NO792118L

NO792118L - PROCEDURE FOR THE PREPARATION OF STEROID (16ALFA, 17-B) NAFTALENO AND CYCLOH WITCH 21-CARBOXYLIC ACID RESTREES

Info

Publication number: NO792118L
Application number: NO792118A
Authority: NO
Inventors: Ravi K Varma
Original assignee: Squibb & Sons Inc
Priority date: 1978-06-26
Filing date: 1979-06-25
Publication date: 1979-12-28
Also published as: HU180089B; SE7905568L; GB2106116B; GB2023608B; ES481866A1; PT69818A; AU524173B2; AU4748179A; CS208159B2; FI791934A; FR2429796A1; IE49178B1; SU1055334A3; PL216614A1; DD144550A5; CH642087A5; CA1142916A; GR72244B; ES481875A1; DK267079A

Description

"Fremgangsmåte for fremstilling av steroid [16a,17-b]-naftaleno- og cykloheksen- 21- karboksylsyreestere " "Procedure for the production of steroid [16a,17-b]-naphthaleno- and cyclohexene-21-carboxylic acid esters"

Steroider med formelen Steroids with the formula

og estere derav er nyttige som lokale anti-inflammatoriske midler. I formel I og i det følgende har symbolene de nedenfor angitte betydninger: X er hydrogen eller halogen; and esters thereof are useful as topical anti-inflammatory agents. In formula I and in what follows, the symbols have the following meanings: X is hydrogen or halogen;

Y er hydrogen, fluor eller metyl; Y is hydrogen, fluorine or methyl;

R4er klor, fluor eller hydroksy, og R5er hydrogen,R4 is chlorine, fluorine or hydroxy, and R5 is hydrogen,

• eller og R,- sammen er =0; • or and R,- together is =0;

R2og R^er like eller forskjellige og er hydrogen, alkyl eller aryl, eller sammen med dobbeltbindingen som de er knyttet til, R2 and R^ are the same or different and are hydrogen, alkyl or aryl, or together with the double bond to which they are attached,

danner de en benzenring; they form a benzene ring;

Rg og R-, er like eller forskjellige og er hydrogen, alkyl, Rg and R-, are the same or different and are hydrogen, alkyl,

alkoksy, formyl, alkyl-COO-, fenyl eller cyano, og dessuten hydroksy, halogen, karbalkoksy og alkylkarbonyl når R2og R^er separate, med det forbehold at når Rg og R^er forskjellige, er en av Rg og R^hydrogen; og alkoxy, formyl, alkyl-COO-, phenyl or cyano, and also hydroxy, halogen, caralkyloxy and alkylcarbonyl when R2 and R^ are separate, with the proviso that when Rg and R^ are different, one of Rg and R^ is hydrogen; and

RQer hydrogen eller CH-RnRn hvor Rn og R,_ er like ellerRQ is hydrogen or CH-RnRn where Rn and R,_ are equal or

o y iu y iuo y iu y iu

forskjellige og er hydrogen eller alkyl.different and are hydrogen or alkyl.

Den prikkede linje mellom 1- og 2-stillingene represen-terer en eventuell etylenisk umettethet. The dotted line between the 1 and 2 positions represents any ethylenic unsaturation.

Betegnelsene "alkyl" og "alkoksy" som her anvendt, omfatter både lineære og forgrenede grupper med 1-6 karbonatomer. The terms "alkyl" and "alkoxy" as used here include both linear and branched groups with 1-6 carbon atoms.

Betegnelsen "aryl" som her anvendt, omfatter fenyl eller fenyl substituert med én eller flere halogen-, alkyl- The term "aryl" as used herein includes phenyl or phenyl substituted with one or more halogen, alkyl

og alkoksygrupper.and alkoxy groups.

Betegnelsen "halogen" som her anvendt, omfatter fluor, klor, brom og jod. The term "halogen" as used herein includes fluorine, chlorine, bromine and iodine.

Estrene omfatter C2_~C]_0alkyl-, aryl- og aralkyl-estrene. The esters include the C 2 -C 1 -O alkyl, aryl and aralkyl esters.

Steroidene med formel I kan fremstilles fra de tilsvarende 21-hydroksy-steroid-[16a,17-b]-cykliske-ener med den generelle formel The steroids of formula I can be prepared from the corresponding 21-hydroxy-steroid-[16a,17-b]-cyclic-enes of the general formula

hvor symbolene er som ovenfor angitt. Steroidene med formel II er tidligere kjent, f.eks. fra US-patenter 3.927.720, 3.994.935 og 3.944.584. where the symbols are as above. The steroids of formula II are previously known, e.g. from US Patents 3,927,720, 3,994,935 and 3,944,584.

Et steroid med formel II kan oksyderes til det tilsvarende aldehyd med formelen under anvendelse av en katalysator så som kobberacetat. Omsetningen kan foretas i et alkoholisk oppløsningsmiddel. A steroid of formula II can be oxidized to the corresponding aldehyde of formula using a catalyst such as copper acetate. The reaction can be carried out in an alcoholic solvent.

Hvis den ovenfor beskrevne oksydasjonsreaksjon utføresIf the oxidation reaction described above is carried out

i nærvær av oksygen (f.eks. ved å boble luft gjennom reaksjonsblandingen), vil omsetningen vanligvis føre til, i tillegg til et steroid-21-aldehyd med formel III, det tilsvarende steroid-21-acetal dannet med alkohol-oppløsningsmidlet (R^-OH); dvs. et steroid med formelen in the presence of oxygen (e.g., by bubbling air through the reaction mixture), the reaction will usually lead, in addition to a steroid-21-aldehyde of formula III, to the corresponding steroid-21-acetal formed with the alcohol solvent (R ^-OH); i.e. a steroid with the formula

Oksydasjonsreaksjonen vil vanligvis være fullført i løpet av forholdsvis kort tid, dvs. ca. 1 time. The oxidation reaction will usually be completed within a relatively short time, i.e. approx. 1 hour.

Hvis den ovenfor beskrevne reaksjon får fortsette i lengere, tid, f.eks. mer enn ca. 24 timer, vil hovedproduktet være 20-hydroksy-21-karboksylsyreesteren med formelen ■ Hvis vann er til stede som et med-oppløsningsmiddel ved oksydasjonsreaksjonen, og man lar reaksjonen finne sted i lengere tid, vil det i tillegg til 20-hydroksy-21-karboksylsyreesteren med formel V, dannes den tilsvarende 20-hydroksy-21-karboksylsyre, dvs. et steroid med formelen If the reaction described above is allowed to continue for a longer time, e.g. more than approx. 24 hours, the main product will be the 20-hydroxy-21-carboxylic acid ester with the formula ■ If water is present as a co-solvent in the oxidation reaction, and the reaction is allowed to take place for a longer time, in addition to 20-hydroxy-21- the carboxylic acid ester of formula V, the corresponding 20-hydroxy-21-carboxylic acid is formed, i.e. a steroid of the formula

Steroidene med formlene V og VI eksisterer som blandinger av The steroids of formulas V and VI exist as mixtures of

20a- og 20(3-hydroksysteroidene. Omsetning åv et steroid med formel III eller IV eller en blanding derav med en uorganisk cyanidkatalysator, et oksydasjonsmiddel, et inert oppløsnings-middel, en alkohol og en organisk syre gir produktet med formel I. Mer spesielt kart et produkt med formel I fremstilles ved omsetning av et steroid-21-aldehyd med formel III eller det tilsvarende steroid-21-acetal med formel IV eller en blanding derav med en blanding av (i) en uorganisk cyanidkatalysator (f.eks. The 20a- and 20(3-hydroxysteroids. Reaction of a steroid of formula III or IV or a mixture thereof with an inorganic cyanide catalyst, an oxidizing agent, an inert solvent, an alcohol and an organic acid gives the product of formula I. More particularly map a product of formula I is prepared by reacting a steroid-21-aldehyde of formula III or the corresponding steroid-21-acetal of formula IV or a mixture thereof with a mixture of (i) an inorganic cyanide catalyst (e.g.

et alkalimetallcyanid så som kaliumcyanid); (ii) et oksydasjonsmiddel, f.eks. et tungmetalloksyd så som aktivert mangandioksyd an alkali metal cyanide such as potassium cyanide); (ii) an oxidizing agent, e.g. a heavy metal oxide such as activated manganese dioxide

eller blydioksyd, (iii) et inert oppløsningsmiddel, f.eks. et halogenert hydrokarbon-oppløsningsmiddel så som diklormetan eller kloroform; (iv) en primær eller sekundær alkohol, R^'-0H '•■{idet R^' betyr en primær eller sekundær R-^-gruppe) ; og (v) en syre, f.eks. eddiksyre, som tjener til å nøytralisere alkalicyanid-katalysatoren. Produktene fra den ovenfor beskrevne omsetning har formelen: or lead dioxide, (iii) an inert solvent, e.g. a halogenated hydrocarbon solvent such as dichloromethane or chloroform; (iv) a primary or secondary alcohol, R^'-OH '•■{wherein R^' means a primary or secondary R-^ group) ; and (v) an acid, e.g. acetic acid, which serves to neutralize the alkali cyanide catalyst. The products from the turnover described above have the formula:

20a- og 203~hydroksysteroidene med formlene V og VI kan oksyderes for å danne de tilsvarende 20-ketosteroider som har henholdsvis formlene og The 20a- and 203-hydroxysteroids of the formulas V and VI can be oxidized to form the corresponding 20-ketosteroids having the formulas and

Eksempler på egnede oksydasjonsmidler er mangandioksyd og krom-dioksyd. Når 20a- og 203-hydroksysteroidene som oksyderes, inneholder en 113-hydroksysubstituent, vil produktene med formlene I og VIII være blandinger av 113-hydroksy- og 11-keto-steroider. Examples of suitable oxidizing agents are manganese dioxide and chromium dioxide. When the 20a- and 203-hydroxysteroids that are oxidized contain a 113-hydroxy substituent, the products of formulas I and VIII will be mixtures of 113-hydroxy and 11-keto steroids.

Estrene med formel I kan også fremstilles ved forestring av den tilsvarende steroid-'21-syre med formel VIII. The esters of formula I can also be prepared by esterification of the corresponding steroid-'21 acid of formula VIII.

(Et steroid med formel VIII kan fremstilles som beskrevet ovenfor, eller alternativt ved forsepning av en tilsvarende steroid-21-syreester med formel I). (A steroid of formula VIII can be prepared as described above, or alternatively by saponification of a corresponding steroid-21-acid ester of formula I).

En annen metode for fremstilling av produktene med formel I hvor R^er en ikke-tertiær alkylgruppe med 1 til 10 karbonatomer eller aryl, er omforestring av en annen ester med formel I. Utgangssteroidet omsettes med den passende alkohol i nærvær av et basisk alkoksyd (f.eks. natriumetoksyd eller aluminiumisopropoksyd) eller fortrinnsvis en kilde for cyanid-ion (f.eks. et alkalimetallcyanid så som natriumcyanid eller kaliumcyanid) for å danne omforestringsproduktet. Another method for the preparation of the products of formula I where R^ is a non-tertiary alkyl group of 1 to 10 carbon atoms or aryl is the transesterification of another ester of formula I. The starting steroid is reacted with the appropriate alcohol in the presence of a basic alkoxide ( eg sodium ethoxide or aluminum isopropoxide) or preferably a source of cyanide ion (eg an alkali metal cyanide such as sodium cyanide or potassium cyanide) to form the transesterification product.

Steroidene med formel I er nyttige lokale anti-inflammatoriske midler som kan anvendes istedenfor kjente gluko-corticoider ved behandling av slike lidelser som dermatitt, psoriasis, solbrenthet, neurodermatitt, eksem og anogenital pruritus. Steroidene kan administreres i form av en vanlig krem, salve, oppløsning eller spray inneholdende 0,01 til 5,0 vekt%, fortrinnsvis 0,025 til 2,0 vekt% aktiv bestanddel. The steroids of formula I are useful local anti-inflammatory agents that can be used instead of known glucocorticoids in the treatment of such disorders as dermatitis, psoriasis, sunburn, neurodermatitis, eczema and anogenital pruritus. The steroids may be administered in the form of a conventional cream, ointment, solution or spray containing 0.01 to 5.0% by weight, preferably 0.025 to 2.0% by weight of active ingredient.

Ved en alternativ fremgangsmåte kan steroidene med formel I fremstilles fra de tilsvarende 21-hydroksy-A 16-steroider med formelen: By an alternative method, the steroids of formula I can be prepared from the corresponding 21-hydroxy-A 16 steroids of the formula:

ved først å omdanne 21-hydroksygruppen til en 21-karboksylsyregruppe, og derefter kondensere cykloheksen- og tetrahydronaftalen-gruppene i 16,17-stilling. by first converting the 21-hydroxy group to a 21-carboxylic acid group, and then condensing the cyclohexene and tetrahydronaphthalene groups in the 16,17 position.

