Edoxaban key intermediate and its synthesis method

Abstract

The present invention discloses a key intermediate of edoxaban and a method for synthesizing the same. The key intermediate of edoxaban is [Formula 1] TIFF2024546285000025.tif43170, which can be obtained by aminolysis of the raw material. The intermediate can be used to prepare edoxaban p-toluenesulfonate monohydrate. The new method and route are simple and effectively reduce the cost of producing edoxaban p-toluenesulfonate hydrate on an industrial scale.

Description

[Technical field]

[0001] The present invention relates to a key intermediate of edoxaban and a method for synthesizing the same, and further relates to a method for producing edoxaban p-toluenesulfonic acid monohydrate using the key intermediate as a raw material. [Background technology]

[0002] Edoxaban p-toluenesulfonate monohydrate is a small molecule drug developed by Daiichi Sankyo Co., Ltd. and is a blood coagulation factor Xa inhibitor. Currently, the highest research and development stage of the drug is to obtain marketing approval, and it treats pulmonary embolism, venous thromboembolism, stroke, venous thrombosis and embolism. On April 22, 2011, Edoxaban toluenesulfonate was approved by the Pharmaceuticals and Medical Devices Agency (PMDA) and is marketed by Daiichi Sankyo Co., Ltd. On January 8, 2015, Edoxaban toluenesulfonate was approved by the US Food and Drug Administration (FDA) and is marketed by Daiichi Sankyo Inc. under the trade name Savaysa®. (NDA206316) On June 19, 2015, Edoxaban toluenesulfonate was approved by the European Medicines Agency (EMA) and is marketed by Daiichi Sankyo Europe Gmbh under the trade name Lixiana®. (EMEA / H / C / 002629) On December 25, 2018, edoxaban toluenesulfonate was approved by the China National Medical Products Administration (NMPA) and is marketed by Daiichi Sankyo Europe Gmbh under the trade name Lixianan®.

[0003] Edoxaban has three chiral centers and has a total of eight isomers, but only one configuration has good activity. The structure of edoxaban is as follows: [ka]

[0004] The synthetic route disclosed by Nippon Daiichi Sankyo Polymer Co., Ltd. in US2005119486A1 is as follows. [ka]

[0005] In this route, a chiral amine compound and a lithium salt of an oxamide derivative are used to generate an amide under the action of a condensing agent, the Boc-protecting group is removed under acidic conditions, and then an amide is formed under the conditions of a lithium salt of a 2-thiazolecarboxylic acid derivative and a condensing agent to produce edoxaban.

[0006] US2005119486A1 further discloses alternative synthetic routes. [ka]

[0007] In this route, a chiral azide compound is used as the starting material, and the Boc protection is first removed, followed by the formation of an amide under the conditions of a lithium salt of a 2-thiazolecarboxylic acid derivative and a condensing agent, and then the azide group is reduced to an amino group, and the amide is generated under the action of a lithium salt of an oxamide derivative and a condensing agent to produce edoxaban.

[0008] The synthetic route disclosed by Nippon Daiichi Sankyo Co., Ltd. in WO2008156159A1 is as follows: Racemic S-1 is decomposed in the presence of chiral amine S-2, and then undergoes intramolecular nucleophilic attack under the action of electrophilic bromination reagent to obtain bridged ring compound S-4. S-4 is aminolyzed and ring-opened via propylene oxide intermediate S-6 under the action of NH4OH to obtain amino alcohol compound S-7. S-7 is then protected by Boc for amino group protection, Ms for alcohol hydroxy group protection, and NaN3 attack to introduce N3 group to obtain compound S-10. Then, the amino group is obtained by hydrogenation reduction, and then condensed with S-13 to obtain compound S-14. Compound S-14 is subjected to removal of the Boc protecting group under acidic conditions, and then condensed with carboxylic acid S-16 to obtain the final compound S-17, which can be converted to TsOH salt to obtain edoxaban. The synthetic route of the process is as follows: [ka]

[0009] The difficulty in synthesizing this compound is the preparation of chiral substrates such as compound S-10. Summary of the Invention

[0010] The technical problem to be solved by the present invention is to provide a novel key intermediate of edoxaban and a method for producing the same, and further to produce edoxaban p-toluenesulfonic acid monohydrate using the key intermediate as a raw material.

[0011] In order to solve the above problems, the present invention uses the following technical means.

