--a Office 3,049,554 Paiented Aug. 14, 1962

2 3,049,554 above. The preferred compounds of our invention are 9,1-D HALOGENG-320-D2 KETOPRESNANES AND the 9c, 11,3-difluoropregnenes and pregnadienes. The di PRO CESSES FOR THER EAANUEFACTURE flucro compounds of the general formula having a 17 c.21 David H. Gould, Leonia, and Hans Reinana, Siocrified, dihydroxy function and in particular a A1-bond are highly N.J., assignors to Sciering Corporation, Soon fied, potent agents useful in the treatment of inflammations, N.J., a corporation of New Jersey burns and atopic dermatoses. No Drawing. Filled Juae i, 1959, Ser. No. 837,843 in olir co-pending application Serial No. 743,492, filed 9 (Ciaias. (C. 269-397.3) ine 20, 1958, now U.S. Patent No. 2,894,963, of which this application is a continuation-in-part, we described This invention relates to a novel class of halogenated 0. 9,11-dihalcgeno-4-pregnene-170,21-diol-3,20-diones and steroids which are therapeutically useful. More specifi the corresponding 1,4-pregnadienes wherein the more elec cally, our invention relates to a particular group of 9,11 tronegative atom appeared at C-11 in the case wherein dihalogenated pregnanes wherein the halogen atom at C-9 the 9- and 11-substituent were different. Due to the limi is at least as electronegative as the halogen substituent at tations of the process described in said application, com C-11. By the term pregnane series we mean pregnanes polinds containing fluorine at C-9, or in the case of a containing the A-3,20-diketo and A.-3,20 diketo systems. mixed dihalide compound containing the more electro Our novel compounds are of the group consisting of negative atom at C-9, could not be prepared and were pregnanes having the following formula: specifically disclaimed. We have now found methods for CE.R. preparing such 9oz-fluoro compounds and compounds con taining the more electronegative halogen at C-9 as de -9 scribed by Formula i. Our novel compounds are prepared either from a A9(11). dehydro precursor or from a 9oz-halo-11-hydroxy pre r) cursor; the choice depending upon the halogen atoms to / 25 be present in the final product. k In order to prepare the difluoro compound of our in vention several routes are available. Starting with a o-\/\/ AC-pregnene such as 1,4,9011) - pregnatriene - 170,21 and the 1,2-dihydro analogs thereof, wherein R is a mem diol-3,20-dione 21-acetate and subjecting same to the ber of the group consisting of H, OH, and O-acyl, the acyl 30 action of a Suitable fluorinating agent there is obtained function being an acid radical of the group consisting of the 90,11.f3-difluoro analog. We have found agents such lower alkanoic acids having up to eight carbon atoms, as lead tetrafluoride, lead dioxide in conjunction with hy dibasic organic acids having up to eight carbon atoms, and drogen fluoride, iodosobenzene diacetate in conjunction phosphate; Z is a member of the group consisting of H, with hydrogen fluoride to be useful in effecting the trans OH and O-acyl, X and Y are halogen pairs of the group formation. Other fluorinating agents such as antimony consisting of (F, F), (F, Cl), (F, Br) and (Cl, Br) re pentafluoride, iodine heptafluoride, and bromine trifluo spectively, and the 2a-methyl, 6a-methyl, 16-lower alkyl ride also are useful. (c. or (3) analogs thereof. The reaction is usually carried out in an inert solvent Illustrative of the 21-esters falling within the foregoing at reduced temperatures, generally at -20° to -30° C. are lower alkanoates such as acetate, propionate, t-butyi 40 Representative of inert reactions solvents are chloroform, acetate, cyclopentyl propionate, and the like. Other esters methylene chloride, and tetrahydrofuran and the like. are prepared from dibasic organic acids such as succinate, Thus by our preferred method, 1,49(11)-pregnatriene phthalate, sulfobenzoate and the like. Representative of 170,21-diol-3,20-dicine 21-acetate is reacted with lead tet the 17-esters are acetate, propionate, caproate and the like. rafluoride in chloroform at -30° C. and there is ulti Curnovel compounds having the 1,4-pregnadiene-17,21 45 mately obtained 9a, 11g-difluoro-1,4-pregnadiene-17a,21 diol system are glucocorticoids useful in the treatment of diol-3,20-dione 21-acetate. inflammatory conditions. They are especially useful in Alternatively, the two halogen atoms may be introduced topical formulations such as creams or ointments. The in a sequence of two distinct reactions rather than through corresponding 1,2-dihydro analogs also exhibit these prop a simultaneous introduction. While this method is par erties but