EP0431107A1 - NOVEL METHODS FOR OBTAINING 6-METHYL 19-NOR STEROIDS AND CONVERTING THEM INTO 17$g(a)-SUBSTITUTED 19-NOR PREGNADIENES - Google Patents

NOVEL METHODS FOR OBTAINING 6-METHYL 19-NOR STEROIDS AND CONVERTING THEM INTO 17$g(a)-SUBSTITUTED 19-NOR PREGNADIENES

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Publication number
EP0431107A1
EP0431107A1 EP19900908555 EP90908555A EP0431107A1 EP 0431107 A1 EP0431107 A1 EP 0431107A1 EP 19900908555 EP19900908555 EP 19900908555 EP 90908555 A EP90908555 A EP 90908555A EP 0431107 A1 EP0431107 A1 EP 0431107A1
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EP
European Patent Office
Prior art keywords
estra
diene
oxo
methyl
ene
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.)
Withdrawn
Application number
EP19900908555
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German (de)
French (fr)
Inventor
Claude Tchernatinsky
Nejib Mohamed Nasraoui
Alain Piasco
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Laboratoire Theramex SAM
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Laboratoire Theramex SAM
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Application filed by Laboratoire Theramex SAM filed Critical Laboratoire Theramex SAM
Publication of EP0431107A1 publication Critical patent/EP0431107A1/en
Withdrawn legal-status Critical Current

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Classifications

    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J7/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms
    • C07J7/0005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21
    • C07J7/001—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group
    • C07J7/0015—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group not substituted in position 17 alfa
    • C07J7/002—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group not substituted in position 17 alfa not substituted in position 16
    • 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
    • C07J1/0055—Estrane derivatives not substituted in position 17

Definitions

  • the present invention relates to the field of steroid chemistry and in particular to 6-methylated estrogenic steroid derivatives.
  • A represents hydrogen or a lower oxoalkyl radical
  • B represents hydrogen or a lower oxoalkyl radical or else A is a free or esterified hydroxyl and B is a lower alkyl radical or a lower alkynyl radical
  • R 1 represents hydrogen or a lower alkyl radical, and in particular 6-methyl 3,20-dioxo 19-nor pregna 4,6-diene.
  • R 2 is a lower alkyl radical having from 1 to 4 carbon atoms
  • R 3 is hydrogen, hydroxyl or an OR 5 group in which R 5 is an acyl residue derived from an organic carboxylic, aliphatic or aromatic acid having from 1 to 10 atoms
  • R 1 represents hydrogen or a lower alkyl radical
  • R 4 represents hydrogen or an acyl residue of an aliphatic or aromatic organic carboxylic acid having from 1 to 10 carbon atoms, and in particular 17 ⁇ -acetoxy 17ot-ethynyl 6-methyl 3-oxo estra
  • R 3 represents the acyl residue of an organic carboxylic acid, aliphatic or aromatic, having from 1 to 10 carbon atoms.
  • the invention relates to a process for obtaining 3-oxo 6-methyl extra 4,6-diene of formula I A which consists in starting from 3-oxo estra 4-ene to subject the latter to the action of an agent etherifying in an acid medium to form a 3-alkoxy estra 3,5-diene, which is formulated into 3-alkoxy 6-formyl estra 3,5-diene, reduced this by means of a mixed alkali metal hydride to 3-alkoxy 6-hydroxymethyl estra 3,5-diene, dehydrates the latter by treatment in an acid medium to form a 3-oxo 6-methylene estra 4-ene which is isomerized to 3-oxo 6-methyl estra 4, 6-diene by heating in the presence of an isomerization catalyst.
  • the invention relates to a process for obtaining 3,20-dioxo 6-methyl 19-nor pregna 4,6-diene of formula I B which consists in subjecting a 3,20-dioxo 19-nor pregna 4-ene to the action of an etherification agent in an acid medium to obtain a 3-alkoxy 20-oxo 19-nor pregna 3,5-diene, treat the latter with a formylating agent to obtain a 3- 6-formyl alkoxy 20-oxo 19-nor pregna 3,5-diene which is reduced to 3-alkxy 6-hydroxymethyl 20-oxo 19-nor pregna 3,5-diene which is reduced to 3-alkoxy 6 -hydroxymethyl 20-oxo 19-nor pregna 3,5-diene by a mixed hydride of alkali metal, dehydrates the latter in an acid medium to form the 3,20-dioxo 6-methylene 19-nor pregna 4-ene which is isomerized to 3.20-dioxo 6-methyl 19
  • the invention relates to a process for obtaining 17 ⁇ -acyloxy or 17 ⁇ -hydroxy 17 ⁇ -alkynyl 6-methyl estra 4,6-dienes of general formula I D which consists in subjecting a 3-alkoxy 17-oxo 19 -nor estra 3,5-diene to the action of an etherifying agent to form a 3-alkoxy 17-oxo 19-nor estra 3,5-diene then to a formylating agent under the reaction conditions of Vilsmeier-Hack to form a 3-alkoxy 6-formyl 17-oxo estra 3,5-diene, which is reduced by the action of a mixed alkali metal hydride to the corresponding 6-hydroxymethylated derivative, treats the latter with an aqueous solution of strong acid mineral, to form 3-oxo 6-methylene 17 ⁇ -hydroxy estra 4-ene, isomerizes the latter by heating with an isomerization agent, a 3-oxo 6-methyl 17 ⁇ -hydroxy estra 4, 6-diene which is
  • the same compounds can also be obtained by a process which consists in subjecting a 3-oxo 6-methylene 17 ⁇ -acyloxy 17 ⁇ -alkynyl estra 4-ene to the action of an isomerization agent and forming a 3-oxo 6- methyl 17 ⁇ -acyloxy 17 ⁇ -alkynyl estra 4,6-diene.
  • the compounds of formula I D can also be obtained according to the invention by a process which consists in subjecting a 17 ⁇ -acyloxy 17 ⁇ -ethynyl 3-oxo estra 4-ene to the action of an agent etherification in an acid medium to obtain a 3-alkyloxy 17 ⁇ -acyloxy 17 ⁇ -ethynyl estra 3,5-diene, treats it with a formylation reagent under the conditions of the Vilsmeier-Hack reaction to form the derivative 6 -formylated which is reduced by means of a mixed hydride of alkali metal to 6-hydroxymethyl derivative, dehydrates the latter in an acid medium to form a 3-oxo 6-methylene 17 ⁇ -acyloxy 17 ⁇ -ethynyl estra 4-ene then isomerized this in the presence of a 3-oxo 6-methyl 17 ⁇ -acyloxy 17 ⁇ -ethynyl estra 4,6-diene isomerization catalyst.
  • the invention further extends to obtaining 3,17-dioxo 6-methyl estra 4,6-diene of formula I E by a process which consists in subjecting 3,17-dioxo estra 4-ene to an etherification reagent in an acid medium to form a 3-alkoxy 17-oxo estra 3,5-diene, treats this with a formylation reagent to form 3-alkoxy 17-oxo 6-formyl estra 3,5-diene, reduced this by a mixed hydride of alkali metal to 3-alkoxy 6-hydroxymethyl 17 ⁇ -hydroxy estra 3,5-diene which is dehydrated in an acid medium to 3-oxo 6-methylene 17 ⁇ - hydroxy estra 4-ene, isomerizes it with an isomerization catalyst into 6-methyl 3-oxo 17-hydroxy estra 4,6-diene then if desired reoxides the latter with a metal oxidant to form 3,17-dioxo 6-methyl estra 4,6-diene or else subjects
  • the compounds of general formula I are presented for therapeutic purposes in one of the forms which are suitable for parenteral, oral, rectal, percutaneous or permucosal administration.
  • the compounds of general formula I are above all precious synthesis intermediates, which allow access to pharmacologically active 6-methyl 19-nor pregna 4,6-dienes such as 17ot-acetpxy 6-methyl 3,20-dioxo 19- nor pregna 4,6-diene, 6-17 ⁇ -dimethyl 3,20-dioxo 19-nor pregna 4,6-diene, 6-17 ⁇ , 21-trimethyl 3,20-dioxo 19-nor pregna 4,6-diene, the gestational and progestomimetic properties of which have already been described (cf. French patent application No. 89.04910 in the name of the applicant and French patent 2,271,833).
  • the compounds of general formula I D are converted by hydration then by alkylation to 6-methyl 17 ⁇ -alkyl 3.20-dioxo 19-nor estra 4,6-dienes.
  • the 17-oxo 6-methyl estra 4,6-dienes or the estra 4,6-dienes of general formula I E after oxidation are converted by a triphenylethylphosphonium halide to the 17-ethylidenene derivative which by bis-hydroxylation by means of Osmium tetroxide and triethylamine or morpholine N-oxide hydroperoxide leads to 17ot-hydroxy 3.20-dioxo 6-methyl 19-nor pregna 4,6-diene.
  • 3,17-dioxo 6-methyl estra 4,6-diene is a synthetic intermediate which allows either by reaction with an alkyl magnesium salt to form a derivative 17 ⁇ -hydroxy 17 ⁇ -alkylated, or by reaction with a salt d 'alkyl triphenyl phosphonium to form an alkylidene derivative which is oxidized to 17 ⁇ -hydroxy derivative 19-nor pregna 20-one, or again by reaction with a metallic acetylide to form a 17 ⁇ -hydroxy derivative 17 ⁇ -ethynylated.
