NO762102L

NO762102L -

Info

Publication number: NO762102L
Application number: NO762102A
Authority: NO
Inventors: P Bollinger; M Krieger
Original assignee: Sandoz Ag
Priority date: 1975-06-25
Filing date: 1976-06-17
Publication date: 1976-12-28
Also published as: ZA763810B; FR2351974B1; DD124727A5; FR2316930A1; FR2351974A1; IL49889A0; PT65265A; PT65265B; SE7606972L; NZ181264A; CA1095032A; FR2316930B1; ATA460476A; NL7606709A; ES449147A1; BE843318A; DK270176A; AU511527B2; AU1532676A; IL49889A

Description

Foreliggende oppfinnelse vedrører en fremgangsmåte for fremstilling av mono-deuterte prostaglandiner og mellomforbindelser for deres fremstilling. Disse protaglandiner og deres mellomforbindelser er ikke radioaktive ved at de f.eks. ikke inneholder noen hydrogenatomer med mer enn den naturlige mengde av radioaktive isotoper, f.eks. tritium. The present invention relates to a method for the production of mono-deuterated prostaglandins and intermediate compounds for their production. These protaglandins and their intermediate compounds are not radioactive in that they e.g. does not contain any hydrogen atoms with more than the natural amount of radioactive isotopes, e.g. tritium.

Spesielt vedrører oppfinnelsen en fremgangsmåte for fremstillingIn particular, the invention relates to a method for production

av prostaglandiner som både inneholder en hydroksygruppe som ogsåof prostaglandins which both contain a hydroxy group which also

et deuteriumatom bundet til karbonatomet i 15-stillingen. Disse prostaglandiner kan opptre i rasemisk form eller i optisk aktiv form. a deuterium atom bonded to the carbon atom in the 15-position. These prostaglandins can appear in racemic form or in optically active form.

Oppfinnelsen vedrører videre en fremgangsmåte for fremstilling av prostaglandiner, som i 15-stillingen inneholder bundet såvel et deuteriumatom som også en hydroksygruppe, og det særegne ved fremgangsmåten i henhold til oppfinnelsen er at en beskyttelsesgruppe avspaltes fra en hydroksy- og/eller karboksylgruppe i et tilsvarende prostaglandin. The invention further relates to a method for the production of prostaglandins, which in the 15-position contain bound both a deuterium atom and also a hydroxy group, and the distinctive feature of the method according to the invention is that a protective group is cleaved from a hydroxy and/or carboxyl group in a corresponding prostaglandin.

Spesielt vedrører oppfinnelsen en fremgangsmåte for fremstilling av forbindelser med formel I In particular, the invention relates to a method for producing compounds of formula I

hvori A betyr grupper med formlene og B står for grupper med formlene where A means groups with the formulas and B stands for groups with the formulas

hvori X står for hydroksy, alkoksy med 1-10 karbonatomer, lysergyloksy, lysergylamino eller dihydrolysergylamino, og C står for en prostaglandin-endegruppe. wherein X stands for hydroxy, 1-10 carbon atom alkoxy, lysergyloxy, lysergylamino or dihydrolysergylamino, and C stands for a prostaglandin end group.

A er foretrukket A2, A3 eller A4.A is preferably A2, A3 or A4.

B er foretrukket Bl eller B4. X er foretrukket hydroksy eller alkoksy. Hvis X står for alkoksy, har dette foretrukket 1-4 karbonatomer, spesielt betyr X metoksy eller etoksy. B is preferably B1 or B4. X is preferably hydroxy or alkoxy. If X stands for alkoxy, this preferably has 1-4 carbon atoms, in particular X means methoxy or ethoxy.

C er en prostaglandin-endegruppe av naturlige eller syntetiske prostaglandiner. Spesielt kan C bety en hydrokarbongruppe som har opp til 16 karbonatomer og utover dette eventuelt også inneholder oykliske og/eller umettede grupper og/eller et heteroatom som oksygen. Prostaglandin-endegrupper, som er anvendbar ved oppfinnelsen, omfatter C is a prostaglandin end group of natural or synthetic prostaglandins. In particular, C can mean a hydrocarbon group which has up to 16 carbon atoms and, beyond this, optionally also contains cyclic and/or unsaturated groups and/or a heteroatom such as oxygen. Prostaglandin end groups useful in the invention include

a) alkylgrupper med 1-16 karbonatomer, spesielt grupper med formel a) alkyl groups with 1-16 carbon atoms, especially groups with the formula

hvori R-j^ og R 2 uavhengig av hverandre står for hydrogen eller alkyl med 1 til 4 karbonatomer, in which R-j^ and R 2 independently of each other stand for hydrogen or alkyl with 1 to 4 carbon atoms,

b) grupper med formelb) groups with formula

idet og R2har den ovennevnte betydning, Z står for -CI^-eller -0-, og R^står for hydrogen, fluor, klor eller trifluor-metyl, and R2 has the above meaning, Z stands for -Cl^- or -O-, and R^ stands for hydrogen, fluorine, chlorine or trifluoromethyl,

c) alkenylgrupper med 3-10 karbonatomer, ellerc) alkenyl groups with 3-10 carbon atoms, or

d) cykloalkylgrupper med 3-10 karbonatomer, som enten er usubstituert eller som kan være substituert med alkylgrupper d) cycloalkyl groups with 3-10 carbon atoms, which are either unsubstituted or which can be substituted with alkyl groups

med høyst 6 karbonatomer.with no more than 6 carbon atoms.

C er foretrukket Ca), som ovenfor angitt. R^og/eller R2 har hvis de står for alkyl, 1 eller 2 karbonatomer, spesielt står de for metyl. Hvis en av substituentene R^og R2står for alkyl, og den andre av disse substituenter betyr hydrogen, kan det karbonatom som befinner seg i 16-stillingen ha R- eller S-konfigurasjon. C is preferably Ca), as indicated above. R 1 and/or R 2 have, if they stand for alkyl, 1 or 2 carbon atoms, in particular they stand for methyl. If one of the substituents R 1 and R 2 stands for alkyl, and the other of these substituents means hydrogen, the carbon atom located in the 16-position can have the R or S configuration.

I den foreliggende fremstilling og i formlene står D for deuterium. In the present formulation and in the formulas, D stands for deuterium.

Bølgelinjene i formel I betegner at de på 15-karbonatomet bundne The wave lines in formula I denote that those on the 15-carbon atom are bound

hydroksygrupper kan ha a - eller (3 -konfigurasjon.hydroxy groups can have a - or (3) configuration.

De stiplede linjer i formel I betegner at de karbonatomer som befinner seg i 5- og 6-stillingen kan være forbundet med en enkel binding eller en cis-dobbeltbinding og de karbonatomer som befinner seg i 13- og 14-stillingen kan være forbundet med en enkel binding eller en trans-dobbeltbinding. The dashed lines in formula I denote that the carbon atoms in the 5- and 6-position can be connected by a single bond or a cis-double bond and the carbon atoms in the 13- and 14-position can be connected by a single bond or a trans double bond.

Oppfinnelsen vedrører videre en fremgangsmåte for fremstilling av forbindelser med formel I, og det særegne ved fremgangsmåten er at de syre-ømfindlige beskyttelsesgrupper ved hjelp av en syre avspaltes fra forbindelser med formel II The invention further relates to a method for producing compounds of formula I, and the peculiarity of the method is that the acid-sensitive protecting groups are cleaved from compounds of formula II with the aid of an acid

hvori A<1>har betydningen av A eller står for A7 eller A8 hvori Rj og R,- uavhengig av hverandre står for hydrogen eller en syreømfindtlig beskyttelsesgruppe, B<1>står for B, som har den ovennevnte betydning, eller betyr in which A<1> has the meaning of A or stands for A7 or A8 in which Rj and R, - independently of each other stand for hydrogen or an acid-sensitive protecting group, B<1> stands for B, which has the above meaning, or means

hvori Rg står for en syre^mfindlig beskyttelsesgruppe og C har den ovennevnte betydning, ved den betingelse at det i formel II in which Rg stands for an acid-soluble protecting group and C has the above-mentioned meaning, on the condition that in formula II

foreligger minst en syreømfindtlig: beskyttelsesgruppe.at least one acid-sensitive: protecting group is present.

Avspaltingen av beskyttelsesgruppen kan gjennomføres på i og forThe splitting off of the protection group can be carried out on i and for

seg kjent måte.known way.

