Preparation method of dotenorad

Abstract

The invention relates to a novel preparation method of dotenorad, which is characterized in that 2-aminobenzenethiol and 3, 5-dichloro-4-methoxybenzoic acid are used as starting materials, and the target product dotenorad is prepared through the steps of acylation, condensation, cyclization, demethylation, oxidation and the like. The route is high in total yield, and the obtained product is high in purity; post-treatment of the reaction is simple, and column chromatography is not needed; compared with the prior art, the method provided by the invention is more economical and more suitable for industrial production.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical technology, and particularly relates to a new preparation method of Dotinurad. Background Art

[0002] Dotinurad was developed by Fujifilm Pharmaceutical Co., Ltd. and jointly promoted by Fujifilm Pharmaceutical and Morita Pharmaceutical starting from the Japanese Phase III clinical trial for the treatment of gout and hyperuricemia. It was approved for marketing in Japan in January 2020 under the trade name URECE (ユリス), with specifications of 0.5 mg, 1 mg, and 2 mg. Eisai has obtained the exclusive development and sales rights of Dotinurad tablets in China from Fujifilm Pharmaceutical.

[0003] Dotinurad tablets are a new type of drug for the treatment of gout and hyperuricemia. This product modifies the adjacent ring structure of the benzene ring on the basis of the structure of benzbromarone, and its metabolites do not contain "p-benzoquinone" or analogs, so it avoids the hepatotoxicity of benzbromarone and maintains good efficacy. Clinical studies have shown that the highest main efficacy endpoint of the test group of this product is 63.52% higher than that of the placebo group at most, while the highest secondary efficacy endpoint is 95.2% higher than that of the placebo group at most. Hyperuricemia in China is the second most common metabolic disease after diabetes, with the number of patients exceeding 200 million and the market scale exceeding 3 billion yuan. The market potential for developing low-toxic and highly effective gout drugs is huge.

[0004] Its structural formula is shown as follows:

[0005] The currently reported synthesis methods of Dotinurad are as follows: Method 1: Patent CN201080042866.9 is a patent for Dotinurad compound. Using 2-aminobenzenethiol as the raw material, it is acylated to obtain 2,3-dihydro-1,3-benzothiazole, and then condensed with 3,5-dichloro-4-methoxybenzoyl chloride (prepared from 3,5-dichloro-4-methoxybenzoic acid) to obtain an amide intermediate. The amide intermediate is then oxidized, and finally deprotected to obtain Dotinurad. When deprotecting the last step, deprotection is required at a high temperature of about 140 °C, with a long reaction time, many impurities in the reaction system, and it is difficult to refine and remove; ; Method 2: Patent CN202010693795.4, this route is the preparation process route reported by Suzhou Mingrui Pharmaceutical Technology. This route uses expensive condensation reagents, with a high cost and is not suitable for industrial production; ; Method 3: Patent CN20201069241.6. This route is another preparation process route reported by Suzhou Mingrui Pharmaceutical Technology. This route also uses expensive condensation reagents, with high costs and is not suitable for industrial production; 。

[0006] Therefore, developing a method with mild reaction conditions and a simple operation process for the industrial production of dolutegravir is a technical problem that urgently needs to be solved in the current field. Summary of the Invention

[0007] To solve the above problems, the present invention discloses a preparation method of dolutegravir with mild reaction conditions and a simple operation process.

