公开(公告)号：EP1178805A1

公开(公告)日：2002-02-13

申请号：EP00923457.6

申请日：2000-04-18

申请人： Teva Pharmaceutical Industries Limited ,  Teva Pharmaceuticals USA, Inc. ,  Singer, Claude ,  Liberman, Anita

发明人： SINGER, Claude ,  LIBERMAN, Anita ,  FINKELSTEIN, Nina

IPC分类号： A61K31/55 ,  A61P25/24 ,  C07D401/04 ,  C07D487/12

CPC分类号： C07D401/04 ,  C07D471/14

摘要： 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.

摘要翻译： 本发明涉及制备含哌嗪环化合物，特别是米氮平的方法。 根据本发明，米氮平中间体1-（3-羧基吡啶-2）-4-甲基-2-苯基 - 哌嗪是通过水解1-（3-氰基吡啶基-2）-4-甲基-2-苯基 - 哌嗪与碱相比，每1摩尔1-（3-氰基吡啶基-2）-4-甲基-2-苯基 - 哌嗪，碱的含量最多为约12摩尔碱。 米氮平中间体1-（3-羧基吡啶-2）-4-甲基-2-苯基 - 哌嗪可以通过用氢氧化钾水解1-（3-氰基吡啶基-2）-4-甲基-2-苯基 - 哌嗪来制备 温度至少约130℃。本发明的方法还包括使2-氨基-3-羟甲基吡啶与N-甲基-1-苯基-2,2'-亚氨基二乙基氯反应形成1-（3- 羟甲基吡啶-2）-4-甲基-2-苯基哌嗪，并向1-（3-羟甲基吡啶-2） - 苯基-4-甲基哌嗪中加入硫酸以形成米氮平。 本发明还涉及来自粗米氮平的米氮平重结晶的新方法。

公开(公告)号：EP1133459A1

公开(公告)日：2001-09-19

申请号：EP99959091.2

申请日：1999-11-24

申请人： Teva Pharmaceuticals USA, Inc.

发明人： SCHWARTZ, Eduard ,  NIDAM, Tamar ,  LIBERMAN, Anita ,  MENDELOVICI, Marioara ,  ARONHIME, Jehudit ,  SINGER, Claude ,  VALDMAN, Evgeni

IPC分类号： C07C1/00

CPC分类号： C07C211/42

摘要： The present invention is directed to forms II, III, V, VI, VII, VIII, IX and X of sertraline hydrochloride and novel methods for their preparation. According to the present invention, sertraline hydrochloride polymorph II may be produced by slurrying sertraline hydrochloride polymorph VI in aprotic organic solvent. Sertraline hydrochloride polymorphic form III may be produced by heating sertraline hydrochloride polymorphs V and VI. Sertraline hydrochloride forms V and VI may be produced from either sertraline hydrochloride or sertraline base by crystallization. Sertraline hydrochloride Form VII may be produced by suspending sertraline chloride polymorph V in water, followed by filtration. Sertraline hydrochloride Forms VIII and IX may be produced by suspending sertraline base in water followed by acidification and filtration. Sertraline hydrochloride Form X and be produced by suspending sertraline hydrochloride in benzyl alcohol with heating, followed by filtration.