Preparation method of dotenorad

Abstract

The invention relates to a preparation method of dotenorad, which comprises the following steps: generating a compound 3 from a compound 1 and a compound 2 under the action of a condensing agent and alkali, generating a compound 4 under the oxidation of an oxidizing agent, and debenzylating to obtain a target compound. According to the preparation method disclosed by the invention, the use of materials with high toxicity and high irritation is avoided in the reaction process, the protection group removal condition is mild, the violent reaction is avoided, the reaction condition is mild, the reaction steps are few, the raw materials are simple and easy to obtain, the operation is simple, the industrial production is facilitated, and the product purity and yield are high.

Description

Technical Field

[0001] The present invention belongs to the technical field of organic synthesis route design and raw material drug and intermediate preparation, and particularly relates to a method for preparing a key intermediate of the drug dotenod which can be used to treat some hyperuricemia and gout. Background Art

[0002] Dotinurad is an oral tablet jointly developed by Fuji Yakuhin and Mochida Pharmaceuticals of Japan for the treatment of some hyperuricemia and gout. Dotinurad was approved for marketing by the Pharmaceuticals and Medical Devices Agency (PMDA) of Japan on January 23, 2020, with the trade name URECE. The drug is a urate reabsorption inhibitor that can target and inhibit the activity of the urate reabsorption transporter (URAT1). By selectively inhibiting the transporter protein (URAT1) for uric acid reabsorption in the kidney, uric acid reabsorption is inhibited and uric acid levels in the blood are reduced. 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: (3,5-dichloro-4-hydroxyphenyl)(1,1-dioxide-3(2H)-benzothiazolyl)methanone. Its structural formula is as follows: The currently reported preparation methods of polytetracycline are as follows:

[0004] Method 1: Patent CN102639518B reports a method for preparing polythiophene. It uses 2-aminobenzenethiol as a starting material, and reacts with formaldehyde to obtain benzothiazole. Another starting material, 3,5-dichloro-4-methoxybenzoic acid, is reacted with thionyl chloride to prepare an acyl chloride, and the acyl chloride undergoes an amidation reaction to obtain a hydroxyl-protected benzothiazole benzamide intermediate. The intermediate can be used to obtain the target compound polythiophene through oxidation of thioether and deprotection of the hydroxyl group. This route uses thionyl chloride, which is highly irritating and inconvenient to operate. According to literature reports, the yield is low and the cost is high, which is not suitable for industrial production. The reaction route is as follows:

[0005]

[0006] Method 2: Patent CN111675675A reports another method for preparing polythiophene, which uses 2-aminobenzenethiol as the starting material, reacts with acyl chloride to obtain amide, then cyclizes under the conditions of diiodoform, and then oxidizes with m-chloroperoxybenzoic acid to obtain the target product polythiophene. The 3,5-dichloro-4-hydroxybenzoyl chloride used in this route is difficult to prepare, and thionyl chloride is also required, which is highly corrosive, irritating, and highly exothermic. The stability of the acyl chloride is poor, and it is not suitable for industrial production:

[0007]

[0008] Method 3: Patent CN118271255A reports a method for preparing polytetracycline, which uses 2-aminobenzenethiol as the starting material, undergoes a formaldehyde condensation reaction, and then synthesizes amide under the conditions of NCS and triphenylphosphine, and then undergoes oxidation and deprotection to synthesize the target product polytetracycline. This route uses a large amount of raw materials and has a low yield, which also has certain limitations on industrialization.

[0009] Summary of the invention

[0010] The technical problem to be solved by the present invention is to provide a method for preparing polytinol with mild conditions and simple operation.

[0011] In order to solve the problems existing in the prior art, the present invention provides a new method for preparing polytinol, avoids the use of irritating reagents for preparing acyl chloride, obtains the target product by condensation, oxidation, and finally hydrogenation debenzylation, avoids the use of DMF which may introduce nitrosamine impurities, and finally hydrogenation debenzylation has mild conditions, is not easy to generate impurities, and is simple to purify.

[0012] The technical solution of the present invention to solve the above technical problems is as follows:

[0013] A method for preparing polytinorel, characterized by comprising the following steps:

[0014] Step 1: Compound 1 and compound 2 react with a condensing agent and a base to generate compound 3;

[0015] Step 2: Compound 3 is oxidized by an oxidant to generate compound 4;

[0016] Step 3: Compound 4 is debenzylated to obtain the target compound, and the reaction formula is as follows:

[0017]

[0018] As a specific embodiment, in the step 1, the base is selected from triethylamine, DIEA, and sodium carbonate.

