KR102333564B1 - A novel synthetic route for the production of optically active diamine derivative and thiazole derivate - Google Patents

Abstract

It relates to a method for preparing an intermediate for the preparation of edoxaban, which is an optically active diamine derivative (compound 7) and thiazole derivative (compound 10), which are intermediates of edoxaban, without the use of high-pressure equipment and metal catalysts, with high yield and purity It relates to a method for producing an intermediate for the production of edoxaban that can be obtained as

Description

A NOVEL SYNTHETIC ROUTE FOR THE PRODUCTION OF OPTICALLY ACTIVE DIAMINE DERIVATIVE AND THIAZOLE DERIVATE

The present invention relates to a main intermediate of a blood coagulation factor Xa (fXa) inhibitor compound and a method for preparing a salt thereof, and more particularly, the clotting factor inhibitor is edoxaban, and an optically active diamine derivative ( 7) and a thiazole derivative (compound No. 10), which can be obtained in high yield and purity without the use of high-pressure equipment and metal catalysts, and relates to a method for preparing an intermediate for the preparation of edoxaban.

Edoxaban and its salts or hydrates exhibit FXa inhibitory effects as disclosed in Patent Documents 1 to 8 described in the following “Prior Art Documents”, and act as an anticoagulant. Accordingly, it is usefully used as a preventive or therapeutic agent for embolic diseases and thrombosis.

Scheme 1 below shows the general synthesis of edoxaban, tert-butyl ((1R,2S,5S)-5-(dimethylcarbamoyl)-2-(1,3-dioxoisoindolin-2-yl)cyclohexyl represented by compound 7 ) 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylic acid represented by carbamate and compound 10 or a salt thereof to produce edoxaban represented by compound 11 It is a major intermediate.

[Scheme 1]

Referring to Scheme 2, Patent Document 6 discloses a method for preparing a major intermediate compound 7 for preparing edoxaban. First, azide compound 16 is prepared from mesyloxy compound 15, and compound 7 is produced through a reduction reaction with metal. An alternative method for preparing compound 7 is disclosed in the same patent and is shown in Scheme 3.

[Scheme 2]

[Scheme 3]

Scheme 4 shows a method for preparing compound 7 due to stereoselective intramolecular cyclization using a sulfonamide derivative, and is disclosed in Patent Document 9 (WO2014/157653).

[Scheme 4]

The process of salt of compound 7 is disclosed in Patent Document 6 (WO2007/032498). As shown in Scheme 5 below, azide compound 27 was prepared from mesyloxy compound 26, reduced, and then compound 7 was induced by deprotecting the benzyl group.

[Scheme 5]

The preparation method of compound 10 is a method of producing a bromide derivative by diazotation reaction from 1-methylpiperidine-4-one represented by compound 31, and converting it into a carboxylic acid compound. A method for preparing by decomposition is disclosed in Patent Document 5 (WO2005/047296).

[Scheme 6]

In addition, as shown in Scheme 7, a method for preparing a carboxylic acid salt form 10a by making a bromide derivative through a Sandmayer-like reaction from an amine derivative and reacting it with carbon dioxide to nucleophilic acid is disclosed in Patent Document 10 (WO2012/017932).

[Scheme 7]

However, since the above methods use high-pressure equipment and a metal catalyst to produce a major intermediate, and use explosive hydrogen, safety concerns are high when commercially produced.

Patent Document 1: International Publication No. WO2003/000657 (A1) Patent Document 2: International Publication No. WO2003/000680 (A1) Patent Document 3: International Publication No. WO2004/058715 (A1) Patent Document 4: International Publication No. WO2004/058728 (A1) Patent Document 5: International Publication No. WO2005/047296 (A1) Patent Document 6: International Publication No. WO2007/032498 (A1) Patent Document 7: International Publication No. WO2008/16159 (A1) Patent Document 8: International Publication No. WO2008/129846 (A1) Patent Document 9: International Publication No. WO2014/157653 (A1) Patent Document 10: International Patent Publication No. WO2012/017932 (A1)

Since the existing method for preparing the edoxaban intermediate uses high-pressure equipment and a metal catalyst, there was a problem that there was a great concern about safety when commercially produced because it uses explosive hydrogen, so the researchers of the present invention The present invention was reached by conducting a study on a new preparation method capable of ensuring safety and having a high yield in the preparation method of compound 7 and compound 10 or a salt thereof, which are major intermediates.

