NO174709B - Fremgangsmaate for fremstilling av et pyrrol-heptansyre-derivat - Google Patents

Fremgangsmaate for fremstilling av et pyrrol-heptansyre-derivat Download PDF

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NO174709B
NO174709B NO903251A NO903251A NO174709B NO 174709 B NO174709 B NO 174709B NO 903251 A NO903251 A NO 903251A NO 903251 A NO903251 A NO 903251A NO 174709 B NO174709 B NO 174709B
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pyrrole
methylethyl
fluorophenyl
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Bruce David Roth
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Warner Lambert Co
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/325—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
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    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members 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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Abstract

Forbindelsene [R-(R*,R*)--(-uorfenyl)-p,S-di-hydroksy-5-(l-metyletyl)-3-fenyl-4-[(fenylamino)-karbonyl]-lH-pyrrol-l-heptansyre (I) eller (2R-trans)-5-(4-fluorfenyl)-2-(i-metyletyl)-N,4-difenyl-l-[2-(tetrahydro-4-hydroksy-6-okso-2H-pyran-2-yl)etyl]-lH-pyrrol-3-karboksamid (II) og farmasøytiske akseptable salter av cholesterol.Forbindelsen hemmer biosyntesen av cholesterol. Deres fremstilling er beskrevet.Forbindelsene er henholdsvis formlene:

Description

Trans-(±)-5-(4-fluorfenyl)-2-(1-metyletyl)-N,4-difenyl-1-[2-(tetrahydro-4-hydroksy-6-okso-2H-pyran-2-yl)etyl]-1H-pyrrol-3-karboksamider er blant de forbindelser som beskrives i US patentskrift nr. 4.681.893, hvilke er nyttige som inhibitorer av cholesterolbiosynteser. Forbindelsene der omfatter i store trekk 4-hydroksypyran-2-oner og de tilsvarende ringåpnede syrer avledet derav.
Det har nå uventet vist seg at enantiomeren med R-konfigurasjon av den ringåpnede syre av trans-5-(4-fluorfenyl)-2-(1-metyletyl)-N,4-difenyl-1-[2-(tetrahydro-4-hydroksy-6-okso-2H-pyran-2-yl)etyl]-lH-pyrrol-3-karboksamid, dvs. [R-(R*,R*)]-2-(4-fluorfenyl)- p, 6-dihydroksy-5-(1-metyletyl)-3-fenyl-4-[(fenylamino)-karbonyl]-lH-pyrrol-1-heptansyre, tilveiebringer overraskende inhibering av biosyntesen av cholesterol.
Det er kjent at 3-hydroksy-3-metylglutaryl-coenzym A (HMG-CoA) eksisterer som 3R-stereoisomeren. Videre ligger, som vist ved studiet av en rekke 5-substituerte 3,5-dihydroksypentansyrer av Stokker et al., i "3-Hydroxy-3-methylglutaryl-Coenzyme A Reductase Inhibitors. 1. Structural Modification of 5-Substituted 3,5-Dihydroxypentanoic acids and Their Lactone Derivatives", J. Med. Chem. 1985, 28, 347-358, all den biologiske aktivitet i det vesentlige hos trans-diastereomeren av (E)-6-[2-(2,4-diklorfenyl)etenyl]-3,4,5,6-tetrahydro-4-hydroksy-2H-pyranon med positiv rotasjon. Videre kreves tilsynelatende absolutt konfigurasjon av /3-hydroksy-é"-lakton-delen felles med mevinolin med formelen (la) og compactin med formelen (lb)
til inhibering av HMG-CoA reduktase. Dette er beskrevet av Lynch et al. i "Synthesis of an HMG-CoA Reductase Inhibitor; A Diastereoselective Aldol Approach" i Tetrahedron Letters, Vol. 28, nr. 13, s. 1385-1388 (1987) som 4R,6R-konfigurasjonen.
Imidlertid kunne fagmannen ikke på bakgrunn av ovennevnte beskrivelser forutse den uventede og overraskende inhibering av cholesterolbiosyntesen som oppnås ved hjelp av den foreliggende oppfinnelse.
