Organic compounds -- part of the class 532-570 series – Organic compounds – Amino nitrogen containing
Reexamination Certificate
1999-03-02
2001-02-20
Kumar, Shailendra (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Amino nitrogen containing
C564S412000, C564S442000
Reexamination Certificate
active
06191309
ABSTRACT:
The present invention relates to a process for preparing 2-amino- or 2-acetamidotrifluoromethylbenzene derivatives halogenated in position 5 on the benzene ring.
5-Chloro-2-aminotrifluoromethylbenzene is a synthetic intermediate which is used in particular in the manufacture of dyes, or of a fungicide, triflumizole.
Many synthetic routes have been proposed to reach this compound, usually in at least two steps starting from a simple precursor.
Thus, patent FR-A-800,343 describes the preparation of 5-chloro-2-aminotrifluoromethylbenzene from 3-chlorotrifluoromethylbenzene by nitration in a nitric acid/sulphuric acid mixture, followed by a reduction.
More recently, one-step processes have been proposed. Patent JP-A-57,018,638, dated Jul. 7, 1980 describes the trifluoromethylation of p-chloroaniline.
Chlorination of 2-aminotrifluoromethylbenzene has also been envisaged, but it is difficult to obtain the desired chlorination product with sufficient selectivity.
Patent U.S. Pat. No. 4,008,278 presents a solution for avoiding the formation of monochlorination products other than 5-chloro-2-aminotrifluoromethylbenzene. This consists in reacting 2-aminotrifluoromethylbenzene, or an N-acetyl or N-formyl derivative, with hydrochloric acid in the presence of an oxidant.
The starting reagent is converted into 5-chloro-2-aminotrifluoromethylbenzene to 64.5%, to 3,5-dichloro-2-aminotrifluoromethylbenzene to 34.2% and only traces of 3-chloro-2-aminotrifluorobenzene are detected.
However, the selectivity of the reaction under these conditions remains insufficient since the mono- and dichlorination products are obtained in a ratio of about 2:1. This imposes a final step of separation of the isomers, in which a large volume of reaction product needs to be treated in order to isolate the desired compound. The production efficiency of such processes is thus poor.
The aim of the invention is to propose operating conditions which impose high selectivity on the halogenation reaction of 2-amino- or 2-acetamidotrifluoromethylbenzene for improved production efficiency.
Other aspects of the invention relating to this objective will become apparent later.
It turns out that improved selectivity can be achieved by carrying out the halogenation under the action of a dihalogen gas in a specific solvent.
Thus, the subject of the invention is a process for preparing 2-amino- or 2-acetamidotrifluoromethylbenzene which is halogenated in position 5, comprising a step of halogenating a compound of formula (1)
in which Q represents an NH
2
group optionally in the form of an addition salt with an acid such as hydrochloric acid, or an NHCOCH
3
group, by using a compound of formula X
2
where X represents a halogen atom, in a solvent chosen from an anhydrous halogenated hydrocarbon, a mixture of water and of halogenated hydrocarbon and the compound of formula (1) itself, to give mainly a compound of formula (2) or (3)
in which formulae Q and X are as defined above.
The starting material of formula (1) can be 2-aminotrifluoromethylbenzene (Q=NH
2
), in which the amino group is optionally in the form of an addition salt with an acid which is known per se, in particular such as hydrochloric acid, or alternatively, 2-acetamidotrifluoromethylbenzene (Q=NHCOCH
3
).
These compounds have more or less identical reactivity with respect to halogenation under the conditions of the invention.
The halogenation reaction according to the present invention does not require the presence of an organic base.
The halogen atom(s) which can be grafted onto the benzene ring according to the invention comprise iodine, bromine and chlorine, with a preference for bromine and chlorine, most particularly for chlorine.
The halogenation reagent will be chosen, as a function of the desired halo derivative, from Cl
2
, Br
2
and I
2
.
It is seen that the choice of solvent makes it possible to direct the regioselectivity for the introduction of the halogen atom(s).
Thus, when the reaction is carried out in an anhydrous halogenated hydrocarbon, the product of formula (2) is mainly obtained. The isomer monochlorinated in position 3 is present at the end of the reaction only in trace amounts.
In point of fact, it has been demonstrated that this compound can be formed during the reaction but is totally converted into dihalo compound of formula (3) as the reaction proceeds. The compound of formula (3) is formed in only limited amounts, and the yields of compounds (2) and (3) are in a (2)/(3) molar ratio of at least 3:1.
In order to guarantee maximum selectivity and to avoid the presence of isomer monohalogenated in position 3, it is preferable to carry out the process until complete or virtually complete conversion. Advantageously, the halogenation reaction is carried out until the degree of conversion of the compound of formula (1) is at least 80%, preferably at least 85% and even at least 90% (the degree of conversion DC being the molar ratio of the amount of compound (1) consumed during the reaction to the initial amount of compound (1).
The yield for conversion of the compound of formula (1) into compound of formula (2) which is generally achieved is about 70% or more, advantageously at least 75% and even at least 80% (the yield for conversion CY of (1) into (2) being the molar ratio of the amount of compound (2) formed to the amount of compound (1) consumed).
As regards the appropriate halogenated hydrocarbons, these can be either aliphatic or aromatic hydrocarbons. Mention may be made in particular of dichloromethane, monochlorobenzene, dichlorobenzene or trifluoromethylbenzene.
Advantageously, the reagent X
2
is introduced gradually into the reaction solvent during the reaction, optionally portionwise, preferably continuously.
Advantageously, the amount of X
2
introduced into the reaction medium is such that the molar ratio of the amount of X
2
introduced to the amount of compound of formula (1) is from 1 to 2 approximately.
The compound of formula (1) can be introduced in a single portion into the reaction mixture at the start of the reaction, or it can be introduced gradually, in the same way as the halogenation reagent, during the reaction.
According to one variant of the invention, it is possible to carry out the halogenation reaction without solvent or, more exactly, in a solvent consisting of the compound of formula (1) itself.
Under these conditions, the compound of formula (2) is also mainly formed, with a yield for conversion of (1) into (2) of about 70% or more, in particular of at least 75%, advantageously of at least 80%.
In order for some of the compound of formula (1) to be able to act as solvent, this compound must be in relative excess relative to the halogenation reagent introduced. Advantageously, the molar ratio of the amount of X
2
introduced to the initial amount of compound of formula (1) is from about 0.1 to about 0.5.
The degree of conversion of the compound of formula (1) will be proportionately more limited the greater the excess of this compound. In contrast with the preceding variant, on account of the incomplete conversion, a mixture of isomers monohalogenated mainly in position 5 and to a minor extent in position 3 is obtained.
However, on account of the larger amount of compound (1) capable of reacting in a given volume of reactor and on account of the very high conversion yield (selectivity) in favour of the 5-halo isomer, the production efficiency of this isomer is excellent, being about 300 kg/m
3
of reaction mixture. Under these conditions, the separation of the isomers by distillation does not place an excessive burden on the production cost and the overall production efficiency is thus satisfactory.
According to a third variant, the selectivity can be totally reversed in favour of the dihalo compound of formula (3) by choosing a solvent consisting of a mixture of water and a halogenated hydrocarbon, such as those described above, and by introducing the compound of formula (1), along with the reagent X
2
, gradually, advantageously continuously, into the reaction solvent.
Preferably, the sol
Burns Doane Swecker & Mathis L.L.P.
Kumar Shailendra
Rhodia Chimie
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