Intermediate of edoxaban tosylate and method for producing the same

Abstract

The present invention relates to the field of organic chemical synthesis, in particular to an intermediate of edoxaban toluenesulfonate and a preparation method thereof, which has the advantages of simple preparation process, mild reaction conditions, low cost, and easy availability of raw materials. The synthesis steps include: using the compound N-methyl-4-piperidone as a raw material, a substitution reaction with bromine to produce a compound represented by formula (II); a thio reaction of the compound represented by formula (II) with sodium sulfide to obtain a compound represented by formula (III); a cyclization reaction of the compound represented by formula (III) with glyoxylic acid to obtain a compound represented by formula (IV); an esterification reaction of the compound represented by formula (IV) with an alcohol to obtain a compound represented by formula (V), which is further reacted to obtain a compound represented by formula (VI), or a direct reaction of the compound represented by formula (IV) with an alcohol and an acid to obtain a compound represented by formula (VI); and an alkali hydrolysis and acid neutralization of the compound represented by formula (VII) are obtained from the compound represented by formula (VII). The reaction formula is as follows: There are 76159 JPEG2024526838000058.jpg.

Description

Technical Field

[0001] The present invention relates to the field of organic chemical synthesis, and particularly to an intermediate of edoxaban tosylate and a method for producing the same.

Background Art

[0002] Edoxaban tosylate is a direct anticoagulant factor Xa inhibitor for treating venous thromboembolism in patients after total knee arthroplasty, total hip arthroplasty or hip fracture surgery, and is a method for producing a pharmacologically acceptable salt or a hydrate thereof.

[0003] Edoxaban tosylate was developed by Daiichi Sankyo Co., Ltd., and its sale was approved by the Pharmaceuticals and Medical Devices Agency (PMDA) on April 22, 2011. Subsequently, its sale was approved by the US Food and Drug Administration (FDA) on January 8, 2015, by the European Medicines Agency (EMA) on June 19, 2015, and by the National Medical Products Administration (NMPA) of China on December 25, 2018. It is sold in Japan by Daiichi Sankyo Co., Ltd. as an oral tablet under the trade name Lixiana (registered trademark).

[0004] In the current market, there are many synthetic processes for edoxaban tosylate, but most of the process routes are synthesized by its main intermediate 4,5,6,7-tetrahydro-5-methyl-thiazolo[5,4-c]pyridine-2-carboxylic acid. Therefore, it is very important for the synthesis research of the edoxaban tosylate intermediate, and the structural formula of the main intermediate is shown in JPEG0007716833000001.jpg4297. Shown in JPEG0007716833000001.jpg4297.

[0005] The main routes of the current reported methods for producing 4,5,6,7-tetrahydro-5-methyl-thiazolo[5,4-c]pyridine-2-carboxylic acid are as follows. 1) 109C6x Synthesis Route 1 (US2005119486A1) JPEG0007716833000002.jpg39170。

Summary of the Invention

Problems to be Solved by the Invention

[0006] In this route, starting from 4-aminopyridine and reacting with Boc-anhydride, 109H1-00 is obtained. Then, under the action of n-butyllithium and S element, compound 109H2-00 is obtained. By carrying out a ring-closing reaction with formic acid, compound 109H3-00 is obtained. Further reacting with methyl iodide, the corresponding pyridinium quaternary ammonium compound 109H4-00 is obtained. By carrying out a reduction reaction with a boron hydride compound, compound 109C4-00 is obtained. It is produced by n-butyllithium and carbon dioxide gas to obtain the corresponding lithium carboxylate compound 109C6-10. Finally, a salt is formed by hydrochloric acid neutralization to obtain compound 109C6-20. In this route, expensive and flammable n-butyllithium and S element with flammability and explosiveness are used twice. In the process, methyl iodide reagent with a low boiling point, high cost and high toxicity is also used. Therefore, from the perspective of production safety, there are many risks, and it is not helpful for cost management and is not suitable for industrial production.

[0007] 2) 109C6x synthesis route (US9233980B2) JPEG0007716833000003.jpg46161。

[0008] When this route uses N-methyl-4-piperidone as a starting material and undergoes a cyclization reaction with an aqueous solution of cyanamide and S element to obtain the corresponding thiazoleamine compound 109C2-00, sodium nitrite is diazotized with hydrobromic acid to obtain bromide 109C3-00, and lithium carboxylate is obtained by reacting with n-butyl chloride and carbon dioxide gas under low-temperature conditions. Finally, a salt is formed by hydrochloric acid neutralization to obtain compound 109C6-20. In this route, due to the use of S element with flammability and explosiveness, and expensive and flammable n-butyllithium, there are many production risks and it is not helpful for cost management, so it is not suitable for industrial production.

