DE1593311C - Process for the production of the 10.11 lactone der 3 Oxo 11 beta, 17 beta dihydoxy 17 alpha athinyl ostra 4 en 10 beta carbon acid - Google Patents
Process for the production of the 10.11 lactone der 3 Oxo 11 beta, 17 beta dihydoxy 17 alpha athinyl ostra 4 en 10 beta carbon acidInfo
- Publication number
- DE1593311C DE1593311C DE1593311C DE 1593311 C DE1593311 C DE 1593311C DE 1593311 C DE1593311 C DE 1593311C
- Authority
- DE
- Germany
- Prior art keywords
- beta
- lactone
- oxo
- carboxylic acid
- der
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
- 238000000034 method Methods 0.000 title claims description 5
- 150000002596 lactones Chemical class 0.000 title description 4
- 239000002253 acid Substances 0.000 title description 3
- 238000004519 manufacturing process Methods 0.000 title description 2
- VOXZDWNPVJITMN-ZBRFXRBCSA-N 17β-estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 VOXZDWNPVJITMN-ZBRFXRBCSA-N 0.000 title 1
- 241000237519 Bivalvia Species 0.000 title 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 title 1
- 229910052799 carbon Inorganic materials 0.000 title 1
- 125000004043 oxo group Chemical group O=* 0.000 title 1
- 238000005903 acid hydrolysis reaction Methods 0.000 claims description 3
- 239000003513 alkali Substances 0.000 claims description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 2
- 238000007796 conventional method Methods 0.000 claims description 2
- VWWMOACCGFHMEV-UHFFFAOYSA-N dicarbide(2-) Chemical compound [C-]#[C-] VWWMOACCGFHMEV-UHFFFAOYSA-N 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims description 2
- 150000004820 halides Chemical class 0.000 claims 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 10
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- KRVSOGSZCMJSLX-UHFFFAOYSA-L Chromic acid Chemical compound O[Cr](O)(=O)=O KRVSOGSZCMJSLX-UHFFFAOYSA-L 0.000 description 4
- VLTRZXGMWDSKGL-UHFFFAOYSA-N Perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 4
- 230000002280 anti-androgenic Effects 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- FYYHWMGAXLPEAU-UHFFFAOYSA-N magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 4
- 239000011777 magnesium Substances 0.000 description 4
- 229910052749 magnesium Inorganic materials 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- FKHIFSZMMVMEQY-UHFFFAOYSA-N Talc Chemical compound [Mg+2].[O-][Si]([O-])=O FKHIFSZMMVMEQY-UHFFFAOYSA-N 0.000 description 3
- 239000000284 extract Substances 0.000 description 3
- 239000000391 magnesium silicate Substances 0.000 description 3
- 229910052919 magnesium silicate Inorganic materials 0.000 description 3
- 235000019792 magnesium silicate Nutrition 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- GZUXJHMPEANEGY-UHFFFAOYSA-N Bromomethane Chemical compound BrC GZUXJHMPEANEGY-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M NaHCO3 Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N P-Toluenesulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 230000001548 androgenic Effects 0.000 description 2
- 230000000875 corresponding Effects 0.000 description 2
- 230000002124 endocrine Effects 0.000 description 2
- 230000001076 estrogenic Effects 0.000 description 2
- -1 ethynyl magnesium halide Chemical class 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- RMGHERXMTMUMMV-UHFFFAOYSA-N 2-methoxypropane Chemical compound COC(C)C RMGHERXMTMUMMV-UHFFFAOYSA-N 0.000 description 1
- 206010000496 Acne Diseases 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- VUHJZBBCZGVNDZ-TTYLFXKOSA-N Chlormadinone Chemical compound C1=C(Cl)C2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)C)(O)[C@@]1(C)CC2 VUHJZBBCZGVNDZ-TTYLFXKOSA-N 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- 239000007818 Grignard reagent Substances 0.000 description 1
- 206010020112 Hirsutism Diseases 0.000 description 1
- BLQJIBCZHWBKSL-UHFFFAOYSA-L Magnesium iodide Chemical compound [Mg+2].[I-].[I-] BLQJIBCZHWBKSL-UHFFFAOYSA-L 0.000 description 1
- 206010067572 Oestrogenic effect Diseases 0.000 description 1
