DK146017B - ANALOGY PROCEDURE FOR PREPARING 17ALFA-ACYLOXY-9ALFA, 21-DIHALOGEN-11BETA-HYDROXY-6ALFA-FLUOR-16BETA-METHYL-PREGNA-1,4-DIEN-3,20-DION COMPOUNDS - Google Patents

Description

i U6017in U6017

Patent nr. 143.708 angår en analogifremgangsmåde til fremstilling af 17a-acyloxy-9a, 21-dihalogen-ll|3-hydroxy-6a-fluor-16a-methyl-pregna-l,4-dien-3,20-dion-forbindelser med formlen CH0-X2 CH, C=0 HO ^ J 0 _ —-O-R2 5 rI / y (A)Patent No. 143,388 relates to an analogous process for the preparation of 17α-acyloxy-9α, 21-dihalogen-11β-hydroxy-6α-fluoro-16α-methyl-pregna-1,4-diene-3,20-dione compounds with the formula CHO-X2 CH, C = O HO 2 J 0 _ -O-R2 5 rI / y (A)

X JX J

oAAy ioAAy i

FF

1 2 1 hvori X er chlor eller fluor, X brom eller chlor, R hydro- 2 gen eller chlor og R en alkanoylgruppe med højst 7 C-atomer, og det ejendommelige ifølge hovedpatentet er, at man a) behandler en forbindelse med formlen CH0-X2 CEL C=0 /\-----0-R2 R1 CH3 y°1 2 1 wherein X is chlorine or fluorine, X is bromine or chlorine, R is hydrogen or chlorine and R is an alkanoyl group having a maximum of 7 C atoms, and the peculiarity of the main patent is that a) a compound of formula CH -X2 CEL C = 0 / \ ----- 0-R2 R1 CH3 y °

VyW'.VyW '.

CELCEL

10 0AÅ/ t <10 0Å / h <

FF

12 2 hvori R , R og X har den ovennævnte betydning, med hydro-genchlorid eller hydrogenfluorid eller med et middel, der afgiver et af disse hydrogenhalogenider, eller b) i en forbindelse med den almene formel 2 146017 CHo-0-Ra I 2 CH C=0 "V'nLJ----O-E2 E1 =¾] i ..Wherein R, R and X are as defined above with hydrogen chloride or hydrogen fluoride or with an agent giving off one of these hydrogen halides, or b) in a compound of the general formula 2 CHO-O-Ra I 2 CH C = 0 "V'nLJ ---- O-E2 E1 = ¾] i.

»>»>

FF

12 1 hvori R , RZ og Xx har den ovennævnte betydning, og Ra er resten af en organisk sulfonsyre, erstatter sulfonyl-oxygruppen med brom eller chlor, eller 5 c) til fremstilling af forbindelser med formlen A, hvori X^· betyder chlor, behandler en 9 (11)-umættet forbindelse med formlen CH--X2 I 2 CH3 c=o ------O-R2Wherein R, RZ and Xx are as defined above and Ra is the residue of an organic sulfonic acid, replacing the sulfonyl-oxy group with bromine or chlorine, or c) for the preparation of compounds of formula A wherein X treats a 9 (11) unsaturated compound of formula CH - X2 I 2 CH3 c = o ------ O-R2

R1 CH3 IR1 CH3 I

oWoW

• ( i• (i

FF

12 2 hvori R , R og X har den ovennævnte betydning, med chlor-10 undersyrling eller et chlorundersyrlingafgivende middel, eller d) til fremstilling af en forbindelse med formlen A, hvori R1 er hydrogen, dehydrogenerer en forbindelse med formlen 3 146017 CEL-X2 CH3 9=0Wherein R, R and X are as defined above with chloro-10 acid or a chloro-acid acid release agent, or d) to prepare a compound of formula A wherein R 1 is hydrogen dehydrogenates a compound of formula 3 CEL-X2 CH3 9 = 0

H0 A OH0 A O

------O-R2 CH, oAÅ/------ O-R2 CH, oAÅ /

FF

2 1 2 hvori R , X og X har den ovennævnte betydning, i 1,2-stil-1ingen, og, om ønsket, i en ifølge fremgangsmåden opnået forbindelse 5 med formlen A, hvori R^ betyder hydrogen, og de øvrige symboler har den ovennævnte betydning, adderer chlor til 1,2-dobbeltbindingen og fra den opnåede forbindelse med formlen p-x2 CH, C=02 1 2 wherein R, X and X have the above meaning, in the 1,2-position, and, if desired, in a compound obtained according to the process of formula A wherein R 1 is hydrogen and the other symbols have the above meaning, chlorine adds to the 1,2-double bond and from the obtained compound of formula p-x2 CH, C = O

HO yw OHO yw O.

-----O-R2----- O-R 2

Cl Kl 1 ..Cl Kl 1..

T N/iYV CH3T N / iYV CH3

FF

2 1 2 hvori R , x og X har den ovennævnte betydning, fraspalter 10 hydrogenchlorid, idet man under et vilkårligt af de to fremgangsmådetrin kan arbejde under forbigående beskyttelse af Ιΐβ-hydroxylgruppen ved overføring i trifluoracetatet.In which R, x and X have the above meaning, 10 hydrogen chloride is decomposed, during which any of the two process steps can be worked under transient protection of the β-hydroxyl group by transfer into the trifluoroacetate.

Den foreliggende opfindelse angår en analogifremgangsmåde ifølge patent nr. 143.708 til fremstilling af hidtil ukendte 15 17a-acyloxy-9a,21-dihalogen-113-hydroxy-6a-fluor-160-methyl-pregna-l,4-dien-3,20-dion-forbindelser med formlen 4 146017 CH--X2 I 2 CH- C=0 H° Λ -γΝ------O-R2 R1 CH3 (I) X °The present invention relates to an analogous process according to Patent No. 143,708 for the preparation of novel 17α-acyloxy-9α, 21-dihalo-113-hydroxy-6α-fluoro-160-methyl-pregna-1,4-diene-3.20 -Dione Compounds of Formula 4 146017 CH - X2 I 2 CH- C = 0 H ° Λ -γΝ ------ O-R2 R1 CH3 (I) X °

A/VOUCH

0 :0:

FF

1 2 1 hvori X er chlor eller fluor, X brom eller chlor, R1 2 1 wherein X is chlorine or fluorine, X bromine or chlorine, R

2 hydrogen eller chlor og R en alkanoylgruppe med højst 7 C-atomer.2 is hydrogen or chloro and R is an alkanoyl group having a maximum of 7 C atoms.

Fremgangsmåden ifølge opfindelsen er ejendommelig ved, 5 at man a) behandler en forbindelse med formlen CH0-X2 I 2 CH3 c=o -,----ο-R2 (II) s1 °v° 1 ..The process of the invention is characterized in that a) a compound of the formula CHO-X2 I 2 CH3 c = o -, ---- ο-R2 (II) s1 ° v ° 1. is treated.

\^/yv^cH3\ ^ / Yv ^ CH3

oVVÖVV

ll

FF

12 2 hvori R , R og X har den ovennævnte betydning, med hydro-genchlorid eller hydrogenfluorid eller med et middel, der 10 afgiver et af disse hydrogenhalogenider, eller b) i en forbindelse med den almene formel 5 146017 CHo-0-Ra I 2 CH, C=0 H0Y^_|----O-R2 R1 CH31 J 1 (IV) οΛΑ/Wherein R, R and X are as defined above with hydrogen chloride or hydrogen fluoride or with an agent which gives off one of these hydrogen halides, or b) in a compound of general formula 50101 CHO-O-Ra I 2 CH, C = 0 H0Y ^ _ | ---- O-R2 R1 CH31 J 1 (IV) οΛΑ /

FF

hvori R1, R2 og X1 har den ovennævnte betydning, og Ra er resten af en organisk sulfonsyre, erstatter sulfonyl-oxygruppen med brom eller chlor, eller 5 c) til fremstilling af en forbindelse med formlen I, hvori X*· betyder chlor, behandler en 9 (11)-umættet forbindelse med formlen CH0-X2 I 2 CH, C=0 ✓N—1----O-R2 „1 CH, I (VII) γ^Ργ\ΛοΗ3 oAvwherein R 1, R 2 and X 1 have the above meaning and R a is the remainder of an organic sulfonic acid, replacing the sulfonyl oxy group with bromine or chlorine, or c) to prepare a compound of formula I wherein X a 9 (11) unsaturated compound of formula CHO-X2 I 2 CH, C = 0 ✓N-1 ---- O-R2 "1 CH, I (VII) γ ^ Ργ \ ΛοΗ3 oAv

FF

12 2 hvori R , R og X har den ovennævnte betydning, med chlor-10 undersyrling eller et chlorundersyrlingafgivende middel, eller d) til fremstilling af en forbindelse med formlen I, hvori R·*· betyder hydrogen, dehydrogenerer en forbindelse med formlen 6 146017 CH„-X2 I 2 CH- C=0 HO ^ , v'N------O-R2 ^H3l 1 1 (VIII) ΛΙΥ^^ 0AyvWherein R, R and X are as defined above with chloro-10 acid or a chloro-acid acid release agent, or d) for the preparation of a compound of formula I wherein R · represents hydrogen, dehydrogenates a compound of formula 6 CH2 -X2 I 2 CH- C = O HO2, v'N ------ O-R2 ^ H3l 1 1 (VIII) ΛΙΥ ^^ 0Ayv

JJ

iin

FF

2 1 2 hvori R , X og X har den ovennævnte betydning, i 1,2-stillingen, og, om ønsket, i en ifølge fremgangsmåden opnået forbin-5 delse med formlen I, hvori R^ betyder hydrogen, og de øvrige symboler har den ovennævnte betydning, tillejrer chlor til 1,2-dobbeltbindingen og fra den opnåede forbindelse med formlen CH„-X2 I 2 CH-. C=0 ΓγΑ--»-*2Wherein R, X and X have the above meaning, at the 1,2-position, and, if desired, in a compound of formula I obtained according to the process wherein R 1 is hydrogen and the other symbols have of the above-mentioned meaning, chlorine adds to the 1,2-double bond and from the obtained compound of formula CH 2 -X 2 I 2 CH-. C = 0 ΓγΑ - »- * 2

Cl ΙψΙ ICl ΙψΙ I

T ^ ch3T ^ ch3

oWoW

iin

FF

2 1 2 10 hvori R , X og X har den ovennævnte betydning, fraspalter hydrogenchlorid, idet man under begge fremgangsmådetrin eventuelt arbejder under forbigående beskyttelse af 11β-hydroxylgruppen ved overføring til trifluoracetatet.2 1 2 10 wherein R, X and X are as defined above, hydrogen chloride is cleaved, optionally, during both process steps, working under transient protection of the 11β-hydroxyl group upon transfer to the trifluoroacetate.

I det følgende med "lav" betegnede carbonholdige forbin-15 delser og grupper indeholder højst 7 carbonatomer.Carbonaceous compounds and groups hereinafter referred to as "low" contain at most 7 carbon atoms.

En alkanoylgruppe kan være ligekædet eller forgrenet og er f.eks. acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, 2-ethyl-butyryl, 2,2- eller 3,3- 7 146017 dimethyl-butyryl, hexanoyl eller heptanoyl.An alkanoyl group may be straight or branched and is e.g. acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, 2-ethyl-butyryl, 2,2- or 3,3- dimethyl-butyryl, hexanoyl or heptanoyl.

Forbindelserne med formlen I har værdifulde farmakologiske egenskaber. Således udmærker de sig ved en fremragende antiinflammatorisk virkning med ringe systemisk virkning.The compounds of formula I have valuable pharmacological properties. Thus, they are distinguished by an excellent anti-inflammatory effect with little systemic effect.

