WO2013118130A1

WO2013118130A1 - A process for the preparation of 5-chloro-n-({(5s)-2-oxo-3-[4-(3-oxo-4-morpholinyl) phenyl]-1,3-oxazolidin-5-yl}methyl)-2-thiophene carboxamide

Info

Publication number: WO2013118130A1
Application number: PCT/IN2012/000086
Authority: WO
Inventors: Dodda Mohan Rao; Buthukuri Venkat Reddy
Original assignee: Symed Labs Limited
Priority date: 2012-02-06
Filing date: 2012-02-06
Publication date: 2013-08-15

Abstract

The present invention relates to a process for the preparation of 5-chloro-N-( {(5S)-2-oxo-3-[ 4-(3-oxo-4-morpholinyl) phenyfj-l, 3-oxazolidin-5-yl} methyl)-2-thiophene-25 carboxamide (I). In an aspect, the present invention relates to a process for the preparation of 5-chloro-N({(5S)-2-oxc-3-[ 4-(3-oxo-4-morpholinyl) phenyl]: 1, 3-oxazolidin-5-yl} methyl)-2-thiophenecarboxamide of formula (I). Hence, there is a need to provide improved process for the preparation of rivaroxaban, which avoids the use of hazardous, expensive chemicals and also to avoid the formation of isomeric and other process related impurities while affording the compound desired yield and purity.

Description

"A PROCESS FOR THE PREPARATION OF 5-CHLORO-N-({(5S)-2-OXO-3-[4-(3- OXO-4-MORPHOLINYL) PHENYL]-l,3-OXAZOLIDIN-5-YL}METHYL)-2-

THIOPHENE CARBOXAMIDE"

BACKGROUND OF THE INVENTION

1. Technical Field

The present invention relates to a process for the preparation of 5-chloro-N-({(5S)-2- oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-l,3-oxazolidin-5-yl}methyl)-2-thiophene-carboxamide.

2. Description of the Related Art

Rivaroxaban is a novel anticoagulant approved in US and Europe for the prevention of venous thromboembolism in adult patients undergoing elective hip or knee replacement surgery and for non-valvular atrial fibrillation to reduce stroke risk in cardiac patients.

Rivaroxaban is structurally related to the antibacterial compound Linezolid (Zyvox) is enantiomerically pure. Rivaroxaban is available in the market under the brand name Xarelto® as 10 mg tablets in Europe and US.

Rivaroxaban is chemically described as 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4- morpholinyl)phenyl]-l,3-oxazolidin-5-yl}methyl)-2-thiophene-carboxamide (herein after referred by generic name rivaroxaban) and is represented by the structural formula I shown below:

U.S. Patent No. US 7,585,860 describes morpholinyl oxazolidinone thiophene

carboxamides including rivaroxaban or pharmaceutically acceptable acid addition salts thereof, a pharmaceutical composition and a method of treatment. Th xaban which is illustrated

U.S. Patent No. 7,351,823 describes a synthesis of intermediate (II) going upto rivaroxaban which is illustrated by scheme below:

The final steps of aforementioned processes has several disadvantages like

a) The processes involves the use of hazardous reagents like thionyl chloride, oxalyl chloride, phosgene for the preparation of acid chloride which releases corrosive and volatile bye-products and moreover the handling of these reagents on commercial scale are very difficult and also the acid chloride intermediate 5-chloro-thiophene-2-carbonyl chloride is also corrosive. b) The acid chloride intermediate 5-chloro-thiophene-2-carbonyl chloride is unstable and handling of this on commercial scale is also difficult,

c) The processes also involve base like pyridine (US'860) and sodium carbonate (US' 823), pyridine is carcinogenic and hence it is difficult to handle pyridine on commercial scale, moreover the usage of base makes the process expensive.

d) The above processes involves two steps (first step is preparation of acid chloride from acid and second step is the condensation of acid chloride with the amine intermediate to produce rivaroxaban) which is time consuming, expensive and difficult to handle on commercial scale.

e) the final compound is being purified by chromatography, which is not possible on commercial scale.

Hence, there is a need to provide improved process for the preparation of rivaroxaban, which avoids the use of hazardous, expensive chemicals and also to avoid the formation of isomeric and other process related impurities while affording the compound desired yield and purity.

