A method for synthesizing a multiple tinoform intermediate
Dotenoraz intermediates were directly synthesized by reacting compound 1 with pivaloyl chloride or pivaloyl anhydride in an alkaline environment and organic solvent. This method solves the problems of high equipment requirements and environmental pollution in existing technologies, and achieves high yield and high purity synthesis results, making it suitable for industrial production.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- HANGZHOU SHANLI BIOMEDICAL TECH CO LTD
- Filing Date
- 2024-09-27
- Publication Date
- 2026-07-07
AI Technical Summary
Existing methods for synthesizing dotenororil suffer from problems such as high equipment requirements, difficulty in scale-up operations, serious environmental pollution, low yield and purity, and are not suitable for industrial production.
Compound 2 is obtained directly by reacting compound 1 with pivaloyl chloride or pivalic anhydride without post-treatment. Compound 4 is obtained directly by reacting compound 1 with compound 3, simplifying the operation. The reaction is carried out in an alkaline environment and organic solvent, with the reaction temperature and time controlled between 0 and 40 °C. Post-treatment involves cooling, concentration, and layer purification to obtain the target product.
This method enables the synthesis of dotenoroxetine intermediates with high yield and high purity, simplifies the operation process, reduces raw material costs, and is suitable for industrial production.
Smart Images
Figure CN119241468B_ABST
Abstract
Description
Technical Field
[0001] This invention relates to the field of pharmaceutical intermediate synthesis technology, and in particular to a method for synthesizing a dotenoroxetine intermediate. Background Technology
[0002] Dotinurad, also known as dotinuride, has the chemical name (3,5-dichloro-4-hydroxyphenyl)(1,1-dioxide-3(2H)-benzothiazolyl) methyl ketone, and its structural formula is as follows:
[0003]
[0004] Dotinurad is an oral tablet jointly developed by Fuji Yakuhin Pharmaceutical and Mochida Pharmaceutical in Japan for the treatment of certain types of hyperuricemia and gout. Dotinurad was approved for marketing by the Pharmaceuticals and Medical Devices Agency (PMDA) of Japan on January 23, 2020, under the brand name URECE. This drug is a urate reabsorption inhibitor that targets and inhibits the activity of the urate reabsorption transporter (URAT1). By selectively inhibiting the urate reabsorption transporter (URAT1) in the kidneys, it inhibits urate reabsorption and lowers uric acid levels in the blood.
[0005] Currently, dotenoroxetine has the following synthetic methods:
[0006] Method 1: Patent CN102639518B reports the synthetic route and preparation method of dotenorad. The basic synthetic idea is to condense 2-aminobenzylthiol with formaldehyde to obtain benzothiazole, which then undergoes an amidation reaction with a hydroxyl-protected side chain benzoyl chloride to obtain a hydroxyl-protected benzothiazole benzamide intermediate. This intermediate can be used to obtain the target compound dotenorad through oxidation of a thioether and deprotection of the hydroxyl group. The reaction route is as follows:
[0007]
[0008] This reaction route involves the preparation of acyl chlorides, which requires sophisticated equipment and is difficult to scale up. Furthermore, the large-scale use of thionyl chloride generates waste that pollutes the environment, while the yield and purity are also low.
[0009] Method 2: Patent CN111675675A reports a method for synthesizing dotenord, using 2-aminobenzylthiol as a starting material, and synthesizing the target product dotenord through acylation, diiodomethyl cyclization, and oxidation reactions. The reaction route is as follows:
[0010]
[0011] This route uses acyl chloride for amidation, which is highly exothermic and has poor stability, making it unsuitable for industrial production. Furthermore, this route uses diiodomethane as a cyclizing agent, which is easily decomposed in air, highly toxic, and releases toxic iodide fumes when burned, making it unsuitable for industrial production.
[0012] Method 3: Patent CN111662247A reports a method for synthesizing dotenord, using 2,3-dihydrobenzothiazole as a starting material, and synthesizing the target product dotenord through oxidation and condensation reactions. The reaction route is as follows:
[0013]
[0014] The conventional condensing agents used in this route are difficult to use to achieve condensation.