to a lesser extent and are more valuable as inter ticularly valuable for diheterohalogenation such as in pre mediates. paring a 9oz-fluoro-11p-chloropregnene, it is equally appli Those compounds of our invention which are devoid of cable to homohalogenation such as in preparing a 9a–116 oxygen at C-21 are active progestational agents which are difluoropregnene. By this route, a 96,11(3-oxidopregnene specific in their action and from which is absent andro is treated with hydrohalic acid and there is obtained the genic, estrogenic or corticoid activity. They are accord corresponding 9 cy-halo-11p-hydroxy compound. The halo ingly useful for conditions requiring progestational agents hydrin is subjected to one of several reaction sequences such as functional dysmenorrhea, premenstrual tension, described below whereby the 11,3-hydroxy function is re habitual or threatened abortion, and the maintenance of placed by the desired 11 (3-halogen group. pregnancy. In the direct replacement of an esterified 11-hydroxy Our novel compounds are essentially devoid of systemic 60 group an inversion of the configuration at C-11 appar mineralo effects such as salt retention. Thus our novel ently occurs. Thus, in order to obtain an 116-halogen via compounds, containing a 9a-fluoro group or 9a-chloro this route, it is necessary to start with an 11oz-hydroxy group-heretofore believed to be potent salt retention function. Starting with a 9oz-halogeno-1 16-hydroxy com factors are singularly devoid of such action and accord pound prepared as described above, the desired 9oz-halo ingly lend themselves to use in the conditions described geno-11&-hydroxy compound is obtained by oxidation to 3,049,554 3 4. the 11-keto function, as for example with chromic acid, Alternatively, the halogen at C-11 may be introduced followed by stereospecific reduction. The stereospecific through treatment of a 9oz-fluoro-11oz-amino-pregnane with reduction to the ox-configuration is preferably effected with a nitrosyl halide or of 9oz-fluoro-116-amino-pregnane with Sodium amalgam in alcohol and there is thus formed the an alkyl nitrite followed by a hydrohalic acid. The req 90-fluoro-110-hydroxy compound. Other reducing agents uisite 9c.-fluoro-11 (c. and (3)-amino-pregnanes are pre Such as lead-sodium alloys are also useful. pared for example as follows: To prevent reduction by the sodium amalgam and al Treatment of 9oz-fluorocortisone with formaldehyde as cohol of ketonic functions other than that at C-11, the described above yields 9oz-fluoro-17 (20),20C21)-bis 3- and 20-keto groups of a 3,11,20-triketonic pregnene are methylenedioxy-4-pregnene-3,11-dione which upon cata preferably protected prior to reduction. The C-3-keto O lytic reduction first with hydrogen and palladium catalyst group is preferably protected by reacting with ethylene in pyridine followed secondly with hydrogen and platinum glycol in the presence of acid catalyst to form the 3-ethyl catalyst affords 9oz-fluoro-17 (20).20(21)-bismethylenedi eneketal. In those compounds where the 17a,21-dihy oxypregnane-3-ol-11-one. This pregnanolone when treat droxy-20-keto corticoid side chain is present, treatment ed according ot the process analogous to that described in with formaldehyde in the presence of a strong acid, results 15 the copending application of Oliveto and Rausser, Serial in formation of the 17 (20),20C21)-bismethylenedioxy No. 657,030, is converted to the 11-oxime and the oxime function. In those compounds possessing only the 20 is then catalytically reduced to the two amino stereoiso keto or 17a-hydroxy-20-keto side chain, the 20-keto group mers, 9oz-fluoro-11c -amino-17a (20),20C21)-bismethylene is protected by formation of a 20-ethyleneketal concur dioxypregnane-3-ol and 9oz-fluoro-11p-amino-17 oz (20),20 rently to the formation of the 3-ethyleneketal. There is 20 (21)-bismethylenedioxypregnane-3-ol. These two epi thus obtained as a result a 3,20-bisethyleneketal. mers are separated by chromatography. Thus, 9oz-fluoro - 4 - pregnene-17a,21-diol-3,11,20-tri The 9oz-fluoro - 11c - aminopregnane is then treated one upon treatment with formaldehyde in the presence of with an appropriate nitrosyl halide, for example, nitrosyl p-toluenesulfonic, sulfuric, or hydrochloric acid yields 9a chloride, whereupon there is obtained 9oz-fluoro-11g fluoro-17 (20).20(21)-bismethylenedioxy - 4 - pregnene 25 chloro-17 c. (20).20(21)-bismethylenedioxypregnane - 21 3,11-dione. Further, treatment with ethylene glycol in ol. The identical compound is obtained by treatment of the presence of acid catalysts similar to those described