CA1262144A - Process for producing n-acyl-hydroxy and n-acyl- acyloxy aromatic amines - Google Patents

Abstract

A B S T R A C T

PROCESS FOR PRODUCING
N-ACYL-HYDROXY AND N-ACYL-ACYLOXY
AROMATIC AMINES
This invention relates to a process for producing N-acyl-hydroxy aromat-ic amines, such as N-acetyl-para-aminophenol (APAP), and N-acyl-acyloxy aromatic amines, such as 4-acetoxyacetanilide (AAA), from hydroxy aromatic ketones, such as 4-hydroxyacetophenone. Preferably the hydroxy aromatic ketones are produced 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

ER2CESS FOR ~R~ WCING
N-ACYIrHYIR~XY AND N-A~3nri4cyL~xy AR~C ~lES

It is known to produce N-acyl-a~yloxy aromatic amines, e.g. 4-acetoxy-acetanilide, by preparing the sodium salt of the correspondiny N-acyl-hydroxy ~ tic am1ne, e.g. N-acetyl-para-am mcphenol ~APAP), and reacting the sodium salt with the appropriate carboxylic acid anhydride, e.g. acetic anhydride. The N-acyl-hydrvxy arcmatic amine, e.g. AP~P, used as the starting material for the foregoing reaction is m turn prepared ~y acyla~ing the c~rrespondln~ hydr~xy aromatic amlne, e.g.
para-am mophenol~ with an acylating agent ~u~h as an anhydride, e.g.
acetic anhydride. However the latter reaction may cause problems such as the difficulty of mono-acylating the hydraxy aromatic ~m m e, oligcmerization of the hydroxy arc~atic amlne, and color bcdy formation.

Furthermore, when APAP is p ~ ~rom para-aminophenol, nitr~-benzene t~pically is catalytically h~drogenatel and concomitantly rearran~ed in the presence o~ a platinum catalyst to produce the para-am m oEhenol, presenting the prcblem of recoverin~ the dissolved platinum catalyst~

It is also known to prepare ~PAP by hydrogenating 4-nitro-~hlorcbenzene to a 4-chloroaniline which is then reac~ed with aqueous KOH to form para-aminc~henol. This is ~hen acetylated as described previously to ~orm the N-acetyl--para-aminophenol. This process is relatively ccmplex rec~liring a ~air number of xeaction and puri~ication steps. Morecver, th~ acetylation step in this process is believed to give rise to the same prcblems as occurs in the ac3tylation step o~ th~ nitrobenzene process described previously.

...

126~'a4 The pr~paration o~ h~droxy ar~matic ketones by the Fries rearrangement of arcmatic esters is well-known in the art. qhus, Lewis, U.S. Patent No. 2,833,825 shows th~ rearrangement o~ ~henyl or other aromatic esters to acylphenol3 or other hydr3xy arcmatic ketones using anhydrous hydro-gen fluoride as catalyst. The examples of this patent are l~mited tothe rearrangement of esters of higher fatty acids with the yields ranging frcm 55 to ~5%.

Simons et al, Journal of the American Chemi~al Society, 62, 485 and 486 (1940) show the use of hydrogen fluoride as a condensing agent for various rearrangements and at page 486 show the Fries rearrangement of phenyl acetate to obtain p-hydroxyacetophenone.

Dann and ~ylius in a dissertation included as part of a series of Reports from the Institute for Applied Chemistry of the University of Erlangen, received f~r pNbli~ation on January 7, 1954 and published in Annalen der Chemie 587 Eand, pages 1 to 15 ~1954), show the rearrange-ment of phenyl acet~te in hydrogen fluoride to 4-hydroxyaceto~henone, with a maxImum yield of 81~ after 24 hours of reaction tIme, and rep~rt a yield of 92% stated to be obtained by R. Weichert as rep~rted in Angewandte Chemie 56, 338 (1343). However, Dann and Mylius suggest that the differen-e in yields may be at least partly due to the previous ignorLng by Weichert of the acccmpanying 2-hydro~yacetophenone.

Dann and ~ylius ~1so disclose the reaction of phenol and glacial aceticacid in the p~esence of hydrogen fluoride to produce 4-hydroxyaceto-phenone at a yield of 61.6~. qhis reaction may be conventionally ch~racterized as a Friedel-Craf~s acetylation of phenol with acetic acid as the acetylating agent~

S~mons et al, Journal of the American Chemical Society, 61, 1795 and 1796 (1939) teach the acylation of aromatic compounds using hydrogen fluoride as a condensing agent and in Table 1 on page 1796 show the acetylation o~ phenol wi~h acetic acid to produce p-hydroxyacetophenone in 40% yield.

i2~

Meussdoerffer e~ al, German Offenlegungsschrif~ 26 16 986 publislled October ~7, 1977 and assiyned to Bayer AG, disclose the acylation of phenolic compounds such as phenol itself with an acyl ha].icle such as acetyl chloride to form hydroxy aromatic ketone~.
Auwers et al, Chemische Berichte, 58, 36-51, (1925) show the BecXmann rearrangement of a large number of oximes of aromatic ketones most of which are substituted ac~etophenones.
However, the only attemp~ed rearrangement of the oxime of a ring-unsubstituted hydroxy aromatic ketone was that of the oxime of o-hydroxyacetophenone, but no amine was forrned, i.e.
the attempted rearrangement was unsuccessful; see page 41.
Ganboa et al, Synthetic Communications 13(11), 941-944 (1983) show the production of acetanilide from acetophenone by refluxing in a solution of hydroxylamine hydrochloride.
There i5 however no suggestion of the synthesis of N-acylacyloxy aromatic amines such as 4-acetoxyacetanilide (AAA) or of the synthesis of N-acylhydroxy aromatic amines such as N-acetyl-para-aminophenol (APAP).
Pearson et al, Journal of the A~erican Chemical Society 75 5905-5908 (Dec. 5, 1953) disclose the formation of hydrazones ~rom ketones by reaction with hydrazine hydrate and the rearrangement of the hydrazone to the amide by reaction with sodium nltrite and concentrated sulfuric acid.
Specifically, on page 5907 Pearson et al show the rearrangemen~
of p-hydroxyacetophenone hydrazone to p-hydroxyacetanilide, i.e. APAP.
The present invention provides a process comprising contacting a hydroxy disubstituted arornatic ketone with a hydroxylamine salt and a base to form the ketoxime of said ketone, and (i) contacting said katoxime with a Beckmann ~,,, . .