I overensstemmelse hermed tilveiebringer den foreliggende oppfinnelse en fremgangsmåte for fremstilling av [R-(R*,R*) ]-2-(4-f luorfenyl) -)9, <S-dihydroksy-5- (1-metyletyl) -3-fenyl-4-[(fenylamino)-karbonyl]-lH-pyrrol-1-heptansyre (forbindelse med formel I), farmasøytisk akseptable salter derav og (2R-trans)-5-(4-fluorfenyl)-2-(1-metyletyl)-N,4-difenyl-1-[2-(tetrahydro-4-hydroksy-6-okso-2H-pyran-2-yl)-etyl]-lH-pyrrol-3-karboksamid (laktonformen av heptansyren eller forbindelsen med formel II) .
De farmasøytisk akseptable salter som kan fremstilles ved fremgangsmåten ifølge oppfinnelsen er slike som vanligvis avledes ved oppløsning av den frie syre eller laktonet, fortrinnsvis laktonet i vann eller vandig alkoholoppløsnings-middel eller andre egnede oppløsningsmidler med en passende base og isolering av saltet ved inndampning av oppløsningen eller ved omsetning av den frie syre eller laktonet, fortrinnsvis laktonet og base i et organisk oppløsningsmiddel, hvor saltet utskilles direkte eller kan oppnås ved konsentrering av oppløsningen.
I praksis er anvendelse av saltformen det samme som anvendelse av syre- eller laktonformen. Passende farmasøytisk akseptable salter innenfor oppfinnelsens rammer er slike avledet fra baser så som natriumhydroksyd, kaliumhydroksyd, litiumhydroksyd, kalsiumhydroksyd, l-deoksy-2-(metylamino)-D-glucitol, magnesiumhydroksyd, sinkhydroksyd, aluminiumhydroksyd, jern(II)-eller jern(III)hydroksyd, ammoniumhydroksyd eller organiske aminer så som N-metylglucamin, cholin, arginin eller lignende. Fortrinnsvis fremstilles litium-, kalsium-, magnesium-, aluminium- og jern(II)- eller jern(III)saltene fra natrium- eller kaliumsaltet ved tilsetning av det passende reagens til en oppløsning av natrium- eller kaliumsaltet, dvs. tilsetning av kalsiumklorid til en oppløsning av natrium- eller kaliumsaltet av forbindelsen med formel I, gir kalsiumsaltet derav.
Den frie syre kan fremstilles ved hydrolyse av laktonformen med formel II eller ved å lede saltet gjennom en kationbytterharpiks (H+<-> harpiks) og avdampning av vannet.
Den mest foretrukne utførelsesform av den foreliggende oppfinnelse er fremstilling av [R-(R<*>,R*)]-2-(4-fluorfenyl)-jS, (5-dihydroksy-5-(1-metyletyl) -3-fenyl-4-[ (fenylamino) - karbonyl]-lH-pyrrol-l-heptansyre,hemikalsiumsaltet.
Forbindelsene I eller II kan generelt fremstilles ved en fremgangsmåte som karakteriseres ved at man
1) behandler et transracemat med formelen
med en forbindelse med formelen for å oppnå forbindelser"med formelen
2) behandler forbindelsene med en sterk base,
3) tilbakeløpskjøler produktet fra trinn 2 og renser frak-sjonene for å oppnå (2R-trans)-5-(4-fluorofenyl)-2-(1-metyletyl) -N,4-difenyl-l-[2-(tetrahydro-4-hydroksy-6-okso-2H-pyran-2-yl)etyl]-lH-pyrrol-3-karboksamid, som eventuelt hydrolyseres til å gi [R-(R*,R*) ]-2-(4-fluorofenyl)-/3, 6-dihydroksy-5-(1-metyletyl)-3-fenyl-4-[(fenylamino)-karbonyl]-lH-pyrrol-1-heptansyre.
Racematet fremstilles ved fremgangsmåten beskrevet i US patentskrift nr. 4.681.893 som herved inkorporeres som referanse.
