NO329020B1 - Difluorpyridiner - Google Patents

Difluorpyridiner Download PDF

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NO329020B1
NO329020B1 NO20045259A NO20045259A NO329020B1 NO 329020 B1 NO329020 B1 NO 329020B1 NO 20045259 A NO20045259 A NO 20045259A NO 20045259 A NO20045259 A NO 20045259A NO 329020 B1 NO329020 B1 NO 329020B1
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mol
alkyl
stirred
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added
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NO20045259L (no
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Arnold Paessens
Juergen Stoltefuss
Siegfried Goldmann
Thomas Kramer
Ulrich Niewohner
Karl-Heinz Schlemmer
Olaf Weber
Erwin Graef
Stefan Lottmann
Kark Deres
Jorn Stolting
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Bayer Schering Pharma Ag
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/20—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D239/22—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to ring carbon atoms
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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    • 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
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • 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
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    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

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Abstract

Difluorpyridiner med formel: samt salter derav.

Description

Foreliggende oppfinnelse angår nye difluorpyridinforbindelser. Forbindelsene ifølge oppfinnelsen kan anvendes som mellomprodukt for fremstilling av terapeutisk aktive dihydropyrimidinforbindelser.
Fra EP 103 796 A2 er det allerede kjent dihydropyirmidiner med en kretsløppåvirkende virkning.
Forbindelsene ifølge foreliggende oppfinnelse finner anvendelse ved fremstilling av nye dihydropyrimidinforbindelser med den generelle formel (I)
henholdsvis den isomere form (Ia)
der
R<1> betyr fenyl, furyl, tienyl, triazolyl, pyridyl, cykloalkyl med 3 til 6 karbonatomer eller rester med formlene hvorved ovenfor angitteringsystemer eventuelt kan være substituert med en eller flere, like eller forskjellige substituenter valgt fra gruppen halogen, trifluormetyl, nitro, cyano, trifluormetoksy, karboksyl, hydroksyl, (Ci-C6)-alkoksy, (Ci-Ce)-alkoksykarbonyl og (Ci-C6)-alkyl, som i sin tur kan være substituert med aryl med 6 til 10 karbonatomer eller halogen,
og/eller de anførte ringsystemer eventuelt er substituert med grupper med formlene -S-R<6>, NR<7>R<8>, CO-NR9R' °, SO2-CF3 og -A-CH2-R11,
der
R<6> betyr fenyl som eventuelt er substituert med halogen,
R<7>, R<8>, R<9> og R<10> er like eller forskjellige og betyr hydrogen, fenyl, hydroksy-substituert fenyl, hydroksy, (Ci-Ce)-acyl eller (Ci-C6)-alkyl, som i sin tur kan være substituert med hydroksy, (Ci-C6)-alkoksykarbonyl, fenyl eller hydroksy substituert fenyl,
A betyr en rest O, S, SO eller S02,
R<11> betyr fenyl som eventuelt er substituert en eller flere ganger, likt eller forskjellig,
med substituenter valgt fra gruppen halogen, nitro, trifluormetyl, (Ci-Ce)-alkyl og (Ci-C6)-alkoksy,
