US2888456A - Bisdioxy steroids and method of making same - Google Patents

Description

United Sttes atent BISDIOXY STEROIDS AND lVIETHOD OF MAKING SAME Roger E. Beyler, Westfield, and Lewis H. Sarett, Princeton, N.J., assignors to Merck & Co., Inc, Rahway, NJ., a corporation of New Jersey No Drawing. Application August 18, 1958 Serial No. 755,400

24 Claims. c1. zen-239.55

This invention relates generally to new compounds derived from steroids which have attached to the condensed ring nucleus a dihydroxyacetone side chain. More particularly it is concerned with new steroids in which a dihydroxyaceton'e side chain of a pregnane or unsaturated pregnane is deactivated by formation of a bismethylenedioxy or a bis-substituted methylenedioxy derivative. It is further concerned with a method for making such new compounds from steroids having a free or esterified dihydroxyacetone side chain.

This application is a continuation-in-part of our copending application Serial No. 632,009, filed January 2, 1957, now abandoned.

It is well known that the vast majority of physiologically-active steroids are members of the pregnane series having a free or esterified dihydroxyacetone side chain at the C-17 position. This side chain is subject to oxidation at C-21, to reduction at C-20, to rearrangement leading to a D-homo steroid and to decomposition under strongly acidic or basic conditions. Since such reactions and reaction conditions are often necessary to modify or introduce functional substituents in the nucleus of the steroid molecule, the ability to deactivate or block the dihydroxyacetone side chain is important for the practical synthesis of physiologically-active steroids. Some success has been achieved by forming C-20 ethylenedioxy steroids but this blocking group is not completely satisfactory since it is quite acid labile and serves to deactivate only one portion of the dihydroxyacetone side chain, the ketone function.

It is an object of our invention to provide a new series of steroid compounds in which the dihydroxyacetone side chain of a pregnane or unsaturated pregnane is deactivated by a very stable group wherein all three of the carbon atoms in the dihydroxyacetone chain are protected. It is a further object to protect the side chain of 17a,2l-dihydroxy-ZO-keto pregnanes and unsaturated derivatives thereof with a group that can be conveniently removed to regenerate the dihydroxyacetone moiety. A more specific object is to provide new derivatives, of steroids having a dihydroxyacetone side chain in which this functional moiety is protected by a bismethylene-(or substitutedmethylene) dioxy group. An additional object is aprocess for making this new type of steroid from a steroid having the dihydroxyacetone side chain. Other and further objects will become evident from the detailed explanation of our invention hereinbelow.

We have found that when a steroid having a dihydroxyacetone side chain attached to the condensed ring steroid nucleus is treated with formaldehyde or a lower alkyl aldehyde in the presence of a strong acid there is obtained a bismethylenedioxy or bis-substituted-methylenedioxy steroid in which all three carbon atoms of the dihydroxyacetone moiety are a part of at least one of the fivemembered rings thus formed. We have also found that the presence of nuclear substituents or nuclear double bonds do not interfere with or prevent the formation of such bis-dioxy steroids. Thus, when the dihydroxyacetone 2,888,456 Patented May 26, 1959 21 Han-u Cn-C wherein n is a whole number and may vary from 0-5 inclusive.

As aldehydes in our process, we employ formaldehyde or straight chain aliphatic aldehydes of the formula RCHO, wherein R is a lower alkyl radical. The lower alkyl radical may have up to six carbon atoms, acetaldehyde, propionaldehyde, n-butyraldehyde, n-valeraldehyde, n-caproaldehyde and n-heptaldehyde being exemplary of the lower alkyl aldehydes. Formaldehyde is the preferred reagent since the resulting 17-20,20-2l bismethylenedioxy steroids are obtained in good yield in crystalline form.

The new process may then be pictured structurally as applied to a steroid of the pregnane series having a dihydroxyacetone side chain at C-l7 as follows:

wherein R is hydrogen or a lower alkyl radical. By the dihydroxyacetone side chain is meant the 176t-hydroxy- 20-keto-2l-hydroxy moiety of a steroid such as I. We refer to such new steroids as 17-20, 20-21 bismethylenedioxy (where R is hydrogen) or l7-20,20-21 bis-substituted-methylenedioxy (where R is lower alkyl) steroids. Although the dihydroxyacet'one moiety must be unsubstituted in order to react as shown above, the steroid actually charged to the reaction mixture may, if desired for convenience sake, be esterified at either or both of the hydroxy groups since such ester groups are hydrolyzed under the reaction conditions.

It will be evident that a dihydroxyacetone side chain located at positions of the steroid condensed ring nucleus other than at C-17, e.g. at 0-16, at C-17a in D-homo steroids, and at other positions in the nucleus may also be converted by treatment with an aldehyde under our reaction conditions to the corresponding bismethylenedioxy or bis-substituted-methylenedioxy compounds. However, since the physiologically-active steroids known at the present time have this function at C-l7, we will discuss primarily those compounds, which may be described as 1711,21-dihYdIOXY-20-k6t0 steroids of' the pregnane series.

17 20,20-21 bismethylenedioxy (or his substituted- Inethylenedioxy) steroids of the pregnane series are prepared by treating a l7a,2l-dihydroxy-20-keto steroid of the pregnane series with a suitable aldehyde in the presence of a strong acid. An excess of aldehyde is employed in order to obtain the optimum yield of bis -dioxy compound. We prefer to employ formaldehydeor' a source of formaldehyd'eto obtain the 17-20,20-21 bism'ethylenedioxy steroid. Acetaldehyde, propionaldehyde, buty'rgssaaee o a aldehyde and valeraldehyde are examples of other aldehydes which react satisfactorily with a 17a,2l-dihydroxy- ZO-keto steroid to form respectively 17-20,20-21 bisethylidenedioxy; 17-20,20-21 bisvaleraldioxy; and 17-20,20-21 bisbutyraldioxy steroids of the pregnane series.

