WO2009059765A2 - Procédé de préparation de drospirénone - Google Patents

Procédé de préparation de drospirénone Download PDF

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Publication number
WO2009059765A2
WO2009059765A2 PCT/EP2008/009372 EP2008009372W WO2009059765A2 WO 2009059765 A2 WO2009059765 A2 WO 2009059765A2 EP 2008009372 W EP2008009372 W EP 2008009372W WO 2009059765 A2 WO2009059765 A2 WO 2009059765A2
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WO
WIPO (PCT)
Prior art keywords
give
drospirenone
dione
diene
compound
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/EP2008/009372
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English (en)
Other versions
WO2009059765A3 (fr
Inventor
Guido Galliani
Vincenzo Radaelli
Alberto Terraneo
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.)
Chorisis SRL
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Chorisis SRL
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 Chorisis SRL filed Critical Chorisis SRL
Publication of WO2009059765A2 publication Critical patent/WO2009059765A2/fr
Publication of WO2009059765A3 publication Critical patent/WO2009059765A3/fr
Anticipated expiration legal-status Critical
Ceased 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
    • C07J1/0003—Androstane derivatives
    • C07J1/0011—Androstane derivatives substituted in position 17 by a keto group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/18—Feminine contraceptives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J31/00—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring
    • C07J31/003—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring the S atom directly linked to a ring carbon atom of the cyclopenta(a)hydrophenanthrene skeleton
    • 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
    • C07J53/004—3 membered carbocyclic rings
    • C07J53/008—3 membered carbocyclic rings in position 15/16

