DE2455272A1 - STEROID COMPONENTS AND METHOD FOR MANUFACTURING THEM - Google Patents

Description

8'1 ¹ EELE GHEIUiCAL Cü. LTD., 265 Hymus Boulevard, Pointe Ciaire,

Quebec, Canada

Steroi & components and process for their manufacture.

The invention relates to novel steroid components and to methods of making such sterol components.

In particular, according to one embodiment of the invention, new components of the formula are proposed

where Ui to Eg and XX have the meanings given below, and the dashed lines optionally represent double bonds. In the embodiment where three and five

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If positions of these components are saturated, the substituents R _x , and R _x - can be in either the alpha or beta positions.

For a better understanding of the present invention, the novel components can be classified as one of two groups of components in which, in one embodiment, the components of formula (1) have saturated A, B, C and D rings, and in which R _x , either hydroxy or OAc, Rp represents either CHpOH or CHO, R _{7 is} H, R ^, and R _{1 are} - CHp-O, R _x - is either 50- or 5β-H, and X and Y together represent :

C — CH, C CH, C CH, C CH,

OH Br OH ■ 01 0 OH OAc

C CH, C CH ₀ and C

i - =, J ^d i
CH OCOC (CH,)., OCHO OAc

on the other hand, the components according to a further embodiment of the invention are those components in which represent

IL: H, O =, HCO ₀ , (CH-J- ^ CCO ₀ , 01-, 00O ₀ , (C ₀ Hc-O) ₀ P (O) CH ₀ CO ₀ ,? "; Γ 1" 2 ' ^v 5 5 2' 5 2 '2 ρ 2 2 2'Il

Vq / CO ₀ ,

C ₂ H ₅ O ₂ C

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G-CO ₂ , H ₂ C = CH-CO ₂ , (HO) (CH ₃ ) CHCO ₂ , (HO) HO ₂ C (CHOH) ₂ CO ₂ ? HO ₂ C (CH ₂ ) ₂ 00g, ^H0 2 ^GGH 2 ⁰⁰ 2 ' ^CH 3 °' C ₆ H CH ₂ O, HC = CCH ₂ O, tetraliydropyran-2-xloxy, 3 *, 9 «-oxido and 3- hydroxy-3a, 9a: -0xido, R _3: HCO ₂ CH _2, (0H) 000 ₂ CH _2; CC

H ₇ O
3

H-

ITi-:

COoCH,

Γ7Γ 2 2

-CH

CpH ₁ -UpC

; HC = ■ C-CO ₂ CH ₂ ,

(HU) (CH ₃ ) CHCO ₂ CH ₂ , (H0) CCH ₃ ) ₂ CC0 ₂ CH, HO ₂ C (CHOH) ₂ CO ₂ CH ₂ , HO ₂ C (CH ₂ ) _{2 CO 2} , HU ₂ CCH ₂ CO ₂ CH ₂ , CH ₃ OCH ₂ , (CH ₃ ) JCOCH ₂ , C ₆ H CH ₂ OCH ₂ , HOSCOH ₂ OOH ₂ , Tetraaydropyr.an-2'-xloxyinethyl, CH ₂ Ci, CH ₃ , 8.19- Oxido, 19 "** 8-lactone, 19 ^ 8-lactol, and 6,19-oxido; R ₃ : H, CO ₂ H, CO ₂ OH ₂ O ₆ H ₅ .; 'CO ₂ CH ₃ , CO ₂ CH ₂ CH ₂ OH, CO ₂ CH ₂ -C = CH and CIT; R ₄ , R ₅ : CH ₂ -O, R4-: CH ₃ ; R ₅ ; OCH ^ H OCH ₃₅ OH OCH ₂ CH ₂ OH and UCH ₂ -C = CH, R ₅ : H, Cl, Br or 5 * 3 · -OH, "X - X:

the groups defined by cTben or the group C-CH; C = GH;

or CH-GH ₂ ; and where double bonds are in the 2,4,6,8 (14; -; 4.68 (14) -; 4,6,8 (9) -; 4,6-; 4-; 5- *, 5.7 -i

3,5j7 ~ ^ ^{) o} sitions are.

In a further aspect of the present invention, methods of making the above components and components are general

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according to the formula

(D

proposed, where R, to Rg and X and X have the meanings defined above and, in addition, if the A, B, C and D rings of the components are saturated, represent components in which: X and I are C - ÖE _O or C = CH ₀ , R ₁ is OH or Ac,

OH

R ₂ is CH ₂ OH or CHO, R ₅ is H and R ₄ ^ is CH ₂ O; in accordance with this embodiment of the invention, the method is selected from the group consisting of

(a) Treatment of a component of the IOrmel 2

_r R _r = 0

(2)

where R-, R ₂ , R ^, X and X and the dashed lines correspond to those defined above and R _{7 is} OH, and where a

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«. -Substituted acetic acid one component of the formula

forms

, -0- (U-CH ₂ Z

(3)

where IL, E ₂ , Rg, X and X and the dashed lines correspond to those defined above, and where Z is a substituent selected from those that enhance the acidity of the adjacent methylene group, and finally where the component of formula (3 ) is treated with a base to form a component of formula (1), where E-,, Ep, E ^, E, -, X and Y and the double bonds correspond to those defined above, and E ^ and E are CHp-O .

(b) treating a component of formula (2) where E _{7 is} either OH, OCOCTL or H with an alkali alkoxyacetylide and then with an alcohol or water to form an intermediate component of formula (4)

C = C-Oalkyl

(4)

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R _{7 is} OH or H and alkyl is CH ₂ H ₅ , OH _3, or OH ₂ O ₆ H ₅ , the latter. Component is subjected to an acid treatment so that a component of the formula (1) is formed in which IU is H and R ^ and R ₁ are - CH 2 -O- when R ₇ in the component of the formula (4) is OH, or R _{5 is} H, R ₄ CH ₃ and R ₅ OCH ₂ H ₅ , OCH ₃ or OCH ₂ CgH ₁ - when R ₇ in the component of formula (4) is H.

(c) treating a component of formula (1) in which R-, R, R ₂ , Rg, X and X and the dashed lines are as defined above, while R 1 and R _{5 are} CH ₂ -O and R ₅ CO ₂ H, CO ₂ CH ₂ C ₆ H ₅ ; CO ₂ CH ₅ ; CO ₂ CH ₂ CH ₂ OH or CO ₂ CH ₂ -C = CH, where zinc and a carboxylic acid form a component of the formula (1) in which R ^ represents a part selected from the group consisting of CO _{2 is} H, CO ₂ CH ₂ C ₆ H, CO ₂ CH ₃ , CO ₂ CH ₂ CH ₂ OH, and C0 ₂ CH ₂ -C = ~ CH; R _{4 is} CH ₃ , and R _{5 is} OH, OCH ₂ CH ₂ C ₆ H, OCH ₃ , OCH ₂ CH ₂ OH, or OCH ₂ -C = CH.

In the processes described above, the conversion of the 21-alcohols of the formula (2), in which Rr _{7 is} OH, into the corresponding components of the formula (1) according to process (a) is most conveniently carried out in that the 21-alcohols with an ex-substituted acetic acid, e.g. (diethylphosphono) acetic acid, (benzyloxycarbonyl) acetic acid or cyanoacetic acid in the presence of a cyanamide (e.g. dicyclohexylcyanamide) and a / water

with

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Immiscible solvents, e.g. methylene chloride or benzene are treated and a treatment of the resulting reaction mixture follows, the 21-acylate (3) as an intermediate with a water-stable base, e.g. aqueous potassium hydroxide or aqueous or anhydritic t-butylamine. The reaction is preferably carried out at room temperature, although higher or lower temperatures were also used if so desired.

In a modified embodiment of the above method (a) the 21-alcohol to between 50 and 15O ⁰ G can be a ketone regard solvent, for example acetone or methyl isobutyl ketone are heated with the appropriate λ-substituted acetic acid in the presence. If the radical Z is OO ₂ H, the resulting 21-hemimalonate can then be esterified by an appropriate conventional technique, for example for treatment with a corresponding diazoalkane, for example diazomethane or diazotoluene, so that components of the formula (3) in which Z is Is COp-alkyl. Similarly, in a corresponding embodiment according to process (a), the 21-alcohol can be mixed with a derivative of a ft -substituted acetic acid, for example acid chloride, ZOHgOOCl anhydride, (ZOH ₂ CO) ₂ O, mixed anhydrides, ZCH ₂ OO-O- OOR, where Z is as defined above and R (ΟΗ - ^ -, Ο, FO or Cl-, G, or ester, ZOH ₂ GO ₂ -alkyl, where the alkyl is OH ₅ , C ₂ H ₅ , CH ₂ C ₆ H ₅ or CH ₂ -G ~ _ CH, are treated. When the carboxylic acid derivative of an acid chloride or anhydride is mixed oder.ein. anhydride, treatment at room temperature in the presence of a weak base may be, for example, pyridine carried

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leads to be; if the carboxylic acid derivative is an ester, the conversion into the 21-acylate can be carried out by. Heating .of the 21-alcohol with the ester "at a temperature of between about 50 unci 22O ⁰ C are performed, the base treatment of the process (a), preferably with a strong aqueous base, for example 1 -. 80% aqueous potassium or sodium hydroxide be performed.

