US2395337A - Sapogenin derivatives and preparation of same - Google Patents

Description

Patented Feb. 19, 1946 SAPOGENIN DERIVATIVES AND PREPARA- TION. F SAME Russell Earl Marker,

Harry Means Crook Wittle, Detroit, Mich.,

Mexico City, Mexico, 'and s, Jr., and Eugene Leroy assig'nors to Parke,

Davis & Company, Detroit, Mich., a corporation of Michigan No Drawing. Original application May 15, 1941,

Serial No. 393,666. Divided and this application May 24, 1944, Serial N0. 537,196

Claims.

The invention relates to the preparation of steroidal compounds, and this application is a division of our copending application, Serial No. 393,666, filed May 15, 1941, now Patent No. 2,352,851, issued July 4, 1944.

This application relates more particularly to the preparation of glycosidic derivatives of pseudo-sapogenin compounds unacylated at least at the exo-hydroxyl group and in the sugar residues, oxidizing said derivatives in the side chain attached to ring D and hydrolyzing the oxidation product to obtain A -20-keto compounds having hydroxyl groups in place of the sugar residues.

According to this invention, the pseudo-sapogenins or their ring A and/or B glycosidic derivatives are prepared by reacting glycosidic derivatives of the sapogenins with acidic agents, for example, acylating agents such as acid anhydrides, under conditions more vigorous than those required merely for acylation.

By glycosidic derivatives of the sapogenins we means sapogenin derivatives in which sugar residues are attached through a hemi-acetal linkage to the cyclopentanoperhydrophenanthrene nucleus. In general, the exact nature of the structures of these substances are not known with certainty. The following formulae illustrate various types of the above sapogenin gLvcosides:

I JH:--- CH OH VIII. Sarsasaponin CH; CH:

' CH CHg-CH: C CH-CH:

J O-C (\3/ T CH CH 'JHOH HQ HOH HOH (EHOH HOH JH I H CH HaOH v IX. Trillarin CH CH: Cm on CHI-CH:

p C CH-CH: O-C: /\/W/ k/ C CHOH HOH HOE a HaOH X. Trillin Generally speaking the glycosides of the steroi dal sapogenins may be classified as 1) sa-ponins; (2) simpler glycosidea. The former usually contain from three to six sugar units, all of which may be the same, or they may be different. The most commonly occurring sugar units are those of glucose, galactose, rhamnose, and xylose. The simpler glycosides difier from the saponins in that (1) they contain fewer, i. e., one to three, sugar units; 2) they are more readily obtained crystalline; (3) they do not show marked capillary active properties. In most cases, including the compounds represented by VIII, IX, and X, the exact nature of the glycosidic linkages is not definitely known; that is, it is not known whether the sugars have a furanose or pyranose structure, nor which carbon atoms of the different sugar units are (through oxygen) united. In many cases even the number and kind of sugar units present are not known.

See further, Fieser, Chemistry of Natural Products Related to Phenanthrene, 2nd ed., p. 333 if. (Reinhold Publishing Corporation, New York city,

Since the steroidal sapogenins occur in nature, not in the free form, but combined with sugar units as glycosidic derivatives, the present invention makes it unnecessary to isolate the sapogenins. Instead, their more readily available glycosidesmay be converted directly to pseudosapogenin derivatives. This elimination of a formerly essential step results in higher yields of steroidal hormones from plant sources.

As naturally occurring glycosidic derivatives of steroidal sapogenins which may be 'used in the practice of this invention, there may be mentioned amolonin, sarsasaponin, digitonin, or like steroidal saponins. Also, there may be used partially degraded glycosidic derivatives of these saponins, such as trillarin ortrillin. Such partially .degraded glycosidic derivatives of saponins are obtained by hydrolyzing the saponin at some of the oligosacharide linkages by means of enzymes or dilute acids or similar reagents. Again, there may be used synthetic glycosidic derivatives of steroidal sapogenins such as the synthetic galactosides, glucosides, ribosides, and other glycosides of sapogenins such as sarsasapogenin,

diosgenin, or other steroidal sapogenins containing reactive nuclear hydroxyl groups. Synthetic 'glycosides suitable for the practice of this inventionmay also ,be prepared from sapogenins which have reactive nuclear hydroxylgroups, but which are not agly cones of naturallyoccurring saponins. For example, although neither episarsasapogenins nor its glycosides occur in nature, glycosides of epi-sarsasapogenin may be prepared synthetically from sarsasaponin by converting the latter into its aglycone, sarsasapogenin, and then co nverting this into epi-sarsasapogenin. The epi-sarsasapogenin may then be treated to form the glycoside as for example by treatment with bromoacetoglucose.

The conversion of the glycosidic derivative of the steroidal sapogenin into an acylated glycosidic pseudo-sapogenin may be effected by treating the former with an acylating agent under conditions more vigorous than those required for mere acylation. This step may be effected, for example, by treatment of the glycosidic derivatives of the sapogenins with a carboxylic anhydride at 175-250 C. We have found that best results are obtained with lowerfatty acid anhydrides 'while maintaining the reaction temperature in the neighborhood of 200 C. The product thus formed is an acylated glycosidic pseudo-sapogenin derivative acylated at least at the exo-hydroxyl group and in the sugar residues.

