DE3038778A1 - METHOD FOR PRODUCING 3- (4-PYRIDINYL) ANILINE FROM 3- (4-PYRIDINYL) -2-CYCLOHEXEN-1-ON-OXIM - Google Patents

Description

Case 3673A -2-

20/10 / week

STERLING DRUG INC., New York, USA

from 3- (4-pyridinyI) -2-cyclohexen-1-one oxime

The invention relates to an improved process for the preparation of 3- (4-pyridinyl) aniline, an intermediate for the preparation of rosoxacin, an antibacterial agent.

U.S. Patents 4,026,900 and 4,075,217 disclose heating the oxime of 3- (4-pyridir.yl) -2-cyclohexen-1-one with an acetylating agent to produce the resulting O-acetyloxime and then heating the O. -Acetyloxime under acidic conditions, preferably in the presence of a strong mineral acid. The acetylation and the subsequent heating steps were preferably carried out in combination by heating the oxime with acetic acid, acetic anhydride and hydrogen halide, preferably hydrogen chloride gas. The reaction was in the range of about 8O ⁰ C to 140 ⁰ C, preferably from 100 ⁰ C to 120 ⁰ C is performed. The N-acetyl-3- (4-pyridinyl) aniline was then hydrolyzed to produce 3- (4-pyri <?. inyl) aniline, an intermediate in the production of rosoxacin.

Newiiian and Hung / J. Org.Chem. 2§ '4073-4074 (1973) / showed the Conversion of certain oximes of <^ tetralones (7-methyl- and 7-chloro-oC-tetralonen) to the corresponding N- (1-naphthyl) acetamides by heating the oxime in acetic anhydride and anhydrous phosphoric acid at 80 ° C for 30 minutes. Unsatisfactory results resulted from side reactions when using them

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ORIGINAL INSPECTED

Reaction conditions with the oxime of 6-methoxy-tetralone. Phosphorus pentoxide was used to make the anhydrous phosphoric acid;

The invention relates to an improvement in the process for converting 3- (4-pyridinyl) -2-cyclohexen-1-one oxime to 3- (4-pyridinyl) aniline / the improvement being in heating this oxime with an excess of both acetic anhydride and anhydrous Phosphoric acid / distilling off the acetic acid formed from the reaction and then hydrolyzing the N-acetyl-3- (4-pyridinyl) aniline, consists..

The invention relates to an improvement in the process for the production of 3- (4-pyridinyl) aniline by acetylating 3- (4-pyridinyl) -2-cyclohexene-1-oxime to produce the corresponding O-acetyloxime and heating the latter under acidic conditions The improvement is that 3- (4-pyridinyl) -2-cyclohexen-1-one oxime is heated with an excess of both acetic anhydride and anhydrous phosphoric acid, the acetic acid by-product and the excess of acetic anhydride are distilled off and the remaining N -Acetyl-3- (4-pyridinyI) -aniline hydrolyzed under alkaline conditions. According to a preferred. In the first embodiment of the process, about 7 to 10 mol equivalents of acetic anhydride and about 3 to 10 mol equivalents of anhydrous phosphoric acid were used per mol equivalent of oxime and the reactants were heated ^{at about 90 to 120 °} C., preferably 95 to 120 ^{° C.} .

The anhydrous phosphoric acid used in the process was obtained by dehydrating 85% phosphoric acid by reaction the same made with acetic anhydride.

The first stage of the process can be using more acetic anhydride and anhydrous phosphoric acid, namely up to about a

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-A-

15 to 20 mole equivalents of each per mole equivalent of oxime, but not be used to any particular advantage.

The second stage is usually using an aqueous Alkali metal hydroxide, preferably sodium hydroxide, carried out.

The following examples illustrate the invention in detail.

example 1

3- (4-pyridinyl) aniline, alternatively referred to as 3- (4-pyridinyl) benzene amine.

Anhydrous phosphoric acid <j was prepared by adding 1.020 g (10 mol, d 1.082, 940 ml) acetic anhydride to 540 g (4.68 mol, d 1.7, 320 ml) of vigorously stirred 65% phosphoric acid within 20 minutes, the Temperature rrhe was kept at 50 ⁰ C by occasional cooling. 1.58 g (1 mol) of 3- (4-pyridinyl) -2-cyclohexen-1-one oxime were added all at once to the clear, warm solution. The initially clear yellow solution was heated on a steam bath to about 95 ⁰ C, where the water vapor wurde.An parked this point began, the reaction mixture between the two layers to separate, and, where appropriate, a movable water white top layer and a yellowish-brown viscous Formed gum. The internal temperature of the reaction mixture rose sharply gradually to about 11O ⁰ C to 120 ⁰ C on. Once the temperature began to drop, steam was again applied over 90 minutes. The generated acetic acid (colorless upper layer - 650 to 700 ml) was then removed by vacuum distillation, followed by removal of the excess acetic anhydride in vacuo. The continuously stirred and heated viscous residue was easily dissolved in 500 ml v / lean water. The clear solution was dunke ml gradually and with occasional cooling with about 800 at 35% aqueous sodium hydroxide at 60 ⁰ C to 8O ⁰ C to a