rearrangemellt ca~aly~t to form an N-acyl-hydroxy di,substituted aromatic amine, or (ii) contact:Lng saicl ketoxime with a carboxylic acid anhyclride and a Beckmann rearrangement catalyst to form an ~-acyl-acyloxy disubstituted a.romatic amine.
In accordance with one aspect of this invention, N-acyl-hydroxy aromatic amines, e.g. N-acetyl-para-aminophenol (APAP), are produced by reacting a hydroxy aromatic ketone, e.g. 4-hydroxyacetophenone (4-HAP), with a hydroxylamine salt, to form the ketoxime of the ketone and subjecting the ketoxime to a Beckmann rearranyement in the presence of a catalyst to form the N-acyl-hydroxy aromatic amine.
In one specific emhodiment, N-acetyl-para-aminophenol (APAP~, also known as acetaminophen, is produ~ed from phenyl acetate, or phenol ancl an acetylating agent such as acetic acid, by means of an intagrated process including the steps of converting the phenyl acetate, or phenol and an 3a , .

~L26~1~4 ~L

acetylatin~ agent, to 4-hydroxyacetophenone by a Fries rearrangement or Friedel-Crafts acetylation respectively, and conv~rting the 4-hydroxy-acetophenone to the corresponding ketoxlme with hydroxylam m e or a hydroxylamine salt. The ke~oxLme is then subjected to a Eeckmann rearrangement in the presence of a catalyst to form the N-acetyl-para-amln~phen~l.

In accordance with another aspect of this invention, N-acyl-acyloxy a m matic amines, e.g. 4-acetoxyacetanilide (AAA), æe produced by reacting a hydroxy aromatic ke~one, e.g. 4-hydroxyacetophenone (4-HAP~, with hydroxylamine or a hydroxylamlne salt, to form the ketoxIme of the ketone and subjec~ing the ketoxime to a Beckmann rearrangement and acccmpanying acylation by contactLng the ketoxime wi~h a carboxylic acid anhydride and a Beckmann rearrangem~n~ catalyst to fonm the N-acyl-acyloxy arcmatic amm e.

In anothsr spscific embodimcnt, 4-aceto~yacetanilide (AA~) is produced ~rcm ph~nyl acetate, or phenol and an acetylatLng agent such as acetic acid, by mans o~ an inte~rated process including the steps o~ convert-ing the phenyl acetate, or phenol and ~n ace~ylating agent, to 4-hydr~xyacetcphenons by a Fries rcarrangement or Friedel-Crafts acetyl ation respectively, and converting the 4-hydroxyacetc ~ enone to the correspondLng ketoxime with hydroxylamine or a hydroxylamune salt. The ketoxime is then subjected to a Beckmann rearrangement and acc~panying acetylation by contacting the ketoxIme with acetic anhydride and a Beckmann rearrangement catalyst to form the 4-acetoxyacetanilide.

~hen carrying out the process o~ this m vention using phenyl acetate as the starting material, the initial Fries rearrangement to prcduce 4-hydroxyace~ophenone (4-H~P) frcm phenyl acetate is defin0d by equation CH
0-CCH3 Catalyst >~10 {0 ~ C=0 (I) ~L26Z~

I~ phenol and an acetylating agent are used as the ~taring material, the resultl~g ac~tylation react~on to form 4-~P i5 Lndicated by equation (~I) HO ~ + CH3COX Catalyst ~ ~10 ~ C=H30 + HX (II) where X i5 the residue minus an acetyl ~ p of compounds which are known acetylating agents. X ma~ be, for example, h~droxy, acetoxy, or halide including fluoride, chloride, brcmide, or iodide. Acet~lating agents which m~ be used ar2 for ~J~mple, acetic acid, acetic anhydride, aoetyl fluoride, acetyl chloride and acetyl bromide.

m e ketoxIme formation of this inven~ion proceeds as in~icated in e~uation (III):

R R
: HOAr1-C=0 ~ "NH20H" base ~HoArl-c=NoH + H20 (III) :
The formation of the ketoxIme of 4-H~P, l.e. 4-H~P oxime, proceeds as in equation (IV):

HO ~ C=O + "NH20H" base ~HO ~ C=NOH ~ H20 (IV) When N-acyl-hydr~y arcmatic amines are the desired produat/ the Bed~-ma~n rearrangement of this inNention proceeds as m equation ~V):
~ .
R H R
HOArl-e=NOH catalyst ? HOArl-N-C=O (V)

2~

while the Eec~kann rearrangen~lt when APAP is the desired product proc~#~ as in e~uation (Vl):
1H3 IH C1~13 HO~C=NOH catalyst ~ Ho~ N-C=O (Vl) When N-acyl-acyloxy aromatic amines are the desirad product, the Beckmann rearrangemen~ an~ accompanying acylation o~ this invention proceeds as m equation (VII):
CH3 o H R
catalyst HOAr1 - C = NOH + (RCO)20 ~ 'R - COAr~ - N - C + RCOOH (VII) while the Beckmann ~ ement and accumpa~ying acetylation when A~A
s t`he desired pr~duct proceeds as in equation (VIII3:

HO~ I - NOH + (CH3CO)20 ~ ~ -~ ~ CH3 - L~}N c - (VIII) + CH3COOH
In equations (III~, (V~, ~nd ~VII), Ar is a divalent arcmatic radical.
The specific nature of th~ radical is not critical but it is preferably a radical r~sulting from the remcval of two ring hy ~ en atoms from benzene, naph~halene, or biphenyl, either unsubstituted or wi~h rin~
ens substituted with radicals such as alkyl, alkenyl, alkynyl, alk~xy or acyloxy containing 1 to 18 carbon atcms, aralkyl contain mg 7 to 18 carbon atoms: halogen, e.g. chlorine, bromine, or iodine; hydroxy;
~ o; or sulfhydryl. Arl is preferably lt4-phenylene, 2,1-naphthylene, 2,6-naphthylene, 5-phenyl-1,2-phenylene, 3-phenyl-1,4-phenylene or

3-methyl-1,4-phenylene with the ketccarbon and corresponding groups occupying the first stat0d numbered pasition o~ Arl when the positions ~re not equlvalent. ~ost preferably Arl is 1,4-phenylene.

The R groups in tha foregoing equa~ions may be the same or different and are each a monc~alent organio radical containing, for example 1 to 18 carbon atcn~ pre~erably 1 to 4 carbon atcms. R may be, for example, alkyl, alkenyl, alkynyl, alkoxy, acyl or acyloxy containing 1 to 18 carbon atcms, either unsubstituted or substituted with radicals such as halogen, e.g. chlor m e, brom m e, or iodine, hydroxy; am m o; sulfhydryl;
or an aryl radical, Ar which may be a monovalent radical correspon~ing to the definition of Arl given akcve except that the carbon bonded to OH
is bonded to a hydro~en instead. Pref~rably, R is the same in all occurrences in equations (III), (V), and (VII) and is methyl, eth~l, propyl, or n-butyl and most preferably methyl corresponding to the use of acetate e~ters and methyl ketones in the latter equations. The pre-ferred specific hydroxy aramatic ketone used to form the oxime is

4-hydroxyacetcphenone (4-H~P) and the preferred produc~s are 4-acetoxy-acetanilide (AAA) and N-acetyl-para-aminophenol (APAP).

~le hydroxy arcmatic ke~one used to form the oxIme may be prepared by any me~hod known in the art. For example, it may be prepared by the Fries re 9 ement of the corresponding aromatic ester as indicated by the following eguation, which is a generalized form of equation (I), whe~e Ar, Arl an~ R have the definitions given above:
O O
ArOCR cata 1 ys t ,~ HO-Arl -CR ( I X ) Alternati~el~, a Fhenolic ccm~ound ahd an acylat mg agent may ke reacted in a Friedel~Crafts acylation to form the hydroxy aromatic ketone, in accor~ance with the followLng equation, whi~h is a generalization ~orm of e~uation (II):

ArOH + R e x catalyst ~IQ Arl ~ R ~ HX (X) where Ar, Axl and R have the ~ given previously and X is the residue minu~ the acyl gro~[p, , of the compounds which are known acylatin~ agen~s, su~h as hydroxy, acyloxy, e.g. acetoxy, and halide, e.g. fluoride, chloride, brcmide, and iod~de. Examples of ~henolic ~2 E;Z~

ccmpcunds which may be employed are phenol, l-naph~holl 2-naphthol, 2 phenylphenol, 4-phenylphenol and o-cresol. Acylating agents which may be us~d are ~or example aIkanoic acids, e.g. acetic and propionic acids, alkanoic acid anhy~rides, e.g. aetic and propionic anhydrides, and acyl halides, e.g. acetyl and propionyl fluorides, chlorides, and bromides.
Note that although the reaction of a Fhenolic compound and an acylating agent is characterized herein as a "~riedel-Crafts acylation," no opinion as to the mechanism o~ reaction should be implied by this characterization.
The catalyst for both o~ the ~oregoing reactions is preferably hydrogenflu~ride but any other catalyst known in the art to be effecti~e for the Fries and Friedel-Crafts reactions may be used, e.g. alum mum chloride, zinc chloride, or boran tri~luoride.
In carrying ou~ the reaction, the arcmatic ester or phenolic compound and asylating agent, catalyst and if desired when an aromatic ester is the start m g material, an additive for ~he reaction such as acetic anhydride or ace~ic acid, ma~ be charged to a corrosion-resistant reac~or and the mixture ma mtained at a temperature, for example, of about 20 to cibout 100C for a period, for e ~ le, of about l/2 to about 4 hours, at a pressure, for e~ample, of about 50 to about 500 psia (3.4 to 34 bar). If HF is used as the cataly~st it may be charged as a liquid or a gas using technologies of handl~ng well-kncwn to those skilled in the art. In carrying out the reaction, an mert gas such as nitrogen may be used to keep ~he reaction space under the desired pressure and sufficient HF m ~ tact with th~ react m g liquid. An excess of HF is gensrally used, for example, about 7 to about 75 moles per mole of arcmatic ester or phenolic c~mpound mitially present in the reaction zone. If AAA or APAP is the desired product of the reac~ion, the starting material if a Fries rearrangement is employed will be phenyl acetate while phenol and an acetylat mg agent suc~h as acetic acid is the starting material if a Friedel-Crafts acylation is utilized. In both cases, the starting material is converted to 4-H~P which is in turn converted by ~he process o~ this invention to AAA or AP~P.