[0015] Method 4: Patent CN111793039A reports a method for synthesizing dotenord, using 2-aminobenzylthiol as a starting material, and synthesizing the target product dotenord through condensation, cyclization, and oxidation reactions. The reaction route is as follows:
[0016]
[0017] The conventional condensing agents used in this route are difficult to use to achieve condensation. Summary of the Invention
[0018] The present invention aims to overcome the aforementioned problems in existing methods for preparing dotenoroxetine and provides a method for synthesizing dotenoroxetine intermediates. The method of the present invention has mild conditions, is simple to operate, and is suitable for industrial production.
[0019] To achieve the above objectives, the present invention adopts the following technical solution:
[0020] A synthetic method for a dotenorfed intermediate, the reaction route is as follows:
[0021]
[0022] This invention allows for the direct reaction of compound 1 with pivaloyl chloride or pivalic anhydride to obtain compound 2, without the need for post-processing. Compound 4 can be directly added to compound 3 to obtain compound 4, thus avoiding the deprotection step in existing methods for synthesizing dotenoroxetine intermediates and simplifying the operation. Furthermore, the reaction route of this invention has a high reaction yield and uses simple raw materials, all of which are readily available. Compared with existing technologies, the method of this invention is more economical and more suitable for industrial production.
[0023] Preferably, in step (1), the molar ratio of compound 1 to pivaloyl chloride or pivaloyl anhydride is 1 to 1:2.
[0024] Preferably, in step (1), compound 1 reacts with pivaloyl chloride or pivaloic anhydride in an alkaline environment.
[0025] Preferably, the alkaline environment is formed by adding an alkaline substance; the alkaline substance is one or more of triethylamine, DIEA, pyridine, potassium carbonate, and sodium carbonate.
[0026] Preferably, the molar ratio of compound 1 to the alkaline substance is 1:1 to 8.
[0027] Preferably, the molar ratio of compound 2 to compound 3 in step (2) is 1:2 to 4.
[0028] Preferably, the reactions in steps (1) and (2) are carried out in an organic solvent.
[0029] Preferably, the organic solvent is one or more of acetonitrile, dichloromethane, chloroform, tetrahydrofuran, and 1,4-dioxane.
[0030] Preferably, the reaction temperature in steps (1) and (2) is 0–40°C and the reaction time is 1–5 h.
[0031] Preferably, the reactions in steps (1) and (2) are carried out under nitrogen protection.
[0032] Preferably, after obtaining compound 4 in step (2), the product is post-processed. The post-processing method is as follows: the reaction product is cooled and concentrated, then ethyl acetate and water are added, the mixture is stirred to separate the layers, the organic layer is dried and concentrated, and then purified with ethanol to obtain the processed product. The post-processing of the reaction in this invention is simple and does not require column chromatography, making it more economical and suitable for industrial production compared with existing technologies.
[0033] Therefore, the present invention has the following beneficial effects: the present invention provides a new route for the preparation of dotenoroxetine intermediates; the reaction route of the present invention has a high reaction yield and uses simple raw materials; the post-processing of the reaction is simple and does not require column chromatography; and the raw materials required by the route of the present invention are relatively easy to obtain. Compared with the prior art, the method of the present invention is more economical and more suitable for industrial production. Detailed Implementation
[0034] The present invention will be further described below with reference to specific embodiments.
[0035] In this invention, unless otherwise specified, all equipment and raw materials are commercially available or commonly used in the industry. The methods described in the following embodiments, unless otherwise specified, are conventional methods in the art. In cases where the Chinese nomenclature of a compound conflicts with its structural formula, the structural formula shall prevail, except where the structural formula is obviously incorrect.
[0036] General Implementation Examples:
[0037] A synthetic method for a dotenorfed intermediate, the reaction route is as follows:
[0038]
[0039] In one specific implementation, the molar ratio of compound 1 to pivaloyl chloride or pivaloyl anhydride in step (1) is 1 to 1:2.
