NO309766B1 - Fremgangsmåte for fremstilling av 2-aryloksy-4-klorpyridiner - Google Patents
Fremgangsmåte for fremstilling av 2-aryloksy-4-klorpyridiner Download PDFInfo
- Publication number
- NO309766B1 NO309766B1 NO975712A NO975712A NO309766B1 NO 309766 B1 NO309766 B1 NO 309766B1 NO 975712 A NO975712 A NO 975712A NO 975712 A NO975712 A NO 975712A NO 309766 B1 NO309766 B1 NO 309766B1
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- Norway
- Prior art keywords
- compound
- formula
- alkyl
- potassium
- base
- Prior art date
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- 238000000034 method Methods 0.000 title claims abstract description 14
- 238000002360 preparation method Methods 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 29
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims abstract description 10
- 150000003839 salts Chemical class 0.000 claims abstract description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims abstract description 3
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 9
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical group [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 5
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 4
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
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- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical group [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 3
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- 238000006243 chemical reaction Methods 0.000 claims description 3
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- 229910021591 Copper(I) chloride Inorganic materials 0.000 claims description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 2
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- 229910052751 metal Inorganic materials 0.000 description 1
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- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 235000020824 obesity Nutrition 0.000 description 1
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- 201000008482 osteoarthritis Diseases 0.000 description 1
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- 239000000312 peanut oil Substances 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 208000019899 phobic disease Diseases 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 208000028173 post-traumatic stress disease Diseases 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000000306 recurrent effect Effects 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
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- 208000019116 sleep disease Diseases 0.000 description 1
- 208000022925 sleep disturbance Diseases 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 210000000278 spinal cord Anatomy 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
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- 239000000126 substance Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
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- 239000003765 sweetening agent Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen 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
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/64—One oxygen atom attached in position 2 or 6
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen 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
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/64—One oxygen atom attached in position 2 or 6
- C07D213/643—2-Phenoxypyridines; Derivatives thereof
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyridine Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
Foreliggende oppfinnelse vedrører en fremgangsmåte for fremstilling av 2-aryloksy-4-klorpyridiner. Disse forbindelsene er mellomprodukter i syntesen av farmasøytisk aktive 2-fenoksypyridinderivater som viser aktivitet som kortikotropin-frigjørende faktor (CRF) antagonister og er anvendelige ved behandling av flere neurologiske forstyrrelser. Slike farmasøytisk aktive forbindelser, fremgangsmåter for fremstilling av dem og de neuro-logiske forstyrrelser som de er anvendelige i behandling av, er beskrevet i US patentsøknad nr. 08/255.514, som ble innsendt 8. juni 1994. Denne patent-søknad er herved inntatt som henvisning i sin helhet.
Denne oppfinnelsen vedrører en fremgangsmåte for fremstilling av en forbindelse
med formel
hvori
R<1> er (d-C4)alkyl;
R<2> er metyl eller etyl; og
R<3>, R4 og R5 er uavhengig valgt fra (Ci-C4)alkyl og (Ci-C4)alkoksy; eller et farmasøytisk akseptabelt salt derav;
omfattende omsetning av en forbindelse med formelen
hvori R<1> og R<2> er som definert ovenfor, med en forbindelse med formelen
hvori
R<3>, R4 og R5 er som definert ovenfor, i nærvær av en base som er i stand tii å deprotonere forbindelsen med formel III, i nærvær av kobber (I) bromid, kobber(l)klorid eller kobber(l)jodid og py rid in, og deretter eventuelt overføre den resulterende forbindelse med formel I til et farmasøytisk akseptabelt salt av en slik forbindelse.
Egnede baser for denne reaksjonen er natriumhydrid, kaliumhydrid, kaiium-karbonat, cesiumkarbonat, ammoniumhydroksyd, n-butyllitium og litium, natrium eller kalium(Ci-C4)alkoksyd. Eksempler på egnede organometalliske halogenider og oksyder er kobber(l)bromid, -jodid eller -klorid, kobber(ll)oksyd, kobber(l)oksyd, kobbermetall og trialkyltinnklorid. Eksempler på egnede løsningsmidler er tetra-hydrofuran (THF), dimetylsulfoksyd (DMSO), acetonitril, metylenklorid (CH2CI2), 1-metyl-2-pyrrolidinon, pyridin, kinolin, N,N-dialkylacetamid, 2,4,6-trimetylpyridin, N,N-dialkylacetamid, N,N-dialkylformamid (f.eks. N,N-dimetylformamid), heksa-metylfosforamid og toluen. Omsetningstemperaturen kan variere fra ca. 0°C til ca. 180°C, og er fortrinnsvis mellom ca. romtemperatur og ca. 150°C.