The ConverSiQn of hydroxy aromatic ketones, e.g. 4-HAP, into N-acyl-acyloxy arcmatic amines, e.g. A~, or int:o N-acyl-hy~roxy ar~matic a D es, e.g., APAP, is accomplished by ~irst formlng the ketoxime ~rom the hydroxy arcmatic ke~one as in~icated ~y equations (III) and (IV), by contacting the ketone with hydroxylam m e or a hydroxylamine salt, e.g.
hydroxylamine hydrochloride, h~droxylam me sulfate, hydroxylamine bisulfate, or hy~roxylamlne phospha~e, and a base, e.g. ammonium hydrox-ide, potassium hydroxide, sodium hydroxide, or lit~ium hydroxide in an amount, ~or exa~ple, of 1 to 3 moles per mole of hydroxylamlne, at a temperature, for example of 0 to 60& for a period, for example, of l to 4 hours. Any pressure may bs used, e.g. 80 mm. of mercury to 10 atmo-spheres absolute (0.1 bar to 10.1 bar). The reaction is preferably carried out in an aqueous or alccholic medium, i.e. in the presence of water anq/or an alcohol such as methanol, ethanol, or iscpropanol.
As discussed abcNe, in accordance with one embodiment of the invention, the ketoxLme may be conv~rted into the correspanding N-acyl-hydroxy aromatic amlne by a Beckmann r ~ ement as shown in equations (V~ and (VI), by contactmg the ketoxime with ~ catalyst for the reac~ion at a temperature, for example of -70& to 118 & for a period for exa~ple of ten minutes ~o 4 hours. me pressure is not critical and may be, for example, in the range of 80 mm. of mÆrcury to lO a ~ heres absolute (0.1 bar to 10.1 bar). Preferably, ~he rearrangement is conducted at a temperature of frcm about -70& to about 40C and at a molar ratio of ketoxime to catalyst from abou~ 1:0.001 to about 1:0.1, for a reaction t~me of abou~ ten ~unutes at about two hours. Any Beckmann rearrange-mnt catalyst may ke used, as for ~xample, an acid, e.g. mineral acid such as sulfuric or hydrochloric acid, an organic acid such as : trlfluoroacatic acid, para-toluenesulfom c acid, benzenesul~onic acid or methanesulfonic acid, an acidic ion-exchange resin such as kmberlyst 15 or Nafion 501 which æ e suLfonic acid ion-exchange resins, or thionyl ~ Loride in liquid suLfur dioxide, diethyl eth~r, ethylacetate, acetone, tetrahydrofuran, or methylene chloride. Pre~erably the Beckmann rear~
rangement is conducted with thionyl chLoride in liquid sulfur dioxide.
Ihe reaction may be advantageously carried out in the presence of the glacial carboxylic acid correspondin~ to the N-acyl group of the desired product which will ordinari:Ly yieLd the hydroxy derivativa. m e to~al e~ 7 1~

~z~

amount of glacial carboxylic acid is not critical but is usually present such that the ketoxi~ concentration is in the range o~ 2 to 50% by weight at the start of the reaction.

S In accordance with another emkodiment of the m vention, the ketoxime may be converted into the corresponding N-acyl-acyloxy aromatic amine by a Beckmann rearrangement and a~companyLng acylation as shcwn in e~uations ~VII) and (VIII~, by contact m g the ketoxImQ with the appropriate carboxylic acid anhydride and a Beckmann rearrangement catalyst at a t~mperature, for example of o to 118 & for a period for example of 1 to 4 hours. As def med in the for~going e~uations, any of a broad class of anhydrides may be used but the anhydride is preferably that of an alkanoic acid contamIng 2 to 4 carbon atoms, e.g. acetic anhydride, prop~onic anhydride, or n-bu~yric anhydride. The p~essure is not criti~al and may be; for ex3mple, m the range of 80 mm. of mÆrcury to 10 atmospheres absolute (0.1 to 10.1 bar). hgain, any BecXmann rear-rangement ca~alyst may be used, as discussed abcve. The reaction may be advantageously carried out in the presence of the glacial carboxylic acid correspond m g to the anhydride e~ployed in the reacti~n Ln an amount, ~or example up to 50% by w2ight of the anhydride. The total amount of ~lacial carkoxylic acid is not critical but the total amaunt of anhy~ride or anhydride/acid mixture is such that the ketoxIme concen~
tration is in mKst cases in the range of about 2 to 50% by weight at the stæt of the reaction.
me ~ollcwiT~ ex~ples ~rth~r illustrate the ~mrention.

13xample 1 ~is exanple illustrates th~ preparation of 4-hydro~acetc~enone by the 30 Erie re~rr~3nt of phenyl ace~ate usin~ hy 3roge3;~ fluoride as cata-lys~.

To a 300 cc Hastelïoy C autoGlave was c~arged 40.8 g (0.3 m~l) of phenyl acetate. The autoclave was sealed, i~sed in a ~y Ice/isopr~panol 35 bath and cooled in~ernally to -45C, and evacuated to ca. 100 I~rr (0.13 bar). Addltion of 120 g (6.0 mol) of anhydrous hydrog~n Iluoride wa~
perfonTuad in a ma~er such a~ that the internal ten~perat~re of the ~6~

autoclave did not exceed 0C. Ihe internal pressure o~ the reactor was then adjusted to 0 psig (1.1 bar) with nitrogen. m e conkents of the autoclave were stirred and heated to 75C for l h. m e hydrogen fluo-ride was vented over a 45 min period at ca. 45C. The mixture was

5 poured onto 25 g of ice and neutralized with 45% potassium hydroxide solution. The aqueous mix*ure was extracted with ethyl acetate. ~he organic fraction was then driPd over anhydrous m~gnesium sulfate, filtered, and the solvent was removed on a rotary evaporator to yield 44.0 g of a dark green solid corresponding to 99.9% cor~ersion of phenyl acetate and 94.3% seleckivity to 4-hydroxyacetophenone.