R<2> betyr en rest med formelen -XR<12> eller -NR13R14
der
X betyr en binding eller oksygen,
R12 betyr hydrogen, rett eller forgrenet (Ci-Ce)-alkoksykarbonyl eller en rett,
forgrenet eller cyklisk, mettet eller umettet (Ci-C8)-hydrokarbonrest, som eventuelt inneholder en eller to like eller forskjellige heterokjedeledd fra gruppen O, CO, NH, -NH-(Ci-C4)-alkyl, -N-((Ci-C4)-alkyl)2, S eller S02 og som eventuelt er substituert med halogen, nitro, cyano, hydroksy, aryl med 6 til 10 karbonatomer eller aralkyl med 6 til 10 karbonatomer, heteroaryl eller en gruppe med formelen -NR15R<16>,
der
R<15> og R<16> er Uke eller forskjellige og betyr hydrogen, benzyl eller (Ci-C6)-alkyl,
R13 og R<14> er like eller forskjellige og betyr hydrogen, (Ci-Ce)-alkyl eller cykloalkyl med 3 til 6 karbonatomer,
R<3> betyr hydrogen, amino eller en rest med formelen,
eller betyr formyl, cyano, trifluormetyl eller pyridyl, eller betyr en rett, forgrenet eller cyklisk, mettet eller umettet hydrokarbonrest med opp til 8 karbonatomer som eventuelt er substituert en eller flere ganger, likt eller forskjellig, med aryloksy med 6 til 10 karbonatomer, azido, cyano, hydroksy, karboksyl, (Ci-C6)-alkoksykarbonyl, en 5- til 7-leddet heterocyklisk ring, (C]-C6)-alkyltio eller (Ci-C6)-alkoksy, som på sin side kan være substituert med azido eller amino,
og/eller er substituert med triazolyl som på sin side kan være substituert opp til tre ganger med (Ci-C6)-alkoksykarbonyl,
og/eller kan være substituert med grupper med formlene -OSO2-CH3 eller (CO)a-NR<1>7R18,
der
a er ettall 0 eller 1,
R<17> og R<18> er like eller forskjellige og betyr hydrogen eller aryl, aralkyl med 6 til 10 karbonatomer,
eller betyr (Ci-C6)-alkyl som eventuelt er substituert med (Ci-Ce)-alkoksykarbonyl, hydroksyl, fenyl eller benzyl, hvorved fenyl eller benzyl eventuelt er substituert en eller flere ganger, lik eller forskjellig, med hydroksy, karboksyl, (Ci-C6)-alkyl eller (Ci-CeHlkoksy,
eller (Ci-C6)-alkyl som eventuelt er substituert med grupper med formlene NH-CO-CH3 eller NH-CO-CF3,
eller
R<17> og R18 sammen med nitrogenatomet danner en morfolin-, piperidinyl- eller pyrrolidinylring,
eller
R<3> betyr fenyl som eventuelt er substituert med metoksy,
eller
R<2> og R<3> danner sammen en rest med formelen
R<4> betyr hydrogen, (Ci-C4)-alkyl, (C2-C4)-alkenyl, benzoyl eller betyr acyl med 2 til
6 karbonatomer,
R<5> betyr pyridyl som er substituert opp til 3 ganger, likt eller forskjellig, med halogen, hydroksy, cyano, trifluormetyl, (Ci-C6)-alkoksy, (Ci-C6)-alkyl, (Ci-Ce)-alkyltio, karbalkoksy, (Ci-C6)-acyloksy, amino, nitro, mono- eller (Ci-Ce)-dialkylamino,
samt deres salter.
Eksempler på forbindelser som kan fremstilles ved anvendelse av forbindelsen ifølge oppfinnelsen er gitt i den etterfølgende tabellen.
Foreliggende oppfinnelsen vedrører en forbindelse med formelen:
samt salter derav. De tidligere nevnte sluttprodukter kan fremstilles ved anvendelse av denne forbindelsen. Når det gjelder saltene av denne forbindelsen, skal det henvises til de ovenfor nevnte syreaddisjonssalter og særlig til hydroklond. Fremstillingen av disse forbindelser skjer som beskrevet i eksemplene og med henblikk på dette, henvises det til det nedenfor viste reaksjonsskjema.
