Preparation of trifluorobenzoic acids

Details Preparation of trifluorobenzoic acids Preparation of trifluorobenzoic acids

1999-11-03

2002-03-26

Killos, Paul J. (Department: 1623)

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

Organic compounds

Carboxylic acids and salts thereof

C562S480000, C558S411000

Reexamination Certificate

active

06362365

ABSTRACT:

CROSS-REFERENCE TO RELATED APPLICATION
The present invention is described in the German priority application No. DE 19850788, filed Nov. 4, 1998, which is hereby incorporated by reference as is fully disclosed herein.
BACKGROUND OF THE INVENTION
The present invention relates to the preparation of trifluorobenzoic acids of the formula
Such 2,4,5-trifluorobenzoic acids which are substituted in the 6-position by a radical R and which can also be referred to as 3,4,6-trifluorobenzoic acids which are substituted in the 2-position are interesting starting materials for preparing quinoline derivatives having antibacterial action. In Bioorganic & Medicinal Chemistry 3 (1995) 1699-1706, H. Miyamoto et al. describe the preparation of 5-methylquinolinecarboxylic acid derivatives which are highly active against gram-positive bacteria, starting from 3,4,6-trifluoro-2-methylbenzoic acid (=6-methyl-2,4,5-trifluorobenzoic acid). Compare also page 1699, left-hand column.
The preparation of the required 3,4,6-trifluoro-2-methylbenzoic acid (6-methyl-2,4,5-trifluorobenzoic acid) is illustrated in simplified form by the reaction scheme below. Compare also p. 1700, preparation of compounds 1 to 4.
The preparation, which is characterized by a large number of individual steps and starts with 2,4,5-trifluoroaniline, is described on page 1703, left-hand column, in the examples relating to the preparation of 3,4,6-trifluoro-2-methylaniline, 3,4,6-trifluoro-2-methylbenzonitrile and 3,4,6-trifluoro-2-methylbenzoic acid (6-methyl-2,4,5-trifluorobenzoic acid).
This preparation has the disadvantages that, on the one hand, it requires a relatively large number of individual steps, inter alia, the use of dimethylsulfide in the preparation of 3,4,6-trifluoro-2-methylaniline, which is not without problems, and, on the other hand, that the 2,4,5-trifluoroaniline, which is used as starting material, is not easily obtainable and can only be obtained via a multi-step synthesis.
It is furthermore disadvantageous that the yield of 3,4,6-trifluoro-2-methylaniline is only 40%, that of 3,4,6-trifluoro-2-methylbenzonitrile is only 38% and that of 3,4,6-trifluoro-2-methylbenzoic acid (6-methyl-2,4,5-trifluorobenzoic acid) is 79%. This corresponds to an overall yield of only 12%, based on 2,4,5-trifluoroaniline. This very low overall yield is no incentive to realize this route of preparation industrially.
Another 4-step preparation which starts with 1-bromo-2,4,5-trifluorobenzene and which is represented in a simplified manner by the reaction scheme below, is described in J. Heterocycl. Chem. 27 (1990)1609-1616.
This preparation route is very expensive. The first and the second synthesis step each involve reaction with butyllithium and diisopropylamine in tetrahydrofuran at −78° C., and the third synthesis step involves reaction with butyllithium in ether, likewise at −78° C. In the first step, 1-bromo-2,4,5-trifluorobenzene is reacted first with lithium diisopropylamide and then with trimethylsilyl chloride, the resulting 1-bromo-2,4,5-trifluoro-3-(trimethylsilyl)benzene (88% yield) is once more reacted with lithium diisopropylamide and subsequently with methyl trifluoromethanesulfonate, the resulting 1-bromo-2,4,5-trifluoro-6-methyl-3-(trimethylsilyl)benzene (75% yield) is reacted with butyllithium and subsequently with CO
2
in the form of dry ice, and the resulting 2,4,5-trifluoro-6-methyl-3-(trimethylsilyl)- benzoic acid (62% yield) is reacted with cesium fluoride in acetonitrile to give 6-methyl-2,4,5-trifluorobenzoic acid (89% yield).
This synthesis route comprises many individual steps, makes use of some very expensive materials (for example methyl trifluoromethanesulfonate, cesium fluoride) and affords the end product in an overall yield of only 36.4%, based on 1-bromo-2,4,5-trifluorobenzene. Compare also the examples in J. Heterocycl. Chem. 27 (1990) page 1612, right-hand column, bottom, and page 1614, left-hand column.
