Name: 480449-70-5|N1-(5-Chloropyridin-2-yl)-N2-((1S,2R,4S)-4-(dimethylcarbamoyl)-2-(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamido)cyclohexyl)oxalamide|98%
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[ 480449-70-5 ]
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Yield	Reaction Conditions	Operation in experiment
99.8%	In tetrahydrofuran at 20℃;	1-31; 1-4; 2-10 Example 30. Amorphous synthesis of edoxaban p-toluenesulfonate monohydrate Edoxaban free base (1.0 g, 1.8 mmol) and p-toluenesulfonic acid monohydrate (0.364 g, 1.9 mmol) were added to 15.0 mL of tetrahydrofuran, followed by suspension and stirring at 20°C. The suspension was filtered and the obtained solid was dried to obtain edoxaban p-toluenesulfonate monohydrate (amorphous or low crystalline) (1.35 g, yield 99.8%, purity 99.77%, water content 2.60% by weight).
98%	In ethanol; water at 75℃; for 2h;	29 Example 29 Preparation of N1-(5-chloropyridin-2-yl)-N2-{(1S,2R,4S)-4-(dimethylcarbamoyl)-2-[(5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carbonyl)amino]cyclohexyl}ethanediamide p-toluene sulfonic acid mono hydrate (Edoxaban tosylate monohydrate) Example 29 Preparation of N1-(5-chloropyridin-2-yl)-N2-{(1S,2R,4S)-4-(dimethylcarbamoyl)-2-[(5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carbonyl)amino]cyclohexyl}ethanediamide p-toluene sulfonic acid mono hydrate (Edoxaban tosylate monohydrate) To a suspension of N1-(5-chloropyridin-2-yl)-N2-{(1S,2R,4S)-4-(dimethylcarbamoyl)-2-[(5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carbonyl)amino]cyclohexyl}ethanediamide (1.0 g, 1.82 mmol) in absolute ethanol (6 mL) and water (2 mL) was added p-toluene sulfonic acid monohydrate (365 mg, 1.91 mmol). A thick suspension was formed. The suspension was heated in an oil bath at 75° C. for 2 hours and then cooled to room temperature. The solids were filtered and washed with ethanol (2*5 mL) to afford N1-(5-chloropyridin-2-yl)-N2-{(1S,2R,4S)-4-(dimethylcarbamoyl)-2-[(5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carbonyl)amino]cyclohexyl}ethanediamide p-toluene sulfonic acid mono hydrate (1.32 g, 98% yield) as a crystalline white solid, 99.3 area % purity by HPLC.
95.5%	In ethanol; dichloromethane; water at 20℃;	1.3; 2.5 Example 1.3 Preparation of edoxaban tosylate monohydrate To 11.0 g (20.1 mmol, 1.0 eq) of edoxaban obtained in Example 1.2, methylene chloride (MC) 55 mL (5 v / v), 95% ethanol (EtOH) 55 mL (5 v / v) was added. ρ-toluenesulfonic acid monohydrate 4.2g (22mmol, 1.1eq) was added and dissolved at room temperature. The reaction solution was filtered and washed with 10 mL of MC. The filtrate was concentrated at 40° C. or lower. EtOH 72.6mL (6.6v/v) and purified water 26.4mL (2.4v/v) were added and dissolved by heating at 70°C. After cooling to room temperature, crystals were precipitated, and 165 mL of EtOH (15 v/v) was added. After stirring at room temperature for 12 hours or more (overnight), the mixture was stirred at 5° C. or less for 1 hour. The product was filtered and washed with 40.0 mL EtOH. The filtrate was dried at 45° C. to obtain 14.19 g (19.2 mmol, 95.5% yield, purity 98.883%) of a white solid compound.