The treatment of the 21-alcohol or 21-acetate of process ("b) with an alkaline alkoxy-acetylide can be carried out in the manner described by S ^1. Sondheimer, Chemistry in Britain, 1, 4-5 ^" (1965) described; it can preferably be carried out at room temperature in an anhydrite ether, for example diethyl ether or tetrahydrofuran, and, for example, the alkaline alkoxy-acetylide-lithium methoxyl. On the other hand, thoxyacetylide can be used. The subsequent acid treatment can also be carried out at room temperature. Dilute, aqueous, strong inorganic acids, e.g. hydrochloric acid, sulfuric acid or perchloric acid, are preferably used as the acid, while the solvent for the intermediate steroidal 20-alkoxyethynyl-20-alcohol of the formula (A) is a water-immiscible solvent, e.g. benzene, ether or methylene chloride, is conveniently used.

I \

Treatment of the 22-substituted cardenolide by process (c) with zinc and a carboxylic acid can preferably at room temperature and in the presence of an inert solvent, e.g. toluene, methylene chloride or ethyl acetate,

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and as the carboxylic acid, formic acid, acetic acid and substituted acetic acids such as irimethyl acetic acid or trifluoroacetic acid can be used. The various methods of the present invention have some unexpected and advantageous properties. Thus, in connection with process (a), it cannot be foreseen that the esterification of the 21-alcohol to form components of the formula (2) in "in which Z is COpH can achieve improved results when ketonic solvents, for example methyl isobutyl ketone, are used, and in that the esterification j_ progresses _n largely selective manner, with virtually only the 21-Hemimalonat is obtained, wherein one of the 2-carboxylic acid groups of malonic acid which is used as a reactant remains unreacted. In connection with process (a) is not foreseeing that the conversion of the 21- (dialkylphosphono) acetates according to formula (3), where Z (alkyl) 'is P (0), into the corresponding gardenolides of formula (1), where E, H, E ^, E ₁ - CE ^ O are achieved by a base with a relatively weak basic activity, e.g. aqueous alkali hydroxide or alkylamine, since this conversion is a phosphonate modification of the Wittig reaction (cf. e.g. LFFieser and M. Fieser, John Wiley and Sons, I. nc., 1967 »pages 1319 and 251), ^xm - ^ ⁱ thus, in accordance with the known technique of carrying out the Wittig reactions, a very strong base, for example n-butyl lithium, sodium hydride and potassium t-butoxide (above literature, Page 1319) as one of the reactants. In contrast to the weak bases according to the present invention, the very strong bases have in common that they are quickly destroyed by water.

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Further, the above conversion of formula (3) to formula (1) was not expected to be accomplished by using one with water immiscible, non-polar solvent, e.g. benzene can be achieved as a solvent for the steroid. As as is known to those skilled in the art, reactions brought about by the action of a chemical reactant are generally used significantly increased when the reactant is soluble in the solvent used to dissolve the reactant is used.

Furthermore, was not to be expected and is another new one

*
The feature of process (a) that the / for the conversion of components of the formula (3), where Z (alkyl) is P (0), into components of the formula (1), where RH is, were developed, also very well suited for converting components of the formula (3), where Z is ON and OOo-alkyl, into components of the formula (1), where R is CN and C02-alkyl. The latter type of conversion is no longer a Wittig reaction, but rather resembles the Knoevenagel condensation (cf., for example, RC Denney "Named Organic Reactions", Butterworth, London 1969, page 50).

The wide scope of method (a) due to which this Method can be applied to 21-esters of formula (3), in the Z not only (alkyl) P (0), but also ON and COg-alkyl represents a special advance in this process.

Another advantage of method (a) according to the present invention can be seen in the fact that the conversion of (3) into (1) * Conditions that SO9823 / 0 9 = 3 S

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in a simple manner by bases of relatively low effectiveness can be performed as this enables the transformation of actants that have groups "which are change chemically if the usual stronger bases of a Wittig reaction are used ...

Another advantage of method (a) "is that the formation of the phosphonoacetate (3) from 21-alcohol (2) and the Conversion (3) into. (1) can be carried out in "a vessel, and that no intervening evaporation of solvents is required in the "two conversions. It is however, furthermore advantageous that - since the relatively weak bases which are used in the case of the present invention, not affected by water - no special precautions must be observed to ensure that the conversion of (3) to (1) under anhydrite conditions is carried out. The conversion of (3) to (1) via (2) can thus be carried out in a manner that is essential is simpler and more economical than the previous method of selection in the conversion of 21-hydroxy-20 of the pregnane series in cardenolide (cf. W. Eberlein, J. Nicki, J. Heider, G. Johns and H. Machleidt, Ohem.reports, 105, 3686 (1972), who made 22-halo, alkyl and alkoxy carddenolides).

In process (b) it is advantageous that the conversion of the alkyloxyacetylene inclusion compound (4) into the corresponding 20. (22) -en-23-coic acid ester or qardenolide of the formula (1) by treating a solution (4) in a water that is immiscible

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Ren inert solvent (e.g. benzene, hexane or ether) with a dilute, aqueous solution of a mineral acid, e.g. perchloric acid, hydrochloric acid or sulfuric acid can be brought about. In contrast, the previous Method of converting the inclusion compound '(4) into the ester (1) of the latter with a mixture of alcohol and aqueous sulfuric acid ". Since alcohols are present of acid are not inert solvents, they can, for example, result in an exchange of the alkoxy group in ester (1) (F.S. Khristulas, M.B. Gorovich and N.E. Abubakirov, Khimya Prirodnikh Soedinenii, 5, 545 (1970) page 551)? the method of the present invention, in which inert solvents are used for the above conversion, has a greater synthetic benefit. A further increase in the benefit results from the fact that in the inventive Method, the reaction products can be isolated from the reaction mixture in a simpler manner, namely by a simple process of extracting the organic, water-immiscible phase with water until the extracts are obtained are neutral, and subsequent evaporation of the inert solvent. It also turns out that the process is better is applicable to those components of the formula (4) which are not or only partially soluble in acidic, aqueous alcohol used in the known method. As is known, steroids are generally better in water-immiscible organic solvents than in aqueous alcohols soluble.

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With regard to process (c) it turns out that no method is known which "converts cardenolides into the corresponding 22-alkoxycarboxyl-21-methyl-20 (22) -en-23-oico acids or the corresponding 23, 24 -dioc acids teaches, as given by the formula (1), in which IU is an alkoxycarbonyl, H _{1 is} a methyl group and R ₁ - is the hydroxyl group of a carboxylic acid

it
in that / gives stereospecific idutes after (22-E) and (22-Z) 22-substituted 20 (22) -enes. In contrast to this, the known processes for the preparation of 21-methyl-22-substituted 20 (22 ) -enes, the stereochemistry of which is generally not specified (cf. for example F. Sondheimer and! PS Khristulas, as stated above, and also M. Okada and J. Saito, Chem. Pharm. Bull., 1.6, 2223. (1968 )) no such stereo-specific wooden bowls are planned.

Many of the products of the present invention have the formula (1) have properties similar to the components of the formula

OH

where R _{8 is selected} from the group of H, CHgOH, CH ₂ -O-CO-KH-C (CH ₅ ) ^, CHpO-alkyl and CHpO-acyl, where -alkyl is tetrahydropyranyl, lower alkyl, preferably methyl, or a

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substituted methyl in which the substituent is selected from the group consisting of phenyl, halogen, preferably chlorine and bromine, methoxy, CH ₀ = CH and HC = C, and where acyl represents a group consisting of such G-rurf ·· -flail s is selected, the acetate, lower trialkyl acetate, where the lower alkyl group is preferably methyl or ethyl, monohaloacetates and trihaloacetates, where the halogen is preferably chlorine, fluorine and bromine. The components of the above formula and their glycosides are known for the treatment of heart disease, as described, for example, in "Angewandte Chemie". Volume 9, No. 5, pages 321-332, and Fieser and Fieser, Chapter 20, "Steroids", Reinholf, IiY 67. In addition, the components of the formula (1) may in some cases be used as intermediates in the preparation of components of the formula (1) given above by converting the ingredients of the formula (1) by conventional techniques or otherwise by processes similar to those in the following Examples are. Furthermore, certain constituents of the formula (1) - for example those without 14 [beta] oxygen - can be useful as modifiers of cardiac constituents, for example by selective suppression of their toxic activity. Such constituents, which are 3-deoxy steroids or 22-substituted cardenolides or 24 ~ nor-chol-20 (22) -enoate, have similar properties to the known 3 oxygenated-22-unsubstituted cardenolide analogs, as for example in Annular Reports in Medicinal Chemistry, 1970, page 174 and the reference list there,

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W. Eberlein and others, Chem. Ber. Volume IO5, 3686 (1972); J.S. Boutagy, R. Thomas, Australian Journal of Chemistry, Vol. 24-, 2723 (1971).

example 1

A mixture obtained by successively adding 3-94-2 ml of a 10% solution of 'jDiethylphosphono. 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 a solution of 600 mg of 3β-acetoxy-21-hydroxy-8,19-0xicio-5 & pregn-14-en-20-one in 30 ml of benzene was stirred under nitrogen at room temperature for 18 minutes, followed by a small Fraction was removed and one volume of water was added. Evaporation of the organic phase gave 3ß-acetoxy-21-p-diethylphosphono] acetoxy-8,19-oxido-5 & pregn-14-en-20-ones, as determined by tlc- ^ analysis and subsequent transformations resulted.

