EP0000300B1 - Substituted estra-1,3,5(10),6-tetraenes, process for their preparation and use in the synthesis of tritium labelled steroids - Google Patents

Substituted estra-1,3,5(10),6-tetraenes, process for their preparation and use in the synthesis of tritium labelled steroids Download PDF

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EP0000300B1
EP0000300B1 EP78400016A EP78400016A EP0000300B1 EP 0000300 B1 EP0000300 B1 EP 0000300B1 EP 78400016 A EP78400016 A EP 78400016A EP 78400016 A EP78400016 A EP 78400016A EP 0000300 B1 EP0000300 B1 EP 0000300B1
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methoxy
estra
agent
diol
radical
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EP0000300A1 (en
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Alain Jouquey
Jean-Pierre Raynaud
Jean Salmon
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Sanofi Aventis France
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Roussel Uclaf SA
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
    • C07J1/0051—Estrane derivatives
    • C07J1/0066—Estrane derivatives substituted in position 17 beta not substituted in position 17 alfa
    • C07J1/007—Estrane derivatives substituted in position 17 beta not substituted in position 17 alfa the substituent being an OH group free esterified or etherified

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  • the subject of the invention is the steroids of general formula I in which R represents hydrogen or R ', R' being an acyl radical having from 1 to 5 carbon atoms, the benzoyl radical substituted or not, or a tetrahydropyranyl, trityl or trimethylsilyl radical, and R 1 represents an acyl radical having from 1 to 5 carbon atoms, the substituted or unsubstituted benzoyl radical or a tetrahydropyranyl, trityl or trimethylsilyl radical.
  • R and / or R 1 represents an acyl radical having from 1 to 5 carbon atoms, it may for example be the remainder of formic, acetic, propionic, butyric or valeric acids.
  • the reaction mixture consisting of 45.2 mg of methoxy-11 ⁇ diacetate estra-1,3,5 (10), 6 tetraene diol-3, 17 ⁇ , 10 mg of palladium black and 0.6 is cooled with liquid nitrogen. cm3 of redistilled ethyl acetate, then introduced under vacuum 3.87 cm3 of tritium, measured at 0 ° C. and at normal pressure with a total activity of 10 Ci.
  • reaction mixture is allowed to return to ambient temperature, maintains with stirring for 3 hours, collects the excess tritium, filters, distills the solvent under reduced pressure and, after removal of the labile tritium, obtains 46 mg of diacetate / 6,7- 3 H / methoxy-11 ⁇ estra-1, 3.5 (10) triene dio-3.17 ⁇ sought for a specific activity of 54.03 Ci / mM.
  • Stage B / 6.7- 3 H / methoxy-1 1 ⁇ estra-1,3,5 (10) triene diol-3, 17 ⁇

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  • Organic Chemistry (AREA)
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Description

La présente invention concerne de nouveaux stéroïdes de la série des estratétraénes substitués, leur procédé de préparation et leur application à la synthèse de dérivés de la série des estradiols marqués au tritium.The present invention relates to new steroids from the series of substituted estratetraenes, their preparation process and their application to the synthesis of derivatives from the series of tritium-labeled estradiols.

L'état de la technique révèle les documents suivants:

  • - la publication de Chemical Abstracts, Vol 82 (1975), 43644Y et YAKUGAKU ZASSHI, 1974, 94 (11) 1484-8, a relative à la préparation du 2-hydroxy estra-1, 3, 5 (10)-trien 17β-ol [6,7-3H] au moyen de tritium gazeux à partir du dérivé 2-OR estra-1, 3, 5 (10), 6-tetraen 17β-OR1 correspondant;
  • - le brevet britannique 1 151 404 relatif aux 11β-alcoxy 13/3-alkyl gona-1, 3, 5 (10) triènes et leur préparation lors de laquelle le produit△4,9 correspondant est aromatisé par l'isomérisation catalytique;
  • - lé brevet US 3 020 294 relatif à un dibromoA4-3-ceto stéroïde, susceptible d'être de hidrohalogène pour former le △1,46-3-céto stéroïde correspondant, dont on aromatise ensuite le noyau A par une hydrogénation catalytique.
The state of the art reveals the following documents:
  • - the publication of Chemical Abstracts, Vol 82 (1975), 43644Y and YAKUGAKU ZASSHI, 1974, 94 ( 11 ) 1484-8, a relating to the preparation of 2-hydroxy estra-1, 3, 5 (10) -trien 17β -ol [6,7- 3 H] by means of gaseous tritium from the derivative 2-OR estra-1, 3, 5 (10), 6-tetraen 17β-OR 1 corresponding;
  • - British patent 1,151,404 relating to 11β-alkoxy 13/3-alkyl gona-1, 3, 5 (10) trienes and their preparation in which the corresponding product △ 4.9 is flavored by catalytic isomerization;
  • - US Pat. No. 3,020,294 relating to a steroid dibromoA 4- 3-keto, capable of being hidrohalogen to form the corresponding △ 1.46 -3-keto steroid, the nucleus A of which is then flavored by catalytic hydrogenation.