Videre angår oppfinnelsen også en forbindelse med den følgende formel, fra hvilken det tilsvarende amidinmellomprodukt kan fremstilles på den i eksemplene beskrevne måte:
Fremgangsmåten ovenfor illustreres når det gjelder 3,5-difluorpyridylforbindelsene ved det følgende reaksjonsskjema:
Oppfinnelsen skal illustreres nærmere ved de følgende eksempler.
Eksempel 1
3 -fluorpyridin-N-oksid
11,10 g (114,324 mmol) 3-fluorpyridin ble oppløst i 74,00 ml eddiksyre. Dertil ble det satt til 22,20 ml H2O2 og det hele ble omrørt i 7 timer ved en badtemperatur på 100°C. Deretter ble det hele dampet inn til 30 ml, 30 ml vann ble tilsatt og det hele ble dampet inn nok en gang til 30 ml. Oppløsningen ble omrørt med diklormetan, gjort basisk ved tilsetning av K2CO3, separert og den vandige fase rystet ut ganger med diklormetan, tørket og dampet inn.
Utbytte: 11,5 g (88,9%)
Smeltepunkt: 66 - 68°C
Eksempel II
2-cyano-3-fluorpyridin
5,20 g (45,980 mmol) av forbindelsen fra Eksempel 1 ble oppløst i 50 ml acetonitril. Under argon ble det tilsatt 13,70 g (138,092 mmol) trimetylsilylnitril
og man lot langsomt 12,80 ml trietylamin dryppe til. Løsningen ble så omrørt i 7 timer under tilbakeløp over natten ved romtemperatur. Etter inndamping med en vannstrålepumpe ble det hele tatt opp i diklormetan, rystet med 2 x 50 ml 2N natriumkarbonat, vasket med vann, tørket og dampet inn.
Utbytte (urent): 5,3 g (olje)
Søylekromatografi: metylenklorid -> metylenklorid:eddikester 10:1.
Oljen ble fast!
Eksempel III
2-amidino-3-fluorpyridin-hydroklorid
10,30 g (84,355 mmol) av forbindelsen fra Eksempel II ble oppløst i 30 ml metanol. Oppløsningen ble tilsatt en oppløsning av 0,40 g (17,391 mmol) natrium i 65 ml metanol og omrørt i 72 timer ved 20°C. 5,44 g (101,682 mmol) ammoniumklorid (knust i morter) og 17,39 mmol (1,04 ml) eddiksyre ble tilsatt, det hele så omrørt i 28 timer ved 40°C og avkjølt. Det ble sugd av fra ikke-oppløselig salt (1,78 g), dampet inn med aceton og deretter omrørt med aceton, sugd av og vasket.
Utbytte: 10,6 g
Smeltepunkt: « 150°C under spalting.
Eksempel IV
2-cyano-3,5-diklor-pyridin
Metode 1:
26 g (0,158 mol) 3,5-diklor-pyridin-l-oksid (Johnson et al., J.Chem.Soc.B, 1967, 1211) ble oppløst i 80 ml CH2C12 og deretter ble det tilsatt 21,8 ml (0,174 mol) trimetylsilylcyanid og 14,6 ml (0,158 mol) dimetylkarbamidsyreklorid og det hele så omrørt i 48 timer ved romtemperatur. Deretter ble det tilsatt 100 ml av en 10%-ig NaHC03-oppløsning og det hele omrørt intenst i 10 minutter. Etter separering av fasene, ble det rystet ut lx med CH2C12 og de rensede organiske fasene ble tørket og dampet inn. Resten ble kromatografert med CH2C12 på kiselgel og omkrystallisert fra noe metanol.
Man oppnådde 11 g (40,2%) 2-cyano-3,5-diklor-pyridin (Smp.: 102°C).
Metode 2:
Analogt Troschuetz, R. Et al., J. Heterocycl. Chem. 1996, 33, 1815-1821 ble 150 ml dietylenglykoldimetyleter (diglyme), 47,68 g (0,261 mol) 2,3,5-triklorpyridin, 2,0 g (0,005 mol) tetrafenylfosfoniumbromid, 4,0 g (0,024 mol) finpulveret kaliumjodid og 75,0 g (0,838 mol) kopper(I)cyanid blandet under nitrogen og omrørt i 24 timer under tilbakeløp. Deretter ble det tilsatt ytterligere 100 ml diglym, 2,0 g (0,005 mol) tetrafenylfosfoniumbromid, 4,0 g (0,024 mol) finpulveret Kl og 75 g (0,838 mol) CuCN og man omrørte i ytterligere 89 timer under tilbakeløp. Etter avkjøling til romtemperatur ble det hele sugd av og filteret i høy grad befridd for diglym destillativt. Resten ble tatt opp i toluen og så vasket med en vandig oppløsning av Mohrs salt- og så med NaHC03-oppløsning (peroksidtest). Deretter ble det hele vasket diglymfritt med vann. Det ble filtrert over celitt og filtratet tørket over MgS04 hvorved oppløsningen ble dampet inn.
Man oppnådde 18,0 g (40,0%) 2-cyano-3,5-diklorpyridin.
Eksempel V
3,5-difluor-pyridin-2-karbonitril
50 g (0,29 mol) 3,5-diklor-pyridin-2-karbonitril (Eksempel IV), 33,6 g (0,58 mol) kaliumfluorid og 10 g polyetylenglykol 8000 ble tilsatt 125 ml DMSO og det hele oppvarmet i 30 minutter til 160°C. Etter avkjøling ble produktet destillert av sammen med DMSO under høyvakuum, destillatet tilsatt vann, ekstrahert med toluen og tørket over Na2S04. Produktet ble benyttet videre som toluenoppløsning.
(Rf-verdi: 0,43, cykloheksan:eddiksyre = 7:3).
Eksempel VI
3,5-difluor-2-pyridinkarboksimidamid-hydroklorid
33,4 g (0,624 mol) ammoniumklorid ble suspendert i 1 1 toluen og avkjølt til 0 - 5°C. Deretter ble det dryppet 328 ml trimetylaluminium (2 M i heksan, 0,624 mol) og det hele omrørt ved romtemperatur inntil metanutviklingen var ferdig. Deretter ble toluenoppløsningen av 3,5-diklor-pyridin-2-karbonitril (oppløsning fra Eksempel V) dryppet til og det hele så omrørt over natten ved 80°C. Etter avkjøling til 0 til -5°C ble MeOH dryppet til, til avsluttet gassutvikling, saltene sugd av og vasket 2x med litt MeOH. Det hele ble dampet inn med en rotasjonsfordamper, resten oppløst i 500 ml CH^C^MeOH (9:1) og så sugd av igjen fra uorganiske salter. Etter innrotering var det tilbake 23,6 g (39,1%) 3,5-difluor-2-pyridinkarboksimidamid som hydroklorid (Smp. 183°C).
<!>H-NMR (DMSO-D6): 8,3 - 8,45 (m, 1H), 8,8 (d, J=2Hz,lH), 9,7 (s, bred, 4H) ppm.

Claims (2)

1. Forbindelse, karakterisert ved formelen: samt salter derav.
2. Forbindelse, karakterisert ved formelen:
NO20045259A 1998-04-18 2004-12-01 Difluorpyridiner NO329020B1 (no)

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Application Number Priority Date Filing Date Title
DE19817264A DE19817264A1 (de) 1998-04-18 1998-04-18 Neue Dihydropyrimidine
PCT/EP1999/002344 WO1999054326A1 (de) 1998-04-18 1999-04-07 Dihydropyrimidine

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NO20045259L NO20045259L (no) 2000-12-13
NO329020B1 true NO329020B1 (no) 2010-07-26

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NO20005215A NO321985B1 (no) 1998-04-18 2000-10-17 Dihydropyrimidinforbindelser, fremgangsmater for fremstilling av slike, samt fremgangsmate for fremstilling av farmasoytiske preparater og anvendelse av forbindelsene i farmasoytiske preparater for behandling av virussykdommer, saerlig hepatitt B
NO20045259A NO329020B1 (no) 1998-04-18 2004-12-01 Difluorpyridiner

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