Preparation method of dotenorad key intermediate
By using benzothiazole as a starting material, ring-opening, recyclization, acylation, and condensation reactions were carried out, which solved the problems of instability and harsh reaction conditions of 2-aminothiophenol and achieved efficient and safe preparation of key intermediates of dotenorazole, suitable for industrial production.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- JIANGSU YURUI MEDICAL TECH CO LTD
- Filing Date
- 2026-01-26
- Publication Date
- 2026-05-15
AI Technical Summary
In the existing technology, the synthesis of dotenoramide using 2-aminothiophenol as a starting material has problems such as instability, difficulty in controlling impurities, harsh reaction conditions, high cost, and significant safety hazards, making it difficult to meet the requirements of industrial production.
Using benzothiazole as the starting material, key intermediates of dotenorazole are prepared through ring-opening and recyclization, acylation and condensation reactions, using ester solvents and a small amount of catalyst. The reaction process is simple, safe and suitable for industrial production.
It achieves high yield (90%) and high purity (over 99%) of key intermediates of dotenoroxetine, reducing material costs and production risks, and is suitable for industrial applications.
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Figure CN122036643A_ABST
Abstract
Description
Technical Field
[0001] This invention relates to the field of drug synthesis, and in particular to a method for preparing a key intermediate for dotenorolac. Background Technology
[0002] Dotinurad (trade name: Urexa) is a novel, highly selective URAT1 inhibitor used to treat gout with hyperuricemia.1 It promotes uric acid excretion by precisely inhibiting the renal uric acid reabsorption transporter URAT1, while also having a dual regulatory effect of mildly inhibiting uric acid production.
[0003] The structure of dotenorazole is shown below: its chemical name is (3,5-dichloro-4-hydroxyphenyl) (1,1-dioxo-1,2-dihydro-3H-1λ6-1,3-benzothiazol-3-yl) methyl ketone, and its structure is shown in Formula I. The key intermediate of dotenorazole has the chemical name 3-(3,5-dichloro-4-methoxybenzoyl)-2,3-dihydro-1,3-benzothiazolium, and its structure is shown in Formula II.
[0004]
[0005] In the industry, 2-aminobenzylthiophenol or benzothiazoline are often used as starting materials to synthesize dotenororil. However, 2-aminobenzylthiophenol (structure shown in Formula III) is extremely unstable and is prone to degradation in air, producing dimer impurities (structure shown in Formula IV). The purity is significantly affected by the different usage periods after opening and the different storage conditions. It is also unstable during the detection process, and the dimer impurities (structure shown in Formula IV) cannot be accurately detected, making it difficult to effectively control the quality of 2-aminobenzylthiophenol.
[0006]
[0007] For example, the original patent CN102639518B directly uses the condensation of 2-aminothiophenol and formaldehyde, resulting in significant side reactions and insufficient product purity, making it difficult to meet the requirements for the preparation of key intermediates in dotenorazole. Patent application CN119462557A reduces byproducts by generating sodium 2-aminothiophenol through alkalization followed by cyclization, but introduces the highly hazardous reagent sodium hydride (explosive and highly reactive), and the process is cumbersome, posing a high risk for industrialization. Patent application CN119504641A uses solubilizers and activators, and precisely controls the amount of paraformaldehyde (1.0-1.2 equivalents) and the reaction temperature (20-60℃), which improves the yield. However, this method increases material costs and imposes stringent process conditions, limiting its feasibility for large-scale production. Patent application CN120398788A describes reacting 2-aminobenzylthiophenol with formaldehyde in tetrahydrofuran at 70°C for 12 hours to obtain compound 2. However, the described reaction conditions are harsh, the reaction time is long, and concentration and solvent removal are required, significantly increasing production costs. Furthermore, the subsequent synthesis of compound 2 into a key intermediate for dotenorolac requires the addition of a large amount of acid-binding agent, a long reaction time, and the use of highly toxic organic solvents such as toluene and xylene. Therefore, the reported method for preparing the key intermediate for dotenorolac is not an ideal industrial production process. Patent application CN120842167A uses benzothiazoline as a raw material, reducing benzothiazolium with sodium borohydride to prepare benzothiazoline. Sodium borohydride is a high-risk reagent, generating hydrogen gas during production, resulting in a violent reaction and serious safety hazards. Additionally, the patent report states that the purity of the reduced benzothiazoline is only 85%, with numerous reaction impurities, which is detrimental to subsequent reactions.
