NO177706B - Improved Process for Preparation of Trans-6- [2- (Substituted-Pyrrol-Yl) Alkyl-Pyran-2-One Cholesterol Synthesis Inhibitors - Google Patents

Description

US patentskrift nr. 4.647.576, hvis innhold anses for å utgjøre en del av den foreliggende beskrivelse, omhandler visse trans-6- [ 2 - (substituert-pyrr.ol-l-yl) alkyl ] -pyran-2-oner. US Patent No. 4,647,576, the contents of which are considered to form part of the present disclosure, relates to certain trans-6-[2-(substituted-pyrr.ol-1-yl)alkyl]-pyran-2-ones.

US patentskrift nr. 4.681.893, hvis innhold anses for å utgjøre en del av den foreliggende beskrivelse, omhandler visse trans-6-[2-(3- eller 4-karboksamido-substituert pyrrol-1- yl)alkyl]-4-hydroksy-pyran-2-oner. US Patent No. 4,681,893, the contents of which are considered to form part of the present disclosure, relates to certain trans-6-[2-(3- or 4-carboxamido-substituted pyrrol-1-yl)alkyl]-4- hydroxy-pyran-2-ones.

De i ovennevnte US patentskrifter beskrevne forbindelser The compounds described in the above-mentioned US patent documents

er nyttige som inhibitorer av enzymet 3-hydroksy-3-metyl-glutaryl-coenzym A reduktase (HMG-CoA reduktase) og er således nyttige hypolipidemiske og hypocholesterolemiske midler. are useful as inhibitors of the enzyme 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMG-CoA reductase) and are thus useful hypolipidemic and hypocholesterolemic agents.

Særlig verdifulle som hypolipidemiske og hypocholesterolemiske midler er 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 og (2R-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. Ovennevnte forbindelser er blitt fremstilt ved en lineær syntetisk rute, Particularly valuable as hypolipidemic and hypocholesterolemic agents are trans(±)-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo -2H-pyran-2-yl)-ethyl]~1H-pyrrole-3-carboxamide and (2R-trans)-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1 -[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide. The above compounds have been prepared by a linear synthetic route,

som gjorde bruk av to reaksjoner utført ved lave temperaturer (-78°C) under omhyggelig kontrollerte betingelser. De to reaksjoner omfattet addisjon av dianionet av etylacetoacetat til et aldehyd og reduksjon av hydroksyketonet fremstilt ved denne reaksjon med natriumborhydrid og et trialkylboran. Selv om disse reaksjoner tilveiebringer de ønskede målforbindelser i høyt diastereomert overskudd, er de vanskelige å utføre i stor skala, og de anvender kostbare reagenser som er vanskelige å håndtere. De frembringer heller ikke enantiomert rene produkter. De ved de tidligere fremgangsmåter fremstilte materialer kan separeres til enantiomert rene produkter, men prosessen er meget dyr og tidkrevende, og den resulterer i tap av mer enn 50% av utgangsmaterialet. which made use of two reactions carried out at low temperatures (-78°C) under carefully controlled conditions. The two reactions involved addition of the dianion of ethyl acetoacetate to an aldehyde and reduction of the hydroxyketone produced by this reaction with sodium borohydride and a trialkylborane. Although these reactions provide the desired target compounds in high diastereomeric excess, they are difficult to perform on a large scale, and they use expensive reagents that are difficult to handle. They also do not produce enantiomerically pure products. The materials produced by the previous methods can be separated into enantiomerically pure products, but the process is very expensive and time-consuming, and it results in the loss of more than 50% of the starting material.

Den foreliggende oppfinnelse tilveiebringer en forbedret fremgangsmåte for fremstilling av ovennevnte forbindelser ved anvendelse av en hittil ukjent syntese. The present invention provides an improved method for the preparation of the above compounds using a hitherto unknown synthesis.

Ytterligere har man uventet funnet at de særlig Furthermore, it has been unexpectedly found that they particularly

verdifulle hypolipidemiske og hypocholesterolemiske midler trans(±)-5-(4-fluorfenyl)-2-(1-metyletyl)-N,4-difenyl-l-[2- valuable hypolipidemic and hypocholesterolemic agents trans(±)-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-l-[2-

(tetrahydro-4-hydroksy-6-okso-2H-pyran-2-yl)etyl]-lH-pyrrol-3-karboksamid og (2R-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 kan fremstilles fra et hittil ukjent mellomprodukt ved hjelp av færre trinn og med høyere utbytter enn ved de tidligere fremgangsmåter. Hertil kommer at den foreliggende fremgangsmåte går ut fra billige utgangsmaterialer og er anvendelig til syntese i stor skala. (tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide and (2R-trans)-5-(4-fluorophenyl)-2-(1-methylethyl) )-N,4-diphenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide can be prepared from a hitherto unknown intermediate by using fewer steps and with higher yields than with the previous methods. In addition, the present method starts from cheap starting materials and is applicable for synthesis on a large scale.

Følgelig er et første aspekt av den foreliggende oppfinnelse en forbedret fremgangsmåte for fremstilling av en forbindelse med formel I Accordingly, a first aspect of the present invention is an improved process for the preparation of a compound of formula I

og en dihydroksysyre og farmasøytisk akseptable salter derav svarende til den åpnede laktonring av en forbindelse med formel I, and a dihydroxy acid and pharmaceutically acceptable salts thereof corresponding to the opened lactone ring of a compound of formula I,

hvor R1 er where R1 is

1- naftyl, 1- naphthyl,

2- naftyl, 2- naphthyl,

fenyl eller phenyl or

fenyl substituert med phenyl substituted with

fluor, fluoride,

klor eller chlorine or

brom, bromine,

R2 eller R3 uavhengig av hverandre er R2 or R3 independently of each other is

hydrogen, hydrogen,

fenyl eller phenyl or

-CONHR_, hvor R, er -CONHR_, where R, is

b o b o

fenyl, phenyl,

R. er R. is

4 4

alkyl med ett til seks karbonatomer, alkyl of one to six carbon atoms,

hvilken fremgangsmåte omfatter at man: which method includes that one:

(a) omsetter 1,6-heptadien-4-ol med (a) reacts 1,6-heptadien-4-ol with

(1) alkyllitium (1) alkyl lithium

(2) efterfulgt av jod og karbondioksyd og (3) behandler det resulterende jodkarbonatmellom-produkt in situ med en base i en vandig alkohol ved 0°C til 40"C for å oppnå en forbindelse med formel IX, (2) followed by iodine and carbon dioxide and (3) treating the resulting iodocarbonate intermediate in situ with a base in an aqueous alcohol at 0°C to 40°C to obtain a compound of formula IX,

(b) behandler forbindelsen med formel IX med (b) treating the compound of formula IX with

(1) en alkalicyanid ved 0°C til 40°C og (1) an alkali cyanide at 0°C to 40°C and

(2) omsetter det resulterende diolmellomprodukt in situ med et ketaldannende reagens i nærvær av en syre for å oppnå en forbindelse med formel (2) reacting the resulting diol intermediate in situ with a ketal-forming reagent in the presence of an acid to obtain a compound of formula

VIII VIII

hvor R7 og Rg uavhengig av hverandre er hydrogen, alkyl med ett til tre karbonatomer, fenyl eller R? og Rg danner sammen - (CH2)n -, where R7 and Rg independently of each other are hydrogen, alkyl with one to three carbon atoms, phenyl or R? and Rg together form - (CH2)n -,

hvor n er 4 eller 5, where n is 4 or 5,

(c) behandler forbindelsen med formel VIII med (c) treating the compound of formula VIII with

(1) ozon i et inert oppløsningsmiddel og (1) ozone in an inert solvent and

(2) omsetter det resulterende mellomprodukt in situ med oksygen og trifenylfosfin ved -20"C til - 78"C for å oppnå en forbindelse med formel VII (2) reacting the resulting intermediate in situ with oxygen and triphenylphosphine at -20°C to -78°C to obtain a compound of formula VII

VII VII

hvor R7 og Rg er som ovenfor definert, where R7 and Rg are as defined above,

(d) behandler forbindelsen med formel VII med et oksydasjonsmiddel ved ca. 0°C for å oppnå en forbindelse med formel VI (d) treating the compound of formula VII with an oxidizing agent at about 0°C to obtain a compound of formula VI

VI WE

hvor R_ og R_ er som ovenfor definert, where R_ and R_ are as defined above,

(e) behandler forbindelsen med formel VI med en forbindelse med formel (e) treating the compound of formula VI with a compound of formula

hvor Hal er halogen, og RQa er alkyl med ett til åtte karbonatomer eller en tre- til seksleddet cykloalkylgruppe, i nærvær av en base for å oppnå en forbindelse med formel V wherein Hal is halogen, and RQa is alkyl of one to eight carbon atoms or a three- to six-membered cycloalkyl group, in the presence of a base to obtain a compound of formula V

hvor R_, RQ og R_ er som ovenfor definert, where R_, RQ and R_ are as defined above,

/ o y a / o y a

eller behandler forbindelsen med formel VI med en forbindelse med formel or treating the compound of formula VI with a compound of formula

hvor Rgb er tertiær butyl, tertiær amyl eller a, a-dimetylbenzyl, i nærvær av et aktiveringsmiddel, en katalytisk mengde av en base og et inert oppløsningsmiddel for å oppnå en forbindelse med wherein Rgb is tertiary butyl, tertiary amyl or α,α-dimethylbenzyl, in the presence of an activating agent, a catalytic amount of a base and an inert solvent to obtain a compound of

formel V, formula V,

b b

hvor R7, Rg og Rgb er som ovenfor definert, where R7, Rg and Rgb are as defined above,

(f) behandler forbindelsen med formel V Sl med hydrogen i nærvær av en katalysator og en syre ved 0°C til 70°C for å oppnå en forbindelse med formel IV (f) treating the compound of formula V Sl with hydrogen in the presence of a catalyst and an acid at 0°C to 70°C to obtain a compound of formula IV

hvor R„, R_ og R. er som ovenfor definert, where R„, R_ and R. are as defined above,

7 8 9a 7 8 9a

eller behandler forbindelsen med formel V, b med hydrogen i nærvær av en katalysator og en syre eller en katalysator og en base ved 0°C til 70°C for å oppnå en forbindelse med formel IV^or treating the compound of formula V, b with hydrogen in the presence of a catalyst and an acid or a catalyst and a base at 0°C to 70°C to obtain a compound of formula IV^

R? R8R? R8

hvor R7, Rg og R9b er som ovenfor definert, where R7, Rg and R9b are as defined above,

(g) behandler forbindelsen med formel IV clmed en forbindelse med formel III (g) treating the compound of formula IV with a compound of formula III

hvor R1# R2, R3 og R4 er som ovenfor definert i et inert oppløsningsmiddel for å oppnå en forbindelse where R1 # R2, R3 and R4 are as defined above in an inert solvent to obtain a compound

med formel II with formula II

a a

hvor Rlf R2, R3, R4, R7, Rg og Rga er som ovenfor definert, where Rlf R2, R3, R4, R7, Rg and Rga are as defined above,

eller behandler forbindelsen med formel IV. b med en forbindelse med formel III i et inert oppløsningsmiddel for å oppnå en forbindelse med formel II. or treating the compound of formula IV. b with a compound of formula III in an inert solvent to obtain a compound of formula II.

b b

hvor Rx, R2, R3, R R <R>g og Rgfo er som ovenfor where Rx, R2, R3, R R <R>g and Rgfo are as above

definert, defined,

(h) og endelig behandler en forbindelse med formel IIcl (h) and finally treating a compound of formula IIcl

med with

(1) en syre i nærvær av et inert oppløsningsmiddel (1) an acid in the presence of an inert solvent

(2) efterfulgt av hydrolyse med en base (2) followed by hydrolysis with a base

(3) efterfulgt av nøytralisering med en syre og (4) oppløsning og/eller oppvarmning i et inert oppløsningsmiddel under samtidig fjernelse av vann for å oppnå en forbindelse med formel I, eller behandler en forbindelse med formel Ilb med (1) en syre i nærvær av et inert oppløsningsmiddel (3) followed by neutralization with an acid and (4) dissolving and/or heating in an inert solvent while simultaneously removing water to obtain a compound of formula I, or treating a compound of formula IIb with (1) an acid in presence of an inert solvent

(2) efterfulgt av tilsetning av en base (2) followed by the addition of a base

(3) efterfulgt av nøytralisering med en syre og (4) oppløsning og/eller oppvarmning i et inert oppløsningsmiddel under samtidig fjernelse av vann for å oppnå en forbindelse med formel I, (i) og eventuelt omdanner den resulterende forbindelse med formel I til en dihydroksysyre svarende til den åpnede laktonring av strukturformel I ved hjelp av konvensjonell hydrolyse og ytterligere eventuelt omdanner dihydroksysyren til et tilsvarende farma-søytisk akseptabelt salt på konvensjonell måte og, såfremt det ønskes, omdanner det tilsvarende farma-søytisk akseptable salt til en dihydroksysyre på konvensjonell måte og, såfremt det ønskes, omdanner dihydroksysyren til en forbindelse med formel I ved oppvarmning i et inert oppløsningsmiddel. (3) followed by neutralization with an acid and (4) dissolving and/or heating in an inert solvent while simultaneously removing water to obtain a compound of formula I, (i) and optionally converting the resulting compound of formula I into a dihydroxy acid corresponding to the opened lactone ring of structural formula I by means of conventional hydrolysis and further optionally converting the dihydroxy acid into a corresponding pharmaceutically acceptable salt in a conventional manner and, if desired, converting the corresponding pharmaceutically acceptable salt into a dihydroxy acid in a conventional manner and, if desired, converts the dihydroxy acid to a compound of formula I by heating in an inert solvent.

Et annet aspekt av den foreliggende oppfinnelse er et hittil ukjent mellomprodukt med formel II hvor Rg er alkyl med ett til åtte karbonatomer, en tre- til seksleddet cykloalkylgruppe eller a,a-dimetylbenzyl, og R , <R>2,<R>3,<R>4, R7 og Rg er som ovenfor definert, hvilket er nyttig ved fremstillingen av cholesterolbiosynteseinhibitorer med formel I. Another aspect of the present invention is a hitherto unknown intermediate of formula II where Rg is alkyl of one to eight carbon atoms, a three- to six-membered cycloalkyl group or α,α-dimethylbenzyl, and R , <R>2,<R>3 ,<R>4, R7 and Rg are defined as above, which is useful in the preparation of cholesterol biosynthesis inhibitors of formula I.

I den foreliggende oppfinnelse betyr uttrykket "alkyl" en rettkjedet eller forgrenet hydrokarbongruppe, som har fra ett til åtte karbonatomer, og som for eksempel omfatter metyl, etyl, n-propyl, isopropyl, n-butyl, isobutyl, tertiær-butyl, n-pentyl, tertiær-amyl, n- heksyl, n-heptyl, n-oktyl og lignende. In the present invention, the term "alkyl" means a straight-chain or branched hydrocarbon group, having from one to eight carbon atoms, and which includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tertiary-butyl, n- pentyl, tertiary-amyl, n-hexyl, n-heptyl, n-octyl and the like.

"Cykloalkyl" refererer til en tre- eller seksleddet mettet hydrokarbonring og omfatter for eksempel cyklobutyl, cyklopentyl, cykloheksyl og lignende. "Cycloalkyl" refers to a three- or six-membered saturated hydrocarbon ring and includes, for example, cyclobutyl, cyclopentyl, cyclohexyl and the like.

"Alkoksy" er O-alkyl, hvor alkyl er som ovenfor definert. "Alkoxy" is O-alkyl, where alkyl is as defined above.

"Alkanoyloksy" er en alkylgruppe som ovenfor definert, bundet til en karbonylgruppe og derfra gjennom et oksygenatom til den molekylære stamrest. "Alkanoyloxy" is an alkyl group as defined above, attached to a carbonyl group and thence through an oxygen atom to the molecular parent residue.

"Karboalkoksy" er en alkylgruppe som ovenfor definert, bundet til et oksygenatom og derfra gjennom en karbonylgruppe til den molekylære stamrest. "Carboalkoxy" is an alkyl group as defined above, bound to an oxygen atom and from there through a carbonyl group to the molecular parent residue.

"Norbornenyl" er en gruppe avledet ved fjernelsen av et hydrogenatom (dog ikke fra et brohodekarbonatom) fra bicyklo-[2.2.1]hept-2-en. "Norbornenyl" is a group derived by the removal of a hydrogen atom (but not from a bridgehead carbon atom) from bicyclo-[2.2.1]hept-2-ene.

"Halogen" er jod, brom og klor. "Halogen" is iodine, bromine and chlorine.

"Alkalimetall" er et metall i gruppe IA i det periodiske system og omfatter for eksempel litium, natrium, kalium og lignende. "Alkali metal" is a metal in group IA of the periodic table and includes, for example, lithium, sodium, potassium and the like.

"Jordalkalimetall" er et metall i gruppe IIA i det periodiske system og omfatter for eksempel kalsium, barium, strontium og lignende. "Alkaline earth metal" is a metal in group IIA in the periodic table and includes, for example, calcium, barium, strontium and the like.

"Edelmetall" er platina, palladium, rhodium, ruthenium og lignende. "Precious metal" is platinum, palladium, rhodium, ruthenium and the like.

En foretrukken forbindelse med formel I fremstilt ved hjelp av den forbedrede fremgangsmåte ifølge den foreliggende oppfinnelse er én, hvor R er 1-naftyl, fenyl, A preferred compound of formula I prepared by the improved process of the present invention is one wherein R is 1-naphthyl, phenyl,

eller fenyl substituert med or phenyl substituted with

fluor, fluoride,

klor eller chlorine or

brom. bromine.

Likeledes foretrukket er en forbindelse med formel I fremstilt ved hjelp av den forbedrede fremgangsmåte ifølge den foreliggende oppfinnelse, hvor R4 er alkyl med ett til seks karbonatomer. Equally preferred is a compound of formula I prepared by means of the improved method according to the present invention, where R 4 is alkyl with one to six carbon atoms.

Særlig foretrukne forbindelser med formel I fremstilt ved hjelp av den forbedrede fremgangsmåte ifølge den foreliggende oppfinnelse er følgende: trans-6-[2-[2-(4-fluorfenyl)-5-(trifluormetyl)-lH-pyrrol-1-yl]etyl]tetrahydro-4-hydroksy-2H-pyran-2-on, Particularly preferred compounds of formula I prepared by means of the improved process according to the present invention are the following: trans-6-[2-[2-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrrol-1-yl] ethyl]tetrahydro-4-hydroxy-2H-pyran-2-one,

trans-6[2-[2-(4-fluorfenyl)-5-metyl-lH-pyrrol-l-yl]etyl]-tetrahydro-4-hydroksy-2H-pyran-2-on, trans-6[2-[2-(4-fluorophenyl)-5-methyl-1H-pyrrol-1-yl]ethyl]-tetrahydro-4-hydroxy-2H-pyran-2-one,

trans-6-[2-[2-(4-fluorfenyl)-5-(1-metyletyl)-lH-pyrrol-1-yl]etyl]tetrahydro-4-hydroksy-2H-pyran-2-on, trans-6-[2-[2-(4-fluorophenyl)-5-(1-methylethyl)-1H-pyrrol-1-yl]ethyl]tetrahydro-4-hydroxy-2H-pyran-2-one,

trans-6-[2-[2-cyklopropyl-5-(4-fluorfenyl)-lH-pyrrol-1-y1]etyl]tetrahydro-4-hydroksy-2H-pyran-2-on, trans-6-[2-[2-cyclopropyl-5-(4-fluorophenyl)-1H-pyrrol-1-yl]ethyl]tetrahydro-4-hydroxy-2H-pyran-2-one,

trans-6-[2-[2-(1,1-dimetyletyl)-5-(4-fluorfenyl)-1H-pyrrol-1-y1]etyl]tetrahydro-4-hydroksy-2H-pyran-2-on, trans-6-[2-[2-(1,1-dimethylethyl)-5-(4-fluorophenyl)-1H-pyrrol-1-yl]ethyl]tetrahydro-4-hydroxy-2H-pyran-2-one,

trans-1etrahydro-4-hydroksy-6-[2-[2-(2-metoksyfenyl) -5-metyl-lH-pyrrol-l-yl]etyl]-2H-2-on, trans-1-tetrahydro-4-hydroxy-6-[2-[2-(2-methoxyphenyl)-5-methyl-1H-pyrrol-1-yl]ethyl]-2H-2-one,

trans-tetrahydro-4-hydroksy-6-[2-[2-(2-metoksyfenyl) -5-(1-metyletyl)-lH-pyrrol-l-yl]etyl]-2H-pyran-2-on, trans-tetrahydro-4-hydroxy-6-[2-[2-(2-methoxyphenyl)-5-(1-methylethyl)-1H-pyrrol-1-yl]ethyl]-2H-pyran-2-one,

trans-tetrahydro-4-hydroksy-6-[2-[2-metyl-5-(1-naftalenyl)-lH-pyrrol-l-yl]etyl]-2H-pyran-2-on, trans-tetrahydro-4-hydroxy-6-[2-[2-methyl-5-(1-naphthalenyl)-1H-pyrrol-1-yl]ethyl]-2H-pyran-2-one,

trans-6-[2-(2-bicyklo[2,2,1]hept-5-en-2-yl-5-metyl-lH-pyrrol-l-yl)etyl]tetrahydro-4-hydroksy-2H-pyran-2-on, trans-6-[2-(2-bicyclo[2,2,1]hept-5-en-2-yl-5-methyl-1H-pyrrol-1-yl)ethyl]tetrahydro-4-hydroxy-2H- pyran-2-one,

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-karboksamid, trans(±)-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl )ethyl]-1H-pyrrole-3-carboxamide,

(2R) -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-karboksamid, (2R)-trans)-5-(4-fluorophenyl)-2-(1-methylethyl)-N> 4-diphenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2 -yl)ethyl]-1H-pyrrole-3-carboxamide,

trans-2-(4-fluorfenyl)-N,4-difenyl-l-[2-(tetrahydro-4-hydroksy-6-okso-2H-pyran-2-yl)etyl]-5-trifluormetyl-lH-pyrrol-3-karboksamid, trans-2-(4-fluorophenyl)-N,4-diphenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-5-trifluoromethyl-1H-pyrrole -3-carboxamide,

trans-5-(4-fluorfenyl)-N,4-difenyl-l-[2-(tetrahydro-4-hydroksy-6-okso-2H-pyran-2-yl)etyl]-2-trifluormetyl-lH-pyrrol-3-karboksamid og trans-5-(4-fluorophenyl)-N,4-diphenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-2-trifluoromethyl-1H-pyrrole -3-carboxamide and

en dihydroksysyre og farmasøytisk akseptable salter derav svarende til den åpne laktonring av forbindelser med struktur-fomtel I. a dihydroxy acid and pharmaceutically acceptable salts thereof corresponding to the open lactone ring of compounds of structure I.

Som beskrevet ovenfor er forbindelsene med formel I nyttige som inhibitorer av enzymet 3-hydroksy-3-metylglutaryl-coenzym A reduktase (HMG CoA reduktase) og er således nyttige som hypolipidemiske eller hypocholesterolemiske midler. As described above, the compounds of formula I are useful as inhibitors of the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG CoA reductase) and are thus useful as hypolipidemic or hypocholesterolemic agents.

Fremgangsmåten ifølge den foreliggende oppfinnelse er i sitt første aspekt en ny, forbedret, økonomisk og kommersielt gjennomførbar fremgangsmåte for fremstilling av HMG CoA reduktaseinhibitorer med formel I. Fremgangsmåten ifølge den foreliggende oppfinnelse i dens første aspekt er skissert i skjema I: The process according to the present invention is, in its first aspect, a new, improved, economically and commercially feasible process for the production of HMG CoA reductase inhibitors of formula I. The process according to the present invention, in its first aspect, is outlined in Scheme I:

En forbindelse med formel IX fremstilles fra den kjente 1,6-heptadien-4-ol (XI) under anvendelse av fremgangsmåten beskrevet av Bongini, A., et al, Journal of Organic Chemistry, 47., side 4626-4633 (1982) og Majewski, M. , et al, Tetrahedron Letters, 25, side 2101-2104 (1984). Således reageres den homoallyliske alkohol (XI) med et alkyllitium som for eksempel n-butyllitium efterfulgt av jod og karbondioksyd for å oppnå jodkarbonat (X) ved -35°C til -20°C, hvilket ikke isoleres, men behandles in situ med en base, så som et alkali- eller jordalkalimetallhydroksyd eller -karbonat, for eksempel natriumhydroksyd, kaliumhydroksyd, kalsiumhydroksyd, natriumkarbonat, kaliumkarbonat, kalsiumkarbonat og lignende i en vandig alkohol med ett til tre karbonatomer som for eksempel metanol, etanol, isopropanol og lignende ved ca. 0°C til ca. 40°C for å oppnå epoksydet med formel IX. Reaksjonen utføres fortrinnsvis med kaliumkarbonat i vandig metanol ved ca. 0°C til ca. 40°C, fortrinnsvis 0°C. Epoksydringen med formel IX åpnes med enten kalium- eller natriumcyanid i en vandig alkohol, som for eksempel metanol, etanol, tertiær butanol, isopropanol og lignende ved ca. 0°C til ca. 40°C. Reaksjonen utføres fortrinnsvis med kaliumcyanid i vandig isopropanol ved ca. 25"C. Det resulterende diolmellomprodukt isoleres ikke, men behandles in situ med et ketaldannende reagens som for eksempel aceton, dimetoksypropan, 2-metoksypropen, benzaldehyd, cyklopentan, cykloheksanon, 1,1-dimetoksycyklopentan, 1,1-dimetoksycykloheksan og lignende i nærvær av en syre som for eksempel kamfersulfonsyre, para-toluensulfonsyre og lignende i nærvær av overskudd av reagens eller i et inert oppløsningsmiddel som for eksempel diklormetan og lignende ved ca. 0°C til reagensets eller oppløsningsmidlets tilbakeløpskjølingstemperatur for å oppnå en forbindelse med formel VIII, hvor R7 og Rg uavhengig av hverandre er hydrogen, alkyl med ett til tre karbonatomer, fenyl eller R_ / og Ro Q sammen er -(CH0) n-, hvor n er 4 eller 5. En forbindelse med formel VIII behandles med ozon i et inert oppløsningsmiddel som for eksempel diklormetan og lignende, og det resulterende mellomprodukt ozonid som ikke isoleres, skylles in situ med oksygen for å fjerne ozonet og behandles derefter med trifenylfosfin eller dimetylsulfid ved ca. -20°C til ca. -78°C, fortrinnsvis ca. -78°C for å oppnå en forbindelse med formel VII, hvor R_ og RQ er som ovenfor definert. En forbindelse med formel VII behandles med et oksyderingsmiddel som for eksempel kromtrioksyd-svovelsyre-vann og lignende ved ca. 0°C for å oppnå en forbindelse med formel VI, hvor R7 og Rg er som ovenfor definert. En forbindelse med formel VI behandles med en forbindelse med formel hvor Hal er halogen som for eksempel jod, klor, brom, og R_ er alkyl med ett til åtte karbonatomer eller en tre- til seksleddet cykloalkylgruppe, fortrinnsvis isopropyl, isobutyl og lignende i nærvær av en base som for eksempel 1,8-diazabi-cyklo[5.4.0]undec-7-en (DBU) og lignende for å oppnå en forbindelse med formel V . hvor R_, RQ og R_ er som ovenfor A compound of formula IX is prepared from the known 1,6-heptadien-4-ol (XI) using the method described by Bongini, A., et al, Journal of Organic Chemistry, 47., pages 4626-4633 (1982) and Majewski, M., et al, Tetrahedron Letters, 25, pp. 2101-2104 (1984). Thus, the homoallylic alcohol (XI) is reacted with an alkyllithium such as n-butyllithium followed by iodine and carbon dioxide to obtain iodocarbonate (X) at -35°C to -20°C, which is not isolated but treated in situ with a base, such as an alkali or alkaline earth metal hydroxide or carbonate, for example sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, calcium carbonate and the like in an aqueous alcohol with one to three carbon atoms such as methanol, ethanol, isopropanol and the like at approx. 0°C to approx. 40°C to obtain the epoxide of formula IX. The reaction is preferably carried out with potassium carbonate in aqueous methanol at approx. 0°C to approx. 40°C, preferably 0°C. The epoxy ring of formula IX is opened with either potassium or sodium cyanide in an aqueous alcohol, such as methanol, ethanol, tertiary butanol, isopropanol and the like at approx. 0°C to approx. 40°C. The reaction is preferably carried out with potassium cyanide in aqueous isopropanol at approx. 25"C. The resulting diol intermediate is not isolated, but is treated in situ with a ketal-forming reagent such as acetone, dimethoxypropane, 2-methoxypropene, benzaldehyde, cyclopentane, cyclohexanone, 1,1-dimethoxycyclopentane, 1,1-dimethoxycyclohexane and the like in the presence of an acid such as camphorsulfonic acid, para-toluenesulfonic acid and the like in the presence of an excess of reagent or in an inert solvent such as dichloromethane and the like at about 0°C to the reflux temperature of the reagent or solvent to obtain a compound of formula VIII, where R7 and Rg independently of each other are hydrogen, alkyl of one to three carbon atoms, phenyl or R_ / and Ro Q together are -(CH0) n-, where n is 4 or 5. A compound of formula VIII is treated with ozone in a inert solvent such as dichloromethane and the like, and the resulting intermediate ozonide which is not isolated is flushed in situ with oxygen to remove the ozone and then treated with d triphenylphosphine or dimethyl sulphide at approx. -20°C to approx. -78°C, preferably approx. -78°C to obtain a compound of formula VII, where R_ and RQ are as defined above. A compound of formula VII is treated with an oxidizing agent such as chromium trioxide-sulfuric acid-water and the like at approx. 0°C to obtain a compound of formula VI, where R7 and Rg are as defined above. A compound of formula VI is treated with a compound of formula where Hal is halogen such as iodine, chlorine, bromine, and R_ is alkyl with one to eight carbon atoms or a three- to six-membered cycloalkyl group, preferably isopropyl, isobutyl and the like in the presence of a base such as 1,8-diazabi-cyclo[5.4.0]undec-7-ene (DBU) and the like to obtain a compound of formula V . where R_, RQ and R_ are as above

a / ■ o ?a a / ■ o ?a

definert. Videre behandles forbindelsen med formel VI med en forbindelse med formel defined. Furthermore, the compound of formula VI is treated with a compound of formula

hvor Rgk er tertiær butyl, tertiær amyl eller a,a-dimetylbenzyl i nærvær av et aktiveringsmiddel som for eksempel dicykloheksylkarbodiimid, 1,1'-karbonyldiimidazol og lignende i nærvær av en base som for eksempel 4-dimetylaminopyridin og lignende i et inert oppløsningsmiddel som for eksempel diklormetan, tetrahydrofuran og lignende for å oppnå en forbindelse med formel V^, hvor R7, Rg og Rgb er som ovenfor definert. En forbindelse med formel va„ behandles med hydrogen i nærvær av en katalysator så som et edelmetall, for eksempel platina, palladium, rhodium, ruthenium, derivater derav og lignende, eller Raney-nikkel, fortrinnsvis platinadioksyd, og en syre som for eksempel eddiksyre, ved ca. 0°C til ca. 70°C og et trykk på ca. 14 til 100 pund pr. kvadrattomme for å oppnå en forbindelse med formel IVa, hvor R_, RD og R_ er som ovenfor definert. Videre behandles en where Rgk is tertiary butyl, tertiary amyl or α,α-dimethylbenzyl in the presence of an activating agent such as dicyclohexylcarbodiimide, 1,1'-carbonyldiimidazole and the like in the presence of a base such as 4-dimethylaminopyridine and the like in an inert solvent such as for example dichloromethane, tetrahydrofuran and the like to obtain a compound of formula V^, where R7, Rg and Rgb are as defined above. A compound of formula va„ is treated with hydrogen in the presence of a catalyst such as a noble metal, for example platinum, palladium, rhodium, ruthenium, derivatives thereof and the like, or Raney nickel, preferably platinum dioxide, and an acid such as acetic acid, at approx. 0°C to approx. 70°C and a pressure of approx. 14 to 100 pounds per square inch to obtain a compound of formula IVa, wherein R_, RD and R_ are as defined above. Furthermore, one is treated

/ o y a / o y a

forbindelse med formel V^ med hydrogen i nærvær av en katalysator så som et edelmetall, for eksempel platina, palladium, rhodium, ruthenium, derivater derav og lignende, og en syre som for eksempel eddiksyre, propansyre og lignende eller en katalysator som for eksempel Raney-nikkel, Raney-kobolt og lignende i et inert oppløsningsmiddel som for eksempel metanol, etanol, isopropanol, tetrahydrofuran og lignende, mettet med vannfri ammoniakk eller mettet med vandig ammoniumhydroksyd eller vandig natriumhydroksyd, fortrinnsvis utføres reaksjonen med Raney-nikkel i metanol mettet med vannfri ammoniakk ved ca. 0°C til ca. 70°C og et trykk på ca. compound of formula V^ with hydrogen in the presence of a catalyst such as a noble metal, for example platinum, palladium, rhodium, ruthenium, derivatives thereof and the like, and an acid such as for example acetic acid, propanoic acid and the like or a catalyst such as Raney -nickel, Raney cobalt and the like in an inert solvent such as methanol, ethanol, isopropanol, tetrahydrofuran and the like, saturated with anhydrous ammonia or saturated with aqueous ammonium hydroxide or aqueous sodium hydroxide, preferably the reaction is carried out with Raney nickel in methanol saturated with anhydrous ammonia at approx. 0°C to approx. 70°C and a pressure of approx.

