CS259542B2 - Method of n-acyl-(4-acyloxyphenyl) amines production - Google Patents

Abstract

Production method N-acyl- (4-acyloxyphenyl) - of the amines of the formula I wherein R and R are the same or different C1 to C3 alkyls the reaction of an aromatic hydroxyketone of formula II with a hydroxylamine salt and base to form the corresponding ketoxin, treated with carboxylic anhydride of the formula III and a catalyst Beckmann's rearrangement. Produced The compounds can be used as monomers for the production of polyesteramides capable of forming anisotropic melt and suitable for processing into various shaped articles.

Description

The invention relates to a process for the preparation of N-acyl- (4-acyloxyphenyl) amines.

It is known to produce aromatic N-acyl-acyloxyamines, for example 4-acetoxyacetanilide, by preparing a sodium salt of the corresponding aromatic amine, for example N-acetyl-p-aminophenol, and reacting the sodium salt with the corresponding carboxylic acid anhydride, for example acetic anhydride. The aromatic N-acyl-hydroxyamine, for example N-acetyl-β-aminophenol, is prepared by acylating the corresponding aromatic hydroxyamine, for example p-aminophenol, with an acylating agent such as an anhydride, for example acetic anhydride. However, the latter reaction can cause a number of problems, such as the difficult mono-acylation of the aromatic hydroxyamine, the oligomerization of the aromatic hydroxylamine and the formation of colored impurities.

Further, when N-acetyl-p-aminophenol is produced from p-aminophenol, it is usually practiced that the nitrobenzene is catalytically hydrogenated and at the same time rearrangements in the presence of a platinum catalyst to form p-aminophenol, which entails the problem of isolating the platinum catalyst dispersed in the product.

It is also known to prepare N-acetyl-p-aminophenol by hydrogenating 4-nitro-chlorohenzene to 4-chloroaniline, which is then reacted with aqueous potassium hydroxide to give p-aminophenol, which is acetylated to N-acetyl-p- aminophenol. This process is relatively complex and requires a considerable number of reaction and purification steps. In addition, the acetylation step of the process may give rise to the same problems encountered in the acetylation of nitrobenzene.

Auwers et al. in Chemische Berichte 58, 36-51 (1925) describe Beckmann rearrangement of a large number of aromatic ketone oximes, most of which are substituted acetophenones. The only attempt to rearrangement of the unsubstituted aromatic hydroxyketone oxime was the o-hydroxyacetophenone oxime rearrangement, but no amine was formed, so the rearrangement attempt was unsuccessful (see page 41).

Ganboa et al. in Synthetic Communications 13, (11), 941-944 (1983) describe the preparation of acetanilide from acetophenone under reflux in a hydroxylamine hydrochloride solution. However, there is no mention of the synthesis of aromatic N-acyl-acyloxyamines, such as 4-acetoxyacetanilide, or of the synthesis of aromatic N-acyl-hydroxyamines, such as N-acyl-p-aminophenol.

Pearson et al. in the Journal of the American Chemical Society 75, 5,905 to 5,908 (December 5, 1953) describe the preparation of hydrazones from ketones by reaction with hydrazine hydrate and the rearrangement of hydrazones to amides by treatment with sodium nitrite and concentrated sulfuric acid. Pearson et al. Rearrangement of p-hydroxyacetophenone hydrazones to ρ-hydroxyacetanilide, i.e. to N-acetyl-p-aminophenol.

In accordance with the invention, N-ucyl- (4-acyloxyphenyl) amines such as 4-acetoxyanilide are produced by reacting an aromatic hydroxyketone such as 4-hydroxyacetophenone with hydroxylamine or a hydroxylamine salt to form a ketoxime derived from the corresponding ketone, which ketoxime is subjected to Beckmann and simultaneous acylation by contacting the carboxylic acid anhydride and a Beckmann rearrangement catalyst to form the corresponding aromatic N-acyl-acyloxyamine.

