Method for synthesizing dotenorad

Abstract

The invention belongs to the technical field of chemical synthesis of drugs, and particularly discloses a novel synthetic route of an anti-hyperuricemia drug dotinirad (Dotinirad, the CAS number is 1285572-51-1, and the chemical name is 3-(3, 5-dichloro-4-hydroxybenzoyl)-1, 1-dioxo-2, 3-dihydro-1, 3-benzothiazole). The invention further discloses a preparation method of the dotinirad, the CAS number is 1285572-51-1, and the chemical name is 3-(3, 5-dichloro-4-hydroxybenzoyl)-1, 1-dioxo-2, 3-dihydro-1, 3-benzothiazole. According to the route, p-hydroxybenzoic acid which is low in price and easy to obtain serves as a starting raw material, a target product is obtained through four-step reaction of chlorination, acylating chlorination, amide condensation and oxidation, the method has the advantages of being short in step, mild in condition and high in yield, use of 2-aminothiophenol which is odorous and unstable is avoided, benzothiazole which is more stable and low in price is used as a raw material, and the method is suitable for industrial production. The concept of green chemistry is met. The industrial production cost is remarkably reduced, and an efficient and reliable technical scheme is provided for large-scale production of the dotenorad.

Description

Technical Field

[0001] This invention relates to a method for synthesizing dotenoroxetine, belonging to the field of medicinal chemistry. The structure of dotenoroxetine is as follows: . Background Technology

[0002] Hyperuricemia (HU) is defined as a serum uric acid (SUA) level ≥7.0 mg / dL (416.0 μmol / L) in men or ≥6.0 mg / dL (357.0 μmol / L) in women under normal purine dietary conditions. Hyperuricemia is a metabolic disorder characterized by elevated serum uric acid concentrations in extracellular fluid and tissues, coupled with impaired uric acid excretion. The prevalence of hyperuricemia is increasing globally, severely impacting the quality of life for affected individuals.

[0003] Dotinurad, chemically named 3-(3,5-dichloro-4-hydroxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole (CAS number 1285572-51-1), is a novel selective uric acid reabsorption inhibitor developed by Fujifilm Toyama Chemical Co., Ltd. of Japan for the treatment of hyperuricemia and gout. Compared to traditional drugs such as allopurinol and febuxostat, dotinurad has advantages such as faster onset of action, less impact on renal function, and fewer drug interactions, and has broad prospects for clinical application.

[0004] Existing synthetic routes for dotenorazole include: Route 1: Patent ZL201080042866.9. This patent is for the dotenorazole compound and uses 2-aminobenzylthiol as a starting material. It cyclizes 2,3-dihydro-1,3-benzothiazole, which is 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 dotenorazole. This method requires a high temperature of approximately 140°C for the final deprotection step, resulting in a long reaction time, numerous impurities in the reaction system, and difficulty in purification. Furthermore, the starting material 2-aminobenzylthiol has a foul odor and is unstable, and the purification of 2,3-dihydro-1,3-benzothiazole is complex.

[0005] .

[0006] Route 2: This route was reported in ZL202010693795.4. This route is a preparation process reported by Suzhou Mingrui Pharmaceutical Technology. This route uses expensive condensation reagents, which is costly and not suitable for industrial production.

[0007] .

[0008] Route 3: This route was reported in CN111662247A. This synthetic method uses 2,3-dihydrobenzothiazole as the starting material, which undergoes an oxidation reaction to obtain an oxidized intermediate. This intermediate then undergoes a condensation reaction with 3,5-dichloro-4-hydroxybenzoic acid to yield dotenorazole. The starting material 2,3-dihydrobenzothiazole used in this route also requires the use of unstable 2-aminobenzylthiophenol for synthesis, making purification difficult.

[0009] .

