Synthesis method of dotenorad

Abstract

The invention discloses a synthesis method of dotenorad. The invention provides a preparation method of a compound B. The preparation method comprises the following step: reacting 3, 5-dichloro-4-hydroxybenzoic acid with a compound A to generate the compound B in an organic solvent under the action of a condensing agent. The preparation method provided by the invention is short in step, high in reaction yield, high in purity, low in three-waste generation amount, low in production cost and high in product quality, and is a green and environment-friendly preparation method. # imgabs0 #

Description

Technical Field

[0001] The invention relates to a method for synthesizing polytinorethinol. Background Art

[0002] Dotinurad is an oral tablet jointly developed by Fuji Yakuhin and Mochida Pharmaceuticals for the treatment of hyperuricemia and gout. Dotinurad is a urate transporter 1 (URAT1) inhibitor (uricosuric drug), which mainly inhibits the function of URAT1 to promote the excretion of uric acid from the kidneys, thereby reducing blood uric acid levels. Dotinurad was approved for marketing in Japan in January 2020 under the trade name URECE ® On January 22, 2024, the official website of Eisai (China) announced that the new drug application for Dotinurad tablets has been accepted by the Center for Drug Evaluation (CDE) of the National Medical Products Administration. Because the drug has not yet been officially launched in my country and does not have a standard Chinese translation, the applicant hereby transliterates it as "Dotinurad".

[0003] The chemical name of dotinorel is: 3-(3,5-dichloro-4-hydroxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole, and the structural formula is as follows:

[0004] Dotinurad

[0005] WO2011040449 reports a method for synthesizing polytinol. The method comprises condensing 2-aminobenzenethiol with formaldehyde to obtain benzothiazoline, which is then condensed with 3,5-dichloro-4-methoxybenzoyl chloride to obtain an intermediate. The intermediate is oxidized and then demethylated to obtain polytinol. The synthesis method is as follows:

[0006] ;

[0007] The preparation method has the disadvantages of long reaction steps, acyl chloride preparation and high-temperature reaction, and high requirements on equipment; large amounts of thionyl chloride are used, resulting in large amounts of three wastes, which will pollute the environment; in addition, the overall yield of the route and the purity of the finished product are both low.

[0008] Patent CN111662247A reports a method for synthesizing polytinol. The method uses 2,3-dihydrobenzothiazole as a starting material, obtains an oxidation intermediate after an oxidation reaction, and the intermediate undergoes a condensation reaction with 3,5-dichloro-4-hydroxybenzoic acid to obtain polytinol. The applicant repeated the patent method and failed to achieve the oxidation reaction described in the route;

[0009] .

[0010] Patent CN111675675A reports a method for synthesizing polytinol. It uses 2-aminobenzenethiol as the starting material and sequentially undergoes amidation reaction, diiodomethane cyclization reaction and oxidation reaction to prepare polytinol. This route has a long synthesis process, the acid chloride intermediate used has poor stability, and the reaction is highly exothermic; the reagent diiodomethane is highly toxic and unstable, and it is easily decomposed into toxic iodide in the air, so this route is not suitable for industrial production;

[0011] .

[0012] Patent CN111793039A reports a method for synthesizing polytinol. It uses 2-aminobenzenethiol as the starting material and sequentially undergoes condensation reaction, cyclization reaction and oxidation reaction to prepare polytinol. The conventional condensing agent used in this route was not achieved by the applicant in repeating the patented method.

[0013] .

[0014] Patent CN118271256A reports a method for synthesizing polytinol. It uses 2-aminobenzenethiol as the starting material and sequentially prepares polytinol through cyclization reaction, oxidation reaction, condensation reaction and demethylation reaction. This route has a long reaction process, and demethylation is a high-temperature reaction, which requires high equipment and is not conducive to industrial production. The oxidation reaction described in this route could not be achieved by the applicant in repeating the patent method;

[0015] .

[0016] Patent CN118271255A reports a method for synthesizing polytinol. It uses 2-aminobenzenethiol as the starting material and sequentially undergoes cyclization, condensation, oxidation, and demethylation reactions to prepare polytinol. This route has a long reaction process, and demethylation is a high-temperature reaction, which requires high equipment and generates a large amount of three wastes, making it unfavorable for industrial production.

