DD238228A5 - PROCESS FOR PREPARING AROMATIC N-AZYL HYDROXY- AND N-AZYLAZYLOXYAMINES - Google Patents

Abstract

The invention relates to a process for the production of aromatic N-Azylhydroxyaminen, such as N-acetyl-p-aminophenol (APAP), and of aromatic N-Azylazyloxyaminen, such as 4-Acetetoazetanilid (AAA), from aromatic hydroxyketones, such as 4-hydroxyazetophenone , Preferably, the aromatic hydroxy ketones are prepared from an aromatic ester such as phenyl acetate or from a phenolic compound such as phenol and an acylating agent such as acetic acid.

Description

Field of application of the invention

The invention relates to the preparation of aromatic N-Azylhydroxy- and N-Azylazy! Oxyamines, which are used in the chemical industry as intermediates for syntheses.

Characteristic of the known technical solutions

It is known that aromatic N-Azylazyloxyamine, z. B. 4-acetoxy-azetanilide by the sodium salt of the corresponding aromatic N-Azylhydroxyamins, z. B. N-acetyl-p-aminophenol (APAP) prepared and the sodium salt with the appropriate carboxylic anhydride, eg. B. acetic anhydride can react. The aromatic N-acylhydroxyamine used as starting material for the preceding reaction, e.g. B. APAP, in turn, by azylation of the corresponding aromatic hydroxyamine, z. P-aminophenol, with an acylating agent such as an anhydride, e.g. B.

Prepared acetic anhydride. However, the latter reaction may cause problems such as the difficulty of monoacylation of the aromatic hydroxyamine, the oligomerization of the aromatic hydroxyamine and the formation of color bodies.

In addition, when the APAP is prepared from p-aminophenol, typically nitrobenzene is catalytically hydrogenated and rearranged simultaneously in the presence of a platinum catalyst to produce the p-aminophenol with the problem of recovering the dissolved platinum catalyst.

It is also known to react APAP by hydrogenating 4-nitro-chlorobenzene to 4-chloroaniline, which is then reacted with aqueous potassium hydroxide to form p-aminophenol. This process is relatively complicated because it requires a considerable number of reaction and purification operations. In addition, it is believed that the acylation process in this process causes the same difficulties as those of the azylation process of the nitrobenzene.

The production of aromatic hydroxyketones by the Fries rearrangement of aromatic esters is well known in the art. Thus, US Pat. No. 2,833,825 discloses the rearrangement of phenyl or other aromatic esters to give azy [phenols or other aromatic hydroxy ketones by using anhydrous fluoride as catalyst. The examples of this patent are limited to the rearrangement of esters of higher fatty acids in yields of 55% to 95%.

SIMONS and in Journal of the American Chemical Society, No.62, pp. 485 and 486 (1940) show the use of hydrogen fluoride as a condensation agent for various rearrangements and, on page 486, disclose the Fries rearrangement of phenyacetate to p-hydroxyazetophenone to obtain.

In an article included in a series of reports of the Institute of Applied Chemistry of the University of Erlangen, received for publication on January 7, 1954, and published in the Annals of Chemistry, Volume 587, pages 1-15 (1954), DANN and MYLIUS disclose Rearrangement of phenyl acetate in hydrogen fluoride to 4-hydroxyazetophenone with a maximum yield of 81% after 24 hours reaction time and report a reported by K. WEICHERT achieved yield of 92%, as in the journal "Angewandte Chemie", Volume 56, page 338 (1943) reported.

THEN and MYLIUS, however, believe that the difference in yields may be due at least in part to WEICHERT's prior ignorance of the accompanying 2-hydroxyacetone phenone.

THEN and MYLIUS also disclose the reaction of phenol and glacial acetic acid in the presence of hydrogen fluoride to produce 4-hydroxyazetophenone in 61.6% yield. This reaction can be conveniently characterized as a FRIEDEL-CRAFTS acetylation of phenol with acetic acid as the acetylating agent.

SIMONS et al. Describe in Journal of the American Chemical Society, Volume 61, pages 1795 and 1796

(1939) acetylating aromatic compounds using hydrogen fluoride as the condensing agent and show in Table 1 on page 1796 the acetylation of phenol with acetic acid to produce p-hydroxyacetone phenone in 40% yield.

DT Patent Publication 2616986 discloses the acylation of phenolic compounds such as phenol with an acyl halide such as acetyl chloride to form aromatic hydroxy ketones.

Auwers and others, in the journal "Chemische Berichte," volume 58, pages 36-51 (1925), show the BECKMANN rearrangement of a large number of oximes of aromatic ketones, most of which are substituted acetophenones, but the only attempted rearrangement of the oxime of a non-ring-substituted aromatic hydroxyketone that of the oxime ms of o-hydroxyazetophenone, but no amine was formed, ie the attempted rearrangement was unsuccessful, see page 41.

GANBOA and others, in the journal "Synthetic Communications", Volume 13 (11), pages 941-944 (1983), show the production of acetanilide from acetophenone by refluxing in a solution of hydroxylamine hydrochloride but there is no suggestion to achieve the synthesis of aromatic N-azylazyloxyamines such as 4-acetoxyazetanilide (AAA) or the synthesis of aromatic N-azylhydroxyamines such as N-acetyl-p-aminophenol (APAP).