En foretrukket utførelsesform av denne oppfinnelsen vedrører den ovennevnte framgangsmåte, hvori forbindelsen med formel I som dannes, er en forbindelse hvori alle R<1>, R<2>, R<3>, R4 og R<5> er metyl, løsningsmiddelet er pyridin, det organometalliske halogenid eller oksyd er kobber(l)jodid, og basen er kalium-t-butoksyd.
Forbindelser med formel I er anvendelige som mellomprodukter ved syntesen
av 2-fenoksypyridinderivater som er kortikotropinfrigjørende faktor (CRF) antagonister, og er anvendelige ved behandling av forstyrrelser for hvilke behandling kan utføres eller lettes ved antagonisering av CRF. Eksempler på slike forstyrrelser er slike valgt fra inflammatoriske forstyrrelser, såsom reumatoid artritt og osteoartritt, smerte, astma, psoriasis og allergier; generaliserte angst-forstyrrelser; panikk; fobier; vekttvangsforstyrelser; post-traumatiske stress-forstyrrelser; søvnforstyrrelser indusert ved stress; smertefølelse såsom fibro-myalgi; synsforstyrrelser såsom depresjon, innbefattende allmen depresjon, enkle episodedepresjon, gjentatt depresjon, barnemishandlingsindusert depresjon og post-partumdepresjon; dystemi; bipolare forstyrrelser; cyklotymi; tretthetssyndrom;
stressindusert hodepine; kreft; irritabelt tarmsyndrom, Crohn's sykdom; tykktarms-kramper; humant immunsviktvirus (HIV) infeksjoner; neurodegenerative sykdommer som Alzheimers sykdom, Parkinson's sykdom og Huntington's sykdom; gastrointestinale sykdommer; spiseforstyrrelser som anoreksia og bulimi nervosa; hemoragisk stress; kjemiske avhengigheter og tilvenninger (f.eks. avhengighet av alkohol, kokain, heroin, benzodiazepiner eller andre droger); droge- eller alkohol-abstinenssymptomer; stressinduserte psykotiske episoder; eutyroide sykdoms-syndromer; syndrom på utilstrekkelig antidiaretisk hormon (ADH); fedme; ufruktbarhet; hodetraumaer; ryggmargtraume; ischemisk neuronal skade (f.eks. cerebral ischemi såsom cerebral hippokampalisk ischemi); eksitotoksisk neuronal skade; epilepsi; slag; immundysfunksjoner .innbefattet stressindusert immundysfunksjoner (f.eks. svinestressyndrom, kveg-"shipping"- feber, hesteparoksysmal fibrillering og dysfunksjoner indusert ved plassmangel hos kyllinger, innesperrings-stress hos sau eller menneske-dyrsamvirkerelatert stress hos hunder); muskel-kramper; urininkontinens; senil dementia av Alzheimers typen; multiinfarkt dementia; amyotropisk lateral sklerose; og hypoglykemi hos pattedyr, innbefattet mennesker.
De farmasøytisk aktive CRF-antagonister som kan fremstilles ved bruk av mellomproduktene med formel I, som fremstilles ved fremgangsmåten i denne oppfinnelsen, er vist nedenunder.
I disse forbindelser er B-NR<6>R<7>, -NHCHR<6>R<7>, -OCHR6R<7> eller -SCHR6R7.