[0008] Therefore, developing a green, safe, simple, and efficient synthetic method for dotenorazole key intermediates, overcoming the aforementioned problems in the preparation of dotenorazole key intermediates using 2-aminothiophenol or benzothiazoline compounds as starting materials, reducing byproducts and impurities, increasing yield, and lowering material costs is the future development direction of the dotenorazole API market. Summary of the Invention
[0009] To address the technical problems existing in the prior art, this invention provides a method for preparing a key intermediate of dotenorazole. This invention uses benzothiazole as the starting material, and sequentially performs ring-opening and recyclization, acylation, and condensation to synthesize the key intermediate of dotenorazole, 3-(3,5-dichloro-4-methoxybenzoyl)-2,3-dihydro-1,3-benzothiazole. The starting materials in this invention are readily available and highly stable. The process involves multiple steps with continuous feeding, and the compounds involved react directly and continuously in solution form. The operation is simple, green, and safe, making it particularly suitable for industrial production. During the reaction, an ester solvent (ethyl acetate or isopropyl acetate) is used. The condensation reaction in step 4 requires only a small amount of catalyst to react with compound 3 to obtain the key intermediate of dotenorazole, without the need for excessive acid-binding agents. Furthermore, the overall yield of the obtained key intermediate of dotenorazole is as high as 90%, with a purity of over 99%.
[0010] To achieve the above-mentioned objectives, the present invention provides the following technical solution:
[0011] A method for preparing a key intermediate of dotenorazole, the reaction route is as follows:
[0012]
[0013] Specifically, it includes the following steps:
[0014] Step 1: Using benzothiazole SM1 as the starting material, a ring-opening reaction is carried out in an alkaline aqueous solution under heating conditions to prepare an aqueous phase containing compound 1.
[0015] Step 2: In the aqueous solution containing compound 1 from step 1, paraformaldehyde and solvent are added to prepare an organic phase containing compound 2 by reaction.
[0016] Step 3: React compound SM2 with thionyl chloride in a solvent under heating conditions to generate a solution containing compound 3.
[0017] Step 4: The organic phase containing compound 2 obtained in step 2 and the reaction solution of compound 3 obtained in step 3 undergo a condensation reaction under the action of a catalyst. After separating the aqueous phase and concentrating to remove the organic phase, isopropanol is added for slurry purification to prepare the dotenoroxetine key intermediate.
[0018] Preferably, in step 1, the molar ratio of compound SM1 to the base is 1.0:2.0-5.0, more preferably 1:(2~3); the base is potassium hydroxide or sodium hydroxide, more preferably potassium hydroxide; the reaction temperature is 80-100℃, more preferably 85-95℃; and the reaction time is 6h-12h, more preferably 10h-12h.
[0019] Preferably, in step 2, the molar ratio of compound 1 to paraformaldehyde is 1.0:1.5-3.0, more preferably 1:1.5-2.0; the organic solvent is ethyl acetate or isopropyl acetate, more preferably isopropyl acetate; the reaction temperature is 0-30℃, more preferably 0-10℃; and the reaction time is 1h-4h, more preferably 3h.
[0020] Preferably, in step 3, the molar ratio of compound SM2 to thionyl chloride is 1.0:1.0-1.5, more preferably 1.0:1.2-1.4; the solvent is ethyl acetate or isopropyl acetate, more preferably isopropyl acetate; the reaction temperature is 50-70℃, more preferably 60-70℃; and the reaction time is 1h-4h, more preferably 3h.
[0021] Preferably, in step 4, the molar ratio of compound 2 to catalyst is 1.0:0.2-0.5; more preferably 1.0:0.2-0.3; the catalyst is lithium chloride, magnesium chloride, or zinc chloride, preferably lithium chloride; the reaction temperature is 20-50℃, preferably 40-50℃; and the reaction time is 1h-3h, preferably 2h.
[0022] Beneficial effects: The raw materials used in the preparation process of this invention are readily available and highly stable. The intermediate processes involve continuous feeding in the form of reaction liquid, eliminating the need for separation and purification. The operation is simple, green, and safe, making it particularly suitable for industrial production. Step 4 does not require the addition of excessive acid-binding agents; only a small amount of catalyst is needed. The key intermediate of polytenoxanone can be obtained in 1-3 hours of reaction, with a total yield of up to 90% and a purity of over 99%. It is suitable for large-scale industrial production. Attached Figure Description
[0023] Figure 1 This is a synthetic route diagram of the key intermediate of dotenoroxetine in this invention;
[0024] Figure 2 The HPLC chromatogram of compound 2 obtained in Example 1 is shown below.
