DESC:FIELD OF THE INVENTION
The present invention relates to an industrially advantageous process for the purification of rivaroxaban intermediate, specifically rivaroxaban amino intermediate. More specifically, the present invention provides rivaroxaban with high chemical and enantiomeric purity by using pure rivaroxaban amino intermediate substantially free from enantiomeric impurities.
BACKGROUND OF THE INVENTION
Rivaroxaban of Formula I, chemically known as 5-chloro-N-({(5S)- 2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)thiophene-2-carboxamide is an orally active direct factor Xa (FXa) inhibitor drug developed by Bayer and approved by United states Food and Drug Administration (USFDA) in July 2011 under the trade name Xarelto.

Formula I

Rivaroxaban has been used for the prevention and treatment of various thromboembolic diseases, in particular pulmonary embolism, deep venous thrombosis, myocardial infarction, angina pectoris, reocclusion and restenosis after angioplasty or aortocoronary bypass, cerebral stroke, transitory ischemic attacks, and peripheral arterial occlusive diseases.
The linear approach of preparing rivaroxaban has been first time reported in US patent 7,157,456. The synthesis involves condensation of morpholin-3-one with fluoro nitrobenzene using sodium hydride as a base in N-methyl pyrrolidone (NMP) to get nitro morpholinone, the nitro group is reduced by using palladium on carbon (Pd–C) and hydrogen in tetrahydrofuran (THF) to achieve 4-(4-aminophenyl)- 3-morpholinone which is then condensed with 2-[(2S)-2-oxiranylmethyl]-1H-isoindole-1, 3(2H)-dione in ethanol and water mixture to provide amino alcohol. Cyclization of amino alcohol by using N, N'-carbonyl diimidazole (CDI) in presence of 4-dimethylaminopyridine (DMAP) in THF to obtain 2-({(5S)-2-oxo-3-[4-(3-oxomorpholin4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)-1H-isoindole1,3(2H)-dione. The deprotection of resulting compound by using methyl amine in ethanol yields 4{-4-[(5S)-5-(amino methyl)-2-oxo-1, 3-oxazolidin-3-yl] phenyl} morpholine-3-one, commonly called rivaroxaban amino intermediate. The said amino intermediate is further condensed with 5-chlorothiophene-2-carbonyl chloride in pyridine provides rivaroxaban with an overall yield of 4.5% starting from the morpholin-3-one. The process is depicted below:

The process for the preparation of rivaroxaban described in the aforementioned prior art suffers from several disadvantages such as the use of highly hazardous materials like thionyl chloride and pyridine, and use of tedious and cumbersome procedures like low temperatures, multiple process steps, column chromatographic purifications, multiple isolations/ re-crystallizations, and thus resulting in a low yield and poor quality of the product. Methods involve column chromatographic purifications which are generally undesirable for large-scale operations, thereby making the process commercially unfeasible.
In PCT publication WO 2005/068456 hereinafter referred to as the ‘456 publication, rivaroxaban is prepared by reacting 4-{4-(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl) phenyl}morpholine-3-one hydrochloride salt [rivaroxaban amino intermediate] with 5-chlorothiophene-2-carbonyl chloride in the presence of an inorganic base, preferably sodium carbonate, in a solvent selected from the group consisting of ether, alcohol, ketone and water or in a mixture thereof. As per the process exemplified in the ‘456 publication, the preparation of rivaroxaban is carried out in three steps. According to the first step, 5-chlorothiophene-2- carbonyl chloride is prepared by reacting 5-chlorothiophene 2-carboxylic acid with thionyl chloride in toluene at a temperature of 75 to 80°C. According to the second step, 4{-4- [(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholine-3-one hydrochloride salt is reacted with 5-chlorothiophene-2-carbonyl chloride (30% strength solution in toluene) in the presence of sodium carbonate in a solvent mixture containing water and acetone to produce crude rivaroxaban. In the third step, the solvent-containing crude product is purified by recrystallization from acetic acid.
The above said ‘456 publication is silent about the HPLC purity of certain intermediates let alone that of the end product rivaroxaban. The rivaroxaban amino intermediate i.e., 4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl] phenyl} morpholin-3-one hydrochloride salt is obtained according to international patent application with a yield of 82.7%, while there is no disclosure relating to the purity thereof. As per prior art reference i.e., US 9,556,163, on reproducing the example of said PCT publication precisely after the removal of the phthalyl protecting group, the quality of rivaroxaban amino intermediate is not feasible for the preparation of a pharmaceutical grade end product due to the presence of impurities specifically unacceptable level of enantiomeric impurities.
Therefore, to get the desired quality of final product, crude rivaroxaban needs to be subjected to recrystallization or any other purification method. However, the inclusion of purification step in the final stage decreases the overall yield of the process and makes the process unattractive from the cost point of view.
In PCT publication WO2013/053739, rivaroxaban is prepared by treating 4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxozoladine-3-yl]phenyl}morpholin-3-one with an organic acid to obtain organic acid salt of a 4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3- oxozoladine-3-yl]phenyl}morpholin-3-one which is further reacted 5- chlorothiophene-2-carbonyl chloride in the presence of base and solvent to obtain rivaroxaban. However, the said publication is silent about the level of enantiomeric impurities in intermediate as well as in rivaroxaban.
In another PCT publication WO2013/121436, rivaroxaban is prepared by reacting 4-(4-aminophenyl)morpholine-3-one with 2- [(2S)-oxiran-2-ylmethyl]-1 H-isoindole-1,3(2H)-dione in a first solvent such as aliphatic hydrocarbon to obtain 2-[(2R)-2-hydroxy-3-{[4-(3-oxomorpholin-4-yl)phenyl]amino}propyl]-1-H-isoindole-1 ,3(2H)-dione which is then subjected for treatment with phosgene or phosgene equivalents or anhydrides or bis (aryl) carbonate in the presence of base and second solvent such as ester, ether to obtain 2- ({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)-1H-isoindole-1, 3(2H)-dione. The elimination of the pthalamide group is carried out in the presence of de-protecting agent and solvent to obtain 4-{4-[(5S)-5- (aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one which is further converted into its acid addition salt followed by treatment with 5- chlorothiophene-2-carbonyl chloride in a third solvent such as halogenated aliphatic hydrocarbon and in presence of a base to obtain rivaroxaban.
In one of the examples of the above said PCT publication, rivaroxaban amino intermediate is reported to have 98% purity by HPLC, which may be utilized for the preparation of final product wherein rivaroxaban has purity of 99%. Further, the said publication is silent about the level of enantiomeric impurities in intermediate as well as in rivaroxaban.
In most of prior art processes many by-products and analogous impurities formed during the deprotection reaction. Based on the understanding of impurities purification of rivaroxaban amino intermediate has been established by recrystallization using different solvent systems such as methanol and dichloromethane to eliminate these impurities along with enantiomeric impurities. Rivaroxaban amino intermediate is S-isomer i.e., 4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one hydrochloride salt wherein R-isomer i.e., 4-{4-[(5R)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl] phenyl}morpholin-3-one hydrochloride salt is an enantiomeric impurity. Traces of these impurities, specifically enantiomeric impurities, if left behind at intermediate stage, will be carried forward with desired S-isomer which impacts the purity of rivaroxaban. Thus, it is necessary to eliminate these impurities at intermediate stage only.
It is known that the biological activity of enantiomers of racemic compounds can differ considerably depending on the two enantiomers. Enantiomers differ in their configuration (R or S) at the stereogenic center. Consequently, there is often one enantiomer that has more pronounced activity, making it more advantageous as an active principle in a medicament. The use of this enantiomer instead of the racemate is advantageous. Specifically, the higher activity of the identified enantiomer makes it possible to reduce the dosage of active principle in the medicament. The lower dosage then allows a reduction of the adverse side effects. It is thus desirable for an active principle to be composed of only the pure enantiomer that has the largest desired biological effects. In rivaroxaban, S-isomer is an active isomer wherein R-isomer is considered as a known enantiomeric impurity which is to be controlled in the final product as per ICH guidelines.
n synthetic organic chemistry, getting
a single end – product with 100% yield is seldom. There is
always a chance of having by-products. Because they can
be formed through variety of side reactions, such as
incomplete reaction, over reaction, isomerization,
dimerization, rearrangement or unwanted reactions
between starting materials or intermediate with chemical
12
reagents or catalysts
n synthetic organic chemistry, getting
a single end – product with 100% yield is seldom. There is
always a chance of having by-products. Because they can
be formed through variety of side reactions, such as
incomplete reaction, over reaction, isomerization,
dimerization, rearrangement or unwanted reactions
between starting materials or intermediate with chemical
12
reagents or catalysts
n synthetic organic chemistry, getting
a single end – product with 100% yield is seldom. There is
always a chance of having by-products. Because they can
be formed through variety of side reactions, such as
incomplete reaction, over reaction, isomerization,
dimerization, rearrangement or unwanted reactions
between starting materials or intermediate with chemical
12
reagents or catalysts
n synthetic organic chemistry, getting
a single end – product with 100% yield is seldom. There is
always a chance of having by-products. Because they can
be formed through variety of side reactions, such as
incomplete reaction, over reaction, isomerization,
dimerization, rearrangement or unwanted reactions
between starting materials or intermediate with chemical
12
reagents or catalysts
Nevertheless, besides the existing routes of preparation as well as purification of rivaroxaban and their intermediate thereof, to overcome the aforementioned drawbacks associated in the prior art processes i.e., traces of the impurities if left behind at that particular stage will be carried forward with penultimate rivaroxaban amino intermediate to impact the purity of rivaroxaban. There is a continuing need in the art to optimize the preparation process of rivaroxaban or develop an efficient purification process at intermediate stage which will purge the impurities down to the desired level as per ICH guidelines.
OBJECT OF THE INVENTION
The principal object of the present invention is to provide an efficient and industrially advantageous process for the purification of rivaroxaban amino intermediate wherein individual impurity especially enantiomeric impurity can be controlled to a level of less than 0.10% and total impurities to a minimal level.
Another object of the present invention is to provide an efficient process for the preparation of pure rivaroxaban wherein level of impurities is controlled as per ICH guidelines by using pure rivaroxaban amino intermediate.
One another object of the present invention is to provide an effective method preparation of pure rivaroxaban which is substantially free from enantiomeric impurities.

