Preparation method of apixaban

Abstract

The invention discloses a preparation method of apixaban.The method comprises the steps that paranitroaniline serves as the raw material, paranitroaniline and delta-valerolactone are subjected to amidation ring-opening, substituting and ring-closing reactions under the action of AlMe3, and a compound 8 is obtained; the compound 8 is subjected to alpha-position dichloro substituting and condensation-elimination reactions, and a compound 7 is obtained; the compound 7 and a compound 6 are subjected to [3+2] cyclization-elimination and nitro reduction, and a compound 4 is obtained; the compound 4 sequentially reacts with delta-valerolactone and ammonium chloride under the action of AlMe3, and a compound 3 is obtained; the compound 3 is subjected to substituting and ring closing, and apixaban is obtained.According to the preparation method of apixaban, paranitroaniline and delta-valerolactone which are low in price are adopted to serve as the raw materials, operation of the whole route is simple, conditions of each reaction are mild, and the synthesizing method is easy to operate, high in yield and purity and suitable for industrial production.

Description

technical field [0001] The invention relates to the technical field of medicine and chemical industry, in particular to a preparation method of apixaban. Background technique [0002] Apixaban (Apixaban) is an oral anticoagulant drug with selectivity and affinity for coagulation factor Xa, jointly developed by Bristol-Myers Squibb and Pfizer, and its trade name is Eliquis, which was launched in March 2011 The European Union approved the marketing, and in December 2012, the FDA approved the drug to be marketed in the United States, and then it was marketed in other regions and countries accordingly. Among them, the chemical name: 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, CAS number: 503612-47-3, molecular formula: C 25 h 25 N 5 o 4 . Clinically, it has an important preventive effect on venous thromboembolism (VTE) in patients after hip or knee replacement. In addition, apixaban can also be us...

AI Technical Summary

Problems solved by technology

[0005] Route 1: As reported in patents WO2010030983A2, WO2012168364A1 and WO20141075648A1, p-iodoaniline and 5-bromopentanoyl chloride are used as starting materials, followed by amidation-cyclization, α-position dichlorination, condensation-elimination, [3+2] ring Combination-elimination, Ullmann coupling and high-pressure ammonolysis reaction to obtain the target compound apixaban; the shortcoming of this route is: the price of starting materials (p-iodoaniline and 5-bromovaleryl chloride) is higher, which increases the production cost; the compound The Ullmarm coupling reaction of 13 with δ-valerolactam has harsh conditions and needs to be carried out under nitrogen protection. The catalyst (cuprous iodide and 1,10-phenanthroline) is expensive, and the single-step yield is extremely low (only 29%); the high-pressure ammonolysis reaction of compound 14 requires higher equipment requirements, and the reaction process is not easy to monitor, and the yield of this step is extremely low (only 28%); the total yield of this route is only 1.3%, so the The synthetic route is not suitable for industrial production; the synthetic route is shown below

[0007] Route 2: It is reported in the literature "Tao Haiyan et al. Synthesis of Apixaban. Chinese Journal of Medicinal Chemistry, 2013", WO2003049681A2 and CN103342704A, using δ-valerolactam as the starting material, followed by α-position two Chlorination, elimination-condensation, [3+2] ring closure-elimination and Ullmarm coupling reaction to obtain compound 2 (apixaban acid), compound 2 reacts with isobutyl chloroformate to form mixed anhydride, and then undergoes ammonolysis with ammonia Obtain target compound Apixaban; The shortcoming of this route is: the elimination-condensation reaction of compound 15 to compound 16, two-step yield is only 26.7%; The yield is only 62%; the starting material (p-iodoaniline) required for the preparation of compound 18 is more expensive, and the production cost is high; the Ullmann coupling reaction of compound 17 and compound 18 needs to be carried out under nitrogen protection, and the catalyst (iodide Copper and 8-hydroxyquinoline) are expensive, and the reaction time is longer, the temperature is higher, and the aftertreatment is loaded down with trivial details

[0009] Route 3: CN103626759A, CN103626689A, CN101967145A, CN103709095A, WO2010118367A2 and WO2010054279A1 reported that p-nitroaniline and 5-chlorovaleryl chloride were used as starting materials, followed by amidation-cyclization, α-position dichlorination, condensation- Elimination, sodium sulfide reduction, amidation-cyclization, [3+2] cyclization-elimination and high-pressure ammonolysis reactions to obtain the target compound apixaban; the disadvantage of this route is that potassium tert-butoxide or sodium hydride is used as the amide The condensing agent in the chemical-cyclization step has high production cost and high risk of operation; the reaction of compound 7 through sodium sulfide reduction is easy to generate impurities, which affects the yield and purity of the product; the high-pressure ammonolysis reaction of compound 19 is harmful to equipment. High requirements, difficult to monitor the reaction process

[0011] Route 4, CN102675314A, CN103159670A, CN103694237A and US20060069258A1 and other documents report that p-nitroaniline and 5-bromovaleryl chloride are used as starting materials, followed by amidation-cyclization, α-position dichlorination, elimination, [3+ 2] cyclization-elimination, catalytic hydrogenation reduction, amidation-cyclization and high-pressure ammonolysis (or formamide ammonolysis) to obtain the target compound apixaban; the shortcoming of this route is: the starting material (5-bromopentyl Acyl chloride) is more expensive, and the production cost is large; the elimination reaction of compound 8 to compound 20 needs to be carried out under nitrogen protection, which increases the operation steps: the high-pressure ammonolysis reaction of compound 19 has higher requirements for equipment, and the reaction process is not easy to monitor; compound 19 The process of ammonolysis of formamide needs to be carried out after expensive chemical reagents (triethyl orthoformate and trifluoroacetic acid, etc.) dehydrate the solvent, otherwise the hydrolysis of compound 19 will easily occur, resulting in a decrease in the yield and purity of the final product. This route The total yield is 30-37%

[0017] Summarizing the above routes, there are the following defects in the process of preparing apixaban: expensive iodine-containing organic compounds and / or halovaleryl chlorides are used, the intermediates used directly are not easy to obtain, and the amount of auxiliary reagents used is large and more expensive

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