94.2%	In ethanol; water at 10 - 70℃;	3 (Test Example 3) Based on the results of Test Examples 1 and 2, the present inventor had an idea that the excess of p-toluenesulfonic acid that promotes the decomposition of compound B be avoided for dissolving compound B under high temperatures, and the excess of p-toluenesulfonic acid under low temperatures be created for crystallization to reduce the solubility of compound A, resulting in improvement in the yield of step (a). An attempt was made to perform a p-toluenesulfonic acid division method reflecting this idea. Specifically, 21 ml of water, 49 ml of ethanol, and 3.30 g of TsOH·H2O (0.95 molar equivalent with respect to compound B) were added to 10.0 g of compound B, followed by dissolution at 70°C. The dissolved solution was filtered through a filter, and the filter was washed with a mixed solution of 3 ml of water and 17 ml of ethanol. Subsequently, a mixed solution of the filtered mother liquor and the washes was slowly cooled, and 521 mg of TsOH·H2O (0.15 molar equivalent with respect to compound B) and 150 ml of ethanol were added thereto. After stirring at 10°C, crystals of compound A were collected by filtration, and its yield was determined. Moreover, two lots of compound B were used to evaluate reproducibility. To prepare a control, 21 ml of water, 49 ml of ethanol, and 3.47 g of TsOH·H2O (1.0 molar equivalent with respect to compound B) were added to 10.0 g of compound B, followed by dissolution at 70°C. The dissolved solution was filtered through a filter, and the filter was washed with a mixed solution of 3 ml of water and 17 ml of ethanol. Subsequently, a mixed solution of the filtered mother liquor and the washes was slowly cooled, and 150 ml of ethanol was added thereto. After stirring at 10°C, crystals of compound A were collected by filtration, and its yield was determined. A loss into the mother liquor means the compound A remaining in the mother liquor without being deposited as crystals. Loss into mother liquor (%) described in Table 1 was calculated by converting the weight of the compound A remaining in the mother liquor into the weight of the compound B and indicating this weight as a ratio (%) to the weight of the compound B before the start of the reaction. The results are shown in Table 3.
92%	Stage #1: edoxaban; toluene-4-sulfonic acid In ethanol; 1,2-dichloro-ethane at 20℃; Stage #2: In ethanol; water at 20 - 60℃; for 1h;	2 N¹-(5-chloropyridin-2-yl)-N²-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-[(5-methyl-4,5,6,7-tetrahydrothiazole[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)ethanediamide 4-toluene sulfonic acid monohydrate 0.25 g of the compound synthesized in Experimental Example 1 was usedN1- (5-chloropyridin-2-yl) -N2- ((lS, 2R, 4S)4 - [(dimethylamino) carbonyl] -2 - [(5-methyl-4,5,6,7-tetrahydrothiazole [5,4-c]Pyridin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide was dissolved in 5 ml of dichloroethane, 0.52 ml of 1 mol per liter of p-toluenesulfonic acid ethanol solution was added,The mixture was stirred at room temperature. The solvent was then distilled off.Add 3.9 ml of 15% aqueous ethanol to the residue,And the mixture was dissolved with stirring at 60 ° C.The mixture was then allowed to cool to room temperature and stirred for 1 hour.The precipitated crystals were collected by filtration and rinsed with ethanol,And then dried under reduced pressure at room temperature for 2 hours to obtain0.29 g of the title compound (yield 92%).
92%	In ethanol; water at 70℃; for 1h;	4; 5; 9 Preparation of edoxaban p-toluenesulfonic acid monohydrate To a 1 L three-necked flask, 68 g of DXB-ABC and 332 ml of absolute ethanol, 147 ml of purified water were added, stirred, and 22.4 g of p-toluenesulfonic acid monohydrate was added at room temperature, heated to 70 ° C, all solids were dissolved, filtered while hot, and used. The filter cake was rinsed with 128 ml of 85% ethanol, transferred to a 1 L three-necked flask, and 3.6 g of p-toluenesulfonic acid monohydrate and 1020 ml of absolute ethanol were added thereto, and the mixture was cooled to 5-10 ° C, and stirred for lh. After suction filtration, the cake was dried under vacuum at 30-40 ° C to give a white solid. The yield was 95% and the purity was 99.82%. 5. Purification of edoxaban p-toluenesulfonic acid monohydrate80 g of edoxaban p-toluenesulfonic acid monohydrate and 34 ml of absolute ethanol, 6 ml of purified water were added to a 250 ml three-necked flask, stirred, stirred at room temperature for 20 h, cooled to 5-10 ° C and stirred for 1 h. Filter by suction and the filter cake was dried under vacuum. Yield: 92%, purity: 99.94%.
88.3%	With water In ethanol at 75 - 80℃;	11 Example 11 N1-(5-Chloro-2-pyridyl)-N2-[(1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-[[(4,5,6,7-Tetrahydro-5-methylthiazolo[5,4-c]pyridin-2-yl)carbonyl]amino]cyclohexyl]oxalamide p-toluenesulfonateSynthesis of compound (Edoxaban tosylate hydrate) Add absolute ethanol (2700g) to the reaction flask, add purified water (1350g), then add 109TM-01 (540g, 0.9853mol) obtained in Example 10, stir and disperse evenly, add p-toluenesulfonic acid monohydrate ( 200g, 1.051mol), heated to 7580 to completely dissolve, add activated carbon, keep warm and stir to decolorize for about 3040min; filter while hot, rinse the filter residue with absolute ethanol, collect the filtrate and cool to 05, keep warm Crystallize for about 2 to 4 hours; filter, rinse the filter cake with 75% ethanol, and collect the solids; blow drying at about 40° C. to obtain about 642 g (theoretical amount: 727.4 g) of dry 109TM-11 with a purity of 99.93%. Yield: 88.3%.
82%	In water; acetone at 0.5 - 0.6℃; for 0.01h;	4E Example 4E: Preparation of Ethanediamide, /Vⁱ-(5-chloro-2-pyridinyl)-/V²-[(lS, 2R,4S) -4- [(dimethylamino)carbonyl] -2- [ [(4, 5, 6, 7 -tetrahydro-5-methy lthiazolo[5, 4, c]-pyridin-2-yl)carbonyl]amino]cylohexyl]-, 4-methyl benzene sulfonate, hydrate (1:1:1) (compound of formula I) The compound of formula I-A (20.0g) as obtained in Example 3E -3F was added to acetone (125 mL), water (125 mL) mixture and p-toluene sulfonic acid 8.30g) was added to it and flushed with 50% aq. (50 mL). The reaction mass was then heated to about 50°C to 60°C to get clear solution. The obtained clear solution was stirred for about 60 min and hot filtered and washed with acetone and water mixture. The filtrate was then cooled to about 5°C to 10°C and maintained at same temperature for about 240 minutes. The reaction mass was then filtered and dried at about 45°C to 50°C for about 12 hours to get compound of formula I. Yield: 22.0g (82.0%), HPLC purity 99.94%
75%	In ethanol; dichloromethane	12 Example 12: Preparation of Edoxaban Tosylate (Formula 1): P-toluenesulfonic acid (1.73g) was added to a stirred solution of Edoxaban(5.0g), methylene dichloride(5ml),and ethanol(85ml). The mixture was distilled under atmospheric pressure and water(12.5 ml) was addedand the mixturewas heated to 70-75 °C to obtain a clear solution. The reaction mixture was cooled to room temperature and stirred for 16 hours. The solution was filtered to obtain a white precipitate, which was washed with ethanol (5ml) then dried under reduced pressure at room temperature to obtain Formula 1 (5.0g, yield: 75%, HPLC Purity: 99.7%).
75%	In ethanol; water at 65℃;	4: Preparation of compound (VII) In a 5000mL three-necked flask, add 625mL of absolute ethanol, 250mL of purified water, 125g of compound (VI), and 50g of p-toluenesulfonic acid monohydrate, heat up to 65°C until the system is completely dissolved, add 6.3g of activated carbon and stir for 40min, Heat rate, the filtrate was transferred to a 5000mL three-necked flask, cooled to 50°C, 2250mL of ethanol was added dropwise to the system, and the temperature was lowered to 0°C for crystallization for 3h after the dropwise addition. Suction filtration, the filter cake was rinsed with 300 mL of water 10% anhydrous ethanol for 3 times, dried at 30 °C,An off-white solid was obtained, namely edoxaban tosylate monohydrate, and the molar yield was 75%.
		311 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 p-toluenesulfonate monohydrate: [Example 311] N1-(5-Chloropyridin-2-yl)-N2-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)ethanediamide p-toluenesulfonate monohydrate: The compound (6.2 g) obtained in Example 310 is dissolved in methylene chloride (120 ml), a 1 mol/L ethanol solution (11.28 ml) of p-toluenesulfonic acid was added to the solution, and the solvent was distilled off.. ethanol (95 ml) containing 15% water was added to the residue, and the mixture was stirred at 60°C to dissolve it.. The solution was then cooled to room temperature and stirred for a day.. Crystals deposited were collected by filtration, washed with ethanol and dried at room temperature for 2 hours under reduced pressure to obtain the title compound (7.4 g).1H-NMR (DMSO-d6) δ: 1.45-1.54(1H,m),1.66-1.78(3H,m),2.03-2.10(2H,m),2.28(3H,s),2.79(3H,s),2.91-3.02(1H,m), 2.93(3H,s),2.99(3H,s),3.13-3.24(2H,m),3.46-3.82(2H,m), 3.98-4.04(1H,m),4.43-4.80(3H,m),7.11(2H,d,J=7.8Hz), 7.46(2H,d,J=8.2Hz),8.01(2H,d,J=1.8Hz),8.46(1H,t,J=1.8Hz), 8.75(1H,d,J=6.9Hz),9.10-9.28(1H,br),10.18(1H,br), 10.29(1H,s). MS (ESI) m/z: 548(M+H)+. Elemental analysis: C24H30ClN7O4S·C7H8O3S·H2O. Calculated: C;50.43,H;5.46,N;13.28,Cl;4.80,S;8.69. Found: C;50.25,H;5.36,N;13.32,Cl;4.93,S;8.79. mp (decomposed): 245∼248°C.
	In ethanol; dichloromethane	7 (Reference Example 7) N1-(5-Chloropyridin-2-yl)-N2-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)ethanediamide mono-p-toluenesulfonate monohydrate (A-a) N1-(5-Chloropyridin-2-yl)-N2-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)ethanediamide (A) (6.2 g) was dissolved in methylene chloride (120 ml). To the solution, a 1 mol/L solution of p-toluenesulfonic acid in ethanol (11.28 ml) was added, and the solvent was distilled off. To the residue, 15% hydrous ethanol (95 ml) was added, and the mixture was dissolved by stirring at 60°C. Then, the mixture was cooled to room temperature and stirred for 1 day. The precipitated crystals were collected by filtration, washed with ethanol, and then dried under reduced pressure at room temperature for 2 hours to obtain the title compound (A-a) (7.4 g). 1H-NMR (DMSO-d6) δ: 1.45-1.54 (1H, m), 1.66-1.78 (3H, m), 2.03-2.10 (2H, m), 2.28 (3H, s), 2.79 (3H, s), 2.91-3.02 (1H, m), 2.93 (3H, s), 2.99 (3H, s), 3.13-3.24 (2H, m), 3.46-3.82 (2H, m), 3.98-4.04 (1H, m), 4.43-4.80 (3H, m), 7.11 (2H, d, J=7.8 Hz), 7.46 (2H, d, J=8.2 Hz), 8.01 (2H, d, J=1.8 Hz), 8.46 (1H, t, J=1.8 Hz), 8.75 (1H, d, J=6.9 Hz), 9.10-9.28 (1H, br), 10.18 (1H, br), 10.29 (1H, s). MS (ESI) m/z: 548 (M+H)+. Anal.: C24H30ClN7O4S·C7H8O3S·H2O Theoretical: C; 50.43, H; 5.46, N; 13.28, Cl; 4.80, S; 8.69. Found: C; 50.25, H; 5.36, N; 13.32, Cl; 4.93, S; 8.79. mp (dec.) : 245-248°C. (Example 1) Tert-butyl {(1R,2R,5S)-2-azido-5-[(dimethylamino)carbonyl]cyclohexyl}carbamate (1) wherein Boc is as defined above.
	In ethanol; dichloromethane at 20℃;	5 (Reference Example 5) N1-(5-Chloropyridin-2-yl)-N2-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)ethanediamide mono-p-toluenesulfonate monohydrate (A-a) N1-(5-Chloropyridin-2-yl)-N2-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)ethanediamide (A) (6.2 g) was dissolved in methylene chloride (120 ml). To the solution, a 1 mol/L solution of p-toluenesulfonic acid in ethanol (11.28 ml) was added, and the mixture was stirred at room temperature. Then, the solvent was distilled off. To the residue, 15% hydrous ethanol (95 ml) was added, and the mixture was dissolved by stirring at 60°C. Then, the mixture was cooled to room temperature and stirred for 1 day. The precipitated crystals were collected by filtration, washed with ethanol, and then dried under reduced pressure at room temperature for 2 hours to obtain the title compound (7.4 g). 1H-NMR (DMSO-d6) δ: 1.45-1.54 (1H, m), 1.66-1.78 (3H, m), 2.03-2.10 (2H, m), 2.28 (3H, s), 2.79 (3H, s), 2.91-3.02 (1H, m), 2.93 (3H, s), 2.99 (3H, s), 3.13-3.24 (2H, m), 3.46-3.82 (2H, m), 3.98-4.04 (1H, m), 4.43-4.80 (3H, m), 7.11 (2H, d, J=7.8 Hz), 7.46 (2H, d, J=8.2 Hz), 8.01 (2H, d, J=1.8 Hz), 8.46 (1H, t, J=1.8 Hz), 8.75 (1H, d, J=6.9 Hz), 9.10-9.28 (1H, br), 10.18 (1H, br), 10.29 (1H, s). MS (ESI) m/z: 548 (M+H)+. Anal.: C24H30ClN7O4S·C7H8O3S·H2O Theoretical: C;50.43, H;5.46, N;13.28, Cl;4.80, S;8.69. Found: C;50.25, H;5.36, N;13.32, Cl;4.93, S;8.79. mp (dec.): 245-248°C.
7.4 g	Stage #1: edoxaban; toluene-4-sulfonic acid In ethanol; dichloromethane Stage #2: In ethanol; water at 20 - 60℃; for 24h;	7 (Reference Example 7) N1-(5-Chloropyridin-2-yl)-N2-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)ethanediamide mono-p-toluenesulfonate monohydrate (X-a) (production method described in the pamphlet of International Publication No. WO 2007/032498) N1-(5-Chloropyridin-2-yl)-N2-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)ethanediamide (X) (6.2 g) was dissolved in methylene chloride (120 ml). To the solution, a 1 mol/L solution of p-toluenesulfonic acid in ethanol (11.28 ml) was added, and the solvent was distilled off. To the residue, 15% hydrous ethanol (95 ml) was added, and the mixture was dissolved by stirring at 60°C. Then, the mixture was cooled to room temperature and stirred for 1 day. The precipitated crystals were collected by filtration, washed with ethanol, and then dried under reduced pressure at room temperature for 2 hours to obtain the title compound (X-a) (7.4 g). 1H-NMR (DMSO-d6) δ : 1. 45-1. 54 (1H, m), 1.66-1.78 (3H, m), 2.03-2.10 (2H, m), 2.28 (3H, s), 2.79 (3H, s), 2.91-3.02 (1H, m), 2.93 (3H, s), 2.99 (3H, s), 3.13-3.24 (2H, m), 3.46-3.82 (2H, m), 3.98-4.04 (1H, m), 4.43-4.80 (3H, m), 7.11 (2H, d, J = 7.8 Hz), 7.46 (2H, d, J = 8.2 Hz), 8.01 (2H, d, J = 1.8 Hz), 8.46 (1H, t, J = 1.8 Hz), 8.75 (1H, d, J = 6.9 Hz), 9.10-9.28 (1H, br), 10.18 (1H, br), 10.29 (1H, s). MS (ESI) m/z: 548 (M+H)+. Anal.: C24H30ClN7O4S·C7H8O3S·H2O Theoretical: C; 50.43, H; 5.46, N; 13.28, Cl; 4.80, S; 8.69. Found: C; 50.25, H; 5.36, N; 13.32, Cl; 4.93, S; 8.79. mp (dec.): 245-248°C.
7.4 g	In ethanol; dichloromethane	8 N1-(5-chloropyridin-2-yl)-N2-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)ethanediamide mono-p-toluenesulfonate monohydrate (E-a) Reference Example 8 N1-(5-chloropyridin-2-yl)-N2-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)ethanediamide mono-p-toluenesulfonate monohydrate (E-a) N1-(5-Chloropyridin-2-yl)-N2-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)ethanediamide (E) (6.2 g) was dissolved in methylene chloride (120 ml). To the solution, a 1 mol/L solution of p-toluenesulfonic acid in ethanol (11.28 ml) was added, and the solvent was distilled off. To the residue, 15% aqueous ethanol (95 ml) was added, and the mixture was dissolved by stirring at 60° C. Then, the mixture was cooled to room temperature and stirred for 1 day. The precipitated crystals were collected by filtration, washed with ethanol, and then dried under reduced pressure at room temperature for 2 hours to obtain the title compound (E-a) (7.4 g). 1H-NMR (DMSO-d6) δ: 1.45-1.54 (1H, m), 1.66-1.78 (3H, m), 2.03-2.10 (2H, m), 2.28 (3H, s), 2.79 (3H, s), 2.91-3.02 (1H, m), 2.93 (3H, s), 2.99 (3H, s), 3.13-3.24 (2H, m), 3.46-3.82 (2H, m), 3.98-4.04 (1H, m), 4.43-4.80 (3H, m), 7.11 (2H, d, J=7.8 Hz), 7.46 (2H, d, J=8.2 Hz), 8.01 (2H, d, J=1.8 Hz), 8.46 (1H, t, J=1.8 Hz), 8.75 (1H, d, J=6.9 Hz), 9.10-9.28 (1H, br), 10.18 (1H, br), 10.29 (1H, s). MS (ESI) m/z: 548 (M+H)+.
102.9 g	In ethanol; water at 70℃; for 1h;	6 Synthesis of N’-(5-chloropyridin-2-yl)-N2-((1S,2R, 45)-4-[(dimethylamino)carbonyl]-2-{ [(5-methyl-4,5, 6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino }cyclohexyl)ethanediamide p-toluenesulfonic acid monohydrate (X-a) (the Method Described in International Publication No. WO 07/032498) 10100] N’ -(5-Chloropyridin-2-yl)-N2-((1 S,2R,45)-4-[(dimethylamino)carbonyl] -2-{ [(5-methyl-4,5,6,7-tetrahy-drothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)ethanediamide (86.8 g) was dissolved in 30% aqueous ethanol (418 ml) at 60° C., and a solution ofp-toluenesulfonic acid monohydrate (29.0 g) in 30% aqueous ethanol (167 ml) was then added to the above obtained solution. The reaction mixture was stirred at 70° C. for 1 hour, and thereafier, it was gradually cooled to room temperature. Afier that, ethanol was added to the mixture, and the obtained mixture was stirred for 16 hours. The reaction solution was stirred under cooling on ice for 1 hour, and a crystal was collected by filtration to obtain 102.9 g of the title compound.
7.4 g	In ethanol; water at 20 - 60℃; for 24h;	11 N¹-(5-chloropyridin-2-yl)-N²-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-[(5-methyl-4,5,6,7-tetrahydrothiazolone[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)ethanediamide mono p-toluenesulfonic acid salt monohydrate N1-(5-chloropyridin-2-yl)-N2-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-[(5-methyl-4,5,6,7-tetrahydrothiazolone[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)ethanediamide (X) (6.2g), It dissolved in the methylene chloride (120 ml), the p-toluenesulfonic acid/ethanol solution (1 mol/L solution: 11.28 ml) was added, and the solvent was distilled off. Hydrated ethanol (95 ml) was added to residue 15%, and it agitated and dissolved at 60 degrees C. Then, to the room temperature, it cooled and agitated on the 1st. Precipitated crystal was separated, and it dried in vacuum at the room temperature after washing by ethanol for 2 hours, and obtained the title compound (X-a) (7.4g).
23 g	In ethanol; dichloromethane at 38℃; for 1h;	2 ((1S, 2R, 4S) -4 - [(dimethylamino) carbonyl] -2 - [(5-methyl-Tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide p-toluenesulfonic acid monohydrate,Preparation of Compound (1-a) A 500 mL autoclave was charged with 220 mL of methylene chloride, 20.9 g of N- (5-chloropyridin-2-yl) -N '- ((1S, 2R,4S) -4 - [(Dimethylamino) carbonyl] -2 - [(5-methyl- 4,5,6,7-tetrahydrothiazolo [5,4-c] Carbonyl]Amino} cyclohexyl) ethanediamide, stirred to dissolve all solids,25 ± 2 was added 38.2ml1mol / L of p-toluenesulfonic acid ethanol solution, the reaction 1h, the reaction was completed, the net solvent was removed under reduced pressure to the residue was added 313.5mL of 85% aqueous ethanol, 60 ± 2 incubated 1h, Cooling to 10 ° C suction filtration, 25 ° C under vacuum to constant weight to give 23.0g white solid.
	In water; acetonitrile at 2 - 70℃; for 5.5h;	1a Example 1 a: Preparation of edoxaban tosylate monohydrate in ACN/H?Q N1-(5-Chloropyridin-2-yl-)-N2-((1S,23,4S)-4-[(dimethylamino)carbonyl]-2-[(5-methyl-9,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-yl)carbonyl]amino}cyclohexyl)ethanediamide (1 .6 g) (purity by HPLC: 98.1 %a/a, Imp. A: 0.69%a/a) and p-toluenesulfonic acid monohydrate (0.58 g) were mixed with a mixture of ACN and water 1 : 1 (6.4 ml). The mixture was heated to 70 °C (0.47 °C/min) and after 30 minutes at this temperature a mixture of ACN and water 1 : 1 (1 .6 ml) was added. The temperature was reduced to 50 °C (0.2 °C/min) and after 120 minutes at this temperature, to 2 °C (0.1 °C/min). Water (12 ml) was added at 2 °C in 120 minutes to the suspension. Then the reaction was stirred 60 minutes at 2 °C and filtered by vacuum. The crystals were washed with a solution of H20: ACN 8:2 and dried at 50 °C under reduced pressure. The outcome yield of the compound N 1-(5-Ch loropyrid in-2-yl-)-N2-(( 1 S,23 ,4S)-4-[(d imethylamino)carbonyl]-2-[(5- methyl-9 ,5,6 ,7-tetrahyd roth iazolo[5,4-c]pyrid ine-2-yl)carbonyl]amino}cyclohexyl ) ethanediam ide p-toluenesulfonate monohydrate was 1 .835 g (84.9%). Analysis by XRPD gave a diffractogram essentially the same as that represented by Figure 1 . Purity by HPLC: 99.6%a/a, imp. A: 0.05%a/a.
102.9 g	In ethanol at 70℃; for 18h;	1 Reference Example 1 (0050) Synthesis of N¹-(5-chloropyridin-2-yl)-N²-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]aminolcyclohexyl)ethanediamide p-toluenesulfonic acid monohydrate (1a) Reference Example 1 (0050) Synthesis of N1-(5-chloropyridin-2-yl)-N2-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]aminolcyclohexyl)ethanediamide p-toluenesulfonic acid monohydrate (1a) (the method described in International Publication No. WO 07/032498) (0051) N1-(5-Chloropyridin-2-yl)-N2-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]aminolcyclohexyl)ethanediamide (86.8 g), which had been produced by the method described in International Publication No. WO 07/032498, was dissolved in 70% aqueous ethanol (418 ml) at 60° C., and thereafter, a solution of p-toluenesulfonic acid monohydrate (29.0 g) in 70% aqueous ethanol (167 ml) was added to the above obtained solution. The reaction mixture was stirred at 70° C. for 1 hour, and thereafter, the reaction solution was gradually cooled to room temperature. Ethanol was added to the reaction solution, and the obtained mixture was then stirred for 16 hours. Thereafter, the reaction solution was stirred for 1 hour under cooling on ice, and crystals were then collected by filtration to obtain 102.9 g of the title compound. (0052) It was found that the obtained compound had an absorption peak with the same strength at the same wave number as that of a standard preparation (known compound) in the IR. (0053) Moreover, as a result of the analysis of the obtained compound using HPLC, a plurality of impurity peaks (all of which were 0.03% by weight or less) were observed as impurities, and the total content of all impurities was 0.16% by weight. Thus, the purity thereof was found to be 99.84% (wherein % by content indicates % with respect to the HPLC area value of a free form of the compound represented by formula (1a)). (0054) H-NMR (DMSO-d6) δ: 1.45-1.54 (1H, m), 1.66-1.78 (3H, m), 2.03-2.10 (2H, m), 2.28 (3H, s), 2.79 (3H, s), 2.91-3.02 (1H, m), 2.93 (3H, s), 2.99 (3H, s), 3.13-3.24 (2H, m), 3.46-3.82 (2H, m), 3.98-4.04 (1H, m), 4.43-4.80 (3H, m), 7.11 (2H, d, J =7.8 Hz), 7.46 (2H, d, J =8.2 Hz), 8.01 (2H, d, J=1.8 Hz), 8.46 (1H, t, J=1.8 Hz), 8.75 (1H, d, J=6.9 Hz), 9.10-9.28 (1H, br. s), 10.18 (1H, br. s), 10.29 (1H, s). (0055) Elemental analysis: Anal. Calcd. For: C; 50.43%, H; 5.46%, N; 13.28%. (0056) Found: C; 50.25%, H; 5.36%, N; 13.32%
	Stage #1: edoxaban With triethylamine In dichloromethane at 55℃; for 1h; Stage #2: toluene-4-sulfonic acid
95.5 %	In ethanol; dichloromethane at 20℃;	1.3; 2.5 Example 1.3 Preparation of edoxaban tosylate monohydrate To 11.0 g (20.1 mmol, 1.0 eq) of edoxaban obtained in Example 1.2, methylene chloride (MC) 55 mL (5 v / v), 95% ethanol (EtOH) 55 mL (5 v / v) was added. ρ-toluenesulfonic acid monohydrate 4.2g (22mmol, 1.1eq) was added and dissolved at room temperature. The reaction solution was filtered and washed with 10 mL of MC. The filtrate was concentrated at 40° C. or lower. EtOH 72.6mL (6.6v/v) and purified water 26.4mL (2.4v/v) were added and dissolved by heating at 70°C. After cooling to room temperature, crystals were precipitated, and 165 mL of EtOH (15 v/v) was added. After stirring at room temperature for 12 hours or more (overnight), the mixture was stirred at 5° C. or less for 1 hour. The product was filtered and washed with 40.0 mL EtOH. The filtrate was dried at 45° C. to obtain 14.19 g (19.2 mmol, 95.5% yield, purity 98.883%) of a white solid compound.
92 %	In ethanol; water at 0 - 75℃;	8-9 Preparation of edoxaban p-toluenesulfonate monohydrate (compound of formula 7) In the reaction flask, add edoxaban (compound of formula 6) (5.0g, 9.1mmol), 25mL of absolute ethanol and 10mL of purified water in sequence, and add p-toluenesulfonic acid monohydrate (1.6g, 8.4mmol ), heated up to 70-75°C and stirred to dissolve, then lowered the temperature, and when the system dropped to 55-60°C, added p-toluenesulfonic acid monohydrate (0.3g, 1.6mmol) to the system. Add 50mL of absolute ethanol dropwise to the system, then lower it to 20-25°C and stir for 1 hour, then lower it to 0-10°C and stir for 1 hour, filter with suction, wash with 2×10mL of absolute ethanol and dry under reduced pressure at 45°C to obtain the compound (compound of formula 7), 6.2 g, yield 92%.
95.5 %	In ethanol; dichloromethane at 20℃;	1.3; 2.5 Example 1.3 Preparation of edoxaban tosylate monohydrate To 11.0 g (20.1 mmol, 1.0 eq) of edoxaban obtained in Example 1.2, methylene chloride (MC) 55 mL (5 v / v), 95% ethanol (EtOH) 55 mL (5 v / v) was added. ρ-toluenesulfonic acid monohydrate 4.2g (22mmol, 1.1eq) was added and dissolved at room temperature. The reaction solution was filtered and washed with 10 mL of MC. The filtrate was concentrated at 40° C. or lower. EtOH 72.6mL (6.6v/v) and purified water 26.4mL (2.4v/v) were added and dissolved by heating at 70°C. After cooling to room temperature, crystals were precipitated, and 165 mL of EtOH (15 v/v) was added. After stirring at room temperature for 12 hours or more (overnight), the mixture was stirred at 5° C. or less for 1 hour. The product was filtered and washed with 40.0 mL EtOH. The filtrate was dried at 45° C. to obtain 14.19 g (19.2 mmol, 95.5% yield, purity 98.883%) of a white solid compound.
96 %	In ethanol; water at 70 - 80℃; Inert atmosphere;	5 Example 5Synthesis of Edoxaban p-Toluenesulfonate Monohydrate (Compound 9) Under nitrogen protection, in a 500ml reaction flask equipped with a condensing device, add 61.2g of purified water, 171.5g of 95% ethanol, 30g of compound 8 solid (0.064mol, 1.0Eq), start stirring, and add p-toluenesulfonic acid monohydrate thing12.8g (0.067mol, 1.05Eq),Start heating to 70-80°C to dissolve, start hot filtration, add 203.0g of 95% ethanol to the filtrate, continue heating to 75-80°C to dissolve, keep stirring for 5-10 minutes, stop heating, and slowly cool down to - Suction filtration at 5-0°C, soak the filter cake in 95% ethanol, filter, and drain to obtain a wet product of the filter cake, put it in a vacuum oven at 50-55°C to dry, and obtain solid Edoxaban p-toluenesulfonate monohydrate , 96% molar yield.

