WO2014049552A2 - Process for the preparation of rivaroxaban - Google Patents

Process for the preparation of rivaroxaban Download PDF

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Publication number
WO2014049552A2
WO2014049552A2 PCT/IB2013/058897 IB2013058897W WO2014049552A2 WO 2014049552 A2 WO2014049552 A2 WO 2014049552A2 IB 2013058897 W IB2013058897 W IB 2013058897W WO 2014049552 A2 WO2014049552 A2 WO 2014049552A2
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Prior art keywords
carbonate
formula
process according
dialkyl
base
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PCT/IB2013/058897
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French (fr)
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WO2014049552A3 (en
Inventor
Mohammed Salman Hashmi
Yoginder Pal Sachdeva
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Ranbaxy Laboratories Ltd
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Ranbaxy Laboratories Ltd
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Priority to IN2600DEN2015 priority Critical patent/IN2015DN02600A/en
Priority to EP13805537.1A priority patent/EP2900663A2/en
Priority to US14/430,279 priority patent/US20150218145A1/en
Publication of WO2014049552A2 publication Critical patent/WO2014049552A2/en
Publication of WO2014049552A3 publication Critical patent/WO2014049552A3/en
Anticipated expiration legal-status Critical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the present invention provides a process for the preparation of rivaroxaban.
  • Rivaroxaban chemically is 5-chloro-N-( ⁇ (5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl) phenyl]- 1 ,3-oxazolidin-5-yl ⁇ methyl)-2-thiophenecarboxamide of Formula I.
  • Rivaroxaban is used as an anti-thrombotic agent.
  • U.S. Patent No. 7,157,456 provides rivaroxaban and processes for its preparation.
  • Example 44 of the '456 Patent provides a process of making rivaroxaban.
  • Example 44 does not disclose a step of cyclizing a compound of Formula II with a dialkyl carbonate to produce the compound of Formula I.
  • U.S. Patent No. 8,106, 192 provides a process for the preparation of rivaroxaban, wherein N- ⁇ (R)-2-hydroxy-3-[4-(3-oxomorpholin-4-yl)phenylamino]propyl ⁇ -5- chlorothiophene-2-carboxamide is treated with ⁇ , ⁇ -carbonyldiimidazole in the presence of 1 -methyl-2-pyrrolidone and toluene.
  • ⁇ , ⁇ -Carbonyldiimidazole is costly, toxic, moisture sensitive, and may produce toxic by-products during the reaction.
  • the present invention provides processes for the preparation of rivaroxaban.
  • Embodiments of the process may include one or more of the following features.
  • the compound of Formula II may be cyclized with the dialkyl carbonate in the presence of a base.
  • the dialkyl carbonate may be selected from one or more of dimethyl carbonate, diethyl carbonate, dipropyl carbonate, diisopropyl carbonate, dibutyl carbonate, or diisobutyl carbonate.
  • the base may be selected from sodium carbonate, potassium carbonate, calcium carbonate, sodium hydroxide, potassium hydroxide, or a mixture thereof.
  • the base may be added to a solution of N- ⁇ (R)-2-hydroxy-3-[4-(3- oxomorpholin-4-yl)phenylamino]propyl ⁇ -5-chlorothiophene-2-carboxamide (Formula II) in the alkyl carbonate and the mixture refluxed.
  • the process may further include the steps of (a) recovering the solvent under vacuum at 60°C to 65°C; (b) treating the solid material obtained with dichloromethane; and (c) filtering the solid material to remove any inorganic salt.
  • the process may still further include (a) recovering the solvent under vacuum; and (b) crystallizing the material obtained from dichloromethane.
