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Preparation methods for rivaroxaban and intermediate thereof, and intermediate compounds

A technology for rivaroxaban and compounds is applied in the preparation of rivaroxaban and its intermediates, as well as in the field of intermediate compounds, and can solve problems such as tediousness, potential safety hazards, and unfavorable industrialized production.

Active Publication Date: 2013-04-03
联化科技(上海)有限公司 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0021] The technical problem to be solved by the present invention is to overcome the harsh operating conditions in the existing preparation methods of rivaroxaban and its intermediates, which are not conducive to industrial production, have high requirements for equipment, have certain potential safety hazards, and have low yields. , difficult separation of by-products, high cost, unavailable chiral raw materials and cumbersome processes, etc., and provides a preparation method of rivaroxaban and its intermediates and its intermediates

Method used

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  • Preparation methods for rivaroxaban and intermediate thereof, and intermediate compounds
  • Preparation methods for rivaroxaban and intermediate thereof, and intermediate compounds
  • Preparation methods for rivaroxaban and intermediate thereof, and intermediate compounds

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0069] Example 1 (S)-4-(4-(5-((dibenzylamino)methyl)-2-oxooxazolidin-3-yl)phenyl)morpholinyl-3-one (compound 4) Preparation

[0070] tert-butoxycarbonyl-4-(3-oxomorpholinyl)aniline (100.0g, 0.34mol) was added to 500mL DMF, cooled to 0-10°C, and lithium tert-butoxide / THF (410.0g, 1.03mol ), the temperature of the control material is lower than 20°C, and the dripping is completed in half an hour. Add (S)-1-chloro-3-(dibenzylamino)-propan-2-ol (129.0g, 0.45mol) to control the temperature of the feed liquid below 45°C, raise the temperature to 40-50°C, and maintain the reaction for 40 hours until the reaction is complete. After cooling to room temperature, 250 mL of ammonium chloride aqueous solution and 100 mL of methanol were added, the feed solution was cooled to -20°C and stirred for 3 hours, filtered, washed with ice methanol, and dried to obtain 123.1 g of a white solid with a yield of 76.9%.

[0071] 1 H NMR (300MHz, CDCl 3 )δ: 2.86 (m, 2H, CHC H 2 N), 3.51 (m, 2H, N...

Embodiment 2

[0073] Example 2 (S)-4-(4-(5-((dibenzylamino)methyl)-2-oxooxazolidin-3-yl)phenyl)morpholinyl-3-one (compound 4) Preparation

[0074] tert-butoxycarbonyl-4-(3-oxomorpholinyl)aniline (0.29g, 1mmol) was added to 5mL DMF (N,N-dimethylformamide), and the nitrogen gas was exhausted, and the temperature of the feed solution was reduced to -10~ At 0°C, 2.5 mL of lithium tert-butoxide (2.5 mmol) tetrahydrofuran solution was added dropwise, and the mixture was naturally raised to room temperature (25°C) and stirred for 2 hours. (S)-1-Chloro-3-(dibenzylamino)-propan-2-ol (0.32 g, 1.1 mmol) was added, and the reaction was maintained at room temperature for 20 hours until the reaction was complete. Saturated ammonium chloride aqueous solution and ethyl acetate were added, and the layers were separated. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered, and evaporated to dryness to obtain 0.32 g of a white solid, with a yield of 67.94%.

[0075] HP...

Embodiment 3

[0076] Example 3 (S)-4-(4-(5-((dibenzylamino)methyl)-2-oxooxazolidin-3-yl)phenyl)morpholinyl-3-one (compound 4) Preparation

[0077] tert-butoxycarbonyl-4-(3-oxomorpholinyl)aniline (0.29g, 1mmol) and lithium tert-butoxide (0.19g, 2.4mmol) were added to 10mL of tetrahydrofuran, exhausted with nitrogen, and stirred at room temperature for 2 hours. (S)-1-Chloro-3-(dibenzylamino)-propan-2-ol (0.32 g, 1.1 mmol) was added, and the feed solution was heated to 60° C. for 8 hours until the reaction was complete. Saturated ammonium chloride aqueous solution and ethyl acetate were added, and the layers were separated. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered, and evaporated to dryness to obtain 0.34 g of off-white solid with a yield of 72.18%.

[0078] HPLC: 96.35%. The NMR data is the same as in Example 1.

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Abstract

The present invention discloses a preparation method for a rivaroxaban intermediate compound represented by a formula 5, wherein the preparation method comprises the following steps: carrying out a benzyl group removing reaction of a compound 4 in a solvent to prepare a compound 5. The present invention further discloses a rivaroxaban preparation method and intermediate compounds. According to the preparation method, chiral raw materials are easy to obtain, and have cheap price, the process is simple, the post treatment is simple, the intermediate and the final product are easy to purify, the total yield is high, the purity is high, and industrial production is easily achieved.

Description

technical field [0001] The present invention specifically relates to a preparation method of rivaroxaban and its intermediate, as well as the intermediate compound. Background technique [0002] Rivaroxaban, the English name is Rivaroxaban, the chemical name is 5-chloro-N-[[(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl] -5-oxazolyl]methyl]-2-thiophenecarboxamide, its structural formula is as follows. [0003] [0004] Rivaroxaban is the world's first oral direct factor Xa inhibitor developed by Bayer / Johnson & Johnson. In October 2008, it was approved for marketing in Canada and the European Union under the product name Xarelto. In March 2009, the US FDA Advisory Committee agreed that the clinical data of rivaroxaban has a good benefit-risk ratio. At present, rivaroxaban has been registered and approved in Canada, the European Union, South America, China, Australia and other countries and regions. In the second half of 2009, a launch conference was held in China, and the...

Claims

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Application Information

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IPC IPC(8): C07D413/10C07D413/14C07D265/32C07D303/36C07C215/08C07C213/04
CPCY02P20/55
Inventor 王萍潘强彪李杨州郑道亮邹本立彭寅生
Owner 联化科技(上海)有限公司
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