HU204500B - Process for producing diphenyl-amines - Google Patents

Abstract

Prepn. of diohenylamines of formula (I) comprises (a) formylation of X-substd. aniline (II) to formanilide (III); and

Description

The present invention relates to an improved process for the preparation of diphenylamine of formula (I) wherein X is hydrogen, halogen, trifluoromethyl or (C 1 -C 4) alkoxy, aniline of formula (O) wherein X is as defined above, fumylation of the resulting formanilide of formula (H1), wherein X is as defined above, and UUmann condensation of a halobenzene of formula (V), wherein Hal is a halogen atom, preferably bromine, an alkali metal carbonate and a copper containing catalyst; formed from the N-formyldiphenylamine of Formula IV, wherein X is as defined above, by removing the formyl group by formylation of the aniline of Formula (Π) in the presence of halobenzene of Formula (V). without reacting the resulting compound of formula (H1) with the compound of formula (V) present. and forming the resulting N-formyl diphenylamine of formula IV in the presence of a polyoxyethylene sorbitan fatty acid ester at 150-165 ° C.

The diphenylamine compound of formula (I) is a starting material for the synthesis of therapeutically active phentiazine derivatives.

Several Methods for the Preparation of Diphenylamine of Formula I One of the known processes comprises reacting aniline of formula H with o-halobenzoic acid and then decarboxylating the resulting N-substituted phenylanthranilic acid [Farm. Polska,

14, 77 (1959); C.A., 52, 16358b (1958)]. The disadvantage of the process is that the decarboxylation produces a significant amount of tar which is difficult to purify at great expense. In addition, the preparation of the starting o-halobenzoic acid requires a separate reaction step.

According to another known process, the aniline of formula (Π) is N-acetylated and the N-acetyl salt is reacted with a halobenzene of formula (V) in the presence of potassium carbonate and a copper-containing catalyst under conditions of Ullmann condensation. N-acetyl (substituted diphenyl) amine is deacetylated [Zsur.Priklad. Male. 31,661 (1958); C.A.

52.18 18 274e (1958)]. The Ullmann condensation step of this known process proceeds only slowly despite the presence of the activating acetyl group, requiring a reaction time of 1044 hours. The deacetylation is carried out in a separate step 45 and the calculated total aniline of formula (Π) is only 46-74%.

According to yet another known process, U.S. Pat. U.S. Pat. C.A.,

54.18434i (1959); and CA, 94.83, 694u (1981)] 50 N-foymylate the aniline of formula (Π) and then react the formanilide of formula (-) with a halobenzene of formula (V) under conditions of Ullmann condensation, or in the presence of potassium carbonate and a copper-containing catalyst, such as copper (H) -carbonate, at least 170 ° C, generally 200220 ° C. In order to avoid that the formyl group of the resulting compound of formula (IV) has to be hydrolyzed in a separate step, the formyl group is removed by heat treatment. It has been found that at higher temperatures, the formyl group is cleaved faster and a maximum temperature of 240 ° C can be used. The heat treatment is preferably carried out at a temperature of about 210 ° C

The latter known method is relatively simple to carry out, but has several disadvantages. These are:

- High heat demand due to long term heat treatment at high temperatures.

- The product is damaged by heat treatment for at least 10 hours at temperatures above 200 ° C. This process is particularly important in the case of larger reaction sizes.

The formyl group is not quantitatively cleaved during the heat treatment, so the product of formula I may contain up to 5-10% of the N-formyl derivative as described in U.S. Patent No. 2,924,620. Examples are shown in U.S. Pat.

^1- The yield of formanylide (TH) from the contaminated product at laboratory scale is 70-83%. Considering that formanilide can be obtained by reaction of the appropriate aniline with formic acid in about 95% yield (Organikum, Technical Publishing House, Budapest, 1967, 377), the total yield calculated for the aniline of formula (II) is is in any case below 80%. SUMMARY OF THE INVENTION It is an object of the present invention to provide a process for the preparation of diphenylamine of general formula (I) which is economically and easily practicable.

It has been found that the above object, when formylation of the aniline of formula (II) in the presence of halobenzene of formula (V), the resulting formanilide of formula (II) is reacted in the production reaction mixture of formula (V). and the resulting N-formyldiphenylamine of formula (IV) in the presence of a polyoxyethylene sorbitan fatty acid ester at 150-165 ° C.

On the one hand, the invention is based on the discovery that formylation of aniline of formula (Π) does not require separation of the formanilide of formula (H1) formed, but that the Ullmann reaction can be carried out in the production reaction mixture.

On the other hand, the present invention is based on the discovery that the formyl group of Nformyl diphenylamine (IV) formed by the Ullmann reaction can be quantitatively removed in the presence of a polyoxyethylene sorbitan fatty acid ester by heat treatment at 150-165 ° C for several hours.

