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A kind of intermediate of betrixaban and its preparation method and application

A betrixaban maleate and reaction technology, applied in the intermediates of betrixaban and preparation thereof, benzoxazinone compounds and the field of preparation thereof, can solve the problem of not effectively shortening the synthesis route of betrixaban , Commercial sources are not easy to obtain, poor stability of starting materials, etc., to achieve the effects of cheap raw materials, shortening the synthesis route, and reducing synthesis steps

Active Publication Date: 2021-05-04
ZHEJIANG HONGYUAN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although the hydrogenation reduction process is avoided in route 3, the process does not effectively shorten the synthesis route of betrixaban, and the overall yield is not ideal, and the stability of the starting materials used is poor, and commercial sources are not easy to obtain

Method used

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  • A kind of intermediate of betrixaban and its preparation method and application
  • A kind of intermediate of betrixaban and its preparation method and application
  • A kind of intermediate of betrixaban and its preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0072] Example 1: Preparation of 2-(4-cyanophenyl)-6-methoxybenzo[d]-1,3-oxazin-4-one (I)

[0073]

[0074] Add 5.0g of 5-methoxy-2-aminobenzoic acid (29.9mmol) and 25mL of dichloromethane into a 150mL reaction flask, stir to dissolve and add 5.0mL of triethylamine (TEA) (36.1mmol). The mixture was cooled to 0-10°C, 5.9 g of 4-cyanobenzoyl chloride (35.6 mmol) in toluene (25 mL) was added dropwise to the mixture, and the reaction solution was warmed to room temperature and stirred for 8 hours. After the reaction of 5-methoxy-2-aminobenzoic acid was detected by TLC, 35 mL of purified water was added to wash the reaction solution. The organic layer was separated, heated to the reflux temperature of toluene and stirred for 2 hours. After the completion of the reaction as detected by TLC, the reaction solution was slowly cooled to 0-10° C., and the precipitated solid was filtered, washed and dried to obtain 7.36 g of compound I with a yield of 88.6% and a purity of 99.8%. 1 H...

Embodiment 2

[0075] Example 2: Preparation of 2-(4-cyanophenyl)-6-methoxybenzo[d]-1,3-oxazin-4-one (I)

[0076]

[0077] Add 2.0g of 5-methoxy-2-aminobenzoic acid (12.0mmol), 10mL of dichloromethane and 1mL of N-methylmorpholine (NMM) into a 100mL reaction flask, stir to dissolve and cool to 0-10°C. 1.76 g of 4-cyanobenzoic acid (12.0 mmol) and 1.8 g of isobutyl chloroformate were added to the mixture. The reaction solution was warmed up to room temperature and stirred for 5 hours. TLC detects that after the reaction of 5-methoxy-2-aminobenzoic acid is completed, the reaction solution is 35-45 ° C, concentrated to dryness under reduced pressure, and 10 mL of carbon tetrachloride (CCl 4 ) and 3.46g triphenylphosphine (13.2mmol), reacted at 30-35°C and stirred for 5 hours. After the reaction was detected by TLC, 50mL of n-hexane was added to the reaction solution, and the suspended matter was precipitated and stirred for 30 minutes, filtered, and the solid was dried 2.84 g of compound I...

Embodiment 3

[0078] Example 3: Preparation of 2-(4-cyanophenyl)-6-methoxybenzo[d]-1,3-oxazin-4-one (I)

[0079]

[0080] Add 2.0 g of 5-methoxy-2-aminobenzoic acid (12.0 mmol), 10 mL of dichloromethane and 5.1 g of 1-ethyl-(3-dimethylaminopropyl)carbodiene to a 100 mL reaction flask Amine hydrochloride (EDC) (26.4mmol), stirring to dissolve and cooling to 0-10°C, adding 1.76g 4-cyanobenzoic acid (12.0mmol) and 1.9g 1-hydroxybenzotriazole to the mixture (14.4 mmol) (HOBT). The reaction solution was warmed to room temperature and stirred for 12 hours. After the reaction of 5-methoxy-2-aminobenzoic acid was detected by TLC, 50 mL of n-hexane was added to the reaction solution, and the suspended matter was precipitated and stirred for 30 minutes, filtered, and the solid was dried to obtain 2.83 g of compound I, with a yield of 84.8%. The purity is 99.3%.

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Abstract

The invention discloses an intermediate of betrixaban and its preparation method and application. The structure of the intermediate is shown in formula I. The intermediate can be efficiently synthesized with cheap and easy-to-obtain raw materials. At the same time, using the When the raw material is used to synthesize betrixaban, the follow-up reaction yield is high, the post-treatment is simple, the obtained product has high purity, and has high industrial application prospect.

Description

technical field [0001] The invention belongs to the technical field of organic chemistry and medicinal chemistry, and relates to an intermediate of betrixaban, a preparation method and application thereof. More specifically, the present invention relates to a benzoxazinone compound and a method for its preparation. Background technique [0002] Venous and arterial thromboembolic diseases have a significant impact on human morbidity and mortality, therefore, novel therapies for thromboembolism remain a major focus of drug development. In the coagulation cascade, vitamin K is an important cofactor for hepatic γ-glutamyl carboxylase, which can add activated carboxylate to a series of proteases, such as factors II, VII, IX or X. Activated factor X plays a dominant role in the coagulation cascade, it can connect the intrinsic and extrinsic coagulation pathways, and is the rate-limiting step of thrombin generation. Therefore, the effect of activating factor X on the coagulation ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D265/22C07D213/75C07C57/145C07C51/41
CPCC07D213/75C07D265/22
Inventor 汪海波李霆金辉梅光耀欧阳晓辉冯尚军郑海成徐彩娥
Owner ZHEJIANG HONGYUAN PHARMA
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