WO1994001394A1

WO1994001394A1 - Preparation of n-aryl amides

Info

Publication number: WO1994001394A1
Application number: PCT/AU1993/000326
Authority: WO
Inventors: Christopher Roy Strauss; Paul Gurr; Teresa Cablewski
Original assignee: Commonwealth Scientific And Industrial Research Organisation
Priority date: 1992-07-02
Filing date: 1993-07-02
Publication date: 1994-01-20

Abstract

A process for the amidation of an aromatic compound to give an N-aryl amide, in particular for production of 4'-hydroxyacetanilide (1a) (also known as paracetamol and acetaminophen), which process can be performed in a single reaction vessel. 4'-Hydroxyacetanilide has commercial applications in the pharmaceutical industry as an analgesic and an antipyretic; it and related compounds are used in the manufacture of azo dyes and photographic chemicals.

Description

Preparation of N-aryl Amides

This invention concerns a novel process for ^■the amidation of an aromatic compound to give an N-aryl amide, in particular for production of 4' -hydroxyacetanilide (la) (also known as paracetamol and acetaminophen) , which process can be performed in a single reaction vessel. 4' -Hydroxyacetanilide has commercial applications in the pharmaceutical industry as an analgesic and an antipyretic; it and related compounds are used in the manufacture of azo dyes and photographic chemicals.

4' -Hydroxyacetanilide is generally prepared by two procedures (H.H. Szmant, "Organic Building Blocks of the Chemical Industry" John Wiley & Sons, New York 1989 at p.10 and pp. 503-5) . In the older process, shown in Scheme 1, a para-selective nitrosation of phenol under strong acid conditions is followed by reduction and then N-acylation of the intermediate p-aminophenol. This procedure involves several manipulative steps and presents difficulties with both yield in the nitrosation step and with the nature and volume of the effluent. In a modification of this process, nitration of phenol can be the first step.

Scheme 1: Conventional process to paracetamol from phenol. In the more recent method, shown in Scheme 2 and disclosed in US patent 4,524,217 and US 4,560,789 to K.G. Davenport and C.B. Hilton of the Hoechst-Celanese Corporation, phenyl acetate is converted in a Fries rearrangement to 4' -hydroxyacetophenone using hydrofluoric acid as a catalyst. The ketone after isolation is treated with hydroxylamine under basic conditions to give the oxime anti-isomer with respect to the aryl ring. The oxime is isolated and then subjected to a Beckmann rearrangement under acid catalysis. The product (la) may be purified as its 0-acetyl derivative (lb) which is subsequently deacetylated by hydrolysis in dilute methanesulfonic acid. The main difficulties with this procedure are the relatively high cost, the handling and use of the aggressive reagents (particularly HF) , the large number of steps involved and the problems of effluent disposal.

Scheme 2: Hoechst-Celanese patented process

Accordingly, it is an object of the present invention to overcome or alleviate at least one of the problems associated with the prior art.

We have now surprisingly found that it is possible to carry out Friedel-Crafts reactions or Fries re-arrangements, oximations and Beckmann rearrangements in a single reaction vessel or pot without isolation of intermediate compounds.

There appears to be only one previous report (I. Ganboa and C. Palomo, Synthetic Commun. 13, 941 (1983)) of acid-catalysed oximation followed by Beckmann rearrangement in a single pot. In that work the reactions were conducted over several hours in refluxing formic acid containing trifluoromethanesulfonic acid. None of the examples given involved paracetamol production.

The present invention is further distinguishable from the prior art as it is the first reported example of oximation and Beckmann rearrangement being achievable with a catalyst other than formic acid/trifluoromethanesulfonic acid.

In a first aspect the present invention provides a process for the preparation of an N-aryl amide in a single reaction vessel, including the reaction of an aromatic compound with a C-acylation reagent and a hydroxylamine salt or derivative in the presence of an acidic catalyst.

The process of the invention may be carried out in a single step or in a two step procedure whereby the aromatic compound is first reacted with a C-acylating reagent in the presence of said catalyst followed by addition of the hydroxylamine salt or derivative

If the aromatic compound is phenolic the reaction of the invention may provide a mixture of products which may be subsequently diluted with water and hydrolysed to produce the product N-aryl amide. In a preferred embodiment the mixture of products may be hydrolysed by adding aqueous alkali and heating under reflux. Any suitable aromatic compound may be used in the invention. Suitable aromatic compounds include, phenol, phenyl acetate, anisole, phenetole, diphenyl carbonate, triphenyl phosphate, triphenyl phosphine, 1,1-diphenoxyethane, triphenylorthoformate, phenyl vinyl ether, t-butyl phenyl ether, dichloromethyl phenyl ether, the tetrahydropyranyl ether of phenol, veratrole, guaiacol, alkyl substituted benzene, di-2-phenoxyethyl ether, chroman, thiophene, 2-methylthiophene, 3-methylthiophene, 2-chlorothiophene, 2-bromothiophene, 2,2' -dithienyl, indole, pyrrole, toluene, xylenes, indane, tetralin, cu ene, catechol, resorcinol, phloroglucinol, tolyl methyl ether, resorcinol dimethyl ether, hydroquinone dimethyl ether, pyrogallol trimethyl ether, diphenyl ether, naphthalene, α-naphthol, β-naphthol, furan, 2-methylfuran and benzofuran.