In making a 17-20,20-21 bismethylenedioxy steroid we are able to use formaldehyde itself, the readily available 40% aqueous formaldehyde solution (formalin) or other compounds which act as a source of formaldehyde in the reaction mixture. Paraformaldehyde, formal and trioxane are examples of compounds which act as a source of formaldehyde.

The reaction is carried out in the presence of a strong acid, such as hydrochloric, perchloric, hydrobromic, sulfuric, phosphoric and like acids. Acids which have a -log k of less than 2.25 are considered strong acids for our process and any of these may be employed. The log k of a large number or organic and inorganic acids appears in Langes Handbook of Chemistry, Handbook Publishers Inc., 8th ed., 1952, pages 1229-1233. This and similar tables in other texts provide ready information as to the log k values of different acids so that acids suitable for use in our invention may be determined readily. Lewis acids or formic acid may also be used as the acid catalyst in preparing the 17-20,20-21 bis-dioxy steroids although the log k of formic acid is 3.75.

The reaction of a 17oz,21-dihydroxy-20-keto steroid with formaldehyde, or other aldehydes, is carried out in an organic solvent inert under the reaction conditions. This may be a water-miscible solvent such as dioxane or tetrahydrofuran in which case the reaction takes place in a one-phase solvent system. Alternatively, and preferably, formation of the 17-20,20-21 bismethylenedioxy or bissubstituted-methylenedioxy steroid is eflfected in a twophase reaction mixture wherein the steroid is dissolved in a water-immiscible organic solvent and the second phase is the aqueous acid-aldehyde phase. Such an aqueouszorganic solvent two-phase reaction mixture is very satisfactory and is preferred for optimum yields under our operating conditions. It is desirable that both the starting material and the reaction product be soluble in the organic solvent, but satisfactory yields and quality of 17-20,20-21 bismethylenedioxy steroid are obtained when the end product is soluble and the starting 17a,21-dihydroxy-ZO-keto steroid is insoluble in the organic solvent. Suitable water-immiscible organic solvents for our process are chloroform, methylene chloride, ethylenedichloride, carbon tetrachloride, ethylene dibromide, methylene bromide, benzene, ethyl ether and the like, the chlorinated solvents being most satisfactory.

Formation of our new 17-20,20-21 bismethylenedioxy (or bis-substituted-methylenedioxy) steroids of the pregnane series is ordinarily conducted at temperatures from about 30 C. to about +50 C. For ease of operation temperatures of C. to about +35 C. are preferred and satisfactory yields are realized at such temperatures with most steroids.

The time required for obtaining optimum yields of 17-20,20-21 bismethylenedioxy steroids or 17-20,20-21 bis-substituted-methylenedioxy steroids will depend to some extent on the particular reaction temperature utilized. We have also found that the reaction time necessary for good yields is a function of the type of 1711,21- dihydroxy-ZO-keto steroid employed as starting material. For instance, in a chloroforrn-formalin-hydrochloric acid reaction system, about 40-50 hours are required for optimum conversion of cortisone to 17-20,20-21 bismethylenedioxy-4-pregnene-3,1l-dione, whereas only -30 minutes are needed to convert prednisolone in high yield to 17-20,20-21 :bismethylenedioxy-1,4-pregnadiene-l119-01-3- one.

This ditference in steroid reactivity does not, however, present any serious difiiculty in readily determining the proper length of time to run the reaction under any desired process condition. The course of conversion of the 41 17a,21-dihydroxy-20-keto moiety of a steroid of the pregnane series to a 17-20,20-21 bismethylenedioxy or bis-substituted-methylenedioxy derivative is readily followed by use of a dianisole bisphenyltetrazolium chloride reagent, commonly known as the B.T. reagent or the B.T. test. This reagent reacts specifically with a dihydroxyacetone grouping to give a deep blue solution. It does not form a blue color with the 17-20,20-21 bismethylenedioxy or bis-substituted-methylenedioxy steroids. By means of this B.T. test, therefore, the degree of reaction can be followed quantitatively, or if desired only semi-quantitatively, since the intensity of the blue color is a function of the amount of 17a,21-dihydroxy-20-keto steroid present in the solution tested. This intensity of color can conveniently be measured against a known standard solution and the extent of reaction easily calculated. Use of the Blue Tetrazolium (B.T.) reagent in assaying for the presence of a dihydroxyacetone moiety is described more fully in a publication by Mader et al., Anal. Chem. 24, 666 (1952). 1

By the process discussed above, and where necessary following the course of reaction by the B.T. test, any 17u,21-dihydroxy-20-keto steroid of the pregnane series may be converted to a 17-20,20-21 'bismethylenedioxy or bis-sub-stituted-methylenedioxy steroid.

Functional groups or substituents in other parts of the pregnane molecule do not interfere with formation of the bis-dioxy side chain and in most cases are not themselves destroyed or modified under the reaction conditions. Since strong acid is present, during the reaction, any unusually acid-sensitive substituents in other portions of the molecule might possibly react and we prefer, where such side reactions are undesired, and apt to occur, to temporarily form, if feasible, an acid stable derivative of such substituents. In the case of ll-hydroxylated steroids. reaction at the ll-position may be substantially eliminated by carrying out our process in a solvent system essentially free of alcohols, particularly the lower alkanols. Thus, in an alcohol free system, hydrocortisone and prednisolone are readily converted by treatment with formaldehyde and strong acid to 17-20,20-21 bismethylenedioxy-4-pregnene- 11 3-ol-3-one and 17-20,20-21 bismethylenedioxy-1,4- pregnadiene-llfi-ol-Ii-one respectively. If alcohol should be present the 17-20,20-21 bismethylenedioxy derivative, of course, forms but an alkoxymethyl ether derivative of the ll-hydroxy group is also formed. This is, however, cleaved during removal of the bismethylenedioxy function.

Where functional substituents in other parts of the molecule, such as amines, are those that normally react with aldehydes, they will react during our process. This is not a serious difficulty since in most instances the original functional group can be regenerated readily.

