Separation method of edoxaban and isomers thereof

A technology of edoxaban and a separation method is applied in the field of chromatographic separation of edoxaban and its enantiomers and diastereomers, and the analysis of edoxaban and its isomer impurities. Solve problems such as separation of substances and separation of isomers and impurities

Active Publication Date: 2016-10-12
北京康派森医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, the synthesis methods of edoxaban enantiomers and diastereomers have been reported in the literature, such as the synthesis of edoxaban and its seven enantiomers and diastereomers reported in US2012/0053349A1 method, and disclosed tw

Method used

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  • Separation method of edoxaban and isomers thereof
  • Separation method of edoxaban and isomers thereof
  • Separation method of edoxaban and isomers thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1N

[0051] Example 1N 1 -(5-chloropyridin-2-yl)-N 2 -((1R,2S,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c Synthesis of ]pyridin-2-yl)carbonyl]amino}cyclohexyl)ethylenediamine (YDB-RSS)

[0052] 1-1: Synthesis of (1R,4R,5R)-4-iodo-6-oxabicyclo[3.2.1]oct-7-one (YDB-A02)

[0053]

[0054] Add YDB-A001 (236g, 0.954mol) into ethyl acetate (1180ml) and 2M hydrochloric acid (1062ml), stir for 1h, separate the liquids, extract the aqueous phase with ethyl acetate, combine the organic phases, use water for the organic phases, and saturated chlorinate After washing with sodium, drying over anhydrous sodium sulfate, the mother liquor was concentrated to dryness under reduced pressure to obtain 115 g of an oily product (YDB-A01).

[0055] Add YDB-A01 (115g, 0.911mol), potassium iodide (196.7g, 1.185mol), sodium bicarbonate (99.56, 1.185mol) into dichloromethane (1150ml) and water (1140ml), and stir for 10min. Cool down to 10°C, add iodine (300.8g, 1185mo...

Embodiment 2

[0077] Example 2N 1 -(5-chloropyridin-2-yl)-N 2 -((1R,2S,4R)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c Synthesis of ]pyridin-2-yl)carbonyl]amino}cyclohexyl)ethylenediamine (YDB-RSR)

[0078] 2-1:

[0079]

[0080] Dissolve YDB-AC-RSR (11.9g, 0.025mol) in ethanol (600ml), add saturated hydrochloric acid-ethanol solution (130ml), and react at room temperature for 18h. The reaction solution was concentrated under reduced pressure. The product was dissolved in DMF (600ml), and triethylamine (16.4g, 0.163mol), EDCI (5.75g, 0.03mol), HOBT (18.3g, 0.136mol), 5-methyl-4,5,6, 7-Tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxylate hydrochloride (7.04g, 0.03mol), reacted at room temperature for 12h. Add water and dichloromethane, extract, separate liquid, extract the aqueous phase with dichloromethane, combine the organic phases, wash with saturated sodium chloride, dry over anhydrous sodium sulfate, concentrate to dryness under reduced pressure, ...

Embodiment 3

[0082] Example 3N 1 -(5-chloropyridin-2-yl)-N 2 -((1S,2S,4S)-4-[(Dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c Synthesis of ]pyridin-2-yl)carbonyl]amino}cyclohexyl)ethylenediamine (YDB-SSS)

[0083] 3-1: (1S,2S,4R)-2-[(tert-butoxycarbonyl)amino]-4-[(dimethylamino)carbonyl]cyclohexylcarbamate benzyl ester and (1S,2S,4S Synthesis of )-2-[(tert-butoxycarbonyl)amino]-4-[(dimethylamino)carbonyl]cyclohexylcarbamate benzyl ester (YDB-B11)

[0084]

[0085] Under the protection of argon, dissolve YDB-B08 (22g, 0.052mol) in 220ml ethanol, add dropwise 20% sodium ethoxide solution (24.5ml, 0.063mol), react at 20-30°C for 10h, cool in an ice bath, add 1mol / L Sodium dihydrogen phosphate (440ml), ethyl acetate (500ml), extraction, liquid separation, the aqueous phase was extracted with ethyl acetate, the organic phases were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain ...

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Abstract

The invention provides a method for separating and purifying edoxaban by chromatography. The separation method is chromatography, and the chromatographic conditions are as follows: the filler is an amylose-tri(3,5-xylylcarbamate) bonded silica gel, and the mobile phase is selected from a mixed solution comprising a non-polar solvent and a polar solvent. By selecting the chromatographic conditions, the edoxaban and seven enantiomers and nonenantiomers thereof can be simultaneously separated, and thus, the method has the characteristics of high speed, high simpleness, high efficiency and the like.

Description

technical field [0001] The invention relates to a method for analyzing impurities of edoxaban and its isomers, in particular to a method for separating edoxaban and its enantiomers and diastereoisomers by chromatography, belonging to pharmaceutical chemistry field. Background technique [0002] Edoxaban (trade name: Savaysa) is a small-molecule oral anticoagulant developed by Daiichi Sankyo Co., Ltd., a coagulation factor X (FXa) blocker, approved by the US FDA on January 8, 2015 Marketed to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation (AF). Its chemical name is N-(5-chloropyridin-2-yl)N'-[(1S,2R,4S)-4-(N,N-dimethylcarbamoyl)]-2-[(5- Methyl-4,5,6,7-tetrahydro-1,3-thiazolo[5,4c]-pyridine-2-carboxamido)cyclohexyl]oxalamide. Edoxaban is obtained by chemical synthesis. Its molecules have chiral centers at the 1, 2, and 4 positions respectively, and can theoretically form 7 enantiomers and diastereoisomers. Their structural f...

Claims

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Application Information

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IPC IPC(8): C07D513/04G01N30/02G01N21/33
CPCC07D513/04G01N21/33G01N30/02G01N2030/027
Inventor 程增江李成云梁飞郑晶郑祖爽祝晓艳
Owner 北京康派森医药科技有限公司
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