The remaining reaction mixture was under nitrogen with Add 15 ml of 50% aqueous potassium hydroxide for 15 minutes Stirred room temperature, whereupon 75 ml of a mixture of Water and ice were added. Making the mixture acidic with acetic acid-water 1:10 and then diluting with Ether-methylene chloride 4: 1, five extractions of the organic phase with 1/4 volume of water, evaporation at reduced Pressure and drying under high vacuum gave a residue

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which was stirred with 30 ml of methylene chloride under nitrogen for 15 minutes. The undissolved pesticide was then removed by filtration. A concentration of the filtrate with subsequent addition of hexane until a slight cloudiness appeared, filtering through the diatomaceous earth, concentration of the filtrate under reduced pressure with intermittent addition of hexane and ether, standing at minus 5 C for 2 hours and filtering gave 524 mg of 3.beta.-acetoxy-8,19-Öxido-5o: -Carda-14,20 (22) -Dienolid, mp 214.220 to 221 ⁰ C. recrystallization from methanol-water gave a purified sample, melting point 219, 222 -224 ⁰ C. , uv (MeOH) 219 mu.

Example 2

A mixture obtained 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 0.4-55 ml of a 0.2 molar solution of dicyclohexylcarbodiimide ( 2.6 moles per mole of 3 »21-diol) in benzene to a suspension of 12 mg of 3B>, 21-dihydroxy-8,19-0xido-5 <£, -pregn-14 ~ en-20-ones in 0.175 ml Benzene was stirred under nitrogen at room temperature. A tlc analysis on a sample that was removed after 20 minutes showed that all of the starting material was converted into 3 [beta] 21-di {^ diethylphosphonium} acetoxy-8,19-oxido.-5 <sc -pregn-14- en-20 -one had been converted.

After stirring for 35 minutes, 0.115 ml of 50% aqueous Potassium hydroxide was added and it was left for another 30 minutes stirred, with 0.4-55 ml of water being added. The mixture

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was then filtered, the phases were separated, the aqueous phase of the filtrate acidified. Filtration of the precipitate obtained gave Jβ- [piäthylphosphonq] acetoxy-8,19-oxido-5a-carda-14,20 (22) -dienolide, uv (MeOH) 219mu, ir (KBr) 3070, 1777,1748,1628, 1110,1050,1003,926,890,860 and 818 cm " ¹ '.

Example 5

A mixture obtained by adding 3.35 ml of a 0.2 molar solution of dicylohexylcarbodiimide (1.3 moles per mole of 21-Hydroxy.-20-one) in benzene to a solution of 130 mg of benzyl? Hemimalonate (1.3 moles per mole of 21-hydroxy ~ 20-one). and 200mg of 3ß-acetoxy-21-hydroxy-8,19-0xido-5 <t-pregn-14-en-20-one in 10 ml of benzene was stirred under nitrogen at room temperature. A tlc analysis on a sample removed after 15 minutes showed all of the starting material in 3β-acetoxy-21-benzyloxycarbonyl Acetoxy-8,19-oxido-5 «- -pregn-14-en-20-one converted had been.

The mixture was then left under nitrogen for 2 hours and 15 minutes stirred for a long time with 2.5 ml of 10% aqueous potassium hydroxide, whereupon 4.0 ml of water and 2.0 ml of acetic acid-water 1:10 and 2 volumes of ether were added. The mixture was stirred and the fine, undissolved precipitate is removed by filtering. The organic phase of the two-phase filtrate was Extracted 5 times with water and then evaporated. A crystalline

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Sation of the residue from ether-hexane gave 216 mg of a precipitate, which after a further recrystallization from the same solvent system 3ß-acetoxy-22-benzyloxycarbonyl-8,19-0xido-5 "-Carda-14.20 (22) -Dienolid, mp 174, 212 and 229 yielded 176-178 ⁰ C, uv (MeOH) MJI.

Example 4

When 40 mg of 3β-acetoxy-21-hydroxy-.8, -19-0xido-5 "-pregn-14-en-20-one Were subjected to reaction conditions substantially the same as described in Example 3 with the Exception that oyanacetic acid is used instead of benzyl hemimalonate became the 21-cyanoacetate of the starting material obtained as an intermediate product, which after the basic treatment and the chromatographic separation on with silicon gel G coated glass plates with ethyl acetate-benzene 1: 1 as eluant 3ß-acetoxy-22-cyano-8,19-0xido-5ct-Carda-14,20 (22) -dienolide, uv (MeOH) 210 and 234 mu, and 22-Gyano-3ß-Hydroxy-8,19-0xido-5cr-0arda-14,20 (22) -dienolide, uv (MeOH) 209 and 234 mu.

example 3

When 23 mg of 3β, 19-Diacetoxy-21-Hydroxy-5 # -Pregn-14-en-2C-one Were subjected to reaction conditions approximately the same as those described in Example 1, with the exception that instead of 1.3 moles 1.5 moles per mole of starting material of Ipiäthylphosphono] acetic acid and.DicyooLhexylcarbodiimid used

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the 21- [diethylphosphonyl acetate of the starting material was obtained as an intermediate. Subsequent base treatment, followed by chromatographic purification of the crude product on glass plates coated with silicon gel, using ethyl acetate-benzene 1: 7 as the eluant and an extract of the purified material with pentane, gave Jß * 19-Diac: etoxy-5a, -Carda-14,20 (22) -Dienolid, melting point 155-162 ⁰ C.

Example 6

When 97.38 mg of i9-acetoxy-21-hydroxy-pregna-4,6-diene-3,20-

the dione was subjected to reaction conditions similar to those described in Example 1 except that 2.6 moles per mole of starting material of [diethylphosphono} acetic acid and dicyclohexylcarboniimide was used instead of 1.3 moles, the 21-ethylphosphono was used ] Acetate of the starting material obtained as an intermediate. The subsequent base treatment and chromatographic purification of the crude product on glass plates coated with silicon gel G with ethyl acetate-benzene 2: 1 as the eluant gave 19-acetoxy-3-oxo-Carda-4,6 £ 0 (22) -trienolide, melting point 180, 197-199 °, uv (MeOH) 218 and 285 W-

Example 7

When 172.2 mg of 8,19-0xido-21-hydroxypregn-4-ene-3,20-dione Were subjected to reaction conditions which were essentially the same as those described in Example 6, with the exception that the intermediate 21- ^ iäthylphosphoncTJ Acetate isolated from the starting material and from the remainder

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Starting material separated by chromatography on silicon-coated glass plates and then subjected to base treatment, recrystallization of the final crude product from ethyl acetate-pentane gave 36.3 mg of a crystalline material consisting essentially of 3-oxo-8,19-oxido-carda -4.20 (22) dienolide, which contained a more polar alcohol than an impurity. Treatment of the latter product with pyridine-acetic anhydride at plus 5 C for 2 - ^ days and subsequent addition of water, filtration and recrystallization of the precipitate collected with methylene chloride ether gave 18 mg of the purified product, melting point 227, 228-231 ⁰ C, ir ( NUJOL) 3105 (weak), 1778, 174-5, 1670, 1622, 1375, 1305., 1258, 1045, 1020, 966, 890, 882 and 815 cm " ¹ .

Example 8

When 400 mg of 3β-acetoxy-21-hydroxypregn-5-en-20-ones were subjected to reaction conditions approximately identical to those in Example 1, 336 mg of 3ß-acetoxycarda-5.20 (22) -dienolide, Melting point 168, 169-173 ° C via the 21-diethylphosphono acetate of the starting material.

Example 9

When 166.25mg (0.5 millimoles) of 3ß-21-dihydroxy-pregn-5-en-20-one Subjecting reaction conditions substantially the same as those described in Example 2 resulted the base treatment of the intermediate 3ß, 21-di diethylphosphono

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Ace, (.., gr-Eregn - ^ - en ^ O-one das 3ß- JDiethylphosphono] Acetoxy-Carda-5.20 (22) -Dienolide, ir (KBr). 2970, 1785, 1755, -173O, 1635 , 1260, 1250, 1145, 1120, 1070, IO25, 900, 875 and 790 cm " ¹ .

Example 10

When 400 mg of 5β-acetoxy-21-hydroxypregn-5-en-20-ones were treated under reaction conditions, which were approximately the same as those described in Example 3 ", with the exception that the intermediate 3β-acetoxy ~ 21- Benzyloxycarbonyl ~ | - Acetoxy-Pregn-5-en-20-one was isolated and purified by precipitation with hexane from a methylene chloride solution, resulted in a relocation of the crude end product in methylene chloride and subsequent precipitation with hexane 551 mg of 3ß-acetoxy-22 - ^t Benzyloxycarbonylj-Garda-5.20 (22) -dienolide, as revealed by comparison with a sample from another batch which had uv (MeOH) 216 and 230 mu.

Example 11

A mixture made by sequentially adding 118.8 mg of cyanoacetic acid (1.3 moles per mole of 21-hydroxy-20-ketone) and 6.96 ml of a 0.2 molar solution of dicylohexyl-garbodiimide (1.3 moles per mole of 21-hydroxy-20-ketone) in benzene to a solution of 400 mg of 3ß-acetoxy-21-hydroxy-pregn-5-en-20-one in 20 ml of benzene was made under nitrogen stirred. A Tlc analysis on a sample after 80 minutes, removed, showed that all of the starting material has been converted into the corresponding -21-cyanoacetate

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was. The mixture was washed with 6.0 ml of 10% aqueous potassium hydroxide stirred under nitrogen for 10 minutes, after which 160 ml of water and 200 ml of ether were added. The lower one, aqueous phase was separated, acidified with 9.0 ml of 2N aqueous sulfuric acid and extracted with ether. The ethereal solution was extracted with water until the aqueous extracts

at neutral, dried with sodium sulfate and / reduced Pressure evaporates. Dissolution of the residue, achieved in methylene chloride, adding hexane until the solution is slightly cloudy filtering through diatomaceous earth, concentrating the filtrate with intermittent addition of hexane, the Standing at minus 5 C and filtering gave 355 mg of 3ß-acetoxy-22-cyanocarda-5.20 (22) -dienolide, melting point 200-215 ° 0, uv (MeOH) 241 mn as by ir and nmr spectroscopy was established.