Spesielt anvendes beskyttelsesgrupper som er stabile overforIn particular, protective groups are used which are stable against

basiske betingelser. Egnede beskyttelsesgrupper er tetra-hydropyranyl-og tert.-butyldimetylsilylgrupper. Egnede avspaltingsbetingelser er kjente, f.eks. kan avspaltingen skje ved hjelp av eddiksyre/ tetrahydrofuran/vann; metanol/saltsyre; svovelsyre; aceton/saltsyre. Egnede temperaturer utgjør -10 til 5 0°C, foretrukket skjer avspaltingen ved romtemperatur. basic conditions. Suitable protecting groups are tetra-hydropyranyl and tert-butyldimethylsilyl groups. Suitable cleavage conditions are known, e.g. can the cleavage take place with the aid of acetic acid/tetrahydrofuran/water; methanol/hydrochloric acid; sulfuric acid; acetone/hydrochloric acid. Suitable temperatures are -10 to 50°C, preferably the cleavage takes place at room temperature.

Prostaglandinene med formel I og II kan overføres i andre prostaglandiner med formler I og II under anvendelse av for slike omsetninger kjente metoder. The prostaglandins of formulas I and II can be converted into other prostaglandins of formulas I and II using methods known for such conversions.

F.eks. kan lysergsyreestere, lysergsyreamider og dihydrolysergsyre-amider fremstilles på for fremstilling av estere og amider kjent måte, f.eks. som beskrevet i eksempel 32. I tillegg til dette kan gruppen A2 overføres i gruppen A6 ved omsetning med imidazol ved en for anleiring- av aminer til en dobbeltbinding i et a , (3 -umettet keton kjent måte. Egnede betingelser er omsetningen med imidazol ved romtemperatur i flere døgn. Herved kan imidazolet befinne seg i fri form eller i form av karbonyldiimidazolet. Videre reaksjons-betingelser gis i eksempel 33, som omfatter begge estergrupper og beskriver overføringen av gruppen A2 i gruppen A6. E.g. lysergic acid esters, lysergic acid amides and dihydrolysergic acid amides can be prepared in a manner known for the preparation of esters and amides, e.g. as described in example 32. In addition to this, the group A2 can be transferred into the group A6 by reaction with imidazole in a known way. Suitable conditions are the reaction with imidazole at room temperature for several days. Hereby, the imidazole can be in free form or in the form of the carbonyldiimidazole. Further reaction conditions are given in example 33, which includes both ester groups and describes the transfer of the group A2 into the group A6.

Forbindelsene med formel II kan fremstilles på i og for seg kjent måte. F.eks. kan forbindelser med formel III The compounds of formula II can be prepared in a manner known per se. E.g. can compounds of formula III

hvori E står for og hvori R4, R,- og C har den ovennevnte betydning, under betingelsene for en Wittig-omsetning omsettes med forbindelser med formel IV hvori B har den ovennevnte betydning, idet de erholdte forbindelser eventuelt deretter kan underkastes en videre omsetning, f.eks. en sellektiv oksydasjon i 9-stillingen. Forbindelser med formel III kan fremstilles ved at Lacton-gruppen i forbindelser med formel V hvori C har den ovennevnte betydning og F står for in which E stands for and in which R 4 , R 1 - and C have the above-mentioned meaning, under the conditions for a Wittig reaction are reacted with compounds of formula IV in which B has the above-mentioned meaning, as the obtained compounds can optionally then be subjected to a further reaction, e.g. a selective oxidation in the 9-position. Compounds of formula III can be prepared by the Lactone group in compounds of formula V in which C has the above meaning and F stands for

hvori R. og R,- har den ovennevnte betydning, reduseres f.eks. under anvendelse av diisobutylaluminiumhydrid. in which R. and R,- have the above meaning, is reduced e.g. using diisobutylaluminum hydride.

Oppfinnelsen vedrører videre en fremgangsmåte for fremstilling av forbindelser med formel V ved deutering av forbindelser med formel The invention further relates to a method for preparing compounds of formula V by deuterating compounds of formula

VI WE

hvori C har den ovennevnte betydning og F<1>står for Fl, F2, F3 eller in which C has the above meaning and F<1> stands for Fl, F2, F3 or

idet Ry betyr hydrogen eller en voluminøs gruppe som kan innvirke på forholdet "mellom de dannede oe :|3 -alkoholer og om ønsket, over-føring av hver R^-gruppe i en R^-gruppe og, om ønsket, beskyttelse av en 3-hydroksygruppe ved hjelp av en syreømfindtlig beskyttelsesgruppe. wherein Ry means hydrogen or a bulky group which can affect the relationship between the oe :|3 alcohols formed and, if desired, transfer of each R^ group into an R^ group and, if desired, protection of a 3-hydroxy group by means of an acid-sensitive protecting group.

Deuteringen kan gjennomføres på i og for seg kjent måte, idet man også tar hensyn til de øvrige tilstedeværende grupper. F.eks. kan det som deuteringsmiddel anvendes natrium- eller sink-bordeuterid. The deuteration can be carried out in a manner known per se, taking into account the other groups present. E.g. sodium or zinc bordeuteride can be used as deuterating agent.

Reaksjonen skjer hensiktsmessig i et vannfritt inert organisk løsningsmiddel, som dimetylformamid eller dimetoksyetan, ved temperaturer på -40 til -50°C, foretrukket under inertgass-atmosfære. The reaction conveniently takes place in an anhydrous inert organic solvent, such as dimethylformamide or dimethoxyethane, at temperatures of -40 to -50°C, preferably under an inert gas atmosphere.

De derved dannede a- og (3 -alkoholer kan separeres på i og for seg kjent måte. The a- and (3)-alcohols thus formed can be separated in a manner known per se.

Gruppen R- velges slik at den som følge av sitt volum forandrer forholdet mellom den dannede cx : |3 -alkohol, idet vanlig andelen av a -alkoholen tiltar. De for dette egnede grupper er kjent. The group R- is chosen so that, as a result of its volume, it changes the ratio between the formed cx : |3 -alcohol, as the proportion of the a -alcohol usually increases. The suitable groups for this are known.

En eksempelvis anvendt gruppe R^ er p-fenyl-benzoyl- eller benzoylgruppen. Disse grupper kan avspaltes under alkaliske betingelser og kan på i og for seg kjent måte erstattes med en gruppe R5. An exemplary group R 1 used is the p-phenyl-benzoyl or benzoyl group. These groups can be split off under alkaline conditions and can be replaced in a manner known per se with a group R5.

3-hydroksygruppen kan beskyttes på i og for seg kjent måte. The 3-hydroxy group can be protected in a manner known per se.

Prostaglandiner i fri form, som er basiske, dvs. forbindelser med formel I, hvori A står for A6 eller X for lysergyloksy, lysergylamino eller dihydrolysergylamino, kan på i og for seg kjent måte overføres i sine syreaddisjonssalter og omvendt. En egnet syre er metansulfonsyren. Prostaglandiner i fri form, som er sure, dvs. forbindelser med formel I, hvori X står for hydroksy, kan på i og for seg kjent måte overføres i kationiske saltformer og omvendt. Prostaglandins in free form, which are basic, i.e. compounds of formula I, in which A stands for A6 or X for lysergyloxy, lysergylamino or dihydrolysergylamino, can be transferred in a manner known per se into their acid addition salts and vice versa. A suitable acid is methanesulfonic acid. Prostaglandins in free form, which are acidic, i.e. compounds of formula I, in which X stands for hydroxy, can be transferred in a manner known per se into cationic salt forms and vice versa.

Et egnet kation er natriumkationet.A suitable cation is the sodium cation.

I den utstrekning fremstillingen av utgangsforbindelsene ikke er beskrevet er disse forbindelser kjente eller kan fremstilles og renses under anvendelse av kjente metoder eller under anvendelse av de her eller i eksemplene beskrevne metoder. To the extent that the preparation of the starting compounds is not described, these compounds are known or can be prepared and purified using known methods or using the methods described here or in the examples.

Optisk aktive sluttforbindelser kan erholdes fra optisk aktive utgangsforbindelser. Optically active end connections can be obtained from optically active output connections.

Deuterte prostaglandiner fremstilt i henhold til oppfinnelsen, spesielt forbindelsene med formel I, fremviser interessante farmakodynamiske virkninger. Spesielt fremviser de deuterte prostaglandiner den samme virkning som deres ikke-deuterte analoge forbindelser, men de har dog en mer langvarig virkning. Således har forbindelsene med formel I generelt og PGE og PGFa -forbindelsene spesielt en uteroton virkning, påvist ved resultatene av den av Bisset et al. i "Memoirs of the Society for Endocrinology Nr. 14 - Endogenous substances affecting the myometrium"- utgitt av W.R. Pickles og R.J. Fitzpatrick, Cambridge University 1966, sidene Deuterated prostaglandins prepared according to the invention, especially the compounds of formula I, exhibit interesting pharmacodynamic effects. In particular, the deuterated prostaglandins exhibit the same effect as their non-deuterated analog compounds, but they have a more prolonged effect. Thus, the compounds of formula I in general and the PGE and PGFa compounds in particular have a uterotonic effect, demonstrated by the results of that by Bisset et al. in "Memoirs of the Society for Endocrinology No. 14 - Endogenous substances affecting the myometrium" - published by W.R. Pickles and R.J. Fitzpatrick, Cambridge University 1966, pp

185 - 198. 185 - 198.

