DE1768139A1 - Synthesis of steroids - Google Patents

Description

- / - DR. BERG DIPL.-ING. STAPF

PATENTANWÄLTE 8 MÜNCHEN 2. H ILBLESTR ASSE 2O 17681

Dr. Owl dr Berg Dipl.-Ing. Stapf, 8 Manchen 2, HilblestroSe 20 Your reference Our reference date

Lawyer File 1? οβ $
Be / bch

American Home Products Corporation, t> 85 i'nird Avenue,

New fork 1'7 / UBA

'bynthesis of steroids "

This invention relates to new 13-alkylated 18,19-dinorpregn-4-en-3-one compounds, new processes for their production and new intermediate products useful for their production.

in particular, this invention relates to compounds of

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209816/1500

general formula (1)

(I)

where ± i is an alkyl group of 2 to 6 carbon atoms, d is hydrogen or an acyl group, λ is a carbonyl or hydroxymethylene group and the hydrogen atoms are rl in the δ, 9 and 14 positions and the group ii in the 1 ^ position in the trans-anti-trans configuration are, the hydrogen in position 10 and the group -χ-ϋή-, cis to the group in the 1 $ position and the group -OK trans to the group in the 13 position «R is preferably an ethyl, n-propyl, n-butyl or isobutyl group.

Among the acyl radicals that are suitable as group it, the acyl radical can be a hydroxy carbon carboxylic acid of less than 12 carbon atoms, such as, for example, the lower alkanoic acids (for example biting, propionic, butyric, caproic and enanthic acid), the lower Alkenoic acids, the cycloalkanecarboxylic acid, and the monocyclic aryl lower alkanoic acids (for example phenylacetic and ß-phenylpropionic acid) .

Compounds of formula (I) have physiological activity (for example as progestational agents and androgenic.

209816 / 1SOO

-3- 1768133

Antagonists or they are useful as intermediates for steroids that have physiological activity.

The compounds can be administered for therapeutic use, with the concentration and / or dosage tailored to the activity of the particular compound and the needs of the patient.

present iorfinaung scnafft eoenso a process for the production of the »/ eroindungen of the marble 1, in v / elcnem a functional x; erivat dee ^ -Keto-Δ - the i'ormel 1 in the ^; ; -1 \ θΐοΔ -steroid which l'Orrael 1 is converted.

A 4

functional derivative of the> -ueto-z! i -steroid can oeitjV / eibe a v'erbiriu.un; r the roriael ül) be

(II)

": ori., Ju iüiii o-iü j.onri /ur-.'uionen uei den 9-, ^ j-, '1 ^ -, 14- and" iy-.jteiiu: i _; ^: S the -ieicaen above erjl ".. utero are α oiric j ·. -I ¹ OCx: ^ -! -, x _t , uroXynotn ^ ltiu- oaer icetalized ■ ^ r.rr.oii ^ i Tuop-- and χ cine a ^ droijsierucre used Uxo-: rU: .i · ■ :. J. · _; L "UiI '. ¹ -.1Xo! ^ ΧΙΙ ,, Ό Jj. ViiiCL sj GXL θ ΰ.Οι. · ρθΐ" ΰ6 jjixiXuilg in - -' ^ - 'v>; -, ^ \>' ^ J ~ o ·: ^ r ^ ij ~ t ^ xlun.-: -.ii'c caor oune a ■:.: - Λ: ζ-, 'jo elvv, xn-un, Iu υοχ · L · ^; - c. ..oi · ^

2098 16/1 SOO

- ■ 4- · -

§AÜ ÜHKaiNAL

become compounds of the formula (I) by hydrolysis and, if necessary, by isomerizing a 3-iveto- Δ ^ (ΐϋ) -steroid to the ^ -iieto- ^ 4-steroid, and, if desired, by reducing the Product in which X is a carbonyl group to a compound in which λ is a hydroxymethylene group, by oxidizing the product in which X is a hydroxymethylene group to form a compound in which X is a carbonyl group, or by acylating a compound, in which R is hydrogen to form a compound in which H is an acyl group.

The product in which X is a carbonyl group can be

en a compound in which X is a hydroxymethyl group by a mild reducing agent such as sodium borohydride in pyridine or, alternatively, the 3,20-diketo compound can be reduced to the ^, 20-diol (for example with lithium aluminum hydride) and this diol can then be selectively oxidized, for example with manganese dioxide or 2,3-dichloro-5,6-dicyanobenzoquinone, to which desired compound of Porrael 1, in which X is a is a hydroxymethylene group.

each 4-ene-17-hydroxy-3 »2u-diketo compound can be according to any HerKÖmiülicnen method are acylated, such as durc.i treatment with an acid anhydride or a

with formation of the corresponding ^ -en-iydiketo compound. For the preparation of a compound of the general formula (I) in which X is an iiyctroxymetnylengrup-

1
pe and R is an acyl group, the 1-hydroxy group of a 4-yn-3-one-17-20-diol can be protected, for example to form a tetrahydropyranyl ether, the resulting compound acylating and the protected group

then removed. W.

Y can be a single substituted or unsubstituted aliphatic hydrocarbon group or acyl group, which is linked to King A by oxygen, nitrogen or sulfur in connection with two ethylenic turns, one of these bonds in the position and the other in the ^ - position ends; It can also have two substituted or unsubstituted aliphatic hydrocarbon groups (which are connected to one another -

can), these with the King a. via oxygen or sulfur in connection with a single ethylenic bond, which ends in the 5- ^ position, are connected.

Preferably the organic reads from ι a complete i'Ohlenwasserstorfrest. i can be and is preferably alkoxy (for example methoxy or ethoxy) or it is icarmoine, substituted alkoxy group (for example a

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kethoxy-methoxy or dihydroxypropyloxy group), it can be an alkylthio group (for example AthyIthiο or -3enzylthio) or acyloxy group (e.g. ac et oxy) or a disubstituted amino group (for example H-pyrrolidinyl) be. It can also be an alkylundioxy group (For example an atnylenedioxy group or an AlKylen be dithio or alkylenethiooxy group.

It can therefore be used, for example, as compounds of the formula (II) the J-itoolethers, J-eftolacylates, 3-Enolthioether and 3-Knamine of the corresponding 3-ketones or the ketals, thioketals or hemithioketals of 4,5- or 5 (10) -ethylenic 3-ketones.

The compound of the formula (II) is preferably an enol ether of the general formula (III)

(ΙΠ)

wherein H and X and the configurations in the 8-, 9-, 13-, 14- and 17-positions have the same meaning as above and Z is a substituted or unsubstituted aliphatic hydrocarbon group of a kind whose bond with the permanent atom as opposed to the action of a

-7-209 818/1500 bath

AlKali metal is stable in liquid ammonia.

The hydrolysis of a compound of the general formula (Ii) is usually carried out with acid, but the valued group is an ester group, it can also be hydrolyzed by a must and certain amino amines can be hydrolyzed under neutral or basic conditions v / earth. The unsaturation in the Hing κ is such that the hydrolysis removes the organic part of the urup I and. converts it and any ethylenic bond that ends in the o- position to an oxo group. Under sufficient acidic conditions or under basic conditions, the ethylenic bond ending in the 5-part, if it is not already in the 4, 5-position, can be rearranged to this position, normally for this purpose strong acids such as mineral acids, converted to xieiooiel -jalzs ^ .ui'e oil alkali. A weaker acid v / ie an organic acid (for example oxalic acid) can be used for hydrolysis, v; o the double bond exists on the side of the 4-, 5-position, or it can v. aiuv.'cise a double bond in the p (10) or p, u- ^ ■ position to be isomerized to egg 4, p-.oteliung.