Stirring 34.4 mg of the above compound dissolved in 3.5 ml of benzene with 3.4-5 ml of 50% strength aqueous potassium hydroxide over a period of 3 hours and then acidifying with 2N aqueous sulfuric acid and isolating the steroidal product by a procedure which was essentially the same as that described above gave 3β-hydroxy-22-cyanocarda-5.20 (22) -dienolide, mp 211-225 ° C, uv (MeOH) 239 mp, ir (KBr) 3550, 2225, 1760, 1665, 104-5, 1025 and 760 em " ¹ .

B ei s ρ ie 1 12 If 50 mg of 21-Hydroxy-8,19-0xido-5a-Pregn-14-en-20-one

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Eeaktionsbedingungen were subjected to were about the same as described in connection with Example 1 "was 44 mg of 8,19-0xido-5" -Carda-14,20 (22) -Dienolid, melting point 177, 179-184 ⁰ C, uv (OEUOH) 218 must be obtained from the 21- (diethylphosphono) acetate of the starting material.

Example 15

When 20 mg of 21-Hydroxy-8,19-Oxido-5ct-Pregn-14-en-20-ones were exposed to reaction conditions substantially the same as those described in Example 4, 21-Zyanoacetoxy-8,19-Oxido became -5d-Pregn-14-ene obtained as an intermediate stage and 22-Zyano-8, i9-0xido-5a.- ° ^arda - ^'14 ₅ 20 (22) -Dienolide, ir (CFU) 2220, 1774, 1625 and 1572 cm " ^1. A methanol solution of the latter compound had uv 237 μιμί after adding a small amount of aqueous potassium hydroxide it was uv 256 μl.

Example 14

A mixture of 250 mg of 3ß-acetoxy-8,19-0xido-5ct-Carda-14, 20 (22) dienolide, 7.5 g zinc, 18.75 ml toluene and 6.25 ml formic acid were shaken for 16 hours and then the above floating phase poured off. The remaining part was briefly shaken with 25 ml of benzene, which was then poured off. the Benzene extraction was repeated another 4 times. The poured off liquids floating above were filtered and combined and evaporated at reduced pressure. The Eest was made in methylene

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chloride and hexane was added to the solution until it became slightly cloudy. The mixture was filtered through diatomaceous earth and the filtrate concentrated under reduced pressure with intermittent addition of hexane and ether. Letting the mixture stand at minus 5 ° C. and then filtering gave 237 mg of 3β-acetoxy-19- £ ormyloxy-5qL-Carda-14.20 (22) -dienolide, uv ^ MeOH) 218 mu, ir (KBr) 3065 (weak) 1795, 1767, I74-O, 1730, 164-0, 1255, 1207, 1170, -1141, 1081, IO59, IO3O, 911, 895, 867, 815 and 74-5 cm " ^1. The tlc- Analysis indicated that the reaction proceeded via 3β-acetoxy-19-hydroxy-5a.-Carda-14,20 (22) -dienolide.

Example 15

A reduction of 70 mg of 8.19-0xido-5a-Carda-14.20 (22) ~ dienolide with zinc in the presence of formic acid under conditions similar to those described in Example 14 gave 39.8 mg of 19- hydroxy-5a-Carda-14,20 (22) -Dienolid 19 format, having a melting point of 131, 135 to 136.5 ⁰ C over 19-hydroxy-5a-Carda-14,20 (22) -Dienolid.

Example 16

A mixture of about 38 mg of 3-ß-acetoxy-8,19-0xido-5cL-Carda-14,20 (22) -dienolide, 3.8 ml of glacial acetic acid, 0.97 ml of water and 77 mg of zinc dust were briefly stirred at room temperature and then by outside in an oil bath at a temperature between 65 and 69 ° C heated up. After stirring for 5 minutes in an oil bath, 388 mg Zinc added slowly over 3 minutes, followed by three

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more slow additions during 3 "to 4 minutes equal amount of zinc after 36, 227 and 254 minutes. That The mixture was then filtered and the precipitate washed with acetic acid-water 4-: 1 and ethyl acetate. The JFiltrate was then 3 times with reduced pressure to 1/2 volume "with inter-

Concentrated by adding 3 times 30 ml of water. The resulting mixture was neutralized with saturated aqueous sodium bicarbonate and allowed to stand at plus 5 ° C for 2 1/2 days. Filtration gave 28 mg of a product containing 3β-acetoxy-19-hydroxy-5α-garda-14,20 (22) -dienolide as the main component as determined by tlc analysis. The latter material, 0.11 ml of pyridine and. 0.056 ml of acetic anhydride was then left to stand under nitrogen for 16 hours at room temperature and then diluted with hexane-ether 2: 1 and filtered. The filtrate was concentrated under reduced pressure with intermittent addition of toluene. The chromatography of the resulting resin on glass plates coated with silicon gel G with ethyl acetate-benzene 1: 4- as the eluant and subsequent igmentation with pentane of the isolated fraction gave 10 mg of 3β, 19-diacetoxy-5OrGarda-14-, 20 (22) - Dienolid, melting point 162, 163-164- ⁰ C, which due to the IR spectrum and melting point to be identical with ß-Anhydrocoroglaucigenin 3> 19-acetate, melting point 161-163 ° Cfestgestellt was (A. hunger and T. Reichstein, Helv 35, 1073 (1952).

Example 17 "

A mixture of 30mg of 3ß-acetoxy-i9-i ^t ormyloxy-5 CL-Carda-

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14,2O (22) -Dienolide, 1.2 ml of acetone and 0.6 ml of a solution of 60 mg of N-bromoacetamide in 1 ml of water was stirred under nitrogen in the dark in an ice bath for 97 minutes, whereupon 18 ml of ice water and 1.2 ml of a 1/2 saturated aqueous sodium bisulfite solution was added. After stirring for a further 30 minutes, filtering and subsequent drying under high vacuum, 3 [beta] -acetoxy-15a-bromo-19-lormyloxy-14 [beta] -hydroxy-5Q; -Card-20 (22) -Enolid obtained, ir (KBr) J425 (broad), 32.95 (sharp), 3070 (weak) 1735, 1727, 1719, 1710, 1705, I6I9, 1565, 1370, 1355, 1239 , 1115, x 1021, 901, 890 and 882 cm "¹; the ir spectrum of a chloroform solution had a strong peak at 3570 instead of the peaks at 3425 and 3295 cm" ¹ .

Example 18

When 11 mg of 3ß-19-diacetoxy-5a-0arda-14,20 (22) -dienolide were subjected to reaction conditions substantially the same as in the previous example, filtration of the aqueous solution gave 3ß, 19-diacetoxy-15a Bromo-14β-hydroxy-5ft-carda- (22) enolide; uv. (MeOH) 217 mu; ir (NUJOL), 3470 (broad), 3390 (weak), 3360 (weak), 3090 (weak), 1769, 1735, 1720, 1705, 1620, 1450, 1368, 1355, 1237, 1025, 951, 880 and 865 cm "" ¹ .

Example 19

A mixture made by adding a freshly made solution of 180 mg of N-bromoacetamide in 3 x 0 ml of water to 6.0 ml Acetone and 150 mg of 3β-acetoxy-19-formyroxy-5Q-Carda-14.20 (22) -Dienolide was prepared in the dark under nitrogen

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stirred and cooled from the outside by an ice bath for 2 hours, whereupon 90 ml ice water and 6.0 ml half-saturated aqueous sodium bisulfite were added and the mixture was stirred for a further hour. Filtration gave 3β-acetoxy-15 <2B ^{I> OTno-} '' 19 ~ formyloxy-14β-hydroxy-5α-Gard-20 (22) enolide, which was dissolved in 30 ml of methylene chloride and mixed with a mixture for 16 hours was shaken by 3.0 ml of pivalic acid-methylene chloride 1:10, 60 ml of water and Raney nickel; the latter was freshly prepared _r 0g of a 50% nickel-aluminum alloy from 9-;. The addition of ether methylene chloride 4: 1, the subsequent filtering through filter pulp, the extraction of the organic phase with half-saturated, aqueous sodium bicarbonate and water, the drying with sodium sulfate and evaporation under reduced pressure, the combination of the crude product with that of another reaction in which 50 ^ g "of 3ß-acetoxy-19-formyloxy-5ä-carda-14,20 (22) -dienolide was used as the starting material, - and resulted in various recrystallizations of the combined products from ether-hexane 50.65 mg of the product, melting point 232, 234-239 C. A further refinement: of 24 mg of this material by chromatography on glass plates coated with silicon gel G with ethyl acetate-benzene 1: 2 as eluant gave 19 mg of a fraction which recrystallization from ether-hexane to 16,76 mg of purified Goroglaucigenin 3-acetate 19-format, melting point 248.5 - 250.2 ⁰ C were revealed the mother liquors when used in the manner of chromate. were subjected to further ography

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Amounts of the latter component as well as various fractions amounting to about 20 mg of 3ß-acetoxy-19-JPormyloxy-14-ß-, 15ß-oxido-5 a-Card-20 (22) -Enolid.