21-hydroksy-A 1 r-steroidene med formel IX, som utgjør utgangspunktet for den alternative fremgangsmåte, eller de tilsvarende 21-acyloksy-steroider, er kjent fra litteraturen. 21-acyloksysteroidene omdannes lett til de tilsvarende 21-hydroksy-steroider under anvendelse av vanlige metoder. The 21-hydroxy-A 1 r steroids of formula IX, which form the starting point for the alternative method, or the corresponding 21-acyloxy steroids, are known from the literature. The 21-acyloxysteroids are readily converted to the corresponding 21-hydroxysteroids using conventional methods.

Et steroid med formel IX kan oksyderes til det tilsvarende aldehyd med formelen: A steroid of formula IX can be oxidized to the corresponding aldehyde of the formula:

under anvendelse av oksygen (eller luft) og en.katalysator så som kobberacetat. Omsetningen kan foretas i et alkoholisk oppløsnings-middel. using oxygen (or air) and a catalyst such as copper acetate. The reaction can be carried out in an alcoholic solvent.

Hvis den ovenfor beskrevne oksydasjonsreaksjon utføres i nærvær av oksygen (f.eks. ved å boble luft gjennom reaksjonsblandingen), vil omsetningen vanligvis føre til at man i tillegg til et steroid-21-aldehyd med formel X får det tilsvarende steroid-21-acetal dannet med alkohol-oppløsningsmidlet (R1~OH), dvs. et steroid med formelen: If the above-described oxidation reaction is carried out in the presence of oxygen (e.g. by bubbling air through the reaction mixture), the reaction will usually lead to obtaining, in addition to a steroid-21-aldehyde of formula X, the corresponding steroid-21-acetal formed with the alcohol solvent (R1~OH), i.e. a steroid with the formula:

Hvis den ovenfor beskrevne omsetning får finne sted i lengere tid, f.eks. mer enn ca. 24 timer, vil hovedproduktet være 20-hydroksy-21-karboksylsyreesteren med formelen If the turnover described above is allowed to take place for a longer period of time, e.g. more than approx. 24 hours, the main product will be the 20-hydroxy-21-carboxylic acid ester with the formula

Hvis vann er til stede som et med-oppløsningsmiddel ved oksydasjonsreaksjonen og omsetningen får finne sted i lengere tid, vil man i tillegg, til 20-hydroksy-21-karboksylsyreesteren med formel XI får den tilsvarende 20-hydroksy-21-karboksylsyre, dvs. et steroid med formelen Steroidene med formlene XII og XIII eksisterer som blandinger av 20a- og 200-hydroksy-steroidene. Hvis et steroid med formlene X eller XI eller en blanding av disse omsettes med en uorganisk cyanidkatalysator, et oksydasjonsmiddel, et inert oppløsnings-middel, en alkohol og en organisk syre, får man produktet med formel I. Et produkt med formel I kan erholdes ved at et steroid-21-aldehyd med formel X eller det tilsvarende steroid-21-acetal med formel XI eller en blanding av disse, omsettes med en blanding av (i), en uorganisk cyanidkatalysator (f.eks. et alkalimetallcyanid så som kaliumcyanid); (ii) et oksydasjonsmiddel, f.eks. et tungmetalloksyd så som aktivert amngandioksyd eller blydioksyd; (iii) et inert oppløsningsmiddel, f.eks. et halogenert hydrokarbonoppløsningsmiddel så som diklormetan eller kloroform; (iv) en primær eller sekundær alkohol,<1->0H (hvor R^ ' betyr en ikke-tertiær R^-gruppe); og (v) en syre, f.eks. eddiksyre, som tjener til å nøytralisere alkalicyanid-katalysatoren. Produktene fra den ovenfor beskrevne, omsetning har formelen: If water is present as a co-solvent in the oxidation reaction and the reaction is allowed to take place for a longer time, in addition to the 20-hydroxy-21-carboxylic acid ester of formula XI, the corresponding 20-hydroxy-21-carboxylic acid is obtained, i.e. a steroid of the formula The steroids of the formulas XII and XIII exist as mixtures of the 20a- and 200-hydroxy steroids. If a steroid of formulas X or XI or a mixture of these is reacted with an inorganic cyanide catalyst, an oxidizing agent, an inert solvent, an alcohol and an organic acid, the product of formula I is obtained. A product of formula I can be obtained by that a steroid-21-aldehyde of formula X or the corresponding steroid-21-acetal of formula XI or a mixture of these is reacted with a mixture of (i), an inorganic cyanide catalyst (e.g. an alkali metal cyanide such as potassium cyanide) ; (ii) an oxidizing agent, e.g. a heavy metal oxide such as activated manganese dioxide or lead dioxide; (iii) an inert solvent, e.g. a halogenated hydrocarbon solvent such as dichloromethane or chloroform; (iv) a primary or secondary alcohol,<1->OH (wherein R^' means a non-tertiary R^ group); and (v) an acid, e.g. acetic acid, which serves to neutralize the alkali cyanide catalyst. The products from the turnover described above have the formula:

20a- og 20(3-hydroksysteroidene med formlene XII og XIII kan oksyderes for å gi de tilsvarende 20-keto-steroider som har henholdsvis formlene The 20a- and 20(3-hydroxysteroids of the formulas XII and XIII can be oxidized to give the corresponding 20-keto-steroids of the formulas respectively

Eksempler på egnede oksydasjonsmidler er mangandioksyd og krom-dioksyd. Hvis 20a- og 20[3-hydroksysteroidene som oksyderes, har en lip-hydroksysubstituent, vil steroidene med.formlene XV og XVI være blandinger av ll(3-hydroksy- og lip-keto-steroider. Examples of suitable oxidizing agents are manganese dioxide and chromium dioxide. If the 20a- and 20[3-hydroxysteroids which are oxidized have a lip-hydroxy substituent, the steroids of formulas XV and XVI will be mixtures of 11(3-hydroxy- and lip-keto-steroids.

Mellomproduktene med formel XV kan også fremstilles ved forestring av den tilsvarende steroid-21-syre med formel XVI.. The intermediates of formula XV can also be prepared by esterification of the corresponding steroid-21-acid of formula XVI..

(Et steroid med formel XVI kan fremstilles som beskrevet ovenfor eller alternativt ved forsepning av en tilsvarende steroid-21-syreester med formel XV). (A steroid of formula XVI can be prepared as described above or alternatively by saponification of a corresponding steroid 21-acid ester of formula XV).

En annen metode for fremstilling av mellomprodukteneAnother method for producing the intermediates

med formel XV hvor R^er en ikke-tertiær gruppe, er omforestring av en annen ester med formel XIV eller XV. Utgangssteroidet omsettes med den passende alkohol i nærvær av et basisk alkoksyd (f.eks. natriumetoksyd eller aluminiumisopropoksyd), eller fortrinnsvis en kilde for cyanid-ion (f.eks. et alkalimetallcyanid så som natriumcyanid eller kaliumcyanid) for å danne omforestrings- of formula XV where R^ is a non-tertiary group is the transesterification of another ester of formula XIV or XV. The starting steroid is reacted with the appropriate alcohol in the presence of a basic alkoxide (eg sodium ethoxide or aluminum isopropoxide), or preferably a source of cyanide ion (eg an alkali metal cyanide such as sodium cyanide or potassium cyanide) to form transesterification-

Et steroid med formlene XIV, XV eller XVI kan omdannes til det tilsvarende.produkt med formel I ved omsetning av dette med et benzocyklobuten med formelen eller med et butadien med formelen A steroid of the formulas XIV, XV or XVI can be converted into the corresponding product of the formula I by reacting this with a benzocyclobutene of the formula or with a butadiene of the formula

under anvendelse av en Diels-Alder reaksjon. using a Diels-Alder reaction.

Når det gjelder forbindelsen XVII, kan omsetningen foretas uten tilsetninger eller i et inert oppløsningsmiddel, f.eks. o-diklorbenzen eller dietylbenzen. Fortrinnsvis foretas omsetningen uten tilsetninger,• i en inert atmosfære, ved temperaturer opp til oppløsningens kokepunkt. En fri radikal-inhibitor kan settes til blandingen. In the case of compound XVII, the reaction can be carried out without additives or in an inert solvent, e.g. o-dichlorobenzene or diethylbenzene. The reaction is preferably carried out without additives,• in an inert atmosphere, at temperatures up to the boiling point of the solution. A free radical inhibitor can be added to the mixture.

Når det gjelder forbindelsen XVIII, er de foretrukne katalysatorer for omsetningen vannfritt aluminiumklorid og vannfritt aluminiumbromid. Omsetningen kan foretas i et organisk oppløsningsmiddel, f.eks. et halogenert hydrokarbon så som diklormetan. Den ovenfor beskrevne Diels-Alder reaksjon er meget selektiv og finner sted utelukkende ved dobbeltbindingen i 16-stilling, selv i nærvær av A 1 ' 4-3-keto-funksjonen. I de tilfeller hvor butadienet er ustabilt i nærvær av en Lewis-syre-katalysator, foretas Diels-Alder-reaksjonen i nærvær av en fri radikal-inhibitor ved forhøyet temperatur. In the case of compound XVIII, the preferred catalysts for the reaction are anhydrous aluminum chloride and anhydrous aluminum bromide. The reaction can be carried out in an organic solvent, e.g. a halogenated hydrocarbon such as dichloromethane. The Diels-Alder reaction described above is very selective and takes place exclusively at the double bond in the 16-position, even in the presence of the A 1 ' 4-3-keto function. In cases where the butadiene is unstable in the presence of a Lewis acid catalyst, the Diels-Alder reaction is carried out in the presence of a free radical inhibitor at an elevated temperature.

Hvis steroidet med formel XIV, XV eller XVI inneholder enn llft-hydroksygruppe, er detønskelig å først beskytte gruppen før Diels-Alder-reaksjonen foretas. Selv om mange metoder til beskyttelse av den funksjonell gruppe i 11-stilling vil være nærliggende for en fagmann på steroid-området, er en særlig foretrukket metode å acylere gruppen. Acyleringsreaksjonen kan foretas under anvendelse av et syreanhydrid, f.eks. eddiksyre anhydrid, i nærvær av en Lewis katalysator, f.eks. bortrifluorid-eterat. Efter at Diels-Alder-reaksjonen er foretatt, kan den beskyttende gruppe fjernes under anvendelse av vanlig teknikk. If the steroid of formula XIV, XV or XVI contains more than 11ft-hydroxy group, it is desirable to first protect the group before the Diels-Alder reaction is carried out. Although many methods of protecting the functional group in the 11-position will be obvious to a person skilled in the steroid field, a particularly preferred method is to acylate the group. The acylation reaction can be carried out using an acid anhydride, e.g. acetic anhydride, in the presence of a Lewis catalyst, e.g. boron trifluoride etherate. After the Diels-Alder reaction is carried out, the protecting group can be removed using conventional techniques.

Eksempel 1 Example 1

9- f luor- 1' , 2 ' , 3 ' , 4 ' - tetrahydro- llf3- hydroksy- 3 , 20- dioksopregna-1, 4- dieno[ 16a, 17- b] naftalen- 21- syre- metylester 9-fluoro-1',2',3',4'-tetrahydro-llf3-hydroxy-3,20-dioxopregna-1,4-dieno[16a,17-b]naphthalene-21-acid methyl ester

9-f luor-1' , 2 ' , 3 1 , 4 1 -tetrahydro-ll|3 , 21-dihydroksypregna-1,4-dieno[16a,17-b]naftalen-3,20-dion (1,0 g) oppløses i vannfri metanol (170 ml) ved oppvarmning, og oppløsningen av-kjøles til romtemperatur. Kobber (II)acetat-hydrat (250 mg) tilsettes, og under omrøring føres en langsom strøm av luft inn i oppløsningen. I løpet av 10 minutter forsvinner utgangssteroidet for å gi i alt vesentlig et enkelt,' mindre polart materiale, som bedømt ved tynnskiktkromatografi (TLC). 9-fluoro-1' , 2 ' , 3 1 , 4 1 -tetrahydro-11|3 , 21-dihydroxypregna-1,4-dieno[16a,17-b]naphthalene-3,20-dione (1,0 g) is dissolved in anhydrous methanol (170 ml) by heating, and the solution is cooled to room temperature. Copper (II) acetate hydrate (250 mg) is added and, while stirring, a slow stream of air is introduced into the solution. Within 10 minutes, the starting steroid disappears to give essentially a single, less polar material, as judged by thin layer chromatography (TLC).

