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‘ ,, .. Unite "1 States Patent 0 ice 3,080,397 PM“ Ma, 5, 1,63 1 3,080,397. ll-UNSUBSTITUTED AM-PREGNADIENE-Uu-OL ' ' 1,201-DI0NES ' ' ' ' Albert Bowers and Lawrence; H. Knox, Mexico City, Mexico, assistants,v by meme assignments, to Syntax Corporation, a corporationof Panama No Drawingf Filed Felt’.v 14, 1962', Set. No. 173,136 11 Claims. (Cl. ?ll-#391743) The present invention relates to novel cyclopentano phenanthrene denivatives ‘and to a process‘ ‘for the produc tion thereof. 7 ‘More particularly the present ‘invention relates to A2-4 pregna-dien-17u-o1-l,20-dione,_the, 1604- and lé?-rnethyl, _ and/or. 2l-hydroxy derivatives thereof. The novel‘ compounds of the present invention are representedby the following formulas: CHzOH ‘ CH3 8 I535” In the ‘above, formulas R represents hydrogen or -a_ hydrocarbon carboxylic acyl group of less than 12 car bon atoms and. R3 represents hydrogen, wmethyl or Be methyl. The acyl group is derived from hydrocarbon ca-r b'pxylic acids containing less than 12carbon atoms’which may be saturated or unsaturated, of straight, bremched, cyclic or cyclic-aliphatic chain, aromatic and may be sub stituted by functional groups ‘such as hydroxy, valkoxy containing up to 5 carbon atoms, 'acyloxy containing up to 12 carbon atom-s, nitro, amino or halogen. Typical ester groupsv arev the acetate, p‘ropi'orrate, enanthate, 4 benzoate, trimethylacetate, t-butylaoetate, phenoxy'ace tate, cyclopentylpropionate, aminoacetate and ,B-chlo-ro propionate. The compounds represented by the above formulas are progestationail agents with oral activity, useful in fertility control aswell as exhibiting an-til-estrogenic and antisgonadotrophic ‘activities. In addition theyv lower the cholesterol level in the" blood ‘serum and adrenals. The novel compounds of this invention are prepared by the process illustrated as follows; ‘ ‘ in the above formulas R and B1 have the same mean ing as previously set forth and Ac represents vthe acetyl sedisal In‘ practicing the; process outlined, above,- the starting compound, lheichsteinfs compound “S’? or the 165 methyl mmmmetm derivative thereof, is conventional— ly.v treated with, tormaldehyde in; the presence" of; an acid to givethe'respeetive 17,20;20,2lsbisrnethylenedioxy assess? . 3 ii _ moniurn chloride and the ammonia was allowed to evap derivative v(l). Reduction of the A4-3-keto-moiety of the latter derivative, with an alkali metal, preferably orate. The product was extracted with ether, Washed with water, dried and the ether evaporated to afford a lithium, in liquid ammonia, yields the corresponding 17,20;20,2l - bismethylenedioxy-allopregnan-3-one corn gum which was absorbed from 200 cc. of benzene onto pound (ll). This compound is treated with ‘approxi 200 g. of alumina. Elution with benzene-ether afforded a product which upon recrystallization from acetone rna-tely 1 molar equivalent of bromine in the presence of hexane gave 17,20;20,21Jbismethylenedioxy-l6a-methyl hydrogen bromide to give the Zea-bromo derivative there allopregnan-3-one. of which upon dehydrobromination, preferably with By the same technique 17,20;20,21-bismethylene calcium carbonate in dimethylformamide affords the corresponding 17,20;20,21 — ‘bismethylenedioxy-Al-allo 10 dioxy-165-methyl-M-pregnen-3-one was converted into 17,20;20,2lebismethylenedioxy-l6B-methyl-allopregnan-5 pregnen-3-one (ill). The latter compound is treated with hydrogen peroxide in the presence of sodium hy one. Example III A solution of 3 g. of 17,20,202lebismethylenedioxy droxide to give the corresponding lulu-oxide (1V) which upon reduction, preferably with