DK157018B - Fremgangsmaade til fremstilling af 4-hydroxyquinoliner - Google Patents
Fremgangsmaade til fremstilling af 4-hydroxyquinoliner Download PDFInfo
- Publication number
- DK157018B DK157018B DK277783AA DK277783A DK157018B DK 157018 B DK157018 B DK 157018B DK 277783A A DK277783A A DK 277783AA DK 277783 A DK277783 A DK 277783A DK 157018 B DK157018 B DK 157018B
- Authority
- DK
- Denmark
- Prior art keywords
- tetrahydroquinolin
- chloro
- preparation
- hydroxyquinoline
- reaction
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 10
- 238000002360 preparation method Methods 0.000 title claims abstract description 5
- 150000004331 4-hydroxyquinolines Chemical class 0.000 title description 6
- BUWPZNOVIHAWHW-UHFFFAOYSA-N 2,3-dihydro-1h-quinolin-4-one Chemical compound C1=CC=C2C(=O)CCNC2=C1 BUWPZNOVIHAWHW-UHFFFAOYSA-N 0.000 claims abstract description 15
- PMZDQRJGMBOQBF-UHFFFAOYSA-N quinolin-4-ol Chemical compound C1=CC=C2C(O)=CC=NC2=C1 PMZDQRJGMBOQBF-UHFFFAOYSA-N 0.000 claims abstract description 9
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims abstract description 5
- 239000001301 oxygen Substances 0.000 claims abstract description 5
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 5
- 125000005843 halogen group Chemical group 0.000 claims abstract description 4
- 238000006243 chemical reaction Methods 0.000 claims description 21
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical group [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 18
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims description 6
- 239000007864 aqueous solution Substances 0.000 claims description 2
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims 1
- -1 alkyl radicals Chemical class 0.000 abstract description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 abstract description 2
- 230000001590 oxidative effect Effects 0.000 abstract description 2
- 125000004432 carbon atom Chemical group C* 0.000 abstract 2
- 125000001424 substituent group Chemical group 0.000 abstract 2
- WZKSXHQDXQKIQJ-UHFFFAOYSA-N F[C](F)F Chemical compound F[C](F)F WZKSXHQDXQKIQJ-UHFFFAOYSA-N 0.000 abstract 1
- 239000000126 substance Substances 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- HOLTZTRNTRXTNX-UHFFFAOYSA-N 7-chloro-2,3-dihydro-1h-quinolin-4-one Chemical compound O=C1CCNC2=CC(Cl)=CC=C21 HOLTZTRNTRXTNX-UHFFFAOYSA-N 0.000 description 9
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 8
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 8
- 239000000203 mixture Substances 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- XMFXTXKSWIDMER-UHFFFAOYSA-N 7-chloro-1h-quinolin-4-one Chemical compound ClC1=CC=C2C(O)=CC=NC2=C1 XMFXTXKSWIDMER-UHFFFAOYSA-N 0.000 description 5
- 238000004817 gas chromatography Methods 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- HXEWMTXDBOQQKO-UHFFFAOYSA-N 4,7-dichloroquinoline Chemical compound ClC1=CC=NC2=CC(Cl)=CC=C21 HXEWMTXDBOQQKO-UHFFFAOYSA-N 0.000 description 4
- 229910015900 BF3 Inorganic materials 0.000 description 4
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical compound C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 description 4
- 229930185107 quinolinone Natural products 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 238000004811 liquid chromatography Methods 0.000 description 3
- YHXKNYLHVMSFKC-UHFFFAOYSA-N 3-(3-chloroanilino)propanoic acid Chemical compound OC(=O)CCNC1=CC=CC(Cl)=C1 YHXKNYLHVMSFKC-UHFFFAOYSA-N 0.000 description 2
- AQKKRXMVSOXABZ-UHFFFAOYSA-N 3-anilinopropanoic acid Chemical compound OC(=O)CCNC1=CC=CC=C1 AQKKRXMVSOXABZ-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- WHTVZRBIWZFKQO-UHFFFAOYSA-N chloroquine Natural products ClC1=CC=C2C(NC(C)CCCN(CC)CC)=CC=NC2=C1 WHTVZRBIWZFKQO-UHFFFAOYSA-N 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000006356 dehydrogenation reaction Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 210000002196 fr. b Anatomy 0.000 description 2