Reference： [1]Current Patent Assignee: CHONG KUN DANG PHARMACEUTICAL CORP. - KR2021/30109, 2021, A Location in patent: Paragraph 0164-0280; 0289-0338
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[3]Current Patent Assignee: BORYUNG PHARM CO.,LTD.; BORYUNG - WO2022/103239, 2022, A1 Location in patent: Paragraph 47-48; 141; 151-153; 154; 171-172
[4]Current Patent Assignee: DAIICHI SANKYO COMPANY, LIMITED - EP2371830, 2011, A1 Location in patent: Page/Page column 9-10
[5]Current Patent Assignee: CHINA CHEMICAL PHARMACEUTICAL GROUP; CHUNGWHA CHEMICAL SYNTHESIS BIOTECH - TWI571460, 2017, B Location in patent: Paragraph 0042-0043
[6]Current Patent Assignee: BEIJING SUN NOVO PHARMACEUTICAL RES - CN108484641, 2018, A Location in patent: Paragraph 0066-0069; 0097-0098
[7]Current Patent Assignee: INNER MONGOLIA JINGDONG PHARMACEUTICAL - CN111393456, 2020, A Location in patent: Paragraph 0099-0101
[8]Current Patent Assignee: GLENMARK PHARMACEUTICALS LTD - WO2021/1728, 2021, A1 Location in patent: Paragraph 19-20
[9]Current Patent Assignee: VIATRIS INC - WO2018/11823, 2018, A1 Location in patent: Page/Page column 28
[10]Current Patent Assignee: HARBIN PHARMACEUTICAL GROUP CO., LTD. - CN114736218, 2022, A Location in patent: Paragraph 0040-0044; 0053-0054
[11]Current Patent Assignee: DAIICHI SANKYO COMPANY, LIMITED - EP1405852, 2004, A1 Location in patent: Page 424
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2
[ 480452-37-7 ]
[ 720720-96-7 ]
edoxaban [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
77.2%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In acetonitrile at 0 - 20℃;	53 Example 53 Synthesis of N¹-(5-chloro-2-pyridyl)-N²-[(1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-[[(4,5,6,7-tetrahydro-5-methylthiazolo[5,4-c]pyridin-2-yl)carbonyl]amino]cyclohexyl]ethanediamide(Edoxaban) To 18 g (48.93 mmol) of the residue 109T2-01 obtained in Example 50, 270 g of acetonitrile was added. Stir and dissolve, Add 12g (118.6mmol) of triethylamine, stir and cool to 0 ~ 5 ° C; Further, 12.6 g (53.69 mmol) of 109C6-20, 10.5 g (68.56 mmol) of HOBt·H 2 O, 13.0 g (67.81 mmol) of EDCI·HCl were added; and the reaction was stirred at room temperature for about 20 to 24 hr. After the reaction is completed, 180 g of water is added to the reaction system; After stirring uniformly, the mixture was filtered to remove insoluble matter, and the residue was rinsed with 120 g of dichloromethane; The filtrate was collected, and then 300 g of dichloromethane was added thereto, and the mixture was thoroughly stirred; The aqueous phase was extracted once more with 200 g of dichloromethane, and the organic phases were combined and dried over anhydrous sodium sulfate. Filtration, the residue was washed with dichloromethane, and the filtrate was collected and concentrated under reduced pressure to give a residue. Add 25g of methanol to the residue, heat to 40 ~ 50 ° C to disperse evenly, cooled to 5 ~ 10 ° C, heat crystallization for about 2 ~ 3hr; Filtration, the filter cake was rinsed with methanol, and the solid was collected; After drying, about 109 g of dry product of 109TM-01 was obtained (theoretical amount: 26.82 g). Yield: 77.2%.
75.5%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine at 15 - 25℃;	2 Comparative example 2. N1-(5-chloro-2-pyridyl)-N2-[(1S, 2R, 4S)-4-[(dimethylamino)carbonyl]-2-[[(4,5,6, Synthesis of 7-tetrahydro-5-methylthiazolo[5,4-c]pyridin-2-yl)carbonyl]amino]cyclohexyl]oxalamide (Edoxaban) Add acetonitrile (2850g) to the reaction flask, add 109T1-01 (190g, 406.0mmol) obtained in Comparative Example 1, add methanesulfonic acid (200g, 2081.2mmol), stir and react for 16-20hr; after the reaction is complete, cool down; Add triethylamine (315g, 3113.0mmol); add 109C6-20 (105g, 447.4mmol) obtained in Example 7, add HOBt (60kg, 444.0mmol), add EDCI·HCl (108g, 563.4mmol); addition is complete Then, control the temperature to 15-25, and stir the reaction for about 20-30hr; after the reaction is complete, add drinking water (1500g); stir evenly, filter, and collect the solid for use; collect the filtrate; add methylene chloride (4000g) to the collected filtrate ), stirring and extracting, standing for liquid separation; the aqueous phase was extracted with dichloromethane (3000g) once; the organic phases were combined, and the solid collected by the above filtration was added; stirring for 2-3hr; filtered, collected the filtrate, concentrated to dryness Add methanol to the residue, stir and disperse, heat to 4050 for hot beating, cool to 510, and crystallize for 34hr. Filter and collect the obtained solid; dry to obtain about 168 g of 109TM-01 dry product (theoretical amount: 222.5 g). Yield: 75.5%.
	Stage #1: N¹-[(1S,2R,4S)-2-amino-4-[(dimethylamino)carbonyl]cyclohexyl]-N²-(5-chloro-2-pyridyl)ethanediamide; 5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxylic acid hydrochloric acid salt With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl acetamide at 20℃; for 13h; Stage #2: With triethylamine In N,N-dimethyl acetamide; water	16 N1-{(1S, 2R, 4S)-2-Amino-4-[(dimethylamino)carbonyl]cyclohexyl}-N2-(5-chloropyridin-2-yl)ethanediamide (553.4 mg) was dissolved in dimethylacetamide (7 mL), and to the solution were added 1-hydroxybenzotriazole monohydrate (245.1 mg), 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylic acid hydrochloride (386.0 mg), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (345.0 mg) at room temperature. The resultant mixture was stirred for 13 hours, and triethylamine and water were added thereto. The precipitated crystals were collected by filtration, and were dried, to thereby give 674.1 mg of the title compound. 1H-NMR(CDCl3)δppm: 1.60-1.98(3H,m), 2.00-2.16(3H,m), 2.52 (3H,s), 2.78-2.90 (3H,m), 2.92-2.98(2H,m), 2.95(3H,s), 3.06 (3H,s), 3.69(1H,d,J=15.4Hz), 3.75(1H,d,J=15.4Hz) 4.07-4.15 (1H,m), 4.66-4.72 (1H,m), 7.40 (1H,d,J=8.8,0.6Hz), 7.68 (1H,dd,J=8.8,2.4Hz), 8.03 (1H,d,J=7.8Hz), 8.16 (1H,dd,J=8.8,0.6Hz), 8.30(1H,dd,J=2.4,0.6Hz), 9.72(1H,s). MS(ESI)m/z; 548(M+H)+.

0.317 g

With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine at 20℃; for 16h; Cooling with ice;

1 Synthesis of N1- (5-chloropyridin-2-yl) -N2 - ((1S, 2R, 4S) -4 - [(dimethylamino) carbonyl]2 - [(5-methyl-4,5,6,7-tetrahydrothiazole[5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide Take 0.30g of t-butyl (1R, 2S, 5S) -2 - ({2 - ((5-chloropyridin-2-yl)2-glyoxylic acid} amino) -5 - [(dimethylamino) carbonyl]Cyclohexanecarbamate was suspended in 6 ml of acetonitrile,0.21 ml of methanesulfonic acid was added and the mixture was stirred at room temperature for about 2 hours.Under ice bath, 0.49 ml of triethylamine,0.164 g of 5-methyl-4,5,6,7-tetrahydro [1,3]Thiazole [5,4-c] pyridine-2-carboxylic acid hydrochloride,0.117 g of hydroxybenzotriazole monohydrate,0.149 g of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride was added to the mixture,And the mixture was stirred at room temperature for 16 hours. Then add triethylamine and water,And the mixture was stirred under ice-cooling for 1 hour.The crystals were then collected by filtration to obtain 0.317 g of the title compound(Equivalent recovery rate of 87%).

Reference： [1]Current Patent Assignee: INNER MONGOLIA JINGDONG PHARMACEUTICAL; BEIJING SIHUAN KEBAO PHARMACEUTICAL - CN109942600, 2019, A Location in patent: Paragraph 0239-0241
[2]Current Patent Assignee: INNER MONGOLIA JINGDONG PHARMACEUTICAL - CN111393456, 2020, A Location in patent: Paragraph 0091-0096
[3]Current Patent Assignee: DAIICHI SANKYO COMPANY, LIMITED - EP1683800, 2006, A1 Location in patent: Page/Page column 59; 60
[4]Current Patent Assignee: CHUNGWHA CHEMICAL SYNTHESIS BIOTECH; CHINA CHEMICAL PHARMACEUTICAL GROUP - TWI571460, 2017, B Location in patent: Paragraph 0040-0041

3
[ 720720-96-7 ]
[ 480452-36-6 ]
N¹-(5-chloropyridin-2-yl)-N²-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)ethanediamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
99.69%	Stage #1: tert-butyl [(1R,2S,5S)-2-([(5-chloropyridin-2-yl)amino](oxo)acetyl}amino)-5-(dimethylaminocarbonyl)cyclohexyl]carbamate With 3-butyl-1-methyl-1H-imidazol-3-ium hydroxide; methanesulfonic acid In acetonitrile for 10h; Stage #2: 5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxylic acid hydrochloride With pyridine; benzotriazol-1-ol; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride; triethylamine In acetonitrile at 10℃; for 20h;	2; 5-8 2. Preparation of DXB-ABC 100 g of DXB-AC and 2 L of acetonitrile were added to the three-necked flask, and the mixture was stirred, and the system was white turbid. About 1.65 g of 1-butyl-3-methylimidazolium hydroxide and 102.7 g of methanesulfonic acid were added in about 5 min, and the system was dissolved to be transparent, and then gradually turned into white turbidity, and stirred for 10 hours. The ice water bath was cooled to 10 ° C, and 97.3 g of triethylamine and 16.9 g of pyridine were added under stirring, and then 57.4 g were sequentially added.EDCI, 39.3g HoBt, 55.2g DXB-B, after the addition, the ice bath was withdrawn, stirred for 20h, TLC (DCM: MeOH = 10:1 UV, using the deboc reaction solution as a control point), the basic reaction was complete. The ice water bath was cooled to 10 ° C, 21.6 g of triethylamine was added, and the mixture was stirred for about 30 minutes. Filter by suction and rinse with 100 ml of acetonitrile. The filter cake was dried by blasting at 45 ° C to obtain a white solid, the yield was 97%, and the purity was 98.05%; 3. Refinement of DXB_ABCThe DXB-ABC crude product and 2 L of dichloromethane were added to a 5 L three-necked flask, and the mixture was stirred for 20-30 min, and the solid was substantially dissolved. After suction filtration, the filtrate was transferred to a 10 L bottle, and 4 L of n-hexane was added thereto with stirring, stirred for 30 min, and suction filtered. The filter cake was dried by blasting at 45 ° C to obtain a pale yellow to off-white solid powder;The above white solid was added to a 2 L bottle, 1275 ml of methanol was added, stirred at room temperature for 10-15 h, suction filtered, and the filter cake was blast dried to constant weight at 45 ° C to obtain a pale yellow to off-white solid;The above white solid was added to a 2 L bottle, 1125 ml of methanol was added, stirred at room temperature for 10-15 h, suction filtered, and the filter cake was air-dried at 45 °C. A white solid is obtained. The HPLC purity was 99.69%, single impurity <0.1%, total impurity <0.5%. For the product obtained (DXB-ABC)Perform structural characterization:
96.4%	Stage #1: tert-butyl [(1R,2S,5S)-2-([(5-chloropyridin-2-yl)amino](oxo)acetyl}amino)-5-(dimethylaminocarbonyl)cyclohexyl]carbamate With methanesulfonic acid In acetonitrile at 20 - 60℃; for 3h; Large scale; Stage #2: 5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxylic acid hydrochloride With triethylamine; ethyl (hydroxyimino)cyanoacetate; diisopropyl-carbodiimide In acetonitrile at 0 - 25℃; for 5h; Large scale;	3 Example 3. Synthesis of N- (5-chloropyridin-2-yl ) -N' - ( (IS, 2R, 4S) - 4- (dimethylcarbamoyl) -2- ( (5-methyl-4, 5, 6, 7- tetrahydrothiazol [5, 4-c] pyridin-2-carbonyl) amino) cyclohexyl ) oxamide of formula (II) 1000 g (2.14 mol) of tert-butyl N- ( (1R, 2S, 5S ) -2- ( (2- ( (5- chloropyridin-2-yl ) amino) -2-oxoacetyl) amino) -5-(dimethylcarbamoyl ) cyclohexyl ) carbamate (of formula (I)), obtained according to any one of the methods described in Examples 1 or 2, were mixed with 12.5 L of acetonitrile. The temperature of the resulting mixture was maintained between 20 and 25 °C during the subsequent addition of 278 mL (411.4 g, 4.28 mol, 2 molar eq. ) of methanesulfonic acid. The resulting mixture was heated at a temperature of about 60 °C and kept under stirring for 3 hours at the indicated temperature. The reaction mixture was then cooled at a temperature of between 0 and 5 °C and 625 mL (453.7 g, 4.49 mol, 2.10 molar eq.) of triethylamine were slowly added, maintaining the temperature below 5 °C. The mass reaction temperature was controlled to keep it between 20 and 25 °C, and then 527 g (2.24 mol, 1.05 molar eq.) of the 5-methyl-4, 5, 6, 7- tetrahydrothiazol [5, 4-c] pyridin-2-carboxylic acid hydrochloride salt, 30.4 g of OximaPure (cyano (hydroxyimino) ethyl acetate) (0.214 mol, 0.1 molar eq. ) , and 384 mL (313 g, 2.48 mol, 1.16 molar eq. ) of diisopropylcarbodiimide were added, while keeping the temperature between 20 and 25 °C. The reaction mixture was kept under stirring for 5 hours in said temperature range. 2 L of triethylamine were then added, keeping the temperature between 20 and 25 °C, and subsequently 5 L of water were added in the same temperature range. The resulting mixture was cooled at a temperature of about 3 °C and filtered. The resulting solid was washed three times 1 L of water each, and subsequently dried. 1129.0 g (yield of 96.4%) of a white solid corresponding to N- (5-chloropyridin-2-yl ) -N' - ( (IS, 2R, 4S ) -4-(dimethylcarbamoyl ) -2- ( (5-methyl-4, 5, 6, 7-tetrahydrothiazol [5, 4- c] pyridin-2-carbonyl ) amino ) cyclohexyl ) oxamide were thereby obtained. Product purity was analyzed by means of HPLC, obtaining a value of 98.19%.
85%	Stage #1: tert-butyl [(1R,2S,5S)-2-([(5-chloropyridin-2-yl)amino](oxo)acetyl}amino)-5-(dimethylaminocarbonyl)cyclohexyl]carbamate With methanesulfonic acid In dichloromethane at 20℃; for 2h; Stage #2: 5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxylic acid hydrochloride With benzotriazol-1-ol; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride; triethylamine In dichloromethane at 20℃; for 18h; Cooling with ice;	11 Example 11: Preparationof Edoxaban: A solution offormula (XI) (7.0g, 0.014moles) inmethylene dichloride(56ml) andmethane sulfonic acid (4.85ml, 0.074 moles) was stirred for 2 hours at room temperature. After completion of the reaction, triethylamine( 15.63ml,0.1 12moles),5-methyl-4,5,6,7-tetrahydrothiazolo-[5,4- c]pyridine-2-carboxylic acid hydrochloride^.86 g,0.0164moles),N-(3-dimethylaminopropyl)-N'- ethylcarbodiimidehydrochloride (3.44g,0.017moles),and 1-hydroxybenzotriazole (0162) (2.43g,0.0158moles) was added while the reaction mixture was cooled with ice. Thereaction mixture was stirred for 18 hours at room temperature after which water (35ml)and methylene dichloride(70ml) was added. The layers were separated the layers and organic layer was concentrated under reduced pressure to get Edoxabanas a solid (7.0g, yield: 85%, HPLC Purity: >99%).

