C - Chemistry – Metallurgy – 07 – D
Patent
C - Chemistry, Metallurgy
07
D
C07D 471/14 (2006.01) A61K 31/55 (2006.01) A61P 25/24 (2006.01) C07D 401/04 (2006.01) C07D 471/12 (2006.01)
Patent
CA 2368815
The present invention is directed to methods for the preparation of piperazine ring-containing compounds, particularly mirtazapine. According to the present invention, the mirtazapine intermediate 1-(3-carboxypyridyl-2)-4-methyl-2- phenyl-piperazine is made by hydrolyzing 1-(3-cyanopyridyl-2)-4-methyl-2- phenyl-piperazine with a base where the base is present in a ratio of up to about 12 moles of the base per one mole of 1-(3-cyanopyridyl-2)-4-methyl-2- phenyl-piperazine. The mirtazapine intermediate 1-(3-carboxypyridly-2)-4- methyl-2-phenyl-piperazine may be made by hydrolyzing 1-(3-cyanopyridyl-2)-4- methyl-2-phenyl-piperazine with potassium hydroxide at a temperature of at least about 130 ~C. The method of the present invention also includes reacting 2-amino-3-hydroxymethyl pyridine with N-methyl-1-phenyl-2, 2'-iminodiethyl chloride to form 1-(3-hydroxymethylpyridyl-2)-4-methyl-2-phenyl piperazine, and adding sulfuric acid to the 1-(3-hydroxymethylpyridyl-2)-phenyl-4- methylpiperazine to form mirtazapine. The present invention also relates to new processes for recrystallization of mirtazapine form crude mirtazapine.
L'invention concerne des procédés de préparation de composés contenant de la pipérazine, notamment de la mirtazapine. Selon l'invention, l'intermédiaire de mirtazapine 1-(3-carboxypyridyl-2)-4-méthyl-2-phényl-pipérazine est fabriqué par l'hydrolyse de 1-(3-cyanopyridyl-2)-4-méthyl-2-phényl-pipérazine avec une base, laquelle est présente selon un rapport pouvant atteindre environ 12 moles de la base par mole de 1-(3-cyanopyridyl-2)-4-méthyl-2-phényl-pipérazine. L'intermédiaire de mirtapazine de 1-(3-carboxypyridyl-2)-4-méthyl-2-phényl-pipérazine peut être fabriqué par hydrolyse de 1-(3-cyanopyridyl-2)-4-méthyl-2-phényl-pipérazine avec de l'hydroxyde de potassium, à une température d'au moins environ 130 ·C. Le procédé de l'invention consiste également à faire réagir du 2-amino-3-hydroxyméthyl pyridine avec du chlorure de N-méthyl-1-phényl-2, 2'-iminodiéthyle, de sorte que de la 1-(3-hydroxyméthylpyridyl-2)-4-méthyl-2-phényl pipérazine soit formée, et à ajouter de l'acide sulfurique à la 1-(3-hydroxyméthylpyridyl-2)-phényl-4-méthylpipérazine, de sorte que de la mirtazapine soit formée. L'invention porte également sur des nouveaux procédés de cristallisation de la mirtazapine, permettant la production de mirtazapine brute.
Finkelstein Nina
Liberman Anita
Singer Claude
Ridout & Maybee Llp
Teva Pharmaceutical Industries Ltd.
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