Example 2 This example illustrates the preparation of 4-hydroxyacetophenone by the Fries rearrangement of phenyl acetate using hydrcgen fluoride as cata-lyst with acetic anhydride as additive.

Io a 300 cc Hastelloy C autoclave were added 30.6 grams (0.3 mole) of acetic anhy~ride. Ihe autoclave was cooled to -50C and evacuated to 5 Torr (0.007 bar) whereupon 120 g (6.0 mole) of anhydrous hydrogen fluoride was transferred fr~m a cylinder to the autoclave. After the trans~er of hydrogen fluoride was completed, ~he internal ~emperature and the internal pressure of the autoclav~ was adjusted to -50 & and l.l bar us mg nitrcgen, respectively. To the stirre~ autoclave was added 81.6 g (0.6 mol) o~ phenyl acetate at such a rate ~hat the temperat~re of ~he mi~ture did no~ exceed -23 & . Upon ~ompletion of ~henyl acetate addition, the contents were warmRd to 50C and stirred for 3 h during which time a pressure of ca. 40 psig (3.9 bar) was generated. At the end of the run, the hydrogen fluoride was vented through a caustic scrubber and the contents of the autoclave were poured onto ca. 30 g o~
30 ice. The pH of the mixture was ad~usted to 6.5 us~ng 45% potassium hydroxide and the mixture was then extracted with 75 ml OI ethyl acetate (3x). Ihe organic solution was dried over a~y~ous l[agnesi~n sul~ate, ~ilter~d, an~ the solvent was re~ved using a rotary evaporator.

35 ~ne reaction proceeded wi~h 98.1% conversion o~ phenyl acetate and with the Iolla~ seleativities: ~enol 1~, 4-hydroxyacetophenone (4 82 . 396; 2-hydro~acetophenone (2-~P) 4 . 3%; 3-h~ro~acetophenone (3 ~,26:Z ~4~

0.1~; 4-acetoxyacetophenone (4-AAP) 3.8%; and 4-(4'-hydrox~phenyl)-aceto~henone (HPAP) 0.4%.

Ex~mE~e 3 S Ihis example describes the formation of 4-hydroxyacetophenone by the Fri~s rearrangement of phenyl acetate using hydrogen fluoride as cata-lyst and acetic acid as additive.

m e procedure for Example 2 ~lS repeated e~cept that 18 grams (0.3 mole) of acetic acid rather than acetic anhydride were charged to the reactor before it ~as cooled and charged with the hydrogen fluoride. A conver-sion of 99.0% o~` phen~l ace~ate was obtained with the following selec-tivities: phe~ol 3.3~; acetic acid 0.8%; 4-H~P 80.8~; 3-H~P Q; 2-H~P
5.~%; 4-A~P 0.3%; anl HPAP 0.3%.
E~ample 4 This example illustrates the preparation of 4-hydroxyacetophenone (4HAP) by ~he Friedel-Cxafts acetylation of phenol wi~h acetic acid as the acetylating agent.
Ehenol (9.4 g, 0.1 moles) and acetic acid (12.0 g, 0.2 moles) were charg~d to a 300 ml Hastelloy C autoclave at rocm te~perature. ~he reactor was ev~cuated and cooled to -20 &. HF (100 g, 5 moles) was then transferred into ~he reactor. Ih~ reactor was heated to 80& and mainta med for 1 hour at reaction ~emperature. At the end of ~he reaction ~he reactor was cooled to 20& and the excess HF was vented to a X~H scrubber. Ethyl acetate was added to the cantents of the reactor.
m e mixture was then neutralized with 45% aqueous KOH. m e xesulting o ~ c phase was separated, dried ov~r MgS04 and eNaporated to afford a yellow solid which canta med 13.1 g (0.096 moles) of 4-H~P.

Example 5 This example illustrate~ the formation of 4-hydroxyacetophe~one oxime frcm ~-hydroxyacetophenone and hydroxylamine hydro~hloride.
A solution was prepared by adding 13.6 ~ (0.1 mol) of 4-hydroxyaceto-ph~none, 7.6 g (0.11 mol) of hydro~ylamine hydrochloride, and 10 g of ~26~

water to 40 mL of ethk~nol. To the solution was added 5.0 g of 30%
al~monium hy~roxide which was then heated at reflux for 2 h. m e ethanol ~as remcved on a rotary evaporator to yield a yellcw oil. An extractive rk-up afforded 15.1 g (99~) of 4-hydroxyacatophenone oxime..
s Exampla 6 This exa~ple illustra~es the ~ormation of 4-hydro~yacetophenone oxime fr~m 4-hydroxyace~ophenone and hydroxylamine sulfate.

A solution was prepared by adding 2054 g (0.15 mol) of 4-hydro~yaceto-phenone and 13.0 g (0.08 mol) of hydroxylamlne sulfate to 100 mL of wa~er at 70 &. To the solution was added 16.3 mL of 30% ammonium hydroxide ~hich was then heated a~ refl~x for 0.5 h. White c~ystals formed upon cool m g yieldlng 21.0 g (92.6%) of 4-hydroxyacetophenone oxIme.