85.13%	Stage #1: tert-butyl [(1R,2S,5S)-2-([(5-chloropyridin-2-yl)amino](oxo)acetyl}amino)-5-(dimethylaminocarbonyl)cyclohexyl]carbamate With hydrogenchloride; lithium hydroxide monohydrate In propan-2-one at 0.25 - 0.3℃; for 2h; Stage #2: 5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxylic acid hydrochloride With benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine; dicyclohexyl-carbodiimide In dichloromethane at 0.35 - 0.4℃; for 0.5h;	3E Example 3E: Preparation of Edoxaban Free base (compound of formula I-A) directly from Carbamic acid, N-[(1R, 2S, 5S)-2-[[2-[(5-chloro-2-pyridinyl) amino]-2-oxoacetyl] amino] -5- [(dime thy lamino) carbonyl] cyclohexyl]-l, 1- dimethylethyl ester (compound of formula IV): The compound of formula IV (25.0g) obtained from example IB was added to acetone(250 mL) and concentrated hydrochloric acid (50 mL) was then added to it. The reaction mass was then stirred for about 2 hours at about 25°C to 30°C. After completion of the reaction mass, filtered the slurry mass, washed with acetone and suck dried. The obtained wet cake was suspended in methylene dichloride (250 mL) and added 5-Methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylic acid hydrochloride (compound of formula III, 15.05g, diisopropyl ethyl amine (34.5g), N,N- dicyclohexyl carbodiimide (DCC) ( 16.5 lg) and 1-hydroxybenzotriazole (HOBt, 3.62g). The reaction mass was heated to about 35°C to 40°C for about 5 hours. After completion ,the reaction mass was cooled to about 0°C to 5°C for about 1 hour, filtered. The combined filtrate was washed with 5% aq. NaHCCL followed by brine solution. The solvent was distilled to obtain the crude product (compound of formula I-A) to which methanol (200 mL) was added and heated to 60°C to 65 °C for about 1 hour then cooled to 25 °C to 30°C for 1 hour, filtered, washed with methanol to obtained wet cake which was dried in tray drier at 40°C to 45 °C to obtain compound of formula I- A (24.90g, 85.13%), HPLC purity 99.47.
	Stage #1: tert-butyl [(1R,2S,5S)-2-([(5-chloropyridin-2-yl)amino](oxo)acetyl}amino)-5-(dimethylaminocarbonyl)cyclohexyl]carbamate With methanesulfonic acid In acetonitrile at 20℃; for 2h; Stage #2: 5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxylic acid hydrochloride With benzotriazol-1-ol; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride; triethylamine In acetonitrile at 0 - 20℃; for 17h;	2 Referential Example 2: N-(5-Chloropyridin-2-yl)-N'-[(1S,2R,4S)-4-(dimethylcarbamoyl)-2-[(5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl]ethanediamide Methanesulfonic acid (66 mL) was added at room temperature to a suspension of t-butyl [(1R,2S,5S)-2-([(5-chloropyridin-2-yl)amino](oxo)acetyl}amino)-5-(dimethylaminocarbonyl)cyclohexyl]carbamate (95.1 g) in acetonitrile (1,900 mL), and the mixture was stirred at the same temperature for 2 hours. Triethylamine (155 mL), 5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxylic acid hydrochloride (52.5 g), 1-hydroxybenzotriazole (33.0 g), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (46.8 g) were added to the reaction mixture under ice-cooling, and the mixture was stirred at room temperature for 16 hours. Triethylamine and water were added thereto, followed by stirring under ice-cooling for 1 hour. The formed crystals were recovered by filtration, to thereby yield 103.2 g of the title compound. 1H-NMR(CDCl3)δ:1.60-1.98(3H,m),2.00-2.16(3H,m),2.52(3H,s), 2.78-2.90(3H,m),2.92-2.98(2H,m),2.95(3H,s),3.06(3H,s), 3.69(1H,d,J=15.4Hz),3.75(1H,d,J=15.4Hz),4.07-4.15(1H,m), 4.66-4.72(1H,m),7.40(1H,dd,J=8.8,0.6Hz), 7.68(1H,dd,J=8.8,2.4Hz),8.03(1H,d,J=7.8Hz), 8.16(1H,dd,J=8.8,0.6Hz),8.30(1H,dd,J=2.4,0.6Hz),9.72(1H,s).
	Stage #1: tert-butyl [(1R,2S,5S)-2-([(5-chloropyridin-2-yl)amino](oxo)acetyl}amino)-5-(dimethylaminocarbonyl)cyclohexyl]carbamate With methanesulfonic acid In acetonitrile at 20℃; for 2h; Stage #2: 5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxylic acid hydrochloride With benzotriazol-1-ol; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride; triethylamine In acetonitrile at 20℃; for 16h; Cooling with ice;	6 (Reference Example 6) N1-(5-Chloropyridin-2-yl)-N2-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)ethanediamide (A) Methanesulfonic acid (66 ml) was added to a suspension of tert-butyl [(1R,2S,5S)-2-([(5-chloropyridin-2-yl)amino](oxo)acetyl}amino)-5-(dimethylaminocarbonyl)cyclohexyl]carbamate (8) (95.1 g) in acetonitrile (1900 ml) at room temperature, and the mixture was stirred at this temperature for 2 hours. To the reaction solution, triethylamine (155 ml), 5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxylic acid hydrochloride (10) (52.5 g), 1-hydroxybenzotriazole (33.0 g), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (46.8 g) were added under ice cooling, and the mixture was stirred at room temperature for 16 hours. Triethylamine and water were added thereto, and the mixture was stirred for 1 hour under ice cooling. Then, crystals were collected by filtration to obtain the title compound (A) (103.2 g). 1H-NMR (CDCl3) δ: 1.60-1.98 (3H, m), 2.00-2.16 (3H, m), 2.52 (3H, s), 2.78-2.90 (3H, m), 2.92-2.98 (2H, m), 2.95 (3H, s), 3.06 (3H, s), 3.69 (1H, d, J=15.4 Hz), 3.75 (1H, d, J=15.4 Hz), 4.07-4.15 (1H, m), 4.66-4.72 (1H, m), 7.40 (1H, dd, J=8.8, 0.6 Hz), 7.68 (1H, dd, J=8.8, 2.4 Hz), 8.03 (1H, d, J=7.8 Hz), 8.16 (1H, dd, J=8.8, 0.6 Hz), 8.30 (1H, dd, J=2.4, 0.6 Hz), 9.72 (1H, s). MS (ESI) m/z: 548 (M+H)+.
	Stage #1: tert-butyl [(1R,2S,5S)-2-([(5-chloropyridin-2-yl)amino](oxo)acetyl}amino)-5-(dimethylaminocarbonyl)cyclohexyl]carbamate With methanesulfonic acid In acetonitrile at 20℃; for 2h; Stage #2: 5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxylic acid hydrochloride With benzotriazol-1-ol; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride; triethylamine In acetonitrile at 20℃; for 16h; Cooling with ice;	4 (Reference Example 4) N1-(5-Chloropyridin-2-yl)-N2-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)ethanediamide (A) Methanesulfonic acid (66 ml) was added to a suspension of tert-butyl [(1R,2S,5S)-2-([(5-chloropyridin-2-yl)amino](oxo)acetyl}amino)-5-(dimethylaminocarbanyl)cyclohexyl]carbamate (1) (95.1 g) in acetonitrile (1900 ml) at room temperature, and the mixture was stirred at this temperature for 2 hours. To the reaction solution, triethylamine (155 ml), 5-methyl-4,5,6,7-tetrahydro[1,3]thiazalo[5,4-c]pyridine-2-carboxylic acid hydrochloride (8) (52.5 g), 1-hydroxybenzotriazole (33.0 g), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (46.8 g) were added under ice cooling, and the mixture was stirred at room temperature for 16 hours. Triethylamine and water were added thereto, and the mixture was stirred for 1 hour under ice cooling. Then, crystals were collected by filtration to obtain the title compound (103.2 g). 1H-NMR (CDCI3) δ: 1.60-1.98 (3H, m), 2.00-2.16 (3H, m), 2.52 (3H, s), 2.78-2.90 (3H, m), 2.92-2.98 (2H, m), 2.95 (3H, s), 3.06 (3H, s), 3.69 (1H, d, J=15.4 Hz), 3.75 (1H, d, J=15.4 Hz), 4.07-4.15 (1H, m), 4.66-4.72 (1H, m), 7.40 (1H, dd, J=8.8, 0.6 Hz), 7.68 (1H, dd, J=8.8, 2.4 Hz), 8.03 (1H, d, J=7.8 Hz), 8.16 (1H, dd, J=8.8, 0.6 Hz), 8.30 (1H, dd, J=2.4, 0.6 Hz), 9.72 (1H, s). MS (ESI) m/z: 548 (M+H)+.
103.2 g	Stage #1: tert-butyl [(1R,2S,5S)-2-([(5-chloropyridin-2-yl)amino](oxo)acetyl}amino)-5-(dimethylaminocarbonyl)cyclohexyl]carbamate With methanesulfonic acid In acetonitrile at 20℃; for 2h; Stage #2: 5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxylic acid hydrochloride With benzotriazol-1-ol; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride; triethylamine In acetonitrile at 20℃; for 16h; Cooling with ice;	6 (Reference Example 6) N1-(5-Chloropyridin-2-yl)-N2-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)ethanediamide (X) (production method described in the pamphlet of International Publication No. WO 2007/032498) Methanesulfonic acid (66 ml) was added to a suspension of tert-butyl [(1R,2,S,5S)-2-([(5-chloropyridin-2-yl)amino](oxo)acetyl}amino)-5-(dimethylaminocarbonyl)cyclohexyl]carbamate (5) (95.1 g) in acetonitrile (1900 ml) at room temperature, and the mixture was stirred at this temperature for 2 hours. To the reaction solution, triethylamine (155 ml), 5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyrzdine-2-carboxylic acid hydrochloride (8) (52.5 g), 1-hydroxybenzotriazole (33.0 g), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (46.8 g) were added under ice cooling, and the mixture was stirred at room temperature for 16 hours. Triethylamine and water were added thereto, and the mixture was stirred for 1 hour under ice cooling. Then, crystals were collected by filtration to obtain the title compound (X) (103.2 g). 1H-NMR (CDCl3) δ : 1.60-1.98 (3H, m), 2.00-2.16 (3H, m), 2.52 (3H, s), 2.78-2.90 (3H, m), 2.92-2.98 (2H, m), 2.95 (3H, s), 3.06 (3H, s), 3.69 (1H, d, J = 15.4 Hz), 3.75 (1H, d, J = 15.4 Hz), 4.07-4.15 (1H, m), 4.66-4.72 (1H, m), 7.40 (1H, dd, J = 8.8, 0.6 Hz), 7. 68 (1H, dd, J = 8.8, 2.4 Hz), 8.03 (1H, d, J = 7.8 Hz), 8.16 (1H, dd, J = 8.8, 0.6 Hz), 8.30 (1H, dd, J = 2. 4, 0.6 Hz), 9.72 (1H, s). MS (ESI) m/z: 548 (M+H)+.
103.2 g	Stage #1: tert-butyl [(1R,2S,5S)-2-([(5-chloropyridin-2-yl)amino](oxo)acetyl}amino)-5-(dimethylaminocarbonyl)cyclohexyl]carbamate With methanesulfonic acid In acetonitrile at 20℃; for 2h; Stage #2: 5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxylic acid hydrochloride With benzotriazol-1-ol; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride; triethylamine In acetonitrile at 20℃; for 17h; Cooling with ice;	3 Referential Example 3 N¹- (5-Chloropyridin-2-yl) -N²- [ (IS, 2R, 4S) -4- (dimethylcarbamoyl) -2 - { [ (5-methyl-4 , 5,6, 7-tetrahydro [1,3] thiazolo [5 , 4-c] yridin-2 -yl ) carbonyl] amino} cyclohexyl] ethanediamide (Edoxaban) Referential Example 3 N1- (5-Chloropyridin-2-yl) -N2- [ (IS, 2R, 4S) -4- (dimethylcarbamoyl) -2 - { [ (5-methyl-4 , 5,6, 7-tetrahydro [1,3] thiazolo [5 , 4-c] yridin-2 -yl ) carbonyl] amino} cyclohexyl] ethanediamide (Edoxaban) Methanesulfonic acid (66 mL) was added at room temperature to a suspension of ' tert-butyl [ (1R, 2S, 5S) -2- ( { [ (5-chloropyridin-2-yl) amino] (oxo)acet yl }amino) -5- (dimethylaminocarbonyl) cyclohexyl] carbamate (95.1 g) in acetonitrile (1,900 mL) , and the mixture was stirred at the same temperature for 2 hours. Triethylamine (155 mL) , 5-methyl-4 ,5,6, 7-tetrahydro [1,3] thiazolo [5 , 4-c] pyridine-2 -carbox ylic acid hydrochloride (52.5 g) , 1 -hydroxybenzotriazole (33.0 g) , and l-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (46.8 g) were added to the reaction mixture under ice-cooling, and the mixture was stirred at room temperature for 16 hours. Triethylamine and water were added thereto, followed by stirring under ice-cooling for 1 hour. The formed crystals were recovered by filtration, to thereby yield 103.2 g of the title compound.
103.2 g	Stage #1: tert-butyl [(1R,2S,5S)-2-([(5-chloropyridin-2-yl)amino](oxo)acetyl}amino)-5-(dimethylaminocarbonyl)cyclohexyl]carbamate With methanesulfonic acid In acetonitrile at 20℃; for 2h; Stage #2: 5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxylic acid hydrochloride With N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride; triethylamine In acetonitrile at 20℃; for 16h;	5 Reference Example 5N’-(5-Chloropyridin-2-yl)-N2-[(1 S,2R,45)-4-(dim- ethylcarbamoyl)-2-{ [(5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl]ethanediamide [edoxaban] (X) 10098] tert-Hutyl[(1R,25,55)-2-([(5-chloropyridin-2-yl)amino] (oxo)acetyl}amino)-5-(dimethylaminocarbonyl)cy-clohexyl]carbamate (12) (95.1 g) was suspended in acetonitrile (1900 mE), and methanesulfonic acid (66 mE) was addedto the suspension at room temperature. The obtained mixturewas stirred at the same temperature as described above for 2hours. While the reaction mixture was stirred under coolingon ice, triethylamine (155 mE), 5-methyl-4,5,6,7-tetrahydro[1 ,3]thiazolo[5,4-c]pyridine-2-carboxylate hydrochloride(52.5 g), 1-hydroxybenzotriazole (33.0 g), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (46.8 g)were added to the mixture. The reaction mixture was stirred atroom temperature for 16 hours. Triethylamine and water wereadded to the reaction mixture, and the obtained mixture wasthen stirred under cooling on ice for 1 hout A precipitatedcrystal was collected by filtration and was dried to obtain103.2 g of the title product.
103.2 g	Stage #1: tert-butyl [(1R,2S,5S)-2-([(5-chloropyridin-2-yl)amino](oxo)acetyl}amino)-5-(dimethylaminocarbonyl)cyclohexyl]carbamate With methanesulfonic acid In acetonitrile at 20℃; for 2h; Stage #2: 5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxylic acid hydrochloride With benzotriazol-1-ol; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride; triethylamine In lithium hydroxide monohydrate; acetonitrile at 20℃; for 17h;	10 N¹-(5-chloropyridin-2-yl)-N²-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-[(5-methyl-4,5,6,7-tetrahydrothiazolone[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)ethanediamide The tert-butyl [. (1R,2S,5S)-2-([(5-chloropyridin-2-yl)amino](oxo)acetyl} amino)-5-(dimethylaminocarbonyl)cyclohexyl carbamate (A-9) (95.1g), to the acetonitrile (1900 ml) suspension of a under a room temperature, Methanesulfonic acid (66 ml) was added and it stirred at a temperature as it is for 2 hours. The bottom of ice-cooling to reaction mixture, triethylamine (155 ml), 5-methyl-4,5,6,7-tetrahydro [1,3]thiazolo [5,4-c]pyridin-2-carboxylic acid hydrochloride (52.5g), 1-hydroxybenzotriazol (33.0g) and a 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (46.8g) were added, and it stirred at the room temperature for 16 hours. Triethylamine and water were added, the crystal was separated the bottom of ice-cooling, and after 1-hour stirring, and title compound (X) (103.2g) was obtained.
125.3 g	Stage #1: tert-butyl [(1R,2S,5S)-2-([(5-chloropyridin-2-yl)amino](oxo)acetyl}amino)-5-(dimethylaminocarbonyl)cyclohexyl]carbamate With methanesulfonic acid In acetonitrile at 25℃; for 2h; Stage #2: With triethylamine In acetonitrile at 10℃; for 0.166667h; Stage #3: 5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxylic acid hydrochloride With benzotriazol-1-ol; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride In acetonitrile at 25℃; for 18h;	2 Example 2 N- (5-Chloropyridin-2-yl)-N '- ((1S, 2R, 4S)-4 - [(dimethylamino) carbonyl] -2 - [(5-methyl-4,5,6,7-tetrahydrothiazole[5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) ethanediamide, Preparation of Compound (1) A 10 L reaction flask was charged with 2560 mL of acetonitrile, 128.0 g of (1R, 2S, 5S) -2 - ({2- [5-chloropyridin-Yl] -2-oxoacetyl} amino) -5 - [(dimethylamino) carbonyl] cyclohexylcarbamate was added with stirring and 131.4 g of methanesulfonic acid was added with stirring at 25 ± 2 ° C. The reaction was incubated for 2 h , TLC no raw material point, cooling, 10.2 ° C was added 152.2g triethylamine, stirred 10min, followed by addition of 70.6g 5-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxylic acid hydrochloride,40.7 g of 1-hydroxybenzotriazole and 62.9 g1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride,Warming to 25 , 25 ± 2 reaction 18h. TLC detection of raw material point. Developing solvent: dichloromethane: methanol = 10: 1.After the reaction, lowering the temperature to 10 °C, add saturated aqueous solution of sodium bicarbonate, 10 ± 2 °C insulation crystallization 1h, filtered, the filter cake washing, 45 °C drying by blowing 12h, shall 125.3g white solid
103.2 g	Stage #1: tert-butyl [(1R,2S,5S)-2-([(5-chloropyridin-2-yl)amino](oxo)acetyl}amino)-5-(dimethylaminocarbonyl)cyclohexyl]carbamate With methanesulfonic acid In acetonitrile at 20℃; for 2h; Stage #2: 5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxylic acid hydrochloride With triethylamine In acetonitrile at 20℃; for 16h; Cooling with ice;	4 {Tert-Butyl [(1R, 2S, 5S) -2-({(5-chloropyridin-2-yl) amino} (oxo) acetyl) amino] -5-dimethylaminocarbonyl in acetonitrile (1900 ml)Cyclohexyl] carbamate(95.1g), Methanesulfonic acid (66 ml) is added at room temperature,The mixture was stirred at room temperature for 2 hours,The reaction solution, trimethylamine (155 ml),5-Methyl-4,5,6,7-tetrahydro [1,3] thiazo [5,4-c] pyridine-2-carboxylic acid hydrochloride (46.8 g) was added under ice cooling, and the mixture was added. Stirred at room temperature for 16 hours.Triethylamine and water were added thereto, and the mixture was stirred under ice cooling for 1 hour. Thereafter, the crystals were collected by filtration to obtain the title compound (103.2 g).
103.2 g	Stage #1: tert-butyl [(1R,2S,5S)-2-([(5-chloropyridin-2-yl)amino](oxo)acetyl}amino)-5-(dimethylaminocarbonyl)cyclohexyl]carbamate With methanesulfonic acid In acetonitrile at 20℃; for 2h; Stage #2: 5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxylic acid hydrochloride With benzotriazol-1-ol; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride; triethylamine In acetonitrile at 20℃; for 16h; Cooling with ice;	1-2; 1-15 Refer to the technical scheme disclosed in patent US8686189B2, selectN-(5-chloropyridin-2-yl)-N'-[(1S,2R,4S)-4-(N,N-dimethylformylamino)-2-(5-methyl-4, 5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxamide)cyclohexyl]oxalamide as a raw material,Prepare compound (1): At room temperature, toN-(5-Chloropiperidin-2-yl)-N'-[(1S,2R,4S)-4-(N,N-dimethylformylamino)-2-(amino tert-butoxycarbonyl ) Cyclohexyl] oxamide (95.1g) in acetonitrile (1900ml) suspension was added with methanesulfonic acid (66ml),Stir at this temperature for 2 hours.Under ice cooling, triethylamine (155ml), 4,5,6,7-tetrahydro-5-methyl-thiazolo[5,4-c]pyridine-2-carboxylic acid hydrochloride ( 52.5g), 1-hydroxybenzotriazole (33.0g), 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (46.8g), stirred at room temperature for 16 hours . Triethylamine and water were added, and after stirring for 1 hour under ice cooling, the crystals were filtered out to obtain 103.2 g of compound (1)
	Stage #1: tert-butyl [(1R,2S,5S)-2-([(5-chloropyridin-2-yl)amino](oxo)acetyl}amino)-5-(dimethylaminocarbonyl)cyclohexyl]carbamate With hydrogenchloride In dichloromethane; lithium hydroxide monohydrate at 20℃; for 1.16h; Stage #2: 5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxylic acid hydrochloride With N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride; triethylamine In ethanol at 20℃;	1-2 Example 1 (5-chloropyridin-2-yl)-N2-((1S,2R,4S)-2-[(tert-Butoxycarbonyl)Amino]-4-[(dimethylamino) carbonyl]-cyclohexyl)oxalamide (Formula 2) 11.0 g is added to MC 146.3g and stirred at room temperature. 4.9 g of 35% hydrochloric acid is added, and the mixture is stirred until the reaction is completed, and when the reaction is completed, it is completely concentrated. TEA 7.1g and ethanol 39.5g were added to the concentrate and stirred at room temperature. 4,5,6,7-tetrahydro-5-methylthiazolo[5,4-c]pyridine-2-carboxylic acid hydrochloride (Formula 4) 6.1g and EDCI 5.5g are added and stirred until the reaction is complete. 292.6 g of MC and 220 mL of water are added, stirred, and the MC layer is first separated. After the separation, 146.3 g of MC was added to the water layer again, stirred, and then the layers were separated a second time. 110 mL of water is added to the entire MC layer separated from the first and second water layers, stirred, and then the third layer is separated again. After the tertiary MC layer was concentrated, 35.1 g of MC, 9.2 g of ethanol, and 6 mL of water were added to the concentrate and stirred. Add 5.7 g of benzenesulfonic acid and stir at room temperature for about 10 minutes. After adding 110 mL of ethyl acetate to the stirred reaction solution, the mixture was stirred for 1 hour. After cooling the mixed solution in which crystals are formed by the stirring to 0-5° C., the mixture is stirred again for 1 hour to completely form crystals from the mixed solution. The resulting crystals were filtered and dried under vacuum at 50° C. for 12 hours to obtain the title crystals (yield: 89%, purity: 99.980%)