[0010] Therefore, developing a method with mild reaction conditions and simple operation for the industrial production of dotenoroxetine is a technical problem that urgently needs to be solved in this field. Summary of the Invention

[0011] This invention provides a method for synthesizing dotenororic acid to overcome the above-mentioned defects of the prior art. This method has a short reaction step, uses more stable raw materials and reagents, is more environmentally friendly, and has the advantages of high yield, low cost and environmental friendliness.

[0012] The technical solution of the present invention is as follows: A method for synthesizing the antiuric acid drug dotenorfat, characterized by comprising the following steps: Step 1: Using p-hydroxybenzoic acid as the starting material, a chlorination reaction is carried out in a mixed solvent of AcOH / H2O under the action of chlorination reagents FeCl3 / H2O2 / HCl at 40°C to obtain the intermediate 2,6-dichloro-4-hydroxybenzoic acid; Step 2: The intermediate 2,6-dichloro-4-hydroxybenzoic acid reacts with SOCl2 in the presence of DMF in toluene solvent under certain conditions to give the intermediate 2,6-dichloro-4-hydroxybenzoyl chloride. Step 3: The intermediate 2,6-dichloro-4-hydroxybenzoyl chloride and benzothiazole undergo an amide condensation reaction in acetonitrile solvent under the action of BH3·NMe3 to obtain the intermediate 3-(3,5-dichloro-4-hydroxybenzoyl)-2,3-dihydro-1,3-benzothiazole; Step 4: The intermediate 3-(3,5-dichloro-4-hydroxybenzoyl)-2,3-dihydro-1,3-benzothiazole was oxidized with mCPBA in DCM solvent at room temperature to obtain the target product dotenorazole.

[0013] The reaction route for this synthesis method is as follows: ; Preferably, in step 1, the amount of FeCl3 used is 0.01-0.1 times (catalytic amount) of the molar amount of p-hydroxybenzoic acid, preferably 0.01 times.

[0014] Preferably, in step 1, the volume ratio of AcOH to H2O in the AcOH / H2O mixed solvent is 8:1 to 1:1, preferably 8:1.

[0015] Preferably, in step 1, the ratio of 30% hydrogen peroxide and 36% concentrated hydrochloric acid to p-hydroxybenzoic acid is 2.2 ml: 3.1 ml: 1 g; and the reaction temperature in step 1 is 40°C.

[0016] Preferably, in step 2, the molar ratio of SOCl2 and DMF to the intermediate 2,6-dichloro-4-hydroxybenzoic acid is 1-3.5 : 0.05-0.1 : 1, preferably 2:0.1:1; and the reaction temperature in step 1 is 60°C.

[0017] Preferably, in step 3, the molar ratio of BH3·NMe3 and benzothiazole to the intermediate 2,6-dichloro-4-hydroxybenzoyl chloride is 1-1.2:1-1.05:1, preferably 1.2:1:1; and the reaction temperature in step 1 is 20-25℃.

[0018] Preferably, in step 4, the molar ratio of mCPBA to the intermediate 3-(3,5-dichloro-4-hydroxybenzoyl)-2,3-dihydro-1,3-benzothiazole is 2-6:1, preferably 6:1; and the reaction temperature in step 1 is 20-25°C.

[0019] Compared with the prior art, the beneficial effects of the present invention are as follows: The main route of this invention is relatively short, and the target product dotenoroxetine is obtained through four steps of reaction: chlorination, acyl chloride, amide condensation and oxidation. It has the advantages of short steps, mild conditions and high yield, which is conducive to industrial production.

[0020] Compared to existing methods, this invention avoids the use of 2-aminothiophenol, which has an irritating odor and is unstable. By using a new activator, BH3·NMe3, the amide condensation reaction can also be completed using benzothiazole, which is more stable and inexpensive. This aligns with the principles of green chemistry, is environmentally friendly, and provides an efficient and reliable technical solution for the large-scale production of dotenorazole. Detailed Implementation

[0021] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of protection of the present invention. Improvements and adjustments made by those skilled in the art based on the present invention in practical applications still fall within the scope of protection of the present invention.

