A preparation method of 6-benzothiazolesulfonyl chloride

Abstract

The invention discloses a one-pot preparation method of 6-benzothiazolesulfonyl chloride. The method has cheap and readily available raw materials, a high reaction conversion rate, few impurities, mild reaction conditions, simple operation, and is suitable for industrial production.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical intermediate synthesis, and in particular to a method for preparing 6-benzothiazolesulfonyl chloride. Background Art

[0002] 6-Benzothiazolesulfonyl chloride is an important intermediate for the preparation of benzothiazole derivatives, which can be used to prepare the new indole derivative drug Lanifibranor (J.Med.Chem.2018,61,2246-2265). Lanifibranor is an oral small molecule agonist of three subtypes of peroxisome proliferator-activated receptors (PPARs). It is currently in Phase III clinical development for the treatment of non-cirrhotic non-alcoholic steatohepatitis (NASH) liver fibrosis in stage F2 / F3. In addition, Lanifibranor is in Phase II clinical evaluation for the treatment of patients with non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes.

[0003]

[0004] Chinese patent CN102108069B discloses a method for synthesizing 6-benzothiazolesulfonyl chloride, as shown in the following formula:

[0005]

[0006] The method uses 2-amino-6-nitrobenzothiazole as a starting material, first deaminates the 2-nitrobenzothiazole through diazotization to obtain 6-nitrobenzothiazole, then reduces the nitro substituent to generate an amino group, performs a diazotization reaction, and reacts the generated diazonium salt with sulfur dioxide and chlorine to prepare 6-benzothiazolesulfonyl chloride.

[0007] This process has a long reaction path and involves hydrogenation, which requires the use of precious metal catalysts and pressure, resulting in high costs. Furthermore, the process uses a two-step diazotization reaction, which is dangerous and highly polluting. The final step uses harmful gases, sulfur dioxide and chlorine. In summary, this process has no prospects for industrial production.

[0008] 6-Benzothiazolesulfonyl is used as an active fragment in multiple new drug research and development projects and has a large market demand. Therefore, it is necessary to research and develop a feasible synthetic route with simple process, low cost, easy separation and purification, and suitable for industrial production. Summary of the Invention

[0009] Purpose of the invention: The purpose of the present invention is to provide a method for synthesizing 6-benzothiazolesulfonyl chloride to overcome the defects of the existing 6-benzothiazolesulfonyl chloride, such as complicated process, high cost, high risk and unsuitability for industrial production.

[0010] The present invention provides a method for preparing a compound of formula I:

[0011]

[0012] The compound of formula II is first reacted with a sulfonating agent, and then a chlorinating agent is added to react; the sulfonating agent is selected from fuming sulfuric acid, concentrated sulfuric acid or chlorosulfonic acid; the chlorinating agent is selected from thionyl chloride, phosphorus oxychloride or phosphorus trichloride.

[0013] Preferably, the sulfonating agent is selected from fuming sulfuric acid or concentrated sulfuric acid;

[0014] More preferably, the sulfonating agent is fuming sulfuric acid with a mass concentration of 20%;

[0015] Preferably, the chlorination agent is thionyl chloride;

[0016] Preferably, the mass ratio of the compound of formula II to the sulfonating agent is in the range of 1:4 to 6;

[0017] Preferably, the temperature range of the reaction of the compound of formula II with the sulfonating agent is 60-100°C;

[0018] More preferably, the temperature range for the reaction of the compound of formula II with the sulfonating agent is 80-90°C;

[0019] Preferably, the molar ratio of the compound of formula II to the chlorination agent is in the range of 1:5 to 10;

[0020] More preferably, the molar ratio of the compound of formula II to the chlorinating agent is in the range of 1:6 to 8;

[0021] Preferably, the temperature range of the reaction with thionyl chloride is 10 to 40°C;

[0022] Preferably, the post-reaction treatment is performed by adding the reaction solution dropwise into a mixture of water and an organic solvent, wherein the organic solvent is toluene or dichloromethane.

[0023] Beneficial effects

[0024] The method for preparing 6-benzothiazolesulfonyl chloride of the present invention utilizes the readily available and inexpensive raw material, benzothiazole, under mild reaction conditions, and can be completed in a one-pot process, resulting in simple operation. Post-reaction treatment involves dropwise addition of the reaction solution to a mixture of water and an organic solvent to quench the reaction while simultaneously extracting the product into an organic phase, thereby avoiding the risk of hydrolysis of the product in the aqueous phase after quenching. The method can achieve a total yield of 44%, making it suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the following briefly introduces the drawings required for use in the embodiments or the description of the prior art. Obviously, the drawings described below are some embodiments of the present invention.

[0026] Figure 1 For the final product of Example 1 of the present invention 1 H-NMR spectrum;

[0027] Figure 2 GC spectrum of the final product of Example 1 of the present invention. DETAILED DESCRIPTION

[0028] The present invention will be further illustrated below with reference to specific examples. These examples are implemented based on the technical solutions of the present invention. It should be understood that these examples are only used to illustrate the present invention and are not used to limit the scope of the present invention.