De deuterte prostaglandiner kan tilføres på den samme måte og iThe deuterated prostaglandins can be administered in the same way and i

den samme dose som de ikke-deuterte prostaglandiner. Som angitt skal den daglig tilførte dose for oppnåelse av en uteroton virkning utgjøre 0.1 - ca. 20 mg, som hensiktsmessig kan tilføres i mindre doser 2 til 4 ganger daglig på 0.02 til ca. 10 mg eller i retard-form. Hvis prostaglandinet er basisk kan det anvendes et farmakologisk tålbart syreaddisjonssalt. Hvis prostaglandinet er surt kan det anvendes et farmakologisk tålbart kationisk salt. Slike salter kan fremstilles på i og for seg kjent måte og de har the same dose as the non-deuterated prostaglandins. As stated, the daily administered dose to achieve a uterotonic effect must amount to 0.1 - approx. 20 mg, which can conveniently be administered in smaller doses 2 to 4 times a day of 0.02 to approx. 10 mg or in retard form. If the prostaglandin is basic, a pharmacologically tolerable acid addition salt can be used. If the prostaglandin is acidic, a pharmacologically tolerable cationic salt can be used. Such salts can be prepared in a manner known per se and they have

en virkning som ligger innen den samme størrelsesorden som for prostaglandinene. Det kan fremstilles farmasøytiske preparater som inneholder prostaglandinene, hvori såvel en hydroksygruppe som også et deuteriumatom er bundet til karbonatomet i 15-stillingen, eller forbindelser med formel I, sammen med et farmasøytisk tålbart bærer-eller fortynningsmiddel. Slike preparater kan sammensettes på i og for seg kjent måte som tabletter eller som løsning. En gruppe av forbindelser med formel I og V omfatter dem hvori C står for Cl, hvori R-^ og R2uavhengig av hverandre står for hydrogen eller metyl, eller C2, hvori Z står for 0 og R^ står for p- eller m-fluoro-eller p- eller m-kloro- eller m-trifluorometyl. an effect that is within the same order of magnitude as for the prostaglandins. Pharmaceutical preparations can be prepared containing the prostaglandins, in which both a hydroxy group and a deuterium atom are bound to the carbon atom in the 15-position, or compounds of formula I, together with a pharmaceutically acceptable carrier or diluent. Such preparations can be composed in a manner known per se as tablets or as a solution. A group of compounds of formulas I and V includes those in which C stands for Cl, in which R-^ and R2 independently of each other stand for hydrogen or methyl, or C2, in which Z stands for 0 and R^ stands for p- or m-fluoro -or p- or m-chloro- or m-trifluoromethyl.

I de etterfølgende eksempler er alle temperaturangivelser i °C.In the following examples, all temperature indications are in °C.

IR viser karakteristiske bånd som opptrer i et infrarød-spektrum i metylenklorid-løsning. IR shows characteristic bands that appear in an infrared spectrum in methylene chloride solution.

Eksempel 1: 15- deutero- l] pt, 15R- dihydroksy- 16, 16- dimetyl- 9- keto-2, 3-(-)- trans- metylen- prosta- 5cis, 13 trans- diensyre. Example 1: 15-deutero-1]pt, 15R-dihydroxy-16,16-dimethyl-9-keto-2,3-(-)-trans-methylene-prosta-5cis,13 trans-dienoic acid.

400 mg 15-deutero-lla ,15 a-bis-tetrahydro-pyranyloksy-16,16-dimetyl-9-keto-2,3-(-)-trans-metylen-prosta-5cis, 13trans-diensyre-tert.-butyldimetyl-silylester oppløses i 18 ml av en blanding av like mengder eddiksyre, tetrahvJrofuran og vann. Reaksjonsblandingen settes bort i 38 timer ved romtemperatur og inndampes deretter i vakuum. Resten kromatograferes på silikagel under anvendelse av kloroform + 2% metanol som elueringsmiddel. Herved erholdes den i overskriften nevnte forbindelse i ren form. 400 mg 15-deutero-lla,15a-bis-tetrahydro-pyranyloxy-16,16-dimethyl-9-keto-2,3-(-)-trans-methylene-prosta-5cis, 13trans-dienoic acid-tert.- butyl dimethyl silyl ester is dissolved in 18 ml of a mixture of equal amounts of acetic acid, tetrahydrofuran and water. The reaction mixture is set aside for 38 hours at room temperature and then evaporated in vacuo. The residue is chromatographed on silica gel using chloroform + 2% methanol as eluent. Hereby, the compound mentioned in the title is obtained in pure form.

IR 3550, 3400, 1720, 1695 cm"<1>.IR 3550, 3400, 1720, 1695 cm"<1>.

Under anvendelse av den i eksempel 1 beskrevne fremgangsmåteUsing the method described in example 1

erholdes ved avspalting av beskyttelsesgruppene fra de tilsvarende 15-tetrahydropyranetere de i det følgende angitte forbindelser med formel I. Hvis det i reaksjonsproduktet inneholdes en 11-hydroksygruppe, går. man derved ut fra den tilsvarende 11,15-bis-tetrahydro-pyranyleter. Hvis det i reaksjonsproduktet inneholdes en 9-keto-gruppe beskyttes denne gruppe i utgangsmaterialet med en tert.-butyldimetyl-silylester. Ellers anvendes den fri syre som utgangsforbindelse. are obtained by removing the protective groups from the corresponding 15-tetrahydropyranethers the following compounds of formula I. If the reaction product contains an 11-hydroxy group, one thereby starts from the corresponding 11,15-bis-tetrahydro-pyranyl ether. If the reaction product contains a 9-keto group, this group is protected in the starting material with a tert-butyldimethylsilyl ester. Otherwise, the free acid is used as starting compound.

Eksempel 2 ; 15-deutero-16,16-dimetyl-2,3-(+)-trans-metylen-9 a,11a,-15R-trihydroksy-prosta-5cis-13trans-diénsyre. Example 2; 15-deutero-16,16-dimethyl-2,3-(+)-trans-methylene-9α,11α,-15R-trihydroxy-prosta-5cis-13trans-dienoic acid.

IR 3600, 3400, 1695 cm<-1>. IR 3600, 3400, 1695 cm<-1>.

Eksempel 3: 15-deutero-ll a,15R-dihydroksy-16,16-dimetyl-9-keto-2,3-• ( + )-trans-metylen-prosta-5cis,13trans-diensyre. Example 3: 15-deutero-11α,15R-dihydroxy-16,16-dimethyl-9-keto-2,3-• ( + )-trans-methylene-prosta-5cis,13trans-dienoic acid.

IR 3600, 3450, 1740, 1695 crn^<1>. IR 3600, 3450, 1740, 1695 cr^<1>.

Eksempel 4: 15-deutéro-16,16-dimetyl-15R-hydroksy-2,3-(+)-trans-metylen-9-keto-prosta-5cis,10,13trans-triensyre. Example 4: 15-deutero-16,16-dimethyl-15R-hydroxy-2,3-(+)-trans-methylene-9-keto-prosta-5cis,10,13trans-trienoic acid.

IR 3600, 1700, 1140 cm"<1>. IR 3600, 1700, 1140 cm"<1>.

Eksempel 5: 15-deutero-16,16-dimetyl-2,3-(+)-trans-metylen-9 a ,11 a ,-15R-trihydroksy-prosta-5cis, 13trans-diensyre-metylester. Example 5: 15-deutero-16,16-dimethyl-2,3-(+)-trans-methylene-9a,11a,-15R-trihydroxy-prosta-5cis,13trans-dienoic acid methyl ester.

IR 3600, 3400, 1720, 1710 cm<-1>. IR 3600, 3400, 1720, 1710 cm<-1>.

Eksempel 6; 15-deutero-16,16-dimetyl-2,3-(-)-trans-metylen-9a ,11a , - Example 6; 15-deutero-16,16-dimethyl-2,3-(-)-trans-methylene-9a ,11a , -

15R-trihydroksy-prosta-5cis, 13trans-diensyre.15R-trihydroxy-prosta-5cis, 13trans-dienoic acid.

IR 3600, 3500, 1715, 1700 cm<-1>. IR 3600, 3500, 1715, 1700 cm<-1>.

Eksempel 7: 15-deutero-16,16-dimetyl-2,3-(-)-trans-metylen-9a ,11a ,-15R-trihydroksy-prosta-13trans-ensyre. Example 7: 15-deutero-16,16-dimethyl-2,3-(-)-trans-methylene-9a,11a,-15R-trihydroxy-prosta-13trans-enoic acid.