PEARSON et al., Journal of the American Chemical Society, Vol. 75, pp. 5905-5908 (5 December 1953) disclose the formation of hydrazones from ketones by reaction with hydrazine hydroxide and the rearrangement of the hydrazone to the amide by reaction with sodium nitrite and concentrated sulfuric acid.

In particular, on page 5907, PEARSON and others show the rearrangement of p-hydroxyacetophenone hydrazone to p-hydroxyazetanilide, i. APAP.

Object of the invention

The aim of the invention is to develop processes for the preparation of aromatic N-Azylhydroxy- and N-Azylazyloxyaminen, which give a high yield.

Explanation of the essence of the invention

The invention has for its object to provide a process for the preparation of aromatic N-Azylhydroxy- and N-Azylazyloxyaminen using aromatic hydroxyketones.

According to the invention the object is achieved by aromatic N-Azylhydroxyamine, z. N-acetyl-p-aminophenol (APAP) by reaction of an aromatic hydroxy ketone, e.g. 4-hydroxyazetophenone (4-HAP) with a hydroxylamine salt to form the ketoxime of the ketone and by subjecting the ketoxime of a BECKMANN rearrangement in the presence of a catalyst.

In a specific embodiment, N-acetyl-p-aminophenol (APAP), also known as acetaminophen, is made from phenyl acetate or phenol and an acetylating agent such as acetic acid, by an integrated process comprising the steps of converting the phenyl acetate or the phenol and a Acetylating agent in 4-hydroxyazetophenone by a FRIESsche rearrangement or a FRIEDEL-CRAFTSsche rearrangement and the conversion of 4-hydroxy-azetophenons in the corresponding ketone with hydroxylamine or a hydroxylamine salt comprises. The ketoxime is then subjected to BECKMANN rearrangement in the presence of a catalyst to form the N-acetyl-p-aminophenol. According to one embodiment of this invention, aromatic N-Azylazyloxy-amines, z. B. 4-Acetoxyazetanilid (AAA) by reaction of an aromatic hydroxyketone, z. B. 4-hydroxyazetophenone (4-HAP) with hydroxylamine or a hydroxylamine salt to form the ketoxime of the ketone and subjecting the ketoxime of a BECKMANN rearrangement and concomitant acylation by contacting the ketoxime with a carboxylic acid anhydride and a catalyst prepared for the BECKMANN rearrangement.

In another particular embodiment, the 4-acetoxyazetanilide (AAA) is prepared from phenyl acetate or phenol and an acetylating agent such as acetic acid by an integrated process comprising the steps of converting the phenyl acetate or phenol and an acetylating agent into 4-hydroxyazetophenone by one FRIEND Rearrangement or FRIEDEL-CRAFTS acetylation and conversion of 4-hydroxyazetophenone to the corresponding ketoxime with hydroxylamine or a hydroxylamine salt. The ketoxime is then subjected to BECKMANN rearrangement and concomitant acetylation with acetic anhydride and a catalyst for BECKMANN rearrangement to form the 4-acetoxyazenilide.

In carrying out the process of the present invention using phenyl acetate as the starting material, the original FRIES rearrangement for producing 4-hydroxyazetophenone (4-HAP) from phenyl acetate is determined by the following equation (I).

O - CEL

Ii catalyst / ^ Λ Ι

0-CCH ₃ - 3 * ΗΟ- / Γ JVC = O (I)

When phenol and an acetylating agent are used as the starting material, the resulting acetylation reaction to form 4-HAP is represented by the following equation (II):

O \ Catalyst / • "-χ \ ',

y + CH ₃ COX -s * ΗΟ-Ζς JVC = O + HX (II)

wherein X denotes the residue minus an acetyl group of compounds which are known acetylating agents. X may be, for example, hydroxy, acetoxy or halide, such as fluoride, chloride, bromide or iodide. Acetylating agents which can be used are e.g. Acetic acid, acetic anhydride, acetyl fluoride, acetyl chloride and acetyl bromide. The formation of ketoximes according to this invention is carried out according to the following equation (III):

R R

I Base ₁ I

HOAr-C = O + "NH ₂ OH" -r ". HOAr-C = NOH + HgO (III)

The formation of the ketoxime of 4-HAP, i. of the 4-HAP oxime is carried out according to the following equation (IV):

CH ₃ CH ₃ .

/ s- ~ * \ ' ^Base / £ -ν \'

^H0 \ C J / ^{G = 0 + Π1ΙΗ} 2 ^0Η "- =" ^H ° - \ CJ VC = NOH + H ₂ O (IY)

When aromatic N-acylhydroxy amines form the desired product, the BECKMANN rearrangement according to the invention takes place according to the following equation (V):

R H R

_Λ I catalyst ₁ II

HOAr-C = NOH --- * - HOAr-N-C = O (V)

while the BECKMANN rearrangement, when APAP is the desired product, is according to the following equation (VI):

CH. H CH

Catalyst / y ~ \ JL ',,, .- ^

HO- / ( IV-C = NOH - - ** EO- ( IVN-C = O (VI)

When aromatic N-azylazyloxy amines are the desired product, BECKMANN rearrangement and the concomitant acylation according to this invention are according to the following equation (VII):

