DE1093794B - Process for the preparation of saturated or unsaturated 20-oxopregnane-21-acids and their derivatives in the 16,17-position - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY

GERMAN / 29SVgSSS. PATENT OFFICE

KL. 12 ο 25/05

INTERNAT. Tbsp. C 07 C EDITORIAL EDITORIAL 1093 794

C17934IVb / 12o

REGISTRATION DATE: NOVEMBER 26, 1958

NOTICE
THE REGISTRATION
AND ISSUE DEK
LEGEND: DECEMBER 1, 1960

Among the 18-oxygenated steroids, particularly possesses the hormone aldosterone, which is isolated from the adrenal glands, because of its specific effect on mineral metabolism outstanding meaning. But since on the one hand the amounts occurring in animal organs for a economic production of the hormone are too low and on the other hand it was not previously possible to use aldosterone To prepare partially synthetically from other, naturally occurring steroids, indicates the total synthetic production great technical interest.

A new process has now been found by which it is possible to obtain aldosterone and its derivatives in a simple manner from a Δ ⁴ > ¹⁸ -3,16-dioxo- 1β, 18a-oxido-18a-methyl-18-homo-androstened formula

or to build up a corresponding 3-ketal, which can also have a further double bond in the 14 (15) position.

The new process can be divided into four main parts:

A) Degradation of the cyclic enol ether grouping on ring C to the 18,11-cyclohemiacetal structure typical of aldosterone.

B) Condensation with an oxalic acid ester in the 17-position and preparation of derivatives for protecting the 20-oxo group.

ίο

Method of manufacture

of those saturated in the 16,17-position

or unsaturated 20-oxopregnan-

21-acids and their derivatives

Applicant:
CIBA Aktiengesellschaft, Basel (Switzerland)

Representative: Dipl.-Ing. E. Splanemann, patent attorney, Hamburg 36, Neuer Wall 10

Claimed priority:

Switzerland of December 5, 1957, May 8, June 13 and October 29, 1958

Dr. Albert Wettstein, Dr. Karl Heusler, Basel,

Dr. Hellmut Ueberwasser, Riehen,

and Dr. Peter Wieland, Basel (Switzerland),

has been named as the inventor

3o

C) Hydrogenation of the 14 (15) double bond and elimination of the oxygen function in position 16.

D) Conversion of the side chain into the ketol side chain of aldosterone.

An embodiment of the synthesis is compiled in the following equation:

Part A.

H ₂ O ₂
NaOH

AcO CHO

NaJO ₄

Pyridine
Trace OsO ₄

II

009 650/438

Ό O

, —Ο

H ₉ -Pd

OH

VI

[Al ₂ O ₃

^x o ^y

Ο -

TeUB:

VII

NaH _Y (COOCH ₃ ) ₂

0 COOCH ₃ CO

0 '0

HN

; ο

Part C:

VIII

O COOCH,

III

OH

O Ο -

O CON _x CO

Ac ₂ O-pyridine

IX

\ ) - O COOH

Esterification

, 0.

IV

O O

O CON

- OAc

, 0

XIII

Pd-H ₉

J-O CON

OAc

OH

XI

γ XIV

H ₂ , Pd

/ y4

XIII

_x y-0 COOCB

XIV

0 CH ₈ OH

CHOH

XV

HO CH ₂ OAc

Aldosterone monoacetate

⁰ XVII

The present patent relates to part C of the synthesis described above, namely the hydrogenation of the 14 (15) double bond and removal of the 16-oxo group. , _

The procedure consists in that in a compound of the formula

COR'O-X

—OAcyl

45

wherein R is a ketalized oxo group, R 'is an alkoxy or preferably a substituted amino group, e.g. B. a morpholino group, and X the remainder

CH ₃ Y

C ^ or -CH

CH

55

60

means, where Y stands for a protected, in particular an etherified hydroxyl group which catalytically hydrogenates the 14 (15) double bond in a known manner, simultaneously or subsequently reduces the 16-oxo group in a known manner to the hydroxyl group, this by the action of alkaline agents with simultaneous cleavage of the 20-acyl group and formation of a <d ¹⁶ -20-ketone removed in a known manner, optionally a 21-acid derivative saponified to the free 21-acid and a free 21-acid group, if desired, esterified by known methods.

The catalytic hydrogenation of the 14 (15) double bond is advantageously carried out in the presence of a palladium catalyst z. B. with palladium on calcium carbonate, barium sulfate, zinc carbonate or on animal charcoal, in strongly or weakly polar solvents, e.g. B. in methanol, ethanol, ethyl acetate, dimethylformamide or mixtures thereof. The hydrogen uptake takes place at room temperature and normal pressure, however, higher temperatures and excess pressure can also be used to accelerate the reaction. When using palladium catalysts, the double bond in the 5 (6) position is on the carrier substances mentioned practically not attacked. In contrast, the hydrogenation usually remains after the absorption for saturation the amount of hydrogen calculated from the 14 (15) double bond is not present. Surprisingly, the unsaturated grouping to which hydrogen is added after the 14 (15) double bond is saturated the 17 (20) -enol double bond, but the 16-oxo group, which can also be reduced to the hydroxyl group with the above-mentioned catalysts. In the case of the 21-acid esters, however, the 17 (20) -enol double bond is also partially attacked. However, it has now been found that, surprisingly, this can largely be avoided if one instead of the 21-acid ester the corresponding 21-acid amide hydrogenated. In these is the 17 (20) -enol double bond deactivated to such an extent that it can no longer be hydrogenated in the presence of the palladium catalysts mentioned.

Since the hydrogenation of the 16-oxo group is slow, it is often advantageous to interrupt the catalytic hydrogenation after the uptake of 1.2 to 1.5 molar equivalents of hydrogen and the reduction of the 16-oxo

7 8

group to end bonds with the help of a complex metal hydride. Racemates can be carried out in a manner known per se respectively. Sodium borohydride, which is split into optically active compounds, is particularly suitable for this purpose. which is used in such amounts that the starting materials for the present patent become

20-acyloxy group is not saponified. The hydride reduction, for example, as described in the patent application C17926VIb / 12o, can be obtained in the anhydrous or also advantageously 5 by being carried out in the 16 (17) position in an aqueous medium, for example in saturated or unsaturated Zl ^{6 '14} -16-oxo-androstadiene -Pyridine, methanol, dioxane or tetrahydrofuran. compounds of the formula

If the hydrogenation has not been completed, then ' q X

it succeeds from the crude hydrogenation product after saponification of the 20-acyloxy group in the 14 (15) position io to isolate saturated 16,20-dioxo-pregnane-21-acid amide.

