NO803010L - PROCEDURE FOR THE PREPARATION OF 3- (4-PYRIDINYL) ANILIN FROM 3- (4-PYRIDINYL) -2-CYCLOHEXE-1-ON-OXIM. - Google Patents

Description

The present invention relates to an improved process for the production of 3-(4-pyridinyl)aniline,

an intermediate for the manufacture of rozoxacin, an anti-bacterial agent.

US Patent Nos. 4,026,900 and 4,075,217 describe heating the oxime compound of 3-(4-pyridinyl)-2-cyclohexen-1-one with an acetylating agent to form the resulting O-acetyl oxime and then heating the O- the acetyl oxime compound under acidic conditions, preferably in the presence of a strong mineral acid. The acetylation and the subsequent heating steps are preferably carried out in combination by heating the oxime compound with acetic acid, acetic anhydride and hydrogen halide, preferably hydrogen chloride gas. The reaction is carried out in the area of approx. 80-140°C, preferably 100-120°C. The N-acetyl-3-(4-pyridinyl)aniline compound is then hydrolyzed to form 3-(4-pyridinyl)aniline, an intermediate for the preparation of rosoxacin.

Newman and Hung (J. Org. Chem. 38, 4073-4074 (1973)) showed the conversion of certain oximes of α-tetralones (7-methyl- and 7-chloro-α-tetralones) to the corresponding N-(1- naphthyl)acetamides by heating the oxime compound in acetic anhydride and aqueous phosphoric acid at 80°C for 30 min.

Unsuccessful results were obtained due to acid reactions

using these reaction conditions with the oxime compound of 6-methoxy-α-tetralone. Phosphorus pentoxide was used to prepare the anhydrous phosphoric acid.

The present invention relates to an improvement in the process for converting 3-(4-pyridinyl)2-cyclo-hexen-1-one-oxime to 3-(4-pyridinyl)aniline, and the improvement comprises heating said oxime compound with a excess of each of acetic anhydride and anhydrous phosphoric acid, distills off the acetic acid formed by the reaction and then hydrolyzes N-acetyl-3-(4-pyridinyl)aniline.

The invention lies in an improvement of the process for the production of 3-(4-pyridinyl)aniline, by acetylating 3-(4-pyridinyl)-2-cyclohexene-1-oxime to form the corresponding O-acetyl oxime and heating this compound under acidic conditions, said improvement consisting in heating 3-(4-pyridinyl)-2-cyclohexen-1-one-oxime with an excess of acetic anhydride and anhydrous phosphoric acid, distilling off the acetic acid by-product and excess acetic anhydride, and hydrolyzing it residual N-acetyl-3-(4-pyridinyl)aniline under alkaline conditions.

In a preferred embodiment, the first step in the method is carried out using approx. 7-10 mole equivalents of acetic anhydride and approx. 3-10 mole equivalents of anhydrous phosphoric acid per mol-equivalent oxime and heating the reactants at approx. 90-120°C, preferably 95-120°C.

The anhydrous phosphoric acid used in the method was produced by dehydrating 85% phosphoric acid by reacting it with acetic anhydride.

The first step in the process can be carried out by using more acetic anhydride and anhydrous phosphoric acid, namely up to approx. 15-20 mole equivalents of each per molar equivalent oxime, but not with any particular advantage.

The second step is conveniently carried out using an aqueous alkali metal hydroxide, preferably sodium hydroxide.

The following examples further illustrate the invention.

3-(4-pyridinyl)aniline, alternatively called 3-(4-pyridinyl)benzenamine. Anhydrous phosphoric acid was prepared by adding 1020 g (10 mol, d 1.082, 940 ml) of acetic anhydride to 540 g (4.68 mol, 1.7, 320 ml) of vigorously stirred 85% phosphoric acid over 20 min. while maintaining the temperature close to 50°C with occasional cooling. To the clear, warm solution was added 188 g (1 mol) of 3-(4-pyridiny2)-2-cyclohexen-1-one-oxime in one portion. The initially clear, yellow solution was heated on a steam bath to approx. 95°C where the steam was shut off. At this point, the reaction mixture began to separate into two layers, eventually forming