[0017] . Summary of the invention

[0018] The technical problem to be solved by the present invention is to overcome the defects of the prior art and provide a more efficient preparation method of polytinol. The present invention provides a synthesis method of polytinol. The synthesis method provided by the present invention has short steps, high reaction yield, high purity, low amount of three wastes generated, low production cost, high product quality, and is a green and environmentally friendly preparation method.

[0019] The present invention solves the above technical problems through the following technical solutions.

[0020] The present invention provides a method for preparing a compound B, which comprises the following steps: in an organic solvent, under the action of a condensing agent, 3,5-dichloro-4-hydroxybenzoic acid reacts with a compound A to generate a compound B;

[0021] .

[0022] In some embodiments of the present invention, the organic solvent may be an ether solvent or a halogenated alkane solvent; the ether solvent is preferably tetrahydrofuran; the halogenated alkane solvent is preferably dichloromethane.

[0023] In some embodiments of the present invention, the condensing agent may be a mixture of triphenylphosphine and a ligand, wherein the ligand is selected from carbon tetrachloride, carbon tetrabromide, hexachloroacetone, N-bromosuccinimide, N-chlorosuccinimide and iodine; preferably, the condensing agent is a mixture of triphenylphosphine and N-chlorosuccinimide.

[0024] In some embodiments of the present invention, the molar volume ratio of the compound A to the organic solvent may be 0.1-1 mmol / mL; preferably 0.8 mmol / mL.

[0025] In some embodiments of the present invention, the molar ratio of the compound A to the 3,5-dichloro-4-hydroxybenzoic acid may be 1:(0.3-1); preferably 1:0.4.

[0026] In some embodiments of the present invention, the molar ratio of the triphenylphosphine to the complexing agent is 1:1.

[0027] In some embodiments of the present invention, the molar ratio of the compound A to the complexing agent may be 1:(0.5-2); preferably 1:0.5.

[0028] In some embodiments of the present invention, the reaction temperature of the reaction may be -5 to 30°C, preferably 5 to 15°C.

[0029] In some embodiments of the present invention, the reaction progress of the reaction is detected by conventional monitoring methods of such reactions in the art, such as HPLC, TLC, etc. Preferably, the reaction endpoint is when compound A is completely converted or compound B is no longer generated; the reaction time may be 2 to 4 hours.

[0030] In some embodiments of the present invention, the reaction comprises the following steps: 3,5-dichloro-4-hydroxybenzoic acid, triphenylphosphine and tetrahydrofuran are mixed, and after cooling, N-chlorosuccinimide and compound A dissolved in tetrahydrofuran are added to react; the cooling is preferably to 0-15°C.

[0031] In some embodiments of the present invention, the reaction further comprises the following steps: after the reaction is completed, filtering, concentrating the filtrate, crystallizing with anhydrous methanol, filtering and drying to obtain compound B.

[0032] In some embodiments of the present invention, the method for preparing compound B further comprises the preparation of compound A, which comprises the following steps: in an organic solvent, 2-aminobenzenethiol and a formaldehyde aqueous solution undergo a cyclization reaction to generate compound A;

[0033] .

[0034] In some embodiments of the present invention, in the preparation of the compound A, the organic solvent may be an ether solvent or a halogenated alkane solvent; the ether solvent is preferably methyl tert-butyl ether; the halogenated alkane solvent is preferably dichloromethane.

[0035] In some embodiments of the present invention, in the preparation of the compound A, the mass concentration of the formaldehyde aqueous solution may be 5% to 42%, preferably 7% to 8%, and more preferably 7.65%.

[0036] In some embodiments of the present invention, in the preparation of the compound A, the molar volume ratio of the 2-aminobenzenethiol to the organic solvent may be 2-5 mmol / mL; preferably 2.4 mmol / mL.

[0037] In some embodiments of the present invention, in the preparation of the compound A, the molar ratio of the 2-aminobenzenethiol to the formaldehyde may be 1:(1.0-6.0), preferably 1:(1.2-1.4).

[0038] In some embodiments of the present invention, in the preparation of the compound A, the reaction temperature of the cyclization reaction can be room temperature, preferably 20-30°C.