IR 3550 - 3400, 1700 cm"<1>. IR 3550 - 3400, 1700 cm"<1>.

Eksempel 8: 15-deutero-lla , 15R-dihydroksy-16 ,16-dimetyl-9-keto-2.3-(-)-trans-metylen-prosta-13-trans-ensyre Example 8: 15-deutero-lla, 15R-dihydroxy-16,16-dimethyl-9-keto-2.3-(-)-trans-methylene-prosta-13-trans-enoic acid

IR 3600 - 3400, 1740, 1695 cm<-1>. IR 3600 - 3400, 1740, 1695 cm<-1>.

Eksempel 9: 15-deutero-16,16-dimetyl-15R-hydroksy-9-keto-2,3-(-) - Example 9: 15-deutero-16,16-dimethyl-15R-hydroxy-9-keto-2,3-(-)-

trans-metylen-prosta-10, l3tr;ans-diensyre.trans-methylene-prosta-10, l3tr;ans-dienoic acid.

IR 3600, 1700 cm"<1>. IR 3600, 1700 cm"<1>.

Eksempel 10; 15-deutero-2-etylen-16,16-dimetyl-9a,11 a,15R-trihydroksy-prosta-5cis, 13trans-diensyre. Example 10; 15-deutero-2-ethylene-16,16-dimethyl-9a,11a,15R-trihydroxy-prosta-5cis,13trans-dienoic acid.

IR 3400, 1690 cm"<1>. IR 3400, 1690 cm"<1>.

Eksempel 11; 15-deutero-2-etylen-16,16-dimetyl-ll a,15R-dihydroksy-9-keto-prosta-5cis,13trans-diensyre. Example 11; 15-deutero-2-ethylene-16,16-dimethyl-11α,15R-dihydroxy-9-keto-prosta-5cis,13trans-dienoic acid.

IR 3400, 1740 - 1730, 1700 - 1680 cm"<1>. IR 3400, 1740 - 1730, 1700 - 1680 cm"<1>.

Eksempel 12; 15-deutero-2-etylen-16,16-dimetyl-15R-hydroksy-prosta-5cis,10,13trans-triensyre. Example 12; 15-deutero-2-ethylene-16,16-dimethyl-15R-hydroxy-prosta-5cis,10,13trans-trienoic acid.

IR 3600, 1710- - 1685 cm"<1>. IR 3600, 1710- - 1685 cm"<1>.

Eksempel 13; 16-n-butyl-15-deutero-2,3-(-)-trans-metylen-9oe ,11 a - Example 13; 16-n-butyl-15-deutero-2,3-(-)-trans-methylene-9oe ,11 a -

15S-trihydroksy-prosta-5cis, 13trans-diensyre.15S-trihydroxy-prosta-5cis, 13trans-dienoic acid.

IR 3550 - 3350, 1715 - 1680 cm"<1.>IR 3550 - 3350, 1715 - 1680 cm"<1.>

Eksempel 14; 16-n-butyl-15-deutero-11 a ,15S-dihydroksy-9-keto-2,3-(-)-trans-metylen-prosta-5cis,13trans-diensyre. Example 14; 16-n-butyl-15-deutero-11α,15S-dihydroxy-9-keto-2,3-(-)-trans-methylene-prosta-5cis,13trans-dienoic acid.

IR 3550- 3350, 1745 1690 cm"<1>. IR 3550- 3350, 1745 1690 cm"<1>.

Eksempel 15; 16-n-butyl-15-deutero-15S-hydroksy-9-keto(2,3)-(-)-trans-metylen-prosta-5cis, 10,13trans-triensyre. Example 15; 16-n-butyl-15-deutero-15S-hydroxy-9-keto(2,3)-(-)-trans-methylene-prosta-5cis, 10,13trans-trienoic acid.

IR 3600, 1745 - 1690 cm"<1>. IR 3600, 1745 - 1690 cm"<1>.

Eksempel 16: 15-deutero-lla ,15R-dihydroksy-9-keto-16R-metyl-2,3-(-)-trans-metylen-prostansyre. Example 16: 15-deutero-lla,15R-dihydroxy-9-keto-16R-methyl-2,3-(-)-trans-methylene-prostanic acid.

IR 3600 - 3300, 1740 - 1690 em"<1>. IR 3600 - 3300, 1740 - 1690 em"<1>.

Eksempel 17: 15-deutero-lla ,15R-dihydroksy-9-keto-16R-metyl-2,3-(-)-trans-metylen-prosta-5cis-ensyré. Example 17: 15-deutero-lla,15R-dihydroxy-9-keto-16R-methyl-2,3-(-)-trans-methylene-prosta-5cis-enic acid.

IR 3600 - 3350, 1735 - 1685 cm<-1>. IR 3600 - 3350, 1735 - 1685 cm<-1>.

Eksempel 18: 15-deutero-lla ,15R-dihydroksy-16,16-dimetyl-9-keto-2,3-(-)-trans-metylen-prosta-5cis,13trans-diensyre-metylester. Example 18: 15-deutero-lla,15R-dihydroxy-16,16-dimethyl-9-keto-2,3-(-)-trans-methylene-prosta-5cis,13trans-dienoic acid methyl ester.

IR 3600 - 3400, 1750 - 1700 cm"<1>. IR 3600 - 3400, 1750 - 1700 cm"<1>.

Eksempel 19: 15-deutero-16,16-dimetyl-9 a,11 a-15R-trihydroksy-17,18,19,20-tetranor-16-(3'-trifluormetyl-fenoksy)-2,3-(-)-trans-metylen-prosta-5cis,13trans-diensyre. Example 19: 15-deutero-16,16-dimethyl-9α,11α-15R-trihydroxy-17,18,19,20-tetranor-16-(3'-trifluoromethyl-phenoxy)-2,3-(- )-trans-methylene-prosta-5cis,13trans-dienoic acid.

IR 3500 - 3300, 1730 - 1670 cm"<1>. IR 3500 - 3300, 1730 - 1670 cm"<1>.

Eksempel 20: l-dekarboksy-15-deutero-16,16-dimetyl-2-(5<1->tetrazolyl)-9 a,11 a,15R-trihydroksy-17,18,19,20-tetranor-16-(3'-trifluormetylfenoksy)-prosta-5cis,13trans-diensyre. Example 20: 1-decarboxy-15-deutero-16,16-dimethyl-2-(5<1->tetrazolyl)-9α,11α,15R-trihydroxy-17,18,19,20-tetranor-16- (3'-Trifluoromethylphenoxy)-prosta-5cis,13trans-dienoic acid.

IR 3500 - SSOOcm"<1>.IR 3500 - SSOOcm"<1>.

Eksempel 21: 15-deutero-ll a,15Rrdihydroksy-16,16-dimetyl-2,3-(-)-trans-metylen-9-keto-17,18,19,20-tetranor-16-(3<1->trifluormetylfenoksy)-prosta-5cis,13trans-diensyre. Example 21: 15-deutero-11α,15Rdihydroxy-16,16-dimethyl-2,3-(-)-trans-methylene-9-keto-17,18,19,20-tetranor-16-(3<1 ->trifluoromethylphenoxy)-prosta-5cis,13trans-dienoic acid.

IR 3500 - 3300, 1760 - 1720, 1720 - 1670 cm"<1>. IR 3500 - 3300, 1760 - 1720, 1720 - 1670 cm"<1>.

Eksempel 22: 15-deutero-9 a,11 a,15S-trihydroksy-prosta-5cis,13trans-diensyre-lysergylester. Example 22: 15-deutero-9α,11α,15S-trihydroxy-prosta-5cis,13trans-dienoic acid lyseryl ester.

IR 3550 - 3400, 1740 cm"<1>. IR 3550 - 3400, 1740 cm"<1>.

Eksempel 23: 15-deutero-15S-hydroksy-lloc ,imidazol-1'-yl-9-keto-prosta-5cis,13trans-diensyre-(1<1->decanyl)-ester. Example 23: 15-deutero-15S-hydroxy-1loc,imidazol-1'-yl-9-keto-prosta-5cis,13trans-dienoic acid-(1<1->decanyl)-ester.

IR 3550 - 3350, 1740, 1720 cm"<1>. IR 3550 - 3350, 1740, 1720 cm"<1>.

Eksempel 24: 15-deutero-15S-hydroksy-lloc -imidazol-1'-yl-9-keto-prosta-13trans-ensyre-lysergylester. Example 24: 15-deutero-15S-hydroxy-1loc-imidazol-1'-yl-9-keto-prosta-13trans-enoic acid lyseryl ester.