[0009] In view of these, the object of the present invention is to provide a method for producing 4,5,6,7-tetrahydro-5-methyl-thiazolo[5,4-c]pyridine-2-carboxylic acid with a simple manufacturing process, mild reaction conditions, low cost, and easily available raw materials in order to overcome the above-mentioned defects existing in the prior art.

Means for Solving the Problems

[0010] The present invention provides an intermediate for producing edoxaban tosylate and a method for producing the same, and the method has the advantages of simple process, mild reaction conditions, low cost, and easily available raw materials.

[0011] In order to achieve the above object of the invention, the present invention is realized by the following technical solutions. According to a first aspect, the present invention provides an intermediate having the formula (II) for producing edoxaban tosylate, and its structural formula is JPEG0007716833000004.jpg5183.

[0012] According to a second aspect, the present invention provides a method for producing an intermediate represented by formula (II) for producing edoxaban tosylate. The synthesis step of the compound of formula (II) includes reacting compound N-methyl-4-piperidone with bromine through a substitution reaction to produce compound 3-bromo-N-methyl-4-piperidone represented by formula (II).

[0013] Preferably, the reaction temperature during the substitution reaction with bromine is 20 - 25 °C. At this temperature, the occurrence of side reactions can be effectively prevented, and finally, the yield of the compound represented by formula (II) can be maintained at a high level.

[0014] According to a third aspect, the present invention provides an intermediate represented by formula (III) for producing edoxaban tosylate, and its structural formula is JPEG0007716833000005.jpg55107.

[0015] According to a fourth aspect, the present invention provides a method for producing an intermediate represented by formula (III) for producing edoxaban tosylate. The synthesis step of the compound of formula (III) includes subjecting the compound represented by formula (II) to a thio-reaction with sodium sulfide to obtain the compound represented by formula (III), and the reaction formula is JPEG0007716833000006.jpg53127.

[0016] Preferably, the holding reaction temperature in the thio-reaction process is -5 - 0 °C, and the reaction time is 20 - 60 min.

[0017] According to a fifth aspect, the present invention provides an intermediate represented by formula (IV) for producing edoxaban tosylate, and its structural formula is JPEG0007716833000007.jpg59119, where R1 = NH4 or H.

[0018] According to the sixth aspect, the present invention provides a method for producing an intermediate represented by formula (IV) for producing edoxaban tosylate. Using compound N-methyl-4-piperidone as a raw material, through a substitution reaction with bromine, a compound represented by formula (II) is generated, By subjecting the compound represented by formula (II) to a thio reaction with sodium sulfide, a compound represented by formula (III) is obtained, By subjecting the compound represented by formula (III) to a cyclization reaction with glyoxylic acid, a compound represented by formula (IV) is obtained. The reaction formula is JPEG0007716833000008.jpg33156, where R1 = NH4 or H.

[0019] According to the seventh aspect, the present invention provides an intermediate represented by formula (IV-1) for producing edoxaban tosylate, and its structural formula is JPEG0007716833000009.jpg55113.

[0020] According to the eighth aspect, the present invention provides a method for producing an intermediate represented by formula (IV-1) for producing edoxaban tosylate. The synthesis step of the compound represented by (IV-1) includes subjecting the compound represented by formula (III) to a cyclization reaction with glyoxylic acid and ammonia to obtain the compound N-methyl-4-piperidinedihydrothiazolecarboxylic acid ammonium represented by formula (IV-1). The reaction formula is JPEG0007716833000010.jpg39132.

[0021] According to the ninth aspect, it is an intermediate represented by formula (IV-2) for producing edoxaban tosylate, and its structural formula is JPEG0007716833000011.jpg52114.

[0022] According to the 10th aspect, it is a method for producing an intermediate whose formula for producing edoxaban toluenesulfonate is (IV-2), and the synthesis step of the compound represented by the formula (IV-2) includes oxidizing the compound represented by the formula (IV-1) and then obtaining the compound represented by the formula (IV-2).

[0023] Preferably, in the cyclization reaction process, the holding reaction temperature is 20-25 °C, and the reaction is carried out for 18-36 h with stirring.

[0024] According to the 11th aspect, the present invention provides an intermediate for producing edoxaban toluenesulfonate, which is characterized by having the following structural formula and whose formula is (V). JPEG0007716833000012.jpg53110, where R2 is an aliphatic hydrocarbon selected from C1-C6, a phenyl group or a substituted phenyl group.

[0025] According to the 12th aspect, the present invention provides a method for producing an intermediate whose formula for producing edoxaban toluenesulfonate is (V). The synthesis step of the compound represented by the formula (V) includes subjecting the compound represented by the formula (IV) to an esterification reaction under alcohol and an acid catalyst to obtain the compound represented by the formula (V), and the reaction formula is as follows. JPEG0007716833000013.jpg36138, and here, R1 is selected from NH4 or H, and R2 is an aliphatic hydrocarbon selected from C1-C6, a phenyl group or a substituted phenyl group.