a mobile water-white upper layer and a yellow-brown viscous gum. The internal temperature in the reaction mixture was gradually increased to approx. 110-120°C. As soon as the temperature began to drop, steam was again allowed to act for 90 min. The acetic acid formed (colorless upper layer, 650-700 ml) was then removed by vacuum distillation followed by removal of excess acetic anhydride in vacuo. The continuously stirred and heated viscous residue was easily dissolved in 500 ml of hot water. The clear, dark solution was treated gradually and under occasional cooling with approx. 800 ml of 35% aqueous sodium hydroxide at 60-80°C to a slightly basic pH value (8-9). Some precipitated solid was solubilized by adding 500 ml of ethanol

and heating to 80°C. The colorless, viscous lower layer containing mostly phosphate salts was removed while still hot (1 liter, 1430 g); it solidified at ambient temperature. To the remaining dark solution was added 320 ml of 35% aqueous sodium hydroxide and the resulting two-phase reaction mixture was heated at reflux overnight (about 16 hours). The dark, homogeneous solution was cooled to 5°C. The crystallized solid was filtered, pressed well, and then washed with a minimum amount (an amount that just covered the solid) of ice-methanol and chilled 50% aqueous ethanol.

To remove any remaining inorganic salts in the filter cake, the solid was washed repeatedly with hot water (about 35-50°C). The residue was dried in vacuo at 60°C to give 134.5 g (79%) of the desired beige-colored product, 3-(4-pyridinyl)aniline, m.p. 168-171°C; single spot by thin-layer chromatography (silica; CHCl^: CH^OH: i-C3H7NH290:5:5; UV).

Example<pel>_<2>

3-(4-pyridinyl)aniline was prepared in comparable yields in a laboratory pilot plant using the same method, as follows: Acetic anhydride, 55 kg, was fed to a 113.6 liter capacity glass-lined reactor in a distillation unit. The phosphoric acid was added over the course of j hour

the temperature rose to 100°C. The solution was heated to 120°C and the steam shut off. A solution of 14.6 kg of oxime in 36 liters of acetic acid was added at such a rate that reflux was maintained, but without effecting distillation. About 3/4 of the solution was added over the course of an hour and a half, resulting in a full kettle. Pressurized steam (15.75-18 kg) was used to begin the distillation of acetic acid. After \hour there was room in the kettle, and the resulting oxime solution was slowly added while maintaining distillation. The clear acetic acid layer was distilled off at atmospheric pressure over 2 hours, leaving a dark and viscous but stirrable residue at 120°C. Vacuum was applied gradually to remove residual acetic acid and acetic anhydride, keeping the flask temperature above 100°C. While the residue was stirred at 100°C ("heat off"), 20 liters of water were added over 5 min. The temperature dropped to 85°C, but stirring was maintained. The boiler was cooled with water to 60°C and 54 kg of 35% aqueous sodium hydroxide was added over 1 hour, temperature 50-65°C. Ethanol, 20 liters, was added and the mixture cooled to 30°C before being allowed to separate. A clear aqueous layer, 66 liters, was withdrawn and the very dark organic layer, 56 liters, was transferred to a stainless steel kettle. 35% aqueous sodium hydroxide, 34 kg, was added to the kettle and the mixture refluxed (83°C) for 12 hours. In the morning, the mixture was cooled from 60 to 5°C before filtration. The dark solids were washed with 3x6 liters of cold 25% ethanol to give a light brown product. The wet cake was slurried in 40 liters of water at 30°C for 1 hour and refiltered. The solids were washed well with water and dried at 60°C in air overnight. This gave 10.08 kg, or 10080/77.8 x 170 = 76.3% of the theoretical yield, of the light brown product, 3-(4-pyridinyl)aniline, m.p. 165-167°C.

Claims (3)

1. Process for the preparation of 3-(4-pyridinyl)-aniline by acetylating 3-(4-pyridinyl)-2-cyclohexen-1-one oxime to form the corresponding O-acetyl oxime and heating this compound under acidic conditions, characterized by heating 3-(4-pyridinyl)-2-cyclohexen-1-one-oxime with an excess of each of acetic anhydride and anhydrous phosphoric acid, distilling off the acetic acid by-product and excess acetic anhydride, and hydrolyzing the remaining N-acetyl -3-(4-pyridinyl)aniline. 2. Method according to claim 1, characterized in that one uses approx. 7-10 mol-equivalents of acetic anhydride and approx. 3-10 mol-equivalents of anhydrous phosphoric acid per molar equivalent oxime. 3. Method according to claim 2, characterized in that the reactants in the first step are heated at approx. 90-120°C.