[0019] As a specific embodiment, in the step 1, the condensation agent is PPh3 / NBS, PPh3 / NCS, N,N'-carbonyldiimidazole (CDI), N,N'-diisopropylcarbodiimide (DIC) N,N'-dicyclohexylcarbodiimide (DCC), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI), 1-hydroxybenzotriazole (HOBt), 0-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), 0-benzotriazole-tetramethyluronium hexafluorophosphate (HBTU) or 2-chloro-1-methylpyridinium iodide (CMPI).

[0020] As a specific implementation, in the step 1, the molar ratio of the compound 1, compound 2, condensing agent, and base is 1:1-5:1-6:1-5, preferably 1:1.1-2.0:1.1-3:2.0.

[0021] As a specific implementation manner, in the step 1, the ratio of the condensing agent PPh3:NCS / NBS is 1:1, and the equivalent is 1 to 5 equivalents.

[0022] As a specific implementation manner, in the step 1, the reaction temperature is 50-100° C., and the reaction time is 3-24 hours.

[0023] As a specific implementation, in step 2, the oxidant is selected from ozone, peracetic acid, perbenzoic acid, hydrogen peroxide, hypochlorous acid or meta-chloroperbenzoic acid, preferably meta-chloroperbenzoic acid.

[0024] As a specific implementation manner, in the step 2, the amount of the oxidant added is 2 to 8 equivalents, preferably 4 to 6 equivalents.

[0025] As a specific implementation, in the step 2, the solvent is dichloromethane, chloroform, ethyl acetate, toluene, xylene, dioxane or tetrahydrofuran.

[0026] As a specific implementation manner, the temperature of step 2 is 0-50°C, preferably 20-30°C; and the reaction time is 8h.

[0027] As a specific implementation, in step three, the debenzylation reagent is trifluoroacetic acid or Pd / C / H2.

[0028] As a specific implementation, in the step 3, when the debenzylation reagent is Pd / C / H2, the amount of Pd / C added is 1% to 30% by mass of compound 4, preferably 5% to 10%.

[0029] As a specific implementation, in the step 3, when the debenzylation agent is trifluoroacetic acid, the amount of trifluoroacetic acid added is 5 to 10 V / m.

[0030] As a specific implementation manner, the temperature of step three is 20-80° C., preferably 50° C.; the reaction time is 3-24 h, preferably 3 h to 6 h.

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

[0032] The method described in the present invention avoids the use of highly toxic and irritating materials during the reaction process, has mild conditions for deprotection, avoids violent reactions, has mild reaction conditions, fewer reaction steps, simple and easily available raw materials, simple operation, is conducive to industrial production, and has high product purity and yield. DETAILED DESCRIPTION

[0033] Unless otherwise specified, the reagents and raw materials used in the present invention are commercially available. If there is a conflict between the Chinese name of the compound in the present invention and the structural formula, the structural formula shall prevail, unless there is an obvious error in the structural formula.

[0034] Example 1

[0035] First step: Synthesis of intermediate 3

[0036] Into a 500mL single-necked bottle, 3,5-dichloro-4-phenylmethoxybenzoic acid (10.00g, 33.66mmol), benzothiazoline (6.93g, 50.48mmol), HATU (19.20g, 50.49mmol) and acetonitrile (100.0ml) were added, and DIEA (51.90g, 401.54mmol) was added dropwise at room temperature. The addition took about 30 minutes, and then the reaction solution was heated to reflux for 6.0h. The temperature was lowered, and the reaction solution was concentrated by rotary evaporation to remove acetonitrile. Dichloromethane (400.0 mL) and 2N hydrochloric acid aqueous solution (250.0 mL) were added to the concentrate. After stirring for 20 min, the mixture was allowed to stand and separated. The organic phase was washed once with saturated sodium bicarbonate aqueous solution (100.0 mL) and once with saturated sodium chloride aqueous solution (100.0 mL). The concentrate was concentrated by rotary evaporation, and the concentrate was recrystallized with isopropanol (300.0 mL) to give a white solid (10.67 g, yield: 74.5%, purity: 97.33%).

[0037] Example 2

[0038] First step: Synthesis of intermediate 3

[0039] 3,5-dichloro-4-phenylmethoxybenzoic acid (10.00 g, 33.66 mmol), benzothiazoline (6.93 g, 50.48 mmol), EDCI (19.20 g, 50.49 mmol) and DMF (100.0 ml) were added to a 500 mL single-mouth bottle, and DIEA (51.90 g, 401.54 mmol) was added dropwise at room temperature. The addition was completed in about 30 minutes, and then the reaction solution was heated to reflux for 6.0 hours. After cooling, the reaction solution was poured into DMF water, and extracted with dichloromethane (200.0 mL x 3). The organic phases were combined and washed once with saturated sodium chloride aqueous solution (100.0 mL), concentrated by rotary evaporation, and the concentrate was recrystallized with isopropanol (300.0 mL) to obtain a white solid (12.89 g. Yield: 92.0%, purity: 98.0%).