The present invention can be synthesized by a new method for preparing the compounds represented by Chemical Formulas 7 and 10 or salts thereof, which are major intermediates of Fxa inhibitor compounds, which can be safely produced in high yield without using high-pressure equipment, explosive gases and metal catalysts. is to provide

In order to solve the above problems, the present invention provides means for solving various aspects as follows.

In one aspect of the present invention, in the method for preparing an edoxaban intermediate compound represented by the following formula (7), the method comprises reacting the compound represented by the following formula (4) with phthalimide to obtain a compound represented by the formula (6) manufacturing; And reacting the compound represented by Formula 6 in the presence of methylamine or hydrazine hydrate to prepare a compound represented by Formula 7; Edoxaban intermediate represented by Formula 7, including; Methods for preparing the compounds are provided:

[Formula 7]

[Formula 4]

[Formula 6]

.

.

In one aspect of the present invention, in the method, the compound represented by the following formula (3) is reacted with triphenylphosphine and then reacted with di-tert-butyl dicarbonate (di-tert-butyl dicarbonate) It provides a preparation method, further comprising the step of preparing a compound represented by 4:

[Formula 3]

.

.

In one aspect of the present invention, the method further comprises the step of reacting the compound represented by the following formula (2) with sodium azide in the presence of ammonium chloride to prepare a compound represented by the formula (3) There is provided a manufacturing method comprising:

[Formula 2]

In one aspect of the present invention, the method is a compound represented by the following formula (1) dicyclohexylcarbodiimide (Dicyclohexylcarbodiimide, DCC), hydroxybenzotriazole (Hydroxybenzotriazole, HOBt), triethylamine (triethylamine) and dichloro It provides a preparation method, further comprising the step of preparing a compound represented by Formula 2 by reacting with dimethylamine hydrochloride in the presence of methane (dichloromethane):

[Formula 1]

In one aspect of the present invention, the phthalimide is used in 1 to 3 equivalents based on the compound represented by Formula 4, and the methylamine is used in 2 to 8 equivalents based on the compound represented by Formula 6 A manufacturing method is provided.

In one aspect of the present invention, the triphenylphosphine is used in an amount of 1 to 6 equivalents based on the compound represented by Formula 3, and provides a preparation method.

In one aspect of the present invention, the sodium azide is used in an amount of 1 to 5 equivalents based on the compound represented by Formula 2, to provide a preparation method.

In one aspect of the present invention, the dicyclohexylcarbodiimide is used in 1 to 2 equivalents based on the compound represented by Formula 1, and the hydroxybenzotriazole is 1 based on the compound represented by Formula 1 used in equivalents to 2 equivalents, is provided.

In another aspect of the present invention, in the method for preparing an edoxaban intermediate compound represented by the following formula (7), the method is a reduction reaction of the compound represented by the following formula (16) in the presence of triphenylphosphine and a solvent to edoxa represented by the formula (7) A process for preparing a semi-intermediate compound is provided, comprising the steps of:

[Formula 7]

[Formula 16]

.

.

In another aspect of the present invention, the solvent is tetrahydrofuran or ethanol.

In another aspect of the present invention, in the method for preparing an edoxaban intermediate compound or a salt thereof represented by the following formula (10), the method comprises (a) a compound represented by the following formula (8) under basic conditions with dimethylsulfate (dimethylsulfate) and reacting to prepare a compound represented by Formula 9; and (b) preparing a compound represented by Formula 10 by reacting the compound represented by Formula 9 with sodium borohydride and hydrolysis with an inorganic base;

[Formula 10]

[Formula 8]

[Formula 9]

.

.

In another aspect of the present invention, the method comprises the steps of (c) reacting the edoxaban intermediate compound represented by Formula 10 with hydrochloride to prepare a salt of the edoxaban intermediate compound represented by Formula 10; It provides a manufacturing method comprising:

In another aspect of the present invention, in step (a), dimethyl sulfate is used in an amount of 1 to 4 equivalents based on the compound represented by Formula 8, the base is an inorganic base, and the step is dimethylformamide ( N,N-dimethylformamide), dichloromethane (dichloromethane), chloroform (chloroform), and tetrahydrofuran (tetrahydrofuran) in the presence of a solvent selected from the reaction, provides a preparation method.

