FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
Title of the Invention: A PROCESS FOR PRODUCTION OF 4-{4-AMINOPHENYL) - 3-
MORPHOLINONE
Applicant Name and Address: Megafine Pharma (P) Ltd
An Indian Company having registered address of
4th Floor, Sethna, 55, Maharshi Karve Road, Marine Lines,
Mumbai-400 002,
Maharashtra,
India.
The following specification particularly describes the nature of this invention and the manner in which it is to be performed:

FIELD OF THE INVENTION:
The present invention relates to a method for the preparation of 4-(4-aminophenyl)-morpholin-3-one formula (I).

Particularly, the present invention relates to an improved, commercially viable and production friendly process for the preparation of 4-{4-mJnophenyl) morpholin-3-one of formula (I), which is substantially free from impurities.
4-{4-aminophenyl) morpholin-3-one of formula (I) can be further used for the manufacturing of rivaroxaban by any method known in the art.
BACKGROUND OF THE INVENTION:
4-(4-aminophenyl)-3-morpholinone of formula (I) is a central precursor of 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl} methyl)thiophene-2-carboxamide (herein "Rivaroxaban"). 4-(4-aminophenyl)-3-morpholinone of formula (I) has a CAS number of 438056-69-0, a molecular formula of C10H12N2O2 and the following structure:

WO 01/47919 application describes a method for preparing 4-(4-aminophenyl)-3-morpholinone of formula (I), wherein morpholin-3-one (V) is reacted with 4-fluoronitrobenzene (VI) in the presence of sodium hydride (NaH) to give 4-(4-nitrophenyl)-morpholin-3-one of formula (VII). Catalytic hydrogenation of (VII) with hydrogen over palladium on activated carbon in tetrahydrofuran as a solvent affords 4-(4-aminophenyl)-morpholin-3-one of formula (I) as shown in scheme-1;

However, we have analyzed the process disclosed in the above prior art WO 01/47919 and observed the following limitations:
• The process is lengthy and time consuming with low chemical yield i.e. 17 to 30%. Hence, this route of synthesis is costly and not feasible at industrial scale.
• The starting material morpholin-3-one of formula (V) is expensive and involves the use of hazardous sodium hydride in the preparation of compound of formula (V!l) which further employs high volumes of solvent.
• Conventional reduction process of 4-{4-nitrophenyl)-morpholin-3-one (VII) to 4-(4-aminophenyl)- -morpholin-3-one of formula (I) employed in the above prior art involves requirement of special set of apparatus

like autoclave and risk of using hazardous hydrogen gas, and hence, industrially not feasible.
• The reported process involves column chromatographic purification
thereby making the process undesirable for large scale operations,
and hence, economically unfeasible.
US 7598378 describes a method for preparing 4-(4-aminophenyl)-3-morpholinone of formula (1); wherein 4-(4-nitrophenyl)-3-morpholinone (VII) is reduced with hydrogen in the presence of a hydrogenation catalyst, preferably palladium on activated carbon (5%), in aliphatic alcohols, between 75 and 85° C. and a hydrogen pressure of 5 bar.
However, the process disclosed in the above prior art US 7598378 has the following limitations:
• Conventional reduction process of 4-(4-nitrophenyl)-3-morpholinone
(VII) to 4-(4-aminophenyl)-3-morpholinone of formula (I) employed in
the above prior arts involves requirement of special set of apparatus
like autoclave and risk of using hazardous hydrogen gas, and hence,
industrially not feasible.
Bioorganic & Medicinal Chemistry Letters 14 (2004) 5817-5822 describes a method of preparing 4-(4-aminophenyl)-3-morpholinone of formula (I) wherein 2-(2-chloro ethoxy) acetic acid is converted into its acid chloride using chlorinating agent like phosphorus oxychloride, thionyl chloride etc., which is not environment friendly and further results in low yield as shown in scheme below:


Further the above prior art employs conventional reduction process of 4-(4-nitrophenyl)-3-morpholinone (VII) to 4-{4-aminopheny1)-morpholin-3-one of formula (I) which involves requirement of special set of apparatus like autoclave and risk of using hazardous hydrogen gas, and hence, industrially not feasible.
Hence, there is a need for a solution that overcomes the above stated limitations.
The present invention proposes a process for preparation of 4-(4-aminophenyl)-morpholin-3-one; which is economic, efficient, eco-friendly, and eliminates extensive laborious work-up.
OBJECTS OF THE PRESENT INVENTION
The primary object of the present invention is to provide an improved process for preparation of 4-(4-aminophenyl)-morpholin-3-one of formula (I).

Yet another object of the present invention is to provide a process for preparation of 4-(4-aminophenyl)-morpholin-3-one of formula (I); wherein the said process eliminates laborious workup and avoids use of special apparatus like autoclave for pressured reactions. Hence, makes the process simple, easy and user friendly.
Yet another object of the invention is to provide a simple, efficient, production friendly, commercially viable and economical process for preparation of 4-(4-aminophenyl)--morpholin-3-one of formula (I) with high yield and purity.
Yet another object of the present invention is to provide a process for preparation of 4-(4-aminophenyl)-3-morpholinone of formula (I), wherein the obtained 4-(4-aminophenyl)-3-morpholinone of formula (I) is substantially free from impurities.
DETAILED DESCRIPTION OF THE INVENTION:
Before the present invention is described, it is to be understood that this invention is not limited to particular methodologies and materials described, as these may vary as per the person skilled in the art. It is also to be understood that the terminology used in the description is for the purpose of describing the particular embodiments only, and is not intended to limit the scope of the present invention.
Before the present invention is described, it is to be understood that the terms 4-{4-aminophenyl)morpholin-3-one and 4-(4-aminophenyl)-3-morpholinone have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

Before the present invention is described, it is to be understood that unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Further, it is to be understood that the present invention is not limited to the methodologies and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are described, as these may vary within the specification indicated. Unless stated to the contrary, any use of the words such as "including," "containing," "comprising," "having" and the like, means "including without limitation" and shall not be construed to limit any general statement that it follows to the specific or similar items or matters immediately following it. Embodiments of the invention are not mutually exclusive, but may be implemented in various combinations. The described embodiments of the invention and the disclosed examples are given for the purpose of illustration rather than limitation of the invention as set forth the appended claims. Further the terms disclosed embodiments are merely exemplary methods of the invention, which may be embodied in various forms.
A term herein "reflux temperature" means the temperature at which the solvent or the solvent system refluxes or boils at atmospheric pressure.
The term "substantially free of in reference to a composition, as used herein, means that an absent substance cannot be detected in the composition by methods known to those skilled in the art at the time of the filing of this application.

In one of the embodiments, the present invention provides an improved and
efficient process for the preparation of 4-(4-aminophenyl)-3-morpholinone of
formula (I) comprising:
a. condensing 2-(2-chloroethoxy) acetic acid of formula (II) with 4-nitro aniline of formula (III) in a solvent and in the presence of an inorganic acid to produce 2-(2-ch!oroethoxy)-A/-(4-nitrophenyl) acetamide of formula (IV);

b. cyclizing 2-(2-chloroethoxy)-N-(4-nitrophenyl) acetamide of formula (IV) of step (a) using a base and a catalyst in solvent to obtain 4-(4-nitrophenyl)-3-morpholinone of formula (VII);

d. optionally, purifying 4-(4~aminophenyl)- -morpholin-3-one of formula (I).
c. reducing 4-(4-nitrophenyl)-3-morpholinone of formula (VII) of step (b) using ammonium formate in a solvent, and a catalyst, to obtain 4-(4-aminophenyl)-3-morphoiinone of formula (!); and