The acylated glycosidic pseudo-sapo enin derivatives may be hydrolyzed with alkaline reagents with production of a glycosidic derivative of a pseudo-sapogenin unacylated at least at'the exo-hydroxyl group and in the sugarresidues.

The pseudo-sapogenins are characterized y the pseudo-sapogenins are isomerized to the corresponding steroidal sapogenins: The side chain of the pseudo-sapogenins contains a reactive hydroxyl group which may be acylated, for example, acetylated.

It is believed that the properties of pseudosapogenins are best explained if the side chain attached to ring D of the cyclopentanoperhydrophenanthrene nucleus be represented by one of the following partial formulae:

01 these formulae, III seems to account best for the transformations described in thepresent invention. It will be observed that the partial formulae I, II and 111 all contain a reactive hydroxyl group. The prefix exo in the term exohydroxyl group has the same significance that it does in other branches or organic chemistry, namely, that the particular function involved is exterior to a ring system and in a'position not known with greater certainty.

The glycosidic derivative of a pseudo-sapogenin. unacylated at least at the exo-hydroxyl group and in the sugar residues is then mildly oxidized in the side chain attached to ring D, thus producin an oxidation product in which the sugar residues are not acylated.

This oxidation product, which is a new intermediate compound, is subjected to hydrolysis with an acidic reagent with production oi! a steroid having in ring D the structure oxide, and the like may thisv step. Particularly satisfactory results are oxidizing agents such as ozone, hydrogen pereffectively be employed in the sugar residues from the steroid nucleus is best achieved by boiling the substance with alcoholic hydrochloric acids. However, other acidic reagents such as dilute sulfuric acid, or other mineral acids may be used instead.

Our invention may be further illustrated by the following examples.

, Example 1 The saponin from Trillium erectum is obtained and converted into the acetate of Trillium erectum pseudo-saponin as described in our application, Serial No. 393,666. This product is then hydrolyzed with alkaline reagents a above described, producing a compound unacylated at the exo-hydroxyl group and in the sugar residues and having the'following formula CH! CH:

EIUCOSG tate is prepared as described in application, Serial No. 393,666. This substance may be represented by the following structural formula,

It is then hydrolyzed with alkaline reagent to remove the acetyl groups, all as described above, to produce the corresponding 3-hydroxy-A"-20 to compound. What we claim as our invention is: 1. The process which comprises subjecting a glycosidic derivative of a pseudo-sapogenin unacylated at the exo-hydroxyl group, to mild oxidation in the side chain attached to ring D, and subjecting the oxidation product to hydrolysis with an acidic agent, with production of a steroid having in ring D the structure CH: CH:

and having in the remainder of the steroid skeIeton, hydroiwl groups dues.

2. The process which low C. a glycosidic sapogenin unaoylated at by means of an oxidizing agent of the class consisting of chromic and permanganic acids and their salts, and subjecting the oxidation product to hydrolysis with an acidic agent, with production 01' a steroid having in in place of the sugar resicomprises oxidizing be derivative of a pseudothe exo-hydroxyl group CH: CH: 0

and having in the remainder of the steroid skele ton, hydroxyl groups in place of the sugar residues.

3. The process which comprises subjecting a glycosidic derivative of a pseudo-sapogenin unacylated at least at the exo-hydroxyl group and in the sugar residues to mildoxidation in the side chain attached to ring D thereby obtaining an oxidation product having an unacylated sugar residue attached to the steroid nucleus.

4. The process for the preparation of steroidal compounds which comprises subjecting a glycosidic derivative of a pseudo-sapogenin acylated at least at theexo-hydroxyl group and in the sugar residues to hydrolysis with an alkaline reagent, with production of a glycosidic derivative of a pseudo-sapogenin unacylated at least at the exo-hydroxyl group and in the sugar residues, mildly oxidizing said glycosidic pseudo-sapogenin derivative in the side chain attached to ring D,

' and subjecting the oxidation product to hydrol- HaOAc ring D the structure and having, in the remainder of the steroid skeleton, hydroxyl groups in place of the sugar residues.

5. The process for the preparation of steroidal compounds which comprises isomerizing and acylating the side chain attached to ring D of a glycosidic derivative of a steroidal sapogenin by reacting said glycosidic derivative with an acylating agent under conditions more vigorous than those required for mere acylation, with produc tion or a glycosidic derivative of a pseudosapogenin acylated at least at the exo-hydroxyl group and in the sugar residues, subjecting said acylated glycosidic pseudo-sapogenin derivative aseassv to hydrolysis with an alkaline reagent, with production of a glycosidic derivative of a pseudosapogeninunacylated at least at the exo-hy-.

droxyl group and in the sugar residues, mildly oxidizing said giycosidic pseudo-sapogenin derivative in the side chain attached to ring D, and subjecting the oxidation product to hydrolysis with an acidic. reagent, with production of a a steroid having in ring D the structure CH: CH:

J Dell N and having, in the remainderv of the steroid