An edoxaban intermediate compound

Abstract

The application belongs to the technical field of medicine synthesis, and particularly relates to an intermediate compound of edoxaban. The application takes 2-bromo-5-methyl-3a, 4, 5, 6, 7, 7a-hexahydrothiazolo[5, 4-c] pyridine as a starting material, and a lactam product is obtained by undergoing a carbonylation reaction with (3R, 4R)-3-amino-4-hydroxy-N, N-dimethylcyclohexane-1-carboxamide under the action of a catalyst, and the obtained lactam product undergoes a Mitsunobu reaction with N-(4-chlorophenyl) oxamide to obtain edoxaban. The preparation method of edoxaban provided by the application introduces a lactam by using a copper-catalyzed carbonylation reaction, and the whole synthesis method is simple in operation, high in reaction yield and purity; can effectively avoid the addition of n-butyllithium and low-temperature operation required by the carboxylation in the prior art, improve the operation safety, and has the advantages of mild use conditions, high conversion rate and simple operation.

Description

Technical Field

[0001] This invention belongs to the field of drug synthesis technology, and specifically relates to an edoxaban intermediate compound. Background Technology

[0002] Edoxaban (English name: edoxaban) has the chemical name: N-(5-chloropyridin-2-yl)-N-[(1S,2S,4S)-4-(N,N-dimethylcarbamoyl)]-2-[(5-methyl-4,5,6,7-tetrahydro-1,3-thiazo[5,4-c]-pyridin-2-carbamoyl)cyclohexyl]oxalamide. Edoxaban p-toluenesulfonate hydrate is a small-molecule oral anticoagulant developed by Daiichi Sankyo Co., Ltd. It was first launched in Japan in April 2011 under the brand name Lixiana. It is used to prevent stroke and systemic embolism in patients with atrial fibrillation (AF). Edoxaban is Japan's first oral anticoagulant drug, selectively and reversibly inhibiting coagulation factor Xa to inhibit thrombus formation. Clinically, this drug has shown good oral absorption, tolerability, and anticoagulant activity, thus possessing promising clinical application prospects. Its chemical structure is as follows:

[0003]

[0004] Currently, the most commonly used synthetic route for edoxaban is the one reported in the original study US2005119486. In this route, a chiral amine compound 1 reacts with a lithium salt of an oxalamide derivative 2 under the action of a condensing agent to generate an amide compound 3; compound 3 is then deprotected under acidic conditions to form compound 4; this compound 4 is then reacted with a lithium salt of a 2-thiazocarboxylic acid derivative 5 under condensing conditions to form an amide, thus preparing edoxaban. The synthetic route is as follows:

[0005]

[0006] However, this process route uses condensation reactions twice in reverse. Since condensation reactions require a large amount of condensation reagent, a large amount of racemic mixture is generated. The preparation conditions for the important intermediate compound 5 are demanding. Original patents WO2003000657 and WO2003000680 report two methods for preparing compound 5:

[0007] Route 1: Starting with thiazo[5,4-c]-pyridine as the initial raw material, it reacts with iodomethane, followed by reduction with sodium borohydride to obtain compound 7, namely 5-methyl-4,5,6,7-tetrahydrothiazo[5,4-c]pyridine. Compound 7 reacts with carbon dioxide in the presence of n-butyllithium to give lithium 5-methyl-4,5,6,7-tetrahydrothiazo[5,4-c]pyridine-2-carboxylate. The synthetic route is as follows:

[0008]

[0009] The disadvantage of this route is that the reaction uses flammable and explosive n-butyllithium, and the carboxylation reaction needs to be carried out at -78°C, which is difficult to control.

[0010] Route 2: Starting with 2-bromo-4,5,6,7-tetrahydrothiazo[5,4-c]pyridine, the reaction proceeds with formaldehyde, followed by reduction with sodium triacetoxyborohydride to yield compound II, namely 2-bromo-5-methyl-4,5,6,7-tetrahydrothiazo[5,4-c]pyridine. Compound II then reacts with carbon dioxide in the presence of n-butyllithium to yield compound 5. The synthetic route is as follows:

[0011]

[0012] This route uses bromine as a lead group, which lowers the conditions for the carboxylation reaction, but it still does not avoid the use of n-butyllithium and still requires a temperature of -40°C, making the reaction relatively harsh.

