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Title:
高純度な17α−シアノメチル−17β−ヒドロキシ−エストラ−4,9−ジエン−3−オン及びその合成方法
Document Type and Number:
Japanese Patent JP5399711
Kind Code:
B2
Abstract:
The invention relates to a new process for the synthesis of high purity 17α-cyanomethyl-17β-hydroxy-estra-4,9-diene-3-one (further on dienogest) of formula (I) from 3-methoxy-17-hydroxy-estra-2,5(10)-diene of formula (V). The invention relates also to the high purity 17α-cyanomethyl-17β-hydroxy-estra-4,9-diene-3-one and pharmaceutical compositions containing that as active ingredient. The pharmaceutical compositions according to this invention contain high purity dienogest of formula (I) in which the total amount of impurities is less than 0.1%, while the amount of 4-bromo-dienogest is under the detection limit (0.02%) as active ingredient or at least one of the active ingredients and auxiliary materials, which are commonly used in practice, such as carriers, excipients or diluents. According to our invention the dienogest of formula (I) is synthesized the following way: i) 3-methoxy-17-hydroxy-estra-2,5(10)-diene of formula (V) is reacted with aluminum isopropylate in the presence of cyclohexanone in an inert organic solvent under heating; ii) the so obtained 3-methoxy-estra-2,5(10)-diene-17-one of formula (IV) is reacted with cyanomethyl lithium at a temperature between 0 and −30° C.; iii) the obtained 3-methoxy-17α-cyanomethyl-17β-hydroxy-estra-2,5(10)-diene of formula (III) is reacted with a strong organic acid in tetrahydrofuran solution; iv) the obtained 17α-cyanomethyl-17β-hydroxy-estr-5(10)-ene-3-one of formula (II) is reacted with 1-1.5 equivalent of pyridinium tribromide in pyridine solution at a temperature between 0 and 60° C., then the obtained crude dienogest of formula (I) is purified by recrystallization and preparative HPLC.

Inventors:
Danzi, ラヨスネー
マホー, サーンドル
アラニュイ, Antall
ホルバース, Ya Noss
Application Number:
JP2008543921A
Publication Date:
January 29, 2014
Filing Date:
October 11, 2006
Export Citation:
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Assignee:
Richter ゲデオン nil バーノ -- pretty ミーケデーレス venue tar シャシャーグ
International Classes:
C07J41/00; A61K31/57; A61P5/34; A61P15/00; A61P15/18; C07B53/00; C07B57/00
Attorney, Agent or Firm:
Haruo Hamada