Process for preparing 4-(4-aininophenvI)-3-morphoIinone
The present invention relates to a process for preparing 4-(4-aniinophenyl)-3-morpholinone
by reacting 4-(4-nitrophenyI)-3-morpholinone with hydrogen in the presence of a
hydrogenation catalyst, characterized in that the reaction is effected in an aliphatic alcohol.
4-(4-Aminophenyl)-3-morpholinone is a central precursor in the synthesis of 5-chloro-iV-
({(5iS)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-l,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide,
an inhibitor of the blood clotting factor Xa, which can be used for the
prophylaxis and/or treatment of various thromboembolic disorders (on this subject, see
WO-A 01/47919, whose disclosure-content is hereby incorporated by reference).
5-Chloro-iV-({(55)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-l,3-oxazolidin-5-yl}methyl)-
2-thiophenecarboxamide (IV) is synthesized according to WO-A 01/47919 starting from
4-(4-aminophenyl)-3-morpholinone (I), 2-[(25)-2-oxiranyhnethyl]-l^-isoindole-l,3(2//)-
dione (II) and 5-chlorothiophene-2-carbonyl chloride (EI):
Q ^ - - KXP —>
(D (ID
o
o o
CI
0 N--f y-N I H U=/
O O
av)
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WO-A 02/48099 likewise describes 4-(4-aminophenyl)-3-morpholinone as a precursor for
the synthesis of active ingredients, but there is no information there whatsoever on the
preparation of this compound.
In contrast^ WO-A 01/47919 also describes a preparation method for 4-(4-aminophenyl)-3-
morpholinone (I). In this method, morpholin-3-one (V) is first deprotonated with sodium
hydride and then reacted with 4-fluoronitrobenzene (VI) to give 4-(4-nitrophenyl)-3-
morpholinone (VII)- Catalytic hydrogenation of (VII) with hydrogen .over palladium on
activated carbon in tetrahydrofuran as a solvent affords 4-(4-aminophenyl)-3-morpholinone
a):
q N ^ O N—/ \-NO2
^ ^=^(VI) (Vll)
H2,Pd/c ^r-\ /^-^
^ O N - ( V - N H2
(I)
However, the yield of this process at 17.6% of theory in the first stage and 37.6% of theory
""in the second stage is xinsatisfactory. In the second stage, the hydrogenation of the nitre
group of (Vn), one reason for this low yield will certainly be the drastic reaction
conditions, specifically eight hours of reaction time at 70°C and a hydrogen pressure of
50 bar. Moreover, the high pressure entails considerable apparatus complexity. The
resulting product also has to be purified by crystallization. These disadvantages complicate
the reaction on a larger scale in particular.
This gives rise to the object of the present invention, of providing a simplified process for
preparing 4-(4-aminophenyl)-3-morpholinone (I) which is suitable especially for the
preparation of relatively large amounts.
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It has been found that, surprisingly, the reaction of 4-(4-nitrophenyl)-3-morpholinone (VII)
with hydrogen can be carried out in the presence of a hydrogenation catalyst, preferably
palladium on activated carbon (5%), in aliphatic alcohols, preferably in alcohols having 1
to 4 carbon atoms such as methanol, ethanol or n-butanol. The reaction more preferably
takes place in ethanol, in solution or in suspension. The use of ethanol as the solvent at
temperatures between 40 and 120°C, preferably 75 to 85°C, and a hydrogen pressure of 2 •
to 10 bar, preferably 4.5 to 5.5 bar, can distinctly shorten the reaction time. In general, the
reaction is complete after only about one hour. These mild reaction conditions lead to the
product (I) being obtained in excellent yield and in high purity.
In the case of ethanol as the solvent, the reaction mixture is worked up merely by admixing
with water and ethanol and filtering off the catalyst firom the product solution at 40°C.
4-(4-Aminophenyl)-3-morpholinone (I) is isolated by concentration of the filtrate under
reduced pressure. When other solvents are used, the workup conditions are adjusted
appropriately.
In a preferred embodiment, the product-containing filtrate is reacted further directly
without isolating 4-(4-aminophenyl)-3-morpholinone (I) in substance.
