A method for preparing a high-purity dotenorazole key intermediate
By using a one-pot process to reduce 2-aminothiophenol, oxidize impurities, and directly cyclize and amidate it in the same reaction system, the problem of low purity and yield of key intermediates in dotenorazole has been solved, enabling efficient industrial production.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- BEIJING DONGXURI PHARM TECH CO LTD
- Filing Date
- 2026-04-14
- Publication Date
- 2026-06-30
AI Technical Summary
In the existing technology, 2-aminobenzylthiophenol and benzothiazoline have low stability, resulting in low yield and purity of key intermediates in dotenorazole, making them unsuitable for industrial production.
A one-pot process is adopted, in which a reducing agent is used in a mixture of organic solvent and water to oxidize and reduce 2-aminothiophenol impurities, which are then directly cyclized with formaldehyde and then subjected to an amidation reaction with 3,5-dichloro-4-methoxybenzoyl chloride. This process avoids separation steps and improves purity and yield.
It significantly improves the purity and yield of key intermediates in dotenoroxetine, simplifies the operation process, reduces production costs, and is suitable for industrial production.
Smart Images
Figure SMS_1 
Figure SMS_2 
Figure SMS_3
Abstract
Description
Technical Field
[0001] This invention belongs to the field of drug synthesis technology, and specifically relates to a method for preparing a high-purity dotenorazole key intermediate. Background Technology
[0002] Dotenorolac is a novel selective urate transporter inhibitor jointly developed by Fuji Pharmaceutical and Mochida Pharmaceutical. Eisai entered into a licensing agreement with Fuji Pharmaceutical in 2020, obtaining exclusive development and sales rights for this product in China. Compared to traditional gout medications, dotenorolac selectively inhibits urate reabsorption, resulting in a higher efficiency in lowering blood uric acid levels; it also does not affect intestinal uric acid excretion, thus reducing the burden on the kidneys. On December 6, 2024, the novel urate reabsorption inhibitor dotenorolac tablets (trade name: Ulexi) received approval from the National Medical Products Administration (NMPA) in China for the indication of gout with hyperuricemia.
[0003] Currently, the main routes for synthesizing dotenororil are as follows: Route 1: The original patent CN102639518B reports the synthetic route and preparation method of dotenororil. The synthetic approach involves condensing 2-aminothiophenol with formaldehyde to obtain benzo[d]thiazoline, which is then amidated with substituted benzoyl chloride to prepare the key intermediate benzo[d]thiazo-3(2H)-yl(3,5-dichloro-4-methoxyphenyl) ketone. This intermediate is then oxidized and demethylated to obtain the target compound dotenororil.
[0004]
[0005] The key intermediate compound of dotenorazole is named as: [d]thiazolyl-3(2H)-yl(3,5-dichloro-4-methoxyphenyl) methyl ketone The key intermediate structure of dotenorazole is as follows:
[0006] According to the synthesis method reported in the original patent CN102639518B, in the actual reproducibility experiment, it was found that 2-aminothiophenol itself is oxidized to produce a lot of 2,2'-dithiodiphenylamine, and the product benzothiazoline itself has poor stability. The post-processing involves complicated operations such as separation, extraction, brine washing, drying, and concentration, resulting in very poor purity of benzothiazoline. The yield after subsequent reaction with acyl chloride is only 30%, and the purity is not high.
[0007] Route 2: The routes reported in patents CN118271256 and CN111662247 are similar. After synthesizing benzothiazoline from 2-aminobenzylthiol, it is first oxidized to obtain benzothiazoline dioxide; then condensed with substituted benzoic acid, or after demethylation, to finally obtain dotenororil. The reaction route is as follows:
[0008] Both patents include a step of benzothiazoline oxidation, but due to the low stability of benzothiazoline itself, the purity and yield of the final oxide are extremely low, making it unsuitable for industrial production. Furthermore, the inventors were unable to reproduce the patent.
[0009] Route 3: Patent CN11675675 reports the synthesis of dotenoroxetine from 2-aminothiophenol as the starting material through amidation, cyclization and oxidation reactions.