L'invention a pour objet les stéroïdes de formule générale I

Figure imgb0001
dans laquelle R représente de l'hydrogène ou R', R' étant un radical acyle ayant de 1 à 5 atomes de carbone, le radical benzoyle substitué ou non, ou un radical tétrahydropyranyle, trityle ou triméthylsilyle, et R1 représente un radical acyle ayant de 1 à 5 atomes de carbone, le radical benzoyle substitué ou non ou un radical tétrahydropyranyle, trityle ou triméthylsilyle.The subject of the invention is the steroids of general formula I
Figure imgb0001
 in which R represents hydrogen or R ', R' being an acyl radical having from 1 to 5 carbon atoms, the benzoyl radical substituted or not, or a tetrahydropyranyl, trityl or trimethylsilyl radical, and R 1 represents an acyl radical having from 1 to 5 carbon atoms, the substituted or unsubstituted benzoyl radical or a tetrahydropyranyl, trityl or trimethylsilyl radical.

Lorsque R et/ou R1 représente un radical acyle ayant de 1 à 5 atomes de carbone, il peut être par exemple le reste d'acides formique, acétique, propionique, butyrique ou valérique.When R and / or R 1 represents an acyl radical having from 1 to 5 carbon atoms, it may for example be the remainder of formic, acetic, propionic, butyric or valeric acids.

Lorsque R et/ou R, représente un radical benzoyle substitué, il peut être substitué par exemple par un halogène tel que le chlore ou le brome, par un radical alcoyle ayant de 1 à 5 atomes de carbone, par le radical trifluorométhoxy, ou par un radical alcoyloxy ayant de 1 à 5 atomes de carbone. Parmi les produits de formule I, on citera notamment:

  • -l'acétate 17β de méthoxy-11β estra-1, 3, 5 (10), 6-tetraen diol-3, 17β
  • -le diacétate de méthoxy-11β estra-1, 3, 5 (10), 6-tetraen diol-3, 17β.
When R and / or R represents a substituted benzoyl radical, it can be substituted for example by a halogen such as chlorine or bromine, by an alkyl radical having from 1 to 5 carbon atoms, by the trifluoromethoxy radical, or by an alkyloxy radical having from 1 to 5 carbon atoms. Among the products of formula I, there may be mentioned in particular:
  • -methoxy-11β acetate 17β estra-1, 3, 5 (10), 6-tetraen diol-3, 17β
  • -methoxy-11β diacetate estra-1, 3, 5 (10), 6-tetraen diol-3, 17β.

Les produits de formule générale I sont utiles en tant que produits de départ pour la synthèse de dérivés stéroïdes substitués marqués au tritium.The products of general formula I are useful as starting materials for the synthesis of substituted steroid derivatives labeled with tritium.

L'invention a également pour objet un procédé de préparation des produits répondant à la formule générale I ci-dessus.The subject of the invention is also a process for preparing the products corresponding to general formula I above.

Ce procédé est caractérisé en ce que l'on:

  • -bloque la fonction hydroxyle en position 17β de la 11β-méthoxy nor-testostérone au moyen d'un agent d'estérification ou d'éthérification.
  • -soumet la OR1-17β méthoxy-11 1β nor-testostérone obtenue, R1 ayant ici et dans ce qui suit les significations précitées, à l'action d'un agent d'halogénation.
  • fait agir sur le OR1-17β dihalogéno-2,6 méthoxy-11β estren-4 one-3 résultant un agent de déshalohydratation pour obtenir le OR1-17β méthoxy-11 β estra-1,3,5(10),6-tetraen ol-3 cherché, dont on bloque, le cas échéant, la fonction hydroxyle en 3 au moyen d'un agent d'estérification ou d'éthérification pour obtenir le OR'-3, OR1-17β méthoxy-11β estra-1,3,5(10),6-tetraene, R' ayant les significations précitées.
This process is characterized in that:
  • -blocks the hydroxyl function in position 17β of 11β-methoxy nor-testosterone by means of an esterification or etherification agent.
  • -submits the OR 1 -17β methoxy-11 1β nor-testosterone obtained, R 1 having here and in what follows the abovementioned meanings, to the action of a halogenating agent.
  • acts on OR 1 -17β 2,6-dihalo-methoxy-11β estren-4 one-3 resulting in a dehalohydration agent to obtain OR 1 -17β methoxy-11 β estra-1,3,5 (10), 6 -tetraen ol-3 sought, which is blocked, where appropriate, the hydroxyl function in 3 by means of an esterification or etherification agent to obtain the OR'-3, OR 1 -17β methoxy-11β estra- 1,3,5 (10), 6-tetraene, R 'having the aforementioned meanings.