- RJKFOVLPORLFTN-STHVQZNPSA-N Progesterone Natural products O=C(C)[C@@H]1[C@@]2(C)[C@H]([C@H]3[C@@H]([C@]4(C)C(=CC(=O)CC4)CC3)CC2)CC1 RJKFOVLPORLFTN-STHVQZNPSA-N 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- RJKFOVLPORLFTN-LEKSSAKUSA-N Syngestrets Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 RJKFOVLPORLFTN-LEKSSAKUSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000001058 adult Effects 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminum Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 239000003098 androgen Substances 0.000 description 1
- 239000011260 aqueous acid Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229960003996 chlormadinone Drugs 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000010573 double replacement reaction Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000002159 estradiols Chemical class 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 150000004795 grignard reagents Chemical class 0.000 description 1
- 230000000977 initiatory Effects 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 229910001641 magnesium iodide Inorganic materials 0.000 description 1
- LROBJRRFCPYLIT-UHFFFAOYSA-M magnesium;ethyne;bromide Chemical compound [Mg+2].[Br-].[C-]#C LROBJRRFCPYLIT-UHFFFAOYSA-M 0.000 description 1
- 229940102396 methyl bromide Drugs 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- QDHHCQZDFGDHMP-UHFFFAOYSA-N monochloramine Chemical compound ClN QDHHCQZDFGDHMP-UHFFFAOYSA-N 0.000 description 1
- SFDZETWZUCDYMD-UHFFFAOYSA-N monosodium acetylide Chemical compound [Na+].[C-]#C SFDZETWZUCDYMD-UHFFFAOYSA-N 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 229960003387 progesterone Drugs 0.000 description 1
- 239000000186 progesterone Substances 0.000 description 1
- 230000000962 progestomimetic Effects 0.000 description 1
- 231100000486 side effect Toxicity 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000002194 synthesizing Effects 0.000 description 1
Description
Es sind bereits zahlreiche Substanzen bekannt, die mit antiandrogenen Eigenschaften ausgestattet sind. Die Mehrzahl dieser Substanzen hat jedoch den Nachteil, daß sie darüber hinaus auch noch endokrine Eigenschaften aufweist. So hat das Progesteron oder das Chlormadinon offensichtlich progestative Eigenschaften, die Östradiolderivate haben eine östrogene Wirkung, das A-nor-Testosteron oder das B-nor-17-Methyltestosteron besitzen eine androgene Wirkung. Andere antiandrogene Verbindungen schließ- xo lieh, wie die Testololactone, besitzen bei geringen Dosierungen eine antiandrogene Wirkung, die sich bei höheren Dosierungen in das Gegenteil verkehrt. Numerous substances are already known which are endowed with anti-androgenic properties. However, the majority of these substances have the disadvantage that they are also endocrine Has properties. Progesterone or chlormadinone obviously has progestative properties, the estradiol derivatives have an estrogenic effect, the A-nor-testosterone or the B-nor-17-methyltestosterone have an androgenic effect. Other anti-androgenic compounds, such as testololactones, are also found to be low Dosages have an anti-androgenic effect which is reversed at higher dosages.
Das 10,11-Lacton der 3-Oxo-ll/?,17/?-dihydroxy-17,%-äth!nyl-östra-4-en-10^-carbonsäure zeigt in bezug auf alle diese bekannten Substanzen den doppelten Vorteil, daß es keinen endokrinen Nebeneffekt zeigt, und zwar weder einen androgenen, noch einen östrogenen oder progestomimetischen, und daß es außerdem eine konstante Wirkung hat, die den verabreichten Dosierungen proportional ist. Darüber hinaus ist das 10,11-Lacton der 3-Oxo-ll/U7/?-dihydroxy-17.A-äthinyl-östra-4-en-10/?-carbonsäure bei buccaler Verabreichung aktiv, was seine Applikation sehr erleichtert. The 10,11-lactone of 3-Oxo-II / ?, 17 /? - dihydroxy-17,% - eth! Nyl-oestra-4-en-10 ^ -carboxylic acid shows with respect to all these known substances the double advantage that it shows no endocrine side effect, and neither an androgenic nor an estrogenic one or progestomimetic, and that it also has a constant effect that the administered Dosages is proportional. In addition, the 10,11-lactone is the 3-oxo-II / U7 /? - dihydroxy-17.A-äthinyl-oestra-4-en-10 /? - carboxylic acid active when administered buccally, which makes its application much easier.