[0026] Preferably, the alcohol is any one selected from methanol, ethanol, propanol, isopropanol, phenol, etc.

[0027] Preferably, the acid is concentrated sulfuric acid.

[0028] Preferably, in the esterification reaction process, the holding reaction temperature is 20-25°C, and the reaction is carried out with stirring for 8-12 hours. After the reaction is completed, sodium bicarbonate is used to neutralize until the pH reaches 7-8.

[0029] According to the 13th aspect, the present invention provides an intermediate with the formula (V-1) for producing edoxaban toluenesulfonate, and its structural formula is JPEG0007716833000014.jpg5399.

[0030] According to the 14th aspect, the present invention provides a method for producing an intermediate with the formula (V-1) for producing edoxaban toluenesulfonate. The synthesis step of the compound shown in (V-1) includes subjecting the compound shown in formula (IV-1) to an esterification reaction with ethanol under an acid catalyst to obtain the compound of formula (V-1), and its reaction formula is JPEG0007716833000015.jpg35157.

[0031] According to the 15th aspect, the present invention provides an intermediate with the formula (VI) for producing edoxaban toluenesulfonate, and its structural formula is JPEG0007716833000016.jpg45106, where R2 is an aliphatic hydrocarbon selected from C1-C6, a phenyl group or a substituted phenyl group.

[0032] According to the 16th aspect, the present invention provides a method for producing an intermediate with the formula (VI) for producing edoxaban toluenesulfonate. The synthesis step of the compound shown in formula (VI) includes obtaining the compound shown in formula (V) by subjecting the compound shown in formula (IV) to an esterification reaction with an alcohol, and then further reacting to obtain the compound shown in formula (VI), or directly reacting the compound shown in formula (IV) under the action of an alcohol and an acid to obtain the compound shown in formula (VI), and its reaction formula is JPEG0007716833000017.jpg34155, or JPEG0007716833000018.jpg is 34124, Here, R1 is selected from NH4 or H, and R2 is an aliphatic hydrocarbon selected from C1-C6, a phenyl group, or a substituted phenyl group.

[0033] According to the 17th aspect, the present invention provides an intermediate whose formula for producing edoxaban tosylate is (VI-1), and its structural formula is JPEG0007716833000019.jpg is 41114.

[0034] According to the 18th aspect, the present invention provides a method for producing an intermediate whose formula for producing edoxaban tosylate is (VI-1). The synthesis step of the compound shown in the formula (VI-1) is to obtain the compound shown in the formula (V-1) by subjecting the compound shown in the formula (IV-1) to an esterification reaction with ethanol, and then further reacting to obtain the compound shown in the formula (VI-1), or obtaining the compound shown in the formula (VI-1) by reacting the compound shown in the formula (IV-1) with ethanol under the action of an acid. The reaction formula is JPEG0007716833000020.jpg is 30150, Or JPEG0007716833000021.jpg is 33122.

[0035] According to the 19th aspect, the present invention provides a method for producing an intermediate whose formula for producing edoxaban tosylate is (VII). The synthesis step of the compound shown in the formula (VII) is Using compound N-methyl-4-piperidone as a raw material, reacting with bromine through a substitution reaction to generate the compound shown in the formula (II), Reacting the compound shown in the formula (II) with sodium sulfide through a thio reaction to obtain the compound shown in the formula (III), Reacting the compound shown in the formula (III) with glyoxylic acid through a cyclization reaction to obtain the compound shown in the formula (IV), By subjecting the compound represented by formula (IV) to an esterification reaction with an alcohol, a compound represented by formula (V) is obtained, and further reacting to obtain a compound represented by formula (VI), or by directly reacting the compound represented by formula (IV) under the action of an alcohol and an acid to obtain a compound represented by formula (VI), including obtaining a compound represented by formula (VII) after the compound represented by formula (VI) undergoes alkali hydrolysis and acid neutralization, wherein the reaction formula is JPEG0007716833000022.jpg61143, wherein R1 is selected from NH4 or H, and R2 is an aliphatic hydrocarbon selected from C1-C6, a phenyl group or a substituted phenyl group.

[0036] According to the 20th aspect, the present invention provides a method for producing an intermediate whose formula for producing edoxaban tosylate is (VII), and the synthesis steps of the compound represented by the formula (VII) are using compound N-methyl-4-piperidone as a raw material and subjecting it to a substitution reaction with bromine to produce a compound represented by formula (II), subjecting the compound represented by formula (II) to a thio reaction with sodium sulfide to obtain a compound represented by formula (III), subjecting the compound represented by formula (III) to a cyclization reaction with glyoxylic acid to obtain a compound represented by formula (IV-1), by subjecting the compound represented by formula (IV) to an esterification reaction with an alcohol, a compound represented by formula (V-1) is obtained, and further reacting to obtain a compound represented by formula (VI-1), or by directly reacting the compound represented by formula (IV-1) under the action of an alcohol and an acid to obtain a compound represented by formula (VI-1), including obtaining a compound represented by formula (VII) after the compound represented by formula (VI-1) undergoes alkali hydrolysis and acid neutralization, wherein the reaction formula is JPEG0007716833000023.jpg62136.

