LV10090B - Nitrogen and sulphur containing heterocyclic compounds, method of preparation thereof, pharmaceutical composition and method of preparation thereof - Google Patents
Nitrogen and sulphur containing heterocyclic compounds, method of preparation thereof, pharmaceutical composition and method of preparation thereof Download PDFInfo
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- LV10090B LV10090B LVP-92-685A LV920685A LV10090B LV 10090 B LV10090 B LV 10090B LV 920685 A LV920685 A LV 920685A LV 10090 B LV10090 B LV 10090B
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- propan
- thiazolidinyl
- μπμ
- phenyl
- alkyl
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/04—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/04—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D277/06—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
- C07D279/04—1,3-Thiazines; Hydrogenated 1,3-thiazines
- C07D279/06—1,3-Thiazines; Hydrogenated 1,3-thiazines not condensed with other rings
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- Chemical & Material Sciences (AREA)
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- Engineering & Computer Science (AREA)
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- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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- Animal Behavior & Ethology (AREA)
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- Urology & Nephrology (AREA)
- Hospice & Palliative Care (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Psychiatry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Adhesives Or Adhesive Processes (AREA)
- Thiazole And Isothizaole Compounds (AREA)
Description
LV 10090
CnOCOB ΠΟΓΙΥΗΕΗΜΑ A30T- M CEPO-COJļEP>KAlUMX ΓΕΤΕΡΟΜΜΚΠΜΗΕΟΚΜΧ COEflMHEHMI/ί, CAMM COEflMHEHMfl, ΦΑΡΜΑΜΕΒΤΜΗΕΟΚΜΙλ COCTAB, M CnOCOB ΕΓΟ ΠΟ/ΊΥΗΕΗΜΑ, CnOCOB J1EHEHMR.
OnncaHue R6 I Ar-R-CH—(CH2)-
Μ3θ6ρβτβΗΜβ OTHOCMTca κ HOBbiM a30T- m cepocopep>KamMM reTepoLļMKnuHecKMM οοθαμηθημλμ φορΜγπΜ (1) (1) 2 ripu ycnoBnn, Ητο R^ o6o3HaHaeT Βορορορ, Korpa m paBHO 0, TaioKe KaK m mx cormM npucoeflMHeHna kmchotu m k (papMaueBTMHecKMM cociaBaM, copepxamnM stm οοθρμηθημπ. KpoMe τογο, μ3ο6ρθτθημθ othocmtch κ cnoco6y nonyHeHMH θτμχ οοθρμηθημμ. Οοθημηθημα (popMynbi (1) comacHO paHHOMy Μ3θ6ρβτβΗΜΐο βΜοποηΐΗβοκΜ aKTMBHbi - ohm oSnaparoT 3HaHmenbHbiM πθμοτβμθμ προτμβ γμποκομμ M03ra. B οοθπμηθημηχ $opMynbi (1) "apMnbHbiM” 3aMecTmenb 03HaHaeT 0eHnnbHyio rpynny, bo3moxho 3aKoribuoBaHHy»o c npyrnM apoMaTMnecKMM KonbuoM; npepnoMTmenbHO $eHnnbHyK3, HaφτMΠbHyκ> μπμ $BHaHTpeHnnbHyK>I 6onee npepnoHTmenbHO $eHnnbHyio rpynny.
TeTepoapunbHafl” rpynna 03HaHaeT 5-tm HneHHyio reTepoumaiMHecKyK) rpynny, copep>KamyK3 cepy μπμ Kucnopop b KanecTBe reTepoaTOMa, npeflnoHTmenbHbiM npepcTaBUTeneM κοτοροτο πβππθτοπ TMeHMnbHan rpynna.
ApMnbHaa m reTepoapunbHaa rpynnw MoryT 6biTb moho- μπμ ποπμ-3aMemeHHbiMM aTOMOM ranoreHa, C-j.g anKMnbHoii, C-ļ _q anKOKCMnbHoii, ΗΜτρο, φβΗΜΠ (C-j_4 anKOKCM), Cļ.0 3πκμπτμο, C-ļ.g aπκMπcyπbφMHMΠbHOMf ranc^eHMnbHoii, Φθημπβηομ μπμ nnnepnflMHo-rpynnoM.
AnKMnbHbie rpynnbi b hmctom βμρθ μπμ KaK MacTb ppymx rpynn BKniOHaHDT HacbiuļeHHbie rpynnbi c πρπΜοίί μπμ ρ33βθτβπθηηομ uenbīo, κοτορ^β b 3aBMCMM0CTM ot οπρΘβΘΠΘΗΗΟΓΟ HMcna aTOMOB yrnepofla, MoryT npepcTaBnHTb co6om, HanpuMep, MeTunbHbie, θτμποβμθ, η- μπμ M3onponnnoBbie, η-, Βτορ- μπμ TpeT-6yTnnoBbie, TaioKe KaK m h- μπμ μ30πθητμποβμθ μπμ η- μπμ M3oreKCnnbHbie rpynnw. B 3Η3ΜΘΗΜΜ R1 (C2-6 βΠΚΘΗΜΠ) Kap60HMnbHafl HaCTb npepnOMTMTenbHO o6o3HaMaeT 3TMneHKap6oHMnbHyio rpynny.
TanoreH” o6o3HanaeT φτορ, χηορ, 6poM μπμ moa b KanecTBe 3aMecTMTena. B 3HaHeHMM R^ φβΗΜΠ (C-ļ.4 anKMn) npepnoHTMTenbHo o6o3HaHaeT 6eH3MnbHyK3 rpynny. B 3aBMCMMOCTM OT 3Η3ΗβΗΜΠ ΠΓ1, ΟΟβρΜΗΘΗΜΠ φopMyΠbl (1) ΜΟίγΓ paccMaTpMBaTbcn KaK α- μπμ β-aMMHOKeTOHbi, y κοτορ^χ aTOM a30Ta λβπηθτοη
ΟΡΗΟΒρΘΜΘΗΗΟ ΗΠΘΗΟΜ ΓΘΤβρΟΜΜΚΠΜΗΘΟΚΟΓΟ KOnblļa, ΟΟβθρΧΟΙΜΘΓΟ Μ aTOM cepbi. β-aMMHOKeTOHbl (MHbIMM 0Π0Β3ΜΜ ΚΘΤΟΗΜ MaHHMXa) XOpOUUO M3BeCTHbl. Μχ χμμμηθοκμθ CBOMCTBa o63opHo πρμβθρθηη, cpepM nponero b F.F.Blicke: Organic Reactions, Vol.1, page 303-341; J.Wiley, New-York, London (1942); B.Rarchert: Die Mannich-Reaction, Springer Vepiag, Berlin, Gottingen-Heideiberg (1959); 3 LV 10090
TaioKe KaK m H.Hell and G.Opitz: a-aMMHoanKumīpoBaHne Veriag Chemie, VVernheim/Bergstr. (1960).
Tnnbi οοθρμηθημμ, onncaHHbie po HacTOflipero βρθμθημ b 3ToiS o6nacTM, oweHb pa3nnHHbi, m HMcno cneMnanbHo onncaHHbix BemecTB oneHb βθπμκο. C TepaneBTMHeKCKoii tohkm 3peHna, 6onee 3HaMaipnMn β-κθτοΗ3Μΐι ηβπηιοτοα, HanpMMep, nponnnoKanHrnflpoxnopnfl/3 (1 -nnnepnpMHiin)-1 -(4-προποκοΜφθΗΜπ)-1 -nponaHOH/, npepcTaBnBramnii οοδοίί aHecTe3npyioinee βθιρθοτβο μθοτηογο neiicTBMB, onncaHHoe b onncaHnn κ naTeHTaM flfl NN 9330 m 8565; T0nbnepM30HrMflp0Xn0pMfl, /2 -ΜΘΤΜΠ-1 -(4-ΜΘΤΜΠφθΗΜΠ)-3-(1 -ΠΜΠθρΜρΜΗΜΠ)-1 -nponaHOH/, npepcTaBnaroiMHH οοδοίί cocypopacuinpaiomee h paccna6naioiiiee MycKynbHoe cpepcTBO ueHTpanbHoro peiiCTBMfl, oniicaHHoe b onticaHMii κ BeHrepcKOMy naieHTy N 144997; οκοΜφβρρΜΗΓκρροχπορΜρ/R(R*, S*)-3-(2-okcm-1 -ΜΘΤΜη-2-φθΗΜΠ3ΤΜΠ)-3ΜΜΗΟ-1-(3-ΜΘΤΟΚΟΜφθΗΙ1π)-1-nponaHOH/, OnMCaHHblii B oniicaHMM κ naieHTy ΦΡΓ N 439574; TaioKe KaK m oc-pepenTop, 6noKMpyiomHii 6-/3-(3-φθΗΜΠΠΜρρθΠΜΡΜΗΜ/ΐ) Πρ0ΠΜ0ΗΜΠ/-6θΗ30ΡΜ0Κ03Η, OnMCaHHblii B ony6nnKOBaHHoii 3aflBKe Ha naieHT ΦΡΓ N 2252344. M.Celadnik, K.Palat, A.Sehare and Vrba / Arch. Pharm. 291,3 (1958) / onncbiBaiOT pea β-aMMHOKeTOHa, 3aMeipeHHbie μορΦοπμημπβηοη rpynnoii; ynoMMHaeTCH μθοτημμ aHecTe3MpyiomMii Θφφβκτ.
CpepM α-aMHHOKeTOHOB, cTpyKTypHo οτηοοαιμμχοα κ οοθπμηθημαμ φορι^πΒΐ (1), ροπχΘΗ 6biTb ynoMaHyT ranonepMpon /4-/4-(4-χπορφβΗΜπ)-4-οκοΜ-1-nnnepnflMHMn/-1 -(4-φτορφΘΗΜπ)-1 -6yTaHOH/, npepcTaBnaiomMM οοδοίί HeiiponenTMHecKoe neKapcTBeHHoe cpepcTBO, y κοτοροΓΟ μ3βθοτηο čonbmoe HHcno CTpyKTypHbix aHanoroB. Πμτθηορμπ /2-/4/(3-τθηομππροπμπ)-1 -nnnepa3MHnn/9Tnn-flHMeTnnKap6aMaT/, npepcTaBnaiomMM οοδοίί προτκΒΟ-rnnepTOHMHecKoe cpepcTBO, othocmtcb TaioKe κ 3T0My Knaccy οοθρμηθημμ. MeiapoH (6-ρμμθτμπ-3Μμηο-4,4-ρμΦθημπ-3-γθπτ3ΗΟη), npepcTaBnfliomMii οοδοίί γ-aMMHOKeTOH aHanbre3npyiomero peficTBMfl, onnoaH b onncaHMM κ naTeHTaM ΦΡΓ NN 865314 M 870700.
Korpa n paBeH 1, οοθρμηθημη φopMyπbι (1) npepcTaB/inioT οοδοίί . np0H3B0PHbie TMa30ilMpMHa. Ι43ΒΘΟΤΗΟ TOnbKO COBCeM Mano φ3ρΜ3ρθΒΤΜΗΘΟΚΜ aKTHBHbix nponBopHbix TMa3omipMHa, b KanecTBe npMMepa mojkho ynoMAHyTb HMTpOpaH /3-ΜβΤΜΠ5-(4-ΗΜΤρθφΘΗΜΠ33θ)-2-ΤΜΟΚΟΟ-4-ΤΜ330ΠΜΡΜΗΟΗ/, npepcTaBnaioiuMii οοδοίί προτμβογπμοτηοθ neKapcTBeHHoe cpepCTBO.
Korpa n paBHo 2, οοθρμηθημη φopMyπbι (1) npepcTaBnaiOT οοδοίί npon3BopHbie TeTparwppo-1,3-Tna3HHa. \Λζ cTpyiaypHO nopo6Hbix οοθρμηθημμ, Kcnna3aH, copep>KainMii 5,6-pnrvippo-4H-1,3-Tna3MHOBy»o CTpyicrypy, ho 4 OTHOcmciļ κ Knaccy βΜΜΗΟκβτοΗΟΒ. Kcnna3WH ΗΒΠΒβτοπ xnpyprnMecKWM aHa/ibreTMKOM, ncnonb3yeMbiM b BeTepnHapHoii μθαμμμηθ.
HanpoTne, 6bino o6HapyxeHo, ητο οοθαμηθημβ $opMynw (1) b κοτοροίί Ar, R1, R2, r3, r4 R5( R6 M m flBHfllOTCfl TaKMMM )ΚΘ, HTO M npMBeaeHHbie flTIfl <ļ)opMynbi (1), oSnapaiOT 3HaMMTenbHoii aKTMBHocTbio προτνίΒ runoKCMH M03ra. AKTMBHocTb προτΜΒ runoKcuM 6bina nccneflOBaHa Ha Haxoflamnxca b C03HaHMM Mbmiax B ycnOBMBX ynopBflOHeHHOti rUDOKCMM. n«Tb CBMLļOB Mbimeii noMemann, κβοκαογο b οτθκπηηημμ μμπμηαρ o6tēMOM 3 n, nepe3 KOTopbin nponycKann ra30Byio CMecb, coaep>KamyK> 98 % a30Ta n 4% Kucnopoaa. HHTepBan, Πρ0Χ0Β?Μ1ΜΜ ΟΤ nOMemeHMB )KMBOTHblX flO npeKpameHMB MX pecnupaTopHoro ρβμχθημα, perncTpnpoBann xax BpeMfl BbDKnBaHMfl. >Κμβοτηβιθ, BbDKUBatomne b τθηθημθ ΒρβΜβΗΜ, npeBbiiuaioiitero b flBa pa3a BpeMH KOHTpOJlbHOM rpynnbl, paCCMaTpMBa/lMCb KaK 3amnmeHHbie. fleCBTb >KMBOTHblX B OTflenbHOCTM ΒΒΟΠΙ4ΠΜ MHTpanepMTOHeaJlbHO (Μ.Π.) fl03y B 50 μγ/κγ Beca Teņa (Hnace coKpameHHo: μγ/κγ) stmx βθιμθοτβ 3a 30 MMHyT no pa3MemeHna B CTe«aaHHbix unnnHApax. CpeaHee BpeMa BbDKMBaHua, npoaeHT yBennHeHMa βρθμθημ BbDKMBaHua no cpaBHeHnio co βρθμθηθμ BbixnBaHna KOHTponbHofi rpynnbi n npoLtem 3ammneHHbix χμβοτημχ noKa3aHbi b Ta6n.1.