5 Man kan f.eks. ved lokal anvendelse ved råbomuld-granulom-test hos rotter påvise en hæmning af betændelsestilstande i et dosisområde fra ca. 0,001 til ca. 0,10 mg/pellet, idet de første tegn på en systemisk virkning først bemærkes ved eller endog over den øverste grænse for dette dosis-10 område, og vægtformindskelse af thymus først fremkommer over 0,03 mg/pellet,af binyrer over 0,1 mg/pellet og af den totale legemsvægt over 1,0 mg/pellet. ved topisk administration (rotteøreprøve efter Tonelli) ligger ED^g endog ved ca. 10-30 mcg/ml. På grund af disse biologiske egen-15 skaber er forbindelserne (I) anvendelige ved alle indikationer, hvortil -glucocorticoid-steroider med betændelseshæmmende egenskaber egner sig, især dog som topisk anvendelige antiinflammatoriske glucocorticoider, f.eks. til behandling af betændelsesdermatoser, såsom eksemer, der-20 matider eller partielt corticoidresistente dermatoser, f.eks. psoriasis.For example, one can by topical use in crude cotton granuloma testing in rats, demonstrating an inhibition of inflammatory conditions in a dose range of ca. 0.001 to approx. 0.10 mg / pellet, the first signs of a systemic effect being first noticed at or even above the upper limit of this dose range, and thymus weight reduction first exceeding 0.03 mg / pellet, of adrenal glands above 0; 1 mg / pellet and of the total body weight above 1.0 mg / pellet. in topical administration (rat ear test after Tonelli), ED 10-30 mcg / ml. Because of these biological properties, compounds (I) are useful in all indications suitable for -glucocorticoid steroids with anti-inflammatory properties, especially as topically useful anti-inflammatory glucocorticoids, e.g. for the treatment of inflammatory dermatoses such as eczema, dermatides or partially corticoid resistant dermatoses, e.g. psoriasis.

Det er kendt, at 21-substituerede 6a-fluor-16-methylpreg-na-l,4-dien-3,20-dioner, som er nær beslægtede med forbindelserne med formlen (I), har antiinflammatorisk virk-25 ning. Fra dansk fremlæggelsesskrift nr.129.835 kendes således antiinflammatorisk virksomme 2-chlor-6o-fluor-16a-methylpregna-l,4-dien-3,20-dioner med den almene formel 8 146017 CH2r1 =0It is known that 21-substituted 6α-fluoro-16-methylpreg-na-1,4-diene-3,20-dione, which is closely related to the compounds of formula (I), has anti-inflammatory action. Thus, Danish Patent Specification No. 129,835 discloses anti-inflammatory activity of 2-chloro-6-fluoro-16a-methylpregna-1,4-diene-3,20-dione of the general formula 8 146017 CH2r1 = 0

H0V XVH0V XV

'γ ______OH'γ ______OH

x 3 ολΛ/x 3 ολΛ /

FF

hvor R"*“ er en fri eller en med en svovlsyre, en phosphor-syre eller en carboxylsyre med højst 18 C-atomer forestret eller en med en α-tetrahydropyranol eller a-tetrahydro-5 furanol forethret hydroxygruppe, og X er et hydrogen- eller fluoratom. Forbindelserne med formlen (I) har en overraskende god antiinflammatorisk virkning i forhold til de kendte forbindelser, hvilket fremgår af nedenstående sammenligningsforsøg .is a free or one having a sulfuric acid, a phosphoric acid or a carboxylic acid having a maximum of 18 C atoms esterified or one having an α-tetrahydropyranol or α-tetrahydrofuranol etherified hydroxy group and X is a hydrogen The compounds of formula (I) have a surprisingly good anti-inflammatory effect over the known compounds, as shown in the comparative experiments below.

10 Ved sammenligningsforsøget bestemmes nedenstående forbindelsers lokale antiinflammatoriske virkning samt deres systemiske bivirkninger. Der anvendes følgende forsøgsforbindelser:In the comparison experiment, the local anti-inflammatory effect of the compounds below and their systemic side effects are determined. The following test compounds are used:

St - 2-Chlor-6a,9a-difluor-118,17a,21-trihydroxy-16a-methyl-15 pregna-l,4-dien-3,20-dion (kendt).St - 2-Chloro-6a, 9a-difluoro-118,17a, 21-trihydroxy-16a-methyl-pregna-1,4-diene-3,20-dione (known).

A - 21-Chlor-6a,9a-difluor-118,17a-dihydroxy-163_methyl-pregna-1,4-dien-3,20-dion-17-propionat.A - 21-Chloro-6a, 9a-difluoro-118,17a-dihydroxy-163-methyl-pregna-1,4-diene-3,20-dione-17-propionate.

B - 2,2i-Dichlor-6a,9a-difluor-113,17a-dihydroxy-163-methyl-pregna-1,4-dien-3,20-dion-17-propionat.B - 2,2i-Dichloro-6a, 9a-difluoro-113,17a-dihydroxy-163-methyl-pregna-1,4-diene-3,20-dione-17-propionate.

20 C - 9a,21-Dichlor-6a-fluor-113,17a-dihydroxy-168-methyl-pregna-1,4-dien-3,20-dion-17-propionat.C-9a, 21-Dichloro-6a-fluoro-113,17a-dihydroxy-168-methyl-pregna-1,4-diene-3,20-dione-17-propionate.

Sammenligningsforbindelsen St hører til de kraftigt virkende kendte corticoider og er kendt fra dansk fremlæggelses-skrift nr. 129.835.The comparative compound St belongs to the powerfully known known corticoids and is known from Danish Patent Specification No. 129,835.

9 1460179 146017

Under anvendelse af den konventionelle råbomuld-granulomtest foretages dobbeltsidig implantation af en vatpellet i normale han-albinorotter. Den ene pellet er imprægneret med en bestemt dosis af forsøgsforbindelsen, hvorimod den anden 5 er ubehandlet. Til bedømmelse af den antiinflammatoriske virkning bestemmes vægten af dannede granulomer efter isolering. Vægtforskellen mellem det ubehandlede og det behandlede granulom udtrykkes for hver enkelt dyr som den procentvise formindskelse af granulomvægten ved den specifikke do-10 sis. En ca. 30%'s formindskelse af granulomvægten betragtes som signifikant for den antiinflammatoriske virkning, og den tilsvarende dosis betegnes som ED20-30*Using the conventional raw cotton granuloma test, double-sided implantation of a cotton pellet is performed in normal male albino rats. One pellet is impregnated with a specific dose of the test compound, while the other 5 is untreated. To assess the anti-inflammatory effect, the weight of granulomas formed is determined after isolation. The weight difference between the untreated and the treated granuloma is expressed for each animal as the percentage reduction of the granuloma weight at the specific dose. One approx. 30% reduction in granuloma weight is considered significant for the anti-inflammatory effect and the corresponding dose is designated as ED20-30 *

Ved samme forsøg foretages også samtidig bestemmelse af forsøgsforbindelsernes uønskede bivirkninger, idet der foreta-15 ges en bestemmelse af vægtformindskelsen af binyrerne og thymus i de behandlede dyr i sammenligning med ubehandlede kontroldyr, dvs. dyr, som har fået foretaget dobbeltsidig implantation med uimprægnerede råbomuld-pellets. Også i dette tilfælde betragtes en ca. 30%'s formindskelse af organ-20 vægten som signifikant for den pågældende virkning, der for binyrernes vedkommende er inhiberingen af binyrerne, og for thymus vedkommende den thymolytiske virkning. De tilsvarende doser betegnes også her ED2o-30‘In the same experiment, the undesirable side effects of the test compounds are also determined simultaneously, with a determination of the weight reduction of the adrenal glands and thymus in the treated animals compared to untreated control animals, ie. animals that have had double-sided implantation with impregnated raw cotton pellets. In this case too, an approx. 30% decrease in organ weight as significant for the effect of adrenal gland inhibition of the adrenal gland and for thymus the thymolytic effect. The corresponding doses are also referred to herein as ED 20

Resultaterne fremgår af nedenstående tabel.The results are shown in the table below.

25 Forbin- ED20-30 (^osis i yg/pellet, som fremkalder en vægt-delse formindskelse på 30%)Compound ED20-30 (λ osis in yg / pellet which produces a weight reduction of 30%)

Granulom Thymus = T Binyre 1 = — (G) (T) (N)Granuloma Thymus = T Adrenal 1 = - (G) (T) (N)

St 3 3 1 100 0,03 30 A 1 10 0,1 100 0,01 B 10 100 0,1 >100 <0,1 C 1-3 >1000 <0,003- >1000 0,003- 0,001 -0,001 ίο 146017St 3 3 1 100 0.03 30 A 1 10 0.1 100 0.01 B 10 100 0.1> 100 <0.1 C 1-3> 1000 <0.003-> 1000 0.003- 0.001 -0.001 ίο 146017

Det fremgår af de ovenfor anførte resultater, at med hensyn til den ønskede lokale antiinflammatoriske virkning har forbindelse A og C en ca. tre gange så stor virkning som sammenligningsforbindelsen St, og forbindelse B har 5 en trediedel af virkningen af sammenligningsforbindelsen.It is evident from the results set forth above that with respect to the desired local anti-inflammatory effect, compounds A and C have a ca. three times the effect of the comparative compound St, and compound B has a third of the effect of the comparative compound.

Med hensyn til den uønskede binyre-inhibition har forbindelse A ca. en trediedel af virkningen af sammenligningsforbindelsen St, forbindelse C en tiendedel til en tredivtedel af virkningen af sammenligningsforbindelsen St, hvori-10 mod forbindelse B har en tre gange så stor binyre-inhibition som sammenligningsforbindelsen St. Med hensyn til den uønskede thymolytiske virkning har forbindelsen A og B en ti gange bedre virkning end sammenligningsforbindelsen, og forbindelse G har en tusind gange bedre virkning end 15 sammenligningsforbindelsen, beregnet på den ønskede antiinflammatoriske virkning.With respect to the undesirable adrenal inhibition, Compound A has approx. one-third of the effect of Comparative Compound St, Compound C one-tenth to one-third of the effect of Comparative Compound St, wherein Compound B has a three-fold greater adrenal inhibition than Comparative Compound St. In terms of the undesirable thymolytic effect, compounds A and B have a ten times better effect than the comparison compound, and compound G has a thousand times better effect than the comparison compound, calculated on the desired anti-inflammatory effect.

Det er ifølge opfindelsen særlig fordelagtigt at fremstille forbindelser med formlen I, hvori X1 er fluor eller chlor, 2 1 2 X chlor, R hydrogen og R alkanoyl, især propionyl, ellerAccording to the invention, it is particularly advantageous to prepare compounds of formula I wherein X 1 is fluorine or chlorine, 2 1 2 X chlorine, R hydrogen and R alkanoyl, especially propionyl, or

1 2 12 20 hvori X er fluor eller chlor, X chlor, R chlor og R1 2 12 20 wherein X is fluorine or chlorine, X is chlorine, R is chlorine and R is

alkanoyl, især propionyl.alkanoyl, especially propionyl.

Ved fremgangsmåde a) foretages fraspaltningen af 9β,11β-oxidogruppen i et udgangsmateriale med formlen II ved behandling med hydrogenchlorid eller hydrogenfluorid på i 25 og for sig kendt måde, idet man hensigtsmæssigt anvender et vandfrit hydrogenhalogenid, eventuelt under tilstedeværelse af et inert opløsningsmiddel, såsom chloroform, tetra-hydrofuran eller især dimethylformamid, men hydrogenfluorid kan dog også anvendes i vandig opløsning.In process a) the cleavage of the 9β, 11β oxido group is carried out in a starting material of formula II by treatment with hydrogen chloride or hydrogen fluoride in a manner known per se, suitably using an anhydrous hydrogen halide, optionally in the presence of an inert solvent such as chloroform, tetrahydrofuran or especially dimethylformamide, but hydrogen fluoride can also be used in aqueous solution.

30 I stedet for hydrogenchlorid eller -fluorid kan man også anvende et hydrogenfluorid- eller hydrogenchloridafgi-vende middel, såsom saltet af en sådan syre med en tertiær organisk base, f.eks. pyridin eller, især for hydrogenfluorids vedkommende, en lignende egnet additionsforbin 11 146017 delse. En særlig gunstig fremgangsmåde beskrives i USA-patent nr. 3.211.758, ifølge hvilken man anvender hydrogenfluorid i form af et addukt med et carbaminsyre- eller thiocarbaminsyrederivat, især med urinstof.Instead of hydrogen chloride or fluoride, one may also use a hydrogen fluoride or hydrogen chloride release agent such as the salt of such an acid with a tertiary organic base, e.g. pyridine or, especially in the case of hydrogen fluoride, a similar suitable addition compound. A particularly favorable process is disclosed in U.S. Patent No. 3,111,758, which uses hydrogen fluoride in the form of an adduct with a carbamic acid or thiocarbamic acid derivative, especially with urea.

