Preparation method of dotenod

Abstract

The invention discloses a preparation method of dotenod, and belongs to the technical field of organic synthesis route design and preparation of raw material medicines and intermediates thereof. According to the method, 3, 5-dichloro-4-methoxybenzoic acid and 2-aminobenzenethiol are used as raw materials and are sequentially subjected to an acylation reaction, an amidation reaction, a ring closing reaction, an oxidation reaction and a demethylation reaction, and finally dotenoid is prepared. In the preparation process, the acylation reaction and the amidation reaction are continuously fed, an intermediate does not need to be separated and purified, the process is controllable, the yield is high, few three wastes are generated, the production cost is low, and large-scale industrial production can be achieved.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis route design and raw material drug and intermediate preparation, and specifically relates to a method for preparing doxetinolide. Background Art

[0002] Dotinurad was approved for marketing by the Pharmaceuticals and Medical Devices Agency (PMDA) of Japan on January 23, 2020. It was jointly developed by Fujiyama Pharmaceutical and Mochida Pharmaceutical of Japan. The drug is used to treat hyperuricemia and gout. It is the second urate transporter (URAT1) inhibitor approved for marketing worldwide. It can inhibit uric acid reabsorption and reduce uric acid levels in the blood by selectively inhibiting the transporter for uric acid reabsorption in the kidney. Dotinurad is also a reagent widely used in the preparation of synthetic drugs. Its chemical properties make it an ideal intermediate that can be used to synthesize various types of compounds. Therefore, it is widely used in the fields of medicine, agriculture, and chemical industry. It is an important catalyst with a relatively simple synthesis route. The traditional synthesis route is: first synthesize aromatic ketones, then perform an amination reaction, then perform a carboxylic acid esterification reaction, and finally perform an amidation reaction to finally obtain Dotinurad.

[0003] Chinese patent CN2010800428669 provides a method for preparing polythiophene and its intermediates, which is to prepare benzothiazole by condensing 2-aminobenzenethiol with formaldehyde, and then reacting with substituted benzoyl chloride obtained by acylation of 3,5-dichloro-4-methoxybenzoic acid to undergo amidation reaction, followed by oxidation of thioether and deprotection of hydroxyl groups, to finally obtain the target compound polythiophene. However, the intermediates in the preparation process of this method have poor stability, low total yield, and a large amount of three wastes are generated overall.

[0004] Chinese patent CN2020106937954 provides a method for preparing polytetracycline, which uses 3,5-dichloro-4-hydroxybenzoic acid and 2-aminobenzenethiol to undergo condensation reaction, cyclization reaction, and oxidation reaction in sequence to finally prepare polytetracycline. However, although this method solves the problem of unstable intermediates, the exposed phenolic hydroxyl group is easily oxidized in the final oxidation step to produce stubborn impurities, which are difficult to remove.

[0005] Therefore, it is necessary to provide a method for preparing polytenod. Summary of the invention

[0006] In view of the above problems existing in the prior art, the first technical problem to be solved by the present invention is to provide a method for preparing polytenod, in which the acylation reaction and the amidation reaction are continuously fed during the preparation process, the intermediate does not need to be separated and purified, and the process is controllable, the yield is high, the three wastes are less, and the production cost is low. The second technical problem to be solved by the present invention is to provide a method for preparing polytenod, which is simple and convenient with high yield.

[0007] In order to solve the above problems, the technical solution adopted by the present invention is as follows:

[0008] A preparation method of dotinod, comprising the steps of first subjecting 3,5-dichloro-4-methoxybenzoic acid, tetrahydrofuran, N,N-dimethylformamide and oxalyl chloride to an acylation reaction to obtain an acyl chloride intermediate, then mixing the acyl chloride intermediate with 2-aminobenzenethiol, a solvent and an acid-binding agent to undergo an amidation reaction to obtain N-(3,5-dichloro-4-methoxybenzoyl)-2-aminobenzenethiol, then mixing the acyl chloride intermediate with formalin to obtain (3,5-dichloro-4-methoxyphenyl)(3(H)-benzothiazolyl)methanone, then mixing the acyl chloride intermediate with m-chloroperbenzoic acid and a solvent to undergo an oxidation reaction to obtain 3-(3,5-dichloro-4-hydroxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole, and finally mixing the acyl chloride intermediate with a demethylation agent and a solvent to remove the methyl group to obtain dotinod.

