Novel method for preparing edoxaban

Abstract

The present invention relates to a novel method for preparing edoxaban, specifically to a novel method that can facilitate mass production of edoxaban by using an intermediate activation method, that is, a novel industrial method for preparing edoxaban that uses the anhydrous form of an intermediate.

Description

A novel method for manufacturing edoxaban

[0001] The present invention relates to a novel method for manufacturing edoxaban, and more particularly, to a novel method for manufacturing edoxaban capable of mass-producing edoxaban by a novel industrial manufacturing method utilizing an activation method of an intermediate.

[0002] Edoxaban is a compound represented by the following chemical formula 1, and its chemical name is N-(5-chloropyridin-2-yl)-N'-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydropyridinyl)

[0003] Drotiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)ethanediamide.

[0004]

[0005]

[0006] <Chemical Formula 1>

[0007]

[0008] The edoxaban compound of the above chemical formula 1 exhibits an inhibitory effect on activated blood coagulation factor X (FXa), usually in the form of a pharmacologically acceptable salt or hydrate thereof, and is therefore useful as a drug for the prevention and / or treatment of thrombotic diseases.

[0009]

[0010] There are many known manufacturing methods for producing edoxaban of the above chemical formula 1, which exhibits such efficacy.

[0011]

[0012] The general synthesis method of edoxaban is the method represented by the following reaction scheme 1.

[0013]

[0014]

[0015] <Reaction Scheme 1>

[0016]

[0017] First, through the coupling reaction of the compound 2, 't-butyl{(1R,2S,5S)-2-amino-5-(dimethylcarbamoyl)cyclohexyl}carbamate' and the compound 3, '2-{(5-chloropyridin-2-yl)amino}-2-oxoacetic acid', the compound 4, 't-butyl((1R,2S,5S)-2-(2-((5-chloropyridin-2-yl)amino)-2-oxoacetamido)-5-(dimethylcarbamoyl)cyclohexyl)carbamate', was synthesized, and then the protecting group 'Boc' was removed through a deprotection reaction in the compound 4 to obtain the compound having the chemical formula 5. Synthesis of 'N1-((1R,2S,5S)-2-amino-4-(dimethylcarbamoyl)cyclohexyl)-N2-(5-chloropyridin-2-yl)oxalamide'.

[0018] The above synthesized compound 5 produces the desired 'edoxaban' of the above chemical formula 1 through a coupling reaction with the above compound 6, '5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylic acid'.

[0019]

[0020] As described above, in the above reaction scheme 1, two coupling reactions are performed, and HOBT (1-Hydroxybenzotriazole), EDCI {1-(3-Dimethyl aminopropyl)-3-ethylcarbodiimide hydrochloride}, etc. are used as reagents for the coupling reaction.

[0021] Coupling reactions using HOBT, EDCI, and others described above require long-term reactions at high temperatures. Consequently, the yield of the coupling reaction is only about 80%, and the product suffers from low purity. HOBT, in particular, is an explosive substance, making handling difficult. Its high price also makes it unsuitable for mass production.

[0022]

[0023] Another known method for manufacturing edoxaban is the following reaction schemes 2 and 2-1.

[0024]

[0025] <Reaction Formula 2>

[0026] Looking at the above reaction scheme 2, compound a, 'phenyl 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylate' and compound b, '1-((1R,2S,5S)-2-amino-4-(dimethylcarbamoyl)cyclohexyl)-N2-(5-chloropyridin-2-yl)oxalamide' are reacted in K3PO4 / DMF for 3 days to produce compound c, 'edoxaban'.

[0027]

[0028]

[0029] <Reaction Formula 2-1>

[0030] In addition, in the manufacturing method of the above reaction scheme 2-1, compound ①, '2-bromo-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine' and compound ②, '1-((1R,2S, 5S)-2-amino-4-(dimethylcarbamoyl)cyclohexyl)-N2-(5-chloropyridin-2-yl)oxalamide' are reacted under palladium (Pd), Xantphos, and carbon monoxide (CO) to manufacture compound ③, 'edoxaban'.