The transfer of the resulting from the hydrogenation

Δ ¹⁷ -16-hydroxy-20-acetoxy-compounds in ^Δ 1β -20-Οχο- Α

Compounds takes place under the action of alkaline 15 ^

Middle. When using alkali metal hydroxides · "·

or carbonates in an aqueous medium, e.g. B. in aqueous where R and X have the meanings mentioned, with a dioxane, tetrahydrofuran or tert. Butanol, the same oxalic acid dialkyl ester is condensed, if necessary the early saponification of the 20-acyloxy group and the 21-ester obtained are reacted with an amine and then the 16-hydroxyl group is split off the 21-acid ester-20 an enolic hydroxyl group of the condensation or. 21-acid amide group saponified, and the product obtained 21-acid ester or the corresponding / l ^ie -20-oxopregnene-21-acids. But it is also possible to esterify the acid amide.

the 16-hydroxy and the 20-acyl groups with retention The invention is illustrated in the examples below

split off the 21-acid amide group. This succeeds over-described. The temperatures are surprisingly easily given in degrees Celsius by treating the ^ I ¹⁷ -16-hydroxy-35.

20-acyloxy-21-acid amide with aluminum oxide at -p,. ■ \ \

elevated temperature in an inert solvent, such as "

Benzene, toluene, etc. But it is also possible through 500 mg d, I- ^ ⁶ > ^{14 '17} > ¹⁸ -3-ethylenedioxy-ll / ?, 18a-oxido-

Treatment with an amine, in particular with the amine contained in the lo-oxo-lSa-methyl ^ O-acetoxy-lS-homo-pregnatetraeneamide group, the enol acetate group 30, 21-methyl ester are ^{selective in 125 cm 3 of} methanol by aminolysis split off. It is sufficient to add 250 mg of 10% PaUadium-Calciumcardas amid-enolacetat with the amine, preferably in a bonat catalyst in a hydrogen atmosphere in the presence of an inert anhydrous or water-agitated. After about 2 hours, the amount of gas calculated for 2 molar equivalents of solvent, such as benzene, toluene, dioxane, has been taken up. Tetrahydrofuran, etc., are stopped heating. In the obtained 35 the hydrogenation, separates from the catalyst and evaporates. Δ ¹⁶ -20-Oxo-pregnen-21-acid amides can before or after the solution in a water jet vacuum to dryness. Hydrogenation of the 16 (17) double bond of the acid amide By crystallizing the residue from the methanol group, as indicated above, in an aqueous medium with ether, 109 mg of the d, kd ^{5 are obtained} . ¹⁷ - ¹⁸ -3-ethylene can be saponified with the aid of alkaline agents. dioxy-llß.lSa-oxido-lo-hydroxy-lSa-methyl ^ O-acetoxy-

The esterification of the 40 lS-homo-M / S-pregnatriene-l-acid methyl ester, which is saturated in the 16 (17) position, or unsaturated 20-oxo-pregnene-21-acids takes place after recrystallization from acetone-ether or from after methods known per se. Diazomethane is used for methanol melting at 201 to 203 °. UV spectrum: the esterification is not particularly suitable, since both the maximum at 228 ΐημ (ε = 11 600). IR spectrum in 16 (17) double bond and especially the 20-oxo-CH ₂ Cl ₂ : 2.84 μ (hydroxyl); 5.67 µ (enol acetate); 5.94 µ group in the compounds of the present invention 45 (dihydropyran); 6.05 μ (Enol) and 9.05 μ to 9.10 μ easily add diazomethane. Isolation of the in (Ketal).

16 (17) position of saturated 20-oxopregnane-21-acid ester The mother liquor, which on the basis of the UV spectrum

only with a very short exposure to diazomethane (ε ₂₂₉ = 8300) can another amount of the above be achieved at low temperature. The esterification also succeeds, the 16-hydroxy compound is obtained on 12 g of aluminum if chromatography is carried out on an alkali salt of the acid dimethyl sulfate 50 oxide (activity II). Leave the first or methyl iodide to act. It is particularly simple, with a total of 180 cm ^{3 of} benzene eluted fractions, the acid in an anhydrous medium with methyl iodide is obtained by crystallization from ether-hexane or without a diluent in the presence of over 106 mg of crystals, which after further recrystallization of excess, anhydrous potassium carbonate to esterify. from methanol the d, l- / I ⁵ ' ¹⁷ ' ¹⁸ -3-ethylenedioxy-llß, 18a-Die in the individual stages of the present process 55 oxido-16-oxo-18a-methyl-18-homo-14 /? -pregnatrienverfahren used reactions are in the 21-acid methyl ester in yellow prisms from the enamel trap of 18-unsubstituted pregnane derivatives from the point 181 to 185 °.

Already known from literature (cf. for example Journ. Amer. UV spectrum in fine spirits: maximum at 240 ηιμ

Chem. Soc, Vol. 76, 1954, p. 2943; Journ. Biol. Chem., (Ε = 6660). IR spectrum in CH ₂ Cl ₂ : between 5.75 µ Vol. 213, 1955, p. 343, and Journ. Amer. Chem. Soc, 60 and 6.25 μ bands at 5.78 μ (with inflection at 5.85 μ), Vol. 78, 1956, pp. 1738 ff.) 5.94 μ, 6.03 μ and 6, 24 µ.

The present invention, which in the transfer from the first subsequent, with benzene-ethyl acetate-

of these known methods on the new fraction eluted as the starting (1: 1) mixture is still recovered substances used consists of 18-oxygenated steroids, another 50 mg of the 16-Hydroxystellt described above a new possibility for the synthetic connection from the melting point 201 to 203 °. establishing various important connections with

Oxygen in the 18-position, such as. B. Aldosterone and its example 2

Derivatives.

In the compounds which can be prepared _{according to the process, 23.03 gd, l- <} d ^s ' ¹⁴ ' ¹⁷ > ¹⁸ -3-ethylenedioxy-11j8,18a-oxido-

it is a matter of racemates or optically active compounds.