lithium 'al-unnnum hydride yields the corresponding 17,20;20,21-bismethyl enedioxy-allopregnane-la, 3,8-diol (V). Acetylation of l-éa-methyl-allopregnan-3-one, in 100 cc. of acetic acid was treated with a few drops of hydrogen bromide in the latter steroid with approximately 1 molar equivalent ‘acetic acid and subsequently dropwise and with stirring, of acetic anhydride in pyridine gives the Iii-acetate there with a solution of 1.1 molar equivalents of bromine in 50 cc. of acetic acid. After all the bromine had ‘been consumed, water was ‘added; the formed precipitate ?l tered, washed with water so neutral and dried under vacuum. Recrystallization from acetone-hexane yielded of (V1) which upon oxidation, such as with Jones re agent (8 ’N chromic acid), yields the corresponding 17,20;20,21 -' bismethylenedioxycllopregnan-B?-oLl-one acetate (Vii), Treatment of'ithe latter compound with potassium ‘acetate in a suitable solvent such as methanol, at re?ux temperature, for a period of time of the order 2a-bromo-l7,20;20,21-bismethylenedioxy-1‘6a-methyl-allo pregnan-Ii-one. of 2 hours, ‘affords the corresponding l7,20;20,2l-bis— Upon treatment of 17,2*O;20,‘21=bismethylenedioxy-16,8 methyl-allopregnan-3-one by the above method, Zia-bromo methylenedioxy-hz-allopregnen-l-one (VIII). This com pound is treated with N-bromosucoinimide in an inert solvent such as carbon tetrachloride, preferably under irradiation with an electric lamp, thus‘furnish-ing the Lin-bromo derivative which upon dehydnobromination, preferably with calcium carbonate in dimethyl form 17,20;20,2l-bismethylenedioxy-16?-methyl-allopregnan-3 one was obtained. 30. 1 Example IV 2 g. of 2c~bromo-17,20;20,21-bismethylenedioxy-16a methyl~allopregnan-3-onc, in 40 cc. of cold dimethyl iamid'e, produces 2the corresponding 17,20;20,2l-bis— methylenedioxy-Azd-pregnadien-leone (IX); The 17,20; 20,21—bismethylenedioxy group is conventionally 11y formamide was added over 15 minutes to a suspension of 5 g. of ?nely divided calcium carbonate in 15 cc. of re drolyzcd with an 'acid, such as formic acid, to produce 35 ?uxing dimethylformamide. The mixture was re?uxed for 30 minutes further, cooled and ?ltered. The ?ltrate the 17c,21-dihydroxy-20—-keto<compounds (X). Elimi nation of the ll-hydroxyl group takes place by treat was diluted with water and extracted with ethyl acetate. The extract was washed with dilute hydrochloric acid, ment with ttosyl chloride in pyridine and sub-sequent water, aqueous sodium bicarbonate solution and water, detosylaltion of the 21-tosylate formed, as by re?uxing with sodium iodide in ‘acetic acid, thus yielding the 21 40 then dried over anhydrous sodium sulfate and evaporated desoxy compounds (XI: R=H). Conventional acyla to dryness. tion of these compounds with an acylating agent such as the lanh-ydride of a hydrocarbon oarboxylic acid of the type previously de?ned, in the presence of p-toluene lization .aiforded methyl-Al-allopregnen-B'-0ne. sulfonic acid, affords the l7-acylates of said compounds. The following speci?c examples serve to illustrate, methyl-allopregnan-3-one was treated following the vabove but are not intended to limit" the scope of the present methyl-A1-allopregnen-3-one. invention: procedure to give 17,20;20,2l-bismethylenedioxy-l6B Example V Example I 50 with the foregoing example) in 350 cc. of methanol was treated while stirring with 20 cc. of a 4 N aqueous solu tion of sodium hydroxide and 20 cc. of 30% hydrogen of chloroform were added 40 cc. of 37% aqueous form aldehyde and 5 cc. of concentrated hydrochloric acid and peroxide, keeping the temperature at approximately 15° the mixture was stirred for 48 hours at room