5- Fluoro steroids

Steroids possessing an epoxide grouping in the side chain have likewise been converted to fluorohydrins. Thus, 20-cyano-17,20-epoxides of structure (19) furnish the 17a-fluoro-20-ketones (20) after treatment of the intermediate cyanohydrins with boiling collidine. The epimeric 5a,6a 20,21-oxides (21) afford the expected bis-fluorohydrins (22). The reaction of the allylic... 

Interesting results are obtained with the 19-hydroxy steroids (12) and (15). 19-Hydroxyandrost-4-ene-3,17-dione (12), when refluxed with the fluoro-... 

Mechanism On the basis of the available evidence a mechanism has been proposed which envisions rapid formation of the intermediate (25), which may undergo an SNj reaction to form fluoro products with inversion of configuration, as is the case with 3a- and 15a-ols. More frequently this substitution reaction is accompanied by decomposition of (25) to the steroidal cation Sf ", which in turn may undergo rearrangement or elimination as discussed above. 

The addition of HF to the 5,6-double bond in 3-hydroxy-A -steroids has been investigated intensively. Bowers et al. prepared the 5oc-fluoro derivative (32) from pregnenolone acetate (31) in 10 % yield using methylene dichloride-THF as solvent at 0°. Pregnenolone itself is converted in 30%... 

The enamines, enol ethers and enol acetates of A -3-keto steroids provide important substrates for fluorination with FCIO3. Reaction of such A -enol ethers and acetates (6) with perchloryl fluoride results in 6a- and 6jff-fluoro-A -3-ketones (7) and (8), the latter representing the more abundant isomer. Tetrahydrofuran or dioxane-water mixtures appear to be particu-... 

In contrast to the wide application that nitrosyi chloride has found in terpene chemistry, nitrosyi fluoride has only recently been discovered. Its first use in steroid chemistry was reported by Boswell who treated cholesterol acetate with nitrosyi fluoride at 0° in methylene dichloride and obtained the 5a-fluoro-6-nitrimine (31) already mentioned in section VI (page 461) in connection with the synthesis of 6,6-difluoro steroids. This... 

A -Steroids react sluggishly with nitrosyl fluoride to yield after alumina chromatography the nitro-olefin (44) (14 %), and 0.7 % of the 2a-fluoro ketone (45), the former probably arising by alumina-catalyzed dehydrofiuorination of an intermediate 2-fluoro-3-nitro adduct. 

The reaction of 9(1 l)-dehydro steroids with nitrosyl fluoride was studied by Grantz and Rosenthal in pursuit of an alternate source for the important 9a-fluoro-11-oxygenated steroids. As expected, reaction at the more hindered 9(1 l)-double bond proceeds more slowly than at either the 4- or 5-double bonds. After 10 days at 3°, 3 -acetoxy-5a-pregn-9(l l)-en-20-one (50) affords a 45% yield of the 9a-fluoro-ll-nitrimine (51). Other 9a-fluoro-ll-nitrimines were prepared and it was found that the presence of additional keto groups, particularly the 3-keto group gives rise to side products with a concomitant reduction in yield of the desired 9a-fluoro-ll-nitrimines. In the case of the A" -3-ketones the yield is reduced to 10 %. The steric hindrance... 

Mechanism The reaction of and A -steroids with nitrosyl fluoride to form ni trimines is best discussed in conjunction with the nitrosyl chloride reaction leading tothe5a-chloro-6 -nitro steroids (33). Since nitroso alkanes are oxidized with nitrosyl chloride to nitro alkanes it is believed that 5a-chloro-6j5-nitro steroids are formed in this way from an initially formed 5a-chloro-6 -nitroso adduct. The same is true for nitrosyl fluoride up to the stage of the nitroso fluoride (56). Since NOF is a weaker oxidizing agent than NOCl the nitroso fluoride tautomerizes to the fluoro oxime (57) at a rate... 

In the course of synthetic efforts aimed at obtaining 6j5-fluoro steroids, Kirk and Petrow treated a 3)5-acetoxy-6-raethyl-5a,6a-epoxide with boron trifluoride etherate and unexpectedly obtained a fluorine-free acetoxy ketone." Later transformations established that the product was the A-homo-B-norsteroid (104). 

The reaLUons of phenyltetrafluorophosphorane with numerous silylated secondary or tertiary a- or (1-hydroxy esters, ketones, nitriles, ethers, nitro, and trichloromethyl derivatives have been investigated, the corresponding a or p fluoro derivatives are obtained in yields varying from reasonable to nearly quantitative [24, 25, 26, 27 The application of phenyltetrafluorophosphorane for fliiorination of silyloxy steroids has also been reported [28]... 