For the production of 4' -hydroxyacetanilide, preferred aromatic compounds on the grounds of costs, availability and yield are phenol, phenyl acetate and anisole. Anisole reacts most readily and cleanly to produce p-methoxyacetanilide which may be demethylated by any suitable agent. Preferably p-methoxyacetanilide may be demethylated in high yield with A1C1- (approximately 2 equivalents) in the absence of a solvent. From the viewpoint of cost, phenol is the most appropriate starting material for the production of 4' -hydroxyacetanilide.

Any suitable C-acylation reagent may be used in the invention. Suitable C-acylation agents are carboxylic acids, anhydrides, or acid halides either alone or in combination. Carboxylic acids or anhydrides are preferred for giving the cleanest product in the shortest time.

The key to the process lies with the catalyst, which should be inexpensive and have the capability to fulfill several functions, either in solution or under heterogenous conditions. It should effect the highly para-selective acylation of the aromatic compound and allow oximation" to proceed affording the anti-oxime with respect to the aryl ring. It should also facilitate Beckmann rearrangement of the oxime to give the desired amide. Finally, it should carry out all of the above functions under fairly uniform conditions of temperature, without significant by-product formation, and within a reasonable time.

Catalysts for Friedel-Crafts acylations, Fries rearrangements and Beckmann rearrangements are well known. Acidic oximation catalysts are less well known. Catalysts with the combination of properties required for this invention have not previously been recognised.

Several catalysts were investigated for carrying out the one-pot processes. Among these were P.O_ς, H^SO., ion exchange resins in the sulfonic acid and phosphonic acid forms, and polyphosphoric ester. Some of these were employed in the presence of co-solvents with the aim of removing water from the reaction mixtures by azeotropy. Some gave little or no reaction, and others considerable by-products or extensive decomposition.

We have discovered that polyphosphoric acid (PPA) , P-^C in methanesulfonic acid or hydrogen fluoride are suitable catalysts. Polyphosphoric acid (PPA) is preferred because of its solvent properties, its mild acid characteristics and its demonstrated applicability as a catalyst for Friedel-Crafts reactions, Fries rearrangements and Beckmann rearrangements, as reviewed by U lig and Snyder (Adv. in Org. Chem. 1, 35 (1960) ) . PPA has not been reported previously as useful for oximation. This procedure has traditionally been conducted under basic conditions in the presence of compounds such as pyridine. Hydrogen fluoride is a_ useful, albeit less desirable catalyst, because of its corrosive nature. Any suitable quantity of PPA may be used in the invention. Preferably the PPA has a composition equivalent " to approximately 121% to 116% H_P0 . Preferably the amount of catalyst used is within the range of approximately 7-10g per gram of aromatic compound.

Any suitable hydroxylamine salt or derivative may be used in the process of the invention. Suitable hydroxylamine salts include the hydrochloride, sulphate and phosphate; suitable derivatives include hydroxylamine 0-sulfonic acid and O-acetylhydroxylamine.

The reaction may be carried out under any suitable conditions. Preferably the process is carried out at moderate temperatures and in the absence of organic solvent. For example, the process may be carried out at a temperature in the range of 70^βC-120°C. 80°C is the preferred temperature for the production of 4' -hydroxyacetanilide.

The process will now be discussed in more detail in reference to the production of 4' -hydroxyacetanilide wherein the process is carried out in a two step procedure. It will be appreciated by those skilled in the art that various modifications and changes to the process described may be made and thus the following discussion should not be seen as limiting in any way.

STEP 1. Formation of a mixture of 4' - hydroxyacetophenone and 4' -acetoxyacetophenone.

In the first step, a mixture of 4' -hydroxyacetophenone and 4' -acetoxyacetophenone is produced by a regioselective Friedel-Crafts reaction from phenol at a moderate temperature (around 80°C) or by a similarly selective Fries rearrangement of phenyl acetate. An esterification of phenol followed by a Fries rearrangement may be carried out as a further alternative. Such reactions on these substrates have been well documented over the past four decades.

Friedel-Crafts reaction on phenol or phenyl acetate appears to be the preferred alternative. Under the conditions used here, the Fries rearrangement was slower than Friedel-Crafts acylation and was partially reversible. Since cost is a major consideration, the use of phenol as a starting material is preferable to other aromatic compounds such as anisole or phenyl acetate.

The optimal reaction temperature for para-selectivity of phenol occurred near 80°C; temperatures over 100°C give rise to increasing proportions of the ortho isomer. At temperatures below 80°C the reaction slows considerably, and below 60°C phenyl acetate is the major product.