Advantages of the Invention

[0037] Therefore, the present invention has the following beneficial effects. (1) Simple and easy to implement: Each raw material of the synthetic route used in the present invention can be easily manufactured, and the stability of the products at each stage is greatly improved. The transportation stability, storage stability, and use stability during production in the factory are all significantly improved. Therefore, the quality control of each intermediate in the reaction is more convenient, the requirements for equipment are reduced, and there are no complex reactions in the synthetic route. Thus, the entire synthetic route is simple and easy to operate. (2) Low cost: Since no expensive catalysts or auxiliary reagents are used in each raw material and reaction of the synthetic route of the present invention, the pollution caused by the three wastes generated in each process is small and easy to treat. The reaction is green and environmentally friendly, and at the same time, the cost is significantly reduced. (3) High yield: In the new intermediate of edoxaban toluenesulfonate and its manufacturing method of the present invention, the yield of each step reaction is relatively high, the post-treatment is simple and convenient, and the management during mass production becomes easy.

Brief Description of the Drawings

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Figure 1

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Figure 2

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Figure 3

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Figure 4

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Figure 5

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Figure 6

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Figure 7

Embodiments for Carrying Out the Invention

[0045] Hereinafter, the present invention will be further described in accordance with specific examples. Those skilled in the art can implement the present invention based on these descriptions. Also, the examples of the present invention related to the following descriptions are usually part of the examples of the present invention, not all examples. Therefore, based on the examples of the present invention, those skilled in the art can obtain all other examples without creative effort, and all of them are included in the claims of the present invention.

[0046] Example 1 This intermediate of edoxaban toluenesulfonate, 4,5,6,7-tetrahydro-5-methyl-thiazolo[5,4-c]pyridine-2-carboxylic acid, was obtained by the following process steps.

[0047] (1) Synthesis of Compound (II) Add 40 g of glacial acetic acid to a reaction flask, dropwise add 22.6 g (199.7 mmol) of N-methyl-4-piperidone at a temperature of 25 °C or lower, dropwise add a solution prepared with 34 g (201.7 mmol) of 48% hydrobromic acid aqueous solution and 40 g of glacial acetic acid, dropwise add a solution prepared with 32 g (200.2 mmol) of bromine and 30 g of glacial acetic acid at a temperature of 20 °C or lower. After the dropping is completed, keep the temperature at 20 - 25 °C, stir overnight, filter, rinse the filter cake with ethyl acetate, collect the solid, dry it, and obtain 52 g of compound II with a yield of 95.4%.

[0048] (2) Synthesis of Compound (III) 10 g of water and 3.7 g (22.0 mmol) of Na2S·5H2O were added to a reaction flask, dissolved with stirring, the temperature was lowered to -5~0 °C, and 5 g (18.3 mmol) of 3-bromo-N-methyl-4-piperidone was added in several portions. After the addition was complete, the mixture was kept at -5~0 °C and reacted with stirring for 0.5 h, then filtered. The filter cake was rinsed with water, the solid was collected and dried to obtain 2.4 g of Compound III with a yield of 90%.

[0049] (3) Synthesis of Compound (IV-1) 45 g of methanol, 2.5 g (27 mmol) of glyoxylic acid monohydrate and 4 g (27 mmol) of Compound III were added to a reaction flask, dissolved with stirring, the temperature was controlled below 30 °C, and 16 ml (108 mmol) of 7M ammonia / methanol solution was added dropwise. After the addition was complete, the mixture was kept at 20~25 °C and reacted with stirring for 24 h. The reaction solution was concentrated under reduced pressure at 40 °C to obtain 6.4 g of the crude solid product Compound IV-1 with a yield of 50%.

[0050] (4) Synthesis of Compound (V-1) 10 ml of ethanol and 0.6 g of the crude product of Compound IV were added to a reaction flask, dissolved with stirring, the temperature was controlled at 0~5 °C, and 0.5 ml (5 mmol) of concentrated sulfuric acid was added dropwise. After the addition was complete, the temperature was gradually raised to 20~25 °C and kept warm, and the mixture was reacted with stirring for 10 h. It was neutralized with saturated sodium bicarbonate solution until pH = 7~8. The reaction solution was concentrated under reduced pressure at 50 °C, 10 ml of methanol was added to the concentrate and stirred, then filtered. The filtrate was concentrated under reduced pressure at 40 °C to obtain 0.6 g of the crude product of Compound V-1.