- GWOFUCIGLDBNKM-UHFFFAOYSA-N glafenine Chemical compound OCC(O)COC(=O)C1=CC=CC=C1NC1=CC=NC2=CC(Cl)=CC=C12 GWOFUCIGLDBNKM-UHFFFAOYSA-N 0.000 description 2
- 229960001650 glafenine Drugs 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 2
- 239000011976 maleic acid Substances 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- WHTVZRBIWZFKQO-AWEZNQCLSA-N (S)-chloroquine Chemical compound ClC1=CC=C2C(N[C@@H](C)CCCN(CC)CC)=CC=NC2=C1 WHTVZRBIWZFKQO-AWEZNQCLSA-N 0.000 description 1
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- HTKGKUISLUERQX-UHFFFAOYSA-N 2-[(7-chloroquinolin-4-yl)amino]benzoic acid Chemical compound OC(=O)C1=CC=CC=C1NC1=CC=NC2=CC(Cl)=CC=C12 HTKGKUISLUERQX-UHFFFAOYSA-N 0.000 description 1
- JYYLQSCZISREGY-UHFFFAOYSA-N 2-amino-4-chlorobenzoic acid Chemical compound NC1=CC(Cl)=CC=C1C(O)=O JYYLQSCZISREGY-UHFFFAOYSA-N 0.000 description 1
- KNDOFJFSHZCKGT-UHFFFAOYSA-N 4-chloroquinoline Chemical compound C1=CC=C2C(Cl)=CC=NC2=C1 KNDOFJFSHZCKGT-UHFFFAOYSA-N 0.000 description 1
- 150000005653 4-chloroquinolines Chemical class 0.000 description 1
- CVICEEPAFUYBJG-UHFFFAOYSA-N 5-chloro-2,2-difluoro-1,3-benzodioxole Chemical group C1=C(Cl)C=C2OC(F)(F)OC2=C1 CVICEEPAFUYBJG-UHFFFAOYSA-N 0.000 description 1
- DUQIMDPEIHBKCJ-UHFFFAOYSA-N 7-chloro-3h-quinolin-4-one Chemical compound O=C1CC=NC2=CC(Cl)=CC=C21 DUQIMDPEIHBKCJ-UHFFFAOYSA-N 0.000 description 1
- OVCDSSHSILBFBN-UHFFFAOYSA-N Amodiaquine Chemical compound C1=C(O)C(CN(CC)CC)=CC(NC=2C3=CC=C(Cl)C=C3N=CC=2)=C1 OVCDSSHSILBFBN-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N N-phenyl amine Natural products NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 1
- 229910019213 POCl3 Inorganic materials 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 229910000831 Steel Inorganic materials 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 150000001448 anilines Chemical class 0.000 description 1
- 230000000078 anti-malarial effect Effects 0.000 description 1
- 238000005899 aromatization reaction Methods 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 229960003677 chloroquine Drugs 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000005695 dehalogenation reaction Methods 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 210000003918 fraction a Anatomy 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000003822 preparative gas chromatography Methods 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- VSGPVHSTVTXREH-UHFFFAOYSA-N quinolin-4-one Chemical compound C1=CC=C[C]2C(=O)C=CN=C21 VSGPVHSTVTXREH-UHFFFAOYSA-N 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000010959 steel Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or 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
- C07D215/20—Oxygen atoms
- C07D215/22—Oxygen atoms attached in position 2 or 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or 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
- C07D215/20—Oxygen atoms
- C07D215/22—Oxygen atoms attached in position 2 or 4
- C07D215/233—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 4
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Quinoline Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
DK 157018 B
Den foreliggende opfindelse angàr en særlig frem-gangsmâde til fremstilling af 4-hydroxyquinoliner med den almene formel I
OH
5 ΗΊ (I) *<s yk hvori R betyder 1-3 halogenatorner i stillingerne 2, 3, 5, 10 6, 7 eller 8, ud fra en 1,2,3,4-tetrahydroguinolin-4-on
med den almene formel II
(II) 15 ^
H
hvori R har den ovenfor angivne betydning.
Forbindelserne med den almene formel I er mellempro-dukter, der er af særlig interesse til syntese af terapeutisk 20 virksomme forbindelser sâsom glafenin, dvs. dihydroxypropyl-esteren af N-(7-chlor-4-quinolyl)-anthranilsyre, der er et kraftigt analgetikum, samt klorokin, dvs. 7-chlor-4-(4-di-ethylamino-l-methylbutylamino)-quinolin, og amodiakin, dvs.
7-chlor-4- (3-diethylaminomethyl-4-hydroxyphenylamino) -quino-25 lin, der udviser bemærkelsesværdige egenskaber mod malaria.