[0012] The structural formula of the key intermediate of edoxaban is represented by Formula 1. [ka]

[0013] The present invention further provides a method for synthesizing the above-mentioned key intermediate of edoxaban by aminolysis reaction of a compound of formula 2 with a compound of formula 3 according to the following synthetic route: [ka]

[0014] Preferably, the solvent used in the aminolysis reaction is at least one of acetonitrile, tetrahydrofuran, ethanol, toluene, and butanone, and the base used in the aminolysis reaction is at least one of triethylamine, diisopropylethylamine, pyridine, and DBU.

[0015] Preferably, the temperature of the aminolysis reaction is 50 to 100°C.

[0016] Preferably, the ratio of the amount of substance of the compound of formula 2 to the compound of formula 3 is 1:1.1 to 1.5.

[0017] The present invention further provides a use of the above-mentioned key intermediate of edoxaban for preparing edoxaban p-toluenesulfonate monohydrate, specifically, In the following synthetic route, step 1) of reducing a compound of formula 1 to obtain a compound of formula 4; [ka] Step 2) of subjecting a compound of formula 4 to a condensation reaction to obtain a compound of formula 6 according to the following synthetic route; [ka] and 3) salifying the compound of formula 6 with p-toluenesulfonic acid, followed by obtaining edoxaban p-toluenesulfonate monohydrate, i.e., the compound of formula 7. [ka]

[0018] Preferably, the reducing agent used in the step 1) is at least one of Pd / C, Raney nickel, lithium aluminum hydride, sodium borohydride, and triphenylphosphine.

[0019] Preferably, the solvent used in the condensation reaction in step 2) is at least one of acetonitrile, ethanol, tetrahydrofuran, and dichloromethane.

[0020] Preferably, in step 2), the compound of formula 5 is reacted as an acid chloride or with a condensation reagent, and the condensation reagent is at least one of CDI, DCC, and EDCI.

[0021] Preferably, the step 3) is carried out in a reaction solvent, and the reaction solvent is at least one of ethanol, acetonitrile, and acetone, the controlled temperature in the step 3) is 50 to 100°C, and the chlorination temperature in the step 3) is -10 to 30°C.

[0022] The present invention provides a novel key intermediate of edoxaban and a method for producing the same. Furthermore, by using the key intermediate as a raw material to produce edoxaban p-toluenesulfonate monohydrate, it is possible to achieve high yield and chiral purity, and the reaction conditions are mild and the process operation is simple, making it suitable for industrial production. [Brief description of the drawings]

[0023] [Figure 1] FIG. 1 is an HPLC spectrum of N1-((1S,2R,4S)-2-azido-4-(dimethylcarbamoyl)cyclohexyl)-N2-(5-chloropyridin-2-yl)oxamide (compound of formula 1). [Diagram 2] 1 is an HPLC spectrum of edoxaban p-toluenesulfonate monohydrate (compound of formula 7). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0024] In order that the present invention may be more clearly understood, a preferred embodiment will now be described in detail with reference to the drawings.

[0025] Example 1 Preparation of N1-((1S,2R,4S)-2-azido-4-(dimethylcarbamoyl)cyclohexyl)-N2-(5-chloropyridin-2-yl)oxamide (compound of formula 1) [ka] 2-((5-chloropyridin-2-yl)amino)-2-oxoethyl acetate (compound of formula 3) (150.7 g, 568.7 mmol) and 500 mL of ethanol were added to the reaction flask in sequence, the reaction system was cooled to about 0 to 10 ° C., triethylamine (43.1 g, 426.7 mmol) was gradually added, and then (1S, 3R, 4S)-4-amino-3-azido-N, N-dimethylcyclohexane-1-carboxamide (compound of formula 2) (100.0 g, 473.9 mmol) was added. After the addition was completed, the reaction system was heated to 70 to 75 ° C., and when the system was heated to 55 to 60 ° C., triethylamine (14.4 g, 142.6 mmol) was added to the system, and then the temperature of the reaction system was maintained at 70 to 75 ° C. and stirred for 16 hours. The reaction was monitored in the liquid phase. After the reaction was completed, the temperature of the system was lowered to 50-55°C, and 900 mL of purified water was added dropwise. After the addition was completed, the temperature was lowered to 20-25°C, and the mixture was stirred for 1 hour and then filtered by suction to obtain 163.9 g of a compound (compound of formula 1), with a yield of 88.0%.

