EP0000300A1 - 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 PDFInfo
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- EP0000300A1 EP0000300A1 EP78400016A EP78400016A EP0000300A1 EP 0000300 A1 EP0000300 A1 EP 0000300A1 EP 78400016 A EP78400016 A EP 78400016A EP 78400016 A EP78400016 A EP 78400016A EP 0000300 A1 EP0000300 A1 EP 0000300A1
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- methoxy
- estra
- diol
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- trien
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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
Definitions
- the present invention relates to new steroids from the series of substituted estratetraene, their preparation process and their application to the synthesis of derivatives of the series of astradiols labeled with tritium.
- 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 carbon, it may be for example the residue of formic acid, acetic acid, p ropionique, butyric or valeric acids.
- R and / or R 1 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.
- a halogen such as chlorine or Bromine
- the subject of the invention is also a process for preparing the products corresponding to the general formula above.
- tissues of other classes of steroid hormones glucocorticoids, mineral corticosteroids, androgens or progestogens.
- Stage B Acetoxy-17 ⁇ dibromo-2, 6 methoxy-11 ⁇ estrene 4 one-3
- 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 0.3 cc is cooled with liquid nitrogen. 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, maintained under stirring for 3 hours, collects the excess of 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 diol-3, 17 ⁇ sought for a specific activity of 54.03 Ci / mM.
- Stage B / 6. 7- 3 H / methoxy-11 ⁇ estra-1, 3, 5 (10) triene diol-3.17 ⁇
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- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Steroid Compounds (AREA)
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- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
L'invention a pour objet les stéroïdes nouveaux de formule I: <IMAGE> dans laquelle R représente de l'hydrogène ou R', R' représente un acyle, un benzoyle substitué ou non, un radical tétrahydropyranyle, trityle ou triméthylsilyle et R1 représente un acyle, un benzoyle substitué ou non, un radical tétrahydropyranyle, trityle ou triméthylsilyle, ainsi que leur procédé de préparation et leur application à la préparation de stéroïdes marqués au tritium.The subject of the invention is the new steroids of formula I: <IMAGE> in which R represents hydrogen or R ', R' represents an acyl, a substituted or unsubstituted benzoyl, a tetrahydropyranyl, trityl or trimethylsilyl radical and R1 represents an acyl, a substituted or unsubstituted benzoyl, a tetrahydropyranyl, trityl or trimethylsilyl radical, as well as their process of preparation and their application to the preparation of steroids labeled with tritium.
Description
La présente invention concerne de nouveaux stéroïdes de la série des estratétraènes substitués, leur procédé de préparation at leur application à la synthèse de dérivés de la série des astradiols marqués au tritium.The present invention relates to new steroids from the series of substituted estratetraene, their preparation process and their application to the synthesis of derivatives of the series of astradiols labeled with tritium.
L'invention a pour objet les stéroides de formule générale I
Lorsque R et/ou R1 représente. un radical acyle ayant de 1 à 5 atomes le carbone, il peut être par exemple le reste d'acides formique, acetique, propionique, butyrique ou valérique.When R and / or R 1 represents. an acyl radical having from 1 to 5 carbon carbon, it may be for example the residue of formic acid, acetic acid, p ropionique, butyric or valeric acids.
Lorsque R et/ou R1 représente un radical benzoyle substitue, 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 trifluoro- méthoxy, ou par un radical alcoyloxy ayant de 1 à 5 atomes de carbone.When R and / or R 1 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.
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
- - 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 1 cynthèse de dérivés stéroides 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 ci-dessus.The subject of the invention is also a process for preparing the products corresponding to the general formula above.
Ce procédé est caractérisé en ce que l'on :
- - bloque la fonction hydroxyle en position 11β de la 11β -méthoxy nor-testostérone au moyen d'un agent d'estérification ou d'éthérification,
- - soumet la OR1-17β méthoxy-11β 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 déshalohydrataticn pour obtenir le OR1-17β méthoxy-11β estra-1,3,5(10),6-tetraen ol-3 cherché, dont on bloque, le cas échéant, la fonction hydroxyle en 9 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 .
