A method of synthesis of an intermediate useful for the preparation of edoxaban
By selecting suitable reactants and conditions, compound A is generated using N-methyl-4-piperidinone, cyanamide, tetrahydropyrrole, and sulfur powder. Compound B is then reacted with hypophosphorous acid and sodium nitrite to generate compound B. Finally, compound B is reacted with acetyl chloride to generate an intermediate of edoxaban. This method solves the problem of low yield in existing processes and achieves high-yield and stable intermediate preparation.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- CANGZHOU SENARY CHEM SCI TEC
- Filing Date
- 2023-10-12
- Publication Date
- 2026-07-10
AI Technical Summary
Existing synthesis processes for edoxaban intermediates have low yields and high costs, making it difficult to meet the needs of industrial production.
Using N-methyl-4-piperidinone, cyanamide, tetrahydropyrrole, and sulfur powder as reactants, compound A is generated, which then reacts with hypophosphite and sodium nitrite to generate compound B. Finally, it reacts with acetyl chloride to generate an intermediate of edoxaban. The specific steps include controlling the temperature and pH value.
This improved the yield of each step, and the resulting intermediates were highly stable and pure, making them suitable for industrial production.
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Figure CN117384186B_ABST
Abstract
Description
Technical Field
[0001] This invention belongs to the field of compound synthesis and relates to a method for synthesizing pharmaceutical intermediates, and more particularly to a method for synthesizing intermediates that can be used to prepare edoxaban. Background Technology
[0002] Edoxaban is a coagulation factor blocker and the world's first marketed oral anticoagulant. It was developed by Daiichi Sankyo Co., Ltd. of Japan and launched in Japan in July 2011 and included in the National Essential Medicines List. It was approved by the National Medical Products Administration of China in 2018 and is also known as "edoxaban" in my country.
[0003] Currently, there are various synthetic processes and routes for preparing edoxaban. However, most of these processes require the use of 5-methyl-4,5,6,7-tetrahydrothiazo[5,4-c]pyridine-2-carboxylic acid or its hydrochloride, lithium 5-methyl-4,5,6,7-tetrahydrothiazo[5,4-c]pyridine-2-carboxylic acid, etc. Among them, 5-methyl-4,5,6,7-tetrahydrothiazo[5,4-c]pyridine-2-carboxylic acid hydrochloride, with the structure shown in Formula 1, is more stable and easier to store, which is beneficial for industrial production.
[0004] Formula 1:
[0005] Regarding the research on the intermediates of edoxaban mentioned above, Chinese invention patent application No. 202111529593.7, entitled "Intermediate of Edoxaban Tosylate and Preparation Method Thereof," discloses an intermediate of edoxaban tosylate, and the disclosed synthetic route is as follows:
[0006]
[0007] Where R1 = NH4 or H.
[0008] In the above synthetic route, the yield of compound IV prepared from compound III is relatively low, that is, the yield of synthesizing the main structure, tetrahydrothiazopyridine conjugated structure, is only 50%, which leads to an even lower overall process yield. The precursor raw materials with thiazopyridine conjugated structure are very expensive on the market. Therefore, it is necessary to develop a synthetic method for intermediates of edoxaban with higher yield and more suitable for industrial production. Summary of the Invention
[0009] The purpose of this invention is to provide a method for synthesizing intermediates of edoxaban with higher yield, simpler process, milder reaction conditions, lower cost, and suitability for industrial production.
[0010] To achieve the above objectives, the technical solution adopted by the present invention is a synthetic method for preparing intermediates of edoxaban. The key is that N-methyl-4-piperidinone, cyanamide, tetrahydropyrrole, and sulfur powder are used as reactants. Under the combined action of tetrahydropyrrole and sulfur powder, compound A is generated. Compound A is dissolved in hydrobromic acid solution and reacts with hypophosphorous acid and sodium nitrite to generate compound B. Compound B reacts with acetyl chloride under the action of an acid-binding agent to generate the intermediate of edoxaban.
[0011] Furthermore, the aforementioned compound A is 5-methyl-4,5,6,7-tetrahydro[1,3]thiazo[5,4-c]pyridine-2-amine, with the structural formula as follows: Compound B mentioned above is 4,5,6,7-tetrahydro-5-methyl-thiazo[5,4-c]pyridine, with the structural formula shown below.