STEP 2 Concomitant oxime formation and Beckmann rearrangement.

After allowing sufficient time for the acylation or Fries rearrangement, the mixture of 4' -hydroxyacetophenone and 4' -acetoxyacetophenone is treated in situ with a salt of hydroxylamine and a mixture of la and lb is formed.

Only a small excess of hydroxylamine salt is needed t achieve total conversion of ketone to amide. It is though that under the influence of PPA the Beckmann rearrangement i far more rapid than oxime formation, so no oxime is observe in the reaction mixture. By contrast, when sulfuric acid i used for this step, the oximes can be observed amongst th reaction products.

The oxime formation-Beckmann rearrangement process i complete within a matter of minutes, when carried out a 80° in PPA. This compares favourably with literatur conditions which employed refluxing formic acid over severa hours to produce a number of amide examples in variabl yields.

It is noteworthy that Beckmann rearrangements ar stereospecific, involving migration of the group, which i anti to the leaving group on nitrogen. This has been so wel established that Beckmann rearrangements have been used t establish the stereochemistry of oximes. In the presen case, if a syn-oxime is formed as an intermediate, th products of the rearrangement would be the undesired N-methy 4' -hydroxybenzamide and N-methyl 4' -acetoxybenzamide. It i important therefore, that oximation occur with the desire stereochemistry to allow optimal yields of (la) and (lb) t be obtained and easily purified. Under the condition established here, little of the unwanted amides were observe in the product distribution after Beckmann rearrangements.

HYDROLYSIS OF O-ACYL COMPOUNDS AM) PHOSPHATES IN REACTION MIXTURE.

Recovery of N-aryl amide from a mixture of reaction product in catalyst/solvent, requires conditions that enabl preferential hydrolysis of an O-acyl function in the presenc of an N-acyl moiety. That is, the O-acyl compound should b selectively hydrolysed to phenol without any side reactions or decomposition of the anilide moeity.

If PPA is used as a catalyst for amidation of a phenolic compound, phosphate esters may be formed; these phosphate esters would also need to undergo hydrolysis for the phenolics to be liberated.

We have found that fortuitously these phosphate esters may be hydrolysed at acid pH under conditions which also facilitate hydrolysis of O-acyl groups yet allow an amide linkage to remain intact. Following completion of reaction, the reaction mixture may simply be diluted with water, or alkali may be added and the reaction mixture heated for an appropriate time dependent upon the temperature used. For 0-acetyl compounds at pH4 the hydrolysis is essentially complete after 2 hours at 60°C. At alkaline pH the hydrolysis is more rapid.

If the process of the invention is carried out as a -one step procedure the aromatic compound, the C-acylating agent and the hydroxylamine salt or derivative are introduced to a suitable reaction vessel at the commencement of the reaction. The ketonic intermediates are rapidly converted to their amide analogues virtually as they form. This has the added advantage of ensuring that the concentration of ketones on the reaction mixture remains low throughout, and hence the opportunities for formation of by-products are significantly reduced. By this process, a mixture of amide and its O-acyl derivative is obtained without significant by-product formation and there is considerably less discolouration associated with both the by-product and the solvent. If phenol itself is acetylated the reaction gives a mixture of (la) and (lb) which is then converted hydrolytically to (la) . The process is further illustrated in the following non-limiting examples:

2 STEP PROCEDURE

Example 1

Phenol (3.0g; 0.032mol) and glacial acetic acid (2.9g; 0.048mol) were heated in PPA (30g) with stirring at 80° C for 40 minutes. Hydroxylamine sulphate (2.6g; O.Olmol) was added in a batch and the mixture stirred for an additional 5 minutes at 80° C, and then cooled. Ice water (50ml) was added and the solution extracted with ethyl acetate

(3x60ml) . The pooled organic extract was dried with MgSO , filtered and evaporated to dryness to afford an oily residue

(2.3g) , which, by GC analysis, contained 40% (la) and 44%

(lb) .

The pre-extracted aqueous residue was adjusted to pH4 with aqueous NaOH solution, and heated at reflux for- 1 hour, cooled and further extracted with ethyl acetate (3 x 60ml) . This organic extract afforded an additional oily residue (0.5g) , which by GC analysis, contained 64% (la) and 3% (lb) .

Example 2

Phenol (3.0g; 0.032mol) and glacial acetic acid (3.8g; 0.064mol) were heated in PPA (30g) with stirring at 80°C for 40 minutes. Hydroxylamine sulphate (2.6g; 0.016mol) was added in a batch and the mixture stirred for an additional 5 minutes at 80°C and then cooled. Ice water (50ml) was added and the solution extracted with ethyl acetate (3x60ml) . The pooled organic extract was dried with MgSO , filtered and evaporated to dryness to afford an oily residue (3.3g) , which, by GC analysis, contained 11% (la) and 71% (lb) . A further extraction with ethyl acetate (1 x 60ml) returned additional product (0.4g) which contained 49% (la) and --16% (lb) .