[0010]
[0011] This route involves the direct reaction of 2-aminothiophenol with 3,5-dichloro-4-hydroxybenzoyl chloride. Due to the high reactivity of the amino and thiol groups in the structure, there are numerous reaction sites. Many byproducts are produced, and the resulting amide itself undergoes oxidative dehydration to form a thiazole ring impurity. This route has no practical reference value. Summary of the Invention
[0012] This invention addresses the shortcomings of existing technologies, such as the low stability of the starting material 2-aminobenzylthiol and the intermediate benzothiazoline, leading to low yields and purity of key intermediates requiring subsequent purification and ultimately resulting in high costs for the synthesis of dotenorolac. Compared to existing technologies, the method for preparing key intermediates of dotenorolac provided in this invention is more suitable for industrial production.
[0013] This invention provides a method for preparing a compound of formula I, comprising the following steps: The compound of formula III was reduced in a mixture of organic solvent and water under the action of a reducing agent. The product obtained in step one is directly cyclized with formaldehyde without separation to generate formula II; In the same reaction system, under the presence of a base, an amidation reaction is carried out with 3,5-dichloro-4-methoxybenzoyl chloride (Formula IV) to prepare the dotenoroxetine key intermediate shown in Formula I in a one-pot process.
[0014] The reaction formula is as follows:
[0015] In one specific embodiment, the compound of formula III in step (1) includes 2-aminothiophenol, 2,2'-dithiodiphenylamine, or a mixture thereof. Preferably, 2-aminothiophenol contains a small amount of oxidative degradation products, which can reduce the amount of reducing agent required.
[0016] In one specific embodiment, the reducing agent in step (1) includes one or more of tris(2-carboxyethyl)phosphine hydrochloride, dithiothreitol, β-mercaptoethanol, and sodium hydrosulfite. Tris(2-carboxyethyl)phosphine hydrochloride is preferred.
[0017] In one specific embodiment, the mixed solvent of organic solvent and water in step (1) is dichloromethane / water, ethyl acetate / water, tetrahydrofuran / water, or methyl tert-butyl ether / water. Dichloromethane / water or ethyl acetate / water is preferred.
[0018] In one specific implementation, the amount of tris(2-carboxyethyl)phosphine hydrochloride in step (1) is 0.05~0.5 eq, preferably 0.1 eq.
[0019] In one specific implementation, the reduction reaction temperature in step (1) is 0~40℃, preferably 20~30℃.
[0020] In one specific implementation, the amount of formaldehyde used in step (2) is 1~1.30eq, preferably 1.3eq.
[0021] In one specific implementation, the cyclization reaction temperature in step (2) is 0~40℃, preferably 10~30℃.
[0022] In one specific implementation, the cyclization reaction time in step (2) is 1 to 3 hours, preferably 2 hours.
[0023] As a specific implementation, the amount of 3,5-dichloro-4-methoxybenzoyl chloride IV used in step (3) is preferably 1.0 eq.
[0024] In one specific implementation, the type of alkali in step (3) is one of potassium bicarbonate, potassium hydroxide, sodium bicarbonate, sodium hydroxide, triethylamine, and pyridine, and is more preferably potassium bicarbonate or sodium bicarbonate.
[0025] In one specific implementation, the amount of alkali used in step (3) is 1-3 eq, preferably 1.4-2 eq, and more preferably 1.5-1.7 eq.
[0026] As a specific implementation method, the reaction temperature in step (3) is 0~30℃, and more preferably 20~30℃.
[0027] Compared with existing technologies, the advantages of this invention are as follows: 1) The oxidized impurity 2,2'-dithiodiphenylamine generated during the production and storage of 2-aminobenzylthiophenol is first reduced back, without affecting the subsequent cyclization reaction, thus improving purity and yield. It also reduces the severity of storage conditions for 2-aminobenzylthiophenol. 2) All three steps are carried out in the same system without separation, which not only simplifies operation but also avoids the degradation of benzothiazoline, significantly improving the yield and purity of the key intermediate. 3) The one-pot preparation process greatly simplifies operation, avoiding the repeated extraction, washing, and concentration steps required in traditional processes, and minimizing the possibility of continuous oxidation of 2-aminobenzylthiophenol during repeated operations, thereby ensuring the prevention of oxidized impurity formation during the process. The reaction conditions are mild, making it more suitable for industrial-scale production. Detailed Implementation
[0028] The present invention will be described in detail below with reference to embodiments. These embodiments will help those skilled in the art to further understand the present invention, but do not limit the invention in any way. It should be noted that those skilled in the art can make several adjustments and improvements without departing from the concept of the present invention. These all fall within the protection scope of the present invention.