Dans les conditions préférentielles de mise en oeuvre, le procédé de l'invention est caractérisé en ce que:

  • -l'agent d'estérification au moyen duquel on bloque la fonction hydroxyle en position 17 ou en position 3 est un acide ou un dérivé fonctionnel d'acide; ce dérivé fonctionnel peut être l'anhydride acétique ou le chlorure de benzoyle;
  • -l'agent d'étherification au moyens duquel on bloque la fonction hydroxyle en position 17 ou en position 3 est le dihydropyran, le chlorure de trityle ou le chlorure de triméthylsilyle;
  • -l'agent d'halogénation à l'action duquel on soumet la OR1-17β méthoxy-11β nor-testérone est le brome dans l'acide acétique;
  • -l'agent de déshalohydratation que l'on fait agir sur le OR1-17β dihalogéno-2,6 méthoxy-11β estren-4-one-3 est le chlorure de lithium dans le diméthyl formamide et on opère sous atmosphère inerte.
Under the preferential conditions of implementation, the method of the invention is characterized in that:
  • the esterification agent by means of which the hydroxyl function is blocked in position 17 or in position 3 is an acid or a functional acid derivative; this functional derivative can be acetic anhydride or benzoyl chloride;
  • the etherification agent by means of which the hydroxyl function is blocked in position 17 or in position 3 is dihydropyran, trityl chloride or trimethylsilyl chloride;
  • -the halogenating agent to which the OR 1 -17β methoxy-11β nor-testone is subjected is bromine in acetic acid;
  • -the dehalohydratation agent which is made to act on OR 1 -17β 2,6-dihalo-methoxy-11β estren-4-one-3 is lithium chloride in dimethyl formamide and the reaction is carried out under an inert atmosphere.

Au cours de l'exécution de ce procédé, les produits industriels nouveaux suivants ont été préparés:

  • -l'acétate de méthoxy-11 β nor-testostérone
  • -l'acétoxy-17β dibromo-2,6 méthoxy-11β estren-4 one-3.
During the execution of this process, the following new industrial products were prepared:
  • -methoxy-11 β nor-testosterone acetate
  • -acetoxy-17β dibromo-2,6 methoxy-11β estren-4 one-3.

Comme déjà indiqué les produits de formule générale I sont les produits de départ pour la synthèse de dérivés stéroïdes marqués au tritium. Leur application en tant que tels est également un objet de la présente invention et est caractérisée en ce que l'on:

  • -réduit un produit de formule générale I, dans laquelle R et R, ont les significations précitées, par action d'hydrogène tritié en présence d'un catalyseur,
  • -soumet le /6, 7 3H/ OR-3 OR1-17β méthoxy-11β estra-1,3,5(10)-triene à l'action d'une base forte, ou d'un acide faible en milieu aqueux, ou d'un hydracide, pour obtenir le /6,7-3H/me"thoxy-11β estra-1,3,5(10)-trien diol-3,17b que l'on oxyde, selon la réaction d'Openauer, en /6,7-3H/ hydroxy-3 méthoxy-11β estra-1,3,5(10)-trien one-17, au moyen de cyclohéxanone en présence d'isopropylate d'aluminium;
  • -soumet ce dernier à l'action d'un agent d'éthynylation, en présence de ter-amylate de sodium dans le toluène et obtient le /6,7-3H/ méthoxy-11β éthynyl-17α estradiol.
As already indicated, the products of general formula I are the starting products for the synthesis of steroid derivatives labeled with tritium. Their application as such is also an object of the present invention and is characterized in that one:
  • -reduces a product of general formula I, in which R and R have the abovementioned meanings, by the action of tritiated hydrogen in the presence of a catalyst,
  • -submits on / 6,7 3 H / OR-3 OR 1 -17β methoxy-11β estra-1,3,5 (10) -triene to the action of a strong base, or of a weak acid in medium aqueous, or a hydracid, to obtain the / 6,7- 3 H / me "thoxy-11β estra-1,3,5 (10) -trien diol-3,17b which is oxidized, according to the reaction Openauer, en / 6,7- 3 H / hydroxy-3 methoxy-11β estra-1,3,5 (10) -trien one-17, using cyclohexanone in the presence of aluminum isopropylate;
  • -submits the latter to the action of an ethynylating agent, in the presence of sodium ter-amylate in toluene and obtains / 6,7- 3 H / methoxy-11β ethynyl-17α estradiol.

