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Synthesis method of edoxaban

A compound and tertiary amine technology, applied in the field of compound preparation, can solve the problems of large solvent consumption, cumbersome post-processing, unsuitable for industrial production, etc., and achieve the effects of improving yield and simple operation

Active Publication Date: 2015-07-08
SHENZHEN KEXING PHARM CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] It has been found that in the disclosed methods for preparing compound (1) in Document 1 and Document 2, it is mentioned that the post-treatment of the product is cumbersome, the solvent consumption is large, and the purification of the product needs to pass through a silica gel column. As a result, it is confirmed that the method is not suitable Industrial production

Method used

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  • Synthesis method of edoxaban
  • Synthesis method of edoxaban
  • Synthesis method of edoxaban

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] (1R,2S,5S)-2-({2-[5-Chloropyridin-2-yl)amino]-2-oxoacetyl}amino)-5-[(dimethylamino)carbonyl]cyclohexyl - tert-butyl carbamate, preparation of compound (2)

[0045]

[0046] where Boc represents tert-butoxycarbonyl

[0047] Add 560mL acetonitrile, 560.0g (1S,2R,4S)-1-amino-4-(dimethylaminocarbonyl)-cyclohexyl-2-carbamic acid tert-butyl oxalate to a 1000mL reaction flask, stir, 25 Add 64.9g triethylamine at ±2°C, stir for 10min, add 47.5g ethyl 2-[(5-chloropyridine)amino]-2-oxoacetate monohydrochloride, heat up to 60°C, and react at 60±2°C 6h, lower the temperature to 25°C, react at 25±2°C for 16h, no raw material point detected by TLC. Developing solvent: dichloromethane: methanol = 10:1.

[0048] After the reaction is complete, add pure water to crystallize, cool to 10°C, keep warm at 10±2°C for crystallization for 1 hour, filter with suction, wash the filter cake with water, and air-dry at 50°C for 10 hours to obtain 51.4 g of white solid.

Embodiment 2

[0050] N-(5-chloropyridin-2-yl)-N'-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5 , 6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)oxalamide, the preparation of compound (1)

[0051]

[0052] Add 2560mL acetonitrile, 128.0g (1R,2S,5S)-2-({2-[5-chloropyridin-2-yl)amino]-2-oxoacetyl}amino)-5- [(Dimethylamino)carbonyl]cyclohexyl-tert-butyl carbamate, stir, add 131.4g methanesulfonic acid at 25±2°C, keep the reaction for 2h, TLC detects that there is no raw material point, cool down, add 152.2g three at 10°C Ethylamine, stirred for 10min, then added 70.6g 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylate hydrochloride, 40.7g 1-hydroxybenzene Triazole and 62.9g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride were heated up to 25°C and reacted at 25±2°C for 18h. TLC detects that there is no raw material point. Developing solvent: dichloromethane: methanol = 10:1.

[0053] After the reaction, cool down to 10°C, add ...

Embodiment 3

[0063] N-(5-chloropyridin-2-yl)-N'-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5 , 6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)oxalamide p-toluenesulfonic acid monohydrate, the preparation of compound (1-a)

[0064]

[0065] 220mL dichloromethane, 20.9g N-(5-chloropyridin-2-yl)-N'-((1S,2R,4S)-4-[(dimethylamino)carbonyl]- 2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)oxalamide, stirred to make all the solids Dissolve, add 38.2ml 1mol / L p-toluenesulfonic acid ethanol solution at 25±2°C, react for 1h, after the reaction is completed, remove the solvent under reduced pressure, add 313.5mL 85% ethanol aqueous solution to the residue, and keep warm at 60±2°C After 1 hour, the temperature was lowered to 10°C for suction filtration, and vacuum-dried to constant weight at 25°C to obtain 23.0 g of a white solid.

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Abstract

The invention provides a synthesis method of edoxaban, which includes: [step 1]: adding a compound (2) to a solvent of a nitrile being 2-4 in carbon atom number to remove an N-Boc protective group under an acidic condition to obtain a compound (2-a); and [step 2]: treating a reaction liquid in the (step 1) with an tertiary amine and adding a compound (3) to carry out a reaction, and finally treating the reaction liquid after the reaction finished with an alkali liquid. Compared with a method of synthesizing the edoxaban in the prior art in references, the method is mild in the conditions of the reactions and is high in yield. The raw materials are easy to obtain. The method is simple in operations and is stable in processes, is free of column chromatography for purifying the product and can enable the product to achieve a medicinal requirement just by one time of purification, so that the method is more suitable for industrialized production.

Description

technical field [0001] The present invention relates to the preparation method of compound, described compound N-(5-chloropyridin-2-yl)-N'-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2- Preparation of {[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)oxalamide and its monohydrate , the compound has inhibitory effect on activated blood coagulation factor X (FXa), and can be used as a preventive and / or therapeutic drug in thrombotic diseases. Background technique [0002] Compound (1) is Edoxaban, chemical name: N-(5-chloropyridin-2-yl)-N'-((1S,2R,4S)-4-[(dimethylamino)carbonyl]- 2-{[(5-Methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)oxalamide, formulated with toluene Sulfonate. It is a small-molecule oral anticoagulant developed by Daiichi Sankyo Co., Ltd., and is a coagulation factor X (FXa) inhibitor. During the blood coagulation process, activated coagulation factor X (FXa) activates prothrombin (FII) into th...

Claims

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Application Information

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IPC IPC(8): C07D513/04
CPCY02P20/55
Inventor 崔宁董祥君邢圣桐何社辉张水华王国振王璐杨利娜
Owner SHENZHEN KEXING PHARM CO LTD
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