CA1049498A

CA1049498A - Steroid compounds and processes therefor

Info

Publication number: CA1049498A
Application number: CA186,960A
Authority: CA
Inventors: Gunther Kruger
Original assignee: STEELE CHEMICALS CO
Current assignee: STEELE CHEMICALS CO
Priority date: 1973-11-29
Filing date: 1973-11-29
Publication date: 1979-02-27
Also published as: DE2455272A1; GB1495513A

Abstract

ABSTRACT OF THE DISCLOSURE
Novel steroids of the formula (1)

Description

9~9~3 This lnvent1on relates in one embodiment to new .
steroid compounds, and in a further embodiment, to processes for preparing steroid compounds.
More particularly, according to one embodiment of the present inventlon, there are provided new compounds of the formula R ~ ~ ~1) wherein Rl to R6 and X - Y have the meanings defined below, and wherein the dotted lines répresent optional double bonds. In the embodiment where the 3 and S positions of ~.
these compounds are saturated, the substituents Rl and R6 may either be in the alpha or be-ta positions.
For a greater understandiny of the present invention, the novel compounds may be classified as being of one of two groups of compounds, in which accordiny to one embodiment, the compounds of Formula 1 have saturated A, B, C and D - rings and in which Rl represents either hydroxy or OAc, R2 represents CH2OH or CHO, R3 is H, R4 and R5 are CH2-O, R6 is either 5~ or 5~-H, and X and Y
together represent C - CH, C CH, C CH, C~ CH, i OH Br OH Cl O OH OAc C _ CH , C CH2 and C - CH2 OH OCOC(CH3)3 gCHO OAc - ~49~91!~
alternatively, the compounds according to a ~urther embodimen-t are those compounds in which Rl represents H, 0=, HC02, 3 3 2' C13CC2' (C2H5)22()cH2c2' ~ 2

2 H3C ~ C~I32 H3C ~ ~ C 3 ~ H3C ~ ~ C 2 - HC--C-C02, H2C=CH-C02, (H0)(CH3)CH C02, (HO)(CH3)2CC02, 2 2 2' H02C(cH2)2co2~ H02CCH2Co2, CH30 (CH ) C0 C6H5CH20, HC. - CCH20, tetrahydropyran- 2-yloxy, 3~,9a- oxido and

3-hydroxy-3a,9a~ oxido, R2 represents HC02CH2, (CH3)3CC02CH2;
3 2CH2; (C2H5o) 2p~o)cH2co2cH2; ~o2CH2 2CH2 H3C ~ C02CH2 H3C 11 ~ 2CH2 : ` `
; H ~ ~ CH3 ;H3C ~ ~ CH3 C 2H50 2C~ CH3 H3CJ~ JLC02CH2 ; ~IC_C-C02C~I2, H2C--C-co2cH

(H0)(CH3)CHC02CH2, (H0) ~CH3) 2CC02CH, H02C~CHOH) 2C2CH2, 2 2 2 2' H2CCH2C2CH2' CH30CH2' ~CH ) C0CH
C6H5CH20CH2, HC~ CCH20CH2, tetrahydropyran- 2'-yloxymethyl, :~
CH2Cl, CH3, 8,19-oxido, 19~ 8-lactone, 19~~ 8-lactol, and 6,19-oxido; R3 represents H, C02H, C02CH2C6H5; C02CH3, CO~CH2CH20H, C02CH2-C~ CH and C~; R4, R5 represent CH2-0, :
-2- ~
~ :`

949~
R4 represents CH3; R5 rep.resents OH, OCH2C6H5, OCH3, OCH2CH20H and OCH2-C_ CH, R6 represents H, Cl, Br or 5~-OH, X - Y represents the groups defined above or the group C-CH; C=CH; or CH-CH2; and wherein double bonds OH
may be present in the 2,4,6,8(14)-; 4,6,8~14)-; 4,6,8~9)-

4,6 ; 4-; 5-; 5,7-; and 3,5,7-positions.
In accordance wlth a further aspect of the present invention, there are provided processes -for preparing the above compounds and compounds generally of the formula DC C
R2~ ~ ~ 3 Rl-r ~
R (1) wherein Rl khrough R6, X and Y have the above-deEined meanings and additionally may represent, when the A, B, C
and D rings of the compounds are saturated, compounds in which X and Y are 8 - CH2 or C C 2' OH
R2 is CH20H or CHO, R3 is H and R4 5 is CH20; in accordance with this embodiment of the invention, the process is selected from the group consisting o~

_3 .......... .

g~ :
(a) treating a compound of the formula 2 =o7 R ~ (2) wherein Rl, R2, R6, X and Y and the dotted lines are as defined above, and R7 is OH, with an ~-substituted acetic acid to form a compound of the formula~3) O

-O ;~:

R2 ~--J~ ~i ~X~~Y
Rl ~ ~!1 ~ (3) ~ , wherein Rl, R2, R6, X and Y and the dotted lines are as defined above and wherein Z is a substituent chosen from those enhancing the acidity of the adjacent methylene group, and finally treating the compound of the formula~3)with a base to form a compound of the formulall~, in which Rl, R2, ~-R3, R6, X and Y and the double bonds are as defined above and in whlch R4 and R5 are CH2-O, ... ...

:~ .

.

(b) treating a compound of the formula~2~in which R7 is OH, OCOCH3 or H, wlth an alkali alkoxyacetylide and then with an alcohol or water to form an intermediate compound o-f the formula~4) r 7 HO - -C-- C- Oalkyl ~ ~ ~X--Y t4) wherein R7 is OH or H and in which alkyl is CH2H5, CH3 or CH2C6H5, subjecting the latter compound to acid treatment to form a compound o-f the formula~l)in which R3 is H and R4, and R5 is CH2-O- when R7 in the compound of formula~4) is OH, or in which R3 is H, R4 is CH3 and R5 is OCH2H5, OCH3 or OCH2C6H5 when R7 in the compound of formula~4)is H;

(c) treating a compound of the formula~l~ in which Rl, R2, R6, X and Y and the dotted lines are asdefined above, while R4 and R5 represent CH2-O and R3 represents CO2H, C2cH2c6H5; C2CH3; CO2CH2CH2OH or CO2CH2_C -CH with zinc and a carboxylic acid to form a compound o the formula(l), :~
in which R3 represents a member selected from the group consisting of CO2H, CO2CH2C6H5, CO2CH3, 2 2 2 C2CH2-C- CN; R4 is CH3, and R5 lS OH, OCH2CH2C6H5, OCH3, OcH2cH2oH or OCH2-C _CH-~04~9~9~ ~
In greater detail of the above processes, the conversion of the 21-alcohols of the ~ormula~23, where R7 is OH, to the corresponding compounds of formula 1 by process (a) is most pre~erably carried out by treatment of the 21-alcohols with an a-substituted acetic acid, such as (diethylphosphono) acetic acid, (benzyloxycarbonyl) acetic acid or cyanoacetic acid in the presence of a carbodiimide (~or example, dicyclohexylcarbodiimide and a water immiscible solvent such as methylene chloride or benzene, and subsequent treatment of the resulting reaction mixture, containing 21-acylate (3~ as an intermediate with a water stable base-or example aqueous potassium hydroxide or aqueous or anhydrous t-butylamine. The reaction is preferably carried out at room temperature, though higher or lower temperatures may be employed if desired.
In an alternate embodiment of the above process (a), the 21-alcohol may be heated between 50 to ~ ~-about 150C. with the corresponding ~-substituted -acetic acid in the presence of a ketonic solvent, such as acetone or methyl isobutyl ketone. Where the radical Z
is CO2H, the resulting 21-hemimalonate may be then esteri~ied by a suitable conventional technique - such as or example, to treatment with an appropriate diazoalkane, such as diazomethane or diazotoluene to yield compounds of the formulal3)in which Z is CO2alkyl. Similarly, in a related embodiment of process (a), the 21-alcohol may be treated with a derivative of an ~-substikuted acetic acid, such as an acid chloride, ZCH2COCl anhydride, (ZCH2CO)2O, mixed anhydrides, ZCH2CO~O-OCR, wherein ~ is as defined above and ~ is (~H3)3C, F3C or C13C, or ester, ZCH2CO2alkyl, wherein : .

~ 94~
alkyl is C~I3, C2H5, CH2C6~I5 or CH2-C - CH. ln the case wnere the carboxylic acid derivative is an acicl chloride, or an anhydride or mixed anhydride, the treatment may be carried out at room temperature in the presence of a mild base such as pyridine, in the case where the carboxylic acid derivative is an ester the conversion to the 21-acylate may be brought about by heating the 21-alcohol with the ester at a tempera-ture of between about 50 to 220C. The base treatment of process (a) may be preferably carried out with a strong aqueous base such as 1 - 80% aqueous potassium or sodium hydroxide.
The treatment of the 21-alcohol or 21-acetate of ;
process (b) with an alkali alkoxy acetylide may be carried out as described by F. Sondheimer, Chemistry in Britain, 1, 454 (1965); preferably it may be carried out at room tempera-ture in an anhydrous ether such as diethyl e-~her or tetrahydrofuran and as the alkali alkoxy acetylide lithium methoxy. Alternatively, ethoxyacetylide may be employed. The subsequen~ acid treatment may also be carried out at room temperature. Dilute aqueous strong inorganic acids, such as hydrochloric, sulfuric or perchloric acid are preferably employed as the acid, while as the solvent or the intermediate s~eroidal 20-alkoxyethynyl-20-alcohol of formula 4 a water-immiscible solvent, such as benzene, ether or methylene chloride, is preerably used.
The treatment of the 22-substituted cardenolide o process (c) with zinc and a carboxylic acid may be preferably carried out at room temperature in the presence of an inert soIvent such as toluene, methylene chloride or ' .. . . . . . .

~0~49 !3 ethyl acetate and as the carboxylic acid formic acid, acetic acid and substituted acetic acids such as trimethylacetic or trifluoroacetic acid may be employed.
The various processes of the present invention possess several unexpected and advantageous -features. Thus, with regard to process (a) it is unexpected that the esterification of the 21-alcohol to compounds of formula~21, ln which Z is CO2H, gives improved yields when ketonic solvents, such as methyl isobutyl ketone, are used and that the esterification proceeds in a highly selective manner, yielding practically only the 21-hemimalonate, in which one of the 2-carboxylic acid groups of the malonic acid employed as the reagent remains still unreacted.
With regard to process (a) i-t is also unexpected ~hat the conversion of the 21-(dialkylphosphono)acetates of formulal3~, Z being (alkyl)P(0) to the corresponding cardenolides of formula~l~, R3 being H, R4, R5 being CH20 can be effected by a base of only moderate basic strength, such as an aqueous alkali hydroxide or alkylamine since this conversion is a phosphonate modification of the Wittig reaction (see for example L. F. ~ieser and M. Fieser, ~ohn Wiley and Sons, Inc., 1967, p. 1319 and 251) and hence, according to the prior art of carrying out Wittig reactions, requires a very strong base such as n-butyl lithium, sodium hydride and potassium t-butoxide (ibid. p 1319), as one of the reagents. In contrast to the moderate bases of this invention, the lat-ter, very strong bases have in common that they are rapidly destroyed by water.
It is fur-ther unexpected that the above conversion o formula~3)to formula~l)can be accomplished by employing ..
a water-immiscible, non~polar solvent, such as benzene as :
~he solvent for ~he s~eroid. As is we~l known to those ~ . . . .