In another aspect of the present invention, in step (b), sodium borohydride is used in an amount of 1 to 3 equivalents based on the compound represented by Formula 9, and the inorganic base in step (b) is represented by the above formula It provides a preparation method, which is used in an amount of 1 to 5 equivalents based on the compound represented by 9.

In another aspect of the present invention, in step (c), hydrochloride is used in an amount of 1 to 6 equivalents based on the compound represented by Formula 10, to provide a preparation method.

According to the manufacturing method of the intermediate for the preparation of edoxaban according to an aspect of the present invention, it is possible to mass-produce the intermediate for the preparation of edoxaban with high yield and purity.

According to the manufacturing method of the intermediate for the preparation of edoxaban according to an aspect of the present invention, it is possible to mass-produce an intermediate for the preparation of edoxaban that can be safely mass-produced without the use of high-pressure equipment and a metal catalyst.

The above objects, other objects, features and advantages of the present invention will be easily understood through the following preferred embodiments in conjunction with the accompanying drawings. However, the present invention is not limited to the embodiments described herein and may be embodied in other forms. Rather, the embodiments introduced herein are provided so that the disclosed content may be thorough and complete, and the spirit of the present invention may be sufficiently conveyed to those skilled in the art.

Unless otherwise specified, all numbers, values, and/or expressions expressing ingredients, reaction conditions, and amounts of ingredients used herein refer to a variety of measures that may occur in obtaining such values, among others, in which such numbers are inherently different. Since they are approximations reflecting uncertainty, it should be understood as being modified by the term "about" in all cases. Also, where the disclosure discloses numerical ranges, such ranges are continuous and inclusive of all values from the minimum to the maximum inclusive of the range, unless otherwise indicated. Furthermore, when such ranges refer to integers, all integers inclusive from the minimum to the maximum inclusive are included, unless otherwise indicated.

In this specification, when a range is described for a variable, the variable will be understood to include all values within the stated range including the stated endpoints of the range. For example, a range of “5 to 10” includes the values of 5, 6, 7, 8, 9, and 10, as well as any subranges such as 6 to 10, 7 to 10, 6 to 9, 7 to 9, etc. It will be understood to include any value between integers that are appropriate for the scope of the recited range, such as 5.5, 6.5, 7.5, 5.5 to 8.5 and 6.5 to 9, and the like. Also for example, a range of "10% to 30%" includes values such as 10%, 11%, 12%, 13%, and all integers up to and including 30%, as well as 10% to 15%, 12% to It will be understood to include any subrange, such as 18%, 20% to 30%, etc., as well as any value between reasonable integers within the scope of the recited range, such as 10.5%, 15.5%, 25.5%, and the like.

In the present application, terms such as “comprise” or “have” are intended to designate that a feature, number, step, operation, component, part, or combination thereof described in the specification exists, but one or more other features It is to be understood that it does not preclude the possibility of the presence or addition of numbers, steps, operations, components, parts, or combinations thereof.

In the present specification, "a compound represented by Formula X" and "Compound X" are used with the same meaning. In one embodiment, "compound represented by formula 7" means "compound 7", and "compound 7" means "compound represented by formula 7".

A method for preparing the compounds represented by Chemical Formulas 7 and 10 or salts thereof, which are major intermediates according to an embodiment of the present invention, will be described in the following steps.

First, in order to prepare compound 7, a step of reacting from compound 1 represented by formula 1 with dimethyl amine hydrochloride in the presence of a coupling reagent to obtain compound 2 represented by formula 2, and ring opening reaction of epoxide with sodium azide preparing compound 3 represented by formula 3 by To provide compound 6 represented by formula 6 by stereochemical inversion through Mistunobu reaction under .

The present invention also provides a step for preparing compound 7 by reducing the azide compound with triphenylphosphine.

The manufacturing process of compound 1 is reported in Journal of the American Chemistry Society, 1990, 112, 2993-3017, and compound 16 is described in Bioorganic & Medicinal chemistry 17 (2009) 8206-8220.

[Formula 1]

[Formula 2]

[Formula 3]

[Formula 4]

[Formula 6]

[Formula 7]

[Formula 16]

The steps of the preparation method of the compound represented by the formula 10 include the steps of obtaining the compound 9 represented by the formula 9 by reacting the compound 8 represented by the formula 8 with dimethyl sulfate under basic conditions, and a reduction reaction of the obtained compound 9 with sodium borohydride. and hydrolyzing with an inorganic base to obtain Compound 10 represented by Formula 10 or a salt thereof.