In the present invention, differently to the description in WO-A 01/47919, 4-(4-
mtrophenyl)-3-morpholinone (VE) is prepared by nitrating 4-phenyl-3-morpholinone
(Vffl).
1. H2SO4 (8eq.)
2. HNO3 (1.05 eq.)
M ^=^ 3.NH3aq. M ; ^ =^
O . O
(vni) "^^ ^'"^^""^ C^n)
In this reaction, 4-phenyl-3-morpholinone (VIII) is added at an internal temperature of 5 to
15°C in portions to 7 to 8 equivalents of concentrated sulphuric acid and the mixture is
then stirred at 25°C for approx. 30 minutes. Subsequently, the reaction mixture is admixed
at -10 to 0°C with 0.9 to 1.2 equivalents of 65% nitric acid. As is frequently the case in
nitrations, this forms not only the desired para-isomer but also the undesired ortho- and
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meta-isomers. For workup, water and 25% aqueous ammonia solution are added at 5 to
15°C to the reaction mixture until a pH of 7 to 7.5 has been attained.
It has been found that, surprisingly, the desired para-isomer (VII), after addition of acetone
and heating of the reaction mixture to 40°C, is dissolved selectively in the organic phase
and can be removed by extraction in a simple and advantageous manner in this way.
The concentration of the organic phase crystallizes the product (VII) out of the
acetone/water mixture, thus allowing it to be isolated.
For the preparation of 4-phenyl-3-morpholinone (Vm), the literature describes various
syntheses:
According to US 3,092,630, 1,4-dioxan-2-one and aniline are reacted in an autoclave at
340°C to obtain a certain but unspecified amount of (Vm).
J. Heterocycl. Chem. 2000, 37, 109 - 110 describes the preparation of (VHI) by phase
transfer-catalysed oxidation of 4-phenylmorpholine with potassiimi permanganate.
However, a further reaction product formed here is readily ignitable mangaaese dioxide.
Furthermore, the yield is only 45% of theory and the reaction can be carried out on a larger
scale only with difficulty.
The reaction of ethyl 2-chloroacetate with 2-anilinoethanol is described in Bull. Soc. Chim.
France 1956,1210 - 1212 and also in Zhumal Organicheskoi Khimii 1970, 6, 1305 - 1308
[CA 73:66523]. However, the deprotonation is effected here with sodium in toluene and in
benzene respectively.
The drastic reaction conditions described in the prior art, or reaction conditions, reagents or
solvents which are technically difficult to handle, can be avoided by, in accordance with
the invention, preparing 4-phenyl-3-morpholinone (VIII) by reaction of chloroacetyl
chloride with 2-anilinoethanol.
^ _ ^ ^_. NaOH /—\ / -^
V> ethanol n
O
(VIII) _
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This process is in particular efficiently employable even on an industrial scale. In this
process, 2-anilinoethanol is initially charged in aqueous alcoholic, preferably ethanolic,
solution. 2.5 to 3.5 equivalents of chloroacetyl chloride and 4 to 8, preferably 5 to 7,
equivalents of base are metered in simultaneously. The bases used are alkali metal or
alkaline earth metal hydroxide solutions, preferably sodium hydroxide or potassium
hydroxide solutions, in particular aqueous sodium hydroxide solution. The addition is •
effected at an internal temperature of the reaction solution of 30 to 50^C, preferably of 35
to 45°C. The rate of addition is also adjusted such that the pH of the reaction solution is
between 10 and 13.5, preferably between 12 and 12.5.
After the reactioji solution has been cooled to 0 to 10°C, the product (VUI) crystallizes out
and can be obtained in good yield and high purity by filtration and washing with cold
water.
The present invention further provides 4-(4-aminophenyl)-3-morpholinone prepared in
accordance with the invention.
The present invention further provides for the use of 4-(4-aminophenyl)-3-morphoUnone
prepared in accordance with the invention for preparing 5-chloro-A^-({(5iS)-2-oxo-3-[4-(3-
oxo-4-morpholinyl)phenyl] -1,3 -oxazolidin-5-yl} methyl)-2-thiophenecarboxamide (IV).
The invention is illustrated in detail below by a preferred working example, to which it is
not, however, restricted. Unless stated otherwise, all amounts reported are percentages by
*weight.