[0009] Furthermore, the solvent in the amidation reaction is one or more of dichloromethane, acetonitrile, toluene, chloroform and tetrahydrofuran.

[0010] Furthermore, the acid-binding agent is one or more of triethylamine, pyridine, diisopropylethylamine, N-methylmorpholine, 2,6-lutidine and 1,8-diazabicyclo[5.4.0]undec-7-ene.

[0011] Furthermore, the equivalent ratio of the 2-aminobenzenethiol to 3,5-dichloro-4-methoxybenzoic acid is 1 to 2:1.

[0012] Furthermore, the equivalent ratio of the paraformaldehyde to N-(3,5-dichloro-4-methoxybenzoyl)-2-aminobenzenethiol is 2 to 6:1.

[0013] Furthermore, the solvent in the oxidation reaction is one or more of chloroform, dichloromethane, carbon tetrachloride, acetonitrile, tetrahydrofuran and toluene.

[0014] Furthermore, the solvent in the demethylation reaction is one or more of N,N-dimethylformamide, N,N-dimethylacetamide, toluene, acetonitrile and dimethyl sulfoxide.

[0015] Furthermore, the demethylation agent is one or more of hydrogen bromide / acetic acid, acetic anhydride, lithium chloride, trimethylsilyl iodide and aluminum chloride.

[0016] Further, the specific steps are as follows:

[0017] 1) 3,5-dichloro-4-methoxybenzoic acid, tetrahydrofuran, N,N-dimethylformamide and oxalyl chloride are mixed, and an acylation reaction is carried out at 55-65° C. After the reaction is completed, the mixture is concentrated under reduced pressure to obtain an acyl chloride intermediate, and then the acyl chloride intermediate, 2-aminobenzenethiol, a solvent and an acid binding agent are mixed, and an amidation reaction is carried out at 25-35° C. After the reaction is completed, the pH is adjusted, the mixture is concentrated, extracted, washed and dried to obtain N-(3,5-dichloro-4-methoxybenzoyl)-2-aminobenzenethiol;

[0018] 2) N-(3,5-dichloro-4-methoxybenzoyl)-2-aminobenzenethiol, formalin and ethanol are mixed. After the reaction is completed, the reaction is quenched with water, concentrated to remove ethanol, extracted with ethyl acetate three times, the organic phases are combined, washed with 10% sodium chloride aqueous solution, the solvent is concentrated under reduced pressure, and the residue is recrystallized with ethanol to obtain (3,5-dichloro-4-methoxyphenyl)(3(H)-benzothiazolyl)methanone;

[0019] 3) mixing (3,5-dichloro-4-methoxyphenyl)(3(H)-benzothiazolyl)methanone and a solvent, adding m-chloroperbenzoic acid in batches at 0-5° C., neutralizing after the reaction is completed, washing the organic phase, concentrating under reduced pressure to remove the solvent, and recrystallizing the residue from ethyl acetate to obtain 3-(3,5-dichloro-4-hydroxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole;

[0020] 4) Mix 3-(3,5-dichloro-4-hydroxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole, a demethylating agent and a solvent, react at 110-120° C., add dilute hydrochloric acid to adjust the pH, extract with ethyl acetate, wash the organic phase, concentrate under reduced pressure to remove ethyl acetate, and recrystallize the residue with ethanol to obtain Duotenod.

[0021] The polytenod prepared by the method.

[0022] Beneficial effects: Compared with the prior art, the advantages of the present invention are:

[0023] The present invention uses 3,5-dichloro-4-methoxybenzoic acid and 2-aminobenzenethiol as raw materials, and sequentially undergoes acylation reaction, amidation reaction, ring-closing reaction, oxidation reaction and demethylation reaction to finally prepare polytenod. In the preparation process of the present invention, the acylation reaction and the amidation reaction are continuously fed, the intermediate does not need to be separated and purified, the process is controllable, the yield is high, the three wastes are less, the production cost is low, and large-scale industrial production can be carried out. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1 A flow chart for preparing doxetinod according to the present invention;

