WO2003033458A1

WO2003033458A1 - Process for the preparation of halo-benzonitriles

Info

Publication number: WO2003033458A1
Application number: PCT/IB2002/004131
Authority: WO
Inventors: Maurizio Bertola; Roberto Rossato
Original assignee: Miteni S.P.A.
Priority date: 2001-10-16
Filing date: 2002-10-11
Publication date: 2003-04-24
Also published as: ITMI20012131A1; ITMI20012131A0

Abstract

The invention relates to the preparation of a benzonitrile, comprising reacting a halo-aldehyde with hydroxylamine in a solvent selected from acetic acid and propionic acid, adding the anhydride corresponding to the acid used as solvent and removing of the solvent by distillation to obtain the product of formula (I).

Description

"Process for the preparation of halo-benzonitriles" FILED OF THE INVENTION

The present invention concerns a process for the preparation of benzonitriles, in particular for the preparation of benzonitriles substituted with a halogen, hereinafter halo-benzonitriles. BACKGROUND OF THE INVENTION

Many benzonitriles and more in general many aromatic nitriles are products well known in the art, widely used in industry generally as intermediates in the paint field and in the pharmaceutical and phyto-pharmaceutical fields. Various processes for the preparation of benzonitriles are known, for example the reaction to substitution of a halogen with metallic cyanides, Sandemeyer's aniline reaction, the dehydration of benzoic amides, of aldoximes etc. In addition, G.A. Olah et al. (Synthesis, 1979, 2:112-113) described the preparation of aromatic nitriles starting from the corresponding aldehyde by means of a solution of formic acid at the reflux temperature in the presence of hydroxylamine followed by dilution of the acid and subsequent extraction of the required product with an organic solvent. However, the latter process is difficult to implement at industrial level, making the entire production process non-competitive.

In an attempt to make the process described by G.A. Olah at al. industrially feasible, the inventors repeated the process described above, trying to isolate the finished product by means of distillation; the tests performed gave however very low yields as the presence of the water that had formed during the reaction between the hydroxylamine and the aldehyde led to the hydrolysis of the nitrile group to amides and carboxylic acid respectively. SUMMARY OF THE INVENTION

The aim of the present invention is to provide a synthesis of benzonitriles that can be easily produced on an industrial scale and which is industrially expedient, in particular to provide benzonitriles with a high purity level, at the same time permitting recycling of the solvents used, consequently reducing waste and costs. Furthermore, the possibility of recycling the solvents used in the process also makes it possible to reduce the problem of environmental impact, a particularly critical factor for the chemical industry.

DETAILED DESCRIPTION OF THE INVENTION

The first object of the present invention is therefore a process for the preparation of a halo-benzonitrile of formula (I)

wherein Hal represents a halogen, which comprises: a) reacting a halo-benzaldehyde of formula (II)

wherein Hal is as previously defined, with hydroxylamine in a solvent selected from acetic acid and propionic acid; a') optionally reducing the solution by distillation; b) adding the anhydride corresponding to the acid used as solvent; c) removing the solvent by distillation to obtain the product of formula (I). According to the present invention, Hal corresponds to a halogen substituent selected from bromine, chlorine, iodine and fluorine.

According to a preferred embodiment of the invention, Hal represents a fluorine substituent. According to another preferred embodiment, Hal is a halogen in position 4, advantageously the substituent 4-fluorine.

At the end of the reaction process (a) it is preferable to concentrate the solution by means of a first distillation [step (a')] which permits the removal of part of the acidic solvent and the water that has formed. This operation provides for higher final product yields and is therefore particularly advantageous.

According to a preferred embodiment of the present invention, the hydroxylamine is added in the form of one of its salts, more preferably in the form of sulphate, hydrochloride, phosphate or acetate salt, hydroxylamine hydrochloride being particularly advantageous.