[0013] In summary, how to further reduce the harsh conditions of the carboxylation reaction or avoid the use of compound 5 in the synthesis of edoxaban is an urgent problem to be solved in the preparation of edoxaban. Summary of the Invention

[0014] To address the problems of demanding preparation conditions for raw material 5 and the chiral racemic reaction caused by the condensation reaction in existing edoxaban preparation techniques, this invention provides a new edoxaban intermediate and a method for preparing the new intermediate. The preparation of edoxaban using this new intermediate can avoid the use of compound 5, and at the same time, replacing the condensation reaction with a nucleophilic substitution reaction avoids the generation of chiral racemic compounds. The operation process is safe and simple, and the target product obtained has high purity and yield.

[0015] A first aspect of the present invention provides a novel edoxaban intermediate compound having the structure shown in Formula IV:

[0016]

[0017] A second aspect of this invention provides a method for preparing edoxaban intermediate compound IV, comprising the following steps:

[0018] Compounds II and III were added to organic solvent A, and catalyst A, ligand, base, molybdenum hexacarbonyl and DBU were added with stirring. The reaction was carried out under inert gas protection, and the temperature was increased and stirred. After the reaction was completed, compound III was obtained by recrystallization. The synthetic route is as follows:

[0019]

[0020] Preferably, the catalyst A is selected from cuprous chloride, cuprous iodide, copper sulfate, and copper acetate, with cuprous chloride being particularly preferred.

[0021] Preferably, the ligand is selected from one of 1,10-phenanthroline, triphenylphosphine, tricyclohexylphosphine, and 2,2′-bipyridine, with 1,10-phenanthroline being particularly preferred.

[0022] Preferably, the alkali is selected from one of cesium carbonate, potassium carbonate, sodium bicarbonate, potassium tert-butoxide, and lithium tert-butoxide, with cesium carbonate being particularly preferred.

[0023] Preferably, the molar ratio of compound II, compound III, catalyst A, ligand, and base is 1:1.0-1.5:0.05-0.12:0.05-0.12:1.5-2.0, and particularly preferred is 1:1.1:0.08:0.08:1.6.

[0024] Preferably, the molar ratio of compound II, molybdenum hexacarbonyl, and DBU is 1:0.5-1.2:1.5-2.5, and particularly preferably 1:0.8:2.0.

[0025] Preferably, the organic solvent A is selected from toluene, N,N-dimethylformamide, 1,4-dioxane, or a combination thereof.

[0026] Preferably, the reaction temperature is 80–110°C, and particularly preferably 90–100°C.

[0027] In a preferred embodiment, a post-processing operation is required after the reaction is completed. The specific steps are as follows: after the reaction is completed, the reaction solution is filtered, the filter cake is washed with ethyl acetate, the filtrate is washed with saturated sodium bicarbonate and saturated brine, and then stirred with ethanol / n-heptane (1:2, volume ratio) at 5-15°C to crystallize and obtain compound IV.

[0028] A third aspect of the present invention provides the use of compound IV in the preparation of edoxaban.

[0029] The method for preparing edoxaban using compound IV includes the following steps: Compound IV, compound V, and catalyst B are added to organic solvent B, and the mixture is stirred under controlled temperature until the reaction is complete. The resulting edoxaban is post-treated. The synthetic route is as follows:

[0030]

[0031] Preferably, the catalyst B is selected from a mixed catalytic system of organophosphorus / phosphine and diiodoalkane, wherein the organophosphorus is one or a combination of triphenyl phosphate, triphenylphosphine, tributylphosphine, diphenyltolylphosphine, and tri-p-phenylmethylphosphine; the diiodoalkane is selected from one or a combination of 1,2-diiodoethane, 1,3-diiodopropane, and 1,4-diiodobutane; and the triphenyl phosphate / 1,2-diiodoethane catalytic system is particularly preferred.

[0032] Preferably, the molar ratio of intermediate IV, compound V, organophosphorus / phosphine, and diiodoalkane compound is 1:1.2-2.0:1.0-2.0:1.0-2.0, more preferably 1:1.4:1.2:1.2.

[0033] Preferably, the reaction temperature is 30–50°C, and more preferably 40°C.

[0034] Preferably, the organic solvent B is selected from one or a combination of tetrahydrofuran, 1,4-dioxane, 2-methyltetrahydrofuran, N,N-dimethylformamide, and acetonitrile, with tetrahydrofuran being particularly preferred.

