Патент USA US3033873код для вставки
3,@33,853 Patented May 8, 1962 2 3,033,863 butyric acid, valeric acid, isovaleric acid, trimethyl acetic Gaston Amiard, Noisy-ie-Sec (Seine), and Rene Heymes, acid, lauric acid, myristic acid, palmitic acid and stearic acid, caproic acid, ?-trimethyl propionic acid, heptanoic acid, caprylic acid, pelarginic acid, capric acid, undecylic 18-NOR-CORTISONES AND PRGCESS FOR THEE PREPARATEGN Romainville (Seine), France, assignors, by mesne as signments, to Roussel-UCEAF, §.A., Paris, France, a corporation of France No Drawing. Filed (Set. 10, 1961, Ser. No. 144,836 Claims priority, application France Get. 2t), 1969 14 Claims. (Cl. 260-23955) The invention relates to novel 16a-methyl-18-nor cortisones having the formula acid; alkenoic ‘acids such as undecylenic acid and oleic acid; cycloalkyl carboxylic acids such as cyclopentyl car boxylic acid, cyclopropyl carboxylic acid, cyclobutyl car boxylic acid and cyclohexyl carboxylic acid; cyc-loalkyl alkanoic acids such as cyclopentyl acetic acid, cyclohexyl acetic acid, cyclopentyl propionic acid and cyclohexyl propionic acid; arylalkanoic acids such as phenyl acetic acid and phenyl propionic acid; aryl carboxylic acids such as :benzoic acid and 2,4-dinitrobenzoic acid; phenoxy alkanoic acids such as phenoxy acetic acid, p-chloro phenoxy acetic acid, 2,4-dichlorophenoxy acetic acid, 4 ter-butylphenoxy acetic acid, 3-phenoxy propionic acid and 4-phenoxy butyric acid; heterocyclic carboxylic acids such as furane-Z-carboxylic acid, S-ter-butylfurane-Z carboxylic acid, 5-bromofurane-2-carboxylic acid and nicotinic acids; ,B-ketoalkanoic acids, such as acetylace tic acid, propionylacetic acid and butyrylacetic acid; I amino acids such as diethylaminoacetic acid and aspartic wherein R is selected from the group consisting of hydro acid. gen and an acyl radical of an organic carboxylic acid The 16ot-methyl-18-nor-cortisone and its esters are having 1 to 18 carbon atoms. The invention further relates to a novel process for the preparation of said com 25 prepared by reacting 3-ethylenedioxy-16a-methyl-18-nor pregnane-11,20-dione with oxygen in the presence of an pounds and novel intermediates thereof. alkali metal tertiary butylate to form 3-ethylenedioxy Compounds such as cortisone, hydrocortisone, predni sone, prednisolone and dexarnethasone are known to 17cc - hydroperoxy - 16cc - methyl-18-nor-pregnane-11,20 possess glucocorticoidal activity, but it is also known that dione, reducing the latter to form 3-ethylenedioxy-16u mum of side e?ects. nane-17ot-o1-3,11,20-trione, dehydrobrominating the said these products when administered over a period of time 30 methyl-18-nor-pregnane-17a-ol-11,20-dione, hydrolyzing the latter under acidic conditions to form 16a-methy1-18 have undesirable side e?ects such as the retention of sodi~ nor-pregnane-lh-ol-SJ1,20-trione, reacting the latter um and water and are ulcergenic. The compounds of with bromine to form 4,8-bromo-16a-methyl-18-nor-preg Formula I possess glucocorticoidal activity with a mini '' 4B-bromo-steroid to form 16u-methyl-18-nor-A4-preg It is an object or" the invention to provide novel 18 nor-cortisones of Formula I. nene-17a-0l-3,11,20-trione, introducing a hydroxyl group in the 21-position of the latter to form 16a-methyl-18 It is another object of the invention to provide a novel nor-cortisone