[0039] In some embodiments of the present invention, in the preparation of the compound A, the progress of the cyclization reaction is detected by conventional monitoring methods for such reactions in the art, such as HPLC, TLC, etc. Preferably, the reaction endpoint is the complete conversion of 2-aminobenzenethiol or the no longer generation of compound A; the reaction time may be 2 to 3 hours.

[0040] In some embodiments of the present invention, in the preparation of the compound A, the cyclization reaction comprises the following steps: 2-aminobenzenethiol is mixed with dichloromethane, cooled and then an aqueous solution of formaldehyde is added to react; the cooling is preferably to 10-20°C.

[0041] In some embodiments of the present invention, in the preparation of the compound A, the cyclization reaction further comprises the following steps: after the reaction is completed, the liquids are separated, the organic phase is washed with water, the liquids are separated, dried over anhydrous magnesium sulfate, filtered, and the organic phase is dried under reduced pressure to obtain compound A.

[0042] The present invention also provides a method for preparing the compound as shown in formula I, which comprises the following steps:

[0043] Step 1, preparing compound B according to the preparation method of compound B above;

[0044] Step 2, in an organic solvent, subjecting the compound B prepared in step 1 to an oxidation reaction with m-chloroperbenzoic acid to generate a compound as shown in formula I;

[0045] .

[0046] In some embodiments of the present invention, the reaction conditions of step 1 are as described in any of the aforementioned embodiments of the present invention.

[0047] In some embodiments of the present invention, in step 2, the organic solvent may be an amide solvent, an ether solvent or a halogenated alkane solvent; the amide solvent is preferably N-methylpyrrolidone; the ether solvent is preferably tetrahydrofuran; and the halogenated alkane solvent is preferably dichloromethane.

[0048] In some embodiments of the present invention, in step 2, the molar volume ratio of the compound B to the organic solvent may be 0.1-1.0 mmol / mL, preferably 0.6 mmol / mL.

[0049] In some embodiments of the present invention, in step 2, the molar ratio of the compound B to the meta-chloroperbenzoic acid may be 1:(2.0-4.0), preferably 1:(2.0-3.0), and more preferably 1:3.0.

[0050] In some embodiments of the present invention, in step 2, the reaction temperature of the reaction may be 20-60°C, preferably 40-50°C.

[0051] In some embodiments of the present invention, in step 2, the progress of the reaction is detected by conventional monitoring methods for such reactions in the art, such as HPLC, TLC, etc. Preferably, the reaction endpoint is when compound B is completely converted or compound I is no longer generated; the reaction time may be 1 to 2 hours.

[0052] In some embodiments of the present invention, in step 2, the reaction comprises the following steps: compound B is mixed with N-methylpyrrolidone, and after cooling, m-chloroperbenzoic acid is added to react; the cooling is preferably to 0-15°C.

[0053] In some embodiments of the present invention, in step 2, the reaction further comprises the following steps: after the reaction is completed, extraction is performed using an aqueous sodium thiosulfate solution and ethyl acetate, back-extraction is performed with purified water, the organic phase is concentrated, and recrystallization is performed with anhydrous ethanol to obtain a compound as shown in Formula I; the concentration of the aqueous sodium thiosulfate solution is preferably 10%.

[0054] In the present invention, the room temperature is 10-35°C.

[0055] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

[0056] The reagents and raw materials used in the present invention are commercially available.

[0057] The positive and progressive effects of the present invention are:

[0058] (1) The preparation route of the present invention has short synthesis steps and simple post-processing operation;

[0059] (2) The preparation method of the present invention has high reaction yield and high purity;

[0060] (3) The preparation method of the present invention generates less three wastes, has low production cost and high product quality, and is a green and environmentally friendly preparation method. DETAILED DESCRIPTION

[0061] The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. The experimental methods in the following examples without specifying specific conditions are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0062] ;

[0063] Example 1: Synthesis of Compound A

[0064] Add SM1 (10 g) and dichloromethane (44 g) to the reaction flask, stir and cool. Control the internal temperature at 10-20°C, slowly add formaldehyde aqueous solution (8.6 g of 37% formaldehyde aqueous solution dissolved in 33 g of water), then keep warm and stir at 20-30°C for 1-3 hours. Separate the liquid, take the organic phase, add 30 g of water, and stir at 10-20°C for 30-60 minutes. Separate the liquid, take the organic phase, use 8 g of anhydrous magnesium sulfate, and dry at 10-20°C for 2-4 hours. Filter, take the organic phase, and dry under reduced pressure at 20-30°C to obtain 10.8 g of yellow liquid, with a yield of 98% and an HPLC purity of 97%.

