulfoksids.
  3. 3. Paņēmiens pēc z. punkta, kas atšķiras ar to, ka par oksidējošo sistēmu izmanto acetanhidrīdu un dimetilsulfoksidu, veicot oksidēšanu piridīna un skābes klātbūtnē.
  4. 4. Paņēmiens pēc 2. punkta, kas atšķiras ar to, ka par oksidējošo sistēmu izmanto mangāna dioksīdu, veicot oksidēšanu etilacetāta klātbūtnē..
  5. 5. Paņēmiens pēc 2. punkta, kas atšķiras ar to, ka par oksidējošo sistēmu izmanto piridīna hromētu un acetanhidrīdu.
  6. 6. Paņēmiens pēc 1. punkta, kas atšķiras ar to, ka 5-0-(p-nitrobenzoil)-23-okso-LL-F-28249 attīra pārkristalizējot no piemērota šķīdinātāja.
  7. 7. Paņēmiens pēc 1. punkta, kas atšķiras ar to, ka reakcija ar CMalkoksiamīnu vai tā sāli iegūto starpproduktu attīra pārkristalizējot no piemērota šķīdinātāja.
LVP-93-697A 1989-09-11 1993-06-28 Method for producing of ll-f-28249 23-(c1-c6-alkyloxime) LV10503B (en)

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EP0750907B1 (en) * 1995-06-30 2002-03-20 American Cyanamid Company Stable macrolide and macrolide vaccine compositions
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CN104277050B (zh) * 2013-07-04 2016-05-04 北大方正集团有限公司 一种制备莫西克汀的方法
CN104017001B (zh) * 2014-06-18 2016-01-13 大连九信生物化工科技有限公司 一种化学合成莫西克汀的方法
CN104292239A (zh) * 2014-09-30 2015-01-21 大连九信生物化工科技有限公司 一种消除莫西克汀生产过程中副产物二甲基硫醚的方法
CN104628740B (zh) * 2015-02-13 2017-06-16 河北圣雪大成制药有限责任公司 一种化学合成及纯化莫西克汀的方法
CN104860961B (zh) * 2015-04-10 2017-08-04 新宇药业股份有限公司 一种制备5‑氧(对‑硝基苯甲酰)‑尼莫克汀的方法
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