The pre-extracted aqueous residue was adjusted to pH4 with aqueous NaOH solution and heated at reflux for 1 hour, cooled and further extracted with ethyl acetate (3 x 60ml) . This organic extract afforded an additional oily residue (0.3g), which by GC analysis, contained 25% (la) and 3% (lb) .

2 STEP PROCEDURE WITH SUBSEQUENT DILUTION AND HYDROLYSIS

Example 3

Phenol (3.0g; 0.032mol) and glacial acetic acid (3.8g; 0.064mol) were heated in PPA (30g) with stirring at 80°C for 40 minutes. Hydroxylamine sulphate (2.6g; 0.016mol) was added in a batch and the mixture stirred for an additional 5 minutes at 80°C, and then cooled.

Ice water (50ml) was added and the pH adjusted to pH4 with 10% aqueous NaOH solution (ca 150ml) . The solution was heated at reflux for 2.5 hours, cooled and extracted with ethyl acetate (3 x 60ml) . The organic extract was dried over MgSO. and concentrated to give crude (la) (2.9g) as a brown solid which was 93% pure by GC/MS analysis.

1 STEP PROCEDURE

Example 4

Phenol (3.0g; 0.032mol), glacial acetic acid (3.8g; 0.064mol) and hydroxylamine sulfate (2.6g; 0.016mol) were heated in PPA (30g) with stirring at 80°C for 30 minutes and then cooled for 15 minutes. Ice water (90ml) was then added and after 15 minutes white crystals were filtered off from the solution and dried to afford 1.7g of solid which was found by GC analysis to contain 85% (lb) and 9% (la) . Extraction of the aqueous layer with ethyl acetate (3 x 60ml) afforded a solid (1.345g) which was found by GC analysis to contain 31% (lb) and 12% (la) .

Example 5

Phenol (3.0g; 0.032mol) , glacial acetic acid (5.8g; 0.096mol) and hydroxylamine hydrochloride (2.4g; 0.036mol) were heated in PPA (30g) with stirring at 80° C for 80 minutes and then cooled for 15 minutes. Ice water (80ml) was added and after 15 minutes light yellow crystals were filtered off from the solution and dried to afford (lb) (3.5g; 53% yield, 99% pure by GC analysis) .

Example 6

Phenyl acetate (3.0g; 0.022mol) , glacial acetic acid (2.64g; 0.044mol) and hydroxylamine hydrochloride (1.68g; 0.024mol) were heated in 30g PPA (116% H-P0₄) with stirring at 80° C for 60 minutes and then cooled for 10 minutes. Ice water (100ml) was added and yellow crystals were filtered off from the solution. The yellow crystals were recrystallised from water (30ml) to afford light yellow crystals of (lb) (1.75g; 41% yield, 98% pure by GC analysis) . Extraction of the mother liquor with ethyl acetate afforded 0.33g of crude material which was found by GC analysis to contain 86% (lb) , 5% (la) . The aqueous filtrate from the first isolation was extracted with ethyl acetate to afford 0.86g of crude material which was found by GC analysis to contain 64% (lb) and 6% (la) .

Example 7

Anisole (2.0ml; 0.018mol), glacial acetic acid (1.6ml; 0.028mol) and hydroxylamine sulfate (1.51g; 0.0092mol) were heated in PPA (18g) with stirring at 80°C for 1 hour. The reaction was monitored by GC analysis. After 1 hour GC analysis indicated that p-methoxyacetanilide (59%) p-methoxyacetophenone (28%) and o-methoxyacetanilide (4%) were present.

Example 8

Preparation of

N- (3, 4-dimethoxyphenyl) acetamide (ie 3, 4-dimethoxyacetanilide) .

Experiment A.

Veratrole (3.0g; 0.02 mol), glacial acetic acid (1.3g; 0.02 mol) and hydroxylamine hydrochloride (1.7g; 0.02 mol) were added to PPA (30g; 112-116% H3PO4) which was mechanically stirred at 70° for 8 hours and was then cooled to room temperature. Cold water (100 ml) was added with stirring. Extraction with ethyl acetate (3 x 60 ml) , followed by evaporation of the solvent afforded a crystalline solid (3.8g; 82% isolated yield) , which was found by GC analysis to contain N- (3, 4-dimethoxyphenyl) acetamide in 92% purity.

EIMS [m/z, (rel. int. %) ] : 195 (M⁺, 78), 153 (M⁺-ketene, 35) 139(10), 138(100), 110(32), 55(10), 43(33)

-^■R NMR (CDCI3, 200MHz) : δ 2.1 (3H, s, COCH3) , 3.7 (3H, s, OCH3) , 3.8(3H, s, OCH3), 6.7(H, d, H-C6), 6.9(H, dd, H-C51, 7.3(H, d, H- C3) , 8.6 (1H, bs, NH) .