Reference： [1]Current Patent Assignee: BEIJING SUN NOVO PHARMACEUTICAL RES - CN108484641, 2018, A Location in patent: Paragraph 0050-0055; 0089-0096
[2]Current Patent Assignee: MOEHS IBERICA S L - WO2019/158550, 2019, A1 Location in patent: Page/Page column 15-16
[3]Current Patent Assignee: VIATRIS INC - WO2018/11823, 2018, A1 Location in patent: Page/Page column 27
[4]Current Patent Assignee: GLENMARK PHARMACEUTICALS LTD - WO2021/1728, 2021, A1 Location in patent: Page/Page column 17-18
[5]Current Patent Assignee: DAIICHI SANKYO COMPANY, LIMITED - EP1925611, 2008, A1 Location in patent: Page/Page column 47-48
[6]Current Patent Assignee: DAIICHI SANKYO COMPANY, LIMITED - EP2407450, 2012, A1 Location in patent: Page/Page column 21
[7]Current Patent Assignee: DAIICHI SANKYO COMPANY, LIMITED - EP2407457, 2012, A1 Location in patent: Page/Page column 16
[8]Current Patent Assignee: DAIICHI SANKYO COMPANY, LIMITED - EP2589590, 2013, A1 Location in patent: Paragraph 0144; 0145
[9]Current Patent Assignee: DAIICHI SANKYO COMPANY, LIMITED - WO2014/81047, 2014, A1 Location in patent: Page/Page column 22
[10]Current Patent Assignee: DAIICHI SANKYO COMPANY, LIMITED - US2015/353577, 2015, A1 Location in patent: Paragraph 0097; 0098
[11]Current Patent Assignee: DAIICHI SANKYO COMPANY, LIMITED - JP5801011, 2015, B2 Location in patent: Page/Page column 0210-0212
[12]Current Patent Assignee: SHANDONG KEXING BIOPRODUCTS; SHENZHEN KEXING BIOTECH - CN104761571, 2017, B Location in patent: Paragraph 0049; 0050; 0051; 0052; 0053
[13]Current Patent Assignee: GAPI BIO; DONGBANG FTL; GABI BIO - JP2019/210273, 2019, A Location in patent: Paragraph 0043; 0048
[14]Current Patent Assignee: ZHEJIANG SUPOR PHARMACEUTICALS CO LTD - CN111606927, 2020, A Location in patent: Paragraph 0023-0062
[15]Current Patent Assignee: PHARMACOSTECH CO LTD - KR2021/152213, 2021, A Location in patent: Paragraph 0055-0057; 0060; 0062

4
[ 480449-70-5 ]
[ 87-69-4 ]
[ 1234476-75-5 ]

Yield	Reaction Conditions	Operation in experiment
71%	In ethanol; dichloromethane	1.1 409 mg of N1-(5-chloropyridin-2-yl)-N2-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)ethanediamide (compound A) was dissolved in 20 mL of methylene chloride, and then an equimolar amount of a solution of (+)-tartaric acid in ethanol was added thereto. The solvent was distilled off to obtain a dry solid. To the dry solid, 31 mL of 30% aqueous ethanol was added, and the mixture was dissolved with heating and then left at room temperature. The deposited material was suction-filtered and then dried in air at room temperature to obtain the compound of interest (378 mg, yield: 71%). Form I was confirmed by powder X-ray diffraction. Theoretical (in terms of monotartrate monohydrate): C 46.96%, H 5.35%, N 13.69%, Cl 4.95%, S 4.48% Found: C 46.80%, H 5.11%, N 13.73%, Cl 5.08%, S 4.64% Form I had the following characteristic diffraction peaks in powder X-ray diffraction: 2θ=14.5, 17.2, 20.4, 21.3, 22.1, and 23.4°.
64%	In ethanol; water at 80℃; for 2h;	16 <Example 16> Preparation of edoxaban L-tartaric acid salt of the present invention 0.5 g of edoxaban free base was added to the reaction unit, and then 14 mL of ethanol and 6 mL of distilled water were added to dissolve it. After adding 0.14 g of L-tartaric acid, the temperature was raised to 80° C. and stirred for 2 hours. After cooling to room temperature and stirring overnight, the resulting solid was filtered. Vacuum-dried overnight at room temperature to give the title compound 0.44g (64%).

Reference： [1]Current Patent Assignee: DAIICHI SANKYO COMPANY, LIMITED - EP2383272, 2011, A1 Location in patent: Page/Page column 6-7
[2]Current Patent Assignee: DONG-A ST CO., LTD. - KR2020/53270, 2020, A Location in patent: Paragraph 0221-0222

5
[ 1210348-34-7 ]
[ 480449-70-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: triethylamine / acetonitrile / 6 h / 60 °C 2.1: methanesulfonic acid / acetonitrile / 2 h / 20 °C 2.2: 16 h / 20 °C / Cooling with ice
	Multi-step reaction with 2 steps 1.1: triethylamine / acetonitrile / 7 h / 60 - 75 °C 2.1: methanesulfonic acid / acetonitrile / 2 h / 20 °C 2.2: 16 h / 20 °C / Cooling with ice
	Multi-step reaction with 2 steps 1.1: triethylamine / acetonitrile / 22 h / 20 - 60 °C 2.1: methanesulfonic acid / acetonitrile / 2 h / 20 °C 2.2: 16 h / 20 °C / Cooling with ice

	Multi-step reaction with 2 steps 1.1: triethylamine / acetonitrile / 22 h / 20 - 60 °C 2.1: methanesulfonic acid / acetonitrile / 2 h / 20 °C 2.2: 16 h / 20 °C
	Multi-step reaction with 2 steps 1.1: triethylamine / acetonitrile / 22 h / 20 - 60 °C 2.1: methanesulfonic acid / acetonitrile / 2 h / 20 °C 2.2: 17 h / 20 °C
	Multi-step reaction with 2 steps 1.1: triethylamine / acetonitrile / 0.17 h / 25 °C 1.2: 6 h / 60 °C 2.1: methanesulfonic acid / acetonitrile / 2 h / 25 °C 2.2: 0.17 h / 10 °C 2.3: 18 h / 25 °C
	Multi-step reaction with 2 steps 1.1: 3-butyl-1-methyl-1H-imidazol-3-ium hydroxide; triethylamine; pyridine / acetonitrile / 4 h / 45 - 60 °C 2.1: 3-butyl-1-methyl-1H-imidazol-3-ium hydroxide; methanesulfonic acid / acetonitrile / 10 h 2.2: 20 h / 10 °C
	Multi-step reaction with 3 steps 1: anhydrous Sodium acetate / N,N-dimethylformamide-d<SUB>7</SUB> / 40 - 110 °C 2: methanesulfonic acid / dichloromethane / 5 h / 10 °C 3: triethylamine / 24 h / 25 °C
	Multi-step reaction with 2 steps 1.1: 1,1′-carbonyldiimidazole; pyridine / dichloromethane / 2 h / 20 - 25 °C 1.2: 2 h / 20 °C 2.1: methanesulfonic acid / acetonitrile / 2 h / 20 °C 2.2: 16 h / 20 °C / Cooling with ice
	Multi-step reaction with 3 steps 1.1: 1,1′-carbonyldiimidazole; pyridine / dichloromethane / 2 h / 20 - 25 °C 1.2: 2 h / 20 °C 2.1: trifluoroacetic acid / dichloromethane / 4 h / 20 °C 3.1: 1,1′-carbonyldiimidazole; pyridine / dichloromethane / 1 h / 20 - 25 °C 3.2: 2 h / 20 °C
	Multi-step reaction with 3 steps 1.1: 1,1′-carbonyldiimidazole; pyridine / dichloromethane / 2 h / 20 - 25 °C 1.2: 2 h / 20 °C 2.1: trifluoroacetic acid / dichloromethane / 4 h / 20 °C 3.1: triethylamine / dichloromethane / 3 h / 0 - 20 °C / Reflux
	Multi-step reaction with 3 steps 1: triethylamine / acetonitrile / 50 - 60 °C 2: acetonitrile / 20 - 25 °C 3: triethylamine / acetonitrile / 20 - 40 °C
	Multi-step reaction with 3 steps 1: triethylamine / acetonitrile / 50 - 60 °C 2: methanesulfonic acid / acetonitrile 3: triethylamine; benzotriazol-1-ol; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride / 15 - 25 °C
	Multi-step reaction with 2 steps 1.1: triethylamine / dimethyl sulfoxide / 0.5 - 0.6 °C 2.1: hydrogenchloride; lithium hydroxide monohydrate / propan-2-one / 2 h / 0.25 - 0.3 °C 2.2: 0.5 h / 0.35 - 0.4 °C
	Multi-step reaction with 3 steps 1: triethylamine / acetonitrile / 6 h / 60 °C 2: methanesulfonic acid / acetonitrile / 2 h / 20 °C 3: triethylamine; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride; benzotriazol-1-ol / 16 h / 20 °C
	Multi-step reaction with 3 steps 1: triethylamine / acetonitrile / 6 h / 60 °C 2: acetonitrile; propan-2-one / 12 h / 20 °C 3: triethylamine; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride; benzotriazol-1-ol / acetonitrile / 16 h / 20 °C

Reference： [1]Current Patent Assignee: DAIICHI SANKYO COMPANY, LIMITED - EP2407450, 2012, A1 Current Patent Assignee: DAIICHI SANKYO COMPANY, LIMITED - EP2407457, 2012, A1
[2]Current Patent Assignee: DAIICHI SANKYO COMPANY, LIMITED - EP2407457, 2012, A1
[3]Current Patent Assignee: DAIICHI SANKYO COMPANY, LIMITED - EP2589590, 2013, A1
[4]Current Patent Assignee: DAIICHI SANKYO COMPANY, LIMITED - US2015/353577, 2015, A1
[5]Current Patent Assignee: DAIICHI SANKYO COMPANY, LIMITED - JP5801011, 2015, B2
[6]Current Patent Assignee: SHENZHEN KEXING BIOTECH; SHANDONG KEXING BIOPRODUCTS - CN104761571, 2017, B
[7]Current Patent Assignee: BEIJING SUN NOVO PHARMACEUTICAL RES - CN108484641, 2018, A
[8]Current Patent Assignee: JILIN YATAI (GROUP) CO., LTD. - CN107641131, 2018, A
[9]Current Patent Assignee: GAPI BIO; DONGBANG FTL; GABI BIO - JP2019/210273, 2019, A
[10]Current Patent Assignee: GAPI BIO; DONGBANG FTL; GABI BIO - JP2019/210273, 2019, A
[11]Current Patent Assignee: GAPI BIO; DONGBANG FTL; GABI BIO - JP2019/210273, 2019, A
[12]Current Patent Assignee: INNER MONGOLIA JINGDONG PHARMACEUTICAL - CN111393456, 2020, A
[13]Current Patent Assignee: INNER MONGOLIA JINGDONG PHARMACEUTICAL - CN111393456, 2020, A
[14]Current Patent Assignee: GLENMARK PHARMACEUTICALS LTD - WO2021/1728, 2021, A1
[15]Current Patent Assignee: BORYUNG; BORYUNG PHARM CO.,LTD. - WO2022/103239, 2022, A1
[16]Current Patent Assignee: BORYUNG; BORYUNG PHARM CO.,LTD. - WO2022/103239, 2022, A1

6
[ 1243308-37-3 ]
[ 480449-70-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: triethylamine / acetonitrile / 6 h / 60 °C 2.1: methanesulfonic acid / acetonitrile / 2 h / 20 °C 2.2: 16 h / 20 °C / Cooling with ice
	Multi-step reaction with 2 steps 1.1: triethylamine / acetonitrile / 22 h / 20 - 60 °C 2.1: methanesulfonic acid / acetonitrile / 2 h / 20 °C 2.2: 17 h / 20 °C
	Multi-step reaction with 3 steps 1: N-ethyl-N,N-diisopropylamine / dimethyl sulfoxide / 7 h / 66 - 70 °C 2: methanesulfonic acid / acetonitrile / 2 h / 20 °C 3: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine / 16 h / 20 °C / Cooling with ice

	Multi-step reaction with 2 steps 1.1: triethylamine / acetonitrile / 0.17 h / 25 °C 1.2: 6 h / 60 °C 2.1: methanesulfonic acid / acetonitrile / 2 h / 25 °C 2.2: 0.17 h / 10 °C 2.3: 18 h / 25 °C
	Multi-step reaction with 2 steps 1.1: 1-butyl-3-methylimidazolium hydroxide; triethylamine; pyridine / acetonitrile / 4 h / 45 - 60 °C 2.1: 1-butyl-3-methylimidazolium hydroxide; methanesulfonic acid / acetonitrile / 10 h 2.2: 20 h / 10 °C
	Multi-step reaction with 3 steps 1: triethylamine / acetonitrile / 50 - 60 °C 2: acetonitrile / 20 - 25 °C 3: triethylamine / acetonitrile / 20 - 40 °C
	Multi-step reaction with 3 steps 1: triethylamine / acetonitrile / 50 - 60 °C 2: methanesulfonic acid / acetonitrile 3: triethylamine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / 15 - 25 °C
	Multi-step reaction with 2 steps 1.1: triethylamine / dimethyl sulfoxide / 0.5 - 0.6 °C 2.1: hydrogenchloride; water / acetone / 2 h / 0.25 - 0.3 °C 2.2: 0.5 h / 0.35 - 0.4 °C

Reference： [1]Current Patent Assignee: DAIICHI SANKYO COMPANY, LIMITED - EP2407450, 2012, A1 Current Patent Assignee: DAIICHI SANKYO COMPANY, LIMITED - EP2407457, 2012, A1
[2]Current Patent Assignee: DAIICHI SANKYO COMPANY, LIMITED - JP5801011, 2015, B2
[3]Current Patent Assignee: CHUNGWHA CHEMICAL SYNTHESIS BIOTECH; CHINA CHEMICAL PHARMACEUTICAL GROUP - TWI571460, 2017, B
[4]Current Patent Assignee: SHENZHEN KEXING BIOTECH; SHANDONG KEXING BIOPRODUCTS - CN104761571, 2017, B
[5]Current Patent Assignee: BEIJING SUN NOVO PHARMACEUTICAL RES - CN108484641, 2018, A
[6]Current Patent Assignee: INNER MONGOLIA JINGDONG PHARMACEUTICAL - CN111393456, 2020, A
[7]Current Patent Assignee: INNER MONGOLIA JINGDONG PHARMACEUTICAL - CN111393456, 2020, A
[8]Current Patent Assignee: GLENMARK PHARMACEUTICALS LTD - WO2021/1728, 2021, A1

7
[ 480449-70-5 ]
[ 104-15-4 ]
[ 480449-71-6 ]

Yield	Reaction Conditions	Operation in experiment
86%	In ethanol; water at 20 - 60℃; for 24h;	2 (Example 2) Synthesis of Form I crystals of N¹-(5-chloropyridin-2-yl)-N²((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)ethanediamide p-toluenesulfonate monohydrate (compound I) aqueous ethanol at 60°C. The compound was dissolved by the addition of 7.42 mL of a 1 mol/L solution of p-toluenesulfonic acid in ethanol and then an additional 40 mL of 15% aqueous ethanol. Then, the solution was cooled to room temperature and stirred for 1 day. Deposited crystals were collected by filtration, washed with ethanol, and then dried under reduced pressure at room temperature for 2 hours to obtain 4.7 g of the title crystals (86%). Melting point (decomp.): 246 to 250°C.

Reference： [1]Current Patent Assignee: DAIICHI SANKYO COMPANY, LIMITED - EP2548879, 2013, A1 Location in patent: Paragraph 0047-0048

8
[ 480452-36-6 ]
[ 720720-96-7 ]
[ 480449-70-5 ]

Yield	Reaction Conditions	Operation in experiment
103.2 g	Stage #1: carbamic acid, N-[(1R,2S,5S)-2-[[2-[(5-chloro-2-pyridinyl)amino]-2-oxoacetyl]amino]-5-[(dimethylamino)carbonyl]cyclohexyl]-1,1-dimethylethyl ester With methanesulfonic acid In acetonitrile at 20℃; for 2h; Stage #2: 5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxylic acid hydrochloride With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In acetonitrile at 20℃; for 16h; Cooling with ice;	7 N1-(5-chloropyridin-2-yl)-N2-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)ethanediamide (E) Reference Example 7 N1-(5-chloropyridin-2-yl)-N2-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)ethanediamide (E) Methanesulfonic acid (66 ml) was added to a suspension of tert-butyl [(1R,2S,5S)-2-([(5-chloropyridin-2-yl)amino](oxo)acetyl}amino)-5-(dimethylaminocarbonyl)cyclohexyl]carbamate (17) (95.1 g) in acetonitrile (1900 ml) at room temperature, and the mixture was stirred at this temperature for 2 hours. To the reaction solution, triethylamine (155 ml), 5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxylic acid hydrochloride (13a) (52.5 g), 1-hydroxybenzotriazole (33.0 g), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (46.8 g) were added under ice cooling, and the mixture was stirred at room temperature for 16 hours. Triethylamine and water were added thereto, and the mixture was stirred for 1 hour under ice cooling. Then, the crystals were collected by filtration to obtain the title compound (E) (103.2 g). 1H-NMR (CDCl3) δ: 1.60-1.98 (3H, m), 2.00-2.16 (3H, m), 2.52 (3 H, s), 2.78-2.90 (3H, m), 2.92-2.98 (2H, m), 2.95 (3H, s), 3.06 (3H, s), 3.69 (1H, d, J=15.4 Hz), 3.75 (1H, d, J=15.4 Hz), 4.07-4.15 (1H, m), 4.66-4.72 (1H, m), 7.40 (1H, dd, J=8.8, 0.6 Hz), 7.68 (1H, dd, J=8.8, 2.4 Hz), 8.03 (1H, d, J=7.8 Hz), 8.16 (1H, dd, J=8.8, 0.6 Hz), 8.30 (1H, dd, J=2.4, 0.6 Hz), 9.72 (1 H, s). MS (ESI) m/z: 548 (M+H)+.