[0025] Figure 3 The hydrogen nuclear magnetic resonance spectrum of compound 2 obtained in Example 1;
[0026] Figure 4 This is an HPLC chromatogram of the key intermediate of dotenorazole obtained in Example 1;
[0027] Figure 5 The hydrogen nuclear magnetic resonance spectrum of the key intermediate of dotenoroxetine obtained in Example 1;
[0028] Figure 6 The HPLC chromatogram of compound 2 obtained in Example 2 is shown below.
[0029] Figure 7The HPLC chromatogram of the key intermediate of dotenorazole obtained in Example 2. Detailed Implementation
[0030] The technical solutions of this invention will be clearly and thoroughly described below with reference to the embodiments thereof. Obviously, the described embodiments are merely a part of the embodiments of this invention, and not all of them. All other embodiments obtained by those skilled in the art based on the embodiments of this invention without creative effort are within the scope of protection of this invention.
[0031] Example 1
[0032] A method for preparing a key intermediate of dotenoroxetine includes the following steps:
[0033] (1) Synthesis of compound 1
[0034] Add benzothiazole SM1 (60g, 0.44mol), water (300ml), and potassium hydroxide (62.25g, 1.1mol) to the reaction flask. Turn on the stirrer and heat to 90-95℃. Keep the temperature and stir for 10h. Cool down to below 20℃, add 300ml of isopropyl acetate, stir for 10min, separate the liquids, and collect the aqueous phase containing compound 1. Use it directly for the next step of synthesis.
[0035] (2) Synthesis of compound 2
[0036] In the solution of compound 1 obtained in step (1), 500 ml of isopropyl acetate was added, followed by paraformaldehyde (19.8 g, 0.66 mol). The mixture was kept at 0-5 °C for 3 h, then allowed to stand and separated. The organic phase was collected, and the solution of compound 2 was obtained. This solution was then directly used for the next reaction, with a purity of 98.8% (purity results are shown in the figure). Figure 2 (As shown).
[0037] After concentrating the solution of compound 2, the 1H NMR spectrum is as follows: Figure 3 As shown, 1 H NMR (CDCl3, 400MHz) δ: 7.11-7.09 (m, 2H), 6.99-6.95 (m, 2H), 6.78-6.74 (m, 2H), 6.65-6.63 (m, 2H), 4.82 (s, 4H), 4.55 (s, 2H).
[0038] (3) Synthesis of compound 3
[0039] Add 3,5-dichloro-4-methoxybenzoic acid (compound SM2, 79 g, 0.4 mol), 500 ml of isopropyl acetate, and thionyl chloride (57 g, 0.48 mol) to the reaction flask, heat to 60-65℃, react for 3 h, concentrate at 60℃ to remove 250 ml of isopropyl acetate, and then proceed directly to the next step of the reaction with the remaining compound 3 solution.
[0040] (4) Synthesis of key intermediates of dotenororai
[0041] The organic phase of compound 2 obtained in step 2 was added to the reaction flask, along with 800 ml of water and lithium chloride (3.4 g, 0.08 mol). Stirring was started, and the reaction solution of compound 3 obtained in step 3 was slowly added dropwise at room temperature. After the addition was complete, the temperature was raised to 40-45°C and the reaction was maintained for 2 hours. After the reaction was complete, the mixture was allowed to stand and separated. The aqueous phase was removed, and 500 ml of isopropyl acetate was concentrated to remove the aqueous phase. 500 ml of isopropanol was added for purification, and the mixture was stirred at 60°C for 2 hours. The temperature was then lowered to 5°C and stirring was continued for 1 hour. The mixture was then filtered, and the filter cake was collected and dried to obtain 122.5 g of the key intermediate of dotenoroxetine, with a yield of 90% and a purity of 99.8% (purity results are shown in the figure). Figure 4 (As shown).
[0042] The NMR spectrum of the obtained dotenororil key intermediate is as follows: Figure 5 As shown, 1 H NMR (DMSO-d6, 400MHz) δ: 7.79 (m, 2H), 7.64 (br, 1H), 7.36-7.34 (m, 1H), 7.13-7.07 (m, 2H), 5.33 (s, 2H), 3.89 (s, 3H).
[0043] Example 2
[0044] A method for preparing a key intermediate of dotenoroxetine includes the following steps:
[0045] (1) Synthesis of Compound 1 solution
[0046] Add benzothiazole SM1 (50g, 0.37mol), water (300ml), and potassium hydroxide (62.3g, 1.11mol) to the reaction flask. Turn on the stirrer and heat to 85-90℃. Keep the temperature and stir for 12h. Cool down to below 20℃, add 300ml of isopropyl acetate, stir for 10min, separate the liquid and collect the aqueous phase to obtain the solution of compound 1, which can be used directly for the next step of synthesis.
