Claims:1. A process for the preparation of pure 4-(4-aminophenyl)-3-morpholinone of formula I:

which comprises:
a) reacting 4-phenyl-3-morpholinone of formula III:

with nitric acid in the presence of a suitable activating agent to produce 4-(4-nitrophenyl)-3-morpholinone of formula II:

and;
b) reducing the nitrophenyl compound of formula II using a suitable reducing agent, or by catalytic hydrogenation in the presence of a suitable hydrogenation catalyst in an ester solvent, to produce pure 4-(4-aminophenyl)-3-morpholinone of formula I.

2. The process as claimed in claim 1, wherein the activating agent used in step-(a) is sulphuric acid or acetic acid; and wherein the reaction in step-(a) is optionally carried out in the presence of a suitable solvent.

3. The process as claimed in claim 2, wherein the activating agent used in step-(a) is sulphuric acid; and wherein the solvent used in step-(a) is selected from the group consisting of water, acetone, dichloromethane, dichloroethane, chloroform, and mixtures thereof.

4. The process as claimed in claim 1, wherein the hydrogenation in step-(b) is carried out under hydrogen pressure in the presence of a hydrogenation catalyst; wherein the hydrogenation catalyst used step-(b) is selected from the group consisting of Raney nickel, Palladium on Carbon, Platinum oxide and Platinum on Carbon; and wherein the ester solvent used for catalytic hydrogenation in step-(b) is selected from the group consisting of ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, and mixtures thereof.

5. The process as claimed in claim 4, wherein the hydrogenation catalyst used step-(b) is Raney nickel; and wherein the ester solvent used for catalytic hydrogenation in step-(b) is ethyl acetate.

6. A process for the preparation of pure 4-(4-aminophenyl)-3-morpholinone of formula I:

or a salt thereof, comprising reducing 4-(4-nitrophenyl)-3-morpholinone of formula II:

using a suitable reducing agent, or by catalytic hydrogenation in the presence of a suitable hydrogenation catalyst in an ester solvent, to produce pure 4-(4-aminophenyl)-3-morpholinone of formula I.

7. The process as claimed in claim 6, wherein the hydrogenation is carried out under hydrogen pressure in the presence of a hydrogenation catalyst; wherein the hydrogenation is selected from the group consisting of Raney nickel, Palladium on Carbon, Platinum oxide and Platinum on Carbon; and wherein the ester solvent used for catalytic hydrogenation is selected from the group consisting of ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, and mixtures thereof.

8. The process as claimed in claim 7, wherein the hydrogenation catalyst used is Raney nickel; and wherein the ester solvent used for catalytic hydrogenation is ethyl acetate.

9. The process as claimed in claim 6, wherein the hydrogenation is carried out under hydrogen pressure of about 1 kg/cm2 to about 10 kg/cm2.

10. The process as claimed in claim 6, wherein the hydrogenation is carried out under hydrogen pressure of about 2 kg/cm2 to about 5 kg/cm2.
, Description:FIELD OF THE INVENTION

The present invention relates to improved, cost effective and industrially advantageous process for the production of 4-(4-Aminophenyl)-3-morpholinone with high yield and purity using cheaper raw materials and reagents.

BACKGROUND OF THE INVENTION

US Patent No. US 7,585,860 discloses a variety of substituted oxazolidinone derivatives and their salts, processes for their preparation, pharmaceutical compositions comprising the derivatives, and methods of use thereof. These compounds are anticoagulants which inhibit the blood coagulation factor Xa with increased selectivity. Among them, Rivaroxaban, 5-chloro-N-[[(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]oxazolidin-5-yl]methyl]thiophene-2-carboxamide, acts as inhibitor of clotting factor Xa and which is used as agent for the prophylaxis and/or treatment of thromboembolic disorders, in particular myocardial infarction, angina pectoris, reocclusions and restenoses after angioplasty or aortocoronary bypass, stroke, transient ischaemic attacks, peripheral arterial occlusive diseases, pulmonary embolisms or deep venous thromboses. Rivaroxaban is represented by the following structural formula I:

In the synthesis of Rivaroxaban, 4-(4-Aminophenyl)-3-morpholinone is a key intermediate. Various processes for the preparation of 4-(4-Aminophenyl)-3-morpholinone were reported in U.S. Patent Nos. US 7,157,456, US 7,598,378; and PCT Publication Nos. WO 2011/131316, WO 2013/098833 and WO 2014/175563.
The synthesis of 4-(4-Aminophenyl)-3-morpholinone disclosed in the US‘456 patent is depicted in the below Scheme-1:

The synthesis of 4-(4-Aminophenyl)-3-morpholinone as described in the US‘456 patent involves the following reaction steps: a) morpholin-3-one is reacted with 4-fluoronitro benzene in the presence of sodium hydride in N-methylpyrrolidone solvent, followed by purification using silica gel chromatography and subsequent crystallization from ethyl acetate to produce 4-(4-morpholin-3-onyl)-nitrobenzene as a brownish solid; and b) a solution of 4-(4-morpholin-3-onyl)-nitrobenzene in tetrahydrofuran is hydrogenated using hydrogen gas in the presence of Pd/C (5%) catalyst, followed by purifying the compound using ethyl acetate solvent to produce 4-(4-aminophenyl)-3-morpholinone.
As per the process exemplified in the US Patent No. 7,598,378 (hereinafter referred to as the US’378 patent), the key starting material of Rivaroxaban, 4-(4-aminophenyl)-3-morpholinone, is prepared by catalytic hydrogenation of 4-(4-nitrophenyl)-3-morpholinone using H2 gas and Pd/C catalyst (5%) at 80ºC to produce a reaction mixture, followed by usual workup to produce a white to slightly reddish colored solid. As per the process exemplified in the US’378 patent, 4-(4-nitrophenyl)-3-morpholinone is prepared reacting 4-phenyl-3-morpholinone with concentrated sulphuric acid and nitric acid (65%) to produce a reaction mass, followed by the addition of water and then adjusting the pH of the reaction mixture to 7.4 with 25% aqueous ammonia solution. The resulting suspension is admixed with acetone, followed by workup procedures and isolation of the product to yield 4-(4-nitrophenyl)-3-morpholinone.
However, the processes described in the prior art have the following disadvantages and limitations: i) the process involves the use of highly combustible solvents like tetrahydrofuran; ii) the process involves the use of explosive and difficult to handle reagents like Sodium hydride; and iii) the process involves the use of tedious and cumbersome column chromatographic purifications and multiple re-crystallizations. Methods involving column chromatographic purifications are generally undesirable for large-scale operations, thereby making the process commercially unfeasible.
The object of the present invention is to provide an improved, cost effective and industrially advantageous process for the preparation of 4-(4-aminophenyl)-3-morpholinone with high yield and purity to resolve the problems associated with the process described in the prior art, and that will be suitable for large-scale preparation.

SUMMARY OF THE INVENTION
In one aspect, provided herein is an improved, cost effective and industrially advantageous process for the preparation of 4-(4-aminophenyl)-3-morpholinone comprising reacting 4-phenyl-3-morpholinone with a suitable nitrating agent to produce 4-(4-nitrophenyl)-3-morpholinone, followed by reducing the nitrophenyl compound of formula II using a suitable reducing agent, or by catalytic hydrogenation in the presence of a suitable hydrogenation catalyst, in an ester solvent to produce pure 4-(4-aminophenyl)-3-morpholinone of formula I.
The process for the preparation of 4-(4-aminophenyl)-3-morpholinone disclosed herein has the following advantages over the processes described in the prior art:
i) the process involves the use of cheaper reducing agents like Raney Nickel thereby making the process cost effective;
ii) the process produces the product with high purity;
iii) the process produces the product with high overall yield;
iv) the process avoids the use of highly combustible solvents like tetrahydrofuran;
v) the process avoids the use of explosive and difficult to handle reagents like Sodium hydride; and
vi) the process avoids the use of tedious and cumbersome procedures like column chromatographic purifications and multiple re-crystallizations.

