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United States Patent Office Patented May 21, 1957 1 2,793,218 United States Patent Office Patented May 21, 1957 1. 2,793,218 9-HALO-11.KETO.17-ALKYTLTESTOSTERONES Milton E. Herr, Kalamazoo, Mich., assignor to The Up john Company, Kalamazoo, Mich., a corporation of Michigan No Drawing. Original application August 8, 1955, Serial No. 527,118. Divided and this application May 10, WII 1956, Serial No. 583,922 wherein R is a lower-alkyl group containing less than three carbon atoms, i. e., methyl or ethyl; R is hydrogen 3 Claims. (Cl. 260-397.45) or the acyl radical of a hydrocarbon carboxylic acid con taining from one to twelve carbon atoms, inclusive; X This invention relates to novel 17-alkyl-17-hydroxy 5 is a halogen having an atomic weight from 79 to 127, in steroids and esters thereof. clusive, i. e., bromine or iodine, X is a halogen having It is an object of this invention to provide novel 9a an atomic weight from 19 to 36, inclusive, i. e., fluorine halo - 116 - hydroxy - 17 - alkyltestosterones, 9a - halo or chlorine, and X' is a halogen having an atomic weight 11 - keto - 17 - alkyltestosterones, 17-esters thereof, and from 19 to 127, inclusive, i. e., fluorine, chlorine, bromine intermediates in the production thereof. Another object 20 or iodine. is the provision of processes for the production thereof. Following the series of reactions described hereinafter Other objects will be apparent to those skilled in the art for the conversion of 11o - hydroxy - 17 - methyltestos to which this invention pertains. terone (I) to 9a - hydroxy - 17 - methyltestosterone According to the present invention, the novel 9a-halo testosterone and esters thereof (VII), but substituting 10 116 - hydroxy - 17 - alkyltestosterones, 9a - halo - 11 25 normethyl - 11a - hydroxy - 17 - methyltestosterone keto - 17 - alkyltestosterones and 17 - esters thereof may (U. S. Patent 2,660,586) as the starting steroid, there are be prepared from 9(11) - dehydro - 17 - alkyltestosterone thus - produced 9oz - fluoro - 10 - normethyl - 11ps - hy via the known 3 - pyrrolidyl enamine of 4,9(11)-andros droxy - 17 - methyltestosterone and 17 - esters thereof. tadiene - 3,17 - dione (II) (Heyl and Herr, J. Am. These compounds are also potent oral anabolic agents Chem. Soc., 77,489 (1955)), 11B - hydroxy - 17 - meth 30 possessing androgenic activity. yitestosterone or esters thereof (I) or 11c - hydroxy - 17 Reacting 9(11)-dehydro-17-methyltestosterone with a methyltestosterone or esters thereof (U. S. Patent 2,660,- molar excess of diethyl oxalate and a molar equivalent 586) (I) as shown by the following formulae: of sodium methoxide in tertiary butyl alcohol is produc tive of the sodium enolate of the 2-ethoxyoxalyl deriva 35 CHs CHs tive thereof. After neutralization of the solution with O-R O acetic acid and then brominating with a molar equivalent --CH CH of bromine at about minus ten degrees centigrade, 2 bromo - 2 - ethoxyoxalyl - 9(11) - dehydro - 17 - methyl testosterone is produced. After removing the 2-ethoxy .. 40 oxalyl group with sodium methoxide in methanol, the 2 bromo-9(11)-dehydro-17-methyltestosterone is dehydro halogenated with refluxing collidine to 3-keto-17a-methyl 14,9(11) - androstatrien-176-ol. Employing this com O pound as the starting steroid in the reactions for the con 45 version of 9(11)-dehydro-17-methyltestosterone to 9a fluoro-11p-hydroxy-17-methyltestosterone and 17-esters thereof, there are thus-produced 3-keto-9a-fluoro-17a Cs methyl-1,4- androstadiene - 116,176 - diol and 17-esters O-R' thereof, e. g., a hydrocarbon carboxylic acid ester con !--R 50 taining from one to twelve carbon atoms, inclusive, for example, of an acid named in the paragraph following Example 4. These compounds also possess androgenic activity and marked oral anabolic activity. 55 The novel 9oz - halo-1 16-hydroxy-17-alkyltestosterone and 17-esters thereof (VII) and 9a-halo-11-keto-17-al Os kyltestosterone and 17-esters thereof (VIII) possess II marked androgenic activity and oral anabolic activity. For example, 9a-fluoro-11p-hydroxy-17-methyltestoterone 60 possesses an oral anabolic activity about eighteen to nine CB teen times and an oral androgenic activity about ten O-R' times that of 17-methyltestosterone. Furthermore, it is --R considerably less toxic, and, surprisingly, it does not dem onstrate the undersirable salt retention side-effect which one might expect of a 9oz-fluoro compound. 9a-fluoro 11-keto-17-methyltestosterone possesses an oral andro genic activity which is more than twice that of 17-methyl testosterone and its oral anabolic activity is more than Os Oc - five times that of 17-methyltestosterone. Similarly, the N VI 70 corresponding 9a-chloro analogues possess high oral ana bolic and androgenic activities as do the 17-esters of both the 9a-fluoro and 9a-chloro compounds. 9a-bromo- and 2,793,218 3 4. 