- - blocks the hydroxyl function in position 11β of 11β-methoxy nor-testosterone by means of an esterification or etherification agent,
- - subjects the OR 1 -17β methoxy-11β nor-testosterone obtained, R 1 having here and in the following the abovementioned meanings, to the action of a halogenating agent,
- - acts on OR 1 -17β dihalo-2,6,6 methoxy-11β estren-4 one-3 resulting in a dehalohydrataticn agent to obtain OR 1 -17β methoxy-11β estra-1,3,5 (10), 6 -tetraen ol-3 sought, which is blocked, where appropriate, the hydroxyl function at 9 by means of an esterification or etherification agent to obtain 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 étre l'anhydride acétique cu le chlorure de benzoyle ;
- - l'agent d'éthérification au moyen 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 in OR1-17β méthoxy-11β nor-testérone est le brome dans l'acide acétique ;
- 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 whose action. subject in OR 1 -17β methoxy-11β nor-testone is bromine in acetic acid;
Comme déjà indiqué les produits de formule générale I sont les produits de départ pour la synthèse de dérivés stéroides 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 R1l 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/ méthoxy-11β estra-1, 3, 5(10)-trien diol-3,17β
que l'on oxyde, selon la réaction d'Openauer, en /6, 7- 3H/ hydrexy-3 méthoxy-11β estra-1, 3, 5(10)-trien one-17, au moyen de cyclohéxanone en présence d'isopronylate 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.
- - reduces a product of general formula I, in which R and R 11 have the abovementioned meanings, by the action of tritiated hydrogen in the presence of a catalyst,
- - subjects / 6,7 3H / 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 an aqueous medium , or a hydracid, to obtain the / 6,7- 3 H / methoxy-11β estra-1, 3, 5 (10) -trien diol-3,17β
which is oxidized, according to the Openauer reaction, in / 6, 7- 3 H / 3-hydroxy-methoxy-11β estra-1, 3, 5 (10) -trien one-17, by means of cyclohexanone in the presence aluminum isopronylate; - - Subjects the latter to the action of an ethynylating agent, in the presence of sodium teramylate 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.
- - 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 ethynylation agent is acetylene.
L'invention a également pour objet, à titre de produits industriels nouveaux et notamment à titre d'intermédiaires nécessaires à l'exécution du procédé d'application des produits de formule générale I, objet de l'invention, les produits suivants :
- - le /6, 7- 3H/ diacétate de méthoxy-11β estra-1,3, 5(10)-trien diol-3,17β
- - le /6,7-3H/ méthoxy-11β astra-1, 3, 5(10)-trien diol-3, 17β
- - le /6,7-3H/ hydroxy-3 méthoxy 11β estra 1, 3, 5(10)-trien one-17.
- - the / 6,7- 3 H / methoxy-11β diacetate estra-1,3, 5 (10) -trien diol-3,17β
- - le / 6,7- 3 H / methoxy-11β astra-1, 3, 5 (10) -trien diol-3, 17β
- - le / 6,7- 3 H / hydroxy- 3 methoxy 11β estra 1, 3, 5 (10) -trien one-17.
Parmi ces produits, la /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, the / 6,7- 3 H / methoxy-11β estra-1, 3, 5 (10) -trien diol-3, 17β and the / 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-17α estradiol qui présente une activité spécifique de l'ordre de 53 C1/mM.These products lead in particular to / 6,7- 3 H / methoxy-11β ethynyl-17α estradiol which has a specific activity of the order of 53 C1 / mM.
Ce dernier produit permet l'étude et le dosage du récepteur spécifique d'extrogène présent dans les cellules des tissus ou organes cibles de l'action tissulaires des autres classes d'hormones stéroidiennes (glucocorticoides, minéralccorticoldes, androgènes ou progestogènes).This last product allows the study and the assay of the specific receptor of exogenous present in the cells of the tissues or organs target of the action. tissues of other classes of steroid hormones (glucocorticoids, mineral corticosteroids, androgens or progestogens).
Enfin, il permet le dosage du méthoxy-11β éthynyl-17a estradiol dans le plasma ou d'autres liquides biologiques par radioimmuno essai.Finally, it allows the methoxy-11β ethynyl-17a estradiol to be assayed in plasma or other biological liquids 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. Mc GUIRE et Al., 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 Mc GUIRE et al., 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 2 115 033.The starting product for the process for preparing the products of general formula I, 11β-methoxy nor-testosterone has been described in French patent 2 115 033.