IR 3500 - 3400, 1745, 1725, 1505 cm"<1>. IR 3500 - 3400, 1745, 1725, 1505 cm"<1>.

Eksempel 25: 15-deutero-lla ,15S-dihydroksy-9-keto-prosta-13trans-ensyre-lysergylamid. Example 25: 15-deutero-lla,15S-dihydroxy-9-keto-prosta-13trans-enoic acid-lysergylamide.

IR (CH2C12 + 1% CH30H) 3400 (bred), 1745, 1665, 1525 cm"<1>. IR (CH2C12 + 1% CH3OH) 3400 (broad), 1745, 1665, 1525 cm"<1>.

Eksempel 26: 15-deutero-16 ,16-dimetyl-9 oe, 11 a, 15R-trihydroksy-prosta-5cis,13trans-diensyre. Example 26: 15-deutero-16,16-dimethyl-9oe,11a,15R-trihydroxy-prosta-5cis,13trans-dienoic acid.

IR 3650 - 3300, 1750 - 1700 cm"<1>. IR 3650 - 3300, 1750 - 1700 cm"<1>.

Eksempel 27: 15-deutero-ll a,15R-dihydroksy-16,16-dimetyl-9-keto-prosta-5cis,13trans-diensyre. Example 27: 15-deutero-11α,15R-dihydroxy-16,16-dimethyl-9-keto-prosta-5cis,13trans-dienoic acid.

IR 3600 - 3300, 1760 - 1710, 1710 - 1690 cm"<1>. IR 3600 - 3300, 1760 - 1710, 1710 - 1690 cm"<1>.

Eksempel 28: (+)-15-deutero-15 a-hydroksy-9-ketoprostansyre.Example 28: (+)-15-deutero-15α-hydroxy-9-ketoprostanic acid.

IR 3500, 1760 - 1700 cm"<1>. IR 3500, 1760 - 1700 cm"<1>.

Eksempel 29: (+)-15-deutero-17,18,19,20-tetranor-16-/3<1->trifluormetyl-fenoksy/-9 a, 11 a, 15 a'-hydroksy-prosta-5cis, 13trans-diensyre. Example 29: (+)-15-deutero-17,18,19,20-tetranor-16-/3<1->trifluoromethyl-phenoxy/-9 a, 11 a, 15 a'-hydroxy-prosta-5cis, 13trans-dienoic acid.

IR 3600, 3350, 1710 cm"<1>. IR 3600, 3350, 1710 cm"<1>.

Eksempel 30: 15-deutero-ll a,15R-dihydroksy-9keto-16R-metyl-prosta-5cis-ensyre-metylester. Example 30: 15-deutero-11α,15R-dihydroxy-9keto-16R-methyl-prosta-5cis-enoic acid methyl ester.

IR 3700 - 3300, 1740 cm"<1>. IR 3700 - 3300, 1740 cm"<1>.

Eksempel 31: 15-deutero-ll a ,15S-dihydroksy-9-keto-prosta-5cis, Example 31: 15-deutero-lla,15S-dihydroxy-9-keto-prosta-5cis,

13trans-diensyre-lysergylester.13trans-dienoic acid lyseryl ester.

IR 1740 (bred) cm<-1>.IR 1740 (wide) cm<-1>.

Fremstilling av utgangsforbindelse, f.eks. for eksempel 1:Production of output connection, e.g. for example 1:

a) (-) - 2 (3 - (3 1 -deutero-3 ' a -hydroksy-4', 4 ' -dimetyl-trans-1' -octenyl) - 5 oc -hydroksy-3 a -para-fenylbenzoyloksy-1 a -cyklopentyleddiksyre-^-lacton og (-) -2 (3 - (3' -deutero-3 1 (3 -hydroksy-4 ' ,4'-dimetyl-trans-11 - octenyl)-5 a -hydroksy-3'a -para-fenylbenzoyloksy-1oc -cyklo-pentyleddiksyre- ff lacton (mellomforbindelse. med formel V, a) (-)-2 (3 - (3 1 -deutero-3' a -hydroxy-4', 4 '-dimethyl-trans-1'-octenyl)-5oc -hydroxy-3 a -para-phenylbenzoyloxy- 1 a -cyclopentylacetic acid-^-lactone and (-)-2 (3 - (3'-deutero-3 1 (3-hydroxy-4',4'-dimethyl-trans-11-octenyl)-5 a -hydroxy- 3'a -para-phenylbenzoyloxy-1oc-cyclopentylacetic acid- ff lactone (intermediate compound. of formula V,

som inneholder en voluminøs grunne R^).which contains a voluminous shallow R^).

En løsning av 1.45 g 5 oc -hydroksy-2 (3 - (3 '-okso-4 1 ,4 ' -dimetyl-trans-11-octenyl)-3 oc -para-fenylbenzoyloksy-1 oc -cyklopentyl-eddiksyre- 3<*->lacton i 8 ml absolutt dimetoksyetan tildryppes ved -15°C under nitrogenatmosfære til en suspensjon av 2.26 g sinkbordeuterid i 20 ml absolutt dimetoksyetan. Blandingen omrøres ved 3 - 5°C i 3% time og deretter ved 5 - 10°C i 1 time. Blandingen avkjøles deretter til -15°C og tilsettes langsomt 3 ml av en vandig 10% A solution of 1.45 g of 5 oc -hydroxy-2 (3 - (3 '-oxo-4 1 ,4 ' -dimethyl-trans-11-octenyl)-3 oc -para-phenylbenzoyloxy-1 oc -cyclopentyl-acetic acid- 3 <*->lactone in 8 ml of absolute dimethoxyethane is added dropwise at -15°C under a nitrogen atmosphere to a suspension of 2.26 g of zinc bordeuteride in 20 ml of absolute dimethoxyethane.The mixture is stirred at 3 - 5°C for 3% hour and then at 5 - 10° C for 1 hour.The mixture is then cooled to -15°C and slowly added 3 ml of an aqueous 10%

(vektprosent) natriumhydrogentartrat-løsning. Blandingen ekstraheres to ganger med hver gang 100 ml eter og den organiske fase vaskes med 100 ml av en mettet vandig koksaltløsning, tørkes<oy>^natriumsulfat og inndampes ved redusert trykk, hvorved det erholdes en blanding av de tilsvarende oc - og P -alkoholer. Resten kromatograferes på 50 g nøytralt silikagel idet det med kloroform (5% etylacetat) først elueres - og deretter -isomerene og erholdes rene. (% by weight) sodium hydrogen tartrate solution. The mixture is extracted twice with 100 ml of ether each time and the organic phase is washed with 100 ml of a saturated aqueous sodium chloride solution, dried over sodium sulphate and evaporated under reduced pressure, whereby a mixture of the corresponding oc - and P -alcohols is obtained . The residue is chromatographed on 50 g of neutral silica gel, with chloroform (5% ethyl acetate) first eluting the - and then the - isomers and obtaining them pure.

oc - isomer:oc - isomer:

Tynnskiktkromatografering (silikagel):Thin layer chromatography (silica gel):

Metylenklorid (5% etylacetat) Rf = 0.4, Smp. 107 - 108°CMethylene chloride (5% ethyl acetate) Rf = 0.4, mp. 107 - 108°C

IR (metylenklorid) bl. a. bånd ved 3500, 1770, 1710, 1660 cm<-1>. IR (methylene chloride) p. a. band at 3500, 1770, 1710, 1660 cm<-1>.

- isomer:- isomer:

Tynnskiktkromatografering (silikagel) :Thin layer chromatography (silica gel):

Metylenklorid (5% etylacetat) Rf = 0.3Methylene chloride (5% ethyl acetate) Rf = 0.3

Spektraldata som ved a -isomeren.Spectral data as for the a -isomer.

Den ovenfor beskrevne (-)a -isomer omsettes videre i de etterfølgende fremgangsmåtetrinn b) til f), hvorved det er holdes optisk rene forbindelser: The above-described (-)a -isomer is further reacted in the subsequent method steps b) to f), whereby optically pure compounds are kept:

b) 2a -(3'-deutero-3' a-hydroksy-4',4<1->dimetyl-trans-1<1->octenyl)-b) 2a -(3'-deutero-3'a-hydroxy-4',4<1->dimethyl-trans-1<1->octenyl)-

3 a,5 a-dihydroksy-1 a-cyklopentyl-eddiksyre--lacton 3α,5α-dihydroxy-1α-cyclopentyl-acetic acid--lactone

(forbindelse med formel V hvori R^står for hydrogen).(compound of formula V in which R^ stands for hydrogen).