the 116-amino epimer with an alkyl nitrite, such as ethyl above then yields 9 cy-fluoro-17 (20),20021)-bismethylene nitrite and hydrogen chloride. In both reactions a small dioxy-5-pregnene-11-one-3-ethyleneketal. amount of the 9a-fluoro-11c-chloropregnane is formed Similarly, 9oz-fluoro - 4 - pregnene-3,11,20-trione is 30 and is easily separated by chromatography. treated with an axcess of ethylene glycol in the presence While the foregoing describes the introduction of chlo of an acid catalyst and there is obtained 9a-fluoro-5-preg rine at the 116-position, the fluoro and bromo analogs are nene-11-one-3,20-bisethyleneketal. similarly prepared by employing nitrosyl fluoride or nitro After reduction of the 11-keto function to 11c-hydroxyl syl bromide respectively. Similarly, the 116-aminofunc as above described, the protective groups are cleaved by tion may be replaced by the 11g-fluoro group through use heating the compound in aqueous formic acid or acetic of an alkyl nitrite and hydrogen fluoride. acid for periods of from 4 to 3 hours. The 90,116-dihalogeno - 17 (20),20021) - bismethylene Since the 3-ethyleneketal formation apparently does dioxypregnane-3-ol thus obtained is submitted to chromic not occur with 1,4-dienes, introduction of the 1,4-diene anhydride oxidation to form the corresponding 3-keto system when desired is preferably executed after reduc 40 derivative and converted to the corresponding 4-pregnene tion of the 11-keto group and cleavage of the protective and/or 14-pregnadiene by any of several methods well groups and prior to the introduction of the halogen at known in steroid chemistry. For example, bromination C-11. The dehydrogenation is performed by any of the with one mole of bromine yields the 4-bromo analog methods well known to the art of steroid chemistry. Thus, which upon debromination with lithium chloride in di for example, 9oz-fluoro-4-pregnene-11a, 17 c.21-triol-3,20 5 methylformamide yields the 3-keto-4-pregnene. By sub dione is subjected to the action of the microorganism jecting this compound to the action of a microorganism Corynebacterium simplex according to the procedure an such as Corynebacterium simplex there is obtained the alogous to that of U.S. Patent 2,837,464 and there is ob corresponding 3-keto-1,4-pregnadiene. tained 9oz-fluoro-1,4-pregnadiene-11a, 17 oz,21-triol-3,20-di The protective bismethylenedioxy function is removed 50 by treatment with aqueous acid as heretofore described. Oc.We prefer to esterify the 11oz-hydroxy function prior to For example, treatment of the compound described above replacement by halogen and preferably employ the p with 60% formic acid, yields 9oz-fluoro-116-chloro-1,4- toluenesulfonate and methylsulfonate esters. A com pregnadiene-17o,21-diol-3,20-dione. pound containing a free hydroxy group at C-21 in addi It is apparent from the above that there exists a num tion to one at C-11, is preferably selectively esterified at 5 5 ber of different ways in which our compounds may be C-21 by conventional methods to prevent tosylation at prepared. For example, a 9o, 11,3-difluoro compound this point. Thus, treatment of 9oz-fluoro-1,4-pregnadiene may be prepared by utilizing such starting materials and 11a, 17,21-triol-3,20-dione with one equivalent of acetic reagents as (1) a A9(1)-steroid and lead tetrafluoride, anhydride in pyridine yields the 21-monoacetate. Further (2) a A9011)-steroid and iodosobenzene diacetate and hy treatment with p-toluenesulfonyl chloride then yields the 60 drogen fluoride, (3) a 9oz-fluoro-11a-hydroxy steroid (as corresponding 11a-p-toluenesulfonate. Replacement by the 11-mesylate or 11-tosylate) and lithium fluoride in halogen is effected by reacting the tosylate with a Suitable dimethylsulfoxide, (4) a 9a-fluoro-11a-amino-pregnene source of halide ion in an inert solvent. For example, and nitrosy fluoride, or (5) a 9oz-fluoro-116-aminopreg nene and ethyl nitrite and hydrogen fluoride. upon treatment of the 110-p-tosylate with lithium chloride If not protected by other means, the reactive hydroxy in dimethylsulfoxide or dimethylformamide there is ob 65 group at C-21 is preferably protected prior to the halo tained 9x-fluoro-11p-chloro-1,4-pregnadiene-170,21-diol genation by esterification, as for example, as the acetate. 