[0026] The proton nuclear magnetic resonance spectrum data of the obtained product is as follows:

[0027] 1H NMR(400 MHz,CDCl3)δ9.79(s,1H),8.32(d,J=2.4 Hz,1H),8.19(d,J=8.8 Hz,1H),7.72(dd,J=8.9,2.4 Hz,1H),7.63(d,J=8.8 Hz,1H),4.13(d,J=3.4 Hz,1H),4.02(td,J=9.7,8.9,4.7 Hz,1H),3.09(s,3H),2.95(s,3H),2.93-2.84(m,1H),2.04(dtd,J=23.4,13.2,11.4,6.1 Hz,2H),1.83(dt,J=10.0,5.9 Hz,2H),1.69(d,J=10.1 Hz,2H).

[0028] 13 C NMR(101 MHz, CDCl3)δ173.92,158.32,157.58,148.12,147.17,138.07,128.02,114.62,60.42,50.05,37.17,35.68,33.47,31.63,27.27,26.17.

[0029] LCMS: m / z=393.8 (M+H) + .

[0030] Example 2 Preparation of N1-((1S,2R,4S)-2-azido-4-(dimethylcarbamoyl)cyclohexyl)-N2-(5-chloropyridin-2-yl)oxamide (compound of formula 1) [ka] 2-((5-chloropyridin-2-yl)amino)-2-oxoethyl acetate (compound of formula 3) (150.7 g, 568.7 mmol) and 500 mL of tetrahydrofuran were added to the reaction flask in sequence, the temperature of the reaction system was lowered to about 0 to 10 ° C., triethylamine (43.1 g, 426.7 mmol) was gradually added, and then (1S, 3R, 4S)-4-amino-3-azido-N, N-dimethylcyclohexane-1-carboxamide (compound of formula 2) (100.0 g, 473.9 mmol) was added. After the addition was completed, the reaction system was heated to 60 to 65 ° C., and then triethylamine (14.4 g, 142.6 mmol) was added to the reaction system, and the temperature of the system was maintained at 60 to 65 ° C. and stirred for 16 hours. The reaction was monitored in the liquid phase. After the reaction was completed, 900 mL of purified water was added dropwise to the system. After the addition was completed, the temperature was lowered to 20-25°C, the mixture was stirred for 1 hour, and then filtered by suction to obtain 167.6 g of a compound (compound of formula 1), with a yield of 90.0%.

[0031] The proton nuclear magnetic resonance spectrum data of the obtained product is as follows:

[0032] 1 H NMR(400 MHz,CDCl3)δ9.79(s,1H),8.32(d,J=2.4 Hz,1H),8.19(d,J=8.8 Hz,1H),7.72(dd,J=8.9,2.4 Hz,1H),7.63(d,J=8.8 Hz,1H),4.13(d,J=3.4 Hz,1H),4.02(td,J=9.7,8.9,4.7 Hz,1H),3.09(s,3H),2.95(s,3H),2.93-2.84(m,1H),2.04(dtd,J=23.4,13.2,11.4,6.1 Hz,2H),1.83(dt,J=10.0,5.9 Hz,2H),1.69(d,J=10.1 Hz,2H).

[0033] 13C NMR(101 MHz, CDCl3)δ173.92,158.32,157.58,148.12,147.17,138.07,128.02,114.62,60.42,50.05,37.17,35.68,33.47,31.63,27.27,26.17.

[0034] LCMS: m / z=393.8 (M+H) + .

[0035] Example 3 Preparation of N1-((1S,2R,4S)-2-azido-4-(dimethylcarbamoyl)cyclohexyl)-N2-(5-chloropyridin-2-yl)oxamide (compound of formula 1) [ka] 2-((5-chloropyridin-2-yl)amino)-2-oxoethyl acetate (compound of formula 3) (150.7 g, 568.7 mmol) and 500 mL of acetonitrile were added to the reaction flask in sequence, the reaction system was cooled to about 0 to 10 ° C., triethylamine (43.1 g, 426.7 mmol) was gradually added, and then (1S, 3R, 4S)-4-amino-3-azido-N, N-dimethylcyclohexane-1-carboxamide (compound of formula 2) (100.0 g, 473.9 mmol) was added. After the addition was completed, the reaction system was heated to 60 to 65 ° C., and then triethylamine (14.4 g, 142.6 mmol) was added to the system, and the temperature of the system was maintained at 60 to 65 ° C. and stirred for 16 hours. The reaction was monitored in the liquid phase. After the reaction was completed, 900 mL of purified water was added dropwise to the system. After the addition was completed, the temperature was lowered to 20-25°C, the mixture was stirred for 1 hour, and then filtered by suction to obtain 171.4 g of a compound (compound of formula 1), with a yield of 92.0%.

