Organic compounds -- part of the class 532-570 series – Organic compounds – Four or more ring nitrogens in the bicyclo ring system
Reexamination Certificate
2000-10-27
2002-12-17
Raymond, Richard L. (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Four or more ring nitrogens in the bicyclo ring system
C544S333000, C564S363000, C564S366000
Reexamination Certificate
active
06495685
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a process for preparing piperazine derivatives. More specifically, the present invention relates to a process for preparing piperazine derivatives which can be suitably used as preparation intermediates of mirtazapine, which is useful as an antidepressant.
2. Discussion of the Related Art
Mirtazapine is a compound which is useful as an antidepressant. Conventionally, there have been known piperazine derivatives as preparation intermediates for mirtazapine. As a process for preparing a piperazine derivative, there has been known a process comprising reacting 1-methyl-3-phenylpiperazine with 2-chloro-3-cyanopyridine in the presence of potassium fluoride (Japanese Examined Patent Publication No. Sho 59-42678).
However, since this process uses potassium fluoride, there are some defects in this process that apparatus in which glass is used or apparatus having glass-lining cannot be used in the process because glass is eroded away, and that industrial productivity is poor because tar is generated in the reaction solution in a large amount, thereby making it difficult to take out a desired piperazine derivative.
In addition, as a process for preparing 1-methyl-3-phenylpiperazine, which is an important preparation intermediate for the above-mentioned piperazine derivative, there have been known a process comprising reacting styrene oxide with N-methylethanolamine in water (Japanese Examined Patent Publication No. Sho 53-15520); and a process comprising methylating 2-phenylpiperazine with methyl iodide (U.S. Pat. No. 4,722,705).
However, the former process has some defects in the aspect of productivity because isomers are formed, so that a complicated treatment such as column separation is necessitated. In addition, the latter process has some defects that its industrial productivity is poor because 1-methyl-3-phenylpiperazine cannot be obtained in high yields, and a large amount of acetone is necessitated.
The present invention has been accomplished in view of the prior art described above. An object of the present invention is to provide a process capable of industrially easily preparing piperazine derivatives which are useful as preparation intermediates of mirtazapine, and 1-methyl-3-phenylpiperazine, which is an important preparation intermediate thereof, without requiring complicated procedures. These and other objects of the present invention will be apparent from the following description.
SUMMARY OF THE INVENTION
According to the present invention, there are provided:
(1) a process for preparing a diol compound represented by the formula (I):
comprising reacting styrene oxide with N-methylethanolamine in an aprotic polar organic solvent;
(2) the process for preparing a diol compound according to item (1) above, wherein the aprotic polar organic solvent is dimethylformamide or 1,3-dimethylimidazolidin-2-one;
(3) a process for preparing a dichloro-compound represented by the formula
comprising chlorinating the diol compound obtained in item (1) above without isolating the diol compound;
(4) a process for preparing a salt of a dichloro-compound represented by the formula (III):
wherein HX is an acid,
comprising treating the diol compound obtained in item (1) above with an acid to form a salt, and chlorinating the resulting salt;
(5) a process for preparing 1-methyl-3-phenylpiperazine represented by the formula (IV):
comprising reacting the dichloro-compound obtained in item (3) above or a salt of the dichloro-compound obtained in item (4) above with ammonia;
(6) a process for preparing a piperazine derivative represented by the formula (V):
comprising reacting 1-methyl-3-phenylpiperazine with 2-chloro-3-cyanopyridine in an aprotic polar organic solvent in the presence of a base and an alkali metal halide; and
(7) an oxalate of a piperazine derivative represented by the formula (VI):
REFERENCES:
patent: 3663548 (1972-05-01), Nitta et al.
patent: 4025513 (1977-05-01), Olivie
patent: 4062848 (1977-12-01), van der Burg
patent: 4217452 (1980-08-01), Olivie
patent: 4772705 (1988-09-01), Schmiesing
patent: 6339156 (2002-01-01), Dolitzky
patent: 44-17388 (1969-07-01), None
patent: 5315520 (1978-05-01), None
patent: 5942678 (1984-10-01), None
patent: WO 00/63185 (2000-10-01), None
Iishi Eiichi
Imamiya Yoshiyuki
Maeda Chiharu
Wang Weiqi
Birch & Stewart Kolasch & Birch, LLP
Sumika Fine Chemicals Co., Ltd.
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