SUMMARY OF THE INVENTION
Accordingly, the present invention provides an efficient process for the purification of rivaroxaban amino intermediate of formula II,


Formula II
which comprises the steps of,
i. providing a solution of crude rivaroxaban amino intermediate of formula II in a suitable organic solvent and water,
ii. cooling the solution obtained in step (i) to below ambient temperature, and
iii. isolating pure rivaroxaban amino intermediate of formula II.
In another embodiment, the present invention provides an efficient process for the purification of rivaroxaban amino intermediate of formula II,

Formula II
which comprises the steps of,
i. adding rivaroxaban amino intermediate of formula II in a suitable organic solvent,
ii. heating the reaction mass at reflux temperature,
iii. adding water to the above reaction mass to get a clear solution,
iv. cooling the solution obtained in step (iii) to a suitable temperature, and
v. isolating pure rivaroxaban amino intermediate of formula II.
In one another embodiment, the present invention provides an improved process for the preparation of pure rivaroxaban of formula I,

Formula I

which comprises the steps of,
i. reacting pure rivaroxaban amino intermediate of formula II with 5-chlorothiophene-2-carbonyl halide in the presence of base and suitable organic solvent, and
ii. isolating pure rivaroxaban of formula I.
In one another embodiment, the present invention provides an improved process for the preparation of pure rivaroxaban of formula I, which may be devoid of isomeric/ enantiomeric and other process related impurities while affording the desired product rivaroxaban in high purity.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides an industrial advantageous process for the purification of rivaroxaban amino intermediate of formula II wherein enantiomeric impurities are controlled in less than 0.10% w/w by HPLC.
The present invention provides an industrial advantageous process for the preparation of pure rivaroxaban of formula I by using pure rivaroxaban amino intermediate of formula II wherein enantiomeric impurities is controlled as per prescribed limit of ICH guidelines and in particular less than 0.10% w/w by HPLC.
As used herein, the term “ambient temperature” represents a temperature 25? ± 5?.
The term “substantially free” herein means rivaroxaban having each known impurity less than about 0.15% by area percentage of HPLC or each unknown impurity less than about 0.10% by area percentage of HPLC. In particular, less than about 0.10% by area percentage of HPLC.
As used herein, the term ‘crude’ represents a compound having impurities greater than the limits specified as per ICH guidelines, in particular having any known impurity greater than about 0.15% by area percentage of HPLC or any unknown impurity greater than about 0.10% by area percentage of HPLC.
The term “pure” herein refers to purity of rivaroxaban or its intermediate thereof, which is substantially free from one or more impurities and having purity of greater than 99% or more of about 99.5% or more, particularly of about 99.80% or more by area percentage of HPLC and enantiomeric impurity in less than 0.10% w/w by HPLC.
As per regulatory guidance for drug manufacturers, it requires that impurities generated either through process or degradation to be maintained below set limits by specifying the quality of raw materials, controlling process parameters, such as temperature, pressure, time, and stoichiometric ratios, and including purification steps, such as crystallization, distillation, and liquid-liquid extraction, in the manufacturing process.
The basic idea of the invention is to specifically develop an improved process for the preparation of pure rivaroxaban by using pure rivaroxaban amino intermediate of formula II, which is free from its known enantiomeric impurities.
In one embodiment the present invention provides an efficient process for the purification of rivaroxaban amino intermediate of formula II.
The process comprises of preparing a solution of crude rivaroxaban amino intermediate of formula II in a suitable organic solvent and water.
The solution can be prepared by taking rivaroxaban amino intermediate of formula II in suitable organic solvent and heated the reaction mixture and then water is added to form the clear solution.
In an alternate way, rivaroxaban amino intermediate of formula II can be taken in a mixture of a suitable organic solvent and water and heated the reaction mixture to reflux temperature of organic solvent to form a clear solution.
The suitable organic solvent used herein can be selected from any suitable organic solvent which is selected from the group consisting of nitrile solvent such as acetonitrile, propionitrile, butyronitrile, isobutyronitrile, benzonitrile or mixture thereof; ketone solvent such as acetone, methyl isobutyl ketone, methyl ethyl ketone, diethyl ketone, dimethyl ketone, dipropyl ketone, dibutyl ketone, diisobutyl ketone or mixture thereof; ester solvent such as methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate or mixture thereof. Preferably, nitrile solvent can be used and more preferably the solvent is acetonitrile.