5 Udgangsstofferne med formlen II kan opnås på i og for sig kendt måde, f.eks. ved fraspaltning af vand fra en 6a-fluor-110-hydroxy-160-methyl-2-R1-17a-OR2-21-X2-pregna-l,4-dien- 3,20-dion-forbindelse, f.eks. ved behandling med et egnet syrechlorid, såsom phosphoroxychlorid eller methansulfon-10 syrechlorid, under tilstedeværelse af en base, f.eks. pyr-idin, tillejring af bromundersyrling (som f.eks. anvendes i form af N-bromacetamid eller N-bromsuccinimid) til 9,11-dobbeltbindingen i den således opnåede 6a-fluor-160-methyl-2-R1-17a-OR2-21-X2-pregna-l,4,9(11)-trien-3,20-dion-forbin-15 delse og fraspaltning af hydrogenbromid fra den tilsvarende 9a,110-bromhydrin-forbindelse ved behandling med en base, f.eks. et alkalimetalcarbonat eller -hydroxid, f.eks. kaliumcarbonat eller kaliumhydroxid, under dannelse af det ønskede udgangsmateriale med formlen (II). I de oven-20 stående mellemprodukter har R , R og X de i det foregående angivne betydninger.The starting materials of formula II can be obtained in a manner known per se, e.g. by decomposing water from a 6a-fluoro-110-hydroxy-160-methyl-2-R1-17a-OR2-21-X2-pregna-1,4-diene-3,20-dione compound, e.g. by treatment with a suitable acid chloride such as phosphorus oxychloride or methanesulfonic acid chloride, in the presence of a base, e.g. pyridine, the addition of bromine sub-acid (as used, for example, in the form of N-bromoacetamide or N-bromosuccinimide) to the 9,11-double bond in the thus obtained 6a-fluoro-160-methyl-2-R1-17a-OR2 -21-X2-pregna-1,4,9 (11) -triene-3,20-dione compound and decomposition of hydrogen bromide from the corresponding 9a, 110-bromohydrin compound by treatment with a base, f. eg. an alkali metal carbonate or hydroxide, e.g. potassium carbonate or potassium hydroxide, to give the desired starting material of formula (II). In the above intermediates, R, R and X have the meanings given above.

Ved fremgangsmåde b) erstatter man sulfonyloxygruppen med brom eller chlor på i og for sig kendt måde. Acylresten Ra af en organisk sulfonsyre er især acylresten af en 25 aliphatisk eller carbocyclisk, eventuelt umættet eller aromatisk sulfonsyre. Sådanne syrer er bl.a. eventuelt substituerede, f.eks. halogenerede, lavalkansulfonsyrer, cyclo-alkansulfonsyrer, hvori cycloalkylgruppen kan være monoeller polycyclisk, eller eventuelt med lavalkyl, f.eks.Process b) replaces the sulfonyloxy group with bromine or chlorine in a manner known per se. In particular, the acyl residue Ra of an organic sulfonic acid is the acyl residue of an aliphatic or carbocyclic, optionally unsaturated or aromatic sulfonic acid. Such acids include optionally substituted, e.g. halogenated, lower alkanesulfonic acids, cycloalkanesulfonic acids wherein the cycloalkyl group may be mono or polycyclic, or optionally with lower alkyl, e.g.

30 methyl, lavalkoxy, f.eks. methoxy, halogen, f.eks. chlor eller brom, og/eller nitro, substituerede benzensulfon-syrer. Som typiske eksempler på sådanne syrer skal omtales trifluormethansulfonsyre, (+)-campher-10-sulfonsyre, 4-brom-benzensulfonsyre og 3-nitrobenzensulfonsyre, især p-toluen-sulfonsyre og fremfor alt methansulfonsyre.Methyl, lower alkoxy, e.g. methoxy, halogen, e.g. chlorine or bromine, and / or nitro, substituted benzenesulfonic acids. As typical examples of such acids, mention is made of trifluoromethanesulfonic acid, (+) - campher-10-sulfonic acid, 4-bromo-benzenesulfonic acid and 3-nitrobenzenesulfonic acid, especially p-toluene sulfonic acid and, above all, methanesulfonic acid.

12 14601712 146017

Udskiftningsreaktionen gennemføres sædvanligvis ved, at man behandler udgangsmaterialet med formlen (IV) med et alkalimetalhalogenid med formlen Μ - X2 (V) 5 hvori M står for et alkalimetal, fortrinsvis lithium, under· tilstedeværelse af et aprotisk organisk opløsningsmiddel, hvis dielektricitetskonstant er 29 eller højere.The replacement reaction is usually carried out by treating the starting material of formula (IV) with an alkali metal halide of formula Μ - X2 (V) 5 wherein M represents an alkali metal, preferably lithium, in the presence of an aprotic organic solvent whose dielectric constant is 29 or higher.

Som aprotiske organiske opløsningsmidler kan især anvendes dilavalkylsulfoxider, f.eks. dimethylsulfoxid, N,N-10 dilavalkyl-amideraf-lavaliphatiske carboxylsyrer, f.eks. Ν,Ν-dimethylformamid eller Ν,Ν-dimethylacetamid, lavalkan-eller lavalkennitriler, f.eks. acetonitril, hexalavalkyl-phosphoramider, f.eks. hexamethylphosphoramid, eller ketoner, især aliphatiske eller cycloaliphatiske ketoner 15 med indtil 10 carbonatomer, såsom tilsvarende alkanoner, f.eks. acetone, 2-butanon, 2- eller 3-pentanon, 2-hexanon eller 4-decanon, eller cycloalkanoner med indtil 8 ring-carbonatomer, f.eks. cyclopentanon eller cyclohexanon, eller blandinger af sådanne opløsningsmidler.As aprotic organic solvents, dilavalkyl sulfoxides, e.g. dimethylsulfoxide, N, N-10-dilavalkylamide-lavaliphatic carboxylic acids, e.g. Ν, Ν-dimethylformamide or Ν, Ν-dimethylacetamide, lower alkane or low alkene nitriles, e.g. acetonitrile, hexalavalkyl phosphoramides, e.g. hexamethylphosphoramide, or ketones, especially aliphatic or cycloaliphatic ketones having up to 10 carbon atoms, such as corresponding alkanones, e.g. acetone, 2-butanone, 2- or 3-pentanone, 2-hexanone or 4-decanone, or cycloalkanones with up to 8 ring carbon atoms, e.g. cyclopentanone or cyclohexanone, or mixtures of such solvents.

20 Reaktionen gennemfører man hensigtsmæssigt mellem stuetemperatur og reaktionsblandingens kogepunkt, idet man omsætter med mindst ét ækvivalent af alkalimetalhalogenidet med formlen (V).The reaction is conveniently carried out between room temperature and the boiling point of the reaction mixture, reacting with at least one equivalent of the alkali metal halide of formula (V).

Udgangsstofferne med formlen (IV) er kendte eller kan frem-25 stilles på i og for sig kendt måde, f.eks. ved at man i en 6a-fluor-llf},21-dihydroxy-16£-methyl-2-R^-9a-X^-17a-OR2-pregna-1,4-dien-3,20-dion-forbindelse omdanner 21-hydroxy-gruppen ved behandling med et reaktionsdygtigt derivat af en organisk sulfonsyre med formlen 30 Ra - OH (VI) især med et tilsvarende sulfonsyrechlorid med formlenThe starting materials of formula (IV) are known or can be prepared in a manner known per se, e.g. by adding in a 6α-fluoro-11β, 21-dihydroxy-16β-methyl-2-R R-9a-X ^-17α-OR₂-pregna-1,4-diene-3,20-dione compound converting the 21-hydroxy group by treatment with a reactive derivative of an organic sulfonic acid of formula 30 Ra - OH (VI) especially with a corresponding sulfonic acid chloride of formula

Ra - Cl (Via) under tilstedeværelse af en base, f.eks. pyridin, til den 1A 6 017 13 ønskede organiske sulfonyloxygruppe -0Ra.Ra - Cl (Via) in the presence of a base, e.g. pyridine, to the desired 1A 6 017 13 organic sulfonyloxy group -0Ra.

Ved fremgangsmåde c) tillejres der til 9,11-dobbeltbindin-gen i udgangsstofferne med formlen (VII) på i og for sig kendt måde elementer af chlorundersyrling. Herunder arbej-5 der man f.eks. med vandig chlorundersyrling, eller man kan anvende et chlorundersyrlingafgivende middel, såsom et N-chlor-carboxylsyreamid eller -imid (sml. USA-patent-skrift nr.3.057.886). Reaktionen gennemfører man i et inert opløsningsmiddel, såsom en tertiær alkohol, f.eks. tert-10 butanol, en ether, f.eks. diethylether, methylisopropyl-ether, dioxan eller tetrahydrofuran, eller en keton, f.eks. acetone, under tilstedeværelse af vand og eventuelt en stærk syre.In process c), the 9,11-double bond is prepared in the starting materials of formula (VII) by elements known in the art as chloro-undercutting. Including work 5, e.g. with aqueous chlorine undercutting, or a chlorine undercutting agent such as an N-chloro-carboxylic acid amide or imide can be used (cf. U.S. Patent No. 3,057,886). The reaction is carried out in an inert solvent such as a tertiary alcohol, e.g. tert-butanol, an ether, e.g. diethyl ether, methyl isopropyl ether, dioxane or tetrahydrofuran, or a ketone, e.g. acetone, in the presence of water and possibly a strong acid.

Tillejringen af chlorundersyrling til 9,11-dobbeltbindin-15 gen i udgangsmaterialet med formlen (VII) kan også ske i ikke-vandigt medium. En særlig fordelagtig udførelsesform for denne modifikation er anvendelsen af lavalkylhypo-chloriter, i første række af tert-butylhypochlorit, i et inert, med vand ikke-blandbart opløsningsmiddel, som f.eks.The addition of chlorine sub-acid to the 9,11-double bond in the starting material of formula (VII) can also take place in non-aqueous medium. A particularly advantageous embodiment of this modification is the use of low alkyl hypochlorites, primarily tert-butyl hypochlorite, in an inert, water-immiscible solvent such as e.g.

20 et nitrocarbonhydrid, sædvanligvis under tilstedeværelse af perchlorsyre (sml.tysk patentskrift nr. 2.011.559).20 a nitrocarbon hydride, usually in the presence of perchloric acid (see German Patent No. 2,011,559).

Udgangsstofferne med formlen (VII) kan fremstilles på i og for sig kendt måde, f.eks. ved fraspaltning af vand fra en 6a-fluor-llb-hydroxy-16&-methyl-2-R^-17a-OR^-21-X^-25 pregna-l,4-dien-3,20-dion-forbindelse, f.eks. ved behandling med et egnet syrechlorid, såsom phosphoroxychlorid eller methansulfonsyrechlorid, under tilstedeværelse af en base, f.eks. pyridin.The starting materials of formula (VII) can be prepared in a manner known per se, e.g. by cleavage of water from a 6α-fluoro-11b-hydroxy-16β-methyl-2-R ^-17α-OR ^-21-X ^ -25 pregna-1,4-diene-3,20-dione compound, eg. by treatment with a suitable acid chloride, such as phosphorus oxychloride or methanesulfonic acid chloride, in the presence of a base, e.g. pyridine.

Ved fremgangsmåde d) indføres 1,2-dobbeltbindingen ved de-30 hydrogenering, f.eks. ved behandling med en egnet dehydroge-nerende quinon, såsom 2,3-dichlor-5,6-dicyano-l,4-benzo-quinon.In process d), the 1,2-double bond is introduced by dehydrogenation, e.g. by treatment with a suitable dehydrogenating quinone such as 2,3-dichloro-5,6-dicyano-1,4-benzoquinone.

14 146017 1,2-Dehydrogeneringen af udgangsstoffer med formlen (VIII) kan også ske ved behandling med selendioxid eller mikrobiologisk, f.eks. med egnede mikroorganismer, såsom Coryne-bacterium simplex eller Septomyxa affinis.1,2-Dehydrogenation of starting substances of formula (VIII) may also be effected by treatment with selenium dioxide or microbiologically, e.g. with suitable microorganisms such as Coryne bacterium simplex or Septomyxa affinis.

5 Udgangsstofferne med formlen (VIII) kan man opnå ved overføring af 21-hydroxygruppen i en 6a-fluor-113,21-dihydroxy-1 2 16£-methyl-9a-X -17a-0R -pregn-4-en-3,20-dion-forbindelse, f.eks. ved behandling med et egnet sulfonsyrederivat, såsom methansulfonsyrechlorid, til en 21-organisk sulfonyl-10 oxygruppe og behandling af mellemproduktet med et lithium-halogenid, f.eks. lithiumchlorid.The starting materials of formula (VIII) can be obtained by transferring the 21-hydroxy group into a 6α-fluoro-113,21-dihydroxy-1,216β-methyl-9α-X-17α-OR-precipit-4-ene-3 , 20-dione compound, e.g. by treatment with a suitable sulfonic acid derivative, such as methanesulfonic acid chloride, to a 21-organic sulfonyl-oxy group and treating the intermediate with a lithium halide, e.g. lithium chloride.