[0012] Furthermore, the intermediate of edoxaban is 5-methyl-4,5,6,7-tetrahydrothiazo[5,4-c]pyridine-2-carboxylic acid hydrochloride, with the structural formula as follows: Molecular weight 234.70.
[0013] Furthermore, the above synthesis method includes the following steps:
[0014] S1: At room temperature, N-methyl-4-piperidinone was added to isopropanol, followed by sulfur powder and tetrahydropyrrole. The mixture was stirred and the reaction temperature was controlled at 10℃~20℃. Monocyanamide was added dropwise and the mixture was stirred. The reaction was carried out for 2h~6h. After the reaction was completed, the solution was concentrated to 30%~40% of the original volume, cooled to crystallization, filtered, and dried at 45℃~50℃ to obtain solid compound A.
[0015] S2: At room temperature, 40% hydrobromic acid was added to water with a mass of 1.5 times that of 40% hydrobromic acid, compound A solid was added, hypophosphoric acid was added, the temperature was lowered to -2℃~2℃, sodium nitrite aqueous solution was added dropwise, and the reaction was allowed to proceed for 1h~4h. After the reaction was completed, the pH of the system was adjusted to above 14 with sodium hydroxide solution, dichloromethane was added for extraction and separation, and the organic phase was distilled under reduced pressure to obtain compound B.
[0016] S3: At room temperature, compound B was added to dichloromethane, an acid-binding agent was added, the reaction temperature was controlled at 0℃~5℃, acetyl chloride was added dropwise, and the reaction was carried out for 1h~4h. After the reaction was completed, water was added and the mixture was separated. Potassium permanganate solution was added dropwise to the organic phase to adjust the pH value to 13~14. The mixture was separated, the pH value of the aqueous phase was adjusted to 2~3, the mixture was concentrated, ethanol was added, and the mixture was acidified with hydrochloric acid-ethanol solution. The mixture was cooled to crystallize, filtered, and dried at 35℃~40℃ to obtain the intermediate product of edoxaban.
[0017] Furthermore, the molar ratio of the above-mentioned N-methyl-4-piperidinone, cyanamide, sulfur powder, and tetrahydropyrrole is 1:2.0~2.2:0.11~0.14:0.08~0.15, and the above-mentioned sulfur powder is elemental sulfur with a molecular weight of 256.48.
[0018] Furthermore, the molar ratio of the above-mentioned solid compound A, hypophosphite, hydrobromic acid, and sodium nitrite is 1:2.0-2.2:2.5-3.0:2.0-2.5, and the mass concentration of the above-mentioned aqueous sodium nitrite solution is 15%-20%.
[0019] Preferably, the acid-binding agent is diisopropylethylamine.
[0020] Furthermore, the molar ratio of the above-mentioned compound B, acetyl chloride, and diisopropylethylamine is 1:1.0-1.2:1.1-1.3.
[0021] The beneficial effects of this invention are that it discloses a synthetic method for preparing intermediates of edoxaban. By selecting suitable reaction conditions and reactants, the yield of each step is improved. The entire synthetic process is simple, and the prepared edoxaban intermediate exists in the form of hydrochloride, which has higher stability, is easier to store and use, and its purity can meet the requirements for further preparation of edoxaban. Attached Figure Description
[0022] Figure 1 This is a synthetic route diagram for the intermediates of edoxaban. Detailed Implementation
[0023] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. Where specific conditions are not specified in the embodiments, conventional conditions shall apply; where the manufacturers of reagents or instruments are not specified, they are all conventional products that can be purchased commercially.
[0024] Example 1
[0025] A synthetic method for preparing intermediates of edoxaban, comprising the following steps:
[0026] S1: At room temperature, 666g of isopropanol was added to the reactor, and 113g of N-methyl-4-piperidinone was added to the isopropanol. Stirring was started, and 36.0g of sulfur powder and 8.0g of tetrahydropyrrole were added in sequence. Stirring was continued, and the reaction temperature was controlled at 15℃. 100g of cyanamide was added dropwise, and the reaction was carried out for 4 hours. After the reaction was completed, the solution was concentrated to 30% of the original volume, cooled to crystallization, filtered, and dried at 45℃ to obtain solid compound A with a mass of 148g. The yield of this step was calculated to be 87.4%.