  • 17 ⁇ -acyloxy 17 ⁇ -ethynyl 6-methyl estradien-4,6 are useful raw materials for preparing 6,17 ⁇ -dimethyl 19-nor 20-keto pregnadi ⁇ nes-4,6 according to a process which consists in subjecting the derivative 17 ⁇ - 17 ⁇ -ethynylated acyloxy to a hydration reaction in the presence of a mercuric salt and then to treat the 20-keto 17 ⁇ -acyloxy 19-nor pregnane obtained, to the action of a methylating agent after reduction with a metal to form a 17 ⁇ -methyl 20-keto 19-nor pregnanic derivative.
  • the dry extract After purification by chomatography on a silica column for chomatography, with elution with Toluene, the dry extract delivers 450 mg of white crystals of 17 ⁇ -ethynyl 17-3-hydroxy 6-methyl estra 4,6-diene.
  • Formulation of the Stage I product provides 99% of 6-formylated product, the UV spectrum of which indicates a maximum at 325 nm
  • the 6-hydroxy methyl derivative was dehydrated with 2N sulfuric acid in an eth.anol / dimethyl formamide mixture. 84% of crude product is collected.
  • the IR spectrum indicates a total absence of band at 3400 cm -1 , the UV spectrum shows a maximum absorption at 263 nm.
  • the mixture is brought to reflux for 4 hours, the solvent is evaporated to dryness and the residue is taken up in 50 ml of Toluene and then 1.4 g of potassium terbutylate are added. The mixture is brought to reflux again for 24 h.
  • the ether enolization stage is carried out starting from 15 g of 3-oxo estra 4-ene in 39 ml of ethanol and 20 ml of ethyl orthoformate in the presence of 0.06 g of p.toluene acid sulfonic then at the end of 0.8 ml of triethylamine.
  • the formylation is carried out with the Vilsmeier reagent (DMP 6 ml, POC131.4 ml) introduced at 0 ° C, under inert gas to a solution of 2 g of 3-ethoxy estra 3,5-diene, in 14 ml DMF. After 15 min, 20 ml of aqueous potassium acetate solution are added, stirring 30 min before filtering to recover 0.9 g (41%) of 3-ethoxy 6-formyl estra 3,5-diene.
  • UV: ⁇ max 325 nm ⁇ 14.245
  • the mixture of the two alkoxylated products is hydrolyzed with 36 ml of a sulfuric acid solution (2N) in 40 min followed by the addition of 20 ml of an aqueous solution of potassium carbonate (0.44 g / ml) , the 3-ceto 6-methylenic derivative is obtained.
  • the isomerization of 5 g of 6-methylenic product is carried out with 125 ml of methanol, 2.5 g of paladiated charcoal and 30 minutes of reflux.
  • the product obtained is chromatographed with methylene chloride on 150 g of silica to obtain 2 g (40%) of 6-methylated derivative which is crystallized from methanol.

Abstract

L'invention se rapporte au domaine de la chimie organique et plus particulièrement à la chimie des stéroïdes. Elle a plus particulièrement pour objet de nouveaux 6-méthyl estra 4,6-diènes de formule générale (I) dans laquelle A représente de l'hydrogène ou un radical oxoalcoyle inférieur et B représente de l'hydrogène ou bien A est un hydroxyle libre ou estérifié, et B est un radical alcoyle inférieur, ou un radical alcynyle inférieur ou bien A et B forment ensemble l'oxygène d'une cétone. Cette invention a également pour objet un procédé d'obtention des composés de formule générale (I). Ces composés sont des intermédiaires de synthèse précieux qui permettent l'accès à des 6-méthyl 19-nor pregna 4,6-diènes pharmacologiquement actifs.The invention relates to the field of organic chemistry and more particularly to steroid chemistry. It more particularly relates to new 6-methyl estra 4,6-dienes of general formula (I) in which A represents hydrogen or a lower oxoalkyl radical and B represents hydrogen or A is a free hydroxyl or esterified, and B is a lower alkyl radical, or a lower alkynyl radical, or A and B together form the oxygen of a ketone. This invention also relates to a process for obtaining the compounds of general formula (I). These compounds are valuable synthetic intermediates which allow access to pharmacologically active 6-methyl 19-nor pregna 4,6-dienes.

Description

NOUVEAUX PROCEDES D'OBTENTION DE  NEW PROCESSES FOR OBTAINING
6-METHYL 19-NOR STEROIDES ET LEUR  6-METHYL 19-NOR STEROIDS AND THEIR
CONVERSION EN 19-NOR PREGNADIENES  CONVERSION TO 19-NOR PREGNADIAN
17α-SUBSTITUES  17α-SUBSTITUTS
La présente invention se rapporte au domaine de la chimie steroide et en particulier aux dérivés stéroides 6-méthylés estréniques. The present invention relates to the field of steroid chemistry and in particular to 6-methylated estrogenic steroid derivatives.
Elle a plus particulièrement pour objet des 3-oxo 6-méthyl estra 4,6-diènes, portant ou non en 17, un substituant hydrocarboné. It more particularly relates to 3-oxo 6-methyl estra 4,6-dienes, bearing or not at 17, a hydrocarbon substituent.
Elle a spécifiquement pour objet les nouveaux 6-méthyl estra 4,6-diènes de formule générale I Its specific subject is the new 6-methyl estra 4,6-dienes of general formula I
dans laquelle A représente de l'hydrogène ou un radical oxoalcoyle inférieur in which A represents hydrogen or a lower oxoalkyl radical
B représente de l'hydrogène ou un radical oxoalcoyle inférieur ou bien A est un hydroxyle libre ou estérifié et B est un radical alcoyle inférieur, ou un radical alcynyle inférieur  B represents hydrogen or a lower oxoalkyl radical or else A is a free or esterified hydroxyl and B is a lower alkyl radical or a lower alkynyl radical
ou bien A et B forment ensemble l'oxygène d'une cétone or A and B together form the oxygen of a ketone
Parmi ceux-ci, on distinguera cinq classes de composés préférés : Among these, there are five classes of preferred compounds:
1. le 17-désoxo estradiène de formule IA v 2. les 17-(oxo-alcoyle inférieur) pregnadiènes de formule générale IB 1. 17-deoxo estradiene of formula I A v 2. the 17- (lower oxoalkyl) pregnadienes of general formula I B
dans laquelle R1 représente de l'hydrogène ou un radical alcoyle inférieur, et notamment le 6-méthyl 3,20-dioxo 19-nor pregna 4,6-diène. in which R 1 represents hydrogen or a lower alkyl radical, and in particular 6-methyl 3,20-dioxo 19-nor pregna 4,6-diene.
3. les composés 17 alcoyl-estradiéniques de formule générale IC 3. the 17 alkyl-estradienic compounds of general formula I C
dans laquelle, R2 est un radical alcoyle inférieur ayant de 1 à 4 atomes de carbone in which, R 2 is a lower alkyl radical having from 1 to 4 carbon atoms
R3 est un hydrogène, un hydroxyle ou un groupe OR5 dans lequel R5 est un reste acyle dérivé d'un acide organique carboxylique, aliphatique ou aromatique ayant de 1 à 10 atomes R 3 is hydrogen, hydroxyl or an OR 5 group in which R 5 is an acyl residue derived from an organic carboxylic, aliphatic or aromatic acid having from 1 to 10 atoms
et notamment le 3-oxo 6,17ot-diméthyl 17β-hydroxy estra 4,6-diène. and in particular 3-oxo 6,17ot-dimethyl 17β-hydroxy estra 4,6-diene.
4. les dérivés 17-alcynyl estradiéniques de formule générale ID 4. 17-alkynyl estradienic derivatives of general formula I D
dans laquelle, R1 représente de l'hydrogène ou un radical alcoyle inférieur in which, R 1 represents hydrogen or a lower alkyl radical
R4 représente l'hydrogène ou un reste acyle d'un acide organique carboxylique aliphatique ou aromatique ayant de 1 à 10 atomes de carbone, et notamment le 17β-acétoxy 17ot-éthynyl 6-méthyl 3-oxo estraR 4 represents hydrogen or an acyl residue of an aliphatic or aromatic organic carboxylic acid having from 1 to 10 carbon atoms, and in particular 17β-acetoxy 17ot-ethynyl 6-methyl 3-oxo estra
4,6-diène, le 17β-acétoxy 17ot-(propynyl-l) 6-méthyl 3-oxo estra4,6-diene, 17β-acetoxy 17ot- (propynyl-l) 6-methyl 3-oxo estra
4,6-diène et le 17β-hydroxy 17ot-(propynyl-l) 3-oxo 6-méthyl estra 4,6-diène. 4,6-diene and 17β-hydroxy 17ot- (propynyl-1) 3-oxo 6-methyl estra 4,6-diene.
5. Les dérivés 17-(oxygénés) estradiéniques de formule générale IE 5. The 17- (oxygenated) estradienic derivatives of general formula I E
dans laquelle le substituant R1 est choisi dans le groupe constitué par l'oxygène ou le groupe in which the substituent R 1 is chosen from the group consisting of oxygen or the group
R3 représente le reste acyle d'un acide organique carboxylique, aliphatique ou aromatique, ayant de 1 à 10 atomes de carbone. R 3 represents the acyl residue of an organic carboxylic acid, aliphatic or aromatic, having from 1 to 10 carbon atoms.
