Note: Descriptions are shown in the official language in which they were submitted.
2la3~j~s
HOECHST ARTIENGESELLSCHAFT HOE 92/F 243 Dr. Bi/we
Process for the preparation of aminophenyl acetates
The present invention relates to an improved process,
compared with the prior ~rt, for preparing ~minophenyl
acetates by reaction of the corresponding nitrophenyl
acetates with hydrogen in the presence of a hydrogen~tion
catalyst.
Owing to their functional groups, aminophenyl acetates in
general and 4-aminophenyl acetate in particular are suit-
able starting materials for a multiplicity of differentchemical compounds. They serve, for example, B~ versatile
precursors for the Heck reaction of diazonium salts
prepared in situ as can be seen from R. gikukawa et al.,
J. Org. Chem. 1981, 46, 4885. Furthermore, aminophenyl
acetates can be used as precursors for the preparation of
a large number of fine chemicals, crop protection agents
and pharmaceuticals.
The processes for preparing aminophenyl acetate deriva-
tives previously described in the literature are at least
to some extent fairly complicated and can therefore be
carried out in industry only with very great difficulty
and/or yield the desired valuable products only in low
yields. Thus, according to Hazlet and Dornfeld, J. Am.
Chem. Soc. 1944, 66, 1781, 4-aminophenyl acetate can be p-
repared by reduction of 4-nitrophenyl acetate with iron
and a mineral acid. However, the yield iB only 9 - 13%~
A different route is described by L. Gslatis, Chem. Ber.
1926, 59, 848. p-Aminophenol i~ reacted with b~nzaldehyde
to give the corre~ponding ~enzylidene compound, which is
then subjected to O-acetylation and hydrolyzed in cold
mineral acid. The yield exclusive of the last step is no
more than about 35~, but no yield i~ reported for any of
the preceding steps.
2t Q3~9
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A more recent synthesis ~tarts with 4-aminophenol which
i6 selectively reacted with acetic anhydride in the
presence of cobalt(II) chloride to give the corresponding
O-acetyl compound (S. Ahmad, J. Iqual, J. Chem. Soc.
Chem. Comm. 1987, 114). The yisld is 83~. However, this
method ha~ disadvantages. On the one hand it i~ neces~ary
to work with vigorous exclusion of water and, on the
other, the reaction must be ~arried out under an inert
gas atmosphere.
A further synthesis starting with 4-nitrophenyl acetate
is disclo6ed in Sstoh et al., Chem. Pharm. Bull. 1981,
29, 1443. In this synthesis, 4-nitrophenyl acetate is
reacted with excess tin(II) chloride and sodium boro-
hydride in the presence of an aliphatic alcohol as the
solvent. Although this method is suitable for a
laboratory method, it i6 not suitable for an industrial
proce6s owing to the large amount of tin(II) chloride
required and owing to the use of expensive ~odium boro-
hydride.
As is apparent from R. Feldstein et al., J. Org. Chem.
1961, 26, 1656, the reaction of 4-nitrophenyl acetate
with hydrogen in the pre~ence of platinum oxide as the
catalyst does not produce p-aminophenyl acetate but
results in the formation of the corre~ponding p-aceta-
midophenol, presumably by migration of the acetylradical, in a yield of not less than 77%.
The reaction of p-nitrophenylacyl esters with hydrogen in
the presence of PtO2 as the cataly~t in ethanol described
by J.E. Wynn et al., J. Pharm. Sci. 1932, 7, 772 must ~e
seen as being related thereto. If p-nitrophenyl acstate
and PtO2 as the catalyst and ab~oluts ethanol a8 the
solvent are used, thi~ reaction leads to a yield of only
43% of p-aminophenyl acetate. Hydrogenation of sub6titu-
ted nitrophenyl acetates is not described.
The general difficulties of synthesizing aminophenyl
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-- 3 --
acetates and derivatives thereof may be explained by the
instability of the phenyl ester group which is possibly
due to the presence of an amino group. Obviously, in
solution, the aminophenyl acetates gradually are con-
verted into the thermodynamically more stable acetamido-
phenols by migration of the acetyl group. EP-0,435,263 A1
has shown that traces of acid~ or ba~es catalyze this
process.
