Preparation method of dotenorad key intermediate

Abstract

The invention discloses a preparation method of a dotenorad key intermediate (a compound shown as a formula I), which comprises the following steps: alkalizing 2-aminothiophenol to generate 2-aminothiophenol sodium salt, carrying out cyclization reaction on the 2-aminothiophenol sodium salt and formaldehyde, and finally condensing the 2-aminothiophenol sodium salt and 3, 5-dichloro-4-methoxybenzoyl chloride to obtain the dotenorad key intermediate (the compound shown as the formula I).

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical chemistry, and specifically relates to a method for preparing a key intermediate of polytinorel. Background Art

[0002] Dotinurad is a new type of gout and hyperuricemia treatment drug developed by Fuji Pharmaceuticals. Dotinurad inhibits uric acid reabsorption and reduces uric acid levels in the blood by selectively inhibiting the urate transporter (URAT1) involved in uric acid reabsorption in the kidney. In 2020, Dotinurad tablets were approved for marketing in Japan as a once-daily oral therapy for the treatment of hyperuricemia with or without gout. On January 22, 2024, the official website of the Center for Drug Evaluation (CDE) of the China National Drug Administration announced that Eisai China's application for marketing approval of Dotinurad tablets under registration classification 5.1 has been accepted. The chemical structure of Dotinurad is as follows:

[0003]

[0004] The original patent CN102639518B reported the synthesis route and preparation method of polytinol. The synthesis idea is to obtain benzothiazole by condensing 2-aminothiophenol with formaldehyde, and benzothiazole is prepared by amidation reaction with substituted benzoyl chloride to obtain the key intermediate benzo[d]thiazol-3(2H)-yl(3,5-dichloro-4-methoxyphenyl)methanone, and the intermediate is oxidized and deprotected to obtain the target compound polytinol.

[0005]

[0006] The chemical name of the key intermediate of dotinorel is: benzo[d]thiazol-3(2H)-yl(3,5-dichloro-4-methoxyphenyl)methanone, and the chemical structure is as follows:

[0007]

[0008] According to the synthesis method of polytinol reported in the original research patent CN102639518B, it was found that the starting material 2-aminothiophenol has poor stability and is easy to self-condense to produce the compound bis(2-aminophenyl) disulfide impurity, which is not conducive to the preparation of benzothiazoline. According to the preparation method of CN102639518B in the patent, the product obtained in the first step of the reaction is mainly bis(2,3-dihydrobenzo[d]thiazol-2-yl)methane, and benzothiazoline cannot be obtained, that is, the key intermediate compound of formula I cannot be obtained in the subsequent reaction.

[0009]

[0010] A similar preparation method / route of polytinol is also reported in Chinese patent CN111793039A, which is as follows:

[0011]

[0012] The patent uses p-hydroxybenzoic acid and 2-aminothiophenol as starting materials, performs a condensation reaction under the action of a condensing agent, then undergoes a cyclization reaction with polyformaldehyde, and then undergoes an oxidation reaction with an oxidant to obtain polytinol. This method also cannot avoid the problem of poor reaction effect and many by-products due to the condensation of 2-aminothiophenol. In addition, the use of a condensing agent during the reaction may leave residues in the final product and thus affect the product quality. Summary of the invention

[0013] In view of the shortcomings of the prior art, the present invention aims to provide a simple and easy-to-operate method for preparing a key intermediate of polythiophenol (compound of formula I). ​​In the reaction process, 2-aminothiophenol is first alkalized to generate 2-aminothiophenol sodium salt, which is then cyclized with formaldehyde, and finally condensed with 3,5-dichloro-4-methoxybenzoyl chloride to obtain the key intermediate of polythiophenol (compound of formula I).

[0014] Specifically, the purpose of the present invention is achieved through the following technical solutions:

[0015] (1) reacting the starting material 2-aminothiophenol with an alkaline reagent in an organic solvent to prepare 2-aminothiophenol sodium salt;

[0016]

[0017] (2) 2-aminothiophenol sodium salt undergoes a cyclization reaction with formaldehyde to prepare benzothiazoline;

[0018]

[0019] (3) benzothiazoline is condensed with 3,5-dichloro-4-methoxybenzoyl chloride under the action of an organic base to prepare the key intermediate compound of formula I of dotinorel;

[0020]

[0021] As a specific implementation, in step (1), the alkaline reagent is sodium hydride, and the organic solvent is any one of tetrahydrofuran, toluene, isopropyl ether, and methyl tert-butyl ether.

[0022] As a preference, the organic solvent in step (1) is tetrahydrofuran.

[0023] As a specific implementation manner, in step (1), the molar ratio of 2-aminothiophenol to sodium hydride is 1:1-1:5.

[0024] As a preference, in step (1), the molar ratio of 2-aminothiophenol to sodium hydride is 1:1-1:2.

[0025] As a specific implementation, the reaction temperature of step (1) is -5-10°C.

[0026] As a preference, the reaction temperature of step (1) is -5-5°C.