Ta6nnqa 1.
BeiaecTBO H3 npnMepa Bpeivm BbDKUBaBHna, 3amnTa N mmh % % KOHTpOflbHblii 3Κ3βΜΠΠΛρ 6.32 100 . 0 1 9.35 148 30 8 8.27 131 20 34 12.76 202 70 17 11.00 174 60 10 18 10.58 167 50 19 7.90 125 20 22 9.27 147 30 49 9.72 154 30 KomponbHblM 3Κ3βΜΠΠηρ 5.78 100 0 15 12 10.28 178 40 35a 10.75 186 60 5 LV 10090 ΠροροπχβΗΜθ TaOmmbi 1.
BemecTBo M3 npMMepa N BpeMft BbDKMBaBHMB, MMH % 3aipMTa % 20 7.85 136 20 30 8.40 145 40 37 12.22 211 60 20 38 9.95 172 30 39 10.43 180 40 41 8.91 154 20 KOHTponbHbIM 3Κ3ΘΜΠΠΛΡ 3.05 100 0 25 27 5.32 174 20 70 5.78 189 60 M3flaHHbixTa6n.1 οηθβμρηο, ητο βοθ οοθρμηθημβ, npuroTOBneHHbie COrnaCHO pa3nHHHblM npMMepaM, 06naaaiOT aKTMBHOCTbK) ΠρΟΤΜΒ ΓΜΠΟΚΟΜΜ, , npOBB/lfllOLiļeMCfl B yflJ1MHeHMH BpeMeHH BbDKMBaHMfl. Θφφθκτ προτΜΒ γμποκομμ οοθρμηθημμ comacHo paHHOMy Μ3ο6ρθτθημη3 6bin A0Ka3aH TaioKe b pe3ynbTaTe Mcnonb30BaHMB μθτοροβ 8οΦμκομ3πβηομ aHOKcmi m runoOapMMecKoii γμποκομμ. 3tm MccnepoBaHMH 6binn npoeepeHbi nyieM opanbHoro ββθρθημα, ητο TaioKe πορτβθρρμπο opanbHyK) 3φφθκτΜΒΗοση>, mto penaei B03M0>KHbiM Mcnonb30BaHMB aKTMBHbix οοθρμηθημμ comacHo paHHOMy M3o6peTeHMto b φορΜθ Ta6neTOK.
Mcnonb30BaHHbie μθτορμ onucaHbi ημχθ.
McnbīTaHua Ha acφMκcMaπbHyιo aHOKcmo /C.Cailapd et. al.:Life Sci. 16,1607 (1975)/.
MbiuiM, copepxamMeca b ronope b τθηθημθ 16 nacoB, nonyHann opanbHO ΟΟΘρΜΗΘΗΜΘ COrnaCHO paHHOMy Μ3θ6ρθΤβΗΜΚ>, M CnyCT3 OflMH Hac MX noMemanu b χοροιιιο 3axpbiTbie οτθκπβηηηθ 6yTbinn oātēMOM 100 μπ. MHTepBan βρθμθημ, προχορπιρΜίί ot 3axpbiTna 6yTbinn perucipupoBa/ni xax BpeMa BbDKMBaHMa KOHTponbHOM rpynnbi, paccMaTpnBa^ncb xax 3amMmeHHbie.
McnbīTaHMe rnno6apnHecKOM γμποκομμ /J.Baumel et. al.: Proc. Soc. Exptl. Biol. N Y. 132, 629 (1969)/.
MbtiuM, copepacauļMecfl b ronope β τθηθημθ 16 nacoB, nonynanM opanbHO 6 οοθομηθημθ comacHO naHHOMy μ3ο6ρθτθημιο, m mx noMemanM b aKCMKaTop sepe3 nāc nocne ββθπθημλ οοθημηθημα. flaeneHMe b SKcuKaTope οημχοπμ no 170 mm ρτ. ct. b τβπθΗΜβ 20 ceicyHn, m c stoto MOMeHTa perMCTpMpOBanM BpeMfl Bbl>KMBaHH3 flO npeKpameHUa ΑΒΜΧΘΗΜΒ AblxaHMfl. >KMBOTHbie, BbDKMBUlMe B τθΗΘΗΜβ flByxKpaTHoii cpenHeii nnMTenbHOCTM βμ>κμβ3ημη KOHTponbHOM rpynnbi, paccMaTpuBa/incb xax 3amMmeHHbie. B cnynae o6omx cnocoSoB 3Η8μθημβ Bflso, to ecTb no3bi, 3aiuMmaioiueM nonoBMHy noflBeprHyTbix o6pa6oTKe >κμβοτημχ ot γμποκομμ, 6binn BbiHMcneHbi c ncnonb30BaHneM npo6m aHann3a.
Pe3ynbTaibi McenenoBaHMii 3φφβκτο προτΜΒ γμποκομμ nocne opanbHoro ββθαθημβ CBeneHbi b Ta6n.2.
Ta6nnqa 2.
BemecTBo nnn npMMepa N 3Ū50· ΜΓ^ΚΓ. opanbHO ΑθφΜΚΟΜ3^Η3Η Γ MnočapMMecKan aHOKCMB ΓΜΠΟΚΟΜΗ 35a 18,3 58,7 17 55,0 60,0 flaHHbie M3 Ta6n.2 noKa3biBaK)T οοθαμηθημα cornacHo μ3ο6ρθτθημιο, KOTopbie očnanaiOT θΦΦθκτμβηοοτβιο m npn opanbHOM ββθαθημμ. Κβοκβτοη, hto oco6o npennoHTMTenbHbiM nenneTcn 3aMemeHne 4-φτορφβΗΜΠ8. fleilCTBMe προτΜΒ ΓΜΠΟΚΟΜΜ 3ΤΜΧ ΟΟΘΑΜΗΘΗΜΜ Τ3ΙΟΚΘ ΜΟ)ΚΘΤ 6blTb Mcnonb30BaHo b TepanMM ηπη πθηθημη ποβρθχαθημμ M03ra οτ γμποκομμ, μμθκμαμχ pa3nMHHoe προΜοχοχφβΗΜβ, τ3κμχ κβκ CTapnecKoe cna6oyMMe, 6one3Hb AnbLireūMepa, γμποκομμ, cnenyioinan 3a aTepocKnepo30M, cna6oyMMe OT MHOrOKpaTHblX ΜΗφβρΚΤΟΒ M HapyweHMfl n03HaBaTenbH0M φyHK^MM. BenMHMHbi TepaneBTMMecKoii qo3bi cocTaBnniOT ot 0,1 no 40 μγ/κγ.
ToKCMHHOcTb aKTMBHoro οοθαμηθημη M3 rīpMMepa 35a comacHO naHHOMy Μ3θδρβτθΗΜΐο 6bina onpeneneHa Ha Mbiinax. 3flso aKTMBHoro οοθπμηθημλ 0Ka3anacb paBHOM 646 μγ/κγ opanbHO m 108 μγ/κγ BHyTpMBeHHO.
CornacHo npyroMy acneiay naHHoro μ3ο6ρθτθημβ npenycMOTpeH cnoco6 nonyMeHMM οοθαμηθημμ φopMyπbl (1) m mx coneii npMcoenMHeHMn κμοποτμ, KOTopbiii BKmonaeT a) ββθαθημθ b peaKUMio κθτοη3 φopMyπbι (4) (4) 7 LV 10090
Ar—R1—CH—(CH2)m—X 12
Ar, R1, R2, m m μμθιοτ BbiuieyKa3aHHbie θηθηθημπ, a X o6o3HaHaeT aTOM ranoreHa, c γθτθρομμκπμηθοκμμ οοθαμηθημθμ φορΜγπω (3)
/ \ H-Ņ S I I
(3) copepjKainMM cepy m a30T, b κοτοροίί R3, R4, r5( r6( m n μμθιοτ Bbirne-yKa3aHHbie θηθηθημπ, m npM Heo6xoflMMOCTM, npeBpameHMe nonyHeHHoro οοθαμηθημη $opMynbi (1) b ero conb πρμοοθαμηθημπ KMcnoTbi; μπμ
6) ΒΒΘΗΘΗΜΡ R nAaifiiM ifpJOHa 0OpMynbl (2) (2) B κοτοροίί
Ar, R1, R2 μμθιοτ BbiuieyKa3aHHbie 3ηθηθημπ, c coribto γθτθροαμκπμηθοκογο οοθαμηθημα $opMynbi (3), coflep)KamMM cepy m a30T, β κοτοροίί R3, R4, R3 R6f μ η μμθιοτ Bbiuje-yKa3aHHbie 3HaHeHM5i, m c cfiopManbAerMnoM μπμ mctomhmkom $opManbflerMfla απβ nonyHeHMn οοθαμηθημμ φopMyπbι (1), β κοτοροίί Ar, R“1, R2, R3, R4, R3, r6, m η μμθιοτ BbiujeyKa3aHHbie θηθηθημπ, a m paBHo 1.
ComacHO npeanoHTMTenbHOMy BapMaHTy npoLjecca a) comacHo naHHOMy Μ3θ6ρθΤΘΗΜΚ), OCHOBHafl φθρΜ3 ΓΘΤθρ0ί1ΜΚΠΜΗΘ0Κ0Γ0 ΟΟΘΑΜΗΘΗΜΗ φopMyΠbl (3) BBOflMTcn β peaKUMio c aTOMOM ranoreHa, npoM3BOflHbiM φopMyπbι (4), b nonnpHOM pacTBopMTene, TaKOM KaK aLieTOH, STaHon μπμ 3μθτοημτρμπ, β npMCyTCTBMM CBn3blBaiOUļMX ΚΜΟΠΟΤγ BemeCTBa, κοτοροθ CnOCOāHO CBH3blBaTb KMcnoTy HX, o6pa3yioiuyiocfl β xope peaKLļMM. Ημ31ιιμθ TpeTMMHbie aMMHbi, ΠρθΑΠΟΗΤΜΤΘΠΒΗΟ ΤρΜ3ΤΜΠ3ΜΜΗ ΜΠΜ 1-ΜΘΤΜΠΠΜΠθρΜΑΜΗ, ΜΠΜ ΟΟΠΜ KMCHOT, KOTopbie cna6ee ΗΧ, ποαχοαπιμμθ οοπμ οργβημμθοκμχ κμοποτ, npeAnoHTMTenbHO aqeTaT HaTpMn, πρθαοτθβππιοτ οοβοίί none3Hbie CBfl3biBaioiuMe ΚΜοηοτγ BemecTBa. ΠρΜ Mcnonb30BaHMM οοθαμηθημμ φopMyπbl (4), β κοτορ^χ paBHo 0, Menecoo6pa3HO oxnaAMTb peaKMMOHHyio CMecb. Οοθαμηθημπ φopMyπbι (1), nonyneHHbie β φορΜθ οβο6οαηογο οοηοβ3ημπ, Moryr 6biTb npeBpaineHbi, npM ηθοΟχοαμμοοτμ, β μχ οοπμ. βΠΠ 06pa30BaHMn ΟΟΠθίί HaM6onee ΓίρΜΘΜΠΘΜΜΜΜ ΠΒΠΠΙΟΤΟΠ φ3ρΜ3- 8 ueBTvmecKM npneMneMbie MUHepanbHbie kmcjiotu, TaKne KaK xnopMcim-BOflopoflHa« KMcnoTa, 6poMMCTOBOAOpOAHan, cepHaa KiīcnoTa, nna οοθαμηθημμ KaK φορΜγπΜ (1), TaK m (3). B cnynaax οοθαμηθημμ φορΜγπΜ (1) μοχηο ncnonb30BaTb $apMaueBTHHecKM πρμθμπθμμθ oprammecKMe Kucnoibi, npeflnoHTMTenbHo MeTaHcynb$oHKncnoia, $yMapoBaa KucnoTa m TOMy ποποβΗοβ, rnaBHbiM o6pa30M pna o6pa30BaHMfl coneii απη ποβμιιιθημη BOflOpaCTBOpMMOCTM flaHHOro ΟΟΘΑΜΗΘΗΜΗ.
Cbipoii προηγκτ ΜΟΧΘΤ 6blTb ΟΗΜίαβΗ ΠΘρΘΚρΜ0Τ3ΠΠΜ3314ΜΘΜ.