The preparation method of compound 8 is described in Journal of Heterocyclic chemistry, 27, 1990, 563-566, Bioorganic and medicinal chemistry, 2004, 12, 5579-5586.

[Formula 8]

[Formula 9]

[Formula 10]

Scheme 8 below shows a scheme schematically illustrating a method for preparing compound 7.

[Scheme 8]

In the step of preparing compound 2, N,N'-dicyclohexylcarbodiimide (DCC) is used in 1 to 2 equivalents based on compound 1, preferably 1 equivalent. Hydroxy benzotriazole is used in 1 to 2 equivalents based on Compound 1, preferably 1 equivalent. There are no restrictions on the use of bases and solvents, but triethylamine and dichloromethane are used.

Sodium azide used in the step of preparing compound 3 is used in an amount of 1 to 5 equivalents, but preferably 3 equivalents based on 1 mole of compound 2 is appropriate. Ammonium chloride is used in an amount of 1 to 4 equivalents, and it is preferable to use 2 equivalents based on Compound 2. The solvent includes one of methanol, ethanol, and isopropyl alcohol, and preferably methanol is used. The reaction conditions are typically in the range of 80°C to 95°C, stirring for 10 to 20 hours, and preferably stirring for 15 hours.

Triphenylphosphine in the preparation step of compound 4 is used in 1 to 6 equivalents based on compound 3, but preferably 2 equivalents, and di-tert-butyldicarbonate is preferably used in 2 equivalents within the range of 1 to 3 equivalents. The base and solvent are not limited, but relatively triethylamine and tetrahydrofuran are used.

In the preparation of compound 6, 1 to 3 equivalents of pthalimide are used based on compound 4, but preferably 1 equivalent is used for the reaction, and 1.1 equivalents of triphenylphosphine is preferably used within the range of 1 to 2 equivalents. Diisopropylazodicarboxylate is preferably used in an amount of 1.1 equivalents in the range of 1 to 3 equivalents. As the solvent, tetrahydrofuran is used, and the reaction can be carried out at room temperature for 5 to 20 hours, but preferably 10 hours is appropriate. As a purification solvent for crystallization of the product, diethylether, diisopropylether, or methyl tert-butylether may be used, and diisopropylether is preferable.

In the step for preparing compound 7, 4 equivalents of methylamine is appropriate within the range of 2 to 8 equivalents. As the solvent, methyl alcohol or ethyl alcohol may be used, but ethyl alcohol is preferably used.

Referring to Scheme 9 below, a method for preparing compound 10 will be schematically described.

[Scheme 9]

In the step of preparing compound 9, the reaction proceeds under basic conditions, and 2 equivalents of dimethylsulfate is appropriate within the range of 1 to 4 equivalents. As the base used, inorganic bases such as sodium carbonate and potassium carbonate are used, but potassium carbonate is appropriate. . The solvent includes N,N-dimethylformamide, dichloromethane, chloroform, and tetrahydrofuran, and N,N-dimethylformamide is suitable.

In the step of preparing Compound 10 or a salt thereof, 1 to 3 equivalents of sodium borohydride is used based on Compound 9, and preferably 1.3 equivalents is appropriate. As the base used, an inorganic base such as sodium hydroxide or potassium hydroxide is used, but sodium hydroxide is preferably used, and 3 equivalents is appropriate within the range of 1 to 5 equivalents based on compound 9. In order to prepare the salt of compound 10, hydrochloric acid is used, and 5eq of 6N is suitable within the range of 1N to 6N and 1 equivalent to 6 equivalents.

Hereinafter, the present invention will be described in more detail through specific examples. The following examples are merely examples to help the understanding of the present invention, and the scope of the present invention is not limited thereto.