The process of the present invention is simple, eco-friendly, economic, reproducible, robust and is well suited on commercial scale.

SUMMARY OF THE INVENTION

The present invention relates to a process for the preparation of 5-chloro-N-({(5S)-2- oxo-3-[4-(3-oxo-4-morpholinyl) phenyl]- 1, 3-oxazolidin-5-yl} methyl)-2-thiophene- carboxamide (I).

In an aspect, the present invention relates to a process for the preparation of 5-chloro-N- ({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl) phenyl]- 1, 3-oxazolidin-5-yl} methyl)-2-thiophene- carboxamide of formula (I)

comprising:

reacting a compound 4-{4-[(5S)-5-(aminomethyl)-2-oxo-l ,3-oxazolidin-3- yl]phenyl}morpholin-3-one of formula II

with a compound 5-Chloro-thiophene-2-carbox lic acid of formula (III)

in the presence of boric acid and / or sub. or unsub phenyl boronic acid to give the compound of formula I.

BRIEF DESCRIPTION OF THE DRAWING

Fig. 1 : is a schematic representation of the process of present invention.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to a process for the preparation of 5-chloro-N-({(5S)-2- oxo-3 - [4-(3 -oxo-4-morpholinyl) phenyl] - 1 ,3 -oxazolidin-5 -yl } methyl)-2-thiophene-carboxamide (I)·

In an embodiment of the present invention, there is provided a process for the preparation of 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl) phenyl]- 1 , 3-oxazolidin-5- yl} methyl)-2-thiophene-carboxamide of formula (I),

(I)

comprising:

reacting a compound 4-{4-[(5S)-5-(aminomethyl)-2-oxo-l,3-oxazolidin-3- yl]phenyl}morpholin-3 -one of formula II

(II)

with a compound 5-chloro-thiophene-2-carboxylic acid of formula (III)

The substituted phenyl boronic acids that can be used include but are not limited to 3,4,5- triflourophenyl boronic acid, 3,5-bis(trifluoromethyl) phenyl boronic acid, 4-nitrophenyl boronic acid, 2-iodophenyl boronic acid, 2-bromo phenyl boronic acid and the like; preferably 2- iodophenyl boronic acid.

The molar equivalents of reagent boric acid and / or sub. or unsub. phenyl boronic acid employed herein can be typically in the range from about 0.05 mole to about 5 moles on 1 mole of compound of formula III taken. Preferably, from about 0.01 mole to about 0.25 mole on 1 mole of the compound of formula III taken.

The solvents that can be used in the reaction between compound of formula II and III include but are not limited to halogenated solvents such as dichloromethane, ethylene dichloride, chloroform, chlorobenzene and the like; hydrocarbons such as toluene, xylene, n-heptane and the like; or a mixture thereof. Preferably dichloromethane or toluene is being used.

Optionally the reaction can be performed in the absence of solvent(s) i.e., neat.

The reaction can be performed at temperature typically from about 25°C to about boiling point of the solvent(s) used.

The reaction time required for the completion may range from about 24 hours to about 96 hours, preferably from about 24 hours to about 48 hours.

For example, the working-up of reaction mixtures, especially in order to isolate desired compounds, follows customary procedures, known to the organic chemists skilled in the norms of the art and steps, e.g. selected from the group comprising but not limited to extraction, neutralization, crystallization, chromatography, evaporation, drying, filtration, centrifugation and the like.

Advantageously, the process of present invention avoids the use of hazardous reagents like thionyl chloride and intermediate 5-chloro-thiophene-2-carbonyl chloride and carcinogenic reagent pyridine which were used in the process described in patent US ' 860.

The reagents used herein like boric acid or sub. or unsubstituted phenyl boronic acids are cheaper and commercially available and also does not give rise to the formation of impurities or side products unlike in prior art processes.

The process of present invention also avoids base and process step like decomposition, extractions, washings unlike processes described in prior art.

Advantageously the process is carried out in single step unlike two steps as disclosed in patent US '860.

It additionally avoids the complicated chromatographic purification of the product (I) thus making the process cost-effective and ecofriendly.