3,20-dioneIn a similar 21-acetate. manner starting with the 11c-p-tosylate of Thus, for example, 4,9(11)-pregnadiene-17 oz,21-diol-3,20 a 9oz-chloro-11oz-hydroxy compound and treating same dione is treated with acetic anhydride to form the 21 with lithium bromide in dimethylsulfoxide there is ob 70 acetate which is then fluorinated with lead dioxide and hy tained the corresponding 9a-chloro-116-bromo compound. drogen fluoride to yield 9oz,11.f3-difluoro-4-pregnene-17c, There is obtained in this manner from 9o-chloro-1,4- 21-diol-3,20-dione 21-acetate. pregnadiene-11a, 17a,21-triol - 3,20 - dione-11p-toluene The 90,116-dihalogeno-21-esters resulting from the sulfonate 21-acetate, the compound 9o-chloro-11 f-bromo processes outlined above are conveniently saponified to 14-pregnadiene-17o,21-diol-3,20-dione 21-acetate. 75 the corresponding alcohols either chemically by the use st 3 6 of dilute acid or base or microbiologically. Alternatively, 11 c,17a,21-triol-3,20-dione-11 ce-p-tosylate 21-acetate in 40 a dihalogeno free alcohol prepared by our process is con ml. of dimethylsulfoxide is added 3.0 g of lithium bro verted to an ester by the usual methods. mide. The reaction mixture is stirred at 90 for 15 hours The following examples are illustrative of the proce and then poured into ice-water. The solid material is dures employed in preparing the compounds of this in collected by filtration, washed well with water, dried, dis vention but are not to be construed as limiting the scope Solved in acetone and crystallized by addition of hexane thereof, the scope of our invention being limited only by to yield the product of this example, 9oz-fluoro-11 (3-bromo the appended claims. 4-pregnene-i7c.,21-diol-3,20-dione 21-acetate. EXAMPLE 1. 10 EXAMPLE 2 9oz-Fluoro-11p-Brono-4-Fregnene-17a,21-iDiol-3,20 9o-Fluoro-1 IB-Brono-1,4-Pregnadiene-17a,21-Diol Dione 21-Acetate 3,20-Dione 21-Acetate A. To a solution of 1.2g. of 9a-fluoro-4-pregnene-17C, 21-diol-3,11,20-trione in 48 ml. cf chioroform is added 9o-fluoro-4-pregnene-17 oz,21-diol-3,11,20-trione is treat 12 mi. of 37% aqueous formaldehyde and 12 mi. of coin 5 ed as described in Examples 1A and iB. The compound centrated hydrochloric acid. The mixture is stirred with thus obtained, 9cz-fluoro-4-pregnene-11 c. 17 c.21-triol-3,20 rapid agitation for 48 hours and at the end of this tirne dicine is dehydrogenated by subjecting it to the action of the solution is extracted with chloroform aid the ex the microorganism Corynebacteriuin simplex according tracts washed with water. After drying over nagesilin to the procedure of U.S. Patent 2,837,464. There is thus sulfate, the chloroform solution is evaporated to a residue 20 obtained as a crystalline solid, 9oz-fluoro-1,4-pregnadiene and upon recrystallization of the residue from acetolie 11a, 17c,24-triol-3,20-dione. hexane, there is obtained 9oz-fluoro-17 (20).20 (21)-bis This compound is then reacted according to the proce methylenedioxy-4-pregnene-3,11-dione M.P. 290-295 C. dures of Examples 1C, 1 D and 1E. There is thus ob Four hundred milligrams of the bisimethyienedioxy tained the compound of this example, 9oz-fluoro-16-bro compound so obtained is dissolved in 40 ml. of benzene no-1,4-pregnadiene-170,21-diol-3,20-diene 21-acetate. and to the solution is added 1.6 mi. of ethylene giycol and EXAMPLE 3 40 mg. of p-toluenesulfonic acid. The mixture is refluxed for 24 hours and at the end of this time allowed to attain 9a-Fluoro-1 Ig-Chloro-4-Pregnene-17a,21-Diol-3,20 room temperature. The solution is then extracted with Dione 21-Acetate chloroform and chloroform extracts washed with water. 30 By substituting lithium chloride for lithium bromide in The solution is then dried over magnesium Suifate and part E of Example 1 and treating 9a-fluoro-4-pregnene the solvent removed by evaporation in vacuo. Recrystal 11 c,170,21-triol-3,20-dione-11 Cz-p-tosylate 21-acetate as lization of the residue from acetone-hexane then yields therein described, there is obtained the compound of this the compound of this example, 9a-fluoro-17 (20).20(2i)- example, 9oz-fluoro-11p-chloro-4-pregnene-17c.,21-diol-3, bismethylenedioxy-5-pregnene-11-one-3-ethyleneketal. 35 20-dione 21-acetate. B. A solution of 1 g of 9oz-fluoro-17 (20).20(21)-bis EXAMPLE 4 methylenedioxy-5-pregnene-11-one-3-ethyleneketal is dis 9a-Fluoro-11ps-Chloro-1,4-Pregnadiene-17o,21-Dioi-3, solved in 20 ml. of 95% ethanol and 20 ml. of tetra hydrofuran. The solution is cooled to -20° C. and to 20-Dione 21-Acetate it is added in several small portions 11.4g. of 3% sodium 40 The procedure as described in Example 2 for 9a-fluoro amalgam. At the end of the reaction as indicated by the 11g-bromo-1,4-pregnadiene-17 oz,21-diol-3,20-dione 21-ace cessation of gas evolution, the residual metal is removed tate is followed to prepare the compound of this exampie by filtration and to the filtrate is added 20 mi. of water. with the exception of