[0025] Figure 2 The HPLC spectrum of intermediate 1 prepared by the method of Example 1 of the present invention;

[0026] Figure 3 is the MS spectrum of intermediate 1 prepared by the method of Example 1 of the present invention;

[0027] Figure 4 The intermediate 1 prepared by the method of Example 1 of the present invention 1 H-NMR spectrum;

[0028] Figure 5 The HPLC spectrum of intermediate 2 prepared by the method of Example 1 of the present invention;

[0029] Figure 6 is the MS spectrum of intermediate 2 prepared by the method of Example 1 of the present invention;

[0030] Figure 7 The intermediate 2 prepared by the method of Example 1 of the present invention 1 H-NMR spectrum;

[0031] Figure 8 The HPLC spectrum of intermediate 3 prepared by the method of Example 1 of the present invention;

[0032] Fig. 9 The intermediate 3 prepared by the method of Example 1 of the present invention is 1 H-NMR spectrum;

[0033] Fig.10 This is the HPLC spectrum of dotenod prepared by the method of Example 1 of the present invention;

[0034] Fig.11 This is the MS spectrum of doxetinod prepared by the method of Example 1 of the present invention;

[0035] Fig.12 The polytetracycline prepared by the method of Example 1 of the present invention 1 H-NMR spectrum. DETAILED DESCRIPTION

[0036] The present invention is further described below in conjunction with specific embodiments.

[0037] The sources of 3,5-dichloro-4-methoxybenzoic acid and 2-aminothiophenol used in the following examples are commercially available. The sources of 3,5-dichloro-4-methoxybenzoic acid and 2-aminothiophenol are Nanjing Furuisi Pharmaceutical Technology Co., Ltd., and the CAS numbers are 37908-97-7 and 137-07-5, respectively.

[0038] Example 1

[0039] The preparation of dotinod is as follows:

[0040] (1) Synthesis of N-(3,5-dichloro-4-methoxybenzoyl)-2-aminobenzenethiol (Intermediate 1)

[0041] Add tetrahydrofuran (1000 mL), 3,5-dichloro-4-methoxybenzoic acid (200 g), N,N-dimethylformamide (2 g) and oxalyl chloride (171.4 g) to the reaction bottle, stir and react at 60°C for 3 h. After the reaction is completed, distill off tetrahydrofuran and residual oxalyl chloride at 50-60°C under reduced pressure to obtain an acyl chloride intermediate. Add acetonitrile (500 mL), 2-aminothiophenol (169.0 g) and triethylamine (182.1 g) to the acyl chloride intermediate, react at 30°C for 2 h. After the reaction is completed, adjust the pH to 4-5 with 1N hydrochloric acid, and concentrate at 40-50°C under reduced pressure to remove acetonitrile. 300 mL of ethyl acetate and 200 mL of water were added to the system, stirred and separated, the organic phase was concentrated to half of the residual volume, the system was cooled to 0-10 ° C, crystallized for 1 h, filtered, and dried to obtain 285.1 g of off-white solid N-(3,5-dichloro-4-methoxybenzoyl)-2-aminobenzenethiol, with a purity of 99.80%, a yield of 96.0%, and MS (m / z): 328 [M+H] + ; 1 HNMR (CDCl3): 3.21 (1H, s), 4.00 (3H, s), 7.12 (1H, dd, J = 8.0, 8.0 Hz), 7.40 (1H, dd, J = 8.0, 8.0 Hz), 7.60 (1H, d, J = 8.0 Hz), 7.90 (2H, s), 8.39 (1H, s), 8.80 (1H, brs). The flow chart of the present invention is as follows Figure 1 The HPLC spectrum, MS spectrum and 1 H-NMR spectrum Figures 2 to 4 shown.

