NO793411L - PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE IMIDAZOLD DERIVATIVES. - Google Patents

PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE IMIDAZOLD DERIVATIVES.

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Publication number
NO793411L
NO793411L NO793411A NO793411A NO793411L NO 793411 L NO793411 L NO 793411L NO 793411 A NO793411 A NO 793411A NO 793411 A NO793411 A NO 793411A NO 793411 L NO793411 L NO 793411L
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halogen
stated
formula
hydrogen
procedure
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NO793411A
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Norwegian (no)
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Hans Hoehn
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Squibb & Sons Inc
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Priority claimed from US05/954,730 external-priority patent/US4191831A/en
Priority claimed from US05/954,728 external-priority patent/US4202985A/en
Application filed by Squibb & Sons Inc filed Critical Squibb & Sons Inc
Publication of NO793411L publication Critical patent/NO793411L/en

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    • 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
    • C07D213/61—Halogen atoms or nitro radicals

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

Abstract

"Fremgangsmåte for fremstilling av terapeutisk aktive iinidazolderivater""Process for the preparation of therapeutically active iinidazole derivatives"

Description

Denne oppfinnelse angår fremstilling av nye 2-(lH-imidazol-l-yl)etoksy-derivater av pyridin-5-metanol-og kinolin-3-metanol-forbindelser, og.syreaddisjonssaltene av disse forbindelser. Disse nye forbindelser har de følgende formler: This invention relates to the preparation of new 2-(1H-imidazol-1-yl)ethoxy derivatives of pyridine-5-methanol and quinoline-3-methanol compounds, and the acid addition salts of these compounds. These new compounds have the following formulas:

Symbolene har i formlene I og II og ellers i The symbols have in the formulas I and II and otherwise i

beskrivelsen de følgende betydninger:description the following meanings:

R til R kan hver være hydrogen, hydroksy, halogen, lavere alkoksy, lavere alkyltio eller lavere alkyl. R to R can each be hydrogen, hydroxy, halogen, lower alkoxy, lower alkylthio or lower alkyl.

Betegnelsen lavere alkyl omfatter lineære eller forgrende hydrokarboner inneholdende 1 til 7 karbonatomer. Eksempler omfatter metyl, etyl, propyl, isopropyl og lignende. Betegnelsen lavere alkoksy og lavere alkyltio omfatter slike lavere alkylgrupper bundet til henholdsvis et oksygen- eller svovel-atom, f.eks. metoksy, etoksy, propoksy, butoksy,'t-butoksy, metyltio, etyltio, propyltio, butyltio, isobutyltio,'osv. The term lower alkyl includes linear or branched hydrocarbons containing 1 to 7 carbon atoms. Examples include methyl, ethyl, propyl, isopropyl and the like. The terms lower alkoxy and lower alkylthio include such lower alkyl groups bound to an oxygen or sulfur atom respectively, e.g. methoxy, ethoxy, propoxy, butoxy, t-butoxy, methylthio, ethylthio, propylthio, butylthio, isobutylthio, etc.

I alle disse foretrekkes C-^-C^ lavere alkylgrupper, spesielt<c>r<c>2- In all of these, C-^-C^ lower alkyl groups are preferred, especially<c>r<c>2-

Halogenene er de fire vanlige halogener, idet klor og brom foretrekkes i nevnte rekkefølge. Fortrinnsvis er alle halogener i en enkelt forbindelse like. The halogens are the four usual halogens, chlorine and bromine being preferred in the order mentioned. Preferably, all halogens in a single compound are the same.

Foretrukne forbindelser med formel I og II er de hvorPreferred compounds of formula I and II are those where

R"*" til R"*"0 er hydrogen, lavere alkyl med 1 til 4 karbonatomer eller halogen. R"*" to R"*"O are hydrogen, lower alkyl of 1 to 4 carbon atoms or halogen.

Spesielt foretrukne forbindelser med formel I er de hvor R til R^ er hydrogen, halogen eller lavere alkyl med 1 til 4 karbonatomer, spesielt de hvor R^ er hydrogen eller C,-C. alkyl, Particularly preferred compounds of formula I are those where R to R 1 are hydrogen, halogen or lower alkyl of 1 to 4 carbon atoms, especially those where R 1 is hydrogen or C 1 -C . alkyl,

2 4 5 6 3 2 4 5 6 3

R , R , R og R er hver klor, og R er hydrogen.R , R , R , and R are each chlorine, and R is hydrogen.

Foretrukne forbindelser med formel II er de hvorPreferred compounds of formula II are those where

R"i , R 7 og R nn hver er hydrogen eller halogen, særlig hydrogen; R"i , R 7 and R nn are each hydrogen or halogen, especially hydrogen;

R^, R^, R^ og R^ er hver hydrogen eller halogen, særlig halogen og spesielt klor, og R 5 og R 6 er bundet til henholdsvis 2- og 4-stilling i fenylringen. R^, R^, R^ and R^ are each hydrogen or halogen, especially halogen and especially chlorine, and R 5 and R 6 are bound to the 2- and 4-position respectively in the phenyl ring.

De nye forbindelser med formel I fremstilles ved den følgende serie av reaksjoner. The new compounds of formula I are prepared by the following series of reactions.

En pyridin-5-karboksylsyreester med formelenA pyridine-5-carboxylic acid ester with the formula

reduseres ved hjelp av et reduksjonsmiddel, f.eks. et metall-hydrid så som litiumaluminiumhydrid eller natriumborhydrid6.1., for å danne en alkohol med formelen Alkoholen med formel IV omdannes derefter til halogen-metylderivatet med formel V hvor X betyr et halogenatom, fortrinnsvis klor, brom eller jod, ved hjelp av et uorganisk syrehalogenid så som tionylklorid, fosforoksybromid osv. Produktet med formel I fremstilles derefter ved omsetning av halogenforbindelsen med formel V med en substituert 1-(feny1)-2-(lH-imidazol-l-y1)etanol med formelen Den uorganiske syre som dannes under omsetningen, nøytraliseres med en base, f.eks. alkalimetallhydroksyd, -karbonat, -amin, -alkoholat eller andre lignende kjente midler. is reduced using a reducing agent, e.g. a metal hydride such as lithium aluminum hydride or sodium borohydride6.1., to form an alcohol of the formula The alcohol of formula IV is then converted into the halomethyl derivative of formula V where X represents a halogen atom, preferably chlorine, bromine or iodine, by means of a inorganic acid halide such as thionyl chloride, phosphoroxybromide, etc. The product of formula I is then prepared by reacting the halogen compound of formula V with a substituted 1-(phenyl)-2-(1H-imidazole-1-y1)ethanol of the formula The inorganic acid formed during turnover, is neutralized with a base, e.g. alkali metal hydroxide, -carbonate, -amine, -alcoholate or other similar known agents.