; _R - '0 HR

I - Catalyst Il ₁ II HOAr ^1. -C = NOH + (RCO) ₂ O * R-COArVN-C = O + RCOOH

(YII)

whereas the BECKMANN charge and the accompanying acetylation, when AAA is the desired product η is, are given by the following equation (VIII):

": gh ,,"'""""'"0 H CH ₃

I ^J catalyst I! / ^ TX II >

E0 - (( ^ Vc = NOH + (CHoCO) ₉ O __ ^, CH, -C0 - <() VN-C = O

+ CH ₃ COOH / viii)

In equations (111), (V) and (VII), Ar ¹ denotes a bivalent aromatic divalent radical. The specific one

The nature of the radical is not critical, but it is preferably a radical that forms after removal of two hydrogens from the benzene-naphthalene or biphenyl ring. The radicals may be substituents such as alkyl, alkenyl, alkynyl, alkoxyl or 1 to 18 carbon atoms containing acyloxy, 7 to 18 hydrocarbon atoms containing aralkyl, halogen, ζ. Β carry chlorine, bromine or iodine, hydroxy, amino or sulfurhydryl. Ar ¹ is preferably 1,4-phenylene, 2,1-naphthylene, 2,6-Nahptylen, 5-phenyl-1,2-phenylene, 3-phenyl-1,4-phenylene or 3-methyl-1, 4-phenylene, wherein the ketocarbon group occupying the first indicated numbered position of Ar ¹ when the positions are not equivalent. Ar ¹ is most preferably 1,4-phenylene.

The groups R in the preceding equations may be the same or different and are a monovalent organic radical containing 1 to 18 carbon atoms, preferably 1 to 4 carbon atoms. R can z. B. alkyl, alkenyl, alkynyl, alkoxy, acyl or 1 to 18 carbon atoms containing acyloxy, neither unsubstituted or substituted with radicals such as halogen, for example chlorine, bromine or iodine; hydroxy; amino; Schwefelhydryl; or a monovalent aryl radical which corresponds to the definition of Ar ¹ given above, with the exception that the carbon bonded to OH is bonded to hydrogen. Preferably R in the equations (III), (V) and (VII) is identical and represents a methyl, ethyl, propyl or N-butyl group, preferably the methyl group corresponding to the use of acetate esters and methyl ketones in the latter equations. The preferred aromatic hydroxyketone to form the oxime is 4-hydroxyazetophenone (4-HAP) and the preferred products are 4-acetoxy-acetanilide (AAA) and N-acetyl-p-aminophenol (APAP).

The aromatic hydroxyketone used to form the oxime may be prepared by any method known in the art. It may be prepared, for example, by the FRIES rearrangement of the corresponding aromatic ester as indicated by the following equation, which is a generalized form of equation (I) in which Ar, Ar ¹ and R are as defined above:

ο ρ

Ü Catalyst ₁ ü

ArOCR --- * »HO-Ar ¹ -GR (IX)

Alternatively, a phenolic compound and an acylating agent may be allowed to react according to FRIEDEL-CRAFT's acylation to form the aromatic hydroxyketone according to the following equation, which is a generalized form of the equation (II):

O-O

I] catalyst, | l ArOH 4- R-C-X --ss HO-Ar -C-R + HX (X)

Ar, Ar ¹ and R have the meanings given above and X is the residue minus the group RC- of those compounds which contain known acylating agents such as hydroxy, azyloxy, e.g. As acetoxy, and halogen, z. Fluoride, chloride, bromide and iodide. Examples of phenolic compounds which can be used are phenol, 1-naphthol, 2-naphthol, 2-phenylphenol, 4-phenylphenol and o-cresol. Azylating agents which can be used include alkanoic acids such as acetic acid and propionic acid, alkanoic anhydrides such as acetic anhydride and propionic anhydride, and acyl halides such as acetyl and propionyl fluorides, chlorides and bromides.

It should be noted that although the reaction of a phenolic compound and an acylating agent is referred to herein as "FRIEDEL-CRAFTS's acylation", one can not recognize the mechanism of the reaction from this label.

The catalyst for both of the foregoing reactions is preferably hydrogen fluoride, but other catalysts known to be effective for the FRIESsche and FRIEDEL-CRAFTS reactions in the art may be used, such as, for example, aluminum chloride, zinc chloride and boron trifluoride.

In carrying out the reaction, the aromatic ester or the phenolic compound and the acylating agent, the catalyst and, when an aromatic ester is the starting material, an additive for the reaction such as acetic anhydride or acetic acid may be placed in a corrosion-resistant reactor and the mixture at a temperature z. B. from 20 ⁰ C to 100 ⁰ C during a period z. B. from half an hour to 4 hours under a pressure of z. B. 3.4 bar to 34 bar. When hydrogen fluoride HF is used as the catalyst, it may be added as a liquid or gas using methods well known to those skilled in the art. In carrying out the reaction, an inert gas, such as nitrogen, can be used to keep the reaction space below the desired pressure and to provide enough hydrogen fluoride HF for the reaction. An excess of hydrogen fluoride HF of about to 75 moles per mole of aromatic ester or phenolic compound is generally used. If AAA or APAP is the desired product of the reaction, then the starting material for FRIES rearrangement will be phenyl acetate, while phenol and an acetylating agent such as acetic acid will form the starting materials when performing a FRIEDEL-CRAFTSian acylation. In both cases, the starting material is converted to 4-HAP, which in turn is converted to AAA or APAP by the method of the invention.