[0027] As a specific implementation, the reaction solvent in step (2) is toluene and water, wherein the volume ratio of toluene to water is 1:1.

[0028] As a specific implementation, the organic base in step (3) is triethylamine, and the reaction temperature is room temperature.

[0029] The advantages of the present invention are:

[0030] 1) The reaction has a high tolerance to the dimer impurity (bis(2-aminophenyl) disulfide) easily generated during the storage of the starting material 2-aminothiophenol. The dimer impurity (bis(2-aminophenyl) disulfide) contained in 2-aminothiophenol will be decomposed into 2-aminothiophenol (sodium salt) again during the treatment of the alkaline reagent, which does not affect the subsequent reaction, and the yield of benzothiazoline is high;

[0031] 2) The post-treatment is simple. After the reaction is completed, the sodium salt can be obtained by simple filtration, which is easy for industrial production;

[0032] 3) The intermediate synthesis process is simple and does not require the addition of auxiliary reagents such as condensation agents. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] Other features, objects and advantages of the present invention will become more apparent from the detailed description of non-limiting embodiments made with reference to the following drawings:

[0034] Figure 1 NMR spectrum of the key intermediate compound of formula I of dotinorel DETAILED DESCRIPTION

[0035] The synthetic route of the key intermediate compound of formula I of polytinol of the present invention is as follows:

[0036]

[0037] The present invention is described in detail below in conjunction with embodiments. The following embodiments will help those skilled in the art to further understand the present invention, but are not intended to limit the present invention in any form. It should be noted that, for those of ordinary skill in the art, some adjustments and improvements can also be made without departing from the concept of the present invention. These all belong to the protection scope of the present invention.

[0038] Embodiment 1:

[0039] Preparation of benzothiazoline

[0040] In a 100 mL reaction bottle, add 45 mL of tetrahydrofuran, cool to 0°C, add 1.16 g (28.76 mmol) of sodium hydride NaH in batches; control the internal temperature not higher than 5°C, add 3 g (23.96 mmol) of 2-aminothiophenol dropwise, react at 0-5°C for 2 hours, and when the reaction is complete, concentrate under reduced pressure to remove the organic solvent. Slurry the concentrated residue with petroleum ether, filter, and dry under reduced pressure at 40°C to obtain 4 g of a white solid.

[0041] Take 1.15 g (6.79 mmol) of the above solid and add it to a reaction bottle, add 10 mL of water and 10 mL of toluene, add 0.55 g (6.079 mmol) of formaldehyde dropwise, react at room temperature for 2 hours, then heat to 50 ° C, and continue to react for 1 hour; separate the liquids, extract the aqueous phase once with toluene, combine the organic phases, wash twice with saturated brine, dry over anhydrous sodium sulfate, filter, and obtain a benzothiazoline toluene solution, which is directly used in the next step.

[0042] Preparation of benzo[d]thiazol-3(2H)-yl(3,5-dichloro-4-methoxyphenyl)methanone (Intermediate Formula I compound)

[0043] The benzothiazoline toluene solution obtained in the previous step was added to a reaction flask, and 1 g (10.18 mmol) of triethylamine was added. A toluene (5 mL) solution of 1.6 g (6.79 mmol) of 3,5-dichloro-4-methoxybenzoyl chloride was added dropwise at room temperature. The reaction was carried out for about 2 hours, and the organic solvent was removed by concentration under reduced pressure. The concentrated residue was slurried with methyl tert-butyl ether, filtered, and dried under reduced pressure at 40°C to obtain 1.70 g of a white solid with a yield of 77% and a HPLC purity of 99.7%.

[0044] Embodiment 2:

[0045] Preparation of benzothiazoline

[0046] In a 1000mL reaction bottle, add 300mL tetrahydrofuran, cool to 0°C, add 7.7g (191.7mmol) sodium hydride NaH in batches; control the internal temperature not higher than 5°C, add 20g (159.7mmol) 2-aminothiophenol dropwise, react at 0-5°C for 3 hours, and when the reaction is complete, concentrate under reduced pressure to remove the organic solvent. Slurry the concentrated residue with petroleum ether, filter, and dry under reduced pressure at 40°C to obtain 23.4g white solid.

[0047] Take 23.4 g of the above solid and add it to a reaction bottle, add 200 mL of water and 200 mL of toluene, add 14.4 g (159.7 mmol) of formaldehyde dropwise, react at room temperature for 2 hours, then raise the temperature to 50 ° C, and continue to react for 1 hour; separate the liquids, extract the aqueous phase once with toluene, combine the organic phases, wash twice with saturated brine, dry over anhydrous sodium sulfate, filter, and obtain a benzothiazoline toluene solution, which is directly used in the next step.

