Synthesis method of dotenorad intermediate

Abstract

The invention relates to the field of synthesis of bulk drug intermediates, and discloses a synthesis method of a dotenorad intermediate, the reaction route is as follows: # imgabs0 #, the invention provides a new route for preparing the dotenorad intermediate, the reaction route is high in reaction yield, and the used raw materials are simple; post-treatment of the reaction is simple, and column chromatography is not needed; and by adopting the route of the invention, the required raw materials are easy to obtain, and compared with the prior art, the method disclosed by the invention is more economical and more suitable for industrial production.

Description

Technical Field

[0001] The invention relates to the technical field of raw material drug intermediate synthesis, and in particular to a method for synthesizing a polytinoride intermediate. Background Art

[0002] Dotinurad, also known as Dotinurad, has a chemical name of (3,5-dichloro-4-hydroxyphenyl)(1,1-dioxide-3(2H)-benzothiazolyl)methanone, and has the following structural formula:

[0003] Dotinurad is an oral tablet jointly developed by Fuji Yakuhin and Mochida Pharmaceuticals of Japan for the treatment of some hyperuricemia and gout. Dotinurad was approved for marketing by the Pharmaceuticals and Medical Devices Agency (PMDA) of Japan on January 23, 2020, under the trade name URECE. The drug is a urate reabsorption inhibitor that can target and inhibit the activity of the urate reabsorption transporter (URAT1). By selectively inhibiting the transporter protein (URAT1) for uric acid reabsorption in the kidney, uric acid reabsorption is inhibited and uric acid levels in the blood are reduced.

[0004] Currently, there are the following synthesis methods for dotinorex: Method 1: Patent CN102639518B reports the synthesis route and preparation method of polytenol; its basic synthesis idea is to prepare benzothiazole by condensation of 2-aminobenzenethiol and formaldehyde, and then benzothiazole undergoes amidation reaction with hydroxyl-protected side chain benzoyl chloride to prepare hydroxyl-protected benzothiazole benzamide intermediate. The intermediate can be obtained by oxidation of thioether and deprotection of hydroxyl to obtain the target compound polytenol. Its reaction route is as follows:

[0005] This reaction route involves the preparation of acyl chloride, which has high requirements on equipment and is difficult to scale up. In addition, the large amount of use of dichlorothionyl produces three wastes that pollute the environment, and the yield and purity are low.

[0006] Method 2: Patent CN111675675A reports a method for synthesizing polytetracycline, using 2-aminobenzenethiol as the starting material, and synthesizing the target product polytetracycline through acylation, diiodoform ring closure reaction and oxidation reaction. The reaction route is as follows:

[0007] This route uses acyl chloride for amidation reaction, which is highly exothermic and has poor stability, making it unsuitable for industrial production. In addition, this route uses diiodomethane as a cyclization reagent, which is easily decomposed in the air and is highly toxic. Its combustion releases toxic iodide fumes, making it unsuitable for industrial production.

[0008] Method 3: Patent CN111662247A reports a method for synthesizing polytetracycline, which uses 2,3-dihydrobenzothiazole as the starting material and synthesizes the target product polytetracycline through oxidation and condensation reactions. The reaction route is as follows:

[0009] The conventional condensation agent used in this route is difficult to achieve condensation.

[0010] Method 4: Patent CN111793039A reports a method for synthesizing polytetracycline, which uses 2-aminobenzenethiol as the starting material and synthesizes the target product polytetracycline through condensation, cyclization and oxidation reactions. The reaction route is as follows:

[0011] The conventional condensation agent used in this route is difficult to achieve condensation. Summary of the invention

[0012] The present invention aims to overcome the above-mentioned problems existing in the prior art preparation method of polytinol, and provides a method for synthesizing a polytinol intermediate. The method of the present invention has mild conditions, simple operation and is suitable for industrial production.