lithium chloride being substituted The solid material which is thus formed is collected by for lithium bromide in step E of Example 1. There is filtration and washed well with water. The crude prod thus obtained 9o-fluoro-11p-chloro-1,4-pregnadiene-17 oz, uct, consisting essentially of 9a-fiuoro-17 (20).20 (21)-bis 45 21-diol-3,20-dione 21-acetate. methylenedioxy-5-pregnene-11 cc-ol-3-ethyleneketal is heat EXAMPLE 5 ed on a steam bath with 20 ml. of 60% formic acid for 1% hours. At the end of this time, the solution is cooled 9a-Chloro-1 18-Bromo-4-Pregnene-17c.,21-Dioi-320 and water is added to precipitate a solid. The solid is Dione 21-Acetate collected by filtration, and recrystallized from acetone A. One gram of 9a-chloro-4-pregnene-11f8,17a,21-triol hexane to yield 9a-fluoro-4-pregnene-11c., i7 c.21-triol-3, 3,20-dione 21-acetate is treated with 1. g. of chromium tri 20-dione. oxide in 15 ml. of acetic acid and 3 ml. of water at 20° C. C. One gram of 9a-fluoro-4-pregnene-1-10,17a,21-triol for 3 hours. Upon diluting the reaction mixture with 3,20-dione is dissolved in 20 ml. of pyridine and to the 5 5 200 ml. of water and filtering the solid thereby formed, solution is added 0.28 g. of acetic anhydride. The Solu there is obtained 9oz-chloro-4-pregnene-170,21-diol-3, 11, tion is allowed to stand at 0° C. for three hours and then 20-trione 21-acetate. poured into ice and hydrochloric acid. A solid precipi B. This compound is then subjected to the reaction tates and is collected by filtration, then crystallized from Sequence described in Example 1. There is thus obtained aqueous methanol to yield 9a-fluoro-4-pregnene-1 10,170, 60 9oz - chloro - 11g - bromo - 4 - pregnene-17cc,21-diol-3,20 21-triol-3,20-dione 21-acetate. dione 21-acetate. D. One gram of 9a-fluoro-4-pregnene-1 10,170,21-triol EXAMPLE 6 3,20-dione 21-acetate is dissolved in 4 ml. of chloroform 9oz-Chloro-1 16-Brono-1,4-Pregnadiene-17c.,21-Diol-3, and 5 ml. of dry pyridine and the solution chilled in ice. 20-Dione 21-Acetate To the chilled solution is added 1.2 g of p-toluenesuifonyl 65 chloride in small portions and the reaction mixture stirred The intermediate prepared in Example 5A, 9oz-chloro-4- for 90 minutes, and then allowed to stand at room ten pregnene-170,21-diol-3,11,20-trione 21-acetate, is sub perature for 20 hours. At the end of this time the mix jected to the procedure of Exampie 2. There is thus ob ture is poured with rapid stirring into ice-water and then tained the compound of this example, 9a-chloro-1 16-bro extracted with chloroform. The chloroform extracts are 70 mo-1,4-pregnadiene-170,21-diol-3,20-dione 21-acetate. washed with water, dried and then concentrated to a residue under reduced pressure. The residue is then crys EXAMPLE 7 talized from acetone-hexane to yield 9.cx-fluoro-4-preg 9o,II (3-Difluoro-1,4-pregnadiene-17c.,21-Dioi-320 nene-11oz. 17 c.21-triol-3,20-dione-11 ce-p-tosylate 21-acetate. Dione 21-Acetate E. To a solution of 500 mg. of 9ck-fitcro-4-pregnene A. To a solution of 1.0 g. of 14,9(11)-pregnatriene 3,049,554 7 3 17a,21-diol-3,20-dione 21-acetate in 40 ml. of chloro there is added 1 ml. of methanesulfonyl chloride in 20 form, chilled to -30° C. in a Dry Ice-acetone bath, is ml. of pyridine and 20 ml. of dimethylformamide. The added with stirring 750 mg. of lead tetrafluoride. The solution is heated for one hour at 60-80 C., allowed mixture is stirred in the cold for 18 hours, then filtered. to cool, then poured into ice-hydrochloric acid. The The filtrate is evaporated to a residue and the residue solid which precipitates is filtered, washed with water chromatographed on magnesium silicate. The material and then recrystallized from acetone to give 160-methyl eluted with 60% ether-in-hexane to 100% ether is com 1,4,9(11)-pregnatriene-17a,21-diol-3,20-dione 21-acetate. bined and crystallized from acetone-hexane. There is This compound is then treated with lead tetrafluoride thus obtained the compound of this example, 90,116-di in the manner of Example 7A and there is obtained upon fluoro-1,4-pregnadiene-17 oz,21-diol-3,20-dione 21-acetate. 