After preparing a clear solution by any means, the reaction mass may be cooled below ambient temperature. Then, the reaction mass can be stirred for a few minutes to few hours and cooled to a suitable temperature. Preferably, the mass can be cooled at -10 to 10?.
Subsequently after cooling, the reaction mass can be kept at the same temperature for few minutes to few hours. The solid thus obtained can be isolated by using techniques known in art such as filtration, centrifugation etc. Finally, the solid obtained after filtration can be washed with the first solvent and dried at a temperature of 45-65? for 1-8 hours to obtain pure rivaroxaban amino intermediate of formula II. Preferable drying temperature can be 50-60? and preferably, the solid can be dried for 1-4 hours and more preferably for 2-4 hours.
The resulting pure rivaroxaban amino intermediate of formula II may have high purity, wherein rivaroxaban amino intermediate of formula II may be substantially free from enantiomeric impurities. The pure rivaroxaban amino intermediate of formula II may have chemical purity of greater than 99% or more of about 99.5% or more, particularly of about 99.80% or more by area percentage of HPLC and enantiomeric purity of greater than about 99.9% as measured by HPLC, substantially free from enantiomeric impurities specifically wherein R -isomer may be present less than 0.1%.
If crude rivaroxaban amino intermediate of formula II, as such, is utilized for the preparation of rivaroxaban, the impurities present in it, may be carried forward to the final product i.e., rivaroxaban wherein the presence of impurities along with enantiomeric impurity may be unacceptable for the use as per the regulatory guidelines.
It has been observed by the inventors of present invention that during condensation reaction of crude rivaroxaban amino intermediate of formula II with 5-chlorothiophene-2-carbonyl chloride in the presence of inorganic or organic base and solvent, the enantiomeric impurity may be carry forwarded with the final product i.e., rivaroxaban and resulting in a poor quality of the product. Even it is very difficult to remove enantiomeric impurities at final stage or in case it may be removed the process involves use of tedious and cumbersome procedures like low temperatures, multiple process steps, column chromatographic purifications, multiple isolations/ re-crystallizations. The final stage purification to reduce the level of impurities usually causes yield loss of the final product. The methods involving column chromatographic purifications are generally undesirable for large-scale operations, thereby making the process commercially unfeasible. Therefore, it becomes more challenging to remove enantiomeric impurity at early stages in order to obtain pure rivaroxaban of desired quality. The comparative example of the present invention clearly indicates that presence of high level of enantiomeric impurities which makes product unacceptable as per regulatory requirements for drug formulation.
After extensive experimentation, the process of present invention has been developed to remove such enantiomeric impurities. These impurities may be removed at any earlier stages instead of removal of impurities in the final stage to get the desired quality of rivaroxaban.
In another embodiment the present invention provides an improved process for the preparation of pure rivaroxaban of formula I by using pure rivaroxaban amino intermediate of formula II. The process comprises of reacting pure rivaroxaban amino intermediate of formula II with 5-chlorothiophene-2-carbonyl halide in the presence of base and a suitable organic solvent.
The preferable reactant 5-chlorothiophene-2-carbonyl halide can be selected from 5-chlorothiophene-2-carbonyl chloride which may be prepared by mixing 5-chloro-2-thiophenecarboxylic acid with a thionyl halide, preferably thionyl chloride, and an organic solvent or mixtures thereof, preferably N,N- dimethylformamide (DMF), tetrahydrofuran (THF), methylene chloride, acetone, toluene or mixtures thereof. Preferably solvent can be selected from N,N- dimethylformamide (DMF) and methylene chloride or mixture thereof. Afterwards, the reaction mass may be heated to reflux temperature for 3-5 hours and part of the organic solvent can be distilled out in vacuum at 30-70 °C in order to remove the excess of thionyl chloride.
The base used during the reaction herein includes, but is not limited to, inorganic or organic base. Examples of inorganic bases include, but are not limited to, hydroxides, carbonates and bicarbonates of alkali and alkaline earth metals such as sodium carbonate, potassium carbonate, calcium carbonate, magnesium carbonate, sodium bicarbonate, potassium bicarbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide and mixtures thereof. Examples of organic bases may include, but are not limited to, triethylamine, ammonia, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1 ,5-diazabicyclo[4.3.0]non-5-ene, 4-dimethylaminopyridine, diisopropylamine, N,N-diisopropylethylamine, tributylamine, tert-butyl amine, N-methyl morpholine, N,N-dimethyl benzylamine, isopropyl ethyl amine, N-methyl pyrrolidine, propyl ethyl amine, ethanolamine, chloramines, piperidine, pyridine, picoline, lutidine their salts and mixture thereof.
