WO2022100195A1 - Method for preparing 2-fluoro-5-methoxybenzenesulfonyl chloride - Google Patents

Abstract

The present disclosure provides a method for preparing 2-fluoro-5-methoxybenzenesulfonyl chloride. 3-bromo-4-fluoroanisole is used as a raw material and reacts with a metal or metal reagent to obtain an aryl metal reagent, which then reacts with sulfonyl chloride to obtain 2-fluoro-5-methoxybenzenesulfonyl chloride. The method provided by the present disclosure has short reaction steps, simple operation and mild reaction conditions, and is suitable for industrial production.

Description

A kind of method for preparing 2-fluoro-5-methoxybenzenesulfonyl chloride

CROSS-REFERENCE TO RELATED APPLICATIONS

This disclosure claims the priority of the Chinese patent application entitled "A Method for Preparing 2-Fluoro-5-Methoxybenzenesulfonyl Chloride" with application number 202011278152.X filed with the China Patent Office on November 16, 2020 , the entire contents of which are incorporated by reference in this disclosure.

technical field

The present disclosure belongs to the field of medicinal chemistry, and in particular relates to a method for preparing 2-fluoro-5-methoxybenzenesulfonyl chloride.

Background technique

2-Fluoro-5-methoxybenzenesulfonyl chloride (CAS number: 1214334-01-6), whose structure is shown in formula I, is an important intermediate for the synthesis of various new drugs.

Patent WO2014140065 discloses a new compound, N-(4-(azaindol-6-yl)-phenyl)-sulfonamide, which is a valuable pharmacologically active compound that modulates protein kinase activity, especially Serum and glucocorticoid-regulated kinase (SGK) activity is a potential drug for the treatment of diseases with inappropriate SGK activity, such as degenerative joint diseases or inflammatory processes such as osteoarthritis or rheumatism. Wherein, N-[4-(3-amino-4-isobutoxy-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-phenyl]-2-fluoro-5-methoxy yl-benzenesulfonamide; N-[4-(3-Amino-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-phenyl]-2-fluoro-5-methoxy-benzene Sulfonamide; N-{4-[4-(1-Acetyl-piperidin-4-yloxy)-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl] -Phenyl}-2-fluoro-5-methoxy-benzenesulfonamide, etc. are all prepared from 2-fluoro-5-methoxybenzenesulfonyl chloride as a raw material.

Patent WO2015198045 discloses new compounds, 3-substituted 2-aminoindole derivatives and analogs, which are potential drugs for the treatment or prevention of GPR43 receptor-related disorders, such as diabetes, obesity and inflammatory bowel disease. Among them, 2-fluoro-5-methoxybenzenesulfonyl chloride is an important raw material for the synthesis of related compounds, and the synthetic route is shown in Scheme 1.

At present, there is no prior art publicly reporting the preparation method of 2-fluoro-5-methoxybenzenesulfonyl chloride.

SUMMARY OF THE INVENTION

The purpose of the present disclosure is to provide a preparation method of 2-fluoro-5-methoxybenzenesulfonyl chloride which is easy to operate and easy to industrialize in view of the deficiencies of the prior art.

The technical scheme adopted in the present disclosure is as follows:

Wherein, X is selected from F, Cl, Br and I; M is selected from Mg, Zn, Li and combinations thereof.

The operation steps are: using 3-bromo-4-fluoroanisole as raw material, reacting with metal or metal reagent to obtain aryl metal reagent III, and then reacting with sulfonyl chloride to obtain 2-fluoro-5-methoxyl group Benzenesulfonyl chloride.

In some embodiments, the metal or metal reagent is selected from the group consisting of C ₁ -C ₆ straight or branched alkyl magnesium, C ₁ -C ₆ straight or branched alkyl magnesium halide, lithium halide, C ₁ -C ₆ One or a mixture of linear or branched alkyl lithium, metal magnesium, metal zinc, and metal lithium.

In some embodiments, the metal or metal reagent is selected from magnesium metal, _C1 - _C6 straight or branched alkyl magnesium, _C1 - _C6 straight or branched alkyl magnesium halide lithium halide.

In some embodiments, the metal reagent is selected from the group consisting of isopropylmagnesium chloride lithium chloride, isopropylmagnesium bromide lithium chloride, isopropylmagnesium chloride, isopropylmagnesium bromide, preferably isopropylmagnesium chloride lithium chloride .