L'invention concerne un procédé d'obtention du 3-oxo 6-méthyl extra 4,6-diène de formule IA qui consiste au départ du 3-oxo estra 4-ène à soumettre ce dernier à l'action d'un agent éthérifiant en milieu acide pour former un 3-alcoxy estra 3,5-diène, que l'on formyle en 3-alcoxy 6-formyl estra 3,5-diène, réduit celui-ci au moyen d'un hydrure mixte de métal alcalin en 3-alcoxy 6-hydroxyméthyl estra 3,5-diène, déshydrate ce dernier par traitement en milieu acide pour former un 3-oxo 6-méthylène estra 4-ène que l'on isomérise en 3-oxo 6-méthyl estra 4,6-diène par chauffage en présence d'un catalyseur d'isomérisation. L'invention concerne un procédé d'obtention des 3,20-dioxo 6-méthyl 19-nor pregna 4,6-diène de formule IB qui consiste en ce que l'on soumet un 3,20-dioxo 19-nor pregna 4-ène à l'action d'un agent d'éthérification en milieu acide pour obtenir un 3-alcoxy 20-oxo 19-nor pregna 3,5-diène, traite celui-ci par un agent de formylation pour obtenir un 3-alcoxy 6-formyl 20-oxo 19-nor pregna 3,5-diène que l'on réduit en 3-alcσxy 6-hydroxyméthyl 20-oxo 19-nor pregna 3,5-diène que l'on réduit en 3-alcoxy 6-hydroxyméthyl 20-oxo 19-nor pregna 3,5-diène par un hydrure mixte de métal alcalin, déshydrate ce dernier en milieu acide pour former le 3,20-dioxo 6-méthylène 19-nor pregna 4-ène que l'on isomérise en 3,20-dioxo 6-méthyl 19-nor pregna 4,6-diène. The invention relates to a process for obtaining 3-oxo 6-methyl extra 4,6-diene of formula I A which consists in starting from 3-oxo estra 4-ene to subject the latter to the action of an agent etherifying in an acid medium to form a 3-alkoxy estra 3,5-diene, which is formulated into 3-alkoxy 6-formyl estra 3,5-diene, reduced this by means of a mixed alkali metal hydride to 3-alkoxy 6-hydroxymethyl estra 3,5-diene, dehydrates the latter by treatment in an acid medium to form a 3-oxo 6-methylene estra 4-ene which is isomerized to 3-oxo 6-methyl estra 4, 6-diene by heating in the presence of an isomerization catalyst. The invention relates to a process for obtaining 3,20-dioxo 6-methyl 19-nor pregna 4,6-diene of formula I B which consists in subjecting a 3,20-dioxo 19-nor pregna 4-ene to the action of an etherification agent in an acid medium to obtain a 3-alkoxy 20-oxo 19-nor pregna 3,5-diene, treat the latter with a formylating agent to obtain a 3- 6-formyl alkoxy 20-oxo 19-nor pregna 3,5-diene which is reduced to 3-alkxy 6-hydroxymethyl 20-oxo 19-nor pregna 3,5-diene which is reduced to 3-alkoxy 6 -hydroxymethyl 20-oxo 19-nor pregna 3,5-diene by a mixed hydride of alkali metal, dehydrates the latter in an acid medium to form the 3,20-dioxo 6-methylene 19-nor pregna 4-ene which is isomerized to 3.20-dioxo 6-methyl 19-nor pregna 4,6-diene.
L'invention concerne un procédé d'obtention des 17β-acyloxy ou 17β-hydroxy 17α-alcynyl 6-méthyl estra 4,6-diènes de formule générale ID qui consiste en ce qu'on soumet un 3-alcoxy 17-oxo 19-nor estra 3,5-diène à l'action d'un agent d'éthérification pour former un 3-alcoxy 17-oxo 19-nor estra 3,5-diène puis d'un agent de formylation dans les conditions de la réaction de Vilsmeier-Hack pour former un 3-alcoxy 6-formyl 17-oxo estra 3,5-diène, que l'on réduit par action d'un hydrure mixte de métal alcalin en dérivé 6-hydroxyméthylé correspondant, traite celui-ci par une solution aqueuse d'acideminéral fort, pour former le 3-oxo 6-méthylène 17β-hydroxy estra 4-ène, isomérise ce dernier par chauffage avec un agent d'isomérisation, un 3-oxo 6-méthyl 17β-hydroxy estra 4,6-diène que l'on oxyde par un oxydant mét»allique en 3,17-dioxo 6-méthyl estra 4,6-diène, soumet ce dernier à l'action d'un acétylure métallique pour obtenir le dérivé 17α-alcynyl 17β-hydroxylé correspondant et traite celui-ci, si désiré, par un agent d'acylation pour former un 3-oxo 17ot-alcynyl 17β-acyloxy 6-méthyl 19-nor estra 4,6-diène. The invention relates to a process for obtaining 17β-acyloxy or 17β-hydroxy 17α-alkynyl 6-methyl estra 4,6-dienes of general formula I D which consists in subjecting a 3-alkoxy 17-oxo 19 -nor estra 3,5-diene to the action of an etherifying agent to form a 3-alkoxy 17-oxo 19-nor estra 3,5-diene then to a formylating agent under the reaction conditions of Vilsmeier-Hack to form a 3-alkoxy 6-formyl 17-oxo estra 3,5-diene, which is reduced by the action of a mixed alkali metal hydride to the corresponding 6-hydroxymethylated derivative, treats the latter with an aqueous solution of strong acid mineral, to form 3-oxo 6-methylene 17β-hydroxy estra 4-ene, isomerizes the latter by heating with an isomerization agent, a 3-oxo 6-methyl 17β-hydroxy estra 4, 6-diene which is oxidized with a metallic oxidant to 3,17-dioxo 6-methyl estra 4,6-diene, subjects the latter to the action of a metal acetylide to obtain the derivative 17α-alkynyl 17β -hydroxylate corresponding and treats it, if desired, with an acylating agent to form a 3-oxo 17ot-alkynyl 17β-acyloxy 6-methyl 19-nor estra 4,6-diene.
Les mêmes composés peuvent aussi être obtenus par un procédé qui consiste à soumettre un 3-oxo 6-méthylène 17β-acyloxy 17α-alcynyl estra 4-ène à l'action d'un agent d'isomérisation et former un 3-oxo 6-méthyl 17β-acyloxy 17α-alcynyl estra 4,6-diène. The same compounds can also be obtained by a process which consists in subjecting a 3-oxo 6-methylene 17β-acyloxy 17α-alkynyl estra 4-ene to the action of an isomerization agent and forming a 3-oxo 6- methyl 17β-acyloxy 17α-alkynyl estra 4,6-diene.
Les composés de formule ID peuvent encore être obtenus selon l'invention par un procédé qui consiste en ce que l'on soumet un 17β-acyloxy 17α-éthynyl 3-oxo estra 4-ène à l'action d'un agent d'éthérification en milieu acide pour obtenir un 3-alcoyloxy 17β-acyloxy 17α-éthynyl estra 3,5-diène, traite celui-ci par un réactif de formylation dans les conditions de la 'réaction de Vilsmeier-Hack pour former le dérivé 6-formylé que l'on réduit au moyen d'un hydrure mixte de métal alcalin en dérivé 6-hydroxyméthylé, déshydrate ce dernier en milieu acide pour former un 3-oxo 6-méthylène 17β-acyloxy 17α-éthynyl estra 4-ène puis isomérise celui-ci en présence d'un catalyseur d'isomérisation en 3-oxo 6-méthyl 17β-acyloxy 17α-éthynyl estra 4,6-diène. The compounds of formula I D can also be obtained according to the invention by a process which consists in subjecting a 17β-acyloxy 17α-ethynyl 3-oxo estra 4-ene to the action of an agent etherification in an acid medium to obtain a 3-alkyloxy 17β-acyloxy 17α-ethynyl estra 3,5-diene, treats it with a formylation reagent under the conditions of the Vilsmeier-Hack reaction to form the derivative 6 -formylated which is reduced by means of a mixed hydride of alkali metal to 6-hydroxymethyl derivative, dehydrates the latter in an acid medium to form a 3-oxo 6-methylene 17β-acyloxy 17α-ethynyl estra 4-ene then isomerized this in the presence of a 3-oxo 6-methyl 17β-acyloxy 17α-ethynyl estra 4,6-diene isomerization catalyst.
L'invention s'étend en outre à l'obtention du 3,17-dioxo 6-méthyl estra 4,6-diène de formule IE par un procédé qui consiste en ce que l'on soumet le 3,17-dioxo estra 4-ène à un réactif d'éthérification en milieu acide pour former un 3-alcoxy 17-oxo estra 3,5-diène, traite celui-ci par un réactif de formylation pour former le 3-alcoxy 17-oxo 6-formyl estra 3,5-diène, réduit celui-ci par un hydrure mixte de métal alcalin en 3-alcoxy 6-hydroxyméthyl 17β-hydroxy estra 3,5-diène que l'on déshydrate en milieu acide en 3-oxo 6-méthylène 17β-hydroxy estra 4-ène, isomérise celui-ci par un catalyseur d'isomérisation en 6-méthyl 3-oxo 17-hydroxy estra 4,6-diène puis si désiré réoxyde ce dernier par un oxydant métallique pour former le 3,17-dioxo 6-méthyl estra 4,6-diène ou bien le soumet à l'action d'un dérivé fonctionnel d'acide organique carboxylique pour former le 3-oxo 17β-acyloxy 6-méthyl estra 4,6-diène correspondant. The invention further extends to obtaining 3,17-dioxo 6-methyl estra 4,6-diene of formula I E by a process which consists in subjecting 3,17-dioxo estra 4-ene to an etherification reagent in an acid medium to form a 3-alkoxy 17-oxo estra 3,5-diene, treats this with a formylation reagent to form 3-alkoxy 17-oxo 6-formyl estra 3,5-diene, reduced this by a mixed hydride of alkali metal to 3-alkoxy 6-hydroxymethyl 17β-hydroxy estra 3,5-diene which is dehydrated in an acid medium to 3-oxo 6-methylene 17β- hydroxy estra 4-ene, isomerizes it with an isomerization catalyst into 6-methyl 3-oxo 17-hydroxy estra 4,6-diene then if desired reoxides the latter with a metal oxidant to form 3,17-dioxo 6-methyl estra 4,6-diene or else subjects it to the action of a functional derivative of organic carboxylic acid to form the corresponding 3-oxo 17β-acyloxy 6-methyl estra 4,6-diene.