As documented by the above obser~ations, there i8 a need
for a process which avoid~ the difficulties de~cribed
above, can moreover al~o be used on an $ndustrial scale,
can be easily put into practice and u~es auxiliaries
which are readily available in industry. Furthermore, the
process should provide the desired product in high yield
and, at the same time, prevent the formation of by-
products as far as possible.
This object i6 achieved by a process for preparing an
aminophenyl acetate or aminophenyl diacetate. It com-
prises reactin~ a nitrophenyl acetate or a nitrophenyl
diacetate in the pre~ence of a hydrogenation catalyst
with hydrogen at O - 60~C and an H2 pre~sure of at least
4 MPa in the presence of a solvent or a solvent mixture.
In view of the results obtained by R. Feldstein et al.,
J. Org. Chem. 1961, 26, 1656 and J.E. Wynn et al., J.
Pharm. Sci. 1982, 7, 772 by means of catalytic hydrogena-
tion, it was surprising that the proces~ according to the
invention produces aminophenyl acetates by catalytic
hydrogenation of the corresponding nitrophenyl acetate~
in high yields.
Suitable nitrophenyl acetates are not only nitrophenyl
acetates or nitrophenyl diacetates which are unsubstitu-
ted on the aromatic ring but also nitrophenyl acetates or
nitrophenyl diacetates which are mono- or polysubstituted
on the aromatic ring.
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- 4 -
The nitrophenyl acetate which is usually used is a
nitrophenyl acetate which is un~ubstituted or mono- or
polysubstituted on the aromatic ring by an alkyl group
having 1 to 12, in psrticular 1 to 4, carbon atoms, by a
halogen atom, by a hydroxyl group, by an alkyl ether
group having 1 to 4 carbon ~toms in the alkyl radical, by
an aryl ether group, by a nitrile group, by an RS-, R3Si-
or R-CO- group, in which R i8 an alkyl rad~cal h~ving 1
to 4 carbon atoms or an aryl ether group, by a sulfo
group, by a phosphono group, by a sulfonyl group, by a
carboxyl group and/or carboxylate salt group.
Expediently, the nitrophenyl acetate used is a nitro-
phenyl acetate which is unsubstituted or mono- or poly-
substituted on the aromatic ring by an alkyl group having
1 to 12, in particular 1 to 4, csrbon atoms, by a halogen
atom, by a hydroxyl group, by an alkyl ether group having
1 to 4 carbon atoms in the alkyl radical, by an ~ryl
ether group, by a nitrile group, by an R-CO- group, in
which R i~ an alkyl radical havin~ 1 to 4 carbon atoms,
or by a carboxyl group, in particular by an alkyl group
having 1 to 12, preferably 1 to 4, carbon atom~, by a
halogen atom, by an alkyl ether group having 1 to 4
carbon atoms in the alkyl radical, by a nitrile group or
an R-CO- group, in which R is an alkyl radical having 1
to 4 carbon atom~, preferably by an alkyl group having 1
to 12, in particular having 1 to 4, carbon atoms, or by
an alkyl ether group having 1 to 4 carbon atoms in the
alkyl radical.
A suitable material to be u~ed is o-nitrophenyl acetate,
m-nitrophenyl acetate or p-nitrophenyl acetate, each of
which is unsubstituted or mono- or polysubstituted on the
aromatic ring, in particular o-nitrophenyl scetste or
p-nitrophenyl acetate, preferably p-nitrophenyl acetate.
Readily suitable nitrophenyl acetates are o-nitrophenyl
~5 acetate, m-nitrophenyl acetate, p-nitrophenyl ~cetate
or 2-methyl-4-nitrophenyl acetate, in particular
` 2~Q3~3
-- 5 --
p-nitrophenyl acetate or 2-methyl-4-nitrophenyl acetate.
Customary hydrogenation catalysts can be used for carry-
ing out the reaction. As a rule, the hydrogenation
catalysts contain copper, manganese, cobalt, nickel,
S rhodium, platinum and/or palladium, and, if desired,
suitable activators and promoters.
