WO1994001450A1 - PROCEDE DE FABRICATION DE DIOLS STEROIDIENS ETHENO ET ETHANO-16α,17β ET DE LEURS DERIVES - Google Patents

PROCEDE DE FABRICATION DE DIOLS STEROIDIENS ETHENO ET ETHANO-16α,17β ET DE LEURS DERIVES Download PDF

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Publication number
WO1994001450A1
WO1994001450A1 PCT/EP1993/001733 EP9301733W WO9401450A1 WO 1994001450 A1 WO1994001450 A1 WO 1994001450A1 EP 9301733 W EP9301733 W EP 9301733W WO 9401450 A1 WO9401450 A1 WO 9401450A1
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WIPO (PCT)
Prior art keywords
vinyl
radical
general formula
compound
carbon atoms
Prior art date
Application number
PCT/EP1993/001733
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German (de)
English (en)
Inventor
Henry Laurent
Peter Esperling
Original Assignee
Schering Aktiengesellschaft
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 Aktiengesellschaft filed Critical Schering Aktiengesellschaft
Publication of WO1994001450A1 publication Critical patent/WO1994001450A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J53/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by condensation with a carbocyclic rings or by formation of an additional ring by means of a direct link between two ring carbon atoms, including carboxyclic rings fused to the cyclopenta(a)hydrophenanthrene skeleton are included in this class
    • C07J53/002—Carbocyclic rings fused