DETAILED DESCRIPTION OF THE INVENTION
According to one aspect, there is provided an improved, cost effective and industrially advantageous process for the preparation of pure 4-(4-aminophenyl)-3-morpholinone of formula I:

which comprises:
a) reacting 4-phenyl-3-morpholinone of formula III:

with nitric acid in the presence of a suitable activating agent to produce 4-(4-nitrophenyl)-3-morpholinone of formula II:

and;
b) reducing the nitrophenyl compound of formula II using a suitable reducing agent, or by catalytic hydrogenation in the presence of a suitable hydrogenation catalyst in an ester solvent, to produce pure 4-(4-aminophenyl)-3-morpholinone of formula I.
Unless otherwise specified, the term “reflux temperature” means the temperature at which the solvent or solvent system refluxes or boils at atmospheric pressure.
Unless otherwise specified, the term “room temperature” refers to a temperature of about 20ºC to about 35ºC. For example, “room temperature” can refer to a temperature of about 25ºC to about 30ºC.
Exemplary activating agents used in step-(a) include, but are not limited to, sulphuric acid, acetic acid, and the like. In one embodiment, the activating agent used in step-(a) is sulphuric acid.
In one embodiment, the reaction in step-(a) is carried out at a temperature of about -10°C to about 20°C, and most specifically at a temperature of about -5°C to about 10°C. The reaction time may vary from about 30 minutes to about 5 hours and most specifically from about 1 hour to about 3 hours.
The reaction in step-(a) is optionally carried out in the presence of a suitable solvent. Exemplary solvents used in step-(a) include, but are not limited to, water, a ketone, a halogenated hydrocarbon, and mixtures thereof.
Specifically, the solvent used in step-(a) is selected from the group consisting of water, acetone, dichloromethane, dichloroethane, chloroform, and mixtures thereof.
The reaction mass containing the 4-(4-nitrophenyl)-3-morpholinone of formula II obtained in step-(a) may be subjected to usual work up such as a washing, an extraction, a pH adjustment, an evaporation, a layer separation, a decolorization, or a combination thereof. The reaction mass may be used directly in the next step to produce the compound of formula I, or the compound of formula II may be isolated and/or recrystallized and then used in the next step.
In one embodiment, 4-(4-nitrophenyl)-3-morpholinone of formula II obtained in step-(a) may be isolated, purified and/or re-crystallized using a suitable solvent by conventional methods such as cooling, seeding, partial removal of the solvent from the solution, by adding an anti-solvent to the solution, evaporation, vacuum distillation, or a combination thereof.
In another embodiment, the suitable solvent used for isolating, purifying and/or recrystallizing the compound of formula II obtained in step-(a) is selected from the group consisting of water, an alcohol, a ketone, a polar aprotic solvent, an ester, a hydrocarbon, a halogenated hydrocarbon, a nitrile solvent, and mixtures thereof. Specifically, the solvent used for isolating, purifying and/or recrystallizing the compound of formula II obtained by the processes described herein is selected from the group consisting of water, methanol, ethanol, 1-propanol, isopropyl alcohol, ethyl acetate, acetone, cyclohexane, toluene, xylene, dichloromethane, dichloroethane, chloroform, acetonitrile, dimethylformamide, acetic acid, dimethylacetamide, and mixtures thereof.
In one embodiment, the hydrogenation in step-(b) is carried out under hydrogen pressure in the presence of a hydrogenation catalyst. In another embodiment, the hydrogenation is carried out under hydrogen pressure of about 1 kg/cm2 to about 10 kg/cm2, specifically under pressure of about 2 kg/cm2 to about 5 kg/cm2.
Exemplary hydrogenation catalysts used step-(b) include, but are not limited to, Raney nickel, Palladium on Carbon, Platinum oxide, Platinum on Carbon, and the like. Specifically, the hydrogenation catalyst used step-(b) is Raney nickel or Palladium on Carbon, and a most specific hydrogenation catalyst is Raney nickel.
In one embodiment, the ester solvent used for catalytic hydrogenation in step-(b) is selected from the group consisting of ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, and mixtures thereof. A most preferable ester solvent used in step-(b) is ethyl acetate.
In another embodiment, the catalytic hydrogenation in step-(b) is carried out at a temperature of about 10°C to about 80°C; specifically at a temperature of about 20°C to about 75°C; and more specifically at a temperature of about 25°C to about 70°C. The reaction time may vary between about 30 minutes to about 10 hours; specifically from about 45 minutes to about 2 hours.
In another embodiment, the reduction in step-(b) is carried out by using a suitable reducing agent in the presence of a suitable solvent. Exemplary reducing agents used in step-(b) include, but are not limited to, palladium on carbon and ammonium formate, palladium on carbon and hydrazine hydrate, palladium on carbon and formic acid, FeCl3 and ammonium chloride, FeCl3 and hydrazine hydrate, iron powder and acetic acid, iron powder and HCl, Zinc dust and acetic acid, tin(II) chloride, Zinc dust and HCl, Zinc dust and ammonium formate, Zinc dust and ammonium chloride, sodium dithionite, Na2S, LiAlH4, NiBH4, and the like. Specifically, the reducing agent used in step-(b) is selected from the group consisting of FeCl3 and ammonium chloride, FeCl3 and hydrazine hydrate, and iron powder and acetic acid.
Exemplary solvents used for reduction with a suitable reducing agent in step-(b) include, but are not limited to, a nitrile solvent, an ester solvent, a polar aprotic solvent, and mixtures thereof. Specifically, the solvent used for reduction with a suitable reducing agent in step-(b) is selected from the group consisting of acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, and mixtures thereof.
In another embodiment, the reduction with a suitable reducing agent in step-(b) is carried out at a temperature of about 10ºC to the reflux temperature of the solvent used, specifically at a temperature of about 25ºC to the reflux temperature of the solvent used. The reaction time may vary from about 1 hour to about 10 hours.
The reaction mass containing the 4-(4-aminophenyl)-3-morpholinone of formula I obtained in step-(b) may be subjected to usual work up methods such as a washing, a quenching, an extraction, a pH adjustment, an evaporation, a layer separation, decolorization, a carbon treatment, or a combination thereof.
In one embodiment, the 4-(4-aminophenyl)-3-morpholinone of formula I obtained in step-(b) may be isolated and/or re-crystallized from a suitable solvent by conventional methods such as cooling, seeding, partial removal of the solvent from the solution, by adding an anti-solvent to the solution, evaporation, vacuum distillation, or a combination thereof.
The solvent used for isolating, purifying and/or recrystallizing the compound, 4-(4-aminophenyl)-3-morpholinone, of formula I obtained in step-(b) by the process described in the present invention is selected from the group consisting of an ester, a ketone solvent, a halogenated hydrocarbon, and mixtures thereof. Specifically, the solvent is selected from the group consisting of ethyl acetate, isopropyl acetate, butyl acetate, acetone, dichloromethane, dichloroethane, and mixtures thereof. A most specific solvent used for isolating, purifying and/or recrystallizing the compound, 4-(4-aminophenyl)-3-morpholinone, of formula I obtained by the process described in the present invention is ethyl acetate.
According to another aspect, there is provided an improved, cost effective and industrially advantageous process for the preparation of pure 4-(4-aminophenyl)-3-morpholinone of formula I:

or a salt thereof, comprising reducing 4-(4-nitrophenyl)-3-morpholinone of formula II:

using a suitable reducing agent, or by catalytic hydrogenation in the presence of a suitable hydrogenation catalyst in an ester solvent, to produce pure 4-(4-aminophenyl)-3-morpholinone of formula I.
The preparation of 4-(4-aminophenyl)-3-morpholinone of formula I or a salt thereof as described in the above process step can be carried out by using the suitable solvents, reagents, methods, parameters and conditions as described hereinabove.
The pure 4-(4-aminophenyl)-3-morpholinone of formula I obtained by the processes disclosed herein has a purity of greater than about 99.5% as measured by HPLC. For example, the purity of the highly pure 4-(4-aminophenyl)-3-morpholinone of formula I obtained by the processes disclosed herein is about 99.5% to about 99.9% as measured by HPLC.
The compounds of formulae I and II obtained by the above process may be further dried in, for example, a Vacuum Tray Dryer, a Rotocon Vacuum Dryer, a Vacuum Paddle Dryer or a pilot plant Rota vapor, to further lower residual solvents. In one embodiment, the drying is carried out at atmospheric pressure or reduced pressures, such as below about 200 mm Hg, or below about 50 mm Hg, at temperatures such as about 35ºC to about 120ºC. The drying can be carried out for any desired time period that achieves the desired result, such as times about 1 to 10 hours.
Unless otherwise specified, the compound, 4-(4-nitrophenyl)-3-morpholinone, of formula II used as starting material in the present invention can be prepared by the processes known in the art, for example, as per the processes described in the U.S. Patent Nos. US 7,157,456, US 7,598,378, or by the process described herein.

