480449-70-5

Usage

Uses

Used in Pharmaceutical Industry:
Edoxaban is used as an oral factor Xa inhibitor for the treatment of deep vein thrombosis and pulmonary embolism. It works by directly inhibiting factor Xa, a key enzyme in the coagulation cascade, thereby reducing the formation of blood clots and preventing the progression of these conditions.

Indications

Edoxaban is a direct oral anticoagulant (DOAC). It exerts its effects by inhibiting factor Xa (FXa). Edoxaban was FDA approved in early 2015 to treat deep venous thrombosis, pulmonary embolism and decrease the risk of hypercoagulability related illness; stroke, and systemic embolism (SE) in subjects with nonvalvular atrial fibrillation (NVAF).When compared to the popularly used anticoagulant warfarin, edoxaban entails more limited monitoring and possesses a reduced risk for significant bleeding and fewer interactions with other agents.Edoxaban is the most current direct oral anticoagulant (DOAC) and does not associate with the CYP-450 system.Various clinical trials and studies (ENGAGE AF-TIMI and Hokusai-VTE) expressed edoxaban's effectiveness compared to the conventional vitamin K antagonist warfarin. It was demonstrated to be non-inferior in preventing blood clots when compared to warfarin. Edoxaban is the second FDA-approved anticoagulant agent with once-daily administration.Contrary to the other direct oral anticoagulants, apixaban and rivaroxaban, edoxaban has not yet received approval for secondary and postoperative prophylaxis for venous thromboembolism (VTE).FDA-Approved Indications:Deep venous thrombosisPulmonary embolismNonvalvular atrial fibrillation (NVAF)https://www.ncbi.nlm.nih.gov/

Pharmacology

Similar to rivaroxaban and apixaban,edoxaban is an orally active, small-molecule (548 Da), reversible factor Xa inhibitor.As with the other direct oral factor Xa inhibitors,edoxaban exhibits a 10,000-fold greater selectivity for factor Xa compared with other serine proteins such as factor VlIa, t-PA, plasmin,or trypsin.Administered as edoxaban tosylate,the compound competitively inhibits free factor Xa directly without the need for antithrombin and factor Xa incorporated in the prothrombinase complex. The concentration-dependent inhibition of factor Xa leads to reduced thrombin generation and thrombin-induced platelet aggregation. Edoxaban inhibited factor Xa with Ki values of 0.561 nM for free factor Xa and 2.98 nM for prothrombinase.128 Edoxaban exhibits linear pharmacokinetics and produces concentration-dependent increases in the PT,INR, and aPTT.However,changes in these laboratory assays with edoxaban tend to be unpredictable and highly variable, reducing their use as a monitoring tool in clinical practice.Pharmacokinetics and Pharmacodynamics of Edoxaban, a Non-Vitamin K Antagonist Oral Anticoagulant that Inhibits Clotting Factor XaLaboratory measurement of the anticoagulant activity of edoxaban: a systematic reviewPharmacokinetics, biotransformation, and mass balance of edoxaban, a selective, direct factor Xa inhibitor, in humans

Drug interactions

The majority of edoxaban pharmacokinetic drug interactions result from inhibition or induction of the P-gp efflux transporter,which is responsible for intestinal transport.Edoxaban taken with quinidine demonstrates an increase in edoxaban Cmax of 85% and AUS of 77%.Coadministration with dronedarone resulted in a Cmax and AUC increase of 46% and 85%，respectively.This drug interaction also increased the 24-h edoxaban concentration by 158%.Additionally, verapamil increased the edoxaban Cmax by 53%, the AUC by 53%, and the 24-h edoxaban concentration by 29%.146 As per the phase 3 clinical trial, patients receiving quinidine, dronedarone,or verapamil should receive the reduced dose of 30 mg daily instead of 60 mg daily.It should be noted that patients receiving azole antifungal agents, such as ketoconazole, or protease inhibitors were excluded from the phase 3 trial because of concerns about increased edoxaban exposure.Conversely, the use of rifampin, a P-gp inducer, resulted in a significant 34% reduction in the edoxaban AUC.Therefore, the combination of rifampin and edoxaban should be avoided.

Upstream product

• 480452-37-7 N¹-[(1S,2R,4S)-2-amino-4-[(dimethylamino)carbonyl]cyclohexyl]-N²-(5-chloro-2-pyridyl)ethanediamide 
• 720720-96-7 5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxylic acid hydrochloric acid salt 
• 480450-69-9 tert-butyl N-[(1R,2S,5S)-2-azido-5-[(dimethylamino)carbonyl]cyclohexyl]carbamate 
• 1072-98-6 5-chloro-2-pyridylamine 
• 929693-35-6 (1S,3S,6R)-N,N-dimethyl-7-oxabicyclo[4.1.0]heptane-3-carboxamide 
• 929693-36-7 (1S,3R,4R)-3-amino-4-hydroxy-N,N-dimethyl cyclohexanecarboxamide 
• 929693-30-1 (1S,3R,4R)-3-[(tert-butoxycarbonyl)amino]-4-hydroxy-N,N-dimethylcyclohexanecarboxamide 
• 929693-31-2 {(1R,2R,4S)-2-[(tert-butoxycarbonyl)amino]-4-[(dimethylamino)carbonyl]cyclohexyl}methanesulfonate 
• 365998-36-3 (1S,2R,4S)-N₂-(tert-butoxycarbonyl)-4-(N,N-dimethylcarbamoyl)-1,2-cyclohexanediamine 
• 480450-71-3 N-{(1R,2S,5S)-2-amino-5-[(dimethylamino)carbonyl]cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide 
• 480452-36-6 carbamic acid, N-[(1R,2S,5S)-2-[[2-[(5-chloro-2-pyridinyl)amino]-2-oxoacetyl]amino]-5-[(dimethylamino)carbonyl]cyclohexyl]-1,1-dimethylethyl ester 
• 852291-42-0 2-bromo-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine p-toluenesulfonate 