[0040] In one specific implementation, in step (1), compound 1 reacts with pivaloyl chloride or pivaloic anhydride in an alkaline environment.
[0041] In one specific embodiment, the alkaline environment is formed by adding an alkaline substance; the alkaline substance is one or more of triethylamine, DIEA, pyridine, potassium carbonate, and sodium carbonate; preferably pyridine.
[0042] In one specific implementation, the molar ratio of compound 1 to the alkaline substance is 1:1 to 8.
[0043] In one specific implementation, the molar ratio of compound 2 to compound 3 in step (2) is 1:2 to 4.
[0044] In one specific implementation, the reactions in steps (1) and (2) are carried out in an organic solvent.
[0045] In one specific embodiment, the organic solvent is one or more of acetonitrile, dichloromethane, chloroform, tetrahydrofuran, and 1,4-dioxane.
[0046] In one specific implementation, the reaction temperature of steps (1) and (2) is 0 to 40°C, preferably 0 to 10°C; and the reaction time is 1 to 5 hours.
[0047] In one specific implementation, the reactions in steps (1) and (2) are carried out under nitrogen protection.
[0048] As a specific implementation method, after obtaining compound 4 in step (2), the product is post-processed. The post-processing method is as follows: the reaction product is cooled and concentrated, then ethyl acetate and water are added, the mixture is stirred to separate into layers, the organic layer is dried and concentrated, and then purified with ethanol to obtain the processed product.
[0049] This invention allows for the direct reaction of compound 1 with pivaloyl chloride or pivalic anhydride to obtain compound 2, without the need for post-processing. Compound 4 can be directly added to compound 3 to obtain compound 4, thus avoiding the deprotection step in existing methods for synthesizing dotenoroxetine intermediates and simplifying the operation. Furthermore, the reaction route of this invention has a high reaction yield and uses simple raw materials, all of which are readily available. Compared with existing technologies, the method of this invention is more economical and more suitable for industrial production.
[0050] Example 1:
[0051] A method for synthesizing a dotenoroxetine intermediate, comprising the following steps:
[0052] (1) Add 2.0 g (9.66 mmol) of compound 1 to a three-necked flask, add 40 mL of acetonitrile, then add 2.29 g (28.9 mmol) of pyridine, cool to 0 °C under nitrogen protection, add 1.51 g (12.5 mmol) of pentanoyl chloride dropwise, and stir at 0 °C for 1 h.
[0053] (2) Dissolve 2.65 g (19.3 mmol) of compound 3 in 14 mL of acetonitrile, and then add it to the reaction product of step (1). Stir at 0 °C for 1 h.
[0054] (3) After the reaction of the raw materials was basically complete, the mixture was cooled and concentrated. The residue was added to ethyl acetate and water, stirred and separated into layers. The organic layer was dried and concentrated. The residue was purified with ethanol to obtain about 2.68 g of off-white solid. ¹H NMR (300 MHz, DMSO-d6) δ 7.79 (s, 2H), 7.72-7.47 (br, 1H), 7.43-7.31 (m, 1H), 7.19-7.03 (m, 2H), 5.34 (s, 2H). MS: 325.98 (M+H).
[0055] Example 2:
[0056] A method for synthesizing a dotenoroxetine intermediate, comprising the following steps:
[0057] (1) Add 2.0 g (9.66 mmol) of compound 1 to a three-necked flask, add 40 mL of acetonitrile, then add 6.11 g (77.2 mmol) of pyridine, cool to 0 °C under nitrogen protection, add 1.51 g (12.5 mmol) of pentanoyl chloride dropwise, and stir at 0 °C for 1 h.
[0058] (2) Dissolve 1.33 g (9.66 mmol) of compound 3 in 14 mL of acetonitrile, and then add it to the reaction product of step (1). Stir at 0 °C for 1 h.