[0008] To achieve the above object, the technical solution of the present invention is as follows: (1) Using 3,5-dichloro-4-methoxybenzoic acid as the starting material, reacting with thionyl chloride in a solvent to generate 3,5-dichloro-4-methoxybenzoyl chloride; (2) Dissolving 3,5-dichloro-4-methoxybenzoyl chloride in a solvent, and reacting with 2-aminobenzenethiol under the action of an acid-binding agent to generate 3,5-dichloro-N-(2-mercaptophenyl)-4-methoxybenzamide; (3) Dissolving 3,5-dichloro-N-(2-mercaptophenyl)-4-methoxybenzamide in a solvent, and undergoing a cyclization reaction with formaldehyde to generate benzothiazol-3(2H)-yl(3,5-dichloro-4-methoxyphenyl)methanone; (4) Dissolving benzothiazol-3(2H)-yl(3,5-dichloro-4-methoxyphenyl)methanone in a solvent, and generating benzothiazol-3(2H)-yl(3,5-dichloro-4-hydroxyphenyl)methanone under the action of aluminum trichloride; (5) Adding benzothiazol-3(2H)-yl(3,5-dichloro-4-hydroxyphenyl)methanone and m-chloroperoxybenzoic acid in a solvent, and finally obtaining dolutegravir, that is, (3,5-dichloro-4-hydroxyphenyl)(1,1-dioxido-1,2-dihydro-3H-1λ 6 -1,3-benzothiazol-3-yl)methanone.

[0009] The reaction formula is as follows:

[0010] Further, in step (1), the molar ratio of compound 1 to thionyl chloride is 1.0: 1.5 - 2.0. Preferably, the molar ratio of compound 1 to thionyl chloride is 1.0: 1.5; the solvent is dichloromethane; the reaction temperature in step (1) is 20 - 30 °C, and the reaction time is 1 - 2 h.

[0011] Further, in step (2), the molar ratio of compound 2 to compound 3 is 1.0: 1.0 - 1.05. Preferably, the molar ratio of compound 2 to compound 3 is 1.0: 1.0; the solvent is dichloromethane; the acid-binding agent is one or two of potassium carbonate and sodium carbonate. Preferably, the acid-binding agent used is potassium carbonate; the molar ratio of compound 2 to the acid-binding agent is 1.0: 1.0 - 1.1. Preferably, the molar ratio of compound 2 to the acid-binding agent is 1.0: 1.0; the reaction temperature in step (2) is 0 - 10 °C, and the reaction time is 1 - 2 h.

[0012] Further, in step (3), the molar ratio of compound 4 to formaldehyde is 1.0: 2.0 - 2.2. Preferably, the molar ratio of compound 4 to formaldehyde is 1.0: 2.0; the solvent is water; the reaction temperature in step (3) is 20 - 30 °C, and the reaction time is 1 - 2 h.

[0013] Further, in step (4), the molar ratio of compound 5 to aluminum trichloride is 1.0: 2.0 - 3.0. Preferably, the molar ratio of compound 5 to aluminum trichloride is 1.0: 2.0; the solvent is acetonitrile; the reaction temperature in step (4) is 30 - 40 °C, and the reaction time is 1 - 2 h.

[0014] Further, in step (5), the molar ratio of compound 6 to m-chloroperoxybenzoic acid is 1.0: 2.5 - 3.0. Preferably, the molar ratio of compound 6 to m-chloroperoxybenzoic acid is 1.0: 2.5; the solvent is ethyl acetate; the reaction temperature in step (5) is 20 - 30 °C, and the reaction time is 1 - 2 h.

[0015] Compared with the prior art, the beneficial effects of the present invention are as follows: The present invention provides a new route for preparing dolutegravir, and each step of the route has a high yield.

[0016] In step (1) of the reaction route, the preferred molar ratio of compound 1 to thionyl chloride is 1.0: 1.5, and the solvent used is selected from dichloromethane. Under this condition, the yield of this step can reach 100%.

[0017] In step (2) of this reaction route, the molar ratio of compound 2 to compound 3 is preferably 1.0:1.0, the molar ratio of compound 2 to potassium carbonate is preferably 1.0:1.0, dichloromethane is used as the solvent, and the yield of this step can reach 95%.

[0018] In step (3) of this reaction route, the molar ratio of compound 4 to formaldehyde is preferably 1.0:2.0, water is used as the solvent, and the yield of this step can reach 92%.

[0019] In step (4) of this reaction route, the molar ratio of compound 5 to aluminum trichloride is preferably 1.0:2.0, acetonitrile is used as the solvent, and the yield can reach 93%.

[0020] In step (5) of this reaction route, the molar ratio of compound 6 to m-chloroperoxybenzoic acid is preferably 1.0:2.5, ethyl acetate is used as the solvent, and the yield can reach 90%.