We are able, therefore, to carry out our new process on steroids of the pregnane series generally. Ordinarily the steroid reactants will be substituted at the 3-position with an oxygen-containing function or a function reconvertible by hydrolysis to an oxygenated group, such as a keto or hydroxy group, or an ethylenedioxy, enamine, enol ether or ester moiety. The steroids may also have substituents such as hydroxy, keto, halo, ether or lower alkyl groups at other positions of the condensed ring nucleus, as for instance at positions 1, 2, 3, 4, 6, 7, 9, 11, 12, 14, 15 or 16. A preferred group of 17-20,20-21 bis-dioxy steroids of the invention have oxygenated functions at both the 3 and 11 positions of the condensed ring nucleus. Also included within the preferred embodiments of the invention are those bis-dioxy steroids having a halogen group such as chloro-bromo or fiuoro, at the 9-position of the ring. Our new compounds may be completely saturated or have one or more double bonds attached, for example, to carbon atoms 1, 4, 5, 6, 7, 11 or 14. For example, there may be double bonds in the 1:2, 4:5, 5:6, 8:9, 9:11 and at other positions of the molecule. Some representative examples of new steroids may by the method of our invention from the corresponding 17a,21-dihydroxy-20-keto steroids are 17-20,20-21 bismethylenedioxy-pregnan-3-ol 17-20,20-21 bismethylenedioxy-4-pregnen-3-one l7-20,20-21 bismethylenedioxy-4-pregnene-3,1l-dione 17 20,20 21 bismethylenedioxy 1,4 pregnadiene-3,1 1-

dione 17 20,20 21 bismethylenedioxy 1,4 pregnadienellfi-ol-3-one 17 20,20 21 bisethylidenedioxy 1,4 pregnadiene- 3,1l-dione 17 20,20 21 bisethylidenedioxy 4 pregnene 3,11-

dione 17 20,20 21 'bisethylidenedioxy 4 pregnene 115- ol-3-one' 17 -20,20-21 bisbutyraldioxy-4-pregnene-3,1l-dione,

17 20,20 21 bisbutyraldioxy 90c chloro 4 pregnene-1l/3-ol-3-one 17 20,20 21 bisvaleraldioxy 9a bromo 4 pregnene-l 1,8-01-3-one 17 20,20 21 bismethylenedioxy 9a fluoro 1,4-

pregnadiene-l 1,6-01-3-one 17 20,20 21 bismethylenedioxy 12 fluoro 1,4-

pregnadiene-3,l l-dione 17 20,20 21 bispropionaldioxy 4 pregnen 6 ol- 3,11-dione 17 20,20 21 bismethylenedioxy 6 methyl 1,4-

pregnadiene-l 1 8-ol-3-one 17 20,20 21 bismethylenedioxy 12oz chloro 4- pregnene- 1 1B-ol-3-one 17 20,20 21 bismethylenedioxy 4,6 pregnadiene- 3,1l-dione 17 20,20 21 bismethylenedioxy 9a fluoro 4- pregnene-l 1 fi-ol-B-one 17 20,20 21 bisrnethylenedioxy 4 pregnen 90:,1113- diol-3'one 17 20,20 21 bismethylenedioxy allopregnanc 3,11-

dione 17 20,20 21 bismethylenedioxy 19 nor 4 pregnene-l 1B-ol-3-one 17-20,20,21 bismethylenedioxy-4-pregnen-6-ol-3-one l7-20,20-21 bismethylenedioXy-4,9( 1 1)-pregnadien-3-one 17-20,20-21 bismethylenedioxy-9a-chloro-4-pregnen-3-one 17 20,20 21 bismethylenedioxy 16 methyl 1,4-

pregnadiene-l 15-01-3 -one 17-20,20-21 bismethylenedioxy-4-pregnene-11B-ol3-one 17 -20,20-21 biscaproaldioxy-pregnane-3 ,1 l-dione 17 20,20 -21 bispropionaldioxy 2 methyl 4 pregnene-3,l l-dione 17 20,20 21 bisethylidenedioxy 4 pregnen 90:,115-

diol-3-one 17 20,20 21 bisethylidenedioxy 9a fiuoro 16- methyl-1,4-pregnadiene-1 1 8-ol-3-one 17 20,20 21 bisethylidenedioxy 4 chloro pregnanc- 3,11-dione 17 20,20 21 bispropionaldioxy 16 methyl 4 pregnene 3,11 dione 17-20,20-21 bisethylidenedioxy-1,4-pregnadien-3-one 17 20,20 21 biscaproaldioxy 1,4,6 pregnatriene- 3,11-dione The desired products are isolated from the reaction mixture by extraction into an organic solvent followed by a chromatographic separation or by recrystallization from a suitable solvent. Certain of the 3,11-bisoxygenated-17-20,20-21 bismethylenedioxy ring A unsaturated steroids of the pregnane series have cortisone-like activity and may themselves be used in the treatment of diseases which respond to anti-inflammatory agents. For the most part, however, the greatest value of our new compounds lies in the fact that they represent intermediates in which the important -17 dihydroxyacetone side chain is rendered chemically inert and inaccessible so that reactions and transformations which would destroy an unprotected dihydroxyacetone moiety may be used safely on other portions of the steroid molecule. For example, Claisen condensations at positions alpha to a carbonyl group may be carried out without undesirable reaction in the side chain. In this way Z-methyl cortisone or 2-methyl hydrocortisone may be prepared from cortisone or hydrocortisone by first making the 17-20,20-21 bismethylenedioxy, or 17-20,20-2l bis substituted methylenedioxy, derivative, treating the resulting compound successively with methyl oxalate and a methylating agent, and finally treating the 2-methyl-17-20,20-21 bismethylenedioxy steroid with sulfuric acid to reverse the bismethylenedioxy function and obtain the Z-methyl cortisone or hydrocortisone. This process would not be feasible with an unprotected dihydroxyacetone side chain since extensive side reaction would occur at the 21-position.

Furthermore, after inactivation of the side chain by our method, it is now possible to treat a 17oz,2l-diOl-20- keto steroid of the pregnane series having a nuclear carbonyl or oxide function with a metal alkyl or metal Grignard reagent thereby alkylating the nucleus without adverse reactions in the side chain. These new compounds also provide a convenient method for selectively reducing a carbonyl group in the A ring of the steroid nucleus without also reducing the ZO-keto substituent, and for selectively blocking the 20-keto substituent of a 3,20- diketo steroid.

