DE1493163A1 - Process for the preparation of 17alpha-AEthynyl-18-methyl-delta? -Oestren-3beta-17beta-diol and derivatives - Google Patents

Description

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where R _{1 is} hydrogen, an acyl or a lower alkyl radical and B _{2 is} also hydrogen or an aoyl radical, and a process for their preparation, characterized in that 17a-ethynyl-18-methyl ~ 19- -nor-testosterone according to methods known per se

a) first the 17β-hydroxyl group - optionally with intermediate protection of the ^ -keto group by known ones Modification into less reactive functional groups - esterified or etherified, then by splitting off the before or any protective group introduced with the reaction sets the 3-keto group back in the usual way, the latter is preferably reduced to the 2-hydroxyl group by means of ketal hydrides and, if necessary, then this esterified or

b) initially reduced the 3-üCeto group and if necessary then esterified the ^ -hydroxyl group formed

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Γ. 849 7

It vnirde ^ efundon, according to the process producible ·;

new preconditions therapeutic, very valuable properties demonstrate. They draw sioh both orally and afterwards aubeutaner application through excellent progestative we- ... · kung au3. In particular, the esters or E3ter / ether derivatives, because they have good solubility in have the common solvents for steroid hormones, 2 B. in vegetable oils such as sesamiSl, castor oil and the like, as well as in other synthetic solvents such as glycols, lactic acid esters, benzyl benzoate and the like ·, 'and it · -mög- ... ^ is borrowed, by injection of such solutions of the said Deri-. vate Horiaondepots, '. '

In addition, the new compounds have excellent central effects and are, for example, also highly orally effective: *; .. · '·· Ovulation inhibitors ·' ■■ ..-. ·· · .:. ' . ·· ^- .. * '

In addition, the higher esters still have good protracting

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The production of the new compounds according to the invention is',. ;.; follows the methods customary in steroid chemistry, '...' where the starting product is the well-known 17a-ethynyl-18-methyl-. \ · 19-nor-t it roars eron serves · ', "

The necessary esterification reactions with the desired acid can be carried out in both acidic and alkaline reaction.

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SCHERING A.G. BERLIN - 3 - ■ P. 849 / 6. 2. 1? 6?

medium · The acidic esterification is, however less suitable because it is simultaneous with the 17-monoesterification Aromatization of the Α-ring takes place to a considerable extent. The alkaline esterification, preferably with the anhydride of the desired acid in the presence of one, is therefore expedient organic stickst off base, like pyridine or quinoline, because at the same time the 5-xeto group is protected as an enol ester and thereby the disadvantageous A-ring aromatization is avoided ·. ».

The etherification in the 17-position takes place by means of the usual alkylating agents according to methods also known, preferably in the cold with alkyl iodide in an inert solvent, such as. B. tetrahydrofuran, in the presence of alkali amide, such as sodium or potassium amide. This is necessary before the 2-keto group, z * B * else intermediately to protect a 3-Setal or 3-enol ether, ^r in the usual Vi to potential alkylation. · 'To avoid in the A input ·. .. '".'. -

The 'Sggg 3-Kotogruppe vdrd according to known me-' thodon rait metal hydrides reduced, with the use of Iithiua-tri-tert, -butoi: yaluainiuai-hydride is preferably suitable, because this reducing agent is already present in an ester group. "pen in Ilolekül does not attack and on the other hand the 3-xeto group mainly reduced to the 3ß-hydroxyl group

The combination of the necessary procedural steps is largely determined by the final product that is ultimately desired

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- 4 - P. 849 / February 6, 1969

SCHERING A.G. BERLIN - -

Should ζ. B. Compounds are prepared in which R ₁ = H and R «β H or acyl, the reduction is the. 3-keto group inevitably the first reaction stage · However, if compounds are to be produced in which a »B. die.17- ^; and 3-hydroxy group are functionally modified, it is. expediently the conversion of the 17-OH group. before carrying out reduction of the 3-chain group. In this way it is also easy to prepare compounds in which ' R ₁ and R' are not identical. Acyl radicals b · - ;; ' ¹ , ^ interpret »■; '.', - V- '■' ■ · ■ - ■. , .-. VC :: V. " ) ':'. '■' . '' ■ //,"'. ^: "· ■. ',. <. [ ■. ^; .:" · · -.' · ,: '"V. ■"..'.