temperature. C. The solution was left at 0° C. overnight, then poured into ice water. The formed precipitate was ?ltered, washed with water and dried. Recrystallization from The two layers were separated; the ‘aqueous layer was washed with chloroform and the combined organic solu tions were washed with water to neutral, dried over an acetone-hexane gave lain-oxide-17,20;20,21-bismethyl hydrous sodium sulfate and evaporated to dryness. The enedioxy~16u-methyl-allopregnan-3-one. residue was recrystallized from methanol~ether thus af When applying the above procedure to 17,20;2\(},21-bis methylenedioxy-16,8-methyl-A1-allopregnen-3~0ne, there 17,20;2‘O,21 - bismethylenedioxy - 16a - methyl M-pr'egnenJ-one. was obtained 1a,2u-oxido-l7,20\;20,2l-bismethylenedioxy Following the above procedure there was treated 16;} methyl-A‘Lpregnene-l7oc,2l-diol-3,20-dione . (Djerassi, US. patent application Serial No. 824,199, ?led July 1, 1959), thus giving 17,2G;20,2l-bismethylenedioxy-1??-methyl-M pregnen-3-one. Example 11 A solution of 5 g. of 17,20;20,2l-bismethylenedioxy 116oc-methYl-N-allOptbgnCYl-B~0ne (obtained in accordance diol-3,20-dione (Djerassi et a1.v US. patent application Serial No. 789,248, ?led January 27, 1959) in 200 cc. fording 17,20;20,21 - bismethylenedioxy - 16a - 2a - bromo - 17,20;20,21 - bismethylenedioxy - 16,8 - " To a solution of 5 g. ‘of 16a-methyl-A4-pregnene-17a,21 Silica gel chromatography and recrystal 1é?-methyl-allopregnan-S—one. 65 Example VI A solution of 4 g. of 1a,2a-oxido-17,20;20,2l-bismeth ylenedioxy-16cv-methyl-allopregnan-3-one, in 200 cc. of tetrahydrofuran was added over a 30‘ minute period to a A solution of 4 g. of 17,20;2-0,2l-bismethylenedioxy 70 stirred suspension of 4 g. of lithium aluminum hydride in 200 cc. of anhydrous tetrahydrofuran. The mixture 16a-methyl-A4-pregnen-3-one, in 80 cc. of dioxane-ether was refluxed for 2 hours, then cooled and cautiously (1:1) was added in a steady stream to a solution of 0.4 treated with 20 cc. of ethyl acetate and 5 cc. of water. g. of lithium in 400 cc. of anhydrous liquid ammonia Solid sodium sulfate was added, the inorganic material with good stirring. At'the end of the addition the blue color was discharged by the addition ‘of 20 g. of "am 75 ?ltered off and thoroughly washed with hot ethyl acetate, 5 8,080,397. 6. methvlenediaxy - 16a .*-.methyhai-allopresneml-One the combined organic solutions upon evaporation yielded a crudemate-rial, which-was puri?edby crystallization from acetone-hexane thus giving 17,20;2i0,21-1bismethy1 dien-l-on'e. ‘ enedioxy-l6m-methyl-allopregnane-1a,3;3-diol. ' premadienrlrone éf.6ll%.formic acidvfor washeat'edonthe 1 hour, cqqled,.dilutéd steam. bathwith ‘with 6.0: water. and- thefprecipitate, was- collected» Washed/with water, allopreg-nane-lol,3B-diol.v dried. and. recrystallized from acetone-hexane, thus. a?ordi Exam pleVII . A mixture of 3 g. of 17,20;20,2IJbismethyIene-dioxy 16u-methyl-allopregnane-la,3/8-diol, 14 cc. of pyridine and 1.1 molar equivalents of acetic anhydride was kept at ' Upon treatment of 17,20;20,2l-bisrnethylenedioxy-116B rnethyl-A2»4-pregnadien-l-one by the foregoing1 method, there was produced, 1'6;3;methyl-A2;f?-pregnadierie717a,2l 0° C. overnight, poured into, ice water, the formed precipi 1.5. lenedioxy-16a-methyl-allopregnane-1a,3B-diol-3-acetate. Following the same procedure there was treated 17,20; 20,21 - bismethylenedioxy - 1613 - methyl - allopregnane 10:,3?-di0l, to give 17,20;20,2l-bismethylenedioxy-lo? 2.0,. methyl-allopregnane-lu,3?