Forbindelsene med formel III som anvendes som utgangsmaterialer, fremstilles ved fremgangsmåtene beskrevet i C. R. Acad. Sei. Hebd., Sei. Ser. C 275 , 1317 (1972); Ree. trav. chim. 65, The compounds of formula III used as starting materials are prepared by the methods described in C. R. Acad. Pollock. Hebd., Sei. Looking. C 275 , 1317 (1972); Ree. trot chim. 65,

129 (1946); Chem. Ber. _9_3, 1848 (1960). Forbindelsene med formel VI som anvendes som utgangsmaterialer, fremstilles ved den generelle metode beskrevet i J. Med. Chem.<_>12, 784 (19.69) . 129 (1946); Chem. Pray. _9_3, 1848 (1960). The compounds of formula VI which are used as starting materials are prepared by the general method described in J. Med. Chem.<_>12, 784 (19.69) .

De nye forbindelser med.formel II fremstilles ved den følgende serie av reaksjoner. The new compounds of formula II are prepared by the following series of reactions.

En kinolin-3-karboks.ylsyreester med formelenA quinolin-3-carboxylic acid ester of the formula

reduseres ved hjelp av et reduksjonsmiddel, f.eks. et metall-hydrid så. som litiumaluminiumhydrid eller natriumborhydrid eller lignende, for å danne en alkohol med formelen Alkoholen med formel VIII omdannes til halogenme ty1-derivatet med formelen is reduced using a reducing agent, e.g. a metal hydride then. as lithium aluminum hydride or sodium borohydride or the like, to form an alcohol of the formula The alcohol of formula VIII is converted to the halogen methyl 1 derivative of the formula

hvor X betyr et halogenatom, fortrinnsvis klor, brom eller jod, ved hjelp av et uorganisk syrehalogenid så som tionylklorid, fos foroksybromid etc. where X means a halogen atom, preferably chlorine, bromine or iodine, by means of an inorganic acid halide such as thionyl chloride, phosphorus oxybromide, etc.

Produktet med formel II fremstilles derefter ved omsetning av halogenforbindelsen med formel IX med en substituert 1-(fenyl)-2-(lH-imidazol-l-yl)etanol med formelen The product of formula II is then prepared by reacting the halogen compound of formula IX with a substituted 1-(phenyl)-2-(1H-imidazol-1-yl)ethanol of the formula

Den uorganiske syre som dannes under omsetningen, nøytraliseres med en base, f .eks. alkalimetallhydroksyd, The inorganic acid formed during the reaction is neutralized with a base, e.g. alkali metal hydroxide,

-karbonat, -amin, -alkoholat eller lignende kjente baser. Forbindelsene med formel VII som anvendes som utgangsmaterialer, fremstilles ved fremgangsmåtene beskrevet i -carbonate, -amine, -alcoholate or similar known bases. The compounds of formula VII which are used as starting materials are prepared by the methods described in

Journal of Medicinal Chemistry, vol. 20, 1001 (1977); ibid.,Journal of Medicinal Chemistry, vol. 20, 1001 (1977); ibid.,

vol. _16 875 (1973) Tetrahedron Letters, 51, 4545 (1977), etc. Forbindelsene med formel X som anvendes som utgangsmaterialer, fremstilles ved de generelle metoder beskrevet i Journal of Medicinal Chemistry, vol. 12, 784 (1969).. Vol. _16 875 (1973) Tetrahedron Letters, 51, 4545 (1977), etc. The compounds of formula X used as starting materials are prepared by the general methods described in the Journal of Medicinal Chemistry, vol. 12, 784 (1969)..

Forbindelsene med formlene I og II danner salter som også kan fremstilles ifølge oppfinnelsen. Saltene omfatter syre-'addisjonssalter, særlig de ugiftige, fysiologisk godtagbare salter. Basene med formlene I og II danner salter ved omsetning med én eller flere ekvivalenter av en hvilken som helst av en rekke forskjellige av de vanlige uorganisk og organiske syrer som danner syreaddis jonssalter, innbefattet f.eks. hy.dro-halogenider, (særlig hydroklorid og hydrobromid) , sulfat, nitrat, borat, fosfat, oksalat, maleat, citrat, acetat, askorbat, succinat, benzensulfonat, metansulfonat, cykloheksansulfamat og toluen-sulfonat. Syreaddisjonssaltene representerer ofte en hensiktsmessig form for isolering eller rensning av produktet, f.eks. The compounds with the formulas I and II form salts which can also be prepared according to the invention. The salts include acid addition salts, especially the non-toxic, physiologically acceptable salts. The bases of formulas I and II form salts by reaction with one or more equivalents of any of a variety of the usual inorganic and organic acids which form acid addition ion salts, including e.g. hydrohalides, (especially hydrochloride and hydrobromide), sulphate, nitrate, borate, phosphate, oxalate, maleate, citrate, acetate, ascorbate, succinate, benzene sulphonate, methane sulphonate, cyclohexane sulphonate and toluene sulphonate. The acid addition salts often represent an appropriate form of isolation or purification of the product, e.g.

ved å danne og utfelle et salt (som ikke nødvendigvis er ugiftig)by forming and precipitating a salt (which is not necessarily non-toxic)

i et passende medium i hvilket saltet er uoppløselig, og efter fraskillelse av saltet foretas nøytralisering med en base så som bariumhydroksyd eller natriumhydroksyd for å danne den frie base med formel I. Andre salter kan derefter dannes fra den frie base ved omsetning med én eller flere ekvivalenter av en syre inneholdende den ønskede syregruppe. in a suitable medium in which the salt is insoluble, and after separation of the salt neutralization is carried out with a base such as barium hydroxide or sodium hydroxide to form the free base of formula I. Other salts can then be formed from the free base by reaction with one or more equivalents of an acid containing the desired acid group.