[0036] The proton nuclear magnetic resonance spectrum data of the obtained product is as follows:

[0037] 1H NMR(400 MHz,CDCl3)δ9.79(s,1H),8.32(d,J=2.4 Hz,1H),8.19(d,J=8.8 Hz,1H),7.72(dd,J=8.9,2.4 Hz,1H),7.63(d,J=8.8 Hz,1H),4.13(d,J=3.4 Hz,1H),4.02(td,J=9.7,8.9,4.7 Hz,1H),3.09(s,3H),2.95(s,3H),2.93-2.84(m,1H),2.04(dtd,J=23.4,13.2,11.4,6.1 Hz,2H),1.83(dt,J=10.0,5.9 Hz,2H),1.69(d,J=10.1 Hz,2H).

[0038] 13 C NMR(101 MHz, CDCl3)δ173.92,158.32,157.58,148.12,147.17,138.07,128.02,114.62,60.42,50.05,37.17,35.68,33.47,31.63,27.27,26.17.

[0039] LCMS: m / z=393.8 (M+H) + .

[0040] Example 4 Preparation of N1-((1S,2R,4S)-2-amino-4-(dimethylcarbamoyl)cyclohexyl)-N2-(5-chloropyridin-2-yl)oxamide (compound of formula 4) [ka] N1-((1S,2R,4S)-2-azido-4-(dimethylcarbamoyl)cyclohexyl)-N2-(5-chloropyridin-2-yl)oxamide (compound of formula 1) (5.0g, 12.7mmol), Pd / C (0.1g, 2%wt) and 40mL of methanol were added in sequence to a hydrogen gas reaction vessel, and the mixture was reacted for 8 hours at 50-55℃. The reaction was monitored by TLC. After the reaction was completed, the insoluble matter was removed by filtration, and the filter cake was washed with 2×20mL of methanol. The organic phase was concentrated to obtain a compound (compound of formula 4), which was directly used in the next step with a yield of 100%.

[0041] The proton nuclear magnetic resonance spectrum data of the obtained product is as follows:

[0042] 1 H NMR(400 MHz,CDCl3)δ8.30(d,J=2.3 Hz,1H),8.17(dd,J=8.9,2.1 Hz,1H),7.98(d,J=8.5 Hz,1H),7.70(dt,J=8.9,2.3 Hz,1H),3.91(dt,J=13.0,6.5 Hz,1H),3.35(d,J=4.7 Hz,1H),3.06(d,J=2.1 Hz,3H),2.93(d,J=2.1 Hz,3H),2.89-2.79(m,1H),1.96(tt,J=12.3,2.8 Hz,1H),1.80(q,J=12.6,11.2 Hz,3H),1.73-1.54(m,3H).

[0043] 13 C NMR(101 MHz, CDCl3)δ174.59,158.24,158.09,148.27,147.14,138.02,127.86,114.52,50.88,47.88,37.10,35.67(overlapped),32.84,27.24,25.24.

[0044] LCMS: m / z=367.8 (M+H) + .

[0045] Example 5 Preparation of N1-((1S,2R,4S)-2-amino-4-(dimethylcarbamoyl)cyclohexyl)-N2-(5-chloropyridin-2-yl)oxamide (compound of formula 4) [ka] N1-((1S,2R,4S)-2-azido-4-(dimethylcarbamoyl)cyclohexyl)-N2-(5-chloropyridin-2-yl)oxamide (1) (5.0 g, 12.7 mmol), triphenylphosphine (6.6 g, 25.4 mmol), 30 mL of tetrahydrofuran, and 10 mL of purified water were added to a reaction flask in that order, and the mixture was stirred overnight at 20-25°C. The reaction was monitored by TLC. After the reaction was completed, the system was diluted with 1N HCl was added to adjust pH=2-3, and the mixture was stirred at room temperature for 1 hour, then concentrated to remove tetrahydrofuran, the aqueous phase was washed with 2×30mL dichloromethane, the aqueous phase was reserved, 2N sodium hydroxide was added to adjust pH=9, the aqueous phase was extracted with 2×30mL dichloromethane, the organic phases were combined and concentrated to obtain compound (compound of formula 4), which was directly used in the next step with a yield of 100%.