ComacHO npepnoHTMTenbHOMy BapnaHTy npouecca a) cornacHO naHHOMy Μ3θβρΘΤθΗΜΚ), apoMaTMHecKMii κθτοη cf>opMynbi (2) noflBepraioT ρθθκμμμ KOHfleHcaunM c napa$opManbnernnoM m conbK) γθτθροαμκπμηθοκογο οοθαμηθημη $opMynbi (3) npn pa3orpeBe β nonapHOM pacTBOpmene. SiaHon nnn 2-nponaHon MoryT 6biTb nonxHbiM o6pa30M ncnonb30BaHbi b KanecTBe pacTBopHTeneii b stom peaKUMM. Uenecoo6pa3HO ncnonb3oaTb napa-Φορμθγ^αθγμα b M36biTKe, oSbiMHO b o6tēMe 2.5 Monn (pacnēT no κθτοηυ), m po6aBnaTb ero AByMH ποραμαμμ κ peaKUMOHHoii ομθομ. flenonnMepM3auna πβρΘφορΜΘ^ΑΘΓΜΑΘ μο>κθτ 6biTb KaTanM3MpoBaHa kmchotom, uenecoo6pa3HO κμοποτομ, ncnonb3yeMOM pna o6pa30BaHna conu γθτθροαμιοιμηθοκογό οοθαμηθημη φορΜγπΗ (3). Βμθοτο πβρβφορΜΘ/^ΑΘΓΜΑβ TaioKe mo>kho McnonbsoBaTb Φορμθγ^αθγμα, uenecoo6pa3HO β βμαθ βοαηηογο pacTBOpa. B otom cnyMae peaKUMto npoBonaT b npncyTCTBMM CMeuiMBaiomeroca c boaom opraHnnecKoro οοθαμηθημμ, npep-noHTMTenbHO 3TaHona μπμ MeiaHona, c penbīo ο6θοπθηθημμ γομογθηηοοτμ peaKLinoHHoii cpeflbi. Βμθοτο π3ρ3φορΜ3/^ηθπιη3 τθιοκθ Moiyr MCn0nb30BaTbCa ΟΟΘΑΜΗΘΗΜΜ, ΤρΘΗΟφΟρΜΜργβΜΗΘ Β ΧΟ/1Θ peaKLļMM B φθρΜ3^ΗΘΓΜΑ Μ Β ΑΡΥΓΟΘ ΟΟΘΑΜΗΘΗΜΘ, ΗΘ ΒΠΜΜΚ)111ΘΘ Η3 ΑΘΠΘΒγίΟ ρΘΘΚΑΜΙΟ. 3τομυ Tpe6oBaHmo υαοβπθτβορβιοτ aueTann Φορμθγ^αθγμαθ, o6pa3yeMbie c HM3L1JMMM 3ΠΜφ3ΤΜΗΘ0ΚΜΜΜ ΟΠΜρΤΘΜΜ, ΠρΘΑΠΟΗΤΜΤΘΓ^ΗΟ C ΑΜΜΘΤΟΚΟΜ- Μ
AnaTOKCMMeTaHOM. Uenecoo6pa3HO TaioKe BBOAMTb aueTami β βμαθ AByx nopunii b peaKumo. npOAonx<eHne peaKunu mowho OTcneacMBaTb c ncnonb30BaHneM tohko-οπομηομ χροΜΘτοτρβφΜΜ (Tl C), KOTopaa TaioKe πο3βοπμθτ onpepe/iMTb onTHMJibHoe βρθμμ peaKLļMM. B 6onbuiMHCTBe cnyHaeB οοθαμηθημθ φopMyπbι (1) ocaoKAaeTca b pe3ynbiaie oxnax<AeHMM nocne 3aBepiueHMH peaKLļMM. Μημμ o6pa30M uenecoo6pa3HO ycKOpMTb KpncTannM3aumo nyreM αο68βπθημμ pacTBopmena (HanpMMep, aueTOHa), κοτορωΐί μοχθτ cMeiiiMBaTbCM c pacTBOpnTeneM, πρμμθημθμμμ β χοαθ peaKLļMM. KorAa μθπθβομ προΑγκτ no 9 LV 10090 φορΜγπΘ (1) c τργοοΜ nopBepraeTca KpncTannH3aunH, ocHOBaHue BbiCBo6o>KflaeTca Η3 ceoen conn b pe3ynbTaTe flo6aBneHna KapOoHaia menoHHoro Meianna, HanpnMep, KapSoHaia Kanna, b βοαηομ cpepe, Torpa ocHOBaHne BbiflenatOT b anonapHbin pacTBopmenb n nocne o6bNHon onepaunn OTfleneHna ero npeBpamaiOT b xenaeMyK5 conb.
nepeKpncTannn3auna Cbiporo BemecTBa φορΜγπ^ (1) ocymecTBnaeTca o6bNHbiM o6pa30M. Lļenecoo6pa3HO ncnonb30BaTb oahh MeTaHon nnn CMecb MeTaHon/aTaHon ona 3Τθίί uenn, TaK KaK cbipoii προηγκτ φορΜγπω (1) μο>κθτ 6biTb OMnmeH Η3 conpoBOttnaroinen conn ΓβτβρορηκηηΗβοκοΓΟ οοθαηηθηηη φορΜγπΜ (3) stum ηγτΘΜ. Κοηθμηο, μογ/γ 6biTb ncnonb30BaHbi npyrne nonapHbie pacTBopnTenn, TaKne KaK aueTOH n aqeTOHHTpnn. OflHopoflHocTb κοηθηηογο nponyicra μοχθτ TaiOKe KOHTponnpoBaTbca c ncnonb30BaHneM ΤΟΗΚΟΟΠΟηΗΟη Χρ0Μ3Τ0Γρ3φΜΜ.
McxoflHbie BemecTBa o6uļnx φορΜγη (2), (3) n (4) b o6meM n3BecTHbi n MoryT 6biTb nonyneHbi cnoco6aMn, ο6μηηο ncnonb3yeMbiMn pna cnmre3a coennHeHnn 3Toro Tnna.
CoennHeHnn cornacHO naHHOMy ιΐ3θ6ρβτθΗΐιιο Moryr 6biTb npBpameHbi b φ3ρΜ311ΘΒΤηΜβΟΚΜβ COCTaBbl M3BeCTHb1M 06pa30M. <DapMaueBTMHeCKHe COCTaBbl MoryT 6bm> BBeneHbi opanbHbiM, peicranbHbiM n/nnn napoHTepanbHbiM πγτβΜ. Jļnn opanbHoro BBepeHnn cociaB μοχθτ 6biTb npnroTOBneH, HanpnMep, b Bnpe Ta6neTKn, nnnionb nnn Kancyn. C uenbīo npnroTOBneHnn cocīaBOB nnn opanbHoro npnMeHeHna b KanecTBe Ηοοητβπβη mo)kho ncnonb30BaTb naKT03y nnn KpaxMan. B KasecTee CBa3biBaiomnx nnn rpaHynoo6pa3yiomnx BemecTB npnropHbi xenaTHH, HaTpnnKap6oKcnMeTnnuennK)no3a, MeTnnuenntonoaa, ποπηβηηηπ-nnpponnpoH nnn ηβκοτρηΗ. B KanecTBe pa3pytuaK)imnx cpencre Moryr flo6aenaTbca maBHbiM o6pa30M, KapK^enbHbin KpaxMan nnn Μηκρο-KpncTannnMecKaa uenniono3a, χοτη TaiOKe MoryT ncnonb30Baibca ynbTpa-aMnnoneianH nnn φορΜβηΒηβΓηη-^βηΗ n TOMy nonoČHoe. ΠοπχοηηιιίηΜΗ aHTnaflre3nBaMn n cpepcTBaMn o6ecneHeHnn npocKanb3biBaHna aBnaiOTca TanbK, KonnonflHaa KpeMHēBan Kncnoia, CTeapnH, cieapaT Kanbnnn nnn Mamna n TOMy ποπο6ηοθ. >Knnxne cociaBbi jqna opanbHoro BBeneHnn cornacHO paHHOMy η3θβρβτθΗηκ) MoryT 6biTb npnroToeneHbi b Bnpe, HanpnMep, cycneH3nn, cnpona nnn aneKcnpa, KOTopbie MoryT copepxaTb Bopy, Γπηκοπη, Macna.cnnpTbi, TaiOKe KaK n Kpacaipne n BKycoBbie eeiuecTBa-poGaBKn.
Ta6nencn MoryT 6biTb npnroToeneHbi, HanpnMep, npeccoBaHneM nocne rpaHynnpoBaHHH mokpum cnocoāoM. CMecb aKmBHoro κομποηθητβ c HoenTenaMn n, bo3moxcho, c nacTb» pa3pyuiaioinen poOaBKn nopBepraeTca 10 rpaHynnpOBaHMK) C BOflHbIM, CriMpTOBblM Μ/1Μ BOflHO-enMpTOBbIM paCTBOpOM CBB3yiouiMx BemecTB b noflXOflfliueM nna θτογο o6opynoBaHMM, 3aieM rpaHynaT cyiuaT. Ilocne aioro, cnepoM 3a ομθιιιμβ3ημθμ ocianbHbix pa3pymaioinMx flo6aBOK, cpepcTBa ο6θοπθηθημβ npocKanb3biBaHMa m apre3MB0B c BbicyuieHHbiM rpaHynaTOM, CMecb npeccyiOT b Ta6neTKn. ripu *enaHMM, TaOneTKM MoryT M3roTOBnBTbca c κθηθβκομ βΠΒ οβπβΓΜθΗΜΒ npMŠMa. TaOneTKM τβιοκΘ Moiyr rOTOBMTbCB HenOCpeflCTBeHHO M3 CMeCM, COflepttameii aKTMBHbIM ΚΟΜΠΟΗΘΗΤ M C00TBeTCTByK)mne poOaBKM. TačneTKM MoryT 6biTb, npn acenaHMM, npeepaiueHbi b flpax<e nyTeM Mcnonb30BaHMB oSbiHHO πρΜΜβΗΒβΜΜΧ $apMaueBTMMecKnx no6aBOK, HanpMMep, 3amnTHbix, BKycoBbix m Kpacamnx BemecTB, τοκμχ KaK caxap, npon3BOflHbie i4enmono3bi (μθτμπ- μπμ 3TMfmenniono3a, HaTpMifaapāOKCM-Meinnuenniono3a m TOMy ποπο6ηοθ), ποπμβμημππμρροπμποη, φοοφβτ KanbUMB, Kap6oHaT Ka/ibUMH, πμιμθβμχ Kpacmeneii, KpacaiHMx naKOB, apoMaiM3npyioiiiMX cpepcTB, πμγμθητοβ M3 CMecM xene3a m TOMy ποροβΗοβ. 3aicniOHaeMbie B Kancynbi cocTaebi γοτοββτ nyTeM 3aKniOMeHMa b Kancynbi CMecM aKTMBHoro KOMnoHeHTa c noOaBKaMM. flna peiaa/ibHoro πρμμθηθημβ cociaB comacHO ΜβοβρβτβΗΜίο γοτοββτ b b upe cynno3mopneB, copep>KaiHMX Maccy Hocmena, Tax Ha3biBaeMbiii "adepspro suppositorio ” (npMropHbiM απβ cynno3MTopnB), b po6aBneHMe κ aKTMBHOMy KOMnoHeHTy. B KanecTBe HOCMTeneii ncnonb3yioT pacTMTenbHbie )KMpbi, TaKMe xax OTBep>KfleHHbie pacTMTenbHbie Macna, μπμ TpnrnnuepMflbi >KMpHbix kmcjiot c Ci 2-C-j 8 (npeflnommenbHO ηοομτθπμ, Hocamne TOBapHbiM 3Hax Witepsol). Ακτμβημμ κομποηθητ paBHOMepHO pacnpepeneH b Macce pacnnaBneHHoro HOCHTena, 3aTeM cynno3HTopnn γοτοβητ npeccoeaHMeM b φορΜΜ.