De nye forbindelser med formel I og II og deres salterThe new compounds of formula I and II and their salts

er nyttige som anti-fungale og anti-bakterielle midler.og kan anvendes til å bekjempe infeksjoner i forskjellige pattedyr så som are useful as anti-fungal and anti-bacterial agents. and can be used to fight infections in various mammals such as

mus, rotter, hunder, marsvin o.l., særlig de som skyldes slike organismer som Candida albicans, så vel som slike organismer som Trichomonas vaginalis eller Trichophyton mentagrophytes. F.eks. kan en forbindelse eller en blanding av forbindelser med formel I og II eller fysiologisk godtagbare syreaddisjonssalter derav administreres oralt til et infisert dyr, f.eks. til en mus, 1 en mengde på ca. 5 til 25 mg pr. kg pr. dag i 2 til 4 oppdelte mice, rats, dogs, guinea pigs, etc., especially those caused by such organisms as Candida albicans, as well as such organisms as Trichomonas vaginalis or Trichophyton mentagrophytes. E.g. a compound or a mixture of compounds of formula I and II or physiologically acceptable acid addition salts thereof can be administered orally to an infected animal, e.g. to a mouse, 1 a quantity of approx. 5 to 25 mg per kg per day in 2 to 4 divided

doser. Disse kan hensiktsmessig tilberedes som en tablett, kapsel eller eliksir inneholdende ca. 10 til 250 mg .pr. enhets-dose, ved å blande den aktive bestanddel eller de aktive bestand-deler med de vanlige hjelpestoffer, bæremidler, bindemidler, konserveringsmidler, smaksstoffer og lignende, i henhold til vanlig farmasøytisk praksis. Fortrinnsvis administreres de lokalt, f.eks. intravaginalt i en væske eller i et vanlig krem-grunnlag i en konsentrasjon på ca. 0,01 til 3 vekt% over en periode på ca. 3 til 7 dager, 2-4 ganger daglig. doses. These can conveniently be prepared as a tablet, capsule or elixir containing approx. 10 to 250 mg .pr. unit dose, by mixing the active ingredient or active ingredients with the usual excipients, carriers, binders, preservatives, flavorings and the like, in accordance with usual pharmaceutical practice. Preferably they are managed locally, e.g. intravaginally in a liquid or in a regular cream base in a concentration of approx. 0.01 to 3% by weight over a period of approx. 3 to 7 days, 2-4 times daily.

De følgende eksempler illustrerer oppfinnelsen. Temperaturene er i °C. The following examples illustrate the invention. Temperatures are in °C.

E ksempel 1 Example 1

2 , 4- diklor- 5- [ [ 1- ( 2 , 4- dik- lorfeny 1) - 2- ( lH- imidazol- l- yl) etoksy] - metyl] pyridin- hydroklorid ( 1:1) 2 , 4- dichloro- 5- [ [ 1- ( 2 , 4- dichloropheny 1) - 2-( 1H- imidazol- 1- yl) ethoxy] - methyl] pyridine hydrochloride ( 1:1)

a) 2, 4- diklorpyridin- 5- me tanola) 2, 4-dichloropyridine-5-methanol

66 g 2,4-diklorpyridin-5-karboksylsyre-etyles ter66 g of 2,4-dichloropyridine-5-carboxylic acid ethyl ester

(0,3 mol) oppløses i 120 ml vannfritt tetrahydrofuran.. Nitrogen føres gjennom kolben, og under omrøring og avkjøling til 0° tilsettes porsjonsvis 7,12 g litiumaluminiumhydrid for å holde reaksjonstemperaturen i området 5-10°. Omrøring, fortsettes i ytterligere 2 timer under utvendig avkjøling med isvann, og blandingen får stå natten over. Under omrøring og avkjøling av blandingen med isvann, tilsettes 250 ml saltsyre (3N) dråpevis slik at reaksjonstemperaturen ikke overstiger 5-8°. Den sure oppløsning inndampes derefter til tørrhet i vakuum, og det gjenværende produkt ekstraheres med 500 ml kloroform. Kloroform-ekstrakten behandles med trekull, filtreres, og oppløsningsmidlet avdes ti Ueres for å gi 37,7 g 2 , 4-diklorpyridin-5-metanol, (0.3 mol) is dissolved in 120 ml of anhydrous tetrahydrofuran. Nitrogen is passed through the flask, and while stirring and cooling to 0°, 7.12 g of lithium aluminum hydride are added in portions to keep the reaction temperature in the range of 5-10°. Stirring is continued for a further 2 hours under external cooling with ice water, and the mixture is allowed to stand overnight. While stirring and cooling the mixture with ice water, 250 ml of hydrochloric acid (3N) is added dropwise so that the reaction temperature does not exceed 5-8°. The acidic solution is then evaporated to dryness in vacuo, and the remaining product is extracted with 500 ml of chloroform. The chloroform extract is treated with charcoal, filtered, and the solvent evaporated for ten hours to give 37.7 g of 2,4-dichloropyridine-5-methanol,

sm.p. 73-77°. sm.p. 73-77°.