R 1 til og med R 5 er definert som ovenfor;
R<6> er Ci-C6-alkyl som eventuelt kan være substituert med én eller to substituenter R<8> uavhengig valgt fra gruppen bestående av hydroksy, fluor, klor, brom, jod, CF3 og Ci-C4alkoksy, og hvori CrCealkyl og (Ci-C4)alkylresten i nevnte CrC4alkoksy eventuelt kan inneholde én karbon-karbon-dobbel- eller -trippel-binding; og
R7 er Ci-Ci2-alkyl, aryl eller -(Ci-C4-alkylen)aryl, hvor nevnte aryl er fenyl, naftyl, tienyl, benzotienyl, pyridyl, kinolyl, pyrazinyl, pyrimidyl, imidazolyl, furanyl, benzo-furanyl, benzotiazolyl, isotiazolyl, benzisotiazolyl, benzisoksazolyl, benzimidazolyl, indolyl eller benzoksazolyl; 3- til 8-leddet cykioalkyl eller -(CrC6-alkylen)cykloalkyl, hvor ett eller to av ringkarbonatomene i nevnte cykioalkyl har minst 4 ring-elementer, og cykloalkylresten i nevnte -(Ci-C6-alkylen)cykloalkyl har minst 4 ring-elementer, kan eventuelt være erstattet med et oksygen- eller svovelatom eller med N-R<9>, hvori R<9> er hydrogen eller Ci-C4-alkyl; og hvori hver av de foregående R<7->grupper eventuelt kan være substituert med fra én til 3 substituenter uavhengig valgt fra klor, fluor og CrC4-alkyl, eller med én substituent valgt fra brom, jod, Ci-C6-alkoksy, -O-CCMd-Ce-alkyl), -0-CO-N(Ci-C4-alkyl)-(Ci-C2-alkyl), -S(Ci-C6-alkyl), CN, N02, -SO(Ci-C4-alkyl) og -S02(Ci-C4-alkyl), og hvori nevnte C1-C12-alkyl- og Ci-C4-alkylenrest i nevnte -(Ci-C4-alkylen)aryl eventuelt kan inneholde én karbon-karbon-dobbel- eller-trippel-binding; eller -NR6R7 kan danne en mettet 5- til 8-leddet karbocyklisk ring som eventuelt kan inneholde én eller to karbon-karbon-dobbeltbindinger, og hvori ett eller to av ringkarbonene eventuelt kan være erstattet av et oksygen- eller svovelatom.
De farmasøytisk aktive forbindelser omtalt ovenfor, er beskrevet i US patent-søknad 08/255.514, innsendt 8. juni 1994, og som her inntas som henvisning i sin helhet. Fremgangsmåter for fremstilling av slike forbindelser og deres farmasøy-tisk akseptable salter (heretter kollektivt henvist til som "de aktive reagenser") er også angitt i denne søknad.
De aktive midler kan administreres alene eller i kombinasjon med farmasøytisk akseptable bærere i enkelt- eller multiple doser. Egnede farmasøytiske bærere er inerte faste fortynningsmidler eller fyllmidler, sterile vandige løsninger og forskjellige organiske løsningsmidler. De farmasøytiske blandinger dannet ved å kombinere forbindelser med formel I og farmasøytisk akseptable bærere, kan lett administreres i en rekke doseringsformer såsom tabletter, pulvere, pastiller, sirups, injiserbare løsninger og lignende. Disse farmasøytiske blandinger kan, om ønsket, inneholde ytterligere bestanddeler såsom smaksmidler, bindemidler, eksipienter og lignende. Således, for formålet oral administrering, kan tabletter inneholdende forskjellige eksipienter, såsom natriumcitrat, kalsiumkarbonat og kalsiumfosfat, anvendes sammen med forskjellige spregningsmidler såsom stivelse, metylcellulose, alginsyre og visse komplekse silikater, sammen med bindemidler såsom polyvinylpyrroiidon, sukrose, gelatin og akasia. I tillegg er smøremidler såsom magnesiumstearat, natriumlaurylsulfat og talkum, ofte anvendelige for tabletteringsformål. Faste blandinger av en lignende type kan også anvendes som fyllmidler i fylte myk- og hard-gelatinkapsler. Foretrukne materialer for dette innbefatter laktose eller melkesukker og polyetylenglykoler med høy molekylvekt. Når vandige suspensjoner eller eliksirer er ønsket for oral administrering, kan den vesentlig aktive bestanddel deri kombineres med forskjellige søtnings- eller smaksmidler, fargemidler eller fargestoffer og, om ønsket, emulgerings- eller oppslemmingsmidler, sammen med fortynningsmidler såsom vann, etanol, propylenglykol, glycerol og kombinasjoner derav.
For parenteral administrering, kan løsninger inneholdende en aktiv bestanddel
i sesam- eller jordnøttolje, vandig propylenglykol eller en steril vandig løsning anvendes. Slike vandige løsninger bør hensiktsmessig bufres om nødvendig,
og det væskeformige fortynningsmiddel først gjøres isotont med tilstrekkelig saltvann eller glukose. Disse spesielle vandige løsninger er særlig egnet for intravenøs, intramuskukær, subkutan og intraperitoneal administrering. De sterile vandige medier som anvendes, er alle lett tilgjengelige ved standard-teknikker som er kjent for en fagmann på området.
