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Process for the preparation of rivaroxaban and intermediates thereof

A technology of rivaroxaban and compounds, applied in organic chemistry and other directions, can solve problems such as danger

Inactive Publication Date: 2012-12-12
ENANTIA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

As previously disclosed, the art has so far provided hazardous, multi-step and complex methods for obtaining rivaroxaban

Method used

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  • Process for the preparation of rivaroxaban and intermediates thereof
  • Process for the preparation of rivaroxaban and intermediates thereof
  • Process for the preparation of rivaroxaban and intermediates thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0084] Embodiment 1: Preparation of 4-phenylmorpholin-3-ketone

[0085]

[0086] To a solution of 2-aniline ethanol (6.0 mL, 47.8 mmol) in IPA (6 mL) heated to 40° C. was simultaneously added dropwise chloroacetyl chloride (11.4 mL, 143.4 mmol) and 10 N NaOH (29.6 mL, 296 mmol), keeping A pH of about 7-8. After the addition, the mixture was stirred at 40° C. for 10 min, cooled to 0° C. and stirred at this temperature for 1 hour. The white solid was collected by filtration, washed with cold water and dried to give 4-phenylmorpholin-3-one (5.27 g, 62%) as a white solid. 1 H NMR (400MHz, CDCl 3 )δ7.42(t, J=8.0Hz, 2H), 7.34-7.27(m, 3H), 4.35(s, 2H), 4.04(t, J=5.2Hz, 2H), 3.77(t, J=5.2 Hz, 2H).

Embodiment 2

[0087] Embodiment 2: Preparation of 4-(4-nitrophenyl) morpholin-3-one (compound XI)

[0088]

[0089] To 4-phenylmorpholin-3-one (19.9 g, 0.11 moles) cooled to -10 ° C in 95% H 2 SO 4 (46.6 mL) was carefully added dropwise with 65% HNO over 45 minutes 3 (8 mL). The obtained red solution was stirred at this temperature for 1 h and H 2 O (110 mL). The mixture was washed with 35% NH 4 OH is neutralized to pH=7. The resulting precipitate was filtered, washed with cold water and dried to yield 4-(4-nitrophenyl)morpholin-3-one (or compound XI) as a brown solid (20 g, 83%). 1 H NMR (200MHz, CDCl 3 )δ8.27(d,J=9.4Hz,2H),7.62(d,J=9.4Hz,2H),4.38(s,2H),4.08(t,J=5.0Hz,2H),3.85(t, J=5.0Hz, 2H).

Embodiment 3

[0090] Embodiment 3: Preparation 4-(4-aminophenyl) morpholin-3-ketone (compound X)

[0091]

[0092] To a THF solution (200 mL) of 4-(4-nitrophenyl)morpholin-3-one (19.9 g, 89.5 mmol) was added Pd / C (5%) (1.7 g, water content: 58%). H 2 Filled, the mixture was stirred at 70 °C and 3 bar pressure for 6.5 h. Upon completion of the reaction (by HPLC-MS), more Pd / C (900 mg) was added and the mixture was stirred under the same reaction conditions until all starting material was consumed. The catalyst was filtered through celite, and the filtrate was concentrated to give 4-(4-aminophenyl)morpholine-3 (or compound X) (15.3 g, 89%) as a brown solid. 1 H NMR (400MHz, CDCl 3 )δ7.07(d,J=8.8Hz,2H),6.69(d,J=8.8Hz,2H),4.32(s,2H),4.00(t,J=4.8Hz,2H),3.72(bs, 2H), 3.69 (t, J=4.8Hz, 2H).

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Abstract

A process for the preparation of rivaroxaban, or a pharmaceutically acceptable salt thereof, or a solvate thereof, including a hydrate, comprising submitting an amine compound of formula (III) wherein R1 is a (C4-C10)-alkyl radical which is attached to the N atom by a tertiary C atom, first to an acylation reaction and then to a dealkylation reaction.

Description

[0001] The present invention relates to a process for the preparation of rivaroxaban and some novel intermediates for said process. Background technique [0002] Rivaroxaban is a registered trademark 5-Chloro-N-{[(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)benzene base] International Nonproprietary Name (INN) of oxazolidin-5-yl)methyl)thiophene-2-carboxamide. The CAS accession number is 366789-02-8. Rivaroxaban is currently used as an antithrombotic agent. [0003] The structure of rivaroxaban corresponds to formula (I): [0004] [0005] Rivaroxaban was first disclosed in patent EP 1261606. Rivaroxaban is synthesized via 4-(4-aminophenyl)-3-morpholinone with terminal epoxides such as 2-((oxiran-2-yl)methyl)isoindoline- 1,3-Diketone or 5-chloroN-((oxiran-2-yl)methyl)thiophene-2-carboxamide reacts with subsequent formation of oxazolidinone was proposed. 4-(4-((S)-5-(aminomethyl)-2-oxo For the preparation of oxazolidin-3-yl)phenyl)morpholin-3-one refer to Brickner et al...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D413/10C07D413/14
CPCC07D413/14C07D413/10
Inventor L·拉费卡斯雅内A·C·科梅利A·费拉利C·阿梅拉科尔特斯M·帕斯托阿吉拉
Owner ENANTIA
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