Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acids and salts thereof
Reexamination Certificate
1996-09-11
2002-01-29
Gerstl, Robert (Department: 1204)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acids and salts thereof
C562S435000
Reexamination Certificate
active
06342630
ABSTRACT:
The present invention relates to a process for the purification of diphenyl ether compounds which are useful as herbicides or as intermediates in the synthesis of herbicides. In particular, it relates to a process for obtaining particular nitrated isomers of diphenyl ether compounds from mixtures containing other nitrated isomers.
Diphenyl ether herbicides are known, for example from EP-A-0022610 which relates to herbicides of the formula:
wherein X and Y may be H, F Cl, Br, CF
3
, OCF
2
CHZ
2
(Z=Cl, Br, F), OCH
3
, CN, CO
2
R (R=lower alkyl), C
6
H
5
, O-alkyl, NO
2
or SO
2
lower alkyl;
and also describes a process for making these compounds by nitrating a compound of the formula:
wherein X and Y are as defined above.
Suggested nitrating agents for this reaction include mixtures of nitric and sulphuric acids and the recommended reaction solvent is dichloromethane. The nitration process is said to give a yield of 75.4% but no details are given of the purity of the product or the presence of other nitrated isomers.
U.S. Pat. No. 4,031,131 describes similar compounds to the above which are prepared in a similar manner. Suggested nitrating agents include potassium nitrate or mixed nitric and sulphuric acids and the reaction is carried out in dichloromethane. An extremely high yield (>95%) is claimed for the nitration reaction but, again, there are no details given about the purity of the product. Nitration reactions using mixed nitric and sulphuric acids may also be carried out in the presence of acetic anhydride.
EP-A-0003416 and EP-A-0274194 both relate to the synthesis of herbicidal compounds of the formula:
wherein
R
1
is alkyl optionally substituted with fluorine or optionally substituted phenyl;
R
3
is H, F, Cl, Br, I alkyl, trifluoromethyl or CN;
R
4
is H, F, Cl, Br, I or trifluoromethyl;
R
5
is F, Cl, Br, I or trifluoromethyl; and
R
6
is H or C
1
-C
4
alkyl.
In EP-A-0003416, these compounds may be obtained by nitrating the corresponding carboxylic acid or carboxamide and then converting to the sulphonamide or by nitrating the sulphonamide itself. A nitration reaction is described in Example 7 where the solvent is 1,2-dichloroethane and the nitrating agent is a mixture of potassium nitrate and concentrated sulphuric acid.
EP-A-0274194 relates, in particular, to a process for the nitration of compounds of the formula:
The nitration reaction is said to be carried out using a conventional nitrating agent such as concentrated nitric acid or sodium nitrate or mixtures of these with sulphuric acid. The reaction solvent is one which is resistant to nitration and examples of such solvents are said to include halogenated solvents such as dichloromethane, dichloroethane, dichloropropane, chlorofluorocarbons and aromatic solvents such as nitrobenzene.
However, none of these methods are particularly satisfactory for use on an industrial scale because they all have the common problem that the reaction yields a mixture of the required product and other nitrated isomers. Nitrated isomers of diphenyl ether compounds are often extremely difficult to separate from one another and the quantity of other isomers is often too high for the final product to fulfil the requirements of the regulatory authorities for herbicides. The problem tends to be further exacerbated if the nitrated product is an intermediate in the synthesis of a herbicide rather than the required herbicide itself because the mixture of nitrated compounds means that larger quantities of other reagents must be used than would be necessary if the nitrated isomers could be separated satisfactorily. It is therefore important to ensure that the nitration process produces a product mixture containing the highest possible proportion of the desired isomer.
The problem of obtaining mixtures of isomers from the nitration process was recognised by the authors of GB-A-2103214 who describe a process in which a compound of the formula:
wherein each of
X
1
, X
2
, and X
3
, is H, fluorine, chlorine, bromine, CF
3
, O CF
2
,CHZ
2
(where Z is F, Cl or Br), OCF
3
, CN, COOR (R is lower alkyl), phenyl, lower alkoxy or NO
2
R and at least one of X
1
, X
2
, and X
3
is other than hydrogen; and
Y is COOR or carboxy;
is nitrated to give a product of the formula:
wherein X
1
, X
2
, X
3
and Y are as defined above. The document relates especially to Acifluorfen, the compound in which X
1
is 2-chloro, X
2
is 4-trifluoromethyl, X
3
is hydrogen and Y is COOH.
According to this prior art document, the product is purified by selectively dissolving unwanted isomers and other by-products in a suitable solvent. Examples of solvents which are said to be suitable for this purpose include hydrocarbons such as pentane, hexane, heptane, cyclopentane, cyclohexane, cycloheptane, benzene, toluene, xylenes and mixtures of xylenes, ethylbenzene, cumene, pseudo-cumene, ethyl-toluene and trimethylbenzene. Alternatively, it is suggested that chlorohydrocarbons may be used and examples given are 1,2-dichloroethane, methylene chloride, chloroform and chlorobenzene. Xylenes appear to be especially preferred and suggested amounts are about 0.35 to 0.45 moles of xylenes per mole of crude Acifluorfen. The crude nitration product is dissolved in the chosen solvent at elevated temperature and maintained at this temperature for a considerable period of time. On cooling, Acifluorfen crystallises out and is collected by centrifugation. The product obtained by the authors of GB-A-2103214 is said to be 82% pure.
However, the present inventors have found that the process described in GB-A-2103214, although partially effective, does not appear to give material of this degree of purity. In any case, it is desirable to be able to obtain material of an even greater degree of purity than specified in the prior art, particularly if additional process steps are required in order to obtain the required herbicidal compound.
Therefore in a first aspect of the present invention there is provided a process for the purification of a compound of general formula I:
wherein:
R
1
is hydrogen or C
1
-C
6
alkyl, C
2
-C
6
alkenyl or C
2
-C
6
alkynyl (any of which may potionally be substituted with one or more substituents selected from halogen and OH) or COOH, COH, COOR
4
, COR
6
, CONR
4
R
5
or CONHSO
2
R
4
;
R
4
and R
5
are each independently hydrogen or C
1
-C
4
alkyl optionally substituted with one or more halogen atoms;
R
6
is a halogen atom or a group R
4
;
R
2
is hydrogen or halo;
R
3
is C
1
-C
4
alkyl, C
2
-C
4
alkenyl or C
2
-C
4
alkynyl, any of which may optionally be substituted with one or more halogen atoms, or halo;
or, where appropriate, a salt thereof;
from a mixture containing the compound of general formula I together with one or more isomers or di-nitrated analogues thereof;
the process comprising dissolving the mixture in a suitable crystallising solvent and recrystallising the product from the resulting crystallisation solution;
characterised in that the crystallisation solution contains not more than 25% loading of the compound of general formula I and in that the temperature to which the solution is cooled for crystallisation is not greater than about 30° C.
In the present specification, loading is defined as:
weight
of
pure
compound
of
formula
I
×
100
weight
of
pure
compound
of
formula
I
+
weight
of
solvent
In order to calculate the loading of the crystallisation solution, it is therefore essential to know the amount of isomer of general formula I present in the product mixture.
Using the process of the present invention, it is possible to obtain a product of greater than 90% purity. This is a significant advantage when the product is a herbicide as regulatory authorities usually demand an active ingredient of a very high level of purity with minimal impurities. The advantage may be even
Brown Stephen Martin
Gott Brian David
Gray Thomas
Tavana Seyed Mehdi
Gerstl Robert
Zeneca Limited
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