The conversion of aromatic hydroxyketones, e.g. B. 4-HAP in aromatic N-Azylazyloxyamine, z. B. AAA or in aromatic N-Azylhydroxyamine, z. APAP is carried out by first forming the ketoxime from the aromatic hydroxy ketone as indicated by equations (III) and (IV), the ketone with hydroxylamine or a hydroxylamine salt. Hydroxylamine hydrochloride, hydroxylamine sulfate, hydroxylamine bisulfate or hydroxy la m in phosphate, and a base, e.g. For example, ammonium hydroxide, potassium hydroxide, sodium hydroxide or lithium hydroxide in an amount z. Brings example from 1 bis3MolejeMolvon hydroxylamine at a temperature of for example 0 ⁰ C to 6O ⁰ C for a period for example of 1 to 4 hours in contact.

A pressure of 0.1 to 10.1 bar can be used. The reaction is preferably carried out in an aqueous or alcoholic medium, i. in the presence of water and / or an alcohol such as methanol, ethanol or isopropanol. As explained above, according to one embodiment of the invention, the ketoxime can be converted into the corresponding aromatic N-

Azylhydroxyamine by a BECKMAN Nsche rearrangement, as shown in the equations (V) and (Vl) are converted.

The ketoxime is reacted in the presence of a catalyst for the reaction at a temperature of -70 ° C to 118 ⁰ C during a Daueryon tens of minutes to 4 hours.

The pressure is not critical and can for example be in the range of 0.1 bar to 10.1 bar. Preferably, the rearrangement at a temperature vo is η about - 70 ⁰ C to 40 "C and with a molar ratio of ketoxime to catalyst of 1:. 0.001 to 1: 0.1 conducted for a reaction time of 10 minutes to 2 hours Any Beckmann shear Rearrangement catalyst may be used, for example, an acid, for example, a mineral acid such as sulfuric or hydrochloric acid, an organic acid such as trifluoroethanoic acid, p-toluenesulfonic acid, benzenesulfonic acid or methanesulfonic acid, an acidic ion exchange resin such as Amberlyst 15 or Nafion 501 Preferably, the reaction is carried out with thionyl chloride in liquid sulfur dioxide, the reaction being advantageously carried out in the presence of the N-acyl group of the .sup.- desired substance corresponding anhydrous Karbonsäu from which usually the hydroxy derivative results, are carried out. The total amount of anhydrous carboxylic acid is not critical, usually the concentration of ketoxime is in the range of 2% by weight to 50% by weight at the beginning of the reaction.

According to the embodiment of the invention, the ketoxime can be converted to the corresponding aromatic N -azylazyloxyamine by BECKMANN rearrangement and concomitant acylation as shown in equations (VII) and (VIII) by contacting the ketoxime with suitable carboxylic acid anhydride and a BECKM AN Nsche η rearrangement catalyst at a temperature z. B. from 0 ⁰ C to 118 ⁰ C while einerDauervonz. B. 1 to 4 hours. Any anhydride may be used, preferably the alkanoic acid containing from 2 to 4 carbon atoms,

z. As acetic anhydride, propionic anhydride or n-butyric anhydride.

The pressure is not critical and can range from 0.1 to 10.1 bar. Again, any BECKMANN rearrangement catalyst can be used as discussed above. The reaction may advantageously be carried out in the presence of the anhydrous carboxylic acid corresponding to the anhydride used in the reaction in an amount of up to 50% by weight of the anhydride.

The total amount of anhydrous carboxylic acid is not critical, but the total amount of anhydride or the mixture of anhydride and acid should be such that the concentration of ketoxime at the beginning of the reaction is from 2 to 50% by weight.

embodiment

The following examples illustrate the invention

 example 1

It describes the preparation of 4-hydroxyazetophenone by the Fries rearrangement of phenyl acetate using hydrogen fluoride as a catalyst.

In an autoclave made of Hastelloy C of 300 cm ³ , 40.8 g (0.3 mol) of phenyl acetate were added. The autoclave was sealed, immersed in a dry ice isopropanol bath and internally cooled to -45 ° C and evacuated to 0.13 bar. An amount of 120 g, 6.0 mol of anhydrous hydrogen fluoride was added so that the internal temperature of the autoclave did not exceed ⁰ ° C. The internal pressure of the reactor was then adjusted to 1.1 bar with nitrogen. The contents of the autoclave was stirred and heated to 75 ⁰ C for one hour and heated. The hydrogen fluoride was removed at 45 ° C over a period of 45 minutes. The mixture was poured onto 25 g of ice and neutralized with a 45% potassium hydroxide solution. The aqueous solution was extracted with ethyl acetate. The organic fraction was then dried over anhydrous magnesium sulfate, filtered and the solvent removed on a rotary evaporator. This gives 44.0 g of a dark green solid, which corresponds to a 99.9% conversion of phenyl acetate and 94.3% selectivity in 4-hydroxyazetophenone.

Example 2

It describes the preparation of 4-hydroxyazetophenone by the Fries'sche rearrangement of phenyl acetate when using hydrogen fluoride as a catalyst with acetic anhydride as an additive.