Das erfindungsgemäße Verfahren zur Herstellung des erfindiingsgemäßen tetracyclischen Lactons besteht darin, daß man nach üblichen Methoden das 10,11-Lacton der 3-ÄthyIendioxy-ll/7,17^-dihydroxyöstra-5-en-lO/J-carbonsäure zum entsprechenden 17-Ketoderivat oxydiert, dieses mit einem Alkalianty-Hd oder Äthinylniagnesiumhalogenid äthinyliert, und danach die 3-Ketogriippe des entstandenen 10,11-Lactons der 3-Äthylendioxy-ll/?,17/?-dihydroxy-17<A--äthinyI-östra-5-en-lO^-carbonsäure durch saure Hydrolyse freisetzt.The process according to the invention for producing the tetracyclic lactone according to the invention consists in that the 10,11-lactone of 3-ÄthyIendioxy-II / 7,17 ^ -dihydroxyestra-5-ene-10 / I-carboxylic acid is used according to conventional methods oxidized to the corresponding 17-keto derivative, this with an Alkalianty-Hd or ethynyl magnesium halide, and then the 3-keto group of the 10,11-lactone formed of 3-ethylenedioxy-II / ?, 17 /? - dihydroxy-17 <A - äthinyI-östra-5-en-10 ^ -carboxylic acid released by acid hydrolysis.
Die Oxydation des 10,11-Lactons der 3-Älhylendioxy-ll^,17/?-dihydroxy-östra-5-en-10y9-carbonsäure kann vorteilhafterweise mit Hilfe von Chromsäure in Pyridin bewirkt werden.The oxidation of the 10,11-lactone of 3-ethylenedioxy-ll ^, 17 /? - dihydroxy-estra-5-ene-10y9-carboxylic acid can advantageously be effected with the aid of chromic acid in pyridine.
Diese Oxydation kann auch durch doppelten Austausch der funktionellen Gruppen mit einem Keton in Gegenwart eines Aluminiumalkoholats nach der Methode von Oppenauer durchgeführt werden. This oxidation can also be achieved by double replacement of the functional groups with a ketone in The presence of an aluminum alcoholate can be carried out by the Oppenauer method.
Zur Äthinylierung des 10.11-Lactons der 3-ÄthyIendioxy-U-oxo-ll/f-hydroxy-östra-S-en-lO/J-carbonsäure verwendet man ein Alkaliacetylid, wie Kalium- oder Natriumacetylid. Eine andere Äthinylierungsmethode, die zu guten Ausbeuten führt, besteht in der Einwirkung eines Äthinylmagnesiumhalogenids, wie Äthinylmagnesiumbromid oder -jodid. Es ist überraschend, festzustellen, daß die Lactonfunktion in diesem Falle der Einwirkung eines Grignard-Reagens widersteht.For the ethynylation of the 10.11 lactone of 3-ÄthyIendioxy-U-oxo-II / f-hydroxy-estra-S-en-10 / I-carboxylic acid if an alkali acetylide is used, such as potassium or sodium acetylide. Another ethynylation method, which leads to good yields consists in the action of an ethynyl magnesium halide, such as ethynyl magnesium bromide or iodide. It is surprising to find that the lactone function in this case withstands exposure to a Grignard reagent.
Die saure Hydrolyse des Äthylenketals in 3-StelIung des 10,11-Lactons der 3-Äthylendioxy-lfy?,17/?-dihydroxy-17:v-äthinyl-östra-5-en-10/?-carbonsäure wird in einem protonenhaltigen wäßrigen Lösungsmittel, wie Essigsäure oder in einem niedermolekularen Alkanol wie Methanol oder Äthanol, in Gegenwart einer starken Säure wie Perchlorsäure, Salzsäure, Schwefelsäure oder p-Toluolsulfonsäure bewirkt.The acid hydrolysis of the ethylene ketal in 3-position of the 10,11-lactone of 3-ethylenedioxy-lfy?, 17 /? - dihydroxy-17: v-ethinyl-oestra-5-en-10 /? - carboxylic acid is in a proton-containing aqueous solvent such as acetic acid or in a low molecular weight Alkanol such as methanol or ethanol, in the presence of a strong acid such as perchloric acid, hydrochloric acid, Sulfuric acid or p-toluenesulfonic acid causes.