Nærmere beskrevet kan spaltning av racematet utføres som vist i skjema 1 (hvor Ph er fenyl) nedenfor: "Trans-racematet" i skjema 1 betyr en blanding av følgende:
Betingelsene i trinn (1) og (2) i skjema 1 er generelt som angitt i eksempel 1 og 2 i det følgende.
En fagmann kan erkjenne variasjoner i skjema 1 som er hensiktsmessig for fremstillingen av forbindelsene.
Forbindelsene fremstilt ved fremgangsmåten ifølge oppfinnelsen og særlig forbindelsene med formel I inhiberer
biosyntesen av cholesterol som vist ved CSI-screening, hvilken er beskrevet i US patentskrift nr. 4.681.893 som herefter også er inkorporert som referanse. CSI-data for forbindelse I, dens enantiomer forbindelse II og racematet av disse to
forbindelser er som følger:
Forbindelsene fremstilt ifølge oppfinnelsen kan anvendes i farmasøytiske preparater og administreres til pasienten i dosenivåer fra 10 til 500 mg pr. dag, hvilket for et normalt voksent menneske på ca. 70 kg vil bety en dose på 0,14 til 7,1 mg/kg legemsvekt per dag. Dosen er fortrinnsvis fra 0,5 til 1,0 mg/kg pr. dag.
Dosen administreres fortrinnsvis som enhetsdosefonn. Enhetsdoseformen for oral eller parenteral anvendelse kan varieres eller justeres fra 10 til 500 mg, fortrinnsvis fra 20 til 100 mg i overensstemmelse med den særlige applikasjon og styrken av den aktive ingrediens. Preparatene kan om ønsket også inneholde andre aktive terapeutiske midler. Bestemmelse av optimal dose i en særlig situasjon ligger innenfor fag-mannens kompetanse.
Forbindelsene med formel I og II og deres farmasøytisk akseptable salter er generelt ekvivalente mht. aktivitet ved anvendelse som beskrevet her.
De etterfølgende eksempler illustrerer bestemte fremgangsmåter ifølge oppfinnelsen for fremstilling av forbindelser. Disse eksempler er således ikke begrensende for omfanget av oppfinnelsen.
Eksempel 1
Fremstilling av diastereomer a- metylbenzylamider
En oppløsning av racematet trans-(±)-5-(4-fluorfenyl)-2-(1-metyletyl)-N,4-difenyl-l-[2-(tetrahydro-4-hydroksy-6-okso-2H-pyran-2-yl)etyl]-lH-pyrrol-3-karboksamid (30 g, 55,5 ml) i (R)-(+)-a-metylbenzylamin (575 ml, 4,45 mol, 98% Aldrich) omrøres natten over ved romtemperatur.
Den resulterende oppløsning fortynnes derefter med eter (2 1) og vaskes derefter grundig med 2 M HC1 (4 x 500 ml), vann (2 x 500 ml) og saltvann (2 x 500 ml). Den organiske ekstrakt tørres derefter over MgS04> filtreres og konsentreres i vakuum for å oppnå 28,2 g av de diastereomere a-metylbenzylamider som et hvitt fast stoff, smp. 174,0-177°C. a-metylbenzylamidene separeres ved å oppløse 1,5 g av blandingen i 1,5 ml 98:1,9:0,1 CHC13:CH3OH:NH4OH (1000 mg/ml) og injisere oppløsningen i en preparativ HPLC kolonne (silikagel, 300 mm x 41,4 mm I.D.) med gasstett kanyle og eluere med ovennevnte oppløsningsmiddelblanding. Fraksjoner "oppsamles ved UV overvåkning. Diastereomer 1 eluerer ved 41 minutter. Diastereomer 2 eluerer ved 49 minutter. Mellomliggende fraksjoner oppsamles. Denne prosedyre gjentas tre ganger og lignende fraksjoner kombineres og konsentreres. Undersøkelse av hver ved analytisk HPLC indikerer at diastereomer 1 er 99,84% ren og diastereomer 2 er 96,53% ren. Hver isomer tas for seg i de følgende eksempler.