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Synthesis of 4-(4-aminophenyI)-3-morpholinone (I)
1st step: 4-phenyl-3-morphoIinone (VIII)
o
In a 26-litre tank, 1.65 kg (12.0 mol) of 2-anilinoethanol are dissolved at-room temperature
in 1.53 1 of ethanol and subsequently admixed with 4.58 1 of water with stirring. The
solution is heated to 38°C. 4.07 kg (3.0 equivalents) of chloroacetyl chloride and 6.60 kg of
45% sodium, hydroxide solution (6.2 equivalents) are then added simultaneously at an
internal temperature of 38 to 43 °C within 60 to 80 minutes, so that the pH is kept between
12 and 12.5. The mixture is stirred at a pH of 12 to 12.5 for 10 minutes, then cooled to 2°C
and stirred at this temperature for 30 minutes. The precipitated product is filtered off and
washed twice with 3.3 kg each time of demineralized water at 2°C. The moist product is
dried to constant mass at 50°C imder reduced pressure.
Yield: 1700 g (80% of theory) of a white solid.
Melting point: 114°C.
2nd step: 4-(4-nitrophenyl)-3-morphoImone (VII)
O N—V V—NO,
o
In a 2-litre flask, 177 g (1.0 mol) of 4-phenyl-3-morpholinone (VIII) are introduced at
internal temperature 10°C in 4 portions into 728 g (7.4 equivalents) of concentrated
sulphuric acid. The mixture is then heated to 25°C and stirred at this temperature for 30
minutes. The solution is cooled to -5°C and admixed within one hour with 101.8 g (1.05
equivalents) of 65% nitric acid. The mixture is stirred at -5°C for one hour. 1300 ml of
demineralized water are metered into this solution at 10°C. Subsequently, a pH of 7.4 is
established, likewise at 10°C, with 25% aqueous ammonia solution. The suspension is
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admixed with 2000 g of acetone aiid heated to 40°C. In the course of this, the product goes
into solution, so that the phases can be separated. 1500 g of acetone/water mixture are
distilled off at standard pressure from the organic phase, in the course of which the product
precipitates out. The suspension is cooled to 10°C and stirred for a further 30 minutes, and
the product is isolated. The moist product is washed with 320 g of cold acetone and dried at
50°C under reduced pressure.
Yield: 157 g (70% of theory) of a white solid.
Melting point: 152°C.
3rd step: 4-(4-aflainophenyI)-3-morphoIinone (I)
O N—(/ V—NH,
o
60 g (0.27 mol) of 4-(4-nitrophenyl)-3-morpholinone (VE) are suspended in 480 g of
ethanol, admixed with 3 g of palladium on activated carbon (5%) and contacted with 5 bar
of hydrogen at 80°C for one hour. After hydrogenation has ended, the suspension is
admixed with 80 g of ethanol and 270 g of water and heated to 40°C, and the catalyst is
filtered off. The solution is concentrated under reduced pressure and the remaining solid is
dried to constant weight at 50°C under reduced pressure.
Yield: 48.4 g (93% of theory) of a white to slightly reddish-coloured solid.
Melting point: 171°C.

We claim
1. A process for preparing 4-(4-nitrophenyl)-3-morpholinone wherein the said
compound is prepared by nitrating 4-phenyl-3-morpholinone.
2. The process as claimed in claim 1, wherein the 4-(4-nitrophenyl)-3-morpholinone
prepared by nitration is worked up by extraction with acetone.
3. The process as claimed in claim 2, wherein the 4-(4-nitrophenyl)-3-morpholinone
is isolated by crystallization from an acetone/water mixture after the extraction.
4. The process as claimed in one of claims 1 to 3, wherein 4-phenyl-3-morpholinone
is prepared by reacting 2-anilinoethanol with chloroacetyl chloride.
5. The process as claimed in claim 4, wherein chloroacetyl chloride and base are
metered in simultaneously.
6. The process as claimed in claim 5, wherein the base is aqueous sodium hydroxide
solution.
7. The process as claimed in claim 6, wherein chloroacetyl chloride and sodium
hydroxide solution are added at an internal temperature of 35 to 45°C and while
maintaining a pH of the reaction solution between 12 and 12.5.