[0013] In order to achieve the above object, the present invention adopts the following technical solutions: A method for synthesizing a polytinol intermediate, the reaction route is as follows:

[0014] The present invention obtains compound 2 by directly reacting compound 1 with pivaloyl chloride or pivalic anhydride, and does not require post-treatment. Compound 3 can be directly added to react to obtain compound 4, thereby avoiding the step of removing the protecting group in the existing polytinol intermediate synthesis method and simplifying the operation. In addition, the reaction route of the present invention has a high reaction yield and uses simple raw materials. The required raw materials 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.

[0015] Preferably, in step (1), the molar ratio of compound 1 to pivaloyl chloride or pivalic anhydride is 1 to 1:2.

[0016] Preferably, in step (1), compound 1 reacts with pivaloyl chloride or pivalic anhydride in an alkaline environment.

[0017] 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.

[0018] Preferably, the molar ratio of compound 1 to the alkaline substance is 1:1-8.

[0019] Preferably, in step (2), the molar ratio of compound 2 to compound 3 is 1:2-4.

[0020] Preferably, the reactions in step (1) and step (2) are both carried out in an organic solvent.

[0021] Preferably, the organic solvent is one or more of acetonitrile, dichloromethane, chloroform, tetrahydrofuran, and 1,4-dioxane.

[0022] Preferably, the reaction temperature of step (1) and step (2) is 0 to 40° C., and the reaction time is 1 to 5 hours.

[0023] Preferably, the reactions of step (1) and step (2) are carried out under nitrogen protection.

[0024] Preferably, after obtaining compound 4 in step (2), the product is post-treated, and the post-treatment method is: cooling and concentrating the reaction product, adding ethyl acetate and water, stirring and layering, drying and concentrating the organic layer, and then refining with ethanol to obtain the treated product. The post-treatment of the reaction in the present invention is simple, does not require column chromatography, and is more economical and more suitable for industrial production than the prior art.

[0025] Therefore, the present invention has the following beneficial effects: the present invention provides a new route for preparing polytinore intermediates, the reaction route of the present invention has a high reaction yield and the raw materials used are simple; the post-treatment of the reaction is simple and no column chromatography is required; and by adopting the route of the present invention, the required raw materials 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 DESCRIPTION

[0026] The present invention is further described below in conjunction with specific implementation methods.

[0027] In the present invention, unless otherwise specified, all equipment and raw materials can be purchased from the market or are commonly used in the industry. The methods in the following embodiments, unless otherwise specified, are conventional methods in the art. If there is a conflict between the Chinese name and the structural formula of the compound in the present invention, the structural formula shall prevail, unless there is an obvious error in the structural formula.

[0028] Overall embodiment: A method for synthesizing a polytinol intermediate, the reaction route is as follows:

[0029] As a specific implementation, in step (1), the molar ratio of compound 1 to pivaloyl chloride or pivalic anhydride is 1 to 1:2.

[0030] As a specific embodiment, in step (1), compound 1 reacts with pivaloyl chloride or pivalic anhydride in an alkaline environment.

[0031] As a specific implementation, 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.

[0032] As a specific implementation manner, the molar ratio of compound 1 to the alkaline substance is 1:1-8.

[0033] As a specific implementation, the molar ratio of compound 2 to compound 3 in step (2) is 1:2-4.

[0034] As a specific embodiment, the reactions in step (1) and step (2) are both carried out in an organic solvent.

[0035] As a specific implementation, the organic solvent is one or more of acetonitrile, dichloromethane, chloroform, tetrahydrofuran, and 1,4-dioxane.

[0036] As a specific implementation, the reaction temperature of step (1) and step (2) is 0 to 40°C, preferably 0 to 10°C; and the reaction time is 1 to 5 hours.

[0037] As a specific implementation manner, the reactions of step (1) and step (2) are carried out under nitrogen protection.

[0038] As a specific implementation method, after compound 4 is obtained in step (2), the product is post-treated. The post-treatment method is: the reaction product is cooled and concentrated, and then ethyl acetate and water are added, stirred and separated, and the organic layer is dried, concentrated, and then refined with ethanol to obtain the treated product.

