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Preparation method of edoxaban tosylate and isomers thereof
The invention discloses a preparation method of edoxaban tosylate and isomers thereof. By taking a compound (I) and a compound (II) as starting materials, the method can be used to prepare any one ofhigh-purity edoxaban tosylate (1S, 2R, 4S), edoxaban tosylate enantiomers (1R, 2S, 4R), edoxaban tosylate epimers (1R, 2R, 4S) and edoxaban tosylate epimers (1S, 2S, 4R). Effective guarantee is provided for process research and quality control of the edoxaban tosylate bulk drug and related preparations, the preparation method is suitable for commercialization, the produced edoxaban tosylate bulk drug is high in purity and has great significance and practical value, and the production of the edoxaban tosylate bulk drug and the control of drug quality are facilitated.
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(2021/02/06)

Preparation method of edoxaban and intermediate thereof
The invention relates to a preparation method of edoxaban and an intermediate thereof. A compound 1, a compound 2 and a compound 5 which are taken as initial raw materials are subjected to an ammonolysis reaction, a deprotection reaction, a carboxylation reaction and a condensation reaction to generate edoxaban. Compared with the prior art, the preparation method is higher in operability and safety during amplified production, and the obtained product is high in yield and purity.
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Paragraph 0036-0037

(2021/06/12)

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.
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Page/Page column 12; 20-22

(2021/01/23)

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.
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Paragraph 0074-0076

(2020/07/21)

Improved preparation method of edoxaban intermediate
The invention belongs to the field of organic synthesis, and particularly relates to an improved preparation method of an edoxaban intermediate. In most preparation methods for preparing the compound(1), a system is extremely easy to be in a cured state in the reaction process, the system is difficult to stir, and finally, the problems of product yield reduction, quality deterioration and the like are caused. In order to solve the problem of curing in the system, the improved preparation method of an edoxaban intermediate is expected to be provided. In the process of synthesizing the compound(1), alcohol or a mixture of alcohol and acetonitrile is used as a reaction solvent, so that the reaction system is in a clear state at the beginning, the product is gradually separated out along with the reaction, the product is uniformly dispersed in the solvent in the whole process from the beginning to the end of the reaction and is easy to stir, and the curing problem in the reaction processis effectively solved.
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Paragraph 0023-0064

(2020/10/21)

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
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Paragraph 0032; 0033; 0046

(2020/02/07)

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).
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Page/Page column 14-15

(2019/09/04)

Preparation method of antithrombotic drug
The invention relates to a preparation method of an antithrombotic drug, belongs to the technical field of medicinal chemistry and in particular relates to a preparation method of a direct coagulationfactor Xa inhibitor, which is shown as the following reaction. Compared with the existing process, the preparation method has the advantages of mild reaction condition in each step, high yield, simplicity and convenience operation, stable process and suitability for large-scale industrial production.
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Paragraph 0039; 0040; 0042; 0046; 0050; 0054; 0058

(2018/04/02)

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.
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(2018/02/20)

Preparation method of edoxaban p-toluenesulfonate monohydrate
The invention provides a preparation method of edoxaban p-toluenesulfonate monohydrate. According to the preparation method, an appropriate amount of a specific ionic liquid is added, a specific ratioof a combination of triethylamine and pyridine is selected as a base, the rapid progress of a reaction is facilitated, and improvements on the production rate and the product purity are facilitated.
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Paragraph 0048-0049; 0081-0088

(2018/09/21)

METHOD FOR PRODUCING INHIBITOR OF ACTIVATED BLOOD COAGULATION FACTOR X (FXA)
An object of the present invention is to provide a novel method for producing a compound, a salt thereof, or a hydrate of the compound or the salt, which is an FXa inhibitor. The object can be attained by a production method in which a production method via a compound represented by formula (1-1), etc., from a compound represented by the following formula (1-x), etc., is used for a method for producing a compound represented by the following formula (X), etc. [wherein X represents a halogen atom or the like, and R1 represents an optionally substituted phenyl group].
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Paragraph 0173; 0174

(2017/03/21)

PROCESS FOR PRODUCING DIAMINE DERIVATIVE
The present invention provides a low-toxic and high-recovery industrial process for synthesizing an optically active diamine derivative represented by formula (D), the process comprising the steps of: (a) mixing a compound represented by formula (A) and a compound represented by formula (C) in organic solvents and secondary amine; (b) reaction under heating; (c) cooling and adding water to the mixed solution, allowing it to crystallize to obtain the compound represented by formula (D).
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Paragraph 0038-0039

(2017/08/16)

A according to the synthetic method of sha Ban
The invention provides a synthesis method of edoxaban, which includes: [step 1]: adding a compound (2) to a solvent of a nitrile being 2-4 in carbon atom number to remove an N-Boc protective group under an acidic condition to obtain a compound (2-a); and [step 2]: treating a reaction liquid in the (step 1) with an tertiary amine and adding a compound (3) to carry out a reaction, and finally treating the reaction liquid after the reaction finished with an alkali liquid. Compared with a method of synthesizing the edoxaban in the prior art in references, the method is mild in the conditions of the reactions and is high in yield. The raw materials are easy to obtain. The method is simple in operations and is stable in processes, is free of column chromatography for purifying the product and can enable the product to achieve a medicinal requirement just by one time of purification, so that the method is more suitable for industrialized production.
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Paragraph 0043; 0044; 0045; 0046; 0047; 0048

(2017/08/25)

Preparation method of edoxaban intermediate
The invention belongs to the technical field of chemical drug synthesis, and in particular, relates to a preparation method of an edoxaban intermediate tert-butyl(1S,2R,4S)-1-({2-[(5-chloro-2-pyridine-2-yl)amino]-2-oxoacetyl}amino)-4-(dimethyl aminocarbonyl)cyclohexyl-2-carbamate. The method takes tert-butyl{(1R,2S,5S)-2-amino-5-[(dimethylamino)carbonyl]cyclohexy}carbamate oxalate hydrate and 2-[(5-chloropyridine-2-yl)amino]-2-oxo-acetic acid as raw materials, and the edoxaban intermediate is prepared through condensation reaction of the raw materials. The method has the advantages of moderate technological conditions, simple postprocessing, high purity, low reaction cost, and easy realization of industrialized production.
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Paragraph 0019; 0025

(2017/02/09)

Preparation method for free-state edoxaban
The invention discloses a preparation method for free-state edoxaban.The synthetic route is shown in the description.According to the preparation method, the charging sequence is changed, and a curing problem caused by a traditional method is reduced; according to an existing method, a starting material A and triethylamine are added at first, a starting material B is added, a large amount of solid will appear in the temperature increasing process, and the stirring uniformity is greatly affected, so that the yield is greatly lowered, and the method is adopted for greatly solving the problem and improving the yield; when the compound free-state edoxaban is synthetized, a first amount of a saturated sodium bicarbonate water solution is added at first, the phenomenon that a product is rapidly separated out and impurities are included due to the fact that the added saturated sodium bicarbonate water solution is excessive is avoided, and meanwhile introduction of genotoxicity impurity methanesulfonate is effectively avoided; after the impurities are completely hydrolyzed, a second amount of the saturated sodium bicarbonate water solution is added so that the product can be separated out thoroughly; the method improves the crystallization way, the yield is improved, and generation of impurities is reduced.
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Paragraph 0012

(2016/11/17)

A method for producing an optically active Dimamine deriv.
The problem to be solved is to provide a method for efficiently producing compounds (1) and (1a) that are important intermediate compounds in the production of FXa inhibitors (X) and (X-a). The solutions thereto are a method for producing a compound represented by the formula (8d) using a stereoselective intramolecular cyclization reaction, and a method for producing a compound (If) or a salt thereof, or a hydrate thereof, which is characterized by desulfonylation of the compound (8d). In each formula, R 4a represents a C1-C6 alkyl group, a benzyl group, etc.
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(2016/10/09)

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.
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(2015/12/26)

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).
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(2014/06/11)

PROCESS FOR PREPARING A COMPOUND BY A NOVEL SANDMEYER-LIKE REACTION USING A NITROXIDE RADICAL COMPOUND AS A REACTION CATALYST
The present invention provides a novel process for preparing a substituted aromatic compound such as an aromatic halo compound or a salt thereof through a transformation reaction of an aromatic diazonium salt from an aromatic amino compound at stable high yields utilizing a novel Sandmeyer-like reaction using a nitroxide radical compound as a reaction catalyst.
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Paragraph 0257; 0258; 0259

(2013/06/26)

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.
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(2013/05/22)

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.
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Page/Page column 19

(2012/02/04)

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.
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(2012/02/04)

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.
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Page/Page column 47

(2008/12/05)

Diamine derivatives
A compound represented by the general formula (1): Q1-Q2-T0-N(R1)-Q3-N(R2)-T1-Q4??(1) wherein R1 and R2 are hydrogen atoms or the like; Q1 is a saturated or unsaturated, 5- or 6-membered cyclic hydrocarbon group which may be substituted, or the like; Q2 is a single bond or the like; Q3 is a group in which Q5 is an alkylene group having 1 to 8 carbon atoms, or the like; and T0 and T1 are carbonyl groups or the like; a salt thereof, a solvate thereof, or an N-oxide thereof. The compound is useful as an agent for preventing and/or treating cerebral infarction, cerebral embolism, myocardial infarction, angina pectoris, pulmonary infarction, pulmonary embolism, Buerger's disease, deep venous thrombosis, disseminated intravascular coagulation syndrome, thrombus formation after valve or joint replacement, thrombus formation and reocclusion after angioplasty, systemic inflammatory response syndrome (SIRS), multiple organ dysfunction syndrome (MODS), thrombus formation during extracorporeal circulation, or blood clotting upon blood drawing.
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(2008/06/13)

DIAMINE DERIVATIVES
A compound represented by the general formula (1):Q1-Q2-T0-N(R1)-Q3-N(R2)-T1-Q4 wherein R1 and R2 are hydrogen atoms or the like; Q1 is a saturated or unsaturated, 5- or 6- membered cyclic hydrocarbon group which may be substituted, or the like; Q2 is a single bond or the like; Q3 is a group in which Q5 is an alkylene group having 1 to 8 carbon atoms, or the like; and T0 and T1 are carbonyl groups or the like; a salt thereof, a solvate thereof, or an N-oxide thereof. The compound is useful as an agent for preventing and/or treating cerebral infarction, cerebral embolism, myocardial infarction, angina pectoris, pulmonary infarction, pulmonary embolism, Buerger's disease, deep venous thrombosis, disseminated intravascular coagulation syndrome, thrombus formation after valve or joint replacement, thrombus formation and reocclusion after angioplasty, systemic inflammatory response syndrome (SIRS), multiple organ dysfunction syndrome (MODS), thrombus formation during extracorporeal circulation, or blood clotting upon blood drawing.
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Page 252; 259

(2008/06/13)