Process for the preparation of a key intermediate of multivir.

Abstract

The application belongs to the field of organic synthesis, and discloses a preparation method of a key intermediate of dotinore, which comprises the following steps: S1, reacting p-hydroxybenzoic acid with sodium hypochlorite under alkaline conditions; and S2, reacting the product obtained in step S1 with a methylation reagent to obtain the key intermediate 3,5-dichloro-4-methoxybenzoic acid of dotinore.The preparation method uses p-hydroxybenzoic acid as a raw material, and synthesizes 3,5-dichloro-4-methoxybenzoic acid through a "one-pot method" of chlorination and methylation in sequence.The method avoids using dangerous chlorine, has high yield and high purity, short steps, low cost, does not use any organic solvent, and is suitable for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis, specifically relating to a method for preparing a key intermediate of dotenorazole. Background Technology

[0002] Dotenorazole, chemically named 3-(3,5-dichloro-4-hydroxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole, was jointly developed by Fujiyama and Mochida Pharmaceuticals in Japan and approved for marketing in Japan in January 2020 for the treatment of hyperuricemia. It selectively inhibits the reabsorption of uric acid by transporting proteins in the kidneys, thereby inhibiting uric acid reabsorption and lowering blood uric acid levels. Its chemical structure is as follows:

[0003] .

[0004] 3,5-Dichloro-4-methoxybenzoic acid, as a key intermediate in dotenorazole, has attracted much attention. Its main synthetic methods include:

[0005] Route 1: Chinese invention patent CN120757515A discloses a method for preparing 3,5-dichloro-4-methoxybenzoic acid, the specific synthetic route of which is as follows:

[0006] .

[0007] This route involves four reaction steps to obtain the product, which is quite complicated and costly. The third step also uses relatively dangerous chlorine gas, which is not conducive to industrial production.

[0008] Route 2: Chinese patent CN115057768A discloses a method for preparing 3,5-dichloro-4-methoxybenzoic acid, the specific synthetic route of which is as follows:

[0009] .

[0010] This route has poor repeatability, cannot obtain products with high purity according to the patent, has large impurities, and requires the use of highly toxic organic solvents. Summary of the Invention

[0011] To address the shortcomings of the existing technology, this invention provides a method for preparing a key intermediate of dotenorfat. This method avoids the use of hazardous reagents, does not require organic solvents, and offers high yield, high purity, short steps, and low cost.

[0012] The specific technical solution is as follows:

[0013] A method for preparing a key intermediate of dotenoroxetine includes the following steps:

[0014] S1. p-Hydroxybenzoic acid reacts with sodium hypochlorite under alkaline conditions;

[0015] S2. The product obtained in step S1 is reacted with a methylating agent to obtain the key intermediate of dotenorazole, 3,5-dichloro-4-methoxybenzoic acid.

[0016] This invention uses p-hydroxybenzoic acid as a raw material, synthesizing 3,5-dichloro-4-methoxybenzoic acid through chlorination followed by methylation. After the reaction in step S1, no further processing is required; dimethyl sulfate is directly added for reaction, achieving a one-pot synthesis. The specific synthetic route is as follows:

[0017] .

[0018] Furthermore, in step S1, the reaction temperature is 0~10℃.

[0019] Furthermore, in step S1, the reaction time is preferably 1.5 to 3 hours.

[0020] Further, in step S1: a base or basic salt is added to the reaction; the base is sodium hydroxide and / or potassium hydroxide, and the basic salt is potassium carbonate. Preferably, sodium hydroxide is added to provide alkaline conditions.

[0021] Further, in step S1: after the reaction is complete, the reaction is quenched with an aqueous sodium sulfite solution. The concentration of the aqueous sodium sulfite solution is preferably 5wt%~15wt%, and the preferred ratio of p-hydroxybenzoic acid to the aqueous sodium sulfite solution is 1 g : (20~50) mL.