In one particular embodiment, 4-acetoxyacetanilide is produced from phenylacetate or phenol and an acetylating agent such as acetic acid by a process comprising converting phenylacetate or phenol and acetylating agent by a Fries rearrangement, respectively. Friedel-Crafts acetylation to 4-hydroxyacetophenone, and conversion of 4-hydroxyacetophenone by treatment with hydroxylamine or hydroxylamine salt to the corresponding ketoxime. This ketoxime is then subjected to Beckmann rearrangement and concurrent acetylation by contacting it with acetic anhydride and a Beckmann rearrangement catalyst to form 4-acetoxyacetanilide.

When the process of the invention is carried out using phenylacetate as the starting material, the initial Fries rearrangement of the phenylacetate to 4-hydroxyacetophenone proceeds according to the following Scheme I:

Scheme I <Q> -o ccò

When phenol and an acetylating agent are used as starting materials in the process of the invention, the acetylation reaction leading to the formation of 4-hydroxyacetophenone is carried out according to the following Scheme II:

Scheme II

+ CH ^ CQ ΧΟΗ?

!

ii 'Λ ^ Ο2' M ⁺ wherein X represents a residue of a compound known as aceíylační agent without acetyl groups. The radical X may be, for example, a hydroxyl group, an acetoxy group or a halide anion, including the fluoride, chloride, bromide and iodine III anions. Useful acetylating agents are, for example, acetic acid, acetic anhydride, acetyl fluoride, acetyl chloride and acetyl bromide. '

The formation of the ketoxime according to the invention proceeds according to the following reaction scheme III:

HO Ar ~ C - 0 + Η θ H H 0 Ar ^ C- Η 0 H;

The formation of the 4-hydroxyacetophenone-derived ketoxime, i.e., 4-hydroxyacetophenone-oxi-oxime, is carried out according to the following reaction scheme IV:

CH '

H0 - (O) - + NH2 QH

NO

^CH 3

- C = HCH + bifl

The Beckman rearrangement together with the simultaneous acylation according to the invention proceeds according to the following reaction scheme V:

S c h et a V,

Hoare / θ II / -P ^z.-Q) n R ~ ro. <- H oo + R "COOH of Fe if the desired product 4-acetoxyacet- concurrent acetylation according to the following reanilid, therefore takes place Beckmann rearrangement and action schema VI:

S c bé m a V I

Ch ' ₃ ! I-O-O-HOH + fCH 2 COX 0 (CN) CQO N

V / i A- J

O

CH 2 CO-ZO

OF)

In reaction schemes III and V, the radicals R and R are the same 1,4-phenylene radical. or different, and having the above schemes may have the meaning given above.

R and R‘, wherever present in Schemes III and V, preferably have the same meaning and represent a methyl, ethyl or propyl group, most preferably a methyl group corresponding to the use of acetic esters and methyl ketones in the latter schemes. The preferred particular aromatic hydroxyketone used to prepare the oxime is 4-hydroxyacetophenone and the preferred product is 4-acetoxyacetanilide.

Scheme VII

The aromatic hydroxyketones used to prepare the oximes can be prepared by any method known in the art. For example, such a ketone can be prepared by the Fries rearrangement of the corresponding phenyl ester, as outlined in the following Reaction Scheme VII, which represents a generalized form of Scheme I, wherein Aa and R are as defined above.

Η-Αϊ-OCR ~ A <

O ii _r

Alternatively, the phenol and the acylating agent may be reacted by Friedel-Crafts acylation to form the aromatic Scheme VIII hydroxyketone as outlined in the following Reaction Scheme VIII, which represents a generalized form of Scheme II:

Oll + R---x <3 j ‘A A R τ 11 11 λ

In this scheme, Ar and R are as defined above and X represents the remainder of the compound known as the acylating agent after cleavage of the acyl group

O

II

R —C—, such as a hydroxyl group, an acyloxy group such as an acetoxy group, or a halide anion such as a fluoride, chloride, bromide or iodide anion. Useful acylating agents are, for example, the appropriate alkanoic acids, for example acetic and propionic acid, alkenic anhydrides, for example acetic anhydride or propionic anhydride, and acyl halides, for example acetyl and propionyl fluoride, -chloride and -bromide. It should be emphasized that although the reaction of a phenolic compound with an acylating agent is referred to herein as "Friedel-Crafts acylation", this designation does not express any opinion or belief about the mechanism of the reaction.