Metanolen avdampes hovedsakelig i vakuum ved romtemperatur,The methanol is mainly evaporated in vacuum at room temperature,

og noe steroid utfelles. Konsentratet fortynnes med vann og ekstraheres med kloroform. Kloroformoppløsningen vaskes med en fortynnet ammoniumkloridoppløsning og vann, tørres over vannfritt magnesiumsulfat og inndampes for å gi 0,98 g 9-fluor-1',21 ,3',41-tetrahydro-113-hydroksy-pregna-l,4-dieno [16a,17-b]-naftalen-21-al-3,20-dion. Dette materiale viser en enkelt flekk på TLC (kloroform-metanol, 93:7, silikagel) og har et IR-spektrum i overensstemmelse med strukturen. NMR-spekteret viser imidlertid at det er forurenset med en liten mengde av det tilsvarende 21-dimetylacetal. and some steroid is precipitated. The concentrate is diluted with water and extracted with chloroform. The chloroform solution is washed with a dilute ammonium chloride solution and water, dried over anhydrous magnesium sulfate and evaporated to give 0.98 g of 9-fluoro-1',21,3',41-tetrahydro-113-hydroxy-pregna-1,4-dieno [ 16a,17-b]-naphthalene-21-al-3,20-dione. This material shows a single spot on TLC (chloroform-methanol, 93:7, silica gel) and has an IR spectrum consistent with its structure. However, the NMR spectrum shows that it is contaminated with a small amount of the corresponding 21-dimethylacetal.

En blanding av det urene aldehyd' (950 mg), vannfri metanol (50 ml), tørr diklormetan (50 ml), iseddik (0,9 ml), kaliumcyanid (200 mg) og aktivt mangandioksyd (2,1 g) omrøres ved romtemperatur i 10 timer. Blandingen filtreres derefter gjennom et lag av diatoméjord. Kaken suspenderes påny i kloroform som tilbakeløpsbehandles og filtreres igjen. Filtratene samles, vaskes med en fortynnet natriumbikarbonatoppløsning og vann, tørres over vannfritt magnesiumsulfat og inndampes for å gi 0,86 g av et fast stoff. Dette oppløses i en blanding av diklormetan og metanol. Diklormetanet fjernes under tilbakeløps-. kjøling for å utfelle 675 mg av et fast stoff. Dette underkastes igjen rensning som ovenfor, for å gi 6 30 mg av tittelforbindelsen, som smelter ved 319-321°C (spaltning, misfarvning starter fra ca. 260°C) med overensstemmende spektraldata. A mixture of the crude aldehyde' (950 mg), anhydrous methanol (50 ml), dry dichloromethane (50 ml), glacial acetic acid (0.9 ml), potassium cyanide (200 mg) and active manganese dioxide (2.1 g) is stirred at room temperature for 10 hours. The mixture is then filtered through a layer of diatomaceous earth. The cake is resuspended in chloroform which is refluxed and filtered again. The filtrates are combined, washed with a dilute sodium bicarbonate solution and water, dried over anhydrous magnesium sulfate and evaporated to give 0.86 g of a solid. This is dissolved in a mixture of dichloromethane and methanol. The dichloromethane is removed under reflux. cooling to precipitate 675 mg of a solid. This is again subjected to purification as above to give 630 mg of the title compound, which melts at 319-321°C (decomposition, discoloration starts from about 260°C) with consistent spectral data.

Analyse:Analysis:

Beregnet for C30H33<F>05: C 73,15, H 6,75, F 3,86.Calculated for C30H33<F>05: C 73.15, H 6.75, F 3.86.

Funnet: C 72,85, H 6,95, F 3,65. Found: C 72.85, H 6.95, F 3.65.

Eksempel 2 Example 2

9- fluor- 1', 2', 3', 4'- tetrahydro- llB- hydroksy- 3, 20- dioksopregna-1, 4- dieno[ 16a, 17- b] naftalen- 21- syre- l- metyletylester 9- fluoro- 1', 2', 3', 4'- tetrahydro- 11B- hydroxy- 3, 20- dioxopregna-1, 4- dieno[ 16a, 17-b] naphthalene- 21- acid- 1- methyl ethyl ester

En suspensjon av 9-fluor-1<1>,2<1>,3',4<1->tetrahydro-116-hydroksy-3,20-dioksopregna-1,4-dieno[16a,17-b]naftalen-21-syre-metylester (490 mg, se eksempel 1) i tørr isopropanol (30 ml, nydestillert fra magnesiumspon) inneholdende natriumcyanid (10 mg) tilbakeløpsbehandles under en atmosfære av nitrogen i 20 minutter for å gi en klar oppløsning. En TLC undersøkelse på dette punkt viser fullstendig omdannelse av utgangssteroidet til en mindre polar forbindelse. Blandingen inndampes derefter i vakuum, residuet oppløses i kloroform, vaskes med fortynnet salt-oppløsning og vann, tørres over vannfritt magnesiumsulfat og inndampes for å gi 516 mg av tittelforbindelsen. En krystallisasjon fra etylacetat gir den analytiske prøve av tittelforbindelsen som farveløse nåler (410 mg), sm.p. 269-271°C (spaltning, misfarvning starter fra ca. 250°C) med overensstemmende spektraldata. A suspension of 9-fluoro-1<1>,2<1>,3',4<1->tetrahydro-116-hydroxy-3,20-dioxopregna-1,4-dieno[16a,17-b]naphthalene -21-Acid methyl ester (490 mg, see Example 1) in dry isopropanol (30 ml, freshly distilled from magnesium shavings) containing sodium cyanide (10 mg) is refluxed under an atmosphere of nitrogen for 20 minutes to give a clear solution. A TLC examination at this point shows complete conversion of the starting steroid to a less polar compound. The mixture is then evaporated in vacuo, the residue dissolved in chloroform, washed with dilute brine and water, dried over anhydrous magnesium sulfate and evaporated to give 516 mg of the title compound. A crystallization from ethyl acetate gives the analytical sample of the title compound as colorless needles (410 mg), m.p. 269-271°C (decomposition, discoloration starts from about 250°C) with consistent spectral data.

Analyse:Analysis:

Beregnet for C32<H>37F05: C 73,82, H 7,16, F 3,65Calculated for C32<H>37F05: C 73.82, H 7.16, F 3.65

Funnet: C 73,45, H 7,11, F 3,47. Found: C 73.45, H 7.11, F 3.47.

Eksempel 3 Example 3

9- fluor- 1', 2' , 3 ' , 4'- tétrahydro- 113- hydroksy- 3, 20- dioksopregna-1, 4- dieno[ 16a, 17- b] naftalen- 21- syre- butylester 9- fluoro- 1', 2' , 3' , 4'- tetrahydro- 113- hydroxy- 3, 20- dioxopregna-1, 4- dieno[ 16a, 17-b] naphthalene- 21- acid- butyl ester

9-fluor-1<1>,2<1>,3',4'-tetrahydro-113,21-dihydroksypregna-1,4-dieno[16a,17-b]naftalen-3,20-dion (800 mg) oppløses i n-butanol (150 ml) ved oppvarmning. Oppløsningen avkjøles ved romtemperatur, kobberacetat-hydrat (250 mg) tilsettes, og luft bobles inn i oppløsningen med omrøring i 30 minutter. Meste-parten av n-butanolen fjernes derefter ved inndampning i vakuum ved 40-42°C. Konsentratet fortynnes med vann og ekstraheres med kloroform. Kloroformekstraktene samles, vaskes med en fortynnet ammoniumkloridoppløsning og vann, tørres over vannfritt magnesiumsulfat og inndampes for å gi 850 mg 9-fluor-11,21,3',41 - 9-fluoro-1<1>,2<1>,3',4'-tetrahydro-113,21-dihydroxypregna-1,4-dieno[16a,17-b]naphthalene-3,20-dione (800 mg ) is dissolved in n-butanol (150 ml) by heating. The solution is cooled at room temperature, copper acetate hydrate (250 mg) is added, and air is bubbled into the solution with stirring for 30 minutes. Most of the n-butanol is then removed by evaporation in a vacuum at 40-42°C. The concentrate is diluted with water and extracted with chloroform. The chloroform extracts are combined, washed with a dilute ammonium chloride solution and water, dried over anhydrous magnesium sulfate and evaporated to give 850 mg of 9-fluoro-11,21,3',41 -

tetrahydro-llB-hydroksypregna-1,4-dieno[16a,17-b]naftalen-21-al-3,20-dion. (Dette materiale karakteriseres spektroskopisk. tetrahydro-11B-hydroxypregna-1,4-dieno[16a,17-b]naphthalene-21-al-3,20-dione. (This material is characterized spectroscopically.

En TLC-undersøkelse viser tilstedeværelse av en hovedforbindelse, spor av utgangsmateriale og spor av en annen urenhet som er mindre polar enn utgangsmaterialet og som antas å være 9-fluor-1',2',3 ' ,41-tetrahydro-113-hydroksy-21,21-di-n-butoksy-pregna-1,4-dieno[16a,17-b]naftalen-3,20-dion). A TLC examination shows the presence of a major compound, traces of starting material and traces of another impurity less polar than the starting material and believed to be 9-fluoro-1',2',3',41-tetrahydro-113-hydroxy -21,21-di-n-butoxy-pregna-1,4-dieno[16a,17-b]naphthalene-3,20-dione).

Den ovenfor angitte rå blanding (840 mg) oppløses i en blanding av tørr n-butanol (20 ml) og diklormetan (50 ml). Eddiksyre (0,8 ml), kaliumcyanid (200 mg) og aktivt mangandioksyd (2,0 g) tilsettes, og blandingen omrøres ved romtemperatur i 60 timer. (En kortere reaksjonstid ville være til-strekkelig) . Blandingen filtreres derefter gjennom et lag av diatoméjord. De faste stoffer vaskes med kloroform, filtratet og vaskevæskene samles, vaskes med vann, tørres over vannfritt magnesiumsulfat og inndampes for å gi råproduktet som en gummi. Fra dette råprodukt isoleres hovedkomponenten ved preparativ TLC The above crude mixture (840 mg) is dissolved in a mixture of dry n-butanol (20 ml) and dichloromethane (50 ml). Acetic acid (0.8 ml), potassium cyanide (200 mg) and active manganese dioxide (2.0 g) are added and the mixture is stirred at room temperature for 60 hours. (A shorter reaction time would be sufficient). The mixture is then filtered through a layer of diatomaceous earth. The solids are washed with chloroform, the filtrate and washings are collected, washed with water, dried over anhydrous magnesium sulfate and evaporated to give the crude product as a gum. From this crude product, the main component is isolated by preparative TLC

(fire 2,0 mm silikagelplater utviklet med kloroform-etylacetat 1:1)(four 2.0 mm silica gel plates developed with chloroform-ethyl acetate 1:1)

og identifiseres som tittelforbindelsen (487 mg). En krystallisasjon fra etylacetat. gir 381 mg av den analytiske prøve av tittelforbindelsen, sm.p. 245-246°C med overensstemmende spektraldata. and identified as the title compound (487 mg). A crystallization from ethyl acetate. gives 381 mg of the analytical sample of the title compound, m.p. 245-246°C with consistent spectral data.

Analyse:Analysis:

Beregnet for C33H39<F>05:C74,13, H 7,35, F 3,55Calculated for C33H39<F>05:C74.13, H 7.35, F 3.55

Funnet: C 74,37, H 7,41, F 3,46. Found: C 74.37, H 7.41, F 3.46.

Eksempel 4 Example 4

9- fluor- 1', 2', 3', 4'- tetrahydro- llB- hydroksy- 3, 20- dioksopregna-1, 4- dieno[ 16a, 17- b] naftalen- 21- syre- l, 1- dimetyletylester A) 9- fluor, 1', 2', 3', 4'- tetrahydro- llB- hydroksy- 3, 20- dioksopregna- 1, 4- dieno[ 16 a, 17- b] naftalen- 21- syre 9- fluoro- 1', 2', 3', 4'- tetrahydro- 11B- hydroxy- 3, 20- dioxopregna-1, 4- dieno[ 16a, 17- b] naphthalene- 21- acid- 1, 1- dimethyl ethyl ester A) 9- fluoro, 1', 2', 3', 4'- tetrahydro- 11B- hydroxy- 3, 20- dioxopregna- 1, 4- dieno[ 16 a, 17- b] naphthalene- 21- acid

En oppløsning av 9-fluor-1<1>,2',3<1>,4<1->tetrahydro-116-hydroksypregna-1,4-dieno[16a,17-b]naftalen-2l-al-3,20-dion (3,0 g, se eksempel 1) i en blanding av diklormetan (150 ml) og tetrahydrofuran (150 ml) inneholdende eddiksyre (3,0 ml) og vann (4,0 ml) omrøres med aktivert mangandioksyd (6,0 g) og kaliumcyanid (700 mg) i 20 timer. Blandingen filtreres derefter, og de faste stoffer vaskes med en varm blanding av kloroform og metanol (7:3). Filtratet og vaskevæskene samles og inndampes i vakuum. Residuet vaskes med vann, tørres, renses ved kromatografi og krystalliseres fra metanol-kloroform for å gi tittelforbindelsen, sm.p. 280-281°C (spaltn.). A solution of 9-fluoro-1<1>,2',3<1>,4<1->tetrahydro-116-hydroxypregna-1,4-dieno[16a,17-b]naphthalen-2l-al-3 ,20-dione (3.0 g, see example 1) in a mixture of dichloromethane (150 ml) and tetrahydrofuran (150 ml) containing acetic acid (3.0 ml) and water (4.0 ml) is stirred with activated manganese dioxide ( 6.0 g) and potassium cyanide (700 mg) for 20 hours. The mixture is then filtered, and the solids are washed with a hot mixture of chloroform and methanol (7:3). The filtrate and washing liquids are collected and evaporated in a vacuum. The residue is washed with water, dried, purified by chromatography and crystallized from methanol-chloroform to give the title compound, m.p. 280-281°C (dec.).