[0059] (3) After the reaction of the raw materials was basically complete, the mixture was cooled and concentrated. The residue was added to ethyl acetate and water, stirred and separated into layers. The organic layer was dried and concentrated. The residue was purified with ethanol to obtain about 2.00 g of off-white solid. ¹H NMR (300 MHz, DMSO-d6) δ 7.79 (s, 2H), 7.72-7.47 (br, 1H), 7.43-7.31 (m, 1H), 7.19-7.03 (m, 2H), 5.34 (s, 2H). MS: 325.98 (M+H).
[0060] Example 3:
[0061] A method for synthesizing a dotenoroxetine intermediate, comprising the following steps:
[0062] (1) Add 2.0 g (9.66 mmol) of compound 1 to a three-necked flask, add 40 mL of acetonitrile, then add 2.06 g (15.9 mmol) of DIEA, cool to 0 °C under nitrogen protection, add 1.51 g (12.5 mmol) of pentanoyl chloride dropwise, and stir at 0 °C for 1 h.
[0063] (2) Dissolve 2.65 g (19.3 mmol) of compound 3 in 14 mL of acetonitrile, and then add it to the reaction product of step (1). Stir at 0 °C for 1 h.
[0064] (3) After the reaction of the raw materials was basically complete, the mixture was cooled and concentrated. The residue was added to ethyl acetate and water, stirred and separated into layers. The organic layer was dried and concentrated. The residue was purified with ethanol to obtain about 2.56 g of off-white solid. ¹H NMR (300 MHz, DMSO-d6) δ 7.79 (s, 2H), 7.72-7.47 (br, 1H), 7.43-7.31 (m, 1H), 7.19-7.03 (m, 2H), 5.34 (s, 2H). MS: 325.98 (M+H).
[0065] Example 4:
[0066] (1) Add 2.0 g (9.66 mmol) of compound 1 to a three-necked flask, add 40 mL of acetonitrile, then add 1.32 g (16.7 mmol) of pyridine, cool to 0 °C under nitrogen protection, add 1.51 g (12.5 mmol) of pentanoyl chloride dropwise, and stir at 0 °C for 1 h.
[0067] (2) Dissolve 3.98 g (28.98 mmol) of compound 3 in 14 mL of acetonitrile, and then add it to the reaction product of step (1). Stir at 0 °C for 1 h.
[0068] (3) After the reaction of the raw materials was basically complete, the mixture was cooled and concentrated. The residue was added with ethyl acetate and water, stirred to separate the layers, dried the organic layer, concentrated, and purified with ethanol to obtain about 2.71 g of off-white solid. ¹H NMR (300 MHz, DMSO-d6) δ 7.79 (s, 2H), 7.72–7.47 (br, 1H), 7.43–7.31 (m, 1H), 7.19–7.03 (m, 2H), 5.34 (s, 2H). MS: 325.98 (M+H).
[0069] Example 5:
[0070] (1) Add 2.0 g (9.66 mmol) of compound 1 to a three-necked flask, add 40 mL of acetonitrile, then add 1.32 g (16.7 mmol) of pyridine, cool to 0 °C under nitrogen protection, add 1.51 g (12.5 mmol) of pentanoyl chloride dropwise, and stir at 25 °C for 1 h.
[0071] (2) Dissolve 3.98 g (29.98 mmol) of compound 3 in 14 mL of acetonitrile, and then add it to the reaction product of step (1). Stir at 35 °C for 1 h.
[0072] (3) After the reaction of the raw materials was basically complete, the mixture was cooled and concentrated. The residue was added to ethyl acetate and water, stirred and separated into layers. The organic layer was dried and concentrated. The residue was purified with ethanol to obtain about 2.64 g of off-white solid. ¹H NMR (300 MHz, DMSO-d6) δ 7.79 (s, 2H), 7.72-7.47 (br, 1H), 7.43-7.31 (m, 1H), 7.19-7.03 (m, 2H), 5.34 (s, 2H). MS: 325.98 (M+H).