Ππβ napeHTepanbHoro πρμμθηθημβ cociaB comacHO paHHOMy Μ3οβρβτβΗΜΐο ΓΟΤΟΒΒΤ B BMfle BBOflMMOTO ΙΙΙΠρΜΜβΒΘΗΜβΜ paCTBOpa. JlflH ΠρΜΓΟΤΟΒΠβΗΜΗ 3ΤΜΧ BBOflMMblX UinpMqeBaHMeM paCTBOpOB aKTHBHbie KOMnOHeHTbl paCTBOpHJOT B flHCTMnMpOBaHHOii BOfle M/ΜΠΜ B pa3miHHblX OpraHMHeCKHX paCTBOpmenBX, HanpMMep, ΓΠΜκοηΒθφΜρΜ, npH xenaHMM, b npncyTCTBMH como6nnM3npyK)mnx BemecTB, TaKnx xaK nonMOKCM3TMneHCop6MTaH-MOHonaypMHaT, μπμ μοηοοπθτθ, μπμ MOHocTeapaT (Tbmh 20, Tbmh 60, Tbmh 80), οοοτβθτοτβθηηο. BBOflMMbiii BnpbiCKMBaHMeM pacTBOp μοχθτ TaiOKe conep)KaTb pa3nnMHbie poSaBKM (BcnoMoraTenbHbie BeuiecTBa), HanpMMep, KOHcepBaHTbi, TaKMe KaK θτμπθη-flMaMMHTeTpaaueiaT, TaiOKe KaK μ ρΗ-μ3μθηβιοιιιμθ m 6yφepHbιe BemecTBa, μπμ npM )Ke/iaHMM, μθοτηοθ aHecTe3Mpyiomee cpepcTBO, TaKoe KaK πμποκ3μη. riepep 3anonHeHMeM aMnyn ββοαμμμμ BnpbiCKMBaHMeM pacTBOp, copepacainMM cociaB 11 LV 10090 comacHO Μ3θ6ρβτβΗΜΐο, φΜ/η/φγιοτ m nocne 3anonHeHMn nopBepraiOT CTepnnM3aunM. ripu ΠρΜΜβΗβΗΜΜ φ3ρΜ314ΘΒΤΜΜβ0Κ0Γ0 COCTaBa COmaCHO Μ3θ6ρβΤΘΗΜΚ) nai4neHTy bboaht Tpe6yeMyio po3y ρπη οΟθοπθμθημη xenaeMoro Θφφβκτβ. 3īa fl03a 3aBMCMT ot HecKonbKnx φ3κτοροΒ, TaKnx xax cepbē3H0CTb 3a6oneBaHnn, Bec Teņa nauMema m nyTb ββθπθημβ. npeflHa3HaHeHHan pnn πρΜΜβΗβΗΜ* po3a b πκ)6ομ cnywae ponxHa 6biTb onpepeneHa TepaneBTOM. M3o6peTeHne TaioKe othocmtcb k cnoco6y πθηθημη ποβρθχρθημμ M03ra οτ mnoKCMM pa3nMHHoro nponcxo>KfleHMfl, T3kmx Kax ciapnecKoe 6e3yMne, 6one3Hb A/ibureiiMepa, γμποκομη, cnepyK)tnafl nocne aiepoci<nepo3a, cna6oyMne ot MHoroKpaTHbix ΜΗφβρκτοΒ μ HapyuieHMB φyHKL^^1^ι no3HaBaHMn. 3tot cnoco6 BKmonaeT Bsepemie TepaneBTimecKM θφφβκτΜΒΗΟΓΟ KonnwecTBa 3κτμβηογο κομποηθητ3 φορΝ^ι (1) μπμ Φ3ΡΜ311θβτμμθοκμ πρμθμπθμομ conu npucoeflMHeHnn KMcnoTbi stoto κομποηθητβ nauneHTy. flaHHoe M3o6peTeHne nnmocTpnpyeTcn noppoČHo c noMombio cnepyiomMx HeorpaHMMMTenbHbix npMMepoB. npuBeneHHbie Bbixopbi omocmcn κ coepHHeHMflM, OHmueHHbiM no ροοτιιχΘΗΜίΐ ποοτολνηομ TeMnepairypbi nnaBneHMn. npmviep 1. l1onyHeHMe 1 ^eHnn-3-(TMa3onnflMHMn)nponaH-1 -OHa CycneH3mo, copep>Kainyio 24,0 r (0,2 Μοπη) θμθτοΦθηοηβ, 25,12 r (0,2 Monn) Tna3onMflMHrnflpoxnopMfla m 9,0 r (0,3 Monn) π3ρ3φορΜ3ηΒρθΓΜρ3 b 60 μπ STaHona, HarpeBaioT c očpaTHbiM xonoflnnbHw<oM npn nepeMemuBaHMM. Cnycra nāc fločaBnnraT nononHMTenbHoe κοπμηθοτβο b 6,0 r (0,2 Mona) napa-φορΜ3ηΒηβΓΜρ3 κ peaKUMOHHOii CMecn. nocne 3-nacoBoii peaKLinn cMecb oxna>KflaioT, ocapoK οτφι^τροΒΜΒ3ΐοτ m npoMbiBaioT aueTOHOM pnn nonyHeHMn 39,5 r KpMCTanmiHecKoro npopyKTa, κοτορυίί 3aTeM nepeKpncTannn30BbiBaK)T M3 1400 Mn MeTaHona pna nonyHeHMn 30,7 (59,6 %) OflHopoflHoro rnflpoxnopnfla ueneBoro coeflMHeHMn, TeMnepaTypa nnaBneHnn: 170-171 °C. Γ*Μαρο6ροΜΜΠ SToro npopyKTa nnaBmcn npM 169 °C.
CoeflMHeHnn φopMynbl (1), b κοτοροίί R1 03HanaeT Kap6oHnnbHyio rpynny R3, R4, R5, R3 o6o3HaMaraT aTOM eonopopa, a m , TaioKe xax μ n paBHbi 1, γοτοβμρμ TaK, xax onncaHO b ΠρΜΜβρβ 1, m ohm npMBepeHbi b Hnxecnepyioineii Ta6nnqe 3. (B Ta6nnqax pacTBopuTenu nepeKpncTannM3aqviM panbi b CKo6xax nocne 3HaweHnn TeMnepaTypbi nnaBneHMa). 12
Ta6mma 3. npMMep Ar R2 N Conb T-pa nnaBneHMfl,°C Bbixon,% 2 4-ΜΘΤΜΠφβΗΜΠ Η HBr 166 (BtOH-MeOH) 48,5 2a 4-ΜβΤΜΠφΘΗΜΠ Η HCI 156-157 (BtOH) 3 3-ΜΘΤΜΠφθΗΜΠ Η HBr 139 (BtOH) 39,2 3a 3-ΜΘΤΜΠφθΗΜΠ Η HCI 138-139 (BtOH-MeOH) 4 2,4βΜΜβΤΜΠφθΗΜΠ Η HBr 171 (ai4eTOHmpnn) 50,5 4a 2,4βΜΜΘΤΜΠφΘΗΜΠ Η HCI 165-166 (MeOH) 5 4-φθΗΜΠφβΗΜΠ Η HBr 189 (aiaHflMOH-EtOH) 91,3 5a 4-φΘΗΜΠφβΗΜΠ Η HCI 173 (3TaHflM0H-EtOH) 6 2-ΜΘΤ0Κ0ΜφθΗΜΠ Η HCI 139-140 (ΜθΟΗ-προοτοίί 3φνιρ) 33,4 7 3-ΜΘΤΟΚΟΜφθΗΜΠ Η HCI 149-150 (MeOH) 69,0 8 4-ΜΘΤΟΚΟΜφθΗΜΠ Η HBr 162 (EtOH-aLjeTOH) 69,1 9 3,5-ΑΜΜΘΤΟΚΟΜφβ- Η HCI 173 (MeOH) 59,4 10 3,4-ηΜΜβΤΟΚΟΜφΘ- Η HCI 171-172 (MeOH) 78,8 11 2,4-ηΜΜΘΤΟΚΟΜφθ- Η HBr 152-153 (MeOH-aueTOH) 21,3 12 2-μθτμπ-4-μθτοκ- Η ΟΜφΘΗΜΠ HCI 153 (EtOH) 48,6 13 3-μθτμπ-4-μθτοκ- Η ΟΜφΘΗΜΠ HCI 150-151 (EtOH) 56 14 3,4,5-ΤρΜΜΘΤΟΚΟΜ- Η φΘΗΜΠ HCI 162-163 (EtOH) 76,2 15 4-(4-φΤ0ρφΘΗΜΠ)- Η φθΗΜΠ HCI 173 (pa3no>K.) 69,1 16 2-φΤ0ρφΘΗΜΠ Η HBr 165-167 (EtOH-aqeTOH) 62,5 17 4-χπορφβΗΐιπ Η HBr 189 (MeOH-EtOH) 57,6 18 4-6ρ0ΜφθΗΜΠ Η HBr 189-189,5 (EtOH-aMeTOH) 56,9 19 3,4-ρΜχηορφβΗΜΠ Η HCI 155-158 (MeOH ) 11 20 3-ΗΜΤρθφθΗΜΠ Η HCI 148-149 (MeOH ) 28 21 3-ΧΠ0ρ-4-φΤ0ρφθΗΜΠ Η HCI 137-139 (2-nponaHon) 38,2 22 φθΗΜΠ - CH3 HBr 136 (2-nponaHon) 64,9 23 4-ΜΘΤΜΠφθΗΜΠ - CH3 HBr 145 (2-6yTaHOH- aueTOHmpiin) 36,49 24 2,4-ΑΜΜβΤΜΠφ0ΗΜΠ - CH3 HBr 151 (2-nponaHon) 54,2 25 4-ΜΘΤΟΑΜφθΗΜΠ - CH3 HCI 138-139 (aMeTOHmpun) 83,7 26 4-6θΗ3ΜΠ0Κ0ΜφθΗΜΠ - CH3 HCI 138-139 (aMeTOHMTpun) 83,7 27 4-φτορφθΗΜΠ - CH3 HCI 146-147 (EtOH-) 32,2 npOCTOM 3φΜρ) 13 LV 10090 ΠροηοιυκΘΗΜθ TačnMiļbi 3. ΠρΜΜβρ Ar N Conb T-pa nnaBneHMa,°C Bbixoq,% 28 4-ΧΠθρφΘΗΜΠ - ch3 HBr 168 (aueTOHMTpMn) 36,1 29 3,4-πηχπορφΘΗΜΠ •ch3 HCI 146-148 (2-nponaHon) 12,4 30 4-6ρθΜφΘΗΜΠ -ch3 HCI 158-160 (MeOH) 67 31 4-MeTnncynb$n- ΗΜΠφβΗΜΠ H HCI 165,5-166 (MeOH) 32,5 32 4-ΧηθρφβΗΜΠ "C2H5 HCI 150-151 (EtOH) 31,2 33 4-(4-φΤ0ρφΘΗΗΠ)- φΘΗΜΠ -ch3 HCI 164,5 (MeOH) 50,8
CoKpameHMA, ncnonb30BaHHbie b TaSnuMe: MeOH 03HanaeT MeTaHon, EtOH 03HanaeT 3TaHon. flpuMep 34. ΠοπγΗΘΗΜβ 1 -(4-MeTMnTM0$eHMn)-3-(3-TMa3onnflMHMn)nponaH-1 -OHa CMecb, copep)KamyK) 16,62 r (0,2 Mona) 4-μθτηπτμο314ΘτοΦθηοη3,12,56 r (0,1 ΜΟΠΠ) THa30nMflMHrMflpOXnopMfla, 4,5 Γ (0,15 MOna) ΠΘρΘφορίΥ^ΒΠΘΓΜί^ 35 μπ aiaHona η 3 Kannu KOHueHTpnpoBaHHoii οοππηομ κμοποτμ, HarpeeaioT c oSpaTHbiM xonoflnnbHMKOM npn nepeMeuiMBaHMM. CnycTa Mac κ peaKiļMOHHOii CMecu flo6aBnniOT nononHMTenbHoe κοπμμθοτβο b 3,0 r (0,1 Mona) napa-φορΜ3ΠΒΠΘΓΜΠ3. Ocax<neHHbie KpncTannbi, Becamne 20,3 r nepeKpncTan-nn30BbiBaioT n ocHOBaHne BbinenaeTca flo6aBneHneM KOHpeHTpvīpoBaHHoro KapčoHaTa Kanna b pacTBope nna nocnenyK>ineii ommctkm. rionyMeHHbin npaKTunecKn 6ecuBeTHbiii MacnaHMCTbiM nponyKT BHOBb npeepamaiOT b rnnpoxnopnn αο6ββπθημθμ 3φηρΗ0Γ0 pacTBopa xnopncioro BOflopopa. nonyMeHHbiii rnnpoxnopnn nepeKpncTannn30BbiBai0T n3 MeTaHona pna nonyseHna 12,73 r (41,9 %) rnnpoxnopnqa μθπθβογο οοθημηθημπ, TeMnepaiypa nnaBneHna: 153-154,5 °C. ripnMep 35. flonyHeHne 1 -(4-φτορφβΗηπ)-3-(3-ΤΜ33οηηηηΗηπ)προπ3Η-1 -OHa CMecb, coflep>Kainyio 25,51 r (0,15 Mona) Tna3onnflHHrnflpo6poMnna, 20,7 r (0,15 Mona) 4-φτορ3ΐ4βτοφβΗθΗ3, 6,75 r (0,225 Mona) Π3ρ3φορΜ3ΠΒΑΘηιη3,40 μπ aTaHona n 3 Kannu 48 % 6poMncTOBOflopoflHoii KncnoTbi, HarpeBaioT c očpaTHbiM xonoflnnbHHKOM npn nepeMeuinBaHnn. CnycTa oamh Mac nopunaMn flOčaenaiOT nononHMTenbHoe κοπμμθοτβο b 4,50 r (0,15 Mona) napa- 14 cļjopMa/ibflerMfla κ peaKUMOHHoii CMecu, κοτοργιο 3aieM HarpeBaiOT c o6paTHbiM xonoflnnbHMKOM b τθηθημθ pononHMTenbHbix 2 HacoB. Mexcpy τθμ HaMMHaeTca oSunbHoe oca>KfleHMe. CMecb oxnax<paioT no KOMHaTHoii TeMnpaTypbi m οτΦμπβτροβμββιοτ po nonyMeHnn 39,2 r KpiicTanniinecKoro npopyicra, KOTopbiii 3aieM flBax<flbi nepeKpncTannn30BbiBaiOT M3 MeTaHona po nonyMeHiw 23,6 r (59,5 %) KpucTannuHecKoro xpoMaiorpa0MHecKn opHopopHoro rnppo6poMnpa ueneBoro coepMHeHMn, TeMnepaiypa nnaBneHMn: 173*174 °C. 6) Γnppoxnopnp peneBoro Ha3HaHeHtin nnaBMTcn npn 146,5-147,5 °C nocne nepeKpncTannM3ai4MM M3 sianona. ΠριίΜβρ 36. ΠΟΓψΗΘΗΜΘ 1 -(4-nMnepMflMH0$eHHn)-3-(3-TMa30nMflMHMn)np0naH-1 -OHa CMecb, copep>Kamyio 20,4 r (0,085 Monn) Tna3onMpMHrnppoxnopMpa, 3,60 r (0,12 MO/ia) napa$opManbflernpa 50 μπ 2-nponaHona h 2 Kannu KOHiļeHTpM-pOBaHHoii connHoii KucnoTbi, HarpeBaiOT c o6paTHbiM xononnnbHHKOM npw nepeMeiiiMBaHun. Hac cnyom, πορριιηΜΜ poāaBnnioT pononHMTenbHoe KonMnecTBO b 2,40 r (0,08 μοπα) napa$opManbflernfla n peaKi4MOHHyio CMecb HarpeeaioT pononHMTenbHO b τθμθημθ 4 nacoB. nocne Bbipep>KMBaHMn CMecii b xonopnnbHMKe b τθηθημθ homu, ocapoK οτΦμπβτροβμββιοτ pnn nonyHeHMn 20,7 r npaKTMHecKii KpnciannnHecKoro npopyKTa, KOTopbiii 3aTeM nepeKpMCTan-nn30BbiBai0T TpioKflbi m MeTaHona po nonyneHMn 8,60 r (26,2 %) pnrappo-xnopnpa ueneBoro coepMHeHMn, TeMnepaiypa nnaeneHMfl: 156-158 °C. ΠρΜΜβρ 37. nonyHeHne 1 -(2-TneHMn)-3-TMa3onnpMHMn-nponaH-1 -OHa CMecb, copepxamyio 7,0 r (0,055 Monn) 2-3ρθτμπτμοΦθη3, 6,91 r (0,055 Monn) Tpna3onnpMHrMppoxnopMpa, 2,50 r (0,083 Monn) πβρβφορΜβη^ pempa, 25 μπ aTaHona m 2 Kannu κοΗρβΗτρκροΒβΗΗοίί οοππηομ KMcnoTbi, HarpeBaiOT c o6paTHbiM xonopnnbHMKOM npw nepeMemiiBaHHM. CnycTn 3 Mača nocne Hanana peaKumi πορμμλμμ ροδβΒπηιοτ pononHMTenbHoe κοπμμθοτβο b 1,63 r (0,054 Monn) naf^opManbperapa m peaKpnoHHyio CMecb HarpeBaiOT b TeneHHe ροποπΗητβπΒΗΗΧ 4 nacoB. nocne oxnax<peHMn κ cMecH ροδβΒπηιοτ 50 μπ apeTOHa, ocapoK (11,28 r) oτφHΠbτpOBblBaeτcn n nepeKpncTannn30BbiBaeTcn M3 MeTaHona po nonyHeHnn 8,0 r (55,1 %) rnppoxnopnpa ueneBoro coepMHeHMn, TeMnepaTypa nnaeneHMn: 176 °C.