9~
skilled in the art, reactions being brought about by -the action of a chemical reagent are generally greatly enhanced when the reagent is soluble in the solvent employed for the dissolution o-f the reactant.
It is also unexpected and a novel feature of process (a) that the conditions developed for the conversion of compounds of formula¦3), Z being (alkyl)P(O), to compounds of formula(l), R being H, are also very suitable for the conversion of compounds of formulal3), where Z is C~ and CO2alkyl to compounds of formula~l~, where R is CN and CO2alkyl. The latter type of conversion is no longer a Wittig reaction but resembles the Knoevenagel condensation (see for example R. C. Denney "~amed Organic Reactions", ~3utterworth, London 1969, p 50).
The wide scope of process (a) owing to which it can be applied to 21-esters of formula¦3~in which Z is not only ~alkyl)P~O) but also CN and CO2alkyl, is a special advantage of this process.
It is another advantage of the process (a) of this invention that the convexsion of~3)to(1~can readily be brought about by bases of only moderate strength as this allows the transformation of reactants possessing groups which would be chemically changed if the usual stronger bases o a Wittig reaction were used.

It is a further advantage of process (a) that the formation o the phosphonoacetatel3)from 21-alcohol(2)and the conversion~3)to~1)can be carried out in one vessel and that no intermittent evaporations of solvents are used in the two conversions are required. It is yet another advantage that, since the moderately strong bases employed ; in thls invention are ;not affected by water, no special precautions have to be observed to ensure that the co;nversion _9_ ofl3)to~1~is carried out under anhydrous conditions. The conversion ofl3~toll~via~2~can thus be carried out in a manner which is considerably more simple and economical than the previous procedure of choice of converting 21-hydroxy-20-ones of the pregnane series to cardenolides (see W. Eberlein, J. ~ickl, J. Heider, G. Johns and H. Machleidt, Chem. Ber., 105, 3686 (1972). who prepared 22-halo, alkyl- and alkoxycardenolides).
It is an advantage of process (b) that the conver-sion of the alkyloxyacetylene adduct(4)to the corresponding 20(22)-en-23-oic acid esters or cardenolides of formula~l), respectively, can be brought about by treatment of a solution ofl4~in a water immiscible inert solvent,(e.g. benzene, hexane, or ether) with a dilute aqueous solution of a mineral acid, such as perchloric, hydrochloric or sulfuric acid. By contrast in the previous method of converting the adduct ~4) to the ester~l~ the latter are treated with a mixture of an alcohol and aqueous sulfuric acid. Since alcohols in the presence o acid are not inert solvents, e.g. they may cause an exchange of the alkoxy group in esters 1 (F. S. Khristulas, . B. Gorovich and N. K. Abubakirov, Khimya Prirodnikh Soedinenii, 5, 545 (1970) p 551), the method o this invention employing inert solvents for the above conversion has a greater synthetic utility. ~urther enhanced utility derives fro~ the act that in the method of this invention the reaction~products can be more readily isolated from the ~ -reaction mi~ture, i.e. by the simple procedure of extracting the organic, water immiscible phase with water till the extracts are neutral and subse~uent evaporation of the inert solvent. Yet further utility derives from the fact that `10- ~, ' .

g9L9~3 the method is more applicable to such compounds of formula (4), which are not soluble or only partially soluble ln the acidic aqueous alcohol employed in the prior art. As is well known, steroids are generally more soluble in water immiscible organic solvents than in aqueous alcohols.
With regard to process (c), it is submitted that there is no prior art which teaches the conversion of cardenolides into the corresponding 22-alkoxycarboxyl-21-methyl-20(22)-en-23-oic acids or the corresponding 23,24-dioc acids, such as represented by ~ormula ~1), where R3 is an alkoxycarbonyl, R4 is a methyl group and R5 is the hydroxy group of a carboxylic acid. It is a special advantage of process (c) that it provides stereo-specific routes towards (22-E) and ~22-Z) 22-substituted 20~22)-enes.
By contrast, no such stereo-specific routes are provided for by the previous methods o:E preparing 21-methyl-22-substituted 20(22)-enes the stereochemistry of which is generally left unspecified (see, for example, F. Sondheimer and F.S.
Khristulas, cited above, and also M. Okada and ~. Saito, Chem. Pharm. Bull., 16, 2223 (1968)).
Many oE the products of the present invention of formula (1) have been found to have similar properties to the compounds of -formula f3 1-~ OH ~5~ ~

- . - . , ._ , ., . ,, ... : , ~ :
.

49~3 wherein R8 is chosen from the group oE H, CH20H, CH~ CO-~H-C(CH3)3, CH20alkyl and CH2Oacyl, wherein alkyl is - tetrahydrop~ranyl, lower alkyl, preferably methyl, or a substituted methyl wherein the substituent is selected from the group consisting oE phenyl, halogen, preferably chlorille and bromine, methoxy, CH2=CH and Hc-c~ and wherein acyl represents a group selected from those consisting of acetate, lower trialkyl acetates, wherein the lower alkyl group is preferably methyl or ethyl, monohalo acetates and trihalo acetates, preferably wherein the haloge~ is chlorine, fluorine and bromine. The compounds of the above formula and their glycosides are known for treatment of cardiac insufficiency, as for example disclosed in Angewandte Chemie vol. 9, No. 5, pp 321-332, and Fieser and Fieser, Chap. 20, "Steroids", Reinhold, NY 67. In addition, the compounds of formula (1) may in some cases be also used as intermediate~
for the preparation oE compounds of the above given formula, by converting the compounds of formula (1) by conventional techniques, or alternatively, by methods similar to those described in the following Examples. Still further, certain of the compounds o formula (1) - i.e. those without a 14~
o~cygen, may be useEul as modifiers oE cardiatonic compo~nds -e.g. by suppressing selectiveIy their toxic activi ty. Those compounds which are 3-deox~7 steroids or 22-substituted cardeno-lides or 24-nor-chol-20(22)-enoates have similar properties to the known 3 oxygenated-22-unsubstituted cardenolide analogs, as described in, e.g., Annular Reports in Medicinal Chemistry, 1970, page 174 and the references therein; W. Eberlein et al, Chem. Ber Vol 105, 3686 (1972); J.S. Boutagy, R. ~homas, Aus-~ralian Journal of Chemistry, Vol. 24, 2723 ~1971).

~ -12-il ~4~49~
Example 1 A mixture, prepared by successive addition of 3.942 ml of a 10D~ solution of [diethylphosphono~acetic acid (1.3 moles per mole of 21-hydroxy-20-ketone) in benzene and 10.05 ml of a 0.2 molar solution of dicyclohexylcarbodiimide (1.3 moles per mole of 21-hydroxy-20-ketone) in benzene to a solution of 600 mg of 3~-acetoxy-21-hydroxy-~,19-oxido-5~-pre~n-14-en~20-one in 30 ml of benzene, was stirred under nitrogen at room temperature for 18 minutes, whereupon a small fraction was withdrawn and added to 1 volume of water.
Evaporation of the organic phase gave 3~-acetoxy-21-[diethylphosphono~acetoxy-8,19-oxido-5~-pregn-14-en-20-one as evidenced by tlc analysis and subsequent tran.sformations.
The remaining major reaction mixture was stirred under nitrogen with 15 ml of 50% aqueous potassium hydroxide for 15 minutes at room temperature, whereupon 75 ml of a mixture of water and ice was added. Acidification of the mixture with acetic acid-water 1:10, followed by dilution with ether-methylene chloride 4:1, five extractions of the organic phase with 1/4 volume of water, evaporation at reduced pressure and drying at high vacuum gave a residue which was stirred with 30 ml of methylene chloride under nitrogen for 15 minutes. The undissolved solid was then removed by fil-tration. Concentration of the filtrate, followed by addition of hexane till a faint turbidity appeared, filtration through diatomaceous earth, concentration of the filtrate at reduced pressure with intermittent addition of hexane and ether, standing at -5C for 2 hours and filtration gave 524 mg of 3~-acetoxy-8,19-oxido-5~-carda-14,20~22)-dienolide, mp 214,220-221C.
Recrystallisation ~rom methanol water ~ave a purified sample, mp 219,222-224C., uv (MeO~I) 219 m~.

.

.

: L~494g~3 -Example 2 A mixture, prepared by successive addition of 17.7 mg of [diethylphosphono]acetic acid (2.6 moles per mole of 3,21-diol), 0.175 ml of benzene and 0~455 ml of a 0.2 molar solution of dicyclohexylcarbodiimide (2.6 moles per mole of 3,21-diol) in benzene to a suspension of 12mg of 3~,21-dihydroxy-8,19 oxido-5a-pregn-l4-en-2o-one in 0.175 ml of benzene, was stirred under nitrogen at room temperature. Tlc analysis on a sample withdrawn after 20 minutes indicated that all starting material had been conver~ed to 3~,21-di[diethylphosphono]acetoxy- -8,19-oxido-5a-pregn-14-en-20-one.
After 35 minutes of stirring 0.115 ml of 50% aqueous potassium hydroxide was added and stirring was continued for 30 minutes, whereupon 0.455 ml of water was added. The mixture was then Eiltered, the phases were separated, the aqueous phase of the filtrate was acidified. Filtration of the resulting precipitate yielded 3~-[diethylphosphono~acetoxy- -8~l9-oxido-5a-carda-l4~2o(22)-dienolide~ uv(MeOH) 21~ m~, ir (KBr)3070, 1777, 1748, 1628, 1110, 1050, 1003, 926, 890, 860 and 818 cm 1.
Example 3 ~ mixture, prepared by successive addition of 3.35ml of a 0.2 molar solution of dicyclohexylcarbodiimide (1.3 moles per mole o 21-hydroxy-20-one) in benzene to a solution of 130 mg o benzyl hemimalonate (1.3 moles per mole of 21-hydroxy-20-one) and 200 mg of 3~-acetoxy-21-hydroxy-8,19-oxido-5a pregn-14-en-20-one in 10 ml of benzene, was stirred under nitrogen at room temperature. Tlc analysis on a sample with-drawn after 15 minutes indicated that all starting material had been converted ta 3~-acetoxy-21-~benzyloxycarbonyl~acetoxy-8,19-oxido-5~-pregn-14-en-20-one.
The mixtuxe was then stirred und0x nit~o~en ~or 2-1/4 , : ~ , , - . .: ~

hours with 2.5 ml of 10% aqueous potassium hydroxide, where-upon 4.0 ml of water and 2.0 ml of acetic acid-water 1:10 and 2 volumes o~ ether was added. The mixture was agitated and the fine, undissolved precipitate was removed by filtration.
The organic phase o-f the biphasial filtrate was extracted 5 times wlth water and then evaporated. Recrystallisation of the residue from ether-hexane gave 216 mg of a precipitate which after a further recrystallisation -from the same solvent system gave 3~-acetoxy-22-benzyloxycarbonyl-8,19-oxido 5 carda-14,20(22)-dienolide, mp 174, 176-178C,uv tMeOH) 212 and 229 m~u.
Example ~
When 40 mg o-f 3~-acetoxy-21-hydroxy-8,19-oxido-5~regn-14-en-20-one waæ ~ub jected toreaction conditions, which were essentially the same as those described in Example 3 except that cyanoacetic acid instead of benzyl hemimalonate was used, the 21 -cyanoacetate of the starting material was obtained as the intermediate product, which a~ter the base-treatment and -chromatographic separation on silica geI G coated glass plates 2~ with ethyl acetate-benzene 1:1 as the elu~nt gave 3~-acetoxy-22-cyano-8,19-oxido-5~_carda-14,20(22)-dienolide, u~ ~MeOH) 210 and 234 m~, and 22-cyano-3~-hydroxy-8~19-oxido-5X-carda-14-,20(22~-dienolide, uv (MeO~I) 209 and 234 m,u.
Example 5 When 23 mg of 3~,19-diacetoxy-21-hydroxy-5x-pregn-14-en 20-o~e was subjected to reaction conditions, which were essen-tially the same as those described in Example 1, except that, ins-tead of 1.3 moles, 1~5 moles per mole starting material of ~diethylphosphono~acetic acid and dicyclohexylcarbodiimide .. . . .
were used, the 21-~diethylphosphono~acetate of the starting ma~erial was obtained as an intermediate. The subsequent ~4gg~91~
base-trea-tmen-t, followed by chroma-tographic puri-fication of the crude produc-t on silica gel coa-ted glass plates, with ethyl ace-tate-benzene 1:7 as the eluant, and digestion of the purified ma-terial with pentane afforded 3~,19-diacetoxy-5~-carda-14,20(22)-dienolide, mp 155-162C.
Example 6 When 97038 mg of 19-acetoxy-21-hydroxy-pregna-4,6-diene-3~2o-dione was subjected to reaction condi-tions, which were essentially the same as those described in Example l, except -that 2.6 moles per mole of starting material of [diethylphosphono]acetic acid and dicyclohexylcarbodiimide were used instead of 1.3 moles each, the 21-[diethylphosphono]-acetate of the starting material was obtained as an inter-mediate. The subsequent base-treatment, and chromato-graphic purification of -the crude product on silica gel G
coa-ted glass plates, ethyl acetate-benzene 2:1 being the eluant, afforded 19-acetoxy-3-oxo-carda-4,6,20(22)-trienolide, mp 180,~97-199, uv (MeOH) 218 and 285 ~u Example 7 When 172.2 mg of 8,19-oxido-21-hydroxypregn-4-en-3~20-dione was subjected to reaction condi-tions which were essentially the same as those descr:ibed in Example 6, except that the :Lntermediate 21-Cdiethylphosphono] acetate of the starting material was isolated~and separated -from residual starting material by chromatography on silica coated glass plates and then subjected to the base-treatment, recrystall~
isation of the final crude product from ethyl acetate-pen-tane gave 36.3 mg of a crystalline material consisting essentially of 3-oxo-8,19-oxido-carda-4,20(22)-dienvlide cont~ining a more polar alcohol-as an impurity~ Treatment of the latter product with pyridine-a¢etic anhyd~ide at -~5 C~ for 21 days, followed .