In an autoclave Hastelloy C of 300cm ³ , 30.6 g, 0.3MoI, acetic anhydride submitted. The autoclave was cooled to -50 ° C and evacuated to 0.007 bar, whereupon 120 g, 6.0 moles of anhydrous hydrogen fluoride were added to the autoclave. After completion of the transfer of hydrogen fluoride, the internal temperature and the internal pressure using nitrogen, respectively to -50 ⁰ C and 1.1 bar were adjusted. To the stirred autoclave contents was added 81.6 g, 0.6 mol, phenyl acetate at such a rate that the temperature of the mixture did not exceed -23 ° C. After completion of the Phenylazetatzusatzes the contents were heated to 50 ⁰ C and stirred for 3 hours, while a pressure of about 3.9 bar was maintained. At the end of the reaction, the hydrogen fluoride was removed by an alkaline spray washer and poured the contents of the autoclave to about 30g of ice. The pH of the mixture was adjusted to 6.5 with 45% potassium hydroxide, and the mixture was then extracted with 75 ml of ethyl acetate (3x). The organic solution was dried over anhydrous magnesium sulfate, filtered and the solvent! removed by using a rotary evaporator.

The reaction proceeded with a 98.1% conversion of phenyl acetate and the following selectivity: phenol 1%, 4-hydroxyazetophenone (4-HAP) 82.3%; 2-hydroxyazetophenone (2-HAP) 4.3%; 3-hydroxyazetophenone (3-HAP) 0.1%; 4-acetoxyazetophenone (4-AAP) 3.8%; and 4- (4'-hydroxyphenyl) -azetophenone (HPAP) 0.4%.

Example 3

The preparation of 4-hydroxyazetophenone by the Fries rearrangement of phenyl acetate using hydrogen fluoride as catalyst and of acetic acid as additive is described.

The procedure of Example 2 was repeated, except that 18g, 0.3 moles of acetic acid instead of acetic anhydride were added to the reactor before it was cooled and filled with the hydrogen fluoride. A conversion of 99.0% phenyl acetate was achieved with the following selectivities: phenol 3.3%; Acetic acid 0.8%; 4-HAP 80.8%, 3-HAP 0%; 2-HAP 5.8%; 4-AAP 0.3%; and HPAP 0.3%.

Step Example! 4

This example describes the preparation of 4-hydroxyazetophenone (4 HAP) by the Friedel-Crafts acetylation of phenol with acetic acid as the acetylating agent.

Phenol 9.4 g, 0.1 mol, and acetic acid 12.0 g, 0.2 M oo I, were placed in a Haste 11 oy Cvon 300 ml autoclave at room temperature. The reactor was evacuated and cooled to -20 ° C. Hydrogen fluoride HF 100 g, 5 moles, was then transferred to the reactor. The reactor was heated to 80 ° C and held at reaction temperature for one hour. At the end of the reaction, the reactor was cooled to 20 ^° C. and the excess of hydrogen fluoride HF was removed to a potassium hydroxide spray scrubber. Ethyl acetate was added to the contents of the reactor. The mixture was then neutralized with 45% aqueous potassium hydroxide (KOH). The resulting organic phase was separated, dried over magnesium sulfate (MgSO ₄ ) and evaporated to give a yellow solid containing 13.1 g, 0.096 mol, of 4-HAP.

Example 5

This example describes the preparation of 4-hydroxyazetophenone oxime from 4-hydroxyazetophenone and hydroxylamine hydrochloride.

A solution was prepared by adding 13.6 g, 0.1 mol, 4-hydroxyazetophenone, 7.6 g, 0.11 mol, hydroxylamine hydrochloride and 10 g of water to 40 ml of ethanol. To the solution was added 5.0 g of 30% ammonium hydroxide, which was heated at reflux for 2 hours. The ethanol was removed on a rotary evaporator to give a yellow oil. An extraction procedure gave 15.1 g (99%) of 4-hydroxyazetophenone oxime.

Example 6

This example illustrates the preparation of 4-hydroxyazetophenone oxime from 4-hydroxyazetophenone and hydroxylamine

Sulfate. ;

ICreate a solution was prepared by adding 20.4 g, 0.15 moles, 4-Hydroxyazetophenon and 13.0 g, 0.08 mol, of hydroxylamine sulfate to 100 mL of water at 7O ⁰ C. To the solution was added 16.3 ml of 30% ammonium hydroxide and then heated at reflux for half an hour. White crystals formed upon cooling to give 21.0 g (92.6%) of 4-hydroxyazetophenone oxime.

Step Example! 7

This example illustrates the preparation of 4-hydroxyazetophenone oxime from 4-hydroxyazetophenone and hydroxylamine phosphate.

A solution was prepared by adding 20.4 g, 0.15 mol, 4-hydroxyazetophenone and 12.9 g, 65.6 mmol, hydroxylamine-phosphate to 100 mL of water at 70 ° C. To the solution was added 16.3 ml of 30% ammonium hydroxide and heated at reflux for ½ η for half an hour. White crystals formed upon cooling to give 21.0 g (92.6%) of 4-hydroxyazetophenone oxime.