[0039] The present invention obtains compound 2 by directly reacting compound 1 with pivaloyl chloride or pivalic anhydride, and does not require post-treatment. Compound 3 can be directly added to react to obtain compound 4, thereby avoiding the step of removing the protecting group in the existing polytinol intermediate synthesis method and simplifying the operation. In addition, the reaction route of the present invention has a high reaction yield and uses simple raw materials. The required raw materials 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.

[0040] Embodiment 1: A method for synthesizing a polytinol intermediate, comprising the following steps: (1) Add 2.0 g (9.66 mmol) of compound 1 into 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 pivaloyl chloride dropwise, and stir at 0°C for 1 h; (2) 2.65 g (19.3 mmol) of compound 3 was dissolved in 14 mL of acetonitrile, then added to the reaction product of step (1), and stirred at 0° C. for 1 h; (3) After TLC detection, the raw material was basically reacted, cooled and concentrated, ethyl acetate and water were added to the residue, stirred and separated, the organic layer was dried and concentrated, and the residue was purified by ethanol to obtain about 2.68 g of off-white solid. HNMR (300 MHz, DMSO-d6) δ7.79 (s, 2H), 7.72-7.47 (br, 1H), 7.437.31 (m, 1H), 7.19-7.03 (m, 2H), 5.34 (s, 2H). MS: 325.98 (M+H).

[0041] Embodiment 2: A method for synthesizing a polytinol intermediate, comprising the following steps: (1) Add 2.0 g (9.66 mmol) of compound 1 into 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 pivaloyl chloride dropwise, and stir at 0°C for 1 h; (2) 1.33 g (9.66 mmol) of compound 3 was dissolved in 14 mL of acetonitrile, then added to the reaction product of step (1), and stirred at 0° C. for 1 h; (3) After TLC detection, the raw material was basically reacted, cooled and concentrated, ethyl acetate and water were added to the residue, stirred and separated, the organic layer was dried and concentrated, and the residue was purified by ethanol to obtain about 2.00 g of off-white solid. HNMR (300 MHz, DMSO-d6) δ7.79 (s, 2H), 7.72-7.47 (br, 1H), 7.437.31 (m, 1H), 7.19-7.03 (m, 2H), 5.34 (s, 2H). MS: 325.98 (M+H).

[0042] Embodiment 3: A method for synthesizing a polytinol intermediate, comprising the following steps: (1) Add 2.0 g (9.66 mmol) of compound 1 into 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 pivaloyl chloride dropwise, and stir at 0 °C for 1 h; (2) 2.65 g (19.3 mmol) of compound 3 was dissolved in 14 mL of acetonitrile, then added to the reaction product of step (1), and stirred at 0° C. for 1 h; (3) After TLC detection, the raw material was basically reacted, cooled and concentrated, ethyl acetate and water were added to the residue, stirred and separated, the organic layer was dried and concentrated, and the residue was purified with ethanol to obtain about 2.56 g of off-white solid. HNMR (300 MHz, DMSO-d6) δ7.79 (s, 2H), 7.72-7.47 (br, 1H), 7.437.31 (m, 1H), 7.19-7.03 (m, 2H), 5.34 (s, 2H). MS: 325.98 (M+H).

[0043] Embodiment 4: (1) Add 2.0 g (9.66 mmol) of compound 1 into 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 pivaloyl chloride dropwise, and stir at 0°C for 1 h; (2) 3.98 g (28.98 mmol) of compound 3 was dissolved in 14 mL of acetonitrile, then added to the reaction product of step (1), and stirred at 0° C. for 1 h; (3) After TLC detection, the raw material was basically reacted, cooled and concentrated, ethyl acetate and water were added to the residue, stirred and separated, the organic layer was dried and concentrated, and the residue was purified by ethanol to obtain about 2.71 g of off-white solid. HNMR (300 MHz, DMSO-d6) δ7.79 (s, 2H), 7.72-7.47 (br, 1H), 7.437.31 (m, 1H), 7.19-7.03 (m, 2H), 5.34 (s, 2H). MS: 325.98 (M+H).