Definitions

  • the present invention relates to a new process for the preparation of 14,17 ⁇ -etheno- and 14,17 ⁇ -ethano-16 ⁇ , 17ß-steroid diols and their derivatives of the general formula I,
  • ST for the rest (ABC rings) of a steroid molecule AB for a CC double or CC single bond
  • Halogen atoms F, Cl, Br
  • the DIELS-ALDER addition of ⁇ -acetoxyacrylonitrile to 1 yields the ethenonitrile 2, which after conversion into the 16-ketone 3 with sodium in liquid ammonia stereoselectively gives the ethenotriol 4.
  • the desired ethanotriol 5 is obtained by catalytic hydrogenation of the etheno double bond.
  • a disadvantage of this synthesis is the use of the highly toxic and expensive ⁇ -acetoxyacrylonitrile, a second in the complex method for reducing the ketone 3 with sodium in ammonia.
  • the 14,17 ⁇ -etheno bridge in the compounds la is hydrogenated if desired, the ester groups present are saponified if desired, and then the free hydroxyl groups are then partially and / or successively or completely with a straight or branched chain alkanoyl chloride or bromide or a corresponding one if desired esterified the alkane carboxylic anhydride with 1 or 4 to 10 carbon atoms or with benzoyl chloride.
  • an estratriene derivative which is optionally substituted in the A, B and / or C ring is preferably reacted according to the invention.
  • a compound of the general formula II to be used preferably has in the 3-position a straight-chain or branched-chain alkanoyloxy radical having 1 or 4 to 10 carbon atoms, in particular the acetyloxy radical, or in the 3-position a saturated or unsaturated one , straight-chain hydrocarbonoxy radical with 1 or 2 to 10 carbon atoms or branched-chain hydrocarbonoxy radical with 3 to 10 carbon atoms, in particular the methoxy radical.
  • the substituent R "on the oxygen atom of the C-17 atom represents a straight-chain, saturated alkanoyl radical having 2 to 5 carbon atoms, in particular the acetyl radical.
  • 3,17-Diacetoxy-estra-l, 3,5 (10), 14,16-pentaen and 17-acetoxy-3-methoxy-estra-l are very particularly suitable as compounds of the general formula ⁇ for the new process , 3.5 (10), 14.16-pentaen.
  • vinyl esters with a straight-chain or branched-chain saturated alkanoyl radical with 1 or 4 to 20 carbon atoms or vinyl benzoate are suitable, the alkanoyl radical or the benzoyl radical with one or more halogen atoms (F, Cl , Br) can be substituted.
  • vinyl esters of the general formula m The following, practically non-toxic and commercially available vinyl esters may preferably be mentioned as vinyl esters of the general formula m:
  • the vinyl acetate (vinyl acetate) is particularly noteworthy, since it is manufactured on an industrial scale and is therefore extremely inexpensive to obtain (approx. 10 DM / 1).
  • the vinyl ester of the general formula DI is reacted as dienophu in a cycloaddition with the diene of the general formula D (DiELS-ALDER reaction).
  • DI dienophu
  • D diene of the general formula D
  • the reaction of 3,17-di-acetoxy-estra-1,3,5 (10), 14,16-pentaen (1) with vinyl acetate is given as an example in the scheme below.
  • the ethenotriol triacetate 6 can thus be obtained directly; a complex step such as the difficult reaction of the 16-ketone 3 with sodium in liquid ammonia is eliminated.
  • the triol 5 can be obtained by catalytic hydrogenation to ethanotriol triacetate 7 and its saponification.
  • Compounds 6 and 7, like triol 5, are compounds of general formula I.
  • Compounds 5, 6 and 7 (or their analogous compounds if another compound of general formula D was used as compound 1 or a vinyl ester other than vinyl acetate ) can be converted into other compounds of the general formula I by conventional organic chemistry processes.
  • the 3-, 16- and 17-alkanoyloxy or hydroxy groups have different reactivities.
  • the compound of the general formula D has an alkanoyloxy radical or a hydrocarbonoxy radical in the 3-position, the 3-hydroxy group is released by saponification or ether cleavage with a LEWIS acid using conventional methods, and the esterification or etherification thereof to other compounds of the general formula I leads.
  • the cycloaddition is carried out at higher temperatures in order to improve the reactivity of the vinyl ester component.
  • a high-boiling solvent such as. As mesitylene, xylene or toluene, preferably under pressure, which sets itself in the closed reaction vessel.
  • the typical reaction conditions for the addition of vinyl acetate (boiling point: 72-73 ° C.) to 3,17-diacetoxy-estra-1,3,5 (10), 14,16-pentaen (1) are given here as an example :
  • Reaction temperature 180 - 200 ° C
  • pressure approx. 8 - 10 bar.
  • the yield of the DiELS-ALDER adduct 6, which forms stereo- and regioselectively under these conditions, is approximately 50% of theory.
  • a solution of 25.0 g of 3,17-diacetoxy-estra-l, 3,5 (10), 14,16-pentaen in 75 ml of vinyl acetate is in a pressure vessel in an oil bath for 3 days at 190 ° C and 2 days at 215 ° C heated.
  • the reaction mixture is evaporated in vacuo.
  • the residue, 45.1 g of oily product, is chromatographed on silica gel: (diameter of the column 7 cm, filling height 35 cm, particle size 0.015-0.04 mm).
  • a suspension of 1.0 g of 17-acetoxy-3-methoxy-estra-l, 3.5 (10), 14.16-pentaen in 1 ml of xylene is mixed with 2 ml of vinyl acetate and in a pressure vessel in an oil bath at 190 ° for 11 days C. heated. The reaction mixture is evaporated in vacuo. The residue, 2.10 g of oily product, is chromatographed on silica gel (diameter of the column 4.5 cm, filling height 20 cm, particle size 0.015-0.04 mm).
  • a solution of 2.9 g of 3,16 ⁇ , 17ß-triacetoxy-14,17 ⁇ -ethano-estra-l, 3,5 (10) -triene in 30 ml of methanol is mixed with 8.5 ml of 2N sodium hydroxide solution and 60 min at 60 ° C. touched.
  • the reaction mixture is then neutralized with 17 ml of 1N hydrochloric acid, mixed with 15 ml of deionized water and stirred for 15 minutes.
  • the crystallized product is washed with water and dried.
  • the yield is 2.06 g of 14,17 ⁇ -ethano-estra-l, 3,5 (10) -trien-3.16 ⁇ , 17ß-triol. Melting point 324 ° C.

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

Abstract

L'invention concerne un nouveau procédé de fabrication de diols stéroïdiens 14,17α-éthéno et 14,17α-éthano-16α,17β et de leurs dérivés, notamment d'estriols 14,17 α-éthéno- et 14,17 α-éthano-3,16α,17β et de leurs esters qui constituent des ÷strogènes très actifs et efficaces par voie orale, en procédant à une addition par réaction de Diels-Alder d'esters vinyliques, de préférence de l'acétate vinylique, à 17-alcanoyloxy-14,16-diènes.
PCT/EP1993/001733 1992-07-03 1993-06-30 PROCEDE DE FABRICATION DE DIOLS STEROIDIENS ETHENO ET ETHANO-16α,17β ET DE LEURS DERIVES WO1994001450A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19924222316 DE4222316A1 (de) 1992-07-03 1992-07-03 Verfahren zur Herstellung von Etheno- und Ethano-16â,17µ-Steroiddiolen und deren Derivaten
DEP4222316.4 1992-07-03