ι uys / y4

9 10

21-acid morpholide are in 750 cm ^{3 of} dimethylform Beismel 4

amide by addition of 7.5 g of 10 ° / ₀ palladium-

Calcium carbonate catalyst at room temperature hy- A solution of 25.41 gd, l- / l ^{B '17} > ¹⁸ -3-ethylenedioxy-

dries. After about 6 ¹ Z ₂ hours, the 2 molar equivalents of 1 l ^, 18a - oxido -16 - hydroxy - 18a - methyl - 20 - acetoxy added calculated amount of hydrogen. 5 IS-homo-Hß-pregnatrien ^ l-acid morpholide in 2.5 l is separated from the catalyst by filtration, washed with benzene, with 125 g of alkaline aluminum oxide, dimethylformamide, and the filtrate is stirred under reflux for 6 hours. It is then cooled, 1.5 mg of Hg and a bath temperature of 50 to 60 ° to dryness, suctioned off from the aluminum oxide and washed with chloroein. ^{From the residue, 20.44 g of the pure io are recovered from about 50 cm 3 of} methanol by crystalline form, chloroform-methanol (1: 1) mixture and methanol, and the filtrate is evaporated in a water-jet vacuum d, l- / l ^{5>17> 18} -3-ethylenedioxy-llj (3,18a-oxido-16-hydroxy- to dryness. When treated with a little ether, 18a-methyl-20-acetoxy-18-homo-14 /? - pregnatriene crystallizes the residue almost completely. By 21-acid morpholids. A sample recrystallized again from methanol from methylene chloride-methanol recrystallized melts at 236 to 238 ° (in vacuo, 20.62 g of pure d, lJ ⁵ ' ^le ' ¹⁸ -3-ethylenedioxy-II / 3.18a-decomposition). 15 oxido-18a-methyl-20-oxo ~ 18-homo-14 / J-pregnatriene-

No absorption maximum above 210 ηιμ, strong 21-acid morpholide with a melting point of 203 to 207 °. Final absorption. IR spectrum in CH ₂ Cl ₂ : 2.93 μ (hydro- A sample crystallized again from methanol melts xyl); 5.67 µ (enol acetate); 5.96 μ (dihydropyran) and at 208 to 210 ° (in a vacuum). 6.15 µ (amide + enol). UV spectrum: maximum at 249 πιμ (ε = 7400).

If 400 mg of the above Δ ¹⁴ -16-keto-morpho-20 IR spectrum are hydrogenated in CH ₂ Cl ₂ : between 5.75 μ and 6.50 μ lids in 100 cm ^{3 of} ethyl acetate in the presence of 400 mg of bands at 5, 99 µ, 6.07 µ and 6.26 µ. 10 ° / ₀ palladium-calcium carbonate catalyst until it is obtained by hydrogenation in Essigester

to cease hydrogen uptake, 16-oxymorpholide is obtained with aluminum as indicated above Crystallization of the evaporation residue treated from oxide, a crude product is obtained from Methanol 362 mg of the above-described 16-hydroxy-25 which by chromatography on aluminum oxide compound from melting point 236 to 238 °. in addition to the one with benzene and benzene-ether (1: 1) mixture

80 mg of the 16-hydroxy compound described above, Δ ¹⁶ -20-ketone eluted a small amount of acetone which could be removed for 2 days in a mixture of 1.0 cm ^{3 of} pyridine ethyl acetate, after recrystallization from 1.0 cm ^{3 of} acetic anhydride at room temperature —Ether and methanol stored melted at 225 to 227 °. The usual work-up gives 96 mg of the compound can be obtained. In the crude product, from which substance crystallizes from fine needles, acetone and methanol are likely to be the d, l- / J ⁵ - ¹⁷ > ¹⁸ -3 ~ ethylenedioxy- around the d, l-zl ^{6 '18} -3- Ethylenedioxy-ll _j 8,18a-oxido-16-oxoll / ?, 18a-oxido-16,20-diacetoxy-18a-methyl-18-homo-14 ^ - 18a-methyl-18-homo-14 /? - pregnadiene -21-acid-morpholide pregnatrien-21-acid-morpholide act with melting point 249,
up to 251 ° (in vacuum, decomposition) is obtained. 35 5.00 g raw d, lJ ⁵ . ¹⁶ > ¹⁸ -3-ethylenedioxy-II / 3,18a-oxido-

No maximum in UV over 210 πιμ. lSa-methyl ^ O-oxo-lS-homo-M ^ -pregnatrien ^ l-acid-

IR spectrum in CH ₂ Cl ₂ : no hydroxyl band; Morpholide are dissolved in 100 cm ^{3 of} glacial acetic acid and after between 5.5 μ and 6.25 μ bands at 5.74 μ (with the addition of 50 cm ^{3 of} water for 30 minutes at 100 ° with inflection at 5.69 μ), 5, 95 µ and 6.08 µ. Nitrogen held. Then it is allowed to cool, poured on

. . 40 200 cm ^{3 of} ice water and extracted several times with methylene

Example ά chloride. The extracts are made with sodium hydrogen

If the hydrogenation of the d, l-zl ⁵ ' ¹⁴ ' ^{17 '18} -3-ethylene carbonate solution is washed neutral, dried and evaporated into dioxy-II / J.lSa-oxido-lo-oxo-lSa-methyl-O-acetoxy. By crystallization of the residue from 18-homo-pregnatetraen-21-acid morpholids, as in the case of methanol-ether, 3.72 g of the d, l-Zl ^{4 '16} > ¹⁸ -spiel2 described, with palladium-calcium carbonate 45 S ^ O-Dioxo-ll / S.lSa-oxido-lSa-methyl-lS-homo-pregna catalyst in ethyl acetate through, but only up to the trien-21-acid morpholids. An uptake of 2 molar equivalents of hydrogen from benzene-ether contains the crystallized sample melts at 193 ° to 197 ° (decomposition), the crude product in addition to the 14 (15) -saturation. The crystals contain 1 mol of water of crystallization. 16-Hydroxy compound also has some amount of the IR spectrum in CH ₂ Cl ₂ : between 5.75 μ and 6.50 μ

corresponding 16-oxo compound. These two substances 50 bands at 5.99 μ, 6.07 μ (both intense) and 6.27 μ. cannot be separated from each other by crystallization

separate. When treating the crude product with Example 5

The 16-oxo compound, however, becomes alumina much

more strongly adsorbed on aluminum oxide than that from the A solution of 1.623 gd, l-Zl ⁵ ' ¹⁶ ' ¹⁸ -3-ethylenedioxy-