-diol-3-acetate. Example. VIII acetone was'cooled to 0° C. and treated underv an atmos ' 3.v s- of.17,2Q;29,,2.l:bismethylenedioxyél?e:methylrAzd verted into. l_7,2_0;20,21bismethylenedioxyd6§=methyl A solution of 2 g. of 17,20;20,2l-bismethylenesdioxy lée-methyl-allopregnane-1u,3;8-diol-3-acetate, in 20 cc. of ' Exlurlnle.2H,v By the same procedure 10:,2op-OXidO-17,20;20,21-bi$~ methylenedioxy-l?li-methyl-allopregnan-fa'-one was ecu; tate was ?ltered, washed with Water and dried. Crystalli zat-ion from acetone-hexane gave 17,20;20,21-bismethy and. 1.720202% bismethylenedisxy - l??eniethyl-Ajt'epregna diol-1,20-di0ne. ' ' ' Example XII A solution of 2.5 g. of ‘16u-rnethyl-A2d-pregnadiene-17a, 21-diol-1,20-dione, in 25'- cc. of pyridine was cooled to 0° C. Under stirring-there was added 0.7 g. of tosyl chlo ride, the mixture was kept for 16 hours at 0° C., diluted with 100 cc. of chloroform, washed ‘with dilute hydrochlo ric acid, water, aqueous sodium bicarbonate solution and again with water, dried over anhydrous sodium sulfate and then evaporated to dryness under reduced pressure. Thus 2.5. there was obtained the crude, 16a-methyl-AZA-pregnadiene 170;,21~diol-'1,20-dione-2l-tosylate. phere of nitrogen and with. stirring, with a solution of 8. N chromic acid (prepared by mixing 26 g. of chromium tri l V i A solution of 2.0 ‘g. ofjthe above crude compound in 100 cc. of glacial acetic acid was treatedwith 7 g. of oxide with 23 cc. of concentrated sulfuric acid and diluting sodium iodide and‘ themixtu're was re?uxed for- 2 hours, with water to 100 cc.), until the color of the reagent per 30 poured into ice water and extracted several times with sisted in the mixture. It was stirred for 5 minutes further methylene chloride; the extracts were combined, washed at 0-5” C. and diluted with water. The precipitate was successively with aqueous sodium carbonate solution, so collected, washed with water and dried under vacuum, dium sul?te solution and water and then evaporated. By thus affording a crude product which upon recrystalliza crystallization of the residue from acetone-hexane there tion from acetone-hexane gave 17,20;20,2l-bismethylene was obtained 16uemethyl-AM-pregnadien-17a-ol-1,20= dioxy-l6a-methyl-allopregnan-3?-Ol-1-One-3-aCetate. dione. By the same method l7,20;20',2l-bismethylenedioxy 1613-methyl-allopregnane-1u,3/3-diol-3-aoetate was trans Following the two foregoing procedures there was treated formed into 17,20;20,21-bismethylenedioxy-hip-methyl 16B - methyl - A“ - pregnadiene , 17a,21 - diol 1,20-dione, affording successively 16/3-methyl-A2-4-pregna allopregnan-3?-0L1-one-3-acetate. diene-l7a,2l-diol-1,20-dione-21-tosylate and lop-methyl A214—pregnadien-17a-01-1,20—di011e. Example IX Example XIII Reic'hstein’s “S” compound (A4-pregnen-1'7a,21-diol A mixture of 5 g. of 17,20;20,2l-bismethy1ene-dioxy~ 16a-methyl-al1opregnan-3?-ol-1-one-3-acetate (obtained in accordance with the foregoing example), 10 g. of potas 45 3,20-dione) was treated by the procedures described in the above examples, thus affording consecutively 17,20; re?ux for 2 hours, thereafter, it was cooled and poured 20,21-bismethylenedioxy-A4-pregnene-3-one, 17,20;20,21 sium acetate and 250 cc. of methanol, was boiled under into Water. The formed precipitate was ?ltered oil, dried bismethylenedioxy - allopregnan-B-one, and recrystallized from methylene. chloride-hexane to give 17,20;20,2l - bismethylenedioxy - 16a - methyl - A2 - allo pregnen-l-one. 2a-bromo<l7,20; 20,21~bismethylenedioxy-allopregnan-3-0ne, 17,20;20,21 50 bismethylenedioxy - A1 ~ allopregnen-3-one, 17 ,20;20,2l-bismethylenedioxy-16B-methyl-allopregnan~ 3B-ol-1-one-3-acetate was treated by the foregoing proce dure, thus yielding 17,20;20,21~bismethylenedioxy-l6? methyl-az-allopregnan-l-one. Example X 4.2 g. of 17,20;20,21-bismethylenedioxy-IGu-methyI-AZ 1a,2ol-OXidO 17,20;20,21-bismethylenedioxy-allopregnan-S-one, 17,20; 20,21-bismethylenedioxy-allopregnane-10:,3/8-di0l, 17,20; 20,21 - blsmethylenedioxy-allopregnane-1a,3B-diol-3-ace tate, 17,20;20,21ebismethylenedioxy-allopregnan-3B-ol-1 one - 3 - acetate, 17,20;20,2l-bismethylenedioxy-A2-allo pregnen-l-one, 4?