The suitable organic solvent used in above reaction can be selected from but are not limited to alcohol solvents such as methanol, ethanol, isopropanol, butanol and the like; ester solvents such as ethyl acetate, methyl acetate, isopropyl acetate, n-butyl acetate and the like; halogenated solvent such as methylene chloride, ethylene dichloride, carbon tetrachloride, chloroform and the like; ether solvents such as tetrahydrofuran, diethyl ether, methyl tert-butyl ether, dioxane and the like; ketone solvents such as acetone, methyl isobutyl ketone, methyl ethyl ketone and the like; and water or in a mixture thereof.
After complete recovery of solvent, reaction mass can be cooled to 10-30°C. Preferably, reaction mass can be cooled to 20-30°C. Thereafter, organic solvents can be added to reaction mass which can be utilized for the reaction.
Then, pure rivaroxaban amino intermediate of formula II can be dissolved in a suitable organic solvent under stirring followed by addition of base to obtain reaction mass which can be cooled to 5-25°C. Preferably reaction mass can be cooled to 10-20°C. Afterwards, 5-chlorothiophene-2-carbonyl chloride can be added slowly into reaction mass at 5-25°C and stirred for 1-5 hours till reaction completion. Preferably, reaction mass can be kept at 10-20°C and stirred for 2-3 hours.
After reaction completion, water or a suitable solvent can be added at the same temperature and can be stirred for 1-5 hours at 20-30°C. Preferably, reaction mass can be kept at 20-30°C and stirred for 2-3 hours.
The solid mass obtained can be isolated by using techniques known in art such as filtration, centrifugation etc. Finally, the solid obtained after filtration can be washed with the organic solvent and dried at a temperature of 45-65? for 4-14 hours to obtain pure rivaroxaban. Preferable drying temperature can be 50-60? and preferably, the solid can be dried for 6-12 hours and more preferably for 8-12 hours.
The resulting pure rivaroxaban of formula I may have chemical purity of greater than about 99% or more of about 99.5% or more, particularly of about 99.9% or more as measured by HPLC and enantiomeric purity of greater than about 99.9% as measured by HPLC, substantially free from enantiomeric impurities specifically wherein R -isomer may be present less than 0.1%.
In another embodiment, the pure rivaroxaban of formula I obtained by the process disclosed in the present invention has a total purity, includes both chemical and enantiomeric purity, of greater than about 99%, specifically greater than about 99.5% and more specifically greater than about 99.9 as measured by HPLC.
The present invention provides pure rivaroxaban of formula I which has HPLC purity [w/w] more than 99.90% and impurities are found to be reduced considerably and present within acceptable limit wherein the level of individual specified, and unspecified impurities is controlled at a level of equal to or less than 0.15% and 0.10% respectively and total impurities at a level of less than 1.0 % as per regulatory guidelines.
The crude rivaroxaban amino intermediate of formula II can be prepared by the methods reported in literature or by the process given in the present specification. The process involves condensation of 4-(4-aminophenyl) - 3-morpholinone with 2-[(2S)-2-oxiranylmethyl]-1H-isoindole-1, 3(2H)-dione in a suitable alcoholic solvent and water mixture to provide 2-[(2R) -2-hydroxy-3-{[4-(3-oxomorpholin-4-yl)phenyl]amino} propyl]-2,3-dihydro -1H- isoindole-1, 3-dione (amino alcohol). The suitable alcoholic solvents used herein may include but not limited to methanol, ethanol, isopropyl alcohol, n-butanol, tertiary-butyl alcohol, and the like. The resulting amino alcohol compound can be purified using suitable alcoholic solvents as defined above, and water to achieve the desired purity.
Thereafter, the amino alcohol is cyclized using acid binding reagent like N,N'-carbonyl diimidazole (CDI) in the presence of 4-dimethylaminopyridine (DMAP) in a suitable solvent to furnish 2-({(5S)-2-oxo-3-[4-(3-oxomorpholin4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)-1H-isoindole1,3(2H)-dione [oxazolidine intermediate]. The suitable solvent used in the above step is an ether solvent. Examples of suitable ether solvents include but are not limited to tetrahydrofuran, dimethyl ether, diisopropyl ether, methyl tert-butyl ether, 1,4-dioxane, and mixtures thereof. In a particular embodiment, the suitable solvent is tetrahydrofuran. The resulting oxazolidine intermediate compound can be purified using suitable ether solvent as defined above, to achieve the desired purity.
Finally, deprotection of the resulting compound using methyl amine in alcoholic solvent furnish 4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl] phenyl}morpholin-3-one free base which can be treated with hydrochloric acid to provide crude rivaroxaban amino intermediate of formula II.
The present invention provides an efficient process for the preparation of pure rivaroxaban of formula I wherein final stage purification can be avoided by providing pure rivaroxaban amino intermediate of formula II.
Although the following examples illustrate the practice of the present invention in some of its embodiments, the examples should not be construed as limiting the scope of invention. Other embodiments will be apparent to one skilled in the art from consideration of the specification and examples.