[0029] Example 1 Preparation of 3,5-dichloro-4-methoxybenzoyl chloride (Formula IV)
[0030] 3,5-Dichloro-4-methoxybenzoyl chloride (88.28 g) was dissolved in tetrahydrofuran (441 ml), and then N,N-dimethylformamide (2.92 g) was added. The mixture was stirred and cooled to 0–20 °C. Thionyl chloride (61.77 g) was added dropwise while maintaining the temperature below 20 °C. After the addition was complete, the mixture was refluxed for 1 hour. After the reaction was complete, the solution was concentrated under reduced pressure until no solvent remained. 3,5-Dichloro-4-methoxybenzoyl chloride (Formula IV) was obtained, with a purity of 99.526% as determined by HPLC. This solution was directly used in the next step.
[0031] Example 2 Preparation of benzothiazoline (Formula II)
[0032] 50.00 g of 2-aminothiophenol (Formula III) was dissolved in 500 ml of dichloromethane and stirred. 11.45 g of tris(2-carboxyethyl)phosphonic acid hydrochloride was dissolved in 250 ml of purified water and added to the reaction mixture. The mixture was stirred at room temperature for 1 hour (the reaction solution gradually changed from deep yellow to colorless). After the reaction was complete, 59.91 g of potassium bicarbonate was dissolved in 500 ml of purified water, and 42.14 g of 37% formaldehyde solution was added and shaken well before being added to the reaction mixture. The mixture was kept at this temperature for 1 hour. HPLC analysis showed a purity of 97.889%, which was then used directly in the next reaction step.
[0033] Example 3 Preparation of [d]thiazol-3(2H)-yl(3,5-dichloro-4-methoxyphenyl) methyl ketone (Formula I)
[0034] The compound of formula IV obtained in Example 1 was dissolved in dichloromethane (500 ml) and added dropwise to the benzothiazoline reaction solution in Example 2. After the addition was complete, the reaction was allowed to proceed at room temperature for 1 h. The mixture was allowed to stand and separated. The organic phase was washed with 1M hydrochloric acid (1000 ml) and concentrated under reduced pressure until a large amount of solid precipitated. Isopropanol (500 ml) was added dropwise, the mixture was cooled to room temperature, filtered, and the filter cake was first washed with isopropanol (150 ml), then with purified water (150 ml), and dried under reduced pressure at 45 °C to obtain 123.73 g of white solid (formula I), yield 91.06%, HPLC purity 99.518%. MS (ESI+): m / z = 340.10, 342.05 [M+H] + Comparative Example 1 (Benzothiazoline (Formula II) was isolated and Formula I was synthesized stepwise) 1) Preparation of 3,5-dichloro-4-methoxybenzoyl chloride (Formula IV) 3,5-Dichloro-4-methoxybenzoyl chloride (8.83 g) was dissolved in tetrahydrofuran (44 ml), and then N,N-dimethylformamide (0.29 g) was added. The mixture was stirred and cooled to 0–20 °C. Thionyl chloride (6.18 g) was added dropwise while maintaining the temperature below 20 °C. After the addition was complete, the mixture was refluxed for 1 hour. After the reaction was complete, the solution was concentrated under reduced pressure until no solvent remained. 3,5-Dichloro-4-methoxybenzoyl chloride (Formula IV) was obtained and used directly in the next step.
