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Intermediate for the preparation of edoxaban free base and its preparation method and application

A technology for edoxaban and free base is applied in the preparation of intermediates for edoxaban free base and the field of preparation thereof, and achieves the effects of simple production process, low production cost and high purity

Active Publication Date: 2021-05-25
ZHUHAI HAIRUIDE NEW MATERIAL TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] Based on this, the purpose of the present invention is to provide a new preparation method of edoxaban free base, to solve the problems of existing methods in environmental protection, production safety and drug safety

Method used

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  • Intermediate for the preparation of edoxaban free base and its preparation method and application
  • Intermediate for the preparation of edoxaban free base and its preparation method and application
  • Intermediate for the preparation of edoxaban free base and its preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0089]

[0090] Under nitrogen protection, 23.47g (0.1mol) of 5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2- Formic hydrochloride, 250ml dichloromethane, 20ml N,N-dimethylacetamide, 2ml 4-picoline. Adjust the temperature to -10 to -15°C, and slowly add 20.24 g (0.2 mol) of triethylamine dropwise. Control the temperature from -10 to -15°C, and add 12.06 g (0.1 mol) of pivaloyl chloride dropwise. After the dropwise addition, the temperature was controlled at -10 to -15°C and the reaction was stirred for 2 hours to obtain solution A, which was kept at -10 to -15°C for later use. Solution A needs to be freshly prepared immediately before use and stored at low temperature.

[0091]

[0092] Wherein, R is a trimethylacetyl group.

[0093] In another 1000ml reaction flask, 56g (0.1mol) of methanesulfonate of compound (IV) and 250ml of dichloromethane were added. The temperature was lowered to -10 to -15°C, and 20.24 g (0.2 mol) of triethylamine was added dropwis...

Embodiment 2

[0097]

[0098] Under nitrogen protection, 23.47g (0.1mol) of 5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2- Formic hydrochloride, 250ml dichloromethane, 20ml N,N-dimethylacetamide, 2ml 4-picoline. Adjust the temperature to -35 to -40°C, and slowly add 20.24 g (0.2 mol) of triethylamine dropwise. Control the temperature from -35 to -40°C, and add 12.06 g (0.1 mol) of pivaloyl chloride dropwise. After the dropwise addition is completed, the temperature is controlled at -35 to -40°C and the reaction is stirred for 2 hours to obtain solution A, which is kept at -35 to -40°C for later use. Solution A needs to be freshly prepared immediately before use and stored at low temperature.

[0099]

[0100] Wherein, R is a trimethylacetyl group.

[0101] In another 1000ml reaction flask, 56g (0.1mol) of methanesulfonate of compound (IV) and 250ml of dichloromethane were added. The temperature was lowered to -35 to -40°C, and 20.24 g (0.2 mol) of triethylamine was add...

Embodiment 3

[0104]

[0105] Under nitrogen protection, 23.47g (0.1mol) of 5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2- Formic hydrochloride, 250ml dichloromethane, 20ml N,N-dimethylacetamide, 2ml 4-picoline. Adjust the temperature to 5 to 10° C., and slowly add 20.24 g (0.2 mol) of triethylamine dropwise. Control the temperature from 5 to 10°C, and add 12.06 g (0.1 mol) of pivaloyl chloride dropwise. After the dropwise addition is completed, the temperature is controlled at 5 to 10°C and the reaction is stirred for 2 hours to obtain solution A, which is kept at 5 to 10°C for later use. Solution A needs to be freshly prepared immediately before use and stored at low temperature.

[0106]

[0107] Wherein, R is a trimethylacetyl group.

[0108] In another 1000ml reaction flask, 56g (0.1mol) of methanesulfonate of compound (IV) and 250ml of dichloromethane were added. The temperature was lowered to 5 to 10°C, and 20.24 g (0.2 mol) of triethylamine was added dropwise. ...

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Abstract

The present invention relates to an intermediate for preparing edoxaban free base and its preparation method and application. The preparation method of the intermediate comprises the following steps: in an organic solvent, under the action of a base, 5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c] Pyridine-2-carboxylic acid or its salt is reacted with acid chloride to obtain. Using the intermediate, the free base of edoxaban can be synthesized in a low-cost, green, environmentally friendly, simple, efficient and safe manner, and the drug safety of the obtained edoxaban product can be improved. The steps for preparing edoxaban free base are as follows: in an organic solvent, compound (II) and compound (IV) react to obtain; or, in an organic solvent, under the action of a base, compound (II) and compound ( IV) salt reaction, that is, obtained. The structures of compound (II), edoxaban free base, and compound (IV) are respectively as follows.

Description

[0001] field of invention [0002] The invention belongs to the technical field of organic synthesis, and in particular relates to an intermediate used for preparing edoxaban free base, a preparation method and application thereof. Background technique [0003] Edoxaban is a small molecule oral anticoagulant developed by Daiichi Sankyo Co., Ltd., which is a factor X (FXa) blocker. The structural formula of edoxaban free base is represented by following formula (I), and chemical name is N 1 -(5-chloropyridin-2-yl)-N 2 -((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c] Pyridin-2-yl)carbonyl]amino}cyclohexyl)oxalamide, and its p-toluenesulfonate monohydrate (represented by the following formula (I-a)) is the active pharmaceutical ingredient (API) of Edoxaban. [0004] [0005] The method for preparing compound (I) or (I-a) in existing publications usually goes through the following steps: [0006] [0007] This method has the follow...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D513/04
CPCC07D513/04C07B2200/07
Inventor 张泓泉习丹黄金刘文达戴新荣
Owner ZHUHAI HAIRUIDE NEW MATERIAL TECH CO LTD
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