Det er kendt, at fremstille en 4-hydroxyquinolin ud fra en tilsvarende quinolin-4-on, enten ved katalytisk dehy-drogenering i nærværelse af palladium pâ carbon (W.S. Johnson og B. G. Buell, J. Amer. Chem. Soc., 74., 4513 (1952) eller 30 ved hydrogenoverf0ring katalyseret af palladium pâ carbon i nærværelse af maleinsyre, jfr. US-patentskrift nr. 2.558.211.
Nâr der anvendes en l,2,3,4-tetrahydroquinolin-4-on med formlen II, hvori R betyder et halogenatom, efterfolges aromatiseringen imidlertid af en dehalogenering, hvilket 35 f0rer til, at der fâs en blanding af halogeneret 4-hydroxyquinolin og 4-hydroxyquinolin.
2
DK 157018 B
Det har nu if0lge den foreliggende opfindelse vist sig, at 4-hydroxyquinoliner med den almene formel I kan fâs ved, at tilsvarende 1,2,3,4-tetrahydroquinolin-4-oner oxide-res i basisk medium under tryk ved hjælp af oxygen eller 5 luft i overskud ved en temperatur mellem 80 og 150°c.
Oxidationen gennemfores i et basisk medium, der for-trinsvis bestâr af en vandig oplosning af et alkalimetal-hydroxid, sâsom natriumhydroxid. Det er særlig hensigtsmæs-sigt at anvende 0,5-3 mol alkalimetalhydroxid pr. mol 10 l,2,3,4-tetrahydroquinolin-4-on. En for0gelse af koncentra-tionen af alkalimetalhydroxid medf0rer sædvanligvis en for-0gelse af reaktionshastigheden.
For at reaktionen skal kunne gennemf0res, er det n0dvendigt at arbejde ved et tryk, der sædvanligvis er mellem 15 2 og 15 bar, idet luft eller oxygen indspr0jtes i passende mængde i den omr0rte reaktionsblanding. En for0gelse af trykket medf0rer sædvanligvis en for0gelse af reaktionshastigheden .
Af bekvemmelighedsgrunde er det særlig hensigtsmæssigt 20 at gennemf0re reaktionen ved en temperatur mellem 90 og 100°, ved et tryk mellem 5 og 10 bar og under anvendelse af 1- 2 mol natriumhydroxid pr. mol 1,2,3,4-tetrahydroquinolin- 4-on. Under disse betingelser er reaktionen afsluttet efter 2- 6 timers opvarmning.
25 Ved fremgangsmâden if0lge opfindelsen er det muligt at fâ den fremstillede halogen-4-hydroxyquinolin praktisk taget fri for 4-hydroxyquinolin.
Den if0lge den foreliggende opfindelse fremstillede 4-hydroxyquinolin med den almene formel I kan skilles fra 30 reaktionsblandingen og renses ved anvendelse af sædvanlige metoder, sâsom krystallisation eller chromatografi.
Den som udgangsforbindelse anvendte 1,2,3,4-tetrahy-droquinolin-4-on med formlen II kan hensigtsmæssigt fremstil-les ved en ringslutning af en tilsvarende 3-anilinopropion-35 syre ved hjælp af en blanding af flussyre og bortrifluorid.
3
DK 157018 B
3-Anilinopropionsyren kan fremstilles ved, at acryl-syre omsættes med et overskud af en pâ passende mâde sub-stitueret anilin. Denne reaktion gennemfdres sædvanligvis i vand ved en temperatur mellem 70 og 100°C. Reaktionstiden 5 er mellem 1 og 4 timer.
Ifdlge den foreliggende opfindelse fremstillet 7-chlor-4-hydroxyquinolin kan omdannes til glafenin if0lge metoden, der beskrives i FR-patentskrift nr. 2413 M, efter omdannelse til 4,7-dichlorquinolin ved hjælp af f.eks. phos-10 phoroxychlorid.
Opfindelsen illustreres ved de fdlgende eksempler. Eksempel 1 I en autoklav af stâl med et volumen pâ 400 cm3f der 15 er forsynet med bladomr0rer, en kdler og en anordning til tilledning eller fjernelse af gas, anbringes 18,15 g (100 mmol) 7-chlor-l,2,3,4-tetrahydroquinolin-4-on, 8,0 g (200 mmol) natriumhydroxid og 200 g vand.