Parmi les composés de formule I, on peut citer comme composé préféré le 3-oxo 6-méthyl estradiène-4,6 qui présente de remarquables propriétés antiandrogènes. Among the compounds of formula I, there may be mentioned as preferred compound 3-oxo 6-methyl estradiene-4,6 which exhibits remarkable antiandrogenic properties.
Les composés de formule générale I sont présentés aux fins thérapeutiques sous une des formes qui conviennent pour l'administration parentérale, orale, rectale, percutenée ou permuqueuse. The compounds of general formula I are presented for therapeutic purposes in one of the forms which are suitable for parenteral, oral, rectal, percutaneous or permucosal administration.
Les composés de formule générale I sont surtout des intermédiaires de synthèse précieux, qui permettent l'accès à des 6-méthyl 19-nor pregna 4,6-diènes pharmacologiquement actifs comme le 17ot-acétpxy 6-méthyl 3,20-dioxo 19-nor pregna 4,6-diène, le 6-17α-diméthyl 3,20-dioxo 19-nor pregna 4,6-diène, le 6-17α, 21-triméthyl 3,20-dioxo 19-nor pregna 4,6-diène dont les propriétés gestatives et progestomimétiques ont déjà été décrites (cf. demande de brevet français n° 89.04910 au nom de la demanderesse et brevet français 2.271.833). The compounds of general formula I are above all precious synthesis intermediates, which allow access to pharmacologically active 6-methyl 19-nor pregna 4,6-dienes such as 17ot-acetpxy 6-methyl 3,20-dioxo 19- nor pregna 4,6-diene, 6-17α-dimethyl 3,20-dioxo 19-nor pregna 4,6-diene, 6-17α, 21-trimethyl 3,20-dioxo 19-nor pregna 4,6-diene, the gestational and progestomimetic properties of which have already been described (cf. French patent application No. 89.04910 in the name of the applicant and French patent 2,271,833).
En particulier, les composés de formule générale ID sont convertis par hydratation puis par alcoylation en 6-méthyl 17α-alcoyl 3,20-dioxo 19-nor estra 4,6-diènes. In particular, the compounds of general formula I D are converted by hydration then by alkylation to 6-methyl 17α-alkyl 3.20-dioxo 19-nor estra 4,6-dienes.
Les 17-oxo 6-méthyl estra 4,6-diènes ou les estra 4,6-diènes de formule générale IE après oxydation sont convertis par un halogénure de triphényl-éthylphosphonium en dérivé 17-éthylidénique qui par bis-hydroxylation au moyen de Tétroxyde d'osmium et d'hydroperoxyde de N-oxyde de triéthylamine ou de morpholine conduit au 17ot-hydroxy 3,20-dioxo 6-méthyl 19-nor pregna 4,6-diène. The 17-oxo 6-methyl estra 4,6-dienes or the estra 4,6-dienes of general formula I E after oxidation are converted by a triphenylethylphosphonium halide to the 17-ethylidenene derivative which by bis-hydroxylation by means of Osmium tetroxide and triethylamine or morpholine N-oxide hydroperoxide leads to 17ot-hydroxy 3.20-dioxo 6-methyl 19-nor pregna 4,6-diene.
Le 3,17-dioxo 6-méthyl estra 4,6-diène est un intermédiaire de synthèse qui permet soit par réaction avec un sel d'alcoyl magnésium de former un dérivé 17β-hydroxy 17α-alcoylé, soit par réaction avec un sel d'alcoyl triphényl phosphonium de former un dérivé alcoylidénique que l'on oxyde en dérivé 17β-hydroxy 19-nor pregna 20-one, soit encore par réaction avec un acétylure métallique pour former un dérivé 17β-hydroxy 17α-éthynylé. 3,17-dioxo 6-methyl estra 4,6-diene is a synthetic intermediate which allows either by reaction with an alkyl magnesium salt to form a derivative 17β-hydroxy 17α-alkylated, or by reaction with a salt d 'alkyl triphenyl phosphonium to form an alkylidene derivative which is oxidized to 17β-hydroxy derivative 19-nor pregna 20-one, or again by reaction with a metallic acetylide to form a 17β-hydroxy derivative 17α-ethynylated.
Les 17β-acyloxy 17α-éthynyl 6-méthyl estradiènes-4,6 sont des matières premières utiles pour préparer des 6,17α-diméthyl 19-nor 20-céto pregnadiënes-4,6 selon un procédé qui consiste à soumettre le dérivé 17β-acyloxy 17α-éthynylé à une réaction d'hydratation en présence d'un sel mercurique puis à traiter le 20-céto 17β-acyloxy 19-nor pregnane obtenu, à l'action d'un agent méthylant après réduction par un métal pour former un dérivé 17α-méthyl 20-céto 19-nor pregnanique. 17β-acyloxy 17α-ethynyl 6-methyl estradien-4,6 are useful raw materials for preparing 6,17α-dimethyl 19-nor 20-keto pregnadiënes-4,6 according to a process which consists in subjecting the derivative 17β- 17α-ethynylated acyloxy to a hydration reaction in the presence of a mercuric salt and then to treat the 20-keto 17β-acyloxy 19-nor pregnane obtained, to the action of a methylating agent after reduction with a metal to form a 17α-methyl 20-keto 19-nor pregnanic derivative.
Les exemples suivants et la planche I annexée, illustrent l'invention sans toutefois la limiter : The following examples and the attached plate I illustrate the invention without however limiting it:
EXEMPLE I EXAMPLE I
17β-acétoxy 17α-éthynyl 6-siéthyl estra 4,6-diène à partir de 3,17-dioxo estrar-4 ène Stade 1 : 3-éthoxy 6-formyl 17-oxo estra 3,5-diène 17β-acetoxy 17α-ethynyl 6-siethyl estra 4,6-diene from 3,17-dioxo estrar-4 ene Stage 1: 3-ethoxy 6-formyl 17-oxo estra 3,5-diene
Sous courant d'azote à 2°C, on ajoute goutte à goutte 14 ml d'oxychlorure de phosphore à 100 ml de Diméthylformamide sec et l'on garde sous agitation pendant 5 mn. Cette solution est additionnée à son tour, goutte à goutte, sous azote à 25 g de 3-éthoxy 17-oxo estra 3,5-diène dans 200 ml de diméthylformamide à 2°C, laisse agiter ½ heure à 5-10°C. Under a stream of nitrogen at 2 ° C., 14 ml of phosphorus oxychloride are added dropwise to 100 ml of dry dimethylformamide and the mixture is stirred for 5 min. This solution is added in turn, dropwise, under nitrogen to 25 g of 3-ethoxy 17-oxo estra 3,5-diene in 200 ml of dimethylformamide at 2 ° C, left to stir for ½ hour at 5-10 ° C .
On introduit en 30 mn, une solution de 75 g d'acétate de potassium dans 100 ml d'eau, agite 1 heure et précipite dans 21 d'eau. On filtre et sèche. On obtient 25 g de 3-éthoxy 6-formyl 17-oxo estra 3,5-diène. A solution of 75 g of potassium acetate in 100 ml of water is introduced over 30 minutes, stirred for 1 hour and precipitated from 21 of water. It is filtered and dried. 25 g of 3-ethoxy 6-formyl 17-oxo estra 3,5-diene are obtained.
Spectre U.V : λ max = 324 nm ε = 16.670 U.V spectrum: λ max = 324 nm ε = 16.670
Spectre I.R : 1738 cm-1 IR spectrum: 1738 cm -1
1651 cm-1 1651 cm -1
1609 cm-1 1609 cm -1
1676 cm-1 1676 cm -1
Stade 2 : 6-méthylène 17β-hydroxy 3-oxo estra 4-ène Stage 2: 6-methylene 17β-hydroxy 3-oxo estra 4-ene
On ajoute, à température ambiante, sous azote et par petites fractions, 152 mg de bh.na à une solution de 2 g du dérivé 6-formylé obtenu ci-dessus dans 5,7 ml d'éthanol et 4,7 ml de diméthylformamide. on laisse agiter pendant 2 heures puis glace à 0°C et ajoute en 2 mn, 5 ml d'une solution 2n d'acide sulfurique, agite encore 10 mn et verse dans une solution aqueuse de 1,1 g de bicarbonate de sodium, on essore le précipité qu'on lave et sèche, on obtient des cristaux de 6-méthylène 17β-hydroxy 3-oxo estra 4-ène. 152 mg of bh.na are added at room temperature, under nitrogen and in small fractions, to a solution of 2 g of the 6-formylated derivative obtained above in 5.7 ml of ethanol and 4.7 ml of dimethylformamide. . the mixture is left stirring for 2 hours then ice-cold at 0 ° C. and added in 2 min, 5 ml of a 2n solution of sulfuric acid, stirred for another 10 min and poured into an aqueous solution of 1.1 g of sodium bicarbonate, the precipitate is drained, washed and dried, crystals of 6-methylene 17β-hydroxy 3-oxo estra 4-ene are obtained.