  • the alkyl groups in the dialkyl carbonate may be the same or different.
  • the invention relates to a process for the preparation of rivaroxaban of Formula I
  • the process includes the steps of adding the base to a solution of N- ⁇ (R)-2-hydroxy-3-[4-(3-oxomorpholin-4-yl) phenylamino]propyl ⁇ -5-chlorothiophene-2-carboxamide (Formula II) in the alkyl carbonate and refluxing the resultant mixture;
  • Embodiments of the process may include one or more of the following steps.
  • the dialkyl carbonate may be selected from one or more of dimethyl carbonate, diethyl carbonate, dipropyl carbonate, diisopropyl carbonate, dibutyl carbonate, or diisobutyl carbonate.
  • the base may be selected from sodium carbonate, potassium carbonate, calcium carbonate, sodium hydroxide, potassium hydroxide, or a mixture thereof.
  • the solvent may be recovered under vacuum at a temperature of 60°C to 65°C.
  • the alkyl groups in the dialkyl carbonate may be the same or different.
  • a first aspect of the present invention provides a process for the preparation of rivaroxaban of Formula I
  • a second aspect of the present invention provides a process for the preparation of rivaroxaban of Formula I
  • dimethyl carbonate diethyl carbonate, dipropyl carbonate, diisopropyl carbonate, dibutyl carbonate, or diisobutyl carbonate.
  • a third aspect of the present invention provides a process for the preparation of rivaroxaban of Formula I
  • the compound of Formula II may be prepared according to the process provided in the art, for example, the process described in U.S. Patent No. 8,106,192.
  • the compound of Formula II is cyclized with a dialkyl carbonate, optionally in the presence of a base.
  • the dialkyl carbonate may be, for example, dimethyl carbonate, diethyl carbonate, dipropyl carbonate, diisopropyl carbonate, dibutyl carbonate, or diisobutyl carbonate or combinations of dialkyl carbonates. It is expected that other dialkyl carbonates in which the alkyl groups are not the same will also function in the above reaction to cyclize the compound of Formula II.
  • the dialkyl carbonate is a compound in which the alkyl groups in the dialkyl carbonate are the same.
  • the alkyl groups in the dialkyl carbonate are not the same.
  • the base may be, for example, sodium carbonate, potassium carbonate, calcium carbonate, sodium hydroxide, potassium hydroxide, or a mixture thereof.
  • the compound of Formula II may be heated with dialkyl carbonate for about 1 hour to about 8 hours above the boiling point of the alkanol produced during the reaction.
  • the product may be isolated from the mixture by methods including concentration, distillation, decantation, filtration, evaporation, centrifugation, or a combination thereof, and may further be crystallized.
  • dialkyl carbonate refers to a carbonate group flanked by two alkyl groups.
  • alkyl refers to saturated, aliphatic hydrocarbon groups, either straight or branched-chain, containing from one to four carbon atoms, as exemplified by methyl, ethyl, propyl, isopropyl, butyl, or isobutyl.
  • alkanol refers to an “alkyl” as defined above containing at least one hydroxyl group.
  • the diethyl carbonate may be replaced by any of dimethyl carbonate, dipropyl carbonate, diisopropyl carbonate, dibutyl carbonate, diisobutyl carbonate or other dialkyl carbonate.
  • the base used in the example, potassium carbonate may be replaced by sodium carbonate, calcium carbonate, sodium hydroxide, potassium hydroxide, or a mixture thereof.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Description