Reference： [1]Current Patent Assignee: DAIICHI SANKYO COMPANY, LIMITED - US2013/144061, 2013, A1 Location in patent: Paragraph 0260; 0261; 0262; 0263

9
[ 720720-96-7 ]
edoxaban [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With methanesulfonic acid; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In water; acetonitrile	R.10 N1-(5-Chloropyridin-2-yl)-N2-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)ethanediamide (X) (the production method described in the pamphlet of International Publication No. WO 2007/032498) Reference Example 10 N1-(5-Chloropyridin-2-yl)-N2-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)ethanediamide (X) (the production method described in the pamphlet of International Publication No. WO 2007/032498) Methanesulfonic acid (66 ml) was added to a suspension of tert-butyl[(1R,2S,5S)-2-([(5-chloropyridin-2-yl)amino](oxo)acetyl}amino)-5-(dimethylaminocarbonyl)cyclohexyl]carbamate (A-9) (95.1 g) in acetonitrile (1900 ml) at room temperature, and the mixture was stirred at this temperature for 2 hours. To the reaction solution, triethylamine (155 ml), 5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxylic acid hydrochloride (52.5 g), 1-hydroxybenzotriazole (33.0 g), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (46.8 g) were added under ice cooling, and the mixture was stirred at room temperature for 16 hours. Triethylamine and water were added thereto, and the mixture was stirred for 1 hour under ice cooling. Then, crystals were collected by filtration to obtain the title compound (X) (103.2 g).
	Multi-step reaction with 2 steps 1.1: triethylamine / dichloromethane / 0.17 h / 25 °C 1.2: 7 h / 25 °C 2.1: triethylamine / 24 h / 25 °C
	Multi-step reaction with 2 steps 1.1: triethylamine; pyridine / dichloromethane / 3 h / -15 - -10 °C / Inert atmosphere 2.1: dichloromethane / 0.5 h 2.2: 2 h / -15 - -10 °C

	Multi-step reaction with 2 steps 1.1: picoline; triethylamine / dichloromethane; N,N-dimethyl acetamide / 2 h / -40 - -35 °C / Inert atmosphere 2.1: triethylamine / dichloromethane / 0.5 h / -40 - -35 °C 2.2: 1 h / -40 - -35 °C
	Multi-step reaction with 2 steps 1: triethylamine; triphenylphosphine / dichloromethane / 5 h / 0 - 10 °C / Inert atmosphere 2: triethylamine / dichloromethane; isopropyl alcohol; water / 2 h / 0 - 10 °C

Reference： [1]Current Patent Assignee: DAIICHI SANKYO COMPANY, LIMITED - US2016/16974, 2016, A1
[2]Current Patent Assignee: JILIN YATAI (GROUP) CO., LTD. - CN107641131, 2018, A
[3]Current Patent Assignee: ZHUHAI HAIRUIDE NEW MATERIAL TECH; ZHUHAI HAIRUIDE NEW MATERIALS TECH - CN111763222, 2020, A
[4]Current Patent Assignee: ZHUHAI HAIRUIDE NEW MATERIAL TECH; ZHUHAI HAIRUIDE NEW MATERIALS TECH - CN111763222, 2020, A
[5]Current Patent Assignee: ZHUHAI HAIRUIDE NEW MATERIAL TECH - CN111848647, 2020, A

10
[ 2770688-74-7 ]
[ CAS Unavailable ]
[ 480449-70-5 ]

Yield	Reaction Conditions	Operation in experiment
83.9%	With potassium phosphate In N,N-dimethyl-formamide at 20℃; for 72h;	10 N1-(5-Chloropyridin-2-yl)-N2-[(1S,2R,4S)-4-(dimethylcarbamoyl)-2-[(5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl]ethanediamide (X) [production method via compound (1-p1)] Example 10 N1-(5-Chloropyridin-2-yl)-N2-[(1S,2R,4S)-4-(dimethylcarbamoyl)-2-[(5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl]ethanediamide (X) [production method via compound (1-p1)] To a 50 mL flask, compound (5-ms) (compound of Reference Example 8) (1.0 g, 2.16 mmol), compound (1-p1) (1.18 g, 4.31 mmol), K3PO4 (1.83 g, 8.64 mmol), and DMF (10 mL) were added, and the mixture was stirred at room temperature for 3 days. To the reaction solution, H2O (20 mL) was added, and the slurry obtained was stirred at room temperature for 1 hour, then cooled to 0 to 5° C., and further stirred for 1 hour, followed by the filtration of the solid. The solid obtained was washed with H2O (10 mL) and dried under reduced pressure to obtain the title compound (0.99 g, 83.9%) as a white solid.

Reference： [1]Current Patent Assignee: DAIICHI SANKYO COMPANY, LIMITED - US2017/50983, 2017, A1 Location in patent: Paragraph 0203

11
[ 2770688-74-7 ]
[ 1807316-00-2 ]
[ 480449-70-5 ]

Yield	Reaction Conditions	Operation in experiment
92.9%	With potassium phosphate In N,N-dimethyl-formamide at 20℃; for 3h;	11 Example 11 N1-(5-Chloropyridin-2-yl)-N2-[(1S,2R,4S)-4-(dimethylcarbamoyl)-2-[(5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl]ethanediamide (X) [production method via compound (1-p2)] N1-(5-Chloropyridin-2-yl)-N2-[(1S,2R,4S)-4-(dimethylcarbamoyl)-2-[(5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl]ethanediamide (X) [production method via compound (1-p2)] To a 10 mL test tube, compound (5-ms) (compound of Reference Example 8) (100 mg, 0.216 mmol), compound (1-p2) (81.4 mg, 0.216 mmol), K3PO4 (91.7 mg, 0.432 mmol), and DMF (1 mL) were added, and the mixture was stirred under a condition of room temperature for 3 hours. To the reaction solution, H2O (2 mL) was added, and the slurry obtained was stirred overnight at room temperature, followed by the filtration of the solid. The solid obtained was washed with H2O (1 mL) and dried under reduced pressure to obtain the title compound (110.0 mg, 92.9%) as a solid. 1H-NMR (500 Hz, CDCl3) δ: 9.72 (s, 1H), 8.30 (dd, 1H, J=2.5, 0.5 Hz), 8.17 (dd, 1H, J=9.0, 0.5 Hz), 8.03 (d, 1H, J=8.5 Hz), 7.68 (dd, 1H, J=9.0, 2.5 Hz), 7.39 (d, 1H, J=8.5 Hz), 4.70-4.67 (m, 1H), 4.13-4.09 (m, 1H), 3.73 (d, 1H, J=16.0 Hz), 3.70 (d, 1H, J=16.0 Hz), 3.06 (s, 3H), 2.96-2.93 (m, 2H), 2.95 (s, 3H), 2.89-2.79 (m, 3H), 2.52 (s, 3H), 2.14-2.06 (m, 3H), 1.96-1.90 (m, 1H), 1.84-1.78 (m, 1H), 1.69-1.62 (m, 1H).

Reference： [1]Current Patent Assignee: DAIICHI SANKYO COMPANY, LIMITED - US2017/50983, 2017, A1 Location in patent: Paragraph 0204

12
[ 852291-42-0 ]
[ CAS Unavailable ]
[ 2770688-74-7 ]
[ 480449-70-5 ]

Yield	Reaction Conditions	Operation in experiment
50.7%	With palladium diacetate; triethylamine; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In N,N-dimethyl-formamide at 60℃; for 17h; Inert atmosphere;	9 Example 9 N1-(5-Chloropyridin-2-yl)-N2-[(1S,2R,4S)-4-(dimethylcarbamoyl)-2-[(5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl]ethanediamide (X) N1-(5-Chloropyridin-2-yl)-N2-[(1S,2R,4S)-4-(dimethylcarbamoyl)-2-[(5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl]ethanediamide (X) To a 50 mL flask, compound (1-br-ts) (2.0 g, 4.93 mmol), compound (5-ms) (compound of Reference Example 8) (2.52 g, 5.43 mmol), Pd(OAc)2 (33 mg, 0.148 mmol), and xantphos (171 mg, 0.296 mmol) were added. In a glove box under a current of nitrogen, a solution containing Et3N (2.4 mL, 17.26 mmol) in degassed DMF (20 mL: the degassing was carried out by repeated reduction in pressure and purging with nitrogen three times) was added to the reaction mixture, and reduction in pressure and purging with carbon monoxide were repeated three times for the reaction system. After creation of a carbon monoxide atmosphere, the mixture was stirred at 60° C. for 17 hours. The title compound produced in the reaction solution obtained was quantified (1.37 g, 50.7%) under HPLC conditions [3].

Reference： [1]Current Patent Assignee: DAIICHI SANKYO COMPANY, LIMITED - US2017/50983, 2017, A1 Location in patent: Paragraph 0201; 0202

13
[ 1243308-37-3 ]
[ 2230882-30-9 ]
[ 480449-70-5 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 2-methylhexan-2-yl {(1S,2R,4S)-4-(dimethylcarbamoyl)-2-[(5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carbonyl)amino]cyclohexyl}carbamate With methanesulfonic acid In acetonitrile at 20℃; for 10h; Stage #2: [(5-chloropyridin-2-yl)amino]-2-glyoxylic acid ethyl ester monohydrochloride With triethylamine for 20h; Reflux;	26 Example 26 Preparation of N1-(5-chloropyridin-2-yl)-N2-{(1S,2R,4S)-4-(dimethylcarbamoyl)-2-[(5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carbonyl)amino]cyclohexyl}ethanediamide (Formula (1), Edoxaban) Example 26 Preparation of N1-(5-chloropyridin-2-yl)-N2-{(1S,2R,4S)-4-(dimethylcarbamoyl)-2-[(5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carbonyl)amino]cyclohexyl}ethanediamide (Formula (1), Edoxaban) To a solution of 2-methylhexan-2-yl {(1S,2R,4S)-4-(dimethylcarbamoyl)-2-[(5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carbonyl)amino]cyclohexyl}carbamate (520 mg, 1.02 mmol) in acetonitrile (5 mL) was added methanesulfonic acid (0.4 mL, 5.1 mmol) at room temperature. The reaction mixture was stirred at room temperature for 10 hours and following the completion of the deprotection reaction (TLC), triethylamine (2.2 mL, 15.3 mmol) and 2-[(5-chloropyridin-2-yl)amino]-2-oxoacetate ethyl ester monohydrochloride (300 mg, 1.123 mmol) were added. The reaction mixture was heated to reflux for 20 hours. Water (0.5 mL) was added and the reaction mixture was cooled to room temperature. The resulting suspension was treated with a mixture of acetonitrile (4 mL) and water (1 mL). Most of the solids dissolved. The solvents were then evaporated to dryness and the residue was triturated with small quantities of ethyl acetate and water. The solid was collected by filtration, washed with water and then ethyl acetate to yield a sticky solid. 1HNMR (CDCl3) corresponded with the mesylate salt of the compound of Formula (1). A small sample was free-based with aqueous sodium bicarbonate to afford N1-(5-chloropyridin-2-yl)-N2-{(1S,2R,4S)-4-(dimethylcarbamoyl)-2-[(5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carbonyl)amino]cyclohexyl}ethane diamide. 1H-NMR (CDCl3, 300 MHz) δ: 1.62-2.14 (6H, m), 2.52 (3H, s), 2.78-2.89 (3H, m), 2.89-2.95 (2H, m), 2.95 (3H, s), 3.06 (3H, s), 3.67 (1H, B of AB quartet, J=15.45 Hz), 3.75 (1H, A of AB quartet, J=15.45 Hz), 4.08-4.14 (1H, m), 4.67-4.71 (1H, m), 7.39 (1H, d, J=8.5 Hz), 7.69 (1H, dd, J=8.8, 2.4 Hz), 8.02 (1H, d, J=7.7 Hz), 8.17 (1H, d, J=8.8 Hz), 8.30 (1H, d, J=2.3 Hz), 9.72 (1H, broad s).

Reference： [1]Current Patent Assignee: APOTEX INC - US2018/179226, 2018, A1 Location in patent: Paragraph 0327; 0328; 0329

14
[ 1243308-37-3 ]
[ 2230882-38-7 ]
[ 480449-70-5 ]

Yield	Reaction Conditions	Operation in experiment
83%	Stage #1: 1-methylcyclohexyl {(1S,2R,4S)-4-(dimethylcarbamoyl)-2-[(5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carbonyl)amino]cyclohexyl}carbamate With methanesulfonic acid In acetonitrile at 20℃; for 4h; Stage #2: [(5-chloropyridin-2-yl)amino]-2-glyoxylic acid ethyl ester monohydrochloride With triethylamine In acetonitrile at 70℃; for 2h;	38 Example 38 Preparation of N1-(5-chloropyridin-2-yl)-N2-{(1S,2R,4S)-4-(dimethylcarbamoyl)-2-[(5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carbonyl)amino]cyclohexyl}ethanediamide (Edoxaban(1)) Example 38 Preparation of N1-(5-chloropyridin-2-yl)-N2-{(1S,2R,4S)-4-(dimethylcarbamoyl)-2-[(5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carbonyl)amino]cyclohexyl}ethanediamide (Edoxaban(1)) To a solution of 1-methylcyclohexyl {(1S,2R,4S)-4-(dimethylcarbamoyl)-2-[(5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carbonyl)amino]cyclohexyl}carbamate (2.22 g, 4.39 mmol) in acetonitrile (3 mL) was added methanesulfonic acid (1.2 mL, 17.6 mmol). The reaction mixture was exothermic with gas evolution. The reaction was stirred at room temperature for 4 hours and 1H NMR analysis of an aliquot indicated the completion of the deprotection reaction. 2-[(5-Chloropyridin-2-yl)amino]-2-oxoacetate ethyl ester monohydrochloride (1.4 g, 5.27 mmol), and triethylamine (4.9 mL, 35.12 mmol) were carefully added as fumes were formed. The reaction mixture was heated in an oil bath at 70° C. for 20 hours and cooled to room temperature. Water (6 mL) was added and the mixture cooled in an ice bath. The solids were filtered, washed with acetonitrile-water (1:5, 10 mL) and dried in vacuo at 50° C. for 18 hours to afford N1-(5-chloropyridin-2-yl)-N2-{(1S,2R,4S)-4-(dimethylcarbamoyl)-2-[(5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carbonyl)amino]cyclohexyl}ethanediamide (2.0 g, 83% yield).

Reference： [1]Current Patent Assignee: APOTEX INC - US2018/179226, 2018, A1 Location in patent: Paragraph 0365; 0366; 0367

15
[ 480449-70-5 ]
[ 6192-52-5 ]
[ 1229194-11-9 ]

Yield	Reaction Conditions	Operation in experiment
97.2%	In ethanol; lithium hydroxide monohydrate at 70℃; for 2h;	4 <Example 4> Preparation of N1-(5-chloropyridin-2-yl)-N2-((1S,2R,4S)-4-(dimethylcarbamoyl)-2-(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamido)cyclohexyl)oxalamide tosylate monohydrate 12 g (0.022 mol) of the compound of Example 3 was put into the reactor, 72 mL of ethyl alcohol and 24 mL of purified water were put into the reactor, 4.4 g (0.023 mol) of p-toluenesulfonic acid monohydrate was added, and the reaction solution was heated to 70° C. It heated up and stirred for 2 hours.The reaction solution was cooled to 20 °C, stirred for 1 hour, filtered, and dried under reduced pressure to obtain 15.5 g (0.021 mol, yield 97.2%) of the title compound.

Reference： [1]Current Patent Assignee: MIRAE FINE CHEMICAL CO LTD - KR2022/87933, 2022, A Location in patent: Paragraph 0123-0126

16
[ 480450-71-3 ]
[ 1243308-37-3 ]
[ 480449-70-5 ]

Yield	Reaction Conditions	Operation in experiment
58%	With triethylamine In acetonitrile at 60℃; for 0.18h;	20 Example 20 Preparation of N-1-(5-chloropyridin-2-yl)-N2-{(1S,2R,4S)-4-(dimethylcarbamoyl)-2-[(5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carbonyl)amino]cyclohexyl}ethanediamide (Edoxaban (1)) Example 20 Preparation of N-1-(5-chloropyridin-2-yl)-N2-{(1S,2R,4S)-4-(dimethylcarbamoyl)-2-[(5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carbonyl)amino]cyclohexyl}ethanediamide (Edoxaban (1)) To a suspension of N-[(1R,2S,5S)-2-amino-5-(dimethylcarbamoyl)cyclohexyl]-5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxamide (440 mg, 1.203 mmol), 2-[(5-chloropyridin-2-yl)amino]-2-oxoacetate ethyl ester monohydrochloride (390 mg, 1.45 mmol) in acetonitrile (3 mL) was added triethylamine (0.9 mL, 6.1 mmol). The mixture was heated in an oil bath at 60° C. for about 18 hours. Water (0.6 mL) was added and the solids were filtered, washed with water (2*3 mL) and dried in vacuo at 60° C. for 12 hours to afford N-1-(5-chloropyridin-2-yl)-N2-{(1S,2R,4S)-4-(dimethylcarbamoyl)-2-[(5-methyl-4,5,6,7-tetrahydro [1,3]thiazolo[5,4-c]pyridine-2-carbonyl)amino]cyclohexyl}ethanediamide (380 mg, 58% yield). 1H-NMR (CDCl3, 300 MHz) δ: 1.62-2.14 (6H, m), 2.52 (3H, s), 2.78-2.89 (3H, m), 2.89-2.95 (2H, m), 2.95 (3H, s), 3.06 (3H, s), 3.67 (1H, B of AB quartet, J=15.45 Hz), 3.75 (1H, A of AB quartet, J=15.45 Hz), 4.08-4.14 (1H, m), 4.67-4.71 (1H, m), 7.39 (1H, d, J=8.5 Hz), 7.69 (1H, dd, J=8.8, 2.4 Hz), 8.02 (1H, d, J=7.7 Hz), 8.17 (1H, d, J=8.8 Hz), 8.30 (1H, d, J=2.3 Hz), 9.72 (1H, broad s).