¹³C NMR (CDCI3, 50MHz) : δl69.0, 148.7, 145.6, 131.9, 112.3, 111.2, 105.1, 77.8, 77.2, 76.6, 56.0, 55.6, 24.1

Experiment B.

The procedure in Experiment A was carried out at 80°C, using the same reactants and proportions, with the exception that two equivalents of acetic acid (2.6g, 0.04 mol) was employed. After

2.5 hours, the reaction mixture contained 57%

N- (3, 4-dimethoxyphenyl) acetamide and 38%

3, -dimethoxyacetophenone, as determined by GC analysis. - 15 -

Experiment. C

The procedure was conducted at 115°C, using the same reactants an proportions as those quoted for Experiment B. After 5 minutes the reaction mixture contained 32% N- (3, -dimethoxyphenyl) acetamide a 55% of 3, 4-dimethoxyacetophenone.

EXAMPLE 9

Preparation of 4-Methoxyacetanilide (ie p-Acetanisidine) .

Experiment A

Anisole (3.0g; 0.03 mol),glacial acetic acid (3.3g; 0.06 mol) and hydroxylamine hydrochloride (2.1g; 0.03 mol) were added to PPA ⁽30g; 112-116% H3PO4) and the mixture heated with stirring at 70° for 2 hours. The mixture was allowed to cool over 30 minutes and cold water (110 ml) was added. Chloroform extraction (3 x 80 ml) afforded a light brown crystalline solid ⁽4.5g⁾ after solvent evaporation. By GC analysis, this material contained 93% 4-methoxyacetanilide.

Experiment B

Using the same reactants and proportions as those in Experiment A, the procedure was carried out at 80°C. After 2 hours, the mixture was left for 30 min to cool. Ice cold water ⁽110ml) was added and the product (4.4g) crystallised in 96% purity and was filtered off. Ethyl acetate extraction of the mother liquor gave additional product (0.8g), making the isolated yield 91%. The crude material had p: 126-127°C, [ cf The Merck Index Eleventh Ed., p39 (1989); mp: 130-132°C] .

EIMS m/z (rel. int. %) : 165(M+, 44), 123 (M+-ketene, 66), 108(100), 80(18), 53(11), 52(18), 43(42) .

l-H NMR (d6 Acetone, 200MHz) : 62.05 (3H, s, NHCOCH3) , 3.7 (3H, s, OCH3) , 6.85 (2H, d, CH) , 7.55 (2H, d, CHI

SUBSTITUTE SHEET 16 -

¹³C NMR (dδ Acetone, 50MHz) : δ206.7, 168.8, 156.7, 133.6, 121.7, 114.6, 55.7, 24.1.

EXAMPLE 10

Preparation of 4-Ethoxyacetanilide (ie phenacetin) .

Phenetole ⁽3.0g; 0.02 mol),glacial acetic acid (3.0g; 0.05 mol) and hydroxylamine hydrochloride (1.9g; 0.03 mol) were added to PPA ⁽30g; 112-116% H3PO4) with stirring at 80°C. After 2.5 hours the mixture was cooled for 15 minutes, ice water (100 ml₎ was then added and within a few minutes the product began to crystallise. It was filtered off, and recrystallised from water to give 4-ethoxyacetanilide as colourless flakes (2.7g; 61% yield after recrystallisation); mp: 132-133°C, [cf The Merck Index Eleventh Ed., pll41 (1989); mp: 134-135°C] . Ethyl acetate extraction of aqueous residues afforded additional crude material, making the overall yield 75%.

EIMS, m/z, (rel. int. %) : 179 (M+, 72), 137 (M+-ketene, 47), 109⁽93⁾, 108(100), 81(17), 80(19), 53(16), 52(13), 43(41) .

¹H NMR (d6 Acetone, 200MHz) : δ 1.35 (3H,t, CH2CH3) , 2.05⁽3H,s,NHCOCH3), 4.0 (2H,q,CH2CH3) , 6.9 (2H,d,CH) , 7.55(2H,d,CH) , 9.1 (lH,bs,NH) .

¹³C NMR (d6 Acetone, 50MHz) : 6206.4, 168.5, 156.4, 133.3, 121.6, 115.2, 64.1, 15.2.

SUBSTITUTE SHEET EXAMPLE 11

Preparation of 4-Acetoxy-3- ethoxyacetanilide.