Dans les conditions préférentielles de mise en oeuvre, cette application est caractérisée en ce que:

  • -le catalyseur est l'hydroxyde de palladium,
  • -la base forte est la soude et on opère dans le méthanol,
  • -l'acide aqueux faible est l'acide acétique,
  • -l'hydracide est l'acide chlorhydrique,
  • -et l'agent d'éthynylation est l'acétylène.
Under the preferential conditions of implementation, this application is characterized in that:
  • the catalyst is palladium hydroxide,
  • -the strong base is soda and we operate in methanol,
  • the weak aqueous acid is acetic acid,
  • the hydracid is hydrochloric acid,
  • -and the ethynylating agent is acetylene.

Au cours de l'exécution de ce procédé d'application les produits industriels nouveaux suivants ont été préparés:

  • -le /6,7-3H/ diacétate de méthoxy-11β estra-1,3,5(10)-trien diol-3,17β
  • -le /6,7-3H/ méthoxy-11β estra-1,3,5(10)-trien diol-3,17β
  • -le /6,7-3H/ hydroxy-3 méthoxy 11β estra 1,3,5(10)-trien one-17.
During the execution of this application process the following new industrial products were prepared:
  • -he / 6.7- 3 H / methoxy-11β diacetate estra-1,3,5 (10) -trien diol-3,17β
  • -he / 6.7- 3 H / methoxy-11β estra-1,3,5 (10) -trien diol-3,17β
  • -he / 6,7- 3 H / hydroxy-3 methoxy 11β estra 1,3,5 (10) -trien one-17.

Parmi ces produits, le /6,7-3H/ méthoxy-11β estra-1,3,5(10)-trien diol-3,17β et le /6,7-3H/ hydroxy-3 méthoxy-11β estra-1,3,5(10)-trien one-17, présentent un intérêt particulier.Among these products, / 6,7- 3 H / methoxy-11β estra-1,3,5 (10) -trien diol-3,17β and / 6,7- 3 H / hydroxy-3 methoxy-11β estra -1,3,5 (10) -trien one-17, are of particular interest.

Ces produits conduisent notamment au /6,7-3H/ méthoxy-11β éthynyl-17a estradiol qui présente un activité spécifique de l'ordre de 52 Ci/mM.These products lead in particular to / 6,7 3 H / methoxy-11β-ethynyl estradiol 17a which has a specific activity of approximately 52 Ci / mM.

Ce dernier produit permet l'étude et le dosage du récepteur spécifique d'estrogène présent dans les cellules des tissus ou organes cibles de l'action des estrogènes, comme l'utérus, le vagin, l'hypophyse, l'hypotalamus et les tumeurs, comme par exemple du sein, de la prostate ou de l'adénome, aussi bien chez l'animal que chez l'homme. En effet ce produit ne se fixe pas avec les protéines plasmatiques liant les hormones telles que la testostérone et l'estradiol, chez la femme c'est un marqueur de choix du récepteur tissulaire des estrogènes avec lequel il forme un complexe de forte affinité et de grande stabilité, d'autant qu'il n'a aucune interaction avec les récepteurs tissulaires des autres classes d'hormones stéroidiennes (glucocorticoïdes, minéralocorticoïdes, androgènes ou progestogènes).This last product allows the study and the dosage of the specific estrogen receptor present in the cells of tissues or organs targeted by the action of estrogens, such as the uterus, the vagina, the pituitary gland, the hypotalamus and tumors. , such as breast, prostate or adenoma, both in animals and in humans. Indeed, this product does not bind with the plasma proteins binding hormones such as testosterone and estradiol, in women it is a marker of choice for the tissue estrogen receptor with which it forms a complex of strong affinity and high stability, especially since it has no interaction with tissue receptors of other classes of steroid hormones (glucocorticoids, mineralocorticoids, androgens or progestogens).

Enfin, il permet le dosage du méthoxy-11β éthynyl-17α estradiol dans le plasma ou d'autres liquides biologiques par radioimmuno essai.Finally, it allows the determination of methoxy-11β ethynyl-17α estradiol in plasma or other biological fluids by radioimmunoassay.

L'utilisation du /6,7-3H/ méthoxy-11β éthynyl-17a estradiol a été décrite par J. P. RAYNAUD et coll., "Progesterone receptors in normal and Neoplastic Tissues", ed. W. L. McGUIRE et AI., Raveh Press, New York, 1977, p.p. 171-191.The use of / 6,7- 3 H / methoxy-11β ethynyl-17a estradiol has been described by JP RAYNAUD et al., "Progesterone receptors in normal and Neoplastic Tissues", ed. WL McGUIRE and AI., Raveh Press, New York, 1977, pp 171-191.

Le produit de départ du procédé de préparation des produits de formule générale I, le 11β-méthoxy nor-testostérone a été décrit dans le brevet français 2 1 15 033.The starting product of the process for preparing the products of general formula I, 11β-methoxy nor-testosterone has been described in French patent 2 1 15 033.