Publications (1)

Publication Number Publication Date
WO1994001450A1 true WO1994001450A1 (fr) 1994-01-20

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PCT/EP1993/001733 WO1994001450A1 (fr) 1992-07-03 1993-06-30 PROCEDE DE FABRICATION DE DIOLS STEROIDIENS ETHENO ET ETHANO-16α,17β ET DE LEURS DERIVES

Country Status (2)

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DE (1) DE4222316A1 (fr)
WO (1) WO1994001450A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996005216A1 (fr) * 1994-08-09 1996-02-22 Jenapharm Gmbh Derives estra-1,3,5(10)-triene, leurs procedes de preparation et compositions pharmaceutiques les contenant
WO1996005217A1 (fr) * 1994-08-09 1996-02-22 Jenapharm Gmbh Compositions pharmaceutiques comprenant des derives estra-1,3,5(10)-triene

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1988001275A1 (fr) * 1986-08-20 1988-02-25 Schering Aktiengesellschaft Berlin Und Bergkamen 14,17beta-ETHANO-14beta-ESTRATRIENES ET ESTRATETRAENES, PROCEDE POUR LEUR FABRICATION ET PREPARATIONS PHARMACEUTIQUES LES CONTENANT
EP0372665A1 (fr) * 1988-11-11 1990-06-13 Schering Aktiengesellschaft 14alpha, 17alpha-éthano-estratriènes
EP0410554A2 (fr) * 1989-07-28 1991-01-30 Schering Aktiengesellschaft 14,17-Alpha-éthano- et éthano-oestratriènes, leur procédé de préparation et leur application à la production de produits pharmaceutiques
EP0430386A1 (fr) * 1989-11-29 1991-06-05 Schering Aktiengesellschaft 14Alpha, 17alpha portés-16-hydroxyestratriènes

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1988001275A1 (fr) * 1986-08-20 1988-02-25 Schering Aktiengesellschaft Berlin Und Bergkamen 14,17beta-ETHANO-14beta-ESTRATRIENES ET ESTRATETRAENES, PROCEDE POUR LEUR FABRICATION ET PREPARATIONS PHARMACEUTIQUES LES CONTENANT
EP0372665A1 (fr) * 1988-11-11 1990-06-13 Schering Aktiengesellschaft 14alpha, 17alpha-éthano-estratriènes
EP0410554A2 (fr) * 1989-07-28 1991-01-30 Schering Aktiengesellschaft 14,17-Alpha-éthano- et éthano-oestratriènes, leur procédé de préparation et leur application à la production de produits pharmaceutiques
EP0430386A1 (fr) * 1989-11-29 1991-06-05 Schering Aktiengesellschaft 14Alpha, 17alpha portés-16-hydroxyestratriènes

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, vol. 78, no. 1, 8 January 1973, Columbus, Ohio, US; abstract no. 3776, V. A. KRON ET AL: "Reactions of Dimethoxytetrachlorocyclopentadiene with Some Dienophiles" page 315; column 2; *
IZV. NAUCH.-ISSLED. INST. NEFTE- UGLEKHIM. SIN. IRKUTSK. UNIV., vol. 11, no. 1, 1969, pages 68 - 70 *
K. SEGUCHI ET AL: "Steric Control in the Diels-Alder Reaction", BULLETIN OF THE CHEMICAL SOCIETY OF JAPAN., vol. 49, no. 12, December 1976 (1976-12-01), TOKYO JP, pages 3558 - 3563 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996005216A1 (fr) * 1994-08-09 1996-02-22 Jenapharm Gmbh Derives estra-1,3,5(10)-triene, leurs procedes de preparation et compositions pharmaceutiques les contenant
WO1996005217A1 (fr) * 1994-08-09 1996-02-22 Jenapharm Gmbh Compositions pharmaceutiques comprenant des derives estra-1,3,5(10)-triene
US6080735A (en) * 1994-08-09 2000-06-27 Jenapharm Gmbh & Co. Kg Estra-1,3,5(10)-trien derivatives, processes for their preparation and pharmaceutical compositions containing these compounds

Also Published As

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DE4222316A1 (de) 1994-01-05

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