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.
- Point de fusion : + 140°C.
- Analyse : C21H30O4
- Calculé : C% 72, 80 H% 8, 73 O% 18, 47.
- Trouvé : 72,9 8, 5
- /α/D = + 58°35 (C = 1,2 % dans l'éthanol)
- Melting point: + 140 ° C.
- Analysis: C 21 H 30 O 4
- Calculated: C% 72, 80 H% 8, 73 O% 18, 47.
- Found: 72.9 8.5
- / α / D = + 58 ° 35 (C = 1.2% in ethanol)
On dissout 11,7 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 1 5 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. Stade C : Acétate-17β méthoxy-11β estra-1, 3, 5(10), 6 tetraène diol -3, 17β11.7 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 cm 3 of acetic acid are added over 30 minutes. The mixture is stirred again for 15 minutes and then the ether is removed in vacuo 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. Stage C: Acetate-17β methoxy-11β estra-1, 3, 5 (10), 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 110-115°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 110-115°C sous agitation et sous azote. On refroidit à + 20°C et on verse sur 500 cm3 d'eau et de glace. La gomme obtenue est eextraite par du chlorure de méthylene. On lave la phase organique avec une solution saturée de bicarbonate de sodium puis à l'eau. On sèche sur sulfate de sodium. Aprés 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.10.53 g of lithium chloride and 117 cm 3 of dimethyl formamide are mixed. The mixture is heated with stirring and under nitrogen to 110-115 ° 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 110-115 ° C with stirring and under nitrogen. Cool to + 20 ° C and pour over 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.
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.
- Mp = + 189 ° C
- The mother liquors taken up in benzene give a second jet of 860 mg of product melting at + 189 ° C.
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.
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, 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 diol-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 0.3 cc is cooled with liquid nitrogen. 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, maintained under stirring for 3 hours, collects the excess of 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 diol-3, 17β sought for a specific activity of 54.03 Ci / mM.
On agite sous courant d'azote 41 mg du produit obtenu au stade précédent, 4 cm3 de méthanol redistillé, 0, 5 cm3 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 at 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 produit cherché.
- F. = + 245°C
- Activité spécifique 52 Ci/mM.
- Mp = + 245 ° C
- Specific activity 52 Ci / mM.
On amène à 50°C, sous argon, 20, 9 mg du produit obtenu au stade pracédent 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 a.l 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 minutes au reflux sous argon. Ensuite on introduit, en distillant au fur et à mesure, une solution de 1 g de tartrats de sodium et de potassium dans 10 cm3 d'eau. On antraîne 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 tampérature ambiante. on obtient 18,8 mg de produit brut que l'on utilise tal 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 cm 3 of toluene and 2 cm 3 of cyclohexanone. Distilled under passage of argon 1 cm3 of toluene. Then, in 30 minutes a.l 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 tartrates in 10 cm 3 of water is introduced, while distilling off gradually. The solvents are swept away with 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 ambient temperature. 18.8 mg of crude product are obtained which is used as is for the next stage of the synthesis.