[0031] The manufacturing method of the above reaction formula 2-1 is not suitable for mass production due to the long reaction time of 17 hours and the high manufacturing cost caused by the use of very expensive palladium (Pd) and xantphos.

[0032]

[0033] Finally, edoxaban can be manufactured by the manufacturing method of the following reaction scheme 3.

[0034]

[0035]

[0036] <Reaction Formula 3>

[0037] The manufacturing method of the above reaction scheme 3 generates '5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylic acid' of compound 6 by a chlorination reaction of carboxylic acid using thionyl chloride (SOCl2) to produce '5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carbonyl chloride'.

[0038] The product of the above-mentioned carbonyl chloride is reacted with the compound 5's '1-((1R,2S,5S)-2-amino-4-(dimethylcarbamoyl)cyclohexyl)-N2-(5-chloropyridin-2-yl)oxalamide' to produce 'edoxaban' of the compound 1.

[0039] However, thionyl chloride (SOCl2) currently used in the above reaction formula 3 is one of the items for which the production and stockpile of the substance is limited, such as silane and bromine, and the punishment standards in the event of a chemical accident related to thionyl chloride (SOCl2) are strengthened.

[0040] In addition, thionyl chloride (SOCl2) is an acutely toxic and corrosive substance, making it difficult to apply to mass production, and the thionyl chloride and sulfur dioxide remaining after the reaction are also harmful to the environment as air pollutants.

[0041]

[0042] Conventional methods for producing edoxaban, such as those in the above reaction schemes 1, 2, 2-1, and 3, are not suitable for mass production of edoxaban due to the above problems.

[0043]

[0044] Therefore, a new manufacturing method capable of mass producing edoxaban, which is effective in treating and preventing thrombosis, is required.

[0045] The purpose of the present invention is to provide a novel method for producing edoxaban, which is capable of mass production through an activation method of an intermediate required for producing edoxaban, and which also has a high yield and purity.

[0046] The novel method for manufacturing edoxaban of the present invention comprises the following steps to achieve the above-mentioned purpose.

[0047] (a) a step of preparing an intermediate compound represented by the following chemical formula 3 by coupling a compound of the following chemical formula 5 and a compound of the following chemical formula 4 ('intermediate compound preparation step'); and

[0048] (b) a step of producing edoxaban represented by the following chemical formula 1 through a coupling reaction of the compound of the above-mentioned chemical formula 3, which is an intermediate compound, with the compound of the following chemical formula 2 ('edoxaban producing step');

[0049]

[0050]

[0051] <Chemical Formula 1>

[0052]

[0053] <Chemical Formula 2>

[0054]

[0055] <Chemical Formula 2-1>

[0056]

[0057]

[0058] <Chemical Formula 3> <Chemical Formula 4>

[0059]

[0060] <Chemical Formula 5>

[0061] (In the above chemical formulas 3 and 4, R may be a C1~C6 alkyl group that may include a side chain, OMe, OEt, Ot-Bu, OBn, or a phenyl group, and X in chemical formula 4 may be a leaving group, halogen, OMe, OEt, Ot-Bu, or OBn)

[0062]

[0063] The intermediate compound manufacturing step of the above (a) is specifically

[0064] (a-1) a step of cooling a mixture of the compound of the above chemical formula 5 dissolved in a solvent to 10°C or lower ('the step of preparing the compound of the above chemical formula 5'); and

[0065] (a-2) A step of producing a compound of the above chemical formula 3 by adding the compound of the above chemical formula 4 to the compound mixture of the above chemical formula 5 and reacting the same ('step of producing a compound of the above chemical formula 3').

[0066]

[0067] The solvent of the above step (a-1) may be at least one of dichloromethane, dichloroethane, acetonitrile, chloroform, tetrahydrofuran, N,N-dimethylformamide, dimethylacetamide, dimethyl sulfoxide, and dimethoxyethane.