Step Example! S

This example describes the preparation of 4-acetoxyazetanilide (AAA) by the Beckmann rearrangement and concomitant acetylation of 4-hydroxyazetophenone oxime using an acidic ion exchange resin as the catalyst. A mixture of 3.0 g, 22.0 mmol, 4-hydroxyazetophenone oxime, 3.0 g of Amberlyst 15 (a sulfonic acid ion exchange resin made by ROHM & HAAS) and 75 mL of a mixture of glacial acetic acid and acetic anhydride (1: 1) was added Reflux under nitrogen for 4 hours. The ion exchange resin was then removed and the mixture consisting of acetic acid and acetic anhydride distilled off in vacuo. This gives yellow-white crystals. The crystals were dissolved in ethyl acetate and treated with activated charcoal and anhydrous magnesium sulfate. The mixture was filtered and the solvent removed on a rotary evaporator. 3.4 g (80.4%) of yellow crystals of 4-acetoxyazetanilide (AAA) were obtained.

Example 9

This example illustrates the preparation of 4-acetoxyazetanilide (AAA) by Beckmann rearrangement and concomitant acetylation of 4-hydroxyazetophenone oxime using methanesulfonic acid as the catalyst.

A solution of 10 g, 66.2 mmol, of 4-hydroxyazetophenone oxime, 1.6 g of 70% methanesulfonic acid, 50 g of acetic anhydride and 100 g of glacial acetic acid was heated at reflux under nitrogen for 2 hours. After treatment in a rotary evaporator, 17.0 g of slightly brown crystals are obtained. Recrystallization in water gave 6.7 g (52.4%) of 4-acetoxyazetanilide (AAA). The mother liquor still contained 32.0% AAA, which corresponds to an overall yield of 84.4%.

Example 10

This example describes the preparation of 4-acetoxyazetanilide (AAA) by Beckmann rearrangement and concomitant acetylation of 4-hydroxyazetophenone oxime using phosphoric acid (H ₃ PO ₄ ) as the catalyst. To a mixture of 100 g of glacial acetic acid, 50 g of acetic anhydride and 3.6 g of 85% phosphoric acid H ₃ PO ₄ under nitrogen was added 10 g of 4-hydroxyazetophenone oxime over 30 minutes. The mixture was heated at reflux for 1 hour under a nitrogen atmosphere, then cooled to room temperature and neutralized with 13% sodium carbonate, Na ₂ CO ₃ . The mixture was evaporated to dryness using a rotary evaporator and the solid dissolved in 200g of boiling water. After hot filtration, the solution was allowed to cool overnight. The resulting white crystals were collected, washed with 20 ml of water and dried for 2 hours in a vacuum oven (6O ⁰ C, 0,13bar). After drying, 9.4 g (73.9%) of white crystalline plates of 4-acetoxyacetanilide having a melting point of 148 ° C to 150 ° C were obtained. An additional 0.8 μg of AAA and 1.5 g of N-acetyl-p-aminophenol (APAP) were recovered from the mother liquor.

The methods η of Examples 8 to 10 can also be used to prepare N-acetyl- (4-acetoxy-3-methylphenyl) arnine from o-cresyl acetate or o-cresol and acetic acid and acetic anhydride; N-propionyl- (4-propionoxyphenyl) amine from phenylpropionate or phenol and propionic acid and propionic anhydride; and N-n-butyryl- (4-n-butyroxyphenyl) amine from phenyl n-butyrate or phenol and n-butyric acid and n-butyric anhydride.

The aromatic N-azylazyloxyamines ^. For example, AAA according to this invention can be used as monomers for the preparation of polyester amides capable of forming an anisotropic melt phase and capable of being further processed into shaped articles such as fibers and films, as described e.g. In U.S. Patent Nos. 4,330,457, 4,339,375, 4,341,688, 4,351,918 and 4,355,132.

The aromatic N-Azy! Azyloxyamine according to the invention, for. B. AAA, can also be hydrolyzed to the corresponding aromatic N-Azylhydroxyamin, z. B. N-acetyl-p-aminophenol (APAP), which is one of the most common painkillers to form. The following example explains this procedure.

Example 11

A mixture of 5 g, 25.9 mmol, 4-acetoxyazetanilide (AAA), 1.4 g of 70% methanesulfonic acid and 50 g of water was heated at reflux for 1 hour. Upon cooling, white crystals formed. A (GLC) analysis of the crystals and the aqueous solution showed a 90% conversion of the AAA to N-acetyl-p-aminophenol (APAP).

Example 12

This example! illustrates the preparation of N-acetyl-p-aminophenol by the Beckmann rearrangement of 4-hydroxyazetophenone oxime using an acidic ion exchange resin as the catalyst. A mixture of 3.0 g Amberlyst 15 (a sulfonic acid ion exchange resin made by ROHM & HAAS), 3.0 g 22.0 moles, 4-hydroxyazetophenone oxime and 50 ml acetic acid was heated at reflux under nitrogen atmosphere for 2 hours. The ion exchange resin was then removed and the acetic acid distilled off in vacuo. This gives an orange residue. The residue was dissolved in ethanol and treated with activated charcoal and anhydrous magnesium sulfate. After removal of the ethanol using a rotary evaporator erg starting from 2.9 g egg yellow oil, which after drying 2,0g (66,7%) N-acetyl-p-aminophenol furnished.

Step Example! 13

This example illustrates the preparation of N-acetyl-p-aminophenol by the Beckmann rearrangement of 4-hydroxyazetophenone oxime using trifluoroacetic acid as the catalyst.