Das als Ausgangsprodukt verwendete 10,11-Lacton der 3 -Äthylendioxy-11/5,17/3 - dihydroxy - östra - 5 -en-10/?-carbonsäure kann nach dem in der Patentschrift 1 297 104 beschriebenen Verfahren hergestellt werden.The 10,11-lactone of 3-ethylenedioxy-11 / 5,17 / 3-dihydroxy-estra-5-en-10 /? -Carboxylic acid used as the starting product can be prepared by the process described in US Pat. No. 1,297,104.
Herstellung des 10,11-Lactons derProduction of the 10,11-lactone der
3-Oxo-ll^,17^9-dihydroxy-17a-äthinyl-östra-4-en-3-Oxo-ll ^, 17 ^ 9-dihydroxy-17a-ethinyl-oestra-4-en-
10/?-carbonsäure10 /? - carboxylic acid
Stufe A: 10,11-Lacton derGrade A: 10,11-lactone der
3-Äthylendioxy-17-oxo-ll/?-hydroxy-östra-5-eιl-3-ethylenedioxy-17-oxo-ll /? - hydroxy-oestra-5-eιl-
10/?-carbonsäure10 /? - carboxylic acid
Man suspendiert 3,2 g Chromsäure in 32 cm3 Pyridin, kühlt auf etwa 00C, rührt eine Viertelstunde und fügt dann langsam eine Lösung von 3,2 g 10,11-Lacton der 3 Äthylendioxy-ll/?,17/9-dihydroxy-östra-5-en-10/?-carbonsäure, gelöst in 32 cm3 redestilliertem Pyridin, zu.Suspending 3.2 g of chromic acid in 32 cm 3 of pyridine, cooled to about 0 0 C, stirred for fifteen minutes and then added slowly a solution of 3.2 g of 10,11-lactone of 3-ethylenedioxy ll / ?, 17/9 -dihydroxy-oestra-5-en-10 /? - carboxylic acid, dissolved in 32 cm 3 of redistilled pyridine.
Man rührt das Reaktionsgemisch bei Zimmertemperatur 16 Stunden, versetzt dann mit 3,2 cm3 Methanol und setzt das Rühren noch eine Viertelstunde fort. Man extrahiert mit Methylenchlorid, wäscht den Extrakt mit Wasser, trocknet und chromatographiert an Magnesiumsilikat. Man eluiert mit Methylenchlorid, das 3% Pyridin enthält, und erhält 3,092 des Produktes, das so, wie es ist, für die folgende Synthese verwendet werden kann.The reaction mixture is stirred at room temperature for 16 hours, then 3.2 cm 3 of methanol are added and stirring is continued for a quarter of an hour. It is extracted with methylene chloride, the extract is washed with water, dried and chromatographed on magnesium silicate. It is eluted with methylene chloride containing 3% pyridine to obtain 3.092 of the product, which can be used as it is for the following synthesis.
Für die Analyse teigt man das erhaltene Produkt mit einem Gemisch aus Methylalkohol—Isopropyläther (1 : 4) an. saugt ab, wäscht und trocknet. Man erhält eine Probe des 10,11-Lactons der 3-Äthylendioxy-ll/J-hydroxy-n-oxo-östrao-en-lO/J-carbonsäure, F. = 236°C, [x]f = -i-S5°±l (c = 0,4% Methanol).For the analysis, the product obtained is made into a paste with a mixture of methyl alcohol and isopropyl ether (1: 4). sucks, washes and dries. A sample of the 10,11-lactone of 3-ethylenedioxy-II / I-hydroxy-n-oxo-oestra-en-IO / I-carboxylic acid, m.p. = 236 ° C, [x] f = -i- S5 ° ± l (c = 0.4% methanol).
Analyse: C21H2nO5 = 358,42.Analysis: C 21 H 2n O 5 = 358.42.
Berechnet
gefundenCalculated
found
C 70,36%, H 7,31%:
C 70,0%, H 7,2%.C 70.36%, H 7.31%:
C 70.0%, H 7.2%.