Reaktionsbeholderen opvarmes til 90 eC. Trykket ind-20 stilles pâ 10 bar. Luft indeholdende 21% oxygen indsprdjtes i overskud i den omrdrte reaktionsmasse i en mængde pâ 12 g/time.
Efter opvarmning i 2 timer og 30 minutter afk0les reaktionsbeholderen til en temperatur nær 20"C, og trykket 25 saenkes til atmosfæretryk.
Reaktionsmassen ekstraheres med methylenchlorid. Methylenchloridfasen inddampes til tdrhed. Herved fâs 0,96 g af et lysegult fast stof indeholdende 98,2% 7-chlor- 1,2,3,4-tetrahydroquinolin-4-on (5,2 mmol) bestemt ved væske-30 chromatografi.
Vandfasens pH-værdi indstilles pâ 6,0 ved tilsætning af IN svovlsyre. Det hvide mælkeagtige bundfald frafiltreres og tdrres. Herved fâs 15,92 g af et flddefarvet produkt, der indeholder 98,15 vægtprocent 4-hydroxy-7-chlorquinolin 35 (87,0 mmol) bestemt ved væskechromatografi.
4
DK 157018 B
Filtratet gores surt til en pH-værdi pâ 2,5 ved til-sætning af IN svovlsyre og ekstraheres derefter med methy-lenchlorid. Methylenchloridfasen inddampes til torhed. Herved fâs 1,15 g af et brunt produkt. Ved hjælp af væskechromato-5 grafi vises det, at dette produkt indeholder 0,59 g (3,4 mmol) 4-hydroxy-7-chlorquinolin og 0,31 g (1,8 mmol) 2-amino--4-chlorbenzoesyre.
Mængden af chloridioner i den tilbageværende vandfase bestemmes til 2,9 mmol ved hjælp af argentimetri.
10 Graden af omdannelse af 7-chlor-l,2,3,4-tetrahydro- quinolin-4-on er 94,8% og udbyttet af 4-hydroxy-7-chlor-quinolin er 95,3% beregnet pâ omdannet 7-chlor-l, 2,3,4-tetra-hydroquinolin-4-on.
Den som udgangsforbindelse anvendte 7-chlor-l,2,3,4-15 -tetrahydroquinolin-4-on kan fremstilles pâ folgende mâde.
I en reaktionsbeholder af rustfrit stâl indeholdende 50 g flydende flussyre afkdlet til 5eC anbringes 10 g 3-m--chloranilinopropionsyre (94,5%'s). Oplosningen mættes med gasformigt bortrifluorid. Indholdet i reaktionsbeholderen 20 holdes herved ved 20“C og mættes med gasformigt bortrifluorid under et tryk pâ 12 bar i 1 time. Reaktionsbeholderen lukkes derefter og opvarmes ved 80°C i 20 timer.
Under opvarmningen stiger trykket forst til 20 bar, hvorefter det gradvist faider og stabiliserer sig ved 16 25 bar. Reaktionsbeholderen afkoles derefter til 10°C, hvorefter den âbnes pâ en sâdan mâde, at bortrifluoridet frig0res.
Den fremkomne rodlige væske hældes i en blanding af vand og is. Efter ekstraktion med 3 x 100 cm3 chloroform vaskes det organiske lag flere gange med 100 cm3 vand, indtil pH-værdien 30 er mellem 3 og 4, hvorefter det organiske lag tdrres over natriumsulfat. Efter filtrering og koncentrering til t0rhed under formindsket tryk (10 mm Hg) fâs 9 g krystalliseret 7-chlor-l,2,3,4-tetrahydroquinolin-4-on, hvis renhedsgrad bestemmes til 94,5% ved hjælp af gaschromatografi.
35 Omdannelsesgraden er 100%, og udbyttet er 99%, bereg net pâ 3-m-chloranilinopropionsyre.
5
DK 157018 B
Ved hjælp af gaschromatografi bestemmes indholdet af 5-chlorisomer til ca. 0,7%.
Eksempel 2-9 5 Der gâs frem pâ samme mâde som i eksempel 1 og gâs hver gang ud fra 18,15 g (100 mmol) 7-chlor-l,2,3,4-tetrahy-droquinolin-4-on, men reaktionsparametrene varieres. De opnâede resultater er sammenfattet i tabellen nedenfor. De i tabellen anvendte forkortelser har f0lgende betydninger.