When the desired reactions have been performed on the steroid with the protected dihydroxyacetone side chain, the side chain can be readily regenerated by treatment of the 17-20,20-21 bismethylenedioxy or bis-substituted-methylenedioxy compound with acid. This process of reforming the 17oc-21-dihydroxy-20-keto steroid of the pregnane series is more fully described in our copending application Serial No. 632,026, filed January 2, 1957, now Patent No. 2,866,799.

The following examples are given for purposes of i1- lustration and not by way of limitation:

EXAMPLE 1 17-20,20-21-bismethylenedioxy-4-pregnene-3,II-dione 500 mg. of cortisone is suspended in 40 ml. of chloroform and 10 ml. of formalin (40% aqueous formaldehyde) and 10 ml. of concentrated hydrochloric acid are added. This two-phase system is stirred vigorously at room temperature for 52 hours. The aqueous phase is then made alkaline with aqueous sodium hydroxide, separated and extracted twice with chloroform. After washing with sodium bisulfite solution the chloroform is evaporated to give 685 mg. of crystalline residue. After recrystallization from acetone and methanol, 17-20,20-21- bismethylenedioxy-4-pregnene-3,1l-dione of melting point 253259 C. is obtained. Further purification raises the melting point to 259-262 C.

EXAMPLE 2 1 7-20,20-21-bismethylenedioxy-4-pregnene-3JI-diohe 500 mg. of cortisone free alcohol is suspended in 25 ml. of chloroform. To this mixture is added a solution of 10 ml. of concentrated hydrochloric acid and 10 ml. of formalin. The two-phase reaction mixture is stirred at room temperature for 19 hours, and at the end of this time, the chloroform layer is separated. It is washed with a saturated solution of sodium bicarbonate, dried and concentrated under vacuum to an amorphous residue. Upon treatment with boiling methanol, a crystalline product separates weighing 328 mg. and having a melting point of 220247 C. Further recrystallization from acetone-methylene chloride yields substantially pure l7-20,20-21-bismethylenedioxy-4-pregnene-3, 1 l-dione.

The same product is obtained when a methylene chloride solution of cortisone is heated with formalin and perchloric acid under the conditions described above.

EXAMPLE 3 J 7-20,20-21-bismethylenedioxy-4-pregnene-3, l1 -dine To a solution of 500 mg. of cortisone acetate in 25 ml. of chloroform is added a mixture of 10 ml. of formalin and 10 ml. concentrated hydrochloric acid. This two-phase reaction mixture is stirred at room temperature for 70 hours. At the end of this time, the chloroform layer is separated and the inorganic layer extracted with chloroform. This chloroform extract is added to the original chloroform layer and the solution washed with dilute sodium bisulfate, then dried over magnesium sulfate. The chloroform is removed under reduced pressure and an amorphous gum obtained, Weighing 475 mg. After purification by chromatographing on acid washed alumina and elution with ether 180 mg. of 17-20,20-21-bismethylene-dioxy-4-pregnene-3,1l-dione is obtained.

In like manner 4,9(1l)-pregnadien-l7a,21-diol-3,20- dione is converted to 17 20,20-21 bismethylene dioxy- 4,9(11)-pregnadien-3-one, and 4-pregnen-17a,21-diol-3, 20-dione 21-acetate to 17-20,20-2l-bismethylene-dioxy-4- pregnen-3-one.

EXAMPLE 4 17-20,20-2I-bismethylenedioxy-4-pregnene-11j3-ol-3-0ne 17-20,20-21-bismethylenedioxy-4-pregnene-3,1I-dione To 500 mg. of hydrocortisone suspended in 25 ml. of chloroform is added a mixture of 10 ml. of formalin and 10 ml. of concentrated hydrochloric acid. The twophase reaction mixture is stirred at room temperature for a period of 72 hours. At the end of this time, the layers are separated and the inorganic layer washed with chloroform. The combined chloroform extracts are washed with a saturated solution of sodium bicarbonate and then dried and concentrated under reduced pressure. The resulting gum is chromatogrammed on acid Washed alumina and washed alumina and a non-crystalline product obtained which is negative in the RT. test and has the infrared spectrum expected for 17-20,20-21-bismethylenedioxy-4-pregnene-1 1 fi-ol-3 -one.

This non-crystalline material is dissolved in 2 ml. of acetic acid and to this solution is added 60 mg. of chromium trioxide. The reaction mixture is allowed to stand at room temperature for ten minutes and at the end of this time, 5 ml. of water added to the mixture. The mixture is extracted several times with methylene chloride, the methylene chloride extracts Washed with dilute sodium bicarbonate, then dried and concentrated to yield 17-20,20-21-bismethylenedioxy-4-pregnene-3,11- dione.

EXAMPLE 5 1 7-20,20-21-bismethylenedioxy-1,4-pregnadiene- 3,11-di0ne To a suspension of 500 mg. of prednisone in 25 ml. of chloroform is added a mixture of 10 ml. of formalin and 10 ml. of concentrated hydrochloric acid. The twophase system is stirred at room temperature for 70 hours, and the two layers are then separated. The aqueous layer is extracted once with chloroform and the chloroform extract combined with the original organic solvent layer. The chloroform is washed with a saturated solution of sodium bicarbonate, dried and concentrated under reduced pressure to a semi-crystalline solid weighing 712 mg. This crude product is triturated with boiling methanol and 352 mg. of crystalline material obtained, melting point 175-195 C. After recrystallization of this material from acetone and methanol, a pure sample of 17-20,20-21 bismethylenedioxy 1,4 pregnadiene-3,1 l dione, melting point 214217 C., is obtained.

The same product is obtained by using sulfuric acid in place of hydrochloric acid.