Saltproduktet, som er residuet efter eks tråksjonen med kloroform, nøytraliseres med natriumhydroksyd, og saltblandingen ekstraheres igjen med kloroform i et Soxhlet-apparat, hvilket gir en ytterligere porsjon på 5,2 g. Totalt utbytte 42,9 g (80%). Efter omkrystallisering fra heksan smelter 2,4-diklorpyridin-5-metanol ved 82-85°. The salt product, which is the residue after the extraction with chloroform, is neutralized with sodium hydroxide, and the salt mixture is extracted again with chloroform in a Soxhlet apparatus, giving a further portion of 5.2 g. Total yield 42.9 g (80%). After recrystallization from hexane, 2,4-dichloropyridine-5-methanol melts at 82-85°.

b) 5- klormetyl- 2, 4- diklorpyridinb) 5-chloromethyl-2,4-dichloropyridine

20,2 g 2,4-diklorpyridin-5-metanol (0,11 mol) og20.2 g of 2,4-dichloropyridine-5-methanol (0.11 mol) and

150 ml fosforoksyklorid tilbakeløpsbehandles i 19 timer. Derefter fjernes overskudd av fos foroksyklorid i vakuum, og is settes til residuet. 5-klormety1-2,4-diklorpyridin frafiltreres, vaskes med vann, tørres i eksikator over P2°5°9omkrystalliseres fra heksan; utbytte 17,95 g (83%), sm.p. 55-56°. 150 ml of phosphorus oxychloride are refluxed for 19 hours. Excess phosphorus oxychloride is then removed in vacuo, and ice is added to the residue. 5-chloromethyl-2,4-dichloropyridine is filtered off, washed with water, dried in a desiccator over P2°5°9, recrystallized from hexane; yield 17.95 g (83%), m.p. 55-56°.

c) 2, 4- diklor- 5-[[ 1-( 2, 4- diklorfeny1)- 2-( lH- imidazol- l- yl)-e toksy ] me tyl ] py r i din- hy dr ok lor id ( 1:1) c) 2,4-dichloro-5-[[1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl)-ethoxy]methyl]pyridine-hydrochloride ( 1:1)

I en trehalset kolbe utstyrt med rører, tilbakeløps-kjøler og gassinnløpsrør innføres 29,3 g natriumhydroksyd 29.3 g of sodium hydroxide are introduced into a three-necked flask equipped with a stirrer, reflux condenser and gas inlet pipe

(0,73 mol) og 27 ml vann. Mens nitrogen føres gjennom kolben, avkjøles oppløsningen til 45°, og derefter tilsettes 7,71 g l--(2, 4-diklorfenyl)-2-(lH-imidazol-l-yl)etanol (0,03 mol) (0.73 mol) and 27 ml of water. While nitrogen is passed through the flask, the solution is cooled to 45°, and then 7.71 g of 1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl)ethanol (0.03 mol) is added

[fremstilt ved fremgangsmåten ifølge J. Med. Chem. 1_2 , 784 (1969)], 0,5 g benzyltrimetylammoniumklorid og 30 ml tetrahydrofuran. Til blandingen, som oppvarmes til 50°, settes 5,9 g 5-klormetyl-2,4-diklorpyridin, og blandingen omrøres kraftig i 2 timer ved 60°. Den filtrerte to-f ase-oppløsning overføres til en skille trakt-, [prepared by the method according to J. Med. Chem. 1_2 , 784 (1969)], 0.5 g of benzyltrimethylammonium chloride and 30 ml of tetrahydrofuran. 5.9 g of 5-chloromethyl-2,4-dichloropyridine are added to the mixture, which is heated to 50°, and the mixture is stirred vigorously for 2 hours at 60°. The filtered two-phase solution is transferred to a separating funnel,

og det nedre vandige natriumhydroksydlag ekstraheres med 10 ml tetrahydrofuran. De samlede tetrahydrofuranlag behandles med trekull og tørres ved hjelp av natriumsulfat. Eter settes derefter til tetrahydrofuranekstrakten for å fjerne et olje-aktig biprodukt. Til den klare oppløsning av den frie base settes dråpevis alkoholisk saltsyre. Det utfelte 2,4-diklor-5-[[1-(2,4-diklorfenyl) -2- (lH-imidazol-l-y.1 ) etoksy ]metyl] pyridin-hydroklorid (3,5 g) behandles med acetonitril. En ytterligere porsjon oppnås ved å fjerne tetrahydrofuran/alkohol-moderluten og behandle residuet med acetonitril (3,5 g), sm.p. 177°. Totalt utbytte 7 g (52%). Omkrystallisering fra acetonitril hever smeltepunktet til 181-182°. and the lower aqueous sodium hydroxide layer is extracted with 10 ml of tetrahydrofuran. The combined tetrahydrofuran layers are treated with charcoal and dried using sodium sulphate. Ether is then added to the tetrahydrofuran extract to remove an oily by-product. Alcoholic hydrochloric acid is added dropwise to the clear solution of the free base. The precipitated 2,4-dichloro-5-[[1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-y.1)ethoxy]methyl]pyridine hydrochloride (3.5 g) is treated with acetonitrile. A further portion is obtained by removing the tetrahydrofuran/alcohol mother liquor and treating the residue with acetonitrile (3.5 g), m.p. 177°. Total yield 7 g (52%). Recrystallization from acetonitrile raises the melting point to 181-182°.

Eksempel 2 Example 2

2, 4- diklor- 6- metyl- 5-[[ 1-( 2, 4- diklorfeny1)- 2-( lH- imidazo1- 1- y1)-etoksy] metyl] pyridin- hydroklorid 2, 4- dichloro- 6- methyl- 5-[[ 1-( 2, 4- dichlorophenyl)- 2-( 1H- imidazo1- 1- y1)-ethoxy] methyl] pyridine hydrochloride

Ved å anvende 0,3 ml 2,4-diklor-6-me'tylpyridin-5-karboksylsyre-etylester istedenfor 2,4-diklorpyridin-5--karboksylsyre-etylester ved fremgangsmåten ifølge eksempel 1, By using 0.3 ml of 2,4-dichloro-6-methylpyridine-5-carboxylic acid ethyl ester instead of 2,4-dichloropyridine-5-carboxylic acid ethyl ester in the method according to example 1,

får man 2,4-diklor-6-metyl-5-[[1-(2,4-diklorfeny1)-2-(lH-imidazol-l-yl) etoksy ] metyl] pyridin • og dets hydroklorid, sm.p. 225-260°, nitrat sm.p. 121-122°. 2,4-dichloro-6-methyl-5-[[1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl)ethoxy]methyl]pyridine • and its hydrochloride, m.p. . 225-260°, nitrate m.p. 121-122°.