Reference： [1]Current Patent Assignee: APOTEX INC - US2018/179226, 2018, A1 Location in patent: Paragraph 0308; 0309; 0310

17
[ 1243308-37-3 ]
[ 720720-52-5 ]
[ 480449-70-5 ]

Yield	Reaction Conditions	Operation in experiment
40 mg	Stage #1: tert-butyl {(1S,2R,4S)-4-(dimethylcarbamoyl)-2-[(5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carbonyl)amino]cyclohexyl}carbamate With methanesulfonic acid In acetonitrile at 20 - 25℃; for 6h; Stage #2: [(5-chloropyridin-2-yl)amino]-2-glyoxylic acid ethyl ester monohydrochloride With triethylamine In acetonitrile at 70℃; for 11h;	23 Example 23 Preparation of N1-(5-chloropyridin-2-yl)-N2-{(1 SR,2RS,4SR)-4-(dimethylcarbamoyl)-2-[(5-methyl-4,5,6,7-tetrahydro [1,3]thiazolo[5,4-c]pyridine-2-carbonyl)amino]cyclohexyl}ethanediamide (racemic Edoxaban (1)) Example 23 Preparation of N1-(5-chloropyridin-2-yl)-N2-{(1 SR,2RS,4SR)-4-(dimethylcarbamoyl)-2-[(5-methyl-4,5,6,7-tetrahydro [1,3]thiazolo[5,4-c]pyridine-2-carbonyl)amino]cyclohexyl}ethanediamide (racemic Edoxaban (1)) To a solution of racemic tert-butyl {(1 SR,2RS,4SR)-4-(dimethylcarbamoyl)-2-[(5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carbonyl)amino]cyclohexyl}carbamate (160 mg, 0.343 mmol) in acetonitrile (2 mL) was added methanesulfonic acid (0.11 mL, 1.715 mmol) at room temperature. The reaction mixture was stirred at room temperature for 6 hours and following the completion of the deprotection (TLC), the reaction mixture was heated to 70° C. Triethylamine (1 mL, 6.86 mmol) and 2-[(5-chloropyridin-2-yl)amino]-2-oxoacetate ethyl ester monohydrochloride (95 mg, 0.343 mmol) were added and heating at 70° C. was continued for 11 hours. Water (5 drops) was added and the reaction mixture was cooled to room temperature. The resulting suspension was filtered and washed with a mixture of acetonitrile-water (1:1) (5 mL). The damp solids were dried in vacuo at about 55° C. (5 hours) to afford racemic N1-(5-chloropyridin-2-yl)-N2-{(1 SR,2RS,4SR)-4-(dimethylcarbamoyl)-2-[(5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carbonyl)amino]cyclohexyl}ethanediamide at crystalline solid (40 mg). 1H-NMR (CDCl3, 300 MHz) δ: 1.62-2.14 (6H, m), 2.52 (3H, s), 2.78-2.89 (3H, m), 2.89-2.95 (2H, m), 2.95 (3H, s), 3.06 (3H, s), 3.67 (1H, B of AB quartet, J=15.45 Hz), 3.75 (1H, A of AB quartet, J=15.45 Hz), 4.08-4.14 (1H, m), 4.67-4.71 (1H, m), 7.39 (1H, d, J=8.5 Hz), 7.69 (1H, dd, J=8.8, 2.4 Hz), 8.02 (1H, d, J=7.7 Hz), 8.17 (1H, d, J=8.8 Hz), 8.30 (1H, d, J=2.3 Hz), 9.72 (1H, broad s).

Reference： [1]Current Patent Assignee: APOTEX INC - US2018/179226, 2018, A1 Location in patent: Paragraph 0318; 0319; 0320

18
[ 480449-70-5 ]
[ 2244103-96-4 ]

Yield	Reaction Conditions	Operation in experiment
91.9%	With dihydrogen peroxide In ethanol; dichloromethane for 40h; Reflux;	4 Example 5 Synthesis of a large amount of impurities (I) by oxidative degradation of edoxaban 20.00 g of compound (II) (36.5 mmol), ethanol (20 mL), DCM (400 mL) were added to the reaction flask at room temperature.Stirring and stirring, adding 15 equivalents of 30% hydrogen peroxide, heating and refluxing, stirring for 40 h, stirring and cooling to room temperature, suction filtration,The filter cake was dried under reduced pressure at 50 ° C for 6 h to give a white solid, 18.92 g, yield 91.9%. Samples were sent for HPLC (see Figure 2.9).As can be seen from Figure 2.9, the normalized purity of the oxidative degradation impurities was 97.40%.The structure identification data is identical to that of the third embodiment.

Reference： [1]Current Patent Assignee: CHONGQING ZHIEN PHARMACEUTICAL - CN108409754, 2018, A Location in patent: Paragraph 0036-0040; 0045; 0046; 0047; 0048

19
[ 480452-37-7 ]
[ 758685-72-2 ]
[ 480449-70-5 ]

Yield	Reaction Conditions	Operation in experiment
95%	Stage #1: 5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxylic acid With pyridine; 1,1'-carbonyldiimidazole In dichloromethane at 20 - 25℃; for 1h; Stage #2: N¹-[(1S,2R,4S)-2-amino-4-[(dimethylamino)carbonyl]cyclohexyl]-N²-(5-chloro-2-pyridyl)ethanediamide With pyridine In dichloromethane at 20℃; for 2h;	4 Example 4: Production of edoxaban 1 In a flask, 5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxylic acid 2 (4.0 g, 17.04 mmol) was added to dichloromethane (40 ml). . Next, CDI9 (2.76 g, 17.04 mmol) was added to the flask.Was added at room temperature. To this was added pyridine (1.37 ml, 17.04 mmol) at 20-25 ° C. The reaction mixture was then stirred at room temperature for 1 hour. Thereafter, amine 3 (6.26 g, 17.04 mmol) was added at room temperature followed by pyridine (2.75 ml, 34.0).8 mmol) was added. The reaction mixture was then stirred at room temperature for 2 hours. After confirming the completion of the reaction by TLC, purified water (40 mL) was added. The organic phase was then separated with dichloromethane (2 × 20 ml) and the aqueous phase was extracted. The combined organic phases were dried over MgSO4 and concentrated under vacuum to give a white solid. The title compound obtained was dried in an oven at 40 ° C. for 15 hours (8.85 g, 95%).

Reference： [1]Current Patent Assignee: GAPI BIO; DONGBANG FTL; GABI BIO - JP2019/210273, 2019, A Location in patent: Paragraph 0036; 0037; 0048

20
[ 480452-37-7 ]
[ 1057650-82-4 ]
[ 480449-70-5 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine In dichloromethane at 0 - 20℃; for 3h; Reflux;	5 Example 5: Production of edoxaban 1 In a flask, 5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxylic acid 2 (5.0 g, 21.3 mmol) was added to dichloromethane (25 ml). . To this was added a catalytic amount of N, N-dimethylformamide. ThenThionyl chloride (5.07 g, 42.6 mmol) was slowly added to the flask at room temperature. The reaction mixture was then heated to reflux for 1 hour and the solvent was distilled off under rotary vacuum. The obtained solid, 5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carbonyl chloride 11, was added to 25 ml of dichloromethane. Then cooled to 0-5 ° C. To this was added amine 3 (7.83 g, 21.3 mmol), followed by Et3N (8.6 g, 85.21 mmol) at the same temperature. After stirring for 1 hour, the cooling bath was removed and the mixture was stirred at room temperature for 2 hours. After confirming the completion of the reaction by TLC,Dichloromethane (15 mL) and purified water (50 mL) were added.After stirring at room temperature for 30 minutes, the organic phase was separated. The organic phase was dried over anhydrous sodium sulfate (1 g) and concentrated under reduced pressure.Crystallize from isopropyl alcohol (25 mL) to give the title compound 1.

Reference： [1]Current Patent Assignee: GAPI BIO; DONGBANG FTL; GABI BIO - JP2019/210273, 2019, A Location in patent: Paragraph 0038; 0039; 0048

21
[ 480449-70-5 ]
[ 65-86-1 ]
[ 2421154-34-7 ]

Yield	Reaction Conditions	Operation in experiment
96%	In acetonitrile at 60℃; for 5h;	4 <Example 4> Preparation of edoxaban orotate salt of the present invention Edoxaban free base (1.0 g) was suspended by adding acetonitrile (30 mL). After orotic acid (0.33 g) was added, the temperature was raised to 60° C. and stirred for 2 hours. It was cooled to room temperature and stirred for 3 hours. The resulting solid was filtered and dried under vacuum at an internal temperature of 50° C. overnight to obtain 1.27 g (96%) of the title compound.
5.5 g	In ethanol at 65℃;	Preparation of N1-(5-chloropyridin-2-yl)-N2-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)ethanediamide orotinate N1- (5-chloropyridin-2-yl) -N2-((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2-[(5-methyl-4,5,6, 7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino} cyclohexyl) ethanadiamide (5.0 g),A mixture of 85% ethanol (40ml) was heated to 65 ± 5 ° C.Orotic acid monohydrate (1.9 g) was added to the mixture and dissolved by stirring at 65 ± 5 ° C.The dissolved solution was filtered, cooled to room temperature, and stirred for 1 day.The precipitated crystals were collected by filtration, washed with ethanol, and dried under reduced pressure at room temperature for 4 hours to obtain the title compound (5.5 g).

Reference： [1]Current Patent Assignee: DONG-A ST CO., LTD. - KR2020/53270, 2020, A Location in patent: Paragraph 0125-0126
[2]Current Patent Assignee: JW PHARMACEUTICAL CO LTD - KR2020/14553, 2020, A Location in patent: Paragraph 0049; 0050

22
[ 480449-70-5 ]
[ 77-92-9 ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
74%	In ethanol; water at 20℃; for 2h;	5 Example 5- Synthesis of Edoxaban Citrate Add 60 ml of EtOH and 24 ml of H2O to 3 g of Edoxaban free base, heat up to 60 °C to 70 °C to dissolve completely. After adding citric acid 1.05 g, it is gradually cooled to room temperature, stirred for 2 hours, and dehydrated. Wash with 15 ml EtOH. After washing and drying with nitrogen, 3.5 g of Edoxaban Citrate was obtained. (Yield 74%, purity 99.83%)
68%	In ethanol at 80℃; for 2h;	15 <Example 15> Preparation of edoxaban citrate of the present invention 0.5 g of edoxaban free base was added to the reaction unit, and then 14 mL of ethanol and 6 mL of distilled water were added to dissolve it. After adding 0.18 g of citric acid, the mixture was heated to 80° C. and stirred for 2 hours. After cooling to room temperature and stirring overnight, the resulting solid was filtered. Vacuum-dried overnight at room temperature to obtain 0.31g (68%) of the title compound.
60%	In ethanol; dichloromethane; water at 20℃; for 2h;	2 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)ethanadiamide citrate monohydrate crystalline form 3.0 g of edoxaban free base was added to 25.5 ml of ethanol, 4.5 ml of water, and 12 ml of dichloromethane to dissolve. 0.83 g (1.1 eq) of citric acid was dissolved in 4.5 ml of ethanol and added to the edoxaban free base solution. After that, it is stirred at room temperature for 2 hours, cooled, and stirred for 2 hours. Filtered and dried under vacuum at 50° C. for 12 hours to obtain the title crystal (yield: 60%, purity: 99.931%).

Reference： [1]Current Patent Assignee: KYONGBO PHARM - KR2020/33698, 2020, A Location in patent: Paragraph 0099-0103
[2]Current Patent Assignee: DONG-A ST CO., LTD. - KR2020/53270, 2020, A Location in patent: Paragraph 0213-0214
[3]Current Patent Assignee: PHARMACOSTECH CO LTD - KR2020/106737, 2020, A Location in patent: Paragraph 0047-0049

23
[ 480449-70-5 ]
[ 81-07-2 ]
[ 2414668-56-5 ]

Yield	Reaction Conditions	Operation in experiment
87.45%	In ethanol; dichloromethane at 20℃; for 2h;	6 Example 6- Synthesis of Edoxaban Saccharin Add 3.0 g of Edoxaban free base and 45 ml of MC and dissolve completely. Add 1.0 g of Saccharin and 6 ml of EtOH, dissolve and inject. After stirring at room temperature for 2 hours, it is concentrated under reduced pressure. 45 ml of 15% hydrous ethanol is added to the concentrated residue, and the mixture is heated to 60°C to 70°C to dissolve completely. Slowly cooled to room temperature, stirred for 2 hours, and dehydrated. Wash with 15 ml EtOH. After washing and drying with nitrogen, 3.1 g of Edoxaban Saccharin was obtained. (Yield 87.45%, purity 99.96%)

Reference： [1]Current Patent Assignee: KYONGBO PHARM - KR2020/33698, 2020, A Location in patent: Paragraph 0106-0109

24
[ 59-67-6 ]
[ 480449-70-5 ]
[ 2414668-58-7 ]

Yield	Reaction Conditions	Operation in experiment
86.38%	In tetrahydrofuran; dichloromethane at 20℃; for 15h;	7 Example 7- Synthesis of Edoxaban Nicotinate Add 60 ml of MC to 4.0 g of Edoxaban free base and dissolve completely. 1.12 g of Nicotinic acid is dissolved in 60 ml of THF and injected. After stirring at room temperature for 15 hours, it is dehydrated. Wash with 10 ml of MC. After washing and drying with nitrogen, 1.7 g of Edoxaban Nicotinate was obtained. (Yield 86.38%, purity 99.93%)

Reference： [1]Current Patent Assignee: KYONGBO PHARM - KR2020/33698, 2020, A Location in patent: Paragraph 0111-0114

25
edoxaban [ No CAS ]
[ 81-04-9 ]
edoxaban napadisilate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%	In ethanol; water at 20℃; for 3h;	8 Example 8- Synthesis of Edoxaban Napadisilate Add 4.0 ml of EtOH and 56 ml of H2O to 4.0 g of Edoxaban free base and heat up to 60 °C to 70 °C to dissolve completely. After adding 1.90 g of 1.5-Naphthalenedisulfonic acid, it is stirred for 3 hours at room temperature and dehydrated. Wash with 28 ml EtOH. After washing and drying with nitrogen, 8.1 g of Edoxaban Napadisilate was obtained. (Yield 85%, purity 99.92%)

Reference： [1]Current Patent Assignee: KYONGBO PHARM - KR2020/33698, 2020, A Location in patent: Paragraph 0116-0119

26
[ 480449-70-5 ]
[ 120-18-3 ]
[ 2414668-61-2 ]

Yield	Reaction Conditions	Operation in experiment
82%	In ethanol; water at 0 - 20℃; for 5h;	9 Example 9-Synthesis of Edoxaban Napsylate Add 100 ml of EtOH and 40 ml of H2O to 5.0 g of Edoxaban free base and heat up to 60 to 70 °C to dissolve completely. After adding 1.90 g of Naphthalene-2-sulfonic acid, the mixture is stirred for 2 hours at room temperature, cooled to 0° C., stirred for 3 hours, and dehydrated. Wash with 20 ml EtOH. After washing and drying with nitrogen, 3.5 g of Edoxaban Napsylate was obtained. (Yield 82%, purity 99.89%)
81%	In ethanol; water at 70℃; for 5h;	10 <Example 10> Preparation of edoxaban naphthalene-2-sulfonate of the present invention To 1.0 g of edoxaban free base, 40 mL of methylene chloride was added and suspended. Naphthalene-2-sulfonic acid solution (1.82 mL, 1.0M ethanol solution) was added, stirred for 1 hour, and then concentrated. After adding 20 mL of 85% ethanol to the concentrate, the concentrated residue was released, the temperature was raised to 70°C, and the mixture was stirred for 1 hour. It was cooled to room temperature and stirred for 3 hours. The resulting solid was filtered and dried under vacuum at an internal temperature of 50° C. overnight to obtain 1.12 g (81%) of the title compound.

Reference： [1]Current Patent Assignee: KYONGBO PHARM - KR2020/33698, 2020, A Location in patent: Paragraph 0121-0124
[2]Current Patent Assignee: DONG-A ST CO., LTD. - KR2020/53270, 2020, A Location in patent: Paragraph 0173-0174

27
[ 480449-70-5 ]
[ 96-82-2 ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
86.65%	In ethanol; dichloromethane; water at 20℃; for 2h;	10 Example 10-Synthesis of Edoxaban Lactobionate In reactor 1, 4.0 g of Edoxaban free base and 60 ml of MC are added and completely dissolved. In reactor 2, 2.62 g of Lactobionic acid was added to 40 ml of EtOH and 10 ml of H2O, heated to 60°C to 70°C to dissolve, and then injected into reactor 1.After stirring at room temperature for 2 hours, it is concentrated under reduced pressure. 60 ml of 15% hydrous ethanol is added to the concentrated residue, and the mixture is heated to 60°C to 70°C to dissolve completely. Slowly cooled to room temperature, stirred for 3 hours, and dehydrated. Wash with 15 ml EtOH. After washing and drying with nitrogen, 4.89 g of Edoxaban Lactobionate was obtained. (Yield 86.65%, purity 99.94%)

Reference： [1]Current Patent Assignee: KYONGBO PHARM - KR2020/33698, 2020, A Location in patent: Paragraph 0126-0129

28
[ 480449-70-5 ]
[ 141-82-2 ]
[ 2409819-64-1 ]

Yield	Reaction Conditions	Operation in experiment
75.64%	In tetrahydrofuran; dichloromethane at 20℃; for 2h;	1 Example 1-Synthesis of Edoxaban Malonate In reactor 1, add 2.0 g of Edoxaban free base and 30 ml of methylene chloride (MC), and completely dissolve. In reactor 2, 380 mg of malonic acid and 3 ml of tetrahydrofuran (THF) were dissolved and injected. After stirring at room temperature for 2 hours, it is dehydrated.Wash with 10 ml of MC. After washing and drying with nitrogen, 1.8 g of Edoxaban Malonate was obtained. (Yield 75.64%, purity 99.73%)

Reference： [1]Current Patent Assignee: KYONGBO PHARM - KR2020/33698, 2020, A Location in patent: Paragraph 0079-0082

29
[ 480449-70-5 ]
[ 110-16-7 ]
[ 2409819-58-3 ]

Yield	Reaction Conditions	Operation in experiment
73.92%	In tetrahydrofuran; dichloromethane at 20℃; for 2h;	2 Example 2- Synthesis of Edoxaban Maleate Add 2.0 g of Edoxaban free base and 30 ml of MC and dissolve completely. Maleic acid 424 mg THF 6 ml is dissolved and injected. After stirring at room temperature for 2 hours, 30 ml of EtOH is added, dissolved, and concentrated under reduced pressure. After adding and dissolving 10 ml of EtOH in the concentrated residue, 60 ml of isopropyl ether (IPE) is added. After stirring at room temperature for 2 hours, it is dehydrated. Wash with 20 ml of IPE. After washing and drying with nitrogen, 2.1 g of Edoxaban Maleate was obtained. (Yield 73.92%, purity 99.76%)
48%	In water; acetone at 0 - 60℃; for 4h;	5 <Example 5> Preparation of edoxaban maleate of the present invention To 1.0 g of edoxaban free base, 40 mL of acetone was added and suspended. After the maleic acid solution (1.82 mL, 1.0M aqueous solution) was added, the temperature was raised to 60° C. and stirred for 1 hour. After cooling to room temperature and stirring for 3 hours, it was cooled at 0°C. The resulting solid was filtered and dried under vacuum at an internal temperature of 50° C. overnight to obtain 0.58 g (48%) of the title compound.

