Preparation method of Apixaban as anti-thrombotic drug

The technology of an antithrombotic drug, apixaban, is applied in the field of preparation of organic compounds, can solve the problems of large amount of auxiliary reagents, complicated routes, difficult to obtain intermediates and the like, and achieves short steps, improved reaction yield and mild reaction conditions. Effect

Active Publication Date: 2013-10-09
甘肃皓天科技股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0018] It can be seen by analyzing the above prior art that the intermediates directly used in the preparation process of Apixaban are not easy to obtain, and the amount of auxiliary reagents is large or the route is loaded down with trivial details, which is not conducive to economical Ways to prepare Apixaban

Method used

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  • Preparation method of Apixaban as anti-thrombotic drug
  • Preparation method of Apixaban as anti-thrombotic drug
  • Preparation method of Apixaban as anti-thrombotic drug

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] Example 1: In the synthetic route shown in formula 7, R is tert-butoxy, and removing the amino protecting group is trifluoroacetic acid, dichloromethane solution, X is a bromine atom, Y is an ethoxy group, and Z is an iodine atom; compound 11 converted to compound 20a The inorganic base used is cesium carbonate; the compound

[0027]

[0028] 25a converted to compound Apixaban The base used was sodium hydrogen.

[0029] Preparation of compound 20a

[0030] In a 10mL single-necked bottle, the compound 11(0.182g), compound 19a (0.383g) was dissolved in 4.6mL of dioxane, cesium carbonate (0.65g) and catalytic amount of N,N'-dimethylethylenediamine (0.018g) were added successively. A catalytic amount of cuprous iodide (0.019 g) was added under argon protection. The reaction mixture was heated to 110 °C for 11 hours, cooled to room temperature, 40 mL of water was added to the reaction solution, extracted with ethyl acetate (20 mL×2), washed with saturated brine...

Embodiment 2

[0038] Embodiment 2: In the synthetic route shown in formula 8, R is a trifluoromethyl group, and the amino protecting group is removed with a methanol solution of potassium carbonate, X is a chlorine atom, Y is a tert-butoxy group, Z is a bromine atom,

[0039]

[0040] compound 11 convert to compound 20b The inorganic base used is potassium phosphate; compound 25b convert to compound Apixaban The base used was sodium hydroxide.

[0041] Preparation of compound 20b

[0042] Compounds in 10mL single-neck vials 11 (0.182g), compound 19b (0.378g) was dissolved in 4.6mL of dioxane, followed by adding anhydrous potassium phosphate (0.42g) and catalytic amount of N,N'-dimethylethylenediamine (0.018g). A catalytic amount of cuprous iodide (0.019 g) was added under argon protection. The reaction mixture was heated to 110 °C for 11 hours, cooled to room temperature, 40 mL of water was added to the reaction solution, extracted with ethyl acetate (20 mL×2), washed with sat...

Embodiment 3

[0052] Embodiment three: In the synthetic route shown in formula 9, R is benzyloxy, and the amino protecting group is removed with hydrochloric acid solution, X is iodine atom, Y is isopropoxy group, Z is iodine atom, compound 11

[0053] convert to compound 20c The inorganic base used is sodium carbonate; compound 25c convert to compound Apixaban The base used was potassium tert-butoxide.

[0054] Preparation of compound 20c

[0055] Compounds in 10mL single-neck vials 11 (0.182g), compound 19c (0.378g) was dissolved in 4.6mL of dioxane, and anhydrous sodium carbonate (0.40g) and a catalytic amount of N,N'-dimethylethylenediamine (0.018g) were added successively. A catalytic amount of cuprous iodide (0.019 g) was added under argon protection. The reaction mixture was heated to 110 °C for 11 hours, cooled to room temperature, 40 mL of water was added to the reaction solution, extracted with ethyl acetate (20 mL×2), washed with saturated brine, combined with the orga...

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Abstract

The invention discloses a preparation method of a compound Apixaban as an anti-thrombotic drug. The method disclosed by the invention comprises the following steps of: with a compound 11 shown as the formula 1 as a starting raw material, subjecting the compound 11 and amino protected paraiodoaniline 19 to coupling reaction in the existence of a cuprous reagent and an inorganic base to obtain a compound 20; subjecting the compound 20 and a compound 21 to [3+2] cyclization-elimination reaction to obtain a compound 22; removing a protecting group of the compound 22 to obtain a compound 23, or subjecting the compound 20 and the compound 21 to [3+2] cyclization reaction, directly carrying out elimination reaction under an acidic condition, and meanwhile, removing the protecting group to obtain the compound 23; subjecting the compound 23 to ammonolysis reaction to obtain a compound 24; subjecting the compound 24 and 5-chlorovaleryl halogen to amidation reaction to obtain a compound 25; and cyclizing the compound 25 under an alkaline condition to obtain the Apixaban, or subjecting the compound 24 and 5-chlorovaleryl bromine to amidation and cyclization two-step one-pot method reaction under the alkaline condition to obtain a target product, namely the Apixaban.

Description

technical field [0001] The present invention relates to a kind of preparation method of organic compound, exactly one such as formula 1 [0002] [0003] The preparation method of the compound Apixaban for the shown antithrombotic drugs. Background technique [0004] Apixaban as shown in formula 1, chemical name: 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1-yl)phenyl ]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide. [0005] Apixaban, the compound Apixaban, is a new type of oral direct factor Xa inhibitor jointly developed by Bristol-Myers Squibb and Pfizer. It was approved for marketing in the European Union in March 2011. The trade name is Eliquis. It is clinically used for the prevention of elective Venous thromboembolism (VTE) in adult patients undergoing hip or knee replacement. Clinical study results show that enoxaparin 40 mg taken orally twice daily is more effective than once-daily injection in preventing VTE after total knee and total hip art...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04C07D211/76
CPCY02P20/55
Inventor 薛吉军李毅王仕祥郑保富高强徐少军
Owner 甘肃皓天科技股份有限公司
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