[0042] (2) Synthesis of (3,5-dichloro-4-methoxyphenyl)(3(H)-benzothiazolyl)methanone (Intermediate 2)

[0043] Add ethanol (1400 mL), N-(3,5-dichloro-4-methoxybenzoyl)-2-aminobenzenethiol (280 g) and formalin (345 g) to the reaction bottle and mix. Stir at room temperature for 1 h, and quench the reaction with 350 mL of water. Concentrate under reduced pressure at 40-50 ° C to remove ethanol, extract with ethyl acetate 3 times, 400 mL each time, combine the organic phases, wash the organic phase with 500 mL of 10% sodium chloride aqueous solution, and concentrate the organic phase under reduced pressure at 40-50 ° C to dryness. Add 150 mL of ethanol to the residue, heat to reflux to dissolve, cool to 20-30 ° C, stir and crystallize for 1 h, filter and dry to obtain 275.7 g of light yellow solid (3,5-dichloro-4-methoxyphenyl) (3 (H) -benzothiazolyl) ketone, purity 98.70%, yield 95.0%, MS (m / z): 340 [M + H] + ; 1 H NMR (DMSO-d6): 3.90 (3H, s), 5.33 (2H, s), 7.10 (2H, m), 7.35 (1H, m), 7.62 (1H, brs), 7.78 (2H, s). HPLC spectrum, MS spectrum and 1 H-NMR spectrum Figures 5 to 7 shown.

[0044] (3) Synthesis of 3-(3,5-dichloro-4-hydroxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole (Intermediate 3)

[0045] Add dichloromethane (1620 mL) and (3,5-dichloro-4-methoxyphenyl)(3(H)-benzothiazolyl)methanone (270 g) to the reaction bottle and mix. Add m-chloroperbenzoic acid (818 g) in batches at 0-5°C. Stir and react at room temperature for 20 hours. After the reaction is completed, adjust the pH to 7 with 10% sodium thiosulfate, separate the liquids, wash the organic phase with 350 mL of water, and concentrate the organic phase to dryness under reduced pressure at 40-50°C. Add 550 mL of ethyl acetate to the residue, heat to reflux to dissolve, cool to 0-10°C, stir and crystallize for 1 hour to obtain 254.6 g of light yellow solid 3-(3,5-dichloro-4-hydroxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole with a purity of 99.61% and a yield of 86.2%. 1 H NMR (DMSO-d6): 3.91 (3H, s), 5.33 (2H, s), 7.46 (1H, dd, J = 8.0, 8.0 Hz), 7.79 (1H, dd, J = 8.0, 8.0 Hz), 7.86 (2H, s), 7.93 (1H, d, J = 8.0 Hz), 8.15 (1H, d, J = 8.0 Hz). HPLC spectrum of intermediate 3 and1 H-NMR spectrum Figure 8 , 9 shown.

[0046] (4) Synthesis of Dotenod

[0047] Add N,N-dimethylformamide (248 mL), 3-(3,5-dichloro-4-hydroxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole (248 g) and lithium chloride (142.0 g) to the reaction bottle, stir and react at 120°C for 3 h, cool to room temperature, add 150 mL of water, adjust the pH of the system to 5-6 with 1N dilute hydrochloric acid, extract with 300 mL of ethyl acetate, discard the aqueous phase, wash the organic phase with 200 mL of water and 200 ml of 10% sodium chloride aqueous solution in turn, and concentrate the organic phase to dryness under reduced pressure at 40-50°C. Add 650 mL of ethanol to the residue, heat to reflux to dissolve, cool to 10-20°C, stir and crystallize for 2 h, filter and dry to obtain 199.3 g of dotenod, purity 99.50%, yield 83.5%, MS (m / z): 356 [MH] - , 358[M+2-H] - ; 1 H NMR (DMSO-d6): 5.36 (2H, s), 7.44 (1H, dd, J = 7.6, 7.6 Hz), 7.75 (2H, s), 7.76 (1H, dd, J = 8.4, 7.6 Hz), 7.90 (1H, d, J = 7.6 Hz), 8.04 (1H, d, J = 8.4 Hz), 11.04 (1H, brs). HPLC spectrum, MS spectrum and 1 H-NMR spectrum Figures 10-12 shown.