Definitions

  • the present invention discloses a process for the preparation of drospirenone.
  • Drospirenone (I) [chemical name 6 ⁇ ,7 ⁇ ,15 ⁇ ,16 ⁇ -dimethylene-3-oxo- 17 ⁇ -pregn-4-en-21 , 17-carbolactone] is a steroid endowed with progestinic activity used as a birth control agent.
  • the present invention discloses a process for the preparation of drospirenone (I) comprising the following steps: a) reaction of a derivative protected at the carbonyl at the 3 -position of androstenedione, of formula (II):
  • R represents a linear or branched C 1 -C 5 alkyl group, , preferably ethyl, with a sulfinic acid ester, preferably methyl benzenesulfinate, in alkaline conditions to give a compound of formula (III):
  • Step a) is typically performed in an aprotic polar solvent, such as tetrahydrofuran, in alkaline conditions, preferably by using potassium ter-butylate.
  • an aprotic polar solvent such as tetrahydrofuran
  • a solution of the selected base in the selected organic solvent is prepared, into which compound (II) and the sulfmylating agent are added successively.
  • compound (III) obtained is not isolated, but treated directly with a mineral acid, typically 35% hydrochloric acid, by pouring the reaction mixture into acidic water and reacting at room temperature, typically between 20 e 30 0 C.
  • the resulting sulfoxide of formula (IV) is not isolated, but directly subjected to thermal elimination in alkaline conditions to give androsta-4,15-diene-3,17-dione (V).
  • the reaction mixture containing sulfoxide (IV) is poured into an apolar organic solvent, such as toluene, chlorobenzene or xylene, preferably xylene; the organic phase is separated and the aqueous phase is again extracted one or more times with the same organic solvent.
  • Collected organic phases are treated with an inorganic base, for example sodium carbonate, in a molar ratio of approximately 5 : 1 as to 3-ethoxy-androsta-3,5- diene-17-one; the mixture is heated to the boiling point of the solvent, approximately two thirds of which are distilled off; heating is then maintained for about four hours, till completion of the reaction.
  • the reaction mixture is then filtered and the residue is washed with some more solvent.
  • the collected filtrates are evaporated and the residue is purified typically through column chromatography on silica gel to give compound (V).
  • Methylenation reactions are usually performed with trimethyl-sulfoxonium iodide as described in the literature.
  • a solution of trimethylsulfoxonium iodide is treated with sodium hydride, followed by the compound of formula (V) or formula (VII) in an aprotic polar solvent, for example tetrahydrofuran, and reacted till completion, whereby products are isolated.
  • Dehydrogenation is usually carried out with chloranil in the presence of p-toluenesulfonic acid, with acetone as a solvent.
  • the reaction is performed at room temperature, preferably between 20 and 25 0 C, for approximately 20 hours, usually between 20 and 21 hours.
  • the step leading to drospirenone is performed according to standard methods; usually a solution of ethyl malonate and sodium ethoxide in ethanol is prepared, which is treated with 6 ⁇ ,7 ⁇ , 15 ⁇ , 16 ⁇ -dimethylene-17 ⁇ - spirooxiraneandrost-4-en-3-one (VIII), and refluxed till completion (in about 2 hours).
  • the reaction mixture is then cooled and treated, in the order, with an inorganic base, for example with sodium hydroxide, and with a mineral acid, for example with hydrochloric acid, to give carboxylated drospirenone (IV)
  • Drospirenone is obtained by decarboxylation effected according to standard methods, for example by dissolving the product in dimethylformamide and heating it at 130 0 C.
  • raw carboxylated drospirenone may be used, and the crystallization may be performed on final drospirenone.
  • the process of the invention has the advantages of using an inexpensive starting material, being performed in a few steps, and not involving the use of microorganisms.
  • 600 ml of tetrahydrofuran, blanketed with nitrogen, is treated with 30 g (0.095 moles) of 3-ethoxy-androsta-3,5-diene-17-one at 20-30 0 C, whereby a yellow-orange solution is formed.
  • the mixture is stirred at 20-25 0 C for ten minutes, then treated with 26.34 g (0.165 moles) of 98% methyl benzenesulfinate: temperature rises up to 35°C. After stirring at 0-30 0 C for 30 minutes, a dark solution is obtained.
  • the solution is then poured into a mixture of 600 ml of water and 60 ml of 35% hydrochloric acid, in about 20 minutes, keeping temperature between 10° and 20 0 C. Stirring is maintained at such temperature for additional 2.5 hours.
  • Step 3 15 ⁇ ,16 ⁇ -Methylenandrosta-4-ene-3,17-dione
  • the mixture is stirred at 20°/30°C for 1 hour, then treated with a solution of 12 g (0.042 moles) of androsta-4,15-diene-3,17-dione in 60 ml of tetrahydrofuran. After stirring the mixture at 20°/25°C for 15 hours, the solution obtained is poured into a mixture of 300 g of water and 400 g of crushed ice.
  • Phases are separated; the aqueous phase is extracted with 2 x 100 ml of methylene chloride; after separation of phases, the organic ones are collected, washed with 3 x 100 ml of water, and evaporated under reduced pressure. 13.7 g of a yellow solid are obtained, which is dissolved in methylene chloride. The solution is filtered on silica gel; after evaporation, 8.55 g of 15 ⁇ ,16 ⁇ -methylenandrosta-4-ene-3,17-dione are obtained. Molar yield: 68,2%.
  • Step 4 15 ⁇ ,16 ⁇ -MethyIenandrosta-4,6-diene-3,17-dione
  • Step 5 6 ⁇ ,7 ⁇ ,15 ⁇ ,16 ⁇ -Dimethylene-17 ⁇ -spirooxiranoandrost-4-en-3- one
  • a solution of 9.5 g (0.293 moles) of 21% sodium ethoxide and 10.2 g (0.637 moles) of diethyl malonate in 40 ml of ethanol is refluxed for 1 hour; after cooling at 40 0 C, a solution of 5.9 g of raw 6 ⁇ ,7 ⁇ ,15 ⁇ ,16 ⁇ -dimethylene- 17 ⁇ -spirooxiraneandrost-4-en-3-one and 20 ml of ethanol is added.
  • the reaction mixture is refluxed for 2 hours; when the reaction is over, the mixture is evaporated under reduced pressure and the residue is taken up in 18 ml of ethanol.
  • the solution thus obtained is dropped into a solution of 9.5 g of sodium hydroxide in 161 ml of water, cooled at 0 0 C under stirring. The mixture is then stirred at room temperature for additional 15-20 hours. The solution is cooled at 0 0 C and treated dropwise with 25 ml of 35% hydrochloric acid; after stirring at 0 0 C for 2 hours, the suspension is filtered and the solid is washed with water.
  • Carboxylated drospirenone is dissolved in 45 ml of dimethylformamide and the solution is heated at 130 0 C for 2 hours. After cooling at room temperature, the solution is poured into 400 g of water, then extracted with 2 x 100 ml of ethyl acetate, phases are separated and the organc phase is dried under reduced pressure. After purification by crystallization, 1.1 g of drospirenone is obtained.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Reproductive Health (AREA)
  • Medicinal Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Endocrinology (AREA)
  • Gynecology & Obstetrics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Steroid Compounds (AREA)

Abstract

La présente invention décrit un procédé pour la préparation de drospirénone (I) à l'aide d'androstènedione comme matière de départ. En particulier, l'androstènedione protégée sur le groupe carbonyle en position 3 sous la forme d'un énol-éther est fonctionnalisée en position 16 par un groupe sulfoxyde et le dérivé ainsi obtenu subit une élimination thermique en milieu alcalin pour donner l'androsta-4,15- diène-3,17-dione (V) qui est par la suite transformée en Drospirénone (I).
PCT/EP2008/009372 2007-11-08 2008-11-06 Procédé de préparation de drospirénone Ceased WO2009059765A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
ITMI2007A002141 2007-11-08
IT002141A ITMI20072141A1 (it) 2007-11-08 2007-11-08 Procedimento per la preparazione del drospirenone