The catalyst for the two previous reactions is preferably hydrogen fluoride, but any other catalyst known to be effective in the above reactions, such as aluminum chloride, zinc chloride or boron trifluoride, can be used in the Fries reaction and Friedel-Crafts reaction. .

The reaction may be carried out by introducing a phenyl ester or phenol and an acylating agent, a catalyst, and optionally, if the starting material is a phenyl ester, a suitable reaction additive such as acetic anhydride or acetic acid into a stainless steel reactor and the mixture is about 0.5 to It is heated for 4 hours at a temperature of about 20 to 100 ° C under a pressure of about 0.34 to 3.4 MPa.

When hydrogen fluoride is used as the catalyst, it can be used in the reaction either in gaseous or liquid form, using conventional handling technologies. In carrying out the reaction, an inert gas such as nitrogen may be used to maintain the desired pressure in the reaction space and to provide sufficient hydrogen fluoride to contact the reaction liquid.

Generally, an excess of hydrogen fluoride is used, for example about 7 to 75 moles, for each mole of the phenyl ester or phenol initially present in the reaction zone. When the desired reaction product is 4-acetoxyacetanilide, phenylacetate is used as the starting material in the Fries rearrangement and phenol and an acetylating agent such as acetic acid in the Friedel-Crafts acylation. The starting material is converted to 4-hydroxyacetophenone, which is then converted to 4-acetoxyacetanilide by the process of the invention.

Conversion of aromatic hydroxyketones,

239542

For example, 4-hydroxyacetophenone, to aromatic N-acyl-acyloxyamines, for example 4-acetoxyacetanilide, is carried out by first preparing ketoxime from the aromatic hydroxyketone by the procedure outlined in Reaction Schemes III and IV, by reacting the ketone with hydroxylamine, or hydroxylamine salts such as hydroxylamine hydrochloride, hydroxylamine sulphate, hydroxylamine hydrogen sulphate or hydroxylamine phosphate, and throws such as ammonium hydroxide, potassium hydroxide, sodium hydroxide or lithium hydroxide.

The ketone is used in an amount of, for example, 1 mole to 3 moles for each mole of hydroxyl amine, and the reaction is carried out at a temperature of, for example, from 0 to 60 ° C for a period of time, e.g. The reaction may be carried out at any pressure, for example at a pressure of 0.01 to 1.01 MPa. The reaction is preferably carried out in an aqueous or alcoholic medium, i.e. in the presence of water and / or an alcohol such as methanol, ethanol or isopropanol.

In accordance with the method of the invention, ketoxime can be converted to the corresponding N-acyl- (4-acyloxyphenyl) amine by a Beckmann concomitant acylation rearrangement as outlined in Schemes V and VI by contacting the ketoxime with an appropriate carboxylic acid anhydride and a Beckmann rearrangement catalyst at a temperature of, for example, from 0 to 118 ° C for a period of time, for example, from 1 to 4 hours. The pressure does not play a decisive role in the reaction and may be, for example, in the range of bd 0.01 to 1.01 MPa.

In principle, any Bechmns rearrangement catalyst such as an acid such as a mineral acid such as sulfuric acid or hydrochloric acid, an organic acid such as trifluoroacetic acid, p-toluenesulfonic acid or benzenesulfonic acid or methanesulfonic acid, such as an ion exchanger such as amberlystate can be used. 15 or Nafion 501, which are sulfonic acid or thionyl chloride ion exchangers in liquid sulfur dioxide, diethyl ether, ethyl acetate, acetone, tetrahydrofuran or methylene chloride.

The reaction is preferably carried out in the presence of glacial carboxylic acid corresponding to the anhydride used in the reaction, for example up to 50% by weight of the anhydride. The total amount of glacial carboxylic acid does not play a critical role, but the total amount of anhydride or α-acid anhydride mixture is chosen such that at the beginning of the reaction the ketoxime concentration is in the range of about 2 to 50% by weight in most cases.