SUMMARY OF THE INVENTION
With a view to the disadvantages described above, it is an object of the present invention to provide a process which avoids these disadvantages, which uses easily obtainable starting materials, which can be realized at reasonable expense and which affords the desired end product in an acceptable yield.
This object is achieved by a process for preparing trifluorobenzoic acids of the formula
in which R is a straight-chain or branched alkyl radical having 1 to 6 C atoms, an unsubstituted phenyl radical, a substituted phenyl radical which contains one or two alkyl or alkoxy groups having in each case 1 to 4 C atoms, or an araliphatic radical having 7 to 12 carbon atoms.
It is characterized in that a compound of the formula
in which R
1
and R
2
are identical or different and are —CN, —COOR
3
, where R
3
is H, Li, Na, K, MgCl, MgBr, Mgl, ½Mg, ½Ca or an alkyl radical having 1 to 6 C atoms, or —CONR
4
R
5
, where R
4
and R
5
are identical or different and are an alkyl radical having 1 to 6 C atoms, is reacted with at least one organometallic compound of the formula CuR, CuLiR
2
, MgXR, ZnR
2
, LiR, AlX
2
R, AlXR
2
, AlR
3
or Al
2
Cl
3
R
3
, where R is as defined in formula (1) and X is Cl, Br or l, in the presence of an inert solvent at from −80 to +150° C., the reaction product is treated in the presence of water in the absence or presence of an acid at from 0 to 250° C. and the resulting trifluoroisophthalic acid of the formula
is decarboxylated at from 80 to 280° C.
The starting materials of formula (2) required for the process according to the invention can be prepared in a relatively simple manner and in good yields, starting from easily obtainable tetrachloroisophthalonitrile, which can easily be converted into the tetrafluoroisophthalonitrile by chlorine-fluorine exchange (reaction with KF), and, if required, by reacting the tetrafluoroisophthalonitrile by customary methods to give tetrafluoroisophthalic acid, salts of tetrafluoroisophthalic acid, tetrafluoroisophthalic esters and tetrafluoroisophthalamides.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
The process according to the invention is based on a short reaction sequence of only three steps, namely 1. On the reaction of the compound of the formula (2) with the organometallic compound, 2. On the treatment of the resulting reaction product with the acid in the presence of water and 3. On the decarboxylation of the trifluoroisophthalic acid, giving the desired end product of the formula (1), i.e. the 2,4,5-trifluorobenzoic acid which is substituted in the 6-position.
In the reaction of carbonyl groups with organometallic compounds, for example in the reaction of nitrites or carboxylic esters with Grignard reagents, imines or amines and ketones or alcohols, respectively, are usually formed. It is surprising that these reactions do not occur in the process according to the invention.
An exchange of a nitrile group for an alkyl group of a Grignard reagent, as in the reaction of tetrafluoroterephthalonitrile with methylmagnesium bromide, where 4-methyl-2,3,5,6-tetrafluorobenzonitrile is formed (J. Organometallic Chem. 302 (1986), 147-152), does not take place. This was likewise not expected and is also to be considered as surprising.
A further advantage of the process according to the invention is that, in the first step of the synthesis, the exchange of fluorine in the 6-position for the radical R takes place with high selectivity, and other isomers originating from the exchange of other fluorine radicals are only formed in relatively low amounts.
Moreover, it is surprising that, in the last step of the synthesis, the decarboxylation of the 2,4,5-trifluoroisophthalic acid which is substituted in the 6-position proceeds with very high selectivity, affording the corresponding 2,4,5-trifluorobenzoic acid which is substituted in the 6-position.
With good results, a compound of the formula (2) in which R
1
and R
2
are identical or different and are —CN or —COOR
3
, where R
3
is H, Li, Na, K, MgCl, MgBr, Mgl, ½Mg, ½Ca or an alkyl radical having 1 to 6, prefer

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