CoepMHeHMn φopMyπbl (1), b κοτορμχ R1 o6o3HaMaeT Kap6oHnnbHyio rpynny R3, R4, R5, R6o6o3HaMaioTaTOMeopopopa, numo6o3HaMaiOT 1, KOTOpbie 6binn nonyMeHbi cornacHO onncaHmo npMMepa 37, csepeHbi b Ta6nnpe 4. 15 LV 10090
Ta6nnua 4. ΠρΜΜθρ Ar R2 Conb T-pa nnaBneHMn,°C Bbixon,%
N
38 5-3ΤΜΠ-2-ΤΜΘΗΜΠ -ch3 HCI 39 5-ΧΠΟΡ-2-ΤΜΘΗΜΠ Η HCI 40 5-6ρθΜ-2-ΤΜΘΗΜΠ Η HCI 41 2-τμθημπ -ch3 HCI 151-152 (EtOH) 41 149-150 (MeOH) 36,5 162-163 (MeOH 12,3 -ΑΜΜ30ΠΡ0ΠΜΠ . 3φΜρ) 144-146 (EtOH) 6,4 ΠρΜΜθρ 42. ΠοπγΜΘΗΜΘ 1 -(3-ΜΘΤΟΚ0ΜφθΗΜΠ)-3-ΤΜ33ΟΠΜΒΜΗΜΠ-ΠρθΠ3Η-1 -OH3 CMecb, coflep>KamyK) 15,02 r (0,1 μοπβ) 3-MeT0KcnaueT0$eH0Ha, 12,56 r Tna3onnflMHmnpoxnopMfla, 12,02 r (0,25 μοπλ) ημμθτοκομμθτ3Η3, 40 μπ aiaHona m 10 Kanenb κοημθητρμροβθηηομ conaHoii KMcnoTbi, HarpeBaioT c 06paTHblM XOnOflHnbHMKOM ΓφΜ ΠθρθΜΘ111ΜΒ3ΗΜΜ B ΤΘΗΘΗΜΘ 6 HaCOB, 33ΤΘΜ πορημπμμ no6aBnruoT flononHMTenbHoe κοπμηθοτβο b 19,02 r (0,25 μοπη) AUMeTOKCMMeTaHa m peaKi4MOHHyio CMecb pa3orpeBaiOT b τθηθημθ flononHMTenbHO 6 wacoB. (locne oxna>KfleHMfl BbiKpMCTannM30BbiBaeTcn πποτημμ ocapoK. riocne 0nnbTpoBaHna npoflyKTa, οχπθχβθηηογο πριι κομηβτηομ TeMnepaType, nonynaK)T 14,7 r BemecTBa, κοτοροβ 3Θτθμ nepeKpucTan-jin30BbiBai0T M3 MeiaHona pna nonyHeHMa 11,7 r (40,6 %) rnflpoxnopnfla Μθπθβογο οοθβμηθημα, κοτοροβ nonHocTbio μπθητμηηο οοθπμηθημιο, onwcaHHOMy b ΠρΜΜθρθ 7. ΠρΜΜθρ 43. ΠΟ/ψΗΘΗΜΘ 1 -$eHMn-3-(3-TMa30nMfll1H)npOnaH-1 -OHa Γ Mflpoxnopnfl peneBoro οοθβμηθημα nonyHaiOT M3 apen^eHOHa m Tna3onMflMHrnflpoxnopnfla cornacHO npeniuecTByK>meMy !1pnMepy c βμχοβομ 28,4 %, TeMnepaTypa ππθβπθημπ: 169-170 °C nocne nepeKpncTannn3ai4MM M3 MeiaHona. 3ia conb MfleHTMHHa onMcaHHoii b npMMepax 1 m 61. flpuMep 44. nonyweHMe 1 -(4-φτορφθΗΜπ)-3-(τθτρ3ΓΜηρο-1,3-TMa3MH-3-Mn)nponaH-1-OHa CMecb, coflep>Kainyio 8,28 r (0,06 μοπη) 4-φτορ3ΜθτοΗφθΗθΗ3,11,05 r (0,06 Monn) TeTparMflpo-1,3-TM03MHrMflpo6poMMfla, 2,70 r (0,09 μοπη) πβρΒφορΜβ^ηθΓΜΑθ, 25 μπ STaHona m 0,1 μπ 40 % čpoMMCTOBonopoflHOM KMcnoTbi, HarpeBaioT c ofipaTHbiM xonoflMnbHMKOM πρΜ πθρθμθιιιμβθημμ. CnycTn οβμη Mac nopuMnMM ΒοββΒπηιοτ flononHMTenbHoe ΚΟΠΜΗΘΟΓΒΟ B 1,8 Γ (0,06 Μοπη) π3ρ3φορΜ3^ηθΓΜΒ3, peaKHMOHHyio CMecb pa3orpeBaiOT b τθηθημθ 16 flononHMTenbHbix 2 nacoB n 3aTeM ποββΒΠΛίοτ 80 μπ aqeTOHa. CMecb oxnaxnaioT ripu -5 °C jqo nonyHeHna 12,73 r προργκτβ, KOTopbiii nepeKpncian-nn30BbiBai0T M3 MeiaHona pna nonyHeHna 9,02 r (45,0 %) ncKpatneroca rnflpoxnopnpa ueneeoro coepnHeHna, TeMnepaTypa nnaBneHna: 210-203 °C. ΟοβΠΜΗΘΗΜΛ φΟρΜγΠΜ (1), B KOTOpblX R1 o6o3HaHaeT Kap6oHnnbHyio rpynny R®, r4, r5, r6 o6o3HanaK)T aTOM Bopopopa, m paBHO 1, a n paeHO 2, KOTopue 6binn nonyHeHbi cornacHO Μ3ποχθηηομυ b flpwviepe 44, CBepeHbi b Ta6nni4y 5.
Ta6miua 5. ripnMep Ar N R2 . Conb T-pa nnaBneHna,°C Bbixop,% 45 φβΗΜΠ Η ΗΒγ 181 (MeOH-EtOH) 54,7 46 3-ΜΘΤΜΠφθΗΜΠ Η ΗΒγ 168 (MeOH-EtOH) 32,7 47 4-ΜΘΤΜΠφΘΗΜΠ Η ΗΒγ 194 (MeOH-EtOH) 40,0 48 2,4-pH Μ βΤΙΊΠφΘΗΜΠ Η ΗΒγ 167-168 (MeOH-2--nponaHon) 29,5 49 4-φθΗΜπφθΗηη Η ΗΒγ 186-188 (MeOH-EtOH) 59,5 50 3-ΜΘΤΟΚΟΜφθΗΜΠ Η ΗΒγ 164-165 (EtOH) 44,5 51 43-ΜΘΤ0Κ0ΜφθΗΜΠ Η ΗΒγ 201 (ΜβΟΗ-ρΜΜβτηπ-^opManbpernp) 65,5 52 3,4-ΑΜΜΘΤΟΚΟΜφβΗΜΠ Η ΗΒγ 195 (MeOH) 44,5 53 3,4,5-ΤρΜΜΘΤ0Κ0ηφθΗΜΠ Η ΗΒγ 210-212 (MeOH) 58,6 54 4-φΤ0ρφβΗΜΠ -ch3 HCI 166 (2-6yTaHOH-aiie--TOHnTpnn) 38,8 55 4-ΧΠ0ρφβΗΜΠ Η ΗΒγ 205-207 (MeOH) 58,4 56 4-6ρθΜφΘΗΜΠ Η ΗΒγ 210 (MeOH) 56,5 57 5-xnop-2-TneHnn Η ΗΒγ 197-201 (MeOH) 47,5 a npM ΠΟΠγΜΘΗΜΜ 3Τ0Γ0 COepHHeHHa TpyflHOKpnCTannH3yeMblii rMflpo6pOMMfl o6pa6aTbiBaiOT Kap6oHaTOM Kanna, BbipeneHHoe 8μμηοκθτοηοβοθ ocHoeaHne 3KdparnpyK)T b ριιχπορΜβτβΗ h npeo6pa3yiOT b rnppoxnopnfl o6uhhmm o6pa30M. ΠρηΜβρ 58. ΠΟΠγΜΘΗΜΘ 1 -(4-6ρ0ΜφβΗΜΠ)-3-(3-ΤΜ330ΠΜρΜΗΜΠ)-Γΐρ0Π3Η-1 -OHa 12,56 r (0,1 Mona) Tna3onnflHHrnflpoxnopnna, 19,9 r (0,1 Mona) čpoMaueTO-φβΗΟΗΒ, 12 μπ 36 %-Horo pacTBopa φορΜβ^ηβπ/ΐί# (0,144 Mona), 30 μπ 3TaHona n 5 Kanenb KOHiļeHTpnpoBaHHon conaHoii KncnoTbi CMeuīnBaiOT n 3aTeM HarpeBatoT. Ilocne κρβτκοβρθμθηηογο nepnopa KnnaneHna c o6pa*mbiM xonopnnbHHKOM nonyMaiOT roMoreHHbiii pacTBop. flocne 7-nacoBoro pacTBop 17 LV 10090
BbinapMBaioT, MacnnHMCTbiii οοτβτοκ BbinuBatoT b 1000 ΜΠ apeTOHa npn nepe-MeuiMBaHun m oca>KfleHHbiīi ncxopHbifi Maiepnan οτφΜΠΒτροΒβΒΘίοτ. Ποοπθ BbinapMBaHMfi $nnbīpaTa ocTaTOK nepeKpncTannM30BbiBaK>T m aiaHona μπμ MeTaHona po nonyHeHMn rnppoxnopnpa ρθπθβογο οοθρμηθημπ, TeMnepaTypa ππθβπθημη: 170°C. ΠριίΜβρ 59. nonyHeHne 2-(3-TMa3onnpiiHMn)apen^eHOHa
PacTBop, copepjKamviii 5,67 r (0,00637 μοππ) Tna3onnpnHa, 9,84 r (0,0637 μοπη) w-xnopaueTO0eHOHa m 6,50 r (0,0643 μοππ) TpnaTunaMHHa b 30 μπ apeTOHa ocTasnaiOT CTOflTb npn 25 °C β τθηθημθ 12 nacoB. Mexpy τθμ, o6pa3yeTca rydoii κρμοτθππμηθοκμμ ocapoK, KOTOpbifi οτφ^τροΒΜΒΘίοτ, npoMbieaiOT 3 pa3a b 50 μπ ropanero apeTOHa κεοκρωίί pa3 m co6paHHbiii βμθοτθ pacTBop apeTOHa oxnax<paioT po nonyHeHMn 5,30 r KpucTannuHecKoro ocapKa, KOTopbiPi npepcTaBnneT co6oii φopMy ocHOBaHua ρθπθβογο οοθρμηθημπ. Ποοπθ BbinapuBaHun μ3τομηογο pacTBopa m o6pa6oTKM ocTaTKa npocTbiM ΘφΜροΜ nonyHaioT pononHmenbHoe κοπμμθοτβο b 3,00 r, κοτοροβ μρθητμμηο npep-uiecTByiomeMy npopyicry cornacHo τοηκοοπομηομ χρθΜ3Τθφ3φΜΗ. 06a npopyicra COePMHBK)T ΒΜΘΟΤΘ M npeBpaipaiOT Β ΓΜΡΡΟΧΠΟΡΜΡ OČblHHblM o6pa30M. nonyHeHHyio conb nepeKpnciannn30BbiBaK)T H3 MeTaHona po nonyMeHnn 4,35 r (28,0 %) rnRpoxnopnpa ρθπθβογο οοθρμηθημη, TeMnepaTypa nnaBneHnn: 168-171 °C. ΠρΜΜΘρ 60. nonyMeHMe 2-(3-ΤΜ330ΠΜΡΜΗΜΠ)-4'-φΤ0ρ3ρΘΤ0φΘΗ0Η3 npopecc, onncaHHbiii b npMMepe 59, ποβτορηθτοη, 3a μοκπιοηθημθμ τογο, mto b κθηθοτβθ μοχορηογο MaTepnana ncnonb3yioT \Λ/-χπορ-4-φτορ8ρΘτοφΘΗθΗ, pnn nonyHeHMB mppoxnopnpa ρθπθβογο οοθρμηθημη npn 85 %-hom Bbixope b pacHēie Ha cbipoii npopyKT, TeMnepaTypa ππθβπθημπ: 168-171 °C. npMMep 61. nonyMeHne 1^eHiin-3-(3-TMa3onMpMHiin)nponaH-1-oHa