Les exemples suivants illustrent à titre non limitatif la mise en oeuvre de l'invention.The following examples illustrate, without limitation, the implementation of the invention.

Exemple IExample I Diacétate du méthoxy-11β estra-1,3,5(10), 6-tétraène diol-3-17βMethoxy-11β diacetate estra-1,3,5 (10), 6-tetraene diol-3-17β Stade A: Méthoxy-11β-acétoxy-17β nor-testostéroneStage A: Methoxy-11β-acetoxy-17β nor-testosterone

On dissout 15 g de méthoxy-11β nor-testostérone dans 75 cm3 de pyridine et 37,5 cm3 d'anhydride acétique. On agite 13 heures à température ambiante. Puis, on ajoute 350 cm3 d'eau et de glace. Après 30 minutes d'agitation à 0°+5°C, on essore et on lave avec de l'eau glacée. On sèche sous vide à température ambiante et on obtient 16,7 g du produit désiré fondant à +140°C. Ce produit est recristallisé dans l'éther isopropylique.

Figure imgb0002
/a/D =+58°35 (C=1,2% dans l'éthanol)15 g of methoxy-11β nor-testosterone are dissolved in 75 cm3 of pyridine and 37.5 cm3 of acetic anhydride. The mixture is stirred for 13 hours at room temperature. Then, 350 cm3 of water and ice are added. After 30 minutes of stirring at 0 ° + 5 ° C, drain and wash with ice water. It is dried under vacuum at room temperature and 16.7 g of the desired product, melting at + 140 ° C., are obtained. This product is recrystallized from isopropyl ether.
Figure imgb0002
 / a / D = + 58 ° 35 (C = 1.2% in ethanol)

Stade B: Acétoxy-17β dibromo-2,6 méthoxy-11β estrène-4 one-3Stage B: Acetoxy-17β 2.6-dibromo-11h methoxy-11β-4-one

On dissout 11,7 g du produit obtenu au stade A dans 117 cm3 d'éther anhydre. En maintenant la température à 20°C on ajoute, en 30 minutes, 10,78 g de brome en solution dans 58,5 cm3 d'acide acétique. On agite encore 15 minutes puis on chasse l'éther sous vide à 30°C. L'extrait sec est repris par 250 ml d'eau. On extrait la phase aqueuse par du chlorure de méthylène, lave la phase organique avec une solution saturée de bicarbonate et ensuite par de l'eau, la sèche sur sulfate de sodium anhydre. Cette solution d'acétoxy-17β dibromo-2,6 méthoxy-11β estrène-4 one-3 dans le chlorure de méthylène est utilisée telle quelle pour le stade suivant de la synthèse.11.7 g of the product obtained in Stage A are dissolved in 117 cm 3 of anhydrous ether. Maintaining the temperature at 20 ° C., 10.78 g of bromine dissolved in 58.5 cm3 of acetic acid are added over 30 minutes. The mixture is stirred for another 15 minutes and then the ether is removed under vacuum at 30 ° C. The dry extract is taken up in 250 ml of water. The aqueous phase is extracted with methylene chloride, the organic phase is washed with a saturated bicarbonate solution and then with water, dried over anhydrous sodium sulfate. This solution of acetoxy-17β dibromo-2,6 methoxy-11β estrene-4 one-3 in methylene chloride is used as it is for the next stage of the synthesis.

Stade C: Acétate-17β méthoxy-11β estra-1,3,5(10J, 6 tetraène diol-3, 17βStage C: Acetate-17β methoxy-11β estra-1,3,5 (10J, 6 tetraene diol-3, 17β

On mélange, 10,53 g de chlorure de lithium et 117 cm3 de diméthyl formamide. On chauffe sous agitation et sous azote jusqu'à 1 10-1 15°C puis on ajoute la solution chlorométhylénique obtenue au stade précédent. On chasse le chlorure de méthylène par distillation puis on laisse 2 heures à 110-1 15°C sous agitation et sous azote. On refroidit à +20°C et on verse sour 500 cm3 d'eau et de glace. La gomme obtenue est extraite par du chlorure de méthylène. On lave la phase organique avec une solution saturée de bicarbonate de sodium puis à l'eau. On sèche sur sulfate de sodium. Après évaporation à sec sous vide à +30°C, on obtient un résidu que l'on purifie par chromatographie sur silice, (éluant benzène 9 acétate d'éthyle 1 ). Le produit obtenu est lavé au benzène et séché.

  • On obtient 4,267 g de produit cherché.
  • F. =+189°C.

