NO144830B - SUBSTITUTED CYCLOPENTAND DERIVATIVES FOR USE AS INTERMEDIATE BY PREPARING A PHYSIOLOGY ACTIVE PROSTAGLAND CONNECTION OF THE E OR F SERIES - Google Patents

SUBSTITUTED CYCLOPENTAND DERIVATIVES FOR USE AS INTERMEDIATE BY PREPARING A PHYSIOLOGY ACTIVE PROSTAGLAND CONNECTION OF THE E OR F SERIES Download PDF

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NO144830B
NO144830B NO743492A NO743492A NO144830B NO 144830 B NO144830 B NO 144830B NO 743492 A NO743492 A NO 743492A NO 743492 A NO743492 A NO 743492A NO 144830 B NO144830 B NO 144830B
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yloxy
tetrahydropyran
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mmol
acid
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NO144830C (en
NO743492L (en
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Michael Ross Johnson
Hans-Jurgen Ernst Hess
Thomas Ken Schaaf
Jasjit Singh Bindra
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Pfizer
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    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
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    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
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    • C07F9/40—Esters thereof
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Description

Foreliggende oppfinnelse vedrører nye substituerte cyklo-pentanderivater nyttige som mellomprodukter ved fremstilling av de nye fysiologisk aktive prostaglandinforbindelser beskrevet i patent 14 3.741. The present invention relates to new substituted cyclopentane derivatives useful as intermediate products in the production of the new physiologically active prostaglandin compounds described in patent 14 3,741.

Prostaglandinene er C-20 umettede fettsyrer som har for-skjellige fysikalske virkninger. Prostaglandiner av E- og A-seriene er f.eks. kraftige vasodilatatorer (Bergstrom et al, Acta Physiol. Scand. 64:332-33 1965 og Bergstrom et al, The prostaglandins are C-20 unsaturated fatty acids that have different physical effects. Prostaglandins of the E and A series are e.g. powerful vasodilators (Bergstrom et al, Acta Physiol. Scand. 64:332-33 1965 and Bergstrom et al,

Life Sei. 6:449-455, 1967) og senker systemisk arterielt blodtrykk (vasodepresjon) ved intravenøs administrering- (Weeks og King, Federation Proe. 23:327, 1964, Bergstrom et al, 1965, op. eit; Carlson et al., Acta Med. Scand. 183:423-430, 1968; Life Sei. 6:449-455, 1967) and lowers systemic arterial blood pressure (vasodepression) by intravenous administration- (Weeks and King, Federation Proe. 23:327, 1964, Bergstrom et al, 1965, op. eit; Carlson et al., Acta Med. Scand. 183:423-430, 1968;

og Carlson et al., Acta Physiol. Scand. 75:161-169, 1969). and Carlson et al., Acta Physiol. Scand. 75:161-169, 1969).

En annen velkjent, fysiologisk virkning for PGE^ og PGE2 er Another well-known physiological effect of PGE^ and PGE2 is

som en bronkodilatator (Cuthbert, Brit. Med. J. 4:723-726, 1969) .. as a bronchodilator (Cuthbert, Brit. Med. J. 4:723-726, 1969) ..

Enda en annen viktig fysiologisk rolle for de naturlige prostaglandiner er i forbindelse med forplantningscyklusen. PGE2 er kjent for å kunne fremkalle veer (Karim, et al., Yet another important physiological role for the natural prostaglandins is in connection with the reproductive cycle. PGE2 is known to induce labor (Karim, et al.,

J. Obstet. Gynaec. Brit. Cwlth. 77:200-210, 1970), å fremkalle terapeutisk abort (Bygdeman et al., Contraception, £,29 3 J. Obstet. Gynaec. Brit. Cwlth. 77:200-210, 1970), to induce therapeutic abortion (Bygdeman et al., Contraception, £.29 3

(1971) og være nyttig for reguleringen av fruktbarhet (Karim, (1971) and be useful for the regulation of fertility (Karim,

Contraception, 3, 173 (1971)). Det er blitt oppnådd patenter for en rekke prostaglandiner av E- og F-seriene for fremkalling av veer i pattedyr (belgisk patent 754.158 og vesttysk patent 2.034.6 41) og for PGF^, og F3 for regulering av forplantningscyklusen (sydafrikansk patent 69/6089). Det har vist seg at luteolyse kan finne sted som et resultat av administreringen av PGF2ct [Labhsetwar, Nature 230, 528 (1971) ] og prostaglandiner kan således anvendes for regulering av fruktbarheten ved en fremgangsmåte hvor det ikke er nødvendig med stimulering av den glatte muskulatur. Contraception, 3, 173 (1971)). Patents have been obtained for a number of prostaglandins of the E and F series for inducing labor in mammals (Belgian patent 754.158 and West German patent 2.034.6 41) and for PGF^, and F3 for regulating the reproductive cycle (South African patent 69/ 6089). It has been shown that luteolysis can take place as a result of the administration of PGF2ct [Labhsetwar, Nature 230, 528 (1971) ] and prostaglandins can thus be used to regulate fertility by a method where stimulation of the smooth muscles is not necessary .

Ytterligere kjente fysiologiske virkninger for PGE^ er ved hemningen av mavesyresekresjon (Shaw og Ramwell, In: Further known physiological effects of PGE^ are in the inhibition of gastric acid secretion (Shaw and Ramwell, In:

Worcester Symp. on Prostaglandins, New York, Wiley, 1968, Worcester Symp. on Prostaglandins, New York, Wiley, 1968,

s. 55-64) og også av blodplateagglomereringen (Emmons et al, Brit. Med. J. 2:468-472, 1967). pp. 55-64) and also of the platelet agglomeration (Emmons et al, Brit. Med. J. 2:468-472, 1967).

Det er velkjent at slike fysiologiske virkninger kan frem-kalles in vivo for bare en kort tid efter administreringen av et prostaglandin• Litteratur indikerer at grunnen til dette hurtige opphør av virkningen er at de naturlige prostaglandiner hurtig og effektivt deaktiveres metabolisk ved |3^oksydas jon av karboksylsyre-sidekjeden og ved oksydasjon av 15<x-hydroksyl-gruppen (Anggard et al., Acta, Physiol. Scand. 81, 396 (1971) It is well known that such physiological effects can be induced in vivo for only a short time after the administration of a prostaglandin. Literature indicates that the reason for this rapid cessation of action is that the natural prostaglandins are quickly and efficiently deactivated metabolically by |3-oxidation of the carboxylic acid side chain and by oxidation of the 15<x-hydroxyl group (Anggard et al., Acta, Physiol. Scand. 81, 396 (1971)

og referanser angitt her). Det har vist seg at plasseringen av en 15-alkylgruppe i prostaglandinene øker varighetsvirkningen sannsynligvis ved å hindre oksydasjonen av C15-hydroksyl- and references listed here). It has been shown that the placement of a 15-alkyl group in the prostaglandins increases the duration effect probably by preventing the oxidation of C15-hydroxyl-

gruppen [Yankee og Bundy, JACS 94, 3651 (19 72)], Kirton og Forbes, Prostaglandins, 1, 319 (1972) . group [Yankee and Bundy, JACS 94, 3651 (1972)], Kirton and Forbes, Prostaglandins, 1, 319 (1972).