Stufe B: 10,11-Lacton derStage B: 10,11-lactone der
3-ÄthyIendioxy-ll/?,17/?-dihydroxy-17\-äthinyl-3-Ethylenedioxy-II / ?, 17 /? - dihydroxy-17 \ -äthinyl-
östra-5-en-10/9-carbonsäureestra-5-ene-10/9 carboxylic acid
Herstellung des Magnesiumreagens: Man gibt 3 g Magnesium in 165 cm3 wasserfreies Tetrahydrofuran und leitet bis zur völligen Auflösung des Magnesiums Methylbromid ein.Preparation of the magnesium reagent: 3 g of magnesium are added to 165 cm 3 of anhydrous tetrahydrofuran and methyl bromide is introduced until the magnesium has completely dissolved.
Man ersetzt dann den Methylbromidstrom durch einen Acetylenstrom und setzt das Einleiten 3 Stunden fort, wobei man die Temperatur auf etwa 350C hält.Then replacing the Methylbromidstrom by an acetylene and sets the initiating 3 hours continuously, while maintaining the temperature at about 35 0 C.
Man läßt abkühlen und dekantiert.It is allowed to cool and decanted.
Äthinylierung: Man gibt 2,9 g 10,11-Lacton der S-Äthinylendioxy-ll/J-hydroxy-n-oxo-östra-S-en-10/?-carbonsäure in 160 cm3 Magnesiumlösung, erhitzt 2 Stunden unter Rückfluß, läßt abkühlen und schüttet in eine wäßrige Lösung von Ammoniumchlorid. Ethynylation: 2.9 g of 10,11-lactone of S-ethynylenedioxy-II / I-hydroxy-n-oxo-oestra-S-en-10 /? - carboxylic acid are added to 160 cm 3 of magnesium solution, and the mixture is refluxed for 2 hours , allowed to cool and poured into an aqueous solution of ammonium chloride.
Man extrahiert mit Methylenchlorid, wäscht die Extrakte mit Wasser, trocknet und reinigt, indem man über eine Magnesiumsilikatsäule schickt. Man erhält 3,042 g des Produktes.Extract with methylene chloride, wash the extracts with water, dry and purify by sent over a magnesium silicate column. 3.042 g of the product are obtained.
Für die Analyse teigt man das erhaltene Produkt mit einem Gemisch aus Methylalkohol-Isopropyläther (1 : 4) an, saugt dann ab, wäscht und erhält 2,591 g (entsprechend einer Ausbeute von 83 %) 10,11-Lacton der 3-Äthylendioxy-ll/?,17^-dihydroxy-17«-äthinyl-östra-5-en-10/?-carbonsäure. F. = 2700C, [«]*> = -19°±1 (c = 0,5% Tetrahydrofuran). Das Produkt ist weiß, unlöslich in Wasser und verdünnten Säuren, in der Wärme löslich in Alkohol und Aceton, und in der Kälte löslich in Chloroform.For the analysis, the product obtained is pasted with a mixture of methyl alcohol-isopropyl ether (1: 4), then filtered off with suction, washed and obtained 2.591 g (corresponding to a yield of 83%) of 10,11-lactone of 3-ethylenedioxy-II / ?, 17 ^ -dihydroxy-17 «-ethinyl-oestra-5-ene-10 /? - carboxylic acid. F. = 270 0 C, [ «] *> = -19 ° ± 1 (c = 0.5% tetrahydrofuran). The product is white, insoluble in water and dilute acids, soluble in alcohol and acetone in the heat, and in chloroform in the cold.
Analyse: C23H28O5 = 384,45.Analysis: C 23 H 28 O 5 = 384.45.
Berechnet
gefundenCalculated
found
C 71,85%, H 7,3%;
C 71,8%, H 7,3%.C 71.85%, H 7.3%;
C 71.8%, H 7.3%.
