Richter Gedeon Vegyeszeti Gyar Rt

Richter Gedeon Nyrt.

Lajosné Dancsi

Sándor Mahó

János Csörgei

János Horváth

Zoltán Tuba

Antal Aranyi

Endréné Magyari

György Visky

Csaba Molnár

The invention relates to a new process for the synthesis of high purity 17&#x3b1;-cyanomethyl-17&#x3b2;-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 17&#x3b1;-cyanomethyl-17&#x3b2;-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 &#x2212;30&#xb0; C.; iii) the obtained 3-methoxy-17&#x3b1;-cyanomethyl-17&#x3b2;-hydroxy-estra-2,5(10)-diene of formula (III) is reacted with a strong organic acid in tetrahydrofuran solution; iv) the obtained 17&#x3b1;-cyanomethyl-17&#x3b2;-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&#xb0; C., then the obtained crude dienogest of formula (I) is purified by recrystallization and preparative HPLC. 

High purity 17&#x3b1;-cyanomethyl-17&#x3b2;-hydroxy-estra-4,9-diene-3-one and process for the synthesis thereof

A new industrial process for the synthesis of solvate-free 17&#x3b1;-acetoxy-11&#x3b2;-[4-(N,N-dimethyl-amino)-phenyl]-19-norpregna-4,9-diene-3,20-dione [CDB-2914] of formula (I) which is a strong antiprogestogene and antiglucocorticoid agent. The invention also relates to compounds of formula (VII) and (VIII) used as intermediates in the process.

Industrial process for the synthesis of 17&#x3b1;-acetoxy-11&#x3b2;-[4-(N,N-dimethyl-amino)-phenyl]-19-norpregna-4,9-diene-3,20-dione and new intermediates of the process

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Budapest, Hungary

Lajosné Dancsi