INSTRUMENTAL DETAILS:
HPLC Method for measuring Chemical Purity:
The chemical purity was measured by HPLC system with UV detector or its equivalent under the following conditions: Column = Zorbax SB-CN, 250 x 4.6 mm, 5 µm; Detector wavelength = 250 nm; Flow Rate = 0.5 ml/minute; Injection volume = 10 µL; Oven temperature = 45°C; Run time = 40 minutes; Diluent = A mixture of Acetonitrile : Water (50:50 v/v); Elution = Gradient; and Sample Concentration: 0.5 mg/ml.
Mobile Phase-A: A mixture of Tetra n-butyl ammonium Hydrogen sulphate and monobasic sodium phosphate.
Mobile Phase-B: Methanol.

The following examples are given for the purpose of illustrating the present invention and should not be considered as limitation on the scope or spirit of the invention.

EXAMPLES
Example 1
Preparation of 4-(4-Nitrophenyl)-3-morpholinone
Concentrated sulphuric acid (55.5 g) was taken into a reaction flask at 25-30ºC and cooled to 10ºC, followed by slow addition of 4-phenyl-3-morpholinone (13.5 g) and then stirring the reaction mixture for 20 minutes at the same temperature. The temperature of the resulting mass was raised to 25ºC and the resulting clear solution was stirred for 30 minutes at 25ºC. The resulting solution was cooled to -5ºC and then nitric acid (8 g, 68%) was added, followed by stirring for 1 hour at the same temperature. The temperature of the resulting mass was raised to 10ºC, followed by drop-wise addition of water (99 ml) to the resulting mass. The pH of the resulting mass was adjusted to 7.34 with ammonia solution (105 ml), followed by the addition of acetone (152.5 g) and then heating the resulting mixture to 40ºC. The layers were separated and the acetone/water mixture was distilled off from the organic layer. The resulting precipitate was cooled to below 10ºC and then stirred for 40 minutes at the same temperature. The solid obtained was filtered, washed with cold acetone (25 g) and the dried the material at 50ºC under reduced pressure to produce 10 g of 4-(4-nitrophenyl)-3-morpholinone.

Example 2
Preparation of 4-(4-Aminophenyl)-3-morpholinone
A mixture of ethyl acetate (100 ml) and 4-(4-nitrophenyl)-3-morpholinone (2 g) were taken into a hydrogenation flask, followed by the addition of Raney Nickel (1 g) at 25-30ºC. The reaction mixture was hydrogenated under hydrogen pressure of 5 Kg/cm2 and the resulting mass was heated to 65-70ºC and then maintained at the same temperature for about 1-2 hours. After completion of the reaction, the reaction mass was cooled to 25-30ºC and the hydrogen pressure was removed. The resulting mass was filtered to remove Raney Nickel catalyst and then washed with ethyl acetate (20 ml). The solvent was distilled off from the resulting filtrate under reduced pressure to give 1.5 g of 4-(4-aminophenyl)-3-morpholinone [Purity by HPLC: 95.24%].

Example 3
Preparation of 4-(4-Aminophenyl)-3-morpholinone
A mixture of ethyl acetate (100 ml) and 4-(4-nitrophenyl)-3-morpholinone (2 g) were taken into a hydrogenation flask, followed by the addition of 5% Palladium on Carbon (0.2 g) at 25-30ºC. The reaction mixture was hydrogenated under hydrogen pressure of 5 Kg/cm2 and the resulting mass was heated to 65-70ºC and maintained at the same temperature for about 1-2 hours. After completion of the reaction, the reaction mass was cooled to 25-30ºC and the hydrogen pressure was removed. The resulting mass was filtered to remove Palladium on Carbon catalyst and then washed with ethyl acetate (20 ml). The solvent was distilled off from the resulting filtrate under reduced pressure to give 1.5 g of 4-(4-aminophenyl)-3-morpholinone. [Purity by HPLC: 95.86%].