Les eaux mères reprises par du benzène donnent un 2ème jet de 860 mg de produit fondant à +189°C.10.53 g of lithium chloride and 117 cm3 of dimethyl formamide are mixed. The mixture is heated with stirring and under nitrogen to 110 ° -15 ° C. and then the chloromethylenic solution obtained in the preceding stage is added. The methylene chloride is removed by distillation and then left for 2 hours at 110-1 15 ° C with stirring and under nitrogen. Cool to + 20 ° C and pour in 500 cm3 of water and ice. The gum obtained is extracted with methylene chloride. The organic phase is washed with a saturated sodium bicarbonate solution and then with water. Dried over sodium sulfate. After evaporation to dryness under vacuum at + 30 ° C., a residue is obtained which is purified by chromatography on silica (eluent benzene 9 ethyl acetate 1). The product obtained is washed with benzene and dried.
  • 4.267 g of sought product is obtained.
  • Mp = + 189 ° C.

The mother liquors taken up in benzene give a second spray of 860 mg of product melting at + 189 ° C.

Stade D; Diacétate du méthoxy-11β estra-1;3,5(10), 6 tétraène diol-3, 17βStage D; Methoxy-11β diacetate estra-1; 3,5 (10), 6 tetraene diol-3, 17β

On dissout 4,1 g de produit obtenu au stade précédent dans 20 cm3 de pyridine et 10 cm3 d'anhydride acétique. On agite à 20°C pendant 16 heures puis on ajoute 100 cm3 d'eau et de glace. La gomme formée est extraite au chlorure de méthylène. On lave la phase organique à l'acide chlorhydrique N puis par une solution saturée de bicarbonate de sodium et enfin par de l'eau. On sèche sur sulfate de sodium anhydre puis on évapore à sec sous vide. On obtient 4,49 g d'une huile incolore.4.1 g of product obtained in the preceding stage are dissolved in 20 cm 3 of pyridine and 10 cm 3 of acetic anhydride. Stirred at 20 ° C for 16 hours then added 100 cm3 of water and ice. The gum formed is extracted with methylene chloride. The organic phase is washed with N hydrochloric acid and then with a saturated sodium bicarbonate solution and finally with water. It is dried over anhydrous sodium sulfate and then evaporated to dryness under vacuum. 4.49 g of a colorless oil are obtained.

AnalyseAnalysis Spectre UVUV spectrum

Figure imgb0003
Figure imgb0003
Figure imgb0004
Figure imgb0004

Stade A: Diacétate du l6,7-3H/ méthoxy-11β estra-1,3,5(10) triène diol 3, 17βStage A: 16,7- 3 H diacetate / methoxy-11β estra-1,3,5 (10) triene diol 3, 17β

On refroidit par l'azote liquide le mélange réactionnel constitué par 45,2 mg de diacétate de méthoxy-11β estra-1,3,5(10),6 tétraène diol-3, 17β, 10 mg de noir palladié et 0,6 cm3 d'acétate d'éthyle redistillé, puis introduit sous vide 3,87 cm3 de tritium, mesurés à 0°C et à pression normale d'une activité totale de 10 Ci. Puis on laisse revenir le mélange réactionnel à température ambiante, maintient sous agitation pendant 3 heures, récupère l'excès de tritium, filtre, distille sous pression réduite le solvant et, après élimination du tritium labile, obtient 46 mg de diacétate du /6,7-3H/ méthoxy-11β estra-1,3,5(10) triène dio-3,17β cherché d'une activité spécifique de 54,03 Ci/mM.The reaction mixture consisting of 45.2 mg of methoxy-11β diacetate estra-1,3,5 (10), 6 tetraene diol-3, 17β, 10 mg of palladium black and 0.6 is cooled with liquid nitrogen. cm3 of redistilled ethyl acetate, then introduced under vacuum 3.87 cm3 of tritium, measured at 0 ° C. and at normal pressure with a total activity of 10 Ci. Then the reaction mixture is allowed to return to ambient temperature, maintains with stirring for 3 hours, collects the excess tritium, filters, distills the solvent under reduced pressure and, after removal of the labile tritium, obtains 46 mg of diacetate / 6,7- 3 H / methoxy-11β estra-1, 3.5 (10) triene dio-3.17β sought for a specific activity of 54.03 Ci / mM.

Stade B: /6,7-3H/ méthoxy-1 1β estra-1,3,5(10) triène diol-3, 17βStage B: / 6.7- 3 H / methoxy-1 1β estra-1,3,5 (10) triene diol-3, 17β

On agite sous courant d'azote 41 mg du produit obtenu au stade précédent, 4 cm3 de méthanol redistillé, 0,5 cn3 d'eau et 0,5 cm3 de lessive de soude 36°Bé. On porte au reflux sous agitation et sous azote pendant 2 heures: Après refroidissement à 20°C on ajoute 0,5 cm3 d'acide acétique et 1,5 cm3 d'eau. Le produit cristallise. On glace 1 heure puis on essore et lave à l'eau glacée. On sèche sous vide en présence d'anhydride phosphorique. On obtient 30,6 mg de prodiut cherché.