B) 9- fluor- 1', 2', 3', 4'- tetrahydro- llB- hydroksy- 3, 20- dioksopregna-1, 4- dieno[ 16a, 17- b] naftalen- 21- syre- 1, 1- dimetyletylester Til en suspensjon av 9-fluor-1<1>,2<1>,3<1>,4<1->tetrahydro-113-hydroksy-3,20-dioksopregna-l,4-dieno[16 a,17-b]naftalen-21-syre (325 mg) i tørr dioksan (60 ml) inneholdende svovelsyrefosforsyre-katalysator (0,4 ml; fremstilt ved å sette den . beregnede mengde fosforpentoksyd til 96%ig svovelsyre for omsetning med alt vannet) i et trykk-reaksjonskar føres en strøm av isobutylen (inntil ca. 6 ml er tilsatt)'. Reaksjonskaret lukkes og holdes ved omgivelsestemperatur i 30 timer under omrøring. Blandingen helles i en oppløsning av natriumacetat-hydrat (5,0 g) i vann (500 ml) og ekstraheres suksessivt med kloroform og etylacetat. Ekstraktene vaskes med saltoppløsning, samles, tørres over vannfritt magnesiumsulfat og inndampes. Residuet renses ved kromatografi på silikagel■for å gi 145 mg B) 9- fluoro- 1', 2', 3', 4'- tetrahydro- 11B- hydroxy- 3, 20- dioxopregna-1, 4- dieno[ 16a, 17- b] naphthalene- 21- acid- 1, 1- dimethyl ethyl ester For a suspension of 9-fluoro-1<1>,2<1>,3<1>,4<1->tetrahydro-113-hydroxy-3,20-dioxopregna-1,4-dieno[16 a,17-b]naphthalene-21-acid (325 mg) in dry dioxane (60 ml) containing sulfuric acid phosphoric acid catalyst (0.4 ml; prepared by placing the calculated amount of phosphorus pentoxide in 96% sulfuric acid for reaction with all the water) in a pressure reaction vessel is fed a stream of isobutylene (until about 6 ml has been added)'. The reaction vessel is closed and kept at ambient temperature for 30 hours with stirring. The mixture is poured into a solution of sodium acetate hydrate (5.0 g) in water (500 ml) and extracted successively with chloroform and ethyl acetate. The extracts are washed with saline, collected, dried over anhydrous magnesium sulfate and evaporated. The residue is purified by chromatography on silica gel to give 145 mg

av tittelforbindelsen, sm.p. 293-296°C (spaltn., misfarvning starter fra ca. 275°C) efter krystallisasjon fra aceton-heksan. of the title compound, m.p. 293-296°C (dec., discoloration starts from approx. 275°C) after crystallization from acetone-hexane.

Eksempel 5 Example 5

9- fluor- 1', 2', 3 ' , 4 '- tetrahydro- 113~ hydroksy- 3, 20- dioksopregna-1, 4- dieno[ 16a, 17- b] naftalen- 21- syre- 2, 2- dimetylpropylester 9- fluoro- 1', 2', 3 ' , 4 '- tetrahydro- 113~ hydroxy- 3, 20- dioxopregna-1, 4- dieno[ 16a, 17- b] naphthalene- 21- acid- 2, 2- dimethyl propyl ester

En oppløsning av 9-fluor-1<1>,2',3<1>,4'-tetrahydro-113~hydroksy-3,20-dioksopregna-l,4-dieno[16a,17-b]naftalen-21-syre-metylester i tørr dioksan (20 ml, destillert over natrium) og tørr pyridin (15 ml), tilbakeløpsbehandles med neopentylalkohol (2,2 g) og natriumcyanid (100 mg) under en nitrogenatmosfære i 18 timer. Den resulterende oppløsning inndampes i vakuum, og residuet oppløses i kloroform. Kloroformoppløsningen vaskes med fortynnet natriumkloridoppløsning og vann, tørres over vannfritt natriumsulfat og inndampes i vakuum. Residuet oppløses i kloroform-heksan (9:1) og kromatograferes på en 35 g silikagelkolonne. Eluering med kloroform-heksan (9:1) gir 540 mg materiale. Krystallisering fra aceton-heksan gir 460 mg av en analytisk prøve av tittelforbindelsen, sm.p. 329-331°C (spaltn.). A solution of 9-fluoro-1<1>,2',3<1>,4'-tetrahydro-113~hydroxy-3,20-dioxopregna-1,4-dieno[16a,17-b]naphthalene-21 -acid methyl ester in dry dioxane (20 ml, distilled over sodium) and dry pyridine (15 ml), refluxed with neopentyl alcohol (2.2 g) and sodium cyanide (100 mg) under a nitrogen atmosphere for 18 hours. The resulting solution is evaporated in vacuo, and the residue is dissolved in chloroform. The chloroform solution is washed with dilute sodium chloride solution and water, dried over anhydrous sodium sulfate and evaporated in vacuo. The residue is dissolved in chloroform-hexane (9:1) and chromatographed on a 35 g silica gel column. Elution with chloroform-hexane (9:1) gives 540 mg of material. Crystallization from acetone-hexane gives 460 mg of an analytical sample of the title compound, m.p. 329-331°C (dec.).

Analyse:Analysis:

Beregnet for C34H41F05: C 74 , 42 , H 7,53, F 3,46Calculated for C34H41F05: C 74 , 42 , H 7.53, F 3.46

Funnet: C 74,39, H 7,73, F 3,37 Found: C 74.39, H 7.73, F 3.37

Eksempel 6 Example 6

9- fluor- 113- hydroksy- 3, 20- dioksopregna- l, 4- dieno[ 16a, 17- d]-cykloheksen- 2l- syre- metylester 9- fluoro- 113- hydroxy- 3, 20- dioxopregna- l, 4- dieno[ 16a, 17- d]-cyclohexene- 2l- acid- methyl ester

En oppløsning av 1,2 g 9-f luor-113 / 21-dihydroksypregna-^ 1,4-dieno[16a,17-d]cykloheksen-3,20-dion og 300 mg kobberacetat i 150 ml metanol omrøres ved romtemperatur i 1 time mens en strøm av luft bobles gjennom oppløsningen. Oppløsningsmidlet avdampes i vakuum ved 30°C. Residuet - fortynnes med vann og ekstraheres med kloroform og derefter med etylacetat. Kloroform-oppløsningen og etylacetatoppløsningen vaskes med vandig ammonium-kloridoppløsning (10%) og vann, tørres over vannfritt natriumsulfat, inndampes i vakuum og samles for å gi 1,3 g av et fast stoff.. NMR-spekteret for det faste stoff viser at det er en omtrentlig ekvimolar blanding av 21-aldehydet og 21-dimetyl-acetatl-derivatet av utgangssteroidet. A solution of 1.2 g of 9-fluoro-113/21-dihydroxypregna-^1,4-dieno[16a,17-d]cyclohexene-3,20-dione and 300 mg of copper acetate in 150 ml of methanol is stirred at room temperature in 1 hour while a stream of air is bubbled through the solution. The solvent is evaporated in vacuo at 30°C. The residue - is diluted with water and extracted with chloroform and then with ethyl acetate. The chloroform solution and ethyl acetate solution are washed with aqueous ammonium chloride solution (10%) and water, dried over anhydrous sodium sulfate, evaporated in vacuo and collected to give 1.3 g of a solid. The NMR spectrum of the solid shows that it is an approximately equimolar mixture of the 21-aldehyde and the 21-dimethylacetate 1 derivative of the parent steroid.

Det faste produkt fra den ovenfor beskrevne omsetningThe fixed product from the turnover described above

(1,3 g) omrøres i en blanding av 50 ml tørr metanol og 50 ml(1.3 g) is stirred in a mixture of 50 ml of dry methanol and 50 ml

tørr diklormetan ved romtemperatur i ca. 16 timer med aktivert mangandioksyd (2,0 g), iseddik (1,0 ml) og kaliumcyanid (200 mg). Suspensjonen filtreres gjennom et lag av "Hyflo" og vaskes med. kloroform. Filtrat og vaskevæsker samles, vaskes med vann og tørres over.vannfritt magnesiumsulfat. Oppløsningsmidlet avdampes i vakuum for å gi 1,1 g av et fast stoff. Dette oppløses i kloroform og kromatograferes på en 35 g silikagelkolonne.. Eluering med kloroform gir 930 mg materiale. Krystallisasjon dry dichloromethane at room temperature for approx. 16 hours with activated manganese dioxide (2.0 g), glacial acetic acid (1.0 ml) and potassium cyanide (200 mg). The suspension is filtered through a layer of "Hyflo" and washed with. chloroform. Filtrate and washing liquids are collected, washed with water and dried over anhydrous magnesium sulfate. The solvent is evaporated in vacuo to give 1.1 g of a solid. This is dissolved in chloroform and chromatographed on a 35 g silica gel column. Elution with chloroform gives 930 mg of material. Crystallization

fra aceton-heksan gir 650 mg av tittelforbindelsen, sm.p. 256-258°C med overensstemmende spektraldata. from acetone-hexane gives 650 mg of the title compound, m.p. 256-258°C with consistent spectral data.

Analyse:Analysis:

Beregnet for C28<H>31<F>°5<:>C 70'57'H 7'°6'F 4,29Calculated for C28<H>31<F>°5<:>C 70'57'H 7'°6'F 4.29

Funnet: C 70,66, H 7,11, F 4,02. Found: C 70.66, H 7.11, F 4.02.

Eksempel 7 Example 7

9- fluor- 113- hydroksy- 3, 20- dioksopregna- l, 4- dieno[ 16a, 17- d]-cykloheksen- 21- syre- l- metyletylester 9- fluoro- 113- hydroxy- 3, 20- dioxopregna- l, 4- dieno[ 16a, 17- d]-cyclohexene- 21- acid- l- methyl ethyl ester

En oppløsning av 480 mg 9-fluor-113~hydroksy-3,20-dioksopregna-l ,4-dieno[16a,17-d]cykloheksen-21-syre-metylester (se eksempel 1) og 85 mg natriumcyanid i 65 ml tørr isopropylalkohol omrøres under en nitrogenatmosfære ved 100°C i ca. 16 timer. Den resulterende oppløsning inndampes i vakuum, og residuet oppløses i kloroform og vaskes med 25 ml vann. Det vandige lag mettes med natriumklorid og ekstraheres med kloroform. Kloroform-oppløsningene samles, tørres over vannfritt natriumsulfat og inndampes i vakuum. Residuet oppløses i kloroform-heksan (7:3) A solution of 480 mg of 9-fluoro-113-hydroxy-3,20-dioxopregna-1,4-dieno[16a,17-d]cyclohexene-21-acid methyl ester (see example 1) and 85 mg of sodium cyanide in 65 ml dry isopropyl alcohol is stirred under a nitrogen atmosphere at 100°C for approx. 16 hours. The resulting solution is evaporated in vacuo, and the residue is dissolved in chloroform and washed with 25 ml of water. The aqueous layer is saturated with sodium chloride and extracted with chloroform. The chloroform solutions are collected, dried over anhydrous sodium sulfate and evaporated in vacuo. The residue is dissolved in chloroform-hexane (7:3)

og kromatograferes på en 25 g silikagelkolonne. Eluering med kloroform-heksan (7:3) gir 370 mg materiale. Krystallisasjon fra aceton-heksan gir 300 mg av tittelforbindelsen, sm.p. 226-228°C, med overensstemmende spektraldata. and chromatographed on a 25 g silica gel column. Elution with chloroform-hexane (7:3) gives 370 mg of material. Crystallization from acetone-hexane gives 300 mg of the title compound, m.p. 226-228°C, with consistent spectral data.

