Synthetic method of rivaroxaban metabolite 5

A synthetic method and technology of rivaroxaban, which is applied in the field of synthesis of rivaroxaban metabolite 5, can solve the problems that metabolite research has not yet been reported, and achieve a high operability, reasonable process design and high yield. Effect

Active Publication Date: 2018-01-16
TLC NANJING PHARMA RANDD CO LTD
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  • Abstract
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  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Rivaroxaban metabolite 5 is a metabolite in the synthesis process of rivaroxaban, which has not been reported yet. Through the synthesis and research of metabolites, the relevant pharmacology and pharmacokinetics of rivaroxaban can be carried out. and other studies, but studies on this metabolite have not been reported

Method used

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  • Synthetic method of rivaroxaban metabolite 5
  • Synthetic method of rivaroxaban metabolite 5
  • Synthetic method of rivaroxaban metabolite 5

Examples

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Embodiment 1

[0030] (1) Dissolve 10 grams of p-bromonitrobenzene in 50 milliliters of acetonitrile, add 6.5 grams of 2-benzyloxyethylamine to the above solution under ice cooling, then add 20 milliliters of triethylamine, and react at room temperature for 6 hours to obtain yellow Clarify the solution, concentrate the reaction solution under reduced pressure, dissolve it with 200 milliliters of dichloromethane, wash three times with 50 milliliters of water, combine the organic phases, dry with anhydrous sodium sulfate, spin dry after filtration to obtain the crude product, and purify the crude product by column chromatography 10.8 compounds II were obtained with a yield of 91.7%.

[0031] (2) Dissolve 10.8 grams of intermediate II in 250 milliliters of dichloromethane, add 7.67 grams of benzyloxyacetic acid, 26.33 grams of HATU (2-(7-benzotriazole oxide)-N,N, N',N'-tetramethylurea hexafluorophosphate) and 19 ml of N,N-diisopropylethylamine, and then reflux at 40°C for 24 hours. The reactio...

Embodiment 2

[0039] (1) Dissolve 5 grams of p-fluoronitrobenzene in 50 milliliters of acetonitrile, add 5.72 grams of 2-benzyloxyethylamine (A) to the above solution under ice-cooling, then add 9.5 milliliters of triethylamine, and react at 50°C for 8 Hours, a yellow clear solution was obtained, the reaction solution was concentrated under reduced pressure, dissolved with 200 ml of dichloromethane, washed three times with 50 ml of water, the organic phases were combined, dried with anhydrous sodium sulfate, filtered and spin-dried to obtain a crude product. The crude product was purified by column chromatography to obtain 4.5 g of intermediate II as a yellow oil with a yield of 48.1%.

[0040] (2) Dissolve 2 g of intermediate II in 20 ml of dry dichloromethane, add 1.7 ml of dry pyridine under ice-cooling, then dissolve 1.2 g of benzyloxyacetyl chloride in 5 ml of dry dichloromethane, slowly dropwise add The reaction solution was then reacted at 0°C for 5 hours. The reaction solution was ...

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Abstract

The invention provides a synthetic method of rivaroxaban metabolite 5, which belongs to the field of medicine synthesis. The provided preparation method is reasonable in process design, high in operability, moderate in reaction condition, high in yield, and capable of realizing mass production. The p-bromonitrobenzene is adopted as a raw material to synthesize the rivaroxaban metabolite 5 by virtue of eight-step reaction. The rivaroxaban metabolite 5 prepared by the invention provides important evidence for performing the quality, safety and efficacy scientific evaluation, pharmacological research, pharmacokinetics and the like of the rivaroxaban; and moreover, the rivaroxaban metabolite 5 is better in pharmacological activity, can be used for developing a drug for treating adult phlebothrombosis caused by various reasons and is high in application value.

Description

technical field [0001] The invention belongs to the field of drug synthesis, in particular to a method for synthesizing rivaroxaban metabolite 5. technical background [0002] Rivaroxaban is a drug for the treatment of venous thrombosis in adults. It was developed by Bayer and was approved by the FDA in 2011 as an anticoagulant drug. Its chemical name is 5-chloro-N-(((5S)-2 -Oxo-3-(4-(3-oxomorpholin-4-yl)phenyl)-1,3-oxazolin-5-yl)methyl)thiophene-2-carboxamide, trade name Xarelto, the structural formula is as follows: [0003] [0004] Rivaroxaban is an orally available, bioavailable factor Xa inhibitor that selectively blocks the active site of factor Xa and does not require cofactors to exert activity through intrinsic and extrinsic pathways Activated factor X is factor Xa, which plays an important role in the blood coagulation cascade. The anti-factor Xa activity is also affected by rivaroxaban, which is used in adult patients undergoing elective hip or knee replacem...

Claims

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Application Information

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IPC IPC(8): C07D413/12
Inventor 李砚涛毛雨张池刘春崔希林
Owner TLC NANJING PHARMA RANDD CO LTD
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