Example 20

If 15a-bromo-3ß, 19-diacetoxy-14ß-hydroxy-5ot-Card-20 (22) -enolide, that fresh from 11 mg of 3β, 19-Macetoxy-5α-Carda-14.20 (22) -Dienolide, as described in Example 18, was prepared,

was treated under reaction conditions / which essentially

were similar to those in the previous example, with the exception that the reduction was carried out with Raney nickel in a hydrogen atmosphere instead of a nitrogen atmosphere, the chromatography of the crude product on glass plates coated with silicon gel G with ethyl acetate-benzene 1: 2 as eluant and subsequently gave then a recrystallization of ether-pentane 3ß, 19-diacetoxy-14ß-hydroxy-5Q (, _t -Card-20 (22) -enolide (coroclaucigenin diacetate), melting point 207-212 C; coroglaucigenin diacetate, which according to A. Hunger and T. Reichstein, HeIv., 35 ,. 1073 (1952) page 1097 from goroglaucigenin had a melting point of 210-214 ° and 216-219 ° C.

Example 21

3ß-Acetoxy-19-Formyloxy-15a.-Bromo-14ß-Hydroxy-5Q: -Card-20 (22) -Enolide was made from 25 mg of 3ß-acetoxy-19-iOrmyloxy-5cfc-Carda-14,20 (22) -dienolide similar to that described in Example 17

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manufactured. A methanol solution of the freshly filtered bromohydrin was then stirred with a molar excess of concentrated aqueous ammonia at room temperature under nitrogen for several hours and then left to stand at minus ^ ⁰ O for 16 hours, whereupon the base was neutralized with acetic acid in ethyl acetate and the mixture was neutralized under reduced pressure was evaporated. The residue obtained was extracted 3 times with ether-methylene chloride 4-: 1, and the combined extracts were chromatographed on glass plates coated with silicon gel G using ethyl acetate-benzene 1: 2 as the eluant. Recrystallization of the greater part of ether-hexane gave 11.36 mg of 3β-acetoxy-19- £ ormyloxy-14β, 15β-oxido-5QrCard-20 (22) -enolide, melting point 213-215 ° C.

Example 22

A mixture of 15ct-Bromo-Jßj ^ -Diacetoxy-i ^ -ß-Hydroxy ^ ct-Oardenolide, that fresh from 2.6 mg of 3β, 19-diacetoxy-5a-carda-14, 20 (22) -dienolide according to the procedure described in Example 17, and from 0.13 ml of t-butylamine was under nitrogen Left to stand for 30 minutes and then evaporated under reduced pressure. Treating the rest with ether and water, the repeated extraction of the organic phase with water, the evaporation and recrystallization of ether-pentane gave 3ß? 19-diacetoxy-14ß, 15ß-0xido-5a-Card-20 (22) -enolide, Melting point 194-, 200-204 ° C.

Example 23

A mixture of 3ß-acetoxy-19-5 ^l oi ⁱ myloxy-15ct-bromo-14-ß-hydroxy-5oc -Card-20 (22) -enolide, freshly made from 20 mg of 3ß-acetoxy-19- £ ^l ormyloxy-5Ct-Carda-14,20 (22) -dienolide, as described in Example 17, had been prepared and was still moist from 1 ml of Mron t-butylamine and from 0.5 ml of water for 1 hour in a nitrogen atmosphere stirred and then under reduced pressure with intermittent addition of hexane and water

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concentrated. Filtering gave 8.0 mg of crude 3β-acetoxy-19-hydroxy-14β, 15β-oxido-5x-Card-20 (22) -enolide. Recrystallization from hexane-methylene chloride gave the purified sample, melting point 227-229 ⁰ CV

Example 24

A mixture consisting of 7 ml of methanol and crude Iß-Acetoxyi9-i ^l ormyloxy-14ß-hydroxy-5ot-Card-20 (22) -enolide, which consists of 150 mg

of 3β-acetoxy-19- £ ^l ormyloxy-5i * Carda-14,20 (22) -dienolide was prepared as described in Example 19, was stirred under nitrogen at room temperature, 4.9 ml of methanol-2% aqueous potassium hydroxide 20 : 1 was then added over 1/2 hour. After 2 hours, 0.245 ml of ice-cold acetic acid / ethyl acetate 1:50 were then added and the mixture was evaporated under reduced pressure. Extraction of the residue with Ither-methylene chloride 4: 1 and then extraction of the organic phase with water, drying with sodium sulfate evaporation and chromatography on glass plates coated with silicon gel G with ethyl acetate-benzene 1: 1 as eluant gave 37 ^ g ^of 3β-acetoxy -14ß, 19-dihydroxy-5a-card-20 (22) -enolide (Coroglaucigenin 3-acetate), mp 233-234 ⁰ C,

Example 25

The oxidation of 4 mg of coroglaucigenin 3-acetate with t-butyl chromate in t-butanol carbon tetrachloride 1: 6 by a process, essentially that of A-Katz, HeIv., 35> 487 (1957) page 490 gave corotoxigenin 3-acetate, melting point

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220.221-229 ° after, a recrystallization of the crude product with ether-hexane. The IR spectrum of the latter component was identical to that obtained after A * Hunger "and T.Reichstein, Helv. 35 1073 * (1952), the Corotoxigenin 3-acetate, melting point 227-234 ^o 0 and 220-23O ⁰ C. from corotoxigenin. The t-butyl chromate was prepared in the manner described by K. Hensler and A. Wettstein, Hel-v., 35, 284 (1952).

Example 26

A mixture of 6 mg Coroglaucigenin 3-Acetat 19- £ Ormat, 0.3 ^ l t-butylamine and 0.3 ml water was shaken under nitrogen at room temperature for 24 hours, whereupon it was under reduced pressure and with the intermittent addition of ice-cold acetic acid - Water has evaporated 5: 1. The residue was then ground in 0.2 ml of water and the resulting suspension filtered. The precipitate was recrystallized from methanol-ether and gave 3.7 mg of crude coroglaucigenin, melting point 227-230 C. Chromatography on glass plates coated with silicon gel G with ethyl acetate as the eluent and subsequent recrystallization from methanol-ether gave the purified sample; Melting point 241-242, 244 ⁰ C; ir (ICBr) max. 3610, 3350, 3098, 1781, 1750, 1738, 1620, 1445, 1370, 1339, 1309, 1301, 1175, 1148, 1135, IO75, 1035, IO25, IOI9, 959, 891, 887, 880, 869, 790, 780, 741 and 698 cm " ¹ .

Example 27

A mixture consisting of 45 mg of 3ß-acetoxy-carda-5.20 (22) -dienolide, 9.0 ml of methanol and 0.9 ml of 2% aqueous potassium

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hydroxyds were stirred for 4 hours, after which a further 0.9 ml of 2% strength aqueous potassium hydroxide was added. The mixture, in which a precipitate had formed, was left to stand at minus 5 ° C. for 16 hours and then filtered. The precipitate was washed with water-methanol 1: 3 and then with water. The filtrate was concentrated and filtered to give a second precipitate. Both precipitates were combined and chromatographed on glass plates coated with silicon gel G using ethyl acetate-benzene 1: 4 as the eluant. The part with rf 0.2-0.3 was recrystallized from ether hexane and yielded 5.7 mg of 3ß-hydroxy-carda-5.20 (22) -dienolide, ir (KBr) 3460 (broad), 1805, 1730, 1620, 1190, 1170, 1135, 1108, IO7O, 1052, 1030, 985, 965, 905, 870, 812, 745 and 712 cm ~ ¹ .

The latter 3ß-hydroxycardenolide was also determined, as was the tlc analysis shows, obtained when the 3ß- [piäthylphosphono]] -Acetoxy analog the starting material in a similar manner with methanol and 2 / ^ igem aqueous potassium hydroxide was hydrolyzed.

Example 28

If 25 mg of i9-5Ormyloxy-5a-Oarda- 14-, 20 (22) -dienolide with N-bromo-acetamide was oxidized as indicated in Example I7, the corresponding 14-ß-hydroxy-15ct-bromo was obtained analogously. The freshly filtered and still moist bromohydrin gave, when reduced with Eaney nickel as described in Example 17, a crude product obtained by chromatography on silicon

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gel G coated glass plates with ethyl acetate-benzene 1: 1 as eluant. Recrystallization of the fraction with rf 0.3-0.4- from ether-hexane gave 8.4 mg of 14-β, 19-dihydroxy-5a-Card-20 (22) -Enolid'i9 format, melting point 195-198 ° C , ir (KBr) 3565, 34-15 (broad), 3330 (blank), 3090 (small), 1785, I755, 174-2, 1737, 1730, -1721, 1715, 1628 and 1175cm " ¹ '· ^one less polar fraction was isolated was recrystallized from hexane-methylene chloride to give 19-formyloxy-14, 15ß- -Oxido-5ct-14-ß-Gardenolid, melting point 190-192 ⁰ C.

Example 29 :

A freshly prepared mixture, which consists of 11., 2 ml of anhydritic tetrahydrofuran, 0.187 ml of redistilled 'ethoxyacetylene and 1.12 ml of 1.95 K methyl-lithium, in ether, was a solution of 50 mg of 3ß - A- added cetoxy-21-hydroxy-8,19-OxIdO- ^ Qk-Pregn-14 ~ en-20-one in 8..7 ml of tetrahydrofuran, which was protected by a nitrogen atmosphere. After stirring under nitrogen for 4 hours, the solvents were evaporated under reduced pressure. The remainder was treated with moist ether and the ether phase was extracted several times with water until the aqueous extracts were no longer basic. Evaporation gave a resin composed mainly of 20-ethoxyethynyl-3β, 20,21-trihydroxy-8,19-oxy-o-50C-Pregn-14-ene, as indicated by tlc analysis and subsequent transformations revealed. The latter product was then rated with 3 _? 5 ml benzene and 1.75 ml of 2Ή aqueous sulfuric acid were stirred firmly under nitrogen for 4 hours, whereupon the reaction mixture was diluted with benzene and

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was extracted sequentially with water and semi-saturated aqueous sodium bicarbonate. The benzene solution was dried over sodium sulfate and filtered through an acid of 70 mg aluminum oxide. Washing the acid with ethyl acetate gave 21 mg of a product which solidified with hexane and consisted essentially of 5β-hydroxy-8,19-oxido-5cn.-Carda-14, '20 (22) -dienolide. A subsequent. Allowing to stand with 0.084 ml of pyridine and 0.04-2 ml of anhydrous acetic acid for 20 hours in a nitrogen atmosphere and subsequent addition of 20 parts by volume of water, extraction with ether, extraction of the ether phase with water and evaporation ensured the corresponding 3-acetate, which then with zinc and formic acid in the presence of toluene under conditions similar to those of Example 13 was reduced. Chromatography of the total product obtained on glass plates coated with silicon gel G with ethyl acetate-benzene 1: 4 as the eluant gave 9 ₅ 7 mg of 3β, 19-dihydroxy-5ot -Garda- 14-, 20 (22) -dienolide 3-acetate 19 Format as a white, solid product which had an ir spectrum identical to the product according to Example 13.

