"Process for the preparation of l-bromo-3-trifluoromethoxybenzene"

FIELD OF THE INVENTION

The present invention concerns a process for the preparation of l-bromo-3- trifluoromethoxybenzene starting from 2- and/or 4-trifluoromethoxyaniline via a synthesis that provides excellent yields and surprising selectivity. The invention also concerns a new synthesis intermediate.

TECHNICAL BACKGROUND

The compound l-bromo-3 -trifluoromethoxybenzene has been known for some time in the state of the art; its preparation still presents numerous difficulties, however.

Direct bromination of trifluoromethoxybenzene does not produce the required compound, as the trifluoromethoxy group directs the nucleophilic substitution on the benzene ring in the ortho and para positions rather than in the required meta position. hi cases of this type it is normal to assess the possibility of performing the nucleophilic substitution reaction starting from derivatives with an "auxiliary substitute" which activates the non-reactive position and is then eliminated to provide the required product.

For example, on benzene rings, aminic type auxiliary substitutes are normally used, the introduction of which directs the nucleophilic substitution in the ortho/para positions; however, said auxiliary substitutes have the drawback of excessively activating the substrate vis-a-vis the nucleophilic reaction and therefore the nucleophilic substitution takes place in several positions, consequently obtaining substituted derivatives also in undesired positions.

In other words, when an aminic type auxiliary substitute is introduced on a benzene ring in order to direct a nucleophilic substitution in the ortho or para positions, a poly-substitution is obtained, since the product of the first nucleophilic substitution is generally more reactive and competes with the starting product in the substitution reaction.

To remedy this drawback a less "activating" auxiliary substitute is often chosen in order to reduce the risk of nucleophilic poly-substitution, obviously to the detriment of the yield of the reaction. By way of example, when wishing to use a primary

aminic group (-NH ₂ ) as an auxiliary substitute, to avoid excessive activation said aminic group can be transformed into an amidic group, for example an acetylamine, with the drawback of adding further reaction stages to the synthesis process with consequent loss of overall reaction yield. SUMMARY OF THE INVENTION

The object of the present invention is to provide a selective synthesis of the compound l-bromo-3-trifluoromethoxybenzene by means of a bromination reaction that provides excellent yields and does not produce undesired polybrominated byproducts. It has now surprisingly been found out that by performing a bromination reaction on the 2- or 4-trifluoromethoxyaniline or on a mixture of these and a subsequent deaminating reaction, the compound l-bromo-3-trifluoromethoxybenzene can be selectively obtained, with excellent yields and without the need to deactivate the aminic group. SETAILED DESCRIPTION OF THE INVENTION

Thus, according to one of its embodiments, the invention concerns a process for preparation of the compound l-bromo-3-trifluoromethoxybenzene of formula (I)

which comprises

(a) reacting a compound of formula (II) chosen from 2- trifiuoromethoxyaniline, 4-trifluoromethoxyaniline and a mixture of them

wherein one of R ₁ and R ₂ represents the hydrogen and the other a -NH ₂ group in the presence of a weak acid, with a brominating agent that releases Br+ ions in an acid medium, providing the intermediate of formula (III)

wherein R ₁ and R ₂ are as defined above and one of R ₃ and R ₄ represents the hydrogen and the other a bromine atom; and

(b) deaminating of the compound of formula (III) to give the desired compound of formula (I) .

The bromination reaction (a) is performed by means of a brominating agent which releases the electrophile Br+ in an acid medium. It has been ascertained, in fact, that if reagents are used which release H+ or HBr ions (like bromine for example) during the bromination reaction, selectivity and yield are much lower. N-bromosuccinimide (NBS) and l,3-dibromo-5,5-dimethylhydantoin (DBI) or their mixtures can be used, for example, as a brominating agent that releases the electrophile Br+ in an acid medium, the NBS being a preferred bromination agent. The bromination reaction (a) occurs, as said, in an acid medium, in particular in the presence of a weak acid. "Weak acid" means, according to the present invention, an acid having a pKa higher than 4, advantageously a pKa higher than 4.5, for example between 4.5 and 5.5. A weak acid that can be advantageously used in the process of the invention is, for

example, acetic acid- Solvents such as alkanes, chloroalkanes or aromatic solvents deactivated vis-a-vis electrophilic reactions, for example methylene chloride, chloroform, heptane, nitrobenzene, benzotrifluoride, etc. may, but not necessarily, be used in the bromination reaction (a).

However, the weak acid used in the reaction, for example the acetic acid, can also act as a solvent and therefore it is not necessary to add further solvents. The reaction temperature is between -5 ⁰ C and room temperature, advantageously around 0 ⁰ C. The reaction is exothermic and it is therefore advisable to provide an external cooling system.

The molar ratio between starting product/solvent is preferably approximately 1/6, corresponding in the case of acetic acid to a weight ratio of approximately Vz. According to an embodiment of the present invention, the brominating agent is advantageously used in excess, for example at least in a molar excess of 5-10% with respect to the starting product.