Eksempel 2
Fremstilling av 2R- trans- 5-( 4- fluorfenyl)- 2-( 1-metvletyl)- N, 4- difenvl- 1- r2- ftetrahydro- 4- hvdroksy- 6- okso- 2H-pvran- 2- yl) etyl1- lH- pyrrol- 3- karboksamid
Til en etanolisk oppløsning (50 M) av diastereomer 1 fra eksempel 1, [ 3R- [ 3R* (R*) , 5R*] ] - 2- (4-fluorfenyl) - [/?] , [ 5] - dihydroksy-5-(1-metyletyl)-3-fenyl-4-[(fenylamino)karbonyl]-N-(1-fenyletyl-lH-pyrrol-l- heptanamid, (hydroksysentrene er begge R) (lg, 1,5 mmol) settes IN NaOH (3,0 ml, 3 mmol). Den resulterende oppløsning oppvarmes til tilbakeløpskjøling i 48 timer.
Oppløsningen avkjøles til romtemperatur og konsentreres i vakuum. Residuet resuspenderes i vann og gjøres forsiktig surt med 6 N HCl. Den resulterende sure oppløsning ekstraheres med etylacetat. Den organiske ekstrakt vaskes med vann og saltvann, tørres over MgS04, filtreres og konsentreres i vakuum. Dette residuum gjenoppløses i toluen (100 ml) og oppvarmes til tilbakeløpskjøling under azeotrop fjernelse av vann i tre timer. Oppløsningen avkjøles til romtemperatur og konsentreres i vakuum for å oppnå 1,2 g gult semi-fast stoff. Lynkromatografi på silikagel under eluering med 4 0% EtOAc/heksan gir 0,42 g hvitt fast stoff som stadig inneholder urenheter. Det faste stoffet rekromatograferes for å oppnå 0,1 g i det vesentlige ren R,R-enantiomer, 2R-trans-5-(4-fluorfenyl)-2- (1-metyletyl)-N,4-difenyl-1-[2-(tetrahydro-4-hydroksy-6-okso-2H-pyran- 2-yl)etyl]-lH-pyrrol-3-karboksamid som et hvitt skum. HPLC viser at dette materiale er 94,6% kjemisk rent, [a]D = 25,5 , 0,51% i CHC13. Toppen ved romtemperatur = 53,46 minutter settes forsøksvis til å være en ukjent diastereomer resulterende fra de 2% (S)-(-)-a-metylbenzylamin som er tilstede i Aldrich a-metylbenzylaminet.
Eksempel 3
Fremstilling av 2S- trans- 5-( 4- fluorfenvl)- 2-( l-metvletyl)- N, 4- difenvl- 1- f2-( tetrahydro- 4- hvdroksv- 6- okso- 2H-pyran- 2- yl) etyll- lH- pvrrol- 3- karboksamid
Utførelse av prosedyren beskrevet i eksempel 2 på diastereomer 2 gir 0,6 g skumaktig fast stoff som lynkromato-graf eres på silikagel. Eluering med 50% EtOAc/heksan gir 0,4 6 g i det vesentlige ren S,S-enantiomer, 2S-trans-5-(4-fluorfenyl)-2-(1-metyletyl)-N,4-difenyl-1-[2- (tetrahydro-4-hydroksy-6-okso-2H-pyran-2-yl)etyl]-lH-pyrrol-3-karboksamid, som et hvitt skum. HPLC viser at dette materiale er 97,83% kjemisk rent. [a]D<23>= -24,8°, 0,51% i CHC13.
Eksempel 4
Hydrolyse av kjemisk lakton med formel II
Til en oppløsning av laktonet i THF ved romtemperatur settes en oppløsning av natriumhydroksyd i vann. Blandingen omrøres i to timer, HPLC: 99,65% (produkt), 0,34% (utgangs-lakton). Blandingen fortynnes med 3L vann, ekstraheres med etylacetat (2 x 11) og gjøres sur til pH= 4 ved tilsetning av 3 7 ml 5N saltsyre. Den vandige fase ekstraheres med 2 x 1,5L porsjoner etylacetat. De kombinerte etylacetatekstrakter vaskes med 2 x 11 vann, saltvann og tørres, og gir efter filtrering etylacetatoppløsningen av den ønskede hovedsyre. Denne oppløsning anvendes direkte i fraksjonen av N-metylglucaminsaltet.
