A kind of preparation method of Apixaban

Abstract

The invention discloses an Apixaban preparation method. The Apixaban preparation method comprises that 1, an intermediate I and an intermediate II undergo a [3+2] cyclization addition reaction under the alkali action to produce a compound B, and the compound B undergoes a morpholine ring removal reaction under the acid condition to produce a compound C, 2, the compound C is reduced by iron powder to form a corresponding amino compound D, 3, the amino compound D and 5-chlorovaleryl chloride undergo an amidation reaction under the triethylamine action to produce a compound E, 4, the compound E undergoes a cyclization reaction under the strong base action to produce a compound F, 5, the compound F undergoes a hydrolysis reaction under the strong base action to produce a corresponding carboxyl compound G, and 6, the carboxyl compound G and CDI undergo a reaction to produce an active intermediate H and the active intermediate H and ammonia water undergo an aminolysis reaction to produce the desired compound A. The Apixaban preparation method has simple processes, does not need strict reaction conditions, has low equipment requirements, has high reaction yield, utilizes stable intermediates thereby solving intermediate storage problems, and effectively improves product purity.

Description

technical field [0001] The invention belongs to the field of pharmaceutical preparation, in particular to a preparation method of apixaban. Background technique [0002] Apixaban, chemical name: 4,5,6,7-tetrahydro-1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo- 1-Piperidinyl)phenyl]-1H-pyrazolo[3,4-C]pyridine-3-carboxamide, CAS: 503612-47-3, has formula A: [0003] [0004] Apixaban is the third approved oral direct inhibitor of factor Xa, jointly developed by Pfizer and Bristol-Myers Squibb, for the prevention of venous thrombosis in adult patients undergoing elective hip or knee replacement surgery. Due to its good drug safety, low possibility of drug interactions and multiple elimination methods, it is expected to be used for special populations with liver disease or renal impairment. [0005] At present, the preparation methods of apixaban disclosed in the international literature are mainly limited to the following literature reports: 1. WO2003049681; 2. WO2010030983; 3. CN...

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Problems solved by technology

[0023] In this route, in the amidation-cyclization of p-nitroaniline and amino D, 5-bromovaleryl chloride can be used, but its price is more expensive than 5-chlorovaleryl chloride; 5-chlorovaleryl chloride can also be used, However, in the cyclization reaction of amide to lactam (compound F), triethyl orthoformate and trifluoroacetic acid must be used to remove water before the amide contacts with alkoxide base to promote the cyclization reaction, resulting in cumbersome operation , and the chemical dehydration reagent used is expensive, not suitable for industrial production

[0024] Summarizing the above route, there are following defects in the process of preparing apixaban: the use of expensive iodine-containing organic substances, the direct use of intermediates is not easy to get, the amount of auxiliary reagents is relatively large and the price is relatively expensive, etc.

In compound F ammonolysis preparation apixaban this step reaction, adopt the ethylene glycol of ammonia or methanol solution or anhydrous ammonia, carry out ammonolysis in autoclave to obtain target product, this method exists reaction process and is difficult for monitoring, and equipment High defects are required; or the target product is obtained by compound F reacting with 10 times equivalent formamide in the presence of excess sodium methylate. In this method, expensive chemical dehydration reagents need to be added before compound F contacts with alkali, and the moisture content is required to be relatively high. High, otherwise it is easy to hydrolyze the ester, which reduces the yield and is not suitable for industrial production

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