14 til ca. 100 pund pr. kvadrattomme for å oppnå en forbindelse med formel IVb, hvor R7, Rg og Rgb er som ovenfor definert. Raney-nikkel og Raney-kobolt som ovenfor beskrevet er findelte former av nikkel og kobolt. En forbindelse med formel XXI fremstilles ved å behandle en forbindelse med formel VI 14 to approx. 100 pounds per square inch to obtain a compound of formula IVb, wherein R7, Rg and Rgb are as defined above. Raney nickel and Raney cobalt as described above are finely divided forms of nickel and cobalt. A compound of formula XXI is prepared by treating a compound of formula VI

hvor R7 og Rg er som ovenfor definert, med hydrogen i nærvær av en katalysator som for eksempel Raney-nikkel, Raney-kobolt og lignende i findelt form i et inert oppløsningsmiddel som for eksempel metanol, etanol, isopropanol, tetrahydrofuran og lignende, mettet med vannfri ammoniakk eller mettet med vandig ammoniumhydroksydoppløsning eller en katalysator som for eksempel platina, palladium eller lignende i et inert oppløsningsmiddel så som for eksempel metanol, etanol, isopropanol, tetrahydrofuran og lignende i nærvær av en syre som for eksempel eddiksyre, propansyre og lignende ved ca. 0°C til ca. 70°C og et trykk på ca. 14 til ca. 100 pund pr. kvadrattomme for å oppnå en forbindelse med formel XXI. where R7 and Rg are as defined above, with hydrogen in the presence of a catalyst such as Raney nickel, Raney cobalt and the like in finely divided form in an inert solvent such as methanol, ethanol, isopropanol, tetrahydrofuran and the like, saturated with anhydrous ammonia or saturated with aqueous ammonium hydroxide solution or a catalyst such as platinum, palladium or the like in an inert solvent such as methanol, ethanol, isopropanol, tetrahydrofuran and the like in the presence of an acid such as acetic acid, propanoic acid and the like at approx. . 0°C to approx. 70°C and a pressure of approx. 14 to approx. 100 pounds per square inch to obtain a compound of formula XXI.

En forbindelse med formel XXIII fremstilles fra en forbindelse med formel XXV A compound of formula XXIII is prepared from a compound of formula XXV

hvor R_ / og RoQ er som ovenfor definert, under anvendelse av den tidligere beskrevne fremgangsmåte for fremstilling av en forbindelse med formel XXI fra en forbindelse med formel VI. En forbindelse med formel XXV fremstilles ved å behandle en forbindelse med formel VI hvor R7 og Rg er som ovenfor definert, og tertiær butylalkohol med et koblingsreagens som for eksempel dicykloheksylkarbodiimid og lignende i nærvær av en base som for eksempel 4-dimetylaminopyridin og lignende i et inert oppløsningsmiddel som for eksempel diklormetan og lignende for å oppnå en forbindelse med formel XXV. En optisk aktiv (R) forbindelse med formel XXIII clfrem-stilles som skissert i skjema II. Utgangsmaterialet (R)-4-cyano-3-[[(1,l-dimetyletyl)dimetylsilyl]oksy]butansyre med formel XXIX syntetiseres med utgangspunkt i isoaskorbinsyre under anvendelse av synteser som er velkjente for fagmannen. Denne kjemi er identisk med den som er beskrevet i US patentskrift nr. 4.611.067 (Merck & Co. Inc.), som anses for å utgjøre en del av den foreliggende beskrivelse, under anvendelse av askorbinsyre for fremstilling av (S)-4-cyano-3-[[(l,l-dimetyletyl)dimetylsilyl]oksy]-butansyre.1 1US patentskrift nr. 4.611.067 tilla åpenbart ukorrekt konfigurasjonen R til produktet av denne reaksjonssekvens som startet med askorbinsyre. Således fremstilles de optisk aktive forbindelser fra den kjente isoaskorbinsyre under anvendelse av fremgangsmåten beskrevet av Volante R. P. et al, i US patentskrift nr. 4.611.067, men i det tilfelle ved å starte med askorbinsyre. Dette etablerer de i formel XXV a og formel XXIII asom R ønskede optisk aktive sentre. Således behandles (R)-4-cyano-3-[[(1,1-dimetyletyl)dimetylsilyl]oksy]butansyre med formel XXIX med karbonyldiimidazol i tetrahydrofuran ved 0°C til - 40°C, fortrinnsvis -20°C, oppvarmes til 25°C, og det aktiverte syrederivat isoleres ikke, men oppløsningen settes til en suspensjon av et salt av 1,1-dimetyletylmalonsyre som for eksempel kaliumsaltet av 1,1-dimetyletylmalonsyre (halvt ester, halvt salt), vannfri magnesiumklorid og et amin så som for eksempel diisopropyletylamin i acetonitril ved -10°C til 20°C, fortrinnsvis ved 5°C. Blandingen helles i en blanding av IN saltsyre og etylacetat for å oppnå (R) -1,1-dimetyletyl-6-cyano-5-[(1,1-dimetyletyl)dimetylsilyl]oksy-3-oksoheksanoat med formel XXVIII. Ketonet med formel XXVIII behandles med fluoridion ved 0°C til 65°C, fortrinnsvis 25°C for å oppnå (R)-1,l-dimetyletyl-6-cyano-5-hydroksy-3-okso-heksanoatet med formel XXVII. Ketonet med formel XXVII behandles med trietylboran og luft (eller metoksydietylboran uten luft) efterfulgt av natriumborhydrid og metanol i tetrahydrofuran ved - 78°C til -110°C, fortrinnsvis -100°C for å oppnå [R-(R*,R<*>)]-l,l-dimetyletyl-6-cyano-3,5-hydroksyheksanoat med formel XXVI. Diolen med formel XXVI behandles med et ketaldannende reagens som for eksempel aceton, dimetoksypropan, 2-metoksypropen, benzaldehyd, cyklopentanon, cykloheksanon, 1,1-dimetoksycyklopentan, 1,1-dimetoksycykloheksan og lignende i nærvær av en syre som for eksempel kamfersulfonsyre, para-toluensulfonsyre og lignende i nærvær av overskudd av reagens eller i et inert oppløsningsmiddel som for eksempel diklormetan og lignende ved 0°C til reagensets eller oppløsningsmidlets tilbakeløpskjølingstemperatur for å oppnå en forbindelse med formel XXVa, hvor R„ / og Ro0 uavhengig av hverandre er hydrogen, alkyl med ett til tre karbonatomer, where R_ / and RoQ are as defined above, using the previously described method for preparing a compound of formula XXI from a compound of formula VI. A compound of formula XXV is prepared by treating a compound of formula VI where R7 and Rg are as defined above, and tertiary butyl alcohol with a coupling reagent such as dicyclohexylcarbodiimide and the like in the presence of a base such as 4-dimethylaminopyridine and the like in a inert solvent such as dichloromethane and the like to obtain a compound of formula XXV. An optically active (R) compound of formula XXIII cl is prepared as outlined in Scheme II. The starting material (R)-4-cyano-3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]butanoic acid of formula XXIX is synthesized starting from isoascorbic acid using syntheses that are well known to those skilled in the art. This chemistry is identical to that described in U.S. Patent No. 4,611,067 (Merck & Co. Inc.), which is considered part of the present specification, using ascorbic acid to produce (S)-4 -cyano-3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-butanoic acid.1 US Patent No. 4,611,067 obviously added the incorrect configuration R to the product of this reaction sequence starting with ascorbic acid. Thus, the optically active compounds are prepared from the known isoascorbic acid using the method described by Volante R.P. et al, in US Patent No. 4,611,067, but in that case by starting with ascorbic acid. This establishes the desired optically active centers in formula XXV a and formula XXIII as R. Thus (R)-4-cyano-3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]butanoic acid of formula XXIX is treated with carbonyldiimidazole in tetrahydrofuran at 0°C to -40°C, preferably -20°C, heated to 25°C, and the activated acid derivative is not isolated, but the solution is added to a suspension of a salt of 1,1-dimethylethylmalonic acid such as the potassium salt of 1,1-dimethylethylmalonic acid (half ester, half salt), anhydrous magnesium chloride and an amine such as, for example, diisopropylethylamine in acetonitrile at -10°C to 20°C, preferably at 5°C. The mixture is poured into a mixture of 1N hydrochloric acid and ethyl acetate to obtain (R)-1,1-dimethylethyl-6-cyano-5-[(1,1-dimethylethyl)dimethylsilyl]oxy-3-oxohexanoate of formula XXVIII. The ketone of formula XXVIII is treated with fluoride ion at 0°C to 65°C, preferably 25°C to obtain the (R)-1,1-dimethylethyl-6-cyano-5-hydroxy-3-oxo-hexanoate of formula XXVII. The ketone of formula XXVII is treated with triethylborane and air (or methoxydiethylborane without air) followed by sodium borohydride and methanol in tetrahydrofuran at -78°C to -110°C, preferably -100°C to obtain [R-(R*,R< *>)]-1,1-dimethylethyl-6-cyano-3,5-hydroxyhexanoate of formula XXVI. The diol of formula XXVI is treated with a ketal-forming reagent such as acetone, dimethoxypropane, 2-methoxypropene, benzaldehyde, cyclopentanone, cyclohexanone, 1,1-dimethoxycyclopentane, 1,1-dimethoxycyclohexane and the like in the presence of an acid such as camphorsulfonic acid, para -toluenesulfonic acid and the like in the presence of an excess of reagent or in an inert solvent such as dichloromethane and the like at 0°C to the reflux temperature of the reagent or solvent to obtain a compound of formula XXVa, where R„ / and Ro0 independently of each other are hydrogen , alkyl of one to three carbon atoms,

fenyl eller R„ og R_ tatt sammen som -(CH_) -, hvor n er 4 phenyl or R„ and R_ taken together as -(CH_) -, where n is 4

/ o £. n / o £. n

eller 5. or 5.

En forbindelse med formel XXVa behandles med hydrogengass i en alkohol så som metanol mettet med vannfri ammoniakk eller vandig ammoniumhydroksyd i nærvær av en katalysator så som Raney-nikkel eller Raney-kobolt eller med en A compound of formula XXVa is treated with hydrogen gas in an alcohol such as methanol saturated with anhydrous ammonia or aqueous ammonium hydroxide in the presence of a catalyst such as Raney nickel or Raney cobalt or with a

edelmetallkatalysator så som platinaoksyd i nærvær av en alkansyre så som eddiksyre for å oppnå en forbindelse med noble metal catalyst such as platinum oxide in the presence of an alkanoic acid such as acetic acid to obtain a compound with

formel XXIII , hvor R_ og R_ er som ovenfor definert, formula XXIII, where R_ and R_ are as defined above,

a loa laugh

Ytterligere kan en optisk aktiv forbindelse med formel IV eller formel IVfe fremstilles med utgangspunkt i det optisk aktive epoksyd med formel IX. Fremstillingen av det optisk aktive epoksyd med formel IX beskrives av Kocienski, P. J., et al, Journal of the Chemical Society Perkin Transaction I. side 2183-2187 (1987). Furthermore, an optically active compound of formula IV or formula IVfe can be prepared starting from the optically active epoxide of formula IX. The preparation of the optically active epoxide of formula IX is described by Kocienski, P.J., et al, Journal of the Chemical Society Perkin Transaction I. pages 2183-2187 (1987).

Fremgangsmåten for fremstilling av en forbindelse med formel I skisseres i skjema III: The procedure for the preparation of a compound of formula I is outlined in Scheme III:

En forbindelse med formel IV eller formel IV. omsettes A compound of formula IV or formula IV. is traded

a b a b

med en forbindelse med formel III, with a compound of formula III,

hvor R1 er where R1 is

1- naftyl, 1- naphthyl,

2- naftyl, 2- naphthyl,

fenyl eller phenyl or

fenyl substituert med phenyl substituted with

fluor, fluoride,

klor eller chlorine or

brom, bromine,

R2 eller R3 uavhengig av hverandre er R2 or R3 independently of each other is

hydrogen, hydrogen,

fenyl eller phenyl or

-CONHR,,, hvor R, er -CONHR,,, where R, is

o b o b

fenyl, phenyl,

R, er R, is

alkyl med ett til seks karbonatomer, alkyl of one to six carbon atoms,

i et inert oppløsningsmiddel som for eksempel toluen og lignende ved oppløsningsmidlets tilbakeløpskjølingstemperatur for å oppnå en forbindelse med formel II& eller formel 11^, hvor Rx, R2, R3, R4, R?, Rg, Rga og Rgb er som ovenfor definert. Endelig behandles en forbindelse med formel II clmed en syre som for eksempel vandig saltsyre og lignende i et inert oppløsningsmiddel som for eksempel tetrahydrofuran efterfulgt av hydrolyse med en base som for eksempel natriumhydroksyd. Reaksjonen nøytraliseres med en syre som for eksempel vandig saltsyre og oppløses og/eller oppvarmes i et inert oppløsningsmiddel som for eksempel toluen og lignende med samtidig fjernelse av vann for å oppnå en forbindelse med formel I, hvor R , R2, R3 og R4 er som ovenfor definert. in an inert solvent such as toluene and the like at the reflux temperature of the solvent to obtain a compound of formula II& or formula 11^, where Rx, R2, R3, R4, R?, Rg, Rga and Rgb are as defined above. Finally, a compound of formula II is treated with an acid such as aqueous hydrochloric acid and the like in an inert solvent such as tetrahydrofuran followed by hydrolysis with a base such as sodium hydroxide. The reaction is neutralized with an acid such as aqueous hydrochloric acid and dissolved and/or heated in an inert solvent such as toluene and the like with simultaneous removal of water to obtain a compound of formula I, where R , R 2 , R 3 and R 4 are as above defined.

Videre behandles en forbindelse med formel II, b med en syre så som for eksempel vandig saltsyre og lignende i et Furthermore, a compound of formula II, b is treated with an acid such as, for example, aqueous hydrochloric acid and the like in a

inert oppløsningsmiddel så som for eksempel tetrahydrofuran og lignende i ca. 15 timer efterfulgt av tilsetning av en base så som for eksempel natriumhydroksyd og lignende og omrøres i ca. inert solvent such as, for example, tetrahydrofuran and the like in approx. 15 hours followed by the addition of a base such as for example sodium hydroxide and the like and stirred for approx.

3 0 timer. Reaksjonen gjøres atter sur med en syre så som for eksempel vandig saltsyre og oppløses og/eller oppvarmes i et inert oppløsningsmiddel så som for eksempel toluen og lignende med samtidig fjernelse av vann for å oppnå en forbindelse med formel I, hvor R1, R2, R3 og R4 er som ovenfor definert. Visse av forbindelsene med formel III er enten kjente eller kan fremstilles ved fagmessig kjente fremgangsmåter. De ringåpnede dihydroksysyrer med formel 30 hours. The reaction is made acidic again with an acid such as for example aqueous hydrochloric acid and dissolved and/or heated in an inert solvent such as for example toluene and the like with simultaneous removal of water to obtain a compound of formula I, where R1, R2, R3 and R4 is defined as above. Certain of the compounds of formula III are either known or can be prepared by methods known in the art. The ring-opened dihydroxy acids of formula

hvor R , R2, R3 og R4 er som ovenfor definert, kan fremstilles fra laktonforbindelsene med formel I ved hjelp av konvensjonell hydrolyse så som for eksempel natriumhydroksyd i metanol, natriumhydroksyd i tetrahydrofuran-vann og lignende av laktonforbindelsene med formel I. where R , R 2 , R 3 and R 4 are as defined above, can be prepared from the lactone compounds of formula I by means of conventional hydrolysis such as, for example, sodium hydroxide in methanol, sodium hydroxide in tetrahydrofuran-water and the like of the lactone compounds of formula I.

I den ringåpnede dihydroksysyreform reagerer forbindelsene ifølge den foreliggende oppfinnelse for å danne salter med farmasøytisk akseptable metall- og aminkationer dannet fra organiske og uorganiske baser. Uttrykket "farmasøytisk akseptabelt metallsalt" dekker salter dannet med natrium-, kalium-, kalsium, magnesium-, aluminium-, jern- og sinkioner. Uttrykket "farmasøytisk akseptabelt aminsalt" dekker salter med ammoniakk og organiske nitrogenholdige baser som er sterke nok til å danne salter med karboksylsyrer. Baser som er nyttige til dannelsen av farmasøytisk akseptable ikke-toksiske baseaddisjonssalter av forbindelsen ifølge den foreliggende oppfinnelse, utgjør en klasse, hvis grenser er lettforståelige for fagmannen. In the ring-opened dihydroxy acid form, the compounds of the present invention react to form salts with pharmaceutically acceptable metal and amine cations formed from organic and inorganic bases. The term "pharmaceutically acceptable metal salt" covers salts formed with sodium, potassium, calcium, magnesium, aluminum, iron and zinc ions. The term "pharmaceutically acceptable amine salt" covers salts with ammonia and organic nitrogenous bases strong enough to form salts with carboxylic acids. Bases useful in the formation of pharmaceutically acceptable non-toxic base addition salts of the compound of the present invention constitute a class, the limits of which are readily understood by those skilled in the art.

Den frie dihydroksysyreform av forbindelsene ifølge oppfinnelsen kan regenereres fra saltformen, om ønsket ved å bringe saltet i kontakt med en fortynnet vandig oppløsning av en syre så som saltsyre. The free dihydroxy acid form of the compounds according to the invention can be regenerated from the salt form, if desired, by contacting the salt with a dilute aqueous solution of an acid such as hydrochloric acid.

Den ringlukkede laktonform av forbindelsene ifølge oppfinnelsen kan regenereres ved oppløsning av dihydroksysyreformen av forbindelsene ifølge oppfinnelsen i et inert oppløsningsmiddel så som for eksempel toluen, benzen, etylacetat og lignende ved ca. 0°C til ca. oppløsningsmidlets kokepunkt, vanligvis, men ikke nødvendigvis, med samtidig fjernelse av det resulterende vann og vanligvis, men ikke nødvendigvis, med sterk syrekatalysator som for eksempel konsentrert saltsyre og lignende. The ring-closed lactone form of the compounds according to the invention can be regenerated by dissolving the dihydroxy acid form of the compounds according to the invention in an inert solvent such as, for example, toluene, benzene, ethyl acetate and the like at approx. 0°C to approx. the boiling point of the solvent, usually, but not necessarily, with simultaneous removal of the resulting water and usually, but not necessarily, with a strong acid catalyst such as concentrated hydrochloric acid and the like.

Baseaddisjonssaltene kan avvike fra de frie syreformer av forbindelsene ifølge oppfinnelsen i slike fysiske karakteristika som oppløselighet og smeltepunkt, men betraktes ellers som ekvivalente med den frie syreform, hva angår den foreliggende oppfinnelses formål. The base addition salts may differ from the free acid forms of the compounds according to the invention in such physical characteristics as solubility and melting point, but are otherwise considered equivalent to the free acid form, as far as the purpose of the present invention is concerned.

Forbindelsene ifølge oppfinnelsen kan eksistere i solvat-eller ikke-solvatform, og slike former er ekvivalente med ikke-solvatformene, hva angår den foreliggende oppfinnelses formål. The compounds according to the invention can exist in solvate or non-solvate form, and such forms are equivalent to the non-solvate forms, as far as the purpose of the present invention is concerned.

Forbindelsene med strukturformel I ovenfor har to asym-metriske karbonsentre, ett ved 4-hydroksyposisjonen av pyran-2-on-ringen, og det annet ved 6-posisjonen av pyran-2-on-ringen, hvor alkylpyrrolgruppen er bundet. Denne asymmetri gir anledning til fire mulige isomerer, -hvorav de to er 4R,6S-og 4S,6R-isomerene, og hvorav de to andre er 4R,6R- og 4S,6S-isomerene. Den foretrukne isomer ifølge den foreliggende oppfinnelse er 4R,6R-isomeren av forbindelsene med formel I, I cl og XII ovenfor. The compounds with structural formula I above have two asymmetric carbon centers, one at the 4-hydroxy position of the pyran-2-one ring, and the other at the 6-position of the pyran-2-one ring, where the alkylpyrrole group is attached. This asymmetry gives rise to four possible isomers, two of which are the 4R,6S and 4S,6R isomers, and the other two of which are the 4R,6R and 4S,6S isomers. The preferred isomer according to the present invention is the 4R,6R isomer of the compounds of formula I, Icl and XII above.

De følgende ikke-begrensende eksempler belyser den foretrukne fremgangsmåte for fremstilling av forbindelsene ifølge den foreliggende oppfinnelse. The following non-limiting examples illustrate the preferred method for preparing the compounds according to the present invention.

EKSEMPEL 1 EXAMPLE 1

Trans- 6- r 2 - r 2- etvl- 5- ( 4- f luorf envl) - lH- pvrrol- l- vl 1 - etvl 1 - tetrahydro- 4- hydroksy- 2H- pyran- 2- on Trans- 6- r 2 - r 2- etvl- 5- ( 4- fluoro envl) - lH- pvrrol- l- vl 1 - etvl 1 - tetrahydro- 4- hydroxy- 2H- pyran- 2- one

Trinn A: Fremstilling av CR*, R*)- a- 2- propenvloksiranetanol n-Butyllitium, 129 ml (200 mmol) settes dråpevis til en 0°C oppløsning av 1,6-heptadien-4-ol, 22,4 g (0,2 mol), i 200 ml vannfri tetrahydrofuran, inntil trifenylmetanindikatoren blir rød. Derefter tilsettes karbondioksyd under gjennombobling i 30 minutter ("lecture" kolbe karbondioksyd passert gjennom tørremiddel), og den lysegule oppløsning omrø-res i 30 minutter under en ballong med karbondioksyd. Til denne oppløsning settes jod, 101,4 g (0,4 mol), oppløst i "200 ml vannfri tetrahydrofuran i løpet av 60 minutter. Blandingen står til oppvarmning til romtemperatur natten over, fortynnes med etylacetat, vaskes med 10% natriumbisulfittoppløsning, mettet oppløsning av natriumbikarbonat, saltvann og tørres (magnesiumsulfat). Det rå produkt oppløses i 200 ml metanol og 20 ml vann, avkjøles til 0°C, og 0,5 g fast kaliumkarbonat tilsettes. Blandingen omrøres kraftig i seks timer, filtreres, konsentreres og lagdeles mellom etylacetat og saltvann. Efter ekstraksjon av det vandige lag 2x med etylacetat, vaskes de samlede organiske faser med saltvann og tørres (magnesiumsulfat). Lynkromatografi (4:1 heksan-etylacetat) gir efter konsentrasjon i vakuum 18 g (R<*>,R<*>)-a-2-propenyloksiranetanol. Step A: Preparation of CR*, R*)- a- 2- propenvloxiraneethanol n-Butyllithium, 129 ml (200 mmol) is added dropwise to a 0°C solution of 1,6-heptadien-4-ol, 22.4 g (0.2 mole), in 200 ml of anhydrous tetrahydrofuran, until the triphenylmethane indicator turns red. Carbon dioxide is then added while bubbling through for 30 minutes ("lecture" flask carbon dioxide passed through desiccant), and the pale yellow solution is stirred for 30 minutes under a balloon with carbon dioxide. To this solution is added iodine, 101.4 g (0.4 mol), dissolved in "200 ml of anhydrous tetrahydrofuran during 60 minutes. The mixture is allowed to warm to room temperature overnight, diluted with ethyl acetate, washed with 10% sodium bisulfite solution, saturated solution of sodium bicarbonate, brine and dried (magnesium sulfate). The crude product is dissolved in 200 ml of methanol and 20 ml of water, cooled to 0°C, and 0.5 g of solid potassium carbonate is added. The mixture is stirred vigorously for six hours, filtered, concentrated and layered between ethyl acetate and brine. After extraction of the aqueous layer 2x with ethyl acetate, the combined organic phases are washed with brine and dried (magnesium sulfate). Flash chromatography (4:1 hexane-ethyl acetate) gives after concentration in vacuo 18 g (R<*> ,R<*>)-α-2-propenyloxiraneethanol.

200 MHZ NMR (CDC13) <S 1,5-1,65 (m, 1H) , 1,90 (dt, 1H, J = 15, 4 Hz), 2,2 (m, 3H), 2,53 (m, 1H), 2,79 (m, 1H), 3,12 (m, 1H), 3,94 (m, 1H), 5,19 (m, 2H), 5,80 (m, 1H). 200 MHZ NMR (CDCl 3 ) <S 1.5-1.65 (m, 1H), 1.90 (dt, 1H, J = 15, 4 Hz), 2.2 (m, 3H), 2.53 ( m, 1H), 2.79 (m, 1H), 3.12 (m, 1H), 3.94 (m, 1H), 5.19 (m, 2H), 5.80 (m, 1H).

IR (film) 3400, 3077, 2980, 2925, 1643, 1412, 1260, 918, 827 IR (film) 3400, 3077, 2980, 2925, 1643, 1412, 1260, 918, 827

-1 -1

cm cm

Trinn B: Fremstilling av f±)- cis- 2, 2- dimetyl- 6-( 2 - Step B: Preparation of f±)- cis- 2, 2- dimethyl- 6-( 2 -

propenvl)- 1, 3- dioksan- 4- acetonitril. propenyl)-1,3-dioxane-4-acetonitrile.

Kaliumcyanid, 1,3 g (20 mmol) settes til en oppløsning av (R<*>R<*>)-a-2-propenyloksiranetanol, 2,56 g (20 mmol), i 25 ml 4:1 isopropanol-vann ved romtemperatur. Oppløsningen omrøres i 20 timer ved omgivelsestemperatur, konsentreres og lagdeles mellom etylacetat og saltvann. Det vandige lag ekstraheres 2x med etylacetat, og de kombinerte etylacetatekstrakter vaskes med saltvann og tørres (magnesiumsulfat). Det rå produkt oppløses i 20 ml 2,2-dimetoksypropan, kamfersulfonsyre tilsettes, og oppløsningen omrøres i 18 timer ved romtemperatur. Konsentrasjon og lynkromatografi gir 1,30 g (±) -cis-2,2-dimetyl-6-(2-propenyl)-1,3-dioksan-4-acetonitril. Potassium cyanide, 1.3 g (20 mmol) is added to a solution of (R<*>R<*>)-α-2-propenyloxiranethanol, 2.56 g (20 mmol), in 25 ml of 4:1 isopropanol-water at room temperature. The solution is stirred for 20 hours at ambient temperature, concentrated and layered between ethyl acetate and salt water. The aqueous layer is extracted twice with ethyl acetate, and the combined ethyl acetate extracts are washed with brine and dried (magnesium sulfate). The crude product is dissolved in 20 ml of 2,2-dimethoxypropane, camphorsulfonic acid is added, and the solution is stirred for 18 hours at room temperature. Concentration and flash chromatography give 1.30 g of (±)-cis-2,2-dimethyl-6-(2-propenyl)-1,3-dioxane-4-acetonitrile.

200 MHZ NMR (CDC13) S 1,35 (m, 1H), 1,40 (s, 3H), 1,45 (s, 3H) , 1,67 (m, 1H), 2,20 (m, 1H), 2,33 (m, 1H), 2,50 (m, 2H) , 3,89 (m, 1H), 4,10 (m, 1H), 5,10 (m, 2H), 5,7-5,9 (m, 1H) . 200 MHZ NMR (CDCl 3 ) S 1.35 (m, 1H), 1.40 (s, 3H), 1.45 (s, 3H), 1.67 (m, 1H), 2.20 (m, 1H ), 2.33 (m, 1H), 2.50 (m, 2H), 3.89 (m, 1H), 4.10 (m, 1H), 5.10 (m, 2H), 5.7 -5.9 (m, 1H).

IR (film) 2995, 2944, 2255, 1644, 1334 cm"<1.>IR (film) 2995, 2944, 2255, 1644, 1334 cm"<1.>

Trinn C: Fremstilling av ( ±)- cis- 6-( 2- oksoetyl)- 2. 2-dimetyl- 1. 3- dioksan- 4- acetonitril. Step C: Preparation of (±)-cis-6-(2-oxoethyl)-2.2-dimethyl-1.3-dioxane-4-acetonitrile.

En oppløsning av (±)-cis-2,2-dimetyl-6-(2-propenyl)-1,3-dioksan-4-acetonitril, 3 g (15,36 mmol), i 100 ml diklormetan avkjøles til -78°C under nitrogen. Ozon (Welsbach generator, strømningshastighet 0,1, spenning = 90V) passeres derefter gjennom et frittet gassinngangsrør inn i oppløsningen, inntil den blå farve av ozon viser seg. Det slukkes for strømmen, og oksygen bobles igjennom, inntil den blå farve er fjernet. Trifenylfosfin, 4,2 g (16 mmol), tilsettes, og den farveløse oppløsning står til oppvarmning til romtemperatur. Lynkromatograf i gir efter konsentrasjon i vakuum 2,5 g rent (±)-cis-6-(2-oksoetyl)-2,2-dimetyl-l,3-dioksan-4-acetonitril. A solution of (±)-cis-2,2-dimethyl-6-(2-propenyl)-1,3-dioxane-4-acetonitrile, 3 g (15.36 mmol), in 100 ml of dichloromethane is cooled to -78 °C under nitrogen. Ozone (Welsbach generator, flow rate 0.1, voltage = 90V) is then passed through a fritted gas inlet tube into the solution, until the blue color of ozone appears. The current is turned off, and oxygen is bubbled through until the blue color is removed. Triphenylphosphine, 4.2 g (16 mmol), is added and the colorless solution is allowed to warm to room temperature. Flash chromatography gives after concentration in vacuum 2.5 g of pure (±)-cis-6-(2-oxoethyl)-2,2-dimethyl-1,3-dioxane-4-acetonitrile.

200 MHZ NMR (CDC13) 6* 1,30 (m, 1H), 1,39 (s, 3H), 1,48 (s, 3H), 1,78 (m, 1H), 2,46-2,75 (m, 4H), 4,2 (m, 1H), 4,40 (m, 1H), 9,79 (t, 1H, J = 1,6 Hz). 200 MHZ NMR (CDCl 3 ) 6* 1.30 (m, 1H), 1.39 (s, 3H), 1.48 (s, 3H), 1.78 (m, 1H), 2.46-2, 75 (m, 4H), 4.2 (m, 1H), 4.40 (m, 1H), 9.79 (t, 1H, J = 1.6 Hz).

IR (film) 2250, 1720 cm"<1>. IR (film) 2250, 1720 cm"<1>.

Trinn D: Fremstilling av ( ±)- cis- 6-( cvanometvl)- 2. 2-dimetvl- I, 3- dioksan- 4- eddiksyre. Step D: Preparation of ( ± )- cis - 6-( cyanomethyl)- 2, 2-dimethyl- 1, 3- dioxane- 4- acetic acid.

Jones reagens (kromtrioksyd-svovelsyre-vann), 3,8 ml (7,6 mmol), tilsettes dråpevis til en 0°C oppløsning av (±)-cis-6-(2-oksoetyl)-2,2-dimetyl-l,3-dioksan-4-acetonitril, 1,50 g (7,6 mmol), oppløst i 50 ml aceton, inntil den orange farve ikke avgis. Efter omrøring i ytterligere 15 minutter helles blandingen i 300 ml dietyleter og vaskes med saltvann, inntil vaskevannet er farveløst. Dietyleterlaget tørres (magnesiumsulfat) , filtreres og konsentreres for å oppnå 1,2 g av syren som størkner ved henstand. Triturering med isopropyleter gir (±)-cis-6-(cyanometyl)-2,2-dimetyl-l,3-dioksan-4-eddiksyre som et farveløst faststoff, Jones reagent (chromium trioxide-sulfuric acid-water), 3.8 ml (7.6 mmol), is added dropwise to a 0°C solution of (±)-cis-6-(2-oxoethyl)-2,2-dimethyl- 1,3-dioxane-4-acetonitrile, 1.50 g (7.6 mmol), dissolved in 50 ml of acetone, until the orange color is not emitted. After stirring for a further 15 minutes, the mixture is poured into 300 ml of diethyl ether and washed with salt water, until the wash water is colourless. The diethyl ether layer is dried (magnesium sulphate), filtered and concentrated to obtain 1.2 g of the acid which solidifies on standing. Trituration with isopropyl ether gives (±)-cis-6-(cyanomethyl)-2,2-dimethyl-1,3-dioxane-4-acetic acid as a colorless solid,

smp. 92-95°C. m.p. 92-95°C.