[0022] Furthermore, in step S1: the solvent used in the reaction is preferably water. After mixing p-hydroxybenzoic acid, a base or basic salt, and the solvent, sodium hypochlorite solution is added to react. The ratio of p-hydroxybenzoic acid to solvent is 1 g : (4~10) mL.

[0023] Furthermore, in step S2: the methylating agent is at least one of dimethyl sulfate, iodomethane, and methanesulfonic acid, preferably dimethyl sulfate.

[0024] Furthermore, in step S2, the reaction temperature is 90~95℃.

[0025] Furthermore, in step S2, the reaction time is preferably 1.5 to 3 hours.

[0026] Furthermore, the molar ratio of p-hydroxybenzoic acid to sodium hypochlorite is 1:(2.0~3.0), preferably 1:2.5.

[0027] Furthermore, the molar ratio of p-hydroxybenzoic acid to sodium hydroxide is 1:(3.0~5.0), preferably 1:4.0.

[0028] Furthermore, the molar ratio of p-hydroxybenzoic acid to dimethyl sulfate is 1:(2.0~3.0), preferably 1:2.5.

[0029] Furthermore, after the reaction in step S2 is completed, the product undergoes post-treatment; the post-treatment methods include: adjusting the pH value to 1-2 to induce crystallization. Specifically, concentrated sulfuric acid is used to adjust the pH value. Specifically, the temperature is controlled not to exceed 20°C during post-treatment.

[0030] Specifically, the preparation method of the present invention includes the following steps: adding p-hydroxybenzoic acid, sodium hydroxide and water to a reaction vessel, adding sodium hypochlorite aqueous solution dropwise, and stirring the reaction while keeping it warm; after the reaction is completed, quenching with sodium sulfite aqueous solution, adding methylation reagent, stirring the reaction while controlling the temperature, and obtaining 3,5-dichloro-4-methoxybenzoic acid after the reaction is completed.

[0031] Compared with the prior art, the present invention has the following beneficial effects:

[0032] The preparation method of this invention uses p-hydroxybenzoic acid as a raw material and synthesizes 3,5-dichloro-4-methoxybenzoic acid in a one-pot process of chlorination followed by methylation. This method avoids the use of hazardous chlorine gas, has high yield and purity, short steps, low cost, and does not use any organic solvents, making it suitable for industrial production. Attached Figure Description

[0033] Figure 1 The HPLC chromatogram of 3,5-dichloro-4-methoxybenzoic acid prepared in Example 1 of this invention;

[0034] Figure 2 This is the HPLC chromatogram of the blank control in Example 1 of the present invention;

[0035] Figure 3 This is the HPLC chromatogram of 3,5-dichloro-4-methoxybenzoic acid prepared in Example 2 of the present invention. Detailed Implementation

[0036] The embodiments of the present invention will be described in further detail below with reference to the accompanying drawings and examples. The following examples are for illustrative purposes only and should not be construed as limiting the scope of the invention. Unless otherwise specified, the experimental methods used in the following examples are conventional methods. Unless otherwise specified, the materials and reagents used in the following examples are commercially available.

[0037] Example 1

[0038] The preparation steps for 3,5-dichloro-4-methoxybenzoic acid are as follows:

[0039] S1. Add 10 g of p-hydroxybenzoic acid, 11.6 g of sodium hydroxide and 50 mL of water to a 250 mL reaction flask, start stirring, control the temperature at 5℃, slowly add 134.7 g of 10 wt% sodium hypochlorite aqueous solution. After the addition is complete, stir the reaction at 5℃ for 2 h. When the reaction is complete, add 263 mL of 10 wt% sodium sulfite aqueous solution to quench the reaction.

[0040] S2. While maintaining a temperature not exceeding 50℃, slowly add 22.8 g of dimethyl sulfate dropwise. After the addition is complete, raise the temperature to 95℃ and stir the reaction for 2 hours. Once the reaction is complete, maintain a temperature not exceeding 20℃ and add concentrated sulfuric acid (98wt%) dropwise to adjust the pH to 1.5 to induce crystallization. Filter, rinse with 30 mL of water, and dry to obtain 14.2 g of white solid. The overall yield of the two steps is 89.0%, and the purity is 99.939%.