[0051] (5) Synthesis of Compound (VI-1) JPEG0007716833000028.jpg53163Add 20 ml of methanol, 0.6 g of the crude composition of compound IV-1, and 0.6 g of solid Fe2(SO4)3 to a reaction flask, dissolve with stirring, heat up to reflux and react for 10 hours while stirring, filter, concentrate the filtrate under reduced pressure at 50 °C, subject the concentrate to silica gel column chromatography, elute with a solvent of methanol / dichloromethane = 1:20 ratio for purification, and obtain 0.2 g of compound VI-1.

[0052] (6) Synthesis of compound (VII) JPEG0007716833000029.jpg36121Add 1.3 g (5.8 mmol) of compound VI-1 and 10 ml of methanol to a reaction flask, dissolve with stirring, cool the temperature to 0 - 5 °C, dropwise add 6 ml (6 mmol) of 1 M sodium hydroxide solution, keep the temperature at 0 - 5 °C for heat preservation after the dropping is complete, stir for 1.5 hours, adjust the reaction solution to pH = 3 - 4 with 0.5 M dilute hydrochloric acid, concentrate the reaction solution under reduced pressure at 40 - 45 °C to evaporate methanol, filter the concentrate, rinse the filter cake with a mixed solution of 3 ml of ethanol and 6 ml of water, filter, dry the filter cake, and obtain compound VII.

[0053] Example 2 This intermediate of edoxaban tosylate, 4,5,6,7-tetrahydro-5-methyl-thiazolo[5,4-c]pyridine-2-carboxylic acid, was obtained by the following process steps.

[0054] (1) Synthesis of compound (II) Add 30 g of glacial acetic acid to a reaction flask, dropwise add 17.0 g (149.8 mmol) of N-methyl-4-piperidone at a temperature of 25 °C or lower, dropwise add a solution prepared with 25.5 g (151.3 mmol) of 48% aqueous hydrobromic acid solution and 30 g of glacial acetic acid, dropwise add a solution prepared with 24 g (150.2 mmol) of bromine and 22.5 g of glacial acetic acid at a temperature of 20 °C or lower, keep the temperature at 20 - 25 °C for heat preservation after the dropping is complete, stir overnight, filter, rinse the filter cake with ethyl acetate, collect the solid, dry it, and obtain 40 g of compound II with a yield of 97.9%.

[0055] (2) Synthesis of Compound (III) Add 10 g of water and 3.36 g (20.0 mmol) of Na2S·5H2O to the reaction flask, dissolve it with stirring, cool the temperature to -5~0 °C, add 4.55 g (16.7 mmol) of 3-bromo-N-methyl-4-piperidone in several portions. After the addition is complete, keep the temperature at -5~0 °C, react for 1 hour with stirring, filter, rinse the filter cake with water, collect the solid, dry it, and obtain 2.21 g of Compound III with a yield of 91.2%.

[0056] (3) Synthesis of Compound (IV-1) Add 45 g of methanol, 2.5 g (27 mmol) of glyoxylic acid monohydrate and 4 g (27 mmol) of Compound III to the reaction flask, dissolve it with stirring, control the temperature below 30 °C, and add dropwise 16 ml (108 mmol) of 7M ammonia / methanol solution. After the addition is complete, keep the temperature at 20~25 °C, react for 36 hours with stirring, concentrate the reaction solution under reduced pressure at 40 °C, and obtain 6.4 g of the solid crude product Compound IV-1 with a yield of 50%.

[0057] (4) Synthesis of Compound (V-2) JPEG0007716833000030.jpg32117 Add 10 ml of methanol and 0.5 g of the crude product of Compound IV to the reaction flask, dissolve it with stirring, control the temperature at 0~5 °C, add dropwise 0.5 ml (5 mmol) of concentrated sulfuric acid. After the addition is complete, gradually raise the temperature to 20~25 °C and keep it warm, react for 8 hours with stirring, neutralize with saturated sodium bicarbonate solution until pH = 7~8, concentrate the reaction solution under reduced pressure at 50 °C, add 10 ml of methanol to the concentrate, stir, filter, concentrate the filtrate under reduced pressure at 40 °C, and obtain 0.5 g of the crude product of Compound V-2.

[0058] (5) Synthesis of Compound (VI-2) 20 ml of methanol, 0.6 g of the crude product of Compound IV-2, and 0.6 g of solid Fe2(SO4)3 were added to a reaction flask, dissolved with stirring, heated to reflux and reacted for 8 hours while stirring, filtered, the filtrate was concentrated under reduced pressure at 50 °C, the concentrate was applied to a silica gel column, and eluted with a solvent of methanol / dichloromethane = 1:20 ratio for purification to obtain 0.2 g of Compound VI-2.