Analyse:Analysis:

Beregnet for C28H35F05: C 71,46'H 7'50' F 4'04 Funnet: C 71,47, H 7,44, F 3,82. Eksempel 8 9- fluor- 113- hydroksy- 3, 20- dioksopregna- l, 4- dieno[ 16a, 17- d]-cykloheksen- 21- syre- butylester En blanding av 1/0 g 9-fluor-113/21-dihydroksypregna-l,4-dieno[16a,17-d]-cykloheksen-3,20-dion og 250 mg kobberacetat i 50 ml diklormetan og 30 ml n-butanol omrøres ved romtemperatur i 1 time mens en langsom strøm av luft bobles gjennom oppløsningen. Eftersom oksydasjonshastigheten er meget langsom, avdamper diklormetanet og erstattes med 50 ml n-butanol. Ytterligere 200 mg kobberacetat tilsettes, og omsetningen fortsetter i 1,5 time slik at utgangsmaterialet forsvinner. Oppløsningsmidlet avdampes derefter i vakuum ved 35-40°C, og residuet fortynnes med 200 ml vann og ekstraheres, med diklormetan og derefter med etylacet.at. Diklormetanoppløsningen og etylacetatoppløsningen vaskes med ammoniumkloridoppløsning (10%) og vann, samles, tørres over vannfritt natriumsulfat og inndampes i vakuum for å gi 1,2 g fast stoff. NMR-spekteret for det faste stoff viser at-det er en omtrentlig ekvimolar blanding av 21-aldehydet og 21-di-n-butyl-acetal-derivåtet av utgangssteroidet. Calculated for C28H35F05: C 71.46'H 7'50' F 4'04 Found: C 71.47, H 7.44, F 3.82. Example 8 9-fluoro-113-hydroxy-3,20-dioxopregna-1,4-dieno[16a,17-d]-cyclohexene-21-acid-butyl ester A mixture of 1/0 g of 9-fluoro-113/21 -dihydroxypregna-1,4-dieno[16a,17-d]-cyclohexene-3,20-dione and 250 mg copper acetate in 50 ml dichloromethane and 30 ml n-butanol are stirred at room temperature for 1 hour while bubbling a slow stream of air through the resolution. Since the oxidation rate is very slow, the dichloromethane evaporates and is replaced with 50 ml of n-butanol. A further 200 mg of copper acetate is added, and the reaction continues for 1.5 hours so that the starting material disappears. The solvent is then evaporated in vacuo at 35-40°C, and the residue is diluted with 200 ml of water and extracted, with dichloromethane and then with ethyl acetate. The dichloromethane solution and ethyl acetate solution are washed with ammonium chloride solution (10%) and water, combined, dried over anhydrous sodium sulfate and evaporated in vacuo to give 1.2 g of solid. The NMR spectrum of the solid shows that it is an approximately equimolar mixture of the 21-aldehyde and the 21-di-n-butyl acetal derivative of the starting steroid.

Det faste produkt fra den ovenfor beskrevne omsetning (1,2 g) oppløses i 50 ml tørr diklormetan og 30 ml tørr n-butanol og omrøres ved romtemperatur i ca. 16 timer med 2,0 g aktivert mangandioksyd, 1,0 ml iseddik og 200 mg kaliumcyanid. Et tørt kalsiumkloridrør forbindes med kolben for å unngå kontakt med fuktighet. Efter 20 timer tilsettes ytterligere 2,0 g aktivert mangandioksyd og 200 mg kaliumcyanid. Suspensjonen omrøres ved romtemperatur i 7 timer, filtreres gjennom et lag av "Hyflo" og vaskes omhyggelig med diklormetan. Filtrat og vaskevæsker samles og vaskes med en mettet natriumbikarbonatoppløsning og vann, tørres over vannfritt natriumsulfat og inndampes i vakuum. Tittelforbindelsen i residuet kan ikke med hell skilles fra forurensninger på en forhåndsbelagt silikagel TLC-plate'. Den kan imidlertid med hell renses på E. Merck forhåndsbelagt silikagel TLC-plate (2 mm, 2,5:97,5 metanol-kloroform) for å gi 400 mg av et skum. Krystallisasjon fra etylacetat-heksan gir 330 mg av tittelforbindelsen, sm.p. 203-209°C, med overensstemmende spektraldata. The solid product from the reaction described above (1.2 g) is dissolved in 50 ml of dry dichloromethane and 30 ml of dry n-butanol and stirred at room temperature for approx. 16 hours with 2.0 g of activated manganese dioxide, 1.0 ml of glacial acetic acid and 200 mg of potassium cyanide. A dry calcium chloride tube is connected to the flask to avoid contact with moisture. After 20 hours, a further 2.0 g of activated manganese dioxide and 200 mg of potassium cyanide are added. The suspension is stirred at room temperature for 7 hours, filtered through a layer of "Hyflo" and washed thoroughly with dichloromethane. The filtrate and washing liquids are collected and washed with a saturated sodium bicarbonate solution and water, dried over anhydrous sodium sulfate and evaporated in vacuo. The title compound in the residue cannot be successfully separated from impurities on a pre-coated silica gel TLC plate'. However, it can be successfully purified on E. Merck precoated silica gel TLC plate (2 mm, 2.5:97.5 methanol-chloroform) to give 400 mg of a foam. Crystallization from ethyl acetate-hexane gives 330 mg of the title compound, m.p. 203-209°C, with consistent spectral data.

Analyse:Analysis:

Beregnet for C29H37F05: C 71,87, H 7,70, F 3,92Calculated for C29H37F05: C 71.87, H 7.70, F 3.92

Funnet: C 71,98, 1-1 7,73, F 3,62. Found: C 71.98, 1-1 7.73, F 3.62.

' Eksempel 9 ' Example 9

9- fluor- 1IB- hydroksy- 1', 2'- dimety1- 3, 20- dioksopregna- l, 4- dieno-[ 16 a, 17- d] cykloheksen- 21- syre- metylester 9- fluoro- 1IB- hydroxy- 1', 2'- dimethyl- 3, 20- dioxopregna- l, 4- dieno-[ 16 a, 17- d] cyclohexene- 21- acid- methyl ester

En oppløsning av 4,9 g 9-f luor-HB, 21-dihydroksy-l' , 2 1 - dimety1-3,20-dioksopregna-l,4-dieno[16a,17-d]cykloheksen og 1,1 g kobberacetat i 800 ml metanol omsettes med luft ved å følge frem-gangsmåten beskrevet i eksempel 1 (første avsnitt) for å gi 5,0 g av en omtrentlig ekvimolar blanding av 21-aldehydet og 21-dimetylacetal-derivatet av utgangssteroidet. A solution of 4.9 g of 9-fluoro-HB, 21-dihydroxy-1' , 2 1 -dimethyl-3,20-dioxopregna-1,4-dieno[16a,17-d]cyclohexene and 1.1 g copper acetate in 800 ml of methanol is reacted with air following the procedure described in Example 1 (first paragraph) to give 5.0 g of an approximately equimolar mixture of the 21-aldehyde and the 21-dimethylacetal derivative of the starting steroid.

Det faste produkt fra den ovenfor beskrevne omsetning (4,5 g) omrøres. i en blanding av 250 ml tørr metanol og 250 ml tørr diklormetan ved romtemperatur i ca. 16 timer under en nitrogenatmosfære med aktivert mangandioksyd (7,0 g), iseddik (4,0 ml) og kaliumcyanid (700 mg). Den resulterende suspensjon filtreres gjennom et lag av diatoméjord og vaskes med kloroform-metanol (9:1) . Filtrat og vaskevæsker samles og inndampes i vakuum for å gi 5,6 g av et fast stoff. Dette oppløses i kloroform-heksan (9:1) og kromatograferes på en 100 g silikagelkolonne. Eluering med kloroform-heksan (9:1) gir 4,2 g materiale, hvorav The solid product from the reaction described above (4.5 g) is stirred. in a mixture of 250 ml dry methanol and 250 ml dry dichloromethane at room temperature for approx. 16 hours under a nitrogen atmosphere with activated manganese dioxide (7.0 g), glacial acetic acid (4.0 ml) and potassium cyanide (700 mg). The resulting suspension is filtered through a layer of diatomaceous earth and washed with chloroform-methanol (9:1). The filtrate and washings are combined and evaporated in vacuo to give 5.6 g of a solid. This is dissolved in chloroform-hexane (9:1) and chromatographed on a 100 g silica gel column. Elution with chloroform-hexane (9:1) gives 4.2 g of material, of which

1,5 g krystalliseres fra aceton-heksan for å gi 90.0 mg av en analytisk prøve av tittelforbindelsen, sm.p. 256-258°C. 1.5 g is crystallized from acetone-hexane to give 90.0 mg of an analytical sample of the title compound, m.p. 256-258°C.

Analyse:Analysis:

Beregnet for C2gH35F05: C 71,46, H 7,50, F 4,04,Calculated for C2gH35F05: C 71.46, H 7.50, F 4.04,

Funnet: C 71,38, H 7,50, F 3,95. Found: C 71.38, H 7.50, F 3.95.

E ksempel 10 Example 10

9- fluor- 1lB- hydroksy- 1' , 2'- dimetyl- 3, 20- dioksc— regna- 1, 4- dieno-[ 16 a, 17- d] cykloheksen- 21- syre- etylester 9- fluoro- 1lB- hydroxy- 1' , 2'- dimethyl- 3, 20- dioxc— regna- 1, 4- dieno- [ 16 a, 17- d] cyclohexene- 21- acid- ethyl ester

A) 9- fluor- 1IB- hydroksy- 1', 2 '- dimetyl- 3, 20- dioksopregna- l, 4-dieno[ 16a, 17- d] cykloheksen- 21- syre A) 9- fluoro- 1IB- hydroxy- 1', 2 '- dimethyl- 3, 20- dioxopregna- 1, 4-dieno[ 16a, 17-d] cyclohexene- 21- acid

En oppløsning av 9-fluor-llB-hydroksy-1',2'-dimetyl-3,20-dioksopregna-l,4-dieno[16 a,17-d]cykloheksen-21-syre-mety1-ester (2,5 g) i en blanding av metanol (110 ml) og tetrahydrofuran (200 ml) omrøres med en oppløsning av kaliumhydroksyd A solution of 9-fluoro-11B-hydroxy-1',2'-dimethyl-3,20-dioxopregna-1,4-dieno[16a,17-d]cyclohexene-21-acid methyl ester (2, 5 g) in a mixture of methanol (110 ml) and tetrahydrofuran (200 ml) is stirred with a solution of potassium hydroxide

(640 mg) i vann (10 ml) i 1,0 time under en nitrogenatmosfære. Reaksjonsblandingen surgjøres derefter med 5%ig saltsyre og inndampes i vakuum. Den resulterende oppslemning blandes med vann og filtreres for å gi 700 mg av tittelforbindelsen, (640 mg) in water (10 mL) for 1.0 h under a nitrogen atmosphere. The reaction mixture is then acidified with 5% hydrochloric acid and evaporated in vacuo. The resulting slurry is mixed with water and filtered to give 700 mg of the title compound,

sm.p. 234-238°C. sm.p. 234-238°C.

Filtratet inndampes i vakuum og vaskes med kloroform-metan<p>l (4:1). Oppløsningsmidlene avdampes for å gi 1,4 g av den hydratiserte form av tittelforbindelsen, sm.p. 215-240°C. The filtrate is evaporated in vacuo and washed with chloroform-methane<p>l (4:1). The solvents are evaporated to give 1.4 g of the hydrated form of the title compound, m.p. 215-240°C.

B) 9- fluor- 1! B~ hydroksy- 1', 2'- dimetyl- 3, 20- dioksopregna- l, 4-dieno[ 16a, 17- d] cykloheksen- 21- syre- etylester B) 9- fluoro- 1! B~ hydroxy- 1', 2'- dimethyl- 3, 20- dioxopregna- l, 4-dieno[ 16a, 17- d] cyclohexene- 21- acid- ethyl ester

Til en suspensjon av 235 mg 9-fluor-llB-hydroksy-1',2'-dimetyl-3,20-dioksopregna-l,4-dieno[16a,17-d]cykloheksen-21-syre i 5,0 ml tørr diklormetan settes suksessivt 0,5 ml trietylamin og 0,068 ml pivaloylklorid. Efter at den resulterende oppløsning er omrørt ved romtemperatur i 15 minutter, tilsettes 0,116 ml absolutt etanol. Efter 3,0 timer surgjøres blandingen med 50%ig saltsyre, helles i vann og ekstraheres med kloroform. Kloroformekstraktene samles, vaskes med vann, tørres over vannfritt magnesiumsulfat og inndampes. Residuet underkastes preparativ tynnskiktkromatografi for å isolere 97 mg av tittelforbindelsen, sm.p. 198-200°C. To a suspension of 235 mg of 9-fluoro-11B-hydroxy-1',2'-dimethyl-3,20-dioxopregna-1,4-dieno[16a,17-d]cyclohexene-21-acid in 5.0 ml dry dichloromethane, successively add 0.5 ml of triethylamine and 0.068 ml of pivaloyl chloride. After the resulting solution is stirred at room temperature for 15 minutes, 0.116 ml of absolute ethanol is added. After 3.0 hours, the mixture is acidified with 50% hydrochloric acid, poured into water and extracted with chloroform. The chloroform extracts are collected, washed with water, dried over anhydrous magnesium sulfate and evaporated. The residue is subjected to preparative thin layer chromatography to isolate 97 mg of the title compound, m.p. 198-200°C.

E ksempel 11 Example 11

9- fluor- llB- hydroksy- 1', 2'- dimetyl- 3, 20- dioksopregna- l, 4- dieno-[ 16 a, 17- d] cyk' loheksen- 21- syre- l, 1- dime ty le ty les ter 9- fluoro- llB- hydroxy- 1', 2'- dimethyl- 3, 20- dioxopregna- 1, 4- dieno-[ 16 a, 17- d] cyclo'lohexene- 21- acid- 1, 1- dimethyl le ty les ter

En oppløsning av 700 mg 9-fluor-llB_hydroksy-l',2<1->dimetyl-3,20-dioksopregna-l,4-dieno[16 a,17-d]cykloheksen-21-syre. A solution of 700 mg of 9-fluoro-11B-hydroxy-1',2<1->dimethyl-3,20-dioxopregna-1,4-dieno[16a,17-d]cyclohexene-21-acid.