[0046] The proton nuclear magnetic resonance spectrum data of the obtained product is as follows:

[0047] 1 H NMR(400 MHz,CDCl3)δ8.30(d,J=2.3 Hz,1H),8.17(dd,J=8.9,2.1 Hz,1H),7.98(d,J=8.5 Hz,1H),7.70(dt,J=8.9,2.3 Hz,1H),3.91(dt,J=13.0,6.5 Hz,1H),3.35(d,J=4.7 Hz,1H),3.06(d,J=2.1 Hz,3H),2.93(d,J=2.1 Hz,3H),2.89-2.79(m,1H),1.96(tt,J=12.3,2.8 Hz,1H),1.80(q,J=12.6,11.2 Hz,3H),1.73-1.54(m,3H).

[0048] 13 C NMR(101 MHz, CDCl3)δ174.59,158.24,158.09,148.27,147.14,138.02,127.86,114.52,50.88,47.88,37.10,35.67(overlapped),32.84,27.24,25.24.

[0049] LCMS: m / z=367.8 (M+H) + .

[0050] Example 6 Preparation of Edoxaban (Compound of Formula 6) [ka] N1-((1S,2R,4S)-2-amino-4-(dimethylcarbamoyl)cyclohexyl)-N2-(5-chloropyridin-2-yl)oxamide (compound of formula 4) (5.0 g, 13.6 mmol) and 75 mL of acetonitrile were added to a reaction flask, and the reaction system was cooled to about 0 to 10 °C while stirring. Then, triethylamine (1.7 g, 16.3 mmol), 4,5,6,7-tetrahydro-5-methyl-thiazolo[5,4-C]pyridine-2-carboxylic acid (5) (3.5 g, 15.0 mmol), HO BT (2.2g, 16.3mmol) and EDCI (3.6g, 19.0mmol) were added in sequence, the temperature was raised to 20-25°C, and the mixture was stirred for 8 hours. The reaction was monitored in the liquid phase. After the reaction was completed, the mixture was filtered by suction, and the filter cake was taken out. The filter cake was dissolved in 50mL of dichloromethane, and the organic phase was washed with 2 x 25mL of saturated aqueous sodium carbonate solution. The organic phase was concentrated, and 30mL of anhydrous ethanol was added and the mixture was hot-pulped at 70-75°C for 2 hours. The mixture was then cooled to room temperature and filtered by suction to obtain 6.3g of compound (compound of formula 6), with a yield of 85%.

[0051] The proton nuclear magnetic resonance spectrum data of the obtained product is as follows:

[0052] 1H NMR(400 MHz,CDCl3)δ9.76(s,1H),8.32(dd,J=2.4,0.6 Hz,1H),8.18(dd,J=8.8,0.6 Hz,1H),8.04(d,J=7.8 Hz,1H),7.71(dd,J=8.8,2.4 Hz,1H),7.42(dd,J=8.8,0.6 Hz,1H),4.66-4.71(m,1H),4.07-4.13(m,1H),3.78(d,J=15.1 Hz,2H),3.08(s,3H),3.02-2.79(m,8H),2.58(q,J=6.2 Hz,3H),2.11(m,3H),2.01-1.60(m,3H).

[0053] 13 C NMR(101 MHz, CDCl3)δ173.59,160.26,159.92,158.77,157.68,156.55,149.90,148.17,147.12,137.94,12 7.88,114.58,52.49,52.15,51.01,47.79,45.00,37.18,35.76,34.09,32.64,26.99,26.66,25.97.

[0054] LCMS: m / z=547.8 (M+H) + .

