Organic compounds -- part of the class 532-570 series – Organic compounds – Amino nitrogen containing
Reexamination Certificate
1999-07-23
2001-11-20
Kumar, Shailendra (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Amino nitrogen containing
C564S134000, C546S290000, C546S309000
Reexamination Certificate
active
06320078
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a process for preparing a selectively-monoacylated phenylenediamine derivative as a benzamide derivative.
2. Description of the Related Art
Monoacylated phenylenediamine derivatives are very important compounds as chemicals, medicines, agricultural chemicals, animal drugs and intermediates thereof, and their precursors are also very important compounds.
A reaction between a benzoic acid derivative and an amine derivative to synthesize an amide derivative is one of most fundamental reactions in conventional organic synthesis techniques, and many technical accumulations and results are known. However, when the amine derivative has two or more amino groups, methods for selectively acylating one amino group alone are limited. For example, as in the case that one amino group is an aliphatic amino group and the other is an aromatic amino group, if two amino groups are noticeably different in reactivity, it is easy to selectively acylate the amino group alone which has a higher reactivity than the other.
On the other hand, if a large difference of the reactivity is not present between two amino groups as in the case of a phenylenediamine derivative, a monoacylation reaction and in succession a diacylation reaction occur, so that it is difficult to obtain a target compound monoacylated with a good selectivity. For example, since the phenylenediamine has generally two amino groups having similar reactivites, when an acid chloride derivative which is prevalent as an acylating agent is reacted with the phenylenediamine, a diacylated phenylenediamine derivative is produced in large quantities as a by-product under usual reaction conditions such as at room temperature, so that a purity of a monoacylated phenylenediamine derivative is low and its yield is also low.
Furthermore, several methods have also been contrived in which an activator other than the acid chloride is used as the acylating agent to heighten the selectivity, and some reports regarding the monoacylation reaction of the phenylenediamine derivative have been presented. However, such methods are accompanied with various problems, and hence they cannot be applied to the mass production of the monoacylated phenylenediamine derivatives which are useful as chemicals, medicines, agricultural chemicals, animal drugs and intermediates thereof. For example, Arnand et al. have reported on pages 553 to 554 of Synlett in 1994 that a dicarboxylic acid is activated with thiazolidine-2-thione and then reacted with a phenylenediamine derivative to selectively obtain its monoacylated product. However, this reaction has some problems, and for example, a reaction substrate is a peculiar dicarboxylic acid and the reaction must be carried out at room temperature for a long period of 4 days. In addition, Shalaby et al. have also reported on pages 9045 to 9048 of J. Org. Chem., Vol. 61 in 1996 that a carboxylic acid is activated with isobutyl chloroformate and then reacted with a 1,2-phenylenediamine derivative at −20° C., but the phenylenediamine derivative is limited to 4-nitro-1,2-phenylenediamine having a special reactivity. Similarly, Goeker et al. have reported a reaction with methyl 3,4-diaminobenzoate on pages 1767 to 1773 of J. Heterocyclic Chem., Vol. 32 in 1995, and Edmundson et al. have reported a reaction with 2,6-dibromo-1,4-phenylenediamine on pages 2452 to 2453 of J.C.S.(C) in 1971. These methods reported by them are limited to the reactions on substrates in which a difference of the reactivity is caused between two amino groups by a substituent.
That is to say, in order to obtain the monoacylated phenylenediamine derivative with a high selectivity, there have been heretofore required special conditions such as the employment of such a limited structure so as to create a difference of the reactivity between two amino groups; the use of a large amount of the phenylenediamine derivative; or the execution of a reaction at an extremely low temperature; i.e., no general-purpose reaction suitable for the mass production is known. Accordingly, as described in Japanese Patent Laid-Open (Kokai) No. 152462/1998 and the like, it has heretofore been general that one amino group of the phenylenediamine derivative is protected, and an unprotected amino group alone is acylated, followed by removing the protective group, i.e., deprotection, to synthesize the monoacylated phenylenediamine derivative. In this synthesis technique, however, there are required the two steps of the protection and the deprotection which are not inherently necessary for the manufacture of the monoacylated phenylenediamine derivative as a useful skeleton, and for a higher efficiency of the manufacture, it has been very important to omit these additional steps.
SUMMARY OF THE INVENTION
An object of the present invention is to obtain, with a high selectivity, a monoacylated phenylenediamine derivative which is a skeleton useful as any of medicines, agricultural chemicals, animal drugs, chemicals and intermediates thereof by reacting an unprotected phenylenediamine derivative with a benzoic acid derivative without requiring a process including the steps for protection and deprotection in the manufacture of the monoacylated phenylenediamine derivative.
The present inventors have intensively investigated with the intention of achieving the above-mentioned object, and as a result, it has been found that when a benzoic acid derivative is converted into a benzoylimidazole derivative and is then reacted with a phenylenediamine derivative, the reaction can proceed promptly with a high selectivity under moderate conditions. Furthermore, it has also been found that in the case of the reaction with the less reactive phenylenediamine derivative, an acid can be added to the reaction system, whereby the reaction proceeds promptly under the moderate conditions to obtain the desired monoacylated phenylenediamine derivative with a high selectivity. On the basis of these findings, the present invention has been completed.
That is to say, the first aspect of a process for preparing a selectively monoacylated phenylenediamine derivative according to the present invention comprises the steps of converting, into a benzoylimidazole derivative, a benzoic acid derivative represented by the formula (1):
wherein R
1
and R
2
are each independently a hydrogen atom, or a substituent selected form the group consisting of halogen atom, an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, an acyl group having 1 to 4 carbon atoms, an acylamino group having 1 to 4 carbon atoms, an alkylthio group having 1 to 4 carbon atoms, a perfluoroalkyl group having 1 to 4 carbon atoms, a perfluoroalkyloxy group having 1 to 4 carbon atoms and an alkoxycarbonyl group having 1 to 4 carbon atoms, which substituent is located at an optional position on the benzene ring; and R
3
is a hydrogen atom or a substituent which is located at the other optional position than R
1
and R
2
on the benzene ring and is represented by the formula (2)
A—X—Q—(CH
2
)
n
— (2)
wherein A is a phenyl group or a heterocyclic ring which may be substituted by 1 to 4 groups selected from the group consisting of a halogen atom, a nitro group, a cyano group, an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, an acyl group having 1 to 4 carbon atoms, an acylamino group having 1 to 4 carbon atoms, an alkylthio group having 1 to 4 carbon atoms, a perfluoroalkyl group having 1 to 4 carbon atoms, a perfluoroalkyloxy group having 1 to 4 carbon atoms or an alkoxycarbonyl group having 1 to 4 carbon atoms, a phenyl group and a heterocyclic ring; X is a direct bond or one of structures represented by the formulae (3-1) to (3-7) in the formula group (3):
wherein e is an integer of 1 to 4; m is an integer of 0 to 4; R
4
is an alkyl group having 1 to 4 carbon atoms which may be substituted or an acyl group represented by the formula (4)
wherein R
6
an alkyl group having 1 to 4 carbon at
Ando Tomoyuki
Ishibashi Hiroki
Suzuki Tsuneji
Tsuchiya Katsutoshi
Burns Doane Swecker & Mathis L.L.P.
Kumar Shailendra
Mitsui Chemicals Inc.
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