Claims:We Claim:
1. A process for the preparation of 4-phenyl-3-morpholinone of formula I:

which comprises:
(a) reacting Aniline of formula IV:

with 2-chloroethanol of formula III:

to produce highly pure 2-(phenylamino)ethanol of formula II:

wherein the reaction is carried out as a neat reaction; and
(b) reacting the compound of formula II with chloroacetyl chloride in a suitable solvent and in the presence of a suitable base to produce 4-phenyl-3-morpholinone compound of formula I, wherein the base is used in a molar ratio of more than 7.5 equivalents, specifically about 8 equivalents to about 9 equivalents, with respect to the quantity of 2-(phenylamino)ethanol.

2. The process as claimed in claim 1, wherein the reaction in step-(a) is carried out at a temperature of about 70°C to about 95°C; wherein the reaction in step-(b) is carried out at a temperature of about 25°C to about 50°C; and wherein the amount of chloroacetyl chloride employed in step-(b) is about 2 equivalents to about 4 equivalents with respect to the quantity of 2-(phenylamino)ethanol.

3. The process as claimed in claim 2, wherein the reaction in step-(a) is carried out at a temperature of about 80°C to about 85°C; wherein the reaction in step-(b) is carried out at a temperature of about 35°C to about 45°C; and wherein the amount of chloroacetyl chloride employed in step-(b) is about 2.5 equivalents to about 3.5 equivalents with respect to the quantity of 2-(phenylamino)ethanol.

4. The process as claimed in claim 1, wherein the solvent used in step-(b) is selected from the group consisting of an alcohol solvent, a ketone solvent and mixtures thereof; and wherein the base used in step-(b) is selected from the group consisting of sodium hydroxide, potassium hydroxide, ammonium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert.butoxide, potassium tert.butoxide, sodium amide, potassium amide, ammonia, and mixtures thereof.

5. The process as claimed in claim 4, wherein the solvent used in step-(b) is selected from the group consisting of methanol, ethanol, isopropyl alcohol, n-butanol, tert-butanol, acetone, and mixtures thereof; and wherein the base used in step-(b) is aqueous sodium hydroxide solution.

6. The process as claimed in claim 5, wherein the solvent used in step-(b) is ethanol, acetone or a mixture thereof; and wherein the base used in step-(b) is 40% aqueous sodium hydroxide solution.

7. A process for the preparation of 2-(phenylamino)ethanol compound of formula II:

comprising reacting Aniline of formula IV:

with 2-chloroethanol compound of formula III:

to produce highly pure 2-(phenylamino)ethanol of formula II, wherein the reaction is carried out as a neat reaction.

8. The process as claimed in claim 7, wherein the reaction is carried out at a temperature of about 70°C to about 95°C.

9. A process for the preparation of 4-phenyl-3-morpholinone compound of formula I:

comprising reacting 2-(phenylamino)ethanol compound of formula II:

with chloroacetyl chloride in a suitable solvent and in the presence of a suitable base to produce 4-phenyl-3-morpholinone compound of formula I, wherein the base is used in a molar ratio of more than 7.5 equivalents, specifically about 8 equivalents to about 9 equivalents, with respect to the quantity of 2-(phenylamino)ethanol.

10. The process as claimed in claim 9, wherein the reaction is carried out at a temperature of about 25°C to about 50°C; wherein the amount of chloroacetyl chloride employed is about 2 equivalents to about 4 equivalents with respect to the quantity of 2-(phenylamino)ethanol; wherein the solvent used is selected from the group consisting of methanol, ethanol, isopropyl alcohol, n-butanol, tert-butanol, acetone, and mixtures thereof; and wherein the base used in step-(b) is aqueous sodium hydroxide solution.
, Description:FORM 2

THE PATENTS ACT 1970
(Act 39 of 1970)
&
THE PATENTS RULES 2003
(SECTION 10 AND RULE 13)

COMPLETE SPECIFICATION

“PROCESS FOR THE PREPARATION OF 4-PHENYL-3-MORPHOLINONE”

SYMED LABS LIMITED
An Indian Company having its Office at
8-2-293/174/3, B. N. Reddy Colony, Road No. 14,
Banjara Hills, Hyderabad-500 034,
Telangana, India

THE FOLLOWING SPECIFICATION PARTICULARLY DESCRIBES AND ASSERTAINS THE NATURE OF THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED

FIELD OF THE INVENTION

The present invention relates to an improved, cost effective and industrially advantageous process for the production of 4-Phenyl-3-morpholinone with high yield and high purity.