According to another embodiment of the present invention, the said process can be carried out in single pot without isolation of intermediates.
According to another embodiment of the present invention, compounds of formula (IV) and formula (VII) can be optionally purified by either acid-base treatment, or solvent crystallization, or converting into its acid addition salts.
In a preferred embodiment, the solvent used for crystallization of compound of formula (IV) and formula (VII) includes but does not limit to esters, chlorinated hydrocarbons, aliphatic hydrocarbons, aromatic hydrocarbons, halogenated aliphatic hydrocarbons, cyclic amides, dialkylformamides, ethers, esters, cyclic ethers, substituted cyclic ethers, alcohol, ketones, dialkylsulfoxides, dialkylacetamides, nitrites, ionic liquids, and water or mixtures thereof. The crystallization solvent for compound of formula (IV) and formula (VII) may be same or different.
The solvent used in condensation step (a) is an organic solvent selected from the group comprising halogenated hydrocarbons, aliphatic hydrocarbons, aromatic hydrocarbons, halogenated aliphatic hydrocarbons dialkylformamides, esters, ethers, cyclic ethers, substituted cyclic ethers, alcohol, ketones, dialkylsulfoxides, dialkylacetamides, cyclic amides, nitriles, ionic liquids, and water or mixtures thereof.
The inorganic acid used in condensation step (a) is selected from the group comprising boronic acids such as boric acid, phenyl boronic acid, trimethyl borate and the like; sulfuric acid, phosphoric acid, and phosphorus pentoxide.

The step (a) is carried out at temperature in the range of 70°C to 115°C. Usually the reaction may be carried out at temperature up to reflux temperature of the said solvent.
Water liberated during the condensation step (a) can be removed azeotropically at reflux temperature of the said solvent.
The solvent used in step (b) for the preparation of compound of formula (VII) is an organic solvent selected from the group comprising of halogenated hydrocarbons, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons aromatic hydrocarbons, dialkylformamides, ethers, esters, cyclic ethers, substituted cyclic ethers, ketones, dialkylsulfoxides, dialkylacetamides, cyclic amides, nitriles, ionic liquids, or mixtures thereof.
The catalyst used in step (b) for preparation of compound of formula (VII) is a phase transfer catalyst selected from tetra butyl ammonium bromide (TBAB), cetyl trimethyl ammonium bromide (CTAB), tetrabutyl ammonium hydroxide and the like.
The base used in step (b) is selected from group comprising of either organic or inorganic base. The inorganic base is selected from group comprising of alkali metal carbonates such as but not limited to potassium carbonate, sodium carbonate, cesium carbonate and the like; alkali metal hydroxides such as but not limited to sodium hydroxide, potassium hydroxide, lithium hydroxides, barium hydroxide, alkali metal bicarbonates such as but not limited to potassium bicarbonate, sodium bicarbonate, and the like. The

organic base is selected from diisopropyl ethyl amine, N, N-Dimethyl aniline, triethylamine and the like.
The solvent used in reduction step (c) is an organic solvent selected from the group comprising alcohol, halogenated hydrocarbons, aliphatic hydrocarbons, aromatic hydrocarbons, halogenated aliphatic hydrocarbons, dialkylformamides, ethers, cyclic esters, esters, substituted cyclic ethers, cyclic amides, dialkylsulfoxides, dialkylacetamides, nitriles, ionic liquids, and water or mixtures thereof.
The catalyst used in reduction step (c) is selected from the group comprising raney nickel, platinum oxide, rhodium on carbon, palladium on carbon and the like.
In a preferred embodiment of the present invention, reduction step (c) is carried out at a temperature ranging from about 40°C to 80°C; preferably at the temperature ranging from 50°C to 60°C.
Hydrogenation is carried out in presence of Ammonium formate at atmospheric pressure.
4-{4-aminophenyl)-3-morpholinone of formula (I) obtained in step (c) can be optionally purified by either acid-base treatment, or solvent crystallization, or converting into its acid addition salts.
According to the present invention, isolation of crude 4-{4-aminophenyl)-3-morpholinone of formula (I) from reaction mass of step (c) comprises the steps of:

i. filtering the catalyst; ii. chilling the filtrate;
iii. filtering the compound of 4-(4-aminophenyl)-3-morpholinone of formula (I); iv. optionally purifying the 4-{4-aminophenyl)-3-morpholinone of formula (I) obtained in step (iv) by
a. crystallization using solvent to obtain purified 4-(4-
aminophenyl)-3-morpholinone of formula (I); or
b. acid-base treatment to obtain purified 4-(4-aminophenyl)-3-
morpholinone of formula (I); or
c. crystallization in combination with acid-base treatment to obtain
purified 4-(4-aminophenyl)-3-morpholinone of formula (I).
Further, in a preferred embodiment of the present invention, the solvent used for crystallization of the 4-(4-aminophenyl)-3-morpholinone of formula (I) in step (iv) comprises of esters, aliphatic hydrocarbons, aromatic hydrocarbons, dialkylformamides, ethers, cyclic ethers, substituted cyclic ethers, alcohol ketones, dialkylsulfoxides, dialkylacetamides, nitriles, ionic liquids, halogenated aliphatic hydrocarbons and water or mixtures thereof. Preferably water is used as crystallization solvent.
In another embodiment, the obtained purified solid is filtered and may be subjected to drying to get pure 4-(4-aminophenyl)-3-morpholinone of formula (I). Drying may be carried out using conventional methods such as Air tray drier (ATD), Vacuum Tray Drier (VTD), Fluidized bed drier (FBD), Spin Flash Drier (SFD), Flash Drier (FD), and the like.

The pure 4-(4-aminophenyl)-3-morpholinone is dried at temperature ranging from 50 to 100°c, preferably at temperature ranging from 90 to 100°c.
According to the invention, obtained 4-(4-aminophenyl)-3-morpholinone of formula (I) can be further used for the manufacturing of rivaroxaban by any method known in the art.
Further, the overall yield of 4-(4-aminophenyl)-3-morpholinone of formula (I) obtained using the process of the present invention is at least about 40-55 % with purity of at least about 99.5% by HPLC.
More particularly, the total purity of 4-(4-aminophenyl)-morpholin-3-one of formula (I) obtained is at least about 99.80% (by HPLC).
4-(4-aminophenyl)-3-morpholinone of formula (!) prepared as per the present invention, is substantially free from impurities generated either by carryover impurities from starting materials, side products, reagents and solvents etc.
The present invention provides 4-(4-aminophenyl)-3-morpholinone of formula (I) prepared according to the process of the present invention having less than about 0.2% of compound of formula formula (II),(IV), (VI),(VII) and impurity p-phenylene diamine of formula (VIII).


BEST MODE OR EXAMPLES FOR WORKING OF THE INVENTION
The present invention is described in the examples given below; further these are provided only to illustrate the invention and therefore should not be construed to limit the scope of the invention.
EXAMPLE 1
Preparation of 2-(2-chloroethoxy)-N-{4-nitrophenyl)acetamide
Boric acid (13g, 0.21 mole) and 4-nitro aniline (50 g, 0.36 mole) were added in toluene (500 ml) under stirring and the mixture was heated to 110-115 °C, and water was removed completely azeotropically. The reaction mass was cooled to 50-60°C and 2-(2-chloroethoxy)acetic acid (50g,0.36 mole) was added under stirring. The reaction mixture was heated to 110-115°C and maintained for 18 hrs with removal of water azeotropically. The reaction mixture was cooled to 50-60°C, filtered and washed with toluene. The toluene layer was distilled under reduced pressure at a temperature below 50 °C to obtain crude product. Isopropy! alcohol (300 ml) was added to the obtained crude product; the mixture was heated to 80 °C for an hour, slowly cooled to 30-35 °C, chilled to 0-10 °C, and filtered to obtain solid. Obtained solid was purified using isopropyl alcohol(300 ml), filtered to obtain solid, followed by washing with isopropyl alcohol (5 ml), and dried, to afford 2-(2-chloroethoxy)-N-(4-nitrophenyl) acetamide as yellow solid. [Yield = 47 gm (50%); Purity (HPLC) = 98.5%; M.P: 101 - 104°C] 1H NMR (400 MHz, DMSO) δ 10.38.(s, 1 H), 8.22 {d, 2H), 7.91(d, 2H), 4.22(S, 2H), 3.82(s, 4H)
EXAMPLE 2:
Preparation of 4-(4-nitrophenyl)-3-morpholinone
To a solution of 2-(2-chloroethoxy)-N-(4-nitrophenyl)acetamide (50 g, 0.19mol) in dichloromethane {500 ml),TBAB (3.5 g) and NaOH (12 g,0.3 mol)