[0041] The specific synthesis route is as follows:

[0042] .

[0043] HPLC analysis confirmed the successful synthesis of 3,5-dichloro-4-methoxybenzoic acid. Its HPLC chromatogram is shown below. Figure 1 As shown, its blank control HPLC chromatogram is as follows. Figure 2 As shown, the HPLC peak results of the product are shown in Table 1.

[0044] Table 1. HPLC peak results of the product from Example 1

[0045]

[0046] Example 2

[0047] The preparation steps for 3,5-dichloro-4-methoxybenzoic acid are as follows:

[0048] S1. Add 10 g of p-hydroxybenzoic acid, 12.7 g of sodium hydroxide and 50 mL of water to a 250 mL reaction flask, start stirring, control the temperature at 5℃, slowly add 134.7 g of 10 wt% sodium hypochlorite aqueous solution. After the addition is complete, stir the reaction at 5℃ for 2 h. When the reaction is complete, add 263 mL of 10 wt% sodium sulfite aqueous solution to quench the reaction.

[0049] S2. While maintaining a temperature not exceeding 50℃, slowly add 20.1 g of dimethyl sulfate dropwise. After the addition is complete, raise the temperature to 95℃ and stir the reaction for 2 hours. Once the reaction is complete, maintain a temperature not exceeding 20℃ and add concentrated sulfuric acid (98wt%) dropwise to adjust the pH to 1.5 to induce crystallization. Filter, dry, and rinse with 30 mL of water to obtain 13.5 g of white solid. The overall yield of the two steps is 84.4%, and the purity is 99.640%.

[0050] HPLC analysis confirmed the successful synthesis of 3,5-dichloro-4-methoxybenzoic acid. Its HPLC chromatogram is shown below. Figure 3 As shown in Table 2, the HPLC peak results are as follows.

[0051] Table 2. HPLC peak results of the product from Example 2

[0052]

[0053] Example 3

[0054] 3,5-Dichloro-4-methoxybenzoic acid was prepared according to Example 1, except that in step S1, the reaction temperature was 0°C; and in step S2, the reaction temperature was 90°C. Other technical features were the same as in Example 1. The overall yield of the two steps was 84.2%, and the purity was 99.746%.

[0055] Example 4

[0056] 3,5-Dichloro-4-methoxybenzoic acid was prepared according to Example 1, except that in step S1, the reaction temperature was 10°C; and in step S2, the reaction temperature was 90°C. Other technical features were the same as in Example 1. The overall yield of the two steps was 85.3%, and the purity was 99.551%.

[0057] The above embodiments demonstrate that the present invention provides a novel method for preparing 3,5-dichloro-4-methoxybenzoic acid. Compared with Route 1 in the prior art, the present invention has shorter steps, lower cost, and does not require the use of relatively dangerous chlorine gas; compared with Route 2 in the prior art, the product obtained in this application has higher yield and higher purity, and does not require the use of organic solvents.

[0058] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A method for preparing a key intermediate of dotenoroxetine, characterized in that, Includes the following steps: Add p-hydroxybenzoic acid, sodium hydroxide and water to the reaction vessel, add sodium hypochlorite aqueous solution dropwise, keep the temperature at 0~10℃ and stir to react; after the reaction is completed, quench with sodium sulfite aqueous solution, continue to add dimethyl sulfate, keep the temperature at 90~95℃ and stir to react, after the reaction is completed, adjust the pH value to 1~2 and crystallize; The molar ratio of p-hydroxybenzoic acid to sodium hypochlorite is 1:(2.0~3.0); The molar ratio of p-hydroxybenzoic acid to sodium hydroxide is 1:(3.0~5.0); The molar ratio of p-hydroxybenzoic acid to dimethyl sulfate is 1:(2.0~3.0).

2. The preparation method according to claim 1, characterized in that, Use concentrated sulfuric acid to adjust the pH value.

Images