49~
by addition of water, filtration and recrystallisation o-f the precipita-te collectcd with methylene chloride-ether gave 18 mg of the purlfie~ product, mp 227, 228-231C., ir(NUJOL) 3105 tWeak), 1778, 1745, 1670, 1622, 1375, 1305, 1258, 1045, 1020, 966, 890, 882 and 815 cm 1.
Example 8 When 400 mg of 3~-ace-toxy-21-hydroxypreyn-5-en-20-one was subjected to reaction conditions, which were essentially iden-tical to those described in Example 1, 336 mg of 3~-acetoxycarda-5,20(22)-dienolide, mp 168, 169-173C., was obtained via the 21-~diethylphosphono]acetate of the starting material.
Example 9 When 166,25 mg (0.5 millimoles) of 3~ 21~dihydroxy-pregn-5-en-20-one was subJected to reaction conditions, which were essentially the same as those described in Example 2, the base-treatment of the intermediate 3~,21-diCdie-thylphosphono]-acetoxy-pregn-5-en-20-one gav~ 3~-[diethylphosphono]ace-toxy-carda~5,20~22)-dienolide,ir(KBr) 2970, 1785, 1755, 1730, 1635 1260, 1250, 1145, 1120, 1070, 1025, 900, 875 and 790 cm Exam~e 10 When 400 mg of 3~-acetoxy-21-hydroxypreyn 5-en-20-one was treated under reaction condi-tions which were essentially the same as -those described in Example 3 except that the inter-mediate 3~-acetoxy-21-[benzylox~carbonyl]acetoxy-pregn-5~en-20-one was isolated and purified by precipitation with hexane from a methylene chloride solution, dissolution of the crude final product in methylene ohloride, followed by precipitation with hexane, gave 551 mg of 3~-acetoxy-22-[benzyloxycarbonyl]-oarda-5,20(22)-dienolide as evidenced by the comparison with a sample of another batoh~ which had uv(MeOH) 216 and 230 m~.

~9~g8 xample 11 A mixture, prepared by successive addition of 118.8 mg of cyanoacetic acid (1.3 moles per mol~ o-f 21-hydroxy-20-ketone) and 6O96 ml o-f 0.2 molar solution of dicyclohexyl-carbodiimide (1.3 moles per mole of 21-hyclroxy-20-ke-tone) in benzene to a solution oE 400 mg of 3~-acetoxy-21-hydroxy-pregn-5-en-20-one in 20 ml o-f benzene, was stirred under nitro-gen. Tlc analysis on a sample withdrawn after 80 minu-tes showed that all of the starting material had been converted to the corresponding 21-cyanoacetate. The mix-ture was stirred with 6.0 ml of 10% aqueous po-tassium hydroxide under nitrogen for 10 minutes, whereupon 160 ml of water and 200 ml of ether was aclded. The lower, aqueous phase was separated, acidified with 9.0 ml of 2N aqueous sulfuric acid and extracted with ether. The ether solution was extracted with water till the aqueous extracts were neutral, dried with sodium sulfate and evaporated at reduced pressure. Dissolution of the residue obtained in methylene chloride, addition of hexane ~ill the solution became slightly turbid, -filtration through diatom-aceous earth, concentration of *he filtrate with intermitten-t addition of hexanel standing at -5 C and filtration gave 355 mg of 3~-aceto~y-22-cyanocarda-5,20(22)-dienolide, mp 200-215, uv(MeO~)241 m~u, as verified by ir- and nm~-SpeCtroscoPY.
Agitation of 34.4 mg of the above compound, dissolved in 3.45 ml of benzene, with 3.45 ml of 50% aqueous potassium hydroxide for 3 hours, followed by acidification wi-th 2N aqueous sulfuric acid and isolation of the steroidal product by a pro-cedure which was essentially the same as the one outlined above, gave 3~-hydroxy-22-cyanocarda-5,20~223-dienolide mp 211-225, uv(MeOH) 239 m~u,ir (KBr) 3550, 2225, 1760, 1640, 1065, 1045, 1025 and 760 cm 1.

,, 9~
Example 1~
When 50 mg of 21-hydroxy-8,19-o~ido~5~-pregn-:L~en-20-one was subjected to reaction conditions which were essen~ally the same as thosedescribed in Example 1, 4~ mg of 8,19-oxido-

5~-carda-14,20(22)-dienolide, mp 177, 179--18~4~,uv (CH30H) 218m,u was obtained via the 21-[diethylphosphono]ace-tate of the starting material.
Example 13 When 20 mg of 21-hydroxy-8,19-oxido-5a-pregn-1~-en-20-one was subjected to reaction conditions which were essen--tially the same as those described in Example 4, 21-cyanoacetoxy-8~19-oxido-5a-pregn-14-ene was obtained as -the intermecliate and 22-c~ano-8,19-oxido-5~-ca~da-1~,-20(22)dienolide, ir (KBr) 2220, 177~, 1625 and 1572 cm~l as the final product. A methanolic solution of the latter compound had uv 237 m,u; after addition of a small amount of aqueous potassium hydroxide it had uv 256 m~u.
Example 1~
A mixture of 250 mg of 3~-acetoxy-8,19-oxido-5x-carda-14,20(22)-dienolide~ 7.5 g of zinc, 18.75 ml of -toluene and 6.25 ml of formic acid was shaken for 16 hours whereupon the supernatant phase was decanted. The residue was shaken briefly with 25 ml of benzene, which was then decanted. The benzene extrac-tion was repeated ano-ther ~ times. The decanted supernatant liquids were filtered, combined and evaporated at reduced pressure. The residue was dissolved in methylene chloride and hexane was added to the solution till it became faintly turbid. The mixture was fil*ere~ through diatomaceous earth and the filtrate was concentrated at reduced pressure with intermittent addition of hexane and ether.
Standing of the mixture at -5C~, -followed by filtration ga~e - : . ~ . :
.

1~94~
237 mg of 3~-aeetoxy-19-formyloxy~5~-earda-1~,20(22)-dienolide, uv(MeO~I) 218 l~u, ir(KBr) 3065 (weak), 1795, 1767, 17~0, 1730, 1640, 1255, 1207, 1170, 1141, 1081, 1059, 1030, 911, 895, 867, 815 and 745 em~l. TLC analysis showed that the reae-tion proceeds ~ia 3~-aeetoxy-19-hydroxy-5~-earda-14,20(22)-dienolide.
Example lS
Reduetion of 70 mg of 8~l9-oxido-5a-carda-l4~2o(22)-dienolide with zine in presence of -formic aeid under conditions which were essentially the same as those clescribed in Example 14, afforded 39.8 mg of 19-hydroxy~5~-carda-14,2Q(22)-dienolide 19-formate, mp 131jl35-136.5 C., via 19-hydroxy-5~-earda-14, 20(22)-dienolide.
Example 16 A mixture of approximately 38 mg of 3~-acetoxy-8, 19-oxido-5~-carda-1~,20(22)~d:Lenolide, 3.8 ml of glacial acetie acid, 0.97 ml of water and 77 mg of zinc dust was s-tirred briefly at room temperature and then wi-th external heating by an eil-bath having a temperature between 65 to 6~Co A-fter 5 minutes of stirring in the oil-ba-th, 388 mg of zine was added slowly during 3 minu-tes followed by 3 Eurther slow additions during 3-4 minutes of the same quantity of zine a-fter 36~ 227 and 25~ minutes respective:Ly. The mixture was then filtered and the precipitate was ~ashed with acetie acid-water 4:1 and ethyl acetate. The -filtrate was concentrated 3 -times at redueed pressure to 2 ~olume with intermittent addi-tion of 3 x 30 ml of wa-ter. The resulting mix-ture was neutralized with a 1 saturated aqueous sodium biearbonate and left to stand at ~5& for 22 days. Filtration ga~e 28 mg of a produetcon-taining 3~-acetoxy-19-hydroxy-S~-carda-1~,20(22)-dienolide as the major eompound as evidenced by tle. The latter material, 0.11 ml of ~yridine and 0.056 ml of aeetic anhydricle was then .

g~ :
lef-t to stand under nitrogen ~or 16 hours at room temperature, whereupon it was diluted with Ilexane-ether 2:1 and filtered.
The filtrate was concen~trated at reduced pressure wlth inter-mit-tent addition of toluene. Chromatography of the resulting resin on silica gel G coated glass plates with ethyl acetate-benzene 1:4 as the eluant, followed by digestion with pentane of the -fraction isola-ted, gave 10 mg of 3~l9-diacetoxy-5a-carda-14,20~22)-dienolide, mp 162,163-164, which as evidenced by its ir-spectrum and meltin~ point, was :found to be identical with ~-anhydrocoroglaucigenin 3,19-acetate, mp 161-163, (A. Hunger and T. Reichstein, ~Ielv., 35, 1073 (1952).
Exampl~_~
~ mixture of 30 mg of 3~-acetoxy-19-formyloxy-5~-carda-1~,20(22)-dienolide, 1.2 ml of ace-tone and 0.6 ml of a so:Lution of 60 mg of N-bromoacetamide in 1 ml of water was stirred under nitrogen in the dark in an ice-bath ~or 97 minutes whereupon 18 ml of ice-water and 1.2 ml o-f a t saturated aqueous sodium bisulfite solution was added. After 30 minutes of further stirring, filtra-tion, followed by drying at high vacuum afforded 3~-acetoxy-lSo-bromo-19-formylox~J-14~hydroxy-5~-card _ 20(22)-enolide; ir(KBr) 3425 (broad), 3295 (sharp), 3070 (weak), 1735, 1727, 1719, 1710, 1705~ 1619, 1565, 1370, 1355, 1239, 1115, 1021, 901, 890, and 882 cm~l; the the ir-spectrum of a chloroform solution had a strong peak at :
35jO instead of the peaks at 3~25 and 3295 cm~l.
Example 18 ~hen 11 mg o~ 3~19-diacetoxy-5a-carda-1~20(22)-dienolide was subjected to reaction conditions which were ~ssentially the same as those in the preceding example, ~iltration of the aqueous suspension gave 3~j~19-diacetoxy-15a-bromo~ hydroxy-5a-carda-20(22)-enolide;uv`(MeO~I)217 ~;