En løsning av 104 mg natrium i 5.2 ml absolutt metanol tilsettes ved romtemperatur til en løsning av 2.5 g 2(3 - (3'-deutero-3' a-hydroksy-4<1>,4<1->dimetyl-trans-1'-octenyl)-5a -hydroksy-3 a-para-fenylbenzoyloksy-l-cyklopentyl-eddiksyre-#-lacton i 104 ml absolutt metanol ved romtemperatur. Etter 5 timer avkjøles blandingen til 10°C og tilsettes 6.3 ml metanolisk vinsyreløsning. Deretter inndampes blandingen ved redusert trykk, resten opptas i 250 ml metylenklorid, den organiske fase vaskes med 100 ml mettet vandig A solution of 104 mg of sodium in 5.2 ml of absolute methanol is added at room temperature to a solution of 2.5 g of 2(3 - (3'-deutero-3' a-hydroxy-4<1>,4<1->dimethyl-trans- 1'-octenyl)-5α-hydroxy-3α-para-phenylbenzoyloxy-1-cyclopentyl-acetic acid-#-lactone in 104 ml of absolute methanol at room temperature. After 5 hours, the mixture is cooled to 10° C. and 6.3 ml of methanolic tartaric acid solution is added. The mixture is then evaporated under reduced pressure, the residue is taken up in 250 ml methylene chloride, the organic phase is washed with 100 ml saturated aqueous

• natriumkloridløsning, tørkes over natriumsulfat og inndampes ved redusert trykk. Resten kromatograferes på 150 g kiselgel. Med benzen (20% aceton) elueres den i overskriften nevnte forbindelse. Smp. 82 - 84°C. c) 2 |3-(3 1-deutero-3 1 a-hydroksy-4',4'-dimetyl-trans-1<1->octenyl)-3a, 5 a-dihydroksy-1 a-cyklopentyl-eddiksyre-^ -lacton-3,31-bistetrahydropyranyleter. • sodium chloride solution, dried over sodium sulphate and evaporated under reduced pressure. The residue is chromatographed on 150 g of silica gel. The compound mentioned in the title is eluted with benzene (20% acetone). Temp. 82 - 84°C. c) 2 |3-(3 1-deutero-3 1 a-hydroxy-4',4'-dimethyl-trans-1<1->octenyl)-3a, 5 a-dihydroxy-1 a-cyclopentyl-acetic acid- ^-lactone-3,31-bistetrahydropyranyl ether.

(Forbindelse med formel V med syreømfindtlige beskyttelsesgrupper) . (Compound of formula V with acid-sensitive protecting groups).

En løsning med 1,6 g 2 (3-(3 1-deutero-3 1 a -hydroksy-4 1 , 4 1-dimetyl-trans-1<1->octenyl)-3 a,5a -dihydroksy-la -cyklopentyleddiksyre-^<1>- lacton, 31 mg p-toluensulfonsyremonohydrat og 1.33 g 3,4-dihydro-2H-pyran i 103 ml absolutt toluen fremstilles ved -10°C, settes bort for oppvarming til romtemperatur og omrøres i 1 time. Løsningen vaskes deretter med 50 ml av en 10% vandig kaliumbikarbonatløsning og to ganger med hver gang 100 ml av en mettet vandig koksaltløsning, tørkes over natriumsulfat og inndampes ved redusert trykk. Den gulaktige oljeaktige rest kromatograferes på 120 g kiselgel med toluen (+ 5% aceton) og deretter isoleres den rene i overskriften nevnte forbindelse. A solution with 1.6 g of 2 (3-(3 1-deutero-3 1 a -hydroxy-4 1 , 4 1-dimethyl-trans-1<1->octenyl)-3 a,5a -dihydroxy-1a - cyclopentylacetic acid-^<1>- lactone, 31 mg of p-toluenesulfonic acid monohydrate and 1.33 g of 3,4-dihydro-2H-pyran in 103 ml of absolute toluene are prepared at -10°C, set aside to warm to room temperature and stirred for 1 hour. The solution is then washed with 50 ml of a 10% aqueous potassium bicarbonate solution and twice with each time 100 ml of a saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated under reduced pressure. The yellowish oily residue is chromatographed on 120 g of silica gel with toluene (+ 5% acetone) and then the pure compound mentioned in the title is isolated.

Tynnskiktkromatografering (toluen; aceton 2:1), Rf = 0.7 (silikagel) Thin layer chromatography (toluene; acetone 2:1), Rf = 0.7 (silica gel)

IR (metylenklorid) bl. bånd ved 1770 cmIR (methylene chloride) p. band at 1770 cm

d) 2(3 - (3'-deutero-3 ' a -hydroksy-4 ', 4 '-dimetyl-trans-1' -octenyl) - 3 a ,5 a -dihydroksy-1'a -cykbpentyl-acetaldehyd- ^-lactol-3 ,3 ' -bis-tetrahydropyranyleter. d) 2(3 - (3'-deutero-3' a -hydroxy-4 ',4'-dimethyl-trans-1'-octenyl)-3a,5a-dihydroxy-1'a-cyclopentyl-acetaldehyde- β-lactol-3,3'-bis-tetrahydropyranyl ether.

(Forbindelse med formel III)(Compound of formula III)

8.73 ml diisobutylaluminiumhydrid tildryppes under nitrogenatmosfære langsomt under omrøring til en løsning av 2.43 g 2(3 - (3'-deutero-3' a -hydroksy-4',4'-dimetyl-trans-1'-octenyl)-3 a ,5 a -dihydroksy-1 -cyklopentyl-eddiksyre-^ -lacton-3,3'-bis-tetrahydropyranyleter 8.73 ml of diisobutylaluminum hydride are added dropwise under nitrogen atmosphere slowly with stirring to a solution of 2.43 g 2(3 - (3'-deutero-3' a -hydroxy-4',4'-dimethyl-trans-1'-octenyl)-3 a , 5α-dihydroxy-1-cyclopentyl-acetic acid-β-lactone-3,3'-bis-tetrahydropyranyl ether

i 102 ml absolutt toluen ved -70°C. Deretter omrøres i 1 time ved in 102 ml of absolute toluene at -70°C. Then stir for 1 hour

-70°C og deretter tilsettes forsiktig i løpet av 30 minutter 65.3 ml -70°C and then carefully add 65.3 ml over 30 minutes

tetrahydrofuran/vann (2:1). Den organiske fase vaskes ved romtemperatur med 150 ml av en mettet vandig koksaltløsning, tørkes over natriumsulfat og inndampes ved redusert trykk. Derved erholdes den i overskriften nevnte forbindelse som en viskøs olje. tetrahydrofuran/water (2:1). The organic phase is washed at room temperature with 150 ml of a saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated under reduced pressure. Thereby, the compound mentioned in the title is obtained as a viscous oil.

IR (metylenklorid) bl.a. bånd ved 3600, 1200 cm<-1>.IR (methylene chloride) i.a. bands at 3600, 1200 cm<-1>.

e) 15-deutero-16,16-dimetyl-9a -hydroksy-11a ,15 a -bis-tetra-pyanyloksy-2,3-(-)-trans-metylen-prosta-5cis,13trans-diensyre. e) 15-deutero-16,16-dimethyl-9α-hydroxy-11α,15α-bis-tetra-pyanyloxy-2,3-(-)-trans-methylene-prosta-5cis,13trans-dienoic acid.

(Forbindelse med formel II, A = A7).(Compound of formula II, A = A7).