and recovering the latter. The 16a-methyl process for the preparation of 18-nor-cortisones of 18-nor-cortisone may be esteri?ed in the 21-position by Formula I. 40 reacting the said cortisone with an esterifying agent such It is a further object of the invention to provide novel as an acid anhydride or acid halide. intermediates for ls-nor-cortisones of Formula I and particularly: 16a-methyl-18-nor-pregnane-17a-ol-3J 1,20-trione may ‘also be produced by reacting 3-ethylenedioXy-16a-rnethyl (a) 3-ethylenedioxy-l7a-hydroperoxy - 16cc - methyl 18-nor-pregnane-1 1,20-dione (b) 3-ethylenedioxy-16a-methyl-18-nor-pregnane-l7a ol-l1,20-dione (c) 16a-methy1-18-nor-pregnane-‘17u-ol-3,11,20-trione 45 A17<2°>-pregnene-11-one reacting the latter with a peracid such as perbenzoic acid to form 3-ethylenedioxy-16a methyl-17,20-epoxy-20-acetoxy-18-nor - pregnane-ll-one (d) 4B-bromo - 16a - methyl-18-nor-pregnane-1h-ol 3,11,20-trione 50 (e) 16u-methyl - 18 - nor-A‘i-pregnene-17¢x-0l-3,11,20 formed chemically by reacting 16a-methyl-18-nor-A4 pregnene-17a-ol-3,11,20-trione with iodine in the presence obvious from the following detailed description. 55 of a mixture of calcium chloride and calcium oxide to The compounds of the invention have the formula form the corresponding 21-diiodo derivative of the said CH2OR 11 CH3 and subjecting the latter to acid hydrolysis to form 16m methyl-18-nor~pregnane-17ot-ol-3,11,20-trione. The introduction of the ZI-hydroxy group may be per trione. These and other objects and advantages will become 0_/\ 18-nor-pregnane-11,20-dione with acetic acid anhydride to form 3-ethylenedioxy~16a-rnethyl-20-acetoxy-18-n0r steroid, reacting the latter with an alkali metal salt of a =0 lower - alkanoic acid to form the corresponding 21 '--on acyloxy derivative of said steroid and hydrolyzing the latter to the corresponding ZI-hydroxy steroid. The 21 60 hydroxy steroid may also be formed by the action of : i-CHS diastases secreted by microorganisms such as ColletO trichum lindemuthianum (ATCC 12,611) as described in 0: U.S. Patent No. 2,805,978. I wherein R is selected from the group consisting of hydro gen and an acyl radical of an organic carboxylic acid having 1 to 18 carbon atoms. The acyl radical of the organic carboxylic acid having 65 A preferred mode of the process of the invention com prises reacting 3-ethylenedioXy-16a-methy1-18-nor-preg nane-11,20-dione with oxygen in the presence of potas sium tertiary butylate at room temperature to form 3 ethylenedicxy - 17a - hydroperoxy - 16a - methyl - 18 1 to 18 carbon atoms may be derived from an aliphatic, nor-pregnane-l1,20-dione, reacting the latter with zinc aromatic, cycloaliphatic or heterocyclic carboxylic acid. 70 and acetic acid to form 3-ethylenedioxy-16a-rnethyl-l8 Examples of suitable acids are alkanoic acids such as formic acid, acetic acid, propionic acid, butyric acid, iso norapregnane~17wol~11,20-dione, hydrolyzing the latter with hydrochloric acid at re?ux temperatures to form 3,033,868 " V " V > * 4 l6a-methyl-1S-nor-pregnane-lh-ol-L1LZOQtIione, react- ' ing the latter with bromine in acetic ‘acid to form 45 bromo - 16oz - methyl - 18 - nor - pregnane - 17oz - 01 wherein R is selected from the group consisting of hydro~ gen ‘and an acyl radical of an organic carboxylic acid having 1 to 18 carbon atoms. The starting material, S-ethylenedioxy-l6a-methyl-18~ nor-pregnane~1 1,20-dione, is prepared by reacting 3-ethyl enedioxy-l8-nor-A16-pregnene-l1,20-dione described by 3,l1,720-7tri0ne, dehydrobrorninating the latter with a miX1 ture of lithium bromide and lithium carbonate to form 160a - methyl - l8 - nor - A4 - pregnene -17u - ol - 3,11,20 Velluz et ‘all. in Comptes Rendus Acad. 80., vol. 250 (196), trione, introducing .a hydroxyl group in the 21-position page 371, with a methyl magnesium halide in the pres of the latter to form 16u-rnethyl-l8-nor-cortisone and ence of cuprons chloride. recovering the latter. The reaction schemes are outlined 10 In the following examples there are described sev in Table I. O 3 H it ' ' // moo-0H3 / 0 cm 7 3,033,863 6 eral preferred embodiments to illustrate the invention. However, it should be understood that the invention is B was dissolved in 60 cc. of acetone and 12 cc. of 5 N hydrochloric acid were added thereto. The mixture was heated to re?ux for a period of ?ve minutes, 20 cc. of ‘not intended to be limited to the speci?c embodiments. The melting points are instantaneous melting points as water were added and the acetone was removed under determined on the Maquenne block. 5 vacuum. 16a-methyl-18-nor-pregnane-17a - ol - 3,11,20 EXAMPLE I _ trione crystallized. The crystals were vacuum ?ltered Preparation of 3-Ethylenedi0xy-16oc-Methyl-18 washed with water, dissolved in methylene chloride, Nor-Pregnane-l1,20-Di0ne, II treated with animal black, ?ltered and concentrated to a small volume. On the addition of hot ether, 16a-methyl To 40 cc. of ethereal solution of methylmagnesium iodide prepared from 2.2 gm. of magnesium and 9.0 cc. 10 18-nor-pregnane-17a-ol-3,11,20-trione precipitated. The crystals were vacuum ?ltered to give 4.32 gm. of product of methylene iodide, there was added, after cooling to (being 45% with reference to 3-ethylenedioxy-l6ct methyl-l8-nor-pregnane-l1,20-dione), melting at 202° C. and directly utilizable for the next step of the synthesis. precipitate was formed and after having cooled to 0° C., By evaporation of the mother liquors, it was possible 500 mg. of cuprous chloride were added in two por 15 0° C., 120 cc. of tetrahydrofurane without allowing the interior temperature to mount above +5 ° C. A White to recover 1.5 gm. of tions, cooling each time to 0° C., and then 14 gm. of 3 win 65 cc. of tetrahydrofuran were introduced over sev eral minutes under ‘agitation. The reaction mixture was agitated for a period of forty-?ve minutes, then poured into a mixture of 300 gm. of ice and 15 gm. of am monium chloride. After decantation, the solvents were removed under vacuum. The residue comprising 3-ethylenedioXy-16a-methyl— l8-nor-pregnane-11,20-dione crystallized. The aqueous phase resulting from the decantation was extracted with 16a-methyl-lS-nor-pregnane 3,1 1,20-‘trione. For analysis, the 16a-methyl-18-nor-pregnane-17a-ol ethylenedioxy ~ 18 - nor - A16 - pregnene _ 11,20 - dione 3,11,20-trione was puri?ed by recrystallization from methylene chloride to give a sample melting at 204—206° C. and having a speci?c rotation [a]D2°=—|-21° (c.