A kind of synthetic method of Apixaban

Abstract

The invention discloses a synthetic method of novel Apixaban. The method comprises the following steps: (i) hydrolyzing an Apixaban precursor compound (II) to obtain a carboxylic acid product; and (ii) mixing the carboxylic acid product obtained in the step (i) with ethyl chloroformate, reacting in the presence of diisopropylethylamine at the temperature of 0-5 DEG C for 3-5 hours; then introducing ammonia gas and reacting to obtain an ammonolysis product, namely, Apixaban. By adopting the method for preparing Apixaban by using the Apixaban precursor compound (II), the yield of Apixaban can be up to 93 percent. In the entire synthesis route, the minimum yield in each step is over 76 percent at least, and the total yield is about 33 percent. In the entire process, the use of precious catalysts or auxiliary reagents is avoided.

Description

technical field [0001] The invention belongs to the field of medicine synthesis, and in particular relates to a synthesis method of apixaban. Background technique [0002] Apixaban (apixaban), the chemical name is 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1-yl)phenyl]-4 , 5,6,7-tetrahydro-1H-pyrazol[3,4-c]pyridine-3-carboxamide, is a novel direct factor Xa inhibitor jointly developed by Bristol-Myers Squibb and Pfizer, USA Chemical Abstracts registration number CAS: 503612-47-3, with the structure of formula I: (I), has now completed relevant clinical trials for the prevention of venous thromboembolism (VTE) after total hip and total knee arthroplasty, and obtained the European Union's marketing authorization for this indication in May 2011, and in early 2013 China approved the regimen of apixaban 2.5 mg twice daily for the prevention of postoperative venous thromboembolism in adult patients undergoing hip or knee replacement. [0003] WO2010 / 030983 discloses the fo...

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Problems solved by technology

[0005] In the above synthesis method, apixaban precursor II reacted with ammonia in ethylene-propanol solution at 120°C for about 7 hours to obtain apixaban, but the yield of apixaban was only 27.6%.

In addition, when obtaining the apixaban precursor II, an important step is required, that is, the [3+2] ring-closure reaction between the intermediate III and IV, which requires the addition of a large amount of organic base, such as in three The [3+2] cyclization reaction occurs under the action of ethylamine, which is not conducive to the reduction of cost, and increases the difficulty of product separation and waste liquid treatment, which is easy to cause pollution. The yield of the cyclization reaction product is only 49%, and the cyclization The intermediate needs to be further reacted with valerolactam to obtain the apixaban precursor II. This step requires the use of an expensive copper iodide catalyst, and the product yield of this step can only reach 29%

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