[0065] MS: [M+H] + =138.05;

[0066] 1 HNMR(CDCl3): δ=3.82(br. s, 1H), 4.73(s, 2H), 6.51~7.43(m, 4H).

[0067] Example 2: Synthesis of Compound B

[0068] Add SM2 (5.2 g), triphenylphosphine (7.9 g) and tetrahydrofuran (52 mL) to the reaction flask, stir and cool to 0-10 ° C, add N-chlorosuccinimide (N-chlorosuccinimide) solid (3.9 g) while keeping warm, and then add the tetrahydrofuran solution of compound A (8.3 g of A dissolved in 26 mL of tetrahydrofuran). After the addition, control the internal temperature to 5-15 ° C, stir and react for 1-2 hours, and then filter. Take the mother liquor, concentrate to dryness, add anhydrous methanol (26 mL), stir at 40-50 ° C for 1-2 hours, cool to 20-30 ° C, filter, rinse with anhydrous methanol (10 mL), take the solid, and vacuum dry to constant weight to obtain 7.8 g of yellow solid, with a yield of 85% and a HPLC purity of 99.0%.

[0069] MS: [M+H] + =326.01;

[0070] 1 HNMR(d-DMSO): δ=5.36(s, 2H), 7.05~7.65(m, 6H), 10.9(br. s, 1H).

[0071] Example 3: Synthesis of Compound I

[0072] Add B (4.0g) and N-methylpyrrolidone (20mL) to the reaction flask, stir and cool to 0~15℃, keep warm and add 85% m-chloroperbenzoic acid solid (7.3g), after addition, control the internal temperature at 40~50℃, stir and react for 1~2 hours. Then add ethyl acetate (40mL) and 10% sodium thiosulfate aqueous solution (20mL) and stir for 30 minutes. Separate the liquid, add ethyl acetate (20mL) to the aqueous phase, stir for 30 minutes, separate the liquids, and combine the organic phases. Add purified water (20mL) to the organic phase, stir for 30 minutes, separate the liquids, and take the organic phase. The organic phase is concentrated, ethanol is added to the residue, and 3.7g of compound I (polytinore) is crystallized, with a yield of 84%, HPLC purity of 99.9%, and retention time: 8.829 min.

[0073] MS: [M+H] + =357.99;

[0074] 1 HNMR(d-DMSO): δ=5.35(s, 2H), 7.42~8.04(m, 6H), 11.05(br. s, 1H).

[0075] Table 1 Purity results of dotinorel

[0076] .

Claims

1. A method for preparing compound B, characterized in that: The method comprises the following steps: in an organic solvent, under the action of a condensation agent, 3,5-dichloro-4-hydroxybenzoic acid reacts with a compound A to generate a compound B; 。 2. The preparation method according to claim 1, characterized in that The organic solvent is an ether solvent or a halogenated alkane solvent; And / or, the condensing agent is a mixture of triphenylphosphine and a ligand, and the ligand is selected from one or more of carbon tetrachloride, carbon tetrabromide, hexachloroacetone, N-bromosuccinimide, N-chlorosuccinimide and iodine.

3. The preparation method according to claim 2, characterized in that: It meets one or more of the following conditions: (1) The ether solvent is tetrahydrofuran; (2) The halogenated alkane solvent is dichloromethane; (3) The condensing agent is a mixture of triphenylphosphine and N-chlorosuccinimide.

4. The preparation method according to claim 2, characterized in that: It meets one or more of the following conditions: (1) The molar ratio of the triphenylphosphine to the ligand is 1:1; (2) The molar volume ratio of the compound A to the organic solvent is 0.1-1 mmol / mL; (3) The molar ratio of the compound A to the 3,5-dichloro-4-hydroxybenzoic acid is 1:(0.3-1); (4) The molar ratio of the compound A to the complexing agent is 1:(0.5-2); (5) The reaction temperature of the reaction is -5~30°C; (6) The reaction further comprises the following steps: after the reaction is completed, filtering, concentrating the filtrate, crystallizing with anhydrous methanol, filtering and drying to obtain compound B.

