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Synthesizing and refining methods of rivaroxaban

A synthetic method, the technology of rivaroxaban, applied in the field of synthesis and refinement of rivaroxaban, can solve the problems of unfriendly environment, increased temperature control cost, cumbersome operation, etc., to be beneficial to industrial production and reduce temperature control cost , good response effect

Inactive Publication Date: 2019-08-27
SUZHOU ERYE PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The reaction solution is added to water for beating, but ice bath crystallization is required, which increases the cost of temperature control, and the solvent DMF is compatible with beating in water, which is easy to cause DMF residue, which adds trouble to subsequent drying and impurity removal
[0013] Patent CN102250076A adopts column chromatography for refining, high production cost and cumbersome operation
Patent CN200480040552 post-processing refining conditions are relatively high, need to be heated to above 100 ℃, increase energy consumption, low safety, and need repeated refining to get qualified samples
CN1906191B recrystallization uses acetic acid as a solvent, which is greatly restricted in the use of GMP workshops and has adverse effects on equipment and operators
It is not suitable to remove DMF and DMSO residues in the finished product, and they are highly toxic and unfriendly to the environment

Method used

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  • Synthesizing and refining methods of rivaroxaban
  • Synthesizing and refining methods of rivaroxaban
  • Synthesizing and refining methods of rivaroxaban

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0045] (1) Preparation of crude product of rivaroxaban

[0046] At room temperature, add 650g of N,N-dimethylformamide (DMF) into the reaction flask, start stirring, cool down to 0°C, then add 40g of compound (LF-II), 73g of compound (SMI), 39.7g of CDI , the reaction solution is in a suspended state; temperature control is 0-5°C, and 67.6g of triethylamine is added dropwise to the reaction solution, and the internal temperature of the reaction solution is controlled at 0-5°C during the dropwise addition. to room temperature (20-25° C.), insulated and stirred for 2 hours. Suction filtration, the filter cake was washed with 80 g of DMF, the filtrate was added to 1200 g of water, stirred and crystallized at room temperature for 2 hours. Centrifuge the slurry mixture with a centrifuge until the flow is stopped, wash the reaction bottle with 500 g of purified water, and centrifuge the combined washings until the flow is stopped to obtain crude rivaroxaban.

[0047] (2) Refining ...

Embodiment 2

[0050] (1) Preparation of crude rivaroxaban At room temperature, add 600g of N,N-dimethylformamide (DMF) to the reaction flask, start stirring, cool down to 0°C, and then add 36g of compound (LF-II) in sequence , 65.5g compound (SMI), 39g CDI, the reaction solution is in a suspension state, and the temperature is controlled at 0-5°C. Add 60g of triethylamine dropwise to the reaction liquid, and control the internal temperature of the reaction liquid at 0-5°C during the dropwise addition. After the drop is complete, keep stirring for 30 minutes, then raise the temperature to room temperature (20-25°C), and keep stirring for 1.5 hours. Suction filtration, the filter cake was washed with 50g DMF, the filtrate was added to 1000g water, stirred and crystallized at room temperature for 1.5h. Centrifuge the slurry mixture with a centrifuge until the flow is stopped, wash the reaction bottle with 300 g of purified water, and centrifuge the combined washings until the flow is stopped t...

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Abstract

The invention relates to the field of pharmaceutical chemistry, and provides synthesizing and refining methods of rivaroxaban. The synthesis method comprises a step 1) of performing condensation reaction on 4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one(LF-II) and 5-chlorothiophene-2-carboxylic acid (SMI) under an alkaline system to prepare crude rivaroxaban; the refining method further comprises a step 2) of stirring and crystallizing the crude rivaroxaban and an alcohol solution at room temperature to obtain high-purity refined rivaroxaban which meets requirements of desired crystal form. The synthesizing and refining methods are simple in operation of preparation processes, high in yield, low in pollution, and suitable for large-scale industrial production.

Description

technical field [0001] The invention belongs to the field of drug synthesis, in particular to a method for synthesizing and refining rivaroxaban. Background technique [0002] Rivaroxaban (I), English name: Rivaroxaban. Its chemical name is: 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidine -5-yl}methyl)-2-thiophenecarboxamide, its molecular formula is: C 19 h 18 ClN 3 o 5 S. [0003] [0004] Rivaroxaban is a high-efficiency selective factor Xa inhibitor jointly developed by Bayer and Johnson & Johnson. It was approved for marketing in Canada and the European Union in 2008 under the trade name Xarelto. It was officially launched in China in June 2009, and was approved by the US FDA in July 2011. Rivaroxaban is the first oral direct factor Xa inhibitor in the world. It can directly inhibit factor Xa in free or bound state with high selectivity and produce anticoagulant effect. It has high bioavailability and wide spectrum of treatment diseas...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D413/14
CPCC07D413/14C07B2200/13
Inventor 张立冬刘志陈冲顾丰石洵予王蓓陆夕明
Owner SUZHOU ERYE PHARMA CO LTD
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