De effektive doser for de aktive midler vil avhenge av den tilsiktede administre-ringsvei og faktorer såsom alder, vekt og tilstand hos pasienten, som generelt kjent for en lege. Doseringen vil også avhenge av den spesielle sykdom som skal behandles. Den daglige dose for stressinduserte sykdommer, inflammatoriske sykdommer, Alzheimers sykdom, gastrointestinale sykdommer, anoreksia nervosa, hemoragisk stress og droge- eller alkoholabstinens-symptomer, vil generelt ligge fra ca. 0,1 til ca. 50 mg/kg kroppsvekt av pasienten som skal behandles.
De følgende eksperimentelle eksempler illustrerer den nye fremgangsmåten.
EKSEMPEL 1
4- Klor- 3. 6- dimetvl- 2- f2. 4. 6- trimetvlfenoksv) pvridin
Til en 2 liters kolbe utstyrt med mekanisk rører, tilbakeløpskjøler og nitrogen-innløp, sattes 250 ml pyridin. Kolben ble avkjølt i et isbad og fylt med 42,5 g (0,312 mmol) 2,4,6-trimetylfenol og 35,1 g (0,313 mol) kalium-t-butoksyd. Kolben ble oppvarmet til romtemperatur og fylt med 50,0 g (0,284 mol) 2,4-diklor-3,6-di-metylpyridin og 13,5 g (0,071 mol) kobber(l)jodid. Reaksjonsblandingen ble oppvarmet til tilbakeløp i 2 timer og deretter avkjølt til 0°C. Reaksjonen ble fortynnet med 500 ml heksaner, deretter blandet med 1000 ml mettet ammonium-klorid (NH4CI). Etter oppvarming til romtemperatur, ble blandingen rørt natten over. Sjiktene ble skilt fra hverandre, og det organiske sjiktet ble vasket med 3 x 125 ml 1 M ammoniumhydroksyd (NH4OH), 2 x 250 ml 3 N natriumhydroksyd (NaOH), 1 x 250 ml 1 N saltsyre (HCI) og 1 x 250 ml vann. Etter tørking over natriumsulfat (Na2S04), ble faststoffene fjernet ved filtrering og vasket med heksan. Filtratet ble inndampet under vakuum til en brun olje. Resten ble blandet med 250 ml metanol og rørt natten over. Den resulterende oppslemming ble filtrert under vakuum. De gråhvite faststoffer ble vasket med metanol og deretter tørket, hvilket ga 31,6 g (40,4%) av tittelforbindelsen.
<1>H NMR (CDCI3): 6,88 (s, 2H), 6,78 (s, 1H), 2,40 (s, 3H), 2,30 (s, 3H), 2,20 (s, 3H), 2,04 (s, 6H) ppm.
Filtratet ble inndampet under vakuum til en olje, og resten ble blandet med 50 ml metanol Etter røring natten over, ble den resulterende oppslemming avkjølt til 0°C og filtrert under vakuum. Faststoffene ble vasket med minimal metanol og tørket, hvilket ga ytterligere 16,1 g (20,5%) materiale.
Claims (6)
1. Fremgangsmåte for fremstilling av en forbindelse med formelen
hvori R<1> er (Ci-C4)alkyl;
R2 er metyl eller etyl; og
R<3>, R4 og R<5> er uavhengig valgt fra (CrC4)alkyl og (d-C4)alkoksy; eller et farmasøytisk akseptabelt salt derav;
karakterisert ved omsetning av en forbindelse med formelen
hvori
R<1> og R2 er som definert ovenfor, med en forbindelse med formelen
hvori
R<3>, R4 og R<5> er som definert ovenfor, i nærvær av en base som er i stand til å deprotonere forbindelsen med formel III, i nærvær av kobber (I) bromid, kobber(l)klorid eller kobber(l)jodid og pyridin, og deretter eventuelt overføre den resulterende forbindelse med formel I til et farmasøytisk akseptabelt salt av en slik forbindelse.
2. Fremgangsmåte ifølge krav 1, karakterisert ved at basen velges fra natriumhydrid, kaliumhydrid, kaliumkarbonat, cesiumkarbonat, ammoniumhydroksyd, litium(Ci-C4)alkoksyd, natrium- eller kalium(CrC4)alkoksyd og n-butyllitium.
3. Fremgangsmåte ifølge krav 1, karakterisert ved at den gir en forbindelse med formel I, hvori R<1>, R<2>, R3, R4 og R<5> alle er metyl.