For esterification - and thus as an acyl residue - all acids commonly used in steroid chemistry can be used. Preferred suitable are aliphatic ^ carboxylic acids with in particular 1-11 carbon atoms in the acid residue, such as acetic acid, propionic acid, caproic acid, oenanthic acid, undecylic acid and the like, of course the acids can also be unsaturated, branched, polybasic or substituted in the usual way; for example trimethyl acetic acid, t-butyl acetic acid, phenylacetic acid, Cyclopentylpropionic acid, haloacetic acid, aminoacetic acid, Oxypropionic acid, benzoic acid, succinic acid, adipic acid and others.

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SCHERING AG BERLIN "-5- P. β49 / ⁶ - _Γ ² "

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Example 1:

2 g of 17a-ethynyl-18 ~ methyl-19-nor «testoateron are mixed with. 4 g: Lithium titrated butoxyaluminum hydride in 50 ml of abs. I etrahydrpfuran 90 minutes at room temperature. The healing mixture is then poured into 5/5 acetic acid and extracted with ether. The separated ether phase is mixed with aqueous bicarbonate and saline solution Washed neutral and concentrated to dryness in a vacuum · This gives 1.95 g of oily 17a-lthynyl-18-methyl-A ⁴ -estrone-3ß-17ß-diol /

Example 2:. . '

800 mg of oily lTa-ethynyl-lS-methyl-A ^ -östren-JßilTß-dioli. " be with 6 ml of pyridine and heated ö · ⁰ 3 ml of acetic anhydride 4ο minutes loo The cooled Eeaktionsgemisch is then einserülirt in water ·, and the resultant filtered and washed with liiGder3ohlag. Washed neutral in water. The dried crude product (76o mg) is recrystallized from acetone / hexane. Thus obtained 47o mg '17 <xA ^{"thinyl-.18-methyl-4} Ä" -Öotren-3.beta., 17beta-diol '3-aoetat of melting point 175 to 176.5 ° C ^·:' '' ■

3eiapiel3:. ....:.

a) 4 s 17a ~ ethynyl-18-methyl-19-nor-teato3teron are reacted in 2 ml of ethanol and 8 ml of tetrahydrofuran in the presence of 40 mg of p-uoluenesulfonic acid with 8 ml of ortho-aminate ure ether at room temperature. After 3-4 hours the reaction mixture is poured into pyridine-containing V. ^T aDcer and mixed with ether

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SCHERING AG BERLIN ■. Ί '! ^ ^? L! C? ^; -

U93163

extracted «The separated, neutral washed and dried jither solution is finally in a vacuum until 'dry,' narrowed "This gives 4.3 g of crude ^ a-ethynyl-ie-methyl-W-nortöstosterone-3-enolethyl ether, which is further "processed" without further ado ...

b) In about loo ml of liquid ammonia are bei.-8ο ⁰ to -βο ° C * after addition of some Perrisalzkristalle 39o mg iJatrium. added in small pieces, once the blue color has disappeared, 4 * 3 g ^ aA ^ Mnyl-ie-methyl- ^ - iiorwtestosteron- • 3-ethylenol ether are dissolved in 65 ml tetrahydrofuran and after about. 1.2 ml of methyl odide dissolved in 6.5 ml of setrahydrofuran are added dropwise for 2 hours. This reaction mixture is stirred for a further 2 1/2 hours and then poured onto ice and, after acidification with acetic acid, extracted with ether and dried ethereal solution is used up to the ... ■ -. 2dry evaporated and the remaining 17a-lthynyl-18-methyl-19-nor-testosterone-3-ethyl-enol-17i3-methyl diether for enol ether cleavage in about 90-95% aqueous methanol in the presence of 5 g Crystalline oxalic acid is heated to boiling for 3/4 hours.The reaction mixture is then stirred into ice water, the resulting precipitate is filtered off, washed neutral and dried.Han thus receives 3.8 g of crude 17a-a'thynyl-18-methyl-19-nor- testosterone-17-methyl ether, ⁱ which after chromatography on the 45-fold amount of silica gel (Loji water) benzene / Kethylenchlorid (7: 3) and ümkristallisation from pentane depending on dor resulting crystalline form at 76 - ^V 78 ° respectively .. · at loolol ° C. melts.