[0055] Example 7 Preparation of Edoxaban (Compound of Formula 6) [ka] Add 4,5,6,7-tetrahydro-5-methyl-thiazolo[5,4-C]pyridine-2-carboxylic acid (compound of formula 5) (3.8g, 16.3mmol) and 30mL of dichloromethane to the reaction flask in sequence, and under the protection of nitrogen gas, keep the temperature at 20-25℃, slowly add oxalyl chloride (2.6g, 20.4mmol) to the reaction system dropwise, and after the dropwise addition is completed, keep the temperature at room temperature under nitrogen gas and stir for 2 hours, suction filter, and wash with dichloromethane to obtain the compound 4,5,6,7-tetrahydro-5-methyl-thiazolo[5,4-C]pyridine-2-carbonyl chloride hydrochloride, which is stored for use.

[0056] Into another reaction flask, N1-((1S,2R,4S)-2-amino-4-(dimethylcarbamoyl)cyclohexyl)-N2-(5-chloropyridin-2-yl)oxamide (compound of formula 4) (5.0 g, 13.6 mmol), 75 mL of dichloromethane, and triethylamine (3.4 g, 34.0 mmol) were added in that order, and the reaction system was stirred and cooled to 0-5° C. to obtain the 4,5,6,7-tetrahydro-5-methylpyridine-2-yl oxamide. Add thiyl-thiazolo[5,4-C]pyridine-2-carbonyl chloride hydrochloride slowly, and after the addition is completed, warm to room temperature and stir for 2-3 hours, monitor in liquid phase, after the reaction is completed, wash the organic phase with 2 x 25mL saturated aqueous sodium carbonate solution, add 30mL anhydrous ethanol, evaporate dichloromethane under normal pressure, precipitate the solid, and suction filter to obtain 6.6g of compound (compound of formula 6), the yield is 88.6%.

[0057] The proton nuclear magnetic resonance spectrum data of the obtained product is as follows:

[0058] 1 H NMR(400 MHz,CDCl3)δ9.76(s,1H),8.32(dd,J=2.4,0.6 Hz,1H),8.18(dd,J=8.8,0.6 Hz,1H),8.04(d,J=7.8 Hz,1H),7.71(dd,J=8.8,2.4 Hz,1H),7.42(dd,J=8.8,0.6 Hz,1H),4.66-4.71(m,1H),4.07-4.13(m,1H),3.78(d,J=15.1 Hz,2H),3.08(s,3H),3.02-2.79(m,8H),2.58(q,J=6.2 Hz,3H),2.11(m,3H),2.01-1.60(m,3H).

[0059] 13C NMR(101 MHz, CDCl3)δ173.59,160.26,159.92,158.77,157.68,156.55,149.90,148.17,147.12,137.94,12 7.88,114.58,52.49,52.15,51.01,47.79,45.00,37.18,35.76,34.09,32.64,26.99,26.66,25.97.

[0060] LCMS: m / z=547.8 (M+H) + .

[0061] Example 8 Preparation of Edoxaban p-Toluenesulfonate Monohydrate (Compound of Formula 7) [ka] Edoxaban (compound of formula 6) (5.0 g, 9.1 mmol) and 50 mL of dichloromethane were added to a reaction flask, and a 1 mol / L solution of p-toluenesulfonic acid in acetone (9.1 mL) was added to the solution, and the solvent was removed by distillation. Acetone containing 15% water (50 mL) was added to the residue, and the mixture was stirred at 60°C to dissolve the mixture. The solution was cooled to room temperature and stirred for 1 day. The precipitated crystals were collected by filtration, washed with acetone, and dried under reduced pressure at room temperature for 2 hours to obtain 6.0 g of compound (compound of formula 7), with a yield of 89%.

[0062] The proton nuclear magnetic resonance spectrum data of the obtained product is as follows:

[0063] 1H NMR (400 MHz, DMSO-d6) δ10.29(s,1H),10.20(s,1H),9.20(d,J=8.1 Hz,1H),8.76(d,J=7.4 Hz,1H),8.48-8.41(m,1H),8.05-7.97(m,2H),7.45(dd,J=8.0,1.6 Hz,2H),7.10(d,J=7.7 Hz,2H),4.61(s,2H),4.43(dt,J=7.5,3.9 Hz,1H),4.01(ddt,J=12.6,8.5,4.2 Hz,1H),3.64(s,2H),3.18(q,J=5.5 Hz,2H),2.99(s,3H),2.93(s,4H),2.78(s,3H),2.27(s,3H),2.15-1.98(m,2H),1.82-1.62(m,3H),1.56-1.42(m,1H).