De følgende ytterligere produkter med formel C fremstilles ved fremgangsmåten ifølge eksempel 1 ved at den usubstituerte eller substituerte l-fenyl-2-(lH-imidazol-l-yl)-e.tanol med formel A omsettes med det usubs ti tuer te eller substituerte 5-klormetylpyridin med formel B. Substituentene refererer til de. respektive formler. The following further products of formula C are prepared by the method according to example 1 by reacting the unsubstituted or substituted 1-phenyl-2-(1H-imidazol-1-yl)-ethanol of formula A with the unsubstituted or substituted 5-Chloromethylpyridine of formula B. The substituents refer to those. respective formulas.

E ksempel 44 Example 44

4, 6- diklor- 3-[[ 1-( 2, 4- diklorfenyl)- 2-( lH- imidazol- 1- yl) etoksy]-metyl] kinolin- hydroklorid ( 1:1) 4, 6- dichloro- 3-[[ 1-( 2, 4- dichlorophenyl)- 2-( 1H-imidazol- 1- yl) ethoxy]-methyl] quinoline hydrochloride ( 1:1)

a) 4, 6- diklorkinolin- 3- karboksylsyre- etyles tera) 4, 6-dichloroquinoline-3-carboxylic acid ethyl esters

En blanding av 45,2 g 6-klor-4-hydroksykinolin-3-karboksylsyre-etylester (0,18 mol) og 250 ml tionylklorid tilbakeløpsbehandles i 20 timer. Overskudd av- tionylklorid fjernes derefter i vakuum, residuet behandles med 200 ml vann,, A mixture of 45.2 g of 6-chloro-4-hydroxyquinoline-3-carboxylic acid ethyl ester (0.18 mol) and 250 ml of thionyl chloride is refluxed for 20 hours. Excess thionyl chloride is then removed in vacuo, the residue is treated with 200 ml of water,

og esteren ekstraheres med eter. Efter vasking av eterekstrakten to ganger med vann, tørres den med Na2S0^, og oppløsningsmidlet avdestilleres . Den gjenværende 4 , 6-diklorki.nolin-3-karboksylsyre-etylester utgnies med petroleter (40-60°), filtreres og tørres. Utbytte: 45,3 g (93%), sm.p. 87-88°. and the ester is extracted with ether. After washing the ether extract twice with water, it is dried with Na 2 SO 4 , and the solvent is distilled off. The remaining 4,6-dichloroquinoline-3-carboxylic acid ethyl ester is triturated with petroleum ether (40-60°), filtered and dried. Yield: 45.3 g (93%), m.p. 87-88°.

b) 4, 6- diklorkinolin- 3- metanolb) 4, 6-dichloroquinoline-3-methanol

27 g 4,6-diklorkinolin-5-karboksylsyre-etylester (0,1 mol) 27 g 4,6-dichloroquinoline-5-carboxylic acid ethyl ester (0.1 mol)

oppløses i 600 ml vannfritt tetrahydrofuran. Nitrogen føres gjennom kolben, og under omrøring og avkjøling til 0°, tilsettes 2,4 g litiumaluminiumhydrid gradvis for å holde reaksjonstemperaturen ved 0 til +5°. Omrøring fortsettes i ytterligere 5 timer. Derefter tilsettes 2,5 ml vann, 2,0 ml vandig natriumhydroksyd (20%) og igjen 9 ml vann. De utfelte uorganiske salter frafiltreres, og oppløsningsmidlet fjernes ved hjelp av en rotasjonsinndamper. Den resulterende olje oppløses i en liten mengde benzen og oppbevares i kjøleskap. Den krystalliserte 4,6-diklorkinolin-3-metanol frafiltreres og omkrystalliseres fra etylacetat; utbytte: 12,5 g (55%), sm.p. 182°. dissolve in 600 ml anhydrous tetrahydrofuran. Nitrogen is passed through the flask, and while stirring and cooling to 0°, 2.4 g of lithium aluminum hydride is gradually added to maintain the reaction temperature at 0 to +5°. Stirring is continued for a further 5 hours. Then 2.5 ml of water, 2.0 ml of aqueous sodium hydroxide (20%) and again 9 ml of water are added. The precipitated inorganic salts are filtered off, and the solvent is removed using a rotary evaporator. The resulting oil is dissolved in a small amount of benzene and stored in a refrigerator. The crystallized 4,6-dichloroquinoline-3-methanol is filtered off and recrystallized from ethyl acetate; yield: 12.5 g (55%), m.p. 182°.

c) 3- klormety1- 4, 6- dikiorkinolinc) 3-chloromethyl-4,6-dichloroquinoline

11,4 g 4,6-diklorkinolin-3-metanol (0,05 mol) settes 11.4 g of 4,6-dichloroquinoline-3-methanol (0.05 mol) are added

porsjonsvis til 150 ml tionylklorid. Reaksjonsblandingen får stå i 24 timer ved romtemperatur. Derefter filtreres oppløsningen, og overskudd av tionylklorid fjernes ved hjelp av en rotasjonsinndamper. Residuet utgnies med vann, frafiltreres, vaskes igjen med vann og tørres i en eksikator over ?2®5^or ^ ^ 3-klormetyl-4,6-diklorkinolin; utbytte: 11,5 g (93,5%), sm.p. 102-105°. Omkrystallisering fra cykloheksan forandrer ikke smeltepunktet. portionwise to 150 ml of thionyl chloride. The reaction mixture is allowed to stand for 24 hours at room temperature. The solution is then filtered, and excess thionyl chloride is removed using a rotary evaporator. The residue is rubbed with water, filtered off, washed again with water and dried in a desiccator over ?2®5^or ^ ^ 3-chloromethyl-4,6-dichloroquinoline; yield: 11.5 g (93.5%), m.p. 102-105°. Recrystallization from cyclohexane does not change the melting point.