Guaiacol (3.0g; 0.02 mol), glacial acetic acid (3.6g; 0.06 mol) and hydroxylamine hydrochloride (1.8g; 0.03 mol) was added to PPA (30g; 112-116% H3PO4) . The mixture was stirred for 2.5 hours at 80°C and allowed to cool. Ice water (100 ml) was added with stirring and the aqueous phase was extracted with EtOAc (4x80 ml) . The solvent extract was dried, filtered, and evaporated to give a light brown solid (4.1g), which was found, by GC and NMR analysis, to contain 70%■ 4-acetoxy- 3-methoxyacetanilide and 18% 3-acetoxy-4-methoxyacetanilide. A sample of the crude material was recrystallised from methanol to give 4-acetoxy-3-methoxyacetanilide. This compound showed the following spectral properties:

EIMS [m/z, (rel. int. %) ] : 223 (M⁺, 10), 181(48), 140(11), 139(100), 138(11), 124(28), 43(35) .

-R NMR (DMSO, 200MHz) : 62.05 and 2.25 (2x3H, 2s, COCH3) ,

3.7 (3H, s, OCH3), 6.95 (1H, d, CH) , 7.1 (1H, dd, CH) , 7.4 (1H, d, CH) , 10.0 (1H, bs, NH) .

1 _c NMR (DMSO, 50MHz) : 6168.7, 168.3, 150.5, 137.9, 134.5, 122.6, 110.7, 103.8, 55.4, 23.9, 20.2.

The minor product, 3-acetoxy-4-methoxyacetanilide, gave the following EIMS at 70eV; [m/z (rel. int. %) ] : 223 (M⁺, 22), 181 (100), 139 (67), 124 (87), 95 (11), 67 (12), 52 (15), 43 (49) .

SUBSTITUTE SHEET EXAMPLE 12

Preparation of N- (4 -butyroxyphenyl) butanamide .

Phenol (2.0g; 0.02 mol), butyric acid (3.7g; 0.04 mol) and hydroxylamine hydrochloride (1.6g; 0.02 mol) were added to PPA(20g

112-116% H3PO4) with stirring, and the mixture was heated for 4 hours at 80°C, then cooled, and ice water (80ml) added. Yellowish crystals of N- (4-butyroxyphenyl)butanamide formed and were filtere off to give this product in 45% yield. The crude

N- (4-butyroxyphenyl)butanamide; mp: 121-122°C was 95% pure by GC analysis .

EIMS [m/z, (rel. int. %) ] : 249 (M⁺, 2), 179(38), 71(11), 43(30) .

¹H NMR (CDCI3, 200MHz) : δθ.95(6H, 2t partially overlapping, 2xCH2 CH3) 1.7 (4H, m, 2XCH2-CH2-CH3) 2.25 (2H, m, CH2-CH2-CO) , 2.48 (2H m, CH2-CH2-CO) , 6.9(2H, d, CH) , 7. (2H, d, CH) , 7.7 (1H, s, NH) .

EXAMPLE 13

Preparation of Diamfenetide : ie (di- [2- (4-acetamidophenoxy) ethyl] ether) . 2-Phenoxyethyl ether (3.0g; 0.01 mol), glacial acetic acid (1.7g; 0.03 mol) and hydroxylamine hydrochloride (1.8g; 0.03 mol) were added to PPA (30g; 112-116% H3PO₄) . The mixture was heated with stirring for 3 hours at 80°C, then cooled and ice water (200 ml) added. The product crystallised as a pale yellow solid (4.1g; crud yield 95%) which was filtered off and dried, before being recrystallised from acetone-water.

~R NMR (d6 Acetone, 200MHz) : δ 2.05(6H, s, C(0)CJ&3), 3.85(4H, m, 0-CU2-CH2-0) , 4.1(4H, m, O-CH2CH2-O) , 6.85 (4H, d, Cfi) , 7.5(4H, d, CH) , 9.2 (2H, br. s, NH)

¹³C NMR (dδ Acetone, 50MHz) : 6206.5, 168.7, 155.9, 133.9, 121.7, 115.5, 70.6, 68.6, 24.2.

SUBSTITUTE SHEET EXAMPLE 14

Preparation of 4-Ethylacetanilide .

Ethylbenzene (2.0g; 0.02 mol), glacial acetic acid (2.3g; 0.04 mol) and hydroxylamine hydrochloride (1.4g; 0.02 mol) were added to PPA (20g; 112-116% H3PO4) with stirring, and the mixture was heated for several hours at 110°C. At regular intervals, aliquots ( ca 0.2g) of the mixture were taken, diluted with water ( ca 2 ml) and the organics extracted into chloroform ( ca 1 ml) . GC and GCMS analysis and ¹H NMR spectroscopy showed that after 10 hours the starting ethylbenzene had been converted. The product contained 80% 4-ethylacetanilide and 5% 2-ethylacetanilide

EXAMPLE 15

Phenol (3.0g; 0.03 mol),glacial acetic acid (5.8g; 0.1 mol) and hydroxylamine hydrochloride (2.4g; 0.04 mol) were added to PPA (30g; 121% H3PO4) with stirring, and the mixture was heated at 80°C for 2 hrs and then cooled for 15 min. Ice-water (80 ml) was then added and after 15 min yellowish crystals were filtered off from the solution and dried to afford 3.7g of solid which was found by GC analysis to contain 96% of 4-acetoxyacetanilide. Extraction of the aqueous layer with ethyl acetate (3 x 60 ml) afforded further solid (1.6g) which was found by GC analysis to contain 43% 4-acetoxyacetanilide and 4% of 4-hydroxyacetanilide.