When 3β, 21-dihydroxy- or 3β, 21-diacetoxy-8,19 ~ oxido-5rA-pregn- • 14-ene instead of 3ß-acetoxy-21-hydroxy ~ 8, 19-0xido-5 <rt -Pregn-14- ene reacted with ethoxyacethylene in the manner described above, was 20-lthoxyethynyl-3ß, 20,21-trihydroxy-8,19-0xido-5 - x -Pregn-14-ene received.

Example 30
When 3ß-acetoxy-8,19-0xido-5 <X -Pregn-14 ~ en-20-one a reaction

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with ethoxyacetylene according to the example described above received, a component was obtained which as 20-Äthoxyäthynyl-3ß, 20-I) ihydroxy-8,19-0xido-5e ^ -Pregn-14-ene was viewed; similarly gave 8,19 * -oxido-3β-L-tetrahydropyran-2-xloxyJ-5 ÖL-Pregn-14-en-20-one a component known as .20-ethoxy-ethynyl-20-hydroxy-8,19-oxido-3ß-tetrahydropyran-2-yloxy-5 Ol-Pregn-14-ene was viewed. The latter two ethoxyacetylene inclusion compounds revealed when similar with aqueous sulfuric acid the above example were treated, ethyl 3ß-hydroxy-8, i9-0xido-24-nor-5ak -chol-20 (22) -en-23-oate, uv max 222 mu, like resulted from the tlc analysis.

Example 31

When 32 mg of 14β-hydroxy-3β- [pyran-2-yloxyJ -8,19-0xido-5 ^ -pregnan-20-one a reaction with ethoxyacetylene similar to example 29 was received, a product was obtained which 20-ethoxyethynyl-3ß, 14ß-dihydroxy-8,19-oxido-5 ck-pregnan-20-one contained, which was similar after treatment with aqueous sulfuric acid as described in Example 29 (except that ethanol was used as the solvent) gave a product the ethyl 3ß, 14ß-dihydroxy-8,19-0xido-24-nor-5ck -ohol-20 (22) -en-23-oic-acid contained. Acetylation with anhydrous acetic acid-pyridine 1: 2 and subsequent chromatography of the Raw product on glass plates coated with silicon gel G with Ethyl acetate-benzene 1: 4- as eluant gave ethyl 3ß-hydroxy-8,19-0xido-24-nor-5 "-chol-20 (22) -en-oate, uv max. 231 mu; treatment of this product with selenium dioxide in boiling benzene,

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as described by N. Danieli, X. Mazur and F. Sondheimer, J.Am. Chem. Soc, 84, 875 (1962) "described" ben and a subsequent chromatography on glass plates coated with silicon gel G with ethyl acetate -Benzene 1: 4 as eluant resulted in a fraction that was known as 8,19-Oxidouzarigeninacetat with uv max. 218 myi was viewed. Another, more polar fraction also had a value of uv max. 218 ταμ, and was considered to be 14 · «* -Hydroxy-8,19-0xidouzarigenin J-acetate (see F. Sondheimer, Chemistry in Britain, 1, 454 (1965), p

Example 52

A mixture of 200 mg of 3ß-acetoxy-21-hydroxy-pregn-5-en-20-one, 10 ml of methyl isobutyl ketone, 2.0 g malonic acid and 2.0 g calcium chloride were heated under nitrogen at 84 C for two days and then the mixture under reduced pressure under intermittent Addition of benzene evaporates. The residue obtained was treated with water and the resulting precipitate was filtered and washed sufficiently with water. The precipitate was in Dissolved methylene chloride and concentrated the solution with the intermittent addition of pentane. The petroleum ether phase floating above was poured off and the precipitation of pentane was repeated twice. The remaining residue was dissolved in ether methylene chloride dissolved, treated with charcoal and filtered through diatomaceous earth. The concentration of the filtrate at reduced pressure with intermittent addition of hexane and ether and subsequent filtering gave 192 mg of 3β, 21-dihydroxy-pregn-5-en-20-one 3 acetate-21-hemimalonate.

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A solution of the latter component in ether diazotoluene, by briefly mixing 22.5 days of ίΓ-Benzyl-IT'-Hitro-N-Nitrosoguani & in, " 0.040 ml potassium hydroxide-water 1: 1 and 1 ml ether with external cooling by an ice-acetone bath "prepared was then allowed to stand at minus 50 G for 15 minutes. Evaporation at reduced pressure gave a not very good result white solid material composed mainly of 3β-acetoxy-21- [B. enzyl-oxy carbonyl] acetoxy-pregn-5-en-20-one. The treatment of part of the latter product with 20 parts of t-butylamine over a period of 25 minutes at room temperature followed by evaporation gave a product that was mainly from 3ß-acetoxy-22- [benzyloxycarbonyl} -Garda-5.20 (22) -Dienolid existed as shown by the tlc analysis.

Example 55

A mixture of 200 mg of 3β-acetoxy-21-hydroxy-pregn-5-en-20-one, 10 ml dimethylmalonate and 2.0 g calcium chloride were ^{heated under nitrogen in an oil bath at a temperature of 84 °} C. for four days, with 20 ml of toluene were added. The reaction was then subjected to distillation at atmospheric pressure and increases the Badtemperätur to 160 C over a period of 1 _f 5 hours. Subsequently, the temperature 'of the bath was lowered to 84 ° C and the mixture subjected to distillation at high vacuum for 1 _Λ 5 hours. The resulting solid residue was dissolved in 15 ml of ether, 2.5 ml of hexane and some charcoal added. A filtering through diatomaceous earth and a subsequent concentration of the filtrate with inter-

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intermediate addition of hexane and ether resulted in a suspension, after filtering 3ß-acetoxy-21- [llethoxycarbonyl] acetoxy-pregn-5-en-20-one revealed.

Example 34

A mixture of 220 mg of the product according to the previous example and 2.2ml of t-butylamine-benzene T: 10 was at room temperature allowed to stand under nitrogen for 35 minutes and then at reduced pressure with intermittent addition of benzene

ge
concentrated. Then hexane was added until the solution became slightly cloudy. Subsequent filtering through diatomaceous earth and concentration of the filtrate under reduced pressure with intermittent addition of hexane gave a resinous precipitate which was dissolved in ether and precipitated from hexane. The precipitation from hexane was repeated once more and finally gave 127 mg of a beige solid, which consisted mainly of 3β-acetoxy-22-methoxycarbonylcarda-5.20 (22) -dienolide. Chromatography on silicagel G-coated glass plates with ethyl acetate-benzene as eluant 1S6 and subsequent recrystallization from hexane gave a purified sample, melting point 100, 112-120 ⁰ G, uv (MeOH) 229 mu; ir (KBr) 1770, 1725, 1655, 1240 and / 1

1030 cm. A methanol solution of the sample changed upon addition a small amount of aqueous potassium hydroxide rapidly from uv 229 to 235, 286 (higher) ΐημ. During the ohromatographic Development resulted in a pink color, which is typical for 22-alkyloxy-carbonyl-card-20 (22) -enolides is.

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Example 35

A mixture which, by adding 0.1875 ml of anhydrite, appears Tetrahydrofuran to 30 mg methyl [biäthylphosphonoIl-acetate, cooling in an ice bath, adding 2.2 mg of sodium hydride mineral oil 1: 1, warm to room temperature and add 27.75 mg of 21-Hydroxy-6,19-0xido-Pregn-4-en-3-one was stirred at room temperature for 20 hours, followed by a Mixture of 30 mg of methyl / diethylphosphono] acetate, 0.1875 ήΙ anhydrite ischemic tetrahydrofuran and 2.2 mg of sodium hydride mineral oil 1: 1 was added and stirring continued for an additional 2 hours. Evaporation at reduced pressure and then Add 5 ^ l of ethyl acetate, 5 extractions with Water and evaporation of the extracted organic phase under reduced pressure gave a product which, after chromatography on glass plates coated with silicon gel G with ethyl acetate-benzene 1: 1 as eluant and recrystallization of the part with rf 0.35 from ether-pentane to 3-0xo-6,19-0xidocarda-4,20 (22) -dienolide led, uv (MeOH) 225 (broad) ΐημ, which possessed an ir spectrum, which was identical to that of the product according to Example 7.