The beneficial effect of the present disclosure is that the present disclosure provides a new and unreported preparation method of 2-fluoro-5-methoxybenzenesulfonyl chloride, using 3-bromo-4-fluoroanisole as a raw material, The reaction steps are short, the operation is simple, the reaction conditions are mild, and the method is suitable for industrial production.

Description of drawings

Figure 11 HNMR chart of 2-fluoro-5-methoxybenzenesulfonyl chloride in Example ¹

Detailed ways

The technical content of the present disclosure will be further elaborated below in conjunction with the embodiments, the purpose of which is to better understand the content of the present disclosure, but the protection scope of the present disclosure is not limited thereto.

Example 1 Preparation of 2-fluoro-5-methoxybenzenesulfonyl chloride

35 mL of isopropylmagnesium chloride and lithium chloride were added to a 50 mL three-neck flask, and at 0° C., 6.0 g of 3-bromo-4-fluoroanisole was added and the reaction was stirred for 1 hour. The reaction solution was cooled to -30°C, sulfonyl chloride dissolved in tetrahydrofuran was added thereto, and the reaction was continued for 0.5 hour. After the reaction was completed, water was added to quench, and stirring was continued for 0.5 hour. The tetrahydrofuran was removed by rotary evaporation, extracted with dichloromethane, washed with water, and rotary evaporation was performed to obtain a brown liquid, and oil pump distillation was used to obtain 4.2 g of a colorless liquid. The ¹ H NMR chart is shown in FIG. 1 .

Example 2 Preparation of 2-fluoro-5-methoxybenzenesulfonyl chloride

200 mL of isopropylmagnesium bromide was added to a 500 mL three-neck flask, and 60 g of 3-bromo-4-fluoroanisole was added at 0° C. to stir the reaction for 1 hour. The reaction solution was cooled to -30°C, and sulfonyl chloride dissolved in tetrahydrofuran was added thereto, and the reaction was continued for 0.5 hour. After the reaction was completed, water was added to quench, and stirring was continued for 1 hour. The tetrahydrofuran was removed by rotary evaporation, extracted with dichloromethane, washed with water, and rotary evaporated to obtain a brown liquid, and oil pump distillation to obtain 38.1 g of a colorless liquid.

Example 3 Preparation of 2-fluoro-5-methoxybenzenesulfonyl chloride

3 g of metallic lithium was added to a 500 mL three-neck flask, and 5 g of 3-bromo-4-fluoroanisole was added at 0°C to stir the reaction for 4 hours. The reaction solution was cooled to -45°C, and sulfonyl chloride dissolved in tetrahydrofuran was added thereto, and the reaction was continued for 2 hours. After the reaction was completed, water was added to quench, and stirring was continued for 1 hour. The tetrahydrofuran was removed by rotary evaporation, extracted with dichloromethane, washed with water, and rotary evaporation was performed to obtain a brown liquid, and oil pump distillation was used to obtain 2.3 g of a colorless liquid.

Example 4 Preparation of 2-fluoro-5-methoxybenzenesulfonyl chloride

2g of metallic zinc was added to a 500mL three-neck flask, and at 0°C, 5g of 3-bromo-4-fluoroanisole was added and the reaction was stirred for 3 hours. The reaction solution was cooled to -40°C, and sulfonyl chloride dissolved in tetrahydrofuran was added thereto, and the reaction was continued for 1 hour. After the reaction was completed, water was added to quench, and stirring was continued for 1 hour. The tetrahydrofuran was removed by rotary evaporation, extracted with dichloromethane, washed with water, and rotary evaporation was performed to obtain a brown liquid, and oil pump distillation was used to obtain 1.7 g of a colorless liquid.

Claims (2)

1. A method for preparing 2-fluoro-5-methoxybenzenesulfonyl chloride, characterized in that, using 3-bromo-4-fluoroanisole as a raw material, reacting with metal or metal reagent to obtain aryl metal reagent III , and then react with sulfonyl chloride to obtain 2-fluoro-5-methoxybenzenesulfonyl chloride;

   The specific route is as follows:

   

   Wherein, X is selected from F, Cl, Br and I; M is selected from Mg, Zn, Li and combinations thereof.
2. A preparation method as claimed in claim 1, characterized in that, the metal or metal reagent is selected from C ₁ -C ₆ straight-chain or branched alkyl magnesium, C ₁ -C ₆ straight-chain or branched alkyl One or more mixtures of magnesium halide lithium halide, C ₁ -C ₆ linear or branched alkyl lithium, metal magnesium, metal zinc, and metal lithium.

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