--21- :

l~g~8 ir (~UJOL), 3470 (broad), 3390 (weak), 3360 (weak), 3090 (wealc), 1769, 1735, 1720, 1705, 1620, 1~50, 1368, 1355, 1237, 1025, 951, 880 and 865 cm~l.
Example 19 A mixture, prepared by addi-tion of a freshly macle solution of 180 mg of N-bromoacetamide in 3O0 ml of water to

6.o ml of acetone and 150 mg of 3~-acetoxy-19-formyloxy~5~-carda-14,20(22)~dienolide, was stirred in the dark under nitrogen with external cooling by an ice-bath for 2 hours whereupon 90 ml of ice-wa-ter and 6.0 ml of a hal-f-saturated aqueous sodium bisulfite was added and stirring was con-tinued for another hour. Filtration gave 3~-acetoxy-15~-bromo-19-formyloxy-14~-hydroxy-5~-card-20(22)-enolide, which was dis-solved in 30 ml of methylene chloride and shalcen for 16 hours with a mixture of 3.0 ml of pivalic acid-methylene chloride 1:10, 60 ml of water and Raney nickel; the latter had been freshly prepared -from 9.0 g of a 50~ nickel-aluminium alloy.
~ddition of ether-methylene chloride 4:1, followed by -filtra-tion through filter-pulp, extraction of the organic phase with half-saturated aqueous sodium bicarbonate and water, drying with sodium sulfate and evaporation at reduced pressure, combination of the crude procluct obtained with that of another reaction in which 50 mg of 3~-acetoxy-19-formyloxy-5~-carda~
14,20(22)-dienolide were used as the starting material, and several recrystallisations of the combined products from e-ther-hexane gave 50.65 mg of product, mp 232,234-239o Furbher purification of 24 mg of this material by chromatography on Silica gel G coated glass plates with ethyl acetate-benzene 1:2 as the eluant gave 19 mg o- a fraction, which a-fter recrysta~lisa-tion -rom ether-hexane yielded 16 J 76 mg of purified coroglaucigenin 3-acetate 19 format~, mp 248.5-250~2Co The mother liquors, when subjected to chromatography ~22~

1a~4~4911~
as described above, afforded further amounts of the latter compound as well as several fractions amounting to approxi-mately 20 mg of 3~-acetoxy-19-formyloxy-14~-,15~-oxido-5~-card-20(22)-enolide.
Example ~0 When 15~-bromo-3~,19-diacetoxy-14~-hydroxy-5~-card-20(22)-enolide, which had been freshly prepared from 11 mg of 3~,19-diacetoxy-5~~carda-14,20(22)-dienolide as described in Example 18, was treated under reaction conditions, which were essentially similar to those described in the preceding example except that the reduction with Raney Nickel was carried out in an atmosphere of hydrogen instead of nitrogen, chromatography of the crude product on silica gel G coated glass plates with ethyl acetate-benzene 1:2 as the eluant, followed by recrystallisation from ether-pentane, gave 3~,19-diacetoxy-14~-hydroxy-5a-card-20(22)-enolide (coroglaucigenin diacetate), mp 207-212C.; coroglaucigenin diacetate prepared by A. Hunger and T. ~eichstein, Helv., 35, 1073 (1952) p.1097 from coroglaucigenin had mp 210-214 and 216-219C.
Example 21 3~-Acetoxy-l9-formyloxy-15~-bromo-1~-hydroxy-5~-card-20(22)-enolide was prepared ~rom 25 mg o~ 3~-acetoxy-l9-formyloxy-5~carda-14,20(22)-dienolide as described in Example 17. A methànolic solution of the freshly ~iltered -~
bromohydrin was then stirred with a molar excess of concen-trated aqueous ammonia at room temperature under nitrogen for several hours and then left at -5C for 16 hours, where-upon the base was neutralized with acetic acid in ethyl acetate and the mixture was evaporated at reduced pressure. ~--The residue obtained was extracted 3 times with ethex-methy-lene chloride 4~1 and the combined extracts were chromato-~,. ..

499~98 graphed on silica gel G coated glass plates using e-thyl acetate-benzene 1:2 as the eluant. Recrystallisation of the major fraction from ether-hexane gave 11.36 mg of 3~-acetoxy-19-formyloxy-14~,15~-oxido-5a-card-20(22)-enolide, mp 213-215C.
Example 22 A mixture, consisting of 15~-bromo-3~,19-diacetoxy-14~-hydroxy-5a-cardenolide, which had been ~reshly prepared from 2.6 mg of 3~,19-diace~oxy-5a-carda-14,20(22)-dienolide, by the method described in Example 17, and 0.13 ml of t-butylamine was left ~o stand under nitrogen for 30 minutes whereupon it was evaporated at reduced pressure. Treatment of the residue with ether and water, repeate~ ex~raction of the organicphase :
with water, evaporation and recrystallisation from ether-pentane gave 3~l9-diacetoxy-l4~l5~-oxido-5a-card-2Q(22)-enolide~
mp 194, 200-204C.
Example 23 A mixture, consisting of 3~-acetoxy-19-formyloxy-15a-bromo-14~-hydroxy-5a-card-20(22)-enolide, which had been freshly prepared from 20 mg of 3~-acetoxy-19-formyloxy-5a-carda-14, 20(22)-dienolide as described in ~xample 17 and was still wet, 1 ml of t-butylamine and 0.5 ml of water was stirred forl hour in an atmosphere of nitrogen, whereupon it was concentrated at reduced pressure with intermittent addition of hexane and water.
Filtration yielded 8.0 mg of crude 3~-ace~oxy-19-hydroxy-14~, 15~-oxido-5a-card-20(22)-enolide. Recrystallisation from ~hexane-methylene chloride gave the purified sample, mp 227-229C.
Example 24 A mixture, consisting of 7 ml of methanol and crude 3~-acetoxy-19-formyloxy-14~-hydroxy-5a-card-20(22)-enolide, 30 prepared from 150 mg of 3~-acetoxy-19-formyloxy-5a-carda- --14,20(22)-dienolide as described i~ Example 19, was stirred un~x nit-~o~n at ~oom tempera~ure; ~.9 ml of meth~n~l-2%
_ ~,y _ ~L~49149~
aqueous potassium hydroxide 20:1 was then added duriny 1/2 hour. A*ter 2 hours 0.2~5 ml of glacial acetic acid-ethyl acetate 1:50 was added and the mixture was evaporated a-t reduced pressure. Extraction of the residue with ether-methylene chloride 4:1, followed by extraction of the organic phase with water, drying with sodium sulfate evap-oration and chromatography on silica gel G coated glass plates with ethyl acetate-benzene 1:1 as the eluant gave 37 mg of 3~-acetoxy-14~,19-dihydroxy-5~-card-20(22)~enolide (coroglaucigenin 3-acetate), mp 233-234.
Example 25.
Oxidation of 4 mg of coroglaucigenin 3-acetate with t-butyl chromate in t-butanol-carbon tetrachloride 1:6 by a method which was essentially the same as the one described by A. Kat~, Helv., 35, 487 ~1957), p.~90, gave corotoxigenin 3-acetate, mp 220, 221-229, after recrys-tal-lisation of the crude product with ether-hexane. The ir-spectrum o* the latter compound was identical to that obtained by A. Hunger and T. Reichstein, Helv. 35, 1073 (1952), who obtained corotoxigenin 3-acetate, mp 227-234 and 220-230 from corotoxigenin. The t-butyl chromate was prepared as described by K. Hensler and A. Wettstein, Helv., 35, 284 (1952).
Example 26 A mixture of 6 mg of coroglaucigenin 3-acetate 19-formate, 0.3 ml of t-butylamine and 0.3 ml of water was shaken under nitrogen at room temperature for 2~ hours whereupon it was evaporated at reduced pressure with inter-mittent addition of glacial acetic acid-water 5:1. The residue was disintegrated in 0.2 ml o* water and the resulting suspension was filtered. The precipitate was recrystallised rom methanol-ether ~ielding 3. 7 mg of crude . .

9~
coroglaucigenin, mp 227-230. Chromatography on silica gel G coated glass plates with ethyl acetate as the eluant, followed by recrystallisation from methanol-ether, gave the purified sample; mp 241-242, 244 ; ir(KBr) max. 3610, 3350 3098, 1781, 1750, 1738, 1620, 1445, 1370, 1339, 1309, 1301, 1175, 1148, 1135, 1075, 1035, 1025, 1019, 959, 891, 887, 880, 869, 790, 780, 741 and 698 cm 1.
Example 27 A mixture, consisting o~ 45 mg of 3~-acetoxy-carda-5,20(22)-dienolide, 9.0 ml o~ methanol and 0.9 ml of 2%
aqueous potassium hydroxide was stirred for 4 hours whereupon another lot of 0.9 ml of 2% aqueous potassium hydroxide was added. The mixture, in which a precipitate had ormed was left to stand at -5Cfor 16 hours and was then flltered.
The precipitate was washed with water-methanol 1:3 and then with water. The filtrate was concentrated and filtered yielding a second precipitate. Both precipitates were combined and chromatographed on silica gel G coated glass plates using ethyl acetate-benzene 1:4 as the eluant~ The fraction having rf 0.2-0.3 was recrystallised fr~m ether-hexane and yielded 5.7 mg of 3~-hydroxy-carda-5,20~22) dienolide, ir(KBr? 3460 ~broad), 1805 , 1730, 1620, 1190, 1170, 1135, 1108, 1070, 1052, 1030, 985, 965, 905, 870, 812, 745 and 712 cm 1.
The latter 3~-hydroxycardenolide was also obtained, as indicated by tlc analysis, when the 3~-~diethylphosphono]-acetoxy analog of the starting material was similarly hydro-lysed with methanol and 2% aqueous potassium hydroxide.
Exam~le 28 When 25 mg of 19-formyloxy-5~-carda-14,20(22)-dienolide was oxidized with ~-bromo acetamide as outlined in Bxample 17,th~ corresponding 14~-hydr3xy-15~-bromo analog was obtained. The freshly filtered and ~till wet bromo-~9~
hydrin, when reduced with Raney nic~el as described in Example 17, gave a crude product which was purified by chromatography on silica gel G coated glass plates with ethyl acetate-benzene 1:1 as the eluant. Recrystallis-ation of the fraction having rf 0.3-0.~ from ether-hexane gave 8.4 mg of 14~,19-dihydroxy-5~-card-20(22)-enolide 19-formate, mp 195-198qC, ir(KBr) 3565, 3415 (broad), 3330 (shoulder), 3090 (small) 1785, 1755, 1742, 1737, 1730, 1721, 1715, 1628 and 1175 cm 1. A less polar fraction isolated consisted mainly of a product considered to be the 14~,15 oxido analog of the latter compound.
Example 2~
A freshly prepared mixture, consisting of 11.2 ml of anhydrous tetrahydrofuran, 0.187 ml of redistilled ethoxyacetylene and'l.12 ml of 1.95M methyl lithium in ether was added to a solu-tion of 50 mg of 3~-acetoxy-21-hydroxy-8,19~oxido-5~-pregn-14-en-20-one in 8.7 ml of tetra-hydrofuran which was protected by an atmosphere of nitrogen.
After stirring under nitrogen for 4 hours the solvents were evaporated at reduced pressure. The residue was treated '~' ' with wet ether and the ethereal phase was extracted several times with water till the aqueous extracts were no longer basic. Evaporation yielded a resin consisting mainly of 20-ethoxyethynyl-3~,20,21-trihydroxy-8,19-oxido-5~-pregn-14-ene as evidenced by tlc analysis and the subsequent transformations. The latter product was then vigorously stirred with 3O5 ml of benzene and 1.75 ml of 2N aqueous suluric acid under nltrogen for 4 hours, whereupon the reaction mixture was diluted with'b'enzene, and extracted successivel~ with water and half saturated aqueous sodium bicarbonate. The benzene solution was dried over sodium ~ulfa~e and filtered th~ough a colum~ of 70 m~ of aluminlum . .
:- :

