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United States Patent Office Patented Oct 2,721,828 United States Patent Office Patented Oct. 25, 1955 2 tained by subjecting starting steroids to the fermenta 2,721,828 tion process of this invention. For example, androstane 3,11,17-trione (male hormone activity) may be obtained PROCESS FOR PRODUCTION OF by fermentation of allopregnane-3,11,20-trione; etio 17-KETOSTEROOS cholane-3,11,20-trione (general anesthetic activity) from Herbert C. Murray, Hickory Corners, and Darey H. Peter pregnane-3,11,20-trione; 3c- or 3.3-hydroxyeticholane son, Kalamazoo Township, Kalamazoo County, Mich., 17-one (anesthetic activity) from the fermentation of assignors to The Upjohn Company, Kalamazoo, Mich., 3a- or 36-hydroxypregnane-20-one or from pregnane a corporation of Michigan 3,20-dione by the side chain fermentation of this in No Drawing. Application October 1, 1953, 10 vention and subsequent reduction with sodium boro Serial No. 383,701 hydride or lithium aluminum hydride; etiocholane-3,6,17 trione (which may be brominated to 4-bromoetiocholane 20 Claims. (C. 195-51) 3,6,17-trione and dehydrobrominated to give 4-andro stene-3,6,17-trione of estrogenic activity) from preg The present invention relates to a novel process for 5 nane-3,6,20-trione by side chain fermentation; adreno the fermentative degradation of the 17-side chain of sterone from the fermentation of 11-ketoprogesterone, 20-oxygenated steroids, especially 20-ketosteroids to cortisone or cortisone acetate; and other like active 17 yield 17-ketosteroids, especially 17-ketoandrostane and ketosteroids. 17-ketoetiocholane compounds. The starting steroid compounds of the present applica The process of the present invention comprises sub 20 tion are the 20-oxygenated steroids, and preferably the jecting a 20-oxygenated steroid, especially a 20-keto 20-hydroxy steroids and the 20-ketosteroids. The cyclo steroid to the action of a fungus of the genus Gliocladium, pentanopolyhydrophenanthrene radical with a 176-side to produce a 17-ketoandrostane compound. chain may possess keto groups or hydroxy groups in The process of degradation of the 17-side chain of other positions, especially positions 3, 6, 7, 8, 11, 12, steroid compounds to give 17-ketosteroids, especially 17 25 14, 17, and 21, and may have double bonds in various ketoandrostanes and 17-ketoetiocholanes by chemical positions especially in positions 4 and 5. Representa means is well known, but these procedures usually in tive starting materials include: 3ox- and 3,3-hydroxypreg volve a number of steps such as formation of a 17 (20) mane-20-one, 30- and 3,3-hydroxy-5-pregnene-20-one, 3oz double bond and oxidation of this double bond. In and 36-hydroxypregnane-1120-dione, 3.cx,110-, 3a, 116-, such oxidative degradation the steroid nucleus is often 30 3,3,11a- and 36,116-dihydroxypregnane-20-one, proges attacked in other positions, especially double bonds with terone, 11-ketoprogesterone, 110-hydroxyprogesterone, resulting high losses. In order to avoid such losses, 11o-acetoxyprogesterone, 11.f3-hydroxyprogesterone, 14a protection of such positions or groups, which involves hydroxyprogesterone, 140,170,21-trihydroxy-4-pregnene at least two additional steps, is practiced in the art. 3,20-dione, 14oz,17ox - dihydroxy - 21-acetoxy-4-pregnene For example, Bergmann and Stevens, J. Org. Chem. 13, 35 3,20-dione, 11a, 17a-dihydroxyprogesterone, 17a-hydroxy 10 (1948) show the ozonolysis of 22-enol acetate of 11-ketoprogesterone, 3,3,17a,20-allo-pregnanetriol (Reich 36-acetoxybisnor-5,7-choladien-22-all protected by a 5,8 stein's compound “O'”); 17 oz,21-dihydroxy-4-pregnene maleic anhydride adduct group to yield the maleic an 3,20-dione (Reichstein's compound “S”), corticosterone, hydride adduct of 36-acetoxy-5,7-androstadiene-17-one. cortisone, cortisone acetate, dihydrocortisone (Kendall's It is an object of the present invention to provide a 40 compound "F") and 11a, 17a,21-trihydroxy-4-pregnene direct method for the degradation of a 17-side chain 3,20-dione (11-epi "F' pregnane-3,11,20-trione, 17 oz of 20-oxygenated steroids, especially 20-ketosteroids by hydroxypregnane-3,11,20-trione, pregnane-3,12,20-trione, the action of a fungus of the genus Gliocladium. An pregnane-3,20-dione, 17a-hydroxypregnane-3,20 - dione, other object of the present invention is the provision allopregnane-3,11,20-trione, allopregnane-3,20-dione, 30 of a process for the production of 17-ketoandrostane and hydroxy-5-pregnene-20-one, 3c - and 33-hydroxyallo 17-ketoetiocholane compounds which are useful in 45 pregnane-20-one, 3c, 120,21-trihydroxypregnane-20-one, therapy or as intermediates for the synthesis of thera 3oz,17a-dihydroxypregnane-20-one, 6cy- and 6p3-hydroxy peutically useful products from 20-oxygenated steroids. progesterone, pregnane-3,6,20-trione, 21-methylproges Other objects and uses of this invention will be apparent terone, 21-ethylprogesterone, 36,20-dihydroxy-20-methyl to those skilled in the art to which this invention pertains. allopregnane, 38,20-dihydroxy-20-methyl-5-pregnane, The method of the present invention is able to fur 50 