10 Q = 7-chlor-l,2,3,4-tetrahydroquinolin-4-on OCQ = 4-hydroxy-7-chlorquinolin OH/Q = molforholdet mellem natriumhydroxid og 7-chlor-l,2,3,4-tetrahydroquinolin-4-on TT = graden af omdannelse af 7-chlor-l,2,3,4-tetra-15 hydroquinolin-4-on RT = udbyttet i forhold til omdannet 7-chlor--1,2,3,4-tetrahydroquinolin-4-on.
20 25 30 35 6
Γ---—1· DK 157018 B
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DK 157018 B
Sammenliqninqseksempel
Dehydrogenering af 7-chlor-4-quinolinon under beting-elserne if0lge eksempel 1 i US patentskrift nr. 2.558.211.
En blanding af 1,913 g 7-chlor-l,2,3,4-tetrahydro-5 -quinolin-4-on, 2,014 g maleinsyre og 0,1985 g palladium pâ carbon (med 10% palladium) i 50 ml vand omreres under tilbagesvaling i 22 timer.
Efter afkqling tilsættes 10 ml 10N natriumhydroxidop-l0sning til opl0sning af den dannede blanding af 4-hydroxy-10 guinoliner, og de faste faser (katalysator og quinolinon) fraskilles ved filtrering.
Det ikke omdannede quinolinon genvindes ved vaskning af filteret og ekstraktion af filtratet med ether. Der fâs en t0r remanens (A) pâ 0,188 g i form af en gui olie.
15 Filtratet indeholdende blandingen af 4-hydroxyquino- liner g0res surt til en pH-værdi pâ 6 ved tilsætning af salt-syre. 4-Hydroxyquinolinerne ekstraheres med n-butanol.
Der fâs efter inddampning 1,571 g hvidt fast stof (B).
20 Analyse ved gaschromatografi viser, at fraktionen A
ikke indeholder 7-chlor-l,2,3,4-tetrahydro-quinolin-4-on (omdannelsesgrad: 100%).
Fraktion B giver ved tyndtlagschromatografi to plet-ter, hvis Rf-værdier svarer til 4-hydroxyquinolin og 7-chlor-25 -4-hydroxy-quinolin.
En del af fraktionen B behandles med POCI3. De sâledes fremstillede 4-chlorquinoliner analyseres ved gaschromatogra fi.
Der fâs sâledes 4,7-dichlorquinolin med et udbytte 30 pâ 13,7% i forhold til det anvendte quinolinon og 4-chlor-quinolin i et udbytte pâ 50% i forhold til det anvendte quinolinon.
De to sâledes fremstillede produkter er karakteriseret ved: 35 gaschromatografi i forbindelse med massespektrometri, 8
DK 157018 B
deres tilbageholdelsestid i sammenligning med refe-renceprodukter.
For det andet produkt, der er isoleret ved præparativ gaschromatografi, bekræftes 4-stillingen af chlorsubstituen-5 ten ved proton-NMR ved 360 MHz.
Claims (5)
1. Fremgangsmâde til fremstilling af en 4-hydroxy-quinolin med den almene formel I OH
5 Jv (I) hvori R betyder 1-3 halogenatomer i stillingerne 2, 3, 5, 10 6, 7 eller 8, ud fra en l,2,3,4-tetrahydroquinolin-4-on med den almene formel II 0 II R-| I (II) 15 H hvori R har den ovenfor angivne betydning, kendeteg-n e t ved, at forbindelsen med formlen II oxideres i basisk medium under tryk ved hjælp af et overskud af oxygen eller 20 luft ved en temperatur mellem 80 og 150"C.
2. Fremgangsmâde if0lge krav 1, kendeteg- n e t ved, at det basiske medium bestâr af en vandig opl0s-ning af et alkalimetalhydroxid.
3. Fremgangsmâde if0lge krav 2, kendeteg- 25 net ved, at alkalimetalhydroxidet er natriumhydroxid.
4. Fremgangsmâde if0lge krav 2, kendeteg- net ved, at der anvendes 0,5-3 mol alkalimetalhydroxid pr. mol anvendt l,2,3,4-tetrahydroquinolin-4-on.