[0022] Example 1: Step 1: Synthesis of intermediate 2,6-dichloro-4-hydroxybenzoic acid SM1: p-Hydroxybenzoic acid (10.0 g, 72.4 mmol) and FeCl3 (0.12 g, 0.72 mmol) were added to a mixed solvent of AcOH / H2O (8:1 volume ratio, 90 mL) and stirred to dissolve. The temperature was controlled at 40 °C, and 30% H2O2 (22.0 mL) and 36% concentrated HCl (31.0 mL) were added sequentially. The reaction was kept at this temperature for 3 h. The reaction solution was cooled to room temperature, and a solid precipitated. After filtration, the solid was washed three times with deionized water (50 mL each time) and dried under vacuum at 60 °C for 4 h to obtain the intermediate 2,6-dichloro-4-hydroxybenzoic acid (13.8 g, yield 92.3%).

[0023] Step 2: Synthesis of intermediate 2,6-dichloro-4-hydroxybenzoyl chloride SM2: Intermediate SM1 (15.0 g, 72.0 mmol), toluene (150 mL), and DMF (0.42 mL, 5.76 mmol) were added to a flask, and the temperature was controlled at 60 °C. SOCl2 (10.8 mL, 144.0 mmol) was added dropwise, and the reaction was maintained at this temperature for 1 h. After the reaction was completed, excess SOCl2 and toluene were removed by vacuum distillation to obtain a white solid intermediate 2,6-dichloro-4-hydroxybenzoyl chloride SM2 (16.1 g, yield 98.2%).

[0024] Step 3: Synthesis of intermediate 3-(3,5-dichloro-4-hydroxybenzoyl)-2,3-dihydro-1,3-benzothiazole SM3: Benzothiazole (9.5 g, 70.5 mmol) and BH3·NMe3 (6.4 g, 84.6 mmol) were added to acetonitrile (160 mL) and activated by stirring at room temperature (22 °C) for 10 min. An acetonitrile solution of intermediate 2,6-dichloro-4-hydroxybenzoyl chloride SM2 (16.0 g, 70.5 mmol) was added dropwise, and the reaction was maintained at this temperature for 8 h. After the reaction was completed, the mixture was quenched with water, extracted with ethyl acetate (3 × 100 mL), dried the organic phase, and then subjected to column chromatography (petroleum ether: ethyl acetate = 5:1) to give intermediate SM3 (22.8 g, yield 98.7%).

[0025] Step 4: Synthesis of Dotenoror: Intermediate SM3 (22.3 g, 68.5 mmol) was dissolved in DCM (220 mL), and mCPBA (70.9 g, 411 mmol) was added in portions at room temperature. The reaction was carried out for 2 h. After the reaction was completed, the reaction solution was washed with saturated NaHCO3, the organic phase was dried and recrystallized from ethanol to obtain dotenorolac (22.5 g, yield 92.6%).

[0026] Example 2 Step 1: Synthesis of intermediate 2,6-dichloro-4-hydroxybenzoic acid SM1 p-Hydroxybenzoic acid (10.0 g, 72.4 mmol) and FeCl3 (1.2 g, 7.2 mmol) were added to a mixed solvent of AcOH / H2O (1:1 volume ratio, 90 mL) and stirred to dissolve. The temperature was controlled at 40 °C, and 30% H2O2 (22.0 mL) and 36% concentrated HCl (31.0 mL) were added sequentially. The reaction was maintained at this temperature for 3 h. The reaction solution was cooled to room temperature, and a solid precipitated. After filtration, the solid was washed three times with deionized water (50 mL each time) and dried under vacuum at 60 °C for 4 h to obtain the intermediate 2,6-dichloro-4-hydroxybenzoic acid (13.1 g, yield 87.2%).