Det har selvfølgelig vært ansett ønskelig å fremstille analoger av prostaglandiner som har fysiologiske virkninger som er tilsvarende de naturlige forbindelser, men hvor virkningsselektiviteten og virkningsvarigheten er øket. Øket virkningsselektivitet vil forventes å dempe de alvorlige bi-virkninger, spesielt mave- og tarmbivirkninger, som ofte observeres.efter systemisk administrasjon av naturlige prostaglandiner (Lancet, 536, 1971). It has of course been considered desirable to produce analogues of prostaglandins which have physiological effects which are similar to the natural compounds, but where the selectivity of action and the duration of action have been increased. Increased selectivity of action would be expected to reduce the serious side effects, especially stomach and intestinal side effects, which are often observed after systemic administration of natural prostaglandins (Lancet, 536, 1971).

Ifølge oppfinnelsen tilveiebringes mellomprodukter for fremstilling av fysiologisk aktive prostaglandinforbindelser av E- eller F-serien med formelen: According to the invention, intermediate products for the production of physiologically active prostaglandin compounds of the E or F series are provided with the formula:

hvor Ar er a- eller (3-furyl, a- eller 3-tienyl, a- eller |3-naftyl, fenyl, 3,4-dimetoksyfenyl, 3,4-metylendioksyfenyl, 3,4,5-trimetoksyfenyl eller monosubstituert fenyl hvor substituenten er halogen, trifluormetyl, fenyl, lavere alkyl eller lavere alkoksy; where Ar is α- or (3-furyl, α- or 3-thienyl, α- or |3-naphthyl, phenyl, 3,4-dimethoxyphenyl, 3,4-methylenedioxyphenyl, 3,4,5-trimethoxyphenyl or monosubstituted phenyl wherein the substituent is halogen, trifluoromethyl, phenyl, lower alkyl or lower alkoxy;

W er en enkeltbinding eller en cis-dobbeltbinding; W is a single bond or a cis-double bond;

Z er en enkeltbinding eller en tr.ans-dobbeltbinding; Z is a single bond or a trans-double bond;

n er et helt tall fra 0 til 5, med det forbehold at når Ar er fenyl, substituert fenyl eller naftyl, er n 0 eller 1, n is an integer from 0 to 5, with the proviso that when Ar is phenyl, substituted phenyl or naphthyl, n is 0 or 1,

og Z er en enkeltbinding.. Deres fremstilling er beskrevet i patent 14 3.741. and Z is a single bond.. Their preparation is described in patent 14 3,741.

Mellomproduktene ifølge oppfinnelsen har formelen: The intermediate products according to the invention have the formula:

hvor Ar, n, M, W og Z er som ovenfor angitt, og THP er 2-tetrahydropyranyl. De nye mellomprodukter ifølge oppfinnelsen kan fremstilles ved at man omsetter en forbindelse med formel IVA where Ar, n, M, W and Z are as above, and THP is 2-tetrahydropyranyl. The new intermediates according to the invention can be prepared by reacting a compound of formula IVA

hvor Ar, n og Z er som angitt ovenfor, med et ylid med formelen where Ar, n and Z are as indicated above, with a ylide of the formula

(CgH5)3P=CH-CH2-CH2-CH2-COO(<_>) (CgH5)3P=CH-CH2-CH2-CH2-COO(<_>)

og oppnår en forbindelse med formelen and achieves a connection with the formula

hvor Ar, n og Z er som angitt ovenfor og W er en cis-dobbeltbinding, og om nødvendig derefter hydrogenerer forbindelsen slik at man får en forbindelse med formel V hvor Ar, n og Z er som angitt ovenfor og W er en enkeltbinding. where Ar, n and Z are as indicated above and W is a cis-double bond, and if necessary then hydrogenates the compound to give a compound of formula V where Ar, n and Z are as indicated above and W is a single bond.

Forbindelsen med formel V ovenfor, hvor Ar og n er som angitt ovenfor, W er en cis-dobbeltbinding og Z er en trans-dobbeltbinding, kan reduseres for å danne en forbindelse med formel V ovenfor hvor Ar og n er som angitt ovenfor og W og Z er enkeltbindinger. The compound of formula V above, wherein Ar and n are as above, W is a cis double bond and Z is a trans double bond, may be reduced to form a compound of formula V above wherein Ar and n are as above and W and Z are single bonds.

Forbindelsen med formel V ovenfor, hvor Ar og n er som angitt ovenfor, W er en cis-dobbeltbinding og Z er en trans-dobbeltbinding, kan hydrogeneres selektivt for å danne en forbindelse med formel V hvor Ar og n er som angitt ovenfor, W er en enkeltbinding og Z er en trans-dobbeltbinding. Mellomproduktet ifølge oppfinnelsen med formelen: hvor Ar, n, W, Z og THP er som angitt ovenfor, kan så fremstilles ved at man omsetter en forbindelse med formel V The compound of formula V above, wherein Ar and n are as defined above, W is a cis double bond and Z is a trans double bond, may be selectively hydrogenated to form a compound of formula V wherein Ar and n are as defined above, W is a single bond and Z is a trans double bond. The intermediate product according to the invention with the formula: where Ar, n, W, Z and THP are as indicated above, can then be prepared by reacting a compound of formula V

hvor Ar, n, W og Z er som angitt ovenfor, med kromsyre i vandig svovelsyre og aceton. where Ar, n, W and Z are as above, with chromic acid in aqueous sulfuric acid and acetone.

De ovenstående reaksjoner er beskrevet med henvisning til forbindelser hvor 15-tetrahydropyranyletergruppen er i a-konfigurasjon. 15fS-forbindelsene kan fremstilles på samme måte ved å starte fra den passende forbindelse med 3-konfigurasjon. The above reactions are described with reference to compounds where the 15-tetrahydropyranyl ether group is in α-configuration. The 15fS compounds can be prepared in the same way starting from the appropriate 3-configuration compound.

Omdannelse av de nye mellomprodukter ifølge oppfinnelsen til de fysiologisk aktive prostaglandinforbindelser med formel I er beskrevet i patent 143.741. Conversion of the new intermediate products according to the invention to the physiologically active prostaglandin compounds of formula I is described in patent 143,741.

De følgende eksempler er gitt for å illustrere frem-stillingen av de nye mellomprodukter. I disse eksempler er alle temperaturer angitt i °C, alle smelte- og kokepunkter er ukorrigerte og alle biologiske forsøksdata er uttrykt i'The following examples are given to illustrate the production of the new intermediates. In these examples, all temperatures are given in °C, all melting and boiling points are uncorrected and all biological test data are expressed in

% virkning av PGE2 eller administrert ved det samme nivå % effect of PGE2 or administered at the same level

(dvs. PGE2 = 100) dersom intet annet er angitt. (ie PGE2 = 100) if nothing else is stated.