=1% in chloroform). The product occurred in the form of colorless crystals. It was very soluble in chloroform, soluble in alcohol and acetone and slightly soluble in 25 ether and insoluble in water. Analysis. —- CHI-13004; molecular weight = 346.45. Calculated: C, 72.80%; H, 8.73%. Found: C, 72.6%; H, 8.8%. ether and the said pregnane as vacuum ?ltered was re dissolved in combined ethereal extracts. The ethereal The infrared spectra con?rmed the presence of a hy solution was washed with N/lO hyposul?te, then with droxyl by a band at 3607 cmrl. water, dried over magnesium sulfate, passed in the car 30 This compound is not described in the literature. ‘bon black and concentrated to a small volume. The prod Step D.--Preparali0n of 4,8-br0m0-16a-metlzyl-18-n0r uct crystallized. Hexane was added, the ether was re moved, the solution was iced, vacuum ?ltered, washed pregnane-J7a-ol-3,11,20-trione.—4 gm. of l6a-methyl-l8 nor-pregnane-17a-ol-3,l1,20-trione were dissolved in 90 with hexane and dried. 12.4 gm. of 3—ethylenedioxy 16a-methyl-18-nor-pregnane-11,20-dione were obtained 35 cc. of anhydrous chloroform. 9 cc. of acetic acid were added and then 11.5 cc. of a solution cooled to —-60° C. (being a yield of 85%) having a melting point of 148 of bromine in acetic acid were introduced drop by drop. 150° C. and a specific rotation [a]D2°=+32°-_'-2° The solution was prepared from 14.55 gm. of bromine, (c.=1% in chloroform). The product was soluble in 7.3 gm. of hydrobromic acid and a suflicient quantity of ‘alcohol, acetone, benzene, chloroform, slightly soluble in ether, hexane, insoluble in water. 40 acetic acid in order to give a volume of 90 cc. 9.1%. ' This compound is not described in the literature. EXAMPLE II to. The mixture was poured onto a mixture of water and The extracts were washed with a solution of sodium bicarbonate and water, 45 ice and extracted with chloroform. Preparation of the Acetate of 16u-Methyl-18-N0r _ The re action mixture was agitated for a period of thirty minutes at —60° C. and then 2.8 gm. of sodium acetate contain ing 3 mols of water in 15 cc. of water were added there Analysis.-—C23H34O4; molecular weight=374.50. Cal culated: C, 73.76%; H, 9.15%. Found: C, 73.9%; H, then dried over magnesium sulfate.‘ The solution was concentrated to a small volume, vacuum ?ltered and 3.8 Cortisone gm. (being 80%) of 4/3-bromo-16a-methyl-18-nor-preg Step A.——Preparati0n of 3-ethylenedioxy-J(fa-methyl ] 7a-hydr0per0xy-18-nor-pregnane-11,20-a’i0ne.——2 gm. of 50 nane-17a-ol-3,11,20-trione were obtained which was uti potassium were dissolved in 170 cc. of tertiary butanol under agitation and an atmosphere of nitrogen. The mix ture was cooled to 25° C. and 10 gm. of 3-ethylenedioxy lized in the raw state for the next step of the synthesis. This compound is not described in the literature. By treatment with zinc and acetic acid, 0.44 gm. of 16a-methyl-l8-nor-pregnane-11,20-dione were introduced. the 16ot-methy1-18-nor-pregnane-17a - ol - 3,11,20 - trione Oxygen was bubbled into the mixture for a period of 55 were recovered from the mother liquors. Step E.—Preparati0n of l6a-methyl-l8-nor-A4-preg forty-?ve minutes until the absorption of about 650 cc. of oxygen. A solution of 3-ethylenedioxy-17a-hydro peroxy-16a-methyl-18-nor-pregnane-11,20-dione was thus obtained. nene-17a-0l-3,11 ,20-trz'0ne.——3.8 gm. of 4?-bromo-16a~ >methyl-18-nor-pregnane-17a-ol-3,11,20-trione were intro Step B.-—Preparation of 3-ethylenedi0xy-16a-methyl 60 gm. of lithium bromide and 1 gm. of lithium carbonate were added and the mixture was heated under agitation 18-n0r-pregnane-1 7a-ol-11,20-dione.