Spectre I.R : 3437 cm-1 IR spectrum: 3437 cm -1
Spectre U.V : λ max = 260 nm UV spectrum: λ max = 260 nm
Masse : m/e 286 Stade 3 : 17β-hydroxy 6-méthyl 3-oxo estra 3,5-diène Weight: m / e 286 Stage 3: 17β-hydroxy 6-methyl 3-oxo estra 3,5-diene
On porte au reflux 5 g de charbon palladié à 5 % dans 250 ml de methanol pendant 30 mn et on ajoute 10 g de 6-méthylène 17β-hydroxy estrène-4. Après 10 mn, la suspension est filtrée et le filtrat est amené à sec puis cristallisé par chaud et froid dans le methanol. le dérivé 6-méthyl est utilisé tel quel pour le stade suivant de la synthèse. 5 g of 5% palladium-on-carbon are brought to reflux in 250 ml of methanol for 30 min and 10 g of 6-methylene 17β-hydroxy estrene-4 are added. After 10 min, the suspension is filtered and the filtrate is brought to dryness then crystallized by hot and cold in methanol. the 6-methyl derivative is used as it is for the next stage of the synthesis.
Spectre I.R : 3520 cm-1 IR spectrum: 3520 cm -1
1660 cm-1 1660 cm -1
1626 cm-1 1626 cm -1
1580 cm-1 1580 cm -1
Spectre R.M.N : (S, 3H) à 0,85 ppm R.M.N spectrum: (S, 3H) at 0.85 ppm
(dd, 3H) à 1,85 ppm  (dd, 3H) at 1.85 ppm
(Dd, 1H) à 3,75 ppm  (Dd, 1H) at 3.75 ppm
(S, 1H) à 5,95 ppm  (S, 1H) at 5.95 ppm
(S, 1H) à 6,05 ppm  (S, 1H) at 6.05 ppm
Stade 4 : 6-méthyl 3,17-dioxo estra 4,6-diène Stage 4: 6-methyl 3,17-dioxo estra 4,6-diene
Dans 30 ml d'acétone, on dissout 2 g de 17β-hydroxy 6-méthyl 3-OXO estrène-4 et on ajoute 3,8 ml de réactif de Jones (solution hydrosulfurique d'.anhydride chromique) à 15 ml de la solution précédente. Après 15 mn, on ajoute 2 ml de inéthanol et on précipite par de l'eau. Après filtration et séchage, on obtient 1,75 g de 6-méthyl 3,17-dioxo estra 4,6-diène. In 30 ml of acetone, 2 g of 17β-hydroxy 6-methyl 3-OXO estrene-4 are dissolved and 3.8 ml of Jones reagent (hydrosulfuric solution of chromic anhydride) are added to 15 ml of the solution. previous. After 15 min, 2 ml of inethanol are added and the mixture is precipitated with water. After filtration and drying, 1.75 g of 6-methyl 3,17-dioxo estra 4,6-diene are obtained.
Spectre I.R : 1740 cm-1 IR spectrum: 1740 cm -1
1-660 cm-1 1-660 cm -1
1624 cm-1 1624 cm -1
1580 cm-1 Spectre R.M.N : (S, 3H) à 0,95 ppm 1580 cm -1 NMR spectrum: (S, 3H) at 0.95 ppm
(dd, 3H) à 1,90 ppm  (dd, 3H) at 1.90 ppm
(Dd, 1H) à 5,97 ppm  (Dd, 1H) at 5.97 ppm
(S, 1H) à 6,12 ppm  (S, 1H) at 6.12 ppm
(S, 1H) à 6,05 ppm  (S, 1H) at 6.05 ppm
Masse : m/e 284 Mass: m / e 284
Stade 5 : 17α-éthynyl 17β-hydroxy 6-méthyl estra 4.6-diène Stage 5: 17α-ethynyl 17β-hydroxy 6-methyl estra 4.6-diene
Dans 10 ml de tétrahydrofuran et 350 mg de ter.Butylate de potassium, on fait passer pendant une heure un courant d'acétylène pur, puis on ajoute à la suspension 650 mg de 6-méthyl 3,17-dioxo estra 4,6-diène. Après une heure, on verse dans l'eau et on essore les cristaux qui se sont séparés. In 10 ml of tetrahydrofuran and 350 mg of potassium ter.Butylate, a stream of pure acetylene is passed for one hour, then 650 mg of 6-methyl 3,17-dioxo estra 4,6- is added to the suspension. diene. After one hour, pour into water and wring out the crystals which have separated.
Après une purification par chomatographie sur une colonne de silice pour chomatographie, avec élution par le Toluène, l'extrait sec livre 450 mg de cristaux blancs de 17α-éthynyl 17-3-hydroxy 6-méthyl estra 4,6-diène. After purification by chomatography on a silica column for chomatography, with elution with Toluene, the dry extract delivers 450 mg of white crystals of 17α-ethynyl 17-3-hydroxy 6-methyl estra 4,6-diene.
Stade 6 : 17β-acétoxy 17α-éthynyl 6-méthyl estra 4,6-diène a) à partir de 17α-éthynyl 17β-hydroxy 6-méthyl estra 4,6-diène Stage 6: 17β-acetoxy 17α-ethynyl 6-methyl estra 4,6-diene a) from 17α-ethynyl 17β-hydroxy 6-methyl estra 4,6-diene
Dans 4 ml de Dioxanne, on introduit 0,4 ml d'anhydride acétique et 400 mg de 17α-éthynyl 17β-hydroxy 6-méthyl estra 4,6-diène. On ajoute ensuite 40 mg de diméthylamino pyridine. Après 24 heures de contact, le milieu est extrait par du chlorure de méthylène. Les phases organiques amenées à sec, sont cristallisées dans le méth»anol qui livre 310 mg de 17β-acétoxy 17α-éthynyl 6-méthyl estra 4,6-diène. b) à partir de 17β-acétoxy 17α-éthynyl 6-méthylène 3-oxo estra 4-ène 0.4 ml of acetic anhydride and 400 mg of 17α-ethynyl 17β-hydroxy 6-methyl estra 4,6-diene are introduced into 4 ml of Dioxanne. 40 mg of dimethylamino pyridine are then added. After 24 hours of contact, the medium is extracted with methylene chloride. The organic phases brought to dryness are crystallized from methanol which delivers 310 mg of 17β-acetoxy 17α-ethynyl 6-methyl estra 4,6-diene. b) from 17β-acetoxy 17α-ethynyl 6-methylene 3-oxo estra 4-ene
On obtient le 17β-acétoxy 17α-éthynyl 6-méthyl 3-oxo estra 4,6-diène présentant les mêmes constantes que ci-dessus, avec un rendement à 45 % par isomérisation au charbon palladié selon la technique décrite au Stade 3 de l'exemple I. 17β-acetoxy 17α-ethynyl 6-methyl 3-oxo estra 4,6-diene is obtained having the same constants as above, with a yield of 45% by isomerization with palladium carbon according to the technique described in Stage 3 of l 'example I.
EXEMPLE II EXAMPLE II
Préparation du 17β-acétoxy 17α-éthynyl 6-méthyl estra 4,6-diène à partir de 17β-acétoxy 17α-éthynyl 3-oxo estra 4-ène  Preparation of 17β-acetoxy 17α-ethynyl 6-methyl estra 4,6-diene from 17β-acetoxy 17α-ethynyl 3-oxo estra 4-ene
Stade I : 17β-acétoxy 3-éthoxy 17α-éthynyl estra 3,5-diène Stage I: 17β-acetoxy 3-ethoxy 17α-ethynyl estra 3,5-diene
On obtient avec un rendement de 88 %, le produit éthérifié dont la RMN montre : Obtained with a yield of 88%, the etherified product whose NMR shows:
(T, 3H) à 1,30 ppm CH3 de l'éthoxy (T, 3H) at 1.30 ppm CH3 of ethoxy
(multiplet, 2H) à 3,65 ppm CH2 de l'éthoxy  (multiplet, 2H) at 3.65 ppm CH2 of ethoxy
(S, 1H) à 5,20 ppm H en C6  (S, 1H) at 5.20 ppm H at C6
(S, 1H) à 5,30 ppm H en C4  (S, 1H) at 5.30 ppm H in C4
Stade 2 : 17β-acétoxy 3-éthoxy 6-formyl 17α-éthynyl estra 3,5-diène Stage 2: 17β-acetoxy 3-ethoxy 6-formyl 17α-ethynyl estra 3,5-diene
La formylation du produit du Stade I fournit 99 % de produit 6-formylé dont le spectre UV indique un maximum à 325 nm Formulation of the Stage I product provides 99% of 6-formylated product, the UV spectrum of which indicates a maximum at 325 nm
Stade 3 : 17β-acétoxy 3-éthoxy 6-hydroxy méthyl 17α-éthynyl estra Stage 3: 17β-acetoxy 3-ethoxy 6-hydroxy methyl 17α-ethynyl estra
3,5-diène  3,5-diene
La réduction du dérivé 6-formylé par le borohydrure de sodium, donne au bout de 22 h d'agitation, le dérivé hydroxy méthylé caractérisé par son absorption en UV (λ max à 252 nm) Stade 4 : 17β-acétoxy 17α-éthynyl 6-méthylène estra 3,5-diène The reduction of the 6-formylated derivative by sodium borohydride, gives after 22 h of stirring, the hydroxy methyl derivative characterized by its UV absorption (λ max at 252 nm) Stage 4: 17β-acetoxy 17α-ethynyl 6-methylene estra 3,5-diene
Le dérivé 6-hydroxy méthylé eét déshydraté par l'acide sulfurique 2N dans un mélange éth.anol/diméthyl formamide. On recueille 84% de produit brut. Le spectre IR indique une absence totale de bande à 3400 cm-1, le spectre UV montre un maximum d'absorption à 263 nm. The 6-hydroxy methyl derivative was dehydrated with 2N sulfuric acid in an eth.anol / dimethyl formamide mixture. 84% of crude product is collected. The IR spectrum indicates a total absence of band at 3400 cm -1 , the UV spectrum shows a maximum absorption at 263 nm.