Eksempel 1 Example 1

a) 2-[ 5a- hydroksy- 3a-( tetrahydropyran- 2- yloksy)-2ft-( 3a-( tetrahydropyran- 2- yloksy)- 4- fenylbut- T- y1) cyklopen t-la- yl] acetaldehyd, y- hemiacetal a) 2-[5a-hydroxy-3a-(tetrahydropyran-2-yloxy)-2ft-(3a-(tetrahydropyran-2-yloxy)-4-phenylbut-T-y1)cyclopentyl-la-yl]acetaldehyde, y - hemiacetal

En løsning av 1457 mg (3,2 mmol) 2-[5a-hydroksy-3a-(tetrahydropyran-2-yloksy)-23-(3a-(tetrahydropyran-2-yloksy)-4-fenylbut-l-yl)cyklopent-la-yl]eddiksyre, y-lakton i 15 ml tørr toluen ble avkjølt til -78° i tørr nitrogenatmosfære. A solution of 1457 mg (3.2 mmol) of 2-[5α-hydroxy-3α-(tetrahydropyran-2-yloxy)-23-(3α-(tetrahydropyran-2-yloxy)-4-phenylbut-1-yl)cyclopentane -la-yl]acetic acid, γ-lactone in 15 ml of dry toluene was cooled to -78° in a dry nitrogen atmosphere.

Til denne avkjølte løsning ble tilsatt dråpevis 5,0 ml 5.0 ml was added dropwise to this cooled solution

20% diisobutylaluminiumhydrid i n-heksan-(Alfa Inorganics) 20% diisobutylaluminum hydride in n-hexane (Alfa Inorganics)

med en slik hastighet at den indre temperatur ikke oversteg " ca. -6 5° (3 minutter). Efter ytterligere omrøring i 30 minutter ved -78° ble tilsatt vannfri metanol inntil gass-utviklingen opphørte og reaksjonsblandingen fikk lov til å varmes opp til væreIsestemperatur. Reaksjonsblandingen ble - tilsatt 150 ml eter, vasket med 50% natriumkaliumtartrat-løsning (1 x 50 ml), tørret (Na2S0^), konsentrert og kromatografert, ga 1200 mg (81,5%) 2-[5a-hydroksy-3a-(tetrahydropyran-2-yloksy)-20-(3a-(tetrahydropyran-2-yloksy)-4-fenylbut-l-yl)-cyklopent-l-yl]acetaldehyd, y-hemiacetal. at such a rate that the internal temperature did not exceed " about -65° (3 minutes). After further stirring for 30 minutes at -78°, anhydrous methanol was added until gas evolution ceased and the reaction mixture was allowed to warm to The reaction mixture was - added 150 ml of ether, washed with 50% sodium potassium tartrate solution (1 x 50 ml), dried (Na2SO4), concentrated and chromatographed, gave 1200 mg (81.5%) of 2-[5α-hydroxy- 3α-(tetrahydropyran-2-yloxy)-20-(3α-(tetrahydropyran-2-yloxy)-4-phenylbut-1-yl)-cyclopent-1-yl]acetaldehyde, γ-hemiacetal.

b) 9a- hydroksy- lla, 15a- bis-( tetrahydropyran- 2- yloksy)- 16-fenyl- cis- 5- ai- tetranor- prostensyre b) 9a- hydroxy- lla, 15a- bis-(tetrahydropyran-2- yloxy)- 16-phenyl- cis- 5- ai- tetranor- prostenic acid

Til en løsning av 5150 mg (11,6 mmol) (4-karbohydroksy-n-buty1)-trifenylfosfonium-bromid i tørr nitrogenatmosfære i 10,1 ml tørr dimetylsulfoksyd ble tilsatt 10,8 ml (21,1 mmol) av en 1,96M løsning av natriummetylsulfinylmetid i dimetylsulfoksyd. Til denne røde ylidløsning ble dråpevis tilsatt en løsning av 1200 mg (2,6 mmol) 2-[5a-hydroksy-3a-(tetrahydropyran-2-yloksy) -2(3- (3a- (tetrahydropyran-2-yloksy) -4-fenyl-but-l-yl)cyklopent-la-yl]-acetaldehyd, y-hemiacetal fremstilt ovenfor i 7,0 ml tørr dimetylsulfoksyd i løpet av 20 minutter. Efter ytterligere 2 timers omrøring ved værelsestemperatur, 10.8 ml (21.1 mmol) of a 1 .96M solution of sodium methylsulfinyl methide in dimethylsulfoxide. To this red ylide solution was added dropwise a solution of 1200 mg (2.6 mmol) 2-[5α-hydroxy-3α-(tetrahydropyran-2-yloxy)-2(3-(3α-(tetrahydropyran-2-yloxy)- 4-phenyl-but-l-yl)cyclopent-la-yl]-acetaldehyde, γ-hemiacetal prepared above in 7.0 mL of dry dimethyl sulfoxide over 20 min. After stirring for an additional 2 h at room temperature,

ble reaksjonsblandingen hellet ned på isvann. Den basiske vandige løsningen ble surgjort til pH 3 med 10% vandig saltsyre. Den sure løsningen ble ekstrahert med etylacetat the reaction mixture was poured onto ice water. The basic aqueous solution was acidified to pH 3 with 10% aqueous hydrochloric acid. The acidic solution was extracted with ethyl acetate

(3 x 100 ml) og de kombinerte organiske ekstrakter ble vasket en gang med vann (50 ml), tørret (MgS04) og fordampet til en rast rest. Denne faste resten ble triturert med etylacetat og filtrert. Filtratet ble renset ved kolonnekromatografi på silikagel (Baker "Analyzed" reagens 60-200 mesh) ved å anvende etylacetat som elueringsmiddel. Efter fjernelsen av høye Rf-forurensninger fikk man 880 mg 9a-hydroksy-lla,15a-bis- (tetrahydropyran-2-yloksy) -16-feny l-cis-5-ui-tetranor-prosten-syre. (3 x 100 mL) and the combined organic extracts were washed once with water (50 mL), dried (MgSO 4 ) and evaporated to a dry residue. This solid residue was triturated with ethyl acetate and filtered. The filtrate was purified by column chromatography on silica gel (Baker "Analyzed" reagent 60-200 mesh) using ethyl acetate as eluent. After the removal of high Rf impurities, 880 mg of 9α-hydroxy-11a,15α-bis-(tetrahydropyran-2-yloxy)-16-phenyl 1-cis-5-ui-tetranor-prostenic acid was obtained.

Infrarødt spektrum (CHC1.,) viste en karbonyladsorpsjon Infrared spectrum (CHC1.,) showed a carbonyl adsorption

ved -1 at -1

ved 1715 cm at 1715 cm

Det oppnådde produkt kan overføres til 16-fenyl-w-tetranor-13,14-dihydro-PGF2a ved hydrolyse med en 65:35 blanding av eddiksyre og vann og rensning ved kolonnekromatografi på Mallinckrodt CC-4 silikagel under anvendelse av etylacetat The product obtained can be converted to 16-phenyl-w-tetranor-13,14-dihydro-PGF2a by hydrolysis with a 65:35 mixture of acetic acid and water and purification by column chromatography on Mallinckrodt CC-4 silica gel using ethyl acetate

som elueringsmiddel. as eluent.