8 EXAMPLE 6 Preparation of 1 7-2 0,20-21 -bismethylenedi0xy-1 ,4- pregnadiene-I1fl-ol3-one-1I-methoxymethylether To a suspension of 500 mg. of prednisolone in 25 ml. of chloroform is added a mixture of 10 ml. of formalin and 10 ml. of concentrated hydrochloric acid. This twophase system is stirred at room temperature for a period of hours. At the end of this time, the two layers are separated. The aqueous layer is extracted once with chloroform and the chloroform extract combined with the original organic phase. The combined chloroform solution is washed with a saturated solution of sodium bicarbonate, dried and concentrated under reduced pressure to a semicrystalline solid Weighing 500 mg. This product is recrystallized from methanol to yield 300 mg. of product, melting at 19l202 C. Recrystallization from acetone and methanol gives a pure sample of 17-20,20-21- bismethylenedioxy 1,4 pregnadiene 11,3 ol-3-one-11- methoxymethylether, melting point 217-220 C.

EXAMPLE 7 17-20,20-21-bismethylenedi0xy-4,6-pregnadiene- 3,1 1 -di0ne A solution of 1.106 grams of 4,6-pregnadiene-3,11,20- trione-17a,21-diacetate in ml. of anhydrous methanol is stirred in a nitrogen atmosphere for one-half hour. 2.5 ml. of a 2 N methanolic solution of sodium methoxide is added and stirring continued for five minutes. 0.3 ml. of water is then added and stirring continued for an additional five minutes, and the solution then acidified with acetic acid. The solvent is removed under reduced pressure, the residue dissolved in chloroform and the chloroform extracted in sequence with Water, 10% sodium bicarbonate and finally with water. The chloroform solution is dried over sodium sulfate and the solvent removed under reduced pressure to give 1.09 grams of crude 4,6- pregnadien-17a,2l-diol-3,11,20-trione.

A mixture of this diol, 50 ml. of chloroform, 20 ml. of concentrated hydrochloric acid and 20 ml. of formalin is stirred vigorously at room temperature for 64 hours. 50 ml. of chloroform and 50 ml. of water are then added, the layers separated, and the organic phase washed in sequence with water, 10% sodium bicarbonate and again with water. After drying with sodium sulfate, the chloroform is removed under reduced pressure to give a residue of 17-20,20-21 bismethylencdioxy-4,6-pregnadiene-3,1ldione.

This product is dissolved in benzene, adsorbed on acid washed alumina and eluted with ether. Evaporation of the ether gives the desired compound which, when crystallized from methanol, has melting point 239243 C. (dec.) and [a] +119 (chloroform).

Following the reaction conditions described in paragraphs two and three above, and using benzene as the organic solvent and hydrobromic acid in place of hydrochloric acid, 17-20,20-21-bismethylenedioxy-6-methyl-9ufiuoro-1,4-pregnadiene-11fl-ol-3-one is obtained from 6- methyl-9a-fluoro 1,4 pregnadiene-l1p,17a,21-triol-3,20- dione.

EXAMPLE 8 17-20,20-21 -bismethylenedioxy-1,4-pregnadiene-I1B-al- 3-one To a suspension of 500 mg. lfirpregnadiene-llfldh, 21-triol-3,20-dione in 25 ml. of chloroform is added a mixture of 10 ml. of formalin and 10 ml. of concentrated hydrochloric acid. The reaction mixture is stirred vigorously at room temperature for one hour and at the end of this time, the chloroform layer is separated and washed with a saturated solution of sodium bicarbonate. It is dried and concentrated under reduced pressure to give a gum which crystallizes upon trituration with boiling methanol. This product is recrystallized several times 9 from ethyl acetate to yield 17-20',20-'21'-bis'methylen-' dioxy-1,4-pregnadiene-1 1 fi-ol-S-one.

EXAMPLE 9 1740,20-21-bismethylenedioxy-9a fluoro 4-pregnen- 1113-01-3-0112 Five grams of 9u-fluorohydrocortisone acetate are dissolved in 250 ml. of chloroform. To the stirred solution' is added 100 ml. of concentrated hydrochloric acid and 100 ml. of 37% aqueous formaldehyde (formalin). After stirring at room temperature for 18 hours, the chloroform layer is separated, washed with saturated sodium bicarbonate, dried and evaporated to dryness. Trituration of the oil with methanol gives 1.1 grams of 17-20,20-2l bismethylenedioxy 9m fiuoro-4-pregnene- 11fi-ol-3-one, melting point (245) 248-255 C.

EXAMPLE 10 Twenty grams of 9a-fluorohydrocortisone alcohol are dissolved in one liter of chloroform and to this stirred solution is added 400 ml. of concentrated hydrochloric acid and 400 ml. of formalin. The reaction mixture is stirred at room temperature for one hour and worked up as described in Example 9. The product melts at 250- 260 C., 285-290 C.

EXAMPLE 11 Hydrolysis and acetylation of 17-20,20-21-bismethylenedioxy-4-pregnene-3,1J-dione t cortisone acetate To 100 mg. of the bismethylenedioxy derivative obtained as in Example 1 is added ml; of methanol and 5 ml. of 5 N sulfuric acid and the heterogeneous mixture refluxed on the steam bath for one hour (homogeneous after 45 minutes). The methanol is removed in vacuo and the resulting aqueous solution thoroughly extracted with ethyl acetate. The extract is washed with sodium bicarbonate, dried and concentrated to give 96 mg. of residue. This is dissolved in 0.3 ml. of pyridine and 0.3 ml. of acetic anhydride. The mixture is heated for ten minutes on the steam bath and poured into water. The resultant mixture is extracted several times with methylene chloride, the methylene chloride washed with dilute hydrochloric acid and sodium bicarbonate, dried over magnesium sulfate and evaporated. The residue is recrystallized from acetone to givecortisone acetate.