PROCESS FOR THE PREPARATION OF RIVAROXABAN
Field of the Invention
The present invention provides a process for the preparation of rivaroxaban.
Background of the Invention
Rivaroxaban chemically is 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl) phenyl]- 1 ,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide of Formula I.
Figure imgf000002_0001
Formula I
Rivaroxaban is used as an anti-thrombotic agent.
U.S. Patent No. 7,157,456 provides rivaroxaban and processes for its preparation. Example 44 of the '456 Patent provides a process of making rivaroxaban. However, Example 44 does not disclose a step of cyclizing a compound of Formula II with a dialkyl carbonate to produce the compound of Formula I.
U.S. Patent No. 8,106, 192 provides a process for the preparation of rivaroxaban, wherein N- {(R)-2-hydroxy-3-[4-(3-oxomorpholin-4-yl)phenylamino]propyl}-5- chlorothiophene-2-carboxamide is treated with Ν,Ν-carbonyldiimidazole in the presence of 1 -methyl-2-pyrrolidone and toluene. Ν,Ν-Carbonyldiimidazole is costly, toxic, moisture sensitive, and may produce toxic by-products during the reaction.
The prior art processes for the preparation of rivaroxaban make use of chromatography or reagents that are costly, unstable, and have safety concerns.
Accordingly, these processes are not suitable at industrial scale.
The present inventors have developed a simple, safe, efficient, economical, industrially feasible process that provides rivaroxaban in good yield. Summary of the Invention
The present invention provides processes for the preparation of rivaroxaban.
In one general aspect, a process for the preparation of rivaroxaban of Formula I
Figure imgf000003_0001
Formula I
Includes a step of cyclizing a compound of Formula II
Figure imgf000003_0002
Formula II
with a dialkyl carbonate.
Embodiments of the process may include one or more of the following features. For example, the compound of Formula II may be cyclized with the dialkyl carbonate in the presence of a base. The dialkyl carbonate may be selected from one or more of dimethyl carbonate, diethyl carbonate, dipropyl carbonate, diisopropyl carbonate, dibutyl carbonate, or diisobutyl carbonate. The base may be selected from sodium carbonate, potassium carbonate, calcium carbonate, sodium hydroxide, potassium hydroxide, or a mixture thereof.
In the process, the base may be added to a solution of N- {(R)-2-hydroxy-3-[4-(3- oxomorpholin-4-yl)phenylamino]propyl} -5-chlorothiophene-2-carboxamide (Formula II) in the alkyl carbonate and the mixture refluxed.
The process may further include the steps of (a) recovering the solvent under vacuum at 60°C to 65°C; (b) treating the solid material obtained with dichloromethane; and (c) filtering the solid material to remove any inorganic salt. The process may still further include (a) recovering the solvent under vacuum; and (b) crystallizing the material obtained from dichloromethane. In the process, the alkyl groups in the dialkyl carbonate may be the same or different.
In another general aspect, the invention relates to a process for the preparation of rivaroxaban of Formula I
Figure imgf000004_0001
Formula I
using a process that includes cyclizing a compound of Formula II
Figure imgf000004_0002
Formula II
with a dialkyl carbonate in the presence of a base. The process includes the steps of adding the base to a solution of N- {(R)-2-hydroxy-3-[4-(3-oxomorpholin-4-yl) phenylamino]propyl}-5-chlorothiophene-2-carboxamide (Formula II) in the alkyl carbonate and refluxing the resultant mixture;
recovering the solvent under vacuum;
treating the solid material obtained with dichloromethane;
filtering the solid material to remove any inorganic salt;
recovering the solvent under vacuum; and
crystallizing the material obtained from dichloromethane.
Embodiments of the process may include one or more of the following steps. For example, the dialkyl carbonate may be selected from one or more of dimethyl carbonate, diethyl carbonate, dipropyl carbonate, diisopropyl carbonate, dibutyl carbonate, or diisobutyl carbonate. The base may be selected from sodium carbonate, potassium carbonate, calcium carbonate, sodium hydroxide, potassium hydroxide, or a mixture thereof. In the process, the solvent may be recovered under vacuum at a temperature of 60°C to 65°C.
In the process, the alkyl groups in the dialkyl carbonate may be the same or different.
Detailed Description of the Invention
A first aspect of the present invention provides a process for the preparation of rivaroxaban of Formula I
Figure imgf000005_0001
Formula I
wherein the process comprises cyclizing a compound of Formula II
Figure imgf000005_0002
Formula II
with a dialkyl carbonate.
A second aspect of the present invention provides a process for the preparation of rivaroxaban of Formula I
Figure imgf000005_0003
Formula I
wherein the process comprises cyclizing a compound of Formula II
Figure imgf000006_0001
Formula II
with dimethyl carbonate, diethyl carbonate, dipropyl carbonate, diisopropyl carbonate, dibutyl carbonate, or diisobutyl carbonate.
A third aspect of the present invention provides a process for the preparation of rivaroxaban of Formula I
Figure imgf000006_0002
Formula I
wherein the process comprises cyclizing a compound of Formula II
Figure imgf000006_0003
Formula II
with a diethyl carbonate.
The compound of Formula II may be prepared according to the process provided in the art, for example, the process described in U.S. Patent No. 8,106,192. The compound of Formula II is cyclized with a dialkyl carbonate, optionally in the presence of a base. The dialkyl carbonate may be, for example, dimethyl carbonate, diethyl carbonate, dipropyl carbonate, diisopropyl carbonate, dibutyl carbonate, or diisobutyl carbonate or combinations of dialkyl carbonates. It is expected that other dialkyl carbonates in which the alkyl groups are not the same will also function in the above reaction to cyclize the compound of Formula II. Therefore in one general aspect, the dialkyl carbonate is a compound in which the alkyl groups in the dialkyl carbonate are the same. In another general aspect, the alkyl groups in the dialkyl carbonate are not the same. The base may be, for example, sodium carbonate, potassium carbonate, calcium carbonate, sodium hydroxide, potassium hydroxide, or a mixture thereof. The compound of Formula II may be heated with dialkyl carbonate for about 1 hour to about 8 hours above the boiling point of the alkanol produced during the reaction. The product may be isolated from the mixture by methods including concentration, distillation, decantation, filtration, evaporation, centrifugation, or a combination thereof, and may further be crystallized.
The term "dialkyl carbonate", as used herein, refers to a carbonate group flanked by two alkyl groups.
The term "alkyl", as used herein, refers to saturated, aliphatic hydrocarbon groups, either straight or branched-chain, containing from one to four carbon atoms, as exemplified by methyl, ethyl, propyl, isopropyl, butyl, or isobutyl.
The term "alkanol", as used herein, refers to an "alkyl" as defined above containing at least one hydroxyl group.
The term "about", as used herein, when used along with values assigned to certain measurements and parameters means a variation of up to 10% from such values, or in case of a range of values, means up to a 10% variation from both the lower and upper limits of such ranges.
While the present invention has been described in terms of its specific
embodiments, certain modifications and equivalents will be apparent to those skilled in the art, and are intended to be included within the scope of the present invention.
EXAMPLE
Preparation of 5-Chloro-N-i K5S V2-Oxo-3 - Γ4-Γ3 -Oxo-4-MorpholinvnPhenyll - 1.3- Oxazolidin-5-Yl}Methyl)-2-Thiophenecarboxamide (Formula I)
Potassium carbonate (0.64 g; 4.6 mmoles) was added to a solution of N- {(R)-2- hydroxy-3-[4-(3-oxomorpholin-4-yl)phenylamino]propyl}-5-chlorothiophene-2- carboxamide (Formula II; 1 g; 2.24 mmoles) in diethyl carbonate (4 mL). The mixture was refluxed for 4 hours. The solvent was recovered under vacuum at 60°C to 65°C. The solid material obtained was treated with dichloromethane (10 mL) and filtered to remove the inorganic salt. The solvent was recovered under vacuum at 35°C and the material obtained was crystallized from dichloromethane (5 mL).
Yield = 0.9 g (85%).
It should be understood that variations in the above processes are contemplated. For example, the diethyl carbonate may be replaced by any of dimethyl carbonate, dipropyl carbonate, diisopropyl carbonate, dibutyl carbonate, diisobutyl carbonate or other dialkyl carbonate. Similarly, the base used in the example, potassium carbonate, may be replaced by sodium carbonate, calcium carbonate, sodium hydroxide, potassium hydroxide, or a mixture thereof.