[0035] In a preferred embodiment, the post-processing step is as follows: after the reaction is completed, purified water and dichloromethane are added to the reaction mixture and stirred to separate the liquids. The organic phase is dried with anhydrous sodium sulfate, filtered, and the resulting filtrate is concentrated to dryness under reduced pressure to obtain the target product I.

[0036] The beneficial effects of this invention are:

[0037] 1. This invention provides a novel edoxaban intermediate compound and its preparation method. The novel intermediate introduces a lactam via a copper-catalyzed carbonylation reaction. The entire synthesis method is simple to operate, with high reaction yield and purity. It can effectively avoid the need for adding n-butyllithium and low-temperature operation required by existing carboxylation techniques, thus improving operational safety.

[0038] 2. This invention uses hexacarbonylmolybdenum and DBU to generate carbon monoxide in situ as the carbonyl source, eliminating the need for external carbon monoxide. Compared with traditional carbonyl insertion reactions, it does not require a pressure-resistant reactor, reducing the equipment requirements of the reaction. The operating conditions are mild and the conversion rate is high.

[0039] 3. The condensation reaction uses an organophosphorus / phosphine catalytic system, which avoids the generation of chiral racemates caused by traditional condensation reagents, and the resulting product has high chiral purity. Detailed Implementation

[0040] The present invention will be further illustrated by the following embodiments. It should be understood that the embodiments of the present invention are merely for illustrating the present invention and are not intended to limit the present invention. Therefore, any simple improvements to the present invention under the premise of the method of the present invention are within the scope of protection of the present invention.

[0041] The structure of the compound obtained in this invention is confirmed as follows:

[0042]

[0043] ESI-HRMS (m / z): 367.2003 [M+H] + ; 1 H-NMR (400MHz, DMSO-d6) δ9.20-9.28(d,1H,J=16.0Hz),4.07(d,1H,J=6.5Hz),3.96-3.91(m,1H),3.74(m,2H) ,3.11-3.06(m,1H),3.04(m,3H),3.01-2.95(t,2H),2.89-2.85(t,2H),2.83(m,3H),2.54(s,3H),2.42(s,6H); 13 C-NMR (100MHz, DMSO-d6) δ172.3,167.6,157.8,66.7,63.4,60.8,54.3,46.5,38.5,36.0,28.8,26.7,23.5.

[0044]

[0045] ESI-HRMS (m / z): 549.2121 [M+H] + ; 1 H-NMR (400MHz, DMSO-d6) δ9.72 (s, 1H), 8.31-8.29 (d, 1H, J = 2.5Hz), 8.17 (dd, 1H, J = 9.0, 0.5Hz), 8. 03-7.98(d,1H,J=8.5Hz),7.67(dd,1H,J=9.0,2.5Hz),7.40(d,1H,J=8.5Hz),4.70-4.67(m,1H),4. 14-4.09(m,1H),3.73(d,1H,J=16.0Hz),3.70(d,1H,J=16.0Hz),3.05(s,3H),3.04-2.93(m,2H),2. 95(s,3H),2.88-2.79(m,3H),2.58(s,3H),2.14-2.06(m,3H),1.96-1.78(m,2H),1.69-1.62(m,1H); 13C-NMR (100MHz, DMSO-d6) δ173.8,163.3,159.6,158.8,158.4,148.6,147.9,146.,145.3,138.3,137.9,128. 1,126.9,126.7,125.4,115.1,50.5,50.4,49.5,48.1,41.8,36.5,35.0,32.9,31.4,26.7,24.9,23.7,20.8.

[0046] In the following embodiments, the various processes and methods not described in detail are conventional methods known in the art.

[0047] Example 1

[0048] 2-Bromo-5-methyl-4,5,6,7-tetrahydrothiazo[5,4-c]pyridine (II, 23.51 g, 0.10 mol) and compound III (20.49 g, 0.11 mol) were added to toluene (500 ml). Cuprous chloride (0.79 g, 8.0 mmol), 1,10-phenanthroline (1.44 g, 8.0 mmol), and cesium carbonate (52.13 g, 0.16 mol) were added with stirring. Hexacarbonyl was then added. Molybdenum (21.12 g, 0.08 mol) and DBU (30.45 g, 0.2 mol) were reacted under nitrogen protection at 95–100 °C. After the reaction was completed, the reaction solution was filtered, the filter cake was washed with ethyl acetate, the filtrate was washed with saturated sodium bicarbonate and saturated brine, and then crystallized by stirring with ethanol / n-heptane (200 ml, 1:2, volume ratio) at 5–10 °C to obtain compound IV with a yield of 96.6% and an HPLC purity of 99.82%.