This ~ ple illuskrates the formation of 4-hydroxyacetophenone oxime from 4-hydroxyacetoEhenone and hydroxylam m e phosphate.
A ~olution was prepared by adding 20.4 g (0.15 mol) of 4 hydr~xyaceto-phenone and 12.9 g (65.6 mmol) of hydroxylamlne phosphate to 100 mL of water at 70C. To the solution was adde1 16.3 mL of 30% ammonium hydroxide which was then heated at reflux for 0.5 h. White crystals formed upon cooling yielding 21.0 g (92.6~) of 4-hydroxyacetophenone oxime.

Example 8 lhis example illustxates the formation o~ 4-aceto~yaoetanilide (AAA) by the Beckmann rearrangement an~ acccmpanying acetylation of 4-hydroxy-acetophenone oxIme using an acidic ion-e~change resin as ca~alyst.

A mixture of 3.0 g (22.0 1) of 4-hydroxyacetophenone oxime, 3.0 of ~mb~rlyst 15 (a sulfonic acid ion-exchange resin made by Rohm ~ Haas), and 75 m~ of a mlxture of ~lacial acetic acid and acetic anhydride (1:1) was he~ed a~ re~lux under nitrogen for 4 h. m e ion~exchange res~n was th~n remGved and the acetic aciq/a~etic anhydride was distilled in vacuo ~,~2'1E;2~

to yield yellow~white crystals. rnhe ~ystals were dissolved in ethyl acetate and treated w.ith activated carbon and anhydrous magnesium sulfate. Ihe mixture as ~iltered and the solvent was removed on a rotary evaporator to yield 3.4 g ~80.4%~ o~ yellcw crystals of 4-S acetoxyacetanilide (AA~).

Example 9This example illustrates the formation o~ 4-acetoxyacetanilide (~AA) bythe Beckmann rearrangement and accompanying acetylation of 4-hydro~yace-tophenone oxime using methanes~onic acid as catalys~.

A solu~ion of lO g (66.2 mmol) of 4-hydroxyacetophenone oxime, 1.6 of 70% methanesul~onic acid, 50 g of acetic anhydride and lO0 g of glacial acetic acid was heated at reflux under m trogen for 2 h~ Rotary evaFo-ra~ion of the solutio~ yielded 17.0 g of li~h~ brcwn crystals. Re-crystallization from water yielded 6.7 g (52.4%) of 4~acetoxyacetanilide (AAA). ~h2 mother liquor conta med 32.0% of AAA for a total yield of 84.4%.

Example 10 This example illustrates the formation of 4-acetoxyacetanilide (AAA) by ~he Beckmann rearrangement anl accompany.~ng acetylation of 4-hydroxy-acetophenone oxime usLng phcsphoric acid ~H3P~4) as catalyst.

To a mixtNre of 100 g of glacial acetic acid, 50 g of acetia anhydride, a~d 3.6 g o~ 85~ H3P04, sparged with nitrogen for 30 minutes, was added 10 g o~ 4-hydroxyacetcphenone oxlme. Ihe ~ re was heated at reflux for 1 hour under a nitrogen atmosphere, then cooled to rocm temperature and neutralized with 13% Na2oO3. ~he mix*Nre was evapora~ed to dryness using a rotary evapara~or and the solid was dissolved in 200 g of boiling water. After hot filtration, the solution was allowed to cool and 8tand overm ght. The ensuing white crystals were collected, washed with 20 mL of water, and driel in a vacuum oven ~60C/100 mm Hg (0.13 kar)) for 2 hours. Upon dryin~, 9.4 g (73.9~) of white crys~alline plates o~ 4-acetoxyacetanilide having a melting point of 148-150C was obtained. An additional 0.8 g of AA~ and 1.5 ~ of N-aoetyl-para-aminophQnol (AP~P) were xeclaimed from the mother liquor.

~262~

m e prccedNres of examples 8 through 10 may also be usel to prepare N-acetyl-(4-aceto~y-3-methylph~nyl) amine from o-cresyl acetate or o-cresol and ace~ic acid, and acetic anhydride: N-propionyl-(4-pro-pionoxyphenyl) amine from phenyl propionate or phenol and propionic acid, and propionic anhydride; and N-n-butyry1-(4-n-butyroxyphenyl) amine fram phenyl n-butyrate or phenol and n-butyric acid, and n-butyric anhydride, in the first and second reactions resp~ctively.

The N-acyl acyl~y aromatic amines, e.g. AAA, of this invention may be utilized as monamers in the prepara~ion of pvly(ester-amide)s capable of ~orm m g an anisotropic melt phase and sultable for bei2~g formed into shaped articles such as molded articles, fibers and films, as shown, for example In U.S. Patent Nos. 4,330,457; 4,339,375; 4,341,688; 4,351,918;
and 4,355,132.

l~e N-acyl-acyloxy arcmatic amlnes of this invention, e.y. AAA, may also be hydrolyzed to ~orm the corresponding N-acyl-hydroxy æomatic amune, e.gO N-acetyl-para-aminoEher201 ~APAP) w~2ic~ is one of the most widely used over-the-counter analgesics. The following example illustrates this proce~s Example 11 A mixture of 5 g (2509 mmol) of 4-acetoxyacetanilide (AAA), 1.4 g of 70%
m~thanesul~onic acid, and 50 g o~ water was heatel at reflux for 1 h.
~pon cooling, white crystals formed~ Analysis (GIC) of the crystals as well as the a~ueous solution indicated 90~ conversion of the AA~ to N-acetyl-para-am moEhenol (APAP)~

E~m~le 12 This example illustrates the formation of N acetyl-para-aminophenol by the Beckmann rearrangement of 4-hydroxyacetophenone oxime using an acidic ion-exchange resin as catalyst.