Etylacetatekstraktene fra saltvann-vann vasken konsentreres for å oppnå 15,5 g off-white fast stoff.
Eksempel 5
Kalsiumsalt fra natriumsalt og/ eller lakton
Et mol lakton (540,6 g) oppløses i 5 1 MeOH, efter oppløsning tilsettes 11 H20. Under omrøring tilsettes én ekvivalent NaOH og det følges med HPLC inntil 2% eller mindre lakton og metylester av diolsyren er til stede (det kan ikke anvendes overskudd av NaOH, da Ca(0H)2 vil dannes ved tilsetning av CaCl2). Tilsett kaustisk NaOH (51,3 ml, 0,98 ekv.) eller NaOH som tabletter (39,1 g, 0,98 ekv.).
Ovennevnte prosedyre er vist nedenfor:
Efter hydrolysen tilsettes 10 1 H20, derefter vaskes minst to ganger med en 1:1 blanding av EtOAc/heksan. Hver vask bør inneholde 10 1 EtOAc/heksan. Hvis natriumsaltet er rent tilsettes 15 1 MeOH. Hvis det er urent og/eller inneholder farve tilsettes 100 g G-60 trekull, og det omrøres i to timer og filtreres over supercel. Vask med 15 1 MeOH.
Det utføres en vekt/vol.% på reaksjonsblandingen, ved HPLC for å bestemme den eksakte mengde salt i oppløsningen. 1 ekv. eller et lite overskudd CaCl2<*>2H20 oppløses i 20 1 H20. Både reaksjonsblandingen og CaCl2 oppløsningen oppvarmes til 60°C. CaCl2 tilsettes langsomt under kraftig omrystning. Efter endt tilsetning avkjøles langsomt til 15°C og filtreres. Filterkaken vaskes med 5 1 H20. Tørring ved 50 C i vakuumovn.
Filterkaken kan omkrystalliseres ved oppløsning i 4 1 EtOAc (50°C), filtrering over supercel, vask med 1 1 EtOAc, og derefter tilsettes 3 1 heksan til 50°C oppløsningen.
Ovennevnte prosedyre er vist nedenfor:
Eksempel 6
Behandling av etvlacetatoppløsnin<g>en av den fri syre med formel I med N- metvlglucamin
Til en oppløsning av den frie syre med formel I (0,106 M) i etylacetat (3 1) settes en oppløsning av N-metylglucamin (20,3 g, 0,106 M) i (1:1) vann-aceton (120 ml, 120 ml) under kraftig omrøring ved romtemperatur. Omrøring fortsettes i 16 timer og den uklare oppløsning konsentreres i vakuum til "250 ml. Toluen (1 1) tilsettes og blandingen konsentreres til et hvitt fast stoff "100 g. Det faste stoffet oppløses i 1670 ml aceton og filtreres i en trehalset kolbe utstyrt med en mekanisk rører og termostat-kontrollert termometer. Kolben og filteret vaskes med 115 ml (1:1) vann-aceton og den klare oppløsning avkjøles langsomt. Dette tilveiebringer et bunnfall som oppløses påny ved oppvarmning til 65°C. Tilsetning av ytterligere 20 ml vann efterfulgt av vaskning gir et krystallinsk produkt som isoleres ved filtrering. Det faste stoffet vaskes med 1200 ml CH3C1 og vakuumtørres ved 255°C for å oppnå et hvitt fast stoff. Analyse av dette materiale indikerer at det inneholder 4% amin samt 0,4% rest-aceton og 0,67% vann. Analytiske resultater er som angitt nedenfor:
Smeltepunkt: 105-155°C (dekomponering)
Forventet analyse: C= 63,73, H= 6,95, N= 5,57, F2=9,53 Funnet analyse: C= 62,10, H= 6,89, N= 5,34, F2
C= 61,92, H= 7,02, N= 5,38, F2
H20 = 0,47% (KF)
HPLC: MeOH, H20, THF (40, 550, 250)
Econosil: C18, 5/i, 25 CM
256 nm: 1,0 ml/min.