~0~9~98 oxide. Washing of the column with ethyl acetate afforded 21 mg of a product, which solidified with hexane and con_ sisted essentially of3~-hydroxy-8~l9-oxido-5a-carda-l4~2o(22 dienolide. Subs~quent standing with 0.084 ml of pyridine and 0.042 ml of acetic anhydride for 20 hours in a nitrogen atmosphere, followed by addition of 20 volumes oE water, extraction with ether, extraction of the ethereal phase with water and evaporation afforded the corresponding 3-acetate, which was then reduced with zinc and formic acid in presence of toluene under conditions which were similar to those described in Example 14. Chromatography of the total product-obtained on sillca gel G coated glass plates with ethyl acetate-benzene 1:4 as the eluant gave 9.7 my of 3~,19-dihydroxy-5a-carda-14,20(22)-dienolide 3-acetate l9-formate as a white solid, which had an ir spectrum identical to the product of Example 13.
When 3~,21-dihydroxy-or 3~,21-diacetoxy-8,19-oxido-5~-pregn-14-ene instead of 3~-acetoxy-21-hydroxy-8,19-oxido-5a-pregn-l4-ene were reac-ted with ethoxyacetylene as des-cribed above,20-ethoxyethynyl-3~,20,21-trihydroxy~8,19-oxido-5a-pregn-l4-ene was ohtalned.
Example 30 When 3~-acetoxy-8,19-oxido-5a-pregn-14-en-20-one was reacted with ethoxyacetylene as described in the pre-ceding example, a compound considered to be 20 ethoxyethynyl-3~,20-dihydroxy-8,19-oxido-5~-pre~n-14-ene was obtained;
similarly 8~19-oxido-3~-~tetrahydropyran-2-yloxy~-5a-pregn 14-en-20-one gave a compound considered to be 20-ethoxy-ethynyl-20-hydroxy-8,19-oxido-3~-tetrahydropyran-2-yloxy-5~-pregn-14-ene. The latter two ethoxyacetylene adducts, when treated with aqueous sulfuric as described in the pre-c~dlng ~x~mpl~, ~ave èthy`l 3~-hydroxy-~,19-oxido-24--nor-5~-~8 :

- :
. , ~ ,: .

~94~
chol~20(22)-en-23-oate, uv max. 222 m~, as evidenced by tlc analysis.
Exam~e 31 When 32 mg of 14~-hydroxy-3~-[pyran-2-yloxy]-8,19-oxido-5~-pregnan-20-one was reacted with ethoxyacety-lene similarly as described in Example 29, a product con-taining 20-ethoxyethynyl-3~,14~-dihydroxy-8,19-oxido-5~-pregnan-20-one was obtained, which after treatment with aqueous sulfuric acid, similarly as described in Example 29 except that ethanol was used as the solvent, gave a product containing ethyl 3~,14~-dihydroxy-8,19-oxido-24-nor-5~-chol-20(22)-en-23-oic acid. Acetylation with acetic anhydride-pyridine 1:2 followed by chromatography of the crude product on silica gel G coated glass plates with ethyl acetate-benzene 1:4 as the eluant gave ethyl 3~-hydroxy-8,19-oxido-24-nor-5~-chol-20~22)-en-oate, uv max. 231 m~, treatment of this product with selenium dioxide in boiling benzene as described by N. Danieli, Y. Mazur and F. Sondheimer, J.Am.
Chem.Soc., 8~, 875 (1962) followed by chromatography on silica gel G coated glass plates with ethyl acetate-benzene 1:4 as the eluant gave a fraction considered to be 8,19-oxidouzarigenin acetate, uv max. 218 m~u. A further, more polar fraction had also uv max. 218 m~ and was considered to he 14a-hydroxy-8,19-oxidouzarigenin 3-acetate ~cf F. Sondheimer, Chemistry in Britain, 1, 454 (1965), p.459).
Example 32 A mixture o 200 mg of 3~-acetoxy-21-hydroxy-pregn-5-en-20-one, 10 ml of methyl isobutyl ketone, 2.0 g of malonic acid and 2.0 g of calcium chloride was heated under nitrogen at 84C. for 2 days, whereupon it was evapo-rated at reduced pressure with intermittent addition of benzene. The residue obtained was treated with water and ~9 94~
the resulting precipitate was filtered and washed well with water. The precipitate was dissolved in methylene chloride and the solution was concentrated with intermittent addi-tion of pentane. The supernatant petroleum ether phase was decanted and the precipitation from pentane was repeated twice. The remaining residue was dissolved in ether-methylene chloride, treated with charcoal and filtered through diatomaceous earth. Concentration of the filtrate at reduced pressure with intermittent addition of hexane and ether, followed by filtration, gave 192 mg of 3~,21-dihydroxy-pregn-5-en-20-one 3-acetate 21-hemimalonate.
A solution of the latter compound in ether-diazo-toluene, which was prepared by mixing briefly 22.3 mg of N-benzyl-~'-nitro-N-nitrosoguanidine, 0.040 ml oE potassium hydroxide-water 1:1 and 1 ml oE ether with external cooling by an ice-acetone bath, wa.s then left to stand at -50C.
for 15 minutes. Evaporation at reduced pressure gave an off-white solid consisting mainly of 3~-acetoxy-21-~benzyl-oxycarbonyl]acetoxy-pregn-5-en-20-one. Treatment of part 20 of the latter product with 20 parts t-butylamine for 25 minutes at room temperature, followed by evaporation, gave a product consisting mainly of 3~-acetoxy-22-[benzyloxycarbonyl]-carda-5,20(22)-dienolide as evidenced by tlc analysis.
Example 33 A mixture of 200 mg of 3~-acetoxy-21-hydroxypregn-5-en-20-one, 10 ml of dimethyl malonate and 2.0 g of calcium chloride was heated in an oil-bath having a temperature of 84C. for 4 days under nitrogen whereupon 20 ml of toluene was added. The reaction was then arranged for distillation 30 at atmospheric pressure and the bath temperature was raised to 160C. during 1.5 hours. Subsequently the temperature o~ th~ ba~h tempera~u~e wa~ lowered to 84 and the mixt~l~e 3~

:.

,- .

~9~9~
was subjected to distillation at high vacuum for 1.5 hours.
The resulting solid residue was dissolved in 15 ml of ether, 2.5 ml of hexane and some charcoal was added. Filtration through diatomaceous earth, followed by concentration of the filtrate with intermittent addition of hexane and ether gave a suspension which after filtration gave 3~-acetoxy-21-[methoxycarbonyl]acetoxy-pregn-5-en-20-one.
Example 3~
A mixture of 220 mg of the product of the pre-ceding Example and 2.2 ml of t-butylamine-benzene 1:10 was left to stand at room temperature under nitrogen for 35 minutes, whereupon it was concentrated at reduced pressure with intermittènt addition of benzene. Hexane was then added till the solution became slightly turbid. Subse-quent filtration through dia-tomaceous earth and concentra-tion of the iltrate at reduced pressure with intermittent addition of hexane gave resinous precipitate, which was dis-solved in ether and precipitated from hexane. The preci-pitation from hexane was repeated once more yielding finally 127 mg of a beige solid consisting mainly of 3~-acetoxy-22-methoxycarbonylcarda-5,20(22)-dienolide. Chromatography on silica gel G coated glass plates with ethyl acetate-benzene 1:6 as the eluant, followed by recrystallisation from hexane gave a purified sample, mp 100, 112-120, uv (MeOH) 229 m~u;
ir(KBr) 1770, 1725, 1655, 12~0 and 1030 cm 1 A methanOlic solution of the sample, a-fter addition of a small amount of aqueous potassium hydroxide, rapidly changed from uv 229 to 235, 286 (major) m~u. During the chromatographic develop-ment a pink colour, which appears typical for 22-[alkyloxy-carbonyl]card~20(22)-enolides, developed.
.
3~ :

o ~xample 35 A mixture, prepared by addition of 0.1875 ml of anhydrous tetrahydrofuran to 30 mg of methylCdiethylphosphono]-acetate, cooling in an ice-bath, addltion of 2.2 mg of sodium hydride-mineral oil 1:1, warming to room temperature and addition of 27~75 mg of 21-hydroxy-6,19-oxidopregn-4-en-3-one, was stirred at room temperature for 20 hours,where-upon a mixture of 30 mg of methyl [diethylphosphono]acetate.
0.1875 ml of anhydrous tetrahydrofuran and 2.2 mg of sodium hydride-mineral oil 1:1 was added and stirring was con-tinued for another 2 hours. Evaporation at reduced pressure followed by addition of 5 ml of ethyl acetate, 5 extractions with water and evaporation of the extrac-ted organic phase at reduced pressure gave a product whlch, after chromatography on silica gel G coated glass plates with ethyl acetate-benzene 1:1 as the eluant and recrystallisation of the frac-tion having rf 0.35 from ether-pentane gave 3-oxo-6,19-oxidocarda-4,20(22)-dienolide, uv(MeOH) 225 ~road) m~ which had an ir spectrum identical to that of the product of Example 7.
Example 36 A mixture,was prepared by successive addition, against a strqam of nitrogen, of 76 mg of sodium hydride-mineral oil 1 1, a solution oE 0.340 ml of [diethylphosphono~-acetonitrile in 1.2 ml of tetrahydrofuran and 73 mg of -5~-chloro-3~,21-diacetoxy-6,19-oxidopregnan-20-one in 6 ml o-E tetrahydrofuran to 5.2 ml of tetrahydrofuran; during the additions the reaction vessel was cooled by an ice-bath.
The ice-bath was then removed and the mixture was stirred under nitrogen at room temperature for 20 hours. One half of the reaction mixture was then evaporated at reduced pr~ssure and ~he r~idu~ ob~alned was 1~~ to stand wi th ~4~
5.7 ml of 2N aqueous hydrochloric acid in the refrigerator overnight. The precipi-tate which had formed was filtered off and washed with water and ether yielding 3~-acetoxy-5~-chloro-6,19-oxido-23-iminocard-20(22)-enolide hydrochloride, uv(MeOH) 237 m~, ir(KBr) 3375, 1735, 1675, 1605, 1450, 1370, 1245, 1230, 1095, 1035, 1025 and 920 cm l.
A fraction amounting to 1/4 of -the original reaction mixture was then evaporated and the residue obtained was treated with 0.57 ml of concentrated hydrochloric acid and 0.57 ml of ether with external cooling. Heating of the separated acidic aqueous phase at 70C. under nitrogen and subsequent -filtration gave 5~-chloro-3~-hydroxy-6,19,oxido-card-20(22)-enolide, uv(MeOH) 218 mJu, ir(KBr) 3430 (broad), 1775, 1750, 1725, 1620, 1170, 1050, 1030, 1025, 1000, 920, 860 and 795 cm 1, Example 37 i When 33O4 mg of 5~-chloro-3~,21-diacetoxy-6,19-oxidopregn-20-one was subjected for 21 hours to the reaction condition of the preceding Example, evaporation of the reaction mixture at reduced pressure followed by treatment of the residue obtained with ether and 2N aqueous hydro-chloric acid and evaporation of the ethereal phase gave a material, uv (~eOH) 222 m~, whlch contained 3~,21-diacetoxy-5X-chloro-20-cyanome-thylene-6,19-oxidopregnane as the major steroid, as evidenced by tlC analysis.
Example_38 A mixtu~eof 130 mg of 3~-acetoxy-8,19-oxido-5~-22-[benzyloxycarbonyl~carda-14,20(22)-dienolide, 3.9 g of zinc dust, 9.75 ml of toluene and 3.25 ml of 90% formic acid was shaken for 16 hours under nitrogen, whereupon an additional lot of 3.9 g of zinc and o-f 1.3 ml of 9t)~O formic acid was add~d, Af~er 2 days of further shakin~ the super-:

natant liquid phase was decanted, 7.5 ml of benzene-methylene chloride 1:1 was added to the remaining residue, the mixture was shaken briefly and the supernatant liquid was decanted.
~ter 4 further extractions with benzene-methylene chloride 1:1 and 5 subsequent extractions with methylene chloride the combined supernatant liquids were evaporated at reduced pressure. Dissolution of the resultiny residue, followed by addition of pentane till a faint turbidity appeared, fil-- tration through diatomaceous earth, concentration of the filtrate at reduced pressure with intermittent addition of pentane, standing at -5C for 30 minutes, decantation of the supernatant liquid and drying at high vacuum gave 111 mg of a residue which contained 3~-acetoxy-22-benzyloxycarbonyl-l9-Eormyloxy-24-nor-5~-chola-14,20(22)-dien-23-oic acid (probably as the olefinic Z-isomer) and also 3~-acetoxy-22-benzyloxycarbonyl~l9-formyloxy-5a-carda-14,20(22)-dienolide as evidenced by tlc.
Heating of 100 mg of the residue between 110 to 125C in an evacuated tube for 225 minutes followed by chromatographic separation on silica gel G coated glass plates with ethyl acetate-benzene 1:20 as the eluant gave 35 mg of 3~-acetoxy-19-formyloxy-24-nor-5~-chol-20~22)-en-23-oic acid (probably the olefinic Z-isomer) as a colour-less resin; uv (MeOH) 218 and 227 (shoulder; no change after basification of the methanolic sample solution with potassium hydroxide) mju; nmr (CDC13) 8016,7.40, 6.55, 5.84, 5.18, 5.08, 4.4, 3.13, 2.01 and 0.78 ppm; m/e 534, 443 and 337.
The chromatographic sepa~ation also yielded, as the more polar frac~ion, 15 mg o 3~-acetoxy-22-benzyloxycarbonyl-5~-carda-14,20(22)-dienolide; m/e 576 (weak), 485 (medium), ~83 (medium) and 467 (strong), uv (MeOH) 216, 230 and 249 (minor peak) m~u, 2~8 (major peak) m~l a~:er bas.ification 9L9~
o-E the methanolic sample solutlon with aqueous potassium hydroxide.
Example 39 A mixture of 300 mg of 3~-acetoxy-22-benzyloxycar-bonylcarda-5,20(22)-dienolide, 9.0 g of zinc dust, 22.5 ml of -toluene and 7.5 ml o~ 90% formic acid was shaken under nitrogen for 16 hours, whereupon an additional lot of 9 g zinc dust and 3.0 ml of 90% formic acid was added. Shaking was continued for 24 hours,whereupon yet another lot o~ 9 g of zinc dust and 3.0 ml of 90/O formic acid was added. The mixture was then -filtered, the precipitate was washed well with methylene chloride and the combined filtrates were evaporated at reduced pressure. ~he residue obtained was treated with methylene chloride and the resulting suspen-sion was filtered. The filtrate was concentrated with intermittent addition of hexane and then left to stand at room temperature under nitrogen till the supernatant liquid had clarified. Decantation gave a residue containing mainly an acid considered to be (20(22)Z)-3~-acetoxy-22-benzyloxy-carbonyl-24-nor-chola-5,20(22)~dien-23-oic acid in addition to some starting material. A mixture consisting of 4.0 ml of an ethereal solution of the latter compound and 4.0 ml of an ethereal solution of diazome~hane was then left to stand at 0Cfor 20 minutes. Subsequent tlc analysis indi-cated that still substantial amounts of the steroidal carb- -oxylic acid remained and an additional 4 ml of the ethereal diazomethane solution was added. The mixture was then left to stand at 0~ for another 20 minutes,whereupon it was evaporated at reduced pressure. Chromatography of the greenish foam on silica gel G coated glass plates with ethyl acetate-benzene 1:20 gave 55 mg of a more polar fraction as a resln consisting of amixture o-fmethyl ~20(22)Z)-~ and (20~22)E) 3~
, ..

~9~
acetoxy-22-benzyloxycarbonyl-24-norchola-5,20(223-dien-23 oate; uv(MeOH) 213 and 235 (unchanged after basification of the methanolic sample solution with aqueous potassium hydro-xide) m~u; nmr (CDC13) 7.19, 5.21, 5.18, 5.1, 4.55, 3.55, 3.50, 2.5, 2.6, 1.0, 0.68, 0.59 and 0.59 ppm. The chroma-tography also afforded 6.6 mg of a less polar fraction as a resin, which was considered to be a diazomethane adduct of the above methyl enoates.
Example 40 A solution of 60 mg of 3~-acetoxy-22-benzyloxy-carbonylcarda-5,20(22)-dienolide in 12.0 ml of ethanol was stirred at room temperature in an atmosphere of hydrogen ln presence of 6 mg of 5/O palladium on charcoal -~or one hour, whereupon it was filtered through paper-pulp in presence of nitrogen. Evaporation at reduced pressure gave a foam.
A solution of 9/10 of the latter in 9 ml of ethanol was then stirred at room temperature in an atmosphere of hydrogen in presence o 6 mg o 5~ palladium on charcoal for 50 minutes (rehydrogenation). Isolation of the steroidal material as outlined above and treatment of the residue obtained with ether-hexane gave a white solid consisting essentially of 3~-acetoxy-22-carboxylcarda-5,20(22)-dienolide. A small fraction of the latter product, when heated in an evacuated tube at 137-142 for- 20 minutes gave 3~_acetoxycardenolide as evidenced by tlc analysis.
Example 41 A mixture of 40 mg of the produc~ of the latter reaction, when treated repeatedly with zinc dust as des-cribed in Example 39, gave a product containing 2,2-~3~-acetoxypregn-5-en-20-ylidene]malonic acid. Subsequent treatment of the latter with 0.8 ml of ether and 2.4 ml of an ~thereal diazome~hane solution, which was ~r~shly pre-'~

. . .
. : ~ .. .. . . .

1~499L9~
pared as described in Aldrich Chemical Catalog 14, ~969-1970, at 0 or 1-2 hours, concentration at reduced pressure to 1/2 of the original volume, addition of hexane, further concen-tration with intermittent addition of hexane, evaporation and chromatography of the residue obtained on silica gel G
coated glass plates, using ethyl acetate benzene as the eluant, gave a fraction which after recrystallisation from ether-hexane gave 2.5 mg of dimethyl 2,2-[3~-acetoxypregn-5-en-20-ylidene]malonate, uv (MeOH) 219 and 232 (no change after addition of a~ueous potasslum hydroxide to the methanolic sample solution) m~u; m/e 412, 397, 380 and 365.

37 ::

Claims

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A process of preparing a compound of the formula (I) wherein, in the above compound, in the case where the A, B, C and D rings are saturated, R1 represents either hydroxy or OAc, R2 represents CH2OH or CHO, R3 is H, R4 and R5 are CH2-O, R6 is either 5? or 5.beta.-H, and X and Y together represent , , , , , and ;

or R1 may represent H, O=, HCO2, (CH3)3CCO2, Cl3CCO2, (C2H5O)2P(O)CH2CO2, , , , , HC==C-CO2, H2C=CH-CO2, (HO)(CH3)CHCO2, (HO)(CH3)2CCO2, HO2C(CHOH)2CO2, HO2C(CH2)2CO2, HO2CCH2CO2, CH3O, (CH3) CO, C6H5CH2O, HC==CCH2O, tetrahydropyran-2'-yloxy, 3?,9?-oxido and 3-hydroxy-3?,9?-oxido, R2 represents HCO2CH2, (CH3)3CCO2CH2;

Cl3CCO2CH2; (C2G50)2O(O)CG2CI2CG2; ;

; ; ;

(HO)(CH3)CHCO2CH2, (HO)(CH3)2CCO2CH, HO2C(CHOH)2CO2CH2, (HO2C(CH2)2CO2, HO2CCH2CO2CH2, CH3OCH2, (CH3)3COCH2, C6H5CH2OCH2, HC==CCH2OCH2, CCH2OCH2, tetrahydropyran-2'-yloxymethyl, CH2Cl, CH3, 8,19-oxido, 19? 8-lactone, 19?8-lactol, and 6,19-oxido; R3 represents H, CO2H, CO2CH C6H5; CO2CH3, CO2CH2CH2OH, CO2CH2-C = CH and CN; R4, R5 represent CH2-O;
R4 represents CH3; R5 represents OH, OCH2C6H5, OCH3, OCH2CH2OH and OCH2-C - CH, R6 represents ?- or .beta.-H, Cl, Br or 5?-OH, X - Y represents the groups defined above or the group ; C=CH; or CH-CH2; and wherein double bonds may be present in the 2,4,6,8(14)-; 4,6,8(14)-; 4,6,8(9)-, 4,6-;
4-; 5-; 5,7-; and 3,5,7-positions; said process being selected from the group consisting of:
(a) treating a compound of the formula 2 (2) wherein R1, R2,R6, X and Y and the dotted lines are as defined above, and R7 is OH; with an ?-substituted acetic acid to form a compound of the formula (3) (3) wherein R1 R2, R6, X and Y and the dotted lines are as defined above and wherein Z is a substituent chosen from those enhancing the acidity of the adjacent methylene group;
and finally treating the compound of the formula(3)with a base to form a compound of the formula(1), in which R1, R2, R3, R6, X and Y and the double bonds are as defined above and in which R4 and R5 are CH2-O;

(b) treating a compound of the formula(2)in which R7 is OH; OCOCH3 or H; with an alkali alkoxyacetylide and then with an alcohol or water to form an intermediate compound of the formula (4) (4) wherein R7 is OH or H and in which alkyl is CH2H5, CH3 or CH2C6H5, subjecting the latter compound to acid treatment to form a compound of the formula(1)in which R3 is H and R4, and R5 is CH2-O- when R7 in the compound of formula(4) is OH, or in which R3 is H, R4 is CH3 and R5 is OCH2H5, OCH3 or OCH2C6H5 when R7 in the compound of formula(4)is H; .
(c) treating a compound of the formulal(1) in which R1, R2, R6, X and Y and the dotted lines are as defined above while R4 and R5 represent CH2-O and R3 represents CO2H, CO2CH2C6H5; CO2CH3; CO2CH2CH2OH or CO2CH2-C==CH, with zinc and a carboxylic acid to form a compound of the formula(1), in which R3 represents a member selected from the group consisting o C02H, C02CH2C6H5, CO2CH3, CO2 2 2 CO2CH2-C==CH; R4 is CH3, and R5 is OH, OCH2CH2C6H5, OCH3, OCH2CH2OH or OCH2-C==CH.

2. A compound of the formula wherein, R1 through R6, X and Y are as defined in claim 1 and the dotted lines have the meaning defined in claim 1, whenever prepared by the process of claim 1, or by an obvious chemical equivalent thereof.