16-Hydroxy compound resulting zl ^ie -20-Oxo-21-mor-55 ll ^, 18a-oxido-18a-methyl-20-oxo-18-homo-14/3-pregnapholide. Conversely, the 16-oxotriene-21-acid morpholide in 200 cm ^{3 of} ethyl acetate can be separated off after connection if you proceed as follows: Addition of 400 mg of 10% palladium-calcium car-

100 mg of crude hydrogenation ^{product, dissolved in 2.0 cm 3 of} carbonate catalyst, hydrogenated at room temperature. After tetrahydrofuran, the amount of water-1 η-sodium hydroxide solution calculated for 1 mol equivalent is taken up under nitrogen at 80 ° 60 for 12 hours ^{with 6 cm 3 of} water and 2.0 cm ^{3 for 1 hour, and the hydrogenation is heated.} The usual work-up and separation in acidic to a halt. The catalyst is filtered off with suction and washed, and 54 mg of acids are obtained. From this afterwards with ethyl acetate and the filtrate is evaporated in the water separating itself on crystallization from methanol 14 mg jet vacuum to dryness. From the residue of d, LJ ^{5 '18} -3-ethylenedioxy-ll / ?, 18a-oxido-16,20-dioxo- is obtained by crystallization from methanol an LSA-methyl-lS-homo-Hss-pregnadiene ^ l- acid morpholids 6g first fraction of 1.104 g of hydrogenation product from which, after repeated crystallization from Me- melting point 142 to 145 °, which the two in 17-thanol ether at 181 to 183 ° (with decomposition), epimerizes d, l- <d ⁵ > ¹⁸ -3-ethylenedioxy-II / S, 18a-oxide melts. lSa-methyl ^ O-oxo-lS-homo-Mje-pregnadien ^ l-acid-

UV spectrum: neutral: maximum at 280 mμ contains morpholide. The mother liquor of the above crystal (ε = 6700), alkaline: maximum at 312 πιμ (ε = 9900). 7o sation is evaporated to dryness and at 15 g

11 12

Chromatographed aluminum oxide (activity II). The mother liquor is evaporated to dryness and

the with benzene-hexane (1: 1) mixture and with benzene the residue (520 mg) dissolved in benzene-hexane (1: 1)

eluted fractions can be chromatographed by crystallization from 15 g of aluminum oxide (activity II).

Methanol a further 227 mg of the above mixture of epimers From the first fraction (100 cm ^{3 of} benzene-hexane [1: I])

to be isolated. A separation does not succeed here either; 80 mg of the above ester are still obtained. In the

although individual fractions have melting points up to 183 to following, with the same mixture and with pure

Show 186 °. Benzene-eluted fractions are obtained by crystalline

UV spectrum: no maximum above 210 ηιμ. sation from ether 45 mg of that which melts at 197 to 200 °

IR spectrum in CH ₂ Cl ₂ : 5.85 µ (20-ketone), 5.96 µ d, lJ ⁵ . ¹⁸ -3-ethylenedioxy-II / 3.18a; 20.22-bis-oxido-18a-

(Dihydropyran) and 6.08 µ (amide). ίο methyl-lS-homo-Wß-bisnorcholadien- ^ l-acid-methyl-

A solution of 1.50 g d, l-zl ^5-18 -3-Äthylendioxy- ester.

ll / ^ lSa-oxido-lSa-methyl - ^ - oxo-lS-homo-Hß-pregna- IR spectrum in CH ₂ Cl ₂ : 5.72 μ (ester), 5.96 μ diene-21-acid- Morpholide in 30 cm ^{3 of} glacial acetic acid is (dihydropyran) and 9.10 μ (ketal).
15 cm ^{3 of} water are added and the 20-oxo-21-acid methyl ester described above is heated to 100 ° for 30 minutes under nitrogen. It is then poured into ice water, extracted from the crystalline. Keto acid also as follows with methylene chloride and washes the extracts several times: 223 mg of acid are dissolved in 5.0 cm ^{3 of} 0.1 η methanol with water. The residue of the dried methylene potassium hydroxide solution dissolved. The solution is evaporated to dryness in a water jet chloride solution (1.46 g) when rubbed under vacuum and ether 1.07 gd, l-, 4 ^{4 '18} -3,20-Dioxo-ll / ?, l8a-oxido- 18a- dehydrated with benzene. The amorphous potassium methyl-18-homo-14 /? - pregnadiene-21-acid morpholide obtained. 20 salt is in 7.0 cm ³ abs. Benzene dissolved. Then the mixture is stirred. A sample crystallized from acetone-ether melts after the addition of 0.2 cm ^{3 of} dimethyl sulfate overnight at 139 ° to 141 °. Room temperature, diluted with benzene and washed with

Maximum at 240 ΐημ (ε = 16 500). dilute sodium hydrogen carbonate solution and with

IR spectrum in CH ₂ Cl ₂ : 5.86 μ (20-ketone), 5.98 μ water and extracted with benzene-ether (1: 1) mixture

(3-ketone -f- dihydropyran) and 6.09 µ (amide + Δ *). 25 after. From the residue of the combined, dried

A solution of 8.41 gd, 1-Zl ⁸ > ¹⁸ -3-ethylenedioxy-organic solutions is obtained by crystallization

ll / ^ lSa-oxido-lSa-methyl ^ O-oxo-lS-homo-Wß-pregna- from ether — hexane 127 mg d, lz! ⁵ > ¹⁸ -3-ethylenedioxy-

diene-21-acid morpholide in 100 cm ^{3 of} dioxane is given ll / USa-oxido-lSa-methyl ^ O-oxo-lS-homo-M / J-pregna-

40 cm ^{3 of} water and 80 cm ^{3 of} 1 η-sodium hydroxide solution and heated diene-21-acid methyl ester, which after repeated

12 hours under nitrogen at 60 °. Then 30 recrystallization from ether is allowed to melt at 157.5 to 160 °,

cool, diluted with water and extracted several times A solution of 400 mg d, l-zJ ⁵ > ¹⁸ -3-ethylenedioxy-

with a benzene-ether (1: 1) mixture. From the with llß.lSa-oxido-lSa-methyl ^ O-oxo-IS-homo-M / J-pregna-

Extracts washed with water are obtained from the monodiene-21-acid methyl ester in 8 cm ^{3 of} glacial acetic acid and 4 cm ³

evaporate 215 mg of crystallized neutral part. The water is heated to 100 ° for 30 minutes. then

Some aqueous solutions are crystallized with 50 g. 35 is poured into 50 cm ^{3 of} ice water and extracted several times

Sodium sulphate and 20 g potassium dihydrogen phosphate combined with ether. From the neutral washed extracts

and once with chloroform-alcohol (3: 1) mixture, 322 mg of a crystallized residue are obtained,

then extracted three more times with chloroform. After recrystallization from methanol, the melts

the resulting emulsions by suctioning pure d, l- / J ⁴ < ¹⁸ -3,20-Dioxo-II / 3,18a-oxido-l8a-methyl-18-

separated by sintered glass suction cups. 40 homo-14 /? - pregnadiene-21-acid methyl esters are obtained at 182 bis

from the organic extracts a total of 7.51 g of acidic 185 °.