[0040] Example 3

[0041] Into a 500mL single-necked bottle, 3,5-dichloro-4-phenylmethoxybenzoic acid (25.00g, 84.14mmol), benzothiazoline (23.09g, 168.28mmol), triphenylphosphine (33.10g, 126.21mmol), NCS (16.85g, 126.21mmol) and tetrahydrofuran (100.0ml) were charged. DIEA (8.70g, 67.32mmol) was added dropwise at room temperature. The addition took about 30 minutes, and then the reaction solution was heated to reflux for 6.0h. The temperature was lowered, and the reaction solution was concentrated by rotary evaporation to remove tetrahydrofuran. Dichloromethane (400.0 mL) and 2N hydrochloric acid aqueous solution (250.0 mL) were added to the concentrate. After stirring for 20 min, the mixture was allowed to stand and separated. The organic phase was washed once with saturated sodium bicarbonate aqueous solution (100.0 mL) and once with saturated sodium chloride aqueous solution (100.0 mL). The concentrate was concentrated by rotary evaporation, and the concentrate was recrystallized with isopropanol (300.0 mL) to give a white solid (29.04 g, yield: 82.90%, purity: 97.72%).

[0042] Example 4

[0043] Into a 500mL single-necked bottle, 3,5-dichloro-4-phenylmethoxybenzoic acid (4.00g, 18.10mmol), benzothiazoline (2.61g, 19.00mmol), EDCI (3.82g, 50.49mmol) / HOBT (2.56g, 19.00mmol), potassium carbonate (5.00g, 36.20mmol) and acetonitrile (100.0ml) were added and heated to reflux for 6.0h. The temperature was lowered, and the reaction solution was concentrated by rotary evaporation to remove acetonitrile. Dichloromethane (100.0 mL) and 2N hydrochloric acid aqueous solution (50.0 mL) were added to the concentrate. After stirring for 20 min, the mixture was allowed to stand and separated. The organic phase was washed once with saturated sodium bicarbonate aqueous solution (100.0 mL) and once with saturated sodium chloride aqueous solution (100.0 mL). The concentrate was concentrated by rotary evaporation, and the concentrate was recrystallized with isopropanol (100.0 mL) to obtain a white solid (3.50 g, yield: 56.81%, purity: 95.32%).

[0044] Example 5

[0045] Into a 500mL single-necked bottle, 3,5-dichloro-4-phenylmethoxybenzoic acid (2.00g, 9.05mmol), benzothiazoline (1.37g, 9.95mmol), BOP (4.40g, 9.95mmol), DIEA (2.34g, 18.10mmol) and acetonitrile (20.0ml) were added and heated to reflux for 6.0h. The temperature was lowered, and the reaction solution was concentrated by rotary evaporation to remove acetonitrile. Dichloromethane (100.0 mL) and 2N hydrochloric acid aqueous solution (50.0 mL) were added to the concentrate. After stirring for 20 min, the mixture was allowed to stand and separated. The organic phase was washed once with saturated sodium bicarbonate aqueous solution (100.0 mL) and once with saturated sodium chloride aqueous solution (100.0 mL). The concentrate was concentrated by rotary evaporation, and the concentrate was recrystallized with isopropanol (100.0 mL) to obtain a white solid (1.08 g, yield: 35.1%, purity: 96.26%).

[0046] Example 6

[0047] Step 2 Synthesis of Intermediate 4

[0048] Compound 3 (10.00 g, 24.02 mmol) and dichloromethane (200.0 ml) were added to a 1.0 L single-mouth bottle, stirred to dissolve, and then 85% m-chloroperbenzoic acid (16.58 g, 96.08 mmol) was slowly added in batches, and the reaction was allowed to react at room temperature overnight. The reaction solution was transferred to 0 ° C and stirred, and the reaction was quenched with a saturated sodium sulfite aqueous solution (50.0 mL), and then transferred to air temperature, and sodium carbonate (43.17 g) aqueous solution (200.0 ml) was slowly added. After stirring for 20 min, it was allowed to stand and separated. The organic phase was washed once with a saturated sodium bicarbonate aqueous solution (100.0 ml), washed once with a saturated sodium chloride aqueous solution (100.0 ml), and concentrated by rotary evaporation. The concentrate was purified by slurrying with isopropanol (300.0 mL) to obtain a white solid (10.38 g, yield: 96.4%, purity: 98.35%).