Said brominating agent, advantageously NBS, can nevertheless be used in all ratios. In fact, it is also possible to use the brominating agent by defect, thus minimising the production of poly-substituted by-products, for example when it is possible to easily recycle the starting product of formula (II) (non-brominated) in subsequent batches. Although this embodiment of the invention entails greater handling of the starting product, it can produce a higher overall yield and can constitute an advantageous alternative if suitable industrial plants are available.

The phase (a) of bromination by means of a brominating agent, advantageously NBS, as described above, provides high yields and excellent selectivity in terms of mono- substitution.

By way of comparison, bromination reactions were performed on the same substrate with other brominating agents, for example with bromine in an aqueous solvent or in acetic acid; said reactions did not provide satisfactory results in terms of bromination selectivity in the desired position and mono-bromination. Bromination reactions with NBS or DBI in a highly acid medium were also tested but here again results were not satisfactory in terms of selectivity and, consequently,

final yield.

Comparative examples that reproduce said reactions are provided in the experimental section of the present description.

The results obtained with NBS or DBI in a weak acid medium therefore appear surprising and unexpected.

The bromination product of formula (III), whether it is 4-bromo-2- trifluoromethoxyaniline, 2-bromo-6-trifluoromethoxyaniline or 2-bromo-4- trifluoromethoxyaniline, having the formulas (Ilia), (HIb) and (IIIc) respectively

(Ilia) (IHb) (IHc) can be isolated by evaporation of the solvent, optional neutralisation and distillation.

When starting from 2-trifluoromethoxyaniline, a bromination product is obtained which consists of a mixture of compounds of formula (EIa) and (IDb). When starting from 4-trifluoromethoxyaniline, only the compound (IIIc) is obtained. It is obvious that when using a mixture of 2-trifluoromethoxyaniline and A- trifluoromethoxyaniline as the starting product (II), a mixture of all three compounds of formula (III) will be obtained.

The 2-bromo-5-trifluoromethoxyaniline (HIb) is a new compound and constitutes a further subject of the present invention. hi any case, the compound of formula (III), whether (Ilia), (HIb), (IIIc) or a mixture thereof, univocally provides the compound of formula (I) when it undergoes the deaminating reaction (b).

The deaminating reaction (b) can be performed according to any known method.

According to a preferred embodiment, the deaminating is performed by diazotation and subsequent de-diazotation, by reaction of the intermediate (III) with an inorganic or organic nitrite in the presence of an acid and a reducing agent, if necessary in the presence of a solvent.

If an inorganic nitrite is used, water can be used as the solvent and a further reagent as reducing agent, advantageously a reagent that is soluble in water, for example hypophosphorous acid, an alcohol, such as 2-propanol, or DMF. An inorganic nitrite that can be used advantageously is sodium nitrite which is generally used in excess, for example a molar excess of 30% with respect to the compound (III).

A reducing agent that can be used advantageously is 2-propanol which is generally used in excess, for example 10 molar times with respect to the compound (III). When, on the other hand, an organic nitrite is employed, an alcoholic solvent or a hydro-alcoholic solution can be used, which acts at the same time as solvent and reducing agent (cf. Tetrahedron Letters (42) (2001) 5367-5369). Although both types of nitrites described above can be used according to the invention, it is economically preferable to use an inorganic nitrite, such as sodium nitrite, due to the higher costs of organic nitrites which also have greater recovery and ecological problems.

An advantageous acid for the diazotation reaction and subsequent de-diazotation is sulphuric acid, preferably concentrated sulphuric acid. Said acid is advantageously used in a molar ratio of approximately 1/1 with respect to the compound of formula (III).

The reaction temperature of phase (b) is around 30-60 ⁰ C, advantageously around 35-

45 ⁰ C.

The reaction is generally complete in a few hours; the progress of the reaction can be followed by a person skilled in the art using the conventional techniques. The end product of formula (I) is isolated according to the known method, for example by dilution of the reaction mixture with water, separation of the phases, further washing with water and isolation of the end product.

The compound of formula (I) thus isolated can be further purified by distillation, thus obtaining a product with a final titer above 99.5%, even 99.9%. Examples of processes according to the invention and comparative reactions are provided in the experimental section of the present description.

The compound of formula (I) is a versatile intermediate, very useful in the preparation of agro-pharmaceutical active ingredients and susceptible to be used in further chemical transformations. The experimental section that follows illustrates the invention without limiting it in any way.

EXPERIMENTAL SECTION

EXAMPLE l

Preparation of l-bromo-3-trifluoromethoxybenzene (formula (D)

Ia. Preparation of4-bromo-2-trifluoromethoxyaniline (formula (HIa)) 3462 g of acetic acid and 1700 g of 2-trifluoromethoxyaniline are placed at room temperature in a 10 1 lined glass reactor with 4 necks, outlet on bottom, thermostat with brine cryostat, provided with mechanical agitation, bubble condenser and thermometer; the mixture is subsequently cooled to 0-5°C and 1894.26 g of NBS are added, maintaining the temperature at 0-5 ⁰ C. At the end of the reaction the mixture is brought back to room temperature and the acetic acid is eliminated by distillation. The residue is washed with water, the phases are separated, the organic phase is neutralised with NaHCCβ and the phases are separated again, the inorganic phase is washed with water and the product indicated in the title is isolated. B.p. 115°C/30 mmHg Ib. Preparation of 1 -bromo-3-trifluoromethoxybenzene