A mixture o~ 3.0 g of Amberlyst 15 (a sulfonic acid ion-exchange resin made by Rohm & Haas~, 3.0 g (22.0 mmol) of 4-hydroxyacetophenone oxlme, and 50 mL o~ acetie acid was heated at reflux under ni~rogen for 2 h.
The lon exchange resin was then removed an~ the acetie aeid was ~L262~4~

distilled in vacuo to afford an orange residue. The residue was dissolved in athanol and traated with activaked carbon and anhydrou~s magnesium sulfate. Removal of the ethanol usiny a rotary evaporator produc0d 2.9 g of a yellcw oil, which upon dry mg afforded 2.0 g (66.7~) S o~ N-acetyl-para-aminophen~l.

Example 13 Ihis example illustrates the formation o~ N-acetyl-para-aminophenol by the Beckmann re q ement o~ 4-hydro~yacetophenone oxime using tri-fluoroacetic acid as catalyst.

A solution of 10 g (66.2 D 1) of 4-hydroxyacetophenone oxime and 75 g of trifluoroacetic acid was heated at reflux under a nitrcgen atmo-sph~re. lhe trifluoroacetic acid was then remcved in a rotary evapora-tor to afford 14.7 g of oil which was dissoived m 100 mL of water.Upon cooling to o& for 0.5 h, crystalliza~ion o ~ . Filtration and dry m g of the crystals yielded 7.1 g (71~) of N-acetyl-para-aminophenol.

Exa~ple 14 ~his example illustrates ~he formation of N-acetyl-para-aminophenol by the ~ nn re ~ ement of 4-hydroxyaceto~henone oxime using thionyl chloride in liquid sulfur dioxide as catalyst.

A pressure bottle (cooled in a oo~aceto~e bath) was chaxged wi~h 50 mL
of S02, 0.05 mL o~ SOC12, and 15 g of 4-hydro~yac ~ophen~ne oxlme. The oo~acetane bath was rem~ved and the contents of the pr~ssure bottle stirred for 1.5 h at room temperature. The S02 was then vented and the crystals wa~hed from ~he pressure bottle with 50 mL of warm water. ~he pH of the a~ueous slurry was adjusted to 6.5 by dropwisa addition of 30%
NH40H. Ihe slurry was cooled in an ice bath and than filtered. Ihe filtered crystals wera washed with 10 mL of ice wa~er and dried over-night in a vacuum oven (60C/100 mm Hg (0.13 bar)) yielding 13.3 g (88.7~) of white crystals of N-acatyl-para-aminophenol having a melt mg polnt of 166.5-170C.
Ihe procedures o~ example~ 12 through 14 may also ba used to prepare N-acetyl-(4-hydr~xy-3~methylphenyl) amlne ~ram o-oresyl acetate ~r ~,26~

o-cresol and acetic acid; N-propîonyl-para-am mophenol from phenyl propionate or phenol and propionic acid; and N-n-butyryl-para-amino-phenol fr~m phenyl n-butyrate or phenol and n-butyric acid.

Example 15 A 250 ml pressure bottle was ff rst cooled in a Dry Ice/acetone bath and was then charged with 50 ml of S02 (via vacuum tra~sfer), 0.05 mL of SCC12, and 15 g of 4-hydroxyacetophen~ne oxIme. Ihe Dry Ice/acetone bath was rem wed and the contents of the pressure bottle stirred for 1.5 h. at room temperatNre. The S~2 was then vented and the crystal~ washed ~rcm the pressure bottle with 50 mL of warm water. The pH of the aque~us slurry was adjus~ed to 6.5 by ~he d ~ ise addition of concen-trated ammonlum hydroxide. The slurry was cooled in an ice bath and then ~ilter~d~ m e filtered crystals were washed with 10 mL o~ ice water and dried cverni~ht in a ~acuum oven at 60 &, yield mg 13.3 g of ~hite N-acetyl para-amino~hen~l crystals with a mÆlt m g point o~ 166.5-170 &.

Examples 16 The sam2 general procedure as Example 15 was employed except that tap water (24 &) ~as used to wash the crystals from the pressure bottle.
Also, the ~ t of SOC12 was increa~el to 0.1 ml and t'he reaction tlme was decreased to 25 mlnutes. Off-white crystals of N-acetyl para-am mophenol (13.7 g) were recx~rere~ with a m~lting poi~t of 165-169C.
Example 17 Ihis example illustrates the pr~paration o~ 2-methyl-4 ~ydroxy-acetanilide using thionyl chloride as the catal~st ln S02.

r~he same general procedNre as in Example 15 was employed except that 2-m~thyl-4-hydxoxyacetc~henone oxi~e was employed as the oxIme, the amount o~ oxime was reduced to 5 g, the amount of thionyl chloride was increased to 0.5 mL, and thQ reaction time was decreased to one hour at room temperature ~24 &)~ Tan colo~ed crystals o~ 2-methyl-4-hydroxy-acetanilide (1 g) were reccvered with a melting point of 122-128C.

6~

Example 18 m is e~ample il].us~xates the preparation of 2~hydroxyacetanilide by the BeckmaNn rearran~ement o~ 2~hydroxyacetophenone oximQ using thionyl chloride as the ca~alyst in S02.

qhe same general proced~re as Example 15 was employed except that the oxlme was 2-h~roxyacetophenone oxime, the amount of oxime was reduced to 5 g, the amoun~ of thionyl chloride was increased to 2.5 n~, the reaction time was decreased to 45 m mutes, and the reaction tempera~ure was 30 &. Yellow-colored crystals of 2-hydroxyacetanilide (3.6 g) was reccvered with a melt m g poin~ of 201-203C.

Example 19 This example illustrates the preparation of N-acetyl para-aminophenol by the Eeckmann rearrangement of 4-hydr~xyacetophenone using thionyl chloride as c~talyst m diethyl ether.