Stade 5 : Isomérisation Stage 5: Isomerization
L'isomérisation du 6-méthylène 17β-acétoxy 17α-éthynyl 3-oxo estra 4-ène en 3-oxo 6-méthyl 17β-acétoxy 17α-éthynyl estra 4,6-diène est effectuée selon la méthode décrite à l'exemple I - Stade 6b,The isomerization of 6-methylene 17β-acetoxy 17α-ethynyl 3-oxo estra 4-ene to 3-oxo 6-methyl 17β-acetoxy 17α-ethynyl estra 4,6-diene is carried out according to the method described in Example I - Stage 6b,
Spectre RMN représenté à la figure 2 NMR spectrum shown in Figure 2
EXEMPLE III EXAMPLE III
Synthèse du β-méthyl 3-oxo estra 4,6-diène  Synthesis of β-methyl 3-oxo estra 4,6-diene
Stade 1 : 3-oxo estra 4-ène Stage 1: 3-oxo estra 4-ene
On ajoute sous azote 2 ml d'hydrazine à 99 % à une solution de 2 g de 3-éthoxy 17-oxo estra 3,5-diène dans 60 ml d'éthanol et 2,2 ml de triéthylamine. 2 ml of 99% hydrazine are added under nitrogen to a solution of 2 g of 3-ethoxy 17-oxo estra 3,5-diene in 60 ml of ethanol and 2.2 ml of triethylamine.
On porte au reflux pendant 4 heures, on évapore le solvant à sec et on reprend le résidu par 50 ml de Toluène puis on ajoute 1,4 g de terbutylate de potassium. On porte au reflux à nouveau pendant 24 h. The mixture is brought to reflux for 4 hours, the solvent is evaporated to dryness and the residue is taken up in 50 ml of Toluene and then 1.4 g of potassium terbutylate are added. The mixture is brought to reflux again for 24 h.
Après achèvement de la réaction, on coule goutte à goutte dans la solution plongée dans un bain de glace, 25 ml d'une solution d'acide chlorhydrique 2N. After completion of the reaction, 25 ml of a 2N hydrochloric acid solution are poured dropwise into the solution immersed in an ice bath.
Après une nuit d'agitation, on lave à l'eau le précipité puis on épuise au toluène. Le produit résiduel est alors purifié par chromatographie sur silice et élue à l'éther. L'éluat après évaporation est recristallisé du pentane. On recueille 0,8 g soit 48 % de 3-oxo estra 4-ène pur IR : 1674 cm-1, œ en 3 After stirring overnight, the precipitate is washed with water and then exhausted with toluene. The residual product is then purified by chromatography on silica and eluted with ether. The eluate after evaporation is recrystallized from pentane. 0.8 g is collected, i.e. 48% of pure 3-oxo estra 4-ene IR: 1674 cm -1 , œ in 3
1620 cm-1, delta-4 pF 66° C 1620 cm -1 , delta-4 pF 66 ° C
Composition centésimale : C18 H2601 % trouvé % calculé Centesimal composition: C18 H2601% found% calculated
C 84.10 83.66  C 84.10 83.66
H 9.39 10.14  H 9.39 10.14
O 6.49 6.19  O 6.49 6.19
Masse : m/e 258, masse molaire Mass: m / e 258, molar mass
RMN : (S, 3H) à 0.75 ppm CH3-18 NMR: (S, 3H) at 0.75 ppm CH3-18
(S, 1H) à 5.70 ppm H porté par C4  (S, 1H) at 5.70 ppm H carried by C4
Stade 2 : 3-éthoxy estra 3,5-diène Stage 2: 3-ethoxy estra 3,5-diene
On effectue le stade d'éther énolisation au départ de 15 g de 3-oxo estra 4-ène dans 39ml d'éthanol et 20 ml d'ortho- formiate d'éthyle en présence de 0,06 g d'acide p.toluène sulfonique puis à la fin de 0,8 ml de triethylamine. The ether enolization stage is carried out starting from 15 g of 3-oxo estra 4-ene in 39 ml of ethanol and 20 ml of ethyl orthoformate in the presence of 0.06 g of p.toluene acid sulfonic then at the end of 0.8 ml of triethylamine.
Après chromatographie sur alumine basique et élution par le Toluène à 1% de triethylamine, on obtient 13,3 g de 3-éthoxy estra 3,5-diène (soit un rendement de 78%). After chromatography on basic alumina and elution with Toluene containing 1% triethylamine, 13.3 g of 3-ethoxy estra 3,5-diene are obtained (ie a yield of 78%).
Spectre IR : bandes à 1648 et 1620 cm-1 IR spectrum: bands at 1648 and 1620 cm -1
(doubles liaisons 3 et 5)  (double bonds 3 and 5)
Stade 3 : 3-éthoxy 6-formyl estra 3,5-diène Stage 3: 3-ethoxy 6-formyl estra 3,5-diene
La formylation est effectiée avec le réactif de Vilsmeier (DMP 6 ml, POC131,4 ml) introduit à 0°C, sous gaz inerte à une solution de 2 g de 3-éthoxy estra 3,5-diène, dans 14 ml DMF. Après 15 mn, 20 ml de solution aqueuse d'acétate de potassium sont ajoutés, agitation 30 mn avant de filtrer pour récupérer 0,9 g (41%) de 3-éthoxy 6-formyl estra 3,5-diène. UV : λ max 325 nm ε = 14.245 The formylation is carried out with the Vilsmeier reagent (DMP 6 ml, POC131.4 ml) introduced at 0 ° C, under inert gas to a solution of 2 g of 3-ethoxy estra 3,5-diene, in 14 ml DMF. After 15 min, 20 ml of aqueous potassium acetate solution are added, stirring 30 min before filtering to recover 0.9 g (41%) of 3-ethoxy 6-formyl estra 3,5-diene. UV: λ max 325 nm ε = 14.245
Stade 4 : 3-éthoxy 6-hydroxyméthyl estra 3,5-diène Stage 4: 3-ethoxy 6-hydroxymethyl estra 3,5-diene
Une solution de 1,1 g de 3-éthoxγ 6-formyl estra 3,5-diène dans 2,8 ml DMF et 3,3 ml de methanol est traitée avec 150 mg de Borohydrure de Sodium pendant 3 heures. Après dilution par de l'eau et extraction par le toluène, la phase organique livre le 3-éthoxy 6-hydroxyméthyl estra 3,5-diène brut. A solution of 1.1 g of 3-ethoxγ 6-formyl estra 3,5-diene in 2.8 ml DMF and 3.3 ml of methanol is treated with 150 mg of sodium borohydride for 3 hours. After dilution with water and extraction with toluene, the organic phase delivers the crude 3-ethoxy 6-hydroxymethyl estra 3,5-diene.
I.R : 3400 cm-1, bande OH IR: 3400 cm -1 , OH band
1640, 1610 cm-1, bandes delta-3,5 1640, 1610 cm -1 , delta-3,5 strips
U.V : λ max 249,1 nm U.V: λ max 249.1 nm
Stade 5 : 6-méthylène 3-oxo estra 4-ène Stage 5: 6-methylene 3-oxo estra 4-ene
A une solution de 1 g de 3-éthoxy 6-hydroxyméthyl estra 3,5-diène dans 15 ml de methanol, sont ajoutés 3,9 ml d'acide sulfurique 2N. Après 30 mn d'agitation, le milieu réactionnel est versé dans une solution aqueuse de bicarbonate de potassium. Après filtration, on obtient 55 % de 6-méthylène 3-oxo estra 4-ène. To a solution of 1 g of 3-ethoxy 6-hydroxymethyl estra 3,5-diene in 15 ml of methanol are added 3.9 ml of 2N sulfuric acid. After 30 min of stirring, the reaction medium is poured into an aqueous solution of potassium bicarbonate. After filtration, 55% of 6-methylene 3-oxo estra 4-ene is obtained.