EXAMPLES:
Example 1: Preparation of 2-[(2R)-2-hydroxy-3-{[4-(3-oxomorpholin-4-yl)phenyl]amino} propyl]-2,3-dihydro -1H- isoindole-1, 3-dione
4-(4-Aminophenyl) morpholin-3-one (100g) was taken in methanol (1350ml) and water (150ml) followed by addition of 2-[(2S)-oxiran-2-ylmethyl]-1H-isoindole-1,3(2H)-dione (158g; R-isomer=0.80%) at 20-30°C. The reaction mass was then heated to 70-80 °C and stirred for 20-24 hours. Thereafter, the reaction mass was allowed to attain ambient temperature and further cooled at 20-30°C. The reaction mass was again stirred for 2-3 hours at 20-30 °C. Afterwards, the reaction was filtered, and the resulting solid was washed with methanol (25ml) and water (10ml). The solid, thus obtained, was dried at 45-55°C for 8-12 hours to get crude 2-[(2R) -2-hydroxy-3-{[4-(3-oxomorpholin-4-yl)phenyl]amino} propyl]-2,3-dihydro -1H- isoindole-1, 3-dione (170g).
Example 2: Purification of crude 2-[(2R) -2-hydroxyhydroxy-3-{[4-(3-oxomorpholin-4-yl)phenyl]amino} propyl]-2,3-dihydro -1H- isoindole-1, 3-dione
Crude 2-[(2R)-2-hydroxy-3-{[4-(3-oxomorpholin-4-yl)phenyl]amino} propyl]-2,3-dihydro -1H- isoindole-1, 3-dione (170g) was taken in methanol (850ml) and water (85ml) and stirred at 20-30 °C. The reaction mass was then heated to 60-70 °C and stirred under reflux temperature for 3 hours. Thereafter, the reaction mass was allowed to attain ambient temperature and further cooled at 20-30°C. Afterwards, the reaction was filtered, and the resulting solid was dried at 45-55°C for about 10 hours to get pure title compound (130g; S-isomer - 0.36%).
Example 3: Preparation of 2-[[5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl) phenyl]-1, 3-oxazolidin-5-yl] methyl]-1H-isoindole-1, 3(2H)-dione
2-[(2R) 2-Hydroxy-3-{[4-(3-oxomorpholin-4-yl) phenyl]amino} propyl]-2,3-dihydro -1H- isoindole-1, 3-dione (100g, S isomer= 0.36%) was taken in tetrahydrofuran (1500ml) followed by addition of carbonyl diimidazole (CDI, 150g) and 4-dimethylaminopyridine (DMAP, 5g) at 20- 30°C. The reaction mass was then heated to reflux temperature and stirred for around 22 hours. Thereafter, water (500ml) was added to the reaction mass and allowed to attain ambient temperature followed by its slow cooling at -5 to 5 °C. The reaction mass was filtered at the same temperature and the resulting solid was washed with tetrahydrofuran (25ml). The solid was dried for 10 hours at 45-55°C to get title compound having R-isomer=0.35 %.
Example 4: Preparation of crude rivaroxaban amino intermediate of formula II
2-[[5S)-2-Oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl]methyl]-1H-isoindole-1,3(2H)-dione (100g, having 0.35% R-isomer) was dissolved in methanol (250ml) at the room temperature followed by the addition of methylamine solution (38- 48% solution, 100 ml) with constant stirring. Afterwards, the reaction mass was heated to reflux temperature and stirred for about 4 hours. After completion of the reaction, the solvent was recovered from the reaction mass to get the residue mass. Thereafter the residue was again dissolved in methanol (500ml) to get a clear solution. Further, water (200ml) was added to the solution followed by stirring and then hydrochloric acid (40ml) was added to the solution. Finally, the solution was stirred for 4 hours at ambient temperature to ensure the proper crystallization. The solid was dried at 45-55°C for about 6 hours to get the title compound having R-isomer = 0.22 %.
Example 5: Preparation of crude rivaroxaban amino intermediate of formula II
2-[[5S)-2-Oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl]methyl]-1H-isoindole-1,3(2H)-dione (100g, having 0.35% R-isomer) was dissolved in methanol (250ml) at the room temperature followed by the addition of methylamine solution (38- 48% solution, 100ml) with constant stirring. Afterwards, the reaction mass was heated to reflux temperature and stirred for 3 hours. After completion of the reaction, the solvent was recovered from the reaction mass to get the residue 4-{4-[(5S)-5-(aminomethyl) -2-oxo-1, 3-oxazolidin-3-yl] phenyl} morpholin-3-one. Thereafter the residue was again dissolved in methanol (500ml) to get a clear solution. Further, water (200ml) was added to the solution followed by stirring and then hydrochloric acid (40ml) was added to the solution. Finally, the solution was stirred for 2 hours at ambient temperature to ensure the proper crystallization. The solid was dried at 45-55°C for about 8 hours to get the title compound having R-isomer = 0.22 %.
Example 6: Purification of crude rivaroxaban amino intermediate of formula II
Crude rivaroxaban amino intermediate of formula II (100g; R-isomer=0.22%) was taken in acetonitrile (500ml) and heated the reaction mass to reflux (75-85°C) under stirring. Water (200ml) was added into the reaction mass and stirred to get a clear solution. Then the reaction mass was allowed to attain the ambient temperature and stirred for about 1 hour and cooled the reaction mass to -5 to 5°C. Thereafter, reaction mass was further stirred for another hour at this temperature. The reaction mass was filtered at same temperature and the solid mass thus obtained was given running washing with chilled acetonitrile (10ml). The solid mass was dried at 50-60? for about 4 hours to get pure rivaroxaban amino intermediate of formula II (70g, HPLC purity (w/w) = 99.83%, R-isomer was present in 0.08% as per chiral HPLC).