EXAMPLE 12 17-20,20-21-bismethylenedioxy 4-pregnene-11B-ol-3-one 30 grams of hydrocortisone are combined with 1500 ml. of chloroform and to this solution is added a cooled mixture of 600 ml. of concentrated hydrochloric acid and 600 ml. of formalin. The reaction mixture is stirred at room temperature for one hour. The two layers are separated, the aqueous layer extracted with chloroform and the solution combined. They are washed with sodium bisulfate, dried and concentrated in vacuo. The entire residue is chromatographed on acid washed alumina. Elution of the column with 1:4 petroleum etherether yields four grams of crystalline l7-20,20-21-bismethylenedioxy 4 pregnene-l1B-ol-3-one-11-methoxymethylether, melting point ISO-165 C. From the ether elua te there is obtained ten grams of 17-20,20-2l-bismethylenedioxy-4-pregnene-1lB-ol-3-one, melting point 217-222 C.

EXAMPLE 13 17-2 0,20-21 bismethylenedioxy-4-pregnene-11/8-ol-3-0ne Two grams of hydrocortisone are dissolved in 100 ml. of chloroform which had been shaken with sulfuric acid, dried over calcium chloride and distilled. To this mix- .ture is added with cooling 60 ml. of concentrated hydro- 1U tained crystalline 1'7'-20,20-21-bismethylenedioxy-4-pregnene-11B-ol-3-one, melting point 200220 (2., upon trituration of the oil with ethyl acetate.

EXAMPLE 14 l7-20,20-'21 bismezhylenedioxy 9a-chl0ro-4-pregnene- 11B-ol-3-one 1 7-20,20-21 -bismethylenedioxy-l-pregnene-3,11-dione A mixture of four grams of 1-pregnen-l7u,21-diol- 3,11,20-tri0ne, 200 ml. of chloroform, ml. of concentrated hydrochloric acid and 80 ml. of formalin is stirred vigorously at room temperature for 48 hours. At the end of this time the chloroform layer is separted and washed with three small portions of 5% potassium carbonate and then with water until the water washings are neutral. The chloroform solution is dried over magnesium sulfate and the solvent removed in vacuo. There is obtained a light yellow oily solid. On crystallization of this material from acetone and recrystallization from methylene chloride-methanol substantially pure 17-20,20-21-bismethylenedioxy-l-pregnene 3,11 dione, melting point 230 233 C., is obtained.

EXAMPLE 16 17-20,20-21bisethylidenedi0xy4-pregnene-3JI-dione 500 In. of cortisone is suspended in 25 ml. of chloroform and to this suspension, a mixture of 10 ml. of concentrated hydrochloric acid and 10 ml. of 40% aqueous acetaldehyde is added. This two-phase reaction mixture is stirred at room temperature for 72 hours. At the end of this time, the chloroform layer is separated and the inorganic layer is extracted with chloroform. The combined chloroform extracts are washed with a saturated solution of sodium bicarbonate, dried and the solvent removed under reduced pressure. An amorphous residue is obtained, weighing 720 mg. This material is chromatogrammed on acid washed alumina and 17-20,20-2lbisethylidenedioxyl-pregnene 3,11 dione eluted with ether-chloroform mixtures.

EXAMPLE 17 1 7 -20, 20-21 Zn'sbutyraldioxy-4-pregnene,3,I I-diane To a suspension of 500 mg. of cortisone in 25 ml. of chloroform is added a mixture of 10 m1. of 40% aqueous butyraldehyde and 10 ml. of concentrated hydrochloric acid. The resultant two-phase reaction mixture is stirred at room temperature for 68 hours. At the end of this period, the two phases are separated and the aqueous layer is extracted several times with chloroform. The chloroform extracts are combined with the original organic layer and washed with a saturated solution of sodium bicarbonate. The chloroform solution is dried and concentrated under reduced pressure to an oil weighing 1.2 grams. This oil is dissolved in benzene and adsorbed on a column of '30 grams of acetone washed, acid washed alumina. It is eluted with petroleum etherether (6:4 to 2:8). These eluates, upon concentration, yield 17-20,20-21 bisbutyraldioxy*4-pregnene-3,1l-dione as an amorphous solid.

Using prednisone acetate and 'c'aproaldehyde in place of the cortisone and butyraldehyde, and following the ltil above procedure, 17-20,20-21 biscaproaldioxy-l,4-pregnadiene-3,l1-dione is obtained.

EXAMPLE 18 17-20,20-21-bispropionaldi0xy-4-pregnene-1IB-ol-S-one 800 mg. of hydrocortisone acetate in 40 ml. of methylene chloride is mixed with 15 ml. of propionaldehyde and 15 ml. of concentrated hydrochloric acid. The resulting mixture is agitated for hours at 30 C. The layers are then separated and the aqueous layer extracted with 10 ml. of methylene chloride. The methylene chloride solutions are combined, washed with dilute sodium bicarbonate and dried over anhydrous magnesium sulfate. The organic solvent is removed by concentration in vacuo. The residue thus obtained is chromatogrammed on 30 grams of acid washed alumina. Elution with petroleum ether-ether, and removal of the solvent from the efiiuent fractions yields l7-20,20-2l-bispropion aldioxy-4-pregnene-1 -01-3 -one.

EXAMPLE 19 l 7-20,20-21 -bisvaleraldioxy-Qa-fluoro-l ,4-pregnadiene- 1 1,8-01-3-0ne By means of the procedure of Example 18, using 900 mg. of 9a-fiuoro-l,4-pregnadiene-11B,l7u,2l-triol-3,20- dione as the steroid reactant and 15 ml. of valeraldehyde in place of the propionaldehyde, there is obtained 17- 20,20-2l-bisvaleraldioxy-9a-fluoro-1,4-pregnadiene 11,3- ol-3-one.

EXAMPLE 20 1 7-20,20-21-bisbutyraldioxy-4-pregnene-1 1,8-01-3-0112 500 mg. of hydrocortisone are dissolved in ml. of methylene chloride and to the resulting solution is added 10 ml. of 40% aqueous butyraldehyde and 10 ml. of concentrated hydrochloric acid. The reaction mixture is stirred at room temperature for six hours. The solvent layers are separated and the aqueous layer extracted with fresh methylene chloride. The organic solvent solutions are combined, washed with water and dried over magnesium sulfate. The methylene chloride is removed by concentration in vacuo and the residual oil chromatrographed on acid washed alumina. From the 4:1 petroleum ether-ether eluates there is obtained substantially pure 17-20,20-2l-bisbutyraldioxy-4-pregnene-l1,8- o1-3-one as a clear glass.