The quantity of hydroxylamine used is preferably in excess with respect to the aldehyde of formula (II), advantageously in excess by at least 20%. The conversion reaction from 4-fluoro-benzaldehyde to 4-fluoro-benzonitrile occurs optimally at a temperature that varies in the range of 100-115°C. As can be easily understood, when acetic acid is used as the solvent in phase a) of the process of the invention, acetic anhydride will be used in phase b); altematively, propionic anyhdride will be used if propionic acid is used as the solvent. Addition of the anhydride corresponding to the acid used as solvent constitutes the characterising and essential aspect of the process of the invention for the following two reasons:

1 ) the anhydride subtracts from the environment the water that forms during the reaction between the aldehyde and the hydroxylamine forming the corresponding acid which is subsequently removed by distillation together with the share of the same acid initially added as solvent; and

2) the anhydride furthermore catalyses the conversion of the oxime to nitrile via the formation of intermediates such as acetyl-derivatives of the oxime which, when heated, decompose to nitrile.

This original solution therefore permits practical elimination of the water from the reaction mixture in order to prevent hydrolysis of the halo-benzonitrile and to accelerate the conversion reaction of the aldehyde to benzonitrile. The solvent removed by distillation can be further re-used in subsequent work cycles, thus permitting reductions in waste and consequently in costs. The process of the invention provides a halo-benzonitrile of formula (I) having a purity suitable for use as an intermediate for pharmaceutical active ingredients and with excellent yields.

Generally, in fact, the process of the invention permits the preparation of the halo-benzonitriles of formula (I) with yields higher than 85%, normally around 88%, and with purity higher than 99%. For execution of the process of the invention, in step a), a mixture containing the hydroxylamine and the acid selected as solvent can, for example, be heated in a suitable reactor, followed by the addition of the aldehyde of formula (II). To complete the reaction, the anhydride corresponding to the selected acid is added and the solvent is removed by distillation, according to known techniques. Preferably, the acid used as solvent is added in excess with respect to the aldehyde, advantageously the weight ratio between the aldehyde (II) and the acid is between 1/2 and 1/8, for example between 1/3 and 1/6, while the anhydride is added in a quantity that is sufficient to dry the reaction mixture, bearing in mind that part of the water can have been previously removed together with the acid by means of the first distillation as per step (a').

Some reaction examples are given in the experimental part of this description for illustrative purposes.

The aldehyde of formula (II) is a known commercial product.

Alternatively said aldehyde can be derived from the hydrolysis of a halo- benzal-halide of formula (111)

(HI) wherein Hal is as previously defined and X is selected from bromine and chlorine, by reaction in a mixture of water and a solvent selected from acetic acid and propionic acid. The product of formula (III) is inexpensive and easily accessible on a large scale.

The aldehyde of formula (II) obtained from hydrolysis of the product (III) can be subsequently used without further purification or isolation for the process of the invention, optionally still in solution in the acetic or propionic acid. The hydrolysis reaction of the 4-fluorobenzalchloride to 4-fluorobenzaldehyde occurs preferably at temperatures between 90 and 110°C. Thus, according to a further embodiment, the invention relates to a process for the preparation of a halo-benzonitrile of formula (I) which comprises in sequence hydrolysis of a halo-benzalhalide of formula (III) in a mixture of water and an acid which can be acetic acid or propionic acid and the reaction of the aldehyde of formula (II) thus obtained according to steps a) to c) as above.

If required, the reaction can be of the one-pot type in order to make its production industrially more convenient. For the purpose of facilitating elimination of the solvent by distillation, it is obviously expedient to use the same solvent in the two reactions, i.e. in the hydrolysis of the halo-benzal-halide and in the conversion from halo- aldehyde to halo-benzene-nitrile. The following examples illustrate the invention without limiting it in any way. The comparative example shows how the yields drop significantly, when the process of G.A. Olah et al. is reproduced, but isolating the product by distillation instead of by extraction, thus demonstrating that said process is not suitable for industrial production. EXAMPLE 1 PREPARATION OF 4-FLUOROBENZALDEHYDE