[0044] Embodiment 5: (1) Add 2.0 g (9.66 mmol) of compound 1 into 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 pivaloyl chloride dropwise, and stir at 25 °C for 1 h; (2) 3.98 g (29.98 mmol) of compound 3 was dissolved in 14 mL of acetonitrile, then added to the reaction product of step (1), and stirred at 35 °C for 1 h; (3) After TLC detection, the raw material was basically reacted, cooled and concentrated, ethyl acetate and water were added to the residue, stirred and separated, the organic layer was dried and concentrated, and the residue was purified by ethanol to obtain about 2.64 g of off-white solid. HNMR (300 MHz, DMSO-d6) δ7.79 (s, 2H), 7.72-7.47 (br, 1H), 7.437.31 (m, 1H), 7.19-7.03 (m, 2H), 5.34 (s, 2H). MS: 325.98 (M+H).

[0045] Embodiment 6: (1) Add 2.0 g (9.66 mmol) of compound 1 into 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 pivalic anhydride dropwise, and stir at 25 °C for 1 h; (2) 3.98 g (29.98 mmol) of compound 3 was dissolved in 14 mL of acetonitrile, then added to the reaction product of step (1), and stirred at 30 °C for 1 h; (3) After TLC detection, the raw material was basically reacted, cooled and concentrated, ethyl acetate and water were added to the residue, stirred and separated, the organic layer was dried and concentrated, and the residue was purified with ethanol to obtain about 2.47g of off-white solid. HNMR (300MHz, DMSO-d6) δ7.79 (s, 2H), 7.72-7.47 (br, 1H), 7.437.31 (m, 1H), 7.19-7.03 (m, 2H), 5.34 (s, 2H). MS: 325.98 (M+H). The yield and purity of the products obtained in the above examples were detected and calculated, and the results are shown in Table 1.

[0046] Table 1: Product yield and purity test results. 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％

[0047] It can be seen that the reaction route of the present invention is adopted in the embodiment, and a high product yield and purity can be obtained under a simple post-treatment step, and 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.

[0048] It should be noted that the above content only illustrates the technical idea of ​​the present invention and cannot be used to limit the protection scope of the present invention. For ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications all fall within the protection scope of the claims of the present invention.

Claims

1. A method for synthesizing a polytinol intermediate, characterized in that: The reaction route is as follows:

2. The method for synthesizing the polytinol intermediate according to claim 1, characterized in that: In step (1), the molar ratio of compound 1 to pivaloyl chloride or pivalic anhydride is 1 to 1:

2.

3. The method for synthesizing the polytinol intermediate according to claim 1 or 2, characterized in that: In step (1), compound 1 reacts with pivaloyl chloride or pivalic anhydride in an alkaline environment.

4. The method for synthesizing the polytinol intermediate according to claim 3, characterized in that: The alkaline environment is formed by adding alkaline substances; the alkaline substances are one or more of triethylamine, DIEA, pyridine, potassium carbonate and sodium carbonate.

5. The method for synthesizing the polytinol 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 polytinol 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 polytinol intermediate according to claim 1, characterized in that: The reactions in step (1) and step (2) are both 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 polytinol intermediate according to claim 1, characterized in that: Step (1) and step (2) are carried out under nitrogen protection, the reaction temperature is 0 to 40° C., and the reaction time is 1 to 5 hours.

9. The method for synthesizing the polytinol intermediate according to claim 1, characterized in that: After compound 4 is obtained in step (2), the product is post-treated. The post-treatment method is as follows: the reaction product is cooled and concentrated, and then ethyl acetate and water are added, stirred and separated, and the organic layer is dried, concentrated, and then refined with ethanol to obtain the treated product.

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