Example 1: Preparation of (1S,3S,6R)-7-oxabicyclo[4.1.0]heptane-3-carboxylic acid (1) (Journal of the American Chemical Society, 1990, 112, 2998-3017)

In a reactor in which (S)-cyclohex-3-ene-1-carboxylic acid 39 (10.0 g, 0.079 mol) is dissolved in dichloromethane (100 ml), meta-chloroperbenzoic acid (13.6 g, 0.079 mol) in dichloromethane (100 ml) ) was slowly added dropwise and stirred at room temperature for 3 hours. Upon completion of the reaction, 0.2M NaOH (100 ml) was added to extract. After layer separation, the aqueous layer was extracted with dichloromethane (150 ml), and the layers were separated. The separated organic layers were combined and washed with 0.2M NaOH (100 ml) and purified water (150 ml), and then the organic layer was separated. Moisture was removed from the organic layer with Na2SO4, and the solvent was removed through filtration and concentration under reduced pressure. The concentrated resultant was purified by column (MeOH/Dichloromethane) to obtain a product. [9.0 g, 80%]. Purity [98.5%].

Example 2: Preparation of (1S,3S,6R)-N,N-dimethyl7-oxabicyclo[4.1.0]heptane-3-carboxamide (2)

(1S,3S,6R)-7-oxabicyclo[4.1.0]heptane-3-carboxylic acid 1 (15 g, 0.106 mol), dicyclohexylcarbodiimide (21.78 g 0.106 mol), 1-hydroxybenzotriazole (14.26 g, 0.106 mol), Triethylamine (10.6 g, 0.117 mol) was dissolved in dichloromethane (150 ml) and stirred at room temperature for 10 minutes. Then, dimethylamine hydrochloride (8.5 g, 0.106 mol) was added and stirred at room temperature for 12 hours. The resulting solid was filtered and washed by adding 1N NaOH (50 ml) to the filtrate. The aqueous layer was extracted with dichloromethane (2 x 50 ml), the organic layers were combined, dried over MgSO4, filtered, concentrated, and purified by silica column (5% MeOH/CH2Cl2) to obtain a product. [16 g, 90%]. Purity [99%].

Example 3: Synthesis of (1S,3R,4R)-3-azido-4-hydroxy-N,N-dimethylcyclohexane-10carboxamide (3)

(1S,3S,6R)-N,N-dimethyl-7-oxoabicyclo[4.1.0]heptane-3-carboxamide 2 (20 g, 0.118 mol) was dissolved in methanol (200 ml) in a reactor with ammoniumchloride (12, 6 g, 0.236 mol) and sodium azide (23.0 g, 0.354 mol) in purified water (100 ml) were added dropwise at 0° C. for 30 minutes, followed by stirring at 90° C. for 15 hours. Upon completion of the reaction, the reaction mixture was filtered, cooled to room temperature, and concentrated under reduced pressure to remove methanol. Purified water (100 ml) and dichloromethane (200 ml) were added to the concentrated resultant, followed by extraction. The organic layer was washed with purified water (100 ml x 3), the separated organic layers were combined, and moisture was removed with Na2SO4. The organic layer from which moisture was removed was filtered, and the filtrate was concentrated to obtain a product. [21.3 g, 85%]. Purity [98.2%].

Example 4: Synthesis of tert-butyl ((1R,2R,5S)-5-(dimethylcarbamoyl)-2-hydroxycyclohexyl)carbamate (4)

(1S,3S,4R)-3-azido-4-hydroxy-N,N-dimethylcyclohexane-1-carboxamide 3 (15 g, 0.0707 mol) and triphenylphosphine (18.5 in a mixture of THF/H2O (150 ml/5 ml) g, 0.141 mol) and stirred at room temperature for 6 hours. Additionally, THF (50 ml), di-tert-butyl decarbonate (15.4 g, 0.078 mol), and triethylamine (7.15 g, 0.141 mol) were added and stirred at room temperature for 4 hours. After completion of the reaction, THF was removed by concentration under reduced pressure, dichloromethane (300 ml) was added, and extraction was performed. The separated organic layer was filtered after removing moisture with Na2SO4, and the solvent was removed from the filtrate by concentration under reduced pressure. The product was obtained by crystallization with ethyl acetate (100 ml). [18.2 g, 90%]. Purity [99.1%].