d) 4, 6- diklor- 3-[[ 1-( 2, 4- diklorfonyl)- 2-( lH- imidazol- l- yl)-etoksy] metyl] kinolin- hydroklorid ( 1:1) d) 4, 6-dichloro-3-[[1-(2,4-dichlorofonyl)-2-(1H-imidazol-1-yl)-ethoxy] methyl] quinoline hydrochloride (1:1)

■ I en trehalset kolbe, utstyrt med rører, tilbakeløps-kjøler og gassinnløpsrør, innføres 14,8 g natriumhydroksyd (0,37 mol) og 25 ml vann. Mens nitrogen føres gjennom kolben avkjøles oppløsningen til 45°, og derefter tilsettes 3,85 g 1-(2',4-diklorfenyl)-2-(lH-imidazol-l-yl) etanol (0,015 mol) ■ 14.8 g of sodium hydroxide (0.37 mol) and 25 ml of water are introduced into a three-necked flask, equipped with a stirrer, reflux condenser and gas inlet pipe. While nitrogen is passed through the flask, the solution is cooled to 45°, and then 3.85 g of 1-(2',4-dichlorophenyl)-2-(1H-imidazol-1-yl) ethanol (0.015 mol) are added

[fremstilt i henhold til J. Med. Chem., vol. 12, 784 (1969)], 0,25 g benzyltrimetylammoniumklorid og 25 ml tetrahydrofuran. [prepared according to J. Med. Chem., vol. 12, 784 (1969)], 0.25 g of benzyltrimethylammonium chloride and 25 ml of tetrahydrofuran.

Til blandingen, som oppvarmes til 50° settes en oppløsning avA solution is added to the mixture, which is heated to 50°

3,6 g 3-klormety1-4,6-diklorkinolin (0,015 mol) i 10 ml tetra-hydrof uran fra en for-oppvarmet dryppetrakt i løpet av 3 minutter. Blandingen omrøres kraftig i 3 timer ved 60° under anvendelse 3.6 g of 3-chloromethyl-4,6-dichloroquinoline (0.015 mol) in 10 ml of tetrahydrofuran from a pre-heated dropping funnel over 3 minutes. The mixture is stirred vigorously for 3 hours at 60° during use

av et vannbad. Derefter overføres den varme blanding til en skilletrakt, og det nedre, vandige natriumhydroksydlag ekstraheres med 10 ml tetrahydrofuran. De samlede tetrahydrofuranlag tørres ved hjelp av natriumsulfat, og efter at oppløsningsmidlet er fjernet, ekstraheres den gjenværende olje med eter, of a water bath. The hot mixture is then transferred to a separatory funnel, and the lower, aqueous sodium hydroxide layer is extracted with 10 ml of tetrahydrofuran. The combined tetrahydrofuran layers are dried using sodium sulfate, and after the solvent has been removed, the remaining oil is extracted with ether,

behandles med trekull og filtreres. Til oppløsningen av fri base settes dråpevis eterisk saltsyre. Det utfelte 4,6-diklor-3-[[1-(2,4-diklorfeny1-2-(lH-imidazol-l-yl)etoksy]me tyl]kinolin-hydroklorid frafiltreres, tørres i vakuumeksikator og om-'krystalliseres fra absolutt etanol; utbytte: 1,9 g (25%), treated with charcoal and filtered. Add ethereal hydrochloric acid drop by drop to the solution of free base. The precipitated 4,6-dichloro-3-[[1-(2,4-dichlorophenyl-2-(1H-imidazol-1-yl)ethoxy]methyl]quinoline hydrochloride is filtered off, dried in a vacuum desiccator and recrystallized from absolute ethanol; yield: 1.9 g (25%),

sm.p. 148-150°. sm.p. 148-150°.

Eksempel 4 5 Example 4 5

4,7-diklor-3-[[1-(2,4-diklorfeny1)-2-(lH-imidazol-l-y1)etoksy]-me ty1] kinolin- hydroklorid ( 1:2) 4,7-dichloro-3-[[1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl)ethoxy]-methyl]quinoline hydrochloride (1:2)

a) 4, 7- diklorkinolin- 3- karboksylsyre- e tyles tera) 4, 7-dichloroquinoline-3-carboxylic acid ethyl esters

En blanding av 30 g 7-klor-4-hydroksy-kinolin-3-karboksylsyre-etylester, sm.p. 299-301° (0,12 mol) og 250 ml fosforoksyklorid tilbakeløpsbehandles i 4,5 timer. Efter fjernelse av overskudd av fosforoksyklorid utrøres residuet med vann og oppløses i eter. Eteroppløsningen vaskes med vannfritt natrium-karbonat (5%) og vann, tørres med natriumsulfat, og oppløsnings-midlet fjernes. Den gjenværende 4 ,7-diklorkinolin-3-karboksylsyre-etylester utgnies med petroleter (40-60°), frafiltreres og tørres; A mixture of 30 g of 7-chloro-4-hydroxy-quinoline-3-carboxylic acid ethyl ester, m.p. 299-301° (0.12 mol) and 250 ml of phosphorus oxychloride are refluxed for 4.5 hours. After removal of excess phosphorus oxychloride, the residue is stirred with water and dissolved in ether. The ether solution is washed with anhydrous sodium carbonate (5%) and water, dried with sodium sulfate, and the solvent is removed. The remaining 4,7-dichloroquinoline-3-carboxylic acid ethyl ester is triturated with petroleum ether (40-60°), filtered off and dried;

utbytte: 22 g (68%), sm.p. 81-82°.yield: 22 g (68%), m.p. 81-82°.

b) 4 , 7- diklorkinolin- 3- metanolb) 4,7-dichloroquinoline-3-methanol

Ved å følge fremgangsmåten ifølge eksempel lb, girBy following the procedure according to example lb, gives