[0049] Example 7

[0050] Step 2 Synthesis of Intermediate 4

[0051] Compound 3 (10.00 g, 24.02 mmol) and dichloromethane (200.0 ml) were added to a 1.0 L single-mouth bottle, stirred to dissolve, and then hydrogen peroxide (50%) (6.6 gg, 96.08 mmol) was slowly added in batches, and the reaction was allowed to react at room temperature overnight. The reaction solution was transferred to 0 ° C and stirred, and the reaction was quenched with a saturated sodium sulfite aqueous solution (50.0 mL), and then transferred to air temperature. After stirring for 20 min, the mixture was allowed to stand and separated. The organic phase was washed once with a saturated sodium chloride aqueous solution (100.0 mL), concentrated by rotary evaporation, and the concentrate was purified by slurrying with isopropanol (300.0 mL) to obtain a white solid (9.45 g, yield: 87.7%, purity: 98.7%).

[0052] Example 8

[0053] Step 3 Synthesis of polytinol

[0054] The intermediate 4 (10.00 g, 22.31 mmol) was dissolved in methanol (100 mL), Pd / C (10%) was added, and hydrogen was replaced 3 times. The reaction was carried out at 20-30°C overnight. After the raw material was exhausted, it was directly filtered, and the filtrate was concentrated to dryness. The final compound (7.80 g, yield: 97.6%, purity: 99.82%) was obtained by re-precipitation with ethanol.

[0055] Example 9

[0056] Intermediate 4 (10.00 g, 22.31 mmol) was dissolved in trifluoroacetic acid (50 mL), refluxed and stirred for 2 hours. After the starting material was exhausted, saturated sodium bicarbonate solution was added to quench the reaction. The reaction mixture was then extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate and concentrated to obtain a residue, which was purified by ethanol recrystallization to obtain the final compound (7.44 g, yield: 93.1%, purity: 99.89%)

[0057] It should be noted that the above content only illustrates the technical idea of ​​the present invention and cannot be used to limit the protection scope of the present invention. For ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications all fall within the protection scope of the claims of the present invention.

Claims

1. A method for preparing polytinol is as follows, characterized in that: The method is carried out according to the following steps: Step 1: Compound 1 and compound 2 react with a condensing agent and a base to generate compound 3; Step 2: Compound 3 is oxidized by an oxidant to generate compound 4; Step 3: Debenzylation of compound 4 to obtain the target compound, 2. The method for preparing polytinol according to claim 1, characterized in that: In the step 1, the base is selected from triethylamine, DIEA, and sodium carbonate.

3. The method for preparing polytinorel according to claim 1, characterized in that: In the step 1, the condensing agent is selected from one or any combination of PPh3 / NBS, PPh3 / NCS, N,N'-carbonyldiimidazole, N,N-diisopropylcarbodiimide, N,N'-dicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)carbodiimide hydrochloride, 1-hydroxybenzotriazole, benzotriazol-1-yloxytris(dimethylamino)phosphorus hexafluorophosphate, 0-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate, 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, 0-benzotriazole-tetramethyluronium hexafluorophosphate or 2-chloro-1-methylpyridinium iodide.

4. The method for preparing polytinol according to claim 1, characterized in that: In the step 1, the molar ratio of the compound 1, compound 2, condensing agent and base is 1:1-5:1-6:1-5, preferably 1:1.1-2.0:1.1-3:2.

0.

5. The method for preparing polytinorel according to claim 1, characterized in that: In the step 1, the reaction temperature is 50-100° C. and the reaction time is 3-24 hours.

6. The method for preparing polytinol according to claim 1, characterized in that: In the step 2, the oxidant is selected from ozone, peracetic acid, perbenzoic acid, hydrogen peroxide, hypochlorous acid or meta-chloroperbenzoic acid, preferably meta-chloroperbenzoic acid.

7. The method for preparing polytinoride according to claim 1, characterized in that: In the step 2, the amount of the oxidant added is 2 to 8 equivalents.

8. The method for preparing polytinol according to claim 1, characterized in that: In the step 2, the solvent is dichloromethane, chloroform, ethyl acetate, toluene, xylene, dioxane or tetrahydrofuran.

9. The method for preparing polytinol according to claim 1, characterized in that: The temperature of step 2 is 0-50° C., and the reaction time is 2-12 hours.

10. The method for preparing polytinol according to claim 1, characterized in that: The debenzylation reagent is trifluoroacetic acid or Pd / C / H2, and / or, The amount of Pd / C added is 1% to 30% of the mass of compound 4; the volume ratio of trifluoroacetic acid to the mass ratio of compound 4 is 3 to 10 ml / g.

11. The method for preparing polytinol according to claim 1, characterized in that: The temperature of step three is 20-80° C. and the reaction time is 2-8 hours.

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