Hydrocortisone acetate EXAMPLE 21 17-20,20-2Z bismethylenedioxy-allopregnane-I 1 13-0l-3-0ne To a solution of 7.1 grams of allopregnane-1lfi,l7a,21- triol-3,20-dione in 350 ml. of chloroform is added 140 ml. of cold concentrated hydrochloric acid and 140 ml. of cold neutral formalin. The two-phase mixture is stirred for two hours. The solvent layers are separated and the aqueous phase extracted with two 100 ml. portions of chloroform. The chloroform solutions are com bined, washed successively with water, 5% sodium bicarbonate and water, and then dried over anhydrous magnesium sulfate. The chloroform is then removed in vacuo and the resulting residue chromatographed over 180 grams of alumina.

Elution of the column with ethyl other yields, after recrystallization from ether-petroleum ether, 17,20,20-21 bismethylenedioxy-allopregnane-1l5- ol-3-one-ll-methoxymethyl ether; further elution with ethyl ether gives 17-20,20-21 bismethylenedioxy-allopregnane-llfi-ol-3-one, melting point 220-225 C., after recrystallization from ether.

Following the procedure set forth in the above paragraph and starting with 6.5 grams of 9afluoro-1,4-pregnadiene-l1,8,17a,2l-triol-3,20-dione there is obtained 17- 20,20-21 bismethylenedioxy-9a-fluoro-1,4 pregnadienel l 3-ol-3-one.

EXAMPLE 22 (a) Following the procedure of Example 1 hereinabove, treatment of Zoe-methyl cortisone with acetaldehyde in the presence of sulfuric acid yields 17-20,20-21 bisethylidenedioxy-2a-methyl-4-pregnene-3,1l-dione, when Ila-methyl hydrocortisone is used as the starting material there is obtained 17-20,20-21 bisethyldienedioxy- 11a-methyl-4-pregnene-1lfl-ol-3-one.

(b) On treatment of a chloroform solution of 6:- methyl hydrocortisone under the conditions of Example 21 hereinabove using glacial acetic acid in place of formalin there is obtained 17-20,20-21 bisethylidenedioXy-Sa-methyl-4-pregnene-1lfi-ol-3-one. It is important that the reaction medium employed in making this substance be substantially methanol-free.

EXAMPLE 23 1 7 -20,2 0-21 bisethylidenedioxy-4-pregnen-3-one 500 mg. of 4-pregnen-17a,21-diol-3,20-dione in 25 m1. of chloroform is added to a mixture of 10 ml. of concentrated hydrochloric acid and 10 ml. of aqueous acetalde hyde. The resulting two-phase system is stirred at room temperature for 44 hours. At the end of which time the phases are seperated and the aqueous phase extracted with two 25 ml. portions of chloroform. The chloroform extracts are combined, washed with aqueous sodium bicarbonate and with water, dried and finally distilled. The residual solid is washed with petroleum ether to give 327 mg. of l7-20,20-2l bisethylidenedioxy-4-pregnen-3-one.

In a similar fashion by employing 4,9(1l)-pregnadienl7a,2l-diol-3,20dione as the starting material and using sulfuric in place of hydrochloric acid, there is obtained l7-20,20-2l bisethylidenedioxy-4,9( 11)-pregnadien-3-one.

EPLAMPLE 24 1 7-2 0,20-21 bispropionaldioxy-Qa-chloro-4-pregnene- J 1 fi-al-3-0ne One gram of 9u-chloro hydrocortisone acetate in ml. of methylene chloride is added to a pre-cooled mixture of 25 ml. of propionaldehyde in 25 ml. of concentrated hydrochloric acid. The reaction mixture is stirred at room temperature for 18 hours. The methylene chloride layer 0 is then separated and washed with water and a solution of saturated sodium bicarbonate. It is evaporated to dryness in vacuo after having been dried over magnesium sulfate. The resulting crystalline residue is recrystallized from methylene chloride-methanol to give 17-20,20-21 bispropionaldioxy-9a-chloro-4-pregnene-l l,B-ol-3-one.

EXAMPLE 25 1 7-20,20-21 bisethy lidenedi0xy-3-ethylenedIoxy-5- pregnen-l 1 -one 200 mg. of the product of Example 16 above is dissolved in 10 ml. of benzene, 0.5 ml. of ethylene glycol and 0.2 gram of p-toluene sulfonic acid. The resulting mixture is refluxed for 15 hours with continuous removal of water. The mixture is then cooled to room temperature and washed successively with 10 ml. water, sodium bicarbonate solution and again with water. The organic solvent solution is separated, dried over magnesium sulfate and concentrated to dryness in vacuo. On trituration of the resulting solid with ethyl ether there is obtained substantially pure 17-20,20-21-bisethylideiidioiy 3-ethyl enedioXy-S-prgneri-l l-one.

EXA'MBLE 26 17-20,20-21 bis'ethy'lidenedioxy3-pyrfolidyl dfi pfeghd din-I 1 one' One gram of 1-7-20,20-2-1- bisethylidenedioxy-4-preg:

nene-3,11-dion'e is dissolved in 20 ml. of ethanol and 2 ml. of methylene chloride. The resulting solution is concentrated to aboutone-half volume, 1 ml. of pyrrolidine added, and the mixture warmed on the steam bath for about one minute; l7-20,20-21 bisethylidenedioxy-S-pyrrolidyl-3,5-pregadien-1l-one precipitates from; solution.-

where R is a lower alkyl radical having at the 3-position a substitutent selected from the class consisting of keto and hydroxy groups and groups convertible thereto by hydrolysis, and having at the ll-position a substitutent selected from the class consisting of hydrogen, hydroxy and keto groups; and unsaturated derivatives thereof.