380 mg natriumhydrid suspenderes i 3.8 m 1 absolutt dimetylsulfoksyd, og suspensjonen holdes under nitrogen i 55 minutter ved 75°C. Etter avkjøling tildryppes 2.1 ml av denne løsning langsomt til en forhåndsfremstilt løsning av 1.89 g trifenylfosfoniumsalt av (-)-trans-cyklo-propyl-1-(2-brometyl)-karboksylsyre i 5 ml absolutt dimetylsulfoksyd og omrøres under nitrogen i 45 minutter. 4 ml av den således erholdte ylid-løsning tilsettes ved 20°C til en forhånds-tilberedt løsning av 980 mg av 2 (3 - (3'-deutero-3' a -hydroksy-4', 4 '-dimetyl-trans-1'-octenyl)-3 oc , 5 oc -dihydroksy-1 oc -eykbpentyl-acetaldehyd-^<1->lactal-3,3'-bis-tetrahydropyranyleter i 3 ml absolutt dimetylsulfoksyd og 3 ml absolutt tetrahydrofuran. Reaksjonsblandingen holdes i 30 minutter ved 55°C. Etter tilsetning av ytterligere 4 ml av ylidløsningen omrøres på nytt i lh time ved 55°C. Den avkjølte reaksjonsblanding uthelles på 100 g is, den vandige fase innstilles til pH 3 - 4, ekstraheres 3 ganger med kloroform, den organiske fase vaskes, tørkes og inndampes under redusert trykk. Det erholdte råprodukt kromatograferes på 100 g silikagel med kloroform (med 1-5% metanol) hvorved den rene i overskriften nevnte forbindelse erholdes. 380 mg of sodium hydride are suspended in 3.8 m 1 of absolute dimethyl sulphoxide, and the suspension is kept under nitrogen for 55 minutes at 75°C. After cooling, 2.1 ml of this solution is slowly added dropwise to a previously prepared solution of 1.89 g of the triphenylphosphonium salt of (-)-trans-cyclopropyl-1-(2-bromomethyl)-carboxylic acid in 5 ml of absolute dimethylsulfoxide and stirred under nitrogen for 45 minutes. 4 ml of the ylide solution thus obtained is added at 20°C to a previously prepared solution of 980 mg of 2 (3 - (3'-deutero-3' a -hydroxy-4', 4 '-dimethyl-trans- 1'-octenyl)-3 oc , 5 oc -dihydroxy-1 oc -eykbpentyl-acetaldehyde-^<1->lactal-3,3'-bis-tetrahydropyranyl ether in 3 ml of absolute dimethylsulfoxide and 3 ml of absolute tetrahydrofuran. The reaction mixture is kept in 30 minutes at 55° C. After adding a further 4 ml of the ylide solution, stir again for 1 hour at 55° C. The cooled reaction mixture is poured onto 100 g of ice, the aqueous phase is adjusted to pH 3 - 4, extracted 3 times with chloroform , the organic phase is washed, dried and evaporated under reduced pressure. The crude product obtained is chromatographed on 100 g of silica gel with chloroform (with 1-5% methanol) whereby the pure compound mentioned in the title is obtained.

IR (Metylenklorid) bl. av 1 bånd ved 3600, 3500, 1695 cm<-1>.IR (Methylene chloride) p. of 1 band at 3600, 3500, 1695 cm<-1>.

f) 15-deutero-16,16-dimetyl-9-keto-lloc , 15 oc -bis-tetrahydro-pyranyloksy-2,3-(-)-trans-metylen-prosta-5cis,13trans-diensyre-tert.-butyldimetyl-silylester. f) 15-deutero-16,16-dimethyl-9-keto-lloc , 15 oc -bis-tetrahydro-pyranyloxy-2,3-(-)-trans-methylene-prosta-5cis,13trans-dienoic acid-tert.- butyl dimethyl silyl ester.

Til 460 mg 15-deutero-16,16-dimetyl-9 oc -hydroksy-11 oc,15oc-bis-tetrahydropyranyloksy-2,3-(-)-trans-metylen-5cis-13trans-prostadien-syre i 4,5 ml absolutt toluen tilsettes 137. mg tert.-butyldimetyl-klorsilan under nitrogen, hvorved den tilsvarende silylester erholdes. Reaksjonsblandingen avkjøles til 0°C og tilsettes 93 mg trietylamin i 9 ml absolutt toluen, omrøres i 4 timer ved romtemperatur avkjøles til -25°C og tildryppes langsomt i løpet av 30 minutter til en løsning av 500 mg N-klorsuccinimid i 19 ml absolutt toluen og 0.33 ml dimetylsulfid. Etter 3 timer tildryppes 1 ml trietylamin i 5 ml pentan, det omrøres videre i 25 minutter ved romtemperatur og opparbeides med eter/vann, hvorved den i overskriften nevnte forbindelse erholdes. To 460 mg of 15-deutero-16,16-dimethyl-9oc -hydroxy-11oc,15oc-bis-tetrahydropyranyloxy-2,3-(-)-trans-methylene-5cis-13trans-prostadienic acid in 4.5 ml of absolute toluene, 137 mg of tert-butyldimethylchlorosilane are added under nitrogen, whereby the corresponding silyl ester is obtained. The reaction mixture is cooled to 0°C and 93 mg of triethylamine in 9 ml of absolute toluene is added, stirred for 4 hours at room temperature, cooled to -25°C and slowly added dropwise over 30 minutes to a solution of 500 mg of N-chlorosuccinimide in 19 ml of absolute toluene and 0.33 ml of dimethyl sulphide. After 3 hours, 1 ml of triethylamine in 5 ml of pentane is added dropwise, it is stirred for 25 minutes at room temperature and worked up with ether/water, whereby the compound mentioned in the title is obtained.

Under anvendelse av den ovenfor beskrevne fremgangsmåte kan prostaglandiner fremstilles ved å gå ut fra de følgende forbindelser med V, hvori R^ og R^. i det enkelte tilfelle står for hydrogen, Using the method described above, prostaglandins can be prepared starting from the following compounds with V, in which R^ and R^. in the individual case stands for hydrogen,

som på sin side erholdes fra de tilsvarende 3-para-fenylbenzoyl og 3- which in turn is obtained from the corresponding 3-para-phenylbenzoyl and 3-

benzoyl-derivater, og som på sin side omdannes i de tilsvarende 3,3'-bis-tetrahydropyranyletere. benzoyl derivatives, and which in turn are converted into the corresponding 3,3'-bis-tetrahydropyranyl ethers.

ba) 2(3 - (3 1-deutero-3 ' p -hydroksy-4',4'-dimetyl-trans-1'-octenyl)-ba) 2(3 - (3 1-deutero-3' p -hydroxy-4',4'-dimethyl-trans-1'-octenyl)-

3a ,5a -dihydroksy-la -cyklopentyl-eddiksyre-^* -lacton,3a,5a-dihydroxy-1a-cyclopentyl-acetic acid-^*-lactone,

bb) 2(3 -(3'-deutéro-3'a -hydroksy-4'-4'-dimetyl-trans-1'-octenyl)-bb) 2(3-(3'-deutero-3'a-hydroxy-4'-4'-dimethyl-trans-1'-octenyl)-

3a ,5a ,dihydroksy-la -cyklopentyl-eddiksyre- ^-lacton,3a,5a,dihydroxy-1a-cyclopentyl-acetic acid-^-lactone,

be)<*>2(3 -(3'-deutero-3'(3 -hydroksy-4<1>,4<1>-dimetyl-trans-1'-octenyl)-be)<*>2(3 -(3'-deutero-3'(3 -hydroxy-4<1>,4<1>-dimethyl-trans-1'-octenyl)-

3a ,5a -dihydroksy-la -cyklopentyl-eddiksyre-:^<1>lacton,3a,5a-dihydroxy-1a-cyclopentyl-acetic acid-:^<1>lactone,

bd) 2(3 -(3'-deutero-3'a -hydroksy-4'-metyl-trans-1'-octenyl)-bd) 2(3-(3'-deutero-3'a-hydroxy-4'-methyl-trans-1'-octenyl)-

3af'5a -dihydroksy-la -cyklopentyl-eddiksyre- ff -lacton,3af'5a -dihydroxy-1a -cyclopentyl-acetic acid- ff -lactone,

be) 2(3 -(3<1->deutero-31p -hydroksy-4'-metyl-trans-11-octenyl) -be) 2(3 -(3<1->deutero-31p -hydroxy-4'-methyl-trans-11-octenyl) -

3a i 5a -dihydroksy-l&-cyklopentyl-eddiksyre--lacton,3a in 5a -dihydroxy-1&-cyclopentyl-acetic acid--lactone,

bf) 2(3 -(3'-deutero-4,4-dimetyl-3'a -hydroksy-trans-1'-octenyl)-bf) 2(3-(3'-deutero-4,4-dimethyl-3'a-hydroxy-trans-1'-octenyl)-

5a -hydroksy-la -cyklopent-2-enyl-eddiksyre- ^ -lacton,5α-hydroxy-1α-cyclopent-2-enyl-acetic acid-^-lactone,

bg) 2(3 -(4-n-butyl-3'-deutero-31S-hydroksy-trans-1'-octenyl)-bg) 2(3 -(4-n-butyl-3'-deutero-31S-hydroxy-trans-1'-octenyl)-

3a ,5a -dihydroksy-la -cyklopentyl-eddiksyre-^-lacton,3a,5a-dihydroxy-1a-cyclopentyl-acetic acid-^-lactone,

bh) 2|3 - (4-n-butyl-3 ' -deutero-3 ' S-hydroksy-trans-11 -octenyl) -bh) 2|3 - (4-n-butyl-3 ' -deutero-3 ' S-hydroxy-trans-11 -octenyl) -