-bromo-17,20;20,2l-bismethylenedioxy oz-allopregnen-l-one, 17,20;20,21-bismethylenedioxy-A2'4 pregnadien - 1 - one, A214 - pregnadiene-17u,21‘dio1-1,20 dione, AZA-pregnadiene-17a,2l-diol-1,20-dione-21-tosylate, allopregnen-l-one, in 200 cc. of carbon tetrachloride was re?uxed with 2.7 g. of N-bro-rnosuccinimide for 11/2 hours 60 and azr‘i-pregnadiene-17ot-ol~1,20-dione. under irradiation with a GB. 100 w. lamp. The mixture Example XIV was ?ltered to eliminate the succinimide that is formed To a solution of 5 g. of 16oc-methyl-A2'4-pregnadien during the reaction. The ?ltrate was evaporated to dry 17a-ol-1,20-dione, in 100 cc. of anhydrous benzene there ness under reduced pressure. Recrystallization from methylene-chloride-hexane gave 4,B-bromo-l7,20';20,2l 65 were added 1 g. of p-toluenesulfonic acid and 10 cc. of bismethylenedioxy-16aJmethyl-A2-allopregnen-1-one. 4 g. of the above compound was refluxed with 4 g. of calcium carbonate and 200 cc. of dimethylformamide for acetic anhydride and the mixture was allowed to stand for 24 hours at room temperature, poured into ice and water, and the resulting mixture stirred to effect hydrolysis of the excess anhydride. The benzene layer was separated 30 minutes. The mixture ?ltered, the solvent evaporated under reduced pressure and the residue crystallized from 70 and Washed with 10% sodium carbonate solution and water. Drying, evaporation and crystallization of the acetone-hexane to afford 17,20;20,2l-bisme-thylenedioxy 16a~methyl-dzi‘l-pregnadien-l-one. Following the above procedures there was treated 17,20; 20,21 - bismethylenedioxy - 1618 - methyl - A2 - allopreg— nen-l-one giving successively 4,8-brorno-l7,20;20,21-bis 75 residue from ether-hexane produced 16a-methyl-A2'4 pregnadien-17a-0l-1,20-dione-acetate. Following the above procedure were treated A2,“ pregnadien - 17a - ol - 1,20 - dione and IGB-methyI-AM 3,080,397 pregnadien-17a-0l-L20-dione, a?ording respectively A“ pregnadien - 17a-0l-1,20-dione—acetate and 2. AZA-pregnadien-l7a-ol-L2O-dione. 16?-methyl A2,4-pregnadien-17c¢—ol-1,ZO-dione acetate. VExam'ple XV The starting compounds of the foregoing example were V 3. 1o?-methyl-AzA-pregnadien-17a-ol-1,20-dione. 4. 16oc-methyl-Alipregnadien-17a—ol-1,20-dione. r. A214-pregnadien47a-o1-1,ZO-dione-acetate. 5 tate. treated by the procedure described in the sameexample, except that acetic anhydride was substituted by propionicv anhydride, caproic anhydride and cyclopentylpropionic anhydride, thus giving the corresponding propionates, caproates and cyclopentylpropionates of the said com 6. v 7. 16,8 - methy1-A'l»4-pregnadien-l7oa-ol-l,20-dione-acc . 16o‘.-methyLMA-pregnadien-l7m-ol-L20-diorie-ace tate. ' 8. A compound of the following formula: 10 (‘rm-0H 0:0 pounds. We claim: |—-~0H 1. A compound of the following formula: CH3 15 ~w R’ o I! 20 wherein R1 is a member of the group consisting of hy~ wherein R is selected from the group consisting of hy 25 drogen and a hydrocarbon carboxylic acyl group of ‘less than 12 carbon atoms and R1 is a member of the group consisting of hydrogen, oe-methyl and B-methyl. drogen, e-methyl and ?-methyl. 9. Aze-pregnadiene-17a,21-dio1-1,20-dione. 10. 1é?-methyl-Az'4-pregnadiene-17c¢,2l-diol-LZO-dione. 11. 16m-methyl-A2’4-pregnadiene-17a,21»diol-1,20-dione. No references cited.