En ifølge fremgangsmåden opnået forbindelse med formlen (I), hvori R·*· er hydrogen, kan på i og for sig kendt måde overføres til en anden forbindelse med formlen (I), hvori R1 15 er chlor.A compound of formula (I) obtained in accordance with the process in which R 1 is hydrogen may in a manner known per se be converted to another compound of formula (I) wherein R 1 is chloro.

Man kan til dette formål tillej re et molekyle chlor til 1,2-dob-beltbindingen i en sådan forbindelse og fra 1,2-dichlor-pregn-4-en-3,20-dion-mellemproduktet fraspalte et mol hydro-genchlorid. Tillejringen af chlor til 1,2-dobbeltbindingen 20 kan ske ved behandling med elementært chlor eller med en blanding af to forskellige chlorholdige forbindelser, hvoraf den ene afgiver positivt og den anden negativt chlor.For this purpose, a molecule of chlorine can be added to the 1,2-double bond in such a compound and from the 1,2-dichloro-pregn-4-ene-3,20-dione intermediate a mole of hydrogen chloride is decomposed. The addition of chlorine to the 1,2-double bond 20 can be effected by treatment with elemental chlorine or with a mixture of two different chlorine-containing compounds, one of which gives off positive and the other negatively chlorine.

Behandlingen med elementært chlor kan gennemføres i et inert organisk opløsningsmiddel, f.eks. en ether, såsom 25 dioxan eller tetrahydrofuran, et halogeneret carbonhydrid, f.eks. methylenchlorid, eller en carboxylsyre, især en lav-aliphatisk carboxylsyre, såsom eddikesyre eller propion-syre, eller et derivat heraf, såsom et syreamid, f.eks. dimethylformamid, eller et nitril, såsom et lavalkan-30 nitril, f.eks. acetonitril. Med fordel kan man også anvende blandinger af sådanne opløsningsmidler, især blandinger af en ether, såsom dioxan, med en af de nævnte lav- 15 146017 alkancarboxylsyrer. Chloreringen gennemføres sædvanligvis med den støkiometriske mængde chlor ved lavere temperatur, ca. mellem -50°C og +30°C, f.eks. mellem -20 og +10°C, og under udelukkelse af lys.The treatment with elemental chlorine can be carried out in an inert organic solvent, e.g. an ether such as dioxane or tetrahydrofuran, a halogenated hydrocarbon, e.g. methylene chloride, or a carboxylic acid, especially a low-aliphatic carboxylic acid, such as acetic or propionic acid, or a derivative thereof, such as an acid amide, e.g. dimethylformamide, or a nitrile such as a lower alkanol nitrile, e.g. acetonitrile. Advantageously, mixtures of such solvents, in particular mixtures of an ether such as dioxane, may also be used with one of the mentioned lower alkane carboxylic acids. Chlorination is usually carried out with the stoichiometric amount of chlorine at a lower temperature, approx. between -50 ° C and + 30 ° C, e.g. between -20 and + 10 ° C, and excluding light.

5 Ifølge en særligt foretrukket udførelsesform opløses forbindelsen med formlen (I), hvori R1 står for hydrogen, i et af de nævnte opløsningsmidler, f.eks. dioxan, og der tilsættes en opløsning af chlor i en lavaliphatisk carboxylsyre, f.eks. propionsyre; denne opløsning henstår 10 derefter f.eks. ved den nævnte temperatur.According to a particularly preferred embodiment, the compound of formula (I) wherein R 1 stands for hydrogen is dissolved in one of said solvents, e.g. dioxane and a solution of chlorine in a low aliphatic carboxylic acid, e.g. propionic acid; this solution is then left e.g. at said temperature.

I blandinger af to forskellige chloreringsmidler anvender man som reagenser, der kan frigøre positivt chlor, bl.a. chlorerede syreamider eller syreimider, såsom chlor-succinimid eller chloracetamid, medens der som sådanne, 15 der leverer negativt chlor, f.eks. indsættes hydrogen-chlorid og endvidere alkalimetalchlorider.Mixtures of two different chlorinating agents are used as reagents which can release positive chlorine, i. chlorinated acid amides or acid imides such as chloro-succinimide or chloroacetamide, while as such, which delivers negative chlorine, e.g. hydrogen chloride and alkali metal chlorides are also added.

Fraspaltningen af hydrogenchlorid fra 1,2-dichlor-pregn- 4-en-3,20-dion-mellemproduktet gennemføres hensigtsmæssigt ved behandling med et basisk middel. Som basiske midler 20 egner sig f.eks. tertiære organiske nitrogenbaser, såsom lavaliphatiske aminer, f.eks. trilavalkylamin, såsom tri-ethylamin, heteroaromatiske baser, f.eks. pyridin eller collidin, eller blandede aliphatisk-aromatiske baser, såsom Ν,Ν-dilavalkyl-anilin, f.eks. N,N-dimethyl-anilin.The decomposition of hydrogen chloride from the 1,2-dichloro-pregn-4-ene-3,20-dione intermediate is conveniently carried out by treatment with a basic agent. As basic agents 20, e.g. tertiary organic nitrogen bases such as low aliphatic amines, e.g. trilavalkylamine, such as triethylamine, heteroaromatic bases, e.g. pyridine or collidine, or mixed aliphatic-aromatic bases such as Ν, Ν-dilavalkyl-aniline, e.g. N, N-dimethyl-aniline.

25 Fortrinsvis arbejder man med et overskud af basen, der tillige kan tjene som opløsningsmiddel. Man kan dog også anvende uorganiske baser, især de også til hydrolyse af det nedenfor beskrevne Ιΐβ-trifluoracetat anvendte alkalimetal- eller jordalkalimetalsalte, f.eks. kalium- eller 30 natriumacetat eller -hydrogencarbonat, i vandig-alkoholisk opløsning, samt de tilsvarende hydroxider. Dehydrochlore-ringen foretages fortrinsvis i et temperaturområde på fra ca. 20°C til ca. 100°C. Hensigtsmæssigt vælges der sådanne midler og reaktionsbetingelser, som lader de øvrige 16 146017 funktionsgrupper, især funktionsgrupperne i 17- og/eller 21-stilling, upåvirkede.25 Preferably, an excess of the base can be used, which can also serve as a solvent. However, inorganic bases can also be used, in particular the alkali metal or alkaline earth metal salts used for hydrolysis of the Ιΐβ-trifluoroacetate described below. potassium or sodium acetate or hydrogen carbonate, in aqueous-alcoholic solution, and the corresponding hydroxides. The dehydrochlorination is preferably carried out in a temperature range of from approx. 20 ° C to approx. 100 ° C. Conveniently, such agents and reaction conditions are chosen which leave the other functional groups, especially the functional groups in the 17 and / or 21 positions, unaffected.

Hensigtsmæssigt beskyttes inden chlortillejringen til 1,2-dobbeltbindingen i en forbindelse med formlen (I), 5 hvori R1 står for hydrogen, Ιΐβ-hydroxylgruppen, f.eks. ved forestring, fortrinsvis som trifluoracetyloxygruppe, idet man omsætter en forbindelse med formlen (I), hvori R1 står for hydrogen, med et egnet reaktionsdygtigt derivat af en syre, f.eks. med trifluoreddikesyrechlorid el-10 ler -anhydrid, på i og for sig kendt måde. Trifluoracetyl-gruppen kan som bekendt let fraspaltes solvolytisk, f.eks. hydrolytisk eller alkoholytisk, f.eks. ved indvirkning af alkalimetal- eller jordalkalimetalhydroxider, -carbona-ter, -hydrogencarbonater eller -acetater, i et egnet, 15 f.eks. alkoholisk, såsom methanolisk, eller vandigt-alkoholisk medium.En særlig udførelsesform for solvolysen af 11-trifluoracetyloxygruppen er beskrevet i det tyske patentskrift nr.1.593.519, som især kommer i betragtning, fordi en i 17a-stillingen tilstedeværende forestret hydroxyl-20 gruppe derved forbliver uskadt; derved går man frem på den måde, at man behandler Ιΐβ-trifluoracetyloxy-forbin-delsen i en lavalkanol med saltet af en syre, hvis pKa-værdi ligger i området på fra ca. 2,3 til ca. 7,3, såsom med et alkalimetalazid, f.eks. natrium- eller kaliumazid, 25 eller alkalimetalformiat, f.eks. natrium- eller kalium-formiat, idet dette salt eventuelt også kan anvendes i klin katalytiske mængder. Endvidere kan man også fjerne Ιΐβ-trifluoracetylgruppen ved behandling med andre basiske reagenser, f.eks. med aminer, især med heteroaromatiske 30 baser, såsom pyridin eller collidin. I betragtning kommer endelig også spaltningen af trifluoracetyloxygruppen ved indvirkning af silicagel ifølge den i det tyske offent-liggørelsesskrift nr. 2.1441405 beskrevne fremgangsmåde.Conveniently, prior to the chlorine addition to the 1,2-double bond, a compound of formula (I), wherein R 1 stands for hydrogen, is the β-hydroxyl group, e.g. by esterification, preferably as a trifluoroacetyloxy group, reacting a compound of formula (I) wherein R 1 is hydrogen, with a suitable reactive derivative of an acid, e.g. with trifluoroacetic acid chloride or anhydride, in a manner known per se. As is known, the trifluoroacetyl group can be readily decomposed solvolytically, e.g. hydrolytic or alcoholic, e.g. by the action of alkali metal or alkaline earth metal hydroxides, carbonates, hydrogen carbonates or acetates, in a suitable, e.g. alcoholic, such as methanolic, or aqueous-alcoholic medium. A particular embodiment of the solvolysis of the 11-trifluoroacetyloxy group is disclosed in German Patent No. 1,593,519, which is particularly important because an esterified hydroxyl group present in the 17a position thereby remaining intact; thereby proceeding by treating the Ιΐβ-trifluoroacetyloxy compound in a low alkanol with the salt of an acid whose pKa value is in the range of approx. 2.3 to approx. 7.3, such as with an alkali metal azide, e.g. sodium or potassium azide, or alkali metal formate, e.g. sodium or potassium formate, since this salt may also be used in clinical catalytic amounts. Furthermore, the Ιΐβ-trifluoroacetyl group may also be removed by treatment with other basic reagents, e.g. with amines, especially with heteroaromatic bases such as pyridine or collidine. Finally, consideration is also given to the cleavage of the trifluoroacetyloxy group by the action of silica gel according to the procedure described in German Publication No. 2.1441405.

Frigørelsen af Ιΐβ-hydroxylgruppen fra den beskyttede form 35 kan ske umiddelbart efter additionen af chlor til 1,2-dob- 17 146017 beltbindingen eller samtidig med dehydrochloreringen ved hjælp af en base, men eventuelt også separat i tilslutning til dette trin.The release of the β-hydroxyl group from the protected form 35 can occur immediately after the addition of chlorine to the 1,2-double bond or at the same time as the dehydrochlorination by a base, but possibly also separately in connection with this step.

Opfindelsen angår også de udførelsesformer af fremgangsmåden, 5 hvor man danner et udgangsstof under reaktionsbetingelserne.The invention also relates to the embodiments of the process in which a starting material is formed under the reaction conditions.

Fortrinsvis indsætter man i de ovenstående trin i fremgangsmåden de udgangsstoffer, der fører til de tidligere som særligt foretrukne beskrevne forbindelser.Preferably, in the above steps of the process, the starting materials leading to the compounds previously described as particularly preferred are inserted.

10 Farmaceutiske præparater indeholdende forbindelserne med formlen (I) anvendes fortrinsvis til behandling af betændelsestilstande, især i form af topisk anvendelige farmaceutiske præparater.Pharmaceutical compositions containing the compounds of formula (I) are preferably used for treating inflammatory conditions, especially in the form of topically applicable pharmaceutical compositions.

Fremgangsmåden ifølge opfindelsen illustreres nærmere i 15 de følgende eksempler.The process according to the invention is further illustrated in the following examples.