[0049] Example 2

[0050] 2-Bromo-5-methyl-4,5,6,7-tetrahydrothiazo[5,4-c]pyridine (II, 23.51 g, 0.10 mol) and compound III (18.62 g, 0.1 mol) were added to toluene (500 ml). Cuprous iodide (1.52 g, 8.0 mmol), 1,10-phenanthroline (1.44 g, 8.0 mmol), and cesium carbonate (52.13 g, 0.16 mol) were added with stirring. Hexacarbonyl was then added. Molybdenum (21.12 g, 0.08 mol) and DBU (30.45 g, 0.2 mol) were reacted under nitrogen protection at 80–85 °C. After the reaction was completed, the reaction solution was filtered, the filter cake was washed with ethyl acetate, the filtrate was washed with saturated sodium bicarbonate and saturated brine, and then crystallized by stirring with ethanol / n-heptane (200 ml, 1:2, volume ratio) at 5–10 °C to obtain compound IV with a yield of 93.2% and an HPLC purity of 99.52%.

[0051] Example 3

[0052] 2-Bromo-5-methyl-4,5,6,7-tetrahydrothiazo[5,4-c]pyridine (II, 23.51 g, 0.10 mol) and compound III (29.80 g, 0.1 mol) were added to toluene (500 ml). Copper sulfate (2.0 g, 8.0 mmol), 1,10-phenanthroline (1.44 g, 8.0 mmol), and cesium carbonate (52.13 g, 0.16 mol) were added with stirring. Molybdenum hexacarbonyl (…) was then added… 21.12 g (0.08 mol) and DBU (30.45 g, 0.2 mol) were reacted under nitrogen protection at 95–100 °C. After the reaction was completed, the reaction solution was filtered, the filter cake was washed with ethyl acetate, the filtrate was washed with saturated sodium bicarbonate and saturated brine, and then crystallized by stirring with ethanol / n-heptane (200 ml, 1:2, volume ratio) at 10–15 °C to obtain compound IV with a yield of 93.8% and an HPLC purity of 99.48%.

[0053] Example 4

[0054] 2-Bromo-5-methyl-4,5,6,7-tetrahydrothiazo[5,4-c]pyridine (II, 23.51 g, 0.10 mol) and compound III (31.66 g, 0.17 mol) were added to toluene (500 ml). Copper acetate (1.60 g, 8.0 mmol), 1,10-phenanthroline (1.44 g, 8.0 mmol), and cesium carbonate (52.13 g, 0.16 mol) were added with stirring. Molybdenum hexacarbonyl was then added. Compound IV was prepared by reacting 21.12 g (0.08 mol) and DBU (30.45 g, 0.2 mol) at 100–105 °C under nitrogen protection. After the reaction was completed, the reaction solution was filtered, the filter cake was washed with ethyl acetate, the filtrate was washed with saturated sodium bicarbonate and saturated brine, and then crystallized by stirring with ethanol / n-heptane (200 ml, 1:2, volume ratio) at 5–10 °C to obtain compound IV with a yield of 89.8% and an HPLC purity of 98.88%.

[0055] Example 5

[0056] 2-Bromo-5-methyl-4,5,6,7-tetrahydrothiazo[5,4-c]pyridine (II, 23.51 g, 0.10 mol) and compound III (20.49 g, 0.11 mol) were added to N,N-dimethylformamide (500 ml), and cuprous chloride (0.50 g, 5.0 mmol), 1,10-phenanthroline (0.90 g, 5.0 mmol), and potassium carbonate (22.11 g, 0.16 mol) were added with stirring. Add molybdenum hexacarbonyl (21.12 g, 0.08 mol) and DBU (30.45 g, 0.2 mol), and react under nitrogen protection at 95–100 °C. After the reaction is completed, filter the reaction solution, wash the filter cake with ethyl acetate, wash the filtrate with saturated sodium bicarbonate and saturated brine, and then crystallize by stirring with ethanol / n-heptane (200 ml, 1:2, volume ratio) at 0–5 °C to obtain compound IV with a yield of 92.6% and an HPLC purity of 99.61%.