The invention is illustrated by the following non-limiting examples.

Example 1

This example illustrates the preparation of 4-hydroxyacetophenone by Fries rearrangement of phenylacetate using hydrogen fluoride as a catalyst.

40.8 g (0.3 mole) of phenylacetate are introduced into a 300 ml stainless steel (Hastelloy Cj) autoclave. The autoclave is sealed, immersed in a solid carbon dioxide bath in isopropanol, cooled to -45. The temperature of the autoclave is heated to 75 ° C with stirring for 1 hour, the hydrogen fluoride is allowed to drain over 45 minutes at a temperature of about 45 ° C, the mixture is poured onto 25 g of ice and neutralize with 45% potassium hydroxide solution.

The aqueous mixture was extracted with ethyl acetate, the organic fraction was dried over anhydrous magnesium sulfate, and after filtration the solvent was removed by rotary evaporation. 44.0 g of a dark green solid are obtained, corresponding to a 99.9% conversion of phenylacetate and 94.3% selectivity to the formation of 4-hydroxyacetophenone.

Example 2

This example illustrates the preparation of 4-hydroxyacetophenone by Fries rearrangement of phenylacetate using hydrogen fluoride as a catalyst and acetic anhydride as an additive.

A 300 ml stainless steel autoclave is charged with 30.6 g (0.3 mol) of acetic anhydride, the autoclave is cooled to -50 ° C, evacuated to 0.7 kPa and the pressure cylinder is charged with 120 ml. g (6.0 mol) of anhydrous hydrogen fluoride. Upon termination of the hydrogen fluoride feed, the temperature inside the autoclave was adjusted to 5050%! and the pressure is adjusted to 0.11 MPa with nitrogen. 81.6 g (0.6 mol) of phenylacetate are added to the autoclave with stirring at a rate such that the temperature of the mixture does not exceed -23 degrees Celsius. Upon completion of the addition of phenylacetate, the reach of the autoclave was heated to 50 ° C and stirred for 3 hours at a pressure of 0.39 MPa.

At the end of this phase of the reaction, hydrogen fluoride is allowed to flow through a hydroxide scrubber and the contents of the autoclave are poured over approximately 30 g of ice. The pH was adjusted to 6.5 with 45% potassium hydroxide and the mixture was extracted with 75 mL of ethyl acetate. After extraction three times, the organic solution is dried over anhydrous magnesium sulfate, filtered, and the solvent is removed by rotary evaporation.

The reaction proceeds with 98.1% conversion of phenylacetate and the following selectivities: phenol 1%,

4-hydroxyacetophenone 82.3%,

2-hydroxyacetophenone 4.3%,

3-hydroxyacetophenone 0.1%,

4-acetoxyacetofetion 3.8% a

4- (4‘-hydroxyphenyl) acetophenone 0.4%.

Example 3

This example describes the preparation of 4-hydroxyacetophenone by Fries rearrangement of phenylacetate using hydrogen fluoride as a catalyst and acetic acid as an additive.

The procedure of Example 2 was repeated except that 18 g (0.3 mol) of acetic acid was introduced in place of acetic anhydride, prior to cooling and adding HF. The reaction yielded 99.0% conversion of phenylacetate with the following selectivities:

phenol 3,3%, acetic acid 0,8%,

4-hydroxyacetophenone 80.8%,

3-hydroxyacetophenone 0%

2-hydroxyacetophenone 5.8%,

4-acetoxyacetophenone 0.3% a

4- (4‘-hydroxyphenyl) acetophenone 0.3% Example 4

This example illustrates the preparation of 4-hydroxyacetophenone by Friedel-Crafts acetylation of phenol with acetic acid as acetylating agent.

9.4 g (0.1 mole) of phenol and 12.0 g (0.2 mole) of acetic acid are introduced into a 300 ml stainless steel autoclave at room temperature and the reactor is evacuated, cooled to -20 ° C and brought to room temperature. 100 g (5 moles) of hydrogen fluoride are added thereto, the reactor is heated to 80 DEG C. for 1 hour, then the reactor is cooled to 20 DEG C. and excess hydrogen fluoride is transferred to a potassium hydroxide scrubber. The organic phase was separated, dried over magnesium sulphate and evaporated to give a yellow solid product containing 13.1 g (0.096 mol) of 4-hydroxyecetophenone.