18 14601718 146017

Eksempel 1Example 1

En opløsning af 228 mg 21-chlor-6a,9a-difluor-113,17a-di-hydroxy-16p-methyl-pregn-4-en-3,20-dion-17-propionat i 11,4 ml dioxan opvarmes efter tilsætning af 230 mg 5 2,3-dichlor-5,6-dicyano-l,4-benzoquinon (DDQ) i 20 timer underen nitrogenatmosfære til tilbagesvaling. Reaktionsblandingen inddampes i vandstrålevakuum, og den amorfe remanens kromatograferes over den 10O-dobbelte vægtmængde kiselgel (trinsøjle). De med en blanding af methylen-10 chlorid-methanol (99:1) eluerede fraktioner giver det rene 21-chlor-6a, 9a-difluor-l^,17a-dihydroxy-16p-methyl-pregna-1,4-dien-3,20-dion-17-propionat, som efter omkrystallisation fra methylenchlorid/ether smelter ved 220-221°C.A solution of 228 mg of 21-chloro-6α, 9α-difluoro-113,17α-dihydroxy-16β-methyl-pregn-4-ene-3,20-dione-17-propionate in 11.4 ml of dioxane is heated after addition of 230 mg of 5 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) for 20 hours under refluxing nitrogen atmosphere. The reaction mixture is evaporated in water jet vacuum and the amorphous residue is chromatographed over the 10% double weight silica gel (step column). The fractions eluted with a mixture of methylene-10-chloride-methanol (99: 1) give the pure 21-chloro-6a, 9a-difluoro-1,1,17a-dihydroxy-16β-methyl-pregna-1,4-diene. 3,20-dione-17-propionate, which after recrystallization from methylene chloride / ether melts at 220-221 ° C.

15 Det som udgangsstof anvendte 17-monopropionat fremstilles som følger: a. Til en suspension af 1,0 g 21-chlor-9|3, Ιΐβ-epoxy-. 17a-hydroxy-160-methyl-pregn-4-en-3,20-dion-17-prop-ionat i 5,4 ml dioxan og 1,4 ml orthomyresyretri-20 ethylester sættes 0,9 ml af en opløsning bestående af 277 mg p-toluensulfonsyre, 2,7 ml dioxan og 0,55 ml ethylalkohol, og der omrøres i 90 minutter ved stuetemperatur. Efter tilsætning af 3,8 ml pyr-idin fortyndes reaktionsblandingen med ethylacetat, 25 vaskes tre gange med mættet natriumchloridopløsning, tørres og inddampes i vandstrålevakuum. Den således opnåede rå 3-ethyl-enolether (3-ethoxy-21-chlor-98,113-epoxy-17a-hydroxy-163-methyl-pregna-3,5-dien-20-on-17-propionat) opløses i en blanding af 30 50 ml tetrahydrofuran og 10 ml vand og behandles i 40 minutter ved stuetemperatur med gasformigt per-chlorylfluorid. Efter at man derpå i 10 minutter har gennemledet nitrogen, fortyndes reaktionsopløsningen med ethylacetat, vaskes efter hinanden med 35 10%1 s kaliumiodidopløsning, med 10%'s natriumthio- sulfatopløsning og tre gange med mættet natriumchloridopløsning, tørres og inddampes i vandstrålevakuum. Det opstående råprodukt kromatograferes 146017 19 over den 100-dobbelte vægtmængde kiselgel (trinsøjle) . De med en blanding af toluen-ethylacetat (90:10) eluerede fraktioner giver, omkrystalliseret fra methylenchlorid/ether, 21-chlor-6a-fluor-5 9(3, 113-epoxy-17a-hydroxy-16|3-methyl-pregn-4-en-3,20- dion-17-propionat, smp. 174-177°C.The 17-monopropionate used as a starting material is prepared as follows: a. To a suspension of 1.0 g of 21-chloro-9 | 3, β-epoxy-. 17α-hydroxy-160-methyl-pregn-4-ene-3,20-dione-17-propionate in 5.4 ml of dioxane and 1.4 ml of orthomyric acid triethyl ester are added 0.9 ml of a solution consisting of 277 mg of p-toluenesulfonic acid, 2.7 ml of dioxane and 0.55 ml of ethyl alcohol are stirred for 90 minutes at room temperature. After the addition of 3.8 ml pyridine, the reaction mixture is diluted with ethyl acetate, washed three times with saturated sodium chloride solution, dried and evaporated in water jet vacuum. The crude 3-ethyl-enol ether thus obtained (3-ethoxy-21-chloro-98,113-epoxy-17a-hydroxy-163-methyl-pregna-3,5-diene-20-one-17-propionate) is dissolved in a mixture of 30 50 ml of tetrahydrofuran and 10 ml of water and treated for 40 minutes at room temperature with gaseous perchloryl fluoride. After passing through nitrogen for 10 minutes, the reaction solution is diluted with ethyl acetate, washed successively with 10% 1 s potassium iodide solution, with 10% sodium thiosulphate solution and three times with saturated sodium chloride solution, dried and evaporated in water jet vacuum. The resulting crude product is chromatographed over the 100-fold by weight silica gel (step column). The fractions eluted with a mixture of toluene-ethyl acetate (90:10) give, recrystallized from methylene chloride / ether, 21-chloro-6a-fluoro-59 (3, 113-epoxy-17a-hydroxy-16 | 3-methyl) pregn-4-ene-3,20-dione-17-propionate, mp 174-177 ° C.

b, 720 mg af den sidstnævnte forbindelse overhældes i en formstofbeholder med 14,5 ml af et reagens tilberedt ved sammenblanding af 10 g urinstof med 13,25 g 10 vandfrit flydende hydrogenfluorid, og der omrøres i 3 timer under isafkøling. Reaktionsblandingen hældes på 55 ml iskold mættet ammoniakopløsning, gøres svagt sur med eddikesyre og ekstraheres to gange med chloroform. De organiske faser forenes, 15 vaskes med iskold fortyndet natriumhydroxidopløs ning, tørres og inddampes i vandstrålevakuum. Råproduktet kromatograferes over den 100-dobbelte vægtmængde kiselgel (trinsøjle). De med en blanding af toluen-ethylacetat (90:10) eluerede fraktioner giver, 20 omkrystalliseret fra methylenchlorid/ether, 21-chlor- 6a,9a-difluor-113,17a-dihydroxy-163-methyl-pregn-4-en-3,20-dion-17-propionat, smp. 212-213°C.b, 720 mg of the latter compound is poured into a plastic container with 14.5 ml of a reagent prepared by mixing 10 g of urea with 13.25 g of 10 anhydrous liquid hydrogen fluoride and stirring for 3 hours under ice-cooling. The reaction mixture is poured into 55 ml of ice-cold saturated ammonia solution, acidified slightly with acetic acid and extracted twice with chloroform. The organic phases are combined, washed with ice-cold dilute sodium hydroxide solution, dried and evaporated in water jet vacuum. The crude product is chromatographed over the 100-fold weight silica gel (step column). The fractions eluted with a mixture of toluene-ethyl acetate (90:10) give, recrystallized from methylene chloride / ether, 21-chloro-6a, 9a-difluoro-113,17a-dihydroxy-163-methyl-pregn-4-ene. 3.20-dione-17-propionate, m.p. 212-213 ° C.

Eksempel 2Example 2

Til en opløsning af 3,70 g 21-chlor-6a,9a-difluor-113,17a-2 5 dihydroxy-1ββ-methy1-pregna-1,4-dien-3,2 0-dion-17-prop-ionat i 30 ml dioxan sætter man 1,85 ml af en opløsning, der tilberedes ved at indlede 7,7 g chlorgas i 100 ml propionsyre. Reaktionsblandingen henstår i 5 dage ved 3-4°C, fortyndes derefter med chloroform, vaskes efter 30 hinanden med en 10%"s kaliumiodidopløsning, en 10%'s na-triumthiosulfatopløsning, fortyndet natriumhydroxidopløsning og vand, tørres og inddampes i vandstrålevakuum.To a solution of 3.70 g of 21-chloro-6α, 9α-difluoro-113,17α-2,5 dihydroxy-1ββ-methyl-pregna-1,4-diene-3,2-dione-17-propionate in 30 ml of dioxane is added 1.85 ml of a solution prepared by introducing 7.7 g of chlorine gas into 100 ml of propionic acid. The reaction mixture is left for 5 days at 3-4 ° C, then diluted with chloroform, washed successively with 30% potassium iodide solution, 10% sodium thiosulfate solution, dilute sodium hydroxide solution and water, dried and evaporated in water jet vacuum.

Det således opnåede rå l5,25,21-trichlor-6a,9a-difluor-113,17a-dihydroxy-163-methyl-pregn-4-en-3,20-dion-17-35 propionat opløses i methylenchlorid til HCl-fraspaltning 20 146017 og filtreres gennem en søjle af 37 g basisk aluminiumoxid (aktivitet 2). Den eluerede opløsning inddampes og omkrystalliseres fra methylenchlorid-ether, hvorved resulterer 2,21-dichlor-6a, 9a-difluor-ll|3,17a-dihydroxy-163-5 methyl-pregna-l,4-dien-3,20-dion-17-propionat, smp.The crude 1,5,25,21-trichloro-6a, 9a-difluoro-113,17a-dihydroxy-163-methyl-pregn-4-ene-3,20-dione-17-35 propionate thus obtained is dissolved in methylene chloride to give HCl cleavage 20 146017 and filtered through a column of 37 g of basic alumina (activity 2). The eluted solution is evaporated and recrystallized from methylene chloride ether to give 2,21-dichloro-6α, 9α-difluoro-11β, 17α-dihydroxy-163-5 methyl-pregna-1,4-diene-3,20 dione-17-propionate, m.p.

202-204°C.202-204 ° C.

Eksempel 3Example 3

En opløsning af 350 mg 9a,21-dichlor-6a-fluor-lip,17-dihydroxy-16&-methyl-pregn-4-en-3,20-dion-17-propionat 10 og 525 mg 2,3-dichlor-5,6-dicyan-l,4-benzoquinon i 17,5 ml dioxan koges i 20 timer i en nitrogenatmosfære under tilbagesvaling. Den afkølede blanding filtreres, filtratet inddampes, og remanensen opløses i methylenchlorid og filtreres gennem den 15-dobbelte vægtmængde neutralt 15 aluminiumoxid (aktivitet II). Filtratet inddampes og renses ved præparativt tyndtlagskromatografering på silica-gel under anvendelse af en blanding af toluen og methanol i forholdet 9:1 som elueringsmiddel ved det tredie gennemløb. Den ønskede zone lokaliseres 20 ved belysning med UV-lys med en bølgelængde på 254 nm, elueres fra søjlematerialet med ethylacetat og omkrystalliseres fra en blanding af methylenchlorid og ether, og på denne måde fås det ønskede 9a,21-dichlor-6a-f luor-ΙΙβ, 17-dihydroxy-16|3-methyl-pregna-l, 4-dien-25 3,20-dion—17-propionat, med smp. 212-213°C (sønder deling) .A solution of 350 mg of 9α, 21-dichloro-6α-fluoro-lip, 17-dihydroxy-16β-methyl-pregn-4-ene-3,20-dione-17-propionate 10 and 525 mg of 2,3-dichloro 5,6-dicyan-1,4-benzoquinone in 17.5 ml of dioxane is refluxed for 20 hours in a nitrogen atmosphere. The cooled mixture is filtered, the filtrate is evaporated, and the residue is dissolved in methylene chloride and filtered through the 15-fold by weight neutral alumina (Activity II). The filtrate is evaporated and purified by preparative thin layer chromatography on silica gel using a mixture of toluene and methanol in the ratio 9: 1 as the eluent of the third pass. The desired zone is localized by UV light illumination with a wavelength of 254 nm, eluted from the column material with ethyl acetate and recrystallized from a mixture of methylene chloride and ether, thus obtaining the desired 9α, 21-dichloro-6α-fluorine. -Β, 17-dihydroxy-16β-methyl-pregna-1,4-diene-3,20-dione-17-propionate, m.p. 212-213 ° C (decomposition).

a. Det som udgangsmateriale anvendte steroid fremstilles på følgende måde:a. The steroid used as a starting material is prepared as follows:

Til en opløsning af 400 mg 21-chlor-6a-fluor-93,11-30 epoxy-17-hydroxy-16|3-methyl-pregn-4-en-3,20-dion- propionat i 20 ml chloroform sættes i løbet 30 minutter gasformig hydrogenchlorid ved 0°C. Blandingen henstilles i yderligere 30 minutter ved 0°C, fortyndes med chloroform, vaskes med en iskold, mæt-35 tet natriumhydrogencarbonatopløsning, tørres og inddampes i vakuum. Det dannede rå 9a,21-dichlor- 21 146017 6ct-f luor-ΙΙβ, 17^γάΓθχγ·-16β-ιη0ΐ:1ιγ1-ρΓθ9η-4-βη-3,20-dion-17-prop±onat kan anvendes uden rensning ved dehydrogeniseringsreaktionen.To a solution of 400 mg of 21-chloro-6α-fluoro-93,11-30 epoxy-17-hydroxy-16β-methyl-pregn-4-ene-3,20-dione propionate in 20 ml of chloroform is added over 30 minutes gaseous hydrogen chloride at 0 ° C. The mixture is left for another 30 minutes at 0 ° C, diluted with chloroform, washed with an ice cold, saturated sodium hydrogen carbonate solution, dried and evaporated in vacuo. The crude 9a, 21-dichloro-formed 21ct-fluoro-ΙΙβ, 17β-γάΓθχγ · -16β-ιη0ΐ: 1ιγ1-ρΓθ9η-4-βη-3,20-dione-17-propionate can be used without purification by the dehydrogenation reaction.