EXAMPLE 16

Phenol (3.0g; 0.03 mol), acetic anhydride (6.5g; 0.6 mol) and hydroxylamine hydrochloride (2.4g; 0.04 mol) were added to PPA (30g; 112-116% H3PO4) with stirring and the mixture heated at 80°C for 3 hrs . The reaction mixture was then cooled for 15 min and ice-water (80 ml) was added. After 15 minutes yellow crystals were filtered off from the solution and dried to afford 4-acetoxyacetanilide (3.9g; 63% yield) . Recrystallisation from

SUBSTITUTE SHEET water gave colourless crystals of 4-acetoxyacetanilide (2.7g; 44% yield, 97.3 % pure by GC analysis) . The aqueous filtrate from the first isolation was extracted with ethyl acetate and afforded 1.8g of crude material which was found by GC analysis to contain- 4-acetoxyacetanilide (24%) and 4-hydroxyacetanilide (5%) . Total isolated yield was 71%.

EXAMPLE 17

Phenol (3.0g; 0.03 mol), glacial acetic acid (5.8g; 0.1 mol) and hydroxylamine phosphate (3.2g; 0.02 mol) were added to PPA (30g; 116% H3PO4) with stirring, and the mixture was heated at 80°C for 27 hr, and then allowed to stand for 16 hr at room temperature. GC analysis showed that the yield of 4-acetoxyacetanilide was 64%.

EXAMPLE 18

The use of phosphorus pentoxide-methanesulfonic acid as an alternative catalyst to PPA has been published by P. E. Eaton, G. R. Carlson and J. T. Lee, J. Org. Chem . , 38, 4071 (1973) . Phosphorus pentoxide (2.7g) was added in one portion to methanesulfonic acid (27g) and, with efficient stirring, dissolved in 2 hours. The solution was heated to 80°C and glacial acetic acid (5.8g; 0.1 mol), hydroxylamine hydrochloride (2.4g; 0.03 mol) and phenol (3.0g; 0.03 mol) were added.

GC analysis indicated that after 7 hrs, the reaction mixture contained 4-hydroxyacetanilide (22%) and 4-acetoxyacetanilide (2%) .

SUBSTITUTE SHEET EXAMPLE 19 .

Phenol (3.0g; 0.03 mol.), glacial acetic acid (5.8g; 0.1 mol.) and hydroxylamine hydrochloride (2.5g; 0.04 mol.) were placed inside a Kel-F pot equipped with a stirring bead. The vessel was sealed, cooled in liquid nitrogen and evacuated. Hydrogen fluoride (30.lg) was condensed into the reactor and the vessel was warmed to ambient temperature, then placed in a water bath at 84°C for 1.5 hours. During the first 0.5 hour, which was the heating up period, the solution had developed a red colour and this intensified to dark red towards the final stages of heating.

After reaction, the mixture was allowed to cool to room temperature and the HF was removed by cold temperature distillation using liquid nitrogen. This procedure required approximately 3 hours . The residue was dissolved in ethyl acetate (30 ml) and the mixture adjusted to pH 6 using 45% aqueous KOH (20-25 ml) . After separation, the organic phase was dried over MgS0 and the ethyl acetate evaporated to afford an orange oil (5.2g) which contained 10% 4-hydroxyacetanilide, 57% 4-hydroxyacetophenone oxime, 29% 4-hydroxy-acetophenone and 4% 2-hydroxyacetophenone.

EXAMPLE 20

Phenol (3.0g; 0.03 mol), glacial acetic acid (5.8g; 0.10 mol) and hydroxylamine hydrochloride (2.4g; 0.03 mol) were heated in PPA (30g; 116% H3PO4) with stirring at 80°C for 2.5 hrs and the reaction mixture was then cooled to 50°. Ice-water (80 ml) was added and after 15 minutes, yellow crystals were filtered off from the solution and dried to afford 4-acetoxyacetanilide (3.9g, 63% yield) . Hydrolysis of the 4-acetoxyacetanilide (3.3g, 0.02 mol) using a 20% molar excess of NaOH (50 ml, 0.02 mol) gave an overall yield of 90% 4-hydroxyacetanilide with respect to 4-acetoxyacetanilide .