2. l7-20,20-2l bisdioxy pregnanes having at positions 17, 20 and 21 the structure 20 l /CHR REC where R is a lower alkyl radical having at the 3-position a substitutent selected from the class consisting of keto and hydroxy groups and groups convertible thereto by hydrolysis, having at the 9-position a substituent selected from the class consisting of halo and hydroxy groups, and having at the ll-position a substituent selected from the class consisting of hydroxy and keto groups; and unsaturated derivatives thereof.

3. 17-20,20-21 bisethylidenedioxy pregnanes having at the 3-position a substituent selected from the class consisting of keto and hydroxy groups and groups convertible thereto by hydrolysis, and having at the ll-position a substituent selected from the class consisting of hydrogen, hydroXy and keto groups; and nuclearly unsaturated derivatives thereof.

4. 17-20,20-21 bisbutyraldioxy pregnanes having at the 3-position a substituent selected from the class consisting of keto and hydroxy groups and groups convertible there to by hydrolysis, and having at the ll-position a substituent selected from the class consisting of hydrogen, hydroxy and keto groups; and nuclearly unsaturated derivatives thereof.

5. 17-20,20-2l bispropionaldioxy pregnanes having at the 3-position a substituent selected from the class consisting of keto and hydroxy groups and groups convertible thereto by hydrolysis, and having at the ll-position a substituent selected from the class consisting of hydrogen, hydroxy and keto groups; and nuclearly unsaturated derivatives thereof.

14 6. 17-20,2'O-2l bis'valeraldiox'y' pregnanes having at the 3-position a substituent selected from the class consisting of Item and hy'drox'y' groups and groups convertible thereto by hydrolysis, and having at the l'l-position a substit'uent selected from the class consisting of hydrogen,

hydroxy and keto groups; and nuclearly unsaturated /17\ where R is lower alkyl that comprises reacting a member of the class consisting of 3-oxygenated-17a,2ldihydroxy- 20-keto-pregnanes and unsaturated derivatives thereof with an aldehyde of the formula RCHO, where R is as defined above, in the presence of an acid selected from the class consisting of acids having a log k of less than 2.25 and formic acid.

14. The process of claim 13 wherein the acid is a mineral acid.

15. The process for preparing a 17-20,20-21 bisethylidenedioxy steroid that comprises reacting a member of the class consisting of 3,11-bisoxygenated 17a,21-dihY- droxy-20-keto pregnanes and unsaturated derivatives thereof with acetaldchyde in the presence of an acid selected from the class consisting of acids having a log k of less than 2.25 and formic acid.

16. The process for preparing a 17-20,20-21 bisbutyraldioxy steroid that comprises reacting a member of the class consisting of 3,1l-bisoxygenated 17a,21-dihydroxy- 20-keto pregnanes and unsaturated derivatives thereof with butyraldehyde in the presence of an acid selected from the class consisting of acids having a log k of less than 2.25 and formic acid.

17. The process for preparing a 17-20,20-2l bispropionaldioxy steroid that comprises reacting a member of the class consisting of 3,11-bisoxygenated 17a,21-dihydroxy-20-keto pregnanes and unsaturated derivatives thereof with propionaldehyde in the presence of an acid selected from the class consisting of acids having a --log k of less than 2.25 and formic acid.

18. The process for preparing a l7-20,20-21 bisvaleraldioxy steroid that comprises reacting a member of the class consisting of 3,1l-bisoxygenated 17a,2l-dihydroxy- 20-keto pregnanes and unsaturated derivatives thereof with valeraldehyde in the presence of an acid selected from the class consisting of acids having a log k of less than 2.25 and formic acid.

19. The process for preparing a 17-20,20-21 biscaproaldioxy steroid that comprises reacting a member of the class consisting of 3,11-bisoxygenated l7a,2l-dihydroxy- 20-keto pregnanes and unsaturated derivatives thereof with caproaldehyde in the presence of an acid selected RHC assaese from the class consisting of acids having a log k of less than 2.25 and formic acid.

20. The process which comprises reacting 4-pregnen- 17a,21-diol-3,l1,20-trione with acetalclehyde in the presence of an acid selected from the class consisting of acids having a log k of less than 2.25 and formic acid and in an aqueous:organic solvent two-phase reaction medium to produce 17-20,20-21 bisethylidenedioxy-4-pregnene- 3,1 l-dione.

21. The process which comprises reacting 4-pregnen- 17a,21-di0l-3,11,20-t1'i0116 with butyralclehycle in the presence of an acid selected from the class consisting of acids having a -log k of less than 2.25 and formic acid and in an aqueouszorganic solvent two-phase reaction medium to produce 17-20,20-2l bisbutyraldioxy-4-pregnene-3,1ldione.

22. The process which comprises reacting 4-pregnene- 115,17;1-triol-3,20-dione with propionaldehyde in the presence of an acid selected from the class consisting of acids having a log k of less than 2.25 and formic acid '16 and in an aquconszorganic' solvent two-phase reaction medium to produce 17-20,20-21 bispropionaldioXy-4- pregnene-1lp-ol-3-one.

23. The process which comprises reacting 9a-fluoro- 1,4-pregnadiene-l 1,8,17a,21-triol-3,20-dione with valeraldehyde in the presence of an acid selected from the class consisting of acids having a log k of less than 2.25 and formic acid and in an aqueouszorganic solvent two-phase reaction medium to produce 17-20,20-21 bisvaleraldioxy- 9a-fiuoro-1,4-pregnadiene-1 1 3-o1-3-one.

24. The process which comprises reacting 1,4-pregnadien-17a,21-diol-3,11,20-trione with caproaldehyde in the presence of an acid selected from the class consisting of acids having a -log k of less than 2.25 and formic acid and in an *aqueouszorgnnic solvent two-phase reaction medium to produce 17-20,20-2l biscaproaldioxy-1,4-pregnadiene-3 ,1 l-dione.

No references cited.

Claims (1)

1. 17-20,20,21 BISDIOXY PREGNANES HAVING AT POSITIONS 17, 20 AND 21 THE STRUCTURE