Eksempel 4 5 Til en opløsning af 2,8 g 21-chlor-6a-fluor-9p,ll- epoxy-17-hydroxy-168-methyl-pregna-l,4-dien-3,20-dion-propionat i 140 ml chloroform ledes gasformig hydrogen-chlorid i løbet af 30 minutter ved 0°C. Blandingen henstilles i yderligere 30 minutter ved 0°C, fortyndes med 10 chloroform, vaskes med en isafkølet, mættet natriumhydr-ogencarbonatopløsning, tørres og inddampes i vakuum.Example 4 To a solution of 2.8 g of 21-chloro-6a-fluoro-9β, 11-epoxy-17-hydroxy-168-methyl-pregna-1,4-diene-3,20-dione propionate in 140 In chloroform, gaseous hydrogen chloride is passed over 30 minutes at 0 ° C. The mixture is allowed to stand for another 30 minutes at 0 ° C, diluted with 10 chloroform, washed with an ice-cooled saturated sodium hydrogen and carbonate solution, dried and evaporated in vacuo.

Det fremkomne råprodukt kromatograferes på en 100-dobbelt vægtmængde silica-gel (trinsøjle). Det ønskede produkt elueres med en blanding toluen og methanol i for-15 holdet 99:1. Efter krystallisation fra en blanding af methylenchlorid og ether fås 9a,21-dichlor-6a-fluor-ΙΙβ ,17-dihydroxy-16β-methyl-pregna-l/4-dien-3,20-dion-17-propionat med smp. 212-213°C (sønderdeling), som er identisk med det ifølge eksempel 3 fremstillede produkt.The crude product obtained is chromatographed on a 100-fold by weight silica gel (step column). The desired product is eluted with a mixture of toluene and methanol in the ratio 99: 1. After crystallization from a mixture of methylene chloride and ether, 9α, 21-dichloro-6α-fluoro-β, 17-dihydroxy-16β-methyl-pregna-1/4-diene-3,20-dione-17-propionate were obtained, m.p. 212-213 ° C (decomposition), which is identical to the product of Example 3.

a 20 Den som udgangsmateriale anvendte steroidforbindelse fremstilles på følgende måde:a 20 The steroid compound used as a starting material is prepared as follows:

En blanding af 3g 21-chlor-6a-fluor-9B,ll-epoxy-17-hydroxy-16β-methyl-pregn-4-en-3,20-dion-propionat og 3 g 2,3-dichlor-5,6-dicyan-l,4-benzoquinon i 150 ml dioxan 25 koges i 20 timer i en nitrogenatomosfære under tilbagesvaling. Den afkølede blanding filtreres, filtratet inddampes, remanensen opløses i methylenchlorid og filtreres gennem den 15-dobbelt vægtmængde neutralt aluminiumoxid (aktivitet II). Filtratet inddampes, hvorved fås 30 råt 21-ο1ι1θΓ-6α-ί1ηοΓ-9β,11-βροχγ-17-]^^1ι:οχγ-16β-ιηβ^γ1-pregna-l,4-dien-3,20-dion-propionat, som uden yderligere rensning anvendes til omsætningen med hydrogenchlorid.A mixture of 3g of 21-chloro-6a-fluoro-9B, 11-epoxy-17-hydroxy-16β-methyl-pregn-4-ene-3,20-dione propionate and 3g of 2,3-dichloro-5, 6-dicyan-1,4-benzoquinone in 150 ml of dioxane is refluxed for 20 hours in a nitrogen atom. The cooled mixture is filtered, the filtrate is evaporated, the residue is dissolved in methylene chloride and filtered through the 15-fold by weight of neutral alumina (Activity II). The filtrate is evaporated to give crude 21-ο1ι1θΓ-6α-ί1ηοΓ-9β, 11-βροχγ-17 -] - 1β: οχγ-16β-ιηβ propionate, which is used for the reaction with hydrogen chloride without further purification.

22 14601722 146017

Eksempel 5Example 5

Under anvendelse af den i eksempel lb beskrevne fremgangsmåde fremstilles ud fra 21-chlor-6a-fluor-93,ll-epoxy-17-hydroxy-16 β-methy1-pregna-1,4-dien-3,20-dion-5 propionat (fremstillet ifølge eksempel 4a) 21-chlor-6a, 9a-difluor-ΙΙβ, 17a-dihydroxy-16f}-methyl-pregna- l,4-dien~3,20-dion-17-propionat, med smp.220-221°C (fra en blanding af methylenchlorid og ether).Using the procedure described in Example 1b, is prepared from 21-chloro-6α-fluoro-93,11-epoxy-17-hydroxy-16β-methyl-pregna-1,4-diene-3,20-dione-5 propionate (prepared according to Example 4a) 21-chloro-6a, 9a-difluoro-ΙΙβ, 17a-dihydroxy-16f} -methyl-pregna-1,4-diene ~ 3,20-dione-17-propionate, m.p. -221 ° C (from a mixture of methylene chloride and ether).

Eksempel 6 10 Til en opløsning af 2,97 g 2-chlor-6a,9a-difluor-ΙΙβ, 17a,21-trihydroxy-16β-methyl-pregna-l,4-dien-3,20-dion-17-propionat i 60 ml pyridin sættes dråbevis ved ca.Example 6 To a solution of 2.97 g of 2-chloro-6α, 9α-difluoro-β, 17α, 21-trihydroxy-16β-methyl-pregna-1,4-diene-3,20-dione-17-propionate in 60 ml of pyridine is added dropwise at approx.

-10°C under omrøring 2,23 ml methansulfonsyrechlorid, hvorefter blandingen henstilles ved ca. 5°C i yder-15 ligere 21 timer. Derpå hældes reaktionsblandingen i 1,5 1 isvand, og der omrøres i 20 minutter. Det udfældede bundfald frafiltreres, vaskes med vand, optages i chloroform, opløsningen tørres og inddampes under vand-strålevakuum. Det således fremstillede 21-mesylat op-20 fører sig ved tyndtlagskromatografering som et praktisk taget rent stof. Det opløses uden yderligere rensning direkte i 75 ml dimethylformamid, og efter tilsætning af 11,25 g lithiumchlorid omrøres der i 16 timer under nitrogen ved 100°C, hvorefter der afkøles, og blandingen 25 hældes i ca. 1,5 1 isvand. Det udfældede frafiltreres, vaskes med vand og opløses i chloroform, opløsningen vaskes med vand, tørres og inddampes i vakuum. Det fremkomne råprodukt kromatograferes på den 40-dobbelte vægtmængde kiselgel (trinsøjle). Fra de med en blanding 30 af toluen og ethylacetat (95:5) eluerede fraktioner fås efter omkrystallisation fra en blanding af methylenchlorid, methanol og ether rent 2,21-dichlor-6a,9a-di-fluor-ΙΙβ,17α-·dihydroxy-16β-methyl-pregna-l,4-dien- 3,20-dion-17-propionat med smp. 202-204°C.-10 ° C with stirring 2.23 ml of methanesulfonic acid chloride, after which the mixture is left to stand at ca. 5 ° C for an additional 21 hours. Then, the reaction mixture is poured into 1.5 L of ice water and stirred for 20 minutes. The precipitated precipitate is filtered off, washed with water, taken up in chloroform, the solution dried and evaporated under water-jet vacuum. The 21-mesylate thus prepared behaves by thin layer chromatography as a practically pure substance. It is dissolved directly in 75 ml of dimethylformamide without further purification, and after addition of 11.25 g of lithium chloride, it is stirred for 16 hours under nitrogen at 100 ° C, then cooled and the mixture is poured into ca. 1.5 l of ice water. The precipitate is filtered off, washed with water and dissolved in chloroform, the solution washed with water, dried and evaporated in vacuo. The crude product obtained is chromatographed on the 40-fold by weight silica gel (step column). From the fractions eluted with a mixture of toluene and ethyl acetate (95: 5), after recrystallization is obtained from a mixture of methylene chloride, methanol and ether pure 2,21-dichloro-6a, 9a-di-fluoro-ΙΙβ, 17α- · dihydroxy -16β-methyl-pregna-1,4-diene-3,20-dione-17-propionate, m.p. 202-204 ° C.

35 Fra de efterfølgende fraktioner, som elueres med en 23 146017 blanding af toluen og ethylacetat (92:8) genvindes ca.From the subsequent fractions eluted with a mixture of toluene and ethyl acetate (92: 8), ca.

1,3 g uomsat 21-mesylat (2-chlor-6a, 9<x-difluor-llf3,17a, 21-trihydroxy-163-methyl-pregna-l,4-dien-3,20-dion-17-propionat-21-mesylat).1.3 g of unreacted 21-mesylate (2-chloro-6a, 9 <x -difluoro-11,17,17a, 21-trihydroxy-163-methyl-pregna-1,4-diene-3,20-dione-17-propionate 21-mesylate).

5 Det som udgangsmateriale anvendte 17-monopropionat fremstilles på følgende måde: a. En opløsning af 3,0 g 2-chlor-6a,9a-difluor-113, 17a,21-trihydroxy-163-methyl-pregna-l,4-dien-3,20-dion i 15 ml absolut tetrahydrofuran tilsættes 3,6 ml 10 orthopropionsyretriethylester og 100 mg p-toluen- sulfonsyre, og blandingen omrøres i 1,5 timer ved stuetemperatur. Derpå sættes dråbevis 1,2 ml pyr-idin tilreaktionsopløsningen, som hældes i isvand, ekstraheres med 2 gange 400 ml ethylacetat, hvor-15 efter de organiske opløsninger vaskes med 5 gange 100 ml mættet natriumchloridopløsning, tørres og inddampes under vandstrålevakuum. Det fremkomne rå 17,21,ethyl-orthopropionat opløses i 150 ml ethanol.The 17-monopropionate used as starting material is prepared as follows: a. A solution of 3.0 g of 2-chloro-6a, 9a-difluoro-113, 17a, 21-trihydroxy-163-methyl-pregna-1,4 diene-3,20-dione in 15 ml of absolute tetrahydrofuran is added 3.6 ml of orthopropionic acid triethyl ester and 100 mg of p-toluenesulfonic acid, and the mixture is stirred for 1.5 hours at room temperature. Then, 1.2 ml of pyridine is added dropwise to the reaction solution, which is poured into ice water, extracted with 400 ml of ethyl acetate twice, after which the organic solutions are washed with 5 times 100 ml of saturated sodium chloride solution, dried and evaporated under water jet vacuum. The resulting crude 17.21 ethyl orthopropionate is dissolved in 150 ml of ethanol.

Opløsningen omrøres efter tilsætning af 1,1 g oxal-20 syre i 9 ml vand i 1 time ved 55°C, der tilsættes 100 ml vand og inddampes under vandstrålevakuum.The solution is stirred after adding 1.1 g of oxalic acid in 9 ml of water for 1 hour at 55 ° C, adding 100 ml of water and evaporating under water jet vacuum.

Det udfældede bundfald frafiltreres, vaskes med vand og opløses i chloroform. Opløsningen tørres med natriumsulfat og inddampes i vakuum. Det således 25 fremstillede rå 2-chlor-6a,9a-difluor-113,17a,21- trihydroxy-163-methyl-pregna-l,4-dien-3,20-dion-17-propionat opfører sig ved tyndtlagskromatografe-ring som et praktisk taget ensartet stof og kan anvendes direkte uden yderligere rensning ved den 30 ovenfor beskrevne omsætning til den tilsvarende 21-chlor-forbindelse.The precipitated precipitate is filtered off, washed with water and dissolved in chloroform. The solution is dried over sodium sulfate and evaporated in vacuo. The thus-obtained crude 2-chloro-6a, 9a-difluoro-113,17a, 21-trihydroxy-163-methyl-pregna-1,4-diene-3,20-dione-17-propionate behaves by thin layer chromatography. as a virtually uniform substance and can be used directly without further purification in the reaction described above to the corresponding 21-chloro compound.