4, G: .iUiv therefore oebeispielev.'eise emphasized above v. ! ¹ er to that ihil j3-j * i ', j ^ di _(t .i; 3e d a, 9 (' iii) -diätnyleiiiscueu ^ -j.cxiers, ut _'^^; iiül; v / oj; .. 'j nit uiuur sciiwacnen orgauiocuuu oaiire, like

16 / ISOQ

BATH

(3O ⁰ C)
aqueous alcoholic oxalic acid, / can give a 5 (10) -ethylenic-5-ketone, which in turn can easily be isomerized to a 4,5-ethylenic-3-ketone by a stronger acid treatment or with a base; such a
2-ütufen method is a known chemical equivalent to the direct one-step hydrolysis under harder öäurebedingungen, wherein a stronger acid, usually a mineral acid balzsäure, as 6N aqueous hydrochloric acid at 80 ⁰ C was used as is.

The idea of protecting an oxo or carbonyl group as a derivative as noted above and removing it for recovery the Qxo or carbonyl group is known (see Djerassi, Steroid Reactions, Holden-Day 196 $, pages 1 to 66).

The enol ethers of the general formula (III) in which X
is a hydroxymethylene or ketalized carbonyl group can be prepared by reducing a steroid of the general formula (IV)

(HT)

worm R and Z have the meaning given above and. X

—9—

a hydroxymethylene / carbonyl or ketalized carbonyl group is.

The .reduction is preferably carried out in the manner as "described in the bteroid chemistry is known as Birch reduction, and the The conditions used are such as those for Birch hedging are suitable. There can therefore be an alkali metal (lithium, sodium or potassium) in liquid ammonia and the oteroid of the general formula (IV) preferably in Presence of a co-solvent, e.g. tetrahydrofuran, are brought together, and a sufficiently reactive proton donor is then added, Such a proton donor shouldn't be so acidic that it reacts with the alkali metal to produce enough hydrogen gas to seriously cause the desired reaction disturb. Suitable proton denominators are those with a piva between 14 and 20 and include alcohols, for example ethanol, ethanol, tertiary butanol and 1-ethoxy-propan-2-ol and pyrrole. Preferably an alcohol is used which has fewer than 6 carbon atoms.

The itfiolather of the general lormel III, in which X is a carboxyl group can by oxidation of the corresponding Compound in which X is a hydroxymethylene group is to be produced.

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BAD ORKaWAL

Oteroids of the formula (IV) are new compounds. Fertilizers in which A is a carbonyl group can be prepared by treating a nJpoxy compound of the general formula (V)

(V)

(in which H is an acyl group and H and Z are those given above Have meaning) with a base such as dilute sodium hydroxide.

Compounds of the formula (IV) in which X is a hydroxymethylene or ketalized carbonyl group can be prepared from the corresponding compound in which X is carbonyl, by means of reduction (for example with a hydride transfer agent such as sodium borohydride) or by ketalization (for example with ethylene glycol). The reduction of the carbonyl group can be a mixture of 20a and 2Qβ epimers, which are separated by chromatography can, form.

The epoxy compounds of the general formula (V) can be obtained by oxidizing a iiiiolacylate of all-

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common formula (VI)

coff

Preferably, the enol acetate with an oxidizing agent, v; ie m-chloroperbenzoic acid in an inert organic Solvent oxidized.

The enol acylate of the general formula VI can be prepared become the general by reacting a 20-ketone steroid Formula VII

VIl

with an acylating agent such as acetic anhydride, in Presence of a strong acid catalyst such as p-toluenesulfanic acid, ^ sulfuric acid or perchloric acid. The 20 ketone steroids of Formula VII are known compounds which can be prepared by any conventional method such as in US Pat German. Patent application ö 99389 described, produced can be.

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The invention encompasses each of the process steps indicated above, either individually or in combination.

Another example of a functional uerivats of the J- keto- Λ -steroid of the formula I is a steroid of the formula (VIII)

(VIII),

wherein the radicals Q, R, X and the configurations in the 8-, 9- 13- _t "14- and 17-ütellungen the abovementioned meaning and the dotted lines the presence of an ethylenic bond at the 5 (10 *) - or 5 »6 denote bulging. A compound of the formula (VIII)

Ankann to a 3-keto-steroid of the formula I * £ converted are by means of isomerization to rearrange the ethylenic bond in the '4,5- ^ position, if desired, under subsequently oxidizing a product in which X is a hydroxymethylene to form a compound in which X is carbonyl, reducing a compound in which X is carbonyl to form a compound in which X is hydroxymethylene, acylating a compound,

1 in which R is hydrogen or hydrolyze one

Compound in which R is an acyl group.

209 * 16/1500

-13-

The isomerization process can be carried out with a strong acid like an acid, for example hydrochloric acid, in one suitable solvents such as alkanol or aqueous alkanol, can also be carried out by treatment in a base in a similar solvent.

The starting material of the formula (VIII) can be prepared by known methods. For example, a Enol ethers of the general formula (III) with a mild acid hydrolysing agent, such as a weak organic one Acid in a lower alkanol.

Another example of a functional derivative of a compound of the general formula I is a ^ -t steroid of the formula (IX)

(EC)

v / or in K, H, X and the configuration in the 8-, 9-, 3-, 14- and 17-positions are as indicated above and the dotted lines denote an ethylene bond ending in the 5-position. 3-Hydroxysteroids of the formula (Ia) can be converted into the '^ -Keto-Λ -steroids of the formula I by means of oxidation, accompanied where the initial

—14—

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BATH

material contains a 5j6-ethylenic bond, from conjugation of the ethylenic bond with the 3-keto group formed and, if desired, selective deduction of a 20-keto steroid to the corresponding 20-dyeroxysteroid, acylation of a compound in which α ., is hydrogen , to form a compound in which a is an acyl group, or hydrolysis of a compound in which H is an acyl group to form a compound in which R is hydrogen. Such an oxidation can be carried out using an Oppenauer reagent, for example aluminum isopropoxide. Where the conjugation must not take place during the oxidation, it can be effected by treating with alkali or acid.

Another example is a functional derivative of the Formula I is a 3,5-diketo 4-, 5-seco-steroid of the üOriael (X)

(X)

1 1
wherein ii, R, X and the configurations in the positions 8 »9, 13» 14 and 17 have the meaning given above and P and E are oxo or protected, for example ketalized, oxo groups. The functional derivative of the formula

BATH ORIGINAL

(λ ±) can be converted into the 3-keto-A4- steroid the I'Ormel (I) by means of an internal aldol condensation, if desired with subsequent reduction of a compound of the formula I in which X is a carbonyl group, under .formation of a compound in which X is a hydroxymethylene group is, oxidizing a compound in which X is a hydroxymethylene group, to form a compound, in which X is a carbonyl group, or Acy-

lating a compound in which R is hydrogen,

1 to form a compound in which R is an acyl group is.

The internal aldol condensation reaction that forms ring A, can by contacting the starting material with a suitable base or acid, for example a sodium alkoxide or concentrated hydrochloric acid, at suitable temperatures.

In the structural formulas (I) to (X) has a continuous Line connecting an atom or group to the tetracyclic nucleus, none in terms of configuration Meaning, but is used solely to indicate the position in the nucleus in which the atom or group is is verounden. ±; s are therefore in these structural formulas the 15Ji and 1 $ a connections are not expressed separately, unless the product is obtained by synthesis which includes an i'reunung level and, for example,

BATH

wisely using the terminology of the Horeau-Reichstein Convention, as indicated by Fieser and Fieser, Steroide, (1959), page 336, a separate d-enantiomer which has the 8β, 9a, 1Jβ, 14oc configuration, according to which this d-form and its antipode are the 1-enantiomer the Öa-, 9ß-> 13ot, 14ß configuration in equimoleicular Mixture or racemic form will be present, wherein one is iCnantiomer (+) or dextrorotatory and the other (· -) or levorotatory. In the examples below are such structures as (i) -13β compounds designated according to the previously designated convention.

Preferably the starting material in a process according to the invention is a separate d-enantiomer. The invention particularly includes the d-enantiomers with the 13β-alk; yl group in the presence or absence of their 1-enantiomers; it includes the separate d-compounds and the d-form in admixture with the corresponding 1-forms, especially racemic mixtures.

The invention also includes a pharmaceutical preparation, which a steroid of the formula I as indicated above and comprises a pharmaceutically acceptable! 'rager.

The pharmaceutical preparations of the invention can be in liquid or solid form, for example as capsules,

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209816/1500

Tablets, suppositories, powder, disp erable granules and the like by ts-combining them with conventional ones Carriers are presented. Such conventional carriers include magnesium carbonate or stearate, sebum, Sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methyl cellulose, iiatrium carboxymethyl cellulose, low melting wax and cocoa butter. Dilution or extenders, flavorings, solubilizers, Lubricants, bus suspension agents, binders or tablet-dissolving agents can be used. powder and tablets preferably contain ^ or 1ü to 99> & Active ingredient component. The effective oteroid can be in one encasing material with or without other carriers.

liquid preparations such as solutions, suspensions or Emulsions can also be used, such preparations include dispersions in a pharmaceutically acceptable liquid carrier such as arachis oil or sterile water, preferably containing a non-ionic, surface-active agent such as fatty acid esters of polyhydroxy compounds, for example sorbitan (for example i-olefin oxide fatty acid esters such as Tween 80), aqueous starch in iiatriunicarboxymethyl cellulose solution, aqueous propylene glycol or x -ylene glycol. It can therefore be a water propylon glycol solution for parenteral injection under pressure

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Turn of natural or synthetic gums, resins, methyl cellulose or other known suspension agents can be used.

The preparation can be presented in unit dose form in which the unit dose comprises, for example, from 0.1 to about 0 mg of active dteroid, depending on the therapeutic purpose desired. The unit dose form can be a packaged preparation, for example, packaged powders, ampoules, or in the form of capsules or tablets, for example, or in any number of these packaged forms. The pharmaceutical preparations may also contain the active oteroid essentially alone when it is in unit dosage form.

The following examples explain the invention (all temperatures being given in ⁰ U).

example 1

tetraen-2Q-ol, acetate

A solution of 1.0 g of (i) -17β-acetyl-1j> -ethyl -;? - methoxygona-1,3,5 ('10) -triene and 0.53 g of p-toluenesulfonic acid in 100 ml of acetic anhydride is slow distilled through a short Vigreux column at atmospheric pressure for a period of ¹ 1/2 hours, with about 5 < 1 ml '

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BAD ORKSiNAL

orange residue remains. The huckstand is in a a. Ice bath cooled, 1Uu ml of water are added and the mixture is stirred for an additional 15 minutes. The mixture is extracted intestinally with ether and the ether extracts with 1% aqueous sodium hydroxide, saturated aqueous sodium hydroxide u Sodium bicarbonate, water washed, over anhydrous Magnesium sulfate and evaporated the solvent in vacuo to give a brown resin. colon Nenchromatography of the resin over 60 g of Florisil using 100 # hexane as the eluent gives after Recrystallize from methanol, $ 50 mg of a colorless solid which, after recrystallization from methanol, (i) -13-ethyl-3-methoxy-18,19-dinorpregna-1,3,5 (10), 17 (20) -tetraen-2Q-ol, acetate yields with a melting point of 89 to 92;

λ J ^ 5.71, 5.88 µ (weak); λ J ^ ° ^H 284 ΐημ (£ = 1.660); Analysis: Calculated for C ₂₄ H ₅₂ ),: 78.22 # G, 8.75 # H

Found ':? Ö, 22 # G, 8,635 *> H.

Example 2

(-) - 13 - b ^J ropyl ~ 3-methoxy-18 _< 19-dinorpreRna ~ 1 _< 3 _< 5 (10) _< 17 (20) tetraen-20-ol _t acetate

The procedure of Example 1 is followed, but (i) -17-ß-acetyl-13-propyl-3-methoxygona-1,3,5 (10) -triene is substituted for ( ⁱ ) -17ß-acetyl- 13-ethyl-3-methoxygona-1 _l 3,5 (10) -triene and gives (i) -13-eropyl-3-methoxy-18 _f 19-dinorpregna

-20-

209Ö16 / 1S00

1,3,5 (10), 17 (20) -tetraen-20-ol, acetate.

Example 3

(-) - 13-iJUtyl-3-methox.y-18 _< i9- (iinorpre ^ na-1,3 »5 (10), 17 (20) - tetraen-20-ol, acetate

The procedure of Example 1 is followed, but replacing (^) - 17ß-acetyl-13-butyl-3-methoxygona-1,3,5 (10) -triene by (i) -17B-acetyl-13-ethyl-3-methoxygona-1,3,5 (1O) -triene and receives (±) -13-butyl-3-methoxy-18,19-dinorpregna-1,3,5 (10), 17 (20) -tetraen-20-ol, acetate.

Example 4

(-) - 15-Isobutyl-3-methoxy-10, 19-dinorpregna-1,3,5 (10) _< 17 (20> tetraen-20-ol, acetate

The procedure of Example 1 is followed, but replacing (-) - 17β-acetyl-13-isobutyl-3-methoxygona-1,3,5 (10) -triene by (i) -17ß-acetyl-13-ethyl-3-methoxygona-1,5,5 (1O) -triene and receives (-) - 13-isobutyl-3-methoxy-18,19-dinorpregna-1,3 ,! 17 (20) -tetraen-20-ol, acetate.

Example 5

(*) -2OJ-Ac et ox.y-17a, 2oVepoxy-13-ät hyl-3-met hoxy-18,19- dinorpregna-1 ₁ 3.5 (10) -triene

A solution of 0.95 g of m-chloroperbenzoic acid in 9.0 ml Benzene is added to a solution of 1.00 g (-) - 13-Ath, yl-3-methoxy-

209818/1500 "^"

18,19-dinorpregna-i, 3,5 (10), 17 (20) -tetraen-20-ol, acetate in 9.0 ml of benzene was added over a period of 5 minutes with stirring at room temperature. After further Stirring for 20 minutes at room temperature, a turbidity can be seen and after 3 hours, ether is added and the Solution with cold 5 # aqueous sodium hydroxide, saturated aqueous sodium bicarbonate and water, dried over anhydrous magnesium sulfate and then the solution ™ medium under vacuum to give a resin which is crystallized by trituration with hexane. the Recrystallization from isopropanol gives 0.55 g (-) - 2ö ^ - Acetoxy-17a, 2Q "i-epoxy-13-ethyl-3-methoxy-18,19-dinorpr egna-1,3,5 (1O) -triene, Melting point 113 to 125 °; λ 5 5.71; 282 (£ 2,190);

Analysis: Calculated for O ₂₄ H ₅₂ O ₄ : -74.97 # C, 8.39 # H Found: 74.91 # 0, 8.29 # H

Example 6

(±) -2oWoetoxy-17a, 2o £ -epoxy-13 ~ propyl-3-methoxy-18 _f 19-dinorpregna-1, 3i5 (1O) -triene

Follow the procedure of Example 5 »but replace (ΐ) 13 - rt? Opyl-3-methoxy-18,19-dinorpregna-1,3,5 (10), 17 (2O) -tetraen-20-ol, acetate by (£ -) - 13-ethyl-3-methoxy-18,19-dinorpregna-1,3,5 (10), 17 (20) -tetraen-2Q-ol, acetate and receives (i) -20 ^ -acetoxy-17a, 20> -epoxy-13-propyl-3-methoxy-

20981 β / 1600

Example 7

dinorpregna-1 _<

The procedure of Example 5 is followed, but (-) - 13-butyl-3-methoxy-18,19-cLinorpregna-1,3,5 (1ü), 17C2ü) -tetraen-2ü-ol, acetate is replaced by (i ) -1 $ -Athyl-3? -Methoxy-1ö, 19-dinorpregna-1,3,5 (10), 17 (20) -tetraen-20-ol, acetate and contains (± -) - 20S-acetoxy- 17a _t 20 ^ -epoxy-13-butyl-3-metioxy-1b, 19-dinorpregna-1,3,5 (10) -triene.

Example 8

(-) - 20 ^ -Acetox.y-17a, 2Qt-epox.y-13-isobut.yl-3-methox.y-1ü _t 19 dinorpresna - 1.3 «(

The procedure of Example 5 is followed, but (-) - 13-isobutyl-3-methoxy-18,19-dinorpregna-1,3 * 5 (10), 17 (20) -tetraen-20-ol, acetate is replaced by (i) -13-Atoyl-3-methoxy- ^/ 18,19-dinorpregna-1,3,5 (10), 17 (20) -tetraen-20-ol, acetate, and (i) -20j-acetoxy -17a, 2Qi-epoxy-13-isobutyl-3-methoxy-18,19-dinorpregna-1,3,5 (10) -triene.

Example 9 (-) - 13-Ethyl-3-methoxy-18 _% 19-dinorpreKna-1 _< 3 _< 5 (1O) -triene-

Q, 40 g of ( ⁱ ) -20i-acetoxy-17a, 2oVepoxy-13-ethyl- '

Stand 5-methoxy-10, 19-dinorpregna-1, 3,3 (10) -triene at room temperature with 0.48 g of sodium hydroxide in a mixture of 60 ml of ethanol and 20 ml of water for 3 1/2 hours. The equipment is diluted with ether, washed with saturated aqueous sodium carbonate, then washed with water, dried over anhydrous magnesium sulfate and the solvent evaporated under vacuum gives a colorless solid. Recrystallization from absolute ethanol gives 0.26 g (±) _13_ _il thyl-5-methoxy-1 NC, 19-dinorpregna-1,5,5 (1O) -trien-Ί7α-ο1-2θ-οη, bchmelzpumct 164-167 ° , λ ^ tZ 2.96, 5.92 μι

Analysis: -brrectmet for ^G || ^H 30 ^Ü 3 ^: ^ ' ¹ ^ °' ^Ö » ^Ö 5 ^ ^H

Found: 76.91 ^ G, 8.65 ^ Π

Example 10

(-) - 15 - L ~ ropyl-5-raethox _r y ~ 18,19-dinorpregna-1,3,3 (1O) 17a-ol-2O-one

han follows the procedure of Example 9, but replaces (-) - 20 ^ -Ac et oxy-17 <x, 20% -epoxy-13-propyl-3-methoxy-18,19-dinorpi ^ egna-i, 3, 3 (1O) -triene by (i) -20 ^ -acetoxy-17oc, 20 ^ -epoxy-13-ethyl-3-methoxy-16,19-dinorpregna-1,3 _? 3 (1O) -triene and receives (i) -13-i ^J Topyl-3-niethoxy-18,19-Ä.inorpregna-1,3,5 (10) -trien-17a-ol-2ü-one.

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BAD ORKatNAL

Example 11

lzI " ¹ .3- ^ ut, 7l-3-met hox, y-1ö, 19-dinorpreg; na-1,3,5 (10) -trien- 17α-ο1-2υ-οη.

lian follows the procedure of Example 9, but replaces (-) -

pregna-1 , 3,5 (1O) -triene through (i) -20 ^ -Jicetoxy-17a, 20f-epoxy- 13-eth _t > l-3-Eiethox _t > -16,19-dinorpregna-1,3 , i? (1ü) -triene and receives (i) -13-butyl-3-methoxy-10, 19-dinorpregna-1 , 3,5 (10) -trien-17oc "r-ol-20-one .

Example 12

(-) - 13-Isobut.yl-3-methox.y-18,19-dinorprep; na-1,3 _< 3 (10) -trien-17oc-ol-2Q-one

The procedure of Example 9 _{5 is followed} , but (-) - 20ξ-acetoxy-17α, 20ξ-epoxy-13-isobutyl-3-methoxy-1β, 19-dinorpregna-1,3,5 (10) -triene is replaced by ( i) -20 ^ -Acetoxy-17a, 20 ^ - epoxy-13-ethyl-3-methoxy-18,19-dinorpregna-1,3,5 (10) -triene and obtain (i) -13-isobutyl-3 -inethoxy-18,19-dinorpregna-1,3,5 (10) -trien-17a-ol-20-one.

Example 1 $

(- •) ~ 13-Ethyl-17a, 20Vdihydroxy-d-methoxy-18 _t 19 - dinorprep: na 1,3,5 (10) -triene

A solution of 5 _r 40 g (-) - 13-ethyl-3-methoxy-18,19-dinorpregna-1,3,5 (10) -trien-17a-ol-20-one, 10.0 g sodium boron

209816/1500

hydride and 500 ml of absolute ethanol is at room temperature Stirred for 14 hours. An excess of glacial acetic acid, after that Benzene is added and the solution washed with water, saturated aqueous sodium bicarbonate, then water, dried over anhydrous sodium sulfate and the solvent evaporated in vacuo to give 7.0 g of a mixture of (£) -13-ethyl-17oo, 20a-dihydroxy-3-methoxy-18,19-dinorpregna-1,3) 5 (10) -triene and (i) -13-ethyl 17a, 2Gii-dihydroxy-3-methoxy-18,19-dinorpregna-1,3,5 (1u) -triene. (The infrared numbers indicate hydroxyl absorption at 2.90 u and no carbonyl absorption. Thin-layer chromatography shows that the product is a mixture of two compounds).

Example 14

(-) -13 -Pr opyl-17a, 20 Vdih.ydroxy-g- me t hoxy-1o, 1 9-dinor pregn a-i, ^, 5

han follows the procedure of Example 13? but replaces (-) - 13-propyl-3-methoxy-18,19-dinorpregna-1,3 _} 5 (10) -trien-17aol-20-one with (~) -13-ethyl-3 -methoxy ~ 18,19-dinorpregna-1,3,5 (1o) -trien-17a-ol-20-one and gives (i) -13- propyl-17a, 20 ^ -dihydroxy-3-methoxy-18 , 19-dinorpregna-1,3 »5 (10) -triene.

Example 1 ^

(-) - 1 ^ -but _r yl-17oCi20 ^ -dihydroxy-3-methoxy-1ö «19-dinorprep; na-

Follow the procedure of Example 13, but replace (^) -

20dai6 / 1600

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ORiGtMAL BATHROOM

on by (-) - 13- ^ thyl-3-metnoxy-1o, '19-ü.inorpi'ei-: iiii-1,3,5 (1u) -trien-17oc-ol-2Ü-ol and get (±) -13 - üUtyi-17a, 20 ^ -dihydroxy-3-metnoxy-1ä, 19-dinorpregna-1,3,3

Example 16

(-) - 13-Isobut.yl-17a, 20 ^ - d her / drox.y- $ - metaox, y-1ö, i 9-dinor pregna-1,3

I4an follows the procedure of Example 13 ₅ replaces aoer (-) - 13-isobutyl-3-methoxy-18,19-dinorpregna-'i, 9, 5 (iü) -trien-17a-ol-2ü-one with (i ) - '13 - tithyl-3-metnoxy-1ö / iy-dinorpregna-1,3,5 (10) -trien-17a-ol-20-one and receives (±) -13-isobutyl-17a j 2üt, -dihydroxy-3-methoxy-1ö, 19-dinorpr egria-1,3, ^ (10) trien.