En ytterligere triturering/omkrystallisasjon fra isopropyleter gir materiale med smp. 98-103°C. A further trituration/recrystallization from isopropyl ether gives material with m.p. 98-103°C.

200 MHz NMR (CDC13) S 1,35 (m, 1H), 1,42 (s, 3H), 1,49 (s, 3H), 1,82 (m, 1H), 2,4-2,7 (m, 4H), 4,18 (m, 1H), 4,35 (m, 1H) . 200 MHz NMR (CDCl 3 ) S 1.35 (m, 1H), 1.42 (s, 3H), 1.49 (s, 3H), 1.82 (m, 1H), 2.4-2.7 (m, 4H), 4.18 (m, 1H), 4.35 (m, 1H).

13C-NMR(dir-aceton, 50 MHz) S 19,95, 24,91, 30,17, 35,88, 41,34, 65,79, 66,35, 99,70, 117,77, 171,83. 13C-NMR(dir-acetone, 50 MHz) S 19.95, 24.91, 30.17, 35.88, 41.34, 65.79, 66.35, 99.70, 117.77, 171, 83.

IR (KBr) bred OH 3500-2400, 2254, 1711, 940 cm"<1.>IR (KBr) broad OH 3500-2400, 2254, 1711, 940 cm"<1.>

Trinn E: Fremstilling av ( ± )- cis- l- metyletyl- 6-( cyanometyl) - 2. 2- dimetvl- l. 3- dioksan- 4- acetat. Step E: Preparation of (±)-cis-1-methylethyl-6-(cyanomethyl)-2.2-dimethyl-1.3-dioxane-4-acetate.

Til en oppløsning av (±)-cis-6-(cyanometyl)-2,2-dimetyl-1,3-dioksan-4-eddiksyre, 0,6 g (3 mmol), i acetonitril, 2 ml, settes l,8-diazabicyklo[5.4.0]-undec-7-en (DBU), 0,45 ml (3 mmol) og 2-jodpropan, 0,33 ml (3,3 mmol). Oppløsningen omrøres natten over ved romtemperatur, fortynnes med dietyleter, vaskes med saltvann og tørres (magnesiumsulfat). Lynkromatografi gir 0,55 g (±)-cis-l-metyletyl-6-(cyanometyl)-2,2-dimetyl-l,3-dioksan-4-acetat. 90 MHz NMR (CDC12) S 1,22 (d, 6H, J = 7 Hz), 1,3 (m, 1H), 1,35 (s, 3H), 1,40 (s, 3H), 1,75 (m, 1H), 2,2-2,7 (m, 4H), 3,9-4,4 (m, 2H), 4,95 (septet, 1H, J = 7 Hz). To a solution of (±)-cis-6-(cyanomethyl)-2,2-dimethyl-1,3-dioxane-4-acetic acid, 0.6 g (3 mmol), in acetonitrile, 2 ml, is added l, 8-diazabicyclo[5.4.0]-undec-7-ene (DBU), 0.45 mL (3 mmol) and 2-iodopropane, 0.33 mL (3.3 mmol). The solution is stirred overnight at room temperature, diluted with diethyl ether, washed with salt water and dried (magnesium sulfate). Flash chromatography gives 0.55 g of (±)-cis-1-methylethyl-6-(cyanomethyl)-2,2-dimethyl-1,3-dioxane-4-acetate. 90 MHz NMR (CDCl 2 ) S 1.22 (d, 6H, J = 7 Hz), 1.3 (m, 1H), 1.35 (s, 3H), 1.40 (s, 3H), 1, 75 (m, 1H), 2.2-2.7 (m, 4H), 3.9-4.4 (m, 2H), 4.95 (sept, 1H, J = 7 Hz).

Trinn F: Fremstilling av ( ± )- cis- l- metyletyl- 6-( 2-aminoetvl)- 2. 2- dimetyl- l. 3- dioksan- 4- acetat. Step F: Preparation of (±)-cis-1-methylethyl-6-(2-aminoethyl)-2.2-dimethyl-1.3-dioxane-4-acetate.

En blanding av (±)-cis-l-metyletyl-6-(cyanometyl)-2,2-dimetyl-1,3-dioksan-4-acetat, 0,55 g, i iseddiksyre hydrogeneres med platinadioksyd ved 50 pund pr. kvadrattomme (PSI). Konsentrasjon, fortynning med etylacetat og vask med bikarbonat efterfulgt av vask med saltvann og tørring gir 250 mg (±)-cis-l-metyletyl-6-(2-aminoetyl)-2,2- dimetyl-1,3-dioksan-4-acetat. MS 260,1, 244,1 A mixture of (±)-cis-1-methylethyl-6-(cyanomethyl)-2,2-dimethyl-1,3-dioxane-4-acetate, 0.55 g, in glacial acetic acid is hydrogenated with platinum dioxide at 50 pounds per square inch (PSI). Concentration, dilution with ethyl acetate and washing with bicarbonate followed by washing with brine and drying give 250 mg of (±)-cis-1-methylethyl-6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxane-4 -acetate. MS 260.1, 244.1

200 MHZ NMR (CDC12) S 1,25 (d, 6H, J = 7 Hz), 1,32 (m, 1H), 1,36 (s, 3H), 1,45 (s, 3H), 1,60 (m, 1H), 2,33 (dd, 1H, J = 15, 6 Hz), 2,49 (dd, 1H, J = 15, 6 Hz), 2,85 (br t, 2H, J = 6 Hz), 3,40 (br s, 2H) , 4,00 (m, 1H), 4,29 (m, 1H), 12,03 (septet, 1H, J = 7 Hz). 200 MHZ NMR (CDCl 2 ) S 1.25 (d, 6H, J = 7 Hz), 1.32 (m, 1H), 1.36 (s, 3H), 1.45 (s, 3H), 1, 60 (m, 1H), 2.33 (dd, 1H, J = 15, 6 Hz), 2.49 (dd, 1H, J = 15, 6 Hz), 2.85 (br t, 2H, J = 6 Hz), 3.40 (br s, 2H), 4.00 (m, 1H), 4.29 (m, 1H), 12.03 (sept, 1H, J = 7 Hz).

IR (film) 1734, 1387 cm"<1>. IR (film) 1734, 1387 cm"<1>.

Trinn G: Fremstilling av ( ±)- cis- l- metyletyl- 6-\ 2 - Step G: Preparation of (±)-cis-l-methylethyl-6-\ 2 -

f2- etvl- 5- C4- fluorfenvl)- lH- Pvrrol- 1- vll-etyl]- 2, 2- dimetyl- l. 3- dioksan- 4- acetat. f2-ethyl-5-C4-fluorophenyl)-1H-pyrrol-1-v11-ethyl]-2,2-dimethyl-1.3-dioxane-4-acetate.

En oppløsning av (±)-cis-l-metyletyl-6-(2-aminoetyl)-2,2-dimetyl-1,3-dioksan-4-acetat, 0,15 g (0,58 mmol), og l-(4-fluorfenyl)-1,4-heksandion (eksempel A), 0,125 g (0,6 mmol), i 5 ml toluen omrøres og oppvarmes ved tilbakeløpskjøling natten over. Den avkjølte oppløsning konsentreres, og den sterkt UV-aktive pyrrol separeres fra utgangsmaterialet ved preparativ tynnskiktskromatografi, eluering 2x med 4:1 heksan-etylacetat. Dette gir 130 mg rent (±)-cis-l-metyletyl-6-[2-[2-etyl-5-(4-fluorfenyl)-lH-pyrrol-l-yl]etyl]-2,2-dimetyl-l,3-dioksan-4-acetat. A solution of (±)-cis-1-methylethyl-6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxane-4-acetate, 0.15 g (0.58 mmol), and l -(4-Fluorophenyl)-1,4-hexanedione (Example A), 0.125 g (0.6 mmol), in 5 ml of toluene is stirred and heated under reflux overnight. The cooled solution is concentrated, and the highly UV-active pyrrole is separated from the starting material by preparative thin-layer chromatography, eluting 2x with 4:1 hexane-ethyl acetate. This gives 130 mg of pure (±)-cis-1-methylethyl-6-[2-[2-ethyl-5-(4-fluorophenyl)-1H-pyrrol-1-yl]ethyl]-2,2-dimethyl- 1,3-dioxane-4-acetate.

200 MHz NMR (CDC13) 6 1,51 (m, 1H), 1,23 (d, 6H, J = 6 Hz), 1,33 (m, 9H), 1,5-1,6 (m, 3H), 2,27 (dd, 1H, J = 15,3, 6 Hz), 2,44 (dd, 1H, J = 15,3, 6 Hz), 2,66 (q, 2H, J = 7,5 Hz), 3,62 (m, 1H), 3,8-4,2 (m, 3H), 5,03 (septet, 1H, J = 6 Hz), 5,97 (d, 1H, J = 3,5 Hz), 6,11 (d, 1H, J = 3,5 Hz), 7,0-7,4 (m, 200 MHz NMR (CDCl 3 ) δ 1.51 (m, 1H), 1.23 (d, 6H, J = 6 Hz), 1.33 (m, 9H), 1.5-1.6 (m, 3H ), 2.27 (dd, 1H, J = 15.3, 6 Hz), 2.44 (dd, 1H, J = 15.3, 6 Hz), 2.66 (q, 2H, J = 7, 5 Hz), 3.62 (m, 1H), 3.8-4.2 (m, 3H), 5.03 (sept, 1H, J = 6 Hz), 5.97 (d, 1H, J = 3.5 Hz), 6.11 (d, 1H, J = 3.5 Hz), 7.0-7.4 (m,

4H) . 4H).

En oppløsning av (±)-cis-l-metyletyl<r->6-[2-[2-etyl-5-(4-fluorfenyl)-lH-pyrrol-l-yl]etyl]-2,2-dimetyl-l,3-dioksan-4-acetat, 0,13 g (0,3 mmol), i 12 ml 1:2 2M saltsyre-tetrahydrofuran omrøres natten over ved romtemperatur. Dertil settes tilstrekkelig 2M natriumhydroksyd til å bringe pH til 10. Omrøring fortsettes i 30 minutter, vann, 30 ml, tilsettes, og blandingen ekstraheres med dietyleter. Det vandige lag gjøres surt med iskald 6N saltsyre og ekstraheres med etylacetat (2x). Den organiske fase vaskes med saltvann og tørres (magnesiumsulfat). Residuet efter filtrering og konsentrasjon oppløses i toluen (50 ml) og oppvarmes ved tilbakeløpskjøling med azeotrop fjernelse av vann (6 timer). Den avkjølte oppløsning konsentreres og flashkromatograferes for å oppnå 60 mg trans-6-[2-[2-etyl-5-(4-fluorfenyl)-lH-pyrrol-l-yl]etyl]-tetrahydro-4-hydroksy-2H-pyran-2-on (eluering med 2:1 heksan-etylacetat). 90 MHZ NMR (CDC13) S 1,25 (d, 6H, J = 7 Hz) 1,3-1,8 (m, 4H), 2,3 (br s, 1H, -0H), 2,55 (m, 2H), 2,65 (q, 2H, J = 7Hz), 3,9-4,5 (m, 4H), 5,90 (d, 1H, J = 3,5 Hz), 6,05 (d, 1H, J = 3,5 Hz), 6,9-7,4 (m, 4H). A solution of (±)-cis-1-methylethyl<r->6-[2-[2-ethyl-5-(4-fluorophenyl)-1H-pyrrol-1-yl]ethyl]-2,2-dimethyl -1,3-dioxane-4-acetate, 0.13 g (0.3 mmol), in 12 ml of 1:2 2M hydrochloric acid-tetrahydrofuran is stirred overnight at room temperature. To this is added sufficient 2M sodium hydroxide to bring the pH to 10. Stirring is continued for 30 minutes, water, 30 ml, is added and the mixture is extracted with diethyl ether. The aqueous layer is acidified with ice-cold 6N hydrochloric acid and extracted with ethyl acetate (2x). The organic phase is washed with salt water and dried (magnesium sulfate). The residue after filtration and concentration is dissolved in toluene (50 ml) and heated at reflux with azeotropic removal of water (6 hours). The cooled solution is concentrated and flash chromatographed to obtain 60 mg of trans-6-[2-[2-ethyl-5-(4-fluorophenyl)-1H-pyrrol-1-yl]ethyl]-tetrahydro-4-hydroxy-2H- pyran-2-one (elution with 2:1 hexane-ethyl acetate). 90 MHZ NMR (CDCl 3 ) S 1.25 (d, 6H, J = 7 Hz) 1.3-1.8 (m, 4H), 2.3 (br s, 1H, -0H), 2.55 ( m, 2H), 2.65 (q, 2H, J = 7Hz), 3.9-4.5 (m, 4H), 5.90 (d, 1H, J = 3.5 Hz), 6.05 (d, 1H, J = 3.5 Hz), 6.9-7.4 (m, 4H).

EKSEMPEL 2 EXAMPLE 2

Trans-( ± )- 5-( 4- fluorfenvl)- 2-( 1- metvletvl)- N. 4- difenvl- 1- T2-( tetrahvdro- 4- hvdroksy- 6- okso- 2H- pvran- 2- yl) etyl]- lH- pvrrol- 3-karboksamid. Trans-( ± )- 5-( 4- fluorophenyl)- 2-( 1- methylethyl)- N. 4- diphenyl- 1- T2-( tetrahydro- 4- hydroxy- 6- oxo- 2H- pvran- 2- yl ) ethyl]-1H-pyrrole-3-carboxamide.

FREMGANGSMÅTE A METHOD OF PROCEDURE A

Trinn A: Fremstilling av 4- metyl- 3- okso- N- fenvl- 2-( fenylmetylen) pentanamid. Step A: Preparation of 4-methyl-3-oxo-N-phenyl-2-(phenylmethylene)pentanamide.

En suspensjon av 100 kg 4-metyl-3-okso-N-fenylpentanamid (eksempel B) i 660 kg heksan behandles under omrystning under nitrogen med 8 kg /3-alanin, 47 kg benzaldehyd og 13 kg iseddiksyre. Den resulterende suspensjon oppvarmes til tilbakeløpskjøling med fjernelse av vann i 20 timer. Ytterligere 396 kg heksan og 3 kg iseddiksyre tilsettes, og tilbakeløpskjøling fortsettes med fjernelse av vann i én time. Reaksjonsblandingen avkjøles til 20-25°C, og produktet isoleres ved filtrering. Produktet renses ved oppslemning i heksan ved 50-60°C, avkjøling og filtrering. Produktet oppslemmes to ganger med vann ved 20-25<6>C, filtreres og tørres i vakuum for å oppnå 110 kg 4-metyl-3-okso-N-fenyl-2-(fenylmetylen)pentanamid, A suspension of 100 kg of 4-methyl-3-oxo-N-phenylpentanamide (Example B) in 660 kg of hexane is treated with shaking under nitrogen with 8 kg of β-alanine, 47 kg of benzaldehyde and 13 kg of glacial acetic acid. The resulting suspension is heated to reflux with removal of water for 20 hours. A further 396 kg of hexane and 3 kg of glacial acetic acid are added and reflux is continued with removal of water for one hour. The reaction mixture is cooled to 20-25°C, and the product is isolated by filtration. The product is purified by suspension in hexane at 50-60°C, cooling and filtration. The product is slurried twice with water at 20-25<6>C, filtered and dried in vacuum to obtain 110 kg of 4-methyl-3-oxo-N-phenyl-2-(phenylmethylene)pentanamide,

smp. 143,7-154,4°C. m.p. 143.7-154.4°C.

Dampfasekromatografi (VPC): 30 meter DB 5 kapillarkolonne 50-270°C ved 15°C/min. 19,33 min, 99,7% (område). Vapor phase chromatography (VPC): 30 meter DB 5 capillary column 50-270°C at 15°C/min. 19.33 min, 99.7% (range).

Gasskromatografi/massespektrometri (GC/MC): M/Z 293 [M]<+>. Gas Chromatography/Mass Spectrometry (GC/MC): M/Z 293 [M]<+>.

Nuklear magnetisk resonans (NMR): (CDC13) S 1,16 (6H, d), 3,30 (1H, kin.), 7,09 (1H, m), 7,28 (5H, m), 7,49 (5H, m), 8,01 (1H, brs). Nuclear Magnetic Resonance (NMR): (CDCl 3 ) S 1.16 (6H, d), 3.30 (1H, kin.), 7.09 (1H, m), 7.28 (5H, m), 7, 49 (5H, m), 8.01 (1H, brs).

Trinn B: Fremstilling av ( ±) 4- fluor- a- r2- metyl- l-oksopropvl 1 -" Y- okso- N, lf- dif envlbenzenbutan-amidblanding av rR-( R*, R* n. TR-( R* . S*) 1 . rs-( R*. R* n og rs-( R*. S* n isomerer. Step B: Preparation of (±) 4-fluoro-a-r2-methyl-l-oxopropvl1-"Y-oxo-N,lf-diphenylbenzenebutanamide mixture of rR-(R*,R* n. TR-( R* . S*) 1 . rs-( R* . R* n and rs-( R* . S* n isomers.

En oppløsning av 17,5 kg 3-etyl-5-(2-hydroksyetyl)-4-metyltiazoliumbromid i 300 1 vannfri etanol konsentreres ved destillasjon av 275 1 etanol. Under argonatmosfære tilsettes 100 kg (340 mol) 4-metyl-3-okso-N-fenyl-2-(fenylmetylen)pentanamid, 47,5 1 (340 mol) trietylamin og 40 1 (375 mol) 4-fluorbenzaldehyd. Den resulterende oppløsning omrøres og oppvarmes ved 75-80"C i 23 timer. Produktet begynner å dannes som et fast stoff efter ca. 1,5 timer, men ca. 24 timer er nødvendig for en i det vesentlige fullstendig omsetning. Oppslemningen oppløses i 600 1 isopropanol ved 80°C. Den resulterende oppløsning avkjøles langsomt, og (±)4-f luor-a- [2-metyl-l-oksopropyl] -"Y-okso-N, fl-dif enyl-benzenbutanamid-blandingen av [R-(R*,R<*>)], [R-(R<*>,S<*>)], [S-(R<*>,R*)] og [S-(R*,S*)] isomerer isoleres ved filtrering. Vaskning av utfellningsproduktet med isopropanol og tørring i vakuum ga 99 kg (±) 4-fluor-a-[2-metyl-l-oksopropyl]-'Y-okso-N,/3-difenylbenzenbutanamid-blanding av [R-(R*,R*)], [R-(R<*>,S*)], [S-(R*,R*)] og [S-(R*,S*)] isomerer; A solution of 17.5 kg of 3-ethyl-5-(2-hydroxyethyl)-4-methylthiazolium bromide in 300 1 of anhydrous ethanol is concentrated by distillation of 275 1 of ethanol. Under an argon atmosphere, 100 kg (340 mol) of 4-methyl-3-oxo-N-phenyl-2-(phenylmethylene)pentanamide, 47.5 1 (340 mol) of triethylamine and 40 1 (375 mol) of 4-fluorobenzaldehyde are added. The resulting solution is stirred and heated at 75-80°C for 23 hours. The product begins to form as a solid after about 1.5 hours, but about 24 hours are required for substantially complete reaction. The slurry is dissolved in 600 L of isopropanol at 80° C. The resulting solution is cooled slowly, and the (±)4-fluoro-α-[2-methyl-1-oxopropyl]-"Y-oxo-N,fl-diphenyl-benzenebutanamide mixt. of [R-(R*,R<*>)], [R-(R<*>,S<*>)], [S-(R<*>,R*)] and [S-(R *,S*)] isomers are isolated by filtration. Washing the precipitate with isopropanol and drying in vacuo gave 99 kg (±) of 4-fluoro-α-[2-methyl-1-oxopropyl]-'Y-oxo-N,/3-diphenylbenzenebutanamide mixture of [R-(R *,R*)], [R-(R<*>,S*)], [S-(R*,R*)] and [S-(R*,S*)] isomers;

smp. 206,8-207/6°C. m.p. 206.8-207/6°C.

NMR: (CDC13) S 1,03 (3H, d), 1,22 (3H, d), 2,98 (1H, kin.), 4,91 (1H, d, J = 11 Hz), 5,51 (1H, d, J = 11 Hz), 6,98-7,43 (12H, m), 8,17 (2H, dd), 9,41 (1H, brs). NMR: (CDCl 3 ) S 1.03 (3H, d), 1.22 (3H, d), 2.98 (1H, kin.), 4.91 (1H, d, J = 11 Hz), 5, 51 (1H, d, J = 11 Hz), 6.98-7.43 (12H, m), 8.17 (2H, dd), 9.41 (1H, brs).

Høytrykksvæskekromatografi (HPLC): (acetonitril:tetrahydrofuran: vann) (40:25:55) Econosil Clg5/z 25 cm 1,0 ml/min. 254 nm 16,77 min. 99,2% (område). High Performance Liquid Chromatography (HPLC): (acetonitrile: tetrahydrofuran: water) (40:25:55) Econosil Clg5/z 25 cm 1.0 ml/min. 254 nm 16.77 min. 99.2% (range).

Trinn C: Fremstilling av 1- f3, 3- dietoksypropvl)-5-( 4- fluorfenvl)- 2-( 1- metvletvl)- N.4-di f envl- lH- pyrro1- 3- karboksamid. Step C: Preparation of 1- (3,3-diethoxypropyl)-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1H-pyrro1-3-carboxamide.

Til en nitrogenrenset kolbe utstyrt med en mekanisk omrører settes 130 kg (311 mol) (±)4-fluor-a-[2-metyl-l-oksopropyl]-*y-okso-N,/3-difenylbenzenbutanamid-blanding av [R-(R<*>,R*)], [R-(R*,S*)], [S-(R*,R*)] og [S-(R*,S*)] isomerer, 540 1 heptan og 60 1 toluen, 59 kg (400 mol) 3-amino-l,l-dietoksypropan og 22,3 kg (218 mol) pivalinsyre. Blandingen omrøres og oppvarmes til tilbakeløpskjøling under fjernelse av vann med en Dean-Stark-felle. Blandingen tilbakeløpskjøles i 32 timer og avkjøles langsomt til 60-65"C, fortynnes med 500 1 2-propanol-vann (3:2), podes og avkjøles til 20-25°C. Produktet isoleres ved filtrering, vaskes med 300 1 2-propanol og tørres i vakuum for å oppnå 133,5 kg 1-(3,3-dietoksy-propyl)-5-(4-fluorfenyl)-2-(1-metyletyl)-N,4-difenyl-lH-pyrrol-3-karboksamid, To a nitrogen-purged flask equipped with a mechanical stirrer is added 130 kg (311 mol) (±)4-fluoro-a-[2-methyl-1-oxopropyl]-*y-oxo-N,/3-diphenylbenzenebutanamide mixture of [ R-(R<*>,R*)], [R-(R*,S*)], [S-(R*,R*)] and [S-(R*,S*)] isomers, 540 1 of heptane and 60 1 of toluene, 59 kg (400 mol) of 3-amino-1,1-diethoxypropane and 22.3 kg (218 mol) of pivalic acid. The mixture is stirred and heated to reflux while removing water with a Dean-Stark trap. The mixture is refluxed for 32 hours and cooled slowly to 60-65°C, diluted with 500 1 2-propanol-water (3:2), inoculated and cooled to 20-25°C. The product is isolated by filtration, washed with 300 1 2 -propanol and dried in vacuum to obtain 133.5 kg of 1-(3,3-diethoxy-propyl)-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1H-pyrrole -3-carboxamide,

smp. 125,1-127,7°C efter omkrystallisasjon fra etanol. m.p. 125.1-127.7°C after recrystallization from ethanol.

HPLC: (acetonitril:tetrahydrofuran:vann) (40:25:55) 1,5 ml/min 254 nm Econosil C. _ 5/i 25 cm R.T. = 37,70 min 99,4% (område) HPLC: (acetonitrile:tetrahydrofuran:water) (40:25:55) 1.5 ml/min 254 nm Econosil C. _ 5/in 25 cm R.T. = 37.70 min 99.4% (range)

IO IO

NMR: ((CD3)2CO) S 1,04 (6H, m, t), 1,47 (6H, d), 1,82 (2H, m) , 3,40 (5H, m), 3,99 (2H, m), 4,43 (1H, brt), 6,90-7,50 (14H, m), 8,26 (1H, brs) NMR: ((CD3)2CO) S 1.04 (6H, m, t), 1.47 (6H, d), 1.82 (2H, m), 3.40 (5H, m), 3.99 (2H, m), 4.43 (1H, brt), 6.90-7.50 (14H, m), 8.26 (1H, brs)

Ved en med trinn C analog fremgangsmåte under anvendelse av passende utgangsmaterialer fremstilles de følgende forbindelser med formel XVI: 1-( 3. 3- dimetoksypropyl)- 5-( 4- fluorfenyl)- 2-( 1- metyl-etvl) - N. 4- difenyl- lH- pvrrol- 3- karboksamid. By a procedure analogous to step C using suitable starting materials, the following compounds of formula XVI are prepared: 1-(3.3-dimethoxypropyl)-5-(4-fluorophenyl)-2-(1-methyl-ethyl)-N. 4- diphenyl- 1H- pyrrole- 3- carboxamide.

smp. 167-168,2°C. m.p. 167-168.2°C.

5-( 4- fluorfenvl)- 1- r 2-( 4- metyl- l. 3- dioksolan- 2- yl)-etvl1- 2-( 1- metyletvl)- N, 4- difenyl- lH- pyrrol- 3- karboksamid. 5-(4-Fluorophenyl)-1- r2-(4-methyl-1.3-dioxolan-2-yl)-ethyl1-2-(1-methylethyl)-N,4-diphenyl-1H-pyrrole-3 - carboxamide.

kp. 141,5-145,9°C. kp. 141.5-145.9°C.

Trinn D: Fremstilling av 5-( 4- fluorfenyl)- 2-( l-metvletvl)- l-( 3- oksopropyl)- N, 4- difenvl-lH- pyrrol- 3- karboksamid. Step D: Preparation of 5-(4-fluorophenyl)-2-(1-methylmethyl)-1-(3-oxopropyl)-N,4-diphenyl-1H-pyrrole-3-carboxamide.

Til en nitrogenskyllet kolbe utstyret med en "overhead"-omrører, et termometer og en kondensator settes 20 kg (37,8 mol) 1-(3,3-dietoksypropyl)-5-(4-fluorfenyl)-2-(1-metyletyl)-N,4-difenyl-lH-pyrrol-3-karboksamid sammen med 200 1 aceton. Oppløsningen omrøres, og 100 1 2N saltsyreoppløsning tilsettes. Blandingen oppvarmes til tilbakeløpskjøling i fire timer, avkjøles derefter til 50°C ± 5°C, podes og avkjøles til 0°C ± 5°C. Produktet oppsamles ved filtrering, vaskes med 100 1 2-propanol-vann (1:1) og tørres i vakuum ved 50°C i 64 timer for å oppnå 16,2 kg 5-(4-fluorfenyl)-2-(1-metyletyl)-1-(3-oksopropyl)-N,4-difenyl-lH-pyrrol-3-karboksamid som et off-white faststoff. To a nitrogen-flushed flask equipped with an "overhead" stirrer, a thermometer and a condenser is added 20 kg (37.8 mol) 1-(3,3-diethoxypropyl)-5-(4-fluorophenyl)-2-(1- methylethyl)-N,4-diphenyl-1H-pyrrole-3-carboxamide together with 200 1 of acetone. The solution is stirred, and 100 1 2N hydrochloric acid solution is added. The mixture is heated to reflux for four hours, then cooled to 50°C ± 5°C, seeded and cooled to 0°C ± 5°C. The product is collected by filtration, washed with 100 1 2-propanol-water (1:1) and dried in vacuum at 50°C for 64 hours to obtain 16.2 kg of 5-(4-fluorophenyl)-2-(1- methylethyl)-1-(3-oxopropyl)-N,4-diphenyl-1H-pyrrole-3-carboxamide as an off-white solid.

Trinn E: Fremstillin<g> av 2-( 4- fluorofenvl)- <S- hvdroksy-5- ( 1- metyletvl) - fl- okso- 3- fenvl- 4- f ( f enyl-amino) karbonyl]- lH- pvrrol- l- heptansyre, metylester. Step E: Preparation<g> of 2-(4-fluorophenyl)- <S-hydroxy-5-(1-methylethyl)-fluoro-3-phenyl-4- f (phenyl-amino)carbonyl]-lH - pvrrol-l-heptanoic acid, methyl ester.

En 22 1 trehalset kolbe utstyrt med en "overhead"-omrører, et lavtemperaturtermometer og en 2 1 kalibrert skilletrakt tørres ved nitrogenrensning, og 78 g (1,95 mol) 60% natriumhydrid i mineralolje tilsettes efterfulgt av 248 ml (1,76 mol) diisopropylamin og 8 1 tetrahydrofuran. Reaksjonen avkjøles til -10° til 0°C, en signifikant nitrogenrensning av kolben utføres, og 212 ml (1,92 mol) metylacetoacetat tilsettes via en langsom strøm over en periode på 10 til 30 minutter. Omrøring fortsettes ved -10° til 10°C i ytterligere 10 til 30 minutter. Efter avkjøling til -15 til -5°C tilsettes 2,2 1 1,6 M n-butyllitium i heksan i løpet av en 30 til 60 minutters periode, mens temperaturen holdes under 0°C. Omrøring fortsettes ytterligere i 1 til 1,5 timer ved A 22 L three-necked flask equipped with an overhead stirrer, a low-temperature thermometer, and a 2 L calibrated separatory funnel is dried under a nitrogen purge, and 78 g (1.95 mol) of 60% sodium hydride in mineral oil is added followed by 248 mL (1.76 mol ) diisopropylamine and 8 1 tetrahydrofuran. The reaction is cooled to -10° to 0°C, a significant nitrogen purge of the flask is performed, and 212 mL (1.92 moles) of methyl acetoacetate is added via a slow stream over a period of 10 to 30 minutes. Stirring is continued at -10° to 10°C for an additional 10 to 30 minutes. After cooling to -15 to -5°C, 2.2 1 1.6 M n-butyllithium in hexane is added over a 30 to 60 minute period, while maintaining the temperature below 0°C. Stirring is continued for a further 1 to 1.5 hours at

-15° til 0°C og blandingen avkjøles til -35° til -15°C. -15° to 0°C and the mixture is cooled to -35° to -15°C.

I en separat 5 1 kolbe oppløses 0,7 kg (1,54 mol) 5-(4-fluorfenyl)-2-(1-metyletyl)-1-(3-oksopropyl)-N,4-difenyl-lH-pyrrol-3-karboksamid med 2,0 1 tørr tetrahydrofuran, avkjølt til 0° til -5°C og settes til anionoppløsningen over en 30 til 45 minutters periode. Reaksjonen omrøres ved -20° til -15"C i 30 til 45 minutter, stanses derefter ved tilsetning av 4 1 vandig 2 N saltsyreoppløsning over 5 til 15 sekunder under hurtig omrøring. Efter opphør av rystning separeres det lavere lag, og det gjenværende organiske lag vaskes med 4 1 mettet vandig natriumklorid. In a separate 5 L flask, dissolve 0.7 kg (1.54 mol) of 5-(4-fluorophenyl)-2-(1-methylethyl)-1-(3-oxopropyl)-N,4-diphenyl-1H-pyrrole -3-carboxamide with 2.0 L of dry tetrahydrofuran, cooled to 0° to -5°C and added to the anion solution over a 30 to 45 minute period. The reaction is stirred at -20° to -15"C for 30 to 45 minutes, then stopped by the addition of 4 1 of aqueous 2 N hydrochloric acid solution over 5 to 15 seconds with rapid stirring. After cessation of shaking, the lower layer is separated, and the remaining organic layer is washed with 4 1 of saturated aqueous sodium chloride.