Eksempel 7Example 7

Under anvendelse .af den i eksempel 6 beskrevne fremgangsmåde omsættes 1,0 g 9a-chlor-6a-fluor-113,17a,21-tri- U8017 24 hydroxy-16 β-methy1-pregn-4-en-3,20-dion-17-propionat med methansulfonsyrechlorid i pyridin. Det dannede 21-mesylat opløses i 30 ml acetone og 20 ml dimethyl-formamid, og efter tilsætning af 3,9 g lithiumchlorid 5 omrøres der i 16 timer i et indsmeltet trykrør ved 80°C. Den afkølede blanding hældes i isvand, bundfaldet vaskes med vand, optages i methylenchlorid, tørres, og inddampes under vandstrålevakuum. Det fremkomne råprodukt opløses i toluen og kromatograferes på en 50-10 dobbelt vægtmængde kiselgel. De fraktioner, som elueres med en blanding af toluen og ethylacetat (95:5) , giver efter omfældning fra en blanding af methylenchlorid og ether 9α,21-dichlor-6a-fluor-ΙΙβ,17a-dihydroxy—Ιββ-meth-yl-pregn-4-en-3,20-dion-17-propionat, som smelter ved 15 198°C (sønderdeling).Using the procedure described in Example 6, 1.0 g of 9α-chloro-6α-fluoro-113,17α, 21-tri-hydroxy-16β-methyl-pregn-4-ene-3,20 dione-17-propionate with methanesulfonic acid chloride in pyridine. The resulting 21-mesylate is dissolved in 30 ml of acetone and 20 ml of dimethylformamide, and after addition of 3.9 g of lithium chloride 5 is stirred for 16 hours in a molten pressure tube at 80 ° C. The cooled mixture is poured into ice water, the precipitate is washed with water, taken up in methylene chloride, dried, and evaporated under water jet vacuum. The crude product obtained is dissolved in toluene and chromatographed on a 50-10 double weight silica gel. The fractions eluted with a mixture of toluene and ethyl acetate (95: 5) give, after conversion from a mixture of methylene chloride and ether 9α, 21-dichloro-6α-fluoro-ΙΙβ, 17α-dihydroxy-Ιββ-methyl-yl. pregn-4-ene-3,20-dione-17-propionate, which melts at 15 198 ° C (dec.).

Udgangsmaterialet kan fremstilles på følgende måde: a. En opløsning af 20 g 6a-fluor-ΙΙβ,17a,21-trihydr- oxy-16B-methyl-pregn-4-en-3,20-dion-21-acetat i 120 ml dimethylformamid og 40 ml 2,4,6-trimethylpyridin 20 tilsættes dråbevis ved 10°C under omrøring 30 ml af en opløsning fremstillet af 2 g svovldioxid og 40 ml methansulfochlorid (mesylchlorid). Efter opvarmning til 30°C stiger temperaturen spontant under fortsat omrøring i 20 minutter til 55°C. Blandingen 25 hældes i 1500 ml vand, og det dannede bundfald frafiltreres, vaskes med vand og opløses i chloroform. Opløsningen tørres med natriumsulfat og inddampes i vandstrålevakuum. Den mørke remanensolie opløses i methylenchlorid og filtreres gennem en 30 20-dobbelt vægtmængde aluminiumoxid (neutralt, akti vitet 2). Efter afdampning af opløsningsmidlet fra filtratet fås farveløst 6a-fluor-17a,21-dihydroxy-16β-methy1-pregna-4,9(11)-dien-3,20-dion-21-acetat, som ved tyndtlagskromatografering opfører sig som 35 et ensartet stof.The starting material can be prepared as follows: a. A solution of 20 g of 6α-fluoro-β, 17α, 21-trihydroxy-16B-methyl-pregn-4-ene-3,20-dione-21-acetate in 120 ml dimethylformamide and 40 ml of 2,4,6-trimethylpyridine 20 are added dropwise at 10 ° C with stirring 30 ml of a solution made of 2 g of sulfur dioxide and 40 ml of methanesulfochloride (mesyl chloride). After heating to 30 ° C, the temperature increases spontaneously with continued stirring for 20 minutes to 55 ° C. The mixture is poured into 1500 ml of water and the precipitate formed is filtered off, washed with water and dissolved in chloroform. The solution is dried with sodium sulfate and evaporated in water jet vacuum. The dark residual oil is dissolved in methylene chloride and filtered through a 30-fold by weight alumina (neutral, activity 2). Evaporation of the solvent from the filtrate gives colorless 6a-fluoro-17a, 21-dihydroxy-16β-methyl-pregna-4,9 (11) -diene-3,20-dione-21-acetate, which behaves as thin layer chromatography as 35 a uniform substance.

25 146017 b. 5,0 g af den ovenfor under a fremstillede forbindelse overhældes med 100 ml t-butanol og tilsættes under nitrogen og omrøring 6,5 ml 10%'s perchlor-syreopløsning og til sidst 2 ml t-butylhypochlorit.B. 5.0 g of the compound prepared above under a is poured with 100 ml of t-butanol and added with nitrogen and stirring 6.5 ml of 10% perchloric acid solution and finally 2 ml of t-butyl hypochlorite.

5 Efter 3,5 timers yderligere omrøring ved stuetem peratur hældes den gule opløsning i isvand, og produktet optages i chloroform. Den organiske opløsning vaskes med 10%'s kaliumiodidopløsning, 10%'s natriumthiosulfatopløsning og til sidst med is-10 kold fortyndet natriumhydroxidopløsning, hvorefter den tørres og inddampes i vandstrålevakuum. Den rå 9a-chlor-6a-fluor-113,17a,21-trihydroxy-16p-methyl-pregn-4-en-3,20-dion-21-acetat renses ved omfældning fra en blanding af methylenchlorid, 15 methanol og ether.After 3.5 hours of further stirring at room temperature, the yellow solution is poured into ice water and the product is taken up in chloroform. The organic solution is washed with 10% potassium iodide solution, 10% sodium thiosulfate solution and finally with ice-10 cold diluted sodium hydroxide solution, then dried and evaporated in water jet vacuum. The crude 9α-chloro-6α-fluoro-113.17a, 21-trihydroxy-16β-methyl-pregn-4-ene-3,20-dione-21-acetate is purified by reaction from a mixture of methylene chloride, methanol and ether. .

c. En opløsning af 4,5 g af det ovenfor fremstillede 21-acetat i 300 ml methanol tilsættes under nitrogen 22,5 ml af en opløsning af 2,76 g natriumhydrogen-carbonat i 32,4 ml vand, og der omrøres i 3,5 timer 20 ved stuetemperatur. Blandingen tilsættes 1,35 ml iseddike og 225 ml vand, methanolet fjernes fuldstændigt i vakuum. Det udskilte bundfald sugefiltreres, vaskes med vand og sugefiltreres atter skarpt. Remanensen opløses i chloroform, opløs-25 ningen tørres med natriumsulfat og inddampes, hvor ved fås krystallinsk 9a-chlor-6a-fluor-ll|3,17a,21-trihydroxy-16f3-methyl-pregn-4-en-3,20-dion.c. A solution of 4.5 g of the above 21-acetate in 300 ml of methanol is added under nitrogen to 22.5 ml of a solution of 2.76 g of sodium hydrogen carbonate in 32.4 ml of water and stirred for 3 hours. , 5 hours 20 at room temperature. The mixture is added with 1.35 ml glacial acetic acid and 225 ml water, the methanol is completely removed in vacuo. The separated precipitate is suction filtered, washed with water and again suction filtered. The residue is dissolved in chloroform, the solution is dried over sodium sulfate and evaporated to give crystalline 9α-chloro-6α-fluoro-11β, 17α, 21-trihydroxy-16β-methyl-pregn-4-ene-3.20 -dione.

d. En opløsning af 3,12 g af den ovenfor fremstillede forbindelse i 31,2 ml tetrahydrofuran omrøres i 1,5 30 timer ved 20°C med 3,9 ml orthopropionsyretriethyl- ester og 156 mg p-toluensulfonsyre, hvorefter der tilsættes 4 ml pyridin, hvorpå blandingen inddampes let i vakuum og optages i ethylacetat. Ekstrakten vaskes to gange med en mættet natriumchloridop-35 løsning, tørres og inddampes. Som remanens fås rå ethyl,17α,21-orthopropionat af 2,9a-dichlor-6a-fluor- 26 146017 11β,17α,21-trihydroxy-16b-methyl-pregn-4-en-3,20-dion, som anvendes uden rensning i det efterfølgende trin.d. A solution of 3.12 g of the above compound in 31.2 ml of tetrahydrofuran is stirred for 1.5 30 hours at 20 ° C with 3.9 ml of orthopropionic acid triethyl ester and 156 mg of p-toluenesulfonic acid, then 4 The mixture is then evaporated in vacuo and taken up in ethyl acetate. The extract is washed twice with a saturated sodium chloride solution, dried and evaporated. As the residue, crude ethyl, 17α, 21-orthopropionate of 2,9a-dichloro-6a-fluoro-11β, 17α, 21-trihydroxy-16b-methyl-pregn-4-ene-3,20-dione is obtained, which is used. without purification in the subsequent step.

e. En opløsning af 3,10 g af den ovenfor fremstillede 5 orthoester i 155 ml ethylalkohol tilsættes en opløsning af 0,96 g oxalsyre-dihydrat i 8,3 ml vand, og der omrøres ved 50°C, hvorpå der efter ' en time fortyndes med 96 ml vand, inddampes i vakuum og ekstraileres med ethylacetat. Den organiske 10 ekstrakt vaskes to gange med en isafkølet 2N-opløs- ning af kaliumhydrogencarbonat og tre gange med vand, hvorefter der tørres og inddampes. Remanensen består af det rå 9a-chlor-6a-fluor-ΙΙβ,17a,21-trihydroxy-16p-methyl-pregn-4-en-3,20-dion-17-propionat, som 15 renses ved krystallisation fra en blanding af methylenchlorid, methanol og ether.e. A solution of 3.10 g of the above-prepared ortho ester in 155 ml of ethyl alcohol is added to a solution of 0.96 g of oxalic acid dihydrate in 8.3 ml of water and stirred at 50 ° C, after which diluted with 96 ml of water, evaporated in vacuo and extracted with ethyl acetate. The organic extract is washed twice with an ice-cooled 2N solution of potassium hydrogen carbonate and three times with water, then dried and evaporated. The residue consists of the crude 9α-chloro-6α-fluoro-ββ, 17α, 21-trihydroxy-16β-methyl-pregn-4-ene-3,20-dione-17-propionate which is purified by crystallization from a mixture of methylene chloride, methanol and ether.

Eksempel 8Example 8

Under anvendelse af den i eksempel 7 beskrevne fremgangsmåde, idet der imidlertid som udgangsmateriale anvendes 20 9a-chlor-6a-fluor-ΙΙβ ,17a, 21-trihydroxy-16|3-methyl-pregna- l,4-dien-3,20-dion-17-propionat (der kan fremstilles ud fra udgangsmaterialet i eksempel 7 ved dehydrogenering), fremstilles 9a,21-dichlor~6a-fluor-ΙΙβ,17a-dihydroxy-16β-methyl-pregna-l,4-dien-3,20-dion-17-propionat med 25 smp. 212-213°C (sønderdeling).Using the procedure described in Example 7, however, using as starting material, 20α-chloro-6α-fluoro-β, 17α, 21-trihydroxy-16β-methyl-pregna-1,4-diene-3.20 -dione-17-propionate (which can be prepared from the starting material of Example 7 by dehydrogenation), 9a, 21-dichloro-6a-fluoro-ΙΙβ, 17a-dihydroxy-16β-methyl-pregna-1,4-diene-3 are prepared. , 20-dione-17-propionate with 25 m.p. 212-213 ° C (dec.).