2579.53 g of 2-propanol and 1100 g of the product from stage Ia are placed in a 10 litre lined glass reactor with 4 necks and outlet on bottom, and a previously prepared solution of 382.52 g of NaNO2 in 766.18 g of water is added. 459.6 g of concentrated sulphuric acid are then metered slowly. The acids are diluted and the upper organic phase is separated from the lower aqueous phase. The organic phase is washed and a first organic phase and an upper aqueous phase are separated. The latter is further diluted with water until a second organic phase is released. This organic phase is added to the first and everything is washed again, separating an aqueous phase and an organic phase which, after being anhydrified with CaCl ₂ , undergoes distillation to provide the product indicated in the title (final yield 84%). B.p. 156-158°C/760 mmHg

EXAMPLE 2 Preparation of l-bromo-3-trifluoromethoxybenzene ( ^" formula (T))

Ia. Preparation of 4-bromo-2-trifluoromethoxyaniline (formula (Ilia) and 2- bromo-5-trifluoromethoxyaniline (formula (UIb))

Operating as described in example Ia, but performing the reaction at room temperature instead of at 0-5 ⁰ C, a mixture of the compounds indicated in the title is obtained in a 4-bromo-2-trifluoromethoxyaniline (formula (IIIa)/2-bromo-6- trifluoromethoxyaniline (formula (HIb)) ratio of approximately 93/7.

The 2-bromo-6-trifluoromethoxyaniline (formula (IUb)) was identified by GC-MS analysis, using an RTX- 5MS column of 30 metres x 0.25 mm, film 0.25 μm, 5% phenyl - 95% methyl-polysiloxane, programmed temperature 50°C x 2 min, 5°C/min up to 24O ⁰ C for 10'. The peak has rt= 13.45 min, relative MS: m/z=255(M ^+o );

257(M2 ^+O ), 237(M ⁺ ), 215(M ⁺ ), 155(M ⁺ ), 158(M ⁺ ).

Ib. Preparation of l-bromo-3-trifluoromethoxybenzene

Operating as described in example Ib but using the mixture of the two compounds obtained from stage 2a instead of the compound of stage Ia, the compound indicated in the title is obtained.

EXAMPLE 3 (COMPARATIVE)

Preparation of l-bromo-3-trifluoromethoxybenzene with DBI in concentrated sulphuric acid

30.1 g of concentrated sulphuric acid (95-98%) are placed in a 100 ml reactor and 10.1 g of 2-trifluoromethoxyaniline are added, dropwise. During said operation the temperature is maintained at approximately 40 ⁰ C for approximately 30 minutes.

Once a uniform solution has been obtained, it is cooled to 0-5 ⁰ C using a cryostat and the portions of DBI are metered. During addition of the brominating agent, which takes approximately 1 hour, the mixture gradually turns brown. After completion of the reaction (30 minutes) a gas chromatograph analysis is performed: 13.6% of 2-trifluoromethoxyaniline reagent

34.0% of mono-bromo-derivative as per the title

>40% of di-bromo- and tri-bromo-derivatives EXAMPLE 4 (COMPARATIVE)

Preparation of l-bromo-3-trifluoromethoxybenzene with NBS in concentrated sulphuric acid

30.3 g of concentrated sulphuric acid (95-98%) are placed in a 100 ml reactor and 10 g of 2-trifluoromethoxyaniline are added, dropwise, as in the previous example at approximately 40-45 ⁰ C. Once a uniform solution has been obtained, it is cooled to 0- 5°C with cryostat. 10.1 g of NBS are metered in portions over a period of 1 hour, then left to complete for a further 30 minutes. The mixture gradually turns yellow and then brown. A gas chromatograph analysis is performed at the end of the reaction:

15.3% of 2-trifluoromethoxyaniline

66.6% of mono-bromo-derivative as per the title 11.1 % of di-bromo and tri-bromo-derivatives

EXAMPLE 5 (COMPARATIVE)

Preparation of l-bromo-3-trifluoromethoxybenzene with Br? in acetic acid 60 g of acetic acid are placed in a 100 cc flask, then slowly 30 g of 4- trifluoromethoxyaniline are added; the mixture is brought to 0-5°C and 27 g of elementary bromine are metered, slowly. A gas chromatograph analysis is performed at the end of the reaction:

20% of 4-trifluoromethoxyaniline

37% of mono-bromo-derivative as per the title

>41 % of di-bromo-derivative EXAMPLE 6 (COMPARATIVE)

Preparation of l-bromo-3-trifluoromethoxybenzene with Br? in water 17.7 g of 4-trifluoromethoxyaniline and 53 g of water at room temperature are placed in a 100 cc flask, the mixture is brought to 35°C and 32 g of elementary bromine are metered slowly over a period of 2 hours. After 0.8 equivalents, a gas chromatograph analysis is performed:

10% of 4-trifluoromethoxyaniline

% of mono-bromo-derivative as per the title % of di-bromo-derivative