Trinn F: Fremstillin<g> av cis- f4- fluorfenyl)- B . 6 - Step F: Preparation<g> of cis- (4-fluorophenyl)- B . 6 -

dihydroksy- 5- f1- metvletyl)- 3- fenyl- 4- r( fenvlamino)-karbonyl1- lH- pyrrol- l- heptansvremetylester. dihydroxy-5- (1-methylethyl)-3-phenyl-4- r(phenylamino)-carbonyl-1-1H-pyrrole-1-heptanespermethyl ester.

Den fra trinn E oppnådde reaksjonsoppløsning, som oppbevares i et 50 1 glassdestillasjonsapparat forsynt med varmekappe konsentreres ved vakuumdestillasjon til en tykk olje, oppløses derefter med 19 1 tetrahydrofuran og avkjøles til 0°C under en atmosfære av luft. Trietylboran, en 1 molar oppløsning i heksan, (3,20 1, 1,4 ekvivalenter basert på trinn E) tilsettes over en 10 minutters periode, atmosfæren i kolben utskiftes med nitrogen, og kolben kjøles til -105°C i løpet av 3,5 timer. I løpet av denne periode tilsettes to liter The reaction solution obtained from step E, which is stored in a 50 1 glass still equipped with a heating jacket, is concentrated by vacuum distillation to a thick oil, then dissolved with 19 1 tetrahydrofuran and cooled to 0°C under an atmosphere of air. Triethylborane, a 1 molar solution in hexane, (3.20 L, 1.4 equivalents based on step E) is added over a 10 minute period, the atmosphere in the flask is replaced with nitrogen, and the flask is cooled to -105°C over 3 .5 hours. During this period, two liters are added

metanol, når temperaturen når -67°C. Pulverisert natriumborhydrid (184 g, 4,8 mol) tilsettes i 20 til 50 g methanol, when the temperature reaches -67°C. Powdered sodium borohydride (184 g, 4.8 mol) is added in 20 to 50 g

porsjoner i løpet av 1,5 timer, og reaksjonen holdes mellom . -95° og -106°C i 13 timer, derefter mellom -60° og -100°C i 10 timer. Ureagert natriumborhydrid nøytraliseres ved tilsetning av 750 ml (12,7 mol) eddiksyre i 50 ml porsjoner over en 45 minutters periode under gassavgivelse i vesentlige mengder og med temperaturstigning fra -60° til -40°C. Ytterligere nøytralisering fullføres ved tilsetning av en oppløsning av 1,0 1 30% hydrogenperoksyd (9,7 mol), 3,0 1 vann og 100 g dihydrogennatriumfosfat over en 15 minutters periode, hvilket ledsages av en temperaturstigning fra -40° til 0°C. Reaksjonsblandingen står til oppvarmning til romtemperatur natten over, hvorefter det nedre lag frasepareres, og det øvre lag vaskes med 4,0 1 mettet vandig natriumkloridoppløsning. portions over the course of 1.5 hours, and the reaction is kept between . -95° and -106°C for 13 hours, then between -60° and -100°C for 10 hours. Unreacted sodium borohydride is neutralized by the addition of 750 ml (12.7 mol) of acetic acid in 50 ml portions over a 45 minute period while releasing gas in significant quantities and with a temperature rise from -60° to -40°C. Further neutralization is completed by adding a solution of 1.0 L of 30% hydrogen peroxide (9.7 mol), 3.0 L of water and 100 g of sodium dihydrogen phosphate over a 15 minute period, which is accompanied by a rise in temperature from -40° to 0° C. The reaction mixture is allowed to warm to room temperature overnight, after which the lower layer is separated, and the upper layer is washed with 4.0 1 of saturated aqueous sodium chloride solution.

Variasjon av trinn F: Variation of stage F:

Fremstilling av cis- 2-( 4- fluorfenyl) - 0 . <S- dihydroksv- 5- f 1-metyletyl)- 3- fenyl- 4-( fenylamino) karbonyl- lH- pyrrol- 1-heptansyremetylester. Preparation of cis-2-(4-fluorophenyl)-0. (S-dihydroxy-5-[1-methylethyl)-3-phenyl-4-(phenylamino)carbonyl-1H-pyrrole-1-heptanoic acid methyl ester.

Den fra trinn E oppnådde reaksjonsoppløsning konsentreres under vakuum til et volum på 5 til 8 1, oppløses derefter i 20 1 tetrahydrofuran og 4 1 metanol under nitrogenatmosfære. Denne oppløsning avkjøles til -85°C, og 2,1 1 15% oppløsning av metoksydietylboran i tetrahydrofuran (2,1 mol, 1,0 ekvivalent basert på trinn E) tilsettes. Reaksjonen avkjøles til - 97°C i løpet av én time, og 144 g (3,78 mol) natriumborhydrid tilsettes i 20 til 50 g porsjoner i løpet av 1,5 timer. Reaksjonen holdes mellom - 93° og -97°C i 13 timer og står til oppvarmning til romtemperatur og står i 60 timer under The reaction solution obtained from step E is concentrated under vacuum to a volume of 5 to 8 1, then dissolved in 20 1 of tetrahydrofuran and 4 1 of methanol under a nitrogen atmosphere. This solution is cooled to -85°C, and 2.1 1 of a 15% solution of methoxydiethylborane in tetrahydrofuran (2.1 mol, 1.0 equivalent based on step E) is added. The reaction is cooled to -97°C over one hour and 144 g (3.78 moles) of sodium borohydride is added in 20 to 50 g portions over 1.5 hours. The reaction is kept between -93° and -97°C for 13 hours and is allowed to warm to room temperature and is left for 60 hours below

nitrogenatmosfære. nitrogen atmosphere.

Reaksjonen stanses ved tilsetning av 460 ml (7,9 mol) eddiksyre og konsentreres ved vakuumdestillasjon til en olje. Residuet oppløses med 8 1 metanol, konsentreres ved vakuumdestillasjon, oppløses påny med 8 1 metanol og konsentreres igjen ved vakuumdestillasjon til et volum på 6 1. Oppløsningen fortynnes med 8 1 tetrahydrofuran, 4 1 heksan og bringes til neste trinn. The reaction is stopped by the addition of 460 ml (7.9 mol) of acetic acid and concentrated by vacuum distillation to an oil. The residue is dissolved with 8 1 methanol, concentrated by vacuum distillation, dissolved again with 8 1 methanol and concentrated again by vacuum distillation to a volume of 6 1. The solution is diluted with 8 1 tetrahydrofuran, 4 1 hexane and brought to the next step.

Trinn G: Fremstilling av trans-( ± )- 5-( 4- fluorfenyl)-2- f1- metyletvl)- N. 4- difenyl- l- f 2 - ( tetrahydro-4- hvdroksv- 6- okso- 2H- pyran- 2- vl) etyl1-lH- pyrroi- 3- karboksamid. Step G: Preparation of trans-( ± )- 5-( 4- fluorophenyl)-2- f1- methylethyl)- N. 4- diphenyl- 1- f 2 - ( tetrahydro-4- hydroxy- 6- oxo- 2H- pyran-2-vl)ethyl1-1H-pyrroi-3-carboxamide.

Den rå reaksjonsblanding fra trinn F avkjøles til 8"C, 8,0 1 2,0 N vandig natriumhydroksyd tilsettes, og reaksjonen omrøres i 2 timer ved 15° til 18°C. Reaksjonen fortynnes med 12 1 vann, og det øvre lag fjernes. Det gjenværende vandige lag vaskes med 8 1 heksan, derefter tilsettes 8 1 etylacetat efterfulgt av 1 1 konsentrert vandig saltsyreoppløsning. Den velomrørte blanding står til separasjon, det nedre lag kas-seres, og det øvre lag vaskes fire ganger med hver 4 1 2 N vandig saltsyreoppløsning. The crude reaction mixture from step F is cooled to 8"C, 8.0 L of 2.0 N aqueous sodium hydroxide is added, and the reaction is stirred for 2 hours at 15° to 18°C. The reaction is diluted with 12 L of water, and the upper layer is removed The remaining aqueous layer is washed with 8 L of hexane, then 8 L of ethyl acetate is added, followed by 1 L of concentrated aqueous hydrochloric acid solution. The well-stirred mixture is allowed to separate, the lower layer is discarded, and the upper layer is washed four times with each 4 1 2 N aqueous hydrochloric acid solution.

Etylacetatlaget konsentreres til en skummende sirup ved vakuumdestillasjon, og residuet oppløses i 8 1 toluen. Toluenet konsentreres ved vakuumdestillasjon til et volum på 6 1 og står derefter ved romtemperatur i 16 timer. Den resulterende tykke oppslemning filtreres gjennom en Biichnertragt, vaskes med 1 1 kald toluen og 2 1 heksan og tørres i en vakuumovn i 24 timer ved romtemperatur for å oppnå 686 g 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. Filtratene vaskes med 2 N vandig saltsyreoppløsning og konsentreres i vakuum til et volum på 2 1 og står derefter ved romtemperatur i tre dager. Det resulterende faste stoff filtreres, vaskes og tørres som før, hvilket gir 157 g 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. HPLC av de faste stoffer viser 95% trans med 1,3% cis lakton for det første utbytte og 95% trans med 2,3% cis lakton for det annet utbytte. De to utbytter av fast stoff oppløses i 8 1 etylacetat ved oppvarmning til 50 til 60°C og filtreres derefter gjennom en Biichnertragt sammen med 8 1 heksan som er oppvarmet til 50"C. Oppløsningen står til avkjøling til romtemperatur i løpet av 16 timer, den resulterende oppsiemning filtreres gjennom en Biichnertragt, og faststoffet vaskes med 2 1 heksan. Det resulterende faststoff tørres i en vakuumovn i 24 timer ved romtemperatur, hvilket gir 720 g 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 med en 98%:0,9% trans:cis HPLC analyse. Det annet utbytte oppnådd ved konsentrasjon som før er ca. 100 g. The ethyl acetate layer is concentrated to a foaming syrup by vacuum distillation, and the residue is dissolved in 8 1 toluene. The toluene is concentrated by vacuum distillation to a volume of 6 1 and then left at room temperature for 16 hours. The resulting thick slurry is filtered through a Biichner funnel, washed with 1 L of cold toluene and 2 L of hexane and dried in a vacuum oven for 24 h at room temperature to obtain 686 g of trans-(±)-5-(4-fluorophenyl)-2- (1-Methylethyl)-N,4-diphenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide. The filtrates are washed with 2 N aqueous hydrochloric acid solution and concentrated in vacuo to a volume of 2 1 and then left at room temperature for three days. The resulting solid is filtered, washed and dried as before, yielding 157 g of trans-(±)-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[2-( tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide. HPLC of the solids shows 95% trans with 1.3% cis lactone for the first yield and 95% trans with 2.3% cis lactone for the second yield. The two yields of solid are dissolved in 8 L of ethyl acetate by heating to 50 to 60°C and then filtered through a Biichner funnel together with 8 L of hexane that has been heated to 50°C. The solution is allowed to cool to room temperature over 16 hours, the resulting slurry is filtered through a Biichner funnel, and the solid is washed with 2 L of hexane. The resulting solid is dried in a vacuum oven for 24 hours at room temperature, yielding 720 g of trans-(±)-5-(4-fluorophenyl)-2-( 1-methylethyl)-N,4-diphenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide with a 98%: 0.9% trans:cis HPLC analysis The second yield obtained at concentration as before is about 100 g.

FREMGANGSMÅTE B PROCEDURE B

Trinn A: Fremstilling av ( ± )- cis- 6-( 2- aminoetvl)- 2, 2-dimetyl- 1. 3- dioksan- 4- eddiksyre. Step A: Preparation of (±)-cis-6-(2-aminoethyl)-2,2-dimethyl-1.3-dioxane-4-acetic acid.

En oppløsning av 1,04 g (4,88 mmol) (±)-cis-6-(cyanometyl)-2,2-dimetyl-l,3-dioksan-4-eddiksyre i 100 ml metanol mettet med vannfri ammoniakk settes til en Parr-rysteflaske inneholdende 0,53 g vann-fuktet Raney-nikkel #30. Oppløsningen oppvarmes ved 45 °C og 50 psig hydrogentrykk i 17 timer. Suspensjonen avkjøles og filtreres gjennom filterhjelp for å fjerne Raney-nikkel, og bunnfallet vaskes med metanol. Filtratet konsentreres ved redusert trykk. Residuet oppløses i metanol mettet med vannfri ammoniakk, behandles med farvefjernende aktivt kull, filtreres gjennom filterhjelp og inndampes for å oppnå 0,56 g (±)-cis-6-(2-aminoetyl)-2,2-dimetyl-1,3-dioksan-4-eddiksyre, A solution of 1.04 g (4.88 mmol) (±)-cis-6-(cyanomethyl)-2,2-dimethyl-1,3-dioxane-4-acetic acid in 100 ml of methanol saturated with anhydrous ammonia is added to a Parr shaker bottle containing 0.53 g of water-moistened Raney nickel #30. The solution is heated at 45°C and 50 psig hydrogen pressure for 17 hours. The suspension is cooled and filtered through filter aid to remove Raney nickel, and the precipitate is washed with methanol. The filtrate is concentrated under reduced pressure. The residue is dissolved in methanol saturated with anhydrous ammonia, treated with decolorizing activated carbon, filtered through filter aid and evaporated to obtain 0.56 g of (±)-cis-6-(2-aminoethyl)-2,2-dimethyl-1,3 -dioxane-4-acetic acid,

smp. 165° med dekomponering ved 169°C. m.p. 165° with decomposition at 169°C.

Fourier Transformert Infrarød (FTIR) (KBr): 1201,1, 1399,2, 1561,2, 2924,4, 3569,9 cm"<1>. Fourier Transform Infrared (FTIR) (KBr): 1201.1, 1399.2, 1561.2, 2924.4, 3569.9 cm"<1>.

"^H-NMR (D20, 200 MHz) S 0,84 (m, 1H) , 0,96 (s, 3H) , 1,11 (s, 3H) , "^H-NMR (D 2 O, 200 MHz) S 0.84 (m, 1H) , 0.96 (s, 3H) , 1.11 (s, 3H) ,

1,2-1,5 (m, 3H), 1,84 (dd, 1H, J = 14,0 Hz, J =6,6 Hz), 1,99 (dd, 1.2-1.5 (m, 3H), 1.84 (dd, 1H, J = 14.0 Hz, J =6.6 Hz), 1.99 (dd,

1H, J = 14,0 Hz, J = 6,8 Hz), 2,68 (t, 2H, J 7,2 Hz) , 3,6-3 ,85 1H, J = 14.0 Hz, J = 6.8 Hz), 2.68 (t, 2H, J 7.2 Hz) , 3.6-3 .85

(m, 1H), 3,85-4,15 (m, 1H). (m, 1H), 3.85-4.15 (m, 1H).

13C-NMR (D20, 50 MHz) S 19,64, 29,32, 32,94, 35,86, 36,95, 13C-NMR (D20, 50 MHz) S 19.64, 29.32, 32.94, 35.86, 36.95,

44,73, 44.73,

68,16, 68,25, 100,18, 178,56. 68.16, 68.25, 100.18, 178.56.

Massespektrum (GC/MS), m/Z 202, 198, 173, 142, 138, 120, 97, 82, Mass spectrum (GC/MS), m/Z 202, 198, 173, 142, 138, 120, 97, 82,

59, 43. 59, 43.

Trinn B; Fremstilling av trans-( ±)- 5-( 4- fluorfenvl)- 2-( l-metvletyl)- N. 4- difenvl- 1- r2-( tetrahydro- 4- hvdroksv-6- okso- 2H- pyran- 2- yl) etyll- lH- pyrrol- 3- karboksamid. Step B; Preparation of trans-(±)-5-(4-fluorophenyl)-2-(1-methylethyl)-N.4-diphenyl-1- r2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2 -yl)ethyl-1H-pyrrole-3-carboxamide.

En oppløsning av 0,26 g (1,21 mmol) (±)-cis-6-(2-aminoetyl)2,2-dimetyl-l,3-dioksan-4-eddiksyre og 0,504 g (1,20 mmol) (±) -4-fluor-a-[2-metyl-l-oksopropyl]-'Y-okso-N,jS-difenylbenzenbutanamidblanding av [R-(R*,R*)], [R-(R*,S*)], [S-(R*,R*)] og [S-(R*,S*)]isomerer i 5 ml dimetylsulfoksyd oppvarmes ved 105°C i 15 timer. Oppløsningen avkjøles og helles i 100 ml dietyleter og 50 ml mettet ammoniumklorid i vann. Lagene separeres, og det organiske lag vaskes med vann (2 x 50 ml) og 5% natriumhydroksydoppløsning (2 x 100 ml til ekstraksjon av mellomproduktet fra ureagert diketon). Det vandige lag gjøres surt med fortynnet saltsyreoppløsning og ekstraheres med 30 ml etylacetat. En dråpe konsentrert saltsyre settes til etylacetatoppløsningen, og den står i 18 timer. Oppløsningen konsentreres i vakuum, og konsentratet oppløses påny i 30 ml etylacetat og behandles med én dråpe konsentrert saltsyre. Oppløsningen omrøres i to timer, konsentreres i vakuum og oppløses i 6 ml toluen. Trans-(±)-5-(4-fluorfenyl)-2-(1-metyletyl)-N,4-di fenyl-1-[2-(tetrahydro-4-hydroksy-6-okso-2H-pyran-2-yl)etyl]-lH-pyrrol-3-karboksamid utkrystalliserer og isoleres ved filtrering. En total på 0,16 g 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 isoleres i to utbytter. A solution of 0.26 g (1.21 mmol) of (±)-cis-6-(2-aminoethyl)2,2-dimethyl-1,3-dioxane-4-acetic acid and 0.504 g (1.20 mmol) (±)-4-fluoro-α-[2-methyl-1-oxopropyl]-'Y-oxo-N,jS-diphenylbenzenebutanamide mixture of [R-(R*,R*)], [R-(R*, S*)], [S-(R*,R*)] and [S-(R*,S*)] isomers in 5 ml of dimethylsulfoxide are heated at 105°C for 15 hours. The solution is cooled and poured into 100 ml of diethyl ether and 50 ml of saturated ammonium chloride in water. The layers are separated and the organic layer is washed with water (2 x 50 ml) and 5% sodium hydroxide solution (2 x 100 ml to extract the intermediate from unreacted diketone). The aqueous layer is acidified with dilute hydrochloric acid solution and extracted with 30 ml of ethyl acetate. A drop of concentrated hydrochloric acid is added to the ethyl acetate solution, and it stands for 18 hours. The solution is concentrated in vacuo, and the concentrate is redissolved in 30 ml of ethyl acetate and treated with one drop of concentrated hydrochloric acid. The solution is stirred for two hours, concentrated in vacuo and dissolved in 6 ml of toluene. Trans-(±)-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2 -yl)ethyl]-1H-pyrrole-3-carboxamide crystallizes out and is isolated by filtration. A total of 0.16 g of trans-(±)-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo -2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide is isolated in two yields.

FREMGANGSMÅTE C PROCEDURE C

Trinn A: Fremstilling av enten f±)- f2a, 4/ 3. 6/ 3)- eller (±) - Step A: Production of either f±)- f2a, 4/ 3. 6/ 3)- or (±) -

( 2a. 4a f 68 )- 2- fenvl- 6- f 2- propenyl)- 1. 3- dioksan- 4-acetonitril. ( 2a. 4a f 68 )- 2- phenyl- 6- f 2- propenyl)- 1. 3- dioxane- 4-acetonitrile.

Kaliumcyanid 1,3 g (20 mmol) settes til en oppløsning ved romtemperatur av (R*,R*)-a-2-propenyloksiranetanol, 2,56 g (20 mmol), i 25 ml 4:1 isopropanol:vann. Oppløsningen omrøres i 20 timer ved omgivelsestemperatur, konsentreres og lagdeles mellom etylacetat og saltvann. Det vandige lag ekstraheres 2x med etylacetat, og de forenede etylacetatekstrakter vaskes med saltvann og tørres (magnesiumsulfat). Det rå produkt oppløses i 20 ml benzaldehyddimetylacetal, kamfersulfonsyre tilsettes, og oppløsningen omrøres i 18 timer ved romtemperatur. Konsentrasjon og lynkromatografi efter konsentrasjon i vakuum gir 1,30 g av enten (±) - (2a,4/8, 6/3) - eller (±) -(2a,4a, 6/3) -2-fenyl-6-(2-propenyl)-l,3-dioksan-4-acetonitril. Potassium cyanide 1.3 g (20 mmol) is added to a solution at room temperature of (R*,R*)-α-2-propenyloxiranethanol, 2.56 g (20 mmol), in 25 ml of 4:1 isopropanol:water. The solution is stirred for 20 hours at ambient temperature, concentrated and layered between ethyl acetate and salt water. The aqueous layer is extracted twice with ethyl acetate, and the combined ethyl acetate extracts are washed with salt water and dried (magnesium sulfate). The crude product is dissolved in 20 ml of benzaldehyde dimethyl acetal, camphorsulfonic acid is added, and the solution is stirred for 18 hours at room temperature. Concentration and flash chromatography after concentration in vacuum gives 1.30 g of either (±)-(2a,4/8, 6/3) - or (±)-(2a,4a, 6/3)-2-phenyl-6 -(2-propenyl)-1,3-dioxane-4-acetonitrile.

200 MHZ NMR (CDCl3) S 1,48 (m, 1H), 1,71 (m, 1H), 2,41 (m, 2H), 2,58 200 MHZ NMR (CDCl 3 ) S 1.48 (m, 1H), 1.71 (m, 1H), 2.41 (m, 2H), 2.58

(m, 2H), 3,87 (m, 1H), 4,03 (m, 1H), 5,1 5,2 (m, 2H), 5,53 (s, 1H) , 5,87 (m, 1H) , 7,3 - 7,6 (m, 5H) (m, 2H), 3.87 (m, 1H), 4.03 (m, 1H), 5.1 5.2 (m, 2H), 5.53 (s, 1H) , 5.87 (m , 1H) , 7.3 - 7.6 (m, 5H)

13C-NMR (CDC13, 50 MHz) S 24,23, 35,07, 39,79, 71,57, 75,48, 100,44, 116,37, 117,53, 125,89, 127,91, 128,61, 133,05, 137,71. 13C-NMR (CDC13, 50 MHz) S 24.23, 35.07, 39.79, 71.57, 75.48, 100.44, 116.37, 117.53, 125.89, 127.91, 128.61, 133.05, 137.71.

GC/MS m/e 243 (M<+>), 242, 203, 202, 120, 107, 105, 79, 75, 41. GC/MS m/e 243 (M<+>), 242, 203, 202, 120, 107, 105, 79, 75, 41.

FTIR (rent) 699,6, 758,7, 920,8, 1028,8, 1051,9, 1121,4, 1345,2, 1383,7, 1401,7, 2253,1, 2916,6 cm"<1>. FTIR (pure) 699.6, 758.7, 920.8, 1028.8, 1051.9, 1121.4, 1345.2, 1383.7, 1401.7, 2253.1, 2916.6 cm"< 1>.

Trinn B: Fremstilling av enten ( ±)-( 2a. 4a. 6a)- eller (±) - Step B: Preparation of either ( ±)-( 2a. 4a. 6a)- or (±) -

( 2a . 4B . 6/ 3) - 6- ( 2- oksoetvl) - 2- fenvl- 1. 3- dioksan- 4-acetonitril. ( 2a . 4B . 6/ 3 ) - 6 - ( 2 - oxoethyl) - 2 - phenyl - 1. 3 - dioxane - 4 - acetonitrile.

En oppløsning av enten (±) - (2a, 4/3, 66) - eller ( + )-(2a,4a,6a)-2-fenyl-6-(2-propenyl)-1,3-dioksan-4-acetonitril, 4,11 g (16,89 mmol), i 100 ml diklormetan avkjøles til -78°C under nitrogen. Ozon (Welsbachgenerator, strømningshastighet 0,1, spenning = 90V) passeres derefter gjennom et frittet gassinngangsrør inn i oppløsningen, inntil den blå farve av ozon viser seg. Det slukkes for strømmen, og oksygen bobles igjennom, inntil den blå farve er fjernet. Trifenylfosfin, 4,87 g (18,58 mmol), tilsettes, og den farveløse oppløsning står til oppvarmning til romtemperatur. Lynkromatografi gir efter konsentrasjon i vakuum 3,75 g rent enten (±)-(2a,4a,6a)-eller (±) -(2a, 4)3,6/3) -6-(2-oksoetyl) -2-fenyl-l, 3-dioksan-4-acetonitril. A solution of either (±)-(2a,4/3,66)- or (+)-(2a,4a,6a)-2-phenyl-6-(2-propenyl)-1,3-dioxane-4 -acetonitrile, 4.11 g (16.89 mmol), in 100 ml of dichloromethane is cooled to -78°C under nitrogen. Ozone (Welsbach generator, flow rate 0.1, voltage = 90V) is then passed through a fritted gas inlet tube into the solution, until the blue color of ozone appears. The current is turned off, and oxygen is bubbled through until the blue color is removed. Triphenylphosphine, 4.87 g (18.58 mmol), is added and the colorless solution is allowed to warm to room temperature. Flash chromatography gives, after concentration in vacuum, 3.75 g of pure either (±)-(2a,4a,6a)-or (±)-(2a,4)3,6/3)-6-(2-oxoethyl)-2 -phenyl-1,3-dioxane-4-acetonitrile.

GC/MS m/e 245 (M<+>), 244, 123, 105, 95, 94, 77, 51, 41. GC/MS m/e 245 (M<+>), 244, 123, 105, 95, 94, 77, 51, 41.

Trinn C: Fremstilling av enten ( ±)-( 2a. 4a. 6a)- eller (±) - Step C: Preparation of either ( ±)-( 2a. 4a. 6a)- or (±) -

( 2a. 4/ 3. 6/ 3) - 6-( cyanometyl) - 2- fenvl- l. 3- dioksan- 4-eddiksyre. ( 2a. 4/ 3. 6/ 3) - 6-( cyanomethyl) - 2- phenyl- 1. 3- dioxane- 4-acetic acid.

Jones reagens (kromtrioksyd-svovelsyre-vann), 3,8 ml (97,6 mmol), settes dråpevis til en 0°C oppløsning av enten (±)-(2a,4a,6a)- eller (±) - (2a, 4/3, 6/3)-6-(2-oksoetyl)-2-fenyl-1,3-dioksan-4-acetonitril, 1,86 g (7,6 mmol), oppløst i 50 ml aceton, inntil den orange farve forblir. Efter omrøring i ytterligere 15 minutter helles blandingen i 3 00 ml dietyleter og vaskes med saltvann, inntil de vandige skylninger er farveløse. Dietyleterlaget tørres (magnesiumsulfat), filtreres og konsentreres for å oppnå 1,84 g av enten (±)-(2a,4a,6a)- eller (±)-(2a-(2a,4/3,6/3)-6-(cyanometyl)-2-fenyl-1,3-dioksan-4-eddiksyre som en gul gummi. Jones reagent (chromium trioxide-sulfuric acid-water), 3.8 ml (97.6 mmol), is added dropwise to a 0°C solution of either (±)-(2a,4a,6a)- or (±)-(2a , 4/3, 6/3)-6-(2-oxoethyl)-2-phenyl-1,3-dioxane-4-acetonitrile, 1.86 g (7.6 mmol), dissolved in 50 ml acetone, until the orange color remains. After stirring for a further 15 minutes, the mixture is poured into 300 ml of diethyl ether and washed with brine, until the aqueous rinses are colourless. The diethyl ether layer is dried (magnesium sulfate), filtered and concentrated to obtain 1.84 g of either (±)-(2a,4a,6a)- or (±)-(2a-(2a,4/3,6/3)- 6-(cyanomethyl)-2-phenyl-1,3-dioxane-4-acetic acid as a yellow gum.

200 MHZ NMR (CDC13) S 1,61 (m, 1H), 2,04 (m, 1H), 2,6 - 2,8 (m, 3H) 2,82 (dd, 1H, J = 15,9 Hz, J = 7,1 Hz), 4,20 (m, 1H), 4,40 (m, 1H), 5,60 (s, 1H), 7,2 - 7,5 (m, 5H). 200 MHZ NMR (CDCl 3 ) S 1.61 (m, 1H), 2.04 (m, 1H), 2.6 - 2.8 (m, 3H) 2.82 (dd, 1H, J = 15.9 Hz, J = 7.1 Hz), 4.20 (m, 1H), 4.40 (m, 1H), 5.60 (s, 1H), 7.2 - 7.5 (m, 5H).

Trinn D; Fremstilling av enten ( ±)- ( 2a. 4a. 6a)- eller ( ±)-( 2a , 4/ 8 . 66 ) - 6- ( 2- aminoetyl) - 2- f enyl- l. 3- dioksan- 4-eddiksvre. Step D; Preparation of either ( ±)- ( 2a. 4a. 6a)- or ( ±)-( 2a , 4/ 8 . 66 ) - 6-( 2- aminoethyl) - 2- phenyl- l. 3- dioxane- 4 - vinegar sour.

En oppløsning av 0,16 g (0,61 mmol) av enten (±)- A solution of 0.16 g (0.61 mmol) of either (±)-

(2a, 4a, 6a)- eller (±) - (2a, 40,60) -6-(cyanometyl) -2-fenyl-l, 3-dioksan-4-eddiksyre i 50 ml metanol mettet med vannfri ammoniakk settes til en Parr rystekolbe inneholdende 0,2 g vann-fuktet Raney-nikkel #30. Oppløsningen oppvarmes ved 40°C og 50 pund pr. kvadrattomme (psig) hydrogentrykk i 6 timer. Suspensjonen avkjøles og filtreres for å fjerne Raney-nikkel gjennom filterhjelp, og bunnfallet vaskes med metanol. Filtratet konsentreres ved redusert trykk. Residuet oppløses i metanol mettet med vannfri ammoniakk, behandles med farvefjernende aktivt kull, filtreres gjennom filterhjelp og inndampes for å oppnå 0,11 g av enten (±)-(2a,4a,6a) eller (±) - (2a, 4/0, 6/3) -6- (2-aminoetyl) -2-f enyl-l, 3-dioksan-4-eddiksyre, (2a, 4a, 6a)- or (±)-(2a, 40,60)-6-(cyanomethyl)-2-phenyl-1,3-dioxane-4-acetic acid in 50 ml of methanol saturated with anhydrous ammonia is added to a Parr shaking flask containing 0.2 g of water-moistened Raney nickel #30. The solution is heated at 40°C and 50 pounds per square inch (psig) of hydrogen pressure for 6 hours. The suspension is cooled and filtered to remove Raney nickel through filter aid, and the precipitate is washed with methanol. The filtrate is concentrated under reduced pressure. The residue is dissolved in methanol saturated with anhydrous ammonia, treated with decolorizing activated carbon, filtered through filter aid and evaporated to obtain 0.11 g of either (±)-(2a,4a,6a) or (±)-(2a, 4/ 0, 6/3) -6-(2-aminoethyl)-2-phenyl-1,3-dioxane-4-acetic acid,

smp. 215,9 -217,9"C med dekomponering. m.p. 215.9 -217.9"C with decomposition.

200 MHZ NMR (D20) S 1,4 - 1,9 (m, 4H), 2,39 (dd, 1H, J = 14,8 Hz, J = 6,7 Hz), 2,55 (dd, 1H, J = 14,8 Hz, J = 7,4 Hz), 2,73 (t, 2H, J = 7,2 Hz) 4,11 (m, 1H), 4,33 (m, 1H), 5,70 (s, 1H), 7,4 - 7,6 (m, 5H). 200 MHZ NMR (D2O) S 1.4 - 1.9 (m, 4H), 2.39 (dd, 1H, J = 14.8 Hz, J = 6.7 Hz), 2.55 (dd, 1H , J = 14.8 Hz, J = 7.4 Hz), 2.73 (t, 2H, J = 7.2 Hz) 4.11 (m, 1H), 4.33 (m, 1H), 5 .70 (s, 1H), 7.4 - 7.6 (m, 5H).

<13>C-NMR (D20, 50 MHz) S 39,20, 39,78, 40,83, 47,11, 78,34, 78,73, 104,06, 129,15, 131,56, 132,38, 140,51, 181,89. <13>C-NMR (D20, 50 MHz) S 39.20, 39.78, 40.83, 47.11, 78.34, 78.73, 104.06, 129.15, 131.56, 132 .38, 140.51, 181.89.

Trinn E: Fremstilling av trans-( ±)- 5-( 4- fluorfenyl)- 2-( 1-metvletyl)- N. 4- difenyl- l- f2-( tetrahydro- 4- hydroksy-6- okso- 2H- pvran- 2- yl) etyl "[- lH- pyrrol- 3- karboksamid. Step E: Preparation of trans-( ±)- 5-( 4- fluorophenyl)- 2-( 1-methylethyl)- N. 4- diphenyl- 1- f 2-( tetrahydro- 4- hydroxy-6- oxo- 2H- pvran-2-yl)ethyl "[-1H-pyrrol-3-carboxamide.

En oppløsning av 0,31 g (1,21 mmol) av enten (±)-(2a,4a,6a)- eller (±)-(2a,40,60)-6-(2-aminoetyl)-2-fenyl-l,3-dioksan-4-eddiksyre og 0,504 g (1,20 mmol) (±)-4-fluor-a-[2-metyl-l-oksopropyl ] -"Y-okso-N, Ø-dif enylbenzenbutanamidblanding av [R-(R*,R*)], [R-(R*,S*)], [S-(R*,R*)] og [S-(R<*>,S<*>)]-isomerer i 5 ml dimetylsulfoksyd oppvarmes ved 105°C i 15 timer. Oppløsningen avkjøles og helles i 100 ml dietyleter og 50 ml mettet ammoniumklorid i vann. Lagene separeres, og det organiske lag vaskes med vann (2 x 50 ml) og 5% natriumhydroksydoppløsning (2 x 100 ml for å ekstrahere mellomproduktet fra ureagert diketon). Det vandige lag gjøres surt med fortynnet saltsyre, omrøres i tre timer og ekstraheres med 30 ml etylacetat. En dråpe konsentrert saltsyre settes til etylacetatoppløsningen, oppløsningen omrøres og står i 18 timer. Oppløsningen konsentreres i vakuum, og konsentratet oppløses påny i 30 ml etylacetat og behandles med én dråpe konsentrert saltsyre. Oppløsningen omrøres i to timer, konsentreres i vakuum og oppløses i 6 ml toluen. 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 utkrystalliserer og isoleres ved filtrering. En total på 0,16 g 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 isoleres i to utbytter. A solution of 0.31 g (1.21 mmol) of either (±)-(2a,4a,6a)- or (±)-(2a,40,60)-6-(2-aminoethyl)-2- phenyl-1,3-dioxane-4-acetic acid and 0.504 g (1.20 mmol) (±)-4-fluoro-α-[2-methyl-1-oxopropyl ]-"Y-oxo-N, Δ-dif enylbenzenebutanamide mixture of [R-(R*,R*)], [R-(R*,S*)], [S-(R*,R*)] and [S-(R<*>,S<* >)] isomers in 5 ml of dimethylsulfoxide is heated at 105°C for 15 hours. The solution is cooled and poured into 100 ml of diethyl ether and 50 ml of saturated ammonium chloride in water. The layers are separated and the organic layer is washed with water (2 x 50 ml) and 5% sodium hydroxide solution (2 x 100 ml to extract the intermediate from unreacted diketone). The aqueous layer is acidified with dilute hydrochloric acid, stirred for three hours and extracted with 30 ml of ethyl acetate. A drop of concentrated hydrochloric acid is added to the ethyl acetate solution, the solution is stirred and allowed to stand for 18 hours. The solution is concentrated in vacuo, and the concentrate is redissolved in 30 ml of ethyl acetate and treated with one drop of concentrated hydrochloric acid. The solution is stirred for two hours , concentrated in vacuo and dissolved in 6 ml of toluene. Trans-(±)-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2- yl)ethyl]-1H-pyrrole-3-carboxamide crystallizes out and is isolated by filtration. A total of 0.16 g of trans-(±)-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo -2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide is isolated in two yields.

FREMGANGSMÅTE D PROCEDURE D

Trinn A: Fremstilling av ( ±)- cis- 9-( 2- propenyl)- 6. 10-dioksaspiro r 4. 5] dekan- 7- acetonitril. Step A: Preparation of (±)-cis-9-(2-propenyl)-6.10-dioxaspiro r4.5]decane-7-acetonitrile.

Kaliumcyanid, 1,3 g (20 mmol), settes til en oppløsning ved romtemperatur av (R*,R*)-a-2-propenyloksiranetanol, 2,56 g (20 mmol), i 25 ml 4:1 isopropanol:vann. Oppløsningen omrøres i 20 timer ved omgivelsestemperatur, konsentreres og lagdeles mellom etylacetat og saltvann. Det vandige lag ekstraheres 2x med etylacetat, og de samlede etylacetatekstrakter vaskes med saltvann og tørres (magnesiumsulfat). Det rå produkt oppløses i 20 ml 1,1-dimetoksycyklopentan, kamfersulfonsyre tilsettes, og oppløsningen omrøres i 18 timer ved romtemperatur. Konsentrasjon og lynkromatografi efter konsentrasjon i vakuum gir 1,40 g (±)-cis-9-(2-propenyl)-6,10-dioksaspiro[4.5]dekan-7-acetonitril. Potassium cyanide, 1.3 g (20 mmol), is added to a solution at room temperature of (R*,R*)-α-2-propenyloxiraneethanol, 2.56 g (20 mmol), in 25 ml of 4:1 isopropanol:water . The solution is stirred for 20 hours at ambient temperature, concentrated and layered between ethyl acetate and salt water. The aqueous layer is extracted twice with ethyl acetate, and the combined ethyl acetate extracts are washed with salt water and dried (magnesium sulfate). The crude product is dissolved in 20 ml of 1,1-dimethoxycyclopentane, camphorsulfonic acid is added, and the solution is stirred for 18 hours at room temperature. Concentration and flash chromatography after concentration in vacuum gives 1.40 g of (±)-cis-9-(2-propenyl)-6,10-dioxaspiro[4.5]decane-7-acetonitrile.

Trinn B: Fremstilling av ( ±)- cis- 9-( 2- oksoetyl)- 6. 10-dioksaspiro r 4. 5] dekan- 7- acetonitril. Step B: Preparation of (±)-cis-9-(2-oxoethyl)-6.10-dioxaspiro r4.5]decane-7-acetonitrile.

En oppløsning av (±)-cis-9-(2-propenyl)-6,10-dioksa-spiro[4.5]dekan-7-acetonitril, 3,4 g (15,36 mmol), i 100 ml diklormetan avkjøles til -78°C under nitrogen. Ozon A solution of (±)-cis-9-(2-propenyl)-6,10-dioxa-spiro[4.5]decane-7-acetonitrile, 3.4 g (15.36 mmol), in 100 ml of dichloromethane is cooled to -78°C under nitrogen. Ozone

(Welsbachgenerator, strømningshastighet 0,1, spenning = 90V) (Welsbach generator, flow rate 0.1, voltage = 90V)

passeres derefter gjennom et frittet gassinngangsrør inn i oppløsningen, inntil den blå farve av ozon viser seg. Strømmen slås fra, og oksygen bobles igjennom, inntil den blå farve er fjernet. Trifenylfosfin, 4,2 g (16 mmol), tilsettes, og den farveløse oppløsning står til oppvarmning til romtemperatur. Lynkromatografi gir efter konsentrasjon i vakuum 2,5 g rent (±)-cis-9-(2-oksoetyl)-6,10-dioksa-spiro[4.5]dekan-7-acetonitril. is then passed through a fritted gas inlet tube into the solution, until the blue color of ozone appears. The current is switched off, and oxygen is bubbled through until the blue color is removed. Triphenylphosphine, 4.2 g (16 mmol), is added and the colorless solution is allowed to warm to room temperature. Flash chromatography gives, after concentration in vacuum, 2.5 g of pure (±)-cis-9-(2-oxoethyl)-6,10-dioxa-spiro[4.5]decane-7-acetonitrile.

Trinn C: Fremstilling av f±)- cis- 9-( cyanometyl)- 6. 10-dioksaspiro f4. 51dekan- 7- eddiksyre. Step C: Preparation of f±)-cis-9-(cyanomethyl)-6.10-dioxaspiro f4. 51 decano- 7- acetic acid.

Jones reagens (kromtrioksyd-svovelsyre-vann), 3,8 ml (97,6 mmol), settes dråpevis til en 0°C oppløsning av (±)-cis-9-(2-oksoetyl)-6,10-dioksaspiro[4.5]dekan-2-acetonitril 1,70 g (7,6 mmol), oppløst i 50 ml aceton, inntil den orange farve ikke forsvinner. Efter omrøring i ytterligere 15 minutter helles blandingen i 300 ml dietyleter og vaskes med saltvann, inntil de vandige skylninger er farveløse. Dietyleterlaget tørres (magnesiumsulfat), filtreres og konsentreres for å oppnå 1,20 g (±)-cis-9-(cyanometyl)-6,10- Jones reagent (chromium trioxide-sulfuric acid-water), 3.8 ml (97.6 mmol), is added dropwise to a 0°C solution of (±)-cis-9-(2-oxoethyl)-6,10-dioxaspiro[ 4.5]decane-2-acetonitrile 1.70 g (7.6 mmol), dissolved in 50 ml of acetone, until the orange color does not disappear. After stirring for a further 15 minutes, the mixture is poured into 300 ml of diethyl ether and washed with salt water, until the aqueous rinses are colourless. The diethyl ether layer is dried (magnesium sulfate), filtered and concentrated to obtain 1.20 g of (±)-cis-9-(cyanomethyl)-6,10-

dioksaspiro[4.5]dekan-7-eddiksyre som et farveløst faststoff. dioxaspiro[4.5]decane-7-acetic acid as a colorless solid.

Trinn D: Fremstilling av ( ±)- cis- 9-( 2- aminoetyl)-6. 10- dioksaspiro r 4. 5] dekan- 7- eddiksvre. Step D: Preparation of (±)-cis-9-(2-aminoethyl)-6. 10- dioxaspiro r 4. 5] decan- 7- acetic acid.

En oppløsning av 1,17 g (4,88 mmol) (±)-cis-9-(cyanometyl)-6,10-dioksaspiro[4.5]dekan-7-eddiksyre i 100 ml metanol mettet med vannfri ammoniakk settes til en Parr rystekolbe inneholdende 0,53 g vann-fuktet Raney-nikkel #30. Oppløsningen oppvarmes ved 45°C og 50 pund pr. kvadrattomme (psig) hydrogentrykk i 17 timer. Suspensjonen avkjøles og filtreres for å fjerne Raneynikkel gjennom filterhjelp, og bunnfallet vaskes med metanol. Filtratet konsentreres ved redusert trykk. Residuet oppløses i metanol mettet med vannfri ammoniakk, behandles med farvefjernende aktivt kull, filtreres gjennom filterhjelp og inndampes for å oppnå 0,56 g (±)-cis-9-(2-aminoetyl)-6,10-dioksaspiro-[4.5]dekan-7-eddiksyre . A solution of 1.17 g (4.88 mmol) (±)-cis-9-(cyanomethyl)-6,10-dioxaspiro[4.5]decane-7-acetic acid in 100 ml of methanol saturated with anhydrous ammonia is added to a Parr shake flask containing 0.53 g of water-moistened Raney nickel #30. The solution is heated at 45°C and 50 pounds per square inch (psig) of hydrogen pressure for 17 hours. The suspension is cooled and filtered to remove Raney nickel through filter aid, and the precipitate is washed with methanol. The filtrate is concentrated under reduced pressure. The residue is dissolved in methanol saturated with anhydrous ammonia, treated with decolorizing activated carbon, filtered through filter aid and evaporated to obtain 0.56 g of (±)-cis-9-(2-aminoethyl)-6,10-dioxaspiro-[4.5] decane-7-acetic acid.

Trinn E: Fremstillin<g> av trans-( ±)- 5-( 4- fluorfenyl)-2 - ( 1- metvletvl)- N. 4- difenvl- 1- r2-( tetra-hvdro- 4- hydroksy- 6- okso- 2H- pvran- 2- vl) etyl] - lH- pyrrol- 3- karboksamid. Step E: Preparation of trans-(±)-5-(4-fluorophenyl)-2-(1-methylethyl)-N.4-diphenyl-1- r2-(tetra-hydro-4-hydroxy-6 - oxo-2H-pyrrole-2-vl)ethyl] -1H-pyrrole-3-carboxamide.

En oppløsning av 0,295 g (1,21 mmol) (±) -cis-9-(2-aminoetyl) -6,10-dioksaspiro[4.5]dekan-7-eddiksyre og 0,504 g (1,20 mmol) (±) -4-fluor-a-[2-metyl-l-oksopropyl]-'Y-okso-N,/3-difenyl-benzenbutanamidblanding av [R-(R*,R*)], [R-(R*,S*)], [S-(R<*>,R*)] og [S-(R*,S*)]-isomerer i 5 ml dimetylsulfoksyd oppvarmes ved 105°C i 15 timer. Oppløsningen avkjøles og helles i 100 ml dietyleter og 50 ml mettet ammoniumklorid i vann. Lagene separeres, og det organiske lag vaskes med vann (2 x 50 ml) og 5% natriumhydroksydoppløsning (2 x 100 ml - for å ekstrahere den mellomliggende beskyttede syre fra ureagert diketon). Det vandige lag gjøres surt med fortynnet saltsyre-oppløsning, omrøres i tre timer og ekstraheres med 30 ml etylacetat. En dråpe konsentrert saltsyre tilsettes til etyl-acetatoppløsningen som står i 18 timer. Oppløsningen konsentreres i vakuum, og konsentratet oppløses påny i 30 ml etylacetat og behandles med én dråpe konsentrert saltsyre. Oppløsningen omrøres i to timer, konsentreres i vakuum og oppløses i 6 ml toluen. Trans-(±)-5-(4-fluorfenyl)-2-(1-metyletyl) -N, 4-dif enyl-l-[2-(tetrahydro-4-hydroksy-6-okso-2H-pyran-2-yl) etyl]-lH-pyrrol-3-karboksamid utkrystalliserer og isoleres ved filtrering. En total på 0,16 g trans-(±)-5-(4-f luorf enyl) -2 - (1-metyletyl) -N, 4 -di f enyl -1- [ 2 - (tetrahydro-4 - hydroksy-6-okso-2H-pyran-2-yl) etyl] -lH-pyrrol-3-karboksamid isoleres i to utbytter. A solution of 0.295 g (1.21 mmol) (±)-cis-9-(2-aminoethyl)-6,10-dioxaspiro[4.5]decane-7-acetic acid and 0.504 g (1.20 mmol) (±) -4-fluoro-α-[2-methyl-1-oxopropyl]-'Y-oxo-N,/3-diphenyl-benzenebutanamide mixture of [R-(R*,R*)], [R-(R*, S*)], [S-(R<*>,R*)] and [S-(R*,S*)] isomers in 5 ml of dimethylsulfoxide are heated at 105°C for 15 hours. The solution is cooled and poured into 100 ml of diethyl ether and 50 ml of saturated ammonium chloride in water. The layers are separated and the organic layer is washed with water (2 x 50 ml) and 5% sodium hydroxide solution (2 x 100 ml - to extract the intermediate protected acid from unreacted diketone). The aqueous layer is acidified with dilute hydrochloric acid solution, stirred for three hours and extracted with 30 ml of ethyl acetate. A drop of concentrated hydrochloric acid is added to the ethyl acetate solution which stands for 18 hours. The solution is concentrated in vacuo, and the concentrate is redissolved in 30 ml of ethyl acetate and treated with one drop of concentrated hydrochloric acid. The solution is stirred for two hours, concentrated in vacuo and dissolved in 6 ml of toluene. Trans-(±)-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2 -yl)ethyl]-1H-pyrrole-3-carboxamide crystallizes out and is isolated by filtration. A total of 0.16 g of trans-(±)-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[2-(tetrahydro-4-hydroxy -6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide is isolated in two yields.

FREMGANGSMÅTE E PROCEDURE E

Trinn A: Fremstilling av ( ±)- cis- 4-( 2- propenyl)- 1, 5-dioksaspiro r 5. 5 ] undekan- 2- acetonitril. Step A: Preparation of (±)-cis-4-(2-propenyl)-1,5-dioxaspiro r5.5]undecane-2-acetonitrile.

Kaliumcyanid, 1,3 g (20 mmol) settes til en oppløsning ved romtemperatur av (R*,R*)-a-2-propenyloksiranetanol, 2,56 g (20 mmol), i 25 ml 4:1 isopropanol:vann. Oppløsningen omrøres i 2 0 timer ved omgivelsestemperatur, konsentreres og lagdeles mellom etylacetat og saltvann. Det vandige lag ekstraheres 2x med etylacetat og de forenede etylacetatekstrakter vaskes med saltvann og tørres (magnesiumsulfat). Det rå produkt oppløses i 20 ml 2,2-dimetoksycykloheksan, kamfersulfonsyre tilsettes, og oppløsningen omrøres i 18 timer ved romtemperatur. Konsentrasjon og lynkromatografi efter konsentrasjon i vakuum gir 1,50 g (±)-cis-4-(2-propenyl)-l,5-dioksaspiro[5.5]undekan-2-acetonitril. Potassium cyanide, 1.3 g (20 mmol) is added to a solution at room temperature of (R*,R*)-α-2-propenyloxiranethanol, 2.56 g (20 mmol), in 25 ml of 4:1 isopropanol:water. The solution is stirred for 20 hours at ambient temperature, concentrated and partitioned between ethyl acetate and brine. The aqueous layer is extracted twice with ethyl acetate and the combined ethyl acetate extracts are washed with salt water and dried (magnesium sulfate). The crude product is dissolved in 20 ml of 2,2-dimethoxycyclohexane, camphorsulfonic acid is added, and the solution is stirred for 18 hours at room temperature. Concentration and flash chromatography after concentration in vacuum gives 1.50 g of (±)-cis-4-(2-propenyl)-1,5-dioxaspiro[5.5]undecane-2-acetonitrile.

200 MHz NMR (CDC13) S 1,26 (m, 1H), 1,4 - 1,7 (m, 8H), 1,87 (m, 2H), 200 MHz NMR (CDCl 3 ) S 1.26 (m, 1H), 1.4 - 1.7 (m, 8H), 1.87 (m, 2H),

2,1 - 2,3 (m, 2H), 2,51 (d, 2H, J = 6,05 Hz), 3,95 (m, 1H), 4,15 (m, 1H), 5,0 - 5,2 (m, 2H), 5,83 (m, 1H). 2.1 - 2.3 (m, 2H), 2.51 (d, 2H, J = 6.05 Hz), 3.95 (m, 1H), 4.15 (m, 1H), 5.0 - 5.2 (m, 2H), 5.83 (m, 1H).

<13>C-NMR (CDC13, 50 MHz) S 22,16, 24,71, 25,42, 28,20, 35,47, 38,33, 40,30, 64,08, 66,87, 98,84, 116,53, 116,83, 113,46. <13>C-NMR (CDC13, 50 MHz) S 22.16, 24.71, 25.42, 28.20, 35.47, 38.33, 40.30, 64.08, 66.87, 98 .84, 116.53, 116.83, 113.46.

GC/MS m/e 235 (m<+>), 206, 192, 120, 99, 93, 79, 69, 55, 41. GC/MS m/e 235 (m<+>), 206, 192, 120, 99, 93, 79, 69, 55, 41.

FTIR (film) 964,5, 1121,4, 1160,0, 2253,1, 2937,2 cm"<1>. FTIR (film) 964.5, 1121.4, 1160.0, 2253.1, 2937.2 cm"<1>.

Trinn B: Fremstilling av ( ±)- cis- 4-( 2- oksoetyl)- 1. 5-dioksaspiro r 5. 51undekan- 2- acetonitril. Step B: Preparation of (±)-cis-4-(2-oxoethyl)-1.5-dioxaspiro r5.51undecane-2-acetonitrile.

En oppløsning av (±)-cis-4-(2-propenyl)-1,5-dioksaspiro-[5.5]undekan-2-acetonitril 4,26 g (19,42 mmol), i 100 ml diklormetan avkjøles til -78°C under nitrogen. Ozon A solution of (±)-cis-4-(2-propenyl)-1,5-dioxaspiro-[5.5]undecane-2-acetonitrile 4.26 g (19.42 mmol), in 100 ml of dichloromethane is cooled to -78 °C under nitrogen. Ozone

(Welsbachgenerator, strømningshastighet 0,1, spenning = 90V) (Welsbach generator, flow rate 0.1, voltage = 90V)

passeres derefter gjennom et frittet gassinngangsrør inn i oppløsningen, inntil den blå farve av ozon viser seg. Strømmen slukkes, og oksygen bobles igjennom, inntil den blå farve er forsvunnet. Trifenylfosfin, 5,6 g (21,36 mmol) tilsettes og den farveløse oppløsning står til oppvarmning til romtemperatur. Lynkromatografi gir efter konsentrasjon i vakuum 4,04 g rent (±)-cis-4-(2-oksoetyl)-1,5-dioksa-spiro[5.5]undekan-2-acetonitril. is then passed through a fritted gas inlet tube into the solution, until the blue color of ozone appears. The current is turned off, and oxygen is bubbled through until the blue color has disappeared. Triphenylphosphine, 5.6 g (21.36 mmol) is added and the colorless solution is allowed to warm to room temperature. Flash chromatography gives, after concentration in vacuum, 4.04 g of pure (±)-cis-4-(2-oxoethyl)-1,5-dioxa-spiro[5.5]undecane-2-acetonitrile.

200 MHz NMR (CDC13) S 1,3 - 2,0 (m, 12H), 2,5 - 2,7 (m, 4H), 200 MHz NMR (CDCl 3 ) S 1.3 - 2.0 (m, 12H), 2.5 - 2.7 (m, 4H),

4,20 (m, 1H), 4,36 (m, 1H), 9,81 (t, 1H, J = 1,74 Hz). 4.20 (m, 1H), 4.36 (m, 1H), 9.81 (t, 1H, J = 1.74 Hz).

<13>C-NMR (CDC13, 50 MHz) S 22,39, 22,44, 24,97, 25,59, 28,44, 35,82, 38,48, 49,54, 63,25, 64,17, 99,66, 116,57, 199,82. <13>C-NMR (CDC13, 50 MHz) S 22.39, 22.44, 24.97, 25.59, 28.44, 35.82, 38.48, 49.54, 63.25, 64 .17, 99.66, 116.57, 199.82.

GC/MS m/e 237 (m<+>), 208, 194, 122, 94, 81, 55, 42, 41. GC/MS m/e 237 (m<+>), 208, 194, 122, 94, 81, 55, 42, 41.

FTIR (film) 969,6, 1069,9, 1126,5, 1160,0, 1368,3, 1386,3, 1728,4, 2934,6 cm"<1>. FTIR (film) 969.6, 1069.9, 1126.5, 1160.0, 1368.3, 1386.3, 1728.4, 2934.6 cm"<1>.

Trinn C: Fremstilling av ( ±)- cis- 4-( cvanometyl)- 1. 5-dioksaspiro r 5. 51undekan- 2- eddiksyre. Step C: Preparation of (±)-cis-4-(cvanomethyl)-1.5-dioxaspiro r5.51undecane-2-acetic acid.

Jones reagens (kromtrioksyd-svovelsyre-vann), 4,4 ml (8,85 mmol), settes dråpevis til en 0°C oppløsning av (±)-cis-4-(2-oksoetyl)-l,5-dioksaspiro[5.5]undekan-2-acetonitril, 3,62 g (12,6 mmol) oppløst i 30 ml aceton, inntil den orange farve ikke forsvinner. Efter omrøring i ytterligere 15 minutter helles blandingen i 300 ml dietyleter og vaskes med saltvann, inntil de vandige skylninger er farveløse. Dietyleterlaget tørres (magnesiumsulfat), filtreres og konsentreres for å oppnå 3,65 g (±)-cis-4-(cyanometyl)-1,5-dioksaspiro[5.5]undekan-2-eddiksyre som et gult faststoff. Jones reagent (chromium trioxide-sulfuric acid-water), 4.4 ml (8.85 mmol), is added dropwise to a 0°C solution of (±)-cis-4-(2-oxoethyl)-1,5-dioxaspiro[ 5.5]undecane-2-acetonitrile, 3.62 g (12.6 mmol) dissolved in 30 ml of acetone, until the orange color does not disappear. After stirring for a further 15 minutes, the mixture is poured into 300 ml of diethyl ether and washed with salt water, until the aqueous rinses are colourless. The diethyl ether layer is dried (magnesium sulfate), filtered and concentrated to obtain 3.65 g of (±)-cis-4-(cyanomethyl)-1,5-dioxaspiro[5.5]undecane-2-acetic acid as a yellow solid.

200 MHz NMR (Pyridin) S 1,2 - 2,0 (m, 12H), 2,5 - 2,9 (m, 4H), 4,19 (m, 1H) , 4,50 (m, 1H) . 200 MHz NMR (Pyridine) S 1.2 - 2.0 (m, 12H), 2.5 - 2.9 (m, 4H), 4.19 (m, 1H), 4.50 (m, 1H) .

Trinn D: Fremstilling av ( ±)- cis- 4-( 2- aminoetvl)- 1. 5-dioksaspiro\ 5. 5] undekan- 2- eddiksyre. Step D: Preparation of (±)-cis-4-(2-aminoethyl)-1.5-dioxaspiro\5.5]undecane-2-acetic acid.

En oppløsning av 0,13 g (±)-cis-4-(cyanometyl)-1,5-dioksaspiro[5.5]undekan-2-eddiksyre i 20 ml metanol mettet med vannfri ammoniakk settes til en Parr rystekolbe inneholdende 0,2 g vann-fuktet Raney-nikkel #30. Oppløsningen oppvarmes ved 40"C og 50 pund pr. kvadrattomme (psig) hydrogentrykk i 17 timer. Suspensjonen avkjøles og filtreres for å fjerne Raney-nikkel gjennom filterhjelp, og bunnfallet vaskes med metanol. Filtratet konsentreres ved redusert trykk. Residuet oppløses i metanol mettet med vannfri ammoniakk, behandles med farvefjernende aktivt kull, filtreres gjennom filterhjelp og inndampes for å oppnå 0,13 g (±)-cis-4-(2-aminoetyl)-1,5-dioksaspiro-[5.5]undekan-2-eddiksyre. A solution of 0.13 g of (±)-cis-4-(cyanomethyl)-1,5-dioxaspiro[5.5]undecane-2-acetic acid in 20 ml of methanol saturated with anhydrous ammonia is added to a Parr shaking flask containing 0.2 g water-wet Raney nickel #30. The solution is heated at 40°C and 50 pounds per square inch (psig) hydrogen pressure for 17 hours. The suspension is cooled and filtered to remove Raney nickel through filter aid, and the precipitate is washed with methanol. The filtrate is concentrated under reduced pressure. The residue is dissolved in methanol sat. with anhydrous ammonia, treated with decolorizing activated carbon, filtered through filter aid and evaporated to obtain 0.13 g of (±)-cis-4-(2-aminoethyl)-1,5-dioxaspiro-[5.5]undecane-2-acetic acid .

200 MHZ NMR (D20) S 1,1 - 1,7 (m, 10H), 1,75 - 2,1 (m, 4H), 2,19 (dd, 1H, J = 14,6 Hz, J = 6,7 Hz), 2,31 (dd, 1H, J = 14,6 HZ, J = 7,3 Hz), 2,69 (t, 2H, J = 7,1 Hz), 4,09 (m, 1H), 4,34 (m, 1H). 200 MHZ NMR (D2O) S 1.1 - 1.7 (m, 10H), 1.75 - 2.1 (m, 4H), 2.19 (dd, 1H, J = 14.6 Hz, J = 6.7 Hz), 2.31 (dd, 1H, J = 14.6 HZ, J = 7.3 Hz), 2.69 (t, 2H, J = 7.1 Hz), 4.09 (m , 1H), 4.34 (m, 1H).

<13>C-NMR (D20, 50 MHZ) 6 24,50, 24,73, 27,55, 30,80, 38,91, 39,39, 39,63, 40,48, 47,03, 69,37, 69,54, 102,74, 181,33. <13>C-NMR (D20, 50 MHZ) 6 24.50, 24.73, 27.55, 30.80, 38.91, 39.39, 39.63, 40.48, 47.03, 69 .37, 69.54, 102.74, 181.33.

Trinn E: Fremstilling av trans-( ±)- 5-( 4- fluorfenvl)-2- ( 1- metyletyl)- N. 4- difenyl- l- f2-( tetrahydro-4- hydroksy- 6- okso- 2H- pyran- 2- yl) etyl]- lH- pvrrol-3- karboksamid. Step E: Preparation of trans-(±)-5-(4-fluorophenyl)-2-(1-methylethyl)-N.4-diphenyl-1-f2-(tetrahydro-4-hydroxy-6-oxo-2H- pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide.

En oppløsning av 0,31 g (1,21 mmol) (±)-cis-4-(2-aminoetyl)-1,5-dioksaspiro[5.5]undekan-2-eddiksyre og 0,504 g (1,20 mmol) (±)-4-fluor-a-[2-metyl-l-oksopropyl]-'Y-okso-N,)S-difenylbenzenbutanamidblanding av [R-(R<*>,R*)], [R-(R*,S*)], [S-(R*,R*)] og [S-(R*,S*)] isomerer i 5 ml dimetylsulfoksyd oppvarmes ved 105"C i 15 timer. Oppløsningen avkjøles og helles i 100 ml dietyleter og 50 ml mettet ammoniumklorid i vann. Lagene separeres, og det organiske lag vaskes med vann (2 x 50 ml) og 5% natriumhydroksydoppløsning (2 x 100 ml - for å ekstrahere mellomproduktsyren fra ureagert diketon). Det vandige lag gjøres surt med fortynnet saltsyreoppløsning, omrøres i tre timer og ekstraheres med 30 ml etylacetat for å fjerne den beskyttende gruppe før laktonisering. Ekstrakten konsentreres og oppløses i 30 ml etylacetat. En dråpe konsentrert saltsyre settes til etylacetatoppløsningen, og den står i 18 timer. Oppløsningen konsentreres i vakuum, og konsentratet oppløses påny i 30 ml etylacetat og behandles med én dråpe konsentrert saltsyre. Oppløsningen omrøres i to timer, konsentreres i vakuum og oppløses i 6 ml toluen. Trans-(±)-5-(4-fluor-fenyl)-2-(1-metyletyl)-N,4-difenyl-l-[2-(tetrahydro-4-hydroksy-6-okso-2H-pyran-2-yl)etyl]-lH-pyrrol-3-karboks amid utkrystalliserer og isoleres ved filtrering. En total på 0,155 g 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 isoleres i to utbytter. A solution of 0.31 g (1.21 mmol) (±)-cis-4-(2-aminoethyl)-1,5-dioxaspiro[5.5]undecane-2-acetic acid and 0.504 g (1.20 mmol) ( ±)-4-fluoro-α-[2-methyl-1-oxopropyl]-'Y-oxo-N,)S-diphenylbenzenebutanamide mixture of [R-(R<*>,R*)], [R-(R *,S*)], [S-(R*,R*)] and [S-(R*,S*)] isomers in 5 ml of dimethyl sulfoxide are heated at 105"C for 15 hours. The solution is cooled and poured into 100 ml of diethyl ether and 50 ml of saturated ammonium chloride in water. The layers are separated and the organic layer is washed with water (2 x 50 ml) and 5% sodium hydroxide solution (2 x 100 ml - to extract the intermediate acid from unreacted diketone). The aqueous layer is acidified with dilute hydrochloric acid solution, stirred for three hours and extracted with 30 ml of ethyl acetate to remove the protecting group before lactonization. The extract is concentrated and dissolved in 30 ml of ethyl acetate. A drop of concentrated hydrochloric acid is added to the ethyl acetate solution and it stands for 18 hours. The solution is concentrated in vacuum, and the concentrate is dissolved again in 30 ml of ethyl acetate and beh and with one drop of concentrated hydrochloric acid. The solution is stirred for two hours, concentrated in vacuo and dissolved in 6 ml of toluene. Trans-(±)-5-(4-fluoro-phenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran- 2-yl)ethyl]-1H-pyrrole-3-carboxamide crystallizes out and is isolated by filtration. A total of 0.155 g of trans-(±)-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo-2H -pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide is isolated in two yields.

FREMGANGSMÅTE F PROCEDURE F

Trinn A: Fremstillin<g> av ( ±)- cis- 6-( 2- propenyl)- 1. 3-dioksan- 4- acetonitril Step A: Preparation<g> of (±)- cis- 6-( 2- propenyl)- 1. 3-dioxane- 4- acetonitrile

Kaliumcyanid, 1,3 g (20 mmol), settes til en oppløsning ved romtemperatur av (R*,R*)-a-2-propenyloksiranetanol, 2,56 g (20 mmol), i 25 ml 4:1 isopropanol:vann. Oppløsningen omrøres i 20 timer ved omgivelsestemperatur, konsentreres og lagdeles mellom etylacetat og saltvann. Det vandige lag ekstraheres 2x med etylacetat, og de samlede etylacetatekstrakter vaskes med saltvann og tørres (magnesiumsulfat). Det rå produkt oppløses i 20 ml dimetoksymetan, kamfersulfonsyre tilsettes, og opp-løsningen omrøres i 18 timer ved romtemperatur. Konsentrasjon og lynkromatografi efter konsentrasjon i vakuum gir 1,20 g (±)-cis-6-(2-propenyl)-1,3-dioksan-4-acetonitril. Potassium cyanide, 1.3 g (20 mmol), is added to a solution at room temperature of (R*,R*)-α-2-propenyloxiraneethanol, 2.56 g (20 mmol), in 25 ml of 4:1 isopropanol:water . The solution is stirred for 20 hours at ambient temperature, concentrated and layered between ethyl acetate and salt water. The aqueous layer is extracted twice with ethyl acetate, and the combined ethyl acetate extracts are washed with salt water and dried (magnesium sulfate). The crude product is dissolved in 20 ml of dimethoxymethane, camphorsulfonic acid is added, and the solution is stirred for 18 hours at room temperature. Concentration and flash chromatography after concentration in vacuum gives 1.20 g of (±)-cis-6-(2-propenyl)-1,3-dioxane-4-acetonitrile.

Trinn B: Fremstilling av ( ±)- cis- 6-( 2- oksoetyl)- 1. 3-dioksan- 4- acetonitril. Step B: Preparation of (±)-cis-6-(2-oxoethyl)-1.3-dioxane-4-acetonitrile.

En oppløsning av (±)-cis-6-(2-propenyl)-1,3-dioksan-4-acetonitril, 2,57 g (15,36 mmol), i 100 ml diklormetan avkjøles til -78°C under nitrogen. Ozon (Welsbachgenerator, strømningshastighet 0,1, spenning = 90V) passeres derefter gjennom et frittet gassinngangsrør inn i oppløsningen, inntil den blå farve av ozon viser seg. Strømmen slukkes, og oksygen bobles igjennom, inntil den blå farve er forsvunnet. Trifenylfosfin, 4,87 g (28,58 mmol), tilsettes, og den farveløse oppløsning står til oppvarmning til romtemperatur. Lynkromatografi gir efter konsentrasjon i vakuum 2,3 g rent (±)-cis-6-(2-oksoetyl)-1,3-dioksan-4-acetonitril. A solution of (±)-cis-6-(2-propenyl)-1,3-dioxane-4-acetonitrile, 2.57 g (15.36 mmol), in 100 ml of dichloromethane is cooled to -78°C under nitrogen . Ozone (Welsbach generator, flow rate 0.1, voltage = 90V) is then passed through a fritted gas inlet tube into the solution, until the blue color of ozone appears. The current is turned off, and oxygen is bubbled through until the blue color has disappeared. Triphenylphosphine, 4.87 g (28.58 mmol), is added and the colorless solution is allowed to warm to room temperature. Flash chromatography gives, after concentration in vacuum, 2.3 g of pure (±)-cis-6-(2-oxoethyl)-1,3-dioxane-4-acetonitrile.

Trinn C: Fremstilling av ( ± )- cis- 6-( cyanometyl)- 1. 3-dioksan- 4- eddiksyre. Step C: Preparation of (±)-cis-6-(cyanomethyl)-1.3-dioxane-4-acetic acid.

Jones reagens (kromtrioksyd-svovelsyre-vann), 3,8 ml (97,6 mmol), settes dråpevis til en 0°C oppløsning av (±)-cis-6-(2-oksoetyl)-1,3-dioksan-4-acetonitril, 1,29 g (7,6 mmol) oppløst i 50 ml aceton, inntil den orange farve ikke forsvinner. Efter omrøring i ytterligere 15 minutter helles blandingen i 300 ml dietyleter og vaskes med saltvann, inntil de vandige skylninger er farveløse. Dietyleterlaget tørres (magnesiumsulfat), filtreres og konsentreres for å oppnå 1,2 g (±)-cis-6-(cyanometyl)-1,3-dioksan-4-eddiksyre som et farvløst faststoff. Jones reagent (chromium trioxide-sulfuric acid-water), 3.8 ml (97.6 mmol), is added dropwise to a 0°C solution of (±)-cis-6-(2-oxoethyl)-1,3-dioxane- 4-acetonitrile, 1.29 g (7.6 mmol) dissolved in 50 ml of acetone, until the orange color does not disappear. After stirring for a further 15 minutes, the mixture is poured into 300 ml of diethyl ether and washed with salt water, until the aqueous rinses are colourless. The diethyl ether layer is dried (magnesium sulfate), filtered and concentrated to obtain 1.2 g of (±)-cis-6-(cyanomethyl)-1,3-dioxane-4-acetic acid as a colorless solid.

Trinn D: Fremstillin<g> av ( ±)- cis- 6-( 2- aminoetyl)- 1. 3-dioksan- 4- eddiksyre. Step D: Preparation of (±)-cis-6-(2-aminoethyl)-1.3-dioxane-4-acetic acid.

En oppløsning av 1,04 g (4,88 mmol) (±)-cis-6-(cyanometyl)-1,3-dioksan-4-eddiksyre i 100 ml metanol mettet med vannfri ammoniakk settes til en Parr rystekolbe inneholdende 0,53 g vann-fuktet Raney-nikkel #30. Oppløsningen oppvarmes ved 45°C og 50 pund pr. kvadrattomme (psig) hydrogentrykk i 17 timer. Suspensjonen avkjøles og filtreres for å fjerne Raney-nikkel gjennom filterhjelp, og bunnfallet vaskes med metanol. Filtratet konsentreres ved redusert trykk. Residuet oppløses i metanol mettet med vannfri ammoniakk, behandles med farvefjernende aktivt kull, filtreres gjennom filterhjelp og avdampes for å oppnå av 0,56 g (±)-cis-6-(2-aminoetyl)-1,3-dioksan-4-eddiksyre. A solution of 1.04 g (4.88 mmol) (±)-cis-6-(cyanomethyl)-1,3-dioxane-4-acetic acid in 100 ml of methanol saturated with anhydrous ammonia is added to a Parr shaking flask containing 0, 53 g of water-wetted Raney nickel #30. The solution is heated at 45°C and 50 pounds per square inch (psig) of hydrogen pressure for 17 hours. The suspension is cooled and filtered to remove Raney nickel through filter aid, and the precipitate is washed with methanol. The filtrate is concentrated under reduced pressure. The residue is dissolved in methanol saturated with anhydrous ammonia, treated with decolorizing activated carbon, filtered through filter aid and evaporated to obtain 0.56 g of (±)-cis-6-(2-aminoethyl)-1,3-dioxane-4- acetic acid.

Trinn E: Fremstilling av trans-( ±)- 5-( 4- fluorfenyl)-2- ( l- metvletyl)- N. 4- difenyl- l- f 1 -( tetrahydro- 4-hydroksy- 6- okso- 2H- pvran- 2- yl) etyl1- lH- pvrrol-3- karboksamid. Step E: Preparation of trans-(±)-5-(4-fluorophenyl)-2-(1-methylethyl)-N.4-diphenyl-1-f1-(tetrahydro-4-hydroxy-6-oxo-2H - pvran-2-yl)ethyl 1-1H-pvrrol-3-carboxamide.

En oppløsning av 0,26 g (1,21 mmol) (±)-cis-6-(2-aminoetyl)-1,3-dioksan-4-eddiksyre og 0,504 g (1,20 mmol) (±)-4-f luor-a- [ 2-metyl-l-oksopropyl ] -"Y-okso-N, /3-difenylbenzenbutanamid i 5 ml dimetylsulfoksyd oppvarmes ved 105"C i 15 timer. Oppløsningen avkjøles og helles i 100 ml dietyleter og 50 ml mettet ammoniumklorid i vann. Lagene separeres, og det organiske lag vaskes med vann (2 x 50 ml) og 5% natriumhydroksydoppløsning (2 x 100 ml - for å ekstrahere mellomprodukt syren fra ureagert diketon). Det vandige lag gjøres surt med fortynnet saltsyreoppløsning og ekstraheres med 30 ml etylacetat. En dråpe konsentrert saltsyre settes til etylacetatoppløsningen, og den står i 18 timer. Oppløsningen konsentreres i vakuum, og konsentratet oppløses i 30 ml etylacetat og behandles med én dråpe konsentrert saltsyre. Oppløsningen omrøres i to timer, konsentreres i vakuum og oppløses i 6 ml toluen. 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 utkrystalliserer og isoleres ved filtrering. En total på 0,15 g 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 isoleres i to utbytter. A solution of 0.26 g (1.21 mmol) (±)-cis-6-(2-aminoethyl)-1,3-dioxane-4-acetic acid and 0.504 g (1.20 mmol) (±)-4 -fluoro-a-[2-methyl-1-oxopropyl]-"Y-oxo-N, /3-diphenylbenzenebutanamide in 5 ml of dimethylsulfoxide is heated at 105"C for 15 hours. The solution is cooled and poured into 100 ml of diethyl ether and 50 ml of saturated ammonium chloride in water. The layers are separated, and the organic layer is washed with water (2 x 50 ml) and 5% sodium hydroxide solution (2 x 100 ml - to extract the intermediate acid from unreacted diketone). The aqueous layer is acidified with dilute hydrochloric acid solution and extracted with 30 ml of ethyl acetate. A drop of concentrated hydrochloric acid is added to the ethyl acetate solution, and it stands for 18 hours. The solution is concentrated in vacuo, and the concentrate is dissolved in 30 ml of ethyl acetate and treated with one drop of concentrated hydrochloric acid. The solution is stirred for two hours, concentrated in vacuo and dissolved in 6 ml of toluene. Trans-(±)-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2- yl)ethyl]-1H-pyrrole-3-carboxamide crystallizes out and is isolated by filtration. A total of 0.15 g of trans-(±)-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo -2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide is isolated in two yields.

FREMGANGSMÅTE G PROCEDURE G

Trinn A: Fremstilling av enten ( ±) - ( 2a , 4/ 3. 68 ) - eller ( ±)-( 2a . 4a. 6a)-2-metyl-6- f 2- propenyl)- 1. 3-dioksan- 4- acetonitril. Step A: Preparation of either ( ±) - ( 2a , 4/ 3. 68 ) - or ( ±)-( 2a . 4a. 6a)-2-methyl-6- f 2- propenyl)- 1. 3-dioxane - 4-acetonitrile.

Kaliumcyanid, 1,3 g (20 mmol), settes til en oppløsning ved romtemperatur av (R*,R*)-a-2-propenyloksiranetanol, 2,56 g (20 mmol), i 25 ml 4:1 isopropanol:vann. Oppløsningen omrøres i 20 timer ved omgivelsestemperatur, konsentreres og lagdeles mellom etylacetat og saltvann. Det vandige lag ekstraheres 2x med etylacetat, og de samlede etylacetatekstrakter vaskes med saltvann og tørres (magnesiumsulfat). Det rå produkt oppløses i 20 ml 1,1-dimetoksyetan, kamfersulfonsyre tilsettes, og oppløsningen omrøres i 18 timer ved romtemperatur. Konsentrasjon og lynkromatografi efter konsentrasjon i vakuum gir 1,30 g enten (±) - (2a, 4/3, 60) - eller (±)-(2a,4a,6a)-2-metyl-6-(2-propenyl)-1,3-dioksan-4-acetonitril. Potassium cyanide, 1.3 g (20 mmol), is added to a solution at room temperature of (R*,R*)-α-2-propenyloxiraneethanol, 2.56 g (20 mmol), in 25 ml of 4:1 isopropanol:water . The solution is stirred for 20 hours at ambient temperature, concentrated and layered between ethyl acetate and salt water. The aqueous layer is extracted twice with ethyl acetate, and the combined ethyl acetate extracts are washed with salt water and dried (magnesium sulfate). The crude product is dissolved in 20 ml of 1,1-dimethoxyethane, camphorsulfonic acid is added, and the solution is stirred for 18 hours at room temperature. Concentration and flash chromatography after concentration in vacuum gives 1.30 g of either (±) - (2a, 4/3, 60) - or (±)-(2a,4a,6a)-2-methyl-6-(2-propenyl) )-1,3-dioxane-4-acetonitrile.

Trinn B: Fremstilling av enten ( ±)-( 2a, 4a. 6a)- eller f±W2a. 4fl. 6fi)- 2- metvl- 6-( 2- oksoetvl)- 1. 3-dioksan- 4- acetonitril. Step B: Preparation of either ( ±)-( 2a, 4a, 6a)- or f±W2a. 4 fl. 6)-2-methyl-6-(2-oxoethyl)-1.3-dioxane-4-acetonitrile.

En oppløsning av enten (±)-(2a, 40, 60)- eller A solution of either (±)-(2a, 40, 60)- or

(2a,4a,6a)-2-metyl-6-(2-propenyl)-1,3-dioksan-4-acetonitril, 2,78 g (15,36 mmol), i 100 ml diklorometan avkjøles til -78°C under nitrogen. Ozon (Welsbachgenerator, strømningshastighet 0,1, spenning = 90V) passeres derefter gjennom et frittet gassinngangsrør inn i oppløsningen, inntil den blå farve av ozon viser seg. Strømmen slås fra, og oksygen bobles igjennom, inntil den blå farve er forsvunnet. Trifenylfosfin, 4,2 g (16 mmol), tilsettes, og den farveløse oppløsning står til oppvarmning til romtempertur. Lynkromatografi gir efter konsentrasjon i vakuum 2,5 g rent enten (±)-(2a,4a,6a)- eller (±) -(2a, 4/3, 60) -2-metyl-6-(2-okso-etyl) -1, 3-dioksan-4-acetonitril. (2a,4a,6a)-2-methyl-6-(2-propenyl)-1,3-dioxane-4-acetonitrile, 2.78 g (15.36 mmol), in 100 ml dichloromethane cool to -78° C under nitrogen. Ozone (Welsbach generator, flow rate 0.1, voltage = 90V) is then passed through a fritted gas inlet tube into the solution, until the blue color of ozone appears. The current is switched off, and oxygen is bubbled through until the blue color has disappeared. Triphenylphosphine, 4.2 g (16 mmol), is added and the colorless solution is allowed to warm to room temperature. Flash chromatography gives, after concentration in vacuum, 2.5 g of pure either (±)-(2a,4a,6a)- or (±)-(2a,4/3,60)-2-methyl-6-(2-oxo- ethyl)-1,3-dioxane-4-acetonitrile.

Trinn C: Fremstilling av enten ( ±)-( 2a . 4a, 6a)- eller ( ±) - ( 2a, 4) 3, 60 ) - 6- ( cyanometyl) -2-metyl-1. 3- dioksan- 4- eddiksyre. Step C: Preparation of either ( ±)-( 2a . 4a , 6a )- or ( ± )-( 2a , 4 ) 3 , 60 ) - 6-( cyanomethyl)-2-methyl-1. 3- dioxane- 4- acetic acid.

Jones reagens (kromtrioksyd-svovelsyre-vann), 3,8 ml (7,6 mmol), settes dråpevis til en 0°C oppløsning av enten (±)-(2a,4a,6a)- eller (±)-(2a, 40, 60)-2-metyl-6-(2-oksoetyl)-1,3-dioksan-4-acetonitril, 1,40 g (7,6 mmol) oppløst i 50 ml aceton, inntil den orange farve ikke forsvinner. Efter omrøring i ytterligere 15 minutter helles blandingen i 300 ml dietyleter og vaskes med saltvann, inntil de vandige skylninger er farveløse. Dietyleterlaget tørres (magnesiumsulfat), filtreres og konsentreres for å oppnå 1,01 g enten (±)-(2a,4a,6a)- eller (±)-(2a, 40, 60)-6-(cyanometyl)-2-metyl-l,3-dioksan-4-eddiksyre som et farveløst faststoff. Jones reagent (chromium trioxide-sulfuric acid-water), 3.8 ml (7.6 mmol), is added dropwise to a 0°C solution of either (±)-(2a,4a,6a)- or (±)-(2a) , 40, 60)-2-methyl-6-(2-oxoethyl)-1,3-dioxane-4-acetonitrile, 1.40 g (7.6 mmol) dissolved in 50 ml of acetone, until the orange color does not disappear . After stirring for a further 15 minutes, the mixture is poured into 300 ml of diethyl ether and washed with salt water, until the aqueous rinses are colourless. The diethyl ether layer is dried (magnesium sulfate), filtered and concentrated to obtain 1.01 g of either (±)-(2a,4a,6a)- or (±)-(2a,40,60)-6-(cyanomethyl)-2- methyl-1,3-dioxane-4-acetic acid as a colorless solid.

Trinn D: Fremstilling av enten ( ±)- f2a. 4a, 6a)- eller ( ±)- f2a, 40 . 60 )- 6- f2- aminoetyl)-2-metyl-1, 3- dioksan- 4- eddiksvre. Step D: Preparation of either ( ±)- f2a. 4a, 6a)- or ( ±)- f2a, 40 . 60 )- 6- (2- aminoethyl)-2-methyl-1, 3- dioxane- 4- acetic acid.

En oppløsning av 0,97 g (4,88 mmol) enten (±)-(2a,4a,6a)-eller (±)-(2a, 40, 60)-6-(cyanometyl)-2-metyl-l,3-dioksan-4-eddiksyre i 100 ml metanol mettet med vannfri ammoniakk settes til en Parr rystekolbe inneholdende 0,53 g vann-fuktet Raney-nikkel #30. Oppløsningen oppvarmes ved 45°C og 50 psig hydrogentrykk i 17 timer. Suspensjonen avkjøles og filtreres for å fjerne Raney-nikkel gjennom filterhjelp, og bunnfallet vaskes med metanol. Filtratet konsentreres ved redusert trykk. Residuet oppløses i metanol mettet med vannfri ammoniakk, behandles med farvefjernende aktivt kull, filtreres gjennom filterhjelp og inndampes for å oppnå 0,50 g enten A solution of 0.97 g (4.88 mmol) of either (±)-(2a,4a,6a)-or (±)-(2a,40,60)-6-(cyanomethyl)-2-methyl-1 ,3-dioxane-4-acetic acid in 100 ml of methanol saturated with anhydrous ammonia is added to a Parr shake flask containing 0.53 g of water-moistened Raney nickel #30. The solution is heated at 45°C and 50 psig hydrogen pressure for 17 hours. The suspension is cooled and filtered to remove Raney nickel through filter aid, and the precipitate is washed with methanol. The filtrate is concentrated under reduced pressure. The residue is dissolved in methanol saturated with anhydrous ammonia, treated with decolorizing activated carbon, filtered through filter aid and evaporated to obtain 0.50 g of either

(2a,4a,6a)- eller (±)-(2a,4Æ,6/3)-6-(2-aminoetyl)-2-metyl-l,3-dioksan-4-eddiksyre. (2α,4α,6α)- or (±)-(2α,4α,6/3)-6-(2-aminoethyl)-2-methyl-1,3-dioxane-4-acetic acid.

Trinn E: Fremstilling av trans-( ±)- 5-( 4- fluorfenyl)-2-( 1- metvietvl)- N. 4- d i fenvl- 1- r 2-( tetra-hvdro- 4- hvdroksv- 6- okso- 2H- pvran- 2- yl) etvll - lH- pyrrol- 3- karboksamid. Step E: Preparation of trans-( ±)- 5-( 4- fluorophenyl)-2-( 1- methylvietvl)- N. 4- d iphenvl- 1- r 2-( tetra-hydro- 4- hydroxy- 6- oxo-2H-pyrrole-2-yl)ethyl-1H-pyrrole-3-carboxamide.

En oppløsning av 0,31 g enten (±)-(2a,4a,6a)- eller (±)-(2a,4/3,6/3)-6-(2-aminoetyl)-2-metyl-l,3-dioksan-4-eddiksyre og 0,504 g (1,20 mmol) (±)-4-fluor-a-[2-metyl-l-oksopropyl]- y-okso-N,/3-difenylbenzenbutanamid i 5 ml dimétylsulfoksyd oppvarmes ved 105°C i 15 timer. Oppløsningen avkjøles og helles i 100 ml dietyleter og 50 ml mettet ammoniumklorid i vann. Lagene separeres, og det organiske lag vaskes med vann (2 x 50 ml) og 5% natriumhydroksydoppløsning (2 x 100 ml - for å ekstrahere mellomprodukt syren fra ureagert diketon). Det vandige lag gjøres surt med fortynnet saltsyreoppløsning, omrøres i tre timer og ekstraheres med 30 ml etylacetat. En dråpe konsentrert saltsyre settes til etylacetatoppløsningen, og den står i 18 timer. Oppløsningen konsentreres i vakuum, og konsentratet oppløses påny i 30 ml etylacetat og behandles med én dråpe konsentrert saltsyre. Oppløsningen omrøres i to timer, konsentreres i vakuum og oppløses i 6 ml toluen. 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 utkrystalliserer og isoleres ved filtrering. En total på 0,14 g 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 isoleres i to utbytter. A solution of 0.31 g of either (±)-(2a,4a,6a)- or (±)-(2a,4/3,6/3)-6-(2-aminoethyl)-2-methyl-1 ,3-dioxane-4-acetic acid and 0.504 g (1.20 mmol) (±)-4-fluoro-α-[2-methyl-1-oxopropyl]-γ-oxo-N,/3-diphenylbenzenebutanamide in 5 ml dimethyl sulfoxide is heated at 105°C for 15 hours. The solution is cooled and poured into 100 ml of diethyl ether and 50 ml of saturated ammonium chloride in water. The layers are separated, and the organic layer is washed with water (2 x 50 ml) and 5% sodium hydroxide solution (2 x 100 ml - to extract the intermediate acid from unreacted diketone). The aqueous layer is acidified with dilute hydrochloric acid solution, stirred for three hours and extracted with 30 ml of ethyl acetate. A drop of concentrated hydrochloric acid is added to the ethyl acetate solution, and it stands for 18 hours. The solution is concentrated in vacuo, and the concentrate is redissolved in 30 ml of ethyl acetate and treated with one drop of concentrated hydrochloric acid. The solution is stirred for two hours, concentrated in vacuo and dissolved in 6 ml of toluene. Trans-(±)-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2- yl)ethyl]-1H-pyrrole-3-carboxamide crystallizes out and is isolated by filtration. A total of 0.14 g of trans-(±)-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo -2H-pyran-2-yl)-ethyl]-1H-pyrrole-3-carboxamide is isolated in two yields.

FREMGANGSMÅTE H PROCEDURE H

Trinn A; Fremstilling av ( ±)- cis- 1. l- dimetyletyl- 6-( cvanometyl)- 2. 2- dimetyl- l. 3- dioksan- 4- acetat. Step A; Preparation of ( ±)- cis- 1. 1- dimethylethyl- 6-( cvanomethyl)- 2. 2- dimethyl- 1. 3- dioxane- 4- acetate.

(±)-cis-6-(cyanometyl)-2,2-dimetyl-l,3-dioksan-4-eddiksyre (3,72 g, 17,44 mmol) oppløses i 20 ml diklormetan, avkjøles til 0°C, og 0,2 g 4-dimetylaminopyridin (DMAP) tilsettes efterfulgt av t-butylalkohol og efterfulgt av 4,32 g dicykloheksylkarbodiimid (DCC). Denne oppløsning står til langsom oppvarmning til romtemperatur over en 76,5 timers periode. Tynnskiktskromatografi (TLC) viser hovedsakelig produkt og noen svake lavereliggende Rf-biprodukter. Blandingen omrøres i én time, og 50 ml diklormetan tilsettes, og omrøring fortsetter i fem timer, ytterligere 100 ml dietyleter tilsettes, og blandingen filtreres. Bunnfallet vaskes med dietyleter. Filtratet konsentreres til en olje. Det rå produkt kromatograferes på silikagel under eluering med 4:1 heksan:etylacetat. Eluatet konsentreres for å oppnå (±)-cis-1,l-dimetyletyl-6-(cyanometyl)-2,2-dimetyl-l,3-dioksan-4-acetat. (±)-cis-6-(cyanomethyl)-2,2-dimethyl-1,3-dioxane-4-acetic acid (3.72 g, 17.44 mmol) is dissolved in 20 ml of dichloromethane, cooled to 0°C, and 0.2 g of 4-dimethylaminopyridine (DMAP) is added followed by t-butyl alcohol and followed by 4.32 g of dicyclohexylcarbodiimide (DCC). This solution is allowed to slowly warm to room temperature over a 76.5 hour period. Thin layer chromatography (TLC) shows mainly product and some weak lower Rf by-products. The mixture is stirred for one hour, and 50 ml of dichloromethane is added, and stirring is continued for five hours, another 100 ml of diethyl ether is added, and the mixture is filtered. The precipitate is washed with diethyl ether. The filtrate is concentrated to an oil. The crude product is chromatographed on silica gel eluting with 4:1 hexane:ethyl acetate. The eluate is concentrated to obtain (±)-cis-1,1-dimethylethyl-6-(cyanomethyl)-2,2-dimethyl-1,3-dioxane-4-acetate.

200 MHz NMR (CDCl3) S 1,36 (m, 1H), 1,42 (s, 3H), 1,49 (s, 9H), 1,50 200 MHz NMR (CDCl 3 ) S 1.36 (m, 1H), 1.42 (s, 3H), 1.49 (s, 9H), 1.50

(S, 3H), 1,79 (dt, 1H, J = 2,5 Hz, J = 12,1 Hz), 2,40 (dd, 1H, J = 6,2 Hz, J = 15,4 Hz), 2,5 - 2,7 (m, 1H), 2,55 (d, 2H, J = 6,1 Hz) 4,18 (m, 1H), 4,32 (m, 1H). (S, 3H), 1.79 (dt, 1H, J = 2.5 Hz, J = 12.1 Hz), 2.40 (dd, 1H, J = 6.2 Hz, J = 15.4 Hz ), 2.5 - 2.7 (m, 1H), 2.55 (d, 2H, J = 6.1 Hz) 4.18 (m, 1H), 4.32 (m, 1H).

<13>C-NMR (CDC<1>3, 50 MHz) S 19,80, 25,16, 28,30, 29,94, 35,66,,42,56, 65,27, 65,87, 80,96, 99,57, 116,72, 169,83. <13>C-NMR (CDC<1>3, 50 MHz) S 19.80, 25.16, 28.30, 29.94, 35.66,,42.56, 65.27, 65.87, 80.96, 99.57, 116.72, 169.83.

GCMS m/e 254, 199, 198, 154, 138, 59, 57, 43, 41. GCMS w/e 254, 199, 198, 154, 138, 59, 57, 43, 41.

FTIR (rent) 954,2, 987,6, 1152,3, 1201,1, 1257,7, 1316,9, 1368,3, 1383,7, 1728,4, 2253,1, 2942,4, 2983,5 cm"<1>. FTIR (neat) 954.2, 987.6, 1152.3, 1201.1, 1257.7, 1316.9, 1368.3, 1383.7, 1728.4, 2253.1, 2942.4, 2983, 5 cm"<1>.

Trinn B; Fremstilling av ( ±)- cis- 1. 1- dimetyletyl-6- f 2- aminoetyl)- 2. 2- dimetyl- l, 3- dioksan- 4- acetat. Step B; Preparation of ( ±)- cis- 1. 1- dimethylethyl-6- f 2- aminoethyl)- 2. 2- dimethyl- 1, 3- dioxane- 4- acetate.

En oppløsning av 6,75 g (±)-cis-1,l-dimetyletyl-6-(cyanometyl) -2,2-dimetyl-l,3-dioksan-4-acetat i 80 ml metanol mettet med gassformig ammoniakk behandles med 0,7 g Raney-nikkel #30 og hydrogengass i en rystekolbe ved 50 pund pr. kvadrattomme (psig) og 40°C. Efter 10 timer viser tynnskiktskromatografi ingen tilstedeværelse av utgangsnitril. Suspensjonen avkjøles, filtreres gjennom filterhjelp og konsentreres til en olje. Denne rå olje renses ved lynkromatografi på silikagel med 30:20:1 (etylacetat:metanol:ammoniumhydroksyd) som elueringsmiddel for å oppnå 5,48 g (±)-cis-1,l-dimetyletyl-6-(2-aminoetyl)-2,2-dimetyl-l,3-dioksan-4-acetat (98,2 areal %) som en klar olje som størkner efter en tid. A solution of 6.75 g of (±)-cis-1,1-dimethylethyl-6-(cyanomethyl)-2,2-dimethyl-1,3-dioxane-4-acetate in 80 ml of methanol saturated with gaseous ammonia is treated with 0.7 g of Raney nickel #30 and hydrogen gas in a shaking flask at 50 pounds per square inch (psig) and 40°C. After 10 hours, thin-layer chromatography shows no presence of starting nitrile. The suspension is cooled, filtered through filter aid and concentrated to an oil. This crude oil is purified by flash chromatography on silica gel with 30:20:1 (ethyl acetate:methanol:ammonium hydroxide) as eluent to obtain 5.48 g of (±)-cis-1,1-dimethylethyl-6-(2-aminoethyl)- 2,2-dimethyl-1,3-dioxane-4-acetate (98.2 area %) as a clear oil which solidifies after some time.

200 MHz NMR (CDC13) S 1,0 - 1,2 (m, 1H), 1,22 (s, 3H), 1,31 (s, 12H), 1,35 - 1,45 (m, 1H), 1,77 (brS, 2H), 2,15 (dd, 1H, J = 15,1 Hz, J = 6,2 HZ), 2,29 (dd, 1H, J = 15,1 Hz, J = 7,0 Hz), 2,66 (t, 2H, J = 6,6 Hz), 3,82 (m, 1H), 4,12 (m, 1H). 200 MHz NMR (CDCl 3 ) S 1.0 - 1.2 (m, 1H), 1.22 (s, 3H), 1.31 (s, 12H), 1.35 - 1.45 (m, 1H) , 1.77 (brS, 2H), 2.15 (dd, 1H, J = 15.1 Hz, J = 6.2 HZ), 2.29 (dd, 1H, J = 15.1 Hz, J = 7.0 Hz), 2.66 (t, 2H, J = 6.6 Hz), 3.82 (m, 1H), 4.12 (m, 1H).

<13>C-NMR (CDC13, 50 MHz) S 19,56, 27,92, 29,96, 36,43, 38,18, 39,65, 42,55, 66,03, 67,16, 80,19, 98,32, 169,80. <13>C-NMR (CDC13, 50 MHz) S 19.56, 27.92, 29.96, 36.43, 38.18, 39.65, 42.55, 66.03, 67.16, 80 .19, 98.32, 169.80.

GC/MS m/e 258, 216, 215, 202, 200, 142, 113, 100, 99, 72, 57, 43. GC/MS m/e 258, 216, 215, 202, 200, 142, 113, 100, 99, 72, 57, 43.

FTIR (rent) 951,6, 1157,4, 1201,1, 1260,3, 1314,3, 1368,3, 1381,2, 1728,4, 2361,1, 2939,8, 2980,9 cm"<1>. FTIR (pure) 951.6, 1157.4, 1201.1, 1260.3, 1314.3, 1368.3, 1381.2, 1728.4, 2361.1, 2939.8, 2980.9 cm"< 1>.

Trinn C: Fremstilling av trans^( ±)- 5-( 4- fluorfenvl)-2-( 1- metvietvl)- N. 4- di fenvl- 1- f 2-( tetrahydro- 4- hydroksy- 6- okso- 2H- pyran- 2- yl) etvll-lH- pyrrol- 3- karboksamid. Step C: Preparation of trans^( ±)- 5-( 4- fluorophenyl)-2-( 1- methylethyl)- N. 4- diphenyl- 1- f 2-( tetrahydro- 4- hydroxy- 6- oxo- 2H-pyran-2-yl)ethyl-1H-pyrrol-3-carboxamide.

En oppløsning av 0,79 g (2,89 mmol) (±)-cis-1,1-dimetyletyl-6-(2-aminoetyl)-2,2-dimetyl-l,3-dioksan-4-acetat og 1,00 g (2,41 mmol) (±)-4-fluor-a-[2-metyl-l-oksopropyl]-7-okso-N,Æ-difenylbenzenbutanamidblanding av [R-(R*,R<*>)], [R- A solution of 0.79 g (2.89 mmol) of (±)-cis-1,1-dimethylethyl-6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxane-4-acetate and 1 .00 g (2.41 mmol) (±)-4-fluoro-α-[2-methyl-1-oxopropyl]-7-oxo-N,Æ-diphenylbenzenebutanamide mixture of [R-(R*,R<*> )], [R-

(R*,S*)], [S-(R*,R*)] og [S-(R*,S*)]isomerer i 15 ml heptan:toluen (9:1) oppvarmes ved tilbakeløpskjøling i 24 timer. Oppløsningen avkjøles og helles i 100 ml tetrahydrofuran og 50 ml mettet ammoniumklorid i vann. Lagene separeres, og det organiske lag vaskes med saltvann. Til det organiske lag settes 5 ml 10% saltsyreoppløsning, og oppløsningen omrøres i 15 timer. Til denne oppløsning settes 1,2 g natriumhydroksyd, og blandingen omrøres i 30 timer. Reaksjonen stanses ved tilsetning av 50 ml vann, 30 ml heksan og separasjon av lagene. Det vandige lag gjøres surt med fortynnet saltsyreoppløsning, omrøres i tre timer og ekstraheres med 50 ml etylacetat. En dråpe konsentrert saltsyre settes til etylacetatoppløsningen, og oppløsningen står i 18 timer. Oppløsningen konsentreres i vakuum, og konsentratet oppløses påny i 50 ml etylacetat og behandles med én dråpe konsentrert saltsyre. Oppløsningen omrøres i to timer, konsentreres i vakuum og oppløses i 10 ml toluen. 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 isoleres i to utbytter. (R*,S*)], [S-(R*,R*)] and [S-(R*,S*)]isomers in 15 ml of heptane:toluene (9:1) are heated at reflux for 24 h . The solution is cooled and poured into 100 ml of tetrahydrofuran and 50 ml of saturated ammonium chloride in water. The layers are separated, and the organic layer is washed with salt water. 5 ml of 10% hydrochloric acid solution is added to the organic layer, and the solution is stirred for 15 hours. 1.2 g of sodium hydroxide is added to this solution, and the mixture is stirred for 30 hours. The reaction is stopped by adding 50 ml of water, 30 ml of hexane and separating the layers. The aqueous layer is acidified with dilute hydrochloric acid solution, stirred for three hours and extracted with 50 ml of ethyl acetate. A drop of concentrated hydrochloric acid is added to the ethyl acetate solution, and the solution stands for 18 hours. The solution is concentrated in vacuo, and the concentrate is redissolved in 50 ml of ethyl acetate and treated with one drop of concentrated hydrochloric acid. The solution is stirred for two hours, concentrated in vacuo and dissolved in 10 ml of toluene. Trans-(±)-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2- yl)ethyl]-1H-pyrrole-3-carboxamide is isolated in two yields.

FREMGANGSMÅTE I PROCEDURE I

Trinn A: Fremstilling av enten ( ±)-( 2a . 4a. 6a )- eller ( ± )-( 2a . 40. 6B )- 1. l- dimetvletvl- 6-( 2 - cyanometyl) - 2- fenyl- l. 3- dioksan- 4- acetat. Step A: Preparation of either ( ± )-( 2a . 4a . 6a )- or ( ± )-( 2a . 40 . 6B )- 1. l - dimethylethyl- 6-( 2 - cyanomethyl) - 2- phenyl- l 3-dioxane-4-acetate.

Enten (±)-(2a,4a,6a) eller (±)-(2a,4/3, 60) -6-(cyanometyl) - 2-fenyl-l,3-dioksan-4-eddiksyre (3,07 g, 11,75 mmol) oppløses i 15 ml diklormetan, avkjøles til 0°C, og 0,1 g 4-dimetylaminopyridin (DMAP) tilsettes efterfulgt av t-butylalkohol, efterfulgt av 2,91 g dicykloheksylkarbodiimid (DCC). Dennne oppløsning står til langsom oppvarmning til romtemperatur og omrøres over en 16,5 timers periode. Tynnskiktskromatografi (TLC) viser hovedsakelig produkt og noen svake lavereliggende Rf-biprodukter. Blandingen omrøres i én time, og 50 ml diklormetan tilsettes, og omrøring fortsettes i fem timer. Ytterligere 100 ml dietyleter tilsettes og derefter filtreres. Bunnfallet vaskes med dietyleter. Filtratet konsentreres til en olje. Det rå produkt kromatograferes på silikagel under eluering med heksan:etylacetat 4:1. Eluatet kon sentreres for å oppnå enten (±)-(2a,4a,6a)- eller (±) - (2a, 4/3, 60) -1, l-dimetyletyl-6-(2-cyanometyl)-2-fenyl-l,3-dioksan-4-acetat. Either (±)-(2a,4a,6a) or (±)-(2a,4/3,60)-6-(cyanomethyl)-2-phenyl-1,3-dioxane-4-acetic acid (3.07 g, 11.75 mmol) is dissolved in 15 ml of dichloromethane, cooled to 0°C, and 0.1 g of 4-dimethylaminopyridine (DMAP) is added followed by t-butyl alcohol, followed by 2.91 g of dicyclohexylcarbodiimide (DCC). This solution is allowed to slowly warm to room temperature and is stirred over a 16.5 hour period. Thin layer chromatography (TLC) shows mainly product and some weak lower Rf by-products. The mixture is stirred for one hour, and 50 ml of dichloromethane is added, and stirring is continued for five hours. A further 100 ml of diethyl ether is added and then filtered. The precipitate is washed with diethyl ether. The filtrate is concentrated to an oil. The crude product is chromatographed on silica gel eluting with hexane:ethyl acetate 4:1. The eluate is concentrated to obtain either (±)-(2a,4a,6a)- or (±)-(2a,4/3,60)-1,1-dimethylethyl-6-(2-cyanomethyl)-2- phenyl-1,3-dioxane-4-acetate.

GC/MS m/e 260, 244, 202, 138, 107, 105, 77, 57, 41. GC/MS m/e 260, 244, 202, 138, 107, 105, 77, 57, 41.

Trinn B: Fremstilling av enten ( ± )- f 2a . 4a. 6a)- eller ( ±W2a. 40 . 6fl)- l. l- dimetvletvl- 6- r2-aminoetvl)- 2- fenvl- 1. 3- dioksan- 4- acetat. Step B: Preparation of either ( ± )- f 2a . 4a. 6a)- or ( ±W2a. 40 . 6fl)- 1. 1- dimethylethyl- 6- r2-aminoethyl)- 2- phenyl- 1. 3- dioxane- 4- acetate.

En oppløsning av 1,72 g av enten (±)-(2a,4a,6a) eller (±)-(2a, 40, 60)-l,l-dimetyletyl-6-(cyanometyl)-2-fenyl-l,3-dioksan-4-acetat i 30 ml metanol mettet med gassformig ammoniakk behandles med 0,3 g Raney-nikkel #30 og hydrogengass i en rystekolbe ved 50 pund pr. kvadrattomme (psig) og 40°C. Efter 10 timer viser tynnskiktskromatografi ingen tilstedeværelse av utgangsnitril. Suspensjonen avkjøles, filtreres gjennom filterhjelp og konsentreres til en olje. Denne rå olje renses ved lynkromatografi på silikagel med 30:20:1 (etylacetat:metanol:ammoniumhydroksyd) som elueringsmiddel for å oppnå 1,56 g av enten (±)-(2a,4a,6a)-eller (±) -(2a, 4/3, 60) -1, l-dimetyletyl-6- (2-aminoetyl) -2-fenyl-1,3-dioksan-4-acetat (98,2 areal %) som en klar olje som størkner efter en tid. A solution of 1.72 g of either (±)-(2a,4a,6a) or (±)-(2a,40,60)-1,1-dimethylethyl-6-(cyanomethyl)-2-phenyl-1 ,3-dioxane-4-acetate in 30 ml of methanol saturated with gaseous ammonia is treated with 0.3 g of Raney nickel #30 and hydrogen gas in a shaking flask at 50 pounds per square inch (psig) and 40°C. After 10 hours, thin-layer chromatography shows no presence of starting nitrile. The suspension is cooled, filtered through filter aid and concentrated to an oil. This crude oil is purified by flash chromatography on silica gel with 30:20:1 (ethyl acetate:methanol:ammonium hydroxide) as eluent to obtain 1.56 g of either (±)-(2a,4a,6a)-or (±)-( 2a, 4/3, 60) -1,1-dimethylethyl-6-(2-aminoethyl)-2-phenyl-1,3-dioxane-4-acetate (98.2 area %) as a clear oil which solidifies after a time.

200 MHZ NMR (CDC13) S 1,2 - 1,9 (m, 4H) 1,44 (s, 9H), 2,03, (br.s, 2H) , 2,42 (dd,' 1H, J = 15,3 Hz, J = 6,3 Hz), 2,63 (dd, 1H, J = 15,3 Hz, J = 7,0 Hz), 2,89 (t, 2H, J = 6,8 Hz), 3,97 (m, 1H) , 4,26 (m, 1H) , 5,56 (s, 1H) , 7,3 - 7,4 (m, 3H) , 7,4 - 7,5 (m, 2H). 200 MHZ NMR (CDCl 3 ) S 1.2 - 1.9 (m, 4H) 1.44 (s, 9H), 2.03, (br.s, 2H) , 2.42 (dd,' 1H, J = 15.3 Hz, J = 6.3 Hz), 2.63 (dd, 1H, J = 15.3 Hz, J = 7.0 Hz), 2.89 (t, 2H, J = 6.8 Hz), 3.97 (m, 1H) , 4.26 (m, 1H) , 5.56 (s, 1H) , 7.3 - 7.4 (m, 3H) , 7.4 - 7.5 (m, 2H).

<13>C NMR (CDC13, 50 MHz) S 28,07, 36,57, 38,23, 39,25, 42,17, 73,47, 74, 87, 80,60, 100,36, 125,82, 127,88, 128,34, 138,45, 169,73. <13>C NMR (CDC13, 50 MHz) S 28.07, 36.57, 38.23, 39.25, 42.17, 73.47, 74, 87, 80.60, 100.36, 125, 82, 127.88, 128.34, 138.45, 169.73.

GC/MS, m/e 321, 320, 248, 215, 174, 142, 105, 57. GC/MS, m/e 321, 320, 248, 215, 174, 142, 105, 57.

FTIR (film) 699,6, 756,2, 1026,2, 1116,2, 1149,7, 1368,3, 1394,0, 1718,1, 1733,5, 2872,9, 2932,1 cm"<1>. FTIR (film) 699.6, 756.2, 1026.2, 1116.2, 1149.7, 1368.3, 1394.0, 1718.1, 1733.5, 2872.9, 2932.1 cm"< 1>.

Trinn C: Fremstillin<g> av trans- ( ± ) - 5- ( 4- f luorf enyl) - Step C: Preparation<g> of trans-(±)-5-(4-fluoroenyl)-

2- r1- metvletyl)- N. 4- difenvl- 1- r2- ftetra-hydro- 4 - hydroksv- 6- okso- 2H- pyran- 2 - yl) etyl1-lH- pyrrol- 3- karboksamid. 2- r1- methylethyl)- N. 4- diphenyl- 1- r2- ftetrahydro-4- hydroxy- 6- oxo- 2H- pyran-2-yl) ethyl1-1H- pyrrole-3- carboxamide.

Ved en fremgangsmåte analog med fremgangsmåte H oppnås tittelforbindelsen ved å anvende (±)-(2a,4a,6a)- eller (±)-(2a, 40,60)-1,l-dimetyletyl-6-(2-aminoetyl)-2-fenyl-l, 3-dioksan-4-acetat i stedet for (±)-cis-1,l-dimetyletyl-6-(2-aminoetyl)-2,2-dimetyl-l,3-dioksan-4-acetat. In a method analogous to method H, the title compound is obtained by using (±)-(2a,4a,6a)- or (±)-(2a,40,60)-1,1-dimethylethyl-6-(2-aminoethyl) -2-phenyl-1,3-dioxane-4-acetate instead of (±)-cis-1,1-dimethylethyl-6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxane-4 -acetate.

FREMGANGSMÅTE J PROCEDURE J

Trinn A: Fremstilling av ( ± )- cis- 1. l- dimetyletyl- 4-( cyanometyl)- 1. 5- dioksaspiro[ 5. 51undekan- 2- acetat. Step A: Preparation of ( ± )- cis- 1. 1- dimethylethyl- 4-( cyanomethyl)- 1. 5- dioxaspiro[ 5. 51undecane- 2- acetate.

(±) -cis-4-(cyanometyl)-1,5-dioksaspiro[5,5]-undekan-2-eddiksyre 3,32 g (13,12 mmol) oppløses i 15 ml diklormetan, avkjøles til 0°C, og 0,1 g 4-dimetylaminopyridin (DMAP) tilsettes efterfulgt av t-butylalkohol og efterfulgt av 3,25 g dicykloheksylkarbodiimid (DCC). Denne oppløsning omrøres og står til langsom oppvarmning til romtemperatur over en 16,5 timers periode. TLC viser hovedsakelig produkt og noen svake lavereliggende Rf-biprodukter. Blandingen omrøres i én time, og 50 ml diklormetan tilsettes, og omrøring fortsettes i fire timer. 100 ml dietyleter tilsettes og derefter filtreres. Filtratet konsentreres ved redusert trykk. Dette rå konsentrat kromatograferes på silikagel og elueres med 4:1 heksan:etylacetat for å oppnå (±)-cis-1,l-dimetyletyl-4-(cyanometyl) -1,5-dioksaspiro[5,5] undekan-2-acetat. (±)-cis-4-(cyanomethyl)-1,5-dioxaspiro[5,5]-undecane-2-acetic acid 3.32 g (13.12 mmol) are dissolved in 15 ml of dichloromethane, cooled to 0°C, and 0.1 g of 4-dimethylaminopyridine (DMAP) is added followed by t-butyl alcohol and followed by 3.25 g of dicyclohexylcarbodiimide (DCC). This solution is stirred and allowed to slowly warm to room temperature over a 16.5 hour period. TLC shows mainly product and some faint lower Rf by-products. The mixture is stirred for one hour, and 50 ml of dichloromethane is added, and stirring is continued for four hours. 100 ml of diethyl ether are added and then filtered. The filtrate is concentrated under reduced pressure. This crude concentrate is chromatographed on silica gel eluting with 4:1 hexane:ethyl acetate to obtain (±)-cis-1,1-dimethylethyl-4-(cyanomethyl)-1,5-dioxaspiro[5,5]undecane-2- acetate.

200 MHz NMR (CDC13) S 1,1 2,0 (m, 12H) 1,43 (s, 9H), 2,36 (m, 2H), 2,48 (m, 2H), 4,1-4,4 (m, 2H). 200 MHz NMR (CDCl 3 ) S 1.1 2.0 (m, 12H) 1.43 (s, 9H), 2.36 (m, 2H), 2.48 (m, 2H), 4.1-4 .4 (m, 2H).

<13>C-NMR (CDC13, 50 MHz) 22,37, 22,45, 25,08, 28,15, 28,55, 35,80, 38,57, 42,59, 64,31, 64,92, 80,76, 99,56, 116,65, 169,82. <13>C-NMR (CDC13, 50 MHz) 22.37, 22.45, 25.08, 28.15, 28.55, 35.80, 38.57, 42.59, 64.31, 64, 92, 80.76, 99.56, 116.65, 169.82.

GC/MS m/e 309 (m<+>), 266, 224, 210, 138, 120, 99, 57, 55. GC/MS m/e 309 (m<+>), 266, 224, 210, 138, 120, 99, 57, 55.

FTIR (KBr) 964,5, 1149,7, 1157,4, 1332,3, 1368,3, 1712,9, 2939,8 cm'<1.>FTIR (KBr) 964.5, 1149.7, 1157.4, 1332.3, 1368.3, 1712.9, 2939.8 cm'<1.>

Trinn Bt Fremstilling av ( ±)- cis- 1. 1- dimetyletyl-4-( 2- aminoetvl)- 1. 5- dioksaspirof5. 5]- undekan- 2-acetat. Step Bt Preparation of ( ±)- cis- 1. 1- dimethylethyl-4-( 2- aminoethyl)- 1. 5- dioxaspirof5. 5]-undecane-2-acetate.

En oppløsning av 1,19 g (±)-cis-1,1-dimetyletyl-4-(cyanometyl) -1,5-dioksaspiro[5,5]undekan-2-acetat i 30 ml metanol mettet med gassformig ammoniakk behandles med 0,3 g Raney-nikkel #30 og hydrogengass i en rystekolbe ved 50 pund pr. kvadrattomme (psig) og 40°C. Efter 22 timer viser tynnskiktskromatografi ingen tilstedeværelse av utgangsnitril. Suspensjonen avkjøles, filtreres gjennom filterhjelp og konsentreres til en olje. Denne rå olje renses ved silikagel lynkromatografi (30:20:1; etylacetat: metanol:ammoniumhydroksyd) for å oppnå 1,18 g (±)-cis-1,l-dimetyletyl-4-(2-aminoetyl)-1,5-dioksaspiro[5,5]undekan-2-acetat som en klar olje som blir til faststoff ved henstand. A solution of 1.19 g of (±)-cis-1,1-dimethylethyl-4-(cyanomethyl)-1,5-dioxaspiro[5,5]undecane-2-acetate in 30 ml of methanol saturated with gaseous ammonia is treated with 0.3 g of Raney nickel #30 and hydrogen gas in a shaking flask at 50 pounds per square inch (psig) and 40°C. After 22 hours, thin-layer chromatography shows no presence of starting nitrile. The suspension is cooled, filtered through filter aid and concentrated to an oil. This crude oil is purified by silica gel flash chromatography (30:20:1; ethyl acetate:methanol:ammonium hydroxide) to obtain 1.18 g of (±)-cis-1,1-dimethylethyl-4-(2-aminoethyl)-1,5 -dioxaspiro[5,5]undecane-2-acetate as a clear oil which becomes a solid on standing.

200 MHz NMR (CDC13) S 1,2 - 2,0 (m, 12H), 1,43 (s, 9H), 2,34, (m, 2H), 2,50 (br.s, 2H), 2,84 (t, 2H, J = 6,7 Hz), 3,99 (m, 1H), 4,28 (m, 1H). 200 MHz NMR (CDCl 3 ) S 1.2 - 2.0 (m, 12H), 1.43 (s, 9H), 2.34, (m, 2H), 2.50 (br.s, 2H), 2.84 (t, 2H, J = 6.7 Hz), 3.99 (m, 1H), 4.28 (m, 1H).

GC/MS, m/e 313, 270, 214, 185, 144, 142, 99. GC/MS, m/e 313, 270, 214, 185, 144, 142, 99.

FTIR (film) 961,9, 1098,2, 1154,8, 1368,3, 1725,8, 2934,6 cm" 1 FTIR (film) 961.9, 1098.2, 1154.8, 1368.3, 1725.8, 2934.6 cm" 1

Trinn C: Fremstilling av trans-( ± )- 5-( 4- fluorfenyl)-2-( 1- metvletvl)- N. 4- difenvl- 1- r 2- ftetra-hydro- 4- hydroksv- 6- okso- 2H- pyran- 2- vl) etyl]-lH- pyrrol- 3- karboksamid. Step C: Preparation of trans-( ± )- 5-( 4- fluorophenyl)-2-( 1- methylethyl)- N. 4- diphenyl- 1- r 2- ftetra-hydro- 4- hydroxy- 6- oxo- 2H-pyran-2-vl)ethyl]-1H-pyrrole-3-carboxamide.

Ved en fremgangsmåte analog med fremgangsmåte H oppnås tittelforbindelsen ved å anvende (±)-cis-1,l-dimetyletyl-4-(2-aminoetyl)-l,5-dioksaspiro[5,5]undekan-2-acetat i stedet for (±)-cis-1,l-dimetyletyl-6-(2-aminoetyl)-2,2-dimetyl-l,3-dioksan-4-acetat. In a method analogous to method H, the title compound is obtained by using (±)-cis-1,1-dimethylethyl-4-(2-aminoethyl)-1,5-dioxaspiro[5,5]undecane-2-acetate instead of (±)-cis-1,1-dimethylethyl-6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxane-4-acetate.

EKSEMPEL 3 EXAMPLE 3

f2R- trans)- 5- f4- fluorfenvl)- 2- f1- metvletvl)- N. 4- difenvl- 1- r2-( tetrahydro- 4- hydroksy- 6- okso- 2H- pyran- 2- yl) etyl]- lH- pyrrol- 3-karboksamid. f2R- trans)- 5- f4- fluorophenyl)- 2- f1- methylethyl)- N. 4- diphenyl- 1- r2-( tetrahydro- 4- hydroxy- 6- oxo- 2H- pyran- 2- yl) ethyl] - 1H-pyrrole-3-carboxamide.

FREMGANGSMÅTE A METHOD OF PROCEDURE A

Trinn A: Fremstilling av ( R)- 1, l- dimetyletvl- 6- cyano-5- f r ( 1, 1- dimetyletyl) dimetylsilyl] oksvl- 3- oksoheksanoat. Step A: Preparation of (R)-1,1-dimethylethyl-6-cyano-5-fr(1,1-dimethylethyl)dimethylsilyl]oxoyl-3-oxohexanoate.

(R)-4-cyano-3-[[(1,1-dimetyletyl)dimetylsilyl]oksy]butan-syre, 32 g (0,132 mol), oppløses i 300 ml tetrahydrofuran. Oppløsningen avkjøles til -20"C, og karbonyldiimidazol, 27 g (0,165 mol), tilsettes. Oppløsningen omrøres og står til oppvarmning til 25°C over to timer. Oppløsningen settes til en oppslemning av kalium-1,1-dimetyletylmalonat (halvt ester, halvt salt), 60 g (0,3 mol), vannfritt magnesiumklorid, 27,2 g (0,246 mol), diisopropyletylamin, 53 ml (0,3 mol) i 700 ml tørr acetonitril. Blandingen omrøres ved 5°C i 18 timer og ved 15°C i 108 timer. Blandingen helles i en blanding av 1 1 IN saltsyre og 1 1 etylacetat, og det resulterende to-fase system omrøres i 15 minutter. Lagene separeres. Det organiske lag vaskes med 500 ml mettet saltoppløsning og konsentreres for å oppnå en olje. Oljen består av (R)-l,l-dimetyletyl-6-cyano-5-[[(1,1-dimetyletyl)-dimetylsilyl]oksy]-3-oksoheksanoat og noe 1,1-dimetyletylmalonat (halvt ester, (R)-4-cyano-3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]butanoic acid, 32 g (0.132 mol), is dissolved in 300 ml of tetrahydrofuran. The solution is cooled to -20°C, and carbonyldiimidazole, 27 g (0.165 mol), is added. The solution is stirred and allowed to warm to 25°C over two hours. The solution is added to a slurry of potassium 1,1-dimethylethyl malonate (half ester , half salt), 60 g (0.3 mol), anhydrous magnesium chloride, 27.2 g (0.246 mol), diisopropylethylamine, 53 mL (0.3 mol) in 700 mL dry acetonitrile. The mixture is stirred at 5°C for 18 hours and at 15°C for 108 hours. The mixture is poured into a mixture of 1 L hydrochloric acid and 1 L ethyl acetate, and the resulting two-phase system is stirred for 15 minutes. The layers are separated. The organic layer is washed with 500 ml saturated saline and concentrated to obtain an oil. The oil consists of (R)-1,1-dimethylethyl-6-cyano-5-[[(1,1-dimethylethyl)-dimethylsilyl]oxy]-3-oxohexanoate and some 1,1- dimethyl ethyl malonate (half ester,

halvt syre) som anvendes direkte i trinn B. Oljen har akseptable NMR spektre efter fradrag av de oppnådde malonatspektre. half acid) which is used directly in step B. The oil has acceptable NMR spectra after deduction of the obtained malonate spectra.

Trinn B: Fremstilling av ( R)- 1. l- dimetyletyl- 6- cvano-5- hvdroksv- 3- okso- heksanoat. Step B: Preparation of (R)-1.1-dimethylethyl-6-cvano-5-hydroxy-3-oxo-hexanoate.

En oppløsning av rå (R)-l,l-dimetyletyl-6-cyano-5-[[(1,1-dimetyletyl)dimetylsilyl]oksy]-3-oksoheksanoat, 43 g (0,126 mol) i 350 ml tetrahydrofuran behandles med 213 ml tetrabutyl-ammoniumfluoridoppløsning (1,0 M i heksan). Den resulterende blanding omrøres i fem timer ved 25°C. Blandingen behandles med 500 ml vann, 300 ml dietyleter tilsettes, og lagene separeres. Det organiske lag tørres (magnesiumsulfat) og filtreres derefter gjennom en silikagelpropp ved hjelp av vannfri dietyleter. Oppløsningsmidlet fjernes under vakuum for å oppnå 21 g rå (R)-1,l-dimetyletyl-6-cyano-5-hydroksy-3-oksoheksanoat med akseptable NMR, MS og IR spektre. A solution of crude (R)-1,1-dimethylethyl-6-cyano-5-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-3-oxohexanoate, 43 g (0.126 mol) in 350 ml of tetrahydrofuran is treated with 213 ml tetrabutyl ammonium fluoride solution (1.0 M in hexane). The resulting mixture is stirred for five hours at 25°C. The mixture is treated with 500 ml of water, 300 ml of diethyl ether is added, and the layers are separated. The organic layer is dried (magnesium sulfate) and then filtered through a plug of silica gel using anhydrous diethyl ether. The solvent is removed under vacuum to obtain 21 g of crude (R)-1,1-dimethylethyl-6-cyano-5-hydroxy-3-oxohexanoate with acceptable NMR, MS and IR spectra.

200 MHZ NMR (CDC13) S 1,48 (s, 9H), 2,62 (m, 2H), 2,89 (d, 2H, J = 6,1), 3,43 (s, 2H), 4,41 (pentet, 2H, J = 6,1 Hz) 200 MHZ NMR (CDCl 3 ) S 1.48 (s, 9H), 2.62 (m, 2H), 2.89 (d, 2H, J = 6.1), 3.43 (s, 2H), 4 .41 (pentet, 2H, J = 6.1 Hz)

<13>C-NMR (CDC13, 50 MHz) S 25,05, 27,86, 48,03, 50,81, 63,39, 82,43, 117,03, 165,84, 202,03. <13>C-NMR (CDC13, 50 MHz) S 25.05, 27.86, 48.03, 50.81, 63.39, 82.43, 117.03, 165.84, 202.03.

MS (Kjemisk ionisering) m/e 228, 200, 172, 154. MS (Chemical ionization) m/e 228, 200, 172, 154.

FTIR (KBr) 1144,5, 1327,2, 1370,9, 1715,5, 1733,5, 2253,1, 2934,6, 2980,9, 3459,3 cm"<1>. FTIR (KBr) 1144.5, 1327.2, 1370.9, 1715.5, 1733.5, 2253.1, 2934.6, 2980.9, 3459.3 cm"<1>.

Trinn C: Fremstilling av fR-( R*, R* H- 1. 1- dimetvletyl-6- cyano- 3. 5- dihvdroksvheksanoat. Step C: Preparation of fR-( R*, R* H- 1. 1- dimethylethyl-6- cyano- 3. 5- dihydroxhexanoate).

Rå (R)-1,l-dimetyletyl-6-cyano-5-hydroksy-3-oksoheksanoat, 21 g (0,0924 mol), oppløses i 940 ml tetrahydrofuran og 190 ml metanol under nitrogenatmosfære. Denne oppløsning avkjøles til -85°C, og 95 ml 15% oppløsning av metoksydietylboran i tetrahydrofuran tilsettes. Reaksjonen avkjøles til -97"C og 6,5 g (0,172 mol) natriumborhydrid tilsettes i 0,5 g porsjoner over 1,5 timer. Reaksjonen holdes mellom -93°C og -97 °C i 13 timer og står til oppvarmning til romtemperatur og står under nitrogenatmosfære i 60 timer. Reaksjonen stanses ved tilsetning av 25 ml (0,395 mol) eddiksyre og konsentreres ved vakuumdestillasjon til en olje. Residuet oppløses med 500 ml metanol, konsentreres ved hjelp av vakuumdestillasjon, oppløses påny med 500 ml metanol og konsentreres påny ved hjelp av vakuumdestillasjon for å oppnå en mørk, brun olje. Denne olje tas opp i 500 ml etylacetat og filtreres gjennom en propp av silikagel ved hjelp av 250 ml etylacetat. Oppløsningen inndampes for å oppnå 15 g rå [R-(R*,R*)]-1,l-dimetyletyl-6-cyano-3,5-dihydroksyheksanoat som anvendes uten ytterligere rensning. Crude (R)-1,1-dimethylethyl-6-cyano-5-hydroxy-3-oxohexanoate, 21 g (0.0924 mol), is dissolved in 940 ml of tetrahydrofuran and 190 ml of methanol under a nitrogen atmosphere. This solution is cooled to -85°C, and 95 ml of a 15% solution of methoxydiethylborane in tetrahydrofuran is added. The reaction is cooled to -97°C and 6.5 g (0.172 mol) sodium borohydride is added in 0.5 g portions over 1.5 hours. The reaction is kept between -93°C and -97°C for 13 hours and allowed to warm to room temperature and stand under a nitrogen atmosphere for 60 hours. The reaction is stopped by the addition of 25 ml (0.395 mol) of acetic acid and concentrated by vacuum distillation to an oil. The residue is dissolved in 500 ml of methanol, concentrated by means of vacuum distillation, redissolved in 500 ml of methanol and concentrated again by vacuum distillation to give a dark brown oil. This oil is taken up in 500 ml of ethyl acetate and filtered through a plug of silica gel using 250 ml of ethyl acetate. The solution is evaporated to give 15 g of crude [R-(R* ,R*)]-1,1-dimethylethyl-6-cyano-3,5-dihydroxyhexanoate which is used without further purification.

Trinn D: Fremstilling av ( 4R- cis)- 1. l- dimetvletvl- 6-cyanometyl- 2. 2- dimetyl- l. 3- dioksan- 4- acetat. Step D: Preparation of (4R-cis)-1.1-dimethylethyl-6-cyanomethyl-2.2-dimethyl-1.3-dioxane-4-acetate.

Rå [R-(R ,R )]-1,l-dimetyletyl-6-cyano-3,5-dihydroksy-heksanoat, 15 g (61 mol), oppløses i 150 ml 2,2-dimetoksypropan, kamfersulfonsyre tilsettes, og oppløsningen omrøres i 18 timer ved romtemperatur. Konsentrasjon og lynkromatografi efter konsentrasjon i vakuum gir 11,8 g (4R-cis)-l,l-dimetyletyl-6-cyanometyl-2,2-dimetyl-l,3-dioksan-4-acetat som et off-white fast stoff, Crude [R-(R ,R )]-1,1-dimethylethyl-6-cyano-3,5-dihydroxyhexanoate, 15 g (61 mol), is dissolved in 150 ml of 2,2-dimethoxypropane, camphorsulfonic acid is added, and the solution is stirred for 18 hours at room temperature. Concentration and flash chromatography after concentration in vacuo gives 11.8 g of (4R-cis)-1,1-dimethylethyl-6-cyanomethyl-2,2-dimethyl-1,3-dioxane-4-acetate as an off-white solid ,

smp. 64,7-68"C med akseptable IR, NMR, C-NMR og analyse. m.p. 64.7-68"C with acceptable IR, NMR, C-NMR and analysis.

200 MHz NMR (CDC13) S 1,36 (m, 1H) , 1,42 (s, 3H) , 1,49 (s, 9H), 1,50 (S, 3H), 1,79 (dt, 1H, J = 2>5 Hz, J = 12,1 Hz), 2,40 (dd, 1H, J = 6,2 Hz, J = 15,4 Hz), 2,5 - 2,7 (m, 1H), 2,55 (d, 2H, J = 6,1 Hz), 4,18 (m, 1H), 4,32 (m, 1H). 200 MHz NMR (CDCl 3 ) S 1.36 (m, 1H), 1.42 (s, 3H), 1.49 (s, 9H), 1.50 (S, 3H), 1.79 (dt, 1H , J = 2>5 Hz, J = 12.1 Hz), 2.40 (dd, 1H, J = 6.2 Hz, J = 15.4 Hz), 2.5 - 2.7 (m, 1H ), 2.55 (d, 2H, J = 6.1 Hz), 4.18 (m, 1H), 4.32 (m, 1H).

<13>C-NMR (CDC13, 50 MHz) S 19,74, 25,09, 28,24, 29,88, 35,58, 42,50, 65,20, 65,81, 80,87, 99,48, 116,68, 169,75. <13>C-NMR (CDC13, 50 MHz) S 19.74, 25.09, 28.24, 29.88, 35.58, 42.50, 65.20, 65.81, 80.87, 99 .48, 116.68, 169.75.

GC/MS m/e 254, 198, 154, 138, 120, 59, 57, 43, 41. GC/MS m/e 254, 198, 154, 138, 120, 59, 57, 43, 41.

FTIR (KBr) 941,4, 1116,2, 1154,8, 1188,3, 1257,7, 1293,7, 1309,1, 1368,3, 1725,8, 2361,1, 2983,5, 2996,4 cm"<1>. FTIR (KBr) 941.4, 1116.2, 1154.8, 1188.3, 1257.7, 1293.7, 1309.1, 1368.3, 1725.8, 2361.1, 2983.5, 2996, 4 cm"<1>.

Trinn E: Fremstilling av ( 4R- cis)- 1. l- dimetyletyl- 6-( 2- aminoetyl)- 2. 2- dimetyl- l. 3- dioksan- 4- acetat. Step E: Preparation of (4R-cis)-1.1-dimethylethyl-6-(2-aminoethyl)-2.2-dimethyl-1.3-dioxane-4-acetate.

En oppløsning av (4R-cis)-1,l-dimetyletyl-6-cyanometyl-2 , 2-dimetyl-l, 3-dioksan-4-acetat, 5,63 g (0,048 mol), i 100 ml metanol mettet med gassformig ammoniakk behandles med 0,5 g Raney-nikkel #30 og hydrogengass i en rystekolbe ved 50 psi og 40°C. Efter 16 timer viser tynnskiktskromatografi ingen tilstedeværelse av utgangsnitril. Suspensjonen avkjøles, filtreres gjennom filterhjelp og konsentreres til en olje. Denne rå olje renses ved lynkromatograf i på silikagel med 30:20:1 (etylacetat:metanol:ammoniumhydroksyd) som elueringsmiddel for å oppnå 4,93 g (4R-cis)-1,l-dimetyletyl-6-(2-aminoetyl)-2,2-dimetyl-l,3-dioksan-4-acetat (98,2 areal %) som en klar olje med akseptable IR, NMR, C-NMR og MS spektre. A solution of (4R-cis)-1,1-dimethylethyl-6-cyanomethyl-2,2-dimethyl-1,3-dioxane-4-acetate, 5.63 g (0.048 mol), in 100 ml of methanol saturated with gaseous ammonia is treated with 0.5 g Raney nickel #30 and hydrogen gas in a shake flask at 50 psi and 40°C. After 16 hours, thin-layer chromatography shows no presence of starting nitrile. The suspension is cooled, filtered through filter aid and concentrated to an oil. This crude oil is purified by flash chromatography on silica gel with 30:20:1 (ethyl acetate:methanol:ammonium hydroxide) as eluent to obtain 4.93 g of (4R-cis)-1,1-dimethylethyl-6-(2-aminoethyl) -2,2-dimethyl-1,3-dioxane-4-acetate (98.2 area %) as a clear oil with acceptable IR, NMR, C-NMR and MS spectra.

200 MHZ NMR (CDC13) 1,0 - 1,2 (m, 1H), 1,22 (s, 3H), 1,31 (s, 12 H), 1,35 - 1,45 (m, 3H), 2,15 (dd, 1H, J = 15,1 Hz, J = 6,2 Hz), 2,29 (dd, 1H, J = 15,1 Hz, J = 7,0 Hz), 2,66 (t, 2H, J = 6,6 Hz), 3,82 (m, 1H), 4,12 (m, 1H). 200 MHZ NMR (CDCl 3 ) 1.0 - 1.2 (m, 1H), 1.22 (s, 3H), 1.31 (s, 12H), 1.35 - 1.45 (m, 3H) , 2.15 (dd, 1H, J = 15.1 Hz, J = 6.2 Hz), 2.29 (dd, 1H, J = 15.1 Hz, J = 7.0 Hz), 2.66 (t, 2H, J = 6.6 Hz), 3.82 (m, 1H), 4.12 (m, 1H).

<13>C-NMR (CDC13, 50 MHz) S 19,60, 27,96, 30,00, 36,50, 38,25, 39,79, 42,61, 66,08, 67,18, 80,21, 98,35, 169,82. <13>C-NMR (CDC13, 50 MHz) S 19.60, 27.96, 30.00, 36.50, 38.25, 39.79, 42.61, 66.08, 67.18, 80 .21, 98.35, 169.82.

GC/MS m/e 202, 200, 173, 158, 142, 140, 114, 113, 100, 99, 97, 72, 57. GC/MS w/e 202, 200, 173, 158, 142, 140, 114, 113, 100, 99, 97, 72, 57.

FTIR (rent) 951,6, 1159,9, 1201,1, 1260,3, 1314,3, 1368,3, 1381,2, 1731,0, 2870,3, 2939,8, 2980,9, 3382,2 cm"<1.>FTIR (neat) 951.6, 1159.9, 1201.1, 1260.3, 1314.3, 1368.3, 1381.2, 1731.0, 2870.3, 2939.8, 2980.9, 3382, 2 cm"<1.>

Trinn F: Fremstilling av ( 4R- cis)- 1. l- dimetyletvl- 6-r2 r2-( 4- fluorfenvl)- 5-( 1- metvletvl)- 3- fenvl- 4-f f fenvlamino) karbonyl1- lH- pyrrol- l- yl1 etyl1-2.2-dimetvl- 1. 3- dioksan- 4- acetat. Step F: Preparation of (4R-cis)-1.1-Dimethylethyl-6-r2r2-(4-fluorophenyl)-5-(1-methylethyl)-3-phenyl-4-f fphenylamino)carbonyl1-1H-pyrrole - 1-yl-1-ethyl-1-2.2-dimethyl-1.3-dioxan-4-acetate.

En oppløsning av (4R-cis)-1,l-dimetyletyl-6-(2-aminoetyl)-2,2-dimetyl-l,3-dioksan-4-acetat, 1,36 g (4,97 mol), og (±) -4-fluor-a-[2-metyl-l-oksopropyl]-'y-okso-N,0-difenylbenzenbutanamidblanding av [R-(R*,R*)], [R-(R*,S*)], A solution of (4R-cis)-1,1-dimethylethyl-6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxane-4-acetate, 1.36 g (4.97 mol), and (±)-4-fluoro-α-[2-methyl-1-oxopropyl]-γ-oxo-N,0-diphenylbenzenebutanamide mixture of [R-(R*,R*)], [R-(R* ,S*)],

[S-(R*,R*)] og [S-(R*,S*)]isomerer, 1,60 g (3,83 mol), i 50 ml heptan:toluen (9:1) oppvarmes ved tilbakeløpskjøling i 24 timer. Oppløsningen avkjøles lett, og 15 ml 2-propanol tilsettes. Blandingen står til avkjøling til 25°C og filtreres for å oppnå 1,86 g (4R-cis)-l,l-dimetyletyl-6-[2[2-(4-fluorfenyl)-5-(1-metyletyl)-3-fenyl-4-[(fenylamino)karbonyl]-lH-pyrrol-l-yl]etyl]-2,2-dimetyl-l,3-dioksan-4-acetat som et gult fast stoff med akseptable PNMR & C-NMR spektre. [S-(R*,R*)] and [S-(R*,S*)]isomers, 1.60 g (3.83 mol), in 50 ml heptane:toluene (9:1) is heated at reflux for 24 hours. The solution is cooled slightly, and 15 ml of 2-propanol is added. The mixture is allowed to cool to 25°C and filtered to obtain 1.86 g of (4R-cis)-1,1-dimethylethyl-6-[2[2-(4-fluorophenyl)-5-(1-methylethyl)- 3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrol-1-yl]ethyl]-2,2-dimethyl-1,3-dioxane-4-acetate as a yellow solid with acceptable PNMR & C- NMR spectra.

^H-NMR (CDC13, 200 MHz) { 1 - 1,7 (m, 5H), 1,30 (s, 3H), 1,36 (S, 3H) , 1,43 (S, 9H), 1,53 (d, 6H, J = 7,1 Hz) , 2,23 (dd, 1H, J = 15,3 HZ, J = 6,3 Hz), 2,39 (dd, 1H, J = 15,3 Hz, J = 6,3 HZ), 3,5 - 3,9 (m, 3H) , 4,0 -4,2 (m, 2H), 6,8 -7,3 (m, 14H) . ^H-NMR (CDCl 3 , 200 MHz) { 1 - 1.7 (m, 5H), 1.30 (s, 3H), 1.36 (S, 3H), 1.43 (S, 9H), 1 .53 (d, 6H, J = 7.1 Hz) , 2.23 (dd, 1H, J = 15.3 HZ, J = 6.3 Hz), 2.39 (dd, 1H, J = 15, 3 Hz, J = 6.3 HZ), 3.5 - 3.9 (m, 3H), 4.0 - 4.2 (m, 2H), 6.8 - 7.3 (m, 14H).

<13>C-NMR (CDC13, 50 MHz) <S 19,69, 21,60, 21,74, 26,12, 27,04, 28,12, 29,95, 36,05, 38,10, 40,89, 42,54, 65,92, 66,46, 80,59, 98,61, 115,00, 115,34, 115,42, 119,52, 121,78, 123,36, 126,44, 128,21, 128,31, 128,52, 128,75, 130,43, 133,01, 133,17, 134,69, 138,38, 141,47, 159,72, 164,64, 169,96. <13>C-NMR (CDC13, 50 MHz) <S 19.69, 21.60, 21.74, 26.12, 27.04, 28.12, 29.95, 36.05, 38.10, 40.89, 42.54, 65.92, 66.46, 80.59, 98.61, 115.00, 115.34, 115.42, 119.52, 121.78, 123.36, 126, 44, 128.21, 128.31, 128.52, 128.75, 130.43, 133.01, 133.17, 134.69, 138.38, 141.47, 159.72, 164.64, 169.96.

Trinn G: Fremstilling av ( 2R- trans)- 5-( 4- fluorfenyl)-2-( 1- metyletvl)- N. 4- difenyl- l- r 2-( tetrahydro-4- hydroksy- 6- okso- 2H- pyran- 2- vi) etyl]- lH- pyrrol- 3-karboksamid. Step G: Preparation of ( 2R- trans )- 5-( 4- fluorophenyl)-2-( 1- methylethyl)- N. 4- diphenyl- 1- r 2-( tetrahydro-4- hydroxy- 6- oxo- 2H - pyran-2-vi)ethyl]-1H-pyrrole-3-carboxamide.

(4R-cis)-1,l-dimetyletyl-6-[2[2-(4-fluorfenyl)-5-(l-metyletyl)-3-fenyl-4-[(fenylamino)-karbonyl]-lH-pyrrol-l-yl]etyl]-2,2-dimetyl-l,3-dioksan-4-acetat, 4,37 g (6,68 mol), oppløses i 200 ml tetrahydrofuran, og 15 ml 10% saltsyreoppløsning tilsettes, og oppløsningen omrøres i 15 timer. Til denne oppløsning settes natriumhydroksyd (3,6 g), og blandingen omrøres i 30 timer. Reaksjonen stanses ved tilsetning av 150 ml vann, 90 ml heksan, og lagene separeres. Det vandige lag gjøres surt med fortynnet saltsyreoppløsning, omrøres i tre timer og ekstraheres med 150 ml etylacetat. En dråpe konsentrert saltsyre settes til etylacetatoppløsningen, (4R-cis)-1,1-dimethylethyl-6-[2[2-(4-fluorophenyl)-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)-carbonyl]-1H-pyrrole -1-yl]ethyl]-2,2-dimethyl-1,3-dioxane-4-acetate, 4.37 g (6.68 mol), is dissolved in 200 ml of tetrahydrofuran, and 15 ml of 10% hydrochloric acid solution is added, and the solution is stirred for 15 hours. Sodium hydroxide (3.6 g) is added to this solution, and the mixture is stirred for 30 hours. The reaction is stopped by adding 150 ml of water, 90 ml of hexane, and the layers are separated. The aqueous layer is acidified with dilute hydrochloric acid solution, stirred for three hours and extracted with 150 ml of ethyl acetate. A drop of concentrated hydrochloric acid is added to the ethyl acetate solution,

og oppløsningen står i 18 timer. Oppløsningen konsentreres i vakuum, og konsentratet oppløses påny i 50 ml etylacetat og behandles med én dråpe konsentrert saltsyre. Oppløsningen omrøres i to timer, konsentreres i vakuum og oppløses i 3,0 ml toluen. (2R-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 (3,01 g) isoleres i to utbytter. and the solution stands for 18 hours. The solution is concentrated in vacuo, and the concentrate is redissolved in 50 ml of ethyl acetate and treated with one drop of concentrated hydrochloric acid. The solution is stirred for two hours, concentrated in vacuo and dissolved in 3.0 ml of toluene. (2R-trans)-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2- yl)ethyl]-1H-pyrrole-3-carboxamide (3.01 g) is isolated in two yields.

FREMGANGSMÅTE B PROCEDURE B

En oppløsning av (4R-cis)-1,l-dimetyletyl-6-(2-aminoetyl)-2,2-dimetyl-l,3-dioksan-4-acetat, 2,56 g (9,36 mol), og (±)-4-fluor-a-[2-metyl-l-oksopropyl]-'Y-okso-N,j8-difenylbenzenbutanamidblanding av [R-(R*,R*)], [R-(R*,S*)], [S-(R*,R*)] og [S-(R*,S*)]-isomerer, 3,00 g (7,20 mol), i 60 ml heptan:toluen (9:1) oppvarmes ved tilbakeløpskjøling i 24 timer. Oppløsningen avkjøles og helles i 300 ml tetrahydrofuran og 150 ml mettet ammoniumklorid i vann. Lagene separeres, og det organiske lag settes til 15 ml 10% saltsyreoppløsning, og oppløsningen omrøres i 15 timer. Til denne oppløsning settes natriumhydroksyd (3,6 g), og blandingen omrøres i 30 timer. Reaksjonen stanses ved tilsetning av 150 ml vann, 90 ml heksan, og lagene separeres. Det vandige lag gjøres surt med fortynnet saltsyreoppløsning, omrøres i tre timer og ekstraheres med 150 ml etylacetat. En dråpe konsentrert saltsyre settes til etylacetatoppløsningen, og oppløsningen står i 18 timer. Oppløsningen konsentreres i vakuum, og konsentratet oppløses påny i 50 ml etylacetat og behandles med én dråpe konsentrert saltsyre. Oppløsningen omrøres i to timer, konsentreres i vakuum og oppløses i 3,0 ml toluen. (2R-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 (2,92 g) isoleres i to utbytter. A solution of (4R-cis)-1,1-dimethylethyl-6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxane-4-acetate, 2.56 g (9.36 mol), and (±)-4-fluoro-a-[2-methyl-1-oxopropyl]-'Y-oxo-N,j8-diphenylbenzenebutanamide mixture of [R-(R*,R*)], [R-(R* ,S*)], [S-(R*,R*)] and [S-(R*,S*)] isomers, 3.00 g (7.20 mol), in 60 mL heptane:toluene ( 9:1) is heated by reflux cooling for 24 hours. The solution is cooled and poured into 300 ml of tetrahydrofuran and 150 ml of saturated ammonium chloride in water. The layers are separated, and the organic layer is added to 15 ml of 10% hydrochloric acid solution, and the solution is stirred for 15 hours. Sodium hydroxide (3.6 g) is added to this solution, and the mixture is stirred for 30 hours. The reaction is stopped by adding 150 ml of water, 90 ml of hexane, and the layers are separated. The aqueous layer is acidified with dilute hydrochloric acid solution, stirred for three hours and extracted with 150 ml of ethyl acetate. A drop of concentrated hydrochloric acid is added to the ethyl acetate solution, and the solution stands for 18 hours. The solution is concentrated in vacuo, and the concentrate is redissolved in 50 ml of ethyl acetate and treated with one drop of concentrated hydrochloric acid. The solution is stirred for two hours, concentrated in vacuo and dissolved in 3.0 ml of toluene. (2R-trans)-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2- yl)-ethyl]-1H-pyrrole-3-carboxamide (2.92 g) is isolated in two yields.

FREMSTILLING AV UTGANGSMATERIALER MANUFACTURE OF STARTING MATERIALS

EKSEMPEL A EXAMPLE A

1-( 4- fluorfenvl)- 1. 4- heksandion. 1-(4-fluorophenyl)-1.4-hexanedione.

En blanding av 36,61 g (295 mmol) 4-fluorbenzaldehyd, 25 A mixture of 36.61 g (295 mmol) of 4-fluorobenzaldehyde, 25

g (297,2 mmol) etylvinylketon, 29 ml (206,9 mmol) trietylamin og 11,94 g (44,25 mmol) 3-benzyl-5-(2-hydroksyetyl)-4-metyl-tiazoliumklorid omrøres og oppvarmes ved 70°C i seks timer. g (297.2 mmol) ethyl vinyl ketone, 29 ml (206.9 mmol) triethylamine and 11.94 g (44.25 mmol) 3-benzyl-5-(2-hydroxyethyl)-4-methyl-thiazolium chloride are stirred and heated at 70°C for six hours.

Den avkjølte oppløsning fortynnes med 2 liter dietyleter og The cooled solution is diluted with 2 liters of diethyl ether and

vaskes med 2 x 300 ml vann, 2 x 100 ml 2M saltsyre, 100 ml vann, 200 ml mettet oppløsning av natriumbikarbonat og salt- washed with 2 x 300 ml water, 2 x 100 ml 2M hydrochloric acid, 100 ml water, 200 ml saturated solution of sodium bicarbonate and saline

vann. Det organiske lag separeres, tørres (magnesiumsulfat), filtreres og konsentreres for å oppnå 55 g 1-(4-fluorfenyl)-1,4-heksandion efter omkrystallisasjon fra metanol, water. The organic layer is separated, dried (magnesium sulfate), filtered and concentrated to obtain 55 g of 1-(4-fluorophenyl)-1,4-hexanedione after recrystallization from methanol,

smp. 56-57°C. m.p. 56-57°C.

EKSEMPEL B EXAMPLE B

4- metyl- 3- okso- N- fenylpentanamid 4- methyl- 3- oxo- N- phenylpentanamide

I en trehalset, 12 1 rundbundet kolbe utstyrt med en In a three-necked, 12 1 round-bottomed flask fitted with a

mekanisk omrører, et termometer og installasjon til destillasjon fylles 2,6 1 toluen, 1,73 kg (12 mol) metyl-4-metyl-3-oksopentanoat og 72 g (1,18 mol) etylendiamin. mechanical stirrer, a thermometer and installation for distillation are filled with 2.6 l toluene, 1.73 kg (12 mol) methyl-4-methyl-3-oxopentanoate and 72 g (1.18 mol) ethylenediamine.

Blandingen oppvarmes til 80"C, og det påfylles 0,49 kg anilin. Blandingen bringes til tilbakeløpskjøling, og destillasjon påbegynnes. Efter 40 minutter påfylles ytterligere 0,245 kg anilin, og med 40 minutters intervaller påfylles ytterligere to porsjoner anilin (0,245 og 0,25 kg). Destillasjon fortsettes i ytterligere én til fem timer, inntil en total på The mixture is heated to 80°C, and 0.49 kg of aniline is added. The mixture is refluxed, and distillation is started. After 40 minutes, a further 0.245 kg of aniline is added, and at 40 minute intervals two further portions of aniline (0.245 and 0.25 kg.) Distillation is continued for a further one to five hours, until a total of

985 ml oppløsningsmiddel er fjernet. Oppløsningen omrøres ved romtemperatur i 16 timer, og ytterligere 550 ml oppløsningsmiddel fjernes ved destillasjon i vakuum (under anvendelse av ca. 85 mm Hg). Blandingen avkjøles, og 2 1 vann påfylles for å oppnå en olje. Blandingen oppvarmes til 40"C, 985 ml of solvent has been removed. The solution is stirred at room temperature for 16 hours, and an additional 550 ml of solvent is removed by distillation in vacuo (using about 85 mm Hg). The mixture is cooled, and 2 1 of water is added to obtain an oil. The mixture is heated to 40"C,

og ytterligere 1,0 1 vann påfylles. Syvhundrede milliliter toluen-vann-blanding fjernes ved destillasjon i vakuum (ca. 20 and a further 1.0 1 of water is added. Seven hundred milliliters of the toluene-water mixture is removed by vacuum distillation (approx. 20

mm Hg). To liter vann påfylles, og blandingen står i 10 dager. Produktet isoleres ved filtrering og vaskes med tre porsjoner heksan. Tørring i vakuum gir 1,7 kg 4-metyl-3-okso-N-fenylpentanamid som et hydrat, mm Hg). Two liters of water are added, and the mixture stands for 10 days. The product is isolated by filtration and washed with three portions of hexane. Drying in vacuo gives 1.7 kg of 4-methyl-3-oxo-N-phenylpentanamide as a hydrate,

smp. 46,5-58,8°C. m.p. 46.5-58.8°C.

HPLC: 98,8% - retensjonstid 3,56 min. 65/35 acetonitril/vann på tørr basis. HPLC: 98.8% - retention time 3.56 min. 65/35 acetonitrile/water on a dry basis.

VPC: 87,6% - retensjonstid 12,43 min. også 10,8% anilin (dek.). VPC: 87.6% - retention time 12.43 min. also 10.8% aniline (dec.).

Claims (4)

1. Fremgangsmåte for fremstilling av en forbindelse med formel I og en dihydroksysyre og farmasøytisk akseptable salter derav svarende til den åpnede laktonring av en forbindelse med formel I, hvor R^ er1. Method for producing a compound with formula I and a dihydroxy acid and pharmaceutically acceptable salts thereof corresponding to the opened lactone ring of a compound of formula I, where R^ is 1- naftyl,1- naphthyl, 2- naftyl, fenyl eller fenyl substituert med fluor, klor eller brom, R2 eller R3 uavhengig av hverandre er hydrogen, fenyl eller -CONHR-, hvor R_ er O D fenyl, R. er 4 er alkyl med ett til seks karbonatomer, karakterisert ved at man (a) omsetter 1,6-heptadien-4-ol med (1) alkyllitium (2) efterfulgt av jod og karbondioksyd og (3) behandler det resulterende jodkarbonatmellom- produkt in situ med en base i en vandig alkohol ved 0°C til 40°C for å oppnå en forbindelse med formel IX, (b) behandler forbindelsen med formel IX med2- naphthyl, phenyl or phenyl substituted with fluoride, chlorine or bromine, R2 or R3 independently of each other is hydrogen, phenyl or -CONHR-, where R_ is O. D phenyl, R. is 4 is alkyl of one to six carbon atoms, characterized by (a) reacting 1,6-heptadien-4-ol with (1) alkyllithium (2) followed by iodine and carbon dioxide and (3) treating the resulting iodocarbonate intermediate product in situ with a base in an aqueous alcohol at 0°C to 40°C to obtain a compound of formula IX, (b) treating the compound of formula IX with (1) en alkalicyanid ved 0°C til 40°C og(1) an alkali cyanide at 0°C to 40°C and (2) omsetter det resulterende diolmellomprodukt in situ med et ketaldannende reagens i nærvær av en syre for å oppnå en forbindelse med formel VIII hvor R7 og Rg uavhengig av hverandre er hydrogen, alkyl med ett til tre karbonatomer, fenyl eller R? og Rg danner sammen - (CH2)n -, hvor n er 4 eller 5, (c) behandler forbindelsen med formel VIII med(2) reacting the resulting diol intermediate in situ with a ketal-forming reagent in the presence of an acid to obtain a compound of formula VIII where R7 and Rg independently of each other are hydrogen, alkyl with one to three carbon atoms, phenyl or R? and Rg together form - (CH2)n -, where n is 4 or 5, (c) treating the compound of formula VIII with (1) ozon i .et inert oppløsningsmiddel og(1) ozone in .an inert solvent and (2) omsetter det resulterende mellomprodukt in situ med oksygen og trifenylfosfin ved -20°C til - 78°C for å oppnå en forbindelse med formel VII hvor R7 og Rg er som ovenfor definert, (d) behandler forbindelsen med formel VII med et oksydasjonsmiddel ved ca. 0°C for å oppnå en forbindelse med formel VI hvor R_ og R_ er som ovenfor definert, / o (e) behandler forbindelsen med formel VI med en forbindelse med formel hvor Hal er halogen, og R y a er alkyl med ett til åtte karbonatomer eller en tre- til seksleddet cykloalkylgruppe, i nærvær av en base for å oppnå en forbindelse med formel V a hvor R7, Rg og Rga er som ovenfor definert, eller behandler forbindelsen med formel VI med en forbindelse med formel hvor R^ er tertiær butyl, tertiær amyl eller a,a-dimetylbenzyl, i nærvær av et aktiveringsmiddel, en katalytisk mengde av en base og et inert oppløsningsmiddel for å oppnå en forbindelse med formel V^ hvor Ry, Rg og Rgfo er som ovenfor definert, (f) behandler forbindelsen med formel V clmed hydrogen i nærvær av en katalysator og en syre ved 0°C til 70°C for å oppnå en forbindelse med formel IV hvor R_, R_ og Rn er som ovenfor definert, 7 8 3 9a eller behandler forbindelsen med formel V^ med hydrogen i nærvær av en katalysator og en syre eller en katalysator og en base ved 0°C til 70°C for å oppnå en forbindelse med formel IV^ hvor R?, Rg og R9b er som ovenfor definert, (g) behandler forbindelsen med formel IV 3.med en for- bindelse med formel III hvor R , R2, R3 og R4 er som ovenfor definert i et inert oppløsningsmiddel for å oppnå en forbindelse med formel II a hvor Rlf R2, R3, R4, R<7,><Rg> og RQa er som ovenfor definert, eller behandler forbindelsen med formel IV. b med en forbindelse med formel III i et inert oppløsningsmiddel for å oppnå en forbindelse med formel 11^ hvor Rlf R2, R3, R4, R7, Rg og Rgb er som ovenfor definert, (h) og endelig behandler en forbindelse med formel IIa med (1) en syre i nærvær av et inert oppløsningsmiddel (2) efterfulgt av hydrolyse med en base (3) efterfulgt av nøytralisering med en syre og (4) oppløsning og/eller oppvarmning i et inert oppløsningsmiddel under samtidig fjernelse av vann for å oppnå en forbindelse med formel I, eller behandler en forbindelse med formel Ilb med (1) en syre i nærvær av et inert oppløsningsmiddel (2) efterfulgt av tilsetning av en base (3) efterfulgt av nøytralisering med en syre og (4) oppløsning og/eller oppvarmning i et inert oppløsningsmiddel under samtidig fjernelse av vann for å oppnå en forbindelse med formel I, (i) og eventuelt omdanner den resulterende forbindelse med formel I til en dihydroksysyre svarende til den åpnede laktonring av strukturformel I ved hjelp av konvensjonell hydrolyse og ytterligere eventuelt omdanner dihydroksysyren til et tilsvarende farma-søytisk akseptabelt salt på konvensjonell måte og, såfremt det ønskes, omdanner det tilsvarende farma-søytisk akseptable salt til en dihydroksysyre på konvensjonell måte og, såfremt det ønskes, omdanner dihydroksysyren til en forbindelse med formel I ved oppvarmning i et inert oppløsningsmiddel. (2) reacting the resulting intermediate in situ with oxygen and triphenylphosphine at -20°C to -78°C to obtain a compound of formula VII wherein R7 and Rg are as defined above, (d) treating the compound of formula VII with a oxidizing agent at approx. 0°C to obtain a compound of formula VI where R_ and R_ are as defined above, / o (e) treats the compound of formula VI with a compound of formula wherein Hal is halogen, and R y a is alkyl of one to eight carbon atoms or a three to six membered cycloalkyl group, in the presence of a base to obtain a compound of formula V a where R7, Rg and Rga are as defined above, or treat the compound of formula VI with a compound of formula where R^ is tertiary butyl, tertiary amyl or α,α-dimethylbenzyl, in the presence of an activating agent, a catalytic amount of a base and an inert solvent to obtain a compound of formula V^ where Ry, Rg and Rgfo are as defined above, (f) treating the compound of formula V with hydrogen in the presence of a catalyst and an acid at 0°C to 70°C to obtain a compound of formula IV where R_, R_ and Rn are as defined above, 7 8 3 9a or treating the compound of formula V^ with hydrogen in the presence of a catalyst and an acid or a catalyst and a base at 0°C to 70°C to obtain a compound of formula IV^ where R?, Rg and R9b are as defined above, (g) treating the compound of formula IV 3. with a pre- bond of formula III where R , R 2 , R 3 and R 4 are as defined above in an inert solvent to obtain a compound of formula II a where Rlf R2, R3, R4, R<7,><Rg> and RQa are as defined above, or treating the compound of formula IV. b with one compound of formula III in an inert solvent to obtain a compound of formula II where Rlf R2, R3, R4, R7, Rg and Rgb are as defined above, (h) and finally treating a compound of formula IIa with (1) an acid in the presence of an inert solvent (2) followed by hydrolysis with a base (3) followed by neutralization with an acid and (4) dissolution and/or heating in an inert solvent while simultaneously removing water to obtain a compound of formula I, or treating a compound of formula IIb with (1) an acid in the presence of an inert solvent (2) followed by addition of a base (3) followed by neutralization with an acid and (4) dissolving and/or heating in an inert solvent while simultaneously removing water to obtain a compound of formula I, (i) and optionally converting the resulting compound of formula I into a dihydroxy acid corresponding to the opened lactone ring of structural formula I by means of conventional hydrolysis and further optionally converting the dihydroxy acid into a corresponding pharmaceutically acceptable salt in a conventional manner and, if desired, converting the corresponding pharmaceutically acceptable salt to a dihydroxy acid of conventional manner and, if desired, converts the dihydroxy acid to a compound of formula I by heating in an inert solvent. 2. Fremgangsmåte ifølge krav 1, karakterisert ved at a) alkyllitium i trinn (a) er n-butyllitium, og/eller b) alkalicyanid i trinn (b) er kaliumcyanid, og/eller c) oksydasjonsreagenset i trinn (d) er kromtrioksyd-svovelsyre-vann, og/eller d) katalysatoren i trinn (f) for fremstilling av en forbindelse med formel IV a. er platinadioksyd, og/eller e) katalysatoren og basen i trinn (f) for fremstilling av en forbindelse med formel IV^ er henholdsvis Raney-nikkel og vannfri ammoniakk, og/eller f) syren i trinn (h) er saltsyre, og/eller g) basen i trinn (h) er natriumhydroksyd. 2. Method according to claim 1, characterized in that a) alkyllithium in step (a) is n-butyllithium, and/or b) alkali cyanide in step (b) is potassium cyanide, and/or c) the oxidation reagent in step (d) is chromium trioxide-sulfuric acid-water, and/ or d) the catalyst in step (f) for the preparation of a compound of formula IV a. is platinum dioxide, and/or e) the catalyst and the base in step (f) for the preparation of a compound of formula IV^ are respectively Raney nickel and anhydrous ammonia, and/or f) the acid in step (h) is hydrochloric acid, and/or g) the base in step (h) is sodium hydroxide. 3. Forbindelse med formel II karakterisert ved at R^ er 1- naftyl, 2- naftyl, fenyl eller fenyl substituert med fluor, klor eller brom, R2 eller R3 uavhengig av hverandre er hydrogen, fenyl, -CONHR-, hvor R, er fenyl, R. er 4 alkyl med ett til seks karbonatomer, R_ og R_ uavhengig av hverandre er hydrogen, alkyl med ett til tre karbonatomer, fenyl, eller R? og Rg sammen er ~(CH2^n~' hvor n er 4 eller 5; og Ry. er alkyl med ett til åtte karbonatomer, en tre- til seksleddet cykloalkylgruppe eller a,a-dimetylbenzyl. 3. Compound of formula II characterized in that R^ is 1-naphthyl, 2-naphthyl, phenyl or phenyl substituted with fluoride, chlorine or bromine, R2 or R3 independently of each other is hydrogen, phenyl, -CONHR-, where R, is phenyl, R. is 4 alkyl of one to six carbon atoms, R_ and R_ independently of each other are hydrogen, alkyl of one to three carbon atoms, phenyl, or R? and Rg together are ~(CH2^n~' where n is 4 or 5; and Ry. is alkyl of one to eight carbon atoms, a three- to six-membered cycloalkyl group, or α,α-dimethylbenzyl. 4. Forbindelse ifølge krav 3, karakterisert ved at a) R-, og RQ er metyl, R_ er tertiær butyl, og de to / o y optisk aktive sentre er R, eller b) R^^ er 4-fluorfenyl, <R>2 og R3 er hydrogen, R4 er etyl, R„ og RQ er metyl, og RQ er isopropyl, eller / o y c) Rx er 4-fluorfenyl, R2 er fenyl, R3 er CgH^NHCO-, R4 er isopropyl, R? og RQ er metyl, og Rg er tertiær butyl, og d) de to optisk aktive sentre under c) er R.4. Connection according to claim 3, characterized in that a) R- and RQ are methyl, R_ is tertiary butyl, and the two / o y optically active centers are R, or b) R^^ is 4-fluorophenyl, <R>2 and R3 are hydrogen, R4 is ethyl, R„ and RQ are methyl, and RQ is isopropyl, or / o y c) Rx is 4-fluorophenyl, R2 is phenyl, R3 is CgH^NHCO-, R4 is isopropyl, R? and RQ is methyl, and Rg is tertiary butyl, and d) the two optically active centers under c) are R.