—-To the refrigerated duced into 38 cc. of anhydrous dimethlformamide. 2 and an atmosphere of nitrogen to 135° C. ‘for a period solution obtained in Step A were added 60 cc. of acetic 'of forty minutes. After cooling and addition of water acid and then 20 gm. of zinc. The mixture was agitated and several cc. of acetic acid, the mixture was extracted for a period of twenty minutes at room temperature, then heated to 60° C. for a period of ?fteen minutes. The 65 with methylene chloride. The extracts were washed with water, dried and concentrated under vacuum. The 16w .zinc was ?ltered, water was added and the organic sol methyl-18-nor-A4-pregnene-17a-ol-3,11,20 - trione crystal vents were eliminated by distillation. After alkaliniza lized and was recovered by vacuum ?ltration. 2.5 gm. tion by addition of sodium hydroxide solution, the mix (being a yield of 81%) of raw productwere obtained ture was extracted with ether. The ethereal solution was was recrystallized from methanol, yielding a prod washed with water, dried, evaporated to dryness and 3 70 which uct having a meltingpoint of ZZZ-224° 7C. and a speci?c _ethylenedioxy-16a-methyl-18 - nor - pregnane - 17a-ol _ 11,20-dione was obtained as a residue. This compound , was used as such for the next step of the synthesis. Step C.—-—Preparati0n of 16a-methyl-18-n0r-pregnane v17ct-ol43,11,20-trione.---The compound prepared in Step 75 rotation [a]D2°=-i-l65°i2° (c.=1% in chloroform). The product occurred in the form of colorless leaflets, very soluble in chloroform, soluble in acetone, very slightly soluble‘ in'alcohol and’ ether and insoluble in water. " 3,033,863 7 7.0 by potassium hydroxide and it was sterilized by heat ing thirty minutes to a temperature of 120° C. After ?ve days of culturing at 25° on a shaking apparatus (85 Calculated: C, 73.22%; H, 8.19%. Found: C, 73.0%.; H, 8.2%. . 8 g The pH of this medium was previously adjusted to _6.8 Analysis. -— CHI-12804; molecular weight = 344.44. . Ultraviolet spectra: Amax- 238 my, e=15',1'00. This compound is not described in the literature. strokes per minute, 8 cc. stroke), 10 cc. of an acetonic solution containing 1% of 16u—methyl->18-nor-A4-preg Step F.—Preparation of 16ot-methyl-2I-dii0d0-18-rwr nene-17u-ol-3,11,20-trione obtained according to Exam A4-pregnene-17m-ol-3J1,20-tri0ne.-— 850 mg. of 16a methyl-lS-nor-N-pregnerie-l704-0143,l 1,20-trione were in ple II, were added‘ to 1,000 cc. of culture. A new incuba tion of twenty-four'hours gave 16a-methyl-l8-nor-corti troduced in 7.5 cc. of methanol. '850 mg. of quick lime 10 some as is evidenced by chromatographic determinations on paper which were effected as follows on 50 cc. of cul were added and the mixture was cooled to -10° C. To ture broth. the mixture were added 1.27 gm. of pulverized iodine and and 3‘cc. of methanol containing 10% calcium chloride The broth was ?ltered and the mycelium washed two times with 5 cc. of acetone which was added to the ?l " A4-pregnene-17a-ol-3J1,20-ttrione formed was vacuum .15 trate. The mycelium was next extracted with 2 aliquots of 50 cc. of chloroform and the preceding ?ltrate was ex ?ltered. The residue was washed with a dilute solution tracted with these 100 cc. of chloroform. Then the ex of acetic acid and with water and utilized without puri?ca tractions were made again two times with 20 cc. of ' chlo tion for the next step of the synthesis. roform each time. The chloroformic extracts were com This compound is not described in the literature. the mixture was agitated in a closed vessel ‘for a period of one hour: The draw 2lv-diiodo-l6wmethyl-l8-nor Step G.