Publications (2)

Publication Number Publication Date
WO2009059765A2 true WO2009059765A2 (fr) 2009-05-14
WO2009059765A3 WO2009059765A3 (fr) 2009-10-15

Family

ID=40314693

Family Applications (1)

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PCT/EP2008/009372 Ceased WO2009059765A2 (fr) 2007-11-08 2008-11-06 Procédé de préparation de drospirénone

Country Status (2)

Country Link
IT (1) ITMI20072141A1 (fr)
WO (1) WO2009059765A2 (fr)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102009031909A1 (de) * 2009-07-01 2011-01-05 Heyl Chemisch-Pharmazeutische Fabrik Gmbh & Co. Kg Verfahren zur Herstellung von Drospirenon aus Prasteron
DE102009038972A1 (de) 2009-08-23 2011-06-30 Heyl Chemisch-pharmazeutische Fabrik GmbH & Co. KG, 14167 Verfahren zur Herstellung von Drospirenon aus 6,7,15,16-Dimethylenandrost-4-en-3,17-dion
DE102010006818A1 (de) 2010-01-31 2011-08-04 Heyl Chemisch-pharmazeutische Fabrik GmbH & Co. KG, 14167 Verfahren zur Herstellung von Drospirenon aus 6ß, 7ß, 15ß, 16ß-Dimethylenandrost-4-en-3,17-dion
CN102395596A (zh) * 2010-03-16 2012-03-28 台州太法药业有限公司 屈螺酮制备方法
US8334375B2 (en) 2009-04-10 2012-12-18 Evestra, Inc. Methods for the preparation of drospirenone
CN104558091A (zh) * 2013-10-16 2015-04-29 天津金耀集团有限公司 一种醋酸阿比特龙的合成方法

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ITMI20040443A1 (it) * 2004-03-08 2004-06-08 Poli Ind Chimica Spa Prpcesso per la preparazione di ..15-16-17-cheto-steroidi e loro uso nella sintesi di composti farmacologicamente attivi
HUP0402466A2 (en) * 2004-11-30 2006-07-28 Richter Gedeon Vegyeszet Industrial process for preparing 17-hydroxy-6-betha, 7-betha, 15-betha, 16-betha-bis-methylene-3-oxo-17-alpha-pregn-4-ene-21-carboxylic acid gamma lacton and the main, intermediates of the process
ITMI20061802A1 (it) * 2006-09-22 2008-03-23 Antibioticos Spa Epossidazione di 17-oxo-15,16-metilen steroidi con ilidi di solfossonio

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8334375B2 (en) 2009-04-10 2012-12-18 Evestra, Inc. Methods for the preparation of drospirenone
DE102009031909A1 (de) * 2009-07-01 2011-01-05 Heyl Chemisch-Pharmazeutische Fabrik Gmbh & Co. Kg Verfahren zur Herstellung von Drospirenon aus Prasteron
DE102009031909B4 (de) * 2009-07-01 2017-02-09 Heyl Chemisch-Pharmazeutische Fabrik Gmbh & Co. Kg Verfahren zur Herstellung von Drospirenon aus Prasteron
DE102009038972A1 (de) 2009-08-23 2011-06-30 Heyl Chemisch-pharmazeutische Fabrik GmbH & Co. KG, 14167 Verfahren zur Herstellung von Drospirenon aus 6,7,15,16-Dimethylenandrost-4-en-3,17-dion
DE102010006818A1 (de) 2010-01-31 2011-08-04 Heyl Chemisch-pharmazeutische Fabrik GmbH & Co. KG, 14167 Verfahren zur Herstellung von Drospirenon aus 6ß, 7ß, 15ß, 16ß-Dimethylenandrost-4-en-3,17-dion
CN102395596A (zh) * 2010-03-16 2012-03-28 台州太法药业有限公司 屈螺酮制备方法
EP2548881A4 (fr) * 2010-03-16 2013-12-11 Taizhou Taifa Pharmaceuticals Co Ltd Procédé de préparation de drospirénone
CN104558091A (zh) * 2013-10-16 2015-04-29 天津金耀集团有限公司 一种醋酸阿比特龙的合成方法

Also Published As

Publication number Publication date
WO2009059765A3 (fr) 2009-10-15
ITMI20072141A1 (it) 2009-05-09

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