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SCHERING Λ * KRLIN. " ⁷ ^

ο) 0.9 β ^ a-ethynyl-ie-methyl-ig-nor-tostosterone - ^ - methyl ethers were reduced with 1.8 g of lithium-tri-tert-butoxyaluminum hydride analogously to Example 1 and worked up 0.88 g of 17athynyl-18-methyl-A-oatren-3tfß-diol-17-methyl-ether as a viscous oil · The methoxyl determination corresponds to the calculated value «

Example 4:

⁾ A) 2.5 g of 17oc-Xthinyl-18-methyl "19-nor-testosterone are in loo ml abs · benzene with 15 ml of ethylene glycol (fresh destil- '% moieties, Kp · 195-196 ° C) in the presence of 1 g of p-2oluenesulfonic acid heated to about 100 ° C for 6 hours The cooled reaction solution is diluted with about 100 ml of ether and washed neutral with no water The dried and filtered solution is evaporated to dryness in vacuo 75 g raw ^ a-ÄtMnyl-lÖ-methyl - ^ - nor-testosteron-S-ethy-, lenketal, which is processed further without further purification

2.3 g of Ta-xthynyl-IS-methyl-ig-nor-teetosterone-S-ethylene ketal are etherified and worked up analogously to Example 3. For the cleavage of the ketal, the isolated crude product is treated with .2o..ml 9 ml acetic acid The reaction mixture is then stirred into ice water and the resulting precipitate is taken up in ither, the ether solution is washed neutral, dried and evaporated to dryness.After chromatography on silica gel and recrystallization from ither hexaene ^ a-ethynyl-lS-methyl - ^ - nort esto st eron-17-methyl ether from 75.5 to 77.5 S chmelzpunkt ⁰ C; identical with the product prepared according to example 5b ether ·

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c) The crude 17a-aet] iinyl-IS-met] ayi-19-nor-testoöteron-17-methylether is analogous to Example 5 c 2uuv J-OH compound processed. <\

Example 5?

0.85 g of 17a-ethinyl-18Hmethyl-A ⁴ -estren-3,17-diol-17-methyl ether (prepared according to Example 3) are heated ^{to about 100 0 for 45 minutes with 6 ml of pyridine and acetic anhydride} ater is then stirred in to V / and the added] 'auegeschiedene acetylation in Ither-llethylenchlorid. The extracted extraction solution is washed immediately with dilute sulfuric acid, bicarbonate solution and water, then dried and evaporated to dryness. Ifane receives o.94 g of lya-ethynyl-lS-methyl-A ^ Östren-J.lTß-diol - ^ - acetate-17-methyl ether, which after recrystallization from hexane melts at 163 °, 164.0 ° C. · ■ '. ■. . .- .. '; _. ·; . ·. ■,. , * .; · ■

B is pi el 6:

α) A solution of 2 g of lTa-a'thynyl-ie-methyl-IS-nor-testoaterone in 26 ml of pyridine is mixed with 13 ml of acetic anhydride and heated to 160 ° C. for 5 hours in a sealed tube. The cooled water mixture is then poured into ice water. The precipitate obtained is filtered off, washed neutral with water and, after drying on silica gel, chromatographed. phiert. This gives 1.2 g of crude 17a-ithynyl-18-ethyl-Δ · -estradiene-3,17i3-diol -diacetate, which after recrystallization from ether at 156-159 °. C melts; Yield 840 mg.