21 g 4,7-diklorkinolin-3-karboksylsyre-etyles ter (0,08 mol) i 500 ml vannfritt tetrahydrofuran og 1,9 g litiumaluminiumhydrid 8,4 g (46%) 4,7-diklorkinolin-3-metanol; sm.p. 144-145° (etylacetat). 21 g of 4,7-dichloroquinoline-3-carboxylic acid ethyl ester (0.08 mol) in 500 ml of anhydrous tetrahydrofuran and 1.9 g of lithium aluminum hydride 8.4 g (46%) of 4,7-dichloroquinoline-3-methanol; sm.p. 144-145° (ethyl acetate).

c) 3- klormetyl- 4, 7- diklorkinolinc) 3-chloromethyl-4,7-dichloroquinoline

8 g 4,7-diklorkinolin-3-metanol (0,035 mol) og 100 ml 8 g of 4,7-dichloroquinoline-3-methanol (0.035 mol) and 100 ml

tionylklorid omsettes ved fremgangsmåten ifølge eksempel lc for å gi 7,1 g (82,5%) 3-klormety1-4,7-diklorkinolin, sm.p. 106-107°. thionyl chloride is reacted by the method according to example 1c to give 7.1 g (82.5%) of 3-chloromethyl-4,7-dichloroquinoline, m.p. 106-107°.

d) 4, 7- diklor- 3- [ [ 1-( 2, 4- diklorfeny1)- 2-( lH- imidazol- l- y1) etoksy]-me tyl] kinolin- hydroklorid ( 1:2) d) 4, 7-dichloro-3-[[1-(2,4-dichlorophenyl)-2-(1H-imidazole-1-y1)ethoxy]-methyl]quinoline hydrochloride (1:2)

5,2 g 1-(2 , 4-diklorfenyl)-2-(lH-imidazol-l-yl) etanol.5.2 g of 1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl) ethanol.

(0,02 mol) oppløst i 45 ml vannfritt tetrahydrofuran og 0,8 g natriumhydrid (55-60% dispersjon i mineralolje) omrøres i 4,5 timer ved romtemperatur. Efter at natriumsaltdannelsen er fullstendig, tilsettes 4,9 g 3-klormety1-4,7-diklorkinolin (0,02 mol) oppløst i. 25 ml vannfritt tetrahydrofuran, og blandingen omrøres ved 50-60° (badtemperatur) i 4 timer. Tetrahydrofuranet fjernes derefter, residuet behandles med vann og ekstraheres med eter. Eterlaget vaskes med vann og tørres med natriumsulfat. Tilsetning av eterisk saltsyre til eteroppløsningen av basen fører til ut-felning av hydrokloridsaltet. For rensning omdannes hydrokloridet til den frie base og ekstraheres igjen og behandles med eterisk saltsyre. Omkrystallisering fra etylacetat gir 2,1 g (20%) 4,7-diklor-3-[[1-(2,4-diklorfenyl)-2-(IH-imidazol-l-y1)etoksy]-me ty1]kinolin-hydroklorid (1:2), sm.p. 148-149°. (0.02 mol) dissolved in 45 ml of anhydrous tetrahydrofuran and 0.8 g of sodium hydride (55-60% dispersion in mineral oil) is stirred for 4.5 hours at room temperature. After the formation of the sodium salt is complete, 4.9 g of 3-chloromethyl-4,7-dichloroquinoline (0.02 mol) dissolved in 25 ml of anhydrous tetrahydrofuran are added, and the mixture is stirred at 50-60° (bath temperature) for 4 hours. The tetrahydrofuran is then removed, the residue treated with water and extracted with ether. The ether layer is washed with water and dried with sodium sulfate. Addition of ethereal hydrochloric acid to the ether solution of the base leads to precipitation of the hydrochloride salt. For purification, the hydrochloride is converted to the free base and extracted again and treated with ethereal hydrochloric acid. Recrystallization from ethyl acetate gives 2.1 g (20%) of 4,7-dichloro-3-[[1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl)ethoxy]-methyl]quinoline -hydrochloride (1:2), m.p. 148-149°.

De følgende ytterligere produkter med formel D fremstilles ved fremgangsmåten ifølge eksempel 44 ved at den usubstituerte eller substituerte l-fenyl-2-(lH-imidazol-l-yl)etanol med formel E omsettes med det usubstituerte eller substituerte 3-klormetylkinolin med formel F. Substi tuen tene refererer til de respektive formler. The following additional products of formula D are prepared by the method according to example 44 by reacting the unsubstituted or substituted 1-phenyl-2-(1H-imidazol-1-yl)ethanol of formula E with the unsubstituted or substituted 3-chloromethylquinoline of formula F Substi tuen tene refers to the respective formulas.

Claims (21)

