Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
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~
71529-2
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
~,,,
. .
L4
71529-2
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):
CH3 CH3
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~
12
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~
13
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~
14
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~
16
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.
19
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.