A solution of 10 g (66.2 moles) of 4-hydroxyazetophenone oxime and 75 g of trifluoroacetic acid was heated at reflux in a nitrogen atmosphere. The trifluoroacetic acid was then removed in a rotary evaporator. This gives 14.7 g of oil, which was dissolved in 100 ml of water. After cooling to 0 ⁰ C within half an hour, the crystallization was carried out. After filtration and drying of the crystals, 7.1 g (71%) of N-acetyl-p-aminophenol are obtained.

Example 14

This example describes the preparation of N-acetyl-p-aminopheno! by the Beckmann rearrangement of 4-hydroxyazetophenone oxime using thionyl chloride in liquid sulfur dioxide as the catalyst.

A pressure bottle cooled in a CO ₂ -acetone bath was filled with 50 m! SO ₂ , 0.05ml SOCl ₂ and 15g 4-hydroxyazetophenone oxime. The Ca ₂ -acetone bath was removed and the contents of the pressure bottle were stirred for 1.5 hours at room temperature.

The sulfur dioxide was then removed and the crystals from the pressure bottle were taken up in 50 ml of warm water. The pH of the aqueous slurry was adjusted to 6.5 by dropwise addition of 30% ammonium hydroxide. The slurry was cooled in an ice bath and then filtered. The filtered crystals were washed with 10 ml of ice water and dried overnight in a vacuum oven (6O ⁰ C, 0.13 bar). This gave 13.3 g (88.7%) of white crystals of N-acetyl-p-aminophenol having a melting point of 166.5 ° C to 17O ⁰ C.

The methods of Examples 12-14 can also be used to prepare N-acetyl- (4-hydroxy-3-methylphenyl) -amine from o-cresyl acetate or ortho-cresol. and acetic acid; To prepare N-propionyl-p-aminophenol from phenylpropionate or phenol and propionic acid and N-n-butyryl-p-aminophenol from pheny! N-butyrate or phenol and n-butyric acid.

Step Example! 15

A 250 ml pressure bottle was first cooled in a bath of dry ice and acetone and then precipitated with 50 ml of sulfur dioxide (by vacuum transfer), 0.05 ml of SOCl ₂ and 15 g of 4-hydroxyazetophenone oxime. The bath of dry ice and acetone was removed and the contents of the pressure bottle were stirred for 1.5 hours at ambient temperature. The sulfur dioxide SO ₂ was then removed and the crystals were washed from the pressure bottle with 50 ml of hot water.

The pH of the aqueous slurry was adjusted to 6.5 by the dropwise addition of concentrated ammonium hydroxide. The slurry was cooled in an ice bath and then filtered. The filtered crystals were washed with 10 ml of ice water and dried overnight in a vacuum oven at 60 ⁰ C. This gives 13.3 g of white crystals of N-acetyl-paminophenol having a melting point of 166.5 ⁰ C to 17O ⁰ C.

Example 16

The procedure of Example 15 was followed except that water from the faucet (24 ° C) was used to wash the crystals from the pressure bottle. Also, the amount of SOCl _{2 was increased} to 0.1 ml and the reaction time was reduced to 25 minutes. White crystals of N-acetyl-p-aminophenol (13.7 g) having a melting point of 165 ° C to 169 ⁰ C were recovered.

Example 17

This example illustrates the preparation of 2-methyl-4-hydroxyazetanilide using thionyl chloride as catalyst in sulfur dioxide SO ₂ .

The procedure of Example 15 was followed except that 2-methyl-4-hydroxyazetophenone oxime was used as the oxime, the amount of oxime was reduced to 5 g, the amount of thionyl chloride was increased to 0.5 ml, and the reaction time was 1 hour at room temperature ( 24 ° C) was lowered. Falbe or fawn-colored crystals of 2-methyl-4-hydroxy-acetanilide (1g) having a melting point of 122 ⁰ C to 128 ⁰ C were obtained.

Step Example! 18

This example illustrates the preparation of 2-hydroxyazetanilide by the Beckmann rearrangement of 2-hydroxyazetophenone oxime using thionyl chloride as the catalyst in sulfur dioxide SO2. The procedure described in Example 15 was used except that the oxime was 2-hydroxyazetophenone oxime, the amount of oxime reduced to 5 g, the amount of thionyl chloride increased to 2.5 ml, the reaction time reduced to 45 minutes, and the Reaction temperature 30 ⁰ C was. Yellow colored crystals of 2-Hydroxyazetanilid (3.6 g) having a melting point of 201 ⁰ C to 203 ° C were obtained.

Example 19

This example illustrates the preparation of N-acetyl-p-aminophenol by the Beckmann rearrangement of 4-hydroxyazetophenone oxime using thionyl chloride as the catalyst in diethyl ether.

A 250 ml round bottom flask equipped with a reflux condenser and an addition funnel was charged with 5 g of 4-hydroxyazetophenone oxime dissolved in 50 ml of anhydrous diethyl ether. A solution of 0.5 ml of thionyl chloride in 15 ml of ether was then added dropwise from the addition funnel. The contents of the flask were stirred during the addition and for an additional 30 minutes after completion of the addition. The ether was removed on a rotovap. The solid residue was then dissolved in 25 ml of hot water, the pH of the solution was adjusted to about 6.5 with ammonium hydroxide and then the solution was cooled in an ice bath. The crystals that were formed were filtered off, washed with about 10 ml of ice water and then dried in a vacuum oven at 65 ° C overnight. Brown crystals of N-acetyl-paminophenol (1.1 g) having a melting point of 161 ⁰ C to 162 ⁰ C were obtained.