[0047] (2) Synthesis of compound 2
[0048] In the aqueous phase containing compound 1 obtained above, 500 ml of isopropyl acetate was added, followed by paraformaldehyde (22.2 g, 0.74 mol). The mixture was kept at 5-10 °C for 3 hours. After standing and separation, the organic phase was collected, and the resulting solution of compound 2 was directly used for the next reaction. The purity was 98.2% (purity results are shown in the figure). Figure 6 (As shown).
[0049] (3) Synthesis of compound 3
[0050] Add 3,5-dichloro-4-methoxybenzoic acid (compound SM2, 73.6 g, 0.33 mol), 500 ml of isopropyl acetate, and 55 g of thionyl chloride (0.46 mol) to the reaction flask. Heat to 65-70 °C and react for 3 h. After removing 250 ml of isopropyl acetate by concentration at 60 °C, the remaining compound 3 solution is directly used for the next reaction.
[0051] (4) Synthesis of key intermediates of dotenororai
[0052] Add the aqueous phase containing compound 2 obtained in step (2) to the reaction flask, add 800 ml of water, lithium chloride (4.23 g, 0.1 mol), and start stirring. Slowly add the solution of compound 3 dropwise at room temperature. After the addition is complete, raise the temperature to 45-50℃ and keep the reaction at this temperature for 2 h. After the reaction is complete, let it stand and separate the liquids. Discard the aqueous phase, concentrate and remove 500 ml of isopropyl acetate, add 500 ml of ethanol, and stir at 60℃ for 2 h. Then cool to 5℃ and continue stirring for 1 h. Filter, collect the filter cake and dry to obtain 102.2 g of dotenoradine key intermediate, with a yield of 91% and a purity of 99.7% (purity results are as follows). Figure 7 (As shown).
[0053] The results of the above examples demonstrate that the method for preparing a key intermediate of dotenorazole provided by this invention uses benzothiazole as the starting material, and sequentially performs ring-opening and recyclization, acylation, and condensation to synthesize the key intermediate 3-(3,5-dichloro-4-methoxybenzoyl)-2,3-dihydro-1,3-benzothiazole. The raw materials used in the preparation process of this invention are readily available and highly stable. The operation involves multiple steps with continuous feeding, and the compounds involved react directly and continuously in solution form. The operation is simple, green, and safe, making it particularly suitable for industrial production. The overall yield of the obtained key intermediate of dotenorazole is as high as 90%, with a purity of over 99%.
[0054] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.
Claims
1. A method for preparing a key intermediate of dotenoroxetine, characterized in that, Includes the following steps: ； (1) Using benzothiazole SM1 as the starting material, a ring-opening reaction occurs in an alkaline aqueous solution, and an aqueous phase containing compound 1 is obtained by separation. (2) Add paraformaldehyde and solvent to an aqueous solution containing compound 1, react, let stand and separate the liquid to prepare an organic phase containing compound 2; (3) Compound SM2 is reacted with thionyl chloride in a solvent to generate a reaction solution containing compound 3; (4) The organic phase containing compound 2 obtained in step (2) and the reaction liquid containing compound 3 obtained in step (3) are subjected to a condensation reaction under the action of a catalyst. The aqueous phase is removed by separation, the organic phase is removed by concentration, and isopropanol is added for slurry purification to prepare the key intermediate of dotenorazole, 3-(3,5-dichloro-4-methoxybenzoyl)-2,3-dihydro-1,3-benzothiazole.
2. The method for preparing a key intermediate of dotenorazole according to claim 1, characterized in that, In step (1), the molar ratio of benzothiazole SM1 to the base is 1.0:2.0-5.0; the base is potassium hydroxide or sodium hydroxide; the reaction temperature is 80-100℃, and the reaction time is 6h-12h.
3. The method for preparing a key intermediate of dotenorazole according to claim 1, characterized in that, In step (2), the molar ratio of compound 1 to paraformaldehyde is 1.0:1.5-3.0; the solvent is ethyl acetate or isopropyl acetate; the reaction temperature is 0-30℃ and the reaction time is 1h-4h.
4. The method for preparing a key intermediate of dotenorazole according to claim 1, characterized in that, In step (3), the molar ratio of compound SM2 to thionyl chloride is 1.0:1.0-1.5; the solvent is ethyl acetate or isopropyl acetate; the reaction temperature is 50-70℃ and the reaction time is 1h-4h.
5. The method for preparing a key intermediate of dotenorazole according to claim 1, characterized in that, In step (4), the molar ratio of compound 2 to catalyst is 1.0:0.2-0.5; the catalyst is lithium chloride, magnesium chloride or zinc chloride; the reaction temperature is 20-50℃ and the reaction time is 1h-3h.