3. A process for preparing a compound of the formula (1) wherein the dotted lines represent covalent bonds which may or may not be present; wherein in the group at the 17.beta.-position R3 is selected from the group consisting of H, CO2H, CO2CH2C6H5, CO2CH3, CO2CH2CH2OH and CN, and when there is a bond between R4 and R5, the latter represents , respectively, wherein, in the absence of a bond between R4 and R5, R4 is CH3 and R5 is OH; R1 is selected from the group consisting of H, OH, ; ; ; O; ;
; and with the proviso that R1 is not chosen from O, OH and an acyloxy group when the 17.beta.-group represents an unsubstituted butenolide ring ;

when there is a bond between R2 and R7 or R2 and R8 the latter represents a member selected from the group consisting of a 6,19-oxide, an 8,19-oxide and a 19?8 lactone group, respectively;
when there is no bond between R2 and R7, or R2 and R8, R2 is selected from the group consisting of CH2OH; CHO;
;;;;
;; and , R6 is selected from the group consisting of H, C1, Br and .alpha.-OH, R7 is H and R8 is selected from the group consisting of OH or H, when the 5-position is H saturated, there may either be present a 5.beta.- or 5.alpha.-hydrogen atom; and X-Y stands for C(.beta.-OH)-CH2, C(.beta.-OH)-CHBr, C(.beta.-OH)-CHCl, C(.alpha.-OH)-CH2, a .beta.-oxide, an .alpha.-oxide, a double bond, C(.alpha.-H)-CH2 or C(.beta.-H)-CH2; said process being selected from the group consisting of (a) treating a compound of the Formula 2 (2) wherein R1, R2, R7, R8, X and Y and the dotted lines are as defined above, and R'7 is OH; with an .alpha.-substituted acetic acid to form a compound of the Formula 3 (3) wherein R1, R2, R7, R8, X and Y and the dotted lines are as defined above and wherein Z is a substituent chosen from those enhancing the acidity of the adjacent methylene group;
and finally treating the compound of the Formula 3 with a base to form a compound of the Formula 1, in which R1, R2, R3, R7, R8, X and Y and the double bonds are as defined above, and in which R4 and R5 are CH2-O;
(b) treating a compound of the Formula 2 in which R'7 is OH, OCOCH3 or H, with an alkali alkoxyacetylide and then with an alcohol or water to form an lntermediate compound of the Formula 4 (4) wherein R'7 is OH or H and in which R9 is C2H5, CH3 or CH2C6H5, and R1, R2,:R7 and R8 are as defined above, subjecting the latter compound to acid trcatment to form a compound of the Formula 1 in which R3 is H and R4 and R5 are CH2-O- when R'7 in the compound of Formula 4 is OH, or in which R3 is H, R4 is CH3 and R5 is OC-OC2H5, OC-OCH3 or OC-OCH2C6H5 when R'7 in the compound of Formula 4 is H;

(c) treating a compound of the formula 1 in which R1, R2, R7, X and Y and the dotted lines are as defined hereinabove, while R4 and R5 represent CH2-O and R3 represents with zinc, and a carboxylic acid to form a compound of the Formula 1, in which R3 represents a member selected from the group consisting of CO2H, CO2CH2C6H5, CO2CH3, CO2CH2CH2OH
and CO2CH2-C==CH; R4 is CH3, and R5 is OC-OH, OC-OCH2CH2C6H5, OC-OCH3, OC-OCH2CH2OH or OC-OCH2-C==CH.

4. A compound of the formula wherein R1 through R8, X and Y, and the dotted lines have the meaning given in claim 3, whenever prepared by the process of claim 3, or by an obvious chemical equivalent thereof.

5. A process for preparing a compound of the formula (1) (1) wherein R1 is selected from the group consisting of O-acyl, H, OH, ;;;O;;

; C6H5CH2O; HC==CCH2O; CH3O; tetrahydropyran-2-yloxy; and , R2 is selected from the group consisting of CH2OH, CHO, ; ;

;;;

; (HO)(CH3)CHCO2CH2, HO2C(CHOH)2CO2CH2;

HO2C(CH2) CO2; HO2CCH2CO2CH2; CH3OCN2; HC==CCH2OCH2, tetrahydropyran-2'-yloxymethyl; CH2C1; CH3; and , R3 is sekected from the group consisting of H; CO2H;

CO2CH2C6H5; CO2CH3; COCH2-CH; CO2CH2CH2OH; and CN, R6 is selected from the group consisting of .alpha.H; .beta.H; Cl;
Br; and .alpha.OH; R7 is H, R8 is selected from the group consisting of OH or H, X-Y are selected from the group consisting of C(.beta.-OH)-CH2, C(.beta.-OH)-CHBr, C(.beta.-OH)-CHCl, C(.alpha.-OH)-CH2, a .beta.-oxide, an .alpha.-oxide, C=C, C(.alpha.-H)-CH2, C(.beta.-H)-CH2, ,, , R2 and R7 together may represent a member selected from the group consisting of 6,19 epoxy group, R2 and R8 together may represent a member selected from the group consisting of an 8,19 epoxy group, a 19?8 lactal group and a 19?8 lactane group, and the dotted lines represent optional double bonds,when there are no sub-stituents present in the 5, 8, 9or 14 positions, comprising the steps of treating a compound of the formula (2) (2) wherein R1, R2, R6, R7, R8, X and Y are as defined above, with an .alpha.-substituted acetic acid or a derivative thereof to form a compound of the formula (3) (3) wherein R1, R2, R6, R7, R8, X and Y are as defined above, and Z is a substituent capable of enhancing the acidity of the adjacent methylene group, and treating the compound of the formula (3) with a base to form a compound of formula (1).

6. A process as defined in Claim 5, wherein R2 and R8 in the compound are together an 8,19 oxido group and which comprises the further step of treating the compound obtained with zinc and a carboxylic acid to form a compound of formula 1 wherein R2 is CH2OH and R8 is H.

7. A process as defined in Claim 5, wherein X-Y in the compound represent C=C; and which comprises the further step of treating the compound with N-bromoacetamide to form a compound of formula 1 wherein X-Y is C(.beta.-OH)-CHBr.

8. A process as defined in Claim 5, which comprises treating the compound in which X-Y is C(.beta.-OH)-CHBr with an acid and Raney nickel to form a compound of formula 1 wherein X-Y represents an epoxy group.

9. A process as defined in Claim 5, wherein R2 is,in the compound, CH2OH and which comprises the further step of treating the compound obtained with a carboxylic anhydride to form a compound of formula 1 wherein R2 is CH2OCHO.

10. A process as defined in 5, wherein R1 is in the compound and which comprises the further step of treatiny the compound obtained with a base followed by an acid to form a compound of formula 1 wherein R1 is OH.

11. A process as defined in Claim 5 wherein X-Y in the compound represents C(.beta.-OH)-CHBr and which comprises the further step of reducing the compound with Raney nickel to form a compound of formula 1 in which X-Y
represents C(.beta.-OH)-CH2.

12. A process as defined in Claim 5, wherein X-Y
in the compound represents C(.beta.-OH)-CHBr and which comprises the further step of treating the compound with ammonia to form a compound of formula 1 in which X-Y is an epoxy group.

13. A process as defined in Claim 5, wherein X-Y in the compound represents C(.beta.-OH)-CHBr, and which comprises the further step of treating the compound with t-butylamine to form a compound of formula 1 in which X-Y is an epoxy group.

14. A process as defined in Claim 5, wherein R2 in the compound represents CH2OCHO and which comprises the further step of treating the compound with a base to form a compound of formula 1 in which R2 is CH2OH.

15. A process as defined in Claim 5, wherein in the compound represents acetate and which comprises the further step of treating the compound with a base to form a compound of the Formula 1 in which R1 is OH.

16. A process as defined in Claim 5, wherein R1 in the compound represents [(diethylphosphono]acetoxy]
and which comprises the rurther step of treating the compound with a base to form a compound of the formula 1 in which R1 is OH.

17. A process as defined in Claim 5, wherein X-Y
in the compound represents C(.beta.-OH)-CHBr and R2 represents CH2OCHO and which comprises the further step of reducing the compound to form a compound of the formula 1 in which R2 is CH2OH and X-Y is C(.beta.-OH)-CH2 and a compound of the formula 1 in which R2 is formyloxy and X-Y is an epoxy group.

18. A process as defined in Claim 5, wherein R1 in the compound is OH and which comprises the further step of treating the compound with an acetylating agent to form a compound of formula 1 in which R1 is acetate.

19. A process as defined in Claim 5, wherein R1 is acetate, R2 and R8 together are an oxido group and which comprises the further step of treating the compound with a carboxylic acid and zinc tu form a compound of formula 1 in which R1 is OH, R2 is CH2OH
and R8 is H.

20. A process as defined in Claim 5 wherein R2 and R8 together represent an 8,19 oxido group and which comprises the further step of treating the compound with zinc and a carboxylic acid to form a compound of the formula 1 in which R2 is CH2OCHO and R8 is H.

21. A process as defined in Claim 5, wherein R3 in the compound is benzyloxycarbonyl and which comprises the further step of treating the compound with hydrogen in the presence of a metal catalyst to form a compound of formula 1 in which R3 is carboxy.

22. A process as defined in claim 5, wherein R3 in the compound is carboxy and which comprises the further step of heating the compound to form a compound of formula (1) in which R3 is H-

23. A process as defined in claim 5, in which X-Y is an epoxy group and which comprises the further step of treating the compound with zinc and a carboxylic acid to form a com-pound of formula (1) in which X-Y is C(?-OH)-CH2.

24. A process as defined in claim 5, wherein the ?-substituted acetic acid is (diethyl-phosphonic) acetic acid or cyanoacetic acid.

25. A process as defined in claim 5, wherein the compound of formula (3) is treated with potassium hydroxide.

26. A process as defined in claim 5, wherein the carboxylic acid is formic acid or acetic acid.

27. A compound of the formula (1) (1) wherein R1, R2, R3, R6, R7, R8, X and Y and the dotted lines have the meaning defined in claim 5, whenever prepared by the process of claim 5, or by an obvious chemical equivalent thereof.

28. A compound as defined in claim 27, whenever prepared by the process of claim 8 or 9, or by an obvious chemical equivalent thereof.

29. A compound as defined in claim 27, whenever prepared by the process of claim 10 or 11, or by an obvious chemical equivalent thereof.

30. A compound as defined in claim 27, whenever prepared by the process of claim 12 or 13, or by an obvious chemical equivalent thereof.

31. A compound as defined in claim 27, whenever prepared by the process of claim 14 or 15, or by an obvious chemical equivalent thereof.

32. A compound as defined in claim 27, whenever prepared by the process of claim 16 or 17, or by an obvious chemical equivalent thereof.

33. A compound as defined in claim 27, whenever prepared by the process of claim 18 or 19, or by an obvious chemical equivalent thereof.

34. A compound as defined in claim 27, whenever prepared by the process of claim 20 or 21, or by an obvious chemical equivalent thereof.

35. A process as defined in claim 3, comprising reacting [diethylphosphono]acetic acid with 3.beta.-acetoxy-21-hydroxy-8,19-oxido-5?-pregn-14-en-20-one to form 3.beta.-acetoxy-21-[diethylphosphono]acetoxy-8,19-oxido-5?-pregn-14-en-20-one and treating the latter with a base to form 3.beta.-acetoxy-8,19-oxido-5?-carda-14,20(22)-dienolide.

36. 3.beta.-acetoxy-8,19-oxido-5?-carda-14,20(22)-dienolide whenever prepared by the process of claim 35, or by an obvious chemical equivalent thereof

37. A process as defined in claim 3, comprising reacting [diethylphosphono]ace-tic acid with 3.beta.,21-dihydroxy-8,19-oxido-5?-pregn-14-en-20-one to abtain 3.beta.,21-di[diethyl-phosphono]acetoxy-8,19-oxido-5?-pregn-14-en-20-one and treating the latter with a base to obtain 3.beta.-[diethylphosphono]-acetoxy-8,19-oxido-5?-carda-14,20(22)-dienolide.

38. 3.beta.-[diethylPhosPhono]acetoxy-8,19-oxido-5?-carda-14,20(22)-dienolide whenever prepared by the process of claim 37, or by an obvious chemical equivalent thereof.

39. A process as defined in claim 3, comprising reacting benzyl hemimalonate with 3.beta.-acetoxy-21-hydroxy-8,19-oxido-5?-p.regn 14-en-20-one to obtain 3.beta.-acetoxy-21-[benzyloxy-carbonyl]acetoxy-8,19-oxido-5?-pregn-14-en-20-one and treating the latter with a base to obtain 3.beta.-acetoxy-22-benzyloxycarbonyl-8,19-oxido-5?-carda-14,20(22)-dienolide.

40. 3.beta.-acetoxy-22-benzyloxycarbonyl-8,19-oxido-5?-carda-14,20(22)-dienolide whenever prepared by the process of claim 39, or by an obvious chemical equivalent thereof.