0 purification as therein described 9a,116-difluoro-16a-meth B. Alternatively, a solution of 1.0 g. of 1,49(11)-preg yl-1,4-pregnadiene-17 oz,21-diol-3,20-dione 21-acetate. natriene-17 oz,21-diol-3,20-dione 21-acetate in a mixture of EXAMPLE 12 20 ml. of tetrahydrofuran and 30 ml. of chloroform, con taining 630 mg. offinely powdered lead dioxide, is chilled 9o,IIB-Difluoro-163-Methyl-1,4-Pregnadiene-176,21 to -20° C. There is then added dropwise with vigorous 5 Diol-3,20-Dione 21-Acetate stirring a solution of 680 mg. of hydrogen fluoride in 5 The requisite intermediate, 166-methyl-1,4-pregnadiene ml. of chloroform-tetrahydrofuran. The mixture is 116,17a,21-triol-3,20-dione 21-acetate is treated accord stirred in the cold for five hours, then diluted with water ing to the reaction sequence of Example 11 and there is and rendered basic by addition of sodium carbonate and thus obtained 9a,11f8-difluoro-166-methyl-1,4-pregnadi stirring for 15 minutes. The organic layer is separated, 20 ene-176,21-diol-3,20-dione 21-acetate. evaporated to a residue and purified by chromatography EXAMPLE 13 as described in Example 7A. C. Alternatively a solution of 850 mg. of iodosoben 9a-Fluoro-11p-Chloro-1,4-Pregnadiene-176,21-Diol zene diacetate in 40 ml. of methylene chloride is chilled 3,20-Dione to -20° C. and added to 1.0 g. of 1,4,9(11)-pregnatriene A solution of 9a-fluoro-116-chloro-1,4-pregnadiene-17a, 17 oz,21-diol-3,20-dione 21-acetate in 20 ml. of methylene 21-diol-3,20-dione 21-acetate (the compound of Example chloride. Gaseous hydrogen fluoride is bubbled into the 4) in 50 ml. of 3:1 methanol-chloroform mixture is stirred solution for five minutes. The reaction mixture chilled in ice and to it is added 60 ml. of 0.1 N sodium is stirred at -20° C. to -15° C. for 6 hours, then poured hydroxide solution. The mixture is stirred at 0° C. for into aqueous sodium carbonate with vigorous stirring. 30 10 minutes, then diluted with water and extracted with The organic layer is separated and evaporated and purified methylene chloride. Evaporation of the solvent and by chromatography as described in Example 7A. recrystallization of the residue from acetone-hexane af D. Alternatively, by following the procedure of Ex fords the product of this example, 9oz-fluoro-11p-chloro ample 2 and substituting lithium fluoride for lithium 1,4-pregnadiene-17o,21-diol-3,20-dione. bromide, there is obtained the compound of this example. In a similar fashion the other 21-acetates prepared above may be saponified to the free 21-hydroxyl com EXAMPLE 8 pounds. Thus by following the procedure described in 9a,116-Difluoro-4-Pregnene-17a,21-Dioi-3,20 this example, there is prepared from the compounds pre Dione 2I Acetate pared above: By substituting 4,9(11)-pregnadiene-17a,21-diol-3,20 40 dione 21-acetate in any of the procedures, Examples 7A, 9o-fluoro-11p-bromo-4-pregnene-17a,21-diol-3,20-dione; 7B, or 7C, there is obtained the compound of this ex 9a-fluoro-11p-bromo-1,4-pregnadiene-17,21-diol-3,20 ample, 90,116-difluoro - 4 - pregnene-17o,21-diol-3,20 9cv-fluoro-11p-chloro-4-pregnene-17a,21-diol-3,20-dione;dione; dione 21-acetate. Alternatively, by substituting lithium fluoride for lithi 90-chloro-11p-bromo-4-pregnene-17a,21-diol-3,20-dione; um bromide in part E of Example 1, there is obtained 9o-chloro-11p-bromo-1,4-pregnadiene-17,21-diol-320 the compound of this example. 9o,dione; 11.f3-difluoro-1,4-pregnadiene-17a,21-diol-3,20-dione; EXAMPLE 9 90,11,3-difluoro-4-pregnene-17a,21-diol-3,20-dione; 6oz-Methyl-9a, IIS-Difluoro-1,4-Pregnadiene-17a,21 60-methyl-9o,11g-difluoro-1,4-pregnadiene-17,21-diol Diol-320-Dione 21-Acetate 20-methyl-90,116-difluoro-4-pregnene-17,21-diol-3,203,20-dione; 6a-methyl-1,4-9(11)-pregnatriene - 17a,21 - diol-3,20 dione; dione 21-acetate is reacted with lead tetrafluoride accord 9o,116-difluoro-160-methyl-1,4-pregnadiene-17,21-diol ing to Example 7A. There is thus obtained the com 3,20-dione; pound of this example, 6a-methyl-9a,116-difluoro-1,4- 55 9a, 11,3-difluoro-166-methyl-1,4-pregnadiene-17,21-diol pregnadiene-17o,21-diol-3,20-dione 21-acetate. 3,20-dione. Alternatively, the fluorinating procedures of Examples 7B or 7C may be used to prepare the compound of this EXAMPLE 1.4 example. 60 9o-Fluoro-11p-Chloro-1,4-Pregnadiene-17-ol-320-Dione EXAMPLE 10 A solution of 12g of 9a-fluoro-11p-chloro-1,4-pregna 2ox-Methyl-90,11f8-Difluoro-4-Pregnene-17,21 diene-17o,21-diol-3,20-dione (prepared in Example 13) Diol-3,20-Dione 21-Acetate in 100 ml of dry pyridine is chilled in a Dry Ice-acetone 2a-methyl-4,9011)-pregnadiene - 17a,21 - diol-3,20-di bath and there is added a solution of 6 g of p-toluene one 21-acetate is subjected to the action of lead tetrafluo 65 Sulfonyl chloride in 50 ml. of methylene chloride. The ride according to the procedure of Example 7A and there mixture is stirred in the cold bath for 2 hours and then is thus obtained the compound of this example 20-methyl kept at -20° C. for 24 hours. At the end of this time, 90,116-difluoro-4-pregnene-17o,21-diol-3,20-dione 21-ace the reaction mixture is diluted with methylene chloride ?tate. and the