Example 7: Purification of crude rivaroxaban amino intermediate of formula II
Crude rivaroxaban amino intermediate of formula II (100g; R-isomer=0.22%) was taken in acetonitrile (500ml) and heated the reaction mass to reflux (75-85°C) under stirring. Water (200ml) was added into the reaction mass and stirred to get a clear solution. Then the reaction mass was allowed to attain the ambient temperature and stirred for about 1 hour and cooled the reaction mass to -5 to 5°C. Thereafter, reaction mass was further stirred for another hour at this temperature. The reaction mass was filtered at same temperature and the solid mass thus obtained was given running washing with chilled acetonitrile (10ml). The solid mass was dried at 50-60? for about 3 hours to get pure rivaroxaban amino intermediate of formula II (70g, HPLC purity (w/w) =99.80%, and R-isomer was present in 0.08% as per chiral HPLC).
Example 8: Preparation of rivaroxaban of formula I from pure rivaroxaban amino intermediate of formula II
5-Chlorothiophene-2-carboxylic acid (65g) was dissolved in methylene chloride (650 ml) at 20-30°C. To this, dimethylformamide (5g) was added and reaction mass was then heated to 40-50°C followed by addition of thionyl chloride (65g) and stirred the reaction mass at same temperature for 3-5 hours. After completion of reaction, the solvent was recovered under vacuum and then methylene chloride (200ml) was added to the resulting 5-chlorothiophene-2-carbonyl chloride.
In another container 100g of pure rivaroxaban amino intermediate of formula II (having R isomer = 0.08% as per example 6) was dissolved in methylene chloride (750ml) and triethylamine (100g) was added at 10-20°C. Afterwards, 5-chlorothiophene-2-carbonyl chloride was added slowly into the reaction mass at 10-20°C and stirred for about 3 hours till reaction completion. After reaction completion, water (500ml) was added at 10-20°C followed by stirring for another 2 hours at 20-30°C. The resulting solid was filtered and dried at 50-60°C for about 11 hours to get pure rivaroxaban of formula I (119 g, having HPLC purity = 99.97% w/w; and R-isomer was present in 0.06% as per chiral HPLC).
COMPRATIVE EXAMPLE
Example 1: Preparation of crude rivaroxaban amino intermediate of formula II
2-[[5S)-2-Oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl]methyl]-1H-isoindole-1,3(2H)-dione (100g, having 0.35% R-isomer) was dissolved in methanol (250ml) at the room temperature followed by the addition of methylamine solution (38- 48% solution, 100ml) with constant stirring. Afterwards, the reaction mass was heated to reflux temperature and stirred for 4 hours followed by reaction monitoring. After completion of the reaction, the solvent was recovered from the reaction mass to get the residue 4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl} morpholin-3-one. Thereafter the residue was again dissolved in methanol (500ml) to get a clear solution. Further, water (200ml) was added to the solution followed by stirring and then hydrochloric acid (40ml) was added to the solution. Finally, the solution was stirred for 3 hours at ambient temperature to ensure the proper crystallization. The solid was dried at 45-55°C for about 7 hours to get the title compound having R-isomer = 0.22 %.
Example 2: Preparation of rivaroxaban of formula I from crude rivaroxaban amino intermediate of formula II
5-Chlorothiophene-2-carboxyllic acid (65g) was dissolved in methylene chloride (650ml) at 20-30°C under stirring. To this, dimethylformamide (5g) was added and reaction mass was then heated to 40-50°C followed by addition of thionyl chloride (65g) and stirred the reaction mass at same temperature for 3-5 hours. After completion of reaction, the solvent was recovered under vacuum and followed by cooling of reaction mass to 20-30°C. Methylene chloride (200ml) was added into the resulting reaction mass 5-chlorothiophene-2-carbonyl chloride.
In another container, 100g of crude rivaroxaban amino intermediate of formula II (having R isomer = 0.22% as per comparative example 1) was dissolved in methylene chloride (750ml) under stirring and triethylamine (100g) was added to reaction mass and then cooled the reaction mass to 10-20°C. Afterwards, 5-chlorothiophene-2-carbonyl chloride prepared as above, was added slowly into the reaction mass at 10-20°C and stirred for further 2-3 hours till reaction completion. After reaction completion, water (500 ml) was added and stirred the reaction mass for another 2-3 hours at 20-30°C. The resulting solid was filtered and dried at 50-60°C for 8-12 hours to get rivaroxaban of formula I, containing 0.18% of R-isomer.
It will be apparent to those skilled in the art that various modifications and variations can be made in the present invention and specific examples provided herein without departing from the spirit and scope of the invention. Thus, it is intended that the present invention covers the modifications and variations of this invention that come within the scope of any claims and their equivalents.
,CLAIMS:We claim:
1. A process for the purification of rivaroxaban amino intermediate of formula II,