[0059] (6) Synthesis of Compound (VII) 1.17 g (5.5 mmol) of Compound VI-2 and 10 ml of methanol were added to a reaction flask, dissolved with stirring, the temperature was lowered to 0 - 5 °C, 6 ml (6 mmol) of 1 M sodium hydroxide solution was added dropwise, after the addition was complete, it was kept warm at 0 - 5 °C and stirred for 1.5 hours, the reaction solution was adjusted to pH = 3 - 4 with 0.5 M dilute hydrochloric acid, the reaction solution was concentrated under reduced pressure at 40 - 45 °C to evaporate methanol, the concentrate was filtered, the filter cake was rinsed with a mixed solution of 3 ml of ethanol and 6 ml of water, filtered, and the filter cake was dried to obtain Compound VII.

[0060] Example 3 This intermediate of edoxaban tosylate, 4,5,6,7 - tetrahydro - 5 - methyl - thiazolo[5,4 - c]pyridine - 2 - carboxylic acid, was obtained by the following process steps.

[0061] Compound (II), Compound (III) and Compound (IV - 1) were shown in Example 1.

[0062] (4) Synthesis of Compound (V - 3) Add 10 ml of isopropanol and 0.6 g of the crude product of Compound IV-1 to a reaction flask, dissolve it with stirring, control the temperature at 0 - 5 °C, dropwise add 0.5 ml (5 mmol) of concentrated sulfuric acid. After the addition is complete, gradually raise the temperature to 20 - 25 °C and keep it warm, react for 12 hours with stirring, neutralize with saturated sodium bicarbonate solution until pH = 7 - 8, concentrate the reaction solution under reduced pressure at 50 °C, add 10 ml of methanol to the concentrate, stir, filter, concentrate the filtrate under reduced pressure at 40 °C to obtain 0.55 g of the crude product of Compound V-3.

[0063] (5) Synthesis of Compound (VI-3) Add 20 ml of methanol, 0.6 g of the crude product of Compound IV-3, and 0.6 g of solid Fe2(SO4)3 to a reaction flask, dissolve it with stirring, heat up to reflux and react for 12 hours, filter, concentrate the filtrate under reduced pressure at 50 °C, apply the concentrate to a silica gel column, elute and purify with a solvent of methanol / dichloromethane = 1:20 ratio to obtain 0.22 g of Compound VI-3.

[0064] (6) Synthesis of Compound (VII) Add 1.32 g (5.5 mmol) of Compound VI-3 and 10 ml of methanol to a reaction flask, dissolve it with stirring, lower the temperature to 0 - 5 °C, dropwise add 6 ml (6 mmol) of 1M sodium hydroxide solution. After the addition is complete, keep it warm at 0 - 5 °C and stir for 1.5 hours. Adjust the reaction solution with 0.5M dilute hydrochloric acid until pH = 3 - 4, concentrate the reaction solution under reduced pressure at 40 - 45 °C, evaporate methanol, filter the concentrate, rinse the filter cake with a mixed solution of 3 ml of ethanol and 6 ml of water, filter, dry the filter cake to obtain Compound VII.

[0065] Example 4 This intermediate of edoxaban tosylate, 4,5,6,7-tetrahydro-5-methyl-thiazolo[5,4-c]pyridine-2-carboxylic acid, was obtained by the following process steps.

[0066] Compound (II), Compound (III) and Compound (IV-1) were shown in Example 1.

[0067] (1) Synthesis of Compound (VI-1) Add 20 ml of ethanol and 1.7 g (4 mmol) of the crude product of Compound IV-1 with a content of 47% to a reaction flask, dissolve it with stirring, control the temperature at 20 - 25°C, dropwise add 1.1 g (11 mmol) of concentrated sulfuric acid. After the addition is complete, keep the temperature at 20 - 25°C and react with stirring for 24 hours. Neutralize with saturated sodium bicarbonate solution until pH = 7 - 8, filter, concentrate the filtrate under reduced pressure at 50°C. Add ethyl acetate and water to the concentrate, stir and separate the layers. Concentrate the organic phase under reduced pressure at 40°C to obtain 0.7 g of Compound VI-1, and the yield was 77.8%.

[0068] (2) Synthesis of Compound (VII) Add 1.3 g (5.8 mmol) of Compound VI-1 and 10 ml of methanol to a reaction flask, dissolve it with stirring, cool the temperature to 0 - 5°C, dropwise add 6 ml (6 mmol) of 1M sodium hydroxide solution. After the addition is complete, keep the temperature at 0 - 5°C and stir for 1.5 hours. Adjust the reaction solution to pH = 3 - 4 with 0.5M dilute hydrochloric acid, concentrate the reaction solution under reduced pressure at 40 - 45°C to evaporate methanol. Filter the concentrate, rinse the filter cake with a mixed solution of 3 ml of ethanol and 6 ml of water, filter, and dry the filter cake to obtain Compound VII.

[0069] Example 5 This intermediate of edoxaban toluenesulfonate, 4,5,6,7-tetrahydro-5-methyl-thiazolo[5,4-c]pyridine-2-carboxylic acid, was obtained by the following process steps.