[0057] Example 6

[0058] 2-Bromo-5-methyl-4,5,6,7-tetrahydrothiazo[5,4-c]pyridine (II, 23.51 g, 0.10 mol) and compound III (20.49 g, 0.11 mol) were added to 1,4-dioxane (500 ml). Cuprous chloride (1.19 g, 14.0 mmol), 1,10-phenanthroline (0.90 g, 5.0 mmol), and sodium bicarbonate (31.44 g, 0.16 mol) were added with stirring. The reaction mixture was prepared by adding molybdenum hexacarbonyl (21.12 g, 0.08 mol) and DBU (30.45 g, 0.2 mol) and heating to 95–100 °C under nitrogen protection. After the reaction was completed, the reaction solution was filtered, the filter cake was washed with ethyl acetate, the filtrate was washed with saturated sodium bicarbonate and saturated brine, and then crystallized by stirring with ethanol / n-heptane (200 ml, 1:2, volume ratio) at 10–15 °C to obtain compound IV with a yield of 93.3% and an HPLC purity of 99.58%.

[0059] Example 7

[0060] 2-Bromo-5-methyl-4,5,6,7-tetrahydrothiazo[5,4-c]pyridine (II, 23.51 g, 0.10 mol) and compound III (20.49 g, 0.11 mol) were added to toluene (500 ml). Cuprous chloride (0.30 g, 3.0 mmol), 1,10-phenanthroline (0.90 g, 5.0 mmol), and potassium tert-butoxide (17.95 g, 0.16 mol) were added with stirring. Hexacarbonyl was then added. Molybdenum (21.12 g, 0.08 mol) and DBU (30.45 g, 0.2 mol) were reacted under nitrogen protection at 75–80 °C. After the reaction was completed, the reaction solution was filtered, the filter cake was washed with ethyl acetate, the filtrate was washed with saturated sodium bicarbonate and saturated brine, and then crystallized by stirring with ethanol / n-heptane (200 ml, 1:2, volume ratio) at 15–20 °C to obtain compound IV with a yield of 88.9% and an HPLC purity of 98.98%.

[0061] Example 8

[0062] 2-Bromo-5-methyl-4,5,6,7-tetrahydrothiazo[5,4-c]pyridine (II, 23.51 g, 0.10 mol) and compound III (20.49 g, 0.11 mol) were added to N,N-dimethylformamide (500 ml), and cuprous chloride (1.39 g, 14.0 mmol), 1,10-phenanthroline (0.90 g, 5.0 mmol), and lithium tert-butoxide (12.82 g, 0.16 mol) were added with stirring. Add molybdenum hexacarbonyl (21.12 g, 0.08 mol) and DBU (30.45 g, 0.2 mol), and react under nitrogen protection at 110–115 °C. After the reaction is completed, filter the reaction solution, wash the filter cake with ethyl acetate, wash the filtrate with saturated sodium bicarbonate and saturated brine, and then crystallize by stirring with ethanol / n-heptane (200 ml, 1:2, volume ratio) at 0–5 °C to obtain compound IV with a yield of 87.5% and an HPLC purity of 98.85%.

[0063] Example 9

[0064] 2-Bromo-5-methyl-4,5,6,7-tetrahydrothiazo[5,4-c]pyridine (II, 23.51 g, 0.10 mol) and compound III (20.49 g, 0.11 mol) were added to toluene (500 ml). Cuprous chloride (0.79 g, 8.0 mmol), triphenylphosphine (2.10 g, 8.0 mmol), and cesium carbonate (48.87 g, 0.15 mol) were added with stirring. Molybdenum hexacarbonyl (…) was then added… 21.12 g (0.08 mol) and DBU (30.45 g, 0.2 mol) were reacted under nitrogen protection at 95–100 °C. After the reaction was completed, the reaction solution was filtered, the filter cake was washed with ethyl acetate, the filtrate was washed with saturated sodium bicarbonate and saturated brine, and then crystallized by stirring with ethanol / n-heptane (200 ml, 1:2, volume ratio) at 5–10 °C to obtain compound IV with a yield of 93.3% and an HPLC purity of 99.61%.