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brought slightly basic pH (8 to 9). Some precipitated solid was solubilized by the addition of 500 ml of ethanol and heating to 80 ⁰ C. The colorless, viscous lower layer, which mostly contained phosphate salts, was peeled off in the heat (11, 1.430 y); it solidified at room temperature. To the remaining dark solution, 320 ml of 35% aqueous sodium hydroxide was added and the resulting two-phase reaction mixture was refluxed overnight (16 hours). The dark homogeneous solution was heated ^{to 5 ° C.} The crystallized solid was filtered, squeezed well and then washed with the minimum amount (just the amount to cover the solid) of 50% aqueous ice-methanol cooled ethanol. In order to remove any remaining inorganic salts in the filter cake, the solid was ^{washed exhaustively with warm water (about 35 to 50 °} C.). The residue was dried in vacuo at 6O ⁰ C / to yield: 134.5 g (79%) of the desired product, beige, 3- (4-pyridinyl) aniline, mp 168-171 °; only spot on thin layer chromatography (silicon dioxide; CHCl ₃ : CH ₃ OH: 1-C ₃ H ₇ NH ₃ 90: 5: 5; UV).

Example 2

3- (4-pyridinyl) aniline was prepared in comparable yield in the experimental laboratory scale using the same procedure as follows: 55 kg of acetic anhydride were placed in a glass-lined 114 1 (30 gallon) reactor to a distillation unit. The phosphoric acid was added within half an hour with a temperature rise to 100 ° C. The solution was heated to 12O ⁰ C and the water vapor off. A solution of 14.6 kg of oxime in 36 liters of acetic acid was added at a rate such that reflux was maintained but distillation was not effected. Approximately three quarters of the solution was added over an hour and a half, resulting in a full kettle. 15.9 to 18.1 kg (35 to 40 pounds) of pressurized steam was used to start distillation of the acetic acid. After an hour and a half it was

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There was clearance in the kettle and the remaining oxime solution was slowly added while maintaining the distillation. The clear layer acetic acid was distilled off at atmospheric pressure over 2 hours, whereby a dunklet and viscous but stirrable residue remained at about 120 ⁰ C. Vacuum was gradually applied in order to remove the remaining acetic acid and the acetic anhydride, the reactor temperature being kept ^{above 100 ° C.} While stirring the residue at 100 ^° C. (without heating), 20 l of water were added over the course of 5 minutes. The temperature dropped to 85 ^° C., but stirring was maintained. The vessel was cooled with water at 60 ⁰ C and 54 kg 35% aqueous sodium hydroxide was added within half an hour at a temperature of 50 to 65 ⁰ C. 20 l of ethanol were added and the mixture was ^{cooled to 30 °} C. before a separation was allowed. A clear aqueous layer, 66 liters, was peeled off and the very dark organic layer * was transferred to a stainless steel kettle. 34 kg of 35% aqueous sodium hydroxide were added to the kettle and the mixture was kept at reflux (83 ° C.) for 12 hours. In the morning, the mixture was ^{cooled from 60 to 5 °} C. before it was filtered. The dark solids were washed with 3x61 cold 2ΰ% ethanol to give a tan product. The moist cake was slurried in 40 l of water at 30 ^° C. within half an hour and again filtered. The solids were washed extensively with water and dried at 60 ° C / air / overnight. The result was 10.08 kg, or 10088 / 77.8 χ 170 = 76.38% of theory of the tan-colored product, 3- (4-pyridinyl) aniline, melting point = 165 to 167 ^° C.

* 56 1

13002S / 0522

Claims (3)

Dr. F. Zumstein Sr. - Dr. E. Asernenn - Dt. R, Koenigsberger Dipl.-Phys. R. Holzbauer - Dip! - lng. F. Klingseisen - Dr. F. Zumstein jun. BOOO Munich 2 · Bräuhausstrasse 4 · Telephone collection no. 225341 · Telegrams Zumpat "elex 529979 Case 3673A 20 / We patent claims 1. Process for the preparation of 3- (4-pyridinyl) aniline by Acetylation of 3- (4-pyridinyl) -2-cyclohexen-1-one oxime for the preparation of the corresponding 0-acetyloxime and heating the latter under acidic conditions, characterized in that one 3- (4-pyridinyl) -2-cyclohexen-1-one oxime heated with an excess of both acetic anhydride and anhydrous phosphoric acid, the acetic acid by-product and the excess acetic anhydride distilled off and the remaining N-acetyl-3- (4-pyridinly) aniline hydrolyzed. 2. The method according to claim 1, characterized in that 7 to 10 mole equivalents of acetic anhydride and about 3 to 10 mole equivalents of anhydrous phosphoric acid per mole equivalent of oxime. 3. The method according to claim 2, characterized in that the reactants are heated ^{at about 90 to 120 0 C in the first stage.} 130025/0522 ORJGiNAL INSPECTED