  • F =+245°C

Activité spécifique 52 Ci/mM.Stirred under a stream of nitrogen 41 mg of the product obtained in the preceding stage, 4 cm3 of redistilled methanol, 0.5 cc of water and 0.5 cm3 of sodium hydroxide solution 36 ° Bé. The mixture is brought to reflux with stirring and under nitrogen for 2 hours: After cooling to 20 ° C., 0.5 cm3 of acetic acid and 1.5 cm3 of water are added. The product crystallizes. Ice for 1 hour then drain and wash with ice water. It is dried under vacuum in the presence of phosphoric anhydride. 30.6 mg of sought product is obtained.
  • F = + 245 ° C

Specific activity 52 Ci / mM.

Stade C: /6,7-3H/ hydroxy-3 méthoxy-11β estra-1,3,5(10) triène one-17Stage C: / 6.7- 3 H / 3-hydroxy-methoxy-11β estra-1,3,5 (10) triene one-17

On amène à 50°C, sous argon, 20,9 mg du produit obtenu au stade precédent avec 5 cm3 de toluène et 2 cm3 de cyclohexanone. On distille sous passage d'argon 1 cm3 de toluène. Puis on introduit, en 30 minutes au total, 4 fois 1 cm3 d'une solution d'isopropylate d'aluminium dans 50 cm3 de toluène, en distillant au fur et à mesure, de façon à maintenir le volume constant. On laisse encore 15 minutés au reflux sous argon. Ensuite on introduit, en distillant au fur et à mesure, une solution de 1 g de tartrate de sodium et de potassium dans 10 cm3 d'eau. On entraîne les solvants à la vapeur d'eau. On refroidit dans un bain de glace. Le produit cristallise. On agite 30 minutes à 0° avant d'essorer. On lave à l'eau, on sèche sous vide en présence d'anhydride phosphorique à température ambiante. On obtient 18,8 mg de produit brut que l'on utilise tel quel pour le stade suivant de la synthèse.20.9 mg of the product obtained in the preceding stage are brought to 50 ° C. under argon with 5 cm3 of toluene and 2 cm3 of cyclohexanone. Distilled under passage of argon 1 cm3 of toluene. Then, in 30 minutes in total, 4 times 1 cm 3 of a solution of aluminum isopropylate in 50 cm 3 of toluene are introduced, distilling as and when required, so as to keep the volume constant. Another 15 minutes are allowed to reflux under argon. Next, a solution of 1 g of sodium and potassium tartrate in 10 cm 3 of water is introduced, while distilling off gradually. Solvents are entrained in water vapor. It is cooled in an ice bath. The product crystallizes. Stirred 30 minutes at 0 ° before wringing. Washed with water, dried under vacuum in the presence of phosphoric anhydride at room temperature. 18.8 mg of crude product are obtained, which product is used as it is for the next stage of the synthesis.

Stade D: /6,7-3H/ méthoxy-11β éthynyl-17α estradiolStage D: / 6.7- 3 H / methoxy-11β ethynyl-17α estradiol

Dans 10 cm3 d'une solution de téramylate de sodium à 2,8 g de Na pour 100 cm3 on fait barboter de l'acétylène pendant 2 heures. Puis on ajoute dans le produit obtenu au stade précédent dissous dans 2,5 cm3 de tétrahydrofurane. On maintient le barbotage d'acétylène pendant 5 heures sous agitation et à température ambiante. On remplace le barbotage d'acétylène par de l'argon et on acidifie immédiatement, en refroidissant dans un bain de glace, par 2 cm3 d'acide acétique à 50% d'eau. On extrait à l'éther et on lave à l'eau jusqu'à neutralité. On sèche sur sulfate de sodium. Cette solution est concentrée sous vide. On obtient 25 mg de produit que l'on dissout dans 1 cm3 de tétrahydrofurane pur, pour faire une chromatographie sur plaque, avec, comme solvant de migration, le système benzène 7 acétate d'éthyle 3. Le produit-est isolé par élution avec un mélange chlorure de méthylène 1 acétone 1. On concentre sous vide et on obtient 11,1 mg de produit solvaté à 26%, soit 8,17 mg en produit non solvaté.
Activité spécifique: 52 Ci/mM.Bubble acetylene for 2 hours in 10 cm3 of a sodium teramylate solution containing 2.8 g of Na per 100 cm3. Then added to the product obtained in the previous stage dissolved in 2.5 cm3 of tetrahydrofuran. The bubbling of acetylene is maintained for 5 hours with stirring and at room temperature. The bubbling of acetylene is replaced by argon and it is immediately acidified, while cooling in an ice bath, with 2 cm 3 of acetic acid at 50% water. Extracted with ether and washed with water until neutral. Dried over sodium sulfate. This solution is concentrated in vacuo. 25 mg of product are obtained which is dissolved in 1 cm 3 of pure tetrahydrofuran, to perform plate chromatography, with, as migration solvent, the benzene 7 ethyl acetate system 3. The product is isolated by elution with a mixture of methylene chloride and acetone 1. Concentration in vacuo gives 11.1 mg of 26% solvated product, ie 8.17 mg of unsolvated product.
Specific activity: 52 Ci / mM.