PacTBop, copep>KainMii 8,43 r (0,05 μοππ) β-χπορπροπιιοφΘΗΟΗβ, 4,10 r (0,05 μοππ) 6θ3βορηογο apeTaTa Haipnn μ 4,01 r (0,045 μοππ) Tna3onnpMHa β 30 μπ STaHona nepeMeiuneaiOT πριι 25 °C β τθηθημθ 8 nacoB. Ποοπθ oτφMΠbτpo-BbiBaHun ocapKa μ BbinapMBaHun pacTBopMTenn M3 pacTBopa, MacnflHMCTbiii )KenTOBaTbiii οοτβτοκ, βθοηιιιμμ 9,3 r, npeBpaipaiOT b rnppoxnopnp β ομθομ apeTOHa m npocToro ΘφπρΘ o6biMHbiM o6pa30M, mto paeT 9,9 r npopyKra. Ποοπθ nepeKpncTannn3ai4mi M3 MeTaHona nonyHeHHbiii τθκμμ o6pa30M rnppoxnopnp 18
LieneBoro nponyiaa nnaBMTca npn 170-171 °C; oh μαθητμμθη rnflpoxnopnfly, onncaHHOMy b IļpviMepax 1 m 43. npMMep 62. l1onyMeHMe 3-(5,5-flMMeTMn-4-3TOKCMKa6oHnn-3-TMa3onMflMHMn)-φΘΗΜ/inpOnaH-l -OHa ΓΜηροχπορΜρ μθπθβογο coeflMHeHMa, TeMnepaTypa nnaBneHMa: 138°C (nocne nepeKpncTannn3aunM M3 STaHona) nonyHaiOT npn 34,6 %-hom Bbixoqe c ncnonb30BaHneM b KanecTBe μοχοαημχ BemecTB (R,S)-5,5-flMMeTMn-4-3TOKCM-Kap6oHnnTMa3onnflMHa μ β-χπορπροπΜθφβΗθΗ3 m cneqya npoqeccy, onncaHHOMy b npMMepe 61. npMMep 63. (1onyMeHMe 1 -(4-χηορφβΗΜπ)-3-(5,5-ΑΜΜβτΜΠ-4-3Τ0Κ0ΜΚ36θΗΜΠ-3-TMa30JlMflMHWl)nponaH-1 -OHa ΓMflpoxnopnfl ueneBoro coeflMHeHMa, TeMnepaiypa nnaBneHMa: 137°C (nocne nepeKpncTannn3auMM M3 STaHona) nonyHaioT c 83,6 %-HbiM βμχοαομ npM Hcnonb30BāHHH (R,S)-5,5-flHMeTnn-4-3TOKCn-Kap6oHnnTMa3onMflHHa μ 4,β-ΑΜΧπορπροπΜθφβΗθΗ3 b κβηθοτβθ μοχοαηβιχ BemecTB m cneflya npoqeccy, onncaHHOMy b npMMepe 61. ΠρΜΜβρ 64. nonyneHMe 1,2-ΑΜφβΗΜη-3-(3-ΤΜ33ΟΠΜΑΜΗΜη)πρ0Π3Η-1-ΟΗ3 CMecb, coflep>Kaiiiyio 9,81 r (0,05 Mona) qe30KCM6eH30MHa, 5,02 r (0,04 Mona) TMa3onMflMHrMflpoxnopMfla, 2,00 r (0,067 Mona) napa-φορΜ3ηΒΑβΓΜΑ3 m 0,1 μπ 37 % conaHoii KMcnoTbi, HarpeBaiOT c o6paTHbiM XOnOflMnbHMKOM ΠρΜ ΠβρβΜΘΙΙΙΜΒΒΗΜΜ. HaC CnyCTa nopUMflMM no5aBnflK)T K γομογθηηομ peaKLļMOHHOM CMecM flononHMTenbHoe κοπμηθοτβο b 1,00 γ (0,033 Mona) π3ρ3φορΜ3ηΒΑβΓΜΑ8. nocne qononHMTenbHbix 4 wacoB peaKLļMM κ CMecM qo6aBnaioT 60 Mn aueTOHa m 3aieM eē oxnaxflaiOT b xonoflMnbHMKe. Ocax<fleHHoe Beuiecreo, Becamee 1,58 r, οτΦμπβτροβμβ3ιοτ M3 stoto pacTeopa. nocne BbinapMBaHMa μβτοηηογο pacTeopa MacnaHMCTbiM ocaflotc 3aTBepneeaK>T. nocne očpafioTKM θτογο npoqyKTa aueTOHOM φΜΠΒτρβΜΜβΜ nonyHaiOT 5,9 r KpMdannMHecKoro BemecTBa, κοτοροβ 3aTeM nepeKpMCTannM30BbiBai0T M3 aueTOHMTpMna, a 3aieM M3 CMecM 5:1 (o6tēM/o6tēM) 2-nponaHona m aTaHona, nna nonyneHMa 2,15 r (16,1 %) οαηοροαηογο rMqpoxnopMqa ueneBoro coeflMHeHMa, TeMnepaiypa nnaBneHMa: 144-146 °C. M3 BbiuieyKa3aHHoro ημοτογο rMqpoxnopMqa ocHoeaHMe BbiCBo6ox<flaK)T nyieM qo6aBneHMa flByyrneKMcnoro HaTpMa m npeo6pa3yioT ero b MeTaHO-cynbφoHOByκD conb, TeMnepaTypa nnaBneHMa: 145-146 °C nocne nepe- 19 LV 10090
KpncTannn3aumi M3 CMecii 1:1 (o6bēM/o6bēM) 2-nponaHona n npocroro flMM3onponnnOBoro 3$npa. ΠρΜΜβρ 65. l1onyHeHMe 1-(4-xnop$eHnn)-3-(4-3TOKCMKap6oHMn-3-Tna3onMflMHnn)nponaH- 1-OHa 10,66 Γ (0,025 ΜΟΠΠ) 4, β-ΑΜΧΠ0ρπρ0ΠΜ0φθΗ0Η3 fl06aBnflK3T Ma/lblMM nopumiMH κ cycneH3mi, copep>Kaineii 8,06 r (0,05 Monn) 4-3TOKCMKap6oHnn-Tna3onnflMHa m 4,31 r (0,0525 Μοηη) 6θ3βοαηογο HaipniiaueTaTa b 30 μπ aSconKDTHoro STaHona npw TeMnepaType ot 20 °C po 25 °C npn nepe-MemuBaHMM. riocne 5-nacoBoro nepeMeuiMBaHHn ocapoK xnopncioro HaTpun OTCļMnbTpOBblBaiOT Μ φΜΠΒΤρΑΤ BbinapMBaiOT. 06nnbHblH MaCnflHHCTblfi >KenTOBaTbiii ocapoK pacreopaioT b 30 μπ cmbcm 2:1 (o6bēM/o6bēM) aueTOHa h ΠρΟΟΤΟΓΟ 3φΜρ8 Μ Β(ΓφΠΧΜΒ3Κ)Τ C 6e3BOflHblM KapOOHaTOM ΚβΠΜΠ. ΠθΟΠΘ φΜΠΒΤρΟΒβΗΜΠ paCTBOp ΠΟρΚΜΟΠΠΙΟΤ θφίφΗΜΜ paCTBOpOM ΧΠΟρΜΟΤΟΓΟ BOflOpOfla μ MacnnHMCTbiM ocapoK Kpuciannu3yK)T po6aBneHneM aueTOHa. nonyMeHHbiii npoflyicr nepeKpncTannn30BbiBaiOT M3 aueTOHa nocne οοβθτβπθημη, nonyHaa 6,40 r (35,1 %) rnnpoxnopnfla ueneBoro οοθαμηθημη, TeMnepaTypa nnaBneHMn: 95-96 °C. ΠριίΜθρ 66. rionyHeHMe 3-(4-3TOKCMKap6oHnn-3-Tna3onMflMHMn)-1 -φβΗΜππροπ3Η-1 -OHa Γnppoxnopnp μθπθβογο οοθαμηθημη nonyHaiOT comacHo onncaHmo b ripHMepe 65 npw 32,7 %-hom Bbixope, TeMnepaiypa nnaBneHMn: 88,5 °C nocne nepeKpncTannn3aunn M3 cMecw aueTOHa m npocToro 3φΜρ3. ΠρΜΜθρ 67. nonyHeHMe 1 -(4-φΤ0ρφβΗΜΠ)-3-(4-3ΤΟΚ0ΜΚ3ρ6θΗΜΠ-3-ΤΜ330ΠΜΑΜΗΜΠ)- nponaH-1-OHa Γ ΜρροχπορΜρ ueneBoro οοθαμηθημη nonyHaioT npw 39,1 %-hom Bbixojqe, TeMnepaTypa nnaBneHnn: 104-105 °C nocne nepeKpMCTanmmuMH H3 aueTOHa. ΠρΜΜβρ 68. nonyneHMe 3-(4-3TOKCMKap6oHnn-3-TMa3onnflHHnn)-1 -(2-TneHnn)nponaH-1 - OHa 8,99 r (0,0515 Monn) 2-(3-χηορπροπΜθΗνιπ)τΜθφβΗ3 no KannnM počaBnnioT κ cycneH3MM, coflepacameii 7,90 r (0,049 μοπβ) 4-3TOKCMKap6oHMn™a3onnflMHa h 4,22 r (0,0515 Monn) 6θ3βοηηογο HaTpuiiaueTaTa b 25 μπ a6coniOTHoro STaHona. nocne nepeMeujHBaHHn b TeneHHe 9 Macoe xnopncTbiii HaTpiM ocaxflancn b BMpe μθπκμχ 6enbix KpucTannoB m οτφΜΠΒτροΒΜΒ3ποη, m nocne BbinapMBaHHn φΜΠΒΤρ3Τ3 3φΜρΗΒΐίί paCTBOp ΧΠΟρΜΟΤΟΓΟ BOflOpOfla flOČaBnflMM K MaCnHHMCTOMy 20 xenTOBaTOMy ocapKy ρππ nonyweHMn 7,65 r (46,5 %) rnflpoxnopnfla μθπθβογο ΟΟΘΡΜΗΘΗΜΛ, ΤβΜΠΘρβΤγρβ ΠΠ3ΒΠΘΗΜΠ: 97-100 °C ΠΟΟΠβ ΠΘρθΚρΜΟΤβΠΠΜββΜΙΙΜ Μ3 aueTOHa. ΠρΜΜβρ 69. nonyMeHne 1 -(4-χπορΦθημπ)-3-(5,5-αμμθτμπ-4-μθτοκομκ3ρ6οημπ-3- TMa3onnflMHnn)nponaH-1 -OHa 10,34 r (0,0509 μοππ) 4, β-βΜχπορπροπΜοφβΗΟΗβ flo6aBnniOT ManbīMM πορμμπμμ κ cycneH3MM M3 8,50 r (0,0485 Mona) 5,5-αμμθτμπ-4-MeTOKCMKap6oHMnTna3omiflMHa m 4,18 r (0,0509 μοππ) 6θ3βοαηογο HaTpuviaueTaTa b 30 μπ a6coniOTHoro 3TaHona npM κομη3τηομ TeMnepa7ype npn nepe-MeiuMBaHUH. Ilocne nepeMeuiMBaHMn b τθηθημθ nononHMTenbHbix 8 HacoB xnopncTbiii HaipMii οτφΜ/ibTpoBbiBaioT m nocne BbinapMBaHMn φΜ^τρ3Τ3. Mac/iflHMCTbiti xenTbiii ocapoK npeepautaiOT b ΓΜρροχπορΜη no6aBneHMeM 3φιιρΗ0Γ0 pacTBopa xnopncToro eopopopa. 3iy conb nepeKpncTannn30BbiBai0T M3 3TaHona pnn nonyHeHMii Bbixojqa b 64,9 %, TeMnepaTypa nnaBneHMn: 140 °C.