3,3,20,21-trihydroxy-20-methyl-5-pregnene, 36-hydroxy nish a variety of useful products. For example, proges 21-ethyl-5-pregnene-20-one, 36,17a-dihydroxy-17 3-(1,2,3- terone subjected to the action of Gliocladium catenu trihydroxypropyl)-androstane, and the like. latum gives 4-androstene-3,17-dione possessing known In carrying out the process of the present invention the androgenic properties, and also known 6,3-hydroxy-4- selected 20-ketosteroid, suitably in a solvent, for example, androstene-3,17-dione IBalant and Ehrenstein, J. Org. 55 is subjected to a growth of a species of fungus of the Chem. 17, 1587 (1952)). The resulting 4-androstene genus Gliocladium. The genus Gliocladium belongs to 3,17-dione can be converted to testosterone in accord the family Aspergillaceae of the order Plectascineae of ance with stavely, U. S. Patent 2,288,854, issued Octo the class Ascomycetes. The classification and definition ber 11, 1941, and the latter by hydrogenation to dihydro of Gliocladium as herein employed is that of Raper, testosterone of therapeutic use (Symposium on Steroids in 60 K. B., and Thom C., "A Manual of the Penicillia,” Experimental and Clinical Practice, The Blakiston Com Williams and Wilkins Company, Baltimore, 1949. Among pany, New York, 1951, p. 375). The other fermenta species of the genus Gliocladium useful in the fermenta tion product, 6B-hydroxy-4-androstene-3,17-dione, can tion of steroids may be mentioned the Gliocladium rose be oxidized by chromic acid to 4-androstene-3,6,17- tri un series, Gliocladium roseum, Gliocladium penicil one which possesses estrogenic activity IButenandt, Ber. 65 loides, Gliocladium vermoesceni (i. e., ATCC 10522); 69, 1163 (1936). Similarly other physiologically and Gliocladium catenulatum series, Gliocladium catenula pharmacologically active 17-ketosteroids or intermediates tum, Gliocladium fimbriatum; Gliocladium deliquescens for the synthesis of such 17-ketosteroids may be ob series, Gliocladium deliquescens (i. e., ATCC 10097), 2,721,828 3. 4. Gliocladium nigro-virescens (C. B. S. v. Beijima Hol wated carbon or other suspendable solid matter, methyl land); Gliocladium luteolitin, Gliocladium flaviiil, ceilulose, carboxymethyl cellulose or aginates may be Gliocladium ciboilii and Gliociadiini yiride. Of these aided to facilitate fermentaticin, aeration and filtration. species, especially preferred for the practice of the preSeit The selected species of fungus is grown on a medium invention are Gliociadiitii1 catentitlatun, American iype suitabiy containing assimilabie non-steroidal carbon, Culture Collection -uinber i0,523, Glioclaidiitiin rosettii, illustratively carbohydrates, silich as Sugar or starches, American Type Cliittire Collection fumber 10,521, assianiiable nitrogen, illustratively soil be or insoluble Gliocladium deliquescens (Centraalibureau voor Schim proteins, peptones or amino acids; and mineral constitu melcultur, Baarn, Holland) and Gliocladiitii iiite is a cris, is y phosphates and magnesium Sulfate, and (Centraal bureau voor Schim meicultur Saarn, zed, desirable additions. The medium the present invention, is in or on a mediurn favorable to the development of the fingi. Solid media may be uti lized, but the preferred media are those which permit quantity growth under aerobic conditic;is. ist scid the fungai growth-supporting medium particulate media, Such as bi'an, Cereal grains, cereal grits, Seiected giS of the genus Gliocladium may be wood chips, shavings, sawdust, cornhusk accoranipiished in any suitable anner. Gliocladium grow rial, such as copra, chestnuts, or upine seeds inay be over a range froii) about twenty to about 38 degrees used. These can be extracted with alcohol, ether or centigrade, with a temperature between about 25 to about other organic solvents, to remove objectionable contami 20 35 degrees pieferred. nants and growth inhibitors prior to fermentation. The The developmental period of fungal growth required carriers may optionaily contain added growth factors and before the Steroid to be ferinented is exposed to the fungus nutrients and may be used in layers cr trays with or with does not appear to be critica. For example, the steroid out auxiliary aeration, in towers as in the vinegar process i.ay be added either before thermal or other steriliza or under conditions of agitation as for example by tum 25 tion of the medium, at the time of inoculating the me bling in a rotating drum. ; liquid inedia, illustratively diuri with the selected Giocladiurn species, or at Some brewer's wori, are well adapted to use under aerobic layer time, for exampie, 24 or 40 hours, later. The steroid or more especially aerobic submerged feinentation con to e ferniented may be added at any suitabie concen ditions. Suitably the finedia should contain Sources of tration although for practical reasons steroid substrate available carbon, nitrogen and lininerais although of 30 at a concentration of about or up to about 0.6 grain course there can be significant growth and development per liter or ever, 0.8 gram per iter of medium is satis under less than optimun conditions.
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