Eksempel 9Example 9

Til en opløsning af 6,0 g 6a,9a-difluor-l^,17a,21-tri-hydroxy-16β-methyl-pregna-l,4-dien-3,20-dion-17-prop-ionat-21-methansulfonat i 150 ml dimethylformamid 30 sættes 18 g tørt lithiumchlorid, og der omrøres i 16 timer ved 100°C under en nitrogenatmosfære. Den afkølede blanding hældes i isvand, det dannede bundfald frafiltreres, vaskes grundigt med vand og opløses i chloroform. Den organiske opløsning inddampes efter 27 146017 tørring under vandstrålevakuum, og remanensen afskilles ved hjælp af præparativt tyndtlagskromatografering på silicagel med en 50:50-blanding af toluen og ethylacetat som flydende fase. Ved udvaskning af hovedzonen med 5 ethylacetat fås 21-chlor-6a,9a-difluor-lip,17a-dihydroxy-1ββ-methy1-pregna-l,4-dien-3,20-dion-17-propionat, som efter omkrystallisation fra en blanding af chloroform, methanol og diethylether smelter ved 220-221°C.To a solution of 6.0 g of 6α, 9α-difluoro-1,7,17α, 21-tri-hydroxy-16β-methyl-pregna-1,4-diene-3,20-dione-17-propionate-21 -Methanesulfonate in 150 ml of dimethylformamide 30 is added 18 g of dry lithium chloride and stirred for 16 hours at 100 ° C under a nitrogen atmosphere. The cooled mixture is poured into ice water, the precipitate formed is filtered off, washed thoroughly with water and dissolved in chloroform. The organic solution is evaporated after drying under water jet vacuum and the residue is separated by preparative thin layer chromatography on silica gel with a 50:50 mixture of toluene and ethyl acetate as liquid phase. Leaching the main zone with 5 ethyl acetate gives 21-chloro-6a, 9a-difluoro-lip, 17a-dihydroxy-1ββ-methyl-pregna-1,4-diene-3,20-dione-17-propionate, which after recrystallization from a mixture of chloroform, methanol and diethyl ether melts at 220-221 ° C.

Under anvendelse af den ovenfor beskrevne fremgangsmåde, 10 idet der dog gås ud fra det tilsvarende 1,2-mættede 17-propionat-21-methansulfonat fremstilles 21-chlor-6a,9a-difluor-lip,17a-dihydroxy-163-methyl-pregn-4-en-3,20-dion-17-propionat med smp. 212-213°C.Using the procedure described above, however, starting from the corresponding 1,2-saturated 17-propionate-21-methanesulfonate, 21-chloro-6a, 9a-difluoro-lip, 17a-dihydroxy-163-methyl pregn-4-ene-3,20-dione-17-propionate, m.p. 212-213 ° C.

Det som udgangsmateriale anvendte 21-methansulfonat af 15 6a,9a-difluor-ΙΙβ,17a,21-trihydroxy-163-methyl-pregna- l,4-dien-3,20-dion-17-propionat eller den tilsvarende 1,2-mættede forbindelse fremstilles ved forestring af 21-hydroxygruppen i det tilsvarende 6a,9a-difluor-113, 17a,21-trihydroxy-17-propionat ved behandling med 20 methansulfonsyrechlorid i nærværelse af pyridin ved 5°C.The starting material used was 21-methanesulfonate of 6α, 9α-difluoro-ββ, 17α, 21-trihydroxy-163-methyl-pregna-1,4-diene-3,20-dione-17-propionate or the corresponding 1,2 -saturated compound is prepared by esterification of the 21-hydroxy group of the corresponding 6a, 9a-difluoro-113, 17a, 21-trihydroxy-17-propionate by treatment with 20 methanesulfonic acid chloride in the presence of pyridine at 5 ° C.

Eksempel 10Example 10

En omrørt suspension af 7,45 g 21-chlor-6a-fluor-17a-hydroxy-16&-methyl-pregna-4,9(11)-dien-3,20-dion-17-25 propionat i 150 ml t-butylalkohol tilsættes under nitrogen 7,55 ml 10%'s perchlorsyreopløsning og derpå 2,15 ml t-butylhypochlorit, hvorefter der omrøres i yderligere 3,5 timer ved stuetemperatur, hvorpå blandingen hældes i isvand. Bundfaldet frasuges, vaskes grundigt med vand 3q og opløses i chloroform og en smule methanol. Opløsningen tørres med en natriumsulfat og inddampes i vand-strålevakuum. Efter omfældning af den fremkomne remanens fra en blanding af methylenchlorid, methanol og ether fås 9a,21-dichlor-6a-fluor-113,17a-dihydroxy-35 163-methyl-pregn-4-en-3,20-dion-17-propionat, som 28 146017 smelter ved 198°C under sønderdeling.A stirred suspension of 7.45 g of 21-chloro-6α-fluoro-17α-hydroxy-16β-methyl-pregna-4,9 (11) -diene-3,20-dione-17-25 propionate in 150 ml of t butyl alcohol is added under nitrogen 7.55 ml of 10% perchloric acid solution and then 2.15 ml of t-butyl hypochlorite, then stirred for an additional 3.5 hours at room temperature, then the mixture is poured into ice-water. The precipitate is aspirated, washed thoroughly with water 3q and dissolved in chloroform and a little methanol. The solution is dried with a sodium sulfate and evaporated in water-jet vacuum. After reaction of the residue obtained from a mixture of methylene chloride, methanol and ether, 9a, 21-dichloro-6a-fluoro-113,17a-dihydroxy-353-methyl-pregn-4-ene-3,20-dione-17 are obtained. propionate, which melts at 146 ° C during decomposition.

Eksempel 11Example 11

Under anvendelse af den i eksempel 10 beskrevne fremgangsmåde fremstilles en suspension af 2,95 g 21-chlor-5 6<x-f luor-17a-hydroxy-163-methyl-pregna-l ,4,9(11) -trien- 3,20-dion-17-propionat i 60 ml t-butylalkohol, som tilsættes 2,95 ml 10%'s perchlorsyreopløsning og 0,85 ml t-butylhypochlorit. Efter oparbejdning fås 9a,21-dichlor-6a-fluor-lip,17a-dihydroxy-163-methyl-pregna-l,4-dien-10 3,20-dion-17-propionat med smp. 212-213°C (sønderdeling).Using the procedure described in Example 10, a suspension of 2.95 g of 21-chloro-5,6 <xfluoro-17α-hydroxy-163-methyl-pregna-1,4,9 (11) -tri-3 is prepared. 20-dione-17-propionate in 60 ml of t-butyl alcohol added to 2.95 ml of 10% perchloric acid solution and 0.85 ml of t-butyl hypochlorite. After working up, 9a, 21-dichloro-6a-fluoro-lip, 17a-dihydroxy-163-methyl-pregna-1,4-diene-10,20-dione-17-propionate are obtained with m.p. 212-213 ° C (dec.).

Claims (3)

146017146017 1. Analogifremgangsmåde ifølge patent nr. 143.708 til fremstilling af 17a-acyloxy-9a,21-dihalogen-ll|3-hydroxy-6a-fluor-163-methylpregna-l,4-dien-3,20-dion-forbindelser 5 med formlen CH0-X2 I 2 CH C=0 \/>-----0-R2 Ri ch3 (I) F 1 2 1 hvori X er chlor eller fluor, X brom eller chlor, R 2 hydrogen eller chlor og R en alkanoylgruppe med højst 7 C-atomer, kendetegnet ved, at man a) behandler en forbindelse med formlen CEL-X2 I 2 CH, C=0 W_|----0-R2 R1 CH3 /° 10 γγγ\ΛθΗ3 111 > 0A/\J i t F 12 2 hvori R , R og X har den ovennævnte betydning, med hydro-genchlorid eller hydrogenfluorid eller med et middel, der afgiver et af disse hydrogenhalogenider, eller b) i en forbindelse med den almene formel 148017 CHo-0-Ra i 2 ch3 c=o HO . J ? X/x------O-R2 R1 CH3I I (IV) οΚίΚ/ F hvori r\ R2 og X1 har den ovennævnte betydning, og Ra er resten af en organisk sulfonsyre, erstatter sulfonyl-oxygruppen med brom eller chlor, eller 5 c) til fremstilling af en forbindelse med formlen I, hvori X*· betyder chlor, behandler en 9 (11)-umættet forbindelse med formlen ch9-x2 I 2 CH3 c=o -----O-R2 'y I ^ ch3 (vii) oAA/ F 12 2 hvori R , R og X har den ovennævnte betydning, med chlor-10 undersyrling eller et chlorundersyrlingafgivende middel, eller d) til fremstilling af en forbindelse med formlen I, hvori R·*· betyder hydrogen, dehydrogenerer en forbindelse med formlen 146017 <jH2—X2 CH, C=0 R°y\ 9 X/^-----O-R2 (vin) oA^V i F 2 1 2 hvori R , X og X har den ovennævnte betydning, i 1,2-stillingen, og, om ønsket, i en ifølge fremgangsmåden opnået forbin-5 delse med formlen I, hvori R"*" betyder hydrogen, og de øvrige symboler har den ovennævnte betydning, tillejrer chlor til 1,2-dobbeltbindingen og fra den opnåede forbindelse med formlen CEL-X2 I 2 CH, C=0 H0 yv o Cl -----°-R CyA>/\AcH3 x1 J oAA/ t F 2 1 2 hvori R , X og X har den ovennævnte betydning, fraspalter 10 hydrogenchlorid, idet man under begge fremgangsmådetrin eventuelt arbejder under forbigående beskyttelse af 11β-hydroxylgruppen ved overføring til trifluoracetatet.An analogous process according to patent No. 143,708 for the preparation of 17α-acyloxy-9α, 21-dihalogen-11β-hydroxy-6α-fluoro-163-methylpregna-1,4-diene-3,20-dione compounds 5 with the formula CHO-X2 I 2 CH C = 0 \ /> ----- O-R2 R1 ch3 (I) F 1 2 1 wherein X is chlorine or fluorine, X is bromine or chlorine, R2 is hydrogen or chlorine and R is alkanoyl group having a maximum of 7 C atoms, characterized in that a) treating a compound of formula CEL-X2 I 2 CH, C = 0 W_ | ---- 0-R2 R1 CH3 / ° 10 γγγ \ ΛθΗ3 111> 0A Wherein R, R and X are as defined above with hydrogen chloride or hydrogen fluoride or with an agent which gives off one of these hydrogen halides, or b) in a compound of general formula 148017 CHO-0 -Ra in 2 ch3 c = o HO. J? X / x ------ O-R2 R1 CH3I I (IV) οΚίΚ / F wherein r \ R2 and X1 have the above meaning and Ra is the remainder of an organic sulfonic acid, replacing the sulfonyl oxy group with bromine or chlorine, or c) for the preparation of a compound of formula I wherein X * = chlorine, a 9 (11) unsaturated compound of formula ch9-x2 is treated with 2 CH3 c = o ----- O-R2 'y Wherein R, R and X have the above meaning, with chloro-10 subcirculation or a chloro-subcooler, or d) to prepare a compound of formula I wherein R4 hydrogen, dehydrogenates a compound of formula 146017 <jH2 - X2 CH, C = 0 R ° y \ 9 X / ^ ----- O-R2 (wine) oA ^ V in F 2 1 2 wherein R, X and X has the above meaning, in the 1,2-position, and, if desired, in a compound of formula I obtained in accordance with the process wherein R "*" means hydrogen and the other symbols having the above meaning, chlorine The 1,2-double bond and from the obtained lining compound of the formula CEL-X2 I 2 CH, C = 0 H0 yv o Cl ----- ° -R CyA> / \ AcH3 x1 J oAA / t F 2 1 2 wherein R, X and X have the above meaning, decomposes 10 hydrochloric acid, optionally during both process steps under the temporary protection of the 11β-hydroxyl group upon transfer to the trifluoroacetate. 2. Fremgangsmåde ifølge krav 1, kendetegnet ved, at man fremstiller 2,21-dichlor-6a,9a-difluor-113,17a-dihydroxy-16P-methylpregna-l,4-dien-3,20-dion-17-propionat.Process according to claim 1, characterized in that 2,2-dichloro-6a, 9a-difluoro-113,17a-dihydroxy-16β-methylpregna-1,4-diene-3,20-dione-17-propionate are prepared. . 3. Fremgangsmåde ifølge krav 1, kendetegnet ved, at man fremstiller 9a,21-dichlor-6a-fluor-113,17a-dihydroxy-163~methylpregna-l,4-dien-3,20-dion-17-propionat.Process according to claim 1, characterized in that 9a, 21-dichloro-6a-fluoro-113,17a-dihydroxy-163-methylpregna-1,4-diene-3,20-dione-17-propionate are prepared.