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Preparation method of betrixaban

A technology of betrixaban and compounds, which is applied in the field of preparation of betrixaban, can solve the problems of increased production cost, amide bond breakage, waste of resources, etc., and achieve the effects of short steps, mild reaction conditions, and low impurity content

Inactive Publication Date: 2016-07-06
CHONGQING MEDICAL UNIVERSITY
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Problems solved by technology

This method adopts the condition of iron powder and ammonium chloride when reducing and preparing N-(5-chloro-2-pyridyl)-5-methoxy-2-aminobenzamide, and a large amount of iron can be produced during industrialized production Mud, not only causes the waste of resources, but also produces great pollution to the environment; Oxybenzamide uses CDI as a condensing agent, which increases the production cost; it adopts Pinner reaction, and the methanolic hydrochloric acid solution is easy to break the amide bond, resulting in degradation impurities

Method used

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  • Preparation method of betrixaban
  • Preparation method of betrixaban
  • Preparation method of betrixaban

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Embodiment Construction

[0024] The present invention is specifically described below through the examples, it is necessary to point out that the following examples are only used to further illustrate the present invention, and can not be interpreted as limiting the protection scope of the present invention, those skilled in the art can according to the above-mentioned present invention Contents Some non-essential improvements and adjustments are made to the present invention. Materials and instruments used in the present invention are commercially available products.

[0025] Synthesis of N-(5-chloro-2-pyridyl)-5-methoxy-2-aminobenzamide (4)

[0026] Under nitrogen protection, 2-amino-5-chloropyridine (11.98g, 93.19mmol), potassium tert-butoxide (20.91g, 186.38mmol), and anhydrous tetrahydrofuran (300mL) were added to a 500mL dry two-necked flask, and After stirring and dissolving at ~27°C, add 5-methoxyisatoic anhydride (18.00g, 93.19mmol) three times. After the addition, stir and react at 23~27°C ...

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Abstract

The invention provides a method for preparing betrixaban. The method comprises the following steps: performing the nucleophilic addition elimination on 5-methoxyisatoic anhydride used as a raw material and 2-amino-5-chloropyridine under the condition of potassium tert-butoxide to obtain N-(5-chloro-2-pyridyl)-5-methoxyl-2-aminobenzamide, allowing a compound 4 to react with cyanobenzoyl chloride to obtain N-(5-chloro-2-pyridyl)-2-[(4-cyano benzoyl) amino]-5-methoxyl benzamide hydrochloride, and finally performing the nucleophilic addition with dimethylamine to obtain a target product betrixaban, wherein the total yield is 57.8 percent. By adopting the preparation method, the raw materials are low in price and easy to get, the reaction conditions are moderate, the reaction controllability is high, and the industrialized application prospect is good.

Description

technical field [0001] The invention relates to betrixaban, in particular to a preparation method of betrixaban. Background technique [0002] Betrixaban is a highly selective coagulation factor Xa inhibitor, developed by Portola Pharmaceuticals, Inc., for the prevention and treatment of acute venous thromboembolism (VTE) in patients with high-risk acute medical diseases. Phase III clinical trials and phase II clinical trials for the prevention and treatment of pulmonary embolism (PE) are currently being conducted in China, the United States, the United Kingdom and other countries. Its chemical name is N-(5-chloro-2-pyridyl)-2-((4-(N,N-dimethylmidyl)benzoyl)amino)-5-methoxybenzamide, CAS The number is 330942-05-7; the structural formula is as follows: [0003] [0004] There are currently four main methods of preparing betrixaban: [0005] The first one: WO2001064643A discloses that 5-methoxy-2-nitrobenzoic acid is used as a starting material, acylated by phosphorus ox...

Claims

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Application Information

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IPC IPC(8): C07D213/75
CPCC07D213/75
Inventor 袁建勇李雁武李伦
Owner CHONGQING MEDICAL UNIVERSITY
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