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 3 heures. Puis on ajoute dans le produit obtenu au stade precédent dissous dans 2, 5 cm3 de téirahydrofurane. On maimient le barbotage d'acétylène pendant 5 heures sous agitation et à températdre ambiante. On remplace le barbotage d'acétylène par de l'argon et on acidifie immédiatement, en refroidissant dans un bain de giace, par 2 cm3 d'acide acétique à 50 % d'eau. On extrait a l'éther Bubble acetylene for 3 hours in 10 cm 3 of a sodium teramylate solution containing 2.8 g of Na per 100 cm 3. Then added to the product obtained in the previous stage dissolved in 2.5 cm3 of téirahydrofurane. The bubbling of acetylene is controlled for 5 hours with stirring and at room temperature. Replacing the bubbling of acetylene with argon and immediately acidifying, cooling in a giace bath, with 2 cm3 of acetic acid at 50% water. Extracted with ether
Claims (8)
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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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 |
Publications (2)
Publication Number | Publication Date |
---|---|
EP0000300A1 true EP0000300A1 (en) | 1979-01-10 |
EP0000300B1 EP0000300B1 (en) | 1982-01-06 |
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ID=9192607
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP78400016A Expired EP0000300B1 (en) | 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 |
Country Status (7)
Country | Link |
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US (1) | US4191697A (en) |
EP (1) | EP0000300B1 (en) |
JP (2) | JPS5412362A (en) |
CA (1) | CA1130277A (en) |
DE (1) | DE2861501D1 (en) |
FR (1) | FR2401173A1 (en) |
IT (1) | IT1105060B (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0431327A1 (en) * | 1989-11-10 | 1991-06-12 | Hoechst Aktiengesellschaft | Synthetic vaccine for the specific induction of cytotoxic T-lymphocytes |
DE102017119621A1 (en) | 2016-12-01 | 2018-06-07 | Pouya Molana | A mayonnaise powder composition and method of making a food product using the same |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE3414508A1 (en) * | 1984-04-13 | 1985-10-24 | Schering AG, 1000 Berlin und 4709 Bergkamen | MULTIPLE TRITLED STEROID-20.17-SPIROLACTONE AND THEIR USE AS TRACER SUBSTANCES |
US4757062A (en) * | 1985-11-01 | 1988-07-12 | E. I. Du Pont De Nemours And Company | Substituted benzoate ester prodrugs of estrogens |
US6416875B1 (en) | 1999-12-15 | 2002-07-09 | Dow Global Technologies Inc. | Multi-component articles prepared from hydrogenated block copolymers |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3020294A (en) * | 1950-03-28 | 1962-02-06 | Syntex Sa | Production of ring a aromatic steroids |
GB1151404A (en) * | 1966-06-07 | 1969-05-07 | Roussel Uclaf | Novel Gona-1,3,5(10)-Trienes, Processes for their Preparation, and Compositions incorporating them |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2115033B1 (en) * | 1970-11-24 | 1974-03-22 | Roussel Uclaf |
-
1977
- 1977-06-27 FR FR7719613A patent/FR2401173A1/en active Granted
-
1978
- 1978-06-12 DE DE7878400016T patent/DE2861501D1/en not_active Expired
- 1978-06-12 EP EP78400016A patent/EP0000300B1/en not_active Expired
- 1978-06-15 US US05/915,601 patent/US4191697A/en not_active Expired - Lifetime
- 1978-06-23 CA CA306,095A patent/CA1130277A/en not_active Expired
- 1978-06-26 JP JP7660378A patent/JPS5412362A/en active Granted
- 1978-06-26 IT IT50022/78A patent/IT1105060B/en active
-
1986
- 1986-11-28 JP JP61282211A patent/JPS62142196A/en active Granted
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3020294A (en) * | 1950-03-28 | 1962-02-06 | Syntex Sa | Production of ring a aromatic steroids |
GB1151404A (en) * | 1966-06-07 | 1969-05-07 | Roussel Uclaf | Novel Gona-1,3,5(10)-Trienes, Processes for their Preparation, and Compositions incorporating them |
Non-Patent Citations (1)
Title |
---|
CHEMICAL ABSTRACTS, vol. 82 (1975) 43644y & YAKUGAKU ZASSHI, 1974 94(11) 1484-8. * |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0431327A1 (en) * | 1989-11-10 | 1991-06-12 | Hoechst Aktiengesellschaft | Synthetic vaccine for the specific induction of cytotoxic T-lymphocytes |
DE102017119621A1 (en) | 2016-12-01 | 2018-06-07 | Pouya Molana | A mayonnaise powder composition and method of making a food product using the same |
Also Published As
Publication number | Publication date |
---|---|
FR2401173A1 (en) | 1979-03-23 |
JPS5412362A (en) | 1979-01-30 |
US4191697A (en) | 1980-03-04 |
EP0000300B1 (en) | 1982-01-06 |
DE2861501D1 (en) | 1982-02-25 |
CA1130277A (en) | 1982-08-24 |
IT7850022A0 (en) | 1978-06-26 |
JPS6360035B2 (en) | 1988-11-22 |
IT1105060B (en) | 1985-10-28 |
JPS6220196B2 (en) | 1987-05-06 |
JPS62142196A (en) | 1987-06-25 |
FR2401173B1 (en) | 1980-04-04 |
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