Downstream Products

• 480449-71-6 [14C]-Edoxaban tosylate 

Relevant academic research and scientific papers

PROCESS FOR PREPARATION OF EDOXABAN

The present invention relates to process for preparation N1-(5-Chloropyridin-2-yl)-N2-[(1S,2R,4S)-4-(N,N-dimethylcarbamoyl)-2-(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-ylcarboxamido)cyclohexyl]oxamide p-toluene sulfonate monohydrate [edoxaban tosylate monohydrate], the compound of formula (I), comprising reacting compound of formula (VI) with compound of formula (V) to obtain the compound of formula (IV) and further converting it to edoxaban tosylate monohydrate in an industrially feasible process.

Method for preparing edoxaban from trichloroacetophenone onium salt derivatives

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.

Preparation method of high-purity edoxaban

The invention belongs to the field of organic synthesis, and particularly relates to a preparation method of high-purity edoxaban. The existing process for synthesizing edoxaban generally has the problems of low product purity, high impurity content, single and low-efficiency purification means, more three wastes and the like, and urgently needs to solve the problems in industry to realize industrialization of the edoxaban. In order to solve the problem, the invention provides the method for industrially producing high-purity edoxaban. According to the method, a halogenated hydrocarbon and analcohol mixed solvent are used for recrystallizing the product, the quality of the product is improved, the impurity content is reduced, the liquid chromatographic purity of the product is not lower than 99.0%, the single impurity content does not exceed 0.1%, and the method provided by the invention is relatively high in yield, less in three wastes, good in product quality and suitable for industrial production.

Methyltetrahydropyridinothiazole active compound and preparation method and application thereof

The invention relates to a methyltetrahydropyridinothiazole active compound (compound (I)) and a preparation method and application thereof. The preparation method comprises the following steps: making 5-methyl-4, 5, 6, 7-tetrahydro[1, 3]thiazolo[5, 4-c]p

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

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]th

Preparation method of edoxaban

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.

METHOD OF PRODUCING EDOXABAN

PROBLEM TO BE SOLVED: To provide a method of producing edoxaban, which exhibits FXa inhibitory effect and is useful as an agent for preventing and/or treating a thrombotic and/or embolic disease, where the method realizes low cost, high reaction efficiency, reduced time consumption, and high product purity and is suitable for large-scale industrial production. SOLUTION: A method of producing edoxaban (formula 1) includes a method illustrated by the reaction formula in the figure. SELECTED DRAWING: None COPYRIGHT: (C)2020,JPOandINPIT

METHOD FOR PREPARING TERT-BUTYL N-((1R,2S,5S)-2-((2-((5-CHLOROPYRIDIN-2-YL)AMINO)-2-OXOACETYL)AMINO)-5-(DIMETHYLCARBAMOYL)CYCLOHEXYL)CARBAMATE

The present invention relates to a method for preparing tert-butyl N- ((1R,2S,5S)-2-((2-((5-chloropyridin-2-yl)amino)-2-oxoacetyl)amino) -5-(dimethylcarbamoyl)cyclohexyl)carbamate of formula (I), or a salt or solvate thereof,characterized in that it comprises the steps of a) mixing tert-butyl N-((1R,2S,5S)-2-amino-5-(dimethylcarbamoyl) cyclohexyl)carbamate of formula (A) with ethyl 2-((5-chloropyridin-2- yl)amino)-2-oxoacetate of formula (B) in an organic solvent; b) mixing a base with the resulting mixture of step (a); and c) stirring the mixture obtained in step (b). The method substantially facilitates the obtention of the compound of formula (I), leading to a reduction in the viscosity of the reaction medium and improving product yield and/or product purity. Formulae (I), (B), (A).

Processes for the Preparation of Edoxaban and Intermediates Thereof

The present invention provides processes for the preparation of Edoxaban (1) and salts thereof, as well as intermediates thereof. In particular, intermediate compounds and/or salts of the Formulae (3), (4), (6-A), (7-A), (8-A), (9-A) and (10-AS) are provided.

SALT OF AMINE-PROTECTED (1S,2R,4S)-1,2-AMINO-N,N-DIMETHYLCYCLOHEXANE-4-CARBOXAMIDE

Disclosed are compounds and methods for the preparation of Edoxaban. In particular, a camphor sulfonate salt of an amine-protected [(1R,2S,5S)-1,2-amino-5-[(dimethylamino)carbonyl] cyclohexane, an intermediate that may be formed in the synthesis of Edoxaban, is disclosed as well as methods of its preparation.