Formula II
which comprises the steps of,
i. providing a solution of crude rivaroxaban amino intermediate of formula II in a suitable organic solvent and water,
ii. cooling the solution obtained in step (i) to below ambient temperature, and
iii. isolating pure rivaroxaban amino intermediate of formula II.

2. The process as claimed in claim 1, wherein solvent in step (i) is selected from the group consisting of nitrile solvent such as acetonitrile, propionitrile, butyronitrile, isobutyronitrile, benzonitrile or mixture thereof; ketone solvent such as acetone, methyl isobutyl ketone, methyl ethyl ketone, diethyl ketone, dimethyl ketone, dipropyl ketone, dibutyl ketone, diisobutyl ketone or mixture thereof; ester solvent such as methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate or mixture thereof.

3. The process as claimed in claim 1, wherein in step i), the solution of crude rivaroxaban amino intermediate of formula II is prepared by:
a) taking crude rivaroxaban amino intermediate of formula II in organic solvent and water followed by heating; or
b) taking crude rivaroxaban amino intermediate of formula II in organic solvent, heating and followed by addition of water.
4. The process as claimed in claim 1, wherein pure rivaroxaban amino intermediate of formula II is having chemical purity of greater than 99% by area percentage of HPLC and enantiomeric purity of greater than about 99.9% in which R -isomer is present less than 0.1%, as measured by HPLC.

5. A process for the preparation of pure rivaroxaban of formula I,
which comprises the steps of,
i. providing a solution of crude rivaroxaban amino intermediate of formula II in a suitable organic solvent and water,
ii. cooling the solution obtained in step (i) to below ambient temperature,
iii. isolating pure rivaroxaban amino intermediate of formula II,
iv. reacting pure rivaroxaban amino intermediate of formula II, obtained in step iii) with 5-chlorothiophene-2-carbonyl halide in the presence of a base and a suitable organic solvent, and
v. isolating pure rivaroxaban of formula I.

6. The process as claimed in claim 5, wherein solvent in step (i) is selected from the group consisting of nitrile solvent such as acetonitrile, propionitrile, butyronitrile, isobutyronitrile, benzonitrile or mixture thereof; ketone solvent such as acetone, methyl isobutyl ketone, methyl ethyl ketone, diethyl ketone, dimethyl ketone, dipropyl ketone, dibutyl ketone, diisobutyl ketone or mixture thereof; ester solvent such as methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate or mixture thereof; 5-chlorothiophene-2-carbonyl halide used in step (iv) is 5-chlorothiophene-2-carbonyl chloride, base used in step (iv) is selected from an organic or inorganic base, and wherein organic solvent in step (iv) is selected from the group consisting of alcohol solvents such as methanol, ethanol, isopropanol, butanol; ester solvents such as ethyl acetate, methyl acetate, isopropyl acetate, n-butyl acetate; halogenated solvent such as methylene chloride, ethylene dichloride, carbon tetrachloride, chloroform; ether solvents such as tetrahydrofuran, diethyl ether, methyl tert-butyl ether, dioxane; ketone solvents such as acetone, methyl isobutyl ketone, methyl ethyl ketone; and water or in a mixture thereof.

7. The process as claimed in claim 6, wherein inorganic base is selected from the group consisting of hydroxides, carbonates and bicarbonates of alkali and alkaline earth metals such as sodium carbonate, potassium carbonate, calcium carbonate, magnesium carbonate, sodium bicarbonate, potassium bicarbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide and mixtures thereof, and organic base is selected from triethylamine, ammonia, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,5-diazabicyclo[4.3.0]non-5-ene, 4-dimethyl-aminopyridine, diisopropylamine, N,N-diisopropylethylamine, tributylamine, tert-butyl amine, N-methyl morpholine, N,N-dimethyl benzylamine, isopropyl ethyl amine, N-methyl pyrrolidine, propyl ethyl amine, ethanolamine, chloramines, piperidine, pyridine, picoline, lutidine their salts and mixture thereof.

8. The process as claimed in claim 6, wherein 5-chlorothiophene-2-carbonyl chloride is prepared by mixing 5-chloro-2-thiophenecarboxylic acid with a thionyl chloride in organic solvent.

9. The process as claimed in claim 8, wherein organic solvent is selected from N,N- dimethylformamide (DMF), tetrahydrofuran (THF), methylene chloride, acetone, toluene or mixtures thereof.

10. The process as claimed in claim 5, wherein pure rivaroxaban of formula I is having chemical purity of greater than 99% by area percentage of HPLC and enantiomeric purity of greater than about 99.9% in which R -isomer is present less than 0.1%, as measured by HPLC.