5. Fremgangsmâde if0lge krav 1, kendeteg- 30 net ved, at reaktionen gennemfores ved et tryk pâ 2-15 bar.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR8210615A FR2528836A1 (fr) | 1982-06-17 | 1982-06-17 | Procede de preparation d'hydroxy-4 quinoleines |
| FR8210615 | 1982-06-17 |
Publications (4)
| Publication Number | Publication Date |
|---|---|
| DK277783D0 DK277783D0 (da) | 1983-06-16 |
| DK277783A DK277783A (da) | 1983-12-18 |
| DK157018B true DK157018B (da) | 1989-10-30 |
| DK157018C DK157018C (da) | 1990-03-26 |
Family
ID=9275118
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK277783A DK157018C (da) | 1982-06-17 | 1983-06-16 | Fremgangsmaade til fremstilling af 4-hydroxyquinoliner |
Country Status (13)
| Country | Link |
|---|---|
| US (1) | US4508902A (da) |
| EP (1) | EP0097585B1 (da) |
| JP (1) | JPS597170A (da) |
| KR (1) | KR900006098B1 (da) |
| AT (1) | ATE18762T1 (da) |
| CA (1) | CA1193262A (da) |
| DE (1) | DE3362676D1 (da) |
| DK (1) | DK157018C (da) |
| FR (1) | FR2528836A1 (da) |
| HU (1) | HU189698B (da) |
| IE (1) | IE55430B1 (da) |
| IN (1) | IN159883B (da) |
| ZA (1) | ZA834437B (da) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH01250380A (ja) * | 1987-12-26 | 1989-10-05 | Tokyo Tanabe Co Ltd | 光学活性ベンゾキノリジン誘導体、その製造方法およびそれを有効成分とする抗菌剤 |
| CN108794396B (zh) * | 2018-07-06 | 2020-06-02 | 浙江工业大学 | 4-氧代-2,3-二氢喹啉类化合物的氧化方法 |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2558211A (en) * | 1949-04-14 | 1951-06-26 | Lilly Co Eli | Preparation of 4-hydroxyquinoline compounds |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2498186A1 (fr) * | 1981-01-16 | 1982-07-23 | Rhone Poulenc Sante | Preparation de la chloro-5, -6, -7 ou -8 hydroxy-4 quinoleine |
-
1982
- 1982-06-17 FR FR8210615A patent/FR2528836A1/fr active Granted
-
1983
- 1983-06-16 CA CA000430583A patent/CA1193262A/fr not_active Expired
- 1983-06-16 DE DE8383401242T patent/DE3362676D1/de not_active Expired
- 1983-06-16 IN IN410/DEL/83A patent/IN159883B/en unknown
- 1983-06-16 KR KR8302692A patent/KR900006098B1/ko not_active Expired
- 1983-06-16 IE IE1422/83A patent/IE55430B1/en unknown
- 1983-06-16 EP EP83401242A patent/EP0097585B1/fr not_active Expired
- 1983-06-16 US US06/504,954 patent/US4508902A/en not_active Expired - Fee Related
- 1983-06-16 DK DK277783A patent/DK157018C/da not_active IP Right Cessation
- 1983-06-16 AT AT83401242T patent/ATE18762T1/de not_active IP Right Cessation
- 1983-06-16 JP JP58106816A patent/JPS597170A/ja active Granted
- 1983-06-16 HU HU832157A patent/HU189698B/hu not_active IP Right Cessation
- 1983-06-16 ZA ZA834437A patent/ZA834437B/xx unknown
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2558211A (en) * | 1949-04-14 | 1951-06-26 | Lilly Co Eli | Preparation of 4-hydroxyquinoline compounds |
Also Published As
| Publication number | Publication date |
|---|---|
| ZA834437B (en) | 1984-03-28 |
| CA1193262A (fr) | 1985-09-10 |
| DK277783A (da) | 1983-12-18 |
| DE3362676D1 (en) | 1986-04-30 |
| DK157018C (da) | 1990-03-26 |
| IE55430B1 (en) | 1990-09-12 |
| ATE18762T1 (de) | 1986-04-15 |
| FR2528836B1 (da) | 1984-12-21 |
| KR840005102A (ko) | 1984-11-03 |
| KR900006098B1 (en) | 1990-08-22 |
| US4508902A (en) | 1985-04-02 |
| HU189698B (en) | 1986-07-28 |
| EP0097585A1 (fr) | 1984-01-04 |
| JPS597170A (ja) | 1984-01-14 |
| FR2528836A1 (fr) | 1983-12-23 |
| EP0097585B1 (fr) | 1986-03-26 |
| DK277783D0 (da) | 1983-06-16 |
| IN159883B (da) | 1987-06-13 |
| JPH0368861B2 (da) | 1991-10-30 |
| IE831422L (en) | 1983-12-17 |
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| Date | Code | Title | Description |
|---|---|---|---|
| PBP | Patent lapsed |