Claims

We Claim:
1. A process for the preparation of rivaroxaban of Formula I
Figure imgf000009_0001
Formula I
wherein the process comprises cyclizing a compound of Formula II
Figure imgf000009_0002
Formula II
with a dialkyl carbonate.
2. The process according to claim 1, wherein the compound of Formula II is cyclized with the dialkyl carbonate in the presence of a base.
3. The process according to claim 1 , wherein the dialkyl carbonate is selected from one or more of dimethyl carbonate, diethyl carbonate, dipropyl carbonate, diisopropyl carbonate, dibutyl carbonate, or diisobutyl carbonate.
4. The process according to claim 2, wherein the dialkyl carbonate is selected from one or more of dimethyl carbonate, diethyl carbonate, dipropyl carbonate, diisopropyl carbonate, dibutyl carbonate, or diisobutyl carbonate.
5. The process according to claim 2, wherein the base is selected from sodium carbonate, potassium carbonate, calcium carbonate, sodium hydroxide, potassium hydroxide, or a mixture thereof.
6. The process according to claim 2, wherein the base is added to a solution of N- {(R)-2-hydroxy-3-[4-(3-oxomorpholin-4-yl)phenylamino]propyl} -5-chlorothiophene-2- carboxamide (Formula II) in the alkyl carbonate and the mixture refluxed.
7. The process according to claim 6, further comprising:
recovering the solvent under vacuum at 60°C to 65°C;
treating the solid material obtained with dichloromethane; and filtering the solid material to remove any inorganic salt.
8. The process according to claim 7, further comprising:
recovering the solvent under vacuum; and
crystallizing the material obtained from dichloromethane.
9. The process according to claim 1, wherein the alkyl groups in the dialkyl carbonate are the same.
10. A process for the preparation of rivaroxaban of Formula I
Figure imgf000010_0001
Formula I
wherein the process comprises cyclizing a compound of Formula II
Figure imgf000010_0002
Formula II
with a dialkyl carbonate in the presence of a base, the method comprising:
adding the base to a solution of N- {(R)-2-hydroxy-3-[4-(3-oxomorpholin-4-yl) phenylamino]propyl} -5-chlorothiophene-2-carboxamide (Formula II) in the alkyl carbonate and refluxing the resultant mixture;
recovering the solvent under vacuum;
treating the solid material obtained with dichloromethane;
filtering the solid material to remove any inorganic salt;
recovering the solvent under vacuum; and
crystallizing the material obtained from dichloromethane.
1 1. The process according to claim 10, wherein the dialkyl carbonate is selected from one or more of dimethyl carbonate, diethyl carbonate, dipropyl carbonate, diisopropyl carbonate, dibutyl carbonate, or diisobutyl carbonate.
12. The process according to claim 10, wherein the base is selected from sodium carbonate, potassium carbonate, calcium carbonate, sodium hydroxide, potassium hydroxide, or a mixture thereof.
13. The process according to claim 10, wherein the solvent is recovered under vacuum at 60°C to 65°C.
14. The process according to claim 10, wherein the alkyl groups in the dialkyl carbonate are the same.
PCT/IB2013/058897 2012-09-26 2013-09-26 Process for the preparation of rivaroxaban Ceased WO2014049552A2 (en)

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IN2600DEN2015 IN2015DN02600A (en) 2012-09-26 2013-09-26
EP13805537.1A EP2900663A2 (en) 2012-09-26 2013-09-26 Process for the preparation of rivaroxaban
US14/430,279 US20150218145A1 (en) 2012-09-26 2013-09-26 Process for the preparation of rivaroxaban

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IN3005DE2012 2012-09-26
IN3005/DEL/2012 2012-09-26

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016030669A1 (en) * 2014-08-25 2016-03-03 Cipla Limited Process for the preparation of rivaroxaban

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7157456B2 (en) 1999-12-24 2007-01-02 Bayer Healthcare Ag Substituted oxazolidinones and their use in the field of blood coagulation
US8106192B2 (en) 2003-01-07 2012-01-31 Bayer Pharma Aktiengesellschaft Method for producing 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide

Family Cites Families (5)

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Publication number Priority date Publication date Assignee Title
DE2655369A1 (en) * 1976-12-03 1978-06-08 Schering Ag 5- (SUBST. PHENYL) -OXAZOLIDINONE AND THEIR SULFUR ANALOGS AND PROCESS FOR THEIR PRODUCTION
EP2354128A1 (en) * 2010-02-10 2011-08-10 Sandoz Ag Method for the preparation of rivaroxaban
US20130253187A1 (en) * 2010-09-14 2013-09-26 Medichem, S.A. Process for Determining the Suitability for Distribution of a Batch of Thiophene-2-Carboxamide Derivative
WO2013046211A1 (en) * 2011-09-27 2013-04-04 Symed Labs Limited Processes 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 and intermediates thereof
WO2013164833A1 (en) * 2012-05-02 2013-11-07 Symed Labs Limited Improved process for preparing rivaroxaban using novel intermediates

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7157456B2 (en) 1999-12-24 2007-01-02 Bayer Healthcare Ag Substituted oxazolidinones and their use in the field of blood coagulation
US8106192B2 (en) 2003-01-07 2012-01-31 Bayer Pharma Aktiengesellschaft Method for producing 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016030669A1 (en) * 2014-08-25 2016-03-03 Cipla Limited Process for the preparation of rivaroxaban

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IN2015DN02600A (en) 2015-09-18
US20150218145A1 (en) 2015-08-06
EP2900663A2 (en) 2015-08-05
WO2014049552A3 (en) 2014-05-15

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