(se eksempel 10A) i 60 ml tørr dioksan inneholdende 12 ml isobutylen og 0,7 ml av en svovelsyre/fosforsyre-katalysator (see Example 10A) in 60 ml of dry dioxane containing 12 ml of isobutylene and 0.7 ml of a sulfuric acid/phosphoric acid catalyst

(fremstilt ved å sette fosforpentoksyd til 96%ig svovelsyre)(made by adding phosphorus pentoxide to 96% sulfuric acid)

holdes i et trykk-reaksjonskar ved romtemperatur i 24 timer.kept in a pressure reaction vessel at room temperature for 24 hours.

En strøm av tørr nitrogen føres derefter gjennom oppløsningen for å fjerne overskudd av isobutylen, og blandingen helles i en mettet natriumbikarbonatoppløsning. Steroidet isoleres ved ekstraksjon med kloroform, og kloroformoppløsningen vaskes med vann, tørres over vannfritt magnésiumsulfat, og oppløsnings-midlene avdampes. Residuet (760 mg) underkastes kromatografi på en kolonne av silikagel for å isolere 500 mg av tittelforbindelsen, sm.p. 209-210°C efter krystallisasjon fra aceton-heksan. A stream of dry nitrogen is then passed through the solution to remove excess isobutylene, and the mixture is poured into a saturated sodium bicarbonate solution. The steroid is isolated by extraction with chloroform, and the chloroform solution is washed with water, dried over anhydrous magnesium sulfate, and the solvents are evaporated. The residue (760 mg) is chromatographed on a column of silica gel to isolate 500 mg of the title compound, m.p. 209-210°C after crystallization from acetone-hexane.

E ksempel 12 Example 12

9- fluor- 113- hydroksy- 3, 20- dioksopregna- l, 4- deino[ 16 a, 17- d]-cykloheksen- 21- syre- 2' 2- dimetylpropylester 9- fluoro- 113- hydroxy- 3, 20- dioxopregna- l, 4- deino[ 16 a, 17- d]-cyclohexene- 21- acid- 2' 2- dimethyl propyl ester

En oppløsning av 9-fluor-113-hydroksy-3,20-dioksopregna-l ,4-dieno-[16a,17-d]cykloheksen-21-syre-metylester (25 mg) i tørr dioksan (2,0 ml) inneholdende tørr neopentylalkohol (400 mg) og natriumcyanid (5,0 mg) tilbakeløpsbehandles under vannfrie betingelser i 2,0 timer. Blandingen avkjøles derefter, settes til vann og ekstraheres med kloroform. Kloroform-ekstrakten vaskes med vann, tørres over vannfritt magnesiumsulfat, inndampes, og residuet krystalliseres fra etylacetat-kloroform for å gi 23 mg av tittelforbindelsen, sm.p. 288°C (spaltn., misfavning starter før smeltepunktet). A solution of 9-fluoro-113-hydroxy-3,20-dioxopregna-1,4-dieno-[16a,17-d]cyclohexene-21-acid methyl ester (25 mg) in dry dioxane (2.0 ml) containing dry neopentyl alcohol (400 mg) and sodium cyanide (5.0 mg) is refluxed under anhydrous conditions for 2.0 hours. The mixture is then cooled, added to water and extracted with chloroform. The chloroform extract is washed with water, dried over anhydrous magnesium sulfate, evaporated, and the residue crystallized from ethyl acetate-chloroform to give 23 mg of the title compound, m.p. 288°C (decompn., discolouration starts before the melting point).

Eksempel 13 Example 13

9- fluor- 1', 2', 3', 4'- tetrahydro- 113- hydroksy- 3, 20- dioksopregna-1, 4- dieno[ 16 a, 17- b] naftalen- 21- syre- metylester 9- fluoro- 1', 2', 3', 4'- tetrahydro- 113- hydroxy- 3, 20- dioxopregna-1, 4- dieno[ 16 a, 17- b] naphthalene- 21- acid- methyl ester

A) 9- fluor- 113~ hydroksy- 3, 20- dioksopregna- l, 4, 16- trien- 21-karboksaldehyd og 9- fluor- 113- hydroksy- 21- dimetoksy-pregna- 1, 4, 16- trien- 3, 20- dion A) 9- fluoro- 113~ hydroxy- 3, 20- dioxopregna-l, 4, 16- trien- 21-carboxaldehyde and 9- fluoro- 113- hydroxy- 21- dimethoxy-pregna- 1, 4, 16- trien- 3, 20-dione

En oppløsning av 9-fluor-113,21-dihydroksypregna-1,4,16-trien-3,20-dion (1,7 g) oppløses i metanol (300 ml) ved oppvarmning, og oppløsningen avkjøles til romtemperatur. Kobberacetat (100 mg) tilsettes, og en strøm av luft føres inn i' oppløsningen under omrøring. Efter ca. 20 minutter forsvinner utgangsmaterialet for å gi mindre polare forbindelser som vist ved tynnskiktkromatografi. Oppløsningen inndampes derefter i vakuum, det gjenværende faste stoff vaskes suksessivt med en fortynnet ammoniumkloridoppløsning og vann og tørres for å gi en tilnærmet ekvimolar blanding (1,9 g) av tittelaldehydet (som hydratet) A solution of 9-fluoro-113,21-dihydroxypregna-1,4,16-trien-3,20-dione (1.7 g) is dissolved in methanol (300 ml) by heating, and the solution is cooled to room temperature. Copper acetate (100 mg) is added and a stream of air is introduced into the solution with stirring. After approx. 20 minutes the starting material disappears to give less polar compounds as shown by thin layer chromatography. The solution is then evaporated in vacuo, the remaining solid washed successively with a dilute ammonium chloride solution and water and dried to give an approximately equimolar mixture (1.9 g) of the title aldehyde (as the hydrate)

og tittel-acetalet som vist ved hjelp av NMR-spekteret; Ved tørring i vakuum (125-130°C, 0,5 mm Hg) i 2,0 timer omdannes, dette materiale til en tilnærmet ekvimolar blanding (1,77 g) and the title acetal as shown by the NMR spectrum; On drying in vacuum (125-130°C, 0.5 mm Hg) for 2.0 hours, this material is converted into an approximately equimolar mixture (1.77 g)

av tittelaldehydet og -acetalet som vist ved NMR- og IR-spektra. of the title aldehyde and acetal as shown by NMR and IR spectra.

B) 9- fluor- 116- hydroksy- 3, 20- dioksopregna- l, 4, 16- trieno- 21-syre- metylester B) 9- fluoro- 116- hydroxy- 3, 20- dioxopregna- l, 4, 16- trieno- 21- acid methyl ester

Til en omrørt oppløsning av blandingen av aldehyd og acetal fremstilt i del A (1,75 g), i en blanding av vannfritt diklormetan (100 ml) og vannfri metanol (20 ml) settes suksessivt aktivert mangandioksyd (4,0 g), kaliumcyanid (500 mg) og iseddik (0,5 ml). I løpet av mindre enn 1,0 time forsvinner utgangsmaterialet for å gi tilnærmet én eneste mindre polar forbindelse som vist ved tynnskiktkromatografi. Reaksjonsblandingen filtreres gjennom et lag av diatoméjord, og filterkaken vaskes med flere små porsjoner av en varm blanding av diklormetan-metanol. Filtrat og vaskevæske samles og inndampes for å gi et fast residuum som vaskes med vann og tørres. Krystallisering av det resulterende materiale fra metanol-'diklormetan ( med fjernelse av diklormetan ved avdampning) gir 1,4 g av tittelforbindelsen, sm.p. 284-286°C. To a stirred solution of the mixture of aldehyde and acetal prepared in Part A (1.75 g), in a mixture of anhydrous dichloromethane (100 ml) and anhydrous methanol (20 ml) is successively added activated manganese dioxide (4.0 g), potassium cyanide (500 mg) and glacial acetic acid (0.5 ml). In less than 1.0 hour, the starting material disappears to give approximately a single less polar compound as shown by thin layer chromatography. The reaction mixture is filtered through a layer of diatomaceous earth, and the filter cake is washed with several small portions of a warm mixture of dichloromethane-methanol. Filtrate and washing liquid are collected and evaporated to give a solid residue which is washed with water and dried. Crystallization of the resulting material from methanol-dichloromethane (with removal of dichloromethane by evaporation) gives 1.4 g of the title compound, m.p. 284-286°C.

C) 9- fluor- 1', 2', 3', 4'- tetrahydro- llB- hydroksy- 3, 20- dioksopregna-1, 4- dieno [ 16a, 17- b] naftalen- 21- syre- metylester C) 9- fluoro- 1', 2', 3', 4'- tetrahydro- 11B- hydroxy- 3, 20- dioxopregna-1, 4- dieno [ 16a, 17-b] naphthalene- 21- acid- methyl ester

En oppløsning av 9-fluor-llB-hydroksy-3,20-dioksopregna-1,4,16-trieno-21-syre-metylester (100 mg) i benzocyklobuten A solution of 9-fluoro-11B-hydroxy-3,20-dioxopregna-1,4,16-trieno-21-acid methyl ester (100 mg) in benzocyclobutene

(5,0 ml) inneholdende 4,4'-tiobis-6-t-butyl-m-kresol (6,0 mg) tilbakeløpsbehandles under en atmosfære av nitrogen i 10 timer, og et fast stoff fraskilles fra oppløsningen. Uomsatt benzocyklobuten utvinnes ved vakuumdestillasjon, og det gjenværende residuum krystalliseres fra metanol-diklormetan (ved fjernelse av diklormetanet ved avdampning) for å gi tittelforbindelsen, sm.p. ^325-326°C (misfarvning starter fra ca. 295°C) . (5.0 mL) containing 4,4'-thiobis-6-t-butyl-m-cresol (6.0 mg) is refluxed under an atmosphere of nitrogen for 10 hours, and a solid is separated from the solution. Unreacted benzocyclobutene is recovered by vacuum distillation, and the remaining residue is crystallized from methanol-dichloromethane (by removal of the dichloromethane by evaporation) to give the title compound, m.p. ^325-326°C (discolouration starts from approx. 295°C) .

Eksempel 14 Example 14

9- fluor- lip- hydroksy- 3, 20- dioksopregna- l, 4, 16- trieno- 21- syre9- fluoro- lip- hydroxy- 3, 20- dioxopregna- l, 4, 16- trieno- 21- acid

En oppløsning av 9-fluor-113~hydroksy-3,20-dioksb-pregna-1,4,16-trieno-21-syre-metylester (100 mg, se eksempel IB) A solution of 9-fluoro-113-hydroxy-3,20-dioxb-pregna-1,4,16-trieno-21-acid methyl ester (100 mg, see Example IB)

i en blanding av metanol (15 ml) og tetrahydrofuran (15 ml) om-røres med 3M natriumhydroksyd (1,0 ml) under en nitrogenatmosfære i 2,0 timer. Blandingen surgjøres derefter med 5%ig saltsyre og inndampes til et residuum. Residuet vaskes med vann og krystalliseres fra kloroform-metanol for å gi tittelforbindelsen. Dette materiale blir sort ved oppvarmning til 400°C, men smelter ikke. in a mixture of methanol (15 ml) and tetrahydrofuran (15 ml) is stirred with 3M sodium hydroxide (1.0 ml) under a nitrogen atmosphere for 2.0 hours. The mixture is then acidified with 5% hydrochloric acid and evaporated to a residue. The residue is washed with water and crystallized from chloroform-methanol to give the title compound. This material turns black when heated to 400°C, but does not melt.

Steroidet ifølge dette eksempel kan forestres under anvendelse av vanlig teknikk og omsettes derefter med et benzocyklobuten som beskrevet i eksempel 13C for å gi et produkt med formel I. The steroid of this example can be esterified using conventional techniques and then reacted with a benzocyclobutene as described in Example 13C to give a product of formula I.

