Novel synthetic process for rivaroxaban

A compound, nitrophenyl technology, applied in the field of heterocyclic chemistry and nitrogen-oxygen heterocyclic chemistry, can solve the problems of difficulty in separation and purification, difficult industrialization, and high toxicity of reagents, and achieves high reaction yield, less by-products, easy to use. The effect of purification

Active Publication Date: 2014-10-15
浙江四维医药科技有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0017] The purpose of the present invention is to overcome the disadvantages of the reagents used in the above-mentioned prior art that are highly tox

Method used

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  • Novel synthetic process for rivaroxaban
  • Novel synthetic process for rivaroxaban
  • Novel synthetic process for rivaroxaban

Examples

Experimental program
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Example Embodiment

[0071] Example 1: Preparation of Compound Ia

[0072]

[0073] A 100ml single-necked round-bottomed flask was sequentially added with compound VIa (3.30g, 19mmol), compound VII (4.15g, 9mmol), 20ml of N-methylpyrrolidone, and magnetic stirring was started. Put in anhydrous lithium bromide (0.5g, 5.8mmol) and tri-n-butyl phosphine oxide (0.5g, 2.3mmol), heat and increase the temperature to 90-95°C, keep the temperature and react for 11 hours. After the reaction was completed, the temperature was lowered to 30°C, 50ml of dichloromethane and 30ml of water were added, stirred for 5 minutes, and filtered. The filtrate is separated into layers, the lower organic phase is removed, and the upper aqueous phase is discarded. After the organic phase was washed with 30ml×3 water, it was concentrated to dryness under reduced pressure, and the residue was subjected to column chromatography (300-400 mesh silica gel). Obtained) 3.3 g of a white solid compound of formula Ia, with a yield of 93....

Example Embodiment

[0074] Example 2: Preparation of Compound Ib

[0075]

[0076] Compound VIb (25.0g, 120.6mmol), Compound VII (20.8g, 95.3mmol), 200ml of N,N-dimethylformamide were sequentially added to a 250ml single-necked round bottom flask, and magnetic stirring was started. Put in 1.5 g of anhydrous lithium bromide and 2.0 g of tri-n-butyl phosphine oxide, heat and increase the temperature to 80-85° C., keep the temperature and react for 10 hours. After the reaction is completed, the temperature is lowered to 30°C, 500ml of dichloromethane and 300ml of water are added, stirred for 10 minutes, and filtered. The filtrate is separated into layers, the lower organic phase is removed, and the upper aqueous phase is discarded. After the organic phase was washed with 300 ml×3 water, it was concentrated to dryness under reduced pressure, and the residue was subjected to column chromatography (200-300 mesh silica gel). Obtained) 36.9 g (77.3 mmol) of white solid compound of formula Ib, the yield wa...

Example Embodiment

[0078] Example 3: Preparation of Compound Ic

[0079]

[0080] Compound VIc (15.0 g, 84.7 mmol), Compound VII (13.2 g, 60.5 mmol), 150 ml of N-methylpyrrolidone were sequentially added to a 250 ml single-neck round bottom flask, and mechanical stirring was started. Add 0.9 g of anhydrous lithium bromide and 1.0 g of tri-n-butyl phosphine oxide, heat and increase the temperature to 90-95° C., heat and react for 7 hours. After the reaction is completed, the temperature is lowered to 30°C, 400 ml of dichloromethane and 250 ml of water are added, stirred for 10 minutes, and filtered. The filtrate is separated into layers, the lower organic phase is removed, and the upper aqueous phase is discarded. After the organic phase was washed with 100 ml×3 water, it was concentrated to dryness under reduced pressure, and the residue was subjected to column chromatography (200-300 mesh silica gel). Obtained) 22.1 g (49.8 mmol) of white solid compound of formula Ic, the yield was 92.5%, and th...

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Abstract

The invention relates to the technical field of heterocyclic chemistry, specifically to the technical field of nitrogen-oxygen heterocyclic chemistry. Specifically speaking, the invention discloses a novel synthetic process for rivaroxaban. According to the process, the R group of a compound with a structure as shown in a formula (I) is removed so as to obtain a compound with a structure as shown in a formula (II) or an acid salt thereof, and the compound with the structure as shown in the formula (II) or the acid salt thereof reacts with a compound with a structure as shown in a formula (III) under the action of alkali so as to prepare rivaroxaban, wherein the formulas are described in the specification, and R in the formulas is a C1-20 aliphatic/aromatic hydrocarbon group.

Description

technical field [0001] The invention relates to the technical field of heterocycle chemistry, in particular to the technical field of nitrogen-oxygen heterocycle chemistry. Background technique [0002] Rivaroxaban (Rivaroxaban), chemical name: 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]- 1,3-Oxazolidin-5-yl}-methyl)-2-thiophene carboxamide is the world's first direct oral factor Xa inhibitor, used to prevent and treat venous thrombosis, especially for the treatment of myocardial Infarction, angina, etc. [0003] [0004] A lot of research work has been carried out on the preparation of rivaroxaban. Among the existing synthetic routes, each route has its own uniqueness and also has some shortcomings. At present, the common synthetic routes at home and abroad mainly include the following types. [0005] Route 1: The route announced in the patent document CN1262551 authorized by Bayer in China is as follows: [0006] [0007] Wherein NMP is N-methylpyrr...

Claims

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Application Information

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IPC IPC(8): C07D413/10C07D413/14C07D409/12
CPCC07D409/12C07D413/10C07D413/14
Inventor 张现毅李原强
Owner 浙江四维医药科技有限公司
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