Eksempel 2 Example 2

9- okso- lla, 15a- bis-( tetrahydropyran- 2- yloksy)- 16- fenyl- cis- 5-a)- tetranor- prostensyre 9- oxol- la, 15a- bis-(tetrahydropyran-2- yloxy)- 16- phenyl- cis- 5-a)- tetranor- prostenic acid

Til en løsning, avkjølt til -10° under nitrogen av 880 mg To a solution, cooled to -10° under nitrogen, of 880 mg

(1,68 mmol) 9a-hydroksy-lla,15a-bis-(tetrahydropyran-2-yloksy)-16-fenyl-cis-5-w-tetranor-prostensyre i 15 ml aceton av analysekvalitet ble dråpevis tilsatt 0,75 ml (2 mmol) av Jones reagens. Efter 20 minutter ved -10° ble tilsatt 0,75 ml 2-propanol og reaksjonsblandingen ble omrørt i ytterligere 5 minutter og ble derefter blandet med 100 ml etylacetat, vasket med vann (3 x 25 ml), tørret (MgSO^) og konsentrert, og gir 775 mg 9-okso-lla,15a-bis-(tetrahydropyran-2-yloksy)-16-fenyl-cis-5-co-tetranor-prostensyre. Infrarødt spektrum (CHC1-.) viste (1.68 mmol) 9α-hydroxy-11a,15α-bis-(tetrahydropyran-2-yloxy)-16-phenyl-cis-5-w-tetranorprostenic acid in 15 ml of analytical grade acetone was added dropwise to 0.75 ml (2 mmol) of Jones reagent. After 20 minutes at -10°, 0.75 ml of 2-propanol was added and the reaction mixture was stirred for a further 5 minutes and was then mixed with 100 ml of ethyl acetate, washed with water (3 x 25 ml), dried (MgSO 4 ) and concentrated , and gives 775 mg of 9-oxo-11a,15a-bis-(tetrahydropyran-2-yloxy)-16-phenyl-cis-5-co-tetranorprostenic acid. Infrared spectrum (CHC1-.) showed

-1 -1

karbonyladsorpsjoner ved 1710 og 1735 cm carbonyl adsorptions at 1710 and 1735 cm

Eksempel 3 Example 3

9a- hydroksy- lla, 15a- bis( tetrahydropyran- 2- yloksy)- 16-( 2- tienyl)-cls- 5- trans- 13- a)- tetranor- prostadiensyre 9a- hydroxy- lla, 15a- bis( tetrahydropyran-2- yloxy)- 16-( 2- thienyl)-cls- 5- trans- 13- a)- tetranor- prostadic acid

Til en løsning av 2,6 g (6 mmol) (4-karbohydroksy-n-butyl)-trifenylfosfonium-bromid i tørr nitrogenatmosfære i 5,0 ml tørt dimetylsulfoksyd ble tilsatt 5,7 ml (11,4 mmol) av en 2,2M løsning av natriummetylsulfinylmetid i dimetylsulfoksyd. Til denne røde ylidløsningen ble dråpevis tilsatt en løsning 5.7 ml (11.4 mmol) of a 2 .2M solution of sodium methylsulfinyl methide in dimethylsulfoxide. A solution was added dropwise to this red ylide solution

av 1,03 g (2,2 mmol) 2-[5a-hydroksy-3a-(tetrahydropyran-2-yloksy)-20-(3a-(tetrahydropyran-2-yloksy)-4-(2-tienyl)-trans-l-buten-1-yl)cyklopent-la-yl]-acetaldehyd, Y-hemiacetal i 5,0 ml tørt dimetylsulfoksyd i løpet av 20 minutter. Efter ytterligere 2 timers omrøring ved værelsestemperatur ble reaksjonsblandingen hellet ned på isvann. Den basiske, vandige løsningen ble vasket to ganger med etylaceatt (20 ml) og surgjort til pH 3 of 1.03 g (2.2 mmol) 2-[5α-hydroxy-3α-(tetrahydropyran-2-yloxy)-20-(3α-(tetrahydropyran-2-yloxy)-4-(2-thienyl)-trans -1-buten-1-yl)cyclopent-la-yl]-acetaldehyde, Y-hemiacetal in 5.0 ml of dry dimethylsulfoxide over 20 minutes. After stirring for a further 2 hours at room temperature, the reaction mixture was poured onto ice water. The basic aqueous solution was washed twice with ethyl acetate (20 mL) and acidified to pH 3

med 10% vandig saltsyre. Den sure løsningen ble ekstrahert with 10% aqueous hydrochloric acid. The acidic solution was extracted

med etylacetat (3 x 20 ml) og de kombinerte organiske ekstrakter ble vasket 1 gang med vann (10 ml), tørret (MgS04) with ethyl acetate (3 x 20 mL) and the combined organic extracts were washed 1 time with water (10 mL), dried (MgSO 4 )

og fordampet til en fast rest. Denne faste resten ble triturert med etylacetat og filtratet konsentrert dg gir 1,02 g 9a-hydroksy-lla,15a-bis-(tetrahydropyran-2-yloksy)-16- (2-tienyl) -cis-5-trans-13-u)-tetranor-prostadiensyre. Infrarødt spektrum viser et sterkt bånd ved 1700 cm ^ sammen med absorpsjoner mellom 2800 til 2600 cm * for karboksylgriippen. and evaporated to a solid residue. This solid residue was triturated with ethyl acetate and the filtrate concentrated to give 1.02 g of 9α-hydroxy-lla,15α-bis-(tetrahydropyran-2-yloxy)-16-(2-thienyl)-cis-5-trans-13- u)-tetranor-prostadic acid. Infrared spectrum shows a strong band at 1700 cm^ along with absorptions between 2800 to 2600 cm* for the carboxyl group.

