DE2547840A1 - METHOD FOR PRODUCING 16- (5'-SPIRO-1 ', 3'-DIOXANYL) STEROIDS - Google Patents

Description

UEXKÜLL & STOlBERG 2 HAMBURG 52

BESELERSTRASSe 4

Judge Gedeon Vegyeszeti Gyar Rt. 21, Gyömröi ut. Budapest X, Hungary

25Λ7840

PATENT LAWYERS

OR. J.-D. FRHR. by UEXKÖLL DR. ULRICH GRAF STOLGEFtG DIPL.-ING. JÜRGEM SUCHANTKE

Priority: October 31, 1974
Hungary No. RI-55o

Hamburg, October 22, 1975

Process for the production of '
16- (5'-spiro-1 · , 3'-dioxanyl) steroids

The invention relates to the production of new 16- (5'-spiro-1 ¹ , 3 * ~ dioxanyl> -steroids of the general formula I

(D

wherein R _{1 is} hydrogen or an acyl group having 1 to 4 carbon atoms, Z is one of the groups of the sub-formulas Z ^ to Z ₅

.V ■

and in these R ₂ hydrogen or an alkyl or acyl group with 1 to 4 carbon atoms, advantageously a methyl r, "
Means ethyl or acetyl group.

A 83P-67 / RI-55O

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Some of these new compounds of general formula I show valuable pharmacological properties. B. the 16 "§'-Spiro-4 * -hydro2: y- -l ^> , 3 ^> -dioxanyl) -androst-5-en ~ 3ß -ol-17-one estrogen and the lG-CS'-SpiroH- '-acetoxy-1', 3 »-dioxanyl) -androst-4-en-3 _> 17-dione-3-enol ether uterotropic effects. In addition, these new compounds of general formula I are valuable ingredients for the production of other pharmacologically active steroid compounds .

The new compounds of the general formula I are produced according to the invention, as steroid compounds are used of the general formula II

CH-OH

αϊ)

wherein Z has the above meaning, is reacted with formaldehyde and the resulting gewlinschtenfalls L6 (5 ^{f f} -spiro- ^{-4-hydroxy-l-t} i3' d ⁱ oxanyl) steroids aoyliert at the 4'-hydroxyl group.

The starting materials of the general formula II defined above are either already known from the literature or can easily be prepared by the methods described in the literature for the preparation of analogous compounds. For example, the compounds 16-hydroxymethylene-5 € * -end3? OBtan-3ß -ol-17-one and lo-hydr'oxymethylene-androst-S-en ^ i * -ol-17-one according to Ruzicka u Employees, HeIv. Chim, Acta ^ J., 1296 (1948), the 16-hydroxymethylene-ÖBtj? Al, 3,5 (LO) -trien-3 (9.- -ol-17-one after J. 0. Bardlan, J. Chem. Soc. 1936 , 1948

eoae 19/111 ö

be made, The αβχ ^ ί. =; n.au & vuu 1.6-fi ^ droxymethylene-androst-4 ~ en-3yl7-dione cannot be carried out using the method which is described for analogous compounds in U.S. Patent No. 3,080,389. Finally, the l-hydroxymethylene rust - ^ - -en-3 »17 ~ dione-3-enol-ethyl ether is a» iB the Andros ^ - described by A. Serini H. Koester _{, reports, JJl 1 1766 (1938)} en ^ jrif-dion-S-onol-äthy lather on the V / exse described in Example 6 for the heat position of the Auagansstoffes produced.