Stade 6 : 6-méthyl 3-oxo estra 4,6-diène Stage 6: 6-methyl 3-oxo estra 4,6-diene
Une solution de 1 g de 6-méthylène 3-oxo estra 4-ène dans 50 ml de methanol est traitée à reflux par 0,5 g de charbon palladié pendant 40 mn. Après récupération incluant une chomatographie sur une colonne de silice pour chromatographie avec élution par le toluène, on obtient le 6-méthyl 3-oxo estra 4,6-diène sous la forme d'une huile fluide n'ayant pu être obtenue à l'état cristallisé et présentant les constantes suivantes : A solution of 1 g of 6-methylene 3-oxo estra 4-ene in 50 ml of methanol is treated at reflux with 0.5 g of palladium on charcoal for 40 min. After recovery including chromatography on a silica column for chromatography with elution with toluene, 6-methyl 3-oxo estra 4,6-diene is obtained in the form of a fluid oil which could not be obtained with crystallized state with the following constants:
I.R : 1670 cm-1, CO en 3 IR: 1670 cm -1 , CO in 3
1620, 1580 delta-4,6 RMN (S, 3H) à 0,80 ppm CH3-18 1620, 1580 delta-4.6 NMR (S, 3H) at 0.80 ppm CH3-18
(S, 3H) à 1,85 ppm CH3 en C-6  (S, 3H) at 1.85 ppm CH3 as C-6
(S, 1H) à 5,95 ppm H en C-7  (S, 1H) at 5.95 ppm H in C-7
(S, 1H) à 6,10 ppm H en C-4  (S, 1H) at 6.10 ppm H in C-4
(selon figure 1)  (according to figure 1)
EXEMPLE IV EXAMPLE IV
Synthèse du 6-méthyl 3,20-dioxo 19-nor pregna 4,6-diène  Synthesis of 6-methyl 3,20-dioxo 19-nor pregna 4,6-diene
Stade I : 3-éthoxy 20-oxo 19-nor pregna 3,5-diène Stage I: 3-ethoxy 20-oxo 19-nor pregna 3,5-diene
On effectue l'énolisation de 36 g de 19-nor progestérone avec 252 ml d'éthanol, 39,5 ml d'orthoformiate d'éthyle, 0,54 g d'acide p.toluène sulfonique et pour stopper la réaction 3,6 ml de Triethylamine. On obtient 27,5 g (70%) de dérivé 3-éthoxy 20-oxo 19-nor pregna 3,5-diène cristallisé. The enolization of 36 g of 19-nor progesterone is carried out with 252 ml of ethanol, 39.5 ml of ethyl orthoformate, 0.54 g of p.toluene sulfonic acid and to stop the reaction 3.6 ml of Triethylamine. 27.5 g (70%) of 3-ethoxy derivative 20-oxo 19-nor pregna 3,5-diene crystallized are obtained.
IR : 1707 cm-1, CO en 20 IR: 1707 cm -1 , CO in 20
1647, 1624 cm-1, delta-3,5 1647, 1624 cm -1 , delta-3,5
RMN : (S, 3H) à 0,65 ppm CH3-18 NMR: (S, 3H) at 0.65 ppm CH3-18
(T, 3H) à 1,30 ppm CH3 de l'éthoxy  (T, 3H) at 1.30 ppm CH3 of ethoxy
(multiplet, 2H) à 3,75 ppm CH2 de l'éthoxy  (multiplet, 2H) at 3.75 ppm CH2 of ethoxy
(S, 1H) à 5,20 ppm H en C7  (S, 1H) at 5.20 ppm H in C7
(S, 1H) à 5,30 ppm H en C4  (S, 1H) at 5.30 ppm H in C4
Stade 2 : 3-éthoxy 6-formyl 20-oxo 19-nor pregna 3,5-diène Stage 2: 3-ethoxy 6-formyl 20-oxo 19-nor pregna 3,5-diene
On procède à la formylation de 20 g du dérivé 3-éthoxylé du Stade 1 dans 160 ml DMF avec une solution de 13,5 ml de POCl3 dans 80 ml de DMF. 20 g of the 3-ethoxylated derivative of Stage 1 are formed in 160 ml DMF with a solution of 13.5 ml of POCl 3 in 80 ml of DMF.
L'hydrolyse, avec 69 g d'acétate de potassium dans 300 ml d'eau, conduit à 19,5 g (90 %) de produit 6-formylé brut (λmax 326 nm, ε=15045) Stade 3 : 6-méthylène 3,20-dioxo 19-nor pregna 4-ène Hydrolysis, with 69 g of potassium acetate in 300 ml of water, leads to 19.5 g (90%) of crude 6-formylated product (λmax 326 nm, ε = 15045) Stage 3: 6-methylene 3,20-dioxo 19-nor pregna 4-ene
On effectue la réduction de 15 g de produit 6-formylé dans 45 ml de methanol, 37,5 ml de DMF et avec 1,59 g de borohydrure de sodium. On obtient un mélange de deux produits méthoxylé et éthoxylé confirmés par spectres IR (3400 cm-1) et UV (λmax 250 nm, ε=18890). The reduction of 15 g of 6-formylated product is carried out in 45 ml of methanol, 37.5 ml of DMF and with 1.59 g of sodium borohydride. A mixture of two methoxylated and ethoxylated products is obtained, confirmed by IR (3400 cm -1 ) and UV (λmax 250 nm, ε = 18890) spectra.
Le mélange des deux produits alcoxylés est hydrolyse par 36 ml d'une solution d'acide sulfurique (2N) en 40 mn suivi d'une addition de 20 ml d'une solution aqueuse de carbonate de potassium (0,44 g/ml), on obtient le dérivé 3-ceto 6-méthylénique. The mixture of the two alkoxylated products is hydrolyzed with 36 ml of a sulfuric acid solution (2N) in 40 min followed by the addition of 20 ml of an aqueous solution of potassium carbonate (0.44 g / ml) , the 3-ceto 6-methylenic derivative is obtained.
UV : λmax 263,7 nm UV: λmax 263.7 nm
Stade 4 : 6-méthyl 3,20-dioxo 19-nor pregna 4,6-diène Stage 4: 6-methyl 3,20-dioxo 19-nor pregna 4,6-diene
L'isomérisation de 5 g de produit 6-méthyléniques se fait par 125 ml de methanol, 2,5 g de charbon paladié et 30 mn de reflux. On chromatographie le produit obtenu par le chlorure de méthylène sur 150 g de silice pour obtenir 2 g (40 %) de dérivé 6-méthylé qui est cristallisé dans le methanol. The isomerization of 5 g of 6-methylenic product is carried out with 125 ml of methanol, 2.5 g of paladiated charcoal and 30 minutes of reflux. The product obtained is chromatographed with methylene chloride on 150 g of silica to obtain 2 g (40%) of 6-methylated derivative which is crystallized from methanol.
UV : λmax 288 nm UV: λmax 288 nm
Composition centésimale : C21 H2602 % trouvé % calculé Percentage composition: C21 H2602% found% calculated
C 80,84 80,73  C 80.84 80.73
H 9,23 9,03  H 9.23 9.03
O 10,14 10,24  O 10.14 10.24
RMN (S, 3H) à 0,70 ppm CH3-18 NMR (S, 3H) at 0.70 ppm CH3-18
(S, 3H) à 1,85 ppm CH3 en C6  (S, 3H) at 1.85 ppm CH3 as C6
(S, 3H) à 2,20 ppm CH3-21  (S, 3H) at 2.20 ppm CH3-21
(S, 1H) à 5,95 ppm H en C7  (S, 1H) at 5.95 ppm H in C7
(S, 1H) à 6,05 ppm H en C4 EXEMPLE V (S, 1H) at 6.05 ppm H in C4 EXAMPLE V
Exemple de compositions pharmaceutiques à base de composés selon l'invention.  Example of pharmaceutical compositions based on compounds according to the invention.
Comprimés à base de 6-méthyl 3-oxo estra 4,6-diène Tablets based on 6-methyl 3-oxo estra 4,6-diene
- 6-méthyl 3-oxo estra 4,6-diène ....................................... 10 g - 6-methyl 3-oxo estra 4,6-diene ..................................... .. 10 g
- Cellulose microcristalline .................................................. 125 g  - Microcrystalline cellulose ............................................... ... 125 g
- Phosphate tricalcique ...............................................................40 g  - Tricalcium phosphate ............................................... ................ 40 g
- Phosphate de magnésium ..................................................... 45 g  - Magnesium phosphate .............................................. ....... 45 g
- Stéarate de Magnésium ...............................................................5 g  - Magnesium stearate .............................................. ................. 5 g
- Polyvinyl pyrrolidone (Kollidone K17) ....................... 5 g  - Polyvinyl pyrrolidone (Kollidone K17) ....................... 5 g
pour 1.000 comprimés finis au poids moyen de 0,22 g. per 1,000 finished tablets at an average weight of 0.22 g.

