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Method for preparing edoxaban from trichloroacetophenone onium salt derivatives

A technology of edoxaban and ethyl ketone, which is applied in the field of medicinal chemistry, can solve problems such as expensive, unsuitable for industrial scale production, and many hidden dangers in production safety, and achieve the effects of simplifying post-processing, saving dosage, and saving production costs

Active Publication Date: 2020-07-10
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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  • Method for preparing edoxaban from trichloroacetophenone onium salt derivatives
  • Method for preparing edoxaban from trichloroacetophenone onium salt derivatives
  • Method for preparing edoxaban from trichloroacetophenone onium salt derivatives

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

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

[0038]

[0039] Add glacial acetic acid (500kg) to the reaction kettle, control the temperature not to exceed 25°C, add 1-methyl-4-piperidone (100kg, 883.6mol) dropwise, and then add 48% hydrobromic acid aqueous solution (150kg, ~ 892.5mol); temperature control is not more than 20 ℃, liquid bromine (141.6kg, 885.8mol) is added dropwise, after dripping, stir at room temperature overnight; shake filter, collect solid, dry; Obtain about 237kg of dry product of 109C1-10 (theoretical Weight: 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] Add dehydrated ethanol (900kg) in reactor, add thiourea (72kg, 945.9mol), add the 109C1-10 (235kg, 860.9mol) that gains in the embodiment 1, heat reflux reaction about 36~48hr; , cooling and crystallization; rejection filtration, rinsing with absolute ethanol to collect the solid; drying 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] Add drinking water (1200kg) in reactor, add 48% hydrobromic acid aqueous solution (600kg,~3559mol), add 240kg (724.9mol) 109C2-10 of gained in the embodiment 2, after stirring, temperature control is no more than 10 ℃, dropwise add a solution prepared by sodium nitrite 75kg (1087mol) and drinking water (360kg), after the dropwise addition, stir and react at room temperature for 3hr. After the reaction is completed, the temperature is controlled not to exceed 20°C, and the pH of the system is adjusted to ≥ 13 with 30% liquid caustic soda; extracted three times with toluene; the organic phases are combined, dried with anhydrous sodium sulfate, filtered, and the toluene is concentrated under reduced pressure to obtain a brown oily residue 109C3-00 is about 123kg (the liquid phase shows that it contains about 8.7% of 109C4-00; the theoretical amount calculated according to...

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Abstract

The invention provides a method for preparing edoxaban by using 2, 2, 2-trichloro-1-(4, 5, 6, 7-tetrahydro-5-methylthiazolo[5, 4-c]pyridinium-1-yl) ethanone chloride. The preparation method comprisesthe following steps: preparing 2, 2, 2-trichloro-1-(4, 5, 6, 7-tetrahydro-5-methylthiazolo[5, 4-c]pyridinium-1-yl) ethanone chloride, namely 109C5-11; the invention discloses a preparation method of N1[(1S, 2R, 4S)-2-amino-4-[(dimethylamino) carbonyl]cyclohexyl]-N2(5-chloro-2-pyridyl) oxalamide dimesylate, namely 109T2-31. The 109C5-11 is used as an acylation reagent to prepare the edoxaban with 109T2-31. The preparation method comprises the following steps: preparing the edoxaban by using the 109C5-11 as the acylation reagent; the novel method overcomes the defect that expensive condensing agents EDCI.HCl and activating agents HOBt need to be used in the prior art. The new method provided by the invention is beneficial to more economically and more efficiently realizing industrial scale production of the Edoxaban p-toluenesulfonate hydrate.

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. Part of the 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 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 It is a direct anticoagulant factor Xa inhibitor. For the treatment of venous thromboembolism in patients following total knee replacement, total hip replacement, or hip fracture surgery. [0004] The main r...

Claims

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Application Information

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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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