[0035] 2) Preparation of benzothiazoline (Formula II) (post-processing separation) 5.00 g of 2-aminothiophenol (Formula III) was dissolved in 50 ml of dichloromethane and stirred. 1.15 g of tris(2-carboxyethyl)phosphonic acid hydrochloride was dissolved in 25 ml of purified water and added to the reaction mixture. The mixture was stirred at room temperature for 1 hour (the reaction solution gradually changed from a deep yellow to colorless). After the reaction was complete, 1.59 g of potassium bicarbonate was dissolved in 50 ml of purified water, and 4.21 g of 37% formaldehyde solution was added and shaken well before being added to the reaction mixture. The mixture was kept at this temperature for 1 hour. The mixture was allowed to stand and separated (under nitrogen protection). The aqueous phase was extracted with 30 ml of dichloromethane. The combined organic phases were washed with 50 ml of saturated saline solution, and the purity was determined by HPLC to be 86.773%. This mixture was then used directly in the next reaction. (Post-treatment observation: Despite nitrogen protection during post-treatment, the organic phase color gradually deepened from pale yellow to a deep yellow after separation, extraction, and washing, indicating that some of the benzothiazoline product was degraded.) 3) Preparation of benzo[d]thiazol-3(2H)-yl(3,5-dichloro-4-methoxyphenyl) methyl ketone (Formula I) The obtained compound II solution was dissolved in 75 ml of purified water with 3.99 g of potassium bicarbonate and added to the reaction mixture. The obtained compound IV solution was dissolved in 50 ml of dichloromethane and added dropwise to the benzothiazoline reaction solution. After the addition was complete, the reaction was allowed to proceed at room temperature for 1 h. The mixture was allowed to stand and separated. The organic phase was washed with 1 M hydrochloric acid (100 ml) and concentrated under reduced pressure until a large amount of solid precipitated. Isopropanol (50 ml) was added dropwise, the mixture was cooled to room temperature, filtered, and the filter cake was first washed with isopropanol (15 ml) and then with purified water (15 ml). The mixture was then dried under reduced pressure at 45 °C to obtain 9.12 g of pale yellow solid, yield 66.84%, HPLC purity 91.71%. (Observations during the reaction: A white, unknown solid was formed, and this impurity was insoluble in any organic solvent. It is speculated that it is a product of the reaction between 2-aminothiophenol, which is a product of the degradation of benzothiazoline, and acyl chloride, and the resulting multi-molecular coupling. Ultimately, this resulted in a yield reduction of about 25% compared to the one-pot process.) Comparative Example 2 (One-pot synthesis of Formula I, and synthesis of Formula II without reducing agent) 1) Preparation of 3,5-dichloro-4-methoxybenzoyl chloride (Formula IV) 3,5-Dichloro-4-methoxybenzoyl chloride (8.83 g) was dissolved in tetrahydrofuran (44 ml), and then N,N-dimethylformamide (0.29 g) was added. The mixture was stirred and cooled to 0–20 °C. Thionyl chloride (6.18 g) was added dropwise while maintaining the temperature below 20 °C. After the addition was complete, the mixture was refluxed for 1 hour. After the reaction was complete, the solution was concentrated under reduced pressure until no solvent remained. 3,5-Dichloro-4-methoxybenzoyl chloride (Formula IV) was obtained and used directly in the next step.
[0036] 2) Preparation of benzothiazoline (Formula II) (reduction without reducing agent) 5.00 g of 2-aminothiophenol (Formula III) was dissolved in 50 ml of dichloromethane under stirring and nitrogen protection. 4.21 g of 37% formaldehyde solution was dissolved in 50 ml of purified water, then added to the reaction mixture after shaking well. The mixture was kept at this temperature for 1 hour and then used directly in the next reaction step. (Reaction phenomenon: Despite nitrogen protection, the organic phase gradually darkened from yellow to a deep yellow.) 3) Preparation of [d]thiazol-3(2H)-yl(3,5-dichloro-4-methoxyphenyl) methyl ketone (Formula I) Add 3.99 g of potassium bicarbonate to the solution of compound II obtained above. Dissolve compound IV obtained in step one in 50 ml of dichloromethane and add it dropwise to the benzothiazoline reaction solution. After the addition is complete, react at room temperature for 1 h. Allow to stand and separate the liquids. Wash the organic phase with 1 M hydrochloric acid (100 ml) and concentrate under reduced pressure until a large amount of solid precipitates. Add isopropanol (50 ml) dropwise, cool to room temperature, filter, wash the filter cake first with isopropanol (15 ml), then with purified water (15 ml), and dry under reduced pressure at 45 °C to obtain 8.65 g of yellow solid ([d]thiazo-3(2H)-yl(3,5-dichloro-4-methoxyphenyl) ketone (formula I), yield 63.63%, HPLC purity 88.73%. (Results Analysis: The starting material 2-aminobenzylthiophenol oxidizes during storage and use to produce 2,2'-dithiodiphenylamine. This impurity can react with Formula IV to generate impurity N,N'-(dithiodimethylbis(2,1-phenylene))bis(3,5-dichloro-4-methoxybenzamide), ultimately resulting in very low yield and purity.) Comparative Example 3 (Preparation method of original patent CN102639518B) 1) Preparation of benzothiazoline Dilute 5.2 mL of 37% formalin with 80 mL of water, add 80 mL of diisopropyl ether and 7.84 g of 2-aminobenzenethiol, and stir at room temperature for 30 minutes. Separate the organic layer, and extract the aqueous layer with 30 mL of diisopropyl ether. Combine the organic layers and wash with 80 mL of saturated brine, then dry with anhydrous sodium sulfate. Remove the solvent by vacuum distillation to obtain a deep yellow oil. Use directly in the next reaction.