[0027] Step 2: Synthesis of intermediate 2,6-dichloro-4-hydroxybenzoyl chloride SM2: Intermediate SM1 (15.0 g, 72.0 mmol), toluene (150 mL), and DMF (0.42 mL, 5.76 mmol) were added to a flask and the temperature was controlled at 60 °C. SOCl2 (10.8 mL, 144.0 mmol) was added dropwise, and the reaction was maintained at this temperature for 1 h. After the reaction was completed, excess SOCl2 and toluene were removed by vacuum distillation to obtain a white solid intermediate 2,6-dichloro-4-hydroxybenzoyl chloride SM2 (15.7 g, yield 98.2%).

[0028] Step 3: Synthesis of intermediate 3-(3,5-dichloro-4-hydroxybenzoyl)-2,3-dihydro-1,3-benzothiazole SM3: Benzothiazole (9.5 g, 70.5 mmol) and BH3·NMe3 (6.4 g, 84.6 mmol) were added to acetonitrile (160 mL) and activated by stirring at room temperature (22 °C) for 10 min. An acetonitrile solution of intermediate 2,6-dichloro-4-hydroxybenzoyl chloride SM2 (16.0 g, 70.5 mmol) was added dropwise, and the reaction was maintained at this temperature for 8 h. After the reaction was completed, the mixture was quenched with water, extracted with ethyl acetate (3 × 100 mL), dried over a column chromatography (petroleum ether: ethyl acetate = 5:1) to give intermediate SM3 (21.1 g, 95% yield).

[0029] Step 4: Synthesis of Dotenoror: Intermediate SM3 (22.3 g, 68.5 mmol) was dissolved in DCM (220 mL), and mCPBA (70.9 g, 411 mmol) was added in portions at room temperature. The reaction was carried out for 2 h. After the reaction was completed, the reaction solution was washed with saturated NaHCO3, the organic phase was dried and recrystallized with ethanol to obtain dotenorolac (19.8 g, yield 85.4%).

[0030] Example 3 Step 1: Synthesis of intermediate 2,6-dichloro-4-hydroxybenzoic acid SM1: p-Hydroxybenzoic acid (10.0 g, 72.4 mmol) and FeCl3 (0.12 g, 0.72 mmol) were added to a mixed solvent of AcOH / H2O (8:1 volume ratio, 90 mL) and stirred to dissolve. The temperature was controlled at 40 °C, and 30% H2O2 (22.0 mL) and 36% concentrated HCl (31.0 mL) were added sequentially. The reaction was kept at this temperature for 3 h. The reaction solution was cooled to room temperature, and a solid precipitated. After filtration, the solid was washed three times with deionized water (50 mL each time) and dried under vacuum at 60 °C for 4 h to obtain the intermediate 2,6-dichloro-4-hydroxybenzoic acid (13.6 g, yield 90.8%).

[0031] Step 2: Synthesis of intermediate 2,6-dichloro-4-hydroxybenzoyl chloride SM2: Intermediate SM1 (15.0 g, 72.0 mmol), toluene (150 mL), and DMF (0.42 mL, 5.76 mmol) were added to a flask, and the temperature was controlled at 60 °C. SOCl2 (10.8 mL, 144.0 mmol) was added dropwise, and the reaction was maintained at this temperature for 1 h. After the reaction was completed, excess SOCl2 and toluene were removed by vacuum distillation to obtain a white solid intermediate 2,6-dichloro-4-hydroxybenzoyl chloride SM2 (15.5 g, yield 95.2%).

[0032] Step 3: Synthesis of intermediate 3-(3,5-dichloro-4-hydroxybenzoyl)-2,3-dihydro-1,3-benzothiazole SM3: Benzothiazole (9.5 g, 70.5 mmol) and BH3·NMe3 (5.3 g, 70.5 mmol) were added to acetonitrile (160 mL) and activated by stirring at room temperature (22 °C) for 10 min. An acetonitrile solution of intermediate 2,6-dichloro-4-hydroxybenzoyl chloride SM2 (16.0 g, 70.5 mmol) was added dropwise, and the reaction was maintained at this temperature for 8 h. After the reaction was completed, the mixture was quenched with water, extracted with ethyl acetate (3 × 100 mL), dried the organic phase, and then subjected to column chromatography (petroleum ether: ethyl acetate = 5:1) to give intermediate SM3 (18.7 g, yield 81.5%).