41. A process as defined in claim 3, comprising reacting 3.beta.-acetoxy-21-hydroxy-8,19-oxido-5?-pregn-14-en-20-one with cyanoacetic acid to obtain the corresponding 21-cyano aceta-te, and treating the latter with a base to obtain 3.beta.-acetoxy-22-cyano-3,19-oxido-5?-carda-14,20(22)-dienolide and 22-cyano-3.beta.-hydroxy-8,19-oxido-5?-carda-14,20(22)-dienolide.

42. 3.beta.-acetoxy-22-cyano-8,19-oxido-5?-carda-14,20(22)-dienolide and 22-cyano-3.beta.-hydroxy-8,19-oxido-5?-carda-14,20(22)-dienolide whenever prepared by the process of claim 41, or by an obvious chemical equivalent thereof.

43. A process as defined in claim 3, comprising reacting 3.beta.,19-diacetoxy-21-hydroxy-5?-pregn-14-en-20-one with [diethylphosphono]acetic acid to obtain the corresponding 21-[diethylphosphono]acetate and treating the latter with a base to obtain 3.beta.,19-diacetoxy-5?-carda-14,20(22)-dienolide.

44. 3.beta.,19-diacetoxy-5?-carda-14,20(22)-dienolide whenever prepared by the process of claim 43, or by an obvious chemical equivalent thereof.

45. A process as defined in claim 3, comprising reacting 19-acetoxy-21-hydroxy-pregna-4,6-diene-3,20-dione with [diethylphosphono]acetic acid to obtain the corresponding 21-[diethylphosphono]acetate and treating the latter with a base to obtain l9-acetoxy-3-oxo-carda-4,6,20(22)-trienolide.

46. 19-acetoxy-3-oxo-carda-4,6,20(22)-trienolide whenever prepared by the process of claim 45, or by an obvious chemical equivalent thereof.

47. A process as defined in claim 3, comprising reacting 8,19-oxido-21-hydroxypregn-4-en-3,20-dione with [diethylphosphono]acetic acid to obtain the corresponding 21-[diethylphosphono] acetate and treating the latter with a base to obtain 3-oxo8,19-oxido-carda-4,20(22)-dienolide.

48. 3-oxo-8,19-oxido-carda-4,20(22)-dienolide whenever prepared by the process of claim 47, or by an obvious chemical equivalent thereof.

49. A process as defined in claim 3, comprising reacting 3.beta.-acetoxy-21-hydroxypregn-5-en-20-one with [diethylphosphono]acetic acid to obtain the corresponding 21-[diethylphosphono] acetate, and treating the latter with a base to obtain 3.beta.-acetoxycarda-5,20(22)-dienolide.

50. A process as defined in claim 3, comprising reacting 3.beta.,21-dihydroxy-pregn-5-en-20-one with [diethyl-phosphono]acetic acid to obtain 3.beta.,21-di[diethylphosphono]-acetoxy pregn-5-en-20-one and treating the latter with a base to obtain 3.beta.-[diethylphosphono]acetoxy-carda-5,20(22)-dienolide.

51. 3.beta.-[diethylphosphono]acetoxy-carda-5,20(22)-dienolide whenever prepared by the process of claim 50, or by an obvious chemical equivalent thereof.

52. A process as defined in claim 3, comprising reacting 3.beta.-acetoxy-21-hydroxypregn-5-en-20-one with benzyl hemimalonate to obtain 3.beta.-acetoxy-21-[benzyloxycarbonyl]-acetoxy-pregn-5-en-20-one and treating the latter to obtain 3.beta.-acetoxy-22-[benzyloxycarbonyl]-carda-5,20(22)-dienolide.

53. A process as defined in claim 3, comprising reacting 3.beta.cetoxy-21-hydroxy-pregn-5-en-20-one with cyanoacetic acid to obtain the corresponding 21-cyanoacetate, and treating the latter with a base to obtain 3.beta.-acetoxy-22-cyanocarda-5,20(22)-dienolide.

54. 3.beta.-acetoxy-22-cyanocarda-5,20(22)-dienolide whenever prepared by the process of claim 53, or by an obvious chemical equivalent thereof.

55. A process as defined in claim 53 comprising treating the product obtained with a base to obtain 3.beta.-hydroxy-22-cyanocarda-5,20(22)-dienolide.

56. 3.beta.-hydroxy-22-cyanocarda-5,20(22)-dienolide whenever prepared by the process oE claim 55, or by an obvious chemical equivalent thereof.

57. A process as defined in claim 3, comprising reacting 21-hydroxy-8,19-oxido-5?-pregn-14-en-20-one with [diethylphosphono]acetic acid to obtain the corresponding 21-[diethylphosphono]acetate, and treating the latter with a base to obtain 8,19-oxido-5?-carda-14,20(22)-dienolide.

58. 8,19-oxido-5?-carda-14,20(22)-dienolide whenever prepared by the process of claim 57 or by an obvious chemical equivalent thereof.

59. A process as defined in claim 3, comprising reacting 21-hydroxy-8,19-oxido-5?-pregn-14-en-20-one with cyanoacetic acid to obtain 21-cyanoacetoxy-8,19-oxido-5?-pregn-14-ene and treating the latter with a base to obtain 22-cyano-8,19-oxido-5?-carda-14,20(22)-dienolide.

60. 22-cyano-8,19-oxido-5?-carda-14,20(22)-dienolide whenever prepared by the process of claim 59, or by an obvious chemical equivalent thereof.

61. A process as defined in claim 35, comprising treating the compound obtained with zinc and formic acid to obtain 3.beta.-acetoxy-19-formyloxy- 5?-carda-14,20(22)-dienolide.

62. 3.beta.-acetoxy-19-formyloxy-5?-carda-14,20(22)-dienolide whenever prepared by the process of claim 61, or by an obvious chemical equivalent thereof.

63. A process as defined in claim 57, wherein the product obtained is treated with zinc and formic acid to obtain l9-hydroxy-5?-carda-14,20(22)-dienolide l9-formate.

64. 19-hydroxy-5?-carda-14,20(22)-dienolide 19-Eormate whenever prepared by the process of claim 63, or by an obvious chemical equivalent thereof.

65. A process as defined in claim 35, which comprises treating the product obtained with zinc and a carboxylic acid to obtain 3.beta.-acetoxy-19-hydroxy-5?-carda-14,20(22)-dienolide.

66. 3.beta.-acetoxy-19-hydroxy-5?-carda-14,20(22)-dienolide whenever prepared by the process of claim 65, or by an obvious chemical equivalent thereof.

67. A process as defined in claim 65 which comprises treating the product obtained with an acid anhydride to obtain 3.beta.,19-diacetoxy-5?-carda-14,20(22)-dienolide.

68. A process as defined in claims 65 and 67 which com-prises treating 3.beta.-acetoxy-19-hydroxy-5?-carda-14,20(22)-dienolide with formic acid to obtain the corresponding 19-formate thereof, and treating the latter with N-bromoaceta-mide to obtain 3.beta.-acetoxy-15d-bromo-19 formyloxy-14.beta.-hydroxy-5?-card-20(22)-enolide.

69. 3p-acetoxy-15?-bromo-19-formyloxy-14.beta.-hydroxy-5 card-20(22)-enolide whenever prepared by the process of claim 68, or by an obvious chemical equivalent thereof.

70. A process as defined in claim 67, which comprises treating the product obtained with N-bromoacetamide to obtain 3.beta.,19-diacetoxy-15?-bromo-14.beta.-hydroxy-5?-carda-20(22)-enolide.

71. 3.beta.19-diacetoxy-15?-bromo-14.beta.-hydroxy-5?-carda-20(22)-enolide whenever prepared by the process of claim 70 or by an obvious chemlcal equivalent thereof.

72. A process as defined in claim 68 which comprises treating the product obtained with Raney nickel to obtain coroglaucigenin 3-acetate l9-formate and 3.beta.-acetoxy-19-formyloxy-14.beta.s-, 15.beta.-epoxy-5?-card-20(22)-enolide.

73. Coroglaucigenin 3-acetate 19-formate and 3.beta.-acetoxy-19-formyloxy-14.beta.-, 15.beta.-epoxy-5?-card-20(22)-enolide whenever prepared by the process of claim 72 or by an obvious chemical equivalent thereof.

74. A process as defined in claim 70, comprising treating the product obtained with Raney nickel to obtain 3.beta.,19-diacetoxy-14.beta.-hydroxy-5?-card-20(22)-enolide.

75. A process as defined in claim 68, which comprises treating the product obtained with a base to obtain 3.beta.-acetoxy-l9-formyloxy-14.beta.,15.beta.-eP°XY-5?-card-20(22)-enolide.

76. 3.beta.-acetoxy-19-formyloxy-14.beta.,15.beta.-epoxy-5?-card-20(22)-enolide whenever prepared by the process of claim 75, or by an obvious chemical equivalent thereof.

77. A process as defined in claim 70, which comprises treating the product obtained with t-butylamine to obtain 3.beta.,19-diacetoxy-14.beta.,15.beta.-epoxy-5?-card-20(22)-enolide.

78. 3.beta.,19-diacetoxy-14.beta.,15.beta.-epoxy-5?-card-20(22)-enolide whenever prepared by the process of claim 76, or by an obvious chemical equivalent thereof.

79. A process as defined in claim 68, comprising treating the product obtained with t-butylamine to obtain 3.beta.-acetoxy-19-hydroxy-14.beta.,15.beta.-epoxy-5?-card-20(22)-enolide.

80. 3.beta.-acetoxy-19-hydroxy-14.beta.,15.beta.-epoxy-5?-card-20(22)-enolide whenever prepared by the process of claim 79, or by an obvious chemical equivalent thereof.

81. A process as defined in claim 3 comprising reacting ethoxyacetylene with a member selected from the group consisting of 3.beta.-acetoxy-21-hydroxy-8,19-oxido-5?-pregn-14-en-20-one and 3.beta.,21-dihydroxy- and 3.beta.,21-diacetoxy-8,19-oxido-5?-pregn-14-ene to thereby obtain a member selected from the group con-sisting of 3.beta.-hydroxy-8,19-oxido-5?-caraa-14,20(22)-dienolide and 20-ethoxyethynyl-3.beta.,20,21-trihydroxy-8,19-oxido-5?-pregn-14-ene.

82. A member selected from the group consisting of 3.beta.-hydroxy-8,19-oxiao-5?-carda-14,20(22)-dienolide and 20-ethoxyethynyl-3.beta.,20,21-trihydroxy-8,19-oxido-5?-pregn-14-ene whenever prepared by the process of claim 81, or by an obvious chemical equivalent thereof.

83. A process as defined in claim 3, comprising reacting ethoxyacetylene with a member chosen from 3.beta.-acetoxy-8,19-oxido-5q-pregn-14-en-20-one and 8,19-oxido-3.beta.-[tetrahydropyran-2-yloxy]-5?-pregn-14-en-20-one to obtain a member chosen from 20-ethoxyethynyl-3.beta.,20-dihydroxy-8,19-oxido-5?-pregn-14-ene and 20-ethoxy-ethynyl-20-hydroxy-8,19-oxido-3.beta.-tetrahydropyran-2-yloxy-5?-pregn-14-ene.

84. A member chosen from 20-ethoxyethynyl-3.beta.,20-dihydroxy-8,19-oxido-5?-pregn-14-ene and 20-ethoxy-ethynyl-20-hydroxy-8,19-oxido-3.beta.-tetrahydropyran-2-yloxy-5?-pregn-14-ene whenever prepared by the process of claim 83 or by an obvious chemical equivalent thereof.

85. A process as claimed in claim 83 which comprises treating the product obtained with a strong inorganic acid to obtain ethyl 3.beta.-hydroxy-8,19-oxido-24-nor-5?-chol-20(22)-en-23-oate.

86. A compound as defined in claim 27, whenever prepared by the process of claim 22 or 23, or by an obvious chemical equivalent thereof.

87. A compound as defined in claim 27, whenever prepared by the process of claim 24 or 25, or by an obvious chemical equivalent thereof.

88. A compound as defined in claim 27, whenever prepared by the process of claim 26, or by an obvious chemical equiva-lent thereof.