[0027] S2: At room temperature, 825g of water and 550g of 40% hydrobromic acid were added to the reactor and stirred until well mixed. Then, 170g of solid compound A and 140g of solid hypophosphoric acid were added. The reactor was cooled to 0℃ and 1066g of 15% sodium nitrite aqueous solution was added dropwise. The reaction was carried out for 2 hours. After the reaction was completed, the pH of the system was adjusted to 14.1 with 25% sodium hydroxide solution. 500g of dichloromethane was added for extraction and separation. The organic phase was distilled under reduced pressure to obtain compound B. Compound B was a reddish-brown viscous substance with a mass of 110g. The yield of this step was calculated to be 71.3%.
[0028] S3: At room temperature, 500g of dichloromethane, 155g of compound B, and 145g of diisopropylethylamine were added to the reactor. The reaction temperature was controlled at 3℃. 85g of acetyl chloride was added dropwise, and the reaction was allowed to proceed for 2 hours. After the reaction was completed, 500g of water was added for separation. Potassium permanganate solution was added dropwise to the organic phase to adjust the pH to 13.5. The phase was then separated, and the pH of the aqueous phase was adjusted to 2.5. The phase was concentrated, ethanol was added, and the solution was acidified with hydrochloric acid-ethanol solution. The mixture was cooled to allow crystallization, filtered, and dried at 40℃ to obtain the intermediate product of edoxaban. The sample number was Sample 1, and the mass was 220g. The yield of this step was calculated to be 93.7%.
[0029] Example 2
[0030] A synthetic method for preparing intermediates of edoxaban, comprising the following steps:
[0031] S1: At room temperature, 665g of isopropanol was added to the reactor, and 113g of N-methyl-4-piperidinone was added to the isopropanol. Stirring was started, and 32.0g of sulfur powder and 6.0g of tetrahydropyrrole were added in sequence. Stirring was continued, and the reaction temperature was controlled at 20℃. 84g of cyanamide was added dropwise, and the reaction was carried out for 2 hours. After the reaction was completed, the solution was concentrated to 35% of the original volume, cooled to crystallization, filtered, and dried at 50℃ to obtain solid compound A with a mass of 150g. The yield of this step was calculated to be 88.6%.
[0032] S2: At room temperature, 825g of water and 505g of 40% hydrobromic acid were added to the reactor. After stirring and mixing, 170g of solid compound A and 132g of solid hypophosphoric acid were added. The reactor was cooled to 2℃, and 789g of 17.5% sodium nitrite aqueous solution was added dropwise. The reaction was carried out for 1 hour. After the reaction was completed, the pH of the system was adjusted to 14.3 with 25% sodium hydroxide solution. 550g of dichloromethane was added for extraction and separation. The organic phase was distilled under reduced pressure to obtain compound B. Compound B was a reddish-brown viscous substance with a mass of 108g. The yield of this step was calculated to be 70.0%.
[0033] S3: At room temperature, 550g of dichloromethane, 155g of compound B, and 142g of diisopropylethylamine were added to the reactor. The reaction temperature was controlled at 0℃. 78.5g of acetyl chloride was added dropwise, and the reaction was carried out for 4 hours. After the reaction was completed, 600g of water was added for separation. Potassium permanganate solution was added dropwise to the organic phase to adjust the pH to 13.0. After separation, the pH of the aqueous phase was adjusted to 2.0, concentrated, ethanol was added, and the acid was adjusted with hydrochloric acid-ethanol solution. The mixture was cooled to crystallize, filtered, and dried at 35℃ to obtain the intermediate product of edoxaban. The sample number was sample 2, and the mass was 222g. The yield of this step was calculated to be 93.7%.