Stufe C: 10,11-Lacton derStage C: 10,11-lactone der
3-Oxo-ll/3,17jS-dihydroxy-ll«-äthinyl-östra-4-en-3-Oxo-II / 3,17jS-dihydroxy-II «-äthinyl-östra-4-en-
10/?-carbonsäure10 /? - carboxylic acid
Man gibt 0,7 g 10,11-Lacton der 3-Äthylendioxylly?-dihydroxy-17«-äthinyl-östra-5-en-10^-carbonsäure zu 70 cm3 Essigsäure, die 10% Perchlorsäure (55°Be) enthält.0.7 g of 10,11-lactone of 3-ethylenedioxylly? -Dihydroxy-17 "-äthinyl-östra-5-en-10 ^ -carboxylic acid is added to 70 cm 3 of acetic acid which contains 10% perchloric acid (55 ° Be) .
Man rührt das Reaktionsgemisch 2 Stunden unter Stickstoffatmosphäre bei Zimmertemperatur. Man fügt dann 350 cm3 Methylenchlorid und 150 cm3 Wasser zu und macht das Gemisch durch Zugabe von Natriumbicarbonat alkalisch.The reaction mixture is stirred for 2 hours under a nitrogen atmosphere at room temperature. 350 cm 3 of methylene chloride and 150 cm 3 of water are then added and the mixture is made alkaline by adding sodium bicarbonate.
Man dekantiert, wäscht und trocknet. Man löst das Produkt in Methylenchlorid, chromatographiert an Magnesiumsilikat und eluiert mit Methylenchlorid, das 2% Aceton enthält.You decant, wash and dry. The product is dissolved in methylene chloride and chromatographed on magnesium silicate and eluted with methylene chloride containing 2% acetone.
Man erhält 290 mg 10,11-Lacton der 3-Oxoll/?47/?-dihydroxy-17«-äthinyI-östra-4-en-10/5-carbonsäure, F. = 2320C, [x]f = +149,5°±1 (c = 0,5%, Methanol).This gives 290 mg of 10,11-lactone of 3-Oxoll / 47 /? - dihydroxy-17 "-äthinyI-estr-4-en-10/5-carboxylic acid, m.p. = 232 0 C, [x] = f + 149.5 ° ± 1 (c = 0.5%, methanol).
Das erhaltene Produkt ist weiß, unlöslich in Wasser und verdünnten wäßrigen Säuren, in der Wärme ziemlich löslich in Alkohol und Aceton, und in der Kälte löslich in Chloroform.The product obtained is white, insoluble in water and dilute aqueous acids, on exposure to heat fairly soluble in alcohol and acetone, and soluble in chloroform in the cold.
Analyse: C21H24O4 = 340,4.Analysis: C 21 H 24 O 4 = 340.4.
Berechnet ... C 74,09%, H 7,11 %;
gefunden . . C 74,0%, H 7,3%.Calculated ... C 74.09%, H 7.11%;
found . . C 74.0%, H 7.3%.
Wie festgestellt wurde, ist das erfindungsgemäß hergestellte 10,11-Lacton der 3-Oxo-ll/S,17^-dihydroxy-17a-äthinyl-östra-4-en-10/?-carbonsäure mit wertvollen pharmakologischen Eigenschaften ausgestattet. 5 Insbesondere besitzt es eine wichtige antiandrogene Wirkung. Die auf der Grundlage dieses Verfahrensproduktes hergestellten pharmazeutischen Zusammensetzungen können zur Behandlung von Hyperandrogenie, Prostatacarcinom, Akne und Hirsutismus verlo wendet werden.As has been found, the 10,11-lactone produced according to the invention is 3-oxo-II / S, 17 ^ -dihydroxy-17a-ethinyl-oestra-4-ene-10 /? - carboxylic acid endowed with valuable pharmacological properties. 5 In particular, it possesses an important antiandrogenic Effect. The pharmaceutical compositions produced on the basis of this process product can be used to treat hyperandrogenia, prostate cancer, acne and hirsutism be turned.
Sie können buccal, perlingual, transkutan oder rectal angewandt werden.They can be applied buccally, perlingually, transcutaneously or rectally.
Die Posologie bewegt sich zwischen 100 und 500 mg pro Dosis und zwischen 200 mg und 1 g der aktiven Verbindung pro Tag beim Erwachsenen in Abhängigkeit von der Art der Verabreichung.The posology ranges between 100 and 500 mg per dose and between 200 mg and 1 g of the active Compound per day in the adult depending on the route of administration.
Claims (1)
Verfahren zur Herstellung des 10,11-Lactons derClaim:
Process for the preparation of the 10,11-lactone of
Family
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