was added under stirring. The reaction mass obtained was stirred at 25-35 °C for 2-2.5 hrs. Upon completion of reaction, water (150mL) was added to the mixture and stirred for 20 minutes. The organic layer was separated and aqueous layer was extracted with 40 ml dichloromethane. The combined organic layer was washed with water and distilled out at a temperature below 50 °C under reduced pressure to provide the crude product. The resulting crude was crystallized with isopropyl alcohol (85 ml). The obtained crystalline solid was washed filtered, obtained solid was washed with isopropyl alcohol(5 ml),and dried to afford 4-(4-nitrophenyl)-3-morpholinone as yellow solid. [Yield = 37.8 gm (90%); Purity (HPLC) = 99.5%; M.P: 148 - 152°C] 1H NMR (400 MHz, DMSO) δ 8.27(d, 2H), 7.77 (d, 2H), 4.27(s, 2H), 4.00(t, 2H), 3.86(t, 2H)
EXAMPLE 3:
Preparation of 4-(4-aminophenyl)-3-morpholinone
To a solution of 4-(4-nitrophenyl)-3-morpholinone {100 g, 0.45mol) in
methanol (1000 mL), Pd/C (10%, 2.0 g, 50% wet) and ammonium formate
(170g) was added. The reaction mixture was stirred at 58-60T for 90
minutes, Upon completion of reaction, the catalyst was filtered off, and the
filtrate was chilled to 5-10 °C to afford 4-(4-aminophenyl)-3-morpholinone (or
compound of formula (I)) as crude solid. The obtained crude solid (100gm)
was dissolved in water (400 ml) at 90°c to 95°c. The contents was cooled,
and slowly chilled to 5-10°c temperature to obtain crystalline solid. The
obtained crystalline solid was filtered, washed with water (20ml) and dried to
get pure 4-(4-aminophenyl)-3-morpholinone of formula (I) as white solid.
[Yield = 65 gm (75 %); Purity (HPLC) = 99.9%; M.P: 169 - 172°C]
1H NMR (400 MHz, DMSO) δ 6.94(d, 2H),6.54 (d, 2H), 5.15(s, 2H), 4.27(S,
2H), 3.90 (t, 2H),3.56(t,2H)

We claim:
1. An improved process for the preparation of 4-(4-aminophenyl)-3-
morpholinone of formula (I) comprising:
a. condensing 2-(2-Chloroethoxy) acetic acid of formula (II) with 4-nitro aniline of formula (III) in a solvent and in the presence of an inorganic acid to produce 2-{2-chloroethoxy)-/V-(4-nitrophenyl) acetamide of formula (IV);

b. cyclizing 2-(2-chloroethoxy)-A/-{4-nitrophenyl) acetamide of formula (IV) of step (a) using a base and a catalyst in a solvent to obtain 4-(4-nitrophenyl)-3-morpholinone of formula (VII);


d. optionally, purifying 4-(4-aminophenyl)-3-morpholinone of formula (I).
c. reducing 4-(4-nitrophenyl)-3-morpholinone of formula (VII) of step (b) using ammonium formate in a solvent, and a catalyst, to obtain 4-(4-aminophenyl)-3-morpholinone of formula (I); and