Part from which by crystallization from aqueous absorption maximum at 239 ΐημ (ε = 17 700).

Methanol 4.83 g crystallized d, l-Zl ⁶ . ¹⁸ -3-ethylenedioxy IR spectrum in CH ₂ Cl ₂ : 5.75 μ (ester), 5.80 μ (20-Ke-

II / 9.18a-oxido-18a-methyl-20-oxo-18-homo-14 ^ -pregnatone), 5.98 µ (3-ketone + dihydropyran) and 6.17 µ (Zl ⁴ ).

diene-21-acid can be isolated. That from aqueous methanol 45. . _

Example 7 deposited in fine needles with 1 mol of water of crystallization

Product melts at 128 to 133 ° (decomposition). 100 mg of the d, l-zl ⁵ . ^{14th 17} -3-ethylenedioxy-II / 3,18-oxido-

IR spectrum in CH ₂ Cl ₂ : 2.69 µ + 6.21 µ (water); lo-oxo-IS-tetrahydropyranyloxy ^ O-acetoxy-pregnatriene-

2.92 µ (hydroxyl); 5.61 μ + 5.82 μ (keto acid) and 21-acid methyl ester are added in 25.0 cm ^{3 of} ethyl acetate

5.95 µ (dihydropyran). 50 Addition of 100 mg of 10% palladium calcium carbonate

Hydrogenated catalyst. After uptake of about 2 mol of hydrogen equivalent to Example 6, the hydrogenation is interrupted (8 hours) and the solution from the catalyst

A solution cooled to 0 ° of 1.55 g crude separated. One wins from the evaporation residue

d, l - Δ ⁵ · ¹⁸ - 3 - ethylenedioxy -1 Iß, 18a - oxido - 18a - methyl - 55 by crystallization from methylene chloride - ether 30 mg

20-oxo-18-homo-14 ^ -pregnadiene-21-acid (obtained from des d, l-Zl ^{5 '17} -3-ethylenedioxy-ll / ?, 18-oxido-16-oxo-18-te-

1.63 g of crystallized morpholide as stated above) in trahydropyranyloxy ^ O-acetoxy-pregnadiene ^ l-acid-me-

a mixture of 15 cm ^{3 of} methanol and 60 cm ^{3 of} ether ethyl ester, which after repeated recrystallization

is mixed with ethereal diazomethane solution, and melts at 234 to 237 °.

after 10 minutes, the excess methylation 60 UV spectrum: maximum at 260 mμ (ε = 7200).
medium destroyed by adding a little glacial acetic acid. Then by reduction with sodium borohydride, as described in the dilution with ether, washing with dilute sodium game 10, the corresponding hydrogen carbonate solution and water are obtained and the 16-hydroxy compound is evaporated, which lent the dried ether solution during saponification. From the residue described in Example 10 / I ¹⁶ gives -20-oxo-21-acid. (1.58 g) is obtained by crystallization from methanol 65

990 mg of the d, l-z1M ⁸ -3-ethylenedioxy-11j8,18a-oxido-18a Example 8

methyl ^ -oxo-lS-homo-H / S-pregnadien ^ l-acid methyl- 64 mg d, l- / | ^s ' ¹⁴ > ¹⁷ ( ²⁰ ) -3-ethylenedioxy-II / U8-oxido-

esters with a melting point of 157 to 160 °. lo-oxo-IS-tetrahydropyranyloxy ^ O-acetoxy-pregnatriene-

IR spectrum in CH ₂ Cl ₂ : 5.74 μ (ester), 5.79 μ of 21-acid morpholide are dissolved in 25 cm ^{3 of} ethyl acetate

(20-ketone), 5.95 µ (dihydropyran) and 9.10 µ (ketal). 70 and after adding 100 mg of 10% palladium-carbon

The catalyst was stirred for 10 hours under hydrogen at 23 ° to 26 ° pyranyloxy-20-acetoxy-pregnadiene-21-acid morpholids and a pressure of 743 mg Hg. About 10.7 cm ³ are dissolved in 15 cm ^{3 of} dioxane, and 1.0 N Na hydrogen is taken up in ^{10.0 cm 3 (of which about 5 cm 3 are added} with tron lye and 5.0 cm ^{3 of} water and added to the molten mass -Catalyst and solvent are absorbed). The tube is heated at 80 ° for 12 hours. Then it is suctioned off, the catalyst washes with methylene chloride 5 100 cm ^{3 of} water, the alkaline solution with well and the filtrate is extracted in water jet ether, then vacuum to dryness with ice cooling and stirring. The residue (68 mg), ^{acidified with 11.75 cm 3} 1 η-hydrochloric acid and immediately which crystallizes when moistened with ether, then extracted several times with methylene chloride, shows a strong absorption maximum at 221 ΐημ (ε = 10800). The methylene chloride extracts are washed with saturated Dasreined, l- ^ ^{5 '17 (20)} -3-ethylenedioxy-ll / ?, 18-oxido-16-hy- io saline solution, combined, dried and in the droxy-lS-tetrahydropyranyloxy ^ O- acetoxy-pregnadiene-water jet vacuum evaporated to dryness. 21-acid morpholide is crystallized from ether in needles, and 470 mg of the α, β-unsaturated keto acid is obtained as a light color with a melting point of 222 to 225 °. yellow foam.

