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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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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

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 toxic, severely corroded equipment, difficult to separate and purify, and difficult to industrialize, and provide a new synthesis process for rivaroxaban

Method used

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

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0071] Embodiment 1: the preparation of compound Ia

[0072]

[0073] Compound VIa (3.30 g, 19 mmol), compound VII (4.15 g, 9 mmol), and 20 ml of N-methylpyrrolidone were sequentially added into a 100 ml single-neck round bottom flask, and magnetic stirring was started. Add anhydrous lithium bromide (0.5g, 5.8mmol) and tri-n-butylphosphine oxide (0.5g, 2.3mmol), heat up to 90-95°C, and keep the reaction for 11 hours. After the reaction is complete, cool down to 30°C, add 50ml of dichloromethane and 30ml of water, stir for 5 minutes, and filter. The filtrate was separated into layers, the lower organic phase was removed, and the upper aqueous phase was discarded. The organic phase was washed with 30ml×3 water, concentrated to dryness under reduced pressure, and the residue was subjected to column chromatography (300-400 mesh silica gel). Obtained) 3.3 g of the compound of formula Ia as a white solid, with a yield of 93.8%.

Embodiment 2

[0074] Embodiment 2: the preparation of compound Ib

[0075]

[0076] Add compound VIb (25.0 g, 120.6 mmol), compound VII (20.8 g, 95.3 mmol), and 200 ml of N,N-dimethylformamide to a 250 ml single-neck round bottom flask in sequence, and start magnetic stirring. Add 1.5g of anhydrous lithium bromide and 2.0g of tri-n-butylphosphine oxide, heat up to 80-85°C, and keep it warm for 10 hours. After the reaction, the temperature was lowered to 30°C, 500ml of dichloromethane and 300ml of water were added, stirred for 10 minutes, and filtered. The filtrate was separated into layers, the lower organic phase was removed, and the upper aqueous phase was discarded. The organic phase was washed with 300ml×3 water, 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 the compound of formula Ib as a white solid, with a yield of 91.1% and an HPLC purity of 99.3%.

[0077] 1 H ...

Embodiment 3

[0078] Embodiment 3: the preparation of compound Ic

[0079]

[0080] Compound VIc (15.0 g, 84.7 mmol), compound VII (13.2 g, 60.5 mmol), and 150 ml of N-methylpyrrolidone were sequentially added into 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-butylphosphine oxide, heat up to 90-95° C., and keep the reaction for 7 hours. After the reaction is complete, cool down to 30°C, add 400ml of dichloromethane and 250ml of water, stir for 10 minutes, and filter. The filtrate was separated into layers, the lower organic phase was removed, and the upper aqueous phase was discarded. The organic phase was washed with 100ml×3 water, 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 the compound of formula Ic as a white solid, with a yield of 92.5% and an HPLC purity of 98.7%.

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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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