Eksempel 15 Example 15

9- fluor- 1lB- hydroksy- 1', 2'- dimetyl- 3, 20- dioksopregna- l, 4- dieno-[ 16 a, 17- d] cykloheksen- 21- syre- n- butylester 9- fluoro- 1lB- hydroxy- 1', 2'- dimethyl- 3, 20- dioxopregna- 1, 4- dieno-[ 16 a, 17- d] cyclohexene- 21- acid- n- butyl ester

A) 9- fluor- 113- hydroksy- 3, 20- dioksopregna- l, 4, 16- trien- 21-karboksaldehyd og 9- fluor- 113- hydroksy- 21- dimetoksypregna-1, 4, 16- trien- 3, 20- dion A) 9- fluoro- 113- hydroxy- 3, 20- dioxopregna-l, 4, 16- trien- 21-carboxaldehyde and 9- fluoro- 113- hydroxy- 21- dimethoxypregna- 1, 4, 16- trien- 3, 20- dione

En oppløsning av 9-fluor-113/21-dihydroksypregna-l,4,16-trien-3,20-dion (1,7 g) oppløses i metanol (300 ml) ved oppvarmning, og oppløsningen avkjøles til romtemperatur. Kobberacetat (100 mg) tilsettes, og en strøm av luft føres inn i opp-løsningen under omrøring. I løpet av ca. 20 minutter forsvinner utgangsmaterialet for å gi mindre polare forbindelser som vist ved tynnskiktkromatografi. Oppløsningen inndampes derefter i vakuum, og det gjenværende faste stoff vaskes suksessivt med en fortynnet ammoniumkloridoppløsning og vann og tørres for å gi en tilnærmet ekvimolar blanding (1,9 g) av tittelaldehydet A solution of 9-fluoro-113/21-dihydroxypregna-1,4,16-trien-3,20-dione (1.7 g) is dissolved in methanol (300 ml) by heating, and the solution is cooled to room temperature. Copper acetate (100 mg) is added, and a stream of air is introduced into the solution while stirring. During approx. 20 minutes the starting material disappears to give less polar compounds as shown by thin layer chromatography. The solution is then evaporated in vacuo and the remaining solid is washed successively with dilute ammonium chloride solution and water and dried to give an approximately equimolar mixture (1.9 g) of the title aldehyde

(som hydratet) og tittelacetalet som vist ved NMR-spekteret.(as the hydrate) and the title acetal as shown by the NMR spectrum.

Ved tørring i vakuum (125-130°C, 0,5 mm Hg) i 2,0 timer omdannes dette materiale til en tilnærmet ekvimolar blanding (1,77 g) On drying in vacuum (125-130°C, 0.5 mm Hg) for 2.0 hours, this material is converted to an approximately equimolar mixture (1.77 g)

av tittelaldehydet og acetalet som vist ved NMR-og IR-spektra.of the title aldehyde and acetal as shown by NMR and IR spectra.

B) 9- fluor- llB- hydroksy- 3, 20- dioksopregna- l, 4 , 16- trieno-21- syre- metylester B) 9- fluoro- 11B- hydroxy- 3, 20- dioxopregna- 1, 4, 16- trieno-21- acid methyl ester

Til en omrørt oppløsning av blandingen av aldehydet og acetalet fremstilt i del A, i en blanding av vannfritt diklormetan (100 ml) og vannfri metanol (20 ml) settes suksessivt aktivert mangandioksyd (4,0 g), kaliumcyanid (500 mg) og iseddik (0,5 ml). I løpet av mindre enn 1,0 time forsvinner utgangsmaterialet for å gi tilnærmet en eneste mindre polar forbindelse som vist ved tynnskiktkromatografi. Reaksjonsblandingen filtreres gjennom et lag av diatoméjord, og filterkaken vaskes med flere små porsjoner av en varm blanding av diklormetan-metanol. Filtratet og vaskevæskene samles og inndampes til et fast residuum som vaskes med vann og tørres. Krystallisering av det resulterende materiale fra metanol-diklormetan (med fordampnings-fjerning av diklormetanet) gir 1,4 g av tittelforbindelsen, To a stirred solution of the mixture of the aldehyde and acetal prepared in part A, in a mixture of anhydrous dichloromethane (100 ml) and anhydrous methanol (20 ml) is added successively activated manganese dioxide (4.0 g), potassium cyanide (500 mg) and glacial acetic acid (0.5 ml). In less than 1.0 hour, the starting material disappears to give approximately a single less polar compound as shown by thin layer chromatography. The reaction mixture is filtered through a layer of diatomaceous earth, and the filter cake is washed with several small portions of a warm mixture of dichloromethane-methanol. The filtrate and washing liquids are collected and evaporated to a solid residue which is washed with water and dried. Crystallization of the resulting material from methanol-dichloromethane (with evaporation removal of the dichloromethane) gives 1.4 g of the title compound,

sm.p. 284-286°C. ' C) HØ- ( acetyloksy) - 9- f luor- 3 , 20- dioksopregna- l, 4 , 16- trieno-21- syre- metylester sm.p. 284-286°C. C) HØ-(acetyloxy)-9-fluoro-3,20-dioxopregna-1,4,16-trieno-21-acid methyl ester

En oppløsning av 9-fluor-llB-hydroksy-3,20-dioksopregna-l ,4,16-trieno-21-syre-metylester (400 mg) i en blanding av iseddik (9,0 ml) og eddiksyreanhydrid (9,0 ml) inneholdende p-toluensulfonsyre (200 mg) omrøres ved romtemperatur i 24 timer. Natriumacetat (300 mg) tilsettes, og blandingen helles i isvann (200 ml) med omrøring. Det utskilte, faste stoff isoleres ved filtrering, vaskes med vann og tørres for- å gi 400 mg av tittelforbindelsen som er forurenset med bare spormengder av urenheter som vist ved tynnskiktkromatografi. Krystallisering av dette materiale fra etylacetat-heksan gir 350 mg av tittelforbindelsen, sm.p. 235-236°C. A solution of 9-fluoro-11B-hydroxy-3,20-dioxopregna-1,4,16-trieno-21-acid methyl ester (400 mg) in a mixture of glacial acetic acid (9.0 ml) and acetic anhydride (9, 0 ml) containing p-toluenesulfonic acid (200 mg) is stirred at room temperature for 24 hours. Sodium acetate (300 mg) is added and the mixture is poured into ice water (200 ml) with stirring. The separated solid is isolated by filtration, washed with water and dried to give 400 mg of the title compound which is contaminated with only trace amounts of impurities as shown by thin layer chromatography. Crystallization of this material from ethyl acetate-hexane gives 350 mg of the title compound, m.p. 235-236°C.

D) 113-( acetyloksy)- 9- fluor- 1', 2'- dimetyl- 3, 20- dioksopregna-1, 4- dieno-[ 16a, 17- d] cykloheksen- 2l- syre- metylester D) 113-(acetyloxy)-9-fluoro-1',2'-dimethyl-3,20-dioxopregna-1,4-dieno-[16a,17-d]cyclohexene-2l- acid methyl ester

Til en omrørt oppløsning av UB- (acetyloksy) -9-f luor-3,20-dioksopregna-l,4,16-trieno-21-syre-metylester (320 mg) i vannfritt diklormetan (25 ml).inneholdende aluminiumklorid To a stirred solution of UB-(acetyloxy)-9-fluoro-3,20-dioxopregna-1,4,16-trieno-21-acid methyl ester (320 mg) in anhydrous dichloromethane (25 ml) containing aluminum chloride

(100 mg) settes 2,3-dimetyl-l,3-butadien (0,25 ml). Blandingen omrøres ved romtemperatur i 1,5 time, helles i vann og ekstraheres med diklormetan. Diklormetanekstrakten vaskes med vann, tørres over vannfritt magnesiumsulfat og inndampes til et (100 mg) is added 2,3-dimethyl-1,3-butadiene (0.25 ml). The mixture is stirred at room temperature for 1.5 hours, poured into water and extracted with dichloromethane. The dichloromethane extract is washed with water, dried over anhydrous magnesium sulfate and evaporated to a

residuum (300 mg). Dette underkastes kromatografi på en kolonne av silikgal (10 g) for å isolere tittelforbindelsen (265 mg). Krystallisering fra etylacetat-heksan gir nåler (160 mg), residue (300 mg). This is subjected to chromatography on a silica gel column (10 g) to isolate the title compound (265 mg). Crystallization from ethyl acetate-hexane gives needles (160 mg),

sm.p.' 172-173°C. sm.p.' 172-173°C.

E) 9- fluor- 113- hydroksy- l', 2'- dimetyl- 3, 20- dioksopregna- l, 4-dieno [ 16a, 17- d] cykloheksen- 21- syre E) 9-fluoro-113-hydroxyl-1',2'-dimethyl-3,20-dioxopregna-1,4-dieno[16a,17-d]cyclohexene-21-acid

En oppløsning av 113-(acetyloksy)-9-fluor-1<1>,2'-dimetyl-3,20-dioksopregna-l,4-dieno[16a,17-d]cykloheksen-21-syre-metylester (235 mg) i en blanding av 90%ig metanol (100 ml), A solution of 113-(acetyloxy)-9-fluoro-1<1>,2'-dimethyl-3,20-dioxopregna-1,4-dieno[16a,17-d]cyclohexene-21-acid methyl ester (235 mg) in a mixture of 90% methanol (100 ml),

og tetrahydrofuran (10 ml) inneholdende 3M natriumhydroksyd (2,0 ml) omrøres under en atmosfære av nitrogen i et bad ved 60-70°C i 2-3 timer. Blandingen surgjøres med en minimal mengde 5%ig saltsyre og inndampes i vakuum. Residuet opparbeides med vann og tørres for å gi 195 mg av tittelforbindelsen. Krystallisering fra en blanding av kloroform-metanol gir den analytiske prøve av tittelforbindelsen, sm.p. 236-239°C. and tetrahydrofuran (10 ml) containing 3M sodium hydroxide (2.0 ml) is stirred under an atmosphere of nitrogen in a bath at 60-70°C for 2-3 hours. The mixture is acidified with a minimal amount of 5% hydrochloric acid and evaporated in vacuo. The residue is worked up with water and dried to give 195 mg of the title compound. Crystallization from a mixture of chloroform-methanol gives the analytical sample of the title compound, m.p. 236-239°C.

F) 9- f luor- 113- h. ydroksy- 1' , 2 ' - dimetyl- 3 , 20- dioksopregna- l , 4-dieno [ 16a, 17- d] cykldheksen- 21- syre- n- butylester F) 9-fluoro-113-hydroxy-1',2'-dimethyl-3,20-dioxopregna-l,4-dieno[16a,17-d]cyclohexene-21-acid-n-butyl ester

Til en oppløsning av- 9-fluor-113-hydroksy-l',2'-dimetyl-3,20-dioksopregna-l,4-dieno[16a,17-d]cykloheksen-21-syre (175 mg) i diklormetan (40 ml) inneholdende noen få dråper metanol settes et overskudd av en eterisk oppløsning av diazobutan. Efter 5 minutter ødelegges overskuddet av diazobutan ved tilsetning av noen få dråper eddiksyre. Oppløsningen inndampes til tørrhet, og residuet krystalliseres fra aceton-heksan for å gi 127 mg av tittelforbindelsen, sm.p. 209-211°C. To a solution of 9-fluoro-113-hydroxy-1',2'-dimethyl-3,20-dioxopregna-1,4-dieno[16a,17-d]cyclohexene-21-acid (175 mg) in dichloromethane (40 ml) containing a few drops of methanol is added an excess of an ethereal solution of diazobutane. After 5 minutes, the excess of diazobutane is destroyed by adding a few drops of acetic acid. The solution is evaporated to dryness and the residue crystallized from acetone-hexane to give 127 mg of the title compound, m.p. 209-211°C.

Eksempel 16 Example 16

( 113, 163)- 9- fluor- 1', 2', 3', 4'- tetrahydro- ll- hydroksy- 3, 20- dioksopregna- l, 4- dieno[ 16, 17- b] naftalen- 21- syre- oktylester ( 113, 163)- 9- fluoro- 1', 2', 3', 4'- tetrahydro- ll- hydroxy- 3, 20- dioxopregna- l, 4- dieno[ 16, 17- b] naphthalene- 21- acid octyl ester

En oppløsning av 500 mg (0,96 mmol) 0.13 / 16a) -9-f luor-1',2<1>,3',4'-tetra-ll-hydroksy-3,20-dioksopregna-l,4-dieno-[16,17-b]naftalen-21-syre-l-metyletylester og 40 mg natriumcyanid i 40 ml tørr oktanol-1 (destillert over kalsiumhydrid) omrøres ved 130°C under nitrogenatmosfære i 1,5 time. Den resulterende oppløsning inndampes i vakuum. Residuet oppløses i diklormetan, vaskes med vann, tørres over vannfritt Na2S0^og inndampes i vakuum for å gi et residuum som oppløses i kloroform-heksan (7:3) og kromatograferes på en 20 g silikagelkolonne. Eluering med kloroform-heksan (7:3) gir 485 mg (97% produkt. Krystallisering fra aceton-heksan gir 370 mg (74%) produkt, sm-.p. 215-216°C. Analyse: Beregnet for C37H47<F>05: C 75,22, H 8,02, F 3,22 A solution of 500 mg (0.96 mmol) 0.13/16a)-9-fluoro-1',2<1>,3',4'-tetra-11-hydroxy-3,20-dioxopregna-1,4 -dieno-[16,17-b]naphthalene-21-acid-1-methylethyl ester and 40 mg of sodium cyanide in 40 ml of dry octanol-1 (distilled over calcium hydride) are stirred at 130° C. under a nitrogen atmosphere for 1.5 hours. The resulting solution is evaporated in vacuo. The residue is dissolved in dichloromethane, washed with water, dried over anhydrous Na 2 SO 4 and evaporated in vacuo to give a residue which is dissolved in chloroform-hexane (7:3) and chromatographed on a 20 g silica gel column. Elution with chloroform-hexane (7:3) gives 485 mg (97% product. Crystallization from acetone-hexane gives 370 mg (74%) product, m.p. 215-216°C. Analysis: Calculated for C37H47<F >05: C 75.22, H 8.02, F 3.22

Funnet: C 75,34, H 8,23, F 3,21. Found: C 75.34, H 8.23, F 3.21.