Claims (6)

1. New steroids of general formula I:
Figure imgb0007
in which R represents hydrogen or R', R' being an acyl radical having from 1 to 5 carbon atoms, the substituted or unsubstituted benzoyl radical or a tetrahydropyranyl, trityl or trimethylsilyl radical and R, represents an acyl radical having from 1 to 5 carbon atoms, the substituted or unsubstituted benzoyl radical or a tetrahydropyranyl. trityl or trimethylsilyl radical.
2. 11 1β-methoxy estra-1,3,5(10),6 tetraene 3,17β-diol acetate.
3. 11β-methoxy estra-1,3,5(10),6 tetraene 3,17β-diol diacetate.
4. Process for preparing the products as defined in Claims 1, 2 or 3, characterised in that:
-the hydroxyl function at position 17β of the 11 β-methoxy nortestosterone is blocked by means of an esterification or etherification agent, -
-the 17β―OR1 11β-methoxy nor-testosterone obtained, R, having here and in the following the aforementioned meanings, is subject to the action of a halogenation agent and
-a dehydrohalogenation agent is reacted with the resultant 17β―OR1 2,6-dihalogeno 11β-methoxy estr-4-en 3-one to obtain the 17β―OR1 1 1β-methoxy estra-1,3,5(10),6-tetraen 3-ol sought of which the hydroxyl function at 3 is blocked, if need be, by means of an esterification or etherification agent to obtain 3-OR', 17β―OR1 11β-methoxy estra-1,3,5(10),6-tetraene, R' having the aforementioned meanings.
5. Use of the products as defined in claims 1, 2 and 3 in the synthesis of steroid compounds labelled with tritium, characterised in that:
- a product of general formula I, in which R and R, have the aforementioned meanings, is reduced by the action of tritiated hydrogen in the presence of a catalyst,
- the resultant [6,7―3H] 3-OR 17β-OR1 11β-methoxy estra-1,3,5(10)-triene is subjected to the action of a strong base or of a weak acid in aqueous medium or of a hydracid to obtain [6,7―3H] 11β-methoxy estra-1,3,5(10)-triene 3,17β―diol which is oxidised into [6,7―3H] 3-hydroxy 11β-methoxy estra-1,3,5(10)-trien 17-one by means of cyclohexanone in the presence of aluminium isopropylate
- the latter is subjected to the action of an ethynylation agent in the presence of sodium teramylate in toluene and [6,7―3H] 11β-methoxy 17α-ethynyl estra diol is obtained.
6. Use according to Claim 5, characterised in that:
- the catalyst is palladium hydroxide,
- the strong base is sodium hydroxide and work is carried out in methanol,
- the weak aqueous acid is acetic acid,
- the hydracid is hydrochloric acid,
- and the ethynylation agent is acetylene.
EP78400016A 1977-06-27 1978-06-12 Substituted estra-1,3,5(10),6-tetraenes, process for their preparation and use in the synthesis of tritium labelled steroids Expired EP0000300B1 (en)

Applications Claiming Priority (2)

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FR7719613A FR2401173A1 (en) 1977-06-27 1977-06-27 NEW STEROIDS, THEIR PREPARATION PROCESS AND THEIR APPLICATION IN THE SYNTHESIS OF STEROIDS TRADEMARKS WITH TRITIUM
FR7719613 1977-06-27

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EP0000300A1 EP0000300A1 (en) 1979-01-10
EP0000300B1 true EP0000300B1 (en) 1982-01-06

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DE3937412A1 (en) * 1989-11-10 1991-05-16 Hoechst Ag SYNTHETIC VACCINE FOR THE SPECIFIC INDUCTION OF CYTOTOXIC T-LYMPHOZYTES
US4757062A (en) * 1985-11-01 1988-07-12 E. I. Du Pont De Nemours And Company Substituted benzoate ester prodrugs of estrogens
ATE305482T1 (en) 1999-12-15 2005-10-15 Dow Global Technologies Inc MULTI-COMPONENT ITEMS MADE OF HYDROGENATED BLOCK COPOLYMERS
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