Claims

REVENDI CATI ONS REVENDI CATI ONS
L'invention a pour objet : The subject of the invention is:
1°- Un procédé d'obtention des 17β-acyloxy 17α-alcynyl 6-méthyl estra 4,6-diènes de formule générale ID 1 ° - A process for obtaining 17β-acyloxy 17α-alkynyl 6-methyl estra 4,6-dienes of general formula I D
dans laquelle, R1 représente de l'hydrogène ou un radical alcoyle inférieur in which, R 1 represents hydrogen or a lower alkyl radical
R4 représente l'hydrogène ou un reste acyle d'un acide organique carboxylique, aliphatique ou aromatique, ayant de 1 à 10 atomes de carbone, R 4 represents hydrogen or an acyl residue of an organic carboxylic, aliphatic or aromatic acid, having from 1 to 10 carbon atoms,
qui consiste en ce qu'on soumet un 3-alcoxy 17-oxo 19-nor estra 3,5-diène à l'action d'un agent d'éthérification pour former un 3-alcoxy 17-oxo 19-nor estra 3,5-diène puis d'un agent de formylation dans les conditions de la réaction de Vilsmeier-Hack pour former un 3-alcoxy 6-formyl 17-oxo estra 3,5-diène, que l'on réduit par action d'un hydrure mixte de métal alcalin en dérivé 6-hydroxyméthylé correspondant, traite celui-ci par une solution aqueuse d'acideminéral fort, pour former le 3-oxo 6-méthylène 17β-hydroxy estra 4-ène, isomérise ce dernier par chauffage avec un agent d'isomérisation, un 3-oxo 6-méthyl 17β-hydroxy estra 4,6-diène que l'on oxyde par un oxydant métallique en 3,17-dioxo 6-méthyl estra 4,6-diène, soumet ce dernier à l'action d'un acétylure métallique pour obtenir le dérivé 17α-alcynyl 17β-hydroxylé correspondant et traite celui-ci, si désiré, par un agent d'acylation pour former un 3-oxo 17α-alcynyl 17β-acyloxy 6-méthyl 19-nor estra 4,6-diènee 2°- Uh procédé d'obtention des 17β-acyloxy 17α-éthynyl 6-méthyl estra 4,6-diènes de formule générale IDselon la revendication 6° qui consite en ce que l'on soumet un 17β-acyloxy 17α-éthynyl 3-oxo estra 4-ène à l'action d'un agent d'éthérification en milieu acide pour obtenir un 3-alcoyloxy 17β-acyloxy 17α-éthynyl estra 3,5-diène, traite celui-ci par un réactif de formylation dans les conditions de la réaction de Vilsmeier-Hack pour former le dérivé 6-formylé que l'on réduit au moyen d'un hydrure mixte de métal alcalin en dérivé 6-hydroxyméthylé, déshydrate ce dernier en milieu acide pour former un 3-oxo 6-méthylène 17β-acyloxy 17β-éthynyl estra 4-ène puis isomérise celui-ci en présence d'un catalyseur d'isomérisation en 3-oxo 6-méthyl 17β-acyloxy 17α-éthynyl estra 4,6-diène. 3°- Un procédé d'obtention du 3-oxo 6-méthyl estra 4,6-diène de formule IA which consists in subjecting a 3-alkoxy 17-oxo 19-nor estra 3,5-diene to the action of an etherifying agent to form a 3-alkoxy 17-oxo 19-nor estra 3, 5-diene then a formylating agent under the conditions of the Vilsmeier-Hack reaction to form a 3-alkoxy 6-formyl 17-oxo estra 3,5-diene, which is reduced by the action of a hydride mixed alkali metal to the corresponding 6-hydroxymethyl derivative, treats it with an aqueous solution of strong acid mineral, to form 3-oxo 6-methylene 17β-hydroxy estra 4-ene, isomerizes the latter by heating with an agent isomerization, a 3-oxo 6-methyl 17β-hydroxy estra 4,6-diene which is oxidized by a metal oxidant to 3,17-dioxo 6-methyl estra 4,6-diene, subjects the latter to action of a metal acetylide to obtain the corresponding 17α-alkynyl 17β-hydroxylated derivative and treats it, if desired, with an acylating agent to form a 3-oxo 17α-alkynyl 17β-acyloxy 6-methyl 19-nor estra 4,6-dienee 2 ° - Uh process for obtaining 17β-acyloxy 17α-ethynyl 6-methyl estra 4,6-dienes of general formula I D according to claim 6 ° which consists in that a 17β-acyloxy 17α-ethynyl is subjected 3-oxo estra 4-ene to the action of an etherification agent in an acid medium to obtain a 3-alkyloxy 17β-acyloxy 17α-ethynyl estra 3,5-diene, treats it with a formylation reagent in the conditions of the Vilsmeier-Hack reaction to form the 6-formylated derivative which is reduced by means of a mixed hydride of alkali metal to 6-hydroxymethylated derivative, dehydrates the latter in an acid medium to form a 3-oxo 6 -methylene 17β-acyloxy 17β-ethynyl estra 4-ene and then isomerized thereof in the presence of an isomerization catalyst into 3-oxo 6-methyl 17β-acyloxy 17α-ethynyl estra 4,6-diene. 3 ° - A process for obtaining 3-oxo 6-methyl estra 4,6-diene of formula I A
qui consiste au départ du 3-oxo estra 4-ène à soumettre ce dernier à l'action d'un agent éthérifiant en milieu acide pour former un 3-alcoxy estra 3,5-diène, que l'on formyle en 3-alcoxy 6-formyl estra 3,5-diène, réduit celui-ci au moyen d'un hydrure mixte de métal alcalin en 3-alcoxy 6-hydroxyméthyl estra 3,5-diène, déshydrate ce dernier par traitement en milieu acide pour former un 3-oxo 6-méthylène estra 4-ène que l'on isomérise en 3-oxo 6-méthyl estra 4,6-diène par chauffage en présence d'un catalyseur d'isomérisation. 4°- Un procédé d'obtention des 3,20-dioxo 6-méthyl 19-nor pregna which consists at the start of the 3-oxo estra 4-ene to subject the latter to the action of an etherifying agent in an acid medium to form a 3-alkoxy estra 3,5-diene, which is formulated into 3-alkoxy 6-formyl estra 3,5-diene, reduces this by means of a mixed alkali metal hydride to 3-alkoxy 6-hydroxymethyl estra 3,5-diene, dehydrates the latter by treatment in an acid medium to form a 3 -oxo 6-methylene estra 4-ene which is isomerized to 3-oxo 6-methyl estra 4,6-diene by heating in the presence of an isomerization catalyst. 4 ° - A process for obtaining 3,20-dioxo 6-methyl 19-nor pregna
4,6-diènes de formule IB dans laquelle R1 représente de l'hydrogène ou un radical alcoyle inférieur 4,6-dienes of formula I B in which R 1 represents hydrogen or a lower alkyl radical
qui consiste en ce que l'on soumet un 3,20-dioxo 19-nor pregna 4-ène à l'action d'un agent d'éthérification en milieu acide pour obtenir un 3-alcoxy 20-oxo 19-nor pregna 3,5-diène, traite celui-ci par un agent de formylation pour obtenir un 3-alcoyloxy 6-formyl 20-oxo 19-nor pregna 3,5-diène que l'on réduit en 3-alcoyloxy 6-hydroxyméthyl 20-oxo 19-nor pregna 3,5-diène par un hydrure mixte de métal alcalin, déshydrate ce dernier en milieu acide pour former le 3,20-dioxo 6-méthylène 19-nor pregna 4-ène que l'on isomérise en 3,20-dioxo 6-méthyl 19-nor pregna 4,6-diène de formule IB 5°-Un procédé d'obtention du 3-oxo 6-méthyl 17-R1 estra 4,6-diène de formule IE which consists in subjecting a 3,20-dioxo 19-nor pregna 4-ene to the action of an etherification agent in an acid medium to obtain a 3-alkoxy 20-oxo 19-nor pregna 3 , 5-diene, treat it with a formylating agent to obtain a 3-alkyloxy 6-formyl 20-oxo 19-nor pregna 3,5-diene which is reduced to 3-alkyloxy 6-hydroxymethyl 20-oxo 19-nor pregna 3,5-diene with a mixed hydride of alkali metal, dehydrates the latter in an acid medium to form 3,20-dioxo 6-methylene 19-nor pregna 4-ene which is isomerized to 3.20 -dioxo 6-methyl 19-nor pregna 4,6-diene of formula I B 5 ° -A process for obtaining 3-oxo 6-methyl 17-R 1 estra 4,6-diene of formula I E
dans laquelle le substituant R1 est choisi dans le groupe constitué par l'oxygène ou le groupe R3 représente un reste acyle d'un acide' organique carboxylique, aliphatique ou aromatique, ayant de 1 à 10 atomes de carbone, qui consiste en ce que l'on soumet le 3,17-dioxo estra 4-ène à un réactif d'éthérification en milieu acide pour former un 3-alccyloxy 17-oxo estra 3,5-diène, traite celui-ci par un réactif de formylation pour former le 3-alcoyloxy 17-oxo 6-formyl estra 3,5-diène, réduit celui-ci par un hydrure mixte de métal alcalin en 3-alcoyloxy 6-hydroxyméthyl 17β-hydroxy estra 3,5-diène que l'on déshydrate en milieu acide en 3-oxo 6-méthylène 17β-hydroxy estra 4-ène, isomérise celui-ci par un catalyseur d'isomérisation en 6-méthyl 17β-hydroxy estra 4,6-diène et si désiré, réoxyde ce dernier par un oxydant métallique pour former le 3,17-dioxo 6-méthyl estra 4,6-diène in which the substituent R 1 is chosen from the group consisting of oxygen or the group R 3 represents an acyl residue of an organic carboxylic acid, aliphatic or aromatic, having from 1 to 10 carbon atoms, which consists in subjecting 3,17-dioxo estra 4-ene to a reagent d etherification in an acid medium to form a 3-alccyloxy 17-oxo estra 3,5-diene, treats this with a formylation reagent to form the reduced 3-alkoxy 17-oxo 6-formyl estra 3,5-diene this by a mixed alkali metal hydride in 3-alkyloxy 6-hydroxymethyl 17β-hydroxy estra 3,5-diene which is dehydrated in an acid medium to 3-oxo 6-methylene 17β-hydroxy estra 4-ene, isomerized this by an isomerization catalyst into 6-methyl 17β-hydroxy estra 4,6-diene and if desired, re-oxidizes the latter with a metal oxidant to form 3,17-dioxo 6-methyl estra 4,6-diene
ou bien acyle l'hydroxyle en 17 par un dérivé fonctionnel d'acide organique carboxylique. or alternatively acyl the hydroxyl at 17 with a functional derivative of organic carboxylic acid.
EP19900908555 1989-05-24 1990-05-23 NOVEL METHODS FOR OBTAINING 6-METHYL 19-NOR STEROIDS AND CONVERTING THEM INTO 17$g(a)-SUBSTITUTED 19-NOR PREGNADIENES Withdrawn EP0431107A1 (en)

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