[0021] The post-treatment of this reaction route is simple, column chromatography is not required, the preparation efficiency is improved, and it is suitable for industrial production.

[0022] Moreover, by adopting this route, the raw materials and reagents required 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.

[0023] Unless otherwise specified, the reagents and raw materials used in the present invention are all commercially available. In the present invention, if there is a conflict between the Chinese naming and the structural formula of the compound, the structural formula shall prevail, except for obvious errors in the structural formula. Brief Description of the Drawings Figure 1 It is the hydrogen spectrum of the product compound 7 obtained in Example 1; Figure 2 It is the carbon spectrum of the product compound 7 obtained in Example 2. Detailed Description of the Invention

[0025] The present invention will be further illustrated below in conjunction with the drawings and the detailed description. It should be understood that the following detailed description is only used to illustrate the present invention and not to limit the scope of the present invention.

[0026] Example 1 Preparation of 3,5-dichloro-4-methoxybenzoyl chloride (compound 2) First, dissolve a certain amount of 3,5-dichloro-4-methoxybenzoic acid in dichloromethane with a volume three times that of the acid. Under nitrogen protection, add thionyl chloride (1.5eq). After the addition, raise the temperature to 20-30°C and stir for 1-2h. Monitor the reaction by TLC until it ends. Concentrate under reduced pressure to obtain 3,5-dichloro-4-methoxybenzoyl chloride with a yield of 100% and a purity of ≥99.5%. It is directly used for the next reaction.

[0027] Example 2 Preparation of 3,5-dichloro-4-methoxybenzoyl chloride (Compound 2) First, dissolve a certain amount of 3,5-dichloro-4-methoxybenzoic acid in dichloromethane with a volume three times that of the acid. Under nitrogen protection, add thionyl chloride (2.0 eq). After addition, raise the temperature to 20 - 30 °C and stir for 1 - 2 h. Monitor the reaction by TLC until it ends. Concentrate under reduced pressure to obtain 3,5-dichloro-4-methoxybenzoyl chloride with a yield of 100% and a purity of ≥99.2%. It is directly used for the next reaction.

[0028] Example 3 Preparation of 3,5-dichloro-N-(2-mercaptophenyl)-4-methoxybenzamide (Compound 4) First, dissolve a certain amount of 3,5-dichloro-4-methoxybenzoyl chloride in dichloromethane with a volume four times that of the acid. Under nitrogen protection, add potassium carbonate (1.0 eq). At 0 - 10 °C, add 2-aminobenzenethiol (1.0 eq). After addition, react at 0 - 10 °C for 1 - 2 h. Monitor the reaction by TLC until it ends. Filter, add water with a volume four times that of the filtrate for washing, dry with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain 3,5-dichloro-N-(2-mercaptophenyl)-4-methoxybenzamide with a yield of 95% and a purity of ≥94.0%. It is directly used for the next reaction.

[0029] Example 4 Preparation of 3,5-dichloro-N-(2-mercaptophenyl)-4-methoxybenzamide (Compound 4) First, dissolve a certain amount of 3,5-dichloro-4-methoxybenzoyl chloride in dichloromethane with a volume four times that of the acid. Under nitrogen protection, add sodium carbonate (1.1 eq). At 0 - 10 °C, add 2-aminobenzenethiol (1.05 eq). After addition, react at 0 - 10 °C for 1 - 2 h. Monitor the reaction by TLC until it ends. Filter, add water with a volume four times that of the filtrate for washing, dry with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain 3,5-dichloro-N-(2-mercaptophenyl)-4-methoxybenzamide with a yield of 92% and a purity of ≥90.0%. It is directly used for the next reaction.

[0030] Example 5 Preparation of benzothiazol-3(2H)-yl(3,5-dichloro-4-methoxyphenyl)methanone (Compound 5) First, add a certain amount of 3,5-dichloro-N-(2-mercaptophenyl)-4-methoxybenzamide to water with a volume 4 times that of the solid. At 20 - 30 °C, add an aqueous formaldehyde solution (2.0 eq). After addition, react at 20 - 30 °C for 1 - 2 h. Monitor the reaction by TLC until it ends. Filter, wash the filter cake with water, and dry it under vacuum to obtain benzothiazol-3(2H)-yl(3,5-dichloro-4-methoxyphenyl)methanone with a yield of 92% and a purity of ≥95.0%. It is directly used for the next reaction.