[0029] Example 1

[0030]

[0031] Preparation of Compound I:

[0032] In a 1000ml four-necked flask, add 500g of fuming sulfuric acid (20%), start stirring and add 100g of benzothiazole dropwise thereto. During the dropwise addition, the heat release is more intense. Control the dropwise rate to keep the internal temperature below 90°C. After the dropwise addition is completed, control the internal temperature of the reaction at 80-90°C. After the reaction for 3h, take a sample for control (take a drop of the reaction solution and dilute it to 1.5mL with acetonitrile, inject 1ul, and the raw material remaining is less than 0.5% and is considered qualified. Otherwise, continue to extend the reaction time). After passing the test, lower the internal temperature of the reaction to 20-30°C and start adding 616g of thionyl chloride dropwise. During the dropwise addition, a large amount of acidic gas will be released. It is necessary to control the dropwise rate of thionyl chloride. After the dropwise addition is completed, gradually raise the internal temperature of the reaction to 20-30°C and stir at this temperature for about 12h. Take a sample for control. After the reaction is qualified, stop the reaction and perform the following post-processing operations.

[0033] The reaction solution was added dropwise to a mixture of water / dichloromethane (2000ml / 2000ml) at 5-15°C; after separation, the aqueous phase was extracted again with 500ml of dichloromethane, the organic phases were combined, 10g of activated carbon and 20g of anhydrous magnesium sulfate were added to the organic phase for decolorization and drying, and after completion, it was filtered, the filtrate was concentrated to 220g, 250ml of n-heptane was added and beaten at 0-5°C for 1-2h, and 66.5g of crude product was obtained by filtration; the crude product was dissolved with 800ml of dichloromethane and the insoluble matter was filtered out, the filtrate was concentrated to 210g and then the concentration was stopped, the temperature was lowered to 0-5°C for crystallization, and the mixture was kept warm for beating for 2h. After filtration, 76.6g of final product was obtained by vacuum drying with a liquid phase purity of 99.8%, a gas phase purity of 99.8%, and a yield of about 44.2%.

[0034] 1 H-NMR (400 MHz, CDCl3) (ppm): 9.3493 (s, 1H), 8.7540-8.7409 (d, J = 5.24 Hz, 1H), 8.3900-8.3681 (d, J = 8.76 Hz, 1H), 8.2239-8.2189 (d, J = 2 Hz, 1H), 8.2019-8.1970 (d, J = 1.96 Hz, 1H); the purity detected by GC was 99.95%.

[0035] Comparative Example 1

[0036]

[0037] The method of reference example 1 was used to investigate the charging amount and temperature of oleum and thionyl chloride.

[0038] Table 1 Screening of sulfonation reaction temperature

[0039] Serial number Sulfonation reagent Temperature (℃) Time (h) Remark 1 Oleum 20% (6w / w) 30～40 20 1.86% of raw materials remaining 2 Oleum 20% (6w / w) 50～60 20 1.33% of raw materials remaining 3 Oleum 20% (6w / w) 60～70 20 0.61% of raw materials remaining 4 Oleum 20% (6w / w) 70～80 20 0.58% of raw materials remaining 5 Oleum 20% (6w / w) 80～90 20 0.31% of raw materials remaining 6 Oleum 20% (6w / w) 90～100 20 0.26% of raw materials remaining

[0040] Table 2 Screening of sulfonation reagent dosage

[0041]

[0042] Table 3 Screening of chlorination reagent equivalents

[0043]

[0044]

[0045] As can be seen from the comparative examples, the preferred reaction conditions of the present application can prepare 6-benzothiazolesulfonyl chloride by a one-pot process, with a high reaction conversion rate, fewer impurities, mild reaction conditions, simple operation, and suitability for industrial production.

Claims

1. A method for preparing a compound of formula I, characterized in that: The compound of formula II is first reacted with a sulfonating agent, and then a chlorinating agent is added to react; wherein the sulfonating agent is fuming sulfuric acid with a mass concentration of 20%; and the chlorinating agent is thionyl chloride; The temperature range of the reaction between the compound of formula II and thionyl chloride is 20 to 30°C; The temperature range for the reaction of the compound of formula II with the sulfonating reagent is 80-90°C; The molar ratio of the compound of formula II to the chlorinating agent is in the range of 1:5-10.

2. The preparation method according to claim 1, wherein: The mass ratio of the compound of formula II to the sulfonation reagent is in the range of 1:4-6.

3. The preparation method according to claim 1, wherein: The molar ratio of the compound of formula II to the chlorinating agent is in the range of 1:6-8.

4. The preparation method according to claim 1, wherein: The post-reaction treatment is to add the reaction solution dropwise into a mixture of water and an organic solvent, wherein the organic solvent is toluene or dichloromethane.

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