Step Example! 20

This example describes the preparation of N-acetyl-p-aminophenol from 4-hydroxyazetophenone oxime using thionyl chloride as the catalyst in ethyl acetate.

The procedure of Example 19 was followed except that ethyl acetate was used as the solvent instead of diethyl ether. Slightly brown crystals of N-acetyl-p-aminophenol (1.9 g) having a melting point of 158 ⁰ C to 161 ° C were obtained.

Example 21

This example illustrates the preparation of N-acetyl-p-aminophenol from 4-hydroxyazetophenone oxime using thionyl chloride as the catalyst in acetone.

The procedure as in Example 19 was followed except that acetone was used as the solvent instead of diethyl ether. Brown crystals of N-acetyl-p-aminophenol (3.7 g) having a melting point of 159 ° C to 161 ⁰ C were obtained.

Step Example! 22

This example illustrates the preparation of N-acetyl-p-aminophenol from 4-hydroxyazetophenone oxime using thionyl chloride as the catalyst in tetrahydrofuran.

The procedure of Example 19 was followed except that tetrahydrofuran was used as the solvent instead of diethyl ether. Hazy crystals of N-acetyl-p-aminophenol (2.5g) having a melting point of 156 ° C to 158 ° C were obtained.

Step Example! 23

This example describes the preparation of N-acetyl-p-aminophenol from 4-hydroxyazetophenone oxime using thionyl chloride as a catalyst in methylene chloride.

The procedure as in Example 19 was followed, but methylene chloride was used as a solvent instead of diethyl ether. Dark brown Kristaile of N-acetyl-p-aminophenol (2.7 g) having a melting point of 152 ⁰ C to 156 ⁰ C were obtained.

Step Example! 24

This example illustrates the preparation of N-acetyl-p-aminophenol from 4-hydroxyazetophenone oxime using thionyl chloride as the catalyst in acetone under vacuum.

The procedure of Example 19 was followed except that acetone was used as the solvent instead of diethyl ether and the system was operated under vacuum (0.48 bar). Hazy crystals of N-acetyl-paminophenol (3.6 g) with a melting point of 162 ° C to 164 ° C were obtained.

Beisple! 25

This example illustrates the fact that the process of the present invention is capable of obtaining almost quantitative yields of the desired aromatic N-azylhydroxyamine.

The procedure of Example 16 was followed except that the filtrate was analyzed for N-acetyl-p-aminophenol to determine the actual yield. 13.7 g was recovered as a solid and the filtrate contained an additional 0.7 g of N-acetyl-p-aminophenol. As a result, a yield of 97% was achieved.

Claims (12)

Invention claim: 1. A process for the preparation of aromatic N-Azylhydroxy- and N-Azylazyloxaminen, characterized in that an aromatic hydroxy ketone is reacted with a hydroxylamine salt and a base to ketoxime of the ketone used and the resulting ketoxime using a suitable catalyst for Beckmann rearrangement to an aromatic N-Azylhydroxyamin is converted or the obtained ketoxime is converted with a carboxylic acid anhydride and a suitable catalyst for a Beckmann rearrangement catalyst to an aromatic N-Azylazyloxyamin. 2. The method according to item!, Characterized in that the aromatic hydroxy ketone is 4-hydroxyazetophenone, the ketoxime 4-hydroxyazetophenone oxime and the aromatic N-Azylhydroxyamin N-acetyl-p-aminophenol. 3. The method according to item 2, characterized in that the ketoxime is reacted with a catalytically effective amount of thionyl chloride in a solvent such as sulfur dioxide, diethyl ether, ethyl acetate, acetone, tetrahydrofuran or methylene chloride. 4. The method of item 3, characterized in that the solvent is sulfur dioxide and the rearrangement at a temperature of - 70 ° C to 40 ⁰ C is performed undbeieinemDruckvon0,1 bisiObar. 5. The method according to item 1, characterized in that the aromatic hydroxy ketone is formed by 4-hydroxyazetophenone, the ketoxime by 4-hydroxyazetophenone oxime, the anhydride by acetic anhydride and the aromatic N-Azylazyloxyamin by 4-Acetetoxyazetanilid. 6. A method according to item 5, characterized in that the 4-acetoxyacetanilide is hydrolyzed to form N-acetyl-paminophenol. 7. The method according to item 1, 2 or 5, characterized in that for the preparation of aromatic hydroxyketones ester of a phenolic compound and a carboxylic acid are reacted with a suitable catalyst for a Fries rearrangement. 8. The method according to item 7, characterized in that the suitable catalyst for Fries rearrangement is hydrogen fluoride. 9. The method according to item 8, characterized in that the ester is formed by Phenyiazetat. 10. The method according to item 1, 2 or 5, characterized in that for the preparation of aromatic hydroxy ketones, a phenolic compound and an acylating agent are reacted with a suitable catalyst for Friedel-Crafts rearrangement. 11. The method according to item 10, characterized in that the suitable catalyst for the Friedel-Crafts'schelagerung is hydrogen fluoride. 12. The method according to item 11, characterized in that the phenolic compound is phenol and the Azylierungsmittel is formed by acetic acid.