4. Fremgangsmåte ifølge krav 1, karakterisert ved at basen er kalium-t-butoksyd.
5. Fremgangsmåte ifølge krav 3, karakterisert ved at basen er kalium-t-butoksyd.
6. Fremgangsmåte ifølge krav 1, karakterisert ved at basen er natriumhydrid eller kalium-t-butoksyd.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| NO975712A NO309766B1 (no) | 1995-06-06 | 1997-12-05 | Fremgangsmåte for fremstilling av 2-aryloksy-4-klorpyridiner |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/IB1995/000437 WO1996039388A1 (en) | 1995-06-06 | 1995-06-06 | Process for converting 2,4-dichloropyridines into 2-aryloxy-4-chloropyridines |
| NO975712A NO309766B1 (no) | 1995-06-06 | 1997-12-05 | Fremgangsmåte for fremstilling av 2-aryloksy-4-klorpyridiner |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| NO975712L NO975712L (no) | 1997-12-05 |
| NO975712D0 NO975712D0 (no) | 1997-12-05 |
| NO309766B1 true NO309766B1 (no) | 2001-03-26 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO975712A NO309766B1 (no) | 1995-06-06 | 1997-12-05 | Fremgangsmåte for fremstilling av 2-aryloksy-4-klorpyridiner |
Country Status (19)
| Country | Link |
|---|---|
| US (1) | US6316631B1 (no) |
| EP (1) | EP0832067B1 (no) |
| JP (1) | JP2989015B2 (no) |
| KR (1) | KR100271513B1 (no) |
| AT (1) | ATE244224T1 (no) |
| CA (1) | CA2222204C (no) |
| CZ (1) | CZ288855B6 (no) |
| DE (1) | DE69531219T2 (no) |
| DK (1) | DK0832067T3 (no) |
| ES (1) | ES2199991T3 (no) |
| FI (1) | FI974435A (no) |
| HU (1) | HU224495B1 (no) |
| IL (1) | IL118482A (no) |
| NO (1) | NO309766B1 (no) |
| NZ (1) | NZ285441A (no) |
| PL (1) | PL177940B1 (no) |
| PT (1) | PT832067E (no) |
| TW (1) | TW371300B (no) |
| WO (1) | WO1996039388A1 (no) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6060478A (en) * | 1996-07-24 | 2000-05-09 | Dupont Pharmaceuticals | Azolo triazines and pyrimidines |
| US6124289A (en) * | 1996-07-24 | 2000-09-26 | Dupont Pharmaceuticals Co. | Azolo triazines and pyrimidines |
| US6313124B1 (en) | 1997-07-23 | 2001-11-06 | Dupont Pharmaceuticals Company | Tetrazine bicyclic compounds |
| US7094782B1 (en) | 1996-07-24 | 2006-08-22 | Bristol-Myers Squibb Company | Azolo triazines and pyrimidines |
| US6191131B1 (en) | 1997-07-23 | 2001-02-20 | Dupont Pharmaceuticals Company | Azolo triazines and pyrimidines |
| US20050171095A1 (en) * | 2004-01-06 | 2005-08-04 | Pfizer Inc | Combination of CRF antagonists and 5-HT1B receptor antagonists |
| DK1919878T3 (da) | 2005-07-21 | 2010-10-25 | Hoffmann La Roche | Pyridazinonderivater som thyroidhormonreceptoragonister |
| EP3137469B1 (en) | 2014-04-28 | 2019-10-09 | Pfizer Inc | Heterocyclic compounds and their use as dopamine d1 ligands |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1210151A (en) | 1967-06-15 | 1970-10-28 | Ishihara Sangyo Co Ltd | Novel compounds of chloro- or methyl substituted pyridyl phenyl ethers |
| EP0001473B1 (en) * | 1977-08-12 | 1988-07-27 | Imperial Chemical Industries Plc | Herbicidal halogenomethyl--pyridyloxy-phenoxy-alkanecarboxylic acids and derivatives, and processes of controlling unwanted plants therewith |
| DD154538A1 (de) | 1979-07-30 | 1982-03-31 | Eberhard Schroetter | Verfahren zur herstellung substituierter 2,4-und 2,6-dihalogen-pyridine |