[0068] In the above step (a-2), the usage ratio (equivalent ratio) of the compound of the above chemical formula 5:the compound of the above compound 4 may be 1:0.9 to 1:1.5.

[0069] In the above step (a-2), the reaction temperature may be -60 to 30°C.

[0070]

[0071] Specifically, the manufacturing step of Edoxaban in the above (b) is as follows:

[0072] (b-1) A step of maintaining the mixture of the compound of the above chemical formula 2 at -60 to 30°C after preparing it ('step of preparing the compound of the chemical formula 2');

[0073] (b-2) a step of adding the compound mixture of chemical formula 2 prepared in step (b-1) to the compound of chemical formula 3 and reacting at a certain temperature for a certain time ('edoxaban reaction step'); and

[0074] (b-3) A step of obtaining edoxaban, a compound of the chemical formula 1, from the step (b-2) above ('step of obtaining edoxaban').

[0075]

[0076] The solvent of the above step (b-1) may be at least one of dichloromethane, dichloroethane, acetonitrile, chloroform, tetrahydrofuran, N,N-dimethylformamide, dimethylacetamide, dimethyl sulfoxide, and dimethoxyethane.

[0077] In the above step (b-2), the usage ratio (equivalent ratio) of the compound of the above chemical formula 2: the compound of the above compound 3 may be 1:1 to 1:1.2.

[0078] In the above steps (b-1) and (b-2), the reaction temperature may be -60 to 30°C.

[0079] The reaction time in the above step (b-2) may be 2 to 10 hours.

[0080] The above step (b-3) is a step of adding purified water to the reactant of the above step (b-2) to separate the organic layer, drying the separated organic layer, and concentrating it to obtain edoxaban.

[0081] According to the novel edoxaban manufacturing method of the present invention, there is an advantage in that edoxaban can be mass-produced in a simple and economical manner with high yield and high purity.

[0082] Hereinafter, the present invention will be described in detail with examples and the like to help understand the present invention. However, the examples according to the present invention may be modified in various different forms, and the scope of the present invention should not be construed as being limited to the following examples.

[0083]

[0084] Below, the novel method for manufacturing edoxaban of the present invention is described in detail.

[0085]

[0086] The novel method for manufacturing edoxaban of the present invention comprises the following steps.

[0087]

[0088] (a) a step of preparing an intermediate compound represented by the following chemical formula 3 by coupling a compound of the following chemical formula 5 and a compound of the following chemical formula 4 ('intermediate compound preparation step'); and

[0089] (b) a step of producing edoxaban represented by the following chemical formula 1 through a coupling reaction of the compound of the above-mentioned chemical formula 3, which is an intermediate compound, with the compound of the following chemical formula 2 ('edoxaban producing step');

[0090]

[0091]

[0092] <Chemical Formula 1>

[0093]

[0094] <Chemical Formula 2>

[0095]

[0096] <Chemical Formula 2-1>

[0097]

[0098] <Chemical Formula 3> <Chemical Formula 4>

[0099]

[0100] <Chemical Formula 5>

[0101] (In the above chemical formulas 3 and 4, R may be a C1~C6 alkyl group that may include a side chain, OMe, OEt, Ot-Bu, OBn, or a phenyl group, and X in chemical formula 4 may be a leaving group, halogen, OMe, OEt, Ot-Bu, or OBn)

[0102]

[0103] The intermediate compound manufacturing step of the above (a) is specifically

[0104] (a-1) a step of cooling a mixture of the compound of the above chemical formula 5 dissolved in a solvent to 10°C or lower ('the step of preparing the compound of the above chemical formula 5'); and

[0105] (a-2) A step of producing a compound of the above chemical formula 3 by adding the compound of the above chemical formula 4 to the compound mixture of the above chemical formula 5 and reacting the same ('step of producing a compound of the above chemical formula 3').

[0106]

[0107] The solvent of the above step (a-1) may be at least one of dichloromethane, dichloroethane, acetonitrile, chloroform, tetrahydrofuran, N,N-dimethylformamide, dimethylacetamide, dimethyl sulfoxide, and dimethoxyethane.

[0108] The compound of formula 5 in the above step (a-1) can be obtained by dissolving the acid group salt form compound of the compound of formula 5 in a solvent, and then adding an amine to remove the acid from the acid group salt form of the compound of formula 5.

[0109] The above amine may be at least one of TEA (triethylamine), DIPEA (N,N-diisopropylethylamine), Pyridine, NMP (N-methylpiperidine), and NMM (N-methylmorpholine).

[0110] The amount of the above amine used may be 2 to 4 times, and preferably 1 to 2.5 times, the molar ratio of the acid group salt form compound of the chemical formula 5. If it exceeds the above range, reaction impurities may be generated, which may result in a disadvantage of lowering the yield of the compound of chemical formula 3.

[0111] In addition, the compound of formula 5 can also be obtained by removing an acid from an acid group salt form compound of the compound of formula 5 by a method known in the art other than the above method.

[0112]

[0113] In the above step (a-2), the usage ratio (equivalent ratio) of the compound of the chemical formula 5: the compound of the chemical formula 4 may be 1:0.9 to 1:1.5. Preferably, it may be 1:0.9 to 1:1.2. If it is less than the above range, the yield of the compound of the chemical formula 3, which is the intermediate, is reduced, and if it exceeds the above range, many impurities are generated during the subsequent reaction between the compound of the chemical formula 3 and the compound of the chemical formula 2, which may have the disadvantage of reducing the yield of edoxaban.

[0114] In the above step (a-2), the reaction temperature may be -60 to 30°C. If it is outside the above range, the reaction may be slowed down or the yield of edoxaban may be reduced due to the generation of impurities by an exothermic reaction.

[0115]

[0116] Specifically, the manufacturing step of Edoxaban in the above (b) is as follows:

[0117] (b-1) A step of preparing a mixture of the compound of formula 2 by dissolving the compound of formula 2 in a solvent and then maintaining the mixture at -60 to 30°C ('step of preparing the compound of formula 2');

[0118] (b-2) a step of adding the compound mixture of chemical formula 2 prepared in step (b-1) to the compound of chemical formula 3 and reacting at a certain temperature for a certain time ('edoxaban reaction step'); and

[0119] (b-3) It may include a step of obtaining edoxaban, a compound of the chemical formula 1, from the step (b-2) above ('step of obtaining edoxaban').

[0120]

[0121] The solvent of the above step (b-1) may be at least one of dichloromethane, dichloroethane, acetonitrile, chloroform, tetrahydrofuran, N,N-dimethylformamide, dimethylacetamide, dimethyl sulfoxide, and dimethoxyethane.

[0122]

[0123] The compound of the above chemical formula 2 in the above step (b-1) can be obtained by dissolving the acid group salt form compound of the above chemical formula 2-1 compound in a solvent, and then adding an amine to remove the acid from the acid group salt form of the above chemical formula 2-1 compound.

[0124] The compound of the above chemical formula 2-1 can be obtained by performing a deprotection reaction on a compound in which the amine group is protected by a “Boc” group using an acid, for example, hydrochloric acid.

[0125] The above amine may be at least one of TEA (triethylamine), DIPEA (N,N-diisopropylethylamine), Pyridine, NMP (N-methylpiperidine), and NMM (N-methylmorpholine).

[0126] The amount of the above amine used may be 2 to 3 times (equivalent ratio) relative to the compound of Chemical Formula 2-1. If it is less than the above range, there is a disadvantage that the dissolution of the compound of Chemical Formula 2-1 may be problematic, making the reaction with the compound of Chemical Formula 3 difficult. In addition, if it exceeds the above range, there may be a disadvantage that the production yield of edoxaban of Chemical Formula 1 may be reduced due to impurities.

[0127] In addition, the compound of chemical formula 2 can also be obtained by removing the acid from the compound of chemical formula 2-1 by a method known in the art other than the above method.

[0128]

[0129] In the above step (b-2), the usage ratio (equivalent ratio) of the compound of the above chemical formula 2: the compound of the above compound 3 may be 1:1 to 1:1.2.

[0130] In the above steps (b-1) and (b-2), the reaction temperature may be -60 to 30°C.

[0131] The reaction time in the above step (b-2) may be 2 to 10 hours, and preferably 2 to 5 hours.

[0132] The above step (b-3) is a step of adding purified water to the reactant of the above step (b-2) to separate the organic layer, drying the separated organic layer, and concentrating it to obtain edoxaban.

[0133] The amount of purified water used can be used in a ratio (volume ratio) of 1:1 to 1:1.5 with respect to the amount of solvent used in (b-1).

[0134] Additionally, the drying may be a conventional drying method such as using magnesium sulfate.

[0135]

[0136] The novel method for manufacturing edoxaban of the present invention may further include a step (c) below, in which edoxaban is crystallized into an acid salt ('edoxaban-acid salt conversion step').

[0137] (c) The above 'edoxaban-carboxylate oxidation step' can be performed by an acid oxidation method of edoxaban known in the art.

[0138] The 'edoxaban-acid salt' manufactured through the above 'edoxaban-acid oxidation step' has the form of the following chemical formula 1-1.

[0139]

[0140] <Chemical Formula 1-1>

[0141]

[0142] Hereinafter, the present invention will be described in more detail through specific examples. The following examples are merely illustrative examples to aid understanding of the present invention and are not intended to limit the scope of the present invention.

[0143] <Example 1>

[0144] N-(5-chloropyridin-2-yl)-N'-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)ethanediamide

[0145]

[0146] 5-Methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylic acid hydrochloride (TPC, 3 g, 12.78 mmol) was dissolved in 54 ml of dichloromethane, and 3.88 g (38.35 mmol, 3.0 equivalents) of triethylamine was added to the hydrochloride, stirred for 30 minutes, and the internal temperature of the resulting reactant mixture was cooled to 0 degrees, and 1.70 g (14.06 mmol, 1.1 equivalents) of pivaloyl chloride (compound of chemical formula 4) was slowly added. The reactant was stirred at 15 degrees for 2 hours and then cooled to 0 degrees to prepare a 'TPC-anhydride' solution ('solution of compound of chemical formula 3').

[0147] Meanwhile, N 1 -((1S,2R,4S)-2-amino-4-(dimethylcarbamoyl)cyclohexyl)-N 2 -(5-chloropyridin-2-yl)oxalamide hydrochloride ('compound of chemical formula 2-1') (COC hydrochloride, 5.6 g, 12.78 mmol) was added with 54 ml of dichloromethane, and then 2.85 g (28.12 mol, 2.2 eq (molar ratio)) of triethylamine was added to the hydrochloride and stirred for 30 minutes to prepare N-(5-chloropyridin-2-yl)-N'-[(1S,2R,4S)-2-amino-4-(N,N-dimethylcarbamoyl)-cyclohexyl]ethanediamide solution ('COC solution of compound of chemical formula 2').

[0148] The 'COC solution of the compound of chemical formula 2' prepared above was slowly added to the 'TPC-anhydride' solution ('solution of the compound of chemical formula 3') prepared above at -30°C. The mixture of compounds of chemical formula 3 and chemical formula 2 was stirred for 2 hours while maintaining the temperature, and then 60 ml of purified water was added, and the organic layer was separated. The organic layer was dried over magnesium sulfate, filtered, and concentrated to obtain the title compound as a solid. (Yield: 98.0%, Purity: 96.443%)

[0149] 1H-NMR (400 MHz, CDCl3): δ9.74(s, 1H), 8.29(d, 1H), 8.15(d, 1H), 8.05(s, 1H), 7.68(s, 1H), 7.42(s, 1H), 4.69(s, 1H), 4.13-4.10(m, 1H), 3.72(t, 2H), 3.07(s, 3H), 2.95(s, 3H), 2.96-2.76(m, 4H), 2.52(s, 3H), 2.15-2.00(m, 3H), 1.98-1.90(m, 1H), 1.88-1.77(m, 1H), 1.74-1.62(m, 1H)

[0150]

[0151] <Example 2>

[0152] N-(5-chloropyridin-2-yl)-N'-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)ethanediamide

[0153]

[0154] In the above Example 1, 1.69 g (14.06 mmol, 1.1 equivalents, molar ratio) of pivaloyl chloride (compound of chemical formula 4) was used instead of 1.32 g (12.20 mmol, 1.05 equivalents, molar ratio) of ethyl chloroformate, and the same procedure was performed to obtain the title compound as a solid (yield: 89.6%, purity: 95.960%).

[0155]

[0156] <Example 3>

[0157] N-(5-chloropyridin-2-yl)-N'-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)ethanediamide benzenesulfonate

[0158]

[0159] “N-(5-chloropyridin-2-yl)-N'-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)ethanediamide” of the above chemical formula 1 was prepared in the same manner as in Example 1, except that 5.17 g (51.15 mmol, 4.0 equivalents) of N-methylmorpholine was used instead of 3.88 g (38.36 mmol, 3.0 equivalents) of triethylamine in the above Example 1.

[0160] The compound of the above-mentioned chemical formula 1 was dissolved in 20 ml of 85% ethanol and 14 ml of dichloromethane, and then benzenesulfonic acid monohydrate (2.9 g, 16.57 mmol) was added at 15 to 30°C and stirred for 10 minutes. 14 ml of ethyl acetate was added to the stirred reaction mixture to form crystals. The temperature of the reaction mixture was raised to 40 to 50°C and stirred for 1 hour, then 43 ml of ethyl acetate was additionally added dropwise, the reaction mixture was slowly cooled to room temperature, stirred for 1 hour, and then cooled to 0 to 5°C. After maintaining the cooling temperature and stirring for 1 hour, the mixture was filtered to obtain edoxaban besylate (yield: 89.4%, purity: 99.815%).

[0161]

[0162] <Example 4>

[0163] Edoxaban besylate was obtained in the same manner as in Example 3, except that “N-(5-chloropyridin-2-yl)-N'-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)ethanediamide” of the above chemical formula 1 prepared in Example 1 was used (yield: 90.9%, purity: 99.920%).

[0164]

[0165] <Comparative Example 1>

[0166] Comparative Example 1 is a manufacturing method described in 'Example 310 of Korean Patent Publication No. 10-0863113' ('Manufacturing method for Example 310'), and in the 'Manufacturing method for Example 310', the compound of the chemical formula 1, "N 1 -(5-chloropyridin-2-yl)-N 2 The reaction time for preparing “-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)ethanediamide” was “overnight”.

[0167]

[0168] Comparative Example 2

[0169] Comparative Example 2 is a manufacturing method described in 'Example 9 of Korean Patent Publication No. 10-2371784' ('Example 9 Manufacturing Method'), and in the 'Example 9 Manufacturing Method', very expensive palladium (Pd) and Xantphos are used to manufacture the compound of the chemical formula 1, "N 1 -(5-chloropyridin-2-yl)-N 2 -((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2- {[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)ethanediamide” was prepared, and the reaction time was 17 hours and the yield was 50.7%.

[0170]

[0171] <Comparative Example 3>

[0172] Comparative Example 3 is a manufacturing method described in 'Example 10 of Korean Patent Publication No. 10-2371784' ('Example 10 Manufacturing Method'), and in the 'Example 10 Manufacturing Method', the compound of the chemical formula 1, "N, is manufactured in K3PO4 / DMF with a reaction time of 3 days. 1 -(5-chloropyridin-2-yl)-N 2-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)ethanediamide” was prepared, and the yield was 83.9%.

[0173]

[0174] The reaction time, yield, and purity of Examples 1 and 2 and Comparative Examples 1 to 3 are shown in Table 1 below.

[0175]

[0176] As shown in Table 1 above, Examples 1 and 2 according to the novel method for producing edoxaban of the present invention produce edoxaban in a high yield and high purity with a short reaction time.

[0177] Therefore, the novel method for manufacturing edoxaban of the present invention has the advantage of being easily mass-produced and thus having great potential for industrial use.

Claims

1. (a) A step of preparing an intermediate compound represented by the following chemical formula 3 through a coupling reaction between a compound of the following chemical formula 5 and a compound of the following chemical formula 4 ('intermediate compound preparation step'); and (b) A method for producing edoxaban, characterized by including a step of producing edoxaban represented by the following chemical formula 1 through a coupling reaction of the compound of the above-mentioned chemical formula 3, which is an intermediate compound, with the compound of the following chemical formula 2 ('edoxaban producing step'). <Chemical Formula 1> <Chemical Formula 2> <Chemical Formula 3> <Chemical Formula 4> <Chemical Formula 5> (In the above chemical formulas 3 and 4, R may be a C1~C6 alkyl group that may include a side chain, OMe, OEt, Ot-Bu, OBn, or a phenyl group, and X in chemical formula 4 may be a leaving group, halogen, OMe, OEt, Ot-Bu, or OBn) 2. In paragraph 1, The intermediate compound manufacturing step of the above (a) is: (a-1) a step of cooling a mixture of the compound of the above chemical formula 5 dissolved in a solvent to 10°C or lower ('the step of preparing the compound of the above chemical formula 5'); and (a-2) a step of adding the compound of the chemical formula 4 to the compound mixture of the chemical formula 5 and reacting the compound of the chemical formula 3 ('step of producing the compound of the chemical formula 3'); The solvent of the above step (a-1) is at least one of dichloromethane, dichloroethane, acetonitrile, chloroform, tetrahydrofuran, N,N-dimethylformamide, dimethylacetamide, dimethyl sulfoxide, and dimethoxyethane, In the above step (a-2), the usage ratio (equivalent ratio) of the compound of the above chemical formula 5: the compound of the above compound 4 is 1:0.9 to 1:1.5, A method for manufacturing edoxaban, characterized in that the reaction temperature in the above step (a-2) is -60 to 30°C.

3. In paragraph 1, The manufacturing step of Edoxaban of the above (b) is: (b-1) A step of preparing a solvent solution of the compound of the above chemical formula 2 and maintaining it at -60 to 30°C ('preparation step of the compound of the chemical formula 2'); (b-2) a step of adding a solvent solution of the compound of formula 2 prepared in step (b-1) to the compound of formula 3 and reacting at a certain reaction temperature for a certain reaction time ('edoxaban reaction step'); and (b-3) A method for producing edoxaban, characterized by including a step of obtaining edoxaban, a compound of the chemical formula 1, from the step (b-2) above ('step of obtaining edoxaban').

4. In paragraph 3, The solvent of the above step (b-1) is at least one of dichloromethane, dichloroethane, acetonitrile, chloroform, tetrahydrofuran, N,N-dimethylformamide, dimethylacetamide, dimethyl sulfoxide, and dimethoxyethane, In the above step (b-2), the usage ratio (equivalent ratio) of the compound of the above chemical formula 2: the compound of the above compound 3 is 1:1 to 1:1.2, In the above step (b-2), the constant reaction temperature and constant reaction time are -60 to 30°C and 2 to 10 hours, A method for producing edoxaban, characterized in that the step (b-3) is a step of adding purified water to the reactant of the step (b-2) to separate an organic layer, drying the separated organic layer, and concentrating it to obtain edoxaban.

5. In paragraph 1, A method for manufacturing edoxaban, characterized in that it further includes a step of crystallizing edoxaban into an acid salt ('edoxaban-acid salt crystallization step') in step (c) below.

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