CoeflMHeHMfl φορΜ7Π^ (1), b κοτορΜχ R1 o6o3HawaeT Kap6oHnnbHyio rpynny R2, R6, o6o3HaHaK)T aTOM Bonopona, R3 o6o3HaMaeT MeTOKCMKap6oHMnbHyio rpynny, R^, r5, o6o3Ha4aiOT MeTvīnbHbie rpynnbi, η m m paBH01, KOTopbie 6binn nonyMeHbi cornacHO onucaHMK) b npMMepe 69, cBeneHbi b Ta6nnuy 6.
Tačnnua 6. ΠρΜΜβρ Ar N Conb T-pa nnaBneHMn.PC Bbixon,% 70 φΤΟρφΘΗΜΠ HCI 134-136 (EtOH) 22,8 71 4-6ρ0ΜφθΗΜΠ HCI 148 (EtOH) 62,1 72 2-nbtybk HCI 138 (EtOH- 36,1 -npocToii 3φΜρ) npMMep 73. rionyHeHMe 1 -φθΗΜπ-3-(τβτρ3ΓΜρρο-1,3-TMa3MH-3-Mn)neHT-3-OHa CMecb, coflepxamyio 5,45 r (0,037 μοππ) 4^eHMn-3-6yTeH-2-OHa, 6,81 r (0,037 μοπλ) TeTparMflpo-1,3-TMa3MHrnqpo6poMMfla, 1,50 r (0,05 μοππ) napa-φορΜβ^βθΓΜί# m 0,1 μπ 48 % 6poMMCTOBOflopoflHoii KMcnoTbi, HarpeeaiOT c o6paTHbiM xonoflnnbHMKOM npn nepeMeuiMBaHMM. CnycT& oamh nac AOČaBnntoT HOnOnHMTenbHOe ΚΟΠΜΜΘΟΤΒΟ B 1,27 Γ (0,042 ΜΟΠλ) Π3ρ3φθρΜ3ΠΒΑΘΓΜΑ3 Μ peaKUMOHHymo CMecb κμππτπτ c o6paTHbiM xonoflnnbHHKOM b τθηθημθ nononHMTenbHbix 2 nacoB. nocne no6aBneHnn 15 μπ aijeTOHa peaKMMOHHyio CMecb, coflepxamyio KpucTannuHecKufi nponyKT, oxnaxflatOT m φnπbτpyIoτ, hto 21 LV 10090 flaēT 8,1 r KpucTannuMecKoro rnapoSpOMuna ueneBoro coepMHeHMfl, KOTopbiii 3aTeM pBa>Kflbi nepeKpMCTannn30BbiBaK)T H3 MeTaHona απα nonyHeHmi 3,95 r HMCToro rMflpoSpoMMfla. OcaflOK, nonyHeHHbiii nocne nepeKpncTannn3aMMM, coflep>KMT conbBaTHbiii MeTaHon, KOTopbiii μοχθτ 6biTb ypaneH npn 78 °C npn ΠΟΗΜ>ΚΘΗΗΟΜ ρβΒΠβΗΜΜ.
Bbixofl cocTaBJifieT 31,2: b pacneTe Ha nepeKpncTannn30BaHHbiii HMCTbiii nponyKT, TeMnepaTypa nnaBneHMn: 179 °C. ΓΙρΜΜΘρ 74. nonyMeHne 1-(4-χηορφβΗΜπ)-5-(τβτρ3ΓΜΑρο-1,3-Tna3MH-3-nn)neHT-1 -OHa Γ Mflpo6poMMfl ueneBoro οοθαμηθημλ nonyHaiOT comacHo onncaHmo b npmviepe 73 c 45 %-HbiM βμχοαομ, TeMnepaTypa nnaBneHiin: 181 -182 °C nocne nepeKpncTannn3aunn M3 MeiaHona. ripnMep 75. nonyHeHne 2-6θη3μπ-1 ^eHMn-3-(TMa3onMflMHnn)nponaH-1-OHa CMecb, conep)KamyK) 10,51 r (0,05 Monn) 1,3-flM0eHnnnponaH-1-OHa, 6,28 r (0,05 MOna) TMa30nMflMrMflp0Xn0pMfla, 1,75 Γ (0,125 MOAfl) Π3ρ3φθρΜ3ΠΒΑβΓΜΑ3 m 25 μη 37 % connHOM KucnoTbi nepeMeuiMBaKjT npw κμπληθημμ c o6paTHbiM xonoflnnbHMKOM b τθμθημθ 6 nācos. nocne oxnax<AeHMa ocaxAaeicn 2,50 r 6enoro npoAyKTa M3 peaKMMOHHoii ομθομ, KOTopbiii npeACTaBnneT co6om Henpe-o6pa30BaHHbiti TMa3onnflMHninpoxnopMA. nocne BbinapMBaHMa Φμπβτρβτβ CBeTno-x<enTbiii ocaAOK, BecninMM 16,52 r, TinaTenbHO npoMbiBaioT Tpn pa3a b 20 μπ npocToro 3φΜρβ Ka)KAbiii pa3. TaKMM o6pa30M nonyHaioT 7,80 r 6enoro nopoiuKoo6pa3Horo BemecTBa, KOTopbiii πβρβΒΟΑητ b cycneH3wo b Bope, b HepacTBOpMMyto nacTb AeaxAbi nepeKpwcTannn30BbiBa>0T M3 2-nponaHona nnn nonyMeHnn 3,50 r (20,1 %) rnApoxnopnna ueneBoro οοθαμηθημη, TeMnepaiypa nnaBneHnn: 134 °C. ΠρΜΜβρ 76. nonyMeHMe 1 -(4-φΤ0ρφ6ΗΜΠ)-3-(2-ΜΘτΜΠ-3-Τνΐ330ΠΜΑΜΗΚΠ)πρ0Π3Η-1 -OHa 3,73 r (0,02 Monn) χπορ-4-φτορπροπΜοφΘΗθΗ3 AOčaBnnioT ManbīMM nopuMjiMM npw KOMHaTHoii TeMnepaType κ cycneH3HM, coAepjKameii 2,06 r (0,02 Monn) 2-MeTMn-TMa3onnAMHa m 1,64 r (0,02 μοπα) 6θ3βοαηογο HaTpMiiaueTaTa b 20 μπ 3TaHona b τβπβΗΜΜ 30 MMHyT npM nepeMeiuHBaHMH. nocne nepe-MeuiMBaHvm b τβΗβΗΜθ AononHMTenbHbix 3 nacoB peaKUMOHHyfo CMecb BbinapHBatoT, AofiaBnnioT HacbimeHHbiii pacTBop AByyrneKncnoro HaTpun κ MacnnHiicTOMy xcenTOMy ocaAKy m ero ABax<Abi 3KCTparnpyraT b 30 Mn npocToro 3φπρ3 Ka>KAbiti pa3. nocne cyuiKH vt BbinapMBaHua sKCTpaicra MacnaHMCTbiii xcenTbiii ocaAOK pacTBopnioT b aueTOHe μ ποακμοπαιοτ 48 %-Hoii SpOMMCTo- 22 BOflopoflHoii KMcnoToii. Τβκμμ o6pa30M nonyMaioT 4,26 r 6enoro Kpucian-nnnecKoro npoflyKTa, KOTopbiii flBaxflbi nepeKpMCTannn30BbiBatoT M3 aiaHona, hto flaēT 2,00 r (29,9 %), rnppo6poMMfla ueneBoro οοθαμηθημη, TeMnepaTypa ππ3βπθημλ: 151-152 °C.
CoeflHHemifl $opMynbi (1), b κοτορΜχ R"! o6o3HawaeT Kap6oHwnbHyio rpynny R^, r3, r4( r5 o6o3HanaK)T aTOM eopopopa, a n, TaiOKe KaK m m paBHbi 1, KOTopbie 6bimi nonyneHbi comacHo onncaHmo ripuMepa 76, οβθαθημ b Ta6nnuy 7.
Ta6nnua 7. ΠρΜΜβρ Ar r6 Co/ib T-pa n/iaBneHMfl,°C Bbixon,%
N 77 4-ΧΠθρφθΗΜΠ 78 4-φτορφβΗΜΠ μθτμπ HBr 3τμπ HBr 154 (EtOH) 160 (EtOH) 56,6 38,4 LV 10090
ΦΟΡΜΥΠΑ M30EPETEHMR 1. A30T- m cepocopepttainMe γθτθρομμκπμηθοκμθ οοθρμηθημπ φορΜγπΜ (1)
Ar-R-CH—(CH2) I R2
/ -N
R' I ,CH
\ S (1) rpe
Ar - cpeHMnbHafl rpynna, KOTopan ripu ηθοΟχοημμοοτμ μοχθτ 6biTb 3aMemeHa OflHMM Cļ_4 a/ΙΚΜΠΟΜ, C-j .4 anKOKCMJlOM, Cļ.4 a/ΙΚΜΠΤΜΟ,ΗΜΤρθ Μ ΠΜ φβΗΜ/lbHOii rpynnoii, ΜΠΜ OflHMM ΜΠΜ flByMfl ranOreHaMM, ΜΠΜ OflHOBpeMeHHO OflHOM Cļ-4 ariKMn m C-ļ .4 anKOKCMrpynnoM, μπμ TMeHMnbHaa rpynna, KOTOpaa npw Heo6xoflMMOCTM μο>κθτ 6biTb 3aMemeHa ranoreHOM μπμ C-j_4 anKMnoM, R"I- KapčoHiīnbHafl μπμ 9TMneHKap6oHMnbHaa rpynna; R2 - aTOM Bopopofla, C-j-4 anKMnbHan, φeHMΠbHafl μπμ 6eH3MnbHan rpynna, R3 - aTOM Bopopofla μπμ C-j .4 anKOKCMKap6oHMnbHan rpynna; R4 m R3 o6o3HaHa»OT, ηθ33Βμομμο npyr OTppyra, aTOM Bopopopa μπμ C1.4-anKMnbHy»o rpynny; R6 - aTOM Bonopopa μπμ C-j .4 anKMnbHan rpynna, m=0 μπμ 1; η=1 μπμ 2, npM ycnoBMM, mto R2 o6o3HanaeT Βορορορ, Korpa m=0, μπμ οοπμ πρΜ-COeflMHeHMfl XnopMCTOBOflOpOflHOM, 6pOMMCTOBOflOpOflHOM ΜΠΜ MeTaH-CyΠbφOHOBOM KMCHOTbl 3ΤΜΧ ΟΟΘΡΜΗΘΗΜΜ, 06naflai0mMe 3ΗΤΜΓΜΠΟΚΟΜΗΘΟΚΟΜ aKTMBHOCTbKD. 2. A30T- m cepocopep>KaLUMe γθτθρορμκπμμθοκμθ οοθαμηθημπ no π.1, rpe Ar - φeHMΠbHaπ μπμ TMeHMnbHaa rpynna, KOTopan npM ηθο6χορμμοοτμ μοχθτ 6biTb 3aMeuļeHa ranoreHOM μπμ C-ļ .4 anKMnoM, μπμ οοπμ πρμοοθρμηθημπ ΧΠΟρΜΟΤΟΒΟΡΟρΟΠΗΟΜ, 6pOMMCTOBOflOpOflHOM ΜΠΜ MeτaHCyΠbφOHOBOM KMCnOTbl 3ΤΜΧ ΟΟΘΡΜΗΘΗΜΜ. 3. Α30Τ- μ cepocopepacaiuMe γθτθρορμκπμμθοκμθ οοθημηθημπ πο π.1, Bbl6paHHbie Μ3 rpynnbl, ΟΟΟΤΟΠίρβΜ Μ3 1 -(4-ΜΘΤΜΠΤΜ0φβΗΜΠ)-3·(3-ΤΜ330ΠΜΡΜΗΜΠ)ηρ0Π3Η-1 -OHa, 1 -(4-ΧΠ0ρφβΗΜΠ)*3"(3-ΤΜ330ΠΜρΜΗΜΠ)ηρ0Π3Η-1 -OHa, 1 -(4-φΤ0ρφβΗΜΠ)-3-(3-ΤΜ330ΠΜΡΜΗΜΠ)ηρ0Π3Η-1 -OHa, 1 -(2-ΤΜΘΗΜΠ)-3-(4-ΤΜε30ΠΜΑΜΗΜΠ)πρ0ΠβΗ-1 -OHa, 1*(4-φΤ0ρφβΗΜΠ)·3*(5Ι5-ΑΜΜΘΤΜΠ-4-ΜβΤ0Κ0ΜΚ3ρ60ΗΜΠ-3-ΤΜ330ΠΜΑΜΗΜ/ΐ)πρ0Π3Η 1-OHa, 1 -(4-6ρ0ΜφβΗΜΠ)-3-(3-ΤΜ330ΠΜΑΜΗΜ/ΐ)πρ0Π3Η-1 -OHa, 1 -(2-ΜΘΤΜη-4-ΜΘΤΟΚ0ΜφβΗΜΠ)-3-(3-ΤΜ330ΠΜΑΜΗΜΠ)πρθΠ3Η“1 -OHa, 1 -(4-6ροΜφθΗΜπ)-2-Μθτιιπ- 3-(3-Tvia3onMflMHMn)nponaH-1 -OHa, 1 -(5-xnop-2-TMeHMn)-3-(3-TMa3onnflMHMn)nponaH-1 -OHa, 1 -φθΗΜΠ- 3-(3-TMa30nMAMHMn)np0naH-1 -OHa, 1 -φθΗΜΠ-2-ΜΘΤΜΠ- 3-(3-THa30nHflMHMn)np0naH-1 -OHa, 1 -(4-ΦθημπΦθημπ)- 3-(3-TeTpamnpo-1,3-Tna3MH-3-nn)nponaH-1 -OHa, ΜΠΜ 1 -(5-3TMn-2-THeHMn)-3-(3-THa30nHAMHHn)np0naH'1 -OHa, ΜΠΜ COJ1I4 ΠρΜΟΟΘΑΜΗΘΗΜΛ ΧΠΟρΜΟΤΟΒΟΑΟρΟΑΗΟίί, 6pOMMCTOBOflOpOflHOM HHM ΜΘΤβΟγΠΒφΟΗΟΒΟίί KHCHOTbl 3ΤΜΧ ΟΟβ/}ΜΗΘΗΜΜ. (56) F.F.Blicke: Organic Reactions, Vol.1, page 303-341; J.Wiley, New-York, London (1942) flaTeHT ΦΡΓ N 2252344, κπ.12ρ 21/00, ony6.1972 r. 28 LV 10090 ΡΕΦΕΡΑΤ Μ3θ6ρβτθΗΜΘ othocmtch κ HOBbiM a30T- u cepocopepaoiHMM ΓΘΤθρΟ-LlMKJIMMeCKMM ΟΟΘβΜΗΘΗΜΑΜ φορΜγπω (1), ΜΧ ΟΟΠΗΜ ΠρΜΟΟΘΑΜΗΘΗΜ* KMCflOTbl, cļjapMaueBTMHecKMM οοοτβββμ, copep^auļUM μχ, μ κ cnoco6y μχ ποπυηθημη. Β φορΜγπθ (1) R6
I
/CHX
Ar-R-CH—(ΟΗ2)πΓΝ S (1) I 2 I I 5 R (ch)-c-r5 R3 R4
Ar o6o3HaHaeT bo3mo>kho moho- μπμ nonn3aMemeHHyio apnnbHyio μπμ reTepoapnnbHyK5 rpynny; R"* o6o3HaHaeT Kap6oHnnbHyio μπμ (C2-6 θπκθημπ) Kap6oHnnbHyra rpynny; R2 0603HaHa8T aTOM BOflOpOfla, C-ļ.g βΠΚΜΠΒΗγίΟ, φθΗΜΠΒΗγΚ) ΜΠΜ φθΗΜΠ(0-1 _4 anKnnbHyK)) rpynny; r3 o6o3HanaeT aTOM BOAopopa unu (C-ļ _g anKOKCM) Kap6oHnnbHyio rpynny; R4 m R5 o6o3HaHaiOT, ηθ38βμομμο npyr ompyra, aTOM Bonopona μπμ Cļ.g· anKnnbHyio rpynny; r6 o6o3HaMaeT aTOM Bonopona, Cļ.g anKMnbHyio rpynny unu γθποΦθημπβηυιο rpynny; m paBHO0 unu 1;u n paBHO 1 unu 2, πριι υοποβμθμ, hto R2 o6o3HanaeT eonopon, Korna m paBHO 0.