A 250 ml round-bottom flask eguipEed with a reflux condenser and addi-tion ~unnel was dharged with 5 g of 4-hydroxyacetophenone oxime dis-sol~ed in 50 mL of anhydrcus diethyl ether. A solu~ion of 0.5 mh of thionyl chloride in 15 m~ of ether was then added dropwise from the a~dition ~unnel. The contents of thQ flask were stir~ed during the addition and for an additional 30 munutes after cx~pletion of the additian. The ether was then removed on a rotovap. m e solid residue was then dissolved in 25 mL of hot water. The pH of the ~olution was adjusted to about 6.5 with ammon~um hydroxlde and suksequ~ntly the solution was cooled in an ice bath. m e crystals which were formed were filtered and waahed with approximately 10 mh of ice water and then dri~d in a ~acuum cven at 65C overni~ht. Brown crystals of N-acetyl para-aminophenol (1.1 g) were obta med wi~h a melt m g point o~ 161-2C.
~ xample 20 m is example illu~trates the preparation of N-acet~l para-ammo~henol frcm 4-hydr3xyacet~phenone, using thion~l chloride as the catalyst in ethyl acetate.

The same procedure a~ Example 19 was employed except thk~t ~thyl acetate was used as the solvent mstead of diethyl etherO Light brown crystals of N-ace~yl para~inophenol tl.9 g) with a melting point of 158-161&
were recovered.

Example 21 Ihis example illustrates the preparation of N-acetylated para-am m o-phenol from 4-hydroxyacetophenone usm g thlonyl chloride as catalyst in acetone.
The same procedure as Example 19 was employed except that acetone was used as the so~vent instead of diekhyl ether. ~rown crystals of N-acetyl p3ra-am mophenol (3.7 g) with a m~lt m g point of 15~-161 & were r~covered.
Example 22 qhis example illuskrates the preparation o~ N-acetyl para-aminophenol fr~m 4-hydroxyacetopheno~e oxime us mg thlon~l ~hloride as catalyst in tetrahydrofuran.
The same procedure as Example 19 was employed except that te~rahydro-~uran was used as the solvent 1ns~e~d o~ diethyl ether. Tan crystals of Nacet~l para-aminophenol (2.5 g) with a melting poLnt of 156-8C were recovered.
Example 23 Ihis example illustrates the prepara~ion of N-acetyl para-amino~henol fr~m 4-h~r3xyaoetophenone oxime us m g thionyl chloride as the catalyst in methylene chloride.
The same procedure as Example 19 was employed but methylene dhloride was used as the solvent instead of diethyl ether. Dark brcwn crystals o~
N-acetyl para-aminophenol (2.7 g) with a meltin~ point of 152-156C were obtained.

;2~

Example 24 This exampls illustrates the preparation of N-acetyl para-aminophenol from 4-hydroxyacetophenone oxime using thionyl chloride as catalyst in acetone, under vacu~Im conditions.

~he same prccedure as Example 19 was employed except that acetone was used as the solvent instead of diethyl ether and the system was run under vacuum ( 360 mm Hg (0.48 bar)). Tan crystal~ of N-acetyl para~
aminophenol (3.6 g) with a melting point of 162-164 & were obtained.

Example 25 ~his example illustra~es the fact that the proces~ of the present invention is capable of producing nearly quantitative yields of the desired N-ac~l~hyd~oxy aromatic amine.

The s~me general procedure as Example 16 wa~ employed excepk that the ~iltrate was also analyzed for N-acetyl para-aminophenol to determine the actual product yield. Ihe reccvered solid weight 13.7 g and the filtrate c~nta med an additional 0.7 g. of N-acetyl para-aminoEhenol.
Therefore, a yield of 97 percent was realized.

Claims (10)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process comprising contacting a hydroxy disubstituted aromatic ketone with a hydroxylamine salt and a base to form the ketoxime of said ketone, and (i) contacting said ketoxime with a Beckmann rearrangement catalyst to form an N-acyl-hydroxy disubstituted aromatic amine, or (ii) contacting said ketoxime with a carboxylic acid anhydride and a Beckmann rearrangement catalyst to form an N-acyl-acyloxy disubstituted aromatic amine.

2. The process of claim 1 wherein said hydroxy disubstituted aromatic ketone is 4-hydroxyacetophenone, said ketoxime is 4-hydroxyacetophenone oxime, and said N-acyl-hydroxy disubstituted aromatic amine is N-acetyl-para-aminophenol.

3. The process of claim 1 wherein said hydroxy disubstituted aromatic ketone is 4-hydroxyacetophenone, said ketoxime is 4-hydroxyacetophenone oxime, said anhydride is acetic anhydride, and said N-acyl-acyloxy disubstituted aromatic amine is 4-acetoxy-acetanilide.

4. The process of claim 3 wherein said 4-acetoxy-acetanilide is hydrolyzed to form N-acetyl-para-aminophenol.

5. The process of claim 1 also comprising contacting an ester of a phenolic compound and a carboxylic acid with a Fries rearrangement catalyst to form the hydroxy disubstituted aromatic ketone.

6. The process of claim 5 wherein said Fries rearrange-ment catalyst is hydrogen fluoride.

7. The process of claim 6 wherein the ester is phenyl-acetate.

8. The process of claim 1 also comprising contacting a phenolic compound and an acylating agent with a Friedel-Crafts catalyst to form the hydroxy disubstituted aromatic ketone.

9. The process of claim 8 wherein said Friedel-Crafts catalyst is hydrogen fluoride.

10. The process of claim 9 wherein the phenolic compound is phenol and the acylating agent is acetic acid.