SUBSTITUTE SHEET EXAMPLE 21

Phenol (3.0g; 0.03 mol), glacial acetic acid (5.8g; 0.1 mol) and hydroxylamine hydrochloride (2.4g; 0.03 mol) were added to PPA (30g; 121% H3PO4) with stirring and heated at 80°C for 2 hrs and the reaction mixture was then cooled to 50°. Ice-water (60 ml) was added and heating continued at 60° for 75 min. The reaction mixture was allowed to cool and extracted with ethyl acetate (3 x 60 ml)and then washed once with water. The ethyl acetate extracts were combined and treated with charcoal (0.25g), filtered and reduced in volume to afford two crops of crystals. The first with a melting point of 162-5° had a mass of 1.9g. The melting point of 4-hydroxyacetanilide is reported as 168-172° in the British Pharmacopoeia, 1988, vol I. Further crystals (0.2g) were obtained and 0.5g of product remained in the mother liquor. Analyses of the three parts indicated that the yield of 4-hydroxyacetanilide was 54%, based on starting phenol.

EXAMPLE 22

Al ternative hydrolysis/demethylation procedure

4-Methoxyacetanilide (1.5g; 0.01mol) and aluminium chloride (2.5g; 0.02 mol) were heated at 135°C under an atmosphere of nitrogen for 2h. The solid mixture was added to cold water and extracted with ethyl acetate. The solvent was removed to give a brown solid (1.2g), which was recrystallised from water to afford 4-hydroxyacetanilide (l.lg; 80% yield) .

SUBSTITUTE SHEET EXAMPLE 23

Phenol (3.0g; 0.03 mol), acetic anhydride (6.5g; 0.6 mol) and hydroxylamine hydrochloride (2.4g; 0.04 mol) were added to PPA (30g; 116% H3PO4) with stirring, and heated at 80°C for 3 hrs and the reaction mixture was then cooled for 15 min. Ice-water (80 ml) was added and after 15 minutes, yellow crystals were filtered off from the solution and dried to afford 4-acetoxyacetanilide (3.9g; 63% yield) . Recrystallisation from water gave colourless crystals of 4-acetoxyacetanilide (2.7g; 44% yield, 97.3 % pure by GC analysis) . The aqueous filtrate from the first isolation was extracted with ethyl acetate and afforded 1.8g of crude material which was found by GC analysis to contain 4-acetoxyacetanilide (24%) and 4-hydroxyacetanilide (5%) . Total isolated yield was 71%.

SUBSTITUTE SHEET

Claims

CLAIMS :

1. A process for the preparation of an N-aryl amide in a single reaction vessel including, the reaction of an aromatic compound with a C-acylation reagent and a hydroxylamine salt or derivative in the presence of an acidic catalyst.

2. A process according to claim 1 wherein the N-aryl amide prepared is an anilide.

3. A process according to claims 1 or 2 wherein the catalyst is selected from di- or polyphosphoric acid, P_0₅ in methanesulfonic acid, or hydrogen fluoride.

4. A process according to any one of the preceding claims wherein a mixture of products are prepared and these products are further diluted with water and hydrolysed to produce the product N-aryl amide.

5. A process according to claim 4 wherein the mixture of products are hydrolysed by adding aqueous alkali and heating.

6. A process according to any one of the preceding claims wherein the aromatic compound is selected from phenol, phenyl acetate, anisole, phenetole, diphenyl carbonate, triphenyl phosphate, triphenyl phosphine, 1,1-diphenoxyethane, triphenylorthoformate, phenyl vinyl ether, t-butyl phenyl ether, dichloromethyl phenyl ether, the tetrahydropyranyl ether of phenol, veratrole, guaiacol, alkyl substituted benzenes, di-2-phenoxy ethyl ether, chroman, thiophene, 2-me hyl hiophene, 3-methylthiophene, 2-chlorothiophene 2-bromothiophene, 2,2' -dithienyl, indole, pyrrole, toluene, xylenes, indane, tetralin, cumene, catechol, resorcinol, phloroglucinol, tolyl methyl ether, resorcinol dimethyl ether, hydroquinone dimethyl ether, pyrogallol trimethyl ether, diphenyl ether, naphthalene, α-naphthol, β -naphthol, furan, 2-methylfuran and benzofuran.

7. A process according to claim 6 wherein the aromatic compound is phenol or phenyl acetate.

8. A process according to any one of the preceding claims wherein the C-acylation reagent is selected from the corresponding carboxylic acid, anhydride or acid halide either alone or in combination.

9. A process according to claim 7 wherein the C-acylation reagent is acetic acid or acetic anhydride.

10. A process according to any one of the preceding claims wherein the hydroxylamine salt or derivative is selected from the hydrochloride, sulphate, or phosphate, 0-acetylhydroxylamine, hydroxylamine O-sulfonic acid.

11. A process according to any one of the preceding claims wherein the process is carried out as a two step procedure whereby the aromatic compound is first reacted with a C-acylation reagent in the presence of said catalyst followed by addition of the hydroxylamine salt or derivative.

12. A process according to any one of claims 1 to 10 wherein the process is carried out as a one step procedure.

13. A process according to any one of the preceding claims wherein 4' -hydroxyacetanilide is prepared.

14. An N-aryl amide prepared by the process as defined by any one of the preceding claims.