Example 56

A mixture was obtained by adding against one in succession Nitrogen flow of 76 mg of sodium hydride mineral oil 1: 1, one Solution of 0.340 ml of [diethylphosphono / acetonitrile in 1.2 ml Tetrahydrofuran and 73 mg of 5ok-chloro-3β, 21-diacetoxy-6, -19-oxidopregnan-20-one in 6 ml of tetrahydrofuran to 5.2 ml of tetrahydrofuran

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hydrofuran produced; during the additions the reaction vessel was cooled by an ice bath. The ice bath was then removed and the mixture stirred under nitrogen at room temperature for 20 hours. One half of the reaction mixture was then evaporated under reduced pressure and the residue obtained was left to ^{stand overnight} in the refrigerator with 5 ?7 ™1ΎΟΐ1-2N aqueous hydrochloric acid. The precipitate that had formed was filtered off and washed with water and ither and gave 3β-acetoxy-5Ä-chloro-6,19-0xido-23-iminocard-20 (22) -enolide hydrochloride, uv (MeOH) 237 mp, ir (KBr)

3375, 1735, 1675, 1605, 1450, 1370, 1245, 1230, 1095, 1035, 1025 and 920 cm " ¹ .

A part up 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. The heating of the separated aqueous acid phase at 70 ° C under nitrogen and subsequent filtration gave 5 <* chloro-3ß-hydroxy-6,19,0xido-Card-20 (22) -enolide, uv (MeOH) 218 ιημ, ir (KBr ) 3430 (wide), 1775, 1750, I725, 1620, I170, IO5O, 1030, IO25, 1000, 920, 860 and 795 cm " ¹ .

Example 37

If 33 * 4 mg of 5Λ-chloro -3ß, 21-diacetoxy-6,19-0xidopregn-20-one Exposure to the reaction condition of the previous example for 21 hours resulted in evaporation of the reaction mixture under reduced pressure and subsequent treatment of the Residue, which is made with Ither and 2N aqueous hydrochloric acid

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as well as evaporation of the ether phase a material with uv (MeOH) 222 mu, the 3ß, 21-diacetoxy-5cs-Ohloro-20-cyanomethylene-6,19-0xidopregnan than contained the major steroid as indicated by tlc analysis.

Example 38

A mixture of 130 mg of 3ß-acetoxy-8,19-0xido-ak-22- [benzyloxycarbonyl} Garda 14.20 (22) dienolide, 3 x 9g zinc dust, 9.75 ml Toluene and 3 x 25 ml 90% formic acid was added for 16 hours Shaken under nitrogen whereupon an additional · 3 »9 g zinc and 1.3 ml ^ 90% formic acid was added. After 2 days Further shaking was used to remove the liquid phase floating above poured off, 7 x 5 ml of benzene-methylene chloride 1: 1 the remaining Add residue, shake the mixture briefly and pour off the liquid floating above. And four more Extractions with benzene-methylene chloride 1: 1 and 5 subsequent For extractions with methylene chloride, the combined floating liquids were evaporated under reduced pressure. the Dissolution of the resulting residue and the subsequent addition of pentane until a slight cloudiness appears, Filter through diatomaceous earth, concentration deg the filtrate reduced pressure with intermittent addition of pentane, standing at minus 5 ° C for 30 minutes, pouring off the above floating liquid and drying under high vacuum 111 mg of a residue, the 3ß-acetoxy-22-benzyloxycarbonyl-19-formyloxy-24-nor-5a -chola-14, 2Q (22) -dien-23-oic acid

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(possibly as the olefinic Z-isomer) and also 3ß-acetoxy-22-benzyloxycarbonyl-19 -]? ormyloxy-5sx-carda-14,20 (22) -dienolide, as the tlc analysis showed. contained

Heating 100 mg of residue to between 110 and 125 ° C. in an evacuated tube for 225 minutes and subsequent chromatographic separation on glass plates coated with silicon gel G with ethyl acetate-benzene 1:20 as the eluant gave 35 ^ g of 3β-acetoxy-19 -5'ormyloxy-24-nor-5d ^l > -chol-20 (22) -en-23-oic acid (possibly the olefinic Z-isomer) as a colorless resin; uv (MeOH) 218 and 227 (flank; no change after base formation of the methanol sample solution with potassium hydroxide) ΐημ; nmr (GDGl ₅ ) 8.16, 7.40, 6.55, 5.84, 5.18, 5.08, 4.4, 3.13, 2.01 and 0 _f 78 ppm; m / e 534, 443 and 337 · The chromatographic separation gave the predominantly polar part 15 ^ g ^of 3ß-acetoxy-22-benzyloxycarbonyl-5 <* - Carda-14, 2O (22) -dienolide; m / e 576 (weak), 485 (medium), 483 (medium) and 467 (strong); uv (MeOIJ) 216, 230 and 24.9 (smaller tip) τημ, 288 (larger tip) ιημ after base formation of the methanol sample solution with aqueous potassium hydroxide.

Example 59

A mixture of 300 mg of 3ß-acetoxy-22-benzyloxycarbonylcarda-5.20 (22) -dienolide, 9.0 g of zinc dust, 22.5 ml of toluene and 7.5 ml of 90% formic acid were left under nitrogen for 16 hours shaken for a long time, then 9 g zinc dust and 3.0 ml 90% strength

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Formic acid added. Shaking was continued for 24 hours and then an additional amount of 9 g zinc dust and 3.0 ml 90% formic acid were added. The mixture was then filtered, the precipitate washed well with methylene chloride and the combined filtrates evaporated under reduced pressure. The residue obtained was treated with methylene chloride and the resulting suspension was filtered. The filtrate was concentrated with the intermittent addition of hexane and then allowed to stand at room temperature under nitrogen until the floating liquid above became clear. Decanting gave a residue which mainly contained an acid which was known as (20 (22) Z) -3ß-acetoxy-22-benzyloxy-carbonyl-24-nor-chola-5.20 (22) -diene-23- oic acid was considered to be in addition to a starting material. A mixture consisting of 4.0 ml of an ethereal solution of the latter component and 4.0 ml of an ethereal solution of diazomethane would then be left to stand at ^{0 0} O for 20 minutes. A subsequent tlc analysis indicated that substantial amounts of steroidal carboxylic acid were still present and a further 4 ml of the essential diazomethane solution was added. The mixture was then left to stand at ⁰ ° C. for a further 20 minutes and then evaporated under reduced pressure. Chromatography of the greenish foam on glass plates coated with silicon gel G with ethyl acetate-benzene 1:20 gave 55 mg of a predominantly polar fraction as a resin consisting of a mixture of methyl (20 (22) Z) - and (20 (22) E ) -Acetoxy-22-benzyloxycarbonyl-24-norchola-5.20 (22) -diene-23-oate; uv (MeOH) was 213 235 (unchanged after base formation of the methanol sample solution

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with aqueous potassium hydroxide) ιημ; nmr (CDCl,) 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. Chromatography also showed 6.6 mg of a less polar one Fraction as a resin of what was considered to be a diazomethane inclusion compound of the above methylenoates.

Example 40

A solution of 60 mg of 3β-acetoxy-22-benzyloxy.-carbonylcarda-5.20 (22) -dienolide in 12.0 ml of ethanol was stirred at room temperature in a hydrogen atmosphere in the presence of 6 mg of 5% palladium on charcoal for one hour and then filtered through pulp in the presence of nitrogen. Evaporation under reduced pressure gave a foam. A solution of 9/10 of the latter ml in 9 ethanol was atmosphere then at room temperature in a hydrogen in the presence of 6 mg ^ follow palladium on charcoal for 50 minutes stirred (Rehydrogenation) The isolation of the steroidal material in the manner described above and the treatment the residue obtained with ether-hexane gave a white solid which essentially consisted of 3β-acetoxy-22-carboxylcarda-5.20 (22) -dienolide. A small portion of the latter product showed after 20 minutes of heating to * 137-14-2 ⁰ C in an evacuated tube 3.beta.-Acetoxycardenolid, as determined by TLC analysis.

Example 41

A mixture of 40 mg of the product of the latter reaction - repeated treated with zinc dust as described in Example 39 - gave a product containing 2-2-f3ß-acetoxypregn-5-en-20-ylidenJ Malon-

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acid contained. Subsequent treatment of the latter with 0.8 ml of ether and 2.4 ml of an essential diazomethane solution which was freshly prepared as in Aldrich Chemical Catalog 14, 1969-1970, at ⁰ ° C. and for 1 to 2 hours, concentration at reduced pressure to the Half of the original volume, addition of hexane, further concentration with intermittent addition of hexane, evaporation and chromatography of the residue obtained on glass plates coated with silicon gel G, using ethyl acetate benzene as the eluant gave a fraction which, after recrystallization from ether-hexane, yielded 2.5 mg of dimethyl 2,2-L3-ß-Äcetoxypregn-5-en-20-Xl-idenl malonate, with uv (HeOH) 219 and 233 (no change due to the addition of aqueous potassium hydroxide to the methanol sample solution) ιημ; m / e 412 , 397, 380 and 365-

Example 42

A mixture of 70 mg of 21-acetoxy-8,19-0xido-5β-Pregn-14-en-20-one, 12.2 ml of anhydric tetrahydrofuran and 17.6 ml of Tetrahydrofuran-ethoxyacetylene - 1.95 N methyllithium in ether 11.2: 0.245: 1.12 was stirred under nitrogen for 2 hours and then evaporated at reduced pressure with minimal access to air. The residue was dissolved in 35 ml of ether and 5 times extracted with 17 * 5 ml of water in a nitrogen atmosphere. Evaporation at reduced pressure gave a product consisting essentially of 2Of, 21-dihydroxy-20 ij-ethoxyethynyl-Sj ^ - consisted of 40 minutes with 5 «95 ml

Ethanol and 1.39 ml of 2N aqueous sulfuric acid under nitrogen

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was stirred, after which 35 ml of water were added. A Extraction of the aqueous mixture with ether and methylene chloride and then repeated extraction of the combined organic Phases with water, evaporation and preparative thin-film chromatography (Silicon gel G, ethyl acetate - benzene 1: 4) of the residue obtained gave 26.32 mg of a yellow solid, that consists essentially of 8.19-0xido-5β-Carda-14.20 (22) -Bienolide consisted, as can be seen from the tlc analysis and from the reactions of the the following examples.

