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WO1995029931A1 - PROCEDE POUR L'INSERTION STEREOSELECTIVE D'UNE CHAINE LATERALE ALKYNYLE SUR DES 13α-ALKYLGONAN-17-ONES A SUBSTITUTION 11β-ARYL - Google Patents

PROCEDE POUR L'INSERTION STEREOSELECTIVE D'UNE CHAINE LATERALE ALKYNYLE SUR DES 13α-ALKYLGONAN-17-ONES A SUBSTITUTION 11β-ARYL Download PDF

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Publication number
WO1995029931A1
WO1995029931A1 PCT/EP1995/001613 EP9501613W WO9529931A1 WO 1995029931 A1 WO1995029931 A1 WO 1995029931A1 EP 9501613 W EP9501613 W EP 9501613W WO 9529931 A1 WO9529931 A1 WO 9529931A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
methyl
lithium
alkyne
addition
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.)
Ceased
Application number
PCT/EP1995/001613
Other languages
German (de)
English (en)
Inventor
Orlin Petrov
Wolfgang Kübler
Jürgen RUPPERT
Harribert Neh
Klaus Nickisch
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bayer Pharma AG
Original Assignee
Schering AG
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Schering AG filed Critical Schering AG
Priority to AU25227/95A priority Critical patent/AU2522795A/en
Publication of WO1995029931A1 publication Critical patent/WO1995029931A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
    • C07J41/0077—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 substituted in position 11-beta by a carbon atom, further substituted by a group comprising at least one further carbon atom
    • C07J41/0083—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 substituted in position 11-beta by a carbon atom, further substituted by a group comprising at least one further carbon atom substituted in position 11-beta by an optionally substituted phenyl group not further condensed with other rings

Definitions

  • Y is a keto function protected in the form of a ketal or thioketal
  • R 1 is a hydrogen atom, a methoxy, thiomethyl, dimethylamino or another group known as a substituent of the 11 ⁇ -phenyl substituent in competitive progesterone antagonists, and
  • R 13 is a methyl or ethyl group
  • progesterone antagonists with a 13 ⁇ -alkyl group can be found, for example, in European Patent 0 186 834 and European Patent Application 0 349 481. Because of their strong affinity for the progesterone receptor, these compounds are able to displace the progesterone from its receptor and thus prevent the progesterone effect. They are therefore suitable for the treatment of hormone-dependent tumors, for example breast cancer, and for influencing progesterone-dependent conditions or processes.
  • Competitive progesterone antagonists can thus be used for induction of birth, termination of pregnancies (both preferably in combination with a prostaglandin or with oxytocin) or for implantation inhibition (female fertility control).
  • the structures of these antagonists are distinguished by a saturated or unsaturated, optionally substituted, hydrocarbon side chain on the carbon atom 17 of the steroid skeleton which generally has at least 3 carbon atoms.
  • the object of the present invention is to provide a method for the stereoselective introduction of C-17-alkynyl sites in the ⁇ -position on 13 ⁇ -alkyl-gonan-17-ones. At the same time, the most complete possible conversion of the starting product would be desirable.
  • Y denotes a common ketal protective group, for example the ethylenedioxy or the 2,2-dimethylpropylene-1,3-dioxy group.
  • Other common keto protection groups are also considered.
  • Y can also mean a protected hy ⁇ oxyg ⁇ ippe and a hydrogen atom, the hydroxyl group then being protected, for example, as methoxymethyl, methoxyethyl, tetrahydropyranyl or silyl ether. Splitting off the protective group and oxidation of the free hydroxy group leads to the keto group. If a terminal, protected hydroxyl group is present in R 2 , the tetrahydropyranyl radical, for example, is well suited as a protecting group.
  • lithium salts can be used to minimize the excess of the alkynyllithium compound required for nucleophilic addition of alkynyllithium compounds to 17-ketosteroids with a natural 13 ⁇ configuration (WO-A 93/15103) and that lithium perchlorate can reduce the Stereoselectivity of the addition of methyl lithium to certain ketones improved (A. Loupy and B. Tchoubar in: Salt Effects in Organic and Organometallic Chemistry, VCH, Weinheim, 1992, p. 156).
  • the 17 ⁇ -hydroxyisomers formed and desired can be isolated after chromatography over aluminum oxide in very high yields of over 85%.
  • the ratio of the desired 17 ⁇ -hydroxyisomer to 17ß-hydroxyisomer also formed is between 7: 1 and 10: 1.
  • the liter alkyne is added with the addition of 1 to 10 equivalents of the lithium salt, based on the compound of the general formula I.
  • All common inorganic lithium salts are suitable as the lithium salt; Lithium chloride, bromide and perchlorate are particularly suitable.
  • the lithium salt can be added to the (to be added) alkyne H- ⁇ -R 2 before or after its deprotonation with an alkyl lithium compound such as methyl, ethyl, propyl or butyllithium to form the reactive species Li-sR 2 .
  • an alkyl lithium compound such as methyl, ethyl, propyl or butyllithium to form the reactive species Li-sR 2 .
  • the lithium salt can also be brought along with the deprotonation reagent.
  • This joint use of deprotonating agent and lithium salt in a complex compound allows a much easier and safer handling of the pure, flammable deprotonating agent methyl lithium.
  • the complex compound mentioned is also cheaper than the salt-free methyl lithium.
  • the addition reaction can be carried out in ethereal solvents; as such, especially tetrahydrofuran, diethyl ether, methyl tert-butyl ether, dioxane or mixtures of these solvents can be mentioned.
  • the reaction temperature for the addition reaction of the alkyne should be between -70 and +20 ° C.
  • the compounds of the general formula Ha (and also those of the general formula IIb) prepared by the new process can be processed further to known biologically active competitive progesterone antagonists by known processes (EP-A 0 129 499; Steroids 1984, 349).
  • the reaction proceeds with bases such as Na or KH, Na or K amide, Na or K alcoholates in an organic solvent such as THF, dimethoxyethane, diethyl ether, dioxane or mixtures thereof (preferably with NaH in THF).
  • bases such as Na or KH, Na or K amide, Na or K alcoholates in an organic solvent such as THF, dimethoxyethane, diethyl ether, dioxane or mixtures thereof (preferably with NaH in THF).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Steroid Compounds (AREA)

