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Intermediate for preparing edoxaban free alkali, and preparation method and application of intermediate

A technology of edoxaban and free base, applied in the preparation of intermediates of edoxaban free base and its preparation field

Active Publication Date: 2020-10-13
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 preparing edoxaban free alkali, and preparation method and application of intermediate
  • Intermediate for preparing edoxaban free alkali, and preparation method and application of intermediate
  • Intermediate for preparing edoxaban free alkali, and preparation method and application of intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0089]

[0090] Under the protection of nitrogen, put 23.47g (0.1mol) 5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-into a 500ml three-necked flask Formate hydrochloride, 250ml dichloromethane, 20ml N,N-dimethylacetamide, 2ml 4-picoline. Adjust the temperature to -10 to -15°C, and slowly add 20.24g (0.2mol) triethylamine dropwise. Control the temperature from -10 to -15°C, and add 12.06g (0.1mol) of pivaloyl chloride dropwise. After the dripping is completed, the temperature is controlled at -10 to -15°C and stirred for 2 hours to obtain solution A, which is kept at -10 to -15°C for later use. Solution A needs to be freshly prepared and stored at low temperature.

[0091]

[0092] Among them, R is a trimethylacetyl group.

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

Embodiment 2

[0097]

[0098] Under the protection of nitrogen, put 23.47g (0.1mol) 5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-into a 500ml three-necked flask Formate hydrochloride, 250ml dichloromethane, 20ml N,N-dimethylacetamide, 2ml 4-picoline. Adjust the temperature to -35 to -40°C, and slowly add 20.24g (0.2mol) triethylamine dropwise. Control the temperature from -35 to -40°C, and add 12.06g (0.1mol) of pivaloyl chloride dropwise. After the dropping 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 and stored at low temperature.

[0099]

[0100] Among them, R is trimethylacetyl.

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

Embodiment 3

[0104]

[0105] Under the protection of nitrogen, put 23.47g (0.1mol) 5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-into a 500ml three-necked flask Formate hydrochloride, 250ml dichloromethane, 20ml N,N-dimethylacetamide, 2ml 4-picoline. Adjust the temperature to 5-10°C, and slowly add 20.24g (0.2mol) triethylamine dropwise. The temperature was controlled at 5 to 10°C, and 12.06g (0.1mol) of pivaloyl chloride was added dropwise. After the dripping 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 newly prepared for immediate use and stored at low temperature.

[0106]

[0107] Among them, R is trimethylacetyl.

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

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Abstract

The invention relates to an intermediate for preparing edoxaban free alkali, and a preparation method and application of the intermediate. The preparation method of the intermediate comprises the following step: reacting 5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5, 4-c]pyridine-2-carboxylic acid or a salt thereof with acyl chloride in an organic solvent under the action of alkali to obtain the intermediate. By utilizing the intermediate, the edoxaban free alkali can be synthesized in a low-cost, green, environment-friendly, simple, efficient and safe manner, and the drug safety of an obtained edoxaban product can be improved. A preparation method of the edoxaban free alkali comprises the following steps: reacting a compound (II) with a compound (IV) in an organic solvent to obtain the edoxaban free alkali, or reacting the salt of the compound (II) with the salt of the compound (IV) in an organic solvent under the action of alkali. The structures of the compound (II), the edoxaban free alkali and the compound (IV) are respectively shown in the specification.

Description

[0001] Invention field [0002] The invention belongs to the technical field of organic synthesis, and specifically relates to an intermediate for preparing edoxaban free base, and a preparation method and application thereof. Background technique [0003] Edoxaban is a small-molecule oral anticoagulant developed by Daiichi Sankyo Co., Ltd., and is a coagulation factor X (FXa) blocker. The structural formula of edoxaban free base is represented by the following formula (I), and the 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 (Ia)) is the pharmaceutical active ingredient (API) of edoxaban. [0004] [0005] The methods used to prepare compound (I) or (I-a) in the existing publications usually go through the following steps: [0006] [0007] This method has the follow...

Claims

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Application Information

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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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