[0065] Example 10

[0066] 2-Bromo-5-methyl-4,5,6,7-tetrahydrothiazo[5,4-c]pyridine (II, 23.51 g, 0.10 mol), compound III (20.49 g, 0.11 mol) were added to toluene (500 ml), and cuprous chloride (0.79 g, 8.0 mmol), tricyclohexylphosphine (2.24 g, 8.0 mmol), cesium carbonate (65.16 g, 0.20 mol), and molybdenum hexacarbonyl (…) were added with stirring. 21.12 g (0.08 mol) and DBU (30.45 g, 0.2 mol) were reacted under nitrogen protection at 100–105 °C. After the reaction was completed, the reaction solution was filtered, the filter cake was washed with ethyl acetate, the filtrate was washed with saturated sodium bicarbonate and saturated brine, and then crystallized by stirring with ethanol / n-heptane (200 ml, 1:2, volume ratio) at 5–10 °C to obtain compound IV with a yield of 93.8% and an HPLC purity of 99.56%.

[0067] Example 11

[0068] 2-Bromo-5-methyl-4,5,6,7-tetrahydrothiazo[5,4-c]pyridine (II, 23.51 g, 0.10 mol) and compound III (20.49 g, 0.11 mol) were added to toluene (500 ml), and cuprous chloride (0.79 g, 8.0 mmol) and 2,2-dichlorophenoxyacetic acid were added with stirring. ′Bipyridine (1.25 g, 8.0 mmol), cesium carbonate (42.36 g, 0.13 mol), molybdenum hexacarbonyl (7.92 g, 0.03 mol), and DBU (19.79 g, 0.13 mol) were added. The mixture was heated to 85–90 °C under nitrogen protection. After the reaction was completed, the reaction solution was filtered, the filter cake was washed with ethyl acetate, and the filtrate was washed with saturated sodium bicarbonate and saturated brine. Then, the mixture was stirred in ethanol / n-heptane (200 ml, 1:2, v / v) at 15–20 °C to crystallize compound IV, with a yield of 88.6% and an HPLC purity of 98.86%.

[0069] Example 12

[0070] 2-Bromo-5-methyl-4,5,6,7-tetrahydrothiazo[5,4-c]pyridine (II, 23.51 g, 0.10 mol) and compound III (20.49 g, 0.11 mol) were added to toluene (500 ml). Cuprous chloride (0.79 g, 8.0 mmol), 2,2′-bipyridine (1.25 g, 8.0 mmol), and cesium carbonate (71.68 g, 0.22 mol) were added with stirring. Molybdenum hexacarbonyl was then added. Compound IV was prepared by reacting 36.96 g (0.14 mol) and DBU (41.10 g, 0.27 mol) at 110–115 °C under nitrogen protection. After the reaction was completed, the reaction solution was filtered, the filter cake was washed with ethyl acetate, the filtrate was washed with saturated sodium bicarbonate and saturated brine, and then crystallized by stirring with ethanol / n-heptane (200 ml, 1:2, volume ratio) at 15–20 °C to obtain compound IV with a yield of 89.5% and an HPLC purity of 98.72%.

[0071] Example 13

[0072] 2-Bromo-5-methyl-4,5,6,7-tetrahydrothiazo[5,4-c]pyridine (II, 23.51 g, 0.10 mol) and compound III (20.49 g, 0.11 mol) were added to toluene (500 ml). Cuprous chloride (0.79 g, 8.0 mmol), 1,10-phenanthroline (1.44 g, 8.0 mmol), and cesium carbonate (52.13 g, 0.16 mol) were added with stirring. Hexacarbonyl was then added. Molybdenum (13.20 g, 0.05 mol) and DBU (22.84 g, 0.15 mol) were reacted under nitrogen protection at 90–95 °C. After the reaction was completed, the reaction solution was filtered, the filter cake was washed with ethyl acetate, the filtrate was washed with saturated sodium bicarbonate and saturated brine, and then crystallized by stirring with ethanol / n-heptane (200 ml, 1:2, volume ratio) at 0–5 °C to obtain compound IV with a yield of 93.7% and an HPLC purity of 99.54%.