■ Example 17

(ί) -13-ii-thyl-17oc _> 2ü ^ -dihydr oxy-3-metnoxy-'1o, 'i 9-dinorpr epcna- 2.5 (/ 10) -diene

A solution of 3> ^ g of (i) -13 - ^^ 1-17 «, 2O-diiijdroxy-3-methoxy-1, 19-dinorpregna-1,3,5 (10) -triene in IUU ml of distilled tetrahydrofuran becomes 7uU ml of distilled liquid ammonia for a period of three and a half minutes with the formation of a bus pension added, in the middle afterwards 5 »O S lithium in small pieces become so fast admitted as possible. The blue mixture will do 2 btws

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BAD ORiGtNAL

: -: ers.Lhrt and 1 ml of aosolutes ethanol are added over a period of IfO minutes to remove the blue color. The addition of wartneva water and the filtering of the renewed precipitation results in 4.4-5 g of a mixture of (-) -19-iitiijl-1? A, 2ua-dihydroxy-3-metaoxy-18,19-dinorpreu- na-2, ^^ 10) -dien and (i) -1 $ -Ath, yl-17a, 20ß-diJiydroxy- ;; -: nütnoxy-10, 19-dinorpregna-2,5 (1ü) -diene, ochmliezpunkt Ipip to 1 ^ °.

at. "- joi el 1Ö

(ί) - 13-x ^J rooyl-17a, 2 ü't; -aih.ydroxy-3-niethox.y-1ö, 19-dinor preffla- 2, ^ (/ 10) -dien

Han folr'-t the procedure of Example 17, but replaces (-] 13-jrropyl-'t7o;, 2U ^ -dihydroxy-3-methoxy-10, 19-dinorpregna-1, .3,; H'iu) - triened by (i) -i3 - iithyl-17a, 2ü ^ -dihydroxy-3-metho: <: y-1c5,19-dinorpregna-1,3,5 (1u) -trien and receives (^) - 13- jt ^ rop ^ li 7a, 20 ^ -dihydroxy-3-metnoxy-18,19-dinorpregna-

example 19

C-) -13- .a ut.yl-17a ■. 20 ^ -dih.ydr ox.y-3-met hoxy-1 ö ₁ 19-dinor ~ pr ep: na-2,5 C10) -diene

han follows the procedure of example 17, but replaces (-) 13-r> utyl-17a, 20 ^ -dihydroxy-3-methoxy-18,19-dinorpregna-1,3, pC'iu) -triene by (-) - 13-ethyl-17a, 2Q ^ -dihydroxy-3-

209816/1500 " ^2Ö "

methoxy-18,19-dinorpregna-1, 3,5 (1O) -triene and receives (-ΟΙ 3-Butyi-17α, 20% -dihydroxy-3-methoxy-16,19-dinorpregna-2,5 (10) -diene ..

Example 20

(+) - 13-Isobutyl-17cx «20J; -dih.ydrox.y-3-methoxy-18« 19 "cLinorpregna-2,

The procedure of Example 17 is followed, but replaces (*) -1J-isobutyl-17oc, 20 ^ -dihydroxy-3-methoxy-18,19-dinorpregna-1,5,5 (10) -triene by (i) -13-ethyl-17a, 20 ^ -dihydroxy-5-raetnoxy-18,19-dinorpregna-1,3,5 (iO) -triene and receives (-) - 1 ^ -Isot) utyl-17a, 20 ^ -dihydroxy-3-methoxy-18,19-dinorpr egna-2, i? (10) -diene.

Example 21

(-) - 1 $ Ethyl ~ 17a _< 2Qa-dih.ydrox.y-18.19-dinorpresn-4-en-3-one and (- ) - 13-Ethyl ~ 17a, 20ß-dihydroxy-18,19- dinorpreKna-4-en ~ 3-one

A solution of 4.20 g (i) -13-Ath ^ l-17a, 20 | -dihydroxy-3-niethoxy-10, 19-dinorpregna-2,5 (1ü) -diene in 117 ml of methanol, 7.8 ml of concentrated hydrochloric acid and 5 »2 ml of water under bticKatoff stirred for 1 otund at room temperature. -uas filter gave 0.31 g of colorless solid with a melting point of 158 ois 168 °. The filtrate is mixed with benzene diluted with saturated aqueous disodium bicarbonate,

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BAD ORKGiNAL

after washed with water, ■ dried over anhydrous sodium sulphate and evaporated the solution in vacuo, giving 3.50 g of a resin, the resin is passed through a column of Woelm neutral alumina sorting 111 and eluted with benzene, which contains increasing amounts of ether; thereafter recrystallized from ethanol to give 0.44 g of (±) -13-ethyl-17a, 20-dihydroxy-1NC, 19-dinorpregn-4-en -> - one, m.p. 150 152 ° ois; ^ _ma x 2 .98,

6.20 µ; λ ^ ° ^H 244 mji (£ 16,500).

Analysis: Calculated for G ₂₁ H ₅₂ O ₅ : 75iö6> b G, 9,? 0 # H Found: 75.30 / ώ 0.10.10 ^ H

Further KLuieren the column with increasing proportions of Λ-ether and recrystallization from methanol and isopropanol gives 0.19 g of the corresponding JO epimer, ^ melting point 1Ö1 to 185 °;

$, 00, 6.02, 6.23 µ; λ ^ ° ^H 24J ιψ (£ 15,500) Analysis: Calculated for G ₂₁ H ₅₂ O ₅ : 75 »ö6> G, 9,? O> 6 H Found: 75.6ö / _ö G, 9.27> ό Η

Example 22

(-) -13 - rt? Opyl- "17cx-, 20ar-dihydr oxy ~ 10, 19 ~ dinorpr egn-4-en - $ - on and (-) - 1 $ -propyl ~ 17a, 20ß-dihydroxy-1β, 19-dinorpregn-4-en-

hau follow the procedure of Example 21, but replace (-) _

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2,5 (10) -diene through (i) -13-> Lthyl-17cx, 2u ^ -dinyarox ^ -3-methox, yi6 ₅ 19-dinorpregna-2,5 (10) -diGn and receives (i) - 13- ± ropyl-17a, 20a-dihydroxy-18,19-dinorpregn-4-en-3-one and (^) - 13-, 20ß-dihydroxy-1u, 19-dinorpreitn-4-eri-3-one.

Example 2

and (-) - 13-butyl-17a, 2Üß-dih.ydrüx, y-'1ö, 19-ainorpre, N .; n-4-eu-

Following the procedure of Example 21 replacing aoer (^; -

2.5 ('lO) -dien through (^ - ^^ -
1ö, 19-dinorpregna-2,5 (10) -dien and get (i) -13-.uut,> l-17a, 20a-dihydroxy-1ö, 19-dinorpregn- ^z f-en-p-one and ( ^ 17o:, 20ίί-din ₍ ydrox _< > -1b, 19-dinorpre _L iα- ' ^ί l -en-3-on.

Example 24

on and (-) - 13-Isobut.yl-17a, 20ß-dihydrox.y-1ö, 19-dinorprefk, n-

The procedure of Example 21 is followed, but replacing (-) - 13-isobutyl-17a, 2üf-dihydroxy-3-methoxy-10, 19-dinorpregna-2,5 (10) -diene by (i) -13-ethyl-17a, 2O ^ -dihydroxy-3-methoxy-10, 19-dinorpregna-2, i? (1ü) -diene and feeds (i) -13-isooutyl-

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BAD ORKStNAL

, c: U "xd.iiiyiroxj-'lo, ''ly-dinorpregi'i— ⁴ J - en-jj-on and (, -) - 1 ^ -

Solution of 1.0 g (£) -1 $ -Ath; yl-3-metlioxy-18,19-dinorpre {pia-'l, i), 5 (10) -trien-17 (x-ol-20- on in 50 ml of ethylene glycol and $ 00 ml of benzene is taken under reflux for ά hours using an i) ian-Ütark water separator. The octhylene glycol layer is separated and the benzene layer is washed with saturated aqueous sodium bicarbonate, then water and evaporated in vacuo. The solid residue is recrystallized from hexane to give 0.85 g of (-) - 13-ethyl-3-methoxy-20-cycloethylenedioxy-18.19 "-dinorpregna-1,315 (10) -trien-1Voc-ol with a melting point of 95 to 99 ° C; Λ max 2.86, 9.25, 9.64 μ analysis; calculated for C ₂₄ H ₅ ^ O ₄ : 7 ^, 57 ^ C, 8.87ife H.