In the process of the invention, the aniline of formula (val) is formylated with formic acid in a manner known per se, but with an excess of the halobenzene of formula (V) as a diluent for use in the subsequent UUmann reaction. Formic acid is used up to a small amount in excess of the equimolar amount, whereby an excess of about 15% is usually sufficient. Halogen benzene of formula (V) is preferred2

HU 204500 Β of bromobenzene is used. After distillation of the water formed during the formylation and the possible excess of formic acid, the reaction mixture is preferably treated with potassium carbonate and a copper-containing catalyst. as described in U.S. Patent No. 2,924,620. U.S. Pat. No. 5,123,123, preferably copper (I) iodide 10 is used. Ullmann condensation usually occurs at the reflux temperature of the reaction mixture within 10 hours. At this time, a polyoxyethylene sorbitan fatty acid ester is added to the reaction mixture, usually in an amount of 0.1 to 2.0% by weight, then maintained at a temperature of 150 to 165 ° C, preferably at the boiling point of the reaction mixture. Under these conditions, the formyl group is quenched quantitatively within a few hours.

As the polyoxyethylene sorbitan fatty acid ester, for example

the following compounds are used: polyoxyethylene sorbitan monolau- Ra [Tween® 20], polyoxyethylene sorbitan monopal- Mita [Tween® 40], polyoxyethylene sorbitan mono- stearate [Tween® 60], polyoxyethylene sorbitan monoole- through [Tween® 80], polyoxyethylene sorbitan tristearate [Tween® 65] obsession polyoxyethylene sorbitan trioleate [Tween® 85].

For the isolation of the diphenylamine of formula I, it is expedient to add water to dissolve the inorganic materials present in the reaction mixture after the cleavage of the formyl group, separating the organic phase containing diphenylamine and excess halobenzene, and evaporating the halobenzene. and the remaining diphenylamine of formula (I) is generally purified by vacuum distillation. The regenerated halobenzene may be used in a subsequent production.

According to the invention, the so-called And a diphenylamine of formula I is prepared in a "one pot" process without isolation of the intermediates. Removal of the formyl group does not require lengthy heat treatment at temperatures above 200 ° C, but the formyl group is quantitatively cleaved from the intermediate of formula (IV). The total yield of aniline of formula (II), even at 200 molar scales, is above 90%.

The invention is illustrated in detail by the following examples:

Example 1

Preparation of 3-Chlorodiphenylamine

A mixture of 25.5 kg (200 mol) of 3-chloroaniline, 12.5 kg (230 mol) of 85% formic acid and 96.6 liters (144.4 kg) of bromobenzene is heated to 95-100 ° C. and reflux for 2 hours. The reflux condenser is removed and the water and excess formic acid present are distilled through a Marcusson flask. To a solution of the resulting 3-chloroformoimililide in bromobenzene was added 62.1 kg (450 moles) of potassium carbonate and 1.0 kg of copper (I) iodide. Using a Marcusson plug and refluxing, the reaction mixture was heated at reflux for 10 hours, then 1.1 L of polyoxyethylene sorbitan monostearate [Tween® 60] was added and refluxed for an additional 3 hours. After cooling to 20 ° C, 100 L of water are added, the mixture is stirred for 30 minutes, then the organic phase is separated off and the bromobenzene is evaporated in vacuo. The residue was fractionated in vacuo.

36.9 kg (90.6%) of 3-chlorodiphenylamine are obtained, m.p. 142-148 ° C at 267 Pa.

Gas chromatography showed only the presence of 3-chlorodiphenylamine. Retention time (Irish) = 5.7 minutes. (Test conditions: 120 cm long 3 mm 35 diameter column with 80-100 mesh Chromosorb W-HP charge, carrier gas nitrogen, column temperature 170 ° C, pressure 4.5 x ^{10 4} Pa.)

Example 2

The following compounds were prepared as described in Example 1:

X is represented by formula (I) M.p. Mp .: ° C Production % t _R , min H 53-54 - 92.0 2.3 trifluoromethyl group - 135-140 / 400 Pa 91.5 1.9 methoxy 50-52 - 90.0 7.7

PATENT CLAIMS

Claims (2)

PATENT CLAIMS A process for the preparation of diphenylamine of formula I wherein X is hydrogen, halogen, trifluoromethyl or C 1-4 alkoxy, by formylation of aniline of formula Π where X is as defined above , the resulting Ullmann condensation of the formanilide of formula (III) wherein X is as defined above and a halobenzene of formula (V) where Hal is a halogen atom, preferably bromine, an alkali metal carbonate and a copper-containing catalyst; formed from the N-formyldiphenylamine of Formula IV, wherein X is as defined above, by removal of the phenyl group, characterized in that the aniline of formula (Π) is foimylated in the presence of a halobenzene of formula (V), the resulting formanilide of formula (ΙΠ) is reacted in the production reaction mixture with the EN 204500 Β with halobenzene and the resulting N-formyldiphenylamine of formula IV in the production reaction mixture is maintained at 150-165 ° C in the presence of a polyoxyethylene sorbitan fatty acid ester. 2. A process according to claim 1 wherein the polyoxyethylene sorbitan fatty acid is polyoxyethylene monobutane monostearate.