[0034] Example 3
[0035] A synthetic method for preparing intermediates of edoxaban, comprising the following steps:
[0036] S1: At room temperature, 665g of isopropanol was added to the reactor, and 113g of N-methyl-4-piperidinone was added to the isopropanol. Stirring was started, and 28.0g of sulfur powder and 11.0g of tetrahydropyrrole were added in sequence. Stirring was continued, and the reaction temperature was controlled at 10℃. 92.5g of cyanamide was added dropwise, and the reaction was carried out for 6 hours. After the reaction was completed, the solution was concentrated to 40% of the original volume, cooled to crystallization, filtered, and dried at 48℃ to obtain solid compound A with a mass of 147g. The yield of this step was calculated to be 86.9%.
[0037] S2: At room temperature, 911.3 g of water and 243.0 g of 40% hydrobromic acid were added to the reactor. After stirring and mixing, 170.0 g of solid compound A and 145.0 g of solid hypophosphite were added. The reactor was cooled to -2℃, and 865.0 g of 20% sodium nitrite aqueous solution was added dropwise. The reaction was carried out for 4 hours. After the reaction was completed, the pH of the system was adjusted to 14.5 with 25% sodium hydroxide solution. 600 g of dichloromethane was added for extraction and separation. The organic phase was distilled under reduced pressure to obtain compound B. Compound B was a reddish-brown viscous substance with a mass of 109 g. The yield of this step was calculated to be 70.7%.
[0038] S3: At room temperature, 600g of dichloromethane, 155g of compound B, and 168.0g of diisopropylethylamine were added to the reactor. The reaction temperature was controlled at 5℃. 86.0g of acetyl chloride was added dropwise, and the reaction was carried out for 1 hour. After the reaction was completed, 550g of water was added for separation. Potassium permanganate solution was added dropwise to the organic phase to adjust the pH to 14.0. After separation, the pH of the aqueous phase was adjusted to 3.0, concentrated, ethanol was added, and acid was adjusted with hydrochloric acid-ethanol solution. The mixture was cooled to crystallize, filtered, and dried at 38℃ to obtain the intermediate product of edoxaban. The sample number was sample 3, and the mass was 219g. The yield of this step was calculated to be 93.3%.
[0039] Comparative Example 1
[0040] The implementation process is the same as in Example 1, except that the reaction temperature in step S1 is adjusted to 50°C and the reaction time is controlled to 2 hours. Compound A solid is prepared with a mass of 95g. The yield of this step is calculated to be 56.1%. Subsequent steps are the same as in Example 1, and control product 1 is prepared.
[0041] Comparative Example 2
[0042] The implementation process is the same as in Example 1, except that the reaction temperature in step S1 is adjusted to 0°C and the reaction time is controlled to 6 hours. Compound A solid is prepared with a mass of 50g. The yield of this step is calculated to be 29.5%. Subsequent steps are the same as in Example 1, and control product 2 is prepared.
[0043] The low yield of the sample prepared in step S1 of Comparative Example 2 indicates that the reaction in step S1 is incomplete. Other technical means are needed to improve the yield, such as using a suitable catalyst, extending the reaction time, or appropriately increasing the reaction temperature to shorten the reaction time, thereby improving the yield of this step.
[0044] The yield in this step was too low and the product contained too many impurities, so subsequent synthesis was not carried out.
[0045] Comparative Example 3
[0046] The implementation process is the same as in Example 1, except that step S2 is performed as follows: at room temperature, 1300g of water and 60% sulfuric acid are added to the reactor, along with 170.0g of solid compound A. The subsequent dissolution is the same as in Example 1, and 86g of compound B is obtained. The yield of this step is calculated to be 55.8%. The subsequent steps are the same as in Example 1, and reference standard 3 is obtained.
[0047] Analysis and testing:
[0048] The intermediate sample of edoxaban prepared by high performance liquid chromatography was tested using the following method:
[0049] Instruments: High-performance liquid chromatograph, ultraviolet detector
[0050] Chromatographic conditions:
[0051] C 18 The chromatographic column was 250 mm × 3 mm, 3 μm; the mobile phase A was an aqueous solution containing 0.10 vol% formic acid and 5 mmol / L ammonium formate, and the mobile phase B was an acetonitrile:methanol (80:20, v / v) solution containing 0.10 vol% formic acid, with gradient elution; the flow rate was 1.2 mL / min, the detection wavelength was 285 nm, the column temperature was 40 °C, and the injection volume was 20 μL.
