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 PDFInfo
- 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
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- vinyl
- radical
- general formula
- compound
- carbon atoms
- Prior art date
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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.
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 |
Family
ID=6462692
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
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)
Country | Link |
---|---|
DE (1) | DE4222316A1 (fr) |
WO (1) | WO1994001450A1 (fr) |
Cited By (2)
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)
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 |
-
1992
- 1992-07-03 DE DE19924222316 patent/DE4222316A1/de not_active Withdrawn
-
1993
- 1993-06-30 WO PCT/EP1993/001733 patent/WO1994001450A1/fr active Application Filing
Patent Citations (4)
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)
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)
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
Publication number | Publication date |
---|---|
DE4222316A1 (de) | 1994-01-05 |
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