[0048] Example 2

[0049] (1) Synthesis of N-(3,5-dichloro-4-methoxybenzoyl)-2-aminobenzenethiol (Intermediate 1)

[0050] Add tetrahydrofuran (5000mL), 3,5-dichloro-4-methoxybenzoic acid (1000g), N,N-dimethylformamide (10g) and oxalyl chloride (857g) to the reaction bottle, stir and react at 60°C for 3h. After the reaction is completed, distill off tetrahydrofuran and residual oxalyl chloride at 50-60°C under reduced pressure to obtain an acyl chloride intermediate. Add acetonitrile (2500mL), 2-aminothiophenol (845g) and triethylamine (910.5g) to the acyl chloride intermediate, react at 30°C for 2h. After the reaction is completed, cool to room temperature, adjust the pH to 4-5 with 1N hydrochloric acid, and concentrate at 40-50°C under reduced pressure to remove acetonitrile. 1500 mL of ethyl acetate and 1000 mL of water were added to the system, stirred and separated, the organic phase was concentrated to half of the residual volume, the system was cooled to 0-10°C, crystallized for 1 h, filtered and dried to obtain 1428.5 g of off-white solid N-(3,5-dichloro-4-methoxybenzoyl)-2-aminobenzenethiol with a purity of 99.80% and a yield of 96.2%.

[0051] (2) Synthesis of (3,5-dichloro-4-methoxyphenyl)(3(H)-benzothiazolyl)methanone (Intermediate 2)

[0052] Add ethanol (7000mL), N-(3,5-dichloro-4-methoxybenzoyl)-2-aminobenzenethiol (1400g) and formalin (1725g) to the reaction bottle and mix. Stir at room temperature for 1h, and quench the reaction with 1750mL of water. Concentrate under reduced pressure at 40-50℃ to remove ethanol, extract with ethyl acetate 3 times, 2000mL each time, combine the organic phases, wash the organic phase with 2500mL of 10% sodium chloride aqueous solution, and concentrate the organic phase under reduced pressure at 40-50℃ to dryness. Add 750mL of ethanol to the residue, heat to reflux to dissolve, cool to 20-30℃, stir and crystallize for 1h, filter and dry to obtain 1386g of light yellow solid (3,5-dichloro-4-methoxyphenyl) (3(H)-benzothiazolyl) ketone, with a purity of 97.82% and a yield of 95.5%.

[0053] (3) Synthesis of 3-(3,5-dichloro-4-hydroxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole (Intermediate 3)

[0054] Dichloromethane (8100 mL) and (3,5-dichloro-4-methoxyphenyl)(3(H)-benzothiazolyl)methanone (1350 g) were added to the reaction flask and mixed. Meta-chloroperbenzoic acid (4090 g) was added in batches at 0-5° C. The mixture was stirred at room temperature for 20 h. After the reaction was completed, the pH was adjusted to 7 with 10% sodium thiosulfate, and the liquid was separated. The organic phase was washed with 1750 mL of water, and the organic phase was concentrated to dryness under reduced pressure at 40-50° C. 2750 mL of ethyl acetate was added to the residue, the temperature was raised to reflux to dissolve, the temperature was lowered to 0-10° C., and the mixture was stirred for crystallization for 1 h to obtain 1277.6 g of light yellow solid 3-(3,5-dichloro-4-hydroxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole with a purity of 99.60% and a yield of 86.5%.

[0055] (4) Synthesis of Dotenod

[0056] Add N,N-dimethylformamide (1240 mL), 3-(3,5-dichloro-4-hydroxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole (1240 g) and lithium chloride (710 g) to the reaction bottle, stir and react at 120°C for 3 h, cool to room temperature, add 750 mL of water, adjust the pH of the system to 5-6 with 1N dilute hydrochloric acid, extract with 1500 mL of ethyl acetate, discard the aqueous phase, wash the organic phase with 1000 mL of water and 1000 mL of 10% sodium chloride aqueous solution in turn, and concentrate the organic phase to dryness under reduced pressure at 40-50°C. Add 3250 mL of ethanol to the residue, heat to reflux to dissolve, cool to 10-20°C, stir and crystallize for 2 h, filter and dry to obtain 1004.7 g of dotenod, with a purity of 99.51% and a yield of 84.2%.