Example 5

This example illustrates the preparation of 4-hydroxyacetophenone oxime from 4-hydroxyacetophenone and hydroxylamine hydrochloride.

By adding 13.6 g (0.1 mol) of 4-hydroxyacetophenone, 7.6 g (0.11 mol) of hydroxylamine hydrochloride and 10 g of water to 40 ml of ethanol, a solution is prepared to which 5.0 g of 30% is added. ammonium hydroxide and the mixture was heated to reflux for 2 hours. The ethanol was evaporated on a rotary evaporator to give an oily yellow colored residue which, by extractive work-up, gave 15.1 g (99%) of 4-hydroxyacetophenone oxime. Example 6

This example illustrates the preparation of 4-hydroxyacetophenone oxime from 4-hydroxyacetophenone and hydroxylamine sulfate.

20.4 g (0.15 mol) of 4-hydroxyacetophenone and 13.0 g (0.08 mol) of hydroxylamine sulfate were dissolved in 100 ml of water at 70 ° C. To the solution was added 16.3 mL of 30% ammonium hydroxide, and the mixture was heated to reflux for 0.5 h. After cooling, 21.0 g (92.6 percent) of 4-hydroxyacetophenone oxime precipitated as white crystals from the reaction mixture.

Example 7

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

20.4 g (0.15 mol) of 4-hydroxyacetophenone and 12.9 g (65.5 mmol) of hydroxylamine phosphate are dissolved in 100 ml of water at 70 ° C. To the solution was added 16.3 mL of 30% ammonium hydroxide, and the mixture was heated to reflux for 0.5 h. After cooling, 21.0 g (92.6%) of 4-hydroxyacetophenone oxime precipitated as white crystals from the reaction mixture.

Example 8

This example illustrates the preparation of 4-acetoxyacetanilide by Beckmann rearrangement and simultaneous acetylation of 4-hydroxyacetophenone oxime using an acidic ion exchanger catalyst.

A mixture of 3.0 g (22.0 mmol) of 4-hydroxyacetophenone oxime, 3.0 g of Amberlyst 15 sulfonic acid ion exchanger and 75 ml of a mixture of equal portions of glacial acetic acid and acetic anhydride was heated under reflux for 4 hours under nitrogen. The ion exchanger was removed and acetic acid together with acetic anhydride were distilled off in vacuo. A yellow-white crystalline residue is obtained, which is dissolved in ethyl acetate. The solution is clarified with charcoal and dried over magnesium sulfate, filtered and the solvent is removed by rotary evaporation. 3.4 g (80.4%) of 4-acetoxyacetanilide are obtained as yellow crystals.

Example 9

This example illustrates the preparation of 4-acetoxyacetanilide by Beckmann rearrangement and simultaneous acetylation of 4-hydroxyacetophenone oxime using methanesulfonic acid catalyst.

A solution consisting of 10 g (66.2 mmol) of 4-hydroxyacetophenone oxime, 1.6 g of 70% methanesulfonic acid, 50 g of acetic anhydride and 100 g of glacial acetic acid was heated under reflux for 2 hours under nitrogen. Evaporation of the solution on a rotary evaporator gave 17.0 g of brownish crystals which, after recrystallization from water, yielded 6.7 g (52.4%) of 4-acetoxyacetanilide. The mother liquor also contains 32.0% of 4-acetoxyacetanilide. The total yield of the product is thus 84.4%.

Example 10

This example illustrates the preparation of 4-acetoxyacetanilide by Beckmann rearrangement and simultaneous acetylation of 4-hydroxyacetophenone oxime using phosphoric acid (H 3 PO 4) as a catalyst.