1031 g of acetic acid and 115 g of water are placed in a 2 litre flask and heated to 100°C. 550 g of 4-fluoro-benzalchloride are then added. After approximately 7 hours the reaction is complete and the exceeding solvent is eliminated by distillation. 4-fluorobenzaldehyde is obtained with a titer of 98.7%. EXAMPLE 2

PREPARATION OF 4-FLUOROBENZONITRILE

1863 g of acetic acid and 243 g of hydroxylamine hydrochloride are placed in a flask and the mixture is heated to 115°C. A solution of 668 g of 4- fluorobenzaldehyde in acetic acid is added dropwise and 560 g of acetic acid are removed by distillation. The mixture is brought to 70°C and 423 g of acetic anhydride are added. The mixture is reacted for 1 hour, and then the acetic acid is distilled off. 327 g of 4-fluorobenzonitrile are thus obtained with a yield of 88% and titer equal to 99.3%. COMPARATIVE EXAMPLE (Process of G.A. Olah et al., with distillation instead of extraction).

322.5 g of formic acid, 36.5 g of hydroxylamine hydrochloride and 50 g of 4- fluoro-benzaldehyde are placed in a flask and the mixture is refluxed (approximately at 100°C) for 2 hours. The gas-chromatographical analysis shows at this point the presence of 95% of 4-fluoro-benzonitrile. Formic acid is removed by distillation at ambient pressure and 19 g of 4-fluoro- benzonitrile are isolated, corresponding to a yield of 40%. EXAMPLE 3

PREPARATION OF THE 4-FLUOROBENZONITRILE 284 g of acetic acid and 39 g of hydroxylamine hydrochloride are placed in a flask and the mixture is heated to 115°C. A solution of 121.4 g of a solution with 50% w/w of 4-fluorobenzaldehyde and acetic acid is added dropwise and heated to 106° for 1 hour. The mixture is cooled to 70°C and 95.6 g of acetic anhydride are added. The mixture is reacted for 1 hour at 100°C and the acetic acid is then distilled off. The residue is solubilised in dichloromethane and washed with water. The organic phase is then dried and, after removal of the dichloromethane solvent, 44.1 g of 4- fluorobenzonitrile are obtained with a yield of 73.5%.

Claims

CLAIMS 1. Process for the preparation of a halo-benzonitrile of formula (I)

wherein Hal is as above defined with hydroxylamine in a solvent selected from acetic acid and propionic acid; b) adding the anhydride corresponding to the acid used as solvent; c) removing of the solvent by distillation to obtain the product of formula (I).

2. Process according to claim 1 , wherein Hal is in position 4 of the benzene.

3. Process according to claims 1 or 2, wherein Hal is fluorine.

4. Process according to claim 1 , wherein the hydroxylamine is in the form of one of its salts selected from sulphate, hydrochloride, phosphate and acetate.

5. Process according to claim 1 , wherein the solvent is acetic acid and the anhydride is acetic anhydride.

6. Process according to claim 1 , wherein the anhydride is added in a sufficient quantity to dry the reaction system.

7. Process according to claim 1 , wherein the reaction temperature is in the range 100 - 115°C.

8. Process according to claim 1 , for preparation of the 4-fluorobenzonitrile, comprising reacting, at a temperature of approximately 115°C, 4- fluorobenzaldehyde with hydroxylamine hydrochloride in acetic acid, heating of the mixture to approximately 70°C, adding the acetic anhydride and removing of the acetic acid by distillation.

9. Process according to claim 1 wherein the halobenzaldehyde of formula (II) is the product of hydrolysis of a halo-benzal-halide of formula (III)

wherein Hal is defined as in claim 1 and X is selected from bromine and chlorine, in a mixture of water and a solvent selected from acetic acid and propionic acid.

10. Process according to claim 9, wherein the halo-benzaldehyde of formula (II) is used without previous isolation or purification.

11. Process according to claims 9 or 10 wherein the halo-benzal-halide of formula (III) is 4-fluorobenzalchloride.

12. Process according to any one of the previous claims wherein the solvent distilled in step c) is reused for a new reaction cycle.