UV spectrum: maximum at 221 ΐημ (ε = 11900). This is dissolved in 10 cm ^{3 of} methyl iodide and the

IR spectrum in CH ₂ Cl ₂ : 2.94 μ (hydroxyl), 5.66 μis solution after adding 1.0 g of powdered, calcined (enol acetate) and 6.15 μ (amide + enol). Potassium carbonate 12 hours under exclusion of water on

Refluxed. Then it is diluted with benzene, Example 9, the solution of, which is clouded by potassium iodide, is decanted

2.00 gd, l-Zl ⁵ ' ¹⁴ ' ^{17 (20)} -3-ethylenedioxy-ll / ?, 18-oxido-solid potassium carbonate and washes well with benzene lo-oxo-IS-tetrahydropyranyloxy ^ O-acetoxy-pregnatriene - 20 after. The organic solution is first mixed with water, 21-acid morpholide is added in 400 cm ^{3 of} ethyl acetate suspension, then some hydrogen carbonate is added, then suspended and, after adding 3.5 g of 10% palladium-diluted saline solution, washed, dried and calcium carbonate -Catalyst evaporated for 30 hours at 25 ° and in a water jet vacuum. The residue 738 mm Hg pressure in a hydrogen atmosphere (370 mg) shows a clear absorption stirring at 251 ΐημ. Then, as described in example 8, the maximum is 25 (ε = 5050). Worked by crystallization from metha. The crude product contains, as can be obtained from the nol, a first crystallization of 167 mg absorption band at 5.81 μ can be closed, d, lJ ⁵ . ¹⁶ -3-Ethylenedioxy-II / ?, 18-oxido-18-tetrahydron and some unreduced 16-ketone. By pyranyloxy-20-oxo-pregnadiene-21-acid methyl ester from crystallization from ether, 1.094 g of crystalline melting point 182 to 185 ° are obtained.
ized mixture with a melting point of 197 ° to 214 °. 30 UV spectrum: maximum at 252 ΐημ (ε = 6200).

100 mg of this mixture of 16-oxo and 16-hydroxy IR spectrum in CH ₂ Cl ₂ : 5.74 μ (ester), 5.94 μ + 6.30 μ

compound are in 25 cm ³ ethyl acetate after addition (zl ^le -20-ketone) and 9.19 μ (ketal),
100 mg of 10 ° / ₀ palladium-carbon catalyst. . ^ ₁₁

hydrogenated again to less than 0.1 cm ³ per hour example

Hydrogen is absorbed. From the conventional 35 100 mg of crude hydrogenation product (prepared as described in the crude product obtained in Example 9), which in addition to the 16-hydroxy crystallization from ether, 75 mg of the in Example 8 also about 30 to 40% 16 Keto compound, wrote pure d, l- / I ⁵ ' ¹ ' ( ²⁰⁾ -3-ethylenedioxy-ll ₍ ö, 18- are dissolved in 20 cm ^{3 of} absolute benzene and treated with 2.0 g of basioxido-lo-hydroxy -IS-tetrahydropyranyloxy ^ O-acetoxychem aluminum oxide (activity II) stirred for 4 hours under pregnadiene-21-acid morpholide with a melting point of 222 40 nitrogen and exclusion of water at a bath temperature of up to 225 °

The filter residue contained in the above crystallized mixture was repeatedly added to the filter residue with benzene and Part of 16-ketone can also be reduced as follows: evaporate the filtrate to dryness in a water jet vacuum

430 mg of the above crystallized mixture of a. The residue (34 mg) is recrystallized from ether, melting point 197 ° to 214 °, in 17.2 cm ^{3 of} tetra- 45. One obtains the d, l- ^ ⁵ . ¹⁶ -3-ethylenedioxy-II / 9,18-oxhydrofuran dissolved, with 0.172 cm ^{3 of} a morpholide freshly prepared from 115 mg of ido-IS-tetrahydropyranyloxy ^ O-oxo-pregnadiene ^ l-acid sodium borohydride and 2.00 cm ^{3 of water} from melting point 182 to 185 °.
Solution is added, and the solution is 3 hours at UV spectrum: maximum at 250 πιμ (ε = 7600).

Let stand 20 to 25 °. It is then acidified with 0.3 cm ^{3 of the} IR spectrum in CH ₂ Cl ₂ : 5.96 μ (20 ketones), 6.06 μ

a mixture of 4.5 cm ³ water and 0.5 cm ³ ice 50 (amide), 6.28 μ (Α ^1β ) and 9.16 μ (ketal),
vinegar, extracted several times with methylene chloride and by saponification and esterification, as in Example 10

washes the extracts twice with water. The combined indicated, the corresponding extracts are obtained in good yield are dried, the 21-acid methyl ester with a melting point of 182 bis in a water jet vacuum evaporated, and the residue becomes crystalline from ether 185 °.

sated. 308 mg of pure d, Wl ^{6 '17} ( ²⁰ ) -3-ethylene- 55 Example 12 are obtained

dioxy-ll / J.lS-oxido-lö-hydroxy-lS-tetrahydropyranyloxy-

20-acetoxy-pregnadiene-21-acid-morpholide from the enamel- 100 mg crystallized, crude hydrogenation product (her-

point 222 to 225 °. placed, as described in Example 9), which next to

The same product is also obtained in the completely analogous to the 16-hydroxy compound also contains 30 to 40% 16-oxo-carried out sodium borohydride reduction of a compound at 60, are dissolved in 2.5 cm ^{3 of} dioxane, 192 to 204 ° melting hydrogenation product, which with 2.5 cm ^{3 of} 30% aqueous ammonium hydroxide based on the IR spectrum and the UV absorption and left to stand overnight at room temperature maximum (ε _270πυΐ = 5800) of almost pure d, l-zl ⁵ > ¹⁷ ( ²⁰ > -. Then if one evaporates in a water-jet vacuum to S-ethylenedioxy-II / ^ lS-oxido-lo-oxo-lS-tetrahydropyra dryness, the residue is taken up in methylene chloride nyloxy ^ O-acetoxy-pregnadiene ^ l-acid morpholide and extracted several times with dilute sodium, hydrogen carbonate solution. 47 mg are obtained from the alkaline extracts acidified with dilute phosphoric acid by extraction with methylene chloride

500 mg of the dl-Zl ⁶ * ¹⁷ * ²⁰ ) described in Example 9 - acidic components. S-ethylenedioxy-llß.1ß-oxido-lo-hydroxy-IS-tetrahydro-7o the ά, Ι-Α ⁵ -3-ethylenedioxy-l / US crystallizes from aqueous methanol

15 16

tetrahydropyranyloxy-pregnen-21-acid morphoIid in Example 15

Crystals containing water of crystallization with a melting point of 213

up to 214 ° (with decomposition). The compound gives a 200 mg of the d, l-Zl ⁵ · ^{17 '18} - described in Example 2