Claims

1. Process for the preparation of a steroid of the formula

and esters thereof, or the 1,2-dehydro derivative thereof, where X is hydrogen or halogen; Y is hydrogen, fluorine or methyl; R4 is chlorine, fluorine or hydroxy and R5 is hydrogen, or R^ and R,, together are =0; R 2 and R 4 are the same or different and are hydrogen, alkyl or aryl, or together, with the double bond to which they are attached, form a benzene ring; Rg and R-, are the same or different and are hydrogen, alkyl., alkoxy, formyl, alkyl-COO-, phenyl or cyano, and also hydroxy, halogen, caralkyloxy and alkylcarbonyl when R^ and R^ are separate, with the proviso that when Rg and R^ are different, is one of R 8 and R 8 hydrogen; Rg is hydrogen or -CH-RgR^Q where Rg and R^ are the same or different and are hydrogen or alkyl, characterized in that the corresponding 21-hydroxy steroid with the formula:

where the symbols have the meanings given above, are oxidized.

2. Method for producing a steroid as stated in claim 1, characterized in that the 21-hydroxy group in a steroid is first oxidized with the formula

to a 21-carboxylic acid group, and then the cyclohexene or tetrahydronaphthalene group is condensed with the formula

in 16,17 position.

3. Method as set out in claims 1 and 2, characterized in that a product is produced with the formula

or the 1,2-dehydro derivative thereof, where is alkyl of 1 to 10 carbon atoms, aryl or arylalkyl.

4. Method as specified in claims 1 and 2, characterized in that a compound with the formula is prepared

or the 1,2-dehydro derivative thereof, where R 1 is alkyl of 1 to 10 carbon atoms, aryl or arylalkyl; X is hydrogen or halogen; Y is hydrogen, fluorine or methyl; R^ is chlorine, fluorine or hydroxy, and R^- is hydrogen, or R^ and R^ together are =0; R₁ and R₂ are the same or different and are hydrogen, alkyl, alkoxy, caralkyloxy, formyl, alkyl-CO-, alkyl-COO-, hydroxy, halogen, phenyl or cyano, with the proviso that when R 1 - and R 1 are different, one of R 8 and R 1 is hydrogen; Rg is hydrogen or -CH- <R> gR^0 , where R^ and R^Q are the same or different and are hydrogen or alkyl.

5. Method as stated in claims 1 and 2, characterized in that a product is produced with the formula

or the 1,2-dehydro derivative thereof, where R 1 is alkyl of 1 to 10 carbon atoms, aryl or arylalkyl; R 2°9 R 3 are the same or different and are hydrogen, alkyl or aryl; R 1 is hydrogen and R 5 is hydroxy, or together R 4 and R 1 =O; X is hydrogen or halogen; and Y is hydrogen, methyl or fluorine.

6. Method as specified in claims 1 and 2, characterized in that a product is produced with the formula

or the 1,2-dehydro derivative thereof, where R is alkyl of 1 to 10 carbon atoms, aryl or arylalkyl; and R 1 are the same or different and are hydrogen, alkyl or aryl; R 1 is hydrogen and R 5 is hydroxy or together R 1 and R 2 =O; and Y is hydrogen, methyl or fluorine.

7. Method as stated in one of claims 1 to 4, characterized in that X is fluorine.

8. Method as stated in e't of claims 1 to 7, characterized in that Y is hydrogen.

9. Method as stated in one of claims 1 to 8, characterized in that is hydroxy and R 1 is hydrogen.

10. Method as stated in one of claims 1 to 4, characterized in that and R is hydrogen.

11. Method as stated in one of claims 1 to 4, characterized in that Rg is hydrogen.

12. Method as stated in one of claims 1 to 4, characterized in that Rg is methyl..

13. Procedure as specified in claim 1 to. 4, characterized in that 9-fluoro-1',2',3',4'-tetrahydro-11B-hydroxy-3,20-dioxopregna-1,4-dieno[16a,17-b]naphthalene-21 is prepared -acid methyl ester.

14. Method as stated in claims 1 to 4, characterized in that 9-fluoro-1',2',31,4'-tetrahydro-113-hydroxy-3,20-dioxopregna-1,4-dieno-[ 16a,17-b]naphthalene-21-acid-1-methylethyl.

15. Process as stated in claims 1 to 4, characterized in that 9-fluoro-1',2',3 <1>,4,-tetrahydro-11B-hydroxy-3,20-dioxopregna-1,4- dieno-[16a,17-b]naphthalene-21-acid butyl ester.

16. Process as stated in claims 1 to 4, characterized in that 9-fluoro-1',2',3<1>,4'-tetrahydro-11B-hydroxy-3,20-dioxopregna-1,4- dieno-[16a,17-b]naphthalene-21-acid 1,1-dimethylethyl ester.

17.. Process as stated in claims 1 to 4, characterized in that 9-fluoro-1',2',3',4'-tetrahydro-113-hydroxy-3,20-dioxopregna-1,4-dieno is produced -[16 a,17-b]naphthalene-21-acid-2,2-dimethylpropyl ester.

18. Procedure as specified in claims 1, 2, 3, 5 and. 6, characterized in that 9-fluoro-11B-hydroxy-3,20-dioxopregna-1,4-dieno[16a,17-d]cyclohexene-21-acid methyl ester is produced.

19. Process as stated in claims 1, 2, 3, 5 and 6, characterized in that 9-fluoro-11B-hydroxy-3,20-dioxopregna-1,4-dieno[16a,17-d]cyclohexene- 21-acid-1-methylethyl ester.

20. Process as set forth in claims 1, 2, 3, 5 and 6, characterized in that 9-fluoro-11B-hydroxy-3,20-dioxopregna-1,4-dieno[16a,17-d]cyclohexene is produced -21-acid butyl ester.

21. Process as stated in claims 1, 2, 3, 5 and 6, characterized in that 9-fluoro-11B-hydroxy-1',2'-dimethyl-3,20-dioxopregna-1,4-dieno[ 16α,17-d]-cyclohexene-21-acid methyl ester.

22. Process as stated in claims 1, 2, 3, 5 and 6, characterized in that 9-fluoro-HB-hydroxy-1',21-dimethyl-3,20-dioxopregna-1,4-dieno[16a ,17-d]- . cyclohexene-21-acid ethyl ester.

23. Method as stated in claims 1, 2, 3, 5 and 6, characterized in that 9-fluoro-113-hydroxy-3/20-dioxopregna-1,4-dieno[16a,17-d]cyclohexene- 21-acid 2,2-dimethylpropyl ester.

24. Process as stated in claims 1, 2, 3, 5 and 6, characterized in that 9-fluoro-113-hydroxy-1',2'-dimethyl-3,20-dioxopregna-1,4-dieno[ 16α,17-d]-cyclohexene-21-acid-1,1-dimethylethyl ester.

25. Steroid, characterized in that it has the formula

or the 1,2-dehydro derivative thereof, where X is hydrogen or halogen; Y is hydrogen, fluorine or methyl; R 4 is chlorine, fluorine or hydroxy and R 1 - is hydrogen, or R 4 and R 1 - together are =0; R 2 and R 3 are the same or different and are hydrogen, alkyl or aryl, or together with the double bond to which they are attached form a benzene ring; Rg and R-, are the same or different and are hydrogen, alkyl, alkoxy, formyl, alkyl-COO-, phenyl or cyano and are additionally hydroxy, halogen, carbalkyloxy or alkylcarbonyl when R2 and R^ are separate, with the proviso that when R, and R_ are different, one of Rc and R_ is hydrogen; D / 0 / Rg is hydrogen or -CH-RgR10, where Rg and R1Q are the same or different and are hydrogen or alkyl.

26. Steroid as stated in claim 25, characterized in that it has the formula

or the 1,2-dehydro derivative thereof, where X is hydrogen or halogen; Y is hydrogen, fluorine or methyl; R. is chlorine, fluorine or hydroxy and R.sub.3 is hydrogen, or R.sub.1 and R.sub.1, together are <=> 0; Rg and R^ are the same or different and are hydrogen, alkyl, alkoxy, caralkyloxy, formyl, alkyl-CO-, alkyl-COO-, hydroxy, halogen, phenyl or cyano, with the proviso that when Rg and R^ are different, one of R 1 and R 1 is hydrogen; RD is hydrogen b / o or -CH-RgR1Q where Rg and R are the same or different and are hydrogen or alkyl.

27. Steroid as stated in claim 25, characterized in that it has the formula

where the symbols have the meanings indicated above.

28. Steroid as stated in claim 25, characterized in that it has the formula

where the symbols have the meanings indicated above.

29. Steroid, characterized in that it has the formula

or the 1,2-dehydro-derivative thereof, where R-, e., r is alkyl of 1 to 10 carbon atoms, aryl or arylalkyl; X is hydrogen or halogen; Y is hydrogen, fluorine or methyl; R^ is chlorine, fluorine or hydroxy and • R,, is hydrogen, or R^ and R^ together are =0; R 9 R 3 are the same or different and are hydrogen, alkyl or aryl, or together with the double bond to which they are attached form a benzene ring; Rg and R^ are the same or different and are hydrogen, alkyl, alkoxy, formyl, alkyl-COO-, phenyl or cyano and are additionally hydroxy, halogen, carbaloxy or alkylcarbonyl when R^ and R^ are separate, with the proviso that when Rg and R^ are different, one of Rg and R- is hydrogen; Rg is hydrogen or -CH-RgR^Q, where Rg and R^q are the same or different and are hydrogen or alkyl..

30. Steroid as stated in claim 29, characterized in that it has the formula

or the 1,2-dehydro derivative thereof, where R is alkyl of 1 to 10 carbon atoms, aryl or arylalkyl; X is hydrogen or halogen, Y is hydrogen, fluorine or methyl; R 4 is chlorine, fluorine or - hydroxy and R 1 - is hydrogen, or R 4 and R 5 together are =O; Rg and R-, are the same or different and are hydrogen, alkyl, alkoxy, carbaloxy, formyl, alkyl-CO-, alkyl-COO-, hydroxy, halogen, phenyl or cyano, with the proviso that when Rg and R-, are different, one of Rg and R7 is hydrogen; Rg is hydrogen or -CH-RnR, „. where Rn and- R, _ are the same or different and y io y io is hydrogen or alkyl.

31. Steroid as stated in claim 29, characterized in that it has the formula

or the 1,2-dehydro derivative thereof, where R 1 is alkyl of 1 to 10 carbon atoms, aryl or arylalkyl; R_°9 ^3 are the same or different and are hydrogen, alkyl or aryl; R 1 is hydrogen and R 1 - is hydroxy, or R 1 and R 1 together are =O; and Rg is hydrogen, methyl or fluorine.

32. Steroid as stated in claim 29, characterized in that it has the formula

33. Steroid, characterized in that it has the formula

or or the 1,2-dehydro derivative thereof, where R is alkyl of 1 to 10 carbon atoms, aryl or arylalkyl; X is hydrogen or halogen; Y is hydrogen, fluorine or methyl; R 1 is chlorine, fluorine or, hydroxy and R 1 - is hydrogen, or R 1 and R 1 - together are =0; R 2 and R 1 are the same or different and are hydrogen, alkyl or aryl, or together with the double bond to which they are attached form a benzene ring; Rg and R^ are the same or different and are hydrogen, alkyl, alkoxy, formyl, alkyl-COO-, phenyl, or cyano and are also hydroxy, halogen, caralkyloxy or alkylcarbonyl when R^ and R^ are separate, with the proviso that when Rg and R7 are different, are. one of Rg and R? hydrogen; Rg is hydrogen or -CH-RgR, where Rg and Rg are the same or different and are hydrogen or alkyl.

34. Steroid as stated in claim 33, characterized in that it has the formula

or

or the 1,2-dehydro derivative thereof, where R, is alkyl with 1 to. 10 carbon atoms, aryl or arylalkyl; X is hydrogen or halogen; Y is hydrogen, fluorine or methyl; R^ is chlorine, fluorine or ,, hydroxy and R^ is hydrogen, or R^ and R^ together are =O'; Rg and R^ are equal or different and are hydrogen, alkyl, alkoxy, carbaloxy, formyl, alkyl-CO-, alkyl-COO-, hydroxy, halogen, phenyl or cyano, with the proviso that when Rg and R7 are different , is one of R, and R_ is hydrogen; RQ is hydrogen or D / CS -CH- <R> gR^0 , where Rg and R.^ are the same or different and are hydrogen or alkyl.

35. Steroid as stated in claim 33, characterized in that it has the formula:

or

36. Steroid as stated in claim 33, characterized in that it has the formula

or