Certain spiro-dioxanyl derivatives of steroid compounds have also been described in the literature; Bans on and colleagues / J. Org. Chem. Ffi> , 3434 (1967J7 were involved in the production of such derivatives. However, these authors have only described those derivatives and their production * in which the 5 »-spiro-4'-hydroxy ti · * . -4 * -acetoxy-l ', 3 ^> -dioxane _i 7l ring in the 2-stem arrangement "around the silicoid skeleton of compounds of the aadrostan-fixed" Pregnane series is bound. Compounds of the ¹ S ^ p d "y general formula I, in which this Spirogroup · is in the 16-position were not known so far. "

For the production of the new 16- (5'-SpIfO- -1 » _t 3» -dioxass ^ l) -steroids of the general formula I we use the "« fact speaking η 16-hydroxymethyleri "si9poid" compounds of the general formula II with 2 Moles of formaldehyde reacted, this reaction, is advantageously carried out in the presence of a neutral (neither basic nor acidic) solvent or solvent mixture.

The formaldehyde can act as a reactivon to this reactivon Gas or in the form of aqueous vapors or of diluted or concentrated solution can be used

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the. The kenge of the formaldehyde used can fluctuate between wide boundaries, but around favorable ones To achieve pleasure it takes more to use as the etoichiometric amount of formaldehyde; A multiple of the stoichiometric is advantageous Amount used.

Neutral, with Polar organic solvents that do not react with the reaction components or mixtures of such solvents are used with waterFrom the point of view of the reaction, it is not necessary to that 'both the starting materials and the end products in the solvent used or solvent mixture should be soluble. The neutralons that can be used as the reaction medium, polar organic solvents know with waaeer be limited or unlimited mixable; as examples of suitable organic solvents, lower, advantageously containing 1 to 5 carbon atoms primary, secondary or tertiary alcohols, as well as asymmetrical or asymmetrical ketones, e.g. Methanol, ethanol, propanol, isopropanol, butanols, amyl alcohols, also methyl ethyl ketone, methyl butyl ketone, Acetone, as well as aqueous mixtures thereof, can be mentioned.

Since the reaction of the compounds of general formula II with formaldehyde is an equilibrium reaction, its equilibrium is determined by the amount of the water present can be influenced, the amount of water - based on preliminary tests - chosen so that the equilibrium in the direction of the formation of the desired end pro-

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should be moved.

In an advantageous embodiment of the process according to the invention become the solution the AuBgc: gav compound of the general formula II of Formaldehyde and that water at the same time, in the Foriu of aqueous formaldehyde solution added.

In carrying out the reaction ea is to be noted that as * reaction product forming l6 ~ (5 "spiro-l ', 3 * -dioxanyl) dasa -ateroide the general formula I in water containing Lösungsiiiittelgemiachen at temperatures above 50-60 ⁰ C decompose quickly, on the other hand at temperatures below * 5 0 a very considerable reduction in the rate of reaction must be expected. Therefore, should the reaction at temperatures between about 5 C and 40 ⁰ O, advantageously be carried out at 15-25 ⁰ O.

The 16- (4 * -acylroxy-5 * -Bpiro-l *, 3'-dioxanyl) -ateroids der'general η formula I. (where'R · »acyl group) can, by acylating in the above manner obtained IS-CS'-Spiro ^ '- hydroxy-l *, 3 »-dioxauyl) -storoide getting produced. As an aoylating agent For this purpose, chlorides or anhydrides of lower Alkanearbonsäureη can be used. the Acylation is conveniently carried out at room temperature., In Presence of an organic base, e.g. pyridine " carried out. You can also stay in a neutral. '. Work in the middle of Löaunga 1, but in this'm? Ali it is Bweckmäaaig to add an inorganic or organic acid binding agent to the reaction.

Be in the inventions. Process ala Auagangsatoff e steroids of the general formula Ii used, which, in place of R _2, a Waaaex-

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at offatom are included in the acylation that obtained by reaction with formaldehyde 4 »-hydroxy compounds the corresponding 3» 4'- -Diacylverbiadungen received as end product «.

By suitable choice of the subatituents in the 3-position of the starting compounds of the general formula II, it is also possible to derive those 3,4-diabetic compounds of the general formula I which contain R 1 and R _{2 in} acyl groups which differ from one another the 3 or 4 'position.