solution washed first with water, then with 10% EXAMPLE 1. sulfuric acid, 10% sodium bicarbonate, very dilute hydro chloric acid and finally with water. The solution is dried 9o, IlB-Difluoro-lócz-Methyl-1,4-Pregnadiene-17021 Over magnesium sulfate, filtered and concentrated to a Diol-3,20-Dione 21 Acetate residue which is dissolved in acetone. The acetone solu To a solution of 3 g. of 16oz-methyl-1,4-pregnadiene tion is warmed on the steam bath, decolorizing carbon 11.f3,17a,21-triol-3,20-dione 21-acetate in 20 ml. of pyridine 5 added, and the solution filtered. To the clarified solution 3,049,554 there is added a warm solution of 10 g. of sodium iodide 10 in acetone. After heating this mixture on the steam bath resulting precipitate is filtered, washed with water and for five minutes, three milliliters of acetic acid are added, crystallized1,4-pregnadiene-17a,21-diol-3,20-dione from acetone-hexane to give 21-propionate. 9oz-1 16-difluoro and the mixture is warmed before adding aqueous sodium Similarly other 21-lower alkanoyl esters may be pre bisulfite. The solution is poured into water and the re 5 pared by reacting the appropriate lower alkanoic acid an Sulting precipitate filtered and washed with water. Re hydride with the free 21-hydroxy compound, as for exam crystallization of the solid from acetone-ether yields 9oz ple, 9oz - chloro-11p-bromo-1,4-pregnadiene-17a,21-diol-3, fluoro-116-chloro-1,4-pregnadiene-17a-ol-3,20-dione. 20-dione 21-butyrate. EXAMPLE 1.5 EXAMPLE 2.0 9oz,11B-Difluoro-1,4-Pregnadiene-17-ol-3,20-Dione 0. 9oz,116-Difluoro-1,4-Pregnadiene-17a,21-Diol-3,20 1,49(11)-pregnatriene-17a-ol-3,20-dione is fluorinated Dione 21-i-Butylacetate with lead tetrafluoride according to the procedure as de 9c,116 - difluoro - 1,4-pregnadiene-17a,21-diol-3,20-di scribed in Example 7A. There is thus obtained 9oz,116 one (5 g.), (prepared as in Example 13) is dissolved in difluoro-1,4-pregnadiene-17a-ol-320-dione. 5 100 ml. of pyridine, the solution is cooled to below 10° C., Similarly the compound of this example is prepared and tertiary butylacetylchloride (1.5 g.) added. The pregnatriene-17a-ol-3,20-dione.according to the procedures of 7B or 7C from 14,9(11)- mixture is stirred at room temperature for 16 hours, then Alternatively, 9 cc, 11 3-difluoro-1,4-pregnadiene-17 c.21 poured into cold, dilute, sulfuric acid. The precipitate diol-3,20-dione (prepared in Example 13) is subjected to which forms is filtered, washed with water, and crystal the reaction sequence of Example 14 and there is obtained 20 lized from acetone to give 90,11(3-difluoro-1,4-pregnadiene the compound of this example. 170,21-diol-3,20-dione 21-t-butylacetate. EXAMPLE 16 EXAMPLE 21 9oz,118-Difluoro-1,4-Pregnadiene-3,20-Dione 25 9-Fluoro-1 16-Chloro-1,4-Pregnadiene-17a,21-Diol-3,20 14,9(11)-pregnatriene-3,20-dione is treated with lead Dione 21-Hennisuccinate tetrafluoride according to the procedure of Example 7A. 9c. - fluoro-11p-chloro-1,4-pregnadiene-17o,21-diol-3,20 There is thus obtained the compound of this example, 9a, dione (5 g), (prepared as in Example 14) is dissolved in 116-difiuoro-1,4-pregnadiene-3,20-dione. pyridine (100 mi.) and succinic anhydride (5 g.) added. The fluorination is also effected by the alternate pro 30 The reaction mixture is stirred 20 hours at room tempera cedures described in Examples 7B and 7C. ture, then is diluted with ice-water and acidified with cold, dilute sulfuric acid. The precipitate which forms is fil EXAMPLE 17 tered, washed with water, dried, and crystallized with 9oz-Fluoro-11p-Chloro-4-Pregnene-3,20-Dione acetone-water to yield 9oz-fluoro-116-chloro-1,4-pregna A. Three grams of 9a-fluoro-4-pregnene-3,11,20-trione 35 dione-17 oz,21-diol-3,20-dione 21-hemisuccinate. in 100 ml. of dry benzene and 40 ml. of ethylene glycol are refluxed for 22 hours in a Dean-Stark separator in EXAMPLE 22 the presence of 50 mg. of p-toluenesulfonic acid. After 9,119-Difluoro-1,4-Pregnadiene-170,21-Diol-3,20-Dione addition of 60 mg. of sodium hydroxide in 2 ml. of metha 40 21-Phosphate nol, the reaction mixture is diluted with water and the To a solution of 1 gram of 1,4-pregnadiene-11.f3,170,21 organic layer separated. The benzene layer is then triol-3,20-dione 21-phosphate in 40 ml. of glacial acetic washed with 5% aqueous sodium bicarbonate and then acid there is added, under an atmosphere of nitrogen, 8 water and concentrated in vacuo to a residue which is ml. of 5.5 N-anhydrous hydrogen bromide in glacial acetic crystallized from benzene-hexane to yield 9a-fluoro-5- 45 acid. The solution is allowed to stand at room tempera