[0048] Preparation of benzo[d]thiazol-3(2H)-yl(3,5-dichloro-4-methoxyphenyl)methanone (Intermediate Formula I compound)

[0049] The benzothiazoline toluene solution obtained in the previous step was added to a reaction flask, and 25 g (247.0 mmol) of triethylamine was added. A toluene (200 mL) solution of 41.4 g (175.7 mmol) of 3,5-dichloro-4-methoxybenzoyl chloride was added dropwise at room temperature. The reaction was carried out for about 2 hours, and the organic solvent was removed by concentration under reduced pressure. The concentrated residue was slurried with methyl tert-butyl ether, filtered, and dried under reduced pressure at 40° C. to obtain 36.8 g of a white solid with a yield of 68% and a HPLC purity of 98.8%. 1 HNMR (CDCl3, 400MHz) δ: 7.49ppm (s, 2H), 7.00-7.26ppm (m, 4H), 5.26ppm (s, 2H), 3.95ppm (s, 3H).

[0050] Comparative Example 1: (Preparation method in patent CN102639518B)

[0051] Preparation of benzothiazoline

[0052] In a 100 mL reaction bottle, add 30 mL of water and 3 mL of formaldehyde, stir, add 30 mL of isopropyl ether and 3 g (23.96 mmol) of 2-aminothiophenol in sequence, and react at 20-30 ° C for 3 hours; after the reaction is completed, stand and separate the liquids, retain the organic phase, extract the aqueous phase with isopropyl ether three times, combine the organic phases, wash the organic phase with saturated brine, dry it with anhydrous sodium sulfate, and concentrate to dryness under reduced pressure. The concentrated residue is directly used in the next step.

[0053] Preparation of benzo[d]thiazol-3(2H)-yl(3,5-dichloro-4-methoxyphenyl)methanone

[0054] Add 100 mL of dichloromethane and the residue from the previous step of concentration to the reaction flask, stir, and the solution becomes clear; add 3 g (29.16 mmol) of triethylamine, and dropwise add a solution of 3.8 g (16.04 mmol) of 3,5-dichloro-4-methoxybenzoyl chloride in dichloromethane (4 mL), and react for 3 hours. The central control shows no reaction, and the target product, benzo[d]thiazol-3(2H)-yl(3,5-dichloro-4-methoxyphenyl)methanone, is not obtained.

[0055] Comparative Example 2: (Preparation method in patent CN102639518B)

[0056] Preparation of benzothiazoline

[0057] In a 1000mL reaction bottle, add 400mL of water and 20mL of formaldehyde, stir, add 400mL of isopropyl ether and 20g of 2-aminothiophenol in sequence, and react at 20-30°C for 3 hours. After the reaction is completed, a large amount of solid precipitates, which is filtered and dried under reduced pressure at room temperature to obtain 10g of solid. HNMR shows bis(2,3-dihydrobenzo[d]thiazol-2-yl)methane. 1 HNMR (CDCl3, 400MHz) δ: 7.11-7.13ppm (m, 2H), 6.97-7.02ppm (m, 2H), 6.76-6.80ppm (m, 2H), 6.63-6.66ppm (m, 2H), 4.82ppm (m, 4H), 4.55ppm (s, 2H).

[0058] The above describes the specific embodiments of the present invention. It should be understood that the present invention is not limited to the above specific embodiments, and those skilled in the art may make various modifications or variations within the scope of the claims, which do not affect the essence of the present invention.

Claims

1. A method for preparing a key intermediate of polytinoride, characterized in that: The method comprises the following steps: (1) reacting the starting material 2-aminothiophenol with an alkaline reagent in an organic solvent to prepare 2-aminothiophenol sodium salt; (2) 2-aminothiophenol sodium salt undergoes a cyclization reaction with formaldehyde to prepare benzothiazoline; (3) benzothiazoline is condensed with 3,5-dichloro-4-methoxybenzoyl chloride under the action of an organic base to prepare the key intermediate compound of formula I of dotinorel; 2. The method for preparing the key intermediate of polytinoride according to claim 1, characterized in that: In step (1), the alkaline reagent is sodium hydride, and the organic solvent is any one of tetrahydrofuran, toluene, isopropyl ether, and methyl tert-butyl ether.

3. The method for preparing the key intermediate of polytinoride according to claim 2, characterized in that: In step (1), the organic solvent is tetrahydrofuran.

4. The method for preparing the key intermediate of polytinoride according to claim 1, characterized in that: In step (1), the molar ratio of 2-aminothiophenol to sodium hydride is 1:1-1:

5.

5. The method for preparing the key intermediate of polytinoride according to claim 4, characterized in that: In step (1), the molar ratio of 2-aminothiophenol to sodium hydride is 1:1-1:

2.

6. The method for preparing the key intermediate of polytinoride according to claim 1, characterized in that: The reaction temperature of step (1) is -5-10°C.

7. The method for preparing the key intermediate of polytinoride according to claim 6, characterized in that: The reaction temperature of step (1) is -5-5°C.

8. The method for preparing the key intermediate of polytinoride according to claim 1, characterized in that: The reaction solvent in step (2) is toluene and water, wherein the volume ratio of toluene to water is 1:

1.

9. The method for preparing the key intermediate of polytinoride according to claim 1, characterized in that: In step (3), the organic base is triethylamine and the reaction temperature is room temperature.

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