5. The preparation method according to claim 4, characterized in that: It meets one or more of the following conditions: (1) The molar volume ratio of the compound A to the organic solvent is 0.8 mmol / mL; (2) The molar ratio of the compound A to the 3,5-dichloro-4-hydroxybenzoic acid is 1:0.4; (3) The molar ratio of the compound A to the complexing agent is 1:0.5; (4) The reaction temperature of the reaction is 5-15°C.

6. The preparation method according to claim 1, characterized in that: The reaction comprises the following steps: 3,5-dichloro-4-hydroxybenzoic acid, triphenylphosphine and tetrahydrofuran are mixed, and after cooling, N-chlorosuccinimide and compound A dissolved in tetrahydrofuran are added for reaction; the cooling is preferably to 0-15°C.

7. The preparation method according to claim 1, characterized in that: The preparation method of the compound B further includes the preparation of the compound A, which includes the following steps: in an organic solvent, 2-aminobenzenethiol and a formaldehyde aqueous solution undergo a cyclization reaction to generate the compound A; 。 8. The preparation method according to claim 7, characterized in that: The preparation of compound A satisfies one or more of the following conditions: (1) The organic solvent is an ether solvent or a halogenated alkane solvent; the ether solvent is preferably methyl tert-butyl ether; the halogenated alkane solvent is preferably dichloromethane; (2) The mass concentration of the formaldehyde aqueous solution is 5% to 42%, preferably 7% to 8%, and more preferably 7.65%; (3) The molar volume ratio of the 2-aminobenzenethiol to the organic solvent is 2-5 mmol / mL, preferably 2.4 mmol / mL; (4) The molar ratio of the 2-aminobenzenethiol to the formaldehyde is 1:(1.0-6.0), preferably 1:(1.2-1.4); (5) The reaction temperature of the cyclization reaction is 10-35°C, preferably 20-30°C; (6) The cyclization reaction comprises the following steps: 2-aminobenzenethiol is mixed with dichloromethane, and after cooling, an aqueous solution of formaldehyde is added to react; the cooling is preferably to 10-20°C; (7) The cyclization reaction further comprises the following steps: after the reaction is completed, the liquid is separated, the organic phase is washed with water, the liquid is separated, dried over anhydrous magnesium sulfate, filtered, and the organic phase is dried under reduced pressure to obtain compound A.

9. A method for preparing a compound as shown in formula I, characterized in that: It includes the following steps: Step 1, obtaining compound B according to the preparation method according to any one of claims 1 to 8; Step 2, in an organic solvent, compound B is subjected to an oxidation reaction with m-chloroperbenzoic acid to generate a compound as shown in formula I; 。 10. The preparation method according to claim 9, characterized in that: Step 2 satisfies one or more of the following conditions: (1) The organic solvent is an amide solvent, an ether solvent or a halogenated alkane solvent; the amide solvent is preferably N-methylpyrrolidone; the ether solvent is preferably tetrahydrofuran; the halogenated alkane solvent is preferably dichloromethane; (2) The molar volume ratio of the compound B to the organic solvent is 0.1-1.0 mmol / mL, preferably 0.6 mmol / mL; (3) The molar ratio of the compound B to the m-chloroperbenzoic acid is 1:(2.0-4.0), preferably 1:(2.0-3.0), and more preferably 1:3.0; (4) The reaction temperature of the reaction is 20-60°C, preferably 40-50°C; (5) The reaction comprises the following steps: Compound B is mixed with N-methylpyrrolidone, and after cooling, m-chloroperbenzoic acid is added to react; the cooling is preferably to 0-15°C; (6) The reaction further comprises the following steps: after the reaction is completed, extracting with sodium thiosulfate aqueous solution and ethyl acetate, back-extracting with purified water, concentrating the organic phase, and recrystallizing with anhydrous ethanol to obtain a compound as shown in Formula I; the concentration of the sodium thiosulfate aqueous solution is preferably 10%.

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