pregnene-11-one-3,20-bisethyleneketal. ture for twenty minutes and then is evaporated in vacuo B. The compound prepared in part A of this example to a residue substantially of 14,9C11)-pregnatriene-17 oz, is treated according to the procedure of Example 1B and 21-diol-3,20-dione 21-phosphate. This residue is then the product so obtained treated according to the proced treated with lead dioxide and hydrogen fluoride in the ure of Example 1D to yield 9oz-fluoro-4-pregnene-11o-ol 50 3,20-dione-21-p-tosylate. manner of Example 7B. There is thus obtained the com C. The compound thus prepared in Example 17B is pound of this example 90,116-difluoro-1,4-pregnadiene treated in the manner of Example 1E with the exception 17 oz,21-diol-3,20-dione 21-phosphate. that lithium chloride is substituted for lithium bromide. EXAMPLE 23 There is thus obtained the compound of this example, 90 55 9,1IB - Difluoro - 14 - Pregnadiene - 17a - Ol - 3.20 - fluoro-1 16-chloro-4-pregnene-3,20-dione. Dione-17-Acetate EXAMPLE 18 A solution of 1. g. of 90,116-difluoro-1,4-pregnadiene 6a-Methyl-9a, 11B-Difluoro-1,4-Pregnadiene-17a-ol-3,20 17-ol-3,20-dione (prepared as in Example 15) is dis Dione 60 solved in 10 ml. of glacial acetic acid and 2 ml. of tri fluoroacetic anhydride. The solution is left at room tem 6 - methyl - 9a,116-difluoro-1,4-pregnadiene-170,21 perature for 24 hours then poured into ice-Water. A diol-3,20-dione (prepared in Example 13) is subjected to solid separates which is filtered, washed with water and the reaction sequence as described in Example 14. There crystallized from acetone hexane to give 9o, 11.f3-difluoro is thus obtained upon purification as therein described 60 65 14-pregnadiene-17a-ol-3,20-dione 17-acetate. methyl-9a,116-difluoro-1,4-pregnadiene-17a-ol-3,20-dione. Similarly other 17-acetates are prepared according to EXAMPLE 19 the above method, as for example, 6cy-methyl-90,116 9,118-Difluoro-1,4-Pregnadiene-17c,21-Diol-3,20-Dione difluoro-1,4-pregnadiene-17a-ol-3,20-dione 17-acetate; 90 21-Propionate fluoro-1 16-chloro-1,4-pregnadiene-17a-ol-3,20-dione 17 70 acetate. To 1.0 g. 9oz,116-difluoro-1,4-pregnadiene-17a,21-diol In an analogous fashion, other esters are obtained by 3,20-dione prepared as in Example 13, there is added 1 substituting the appropriate carboxylic acid for acetic ml. of propionic anhydride in 10 ml. of dry pyridine. acid in the above procedure. There is thus prepared, The reaction mixture is left at room temperature for 3 9,11g-difluoro-1,4-pregnadiene-17 oz-ol - 3.20 - dione 17 hours, then is poured with stirring into ice-water. The 13 butyrate; 9a- fluoro- 116-chloro-1,4-pregnadiene-17a-ol-3, 3,049,554 1. 12 20-dione 17-(6-cyclopentylpropionate); 9a, 116-difluoro 5. 90,116 - difluoro-1,4-pregnadiene - 17a-ol-3,20 1,4-pregnadiene-17a-ol-3,20-dione 17-caproate. dione17-acetate.6.9,iii-difluoro-1,4-pregnadiene - 17a-ol-320 We claim: dione 17-caproate. 1. Compounds selected from the group consisting of 7. The process for preparing 90,116-difluoro-steroids steroids having the formula: 5 of the pregnane series which comprises reacting a A9(11)- pregnene with a member of the group consisting of lead. tetrafluoride, lead dioxide plus hydrogen fluoride, and iodosobenzene diacetate plus hydrogen fluoride; in an () inert organic solvent and isolating the 9a, 116-difluoro product thereby formed. 8. The process for preparing 9o, 116-dihalogeno steroids of the pregnane series wherein said 9oz-halogeno is at least as electronegative as said 116-halogeno, which comprises reacting a 9oz-halogeno-11o-sulfonic acid ester with halide ion in an inert solvent, said 9oz-halogeno hav ing an electronegativity at least as great as said halide IO.9. The process for preparing a 9oz-fluoro-116-chloro and the 1,2-dihydro analogs thereof, wherein B is a mem steroid of the pregnane series which comprises reacting ber of the group consisting of hydrogen and methyl; X a 9oz-fluoro-11oz-tosylate steroid of the pregnane series and Y are halogen pairs of the group consisting of (F, with lithium chloride in an inert polar solvent. F), (F, Cl), (F, Br), and (Cl, Br) respectively; and Z is References Cited in the file of this patent a member of the group consisting of H, OH, and lower alkanoyloxy. 25 UNITED STATES PATENTS 2. 9oz - fluoro - 113 - chloro - 14 - pregnadiene - 17a 2,894,963 Gould et al. ------July 14, 1959 ol - 3,20- dione. OTHER REFERENCES 3. 9oz,11.f3 - difluoro - 14 - pregnadiene - 17a - ol - Oliveto et al.: J. Am. Chem. Soc. 75, 488 (1953). 3,204. -9oz,116-difluoro-1,4-pregnadiene-3,20-dione. dione. 30 Fried et al.: J. Am. Chem. Soc. 75, 2273 (1953).