[0073] Example 6:
[0074] (1) Add 2.0 g (9.66 mmol) of compound 1 to a three-necked flask, add 40 mL of acetonitrile, then add 1.32 g (19.32 mmol) of pyridine, cool to 0 °C under nitrogen protection, add 2.33 g (19.32 mmol) of pentanoic anhydride dropwise, and stir at 25 °C for 1 h;
[0075] (2) Dissolve 3.98 g (29.98 mmol) of compound 3 in 14 mL of acetonitrile, and then add it to the reaction product of step (1). Stir at 30 °C for 1 h.
[0076] (3) After the reaction of the raw materials was basically complete, the mixture was cooled and concentrated. The residue was added to ethyl acetate and water, stirred to separate the layers, dried the organic layer, concentrated, and purified with ethanol to obtain approximately 2.47 g of an off-white solid. ¹H NMR (300 MHz, DMSO-d6) δ 7.79 (s, 2H), 7.72–7.47 (br, 1H), 7.43–7.31 (m, 1H), 7.19–7.03 (m, 2H), 5.34 (s, 2H). MS: 325.98 (M+H).
[0077] The yield and purity of the products obtained in the above embodiments were detected and calculated, and the results are shown in Table 1.
[0078] Table 1: Results of product yield and purity tests.
[0079] project Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Yield (%) 85.08％ 63.49％ 81.27％ 86.03％ 83.14％ 78.41％ purity(%) 98.49％ 98.99％ 98.73％ 99.08％ 98.89％ 99.16％
[0080] As can be seen, the reaction route of the present invention used in the embodiments can achieve high product yield and purity with simple post-processing steps. The raw materials used are simple. Compared with the prior art, the method of the present invention is more economical and more suitable for industrial production.
[0081] It should be noted that the above content merely illustrates the technical concept of the present invention and should not be construed as limiting the scope of protection of the present invention. For those skilled in the art, various improvements and modifications can be made without departing from the principle of the present invention, and all such improvements and modifications fall within the scope of protection of the claims of the present invention.
Claims
1. A method for synthesizing a dotenorphine intermediate, characterized in that, The reaction route is as follows: 。 2. The method for synthesizing the dotenorphine intermediate according to claim 1, characterized in that, In step (1), the molar ratio of compound 1 to pivaloyl chloride or pivaloyl anhydride is 1:1 to 1:
2.
3. The method for synthesizing the dotenororic intermediate according to claim 1 or 2, characterized in that, In step (1), compound 1 reacts with pivaloyl chloride or pivaloyl anhydride in an alkaline environment.
4. The method for synthesizing the dotenororai intermediate according to claim 3, characterized in that, The alkaline environment is formed by adding an alkaline substance; the alkaline substance is one or more of triethylamine, DIEA, pyridine, potassium carbonate, and sodium carbonate.
5. The method for synthesizing the dotenororai intermediate according to claim 4, characterized in that, The molar ratio of compound 1 to the alkaline substance is 1:1~8.
6. The method for synthesizing the dotenororui intermediate according to claim 1, characterized in that, In step (2), the molar ratio of compound 2 to compound 3 is 1:2~4.
7. The method for synthesizing the dotenororui intermediate according to claim 1, characterized in that, The reactions in steps (1) and (2) are carried out in an organic solvent; the organic solvent is one or more of acetonitrile, dichloromethane, chloroform, tetrahydrofuran, and 1,4-dioxane.
8. The method for synthesizing the dotenororui intermediate according to claim 1, characterized in that, Steps (1) and (2) are carried out under nitrogen protection, with a reaction temperature of 0~40℃ and a reaction time of 1~5h.
9. The method for synthesizing the dotenororui intermediate according to claim 1, characterized in that, After obtaining compound 4 in step (2), the product is post-processed. The post-processing method is as follows: the reaction product is cooled and concentrated, then ethyl acetate and water are added, the mixture is stirred and separated into layers, the organic layer is dried and concentrated, and then purified with ethanol to obtain the processed product.