The suitability of cobalt-, nickel-, platinum- and/or
palladium-containing hydrogenation c~talysts which, if
desired, contain fiuitable activators and promoters is
quite good.
Particularly suitable are nickel- and/or palladium-
containing catalysts which, if desired, contain suitable
activators and promoters.
The process according to the invention can be carried out
either by means of a support-free cataly~t or with the
use of a supported catalyst.
If a support-free c~talyst i8 used, Raney cobalt or Raney
nickel, in particular Raney nickel, are reco ~ended. The
supported catalysts contain customarily used ~upport
materials. Suitable support material~ are Al2O3, clay,
pumice, SiO2, ~ilica gel, silica, kieselguhr and/or
activated carbon, in particular Al203, clay, kieselguhr
and/or activated carbon, preferably A1203~ kieselguhr
and/or activated carbon.
The process according to the invention ~8 particularly
easy to carry out using ~upported catalyst~. Supported
cataly~t~ containing noble metAls and supported catalysts
containin~ cobalt and nickel are particularly suitable.
Platinum on activated carbon and/or palladium on acti-
vated carbon, in particular palladium on activated carbonhave proven to be suitable supported catalysts containinq
noble metal. However, platinum on Al2O3 and/or palladium
on Al2O3, in particular palladium on Al2O3, can also be
used. Cobalt- andtor nickel-, in particular nickel-
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containing supported catalysts containing, for example,
clay, SiO2, silica gel, gilica and/or kieselguhr, in
particular ~ilica gel, ~ilica and/or kieselguhr, prefer-
ably kieselguhr, as the support material are also parti-
cularly suitable.
The proces6 can be carried out either batchwise or
continuously. If ~atchwise operation is employed, it is
recommended to suspend the catalyst in comminuted form
and to carry out the reaction by means of the ~uspended
catalyst. If continuous operstion is employed, it iE
recommended to use the cataly~t, for example, in bulk
form and arranged as 8 solid bed. The catalyst arranged
as a solid bed is usually pre~ent in an upright tube.
Depending on the manner of addition of the material to be
hydrogenated, two methods may be distin~ui~hed, the
trickle-phase and the liquid-phase method. In the
trickle-phase method, the material to be hydrogenated is
added to the catalyst arranged as a solid bed from abo~e,
while the hydrogen i8 passed either co-currently from top
to bottom or counter-currently from bottom to top. In the
liquid-phase method, the material to be hydrogenated i8
passed through the catalyst-containing solid bed from
bottom to top. In this method, hydrogen is usually passed
through co-currently.
The process according to the invention i8 carried out at
a temperature of from 0 to 60C. The reaction temperature
to be u~ed al80 depends to a certain extent on the reac-
tivity of the nitrophenyl acetate or nitrophenyl di-
acetate. Relatively reactive nitrophenyl ncetates or
nitrophenyl diacetates permit a reaction at relatively
low temperatures, whereas comparatively inert nitrophenyl
acetates or nitrophenyl diacetates require corres-
pondingly higher temperatures.
Apart from the reactivity of the material used the
activity of the hydrogenation catalyst also affects the
reaction temperature to be used to a certain extent.
Active hydrogenation catalysts allow the reaction to be
210~19
-- 7 --
carried out at comparatively lower temperatur~s, while
less active hydrogenation cataly~ts make it nece~sary to
carry out the reaction at higher temperatures.
In many ca~e~, it has pro~en 6uitab1e to carry out the
reaction at 10 to 50, in particular 15 to 45, pref~rably
20 to 40C. Successful implementation of the process
according to the invention requires that a ~pecific H2
pressure be maintained. The H2 pre~sure ~hould be at
least 4 MPa.
