Process for preparing pyridinemethanol compounds

Details Process for preparing pyridinemethanol compounds Process for preparing pyridinemethanol compounds

2001-10-19

2002-08-20

Bernhardt, Emily (Department: 1624)

Organic compounds -- part of the class 532-570 series

Organic compounds

Unsubstituted hydrocarbyl chain between the ring and the -c-...

C544S360000

Reexamination Certificate

active

06437120

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a pyridinemethanol compound. More specifically, the present invention relates to a process capable of simply and industrially preparing a pyridinemethanol compound, which is an important intermediate for mirtazapine which is useful as an antidepressant, and a process for preparing mirtazapine using the pyridinemethanol compound.
2. Discussion of the Related Art
Conventionally, as a process for preparing a pyridinemethanol compound represented by the formula (II):
there has been proposed a process comprising reducing a pyridinecarboxylic acid represented by the formula (IV):
using lithium aluminum hydride (U.S. Pat. No. 4,062,848).
However, there are some defects in this process that the process is not economical because it is required to use an expensive reagent lithium aluminum hydride in a large amount as much as 8 times equivalent based on pyridinecarboxylic acid.
Also, in this process, pyridinecarboxylic acid is obtained by dissolving a pyridinecarbonitrile compound in ethanol, hydrolyzing the pyridinecarbonitrile compound with potassium hydroxide under reflux for 24 hours, and thereafter adding an acid thereto to liberate pyridinecarboxylic acid.
However, there are some defects in this process that its production efficiency is poor because the hydrolysis requires a long period of time and there is a necessity to liberate the resulting pyridinecarboxylic acid.
In addition, conventionally, as a process for preparing mirtazapine, there has been known a process as disclosed in U.S. Pat. No. 4,062,848.
However, there are some defects in the process that stirring is difficult because concentrated sulfuric acid is added in a thin stream to the pyridinemethanol compound, so that the reaction control would be difficult, and that a large amount of an aqueous ammonia is required in order to make the reaction mixture alkaline with the aqueous ammonia. In addition, there are some defects in the process that even the impurities are extracted because the reaction product is extracted with chloroform, and that mirtazapine having a high purity cannot be obtained because crystallization is inhibited during the crystallization from an ether.
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 economically and efficiently preparing a pyridinemethanol compound.
Another object of the present invention is to provide a process capable of efficiently preparing mirtazapine from the above-mentioned pyridinemethanol compound on an industrial scale, to give mirtazapine having a high purity.
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 pyridinemethanol compound represented by the formula (II):
comprising reducing potassium pyridinecarboxylate represented by the formula (I):
with a metal hydride; and
(2) a process for preparing mirtazapine comprising adding a pyridinemethanol compound represented by the formula (II):
to sulfuric acid.


REFERENCES:
patent: 4062848 (1977-12-01), van der Burg
patent: 5196532 (1993-03-01), Wuest et al.
patent: 6339156 (2002-01-01), Dolitzky
patent: 1543171 (1979-03-01), None
patent: 00/62782 (2000-10-01), None
The chemist's Companion by Arnold Gordon and Richard Ford, pp. 442-443 (1972).*
F. M. Kaspersen et al.,Journal of Labelled Compounds and Radiopharmaceuticals, vol. 27, No. 9, pp. 1055-1068 (1989).

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