Wine-red coloring with methanolic ferric chloride solution S-ethylenedioxy-II / J.lSa-oxido-lo-hydroxy-lSa-methyl- and shows an absorption maximum 5 20-acetoxy-18-nomo-14/3-pregnatrien-21-acid in neutral solution Morpholids at 290 ιημ (ε = 7200), in an alkaline solution such are in 5 cm ^{3 of} tetrahydrofuran and 0.5 cm ^{3 of} water at 310 πιμ (ε = 12,800). dissolved and after adding 0.5 cm ^{3 of} morpholine for 3 hours

IR spectrum in CH ₂ Cl ₂ : refluxed between 5.75 and 6.25 μ at a bath temperature of 80 °. Then bands at 5.94 and 6.12 µ. it is diluted with methylene chloride and washed several times

ίο with water. From the residue of the dried

Example 13 Methylene chloride solution (182 mg; UV absorption at

245 ΐημ: ε = 4500) is obtained by crystallization from

1.5 gd, I-zl ⁵ > ¹⁷ - ¹⁸ -3-ethylenedioxy-ll / 9,18a-oxido-18a ether 110 mg of the pure dJ - ^. ^^ - S-ethylenedioxymethyl-lo-hydroxy ^ O- acetoxy-IS-homo-H / S-pregnatrienll ^, 18a-oxido-18a-methyl-20-oxo-18-homo-14jÖ-pregna-21-acid-morpholide are dissolved in 50 cm ^{3 of} dioxane and 15 triene-21 Acid morphoIids from melting point 208 to after the addition of 20 cm ^{3 of} water and 30 cm ^{3 of} 1 n sodium hydroxide 210 °, which is identical to the liquor described in Example 4 binding overnight under nitrogen at room temperature.
touched. Then the mixture is mixed with 120 cm ^{3 of} water

diluted, twice with 150 cm ³ each of benzene-ether- (1: 2) - example 16

Extracted mixture and the extracts with 75 cm ^{3 of} water 20

washed. ^{25 mg of the d, l-Zl s} ' ¹⁷ < ²⁰ > - described in Example 9 are obtained from the organic solutions.

a total of 85 mg of crystallized neutral product. The S-ethylenedioxy-ll ^ lS-oxido-lo-hydroxy-IS-tetrahydro-purified aqueous solutions are ^{underlaid with 200 cm 3 of} pyranyloxy-20-acetoxy-pregnadiene-21-acid morpholids methylene chloride and, while stirring, are in 0.5 cm dissolved ³ of absolute toluene and brought to 1 η-hydrochloric acid to a p _H of about 4 hours. Then 0.05 cm ^{3 of} morpholine is added for 4 hours at 110 °, the mixture is separated off, and the mixture is extracted a number of times and heated with methylene. Then it is evaporated to the chloride in a water jet vacuum and the extracts are washed with semi-saturated dryness. The residue shows a saline solution at 247 m μ. The combined, dried methylene clear absorption maximum (ε = 3300) and contains chloride solutions on evaporation leave 1.390 g about 50% of the d, l-Zl ⁵ · ¹⁶ -crude acid described in Example 11 (absorption maximum at 247 πιμ = 4500). ₃₀ S-ethylenedioxy-llß.lSa-oxido-lS-tetrahydropyranyloxy-This is dissolved in 15 cm ^{3 of} methyl iodide and, after the addition of 20-oxo-pregnadiene-21-acid morpholids from the melting point, 2.6 g of freshly calcined potassium carbonate for 12 hours at 182 to 185 °.
stirred at 60 ° under reflux and with exclusion of moisture.

It is then diluted with 50 cm ^{3 of} methylene chloride, example 17

canted from the salt residue and washes it with 35

Methylene chloride. The d, l- ^ ⁵ > ^{14 '17} < ²⁰ > -3-ethylenedioxy-

Potassium iodide-cloudy organic solution is washed with water Hß.lS-oxido-lo-oxo-IS-tetrahydropyranyloxy ^ O-acet, dried and oxy-pregnatrien-21-acid-morpholide are evaporated ^{in 100 cm 3 in a water jet vacuum.} 861 mg of neutral product remain. Dissolved methylene chloride and evaporated to dryness in vacuo. By crystallization from ether and methanol, _{40 is obtained.} The oily residue is ^{fresh in 300 cm 3} , the pure d, l- / J ⁵ > ¹⁶ . ¹⁸ -3-ethylenedioxy-llß-18a-ox- distilled and with 10% palladium-calciumido-1 Sa-methyl ^ O-oxo-IS-homo-Mß-pregnatriene ^ l-acid carbonate catalyst prehydrogenated dimethylformamide methyl ester in Skewers with a melting point of 176 to 178 °. was added and treated by adding 1.5 g of 10 ° / ₀

UV spectrum: maximum at 253 mμ (ε = 6800). Palladium-carbon catalyst in a hydrogen

IR spectrum: bands at 5.74 μ (ester), 5.96 μ (uns. 45 atmosphere shaken. After 3 hours, that for ketone + dihydro-pyran), 6.28 μ (Λ ¹⁶ ) and 9.10 μ (Ketal). 2 molar equivalents of calculated amount of gas added.

The hydrogenation is interrupted, the cata-

Example 14 lysator by filtration and the solution evaporated

0.1 mm Hg pressure to dry. By crystallization

539 mg of d described in Example 4, l-zl ^{6> 16> 18} - 50 of the residue from ether-hexane is obtained in S-ethylenedioxy-ll ^ LSA-oxido-LSA-methyl ^ O-oxo-IS-HO 2 fractions in total 7.26 gd, lJ ⁶ . ¹⁷ < ² °) -3-Äthylenmo-14 /? - pregnatrien-21-acid morpholids are treated with dioxy-llß.lS-oxido-lo-hydroxy-lä-tetrahydropyranyl-15 cm ³ dioxane, 6 cm ³ water and 2 , 0 cm ³ 1 η-Natron- oxy - 20 - acetoxypregnadien - 21 - acid - morpholide from the lye in an evacuated vessel for 48 hours at room melting point 222 to 225 °.