| DE3205150A1 (de) * | 1982-02-13 | 1983-08-18 | Celamerck Gmbh & Co Kg, 6507 Ingelheim | Pyridinderivate, ihre herstellung und verwendung |
| US5032168A (en) * | 1987-03-18 | 1991-07-16 | Dowelanco | 4-((aryloxy)phenoxy)fluoroalkanoic acid derivatives and their herbicidal uses |
| MY103631A (en) | 1987-11-07 | 1993-08-28 | Sumitomo Chemical Co | Certain insecticidal 6-(phenoxy-2-pyridyl)-methyl-neo-phental ethers |
| US5068336A (en) | 1989-02-27 | 1991-11-26 | Tosoh Corporation | Process for producing 2-(4'-hydroxphenoxy)-3-chloro-5-trifluoromethylpyridine |
-
1995
- 1995-06-06 KR KR1019970708904A patent/KR100271513B1/ko not_active IP Right Cessation
- 1995-06-06 PL PL95323817A patent/PL177940B1/pl not_active IP Right Cessation
- 1995-06-06 NZ NZ285441A patent/NZ285441A/en unknown
- 1995-06-06 AT AT95918714T patent/ATE244224T1/de not_active IP Right Cessation
- 1995-06-06 JP JP52977096A patent/JP2989015B2/ja not_active Expired - Fee Related
- 1995-06-06 CA CA002222204A patent/CA2222204C/en not_active Expired - Fee Related
- 1995-06-06 ES ES95918714T patent/ES2199991T3/es not_active Expired - Lifetime
- 1995-06-06 HU HU9900626A patent/HU224495B1/hu not_active IP Right Cessation
- 1995-06-06 CZ CZ19973934A patent/CZ288855B6/cs not_active IP Right Cessation
- 1995-06-06 DK DK95918714T patent/DK0832067T3/da active
- 1995-06-06 WO PCT/IB1995/000437 patent/WO1996039388A1/en active IP Right Grant
- 1995-06-06 EP EP95918714A patent/EP0832067B1/en not_active Expired - Lifetime
- 1995-06-06 US US09/254,387 patent/US6316631B1/en not_active Expired - Fee Related
- 1995-06-06 DE DE69531219T patent/DE69531219T2/de not_active Expired - Fee Related
- 1995-06-06 PT PT95918714T patent/PT832067E/pt unknown
-
1996
- 1996-03-26 TW TW085103626A patent/TW371300B/zh active
- 1996-05-30 IL IL11848296A patent/IL118482A/xx not_active IP Right Cessation
-
1997
- 1997-12-05 FI FI974435A patent/FI974435A/fi not_active Application Discontinuation
- 1997-12-05 NO NO975712A patent/NO309766B1/no not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| JP2989015B2 (ja) | 1999-12-13 |
| AU700924B2 (en) | 1999-01-14 |
| NO975712L (no) | 1997-12-05 |
| CZ393497A3 (cs) | 1999-01-13 |
| US6316631B1 (en) | 2001-11-13 |
| DK0832067T3 (da) | 2003-09-29 |
| CZ288855B6 (cs) | 2001-09-12 |
| KR19990022424A (ko) | 1999-03-25 |
| EP0832067A1 (en) | 1998-04-01 |
| PT832067E (pt) | 2003-10-31 |
| IL118482A0 (en) | 1996-09-12 |
| HUT78061A (hu) | 1999-07-28 |
| DE69531219D1 (de) | 2003-08-07 |
| NZ285441A (en) | 1999-07-29 |
| HU224495B1 (hu) | 2005-10-28 |
| EP0832067B1 (en) | 2003-07-02 |
| WO1996039388A1 (en) | 1996-12-12 |
| CA2222204C (en) | 2002-02-19 |
| KR100271513B1 (ko) | 2000-12-01 |
| JPH10506634A (ja) | 1998-06-30 |
| FI974435A0 (fi) | 1997-12-05 |
| DE69531219T2 (de) | 2004-02-12 |
| NO975712D0 (no) | 1997-12-05 |
| ATE244224T1 (de) | 2003-07-15 |
| TW371300B (en) | 1999-10-01 |
| IL118482A (en) | 2000-08-13 |
| FI974435A (fi) | 1997-12-05 |
| CA2222204A1 (en) | 1996-12-12 |
| PL323817A1 (en) | 1998-04-27 |
| PL177940B1 (pl) | 2000-02-29 |
| AU2452995A (en) | 1996-12-24 |
| ES2199991T3 (es) | 2004-03-01 |
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Legal Events
| Date | Code | Title | Description |
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| MM1K | Lapsed by not paying the annual fees |