Found: 74.39 ^ G, 9, G9 *> H

■ example 26
(-) - 13 ~ i ' ^J r opyl-3-methoxy-2Q-cycloäthylenaiQx.Y-18,19-dinor-

hau follows the procedure of Example 25, but replaces (-) 13-J- 'iO [j.yi-3-ii] utao;:. Y-1d, i ^ -äinorpregna-1,5,5 (' lü) -tx ^ ien-

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ol-20-one by (i) -13-ethyl-5-metnoxy-10, 19-d.inorpregna-1,3,5 (10) -trien-17oc-ol-20-one and receives (±) -15-propyl-3-methoxy-2Ü-cycloäthylendioxy-iö, 19-dinorpregna-1,3,5 (10) -trien-17β-ol.

Example 27 C -) - 13 - ßut.yl-3-methox.y-2ü-c.ycloäth.ylenedioxy-18 _< 19-dinor-

preg; na-1,3,5 (10) -trien-17cx-ol .

The procedure of Example 25 is followed, but replacing (-) - 13-butyl-3-methoxy-10, 19-dinorpregna-1,3,5 (10) -trien-17aol-20-one by (i) -13- ^ hyl-3-niethoxy-10, 19-dinprpregna-1,3,5 (10) -trien-17a-ol-20-one and receives (i) -13-butyl-3-methoxy-20-cycloäthylenäioxy-18,19-dinorpregna-1,3,5 (10) -triene-17 «oil.

Example 28

C -) - 13-Isobut.yl-3-methox.y-20-cycloäth.ylenedioxy-18,19-dinorpresna-1,3

Mari follows the procedure of Example 25 but replaces (-) - 13-isobutyl-3-methoxy-18,19-dinorpregna-1,3,5 (1Q) -trien-17a-ol-20-one by (i) -13-ethyl-3-methoxy-1o, 19-dinorpregna-1,3,5 (10) -trien-17a-ol-20-one and receives (±) -13-isobutyl-3-methoxy-20-cycloethylenedioxy-16,19-dinorpregna-1,3,5 (10) -trien-17 <X'-ol.

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Example 29 C-) -13-ethyl-17a-hydrox.y-18,19-dinorprep; n-4-en-3 «20-aion

A solution of 1.0 g of (i) -13-ethyl-3-methoxy-2O-cycloethylenedioxy-18,19-dinorpregna-1,3,5 (10) -trien-17cc-ol in distilled tetrahydrofuran (100 ml) becomes 25Q ml distilled liquid ammonia added over a period of 10 minutes. Immediately thereafter, 0.90 g Lithium added in small pieces as quickly as possible while stirring. The blue solution will be another 2 hours violently stirred. Absolute ethanol is then added dropwise to remove the blue color. Hot water is added and the mixture extracted with ether. The organic extracts are washed with saturated aqueous sodium bicarbonate, then washed with brine, dried over anhydrous sodium sulfate and the solvent under Vacuum evaporates to form 1.10 g (*) - 13-ethyl-3-methoxy-20-cycloäthylendioxy-1ö, 19-dinorpregna-2,5 (10) -diene-17α-ο1, λ max 5.89, 5.994.

1.0 g of the resulting product is ι at 60 ° for 20 minutes in a mixture of 40 ml of methanol, 22.5 ml of water and 7.5 ml of concentrated maltic acid heated. The mixture is cooled to room temperature, diluted with ether, then with water, saturated aqueous sodium bicarbonate and washed again with water, dried over anhydrous sodium sulfate and the solvent evaporated under vacuum.

209816 / 1SOO ~ ³⁴ ~

1758139

The resulting solid residue is made from atnylacetate / Hexane recrystallizes with formation of 0.45 g (-) - 13-Ethyl-17oc-hydroxy-1Ö, 19-dinorpregn-4-en-3,20-dione, bchmelz point 204 to 206 °.

Example 30

Follow the procedure of Example 29, but replace (-) - ^ -Propyl ^ -methoxy ^ O-cycloethylenedioxy-iej ^ -dinorpregna-1,3,5 (10) -trien-17oc-ol by (±) -13-ethyl-3-methoxy-20-cycloethylenedioxy-18,19-dinorpregna-1,3,5 (10) -triene-17otol and receives (i) -13-iropyl-17a-hydroxy-'1ä, 19-dinorpregn-4-en-3,20-dione.

Example 31

(~) -13-Butyl-17a-hydroxy-1ä «19-dinorpresn-4-en-3120-dione

The procedure of Example 29 is followed, but replaces (^) - 13-butyl-3-methoxy-20-cycloäthylenedioxy-1b, 19-dinorpregna-1 »3,5 (10) -trien-17a-ol by (i) -13-ethyl-3-methoxy-20-cycloethylenedioxy-18,19-dinorpregna-1,3 »5 (10) -trien-17 <x-ol and receives (i -) - 13-butyl-17a-hydroxy-18,19-dinorpregn-4-ene-3,20-dione.

Example 32

(±.) -.13-Isobutyl-17α-hydroxy-18 ₁ 19-dinorpregn ~ 4-en-3 «20-dione

Follow the procedure of Example 29 »but replace (^) -

2 ό δ 8 i ß / 1S ö ö " ³⁵ ~

BATHROOM OHIGrNAL

1 3-Isobutyl-3-methoxy-2O-cycloethylenedioxy-18,19-dinorpregna-1,3, iK10) -trien-17a-ol by (±) ~ 13 - h.thyl-3-methoxy-20-cycloethylenedioxy-18,19-olinorpregna-1,3,5 (1ü) -trien-17a-ol and receives (i) -13-isobutyl-17a-hydroxy-18,19-d.inorpregn ~ 4-en-3-) 20-dione.

Example 33

(- ) -13- ^ ethyl-17cc-hydroxy-18 _f 19-dinorpreKn-4-en-3% 20-dione, 17-acetate

To a solution of 0.50 g (i) -13-ethyl-17a-hydroxy-18,19-dinorpregn-4-en-3,2O-dione In 4.0 ml of acetyl chloride, oil, u ml of acetic anhydride, then 0.40 ml of pyridine are added dropwise added with rapid listening. The bchlämme will heated to .ßewirkung a complete solution, then on Chilled to room temperature and 65 hours at this temperature touched. The solvents are evaporated in vacuo leaving a yellow solid residue. The crude product is dissolved in 10.0 ml of tetrahydrofuran and 10.0 ml of methanol and then 10.0 ml of methanolic Potassium hydroxide was added at 0 C under btiorcstoff. That Liunren under nitrogen at 0 0 is continued for 1 hour. Jas mixture is poured into aqueous sodium bicarbonate, diluted with iither, the organic layer washed with water, dried over anhydrous sodium sulfate and the solvent evaporated in vacuo. The residue

20d8i6 / 160Q ³⁶

EAD

is crystallized out after rituring with ether, quickly Chromatograph on a column with neutral alumina and using 100 # benzene and recrystallize from hexane / ethyl acetate gives 0.205 g ("ΟΙ 3-ethyl-17oc ~ hydroxy-18,19-dinorpregn-4 ~ en-3,20-dione, 17-

acetate; Melting point 186 to 189 °; λ ^ Ζ 5.77, 5.83, 5.99,

6.20; ι; λ i ^ ^H 239 ιψ (C 16,100);

Analysis: Calculated for ^G 2b ^E 32 ^O l · " 74.16 # C, 8.66 ^ o H Found: 74.25 # C, 8.66> 6 H

Example 34-

(-) -15 - propyl-17a-hydroxy-18,19-dinorpr egn-4-en-3,20-dione, 17-acetate

The procedure of Example 33 is followed, but replacing (-) - 13- ^ rOPyI-17oc-hydroxy-1ö, 19-dinorpregn-4— en-3,20-dione by (-) - 13-Ethyl-17a-hydroxy-18,19-dinorpregn-4-ene-3,20-dione and receives (i) -13-Kropyl-17a-hydroxy-18,19-dinorpregn-4-en-3,20-dione, 17-acetate.