Selection of the H2 pressure depends to a certain extent
on the reaction temperature selected, on the reactivity
of the material used, and on the activity of the hydro-
genation catalyst. Thus, a comparatively high reaction
temperature and/or a comparativeiy reactive nitrophenyl
acetate or nitrophenyl diacetate and/or a comparatively
active hydrogenation catalyst allows the rQaCtion to be
carried out at relatively low pressures. In contrast, if
a relatively low temperature and/or a relatively inert
nitrophenyl acetate or nitrophenyl diacetate and/or a
hydrogenation catalyst having low activity are used, it
i8 recommended to carry out the reaction at relatively
ele~ated pres~ures.
In most cases, it is sufficient to c~rry out the reaction
at an H2 pre6sure of 4 to 100, in particular 5 to 50,
preferably 5 to 30, MPa.
The nitrophenyl acetate or nitrophenyl diacetate i8
dissolved in a 601vent or colvent mixture, and this
solution is u~ed for the catalytic reaction with hydro-
gen. The solvent used is a straight-chain and/or
branched, monohydric andtor polyhydric aliphatic alcohol,
in particular a branched monohydric alcohol, an aliphatic
ketone, a non-cyclic and/or cyclic aliphatic ether, an
alkyl ester of an aliphatic carboxylic acid, an alkyl-
benzene andtor an aliphatic N,N-dialkylcarboxamide.
2103~19
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It has proved suitable to use, as the solvent, an ali-
phatic alcohol having 3 to 8 carbon atoms, in particular
isopropanol and~or sec.-butanol and/or tert.-butanol, an
aliphatic ketone having 3 to 8 carbon atoms, in parti-
cular acetone and/or methyl ethyl ketone, a non-cyclic
aliphatic ether having 2 to 4 carbon atom~ per alkyl
group, in particular diethyl ether and/or di-n-butyl
ether, a cyclic aliphatic ether having 4 to 5 carbon
atoms in the ring, in particular tetrahydrofuran and/or
dioxane, an aliphatic alkyl carboxylate having 1 to 4
carbon atoms, in particular methylformate or e~hylformate
and/or methyl acetate or ethyl acetate, an alkylbenzene,
such as toluene, xylene and/or isopropylbenzene, in
particular toluene, and/or an aliphatic N,N-dialkyl-
carboxamide having 1 to 4 carbon atom~, in particulardimethylformamide, dimethylacetamide and/or N-methyl-
pyrrolidine. Methanol and/or ethanol are not suitable
solvents if they are used as the only solvent, i.e.
without the addition of another solvent. Methanol and/or
ethanol po6sibly favor the formation of acetamidophenols
which takes place by migration of the acetyl radical.
The solvent mixture u~ed is a ~olvent m$xture comprising
a protie polar ~olvent and an aprotic solvent. The
solvent mixture usually u~ed is a protic polar solvent,
in particular a straight-chain or branched aliphatic
alcohol having 1 to 4 carbon atoms, and an aprotic
solvent, in particular tetrahydrofuran and/or dioxPne.
The use of a ~olvent mixture comprising isopropnnol and
tetrahydrofuran gives a particularly good result.
The solvent mixture usually used i8 composed of 5 to g5,
in particular 10 to 90, preferably 20 to 80, parts by
weight of a protic polar solvent and 95 ~o 5, ~n parti-
cular 90 to 10, preferably 80 to 20, parts by weight of
an aprotic polar solvent.
In many cases, a solvent mixture comprising 30 to
70 parts by weight of a protic polar solvent and 70 to
30 parts by weight of an aprotic polar solvent has proven
- 21~3~9
g
suitable.
The Examples which follow illustrate the invention
without limiting it.
Experimental Section
Example 1
In an autoclsve (volume 250 ml), 8.0 g of p-nitrophenyl
acetate (4-nitrophenyl acetate) are dissolved in a
mixture of 60 ml of i~opropanol and 30 ml of dioxane, and
1.6 g of Raney nickel of medium activity are added.
Hydrogen is then in~ected up to a pressure of 10 MPa, and
the solution of p-nitrophenyl scetate i5 reacted at room
temperature for 4 hours with stirring. The H2 pressure is
kept constant by addition of H2. The hydrogenation
catalyst i8 then removed by filtration, and the resulting
organic solution is concentrated in vacuo at room
temperature to give 6.9 g of a 95~ pure p-aminophenyl
acetate t4-aminophenyl acetate) in the form of sand-
colored crystals (which corre~ponds to a yield of 98%).