—-Preparati0n of the acetate 0]‘ 16a-methyl-18 20 bined and were washed ?rst with an aqueous solution of sodium bicarbonate, then with water and dried over mag n0r-cortis0ne.—,The 21-iodo derivative prepared in 'Step nesium sulfate. The solutions were then evaporated to F was dissolved in acetone. 0.2 cc. of acetic acid and ‘dryness under vacuum. The residue was taken up with 1 cc. of methanol and subjected to paper chromatography. Previous to the chromatographic adsorption, the paper strip was immersed in a solution of 30% propylene glycol. 3 gm. of potassium acetate were added. The mixture was heated to re?ux for a period of one hour and a half and then 10 cc. of water were added and the acetone was re moved under vacuum. The acetate of l6m-methyl-18-nor cortisone crystallized. The product was vacuum ?ltered, washed with water, dried, and taken up by a mixture of After allowing it. to drip, the steroid is chromato graphed with toluene saturated with propylene glycol. and a. development of eight to ?fteen hours is effected. The acetic acid and acetone. 300 mg. of zinc were added. The mixture was re?uxed for a period of several minutes. .30 detection of spots was made by the color reaction of Mader et al. (Anal. Chem. 1952, 24, p. 666) with triphenyl tet The mixture was treated with animal‘ black, ?ltered, con razolium chloride which gives a red-coloration on a white centrated to a small volume and vacuum ?ltered. 'The foundation with steroids possessing the ketol function product was recrystallized from aqueous acetone to give a product melting at 247-248° C. and having a speci?c R—CO—OH2OH. . ' Various modi?cations of the process of the invention rotate .[a]'D2°=+ll5°:2° . (c.=1% in chloroform). 35 may be made without departing from, the spirit or scope The product occurred in the form of square lea?ets, very thereof, and it is to-be understood that the invention is to soluble in chloroform, soluble in acetone, very slightly ‘be limitedonly' as de?ned in the-appended claims. soluble in alcohol and insoluble in water and ether. Weclaim: Analysis.—-C23H3o06; molecular weight=402.47. Cal 40 culated: C, 68.63%; H, 7.51%. Found: C, 68.5%; H, 1. 3-ethylenedioxy - 16a - methyl-l7u-hydroperoxy-l8 nor-pregnane-l1,20-dione. 7.7%. ' . Ultraviolet spectra: Am“. 238 mu, e=15,000. ' 01-1 1,20-_dione. This compound is not described in the literature. EXAMPLE III . 2. 3-ethylenedioxy - 16a - methyl-l8~nor-pregnane-l7a 3. 16a-rnethyl - 18 - nor-pregnane-17a-ol-3,l1,20-tri . .45 Preparation of 16a-Methyl-18-Nor-Cortis0ne ' one. ' ' ' ' ' . 4. 45 - bromo - 16o: - methyl-18-nor-pregnane-17a-ol 3,11,20-trione. 1 gm. of the acetate of, mot-methyl-18<nor-cortisone 5. 16h - methyl - l8 -, nor-M-pregnene-lh-ol-3,11,20 produced in Example III was introduced into 10 cc. of methanol. 0.1 'cc. of a normal solution of‘ sodium meth 50 6-. 16a-methyl-2l-diiodo - l8. - nor-A4-pregnene-17'a-ol ylate in methanol was added and the mixture was heated 3,11,2Q-tri‘one. ' ' at re?ux for aperiod of ?fteen minutes under nitrogen; 7. A process for the preparation of compounds having’ After neutralization and dilution with an equal volume 'the formula of, water, the methanol was removed under vacuum and the 16¢x-methyl-l8-nor-cortisone was recovered.