Example 35

(ί-) -13-Butyl-17a-h.ydrox.y-18,19-dinorpr ei? n-4 ~ en-3,20-dione, 17-acetate

The procedure of Example 33 is followed, but (-) - 13-butyl-17oc-hydroxy-18,19-dinorpregn-4 ~ en-3,20-dione is replaced by ( ^± ) -13-ethyl-17ar-hydroxy- 1 &, 19-dinorpregn-4-en-3,20-dione

209816 / UÜO

and receives (i) -13-ßutyl-17a-hydroxy-18,19-d.inorpregn-4-en-3,20-dione, 17-acetate.

Example 36

(t) -1 3-isobutyl-17a-hydroxy-18, ^ -dinorpregn - ^ - en -:?, 20- dione, 17-acetate

I4an follows the procedure of Example 33 »but replaces (-) - 13-isobutyl-17oc-hydroxy-10, 19-dinorpregn-4-en-3» 20-dione by (i) -13-ethyl-17a-hydroxy- 18,19-dinorpregn-4-en-3,2O ~ dione and receives (i) -13-isobutyl-17a-hydroxy-'16 _t 19-dinor- 'pregn-4-ene-3,20-dione.

Example 37 (-) - 13 - ^ thyl-18 _< 19-dinorpregn-4-en-17a-ol-3 _> 20-dione

The procedure of Example 1 is followed, but (-) - 13ß-Ethyl-5-methoxy-des replaced A-18,19-dinorpregna-5,7,9-trien-2O-one (1) by (i -) - 17-ß-acetyl-13ß-ethyl-3-iaethoxygona-1,3) 5 (lü) -trien and receives (±) -13ß-ethyl-5-methoxy-des A-18,19-dinorpregna-5,7,9,17 (20) -tetraen-2Q-ol.

The procedure of Example 5 is followed, but replaces (-) - 13β-ethyl-5-methoxy-des A-18,19-dinorpregna-5,7,9,17 (2Q> tetraen-20-ol, acetate by (£) -13ß-ütfchyl-3-methoxy-18,19-dinorpregna-1,3ί5 (ΊΟ) i17 (20) -tetraen-20-ol, acetate and receives (i -) - 13ß-Ethyl-17a, 20 ^ -epoxy-5-methoxy-des A-18,19-dinorpregna-5,7,9-trien-20 ^ -ol, acetate.

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209816/1500

The procedure of Example 9 is followed, but replaces (-) - 13β-ethyl-17a, 20 ^ -epoxy-5-methoxy-des A-18,19-dinorpregna-5,7,9-triene-205; -ol, acetate by (±) -13ß-ethyl-3-methoxy-18,19-dinorpregna-1,3,5 (10) -trien-17oc-ol-20-one and receives (±) -13ß-ethyl-5-methoxy-des A-18,19-dinorpregna-5,7,9-trien-17a-ol-20-one.

The procedure of Example 25 is followed, but replacing (-) - 13β-ethyl-5-methoxydes A-18,19-dinorpregna-5,7,9-trien-17ocol-20-on by (i) -13β-ethyl-3-methoxy-18,19-dinorpregna-1,5,5 (10) -trien-17cc-ol-20-one and receives (i -) - 13ß-ethyl-5-methoxy-20-cycloäthylendioxy-des A-18,19-dinorpregria-5.7 > 9-triene-17a-ol.

The procedure of Examples 17 and 21 is followed, replaced but (i) -13ß-iithyl-5-methoxy-20-cycloäthylendioxy-des ΑΙ 8,19-dinorpregna-5,7,9-trien-17a-ol by (±) -13Ji-ethyl-17a, 2u-dihydroxy-3-inethoxy-18,19-dinorpregna-1,3,5 (10) -triene and (-) - Ethyl-5-methoxy-2Ü-cycloäthylenedioxy-des A-18,19-dinorpregna-5 (10), 7-dien-17a-ol by (±) -13ß-Ethyl-17oc, 20-dihydroxy-3-methoxy-18,19-dinorpr egna-2,5 (1 u) -diene and receives (-) - 13β-ethyl-des A-18,19-dinorpregn-9-en-17aol-5,20-dione.

A solution of 200 g of (i) -13β-ethyl-des A-10, 19-dinorpregn-9-en-17 "-ol-5,2Q-dione in 0.4 ml of pyrrolidine is heated at 88 ⁰ O for 1 ½ minutes . After cooling to ⁰ G, 2.0 ml

209616/1500 ~ ⁵⁹ ~

methanol added. The i'eststoff is filtered under Formation of (i) -13ii-iithyl-3ü-pyrrolidinyl-des A-1ö, 19-

To a solution of 0.225 g of potassium iodide in 2.0 ml of dimethylformamide at O ⁰ G, 0.5 g of (i) -13β-iithyl- $ - N-pyrrolidinyl-des A-18,19-dinorpregna-5 (10), 9 (11) -dien-17a-ol-2ü-one was added in the dark. After 15 minutes at ⁰ G, 0.21 ml of 1,3-jjichlor-2-butene are added under nitrogen. Stirring is continued under nitrogen at 0-0 for 4 hours. A 0.4 ml v / assermenge is added and the mixture heated at 90 ⁰ C 2 btunden. After cooling to room temperature and dilution with 20 ml of water, the mixture is extracted with methylene chloride, the extracts are dried over anhydrous sodium sulfate and stripped off under vacuum. The residue is chromatographed over Florisil with formation of (i) -3-chloro-13β-ethyl-1δ, 19-dinorpregn-4,5-seco-2,9-dien-17cx-ol-5j20-dione,

^ u a solution of 0.20 g (±) -3-chloro-13ß-ethyl-18,19-dinorpregna-4,5-seco-2,9-dien-17a-ol-5,2O-dione in 0.3 ml of i-ethyl chloride at 0 G, 1.0 ml of concentrated maltic acid are added admitted. Stirring is continued for 15 minutes while raising the mixture to room temperature leaves. Then 10 ml of water are added and the mixture is extracted with methylene chloride, washing with sodium bicarbonate

-40-

2098i6 / 1S0Ö

BAD ühto

nat, then water and drying over anhydrous sodium sulfate and stripping under vacuum gives (i) -13ß-eth, yl-18,19-dinorpregna - ^ -, 5-seco-9-en-17oc-ol-3,5,20-trione.

A solution of 285 mg of (i) -13ß-ethyl-18,19-dinorpregna- 4,5-seco-9-en-17oc-ol-3 ₎ 5 »20-trione in 5» 7 ml of 95% ethanol and 0.12 ml of diethylamine is hydrogenated at room temperature over 200 mg of palladium black. After filtration and evaporation in vacuo, (i) -13ß-ethyl-18,19-dinorpregna-4,5-seco-17a-ol-3,5> 20-trione is obtained.

A solution of 125 mg (£ -) - 13ß-Ethyl-18,19-dinorpregna-4,5-seco-17a-ol-3,5,20-trione in 1.25 ml of pyrrolidine is taken at 87 ° C for minutes nitrogen heated. The pyrrolidine is evaporated under a stream of nitrogen and 2.5 ml of methanol are added. Cooling to ^{0 0} G and filtering gives (- ) -13ß-ethyl-3N-pyrrolidinyl-18,19-dinorpregna-3,5-dien-17oc-ol-20-one.

A solution of 118 mg (i) -13β-ethyl-3N-pyrrolidinyl-18,19-dinorpregna-3,5-dien-17a-ol-20-one in 0.12 ml of acetic acid is left to stand for five minutes. Then 1.2 Wl of water added and the mixture kept at 25 ° C for 1 hour. Sodium hydroxide solution is added and the filter results (±) 10, 1 y-dinorpregn-4-en-17a-ol- ^, 20-dione.