[0073] Example 14

[0074] 2-Bromo-5-methyl-4,5,6,7-tetrahydrothiazo[5,4-c]pyridine (II, 23.51 g, 0.10 mol) and compound III (20.49 g, 0.11 mol) were added to toluene (500 ml). Cuprous chloride (0.79 g, 8.0 mmol), 1,10-phenanthroline (1.44 g, 8.0 mmol), and cesium carbonate (52.13 g, 0.16 mol) were added with stirring. Molybdenum hexacarbonyl was then added. Compound IV was prepared by reacting 31.68 g (0.12 mol) and DBU (38.06 g, 0.25 mol) at 110–115 °C under nitrogen protection. After the reaction was completed, the reaction solution was filtered, the filter cake was washed with ethyl acetate, the filtrate was washed with saturated sodium bicarbonate and saturated brine, and then crystallized by stirring with ethanol / n-heptane (200 ml, 1:2, volume ratio) at 15–20 °C to obtain compound IV with a yield of 92.9% and an HPLC purity of 99.52%.

[0075] Preparation of Compound I

[0076] Example 15

[0077] At room temperature, intermediate IV (3.66 g, 10 mmol), compound V (2.79 g, 14 mmol), 1,2-diiodoethane (3.38 g, 12 mmol), triphenyl phosphate (3.92 g, 12 mmol), and tetrahydrofuran (50 ml) were added to a 200 ml single-necked flask. The mixture was stirred at 40 °C until intermediate IV was completely consumed. After the reaction was complete, purified water (50 ml) and dichloromethane (50 ml) were added to the reaction mixture. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure. The resulting solid was dried under vacuum to give edoxaban with a yield of 98.5% and an HPLC purity of 99.92%.

[0078] Example 16

[0079] At room temperature, intermediate IV (3.66 g, 10 mmol), compound V (2.40 g, 12 mmol), 1,2-diiodoethane (3.38 g, 12 mmol), triphenylphosphine (3.15 g, 12 mmol), and N,N-dimethylformamide (50 ml) were added to a 200 ml single-necked flask. The mixture was stirred at 30 °C until intermediate IV was completely consumed. After the reaction was complete, purified water (50 ml) and dichloromethane (50 ml) were added to the reaction mixture. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure. The resulting solid was dried under vacuum to give edoxaban with a yield of 94.8% and an HPLC purity of 99.61%.

[0080] Example 17

[0081] At room temperature, intermediate IV (3.66 g, 10 mmol), compound V (3.99 g, 20 mmol), 1,3-diiodopropane (3.55 g, 12 mmol), tributylphosphine (2.43 g, 12 mmol), and tetrahydrofuran (50 ml) were added to a 200 ml single-necked flask. The mixture was stirred at 50 °C until intermediate IV was completely consumed. After the reaction was complete, purified water (50 ml) and dichloromethane (50 ml) were added to the reaction mixture. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure. The resulting solid was dried under vacuum to give edoxaban with a yield of 95.2% and an HPLC purity of 99.58%.

[0082] Example 18

[0083] At room temperature, intermediate IV (3.66 g, 10 mmol), compound V (2.00 g, 10 mmol), 1,4-diiodobutane (3.72 g, 12 mmol), diphenyltolylphosphine (3.32 g, 12 mmol), and tetrahydrofuran (50 ml) were added to a 200 ml single-necked flask. The mixture was stirred at 25 °C until intermediate IV was completely consumed. After the reaction was complete, purified water (50 ml) and dichloromethane (50 ml) were added to the reaction mixture. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure. The resulting solid was dried under vacuum to give edoxaban with a yield of 89.8% and an HPLC purity of 98.98%.

[0084] Example 19

[0085] At room temperature, intermediate IV (3.66 g, 10 mmol), compound V (4.40 g, 22 mmol), 1,4-diiodobutane (3.72 g, 12 mmol), diphenyltolylphosphine (3.66 g, 12 mmol), and tetrahydrofuran (50 ml) were added to a 200 ml single-necked flask. The mixture was stirred at 55 °C until intermediate IV was completely consumed. After the reaction was complete, purified water (50 ml) and dichloromethane (50 ml) were added to the reaction mixture. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure. The resulting solid was dried under vacuum to give edoxaban with a yield of 90.5% and an HPLC purity of 98.82%.

[0086] Example 20

[0087] At room temperature, intermediate IV (3.66 g, 10 mmol), compound V (2.79 g, 14 mmol), 1,2-diiodoethane (2.81 g, 10 mmol), triphenyl phosphate (3.27 g, 10 mmol), and 1,4-dioxane (50 ml) were added to a 200 ml single-necked flask. The mixture was stirred at 30 °C until intermediate IV was completely consumed. After the reaction was complete, purified water (50 ml) and dichloromethane (50 ml) were added to the reaction mixture. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure. The resulting solid was dried under vacuum to give edoxaban with a yield of 94.4% and an HPLC purity of 99.68%.