[0031] Example 6 Preparation of benzothiazol-3(2H)-yl(3,5-dichloro-4-methoxyphenyl)methanone (Compound 5) First, add a certain amount of 3,5-dichloro-N-(2-mercaptophenyl)-4-methoxybenzamide to water with a volume 4 times that of the solid. At 20 - 30 °C, add an aqueous formaldehyde solution (2.2 eq). After addition, react at 20 - 30 °C for 1 - 2 h. Monitor the reaction by TLC until it ends. Filter, wash the filter cake with water, and dry it under vacuum to obtain benzothiazol-3(2H)-yl(3,5-dichloro-4-methoxyphenyl)methanone with a yield of 90% and a purity of ≥94.0%. It is directly used for the next reaction.

[0032] Example 7 Preparation of benzothiazol-3(2H)-yl(3,5-dichloro-4-hydroxyphenyl)methanone (Compound 6) Add a certain amount of benzothiazol-3(2H)-yl(3,5-dichloro-4-methoxyphenyl)methanone to acetonitrile with a volume 3 times that of the solid. Add aluminum trichloride (2.0 eq). After addition, react at 30 - 40 °C for 1 - 2 h. Monitor the reaction by TLC until it ends. At a temperature not higher than 40 °C, add water with a volume 3 times that of the reaction mixture, stir at 30 - 40 °C for 1 - 2 h, filter, wash the filter cake with water, and dry it under vacuum to obtain benzothiazol-3(2H)-yl(3,5-dichloro-4-hydroxyphenyl)methanone with a yield of 93% and a purity of ≥98.0%. It is directly used for the next reaction.

[0033] Example 8 Preparation of benzothiazol-3(2H)-yl(3,5-dichloro-4-hydroxyphenyl)methanone (Compound 6) Add a certain amount of benzothiazol-3(2H)-yl(3,5-dichloro-4-methoxyphenyl)methanone to three times its volume of acetonitrile, and then add aluminum trichloride (3.0 eq). After addition, react at 30 - 40 °C for 1 - 2 h and monitor the reaction to completion by TLC. At a temperature not higher than 40 °C, add three times the volume of water, stir at 30 - 40 °C for 1 - 2 h, filter, wash the filter cake with water, and dry it under vacuum to obtain benzothiazol-3(2H)-yl(3,5-dichloro-4-hydroxyphenyl)methanone with a yield of 88% and a purity of ≥97.0%. It is directly used for the next reaction.

[0034] Example 9 (3,5-Dichloro-4-hydroxyphenyl)(1,1-dioxido-1,2-dihydro-3H-1λ 6 -1,3-benzothiazol-3-yl)methanone (Compound 7) Preparation Add a certain amount of benzothiazol-3(2H)-yl(3,5-dichloro-4-hydroxyphenyl)methanone to three times its volume of ethyl acetate and stir to dissolve. At 0 - 10 °C, slowly dropwise add a solution of m-chloroperbenzoic acid (2.5 eq) in twice its volume of ethyl acetate. After addition, warm up to 20 - 30 °C and stir for 1 - 2 h, and monitor the reaction to completion by TLC. Cool down to 0 - 10 °C, dropwise add twice the volume of saturated aqueous sodium thiosulfate solution, stir for crystallization for 0.5 h, filter, wash the filter cake with water, and dry it under vacuum to obtain (3,5-dichloro-4-hydroxyphenyl)(1,1-dioxido-1,2-dihydro-3H-1λ 6 -1,3-benzothiazol-3-yl)methanone with a yield of 90% and a purity of ≥99.8%.