2. The process as claimed in claim 1, wherein the solvent used in step (a), step (b) is selected from halogenated hydrocarbons, aliphatic hydrocarbons, aromatic hydrocarbons, halogenated aliphatic hydrocarbons dialkylformamides, esters, ethers, cyclic ethers, substituted cyclic ethers, alcohol, ketones, dialkylsulfoxides, dialkylacetamides, cyclic amides, nitriles, ionic liquids, and water or mixtures thereof.
3. The process as claimed in claim 1, wherein the inorganic acid used in condensation step (a) is selected from the group comprising boronic acids such as boric acid, phenyl boronic acid, trimethyl borate and the like; sulfuric acid, phosphoric acid, phosphorus pentoxide, and zinc chloride.
4. The process as claimed in claim 1, wherein the catalyst used in step (b) is a phase transfer catalyst selected from tetra butyl ammonium bromide (TBAB), Cetyl trimethyl ammonium bromide (CTAB), tetrabutyl ammonium hydroxide and the like
5. The process as claimed in claim 1, wherein the base used in step (b) is an organic or inorganic base, wherein inorganic base is selected from but not limited to alkali metal carbonates like potassium carbonate, sodium carbonate, cesium carbonate; alkali metal hydroxides like sodium hydroxide, potassium hydroxide, lithium hydroxides, barium hydroxide, alkali metal bicarbonates like potassium bicarbonate, sodium bicarbonate and the organic base is selected from diisopropyl ethyl amine, N, N-Dimethyl aniline, triethylamine and the like.
6. The process as claimed in claim 1, wherein the solvent used in step (c), is selected from the group comprising alcohol, halogenated hydrocarbons, aliphatic hydrocarbons, aromatic hydrocarbons, halogenated aliphatic

hydrocarbons, dialkylformamides, ethers, cyclic esters, esters, substituted cyclic ethers, cyclic amides, dialkylsulfoxides, dialkylacetamides, nitriles, ionic liquids, and water or mixtures thereof.
7. The process as claimed in claim 1, wherein the solvent used in step (c), is selected from the group comprising raney nickel, platinum oxide, rhodium on carbon, palladium on carbon.
8. The process as claimed in claim 1, wherein isolation of crude 4-(4-aminophenyl)-3-morphoIinone of formula (I) from reaction mass of step (c) comprises the steps of:
i. filtering the catalyst;
ii. chilling the filtrate;
iii. filtering the compound of 4-(4-aminophenyl)-3-morpholinone of
formula (I); iv. optionally purifying the 4-(4-aminophenyl)-3-morpholinone of
formula (I) obtained in step (iv) by
a. crystallization using solvent to obtain purified 4-(4-
aminophenyl)-3-morpholinone of formula (I); or
b. acid-base treatment to obtain purified 4-(4-aminophenyl)-3-
morpholinone of formula (I); or
c. crystallization in combination with acid-base treatment to obtain
purified 4-(4-aminophenyl)-3-morpholinone of formula (I).
9. The process of claim 8, wherein the solvent used for crystallization of the
4-(4-aminophenyl)-3-morpholinone of formula (I) in step (iv) is selected
from esters, aliphatic hydrocarbons, aromatic hydrocarbons,
dialkylformamides, ethers, cyclic ethers, substituted cyclic ethers, alcohol,

ketones, dialkylsulfoxides, dialkylacetamides, nitriles, ionic liquids, halogenated aliphatic hydrocarbons and water or mixtures thereof
10.4-(4-aminophenyl)-3-morpholinone of formula (I) prepared according to claim 1 having less than about 0.2% of compound of formula formula (II),(IV), (VI),(VII) and impurity p-phenylene diamine of formula (VIII)