-41-209016 / 1500 BAD0RK3INAL

Example 38

(~ ) -13ß-Ethyl-18, 19 ~ dinorpreKn-4-en-17a ~ ol-3 _< 2Q-dione

To a solution of 1.0 g of (i) -13ß-ethyl-3-methoxy-20-cycloäthylendioxy-18,19-dinorpregna-2,5 (10) -dien-17a-ol in a mixture of 35 ml of methanol, 9.0 ml of tetrahydrofuran and 6.6 ml of water are added 0.65 S oxalic acid dihydrate. The mixture is stirred at room temperature for 3 hours. Water is then added and filtration gives (i) -13β- W ethyl-18,19-dinorpregn-5 (10) -en-17a-ol-3,20-dione.

A solution of 1.0 g of (i) -13-ß-ethyl-18,19-dinorpregn-5 (10) -en-17a-ol-3 »20-dione in a mixture of 30 ml of methanol, 1.5 ml of water and 2.0 ml of concentrated hydrochloric acid is stirred at room temperature under nitrogen for 30 minutes. Then benzene is added, the mixture with aqueous Sodium bicarbonate, then washed with water, over anhydrous Sodium sulphate dried and stripped off under vacuum, whereby the one designated in the title Connection received.

Example 39

(-) - 13β-Ethyl-17oc, 20-dihydroxy-18 ₁ 19-dinorpresn-4-en-3-one

To a slurry of lithium aluminum hydride in 110 ml 3.5 S '<tetrahydrofuran was added a solution of 2, Qg (£) -> ^ ß-ethyl 17oc-hydroxy-1c3,19-dinorpregn-4-ene-3,20- dione in 60 ml of tetrahydrofuran with stirring at room temperature for 15 minutes

20 * fl1 * / 1600

long admitted. Wax 2-hour Langeni heating under kuckfluß the mixture is cooled to room temperature and washed successively 5 »5 ^m l of water, $, 5 ml 15> and aqueous sodium hydroxide and '10, 5 ml" Vasser added üach filtration is the filtrate diluted with ether , washed with saturated aqueous sodium bicarbonate, then with water, dried over anhydrous sodium sulfate and vacuum stripped to give a mixture of epimers of (-) - 13ß-ethyl-3,17a, 20-trihydroxy-10, 19-dinorpregn -4-en.

To a solution of 2.0 g of (ί) -13Ii-ethyl-3,17a, 20-trihydroxy-18,19-dinorpregn-4-en in 50 ml of dioxane were 2.0 g of 2,3-dichloro-5 »6-dicyanobenzoquinone admitted. Wake up stirring for 2.5 hours at room temperature, the mixture is with Dilute methylene chloride and filter. The filtrate was stripped off under vacuum and the residue over aluminum oxide chromatographed to give the title compound.

It is clear that either the dl-oteroid or the specific d- or 1-isomers can be used as starting materials with similar results.

-43- 200816/1500

Claims (7)

Patent claims: 1. A process for the preparation of a bteroid compound of general formula (I) (I) where Λ cine ΑΙΙς / l group of 2 to 8 carbon atoms, R hydrogen or an acyl group, X is a carbonyl or hydroxymethylene group and the hydrogen atoms H in the δ-, 9- and 14-positions and the group K in the O- ^ position in aer trans-anti-trans-ion configuration, the hydrogen in the 10-position and the group -X-CH ₇ cis to the group in the '! ^> -Position and the group Ok trans to the group m of the IJ position is characterized in that (a) a connection of the x'Oruiel (II) (Π) 1
in white α an aroonyl-jdydroxyiiietujien- or ketalioated Oax-uoivigrappe una χ cine hvdrolyzable protected 209816 / UOO -44-BAD ORfGiNAL ixo group and hinge A and B is a double bond -Lr. the 4 (5), 5 (10) or 5 (6) position with or without a second double bond in the 2 (3) or 3 »(4) position is, is hydrolyzed and, if necessary, a 5-keto- ^ - ^ '-steroid is isomerized to the 3-keto- ^ -steroid and, if desired, the product in which X is an carbonyl group is, is reduced to a compound in which X is a hydroxymethylene group, the product in which X is a Hydroxymettiylengruppe, to a compound, in which X is an carbonyl group oxidizes or the product in which R is hydrogen to form a compound in which H is an acyl group, acylated will. (b) a compound of the general formula (VIII) . (VIII) in which the dotted lines indicate the presence of an ethylene bond in the 5 (10) or 5,6 position, Isomerization takes place with rearrangement of the ethylene Binding in dis 4,5-position and, if desired, the product, in which X is a hydroxymethylene group, is oxidized to form a compound in which X is an Oarbonyl- -45- 20 * 818/1600 ORIGINAL INSPECTED grupp.e is the product in which X is a carbonyl group is reduced to form a compound in which X is a hydroxymethylene group, a compound in which R is hydrogen, is acylated to form a compound in which K is an acyl group or a compound in which R is an acyl group, hydroly- is siert under -bildung a connection in which H Is hydrogen, (c) a 3-hydric oxysteroid of the general formula (IX) (IX) where the dotted lines end in the 5 ~ ^ "elevation Show ethylenic bond is oxidized and if the starting material has an ethylenic bond in the 5,6 position contains, the ethylenic bond is conjugated with the carbonyl group formed, if desired. 2Ü-aeto-steroid is selectively reduced to the corresponding the 20-hydroxysteroid, a compound in which R is hydrogen is acylated to form a compound in which R is an acyl group, or a compound in which K is an acyl group, is hydro, -lyäert under Formation of a compound in which R is hydrogen. -46- - 509816/1500 or (d) a 3 »5-diketo-4-, 5-secosteroid of the formula (a) (X) (wherein R ₁ R and the configurations in the 8, 9, 13, 14 and 17 positions have the meaning given in claim 1, X is a carbonyl, ketalized carbonyl or Is hydroxymethylene group and H and P is oxo or protected Üxo groups are subject to internal aldol condensation and, if desired, a connection to the i'Ormel I, in which X is a carbonyl group is reduced below Formation of a compound in which X- is a hydroxymethylene group is a compound in which X is a hydroxymethylene group is, is oxidized to form a compound in which X is a carbonyl group, .or a Compound in which R is hydrogen is acylated to form a compound in which R is an acyl group is. 2. The method according to claim 1, characterized in that the compound of formula (II) is an enol ether of the general Formula (III) is 20961S / 1500 (III) in which Z such a substituted or unsubstituted aliphatic hydrocarbon group whose bond with the oxygen atom is against the action of an alkali metal is stable in liquid ammonia. 3. The method according to claim 2, characterized in that the enol ether of the general formula (III) is prepared is made by reducing a steroid of the general formula (IV) (IV) and, if necessary, the product in which X is a hydroxymethylene group is oxidized to form -1 a compound in which X is a carbonyl group. she 4. Bteroid connection characterized by the fact that / the all- -48- 209816/1500 has common formula (I) (D where K is an alkyl group from 2 to 6 carbon atoms, H is hydrogen or acyl group, X is a carbonyl or hydroxymethylene group and the hydrogen atoms are H in the δ, 9 and 14 positions and the group K in the 1 position in the trans -anti-trans-configuration, the hydrogen in the 10-position and the group -A-Gii _y cis to the group in the 1 ^ -position and the group ü-i tx -? '. ns to the group in the i ^ - ^ position stand. 5. A compound according to claim 4, characterized in that Ii is an iithyl group. o. Compound according to claim 4, characterized in that ii is a ni-ropyl, η-butyl or isobutyl group. 7. oteroid connection characterized in that they are the has general formula (IV) 209816/1500 BATHROOM 0RK31NAL ν; οι * in ίί and the iioiifigurationen in ö-, 9-, 15-, 14- and 17-ouelluiii; en the meaning given in claim 1 naDen, λ. a Oarbon ^ l-jii.ydroxynieuujlen- or ketalized carbonyl group and Z 'is such a substituted or unsubstituted alipiiatische Kohlerr.vasserstof! group jjinaunjj aer with the oxygen atom gegenüuex ¹ üinv / daii MPACT a iiikalimetails in liquid ammonia is staoil. 209816/1500 BATH