Organic compounds -- part of the class 532-570 series – Organic compounds – Nitriles
Reexamination Certificate
2001-06-07
2002-05-21
Higel, Floyd D. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Nitriles
Reexamination Certificate
active
06392083
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a process for producing salts of cyanobenzylamines, and to the salts of cyanobenzylamines obtained by the process. The salts of cyanobenzylamines obtained according to the present invention serve as useful intermediates in the production of pharmaceuticals and agrochemicals.
2. Description of the Related Art
Conventionally, there have been known, for example, processes for producing salts of cyanobenzylamines, employing p-cyanobenzyl bromide as a starting material, as described below.
J. Org. Chem.,
63 (1998) 19, 6715-6718 discloses a relevant process including reacting p-cyanobenzyl bromide with hexamethylenetetramine and, subsequently, reacting the reaction mixture with hydrogen chloride dissolved in ethanol.
J. Am. Chem. Soc.,
81 (1959), 4328, discloses a process for synthesizing 4-aminobutyronitrile hydrochloride including reacting hydrazine with N-(3-cyanopropyl)phthalimide synthesized from 4-bromobutyronitrile; post-treating the resultant reaction product; and reacting the post-treated product in diethyl ether with anhydrous hydrogen chloride. The reference discloses that p-cyanobenzylamine hydrochloride is synthesized through a method similar to this method.
J. Med. Chem.,
10 (1967), 833-840, discloses a process for producing p-cyanobenzylamine from &agr;-phthalimido-p-tolunitrile and hydrazine. The reference discloses synthesis of p-cyanobenzylamine hydrochloride, but does not disclose details of the method used for the synthesis.
Japanese International Application Domestic Publication No. 10-503477 discloses a process for synthesizing p-cyanobenzylamine hydrochloride including reacting hydrazine with N-(4-cyanophenyl)methylphthalimide prepared from p-cyanobenzyl bromide and potassium phthalimide; post-treating the resultant reaction product; and transforming the treated product into hydrochloride. However, the step of transforming the treated product into hydrochloride is not described in detail.
Japanese International Application Domestic Publication No. 9-509937 discloses a process for synthesizing p-cyanobenzylamine hydrochloride including reacting N-Boc-p-aminomethylbenzonitrile with hydrogen chloride gas in ethyl acetate.
In addition, identification of p-cyanobenzylamine as a hydrochloride thereof is reported in
Chem. Ber.,
34 (1901), 3368, but the identification method is not described.
Thus, these processes for producing salts of cyanobenzylamines are unsatisfactory as industrial production processes, since the processes require a number of reaction steps and attain an insufficient level of production yield.
In addition, the aforementioned references fail to disclose characteristic drawbacks arising during industrial production of cyanobenzylamine hydrochlorides. Specifically, problems in terms of product distribution, such as space required for storage and ease of transportation, and those in terms of production apparatus, such as vessels having the required capacity, are not identified, and the means for solving these problems have not been elucidated.
As far as the present inventors know, cyanobenzylamine hydrochlorides are bulky compounds, having bulk densities of 0.2 g/ml or less. The high bulkiness results in the necessity of providing an extensive area for storage in the case of industrial production and use of cyanobenzylamine hydrochlorides. Generally, suitable transportation means is chosen based on the weight of matter. However, when such bulky matter is handled, the forms of transportation means are limited because of the volume thereof. This is very disadvantageous in view of distribution costs. In addition, when a cyanobenzylamine hydrochloride is handled in a production apparatus, scaling-up the apparatus is needed, due to the low bulk density of the compound, increasing apparatus costs as well as causing inconvenience during operation.
BRIEF SUMMARY OF THE INVENTION
Thus, it is an object of the present invention to provide an industrially suitable process for producing a salt of a cyanobenzylamine at high yield and in a simple manner. It is another object to provide a less-bulky salt of a cyanobenzylamine having a lower bulk density.
The present inventors have conducted extensive studies in order to solve the aforementioned problems, and have found that a salt of a cyanobenzylamine can be produced in a simple manner by reacting a cyanobenzylamine with an acid, and that, when the acid is used in the form of an aqueous solution, the produced cyanobenzylamine salt is endowed with a remarkably high bulk density as compared with a similar compound produced through a conventional process. On the basis of these findings, the inventors have further found that, by applying a salt of a cyanobenzylamine to the industrial production of chemicals, the distribution, including storage and transportation, as well as operability in relation to a production apparatus, can be remarkably improved. The present invention has been accomplished on the basis of the above findings.
Accordingly, the present invention provides a process for producing a salt of a cyanobenzylamine comprising reacting a cyanobenzylamine with an acid.
The invention also provides a salt of a cyanobenzylamine having a bulk density of 0.4 g/ml or more.
DETAILED DESCRIPTION OF THE INVENTION
Upon the practice of the process of the invention, in general, a cyanobenzylamine may advantageously be reacted with an acid, optionally in a solvent, for a predetermined period of time while stirring, to thereby form a suspension of a salt of a cyanobenzylamine.
The cyanobenzylamines usable for the invention may preferably be compounds represented by the following formula.
wherein X
1
, X
2
, X
3
and X
4
each independently represent a hydrogen atom, an alkyl group having 1 to 3 carbon atoms or a halogen atom, and the —CH
2
NH
2
group may be at any position of ortho, metha or para to the —CN group.
Specific examples of the compounds may include unsubstituted cyanobenzylamines such as o-cyanobenzylamine, m-cyanobenzylamine and p-cyanobenzylamine, and substituted cyanobenzylamines such as 2-alkyl-4-cyanobenzylamine, 2-chloro-4-cyanobenzylamine, tetrafluorocyanobenzylamine and tetrachlorocyanobenzylamine.
Cyanobenzylamines can be produced through any of the known processes. For example, m-cyanobenzylamine and p-cyanobenzylamine can be readily synthesized through the process disclosed in Japanese Unexamined Patent Publication (kokai) No. 9-40630 by subjecting one nitrile group of isophthalonitrile and that of terephthalonitrile to reduction, respectively.
In the invention, cyanobenzylamine hydrates can also be employed as the starting material. Examples of the hydrates may include o-, m-, and p-cyanobenzylamine hydrates, with p-cyanobenzylamine hydrate being preferred.
Cyanobenzylamine hydrates can be produced through any of the known processes. For example, m-cyanobenzylamine hydrate and p-cyanobenzylamine hydrate can be readily synthesized through the process disclosed in Japanese Examined Patent Publication (kokoku) No. 40-10133, from m-cyanobenzylamine and p-cyanobenzylamine, respectively.
No solvent may be required in the reaction employed in the process of the invention. However, a solvent may be used so as to dilute the salt of a cyanobenzylamine to facilitate handling of the salt in the form of a suspension. Examples of preferred organic solvents may include toluene, ethyl acetate, and methylene chloride, which do not react with cyanobenzylamines or salts thereof and do not cause side reactions when the reaction system contains an acid. Such an organic solvent is used in an amount such that a salt of a cyanobenzylamine can be handled in the form of a suspension. Typically, the solvent may be used in an amount 0.1-10 times the mass of the employed cyanobenzylamine.
A preferred solvent to be employed in the process of the invention may be water. When water is used as a solvent, a salt, especially hydrochloride, of cyanobenzylamine having a bulk density of 0.4 g/ml or more can be obtained. Such a high-bulk-density
Murakami Masatoshi
Yamagami Isao
Yasuda Hiroshi
Yoshida Toru
Higel Floyd D.
Shameem Golam M. M.
Showa Denko K.K.
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