Facile approach for the synthesis of rivaroxaban using alternate synthon: reaction, crystallization and isolation in single pot to achieve desired yield, quality and crystal form

Sustainable Chemical Processes

Vijayavitthal T Mathad¹  Vijay J Medhane²  Priyank I Patel¹  Hitesh D Lad¹  Divyesh R Joshi¹  Dattatray G Deshmukh¹  Anil C Mali¹ 

[1]Department of Process Research and Development, Megafine Pharma (P) Ltd., 201, Lakhmapur, Dindori, Nashik 422 202, Maharashtra, India

[2]Department of Chemistry, Organic Chemistry Research Center, K. T. H. M College, Nashik 422 002, Maharashtra, India

关键词: 4-Nitrophenyl 5-chlorothiophene-2-carboxylate;    Crystallization;    Polymorph;    Anti-coagulant drug;    Rivaroxaban;   

Others  :  1219791
DOI  :  10.1186/s40508-015-0036-3

 received in 2015-04-27, accepted in 2015-06-03,  发布年份 2015

【 摘 要 】

An efficient and high yielding process for the production of impurity free rivaroxaban (1), an anti-coagulant agent using alternate synthon is reported. The key components of the process involve; synthesis of 4-(4-aminophenyl)-3-morpholinone (5) using easily available inexpensive nitro aniline (17), condensation of 4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one hydrochloride (9) with alternate synthon 4-nitrophenyl 5-chlorothiophene-2-carboxylate (11) in dimethylsulfoxide (DMSO) as a solvent and triethylamine as a base and isolation of the rivaroxaban (1) by designing the crystallization in same reaction pot using specific combination of acetonitrile and methanol as anti-solvents to obtain highly pure rivaroxaban (1) with desired ploymorphic form with an overall yield of around 22% (Calculated from 17). The developed process avoids the use of hazardous chemicals, critical operations and tedious work-ups. Potential impurities arouse during the reaction at various stages and carry-over impurities from starting materials were controlled selectively by designing reaction conditions and tuning the crystallization parameters.

【 授权许可】

   
2015 Mali et al.

【 图 表 】

Figure1.

【 参考文献 】

• [1]Drug index. Xarelto (Rivaroxaban film coated oral tablet); Drug information, desription, user reviews, drug side effects, interactions—prescribing information at Rx List. http://www.rxlist.com/xarelto-drug.htm. Accessed June 2015
• [2]Highlights of prescribing information of XARELTO, rivaroxaban, Extended-Release tablets. http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/202439s001lbl.pdf. Accessed 2011
• [3]Susanne R, Alexander S, Jens P, Thomas L, Josef P, Karl-Heinz S, et al.: Discovery of the novel antithrombotic agent 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)thiophene-2-carboxamide (BAY 59-7939): an oral, direct factor Xa inhibitor. J Med Chem 2005, 48:5900-5908.
• [4]Alexander S, Thomas L, Jens P, Susanne R, Elisabeth P et al (2009) Substituted Oxazolidinones and Their Use in the Field of Blood Coagulation. U.S. Patent 7,576,111
• [5]Rafecas JL, Comely AC, Ferrali A, Amelacortes C, Pasto AM (2011) Process for the preparation of rivaroxaban and intermediates thereof. PCT Int Appl WO2011080341 A1
• [6]Silvo Z, Anica P (2011) Processes for crystallization of rivaroxaban. PCT Int Appl WO2011012321 A1
• [7]Sturm H, Desouza D, Knepper K, Alert M (2011) Method for the preparation of rivaroxaban. PCT Int Appl WO2011098501 A1
• [8]Bodhauri P, Weeratunga G (2012) Processes for the preparation of rivaroxaban and intermediates thereof. PCT Int Appl WO2012051692 A1
• [9]Eva S, Gyorgyi KL, Balazs H, Balazs V, Gyorgy K, Gyorgy R et al (2012) Process for the preparation of a rivaroxaban and intermediates formed in said process. PCT Int Appl WO2012153155 A1
• [10]Rodriguez B, Olondriz M, Soldevilla L, Comas S (2012) Process for obtaining rivaroxaban and intermediate thereof. PCT Int Appl WO2012159992 A1
• [11]Singh PK, Hashmi MS, Sachdeva YP, Khanduri CH (2013) Process for the preparation of rivaroxaban and intermediates thereof. PCT Int Appl WO2013156936 A1
• [12]Halama A, Krulis R, Brichac J (2013) A process for the preparation of rivaroxaban based on saving of 1, 1′-carbonyl diimidazole. PCT Int Appl WO2013120464 A1
• [13]Dwivedi SD, Prasad A, Pal DR, Sharma MHP, Jain KN, Patel NB (2013) Processes and intermediates for preparing rivaroxaban. PCT Int Appl WO2013098833 A2
• [14]Rao MD, Reddy VB (2013) Improved process for preparing rivaroxaban using novel intermediates. PCT Int Appl WO2013164833 A1
• [15]Rao MD, Reddy VB (2013) 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. PCT Int Appl WO2013118130 A1
• [16]Keshav SP, Bhise SS, Kamble HH, Chaudhari G, Patil DS (2014) Process for the preparation of rivaroxaban. PCT Int Appl WO2014155259 A2
• [17]Pradhan NS, Patil NS, Walavalkar RR, Kulkarni NS, Pawar SB, Pawar TS (2014) Rivaroxaban intermediate and preparation thereof. PCT Int Appl WO2014102820 A2
• [18]Silvo Z, Primoz B (2014) A process for preparation of rivaroxaban. PCT Int Appl WO2014096214 A1
• [19]Pradhan NS, Patil NS, Walavalkar RR, Kulkarni NS, Pawar SB, Pawar TS (2014) Aldehyde derivative of substitute oxazolidinones. PCT Int Appl WO2014102822 A2
• [20]ICH Harmonized Tripartite Guideline. Impurities: guideline for residual solvents, Q3C (R5). http://www.ich.org/products/guidelines/quality/quality-single/article/impurities-guidline-for-residual-solvents.html. Accessed 3 Jan 2013
• [21]Grunenburg A, Lenz J, Braun GA, Keil B, Thomas CR (2010) Novel polymorphous form and the amorphous form of 5-chloro-n-({(5s)-2-oxo-3[4-(3-oxo-4-morpholinyl(-phenyl]-1,3-oxazolidine-5-yl}-methyl)-2-thiophene carboxamide. US Patent 20100152189 A1
• [22]Mathad VT (2013)  Crystallization: theory and/vs. practice—few case studies’, a presentation made in Crystallization-2013, held on 16–17 April 2013 by UBM/CPHI-India at Mumbai, India
• [23]Mathad VT, Joshi DR, Lad HD, Patel PI (2012) A process for production of 4-(4-aminophenyl)-3-morpholinone. IN patent 3478/MUM/2012
• [24]ACS GCI Pharmaceutical Roundtable. Green Chemistry Reporting Requirements for an Electronic Laboratory Notebook (ELN); http://portal.acs.org/portal/PublicWebsite/greenchemistry/industriainnovation/roundtable/CNBP_026687. Accessed 2011