Dehydration to olefins, which sometimes accompanies the reaction of alcohols with DAST [95, 108], is seldom as extensive as with a-fluoroamines (FAR and 1,1,2,3,3,3 hexafluoropropyldiethylamine) but occurs in a few cases to the exclusion of fluonnation, thus, 9a-fluoro-11-hydroxysteroids give 9a fluoro-A -steroids [127, 128] Dehydration accompanied by Wagner-Meerwein rearrangement occurs during the fluonnation of testosterone [129] Intermolecular dehydration to form ethers in addition to fluorides is observed in the reaction of benzhydryl alcohols [104] (Table 6)... 

On the other hand, as a result of participation of a neighboring group, complete or predominant retention of configuration takes place in many reactions of hy-droxylic compounds with DAST A number of examples have been reported in the field of steroids [727, 729], m the conversion of vitamins D into fluoro vitamins D [745], and in the fluormation of liquid crystals [146] (equation 72]... 

The most extensive use of enamine halogenations has, hctwever, been in the attachment of fluorine to the steroid skeleton (499-503). The formation of a ]6-fluoro-17-ketosteroid by the reaction of perchlorofluoride with a 17-enamide has also been reported (504). 

The corresponding 63-fluoro steroid also exhibits potent... 

To approximately 1.3 g of hydrogen fluoride contained in a polyethylene bottle and maintained at -60°C was added 2.3 ml of tetrahydrofuran and then a solution of 500 mg (0.0012 mol) of 6a-fluoro-9/3,11/3-epoxy-16a-methyI-17a,21 -dihydroxy-1,4-pregnadiene-3,20-dione-2T acetate in two ml of methylene chloride. The steroid solution was rinsed in with an additional 1 ml of methylene chloride. The light red colored solution was then kept at approximately -30°C for 1 hour and at -10°C for 2 hours. At the end of this period it was mixed cautiously with an excess of cold sodium bicarbonate solution and the organic materiai extracted with the aid of additional methylene chloride. 

Preparation of A -Pregnadiene-9a-Fluoro-11, 16a,17a,2l-Tetrol-3,20-Dione A solution of 100 mg of A -pregnadiene-9a-fluoro-11, 16a,17a,21-tetrol-3,20-dione 16,21-diacetate was dissolved in 10 ml of methanol and cooled to 0°C. After flushing with nitrogen, a solution of 35 mg of potassium hydroxide in 2 ml of methanol was added to the steroid solution. After standing at room temperature for 1 hour, the solution was neutralized... 

The synthesis of halcinonide is summarized in Figure 1, starting with 16a-hydroxy-9a-fluorohydrocortisone (A1 -pregnene-9a-fluoro-llg,16a,17a,21-tetrol-3,20-dione dihydrotriamcinolone, I), which is available commercially.10-13 This tetrahydroxy steroid is slurried in acetone, and then 70% perchloric acid is added slowly. The acetonide, II (9a-fluoro-llg, 16a, 17, 21-tetrahydroxypregn-4-ene-3, 20-dione, cyclic 16,17-acetal with acetone dihydrotriamcinolone-acetonide) precipitates spontaneously from solution. Mesyl chloride is added to the acetonide in pyridine to give the 21-mesylate derivative (dihydrotriamcinolone acetonide-21-mesylate, III). Compound III is dissolved in dimethylformamide, lithium chloride is added and the mixture is refluxed to produce halcinonide (IV), which is recrystallized from a solution of ft-propanol in water. 

The main radiopharmaceuticals labelled with fluorine-18, routinely prepared ([2-i F] fluorodeoxyglucose [ F]FDG [26-28], [i F]fluoro-L-DOPA [29], [i F]altanserin [30, 31], [ F]setoperone [32]) are presented with their uses in Table 2. For comparison, the most common tracers labelled with carbon-11 (methionine [33], palmitic acid [34], flumazenil (RO 15.1788) [35], PK 11195 [36], raclopride [37], deprenyl [38], Way-100635 [39], McN-5652Z [40], CGP 12177 [41]) are shown in Table 3. By far, [ F]FDG is the most widely studied, particularly in oncology for the diagnosis of tumours, detection of sub-clinical diseases, assessment of therapy responses, and detection of recurrence. F-Steroids [42], F-proteins or peptides, or F-labelled tissue specific agents have also been synthesized for the detection and monitoring of various malignancies [43]. 

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