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b) 4oo mg I7O-lthinyl-18-methyl-A ^{i '::>} -östradien-3,17ß- <iiol-diacotat are stirred with 4oo mg IJatriumbicarbonat in 4o ml Ketha-' nol and 4 ml of water for 6 hours at room temperature »Then the reaction mixture is poured into ice water, ·

neutralized with glacial acetic acid, the resulting precipitate filtered off, washed with water and dried. You get 35o mg of crude 17a-ethynyl-18-methyl-19-nor-testosterone acetate with a melting point of 156-157 ° 0 Recrystallized from ether, 26o mg of acetate with a melting point of 162-163 ° C * are obtained

c) o, 2 g ^ a-Ä ^ hinyl-lS-methyl-ig-nor-testosterone-acetate ·. will reduced according to Example 1 · 0.194 g of 17α-ethynyl-18-methyl-Ä * -estren-3β »17β-diol-17-aoetat · '

Example 7t '''

0.6 g of the 17α-xthynyl-18-m.ethyl-Ä estren-3β, 17β-diol-17-aoetate obtained according to Example 6o are aoetylated analogously to Example 2. The isolated crude product (59o mg) is purified by chromatography on silica gel and recrystallized from hexane / pentane.This gives 32o mg of 17α-xthynyl-18-methyl-A ⁴ -estren-3β | 17β-diol-diol-acetate with a melting point of 119-121 ° 0 · _; · _V

Example 8: Γ

From 0.6 g of 17a-ethynyl-8-methyl-A ⁴ -ostren-3fi, 17fi- <iiol-17-acetate, analogously to Example 7 with propionic anhydride / pyridine, 29o mg of 17a-xthynyl-18-methyi-A ^ - Oestrene-3 [beta], 17 [beta] -diol-3-propionate-17-acetate · mp 149-150 ° C. ■ ·

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SCHERING A.G. BERLIN ■

. U93163

Aue 4oo ns l7a-ethynyl-18-aathyl-.Ä * -oatren ~ 3ß "17ß-aiol-17-aootate is obtained analogously to Example 7 with caproic anhydride / pyridine 320 mg of crude 17a-ethynyl-18-methyl" - A ⁴ -öetren-3ß, 173-diol-3-capronate-17-acetate, which, according to ohroiaatographiacher Eoini- snxiQ, sohailzt on silica el and ookriotallize from Hozan at 83-35 ° C; Yield 255 ag ·. ...

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Claims (1)

L-. ^: , \ -. ·· ..... ■ ...- ' P, 849 / February 6, 1969 Ai Claims Ii process for the preparation of compounds of the general Formula. . ' where R ^ is hydrogen, an acyl or a lower alkyl radical and E _{2 is} also '/.'hydrogen or an acyl radical, characterized in that one in ITct-ethynyl-IS-methyl-. 19-nor-testostoron according to methods known per se '. a) first esterified or etherified the 17β-hydroxyl group - optionally with intermediate protection of the 3-keto group by modification known per se into more inert functional groups, then by splitting off the protective group introduced before or, if appropriate, with the reaction, the 3-keto group is converted back into the usual manner Freedom sets, the latter preferably reduced to the 3-IIydroxy group by means of metal hydrides and, if desired, then esterified or b) first the 3-xeto group is reduced and, if desired, "" " then esterified the 3-hydroxyl group formed. 909829/15 3 Q "SCHMNO A.G. BERLIN ^ U9316.3 2 # method according to claim 1, characterized in that the 3-Xotoßruppo deo Auogangoprodukteo by means of lithium-tri-tert · _c . butoxyaluminum hydride is reduced # .. ·. ^: . ' - 3, compounds of the general formula where R ^ is hydrogen, an acyl or a lower alkyl radical and E _{2 is} hydrogen or an acyl radical 5. 17a-ethynyl-18-methyl-A - 6 «17a-Xthynyl-18-methyl-A ⁴ -estren-3ß, 17ß-diol-17-ethyl ether ·., 7 · 17a-Xthynyl-18-methyl-A ⁴ -osstren-3ß, 17ß-diol-5- aoet'at-17 < ₁ ^/ - ' . ; methyl ether ·. . . '·.: ... ^: .. '. ·. ■ _; ... 8 · 17α-Xthynyl-18-methyl-A ⁴ -Ö8tren-5β, 17β-diol-17-aoetate. 9. 17a-ethynyl-18-methyl-A ⁴ oestrone-3.beta. _{<17ßrdioi-3 f-17} diaoetat. .. · 17α-Xthynyl- | 18-methyl-A • öe 12. Medicinal products based on the yepTDetermination ^ n-according to'A ^ aepxuch 5 - Ö! O 98 29/1530 BATH ORIQiNAi.