Abstract

Est décrit un procédé pour l'insertion stéréosélective d'une chaîne latérale alkynyle- -R?2, où R2¿ est un atome d'hydrogène, un groupe méthyle ou un groupe hydroxyméthyle dans lequel le groupe hydroxy est protégé, dans la position 17β d'une 13α-alkylgonan-17-one de formule générale (I), où Y est une fonction céto protégée sous la forme d'un cétal ou d'un thiocétal, R1 est un atome d'hydrogène, un groupe méthoxy, thiométhoxy, diméthylamino ou un autre groupe connu comme substituant du substituant 11β-phényl dans des antagonistes compétitifs de la progestérone, et R13 est un groupe méthyle ou éthyle, l'addition nucléophile de l'alkine lithiée Li- -R2 sur le groupe 17-céto s'effectuant avec l'addition de 1 à 10 équivalents d'un sel de lithium tel que le chlorure, bromure ou perchlorate de lithium. La stéréosélectivité de la réaction d'addition s'en trouve notablement améliorée et le rendement accru.
PCT/EP1995/001613 1994-04-28 1995-04-28 PROCEDE POUR L'INSERTION STEREOSELECTIVE D'UNE CHAINE LATERALE ALKYNYLE SUR DES 13α-ALKYLGONAN-17-ONES A SUBSTITUTION 11β-ARYL Ceased WO1995029931A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU25227/95A AU2522795A (en) 1994-04-28 1995-05-02 Method for stereoselective insertion of an alkynyl side chain in 11beta -aryl substituted 13alpha-alkylgonan-17-ones

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19944415590 DE4415590A1 (de) 1994-04-28 1994-04-28 Verfahren zur stereoselektiven Einführung einer Alkinylseitenkette an 11ß-Aryl-substituierten 13alpha-Alkylgonan-17-onen
DEP4415590.5 1994-04-28

Publications (1)

Publication Number Publication Date
WO1995029931A1 true WO1995029931A1 (fr) 1995-11-09

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1995/001613 Ceased WO1995029931A1 (fr) 1994-04-28 1995-04-28 PROCEDE POUR L'INSERTION STEREOSELECTIVE D'UNE CHAINE LATERALE ALKYNYLE SUR DES 13α-ALKYLGONAN-17-ONES A SUBSTITUTION 11β-ARYL

Country Status (3)

Country Link
AU (1) AU2522795A (fr)
DE (1) DE4415590A1 (fr)
WO (1) WO1995029931A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023000135A1 (fr) * 2021-07-19 2023-01-26 Context Biopharma Inc. Procédés de fabrication d'onapristone et intermédiaires de celle-ci

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0057115A2 (fr) * 1981-01-09 1982-08-04 Roussel-Uclaf Nouveaux dérivés stéroides substitués en 11beta, procédé de préparation, leur application comme médicament et les compositions les renfermant
EP0129499A2 (fr) * 1983-06-15 1984-12-27 Schering Aktiengesellschaft 13-Alpha alcoyle-gonanes, leur préparation et préparations pharmaceutiques les contenant
EP0277676A1 (fr) * 1987-01-23 1988-08-10 Akzo N.V. Dérivés de 11-aryl stéroides

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0057115A2 (fr) * 1981-01-09 1982-08-04 Roussel-Uclaf Nouveaux dérivés stéroides substitués en 11beta, procédé de préparation, leur application comme médicament et les compositions les renfermant
EP0129499A2 (fr) * 1983-06-15 1984-12-27 Schering Aktiengesellschaft 13-Alpha alcoyle-gonanes, leur préparation et préparations pharmaceutiques les contenant
EP0277676A1 (fr) * 1987-01-23 1988-08-10 Akzo N.V. Dérivés de 11-aryl stéroides

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
G. NEEF ET AL: "New Steroids with Antiprogestational and Antiglucocorticoid Activities", STEROIDS, vol. 44, no. 4, SAN FRANCISCO US, pages 349 - 372 *
G. NEEF ET AL: "Synthetic Variations of the Progesterone Antagonist RU 38 486", TETRAHEDRON LETTERS, vol. 25, no. 32, OXFORD GB, pages 3425 - 3428 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023000135A1 (fr) * 2021-07-19 2023-01-26 Context Biopharma Inc. Procédés de fabrication d'onapristone et intermédiaires de celle-ci

Also Published As

Publication number Publication date
AU2522795A (en) 1995-11-29
DE4415590A1 (de) 1995-11-02

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