6-81 min.: 98,76%
Opt. Ret.: [a]<*>b= -10,33° (c= 1,00, MeOH)
Rest oppløsningsmiddel: CH2CH= 0,26%
Titreringer: HC104 (0,1 N) = 203,8%
Bu4N0H (0,1 N) = 98,5%
Andre salter som kan fremstilles analogt med fremgangs-måtene hensiktsmessig valgt blant eksempel 5 og 6 ovenfor kan være kaliumsaltet, hemimagnesiumsaltet, hemisinksaltet eller l-deoksy-2-(metylamino)-D-glucitolkomplekset av forbindelsen med formel I.

Claims (9)

1. Fremgangsmåte for fremstilling av (2R-trans)-5-(4-fluorofenyl)-2-(l- metyletyl)-N,4-difenyl-l-[2-(tetrahydro-4-hydroksy-6-okso-2H-pyran-2- yl)etyl]-lH-pyrrol-3-karboksamid eller [R-(R*,R*)]-2-(4-fluorofenyl)- p,6-dihydroksy-5-(1-metyletyl) -3-fenyl-4-[(fenylamino)-karbonyl]-lH-pyrrol-l-heptansyre, og farmasøytisk akseptable salter derav karakterisert ved at man1) behandler et transracemat med formelen
med en forbindelse med formelen for å oppnå forbindelser mea formelen 2) behandler forbindelsene med en sterk base, 3) tilbakeløpskjøler produktet fra trinn 2 og renser frak-sjonene for å oppnå (2R-trans)-5-(4-fluorofenyl)-2-(1-metyletyl) -N, 4-difenyl-l-[2-(tetrahydro-4-hydroksy-6-okso-2H-pyran-2-yl)etyl]-lH-pyrrol-3-karboksamid, som eventuelt hydrolyseres til å gi [R-(R*,R*) ]-2-(4-f luorofenyl)-/3, <S-dihydroksy-5-(1-metyletyl)-3-fenyl-4-[(fenylamino)-karbonyl]-lH-pyrrol-l-heptansyre.
2. Fremgangsmåte ifølge krav 1,
karakterisert ved at man fra tilsvarende utgangsmaterialer fremstiller [R-(R*,R*)]-2-(4-fluorofenyl)-P,S-dihydroksy-5-(1-metyletyl)-3-fenyl-4-[(fenylamino)-karbo-nyl ]-lH-pyrrol-l-heptansyre.
3. Fremgangsmåte ifølge krav 2,
karakterisert ved at den fremstilte forbindelse omdannes til mononatriumsaltet.
4. Fremgangsmåte ifølge krav 2,
karakterisert ved at den fremstilte forbindelse omdannes til monokaliumsaltet-
5. Fremgangsmåte ifølge krav 2,
karakterisert ved at den fremstilte forbindelse omdannes til hemikalsiumsaltet.
6. Fremgangsmåte ifølge krav 2,
karakterisert ved at den fremstilte forbindelse omdannes til N-metylglucaminsaltet.
7. Fremgangsmåte ifølge krav 2,
karakterisert ved at den fremstilte forbindelse omdannes til hemimagnesiumsaltet.
8. Fremgangsmåte ifølge krav 2,
karakterisert ved at den fremstilte forbindelse omdannes til hemisinksaltet.
9. Fremgangsmåte ifølge krav 2, karakterisert ved at den fremstilte forbindelse omdannes til 1-deoksy-l-(metylamino)-D-glucitol-komplekset.
NO903251A 1989-07-21 1990-07-20 Fremgangsmåte for fremstilling av et pyrrol-heptansyre-derivat. NO174709C (no)

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