BACKGROUND OF THE INVENTION

US Patent No. US 7,585,860 (hereinafter referred to as US’860 patent) 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:

Rivaroxaban is sold by Bayer under the brand name Xarelto® and it is orally administered as tablets containing 10 mg of Rivaroxaban.
Various processes for the preparation of Rivaroxaban and its intermediates are described in US patent Nos. US7585860, US7157456, US7598378, US9376427, US9469628; and PCT Publication No. WO 2012/032533.
In the synthesis of Rivaroxaban and its intermediates, the following compound, 4-(4-aminophenyl)-3-morpholinone, of formula V is used as a key starting material:

In the synthesis of 4-(4-aminophenyl)-3-morpholinone of formula V, the following compound, 4-phenyl-3-morpholinone, of formula I is a key intermediate:

Various processes for the preparation of 4-phenyl-3-morpholinone are described in US Patent No. US3092630; Indian Patent No. IN276286; PCT publication Nos. WO2011/012321 and WO2011/080341; and Journal of Heterocyclic Chemistry 37, 109-110, 2000; and Bull. Soc. Chim. France, 1210-1212, 1956.
In the synthesis of 4-phenyl-3-morpholinone of formula I, the following compound, 2-(phenylamino)ethanol, of formula II is used as a key intermediate:

Various processes for the preparation of 2-(Phenylamino)ethanol are described in Indian Patent No. IN260818; and in the following scientific journals: Journal of American Chemical Society 42, 8, 1720-1725, 1920; Journal of American Chemical Society 45, 3, 785-790, 1923; and Journal of American Chemical Society 60, 1582-1585, 1938.
US Patent No. US3092630 (hereinafter referred to as the US’630 patent), discloses the synthesis of 4-phenyl-3-morpholinone by reacting 1,4-dioxan-2-one and aniline in an autoclave at 340°C, followed by distillation and recrystallization.
Indian Patent No. IN276286 (hereinafter referred to as IN’286 patent) discloses the synthesis of 4-Phenyl-3-morpholinone as depicted below in Scheme-1:

As per the process disclosed in the IN’286 patent, 4-Phenyl-3-morpholinone is prepared by dissolving 2-(Phenylamino)ethanol in ethanol at room temperature and is subsequently admixed with water. The resulting solution is heated to 38°C followed by the addition of chloroacetyl chloride (3 equivalents) and 45% sodium hydroxide solution (5 to 7 equivalents) at a temperature of 38 to 43°C within 60 to 80 minutes, so that the pH is kept between 12 and 12.5. The resulting 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 demineralized water at 2°C. The moist product is dried to constant mass at 50°C under reduced pressure to produce 4-Phenyl-3-morpholinone (Yield: 80%).
PCT Publication No. WO2011/012321 (hereinafter referred to as WO’321 publication) discloses the synthesis of 4-phenyl-3-morpholinone as depicted below in Scheme-2:

As per the process disclosed in WO’231 publication, 4-Phenyl-3-morpholinone is prepared by heating a mixture of water, ethanol and 2-(phenylamino)ethanol to a temperature of 38°C while stirring. Chloroacetyl chloride (3 equivalents) and 45% sodium hydroxide solution (6.2 equivalents) were added simultaneously at a temperature of 38- 45°C within 60 to 80 minutes, so that the pH is 10-13 and stirred at this temperature for 30 minutes. The resulting mass was subjected to usual workup procedure to produce 4-Phenyl-3-morpholinone (Yield: 68%).
PCT Publication No. WO2011/080341 (hereinafter referred to as WO’341 publication) discloses the synthesis of 4-phenyl-3-morpholinone as depicted below in Scheme-3:

As per the process disclosed in WO’341 publication, 4-Phenyl-3-morpholinone is prepared by heating a solution of 2-anilino-ethanol in isopropyl alcohol at 40°C. To the resulting mixture, chloroacetyl chloride and 10 N NaOH were added drop-wise by maintaining the pH around 7-8. After the addition, the resulting mass was stirred for 10 minutes at 40°C followed by usual workup procedure to produce 4-Phenyl-3-morpholinone (Yield: 62%).
Journal of Heterocyclic Chemistry 37, 109-110, 2000 (hereinafter referred to as JHC article) discloses the synthesis of 4-Phenyl-3-morpholinone by phase transfer-catalyzed oxidation of 4-phenylmorpholine with potassium permanganate, However, a further reaction product formed herein is readily ignitable manganese dioxide. Furthermore, the yield is only 45% of theory and the reaction is very difficult to carry out on a larger scale.
Bull. Soc. Chim. France, 1210-1212, 1956 discloses the synthesis of 4-Phenyl-3-morpholinone. However, the deprotonation is effected with Sodium in toluene and in benzene. However, the use of Sodium metal not advisable on industrial scale operations since it is highly pyrophoric and explosive metal.
Indian Patent No. IN260818 (hereinafter referred to as the IN’818 patent) discloses the synthesis of 2-(Phenylamino)ethanol as depicted below in Scheme-4:

As per the process disclosed in the IN’818 patent, 2-(phenylamino)ethanol is prepared by the reaction of aniline with ethylene carbonate using triglyme as solvent and Na-Y zeolite as catalyst. The contents were heated under stirring up to 160°C and maintained for 30 minutes under Nitrogen inert atmosphere. After cooling to room temperature, the reaction mass was filtered to separate the catalyst and the filtrate was analysed on Gas Chromatogram (GC). Analysis of reaction crude by GC showed conversion of aniline to be 100% and yield of N-phenyl ethanolamine to be 100% and no formation of N-phenyl diethanolamine (NPDEA). N-phenyl ethanolamine was also isolated in pure form by column chromatography (silica gel, hexane-ethyl acetate 95:5) and characterized by elemental analysis, 1H NMR, 13C NMR, IR.
Journal of American Chemical Society 42, 8, 1720-1725, 1920 (hereinafter referred to as JACS’1920 article) discloses the synthesis of 2-(Phenylamino)ethanol as depicted below in Scheme-5:

As per the process disclosed in JACS’1920 article, 2-(Phenylamino)ethanol is prepared by reacting aniline with 2-chloroethanol in presence of sodium carbonate resulting in the formation of a mixture of the 2-(phenylamino)ethanol and 2,2’-(phenylimino)diethanol.
However, the processes for the preparation of 4-Phenyl-3-morpholinone and 2-(Phenylamino)ethanol as described in the prior art have the following disadvantages and limitations:
i) the prior art processes involve the use of highly reactive, pyrophoric and difficult to handle reagents such as sodium metal;
ii) the prior art processes involve the use of carcinogenic chemical compound such as benzene;
iii) the prior art processes produce the readily ignitable chemical compound such as manganese dioxide as the byproduct;
iv) the yields of 4-Phenyl-3-morpholinone reported in the prior art are very low;
vi) the prior art processes produce the unwanted by-product such as 2,2’-(phenylimino)diethanol;
vii) the prior art processes involve the use of high boiling solvents such as triglyme;
viii) the prior art processes involve the use of tedious and cumbersome column chromatographic purifications. 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-Phenyl-3-morpholinone and 2-(phenylamino)ethanol with high yield and with high purity to resolve the problems associated with the processes described in the prior art, and that will be suitable for large-scale preparation.

SUMMARY OF THE INVENTION
Provided herein is an improved, commercially viable and industrially advantageous processes for the preparation of 4-phenyl-3-morpholinone.
The present inventors have surprisingly and unexpectedly found that the 4-phenyl-3-morpholinone of formula I can be prepared with higher yield (94%) by carrying out the reaction of 2-(phenylamino)ethanol with chloroacetyl chloride in a suitable solvent in the presence of slightly excess amounts of a base, for example, more than 7.5 equivalents, specifically about 8 equivalents to about 9 equivalents, of base (preferably sodium hydroxide) with respect to the quantity of 2-(phenylamino)ethanol used.
The present inventors have further found that 2-(phenylamino)ethanol can be prepared with higher purity (Purity by HPLC: 99%) by reacting aniline with 2-chloroethanol as a neat reaction (without using any additional solvent).
In one aspect, provided herein is an improved, cost effective and industrially advantageous process for the preparation of 4-phenyl-3-morpholinone with high yield.
In another aspect, provided herein is an improved, cost effective and industrially advantageous process for the preparation of 2-(phenylamino)ethanol with high purity.
The process for the preparation of 4-phenyl-3-morpholinone as disclosed in the present invention may be represented by a schematic diagram as depicted below in scheme-6:

The present invention avoids the problems associated with the processes described in the prior art, and which is more convenient to operate at laboratory scale and on a commercial scale.
The process for the preparation of 4-phenyl-3-morpholinone as disclosed herein has the following advantages over the processes described in the prior art:
i) the process produces the 4-phenyl-3-morpholinone with higher yield (Yield: 94%);
ii) the process produces the 2-(phenylamino)ethanol with high purity (Purity: 99%);
iii) the process avoids the use of high boiling solvents like triglyme in the preparation of 2-(phenylamino)ethanol;
iv) the process avoids the use of tedious and cumbersome procedures like column chromatographic purifications and multiple re-crystallizations;
v) the process does not involve the use of highly reactive, pyrophoric and difficult to handle reagents such as sodium metal;
vi) the process does not produce the readily ignitable chemical compound such as manganese dioxide as a byproduct; and
vii) the process for preparation of 2-(phenylamino)ethanol is carried out as a neat reaction as it does not involve the use of any other solvents.

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

which comprises:
(a) reacting aniline of formula IV:

with 2-chloroethanol of formula III:

to produce highly pure 2-(phenylamino)ethanol of formula II:

wherein the reaction is carried out as a neat reaction; and
b) reacting the compound of formula II with chloroacetyl chloride in a suitable solvent and in the presence of a suitable base to produce 4-phenyl-3-morpholinone compound of formula I, wherein the base is used in a molar ratio of more than 7.5 equivalents, specifically about 8 equivalents to about 9 equivalents, with respect to the quantity of 2-(phenylamino)ethanol.
Unless otherwise specified, the solvent used for isolating, purifying and/or recrystallizing the compounds of formula I and II obtained by the processes described in the present invention is selected from the group consisting of water, an alcohol, a ketone, an ether, an ester, a hydrocarbon, a halogenated hydrocarbon, and mixtures thereof. Specifically, the solvent is selected from the group consisting of water, methanol, ethanol, 1-propanol, isopropyl alcohol, acetone, tetrahydrofuran, diisopropyl ether, methyl tert-butyl ether, ethyl acetate, butyl acetate, cyclohexane, toluene, xylene, dichloromethane, dichloroethane, chloroform, and mixtures thereof.
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.
In one embodiment, the reaction in step-(a) is carried out at a temperature of about 70°C to about 95°C, and most specifically at a temperature of about 80°C to about 85°C. The reaction time may vary from about 20 minutes to about 10 hours and most specifically from about 30 minutes to about 8 hours.
The reaction mass containing the 2-(phenylamino)ethanol of formula II obtained in step-(a) may be subjected to usual work up such as a washing, a quenching, 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, 2-(phenylamino)ethanol compound of formula II obtained in step-(a) may be isolated and/or purified 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.
The solvent used for work up, isolation and/or recrystallization of the compound of formula II obtained by the process described herein is selected from the group as described hereinabove.
The pure 2-(phenylamino)ethanol of formula II obtained by the processes disclosed herein has a purity of greater than about 95%, specifically greater than about 97%, more specifically greater than about 98%, and most specifically greater than about 99% as measured by HPLC.
In one embodiment, the amount of chloroacetyl chloride employed in step-(b) is about 2 equivalents to about 4 equivalents, specifically about 2.5 equivalents to about 3.5 equivalents with respect to the quantity of 2-(phenylamino)ethanol used.
In another embodiment, the solvent used in step-(b) is selected from the group consisting of an alcohol solvent, a ketone solvent and mixtures thereof. Specifically, the solvent used in step-(b) is selected from the group consisting of methanol, ethanol, isopropyl alcohol, n-butanol, tert-butanol, acetone, and mixtures thereof. A most specific solvent used in step-(b) is ethanol, acetone or a mixture thereof.
In one embodiment, the base used in step-(b) includes organic base and inorganic base.
Specifically, the base used in step-(b) is an inorganic base. More specifically, the inorganic base is selected from the group consisting of sodium hydroxide, potassium hydroxide, ammonium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert.butoxide, potassium tert.butoxide, sodium amide, potassium amide, ammonia, and mixtures thereof. A most specific inorganic base used in step-(b) is 40% aqueous sodium hydroxide.
In one embodiment, the reaction in step-(b) is carried out at a temperature of about 25°C to about 50°C, specifically at a temperature of about 35°C to about 45°C. The
Reaction time may vary from about 5 minutes to about 2 hours, specifically from about 10 minutes to about 45 minutes.
The reaction mass containing the 4-phenyl-3-morpholinone compound of formula I obtained in step-(b) may be subjected to usual work up such as a washing, a quenching, an extraction, a pH adjustment, an evaporation, a layer separation, a decolorization, or a combination thereof.
In one embodiment, 4-phenyl-3-morpholinone compound of formula I obtained 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.
The solvent used for work up, isolation and/or recrystallization of the compound of formula I obtained by the process described herein is selected from the group as described hereinabove.
According to another aspect, there is provided a process for the preparation of 2-(phenylamino)ethanol compound of formula II:

comprising reacting Aniline of formula IV:

with 2-chloroethanol compound of formula III:

to produce highly pure 2-(Phenylamino)ethanol compound of formula II, wherein the reaction is carried out as a neat reaction.
The preparation of 2-(phenylamino)ethanol compound of formula II can be carried out by using the methods, parameters and conditions as described hereinabove, for example, as per the process exemplified in the Example 1 described hereinafter.
According to another aspect there is provided a process for the preparation of 4-phenyl-3-morpholinone compound of formula I:

Comprising reacting 2-(phenylamino)ethanol compound of formula II:

with chloroacetyl chloride in a suitable solvent and in the presence of a suitable base to produce 4-phenyl-3-morpholinone compound of formula I, wherein the base is used in a molar ratio of more than 7.5 equivalents, specifically about 8 equivalents to about 9 equivalents, with respect to the quantity of 2-(phenylamino)ethanol used.
The preparation of 4-phenyl-3-morpholinone compound of formula I can be carried out by using the suitable solvents, reagents, methods, parameters and conditions as described hereinabove, for example, as per the process exemplified in the Example 2 described hereinafter.
The compound, 4-Phenyl-3-morpholinone compound of formula I obtained by the process disclosed herein can be further converted to Rivaroxaban or a polymorphic form thereof by known methods as described in the art, for example, as per the processes described in the following patents and/or patent applications: US patent Nos. US9376427, US9469628; and PCT Publication No. WO 2012/032533 filed by the present applicant.

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 = 240 nm; Flow Rate = 1.0 ml/minute; Injection volume = 10 µL; Oven temperature = 45°C; Sample cooler temperature = 5°C; Run time = 40 minutes; Diluent = A mixture of Acetonitrile : Water (50:50 v/v); Elution = Gradient; and Sample Concentration: 0.3 mg/ml.
Mobile Phase-A: A mixture of Buffer and Methanol (90:10 v/v).
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 2-(Phenylamino)ethanol
Aniline (50 g) and 2-Chloroethanol (43.5 g) were taken into taken into a reaction flask at room temperature. The resulting mass was heated to 80-85ºC and maintained for 8 hours at the same temperature. After completion of reaction, the resulting mass was cooled to room temperature, followed by the addition of ethyl acetate (100 ml) and maintained for 30 minutes at the same temperature. The salts were filtered and washed with ethyl acetate (50 ml). Water (125 ml) was added to the mother liquor and basified with 20% sodium carbonate solution. The organic layer was separated and washed with water (125 ml x 2). The combined organic layers were distilled under reduced pressure for the complete removal of the solvent and then the resulting mass was subjected to fractional distillation to produce 32 g of pure 2-(phenylamino)ethanol [Purity by HPLC: 99.0%].

Example 2
Preparation of 4-Phenyl-3-morpholinone
2-(Phenylamino)ethanol (50 g) was added to ethanol (46 ml) at room temperature. The resulting mass was heated to 40°C, followed by the addition of 40% aqueous sodium hydroxide solution (316 g) and chloroacetyl chloride (123 g) simultaneously at the same temperature and then stirred for 10-30 minutes at the same temperature. The resulting mass was cooled to 0-5°C and then stirred for 30 minutes at the same temperature. The solid obtained was filtered, washed with water (50 ml) and then dried at 50-60°C for 1 to 2 hours to produce 61 g of 4-Phenyl-3-morpholinone [Yield: 94%; Purity by HPLC: 99.5%].