The further details of the invention Procedures are illustrated in more detail by the following examples, but it must be noted that . dasa the invention in no way to the 'content d these examples is limited. The melting point values given in the examples were compared with the Kofier's before η-apparatus. Which you are not chromatographic η-R ^ values were determined on "Silicagel G, Merck "Plates of O," determined to be 25 mm thick; the The solvent mixtures used are freely given the individual - ^ - values in brackets. To evaluate the chromatograms, the

Plates kept for 15 minutes in a drying cabinet ^{heated to 100-12P 0} G and then sprayed with 50% aqueous phosphoric acid solution. The Rp values were determined in ultraviolet light of 365 mA wavelength. The optical rotation values were measured in a Bellingham & C Stanley "achen Spekiro" • polarimeter of the type "Pojpol 60".

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- S _

Bt ic pie jl 1:

a) 15.9 g iO, G5 mol) 16 ~ Hydroxymethylene-5 =><.- andro & t ~ -3 (5 -oil -17-O,! are slurried in 200 ml of acetone, then the 30 ml of 40% aqueous formaldehyde solution are added to the suspension and the mixture is stirred for one hour. During this time, the reaction mixture clears and then a crystalline precipitate separates out. This precipitate is filtered off, the filtrate is washed free of formaldehyde with deionized water and washed free of formaldehyde at room temperature in a vacuum 18 g of 16- (5 '"- Spiro-4'-hydroxy-1 ^f , 3 * - ° ^ -dioxanyl) -5p. androst-3 -ol-17-one (93 % of theory ). F .; 126-126 ⁰ C.

Analysis for C ₂₂ H ₃₄ O ₅ (378.512):. Calculated: C 69.81, H 9.05, 5 &;
found: G 69.95, H 8.80 ü,

£ ** ι7ψ = * ^ö0 ° (c = 0.5 in chloroform, 5 cm cuvette). R _f = 0.40 ^ benzene, with 10 % methanol),

0.85 (chloroform, with 10 % glacial acetic acid). Example 2:

• 15.8 g (0.05 mol) of 16-hydroxymethylene-androate- -5-en-3β-ol-17-one are suspended in 250 ml of methyl ethyl ketone, mixed with 30 ml of 40% aqueous formaldehyde solution (0.4 mol ) added and stirred for an hour. The precipitate initially formed dissolves, the reaction mixture clears and then a crystalline precipitate begins to separate out again. To complete the precipitation of the crystals, the mixture is a 24 hour period at 0 ⁰ C allowed to stand, then the crystalline product is filtered, deionized with ,; Water washed free of formaldehyde and dried in a vacuum desiccator at room temperature. It'll be that way

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14 g l6- (ii ^>

-5..βn-3 / ^ ι-ol-17-one (72 % of theory ) obtained; P .: 232-235 ⁰ CU

Analysis for C ₂₂ II ₃₂ O ₅ (.376,496): " ^! "

calculated: C 70.19, H 8.56 %

found: C 70.67, H 7.94%.

/ Pi7n ° ^s + 73 ° ( ^c = °> 5 ⁱⁿ chloroform, 5 cm cuvette). IU: 0.35 (benzene, with 10% methanol), 0.80 (chloroform, with 10% ice cream).

b) 3.76 g (0.01 tool) obtained in the above manner 16- (5'-3piro-4 ^> -hydroxy-l ', 3 * -dioxanyl) -androate-5-en ~ 3A «' -ol- 17-one are dissolved in 20 ml of t'yridine, 4 ml of eaaigaic anhydride are added and the mixture is left to stand for 24 hours. Volume V / ater, extracted the precipitating oily product with benzene, the benzoliache .Extrakt separated, washed with anhydrous sodium sulfate and dried in vacuo, evaporated in a water bath of at most 5 ⁰ C. The oily residue obtained '• is crystallized from petroleum ether (boiling range: 40-6O ⁰ G) Ba are in this way .3, Ig 16- (5'Spiro-4'-acetoxy-.;-L',3'- dioxanyl) -androate-5 ~ en-3β-ol-17-one-3-acetate (67 % of theory) obtained; F.: 118 ₇ 120 ° C. . ·.