To a mixture of 100 g of glacial acetic acid, 50 g of acetic anhydride and 3.6 g of 85% phosphoric acid, which was purged with nitrogen for 30 minutes, was added 10 g of 4-hydroxyacetophenone oxime. The reaction mixture was heated under reflux for 1 hour under nitrogen, then cooled to room temperature and neutralized with 13% sodium carbonate solution. The mixture was evaporated on a rotary evaporator to dryness and the solid residue was dissolved in 200 g of boiling water. The solution was filtered hot, then allowed to cool and allowed to stand overnight.

The precipitated white crystals are collected, washed with 20 ml of water and dried in a vacuum oven at 60 DEG C. under 50 mbar for 2 hours. After drying, 9.4 g (73.9%) of 4-acetoxyacetanilide are obtained in the form of white platelet crystals, m.p. 148-150 ° C. A further 0.8 g of 4-acetoxyacetanilide and 1.5 g of N-acetyl-p-aminophenol are obtained from the mother liquors.

The procedures described in Examples 8-10 can also be used to prepare the following compounds:

N-acetyl- (4-acetoxy-3-methylphenyl) amine from o-cresyl acetate or o-cresol and acetic acid, and acetic anhydride,

N-propionyl- (4-propionyloxyphenyl) amine from phenylpropionate or phenol and propionic acid, and propionic anhydride; and

N-n-butyryl- (4-n-butyryloxyphenyl) amine from phenyl-n-butyrate or phenol and n-butyric acid and n-butyric anhydride.

The aromatic N-acyl-acyloxyamines of the invention, for example 4-acetoxyacetanilide, can be used as monomers to produce polyester amides capable of forming an anisotropic melt and suitable for processing into shaped articles such as moldings, fibers and films, as described, for example, in U.S. Patents Nos. 4,330,457, 4,339,375, 4,341,688, 4,351,918 and 4,355,132.

The aromatic N-acyl-acyloxyamines of the invention, for example 4-acetoxyacetanilide, can also be hydrolyzed to the corresponding aromatic N-acyl-hydroxyamines, for example N-acetyl-p-aminophenol, which is one of the most widely used analgesics. The following example illustrates this procedure.

Example 11

A mixture of 5 g (25.9 mmol) of 4-acetoxyacetanilide, 1.4 g of 70% methanesulfonic acid and 50 g of water was heated under reflux for 1 hour. Upon cooling, white crystals precipitated from the mixture. Analysis of the crystals and aqueous solution by gas chromatography indicated a 90% conversion of 4-acetoxyacetanilide to N-acetyl-p-aminophenol.

Claims (4)

SUBJECT OF THE INVENTION A process for the preparation of N-acyl- (4-acyloxyphenyl) amines of the general formula I: R ~ C-O- / Ol · N H-C (I) wherein R is C 1 -C 3 alkyl and ¹ R 'is C 1 -C 3 alkyl, characterized in that the aromatic hydroxyketone of formula II HO - (0 / O R is as defined above, reacted with a hydroxylamine salt and a base such as ammonium hydroxide, potassium hydroxide, sodium hydroxide or lithium hydroxide to give the corresponding ketoxime which is treated with a carboxylic acid anhydride of formula III R'-C-O-C —R ' O O VII) in which: R‘ is as hereinbefore defined, optionally in combination with the corresponding glacial carboxylic acid and a Beckmann rearrangement catalyst, such as an ion exchanger with sulfo groups, methanesulfonic acid or phosphoric acid. 2. The process of item 1, for producing a 4-acetoxyacetanilide of the formula wherein (n) CH ^C-O Z— \ h V-N-C = O, characterized in that 4-hydroxyacetophenone is used as the starting material, which is converted to 4-hydroxyacetophenone oxime, which is treated with acetic anhydride and Beckmam's rearrangement catalyst. 3. The process of claim 1 wherein the hydroxylamine salt is hydroxylamine hydrochloride, hydroxylamine sulfate, hydroxylamine hydrogen sulfate or hydroxylamine phosphate. 4. A process according to claim 1, wherein the reaction of the compound of formula II with the hydroxylamine salt to form the corresponding ketoxime is carried out in an aqueous or alcoholic medium such as water and / or an alcohol such as methanol, ethanol or isopropanol.