9a-iodo-11-keto-17-methyltestosterone and their 17-esters then cooled to room temperature, acidified with acetic also possess anabolic and androgenic activity. acid and then distilled at reduced pressure until a residual The novel androgens and anabolic agents of this in volume of about 1.5 liters was reached. After adding vention, especially VII and VIII, are useful as male a mixture of 100 milliliters of concentrated hydrochloric gonadal replacement therapy in prepuberal and post pub acid and 100 grams of ice, the residue was extracted with eral castrates, in pituitary dwarfism, Simmond's disease, 800, 500, 400 and 400 milliliter portions of methylene dysmenorrhea and for suppression of lactation. Their chloride. The combined extracts were washed succes anabolic activity is useful in increasing weight, muscle sively with water, dilute sodium hydroxide and water and strength and for increasing the sense of well-being and then dried. The solvent was distilled from the dried positive nitrogen balance in pituitary deficiencies. By 10 solution and the residue dissolved in a mixture of 100 adjustment of the dose, a favorable anabolic response milliliters of methylene chloride and 250 milliliters of can be achieved without noticeable androgenic response, benzene and chromatographed over 700 grams of activat if this is desired, ed alumina. The column was developed with 500 milli The novel androgen and anabolic agents of the pres liters of benzene, two liters of Skellysolve B hexaae hy ent invention are normally administered orally, e. g., as 15 drocarbons plus four percent acetone, two liters of Skelly tablets, capsules or in the form of flavored fluid prep solve B plus seven percent acetone, two liters of Skelly arations, in which may additionally be incorporated, if solve B plus eleven percent acetone, four liters of desired, an estrogen, e.g., estrone, estradiol, estradiol-21 Skellysolve B plus fourteen percent acetone and finally, B-cyclopentylpropionate, for combined androgen-estrogen two liters of Skellysolve B plus seventeen percent acetone. therapy. 20 The eluate fractions containing from eleven to seventeen The following examples are illustrative of the products percent acetone were combined and the solvent distilled and processes of the present invention, but are not to be therefrom to give crude product which, when crystallized construed as limiting. from dilute acetone, gave 26.8 grams of 9(11)-dehydro 17-methyltestosterone (IV) melting at 167 to 170 degrees Example I-9(11)-dehydro-17-methyltestosterone (IV) 25 centigrade. To a stirred solution of 100 grams of 11 (3-hydroxy-4- androstene-3,17-dione in one liter of dry pyridine was Following the procedure of Example 1 exactly, but added, at room temperature and in a nitrogen atmos substituting ethyl magnesium bromide for the methyl phere, sixty grams of N-bromoacetamide all at once. The droxy-17-ethyltestosterone.magnesium bromide, there is thus-produced 9(11)-dehy resulting mixture was stirred for fifteen minutes and then 30 cooled to ten degrees centigrade. Into the cooled solu Example 2-9(11)-dehydro-17-methyltestosterone (IV) tion was bubbled sulfur dioxide gas until the mixture gave a negative test with acidified starch-iodide paper. The One-half gram of 11-keto-17a-methyltestosterone (U. S. mixture was diluted with four liters of water and cooled Patent 2,678,933) was dissolved in three milliliters of to about zero degrees centigrade for three hours. There 35 absolute methanol and mixed with one-half milliliter of was thus precipitated 49(11)-androstadiene-3,17-dione pyrrollidine at a temperature of about fifty degrees centi Heyl and Herr, J. Am. Chem. Soc., 77, 488 (1955)), grade. The mixture was allowed to cool to room tem which after filtering, washing with water and drying, perature, and, after about one-half hour, the 3-enamine weighed eighty grams and melted at 197 to 203 degrees of 11-keto-17-methyl testosterone 3-(N-pyrrolidyl)-17a centigrade. methyl-17B-hydroxy-3,5-androstadien-11-one) which had 40 precipitated was removed by filtration and dried under To a hot solution of 56.8 grams of 4,9(1)-androsta vacuum. The yield of high purity 3-enamine product was diene-3,17-dione in 800 milliliters of methanol was added 0.452 gram melting at 180 to 195 degrees centigrade with 25 milliliters of pyrrollidine, whereupon product began decomposition. to precipitate almost immediately. The solution was A solution of 1.79 grams of the 3-enamine of 11-keto permitted to cool to room temperature and then was 45 17a-methyltestosterone in a mixture of 25 milliliters of refrigerated at zero degrees centigrade for three hours. thiophene-free benzene and 25 milliliters of anhydrous The crystalline precipitate was filtered, washed with meth ether was added dropwise with mechanical stirring to a anol and then dried to give 59 grams of the 3-enamine of mixture of one-half gram of lithium aluminum hydride 4,9(11)-androstadiene-3,17-dione (It) (3-pyrrolidyl-3,5, and 85 milliliters of dry ether.
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