. Example 43

A mixture of 660 mg of zinc dust, 22 mg of 8,19-Oxido-5ß-Carda-14,20 (22) -dienolide, 1.65 ml of toluene and 0.55 ml of 90% formic acid were shaken at room temperature for 19 hours, im Then 2.2 ml of ethyl acetate and 1.1 ml of water were added. Shaking was continued for 1/2 hour and then the mixture is filtered. Repeated extraction of the filtrate with water, evaporation of the organic phase, preparative thin-layer chromatography (Silicon gel G, ethyl acetate-benzene 1: 4-), extraction of the larger product from the scraped-off silicon gel powder with methanol-ethyl format 4: 1, evaporation of the extract under reduced pressure, treatment of the residue with methylene chloride, Filtration and evaporation of the filtrate gave 16.22 mg of 19-formyloxy-5β-8β-0arda-14-, 20 (22) -dienolide as a white material, that was used for the next reaction.

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Example 44

When "12 mg of 19-formyloxy-5β-Garda-14,20 (22) -dienolide was oxidized with N-bromoacetamide under conditions essentially the same as given in Example 17, the corresponding 14β-hydroxy-15a -Bromo obtained analogously, the freshly filtered and still moist bromohydrin was reduced with Raney Hickel under the conditions described in Example 17 ″. The crude product was purified by chromatography on glass plates coated with silicon gel G using ethyl acetate-benzene 1: 4- as the eluant. The fraction rf 0.4-5-0.5 »0.82 mg obviously consisted of 19-formyloxy-14,15β-0xido-5β, 14β-Card-20 (22) -enolide. The fraction rf 0.20-0.25, 6-65 mg consisted of 19-formyloxy-14-hydroxy-5β, 14β-Card-20 (22) -enolide and a small amount of impurity with a similar rf value. The latter fraction, 0.325 ml of methylene chloride, 195 mg of zinc dust and 0.65 ml of methylene chloride saturated with 90% formic acid, were shaken under nitrogen for 55 minutes. Filtering and subsequent dilution of the filtrate with ether, extraction of the organic phase with water, half-saturated aqueous sodium bicarbonate and water, evaporation of the organic solvent, chromatography of the residue as indicated above and recrystallization of the greater part with methylene chloride pentane resulted 4.75 mg of purified 19-formyloxy-14 ~ hydroxy-5β, 14β-Card-20 (22) -enolide, melting point 158-158.5 ° C, ir (KBr) 387I, 3463,3100, 2945, 29IO, 2890, 2880, 1786, 1750, 171.8, 1635, 1628, 14-81, x 14-56, 1381, 1350, 1311, 1270, 1185, 1089, 1072; 1049,1032, 991, 961, 912, 860 and 700 cm "¹; m / e 402, 384, 356 and 325.

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Claims (2)

St / p 7997 -Wf-- Nov. 12, 74 V / We patent claims 1. Component of the formula where in this component at saturated A-, B-, C- and D rings IL either hydroxy or OAc, Rp either CHpOH or CHQ, R ^ is H, R ^ and R _{1 are} - CH ₂ -O, Rg is either 5Cv. or 5β-H, and X and T together represent: C £ 11, C -CH, C CH, υ OH Br OH Cl 0 OH OAc C CH, C CH ₂ and C CH ₃ OH OCOC (CH ,,) -, OCHO. OAc or R ₁ H, O =, HCO ₂ , (CH ^) ₅ CCO ₂ , Cl ₅ CCO ₂ , (C ₂ H ₅ O) ₂ P (O) CH ₂ CO ₂ , Jj "ΤΙ • CO. 0. ^H 3 ° Tj  T ⁰⁰ S ⁰ 2 ^H 5 ⁰ 2 ⁰ ^  jj- OH 503823/0935 St / p 7997 ■ - $ fi -. Ί'2- Nov. 74 W / ¥ e EC Ξ C-CO ₂ , H ₂ C-CH-CO ₂ , (HO) CCH ₅ ) CH CO ₂ , (EO) IiO ₂ C (CKOH) ₂ CO ₂ , HO ₂ C (OHg) ₂ CO ₂ , Eö ^ CHgCOg, CH ₅ O C ₆ H ₅ CH ₂ O, HC sOCiy) _t 'aiötrol3yapopy3? Iai-2-3ao3y, 2a, 9od, -OxLdo and 5-Hydrö3sy-3oi, 9i «-02d.do, H ₂ : HCO ₂ CH ₂ , () (C ₂ H ₅ O) ₂ P (Q) CH ₂ CO ₂ CH ₂ ; _} H ₅ CyJ CO ₂ CH ₂ .CH, I j »« JHO = C-CO ₂ CH ₂ , U ₂ C = CCO ₂ CH ₂ , (HO) (CH ₅₎ CHCO ₂ CH _2, (HO) (CHj) ₂ CCO ₂ CH, HO HO ₂ C (CH _{2) 2} C0 _2, HO ₂ CCH ₂ CO ₂ CH ₂ ZCN ₅ OCH _2, (CHj ) ₅ COCH ₂ , '. , CHj, 8,19-02dLöo, I ^ - ^ O-lactone, 'iO-y-Ö-Laptol, and "; 6,19-Oxidoi Bji H, CO ₂ H, CO ₂ Cn ₂ C ₆ H ₅ ; CO ₂ CH ₅ , CO ₂ CH ₂ CH ₂ OH, CO ₂ CH ₂ -OsCH and CKj B _{4 ,. B 5} S CHg-O,. B4i CH ₅ ; K ₅ ; OCII ₂ C ₆ H ₅ , OCHj, OW , OCH ₂ CH ₂ OH and OCH ₂ -CsCH, H ₆ * H, Cl, Br odor 5 2 0H, S - ¥: ■ the groups which are dofinicrt or the group C-CH; or CH-CH ₂ ; and vioboi Doppolbiadunsoa indea: 5- »5» 7- »uss« i 3 »5» 7-position clad. - 5098237 * 093S ^: St / p 7997 12. Ήσν. 74- W / Ue 2. Process for the preparation of a component of the formula 4 - CX) woboi It ^ bia B ^ as well as X and X dio have the meanings defined above, and ausätzlica, if the A ~, £ ~, C ~ and D- Ein ^ o dor components are saturated; are »lüotapononton darotollon, at donon applies; X and X oind C-CH ₂ odos? C »Cii ₂ , H ₁ is OH or Ac» i ■ · '
.OE E ₂ is CH ₂ OK or GHOyH ₅ iot H and \ ^ ict CII ₂ O ·, according to diocbr AuoXührunssfox ^ i dor invention the Vorr ^ ltrea aua dor Gxruppo · selected, which consists of Ca) treatment öines? Component of the formula 2. ': "·.': = ■ 0 C2) where H ₁ , R ^ _% K ^ ₁ £ and Y and dio gostricholtcn lines denote. . oboxi dofinioirtcn önteprechon and IU OH iot, and woböi one Cfc-substituted acetic acid forms a component of the formula (3): 509823/0935 3t / p 7997 . Hoy. 7 * W / W , -0- (D-OH ₂ Z (3) where E .., Ep, Eg, X and X and the dashed lines denote the above defined, and where Z is a substituent selected from These are selected that reflect the acidity of the neighboring 'methylene group reinforce, and finally taking the component of the formula. (5) treated with a base to form a component of formula (i) becomes, vjobei E. ,, Ep, E ^, Eg, X and T and the double bonds correspond to those defined above, as well as E ^. and E are OHp-O. Cb) treatment of a component of the ■ formula "(.2) in which En is either OH, OGOGH ;, or, H, with an alkali alkoxyacetylide and then with an alcohol or water to form an intermediate component of the formula 0 = 0-Oalkyl 5Q9823 / 093S st / p 7997 - ^ "i2. W. • · Λ · Is OH or H and alkyl is OK ₂ H ₅ , OH ₅ or OH ₂ O ₅ H ₅ , the latter component being subjected to an acid treatment to form a component of formula (1) in which R * is H and R ^ and R _{1 are} - CHg-O- when R _f7 in the component of the formula (4) is OH, or when IU is H, R ^ OH ₅ and R _{5 are} OCH ₂ H ₅ , OCH ₅ or OCHpCgH, -, when R "in the component of" formula (4) is H. Cc) treatment of a component of the formula (1) in which R-. , Rp 1 Rg, X and Y and the dashed lines are those defined above, while R ₄ and R _{5 are} CH ₂ -O and R _{5 are} CO ₂ H, CO ₂ CH ₂ C ₆ H ₅ ; CO ₂ CH ₅ ; CO ₂ CH ₂ CH ₂ OH or OOgGHg-COGH, where zinc and a carboxylic acid form a component of the formula (1) in which R, represents a part selected from the group consisting of CO ₂ H, CO _{2 is} CH ₂ G ₆ H ₅ , CO ₂ CH ₅ , CO ₂ CH ₂ CH ₂ OH, and CO ₂ CH ₂ -CaCH; R ,, CK _x , and H _{K are} OH, OCH ₀ CH ₀ C ^ H ₁ -, OCH. ,, OCH ₀ CH ₀ OH, or OCH ₀ -C-CH. ■ -509823/0335