Analysis for C ₂₆ H ₃₆ O ₅ (460,580):

Calculated: C 67.81, H 7.87 Yo. '

found: C 6β.12, H 7.70 · $. ·

ίΡ <^ ° = t51 ° (c = 0.5 in chloroform, 5 cm cuvette). R _f = 0.8 (benzene, with 10 % methanol). Example 3:

1518 g (0.05 mol) of 16-hydroxymethylene-androate- -5-en-3P-ol-17-one are suspended in 250 ml of n-butanol, with 30 ml of 40 % aqueous formaldehyde solution (0.4 mol) added and stirred for one hour. The initially precipitous reaction mixture clears up

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a crystalline precipitate begins to separate out. To complete the crystallization, the mixture becomes. Left to ^{stand at 0} ° C. for 24 hours. The crystalline precipitate is filtered off, washed free of formaldehyde with deionized water and dried to constant weight in a vacuum desiccator. In this way, 8 g of 16- (5'-SpIrQ-A * -hydroxy-1 *, 3 * -dioxanyI) - -androst-5-en-3β-ol-17-one (41 % of theory) .) obtained: F .: 232-235 ° 0.

Example A ', '

a) 15.6 g (0.05 lio 1) 16-hydroxyinethylene-oestra-1,315 (10) -trien-17-one-3-methyl ether are dissolved in 100 ml of 96% ethanol, with 30 ml of 40% aqueous formaldehyde solution are added and the mixture is left to stand for one hour. The mixture is then diluted with water until it becomes cloudy and left to stand at 50 for 24 hours. The product separates out in crystalline form; it is separated by filtration, washed free of formaldehyde with deionized water and dried in a vacuum desiccator at room temperature. There are 16 g ^ l6- (5 * -Spiro-4 ^f - -hydroxy-l », 3» -dioxanyl) -östra-l, 3 »5 (10) -trien-17-one- -3- rae thy lather (92 j »d. Th.) received; P .: 99-101 ⁰ C.

Analysis for C ₂ ^H 28 2 ° 5 C372,460): calculated; C 70.94, H 7.58 #; found: C 79.64, H: 7.5i #.

Equation 7q ° = x + 120 ° (c = 0.5 in chloroform, 5 cm cuvette). R _f »0.5 (benzene, with 5 % methanol).

* to) 3.7 g (0.01 mol) obtained in the above manner l6- (5 ^t -Spiro-4 »-hydroxy-l» _t 3 »-dioxanyl) -östra-

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-l, 3 »5 (10) -1irien-17-oa-jwaethy itithör are dissolved in a mixture of 10 ml of T. 'ssigsäureanhycirid and 10 inl pyridine and left to stand for 24 pieces in a room above ground. Dana is precipitated by adding vYa & aer the product, separated by filtration and still in the moist. State from a 3 »1 mixture of methanol and water recrystallized. 1,3,5 (10) -trien-17-one- -3-methyl ether (85% of theory) obtained: F .: 84-87 ⁰ C.

; Analysis for C ₂₄ H ₃₀ O ₆ (414.500): Calculated: C 69.55, H £ 7.30. . '
found: C 69.90, H 7.48 Jb.

ßAj ^ ° =, + 143 ° (c = 0.5 in chloroform, 5 cm cuvette). R _f = 0.9 (benzene, with 10 % methanol). Example 5:

18.7 g (0.06 mol) of 16-hydroxymethylene-androate-4-ene-3,17-dione are dissolved in 200 ml of acetone, treated with 30 ml of 40% aqueous formaldehyde solution (0.4 mol) and Left for 24 hours. Then, the Reaktionegemisch with water until the onset of turbidity diluted and 24 hours at 5 ⁰ C for gelasaen. The product separates out in crystalline form; it is separated by filtration, washed free with β nt ionized water formaldehyde and dried in a vacuum desiccator at room temperature. In this way, 12 g of 16- (5'-Spi.ro-4'-hydroxy "-l", 3 ^l -dioxanyl) -androst-4-en-3,17-dione (52 % of theory) are obtained .) obtain; Q .: 135-137 ⁰ C

Analysis for C ₂₂ H ₃₀ ⁰ S (374.480): Calculated: C 70.57, H 8.07 % \ '''''

found: C 70.31, H 8.38 %.