[0033] Step 4: Synthesis of Dotenoror: Intermediate SM3 (22.3 g, 68.5 mmol) was dissolved in DCM (220 mL), and mCPBA (70.9 g, 411 mmol) was added in portions at room temperature. The reaction was carried out for 2 h. After the reaction was completed, the reaction solution was washed with saturated NaHCO3, the organic phase was dried and recrystallized from ethanol to obtain dotenorolac (21.7 g, yield 88.7%).

[0034] The preferred embodiments of the present invention disclosed above are merely illustrative of the invention. These preferred embodiments do not exhaustively describe all details, nor do they limit the invention to the specific implementations described. Clearly, many modifications and variations can be made based on the content of this specification. This specification selects and specifically describes these embodiments to better explain the principles and practical applications of the invention, thereby enabling those skilled in the art to better understand and utilize the invention. The invention is limited only by the claims and their full scope and equivalents.

Claims

1. A method for synthesizing the antiuric acid drug dotenorazole, characterized in that, Includes the following steps: Step 1: Using p-hydroxybenzoic acid as the starting material, a chlorination reaction is carried out in a mixed solvent of AcOH / H2O under the action of chlorination reagents FeCl3 / H2O2 / HCl at 40°C to obtain the intermediate 2,6-dichloro-4-hydroxybenzoic acid; Step 2: The intermediate 2,6-dichloro-4-hydroxybenzoic acid is reacted with SOCl2 in toluene solvent in the presence of a catalytic amount of DMF to undergo an acylation reaction to obtain the intermediate 2,6-dichloro-4-hydroxybenzoyl chloride; Step 3: Intermediate 2,6-dichloro-4-hydroxybenzoyl chloride and benzothiazole undergo an amide condensation reaction in acetonitrile solvent under the action of BH3·NMe3 to obtain intermediate 3-(3,5-dichloro-4-hydroxybenzoyl)-2,3-dihydro-1,3-benzothiazole; Step 4: The intermediate 3-(3,5-dichloro-4-hydroxybenzoyl)-2,3-dihydro-1,3-benzothiazole was oxidized with mCPBA in DCM solvent at room temperature to obtain the target product dotenorazole.

2. The method for synthesizing dotenororic acid according to claim 1, characterized in that, In step 1, the amount of FeCl3 used is 0.01-0.1 times (catalytic amount) of the molar amount of p-hydroxybenzoic acid, preferably 0.01 times.

3. The method for synthesizing dotenororic acid according to claim 1, characterized in that, In step 1, the volume ratio of AcOH to H2O in the AcOH / H2O mixed solvent is 8:1 to 1:1, preferably 8:

1.

4. The method for synthesizing dotenororic acid according to claim 1, characterized in that, In step 1, the ratio of 30% hydrogen peroxide and 36% concentrated hydrochloric acid to p-hydroxybenzoic acid is 2.2ml:3.1ml:1g.

5. The method for synthesizing dotenororic acid according to claim 1, characterized in that, In step 2, the molar ratio of SOCl2 and DMF to the intermediate 2,6-dichloro-4-hydroxybenzoic acid is 1-3.5 : 0.05-0.1 : 1, preferably 2:0.1:

1.

6. The method for synthesizing dotenororic acid according to claim 1, characterized in that, In step 3, the molar ratio of BH3·NMe3 and benzothiazole to the intermediate 2,6-dichloro-4-hydroxybenzoyl chloride is 1-1.2:1-1.05:1, preferably 1.2:1:

1.

7. The method for synthesizing dotenororic acid according to claim 1, characterized in that, In step 4, the molar ratio of mCPBA to the intermediate 3-(3,5-dichloro-4-hydroxybenzoyl)-2,3-dihydro-1,3-benzothiazole is 2-6:1, preferably 6:1.