Claims

1. A method for preparing polytetracycline, characterized in that: First, 3,5-dichloro-4-methoxybenzoic acid, tetrahydrofuran, N,N-dimethylformamide and oxalyl chloride are subjected to acylation reaction to obtain an acyl chloride intermediate, which is then mixed with 2-aminobenzenethiol, a solvent and an acid binding agent to undergo an amidation reaction to obtain N-(3,5-dichloro-4-methoxybenzoyl)-2-aminobenzenethiol, which is then mixed with formalin to obtain (3,5-dichloro-4-methoxyphenyl)(3(H)-benzothiazolyl)methanone, which is then mixed with m-chloroperbenzoic acid and a solvent to undergo an oxidation reaction to obtain 3-(3,5-dichloro-4-hydroxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole, which is finally mixed with a demethylation agent and a solvent to remove the methyl group to obtain Duotenod.

2. The method for preparing polytetracycline according to claim 1, characterized in that: The solvent in the amidation reaction is one or more of dichloromethane, acetonitrile, toluene, chloroform and tetrahydrofuran.

3. The method for preparing polytetracycline according to claim 1, characterized in that: The acid binding agent is one or more of triethylamine, pyridine, diisopropylethylamine, N-methylmorpholine, 2,6-lutidine and 1,8-diazabicyclo[5.4.0]undec-7-ene.

4. The method for preparing polytetracycline according to claim 1, characterized in that: The equivalent ratio of the 2-aminobenzenethiol to 3,5-dichloro-4-methoxybenzoic acid is 1 to 2:

1.

5. The method for preparing polytenod according to claim 1, characterized in that: The equivalent ratio of the paraformaldehyde to N-(3,5-dichloro-4-methoxybenzoyl)-2-aminobenzenethiol is 2-6:

1.

6. The method for preparing polytenod according to claim 1, characterized in that: The solvent in the oxidation reaction is one or more of chloroform, dichloromethane, carbon tetrachloride, acetonitrile, tetrahydrofuran and toluene.

7. The method for preparing polytenod according to claim 1, characterized in that: The solvent in the demethylation reaction is one or more of N,N-dimethylformamide, N,N-dimethylacetamide, toluene, acetonitrile and dimethyl sulfoxide.

8. The method for preparing polytenod according to claim 1, characterized in that: The demethylation agent is one or more of hydrogen bromide / acetic acid, acetic anhydride, lithium chloride, trimethylsilyl iodide and aluminum chloride.

9. The method for preparing polytenod according to claim 1, characterized in that: The specific steps are as follows: 1) 3,5-dichloro-4-methoxybenzoic acid, tetrahydrofuran, N,N-dimethylformamide and oxalyl chloride are mixed, and an acylation reaction is carried out at 55-65° C. After the reaction is completed, the mixture is concentrated under reduced pressure to obtain an acyl chloride intermediate, and then the acyl chloride intermediate, 2-aminobenzenethiol, a solvent and an acid binding agent are mixed, and an amidation reaction is carried out at 25-35° C. After the reaction is completed, the pH is adjusted, the mixture is concentrated, extracted, washed and dried to obtain N-(3,5-dichloro-4-methoxybenzoyl)-2-aminobenzenethiol; 2) N-(3,5-dichloro-4-methoxybenzoyl)-2-aminobenzenethiol, formalin and ethanol are mixed. After the reaction is completed, the reaction is quenched with water, concentrated to remove ethanol, extracted with ethyl acetate three times, the organic phases are combined, washed with 10% sodium chloride aqueous solution, the solvent is concentrated under reduced pressure, and the residue is recrystallized with ethanol to obtain (3,5-dichloro-4-methoxyphenyl)(3(H)-benzothiazolyl)methanone; 3) mixing (3,5-dichloro-4-methoxyphenyl)(3(H)-benzothiazolyl)methanone and a solvent, adding m-chloroperbenzoic acid in batches at 0-5° C., neutralizing after the reaction is completed, washing the organic phase, concentrating under reduced pressure to remove the solvent, and recrystallizing the residue from ethyl acetate to obtain 3-(3,5-dichloro-4-hydroxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole; 4) Mix 3-(3,5-dichloro-4-hydroxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole, a demethylating agent and a solvent, react at 110-120° C., add dilute hydrochloric acid to adjust the pH, extract with ethyl acetate, wash the organic phase, concentrate under reduced pressure to remove ethyl acetate, and recrystallize the residue with ethanol to obtain Duotenod.

10. Dotenod prepared by the method according to any one of claims 1 to 9.

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