[0035] Example 10 (3,5-Dichloro-4-hydroxyphenyl)(1,1-dioxido-1,2-dihydro-3H-1λ 6 -1,3-benzothiazol-3-yl)methanone (Compound 7) Preparation Add a certain amount of benzothiazol-3(2H)-yl(3,5-dichloro-4-hydroxyphenyl)methanone to three times its volume of ethyl acetate and stir to dissolve. At 0 - 10 °C, slowly dropwise add a solution of m-chloroperbenzoic acid (3.0 eq) in twice its volume of ethyl acetate. After addition, warm up to 20 - 30 °C and stir for 1 - 2 h, and monitor the reaction to completion by TLC. Cool down to 0 - 10 °C, dropwise add twice the volume of saturated aqueous sodium thiosulfate solution, stir for crystallization for 0.5 h, filter, wash the filter cake with water, and dry it under vacuum to obtain (3,5-dichloro-4-hydroxyphenyl)(1,1-dioxido-1,2-dihydro-3H-1λ 6 ;-1,3-benzothiazol-3-yl)methanone with a yield of 90% and a purity of ≥98.0%.

[0036] The hydrogen spectrum is as Figure 1As shown below, the hydrogen spectrum data are as follows: 1 H-NMR (DMSO-d6, 400 MHz) δ: 11.045 (1H, br), 8.026 - 8.047 (1H, m), 7.898 - 7.915 (1H, m), 7.721 - 7.759 (3H, m), 7.412 - 7.450 (1H, m), 5.379 (2H, s).

[0037] The carbon spectrum is as shown in Figure 2 As shown below, the carbon spectrum data are as follows: 13 C-NMR (DMSO-d6, 400 MHz) δ: 166.06, 152.67, 139.83, 134.91, 129.40, 129.13, 127.05, 126.37, 122.72, 121.75, 121.03, 67.48.

[0038] 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 those of ordinary skill in the art, without departing from the principle of the present invention, several improvements and refinements can be made, and these improvements and refinements all fall within the protection scope of the claims of the present invention.

Claims

1. A method for preparing polytinoride, characterized in that: The following steps are involved: (1) Compound 1 is used as the starting material and reacted with thionyl chloride in a solvent to generate compound 2 ； (2) Compound 2 is dissolved in a solvent and reacts with compound 3 under the action of an acid-binding agent to generate compound 4. ； (3) Compound 4 is dissolved in a solvent and reacted with formaldehyde to produce compound 5. ； (4) Compound 5 is dissolved in a solvent and reacted with aluminum chloride to generate compound 6. ； (5) Compound 6 and m-chloroperbenzoic acid are added to the solvent to finally obtain compound 7 polytinore 。 2. The method for preparing polytinol according to claim 1, characterized in that: In step (1), the molar ratio of the compound 1 to thionyl chloride is 1.0: 1.5-2.0; the solvent is dichloromethane; the reaction temperature in step (1) is 20-30° C., and the reaction time is 1-2 h.

3. The method for preparing polytinorel according to claim 1, characterized in that: In step (2), the molar ratio of compound 2 to compound 3 is 1.0: 1.0-1.05; the solvent is dichloromethane; the acid binding agent is one or both of potassium carbonate and sodium carbonate; the molar ratio of compound 2 to the acid binding agent is 1.0: 1.0-1.1; the reaction temperature in step (2) is 0-10° C., and the reaction time is 1-2 h.

4. The method for preparing polytinoride according to claim 1, characterized in that: In step (3), the molar ratio of the compound 4 to formaldehyde is 1.0: 2.0-2.2; the solvent is water; the reaction temperature in step (3) is 20-30° C., and the reaction time is 1-2 h.

5. The method for preparing polytinol according to claim 1, characterized in that: In step (4), the molar ratio of the compound 5 to aluminum chloride is 1.0: 2.0-3.0; the solvent is acetonitrile; the reaction temperature in step (4) is 30-40° C., and the reaction time is 1-2 h.

6. The method for preparing polytinol according to claim 1, characterized in that: In step (4), the molar ratio of the compound 5 to aluminum chloride is 1.0: 2.0-3.0; the solvent is acetonitrile; the reaction temperature in step (4) is 30-40° C., and the reaction time is 1-2 h.

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