Ά7 $ ^Ο - + 110 ° (c = 0.5 in chloroform, 5 cm cuvette). R _f i 0.8 (benzene, with 5 % methanol).

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Example 6:

Λ β (0.05 mol) 16-Hydroxyinethyleti-androate "" -4-en-3,17 - ". 'Ion-3-enol-ethylätlier are dissolved in 300 ml of acetone with 30 ml of 40% aqueous Formaldehyde solution is added and the mixture is left to stand for 24 hours. The reaction mixture is then diluted with water until it starts to become cloudy and left to stand for a further 24 hours. The crystalline product which separates out is filtered off, washed free of foamaldehyde with deionized water and dried in a vacuum desiccator to constant weight. In this way 16 g of crystalline 16- (5'-Spiro ~ 4 ^> ~ hydroxy-1 ', 3 ^f -7dioxanyl) -androstT4-en-3,17-dione-3-enol-ether (79 % d . Th.) Received; ί ^1st : 105-107 ⁰ C..

Analysis for C ₂₄ H ₃₄ O ₅ (402.530): Calculated: C 71.61, H 8.51 #; found: -C 71.50 ·, H 8.39 ^.

^ q ⁰ =, + 145 ° (c = 0.5 in chloroform, 5 cm cuvette). 0 »9 (benzene, with 5 % methanol).

The 16-hydroxyinethylene-androate-4-en-3 »17-dione--3-enol-ethyl ether used as starting material in the above example can be prepared in the following way : ■■■ -.- ■

That from 2 g of sodium metal and 100 ml of absolute Uodium methylate produced in methanol is suspended in 50 ml of absolute benzene and mixed with 5 g of androst-4-en-3,17-dione-3-enol-ethyl ether offset. Then * 30 ml are freshly distilled while cooling with ice Ethyl formate was added dropwise and one lets the * mixture settle to the dream temperature warm up and stand for 12 hours. The mixture is then mixed with the calculated amount of aqueous wine acid

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solution the pH = 7 neutralized, diluted with water to ten times its volume and extracted three times with 100 ml of benzene each time. The benzene extracts are combined, dried with anhydrous sodium sulfate, and 4 ^m water jet vacuum evaporated at 45 ⁰ C to dryness. The dry residue obtained is recrystallized from a 1: 1 mixture of acetone and water. In this way, 5.1 g of 16-hydroxymethylene-androate-4-en-3> 17-dione-3-enol ethyl ether are obtained (93 % of theory) obtained; F .: 130-132 ⁰ C.

Analysis for C ₂₂ H ₃₀ O ₃ (342.480): Calculated: G 77.17, H 8.83 M.
found; C 77.35, H 8.70 %.
: 0.8 (benzene, with 5 % methanol).

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Claims (8)