[0088] Example 21

[0089] At room temperature, intermediate IV (3.66 g, 10 mmol), compound V (2.79 g, 14 mmol), 1,2-diiodoethane (5.62 g, 20 mmol), triphenyl phosphate (6.54 g, 20 mmol), and 2-methyltetrahydrofuran (50 ml) were added to a 200 ml single-necked flask. The mixture was stirred at 50 °C until intermediate IV was completely consumed. After the reaction was complete, purified water (50 ml) and dichloromethane (50 ml) were added to the reaction mixture. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure. The resulting solid was dried under vacuum to give edoxaban with a yield of 95.2% and an HPLC purity of 99.55%.

[0090] Example 21

[0091] At room temperature, intermediate IV (3.66 g, 10 mmol), compound V (2.79 g, 14 mmol), 1,2-diiodoethane (6.20 g, 22 mmol), triphenylmethylphosphine (6.70 g, 22 mmol), and acetonitrile (50 ml) were added to a 200 ml single-necked flask. The mixture was stirred at 55 °C until intermediate IV was completely consumed. After the reaction was complete, purified water (50 ml) and dichloromethane (50 ml) were added to the reaction mixture. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure. The resulting solid was dried under vacuum to give edoxaban with a yield of 90.6% and an HPLC purity of 98.95%.

Claims

1. An edoxaban intermediate compound characterized by, The structure is shown as formula IV: 。 2. A process for the preparation of the edoxaban intermediate compound IV according to claim 1, characterized in that, The preparation method comprises the following steps: adding compound II and compound III into an organic solvent A, adding a catalyst A, a ligand, a base and hexacarbonylmolybdenum and DBU under stirring, stirring and heating under inert gas protection, detecting the end of the reaction, and recrystallizing to obtain compound IV, and the synthesis route is as follows: 。 3. The production method according to claim 2, characterized by, The catalyst A is selected from one of cuprous chloride, cuprous iodide, copper sulfate, copper acetate; the ligand is selected from one of 1,10-phenanthroline, triphenylphosphine, tricyclohexylphosphine, 2,2 ′ bipyridine.

4. The preparation method according to claim 2, characterized in that, The base is selected from one of cesium carbonate, potassium carbonate, sodium bicarbonate, potassium tert-butoxide and lithium tert-butoxide.

5. The preparation method according to claim 2, characterized in that, The feeding molar ratio of the compound II, the compound III, the catalyst A, the ligand, the base is 1:1.0-1.5:0.05-0.12:0.05-0.12:1.5-2.0; the feeding molar ratio of the compound II, hexacarbonylmolybdenum and DBU is 1:0.5-1.2:1.5-2.

5.

6. The preparation method according to claim 2, characterized in that, The organic solvent A is selected from toluene, N,N - one of dimethylformamide, 1,4-dioxane or a combination thereof; and the reaction temperature is 80 to 110 °C.

7. The use of the intermediate compound IV of edoxaban in claim 1 for preparing edoxaban.

8. Use of the edoxaban intermediate compound IV of claim 7 for the preparation of edoxaban, characterized in that, The preparation method comprises the following steps: adding compound IV, compound V and catalyst B into an organic solvent B, stirring under temperature control until the reaction is completed, and treating the reaction to obtain edoxaban: 。 9. Use according to claim 8, characterized in that, The catalyst B is selected from a mixed catalytic system of organic phosphorus / phosphine and diiodoalkane, wherein the organic phosphorus is one or a combination of triphenyl phosphate, triphenylphosphine, tributylphosphine, diphenyltolylphosphine, tri-p-phenylphosphine or a combination thereof; and the diiodoalkane is selected from one or a combination of 1,2-diiodoethane, 1,3-diiodopropane and 1,4-diiodobutane.

10. Use according to claim 8, characterized in that, The molar ratio of the intermediate IV, compound V, organic phosphorus / phosphine, diiodoalkyl compound is 1:1.2-2.0:1.0-2.0:1.0-2.0; the organic solvent B is selected from one or a combination of tetrahydrofuran, 1,4-dioxane, 2-methyltetrahydrofuran, N,N dimethylformamide, acetonitrile; the reaction temperature is 30-50°C.

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