Eksempel 4 Example 4

9- okso- lla, 15g- bis-( tetrahydropyran- 2- yloksy)- 16-( 2- tienyl)-. cis- 5- trans- l 3- cii- tetfanor- prostadiensyre 9-oxol-lla, 15g-bis-(tetrahydropyran-2-yloxy)-16-(2-thienyl)-. cis- 5- trans- l 3- cii- tetetphanor- prostadic acid

Til en løsning avkjølt til -10° under nitrogen av 1,02 g (1,86 mmol) 9a-hydroksy-lla,15a-bis-(tetrahydropyran-2-yloksy)-16-(2-tienyl)-cis-5-trans-13-w-tetranor-prostadiensyre i 18 ml aceton av analysekvalitet ble dråpevis tilsatt til 0,82 ml (2,04 mmol) av Jones reagens. Efter 20 minutter ved To a solution cooled to -10° under nitrogen of 1.02 g (1.86 mmol) of 9α-hydroxy-11a,15α-bis-(tetrahydropyran-2-yloxy)-16-(2-thienyl)-cis-5 -trans-13-w-tetranor-prostadic acid in 18 ml of analytical grade acetone was added dropwise to 0.82 ml (2.04 mmol) of Jones reagent. After 20 minutes by

-10° ble tilsatt 0,260 ml 2-propanol og reaksjonsblandingen ble omrørt i ytterligere 5 minutter og ble derefter kombinert med 75 ml etylacetat, vasket med vann (3 x 10 ml), tørret (MgSO^) -10° was added 0.260 mL of 2-propanol and the reaction mixture was stirred for a further 5 minutes and was then combined with 75 mL of ethyl acetate, washed with water (3 x 10 mL), dried (MgSO 4 )

og konsentrert, og gir 952 mg 9-okso-lla,15a-bis-(tetrahydropyran-2-yloksy)-16-(2-tienyl)-cis-5-trans-13-w-tetranor-prostadiensyre som ble kromatografert på silikagel ved å anvende and concentrated, giving 952 mg of 9-oxo-11a,15a-bis-(tetrahydropyran-2-yloxy)-16-(2-thienyl)-cis-5-trans-13-w-tetranor-prostadioic acid which was chromatographed on silica gel by applying

etylacetat som elueringsmiddel og gir 760 mg av ren forbindelse. På samme måte kan fremstilles de tilsvarende 3-tienyl-forbindelser som er epimere ved C^. ethyl acetate as eluent and gives 760 mg of pure compound. In the same way, the corresponding 3-thienyl compounds which are epimeric at C₁ can be prepared.

Eksempel 5 Example 5

9a- hydroksy- llg, 15a- bis-.( tetrahydropyran- 2- yloksy) - 16- ( 2- tienyl) - cis- 5- o)- tetranorprostensyre 9a-hydroxy-llg, 15a-bis-.(tetrahydropyran-2-yloxy)-16-(2-thienyl)-cis-5-o)-tetranorprostenic acid

Til en løsning av 5150 mg (11,6 mmol) (4-karbohydroksy-n-butyl)trifenylfosfoniumbromid i tørr nitrogenatmosfære i 10,1 ml tørr dimetylsulfoksyd tilsettes 10,8 ml (21,1 mmol) av en 1,96M løsning av natriummetylsulfinylmetid i dimetylsulfoksyd. Til denne røde ylidløsningen tilsettes dråpevis en løsning av 1300 mg (2,6 mmol) 2-[5a-hydroksy-3a-(tetrahydropyran-2-yloksy)-20-(3a-(tetrahydropyran-2-yloksy)-4-(2-tienyl)but-l-yl)cyklo-pent-la-yl]-acetaldehyd, ■f-hemiacetal i 7,0 ml tørt dimetyl-sulf oksyd i løpet av 20 minutter. Efter ytterligere 2 timers omrøring ved værelsestemperatur helles reaksjonsblandingen ned på isvann. Den basiske, vandige løsningen surgjøres til pH 3 med 10% vandig saltsyre. Den sure løsningen ekstraheres med etylacetat (3 x 100 ml) og de kombinerte, organiske ekstrakter vaskes en gang med vann (50 ml), tørres (MgSO^) og inndampes til en fast rest i Den faste resten tritureres med etylacetat og filtreres. Filtratet renses ved kolonnekromatografi på silikagel (Baker "Analyzed" reagens 60-200 mesh) ved å anvende etylacetat som elueringsmiddel. Efter fjernelsen av høye R^-forurensninger oppnås 9a-hydroksy-lla,15a-bis-(tetrahydropyran-2-yloksy) -16- (2-tienyl) -cis-5-io-tetranor-prostensyre. To a solution of 5150 mg (11.6 mmol) of (4-carbohydroxy-n-butyl)triphenylphosphonium bromide in a dry nitrogen atmosphere in 10.1 ml of dry dimethyl sulfoxide is added 10.8 ml (21.1 mmol) of a 1.96 M solution of sodium methylsulfinyl methide in dimethylsulfoxide. To this red ylide solution is added dropwise a solution of 1300 mg (2.6 mmol) 2-[5a-hydroxy-3a-(tetrahydropyran-2-yloxy)-20-(3a-(tetrahydropyran-2-yloxy)-4-( 2-thienyl)but-1-yl)cyclo-pent-la-yl]-acetaldehyde, ■f-hemiacetal in 7.0 ml of dry dimethyl sulfoxide during 20 minutes. After a further 2 hours of stirring at room temperature, the reaction mixture is poured onto ice water. The basic, aqueous solution is acidified to pH 3 with 10% aqueous hydrochloric acid. The acidic solution is extracted with ethyl acetate (3 x 100 ml) and the combined organic extracts are washed once with water (50 ml), dried (MgSO 4 ) and evaporated to a solid residue in The solid residue is triturated with ethyl acetate and filtered. The filtrate is purified by column chromatography on silica gel (Baker "Analyzed" reagent 60-200 mesh) using ethyl acetate as eluent. After the removal of high R₂ impurities, 9α-hydroxy-11a,15α-bis-(tetrahydropyran-2-yloxy)-16-(2-thienyl)-cis-5-io-tetranor-prostenic acid is obtained.

Eksempel 6 Example 6

9- okso- lla, 15a- bis-( tetrahydropyran- 2- yloksy)- 16-( 2- tienyl) - cis- 5- a)- tetranorpros tensyre 9-oxol-lla, 15a-bis-(tetrahydropyran-2-yloxy)-16-(2-thienyl)-cis-5-a)-tetranorprosthenic acid

Til en løsning avkjølt til -10° under nitrogen av 950 mg (1,68 mmol) 9a-hydroksy-lla,15a-bis-(tetrahydropyran-2-yloksy)-16-(2-tienyl)-cis-5-ur-tetranorprostensyre i 15 ml aceton av analysekvalitet tilsettes dråpevis 0,75 ml ( 2 mmol) av Jones reagens. Efter 20 minutter ved -10° tilsettes 0,75 ml 2-propanol og reaksjonsblandingen omrøres i ytterligere 5 min. og kombineres derefter med 100 ml etylacetat, vaskes med vann To a solution cooled to -10° under nitrogen of 950 mg (1.68 mmol) of 9α-hydroxy-11a,15α-bis-(tetrahydropyran-2-yloxy)-16-(2-thienyl)-cis-5-ur -tetranorprostenic acid in 15 ml acetone of analytical quality is added dropwise to 0.75 ml (2 mmol) of Jones reagent. After 20 minutes at -10°, 0.75 ml of 2-propanol is added and the reaction mixture is stirred for a further 5 minutes. and then combined with 100 ml of ethyl acetate, washed with water

(3 x 25 ml), tørret (MgSO^) og konsentrert, -og gir 9-okso-lla, 15a-bis-(tetrahydropyran-2-yloksy)-16-(2-tienyl)-cis-5-a>-tetranorprostensyre. (3 x 25 ml), dried (MgSO 4 ) and concentrated, -and gives 9-oxo-lla, 15a-bis-(tetrahydropyran-2-yloxy)-16-(2-thienyl)-cis-5-a> -tetranorprostenic acid.

Eksempel 7 Example 7

a) Metyl- 9g- acetoksy- llg-( tetrahydropyran- 2- yloksy)- 15- okso-trans- 13- 16- ( 3- tienyl) - ix)- tetranorprostenoat a) Methyl- 9g- acetoxy- llg-( tetrahydropyran-2- yloxy)- 15- oxo- trans- 13- 16- ( 3- thienyl)- ix)- tetranorprostenoate

Til en suspensjon av 110 mg (2,61 mmol) av en 57,0% dispersjon av natriumhydrid i mineralolje i 20 ml dimetoksyetan ble tilsatt 646 mg (2,61 mmol) dimetyl-2-okso-3-(3-tienyl)propylfosfonat. Blandingen omrøres i væreIsestemperatur i 1 time under nitrogen. Til denne suspensjon tilsettes en løsning av 0,947 g (2,37 mmol) urenset aldehyd fremstilt i eksempel 6 i 4 ml dimetoksyetan. Den resulterende, noe uklare, brune løsning omrøres i værelsestemperatur i 2 timer under nitrogen. Reaksjonen stoppes derefter ved tilsetning av is-eddik til pH ^ 7 og konsentreres ved roterende fordampning. Råproduktet renses ved kolonnekromatografi på silikagel og To a suspension of 110 mg (2.61 mmol) of a 57.0% dispersion of sodium hydride in mineral oil in 20 ml of dimethoxyethane was added 646 mg (2.61 mmol) of dimethyl-2-oxo-3-(3-thienyl) propyl phosphonate. The mixture is stirred at room temperature for 1 hour under nitrogen. To this suspension is added a solution of 0.947 g (2.37 mmol) of impure aldehyde prepared in example 6 in 4 ml of dimethoxyethane. The resulting somewhat cloudy brown solution is stirred at room temperature for 2 hours under nitrogen. The reaction is then stopped by addition of glacial acetic acid to pH 7 and concentrated by rotary evaporation. The crude product is purified by column chromatography on silica gel and

gir ønsket metyl-9a-acetoksy-lla-(tetrahydropyran-2-yloksy)-15-okso-trans-13-16- (3-tienyl) -co-tetranorprostenoat. gives the desired methyl 9α-acetoxy-11a-(tetrahydropyran-2-yloxy)-15-oxo-trans-13-16-(3-thienyl)-co-tetranorprostenoate.

b) Metyl- 9a- acetoksy- ria-( tetrahydropyrah- 2- yloksy)- 15-hydroksy- trans- 13- 16- ( 3- tienyl) - co- tetranorprostenoat b) Methyl- 9a- acetoxy- ria-( tetrahydropyrah- 2- yloxy)- 15- hydroxy- trans- 13- 16-( 3- thienyl) - co- tetranorprostenoate

Til en løsning av 1,60 g (2,17 mmol) av enonet fremstilt ia) i 6,5 ml dimetoksyetan ble dråpevis tilsatt 2,17 ml (1,08 mmol) av en 0,5M Zn(BH4)2)-løsning i dimetoksyetan. Efter omrøring ved værelsestemperatur under nitrogen i To a solution of 1.60 g (2.17 mmol) of the enone prepared in ia) in 6.5 ml of dimethoxyethane was added dropwise 2.17 ml (1.08 mmol) of a 0.5 M Zn(BH4)2)- solution in dimethoxyethane. After stirring at room temperature under nitrogen i

3 timer ble reaksjonen stoppet ved dråpevis tilsetning av en 3 hours the reaction was stopped by the dropwise addition of a

mettet, vandig løsning av natriumbitartrat inntil gass-utviklingen opphørte. Den heterogene løsningen omrøres ved værelsestemperatur i 5 minutter, fortynnes med metylenklorid, tørres (vannfri magnesiumsulfat) og konsentreres, og gir metyl-9a-acet6ksy-lla-(tetrahydropyran-2-yloksy)-15-hydroksy-trans-13-16- (3-tienyl)-w-tetranorprostenoat. saturated aqueous solution of sodium bitartrate until gas evolution ceased. The heterogeneous solution is stirred at room temperature for 5 minutes, diluted with methylene chloride, dried (anhydrous magnesium sulfate) and concentrated to give methyl-9α-acet6xyl-lla-(tetrahydropyran-2-yloxy)-15-hydroxy-trans-13-16- (3-thienyl)-w-tetranorprostenoate.

c) Metyl- 9a- acetoksy- lla, 15g- dihydroksy- trans- 13- 16-( 3- tienyl)- aV- tetranorprostenoat og metyl- 9a- acetoksy-11a, 15a- dihydroksy- trans- 13- 16- ( 3- tienyl) - co- tetranor-prostenoat c) Methyl- 9a- acetoxy-lla, 15g- dihydroxy- trans- 13- 16-( 3- thienyl)- αV- tetranorprostenoate and methyl- 9a- acetoxy- 11a, 15a- dihydroxy- trans- 13- 16-( 3 - thienyl) - co-tetranor-prostenoate

En løsning av 1,60 g (2,16 mmol) urenset THP-eter fremstilt i b) i 10,7 ml av en 65:35 blanding av eddiksyre:vann om- A solution of 1.60 g (2.16 mmol) of impure THP ether prepared in b) in 10.7 ml of a 65:35 mixture of acetic acid:water re-

røres ved 40 1 2° under nitrogen i 2,5 timer. Reaksjonsblandingen konsentreres derefter og gir urenset epimer diol-blanding. stirred at 40 1 2° under nitrogen for 2.5 hours. The reaction mixture is then concentrated to give impure epimeric diol mixture.

Råproduktet renses ved kolonnekromatografi på silikagel, og gir ønsket metyl-9ct-acetoksy-lla,15B-dihydroksy-trans-13-16-(3-tienyl)-w-tetranorprostenoat og den epimere metyl-9a-.acetoksy-lla,15a-dihydroksy-trans-13-16-(3-tienyl)-w-tetranor-prostenoat. The crude product is purified by column chromatography on silica gel, and gives the desired methyl-9α-acetoxy-lla,15B-dihydroxy-trans-13-16-(3-thienyl)-w-tetranorprostenoate and the epimeric methyl-9a-.acetoxy-lla,15a -dihydroxy-trans-13-16-(3-thienyl)-w-tetranor-prostenoate.

d) Metyl- 9a- acetoksy- lla, 15a- bis-( tetrahydropyran- 2- yloksy)-trans- 13- 16- ( 3- tienyl)- ai- tetranorprostenoat d) Methyl-9a-acetoxy-lla, 15a-bis-(tetrahydropyran-2-yloxy)-trans-13-16-(3-thienyl)- ai-tetranorprostenoate

En blanding av 0,22 3 g (0,510 mmol) av den kromatograferte diol i c), 0,14 ml (1,53 mmol) dihydropyran, 4,2 ml metylenklorid og 1 krystall av p-toluensulfonsyre-monohydrat omrøres ved værelsestemperatur under nitrogen i 20 minutter. Reaksjonsblandingen fortynnes derefter med eter, vaskes med mettet vandig natriumbikarbonat, tørres (vannfritt magnesiumsulfat) og konsentreres og gir ønsket metyl-9a-acetoksy-lla,15a-bis-(tetrahydropyran-2-yloksy) -trans-13-16- (3-tienyl) -co-tetranor-prostenoat. A mixture of 0.223 g (0.510 mmol) of the chromatographed diol in c), 0.14 ml (1.53 mmol) of dihydropyran, 4.2 ml of methylene chloride and 1 crystal of p-toluenesulfonic acid monohydrate is stirred at room temperature under nitrogen for 20 minutes. The reaction mixture is then diluted with ether, washed with saturated aqueous sodium bicarbonate, dried (anhydrous magnesium sulfate) and concentrated to give the desired methyl-9α-acetoxy-lla,15α-bis-(tetrahydropyran-2-yloxy)-trans-13-16-(3 -thienyl) -co-tetranor-prostenoate.

e) 9a- hydroksy- lla, 15a- bis-( tetrahydropyran- 2- yloksy)- trans-13- 16- ( 3- tienyl) - to- tetranorprostensyre (ifølge oppfinnelsen) e) 9a-hydroxy-lla, 15a-bis-(tetrahydropyran-2-yloxy)-trans-13-16-(3-thienyl)-to-tetranorprostenic acid (according to the invention)

En homogen løsning av 0,26 3 g (0,4 36 mmol) av urenset bis-THP-esteren fremstilt i d), 1,3 ml (1,30 mmol) 1,0N vandig natriumhydroksydløsning, 1,3 ml metanol og 1,3 ml tetrahydro-furan omrøres under nitrogen natten over. Reaksjonen stoppes derefter ved tilsetning av 1,30 ml (1,30 mmol) av en 1,0N vandig saltsyreløsning. Løsningen, fortynnes med etylacetat. Det organiske skikt tørres (vannfr-itt magnesiumsulfat) og konsentreres, og gir råproduktet. Råproduktet renses ved kolonnekromatografi på Baker "Analyzed" silikagel (60-200 mesh), og gir 9a-hydroksy-lla,15a-bis-(tetrahydropyran-2-yloksy)-trans-13-16-(3-tienyl)-w-tetranor-"prostensyre. A homogeneous solution of 0.26 3 g (0.4 36 mmol) of the crude bis-THP ester prepared in d), 1.3 ml (1.30 mmol) of 1.0 N aqueous sodium hydroxide solution, 1.3 ml of methanol and 1 .3 ml of tetrahydrofuran is stirred under nitrogen overnight. The reaction is then stopped by the addition of 1.30 ml (1.30 mmol) of a 1.0 N aqueous hydrochloric acid solution. The solution is diluted with ethyl acetate. The organic layer is dried (anhydrous magnesium sulfate) and concentrated, giving the crude product. The crude product is purified by column chromatography on Baker "Analyzed" silica gel (60-200 mesh), and gives 9a-hydroxy-lla,15a-bis-(tetrahydropyran-2-yloxy)-trans-13-16-(3-thienyl)-w -tetranor-"prostenic acid.

f) 9- okso- lla, 15a- bis-( tetrahydropyran- 2- yloksy)- 13- trans- 16-( 3- tienyl) - ai- tetranorprostensyre (ifølge oppfinnelsen) f) 9-oxo-lla, 15a-bis-(tetrahydropyran-2-yloxy)-13-trans-16-(3-thienyl)-a-tetranorprostenic acid (according to the invention)

Til en løsning, avkjølt under nitrogen til -15 til To a solution, cooled under nitrogen to -15 to

-20° av 0,201. g (0,371 mmol) av kromatografert syre fremstilt 1 e) i 4,0 ml aceton tilsettes dråpevis 0,163 ml (0,408 mmol) -20° of 0.201. g (0.371 mmol) of chromatographed acid prepared 1 e) in 4.0 ml of acetone is added dropwise 0.163 ml (0.408 mmol)

av Jones reagens. Reaksjonen omrøres kaldt i 15 minutter og stoppes derefter ved tilsetning av 0,194 ml isopropanol. Reaksjonen omrøres kaldt i 5 minutter og fortynnes derefter med etylacetat. Den organiske løsningen vaskes med vann (2 x) of Jones reagent. The reaction is stirred cold for 15 minutes and is then stopped by the addition of 0.194 ml of isopropanol. The reaction is stirred cold for 5 minutes and then diluted with ethyl acetate. The organic solution is washed with water (2 x)

og mettet saltløsning (1 x), tørres (vannfritt magnesiumsulfat) and saturated salt solution (1 x), dried (anhydrous magnesium sulfate)

og konsentreres og gir ønsket 9-okso-lla,15a-bis-(tetrahydropyran-2-yloksy) -13-trans-16- (3-tieny])-w-tetranorprostensyre . and is concentrated and gives the desired 9-oxo-11a,15a-bis-(tetrahydropyran-2-yloxy)-13-trans-16-(3-thieny])-w-tetranorprostenic acid.

Eksempel 8 Example 8

9g- hydroksy- lla, 15a- bis- ( tetrahydropyran- 2- yloksy) - 17- ( 2- fuiryl) - cis- 5- trans - 13— 03— t r is nor- pros t adien sy re 9g- hydroxyl- lla, 15a- bis- (tetrahydropyran- 2- yloxy) - 17- ( 2- fuiryl) - cis- 5- trans - 13— 03— tris norpros t adiene sy re

Til en løsning av 3,36 g (7,6 mmol) (4-karbohydroksy-n-butyl)-trifenylfosfoniumbromid i tørr nitrogenatmosfære i 15,0 ml tørt dimetylsulfoksyd ble tilsatt 7,0 ml (14,0 mmol) To a solution of 3.36 g (7.6 mmol) of (4-carbohydroxy-n-butyl)-triphenylphosphonium bromide in a dry nitrogen atmosphere in 15.0 ml of dry dimethyl sulfoxide was added 7.0 ml (14.0 mmol)

av en 2,OM løsning av natriummetylsulfinylmetid i dimetylsulfoksyd. Til denne røde ylidløsningen ble dråpevis tilsatt en løsning av 1,3 g (2,81 mmol) 2-[5g<->hydroksy-3a-(tetrahydropyran-2-yloksy)-23-(3a-(tetrahydropyran-2-yloksy)-5-(2-furyl)-trans-l-penten-1-yl)cyklopent-la-yl]-acetaldehyd, Y-hemiacetal i 5,0 ml tørt dimetylsulfoksyd i løpet av 20 minutter. Efter ytterligere of a 2.0M solution of sodium methylsulfinyl methide in dimethylsulfoxide. To this red ylide solution was added dropwise a solution of 1.3 g (2.81 mmol) of 2-[5g<->hydroxy-3a-(tetrahydropyran-2-yloxy)-23-(3a-(tetrahydropyran-2-yloxy) )-5-(2-furyl)-trans-1-penten-1-yl)cyclopent-la-yl]-acetaldehyde, Y-hemiacetal in 5.0 ml of dry dimethylsulfoxide over 20 minutes. After further

2 timers omrøring ved værelsestemperatur ble reaksjonsblandingen hellet ned på isvann. feen basiske vandige løsningen ble vasket to ganger med etylacetat (20 ml) og surgjort til pH ^ 3 med 10% vandig saltsyre. Den surgjorte løsningen ble ekstrahert med etylacetat (3 x 20 ml) og de kombinerte organiske ekstrakter ble vasket en gang med vann (10 ml), tørret (MgSO^) og fordampet til en fast rest. Denne faste resten ble triturert med etylacetat og filtrert. Filtratet ble renset ved kolonnekromatografi på silikagel (Baker "Analyzed" reagens 60-200 mesh) After stirring for 2 hours at room temperature, the reaction mixture was poured onto ice water. The slightly basic aqueous solution was washed twice with ethyl acetate (20 mL) and acidified to pH 3 with 10% aqueous hydrochloric acid. The acidified solution was extracted with ethyl acetate (3 x 20 mL) and the combined organic extracts were washed once with water (10 mL), dried (MgSO 4 ) and evaporated to a solid residue. This solid residue was triturated with ethyl acetate and filtered. The filtrate was purified by column chromatography on silica gel (Baker "Analyzed" reagent 60-200 mesh)

ved å anvende etylacetat som elueringsmiddel. Efter fjernelse av høye R^-forurensninger fikk man 1,53 g 9a-hydroksy-lla,15a-bis- (tetrahydropyran-2-yloksy)-17-(2-furyl)-cis-5-trans-13-w- by using ethyl acetate as eluent. After removal of high R^ impurities, 1.53 g of 9α-hydroxy-11a,15α-bis-(tetrahydropyran-2-yloxy)-17-(2-furyl)-cis-5-trans-13-w-

trisnor-prostadiensyre• trisnor-prostadic acid•

Eksempel 9 Example 9

9- okso- lla, 15a- bis-( tetrahydropyran- 2- yloksy)- 17-( 2- furyl)-cis- 5- tr ans- 13- ai- trisnor- prostadiensyre 9- ox- lla, 15a- bis-(tetrahydropyran-2- yloxy)- 17-( 2- furyl)- cis- 5- tr ans- 13- ai- trisnor- prostadic acid

Til en løsning avkjølt til -10° under nitrogen av 1,1 g (2,01 mmol) 9a-hydroksy-lla,15a-bis-(tetrahydropyran-2-yloksy)-17-(2-furyl)-cis-5-trans-13-w-trisnor-prostadiensyre i 20 ml aceton av analysekvalitet ble dråpevis tilsatt til 0,88 ml (2,2 mmol)- av Jones reagens. Efter 20 minutter ved -10° ble tilsatt 0,260 ml 2-propanol og reaksjonsblandingen ble omrørt i ytterligere 5 minutter og ble tilsatt 75 ml etylacetat, vasket med. vann (3 x 10 ml), tørret (MgS04) og konsentrert, og gir 425 mg 9-okso-lla,15a-bis-(tetrahydropyran-2-yloksy)-17- (2-f uryl) -cis-5-trans-13-a)-trisnor-prostadiensyre. To a solution cooled to -10° under nitrogen of 1.1 g (2.01 mmol) of 9α-hydroxy-11a,15α-bis-(tetrahydropyran-2-yloxy)-17-(2-furyl)-cis-5 -trans-13-w-trisnor-prostadic acid in 20 ml of analytical grade acetone was added dropwise to 0.88 ml (2.2 mmol) of Jones reagent. After 20 minutes at -10°, 0.260 ml of 2-propanol was added and the reaction mixture was stirred for a further 5 minutes and 75 ml of ethyl acetate was added, washed with. water (3 x 10 mL), dried (MgSO 4 ) and concentrated to give 425 mg of 9-oxo-lla,15a-bis-(tetrahydropyran-2-yloxy)-17-(2-furyl)-cis-5- trans-13-a)-trisnor-prostadic acid.

Claims (1)

Substituert cyklopentanderivat for anvendelse som mellomprodukt ved fremstilling av en fysiologisk aktiv prostaglandinforbindelse av E- eller F-serien med formelen:Substituted cyclopentane derivative for use as an intermediate in the preparation of a physiologically active prostaglandin compound of the E or F series with the formula: hvor Ar er a- eller 3-furyl, a- eller 3-tienyl, a- eller 3-naftyl, fenyl, 3,4-dimetoksyfenyl, 3,4-metylendioksyfenyl, 3,4,5-trimetoksyfenyl eller monosubstituert fenyl hvor substituenten er halogen, trifluormetyl, fenyl, lavere alkyl eller lavere alkoksy; W er en enkeltbinding eller en cis-dobbeltbinding;where Ar is α- or 3-furyl, α- or 3-thienyl, α- or 3-naphthyl, phenyl, 3,4-dimethoxyphenyl, 3,4-methylenedioxyphenyl, 3,4,5-trimethoxyphenyl or monosubstituted phenyl where the substituent is halogen, trifluoromethyl, phenyl, lower alkyl or lower alkoxy; W is a single bond or a cis-double bond; Z er en enkeltbinding eller en trans-dobbeltbinding;Z is a single bond or a trans double bond; n er et helt tall fra 0 til 5, med det forbehold at når Ar er fenyl, substituert fenyl eller naftyl, er n 0 eller 1, og Z er en enkeltbinding,n is an integer from 0 to 5, with the proviso that when Ar is phenyl, substituted phenyl or naphthyl, n is 0 or 1, and Z is a single bond, karakterisert ved at det har formelen:characterized in that it has the formula: hvor Ar, n, M, W og Z er sem ovenfor angitt, og THP er 2-tetrahydropyranyl.where Ar, n, M, W and Z are as above, and THP is 2-tetrahydropyranyl.
NO743492A 1972-07-13 1974-09-26 SUBSTITUTED CYCLOPENTAND DERIVATIVES FOR USE AS INTERMEDIATE BY PREPARING A PHYSIOLOGY ACTIVE PROSTAGLAND CONNECTION OF THE E OR F SERIES NO144830C (en)

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US4149006A (en) * 1977-01-24 1979-04-10 G. D. Searle & Co. Prostaglandin derivatives having alkynyl, hydroxy and aryloxy junctions in the 2β side chain
GB8329559D0 (en) * 1983-11-04 1983-12-07 Erba Farmitalia Furyl derivatives of 16-substituted prostaglandins preparations
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US5972991A (en) * 1992-09-21 1999-10-26 Allergan Cyclopentane heptan(ene) oic acid, 2-heteroarylalkenyl derivatives as therapeutic agents
US6602900B2 (en) 1992-09-21 2003-08-05 Allergan, Inc. Cyclopentane heptan(ENE)oic acid, 2-heteroarylalkenyl derivatives as therapeutic agents
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