2 5478AO Pat ^{ent.anspräche:.} ^ .: ^c (J ₁ ] .Verfahren- züjc- production of new 16-C5'- -Spiro-4 ^f -hydroxy- or -4 * -acyloxy-l *, 3'-dioxanyl) -. steroids of the general Porrael I .. ··,; .. where K ₁ V / adseratoff or a ^ cyl group with 1 to 4 carbon atoms, Z one of the groups of the partial formulas ^ ₁ to Z ₅ . V>. ' : ': 6-09819 / 1110 -H- and in these R ₂ denotes hydrogen or an alkyl or acyl group having 1 to 4 carbon atoms, characterized in that steroid compounds of the general formula II ·. CH-OH where Z has the above meaning, reacts with formaldehyde and, if necessary, the 16- (5'- -Spiro-4'-hydroxy-1 *, 3'-Ä.ioxanyl) -st # roide at the 4'-hydroxyl group acylated » 2. The method according to claim 1, characterized by dadurph, that the formaldehyde is used in the form of an aqueous formaldehyde solution. 3. The method according to claim 1 or 2, characterized in that the reaction with aqueous Formaldehyde carried out in the presence of an alcohol or ketone. 4. The method according to claim 3, characterized in that the ketone used is a ketone which is infinitely miscible with water, advantageously acetone. 5. The method according to claim 3, characterized in that the ketone is limited to one with water miscible ketone, preferably using methyl ethyl ketone " 609 * 19/1110 6. The method according to, Aaaprucii j, _i characterized in that the alcohol "" is a. iai-t -iaäsev unlimited miscible alcohol / advantageously Athanbl uses. ; 5 7. The method according to claim 3 »da ^ urcJa characterized, that as alcohol you are limited to vigsefär Miscible alcohol, advantageously n-Butaöbl uses. 8. Werfahreft ';maehrej; neia: 4esE ^ ABAgriiche ^ l ^ to 7 * dadurdh gekenia? S @ i $ hiaej, ^ d & sajimaa .-. The -.- Umeteuag aiit iOrmaldehyd bei rfesperat ure η awische n ,. 5 ° -G, _{r and} n4i .41 ° ^ performs. - - ^ i? · _; ■ ^ ^ _λ-:; ^ - _; ·; » _X: ^ (... . - ^r I.I ': ■ - 9. The method Naeh ^ Ansgrgch ^^^ i ^ ^ dttrc in one daaa than Ae $ lierungs mitt | i, a ilkancarboGsäure _o mp, l _{v: 4;?} Kghle , ν; i ^ Ui 10 * Ίread $
ν on ^ o-C5 * -Sp -androstan ^ ß-ol-rZ-on, thereby
man lfigä Formaldehyde converts. », _; , 12. The method according to claim 1 for the preparation of l6 _r (5 »-Spiro-4'-hydroxy-l ^> , 3 ^> -dioxanyl) -öetra- -l, 3,5 (10) -trien-17-one- 3-uiethyl ether, characterized in that 16-hydroxymethylene-oestra-1.3.5UO) -trien-17-one-3-meth.yl ether is reacted with formaldehyde. 254784Q 13 » Procedure according to. Claim 1 for the division of J6 ~ (5 ^s ~ spiro ~ 4 ⁱ ~ hydroxy-l \ 3 ⁱ "dioxanyl) -and: i? Q t- ~ 4-en-3» 17-dione, characterized in that one l6 ~ Hydroxymethylene-androate-4-en ~ 3 _s 17-dione reacts with formaldehyde. , 14. The method according to claim 1 for Herateilung ν on l6- (5 ⁱ "Spiro-4 ^> -hydroxy-l ⁱ _s 3 ⁹ -dioxanyl) -androet- -4 ~ en-3> l? -Dione-3-etioläthyläther , characterized in that l6-hydroxymethylene ~ androate * -4 ^ eä »~ -3 * 17-dione-3-enolethyl ether is reacted with formaldehyde. , 15. Process according to claim 1 for the production of 16- (5 * -Spiro-4 * -acetoxy-l ^f , 3 »-dioxanyl) -aiEl: rößt ~ 5-en-3 ^ -ol-17-one-3- acetate, characterized by the fact that one lo-hydroxymethylene-androst-S-an- ^ i Reacts with formaldehyde and acetylated the obtained. , 16. Process according to claim 1 for von l6 _r (5 * -Spiro-4'-acetoxy-l ^f , 3'-dioxany-l, 3,5 (10) -trien-17-one-3-methyl ether, dadua? Oh zeiohoet that l6-hydroxymethylene-oestr-t, 3 * S (iÖ ^ *. -trien-17-one-3-methyl ether is acetylated with formaldehyde to give the product obtained * 6 0 9 8 19/1110