[0070] The synthesis of Compound (II) and Compound (III) was shown in Example 1.

[0071] (1) Synthesis of Compound (IV-2) 45 g of methanol, 2.5 g (27 mmol) of glyoxylic acid monohydrate and 4 g (27 mmol) of Compound III were added to a reaction flask, dissolved with stirring, the temperature was controlled below 30 °C, 16 ml (108 mmol) of 7M ammonia / methanol solution was added dropwise. After the addition was complete, the mixture was kept warm at 20 - 25 °C and reacted with stirring for 24 hours. After the reaction was completed, hydrochloric acid was added dropwise to adjust the pH to 6.5. The reaction solution was concentrated under reduced pressure at 40 °C to obtain 6.2 g of the solid crude product Compound IV-2, and the yield was 48.5%.

[0072] (2) Synthesis of Compound (V-1) 10 ml of ethanol and 0.6 g of the crude product of Compound IV-2 were added to a reaction flask, dissolved with stirring, the temperature was controlled at 0 - 5 °C, 1 ml (10 mmol) of concentrated sulfuric acid was added dropwise. After the addition was complete, the temperature was gradually raised to 20 - 25 °C and kept warm, and the reaction was carried out with stirring for 12 hours. It was neutralized with saturated sodium bicarbonate solution until pH = 7 - 8. The reaction solution was concentrated under reduced pressure at 50 °C. 10 ml of methanol was added to the concentrate, stirred, filtered, and the filtrate was concentrated under reduced pressure at 40 °C to obtain 0.6 g of the crude product of Compound V-1.

[0073] (3) The syntheses of Compound (VI-1) and Compound (VII) were shown in Example 1.

[0074] Example 6 This intermediate of edoxaban toluenesulfonate, 4,5,6,7-tetrahydro-5-methyl-thiazolo[5,4-c]pyridine-2-carboxylic acid, was obtained by the following process steps.

[0075] The synthesis of Compound (IV-2) was shown in Example 5.

[0076] (2) Synthesis of Compound (VI-1) 20 ml of ethanol and 1.6 g (4 mmol) of the crude composition of Compound IV-2 with a content of 50% were added to a reaction flask, dissolved with stirring, the temperature was controlled at 20 - 25°C, 1.5 g (15 mmol) of concentrated sulfuric acid was added dropwise, after the addition was complete, the mixture was kept warm at 20 - 25°C and reacted with stirring for 24 hours, neutralized with saturated sodium bicarbonate solution until pH = 7 - 8, filtered, the filtrate was concentrated under reduced pressure at 50°C, ethyl acetate and water were added to the concentrate, stirred and separated into layers, the organic phase was concentrated under reduced pressure at 40°C to obtain 0.73 g of Compound VI-1, and the yield was 79.9%.

[0077] The synthesis of Compound (VII) was shown in Example 1.

[0078] The above general description of the invention related to this application and the description of its specific embodiments should not be understood as limiting the technical solutions of the invention. Those skilled in the art can, based on the disclosure of this application, without contravening the components of the related invention, add, subtract or combine the technical features disclosed in the above general description or / and embodiments to form other technical solutions belonging to the scope of the claims of this application.

Claims

1. An intermediate for producing edoxaban tosylate, the formula of which is (IV), and its structural formula is wherein R １ = NH ４ or H, characterized by the intermediate.

2. A method for producing an intermediate for producing edoxaban tosylate, the formula of which is (IV), wherein the synthesis step of the compound of formula (IV) is using the compound N-methyl-4-piperidone as a raw material and reacting it with bromine by a substitution reaction to produce the compound represented by formula (II); reacting the compound represented by formula (II) with sodium sulfide by a thio reaction to obtain the compound represented by formula (III); and cyclizing the compound represented by formula (III) with glyoxylic acid and ammonia to obtain the compound represented by formula (IV), and the reaction formula is wherein R １ = NH ４ or H, characterized by the production method.

3. An intermediate for producing edoxaban tosylate, the formula of which is (IV-1), and its structural formula is being characterized by the intermediate.

4. A method for producing an intermediate for producing edoxaban tosylate, the formula of which is (IV-1), wherein the synthesis step of the compound represented by (IV-1) includes cyclizing the compound represented by formula (III) with glyoxylic acid and ammonia to obtain the compound N-methyl-4-piperidodihydrothiazolecarboxylic acid ammonium represented by formula (IV-1), and the reaction formula is being characterized by the production method.

5. An intermediate for producing edoxaban tosylate, the formula of which is (IV-2), and its structural formula is being characterized by the intermediate.

6. A method for producing an intermediate for producing edoxaban tosylate, the formula of which is (IV-2), wherein the synthesis step of the compound represented by formula (IV-2) includes oxidizing the compound represented by formula (IV-1) to obtain the compound represented by formula (IV-2), the structural formula of the compound represented by formula (IV-1) is being the structural formula of the compound represented by formula (IV-2) is being, characterized by the production method.