temperature left to stand. Then it is diluted with 55 250 mg of this compound, 75 cm ^{3 of water are dissolved in 5 cm 3 of} dioxane and extracted twice with 80 cm ³ each time. Then 1.15 cm ^{3 of} water and 1.35 cm ^{3 of} ether-benzene mixture (3: 1) are added. 1. The aqueous solution water jet pump and left for 24 hours at 20 to 25 °, 500 mg of sodium acetate are added and 50 cm ³ are left to stand. Then, while stirring vigorously, the mixture is passed under a layer of methylene chloride. The solution is then acidified with carbon dioxide for 2 hours and the dropwise addition of 1η-hydrochloric acid is evaporated to dryness with stirring, then in a water-jet vacuum. and extracted several times with methylene chloride. The residue is taken up in benzene and 420 mg of the crude I ⁵ > ^{ie are obtained} . ¹⁸ -3-Äthylendioxy- dried again by evaporation. Then one sets II / USa-oxido-ISa-methyl ^ O-oxo-IS-homo-Mjg-pregna-10 cm ³ abs. tert-butanol, 200 mg of freshly calcined trien-21-acid (absorption maximum at 247 πιμ = 4000), 65 potassium carbonate and 2.0 cm ^{3 of} methyl iodide and stirred, which, as described in Example 13, is esterified. with exclusion of moisture for 12 hours in a bath

In a completely analogous manner, one obtains from the in from 60 °. Then one dilutes with methylene play 12 described d, lz! ⁵ > ^ie -3-ethylenedioxy-l 1 / 9,18- chloride and washes several times with ice water, whereby the oxido-IS-tetrahydropyranyloxy ^ O-oxo-pregnadiene ^ l- aqueous solutions again with methylene chloride acid morpholide the corresponding 21- Acid. 70 can be extracted. From the combined dried

Methylene chloride solutions give 203 mg of neutral product, from which, by crystallization from methanol, a total of 140 mg of the d, l-Zl ⁵ ' ^ie -3-ethylenedioxy-H / S.lS-oxido-IS-tetrahydropyranyloxy ^ O-oxopregnadiene-21- Acid methyl ester with a melting point of 182 ° to 185 ° can be obtained, which is identical to the compound described in Example 10.

80 mg of this ester are dissolved in 3 cm ^{3 of} glacial acetic acid with heating and, after the addition of 0.3 cm ^{3 of} water, immersed in an oil bath heated to 100 ° for 5 minutes. It is then poured into water and extracted several times with methylene chloride. The extracts are washed with sodium bicarbonate solution and water, combined, dried and evaporated. From the residue (65 mg), crystallization from acetone-ether gives the III-S-cyclohemiacetal of d, l-Zl ⁴ > ¹⁶ -3,18,20-trioxo-II / S-hydroxy-pregnadiene-21-acid methyl ester with a melting point of 195 to 198 °.

UV spectrum: maximum at 241 πιμ (ε = 19100).

IR spectrum in CH ₂ Cl ₂ : bands at 2.72 μ and 2.85 μ (hydroxyl), 5.72 μ (ester), 5.97 μ (3- and 20-ketone), 6.17 μ ( Zl ⁴ ) and 6.28 μ (Zi ¹⁶ ).

Example 18

167 mg of d, l-Zl ^s > ¹⁶ -3-ethylenedioxy-l l / 9-18-oxido-18-tetrahydropyranyloxy -20-oxo-pregnadiene -21-acid methyl ester are dissolved in 35 cm ^{3 of} freshly distilled ethyl acetate, with 85 mg of 10% potassium calcium carbonate catalyst are added and the mixture is then stirred in a water / substance atmosphere until no more gas uptake is observed (about 1 hour). The catalyst is then filtered off with suction, washed with methylene chloride and evaporated to dryness in a water-jet vacuum. By crystallizing the residue from methylene chloride ether, 93 mg of the pure d, l-Zl ⁵ -3-ethylenedioxy-1 , IS- oxido-18-tetrahydropyranyloxy-20-oxopregnene-21-acid methyl ester with a melting point of 220 to 223 are obtained °, IR spectrum in CH ₂ Cl ₂ : 5.70 µ (ester) and 5.79 µ (20 ketone).

80 mg of this α-keto ester with a melting point of 220 to 223 ° are dissolved in 3 cm ^{3 of} glacial acetic acid, heated to 100 °, then 0.3 cm ^{3 of} water are added, and after 5 minutes the solution is poured ^{into 30 cm 3 of water.} The clear solution is extracted several times with methylene chloride and the extracts are washed with sodium bicarbonate solution and with water. The residue obtained from the combined and dried extracts (67 mg) is recrystallized from methylene chloride-ether. The 11,18-cyclohemiacetal of d, l-Zl ⁴ -3,18,20-TnOXO-II /? - hydroxy-pregnen-21-acid methyl ester is obtained in colorless crystals with a melting point of 191 ° to 194 °.

UV spectrum: maximum at 240 ΐημ (e = 14800);

IR spectrum in CH ₂ Cl ₂ : bands at 2.81 µ (OH), 5.72 µ (ester + 20-CO), 5.97 and 6.16 µ (Zl ⁴ -3-ketone).

Claims (2)

Patent claims: 1. A process for the preparation of saturated or unsaturated 20-oxo-pregnane-21-acids in the 16 (17) position and their derivatives, characterized in that a compound of the formula COR ' O-X -O acyl wherein R is a ketalized oxo group, R 'is an alkoxy or a substituted amino group and X is the remainder CH ₃ Y or —CH CH means, where Y stands for a protected hydroxyl group which catalytically hydrogenates the 14 (15) double bond in a known manner, simultaneously or subsequently reduces the 16-oxo group in a known manner to the hydroxyl group, this by the action of alkaline agents with simultaneous cleavage of the 20-acyl group and Formation of an A ¹⁶ -20-ketone is removed in a known manner, if desired, a 16 (17) double bond is hydrogenated in a known manner, if necessary a 21-acid derivative is saponified to the free 21-acid and a free 21-acid group, if necessary, by known methods desired, esterified, or liberates the ketalized keto group in the 3-position. 2. The method according to claim 1, characterized in that a Zl ⁸ ' ¹⁴ ' ^{17 '18} -3-ethylenedioxyl / USa-oxido-lo-oxo-lSa-methyl-lS-homo ^ O-acetoxy - pregnatetraen - 21 - acid - morpholide or an A ⁵ > ¹⁴ > ¹⁷ -3-ethylenedioxy-l 1 ^ 8-oxido-: L6-oxo-18-tetrahydropyr anyloxy - 20 - acetoxy - pregnatriene - 21 - acid morpholide used as starting materials. When the application was announced, four priority documents were displayed. © 009 650/438 11.60