5a -hydroksy-la -cyklopent-2-enyl-eddiksyre-^ -lacton,5α-hydroxy-1α-cyclopent-2-enyl-acetic acid-β-lactone,

bi) 2(3 -(3<1->deutero-3'R-hydroksy-4R-metyl-l'-octenyl)-3a ,5a - bi) 2(3 -(3<1->deutero-3'R-hydroxy-4R-methyl-1'-octenyl)-3a ,5a -

dihydroksy-1 -cyklopentyl-eddiksyre-^<1>-lacton,dihydroxy-1-cyclopentyl-acetic acid-^<1>-lactone,

b j ) 2(3 - (3 ' -deutero-3 ' R-hydroksy-4 ' -metyl-4 ' -/3 "-trif luormetylf enoksy/ b j ) 2(3 - (3'-deutero-3'R-hydroxy-4'-methyl-4'-/3"-trifluoromethylphenoxy/

trans-l-pentenyl)-3a ,5a -dihydroksy-la -cyklopentyl-eddiksyre-^-lacton, trans-1-pentenyl)-3α,5α-dihydroxy-1α-cyclopentyl-acetic acid-β-lactone,

bk) 2(3 -(31-deutero-31S-hydroksy-trans-1'-octenyl)-3a ,5a -dihydroksy-1 -cyklopentyl-eddiksyre- -lacton, bk) 2(3-(31-deutero-31S-hydroxy-trans-1'-octenyl)-3a,5a-dihydroxy-1-cyclopentyl-acetic acid--lactone,

bl) 2p -(3'-deutero-3'S-hydroksy-trans-1<1->octenyl)-5a-hydroksy-bl) 2p -(3'-deutero-3'S-hydroxy-trans-1<1->octenyl)-5a-hydroxy-

la -cyklopent-3-enyl-eddiksyre-^f1 -lacton,1a -cyclopent-3-enyl-acetic acid-^f1 -lactone,

bm) 2p -- (3'-deutero-3'a -hydroksy1-octyl)-5a -hydroksy-1 a-cyklopentyl-eddiksyre-^<1>-lacton, bm) 2p -- (3'-deutero-3'a -hydroxy1-octyl)-5a -hydroxy-1a-cyclopentyl-acetic acid-^<1>-lactone,

bn)<*>2(3 - (3'-deutero-3'a -hydroksy-4'-(3"-trifluormetyl-fenoksy)-trans-1 butenyl)-3a ,5a -dihydroksy-la -cyklopentyl-eddiksyre-^<1>- lacton. bn)<*>2(3 - (3'-deutero-3'a -hydroxy-4'-(3"-trifluoromethyl-phenoxy)-trans-1 butenyl)-3a ,5a -dihydroxy-1a -cyclopentyl-acetic acid -^<1>- lactone.

<*>erholdes i (+) racemisk form og i 3'R eller 3'S optisk aktiv form. <*>is obtained in (+) racemic form and in 3'R or 3'S optically active form.

Eksempel 32: 15- deutero- 9oc - hydroksy- llg , 15S- bis- tetrahydro-pyranyloksy- prosta- 5cis, 13trans- diensyre- lysergylester Example 32: 15-deutero-9oc-hydroxy-llg, 15S-bis-tetrahydro-pyranyloxy-prosta-5cis, 13trans-dienoic acid-lysergyl ester

(Utgangsmaterial for eksempel 22)(Source material for example 22)

a) Ca. 275 mg 15-deutero-9cc -hydroksy-lloc , 15S-bis-tetrahydro-. pyranyloksyprosta-5cis,13trans-diensyre omsettes med 167 mg a) Approx. 275 mg of 15-deutero-9cc-hydroxy-lloc, 15S-bis-tetrahydro-. pyranyloxyprosta-5cis,13trans-dienoic acid is reacted with 167 mg

2,2-ditiopyridin og 199 mg trifenylfosfin i 5 ml xylen ved 20°C i 24 timer. Deretter avdampes løsningsmidlet og den tilbakeblivende olje kromatograferes på "Sephadex LH 20" under anvendelse av metylenklorid og 2% metanol som elueringsmiddel. Herved erholder man den tilsvarende 2-tiopyridylester. 2,2-dithiopyridine and 199 mg of triphenylphosphine in 5 ml of xylene at 20°C for 24 hours. Then the solvent is evaporated and the remaining oil is chromatographed on "Sephadex LH 20" using methylene chloride and 2% methanol as eluent. This gives the corresponding 2-thiopyridyl ester.

b) 190 mg 15-déutero-9oc -hydroksy-lloc ,15S-bis-tetrahydropyranyloksy-prosta-5cis,13trans-diensyre-2-tiopyridylester omsettes med 90 mg lysergol i 5 ml tetrahydrofuran ved 20°C i 24 timer. b) 190 mg of 15-deutero-9oc-hydroxy-1loc,15S-bis-tetrahydropyranyloxy-prosta-5cis,13trans-dienoic acid-2-thiopyridyl ester is reacted with 90 mg of lysergol in 5 ml of tetrahydrofuran at 20°C for 24 hours.

Reaksjonsblandingen opparbeides på "Sephadex LH 20". under anvendelse av metylenklorid og 0.5% metanol, hvorved den i overskriften nevnte forbindelse erholdes. The reaction mixture is worked up on "Sephadex LH 20". using methylene chloride and 0.5% methanol, whereby the compound mentioned in the title is obtained.

Utgangsforbindelsene for eksemplene 25 og 31 kan erholdes påThe output connections for examples 25 and 31 can be obtained at

analog måte under anvendelse av tilsvarende utgangsforbindelser. analogous way using corresponding output connections.

Eksempel 33 : 15- deutero- r5S- tetrahydrQpyranyloksy- ll<x - imidazo- 1' -- yl- 9- kéto- prosta- 13trairs- ensyre- lysergylester Example 33: 15-deutero-r5S-tetrahydrQpyranyloxy-ll<x-imidazo-1'--yl-9-keto-prosta-13trairsenoic acid-lysergyl ester

(Utgangsforbindelse for eksempel 24)(Output connection for example 24)

En løsning av 180 mg 15-deutero-15S-tetrahydropyranyloksy-9-keto-A solution of 180 mg of 15-deutero-15S-tetrahydropyranyloxy-9-keto-

i in

prosta-10,13trans-diensyre i 4 ml absolutt dimetylformamid bringes til reaksjon med 76 mg karbonyldiimidazol under omrøring og under nitrogenatmosfære iløpet av 3\ time under samtidig tilsetning av 145 mg finpulverisert lysergol og en katalytisk mengde av en nyfremstilt løsning av natriumimidazol i tetrahydrofuran. prosta-10,13trans-dienoic acid in 4 ml of absolute dimethylformamide is reacted with 76 mg of carbonyldiimidazole with stirring and under a nitrogen atmosphere during 3 hours with the simultaneous addition of 145 mg of finely powdered lysergol and a catalytic amount of a freshly prepared solution of sodium imidazole in tetrahydrofuran.

Blandingen omrøres i 7 døgn ved romtemperatur. Deretter avdampes løsningsmidlet ved romtemperatur under vakuum og den oljeaktige rest kromatograferes på "Sephadex LH 20" under anvendelse av metylenklorid (1% metanol) hvorved den i overskriften nevnte forbindelse erholdes. The mixture is stirred for 7 days at room temperature. The solvent is then evaporated at room temperature under vacuum and the oily residue is chromatographed on "Sephadex LH 20" using methylene chloride (1% methanol), whereby the compound mentioned in the title is obtained.

Utgangsforbindelsen for eksempel 23 kan fremstilles på analog måte. The output compound, for example 23, can be produced in an analogous manner.

Claims

1. Process for the production of prostaglandins which bound to the carbon atom in the 15-position contain both a hydroxy group as well as a deuterium atom, characterized in that protective groups are split off from hydroxy groups and/or carboxyl groups in corresponding prostaglandins.

2. Process for the preparation of compounds of formula IN

where A stands for the groups of formulas and B means groups of formulas

in which X stands for hydroxy, alkoxy with 1-10 carbon atoms, lysergyloxy, lysergylamino or dihydrolysergylamino, and C stands for a prostaglandin end group, characterized in that acid-sensitive protective groups are removed from compounds of formula II

wherein A <1> stands for A, which has the above meaning, or means the groups

in which R. and R,, in the individual case independently of each other stand for hydrogen or an acid-sensitive protecting group, B<1> stands for B, which has the above meaning, or means

where Rg means an acid-sensitive protecting group, and C has the above-mentioned meaning, with the condition that at least one acid-sensitive protecting group is present in the compounds of formula II, is cleaved off with the help of an acid

3. Process for the preparation of compounds of formula V in which C stands for a prostaglandin end group, and F means the formulas

where R. and R^ independently of each other stand for hydrogen or an acid-sensitive protecting group, characterized in that compounds of formula VI

in which C has the above meaning and F<1> stands for Fl, F2, F^ or F4

in which Ry means hydrogen or a bulky group, which is able to influence the ratio between formed oc : (3-alcohols are deuterated and a present group Ry is optionally transferred into a group R,, and 3-hydroxy groups are optionally protected with acid-sensitive protecting groups.