United States Patent (19) 11) Patent Number: 4,522,758 Ward Et Al

United States Patent (19) 11) Patent Number: 4,522,758 Ward et al. 45) Date of Patent: Jun. 11, 1985 (54) METHOD OF PREPARING Palmer et al., J. Labelled Compas., 16, 14 (1979). 2-FLUORO-176-ESTRADIOL Eakins et al., Int. J. App. Rad, & Iso., 30, 695 (1979). 75) Inventors: John S. Ward; C. David Jones, both Heiman et al., J. Med. Chem., 23,994 (1980). of Indianapolis, Ind. Goswami et al., id., 1002. Ng et al., J. Org. Chem., 46, 2520 (1981). 73 Assignee: Eli Lilly and Company, Indianapolis, Santaniello, J.C.S. Chem. Comm., 217, 1157 (1981). Ind. Njar et al., J. Org. Chem, 48, 1007 (1983). 21) Appl. No.: 564,595 Rozen et al., J.C.S. Chem. Comm., 443 (1981). Shiue, J. Nucl. Med., 23, 899 (1982). 22 Filed: Dec. 22, 1983 Mantescu et al., Radiopharm. & Labelled Compas, 395 51) Int. Cl. ................................................ CO7J 1/00 (1973). 52 U.S.C. .................................................. 260/.397.5 Primary Examiner-Elbert L. Roberts 58) Field of Search ...................................... 260/.397.5 Attorney, Agent, or Firm-James L. Rowe, Arthur R. 56) References Cited Whale PUBLICATIONS 57 ABSTRACT J.C.S. Chem. Comm. (1981) 217, p. 1157, article by 2-Fluoro-17E-estradiol is synthesized by mercurating a Santaniello. 1713-estradiol diacylate or dietherate at C-2, replacing Liehr, Molecular Pharmacology, 23, 278 (1983). the mercury group with fluorine and then cleaving the Utne et al., J. Org. Chem. 33, 2469 (1968). acyl or ether protecting groups. Neeman et al., J. Chem. Soc. (Perkin Trans. 1) 2300 (1972). 7 Claims, No Drawings 4,522,758 1. 2 hexestrol (a phenolic estrogen), ortho to the phenol METHOD OF PREPARING group, during which process an amine group is con 2-FLUORO-17B-ESTRADIOL verted to an arylazide and the azide decomposed in the presence of HF. In this last step, fluorine replaces the BACKGROUND OF THE INVENTION 5 azide grouping. Liehr, Molecular Pharmacology, 23, 278 (1983) dis closes the fact that, as contrasted with 1713-estradiol, Santaniello et al., J.C.S. Chem. Comm., 1981, 217, 2-fluoro-17 (3-estradiol did not induce renal clear-cell 1157 (1981) attempted to prepare orthohalogen deriva carcinoma in male Syrian hamsters at equipotent estro tives of estradiol or of the corresponding ethers or acyl genic doses. 10 compounds. The authors regioselectively chloromer Thus, there is a renewed interest in 2-fluoro-1743 curated the C2-position of 3-methoxy-1713-acetoxyestra estradiol which compound was first described by Utne 1,3,5-triene. This chloromercury derivative was readily et al. J. Org. Chem., 33, 2469 (1968). The Utne proce converted to a 2-bromo and a 2-iodo derivative with dure involved nitration of estrone in the 2-position and Br2 or I2 respectively. An expansion of the original the 4-position, separation of the two isomers, conver 5 sion of the 3-phenolic hydroxyl of the 2-nitro estrone to paper can be found in J.C.S. Chem. Comm., 1157, an ether, reduction of the nitro group to an amine, diaz (1982). otization of the amine including preparation of the fluo Njar et al., J. Org. Chem, 48, 1007 (1983) describe the roborate salt, decomposition of the salt to yield 2 synthesis of 4-fluoro-17 (3-estradiol, 4-fluoroestrone and fluoroestrone 3-methyl ether, reduction of the 17 20 similar compounds. 4-Fluoro-176-estradiol was pre ketone group with sodium borohydride and demethyla pared from 4-fluoro-19-nortestosterone by dehydrogen tion of the ether to regenerate the phenol. This proce ation with selenium dioxide. dure involves many steps, the initial nitration produces Adam et al., Can, J. Chem, 61, 658 (1983) describe a mixture of isomers, and the yields are not as high as the preparation of fluorobenzene from phenyl mercury would be desirable in a commercial process. 25 trifluoroacetate and elemental fluorine. Neeman et al. J. Chem. Soc. (Perkin Transactions 1), 1972, 2300 used a different approach to the preparation The reagent, acetyl hypofluorite, has been described of 2-fluoro-17A-estradiol. This approach involved em by Rozen et al., J.C.S. Chem. Comm., 443 (1981) who ploying, as a starting material, 10g-hydroxyestr-4-ene describe this compound as a new electrophilic fluorinat 3,17-dione. This compound was epoxidized to yield the 30 ing agent. 4(3,-5A-epoxy derivative and the epoxy compound fluo Shiue et al., J. Nucl. Med., 23, 899 (1982) used 18F rinated with gaseous hydrogen fluoride in chloroform labeled acetyl hypofluorite to fluorinate 2-deoxy-D- ethanol to yield, ultimately, a 2-fluoro-10g-hydrox glucose. Yields were about 20%. yestr-4-ene-3,17-dione. Dehydration of this compound Mantescu et al., Radiopharm, and Label Cmpds, 395 with thionyl chloride produced 2-fluoroestrone, reduc 35 tion of which with sodium borohydride yielded 2 (1973) employed a mixture of glacial acetic acid and fluoro-3,1713-estradiol. K18F as a fluorinating agent to prepare certain steroid The ultimate starting material for the Neeman synthe hormones containing radioactive fluorine. These hor sis, 19-nortestosterone, is not readily obtainable. The mones included 4-fluorotestosterone and 2,4-difluoroes authors also refer to their prior specific synthesis of 40 trone. The authors adopted the procedure of iodinating 4-fluoro-17G-estradiol, a compound also prepared by estrone at the 2 and 4 carbons and then replacing the Palmer et al. J. Labelled Cmpds, 16, 14-16 (1979) and iodine with radiofluorine using the KF-acetic anhydride by Eakins et al-see International Journal of Applied procedure. Radiation and Isotopes, 30, 695 (1979). These latter au It is apparent that no commercially feasible synthetic thors also prepared 4-fluoroestrone, 2,4-diiodoestradiol 45 and 2-iodoestradiol. 2-Iodo-17 g-estradiol was prepared route is available for preparing 2-fluoro-17f8-estradiol; from 17g-estradiol and sodium iodide. The preparation i.e., a route based on readily available and inexpensive involved evaporation of any solvent and melting the starting materials, employing a minimal number of steps two solid materials together at 180° C. Since radioactive and capable of giving good yields of all products. It is iodine had been used, autoradiography could be used to 50 an object of the invention to provide such a procedure. distinguish the desired 2-iodo-176-estradiol from all SUMMARY OF THE INVENTION other substances in the mixture; thus separation by chromatography was possible. These radioactively la In fulfillment of the above and other objects, this belled compounds, I125-2-iodoestradiol and F18-4- invention provides a method for preparing 2-fluoro fluoroestradiol, were designed for use in scanning for 55 17g-estradiol by mercurating an estradiol derivative of estrogen dependent tumors or for scanning the prostate. formula I having protected hydroxyl groups at C-3 and Heiman et al., J. Med Chem, 23,994 (1980) sought C-17 with a mercurating agent such as mercury trifluor superior methods of preparing halogenated estrogens oacetate in trifluoroacetic acid to yield a compound of for use as estrogen receptor-based imaging agents. The structure II. Reaction of this intermediate with acetyl authors prepared 3-fluorohexestrol by procedures simi 60 lar to those employed by Utne et al. (loc. cit.) for pre hypofluorite produces 2-fluoro-17 g-estradiol protected paring 2-fluoro-1743-estradiol. at C-3 and C-17 according to structure III. Deprotec An adjacent paper by the same group of authors, tion (removal of ester or ether protecting groups by Goswami et al., J. Med. Chenn., 23, 1002 (1980), dis standard procedures) yields 2-fluoro-17(3-estradiol (IV). cusses the preparation of side-chain halogenated hexes 65 The above reaction scheme is illustrated in the fol trol derivatives. lowing flow chart. Mercury trifluoroacetate in trifluo A third paper from the same group, Ng et al., J. Org. roacetic acid is used as the mercurating agent for illus Chenn., 46, 2520 (1981), describes the fluorination of trative purposes only. - 4,522,758 3 4 diprotected stage of the synthetic procedure (III) or as FLOW CHART final products (IV). It is an advantage of using the . OR1 3,176-diacetate as a starting material that production of OR isomeric products is minimal. In addition to a proper choice of protecting groups, in order to prepare substantially pure 2-fluoro-17A estradiol, the solvent and reagents should be free from other halogens which would be exchangeable with F CF3COO-Hg under the reaction conditions. Presence of chloride, for RO SES-2 sRo 10 example, in the reaction medium or as part of the mer I cois s cury-containing group at C-2 might result in coproduc II tion of 2-chloro-17 (3-estradiol. CH3COOF In the acetyl hypofluorite reaction, trifluoroacetic acid has been specified as the mutual inert solvent, but it 15 will be apparent to those skilled in the art that other OH OR1 equivalent acidic solvents could be employed. It should be emphasized, however, that the solvent, as well as the acetyl hypofluorite reagent itself should be substantially free of other exchangeable halogens to avoid the inad F F 20 vertent production of other 2-halo-17 (3-estradiols. <- Finally, the protecting groups, R and R, must be HO RO removed from the product III in order to obtain the useful final product, 2-fluoro-17 (3-estradiol (IV). If the IV III protecting group is an ester group, base hydrolysis is 25 usually employed, using an alkali metal hydroxide or wherein R and R1 are separately acid-stable hydroxy carbonate as the base. Reduction with LiAlH4 can also protecting groups. By the term "acid-stable' is meant be used as can trans-esterification using an alcohol like an hydroxy protecting group which is stable in the methanol and a acidic catalyst.

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