[0037] 2) Preparation of [d]thiazol-3(2H)-yl(3,5-dichloro-4-methoxyphenyl) methyl ketone (Formula I) The synthesized benzothiazoline was dissolved in chloroform (50 mL), and triethylamine (17.4 mL) and 3,5-dichloro-4-methoxybenzoyl chloride (formula IV) synthesized according to Example 1 were added. The mixture was stirred at room temperature for 1 hour. The solvent was removed by vacuum distillation, and water was added and extracted with ethyl acetate. Observations during the reaction: A white solid was produced after the addition of triethylamine; and after concentration, it could not be dissolved by ethyl acetate. Only a small amount of product was present in the organic phase, along with a large amount of impurity N,N'-(dithiodimethylbis(2,1-phenylene))bis(3,5-dichloro-4-methoxybenzoamide). The experiment was terminated, and no further treatment was performed.
[0038] It should be noted that the above preferred embodiments are merely illustrative of the technical concept and features of the present invention, and are intended to enable those skilled in the art to understand the content of the present invention and implement it accordingly. They should not be construed as limiting the scope of protection of the present invention. All equivalent changes or modifications made in accordance with the spirit and essence of the present invention should be covered within the scope of protection of the present invention.
Claims
1. A process for the preparation of a compound of formula I ###0001### characterized in that, The synthesis method includes the following steps: The compound of formula III was reduced in a mixture of organic solvent and water under the action of a reducing agent. The product obtained in step one is directly cyclized with formaldehyde without separation to generate formula II; In the same reaction system, in the presence of a base, an amidation reaction was carried out with 3,5-dichloro-4-methoxybenzoyl chloride (Formula IV) to prepare the key intermediate of dotenorazole as shown in Formula I in a one-pot process. The reaction formula is as follows: Wherein, the compound of formula III is 2-aminobenzylthiophenol, 2,2'-dithiodiphenylamine or a mixture thereof; the reducing agent is selected from one or more of tris(2-carboxyethyl)phosphine hydrochloride, dithiothreitol, β-mercaptoethanol, and sodium hydrosulfite.
2. The method of claim 1, wherein, The reducing agent is further preferably tris(2-carboxyethyl)phosphine hydrochloride.
3. The method of claims 1-2, wherein, The amount of tris(2-carboxyethyl)phosphine hydrochloride used in step (1) is 0.05~2 eq.
4. The method of claim 1, wherein, The mixed solvent of organic solvent and water mentioned in step (1) is dichloromethane / water, ethyl acetate / water, tetrahydrofuran / water, and more preferably dichloromethane / water.
5. The method of claim 1, wherein, The alkali mentioned in step (3) is one of potassium bicarbonate, potassium hydroxide, sodium bicarbonate, sodium hydroxide, triethylamine, and pyridine, and is more preferably potassium bicarbonate or sodium bicarbonate.
6. The method of claim 1, wherein, The amount of alkali used in step (3) is 1~3 eq, preferably 1.4~2 eq, and more preferably 1.5~1.7 eq.
7. The method according to claims 1 to 4, characterized in that, After step (1) is completed, without separating and purifying the intermediate product, formaldehyde is directly added to the reaction system of step (1) to carry out the cyclization reaction of step (2); after step (2) is completed, without separating and purifying the intermediate product, acid-binding agent and 3,5-dichloro-4-methoxybenzoyl chloride are directly added to the reaction system of step (2) to carry out the amidation reaction of step (3); optionally, the reaction temperature can be adjusted or solvent can be added between each step, but the intermediate product is not separated.
8. The method according to claims 1 to 6, characterized in that, After completing all steps, the content of the related substance specific impurity 2,2'-dithiodiphenylamine in the key intermediate I obtained is less than 0.05%.