The processes reported for the preparation of rivaroxaban (I) results in the formation of various impurities and bye products leading to include additional purification steps at several stages thus resulting in very poor yields and purities of the final product.

Advantageously, the process of present invention does not involve purification steps thus provides the final product rivaroxaban with higher yields and purities.

The processes reported yields rivaroxaban (I) not more than 60%wt/wt whereas the yields of the final product by the process of present invention are usually more than 80%, more precisely, the yield is about 80% to about 90% by weight.

Advantageously, in the process of present invention optically pure compound is being obtained by using the optically pure intermediate compound of formula II and no sign of racemisation is being observed and the pure racemic compound is being obtained by using the racemic intermediate compound of formula II.

The product obtained by the process of present invention can be analyzed by the analytical methods described in Journal of medicinal chemistry 2005, vol. 48, No. 19, pg. 5900- 08. The intermediate compounds of (II), (III) are known per se to the person skilled in the art or can be prepared by customary methods. For ex. US 7,585,860 which is herein incorporated for reference.

The present invention provides simple, ecofriendly, inexpensive, reproducible, robust process for the preparation of rivaroxaban (I) which is well suited on a commercial scale.

The invention is further defined by reference to the following examples describing in detail the preparation of the composition and methods of use of the invention. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention.

EXAMPLES

Example 1: 1.625 gms of 5-chlorothiophene-2-carboxylic acid and 155mg (2.5 mmol) of boric acid and 82 ml of toluene were charged into a clean and dry R.B. flask. To the resultant clear colour less reaction mixture 3.2 g. (11 mmol) of 4-{4-[(5S)-5-(aminomethyl)-2-oxo-l,3- o azolidin-3-yl]phenyl}-mo holin-3-one (chiral purity : 99.7% ) was added. The resultant reaction mixture was heated to reflu for about 48 hours and the water formed was removed azeotropically by dean-Stark apparatus. Then, the reaction mixture was cooled to about 30°C and 10 ml of 10% sodium carbonate solution was added. The resultant reaction suspension was stirred for about 10 min. The solid separated was filtered and washed with water. To the solid 10 ml of dil. hydrochloric acid was added and stirred for 10 mins. The solid was filtered and washed with water. The solid obtained was recrystallized from acetic acid to afford rivaroxaban (I) as white crystalline solid.

Yield : 2.26 gms. (% Yield: 51.9 %); Purity by HPLC: 99.89%; Purity by Chiral HPLC: 99.7%. Example 2: 16.25g (O.lmol) of 5-chloro-thiophene-2-carboxylic acid, 3.25g (0.026 mol) of phenylboronic acid and 820 ml of toluene were charged into a clean and dry R.B. flask. To the clear colorless reaction solution 29. lg (0.1 mol) of 4-{4-[(5S)-5-(aminomethyl)-2-oxo-l,3- oxazolidin-3-yl]phenyl}-morpholin-3-one (chiral purity : 99.8% ) was added and refluxed for 48 hrs. The water formed was removed azeotropically by dean-Stark apparatus. Then, the reaction mixture was cooled to about 30°C and 100ml of 10% sodium carbonate solution was added and stirred for 10 min. The solid separated was filtered and washed with water. The solid was taken in 100 ml of dil. hydrochloric acid and was stirred for 10 min. at about 30°C. The solid filtered and washed with water. The wet solid obtained was recrystallized in acetic acid to yield rivaroxaban (I) as white crystalline solid. Yield : 32.6g, (% Yield : 74.9 %); Purity by HPLC: 99.85%; Purity by Chiral HPLC: 99.8%. Example 3: 1.625g (10 mmol) of 5-chloro-thiophene-2-carboxylic acid, 0.62g (2.5 mmol) of 2- iodophenyl boronic acid and 80 ml of toluene were charged into a clean and dry R.B flask. To the resultant clear colourless reaction solution 2.91g (lOmmol) of 4-{4-[(5S)-5-(aminomethyl)- 2-oxo-l,3-oxazolidin-3-yl]- henyl}-mo holin-3-one (chiral purity : 99.9%) was added and heated to reflux for 36 hrs. The water formed was removed azeotropically by dean-Stark apparatus. Then, the reaction mixture was cooled to about 30°C, 20 ml of water was added and stirred for 15 min at about 30°C. The solid separated was filtered and washed with water and toluene. The wet solid obtained was recrystallized in acetic acid to afford rivaroxaban (I) as white crystalline solid.