7. An intermediate for producing edoxaban tosylate, the formula of which is (V), and its structural formula is being Here, R ２ is an aliphatic hydrocarbon, phenyl group or substituted phenyl group selected from C １ -C ６ and is characterized by being an intermediate thereof.

8. A method for producing an intermediate for producing edoxaban tosylate, the formula of which is (V), The synthesis step of the compound represented by the formula (V) includes obtaining the compound represented by the formula (V) by subjecting the compound represented by the formula (IV) to an esterification reaction with an alcohol under an acid catalyst, and the reaction formula is as follows Here, R １ is selected from NH ４ or H, and R ２ is an aliphatic hydrocarbon, phenyl group or substituted phenyl group selected from C １ -C ６ The manufacturing method is characterized by this. **Claim 9** An intermediate whose formula for producing edoxaban tosylate is (V-1), and its structural formula is as follows An intermediate characterized by the above. **Claim 10** A method for producing an intermediate whose formula for producing edoxaban tosylate is (V-1), wherein the synthesis step of the compound represented by the formula (V-1) includes obtaining the compound represented by the formula (V-1) by subjecting the compound represented by the formula (IV-1) to an esterification reaction with ethanol under an acid catalyst, and the reaction formula is as follows A production method characterized by the above. **Claim 11** A method for producing an intermediate whose formula for producing edoxaban tosylate is (VI), wherein the synthesis step of the compound represented by the formula (VI) includes obtaining the compound represented by the formula (V) by subjecting the compound represented by the formula (IV) to an esterification reaction with an alcohol, and then reacting it under the action of iron sulfate to obtain the compound represented by the formula (VI), or directly reacting the compound represented by the formula (IV) under the action of an alcohol and an acid to obtain the compound represented by the formula (VI), and the reaction formula is 、 or as follows Here, R １ is selected from NH ４ or H, and R ２ is an aliphatic hydrocarbon, phenyl group or substituted phenyl group selected from C １ -C ６ A production method characterized by the above. **Claim 12** A method for producing an intermediate whose formula for producing edoxaban tosylate is (VI-1), wherein the synthesis step of the compound represented by the formula (VI-1) includes obtaining the compound represented by the formula (V-1) by subjecting the compound represented by the formula (IV-1) to an esterification reaction with ethanol, and then reacting it under the action of iron sulfate to obtain the compound represented by the formula (VI-1), or reacting the compound represented by the formula (IV-1) under the action of ethanol and an acid to obtain the compound represented by the formula (VI-1), and the reaction formula is 、 or as follows A production method characterized by the above. **Claim 13** A method for producing an intermediate whose formula for producing edoxaban tosylate is (VII), wherein the synthesis step of the compound represented by the formula (VII) is using the compound N-methyl-4-piperidone as a raw material and subjecting it to a substitution reaction with bromine to produce the compound represented by the formula (II); obtaining the compound represented by the formula (III) by subjecting the compound represented by the formula (II) to a thio reaction with sodium sulfide; By subjecting the compound represented by formula (III) to a cyclization reaction with glyoxylic acid, a compound represented by formula (IV) is obtained, By subjecting the compound represented by formula (IV) to an esterification reaction with an alcohol to obtain a compound represented by formula (V), and further reacting to obtain a compound represented by formula (VI), or by directly reacting the compound represented by formula (IV) under the action of an alcohol and an acid to obtain a compound represented by formula (VI), including obtaining a compound represented by formula (VII) after the compound represented by formula (VI) undergoes alkali hydrolysis and acid neutralization, The reaction formula is as follows, Here, R １ is selected from NH ４ or H, and R ２ is an aliphatic hydrocarbon, phenyl group or substituted phenyl group selected from C １ -C ６ ​ a production method characterized by this.

14. A method for producing an intermediate whose formula for producing edoxaban tosylate is (VII), The synthesis steps of the compound represented by the formula (VII) include: Using compound N-methyl-4-piperidone as a raw material and subjecting it to a substitution reaction with bromine to produce a compound represented by formula (II), Subjecting the compound represented by formula (II) to a thio reaction with sodium sulfide to obtain a compound represented by formula (III), By subjecting the compound represented by formula (III) to a cyclization reaction with glyoxylic acid, a compound represented by formula (IV-1) is obtained, By subjecting the compound represented by formula (IV) to an esterification reaction with an alcohol to obtain a compound represented by formula (V-1), and further reacting to obtain a compound represented by formula (VI-1), or by directly reacting the compound represented by formula (IV-1) under the action of an alcohol and an acid to obtain a compound represented by formula (VI-1), including obtaining a compound represented by formula (VII) after the compound represented by formula (VI-1) undergoes alkali hydrolysis and acid neutralization, The reaction formula is as follows, a production method characterized by this.

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