CoeflMHeHMa φορΜγΠΜ (1) ΠρΟΠΒΠΗΙΟΤ 3HaHMTenbH0e Β03ΑΘΜ0ΤΒΜΘ npOTMB HapyiueHMM M03ra, u τβκμμ o6pa30M, mx mojkho Mcnonb30BaTb πππ πθμθημπ 60ΠΘ3ΗΘΜ, Bbl3BaHHblX ΠΟΒρθΧφΘΗΜΘΜ Μ03Γ8 OT ΓΜΠΟΚΟΜΜ, ΤΒΚΜΜΜ ΚβΚ CTapnecKoe cna6oyMne, 6one3Hb AnbureMMepa unu HapyuieHMn φγΗΚΑΜΜ n03HaHMH.
Claims (3)
- LV 10090 IZGUDROJUMA FORMULA SLĀPEKLI UN SĒRU SATUROŠIE HETEROCIKLISKIE SAVIENOJUMI 1. Slāpekli un sēru saturošie heterocikliskie savienojumi ar formulu 1 R6 i CH Ar-R'-CH -(Clļ^-N/^S R2 (CH)„—C—R5 L K R3 R4 kur Ar - fenilgrupa, kura nepieciešamības gadījumā var būt aizvietota ar vienu Cļ-4 alkil-, C1-4 alkoksil-, C1.4 alkiltio-, nitro- vai fenilgrupu, vai vienu vai diviem halogēniem, vai vienlaicīgi ar vienu Cļ.4 alkil- un C1-4 alkoksigrupu, vai tienilgrupa, kura nepieciešamības gadījumā var tikt aizvietota ar halogēnu vai C1.4 alkilgrupu. R^ - karbonilgrupa vai etilēnkarbonilgrupa, R2 - ūdeņraža atoms, C-ļ_4 alkil-, fenil- vai benzil- grupa, R2 - ūdeņraža atoms vai C1.4 alkoksikarbonilgrupa, R4 un R5 - nozīmē, neatkarīgi vienam no otra, ūdeņraža atomu vai C1.4 alkilgrupu, R® - ūdeņraža atoms vai Cļ.4 alkilgrupa, m=0 vai 1, n=1 vai 2, ar nosacījumu, ka R2 nozīmē ūdeņraža atomu, kad m=0, vai šo savienojumu hlorūdeņraža, bromūdeņraža vai metānsulfoskābes pievienošanas sāli, kuriem piemīt antihipoksiska aktivitāte.
- 2. Slāpekli un sēru saturošie heterocikliskie savienojumi pēc 1 .p-ta, kur Ar - fenil- vai tienilgrupa, kura nepieciešamības gadījumā aizvietota ar halogēnu vai C-j-4 alkilgrupu, vai savienojumu hlorūdeņraža, bromūdeņraža vai metānsulfoskābes pievienošanas sāli.
- 3. Slāpekli un sēru saturošie heterocikliskie savienojumi pēc 1 .p-ta, izvēlēti no grupas, kura sastāv no 1 -(4-metiltiofenil)-3-(3-tiazolidinil)propan-1 -ona, 1 -(4-hlorfenil)-3-(3-tiazolidinil)propan-1 -ona, 1 -(4-fluorfenil)-3-(3-tiazolidinil)propan-1 -ona, 1 -(2-tienil)-3-(4-tiazolidinil)propan-1 -ona, 2 1-(4-fluorfenil)-3-(5,5-dimetil-4-metoksikarbonil-3-tiazolidinil)propan-1-ona, 1 -(4-bromfenil)-3-(3-tiazolidinil)propan-1 -ona, 1 -(2-metil-4-metoksifenil)-3-(3-tiazolidinil)propan-1 -ona, 1 -(4-bromfenil)-2-metil-3-(3-tiazolidinil)propan-1 -ona, 1 -(5-hlor-2-tienil)-3-(3-tiazolidinil)propan-1 -ona, 1 -fenil-3-(3-tiazolidinil)propan-1 -ona, 1 -fenil-2-metil-3-(3-tiazolidinil)propan-1 -ona, 1 -(4-fenilfenil)-3-(3-tetrahidro-1,3-tiazin-3-il)propan-1-ona, vai 1 -(5-etil-2-tienil)-3-(3-tiazolidinil)propan-1 -ona, vai šo savienojumu hlorūdeņraža, bromūdeņraža vai metānsulfoskābes pievienošanas sāli. t
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HU893474A HU204040B (en) | 1989-07-11 | 1989-07-11 | Process for producing new thiazoles and thiazines and pharmaceutical compositions comprising same |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| LV10090A LV10090A (lv) | 1994-05-10 |
| LV10090B true LV10090B (en) | 1995-02-20 |
Family
ID=10964168
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| LVP-92-685A LV10090B (en) | 1989-07-11 | 1992-12-30 | Nitrogen and sulphur containing heterocyclic compounds, method of preparation thereof, pharmaceutical composition and method of preparation thereof |
Country Status (24)
| Country | Link |
|---|---|
| US (1) | US5096902A (lv) |
| EP (1) | EP0411775B1 (lv) |
| JP (1) | JPH0348670A (lv) |
| KR (1) | KR950003496B1 (lv) |
| CN (1) | CN1028229C (lv) |
| AT (1) | ATE135349T1 (lv) |
| AU (1) | AU629660B2 (lv) |
| CA (1) | CA2020805A1 (lv) |
| DD (1) | DD297973A5 (lv) |
| DE (1) | DE69025819T2 (lv) |
| FI (1) | FI903473A0 (lv) |
| HR (1) | HRP920775A2 (lv) |
| HU (2) | HU204040B (lv) |
| IE (1) | IE902499A1 (lv) |
| IL (1) | IL95018A (lv) |
| LT (1) | LTIP1775A (lv) |
| LV (1) | LV10090B (lv) |
| NO (1) | NO903078L (lv) |
| NZ (1) | NZ234440A (lv) |
| PL (2) | PL165125B1 (lv) |
| PT (1) | PT94653A (lv) |
| RU (1) | RU1833377C (lv) |
| YU (1) | YU47797B (lv) |
| ZA (1) | ZA905406B (lv) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE69027472T2 (de) * | 1989-04-07 | 1996-12-05 | Lilly Co Eli | Arylsubstituierte Rhodaninderivate |
| US5458793A (en) * | 1993-05-13 | 1995-10-17 | The Lubrizol Corporation | Compositions useful as additives for lubricants and liquid fuels |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| LU78421A1 (fr) * | 1977-10-31 | 1979-06-01 | Zyma Sa | Procede de preparation de nouveaux composes thiazolidiniques |
| US4656286A (en) * | 1984-08-27 | 1987-04-07 | Polaroid Corporation, Patent Dept. | Aminoethanethiol and thiazolidine compounds |
| US4652649A (en) * | 1985-02-20 | 1987-03-24 | United Pharmaceuticals, Inc. | Anti-spasmodic agents having a ring in the main chain |
| HU198012B (en) * | 1987-07-03 | 1989-07-28 | Richter Gedeon Vegyeszet | Process for producing cyclic amino-acid derivatives and pharmaceutical compositions containing them |
| CA2004028C (en) * | 1988-12-08 | 1998-09-22 | Motoki Torizuka | Condensed benzene derivative |
-
1989
- 1989-07-11 HU HU893474A patent/HU204040B/hu not_active IP Right Cessation
-
1990
- 1990-04-12 US US07/509,473 patent/US5096902A/en not_active Expired - Fee Related
- 1990-07-10 DE DE69025819T patent/DE69025819T2/de not_active Expired - Fee Related
- 1990-07-10 IL IL9501890A patent/IL95018A/en not_active IP Right Cessation
- 1990-07-10 CN CN90104518A patent/CN1028229C/zh not_active Expired - Fee Related
- 1990-07-10 AU AU58815/90A patent/AU629660B2/en not_active Ceased
- 1990-07-10 AT AT90307527T patent/ATE135349T1/de not_active IP Right Cessation
- 1990-07-10 FI FI903473A patent/FI903473A0/fi not_active Application Discontinuation
- 1990-07-10 ZA ZA905406A patent/ZA905406B/xx unknown
- 1990-07-10 EP EP90307527A patent/EP0411775B1/en not_active Expired - Lifetime
- 1990-07-10 NO NO90903078A patent/NO903078L/no unknown
- 1990-07-10 RU SU904830514A patent/RU1833377C/ru active
- 1990-07-10 NZ NZ234440A patent/NZ234440A/xx unknown
- 1990-07-10 IE IE249990A patent/IE902499A1/en not_active Application Discontinuation
- 1990-07-10 PT PT94653A patent/PT94653A/pt not_active Application Discontinuation
- 1990-07-10 YU YU133390A patent/YU47797B/sh unknown
- 1990-07-10 KR KR90010436A patent/KR950003496B1/ko active IP Right Grant
- 1990-07-10 PL PL90285992A patent/PL165125B1/pl unknown
- 1990-07-10 PL PL90300985A patent/PL165110B1/pl unknown
- 1990-07-10 DD DD90342666A patent/DD297973A5/de not_active IP Right Cessation
- 1990-07-10 CA CA002020805A patent/CA2020805A1/en not_active Abandoned
- 1990-07-11 JP JP2181698A patent/JPH0348670A/ja active Pending
-
1992
- 1992-10-01 HR HRP920775AA patent/HRP920775A2/hr not_active Application Discontinuation
- 1992-12-30 LV LVP-92-685A patent/LV10090B/lv unknown
-
1994
- 1994-01-14 LT LTIP1775A patent/LTIP1775A/xx not_active Application Discontinuation
- 1994-10-12 HU HU94P/P00038P patent/HU210074A9/hu unknown
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