[0052] The test results are shown in Table 1.
[0053] Table 1: Summary of Purity Analysis Results of Idoxaban Intermediate Samples
[0054] Sample Name purity(%) Sample 1 98.69 Sample 2 97.78 Sample 3 98.48 Comparison 1 91.12 Comparison 3 95.46
[0055] As can be seen from the results in Table 1, the samples prepared by this invention have higher purity, reaching up to 98.69%.
Claims
1. A method for synthesizing intermediates for preparing edoxaban, characterized in that, Using N-methyl-4-piperidinone, cyanamide, tetrahydropyrrole, and sulfur powder as reactants, compound A is generated. Compound A dissolves in hydrobromic acid solution and reacts with hypophosphorous acid and sodium nitrite to generate compound B. Compound B reacts with acetyl chloride under the action of an acid-binding agent to generate the intermediate of edoxaban. Compound A is 5-methyl-4,5,6,7-tetrahydro[1,3]thiazo[5,4-c]pyridin-2-amine, with the structural formula [insert structural formula here]. Compound B is 4,5,6,7-tetrahydro-5-methyl-thiazo[5,4-c]pyridine, with the structural formula shown below. ; The intermediate of edoxaban is 5-methyl-4,5,6,7-tetrahydrothiazo[5,4-c]pyridine-2-carboxylic acid hydrochloride, with the structural formula as follows: Molecular weight 234.70; Includes the following steps: S1: At room temperature, N-methyl-4-piperidinone was added to isopropanol, followed by sulfur powder and tetrahydropyrrole. The mixture was stirred and the reaction temperature was controlled at 10 ℃~20 ℃. Monocyanamide was added dropwise and the mixture was stirred. The reaction was carried out for 2 h~6 h. After the reaction was completed, the solution was concentrated to 30%~40% of the original volume, cooled to crystallization, filtered, and dried at 45 ℃~50 ℃ to obtain solid compound A. S2: At room temperature, 40% hydrobromic acid was added to water with a mass of 1.5 times that of 40% hydrobromic acid, compound A solid was added, hypophosphoric acid was added, the temperature was lowered to -2 ℃~2 ℃, sodium nitrite aqueous solution was added dropwise, and the reaction was allowed to proceed for 1 h~4 h. After the reaction was completed, the pH of the system was adjusted to above 14 with sodium hydroxide solution, dichloromethane was added for extraction and separation, and the organic phase was distilled under reduced pressure to obtain compound B; S3: At room temperature, compound B was added to dichloromethane, an acid-binding agent was added, the reaction temperature was controlled at 0 ℃~5 ℃, acetyl chloride was added dropwise, and the reaction was carried out for 1 h~4 h. After the reaction was completed, water was added and the mixture was separated. Potassium permanganate solution was added dropwise to the organic phase to adjust the pH value to 13~14. The mixture was separated, the pH value of the aqueous phase was adjusted to 2~3, the mixture was concentrated, ethanol was added, and the mixture was acidified with hydrochloric acid ethanol solution. The mixture was cooled to crystallize, filtered, and dried at 35 ℃~40 ℃ to obtain the intermediate product of edoxaban.
2. The method for synthesizing an intermediate for preparing edoxaban according to claim 1, characterized in that, The molar ratio of N-methyl-4-piperidinone, cyanamide, sulfur powder, and tetrahydropyrrole is 1:2.0-2.2:0.11-0.14:0.08-0.15, and the sulfur powder is elemental sulfur with a molecular weight of 256.
48.
3. The synthetic method for preparing an intermediate of edoxaban according to claim 1, characterized in that, The molar ratio of the solid compound A, hypophosphorous acid, hydrobromic acid, and sodium nitrite is 1:2.0-2.2:2.5-3.0:2.0-2.5, and the mass concentration of the sodium nitrite aqueous solution is 15%-20%.
4. The method for synthesizing an intermediate for preparing edoxaban according to claim 1, characterized in that, The acid-binding agent is diisopropylethylamine.
5. A method for synthesizing an intermediate for preparing edoxaban according to claim 4, characterized in that, The molar ratio of compound B, acetyl chloride, and diisopropylethylamine is 1:1.0-1.2:1.1-1.3.