A kind of method for preparing edoxaban from trichloroethyl ketonium salt derivative

A technology of edoxaban and ethyl ketone, which is applied in the field of medicinal chemistry, can solve the problems of high cost, many production safety hazards, and unsuitability for industrial-scale production, and achieve the effect of saving dosage and simplifying post-processing

Active Publication Date: 2022-07-12
内蒙古京东药业有限公司
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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 are required and expensive and highly flammable n-butyllithium is required
From the perspective of production safety, there are many hidden dangers, and it is not conducive to cost control, so it is not suitable for industrial-scale production

Method used

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  • A kind of method for preparing edoxaban from trichloroethyl ketonium salt derivative
  • A kind of method for preparing edoxaban from trichloroethyl ketonium salt derivative
  • A kind of method for preparing edoxaban from trichloroethyl ketonium salt derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] Example 1 Synthesis of 3-bromo-1-methyl-4-piperidone hydrobromide

[0038]

[0039] In the reactor, add glacial acetic acid (500kg), temperature control is not more than 25 ℃, drip 1-methyl-4-piperidone (100kg, 883.6mol), then drip 48% aqueous hydrobromic acid (150kg, ~ 892.5mol); temperature control is not more than 20 ℃, drip liquid bromine (141.6kg, 885.8mol), after dripping, stir at room temperature overnight; shake off filtration, collect solid, dry; Obtain about 237kg of 10C1-10 dry product (theoretical Quantity: 241.2kg). Yield: 98.3%.

Embodiment 2

[0040] Example 2 Synthesis of 4,5,6,7-tetrahydro-5-methylthiazolo[5,4-c]pyridin-2-amine dihydrobromide

[0041]

[0042] In the reaction kettle, add dehydrated alcohol (900kg), add thiourea (72kg, 945.9mol), add the 109C1-10 (235kg, 860.9mol) gained in Example 1, reflux reaction for about 36~48hr; , cooled and crystallized; filtered, rinsed with absolute ethanol, collected the solid; dried to obtain about 242kg (theoretical amount: 285.0kg) of 109C2-10 dry product. Yield: 84.9%.

Embodiment 3

[0043] Example 3 Synthesis of 2-bromo-4,5,6,7-tetrahydro-5-methylthiazolo[5,4-c]pyridine

[0044]

[0045] In the reactor, add drinking water (1200kg), add 48% aqueous hydrobromic acid solution (600kg, ~ 3559mol), add the 240kg (724.9mol) 109C2-10 gained in Example 2, after stirring, the temperature control is not more than 10 ℃, dropwise add the solution prepared by sodium nitrite 75kg (1087mol) and drinking water (360kg), after the dropwise addition, the reaction is stirred at room temperature for 3hr. After the reaction was completed, the temperature was controlled not to exceed 20°C, and the pH of the system was adjusted to ≥13 with 30% liquid caustic soda; extracted three times with toluene; the organic phases were combined, dried with anhydrous sodium sulfate, filtered, and concentrated in toluene under reduced pressure to obtain a brown oily residue 109C3-00 is about 123 kg (the liquid phase shows that it contains about 8.7% of 109C4-00; the theoretical amount calcul...

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PUM

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Abstract

The present invention provides 2,2,2-trichloro-1-(4,5,6,7-tetrahydro-5-methylthiazolo[5,4-c]pyridinium-1-yl)ethanone Method for preparing edoxaban from chloride. Among them: 2,2,2-trichloro-1-(4,5,6,7-tetrahydro-5-methylthiazolo[5,4-c]pyridinium-1-yl)ethanone chloride , namely the preparation method of 109C5-11; N 1 -[(1S, 2R, 4S)-2-amino-4-[(dimethylamino)carbonyl]cyclohexyl]-N 2 -(5-Chloro-2-pyridyl)oxalamide bis-methanesulfonate, namely the preparation method of 109T2-31; edoxaban was prepared by using 109C5-11 as an acylating reagent and 109T2-31. The new method avoids the disadvantages of using expensive condensing agent EDCI·HCl and activating agent HOBt in the existing process. The novel method of the invention is beneficial to realize the industrialized scale production of edoxaban p-toluenesulfonate hydrate more economically and efficiently.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a new method for preparing edoxaban p-toluenesulfonate hydrate and a key intermediate thereof. Part of intermediates involved in the present invention and edoxaban p-toluenesulfonate hydrate structure are as follows: [0002] Background technique [0003] Edoxaban p-toluenesulfonate hydrate developed by Daiichi Sankyo Co., Ltd. was approved by the Japan Pharmaceutical and Medical Device Agency (PMDA) on April 22, 2011; it was approved on January 8, 2015. The U.S. Food and Drug Administration (FDA) approved it for marketing; it was approved for marketing by the European Medicines Agency (EMA) on June 19, 2015. It is marketed in Japan by Daiichi Sankyo Co., Ltd. under the trade name It is a direct anticoagulant factor Xa inhibitor. For the treatment of venous thromboembolism in patients following total knee arthroplasty, total hip arthroplasty or hip fracture surgery. [...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D513/04C07D213/75C07C309/04C07C303/32
CPCC07D513/04C07D213/75C07C309/04C07C303/32Y02P20/55
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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