‘ 55 H trione. This compound is not described in the literature. . _ " cal Hydrgoxylation in the 21-P0sition1 V 7 ~ 7 EXAMPLE IV Preparation of 16ot-methyl-I8-N0r-C0rtis0ne by Biologi . I 7 H "-on : *Lon. 60 Colletotrz‘clium lindemuthianum (ATCC, 12,611) was cultivated for a period of ten days at 249 on an agar medi: um containing 2% of saccharose and 20% of potato ex- ' . tract. The conidies were collected in distilled water. The wherein R is selected from the group consisting of hydro suspension obtained was used to sterilely inoculate a 1 65 gen and' an acyl radical of an organic carboxylic acid having 1 to 18 carbon atoms which comprises oxidizing 3 liter Erlenmeyer ?ask containing 100 cc. of’ a medium composed as ‘follows: 1 , Pure glucose ' Y ' '_ "Malt extract _ g ‘ ___ 10 .._ _____' "5 _.. Sodium‘ chloride Dry cornv steep. ' Grams. Soy bean meal , a 7 V 7 V __ .._ 5 _____c '5 '7 'Calcium carbonate ~'____'___r_____' ______ -2 _____ __’__ "i. '' Tap water to make 1,000'cc. ' 10 1 ethylenedioxy '- 16oz - methyl-1Y8-nor-pregnane-l”l,20-di , one with oxygen in the presence of an alkali metal tertiary ~butylate ,to form ' 3-ethylenedioxy4l7a-hydroperoxy-16m 70 methyl-lS-nonpregnane-l1,20-dione, reducing the latter 'to form 3gethylenedioxyrl6a-methyl-l8-nor7pregnane-17a- ~ .ol-ll,20-dione,1hydi‘olyzing the latter under-acidic condi tions to form 16ot-methyl-l8-nor-pregnane-17br-ol-3,11,20 trione, reacting the latter with bromine to form lip-bromo l6qc-methyl-18-nor-pregnane-17a-ol-3,l1,20-triohe, dehy 3,083,863 A Z’ 19 drobrominating the latter to form I6a~methyl-18-nor-A4 with oxygen in the presence of potassium tertiary butylate pregnene-l7a-ol-3,l1,20-trione, introducing a hydroxyl to form 3-ethylenedioxy-l7a-hydroperoxy-l6tx-methyl-18 group in the 21-position by microbiological means with Colletotrichum lindemuthianum to form 16a-methyl-18 nor-cortisone and recovering a compound of the above nor-pregnane-l1,20-dione, reducing the latter with zinc and acetic acid to form 3-ethylenedioxy-16a-methy1-18 nor-pregnane~17ot—o1-l1,20-dione, hydrolyzing the latter formula. under acidic conditions to form 16ot-methyl-18-nor-preg 8. The process of claim 7 wherein the oxidation is nane-l7a-ol-3,l1,20-trione, reacting the latterwith bro re?ected with oxygen in the presence of potassium tertiary mine in acetic acid to form 4B-bromo-16ct-methyl-18-nor .butylate. pregnane-17a-ol—3,l1,20-trione, dehydrobrominating the 9. The process of claim 7 wherein the reduction is ef 10 latter in the presence of a mixture of lithium bromide and ' fected with zinc and acetic acid. lithium carbonate to form 1oat-methyl;ls-nor-A‘i-preguene 10. The process of claim 7 wherein the dehydro 17u-ol-3,11,20-trione, subjecting the latter to the action bromination is effected with a mixture of lithium bromide of diastases secreted by Colletotrichum lindemuthianum and lithium carbonate. to form l6a-methyl-18-nor-cortisone and recovering a 11. A process for the preparation of a compound hav 15 compound of the above formula. ing the formula 13. A process for the preparation of 16a-methyl-18 nor-pregnane-17a-ol-3,l1,20-trione which comprises react CHnOR E 0 ing 3-ethylenedioxy-16a-methyl-‘1S-nor-pregnane-l1,20-di =0 one with acetic acid anhydride to