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Preparation method of edoxaban

An edoxaban and compound technology, applied in the field of medicinal chemistry, can solve the problems of hidden dangers of production safety, easy to catch fire, expensive, etc., and achieve the effects of good product quality, stable yield and stable structure

Active Publication Date: 2019-06-28
内蒙古京东药业有限公司 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This route requires the use of flammable and explosive elemental sulfur, cryogenic conditions and expensive n-butyllithium that is extremely easy to catch fire. From the perspective of production safety, there are many hidden dangers and it is not conducive to control. cost, not suitable for industrial scale production

Method used

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  • Preparation method of edoxaban
  • Preparation method of edoxaban
  • Preparation method of edoxaban

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0073]Example 1 Synthesis of 2-[(5-chloro-2-pyridine)amino]-2-oxoacetate allyl hydrochloride

[0074]

[0075] Add 1000g of acetonitrile to the reaction flask, add 200g (1.556mol) of 2-amino-5-chloropyridine, heat to 30-35°C, add 255g (1.717mol) of monoallyl oxalyl chloride dropwise, and keep the temperature constant during the dropwise addition process. Over 50°C; after the dropwise addition, keep warm at 45-50°C for 3-4 hours. After the reaction is completed, lower the temperature to 0-5°C and keep warm for about 2-4 hours. Filter to collect the solid; add the obtained wet product to 1500g of water, beat at room temperature for 2 to 3 hours; filter, rinse with water, collect the solid, and dry to obtain about 416g of the dry product of 109A4-10 (theoretical amount: 431.1g). Yield 96.5%.

Embodiment 2

[0076] Example 2 Synthesis of allyl 2-[(5-chloro-2-pyridine)amino]-2-oxoacetate

[0077]

[0078] Add 900g ethyl acetate to the reaction flask; add 100g (360.9mmol) 109A4-10; under stirring, add 40g (395.3mmol) triethylamine, heat to 40-45°C, keep stirring for about 3-5hr; filter while hot , and the filtrate was collected; ethyl acetate was concentrated under reduced pressure to obtain a residue of about 95 g. Add about 50g of ethyl acetate to the residue, stir to disperse evenly, then add 300g of petroleum ether, heat to 40-45°C, stir for about 1hr; cool to 0-5°C and keep warm for about 1-2hr. The solid was collected by filtration and dried to obtain about 77 g of dry product of 109A4-00 (theoretical amount: 86.8 g). Yield: 88.7%.

Embodiment 3

[0079] Example 3 Synthesis of allyl 2-[(5-chloro-2-pyridine)amino]-2-oxoacetate

[0080]

[0081] Add 1500g ethyl acetate and 300g water to the reaction flask; add 150g (541.3mmol) 109A4-10; add dropwise a solution prepared by 54g (642.8mmol) sodium bicarbonate and 600g water, adjust to pH=8; keep warm at 20 Stir and extract at ~25°C; separate the liquids, and then extract the aqueous phase with about 750 g of ethyl acetate; combine the organic phases and wash once with saturated saline solution; add anhydrous sodium sulfate to dry; filter and collect the filtrate; concentrate the ethyl acetate under reduced pressure, A residue of about 136 g was obtained. Add about 260g of ethyl acetate to the residue, stir to disperse evenly, then add 400g of petroleum ether, heat to 40-45°C, stir for about 1hr; cool to 0-5°C and keep warm for about 1-2hr. The solid was collected by filtration and dried to obtain about 124 g of dry product of 109A4-00 (theoretical amount: 130.3 g). Yiel...

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Abstract

The invention relates to a new preparation route and a new method for a p-toluenesulfonic acid edoxaban hydrate and intermediates thereof. The new method comprises the steps that a high-reactivity compound 109A4x is prepared; a compound 109C6x is prepared by using a new synthesizing method; new compounds 109E8-01, 109E9x and 109T7-01 are prepared; the p-toluenesulfonic acid edoxaban hydrate is prepared by using the intermediates. By using the new method and the new route, the reaction step of copious cooling is omitted, and dangerous elemental sulfur, high-risk n-butyllithium and high-risk azides are prevented from being used. In a word, by means of the method, the p-toluenesulfonic acid edoxaban hydrate and the key intermediates thereof are more easily and safely prepared at a lower coston an industrialization scale.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a new method for preparing edoxaban p-toluenesulfonic acid hydrate and its key intermediate. The structure of edoxaban p-toluenesulfonate hydrate is as follows: [0002] [0003] The structures of some key intermediates currently reported are as follows: [0004] [0005] Part of the intermediate structures involved in the present invention are as follows: [0006] Background technique [0007] Edoxaban p-toluenesulfonate Hydrate developed by Daiichi Sankyo Co., Ltd. was approved for marketing by Japan Pharmaceuticals and Medical Devices Agency (PMDA) on April 22, 2011; The U.S. Food and Drug Administration (FDA) approved for marketing; on June 19, 2015, it was approved for marketing by the European Medicines Agency (EMA). It is marketed and sold in Japan by Daiichi Sankyo Co., Ltd. under the trade name [0008] Edoxaban p-toluenesulfonate is a direct anticoagula...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D513/04C07D213/75C07C271/24
CPCY02P20/55
Inventor 吕关锋肖江郭荣耀
Owner 内蒙古京东药业有限公司
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