1. Fremgangsmåte for fremstilling av en forbindelse med formelen: 1. Procedure for preparing a compound of the formula: hvor R"'" til R er hydrogen, lavere alkyl, lavere alkoksy, lavere alkyltio, hydroksy eller halogen; og syreaddisjonssalter derav, karakterisert ved at en forbindelse med formelen: where R"'" to R is hydrogen, lower alkyl, lower alkoxy, lower alkylthio, hydroxy or halogen; and acid addition salts thereof, characterized in that a compound with the formula: hvor R 5 og R 6 har de ovenfor angitte betydninger, omsettes med en forbindelse med formelen: where R 5 and R 6 have the meanings given above, are reacted with a compound of the formula: hvor X betyr et halogenatom, fortrinnsvis klor, brom eller jod, og R 1, R 2 , R 3 og R 4 har de ovenfor angitte betydninger.where X means a halogen atom, preferably chlorine, bromine or iodine, and R 1 , R 2 , R 3 and R 4 have the meanings given above. 2. Fremgangsmåte som angitt i krav 1, 2 4 karakterisert ved at R og R hver er halogen.2. Procedure as stated in claim 1, 2 4 characterized in that R and R are each halogen. 3. Fremgangsmåte som angitt i krav 1, karakterisert , ved at R og R hver er. halogen.3. Procedure as stated in claim 1, characterized , in that R and R are each. halogen. 4. Fremgangsmåte som angitt, i krav 2, karakterisert ved at hvert halogenatom er klor.4. Method as stated in claim 2, characterized in that each halogen atom is chlorine. 5. Fremgangsmåte som angitt i krav 3, karakterisert ved at hvert halogenatom er klor.5. Method as stated in claim 3, characterized in that each halogen atom is chlorine. 6. Fremgangsmåte som angitt i krav 1, karakterisert ved at R^ til R^ hver er hydrogen, lavere alkyl med 1 til 4 karbonatomer eller halogen.6. Process as stated in claim 1, characterized in that R^ to R^ are each hydrogen, lower alkyl with 1 to 4 carbon atoms or halogen. 7. Fremgangsmåte som angitt i krav 1, 13 karakterisert ved at R og R hver er hydrogen, R og R hver er halogen, R5 er 2-halogen, og R^ er 4-halogen, og fysiologisk godtagbare syreaddisjonssalter derav.7. Procedure as stated in claim 1, 13 characterized in that R and R are each hydrogen, R and R are each halogen, R 5 is 2-halogen, and R 5 is 4-halogen, and physiologically acceptable acid addition salts thereof. 8. Fremgangsmåte som angitt i krav 1, karakterisert ved at R og R <3> hver er hydrogen, R <2> og R hver er klor, R^ er 2-klor og R^ er 4-klor.8. Process as stated in claim 1, characterized in that R and R<3> are each hydrogen, R<2> and R are each chlorine, R^ is 2-chloro and R^ is 4-chloro. 9. Fremgangsmåte som angitt i krav 1, 1 2 4 karakterisert ved at R er metyl, R og R er 3 5 6 klor, R er hydrogen, R er 2-klor, R er 4-klor, og syreaddis jonssaltene derav.9. Procedure as stated in claim 1, 1 2 4 characterized in that R is methyl, R and R are 3 5 6 chlorine, R is hydrogen, R is 2-chloro, R is 4-chloro, and the acid addition ion salts thereof. 10. Fremgangsmåte som angitt i krav. 8, karakterisert ved at hydroklorid-syreaddisjons-saltet fremstilles.10. Procedure as specified in requirements. 8, characterized in that the hydrochloride acid addition salt is prepared. 11. Fremgangsmåte for fremstilling av en forbindelse med. formelen: 11. Method for producing a compound with. the formula: hvor R1, R <2> , R <5> , R <6> , R <7> , R <8> , R9 og R10 hver er hydrogen, lavere alkyl, lavere alkoksy, lavere alkyltio, hydroksy eller halogen; og syreaddisjonssaltene derav, karakterisert ved at en forbindelse med formelen: wherein R1, R<2>, R<5>, R<6>, R<7>, R<8>, R9 and R10 are each hydrogen, lower alkyl, lower alkoxy, lower alkylthio, hydroxy or halogen; and the acid addition salts thereof, characterized in that a compound with the formula: .hvor R^ og R^ har de ovenfor angitte betydninger, omsettes med en forbindelse med formelen: .where R^ and R^ have the meanings stated above, are reacted with a compound of the formula: hvor X betyr et halogenatom, fortrinnsvis klor, brom eller jod, og r\ R <2> , R <7> , R <8> , R <9> og har de ovenfor angitte betydninger.where X means a halogen atom, preferably chlorine, bromine or iodine, and r\ R <2> , R <7> , R <8> , R <9> and have the meanings indicated above. 12. Fremgangsmåte som angitt i krav 11, karakterisert ved at R 8 er halogen.12. Method as stated in claim 11, characterized in that R 8 is halogen. 13. Fremgangsmåte som angitt i krav 11, karakterisert ' ved at R 9 er halogen.13. Process as stated in claim 11, characterized in that R 9 is halogen. 14. Fremgangsmåte som angitt i krav 11, karakterisert ved at R og R hver er halogen.14. Process as stated in claim 11, characterized in that R and R are each halogen. 15. Fremgangsmåte som angitt i krav 14, karakterisert ved at hvert halogenatom er klor.15. Method as stated in claim 14, characterized in that each halogen atom is chlorine. 16. Fremgangsmåte som angitt i krav 11, karakterisert ved at R er 2-klor og R^ er 4-klor.16. Procedure as specified in claim 11, characterized in that R is 2-chloro and R^ is 4-chloro. 17. Fremgangsmåte som angitt i krav 11, karakterisert ved at R" <*> " til R <10> hver er hydrogen, halogen eller C^-C^ lavere alkyl.17. Process as stated in claim 11, characterized in that R" <*> " to R <10> are each hydrogen, halogen or C^-C^ lower alkyl. 18. Fremgangsmåte som angitt i krav 11, karakterisert ved at R <1> til R <10> hver er hydrogen eller halogen.18. Process as stated in claim 11, characterized in that R<1> to R<10> are each hydrogen or halogen. 19. Fremgangsmåte som angitt i krav 11, karakterisert ved at r\ R7 og R"^ hver er 2 5 6 hydrogen, og R , R og R hver er halogen, og syreaddisjonssaltene derav.19. Method as stated in claim 11, characterized in that r\ R7 and R"^ are each 2 5 6 hydrogen, and R , R , and R are each halogen, and the acid addition salts thereof. 20. Fremgangsmåte som angitt i krav 1.1, karakterisert ved at r\ R , R og R^ liver er hydrogen, R2 og R9 hver er klor, R^ er 2-klor og R er 4-klor.20. Method as set forth in claim 1.1, characterized in that r\ R , R and R 1 are hydrogen, R 2 and R 9 are each chlorine, R 1 is 2-chloro and R is 4-chloro. 21. Fremgangsmåte, som angitt i krav 11, 17 9 10 karakterisert ved at R , R , R og R hver er hydrogen, R2 og R8 hver er klor, RJ er 2-klor og R^ er 4-klor.21. Procedure, as stated in claim 11, 17 9 10 characterized in that R , R , R and R are each hydrogen, R 2 and R 8 are each chlorine, RJ is 2-chloro and R 1 is 4-chloro.
NO793411A 1978-10-25 1979-10-24 PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE IMIDAZOLD DERIVATIVES. NO793411L (en)

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