All of the p-nitrophenyl acetate ig converted. Recrystal-
lization in toluene/petroleum ethex g$ves 6.07 g ofp-aminophenyl acetate in a purity of ~ 99~ (which corre~-
ponds to a yield of 91%).
Conversion (p-nitrophenyl acetate)s 100%
p-Aminophenyl acetate selectivitys 98%
Yield after recrystallization: 91%
Comparative Example 1
Example 1 is repeate~, carrying out the reaction at an H2
pressure of 1 MPa.
Reaction time: 24 hours
Conversion (p-nitrophenyl acetate): 58%
p-Aminophenyl acetate selectivity: 84%
Comparative Ex2mple la
Example 1 is repeated, except that 90 ml of ethanol
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,
-- 10 --
(instead of dioxane and isopropanol) are used as the
solvent.
Conversion (p-nitrophenyl acetate): 100~
p-Aminophenyl acetate selectivity: 68% (25% of p-acet-
S amidophenol)
Example 2
Example 1 is repeated, except that 90 ml of isopropanol
(instead of dioxane and isopropanol) are used a~ the
~olvent.
Conversion (p-nitrophenyl acetate): 100%
p-Aminophenyl acetate selectivity: 85% (13% of p-acet-
amidophenol)
Comparative Example 2
Example 2 is repeated, except that 90 ml of isopropanol
(instead of dioxane and isopropanol) are used as the
solvent and the reaction is carried out at an H2 pres~ure
of 1 MPa.
Conversion (p-nitrophenyl acetate): 45%
p-Aminophenyl acetate selectivity: 67% (4 by-products)
Example 3
Example 1 is repeated, except that 1.91 g of a supported
palladium catalyst (5~ of Pd on activated carbon~
(instead of Raney nickel) are used.
Conversion (p-nitrophenyl acetate): 100%
p-Aminophenyl acetate ~electivity: 96%
Comparative Example 3
Example 3 i~ repeated, except that 100 ml of toluene
(instead of dioxane and isopropanol) are used as the
solvent and the reaction is carried out at an H2 pressure
of 1 MPa.
Reaction time: 1 hour
Conversion (p-nitrophenyl acetate): 0%
- 21~3~19
11
Example 4
Example 1 i8 repeated, except that ~0 ml of toluene
(instead of dioxane snd i~opropanol) are u~ed as the
solvent.
Conversion (p-nitrophenyl acetate): 95%
p-Aminophenyl acetate ~electivity: 844 (3 by-products)
Example S
Example 1 i8 repeated, except that 60 ml of methanol and
30 ml of tetrahydrofuran (instead of dioxane and i~opro-
panol) are used as ~he solvent.
Conversion (p-nitrophenyl acetate): 100~
p-Aminophenyl acetate selectivity: 96% (4% of p-acet-
amidophenol)
Example 6
Example 1 i5 repeated, except that 50 ml of dioxane and
40 ml of isopropanol (instead of 30 ml of dioxane and
60 ml of isopropanol) ~re u~ed.
Conversion (p-nitrophenyl acetate): 100%
p-Aminophenyl acetate selectivity: 96% (4% unknown by-
product)
Example 7
Example 1 is repeated, except that 1.0 g of a supported
nickel catalyst containing 52 to 55% by wsight of Ni and
25 to 30~ by weight of kieselguhr as the support (commer-
cial product from Hoech~t AG; designation Ni 55/5 TS)
(instead of Raney nickel) is used. Hydrogen ab~orption:
1 hour; reaction time a total of 4 hours
Conversîon (p-nitrophenyl acetate): 100%
p-Aminophenyl acetate selectivity: 86%
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Example 8
Example 1 is repeated, except that 2-methyl-4-nitrophenyl
acetate (instead of p-nitrophenyl acetate) is used a~ the
starting material.
Conversion (2-methyl-4-nitrophenyl acetate): 100%
2-Methyl-4-aminophenyl acetate ~electivity: 97~
