929693-31-2

Usage

Uses

2-(tert-Butoxycarbonyl) Methanesulfonate Edoxaban is an impurity of Edoxaban (E555520). Edoxaban is an anticoagulant drug which acts as a direct factor Xa inhibitor.

Upstream product

• 19914-91-1 (1RS,4RS,5RS)-4-bromo-6-oxabicyclo<3.2.1>octan-7-one 
• 4771-80-6 1,2,5,6-tetrahydrobenzoic acid 
• 929693-30-1 (1S,3R,4R)-3-[(tert-butoxycarbonyl)amino]-4-hydroxy-N,N-dimethylcyclohexanecarboxamide 
• 124-63-0 methanesulfonyl chloride 
• 67976-82-3 (1S)-3-cyclohexene-1-carboxylic acid (R)-(+)-α-methylbenzylamine salt 
• 139893-81-5 (1S,4S,5S)-4-bromo-6-oxabicyclo<3.2.1>octan-7-one 
• 5708-19-0 (1S)-3-cyclohexenecarboxylic acid 
• 929693-36-7 (1S,3R,4R)-3-amino-4-hydroxy-N,N-dimethyl cyclohexanecarboxamide 

Downstream Products

• 480451-97-6 Tert-butyl {(1R,2R,5S)-2-azido-5-[(dimethylamino)carbonyl]cyclohexyl}carbamate 
• 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 
• 480449-70-5 edoxaban 
• 480449-71-6 [14C]-Edoxaban tosylate 
• 480450-69-9 tert-butyl N-[(1R,2S,5S)-2-azido-5-[(dimethylamino)carbonyl]cyclohexyl]carbamate 
• 365998-36-3 (1S,2R,4S)-N₂-(tert-butoxycarbonyl)-4-(N,N-dimethylcarbamoyl)-1,2-cyclohexanediamine 

Relevant academic research and scientific papers

Development of an Efficient Manufacturing Process for a Key Intermediate in the Synthesis of Edoxaban

We report the development of a novel synthetic method to access a key intermediate in the synthesis of edoxaban. The main features of the new synthetic method are an improvement in the approach for the synthesis of a key chiral bromolactone, application of an interesting cyclization reaction utilizing neighboring group participation to construct a differentially protected 1,2-cis-diamine, and implementation of plug-flow reactor technology to enable the reaction of an unstable intermediate on multihundred kilogram scale. The overall yield for the preparation of edoxaban was significantly increased by implementing these changes and led to a more efficient and environmentally friendly manufacturing process.

METHOD FOR PRODUCING (1S,4S,5S)-4-BROMO-6-OXABICYCLO[3.2.1]OCTAN-7-ONE

It is an object of the present invention to provide a method for efficiently producing (1S,4S,5S)-4-bromo-6-oxabicyclo[3.2.1]octan-7-one (1), which is important as an intermediate compound for the production of an FXa-inhibiting compound. A method for producing (1S,4S,5S)-4-bromo-6-oxabicyclo[3.2.1]octan-7-one (1), which comprises treating an (R)-α-phenylethylamine salt of (S)-3-cyclohexene-1-carboxylic acid with 1,3-dibromo-5,5-dimethylhydantoin or N-bromosuccinimide in a solvent.

PROCESS FOR THE PREPARATION OF (1S,4S,5S)-4-BROMO-6-OXABICYCLO[3.2.1] OCTAN-7-ONE

The present invention relates to an improved and industrially advantageous process for the preparation of (1S, 4S, 5S) -4-bromo-6-oxabicyclo [3.2.1] octan-7-one represented by the following formula (I) which is a key intermediate in the synthesis of edoxaban, a compound that exhibits an inhibitory effect on activated blood coagulation factor X (also referred to as activated factor X or FXa), and is useful as a preventive and/or therapeutic drug for thrombotic diseases. The process includes reacting (1S) -cyclohex-3-ene-1-carboxylic acid of formula (II) with a brominating agent selected from the group consisting of N-bromosuccinimide or 1, 3-dibromo-5, 5-dimethylhydantoin in the presence of a base selected from calcium oxide or calcium hydroxide in a solvent selected from the group comprising of dichloromethane, toluene, tetrahydrofuran, ethy1 acetate, hexanes, cyclopentyl methyl ether (CPME) or a mixture thereof to get ( 1S, 4S, 5S) -4-bromo-6-oxabicyclo [3.2.1] octan-7-one of formula (I).

PROCESS FOR PREPARATION OF OPTICALLY ACTIVE DIAMINE DERIVATIVE SALT

The problem to be solved is to produce, at high yields with high purity, anhydrous crystals of a compound represented by formula (1) that is an important intermediate for preparation of FXa inhibitor compound (X) or a pharmacologically acceptable salt thereof, or a hydrate thereof. The solution thereto is an industrial preparation process that provides, with high purity, anhydrous crystals of a compound represented by the following formula (1), which is an intermediate for the production of FXa inhibitor compound (X) or a pharmacologically acceptable salt thereof, or a hydrate thereof, wherein Boc represents a tert-butoxycarbonyl group.

PROCESS FOR PRODUCING DIAMINE DERIVATIVE

The problem to be solved is to provide an important intermediate for production of an FXa inhibitor. The solution thereto is a process for industrially producing a compound (1) represented by the following formula (1): wherein Boc represents a tert-butoxycarbonyl group.

METHOD FOR PRODUCING OPTICALLY ACTIVE DIAMINE DERIVATIVE

The problem to be solved is to provide an important intermediate for production of an FXa inhibitor. The solution thereto is a method for industrially producing a compound (1) or a compound (4), comprising: [Step 1]: adding a quaternary ammonium salt and a metal azide salt to water to prepare an aqueous solution of an azidification reagent complex comprising quaternary ammonium salt-metal azide salt, and subsequently dehydrating the aqueous solution using an aromatic hydrocarbon solvent to form a mixed solution of the azidification reagent complex comprising quaternary ammonium salt-metal azide salt and the aromatic hydrocarbon solvent with a water content of 0.2% or less; and [Step 2]: adding, to the mixed solution prepared in [Step 1], a compound (2) wherein L represents a leaving group.

OPTICALLY ACTIVE DIAMINE DERIVATIVE AND PROCESS FOR PRODUCING THE SAME

The invention is directed to a process for producing intermediates of a compound which exhibits an activated blood coagulation factor Xa inhibitory action and which is a useful preventive and a therapeutic agent for thrombotic diseases. The intermediate production process is represented by the following reaction scheme.