[0064] 13 C NMR(101 MHz, DMSO-d6)δ174.22,163.73,160.05,159.20,158.83,149.06,148.33,147.33,145.49,138.77,138.44,128.61,127.33,127. 16,125.86,115.49,113.74,100.48,50.94,50.85,49.98,48.60,42.29,36.95,35.41,33.38,31.81,27.18,25.37,24.16,21.20.

[0065] LCMS: m / z=547.8(M+H) + .

[0066] (Example 9) Manufacture of エドキサバンp-トルエンスルホン acid hydride monohydrate (compound of formula 7)

change

[0067] The proton nuclear magnetic resonance spectrum data of the obtained product is as follows:

[0068] 1 H NMR(400 MHz,DMSO-d6)δ10.29(s,1H),10.20(s,1H),9.20(d,J=8.1 Hz,1H),8.76(d,J=7.4 Hz,1H),8.48-8.41(m,1H),8.05-7.97(m,2H),7.45(dd,J=8.0,1.6 Hz,2H),7.10(d,J=7.7 Hz,2H),4.61(s,2H),4.43(dt,J=7.5,3.9 Hz,1H),4.01(ddt,J=12.6,8.5,4.2 Hz,1H),3.64(s,2H),3.18(q,J=5.5 Hz,2H),2.99(s,3H),2.93(s,4H),2.78(s,3H),2.27(s,3H),2.15-1.98(m,2H),1.82-1.62(m,3H),1.56-1.42(m,1H).

[0069] 13C NMR(101 MHz,DMSO-d6)δ174.22,163.73,160.05,159.20,158.83,149.06,148.33,147.33,145.49,138.77,138.44,128.61,127.33,127.16,125.86,115.49,113.74,100.48,50.94,50.85,49.98,48.60,42.29,36.95,35.41,33.38,31.81,27.18,25.37,24.16,21.20。

[0070] LCMS:m / z=547.8(M+H) + 。

Claims

1. A key intermediate of edoxaban, characterized by having a structural formula represented by Formula 1. 【Chemistry 1】

2. 2. The method for synthesizing the key intermediate of edoxaban according to claim 1, characterized in that the compound is obtained by aminolysis reaction of a compound of formula 2 with a compound of formula 3 according to the following synthetic route: 【Chemistry 2】

3. 3. The method for synthesizing a key intermediate of edoxaban according to claim 2, wherein a solvent used in the aminolysis reaction is at least one of acetonitrile, tetrahydrofuran, ethanol, toluene, and butanone, and a base used in the aminolysis reaction is at least one of triethylamine, diisopropylethylamine, pyridine, and DBU.

4. The method for synthesizing a key intermediate of edoxaban according to claim 2, wherein the temperature of the aminolysis reaction is 50 to 100°C.

5. 3. The method for synthesizing a key intermediate of edoxaban according to claim 2, wherein the ratio of the amount of the compound of formula 2 to the amount of the compound of formula 3 is 1:1.1-1.

5.

6. The use of the key intermediate of edoxaban according to claim 1 for the preparation of edoxaban p-toluenesulfonate monohydrate, specifically: In the following synthetic route, step 1) of reducing a compound of formula 1 to obtain a compound of formula 4; 【Chemistry 3】 Step 2) of subjecting a compound of formula 4 to a condensation reaction to obtain a compound of formula 6 according to the following synthetic route; 【Chemistry 4】 and 3) reacting the compound of formula 6 with p-toluenesulfonic acid to obtain edoxaban p-toluenesulfonate monohydrate, i.e., the compound of formula 7. 【Chemistry 5】

7. 7. The use according to claim 6, characterized in that the reducing agent used in step 1) is at least one of Pd / C, Raney nickel, lithium aluminum hydride, sodium borohydride, and triphenylphosphine.

8. The use according to claim 6, characterized in that the solvent used in the condensation reaction in step 2) is at least one of acetonitrile, ethanol, tetrahydrofuran, and dichloromethane.

9. 7. The use according to claim 6, characterized in that in step 2), the compound of formula 5 is reacted as an acid chloride or with a condensation reagent, the condensation reagent being at least one of CDI, DCC, EDCI.

10. The use according to claim 6, characterized in that the step 3) is carried out in a reaction solvent, the reaction solvent being at least one of ethanol, acetonitrile, and acetone, the controlled temperature of the step 3) is 50 to 100°C, and the chlorination temperature in the step 3) is -10 to 30°C.

Images