Reference： [1]Current Patent Assignee: KYONGBO PHARM - KR2020/33698, 2020, A Location in patent: Paragraph 0084-0087
[2]Current Patent Assignee: DONG-A ST CO., LTD. - KR2020/53270, 2020, A Location in patent: Paragraph 0133-0134

30
[ 480449-70-5 ]
[ 110-17-8 ]
[ 2414668-53-2 ]

Yield	Reaction Conditions	Operation in experiment
70.14%	In tetrahydrofuran; dichloromethane at 20℃; for 4h;	3 Example 3- Synthesis of Edoxaban Fumarate Add 2.0 g of Edoxaban free base and 30 ml of MC and dissolve completely. Fumaric acid 424 mg THF 6 ml is dissolved and injected. After stirring at room temperature for 4 hours, it is dehydrated. Wash with 10 ml of MC. After washing and drying with nitrogen, 1.7 g of Edoxaban Fumarate was obtained. (Yield 70.14%, purity 99.73%)

Reference： [1]Current Patent Assignee: KYONGBO PHARM - KR2020/33698, 2020, A Location in patent: Paragraph 0089-0092

31
[ 480449-70-5 ]
[ 110-15-6 ]
[ 2414668-54-3 ]

Yield	Reaction Conditions	Operation in experiment
52.65%	In ethanol; dichloromethane at 20℃; for 2h;	4 Example 4- Synthesis of Edoxaban Succinate Add 5.0 g of Edoxaban free base and 60 ml of MC and dissolve completely. 1.08 g of Succinic acid is dissolved in 15 ml of EtOH and injected. After stirring at room temperature for 2 hours, it is concentrated under reduced pressure. After 15% of the concentrated residue was added, 60 ml of ethanol was added, heated to 60°C to 70°C, dissolved, stirred for 3 hours at room temperature, and dehydrated. Wash with 15 ml EtOH. After washing and drying with nitrogen, 3.2 g of Edoxaban Succinate was obtained. (Yield 52.65%, purity 99.81%)

Reference： [1]Current Patent Assignee: KYONGBO PHARM - KR2020/33698, 2020, A Location in patent: Paragraph 0094-0097

32
[ 480449-70-5 ]
[ 2409819-62-9 ]

Yield	Reaction Conditions	Operation in experiment
90%	With sulfuric acid In acetonitrile at 80℃; for 1h;	13 <Example 13> Preparation of edoxaban sulfate of the present invention 0.5 g of edoxaban free base was added to the reaction unit, and then 10 mL of acetonitrile was added to dissolve it. After adding 49 μL of sulfuric acid, the temperature was raised to 80° C. and stirred for 1 hour. Cooled to room temperature and stirred overnight. The resulting solid was filtered and dried in vacuo at room temperature overnight to obtain 0.53 g (90%) of the title compound.

Reference： [1]Current Patent Assignee: DONG-A ST CO., LTD. - KR2020/53270, 2020, A Location in patent: Paragraph 0197-0198

33
[ 480449-70-5 ]
[ 2409819-60-7 ]

Yield	Reaction Conditions	Operation in experiment
85%	With phosphoric acid In acetonitrile at 80℃; for 1h;	14 <Example 14> Preparation of edoxaban phosphate of the present invention 0.5 g of edoxaban free base was added to the reaction section, and then 10 mL of acetonitrile was added. After adding 62 μL of 85% phosphoric acid, the temperature was raised to 80° C. and stirred for 1 hour. After cooling to room temperature, the resulting solid was filtered. Vacuum-dried overnight at room temperature to give the title compound 0.50g (85%).

Reference： [1]Current Patent Assignee: DONG-A ST CO., LTD. - KR2020/53270, 2020, A Location in patent: Paragraph 0205-0206

34
[ 480449-70-5 ]
[ 86-48-6 ]
[ 2421154-36-9 ]

Yield	Reaction Conditions	Operation in experiment
69%	In ethanol; water at 70℃; for 4h;	7 <Example 7> Preparation of edoxaban 1-hydroxy-2-naphtho acid salt of the present invention To 1.0 g of edoxaban free base, 40 mL of methylene chloride was added and suspended. After adding 1-hydroxy-2-naphthoic acid solution (3.64 mL, 0.5M ethanol solution), the mixture was stirred for 1 hour and then concentrated. After adding 20 mL of 85% ethanol to the concentrate, the concentrated residue was released, the temperature was raised to 70°C, and the mixture was stirred for 1 hour. It was cooled to room temperature and stirred for 3 hours. The resulting solid was filtered and dried under vacuum at an internal temperature of 50° C. overnight to obtain 0.92 g (69%) of the title compound.

Reference： [1]Current Patent Assignee: DONG-A ST CO., LTD. - KR2020/53270, 2020, A Location in patent: Paragraph 0149-0150

35
[ 480449-70-5 ]
[ 98-11-3 ]
[ 2421154-37-0 ]

Yield	Reaction Conditions	Operation in experiment
90%	In ethanol; water at 60℃;	1 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)ethanodiamide·benzenesulfonate monohydrate crystalline form 3.0 g of edoxaban free base was suspended in 25.5 ml of ethanol and 4.5 ml of water, heated to 60°C, and a solution of 0.95 g (1.1 eq) of benzenesulfonic acid hydrate dissolved in 4.5 ml of ethanol was added to the suspension of edoxaban free base. Added. After that, the reaction mixture was cooled to room temperature and allowed to stand for 1 hour. To the reaction mixture in which crystals were formed, 12.75 ml of ethanol and 2.25 ml of water were added, and the reaction mixture was stirred at room temperature for 2 hours, and then cooled to 2°C. Stir for hours. The resulting crystal was filtered and dried under vacuum at 50° C. for 12 hours to obtain the title crystal (yield: 90%, purity: 99.986%).
60%	In ethanol; water at 70℃; for 5h;	8 <Example 8> Preparation of edoxaban besylate of the present invention To 1.0 g of edoxaban free base, 40 mL of methylene chloride was added and suspended. Besylic acid solution (1.82 mL, 1.0M ethanol solution) was added, stirred for 1 hour, and then concentrated. After adding 20 mL of 85% ethanol to the concentrate, the concentrated residue was released, the temperature was raised to 70°C, and the mixture was stirred for 1 hour. It was cooled to room temperature and stirred for 3 hours. The resulting solid was filtered and dried under vacuum at an internal temperature of 50° C. overnight to obtain 0.78 g (60%) of the title compound.
	In ethanol at 20℃;	1; 3 Example 3: Preparation of edoxaban benzenesulfonate crystalline form I Edoxaban free base (1 g) was stirred in ethanol (20 mL) at room temperature, and benzenesulfonic acid (0.32 mg) was dissolved in ethanol (5 mL) and added dropwise to the mixture. Thereafter, the resulting solid was filtered and washed with ethanol. The solid thus obtained was dried under reduced pressure to obtain a crystalline form of edoxaban benzenesulfonate.

Reference： [1]Current Patent Assignee: PHARMACOSTECH CO LTD - KR2020/106737, 2020, A Location in patent: Paragraph 0039-0041
[2]Current Patent Assignee: DONG-A ST CO., LTD. - KR2020/53270, 2020, A Location in patent: Paragraph 0157-0158
[3]Current Patent Assignee: YONSUNG FINE CHEMICAL CO LTD - KR2021/50472, 2021, A Location in patent: Paragraph 0076-0082; 0084-0090

36
edoxaban [ No CAS ]
[ 110-04-3 ]
C₂₄H₃₀ClN₇O₄S*C₂H₆O₆S₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
81%	In ethanol; water at 60℃; for 1h;	11 <Example 11> Preparation of edoxaban edicylate of the present invention 0.5 g of edoxaban free base was added to the reaction unit, and then 14 mL of ethanol and 6 mL of distilled water were added to dissolve it. After adding 0.19 g of edicylic acid, the temperature was raised to 60°C and stirred for 1 hour. After cooling to room temperature, the resulting solid was filtered. Vacuum-dried overnight at room temperature to obtain 0.56g (81%) of the title compound.

Reference： [1]Current Patent Assignee: DONG-A ST CO., LTD. - KR2020/53270, 2020, A Location in patent: Paragraph 0181-0182

37
edoxaban [ No CAS ]
[ 81-04-9 ]
edoxaban heminaphthalenedisulfonate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
86%	In ethanol; dichloromethane at 80℃; for 1h;	12 <Example 12> Preparation of edoxaban hemi 1,5-naphthalenedisulfonic acid salt of the present invention 0.5 g of edoxaban free base was added to the reaction unit, and then 7.5 mL of methylene chloride was added to dissolve it. After adding 0.33 g of 1,5-naphthalenedisulfonic acid dissolved in 7.5 mL of ethanol, the mixture was heated to 80° C. and stirred for 1 hour. Cooled to room temperature and stirred overnight. The resulting solid was filtered and dried in vacuo at room temperature overnight to give 0.57 g (86%) of the title compound.
12.3 g	In ethanol; dichloromethane at 20℃; for 2h;	1-4 [Example 3] Preparation of edoxaban heminaphthalene disulfonate monohydrate crystal form 1 10 g of edoxaban free base prepared in Korean Patent Publication No. 10-2090912 was dissolved in 150 mL of methylene chloride. Thereafter, 0.51 equivalent of naphthalenedisulfonic acid tetrahydrate was dissolved in 50 mL of ethanol. Thereafter, the two solutions were mixed, stirred at room temperature for 2 hours at 400 rpm, filtered (washed with 20 mL of ethylene chloride), dried under vacuum at 40 degrees for 2 days, and then 12.3 g of edoxaban heminaphthalenedisulfonate monohydrate crystal 1 form was added. Obtained.

Reference： [1]Current Patent Assignee: DONG-A ST CO., LTD. - KR2020/53270, 2020, A Location in patent: Paragraph 0189-0190
[2]Current Patent Assignee: UNICEL LAB - KR102215625, 2021, B1 Location in patent: Paragraph 0033-0040

Type	HazMat fee for 500 gram (Estimated)
Excepted Quantity	USD 0.00
Limited Quantity	USD 15-60
Inaccessible (Haz class 6.1), Domestic	USD 80+
Inaccessible (Haz class 6.1), International	USD 150+
Accessible (Haz class 3, 4, 5 or 8), Domestic	USD 100+
Accessible (Haz class 3, 4, 5 or 8), International	USD 200+

Purity	Size	Price	VIP Price	USA Stock *0-1 Day	Global Stock *5-7 Days	Quantity
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CAS No. :	480449-70-5	MDL No. :	MFCD13195544
Formula :	C₂₄H₃₀ClN₇O₄S	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	HGVDHZBSSITLCT-JLJPHGGASA-N
M.W :	548.06	Pubchem ID :	10280735
Synonyms :	DU-176;Savaysa;DU-176b	Chemical Name :	N1-(5-Chloropyridin-2-yl)-N2-((1S,2R,4S)-4-(dimethylcarbamoyl)-2-(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamido)cyclohexyl)oxalamide

Num. heavy atoms :	37
Num. arom. heavy atoms :	11
Fraction Csp3 :	0.5
Num. rotatable bonds :	10
Num. H-bond acceptors :	7.0
Num. H-bond donors :	3.0
Molar Refractivity :	143.24
TPSA :	164.87 Å²

GI absorption :	Low
BBB permeant :	No
P-gp substrate :	Yes
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	Yes
Log Kp (skin permeation) :	-8.63 cm/s

[ CAS No. 480449-70-5 ] {[proInfo.proName]}

Quality Control of [ 480449-70-5 ]

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Physicochemical Properties

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Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 480449-70-5 ]

Application In Synthesis of [ 480449-70-5 ]

[ 480449-70-5 ] Synthesis Path-Downstream 1~37

Precautionary Statements-General

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Log Po/w (iLOGP) :	2.97
Log Po/w (XLOGP3) :	1.42
Log Po/w (WLOGP) :	0.57
Log Po/w (MLOGP) :	-0.57
Log Po/w (SILICOS-IT) :	1.93
Consensus Log Po/w :	1.26

Lipinski :	2.0
Ghose :	None
Veber :	1.0
Egan :	1.0
Muegge :	1.0
Bioavailability Score :	0.17

Log S (ESOL) :	-3.69
Solubility :	0.111 mg/ml ; 0.000203 mol/l
Class :	Soluble
Log S (Ali) :	-4.49
Solubility :	0.0179 mg/ml ; 0.0000326 mol/l
Class :	Moderately soluble
Log S (SILICOS-IT) :	-5.41
Solubility :	0.00213 mg/ml ; 0.00000389 mol/l
Class :	Moderately soluble

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	2.0
Synthetic accessibility :	5.04

Signal Word:	Danger	Class:	9
Precautionary Statements:	P260-P264-P273-P301+P312-P305+P351+P338-P314	UN#:	3077
Hazard Statements:	H302-H319-H372-H410	Packing Group:	Ⅲ
GHS Pictogram:

Precautionary Statements-General
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P101	If medical advice is needed,have product container or label at hand.
P102	Keep out of reach of children.
P103	Read label before use
Prevention
Code	Phrase
P201	Obtain special instructions before use.
P202	Do not handle until all safety precautions have been read and understood.
P210	Keep away from heat/sparks/open flames/hot surfaces. - No smoking.
P211	Do not spray on an open flame or other ignition source.
P220	Keep/Store away from clothing/combustible materials.
P221	Take any precaution to avoid mixing with combustibles
P222	Do not allow contact with air.
P223	Keep away from any possible contact with water, because of violent reaction and possible flash fire.
P230	Keep wetted
P231	Handle under inert gas.
P232	Protect from moisture.
P233	Keep container tightly closed.
P234	Keep only in original container.
P235	Keep cool
P240	Ground/bond container and receiving equipment.
P241	Use explosion-proof electrical/ventilating/lighting/equipment.
P242	Use only non-sparking tools.
P243	Take precautionary measures against static discharge.
P244	Keep reduction valves free from grease and oil.
P250	Do not subject to grinding/shock/friction.
P251	Pressurized container: Do not pierce or burn, even after use.
P260	Do not breathe dust/fume/gas/mist/vapours/spray.
P261	Avoid breathing dust/fume/gas/mist/vapours/spray.
P262	Do not get in eyes, on skin, or on clothing.
P263	Avoid contact during pregnancy/while nursing.
P264	Wash hands thoroughly after handling.
P265	Wash skin thouroughly after handling.
P270	Do not eat, drink or smoke when using this product.
P271	Use only outdoors or in a well-ventilated area.
P272	Contaminated work clothing should not be allowed out of the workplace.
P273	Avoid release to the environment.
P280	Wear protective gloves/protective clothing/eye protection/face protection.
P281	Use personal protective equipment as required.
P282	Wear cold insulating gloves/face shield/eye protection.
P283	Wear fire/flame resistant/retardant clothing.
P284	Wear respiratory protection.
P285	In case of inadequate ventilation wear respiratory protection.
P231 + P232	Handle under inert gas. Protect from moisture.
P235 + P410	Keep cool. Protect from sunlight.
Response
Code	Phrase
P301	IF SWALLOWED:
P304	IF INHALED:
P305	IF IN EYES:
P306	IF ON CLOTHING:
P307	IF exposed:
P308	IF exposed or concerned:
P309	IF exposed or if you feel unwell:
P310	Immediately call a POISON CENTER or doctor/physician.
P311	Call a POISON CENTER or doctor/physician.
P312	Call a POISON CENTER or doctor/physician if you feel unwell.
P313	Get medical advice/attention.
P314	Get medical advice/attention if you feel unwell.
P315	Get immediate medical advice/attention.
P320
P302 + P352	IF ON SKIN: wash with plenty of soap and water.
P321
P322
P330	Rinse mouth.
P331	Do NOT induce vomiting.
P332	IF SKIN irritation occurs:
P333	If skin irritation or rash occurs:
P334	Immerse in cool water/wrap n wet bandages.
P335	Brush off loose particles from skin.
P336	Thaw frosted parts with lukewarm water. Do not rub affected area.
P337	If eye irritation persists:
P338	Remove contact lenses, if present and easy to do. Continue rinsing.
P340	Remove victim to fresh air and keep at rest in a position comfortable for breathing.
P341	If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P342	If experiencing respiratory symptoms:
P350	Gently wash with plenty of soap and water.
P351	Rinse cautiously with water for several minutes.
P352	Wash with plenty of soap and water.
P353	Rinse skin with water/shower.
P360	Rinse immediately contaminated clothing and skin with plenty of water before removing clothes.
P361	Remove/Take off immediately all contaminated clothing.
P362	Take off contaminated clothing and wash before reuse.
P363	Wash contaminated clothing before reuse.
P370	In case of fire:
P371	In case of major fire and large quantities:
P372	Explosion risk in case of fire.
P373	DO NOT fight fire when fire reaches explosives.
P374	Fight fire with normal precautions from a reasonable distance.
P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling