Preparation method of methyl 2-methoxy-5-sulfamoylbenzoate

Abstract

The invention provides a preparation method of methyl 2-methoxy-5-sulfamoylbenzoate. The preparation method comprises the following steps: 2-methoxy-5-methyl chlorobenzoate and sodium amino sulfinate in a mole ratio being 1: (1.05-1.2) as well as a solvent and a catalyst are added to a reactor and react for 10-14 h when the temperature is controlled to be 45-60 DEG C; after reaction, activated carbon is added for decoloration, and the activated carbon, the catalyst and a by-product sodium chloride are removed through filtering; a filtrate is subjected to reduced-pressure concentration, and methyl 2-methoxy-5-sulfamoylbenzoate is obtained. The preparation method of methyl 2-methoxy-5-sulfamoylbenzoate has the advantages that an original process is short, the yield is high, the quality is good, three wastes contaminating the environment are avoided, environmental protection is realized, and the method is suitable for large-scale industrial production.

Description

technical field

[0001] The invention belongs to the technical field of organic compound synthesis, in particular to a preparation method of 2-methoxy-5-sulfamoylbenzoic acid methyl ester. Background technique

[0002] Methyl 2-methoxy-5-sulfamoylbenzoate is an important intermediate of antipsychotic drugs sulpiride and levosulpiride. Such as figure 1 As shown, its synthesis currently uses salicylic acid at home and abroad to obtain the product through methylation, chlorosulfonation, amination, and esterification. COD, high salt, high ammonia nitrogen, mixed wastewater, etc., the treatment is difficult and the treatment cost is extremely high, which seriously restricts the large-scale industrial production of this product. The present invention adopts a brand-new process and line, adopts sodium sulfinate and 2-methoxy-5-chlorobenzoic acid methyl ester in the presence of a small amount of catalyst, and directly condenses to obtain the product, which greatly shortens its synt...

Examples

Embodiment 1

[0016] Such as figure 2 In the synthetic route shown, 300g of tetrahydrofuran, 50g (0.25mol) of methyl 2-methoxy-5-chlorobenzoate, and 1.8g of cuprous bromide (0.0125mol) will be added to a 1000ml reaction bottle equipped with a reflux device , 31g (0.3mol) sodium sulfinate, heated to 60°C, and kept at this temperature for 12 hours, after the heat preservation was completed, 2 grams of activated carbon was added to the reaction solution and filtered under heat, and the filtrate was concentrated to dryness under reduced pressure, at 60°C After vacuum drying, 57.9 g (0.236 mol) of white crystalline powder of methyl 2-methoxy-5-sulfamoylbenzoate was obtained, with a yield of 94.5% and a content of 99.51% (HPLC).

[0017] Among them, HPLC detection conditions: mobile phase: 700 milliliters of water; 200 milliliters of methanol. Detection wavelength: 240nm, flow rate 1.0ml / min, sample 0.01g, dilute to 25ml with mobile phase, injection volume 5μl.

Embodiment 2

[0019] Such as figure 2 In the synthetic route shown, 300g of tetrahydrofuran, 50g (0.25mol) of methyl 2-methoxy-5-chlorobenzoate, and 3.6g (0.025mol) of cuprous bromide will be added to a 1000ml reaction bottle equipped with a reflux device , 26.8g (0.26mol) sodium sulfinate, heated to 45 ° C, and kept at this temperature for 14 hours, after the heat preservation was completed, 2 grams of activated carbon was added to the reaction solution and filtered under heat, and the filtrate was concentrated to dryness under reduced pressure, 60 It was dried under vacuum at ℃ to obtain 58.3 g (0.238 mol) of white crystalline powder of methyl 2-methoxy-5-sulfamoylbenzoate, yield 95.09%, content 99.66% (HPLC).

[0020] Among them, HPLC detection conditions: mobile phase: 700 milliliters of water; 200 milliliters of methanol. Detection wavelength: 240nm, flow rate 1.0ml / min, sample 0.01g, dilute to 25ml with mobile phase, injection volume 5μl.

Embodiment 3

[0022] Such as figure 2 In the synthetic route shown, 300g of tetrahydrofuran, 50g (0.25mol) of methyl 2-methoxy-5-chlorobenzoate, and 2.9g (0.02mol) of cuprous bromide will be added to a 1000ml reaction bottle equipped with a reflux device , 28.3g (0.275mol) sodium sulfinate, heated to 50 ° C, and kept at this temperature for 10 hours, after the heat preservation was completed, 2 grams of activated carbon was added to the reaction solution and filtered under heat, and the filtrate was concentrated to dryness under reduced pressure, 60 After vacuum drying at ℃, 59.2 g (0.241 mol) of white crystalline powder of methyl 2-methoxy-5-sulfamoylbenzoate was obtained, with a yield of 96.55% and a content of 99.51% (HPLC).

[0023] Among them, HPLC detection conditions: mobile phase: 700 milliliters of water; 200 milliliters of methanol. Detection wavelength: 240nm, flow rate 1.0ml / min, sample 0.01g, dilute to 25ml with mobile phase, injection volume 5μl.

[0024] As can be seen fro...

technical field

[0001] The invention belongs to the technical field of organic compound synthesis, in particular to a preparation method of 2-methoxy-5-sulfamoylbenzoic acid methyl ester. Background technique

[0002] Methyl 2-methoxy-5-sulfamoylbenzoate is an important intermediate of antipsychotic drugs sulpiride and levosulpiride. Such as figure 1 As shown, its synthesis currently uses salicylic acid at home and abroad to obtain the product through methylation, chlorosulfonation, amination, and esterification. COD, high salt, high ammonia nitrogen, mixed wastewater, etc., the treatment is difficult and the treatment cost is extremely high, which seriously restricts the large-scale industrial production of this product. The present invention adopts a brand-new process and line, adopts sodium sulfinate and 2-methoxy-5-chlorobenzoic acid methyl ester in the presence of a small amount of catalyst, and directly condenses to obtain the product, which greatly shortens its synt...

Examples

Embodiment 1

[0016] Such as figure 2 In the synthetic route shown, 300g of tetrahydrofuran, 50g (0.25mol) of methyl 2-methoxy-5-chlorobenzoate, and 1.8g of cuprous bromide (0.0125mol) will be added to a 1000ml reaction bottle equipped with a reflux device , 31g (0.3mol) sodium sulfinate, heated to 60°C, and kept at this temperature for 12 hours, after the heat preservation was completed, 2 grams of activated carbon was added to the reaction solution and filtered under heat, and the filtrate was concentrated to dryness under reduced pressure, at 60°C After vacuum drying, 57.9 g (0.236 mol) of white crystalline powder of methyl 2-methoxy-5-sulfamoylbenzoate was obtained, with a yield of 94.5% and a content of 99.51% (HPLC).

[0017] Among them, HPLC detection conditions: mobile phase: 700 milliliters of water; 200 milliliters of methanol. Detection wavelength: 240nm, flow rate 1.0ml / min, sample 0.01g, dilute to 25ml with mobile phase, injection volume 5μl.

Embodiment 2

[0019] Such as figure 2 In the synthetic route shown, 300g of tetrahydrofuran, 50g (0.25mol) of methyl 2-methoxy-5-chlorobenzoate, and 3.6g (0.025mol) of cuprous bromide will be added to a 1000ml reaction bottle equipped with a reflux device , 26.8g (0.26mol) sodium sulfinate, heated to 45 ° C, and kept at this temperature for 14 hours, after the heat preservation was completed, 2 grams of activated carbon was added to the reaction solution and filtered under heat, and the filtrate was concentrated to dryness under reduced pressure, 60 It was dried under vacuum at ℃ to obtain 58.3 g (0.238 mol) of white crystalline powder of methyl 2-methoxy-5-sulfamoylbenzoate, yield 95.09%, content 99.66% (HPLC).

[0020] Among them, HPLC detection conditions: mobile phase: 700 milliliters of water; 200 milliliters of methanol. Detection wavelength: 240nm, flow rate 1.0ml / min, sample 0.01g, dilute to 25ml with mobile phase, injection volume 5μl.

Embodiment 3

[0022] Such as figure 2 In the synthetic route shown, 300g of tetrahydrofuran, 50g (0.25mol) of methyl 2-methoxy-5-chlorobenzoate, and 2.9g (0.02mol) of cuprous bromide will be added to a 1000ml reaction bottle equipped with a reflux device , 28.3g (0.275mol) sodium sulfinate, heated to 50 ° C, and kept at this temperature for 10 hours, after the heat preservation was completed, 2 grams of activated carbon was added to the reaction solution and filtered under heat, and the filtrate was concentrated to dryness under reduced pressure, 60 After vacuum drying at ℃, 59.2 g (0.241 mol) of white crystalline powder of methyl 2-methoxy-5-sulfamoylbenzoate was obtained, with a yield of 96.55% and a content of 99.51% (HPLC).

[0023] Among them, HPLC detection conditions: mobile phase: 700 milliliters of water; 200 milliliters of methanol. Detection wavelength: 240nm, flow rate 1.0ml / min, sample 0.01g, dilute to 25ml with mobile phase, injection volume 5μl.

[0024] As can be seen fro...

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