Yield: 3.6g (% Yield : 82.6%); Purity by HPLC: 99.9%. Purity by Chiral HPLC : 99.9%.

Example 4: 1.625g (10 mmol) of 5-chloro-thiophene-2-carboxylic acid, (0.248 g, (1 mmol) of 2-iodophenyl boronic acid and 50 ml of dichloromethane were charged into a clean and dry R.B flask. To the resultant clear colourless reaction solution 2.91g (lOmmol) of 4-{4-[(5S)-5- (aminomethyl)-2-oxo-l,3-oxazolidin-3-yl]-phenyl}-morpholin-3-one (chiral purity: 99.9%) was added and stirred at about 30°C for about 48 hrs. After the completion of the reaction as indicated by TLC, the solid separated was filtered and washed with dichloromethane and water. Additional material was recovered by evaporation of the filtrate. The wet solid was recrystallized in acetic acid to afford rivaraoxaban (I) as white crystalline solid.

Yield: 3.7g (% Yield : 85%); Purity by HPLC: 99.85%; Purity by Chiral HPLC: 99.9%.

Example 5: 1.625g (10 mmol) of 5-chloro-thiophene-2-carboxylic acid, 0.62g (2.5 mmol) of 2- iodophenyl boronic acid and 80 ml of toluene were charged into a clean and dry R.B Flask. To the resultant clear colourless reaction solution 2.91g (lOmmol) of 4-{4-[5-(aminomethyl)-2-oxo- l,3-oxazolidin-3-yl]-phenyl}-morpholin-3-one was added and heated to reflux for 36 hrs. The water formed was removed azeotropically by dean-Stark apparatus. Then, the reaction mixture was cooled to about 30°C, 20 ml of water was added and stirred for 15 min at about 30°C. The solid separated was filtered and washed with water and toluene. The wet solid obtained was recrystallized in acetic acid to afford racemic rivaroxaban as white crystalline solid.

Yield: 3.6g (% Yield : 82.6%); Purity by HPLC: 99.9%.

Claims

We Claim:

1) A process for the preparation of 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4- morpholinyl) phenyl]- 1, 3-oxazolidin-5-yl} methyI)-2-thiophene-carboxamide of formula (I),

(I)

comprising:

reacting a compound 4-{4-[(5S)-5-(aminomethyl)-2-oxo-l,3-oxazolidin-3- yl]phenyl}morpholin-3-one of formula II

(Π)

with a compound 5-chloro-thiophene-2-carbox lic acid of formula (III)

(III)

in the presence of boric acid and / or sub. or unsub. phenyl boronic acid to give the compound of formula I.

2) The process of claim 1, wherein the substituted phenyl boronic acids that can be used is selected from the group consisting of 3,4,5 -triflourophenyl boronic acid, 3,5- bis(trifluoromethyl) phenyl boronic acid, 4-nitrophenyl boronic acid, 2-iodophenyl boronic acid, 2-bromo phenyl boronic acid and the like; preferably 2-iodophenyl boronic acid. 3) The process of claim 1, wherein the reaction is being performed in the presence of solvent.

4) The process of claim 3, wherein the solvents being used is selected from the group consisting of halogenated solvents like dichloromethane; hydrocarbons like toluene, xylene; or a mixture thereof, preferably dichloromethane.

5) The process of claim 4, wherein the preferable solvent being employed in the reaction is toluene.

6) A process for the preparation of 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl) phenyl]-! , 3-oxazoli de of formula (I),

(I)

comprising:

reacting a compound 4-{4-[(5S)-5-(aminomethyl)-2-oxo-l,3-oxazolidin-3- yl]phenyl}morpholin-3-one of form la II

(II)

with a compound 5-chloro-thiophene-2-carboxylic acid of formula (III)

(III)

in the presence of suitable reagent to give the compound of formula I.

7) The process of claim 6, wherein the suitable reagent is boric acid and / or sub. or unsub phenyl boronic acid.