Example 5: Tert-butyl ((1R,2R,5S)-5-(dimethylcarbamoyl)-2-(1,3-dioxoisoindolin-2-yl)cyclohexyl)carbamate (6)

Tert-butyl ((1R,2R,5S)-5-(dimethylcarbamoyl)-2-hydroxycyclohexyl)carbamate 4, phthalimide 5 (15.41 g, 0.105 mol), triphenylphosphine (30.22 g, 0.115 mol), tetrahydrofuran (200 ml) A solution of diisopropylazodicarboxylate (23.31 g, 0.115 mol) in tetrahydrofuran (100 ml) in tetrahydrofuran (100 ml) was slowly added dropwise at 0° C., stirred for 30 minutes, and then stirred at room temperature for 10 hours. Upon completion of the reaction, a supersaturated aqueous sodium chloride solution (100 ml) was added, followed by extraction with ethylacetate (100 ml x 3). The separated organic layer was dried with NaSO4, filtered, and the solvent of the filtrate was removed by concentration under reduced pressure. The formed crystal was released by ether to obtain a product. [38.3 g, 88%]. Purity [98.3%].

Example 6: Synthesis of tert-butyl ((1R,2S,5S)-2-amino-5-(dimethylcarbamoyl)cyclohexyl)carbamate (7)

Dissolve tert-butyl ((1R,2S,5S)-5-(dimethylcarbamoyl)-2-(1,3-dioxoisoindolin-2-yl)cyclohexyl)carbamate 6 (10 g, 0.024 mol) in ethanol (50 ml) Then, an aqueous solution of monomethyl amine (35 ml) was added at 25-30°C. The reaction mixture was heated to reflux for 3 hours and then concentrated to remove the reaction solvent. After extraction with purified water and dichloromethane, the separated organic layer was dried with Na2SO4. The organic layer was filtered, and the solvent was removed from the filtrate by concentration under reduced pressure to obtain a product [5.84 g, 85%]. Purity [99.8%].

Melting Point: 121.7-121.0℃

Example 7: Synthesis of Tert-butyl((1R,2S,5S)-2-amino-5-(dimethylcarbamoyl)cyclohexyl)carbamate (7):

tert-butyl((1R,2S,5S)-2-azido-5-(dimethylcarbamoyl)cyclohexyl)carbamate 16 (10 g, 0.032 mol), Methanol/H2O (100 ml/5 ml), triphenylphosphine (25.27 g , 0.096 mol) and stirred at room temperature for 10 hours. After completion of the reaction, the reaction solvent is removed by distillation under reduced pressure, and dichloromethane and purified water are added for extraction. After removing moisture from the separated organic layer and filtering, the solvent of the filtrate was removed by concentration under reduced pressure. The concentrated product was crystallized with acetonitrile to obtain a product. [7.79 g, 80%]. Purity [99%].

Example 8: Synthesis of Thiazole [5.4-c] pyridine (33) (Journal of Heterocyclic chemistry, 27,1990,563-566)

4-aminopyridine-3-thiol 39 (10 g, 0.079 mol), ethanol (90 ml), and formic acid (10 ml) were placed in a reactor and heated to reflux for 4 hours. After completion of the reaction, it was poured into purified water (50 ml) and extracted with 5N NaOH and ethyl acetate. The separated organic layer was removed from moisture and concentrated to obtain a product. [9.71 g, 90%]. Purity [97%].

Example 9: Synthesis of Thiazole[5,4-c]pyridine-2-carboxylic acid (8) (Bioorganic and medicinal chemistry, 2004, 12, 5579-5586)

n-BuLi (1.54 M in hexanes, 0.162 mol) was added dropwise to thiazole[5,4-c]pyridine 33 (20 g, 0.147 mol) in Tetrahydrofuran (200 ml) under nitrogen at -78°C for 20 minutes, and CO2 The gas was introduced by bubbling for 30 minutes. After the reaction was allowed to warm to room temperature, the solvent was removed by concentration under reduced pressure to obtain a product. [24.3 g, 92%]. Purity [98.9%].

Example 10: Synthesis of 2-(methoxycarbonyl)-5-methylthiazolo[5.4-c]pyridine-5-ium(9)

Put thiazolo[5,4-c]pyridine-2-carboxylic acid 8 (18 g, 0.1 mol), potassium carbonate (27.64 g, 0.2 mol), dimethylformamide (180 ml) in a reactor and heat to 65°C, then dimethylsulfate (23.5 g, 0.2 mol) was slowly added dropwise over 30 minutes. The reaction mixture was stirred at 80° C. for 1 hour and then poured into ice water. The resulting crystals were filtered and vacuum dried to obtain a product. [18.6 g, 89%]. Purity [99%].

Example 11: Synthesis of 5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxylic acid (10)

2-(methoxycarbonyl)-5-methylthiazolo[5,4-c]pyridine-5-ium 9 (100.0 g, 1.0 eq), methanol (10 V, 1000 ml) was put into a reactor, and the mixture was stirred at room temperature. After cooling to 10° C., sodium borohydride (23.5 g, 1.3 equivalents) was slowly added over 3 times in 30 minutes. The reaction mixture was stirred at room temperature for 5 hours and aqueous NaOH solution (57.4 g of sodium hydroxide in 200 ml of purified water, 3.0 eq.) was added over 10 minutes. After heating to reflux at 75° C. for 2 hours, it was cooled and stirred at room temperature for 1 hour. Acetic acid (100 ml) was added to the reaction mixture, titrated to pH 6.5-7, and the resulting solid was filtered and dried to obtain a product. [79.5 g, 84%]. Purity [98.7%].

Example 12: Synthesis of 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylic acid hydrochloride (10a)

2-(methoxycarbonyl)-5-methylthiazolo[5,4-c]pyridine-5-ium 9 (100.0 g, 1.0 equiv) and methanol (10V, 1000 ml) were added to the reactor and cooled to 10°C. Sodium borohydride (23.5 g, 1.3 equivalents) was added dropwise over 3 times over 30, followed by stirring at room temperature for 5 hours. An aqueous NaOH solution (57.4 g of sodium hydroxide in 200 ml of purified water, 3.0 equivalents) was added to the reactor over 10 minutes and heated to reflux at 75° C. for 2 hours. Upon completion of the reaction, the mixture was stirred at room temperature for 1 hour and then titrated to pH 1-2 by adding 6N HCl (50 ml, 5 equivalents) at 0°C. The resulting solid was filtered and dried to obtain a product. [90.6 g, 81%]. Purity [99%].

In the above, the embodiments of the present invention have been described, but those of ordinary skill in the art to which the present invention pertains will understand that the present invention may be implemented in other specific forms without changing the technical spirit or essential features. . Therefore, it should be understood that the embodiments described above are illustrative in all respects and not restrictive.

Claims (15)

In the method for preparing an intermediate compound of edoxaban represented by the following formula (7), the method comprises:
preparing a compound represented by Formula 4 by reacting the compound represented by the following Chemical Formula 3 with triphenylphosphine and then reacting it with di-tert-butyl dicarbonate;
preparing a compound represented by Formula 6 by reacting the compound represented by Formula 4 with phthalimide; and
Preparing a compound represented by Formula 7 by reacting the compound represented by Formula 6 in the presence of methylamine or hydrazine hydrate; including,
Method for preparing edoxaban intermediate compound represented by Formula 7:
[Formula 7]

[Formula 3]

[Formula 4]

[Formula 6]

.
delete The method of claim 1,
The method further comprises the step of reacting the compound represented by the following formula (2) with sodium azide in the presence of ammonium chloride to prepare a compound represented by the formula (3):
[Formula 2]

.
4. The method of claim 3,
The method is a compound represented by the following formula (1) dicyclohexylcarbodiimide (Dicyclohexylcarbodiimide, DCC), hydroxybenzotriazole (Hydroxybenzotriazole, HOBt), triethylamine (triethylamine) and dichloromethane (dichloromethane) in the presence of dimethyl Further comprising the step of preparing a compound represented by Formula 2 by reacting with amine hydrochloride (dimethylamine hydrochloride), the preparation method:
[Formula 1]

The method of claim 1,
The phthalimide is used in an amount of 1 to 3 equivalents based on the compound represented by Formula 4,
The methylamine is used in an amount of 2 to 8 equivalents based on the compound represented by Formula 6.
The method of claim 1,
The triphenylphosphine is used in an amount of 1 to 6 equivalents based on the compound represented by Formula 3.
4. The method of claim 3,
The sodium azide is used in an amount of 1 to 5 equivalents based on the compound represented by Formula 2, the manufacturing method.
5. The method of claim 4,
The dicyclohexylcarbodiimide is used in an amount of 1 to 2 equivalents based on the compound represented by Formula 1,
The hydroxybenzotriazole is used in an amount of 1 to 2 equivalents based on the compound represented by Formula 1.
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