form 3-ethylenedioxy Mon OH I mam 20 IGa-methyl - 20 - acetoxy-l8-nor-A17(2°)-pregnene-1l-one reacting the latter with perbenzoic acid to form 3-ethyl enedioxy-l6a-methyl - 17,20v - epoxy-20-acetoxy-18-nor pregnane-l l-one and subjecting the latter to acid hydroly sis to form 16oc-methyl-l8-nor-pregnane-17u'-ol~3,11,20 25 trione. ‘ 14. A process for the preparation of compounds hav wherein R is selected from the group consisting of hydro ing the formula gen and an acyl radical of an organic carboxylic acid - having 1 to 18 carbon atoms which comprises oxidizing 3-ethylenedioxy - 16oz - methyl-18-nor-pregnane-11,20-di H _ one wtih oxygen in the presence of potassium tertiary 30 butylate to form 3~ethylenedioxy-17a-hydroperoxy-16a methyl-lS-nor-pregnane-l1,20-dione, reducing the latter CH3 with zinc and acetic acid to form 3-ethylenedioxy-16a methyl-18-nor-pregnane-l7a-ol-11,20-dione, hydrolyzing the latter under acidic conditions to form 16u-methyl-18 0.. nor-pregnane-17a<ol-3,11,20-trione, reacting the latter with bromine in acetic acid to form 4B-bromo-l6a-methyl-18 nor-pregnane-17u~ol-3,11,20 - trione, dehydrobrominating the latter in the presence of a mixture of lithium bromide and lithium carbonate to form 16tz-methyl-l8-nor-A4 wherein R is selected from the group consisting of hydro~ 7 gen and an acyl radical of an organic carboxylic acid hav ing 1 to 18 carbon atoms which comprises oxidizing 3 ethylenedioxy-16a-methyl - 18 - nor-pregnane-11,20-dione pregnene-17a-ol-3,l1,20-trione, reacting the latter with with oxygen in the presence of an alkali metal tertiary iodine in the presence of a mixture of calcium oxide and butylate to form 3-ethylenedioxy-l7u-hydroperoxy-l6a methyl-18-nor-pregnane-11,20-dione, reducing the latter to calcium chloride to form 2l-diiodo-l6a-methyl-l8-nor-A4 pregnene-17a-ol-3,l1,20-trione, reacting the latter with an form 3-ethylenedioxy-l6a-methyl-l8-nor-pregnane-17ot alkali metal salt of a lower alkanoic acid to form 21-acyl 45 ol-11,20-dione, hydrolyzing the latter under acidic condi oxy-16a-methyl - 18 - nor-N-pregnene-l7a-o1-3,11,20-tri tions to form l6a-methyl-18-nor-pregnane-17a-ol-3,11,20 one, hydrolyzing the latter to form 16a-methyl-18-nor cortisone and recovering a compound of the above trione, reacting the latter with bromine to form 4B-bromo l6a-methyl é l8 - nor-pregnane-l7a-ol-3,l1,20-trione, de formula. hydrobrominating the latter to form 16oc-methyl-18-nor ,A4-pregnene-17u-ol-3,11,20-trione, reacting the latter with 12. A process for the preparation of a compound hav ing the formula iodine in the presence of a mixture of calcium oxide and, calcium chloride to form 21-diiodo-16u-methyl-18-nor onion n 0 on . A4-pregnene-17 u-ol-3,11,20-trione, reacting the latter with =0 '--on 55 L0H’ an alkali metal salt of a lower alkanoic acid to form 21 acyloxy-16a-methyl - 18 - nor-A4—pregnenel7a-ol-3,11,20 trigone and hydrolyzing the latter to form 16a-methyl-18 nor-cortisone. 60 wherein R is selected from the group consisting of hydro gen and an acyl radical of an organic carboxylic acid hav ing 1 to 18 carbon atoms which comprises oxidizing 3 ethylenedioxy - 16a - methyl-18-nor-pregnane-11,20-dione 65 References Cited in the ?le of this patent UNITED STATES PATENTS 2,961,441 Bogert et al ___________ _._ Nov. 22, 1960 OTHER REFERENCES Arth et al.: I.A.C.S., June 20, 1958, page 3160'.